COMPOUNDS - 945

COMPOSES 945

English Abstract

A compound of formula (I) or a pharamaceutically acceptable salt thereof,
processes for their preparation, pharmaceutical
compositions containing them and their use in therapy, for example in the
treatment of proliferative disease such as cancer
and particularly in disease mediated by an mTOR kinase and/or one or more PI3K
enzyme.

French Abstract

L'invention porte sur un composé représenté par la formule (I) ou sur un sel pharmaceutiquement acceptable de celui-ci, sur des procédés permettant de préparer, sur des compositions pharmaceutiques les contenant, et sur leur utilisation en thérapie, par exemple dans le traitement d'une maladie proliférative telle que le cancer et, en particulier, dans une maladie à médiation par une mTOR kinase et/ou une ou plusieurs enzymes PI3K.

Claims

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CLAIMS


1. A compound of formula (I)

Image

or a pharmaceutically acceptable salt thereof; wherein
m is 0, 1, 2, 3 or 4;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and
the other is
CR8;
X is a linker group selected from -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -
C.ident.CCR6R7-,
-CR6R7C.ident.C-, -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,

-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7-,
-NR4S(O)2CR6R7-, and -S(O)2NR4CR6R7-;
R1 is a group selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl,
carbocyclyl,
carbocyclylC1-6alkyl, heterocyclyl and heterocyclylC1-6alkyl, which group is
optionally
substituted by one or more substituent group selected from halo, cyano, nitro,
R9, -OR9, -SR9,
-SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10,
-NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2R10;

R2 is a group selected from C1-6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -

R11, -OR11, -SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -
NR11COR12,
-NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19;
each R3, when present, is independently selected from halo, cyano, nitro, -
R13, -OR13, -SR13,
-SOR13, -SO2R13, -COR13, -CO2R13, -CONR13R14, -NR13R14, -NR13COR14, -NR13CO14
and
-NR13SO2R14;
R4 and R5 are independently hydrogen or C1-6alkyl;


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or R1 and R4 together with the atom or atoms to which they are attached form a
4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is
optionally replaced with N, O or S and which ring is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1-6alkyl,
C1-6alkoxy,
haloC1-6alkyl, haloC1-6alkoxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-
6alkoxyC1-6alkyl, C1-
6alkoxyC1-6alkoxy, amino, C1-6alkylamino, bis(C1-6alkyl)amino, aminoC1-6alkyl,

(C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-
6alkylsulfonyl, C1-
6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-
6alkylsulfamoyl,
bis(C1-6alkyl)sulfamoyl, C1-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino,
carbamoyl,
C1-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-
membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is
optionally
replaced with N, O or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy,
haloC1-6alkyl,
haloC1-6alkoxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkyl,
C1-6alkoxyC1-6alkoxy, amino, C1-6alkylamino, bis(C1-6alkyl)amino, aminoC1-
6alkyl,
(C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-
6alkylsulfonyl, C1-
6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-
6alkylsulfamoyl,
bis(C1-6alkyl)sulfamoyl, C1-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino,
carbamoyl,
C1-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1-6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1-6alkyl,
carbocyclyl,
carbocyclylC1-6alkyl, heterocyclyl and heterocyclylC1-6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1-
6alkyl, C1-6alkoxy, haloC1-6alkyl, haloC1-6alkoxy, hydroxyC1-6alkyl, hydroxyC1-
6alkoxy, C1-
6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, C1-6alkylamino, bis(C1-
6alkyl)amino,
aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl,
cyanoC1-6alkyl, C1-
6alkylsulfonyl, C1-6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino,
sulfamoyl, C1-
6alkylsulfamoyl, bis(C1-6alkyl)sulfamoyl, C1-6alkanoylamino, C1-6alkanoyl(C1-
6alkyl)amino,
carbamoyl, C1-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl;
R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-
6alkyl,
carbocyclyl, carbocyclylC1-6alkyl, heterocyclyl and heterocyclylC1-6alkyl
which group is


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optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloC1-6alkoxy, hydroxyC1-
6alkyl, hydroxyC1-
6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, C1-6alkylamino,
bis(C1-
6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-
6alkyl,
cyanoC1-6alkyl, C1-6alkylsulfonyl, C1-6alkanoylamino, C1-6alkanoyl(C1-
6alkyl)amino,
carbamoyl, C1-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl;
R13, R14, R15 and R16 are independently hydrogen or a group selected from C1-
6alkyl,
carbocyclyl, carbocyclylC1-6alkyl, heterocyclyl and heterocyclylC1-6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloC1-6alkoxy, hydroxyC1-
6alkyl, hydroxyC1-
6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, C1-6alkylamino,
bis(C1-
6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-
6alkyl,
cyanoC 1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfonylamino, C1-
6alkylsulfonyl(C1-6alkyl)amino,
sulfamoyl, C1-6alkylsulfamoyl, bis(C1-6alkyl)sulfamoyl, C1-6alkanoylamino, C1-
6alkanoyl(C1-
6alkyl)amino, carbamoyl, C1-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl;
R19 is hydrogen, cyano or a group selected from C1-6alkyl, carbocyclyl,
carbocyclylC1-6alkyl,
heterocyclyl and heterocyclylC1-6alkyl which group is optionally substituted
by one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-
6alkoxy, haloC1-
6alkyl, haloC1-6alkoxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-
6alkyl, C1-
6alkoxyC1-6alkoxy, amino, C1-6alkylamino, bis(C1-6alkyl)amino, aminoC1-6alkyl,
(C1-
6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-
6alkylsulfonyl, C1-
6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-
6alkylsulfamoyl,
bis(C1-6alkyl)sulfamoyl, C1-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino,
carbamoyl, C1-
6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl;
or R18 and R19 together with the nitrogen atom to which they are attached form
a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with
N, O or S and which ring is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloC1-
6alkoxy,
hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-
6alkoxy, amino, C1-
6alkylamino, bis(C1-6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl,
bis(C1-
6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, C1-
6alkylsulfonylamino, C1-
6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-6alkylsulfamoyl, bis(C1-
6alkyl)sulfamoyl, C1-


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6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino, carbamoyl, C1-6alkylcarbamoyl
and bis(C1-
6alkyl)carbamoyl.


2. A compound, or a pharmaceutically acceptable salt thereof, according to
claim 1,
wherein
m is 0, 1 or 2;
1Y and Y2 are independently N or CR8 provided that one of 1Y and Y2 is N and
the other is
CR8;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-,

-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CR6R7- and
-S(O)2NR4CR6R7;
R1 is a group selected from C1-6alkyl, carbocyclyl, carbocyclylC1-6alkyl,
heterocyclyl and
heterocyclylC1-6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -
NR9COR10;
or X-R1 is -CR6R7OH;
R2 is a group selected from carbocyclyl and heterocyclyl which group is
optionally substituted
by one or more substituent group independently selected from halo, cyano,
nitro, -R11, -OR11,

-SR11, -SOR11, -SO2R11, -COR11, -CO2R11, -CONR11R12, -NR11R12, -NR11COR12, -
NR11COCONR12R16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR18R19;
each R3, when present, is selected from cyano, R13, and -CONR13R14;
R4 and R5 are independently hydrogen or C1-6alkyl;

or, when X is -NR4CR6R7-, -NR4C(O)CR6R7- or -NR4C(O)NR5CR6R7-, R1 and R4
together
with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
wherein 1 ring carbon atom is optionally replaced with N or O and which ring
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloC1-6alkoxy, hydroxyC1-6alkyl,
hydroxyC1-6alkoxy,
C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, C1-6alkylamino, bis(C1-
6alkyl)amino,
aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl,
cyanoC1-6alkyl, C1-
6alkylsulfonyl, C1-6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino,
sulfamoyl, C1-
6alkylsulfamoyl, bis(C1-6alkyl)sulfamoyl, C1-6alkanoylamino, C1-6alkanoyl(C1-
6alkyl)amino,
carbamoyl, C1-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl;


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R6 and R7 together with the carbon atom to which they are attached form a 3-
to
10-membered carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom
is optionally
replaced with N, O or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy,
haloC1-6alkyl,
haloC1-6alkoxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-
6alkoxyC1-
6alkoxy, amino, C1-6alkylamino, bis(C1-6alkyl)amino, aminoC1-6alkyl, (C1-
6alkyl)aminoC1-
6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-6alkylsulfonyl, C1-
6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-
6alkylsulfamoyl,
bis(C1-6alkyl)sulfamoyl, C1-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino,
carbamoyl,
C1-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1-6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1-6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloC1-
6alkoxy,
hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-
6alkoxy, amino, C1-
6alkylamino and bis(C1-6alkyl)amino;
R11, R12, R17 and R18 are independently hydrogen or a group selected from C1-
6alkyl,
carbocyclyl and heterocyclyl which group is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy,
haloC1-6alkyl, haloC1-
6alkoxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-
6alkoxyC1-6alkoxy,
amino, C1-6alkylamino and bis(C1-6alkyl)amino;
R13 and R14 are independently hydrogen or a C1-3alkyl which is optionally
substituted by one
or more substituent groups selected from halo, cyano, hydroxy and C1-3alkoxy;
and
R19 is hydrogen, cyano or a group selected from C1-6alkyl, C3-6cycloakyl,
aryl, heteroaryl,
arylC1-6alkyl and heteroarylC1-6alkyl which group is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1-6alkyl, C1-
6alkoxy,
haloC1-6alkyl, haloC1-6alkoxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-
6alkoxyC1-6alkyl, C1-
6alkoxyC1-6alkoxy, amino, C1-6alkylamino, bis(C1-6alkyl)amino, aminoC1-6alkyl,

(C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-6alkyl, cyanoC1-6alkyl, C1-
6alkylsulfonyl, C1-
6alkylsulfonylamino, C1-6alkylsulfonyl(C1-6alkyl)amino, sulfamoyl, C1-
6alkylsulfamoyl,
bis(C1-6alkyl)sulfamoyl, C1-6alkanoylamino, C1-6alkanoyl(C1-6alkyl)amino,
carbamoyl,
C1-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl;


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or R18 and R19 together with the nitrogen atom to which they are attached form
a 6-membered
heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or
O and which
ring is optionally substituted by one or more substituent groups selected from
halo, cyano,
nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloC1-6alkoxy,
hydroxyC1-6alkyl,
hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, C1-
6alkylamino, bis(C1-
6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-
6alkyl,
cyanoC1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfonylamino, C1-
6alkylsulfonyl(C1-6alkyl)amino,
sulfamoyl, C1-6alkylsulfamoyl, bis(C1-6alkyl)sulfamoyl, C1-6alkanoylamino, C1-
6alkanoyl(C1-
6alkyl)amino, carbamoyl, C1-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl.


3. A compound, or a pharmaceutically acceptable salt thereof, according to
claim 1 or 2
wherein 1Y is CH and Y2 is N.


4 A compound, or a pharmaceutically acceptable salt thereof, according to any
one of
claims 1 to 3 wherein X is a-S(O)2CR6R7- linker group


5. A compound, or a pharmaceutically acceptable salt thereof, according to any
one of
claims 1 to 4 wherein R1 is a group selected from methyl, ethyl, propyl,
butyl, isobutyl, tert-
butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl,
imidazolyl,
pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl,
furanylmethyl, thienylmethyl,
thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is
optionally substituted
by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl,
methoxy,
trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3.


6. A compound, or a pharmaceutically acceptable salt thereof, according to any
one of
claims 1 to 5 wherein R2 is


Image

wherein A1 and A2 are selected from CH or N provided that at least one of A1
or A2 is
CH


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7. A compound, or a pharmaceutically acceptable salt thereof, according to any
one of
claims 1 to 6 wherein R19 is hydrogen or a group selected from methyl, ethyl,
propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, phenyl,
thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl
and pyrimidinyl
which group is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C1-6alkyl, C1-6alkoxy, haloC1-6alkyl, haloC1-6alkoxy,
hydroxyC1-6alkyl,
hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-6alkoxy, amino, C1-
6alkylamino, bis(C1-
6alkyl)amino, aminoC1-6alkyl, (C1-6alkyl)aminoC1-6alkyl, bis(C1-6alkyl)aminoC1-
6alkyl,
cyanoC1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfonylamino, C1-
6alkylsulfonyl(C1-6alkyl)amino,
sulfamoyl, C1-6alkylsulfamoyl, bis(C1-6alkyl)sulfamoyl, C1-6alkanoylamino, C1-
6alkanoyl(C1-
6alkyl)amino, carbamoyl, C1-6alkylcarbamoyl and bis(C1-6alkyl)carbamoyl.


8. A compound, or a pharmaceutically acceptable salt thereof, according to any
one of
claims 1 to 7 wherein R6 and R7 together with the carbon atom to which they
are attached
form a 3- to 5-membered carbocyclic ring


9. A compound according to claim 1, or a pharmaceutically acceptable salt
thereof,
wherein the compound of formula (I) is a compound of formula (IA), (IB) or
(IC)


Image

where
X is a-S(O)2CR6R7- linker group;
1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
cyclopentyl,
cyclohexyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2CH2OCHF2,
-CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, -CH2CH2NHMe,


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phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-fluoro-4-
methylaminophenyl,
4-fluoro-2-methylphenyl, 5-fluoro-2-methylphenyl, 3-fluoro-4-(2-
hydroxyethylamino)phenyl,
4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-
chlorophenyl,
3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-
ethylaminophenyl,
3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl,

2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,

2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-
(trifluoromethyl)phenyl,
2-methylphenyl, 4-methylphenyl, 4-(2-hydroxyethylamino)phenyl, 1H-imidazol-2-
yl,
3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl,
5-(dimethylcarbamoyl)pyridin-2-yl, 1-(difluoromethyl)pyrazol-4-yl, 1-
(difluoromethyl)-3,5-
dimethylpyrazol-4-yl, 1,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-
fluoropyridin-2-
yl, 5-fluoropyridin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-
dimethylthiazol-2-yl,
2,4-dimethylthiazol-5-yl, 5-methyl-1,3,4-thiadiazol-2-yl, terahydrofuran-3-yl
and
terahydropyran-4-yl;
R2 is


Image

wherein A1 and A2 are CH;
R17 is hydrogen;
R18 is hydrogen; and
R19 is is hydrogen, cyano or a group selected from methyl, ethyl,
propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl,
-CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH,
-C(CH3)2CH2OH, -CH2C(CH3)2OH, -CH2C(CH3)2CH2OH,
-CH2CH2OH, -CH2CH2CH2OH, -CH2CF3, -CH2CHF2, -CH2CH2F,
-CH2CH2Cl, -CH2CH2SO2Me, -CH2CH(OH)CF3, -CH2CH2CN,
-CH2CN, -CH2CONMe2, -CH2CO2H, 1-(methyl)cyclopropyl,
-CH2(1-hydroxycyclopropyl), 1-(hydroxymethyl)cyclopropyl,
(1R)-2-hydroxy-1-methylethyl, (1S)-2-hydroxy-1-methylethyl, phenyl,
4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4-


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fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,
-CH2CH2(pyrrolidin-1-yl),-CH2(imidazol-2-yl), 1-methylimidazol-4-yl,
oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 1,1-dioxothiolan-3-yl,
5-methylisoxazol-3-yl, -CH2(1-methylpyrazol-4-yl), 1-methylpyrazol-
4-yl, -CH2(1-methylpyrazol-4-yl), 5-methylpyrazin-2-yl,
-CH2(2H-1,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5-
fluoropyridin-2-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl and
1-methylpyrazol-3-yl;
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and
when R3A is hydrogen, R3B is hydrogen, methyl, ethyl, hydroxymethyl,
dimethylcarbamoyl or
carbamoyl; or
when R3, is methyl, R3 is methyl.


10. A compound according to claim 9, or a pharmaceutically acceptable salt
thereof,
wherein the compound of formula (I) is a compound of formula (IA), (IB) or
(IC)


Image

where
X is a-S(O)2CR6R7- linker group;
1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
-CH2CH2OH, -
CH2CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2CH2OCHF2, -CH2CH2OCH3,
-CH2CH2NHC(O)CH3, -CH2CH2NHMe, phenyl, 2-fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-
fluoro-2-
methylphenyl, 3-fluoro-4-(2-hydroxyethylamino)phenyl, 4-
(difluoromethoxy)phenyl,
4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-
fluorophenyl,


-977-

3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl,
3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl,

2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,

2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-methylphenyl, 4-
methylphenyl,
1H-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-
yl,
5-(dimethylcarbamoyl)pyridin-2-yl, 1-(difluoromethyl)pyrazol-4-yl, 1,3-
dimethylpyrazol-4-
yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, 4-
methylthiazol-2-yl,
4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl and 5-methyl-1,3,4-
thiadiazol-2-yl;
R2 is


Image

wherein A1 and A2 are CH;
R17 is hydrogen;
R18 is hydrogen; and
R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-
propyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2,
-CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH,
-CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CH2CN,
-CH2(1-hydroxycyclopropyl), 1-(hydroxymethyl)cyclopropyl,
(1R)-2-hydroxy-1-methylethyl, (1S)-2-hydroxy-1-methylethyl, phenyl,
4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,
-CH2CH2(pyrrolidin-1-yl),-CH2(imidazol-2-yl), 1-methylimidazol-4-yl,
oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 5-methylisoxazol-3-yl,
1-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, 6-methoxypryridin-3-yl,
thiazol-2-yl, 1,2,4-thiadiazol-5-yl and 1-methylpyrazol-3-yl;
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and
when R3A is hydrogen, R3B is hydrogen, methyl or ethyl; or
when R3A is methyl, R3B is methyl.


-978-

11. A compound according to claim 10, or a pharmaceutically acceptable salt
thereof,
wherein the compound of formula (I) is a compound of formula (IA), (IB) or
(IC)


Image

where
X is a -S(O)2CR6R7- linker group;
1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, cyclopropyl, -CH2CH2CH2OH, phenyl,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-
methylphenyl,
5-fluoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl;
R2 is


Image

wherein A1 and A2 are CH;
R17 is hydrogen;
R18 is hydrogen; and
R19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl,
-CH(CH3)CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2,
-CH2CH2F, -CH2CH2CN, (1R)-2-hydroxy-1-methylethyl, (1S)-2-
hydroxy-1-methylethyl, -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-
3-yl, 1-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and
1,2,4-thiadiazol-5-yl;
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and
when R3A is hydrogen, R3B is hydrogen, methyl or ethyl; or


-979-

when R3A is methyl, R3B is methyl.
12. A compound according to claim 11, or a pharmaceutically acceptable salt
thereof,
wherein the compound of formula (I) is a compound of formula (Ia), (Ib) or
(Ic)


Image

or a pharmaceutically acceptable salt thereof;
X is a -S(O)2CR6R7- linker group;
1Y is CH and Y2 is N;
R1 is a group selected from methyl, ethyl, cyclopropyl, -CH2CH2CH2OH, phenyl,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-
methylphenyl,
5-fluoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl;
R2 is


Image

wherein A1 and A2 are CH;
R17 is hydrogen;
R18 is hydrogen; and
R19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl,
-CH(CH3)CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CHF2,
-CH2CH2F, -CH2CH2CN, (1R)-2-hydroxy-1-methylethyl, (1S)-2-
hydroxy-1-methylethyl, -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-
3-yl, 1-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and
1,2,4-thiadiazol-5-yl;
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and


-980-

when R3A is hydrogen, R3B is methyl or ethyl; or
when R3A is methyl, R3B is methyl.


13. A compound according to any one of claims 1 to 12 where R6 and R7 together
with the
carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring


14. A compound of formula (I) according to claim 1 selected from any one of
the
Examples, or a pharmaceutically acceptable salt thereof.


15. A compound of formula (I) according to claim 1 selected from any one of
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-
yl]phenyl]-3-methyl-urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3-cyclopropyl-1-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-
2-
yl]phenyl]urea,
1-[4-[4-[1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-1,3-
thiazol-2-
yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)thiourea,


-981-

3-cyclopropyl-1-[4-[4-[1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]thiourea,
3-cyclopropyl-1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]thiourea,
1-ethyl-3-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]thiourea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[1-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylthiourea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1H-imidazol-2-ylmethyl)thiourea,
3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,
1-[4-[4-[1-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-
4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[1-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(2-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-fluoroethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(2-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(1,3-thiazol-2-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[1-(2-chlorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[1-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2S)-1-hydroxypropan-2-yl]urea,


-982-

1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2S)-1-hydroxypropan-2-yl]urea,
1-[4-[4-[1-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2R)-1-hydroxypropan-2-yl]urea,
3-(2-fluoroethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-1,3-
thiazol-2-
yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-1,3-
thiazol-2-
yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(1,3-thiazol-2-
ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2,2-difluoroethyl)urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2S)-1-hydroxypropan-2-yl]urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2R)-1-hydroxypropan-2-yl]urea,
3-cyclopropyl-1-[4-[4-[(3S)-3-ethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3S)-3-ethylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-
2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[1-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-
4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S,5S)-3,5-dimethylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,


-983-

3-cyclopropyl-1-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,
1-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-methylurea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-cyclopropylurea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2S)-1-hydroxypropan-2-yl]urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(1-hydroxycyclopropyl)methyl]urea,
1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-
yl]phenyl]-
3-(2-hydroxyethyl)thiourea,
1-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-ethylurea,
3-[(2S)-1-hydroxypropan-2-yl]-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(1,3-
thiazol-2-
ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea, and
1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(2-fluoroethyl)urea,
or a pharmaceutically acceptable salt thereof.


16. A compound of formula (I) or a pharmaceutically acceptable salt thereof
according to
any one of claims 1 to 15 for use as a medicament.


-984-

17. The use of a compound of formula (I) or a pharmaceutically acceptable salt
thereof as
defined in any one of claims 1 to 15 in the manufacture of a medicament for
use in the
treatment of proliferative disease.


18. The use of a compound of formula (I), or a pharmaceutically acceptable
salt thereof,
as defined in any one of claims 1 to 15 for the production of an anti-
proliferative effect in a
warm-blooded animal such as man.


19. The use of a compound of formula (I), or a pharmaceutically acceptable
salt thereof,
as defined in any one of claims 1 to 15 in the manufacture of a medicament for
use in the
production of an anti-proliferative effect in a warm-blooded animal such as
man.


20. The use of a compound of formula (I), or a pharmaceutically acceptable
salt thereof,
as defined in any one of claims 1 to 15 in the manufacture of a medicament for
use in the
providing a mTOR kinase inhibitory effect in a warm-blooded animal such as
man.


21. A method for producing an anti-proliferative effect in a warm-blooded
animal, such as
man, in need of such treatment which comprises administering to said animal an
effective
amount of a compound of formula (I), or a pharmaceutically acceptable salt
thereof, as
defined in any one of claims 1 to 15.


22. A method for producing a mTOR kinase inhibitory effect in a warm-blooded
animal,
such as man, in need of such treatment which comprises administering to said
animal an
effective amount of a compound of formula (I), or a pharmaceutically
acceptable salt thereof,
as defined in any one of claims 1 to 15.


23. A method for treating cancer, inflammatory diseases, obstructive airways
diseases,
immune diseases or cardiovascular diseases in a warm blooded animal such as
man that is in
need of such treatment which comprises administering an effective amount of a
compound of
formula (I), or a pharmaceutically acceptable salt thereof, as defined in any
one of claims 1 to
15.


-985-

24. A pharmaceutical composition comprising a compound of formula (I) as
defined in
any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, in
association with a
pharmaceutically acceptable diluent or carrier.

Description

DEMANDE OU BREVET VOLUMINEUX

LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

CECI EST LE TOME 1 DE 3
CONTENANT LES PAGES 1 A 318

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des
brevets

JUMBO APPLICATIONS/PATENTS

THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

THIS IS VOLUME 1 OF 3
CONTAINING PAGES 1 TO 318

NOTE: For additional volumes, please contact the Canadian Patent Office
NOM DU FICHIER / FILE NAME:

NOTE POUR LE TOME / VOLUME NOTE:


CA 02692945 2009-12-23
WO 2009/007748 PCT/GB2008/050546
-1-
Compounds - 945
The present invention relates to morpholino pyrimidine compounds, processes
for their
preparation, pharmaceutical compositions containing them and their use in
therapy, for
example in the treatment of proliferative disease such as cancer and
particularly in disease
s mediated by an mTOR kinase and/or one or more P13K enzyme.
It is now well understood that deregulation of oncogenes and tumour-suppressor
genes
contributes to the formation of malignant tumours, for example by way of
increased cell
proliferation or increased cell survival. It is also known that signalling
pathways mediated by
the PI3K/mTOR families have a central role in a number of cell processes
including
io proliferation and survival, and deregulation of these pathways is a
causative factor in a wide
spectrum of human cancers and other diseases.
The mammalian target of the macrolide antibiotic Rapamycin (sirolimus) is the
enzyme
mTOR. This enzymes belongs to the phosphatidylinositol (PI) kinase-related
kinase (PIKK)
family of protein kinases, which also includes ATM, ATR, DNA-PK and hSMG-1.
mTOR,
is like other PIKK family members, does not possess detectable lipid kinase
activity, but instead
functions as a serine/threonine kinase. Much of the knowledge of mTOR
signalling is based
upon the use of Rapamycin. Rapamycin first binds to the 12 kDa immunophilin
FK506-
binding protein (FKBP12) and this complex inhibits mTOR signalling (Tee and
Blenis,
Seminars in Cell and Developmental Biology, 2005, 16, 29-37). The mTOR protein
consists

20 of a catalytic kinase domain, an FKBP 12-Rapamycin binding (FRB) domain, a
putative
repressor domain near the C-terminus and up to 20 tandemly-repeated HEAT
motifs at the N-
terminus, as well as FRAP-ATM-TRRAP (FAT) and FAT C-terminus domain (Huang and
Houghton, Current Opinion in Pharmacology, 2003, 3, 371-377).
mTOR kinase is a key regulator of cell growth and has been shown to regulate a
wide
25 range of cellular functions including translation, transcription, mRNA
turnover, protein
stability, actin cytoskeleton reorganisation and autophagy (Jacinto and Hall,
Nature Reviews
Molecular and Cell Biology, 2005, 4, 117-126). mTOR kinase integrates signals
from growth
factors (such as insulin or insulin-like growth factor) and nutrients (such as
amino acids and
glucose) to regulate cell growth. mTOR kinase is activated by growth factors
through the
30 PI3K-Akt pathway. The most well characterised function of mTOR kinase in
mammalian cells
is regulation of translation through two pathways, namely activation of
ribosomal S6Kl to


CA 02692945 2009-12-23
WO 2009/007748 PCT/GB2008/050546
-2-
enhance translation of mRNAs that bear a 5'-terminal oligopyrimidine tract
(TOP) and
suppression of 4E-BPl to allow CAP-dependent mRNA translation.
Generally, investigators have explored the physiological and pathological
roles of
mTOR using inhibition with Rapamycin and related Rapamycin analogues based on
their
s specificity for mTOR as an intracellular target. However, recent data
suggests that Rapamycin
displays variable inhibitory actions on mTOR signalling functions and suggest
that direct
inhibition of the mTOR kinase domain may display substantially broader anti-
cancer activities
than that achieved by Rapamycin (Edinger et al., Cancer Research, 2003, 63,
8451-8460). For
this reason, potent and selective inhibitors of mTOR kinase activity would be
useful to allow a
io more complete understanding of mTOR kinase function and to provide useful
therapeutic
agents.
There is now considerable evidence indicating that the pathways upstream of
mTOR,
such as the P13K pathway, are frequently activated in cancer (Vivanco and
Sawyers, Nature
Reviews Cancer, 2002, 2, 489-501; Bjomsti and Houghton, Nature Reviews Cancer,
2004, 4,
is 335-348; Inoki et al., Nature Genetics, 2005, 37, 19-24). For example,
components of the
P13K pathway that are mutated in different human tumours include activating
mutations of
growth factor receptors and the amplification and/or overexpression of P13K
and Akt.
In addition there is evidence that endothelial cell proliferation may also be
dependent
upon mTOR signalling. Endothelial cell proliferation is stimulated by vascular
endothelial cell
20 growth factor (VEGF) activation of the PI3K-Akt-mTOR signalling pathway
(Dancey, Expert
Opinion on Investigational Drugs, 2005, 14, 313-328). Moreover, mTOR kinase
signalling is
believed to partially control VEGF synthesis through effects on the expression
of hypoxia-
inducible factor-la (HIF-la) (Hudson et al., Molecular and Cellular Biology,
2002, 22, 7004-
7014). Therefore, tumour angiogenesis may depend on mTOR kinase signalling in
two ways,
25 through hypoxia-induced synthesis of VEGF by tumour and stromal cells, and
through VEGF
stimulation of endothelial proliferation and survival through PI3K-Akt-mTOR
signalling.
These findings suggest that pharmacological inhibitors of mTOR kinase should
be of
therapeutic value for treatment of the various forms of cancer comprising
solid tumours such as
carcinomas and sarcomas and the leukaemias and lymphoid malignancies. In
particular,
30 inhibitors of mTOR kinase should be of therapeutic value for treatment of,
for example, cancer
of the breast, colorectum, lung (including small cell lung cancer, non-small
cell lung cancer
and bronchioalveolar cancer) and prostate, and of cancer of the bile duct,
bone, bladder, head


CA 02692945 2009-12-23
WO 2009/007748 PCT/GB2008/050546
-3-
and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas,
skin, testes,
thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML),
multiple
myeloma and lymphomas.
In addition to tumourigenesis, there is evidence that mTOR kinase plays a role
in an
s array of hamartoma syndromes. Recent studies have shown that the tumour
suppressor
proteins such as TSCl, TSC2, PTEN and LKBl tightly control mTOR kinase
signalling. Loss
of these tumour suppressor proteins leads to a range of hamartoma conditions
as a result of
elevated mTOR kinase signalling (Tee and Blenis, Seminars in Cell and
Developmental
Biology, 2005, 16, 29-37). Syndromes with an established molecular link to
dysregulation of

io mTOR kinase include Peutz-Jeghers syndrome (PJS), Cowden disease, Bannayan-
Riley-
Ruvalcaba syndrome (BRRS), Proteus syndrome, Lhermitte-Duclos disease and
Tuberous
Sclerosis (TSC) (Inoki et al., Nature Genetics, 2005, 37, 19-24). Patients
with these
syndromes characteristically develop benign hamartomatous tumours in multiple
organs.
Recent studies have revealed a role for mTOR kinase in other diseases (Easton
&
is Houghton, Expert Opinion on Therapeutic Targets, 2004, 8, 551-564).
Rapamycin has been
demonstrated to be a potent immunosuppressant by inhibiting antigen-induced
proliferation of
T cells, B cells and antibody production (Sehgal, Transplantation Proceedings,
2003, 35, 7S-
14S) and thus mTOR kinase inhibitors may also be useful immunosuppressives.
Inhibition of
the kinase activity of mTOR may also be useful in the prevention of
restenosis, that is the
20 control of undesired proliferation of normal cells in the vasculature in
response to the
introduction of stents in the treatment of vasculature disease (Morice et al.,
New England
Journal of Medicine, 2002, 346, 1773-1780). Furthermore, the Rapamycin
analogue,
everolimus, can reduce the severity and incidence of cardiac allograft
vasculopathy (Eisen et
al., New England Journal of Medicine, 2003, 349, 847-858). Elevated mTOR
kinase activity
25 has been associated with cardiac hypertrophy, which is of clinical
importance as a major risk
factor for heart failure and is a consequence of increased cellular size of
cardiomyocytes (Tee
& Blenis, Seminars in Cell and Developmental Biology, 2005, 16, 29-37). Thus
mTOR kinase
inhibitors are expected to be of value in the prevention and treatment of a
wide variety of
diseases in addition to cancer.
30 It is also believed that a number of these morpholino pyrimidine
derivatives may have
inhibitory activity against the phosphatidylinositol (PI) 3-kinases family of
kinases.


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Phosphatidylinositol (PI) 3-kinases (PI3Ks) are ubiquitous lipid kinases that
function
both as signal transducers downstream of cell-surface receptors and in
constitutive intracellular
membrane and protein trafficking pathways. All PI3Ks are dual-specificity
enzymes with a
lipid kinase activity that phosphorylates phosphoinositides at the 3-hydroxy
position, and a less
s well characterised protein kinase activity. The lipid products of PI3K-
catalysed reactions
comprising phosphatidylinosito13,4,5-trisphosphate [PI(3,4,5)P3],
phosphatidylinosito13,4-
bisphosphate [PI(3,4)P2] and phosphatidylinositol 3-monophosphate [PI(3)P]
constitute second
messengers in a variety of signal transduction pathways, including those
essential to cell
proliferation, adhesion, survival, cytoskeletal rearrangement and vesicle
trafficking. PI(3)P is
io constitutively present in all cells and its levels do not change
dramatically following agonist
stimulation. Conversely, PI(3,4)P2 and PI(3,4,5)P3 are nominally absent in
most cells but they
rapidly accumulate on agonist stimulation.
The downstream effects of PI3K-produced 3-phosphoinositide second messengers
are
mediated by target molecules containing 3-phosphoinositide binding domains
such as the
is pleckstrin homology (PH) domain and the recently identified FYVE and phox
domains.
Well-characterised protein targets for P13K include PDKl and protein kinase B
(PKB). In
addition, tyrosine kinases like Btk and Itk are dependent on P13K activity.
The P13K family of lipid kinases can be classified into three groups according
to their
physiological substrate specificity (Vanhaesebroeck et al., Trends in Biol.
Sci., 1997, 22, 267).
20 Class III P13K enzymes phosphorylate PI alone. In contrast, Class II P13K
enzymes
phosphorylate both PI and PI 4-phosphate [PI(4)P]. Class I P13K enzymes
phosphorylate PI,
PI(4)P and PI 4,5-bisphosphate [PI(4,5)P2], although only PI(4,5)P2 is
believed to be the
physiological cellular substrate. Phosphorylation of PI(4,5)P2 produces the
lipid second
messenger PI(3,4,5)P3. More distantly related members of the lipid kinase
superfamily are
25 Class IV kinases such as mTOR (discussed above) and DNA-dependent kinase
that
phosphorylate serine/threonine residues within protein substrates. The most
studied and
understood of the P13K lipid kinases are the Class I P13K enzymes.
Class I PI3Ks are heterodimers consisting of a pl 10 catalytic subunit and a
regulatory
subunit. The family is further divided into Class Ia and Class lb enzymes on
the basis of
3o regulatory partners and the mechanism of regulation. Class Ia enzymes
consist of three distinct
catalytic subunits (p l l Oa, p l l 0(3 and p l 106) that dimerise with five
distinct regulatory
subunits (p85a, p55a, p50a, p85(3 and p55y), with all catalytic subunits being
able to interact


CA 02692945 2009-12-23
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-5-
with all regulatory subunits to form a variety of heterodimers. Class Ia PI3Ks
are generally
activated in response to growth factor-stimulation of receptor tyrosine
kinases via interaction of
their regulatory subunit SH2 domains with specific phospho-tyrosine residues
of activated
receptor or adaptor proteins such as IRS-1. Both pl l0a and pl l0(3 are
constitutively

s expressed in all cell types, whereas pl 106 expression is more restricted to
leukocyte
populations and some epithelial cells. In contrast, the single Class lb enzyme
consists of a
p 1107 catalytic subunit that interacts with a p 101 regulatory subunit.
Furthermore, the Class lb
enzyme is activated in response to G-protein coupled receptor systems (GPCRs)
and its
expression appears to be limited to leukocytes and cardiomyocytes.
There is now considerable evidence indicating that Class Ia P13K enzymes
contribute to
tumourigenesis in a wide variety of human cancers, either directly or
indirectly (Vivanco and
Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, the pl l0a
subunit is
amplified in some tumours such as those of the ovary (Shayesteh et al., Nature
Genetics, 1999,
21, 99-102) and cervix (Ma et al., Oncogene, 2000, 19, 2739-2744). More
recently, activating

is mutations within the catalytic site of the pl 10a catalytic subunit have
been associated with
various other tumours such as those of the colorectal region and of the breast
and lung
(Samuels et al., Science, 2004, 304, 554). Tumour-related mutations in the
p85a regulatory
subunit have also been identified in cancers such as those of the ovary and
colon (Philp et al.,
Cancer Research, 2001, 61, 7426-7429). In addition to direct effects, it is
believed that
2o activation of Class Ia PI3Ks contributes to tumourigenic events that occur
upstream in
signalling pathways, for example by way of ligand-dependent or ligand-
independent activation
of receptor tyrosine kinases, GPCR systems or integrins (Vara et al., Cancer
Treatment
Reviews, 2004, 30, 193-204). Examples of such upstream signalling pathways
include over-
expression of the receptor tyrosine kinase erbB2 in a variety of tumours
leading to activation of
25 PI3K-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102-6114) and
over-expression
of the ras oncogene (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). In
addition, Class Ia
PI3Ks may contribute indirectly to tumourigenesis caused by various downstream
signalling
events. For example, loss of the effect of the PTEN tumour-suppressor
phosphatase that
catalyses conversion of PI(3,4,5)P3 back to PI(4,5)P2 is associated with a
very broad range of

30 tumours via deregulation of P13K-mediated production of PI(3,4,5)P3
(Simpson and Parsons,
Exp. Cell Res., 2001, 264, 29-41). Furthermore, augmentation of the effects of
other P13K-


CA 02692945 2009-12-23
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mediated signalling events is believed to contribute to a variety of cancers,
for example by
activation of Akt (Nicholson and Anderson, Cellular Signalling, 2002, 14, 381-
395).
In addition to a role in mediating proliferative and survival signalling in
tumour cells,
there is evidence that Class Ia P13K enzymes contribute to tumourigenesis in
tumour-
s associated stromal cells. For example, P13K signalling is known to play an
important role in
mediating angiogenic events in endothelial cells in response to pro-angiogenic
factors such as
VEGF (Abid et al., Arterioscler. Thromb. Vasc. Biol., 2004, 24, 294-300). As
Class I P13K
enzymes are also involved in motility and migration (Sawyer, Expert Opinion
Investig. Drugs,
2004, 13, 1-19), P13K enzyme inhibitors should provide therapeutic benefit via
inhibition of

io tumour cell invasion and metastasis. In addition, Class I P13K enzymes play
an important role
in the regulation of immune cells contributing to pro-tumourigenic effects of
inflammatory
cells (Coussens and Werb, Nature, 2002, 420, 860-867).
These findings suggest that pharmacological inhibitors of Class I P13K enzymes
will be
of therapeutic value for the treatment of various diseases including different
forms of the
15 disease of cancer comprising solid tumours such as carcinomas and sarcomas
and the
leukaemias and lymphoid malignancies. In particular, inhibitors of Class I
P13K enzymes
should be of therapeutic value for treatment of, for example, cancer of the
breast, colorectum,
lung (including small cell lung cancer, non-small cell lung cancer and
bronchioalveolar cancer)
and prostate, and of cancer of the bile duct, bone, bladder, head and neck,
kidney, liver,
20 gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes,
thyroid, uterus, cervix and
vulva, and of leukaemias (including ALL and CML), multiple myeloma and
lymphomas.
PI3Ky, the Class lb P13K, is activated by GPCRs, as was finally demonstrated
in mice

lacking the enzyme. Thus, neutrophils and macrophages derived from PI3Ky-
deficient animals
failed to produce PI(3,4,5)P3 in response to stimulation with various
chemotactic substances
25 (such as IL-8, C5a, fMLP and MIP-la), whereas signalling through protein
tyrosine kinase-
coupled receptors to Class Ia PI3Ks was intact (Hirsch et al., Science, 2000,
287(5455), 1049-
1053; Li et al., Science, 2002, 287(5455), 1046-1049; Sasaki et al., Science
2002, 287(5455),
1040-1046). Furthermore, PI(3,4,5)P3-mediated phosphorylation of PKB was not
initiated by
these GPCR ligands in PI3Ky-null cells. Taken together, the results
demonstrated that, at least

30 in resting haematopoietic cells, PI3Ky is the sole P13K isoform that is
activated by GPCRs in
vivo. When murine bone marrow-derived neutrophils and peritoneal macrophages
from wild-
type and PI3Ky /- mice were tested in vitro, a reduced, but not completely
abrogated,


CA 02692945 2009-12-23
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performance in chemotaxis and adherence assays was observed. However, this
translated into
a drastic impairment of IL-8 driven neutrophil infiltration into tissues
(Hirsch et al., Science,
2000, 287(5455), 1049-1053.). Recent data suggest that PI3Ky is involved in
the path finding
process rather than in the generation of mechanical force for motility, as
random migration was

s not impaired in cells that lacked PI3Ky (Hannigan et al., Proc. Nat. Acad.
of Sciences of
U.S.A., 2002, 99(6), 3603-8). Data linking PI3Ky to respiratory disease
pathology came with
the demonstration that PI3Ky has a central role in regulating endotoxin-
induced lung
infiltration and activation of neutrophils leading to acute lung injury (Yum
et al., J.
Immunology, 2001, 167(11), 6601-8). The fact that although PI3Ky is highly
expressed in

io leucocytes, its loss seems not to interfere with haematopoiesis, and the
fact that PI3Ky-null
mice are viable and fertile further implicates this P13K isoform as a
potential drug target.
Work with knockout mice also established that PI3Ky is an essential amplifier
of mast cell
activation (Laffargue et al., Immunity, 2002, 16(3), 441-45 1).
Thus, in addition to tumourigenesis, there is evidence that Class I P13K
enzymes play a
is role in other diseases (Wymann et al., Trends in Pharmacological Science,
2003, 24, 366-376).
Both Class Ia P13K enzymes and the single Class lb enzyme have important roles
in cells of
the immune system (Koyasu, Nature Immunology, 2003, 4, 313-319) and thus they
are
therapeutic targets for inflammatory and allergic indications. Recent reports
demonstrate that
mice deficient in PI3Ky and PI3K8 are viable, but have attenuated inflammatory
and allergic
2o responses (Ali et al., Nature, 2004, 431(7011), 1007-11). Inhibition of
P13K is also useful to
treat cardiovascular disease via anti-inflammatory effects or directly by
affecting cardiac
myocytes (Prasad et al., Trends in Cardiovascular Medicine, 2003, 13, 206-
212). Thus,
inhibitors of Class I P13K enzymes are expected to be of value in the
prevention and treatment
of a wide variety of diseases in addition to cancer.
25 Several compounds that inhibit PI3Ks and phosphatidylinositol (PI) kinase-
related
kinase (PI3KKs) have been identified, including wortmannin and the quercetin
derivative
LY294002. These compounds are reasonably specific inhibitors of PI3Ks and
PI3KKs over
other kinases but they lack potency and display little selectivity within the
P13K families.
Accordingly, it would be desirable to provide further effective mTOR and/or
P13K
30 inhibitors for use in the treatment of cancer, inflammatory or obstructive
airways diseases,
immune or cardiovascular diseases.


CA 02692945 2009-12-23
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-8-
Morpholino pyrimidine derivatives and P13K inhibitors are known in the art.
International Patent Application WO 2004/048365 discloses compounds that
possess

P13K enzyme inhibitory activity and are useful in the treatment of cancer.
These compounds
are arylamino- and heteroarylamino-substituted pyrimidines which differ from
the compounds
s of the present invention by virtue of their arylamino- and heteroarylamino
substituents. WO
2004/048365 does not disclose compounds with the -XR' substituents of the
present
invention. Inhibitors of P13K activity useful in the treatment of cancer are
also disclosed in
European Patent Application 1 277 738 which mentions 4-morpholino-substituted
bicyclic
heteroaryl compounds such as quinazoline and pyrido[3,2-d]pyrimidine
derivatives and 4-
io morpholino-substituted tricyclic heteroaryl compounds but not monocyclic
pyrimidine
derivatives.
W02007/080382, W02008/023180 and W02008/023159 disclose compounds that
possess mTOR and/or P13K enzyme inhibitory activity and are useful in the
treatment of
cancer. W02007/080382, W02008/023180 and W02008/023159 do not disclose
compounds
15 comprising a cyclic moiety in the linker group X in the group -XRi.
A number of compounds such as 4-morpholin-4-yl-6-(phenylsulfonylmethyl)-2-
pyridin-4-yl-pyrimidine and 4-{6-[(phenylsulfonyl)methyl]-2-pyridin-2-
ylpyrimidin-4-
yl}morpholine have been registered in the Chemical Abstracts database but no
utility has been
indicated and there is no suggestion that these compounds have mTOR and/or
P13K inhibitory
2o activity or useful therapeutic properties.
Surprisingly, we have found that certain morpholino pyrimidine derivatives
possess
useful therapeutic properties. Without wishing to be bound by theoretical
constraints, it is
believed that the therapeutic usefulness of the derivatives is derived from
their inhibitory
activity against mTOR kinase and/or one or more P13K enzyme (such as the Class
Ia enzyme

25 and/or the Class lb enzyme). Because signalling pathways mediated by the
PI3K/mTOR
families have a central role in a number of cell processes including
proliferation and survival,
and because deregulation of these pathways is a causative factor in a wide
spectrum of human
cancers and other diseases, it is expected that the derivatives will be
therapeutically useful. In
particular, it is expected that the derivatives will have anti-proliferative
and/or apoptotic
30 properties which means that they will be useful in the treatement of
proliferative disease such
as cancer. The compounds of the present invention may also be useful in
inhibiting the
uncontrolled cellular proliferation which arises from various non-malignant
diseases such as


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-9-
inflammatory diseases, obstructive airways diseases, immune diseases or
cardiovascular
diseases.
Generally, the compounds of the present invention possess potent inhibitory
activity
against mTOR kinase but the compound may also possess potent inhibitory
activity against one
s or more P13K enzyme (such as the Class Ia enzyme and/or the Class lb
enzyme).
In accordance with an aspect of the present invention, there is provided a
compound of
formula (I)

(R3)m
(0)_
N
' Y/~Y2
RlIN, /\ ~
X N Rz
formula (I)
io or a pharmaceutically acceptable salt thereof; wherein
m is 0, l, 2, 3 or 4;
iY and Y2 are independently N or CR8 provided that one of 'Y and Yz is N and
the other is
CRg ;
X is a linker group selected from -CR4=CRsCR6R'-, -CR6R'CRs=CR4-, -C=CCR6R'-,
is -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,

-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R'-, -
NR4S(O)zCR6R'-,
and -S(O)zNR4CR6R7-;
R' is a group selected from hydrogen, C1_6alkyl, Cz_6alkenyl, Cz_6alkynyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is
optionally
20 substituted by one or more substituent group selected from halo, cyano,
nitro, R9, -OR9, -SR9, -
SOR9, -S02R9, -COR9, -C02R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2R10
,
-NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2Rlo;

R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -
25 R11 -OR11 11 11 11 11 11 11 lz 11 lz 11 lz
, , -SR , -SOR , -SO2R , -COR , -CO2R , -CONR R , -NR R , -NR COR , -
NR11COCONR1zR16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;


CA 02692945 2009-12-23
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each R3, when present, is independently selected from halo, cyano, nitro, -R13
-OR13 -SR13
-SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -NR
13 CO14
ZR and
-NR13SOzR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
s or R' and R4 together with the atom or atoms to which they are attached form
a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
haloC1_6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
io 6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
is R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
2o bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
25 R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
30 6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_


CA 02692945 2009-12-23
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6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
s optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
io carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R13 R14 Ris and R16 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
1s 6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
2o R19 is hydrogen, cyano or a group selected from C1_6alkyl, carbocyclyl,
carbocyc1y1C1_6alkyl,
heterocyclyl and heterocyc1y1C1_6alkyl which group is optionally substituted
by one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy, haloCi_
6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCl_6alkyl,
(C1_
2s 6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 3- to
30 1 0-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is
optionally replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_


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6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
s 6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl
for use as a medicament in the treatment of proliferative disease.
In accordance with an aspect of the present invention, there is provided a
compound of
formula (I)

(R3)m
(01~-
N
' Y/~Y2
R'IN,
X N R2
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
m is 0, l, 2, 3 or 4;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
is X is a linker group selected from -CR4=CRsCR6R'-, -CR6R'CRs=CR4-, -C=CCR6R'-
,
-CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,

-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R'-, -
NR4S(O)zCR6R'-,
and -S(O)2NR4CR6R7-;
R' is a group selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6alkynyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is
optionally
substituted by one or more substituent group selected from halo, cyano, nitro,
R9, -OR9, -SR9, -
SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2Rio
,
-NR9CONR1oRls, -NR9COCONR1oRls and -NR9SO2Rlo;

R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -

R", -OR", -SRll, -SORll, -SOZRll, -CORll 11 11 Iz 11 lz 11 lz
, -COZR , -CONR R , -NR R , -NR COR , -
NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;


CA 02692945 2009-12-23
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each R3, when present, is independently selected from halo, cyano, nitro, -R13
-OR13 -SR13
-SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -NR
13 CO14
ZR and
-NR13SOzR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
s or R' and R4 together with the atom or atoms to which they are attached form
a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
haloC1_6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
io 6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
is R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
2o bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
25 R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
30 6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_


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6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
s optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
io carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;

R13 R14 Ris R16 and R19 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
1s 6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
20 or Rig and R19 together with the nitrogen atom to which they are attached
form a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
25 bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl
for use as a medicament in the treatment of proliferative disease.
30 In accordance with another aspect of the present invention, there is
provided a
compound of formula (I)


CA 02692945 2009-12-23
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-15-
O
(R3)m
N
, Y/\Y2
Rl IN, /\ ~
X N Rz
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
m is 0, l, 2, 3 or 4;
s iY and Y2 are independently N or CR8 provided that one of 'Y and Yz is N and
the other is
CRg ;
X is a linker group selected from -CR4=CR5 CR6R7-, -CR6R7 CR5 =CR4-, -C=CCR6R'-
,
-CR6R'C=C-, -NR4CR6R7-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,

-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R'-, -
NR4S(O)zCR6R'-
io and -S(O)2NR4CR6R7-;
R' is a group selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is
optionally
substituted by one or more substituent group selected from halo, cyano, nitro,
R9, -OR9, -SR9, -
SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2Rio
,
is -NR9CONR1oRls, -NR9COCONR1oRls and -NR9SO2Rlo;

or X-Ri is -CR6R'OH;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -

11 11 111111111111 lz 11 lz 11 lz
R , -OR , -SR , -SOR , -SO2R , -COR , -CO2R , -CONR R , -NR R , -NR COR , -
zo NR11COCONR1zR16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;
each R3, when present, is independently selected from halo, cyano, nitro, -R13
-OR13 -SR13
-SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -NR
13 CO14
ZR and
-NR13SOzR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
25 or R' and R4 together with the atom or atoms to which they are attached
form a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent


CA 02692945 2009-12-23
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groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCI-6alkyl,
haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoC1_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
s C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
io 0 or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
15 sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
20 substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCI-6alkyl, haloC1_6alkoxy, hydroxyC1_6alkyl,
hydroxyC1_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
2s 6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
3o hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC i_6alkyl, haloC i_6alkoxy, hydroxyC
i_6alkyl, hydroxyC i_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,


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cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;

R13 R14 Ris R16 and R19 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
s optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
1 o sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
15 halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
20 6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl
for use as a medicament in the treatment of proliferative disease.
In accordance with another aspect of the present invention, there is provided
a
compound of formula (I)

(R3)m
N

,YY2
R'IN,
X N R2
25 formula (I)
or a pharmaceutically acceptable salt thereof; wherein
m is 0, l, 2, 3 or 4;


CA 02692945 2009-12-23
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-18-
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
X is a linker group selected from -CR4=CRsCR6R7-, -CR6R7 CRs=CR4-, -C=CCR6R'-,
-CR6R'C=C-, -NR4CR6R7-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,

s -S(O)zCRV-, -C(O)NR4CR6R7-, -NR4C(O)NRsCR6R7- and -S(O)2NR4CRV-;
R' is a group selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is
optionally
substituted by one or more substituent group selected from halo, cyano, nitro,
R9, -OR9, -SR9, -
SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2Rio
,
io -NR9CONR1oRls, -NR9COCONR1oRls and -NR9SO2Rlo;

or X-Ri is -CR6R'OH;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -

11 11 111111111111 12 11 12 11 12
R , -OR , -SR , -SOR , -SO2R , -COR , -CO2R , -CONR R , -NR R , -NR COR , -
is NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;
each R3, when present, is independently selected from halo, cyano, nitro, -R13
-OR13 -SR13
-SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -NR
13 CO14
ZR and -
NR13SOzR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
20 or R' and R4 together with the atom or atoms to which they are attached
form a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
2s 6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoC1_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoC1_6alkyl, cyanoC1_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
3o R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
0 or S and which ring is optionally substituted by one or more substituent
groups selected from


CA 02692945 2009-12-23
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-19-
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
s sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
io substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
is 6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
2o hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC i_6alkyl, haloC i_6alkoxy, hydroxyC
i_6alkyl, hydroxyC i_
6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;

25 R13 R14 Ris, R16 and R19 are independently hydrogen or a group selected
from C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
30 6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,


CA 02692945 2009-12-23
WO 2009/007748 PCT/GB2008/050546
-20-
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with N,
s 0 or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
1 o sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl
for use as a medicament in the treatment of proliferative disease.
In accordance with another aspect of the present invention, there is provided
the use of
a compound of formula (I)

(R3)m
(01~-
N
, YY2
R'IN,
X N Rz
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
m is 0, l, 2, 3 or 4;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg;
X is a linker group selected from -CR4=CRsCR6R'-, -CR6R7CR5 =CR4-,
-C=CCR6R'-, -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,

-S(0)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R'-, -
NR4S(O)zCR6R'-
and -S(0)2NR4CR6R7-;
R' is a group selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6alkynyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is
optionally
substituted by one or more substituent group selected from halo, cyano, nitro,
-R9, -OR9, -SR9,


CA 02692945 2009-12-23
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-SOR9, -SO2R9, -COR9, -CO2R9, -CONR9Rlo, -NR9Rio, -NR9CORio, -NR9CO2Rio
,
-NR9CONR10Rls, -NR9COCONR10Rls and -NR9SO2R10;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -

s Rll, -ORll, - SRll, -SORll, -SOZRll, -CORll 11 11 Iz 11 lz 11 lz
, -COZR , -CONR R , -NR R , -NR COR ,
-NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;
each R3, when present, is independently selected from halo, cyano, nitro, -R13
-OR13 -SR13 -
SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -NR
13 CO14
ZR and -
NR13SOzR14;
io R4 and R5 are independently hydrogen or C1_6alkyl;
or R' and R4 together with the atom or atoms to which they are attached form a
4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
15 haloC l_6alkoxy, hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC
1_6alkyl, C 1_6alkoxyC 1_
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
20 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
25 6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
3o R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_


CA 02692945 2009-12-23
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6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
6alkyl, (C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC1_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
s 6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
io hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
is R13 R14 Ris and R16 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
20 6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R19 is hydrogen, cyano or a group selected from C1_6alkyl, carbocyclyl,
carbocyc1y1C1_6alkyl,
25 heterocyclyl and heterocyc1y1C1_6alkyl which group is optionally
substituted by one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy, haloCi_
6alkyl, haloC1_6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCl_6alkyl,
(C1_
6alkyl)aminoC 1_6alkyl, bis(C 1_6alkyl)aminoC 1_6alkyl, cyanoC 1_6alkyl, C
1_6alkylsulfonyl, C 1_
30 6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;


CA 02692945 2009-12-23
WO 2009/007748 PCT/GB2008/050546
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or Rig and R19 together with the nitrogen atom to which they are attached form
a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
s 6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl
io in the manufacture of a medicament for use in the treatment of
proliferative disease.
In accordance with another aspect of the present invention, there is provided
the use of
a compound of formula (I)

(R3)m
(01~-
N
, YY2
R'IN,
X N R2
formula (I)
15 or a pharmaceutically acceptable salt thereof; wherein
m is 0, l, 2, 3 or 4;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
X is a linker group selected from -CR4=CRsCR6R'-, -CR6R'CRs=CR4-,
20 -C=CCR6R7-, -CR6R7C=C-, -NR4CR6R7-, -OCRV-, -SCR6R7-, -S(O)CR6R7-,

-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R'-, -
NR4S(O)zCR6R'-
and -S(O)2NR4CR6R7-;
R' is a group selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6alkynyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is
optionally
25 substituted by one or more substituent group selected from halo, cyano,
nitro, -R9, -OR9, -SR9,
-SOR9, -S02R9, -COR9, -C02R9, -CONR9Rlo, -NR9Rio, -NR9COR10, -NR9CO2Rio
,
-NR9CONR1oR15, -NR9COCONR1oR15 and -NR9SO2Rlo;


CA 02692945 2009-12-23
WO 2009/007748 PCT/GB2008/050546
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R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -

11 11 11 1111111111 12 11 12 11 12
R , -OR , - SR , -SOR , -SO2R , -COR , -CO2R , -CONR R , -NR R , -NR COR ,
-NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;
s each R3, when present, is independently selected from halo, cyano, nitro, -
R13 -OR13 -SR13 -
SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -NR
13 CO14
ZR and -
NR13SOzR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
or R' and R4 together with the atom or atoms to which they are attached form a
4- to
io l0-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
is 6alkyl, bis(C1_6alkyl)aminoC1_6alkyl, cyanoC1_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
20 carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is
optionally replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
25 cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
30 substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_


CA 02692945 2009-12-23
WO 2009/007748 PCT/GB2008/050546
-25-
6alkyl, (CI-6alkyl)aminoCI-6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
s Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (CI-6alkyl)aminoCI-6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;

R13 R14 Ris, R16 and R19 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (CI-6alkyl)aminoCI-6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoC1_6alkyl, (CI-6alkyl)aminoCI-6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl
in the manufacture of a medicament for use in the treatment of proliferative
disease.


