Note: Descriptions are shown in the official language in which they were submitted.
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SULFUR-CONTAINING HETEROAROMATIC TRICYCLIC KRAS
INHIBITORS
BACKGROUND
[0001] Embodiments herein relate to compounds, compositions and methods for
the
treatment of RAS-mediated disease, In particular, embodiments herein relate to
compounds
and methods for treating diseases such as cancer via targeting oncogenic
mutants of the K-
RAS isoform.
[0002] Ras proteins are small guanine nucleotide-binding proteins that act as
molecular
switches by cycling between active GTP-bound and inactive GDP-bound
conformations. Ras
signaling is regulated through a balance between activation by guanine
nucleotide exchange
factors (GEFs), most commonly son of sevenless (SOS), and inactivation by
GTPase-
activating proteins (GAPs) such as neurofibromin or p120GAP. The Ras proteins
play an
important role in the regulation of cell proliferation, differentiation, and
survival.
Dysregulation of the Ras signaling pathway is almost invariably associated
with disease.
Hyper-activating somatic mutations in Ras are among the most common lesions
found in
human cancer. Most of these mutations have been shown to decrease the
sensitivity of Ras to
GAP stimulation and decrease its intrinsic GTPase activity, leading to an
increase in the
active GTP-bound population. Although mutation of any one of the three Ras
isoforms (K-
Ras, N-Ras, or H-Ras) has been shown to lead to oncogenic transformation, K-
Ras mutations
are by far the most common in human cancer. For example, K- Ras mutations are
known to
be often associated with pancreatic, colorectal and non-small-cell lung
carcinomas. Similarly,
H-Ras mutations are common in cancers such as papillary thyroid cancer, lung
cancers and
skin cancers. Finally, N-Ras mutations occur frequently in hepatocellular
carcinoma.
[0003] K-Ras is the most frequently mutated oncoprotein in human cancers.
Accordingly,
there is a need to develop selective inhibitors of KRAS mutants. The present
embodiments
meet this and other needs.
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SUMMARY
[0004] In one aspect, the present embodiments provide compounds, or a
pharmaceutically
acceptable salt thereof, of Formula(Ia):
Ll
R7
N
R5
Rzt.s( N 0
ls'Y 1
R3 P R21m (Ia)
wherein
Z is 0 or S;
m is 1 or 2:
pis 1 or 2;
Ll is
N
LN (R1)k
wherein k is an integer from 0 to 4; and each Rl is independently selected
from
methyl, and cyanomethyl, C2-C4 alkyl, cyano, cycloalkyl, halo, haloalkyl,
trifluoromethyl, and
alkoxy; or any two Rl combine to form a fused ring, bridge, or spirocycle
structure optionally
comprising a heteroatom in the bridge or spirocycle selected from S, SO2, 0 or
N, and
wherein the bridge or spirocycle structure is optionally substituted with oxo;
each R2 is independently selected from the group consisting of alkyl, N-
alkylamino, N, N-dialkylamino, alkylamidoalkyl, arylamidoalkyl, -OCH2CONRR',
wherein
R and R. are independently selected from hydrogen, alkyl, and cycloalkyl,
alkylsulfonamidoalkyl, arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl
aminoalkyl,
alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halogen,
haloalkyl, aryl,
aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl,
heterocyclylalkyl, and
heteroaryloxy any of which are optionally substituted; or when m is 2, two R2
combine to
form a spirocyclic 3-6-membered ring optionally containing 1 to 3 heteroatoms
selected from
N, 0, or S:
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R3, R4, R5, and R6 are independently selected from halogen, hydrogen,
hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino, C-amide (-CONRR'), N-
amides (-
NHCOR), urea (-NHCONHR), ether (-OR), sulfonamide (-NHSO2R or -SO2NHR), and
CF3;
wherein each R and R' is independently hydrogen, alkyl, or cycloalkyl; or
any two adjacent R3, R4, R5, or R6 form an optionally substituted fused 5- or
6-
membered ring comprising 0 to 3 heteroatoms selected from N, 0 or S;
provided that one of R3, R4, R5, or R6 is a bond to the 2-
quinazolinone; and
R7 is alkyl, cyano, cycloalkyl, halogen, haloalkyl, trifluoromethyl, and
alkoxy. (I)
[0005] In another aspect, the present embodiments provide a pharmaceutical
composition
comprising a pharmaceutically effective amount of the compounds disclosed
herein, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable
excipient.
[0006] In another embodiment, the present embodiments provide a method of
treating a
subject having cancer, the cancer characterized by the presence of a KRAS G12C
mutation,
the method comprising administering to the subject a therapeutically effective
amount of a
compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition as disclosed herein.
[0007] In another embodiment, the present embodiments provide a method for
manufacturing a medicament for treating a subject having cancer, the cancer
characterized by
the presence of a KRAS G12C mutation, the medicament comprising a compound
disclosed
herein, or a pharmaceutically acceptable salt thereof, or a a pharmaceutical
composition as
disclosed herein, is used.
[0008] In another embodiment, the present embodiments provide for the use of a
compound
disclosed herein, or a pharmaceutically acceptable salt thereof, or a a
pharmaceutical
composition as disclosed herein, for the manufacture of a medicament for the
treatment of
cancer in a subject, the cancer characterized by the presence of a KRAS G12C
mutation.
[0009] In another embodiment, the present embodiments provide the compounds
disclosed
herein, or a pharmaceutically acceptable salt thereof, or a a pharmaceutical
composition as
disclosed herein, for use in the treatment of cancer in a subject, the cancer
characterized by a
KRAS G12C mutation.
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DETAILED DESCRIPTION
I. GENERAL
[0010] The present embodiments provide inhibitors of KRAS G12C exhibiting good
selectivity over wild-type KRAS and are useful for treating a cancer
characterized by a
KRAS G12C mutation.
II. DEFINITIONS
[0011] Unless specifically indicated otherwise, all technical and scientific
terms used
herein have the same meaning as commonly understood by those of ordinary skill
in the art to
which the embodiments belong. In addition, any method or material similar or
equivalent to a
method or material described herein can be used in the practice of the present
embodiments.
For purposes of the present embodiments, the following terms are defined.
[0012] "A," "an," or "the" as used herein not only include aspects with one
member, but
also include aspects with more than one member. For instance, the singular
forms "a," "an,"
and "the" include plural referents unless the context clearly dictates
otherwise. Thus, for
example, reference to "a cell" includes a plurality of such cells and
reference to "the agent"
includes reference to one or more agents known to those skilled in the art,
and so forth.
[0013] "Alkyl" refers to a straight or branched, saturated, aliphatic radical
having the
number of carbon atoms indicated. Alkyl can include any number of carbons,
such as C1-2,
C1-3, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C3-4,
C3-5, C3-6, C4-5, C4-6 and
C5_6. For example, C1_6 alkyl includes, but is not limited to, methyl, ethyl,
propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl
can also refer to
alkyl groups having up to 20 carbons atoms, such as, but not limited to
heptyl, octyl, nonyl,
decyl, etc. Alkyl groups can be substituted or unsubstituted.
[0014] "Alkylene" refers to a straight or branched, saturated, aliphatic
radical having the
number of carbon atoms indicated, and linking at least two other groups, Le.,
a divalent
hydrocarbon radical. The two moieties linked to the alkylene can be linked to
the same atom
or different atoms of the alkylene group. For instance, a straight chain
alkylene can be the
bivalent radical of -(CH2)11-, where n is I, 2, 3, 4, 5 or 6. Representative
alkylene groups
include, but are not limited to, methylene, ethylene, propylene, isopropylene,
butylene,
isobutylene, sec-butylene, pentylene and hexylene. Alkylene groups can be
substituted or
unsubstituted.