CA 02692945 2009-12-23
WO 2009/007748 PCT/GB2008/050546
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In accordance with another aspect of the present invention, there is provided
the use of
a compound of formula (I)

(R3)m
(01~-
N
, Y/\Y2
RlIN, /\ ::'
X N Rz
formula (I)
s or a pharmaceutically acceptable salt thereof; wherein
m is 0, l, 2, 3 or 4;
iY and Y2 are independently N or CR8 provided that one of 'Y and Yz is N and
the other is
CRg ;
X is a linker group selected from -CR4=CR5 CR6R7-, -CR6R7 CR5 =CR4-,

io -C=CCR6R7-, -CRVC=C-, -NR4CR6R7-, -OCRV-, -SCR6R7-, -S(O)CR6R7-,

-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R'-, -
NR4S(O)zCR6R'-
and -S(O)2NR4CR6R7-;
R' is a group selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is
optionally
is substituted by one or more substituent group selected from halo, cyano,
nitro, -R9, -OR9, -SR9,
-SOR9, -SO2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2Rio
,
-NR9CONR1oRls, -NR9COCONR1oRls and -NR9SO2Rlo;

or X-Ri is -CR6R'OH;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
20 substituted by one or more substituent group independently selected from
halo, cyano, nitro, -

Rll, -ORll, - SRll, -SORll, -SOzRll, -CORll 11 11 Iz 11 lz 11 lz
, -COZR , -CONR R , -NR R , -NR COR ,
-NR11COCONR12 R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;

each R3, when present, is independently selected from halo, cyano, nitro, -R13
-OR13 -SR13 -
SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -NR
13 CO14
ZR and -
25 NR13SOzR14;
R4 and R5 are independently hydrogen or C1_6alkyl;


CA 02692945 2009-12-23
WO 2009/007748 PCT/GB2008/050546
-27-
or R' and R4 together with the atom or atoms to which they are attached form a
4- to 10-
membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms
is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
s haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
io 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
is 6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
2o R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
2s 6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
3o Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,


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hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
s carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;

R13 R14 Ris, R16 and R19 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloC1_6alkyl, haloC1_6alkoxy,
hydroxyC1_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
2o bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl
in the manufacture of a medicament for use in the treatment of proliferative
disease.
In accordance with another aspect of the present invention, there is provided
the use of
a compound of formula (I)


CA 02692945 2009-12-23
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O
(R3)m
N
, Y/\Y2
Rl IN, /\ ~
X N Rz
formula (I)
or a pharmaceutically acceptable salt; wherein
m is 0, l, 2, 3 or 4;
s iY and Y2 are independently N or CR8 provided that one of 'Y and Yz is N and
the other is
CRg ;
X is a linker group selected from -CR4=CR5 CR6R7-, -CR6R7 CR5 =CR4-,
-C=CCR6R'-, -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,
-S(O)zCRV-, -C(O)NR4CR6R7-, -NR4C(O)NRsCR6R7- and -S(O)2NR4CRV-;
io R' is a group selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is
optionally
substituted by one or more substituent group selected from halo, cyano, nitro,
-R9, -OR9, -SR9,
-SOR9, -S02R9, -COR9, -C02R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2Rio
,
-NR9CONR10R15, -NR9COCONR10R15 and -NR9SO2Rlo;

15 or X-Ri is -CR6R'OH
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -

Rll, -ORll, - SRll, -SORll, -SOzRll, -CORll 11 11 Iz 11 lz 11 lz
, -COZR , -CONR R , -NR R , -NR COR ,
and -NR11COCONR12 R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;

zo each R3, when present, is independently selected from halo, cyano, nitro, -
R13 -OR13 -SR13 -
SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -R 13
CO14
ZR and -
NR13SOzR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
or R' and R4 together with the atom or atoms to which they are attached form a
4- to
25 10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,


CA 02692945 2009-12-23
WO 2009/007748 PCT/GB2008/050546
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haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoC1_6alkyl, cyanoC1_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
s 6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
1 o halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl,
haloC 1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
is 6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
20 6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCl_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
25 carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
30 6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,


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cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;

R13 R14 Ris, R16 and R19 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
s optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
1 o sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
15 halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
20 6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl
in the manufacture of a medicament for use in the treatment of proliferative
disease.
In accordance with a further aspect of the present invention, there is also
provided a
compound of formula (I)

(R3)m
N

,YY2
R'IN,
X N R2
25 formula (I)
or a pharmaceutically acceptable salt thereof; wherein
m is 0, l, 2, 3 or 4;


CA 02692945 2009-12-23
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iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
X is a linker group selected from -CR4=CRsCR6R'-, -CR6R'CRs=CR4-, -C=CCR6R7-,
-CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,

s -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R'-, -
NR4S(O)zCR6R'-
and -S(O)2NR4CR6R7-;
R' is a group selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6alkynyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is
optionally
substituted by one or more substituent group selected from halo, cyano, nitro,
-R9, -OR9, -SR9,
io -SOR9, -O2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2Rio
,
-NR9CONR1oRls, -NR9COCONR1oRls and NR9SO2R10;

R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -

11 11 111111111111 12 11 12 11 12
R , -OR , -SR , -SOR , -SO2R , -COR , -CO2R , -CONR R , -NR R , -NR COR , -
is NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;
each R3, when present, is independently selected from halo, cyano, nitro, -R13
-OR13 -R13
SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -NR
13 14
C02R and -
NR13SOzR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
20 or R' and R4 together with the atom or atoms to which they are attached
form a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
2s 6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoC1_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoC1_6alkyl, cyanoC1_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
3o R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
0 or S and which ring is optionally substituted by one or more substituent
groups selected from


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halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
s sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
io substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCl_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
is 6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
2o hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC 1_6alkoxy, hydroxyC
1_6alkyl, hydroxyC 1
6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
25 R13 R14 Ris and R16 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
30 6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,


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sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R19 is hydrogen, cyano or a group selected from C1_6alkyl, carbocyclyl,
carbocyc1y1C1_6alkyl,
heterocyclyl and heterocyc1y1C1_6alkyl which group is optionally substituted
by one or more
s substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy, haloCi_
6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCl_6alkyl,
(C1_
6alkyl)aminoC 1_6alkyl, bis(C 1_6alkyl)aminoC 1_6alkyl, cyanoC 1_6alkyl, C
1_6alkylsulfonyl, C 1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In accordance with a further aspect of the present invention, there is also
provided a
compound of formula (I)
O

(R3)m
I YY2

R'~
X N R2
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
m is 0, l, 2, 3 or 4;


CA 02692945 2009-12-23
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iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
X is a linker group selected from -CR4=CRsCR6R'-, -CR6R'CRs=CR4-, -C=CCR6R7-,
-CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,

s -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R'-, -
NR4S(O)zCR6R'-
and -S(O)2NR4CR6R7-;
R' is a group selected from hydrogen, C1_6alkyl, C2_6alkenyl, C2_6alkynyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is
optionally
substituted by one or more substituent group selected from halo, cyano, nitro,
-R9, -OR9, -SR9,
io -SOR9, -O2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2Rio
,
-NR9CONR1oRls, -NR9COCONR1oRls and NR9SO2R10;

R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -

11 11 111111111111 12 11 12 11 12
R , -OR , -SR , -SOR , -SO2R , -COR , -CO2R , -CONR R , -NR R , -NR COR , -
is NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;
each R3, when present, is independently selected from halo, cyano, nitro, -R13
-OR13 -R13
SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -NR
13 14
C02R and -
NR13SOzR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
20 or R' and R4 together with the atom or atoms to which they are attached
form a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
2s 6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoC1_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoC1_6alkyl, cyanoC1_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
3o R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
0 or S and which ring is optionally substituted by one or more substituent
groups selected from


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halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
s sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
io substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCl_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
is 6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
2o hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC 1_6alkoxy, hydroxyC
1_6alkyl, hydroxyC 1
6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;

25 R13 R14 Ris, R16 and R19 are independently hydrogen or a group selected
from C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
30 6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,


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sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with N,
s 0 or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
1 o sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In accordance with a further aspect of the present invention, there is also
provided a
compound of formula (I)

(R3)m
(0)-
N
, YY2
RlIN, /\ ~
X N Rz
15 formula (I)
or a pharmaceutically acceptable salt thereof; wherein
m is 0, l, 2, 3 or 4;
iY and Y2 are independently N or CR8 provided that one of 'Y and Yz is N and
the other is
CRg ;
20 X is a linker group selected from -CR4=CR5 CR6R7-, -CR6R7 CR5 =CR4-, -
C=CCR6R'-,
-CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,

-S(0)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R'-, -
NR4S(O)zCR6R'-
and -S(0)2NR4CR6R7-;
R' is a group selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl,
25 carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group
is optionally
substituted by one or more substituent group selected from halo, cyano, nitro,
-R9, -OR9, -SR9,


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-SOR9, -O2R9, -COR9, -CO2R9, -CONR9Rlo, -NR9Rio, -NR9CORio, -NR9CO2Rio
,
-NR9CONR1oRls, -NR9COCONR1oRls and NR9SO2Rlo;

or X-Ri is -CR6R'OH;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
s substituted by one or more substituent group independently selected from
halo, cyano, nitro, -

Rll, -ORll, -SRll, -SORll, -SOZRll, -CORll 11 11 Iz 11 lz 11 lz
, -COZR , -CONR R , -NR R , -NR COR , -
NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;
each R3, when present, is independently selected from halo, cyano, nitro, -R13
-OR13 -R13
SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -NR
13 CO14
ZR and -
lo NR13SOzR14;
R4 and Rs are independently hydrogen or C1_6alkyl;
or R' and R4 together with the atom or atoms to which they are attached form a
4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
is groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl,
C1_6alkoxy, haloC1_6alkyl,
haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
20 6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
25 halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
30 6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;


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R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
s 6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCl_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
io Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
is 6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;

R13 R14 Ris, R16 and R19 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
20 optionally substituted by one or more substituent groups selected from
halo, cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloC1_6alkyl, haloC1_6alkoxy,
hydroxyC1_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
25 sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1
_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
3o halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,


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cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl..
In accordance with a further aspect of the present invention, there is also
provided a
s compound of formula (I)

(R3)m
(01~_
N
' Y/~Y2
R'IN,
X N R2
formula (I)
or a pharmaceutically acceptable salt thereof; wherein
io m is 0, l, 2, 3 or 4;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
X is a linker group selected from -CR4=CR5 CR6R7-, -CR6R7 CR5 =CR4-,
-C=CCR6R'-, -CR6R'C=C-, -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R'-,
is -S(O)zCRV-, -C(O)NR4CR6R7-, -NR4C(O)NRsCR6R7- and -S(O)2NR4CRV-;
R' is a group selected from C1_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl, which group is
optionally
substituted by one or more substituent group selected from halo, cyano, nitro,
-R9, -OR9, -SR9,
-SOR9, -O2R9, -COR9, -CO2R9, -CONR9R10, -NR9R10, -NR9COR10, -NR9CO2Rio
,
20 -NR9CONR1oRls, -NR9COCONR1oRls and NR9SO2R10;

or X-Ri is -CR6R'OH;
R2 is a group selected from C1_6alkyl, carbocyclyl and heterocyclyl which
group is optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -

11 11 111111111111 12 11 12 11 12
R , -OR , -SR , -SOR , -SO2R , -COR , -CO2R , -CONR R , -NR R , -NR COR ,
25 and -NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;


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each R3, when present, is independently selected from halo, cyano, nitro, -R13
-OR13 -R13
SOR13, -S02R13, -COR13, -C02R13, -CONR13R14, -NR 13 R 14, -NR 13 COR 14, -NR
13 CO14
ZR and -
NR13SOzR14;
R4 and R5 are independently hydrogen or C1_6alkyl;
s or R' and R4 together with the atom or atoms to which they are attached form
a 4- to
10-membered carbocyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon
atoms is optionally
replaced with N, 0 or S and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
haloC1_6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
io 6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
is R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
2o bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
25 R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl,
carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl which group is
optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
30 6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_


CA 02692945 2009-12-23
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6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
s optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
6alkoxy, C1_6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkanoylamino, C 1_6alkanoyl(C
1_6alkyl)amino,
io carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;

R13 R14 Ris, R16 and R19 are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl, carbocyc1y1C1_6alkyl, heterocyclyl and heterocyc1y1C1_6alkyl
which group is
optionally substituted by one or more substituent groups selected from halo,
cyano, nitro,
hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl, hydroxyCl_
1s 6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino, C1_6alkylamino,
bis(C1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
20 or Rig and R19 together with the nitrogen atom to which they are attached
form a 3- to
10-membered heterocyclic ring wherein 1 or 2 ring carbon atoms is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
25 bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
Certain compounds of formula (I) are capable of existing in stereoisomeric
forms. It
30 will be understood that the invention encompasses all geometric and optical
isomers of the
compounds of formula (I) and mixtures thereof including racemates. Tautomers
and mixtures
thereof also form an aspect of the present invention. Solvates and mixtures
thereof also form


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an aspect of the present invention. For example, a suitable solvate of a
compound of formula
(I) is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-
hydrate or a
tri-hydrate or an alternative quantity thereof.
The present invention relates to the compounds of formula (I) as herein
defined as well
s as to salts thereof. Salts for use in pharmaceutical compositions will be
pharmaceutically
acceptable salts, but other salts may be useful in the production of the
compounds of formula
(I) and their pharmaceutically acceptable salts. Pharmaceutically acceptable
salts of the
invention may, for example, include acid addition salts of compounds of
formula (I) as herein
defined which are sufficiently basic to form such salts. Such acid addition
salts include but are
io not limited to furmarate, methanesulfonate, hydrochloride, hydrobromide,
citrate and maleate
salts and salts formed with phosphoric and sulfuric acid. In addition where
compounds of
formula (I) are sufficiently acidic, salts are base salts and examples include
but are not limited
to, an alkali metal salt for example sodium or potassium, an alkaline earth
metal salt for
example calcium or magnesium, or organic amine salt for example triethylamine,
15 ethanolamine, diethanolamine, triethanolamine, morpholine, N-
methylpiperidine, N-
ethylpiperidine, dibenzylamine or amino acids such as lysine.
The compounds of formula (I) may also be provided as in vivo hydrolysable
esters. An
in vivo hydrolysable ester of a compound of formula (I) containing carboxy or
hydroxy group
is, for example a pharmaceutically acceptable ester which is cleaved in the
human or animal
2o body to produce the parent acid or alcohol. Such esters can be identified
by administering, for
example, intravenously to a test animal, the compound under test and
subsequently examining
the test animal's body fluid.
Suitable pharmaceutically acceptable esters for carboxy include
C1_6alkoxymethyl
esters for example methoxymethyl, C1_6alkanoyloxymethyl esters for example
25 pivaloyloxymethyl, phthalidyl esters, C3_gcycloalkoxycarbonyloxyCl_6alkyl
esters for example
1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl esters for example
5-methyl-1,3-dioxolen-2-onylmethyl, and C1_6alkoxycarbonyloxyethyl esters for
example
1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the
compounds of
this invention.
30 Suitable pharmaceutically acceptable esters for hydroxy include inorganic
esters such
as phosphate esters (including phosphoramidic cyclic esters) and a-
acyloxyalkyl ethers and
related compounds which as a result of the in vivo hydrolysis of the ester
breakdown to give


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the parent hydroxy group/s. Examples of a-acyloxyalkyl ethers include
acetoxymethoxy and
2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester
forming groups
for hydroxy include C1-ioalkanoyl, for example formyl, acetyl, benzoyl,
phenylacetyl,
substituted benzoyl and phenylacetyl; C1-ioalkoxycarbonyl (to give alkyl
carbonate esters), for
s example ethoxycarbonyl; di-Cl-4alkylcarbamoyl and N-(di-Cl-4alkylaminoethyl)-
N-
C1-4alkylcarbamoyl(to give carbamates); di-Cl-4alkylaminoacetyl and
carboxyacetyl.
Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl,
C1_
4alkylaminomethyl and di-(C1-4alkyl)aminomethyl, and morpholino or piperazino
linked from
a ring nitrogen atom via a methylene linking group to the 3- or 4- position of
the benzoyl ring.
io Other interesting in vivo hydrolysable esters include, for example,
RAC(O)OC1_6alkyl-CO-,
wherein RA is for example, benzyloxy-Cl-4alkyl, or phenyl. Suitable
substituents on a phenyl
group in such esters include, for example, 4-C1-4piperazino-Cl-4alkyl,
piperazino-Cl-4alkyl and
morpholino-C 1-4alkyl.
The compounds of the formula (I) may be also be administered in the form of a
prodrug
is which is broken down in the human or animal body to give a compound of the
formula (I).
Various forms of prodrugs are known in the art. For examples of such prodrug
derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in
Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press,
1985);
b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and
H.
2o Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard
p. 113-191
(1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);
and
e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
25 In this specification the generic term "Cp_qalkyl" includes both straight-
chain and
branched-chain alkyl groups. However references to individual alkyl groups
such as "propyl"
are specific for the straight chain version only (i.e. n-propyl and isopropyl)
and references to
individual branched-chain alkyl groups such as "tert-butyl" are specific for
the branched chain
version only.
30 The prefix Cp_q in Cp_qalkyl and other terms (where p and q are integers)
indicates the
range of carbon atoms that are present in the group, for example C1_4alkyl
includes Cialkyl


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(methyl), C2alkyl (ethyl), C3alkyl (propyl as n-propyl and isopropyl) and
C4alkyl (n-butyl, sec-
butyl, isobutyl and tert-butyl).
The term Cp_qalkoxy comprises -O-Cp_qalkyl groups.
The term Cp_qalkanoyl comprises -C(O)alkyl groups.
s The term halo includes fluoro, chloro, bromo and iodo.
"Carbocyclyl" is a saturated, unsaturated or partially saturated monocyclic,
bicyclic or
tricyclic ring system containing from 3 to 14 ring atoms, wherein a ring CH2
group may be
replaced with a C=O group. "Carbocyclyl" includes "aryl", "Cp_qcycloalkyl" and
"Cp_qcycloalkenyl".
"aryl" is an aromatic monocyclic, bicyclic or tricyclic carbcyclyl ring
system.
"Cp_qcycloalkenyl" is an unsaturated or partially saturated monocyclic,
bicyclic or
tricyclic carbocyclyl ring system containing at least 1 C=C bond and wherein a
ring CH2 group
may be replaced with a C=O group.
"Cp_qcycloalkyl" is a saturated monocyclic, bicyclic or tricyclic carbocyclyl
ring system
and wherein a ring CH2 group may be replaced with a C=O group.
"Heterocyclyl" is a saturated, unsaturated or partially saturated monocyclic,
bicyclic or
tricyclic ring system containing from 3 to 14 ring atoms of which 1, 2, 3 or 4
ring atoms are
chosen from nitrogen, sulfur or oxygen, which ring may be carbon or nitrogen
linked and
wherein a ring nitrogen or sulfur atom may be oxidised and wherein a ring CH2
group may be
2o replaced with a C=O group. "Heterocyclyl" includes "heteroaryl",
"cycloheteroalkyl" and
"cycloheteroalkenyl".
"Heteroaryl" is an aromatic monocyclic, bicyclic or tricyclic heterocyclyl,
particularly
having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from
nitrogen, sulfur or
oxygen where a ring nitrogen or sulfur may be oxidised.
"Cycloheteroalkenyl" is an unsaturated or partially saturated monocyclic,
bicyclic or
tricyclic heterocyclyl ring system, particularly having 5 to 10 ring atoms, of
which 1, 2, 3 or 4
ring atoms are chosen from nitrogen, sulfur or oxygen, which ring may be
carbon or nitrogen
linked and wherein a ring nitrogen or sulfur atom may be oxidised and wherein
a ring CH2
group may be replaced with a C=O group.
"Cycloheteroalkyl" is a saturated monocyclic, bicyclic or tricyclic
heterocyclic ring
system, particularly having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring
atoms are chosen from
nitrogen, sulfur or oxygen, which ring may be carbon or nitrogen linked and
wherein a ring


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nitrogen or sulfur atom may be oxidised and wherein a ring CH2 group may be
replaced with a
C=O group.
This specification may make use of composite terms to describe groups
comprising
more than one functionality. Unless otherwise described herein, such terms are
to be
s interpreted as is understood in the art. For example carbocyclylCp_qalkyl
comprises Cp_qalkyl
substituted by carbocyclyl, heterocyclylCp_qalkyl comprises Cp_qalkyl
substituted by
heterocyclyl, and bis(Cp_qalkyl)amino comprises amino substituted by 2
Cp_qalkyl groups which
may be the same or different.
HaloCp_qalkyl is a Cp_qalkyl group that is substituted by 1 or more halo
substituents and
io particuarly 1, 2 or 3 halo substituents. Similarly, other generic terms
containing halo such as
haloCp_qalkoxy may contain 1 or more halo substituents and particluarly 1, 2
or 3 halo
substituents.
HydroxyCp_qalkyl is a Cp_qalkyl group that is substituted by 1 or more
hydroxyl
substituents and particularly by 1, 2 or 3 hydroxy substituents. Similarly
other generic terms
15 containing hydroxy such as hydroxyCp_qalkoxy may contain 1 or more and
particularly 1, 2 or 3
hydroxy substituents.
Cp_qalkoxyCp_qalkyl is a Cp_qalkyl group that is substituted by 1 or more
Cp_qalkoxy
substituents and particularly 1, 2 or 3 Cp_qalkoxy substituents. Similarly
other generic terms
containing Cp_qalkoxy such as Cp_qalkoxyCp_qalkoxy may contain 1 or more
Cp_qalkoxy
20 substituents and particularly 1, 2 or 3 Cp_qalkoxy substituents.
Where optional substituents are chosen from "1 or 2", from "1, 2, or 3" or
from "1, 2, 3
or 4" groups or substituents it is to be understood that this definition
includes all substituents
being chosen from one of the specified groups i.e. all substitutents being the
same or the
substituents being chosen from two or more of the specified groups i.e. the
substitutents not
25 being the same.
Compounds of the present invention have been named with the aid of computer
software
(ACD/Name version 8.0).
"Proliferative disease(s)" includes malignant disease(s) such as cancer as
well as non-
malignant disease(s) such as inflammatory diseases, obstracutive airways
diseases, immune
3o diseases or cardiovascular diseases.
Suitable values for any R group or any part or substitutent for such groups
include:
for C1_4alkyl: methyl, ethyl, propyl, butyl, 2-methylpropyl and tert-butyl;


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for C1_6alkyl: C1_4alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and
hexyl;
for C3_6cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
for C3_6cyc1oa1kylCi_4alkyl: cyclopropylmethyl, cyclopropylethyl,
cyclobutylmethyl,
s cyclopentylmethyl and cyclohexylmethyl;
for aryl: phenyl and naphthyl;
for ary1C1_4alkyl: benzyl, phenethyl, naphthylmethyl and naphthylethyl;
for carbocylyl: aryl, cyclohexenyl and C3_6cycloalkyl;
for halo: fluoro, chloro, bromo and iodo;
io for C1_4alkoxy: methoxy, ethoxy, propoxy and isopropoxy;
for C1_6alkoxy: C1_4alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy;
for C1_6alkanoyl: acetyl, propanoyl and 2-methylpropanoyl;
for heteroaryl: pyridinyl, imidazolyl, quinolinyl, cinnolyl, pyrimidinyl,
thienyl,
pyrrolyl, pyrazolyl, thiazolyl, thiazolyl, triazolyl, oxazolyl,
is isoxazolyl, furanyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl,
dibenzofuranyl and benzothienyl;
for heteroarylCl_4alkyl: pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl,
imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl,
furanylethyl, thienylmethyl, theinylethyl, pyridinylmethyl,

20 pyridinylethyl, pyrazinylmethyl, pyrazinylethyl,
pyrimidinylmethyl, pyrimidinylethyl, pyrimidinylpropyl,
pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl,
quinolinylpropyl, 1,3,4-triazolylpropyl and oxazolylmethyl;
for heterocyclyl: heteroaryl, pyrrolidinyl, isoquinolinyl, quinoxalinyl,
25 benzothiazolyl, benzoxazolyl, piperidinyl, piperazinyl,
azetidinyl, morpholinyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, indolinyl, dihydro-2H-pyranyl and
tetrahydrofuranyl.
It should be noted that examples given for terms used in the description are
not limiting.
30 Particular values of m, X, 'Y and Y2X Ri X-Ri R2R3 R4, R6, R9 Rio
> > > > > > > > > R7, > > >
R11 , R1z, R13, R14, Ri7 , Rig and R19are as follows. Such values may be used
idividually or in


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combination where appropriate, in connection with any aspect of the invention,
or part thereof,
and with any of the definitions, claims or embodiments defined herein.
m
In one aspect of the invention m is 0, 1, 2 or 3.
s In another aspect m is 0, 1 or 2.
In a further aspect m is 0 or 1.
In yet another aspect m is 0 so that R3 is absent.
In yet another aspect m is 1 and R3 is methyl.

In yet another aspect m is 1 and R3 is hydroxymethyl.
io In yet another aspect m is 1 and R3 is ethyl.

In yet another aspect m is 1 and R3 is dimethylcarbamoyl.
In yet another aspect m is 1 and R3 is carbamoyl.
In yet another aspect m is 2 and each R3 is methyl.
lY and Y2
is In one aspect of the invention 'Y is N and Y2 is CRg.
In another aspect 'Y is N and Y2 is CH.

In yet another aspect 'Y is CR8 and Y2 is N.

In a further aspect 'Y is CH or CF and Y2 is N.
In yet a further aspect 'Y is CH and Y2 is N.

20 X
In one aspect of the invention X is a linker group selected from -NR4CR6R'-,
-OCR6R'-, -SCR6R'-, -S(O)CR6R7-, -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R'-,
-NR4C(O)NR5CRV- and -S(O)2NR4CR6R7-.
In another aspect X is a linker group selected from -NR4CR6R7-, -OCR6R'-, -
SCR6R'-,
25 -S(O)CR6R'-, -S(O)2CR6R7-, -C(O)NR4CR6R'-, -NR4C(O)CR6R'-, -NR4C(O)NR5CR6R7-
and
-S(O)2NR4CR6R'.
In a further aspect X is a linker group selected from -NR4CR6R7 -, -OCR6R'-, -
SCR6R'-,
-S(O)CR6R7- and -S(O)2CR6R7-.
In a further aspect X is a linker group selected from -NR4CR6R7 -, -OCR6R'-, -
SCR6R'-,
30 -S(O)CR6R7- and -S(O)2CR6R7-.
In yet another aspect X is a linker group selected from -SCR6R7-, -S(O)CR6R7-
and
-S(O)2CR6R7-.


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In another aspect X is -SCR6R7 - or -S(O)2CR6R7-.

In another aspect X is -S(O)zCRV-.
R1
In one aspect of the invention R' is a group selected from C1_4alkyl,
C3_iocycloalkyl,
s aryl, C3_10cyc1oa1ky1C1_4alkyl, ary1C1_4alkyl, cycloheteroalkyl, heteroaryl,
cycloheteroalkylCl_
4alkyl, heteroarylCl_4alkyl, which group is optionally substituted by one or
more substituent
group selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0
and
-NR9CORlo

In another aspect, R' is a group selected from adamantyl, methyl, ethyl,
propyl, butyl,
io isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl,
pyrrolidinyl, pyrrolyl,
imidazolyl, pyrazolyl, furanyl, thiadiazolyl, thiazolyl, thienyl, pyridinyl,
pyrimidinyl,
pyrazinyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl,
pyrrolylethyl,
imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl,
furanylmethyl,
furanylethyl, thiadiazolylmethyl, thiadiazolylethyl, thiazolylmethyl,
thiazolylethyl,
15 thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl,
pyrimidinylmethyl,
pyrimidinylethyl, pyrazinylmethyl and pyrazinylethyl, which group is
optionally substituted by
1, 2 or 3 substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9,
-CONR9R10, -
NR9R10 and -NR9COR10
In another aspect, R' is a group selected from adamantyl, methyl, ethyl,
propyl, butyl,
20 isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl,
pyrrolidinyl, pyrrolyl,
imidazolyl, pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl,
pyrrolidinylmethyl,
pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl,
imidazolylethyl,
pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl,
thienylethyl,
pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl,
pyrazinylmethyl and
25 pyrazinylethyl, which group is optionally substituted by 1, 2 or 3
substituent group selected
from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10
In a further aspect, R' is a group selected from methyl, ethyl, propyl, butyl,
isobutyl,
tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl,
imidazolyl,
pyrrolidinyl, thiadiazolyl, thiazolyl, pyridinyl, pyrazolylethyl,
furanylmethyl, thienylmethyl,
30 thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which group is
optionally substituted
by 1 or 2 substituent group selected from amino, halo, cyano, hydroxy, methyl,
methoxy,
trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3.


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In a further aspect, R' is a group selected from methyl, ethyl, propyl, butyl,
isobutyl,
tert-butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl,
pyridinyl,
pyrazolylethyl, furanylmethyl, thienylmethyl, thiazolylmethyl,
thiadiazolylmethyl and
pyrazinylethyl, which group is optionally substituted by 1 or 2 substituent
group selected from
s amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -
NHCOCH3, -CONH2
and -CONHCH3.
In yet another aspect R' is a group selected from methyl, ethyl, isopropyl,
tert-butyl,
cyclopropyl, cyclopentyl, cyclohexyl, -CHzCHzOH, -CHzCHzCHzOH, -
CH2CH2C(OH)(CH3)2,
-CHzCHzCHzOCHFz, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2,
io -CH2C(O)NHMe, -CH2CH2NHMe, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-
fluorophenyl,
2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-fluoro-2-
methylphenyl,
3-fluoro-4-(2-hydroxyethylamino)phenyl, 4-(difluoromethoxy)phenyl, 4-carbamoyl-
2-
chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-fluorophenyl,
3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl,
is 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-
hydroxyethylamino)phenyl,
2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,
2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-
(trifluoromethyl)phenyl,
2-methylphenyl, 4-methylphenyl, 4-(2-hydroxyethylamino)phenyl, 1 H-imidazol-2-
yl,
3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-
(dimethylcarbamoyl)pyridin-
2o 2-yl, 1-(difluoromethyl)pyrazol-4-yl, 1-(difluoromethyl)-3,5-
dimethylpyrazol-4-yl,
1,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, 5-
fluoropyridin-3-yl,
thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-
dimethylthiazol-5-yl,
5-methyl-1,3,4-thiadiazol-2-yl, terahydrofuran-3-yl and terahydropyran-4-yl.
In yet another aspect R' is a group selected from methyl, ethyl, isopropyl,
tert-butyl,
25 cyclopropyl, cyclopentyl, cyclohexyl, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2OCH3,
-CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, phenyl, 4-fluorophenyl, 4-
chlorophenyl, 2-chlorophenyl, 3,5-difluorophenyl, 2-(trifluoromethyl)phenyl, 2-

methoxyphenyl, 2-methylphenyl, 4-(2-hydroxyethylamino)phenyl, 1H-imidazol-2-
yl,
2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, 4-
acetamidophenyl,
3o 4-aminophenyl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, 5-
fluoropyridin-3-yl,
2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, 5-methyl-1,3,4-
thiadiazol-2-yl and
3-methyl-1,3,4-thiadiazol-2-yl.


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In yet another aspect R' is a group selected from methyl, isopropyl,
cyclopropyl,
cyclohexyl, -CHzCHzOH, -CH2CH2NHC(O)CH3, phenyl, 4-fluorophenyl, 2-
chlorophenyl, 2-
trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-
aminophenyl,
pyridin-4-yl, pyridin-2-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-
2-yl, and 3-
s methyl- 1,3,4-thiadiazol-2-yl.
In yet another aspect R' is a group selected from methyl, ethyl, isopropyl,
tert-butyl,
cyclopropyl, cyclopentyl, cyclohexyl, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2OCH3,
-CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, phenyl, 4-fluorophenyl, 4-
chlorophenyl, 3,5-difluorophenyl, 2-(trifluoromethyl)phenyl, 4-(2-
hydroxyethylamino)phenyl,
io 1H-imidazol-2-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-
(dimethylcarbamoyl)pyridin-2-yl,
pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl,
thiazol-2-yl,
4-methylthiazol-2-yl and 5-methyl-1,3,4-thiadiazol-2-yl.
In yet another aspect R' is a group selected from methyl, ethyl, isopropyl,
tert-butyl,
cyclopropyl, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2C(OH)(CH3)2, -CHzCHzCHzOCHFz,
is -CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2CH2NHMe, phenyl, 2-fluorophenyl,
3-fluorophenyl, 4-fluorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-
methylphenyl,
5-fluoro-2-methylphenyl, 3-fluoro-4-(2-hydroxyethylamino)phenyl,
4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-
chlorophenyl,
3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-
ethylaminophenyl,
2o 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-
hydroxyethylamino)phenyl,
2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,
2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-methylphenyl, 4-
methylphenyl,
1H-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-
yl,
5-(dimethylcarbamoyl)pyridin-2-yl, 1-(difluoromethyl)pyrazol-4-yl, 1,3-
dimethylpyrazol-4-yl,
25 pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, 4-
methylthiazol-2-yl,
4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl and 5-methyl-1,3,4-
thiadiazol-2-yl.
In yet another aspect R' is a group selected from methyl, ethyl, isopropyl,
tert-butyl,
cyclopropyl, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2OCH3, -CH2CH2NHC(O)CH3, phenyl,
4-fluorophenyl, 4-chlorophenyl, 3,5-difluorophenyl, 1H-imidazol-2-yl,
3o 2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl,
pyridin-4-yl, pyridin-
2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, 4-methylthiazol-2-yl and 5-methyl-
1,3,4-thiadiazol-2-
yl.


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In yet another aspect R' is a group selected from methyl, ethyl, cyclopropyl,
-CHzCHzCHzOH, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-
chlorophenyl,
2-methylphenyl, 5-fluoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-
methylthiazol-2-y1.In yet
another aspect R' is a group selected from -CHzCHzCHzOH, phenyl, 4-
fluorophenyl, pyridin-
s 2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl.
In yet another aspect R' is methyl.
In yet another aspect R' is ethyl.
In yet another aspect R' is cyclopropyl.
In yet another aspect R' is -CHzCHzCHzOH.
In yet another aspect R' is phenyl.
In yet another aspect R' is 2-fluorophenyl.
In yet another aspect R' is 3-fluorophenyl.
In yet another aspect R' is 4-fluorophenyl.
In yet another aspect R' is 2-chlorophenyl.
is In yet another aspect R' is 2-methylphenyl.

In yet another aspect R' is 5-fluoropyridin-2-yl
In yet another aspect R' is pyridin-2-yl.

In yet another aspect R' is thiazol-2-yl.
In yet another aspect R' is 4-methylthiazol-2-yl.
X-Rl

In one embodiment X-Ri is -CRVOH.
R2
In one aspect of the invention R2 is a group selected from carbocyclyl and
heterocyclyl
which group is optionally substituted by one or more substituent group
independently selected

from halo, cyano, nitro, -Rl l, -ORl l, -SRl l, -SORl l 11 11 11 11 lz
, -SOZR , -COR , -COZR , -CONR R ,
-NR11R1z> -NRIICORI2> -NRIICOCONR12 R16> -NR11SO2R12> -NRI7CONRisR19 and
-NR17CSNR1sR19

In one aspect of the invention R2 is selected from carbocyclyl or heterocyclyl
which
group is substituted by -NR"CONR'gR19 or -NR"CSNR'gR19 and optionally
substituted by
one or more substituent group independently selected from halo, cyano, nitro, -
R", -OR", -
COR", -CONR11R1z, -NR11Riz and -NRIICORI2.


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In one aspect of the invention R2 is selected from carbocyclyl or heterocyclyl
which
group is substituted by -NHCONR'gR19 or -NHCSNR'gR19and optionally substituted
by one or
more substituent group independently selected from halo, cyano, nitro, -R", -
OR", -COR", -
CONR11R1z, -NR11Riz and -NRIICORI2.
s In one aspect of the invention R2 is selected from carbocyclyl or
heterocyclyl which
group is substituted by -NHCONHR'9 or -NHCSNHR'9and optionally substituted by
one or
more substituent group independently selected from halo, cyano, nitro, -R", -
OR", -COR", -
CONR11R1z, -NR11Riz and -NRIICORI2.
In one aspect of the invention R2 is a group selected from 5 or 6 membered
carbocyclyl
io or heterocyclyl which group is optionally substituted by one or more
substituent group
independently selected from halo, cyano, nitro, -R", -OR", -SR", -SOR" " "
, -SOZR , -COR , -
16 NR11SOzRiz
1z NR"COR ~ -
'~ NR"COCONR12R ~ -
COzR", -CONR"R ~ -
1z NR"R ~ -
~-
NR17CONR18R19 and -NR17CSNR1sR19

In one aspect of the invention R2 is selected from 5 or 6 membered carbocyclyl
or
is heterocyclyl which group is substituted by -NR"CONR'gR19 or -NR"CSNR'gR19
and
optionally substituted by one or more substituent group independently selected
from halo,

12 NR11R12 and -NRIICORI2.
cyano, nitro, -Ri i, -ORi i, -CORi i, -CONR11R ~ -
In one aspect of the invention R2 is selected from 5 or 6 membered carbocyclyl
or
heterocyclyl which group is substituted by -NHCONR'gR19 or -NHCSNR'gR19 and
optionally
20 substituted by one or more substituent group independently selected from
halo, cyano, nitro, -
1z -NR11R12and-NRIICORI2.
R", -ORii> -CORii> -CONR11R >
In one aspect of the invention R2 is selected from 5 or 6 membered carbocyclyl
or
heterocyclyl which group is substituted by -NHCONHR'9 or -NHCSNHR'9 and
optionally
substituted by one or more substituent group independently selected from halo,
cyano, nitro, -
1z -NR11R12and-NRIICORI2.
25 R", -ORii> -CORii> -CONR11R >
In one aspect of the invention R2 is selected from a 6 membered aryl and 5 or
6
membered heteroaryl which group is optionally substituted by one or more
substituent group
independently selected from halo, cyano, nitro, -R", -OR", -SR", -SOR" " "
, -SOZR , -COR , -
16 NR11SOzRiz
1z NR"COR ~ -
'~ NR"COCONR12R ~ -
COzR", -CONR"R ~ -
1z NR"R ~ -
~-
3o NR17CONR18R19 and -NR17CSNR1sR19

In one aspect of the invention R2 is selected from a 6 membered aryl and 5 or
6
membered heteroaryl which group is substituted by -NR'7CONR'gR19 or -
NR'7CSNR'gR19 and


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optionally substituted by one or more substituent group independently selected
from halo,

12 NR11R12and-NRIICORI2.
cyano, nitro, -Rii, -ORii, -CORii, -CONR11R ~ -
In one aspect of the invention R2 is selected from a 6 membered aryl and 5 or
6
membered heteroaryl which group is substituted by -NHCONRigR19 or -NHCSNRigR19
and
s optionally substituted by one or more substituent group independently
selected from halo,

12 NR11R12 and -NRIICORI2.
cyano, nitro, -Ri i, -ORi i, -CORi i, -CONR11R ~ -
In one aspect of the invention R2 is selected from a 6 membered aryl and 5 or
6
membered heteroaryl which group is substituted by -NHCONHR19 or -NHCSNHRI9 and
optionally substituted by one or more substituent group independently selected
from halo,

12 NR11R12 and -NRIICORI2.
io cyano, nitro, -Ri i, -OR", -CORi i, -CONR11R ~ -
In one aspect of the invention R2 is selected from phenyl, pyrrolyl,
imidazolyl,
pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl
which group is
optionally substituted by one or more substituent group independently selected
from halo,
iz NR11Riz
cyano, nitro, -Ri i, -ORi i, -SRi i, -SORi i, -SOzRi i, -CORi i, -COzRi i, -
CONR11R ~ -
~
is -NR11COR12, -NRIICOCONR12R16, -NR11SO2R12, -NRI7CONRigR19 and -
NRI7CSNRisR19
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl,
furanyl,
thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, , which group is
substituted by -
NR"CONR'gR19 or -NR"CSNR'gR19 and optionally substituted by one or more
substituent
group independently selected from halo, cyano, nitro, -R", -OR", -COR", -
CONR"R12
,
20 -NR11R12 and -NRIICORI2.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl,
furanyl,
thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is
substituted by -
NHCONR'gR19 or -NHCSNR'gR19 and optionally substituted by one or more
substituent group
independently selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z 11
12
, -NR R
25 and -NR11COR12.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl,
furanyl,
thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is
substituted by -
NHCONHR19 or -NHCSNHR'9 and optionally substituted by one or more substituent
group
independently selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z 11
12
, -NR R
3o and -NR11COR12.
In one aspect of the invention R2 is selected from phenyl, pyrrolyl,
imidazolyl,
pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl
which group is


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optionally substituted by one or more substituent group independently selected
from fluoro,
methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2,
-NR11COR12, -NR11SO2R12, -NRI7CONRigR19 and -NRI7CSNRisR19
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl,
furanyl,
s thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is
substituted by -
NR"CONR'gR19 or -NR"CSNR'gR19 and optionally substituted by one or more
substituent
group independently selected from fluoro, methyl, methoxy, hydroxymethyl,
cyanomethyl, -
CONHz, -CONHCH3 and -CON(CH3)z.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl,
furanyl,
io thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is
substituted by -
NHCONR'gR19 or -NHCSNR'gR19 and optionally substituted by one or more
substituent group
independently selected from fluoro, methyl, methoxy, hydroxymethyl,
cyanomethyl, -CONH2,
-CONHCH3 and -CON(CH3)z.
In another aspect R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl,
furanyl,
is thienyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl which group is
substituted by -
NHCONHR19 or -NHCSNHR'9and optionally substituted by one or more substituent
group
independently selected from fluoro, methyl, methoxy, hydroxymethyl,
cyanomethyl, -CONH2,
-CONHCH3 and -CON(CH3)z.
In one aspect of the invention R2 is selected from phenyl, pyridinyl or
pyrimidinyl
20 which group is optionally substituted by one or more substituent group
independently selected
from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and
-CON(CH3)2, -NR11COR12, -NR11SO2R12, -NRI7CONRigR19 and -NRI7CSNRisR19
In one aspect of the invention R2 is selected from phenyl or pyridinyl which
group is
optionally substituted by one or more substituent group independently selected
from fluoro,
25 methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -
CON(CH3)2,

-NR11COR12, -NR11SO2R12, -NRI7CONRigR19 and -NRI7CSNRisR19

In another aspect R2 is phenyl, pyridinyl or pyrimidinyl substituted by -
NR"CONR'gR19 or -NR"CSNR'gR19 and optionally substituted by one or more
substituent
group independently selected from fluoro, methyl, methoxy, hydroxymethyl,
cyanomethyl,
30 -CONH2, -CONHCH3 and -CON(CH3)z.
In another aspect R2 is phenyl or pyridinyl substituted by -NR"CONR'gR19 or
-NR"CSNR'gR19 and optionally substituted by one or more substituent group
independently


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selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -
CONHCH3
and -CON(CH3)z.
In another aspect R2 is phenyl or pyridinyl substituted by NHCONR'gR19 or
-NHCSNR'gR19 and optionally substituted by one or more substituent group
independently
s selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -
CONHCH3
and -CON(CH3)z.

In another aspect R2 is phenyl or pyridinyl substituted by -NHCONHR19 or
-NHCSNHR19 and optionally substituted by one or more substituent group
independently
selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -
CONHCH3
io and -CON(CH3)z.
In another aspect R2 is phenyl or pyridinyl optionally substituted by -
NR"CONR'sR19
or -NR17CSNR1sR19

In another aspect R2 is phenyl or pyridinyl optionally substituted by -
NHCONR'gR19 or
-NHCSNR1sR19

is In another aspect R2 is phenyl or pyridinyl optionally substituted by -
NHCONHR19 or
-NHCSNHR19
In another aspect R2 is
1 1
-A2
~ A2 0
S
~ R19 jt / )~ R19
N N~ N N~
R17 R1s R17 R1s
or
wherein A' and A2 are selected from CH or N provided that at least one of A'
or A2 is
20 CH.
In another aspect R2 is

A2 0
~ A2 S
9 ~ ~ R19
AN~N R1
A3N~N
R17 R1s R17 R1s
or
wherein A2 and A3 are selected from CH or N.
In another aspect R2 is


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1
A,~A2 O ~ A2 s

N i
A:R19or AR19
H

wherein A' and A2 are selected from CH or N provided that at least one of A'
or A2 is
CH.
In another aspect R2 is

A2 O ~ A2 S
R19 ~ LR19
N
H R1s H R1s
s or
wherein A2 and A3 are selected from CH or N.
In another aspect R2 is
1
A2 0 ~ A2 s

R19 / /\ R19
N N N N
H H or H H

wherein A' and A2 are selected from CH or N provided that at least one of A'
or A2 is
io CH.
In another aspect R2 is

2
S
9 ~R1
CAR19
N
H H or H H
wherein A2 and A3 are selected from CH or N.
In yet another aspect R2 is 3-(hydroxymethyl)phenyl, 4-(hydroxymethyl)phenyl,
is 4-(cyanomethyl)phenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-
phenoxyphenyl,
3-pyrrolidin-lylphenyl, 3-(aminocarbonyl)phenyl, 4-
(dimethylaminocarbonyl)phenyl, furan-3-
yl, thien-3-yl, 5-(hydroxymethyl)thien-2-yl, pyridin-2-yl, pyridin-4-yl, 2-
methoxypyridin-5-yl,
2-methoxypyrimidin-5-yl, 2-methoxynaphth-6-yl, 5,7-diazabicyclo[4.3.0]nona-
2,4,8,10-
tetraenyl, azaindolyl, indol-5-yl, 1-methylindol-5-yl, quinolin-6-yl,
benzimidazolyl,
2o benzofuran-2-yl, dibenzofuran-1-yl and benzothien-3-yl.


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In yet a further aspect R2 is pyridin-2-yl, 3-hydroxyphenyl, 4-hydroxyphenyl,
3-hydroxymethylphenyl, 4-hydroxymethylphenyl or indol-5-yl.
In yet a further aspect R2 is azaindolyl, indol-5-yl, benzimidazolyl, 3-
hydroxyphenyl,
4-hydroxyphenyl, 3-hydroxymethylphenyl or 4-hydroxymethylphenyl

s In another aspect R2 is pyridin-2-yl.
In a further aspect R2 is 3-hydroxyphenyl or 4-hydroxyphenyl.
In yet another aspect R2 is 3-hydroxymethylphenyl or 4-hydroxymethylphenyl.
In yet a further aspect R2 is indol-5-yl.
In one aspect R2 is morpholinyl.
In another aspect R2 is morpholino.
R3
Each R3 is independently selected from cyano, R13, and -CONR13R14, wherein R13
and
R14 are independently hydrogen or a C1_3alkyl which is optionally substituted
by one or more
substituent groups selected from halo, cyano, hydroxy and C1_3alkoxy.
is Each R3 is independently selected from hydrogen, C1_3alkyl,
hydroxyC1_3alkyl, and
-CONR13R14, wherein R13 and R14 are independently hydrogen or a C1_3alkyl.
Each R3 is independently selected from hydrogen, methyl, ethyl, hydroxymethyl,
carbamoyl and dimethylcarbamoyl.
R4
In one aspect of the invention R4 is hydrogen or methyl.
In another aspect R4 is hydrogen.

R4 and R'

In another aspect of the invention, when X is -NR4CR6R7-, -NR4C(O)CR6R7-,
-NR4C(O)NR5CR6R7- or -NR4S(O)2CRV-, R' and R4 together with the atom or atoms
to
which they are attached form a 4- to 10-membered heterocyclic ring wherein 1,
2 or 3 ring
carbon atoms is optionally replaced with N, 0 or S and which ring is
optionally substituted by
one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
C1_6alkyl, C1_
6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_
6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino,
aminoCl_6alkyl, (C1_
6alkyl)aminoC 1_6alkyl, bis(C 1_6alkyl)aminoC 1_6alkyl, cyanoC 1_6alkyl, C
1_6alkylsulfonyl, C 1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_


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6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.

In another aspect of the invention, when X is -NR4CRV-, -NR4C(O)CRV-,
-NR4C(O)NRsCR6R7- or -NR4S(O)2CRV-, R' and R4 together with the atom or atoms
to
s which they are attached form a 5-, 6- or 7-membered heterocyclic ring
wherein 1 ring carbon
atom is optionally replaced with N or 0 and which ring is optionally
substituted by one or
more substituent groups selected from halo, cyano, nitro, hydroxy, oxo,
C1_6alkyl, C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyC1_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoC1_6alkyl,
(C1_
6alkyl)aminoC 1_6alkyl, bis(C 1_6alkyl)aminoC 1_6alkyl, cyanoC 1_6alkyl, C
1_6alkylsulfonyl, C 1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.

In another aspect of the invention, when X is -NR4CRV-, -NR4C(O)CRV-,

is -NR4C(O)NR5CRV- or -NR4S(0)2CRV-, R' and R4 together with the atom or atoms
to
which they are attached form a 5- or 6-membered heterocyclic ring wherein 1
ring carbon atom
is optionally replaced with N or 0 and which ring is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C 1_6alkyl)amino, aminoC
1_6alkyl, (C 1_
6alkyl)aminoC 1_6alkyl, bis(C 1_6alkyl)aminoC 1_6alkyl, cyanoC 1_6alkyl, C
1_6alkylsulfonyl, C 1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.

In another aspect of the invention, when X is -NR4CR6R7-, -NR4C(O)CR6R7-,
-NR4C(O)NR5CR6R7- or -NR4S(0)2CRV-, R' and R4 together with the atom or atoms
to
which they are attached form a morpholine or piperazine ring which ring is
optionally
substituted by one or more methyl groups.
In another aspect of the invention, when X is -NR4C(O)CRV-, R' and R4 together
with the atom or atoms to which they are attached form a morpholine or
piperazine ring which
ring is optionally substituted by one or more methyl groups.
R5


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In one aspect of the invention R 5 is hydrogen or methyl.
In another aspect R 5 is hydrogen.
In another aspect R 5 is methyl.
R6 and R7
In one aspect of the invention R6 and R7 together with the carbon atom to
which they
are attached form a 3- to 10-membered carbocyclic ring or heterocyclic ring
wherein 1 ring
carbon atom is optionally replaced with N, 0 or S and which ring is optionally
substituted by
one or more substituent groups selected from halo, cyano, nitro, hydroxy,
C1_6alkyl, C1_6alkoxy,
haloC1_6alkyl, haloC1_6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCl_6alkyl,
(C1_
6alkyl)aminoC 1_6alkyl, bis(C 1_6alkyl)aminoC 1_6alkyl, cyanoC 1_6alkyl, C
1_6alkylsulfonyl, C 1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In one aspect of the invention R6 and R7 together with the carbon atom to
which they
are attached form a 3- to 6-membered carbocyclic ring or heterocyclic ring
wherein 1 ring
carbon atom is optionally replaced with N or 0 and which ring is optionally
substituted by one
or more substituent groups selected from halo, cyano, nitro, hydroxy,
C1_6alkyl, C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C 1_6alkyl)amino, aminoC
1_6alkyl, (C 1_
6alkyl)aminoC 1_6alkyl, bis(C 1_6alkyl)aminoC 1_6alkyl, cyanoC 1_6alkyl, C
1_6alkylsulfonyl, C 1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In another aspect R6 and R7 together with the carbon atom to which they are
attached
form a 3- to 6-membered carbocyclic ring.
In another aspect R6 and R7 together with the carbon atom to which they are
attached
form a 3- to 5-membered carbocyclic ring.
In another aspect R6 and R7 together with the carbon atom to which they are
attached
form a 3- to 4-membered carbocyclic ring.
In another aspect R6 and R7 together with the carbon atom to which they are
attached
form a 3-membered carbocyclic ring.


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In another aspect R6 and R7 together with the carbon atom to which they are
attached

form a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl
ring.
R8
In one aspect of the invention Rg is hydrogen or halo.
s In another aspect Rg is hydrogen or fluoro.

In a further aspect Rg is hydrogen.
R9
In one aspect of the invention R9 is hydrogen or C1_4alkyl optionally
substituted by 1, 2
or 3 substituent groups selected from halo, cyano, nitro, hydroxy, C1_4alkoxy,
amino, C1_
4alkylamino and bis(C1_4alkyl)amino.
In another aspect R9 is hydrogen or C1_4alkyl optionally substituted by 1, 2
or 3 halo
substituents.
In a further aspect R9 is hydrogen, methyl or trifluoromethyl.
Ri0

is In one aspect of the invention R10 is hydrogen.
Rl l

In one aspect of the invention R" is hydrogen or a group selected from
C1_4alkyl, aryl
and cycloheteroalkyl which group is optionally substituted by 1, 2 or 3 groups
selected from
halo, hydroxy and cyano.
In another aspect R" is hydrogen, methyl optionally substituted with hydroxy
or cyano,
phenyl or pyrrolidinyl.
In another aspect R" is hydrogen or methyl.
Ri2

In one aspect of the invention R'2 is hydrogen or methyl.
Rl7

In one aspect of the invention R" is hydrogen or a group selected from
C1_4alkyl, aryl
and cycloheteroalkyl which group is optionally substituted by 1, 2 or 3 groups
selected from
halo, hydroxy and cyano.
In another aspect R" is hydrogen, methyl optionally substituted with hydroxy
or cyano,
phenyl or pyrrolidinyl.
In another aspect R" is hydrogen or methyl.
In another aspect R" is hydrogen.


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Ri8

In one aspect of the invention R'g is hydrogen or methyl.
In one aspect of the invention R'g is hydrogen
Ri9
In one aspect of the invention R19 is hydrogen or a group selected from
C1_6alkyl, C3_
6cycloakyl, aryl, heteroaryl, ary1C1_6alkyl and heteroarylCl_6alkyl which
group is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In one aspect of the invention R19 is hydrogen or a group selected from
C1_6alkyl, C3_
6cycloakyl, phenyl, naphthyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl,
furanyl, thienyl,
pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl,
benzimidazolyl,
benzofuranyl, dibenzofuranyl, benzothienyl, pyrrolidinyl, pyrazinyl, oxetanyl,
dioxothiolanyl,
thiazolyl, thiadiazolyl, phenylCl_6alkyl, naphthylCl_6alkyl,
pyrrolylCl_6alkyl, imidazolylCl_
6alkyl, isoxazolylCl_6alkyl, pyrazolylCl_6alkyl, furanylCl_6alkyl,
thienylCl_6alkyl, pyridinylCl_
6alkyl, pyrimidinylC 1_6alkyl, pyridazinylC 1_6alkyl, azaindolylC 1_6alkyl,
indolylC 1_6alkyl,
quinolinylC1_6alkyl, benzimidazolylC1_6alkyl, benzofuranylC1_6alkyl,
dibenzofuranylC1_6alkyl,
benzothienylC 1_6alkyl, pyrrolidinylC 1_6alkyl, pyrazinylC 1_6alkyl, oxetanylC
1_6alkyl,
dioxothiolanylCl_6alkyl, thiazolylCl_6alkyl and thiadiazolylCl_6alkyl which
group is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl,
hydroxyCi_6alkoxy,
C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino,
aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC1_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In one aspect of the invention R19 is hydrogen or a group selected from
C1_6alkyl, C3_
6cycloakyl, phenyl, naphthyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl,
furanyl, thienyl,


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pyridinyl, pyrimidinyl, pyridazinyl, azaindolyl, indolyl, quinolinyl,
benzimidazolyl,
benzofuranyl, dibenzofuranyl, benzothienyl, phenylCl_6alkyl,
naphthylCl_6alkyl, pyrrolylCl_
6alkyl, imidazolylC1_6alkyl, isoxazolylC1_6alkyl, pyrazolylC1_6alkyl,
furanylC1_6alkyl, thienylCl_
6alkyl, pyridinylC 1_6alkyl, pyrimidinylC 1_6alkyl, pyridazinylC 1_6alkyl,
azaindolylC 1_6alkyl,
s indolylCl_6alkyl, quinolinylCl_6alkyl, benzimidazolylCl_6alkyl,
benzofuranylCl_6alkyl,
dibenzofuranylCl_6alkyl, benzothienylCl_6alkyl which group is optionally
substituted by one or
more substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C 1_6alkyl)amino, aminoC
1_6alkyl, (C 1_
6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1 _6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl, C 1_
6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In one aspect of the invention R19 is hydrogen, cyano or a group selected from
methyl,
is ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl,
cyclobutyl, cyclopentyl,
cyclohexyl, phenyl, thienyl, dioxothiolanyl, imidazoylmethyl, isoxazolyl,
oxazolyl, oxetanyl,
pyrazinyl, pyrazolyl, pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl,
thiadiazolyl,
thiazolyl and triazolyl which group is optionally substituted by one or more
substituent groups
selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_6alkoxy,
2o hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino, bis(C1_6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_
6alkyl)aminoC 1_6alkyl, cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C
1_6alkylsulfonylamino, C 1_
6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
2s 6alkyl)carbamoyl.
In one aspect of the invention R19 is hydrogen or a group selected from
methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl,
cyclopentyl,
cyclohexyl, phenyl, thienyl, imidazoylmethyl, isoxazolyl, pyrazolyl,
pyrazolylmethyl, pyridinyl
and pyrimidinyl which group is optionally substituted by one or more
substituent groups
30 selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_


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6alkyl)aminoC 1_6alkyl, cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C
1_6alkylsulfonylamino, C 1_
6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl.
s In one aspect of the invention R19 is hydrogen, cyano or a group selected
from methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl,
cyclobutyl, cyclopentyl,
cyclohexyl, -CH2(cyclopropyl), -CHzCHzNMez, -CH(CH3)CH2OH, -C(CH3)2CH2OH,
-CH2C(CH3)20H, -CH2C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CF3,
-CH2CHF2, -CH2CH2F, -CH2CH2C1, -CHzCHzSOzMe, -CH2CH(OH)CF3, -CH2CH2CN,
io -CH2CN, -CH2CONMe2, -CH2CO2H, 1-(methyl)cyclopropyl, -CHz(1-
hydroxycyclopropyl),
1-(hydroxymethyl)cyclopropyl, (1R)-2-hydroxy-l-methylethyl, (1S)-2-hydroxy-l-
methylethyl,
phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4-
fluorophenyl,
4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CHzCHz(pyrrolidin-1-yl),-
CHz(imidazol-2-
yl), -CHz(imidazol-3-yl), 1-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-
yl,
is 6-oxo-lH-pryrdin-2-yl, oxetan-3-yl, 1,1-dioxothiolan-3-yl, 5-methylisoxazol-
3-yl,
-CHz(1-methylpyrazol-4-yl), 1-methylpyrazol-4-yl, -CHz(1-methylpyrazol-4-yl),
5-methylpyrazin-2-yl, -CHz(2H-1,2,4-triazol-3-yl), 6-methoxypryridin-3-yl,
pyridin-2-yl, 5-
fluoropyridin-2-yl, pyrimidin-2-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl, 1-
methylpyrazol-3-yl
and 1H-pyrazol-3-yl.
20 In one aspect of the invention R19 is hydrogen, cyano or a group selected
from methyl,
ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -
CH2(cyclopropyl),
-CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)20H, -CH2C(CH3)2CH2OH,
-CHzCHzOH, -CHzCHzCHzOH, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2C1,
-CHzCHzSOzMe, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, -CH2CO2H,
25 1-(methyl)cyclopropyl, -CHz(1-hydroxycyclopropyl), 1-
(hydroxymethyl)cyclopropyl,
(1R)-2-hydroxy-l-methylethyl, (1S)-2-hydroxy-l-methylethyl, phenyl, 4-
methylphenyl,
4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl,
3,4-difluorophenyl, -CHzCHz(pyrrolidin-1-yl),-CHz(imidazol-2-yl), 1-
methylimidazol-4-yl,
oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 1,1-dioxothiolan-3-yl, 5-
methylisoxazol-3-yl,
30 -CHz(1-methylpyrazol-4-yl), 1-methylpyrazol-4-yl, -CHz(1-methylpyrazol-4-
yl),
5-methylpyrazin-2-yl, -CHz(2H-1,2,4-triazol-3-yl), 6-methoxypryridin-3-yl,
pyridin-2-yl, 5-
fluoropyridin-2-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl and 1-methylpyrazol-3-
yl.


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In one aspect of the invention R19 is hydrogen, cyano or a group selected from
methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl,
cyclobutyl, cyclopentyl,
cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH,
-CH2C(CH3)20H, -CH2C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CHF2,
s -CHzCHzSOzMe, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, 1-
(methyl)cyclopropyl, 1-(hydroxymethyl)cyclopropyl, phenyl, 4-methylphenyl, 4-
chlorophenyl,
4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-
difluorophenyl, thien-2-yl,
-CHzCHz(pyrrolidin-1-yl),-CHz(imidazol-2-yl), -CHz(imidazol-3-yl), oxazolyl-2-
yl,
isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl, oxetan-3-yl, 1,1-dioxothiolan-3-yl, 5-
methylisoxazol-
io 3-yl, -CHz(1-methylpyrazol-4-yl), 1-methylpyrazol-4-yl, -CHz(1-
methylpyrazol-4-yl),
5-methylpyrazin-2-yl, -CHz(2H-1,2,4-triazol-3-yl), 6-methoxypryridin-3-yl,
pyridin-2-yl, 5-
fluoropyridin-2-yl, pyrimidin-2-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl, 1-
methylpyrazol-3-yl
and 1H-pyrazol-3-yl.
In one aspect of the invention R19 is hydrogen or a group selected from
methyl, ethyl,
is propyl, i-propyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2,
-CH(CH3)CH2OH, -C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CF3, -CH2CHF2,
-CH2CH2F, -CH2CH2C1, -CH2CH2CN, -CHz(1-hydroxycyclopropyl),
1-(hydroxymethyl)cyclopropyl, (1R)-2-hydroxy-l-methylethyl, (1S)-2-hydroxy-l-
methylethyl,
phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,

20 -CHzCHz(pyrrolidin-1-yl),-CHz(imidazol-2-yl), 1-methylimidazol-4-yl,
oxazolyl-2-yl,
isoxazolyl-3-yl, oxetan-3-yl, 5-methylisoxazol-3-yl, 1-methylpyrazol-4-yl, 5-
methylpyrazin-2-
yl, 6-methoxypryridin-3-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl and 1-
methylpyrazol-3-yl.
In one aspect of the invention R19 is hydrogen or a group selected from
methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl,
cyclopentyl,
25 cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH,
-CHzCHzOH, -CHzCHzCHzOH, 4-methylphenyl, 4-chlorophenyl, 4-
trifluoromethylphenyl, 4-
fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl, -CH2(imidazol-2-
yl),
-CHz(imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl, 5-methylisoxazol-
3-yl,
-CHz(1-methylpyrazol-4-yl), 1-methylpyrazol-4-yl, -CHz(1-methylpyrazol-4-yl),

3o 6-methoxypryridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl, and 1H-
pyrazol-3-yl.
In one aspect of the invention R19 is hydrogen, cyano or a group selected from
methyl,
ethyl, propyl, i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -
CH2(cyclopropyl),


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-CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)20H, -CH2C(CH3)2CH2OH,
-CHzCHzOH, -CHzCHzCHzOH, -CH2CHF2, -CHzCHzSOzMe, -CH2CH(OH)CF3, -CH2CH2CN,
-CH2CN, -CH2CONMe2, 1-(methyl)cyclopropyl, 1-(hydroxymethyl)cyclopropyl,
phenyl,
4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-
methoxyphenyl,
s 3,4-difluorophenyl, -CHzCHz(pyrrolidin-1-yl),-CHz(imidazol-2-yl), oxazolyl-2-
yl,
isoxazolyl-3-yl, oxetan-3-yl, 1,1-dioxothiolan-3-yl, 5-methylisoxazol-3-yl,
-CHz(1-methylpyrazol-4-yl), 1-methylpyrazol-4-yl, 5-methylpyrazin-2-yl,
-CHz(2H-1,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5-
fluoropyridin-2-yl,
thiazol-2-yl, 1,2,4-thiadiazol-5-yl, and 1-methylpyrazol-3-yl.
In one aspect of the invention R19 is hydrogen or a group selected from
methyl, ethyl,
propyl, i-propyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2,
-C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2CN,
1-(hydroxymethyl)cyclopropyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-
methoxyphenyl,
3,4-difluorophenyl, -CHzCHz(pyrrolidin-1-yl), -CH2(imidazol-2-yl), oxazolyl-2-
yl, isoxazolyl-
is 3-yl, oxetan-3-yl, 5-methylisoxazol-3-yl, 1-methylpyrazol-4-yl, 5-
methylpyrazin-2-yl,
6-methoxypryridin-3-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl, and 1-
methylpyrazol-3-yl.
In one aspect of the invention R19 is a group selected from methyl, ethyl,
cyclopropyl,
cyclobutyl, -CH(CH3)CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CHF2, -CH2CH2F,
-CH2CH2CN, (1R)-2-hydroxy-l-methylethyl, (1S)-2-hydroxy-l-methylethyl, -
CH2(imidazol-2-
yl), oxazolyl-2-yl, isoxazolyl-3-yl, 1-methylpyrazol-4-yl, 5-methylpyrazin-2-
yl, thiazol-2-yl
and 1,2,4-thiadiazol-5-yl.
In one aspect of the invention R19 is a group selected from methyl, ethyl,
cyclopropyl,
cyclobutyl, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2CN, -CH2(imidazol-2-yl), oxazolyl-
2-yl,
isoxazolyl-3-yl, 1-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and
1,2,4-thiadiazol-
5-yl.
In one aspect of the invention R19 is hydrogen or a group selected from
methyl, ethyl,
cyclopropyl, 1-methylpyrazol-4-yl, and -CHz(1-methylpyrazol-4-yl).
In one aspect of the invention R19 is methyl.
In one aspect of the invention R19 is ethyl.
In one aspect of the invention R19 is cyclopropyl.
In one aspect of the invention R19 is cyclobutyl.

In one aspect of the invention R19 is -CH(CH3)CH2OH.


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In one aspect of the invention R19 is -CHzCHzOH.

In one aspect of the invention R19 is -CHzCHzCHzOH.
In one aspect of the invention R19 is -CH2CHF2.

In one aspect of the invention R19 is -CH2CH2F.
s In one aspect of the invention R19 is -CH2CH2CN.
In one aspect of the invention R19 is (1R)-2-hydroxy-l-methylethyl.
In one aspect of the invention R' 9 is (1S)-2-hydroxy-l-methylethyl.
In one aspect of the invention R19 is -CH2(imidazol-2-yl).
In one aspect of the invention R19 is oxazolyl-2-yl.
In one aspect of the invention R19 is isoxazolyl-3-yl.
In one aspect of the invention R19 is 1-methylpyrazol-4-yl.
In one aspect of the invention R19 is 5-methylpyrazin-2-yl.
In one aspect of the invention R19 is thiazol-2-yl.
In one aspect of the invention R19 is 1,2,4-thiadiazol-5-yl.
is Rlg and R19

In one aspect of the invention, R'g and R' 9 together with the nitrogen atom
to which
they are attached form a 6-membered heterocyclic ring wherein 1 ring carbon
atoms is
optionally replaced with N or 0 and which ring is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
2o haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyC1_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoC1_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
25 C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In one aspect of the invention, R'g and R' 9 together with the nitrogen atom
to which
they are attached form a morpholine ring.
In one aspect of the invention, R'g and R' 9 together with the nitrogen atom
to which
they are attached form a 3-hydroxypyrrolidin-1-yl group.
30 In one aspect of the invention there is provided a subset of compounds of
formula (I),
or a pharmaceutically acceptable salt thereof;
m is 0, 1 or 2;


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iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R7
-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NRsCRV- and
s -S(O)2NR4CR6R';
R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
or X-Ri is -CR6R'OH;
io R2 is a group selected from carbocyclyl and heterocyclyl which group is
optionally substituted
by one or more substituent group independently selected from halo, cyano,
nitro, -R", -OR", -
SR", -SORi i, -SOzRi i, -CORi i 11 11 iz 11 iz 11 iz
, -COZR , -CONR R , -NR R , -NR COR , -
NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19=
~
each R3, when present, is selected from cyano, R13, and -CONR13R14;
is R4 and Rs are independently hydrogen or C1_6alkyl;

or, when X is -NR4CR6~-, -NR4C(O)CRV- or -NR4C(O)NR5CR6R7-, R' and R4 together
with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
wherein 1 ring carbon atom is optionally replaced with N or 0 and which ring
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
20 C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCl_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
25 carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
30 6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,


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sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
s heterocyclyl which group is optionally substituted by one or more
substituent groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCI-6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
io carbocyclyl and heterocyclyl which group is optionally substituted by one
or more substituent
groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCI-6alkyl, haloCi_
6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino and bis(C1_6alkyl)amino;
R13 and R14 are independently hydrogen or a C1_3alkyl which is optionally
substituted by one or
is more substituent groups selected from halo, cyano, hydroxy and C1_3alkoxy;
and
R19 is hydrogen, cyano or a group selected from C1_6alkyl, C3_6cycloakyl,
aryl, heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCI-6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
20 6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino,
aminoCi_6alkyl,
(C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl, cyanoC1_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1 _6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
25 or Rig and R19 together with the nitrogen atom to which they are attached
form a
6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally
replaced with N or 0
and which ring is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_6alkyl,
hydroxyC 1_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
30 6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,


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sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of
formula
(I), or a pharmaceutically acceptable salt thereof;
s m is 0, l or 2;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R7
-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CRV- and

lo -S(O)2NR4CRV;
R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
or X-Ri is -CR6R'OH;
is R2 is a group selected from carbocyclyl and heterocyclyl which group is
optionally substituted
by one or more substituent group independently selected from halo, cyano,
nitro, -R", -OR", -
SRi i, -SORi i, -SOzRi i, -CORi i 11 11 iz 11 iz 11 iz
, -COZR , -CONR R , -NR R , -NR COR , -
NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19;
each R3, when present, is selected from C1_3alkyl, hydroxyCi_3alkyl, and -
CONR13R14;
2o R4 and R5 are independently hydrogen or C1_6alkyl;

or, when X is -NR4CR6~-, -NR4C(O)CRV- or -NR4C(O)NR5CR6R7-, R' and R4 together
with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
wherein 1 ring carbon atom is optionally replaced with N or 0 and which ring
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
25 C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCl_
6alkyl, (C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC1_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
30 carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,


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O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
s cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
io heterocyclyl which group is optionally substituted by one or more
substituent groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
15 carbocyclyl and heterocyclyl which group is optionally substituted by one
or more substituent
groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_
6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino and bis(C1_6alkyl)amino;
R13 and R14 are independently hydrogen or a C1_3alkyl; and
2o R19 is hydrogen, cyano or a group selected from C1_6alkyl, C3_6cycloakyl,
aryl, heteroaryl,
ary1C1_6alkyl and heteroarylC1_6alkyl which group is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
25 (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a
3o 6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally
replaced with N or 0
and which ring is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_6alkyl,


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hydroxyC i_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
s 6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.In
another aspect of
the invention there is provided a subset of compounds of formula (I), or a
pharmaceutically
acceptable salt thereof;
m is 0, 1 or 2;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
io CRg;
X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R7
-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CRV- and
-S(O)2NR4CR6R';
R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
15 heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
or X-Ri is -CR6R'OH;
R2 is a group selected from carbocyclyl and heterocyclyl which group is
optionally substituted
by one or more substituent group independently selected from halo, cyano,
nitro, -R", -OR", -

20 SRll, -SORll, -SOZRll, -CORll 11 11 Iz 11 lz 11 lz
, -COZR , -CONR R , -NR R , -NR COR , -
NR11COCONR1zR16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR1sR19;
each R3, when present, is methyl or ethyl;
R4 and R5 are independently hydrogen or C1_6alkyl;

or, when X is -NR4CR6~-, -NR4C(O)CRV- or -NR4C(O)NR5CR6R7-, R' and R4 together
25 with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
wherein 1 ring carbon atom is optionally replaced with N or 0 and which ring
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
30 6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_


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6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
s 0 or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
1 o sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
15 from halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl,
haloC 1_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl and heterocyclyl which group is optionally substituted by one or
more substituent
20 groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_
6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen, cyano or a group selected from C1_6alkyl, C3_6cycloakyl,
aryl, heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more
25 substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyC1_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoC1_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
30 6alkyl)sulfamoyl, C1_6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;


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or Rig and R19 together with the nitrogen atom to which they are attached form
a
6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally
replaced with N or 0
and which ring is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_6alkyl,
s hydroxyC i_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of
formula
(I), or a pharmaceutically acceptable salt thereof;
m is 0, 1 or 2;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
is X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -
S(O)CR6R7
-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CRV- and
-S(O)2NR4CR6R';
R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
or X-Ri is -CR6R'OH;
R2 is a group selected from carbocyclyl and heterocyclyl which group is
optionally substituted
by one or more substituent group independently selected from halo, cyano,
nitro, -R", -OR", -
SRi i, -SORi i, -SOzRi i, -CORi i 11 11 iz 11 iz 11 iz
, -COZR , -CONR R , -NR R , -NR COR , -
NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19=
~
each R3, when present, is methyl;
R4 and R5 are independently hydrogen or C1_6alkyl;

or, when X is -NR4CR6~-, -NR4C(O)CRV- or -NR4C(O)NR5CR6R7-, R' and R4 together
with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
wherein 1 ring carbon atom is optionally replaced with N or 0 and which ring
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_


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6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
s carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
is R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl and heterocyclyl which group is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_
6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen, cyano or a group selected from C1_6alkyl, C3_6cycloakyl,
aryl, heteroaryl,
ary1C1_6alkyl and heteroarylC1_6alkyl which group is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_


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6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a
6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally
replaced with N or 0
s and which ring is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_6alkyl,
hydroxyC i_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
1 o sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In one aspect of the invention there is provided a subset of compounds of
formula (I),
or a pharmaceutically acceptable salt thereof;
m is 0, 1 or 2;
is iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N
and the other is
CRg ;
X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R7
-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CRV- and
-S(O)2NR4CR6R';
2o R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
or X-Ri is -CR6R'OH;
R2 is a group selected from carbocyclyl and heterocyclyl which group is
optionally substituted
25 by one or more substituent group independently selected from halo, cyano,
nitro, -R", -OR", -
SRi i, -SORi i, -SOzRi i, -CORi i 11 11 iz 11 iz 11 iz
, -COZR , -CONR R , -NR R , -NR COR , -
NR11COCONR1zR16, -NR11SO2R12, -NR17CONR18R19 and -NR17CSNR1sR19;
each R3, when present, is methyl;
R4 and R5 are independently hydrogen or C1_6alkyl;

30 or, when X is -NR4CRV-, -NR4C(O)CRV- or -NR4C(O)NR5CR6R7-, R' and R4
together
with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
wherein 1 ring carbon atom is optionally replaced with N or 0 and which ring
is optionally


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substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
s 6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C
1_6alkyl)amino, sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
io 0 or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
15 sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
20 from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl and heterocyclyl which group is optionally substituted by one or
more substituent
25 groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_
6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen or a group selected from C1_6alkyl, C3_6cycloakyl, aryl,
heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more
30 substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,


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(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
s or Rig and R19 together with the nitrogen atom to which they are attached
form a 6-membered
heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or
0 and which
ring is optionally substituted by one or more substituent groups selected from
halo, cyano,
nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl,
hydroxyC i_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
io 6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In one aspect of the invention there is provided a subset of compounds of
formula (I),
15 or a pharmaceutically acceptable saltthereof;
m is 0, 1 or 2;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R7
-,
20 -S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CRV- and
-S(O)2NR4CR6R';
R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
25 or X-Ri is -CR6R'OH;
R2 is a group selected from aryl and heteroaryl which group is optionally
substituted by one or
more substituent group independently selected from halo, cyano, nitro, -R", -
OR", -SR", -
SOR", -SOzR", -COR", -COzR", -CONR"R'z ~ ~ 12 1 1 12
, -NR R , -NR COR ,
-NR11COCONR12R16> -NR11SO2R12> -NRI7CONRigR19 and -NRI7CSNRisR19=
~
3o each R3, when present, is methyl;
R4 and R5 are independently hydrogen or C1_6alkyl;