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[0015] "Alkenyl" refers to a straight chain or branched hydrocarbon having at
least 2
carbon atoms and at least one double bond. Alkenyl can include any number of
carbons, such
as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6,
C4, C4-5, C4-6, C5, C5-6,
and C6. Alkenyl groups can have any suitable number of double bonds,
including, but not
limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are
not limited to,
vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl,
butadienyl,
1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-
hexenyl, 2-hexenyl,
3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or
1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.
[0016] "Alkenylene" refers to an alkenyl group, as defined above, linking at
least two other
groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the
alkenylene can be
linked to the same atom or different atoms of the alkenylene. Alkenylene
groups include, but
are not limited to, ethenylene, propenylene, isopropenylene, butenylene,
isobutenylene,
sec-butenylene, pentenylene and hexenylene. Alkenylen groups can be
substituted or
unsubstituted.
[0017] "Alkynyl" refers to either a straight chain or branched hydrocarbon
having at least 2
carbon atoms and at least one triple bond. Alkynyl can include any number of
carbons, such
as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6,
C4, C4-5, C4-6, C5, C5-6,
and C6. Examples of alkynyl groups include, but are not limited to,
acetylenyl, propynyl,
1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-
pentadiynyl,
1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-
hexadiynyl,
1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be
substituted or
unsubstituted.
[0018] "Alkynylene" refers to an alkynyl group, as defined above, linking at
least two other
groups, Le., a divalent hydrocarbon radical. The two moieties linked to the
alkynylene can be
linked to the same atom or different atoms of the alkynylene. Alkynylene
groups include, but
are not limited to, ethynylene, propynylene, isopropynylene, butynylene, sec-
butynylene,
pentynylene and hexynylene. Alkynylene groups can be substituted or
unsubstituted.
[0019] "Alkoxy" refers to an alkyl group having an oxygen atom that connects
the alkyl
group to the point of attachment: alkyl-O-. As for alkyl group, alkoxy groups
can have any
suitable number of carbon atoms, such as C1_6. Alkoxy groups include, for
example,
methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-
butoxy,
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tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be further
substituted with a
variety of substituents described within. Alkoxy groups can be substituted or
unsubstituted.
[0020] "Alkoxyalkyl" refers to a radical having an alkyl component and an
alkoxy
component, where the alkyl component links the alkoxy component to the point
of
attachment. The alkyl component is as defined above, except that the alkyl
component is at
least divalent, an alkylene, to link to the alkoxy component and to the point
of attachment.
The alkyl component can include any number of carbons, such as G:1_6, C1-2, C1-
3, C1-4, C1-5,
C1-6, C2-3, C2-4, C2-5, C2-6, C. C3-5, C3-6, C4-5, C44S and C5-6. The alkoxy
component is as
defined above. Examples of the alkoxyalkyl group include, but are not limited
to, 2-ethoxy-
ethyl and methoxymethyl.
[0021] "Alkylhydroxy" or "hydroxyalkyl" refers to an alkyl group, as defined
above, where
at least one of the hydrogen atoms is replaced with a hydroxy group. As for
the alkyl group,
alkylhydroxy groups can have any suitable number of carbon atoms, such as C1-
6. Exemplary
alkylhydroxy groups include, but are not limited to, hydroxy-methyl,
hydroxyethyl (where
the hydroxy is in the 1- or 2-position), hydroxypropyl (where the hydroxy is
in the 1-, 2- or
3-position), hydroxybutyl (where the hydroxy is in the 1-, 2-, 3- or 4-
position), hydroxypentyl
(where the hydroxy is in the 1-, 2-, 3-, 4- or 5-position), hydroxyhexyl
(where the hydroxy is
in the 1-, 2-, 3-, 4-, 5- or 6-position), 1,2-dihydroxyethyl, and the like.
[0022] "Halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
[0023] "Haloalkyl" refers to alkyl, as defined above, where some or all of the
hydrogen
atoms are replaced with halogen atoms. As for alkyl group, haloalkyl groups
can have any
suitable number of carbon atoms, such as C1-6. For example, haloalkyl includes
trifluoromethyl, flouromethyl, etc. In some instances, the term "perfluoro"
can be used to
define a compound or radical where all the hydrogens are replaced with
fluorine. For
example, perfluoromethyl refers to 1,1,1-trifluoromethyl.
[0024] "Haloalkoxy" refers to an alkoxy group where some or all of the
hydrogen atoms
are substituted with halogen atoms. As for an alkyl group, haloalkoxy groups
can have any
suitable number of carbon atoms, such as C1_6. The alkoxy groups can be
substituted with 1,
2, 3, or more halogens. When all the hydrogens are replaced with a halogen,
for example by
fluorine, the compounds are per-substituted, for example, perfluorinated.
Haloalkoxy
includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy,
perfluoroethoxy, etc.
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[0025] "Cycloalkyl" refers to a saturated or partially unsaturated,
monocyclic, fused
bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring
atoms, or the
number of atoms indicated. Cycloalkyl can include any number of carbons, such
as C3-6,
C4-6, C5-6, C3-8, C4-8, C5-8, C6-8, C3-9, C3-10, C3-11, and C3-12. Saturated
monocyclic cycloalkyl
rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and cyclooctyl.
Saturated bicyclic and polycyclic cycloalkyl rings include, for example,
norbomane, [2.2.2]
bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also
be
partially unsaturated, having one or more double or triple bonds in the ring.
Representative
cycloalkyl groups that are partially unsaturated include, but are not limited
to, cyclobutene,
cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers),
cycloheptene,
cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers),
norbomene, and
norbomadiene. When cycloalkyl is a saturated monocyclic C3-8 cycloalkyl,
exemplary groups
include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl
and cyclooctyl. When cycloalkyl is a saturated monocyclic C3-6 cycloalkyl,
exemplary
groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl.
Cycloalkyl groups can be substituted or unsubstituted.
[0026] "Cycloalkylene" refers to a cycloalkyl group having the number of
carbon atoms
indicated, and linking at least two other groups, i.e., a divalent radical.
The two moieties
linked to the cycloalkylene can be linked to the same atom or different atoms
of the
cycloalkylene group. Examples of cycloalkylene rings include cyclopropylene,
cyclobutylene, cyclopentylene and cyclohexylene, among others. Cycloalkylene
groups can
be linked 1,1, 1,2, 1,3, or 1,4. The cyclohexylene ring, for example, can
adopt a number of
conformations, including the boat and chair conformations. The chair
conformation of
cyclohexylene can have substituents in an axial or equatorial orientation. The
divalent nature
of the cycloalkylenes results in cis and trans formations where cis refers to
both substituents
being on the same side (top or bottom) of the cycloalkylene ring, and where
trans refers to
the substituents being on on opposite sides of the cycloaklene ring. For
example, cis-1,2-
and cis-1,4-cyclohexylene can have one substituent in the axial orientation
and the other
substituent in the equatorial orientation, while trans-1,2- and trans-1,4-
cyclohexylene have
both substituents in the axial or equatorial orientation. cis-1,3-
cyclohexylene have both
substituents in the axial or equatorial orientation, and trans-1,3-
cyclohexylene can have one
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substituent in the axial orientation and the other substituent in the
equatorial orientation.
Cycloalkylene groups can be substituted or unsubstituted.
[0027] "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a
cycloalkyl
component, where the alkyl component links the cycloalkyl component to the
point of
attachment. The alkyl component is as defined above, except that the alkyl
component is at
least divalent, an alkylene, to link to the cycloalkyl component and to the
point of attachment.