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or, when X is -NR4CR6~-, -NR4C(O)CRV- or -NR4C(O)NRsCR6R7-, R' and R4 together
with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
wherein 1 ring carbon atom is optionally replaced with N or 0 and which ring
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
s C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
io carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
is 6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
2o R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
2s 6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl and heterocyclyl which group is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_
6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
3o amino, C1_6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen or a group selected from C1_6alkyl, C3_6cycloakyl, aryl,
heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more


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substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyC1_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoC1_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
s 6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1 _6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 6-membered
heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or
0 and which
io ring is optionally substituted by one or more substituent groups selected
from halo, cyano,
nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl,
hydroxyC 1_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
15 sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1
_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In one aspect of the invention there is provided a subset of compounds of
formula (I),
or a pharmaceutically acceptable saltthereof;
m is 0, 1 or 2;
20 iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N
and the other is
CRg ;
X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R7
-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CRV- and
-S(O)2NR4CR6R';
25 R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
or X-Ri is -CR6R'OH;
R2 is selected from aryl and heteroaryl which group is substituted by -
NR"CONR'gR19 or -
3o NR"CSNR'gR19 and optionally substituted by one or more substituent group
independently
selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z, -NR11 iz
R and -
NR"COR'2 ;


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each R3, when present, is methyl;
R4 and R5 are independently hydrogen or C1_6alkyl;

or, when X is -NR4CR6~-, -NR4C(O)CRV- or -NR4C(O)NRsCR6R7-, R' and R4 together
with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
s wherein 1 ring carbon atom is optionally replaced with N or 0 and which ring
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
6alkyl, (C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC1_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
0 or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl and heterocyclyl which group is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_
6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino and bis(C1_6alkyl)amino; and


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R19 is hydrogen or a group selected from C1_6alkyl, C3_6cycloakyl, aryl,
heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
s 6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino,
aminoCi_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
io or Rig and R19 together with the nitrogen atom to which they are attached
form a 6-membered
heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or
0 and which
ring is optionally substituted by one or more substituent groups selected from
halo, cyano,
nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl,
hydroxyC 1_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
is 6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of
formula
20 (I), or a pharmaceutically acceptable salt thereof;
m is 0, 1 or 2;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-
and
25 -S(0)2CR6~-;
R' is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl,
tert-butyl,
cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl,
imidazolyl,
pyrazolyl, furanyl, thiadiazolyl, thiazolyl, thienyl, pyridinyl, pyrimidinyl,
pyrazinyl,
pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl,
imidazolylmethyl,
30 imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl,
furanylethyl,
thiadiazolylmethyl, thiadiazolylethyl, thiazolylmethyl, thiazolylethyl,
thienylmethyl,
thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl,
pyrimidinylethyl,


CA 02692945 2009-12-23
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pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by
1, 2 or 3
substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -
CONR9R10, -NR9R'0 and
-NR9COR10;
or X-Ri is -C(CH3)20H or -CHzOH;
s R2 is selected from 5 or 6 membered aryl and heteroaryl which group is
substituted by
-NHCONR'gR19 or -NHCSNR'gR19and optionally substituted by one or more
substituent
group independently selected from halo, cyano, nitro, -R", -OR", -COR", -
CONR"R12
,
-NR11R1z and -NRIICORI2;
each R3, when present, is methyl;
i o R4 is hydrogen or C 1_6alkyl;
or, when X is -NR4CR6~-, R' and R4 together with the atom or atoms to which
they are
attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom
is optionally
replaced with N or 0 and which ring is optionally substituted by one or more
substituent
groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_
is 6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_6alkyl, bis(C1_
6alkyl)aminoC 1_6alkyl, cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C
1_6alkylsulfonylamino, C 1_
6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
20 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
25 6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
3o R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected


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from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 and Rig are independently hydrogen or a group selected from
C1_6alkyl, carbocyclyl
s and heterocyclyl which group is optionally substituted by one or more
substituent groups
selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen, cyano or a group selected from C1_6alkyl, C3_6cycloakyl,
aryl, heteroaryl,
1 o ary1C 1_6alkyl and heteroarylC 1_6alkyl which group is optionally
substituted by one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
1 s 6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 6-membered
heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or
0 and which
2o ring is optionally substituted by one or more substituent groups selected
from halo, cyano,
nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloC1_6alkyl, haloC1_6alkoxy,
hydroxyC1_6alkyl,
hydroxyC i_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
25 sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of
formula
(I), or a pharmaceutically acceptable salt thereof;
m is 0, 1 or 2;
30 iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N
and the other is
CRg ;


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X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-
and
-S(O)2CR6R'-;
R' is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl,
tert-butyl,
cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl,
imidazolyl,
s pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl,
pyrrolidinylmethyl,
pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl,
imidazolylethyl,
pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl,
thienylethyl,
pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl,
pyrazinylmethyl and
pyrazinylethyl, which group is optionally substituted by 1, 2 or 3 substituent
group selected

io from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10;
or X-Ri is -C(CH3)20H or -CHzOH;
R2 is selected from 5 or 6 membered aryl and heteroaryl which group is
substituted by
-NHCONR'gR19 or -NHCSNR'gR19and optionally substituted by one or more
substituent
group independently selected from halo, cyano, nitro, -R", -OR", -COR", -
CONR"R12
,
ls -NR11R12 and -NRIICORI2;
each R3, when present, is methyl;
R4 is hydrogen or C1_6alkyl;
or, when X is -NR4CR6~-, R' and R4 together with the atom or atoms to which
they are
attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom
is optionally
2o replaced with N or 0 and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloC1_6alkyl, haloCi_
6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_6alkyl, bis(C1_
6alkyl)aminoC 1_6alkyl, cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C
1_6alkylsulfonylamino, C 1_
2s 6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
30 0 or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,


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bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1 _6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
s R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCI-6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 and Rig are independently hydrogen or a group selected from
C1_6alkyl, carbocyclyl
and heterocyclyl which group is optionally substituted by one or more
substituent groups
selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCI-
6alkyl, haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
is 6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen or a group selected from C1_6alkyl, C3_6cycloakyl, aryl,
heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCI-6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl, cyanoC1_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1 _6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 6-membered
heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or
0 and which
ring is optionally substituted by one or more substituent groups selected from
halo, cyano,
nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCI-6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl,
hydroxyC 1_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,


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sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In another particular class of compound of formula (I), or a pharmaceutically
acceptable salt thereof;
s mis0orl;
iY is CH and Y2 is N;
X is a-S(O)zCRV- linker group;
R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclopropyl,
cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl,
thiadiazolyl,
io thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl,
thiazolylmethyl,
thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted
by 1 or 2
substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy,
trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3;
or -XRi is -C(CH3)20H or -CHzOH;
15 R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl,
thienyl, pyridinyl,
pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHCONHR'9
or
-NHCSNHR19and optionally substituted by one or more substituent group
independently
selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z, -NR 11 iz
R and
-NR" COR'2 ;
20 R3, when present, is methyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
25 6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
3o Rii, Ri2 and Rig are independently hydrogen or a group selected from
C1_6alkyl, carbocyclyl
and heterocyclyl which group is optionally substituted by one or more
substituent groups
selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_6alkoxy,


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hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen, cyano or a group selected from C1_6alkyl, C3_6cycloakyl,
aryl, heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more
s substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1 _6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In another particular class of compound of formula (I), or a pharmaceutically
acceptable salt thereof;
mis0orl;
iY is CH and Y2 is N;
X is a-S(O)zCRV- linker group;
R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclopropyl,
cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl,
furanylmethyl,
thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which
group is
optionally substituted by 1 or 2 substituent group selected from amino, halo,
cyano, methyl,
methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONHz and -CONHCH3;
or -XRi is -C(CH3)20H or -CHzOH;
R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl,
pyridinyl,
pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHCONHR'9
or
-NHCSNHR19and optionally substituted by one or more substituent group
independently
selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z, -NR11 iz
R and
-NR" COR'2 ;

R3, when present, is methyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_


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6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
s 6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii, Ri2 and Rig are independently hydrogen or a group selected from
C1_6alkyl, carbocyclyl
and heterocyclyl which group is optionally substituted by one or more
substituent groups
selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen or a group selected from C1_6alkyl, C3_6cycloakyl, aryl,
heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C 1_6alkyl)amino, aminoC
1_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1 _6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In a further particular class of compound of formula (I), or a
pharmaceutically
acceptable salt thereof;
m is 0, 1 or 2;
X is a-S(O)2CR6R'- linker group selected;
iY is CH and Y2 is N.
R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclopropyl,
cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl,
thiadiazolyl,
thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl,
thiazolylmethyl,
thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted
by 1 or 2
substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy,
trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONHz and -CONHCH3;


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R2 is phenyl or pyridinyl substituted by -NHCONHR'9 or -NHCSNHR'9and
optionally
substituted by one or more substituent group independently selected from
fluoro, methyl,
methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2;
R3, when present, is methyl or ethyl;
s R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
i o bis(C 1_6alkyl)amino, aminoC i_6alkyl, (C 1_6alkyl)aminoC i_6alkyl, bis(C
1_6alkyl)aminoC i_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl; and
R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-
propyl, butyl, i-butyl,
is t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
thienyl,
dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl,
pyrazolyl,
pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl
and triazolyl
which group is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_6alkyl,
2o hydroxyC 1_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
25 In a further particular class of compound of formula (I), or a
pharmaceutically
acceptable salt thereof;
m is l;
X is a-S(O)zCR6R'- linker group selected;
iY is CH and Y2 is N.
3o R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclopropyl,
cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl,
thiadiazolyl,
thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl,
thiazolylmethyl,


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thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted
by 1 or 2
substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy,
trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3;

R2 is phenyl or pyridinyl substituted by -NHCONHR'9 or -NHCSNHR'9and
optionally
s substituted by one or more substituent group independently selected from
fluoro, methyl,
methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2;
R3 is methyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
io 0 or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
15 sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl; and
R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-
propyl, butyl, i-butyl,
t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
thienyl,
dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl,
pyrazolyl,
20 pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl,
thiazolyl and triazolyl
which group is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_6alkyl,
hydroxyC i_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
25 cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In a further particular class of compound of formula (I), or a
pharmaceutically
acceptable salt thereof;
30 m is 1;
X is a-S(O)zCR6R'- linker group selected;
1 Y is CH and Y2 is N.


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R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclopropyl,
cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl,
furanylmethyl,
thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which
group is
optionally substituted by 1 or 2 substituent group selected from amino, halo,
cyano, methyl,
s methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3;
R2 is phenyl or pyridinyl substituted by -NHCONHR'9 or -NHCSNHR'9and
optionally
substituted by one or more substituent group independently selected from
fluoro, methyl,
methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2;
R3 is methyl;
io R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
15 bis(C 1_6alkyl)amino, aminoC 1_6alkyl, (C 1_6alkyl)aminoC 1_6alkyl, bis(C
1_6alkyl)aminoC 1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl; and
R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl,
20 pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl,
imidazoylmethyl,
isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl which group
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
2s 6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In a further particular class of compound of formula (I), or a
pharmaceutically
3o acceptable salt thereof;
m is l;
X is a-S(O)zCRV- linker group;


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iY is CH and Y2 is N.
R' is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -
CHzCHzOH,
-CH2CH2NHC(O)CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-
trifluoromethylphenyl,
2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-
yl, pyridin-
s 2-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, and 3-methyl-
1,3,4-thiadiazol-2-
yl;
R2is

1 1
~ A2 O S
~R1s ~-'A2
~ R1s
N N N N .
R17 R1s R17 R1s
or
wherein A' and A2 are selected from CH or N provided that at least one of A'
or
A2 is CH;
Ri' is hydrogen;
Rig is hydrogen;
R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl,
is cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH,
-C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH, 4-methylphenyl, 4-
chlorophenyl, 4-trifluoromethylphenyl, 4-flurophenyl, 4-methoxyphenyl,
3,4-difluorophenyl, thien-2-yl, -CH2(imidazol-2-yl),
-CHz(imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl,
5-methylisoxazol-3-yl, 1-methylpyrazol-4-yl, -CHz(1-methylpyrazol-4-
yl), -CHz(1-methylpyrazol-4-yl), 6-methoxypryridin-3-yl,
5-fluoropyridin-2-yl, pyrimidin-2-yl, and 1H-pyrazol-3-yl;
R3 is methyl; and
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,


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cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In a further particular class of compound of formula (I), or a
pharmaceutically
s acceptable salt thereof;
m is 0, 1 or 2;
X is a-S(O)zCRV- linker group;
iY is CH and Y2 is N.
R' is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
cyclopentyl,
io cyclohexyl, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2C(OH)(CH3)2, -CHzCHzCHzOCHFz,
-CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, -CH2CH2NHMe,
phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-fluoro-4-
methylaminophenyl,
4-fluoro-2-methylphenyl, 5-fluoro-2-methylphenyl, 3-fluoro-4-(2-
hydroxyethylamino)phenyl,
4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-
chlorophenyl,
is 3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-
ethylaminophenyl,
3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl,
2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,
2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-
(trifluoromethyl)phenyl,
2-methylphenyl, 4-methylphenyl, 4-(2-hydroxyethylamino)phenyl, 1 H-imidazol-2-
yl,
2o 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-
(dimethylcarbamoyl)pyridin-
2-yl, 1-(difluoromethyl)pyrazol-4-yl, 1-(difluoromethyl)-3,5-dimethylpyrazol-4-
yl,
1,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, 5-
fluoropyridin-3-yl,
thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-
dimethylthiazol-5-yl,
5-methyl-1,3,4-thiadiazol-2-yl, terahydrofuran-3-yl and terahydropyran-4-yl;

25 R2 is
1 1
~ A2 O S
~R1s ~-'A2
~ R1s
N N N N .
R17 R1s R17 R1s
or
wherein A' and A2 are selected from CH or N provided that at least one of A'
or
A2 is CH;

Ri' is hydrogen;


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Rig is hydrogen;
R19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl,
i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl),
-CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)20H,
s -CH2C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CF3,
-CH2CHF2, -CH2CH2F, -CH2CH2C1, -CH2CH2SO2Me,
-CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, -CH2CO2H,
1-(methyl)cyclopropyl, -CHz(1-hydroxycyclopropyl),
1-(hydroxymethyl)cyclopropyl, (1 R)-2-hydroxy-l-methylethyl, (1 S)-2-
io hydroxy-1-methylethyl, phenyl, 4-methylphenyl, 4-chlorophenyl,
4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl,
3,4-difluorophenyl, -CHzCHz(pyrrolidin-1-yl),-CHz(imidazol-2-yl),
1-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 1,1-
dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CHz(1-methylpyrazol-4-yl),
is 1-methylpyrazol-4-yl, -CHz(1-methylpyrazol-4-yl), 5-methylpyrazin-2-
yl, -CHz(2H-1,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5-
fluoropyridin-2-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl and
1-methylpyrazol-3-yl;
R3, when present, is methyl or ethyl; and
2o R6 and R7 together with the carbon atom to which they are attached form a 3-
to l0-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
25 bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In a further particular class of compound of formula (I), or a
pharmaceutically
3o acceptable salt thereof;
m is l;
X is a-S(O)zCRV- linker group;


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iY is CH and Y2 is N.
R' is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
cyclopentyl,
cyclohexyl, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2OCH3, -CH2CH2NHC(O)CH3,
-CH2C(O)NH2, -CH2C(O)NHMe, phenyl, 4-fluorophenyl, 4-chlorophenyl, 3,5-
difluorophenyl,
s 2-(trifluoromethyl)phenyl, 4-(2-hydroxyethylamino)phenyl, 1H-imidazol-2-yl,
2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, pyridin-
4-yl, pyridin-
2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, thiazol-2-yl, 4-
methylthiazol-2-yl and
5-methyl-1,3,4-thiadiazol-2-yl;
R2is

1 1
A,~ A2 0 A~ s

J~ R19 )~ R19
N N N N
1
R17 R18 R17 R1s
or
wherein A' and A2 are selected from CH or N provided that at least one of A'
or
A2 is CH;

Ri' is hydrogen;
Rig is hydrogen;
is R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-
propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl),
-CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)20H,
-CH2C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CHF2,
-CHzCHzSOzMe, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -
CH2CONMe2, 1-(methyl)cyclopropyl, 1-(hydroxymethyl)cyclopropyl,
phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl,
4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,
-CH2CH2(pyrrolidin-l-yl),-CH2(imidazol-2-yl), oxazolyl-2-yl,
isoxazolyl-3-yl, oxetan-3-yl, 1,1-dioxothiolan-3-yl, 5-methylisoxazol-3-
yl, -CHz(1-methylpyrazol-4-yl), 1-methylpyrazol-4-yl, 5-methylpyrazin-
2-yl, -CHz(2H-1,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl,
5-fluoropyridin-2-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl, and
1-methylpyrazol-3-yl;
R3 is methyl; and


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R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
s 6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In one aspect of the invention there is provided a subset of compounds of
formula (IA),
(IB) or (IC)
O O O
R3A o"N ', R3B R3A.,%`' N R3B R3A oo0o'( N ', R3B

,Y/\Y2 1 Y/\Y2 1 Y/\Y2
R'1-11 /\ ~ R'~ /\ ~ R'~ /\ ~
X N Rz X N Rz X N Rz

(IA) (IB) (IC)
or a pharmaceutically acceptable salt thereof;
is iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N
and the other is
CRg ;
X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R7
-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CRV- and
-S(O)2NR4CR6R';
2o R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
or X-Ri is -C(CH3)20H or -CHzOH;
R2 is selected from aryl and heteroaryl which group is substituted by -
NR"CONR'gR19 or
25 -NR"CSNR'gR19and optionally substituted by one or more substituent group
independently
selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z, -NR 11 iz
R and -
NR"COR'2 ;


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R4 and Rs are independently hydrogen or C1_6alkyl

or, when X is -NR4CR6~-, -NR4C(O)CRV- or -NR4C(O)NRsCR6R7-, R' and R4 together
with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
wherein 1 ring carbon atom is optionally replaced with N or 0 and which ring
is optionally
s substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
C1_6alkyl, C1_6alkoxy, haloCI-6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCl_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCI-6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl and heterocyclyl which group is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCI-6alkyl, haloCi_
6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino and bis(C1_6alkyl)amino;


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R19 is hydrogen or a group selected from C1_6alkyl, C3_6cycloakyl, aryl,
heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
s 6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino,
aminoCi_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1 _6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
io or Rig and R19 together with the nitrogen atom to which they are attached
form a 6-membered
heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or
0 and which
ring is optionally substituted by one or more substituent groups selected from
halo, cyano,
nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl,
hydroxyC 1_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
is 6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl; and
when R3A is hydrogen, R3B is hydrogen, methyl, ethyl, hydroxymethyl,
dimethylcarbamoyl or
20 carbamoyl; or
when R3A is methyl, R3B is methyl..
In one aspect of the invention there is provided a subset of compounds of
formula (IA),
(IB) or (IC)
O O O
R3A o"N ', R3B R3A-,%`' N R3B R3A oooo'( N '', R3B

,YY2 1 YY2 1 Y11\Y2
Rl1-11 /\ ~ Rl~ /\ ~ Rl~ /\ ~
X N Rz X N Rz X N Rz

25 (IA) (IB) (IC)
or a pharmaceutically acceptable salt thereof;


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iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R7
-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NRsCRV- and
s -S(O)2NR4CR6R';
R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
or X-Ri is -C(CH3)20H or -CHzOH;
io R2 is selected from aryl and heteroaryl which group is substituted by -
NR"CONR'gR19 or
-NR"CSNR'gR19and optionally substituted by one or more substituent group
independently
selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z, -NR 11 iz
R and -
NR"COR'2 ;

R3A and R3B independently is hydrogen, methyl or ethyl;
is R4 and R5 are independently hydrogen or C1_6alkyl

or, when X is -NR4CR6~-, -NR4C(O)CRV- or -NR4C(O)NR5CR6R7-, R' and R4 together
with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
wherein 1 ring carbon atom is optionally replaced with N or 0 and which ring
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
20 C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
25 carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
30 6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,


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sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
s heterocyclyl which group is optionally substituted by one or more
substituent groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
io carbocyclyl and heterocyclyl which group is optionally substituted by one
or more substituent
groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_
6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen or a group selected from C1_6alkyl, C3_6cycloakyl, aryl,
heteroaryl,
15 ary1C 1_6alkyl and heteroarylC 1_6alkyl which group is optionally
substituted by one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
20 6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 6-membered
heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or
0 and which
25 ring is optionally substituted by one or more substituent groups selected
from halo, cyano,
nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl,
hydroxyC 1_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
30 sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.


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In one aspect of the invention there is provided a subset of compounds of
formula (Ia)
or (Ib)

O 0
N )", R3 N R3
I Y/~Y2 1 Y/\Y2

R' ~ ~ R'~ ~ ~
N R2 X N R2
(Ia) (Ib)
s or a pharmaceutically acceptable salt thereof;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R7
-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CRV- and

-S(O)2NR4CRV;
R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
or X-Ri is -C(CH3)20H or -CHzOH;
is R2 is selected from aryl and heteroaryl which group is substituted by -
NR"CONR'gR19 or
-NR"CSNR'gR19and optionally substituted by one or more substituent group
independently
selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z, -NR11 iz
R and -
NR"COR'2 ;

R3 is hydrogen, methyl or ethyl;
2o R4 and Rs are independently hydrogen or C1_6alkyl

or, when X is -NR4CR6~-, -NR4C(O)CRV- or -NR4C(O)NR5CR6R7-, R' and R4 together
with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
wherein 1 ring carbon atom is optionally replaced with N or 0 and which ring
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
25 C1_6alkyl, C1_6alkoxy, haloC1_6alkyl, haloC1_6alkoxy, hydroxyC1_6alkyl,
hydroxyC1_6alkoxy, C1_
6alkoxyCl_6alkyl, C1_6alkoxyCl_6alkoxy, amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCl_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_


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6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
s carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is
optionally replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
1 o cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
is heterocyclyl which group is optionally substituted by one or more
substituent groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
20 carbocyclyl and heterocyclyl which group is optionally substituted by one
or more substituent
groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloC1_6alkyl, haloCi_
6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen or a group selected from C1_6alkyl, C3_6cycloakyl, aryl,
heteroaryl,
25 ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted
by one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloC1_6alkyl, haloC1_6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
30 6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;


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or Rig and R19 together with the nitrogen atom to which they are attached form
a
6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally
replaced with N or 0
and which ring is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_6alkyl,
s hydroxyC i_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In one aspect of the invention there is provided a subset of compounds of
formula (Ia)
or (Ib)
O O
N , R3 N R3
I Y/~Y2 1 Y/\Y2

R' ~ R' ~
X N R2 X N R2
(Ia) (Ib)
or a pharmaceutically acceptable salt thereof;
is iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N
and the other is
CRg ;
X is a linker group selected from -NR4CR6R'-, -OCR6R'-, -SCR6R'-, -S(O)CR6R7
-,
-S(O)2CR6R7-, -C(O)NR4CR6R7-, -NR4C(O)CR6R7-, -NR4C(O)NR5CRV- and
-S(O)2NR4CR6R';
2o R' is a group selected from C1_6alkyl, carbocyclyl, carbocyc1y1C1_6alkyl,
heterocyclyl and
heterocyc1y1C1_6alkyl, which group is optionally substituted by one or more
substituent group
selected from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R'0 and -
NR9COR'0;
or X-Ri is -C(CH3)20H or -CHzOH;
R2 is selected from aryl and heteroaryl which group is substituted by -
NR"CONR'gR19 or
25 -NR"CSNR'gR19and optionally substituted by one or more substituent group
independently
selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z, -NR 11 iz
R and -
NR"COR'2 ;


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R3 is methyl;
R4 and R5 are independently hydrogen or C1_6alkyl

or, when X is -NR4CR6~-, -NR4C(O)CRV- or -NR4C(O)NRsCR6R7-, R' and R4 together
with the atom or atoms to which they are attached form a 5- or 6-membered
heterocyclic ring
s wherein 1 ring carbon atom is optionally replaced with N or 0 and which ring
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, oxo,
C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl,
hydroxyCl_6alkoxy, C1_
6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C
1_6alkyl)amino, aminoC i_
6alkyl, (C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC1_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
0 or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 , Ri' and Rig are independently hydrogen or a group selected from
C1_6alkyl,
carbocyclyl and heterocyclyl which group is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_
6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino and bis(C1_6alkyl)amino; and


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R19 is hydrogen or a group selected from C1_6alkyl, C3_6cycloakyl, aryl,
heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
s 6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino,
aminoCi_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
io or Rig and R19 together with the nitrogen atom to which they are attached
form a 6-membered
heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or
0 and which
ring is optionally substituted by one or more substituent groups selected from
halo, cyano,
nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl,
hydroxyC 1_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
is 6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of
formula
20 (Ia) or (Ib)
O O
N )"', R3 N R3
I YY2 1 YY2

R' ~ ~ R'~ ~ ~
N R2 X N R2
(Ia) (Ib)
or a pharmaceutically acceptable salt thereof;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
25 CRg;
X is a linker group selected from -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -S(O)CR6R7-
and
-S(0)2CR6R7-;


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R' is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl,
tert-butyl,
cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl,
imidazolyl,
pyrazolyl, furanyl, thiadiazolyl, thiazolyl, thienyl, pyridinyl, pyrimidinyl,
pyrazinyl,
pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl,
imidazolylmethyl,
s imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl,
furanylethyl,
thiadiazolylmethyl, thiadiazolylethyl, thiazolylmethyl, thiazolylethyl,
thienylmethyl,
thienylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl,
pyrimidinylethyl,
pyrazinylmethyl and pyrazinylethyl, which group is optionally substituted by
1, 2 or 3
substituent group selected from halo, cyano, nitro, R9, -OR9, -COR9, -
CONR9R10, -NR9R'0 and
io -NR9COR10;
or X-Ri is -C(CH3)20H or -CHzOH;
R2 is selected from 5 or 6 membered aryl and heteroaryl which group is
substituted by
-NHCONRigR19 or -NHCSNRigRl9and optionally substituted by one or more
substituent group
independently selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z 11
12
, -NR R
is and -NR11COR12;
R3 is methyl;
R4 is hydrogen or C1_6alkyl;
or, when X is -NR4CR6~-, R' and R4 together with the atom or atoms to which
they are
attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom
is optionally
2o replaced with N or 0 and which ring is optionally substituted by one or
more substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloC1_6alkyl,
haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
25 C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
30 0 or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,


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bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
s R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 and Rig are independently hydrogen or a group selected from
C1_6alkyl, carbocyclyl
and heterocyclyl which group is optionally substituted by one or more
substituent groups
selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
is 6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen, cyano or a group selected from C1_6alkyl, C3_6cycloakyl,
aryl, heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoC1_6alkyl, bis(C1_6alkyl)aminoC1_6alkyl, cyanoC1_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a
6-membered heterocyclic ring wherein 1 ring carbon atoms is optionally
replaced with N or 0
and which ring is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_6alkyl,
hydroxyC i_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,


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sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In another aspect of the invention there is provided a subset of compounds of
formula
(Ia) or (Ib)
O O
N ).", R3 N R3
'Y/~Y2 1 Y/~Y2

R'~ ~ ~ R'1-11
X N R2 X N R2
s
(Ia) (Ib)
or a pharmaceutically acceptable salt thereof;
iY and Y2 are independently N or CR8 provided that one of 'Y and Y2 is N and
the other is
CRg ;
io X is a linker group selected from -NR4CR6R7-, -OCRV-, -SCRV-, -S(O)CR6R7-
and
-S(O)2CR6R'-;
R' is a group selected from adamantyl, methyl, ethyl, propyl, butyl, isobutyl,
tert-butyl,
cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl, pyrrolidinyl, pyrrolyl,
imidazolyl,
pyrazolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl,
pyrrolidinylmethyl,
15 pyrrolidinylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl,
imidazolylethyl,
pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl,
thienylethyl,
pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl,
pyrazinylmethyl and
pyrazinylethyl, which group is optionally substituted by 1, 2 or 3 substituent
group selected
from halo, cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9COR10;

20 or X-Ri is -C(CH3)20H or -CHzOH;
R2 is selected from 5 or 6 membered aryl and heteroaryl which group is
substituted by
-NHCONRigR19 or -NHCSNRigRl9and optionally substituted by one or more
substituent group
independently selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z 11
12
, -NR R
and -NR11COR12;
25 R3 is methyl;
R4 is hydrogen or C1_6alkyl;


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or, when X is -NR4CR6~-, R' and R4 together with the atom or atoms to which
they are
attached form a 5- or 6-membered heterocyclic ring wherein 1 ring carbon atom
is optionally
replaced with N or 0 and which ring is optionally substituted by one or more
substituent
groups selected from halo, cyano, nitro, hydroxy, oxo, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl,
s haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl,
C1_6alkoxyC1_
6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCi_
6alkyl, bis(C1_6alkyl)aminoCi_6alkyl, cyanoCi_6alkyl, C1_6alkylsulfonyl,
C1_6alkylsulfonylamino,
C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C 1_6alkylsulfamoyl, bis(C
1_6alkyl)sulfamoyl, C 1_
6alkanoylamino, C1_6alkanoyl(C1_6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl
and bis(C1_
io 6alkyl)carbamoyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
is 6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
2o R8 is selected from hydrogen, halo, cyano and C1_6alkyl;
R9 and R10 are independently hydrogen or a group selected from C1_6alkyl,
carbocyclyl and
heterocyclyl which group is optionally substituted by one or more substituent
groups selected
from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCi_6alkyl,
haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
2s 6alkylamino and bis(C1_6alkyl)amino;
Rii, Ri2 and Rig are independently hydrogen or a group selected from
C1_6alkyl, carbocyclyl
and heterocyclyl which group is optionally substituted by one or more
substituent groups
selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloCi_6alkyl, haloCi_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
30 6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen or a group selected from C1_6alkyl, C3_6cycloakyl, aryl,
heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more


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substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloCl_6alkyl, haloCl_6alkoxy, hydroxyCl_6alkyl, hydroxyCl_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyC1_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoC1_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
s 6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1 _6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
or Rig and R19 together with the nitrogen atom to which they are attached form
a 6-membered
heterocyclic ring wherein 1 ring carbon atoms is optionally replaced with N or
0 and which
io ring is optionally substituted by one or more substituent groups selected
from halo, cyano,
nitro, hydroxy, C1_6alkyl, C1_6alkoxy, haloCl_6alkyl, haloCl_6alkoxy,
hydroxyCl_6alkyl,
hydroxyC 1_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
15 sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1
_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In another particular class of compound of formula (Ia) or (Ib),
O CO
CN).1R3 N R3

1"~ Y Z 1" Y Z

R'~ 1 i Rl~ 1
X N R2 X N R2
(Ia) (Ib)
20 or a pharmaceutically acceptable salt thereof;
iY is CH and Y2 is N;
X is a-S(O)zCRV- linker group;
R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclopropyl,
cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl,
thiadiazolyl,
25 thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl,
thiazolylmethyl,
thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted
by 1 or 2


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substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy,
trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3;
or -XR' is -C(CH3)20H or -CHzOH;
R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl,
pyridinyl,
s pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHCONHR'9
or
-NR"CSNR'gR19 and optionally substituted by one or more substituent group
independently
selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z, -NR 11 iz
R and -
NR"COR'2 ;

R3 is methyl;
io R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
1s bis(C1_6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
Rii, Ri2 and Rig are independently hydrogen or a group selected from
C1_6alkyl, carbocyclyl
2o and heterocyclyl which group is optionally substituted by one or more
substituent groups
selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloC1_6alkyl, haloC1_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen, cyano or a group selected from C1_6alkyl, C3_6cycloakyl,
aryl,
25 heteroaryl, ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally
substituted by one
or more substituent groups selected from halo, cyano, nitro, hydroxy,
C1_6alkyl, C1_6alkoxy,
haloC1_6alkyl, haloC1_6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyCl_6alkoxy, amino, C1_6alkylamino, bis(C1_6alkyl)amino, aminoCi_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
30 6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.


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In another particular class of compound of formula (Ia) or (Ib),
O O
N )", R3 N R3

1"~ Y Z 1"/\ Y Z

R'~ /\1 i\ Rl~ "\1 i
N R2 X N R2
(Ia) (Ib)
or a pharmaceutically acceptable salt thereof;

s iY is CH and Y2 is N;
X is a-S(O)2CR6R7- linker group;
R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclopropyl,
cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl, pyrazolylethyl,
furanylmethyl,
thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which
group is
io optionally substituted by 1 or 2 substituent group selected from amino,
halo, cyano, methyl,
methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONHz and -CONHCH3;
or -XR' is -C(CH3)20H or -CHzOH;
R2 is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl,
pyridinyl,
pyrimidinyl, pyridazinyl, thiazolyl which group is substituted by -NHCONHR'9
or
is -NR"CSNR'gR19 and optionally substituted by one or more substituent group
independently
selected from halo, cyano, nitro, -R", -OR", -COR", -CONR"R'z, -NR11 iz
R and -
NR"COR'2 ;

R3 is methyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
20 carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is
optionally replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
25 cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;


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Rii, Ri2 and Rig are independently hydrogen or a group selected from
C1_6alkyl, carbocyclyl
and heterocyclyl which group is optionally substituted by one or more
substituent groups
selected from halo, cyano, nitro, hydroxy, C1_6alkyl, C1_6alkoxy,
haloC1_6alkyl, haloC1_6alkoxy,
hydroxyC l_6alkyl, hydroxyC l_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC
1_6alkoxy, amino, C 1_
s 6alkylamino and bis(C1_6alkyl)amino; and
R19 is hydrogen or a group selected from C1_6alkyl, C3_6cycloakyl, aryl,
heteroaryl,
ary1C1_6alkyl and heteroarylCl_6alkyl which group is optionally substituted by
one or more
substituent groups selected from halo, cyano, nitro, hydroxy, C1_6alkyl,
C1_6alkoxy,
haloC1_6alkyl, haloC1_6alkoxy, hydroxyC1_6alkyl, hydroxyC1_6alkoxy,
C1_6alkoxyC1_6alkyl, C1_
6alkoxyC 1_6alkoxy, amino, C 1_6alkylamino, bis(C 1_6alkyl)amino, aminoC
1_6alkyl,
(C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl, cyanoCl_6alkyl,
C1_6alkylsulfonyl, C1_
6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino, sulfamoyl, C
1_6alkylsulfamoyl, bis(C 1_
6alkyl)sulfamoyl, C 1_6alkanoylamino, C 1_6alkanoyl(C 1_6alkyl)amino,
carbamoyl,
C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
is In a further particular class of compound of formula (IA), (IB) or (IC)
O O O
R3A o"N ', R3B R3A..%%" N R3B R3A oo"( N )"', R3B

I YY2 1 YY2 1 Y/~Y2
R'1-11 R'~-' R'1-11
X N Rz X N Rz X N Rz

(IA) (IB) (IC)
or a pharmaceutically acceptable salt thereof;
X is a-S(O)zCR6R7- linker group;
iY is CH and Y2 is N.
R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclopropyl,
cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl,
thiadiazolyl,
thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl,
thiazolylmethyl,
thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted
by 1 or 2
substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy,
trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3;


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R2 is phenyl or pyridinyl substituted by NHCONHR19 or -NHCSNHR'9 and
optionally
substituted by one or more substituent group independently selected from
fluoro, methyl,
methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2;
R 3A and R3B each independently is hydrogen, methyl or ethyl;
s R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyC1_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
i o bis(C 1_6alkyl)amino, aminoC i_6alkyl, (C 1_6alkyl)aminoC i_6alkyl, bis(C
1_6alkyl)aminoC i_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-
propyl, butyl, i-butyl,
is t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
thienyl,
dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl,
pyrazolyl,
pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl
and triazolyl
which group is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_6alkyl,
2o hydroxyC 1_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl; and
25 when R3A is hydrogen, R3B is hydrogen, methyl, ethyl, hydroxymethyl,
dimethylcarbamoyl or
carbamoyl; or
when R3A is methyl, R3B is methyl.
In a further particular class of compound of formula (Ia) or (Ib)


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O O O

R3A N R3B R3A~%`'. N R3B R3A f", N R3B

,YY2 1 YY2 1 YY2
R'~ ~ R'~
X N Rz X N Rz X N Rz
(IA) (IB) (IC)
or a pharmaceutically acceptable salt thereof;
X is a-S(O)2CR6R7- linker group;
s iY is CH and Y2 is N.
R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclopropyl,
cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl,
thiadiazolyl,
thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl,
thiazolylmethyl,
thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted
by 1 or 2
io substituent group selected from amino, halo, cyano, hydroxy, methyl,
methoxy,
trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONHz and -CONHCH3;

R2 is phenyl or pyridinyl substituted by NHCONHR19 or -NHCSNHR'9 and
optionally
substituted by one or more substituent group independently selected from
fluoro, methyl,
methoxy, hydroxymethyl, cyanomethyl, -CONHz, -CONHCH3 and -CON(CH3)2;
is R 3A and R3B each independently is hydrogen, methyl or ethyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
20 6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy,
amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1 _6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl; and
25 R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-
propyl, butyl, i-
butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
phenyl, thienyl,
dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl,
pyrazolyl,


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pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl, thiazolyl
and triazolyl
which group is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_6alkyl,
hydroxyC i_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
s 6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In a further particular class of compound of formula (Ia) or (Ib)
O O
N )"', R3 N R3

I YY2 1 YY2
R'~ ~ ~ R'1-11
X N R2 X N R2
(Ia) (Ib)
or a pharmaceutically acceptable salt thereof;
X is a-S(O)zCR6R7- linker group;
iY is CH and Y2 is N.
R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclopropyl,
cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, imidazolyl, pyrrolidinyl,
thiadiazolyl,
thiazolyl, pyridinyl, pyrazolylethyl, furanylmethyl, thienylmethyl,
thiazolylmethyl,
thiadiazolylmethyl and pyrazinylethyl, which group is optionally substituted
by 1 or 2
substituent group selected from amino, halo, cyano, hydroxy, methyl, methoxy,
trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3;

R2 is phenyl or pyridinyl substituted by NHCONHR19 or -NHCSNHR'9 and
optionally
substituted by one or more substituent group independently selected from
fluoro, methyl,
methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2;
R3 is methyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
0 or S and which ring is optionally substituted by one or more substituent
groups selected from


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halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoC1_6alkyl, (C1_6alkyl)aminoC1_6alkyl,
bis(C1_6alkyl)aminoC1_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
s sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C
1_6alkanoylamino, C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl; and
R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-
propyl, butyl, i-butyl,
t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,
thienyl,
dioxothiolanyl, imidazoylmethyl, isoxazolyl, oxazolyl, oxetanyl, pyrazinyl,
pyrazolyl,
io pyrazolylmethyl, pyridinyl, pyrimidinyl, pyrrolidinyl, thiadiazolyl,
thiazolyl and triazolyl
which group is optionally substituted by one or more substituent groups
selected from halo,
cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_6alkyl,
hydroxyC 1_6alkoxy, C 1_6alkoxyC 1_6alkyl, C 1_6alkoxyC 1_6alkoxy, amino, C
1_6alkylamino, bis(C 1_
6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
15 cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In a further particular class of compound of formula (Ia) or (Ib)
O O
CN).1R3 N R3

1" Y Z 1" Y Z

R'~ /\1 i\ Rl~ 1
X N R2 X N R2
20 (Ia) (Ib)
or a pharmaceutically acceptable salt thereof;
X is a-S(O)zCR6R7- linker group;
iY is CH and Y2 is N.
R' is a group selected from methyl, ethyl, propyl, butyl, isobutyl, tert-
butyl, cyclopropyl,
25 cyclopentyl cyclohexyl, phenyl, benzyl, phenethyl, pyridinyl,
pyrazolylethyl, furanylmethyl,
thienylmethyl, thiazolylmethyl, thiadiazolylmethyl and pyrazinylethyl, which
group is


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optionally substituted by 1 or 2 substituent group selected from amino, halo,
cyano, methyl,
methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -CONHCH3;

R2 is phenyl or pyridinyl substituted by -NHCONHR'9 or -NHCSNHR'9 and
optionally
substituted by one or more substituent group independently selected from
fluoro, methyl,
s methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2;
R3 is methyl;
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
1 o halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl,
haloC 1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
is 6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl;
and
R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl,
pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl,
imidazoylmethyl,
isoxazolyl, pyrazolyl, pyrazolylmethyl, pyridinyl and pyrimidinyl which group
is optionally
substituted by one or more substituent groups selected from halo, cyano,
nitro, hydroxy, C1_
20 6alkyl, C 1_6alkoxy, haloC i_6alkyl, haloC i_6alkoxy, hydroxyC i_6alkyl,
hydroxyC i_6alkoxy, C 1_
6alkoxyC1_6alkyl, C1_6alkoxyC1_6alkoxy, amino, C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCl_
6alkyl, (C1_6alkyl)aminoCl_6alkyl, bis(C1_6alkyl)aminoCl_6alkyl,
cyanoCl_6alkyl, C1_
6alkylsulfonyl, C 1_6alkylsulfonylamino, C 1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_
6alkylsulfamoyl, bis(C1_6alkyl)sulfamoyl, C1_6alkanoylamino,
C1_6alkanoyl(C1_6alkyl)amino,
25 carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In a further particular class of compound of formula (Ia) or (Ib)


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O O
N )"', R3 N R3

1" Y Z 1" Y Z

R'~ 1 i Rl~ 1
X N R2 X N R2
(Ia) (Ib)
or a pharmaceutically acceptable salt thereof;
m is l;
s X is a-S(0)2CR6~- linker group;
iY is CH and Y2 is N.

R' is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
cyclopentyl,
cyclohexyl, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2OCH3, -CH2CH2NHC(O)CH3,
-CHzC(O)NHz, -CHzC(O)NHMe, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2-
chlorophenyl,
io 3,5-difluorophenyl, 2-(trifluoromethyl)phenyl, 4-(2-
hydroxyethylamino)phenyl,
2-methoxyphenyl, 2-methylphenyl, 1H-imidazol-2-yl, 2-
(dimethylcarbamoyl)pyridin-3-yl, 5-
(dimethylcarbamoyl)pyridin-2-yl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-
yl, pyridin-2-
yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 2-oxopyrolidin-3-yl, thiazol-2-
yl,
4-methylthiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl and 3-methyl-1,3,4-
thiadiazol-2-yl;
15 R2 is
1 1
~"'A~ 0 ~ 2 s
I / II R19 R19
R17 R1s R17 R1s
or
wherein A' and A2 are selected from CH or N provided that at least one of A'
or
A2 is CH;

Ri' is hydrogen;
20 Rig is hydrogen; and
R19 is hydrogen, cyano or a group selected from methyl, ethyl, propyl, i-
propyl, butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2,
-CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)20H,


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-CHzC(CH3)zCHzOH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CHF2,
-CHzCHzSOzMe, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN,
-CH2CONMe2, 1-(methyl)cyclopropyl, 1-(hydroxymethyl)cyclopropyl,
phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4-
s fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, thien-2-yl,
-CHzCHz(pyrrolidin-1-yl),-CHz(imidazol-2-yl), -CHz(imidazol-3-yl),
oxazolyl-2-yl, isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl, oxetan-3-yl, 1,1-
dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CHz(1-methylpyrazol-4-yl),
1-methylpyrazol-4-yl, -CHz(1-methylpyrazol-4-yl), 5-methylpyrazin-2-
yl, -CHz(2H-1,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl,
5-fluoropyridin-2-yl, pyrimidin-2-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl,
1-methylpyrazol-3-yl and 1H-pyrazol-3-yl;
R3 is methyl; and
R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
is carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is
optionally replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC_6alkoxy, amino,
C1_6alkylamino,
bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In a further particular class of compound of formula (Ia) or (Ib)
O o
N ', R3 N R3

1"~ Y Z 1" Y Z

Rl~ 1 i Rl~ 1
X N R2 X N R2
(Ia) (Ib)
or a pharmaceutically acceptable salt thereof;
m is l;


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X is a-S(O)zCR6R7- linker group;
iY is CH and Y2 is N.
R' is a group selected from methyl, isopropyl, cyclopropyl, cyclohexyl, -
CHzCHzOH,
-CH2CH2NHC(O)CH3, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-
trifluoromethylphenyl,
s 2-methoxyphenyl, 2-methylphenyl, 4-acetamidophenyl, 4-aminophenyl, pyridin-4-
yl, pyridin-
2-yl, 2-oxopyrolidin-3-yl, thiazol-2-yl, 4-methylthiazol-2-yl, and 3-methyl-
1,3,4-thiadiazol-2-
yl;
R2is

1 1
~A2 0 ~ A2 s
R19 R19
N N N N
R17 R1s R17 R1s
or
io wherein A' and A2 are selected from CH or N provided that at least one of
A' or
A2 is CH;

Ri' is hydrogen;
Rig is hydrogen; and
R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl,
is butyl, i-butyl, t-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH,
-C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH, 4-methylphenyl, 4-
chlorophenyl, 4-trifluoromethylphenyl, 4-flurophenyl, 4-methoxyphenyl,
3,4-difluorophenyl, thien-2-yl, -CH2(imidazol-2-yl),
20 -CHz(imidazol-3-yl), isoxazolyl-3-yl, 6-oxo-lH-pryrdin-2-yl,
5-methylisoxazol-3-yl, 1-methylpyrazol-4-yl, -CHz(1-methylpyrazol-4-
yl), -CHz(1-methylpyrazol-4-yl), 6-methoxypryridin-3-yl,
5-fluoropyridin-2-yl, pyrimidin-2-yl, and 1H-pyrazol-3-yl;
R3 is methyl; and
25 R6 and R7 together with the carbon atom to which they are attached form a 3-
to 10-membered
carbocyclic ring or heterocyclic ring wherein 1 ring carbon atom is optionally
replaced with N,
O or S and which ring is optionally substituted by one or more substituent
groups selected from
halo, cyano, nitro, hydroxy, C 1_6alkyl, C 1_6alkoxy, haloC 1_6alkyl, haloC
1_6alkoxy, hydroxyC 1_
6alkyl, hydroxyCl_6alkoxy, C1_6alkoxyC1_6alkyl, C1_6alkoxyC_6alkoxy, amino,
C1_6alkylamino,


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bis(C1_6alkyl)amino, aminoCi_6alkyl, (C1_6alkyl)aminoCi_6alkyl,
bis(C1_6alkyl)aminoCi_6alkyl,
cyanoC 1_6alkyl, C 1_6alkylsulfonyl, C 1_6alkylsulfonylamino, C
1_6alkylsulfonyl(C 1_6alkyl)amino,
sulfamoyl, C 1_6alkylsulfamoyl, bis(C 1_6alkyl)sulfamoyl, C 1_6alkanoylamino,
C 1_6alkanoyl(C 1_
6alkyl)amino, carbamoyl, C1_6alkylcarbamoyl and bis(C1_6alkyl)carbamoyl.
In a further particular class of compound of formula (Ia) or (Ib)
O O
N ', R3 N R3

1"~ Y Z 1" Y Z

R'~ 1 i Rl~ 1
X N R2 X N R2
(Ia) (Ib)
or a pharmaceutically acceptable salt thereof;
m is l;
io X is a-S(O)zCR6~- linker group;
iY is CH and Y2 is N.
R' is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
cyclopentyl,
cyclohexyl, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2OCH3, -CH2CH2NHC(O)CH3,
-CHzC(O)NHz, -CHzC(O)NHMe, phenyl, 4-fluorophenyl, 4-chlorophenyl, 3,5-
difluorophenyl,
2-(trifluoromethyl)phenyl, 4-(2-hydroxyethylamino)phenyl, 1 H-imidazol-2-yl,
2-(dimethylcarbamoyl)pyridin-3-yl, 5-(dimethylcarbamoyl)pyridin-2-yl, pyridin-
4-yl, pyridin-
2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, thiazol-2-yl, 4-
methylthiazol-2-yl and
5-methyl-1,3,4-thiadiazol-2-yl;
R2is

1 1
~"'A~ 0 ~ 2 S
R19 R19
N N N N
1
R17 R18 R17 R1s
or
wherein A' and A2 are selected from CH or N provided that at least one of A'
or
A2 is CH;

Ri' is hydrogen;
Rig is hydrogen; and


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R19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl,
i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl),
-CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)20H,
-CH2C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CHF2,
s -CHzCHzSOzMe, -CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -
CH2CONMe2, 1-(methyl)cyclopropyl, 1-(hydroxymethyl)cyclopropyl,
phenyl, 4-methylphenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl,
4-fluorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,
-CHzCHz(pyrrolidin-1-yl),-CHz(imidazol-2-yl), oxazolyl-2-yl,
io isoxazolyl-3-yl, oxetan-3-yl, 1,1-dioxothiolan-3-yl, 5-methylisoxazol-3-
yl, -CHz(1-methylpyrazol-4-yl), 1-methylpyrazol-4-yl, 5-methylpyrazin-
2-yl, -CHz(2H-1,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl,
5-fluoropyridin-2-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl, and
1-methylpyrazol-3-yl;
15 R3 is methyl; and
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring.
In a further particular class of compound of formula (IA), (IB) or (IC)
O O O
R3A o"N ', R3B R3A-,%`' N R3B R3A f~", N R3B

,YY2 1 YY2 1 YY2
R'1-11 /\ ~ R'~ /\ ~ R'~ /\ ~
X N Rz X N Rz X N Rz

20 (IA) (IB) (IC)
or a pharmaceutically acceptable salt thereof;
X is a-S(O)zCR6R7- linker group;
iY is CH and Y2 is N;
R' is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
cyclopentyl,
25 cyclohexyl, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2C(OH)(CH3)2, -CHzCHzCHzOCHFz,
-CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, -CH2CH2NHMe,
phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-fluoro-4-
methylaminophenyl,


CA 02692945 2009-12-23
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4-fluoro-2-methylphenyl, 5-fluoro-2-methylphenyl, 3-fluoro-4-(2-
hydroxyethylamino)phenyl,
4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-
chlorophenyl,
3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-
ethylaminophenyl,
3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl,
s 2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-
difluorophenyl,
2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-
(trifluoromethyl)phenyl,
2-methylphenyl, 4-methylphenyl, 4-(2-hydroxyethylamino)phenyl, 1 H-imidazol-2-
yl,
3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-
(dimethylcarbamoyl)pyridin-
2-yl, 1-(difluoromethyl)pyrazol-4-yl, 1-(difluoromethyl)-3,5-dimethylpyrazol-4-
yl,
io 1,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl,
5-fluoropyridin-3-yl,
thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-
dimethylthiazol-5-yl,
5-methyl-1,3,4-thiadiazol-2-yl, terahydrofuran-3-yl and terahydropyran-4-yl;
R2is

1 1
~A2 0 ~ 2 s
R19 R19
N N N N
R17 R1s R17 R1s
or
is wherein A' and A2 are selected from CH or N provided that at least one of
A' or
A2 is CH;

Ri' is hydrogen;
Rig is hydrogen; and
R19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl,
20 i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl),
-CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)20H,
-CH2C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CF3,
-CH2CHF2, -CH2CH2F, -CH2CH2C1, -CH2CH2SO2Me,
-CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, -CH2CO2H,
25 1-(methyl)cyclopropyl, -CHz(1-hydroxycyclopropyl),
1-(hydroxymethyl)cyclopropyl, (1 R)-2-hydroxy-l-methylethyl, (1 S)-2-
hydroxy-1-methylethyl, phenyl, 4-methylphenyl, 4-chlorophenyl,
4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl,
3,4-difluorophenyl, -CHzCHz(pyrrolidin-1-yl),-CHz(imidazol-2-yl),


CA 02692945 2009-12-23
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1-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 1,1-
dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CHz(1-methylpyrazol-4-yl),
1-methylpyrazol-4-yl, -CHz(1-methylpyrazol-4-yl), 5-methylpyrazin-2-
yl, -CHz(2H-1,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5-
s fluoropyridin-2-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl and
1-methylpyrazol-3-yl;
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and
when R3A is hydrogen, R3B is hydrogen, methyl, ethyl, hydroxymethyl,
dimethylcarbamoyl or
io carbamoyl; or
when R3A is methyl, R3B is methyl.
In a further particular class of compound of formula (IA), (IB) or (IC)
O O O
R3A o"N ', R3B R3A-,%`' N R3B R3A f", N R3B

,YY2 1 YY2 1 YY2
R'1-11 /\ ~ R'~ /\ ~ R'~ /\ ~
X N Rz X N Rz X N Rz

(IA) (IB) (IC)
is or a pharmaceutically acceptable salt thereof;
X is a-S(O)zCR6R7- linker group;
iY is CH and Y2 is N;
R' is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
-CHzCHzOH, -
CHzCHzCHzOH, -CH2CH2C(OH)(CH3)2, -CHzCHzCHzOCHFz, -CH2CH2OCH3,
20 -CH2CH2NHC(O)CH3, -CH2CH2NHMe, phenyl, 2-fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-
fluoro-2-
methylphenyl, 3-fluoro-4-(2-hydroxyethylamino)phenyl, 4-
(difluoromethoxy)phenyl,
4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-
fluorophenyl,
3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl,
25 3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-
hydroxyethylamino)phenyl,
2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,
2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-methylphenyl, 4-
methylphenyl,


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1H-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-
yl,
5-(dimethylcarbamoyl)pyridin-2-yl, 1-(difluoromethyl)pyrazol-4-yl, 1,3-
dimethylpyrazol-4-yl,
pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, 4-
methylthiazol-2-yl,
4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl and 5-methyl-1,3,4-
thiadiazol-2-yl;

s R2 is
1 1
~"'A~ 0 ~ 2 S
I / II R19 I / II R19
R17 R1s R17 R1s
or
wherein A' and A2 are selected from CH or N provided that at least one of A'
or
A2 is CH;

Ri' is hydrogen;
Rig is hydrogen; and
R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl,
cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2,
-CH(CH3)CH2OH, -C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH,
-CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2C1, -CH2CH2CN,
is -CHz(1-hydroxycyclopropyl), 1-(hydroxymethyl)cyclopropyl,
(1R)-2-hydroxy-l-methylethyl, (1S)-2-hydroxy-l-methylethyl, phenyl,
4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,
-CHzCHz(pyrrolidin-1-yl),-CHz(imidazol-2-yl), 1-methylimidazol-4-yl,
oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 5-methylisoxazol-3-yl,
1-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, 6-methoxypryridin-3-yl,
thiazol-2-yl, 1,2,4-thiadiazol-5-yl and 1-methylpyrazol-3-yl;
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and
when R 3A is hydrogen, R3B is hydrogen, methyl or ethyl; or

when R3A is methyl, R3B is methyl.
In a further particular class of compound of formula (IA), (IB) or (IC)


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O O O

R3A N R3B R3A~%`'. N R3B R3A f", N R3B

,YY2 1 YY2 1 YY2
R'~ ~ R'~
X N Rz X N Rz X N Rz
(IA) (IB) (IC)
or a pharmaceutically acceptable salt thereof;
X is a-S(O)zCR6R7- linker group;
s iY is CH and Y2 is N;
R' is a group selected from methyl, ethyl, cyclopropyl, -CHzCHzCHzOH, phenyl,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-
methylphenyl,
5-fluoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl;
R2is

1 1
~"'A~ 0 ~ 2 s
I / II R19 R19
1
R17 R18 R17 R1s
or
wherein A' and A2 are selected from CH or N provided that at least one of A'
or
A2 is CH;

Ri' is hydrogen;
Rig is hydrogen; and
is R19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl,
-CH(CH3)CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CHF2,
-CH2CH2F, -CH2CH2CN, (1R)-2-hydroxy-l-methylethyl, (1S)-2-
hydroxy-1-methylethyl, -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-
3-yl, 1-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and
1,2,4-thiadiazol-5-yl;
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and
when R 3A is hydrogen, R3B is hydrogen, methyl or ethyl; or
when R3A is methyl, R3B is methyl.


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In a further particular class of compound of formula (IA), (IB) or (IC)
O O O
R3A o"N ', R3B R3A-,%`' N R3B R3A o#""( N R3B

I YY2 1 YY2 1 YY2
R'1-11 /\ ~ R'~ /\ ~ R'~ /\ ~
X N Rz X N Rz X N Rz

(IA) (IB) (IC)
or a pharmaceutically acceptable salt thereof;
s X is a-S(O)zCR6R7- linker group;
iY is CH and Y2 is N;

R' is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
cyclopentyl,
cyclohexyl, -CHzCHzOH, -CHzCHzCHzOH, -CH2CH2C(OH)(CH3)2, -CHzCHzCHzOCHFz,
-CH2CH2OCH3, -CH2CH2NHC(O)CH3, -CH2C(O)NH2, -CH2C(O)NHMe, -CH2CH2NHMe,
io phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-fluoro-4-
methylaminophenyl,
4-fluoro-2-methylphenyl, 5-fluoro-2-methylphenyl, 3-fluoro-4-(2-
hydroxyethylamino)phenyl,
4-(difluoromethoxy)phenyl, 4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-
chlorophenyl,
3-chloro-4-fluorophenyl, 3-chloro-4-methylaminophenyl, 3-chloro-4-
ethylaminophenyl,
3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl,
is 2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-
difluorophenyl,
2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-
(trifluoromethyl)phenyl,
2-methylphenyl, 4-methylphenyl, 4-(2-hydroxyethylamino)phenyl, 1 H-imidazol-2-
yl,
3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-yl, 5-
(dimethylcarbamoyl)pyridin-
2-yl, 1-(difluoromethyl)pyrazol-4-yl, 1-(difluoromethyl)-3,5-dimethylpyrazol-4-
yl,
20 1,3-dimethylpyrazol-4-yl, pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl,
5-fluoropyridin-3-yl,
thiazol-2-yl, 4-methylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 2,4-
dimethylthiazol-5-yl,
5-methyl-1,3,4-thiadiazol-2-yl, terahydrofuran-3-yl and terahydropyran-4-yl;
R2is

1 1
~A2 0 ~ 2 S
R19 R19
N N N N
R17 R1s R17 R1s
or


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wherein A' and A2 are CH;
Ri' is hydrogen;
Rig is hydrogen; and
R19 is is hydrogen, cyano or a group selected from methyl, ethyl, propyl,
s i-propyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl),
-CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2C(CH3)20H,
-CH2C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CF3,
-CH2CHF2, -CH2CH2F, -CH2CH2C1, -CH2CH2SO2Me,
-CH2CH(OH)CF3, -CH2CH2CN, -CH2CN, -CH2CONMe2, -CH2CO2H,
io 1-(methyl)cyclopropyl, -CHz(1-hydroxycyclopropyl),
1-(hydroxymethyl)cyclopropyl, (1 R)-2-hydroxy-l-methylethyl, (1 S)-2-
hydroxy-1-methylethyl, phenyl, 4-methylphenyl, 4-chlorophenyl,
4-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl,
3,4-difluorophenyl, -CHzCHz(pyrrolidin-1-yl),-CHz(imidazol-2-yl),
is 1-methylimidazol-4-yl, oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 1,1-
dioxothiolan-3-yl, 5-methylisoxazol-3-yl, -CHz(1-methylpyrazol-4-yl),
1-methylpyrazol-4-yl, -CHz(1-methylpyrazol-4-yl), 5-methylpyrazin-2-
yl, -CHz(2H-1,2,4-triazol-3-yl), 6-methoxypryridin-3-yl, pyridin-2-yl, 5-
fluoropyridin-2-yl, thiazol-2-yl, 1,2,4-thiadiazol-5-yl and
20 1 -methylpyrazol-3 -yl;
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and
when R3A is hydrogen, R3B is hydrogen, methyl, ethyl, hydroxymethyl,
dimethylcarbamoyl or
carbamoyl; or
25 when R3~ is methyl, R3 is methyl.
In a further particular class of compound of formula (IA), (IB) or (IC)


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O O O

R3A N R3B R3A~%`'. N R3B R3A f", N R3B

,YY2 1 YY2 1 YY2
R'~ ~ R'~
X N Rz X N Rz X N Rz
(IA) (IB) (IC)
or a pharmaceutically acceptable salt thereof;
X is a-S(O)2CR6R7- linker group;
s iY is CH and Y2 is N;
R' is a group selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
-CHzCHzOH, -
CHzCHzCHzOH, -CH2CH2C(OH)(CH3)2, -CHzCHzCHzOCHFz, -CH2CH2OCH3,
-CH2CH2NHC(O)CH3, -CH2CH2NHMe, phenyl, 2-fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, 2-fluoro-4-methylaminophenyl, 4-fluoro-2-methylphenyl, 5-
fluoro-2-
io methylphenyl, 3-fluoro-4-(2-hydroxyethylamino)phenyl, 4-
(difluoromethoxy)phenyl,
4-carbamoyl-2-chlorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chloro-4-
fluorophenyl,
3-chloro-4-methylaminophenyl, 3-chloro-4-ethylaminophenyl,
3-chloro-4-(2-fluoroethylamino)phenyl, 3-chloro-4-(2-hydroxyethylamino)phenyl,
2-chloro-4-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,
is 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-methylphenyl,
4-methylphenyl,
1H-imidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-(dimethylcarbamoyl)pyridin-3-
yl,
5-(dimethylcarbamoyl)pyridin-2-yl, 1-(difluoromethyl)pyrazol-4-yl, 1,3-
dimethylpyrazol-4-yl,
pyridin-4-yl, pyridin-2-yl, 5-fluoropyridin-2-yl, thiazol-2-yl, 4-
methylthiazol-2-yl,
4,5-dimethylthiazol-2-yl, 2,4-dimethylthiazol-5-yl and 5-methyl-1,3,4-
thiadiazol-2-yl;

2o R2 is
1 1
~"'A~ 0 ~ 2 S
I / II R19 I / II R19
R17 R1s R17 R1s
or
wherein A' and A2 are CH;
Ri' is hydrogen;
Rig is hydrogen; and


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R19 is hydrogen or a group selected from methyl, ethyl, propyl, i-propyl,
cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2NMe2,
-CH(CH3)CH2OH, -C(CH3)2CH2OH, -CHzCHzOH, -CHzCHzCHzOH,
-CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2C1, -CH2CH2CN,
s -CHz(1-hydroxycyclopropyl), 1-(hydroxymethyl)cyclopropyl,
(1R)-2-hydroxy-l-methylethyl, (1S)-2-hydroxy-l-methylethyl, phenyl,
4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,
-CHzCHz(pyrrolidin-1-yl),-CHz(imidazol-2-yl), 1-methylimidazol-4-yl,
oxazolyl-2-yl, isoxazolyl-3-yl, oxetan-3-yl, 5-methylisoxazol-3-yl,
io 1-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, 6-methoxypryridin-3-yl,
thiazol-2-yl, 1,2,4-thiadiazol-5-yl and 1-methylpyrazol-3-yl;
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and
when R 3A is hydrogen, R3B is hydrogen, methyl or ethyl; or
15 when R3A is methyl, R3B is methyl.
In a further particular class of compound of formula (IA), (IB) or (IC)
O O O
f",, N ", R3B
R3A,0' N ()-"' R3B R3A%%1" N R3B R3A

I YY2 1 YY2 1 Y/~Y2
R' ~ ~ R' ~ R' ~
X N Rz X N Rz X N Rz
(IA) (IB) (IC)
or a pharmaceutically acceptable salt thereof;
20 X is a-S(O)zCR6R7- linker group;
iY is CH and Y2 is N;
R' is a group selected from methyl, ethyl, cyclopropyl, -CHzCHzCHzOH, phenyl,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-
methylphenyl,
5-fluoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl;

25 R2 is


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1
~"'A2 0 ~ A2 s
I / II R19 I / II R19
R17 R1s R17 R1s
or
wherein A' and A2 are CH;
Ri' is hydrogen;
Rig is hydrogen; and
s R19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl,
-CH(CH3)CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CHF2,
-CH2CH2F, -CH2CH2CN, (1R)-2-hydroxy-l-methylethyl, (1S)-2-
hydroxy-1-methylethyl, -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-
3-yl, 1-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and
io 1,2,4-thiadiazol-5-yl;
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and
when R 3A is hydrogen, R3B is hydrogen, methyl or ethyl; or
when R3A is methyl, R3B is methyl.
is In a further particular class of compound of formula (IA), (IB) or (IC)
O O O
f",, N ", R3B
R3A,0' N ()-"' R3B R3A%%1" N R3B R3A

I YY2 1 YY2 1 Y/~Y2
R'1-11 R'~-' R'1-11
X N Rz X N Rz X N Rz

(IA) (IB) (IC)
or a pharmaceutically acceptable salt thereof;
X is a-S(O)2CR6R7- linker group;
20 iY is CH and Y2 is N;
R' is a group selected from methyl, ethyl, cyclopropyl, -CHzCHzCHzOH, phenyl,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-
methylphenyl,
5-fluoropyridin-2-yl, pyridin-2-yl, thiazol-2-yl and 4-methylthiazol-2-yl;
R2is


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1
~"'A2 0 ~ A2 S
I / II R19 I / II R19
R17 R1s R17 R1s
or
wherein A' and A2 are CH;
Ri' is hydrogen;
Rig is hydrogen; and
R19 is a group selected from methyl, ethyl, cyclopropyl, cyclobutyl,
-CH(CH3)CH2OH, -CHzCHzOH, -CHzCHzCHzOH, -CH2CHF2,
-CH2CH2F, -CH2CH2CN, (1R)-2-hydroxy-l-methylethyl, (1S)-2-
hydroxy-1-methylethyl, -CH2(imidazol-2-yl), oxazolyl-2-yl, isoxazolyl-
3-yl, 1-methylpyrazol-4-yl, 5-methylpyrazin-2-yl, thiazol-2-yl and
1,2,4-thiadiazol-5-yl;
R6 and R7 together with the carbon atom to which they are attached form a
cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydropyranyl or piperidyl ring; and
when R3A is hydrogen, R3B is methyl or ethyl; or
when R3A is methyl, R3B is methyl.
Another aspect of the invention provides a compound, or a combination of
compounds,
selected from any one of the Examples or a pharmaceutically acceptable salt
thereof.
In another aspect of the invention there is provided a compound, or a
combination of
compounds, selected from any one of
3-Ethyl-l-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]urea,
3-methyl-l-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]urea,
3-Cyclopropyl-l-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-[(1-methylpyrazol-4-yl)methyl]urea,
1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,


CA 02692945 2009-12-23
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3-cyclobutyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(1 H-imidazol-2-ylmethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
s 3-(2-dimethylaminoethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(1-hydroxy-2-methyl-propan-2-yl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-

methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
io yl]phenyl]-3-(1,2-oxazol-3-yl)urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-phenyl-urea,
3-(2-hydroxyethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
is 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-propan-2-yl-urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-propyl-urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
20 yl]phenyl]-3-(2-methylpropyl)urea,
3-(cyclopropylmethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(1-hydroxypropan-2-yl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
25 3-(6-methoxypyridin-3-yl)-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(4-fluorophenyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(3,4-difluorophenyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
30 methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(4-methylphenyl)urea,