In some instances, the alkyl component can be absent. The alkyl component can
include any
number of carbons, such as C1-6, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-
6, C3-4, C3-5, C3-6,
C4-5, C4-6 and C5-6. The cycloalkyl component is as defined within. Exemplary
alkyl-
cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-
cyclobutyl,
methyl-cyclopentyl and methyl-cyclohexyl.
[0028] "Heterocycloalkyl" or "heterocycly1" refers to a saturated ring system
having from
3 to 12 ring members and from 1 to 4 heteroatoms of N, 0 and S. Additional
heteroatoms
can also be useful, including, but not limited to, B, Al, Si and P. The
heteroatoms can also be
oxidized, such as, but not limited to, -5(0)- and -S(0)2-. Heterocycloalkyl
groups can
include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4
to 8, 5 to 8, 6 to 8,
3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of
heteroatoms can be
included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1
to 3, 1 to 4, 2 to 3, 2
to 4, or 3 to 4. The heterocycloalkyl group can include groups such as
aziridine, azetidine,
pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine,
imidazolidine,
piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran,
oxane
(tetrahydropyran), oxepane, thiirane, thietane, thiolane
(tetrahydrothiophene), thiane
(tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine,
isothiazolidine, dioxolane,
dithiolane, morpholine, thiomorpholine, dioxane, dithiane, and hexahydro-1H-
pyrrolizine.
The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring
systems to
form members including, but not limited to, indoline. Heterocycloalkyl groups
can be
unsubstituted or substituted. For example, heterocycloalkyl groups can be
substituted with
C1-6 alkyl or oxo (=0), among many others.
[0029] The heterocycloalkyl groups can be linked via any position on the ring.
For
example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2-
azetidine, pyrrolidine can
be 1-, 2- or 3-pyrrolidine, piperidine can be 1-, 2-, 3- or 4-piperidine,
pyrazolidine can be 1-,
2-, 3-, or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3- or 4-imidazolidine,
piperazine can be
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1-, 2-, 3- or 4-piperazine, tetrahydrofuran can be 1- or 2-tetrahydrofuran,
oxazolidine can be
2-, 3-, 4- or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4- or 5-
isoxazolidine, thiazolidine can
be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4- or 5-
isothiazolidine, and
morpholine can be 2-, 3- or 4-morpholine.
[0030] When heterocycloalkyl includes 3 to 8 ring members and 1 to 3
heteroatoms,
representative members include, but are not limited to, pyrrolidine,
piperidine,
tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine,
imidazolidine, piperazine,
oxazolidine, isoxzoalidine, thiazolidine, isothiazolidine, morpholine,
thiomorpholine, dioxane
and dithiane. Heterocycloalkyl can also form a ring having 5 to 6 ring members
and 1 to 2
heteroatoms, with representative members including, but not limited to,
pyrrolidine,
piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine,
piperazine,
oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, and
hexahydro-1H-
pyrrolizine.
[0031] "Heterocyclalkylene" refers to a heterocyclalkyl group, as defined
above, linking at
least two other groups. The two moieties linked to the heterocyclalkylene can
be linked to
the same atom or different atoms of the heterocyclalkylene.
Heterocycloalkylene groups can
be substituted or unsubstituted.
[0032] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component
and a
heterocycloalkyl component, where the alkyl component links the
heterocycloalkyl
component to the point of attachment. The alkyl component is as defined above,
except that
the alkyl component is at least divalent, an alkylene, to link to the
heterocycloalkyl
component and to the point of attachment. The alkyl component can include any
number of
carbons, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6,
C3-4, C3-5, C3-6, C4-5, C4-6
and Cs-6. In some instances, the alkyl component can be absent. The
heterocycloalkyl
component is as defined above. Alkyl-heterocycloalkyl groups can be
substituted or
unsubstituted.
[0033] "Aryl" refers to an aromatic ring system having any suitable number of
ring atoms
and any suitable number of rings. Aryl groups can include any suitable number
of ring
atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well
as from 6 to 10, 6 to
12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form
bicyclic or
tricyclic groups, or linked by a bond to form a biaryl group. Representative
aryl groups
include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl,
having a methylene
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linking group. Some aryl groups have from 6 to 12 ring members, such as
phenyl, naphthyl
or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl
or naphthyl.
Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be
substituted
or unsubstituted.
[0034] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl
component,
where the alkyl component links the aryl component to the point of attachment.
The alkyl
component is as defined above, except that the alkyl component is at least
divalent, an
alkylene, to link to the aryl component and to the point of attachment. The
alkyl component
can include any number of carbons, such as C0_6, C1-2, C1-3, C1-4, C1-5, C1-6,
C2-3, C2-4, C2-5,
C2-6, C34, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl
component can be
absent. The aryl component is as defined above. Examples of alkyl-aryl groups
include, but
are not limited to, benzyl and ethyl-benzene. Alkyl-aryl groups can be
substituted or
unsubstituted.
[0035] "Arylene" refers to an aryl group, as defined above, linking at least
two other
groups. The two moieties linked to the aryl can be linked to the same atom or
different atoms
of the aryl. Arylene groups can be substituted or unsubstituted.
[0036] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic
aromatic ring
assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms
are a heteroatom
such as N, 0 or S. Additional heteroatoms can also be useful, including, but
not limited to,
B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not
limited
to, -S(0)- and -S(0)2-. Heteroaryl groups can include any number of ring
atoms, such as,
to 6, 5 to 8, 6 to 8, 5 to 9, 5 to 10, 5 to 11, or 5 to 12 ring members. Any
suitable number of
heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or
5, or 1 to 2, 1 to 3,
I. to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups
can have from 5 to 8
ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from
1 to 3
heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from
5 to 6 ring
members and from 1 to 3 heteroatoms. The heteroaryl group can include groups
such as
pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine,
pyrimidine, pyridazine,
triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole,
isothiazole, oxazole, and
isoxazole. The heteroaryl groups can also be fused to aromatic ring systems,
such as a phenyl
ring, to form members including, but not limited to, benzopyrroles such as
indole and
isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine
(quinoxaline),
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benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and
cinnoline,
benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl
rings linked by
a bond, such as bipyridine. Heteroaryl groups can be substituted or
unsubstituted.
100371 The heteroaryl groups can be linked via any position on the ring. For
example,
pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3- and 4-
pyridine, imidazole
includes 1-, 2-, 4- and 5-imidazole, pyrazole includes 1-, 3-, 4- and 5-
pyrazole, triazole
includes 1-, 4- and 5-triazole, tetrazole includes 1- and 5-tetrazole,
pyrimidine includes 2-, 4-,
5- and 6- pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine
includes 4- and
5-triazine, 1,2,4-triazine includes 3-, 5- and 6-triazine, 1,3,5-triazine
includes 2-triazine,
thiophene includes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazole
includes 2-, 4-
and 5-thiazole, isothiazole includes 3-, 4- and 5-isothiazole, oxazole
includes 2-, 4- and 5-
oxazole, isoxazole includes 3-, 4- and 5-isoxazole, indole includes 1-, 2- and
3-indole,
isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-
quinoline, isoquinoline
includes 1-, 3- and 4-isoquinoline, quinazoline includes 2- and 4-
quinoazoline, cinnoline
includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene,
and
benzofuran includes 2- and 3-benzofuran.
[0038] Some heteroaryl groups include those having from 5 to 10 ring members
and from 1
to 3 ring atoms including N, 0 or S, such as pyrrole, pyridine, imidazole,
pyrazole, triazole,
pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers),
thiophene, furan,
thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline,
isoquinoline,
quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and
benzofuran. Other
heteroaryl groups include those having from 5 to 8 ring members and from 1 to
3
heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole,
pyrazine, pyrimidine,
pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan,
thiazole, isothiazole,
oxazole, and isoxazole. Some other heteroaryl groups include those having from
9 to 12 ring
members and from 1 to 3 heteroatoms, such as indole, isoindole, quinoline,
isoquinoline,
quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran
and bipyridine.