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3-(4-chlorophenyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(4-methoxyphenyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
s 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea,
3-(5-fluoropyridin-2-yl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxy-2,2-dimethylpropyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-

io methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(2-pyrrolidin-l-ylethyl)urea,
is 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(3,3,3-trifluoro-2-hydroxypropyl)urea,
3-(2-hydroxy-2-methylpropyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3- [ 1-(hydroxymethyl)cyclopropyl]-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-

20 methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(oxetan-3-yl)urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(l -methylpyrazol-3-yl)urea,
25 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(1,2,4-thiadiazol-5-yl)urea,
3-(cyanomethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
30 yl]phenyl]-3-(2H-1,2,4-triazol-3-ylmethyl)urea,
3-cyclopropyl-1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,


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3-cyclobutyl-1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-pyridin-2-yl-urea,
s 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-methylpropyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-propan-2-yl-urea,
3-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
1 o yl]phenyl]-1-ethyl-urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-dimethylaminoethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
is 3-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-propyl-urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methyl-urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
20 yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-hydroxy-2-methyl-propan-2-yl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
25 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxy-2,2-dimethylpropyl)urea,
3-(2-cyanoethyl)-1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-
methylmorpholin-4-
30 yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-pyrrolidin-1-ylethyl)urea,


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1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3,3,3-trifluoro-2-hydroxypropyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxy-2-methylpropyl)urea,
s 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[ 1-(hydroxymethyl)cyclopropyl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(oxetan-3-yl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(1-methylpyrazol-3-yl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1,2,4-thiadiazol-5-yl)urea,
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
yl]phenyl]urea,
is 3-ethyl-1 -[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
yl]phenyl]urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
20 yl]phenyl]-3-propan-2-yl-urea,
3-cyclobutyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
25 3-(1-hydroxy-2-methyl-propan-2-yl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
30 yl]phenyl]-3-propyl-urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
yl]phenyl]-3-(2-methylpropyl)urea,


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3-(3-hydroxypropyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
s 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
yl]phenyl]-3-pyridin-2-yl-urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
3-(1 H-imidazol-2-ylmethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
io methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-
yl]phenyl]urea,
3-ethyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-
yl]phenyl]urea,
is 3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclobutyl)pyrimidin-
2-yl]phenyl]-
3-propan-2-yl-urea,
3-cyclobutyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-
2o 2-yl]phenyl]urea,
3-(2-hydroxyethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-(1-hydroxy-2-methyl-propan-2-yl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-

methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
25 3-(2-dimethylaminoethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclobutyl)pyrimidin-
2-yl]phenyl]-
3-propyl-urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclobutyl)pyrimidin-
2-yl]phenyl]-
3o 3-(2-methylpropyl)urea,
3-(3-hydroxypropyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,


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1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclobutyl)pyrimidin-
2-yl]phenyl]-
3-[4-(trifluoromethyl)phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclobutyl)pyrimidin-
2-yl]phenyl]-
3-pyridin-2-yl-urea,
s 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]-
3-(1-methylpyrazol-4-yl)urea,
3-(1 H-imidazol-2-ylmethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-cyclobutyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
io ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-pyridin-2-yl-urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(2-methylpropyl)urea,
is 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-propan-2-yl-urea,
3-ethyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-
4-
20 ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-propyl-urea,
25 3-methyl-1 -[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
3-(l -hydroxy-2-methyl-propan-2-yl)- 1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-
(1-pyridin-4-
30 ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,


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1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
s 3-methyl-1 -[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-ethyl-3-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-
io yl]phenyl]-3-propan-2-yl-urea,
3-cyclobutyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
is 3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(l -hydroxy-2-methyl-propan-2-yl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-
(l -propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-propan-
2-
20 ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-1-propyl-urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(2-methylpropyl)urea,
25 3-(3-hydroxypropyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-
30 yl]phenyl]-3-pyridin-2-yl-urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,


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1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methyl-urea,
1-ethyl-3-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
s 3-cyclopropyl-l-[4-[4-[1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-propan-2-yl-urea,
3-cyclobutyl-l-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
io yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-hydroxy-2-methyl-propan-2-yl)urea,
is 3-(2-dimethylaminoethyl)-1-[4-[4-[1-(4-fluorophenyl)sulfonylcyclopropyl]-6-
[(3S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-propyl-urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
2o yl]phenyl]-3-(2-methylpropyl)urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
25 1-[4-[4-[1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-pyridin-2-yl-urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
30 yl]phenyl]-3-cyclopropyl-urea,
3-cyclobutyl-l -[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,


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1-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-pyridin-2-yl-urea,
1-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-methylpropyl)urea,
s 1-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-propan-2-yl-urea,
3-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-ethyl-urea,
1-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(2-dimethylaminoethyl)urea,
1-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
3-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-propyl-urea,
is 1-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methyl-urea,
1-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
1-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
20 yl]phenyl]-3-(1-hydroxy-2-methyl-propan-2-yl)urea,
1-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-(1-cyclopentylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
25 3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-cyclobutyl-l-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[2-
30 (trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]-3-
pyridin-2-yl-urea,
1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]-3-(2-
methylpropyl)urea,


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1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]-3-propan-2-
yl-urea,
1-ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
s 3-(2-dimethylaminoethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[2-
io (trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]-1-propyl-
urea,
3-methyl-l-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]-3-[4-
is (trifluoromethyl)phenyl]urea,
3-(1-hydroxy-2-methyl-propan-2-yl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[
1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
20 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[2-
(trifluoromethyl)phenyl]sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]-3-(1-
methylpyrazol-4-
yl)urea,
3-cyclopropyl-1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-
4-
yl]pyrimidin-2-yl]phenyl]urea,
25 1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-
3-methyl-urea,
1-ethyl-3-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]urea,
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-
3o 3-propan-2-yl-urea,
3-cyclobutyl-l -[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-
4-yl]pyrimidin-
2-yl]phenyl]urea,


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1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-
3-(2-hydroxyethyl)urea,
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-
3-(1-hydroxy-2-methyl-propan-2-yl)urea,
s 3-(2-dimethylaminoethyl)-1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-
1-propyl-urea,
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3 -methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-
i o 3-(2-methylpropyl)urea,
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3 -methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-
3-(3-hydroxypropyl)urea,
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3 -methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-
3-[4-(trifluoromethyl)phenyl]urea,
is 1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-
3-pyridin-2-yl-urea,
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3 -methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-
3 -(1 -methylpyrazol-4-yl)urea,
3-cyclopropyl-l-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-
2-
20 yl]phenyl]urea,
3-methyl-l-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]urea,
3-ethyl-l-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]urea,
3-cyclobutyl-l-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-

yl]phenyl]urea,
25 3-(2-hydroxyethyl)-1-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
3 -(1-hydroxy-2-methylpropan-2-yl)-1-[4-[4-(1-methylsulfonylcyclopropyl)-6-
morpholin-4-
ylpyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)-1-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-
ylpyrimidin-
3o 2-yl]phenyl]urea,
1-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-
propylurea,


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3-(3-hydroxypropyl)-1-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
3-(1-methylpyrazol-4-yl)-1-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
s 3-cyclopropyl-1-[4-[4-(1-methylsulfonylcyclopentyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
3-methyl-1 -[4-[4-(1-methylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-(1-methylsulfonylcyclopentyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
io 3-(1-hydroxy-2-methylpropan-2-yl)-1-[4-[4-(1-methylsulfonylcyclopentyl)-6-
morpholin-4-
ylpyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)-1-[4-[4-(1-methylsulfonylcyclopentyl)-6-morpholin-4-
ylpyrimidin-
2-yl]phenyl]urea,
3-(3-hydroxypropyl)-1-[4-[4-(1-methylsulfonylcyclopentyl)-6-morpholin-4-
ylpyrimidin-2-
is yl]phenyl]urea,
3-cyclopropyl-1-[4-[4-(1-methylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-

yl]phenyl]urea,
3-methyl-1 -[4-[4-(1-methylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-(1-methylsulfonylcyclobutyl)-6-morpholin-4-
ylpyrimidin-2-
20 yl]phenyl]urea,
3-(2-dimethylaminoethyl)-1-[4-[4-(1-methylsulfonylcyclobutyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
3-(3-hydroxypropyl)-1-[4-[4-(1-methylsulfonylcyclobutyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
25 3-cyclopropyl-1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-
methylurea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-
3o ethylurea,
3-cyclobutyl-1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,


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1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(2-
hydroxyethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(1-
hydroxy-2-methylpropan-2-yl)urea,
s 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(2-
dimethylaminoethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-
propylurea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(3-
io hydroxypropyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(1-
methylpyrazol-4-yl)urea,
3-cyclopropyl-1-[4-[4-(1-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
is 1-[4-[4-(1-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-
methylurea,
1-[4-[4-(1-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(2-
hydroxyethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(1-
2o hydroxy-2-methylpropan-2-yl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(2-
dimethylaminoethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopentyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(3-
hydroxypropyl)urea,
25 3-cyclopropyl-1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-
methylurea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(2-
3o hydroxyethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(1-
hydroxy-2-methylpropan-2-yl)urea,


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1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(2-
dimethylaminoethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(3-
hydroxypropyl)urea,
s 3-cyclopropyl-1-[5-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]pyridin-2-yl]urea,
1-[5-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]pyridin-2-yl]-3-methylurea,
1-[5-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]pyridin-2-yl]-3-(2-dimethylaminoethyl)urea,
1-[5-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]pyridin-2-yl]-3-(2-hydroxyethyl)urea,
1-[5-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]pyridin-2-yl]-3-(1-methylpyrazol-4-yl)urea,
is 3-cyclopropyl-l-[5-[4-[1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]pyrimidin-2-yl]urea,
1-[5-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]pyrimidin-2-yl]-3-methylurea,
1-[5-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
2o yl]pyrimidin-2-yl]-3-(2-hydroxyethyl)urea,
1-[5-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]pyrimidin-2-yl]-3-(1-methylpyrazol-4-yl)urea,
3-cyclopropyl-l-[5-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]pyridin-2-yl]urea,
25 1-[5-[4-[1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]pyridin-2-yl]-3-methylurea,
3-(2-dimethylaminoethyl)-1-[5-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-
[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]pyridin-2-yl]urea,
1-[5-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
3o yl]pyridin-2-yl]-3-(2-hydroxyethyl)urea,
1-[5-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]pyridin-2-yl]-3-(1-methylpyrazol-4-yl)urea,


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3-cyclopropyl- 1 -[5-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]pyridin-2-yl]urea,
3-methyl-1 -[5-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
yl]pyridin-2-yl]urea,
s 3-(2-dimethylaminoethyl)-1-[5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]pyridin-2-yl]urea,
3-(2-hydroxyethyl)- 1 -[5-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]pyridin-2-yl]urea,
1-[5-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
io yl]pyridin-2-yl]-3-(1-methylpyrazol-4-yl)urea,
3-cyclopropyl- 1 -[5-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]pyrimidin-2-yl]urea,
3-methyl-1 -[5-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
yl]pyrimidin-2-yl]urea,
is 3-(2-hydroxyethyl)-1-[5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]pyrimidin-2-yl]urea,
1-[5-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
yl]pyrimidin-2-yl]-3-(1-methylpyrazol-4-yl)urea,
3-cyclopropyl-1-[5-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-
methylmorpholin-4-
20 yl]pyrimidin-2-yl]pyrimidin-2-yl]urea,
1-[5-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]pyrimidin-2-yl]-3-methylurea,
1-[5-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]pyrimidin-2-yl]-3-(2-hydroxyethyl)urea,
25 1-[5-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]pyrimidin-2-yl]-3-(1-methylpyrazol-4-yl)urea,
3-(2-hydroxyethyl)-1-[5-[4-[ 1-[4-(2-
hydroxyethylamino)phenyl]sulfonylcyclopropyl]-6-[(3 S)-
3-methylmorpholin-4-yl]pyrimidin-2-yl]pyrimidin-2-yl]urea,
3-cyclopropyl-l-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
30 yl]pyrimidin-2-yl]phenyl]urea,
3-ethyl-l-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3 S)-3 -
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,


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1-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
3-cyclobutyl-l-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
s 3-(2-hydroxyethyl)-1-[4-[4-[1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-

methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1,2,4-thiadiazol-5-yl)urea,
1-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
3-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-propylurea,
1-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
is 3-(2-cyanoethyl)-1-[4-[4-[1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1 H-imidazol-2-ylmethyl)urea,
1-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
2o yl]phenyl]-3-[1-(hydroxymethyl)cyclopropyl]urea,
1-[4-[4-[ 1-(5-fluoropyridin-3-yl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
3-ethyl-l-[4-[4-[ 1-(5-fluoropyridin-3-yl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
25 1-[4-[4-[1-(5-fluoropyridin-3-yl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-cyclopropyl-l-[4-[4-[ 1-(5-fluoropyridin-3-yl)sulfonylcyclopropyl]-6-[(3 S)-
3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
30 yl]phenyl]-3-cyclopropylurea,
1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclobutylurea,


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1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-pyridin-2-ylurea,
1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-methylpropyl)urea,
s 1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-propan-2-ylurea,
1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-ethylurea,
1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(2-dimethylaminoethyl)urea,
1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-propylurea,
is 1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
20 yl]phenyl]-3-(1-hydroxy-2-methylpropan-2-yl)urea,
1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-(1-tert-butylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
25 3-cyclopropyl-l-[4-[4-[1-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-

methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-cyclobutyl-l-[4-[4-[ 1-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
3o yl]pyrimidin-2-yl]phenyl]-3-pyridin-2-ylurea,
1-[4-[4-[ 1-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-methylpropyl)urea,


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1-[4-[4-[ l -(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-propan-2-ylurea,
1-[4-[4-[ l -(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-ethylurea,
s 1-[4-[4-[l-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-dimethylaminoethyl)urea,
1-[4-[4-[ l -(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
io yl]pyrimidin-2-yl]phenyl]-3-propylurea,
1-[4-[4-[ 1-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea,
1-[4-[4-[ 1-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
is 1-[4-[4-[1-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-hydroxy-2-methylpropan-2-yl)urea,
1-[4-[4-[ 1-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-[ 1-(3,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
2o yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(4-
methylsulfonylpiperidin-4-
yl)pyrimidin-2-yl]phenyl]urea,
3-methyl-l-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonylpiperidin-4-
yl)pyrimidin-
2-yl]phenyl]urea,
25 3-(2-dimethylaminoethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(4-
methylsulfonylpiperidin-4-yl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(4-
methylsulfonylpiperidin-4-
yl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonylpiperidin-4-
yl)pyrimidin-2-
3o yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
3-cyclopropyl- l -[4-[4-(4-cyclopropylsulfonylpiperidin-4-yl)-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,


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1-[4-[4-(4-cyclopropylsulfonylpiperidin-4-yl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
1-[4-[4-(4-cyclopropylsulfonylpiperidin-4-yl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
s 1-[4-[4-(4-cyclopropylsulfonylpiperidin-4-yl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1 -Benzyl-4-(3,5-difluorophenyl)sulfonylpiperidin-4-yl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-cyclopropylurea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonyloxan-
4-
io yl)pyrimidin-2-yl]phenyl]urea,
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonyloxan-4-
yl)pyrimidin-2-
yl]phenyl]urea,
3-(2-dimethylaminoethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(4-
methylsulfonyloxan-4-
yl)pyrimidin-2-yl]phenyl]urea,
is 3-(2-hydroxyethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(4-
methylsulfonyloxan-4-
yl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(4-methylsulfonyloxan-4-yl)pyrimidin-
2-yl]phenyl]-
3-(1-methylpyrazol-4-yl)urea,
3-cyclopropyl-l-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(3 S)-3-
methylmorpholin-4-
20 yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
1-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-dimethylaminoethyl)urea,
25 1-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-(4-cyclopropylsulfonyloxan-4-yl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
3o yl]phenyl]-3-methylurea,
1-[4-[4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-dimethylaminoethyl)urea,


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1-[4-[4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
s 1-[4-[4-[4-(4-chlorophenyl)sulfonyloxan-4-yl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-
thiazol-2-
yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-cyclobutyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-
thiazol-2-
io yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-thiazol-2-
yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]-3-pyridin-2-ylurea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-thiazol-2-
yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]-3-(2-methylpropyl)urea,
is 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-l,3-thiazol-2-
yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]-3-propan-2-ylurea,
1-ethyl-3-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-thiazol-2-
yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-
methyl-l,3-thiazol-
2o 2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-
thiazol-2-
yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-thiazol-2-
yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl]-1-propylurea,
25 3-methyl-1 -[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-1,3-thiazol-
2-
yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-thiazol-2-
yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]-3-[4-
(trifluoromethyl)phenyl]urea,
3-(1-hydroxy-2-methylpropan-2-yl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-
[(4-methyl-
30 1,3-thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-
1,3-thiazol-2-
yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl]urea,


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1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-thiazol-2-
yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-(1-cyclohexylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
s 3-cyclobutyl-1-[4-[4-(1-cyclohexylsulfonylcyclopropyl)-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-(1-cyclohexylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-ethylurea,
1-[4-[4-(1-cyclohexylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(2-dimethylaminoethyl)urea,
1-[4-[4-(1-cyclohexylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-(1-cyclohexylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
15 1-[4-[4-(1-cyclohexylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-hydroxy-2-methylpropan-2-yl)urea,
1-[4-[4-(1-cyclohexylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-(1-cyclohexylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
20 yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
1-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclobutylurea,
25 1-[4-[4-[1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-pyridin-2-ylurea,
1-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-methylpropyl)urea,
1-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
3o yl]phenyl]-3-propan-2-ylurea,
1-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,


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3-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-ethylurea,
1-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-dimethylaminoethyl)urea,
s 1-[4-[4-[1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
3-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-propylurea,
1-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
1-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-hydroxy-2-methylpropan-2-yl)urea,
1-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
is 1-[4-[4-[1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-cyclobutyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
20 ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-pyridin-2-ylurea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(2-methylpropyl)urea,
25 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-propan-2-ylurea,
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-dimethylaminoethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-
2-
30 ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,


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3-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-1-propylurea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,
s 3-(1-hydroxy-2-methylpropan-2-yl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-
io yl]phenyl]-3-(1-methylpyrazol-4-yl)urea
[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-
2-
yl]phenyl]urea,
3-cyclopropyl-l-[4-[4-[4-(3,5-difluorophenyl)sulfonylpiperidin-4-yl]-6-[(3 S)-
3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
is 1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-
2-yl]phenyl]-3-propan-2-ylurea,
3-cyclopropyl-l-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
3-cyclobutyl-l-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
20 yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-pyridin-2-ylurea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(2-methylpropyl)urea,
25 1-ethyl-3-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)- 1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-
3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
3o 2-yl]phenyl]-3-methylurea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-[4-(trifluoromethyl)phenyl]urea,


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3-(3-hydroxypropyl)-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-
3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
s 3-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-1-propylurea,
3-(2-dimethylaminoethyl)-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-
[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea
3-(1-hydroxy-2-methylpropan-2-yl)-1-[4-[4-[ 1-(3-
hydroxypropylsulfonyl)cyclopropyl]-6-
io [(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea
N,N-dimethyl-l-[2-[4-(methylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-

yl] cyclopropane-l-carboxamide
3-methyl-1 -[4-[4-[ 1-[(3 S)-3-methylmorpholine-4-carbonyl] cyclopropyl]-6-
morpholin-4-
ylpyrimidin-2-yl]phenyl]urea
is N-cyclopropyl-l-[2-[4-(methylcarbamoylamino)phenyl]-6-morpholin-4-
ylpyrimidin-4-
yl] cyclopropane-l-carboxamide
N-cyclopropyl-N-methyl-l-[2-[4-(methylcarbamoylamino)phenyl]-6-morpholin-4-
ylpyrimidin-
4-yl] cyclopropane-l-carboxamide
3-methyl-l-[4-[4-[ 1-(4-methylpiperazine-l-carbonyl)cyclopropyl]-6-morpholin-4-
ylpyrimidin-
2o 2-yl]phenyl]urea
1-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-yl]-N,N-

dimethylcyclopropane-l-carboxamide
3 -cyclopropyl- 1 -[4- [4- [1-[(3 S)-3 -methylmorpholine-4-carbonyl]
cyclopropyl] -6-morpholin-4-
ylpyrimidin-2-yl]phenyl]urea
25 N-cyclopropyl-l-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-
ylpyrimidin-4-
yl] cyclopropane-l-carboxamide
N-cyclopropyl-l-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-
ylpyrimidin-4-
yl]-N-methylcyclopropane-l-carboxamide
3-cyclopropyl-l-[4-[4-[ 1-(4-methylpiperazine-l-carbonyl)cyclopropyl]-6-
morpholin-4-
30 ylpyrimidin-2-yl]phenyl]urea
1-[2-[4-(2-hydroxyethylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-yl]-
N,N-
dimethylcyclopropane-l-carboxamide


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3-(2-hydroxyethyl)- 1 -[4-[4-[1-[(3 S)-3-methylmorpholine-4-
carbonyl]cyclopropyl]-6-
morpholin-4-ylpyrimidin-2-yl]phenyl]urea
N-cyclopropyl-l-[2-[4-(2-hydroxyethylcarbamoylamino)phenyl]-6-morpholin-4-
ylpyrimidin-
4-yl] cyclopropane-l-carboxamide
s N-cyclopropyl-l-[2-[4-(2-hydroxyethylcarbamoylamino)phenyl]-6-morpholin-4-
ylpyrimidin-
4-yl]-N-methylcyclopropane-l-carboxamide,
3-(2-hydroxyethyl)-1-[4-[4-[ 1-(4-methylpiperazine-l-carbonyl)cyclopropyl]-6-
morpholin-4-
ylpyrimidin-2-yl]phenyl]urea,
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
io yl]phenyl]thiourea,
3-ethyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]thiourea,
3-(2-hydroxyethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
is 3-(2-dimethylaminoethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3- [ 1-(hydroxymethyl)cyclopropyl]-1-[4-[4-[ 1-(3-
hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-
2o 3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1,2,4-thiadiazol-5-yl)urea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1 H-imidazol-2-ylmethyl)urea,
25 1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
3-cyclopropyl-1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
30 yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-cyanoethyl)-1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,


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1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1 H-imidazol-2-ylmethyl)urea,
s 3-cyclopropyl-1-[4-[4-(1-cyclopropylsulfonylcyclopentyl)-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopentyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-cyanoethyl)-1-[4-[4-(1-cyclopropylsulfonylcyclopentyl)-6-[(3 S)-3-
methylmorpholin-4-
io yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopentyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
3-(1 H-imidazol-2-ylmethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-
methyl-1,3-
thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
is 3-(2-cyanoethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-1,3-
thiazol-2-
yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-thiazol-2-
yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]-3-(1,2,4-thiadiazol-5-yl)urea,
3- [ 1-(hydroxymethyl)cyclopropyl]-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[
1-[(4-methyl-
20 1,3-thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-1-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
1-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-2-yl]phenyl]-3-
(1,2,4-
thiadiazol-5-yl)urea,
25 3-(1H-imidazol-2-ylmethyl)-1-[4-[4-(1-methylsulfonylcyclopropyl)-6-
morpholin-4-
ylpyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-
3o 3-[1-(hydroxymethyl)cyclopropyl]urea,
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-
3-(1 H-imidazol-2-ylmethyl)urea,


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1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[ 1-(hydroxymethyl)cyclopropyl]urea,
3-(2-cyanoethyl)-1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
s 1-[4-[4-[1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1,2,4-thiadiazol-5-yl)urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1 H-imidazol-2-ylmethyl)urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
io ylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
is 3-(3-hydroxypropyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
20 ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
25 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclobutyl)pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
3-(l H-imidazol-2-ylmethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
pyridin-2-
ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-cyclopropyl-l-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-
ylpyrimidin-2-
3o yl]phenyl]urea,
3-(2-cyanoethyl)-1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-
4-ylpyrimidin-
2-yl]phenyl]urea,


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1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-
(1,2,4-thiadiazol-5-yl)urea,
1-ethyl-3-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
s 3-[4-[4-[1-(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-1-
methylurea,
3-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-1-(1-
methylpyrazol-4-yl)urea,
3-(2-hydroxyethyl)-1-[4-[4-morpholin-4-yl-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-
io yl]phenyl]urea,
1-(1-methylpyrazol-4-yl)-3-[4-[4-morpholin-4-yl-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-methyl-3-[4-[4-morpholin-4-yl-6-(1-pyridin-4-ylsulfonylcyclopropyl)pyrimidin-
2-
yl]phenyl]urea,
is 1-ethyl-3-[4-[4-morpholin-4-yl-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]urea,
3-cyclopropyl-l-[4-[4-morpholin-4-yl-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]urea,
3-(2-cyanoethyl)-1-[4-[4-morpholin-4-yl-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-
20 yl]phenyl]urea,
3-(3-hydroxypropyl)-1-[4-[4-morpholin-4-yl-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(1,3-thiazol-2-yl)urea,
25 3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-1-(5-methylpyrazin-2-yl)urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(1,3-oxazol-2-yl)urea,
3-(3-hydroxypropyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
30 methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,


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1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclobutylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3,3,3-trifluoro-2-hydroxypropyl)urea,
s 1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-propan-2-ylurea,
3-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-ethylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(2-hydroxyethyl)urea,
3-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-propylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
is 1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-hydroxy-2-methylpropan-2-yl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
20 yl]phenyl]-3-(2-cyanoethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1 H-imidazol-2-ylmethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[ 1-(hydroxymethyl)cyclopropyl]urea,
25 1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(oxetan-3-yl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1,2,4-thiadiazol-5-yl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
30 yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,


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1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
s 1-[4-[4-[1-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopentyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopentyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopentyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopentyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-cyanoethyl)urea,
is 1-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
1-ethyl-3-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
3-cyclopropyl-l-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3 S)-3-
methylmorpholin-4-
20 yl]pyrimidin-2-yl]phenyl]urea,
3-cyclobutyl-l-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-1-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3 S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
25 3-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-propylurea,
3-(2-hydroxyethyl)-1-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
3o yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[4-(3-hydroxypropylsulfonyl)oxan-4-yl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1,3-thiazol-2-yl)urea,


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1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1,3-thiazol-2-yl)urea,
1-cyclopropyl-3-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]-1-methylurea,
s 1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1-methylcyclopropyl)urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3
S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-tert-butyl-l-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
io yl]pyrimidin-2-yl]phenyl]urea,
3-cyano-l-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
3-hydroxy-N-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]pyrrolidine-l-carboxamide,
is 1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-
4-yl]pyrimidin-
2-yl]phenyl]-3-(2-methylsulfonylethyl)urea,
3 -(1, 1 -dioxothiolan-3 -yl)- l -[4- [4- [1-(3-
hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3 -
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
2-[[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-
4-
2o yl]pyrimidin-2-yl]phenyl]carbamoylamino]-N,N-dimethylacetamide,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(1,2,4-thiadiazol-5-yl)urea,
3-(1 H-imidazol-2-ylmethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
25 3-[1-(hydroxymethyl)cyclopropyl]-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(1 H-imidazol-2-ylmethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-[ 1-(hydroxymethyl)cyclopropyl]-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
pyridin-4-
30 ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[4-(benzenesulfonyl)oxan-4-yl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,


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3-[4-[4-[4-(benzenesulfonyl)oxan-4-yl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-ethylurea,
1-[4-[4-[4-(benzenesulfonyl)oxan-4-yl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
s 1-[4-[4-[4-(benzenesulfonyl)oxan-4-yl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-
cyclopropylurea,
3-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-1-
1 o ethylurea,
1-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(2-
hydroxyethyl)urea,
3-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-1-
methylurea,
15 1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(3-
hydroxypropyl)urea,
1-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(2-
cyanoethyl)urea,
1-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-(1,2,4-
20 thiadiazol-5-yl)urea,
3-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-1-(1-
methylpyrazol-4-yl)urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-
thiazol-2-
yl)sulfonyl] cyclopentyl]pyrimidin-2-yl]phenyl]urea,
25 3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-
1,3-thiazol-2-
yl)sulfonyl] cyclopentyl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-
thiazol-2-
yl)sulfonyl] cyclopentyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-
1,3-thiazol-2-
3o yl)sulfonyl]cyclopentyl]pyrimidin-2-yl]phenyl]urea,
N-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-hydroxypyrrolidine-l-carboxamide,


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2-[[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6- [(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]carbamoylamino]acetic acid,
2-[[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6- [(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]carbamoylamino]-N,N-dimethylacetamide,
s 3-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-cyclopropyl-l-methylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(2-cyanoethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1 H-imidazol-2-ylmethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-3-yl)urea,
is 3-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-(5-methyl-1,2-oxazol-3-yl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2,2-difluoroethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
20 yl]phenyl]-3-(1,3-oxazol-2-yl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1,2-oxazol-3-yl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2,2,2-trifluoroethyl)urea,
25 1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylimidazol-4-yl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2S)-1-hydroxypropan-2-yl]urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
30 yl]phenyl]-3-[(2R)-l-hydroxypropan-2-yl]urea,
1-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-chloroethyl)urea,


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1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-
3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
s 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylthiourea,
3-cyclopropyl-1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl] thiourea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(2-hydroxyethyl)thiourea,
3-cyclobutyl-l-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl] thiourea,
3-(2-cyanoethyl)-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea,
is 3-(3-hydroxypropyl)-1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-
[(3S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-methylthiourea,
3-cyclopropyl-l-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-
2o 4-yl]pyrimidin-2-yl]phenyl]thiourea,
3-(2-hydroxyethyl)- 1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-
3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1-methylpyrazol-4-yl)thiourea,
25 1-ethyl-3-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]thiourea,
3-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-1-propylthiourea,
3-(3-hydroxypropyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
30 methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-propylthiourea,


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1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)thiourea,
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-thiazol-
2-
yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]thiourea,
s 3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-1,3-
thiazol-2-
yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]thiourea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-
thiazol-2-
yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]thiourea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-methylthiourea,
3-cyclopropyl-l-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl] thiourea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)thiourea,
is 1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylthiourea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)thiourea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
20 yl]phenyl]-3-(3-hydroxypropyl)thiourea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-cyanoethyl)thiourea,
3-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-ethylthiourea,
25 1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)thiourea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylthiourea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
30 yl]phenyl]-3-(1H-imidazol-2-ylmethyl)thiourea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,


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3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
s 1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-hydroxy-2-methylpropan-2-yl)thiourea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(5-methyl-1,3,4-
thiadiazol-2-
yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(5-methyl-1,3,4-
thiadiazol-2-
io yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(1,3-thiazol-2-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(1,3-thiazol-2-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea,
15 1-[4-[4-[ 1 -(1 H-imidazol-2-ylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-methylurea,
3-cyclopropyl- 1 -[4-[4-[ 1 -(1 H-imidazol-2-ylsulfonyl)cyclopropyl]-6-[(3 S)-
3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
20 methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3-cyclopropyl-l-[4-[4-[ 1-[(4-methyl-1,3-thiazol-2-yl)sulfonyl] cyclopropyl]-6-
morpholin-4-
ylpyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)- 1-[4-[4-[1-[(4-methyl-1,3-thiazol-2-yl)sulfonyl]
cyclopropyl]-6-morpholin-
4-ylpyrimidin-2-yl]phenyl]urea,
25 3-(1-methylpyrazol-4-yl)-1-[4-[4-[1-[(4-methyl-1,3-thiazol-2-
yl)sulfonyl]cyclopropyl]-6-
morpholin-4-ylpyrimidin-2-yl]phenyl]urea,
3-methyl-l-[4-[4-[ 1-[(4-methyl-1,3-thiazol-2-yl)sulfonyl] cyclopropyl]-6-
morpholin-4-
ylpyrimidin-2-yl]phenyl]urea,
1-ethyl-3-[4-[4-[ 1-[(4-methyl-1,3-thiazol-2-yl)sulfonyl] cyclopropyl]-6-
morpholin-4-
30 ylpyrimidin-2-yl]phenyl]urea,
3-cyclobutyl-l -[4-[4-[ 1-[(4-methyl-1,3-thiazol-2-yl)sulfonyl] cyclopropyl]-6-
morpholin-4-
ylpyrimidin-2-yl]phenyl]urea,


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3-(2-cyanoethyl)-1-[4-[4-[ 1-[(4-methyl-1,3-thiazol-2-yl)sulfonyl]
cyclopropyl]-6-morpholin-4-
ylpyrimidin-2-yl]phenyl]urea,
3- [4-[4-[ 1-[(4-methyl-1,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]-1-propylurea,
s 1-[4-[4-[1-[(4-methyl-1,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]-3-propan-2-ylurea,
3-cyclopropyl-l-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
io 2-yl]phenyl]-3-methylurea,
3-(2-hydroxyethyl)- 1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-

methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
is 1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1 H-imidazol-2-ylmethyl)urea,
3-cyclopropyl-l-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopentyl]-6-[(3 S)-3-
methylmorpholin-
2o 4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)- 1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopentyl]-6-[(3 S)-
3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2-cyanoethyl)-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopentyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
25 3-(3-hydroxypropyl)-1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclopentyl]-6-
[(3S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-ethyl-3-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
3o 2-yl]phenyl]-1-propylurea,
3-(3-hydroxypropyl)-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-
3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,


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1-[4-[4-[ l -(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1,2-oxazol-3-yl)urea,
3-(2-fluoroethyl)-1-[4-[4-[ l -(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-

methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
s 3-(2,2-difluoroethyl)-1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-
[(3S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(1-hydroxy-2-methylpropan-2-yl)-1-[4-[4-[ 1-(3-
hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-
3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-[(2S)-1-hydroxypropan-2-yl]-1-[4-[4-[ 1-(3 -
hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-
io methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-[(2R)-1-hydroxypropan-2-yl]-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-
6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1,2,4-thiadiazol-5-yl)urea,
is 1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1,3-thiazol-2-yl)urea,
N-[2-[ 1-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-[(3 S)-3-methylmorpholin-4-

yl]pyrimidin-4-yl]cyclopropyl]sulfonylethyl]acetamide,
N-[2-[ 1-[2-[4-(ethylcarbamoylamino)phenyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-4-
2o yl]cyclopropyl]sulfonylethyl]acetamide,
2-[ 1-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-
yl]cyclopropyl]sulfonylacetamide,
2-[ 1-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-morpholin-4-ylpyrimidin-4-
yl]cyclopropyl]sulfonyl-N-methylacetamide,
25 3-cyclopropyl-l-[4-[4-[1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
1-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-morpholin-4-ylpyrimidin-2-
yl]phenyl]-3-
methylurea,
3-ethyl-l-[4-[4-[ 1-(2-hydroxyethylsulfonyl)cyclopropyl]-6-morpholin-4-
ylpyrimidin-2-
3o yl]phenyl]urea,
1-[4-[4-[ 1-(5-fluoropyridin-2-yl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea,


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3-cyclopropyl-l-[4-[4-[ l -(5-fluoropyridin-2-yl)sulfonylcyclopropyl]-6-[(3 S)-
3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
N,N-dimethyl-6-[ 1-[2-[4-(methylcarbamoylamino)phenyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-4-yl]cyclopropyl]sulfonylpyridine-3-carboxamide,
s 6-[1-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-4-
yl]cyclopropyl]sulfonyl-N,N-dimethylpyridine-3-carboxamide,
N,N-dimethyl-3-[ 1-[2-[4-(methylcarbamoylamino)phenyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-4-yl] cyclopropyl]sulfonylpyridine-2-carboxamide,
3-[ 1-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-4-
io yl]cyclopropyl]sulfonyl-N,N-dimethylpyridine-2-carboxamide,
1-[4-[4-[ 1-(2-methoxyethylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-methylurea,
3-cyclopropyl-l-[2-fluoro-4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
is 1-[2-fluoro-4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-methylurea,
3-ethyl-l-[2-fluoro-4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[2-fluoro-4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
20 yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[2-fluoro-4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
25 3-cyclopropyl-l-[4-[4-[1-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-fluoroethyl)-1-[4-[4-[ 1-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-
3o 4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3
S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,


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1-ethyl-3-[4-[4-[ 1-(3 -fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
s 3-methyl-1 -[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(2-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(2-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(2-
io methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-fluoroethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(2-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(2-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
is 1-ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(2-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(2-
methylphenyl)sulfonylcyclopropyl]pyrimidin-
2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(1,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
2o yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-cyclopropyl-l-[4-[4-[ 1-(1,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3
S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(1,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
25 1-[4-[4-[1-(1,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(1,3-dimethylpyrazol-4-
yl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[ 1-(1,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
3o yl]pyrimidin-2-yl]phenyl]-l-ethylurea,
1-[4-[4-[ 1-(1,3-dimethylpyrazol-4-yl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,


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3-cyclopropyl-l-[4-[4-morpholin-4-yl-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]urea,
3-methyl-l-[4-[4-morpholin-4-yl-6-(1-pyridin-2-ylsulfonylcyclopropyl)pyrimidin-
2-
yl]phenyl]urea,
s 3-ethyl-l-[4-[4-morpholin-4-yl-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-morpholin-4-yl-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]urea,
3-(1-methylpyrazol-4-yl)-1-[4-[4-morpholin-4-yl-6-(1-pyridin-2-
io ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(2-fluoro-4-methylaminophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-cyclopropyl-l-[4-[4-[ 1-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
is 1-[4-[4-[1-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(2,4-difluorophenyl)sulfonylcyclop,ropyl]-6-
[(3 S)-3-
20 methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-[4-[4-[ 1-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-1-ethylurea,
1-[4-[4-[ 1-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
25 1-[4-[4-[1-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-[(1-hydroxycyclopropyl)methyl]urea,
1-[4-[4-[ 1-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
3-cyclopropyl-l-[4-[4-[ 1-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
30 yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,


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3-(2-fluoroethyl)-1-[4-[4-[ 1-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3
S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
s 1-ethyl-3-[4-[4-[1-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(2-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-[(1-hydroxycyclopropyl)methyl]urea,
1- [4-[4-[ 1-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl] cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-cyclopropyl-l-[4-[4-[ 1-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl]
cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
is 1-[4-[4-[1-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1- [4-[4-[ 1-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl] cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-[(3,5-dimethyl-1,2-oxazol-4-
yl)sulfonyl]cyclopropyl]-6-[(3 S)-
2o 3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1- [4-[4-[ 1-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl] cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-[(1-hydroxycyclopropyl)methyl]urea,
3- [4-[4-[ 1-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl] cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-1-ethylurea,
25 1-[4-[4-[1-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-43-yl)urea,
1-[4-[4-[ 1-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-cyclopropyl-l-[4-[4-[ 1-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
30 methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,


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1-[4-[4-[ l -(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-
[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
s 3-[4-[4-[l-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-1-ethylurea,
1-[4-[4-[ 1-(2,5-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-43-yl)urea
1-[4-[4-[ 1-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
io yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-cyclopropyl-l-[4-[4-[ 1-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3
S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
is 3-(2-fluoroethyl)-1-[4-[4-[1-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-
6-[(3S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(5-fluoro-2-
methylphenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-ethyl-3-[4-[4-[ 1-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-
2o 4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(5-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-43-yl)urea,
3-(2-hydroxyethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea,
25 3-(1H-imidazol-2-ylmethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea,
3-[(2S)-1-hydroxypropan-2-yl]-1-[4-[4- [(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea,
3-[(2R)-1-hydroxypropan-2-yl]-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
30 methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea,
3-(3-hydroxypropyl)- l -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea,


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3-(1 H-imidazol-2-ylmethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
pyridin-4-
ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]thiourea,
3-cyclopropyl-l-[4-[4-[ 1-[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-
[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
s 1-[4-[4-[1-[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-[4-[4-[ 1-[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-1-ethylurea,
1-[4-[4-[ l -[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
io yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1-[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-[4-(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
is 3-(2,2-difluoroethyl)-1-[4-[4-[1-[4-
(difluoromethoxy)phenyl]sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-[4-[4-[ 1-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
2o yl]pyrimidin-2-yl]phenyl]-1-ethylurea,
3-cyclopropyl-l-[4-[4-[ 1-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
25 1-[4-[4-[1-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(3,4-difluorophenyl)sulfonylcyclopropyl]-6-
[(3 S)-3-
30 methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-[3-fluoro-4-(2-hydroxyethylamino)phenyl]sulfonylcyclopropyl]-6-[(3
S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,


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1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-hydroxy-2-methylpropan-2-yl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2S)-1-hydroxypropan-2-yl]urea,
s 1-[4-[4-[1-(benzenesulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2R)-1-hydroxypropan-2-yl]urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(2-fluoroethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2,2-difluoroethyl)urea,
15 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1 H-imidazol-2-ylmethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-hydroxy-2-methylpropan-2-yl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
20 yl]phenyl]-3-[(2S)-1-hydroxypropan-2-yl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2R)-1-hydroxypropan-2-yl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
25 3-(2-fluoroethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-[(2S)-1-hydroxypropan-2-yl]-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-
methyl-1,3-
3o thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-[(2R)-l -hydroxypropan-2-yl]-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-
[(4-methyl-1,3-
thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,


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3-(2-fluoroethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-
1,3-thiazol-2-
yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
s 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(1,2-oxazol-3-yl)urea,
1-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2,2-difluoroethyl)urea,
1-[4-[4-[ 1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(1,2-oxazol-3-yl)urea,
3-(2-fluoroethyl)-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-

methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-(1,2-oxazol-3-yl)urea,
15 1-[4-[4-[ 1 -[1-(difluoromethyl)pyrazol-4-yl]sulfonylcyclopropyl]-6-[(3 S)-
3-methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1 H-imidazol-2-ylmethyl)urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
2o yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-hydroxy-2-methylpropan-2-yl)urea,
25 1-[4-[4-[1-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2S)-1-hydroxypropan-2-yl]urea,
1-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2R)-1-hydroxypropan-2-yl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(1,3-thiazol-2-

3o ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(1,3-thiazol-
2-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea,


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3-(1 H-imidazol-2-ylmethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-
(1,3-thiazol-2-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(1,3-thiazol-2-

ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]thiourea,
s 3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(4-
methylphenyl)sulfonylcyclobutyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(4-
methylphenyl)sulfonylcyclobutyl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3R)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-ethylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-ethylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[3-(hydroxymethyl)morpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-ethylurea,
is 1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S,5 S)-3,5-
dimethylmorpholin-4-yl]pyrimidin-2-
yl]phenyl]-3-ethylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3R,5 S)-3,5-dimethylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-ethylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
20 yl]phenyl]-3-methylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
25 1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2,2-difluoroethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
30 yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2S)-l -hydroxypropan-2-yl]urea,


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1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2R)-1-hydroxypropan-2-yl]urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
s 1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(1-hydroxycyclopropyl)methyl]urea,
3-Cyclopropyl- 1 -[4-[4-[ 1-[ 1-(difluoromethyl)-3,5-dimethylpyrazol-4-
yl]sulfonylcyclopropyl]-
6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1 -[1-(difluoromethyl)-3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-
6-[(3 S)-3-
io methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-[4-[4-[ 1 -[1-(difluoromethyl)-3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-
6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-1-ethylurea,
1-[4-[4-[ 1 -[1-(difluoromethyl)-3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-
6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
is 3-(2,2-difluoroethyl)-1-[4-[4-[1-[1-(difluoromethyl)-3,5-dimethylpyrazol-4-
yl]sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-2-
yl]phenyl]urea,
1-[4-[4-[ 1 -[1-(difluoromethyl)-3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-
6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
1-[4-[4-[ 1 -[1-(difluoromethyl)-3,5-dimethylpyrazol-4-yl]sulfonylcyclopropyl]-
6-[(3 S)-3-
20 methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(2-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
1-[4-[4-[ 1-(2-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
25 3-[4-[4-[1-(2-chlorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-ethylurea,
1-[4-[4-[ 1-(2-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1-(2-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
3o yl]phenyl]-3-(2,2-difluoroethyl)urea,
1-[4-[4-[ 1-(2-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,


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1-[4-[4-[ 1-(2-chlorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
s 1-[4-[4-[1-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
3-[4-[4-[ 1-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-1-ethylurea,
1-[4-[4-[ 1-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2,2-difluoroethyl)urea,
1-[4-[4-[ 1-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,
is 1-[4-[4-[1-(4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
3-cyclopropyl-1- [4-[4-[ 1-[(2,4-dimethyl-1,3-thiazol-5-
yl)sulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1- [4-[4-[ 1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
20 yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3- [4-[4-[ 1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-1-ethylurea,
1- [4-[4-[ 1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
25 3-(2,2-difluoroethyl)-1-[4-[4-[1-[(2,4-dimethyl-1,3-thiazol-5-
yl)sulfonyl]cyclopropyl]-6-[(3S)-
3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1- [4-[4-[ 1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
1- [4-[4-[ 1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
30 yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
3-cyclopropyl-l-[4-[4-[ 1-(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-[(3
S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,


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1-[4-[4-[ 1-(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-(2-hydroxyethyl)-1-[4-[4-[ 1-(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-
[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
s 3-(2,2-difluoroethyl)-1-[4-[4-[1-(3-hydroxy-3-
methylbutyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2-fluoroethyl)-1-[4-[4-[ 1-(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-
[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
io yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-ethyl-3-[4-[4-[ 1-(3-hydroxy-3-methylbutyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-[(4,5-dimethyl-1,3-thiazol-2-yl)sulfonyl]
cyclopropyl]-6-[(3 S)-
3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
is 1-[4-[4-[1-[(4,5-dimethyl-1,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-cyclopropyl-1- [4-[4-[ 1-[(4,5-dimethyl-1,3-thiazol-2-
yl)sulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1- [4-[4-[ 1-[(4,5-dimethyl-1,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
20 yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1- [4-[4-[ 1-[(4,5-dimethyl-1,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3- [4-[4-[ 1-[(4,5-dimethyl-1,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-1-ethylurea,
25 1-[4-[4-[1-[(4,5-dimethyl-1,3-thiazol-2-yl)sulfonyl]cyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea,
3-cyclopropyl-l-[4-[4-[ 1-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3
S)-3-
30 methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,


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3-(2-fluoroethyl)-1-[4-[4-[ 1-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-
[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(4-fluoro-2-
methylphenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
s 3-ethyl-l-[4-[4-[1-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1-(4-fluoro-2-methylphenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
io ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-[(2S)-1-hydroxypropan-2-yl]-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
pyridin-4-
ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-[(2R)-1-hydroxypropan-2-yl]-1-[4-[4-[(3 S)-3 -methylmorpholin-4-yl]-6-(l -
pyridin-4-
ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
is 3-(l-hydroxy-2-methylpropan-2-yl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-
(1-pyridin-4-
ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
3-(l H-imidazol-2-ylmethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
pyridin-4-
ylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-ethylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]-
2o 3-methylurea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-ethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-ethylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]-
3-(2-hydroxyethyl)urea,
25 1-[4-[4-[(3S)-3-ethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]-
3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)- 1 -[4-[4-[(3 S)-3-ethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-ethyl-1 -[4-[4-[(3 S)-3-ethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
30 yl]phenyl]urea,
1-[4-[4-[(3 S)-3-ethylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]-
3-(1-methylpyrazol-4-yl)urea


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3-chloro-4-[ 1-[2-[4-(methylcarbamoylamino)phenyl]-6-[(3 S)-3-methylmorpholin-
4-
yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzamide
3-chloro-4-[ 1-[2-[4-(ethylcarbamoylamino)phenyl]-6-[(3 S)-3-methylmorpholin-4-

yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzamide
s 3-chloro-4-[1-[2-[4-(cyclopropylcarbamoylamino)phenyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzamide
3-chloro-4-[ 1-[2-[4-(2-fluoroethylcarbamoylamino)phenyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzamide
3-chloro-4-[ 1-[2-[4-(2-hydroxyethylcarbamoylamino)phenyl]-6-[(3 S)-3-
methylmorpholin-4-
io yl]pyrimidin-4-yl]cyclopropyl]sulfonylbenzamide
1-[4-[4-[ 1-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea
3-[4-[4-[ 1-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-1-ethylurea
is 1-[4-[4-[1-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-cyclopropylurea
1-[4-[4-[ 1-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2,2-difluoroethyl)urea
1-[4-[4-[ 1-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
2o yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea
1-[4-[4-[ 1-(2-chloro-4-cyanophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea
1-[4-[4-[ 1-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-methylurea
25 1-[4-[4-[1-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-ethylurea
3-cyclopropyl-l-[4-[4-[ 1-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea
1-[4-[4-[ 1-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
3o yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,


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3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-
[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ l -(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
s 1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-
(2-hydroxyethyl)urea,
1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-
(1 H-imidazol-2-ylmethyl)urea,
1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-
io (3-hydroxypropyl)urea,
1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-
methylurea,
1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-
(1-hydroxy-2-methylpropan-2-yl)urea,
is 1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-
[(2S)-1-hydroxypropan-2-yl]urea,
1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-
[(2R)-1-hydroxypropan-2-yl]urea,
1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-
20 (3-hydroxypropyl)thiourea,
1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-
(2-hydroxyethyl)thiourea,
1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-
(1 H-imidazol-2-ylmethyl)thiourea,
25 1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-
3-(3-hydroxypropyl)thiourea,
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3 -methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-
3-(2-hydroxyethyl)thiourea,
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-
3o 3-(1H-imidazol-2-ylmethyl)thiourea,
4-[6-[ 1-(benzenesulfonyl)cyclopropyl]-2-[4-
(ethylcarbamoylamino)phenyl]pyrimidin-4-
yl]morpholine-3-carboxamide,


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4-[6-[l -(benzenesulfonyl)cyclopropyl]-2-[4-
(ethylcarbamoylamino)phenyl]pyrimidin-4-yl]-
N,N-dimethylmorpholine-3-carboxamide,
3-cyclopropyl- 1 -[4-[4-[(3 S,5 S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
s 1-[4-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-methylurea,
1-[4-[4-[(3 S,5 S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-ethylurea,
1-[4-[4-[(3 S,5 S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
io yl]phenyl]-3-(2-fluoroethyl)urea,
1-[4-[4-[(3 S,5 S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
3-cyclopropyl-1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S,5 S)-3,5-
dimethylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]urea,
is 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S,5S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-
2-yl]phenyl]-3-(2,2-difluoroethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-
2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-
2o 2-yl]phenyl]-3-methylurea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-
2-yl]phenyl]-3-ethylurea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-
2-yl]phenyl]-3-(2-fluoroethyl)urea,
25 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S,5S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-
2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-2-
30 yl]phenyl]-3-methylurea
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea


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1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-2-
yl]phenyl]-3-(2,2-difluoroethyl)urea
s 1-[4-[4-[1-(benzenesulfonyl)cyclopropyl]-6-[(3S,5S)-3,5-dimethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(oxan-4-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
1-ethyl-3-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(oxan-4-
io ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(oxan-4-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(oxan-4-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
is 1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(oxan-4-
ylsulfonyl)cyclopropyl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea
3-cyclobutyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(oxan-4-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
3-methyl-l-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(oxolan-3-
2o ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
1-ethyl-3-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(oxolan-3-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(oxolan-3-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
25 3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(oxolan-3-
ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(oxolan-3-
ylsulfonyl)cyclopropyl]pyrimidin-2-
yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(3-chloro-4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
30 yl]pyrimidin-2-yl]phenyl]-3-methylurea,
1-[4-[4-[ 1-(3-chloro-4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3 -
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-cyclopropylurea,


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1-[4-[4-[ l -(3-chloro-4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3 -
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ l -(3-chloro-4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3 -
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
s 1-[4-[4-[l-(3-chloro-4-fluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2,2-difluoroethyl)urea,
3-[4-[4-[ l -(3-chloro-4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-1-ethylurea,
1-[4-[4-[ 1-(3-chloro-4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
io yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
1-[4-[4-[ 1-(3-chloro-4-methylaminophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]-3-methylurea,
1-[4-[4-[ 1-[3-chloro-4-(2-hydroxyethylamino)phenyl]sulfonylcyclopropyl]-6-[(3
S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
is 1-[4-[4-[1-[3-chloro-4-(2-fluoroethylamino)phenyl]sulfonylcyclopropyl]-6-
[(3S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
1-[4-[4-[ 1-(3-chloro-4-ethylaminophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-ethylurea,
3-methyl-1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(4-
2o methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(4-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(4-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
25 3-(2-fluoroethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(4-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2,2-difluoroethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(4-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
1-ethyl-3-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(4-
3o methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(4-
methylphenyl)sulfonylcyclopropyl]pyrimidin-
2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,


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1-[4-[4-[ l -[3-(difluoromethoxy)propylsulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-[3-
(difluoromethoxy)propylsulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
s 1-[4-[4-[l-[3-(difluoromethoxy)propylsulfonyl]cyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyramidin-2-yl]phenyl]-3-ethylurea,
1-[4-[4-[ 1-[3-(difluoromethoxy)propylsulfonyl]cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(1-methylpyrazol-4-yl)urea,
3-cyclopropyl-l-[4-[4-[ 1-[3-(difluoromethoxy)propylsulfonyl] cyclopropyl]-6-
[(3 S)-3-
io methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea,
3-methyl-l-[4-[4-[ 1-(2-methylaminoethylsulfonyl)cyclopropyl]-6-morpholin-4-
ylpyrimidin-2-
yl]phenyl]urea,
3-(1-hydroxy-2-methylpropan-2-yl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-
[(4-methyl-
1,3 -thiazol-2-yl)sulfonyl] cyclobutyl]pyrimidin-2-yl]phenyl]urea,
is 3-[(2S)-1-hydroxypropan-2-yl]-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-
[(4-methyl-1,3-
thiazol-2-yl)sulfonyl] cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(l H-imidazol-2-ylmethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-
methyl-l,3-
thiazol-2-yl)sulfonyl] cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-
1,3-thiazol-2-
2o yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-
thiazol-2-
yl)sulfonyl] cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-[(2R)-1-hydroxypropan-2-yl]-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-
methyl-1,3-
thiazol-2-yl)sulfonyl] cyclobutyl]pyrimidin-2-yl]phenyl]urea,
25 3-(l-hydroxy-2-methylpropan-2-yl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-
[1-(1,3-thiazol-
2-ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-[(2S)-1-hydroxypropan-2-yl]-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-
(1,3-thiazol-2-
ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(l H-imidazol-2-ylmethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-
(1,3-thiazol-2-
3o ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(3-hydroxypropyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(1,3-thiazol-
2-
ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,


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3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(1,3-thiazol-2-

ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-[(2R)-1-hydroxypropan-2-yl]-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-
(1,3-thiazol-2-
ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,
s 1-[4-[4-[l-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-
2-yl]phenyl]-3-methylthiourea,
3-cyclopropyl-l-[4-[4-[ l -(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl] thiourea,
1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
io 2-yl]phenyl]-3-(1H-imidazol-2-ylmethyl)thiourea,
3-(1-hydroxy-2-methylpropan-2-yl)-1-[4-[4-[ 1-(3-
hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-
3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea,
1-ethyl-3-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl] thiourea,
is 3-(2-hydroxyethyl)-1-[4-[4-[1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3S)-
3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea,
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3
S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea,
3-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-
2o 2-yl]phenyl]-1-propylthiourea,
3-(3-hydroxypropyl)-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclobutyl]-6-[(3 S)-
3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] thiourea, and
3-(2,2-difluoroethyl)-1-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3
S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea,
25 or a pharmaceutically acceptable salt thereof.
In another aspect of the invention there is provided a compound, or a
combination of
compounds, selected from any one of
1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-
3-methyl-urea,
30 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,


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3-(2-hydroxyethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
3-cyclopropyl-1-[4-[4-(1-methylsulfonylcyclopropyl)-6-morpholin-4-ylpyrimidin-
2-
yl]phenyl]urea,
s 1-[4-[4-[1-(4-chlorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-1,3-
thiazol-2-
io yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
is 1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)thiourea,
3-cyclopropyl-l-[4-[4-[ 1-(4-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
20 yl]pyrimidin-2-yl]phenyl]thiourea,
3-cyclopropyl-l-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-
4-yl]pyrimidin-2-yl]phenyl]thiourea,
1-ethyl-3-[4-[4-[ 1-(3-hydroxypropylsulfonyl)cyclopropyl]-6-[(3 S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl] thiourea,
25 1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
30 yl]phenyl]-3-methylthiourea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(1 H-imidazol-2-ylmethyl)thiourea,


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3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,
s 1-[4-[4-[1-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1-(3-fluorophenyl)sulfonylcyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
3-(2-hydroxyethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(2-
io methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-fluoroethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(2-
methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(1,3-thiazol-2-

ylsulfonyl)cyclopropyl]pyrimidin-2-yl]phenyl]urea,
is 1-[4-[4-[1-(2-chlorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2S)-1-hydroxypropan-2-yl]urea,
1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
20 yl]phenyl]-3-[(2S)-1-hydroxypropan-2-yl]urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclobutyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2R)-1-hydroxypropan-2-yl]urea,
3-(2-fluoroethyl)- 1 -[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-[(4-methyl-
1,3-thiazol-2-
yl)sulfonyl] cyclopropyl]pyrimidin-2-yl]phenyl]urea,
25 3-(2-hydroxyethyl)-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-
1,3-thiazol-2-
yl)sulfonyl] cyclobutyl]pyrimidin-2-yl]phenyl]urea,
3-(2-hydroxyethyl)-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-(1,3-thiazol-2-

ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
30 yl]phenyl]-3-methylurea,
1-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,


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1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,
s 1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2,2-difluoroethyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2S)-1-hydroxypropan-2-yl]urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-methylmorpholin-4-
yl]pyrimidin-2-
io yl]phenyl]-3-[(2R)-1-hydroxypropan-2-yl]urea,
3-cyclopropyl- 1 -[4-[4-[(3 S)-3-ethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S)-3-ethylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]-
3-(2-hydroxyethyl)urea,
is 1-[4-[4-[1-(2,6-difluorophenyl)sulfonylcyclopropyl]-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea,
1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-
2-yl]phenyl]-3-(2-hydroxyethyl)urea,
3-cyclopropyl- 1 -[4-[4-[(3 S,5 S)-3,5-dimethylmorpholin-4-yl]-6-(1-
20 methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea,
1-[4-[4-[(3 S,5 S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,
1-[4-[4-[(3 S,5 S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-(2-hydroxyethyl)urea,
25 1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S,5 S)-3,5-
dimethylmorpholin-4-yl]pyrimidin-2-
yl]phenyl]-3-methylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-2-
yl]phenyl]-3-cyclopropylurea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S,5 S)-3,5-dimethylmorpholin-
4-yl]pyrimidin-2-
30 yl]phenyl]-3-(2-hydroxyethyl)urea, and
1-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(2S)-l -hydroxypropan-2-yl]urea,


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1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(3-hydroxypropyl)urea,
1-[4-[4-[ 1 -(benzenesulfonyl)cyclopropyl]-6-[(3 S)-3-ethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-[(1-hydroxycyclopropyl)methyl]urea,
s 1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-
2-yl]phenyl]-3-
(2-hydroxyethyl)thiourea,
1-[4-[4-[(3 S,5 S)-3,5-dimethylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]-3-ethylurea,
3-[(2S)-1-hydroxypropan-2-yl]-1-[4-[4-[(3 S)-3-methylmorpholin-4-yl]-6-[ 1-
(1,3-thiazol-2-
io ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea, and
1-[4-[4-[ 1-(benzenesulfonyl)cyclopropyl]-6-[(3 S,5 S)-3,5-dimethylmorpholin-4-
yl]pyrimidin-2-
yl]phenyl]-3-(2-fluoroethyl)urea,
or a pharmaceutically acceptable salt thereof.
The invention also provides processes for the preparation of a compound of
formula (I)
is or a pharmaceutically acceptable salt thereof.
A compound of formula (I), wherein X=-S(O)2CR6~-, may be prepared by oxidising
a compound of the formula (I), wherein X = SCR6~-, for example by using Oxone
at room
temperature in a mixed solvent system of water and ethanol
0 0
C~(R3"' ~~(R3"'
N N
s ow
R 'N O p ~N
RI.S N~R2 RI I NR2
R6 R7 R6
(I) (I)

20 A compound of formula (I), wherein R'X = R1OCR6R7-, may be prepared by the
reaction of a compound of formula (I), wherein R'X = HOCR6~-, with a compound
of
formula (II), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.)
optionally in the
presence of a suitable base such as triethylamine and a solvent such as
tetrahydrofuran or N,N-
dimethylformamide.
0
C~(R3"'
N N
s s
R? L1 R I'NI ~ R I'N
(II) HO NJ~R2 R1'O NJR2
R6 R7 R6 R7
25 (I) (I)


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A compound of formula (I), wherein R'X = R1R4NCR6R7-, may be prepared by the
reaction of a compound of formula (I), wherein R'X = HR4NCRV-, with a compound
of
formula (II), wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.)
optionally in the
presence of a suitable base such as triethylamine and a solvent such as
tetrahydrofuran or N,N-
s dimethylformamide; or by the reaction of a compound of formula (I), wherein
R'X =
HR4NCR6R7-, with a compound of formula (III) in the presence of a suitable
reducing agent
such as NaCNBH3.
01
R'(I L' `/ ~ N t(R3m N(R3m
s ~ s \ /
R - N R4 R ~N

R I H R4-N N~R2 R1,N N~R2
I (I)
(III) R s R 7 I (I) R s R 7

A compound of formula (I), wherein Xi =-S(O)2CR6R7-, -SCR6R7-, -OCR6R7-,
io -R4NCR6R7-, -S(O)CR6R7-, may be prepared by the reaction of a compound of
formula (IV),
wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a
compound of formula (V)
optionally in the presence of a suitable base such as triethylamine and a
solvent such as
tetrahydrofuran or N,N-dimethylformamide.
0 0
N N
C)(R3"' () (R3"'

R ~ R$
RLX'H I~ N I~ N
(V) L N~R2 RI'X N~R2
Rs R Rs R7
(IV) (I)
is A compound of formula (I), wherein X=-SCR6~-, may be prepared by the
reaction of
a compound of formula (IV), wherein L1 is a leaving group (such as halo,
tosyl, mesyl etc.),
with thiourea in a suitable solvent such as ethanol to generate a compound of
formula (VI)
which is then subsequently reacted with a compound of formula (II) in the
presence of a
suitable base such as sodium hydroxide and a solvent such as N,N-
dimethylformamide.
0 0 0
SH ~N~(R3m (N}(R3)m R L' (N) (R3m
s _(II) ~
H2N~NH R I~ N R I~ N R N
L N Rz H2N u S N R2 R~~S N~ R2
J~
Rs R~ Nl~s R~ Rs R~
20 (IV) (VI) (I)


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A compound of formula (I), wherein X=-S(O)zCR6R7-, may be prepared by the
reaction of a compound of formula (VIII) with a compound of formula (VII),
wherein R6 &7 is
a 2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon
may be optionally
replaced with 0, N or S, and wherein L1 is a leaving group (such as halo,
tosyl, mesyl etc.), in
s the presence of a suitable base such as sodium hydride or potassium tert-
butoxide in a suitable
solvent such as tetrahydrofuran or N,N-dimethylformamide, or by using aqueous
sodium
hydroxide solution and DCM as a solvent with a suitable phase transfer agent
such as
tetrabutylammonium bromide.
0 0
L Rss~ ` )(R3)"' C ~(R3"
N N
I L1 s ~
O O ~C'N O N
(VII) R .S NJ~IR2 R1 N~R2
(VIII) Rs R7 (I)

A compound of formula (I), wherein X=-S(O)zCR6~-, may be prepared by the
reaction of a compound of formula (VIII) with a compound of formula (IX),
wherein R6 &7 is a
2 to 9 membered, optionally substituted, alkylene chain in which 1 carbon may
be optionally
replaced with 0, N or S, and wherein L1 is a leaving group (such as halo,
tosyl, mesyl etc.), and
L3 is a group which can be transformed to a suitable leaving group (such as
halo, tosyl, mesyl)
at a later stage, to give a compound of formula (X) in the presence of a
suitable base such as
sodium hydride or potassium tert-butoxide in a suitable solvent such as
tetrahydrofuran or N,N-
dimethylformamide, or by using aqueous sodium hydroxide solution and DCM as a
solvent
with a suitable phase transfer agent such as tetrabutylammonium bromide, and
subsequently
converting L3 to an appropriate leaving group (such as halo, tosyl, mesyl
etc.) and then
2o exposing to a suitable base such as sodium hydride or potassium tert-
butoxide in a suitable
solvent such as tetrahydrofuran or N,N-dimethylformamide, or by using aqueous
sodium
hydroxide solution and DCM as a solvent with a suitable phase transfer agent
such as
tetrabutylammonium bromide.
0 0 0
L Rss7 ~ ~(R3"' ~ ~(R3"' C ~(R3"
N N N
13 $ $ $
L
O O NI O NI p NI
(VIII) RS NJ,R2 R~.S NJ~R2 R~.S I NJ~R2
(VIII) Rs&7 Rs R7
~3 (IX) (I)


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A compound of formula (I), wherein R'X = HOCR6R7-, may be prepared by the
reaction of a compound of formula (XI), with suitable organometallic reagent
of fomula (XII)
wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in
which 1 carbon
may be optionally replaced with 0, N or S, such as the grignard reagent in a
suitable solvent.
0 0
C ~(R3"' (}(R3"'
M-Rss ~ N N
M R$ NI ~ R$
(XII) R,O NJ~R2 Ho I N~R2
0 (XI) Rs R7 (I)
A compound of formula (I), wherein R'X = HOCR6R7-, may be prepared by the
reaction of a compound of formula (XI), with suitable organometallic reagent
of fomula (XIII)
wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in
which 1 carbon
may be optionally replaced with 0, N or S, and M1 is a group which can be
transformed into a
io suitable organometallic reagent (such as a grignard reagent) at a later
date, such as the grignard
reagent in a suitable solvent, to give a compound of formula (XIV), and then
subsequent
conversion of M' to a suitable organometallic reagent and subsequent reaction.

ss7 0 0
M-R (0) N(R3)m \N~(R3)m CN}(R3)m
N ~
U R 30 R$ R$
(XIII) R,O I NJ~R2 H~ I NJ,R2 HO I NJ,R2
ss7 s 7
~ (XI) M (XIV) R R (I)

A compound of formula (I) may be prepared from a compound of formula (XV),
is wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(0)2Me
etc.), with a suitable
organometallic reagent (such as the boronic acid R2B(OH)2or the boronic ester
R2B(OR)2etc.)
in the presence of a suitable metal catalyst (such as palladium or copper) in
a suitable solvent
such as 1,4-dioxane. Alternatively where R2 connects to the pyrimidine ring
through a nitrogen,
oxygen or sulphur atom a compound of formula (I) may be prepared from a
compound of
20 formula (XIII), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -
SMe, -S(0)2Me
etc.), by reaction with the required amine, alcohol or thiol in the presence
of a suitable base
such as potassium carbonate in a suitable solvent such as N,N-
dimethylformamide.


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0 0
C}(R3"' C}(R3"'
N N
s s
N
R 'N R '
R~X I N~L 2 R~X I N/~R2
(XV) (I)
It will be appreciated that a compound of formula (XV) may be transformed into
another compound of formula (XV) by techniques such as oxidation, alkylation,
reductive
amination etc., either listed above or otherwise known in the literature.
s A compound of formula (XV), wherein Xl =-S(O)zCR6R7-, -SCR6R7-, -OCR6R7-,
-R4NCR6R7-, -S(O)CR6R7-, may be prepared by the reaction of a compound of
formula (XVI),
wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a
compound of formula (V)
optionally in the presence of a suitable base such as triethylamine and a
solvent such as
tetrahydrofuran or N,N-dimethylformamide.
0 0
N N
C)(R3"' ~~(R3"

R$ R$
R X'H ~ N
(V) L~ I NIL2 R1'X1 ~ N~~2
R6 R R6 R7
(XVI) (XV)
A compound of formula (XV), wherein X=-SCR6R7-, may be prepared by the
reaction of a compound of formula (XVI), wherein L1 is a leaving group (such
as halo, tosyl,
mesyl etc.), with thiourea in a suitable solvent such as ethanol to generate a
compound of
formula (XVII) which is then subsequently reacted with a compound of formula
(II) in the
1s presence of a suitable base such as sodium hydroxide and a solvent such as
N,N-
dimethylformamide.
0 0
C ~(R3m (0) (R3m R L' ` ) (R3)m
SH N N (II) N
0- s ~ s
N
H 2 N N H R - N R - N R -
L I N~L2 H2NUS N~~2 RI.S N~L2
Rs R~ INI ~s R7 R6 R7
(XVI) (XVI I) (XV)
A compound of formula (XV), wherein X=-S(O)zCR6~-, may be prepared by the
reaction of a compound of formula (XVIII), wherein X=-S(O)zCHz-, with a
compound of
formula (VII), wherein R6 & 7 is a 2 to 9 membered, optionally substituted,
alkylene chain in
which 1 carbon may be optionally replaced with 0, N or S, and wherein L1 is a
leaving group
(such as halo, tosyl, mesyl etc.), in the presence of a suitable base such as
sodium hydride or


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potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or N,N-
dimethylformamide, or by using aqueous sodium hydroxide solution and DCM as a
solvent
with a suitable phase transfer agent such as tetrabutylammonium bromide.
0 0
C )(R3"' ` )(R3"'
L? R6&~ N N
~ R$
R
O O ~NI O NI
8
(VII) R1.S I NJ, ~2 R~.S I NJ~L2
(XVIII) R6 R7 (XV)

s A compound of formula (XV), wherein X=-S(O)zCR6~-, may be prepared by the
reaction of a compound of formula (XVIII), wherein X=-S(O)zCHz-, with a
compound of
formula (IX), wherein R6 6& is a 2 to 9 membered, optionally substituted,
alkylene chain in
which 1 carbon may be optionally replaced with 0, N or S, and wherein L1 is a
leaving group
(such as halo, tosyl, mesyl etc.), and L3 is a group which can be transformed
to a suitable
io leaving group (such as halo, tosyl, mesyl) at a later stage, to give a
compound of formula (XIX)
in the presence of a suitable base such as sodium hydride or potassium tert-
butoxide in a
suitable solvent such as tetrahydrofuran or N,N-dimethylformamide, or by using
aqueous
sodium hydroxide solution and DCM as a solvent with a suitable phase transfer
agent such as
tetrabutylammonium bromide, and subsequently converting L3 to an appropriate
leaving group
is (such as halo, tosyl, mesyl etc.) and then exposing to a suitable base such
as sodium hydride or
potassium tert-butoxide in a suitable solvent such as tetrahydrofuran or N,N-
dimethylformamide, or by using aqueous sodium hydroxide solution and DCM as a
solvent
with a suitable phase transfer agent such as tetrabutylammonium bromide.
0l 0 0
L' R3 s7 ~ N *(R3m C N }(R3m \~ ~(R3m
` / N
s 0' s $
(IX) O O I~N O O I- N ~ O p I
R~.S N~L2 R~.S N~L2 RNL2
(XVI I I) Rs ~` 7 Rs 7L3 (XIX) (XV)

20 A compound of formula (XV), wherein R'X = HOCR6~-, may be prepared by the
reaction of a compound of formula (XX), with suitable organometallic reagent
of fomula (XII)
wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in
which 1 carbon
may be optionally replaced with 0, N or S, such as the grignard reagent in a
suitable solvent.


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0 0
C )(R3"' (}(R3"
M-Rss ~ N N
M R$ I~NI R$ I~NI
(XII) R.O N%~L2 HO NJ,L2
O (XX) Rs R (XV)

A compound of formula (XV), wherein R'X = HOCR6~-, may be prepared by the
reaction of a compound of formula (XX), with suitable organometallic reagent
of fomula (XIII)
wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in
which 1 carbon
s may be optionally replaced with 0, N or S, and M1 is a group which can be
transformed into a
suitable organometallic reagent (such as a grignard reagent) at a later date,
such as the grignard
reagent in a suitable solvent, to give a compound of formula (XXI), and then
subsequent
conversion of M' to a suitable organometallic reagent and subsequent reaction.

6&7 0 0
M-R ~N~(R3m (0) N(R3m CN}(R3m

1 R I 0 R$ I~ NI R$ I~ NI
(XIII) R.O NJ~L2 HO NJ,L2 HO NJ,L2
O (~) MR s s 7 (XXI) R 6 R7 (XV)

A compound of formula (IV) may be prepared from a compound of formula (XVI),
wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(0)2Me
etc.) and L' is a
leaving group (such as halo, tosyl, mesyl etc.), with a suitable
organometallic reagent (such as
the boronic acid R2B(OH)2 or the boronic ester R2B(OR)2 etc.) in the presence
of a suitable
metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4-
dioxane.
Alternatively where R2 connects to the pyrimidine ring through a nitrogen,
oxygen or sulphur
atom a compound of formula (IV) may be prepared from a compound of formula
(XVI),
wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(0)2Me
etc.), by reaction
with the required amine, alcohol or thiol in the presence of a suitable base
such as potassium
carbonate in a suitable solvent such as N,N-dimethylformamide.
0 0
N N
C~(R3)"' ()(R3"'
s ~ s
~R ~ N ~R ~ \N
L N~L2 L N~R2
Rs R7 Rs R7
(XVI) (IV)


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A compound of formula (XI) may be prepared from a compound of formula (XX),
wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)zMe
etc.) and R is a
hydrogen or C1_4 alkyl group, with a suitable organometallic reagent (such as
the boronic acid
R2 B(OH)z or the boronic ester R2B(OR)2 etc.) in the presence of a suitable
metal catalyst (such
s as palladium or copper) in a suitable solvent such as 1,4-dioxane.
Alternatively where R2
connects to the pyrimidine ring through a nitrogen, oxygen or sulphur atom a
compound of
formula (XI) may be prepared from a compound of formula (XX), wherein L2 is a
leaving
group (such as halo, tosyl, mesyl, -SMe, -S(O)zMe etc.), by reaction with the
required amine,
alcohol or thiol in the presence of a suitable base such as potassium
carbonate in a suitable

io solvent such as N,N-dimethylformamide.
0 0
N N
C)(R3"' () (R3"'
s ~ s
R I R I N
R"C NN ~L2 R"C N~R2
0 (XX) 0 (XI)

A compound of formula (XXII) may be prepared from a compound of formula
(XXIII),
wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)zMe
etc.), with a suitable
organometallic reagent (such as the boronic acid R2B(OH)2 or the boronic ester
R2B(OR)2 etc.)
15 in the presence of a suitable metal catalyst (such as palladium or copper)
in a suitable solvent
such as 1,4-dioxane. Alternatively where R2 connects to the pyrimidine ring
through a nitrogen,
oxygen or sulphur atom a compound of formula (XXII) may be prepared from a
compound of
formula (XXIII), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -
SMe, -S(O)zMe
etc.), by reaction with the required amine, alcohol or thiol in the presence
of a suitable base
20 such as potassium carbonate in a suitable solvent such as N,N-
dimethylformamide.
0 0
N N
C)(R3m ~~(R3m
~
y Y R ~N R ,N

NC NL2 NC NR2
(XXIII) (XXII)
A compound of formula (XXIV) may be prepared from a compound of formula (XXV),
wherein L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -S(O)zMe
etc.), with a suitable
organometallic reagent (such as the boronic acid R2B(OH)2 or the boronic ester
R2B(OR)2 etc.)
25 in the presence of a suitable metal catalyst (such as palladium or copper)
in a suitable solvent


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such as 1,4-dioxane. Alternatively where R2 connects to the pyrimidine ring
through a nitrogen,
oxygen or sulphur atom a compound of formula (XXIV) may be prepared from a
compound of
formula (XXV), wherein L2 is a leaving group (such as halo, tosyl, mesyl, -
SMe, -S(O)zMe
etc.), by reaction with the required amine, alcohol or thiol in the presence
of a suitable base
s such as potassium carbonate in a suitable solvent such as N,N-
dimethylformamide.
0 0
C~(R3m ()(R3m
N N
s s
R N ~ R ~N
L2 I N~L2 L2 I NR2
(XXV) (XXIV)
A compound of formula (I), wherein L1 is a leaving group (such as halo, tosyl,
mesyl
etc.), may be prepared by the reaction of a compound of formula (XXVI) with a
compound of
formula (XXVII) optionally in the presence of a suitable base such as
triethylamine in a

io suitable solvent such as N,N-dimethylformamide. 1 (0) (R3m

L N
Y
)
0 30
() (R3`" R NI R ~ N
RX I NJ, Rz RI X N~R2
H

(XXVII) (XXVI) (1)

It will be appreciated that a compound of formula (XXV) may be transformed
into
another compound of formula (XXV) by techniques such as oxidation, alkylation,
reductive
amination etc., either listed above or otherwise known in the literature.
is A compound of formula (IV), wherein L1 is a leaving group (such as halo,
tosyl, mesyl
etc.), may be prepared by the reaction of a compound of formula (XXVIII) with
a compound of
formula (XXVII) optionally in the presence of a suitable base such as
triethylamine in a
suitable solvent such as N,N-dimethylformamide.
0
C}(R3m
L N

0 8
()(R3" R \ NI R I~ NI
N L NJ~R2 L NR2
H R6 R7 Rs R
(XXVII) (XXVIII) (IV)
20 A compound of formula (XI), wherein R is a hydrogen or a C1_4 alkyl group,
may be
prepared by the reaction of a compound of formula (XXIX), wherein L1 is a
leaving group
(such as halo, tosyl, mesyl etc.) with a compound of formula (XXVII)
optionally in the


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presence of a suitable base such as triethylamine in a suitable solvent such
as N,N-
dimethylformamide. (0} (R3m

L N

O 8 8
() (R3)m R NI ~ R NI
H R.O I NJ~R2 R.O I NJ~R2
(XXVII) 0 (XXIX) 0 (XI)

A compound of formula (XXII) may be prepared by the reaction of a compound of
s formula (XXX), wherein L1 is a leaving group (such as halo, tosyl, mesyl
etc.), with a
compound of formula (XXVII) optionally in the presence of a suitable base such
as
triethylamine in a suitable solvent such as N,N-dimethylformamide.
0
( )(R3)"
N
CO~(R3"' $ L $ ~
R ~ R
H ~ ~ ~
(XXVII) NC N R2 NC N R2
(XXX) (XXII)
A compound of formula (XXIV), wherein L2 is a leaving group (such as halo,
tosyl,
io mesyl, -SMe, -S(O)zMe etc.), may be prepared by the reaction of a compound
of formula
(XXXI), wherein L' is a leaving group (such as halo, tosyl, mesyl etc.) with a
compound of
formula (XXVII) optionally in the presence of a suitable base such as
triethylamine in a
suitable solvent such as N,N-dimethylformamide.
0
O C ) (R3m
C ~(R3)m L~ N
s s
H R ~N R ~N
(XXVII) L2 I NR2 L2 I N-'JIR2
(XXXI) (XXIV)
is A compound of formula (XV), wherein L2 is a leaving group (such as halo,
tosyl,
mesyl, -SMe, -S(O)zMe etc.), may be prepared by the reaction of a compound of
formula
(XXXII), wherein L' is a leaving group (such as halo, tosyl, mesyl etc.) with
a compound of
formula (XXVII) optionally in the presence of a suitable base such as
triethylamine in a
suitable solvent such as N,N-dimethylformamide.


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0
C }(R3m
L N
8
N R ~ N
H R X I N~~2 RX I N-1j,L2
(XXVII) (XXXII) (XV)
It will be appreciated that a compound of formula (XXXII) may be transformed
into
another compound of formula (XXXII) by techniques such as oxidation,
alkylation, reductive
amination etc., either listed above or otherwise known in the literature.
s A compound of formula (XVI), wherein L1 is a leaving group (such as halo,
tosyl,
mesyl etc.) and L2 is a leaving group (such as halo, tosyl, mesyl, -SMe, -
S(O)zMe etc.), may be
prepared by the reaction of a compound of formula (XXXIII) with a compound of
formula
(XXVII) optionally in the presence of a suitable base such as triethylamine in
a suitable solvent
such as N,N-dimethylformamide.
0
C)(R3m
L N
8 8
~
( )(R3m
L R N~L 2 L
N R NL 2
H Rs R7 Rs R
(xxVI 1) (XXXIII) (XVI)
A compound of formula (XX), wherein L2 is a leaving group (such as halo,
tosyl,
mesyl, -SMe, -S(O)zMe etc.) and R is a hydrogen or a C1_4 alkyl group, may be
prepared by the
reaction of a compound of formula (XXXIV), wherein L1 is a leaving group (such
as halo,
tosyl, mesyl etc.) with a compound of formula (XXVII) optionally in the
presence of a suitable
is base such as triethylamine in a suitable solvent such as N,N-
dimethylformamide.
0
C } (R3m
L N

O 8 8
C~(R3)m R NI R NI
H R.O N%~~2 R.O NJ~L2
(XXVII) O (XXXIV) O (XX)

A compound of formula (XXIII), wherein L2 is a leaving group (such as halo,
tosyl,
mesyl, -SMe, -S(O)zMe etc.), may be prepared by the reaction of a compound of
formula
(XXXV), wherein L' is a leaving group (such as halo, tosyl, mesyl etc.) with a
compound of
formula (XXVII) optionally in the presence of a suitable base such as
triethylamine in a
suitable solvent such as N,N-dimethylformamide.


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0
C ~(R3)"
N
CC~(R3"' $ L $ ~
R R
H ~ I ~ ~
(XXVII) NC N%,L2 NC N L2
(XXXV) (XXIII)

A compound of formula (XXV), wherein L2 is a leaving group (such as halo,
tosyl,
mesyl, -SMe, -S(O)zMe etc.), may be prepared by the reaction of a compound of
formula
(XXXVI), wherein L' is a leaving group (such as halo, tosyl, mesyl etc.), with
a compound of
s formula (XXVII) optionally in the presence of a suitable base such as
triethylamine in a
suitable solvent such as N,N-dimethylformamide.

O
(R3m
O
C ~(R3)m L~ s s
H R ~N ~ R ~N
(XXVII) L2 I N5 L2 L2 NL2
(XXXVI) (XXV)

A compound of formula (XXXVII), wherein R'X = H2NC(O)-, may be prepared from a
compound of formula (XXII) by hydrolysis with, for example, sodium hydroxide
in a suitable
io solvent such as a water ethanol mix.
0
C0~(R3m (N~(R3m
N $
R N R
H 2 N NR2
NC N R2
(XXII) 0 (XXXVII)

A compound of formula (I), wherein R'X = H2NCR6R7-, may be prepared by the
reaction of a compound of formula (XXII), with suitable organometallic reagent
of fomula
(XII) wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene
chain in which 1
is carbon may be optionally replaced with 0, N or S, such as the grignard
reagent or alkyl lithium
reagent in a suitable solvent.
0 0
C )(R3"' (}(R3"'
M-R68 ~ N N
M R$ ~N R$ ~N
(XII) NC I N~R2 H2N I N~R2
(XXII) R6 R7 (I)


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A compound of formula (XV), wherein R'X = H2NCR6~-, may be prepared by the
reaction of a compound of formula (XXIII), with suitable organometallic
reagent of fomula
(XII) wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene
chain in which 1
carbon may be optionally replaced with 0, N or S, such as the grignard reagent
or alkyl lithium
s reagent in a suitable solvent.
0 0
C )(R3)"' ` )(R3"'
M-R68 ~ N N
M R$ ~N R$ I- N
(XII) NC N-1j, L2 H 2 N N-1j,L2
(XXIII) R R (XV)

A compound of formula (VIII) may be prepared by the reaction of a compound of
formula (XXXVIII), wherein L1 is a leaving group (such as halo, tosyl, mesyl
etc.), with a
compound of formula (V), wherein Xi = -S-, -SOz-, optionally in the presence
of a suitable
io base such as triethylamine and a solvent such as tetrahydrofuran or N,N-
dimethylformamide. In
the case where X' = -SH a subsequent oxidation step, for example by using
Oxone at room
temperature in a solvent system of water and ethanol, or for example by using
3-
chloroperbenzoic acid with dichloromethane as solvent will be required.
0 0
N N
C)(R3m ~~(R3m

R$ ~ $
R X'H I~NI p p N
(V) L NJ~R2 R~.S NR2

(XXXVI I I) (VI I I)

15 A compound of formula (VIII) may be prepared by the reaction of a compound
of
formula (XXXVIII), wherein L1 is a leaving group (such as halo, tosyl, mesyl
etc.), with
thiourea in a suitable solvent such as ethanol to generate a compound of
formula (XXXIX)
which is then subsequently reacted with a compound of formula (II) in the
presence of a
suitable base such as sodium hydroxide and a solvent such as N,N-
dimethylformamide, and
20 subsequently oxidised, for example by using Oxone at room temperature in a
solvent system
of water and ethanol, or for example by using 3-chloroperbenzoic acid with
dichloromethane as
solvent.


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0 0 0
C~(R3m C}(R3m R1 L1 C}(R3)m
SH N N (II) N
,ill R$ $ ~ $
H2N NH I~ N R I~ NI Oxidation O; O NI
L NJ~R2 H2NUS NJ~Rz R1.S NJ,R2
(XXXVIII) INI NH (XXXIX) (VIII)

A compound of formula (XVIII), wherein L2 is a leaving group (such as halo,
tosyl
mesyl, -SMe, -S(O)zMe etc.), may be prepared by the reaction of a compound of
formula (XL),
wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with a
compound of formula
s(V), wherein Xl = -S-, -SOz-, optionally in the presence of a suitable base
such as triethylamine
and a solvent such as tetrahydrofuran or N,N-dimethylformamide. In the case
where Xl =-S- a
subsequent oxidation step, for example by using Oxone at room temperature in
a solvent
system of water and ethanol, or for example by using 3-chloroperbenzoic acid
with
dichloromethane as solvent will be required.
0 0
N N
C) (R3m ~~(R3m

R$ R$
R X'H I~N O, ,O I~N
(V) L N~L2 R1'S N-1j,L2

(XL) (XVI I I)

A compound of formula (XVIII), wherein L2 is a leaving group (such as halo,
tosyl
mesyl, -SMe, -S(O)zMe etc.), may be prepared by the reaction of a compound of
formula (XL),
wherein L1 is a leaving group (such as halo, tosyl, mesyl etc.), with thiourea
in a suitable
solvent such as ethanol to generate a compound of formula (XLI) which is then
subsequently
reacted with a compound of formula (II) in the presence of a suitable base
such as sodium
hydroxide and a solvent such as N,N-dimethylformamide, and subsequently
oxidised, for
example by using Oxone at room temperature in a solvent system of water and
ethanol, or for
example by using 3-chloroperbenzoic acid with dichloromethane as solvent.
0 0
C~(R3m (0) (R3m R1 L1 C}(R3)m
SH N N (II) N
R
R$ R
$ $
H2N NH N NI Oxidation O. ;O NI
L N~L2 H2NUS NL2 R~S NL2
NIH
(XL) I (XLI) (XVIII)

It will be appreciated that the substituent R' present in a compound of
formula (I) and
formula (XV) can be transformed into another substituent R' by a series of
chemical


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transformations known in the literature, such as oxidation, reduction,
nucleophilic or
electrophilic reactions, addition and elimination reactions. An example of
such a
transformation would be the reaction of a compound of formula (XLII), wherein
L2 is a leaving
group (such as halo, tosyl mesyl, -SMe, -S(O)zMe etc.), with an electrophile
such as dimethyl
s carbonate in the presence of a base such as sodium hydride in a suitable
solvent such as
tetrahydrofuran, followed by a reduction, such as the conversion to a mixed
anhydride
followed by treatment with a hydride source, to give a compound of formula
(XLIII)
0 0 0
0 ~N~(R3m (N)(R3m (N~(R3m
8 8 8
Me0 OMe
O. N O O..O IN O O IN
N~L2 ~O N~L2 HO~"S N~L2
(XLII) (XLI I I)
It will be appreciated that the R2group may be introduced and subsequently
converted
io to another group of the formula R2 at a subsequent stage in the synthesis
using methods known
in the literature. For example, but not limited to, an R2 containing an alkyl
or aryl amine (which
may be suitably protected as, for example, a nitro or t-butoxycarbamate) may
be introduced at
any stage and then converted, for instance, to a urea by reaction with a
suitable isocyanate (or
by activation to a suitable group, such as isocyanate or phenoxycarbamate, and
subsequent
15 reaction with an amine); or to a thiourea by reaction with a suitable
isothiocyanate (or by
activation to a suitable group, such as an isothiocyanate, and subsequent
reaction with an
amine); or to an amide or sulphonamide by reaction with a suitably activated
carboxylic acid or
sulphonic acid derivative; or by other methods known in the literature.
It will be appreciated that where R6 and R7, together with the carbon to which
they are
2o attached, form a 3-10 membered heterocyclic ring containing a nitrogen atom
that the nitrogen
atom may be suitably protected (for example a t-butoxycarbamate or benzyl
group) and that the
protecting group may be removed and if necessary a further reaction performed
on the nitrogen
(for example an alkylation, reductive amination or amidation) at any stage in
the synthesis.
A compound of formula (XLV) may be prepared by the reaction of an amine of
formula
25 R1R4NH with a compound of formula (XLIV) in the presence of a suitable
coupling agent,
such as HATU, or following suitable activation of (XLIV), such as the
conversion to an acid
chloride.


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O O

R ~N~(R3m (N)(R3m
R4'NH OR$ ~ N ~ OR$ N

HO I N~R2 R"N I N~R2
R6 R7 Ra R6 R
(XLIV) (XLV)

A compound of formula (XLIV) may be prepared from a compound of formula (XLVI)
by hydrolysis, for example with sodium hydroxide in a suitable solvent such as
an
ethanol:water mix.

o
N N
C )(R3"' ()(R3m

s $
R ~N OR ~N
NC I N)'R2 HO N~R2
R6 R7 R6 R7
(XLVI) (XLIV)

A compound of formula (XLVII) may be prepared by the reaction of an amine of
formula R1R4NH with a compound of formula (XLVIII) in the presence of a
suitable coupling
agent, such as HATU, or following suitable activation of (XLVIII), such as the
conversion to
an acid chloride.
0 0
R~ ~~(R3m (N)(R3m
R4'NH OR$ N 'N R$
~ I
HO 2
N R R~ N N~R2
(XLVIII) R4 (XLVII)

A compound of formula (XLIX) may be prepared from a compound of formula
(XLVIII) by hydrolysis, for example with sodium hydroxide in a suitable
solvent such as an
ethanol:water mix.

o
C N )(R3"' (N )(R3m
s $
R ~N w OR N
NC I NR2 HO NR2
(XLIX) (XLVIII)

1s A compound of formula (L), wherein Y = R1R4NC(O)-, ROC(O)-, NC-, may be
prepared by the reaction of a compound of formula (VIII) with a compound of
formula (LI),
wherein R6 & 7 is a 2 to 9 membered, optionally substituted, alkylene chain in
which 1 carbon


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may be optionally replaced with 0, N or S, and wherein L1 is a leaving group
(such as halo,
tosyl, mesyl etc.), in the presence of a suitable base such as sodium hydride
or potassium tert-
butoxide in a suitable solvent such as tetrahydrofuran or N,N-
dimethylformamide, or by using
aqueous sodium hydroxide solution and DCM as a solvent with a suitable phase
transfer agent
s such as tetrabutylammonium bromide.

o
C ~(R3"' (0) (R3"
L Rss~ N N
I1 8 $
L R N R ~N
(VIII) Y I N~Rz Y N' Rz
Rs
(LI) R7 (L)
A compound of formula (LI), wherein Y = NC-, HOC(O)-, may be prepared by the
reaction of a compound of formula (XXXVIII) with a suitable nucleophile, such
as for example
sodium cyanide or for example tris(phenylthio)methane anion followed by a
suitable
io hydrolysis.
0 0
C N )(R3"' ( N )(R3m
R$ $
~
~ \N ~ R I \N
L N R2 y NR2
(XXXVIII) (LI)

A compound of formula (LII), wherein L2 is a leaving group (such as halo,
tosyl, mesyl,
trifluoromethylsulphonyl, -SMe, -S(0)2Me etc.), may be prepared by the
reaction of an amine
of formula R1R4NH with a compound of formula (LIII) in the presence of a
suitable coupling
is agent, such as HATU, or following suitable activation of (LIII), such as
the conversion to an
acid chloride.
0 0
R~ ~N" (R3m (N)(R3m
R4'NH OR$ ~ N ~R$

HO NL2 R"N I N-L2
R6 R7 Ra R6 R7
(LIII) (LII)

A compound of formula (LIII), wherein L2 is a leaving group (such as halo,
tosyl,
mesyl, trifluoromethylsulphonyl, -SMe, -S(0)2Me etc.), may be prepared from a
compound of
20 formula (LIV) by hydrolysis, for example with sodium hydroxide in a
suitable solvent such as
an ethanol:water mix.


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o ~
N N
C) (R3"' ~~(R3m
s $
R N ~ OR I ~N
NC I N%,L2 HO N--L2
R6 R~ 6 7
(LIV) (LIII)

A compound of formula (LV), wherein L2 is a leaving group (such as halo,
tosyl,
mesyl, trifluoromethylsulphonyl, -SMe, -S(O)zMe etc.), may be prepared by the
reaction of an
amine of formula R1R4NH with a compound of formula (LVI) in the presence of a
suitable
s coupling agent, such as HATU, or following suitable activation of (LVI),
such as the
conversion to an acid chloride.
0 0
R ~N~(R3"' (N~(R3m
R4'NH OR$ N W. OR$ N
HO N~L2 R" N I NJ, L2
(LVI) R4 (LV)

A compound of formula (LVI), wherein L2 is a leaving group (such as halo,
tosyl,
mesyl, trifluoromethylsulphonyl, -SMe, -S(O)zMe etc.), may be prepared from a
compound of
io formula (LVII) by hydrolysis, for example with sodium hydroxide in a
suitable solvent such as
an ethanol:water mix.
~
(0) N (R3"' (N ) (R3m
s $
R ~N w OR N
NC I N%, L2 HO N-1j,L2
(LVII) (LVI)
A compound of formula (LVIII), wherein Y RiR4NC(O)-, ROC(O)-, NC-, and L2 is a
leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -
S(O)zMe etc.),
15 may be prepared by the reaction of a compound of formula (VIII) with a
compound of formula
(LIX), wherein R6 6& is a 2 to 9 membered, optionally substituted, alkylene
chain in which 1
carbon may be optionally replaced with 0, N or S, and wherein L1 is a leaving
group (such as
halo, tosyl, mesyl etc.), in the presence of a suitable base such as sodium
hydride or potassium
tert-butoxide in a suitable solvent such as tetrahydrofuran or N,N-
dimethylformamide, or by
20 using aqueous sodium hydroxide solution and DCM as a solvent with a
suitable phase transfer
agent such as tetrabutylammonium bromide.


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0
C ~(R3"' (0) (R3"'
L Rss~ N N

I1 L R ~N ~~N'j, N
(V III) ~' N1Lz Y Lz
(LIX) R7 (LVIII)
Rs
A compound of formula (LIX), wherein Y = NC-, HOC(O)-, and L2 is a leaving
group
(such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)zMe etc.),
may be prepared
by the reaction of a compound of formula (XL) with a suitable nucleophile,
such as for
s example sodium cyanide or for example tris(phenylthio)methane anion followed
by a suitable
hydrolysis.
0 0
CN) (R3) ' (N) (R3)m
R$ $
I 'N ~ R I ~N
L N Lz Y NLz
(XL) (LIX)
A compound of formula (L), wherein Y NC-, ROC(O)-, may be prepared by the
reaction of a compound of formula (XXVII) with a compound of formula (LX),
wherein L2 is a
io leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -
S(O)zMe etc.),
optionally in the presence of a suitable base such as triethylamine in a
suitable solvent such as
N,N-dimethylformamide.

z 0
L CN) (R3m
O
()(R3 R$ 'N R$ N
H Y I NRz Y I NJ~Rz
Rs R Rs R7
(XXVII) (LX) (L)

A compound of formula (LX), wherein Y = NC-, ROC(O)-, and L2 is a leaving
group
is (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)zMe etc.)
may be prepared
by the reaction of a compound of formula (LXI) with a compound of formula
(LXII) and
subsequent conversion of the OH group to a suitable leaving group, such as by
reaction with N-
phenyltrifluoromethanesulfonimide in the presence of a suitable base such as
DBU and a
suitable solvent such as dichloromethane.


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p,R pH L2
$
R$ p NIIH ~ R N R ~N
xIi
Ys p H2NxR2 R N~R Y N~R2
R (LXI) (LXII) s Rs R7 (LX)

A compound of formula (LI), wherein Y NC-, ROC(O)-, may be prepared by the
reaction of a compound of formula (XXVII) with a compound of formula (LXIII),
wherein L2
is a leaving group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -
SMe, -S(O)zMe etc.),
s optionally in the presence of a suitable base such as triethylamine in a
suitable solvent such as
N,N-dimethylformamide.
0
)(R3)"'
L2 C N

C~(R3)", :~~;' N R$ "N
H Y ,R2 Y IN/,R2
(XXVII) (LXIII) (LI)

A compound of formula (LXIII), wherein Y = NC-, ROC(O)-, and L2 is a leaving
group
(such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)zMe etc.)
may be prepared
io by the reaction of a compound of formula (LXIV) with a compound of formula
(LXII) and
subsequent conversion of the OH group to a suitable leaving group, such as by
reaction with N-
phenyltrifluoromethanesulfonimide in the presence of a suitable base such as
DBU and a
suitable solvent such as dichloromethane.

p,R pH L2
R
O NH \N ~ R " N
Y p H2N~R2 YR$N~11R2 Y N-11,R2
(LXIV) (LXII) (LXIII)

is A compound of formula (LVIII), wherein Y = NC-, ROC(O)-, and L2 is a
leaving group
(such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)zMe etc.)
may be prepared
by the reaction of a compound of formula (XXVII) with a compound of formula
(LXV),
wherein L2 is a leaving group (such as halo, tosyl, mesyl,
trifluoromethylsulphonyl, -SMe, -
S(O)zMe etc.), optionally in the presence of a suitable base such as
triethylamine in a suitable
20 solvent such as N,N-dimethylformamide.


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2 0
L CN)(R3m
O
C~(R3) R$ NI R$ 'N
H ~' INJ~L2 Y N/~L2
(XXVII) Rs R~ Rs R~
(LXV) (LVIII)

A compound of formula (LXV), wherein Y = NC-, ROC(O)-, and L2 is a leaving
group
(such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)zMe etc.)
may be prepared
by the reaction of a compound of formula (LXI) with a compound of formula
(LXVI) and
s subsequent conversion of the OH group to a suitable leaving group, such as
by reaction with N-
phenyltrifluoromethanesulfonimide in the presence of a suitable base such as
DBU and a
suitable solvent such as dichloromethane.

O,R OH L2
R$ s
O NH ~ IN R 'N

Ys ~ O H2N~L2 N~L Y NL2
R (LXI) (LXVI) R sR 71
Rs R7 (LXV)

A compound of formula (LIX), wherein Y NC-, ROC(O)-, and L2 is a leaving group
io (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)zMe etc.)
may be prepared
by the reaction of a compound of formula (XXVII) with a compound of formula
(LXVII),
wherein L2 is a leaving group (such as halo, tosyl, mesyl,
trifluoromethylsulphonyl, -SMe, -
S(O)zMe etc.), optionally in the presence of a suitable base such as
triethylamine in a suitable
solvent such as N,N-dimethylformamide.
0
) (R3"'
0 L2 CN
C (R)m
3 $ R ~N ~ :~N
I H Y I N'L2 Y NJ1L2

(XXVII) (LXVII) (LIX)
)
A compound of formula (LXVII), wherein Y = NC-, ROC(O)-, and L2 is a leaving
group (such as halo, tosyl, mesyl, trifluoromethylsulphonyl, -SMe, -S(O)zMe
etc.) may be
prepared by the reaction of a compound of formula (LXIV) with a compound of
formula
(LXVI) and subsequent conversion of the OH group to a suitable leaving group,
such as by
2o reaction with N-phenyltrifluoromethanesulfonimide in the presence of a
suitable base such as
DBU and a suitable solvent such as dichloromethane.


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p,R pH L2
$
R$ p NH ~ Rs~1N ~ R N
Y p H2N~L2 Y N `L2 Y N J,L2

(LXIV) (LX-VI) (LXVII)

It will be appreciated that certain of the various ring substituents in the
compounds of
the present invention may be introduced by standard aromatic substitution
reactions or
generated by conventional functional group modifications either prior to or
immediately
s following the processes mentioned above, and as such are included in the
process aspect of the
invention. For example compounds of formula (I) may be converted into further
compounds of
formula (I) by standard aromatic substitution reactions or by conventional
functional group
modifications. Such reactions and modifications include, for example,
introduction of a
substituent by means of an aromatic substitution reaction, reduction of
substituents, alkylation
io of substituents and oxidation of substituents. The reagents and reaction
conditions for such
procedures are well known in the chemical art. Particular examples of aromatic
substitution
reactions include the introduction of a nitro group using concentrated nitric
acid, the
introduction of an acyl group using, for example, an acyl halide and Lewis
acid (such as
aluminium trichloride) under Friedel Crafts conditions; the introduction of an
alkyl group using
is an alkyl halide and Lewis acid (such as aluminium trichloride) under
Friedel Crafts conditions;
and the introduction of a halogen group. Particular examples of modifications
include the
reduction of a nitro group to an amino group by for example, catalytic
hydrogenation with a
nickel catalyst or treatment with iron in the presence of hydrochloric acid
with heating;
oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.
20 It will also be appreciated that in some of the reactions mentioned herein
it may be
necessary/desirable to protect any sensitive groups in the compounds. The
instances where
protection is necessary or desirable and suitable methods for protection are
known to those
skilled in the art. Conventional protecting groups may be used in accordance
with standard
practice (for illustration see T.W. Green, Protective Groups in Organic
Synthesis, John Wiley
25 and Sons, 1991). Thus, if reactants include groups such as amino, carboxy
or hydroxy it may
be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example,
an acyl
group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group,
for example a
methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an
arylmethoxycarbonyl


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group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
The
deprotection conditions for the above protecting groups necessarily vary with
the choice of
protecting group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl
group or an aroyl group may be removed for example, by hydrolysis with a
suitable base such
s as an alkali metal hydroxide, for example lithium or sodium hydroxide.
Alternatively an acyl
group such as a tert-butoxycarbonyl group may be removed, for example, by
treatment with a
suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic
acid and an
arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed,
for example,
by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment
with a Lewis
io acid for example boron tris(trifluoroacetate). A suitable alternative
protecting group for a
primary amino group is, for example, a phthaloyl group which may be removed by
treatment
with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl
group, for
example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl,
or an
is arylmethyl group, for example benzyl. The deprotection conditions for the
above protecting
groups will necessarily vary with the choice of protecting group. Thus, for
example, an acyl
group such as an alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with
a suitable base such as an alkali metal hydroxide, for example lithium or
sodium hydroxide.
Alternatively an arylmethyl group such as a benzyl group may be removed, for
example, by
2o hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an
esterifying group,
for example a methyl or an ethyl group which may be removed, for example, by
hydrolysis
with a base such as sodium hydroxide, or for example a tert-butyl group which
may be
removed, for example, by treatment with an acid, for example an organic acid
such as
25 trifluoroacetic acid, or for example a benzyl group which may be removed,
for example, by
hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis
using
conventional techniques well known in the chemical art.
Many of the intermediates defined herein are novel and these are provided as a
further
30 feature of the invention.
Biological Assays


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The following assays can be used to measure the effects of the compounds of
the
present invention as mTOR kinase inhibitors, as P13 kinase inhibitors, as
inhibitors in vitro of
the activation of P13 kinase signalling pathways and as inhibitors in vitro of
the proliferation of
MDA-MB-468 human breast adenocarcinoma cells.

s(a)(i) In Vitro mTOR Kinase Assay
The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry,
2003,
313: 234-245) to determine the ability of test compounds to inhibit
phosphorylation by
recombinant mTOR.
A C-terminal truncation of mTOR encompassing amino acid residues 1362 to 2549
of
io mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-tagged
fusion in
HEK293 cells as described by Vilella-Bach et al., Journal of Biochemistry,
1999, 274, 4266-
4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely
maintained at 37 C with 5% COz up to a confluency of 70-90% in Dulbecco's
modified Eagle's
growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No. 41966-029)
is containing 10% heat-inactivated foetal calf serum (FCS; Sigma, Poole,
Dorset, UK, Catalogue
No. F0392), 1% L-glutamine (Gibco, Catalogue No. 25030-024) and 2 mg/ml
Geneticin (G418
sulfate; Invitrogen Limited, UK Catalogue No. 10131-027). Following expression
in the
mammalian HEK293 cell line, expressed protein was purified using the FLAG
epitope tag
using standard purification techniques.
20 Test compounds were prepared as 10 mM stock solutions in DMSO and diluted
into
water as required to give a range of final assay concentrations. Aliquots (2
l) of each
compound dilution were placed into a well of a Greiner 384-well low volume
(LV) white
polystyrene plate (Greiner Bio-one). A 30 l mixture of recombinant purified
mTOR enzyme,
1 M biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-
Leu-Gly-Phe-

25 Thr-Tyr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH2; Bachem UK Ltd),
ATP (20
M) and a buffer solution [comprising Tris-HC1 pH7.4 buffer (50 mM), EGTA (0.1
mM),
bovine serum albumin (0.5 mg/mL), DTT (1.25 mM) and manganese chloride (10
mM)] was
agitated at room temperature for 90 minutes.
Control wells that produced a maximum signal corresponding to maximum enzyme
3o activity were created by using 5% DMSO instead of test compound. Control
wells that
produced a minimum signal corresponding to fully inhibited enzyme were created
by adding


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EDTA (83 mM) instead of test compound. These assay solutions were incubated
for 2 hours at
room temperature.

Each reaction was stopped by the addition of 10 l of a mixture of EDTA (50
mM),
bovine serum albumin (BSA; 0.5 mg/mL) and Tris-HC1 pH7.4 buffer (50 mM)
containing
s p70 S6 Kinase (T389) lA5 Monoclonal Antibody (Cell Signalling Technology,
Catalogue
No. 9206B) and AlphaScreen Streptavidin donor and Protein A acceptor beads
(200 ng; Perkin
Elmer, Catalogue No. 6760002B and 6760137R respectively) were added and the
assay plates
were left for about 20 hours at room temperature in the dark. The resultant
signals arising from
laser light excitation at 680 nm were read using a Packard Envision
instrument.
Phosphorylated biotinylated peptide is formed in situ as a result of mTOR
mediated
phosphorylation. The phosphorylated biotinylated peptide that is associated
with AlphaScreen
Streptavidin donor beads forms a complex with the p70 S6 Kinase (T389) lA5
Monoclonal
Antibody that is associated with Alphascreen Protein A acceptor beads. Upon
laser light
excitation at 680 nm, the donor bead : acceptor bead complex produces a signal
that can be
measured. Accordingly, the presence of mTOR kinase activity results in an
assay signal. In
the presence of an mTOR kinase inhibitor, signal strength is reduced.
mTOR enzyme inhibition for a given test compound was expressed as an IC50
value.
(a)(ii) In Vitro mTOR Kinase Assay (Echo)
The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry,
2003,
2o 313: 234-245) to determine the ability of test compounds to inhibit
phosphorylation by
recombinant mTOR.
A C-terminal truncation of mTOR encompassing amino acid residues 1362 to 2549
of
mTOR (EMBL Accession No. L34075) was stably expressed as a FLAG-tagged fusion
in
HEK293 cells as described by Vilella-Bach et al., Journal of Biochemistry,
1999, 274, 4266-
4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely
maintained at 37 C with 5% COz up to a confluency of 70-90% in Dulbecco's
modified Eagle's
growth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No. 41966-029)
containing 10% heat-inactivated foetal calf serum (FCS; Sigma, Poole, Dorset,
UK, Catalogue
No. F0392), 1% L-glutamine (Gibco, Catalogue No. 25030-024) and 2 mg/ml
Geneticin (G418
sulfate; Invitrogen Limited, UK Catalogue No. 10131-027). Following expression
in the
mammalian HEK293 cell line, expressed protein was purified using the FLAG
epitope tag
using standard purification techniques.


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Test compounds were prepared as 10 mM stock solutions in DMSO and diluted in
into

waterDMSO as required to give a range of final assay concentrations. Aliquots
(120n12 l) of
each compound dilution were acoustically dispensedplaced using a Labcyte Echo
550 into a
well of a Greiner 384-well low volume (LV) white polystyrene plate (Greiner
Bio-one). A

s 1230 l mixture of recombinant purified mTOR enzyme, 1 M biotinylated
peptide substrate
(Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala-Pro-Ser-
Val-Leu-
Glu-Ser-Val-Lys-Glu-NHz; Bachem UK Ltd), ATP (20 M) and a buffer solution
[comprising
Tris-HC1 pH7.4 buffer (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5
mg/mL), DTT
(1.25 mM) and manganese chloride (10 mM)] was incubated at room temperature
for 12090

io minutes.
Control wells that produced a maximum signal corresponding to maximum enzyme
activity were created by using 1005% DMSO instead of test compound. Control
wells that
produced a minimum signal corresponding to fully inhibited enzyme were created
by adding
LY294002EDTA (100uM83 mM) compound. These assay solutions were incubated for 2
15 hours at room temperature.

Each reaction was stopped by the addition of 510 l of a mixture of EDTA (50
mM),
bovine serum albumin (BSA; 0.5 mg/mL) and Tris-HC1 pH7.4 buffer (50 mM)
containing
p70 S6 Kinase (T389) lA5 Monoclonal Antibody (Cell Signalling Technology,
Catalogue
No. 9206B) and AlphaScreen Streptavidin donor and Protein A acceptor beads
(200 ng; Perkin
2o Elmer, Catalogue No. 6760002B and 6760137R respectively) were added and the
assay plates
were left overnight at room temperature in the dark. The resultant signals
arising from laser
light excitation at 680 nm were read using a Packard Envision instrument.
Phosphorylated biotinylated peptide is formed in situ as a result of mTOR
mediated
phosphorylation. The phosphorylated biotinylated peptide that is associated
with AlphaScreen
25 Streptavidin donor beads forms a complex with the p70 S6 Kinase (T389) lA5
Monoclonal
Antibody that is associated with Alphascreen Protein A acceptor beads. Upon
laser light
excitation at 680 nm, the donor bead : acceptor bead complex produces a signal
that can be
measured. Accordingly, the presence of mTOR kinase activity results in an
assay signal. In
the presence of an mTOR kinase inhibitor, signal strength is reduced.
30 mTOR enzyme inhibition for a given test compound was expressed as an IC50
value.
(b)(i) In Vitro P13K Enzyme Assay


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The assay used A1phaScreen technology (Gray et al., Analytical Biochemistry,
2003,
313: 234-245) to determine the ability of test compounds to inhibit
phosphorylation by
recombinant Type I P13K enzymes of the lipid PI(4,5)P2.

DNA fragments encoding human P13K catalytic and regulatory subunits were
isolated
s from cDNA libraries using standard molecular biology and PCR cloning
techniques. The
selected DNA fragments were used to generate baculovirus expression vectors.
In particular,
full length DNA of each of the pl 10a, pl 10(3 and pl 106 Type Ia human P13K
pl 10 isoforms
(EMBL Accession Nos. HSU79143, S67334, Y10055 for pl 10a, pl 10(3 and pl lOb
respectively) were sub-cloned into a pDEST10 vector (Invitrogen Limited,
Fountain Drive,
io Paisley, UK). The vector is a Gateway-adapted version of Fastbacl
containing a 6-His epitope
tag. A truncated form of Type lb human P13K p1107 isoform corresponding to
amino acid
residues 144-1102 (EMBL Accession No. X8336A) and the full length human p85a
regulatory
subunit (EMBL Accession No. HSPI3KIN) were also sub-cloned into pFastBacl
vector
containing a 6-His epitope tag. The Type Ia pl 10 constructs were co-expressed
with the p85a
15 regulatory subunit. Following expression in the baculovirus system using
standard baculovirus
expression techniques, expressed proteins were purified using the His epitope
tag using
standard purification techniques.
DNA corresponding to amino acids 263 to 380 of human general receptor for
phosphoinositides (Grpl) PH domain was isolated from a cDNA library using
standard
20 molecular biology and PCR cloning techniques. The resultant DNA fragment
was sub-cloned
into a pGEX 4T1 E. coli expression vector containing a GST epitope tag
(Amersham
Pharmacia Biotech, Rainham, Essex, UK) as described by Gray et al., Analytical
Biochemistry,
2003, 313: 234-245). The GST-tagged Cnpl PH domain was expressed and purified
using
standard techniques.
25 Test compounds were prepared as 10 mM stock solutions in DMSO and diluted
into
water as required to give a range of final assay concentrations. Aliquots (2
l) of each
compound dilution were placed into a well of a Greiner 384-well low volume
(LV) white
polystyrene plate (Greiner Bio-one, Brunel Way, Stonehouse, Gloucestershire,
UK Catalogue
No. 784075). A mixture of each selected recombinant purified P13K enzyme (15
ng), DiC8-

30 PI(4,5)P2 substrate (40 M; Cell Signals Inc., Kinnear Road, Columbus, USA,
Catalogue No.
901), adenosine triphosphate (ATP; 4 M) and a buffer solution [comprising
Tris-HC1 pH7.6


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buffer (40 mM, 10 l), 3-[(3-cholamidopropyl)dimethylammonio]-l-
propanesulfonate
(CHAPS; 0.04%), dithiothreitol (DTT; 2 mM) and magnesium chloride (10 mM)] was
agitated
at room temperature for 20 minutes.
Control wells that produced a minimum signal corresponding to maximum enzyme
s activity were created by using 5% DMSO instead of test compound. Control
wells that
produced a maximum signal corresponding to fully inhibited enzyme were created
by adding
wortmannin (6 M; Calbiochem / Merck Bioscience, Padge Road, Beeston,
Nottingham, UK,
Catalogue No. 681675) instead of test compound. These assay solutions were
also agitated for
20 minutes at room temperature.

io Each reaction was stopped by the addition of 10 l of a mixture of EDTA
(100 mM),
bovine serum albumin (BSA, 0.045 %) and Tris-HC1 pH7.6 buffer (40 mM).
Biotinylated-DiC8-PI(3,4,5)P3 (50 nM; Cell Signals Inc., Catalogue No. 107),
recombinant purified GST-Grpl PH protein (2.5 nM) and AlphaScreen Anti-GST
donor and
acceptor beads (100 ng; Packard Bioscience Limited, Station Road, Pangboume,
Berkshire,
is UK, Catalogue No. 6760603M) were added and the assay plates were left for
about 5 to
20 hours at room temperature in the dark. The resultant signals arising from
laser light
excitation at 680 nm were read using a Packard AlphaQuest instrument.

PI(3,4,5)P3 is formed in situ as a result of P13K mediated phosphorylation of
PI(4,5)P2.
The GST-Grpl PH domain protein that is associated with AlphaScreen Anti-GST
donor beads
20 forms a complex with the biotinylated PI(3,4,5)P3 that is associated with
Alphascreen
Streptavidn acceptor beads. The enymatically-produced PI(3,4,5)P3 competes
with
biotinylated PI(3,4,5)P3 for binding to the PH domain protein. Upon laser
light excitation at
680 nm, the donor bead : acceptor bead complex produces a signal that can be
measured.
Accordingly, P13K enzme activity to form PI(3,4,5)P3 and subsequent
competition with
25 biotinylated PI(3,4,5)P3 results in a reduced signal. In the presence of a
P13K enzyme
inhibitor, signal strength is recovered.

P13K enzyme inhibition for a given test compound was expressed as an IC50
value.
(b)(ii) In Vitro P13K Enzyme Assa,y (Echo)
The assay used AlphaScreen technology (Gray et al., Analytical Biochemistry,
2003,
3o 313: 234-245) to determine the ability of test compounds to inhibit
phosphorylation by
recombinant Type I P13K enzymes of the lipid PI(4,5)P2.


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DNA fragments encoding human P13K catalytic and regulatory subunits were
isolated
from cDNA libraries using standard molecular biology and PCR cloning
techniques. The
selected DNA fragments were used to generate baculovirus expression vectors.
In particular,
full length DNA of each of the pl 10a, pl 10(3 and pl lOb Type Ia human P13K
pl 10 isoforms
s(EMBL Accession Nos. HSU79143, S67334, Y10055 for pl 10a, pl 10(3 and pl lOb

respectively) were sub-cloned into a pDEST10 vector (Invitrogen Limited,
Fountain Drive,
Paisley, UK). The vector is a Gateway-adapted version of Fastbacl containing a
6-His epitope
tag. A truncated form of Type lb human P13K p1107 isoform corresponding to
amino acid
residues 144-1102 (EMBL Accession No. X8336A) and the full length human p85a
regulatory

io subunit (EMBL Accession No. HSPI3KIN) were also sub-cloned into pFastBacl
vector
containing a 6-His epitope tag. The Type Ia pl 10 constructs were co-expressed
with the p85a
regulatory subunit. Following expression in the baculovirus system using
standard baculovirus
expression techniques, expressed proteins were purified using the His epitope
tag using
standard purification techniques.
is DNA corresponding to amino acids 263 to 380 of human general receptor for
phosphoinositides (Grpl) PH domain was isolated from a cDNA library using
standard
molecular biology and PCR cloning techniques. The resultant DNA fragment was
sub-cloned
into a pGEX 4T1 E. coli expression vector containing a GST epitope tag
(Amersham
Pharmacia Biotech, Rainham, Essex, UK) as described by Gray et al., Analytical
Biochemistry,
2o 2003, 313: 234-245). The GST-tagged Cnpl PH domain was expressed and
purified using
standard techniques.
Test compounds were prepared as 10 mM stock solutions in DMSO and diluted in
DMSO to wateras required to give a range of final assay concentrations.
Aliquots (120n12 l)
of each compound dilution were acoustically dispensed using a Labcyte Echo 550
placed into
25 a well of a Greiner 384-well low volume (LV) white polystyrene plate
(Greiner Bio-one,
Brunel Way, Stonehouse, Gloucestershire, UK Catalogue No. 784075). A mixture
of each
selected recombinant purified P13K enzyme (15 ng), DiC8-PI(4,5)P2 substrate
(40 M; Cell
Signals Inc., Kinnear Road, Columbus, USA, Catalogue No. 901), adenosine
triphosphate
(ATP; 4 M) and a buffer solution [comprising Tris-HC1 pH7.6 buffer (40 mM, 10
l), 3-[(3-
30 cholamidopropyl)dimethylammonio]-l-propanesulfonate (CHAPS; 0.04%),
dithiothreitol


CA 02692945 2009-12-23
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(DTT; 2 mM) and magnesium chloride (10 mM)] was agitatedincubated at room
temperature
for 20 minutes.
Control wells that produced a minimum signal corresponding to maximum enzyme
activity were created by using 1005% DMSO instead of test compound. Control
wells that
s produced a maximum signal corresponding to fully inhibited enzyme were
created by adding
Wwortmannin (6 M; Calbiochem / Merck Bioscience, Padge Road, Beeston,
Nottingham,
UK, Catalogue No. 681675) instead of test compound. These assay solutions were
also
incubatedagitated for 20 minutes at room temperature.

Each reaction was stopped by the addition of 10 10 1 of a mixture of EDTA (100
mM),
io bovine serum albumin (BSA, 0.045 %) and Tris-HC1 pH7.6 buffer (40 mM).
Biotinylated-DiC8-PI(3,4,5)P3 (50 nM; Cell Signals Inc., Catalogue No. 107),
recombinant purified GST-Grpl PH protein (2.5 nM) and AlphaScreen Anti-GST
donor and
acceptor beads (100 ng; Packard Bioscience Limited, Station Road, Pangbourne,
Berkshire,
UK, Catalogue No. 6760603M) were added and the assay plates were left for
about 5 to
15 overnight
20 hours at room temperature in the dark. The resultant signals arising from
laser light
excitation at 680 nm were read using a Packard AlphaQuest instrument.

PI(3,4,5)P3 is formed in situ as a result of P13K mediated phosphorylation of
PI(4,5)P2.
The GST-Grpl PH domain protein that is associated with AlphaScreen Anti-GST
donor beads
20 forms a complex with the biotinylated PI(3,4,5)P3 that is associated with
Alphascreen
Streptavidn acceptor beads. The enymatically-produced PI(3,4,5)P3 competes
with
biotinylated PI(3,4,5)P3 for binding to the PH domain protein. Upon laser
light excitation at
680 nm, the donor bead : acceptor bead complex produces a signal that can be
measured.
Accordingly, P13K enzme activity to form PI(3,4,5)P3 and subsequent
competition with
25 biotinylated PI(3,4,5)P3 results in a reduced signal. In the presence of a
P13K enzyme
inhibitor, signal strength is recovered.

P13K enzyme inhibition for a given test compound was expressed as an IC50
value.
(c) In Vitro phospho-Ser473 Akt assay
This assay determines the ability of test compounds to inhibit phosphorylation
of
30 Serine 473 in Akt as assessed using Acumen Explorer technology (Acumen
Bioscience
Limited), a plate reader that can be used to rapidly quantitate features of
images generated by
laser-scanning.


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A MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem,
Teddington, Middlesex, UK, Catalogue No. HTB-132) was routinely maintained at
37 C with
5% COz up to a confluency of 70-90% in DMEM containing 10% heat-inactivated
FCS and
1% L-glutamine.
s For the assay, the cells were detached from the culture flask using
`Accutase'
(Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No. AT 104)
using
standard tissue culture methods and resuspended in media to give 1.7x105 cells
per mL.
Aliquots (90 l) were seeded into each of the inner 60 wells of a black
Packard 96 well plate
(PerkinElmer, Boston, MA, USA; Catalogue No. 6005182) to give a density of -
15000 cells

io per well. Aliquots (90 l) of culture media were placed in the outer wells
to prevent edge
effects. The cells were incubated overnight at 37 C with 5% COz to allow them
to adhere.
On day 2, the cells were treated with test compounds and incubated for 2 hours
at 37 C
with 5% COz. Test compounds were prepared as 10 mM stock solutions in DMSO and
serially
diluted as required with growth media to give a range of concentrations that
were 10-fold the

is required final test concentrations. Aliquots (10 l) of each compound
dilution were placed in a
well (in triplicate) to give the final required concentrations. As a minimum
reponse control,
each plate contained wells having a final concentration of 100 M LY294002
(Calbiochem,
Beeston, UK, Catalogue No. 440202). As a maximum response control, wells
contained 1%
DMSO instead of test compound. Following incubation, the contents of the
plates were fixed
2o by treatment with a 1.6% aqueous formaldehyde solution (Sigma, Poole,
Dorset, UK,
Catalogue No. F1635) at room temperature for 1 hour.
All subsequent aspiration and wash steps were carried out using a Tecan 96
well
plate washer (aspiration speed 10 mm/sec). The fixing solution was removed and
the contents
of the plates were washed with phosphate-buffered saline (PBS; 50 l; Gibco,
Catalogue No.
25 10010015). The contents of the plates were treated for 10 minutes at room
temperature with an
aliquot (50 1) of a cell permeabilisation buffer consisting of a mixture of
PBS and 0.5%
Tween-20. The `permeabilisation' buffer was removed and non-specific binding
sites were
blocked by treatment for 1 hour at room temperature of an aliquot (50 1) of a
blocking buffer
consisting of 5% dried skimmed milk ['Marvel' (registered trade mark); Premier
Beverages,
30 Stafford, GB] in a mixture of PBS and 0.05% Tween-20. The `blocking' buffer
was removed
and the cells were incubated for 1 hour at room temperature with rabbit anti
phospho-Akt


CA 02692945 2009-12-23
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(Ser473) antibody solution (50 l per well; Cell Signalling, Hitchin, Herts,
U.K., Catalogue No
9277) that had been diluted 1:500 in `blocking' buffer. Cells were washed
three times in a
mixture of PBS and 0.05% Tween-20. Subsequently, cells were incubated for 1
hour at room
temperature with Alexafluor488 labelled goat anti-rabbit IgG (50 l per well;
Molecular
s Probes, Invitrogen Limited, Paisley, UK, Catalogue No. Al 1008) that had
been diluted 1:500
in `blocking' buffer. Cells were washed 3 times with a mixture of PBS and
0.05% Tween-20.
An aliquot of PBS (50 l) was added to each well and the plates were sealed
with black plate
sealers and the fluorescence signal was detected and analysed.
Fluorescence dose response data obtained with each compound were analysed and
the
io degree of inhibition of Serine 473 in Akt was expressed as an IC50 value.

(d) In Vitro MDA-MB-468 human breast adenocarcinoma Proliferation Assay
This assay determines the ability of test compounds to inhibit cell
proliferation as
assessed using Cellomics Arrayscan technology. A MDA-MB-468 human breast
adenocarcinoma cell line (LGC Promochem, Catalogue No. HTB-132) was routinely
is maintained as described in Biological Assay (b) herein.
For the proliferation assay, the cells were detached from the culture flask
using
Accutase and seeded into the inner 60 wells of a black Packard 96 well plate
at a density of
8000 cells per well in 100 l of complete growth media. The outer wells
contained 100 l of
sterile PBS. The cells were incubated overnight at 37 C with 5% COz to allow
them to adhere.
20 On day 2, the cells were treated with test compounds and incubated for 48
hours at
37 C with 5% COz. Test compounds were prepared as 10 mM stock solutions in
DMSO and
serially diluted as required with growth media to give a range of test
concentrations. Aliquots
(50 l) of each compound dilution were placed in a well and the cells were
incubated for 2
days at 37 C with 5% COz. Each plate contained control wells without test
compound.
25 On day 4, BrdU labelling reagent (Sigma, Catalogue No. B9285) at a final
dilution of
1:1000 was added and the cells were incubated for 2 hours at 37 C. The medium
was removed
and the cells in each well were fixed by treatment with 100 l of a mixture of
ethanol and
glacial acetic acid (90% ethanol, 5% glacial acetic acid and 5% water) for 30
minutes at room
temperature. The cells in each well were washed twice with PBS (100 l).
Aqueous

3o hydrochloric acid (2M, 100 l) was added to each well. After 20 minutes at
room temperature,
the cells were washed twice with PBS. Hydrogen peroxide (3%, 50 l; Sigma,
Catalogue No.


CA 02692945 2009-12-23
WO 2009/007748 PCT/GB2008/050546
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H 1009) was added to each well. After 10 minutes at room temperature, the
wells were washed
again with PBS.
BrdU incorporation was detected by incubation for 1 hour at room temperature
with
mouse anti-BrdU antibody (50 l; Caltag, Burlingame, CA, US; Catalogue No.
MD5200) that
s was diluted 1:40 in PBS containing 1% BSA and 0.05% Tween-20. Unbound
antibody was
removed with two washes of PBS. For visualisation of incorporated BrdU, the
cells were
treated for 1 hour at room temperature with PBS (50 l) and 0.05% Tween-20
buffer
containing a 1:1000 dilution of Alexa fluor 488-labelled goat anti-mouse IgG.
For
visualisation of the cell nucleus, a 1:1000 dilution of Hoechst stain
(Molecular Probes,
io Catalogue No. H3570) was added. Each plate was washed in turn with PBS.
Subsequently,
PBS (100 l) was added to each well and the plates were analysed using a
Cellomics array scan
to assess total cell number and number of BrdU positive cells.
Fluorescence dose response data obtained with each compound were analysed and
the
degree of inhibition of MDA-MB-468 cell growth was expressed as an IC50 value.
is Although the pharmacological properties of the compounds of formula (I)
vary with
structural change as expected, in general, it is believed that activity
possessed by compounds of
formula (I) may be demonstrated at the following concentrations or doses in
one or more of the
above tests (a) to (d) :-
Test (a)(i):- IC50 versus mTOR kinase at less than 10 M, in particular 0.001 -
0.5
20 M for many compounds; for example 2b the IC50 was measured on
three occasions, the values were 0.059, 0.005 and 0.023 M.

Test (b)(i):- IC50 versus p1107 Type lb human P13K at less than 10 M, in
particular
0.001 - 0.5 M for many compounds; and IC50 versus pl 10a Type Ia
human P13K at less than 10 M, in particular 0.00 1 - 0.5 M for many
25 compounds;
for example 2b the IC50 was measured, the value was 1.044 M.
Test (c):- IC50 versus Serine 473 in Akt at less than 10 M, in particular 0.1
- 20
M for many compounds); for example 2b the IC50 was measured on
two occasions, the values were 0.052 and 0.025 M.
30 Test (d):- IC50 at less than 20 M.
The following examples were tested in enzyme assay Test (a)(ii):


CA 02692945 2009-12-23
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Ex No. Test (a)(ii) Ex No. Test (a)(ii) Ex No. Test (a)(ii)
ICsa ( M) IC50 ( M) IC50 ( M)
1 0.00276 231 0.00888 52 0.0184
la 0.00279 23m 0.0577 52a 0.0103
2 0.0015 24 0.00517 52b 0.0307
2a 0.0932 25 0.00155 52c 0.0296
2b 0.000169 25a 0.00224 52d 0.00588
2c 0.00186 25b 0.000817 53 0.00218
2d 0.0239 25c 0.00385 53a 0.00229
2e 0.279 25d 0.00152 53b 0.000669
2f 0.00433 25e 0.000277 53c 0.000688
2g 0.000231 25f 0.0547 53d 0.0031
2h 0.000272 25g 0.00143 53e 0.00198
2i 0.00207 25h 0.000993 53f 0.00634
2j 0.012 25i 0.001 54 0.00217
2k 0.00381 25j 0.00576 54a 0.00918
21 0.0116 25k 0.00292 54b 0.00317
2m 0.00589 251 0.000956 54c 0.00453
2n 0.00844 25m 0.00025 54d 0.00882
2o 0.000403 26 0.00605 54e 0.00762
2p 0.0027 26a 0.00672 54f 0.0107
2q 0.000379 26b 0.0039 55 0.00296
2r 0.00103 26c 0.119 55a 0.0213
2s 0.00155 26d 0.0012 55b 0.0161
2t 0.000656 26e 0.00395 55c 0.0189
2u 0.00118 26f 0.00457 55d 0.0351
2v 0.00866 26g 0.00746 55e 0.0204
2w 0.0685 26h 0.004 55f 0.0156
2x 0.00164 27 0.00111 56 0.00231
2y 0.23 27a 0.00388 56a 0.00226
2z 0.0181 27b 0.00425 56b 0.00165


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Ex No. Test (a)(ii) Ex No. Test (a)(ii) Ex No. Test (a)(ii)
ICsa ( M) IC50 ( M) IC50 ( M)
2aa 0.0274 27c 0.014 56c 0.00623
2ab 0.0553 27d 0.00307 56d 0.0043
2ac 0.00641 27e 0.000351 57 0.0119
2ad 0.000705 27f 0.000997 57a 0.0104
2ae 0.00072 27g 0.0213 57b 0.00457
2af 0.0462 27h 0.000244 57c 0.00695
2ag 0.0149 27i 0.00302 57d 0.01
3 0.00195 27j 0.00761 57e 0.00728
3a 0.00445 27k 0.00462 57f 0.0106
3b 0.00385 271 0.00112 57g 0.0585
3c 0.0124 27m 0.00144 58 0.00115
3d 0.0135 28 0.00187 58a 0.00339
3e 0.00166 28a 0.00253 58b 0.002
3f 0.0214 28b 0.00149 58c 0.00327
3g 0.00126 28c 0.00847 58d 0.00293
3h 0.0165 28d 0.00237 58e 0.00256
3i 0.000932 28e 0.000434 58f 0.00267
3j 0.00422 28f 0.0674 58g 0.0102
3k 0.00227 28g 0.00118 59 0.00882
31 0.00257 28h 0.00093 59a 0.0222
3m 0.000497 28i 0.00153 59b 0.00993
3n 0.0396 28j 0.00557 59c 0.0226
3o 0.00596 28k 0.000954 59d 0.032
3p 0.193 281 0.000442 59e 0.293
3q 0.00839 29 0.0042 59f 0.0491
3r 0.0488 30 0.025 59g 0.101
3s 0.0263 31 0.00452 60 0.012
3t 0.00479 31a 0.00265 60a 0.0191
3u 0.000604 31b 0.00497 60b 0.00862


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Ex No. Test (a)(ii) Ex No. Test (a)(ii) Ex No. Test (a)(ii)
ICsa ( M) IC50 ( M) IC50 ( M)
3w 0.00089 31c 0.00131 60c 0.00695
4 0.000699 31d 0.00955 60d 0.0183
4a 0.00217 31 e 0.00107 60e 0.0116
4b 0.00203 31f 0.0016 60f 0.0173
4c 0.0169 31g 0.00323 61 0.0269
4d 0.01 31h 0.000209 61a 0.0326
4e 0.000767 31i 0.00326 61b 0.0136
4f 0.01 31 j 0.00103 61c 0.0211
4g 0.0626 31k 0.00191 61d 0.0438
4h 0.00146 311 0.214 61 e 0.0237
4i 0.0115 31m 0.00591 61f 0.0328
4j 0.00379 32 0.00315 62 0.00205
4k 0.00905 32a 0.0425 62a 0.0393
41 0.00369 32b 0.00829 62b 0.00546
4m 0.00245 32c 0.00288 62c 0.0375
4n 0.0392 32d 0.0131 62d 0.022
0.000802 33 0.00929 63 0.0725
5a 0.000289 33a 0.0584 64 0.00785
5b 0.00052 33b 0.012 64a 0.0052
5c 0.00681 33c 0.00258 64b 0.00678
5d 0.00274 33d 0.133 64c 0.00215
5e 0.000864 34 0.00405 64d 0.0067
5f 0.00485 34a 0.0387 64e 0.00537
5g 0.0668 34b 0.0109 64f 0.00521
5h 0.00234 34c 0.00345 64g 0.0342
5i 0.00988 34d 0.0863 64h 0.00148
5j 0.000173 35 0.00531 64i 0.00135
5k 0.00333 35a 0.00552 64j 0.0012
51 0.000237 35b 0.000577 64k 0.00144


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Ex No. Test (a)(ii) Ex No. Test (a)(ii) Ex No. Test (a)(ii)
ICsa ( M) IC50 ( M) IC50 ( M)
5m 0.000604 35c 0.108 641 0.00111
5n 0.00828 35d 0.00411 64m 0.0408
6 0.001 36a 0.142 64n 0.0161
6a 0.00293 36b 0.00179 64o 0.00345
6b 0.00612 36c 0.114 64p 0.00398
6c 0.00321 36d 0.00317 64q 0.00467
6d 0.000874 36e 0.00667 64r 0.00418
6e 0.0673 36f 0.00278 64s 0.00296
6f 0.000794 36g 0.00841 64t 0.0114
6g 0.00225 36h 0.00314 64u 0.0139
6h 0.000799 36i 0.0518 64v 0.146
6i 0.00462 36j 0.018 64w 0.0161
6j 0.00593 36k 0.0131 64x 0.00761
6k 0.00186 361 0.0428 64y 0.0125
61 0.00119 36m 0.0347 64z 0.00866
6m 0.000936 36n 0.0248 64aa 0.00388
7 0.00315 36o 0.00358 64ab 0.0094
7a 0.00231 36p 0.00161 64ac 0.00529
7b 0.0181 36q 0.0889 64ad 0.00298
7c 0.00646 36r 0.00733 64ae 0.00213
7d 0.0038 36s 0.00475 64af 0.00339
7e 0.00212 36t 0.194 64ag 0.00281
7f 0.00915 36u 0.00922 64ah 0.00684
7g 0.211 36v 0.467 64ai 0.00567
7h 0.0116 36w 0.11 64aj 0.00778
7i 0.0182 36x 0.182 64ak 0.00161
7j 0.0105 36y 0.00131 64a1 0.00558
7k 0.00482 36z 0.00208 65 0.03
71 0.00913 36aa 0.0749 65a 0.00688


CA 02692945 2009-12-23
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Ex No. Test (a)(ii) Ex No. Test (a)(ii) Ex No. Test (a)(ii)
ICsa ( M) IC50 ( M) IC50 ( M)
7m 0.00504 36ab 0.011 65b 0.00342
8 0.000959 36ac 0.00441 65c 0.0151
8a 0.00096 36ad 0.0323 65d 0.00448
8b 0.00123 36ae 0.0151 65e 0.0114
8c 0.00185 36af 0.00275 66 0.00303
8d 0.00134 36ag 0.0013 66a 0.00415
8e 0.000342 36ah 0.00247 66b 0.0246
8f 0.00882 36ai 0.00561 67 0.001
8g 0.0784 36aj 0.00255 68 0.00141
8h 0.00176 36ak 0.00245 68a 0.00174
8i 0.0198 36a1 0.0161 69 0.00788
8j 0.000751 36am 0.0259 70 0.002
8k 0.0173 36an 0.0104 71 0.0182
81 0.00813 36ao 0.014 72 0.00432
8m 0.00136 36ap 0.0156 73 0.00744
9 0.0018 36aq 0.0157 74 0.00237
9a 0.0129 36ar 0.00945 74a 0.00398
9b 0.0215 36as 0.00911 74b 0.00244
9c 0.0483 36at 0.00639 74c 0.00314
9d 0.0151 36au 0.0121 74d 0.00279
9e 0.00187 36av 0.00995 74e 0.00506
9f 0.144 36aw 0.0164 74f 0.00399
9g 0.00127 36ax 0.0211 74g 0.00433
9h 0.0057 36ay 0.00117 74h 0.00321
9i 0.0024 36az 0.00105 74i 0.00925
9j 0.046 36ba 0.00167 75 0.029
9k 0.0115 36bb 0.00513 75a 0.0435
91 0.00395 36bc 0.00285 75b 0.0381
9m 0.00401 36bd 0.00258 75c 0.0339


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Ex No. Test (a)(ii) Ex No. Test (a)(ii) Ex No. Test (a)(ii)
ICsa ( M) IC50 ( M) IC50 ( M)
0.00448 36be 0.00376 75d 0.0399
l0a 0.0395 36bf 0.00457 75e 0.037
lOb 0.0266 36bg 0.00189 75f 0.0608
lOc 0.147 36bh 0.00137 76 0.00687
l0d 0.0432 36bi 0.00231 76a 0.00407
l0e 0.00691 36bj 0.00106 76b 0.00719
lOf 0.174 36bk 0.00433 76c 0.00319
lOg 0.00156 36b1 0.00333 76d 0.00924
l0h 0.0268 36bm 0.00193 76e 0.00566
l0i 0.00591 36bn 0.00637 76f 0.00678
lOj 0.11 36bo 0.0176 77 0.00821
10k 0.0502 36bp 0.00198 77a 0.00524
101 0.0183 36bq 0.00131 77b 0.0086
lOm 0.00497 36br 0.00188 77c 0.00437
11 0.00165 36bs 0.00264 77d 0.0101
lla 0.0059 36bt 0.00188 77e 0.00517
llb 0.00333 36bu 0.00118 77f 0.00919
llc 0.0247 36bv 0.00264 78 0.0418
lld 0.00642 36bw 0.00909 78a 0.0153
lle 0.00197 36bx 0.00269 78b 0.0333
llf 0.00337 36by 0.012 78c 0.0209
llg 0.313 36bz 0.0143 78d 0.0175
llh 0.00913 36ca 0.31 78e 0.0239
lli 0.0294 36cb 0.163 78f 0.0291
llj 0.0122 36cc 0.129 79 0.0186
llk 0.00332 36cd 0.147 79a 0.0222
111 0.00356 36ce 0.42 79b 0.0109
llm 0.00437 36cf 0.286 79c 0.0299
12 0.00421 36cg 0.136 79d 0.0161


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Ex No. Test (a)(ii) Ex No. Test (a)(ii) Ex No. Test (a)(ii)
ICsa ( M) IC50 ( M) IC50 ( M)
12a 0.00167 36ch 0.208 79e 0.0259
12b 0.00271 36ci 0.0386 79f 0.0398
12c 0.00751 36cj 0.00333 80 0.0197
12d 0.00155 36ck 2.62 80a 0.0146
12e 0.00459 36c1 0.0681 80b 0.0103
12f 0.35 36cm 0.00946 80c 0.00921
12g 0.00273 36cn 0.0858 80d 0.00951
12h 0.00392 36co 1.62 80e 0.0143
12i 0.000771 36cp 1.26 81 0.0137
12j 0.00167 36cq 0.114 82 0.00939
12k 0.0043 36cr 0.0435 82a 0.0265
121 0.00138 36cs 1.17 82b 0.00757
12m 0.0101 36ct 0.00157 82c 0.0185
12n 0.238 36cu 0.0686 82d 0.0243
12o 0.00509 36v 0.259 82e 0.0208
l2p 0.0014 36cw 0.0493 82f 0.0273
12q 0.00162 36cx 0.284 83 0.00346
12r 0.000991 36cy 0.0478 83a 0.00483
12s 0.117 36cz 0.0384 83b 0.0114
12t 0.0366 36da 0.0331 83c 0.0124
13 0.00357 36db 0.0209 83d 0.0472
13a 0.00341 36dc 0.00989 84 0.00956
13b 0.0037 36dd 0.00291 84a 0.00909
13c 0.00173 36de 0.00389 84b 0.00385
13d 0.00351 36df 0.00712 84c 0.00829
13e 0.0301 36dg 0.0164 84d 0.00959
13f 0.386 36dh 0.0034 84e 0.00818
13g 0.00479 36di 0.00923 84f 0.0134
13h 0.0106 36dj 0.00891 85 0.00477


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Ex No. Test (a)(ii) Ex No. Test (a)(ii) Ex No. Test (a)(ii)
ICsa ( M) IC50 ( M) IC50 ( M)
13i 0.00275 36dk 0.00905 85a 0.00313
13j 0.0178 36d1 0.00399 85b 0.00526
13k 0.0179 36dm 0.0298 85c 0.00509
131 0.0108 36dn 0.0138 85d 0.00323
13m 0.0532 36do 0.0277 85e 0.0183
13n 0.997 36dp 0.0106 85f 0.0202
13o 0.0287 36dq 0.0245 85g 0.0259
l3p 0.00202 36dr 0.294 85h 0.0426
13q 0.00192 36ds 0.000973 85i 0.0153
13r 0.00198 36dt 0.00037 85j 0.0124
13s 0.00846 36du 0.0152 86 0.00247
13t 0.172 36dv 0.0043 86a 0.00522
13u 0.00477 36dw 0.00624 86b 0.00725
14 0.0465 36dx 0.00262 86c 0.00247
14a 0.0136 36dy 0.00636 86d 0.00382
14b 1.39 36dz 0.00277 86e 0.00223
14c 0.0401 36ea 0.00884 86f 0.00345
14d 0.0143 36eb 0.00311 87 0.00487
14e 0.11 36ec 0.00321 87a 0.0887
14f 0.189 36ed 0.00704 87b 0.0177
14g 0.0857 36ee 0.00958 87c 0.00775
14h 0.14 36ef 0.00841 87d 0.0177
14i 0.0339 36eg 0.00877 87e 0.0103
14j 0.0129 37a 0.026 87f 0.00907
14k 0.275 37b 0.0124 88 0.0321
141 0.0137 37c 0.0033 88a 0.00448
14m 0.0143 37d 0.00439 88b 0.0567
14n 0.0363 37e 0.0049 88c 0.047
14o 0.0217 37f 0.12 88d 0.004


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Ex No. Test (a)(ii) Ex No. Test (a)(ii) Ex No. Test (a)(ii)
ICsa ( M) IC50 ( M) IC50 ( M)
l4p 0.537 37g 0.0179 88e 0.131
14q 0.0265 37h 0.0198 89 0.485
14r 0.0103 37i 0.00379 90 0.0189
14s 0.122 37j 0.0309 91 0.00498
14t 0.197 37k 0.0161 91a 0.00198
14u 0.123 371 0.032 91b 0.00521
14v 0.0823 37m 0.0506 91c 0.00368
14w 0.208 37n 0.0393 91d 0.00356
14x 0.63 37o 0.033 92 0.00793
l4y 0.152 37p 0.00534 92a 0.00551
14z 0.171 37q 0.00294 92b 0.00746
l4aa 0.0186 37r 0.00162 92c 0.0078
15 0.00154 37s 0.00756 92d 0.00807
15a 0.000591 37t 0.00889 92e 0.00599
16 0.00142 37u 0.000395 92f 0.00625
16a 0.0101 37v 0.00549 93 0.00505
16b 0.00577 37w 0.00137 93a 0.00303
16c 0.0016 37x 0.00944 93b 0.0023
16d 0.00364 37y 0.00686 93c 0.0029
16e 0.0214 37z 0.00481 93d 0.000818
16f 0.0212 37aa 0.00567 93e 0.00541
16g 0.0176 37ab 0.00488 94a 0.0136
16h 0.186 37ac 0.0438 94b 0.0122
16i 0.845 37ad 0.00263 94c 0.0118
17 0.00116 37ae 0.00952 94d 0.011
17a 0.000942 37af 0.0233 94e 0.0135
17b 0.000584 37ag 0.0134 94f 0.0151
17c 0.00179 38 0.00131 94g 0.0127
18 0.00135 38a 0.000918 94h 0.0116


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Ex No. Test (a)(ii) Ex No. Test (a)(ii) Ex No. Test (a)(ii)
ICsa ( M) IC50 ( M) IC50 ( M)
18a 0.00714 39 0.000351 94i 0.0121
18b 0.0147 39a 0.000502 94j 0.00605
18c 0.032 40 0.00436 94k 0.0106
18d 0.0151 40a 0.00221 95a 0.0139
18e 0.000654 41 0.0308 95b 0.019
18f 0.12 42 0.000705 95c 0.00706
18g 0.00123 42a 0.00261 95d 0.0126
18h 0.00664 42b 0.00535 95e 0.016
18i 0.00555 42c 0.0036 95f 0.0109
18j 0.0303 42d 0.000607 95g 0.0164
18k 0.0113 42e 0.00257 95h 0.013
181 0.0102 42f 0.00264 95i 0.00479
18m 0.00315 42g 0.00401 95j 0.0131
19 0.00131 42h 0.00412 95k 0.0272
19a 0.00425 43 0.00539 951 0.00109
19b 0.00119 43a 0.00479 95m 0.00202
19c 0.0214 43b 0.00751 95n 0.000668
19d 0.00318 43c 0.0288 95o 0.00473
19e 0.00135 43d 0.011 95p 0.00543
19f 0.0804 43e 0.188 95q 0.00168
19g 0.000274 43f 0.0392 95r 0.00631
19h 0.00246 43g 0.029 96a 0.0177
19i 0.00152 43h 0.133 96b 0.0268
19j 0.0199 43i 0.102 96c 0.0272
19k 0.00415 43j 0.012 96d 0.0209
191 0.00152 43k 0.0257 96e 0.00862
19m 0.000944 431 0.0236 97 0.0882
20 0.0128 43m 0.00531 98a 0.011
20a 0.0163 43n 0.0119 98b 0.00413


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Ex No. Test (a)(ii) Ex No. Test (a)(ii) Ex No. Test (a)(ii)
IC50 ( M) IC50 ( M) IC50 ( M)
20b 0.874 43o 0.0157 98c 0.0267
20c 0.00559 43p 0.0555 98d 0.00441
20d 0.0133 43q 0.028 98e 0.00335
21 0.0253 43r 0.0577 98f 0.00229
21a 0.0378 43s 0.00629 98g 0.0127
21b 0.0133 43t 0.00545 98h 0.00362
21c 0.0234 44 0.0234 98i 0.0285
22 0.503 45 0.00717 98j 0.00374
23 0.00492 46 0.00456 98k 0.00246
23a 0.00459 46a 0.0126 981 0.00789
23b 0.197 47 0.0155 99a 0.0438
23c 0.000831 47a 0.0054 99b 0.0316
23d 0.00534 47b 0.0149 99c 0.239
23e 0.00876 48 0.00072 99d 0.219
23f 0.0199 48a 0.00116 99e 0.0317
23g 1.21 49 0.00187 99f 0.00589
23h 0.00808 49a 0.00267 99g 0.0152
23i 0.0254 50 0.0104 99h 0.0782
23j 0.0314 50a 0.00794 99i 0.0594
23k 1.14 51 0.00332 99j 0.0124
Compounds may be further selected on the basis of further biological or
physical
properties which may be measured by techniques known in the art and which may
be used in
the assessment or selection of compounds for therapeutic or prophylactic
application.
The compounds of the present invention are advantageous in that they possess
pharmacological activity. In particular, the compounds of the present
invention modulate (in
particular, inhibit) mTOR kinase and/or phosphatidylinositol-3-kinase (P13K)
enzymes, such as
the Class Ia P13K enzymes (e.g. PI3Kalpha, PI3Kbeta and PI3Kdelta) and the
Class lb P13K
enzyme (PI3Kgamma). More particularly compounds of the present invention
modulate (in


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particular, inhibit) mTOR kinase. More particularly compounds of the present
invention
modulate (in particular, inhibit) one or more P13K enzyme. The inhibitory
properties of
compounds of formula (I) may be demonstrated using the test procedures set out
herein and in
the experimental section. Accordingly, the compounds of formula (I) may be
used in the
s treatment (therapeutic or prophylactic) of conditions/diseases in human and
non-human
animals which are mediated by mTOR kinase and/or one or more P13K enzyme(s),
and in
particular by mTOR kinase.
The invention also provides a pharmaceutical composition comprising a compound
of
formula (I), or a pharmaceutically acceptable salt thereof, as defined herein
in association with
io a pharmaceutically acceptable diluent or carrier.
The compositions of the invention may be in a form suitable for oral use (for
example
as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions,
emulsions, dispersible
powders or granules, syrups or elixirs), for topical use (for example as
creams, ointments, gels,
or aqueous or oily solutions or suspensions), for administration by inhalation
(for example as a
is finely divided powder or a liquid aerosol), for administration by
insufflation (for example as a
finely divided powder) or for parenteral administration (for example as a
sterile aqueous or oily
solution for intravenous, subcutaneous, intraperitoneal or intramuscular
dosing or as a
suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures
using
20 conventional pharmaceutical excipients, well known in the art. Thus,
compositions intended
for oral use may contain, for example, one or more colouring, sweetening,
flavouring and/or
preservative agents.
The amount of active ingredient that is combined with one or more excipients
to
produce a single dosage form will necessarily vary depending upon the host
treated and the
25 particular route of administration. For example, a formulation intended for
oral administration
to humans will generally contain, for example, from 1 mg to 1 g of active
agent (more suitably
from 1 to 250 mg, for example from 1 to 100 mg) compounded with an appropriate
and
convenient amount of excipients which may vary from about 5 to about 98
percent by weight
of the total composition.
30 The size of the dose for therapeutic or prophylactic purposes of a compound
of formula
I will naturally vary according to the nature and severity of the disease
state, the age and sex of
the animal or patient and the route of administration, according to well known
principles of


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medicine.
In using a compound of formula (I) for therapeutic or prophylactic purposes it
will
generally be administered so that a daily dose in the range, for example, 1
mg/kg to 100 mg/kg
body weight is received, given if required in divided doses. In general, lower
doses will be
s administered when a parenteral route is employed. Thus, for example, for
intravenous
administration, a dose in the range, for example, 1 mg/kg to 25 mg/kg body
weight will
generally be used. Similarly, for administration by inhalation, a dose in the
range, for example,
1 mg/kg to 25 mg/kg body weight will be used. Typically, unit dosage forms
will contain
about 10 mg to 0.5 g of a compound of this invention.
As stated herein, it is known that mTOR kinase and the P13K enzymes have roles
in
tumourigenesis as well as numerous other diseases. We have found that the
compounds of
formula (I) possess potent anti-tumour activity which it is believed is
obtained by way of
inhibition of mTOR kinase and/or one or more of the P13K enzymes.
Accordingly, the compounds of the present invention are of value as anti-
tumour
agents. Particularly, the compounds of the present invention are of value as
anti-proliferative,
apoptotic and/or anti-invasive agents in the containment and/or treatment of
solid and/or liquid
tumour disease. Particularly, the compounds of the present invention are
expected to be useful
in the prevention or treatment of those tumours which are sensitive to
inhibition of mTOR
and/or one or more of the P13K enzymes such as the Class Ia P13K enzymes and
the Class lb
P13K enzyme. Further, the compounds of the present invention are expected to
be useful in the
prevention or treatment of those tumours which are mediated alone or in part
by mTOR and/or
one or more of the P13K enzymes such as the Class Ia P13K enzymes and the
Class lb P13K
enzyme. The compounds may thus be used to produce an mTOR enzyme inhibitory
effect in a
warm-blooded animal in need of such treatment. Certain compounds may be used
to produce
an P13K enzyme inhibitory effect in a warm-blooded animal in need of such
treatment.
As stated herein, inhibitors of mTOR kinase and/or one or more P13K enzymes
should
be of therapeutic value for the treatment of proliferative disease such as
cancer and in
particular solid tumours such as carcinoma and sarcomas and the leukaemias and
lymphoid
malignancies and in particular for treatment of, for example, cancer of the
breast, colorectum,
lung (including small cell lung cancer, non-small cell lung cancer and
bronchioalveolar cancer)
and prostate, and of cancer of the bile duct, bone, bladder, head and neck,
kidney, liver,
gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid,
uterus, cervix and


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vulva, and of leukaemias [including acute lymphoctic leukaemia (ALL) and
chronic
myelogenous leukaemia (CML)], multiple myeloma and lymphomas.
Anti-cancer effects which are accordingly useful in the treatment of cancer in
a patient
include, but are not limited to, anti-tumour effects, the response rate, the
time to disease
s progression and the survival rate. Anti-tumour effects of a method of
treatment of the present
invention include but are not limited to, inhibition of tumour growth, tumour
growth delay,
regression of tumour, shrinkage of tumour, increased time to regrowth of
tumour on cessation
of treatment, slowing of disease progression. Anti-cancer effects include
prophylactic
treatment as well as treatment of existing disease.
io A mTOR kinase inhibitor, or a pharmaceutically acceptable salt thereof, may
also be
useful for the treatment patients with cancers, including, but not limited to,
haematologic
malignancies such as leukaemia, multiple myeloma, lymphomas such as Hodgkin's
disease,
non-Hodgkin's lymphomas (including mantle cell lymphoma), and myelodysplastic
syndromes, and also solid tumours and their metastases such as breast cancer,
lung cancer
is (non-small cell lung cancer (NSCL), small cell lung cancer (SCLC), squamous
cell carcinoma),
endometrial cancer, tumours of the central nervous system such as gliomas,
dysembryoplastic
neuroepithelial tumour, glioblastoma multiforme, mixed gliomas,
medulloblastoma,
retinoblastoma, neuroblastoma, germinoma and teratoma, cancers of the
gastrointestinal tract
such as gastric cancer, oesophagal cancer, hepatocellular (liver) carcinoma,
20 cholangiocarcinomas, colon and rectal carcinomas, cancers of the small
intestine, pancreatic
cancers, cancers of the skin such as melanomas (in particular metastatic
melanoma), thyroid
cancers, cancers of the head and neck and cancers of the salivary glands,
prostate, testis,
ovary, cervix, uterus, vulva, bladder, kidney (including renal cell carcinoma,
clear cell and
renal oncocytoma), squamous cell carcinomas, sarcomas such as osteosarcoma,
25 chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma,
gastrointestinal
stromal tumour (GIST), Kaposi's sarcoma, and paediatric cancers such as
rhabdomyosarcomas
and neuroblastomas.
The compounds of the present invention and the methods of treatment comprising
the
administering or use of a mTOR kinase inhibitor, or a pharmaceutically
acceptable salt thereof,
3o are expected to be particularly useful for the treatment of patients with
lung cancer, prostate
cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney
cancer, gastric


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cancer, sarcomas, head and neck cancers, tumours of the central nervous system
and their
metastases, and also for the treatment of patients with acute myeloid
leukaemia.
According to a further aspect of the invention there is provided a compound of
formula
(I), or a pharmaceutically acceptable salt thereof, as defined herein for use
as a medicament in
s a warm-blooded animal such as man.
According to a further aspect of the invention, there is provided a compound
of formula
(I), or a pharmaceutically acceptable salt thereof, as defined herein for use
in the production of
an anti-proliferative effect in a warm-blooded animal such as man.
According to a further aspect of the invention, there is provided a compound
of formula
io (I), or a pharmaceutically acceptable salt thereof, as defined herein for
use in the production of
an apoptotic effect in a warm-blooded animal such as man.
According to a further feature of the invention there is provided a compound
of formula
(I), or a pharmaceutically acceptable salt thereof, as defined herein for use
in a warm-blooded
animal such as man as an anti-invasive agent in the containment and/or
treatment of
15 proliferative disease such as cancer.
According to a further aspect of the invention, there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein for the
production of an anti-proliferative effect in a warm-blooded animal such as
man.
According to a further feature of this aspect of the invention there is
provided the use of
2o a compound of formula (I), or a pharmaceutically acceptable salt thereof,
as defined herein in
the manufacture of a medicament for use in the production of an anti-
proliferative effect in a
warm-blooded animal such as man.
According to a further aspect of the invention, there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein for the
25 production of an apoptotic effect in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is
provided the use of
a compound of formula (I), or a pharmaceutically acceptable salt thereof, as
defined herein in
the manufacture of a medicament for use in the production of an apoptotic
effect in a warm-
blooded animal such as man.
30 According to a further feature of the invention there is provided the use
of a compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the


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manufacture of a medicament for use in a warm-blooded animal such as man as an
anti-
invasive agent in the containment and/or treatment of proliferative disease
such as cancer.
According to a further feature of this aspect of the invention there is
provided a method
for producing an anti-proliferative effect in a warm-blooded animal, such as
man, in need of
s such treatment which comprises administering to said animal an effective
amount of a
compound of formula (I), or a pharmaceutically acceptable salt thereof, as
defined herein.
According to a further feature of this aspect of the invention there is
provided a method
for producing an anti-invasive effect by the containment and/or treatment of
solid tumour
disease in a warm-blooded animal, such as man, in need of such treatment which
comprises
io administering to said animal an effective amount of a compound of formula
(I), or a
pharmaceutically acceptable salt thereof, as defined herein.
According to a further aspect of the invention there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the
manufacture of a medicament for use in the prevention or treatment of
proliferative disease
is such as cancer in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is
provided a method
for the prevention or treatment of proliferative disease such as cancer in a
warm-blooded
animal, such as man, in need of such treatment which comprises administering
to said animal
an effective amount of a compound of formula (I), or a pharmaceutically
acceptable salt
20 thereof, as defined herein.
According to a further aspect of the invention there is provided a compound of
formula
(I), or a pharmaceutically acceptable salt thereof, as defined herein for use
in the prevention or
treatment of those tumours which are sensitive to inhibition of mTOR kinase
and/or one or
more P13K enzymes (such as the Class Ia enzymes and/or the Class lb P13K
enzyme) that are
25 involved in the signal transduction steps which lead to the proliferation,
survival, invasiveness
and migratory ability of tumour cells.
According to a further feature of this aspect of the invention there is
provided the use of
a compound of formula (I), or a pharmaceutically acceptable salt thereof, as
defined herein in
the manufacture of a medicament for use in the prevention or treatment of
those tumours which
3o are sensitive to inhibition of mTOR kinase and/or one or more P13K enzymes
(such as the
Class Ia enzymes and/or the Class lb P13K enzyme) that are involved in the
signal transduction


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steps which lead to the proliferation, survival, invasiveness and migratory
ability of tumour
cells.
According to a further feature of this aspect of the invention there is
provided a method
for the prevention or treatment of those tumours which are sensitive to
inhibition of mTOR
s kinase and/or one or more P13K enzymes (such as the Class Ia enzymes and/or
the Class lb
P13K enzyme) that are involved in the signal transduction steps which lead to
the proliferation,
survival, invasiveness and migratory ability of tumour cells which comprises
administering to
said animal an effective amount of a compound of formula (I), or a
pharmaceutically
acceptable salt thereof, as defined herein.
According to a further aspect of the invention there is provided a compound of
formula
(I), or a pharmaceutically acceptable salt thereof, as defined herein for use
in providing a
mTOR kinase inhibitory effect and/or a P13K enzyme inhibitory effect (such as
a Class Ia P13K
enzyme or Class lb P13K enzyme inhibitory effect).
According to a further feature of this aspect of the invention there is
provided the use of
is a compound of formula (I), or a pharmaceutically acceptable salt thereof,
as defined herein in
the manufacture of a medicament for use in providing a mTOR kinase inhibitory
effect and/or
a P13K enzyme inhibitory effect (such as a Class Ia P13K enzyme or Class lb
P13K enzyme
inhibitory effect).
According to a further aspect of the invention there is also provided a method
for
providing a mTOR kinase inhibitory effect and/or a P13K enzyme inhibitory
effect (such as a
Class Ia P13K enzyme or Class lb P13K enzyme inhibitory effect) which
comprises
administering an effective amount of a compound of formula I, or a
pharmaceutically
acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a compound
of formula
I, or a pharmaceutically acceptable salt thereof, as defined herein for use in
the treatment of
cancer, inflammatory diseases, obstructive airways diseases, immune diseases
or
cardiovascular diseases.
According to a further feature of the invention there is provided a compound
of formula
I, or a pharmaceutically acceptable salt thereof, as defined herein for use in
the treatment of
solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid
malignancies.
According to a further feature of the invention there is provided a compound
of formula
I, or a pharmaceutically acceptable salt thereof, as defined herein for use in
the treatment of


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cancer of the breast, colorectum, lung (including small cell lung cancer, non-
small cell lung
cancer and bronchioalveolar cancer) and prostate.
According to a further feature of the invention there is provided a compound
of formula
(I), or a pharmaceutically acceptable salt thereof, as defined herein for use
in the treatment of
s cancer of the bile duct, bone, bladder, head and neck, kidney, liver,
gastrointestinal tissue,
oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva,
and of leukaemias
(including ALL and CML), multiple myeloma and lymphomas.
According to a further feature of the invention there is provided a compound
of formula
(I), or a pharmaceutically acceptable salt thereof, as defined herein for use
in the treatment of
io cancer of the bile duct, bone, bladder, head and neck, kidney, liver,
gastrointestinal tissue,
oesophagus, ovary, endometrium, pancreas, skin, testes, thyroid, uterus,
cervix and vulva, and
of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
According to a further feature of the invention there is provided a compound
of formula
(I), or a pharmaceutically acceptable salt thereof, as defined herein for use
in the treatment of
15 lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer,
endometrial cancer,
kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the
central nervous
system and their metastases, and also for the treatment acute myeloid
leukaemia.
According to a further feature of the invention there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the
20 manufacture of a medicament for use in the treatment of cancer,
inflammatory diseases,
obstructive airways diseases, immune diseases or cardiovascular diseases.
According to a further feature of the invention there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the
manufacture of a medicament for use in the treatment of of solid tumours such
as carcinoma
25 and sarcomas and the leukaemias and lymphoid malignancies.
According to a further feature of the invention there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the
manufacture of a medicament for use in the treatment of cancer of the breast,
colorectum, lung
(including small cell lung cancer, non-small cell lung cancer and
bronchioalveolar cancer) and
30 prostate.
According to a further feature of the invention there is provided the use of a
compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the


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manufacture of a medicament for use in the treatment of cancer of the bile
duct, bone, bladder,
head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary,
pancreas, skin, testes,
thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML),
multiple
myeloma and lymphomas.
s According to a further feature of the invention there is provided the use of
a compound
of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein in the
manufacture of a medicament for use in the treatment of lung cancer, prostate
cancer,
melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer,
gastric cancer,
sarcomas, head and neck cancers, tumours of the central nervous system and
their metastases,
io and also for the treatment acute myeloid leukaemia.
According to a further feature of the invention there is provided a method for
treating
cancer, inflammatory diseases, obstructive airways diseases, immune diseases
or
cardiovascular diseases in a warm blooded animal such as man that is in need
of such treatment
which comprises administering an effective amount of a compound of formula
(I), or a
is pharmaceutically acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a method for
treating
solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid
malignancies
in a warm blooded animal such as man that is in need of such treatment which
comprises
administering an effective amount of a compound of formula (I), or a
pharmaceutically
2o acceptable salt thereof, as defined herein.
According to a further feature of the invention there is provided a method for
treating
cancer of the breast, colorectum, lung (including small cell lung cancer, non-
small cell lung
cancer and bronchioalveolar cancer) and prostate in a warm blooded animal such
as man that is
in need of such treatment which comprises administering an effective amount of
a compound
25 of formula (I), or a pharmaceutically acceptable salt thereof, as defined
herein.
According to a further feature of the invention there is provided a method for
treating
cancer of the bile duct, bone, bladder, head and neck, kidney, liver,
gastrointestinal tissue,
oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva,
and of leukaemias
(including ALL and CML), multiple myeloma and lymphomas in a warm blooded
animal such
3o as man that is in need of such treatment which comprises administering an
effective amount of
a compound of formula (I), or a pharmaceutically acceptable salt thereof, as
defined herein.


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According to a further feature of the invention there is provided a method for
treating
lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer,
endometrial cancer,
kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the
central nervous
system and their metastases, and acute myeloid leukaemia in a warm blooded
animal such as
s man that is in need of such treatment which comprises administering an
effective amount of a
compound of formula (I), or a pharmaceutically acceptable salt thereof, as
defined herein.
As stated herein, the in vivo effects of a compound of formula (I) may be
exerted in part
by one or more metabolites that are formed within the human or animal body
after
administration of a compound of formula (I).
The invention further relates to combination therapies wherein a compound of
formula (I), or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition or
formulation comprising a compound of formula (I) is administered concurrently
or sequentially
or as a combined preparation with another treatment of use in the control of
oncology disease.
In particular, the treatment defined herein may be applied as a sole therapy
or may
involve, in addition to the compounds of the invention, conventional surgery
or radiotherapy or
chemotherapy. Accordingly, the compounds of the invention can also be used in
combination
with existing therapeutic agents for the treatment of cancer.
Suitable agents to be used in combination include :-
(i) antiproliferative/antineoplastic drugs and combinations thereof, as used
in medical
oncology such as alkylating agents (for example cis-platin, carboplatin,
cyclophosphamide,
nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas);
antimetabolites (for
example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur,
raltitrexed,
methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour
antibiotics (for
example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,
epirubicin,
idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents
(for example
vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and
taxoids like
paclitaxel and taxotere); and topoisomerase inhibitors (for example
epipodophyllotoxins like
etoposide and teniposide, amsacrine, topotecan and camptothecins);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen,
toremifene, raloxifene,
3o droloxifene and iodoxyfene), oestrogen receptor down regulators (for
example fulvestrant),
antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone
acetate),
LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and
buserelin),


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progestogens (for example megestrol acetate), aromatase inhibitors (for
example as
anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-
reductase such as
finasteride;
(iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-
(6-chloro-
s 2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-
tetrahydropyran-
4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and
N-(2-chloro-6-methylphenyl)-2- {6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-
methylpyrimidin-
4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004,
47, 6658-
6661), and metalloproteinase inhibitors like marimastat and inhibitors of
urokinase
io plasminogen activator receptor function);
(iv) inhibitors of growth factor function: for example such inhibitors include
growth factor
antibodies and growth factor receptor antibodies (for example the anti-erbB2
antibody
trastuzumab [HerceptinTM] and the anti-erbBl antibody cetuximab [C225]); such
inhibitors
also include, for example, tyrosine kinase inhibitors, for example inhibitors
of the epidermal
is growth factor family (for example EGFR family tyrosine kinase inhibitors
such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-
amine
(gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-
amine
(erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-
morpholinopropoxy)quinazolin-4-amine (CI 1033) and erbB2 tyrosine kinase
inhibitors such as
20 lapatinib), inhibitors of the hepatocyte growth factor family, inhibitors
of the platelet-derived
growth factor family such as imatinib, inhibitors of serine/threonine kinases
(for example
Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for
example sorafenib
(BAY 43-9006)) and inhibitors of cell signalling through MEK and/or Akt
kinases;
(v) antiangiogenic agents such as those which inhibit the effects of vascular
endothelial
25 growth factor, [for example the anti-vascular endothelial cell growth
factor antibody
bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as 4-
(4-bromo-
2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
(ZD6474;
Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-
7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 within WO
00/47212),
30 vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and
compounds
that work by other mechanisms (for example linomide, inhibitors of integrin
av(33 function and
angiostatin)];


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(vi) vascular damaging agents such as combretastatin A4 and compounds
disclosed in
International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO
01/92224,
WO 02/04434 and WO 02/08213;
(vii) antisense therapies, for example those which are directed to the targets
listed above,
s such as ISIS 2503, an anti-ras antisense agent;
(viii) gene therapy approaches, including approaches to replace aberrant genes
such as
aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy)
approaches such as those using cytosine deaminase, thymidine kinase or a
bacterial
nitroreductase enzyme and approaches to increase patient tolerance to
chemotherapy or
io radiotherapy such as multi-drug resistance gene therapy; and
(ix) immunotherapeutic approaches, including ex-vivo and in-vivo approaches to
increase
the immunogenicity of patient tumour cells, such as transfection with
cytokines such as
interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating
factor, approaches to
decrease T-cell anergy, approaches using transfected immune cells such as
15 cytokine-transfected dendritic cells, approaches using cytokine-transfected
tumour cell lines
and approaches using anti-idiotypic antibodies.
The invention will now be further explained by reference to the following
illustrative
examples.
Unless stated otherwise, starting materials were commercially available. All
solvents
2o and commercial reagents were of laboratory grade and were used as received.
In the examples 'H NMR spectra were recorded on a Bruker DPX 300 (300 MHz),
Bruker DRX 400 (400 MHz) instrument or a Bruker DRX 500 (500 MHz) instrument.
The
central peaks of chloroform-d (6H 7.27 ppm), dimethylsulfoxide-d6 (6H 2.50
ppm) or acetone-d6
(6H 2.05 ppm) were used as internal references. The following abbreviations
have been used:
25 s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; br, broad.
Column chromatography was carried out using silica gel (0.04-0.063 mm, Merck).
In
general, a Kromasil KR-100-5-C18 reversed-phase column (250 x 20 mm, Akzo
Nobel) was
used for preparative HPLC with mixtures of acetonitrile and water [containing
0.1 %
30 trifluoroacetic acid (TFA)] used as the eluent at a flow rate of 10 mL/min.
The following methods were used for liquid chromatography (LC) / mass spectral
(MS)
analysis :-


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HPLC: Agilent 1100 or Waters Alliance HT (2790 & 2795)
Mass Spectrometer: Waters ZQ ESCi
HPLC Column

The standard HPLC column used is the Phemonenex Gemini C 18 5 m, 50 x 2 mm.
s Acidic HPLC Methods
The mobile phases used are: Mobile phase A: Water
Mobile Phase B: Acetonitrile
Mobile Phase C: 1% Formic Acid in 50:50 Water:MeCN (v/v)
Each method is followed by a rapid equilibration using a 5 mL flow rate for
0.45 min.

Four uneric HPLC methods are available:
5 Minute Monitor Acidic method

Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: C: Rate
/mL/min
0.00 95 0 5 1 1.1
4 0 95 5 6 1.1
4.5 0 95 5 6 1.1
Early Acidic method for early elutinl! compounds
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: C: Rate
/mL/min
0.00 95 0 5 1 1.1
4 57.5 37.5 5 6 1.1
4.5 57.5 37.5 5 6 1.1



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Mid Acidic method for middle elutini! compounds
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: C: Rate
/mL/min
0.00 95 0 5 1 1.1
0.01 67.5 27.5 5 6 1.1
4.5 27.5 67.5 5 6 1.1
Late Acidic method for late elutinl! compounds

Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: C: Rate
/mL/min

0.00 95 0 5 1 1.1
0.01 27.5 67.5 5 6 1.1
4.5 5 95 5 6 1.1
s Basic HPLC methods
In some instances the standard acidic methods may be unsuitable for either the
compound
ionisation or the chromatography separation required. In such cases four
comparable Basic
HPLC methods are available.
The mobile phases used are: Mobile phase A: Water
io Mobile Phase B: Acetonitrile
Mobile Phase D: 0.1% 880 Ammonia in acetonitrile
Each method is followed by a rapid equilibration using a 5 mL flow rate for
0.45 min.



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Minute Monitor Basic method
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: D: Rate
/mL/min
0.00 95 0 5 1 1.1
4 0 95 5 6 1.1
4.5 0 95 5 6 1.1
Early Basic method for early elutinl! compounds

Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: D: Rate
/mL/min

0.00 95 0 5 1 1.1
4 57.5 37.5 5 6 1.1
4.5 57.5 37.5 5 6 1.1
s Mid Basic method for middle elutinl! compounds

Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: D: Rate
/mL/min
0.00 95 0 5 1 1.1
0.01 67.5 27.5 5 6 1.1
4.5 27.5 67.5 5 6 1.1
Late Basic method for late elutinl! compounds
Time Mobile Phase Mobile Phase Mobile Phase Curve Flow
/min A: B: C: Rate
/mL/min
0.00 95 0 5 1 1.1
0.01 27.5 67.5 5 6 1.1
4.5 5 95 5 6 1.1


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The following method was used for liquid chromatography (LC) / mass spectral
(MS)
analysis :- Instrument: Agilent 1100; Column: Waters `Symmetry' 2.1 x 30 mm;
Mass
Spectral analysis using chemical ionisation (APCI); Flow rate: 0.7 mL/min;
Absorption
s Wavelength: 254 nm; Solvent A: water + 0.1% TFA; Solvent B: acetonitrile +
0.1% TFA ;
Solvent Gradient: 15-95% Solvent B for 2.7 minutes followed by 95% Solvent B
for 0.3
minutes.
The following methods were used for LC analysis :-
Method A:- Instrument: Agilent 1100; Column: Kromasil C18 reversed-phase
silica,
io 100 x 3 mm, 5 m particle size; Solvent A: 0.1% TFA/water, Solvent B: 0.08%
TFA/acetonitrile; Flow Rate: 1 mL/min; Solvent Gradient: 10-100% Solvent B for
20 minutes
followed by 100% Solvent B for 1 minute; Absorption Wavelengths: 220, 254 and
280 nm. In
general, the retention time of the product was noted.
Method B :- Instrument: Agilent 1100; Column: Waters `Xterra' C8 reversed-
phase
is silica, 100 x 3 mm, 5 m particle size; Solvent A: 0.015M ammonia in water,
Solvent B:
acetonitrile; Flow Rate: 1 ml/min, Solvent Gradient: 10-100% Solvent B for 20
minutes
followed by 100% Solvent B for 1 minute; Absorption Wavelength: 220, 254 and
280 nm. In
general, the retention time of the product was noted.
The following abbreviations are used herein or within the following
illustrative
2o examples :-

HPLC High Performance Liquid Chromatography

HBTU O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;
HATU O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate;
HOBT 1-hydroxybenzotriazole;

25 HOAT 1-hydroxy-7-azabenzotriazole;
NMP N-methylpyrrolidin-2-one;
DMSO dimethylsulfoxide;

DMF N,N-dimethylformamide;
DMA N,N-dimethylacetamide;
3o THF tetrahydrofuran;

DME 1,2-dimethoxyethane;
DCCI dicyclohexylcarbodiimide;


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MeOH methanol;
MeCN acetonitrile;
DCM dichloromethane;
DIPEA N,N-diisopropylethylamine;
s DBU 1,8-diazabicyclo[5.4.0]undec-7-ene;
RT room temperature (approximately 17 to 25 C);
tR retention time;
m/z mass/charge ratio.
The chemical names were generated by software which used the Lexichem Toolkit
(v. 1.60)
1o from OpenEye Scientific Software (www.eyesopen.com) to generate IUPAC
conforming
names.

Example 1: 3-Ethyl-l-f4-f4-f(3S)-3-methylmorpholin-4-yll-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yll phenyll urea
C0
N)'',
O - N
is I N p
N'k N
15 H H
To a solution of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidine (200 mg, 0.60 mmol) in ethanol was added
toluene
(1.00 niL), water (1.00 mL), [4-(3-ethylureido)phenyl]boronic acid, pinacol
ester (262 mg, 0.90
mmol), tri-potassium orthophosphate (448 mg, 2.11 mmol) and palladiumbis(tri-
tert-
2o butylphosphine) (18.55 mg, 0.04 mmol). The reaction was degassed then
purged with nitrogen
and heated at 80 C for 2 hours. The reaction mixture was diluted with ethyl
acetate (10 mL)
and washed with water (5 mL). The organic layer was dried (MgS04), filtered
and evaporated
to afford crude product which was purified by flash silica chromatography,
elution gradient 0
to 10% (3.5M ammonia in methanol) in DCM, to give the desired material as a
white solid
25 (109 mg).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO-d6) b 1.07 (3H, m), 1.23 (3H, d), 1.56
(2H,
s), 1.67 (2H, s), 3.14 (2H, t), 3.22 (1H, m), 3.30 (3H, s), 3.48 (1H, t), 3.63
(1H, m), 3.76 (1H,


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d), 3.97 (1H, d), 4.21 (1H, d), 4.57 (1H, s), 6.16 (1H, t), 6.76 (1H, s), 7.50
(2H, d), 8.20 (2H,
d), 8.66 (1H, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 460 ; HPLC tR = 1.83 min
mTOR Kinase Assay (Echo): 0.00276 M

The following compound was made in an analogous fashion from the appropriate
boronic ester.
Example Structure NAME LCMS Retention
MH+ time (min)

la c ~ 3-methyl-l-[4-[4-[(3S)-3- 446 1.68
N ethylmorpholin-4-yl]-6-(1-
O. I
s N o ethylsulfonylcyclopropyl)py
"I )~
" H imidin-2-yl]phenyl]urea

Example la: 'H NMR (400.132 MHz, DMSO) b 1.23 (3H, d), 1.31 (3H, s), 1.56 (2H,
m), 1.67
io (2H, m), 2.66 (3H, d), 3.22 (1H, m), 3.48 (1H, m), 3.63 (1H, m), 3.76 (1H,
d), 3.97 (1H, m),
4.21 (1H, d), 4.57 (1H, s), 6.07 (1H, m), 6.76 (1H, s), 7.51 (2H, d), 8.19
(2H, d), 8.75 (1H, s)
mTOR Kinase Assay (Echo): 0.00279 M

The preparation of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidine is described below.
2-Chloro-4-[(3S)-3-methylmorpholin-4-yll-6-(1-
methylsulfonylcyclopropyl)pyrimidine
0
CNloi
O I N
~S O N~CI

2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine
(1.2 g, 3.9
mmol) was dissolved in DMF (20 mL) and sodium tert-butoxide (755 mg, 7.85
mmol) was
added to the reaction, followed by dibromoethane (738 mg, 3.9 mmol). The
reaction was
stirred at RT for 4 hours then at 60 C overnight. Further sodium tert-butoxide
(378 mg, 3.9


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mmol) was added to the reaction, followed by dibromoethane (369 mg, 1.9 mmol)
and the
reaction stirred at 60 C a further 24 hours. DCM (20 mL) was added and the
reaction washed
with 2M aqueous hydrochloric acid (20 mL). The organic phase was dried
(MgSO4), filtered
and concentrated in vacuo. The crude solid was chromatographed on silica,
eluting with 0-50%
s ethyl acetate in DCM, to give the desired material (400 mg, 31 %).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO-d6) b 1.22 (d, 3H), 1.51 (m, 2H), 1.64
(m,
2H), 3.18 (s, 3H), 3.22 (m, 1 H), 3.43 (m, 1 H), 3.5 8(m, 1 H), 3.72 (d, 1 H),
3.93 (m, 1 H), 4.05
(d, 1 H), 4.41 (s, 1 H), 6.93 (s, 1 H)
LCMS Spectrum: m/z (ESI+)(M+H)+ 332, HPLC tR = 1.6 min
lo
2-Chloro-4-[(3S)-3-methylmorpholin-4-yll-6-(methylsulfonylmethyl)pyrimidine
(0)"',

O O I ~N
N-~:kCI

2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine (30 g, 0.13 mol) was dissolved
in
dichloromethane and stirred (under nitrogen) at -5 C. Triethylamine (17.4 mL,
0.13 mol) was
is added to give a clear brown solution. (3S)-3-Methylmorpholine was dissolved
in
dichloromethane and added dropwise keeping the reaction below -5 C. The
cooling bath was
then removed and the mixture stirred for 1 hour. The reaction mixture was
heated at reflux for
2 hours, then the reaction mixture was washed with water, dried then
evaporated. The crude
material was purified by preparative HPLC to give the desired material as a
solid (19.3 g).
2o NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) 61.21 - 1.23 (m, 3H), 3.11 (s,
3H), 3.19 -
3.26 (m, 1 H), 3.42 - 3.49 (m, 1 H), 3.5 8- 3.62 (1 H, m), 3.73 (d, 1 H), 3.92
- 3.96 (m, 2H), 4.27 -
4.31 (m, 1 H), 4.45 (s, 2H), 6.92 (s, 1 H)
LCMS Spectrum: MH+ 306, retention time 1.42 min, Method 5 Min Acid
25 2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine
CI
O O I ~N
N1), CI

6-(Methylsulfonylmethyl)-1H-pyrimidine-2,4-dione (132 g, 0.65 mol) was added
to
phosphorus oxychloride (1.2 L) and the mixture heated to reflux for 16 hours,
then cooled to


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room temperature. The excess phosphorus oxychloride was removed in vacuo, the
residue
azeotroped with toluene (2 x 500 mL) and dissolved in dichloromethane. This
mixture was
then poured slowly onto ice (4 L) and stirred for 20 minutes, then extracted
with
dichloromethane (3 x 1 L) (the insoluble black material was filtered off and
discarded) and
s ethyl acetate (2 x 1 L). The extracts were combined, dried, then evaporated
to leave the desired
material as a dark brown solid (51 g). The material was used without further
purification.
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) 63.13 (s, 3H), 4.79 (s, 2H), 7.87
(s, 1H)
LCMS Spectrum: MH+ 239, retention time 1.21 min, Method 5 Min Acid

io 6-(Methylsulfonylmethyl)-1H-pyrimidine-2,4-dione
O
O O NH
is I N~O
H

6-(Chloromethyl)-1H-pyrimidine-2,4-dione (175 g, 1.09 mol) was dissolved in
DMF (2 L) and
methanesulphinic acid sodium salt (133.5 g, 1.31 mol) was added. The reaction
was heated to
125 C for 2 hours then allowed to cool and the suspension filtered and
concentrated in vacuo
15 to give a yellow solid. The crude material was washed with water, filtered,
then triturated with
toluene. The solid was filtered then triturated with isohexane to leave the
desired compound as
a yellow solid (250 g). The material was used without further purification.
6-(Chloromethyl)-1H-pyrimidine-2,4-dione is a commercially available material.

2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidine can
also be prepared by the method described below.
2-Chloro-4-[(3S)-3-methylmorpholin-4-yll-6-(1-
methylsulfonylcyclopropyl)pyrimidine
C0
N)''i
O O I N
~S N~cl
Sodium hydroxide (50%w/w solution) (115 g, 2877.88 mmol) was addedto 2-chloro-
4-[(3S)-3-
methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (16 g, 52.33 mmol),
1,2-


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dibromoethane (13.53 ml, 156.98 mmol) and tetrabutylammonium bromide (1.687 g,
5.23
mmol) in toluene (128 mL) and the resulting suspension stirred at RT for 4
hours. Water was
added and the mixture was extracted twice with toluene. The toluene was dried
over MgSO4,
filtered and evaporated. The crude product,l5g was purified by flash
silicachromatography,
s elution gradient Oto 20% ethyl acetate in DCM, to give the desired material
(13 g) as a white
solid which was identical to previous samples.

2-Chloro-4- [(3S)-3 -methylmorpho lin-4-yll -6-
(methylsulfonylmethyl)pyrimidine
C(0).",

O O I ~N
~S N~CI

io Methanesulfinic acid, sodium salt (11.75 g, 115.11 mmol) was added in one
portion to 2-
chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (37 g, 104.64
mmol), in
acetonitrile (900 mL) and the resulting solution stirred at 85 Cfor 24 hours.
The organic layers
were combined and washed with water (3 x 100 mL), dried over MgSO4, filtered,
and the
solvent was removed by evaporation to give the crude product as a dark brown
oil, which
is solidifed (36 g). The crude solidwas purified by flash
silicachromatography, elution gradient 0
to 30% ethyl acetate in DCM, to give the desired material (22 g) as a cream
solid which was
identical to previous samples.

2-Chloro-4-(io domethyl)-6- [(3 S)-3 -methylmorpho lin-4-yl]pyrimidine
C0
N)'',
I ~N
I N~CI
Methanesulfonyl chloride (0.245 mL, 3.14 mmol) was added dropwise over a
period of 5
minutes to a solution of triethylamine (0.875 mL, 6.28 mmol) and [2-chloro-6-
[(3S)-3-
methylmorpholin-4-yl]pyrimidin-4-yl]methanol (510 mg, 2.09 mmol) in DCM (30
mL) at 0 C
under nitrogen. The resulting solution was stirred at RT for 45 minutes. The
reaction mixture
was diluted with water (20 mL). The organic layer was dried (MgSO4) and
filtered. Sodium


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Iodide (1569 mg, 10.46 mmol) was added and the reaction was heated to 50 C for
20 hours.
The reaction mixture was filtered and evaporated to afford the desired
material (761 mg).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO) b 1.19 - 1.25 (3H, m), 3.18 - 3.22
(1H, m),
3.40 - 3.47 (1H, m), 3.57 - 3.60 (1H, m), 3.71 (1H, d), 3.90 - 3.94 (1H, m),
3.96 - 3.98 (1H, m),
s 4.28 - 4.32 (3H, m), 6.94 (1H, s).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 354; HPLC tR = 2.10 min.
2-Chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine can also be
prepared by
the dropwise addition of methanesulfonyl chloride (91 mL, 1169.52 mmol) to [2-
chloro-6-
io [(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol (190 g, 779.68 mmol)
and
triethylamine (163 mL, 1169.52 mmol) in DCM (2293 mL) at 0 C under air. The
resulting
solution was allowed to warm up slowly to RT over a period of 4 hours. The
reaction mixture
was quenched with water, extracted with DCM and the organic layer dried over
MgS04,
filtered and evaporated to afford [2-chloro-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidin-4-
1s yl]methyl methanesulfonate as a yellow gum (251 g). Sodium iodide (234 g,
1560.07 mmol)
was added to this material in acetone (3679 mL) and the resulting suspension
stirred at RT for
16 hours. The reaction mixture was evaporated to dryness and redissolved in
DCM and washed
three times with water then with a saturated aqueous solution of sodium
thiosulphate. The
organic layer was dried over MgS04, filtered and evaporated to afford crude
desired product
20 (270 g). This was purified by chromatography to give an off white solid
which was further
triturated with ether to give the desired material which was identical to
previous samples.

f 2-Chloro-6-[(3S)-3-methylmorpholin-4-yllbyrimidin-4-yllmethanol
(0)"',

(N~! HOCI

25 Methyl 2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate
(3.15 g) was
dissolved in dry THF (20 mL) and cooled to 0 C under nitrogen. A solution of
lithium
borohydride (2.OM in THF, 6.09mL) was added dropwise and the solution allowed
to warm to
RT and stirred for 1 hour. The reaction was quenched with water (20 mL) then
evaporated to
dryness, the residue dissolved in ethyl acetate (150 mL) and washed with water
(150 mL)


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followed by brine (50 mL). The organics were evaporated to dryness to give to
the desired
material as a white solid (2.44 g).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO) b 1.20 - 1.21 (3H, m), 3.18 - 3.22
(1H, m),
3.40 - 3.47 (1H, m), 3.56 - 3.60 (1H, m), 3.71 (1H, d), 3.91 - 3.94 (1H, m),
3.98 (1H, d), 4.35
s(3H, d), 5.51 (1H, t), 6.74 (1H, s).
Mass Spectrum; M+H+ 244.
[2-Chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol can also be
prepared by
the dropwise addition of lithium borohydride (2M in THF) (454 mL, 908.17 mmol)
over a
io period of 15 minutes to a solution of inethyl2-chloro-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidine-4-carboxylate (235 g, 864.92 mmol) in the THF (4701 mL) at 0 C.
The mixture
was stirred at RT for 2 hours then water (1500 mL) was added slowly. A white
solid formed
which was decanted off and the THF was removed under vacuum. To the residue
was added
more water (500 mL), and extracted with ethyl acetate (3 x 700 mL). The
combined organics
is were washed with brine, dried over MgS04, filtered, and concentrated to a
white solid which
was identical to previous samples.

Methyl2-chloro-6-[(3S)-3-methylmorpholin-4-yl]12yrimidine-4-carboxylate
C0
N)''i
I ~N
O NiCI
O

20 Methy12,6-dichloropyrimidine-4-carboxylate (5 g) was dissolved in DCM (120
mL). (3S)-3-
Methylmorpholine (2.49 g) dissolved in triethylamine (3.70 mL) and DCM (10 mL)
was added
dropwise to the solution over 10 minute. The reaction was left to stir at room
temperature for 1
hour. The reaction was then evaporated to dryness and dissolved in DCM (300
niL). The
organics were washed once with water (150 mL) and dried (MgS04), filtered and
evaporated.
25 The crude material was chromatographed on silica, eluting with 2.5%
methanol in DCM, to
give the desired material as a white solid (3.15 g).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO) b 1.22 - 1.24 (3H, m), 3.25 (1H, d),
3.41 -
3.48 (1H, m), 3.57 - 3.61 (1H, m), 3.71 (1H, d), 3.87 (3H, s), 3.91 - 3.95
(1H, m), 4.25 (1H, s),
4.45 (1H, s), 7.29 (1H, s).


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Mass Spectrum; M+H+ 272.

Methyl 2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate can
also be
prepared by the addition of inethy12,6-dichloropyrimidine-4-carboxylate (250
g, 1207.65
s mmol) to the DCM (2500 mL).Triethylamine (185 mL, 1328.41 mmol) was added
and the
reaction cooled to 0 C. (3S)-3-Methylmorpholine (128 g, 1268.03 mmol)
dissolved in DCM
(300 mL), was added dropwise over 30 minutes and the mixture stirred at 5
overnight. Water
(800 mL) was added, the phases separated and the aquoeus layer extracted with
DCM (300
mL). The combined organics were washed with brine (300 mL), dried over MgS04,
filtered
io and concentrated to a cream solid. The crude solid was dissolved in hot
ethyl acetate (3
volumes) then isohexane (5 volumes) added the mixture left to cool with
stirring over the
weekend to give the desired material as a solid which was identical to
previous samples.
Example 2: 3-Cyclopropyl-l-f4-f4-f(3S)-3-methylmorpholin-4-yll-6-(1-
1 s methylsulfonylcyclopropyl)pyrimidin-2-yll phenyll urea
0J.,i
CN

O O ~N
S I N a'4~ O
NJ~ N
H H

To a solution of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate (200 mg, 0.39 mmol)
in DMF (2
mL) was added triethylamine (0.164 mL, 1.18 mmol) followed by cyclopropylamine
(0.136
20 mL, 1.97 mmol) and the reaction heated at 50 C for 2 hours.
The solvent was removed under reduced pressure to give the crude product which
was purified
by flash silica chromatography, elution gradient 0 to 10% (3.5M ammonia in
methanol) in
DCM, to give the desired product as a white solid (168 mg).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO-d6) b 0.42 (2H, m), 0.65 (2H, m), 1.24
(3H,
25 d), 1.56 (2H, m), 1.67 (2H, m), 2.56 (3H, m), 3.21 (1H, m), 3.48 (1H, m),
3.63 (1H, m), 3.78
(1H, d), 3.97 (1H, m), 4.21 (1H, d), 4.57 (1H, s), 6.43 (1H, d), 6.77 (1H, s),
7.51 (2H, d), 8.20
(2H, d), 8.54 (1H, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 472; HPLC tR = 1.93 min.


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mTOR Kinase Assay (Echo): 0.0015 M
The compounds below were prepared in an analogous fashion using the
appropriate amine.
Example Structure 4AME LCMS Retention
MH+ time (min)

2a (01 1-[4-[4-[(3S)-3- 526 1.73
N . ethylmorpholin-4-yl]-6-(1-
O O ,N N-;
N o ethylsulfonylcyclopropyl)p
NN
H H yrimidin-2-yl]phenyl]-3-[(I-
methylpyrazol-4-
yl)methyl]urea

2b (01 1-[4-[4-[(3S)-3- 512 1.75
0 ~ , N ethylmorpholin-4-yl]-6-(1-
0S
" J~N ethylsulfonylcyclopropyl)p
H H yrimidin-2-yl]phenyl]-3-(I-
methylpyrazol-4-yl)urea

2c c l 3-cyclobutyl-l-[4-[4-[(3S)-3- 486 2.21
N ethylmorpholin-4-yl]-6-(1-
O O 'N
N 0 ~ ethylsulfonylcyclopropyl)p
N
H H yrimidin-2-yl]phenyl]urea
2d 3-(1H-imidazol-2-ylmethyl)- 512 1.66
CN~..=,
'N 1-[4-[4-[(3 S)-3-
0 0 ~~
~~ N~ NH ethylmorphohn-4-yl]-6-(1-
NN~
" H ethylsulfonylcyclopropyl)p
yrimidin-2-yl]phenyl]urea
2e (01 3-(2-dimethylaminoethyl)-1- 502 1.89
N [4-[4-[(3S)-3-
0 0 'N ~
s N ~ fN` ethylmorpholin-4-yl]-6-(1-
" " ethylsulfonylcyclopropyl)p
yrimidin-2-yl]phenyl]urea


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Example Structure 4AME LCMS Retention
MH+ time (min)
2f (01 3-(1-hydroxy-2-methyl- 503 1.83
N ropan-2-yl)-1-[4-[4-[(3S)-3-
O. O ~N
N o o" ethy1morpholin-4-y1]-6-(1-
~ N'k N-~
" H ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea
2g c ~ 1-[4-[4-[(3S)-3- 498 2.03
N ethy1morpholin-4-y1]-6-(1-
0 0 ,N
oro ethylsulfonylcyclopropyl)p
NN
H H yrimidin-2-yI]phenyI]-3-(1,2-
oxazol-3-yl)urea
2h c l 1-[4-[4-[(3S)-3- 507 2.35
N ethylmorpholin-4-y1]-6-(1-
O o ,N
N 0 ~ ~ ethylsulfonylcyclopropyl)p
N~N ~
H H rimidin-2-yl]phenyl]-3-
henyl-urea
2i c l 3-(2-hydroxyethyl)-1-[4-[4- 475 1.54
N t-I [(3S)-3-methylmorpholin-4-
0 0 ,N
N O OH 1]-6-(1-
I N)~ Nf
" H ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea
2j (01 1-[4-[4-[(3S)-3- 473 2.0
N tt ethylmorpholin-4-y1]-6-(1-
O O ,N
N 1 0 ethylsulfonylcyclopropyl)p
H H rimidin-2-yl]phenyl]-3-
ropan-2-yl-urea


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Example Structure 4AME LCMS Retention
MH+ time (min)
2k c l 1-[4-[4-[(3S)-3- 473 2.02
N ethylmorpholin-4-y1]-6-(1-
0 0 ,N
N 0 ethylsulfonylcyclopropyl)p
N)~ N
H H rimidin-2-yl]phenyl]-3-
ropyl-urea
21 (01 1-[4-[4-[(3S)-3- 487 2.18
N tt ethylmorpholin-4-y1]-6-(1-
0 0 ,N
's N o ethylsulfonylcyclopropyl)p
NN
H H yrimidin-2-yI]phenyI]-3-(2-
methylpropyl)urea
2m c l 3-(cyclopropylmethyl)-1-[4- 485 2.06
N [4-[(3S)-3-methylmorpholin-
0 0 ,N
N 0 4-yl]-6-(1-
~ NNY
" H ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea
2n c l 3-(1-hydroxypropan-2-yl)-1- 489 1.63
N t-I [4-[4-[(3S)-3-
0 0 ~N
N 1 o o" ethylmorpholin-4-y1]-6-(1-
NN
" H ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea
2o (01, 3-(6-methoxypyridin-3-yl)-1- 538 2.11
0 o N [4-[4-[(3S)-3-
. o
" NJIN r ~N , ethylmorpholin-4-y1]-6-(1-
H H
ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea


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Example Structure 4AME LCMS Retention
MH+ time (min)
2p c l 3-(4-fluorophenyl)-1-[4-[4- 525 2.4
[(3 S)-3-methylmorpholin-4-
0 0 ~N
"S N a Jl yl]-6-(I-
011-N N
H H ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea
2q (01 3-(3,4-difluorophenyl)-1-[4- 543 2.52
[4-[(3 S)-3-methylmorpholin-
0 0 N
N'~ ~ ~ ~ F 4-yl]-6-(1-
N N F
H H ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea
2r 1-[4-[4-[(3S)-3- 521 2.49
C N ~.ii
0 0 ,N ethylmorpholin-4-y1]-6-(1-
s " I ~ ~ I ~ ethylsulfonylcyclopropyl)p
N N
H H yrimidin-2-yI]phenyI]-3-(4-
methylphenyl)urea
2s c l 3-(4-chlorophenyl)-1-[4-[4- 541 2.59
t
[(3 S)-3-methylmorpholin-4-
0 0 ~N
N C Jl ~ ~ ~~ 1]-6-(1-
N N
H H ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea
2t c lo, 3-(4-methoxyphenyl)-1-[4- 537 2.29
o. o N [4-[(3S)-3-methylmorpholin-
. o
N a NkN I~ ~ 4_yl]_6_(1_
H H
ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea


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Example Structure 4AME LCMS Retention
MH+ time (min)
2u (01 1-[4-[4-[(3S)-3- 512 2.16
N ethylmorpholin-4-y1]-6-(1-
0 O ~N
N e
thylsulfonylcyclopropyl)p
/ NxN ?:~O
H H yrimidin-2-yI]phenyI]-3-(5-
methyl-1,2-oxazol-3-yl)urea
2v (01 3-(5-fluoropyridin-2-yl)-1- 527 2.35
[4-[4-[(3S)-3-
0 0 " N
N'L~axN N I ethylmorphohn-4-y1]-6-(1-
N H H ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea

2w ( ~ 3-(3-hydroxy-2,2- 518 2.05
N dimethylpropyl)-1-[4-[4-
O. O 'N OH
N [(3S)-3-methylmorpholin-4-
~NN
H H 1]-6-(1-
ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea

2x ( ~ 3-(2-cyanoethyl)-1-[4-[4- 485 1.91
N [(3S)-3-methylmorpholin-4-
0 0 N N
N II 1]-6-(1-
NN
H H ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea
2y (01, 1-[4-[4-[(3S)-3- 529 2.21
~ ethylmorpholin-4-y1]-6-(1-
0 0 ~jk'N
'S " 0
f N ethylsulfonylcyclopropyl)p
N N
H H yrimidin-2-yI]phenyI]-3-(2-
pyrrolidin-


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Example Structure 4AME LCMS Retention
MH+ time (min)
2z 1-[4-[4-[(3S)-3- 544 2.11
N ethylmorpholin-4-yl]-6-(1-
0 0 ~
N N ~ ~II F ~F ethylsulfonylcyclopropyl)p
NxN
H H rimidin-2-yl]phenyl]-3-
(3,3,3-trifluoro-2-
hydroxypropyl)urea

2aa 3-(2-hydroxy-2- 530 1.91
N ethylpropyl)-1-[4-[4-[(3S)-
O. O N
H 3-methylmorpholin-4-yl]-6-
N~ N~
H H (1-

ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea
2ab 3-[1- 502 1.81

N (hydroxymethyl)cyclopropyl
O O iN
's N H ]-1-[4-[4-[(3S)-3-
/ HH
ethylmorpholin-4-yl]-6-(1-
ethylsulfonylcyclopropyl)p
rimidin-2-yl]phenyl]urea

2ac ( )1-[4-[4-[(3S)-3- 488 2.25
N ethylmorpholin-4-yl]-6-(1-
0 0 ~N
N ~ 0 ~o ethylsulfonylcyclopropyl)p
N N
H H rimidin-2-yl]phenyl]-3-
(oxetan-3-yl)urea
2ad (011-[4-[4-[(3S)-3- 512 2.11
0 0 ~~ ethylmorpholin-4-yl]-6-(1-
S~
" I ~ NxN~N ethylsulfonylcyclopropyl)p
H H yrimi


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Example Structure 4AME LCMS Retention
MH+ time (min)
2ae 1-[4-[4-[(3S)-3- 515 1.43
N ethylmorpholin-4-yl]-6-(1-
0 0 ~
~ N N~N~ ~ ethylsulfonylcyclopropyl)p
H H yrimidin-2-yl]phenyl]-3-
(1,2,4-thiadiazol-5-yl)urea

2af 3-(cyanomethyl)-1-[4-[4- 471 1.54
N [(3S)-3-methylmorpholin-4-
=S -N N
N II 1]-6-(1-
~ NxN
H H ethylsulfonylcyclopropyl)p
yrimidin-2-yl]phenyl]urea
2ag 1-[4-[4-[(3S)-3- 513 1.58

N ethylmorpholin-4-yl]-6-(1-
0 0 I ~N
's N- N~~~'N~ ethylsulfonylcyclopropyl)p
H H yrimidin-2-yl]phenyl]-3-(2H-
1,2,4-triazol-3-ylmethyl)urea
Both Example 2 and Example la can be prepared in an analogous fashion to that
described
above but using THF as a solvent. Example la can also be prepared in an
analogous fashion to
that described above but using NMP as a solvent.
Example 2a: 'H NMR (400.132 MHz, DMSO-d6) b 1.22 (3H, d), 1.56 (2H, s), 1.67
(2H, s),
s 3.21 (1H, m), 3.48 (1H, t), 3.63 (1H, d), 3.76 (4H, m), 3.80 (3H, s), 3.97
(1H, d), 4.13 (2H, d),
4.20 (1H, s), 4.57 (1H, s), 6.42 (1H, t), 6.77 (1H, s), 7.35 (1H, s), 7.51
(2H, d), 7.59 (1H, s),
8.20 (2H, d), 8.70 (1H, s)
mTOR Kinase Assay (Echo): 0.0932 M
Example 2b: 'H NMR (400.132 MHz, DMSO-d6) b 1.24 (3H, d), 1.55 - 1.58 (2H, m),
1.66 -
io 1.69 (2H, m), 3.21 (1H, dt), 3.27 - 3.29 (1H, m), 3.29 (3H, s), 3.49 (1H,
dt), 3.64 (1H, dd), 3.79
(3H, s), 3.98 (1H, dd), 4.22 (1H, d), 4.58 (1H, s), 6.78 (1H, s), 7.38 (1H,
s), 7.55 (2H, d), 7.76
(1H, s), 8.23 (2H, d), 8.38 (1H, s), 8.84 (1H, s)
mTOR Kinase Assay (Echo): 0.000169 M
Example 2c: 'H NMR (400.132 MHz, DMSO-d6) b 1.23-1.24 (3H, d), 1.54-1.69 (6H,
m),
15 1.81-1.91 (2H, m), 2.18-2.25 (2H, m), 3.17-3.24 (1H, td), 3.29 (3H, s),
3.45-3.52 (1H, td),


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3.62-3.65 (1H, dd), 3.75-3.78 (1H, d), 3.96-3.99 (1H, dd), 4.10-4.23 (2H, m),
4.57 (1H, bs),
6.45-6.47 (1H, d), 6.77 (1H, s), 7.47-7.50 (2H, d), 8.18-8.21 (2H, d), 8.57
(1H, s).
mTOR Kinase Assay (Echo): 0.00121 M
Example 2d: 'H NMR (400.132 MHz, DMSO-d6) b 1.23-1.25 (3H, d), 1.55-1.66 (2H,
q),
s 1.67-1.69 (2H, q), 3.17-3.25 (1H, td), 3.30 (3H, s), 3.45-3.52 (1H, td),
3.62-3.65 (1H, dd),
3.75-3.78 (1H, d), 3.96-3.99 (1H, dd), 4.20-4.23 (1H, d), 4.32-4.34 (2H, d),
4.57 (1H, bs), 6.61-
6.64 (1H, t), 6.77 (1H, s), 6.77 (2H, bs), 7.51-7.54 (2H, d), 8.21-8.22 (2H,
d), 8.94 (1H, s),
11.84 (1H, bs).
mTOR Kinase Assay (Echo): 0.0239 M
io Example 2e: 'H NMR (400.132 MHz, DMSO-d6) b 1.23-1.24 (3H, d), 1.54-1.58
(2H, q), 1.66-
1.69 (2H, q), 2.19 (6H, s), 2.33-2.36 (2H, t), 3.18-3.22 (2H, t), 3.20-3.25
(1H, td), 3.45-3.52
(1H, td), 3.62-3.65 (1H, dd), 3.75-3.78 (1H, d), 3.96-3.99 (1H, dd), 4.20-4.23
(1H, d), 4.57
(1H, bs), 6.15-6.18 (1H, t), 6.77 (1H, s), 7.49-7.51 (2H, d), 8.19-8.21 (2H,
d), 8.90 (1H, s).
Note:methyl signal obscured by water peak at 3.29.
is mTOR Kinase Assay (Echo): 0.279 M
Example 2f: 'H NMR (400.132 MHz, DMSO-d6) b 1.23-1.25(9H, d), 1.54-1.58 (2H,
q), 1.66-
1.69 (2H, q), 3.17-3.25 (1H, td), 3.39-3.40 (2H, d), 3.45-3.52 (1H, td), 3.62-
3.65 (1H, dd),
3.75-3.78 (1H, d), 3.96-4.00 (1H, dd), 4.20-4.23 (1H, d), 4.56 (1H, bs), 4.94-
4.97 (1H, t), 6.01
(1H, s), 6.77 (1H, s), 7.45-7.47 (2H, d), 8.18-8.20 (2H, d), 8.74 (1H, s).
Note:methyl signal
20 obscured by water peak at 3.29.
mTOR Kinase Assay (Echo): 0.00433 M
Example 2g: 'H NMR (400.132 MHz, DMSO-d6) b 1.24-1.25 (3H, d), 1.56-1.59 (2H,
q), 1.67-
1.70 (2H, q), 3.19-3.26 (1H, td), 3.46-3.53 (1H, td), 3.62-3.66 (1H, dd), 3.76-
3.79 (1H, d),
3.97-4.00 (1H, dd), 4.21-4.24 (1H, d), 4.58 (1H, bs), 6.81 (1H, s), 6.87-6.88
(1H, d), 7.57-7.59
25 (2H, d), 8.27-8.29 (2H, d), 8.75-8.76 (1H, d), 9.08 (1H,s), 9.62 (1H, s).
Note:methyl signal
obscured by water peak at 3.29.
mTOR Kinase Assay (Echo): 0.000137 M
Example 2h: 'H NMR (400.132 MHz, DMSO-d6) b 1.24-1.26 (3H, d), 1.56-1.59 (2H,
q),
1.67-1.70 (2H, q), 3.18-3.26 (1H, td), 3.31 (3H, s), 3.46-3.53 (1H, td), 3.63-
3.66 (1H, dd),
3o 3.76-3.79 (1H, d), 3.96-4.00 (1H, dd), 4.21-4.24 (1H, d), 4.59 (1H, bs),
6.79 (1H, s), 6.98-7.01
(1H, t), 7.28-7.32 (2H, t), 7.46-7.48 (2H, d), 7.57-7.59 (2H, d), 8.25-8.27
(2H, d), 8.71 (1H, s),
8.92 (1H, s).


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mTOR Kinase Assay (Echo): 0.000272 M
Example 2i: 'H NMR (400.132 MHz, DMSO-d6) b 1.23-1.24 (3H, d), 1.54-1.58 (2H,
q), 1.65-
1.70 (2H, q), 3.16-3.25 (1H, td), 3.16-3.21 (2H, q), 3.45-3.52 (1H, td), 3.45-
3.49 (2H, q), 3.62-
3.65 (1H, dd), 3.75-3.78 (1H, d), 3.96-3.99 (1H, dd), 4.20-4.23 (1H, d), 4.57
(1H, bs), 4.72-
s 4.74 (1H, t), 6.25-6.27 (1H, t), 6.77 (1H, s), 7.49-7.51 (2H, d), 8.19-8.21
(2H, d), 8.82 (1H, s).
Note:methyl signal obscured by water peak at 3.29.
mTOR Kinase Assay (Echo): 0.00207 M
Example 2j: 'H NMR (400.132 MHz, DMSO-d6) b 1.11-1.12 (6H, d), 1.23-1.24 (3H,
d), 1.54-
1.58 (2H, q), 1.66-1.69 (2H, q), 3.17-3.25 (1H, td), 3.45-3.52 (1H, td), 3.62-
3.65 (1H, dd),
io 3.74-3.82 (2H, m), 3.96-3.99 (1H, dd), 4.20-4.23 (1H, d), 4.57 (1H, bs),
6.06-6.07 (1H, d), 6.77
(1H, s), 7.48-7.50 (2H, d), 8.19-8.21 (2H, d), 8.54 (1H, s). Note:methyl
signal obscured by
water peak at 3.29.
mTOR Kinase Assay (Echo): 0.012 M
Example 2k: 'H NMR (400.132 MHz, DMSO-d6) b 0.87-0.91 (3H, t), 1.23-1.25 (3H,
d), 1.42-
1s 1.51 (2H, m), 1.54-1.58 (2H, q), 1.66-1.69 (2H, q), 3.05-3.09 (2H, q), 3.17-
3.25 (1H, td), 3.45-
3.52 (1H, td), 3.61-3.65 (1H, dd), 3.75-3.78 (1H, d), 3.96-3.99 (1H, dd), 4.20-
4.23 (1H, d),
4.57 (1H, bs), 6.19-6.22 (1H, t), 6.77 (1H, s), 7.49-7.51 (2H, d), 8.19-8.21
(2H, d), 8.66 (1H,
s). Note:methyl signal obscured by water peak at 3.29.
mTOR Kinase Assay (Echo): 0.00406 M
2o Example 21: 'H NMR (400.132 MHz, DMSO-d6) b 0.88-0.90 (6H, d), 1.23-1.25
(3H, d), 1.54-
1.58 (2H, q), 1.66-1.68 (2H, q), 1.67-1.76 (1H, m), 2.93-2.96 (2H, t), 3.17-
3.25 (1H, td), 3.45-
3.52 (1H, td), 3.62-3.65 (1H, dd), 3.75-3.78 (1H, d), 3.96-3.99 (1H, dd), 4.20-
4.23 (1H, d),
4.57 (1H, bs), 6.24-6.27 (1H, t), 6.77 (1H, s), 7.49-7.51 (2H, d), 8.19-8.21
(2H, d), 8.66 (1H,
s). Note:methyl signal obscured by water peak at 3.29.
25 mTOR Kinase Assay (Echo): 0.0116 M
Example 2m: 'H NMR (400.132 MHz, DMSO-d6) b 0.18-0.22 (2H, m), 0.42-0.46 (2H,
m),
0.93-1.00 (1H, m), 1.23-1.25 (3H, d), 1.54-1.58 (2H, q), 1.66-1.69 (2H, q),
2.98-3.01 (2H, t),
3.17-3.25 (1H, td), 3.45-3.52 (1H, td), 3.62-3.65 (1H, dd), 3.75-3.78 (1H, d),
3.96-3.99 (1H,
dd), 4.20-4.23 (1H, d), 4.57 (1H, bs), 6.25-6.28 (1H, t), 6.77 (1H, s), 7.49-
7.51 (2H, d), 8.19-
3o 8.21 (2H, d), 8.70 (1H, s). Note:methyl signal obscured by water peak at
3.29.
mTOR Kinase Assay (Echo): 0.00589 M


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Example 2n: 'H NMR (400.132 MHz, DMSO-d6) b 1.08-1.10 (3H, d), 1.23-1.25 (3H,
d),
1.54-1.57 (2H, q), 1.66-1.69 (2H, q), 2.98-3.01 (2H, t), 3.18-3.25 (1H, td),
3.30 (3H, s), 3.34-
3.43 (2H, m), 3.45-3.52 (1H, td), 3.62-3.65 (1H, dd), 3.69-3.75 (1H, m), 3.75-
3.78 (1H, d),
3.96-3.99 (1H, dd), 4.20-4.23 (1H, d), 4.57 (1H, bs), 4.77-4.80 (1H, t), 6.09-
6.11 (1H, d), 6.77
s(1H, s), 7.48-7.50 (2H, d), 8.19-8.21 (2H, d), 8.72 (1H, s).
mTOR Kinase Assay (Echo): 0.00844 M
Example 2o: 'H NMR (400.132 MHz, DMSO-d6) b 1.23-1.25 (3H, d), 1.56-1.59 (2H,
q), 1.67-
1.70 (2H, q), 3.18-3.26 (1H, td), 3.30 (3H, s), 3.46-3.53 (1H, td), 3.62-3.66
(1H, dd), 3.76-3.79
(1H, d), 3.83 (3H, s), 3.96-4.00 (1H, dd), 4.21-4.24 (1H, d), 4.58 (1H, bs),
6.79(s, 1H), 6.79-
io 6.81 (1H, d), 7.56-7.58 (2H, d), 7.83-7.86 (1H, dd), 8.21-8.22 (1H, d),
8.25-8.27 (2H, d), 8.62
(1H, s), 8.98 (1H, s).
mTOR Kinase Assay (Echo): 0.000851 M
Example 2p: 'H NMR (400.132 MHz, DMSO-d6) b 1.23-1.25 (3H, d), 1.55-1.58 (2H,
q),
1.66-1.69 (2H, q), 3.18-3.25 (1H, td), 3.30 (3H, s), 3.46-3.52 (1H, td), 3.62-
3.66 (1H, dd),
is 3.76-3.78 (1H, d), 3.96-4.00 (1H, dd), 4.21-4.24 (1H, d), 4.58 (1H, bs),
6.79(s, 1H), 7.11-7.16
(2H, t), 7.46-7.50 (2H, m), 7.56-7.58 (2H, d), 8.24-8.27 (2H, d), 8.74 (1H,
s), 8.92 (1H, s).
mTOR Kinase Assay (Echo): 0.0027 M
Example 2q: 'H NMR (400.132 MHz, DMSO-d6) b 1.24-1.25 (3H, d), 1.56-1.59 (2H,
q),
1.67-1.70 (2H, q), 3.18-3.26 (1H, td), 3.30 (3H, s), 3.46-3.53 (1H, td), 3.62-
3.66 (1H, dd),
2o 3.76-3.79 (1H, d), 3.96-4.00 (1H, dd), 4.21-4.24 (1H, d), 4.58 (1H, bs),
6.80(s, 1H), 7.14-7.17
(1H, m), 7.32-7.39 (1H, q), 7.56-7.59 (2H, d), 7.65-7.71 (1H, qd), 8.26-8.28
(2H, d), 8.93 (1H,
s), 9.00 (1H, s).
mTOR Kinase Assay (Echo): 0.001 M
Example 2r: 'H NMR (400.132 MHz, DMSO-d6) b 1.24-1.25 (3H, d), 1.56-1.59 (2H,
q), 1.67-
25 1.70 (2H, q), 2.26 (3H, s), 3.18-3.26 (1H, td), 3.30 (3H, s), 3.46-3.53
(1H, td), 3.62-3.66 (1H,
dd), 3.76-3.79 (1H, d), 3.96-4.00 (1H, dd), 4.21-4.24 (1H, d), 4.58 (1H, bs),
6.79(s, 1H), 7.09-
7.12 (2H, d), 7.34-7.36 (2H, d), 7.56-7.58 (2H, d), 8.24-8.27 (2H, d), 8.59
(1H, s), 8.87 (1H, s).
mTOR Kinase Assay (Echo): 0.00066 M
Example 2s: 'H NMR (400.132 MHz, DMSO-d6) b 1.24-1.25 (3H, d), 1.56-1.59 (2H,
q), 1.67-
30 1.70 (2H, q), 3.18-3.26 (1H, td), 3.46-3.53 (1H, td), 3.62-3.66 (1H, dd),
3.76-3.79 (1H, d),
3.96-4.00 (1H, dd), 4.21-4.24 (1H, d), 4.58 (1H, bs), 6.79(s, 1H), 7.33-7.36
(2H, d), 7.50-7.52


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(2H, d), 7.56-7.59 (2H, d), 8.25-8.27 (2H, d), 8.87 (1H, s), 8.97 (1H, s).
Note:methyl signal
obscured by water peak at 3.29
mTOR Kinase Assay (Echo): 0.00138 M
Example 2t: 'H NMR (400.132 MHz, DMSO-d6) b 1.24-1.25 (3H, d), 1.56-1.58 (2H,
q), 1.67-
s 1.69 (2H, q), 3.18-3.25 (1H, td), 3.46-3.53 (1H, td), 3.62-3.66 (1H, dd),
3.73 (3H, s), 3.76-3.79
(1H, d), 3.96-4.00 (1H, dd), 4.21-4.24 (1H, d), 4.58 (1H, bs), 6.79(s, 1H),
6.88-6.90 (2H, d),
7.36-7.38 (2H, d), 7.55-7.57 (2H, d), 8.24-8.26 (2H, d), 8.51 (1H, s), 8.84
(1H, s). Note:methyl
signal obscured by water peak at 3.29
mTOR Kinase Assay (Echo): 0.00145 M
io Example 2u: 'H NMR (400.132 MHz, DMSO-d6) b 1.24-1.25 (3H, d), 1.56-1.59
(2H, q),
1.67-1.70 (2H, q), 2.38 (3H, s), 3.18-3.26 (1H, td), 3.46-3.53 (1H, td), 3.62-
3.66 (1H, dd),
3.76-3.79 (1H, d), 3.96-4.00 (1H, dd), 4.21-4.24 (1H, d), 4.58 (1H, bs), 6.57
(1H, s), 6.80 (s,
1H), 7.56-7.58 (2H, d), 8.27-8.29 (2H, d), 9.06 (1H, s), 9.47 (1H, s).
Note:methyl signal
obscured by water peak at 3.29
is mTOR Kinase Assay (Echo): 0.00118 M
Example 2v: 'H NMR (400.132 MHz, DMSO-d6) b 1.24-1.26 (3H, d), 1.56-1.59 (2H,
q), 1.67-
1.70 (2H, q), 3.19-3.26 (1H, td), 3.31 (3H, s), 3.46-3.53 (1H, td), 3.63-3.66
(1H, dd), 3.76-3.79
(1H, d), 3.97-4.00 (1H, dd), 4.22-4.25 (1H, d), 4.58 (1H, bs), 6.80 (1H, s),
7.60-7.63 (2H, d),
7.72-7.77 (1H, td), 7.79-7.82 (1H, dd), 8.28-8.30 (3H, m), 9.40 (1H, s), 9.89
(1H, s).
20 mTOR Kinase Assay (Echo): 0.00866 M
Example 2w: 'H NMR (400.132 MHz, DMSO-d6) b 0.82 (6H, s), 1.23 (3H, d), 1.54 -
1.57
(2H, m), 3.00 (2H, d), 3.15 (2H, d), 3.18 - 3.24 (1H, m), 3.29 (3H, s), 3.48
(1H, dt), 3.63 (1H,
dd), 3.76 (1H, d), 3.97 (1H, dd), 4.17 (1H, d), 4.21 (1H, d), 4.55 - 4.62 (2H,
m), 6.24 (1H, t),
6.76 (1H, s), 7.49 (2H, d), 8.20 (2H, d), 8.77 (1H, s).
25 mTOR Kinase Assay (Echo): 0.0685 M
Example 2x: 'H NMR (400.132 MHz, DMSO-d6) b 1.23 (3H, d), 1.54 - 1.57 (2H, m),
1.66 -
1.68 (2H, m), 2.70 (2H, t), 3.21 (1H, dt), 3.27 (3H, s), 3.35 - 3.40 (2H, m),
3.48 (1H, dt), 3.64
(1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.22 (1H, d), 4.57 (1H, s), 6.53 (1H,
t), 6.77 (1H, s), 7.52
(2H, d), 8.21 (2H, d), 8.93 (1H, s).
30 mTOR Kinase Assay (Echo): 0.00164 M
Example 2y: 'H NMR (400.132 MHz, DMSO-d6) b 1.23 (3H, d), 1.54 - 1.57 (2H, m),
1.65 -
1.67 (2H, m), 1.70 - 1.73 (4H, m), 2.46 - 2.50 (4H, m), 3.20 - 3.24 (4H, m),
3.27 (3H, s), 3.48


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(1H, dt), 3.63 (1H, dd), 3.76 (1H, d), 3.95 - 3.99 (1H, m), 3.97 (1H, dd),
4.21 (1H, d), 4.56
(1H, s), 6.19 (1H, t), 6.76 (1H, s), 7.50 (2H, d), 8.19 (2H, d), 8.88 (1H, s).
mTOR Kinase Assay (Echo): 0.23 M
Example 2z: 'H NMR (400.132 MHz, DMSO-d6) b 1.23 (3H, d), 1.54 - 1.57 (2H, m),
1.66 -
s 1.68 (2H, m), 3.14 - 3.27 (1H, m), 3.29 (3H, s), 3.45 - 3.56 (2H, m), 3.63
(1H, dd), 3.76 (1H,
d), 3.97 (1H, dd), 4.05 - 4.11 (1H, m), 4.21 (1H, d), 4.57 (1H, s), 6.39 (1H,
t), 6.49 (1H, d),
6.77 (1H, s), 7.51 (2H, d), 8.21 (2H, d), 8.94 (1H, s).
mTOR Kinase Assay (Echo): 0.0181 M
Example 2aa: 'H NMR (400.132 MHz, DMSO-d6) b 1.11 (6H, s), 1.23 (3H, d), 1.54 -
1.57
io (2H, m), 1.66 - 1.68 (2H, m), 3.06 (2H, d), 3.18 (1H, d), 3.22 ('H, dd),
3.29 (3H, s), 3.48 (1H,
dt), 3.63 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.21 (1H, d), 4.52 (1H, s),
4.57 (1H, s), 6.25
(1H, t), 6.76 (1H, s), 7.49 (2H, d), 8.20 (2H, d), 8.90 (1H, s).
mTOR Kinase Assay (Echo): 0.0274 M
Example 2ab: 'H NMR (400.132 MHz, DMSO-d6) b 0.63 - 0.67 (2H, m), 0.69 - 0.73
(2H, m),
is 1.23 (3H, d), 1.54 - 1.57 (2H, m), 1.66 - 1.68 (2H, m), 3.18 - 3.24 (1H,
m), 3.29 (3H, s), 3.43 -
3.52 (3H, m), 3.63 (1H, dd), 3.76 (1H, d), 3.97 (1H, dd), 4.21 (1H, d), 4.56
(1H, s), 4.83 (1H,
s), 6.57 (1H, s), 6.77 (1H, s), 7.48 (2H, d), 8.20 (2H, d), 8.69 (1H, s).
mTOR Kinase Assay (Echo): 0.0553 M
Example 2ac: 'H NMR (400.132 MHz, DMSO-d6) b 1.23 (3H, d), 1.54 - 1.57 (2H,
m), 1.66 -
20 1.68 (2H, m), 3.17 - 3.24 (1H, m), 3.29 (3H, s), 3.48 (1H, dt), 3.63 (1H,
dd), 3.76 (1H, d), 3.97
(1H, dd), 4.21 (1H, d), 4.44 (2H, t), 4.56 (1H, s), 4.72 - 4.82 (3H, m), 6.77
(1H, s), 6.95 (1H,
d), 7.50 (2H, d), 8.20 (2H, d), 8.78 (1H, s).
mTOR Kinase Assay (Echo): 0.00641 M
Example 2ad: 'H NMR (400.132 MHz, DMSO-d6) b 1.24 (3H, d), 1.55 - 1.58 (2H,
m), 1.66 -
25 1.69 (2H, m), 3.17 - 3.25 (1H, m), 3.27 (3H, s), 3.49 (1H, dt), 3.64 (1H,
dd), 3.74 (3H, s), 3.77
(1H, d), 3.98 (1H, dd), 4.22 (1H, d), 4.57 (1H, s), 6.25 (1H, d), 6.79 (1H,
s), 7.54 (1H, t), 7.57
(2H, d), 8.25 (2H, d), 8.92 (1H, s), 9.18 (1H, s).
mTOR Kinase Assay (Echo): 0.000705 M
Example 2ae: 'H NMR (400.132 MHz, DMSO-d6) b 1.25 (3H, d), 1.56 - 1.59 (2H,
m), 1.67 -
30 1.70 (2H, m), 3.17 - 3.23 (1H, m), 3.27 (3H, s), 3.49 (1H, dt), 3.64 (1H,
dd), 3.77 (1H, d), 3.98
(1H, dd), 4.24 (1H, d), 4.58 (1H, s), 6.81 (1H, s), 7.64 (2H, d), 8.30 (2H,
d), 8.35 (1H, s), 9.46
(1H, s).


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mTOR Kinase Assay (Echo): 0.00072 M
Example 2af: 'H NMR (400.132 MHz, DMSO-d6) b 1.25 (3H, d), 1.57 - 1.60 (2H,
m), 1.68 -
1.71 (2H, m), 3.18 - 3.24 (1H, m), 3.27 (3H, s), 3.50 (1H, d), 3.65 (1H, d),
3.77 (1H, d), 3.98
(1H, d), 4.08 (2H, s), 4.25 (1H, d), 4.61 (1H, s), 6.86 (1H, s), 7.55 (2H, d),
8.14 (1H, s), 8.35
s (2H, d), 8.44 (1H, d).
mTOR Kinase Assay (Echo): 0.0462 M
Example 2ag: 'H NMR (400.132 MHz, DMSO-d6) b 1.23 (3H, d), 1.54 - 1.57 (2H,
m), 1.66 -
1.68 (2H, m), 3.18 (1H, d), 3.22 (1H, dd), 3.49 (1H, dt), 3.63 (1H, dd), 3.76
(1H, d), 3.97 (1H,
dd), 4.21 (1H, d), 4.38 (2H, s), 4.44 (1H, s), 4.57 (1H, s), 6.66 (1H, d),
6.77 (1H, s), 7.52 (2H,
io d), 8.19 (1H, d), 8.21 (2H, d), 8.95 (1H, s), 13.83 (1H, s), 13.83 (1H, s).
mTOR Kinase Assay (Echo): 0.0149 M

The preparation of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate is described below:
is
Phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yll-6-(1-
methylsulfonylcyclopropyl)pyrimidin-2-
yllbheU l carbamate

N
O O ~N
. I
N~ \ 0 /
/ N~O ~ ~
H

To a solution of 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
20 methylsulfonylcyclopropyl)pyrimidin-2-yl] aniline (1.35 g, 3.48 mmol) in
1,4-Dioxane (17.4
mL) was added sodium bicarbonate (0.438 g, 5.21 mmol) and phenyl chloroformate
(0.437
mL, 3.48 mmol) and the reaction stirred at RT for 2 hours. The reaction
mixture was diluted
with DCM (20 mL), and washed with water (20 niL), the organic layer dried
(MgSO4), filtered
and evaporated. The crude product was purified by flash silica chromatography,
elution
25 gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a
white solid (1.058 g).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO) b 1.24 (3H, d), 1.57 (2H, m), 1.68
(2H, m),
3.23 (1H, m), 3.49 (1H, m), 3.58 (3H, s), 3.64 (1H, m), 3.77 (1H, d), 3.97
(1H, m), 4.23 (1H,


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d), 4.58 (1H, s), 6.81 (1H, s), 7.25 (2H, d), 7.30 (1H, d), 7.45 (2H, m), 7.64
(2H, d), 8.30 (2H,
d), 10.44 (1H, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 509; HPLC tR = 2.48 min.

s 4-[4-[(3S)-3-Methylmorpholin-4-yll-6-(1-methylsulfonylcyclopropyl)pyrimidin-
2-YIlaniline
C0
N)''i
N
O ~'N
is ~

ONH2

To a solution of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopropyl)pyrimidine (1.52 g, 4.58 mmol) in DMF (0.24 mL), DME
(9.33
mL), water (4.0 mL) and ethanol (2.67 mL) was added 4-(tert-
io butoxycarbonylamino)phenylboronic acid (1.629 g, 6.87 mmol), sodium
carbonate (5.73 mL,
11.45 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.161 g, 0.23
mmol) and the
suspension heated at 80 C for 2 hours. The reaction mixture was cooled to RT,
diluted with
ethyl acetate (10 mL) and washed with water (10 mL). The organic layer was
dried (MgS04),
filtered and evaporated. The crude product was dissolved in DCM (6.67 niL) and
is trifluoroacetic acid (0.353 mL, 4.58 mmol) added and the reaction was
stirred at RT for 16
hours. The crude product was purified by flash silica chromatography, elution
gradient 0 to
10% (7.5N ammonia in methanol) in DCM, to give the desired material as a beige
solid (1.283
g).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO) b 1.24 (3H, d), 1.55 (2H, m), 1.67
(2H, m),
2o 3.23 (1H, m), 3.27 (3H, s), 3.47 (1H, m), 3.63 (1H, m), 3.77 (1H, d), 3.97
(1H, m), 4.24 (1H,
s), 4.58 (1H, s), 5.75 (1H, s), 6.68 (2H, d), 8.04 (2H, d)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 389; HPLC tR = 1.82 min.


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Example 3: 3-Cvclonronvl-l-f4-f4-(1-cvclonronvlsulfonvlcvclonronvl)-6-f (3S)-3-

methylmorpholin-4-yll pyrimidin-2-yll phenyll urea
C0
N)''i
O O - N
S IN 1 O
/ NJ~ NA
H H

[4-(3-Cyclopropylureido)phenyl]boronic acid, pinacol ester (199 mg, 0.66
mmol), 2-chloro-4-
s (1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine
(189mg,
0.53 mmol), dichlorobis(triphenylphosphine)palladium(II) (37.1 mg, 0.05 mmol)
and sodium
carbonate (1.32 mL, 2.64 mmol) were dissolved in a solution of 18% DMF in
DME:Water:Ethano17:3:2 (4 mL) and sealed into a microwave tube. The reaction
was heated
to 100 C for 20 minutes in the microwave reactor and cooled to RT. The crude
product was
io purified by ion exchange chromatography, using an SCX column. The desired
product was
eluted from the column using 7M ammonia in methanol and pure fractions were
evaporated to
dryness to afford a crude product. The crude product was purified by
preparative HPLC using
decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents.
Fractions
containing the desired compound were evaporated to dryness to afford the
desired material as
is a colourless gum (69.0 mg).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO) b 0.40 - 0.44 (2H, m), 0.62 - 0.67
(2H, m),
0.91 - 0.97 (1H, m), 0.94 (1H, s), 1.02 - 1.04 (2H, m), 1.23 (3H, t), 1.55 -
1.58 (2H, m), 1.64 -
1.66 (2H, m), 2.56 (1H, s), 2.98 - 3.02 (1H, m), 3.18 (1H, d), 3.46 - 3.52
(1H, m), 3.62 - 3.66
(1H, m), 3.77 (1H, d), 3.96 - 4.00 (1H, m), 4.17 - 4.21 (1H, m), 4.53 (1H, s),
6.42 (1H, d),
2o 6.85 (1H, s), 7.49 - 7.51 (2H, m), 8.20 - 8.22 (2H, m), 8.53 (1H, s).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 498; HPLC tR = 1.95 min.
mTOR Kinase Assay (Echo): 0.00195 M

Example 3, 3-cyclopropyl-l-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-
2s methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]urea, may also be prepared as
described below.
To a solution of phenyl N-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-
methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (150 mg, 0.28 mmol) in
DMF (2


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mL) was added triethylamine (0.177 mL, 0.84 mmol) followed by cyclopropylamine
(0.097
mL, 1.40mmo1) and the reaction heated at 50 C for 2 hours. The crude product
was purified
by preparative HPLC using decreasingly polar mixtures of water (containing 1%
NH3) and
acetonitrile as eluents, to give the desired material as a white solid (103
mg).
s NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 0.40 - 0.44 (2H, m), 0.62 -
0.67 (2H,
m), 0.90 - 0.97 (2H, m), 1.02 - 1.04 (2H, m), 1.24 (3H, d), 1.56 - 1.60 (2H,
m), 1.65 (2H, d),
2.60(1H,t),2.96-3.02(1H,m),3.20-3.24(1H,m),3.46-3.52(1H,m),3.62-3.66(1H,
m), 3.77 (1H, d), 3.96 - 4.00 (1H, m), 4.19 (1H, d), 4.53 (1H, s), 6.42 (1H,
d), 6.85 (1H, s),
7.50 (2H, d), 8.21 (2H, d), 8.53 (1 H, s)
io LCMS Spectrum: m/z (ESI+)(M+H)+ = 498; HPLC tR = 2.13 min.

The following compounds were prepared in an analogous fashion from phenyl N-[4-
[4-(1-
cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-
yl]phenyl]carbamate using the appropriate amine.

is

Example Structure NAME LCMS Retention
MH+ time (min)
3a (01 3-cyclobutyl-l-[4-[4-(1- 512 2.38
N cyclopropylsulfonylcyclopropyl)-
O O " N
lk ~ 6-[(3S)-3-methylmorpholin-4-
N N
" H yl]pyrimidin-2-yl]phenyl]urea
3b 1-[4-[4-(1- 535 2.58
0 CN ' ~. N .
cyclopropylsulfonylcyclopropyl)-
0
0 6-[(3S)-3-methylmorpholin-4-
N~N N
" H yl]pyrimidin-2-yl]phenyl]-3-
pyridin-2-yl-urea
3c c l 1-[4-[4-(1- 514 2.46
N cyclopropylsulfonylcyclopropyl)-
0 0 " N
N o ')o' 6-[(3S)-3-methylmorpholin-4-
N'k N
" H yl]pyrimidin-2-yl]phenyl]-3-(2-
methylpropyl)urea


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Example Structure NAME LCMS Retention
MH+ time (min)
3d c l 1-[4-[4-(1- 500 2.28
N cyclopropylsulfonylcyclopropyl)-
0. O N
~s N~ o 6-[(3S)-3-methylmorpholin-4-
" " 1]pyrimidin-2-yl]phenyl]-3-
ropan-2-yl-urea
3e 3-[4-[4-(1- 486 2.12
(01 N..,
cyclopropylsulfonylcyclopropyl)-
0 ~N
N NxN 6-[(3S)-3-methylmorpholin-4-
" H 1]pyrimidin-2-yl]phenyl]-1-
ethyl-urea

3f (01 1-[4-[4-(1- 529 2.04
N cyclopropylsulfonylcyclopropyl)-
0 ~N I
N NN f N 6-[(3S)-3-methylmorpholin-4-
" H yI]pyrimidin-2-yI]phenyI]-3-(2-
dimethylaminoethyl)urea
3g (01 1-[4-[4-(1- 502 1.79
N cyclopropylsulfonylcyclopropyl)-
0 ~N
N 0 fo" 6-[(3S)-3-methylmorpholin-4-
" " yI]pyrimidin-2-yI]phenyI]-3-(2-
hydroxyethyl)urea
3h 3-[4-[4-(1- 500 2.29
N cyclopropylsulfonylcyclopropyl)-
O O " N
N 0 6-[(3S)-3-methylmorpholin-4-
" " 1]pyrimidin-2-yl]phenyl]-1-
ropyl-urea


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Example Structure NAME LCMS Retention
MH+ time (min)
3i (01 1-[4-[4-(1- 472 1.96
N cyclopropylsulfonylcyclopropyl)-
O. O I 1~
s N o 6-[(3S)-3-methylmorpholin-4-
~ N)~ N"
" H 1]pyrimidin-2-yl]phenyl]-3-
ethyl-urea
3j c l 1-[4-[4-(1- 602 3.00

o ~N0)IN F cyclopropylsulfonylcyclopropyl)-
d~ r FF 6-[(3S)-3-methylmorpholin-4-
H H
1]pyrimidin-2-yl]phenyl]-3-[4-
(trifluoromethyl)phenyl]urea
3k 1-[4-[4-(1- 530 2.10
CN~.,.,
cyclopropylsulfonylcyclopropyl)-
0 0 I N
s 0 ~ H 6-[(3S)-3-methylmorpholin-4-
~ N~N'~
" H 1]pyrimidin-2-yl]phenyl]-3-(1-
hydroxy-2-methyl-propan-2-
1)urea
31 1-[4-[4-(1- 516 1.83
CN~.,.,
O o 'N OH cyclopropylsulfonylcyclopropyl)-
N 0 ~ 6-[(3S)-3-methylmorpholin-4-
N)~ N
" H yI]pyrimidin-2-yI]phenyI]-3-(3-
hydroxypropyl)urea
3m 1-[4-[4-(1- 538 2.00

0 cyclopropylsulfonylcyclopropyl)-
~0 N
d x ~;N- 6-[(3S)-3-methylmorpholin-4-
N N
H H yI]pyrimidin-2-yI]phenyI]-3-(I-
methylpyrazol-4-yl)urea


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Example Structure NAME LCMS Retention
MH+ time (min)
3n 1-[4-[4-(1- 544 2.02
N cyclopropylsulfonylcyclopropyl)-
O O I ~ OH
~s 6-[(3S)-3-methylmorpholin-4-
NN
H H yI]pyrimidin-2-yI]phenyI]-3-(3-
hydroxy-2,2-dimethylpropyl)urea
3o (0)3-(2-cyanoethyl)-1-[4-[4-(1- 511 1.92
N ~~ cyclopropylsulfonylcyclopropyl)-
0 0 ~N ~N
~s " ~ 0 ~ 6- [(3S)-3-methylmorpholin-4-
~ N)~ N
H H 1]pyrimidin-2-yl]phenyl]urea

3p ( ~ 1-[4-[4-(1- 555 2.17
0 0 ; ~~ ~ cyclopropylsulfonylcyclopropyl)-

lmo~-7-~holin-4-
dSZS " N 6- 3S -3-methy `Y
N~N ~ [( )
H H yI]pyrimidin-2-yI]phenyI]-3-(2-
pyrrolidin-

3q ( ) 1-[4-[4-(1- 570 2.01
N cyclopropylsulfonylcyclopropyl)-
0 0 " N F
" ~ ~F 6-[(3S)-3-methylmorpholin-4-
N N
H H 1]pyrimidin-2-yl]phenyl]-3-
(3,3,3-trifluoro-2-
hydroxypropyl)urea
3r 1-[4-[4-(1- 530 1.91
N cyclopropylsulfonylcyclopropyl)-
O O I ~
~s N 0 _~ H 6-[(3S)-3-methylmorpholin-4-
N)~ N
H H yI]pyrimidin-2-yI]phenyI]-3-(2-
hydroxy-2-methylpropyl)urea


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Example Structure NAME LCMS Retention
MH+ time (min)
3s 1-[4-[4-(1- 528 1.91
N cyclopropylsulfonylcyclopropyl)-
O O ~N
s N 0 II
Hx H 6-[(3S)-3-methylmorpholin-4-
/ H
1]pyrimidin-2-yl]phenyl]-3-[ 1-
(hydroxymethyl)cyclopropyl]urea
3t 1-[4-[4-(1- 514 1.92

N cyclopropylsulfonylcyclopropyl)-
0 0 " N
N 0 ~O 6-[(3S)-3-methylmorpholin-4-
N N
" H 1]pyrimidin-2-yl]phenyl]-3-
(oxetan-3-yl)urea
3u (0)1-[4-[4-(1- 538 2.22
N ~/
0 0 ~ ;N cyclopropylsulfonylcyclopropyl)-
d~ N NkNC N 6-[(3S)-3-methylmorpholin-4-
H H yl]

3w 1-[4-[4-(1- 542 1.50
N cyclopropylsulfonylcyclopropyl)-
0 0 " N
N~ oII s'N 6-[(3S)-3-methylmorpholin-4-
/ NlINN
" H 1]pyrimidin-2-yl]phenyl]-3-
(1,2,4-thiadiazol-5-yl)urea
Example 3a: 'H NMR (400.13 MHz, DMSO-d6) b 0.90 - 0.97 (2H, m), 1.02 - 1.04
(2H, m),
1.23 (3H, d), 1.56 - 1.59 (2H, m), 1.63 (2H, d), 1.65 (2H, d), 1.83 (1H, d),
1.86 (1H, t), 2.17 -
2.25 (2H, m), 2.97 - 3.01 (1H, m), 3.17 - 3.24 (1H, m), 3.46 - 3.52 (1H, m),
3.62 - 3.66 (1H,
s m), 3.77 (1H, d), 3.96 - 3.99 (1H, m), 4.11 - 4.17 (1H, m), 4.20 (1H, s),
4.53 (1H, d), 6.45
(1H, d), 6.84 (1H, s), 7.46 - 7.48 (2H, m), 8.20 (2H, d), 8.55 (1H, s).
mTOR Kinase Assay (Echo): 0.00445 M
Example 3b: 'H NMR (400.13 MHz, DMSO-d6) b 0.88 - 0.98 (2H, m), 0.99 - 1.06
(2H, m),
1.25 (3H, d), 1.57 - 1.62 (2H, m), 1.65 - 1.68 (2H, m), 2.99 - 3.05 (1H, m),
3.19 - 3.23 (1H,
io m), 3.47 - 3.54 (1H, m), 3.63 - 3.67 (1H, m), 3.78 (1H, d), 3.97 - 4.01
(1H, m), 4.21 (1H, d),


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4.54 (1H, d), 6.88 (1H, s), 7.02 - 7.05 (1H, m), 7.56 (1H, d), 7.63 (2H, d),
7.75 - 7.77 (1H, m),
8.29 - 8.31 (3H, m), 9.44 (1H, d), 10.58 (1H, s).
mTOR Kinase Assay (Echo): 0.00385 M
Example 3c: 'H NMR (400.13 MHz, DMSO-d6) b 0.88 - 0.90 (6H, m), 0.94 (2H, t),
1.00 -
s 1.06 (2H, m), 1.24 (3H, d), 1.55 - 1.58 (2H, m), 1.64 - 1.66 (2H, m), 1.67 -
1.74 (1H, m), 2.94
(2H, t), 2.98 - 3.02 (1H, m), 3.20 - 3.24 (1H, m), 3.46 - 3.52 (1H, m), 3.62 -
3.66 (1H, m),
3.77 (1H, d), 3.96 - 4.00 (1H, m), 4.19 (1H, d), 4.53 (1H, s), 6.23 (1H, t),
6.84 (1H, s), 7.47 -
7.50 (2H, m), 8.20 - 8.22 (2H, m), 8.63 (1H, s).
mTOR Kinase Assay (Echo): 0.0124 M
io Example 3d: 'H NMR (400.13 MHz, DMSO-d6) b 0.91 - 0.97 (2H, m), 1.00 - 1.05
(2H, m),
1.11 (6H, d), 1.23 (3H, d), 1.55 - 1.58 (2H, m), 1.64 - 1.66 (2H, m), 2.97 -
3.03 (1H, m), 3.17
- 3.24 (1H, m), 3.46 - 3.52 (1H, m), 3.62 - 3.66 (1H, m), 3.76 (2H, d), 3.96 -
4.00 (1H, m),
4.19 (1H, d), 4.53 (1H, s), 6.05 (1H, d), 6.84 (1H, s), 7.46 - 7.49 (2H, m),
8.19 - 8.22 (2H, m),
8.52 (1H, s).
is mTOR Kinase Assay (Echo): 0.0135 M
Example 3e: 'H NMR (400.13 MHz, DMSO-d6) b 0.92 - 0.94 (2H, t), 1.02 - 1.04
(2H, m),
1.07 (3H, t), 1.23 (3H, d), 1.58 (2H, d), 1.64 - 1.66 (2H, m), 2.98 - 3.02
(1H, m), 3.17 - 3.18
(1H, m), 3.14 - 3.24 (2H, m), 3.47 - 3.52 (1H, m), 3.62 - 3.66 (1H, m), 3.77
(1H, d), 3.96 -
4.00 (1H, m), 4.19 (1H, d), 4.53 (1H, s), 6.15 (1H, t), 6.84 (1H, s), 7.47 -
7.51 (2H, m), 8.19 -
2o 8.22 (2H, m), 8.65 (1H, s).
mTOR Kinase Assay (Echo): 0.00166 M
Example 3f: 'H NMR (400.13 MHz, DMSO-d6) b 0.91 - 0.97 (2H, m), 0.98 - 1.05
(2H, m),
1.23 (3H, d), 1.55 - 1.58 (2H, m), 1.64 - 1.66 (2H, m), 2.18 (6H, s), 2.34
(2H, t), 2.97 - 3.03
(1H, m), 3.19 (3H, q), 3.46 - 3.52 (1H, m), 3.62 - 3.66 (1H, m), 3.77 (1H, d),
3.96 - 4.00 (1H,
25 m), 4.19 (1H, d), 4.53 (1H, s), 6.15 (1H, t), 6.84 (1H, s), 7.47 - 7.50
(2H, m), 8.19 - 8.22 (2H,
m), 8.88 (1H, s).
mTOR Kinase Assay (Echo): 0.0214 M
Example 3g: 'H NMR (400.13 MHz, DMSO-d6) b 0.91 - 0.97 (2H, m), 1.00 - 1.05
(2H, m),
1.23 (3H, d), 1.55 - 1.58 (2H, m), 1.64 - 1.66 (2H, m), 2.97 - 3.03 (1H, m),
3.16 - 3.21 (3H,
30 m), 3.44 - 3.52 (3H, m), 3.62 - 3.66 (1H, m), 3.77 (1H, d), 3.96 - 4.00
(1H, m), 4.17 - 4.21
(1H, m), 4.53 (1H, s), 4.72 (1H, t), 6.25 (1H, t), 6.84 (1H, s), 7.47 - 7.50
(2H, m), 8.20 - 8.22
(2H, m), 8.79 (1H, s).


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mTOR Kinase Assay (Echo): 0.00134 M
Example 3h: 'H NMR (400.13 MHz, DMSO-d6) b 0.89 (3H, t), 0.91 - 0.95 (2H, m),
1.02 -
1.04 (2H, m), 1.23 (3H, d), 1.41 - 1.50 (2H, m), 1.56 - 1.60 (2H, m), 1.64 -
1.66 (2H, m), 2.98
- 3.02 (1H, m), 3.04 - 3.09 (2H, m), 3.20 - 3.24 (1H, m), 3.47 - 3.52 (1H, m),
3.62 - 3.66 (1H,
s m), 3.77 (1H, d), 3.96 - 4.00 (1H, m), 4.19 (1H, d), 4.53 (1H, s), 6.20 (1H,
t), 6.84 (1H, s),
7.47 - 7.50 (2H, m), 8.20 - 8.22 (2H, m), 8.64 (1H, s).
mTOR Kinase Assay (Echo): 0.0165 M
Example 3i: 'H NMR (400.13 MHz, DMSO-d6) b 0.92 - 0.95 (2H, m), 1.02 - 1.05
(2H, m),
1.23 (3H, d), 1.56 - 1.60 (2H, m), 1.63 - 1.66 (2H, m), 2.66 (3H, d), 2.98 -
3.02 (1H, m), 3.17
io - 3.24 (1H, m), 3.46 - 3.52 (1H, m), 3.62 - 3.66 (1H, m), 3.77 (1H, d),
3.96 - 4.00 (1H, m),
4.19 (1H, d), 4.53 (1H, s), 6.05 (1H, t), 6.84 (1H, s), 7.48 - 7.51 (2H, m),
8.19 - 8.22 (2H, m),
8.73 (1H, s).
mTOR Kinase Assay (Echo): 0.000932 M
Example 3j: 'H NMR (400.13 MHz, DMSO-d6) b 0.92 - 0.98 (2H, m), 1.01 - 1.05
(2H, m),
is 1.25 (3H, d), 1.57 - 1.62 (1H, m), 1.61 (1H, d), 1.65 - 1.68 (2H, m), 2.97 -
3.04 (1H, m), 3.22
- 3.26 (1H, m), 3.47 - 3.53 (1H, m), 3.63 - 3.67 (1H, m), 3.78 (1H, d), 3.97 -
4.00 (1H, m),
4.21 (1H, d), 4.55 (1H, s), 6.87 (1H, s), 7.57 - 7.59 (2H, m), 7.63 - 7.70
(4H, m), 8.29 (2H, d),
9.04 (1H, s), 9.13 (1H, s).
mTOR Kinase Assay (Echo): 0.00422 M
2o Example 3k: 'H NMR (400.13 MHz, DMSO-d6) b 0.94 (2H, t), 1.04 (2H, d), 1.23
(6H, d),
1.24 (3H, d), 1.56 - 1.59 (2H, m), 1.64 - 1.66 (2H, m), 2.98 - 3.02 (1H, m),
3.18 (1H, d), 3.39
(2H, d), 3.46 - 3.52 (1H, m), 3.62 - 3.66 (1H, m), 3.77 (1H, d), 3.96 - 4.00
(1H, m), 4.19 (1H,
d), 4.52 (1H, s), 4.95 (1H, t), 6.00 (1H, s), 6.84 (1H, s), 7.43 - 7.47 (2H,
m), 8.19 - 8.21 (2H,
m), 8.73 (1H, s).
25 mTOR Kinase Assay (Echo): 0.00227 M
Example 31: 'H NMR (400.13 MHz, DMSO-d6) b 0.91 - 0.94 (2H, m), 1.01 - 1.05
(2H, m),
1.23 (3H, d), 1.55 - 1.58 (2H, m), 1.60 -1.61 (2H, m), 1.65 (1H, m), 2.98 -
3.02 (1H, m), 3.17
(1H, d), 3.18 - 3.23 (2H, m), 3.45 - 3.49 (3H, m), 3.50 (1H, d), 3.62 - 3.66
(1H, m), 3.77 (1H,
d), 3.96 - 4.00 (1H, m), 4.17 (1H, s), 4.47 (1H, t), 4.53 (1H, s), 6.20 (1H,
t), 6.84 (1H, s), 7.48
30 - 7.50 (2H, m), 8.21 (2H, d), 8.70 (1H, s).
mTOR Kinase Assay (Echo): 0.00257 M


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Example 3m: 'H NMR (400.13 MHz, DMSO-d6) b 0.93 - 0.95 (2H, m), 1.02 - 1.05
(2H, m),
1.24 (3H, d), 1.57 - 1.60 (2H, m), 1.65 - 1.67 (2H, m), 2.98 - 3.02 (1H, m),
3.18 (1H, t), 3.46 -
3.50 (1H, m), 3.63 - 3.66 (1H, m), 3.76 (1H, s), 3.79 (3H, s), 3.96 - 4.00
(1H, m), 4.18 (1H, s),
4.53 (1H, s), 6.86 (1H, s), 7.38 - 7.38 (1H, m), 7.55 (2H, t), 7.76 (1H, s),
8.25 (2H, d), 8.38
s (1H, s), 8.83 (1H, s).
mTOR Kinase Assay (Echo): 0.000497 M
Example 3n: 'H NMR (400.13 MHz, DMSO-d6) b 0.81 (6H, s), 0.91 - 0.95 (2H, m),
1.01 -
1.05 (2H, m), 1.23 (3H, d), 1.56 - 1.60 (3H, m), 1.63 - 1.66 (2H, m), 2.98 -
3.02 (2H, m), 3.15
(2H, d), 3.21 (1H, dt), 3.49 (1H, dt), 3.64 (1H, dd), 3.77 (1H, d), 4.19 (1H,
d), 4.53 (1H, s),
io 4.61 (1H, t), 6.26 (1H, t), 6.84 (1H, s), 7.48 (2H, d), 8.21 (2H, d), 8.78
(1H, s).
mTOR Kinase Assay (Echo): 0.0396 M
Example 3o: 'H NMR (400.13 MHz, DMSO-d6) b 0.90 - 0.95 (2H, m), 1.00 - 1.06
(2H, m),
1.24 (3H, d), 1.56 - 1.60 (2H, m), 1.63 - 1.66 (2H, m), 2.70 (2H, t), 2.96 -
3.03 (1H, m), 3.17 -
3.25 (1H, m), 3.35 - 3.39 (2H, m), 3.49 (1H, dt), 3.64 (1H, dd), 3.77 (1H, d),
3.98 (1H, dd),
is 4.19 (1H, d), 4.53 (1H, s), 6.52 (1H, t), 6.85 (1H, s), 7.51 (2H, d), 8.22
(2H, d), 8.91 (1H, s).
mTOR Kinase Assay (Echo): 0.00596 M
Example 3p: 'H NMR (400.13 MHz, DMSO-d6) b 0.93 - 0.94 (2H, m), 1.02 - 1.04
(2H, m),
1.23 (3H, d), 1.56 - 1.58 (2H, m), 1.64 - 1.67 (2H, m), 1.72 (8H, m), 2.94 -
3.02 (1H, m), 3.18
- 3.24 (5H, m), 3.49 (1H, t), 3.64 (1H, d), 3.77 (1H, d), 3.97 (1H, d), 4.19
(1H, d), 4.53 (1H,
20 s), 6.22 (1H, s), 6.84 (1H, s), 7.49 (2H, d), 8.21 (2H, d), 8.88 (1H, s).
mTOR Kinase Assay (Echo): 0.193 M
Example 3q: 'H NMR (400.13 MHz, DMSO-d6) b 0.91 - 0.95 (2H, m), 1.00 - 1.06
(2H, m),
1.23 (3H, d), 1.56 - 1.60 (2H, m), 1.63 - 1.66 (2H, m), 2.96 - 3.03 (1H, m),
3.14 - 3.25 (2H,
m), 3.46 - 3.55 (2H, m), 3.64 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.07 -
4.08 (1H, m), 4.19
25 (1H, d), 4.52 (1H, s), 6.42 (1H, t), 6.49 (1H, s), 6.85 (1H, s), 7.50 (2H,
d), 8.22 (2H, d), 8.95
(1H, s).
mTOR Kinase Assay (Echo): 0.00839 M
Example 3r: 'H NMR (400.13 MHz, DMSO-d6) b 0.91 - 0.95 (2H, m), 1.00 - 1.06
(2H, m),
1.10 (6H, s), 1.23 (3H, d), 1.56 - 1.60 (2H, m), 1.61 - 1.66 (2H, m), 2.97 -
3.02 (1H, m), 3.06
30 (2H, d), 3.22 (1H, dd), 3.49 (1H, dt), 3.64 (1H, dd), 3.77 (1H, d), 3.98
(1H, dd), 4.19 (1H, d),
4.52 (1H, s), 4.54 (1H, s), 6.24 (1H, t), 6.84 (1H, s), 7.48 (2H, d), 8.21
(2H, d), 8.88 (1H, s).
mTOR Kinase Assay (Echo): 0.0488 M


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Example 3s: 'H NMR (400.13 MHz, DMSO-d6) b 0.63 - 0.67 (2H, m), 0.69 - 0.73
(2H, m),
0.91 - 0.95 (2H, m), 1.02 - 1.04 (2H, m), 1.23 (3H, d), 1.56 - 1.60 (2H, m),
1.63 - 1.66 (2H,
m), 2.97 - 3.03 (1H, m), 3.17 - 3.25 (2H, m), 3.44 (1H, d), 3.46 - 3.52 (1H,
m), 3.64 (1H, dd),
3.77 (1H, d), 3.98 (1H, dd), 4.19 (1H, d), 4.52 (1H, s), 4.83 (1H, s), 6.56
(1H, s), 6.85 (1H, s),
s 7.47 (2H, d), 8.21 (2H, d), 8.67 (1H, s).
mTOR Kinase Assay (Echo): 0.0263 M
Example 3t: 'H NMR (400.13 MHz, DMSO-d6) b 0.91 - 0.95 (2H, m), 1.00 - 1.07
(2H, m),
1.23 (3H, d), 1.56 - 1.61 (2H, m), 1.63 - 1.66 (2H, m), 2.96 - 3.02 (1H, m),
3.21 (1H, dt), 3.49
(1H, dt), 3.64 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.19 (1H, d), 4.45 (2H,
t), 4.52 (1H, s),
io 4.72 - 4.83 (3H, m), 6.85 (1H, s), 6.95 (1H, d), 7.49 (2H, d), 8.22 (2H,
d), 8.78 (1H, s).
mTOR Kinase Assay (Echo): 0.00479 M
Example 3u: 'H NMR (400.13 MHz, DMSO-d6) b 0.91 - 0.95 (2H, m), 1.00 - 1.07
(2H, m),
1.23 (3H, d), 1.56 - 1.61 (2H, m), 1.63 - 1.66 (2H, m), 2.96 - 3.02 (1H, m),
3.21 (1H, dt), 3.49
(1H, dt), 3.64 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.19 (1H, d), 4.45 (2H,
t), 4.52 (1H, s),
is 4.72 - 4.83 (3H, m), 6.85 (1H, s), 6.95 (1H, d), 7.49 (2H, d), 8.22 (2H,
d), 8.78 (1H, s).
mTOR Kinase Assay (Echo): 0.000604 M
Example 3v: 'H NMR (400.13 MHz, DMSO-d6) b 0.94 - 0.96 (2H, m), 1.03 - 1.05
(2H, m),
1.24 (3H, d), 1.57 - 1.59 (2H, m), 1.64 - 1.66 (2H, m), 2.98 - 3.03 (1H, m),
3.19 - 3.25 (1H,
m), 3.50 (1H, t), 3.65 (1H, d), 3.74 (3H, s), 3.77 (1H, d), 3.98 (1H, d), 4.21
(1H, d), 4.54 (1H,
20 s), 6.24 (1H, d), 6.86 (1H, s), 7.54 - 7.55 (1H, m), 7.56 (2H, d), 8.26
(2H, d), 8.92 (1H, s),
9.17 (1H, s).
Example 3w: 'H NMR (400.13 MHz, DMSO-d6) b 0.92 - 0.96 (2H, m), 1.02 - 1.06
(2H, m),
1.25 (3H, d), 1.58 - 1.60 (2H, m), 1.66 - 1.67 (2H, m), 2.98 - 3.05 (1H, m),
3.20 - 3.23 (1H,
m), 3.50 (1H, t), 3.65 (1H, d), 3.78 (1H, d), 3.99 (1H, d), 4.21 (1H, d), 4.55
(1H, s), 6.89 (1H,
25 s), 7.63 (2H, d), 8.31 - 8.36 (3H, m), 9.43 (1H, s).
mTOR Kinase Assay (Echo): 0.00089 M

The preparation of phenyl N-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-

methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate is described below:



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Phenyl N-[4-[4-(1-cycloprol2ylsulfonylcycloprol2yl)-6-[(3S)-3-methylmorpholin-
4-
yll12yrimidin-2-yl]phenyll carbamate

N
O O ~N
~

~ N/ / lk ~ I
O
H

Phenyl chloroformate (0.729 mL, 5.79 mmol) was added dropwise to 4-[4-(1-
s cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-
yl]aniline
(2.40 g, 5.79 mmol) and sodium bicarbonate (0.730 g, 8.68 mmol) in dioxane (45
mL) under
nitrogen. The resulting suspension was stirred at 20 C for 2 hours. The
reaction mixture was
evaporated to dryness and redissolved in ethyl acetate (200 mL) and washed
with water (200
mL). The organic layer was dried (MgSO4), filtered and evaporated to afford
the desired
io material as a white solid (3.03 g).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 0.92 - 0.95 (2H, m), 1.03 - 1.05
(2H,
m), 1.25 (3H, d), 1.57 - 1.61 (1H, m), 1.61 (1H, d), 1.65 - 1.68 (2H, m), 2.99
- 3.03 (1H, m),
3.46 - 3.47 (1H, m), 3.49 - 3.53 (1H, m), 3.63 - 3.66 (1H, m), 3.77 (1H, d),
3.96 - 4.00 (1H,
m), 4.22 (1H, d), 4.56 (1H, s), 6.89 (1H, s), 7.26 (1H, t), 7.24 - 7.30 (2H,
m), 7.43 - 7.47 (2H,
is m), 7.60 - 7.65 (2H, m), 8.29 - 8.32 (2H, m), 10.43 (1H, s)
LCMS Spectrum: m/z (ESI+) (M+H)+ = 535; HPLC tR = 2.84 min.
4-[4-(1-Cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-methylmorpholin-4-
yllpyrimidin-2-
1 aniline
N~-'-,

O O N
S N
20 / NH2

Dichlorobis(triphenylphosphine)palladium(II) (0.524 g, 0.75 mmol) was added to
a degassed
solution of 2-chloro-4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3S)-3-
methylmorpholin-4-
yl]pyrimidine (2.67 g, 7.46 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)aniline
(2.043 g, 9.33 mmol) and sodium carbonate (18.65 mL, 37.31 mmol) in 18% DMF in
7:3:2
25 DME:Water:Ethanol (20 mL). The resulting solution was stirred at 85 C for 1
hour. The


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reaction mixture was concentrated and diluted with DCM (150 mL), and washed
with water
(100 mL) and brine (100 mL). The organic layer was dried (MgSO4), filtered and
evaporated
to afford crude product. The crude product was purified by flash silica
chromatography,
elution gradient 0 to 2.5% methanol in DCM, to give the desired material as a
brown solid
(2.40 g).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 0.90 - 0.98 (2H, m), 0.98 - 1.05
(2H,
m), 1.22 (3H, d), 1.52 - 1.59 (2H, m), 1.62 - 1.64 (2H, m), 2.95 - 3.02 (1H,
m), 3.14 - 3.22
(1H, m), 3.45 - 3.51 (1H, m), 3.61 - 3.65 (1H, m), 3.76 (1H, d), 3.95 - 3.98
(1H, m), 4.14 -
4.17 (1H, m), 4.48 - 4.51 (1H, m), 5.53 (2H, d), 6.60 (2H, d), 6.75 (1H, s),
8.03 - 8.06 (2H,
lo m).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 415; HPLC tR = 2.13 min.
2-Chloro-4-(1-cycloprol2ylsulfonylcycloprol2yl)-6-[(3S)-3-methylmorpholin-4-
yl]l2yrimidine
C0
N)''i
0 0 I N
N~CI

is 5N Sodium hydroxide solution (1.74 mL, 8.68 mmol) was added to
tetrabutylammonium
bromide (0.140 g, 0.43 mmol), 1,2-dibromoethane (0.374 mL, 4.34 mmol) and 2-
chloro-4-
(cyclopropylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.44 g,
4.34 mmol)
in DCM (20 mL). The resulting mixture was stirred at 40 C for 2 hours.
Additional solid
sodium hydroxide (4 g, 0.1 mol) was added directly to the reaction and stirred
at 40 C for a
20 further 1 hour. The reaction mixture was diluted with DCM (20 mL) and
washed with water
(50 mL). The organic layer was dried (MgS04), filtered and evaporated to
afford the desired
material (1.68 g).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 358; HPLC tR = 1.87 min.

25 2-Chloro-4-(cycloprol2ylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-
yll12yrimidine
C(0).",

0 0 I N
~/S N~CI


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Cyclopropanesulfinic acid, sodium salt (381 mg, 2.97 mmol) was added in one
portion to 2-
chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (700 mg, 1.98
mmol) in
acetonitrile (20 mL) at RT. The resulting suspension was stirred at 90 C for 3
hours. The
reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and
washed
s with water (50 mL). The organic layer was dried (MgSO4), filtered and
evaporated to afford
crude product. The crude product was purified by flash silica chromatography,
elution
gradient 0 to 40% ethyl acetate in DCM, to gve the desired material as a white
solid (458 mg).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO) b 0.95 - 0.98 (2H, m), 1.02 - 1.06
(2H, m),
1.18 - 1.23 (3H, m), 2.77 - 2.83 (1H, m), 3.19 - 3.25 (1H, m), 3.42 - 3.49
(1H, m), 3.58 - 3.62
io (1H, m), 3.73 (1H, d), 3.92 - 3.96 (2H, m), 4.30 (1H, s), 4.48 (2H, s),
6.92 (1H, s).
LCMS Spectrum: m/z (ESI+) (M+H)+ = 332; HPLC tR = 1.68 min.

The preparation of 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidine was
described earlier.

is
Example 4: 3-Methyl-l-f4-f4-f(3S)-3-methylmorpholin-4-yll-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yll phenyll urea

C(0).",

O O ~N
S I N N~ O
NN
H H

Triethylamine (0.15 mL, 1.1 mmol) was added to a solution of phenyl N-[4-[4-
[(3S)-3-
2o methylmorpholin-4-yl]-6-(1-methylsulfonylcyclopentyl)pyrimidin-2-
yl]phenyl]carbamate
(200 mg, 0.37 mmol) and methylamine (2M in THF, 1.48 mmol) in NMP (2 niL). The
reaction was heated at 80 C for 2 hours the purified by prep HPLC, using a
mixture of water
(containing 1% NH3) and acetonitrile as eluents, to give the desired material
as a solid (126
mg).
25 NMR Spectrum: 'H NMR (400.132 MHz, DMSO-d6) b 1.21 (3H, d), 1.52-1.62 (2H,
m), 1.75-
1.90 (2H, m), 2.38-2.50 (2H, m), 2.65 (3H, d), 2.65-2.78 (2H, m), 2.89 (3H,
s), 3.20 (1H, dd),
3.50 (1H, dd), 3.64 (1H, d), 3.75 (1H, d), 3.95 (1H, dd), 4.25 (1H, d), 4.55
(1H, s), 6.05 (1H,
q), 6.79 (1H, s), 7.50 (2H, d), 8.22 (2H, d), 8.72 (1H, s).


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LCMS Spectrum: m/z (ESI+)(M+H)+ = 474; HPLC tR = 1.96 min
mTOR Kinase Assay (Echo): 0.000699 M

The following compounds were prepeared in an analogous fashion from phenyl N-
[4-[4-[(3S)-
s 3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclopentyl)pyrimidin-2-
yl]phenyl]carbamate
and the appropriate amine.

Example Structure AME LCMS Retention
MH+ time (min)
4a c l 3-ethyl-l-[4-[4-[(3S)-3- 488 2.13
N ethylmorpholin-4-yl]-6-(1-
O. O ~N
0 ethylsulfonylcyclopentyl)p
NNj
H H rimidin-2-yl]phenyl]urea

4b c ~ 3-cyclopropyl-l-[4-[4-[(3S)- 500 2.13
N 3-methylmorpholin-4-yl]-6-
0 INN
aN O N/~ /~ (1-
" H ethylsulfonylcyclopentyl)p
rimidin-2-yl]phenyl]urea
4c (01 1-[4-[4-[(3S)-3- 502 2.29
N ethylmorpholin-4-yl]-6-(1-
O. O ~N
0 ethylsulfonylcyclopentyl)p
Nfl, N
H H rimidin-2-yl]phenyl]-3-
ropan-2-yl-urea
4d (01 3-cyclobutyl-l-[4-[4-[(3S)-3- 514 2.35
N ethylmorpholin-4-yl]-6-(1-
O. O ~N
0
j, ethylsulfonylcyclopentyl)p
N N
H H rimidin-2-yl]phenyl]urea

4e c l 3-(2-hydroxyethyl)-1-[4-[4- 504 1.80
N [(3S)-3-methylmorpholin-4-
O. O ~N
0 ~" l]-6-(1-
I NNf" H ethylsulfonylcyclopentyl)p
rimidin-2-yl]phenyl]urea


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Example Structure AME LCMS Retention
MH+ time (min)
4f c l 3-(1-hydroxy-2-methyl- 532 2.09
N N ropan-2-yl)-1-[4-[4-[(3S)-3-
O. O ~
N o o" ethylmorpholin-4-yl]-6-(1-
~ N'k N-~
H H ethylsulfonylcyclopentyl)p
rimidin-2-yl]phenyl]urea
4g (01 3-(2-dimethylaminoethyl)-1- 531 2.07
N [4-[4-[(3S)-3-
0 ~N
~s N N~N fN~ ethylmorphohri-4-yl]-6-(1-
H H ethylsulfonylcyclopentyl)p
rimidin-2-yl]phenyl]urea

4h c l 1-[4-[4-[(3S)-3- 502 2.28
N ethylmorpholin-4-yl]-6-(1-
O O ~N
s N 0 ethylsulfonylcyclopentyl)p
N)~ N
H H rimidin-2-yl]phenyl]-3-
ropyl-urea
4i c ~ 1-[4-[4-[(3S)-3- 517 2.45
N ethylmorpholin-4-yl]-6-(1-
O O ~N
s N o ethylsulfony1cyclopentyl)p
N~N~
H H rimidin-2-yl]phenyl]-3-(2-
ethylpropyl)urea
4j c l 3-(3-hydroxypropyl)-1-[4-[4- 518 1.84
N tt [(3S)-3-methylmorpholin-4-
O. O ~N OH
0 ~ 1]-6-(1-
I N~N
H H ethylsulfonylcyclopentyl)p
rimidin-2-yl]phenyl]urea


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Example Structure AME LCMS Retention
MH+ time (min)
4k c l 1-[4-[4-[(3S)-3- 604 2.95
t
0 o N F ethylmorpholin-4-yl]-6-(1-
~ "~NkN &F F ethylsulfonylcyclopentyl)p
H H
rimidin-2-yl]phenyl]-3-[4-
(trifluoromethyl)phenyl]urea
41 (01 1-[4-[4-[(3S)-3- 537 2.55
N ethylmorpholin-4-yl]-6-(1-
0 0 INN
s ~~ oII~ ~ ethylsulfony1cyclopentyl)p
~ NxN
H H rimidin-2-yl]phenyl]-3-
yridin-2-yl-urea
4m 01 1-[4-[4-[(3S)-3- 540 1.99
CNl ~i
O ethylmorpholin-4-yl]-6-(1-
O I N
'~ " ~ N~NCN- ethylsulfonylcyclopentyl)p
H H rimidin-2-yl]phenyl]-3-(1-
ethylpyrazol-4-yl)urea

4n (01 3-(1H-imidazol-2-ylmethyl)- 540 1.92
N 1-[4-[4-[(3 S)-3-
0 0 I 'N ~ / /~
-S N NNH N N ethylmorphohn-4-yl]-6-(1-
" H ethylsulfonylcyclopentyl)p
rimidin-2-yl]phenyl]urea
Example 4a: 'H NMR (400.132 MHz, DMSO) b 1.05 (3H, t), 1.21 (3H, d), 1.50-1.62
(2H,
m), 1.78-1.85 (2H, m), 2.35-2.45 (2H, m), 2.65-2.75 (2H, m), 2.89 (3H, s),
3.12 (2H, q), 3.18
(1H, dd), 3.50 (1H, dd), 3.65 (1H, dd), 3.75 (1H, d), 3.96 (1H, dd), 4.24 (1H,
d), 4.55 (1H, s),
s 6.15 (1H, t), 6.78 (1H, s), 7.48 (2H, d), 8.22 (2H, d), 8.65 (1H, s).
mTOR Kinase Assay (Echo): 0.00216 M
Example 4b: 'H NMR (400.132 MHz, DMSO) b 0.41 (2H, q), 0.62 (2H, q), 1.21 (3H,
d),
1.51-1.61 (2H, m), 1.75-1.86 (2H, m), 2.35-2.45 (2H, m), 2.55 (1H, m), 2.65-
2.85 (2H, m),
2.89 (3H, s), 3.20 (1H, dd), 3.50 (1H, dd), 3.65 (1H, dd), 3.75 (1H, d), 3.97
(1H, dd), 4.25
io (1H, d), 4.55 (1H, s), 6.41 (1H, d), 6.78 (1H, s), 7.50 (2H, d), 8.25 (2H,
d), 8.55 (1H, s).


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mTOR Kinase Assay (Echo): 0.00203 M
Example 4c: 'H NMR (400.132 MHz, DMSO) b 1.11 (6H, d), 1.21 (3H, d), 1.50-1.62
(2H,
m), 1.75-1.85 (2H, m), 2.38-2.50 (3H, m), 2.65-2.80 (2H, m), 2.89 (3H, s),
3.20 (1H, dd), 3.50
(1H, dd), 3.65 (1H, dd), 3.75 (1H, dd), 3.99 (1H, dd), 4.23 (1H, d), 4.55 (1H,
s), 6.05 (1H, d),
s 6.79 (1H, s), 7.48 (2H, d), 8.22 (2H, d), 8.54 (1H, s).
mTOR Kinase Assay (Echo): 0.0169 M
Example 4d: 'H NMR (400.132 MHz, DMSO) b 1.21 (3H, d), 1.50-1.65 (4H, m), 1.75-
1.90
(4H, m), 2.15-2.20 (2H, m), 2.35-2.50 (2H, m), 2.65-2.80 (2H, m), 2.88 (3H,
s), 3.20 (1H,
dd), 3.50 (1H, dd), 3.65 (1H, dd), 3.75 (1H, dd), 3.95 (1H, dd), 4.15 (1H, q),
4.22 (1H, d),
io 4.55 (1H, s), 6.42 (1H, d), 6.79 (1H, s), 7.45 (2H, d), 8.22 (2H, d), 8.55
(1H, s).
mTOR Kinase Assay (Echo): 0.01 M
Example 4e: 'H NMR (400.132 MHz, DMSO) b 1.21 (3H, d), 1.50-1.62 (2H, m), 1.78-
1.85
(2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.15-3.22 (3H,
m), 3.40-3.50
(3H, m), 3.65 (1H, dd), 3.75 (1H, d), 3.96 (1H, dd), 4.22 (1H, d), 4.55 (1H,
s), 4.71 (1H, t),
is 6.22 (1H, t), 6.78 (1H, s), 7.45 (2H, d), 8.22 (2H, d), 8.80 (1H, s).
mTOR Kinase Assay (Echo): 0.00119 M
Example 4f: 'H NMR (400.132 MHz, DMSO) b 1.21 (3H, d), 1.50-1.62 (2H, m), 1.75-
1.85
(2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.20 (1H, dd),
3.35-3.40 (2H,
m), 3.50 (1H, dd), 3.65 (1H, dd), 3.75 (1H, d), 3.95 (1H, dd), 4.22 (1H, d),
4.55 (1H, s), 4.95
20 (1H, t), 6.0 (1H, s), 6.78 (1H, s), 7.45 (2H, d), 8.22 (2H, d), 8.72 (1H,
s).
mTOR Kinase Assay (Echo): 0.01 M
Example 4g: 'H NMR (400.132 MHz, DMSO) b 1.21 (3H, d), 1.50-1.60 (2H, m), 1.75-
1.85
(2H, m), 2.18 (6H, s), 2.31 (2H, t), 2.38-2.50 (2H, m), 2.65-2.75 (2H, m),
2.89 (3H, s), 3.15-
3.22 (3H, m), 3.50 (1H, dd), 3.65 (1H, dd), 3.75 (1H, dd), 3.96 (1H, dd), 4.22
(1H, dd), 4.55
25 (1H, s), 6.15 (1H, t), 6.79 (1H, s), 7.48 (2H, d), 8.22 (2H, d), 8.87 (1H,
s).
mTOR Kinase Assay (Echo): 0.0626 M
Example 4h: 'H NMR (400.132 MHz, DMSO) b 0.88 (3H, t), 1.21 (3H, d), 1.45 (2H,
q),
1.50-1.62 (2H, m), 1.75-1.85 (2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m),
2.89 (3H, s),
3.05 (2H, m), 3.20 (1H, dd), 3.50 (1H, dd), 3.65 (1H, dd), 3.75 (1H, d), 3.96
(1H, dd), 4.22
30 (1H, d), 4.55 (1H, s), 6.20 (1H, t), 6.78 (1H, s), 7.48 (2H, d), 8.21 (2H,
d), 8.62 (1H, s).
mTOR Kinase Assay (Echo): 0.00157 M


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Example 4i: 'H NMR (400.132 MHz, DMSO) b 0.88 (6H, d), 1.21 (3H, d), 1.50-1.62
(2H,
m), 1.70 (1H, m), 1.75-1.85 (2H, m), 2.35-2.50 (2H, m), 2.65-2.80 (2H, m),
2.90 (3H, s), 2.94
(2H, t), 3.20 (1H, dd), 3.50 (1H, dd), 3.65 (1H, dd), 3.75 (1H, dd), 3.97 (1H,
dd), 4.24 (1H, d),
4.54 (1H, s), 6.22 (1H, t), 6.78 (1H, s), 7.50 (2H, d), 8.22 (2H, d), 8.63
(1H, s).
s mTOR Kinase Assay (Echo): 0.0115 M
Example 4j: 'H NMR (400.132 MHz, DMSO) b 1.21 (3H, d), 1.50-1.62 (4H, m), 1.75-
1.85
(2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.10-3.22 (3H,
m), 3.45-3.52
(3H, m), 3.65 (1H, dd), 3.75 (1H, d), 3.96 (1H, dd), 4.22 (1H, d), 4.45 (1H,
t), 4.55 (1H, s),
6.1991H, t), 6.79 (1H, s), 7.49 (2H, d), 8.22 (2H, d), 8.70 (1H, s).
io mTOR Kinase Assay (Echo): 0.00461 M
Example 4k: 'H NMR (400.132 MHz, DMSO) b 1.21 (3H, d), 1.50-1.62 (2H, m), 1.75-
1.85
(2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3, 22 (1H, dd),
3.50 (1H, dd),
3.65 (1H, dd), 3.75 (1H, d), 3.96 (1H, dd), 4.25 (1H, d), 4.55 (1H, s), 6.80
(1H, s), 7.58 (2H,
d), 7.62-7.70 (4H, m), 8.30 (2H, d), 9.04 (1H, s), 9.10 (1H, s).
is mTOR Kinase Assay (Echo): 0.00905 M
Example 41: 'H NMR (400.132 MHz, DMSO) b 1.21 (3H, d), 1.55-1.62 (2H, m), 1.78-
1.90
(2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.20 (1H, dd),
3.50 (1H, dd),
3.65 (1H, dd), 3.75 (1H, d), 3.9791H, dd), 4.2591H, d), 4.55 (1H, s), 6.80
(1H, s), 7.02 (1H,
dd), 7.58 (1H, d), 7.61 (2H, d), 7.74 (1H, dd), 8.25-8.35 (4H, m), 9.41 (1H,
s).
20 mTOR Kinase Assay (Echo): 0.00369 M
Example 4m: 'H NMR (400.132 MHz, DMSO) b 1.20 (3H, d), 1.50-1.62 (2H, m), 1.78-
1.85
(2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.20 (1H, dd),
3.50 (1H, dd),
3.65 (1H, dd), 3.75-40 (4H, m), 3.97 (1H, dd), 4.25 (1H, d), 4.55 (1H, s),
6.80 (1H, s), 7.38
(1H, s), 7.55 (2H, d), 7.73 (1H, s), 8.25 (2H, d), 8.35 (1H, s), 8.85 (1H, s).
25 mTOR Kinase Assay (Echo): 0.00245 M
Example 4n: 'H NMR (400.132 MHz, DMSO) b 1.21 (3H, d), 1.50-1.62 (2H, m), 1.75-
1.85
(2H, m), 2.35-2.50 (2H, m), 2.65-2.80 (2H, m), 2.89 (3H, s), 3.20 (1H, dd),
3.50 (1H, dd), 3,
65 (1H, dd), 3.75 (1H, d), 3.97 (1H, dd), 4.24 (1H, d), 4.35 (1H, d), 4.55
(1H, s), 6.65 (1H, t),
6.78 (1H, s), 7.04 (2H, s), 7.52 (2H, d), 8.25 (2H, d), 9.0 (1H, s), 12.6 (1H,
s).
30 mTOR Kinase Assay (Echo): 0.0392 M


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The preparation of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-yl]phenyl]carbamate is described below.

Phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yll-6-(1-
methylsulfonylcyclopentyl)pyrimidin-2-
s yllbheUllcarbamate

N
O O ~N
~
/S N~ 0 /
/ NO \ ~
H

Sodium hydrogen carbonate (1.150 g, 13.68 mmol) was added to 4-[4-[(3S)-3-
methylmorpholin-4-yl]-6-(1-methylsulfonylcyclopentyl)pyrimidin-2-yl]aniline
(3.8 g, 9.12
mmol), in dioxane (100 mL) at 21 C under nitrogen. The resulting mixture was
cooled tol0 C
io and phenyl chloroformate (1.72 mL, 13.68 mmol) added slowly then the
reaction stirred for 3
hours and allowed to warm to RT and left for 16 hours. The reaction mixture
was diluted with
ethyl acetate (250 mL), and washed with water (150 mL). The organic layer was
dried
(NazS04), filtered and evaporated to afford crude product. The crude solid was
triturated with
a mixture of diethyl ether, iso-hexane and acetone to give the desired
material as a white solid
is (4.50 g).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO-d6) b 1.21 (3H, d), 1.50-1.62 (2h, m),
1.75-
1.85 (2H, m), 2.38-2.50 (2H, m), 2.65-2.80 (2H, m), 3.21 (1H, dd), 3.30 (3H,
s), 3.50 (1H,
dd), 3.63 (1H, dd), 3.75 (1H, d), 3.97 (1H, dd), 4.28 (1H, d), 4.57 (1H, s),
6.81 (1H, s), 7.22-
7.30 (3Hh, m), 7.43 (2H, dd), 7.61 (1H, d), 8.32 (2H, d), 10.45 (1H, s).
2o LCMS Spectrum: m/z (ESI+)(M+H)+ = 537 ; HPLC tR = 2.98 min
4-[4-[(3S)-3-Methylmorpholin-4-yl1-6-(1-methylsulfonylcyclopentyl)pyrimidin-2-
yllaniline
C0
N)''i
O N
/S N~ \

NH2


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Bis (triphenylphosphine)palladium (II) chloride (0.390 g, 0.56 mmol) was added
to 2-chloro-
4-[(3S)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclopentyl)pyrimidine
(4.0g, 11.12
mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.17 g, 14.45
mmol) and
sodium carbonate (20 mL, 40.0 mmol) in a mixture of DMF (20 mL), DME (50 mL),
ethanol
s(20 mL) and water (20 mL) at RT under nitrogen. The resulting mixture was
stirred at 95 C
for 12 hours. The reaction mixture was diluted with ethyl acetate (400 mL),
washed twice
with water (200 niL followed by 250 mL), the organic layer dried (NazSO4),
filtered and
evaporated to afford crude product. The crude product was chromatographed on
silica, eluting
with 5 - 50% ethyl acetate in iso-hexane, to give a yellow solid which was
subsequently
io triturated with a mixture of diethyl ether and iso-hexane to give the
desired material as a white
solid (4.25 g).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO-d6) b 1.21 (3H, d), 1.50-1.60 (2H, m),
1.75-
1.90 (2H, m), 2.34-2.43 (2H, m), 2.62-2.78 (2H, m), 2.88 (3H, s), 3.18 (1H,
dd), 3.48 (1H,
dd), 3.65 (1H, dd), 3.75 (1H, dd), 3.95 (1H, dd), 4.20 (1H, d), 4.51 (1H, s),
5.55 (2H, s), 6.62
1s (2H, d), 6.68 (1H, s), 8.09 (1H, d).

Mass Spectrum: m/z (ESI+)(M+H)+ = 417
2-Chloro-4-[(3S)-3-methylmorpholin-4-yll-6-(1-
methylsulfonylcyclopentyl)pyrimidine
C0
N)''i
O O I I-L" N
'S N-), CI

2o Tetrabutylammonium bromide (0.495 g, 1.54 mmol) was added toa mixture of 2-
chloro-4-[
(3S)-3-methylmorpholin-4-yl]-6- (methylsulfonylmethyl)pyrimidine (4.7 g, 15.37
mmol), 1,
4-dibromobutane (1.84 mL, 15.37 mmol) and aqueous sodium hydroxide solution
(30 mL,
368.9 mmol) in DCM (150 mL) at RT under nitrogen. The resulting mixture was
stirred at
40 C for 6 hours. The reaction mixture was diluted with DCM (200 mL), and
washed with
25 water (100 mL). The organic layer was dried (MgS04), filtered and
evaporated to afford crude
product. The crude product was chromatographed on silica, eluting with 5 - 50%
ethyl acetate
in iso-hexane, to give the desired material as a yellow solid (3.90 g).


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NMR Spectrum: 'H NMR (400.132 MHz, DMSO-d6) b 1.20 (3H, d), 1.50-1.60 (2H, m),
1.72-
1.82 (2H, m), 2.30-2.41 (2H, m,), 2.50-2.60 (2H, m), 2.88 (3H, s), 3.20 (1H,
dd), 3.45 (1H,
dd), 3.60 (1H, dd), 3.71 (1H, d), 3.94 (1H, dd), 4.0-4.10 (1H, m), 4.42 (1H,
s), 6.89 (1H, s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 360 ; HPLC tR = 2.22 min

The preparation of 2-chloro-4-[ (3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidine was described earlier.

Example 5: 3-Methyl-1-14-14-1(3S)-3-methylmorpholin-4-yll-6-(1-
1 o methylsulfonylcyclobutyl)pyrimidin-2-yll phenyll urea
0
C N 1"

O - N
S N Nzz O
N N
H H

Triethylamine (0.07 mL, 0.48mmol) was added to a solution of phenyl N-[4-[4-
[(3S)-3-
methylmorpholin-4-yl]-6-(1-methylsulfonylcyclobutyl)pyrimidin-2-
yl]phenyl]carbamate (86
mg, 0.16 mmol) and methylamine (2M in THF, 0.65 mmol) in NMP (2 mL). The
reaction was
is heated at 80 C for 2 hours the purified by prep HPLC, using a mixture of
water (containing
1% NH3) and acetonitrile as eluents, to give the desired material as a solid
(48 mg).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.24 (3H, d), 1.91 (2H, m), 2.08
(2H,
m), 2.62(3H,d), 2.80 (2H, m), 2.87 (3H, s), 3.21 (1H, td), 3.50 (1H, td), 3.65
(1H, dd), 3.77
(1H, d), 3.98 (1H, dd), 4.24 (1H, d), 4.60 (1H, s), 6.07 (1H, d), 6.71 (1H,
s), 7.50 (2H, d), 8.22
20 (2H, d), 8.75 (1H, s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 460; HPLC tR = 1.5 min
mTOR Kinase Assay (Echo): 0.000802 M

The following compounds were prepared in an analogous fashion from phenyl N-[4-
[4-[(3S)-
25 3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclobutyl)pyrimidin-2-
yl]phenyl]carbamate
and the appropriate amine.


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Example Structure AME LCMS Retention
MH+ time (min)
5a 3-ethyl-l-[4-[4-[(3S)-3- 474 1.98
N ethylmorpholin-4-yl]-6-
O O iN
O
NJ~ N (1-
" " ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]urea
5b 3-cyclopropyl-1-[4-[4- 486 2.01

N [(3S)-3-methylmorpholin-
O. O ~N
N N~N 4-yl]-6-(1-
" H ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]urea
5c 1-[4-[4-[(3S)-3- 488 2.15

N ethylmorpholin-4-yl]-6-
O. ~N
~SO IN O
~ Nlul N~ (1-
" H ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]-3-
ropan-2-yl-urea

5d 3-cyclobutyl-l-[4-[4-[(3S)- 500 2.24
N 3-methylmorpholin-4-yl]-
O. O ~N
~ N N ~ l N 6-(1-
"J" ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]urea
5e 3-(2-hydroxyethyl)-1-[4-[4- 490 1.69

N [(3S)-3-methylmorpholin-
0 0 ~N
Ni NfO" 4-yl]-6-(l-
" H ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]urea


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Example Structure AME LCMS Retention
MH+ time (min)
5f 3-(1-hydroxy-2-methyl- 518 1.97
0 N N ropan-2-yl)-1-[4-[4-[(3S)-
S 0 N ~ II o" 3-methylmorpholin-4-yl]-
NxN~
H H 6-(1-
ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]urea
5g 3-(2-dimethylaminoethyl)- 517 1.98
N 1-[4-[4-[(3 S)-3-
. ~ ~N
S N~ f N` ethylmorpholin-4-yl]-6-
~ N~N
H H (1-

ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]urea
5h 1-[4-[4-[(3S)-3- 488 2.16

N ethylmorpholin-4-yl]-6-
O O iN
N N N
(1-
H
H ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]-3-
ropyl-urea

5i ( )1-[4-[4-[(3S)-3- 502 2.33
N ethylmorpholin-4-yl]-6-
O. O ~
'S NI0 N 0 N
H (1-
" ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]-3-(2-
ethylpropyl)urea


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Example Structure AME LCMS Retention
MH+ time (min)
5j 3-(3-hydroxypropyl)-1-[4- 504 1.73
N [4-[(3S)-3-
0 N OH
s N 0II ethylmorpholin-4-yl]-6-
~ NxN
H H (1-

ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]urea
5k ( ~ 1-[4-[4-[(3S)-3- 590 2.84

N ethylmorpholin-4-yl]-6-
0 0 ~ F

N O
N , N &F F (1-
'S
H " ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]-3-[4-
(trifluoromethyl)phenyl]ure
a

51 1-[4-[4-[(3S)-3- 523 2.42
N ethylmorpholin-4-yl]-6-
O O ~N
~s N~ 0 (1-
N N N
H H ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]-3-
yridin-2-yl-urea

5m (0)1-[4-[4-[(3S)-3- 526 1.88
N ethylmorpholin-4-yl]-6-
O N
g i
N a N p NN, CH N- (1-
i" ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]-3-(1-
ethylpyrazol-4-yl)urea


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Example Structure AME LCMS Retention
MH+ time (min)
5n 3-(1H-imidazol-2- 526 1.79
N lmethyl)-1-[4-[4-[(3S)-3-
O O I ~N
S N I~ o
x N~ NH ethylmorpholln-4-yl]-6-
~ NN
H H (1-

ethylsulfonylcyclobutyl)p
rimidin-2-yl]phenyl]urea
Example 5a: 'H NMR (400.132 MHz, DMSO) b 1.07 (3H, t), 1.24 (3H, d), 1.91 (2H,
m),
2.07 (2H, m), 2.81 (2H, m), 2.87 (3H, s), 3.12 (2H, m), 3.22 (1H, m), 3.50
(1H, td), 3.65 (1H,
dd), 3.77 (1H, d), 3.98 (1H, dd), 4.24 (1H, d), 4.59 (1H, s), 6.16 (1H, t),
6.71 (1H, s), 7.49
s(2H, d), 8.22 (2H, d), 8.68 (1H, s).
mTOR Kinase Assay (Echo): 0.000289 M
Example 5b: 'H NMR (400.132 MHz, DMSO) b 0.42 (2H, m), 0.65 (2H, m), 1.24 (3H,
d),
1.92 (2H, m), 2.08 (2H, m), 2.56 (2H, m), 2.80 (2H, m), 2.88 (3H, s), 3.21
(1H, td), 3.54 (1H,
s), 3.65 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.24 (1H, d), 4.59 (1H, s),
6.45 (1H, s), 6.72
io (1H, s), 7.51 (2H, d), 8.22 (2H, d), 8.55 (1H, s).
mTOR Kinase Assay (Echo): 0.000383 M
Example 5c: 'H NMR (400.132 MHz, DMSO) b 1.11(6H, d), 1.24 (3H, d), 1.86 -
1.96 (2H,
m), 2.03 - 2.13 (2H, m), 2.76 - 2.84 (2H, m), 2.86 (3H, s), 3.21 (1H, td),
3.50 (1H, td), 3.65
(1H, dd), 3.73 - 3.80 (2H, m), 3.98 (1H, dd), 4.25 (1H, d), 4.61 (1H, s), 6.05
(1H, d), 6.72
is (1H, s), 7.48 (2H, d), 8.21 (2H, d), 8.54 (1H, s).
mTOR Kinase Assay (Echo): 0.00681 M
Example 5d: 'H NMR (400.132 MHz, DMSO) b 1.23 (3H, d), 1.58 - 1.67 (3H, m),
1.81 -
1.94 (4H, m), 2.02 - 2.11 (2H, m), 2.20 (2H, m), 2.76 - 2.84 (2H, m), 2.87
(3H, s), 3.21 (1H,
td), 3.50 (1H, td), 3.65 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.13 (1H,
quintet), 4.25 (1H, d),
2o 4.61 (1H, s), 6.45 (1H, d), 6.71 (1H, s), 7.47 (2H, d), 8.21 (3H, d), 8.58
(2H, s).
mTOR Kinase Assay (Echo): 0.00385 M
Example 5e: 'H NMR (400.132 MHz, DMSO) b 1.24 (3H, d), 1.87 - 1.97 (2H, m),
2.01 -
2.12 (2H, m), 2.77 - 2.85 (2H, m), 2.88 (3H, s), 3.15 - 3.25 (3H, m), 3.43 -
3.54 (3H, m), 3.65


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(1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.24 (1H, d), 4.60 (1H, s), 4.72 (1H,
t), 6.26 (1H, t),
6.71 (1H, s), 7.49 (2H, d), 8.23 (2H, d), 8.82 (1H, s).
mTOR Kinase Assay (Echo): 0.000864 M
Example 5f: 'H NMR (400.132 MHz, DMSO) b 1.25 (14H, s), 1.87 - 1.95 (2H, m),
2.03 -
s 2.11 (2H, m), 2.76 - 2.83 (7H, m), 2.88 (7H, s), 3.17 - 3.25 (15H, m), 3.39
(2H, d), 3.65 (1H,
dd), 3.77 (1H, d), 3.98 (1H, d), 4.24 (1H, d), 4.59 (1H, s), 4.95 (1H, t),
6.02 (1H, s), 6.72 (1H,
s), 7.44 (2H, d), 8.21 (2H, d), 8.75 (1H, s).
mTOR Kinase Assay (Echo): 0.00736 M
Example 5g: 'H NMR (400.132 MHz, DMSO) b 1.24 (3H, d), 1.87 - 1.96 (2H, m),
2.02 -
io 2.12 (2H, m), 2.21 (6H, s), 2.34 (2H, t), 2.74 - 2.85 (2H, m), 2.88 (3H,
s), 3.15 - 3.26 (3H, m),
3.50 (1H, td), 3.65 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.24 (1H, d), 4.60
(1H, s), 6.15 (1H,
t), 6.72 (1H, s), 7.48 (2H, d), 8.21 (2H, d), 8.91 (1H, s).
mTOR Kinase Assay (Echo): 0.0668 M
Example 5h: 'H NMR (400.132 MHz, DMSO) b 0.89 (3H, t), 1.24 (3H, d), 1.40 -
1.51 (2H,
is m), 1.87 - 1.97 (2H, m), 2.01 - 2.12 (2H, m), 2.76 - 2.84 (2H, m), 2.89
(3H, s), 3.06 (2H, q),
3.17 - 3.27 (1H, m), 3.50 (1H, td), 3.65 (1H, dd), 3.77 (1H, d), 3.98 (1H,
dd), 4.24 (1H, d),
4.57 (1H, s), 6.20 (1H, t), 6.72 (1H, s), 7.49 (2H, d), 8.21 (2H, d), 8.66
(1H, s).
mTOR Kinase Assay (Echo): 0.00234 M
Example 5i: 'H NMR (400.132 MHz, DMSO) b 0.89 (6H, d), 1.24 (3H, d), 1.65 -
1.75 (2H,
20 m), 1.85 - 1.96 (2H, m), 2.01 - 2.12 (2H, m), 2.75 - 2.84 (2H, m), 2.88
(3H, s), 2.89 - 2.99
(3H, m), 3.16 - 3.26 (1H, m), 3.50 (1H, td), 3.65 (1H, dd), 3.77 (1H, d), 3.98
(1H, dd), 4.24
(1H, d), 4.56 (1H, s), 6.24 (1H, t), 6.72 (1H, s), 7.49 (2H, d), 8.22 (2H, d),
8.65 (1H, s).
mTOR Kinase Assay (Echo): 0.00988 M
Example 5j: 'H NMR (400.132 MHz, DMSO) b 1.24 (3H, d), 1.59 (2H, q), 1.86 -
1.96 (2H,
25 m), 2.02 - 2.14 (2H, m), 2.76 - 2.85 (2H, m), 2.88 (3H, s), 3.13 - 3.26
(3H, m), 3.45 - 3.54
(3H, m), 3.65 (1H, dd), 3.77 (1H, d), 3.98 (1H, dd), 4.24 (1H, d), 4.48 (1H,
t), 4.56 (1H, s),
6.20 (1H, t), 6.72 (1H, s), 7.49 (2H, d), 8.21 (2H, d), 8.73 (1H, s).
mTOR Kinase Assay (Echo): 0.000239 M
Example 5k: mTOR Kinase Assay (Echo): 0.00333 M
3o Example 51: mTOR Kinase Assay (Echo): 0.000248 M
Example 5m: 'H NMR (400.132 MHz, DMSO) b 1.24 (3H, d), 1.87 - 1.98 (2H, m),
2.03 -
2.12 (2H, m), 2.76 - 2.84 (2H, m), 2.88 (3H, s), 3.17 - 3.30 (4H, m), 3.51
(1H, td), 3.65 (1H,


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dd), 3.73 - 3.80 (1H, m), 3.98 (1H, dd), 4.25 (1H, d), 4.62 (1H, s), 6.73 (1H,
s), 7.39 (1H, s),
7.54 (2H, d), 7.77 (1H, s), 8.27 (2H, d), 8.40 (1H, s), 8.86 (1H, s).
mTOR Kinase Assay (Echo): 0.00069 M
Example 5n: 'H NMR (400.132 MHz, DMSO) b 1.24 (3H, d), 1.87 - 1.97 (2H, m),
2.03 -
s 2.12 (2H, m), 2.75 - 2.85 (2H, m), 2.88 (3H, s), 3.21 (1H, td), 3.50 (1H,
td), 3.65 (1H, dd),
3.77 (1H, d), 3.98 (1H, dd), 4.25 (1H, d), 4.32 (2H, d), 4.60 (1H, s), 6.62
(1H, t), 6.98 (2H, s),
7.52 (2H, d), 8.24 (2H, d), 11.88 (1H, s).
mTOR Kinase Assay (Echo): 0.00828 M

lo The preparation of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-yl]phenyl]carbamate is described below.

Phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yll-6-(1-
methylsulfonylcyclobutyl)pyrimidin-2-
yl]phenyll carbamate

N
O O - N

N O0
N/ O
15 H
Sodium hydrogen carbonate (0.313 g, 3.73 mmol) was added to 4-[4-[(3,S)-3-
methylmorpholin-4-yl]-6-(1-methylsulfonylcyclobutyl)pyrimidin-2-yl]aniline (1
g, 2.48
mmol), in dioxane (20 mL) at RT under nitrogen. The resulting mixture was
cooled to 10 C
and phenyl chloroformate (0.468 mL, 3.73 mmol) added slowly. The reaction was
stirred for
2o 3 hours then diluted with ethyl acetate (150 mL), and washed with water
(100 mL). The
organic layer was dried (NazS04), filtered and evaporated. The crude solid was
triturated with
a mixture of diethyl ether, iso-hexane and acetone to give the desired
material as a white solid
(1.35 g).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.21(3H,d), 1.88-1.96(2H,m), 2.02-

25 2.11(2H,m), 2.75-2.85(2H,m), 2.85(3H,s), 3.21(1H,dd), 3.50(1H,dd),
3.64(1H,d), 3.75(1H,d),
3.98(1H,dd), 4.25(1H,d), 4.57(1H,s), 6.72(1H,s), 7.20-7.30(3H,m), 7.42(2H,dd),
7.61(2H,d),
8.32(2H,m), 10.44(1H,s).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 523; HPLC tR = 2.88 min


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4-[4-[(3S)-3-Methylmorpholin-4-yll-6-(1-methylsulfonylcyclobutyl)pyrimidin-2-
yllaniline
C0
N)''i
O -N
is N I NH2

Bis(triphenylphosphine)palladium(II) chloride (0.101 g, 0.14 mmol) was added
to 2-chloro-4-
s [(3S)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclobutyl)pyrimidine (1 g,
2.89 mmol),
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.824 g, 3.76 mmol)
and sodium
carbonate (5 mL, 10.00 mmol) in a mixture of DMF (5 mL), DME (50 mL), ethanol
(20 mL)
and water (20 mL) at RT under nitrogen. The resulting mixture was stirred at
95 C for 12
hours. The reaction mixture was diluted with ethyl acetate (400 mL), and
washed twice with
io water (200 mL followed by 250 mL), the organic layer dried (NazSO4),
filtered and
evaporated. The crude product was chromatographed on silica, eluting with 5 -
60% ethyl
acetate in iso-hexane, to give the desired material as a cream solid (0.98 g).
NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.21(3H,d), 1.85-1.95(2H,m), 2.0-
2.10(2H,m), 2.71-2.82(2H,m), 2.82(3H,s), 3.18(1H,dd), 3.50(1H,dd),
3.62(1H,dd),
is 3.75(1H,d), 3.95(1H,dd), 4.20(1H,d), 4.53(1H,s), 5.55(2H,s), 6.60(3H,d),
8.05(2H,d).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 403; HPLC tR = 2.17 min
2-Chloro-4-[(3S)-3-methylmorpholin-4-yll-6-(1-
methylsulfonylcyclobutyl)pvrimidine
C0
N)''i
O e lN
1S N-), CI

2o Tetrabutylammonium bromide (0.45 g, 1.40 mmol) was added to 2-chloro-4-
[(3S)-3-
methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (4.27 g, 13.96 mmol),
1,3-
dibromopropane (1.42 mL, 13.96 mmol) and aqueous sodium hydroxide solution (30
mL,
368.9 mmol) in DCM (100 mL) at RT under nitrogen. The resulting mixture was
stirred at
35 C for 5 hours then diluted with DCM (50 mL), and washed with water (25 mL).
The
25 organic layer was dried (MgS04), filtered and evaporated. The crude product
was


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chromatographed on silica, eluting with 5 - 50% ethyl acetate in iso-hexane,
to give the
desired material (1.0 g).
LCMS Spectrum: m/z (ESI+)(M+H)+ = 346; HPLC tR = 1.92 min
s The preparation of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-
(methylsulfonylmethyl)pyrimidine was described earlier.

Example 6: 3-Cyclobutyl-1-f4-f4-f(3S)-3-methylmorpholin-4-yll-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yll phenyll urea
C0
N)'',
O - N
~~ S I N~ ~ O
N N N A N
N
H H
To a solution of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate (122 mg, 0.21 mmol) in
DMF (2
mL) was added triethylamine (0.088 mL, 0.63 mmol) followed by cyclobutylamine
(0.090
mL, 1.05 mmol) and the reaction heated at 50 C overnight. The crude product
was purified by
1s preparative HPLC using decreasingly polar mixtures of water (containing 1%
NH3) and
acetonitrile as eluents, to give the desired material as a white solid (90
mg).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO-d6) b 1.18-1.20 (3H, d), 1.57-1.70
(4H, m),
1.82-1.91 (2H, m), 1.95-1.98 (2H, q), 2.18-2.25 (2H, m), 3.12-3.20 (1H, td),
3.43-3.50 (1H,
td), 3.59-3.63 (1H, dd), 3.73-3.76 (1H, d), 3.94-3.98 (1H, dd), 4.11-4.17 (2H,
m), 4.46 (1H,
2o bs), 6.42-6.44 (1H, d), 6.67 (1H, s), 7.33-7.35 (2H, q), 7.65-7.67 (2H, d),
7.76-7.78 (2H, q),
8.53 (1H, s), 8.85-8.87 (2H, q).
LCMS Spectrum: m/z (ESI+) (M+H)+549 = HPLC tR =2.25 min.
mTOR Kinase Assay (Echo): 0.001 M

25 The compounds below were prepared in an analogous fashion from phenyl N-[4-
[4-[(3S)-3-
methylmorpholin-4-yl]-6-(1-pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]carbamate using the appropriate amine.


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Example Structure AME LCMS Retention
MH+ time (min)
6a 1-[4-[4-[(3S)-3- 572 2.44
0 0 , ethylmorpholin-4-yl]-6-(1-
. ,
N NxN I yridin-4-
H H lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]-3-pyridin-2-
1-urea
6b 1-[4-[4-[(3S)-3- 551 2.33
O N ethylmorpholin-4-yl]-6-(1-
O ~
N / N Jl ~ yrldin-4-
N N
H H lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]-3-(2-
ethylpropyl)urea

6c 1-[4-[4-[(3S)-3- 537 2.17
O. O ethylmorpholin-4-yl]-6-(1-
~N
~ ~S N I ~ j, yridin-4-
N N N
H H lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]-3-propan-2-
1-urea

6d 3-ethyl-l-[4-[4-[(3S)-3- 523 2.03
ethylmorpholin-4-yl]-6-(1-
0 0 ~
~
N/ N Jl yrldin-4-
N N
H H lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]urea
6e ( ~ 3-(2-dimethylaminoethyl)-1- 566 1.32
N
o. o I" ~ .N i [4-[4-[(3S)-3-
~ ZS 10-
I N ethY `Y lmo7ry-~holin-4-Y1]-6-(1-
N1, N
H H
yridin-4-
lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]urea


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Example Structure AME LCMS Retention
MH+ time (min)
6f 3-(2-hydroxyethyl)-1-[4-[4- 539 1.75
N [(3S)-3-methylmorpholin-4-
O ~t' N
. N~. Jl f OH 1]-6-(1-pyridin-4-
" " lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]urea
6g (0)1-[4-[4-[(3S)-3- 537 2.18

O N - ethylmorpholin-4-yl]-6-(1-
O N
S
N/ N I k~ yrldin-4-
" H lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]-3-propyl-
rea

6h ( )3-methyl-l-[4-[4-[(3S)-3- 509 1.89
N ethylmorpholin-4-yl]-6-(1-
0 0 N
O*r N/ N a " yrldin-4-
" " lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]urea
6i ( 1 1-[4-[4-[(3S)-3- 639 2.84
N =
o N F ethylmorpholin-4-yl]-6-(1-
N5 N~ O ~F
9 NlIN yridin-4-
H H
lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]-3-[4-
(trifluoromethyl)phenyl]urea

6j (0)3-(1-hydroxy-2-methyl- 567 2.01
ropan-2-yl)-1-[4-[4-[(3S)-3-
O O N
N -
N~ S N la- ~ roH ethylmorpholin-4-yl]-6-(1-
N N'~
H H
yridin-4-
lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]urea


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Example Structure AME LCMS Retention
MH+ time (min)
6k 3-(3-hydroxypropyl)-1-[4-[4- 553 1.80

N [(3S)-3-methylmorpholin-4-
O O "N OH
N ~ ' ~ 1]-6-(1-pyridin-4-
" " lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]urea
61 1-[4-[4-[(3S)-3- 575 1.96

o N ethylmorpholin-4-yl]-6-(1-
S N
N / N NJIN~.N yridin-4-
H H
lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]-3-(1-
ethylpyrazol-4-yl)urea
6m 3-cyclopropyl-l-[4-[4-[(3S)- 535 2.12
(01 N.=,
3 -methylmorpholin-4-yl]-6-
0 0 I ~N
~ ~ s ~ ~ ~ (1-pyridin-4-
" H lsulfonylcyclopropyl)pyrimi
din-2-yl]phenyl]urea
Example 6a: 'H NMR (400.132 MHz, DMSO-d6) b 1.19-1.21 (3H, d), 1.69-1.72 (2H,
q),
1.97-2.00 (2H, q), 3.15-3.22 (1H, td), 3.44-3.51 (1H, td), 3.61-3.64 (1H, dd),
3.74-3.77 (1H,
d), 3.95-3.99 (1H, dd), 4.17-4.20 (1H, d), 4.48 (1H, bs), 6.71 (1H, s), 7.02-
7.06 (1H, m), 7.49-
s 7.51 (2H, d), 7.56-7.58 (1H, d), 7.74-7.79 (5H, m), 8.30-8.32 (1H, d), 8.88-
8.89 (2H, q), 9.43
(1H, s), 10.55 (1H, s).
mTOR Kinase Assay (Echo): 0.00293 M
Example 6b: 'H NMR (400.132 MHz, DMSO-d6) b 0.88-0.90 (6H, d), 1.18-1.20 (3H,
d),
1.68-1.74 (3H, m), 1.96-1.98 (2H, q), 2.93-2.96 (2H, t), 3.13-3.20 (1H, td),
3.43-3.50 (1H, td),
io 3.59-3.63 (1H, dd), 3.73-3.76 (1H, d), 3.94-3.99 (1H, dd), 4.15-4.18 (1H,
d), 4.45 (1H, bs),
6.20-6.23 (1H, t), 6.67 (1H, s), 7.34-7.36 (2H, d), 7.65-7.67 (2H, d), 7.77-
7.78 (2H, q), 8.62
(1H, s), 8.86-8.87 (2H, q).
mTOR Kinase Assay (Echo): 0.00612 M


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Example 6c: 'H NMR (400.132 MHz, DMSO-d6) b l.l 1-1.12 (6H, d), 1.18-1.20 (3H,
d),
1.67-1.71 (2H, q), 1.96-1.98 (2H, q), 3.13-3.20 (1H, td), 3.43-3.50 (1H, td),
3.59-3.63 (1H,
dd), 3.73-3.82 (2H, m), 3.94-3.98 (1H, dd), 4.14-4.18 (1H, d), 4.46 (1H, bs),
6.02-6.04 (1H,
d), 6.67 (1H, s), 7.32-7.36 (2H, q), 7.64-7.67 (2H, q), 7.76-7.78 (2H, q),
8.50 (1H, s), 8.86-
s 8.87 (2H, q).
mTOR Kinase Assay (Echo): 0.00321 M
Example 6d: 'H NMR (400.132 MHz, DMSO-d6) b 1.05-1.09 (2H, t), 1.18-1.20 (3H,
d),
1.67-1.71 (2H, q), 1.96-1.98 (2H, q), 3.09-3.20 (4H, m), 3.43-3.50 (1H, td),
3.59-3.63 (1H,
dd), 3.73-3.76 (1H, d), 3.94-3.98 (1H, dd), 4.15-4.17 (1H, d), 4.46 (1H, bs),
6.12-6.15 (1H, t),
io 6.67 (1H, s), 7.35-7.37 (2H, q), 7.65-7.67 (2H, d), 7.77-7.78 (2H, q), 8.63
(1H, s), 8.86-8.87
(2H, q)=
mTOR Kinase Assay (Echo): 0.000874 M
Example 6e: 'H NMR (400.132 MHz, DMSO-d6) b 1.18-1.20 (3H, d), 1.67-1.71 (2H,
q),
1.96-1.98 (2H, q), 2.18 (6H, s), 2.32-2.35 (2H, t), 3.13-3.21 (3H, m), 3.43-
3.50 (1H, td), 3.59-
1s 3.63 (1H, dd), 3.73-3.76 (1H, d), 3.94-3.98 (1H, dd), 4.15-4.18 (1H, d),
4.47 (1H, bs), 6.12-
6.15 (1H, t), 6.67 (1H, s), 7.34-7.37 (2H, q), 7.65-7.67 (2H, d), 7.76-7.78
(2H, q), 8.86-8.87
(3H, m).
mTOR Kinase Assay (Echo): 0.0673 M
Example 6f: 'H NMR (400.132 MHz, DMSO-d6) b 1.18-1.20 (3H, d), 1.67-1.71 (2H,
q),
20 1.96-1.98 (2H, q), 3.13-3.20 (3H, m), 3.43-3.50 (3H, m), 3.59-3.63 (1H,
dd), 3.73-3.76 (1H,
d), 3.94-3.98 (1H, dd), 4.15-4.18 (1H, d), 4.46 (1H, bs), 4.71-4.74 (1H, t),
6.21-6.24 (1H, t),
6.67 (1H, s), 7.34-7.36 (2H, q), 7.65-7.67 (2H, d), 7.76-7.78 (2H, q), 8.77
(1H, s), 8.86-8.87
(2H, q)=
mTOR Kinase Assay (Echo): 0.000794 M
25 Example 6g: 'H NMR (400.132 MHz, DMSO-d6) b 0.87-0.91 (3H, t), 1.18-1.20
(3H, d),
1.41-1.50 (2H, m), 1.67-1.71 (2H, q), 1.96-1.98 (2H, q), 3.04-3.09 (2H, q),
3.13-3.19 (1H, td),
3.43-3.50 (1H, td), 3.59-3.63 (1H, td), 3.73-3.76 (1H, d), 3.94-3.98 (1H, dd),
4.14-4.18 (1H,
d), 4.47 (1H, bs), 6.16-6.19 (1H, t), 6.67 (1H, s), 7.34-7.36 (2H, d), 7.65-
7.67 (2H, dO, 7.77-
7.78 (2H, q), 8.62 (1H, s), 8.86-8.87 (2H, q).
30 mTOR Kinase Assay (Echo): 0.00225 M
Example 6h: 'H NMR (400.132 MHz, DMSO-d6) b 1.18-1.20 (3H, d), 1.67-1.71 (2H,
q),
1.96-1.98 (2H, q), 2.65-2.67 (3H, d), 3.13-3.20 (1H, td), 3.43-3.50 (1H, td),
3.59-3.63 (1H,


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dd), 3.73-3.76 (1H, d), 3.94-3.98 (1H, dd), 4.15-4.17 (1H, d), 4.46 (1H, bs),
6.02-6.06 (1H, q),
6.67 (1H, s), 7.35-7.38 (2H, q), 7.65-7.67 (2H, d), 7.77-7.78 (2H, q), 8.71
(1H, s), 8.86-8.87
(2H, q)=
mTOR Kinase Assay (Echo): 0.000799 M
s Example 6i: 'H NMR (400.132 MHz, DMSO-d6) b 1.19-1.21 (3H, d), 1.69-1.72
(2H, q),
1.97-2.00 (2H, q), 3.14-3.21 (1H, td), 3.44-3.50 (1H, td), 3.61-3.64 (1H, dd),
3.74-3.77 (1H,
d), 3.95-3.98 (1H, dd), 4.16-1.20 (1H, d), 4.48 (1H, bs), 6.70 (1H, s), 7.44-
7.46 (2H, d), 7.64-
7.70 (4H, q), 7.72-7.75 (2H, q), 7.78-7.79 (2H, q), 8.87-8.89 (2H, q), 9.03
(1H, s), 9.11 (1H,
s).
io mTOR Kinase Assay (Echo): 0.00462 M
Example 6j: 'H NMR (400.132 MHz, DMSO-d6) b 1.18-1.20 (3H, d), 1.24 (6H, s),
1.67-1.70
(2H, q), 1.96-1.99 (2H, q), 3.13-3.20 (1H, td), 3.38-3.40 (2H, d), 3.43-3.50
(1H, td), 3.59-3.63
(1H, dd), 3.73-3.76 (1H, d), 3.94-3.98 (1H, dd), 4.15-4.18 (1H, d), 4.46 (1H,
bs), 4.94-4.96
(1H, t), 5.97 (1H, s), 6.67 (1H, s), 7.30-7.32 (2H, d), 7.63-7.65 (2H, q),
7.76-7.78 (2H, q),
is 8.71 (1H, s), 8.86-8.87 (2H, q).
mTOR Kinase Assay (Echo): 0.00593 M
Example 6k: 'H NMR (400.132 MHz, DMSO-d6) b 1.18-1.20 (3H, d), 1.57-1.63 (2H,
m),
1.67-1.71 (2H, q), 1.96-1.98 (2H, q), 3.13-3.20 (3H, m), 3.43-3.50 (3H, m),
3.59-3.63 (1H,
dd), 3.73-3.76 (1H, d), 3.94-3.98 (1H, dd), 4.14-4.18 (1H, d), 4.46 (1H, bs),
4.46-4.49 (1H, t),
2o 6.16-6.19 (1H, t), 6.67 (1H, s), 7.34-7.36 (2H, q), 7.65-7.67 (2H, d), 7.76-
7.78 (2H, q), 8.68
(1H, s), 8.86-8.87 (2H, q).
mTOR Kinase Assay (Echo): 0.00186 M
Example 61: 'H NMR (400.132 MHz, DMSO-d6) b 1.19-1.20 (3H, d), 1.68-1.71 (2H,
q),
1.96-1.99 (2H, q), 3.13-3.21 (1H, td), 3.44-3.50 (1H, td), 3.60-3.63 (1H, dd),
3.74-3.77 (1H,
25 d), 3.79 (3H, s), 3.95-3.98 (1H, dd), 4.16-4.19 (1H, d), 4.47 (1H, bs),
6.68 (1H, s), 7.39-7.42
(3H, m), 7.68-7.70 (2H, d), 7.77-7.79 (3H, m), 8.37 (1H, s), 8.82 (1H, s),
8.86-8.88 (2H, q).
mTOR Kinase Assay (Echo): 0.00119 M
Example 6m: 'H NMR (400.132 MHz, DMSO-d6) b 0.40-0.44(2H, m), 0.63-0.67(2H,
m),
1.18-1.20(3H, d), 1.68-1.71(2H, q), 1.96-1.99(2H, q), 2.53-2.59(1H, m), 3.13-
3.20(1H, td),
3o 3.43-3.63(1H, td), 3.59-3.63(1H, dd), 3.73-3.76(1H, d), 3.94-3.98(1H, dd),
4.15-4.18(1H, d),
4.46(1H, bs), 6.40-6.41(1H, d), 6.67(1H, s), 7.36-7.38(2H, q), 7.65-7.68(2H,
q), 7.77-
7.78(2H, q), 8.51(1H, s), 8.86-8.87(2H, q).


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mTOR Kinase Assay (Echo): 0.000936 M

The preparation of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-

ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate is described below.

Phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yll-6-(1-12yridin-4-
ylsulfonylcycloprogyl)pyrimidin-2-yllphenyllcarbamate
C0
N)''i
O - N
N
0 /
a,,
N0 \ I
H

Phenyl chloroformate (0.341 mL, 2.71 mmol) was added to 4-[4-[(3S)-3-
methylmorpholin-4-
io yl]-6-(1-pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2-yl]aniline (1.224 g,
2.71 mmol) and
sodium bicarbonate (0.342 g, 4.07 mmol) in dioxane (175 mL) at RT under air.
The resulting
slurry was stirred at RT for 2 hours. Additional portions of phenyl
chloroformate (2 x 0.005
mL) were added to the reaction. Water was added to the reaction mixture and
the material
extracted with DCM. The combined organics were dried (MgSO4), filtered and
evaporated.
is The crude product was purified by flash silica chromatography, eluting with
0 to 4% methanol
in DCM, to give the desired material as a beige solid (1.72 g).
NMR Spectrum: 'H NMR (400.132 MHz, CDC13) b 1.28-1.29 (3H, d), 1.60-1.69 (2H,
m),
1.97-2.05 (2H, m), 3.22-3.30 (1H, td), 3.52-3.59 (1H, td), 3.71-3.72 (1H, dd),
3.78-3.81 (1H,
d), 3.99-4.03 (1H, dd), 4.09-4.13 (1H, d), 4.38-4.39 (1H, bs), 6.72 (1H, s),
7.13-7.15 (2H, d),
2o 7.19-7.21 (1H, t), 7.32-7.36 (2H, t), 7.46-7.48 (2H, d), 7.61-7.63 (2H, q),
7.97-7.99 (2H, d),
8.74-8.75 (2H, q).

LCMS Spectrum: m/z (ES+) (M+H)+=450; HPLC tR=2.66 min.


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4- [4- [(3 S)-3 -Methylmorpho lin-4-yll -6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidin-2-
1 aniline

N
L
O NN
\ \
I
N ~ I ~ NH2

s trans-Dichlorobis(triphenylphosphine)palladium (II) (0.095 g, 0.14 mmol) was
added to 2-
chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidine
(1.07 g, 2.71 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(0.89 g, 4.06
mmol) and sodium carbonate (6.77 mL, 13.55 mmol) in 18% DMF in a 7:3:2 mixture
of
DME:water:ethanol (50 mL) at RT under nitrogen. The resulting solution was
stirred at 80 C
io for 5 hours. The reaction was cooled and diluted with ethyl acetate and
water. The reaction
mixture was extracted with ethyl acetate, the combined organics dried (MgSO4),
filtered and
evaporated to afford the desired material (1.224 g).
LCMS Spectrum: m/z (ES+) (M+H)+=452; HPLC tR=2.03 min.

is 2-Chloro-4-[(3S)-3-methylmorpholin-4-yll-6-(1-pyridin-4-
ylsulfonylcyclopropyl)pyrimidine
C0
N)'',
O O I ~N
~ \ N~CI
N

50% v/v Aqueous sodium hydroxide (23 mL, 9.52 mmol) was added to 2-chloro-4-
[(3S)-3-
methylmorpholin-4-yl]-6-(pyridin-4-ylsulfonylmethyl)pyrimidine (3.51 g, 9.52
mmol), 1,2-
dibromoethane (0.820 mL, 9.52 mmol) and tetrabutylammonium bromide (0.307 g,
0.95
20 mmol) in DCM (100 mL) and the reaction warmed to 30 C under air. The
resulting slurry was
stirred at 30 C for 4 hours then allowed to cool, DCM added and the layers
separated. The
organic layer was washed with water, dried (MgS04) and filtered. The resulting
solution was
evaporated on to silica and purified by flash silica chromatography, eluting
with 0 to 60%
ethyl acetate in DCM, to give the desired material as a yellow solid (1.07 g).


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NMR Spectrum: 'H NMR (400.132 MHz, DMSO-d6) b 1.15-1.16 (3H, d), 1.61-1.65
(2H, m),
1.90-1.93 (2H, m), 3.11-3.19 (1H, td), 3.37-3.44 (1H, td), 3.53-3.57 (1H, dd),
3.68-3.71 (1H,
d), 3.89-3.96 (1H, dd), 3.96 (1H, bs), 4.28 (1H, bs), 6.75 (1H, s), 7.74-7.75
(2H, dd), 8.88-
8.90 (2H, dd).
s LCMS Spectrum: m/z (ES+) (M+H)+=395; HPLC tR=1.65 min.

2-Chloro-4- [(3S)-3 -methylmorpho lin-4-yll -6-(pyridin-4-
ylsulfonylmethyl)pyrimidine
(0)"',

O O 1- N
N"j, CI
N

A solution of hydrogen peroxide (1.799 mL, 58.19 mmol) was added dropwise to a
stirred
io solution of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(pyridin-4-
ylsulfanylmethyl)pyrimidine (0.980 g, 2.91 mmol), sodium tungstate dihydrate
(0.005 mL,
0.06 mmol) and 2N sulfuric acid (0.075 mL) in dioxane (200 mL) at 55 C, over a
period of 5
minutes under air. The resulting solution was stirred at 55 C for 3 hours.
Water (200mL) was
added and the reaction was cooled, the solids filtered, washed with water and
dried in the
is vacuum oven at 50 C overnight to give the desired material as a white solid
(0.580 g).
Additional material was obtained by extracting the aqueous layer with DCM. The
extracts
were dried (MgS04), filtered, evaporated and chromatographed on silica,
eluting with 0 - 3%
methanol in DCM, to give a further portion of the desired material (0.144 g).
NMR Spectrum:'H NMR (400.13 MHz, DMSO-d6) b 1.17-1.19(3H, d), 3.14-3.22(1H,
td),
2o 3.40-3.47(1H, td), 3.56-3.60(1H, dd), 3.71-3.74(1H, d), 3.90(1H, bs), 3.91-
3.95(1H, dd),
4.20(1H, bs), 4.79(2H, s), 6.79(1H, s), 7.77-7.79(2H, q), 8.92-8.93(2H, q).
LCMS Spectrum: m/z (ES+) (M+H)+=369; HPLC tR=1.40 min.
2-Chloro-4-[(3S)-3-methylmorpholin-4-yll-6-(pyridin-4-
ylsulfanylmethyl)pyrimidine
C0
N)''i
N
~
a,, S N~CI


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4-Mercaptopyridine (0.752 g, 6.77 mmol) was added to 2-chloro-4-(iodomethyl)-6-
[(3S)-3-
methylmorpholin-4-yl]pyrimidine (1.596 g, 4.51 mmol) in acetonitrile (100 mL)
at RT under
air. DBU (0.3 mL, 2.01 mmol) was then added and the resulting solution was
stirred at RT for
2 minutes. The solvent was removed and DCM was added. The reaction mixture was
washed
s sequentially with water, the organic layer dried (MgSO4), filtered and
evaporated. The crude
product was chromatographed on silica, eluting with 0 - 2% methanol in DCM.
Impure
fractions were further chromatographed on silica, eluting with 0 - 4.5%
methanol in DCM
and combined with the initial pure fractions to give the desired material as a
yellow gum
(0.980 g).
io NMR Spectrum: 'H NMR (400.13 MHz, DMSO-d6) b 1.14-1.16(3H, d), 3.11-
3.18(1H, td),
3.37-3.44(1H, td), 3.53-3.57(1H, dd), 3.64-3.67(1H, d), 3.86-3.90(2H, dd),
4.01(2H, s),
4.14(1H, bs), 6.43(1H, s), 7.04-7.06(2H, d), 8.29-8.30(2H, d).
LCMS Spectrum: m/z (ES+) (M+H)+=337; HPLC tR=1.62 min.

is The preparation of 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-
yl]pyrimidine was
described earlier

Example 7: 3-Methyl-1-14-14-1(3S)-3-methylmorpholin-4-yl1-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-yll phenyll urea
C0
N)''i
O O - N

S I N/ OII
NxN
20 H H
To a solution of phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(1-propan-2-
ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]carbamate (120 mg, 0.22 mmol) in
DMF (2
mL) was added triethylamine (0.094 mL, 0.67 mmol) followed by methylamine (0.5
mL, 1.1
mmol) and the reaction heated at 50 C for 2 hours. The crude product was
purified by
25 preparative HPLC using decreasingly polar mixtures of water (containing 1%
NH3) and
acetonitrile as eluents, to give the desired material as a white solid (71
mg).
NMR Spectrum: 'H NMR (400.132 MHz, DMSO-d6) b 1.23 (3H, d), 1.34 (6H, dd),
1.55 -
1.62 (4H, m), 2.66 (3H, d), 3.17 - 3.24 (1H, m), 3.48 (1H, dt), 3.60 - 3.67
(2H, m), 3.76 (1H,


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d), 3.98 (1H, dd), 4.19 (1H, d), 4.53 (1H, s), 6.07 (1H, d), 6.79 (1H, s),
7.50 (2H, d), 8.18 (2H,
d), 8.74 (1H, s)
LCMS Spectrum: m/z (ESI+)(M+H)+ = 474; HPLC tR = 1.92 min.
mTOR Kinase Assay (Echo): 0.00315 M

The compounds below were prepared in an analogous fashion from phenyl N-[4-[4-
[(3S)-3-
methylmorpholin-4-yl]-6-(1-propan-2-ylsulfonylcyclopropyl)pyrimidin-2-
yl]phenyl]carbamate using the appropriate amine.

Example Structure NAME LCMS Retention
MH+ time
(min)

7a c l 1-ethyl-3-[4-[4-[(3S)-3- 488 1.92
N ethylmorpholin-4-yl]-6-(1-
0 0 ~
s N ~N ropan-2-
N " H ylsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]urea
7b c l 1-[4-[4-[(3S)-3- 502 2.08
N ethylmorpholin-4-yl]-6-(1-
0 0 ~N
S N o ropan-2-
N'A, NJ"
" H ylsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]-3-propan-2-yl-urea
7c 3-cyclobutyl-l-[4-[4-[(3S)-3- 514 2.24

N ethylmorpholin-4-yl]-6-(1-
0 O ~N
N ~ N~N ropan-2-
" H ylsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]urea


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Example Structure NAME LCMS Retention
MH+ time
(min)
7d (01 3-cyclopropyl-l-[4-[4-[(3S)-3- 500 2.34
N ethylmorpholin-4-yl]-6-(1-
0 O " N
s N o ropan-2-
/ Nj,N~
H H lsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]urea
7e col 3-(2-hydroxyethyl)-1-[4-[4- 504 2.09
N [(3S)-3-methylmorpholin-4-yl]-
O I
N NON f~H 6-(1-propan-2-
H H lsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]urea
7f 3-(1-hydroxy-2-methyl-propan- 532 1.77
CN~...,
0 0 N 2-yl)-1-[4-[4-[(3S)-3-

N o H ethylmorpholin-4-yl]-6-(1-
~ N~N
H H ropan-2-
lsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]urea
7g 3-(2-dimethylaminoethyl)-1-[4- 531 2.06
CN~.,
[4-[(3 S)-3-methylmorpholin-4-
O ~ ` N ~
N 0 fN` 1]-6-(1-propan-2-
" " lsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]urea
7h c l 3-[4-[4-[(3S)-3- 502 2.00
N ethylmorpholin-4-yl]-6-(1-
0 ~N
N NN'r ropan-2-
H H ylsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]


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Example Structure NAME LCMS Retention
MH+ time
(min)
7i (01 1-[4-[4-[(3S)-3- 516 2.26
N ethylmorpholin-4-yl]-6-(1-
0 O " N
N ~ o ropan-2-
~ N'kN
H H ylsulfonylcyclopropyl)pyrimidin-
2-yI]phenyI]-3-(2-
methylpropyl)urea

7j ( ~ 3-(3-hydroxypropyl)-1-[4-[4- 518 2.43
N [(3S)-3-methylmorpholin-4-yl]-
0 O N OH
Ys N 0 6-(1-propan-2-
I NN
H H lsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]urea
7k (01 1-[4-[4-[(3S)-3- 604 1.81
0 0 , N F ethylmorpholin-4-yl]-6-(1-
I
N~/ Jl &F F ropan-2-
N N
H H lsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]-3-[4-
(trifluoromethyl)phenyl]urea

71 c l 1-[4-[4-[(3S)-3- 537 2.95
N ethylmorpholin-4-yl]-6-(1-
0 O " N
ropan-2-
I S N
N O N N
H H ylsulfonylcyclopropyl)pyrimidin-
2-yl]phenyl]-3-pyridin-2-yl-urea
7m 1-[4-[4-[(3S)-3- 540 2.54
CN~...-
ethylmorpholin-4-yl]-6-(1-
O O " N
~s N a Jl fZ.N- ropan-2-
N N
H H ylsulfonylcyclopropyl)pyrimidin-
2


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Example 7a: 'H NMR (400.132 MHz, DMSO-d6) b 1.07 (3H, t), 1.23 (3H, d), 1.34
(6H, dd),
1.52 - 1.61 (4H, m), 3.09 - 3.16 (2H, m), 3.16 - 3.23 (1H, m), 3.49 (1H, dt),
3.62 - 3.67 (2H,
m), 3.76 (1H, d), 3.97 (1H, d), 4.19 (1H, d), 4.53 (1H, s), 6.17 (1H, t), 6.79
(1H, s), 7.50 (2H,
d), 8.18 (2H, d), 8.66 (1H, s).
s mTOR Kinase Assay (Echo): 0.00231 M
Example 7b: 'H NMR (400.132 MHz, DMSO-d6) b 1.11 (6H, d), 1.23 (3H, d), 1.34
(6H,
dd), 1.52 - 1.61 (4H, m), 3.15 - 3.24 (1H, m), 3.49 (1H, dt), 3.60 - 3.67 (2H,
m), 3.73 - 3.82
(2H, m), 3.97 (1H, dd), 4.19 (1H, d), 4.53 (1H, s), 6.07 (1H, d), 6.79 (1H,
s), 7.48 (2H, d),
8.18 (2H, d), 8.53 (1H, s).
io mTOR Kinase Assay (Echo): 0.0181 M
Example 7c: 'H NMR (400.132 MHz, DMSO-d6) b 1.23 (3H, d), 1.33 (3H, d), 1.35
(3H, d),
1.52 - 1.66 (6H, m), 1.81 - 1.91 (2H, m), 2.18 - 2.25 (2H, m), 3.20 (1H, dt),
3.48 (1H, dt),
3.60 - 3.67 (2H, m), 3.76 (1H, d), 3.97 (1H, dd), 4.09 - 4.21 (2H, m), 4.53
(1H, s), 6.47 (1H,
d), 6.79 (1H, s), 7.48 (2H, d), 8.18 (2H, d), 8.56 (1H, s).
is mTOR Kinase Assay (Echo): 0.00646 M
Example 7d: 'H NMR (400.132 MHz, DMSO-d6) b 0.40 - 0.44 (2H, m), 0.63 - 0.67
(2H, m),
1.23 (3H, d), 1.33 (3H, d), 1.35 (3H, d), 1.53 - 1.62 (4H, m), 2.54 - 2.58
(1H, m), 3.17 - 3.24
(1H, m), 3.49 (1H, dt), 3.60 - 3.67 (2H, m), 3.76 (1H, d), 3.97 (1H, dd), 4.20
(1H, d), 4.53
(1H, s), 6.44 (1H, d), 6.80 (1H, s), 7.51 (2H, d), 8.19 (2H, d), 8.53 (1H, s).
20 mTOR Kinase Assay (Echo): 0.0038 M
Example 7e: 'H NMR (400.132 MHz, DMSO-d6) b 1.23 (3H, d), 1.33 (3H, d), 1.35
(3H, d),
1.54 - 1.61 (4H, m), 3.16 - 3.24 (3H, m), 3.44 - 3.52 (3H, m), 3.60 - 3.67
(2H, m), 3.76 (1H,
d), 3.97 (1H, dd), 4.19 (1H, d), 4.52 (1H, s), 4.73 (1H, t), 6.26 (1H, t),
6.79 (1H, s), 7.50 (2H,
d), 8.19 (2H, d), 8.80 (1H, s).
25 mTOR Kinase Assay (Echo): 0.00212 M
Example 7f: 'H NMR (400.132 MHz, DMSO-d6) b 1.23 (3H, d), 1.24 (6H, s), 1.34
(3H, d),
1.35 (3H, d), 1.55 - 1.62 (4H, m), 3.15 - 3.23 (1H, m), 3.39 (2H, d), 3.49
(1H, dt), 3.62 - 3.68
(2H, m), 3.76 (1H, d), 3.97 (1H, d), 4.20 (1H, d), 4.52 (1H, s), 4.95 (1H, t),
6.01 (1H, s), 6.79
(1H, s), 7.46 (2H, d), 8.18 (2H, d), 8.73 (1H, s).
30 mTOR Kinase Assay (Echo): 0.00915 M
Example 7g: 'H NMR (400.132 MHz, DMSO-d6) b 1.23 (3H, d), 1.33 (3H, d), 1.35
(3H, d),
1.52 - 1.61 (4H, m), 2.18 (6H, s), 2.34 (2H, t), 3.17 - 3.24 (3H, m), 3.49
(1H, dt), 3.60 - 3.67


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