Still other heteroaryl groups include those having from 5 to 6 ring members
and from 1 to 2
ring atoms including N, 0 or S, such as pyrrole, pyridine, imidazole,
pyrazole, pyrazine,
pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and
isoxazole.
[0039] Some heteroaryl groups include from 5 to 10 ring members and only
nitrogen
heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole,
pyrazine, pyrimidine,
11
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pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), indole, isoindole,
quinoline,
isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline. Other
heteroaryl groups
include from 5 to 10 ring members and only oxygen heteroatoms, such as furan
and
benzofuran. Some other heteroaryl groups include from 5 to 10 ring members and
only sulfur
heteroatoms, such as thiophene and benzothiophene. Still other heteroaryl
groups include
from 5 to 10 ring members and at least two heteroatoms, such as imidazole,
pyrazole,
triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-
isomers), thiazole,
isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and
cinnoline.
[0040] "Heteroarylene" refers to a heteroaryl group, as defined above, linking
at least two
other groups. The two moieties linked to the heteroaryl are linked to
different atoms of the
heteroaryl. Heteroarylene groups can be substituted or unsubstituted.
[0041] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a
heteroaryl
component, where the alkyl component links the heteroaryl component to the
point of
attachment. The alkyl component is as defined above, except that the alkyl
component is at
least divalent, an alkylene, to link to the heteroaryl component and to the
point of attachment.
The alkyl component can include any number of carbons, such as Co_6, C1-2, C1-
3, C1-4, C1-5,
C1-6, C2-3, C2-4, C2-5, C2-6, C. C3-5, C3-6, C4-5, C4-6 and C5-6. In some
instances, the alkyl
component can be absent. The heteroaryl component is as defined within. Alkyl-
heteroaryl
groups can be substituted or unsubstituted.
[0042] The groups defined above can optionally be substituted by any suitable
number and
type of subsituents. Representative substituents include, but are not limited
to, halogen,
haloalkyl, haloalkoxy, -OR', =0, -0C(0)R', -(0)R', -02R", -0NR'R", -
0C(0)NR'R", =NR',
=N-OR', -NR'R", -NR"C(0)R', -NR'-(0)NR"R", -NR"C(0)OR', -NH-(NH2)=NH, -NR'C(
NH2)=NH, -NH-(NH2)=NR' , -SR', -S (0)R' , -S(0)2R', -S (0)2NR' R", -NR' S
(0)2R", -N3
and -NO2. R', R" and R" each independently refer to hydrogen, unsubstituted
alkyl, such as
unsubstituted C1.6 alkyl. Alternatively, R' and R", or R" and R"., when
attached to the same
nitrogen, are combined with the nitrogen to which they are attached to form a
heterocycloalkyl or heteroaryl ring, as defined above.
[0043] "Salt" refers to acid or base salts of the compounds, which can be used
in the
methods disclosed herein. Illustrative examples of pharmaceutically acceptable
salts are
mineral acid (hydrochloric acid; hydrobromic acid, phosphoric acid, and the
like) salts,
organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the
like) salts,
12
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quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is
understood that
the pharmaceutically acceptable salts are non-toxic. Additional information on
suitable
pharmaceutically acceptable salts can be found in Remington's Pharmaceutical
Sciences, 17th
ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein
by reference.
[0044] Pharmaceutically acceptable salts of the acidic compounds disclosed
herein are salts
formed with bases, namely cationic salts such as alkali and alkaline earth
metal salts, such as
sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts,
such as
ammonium, trimethyl-ammonium, diethylammonium, and
tris-(hydroxymethyl)-methyl-ammonium salts.
[0045] Similarly acid addition salts, such as of mineral acids, organic
carboxylic and
organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic
acid, are also
possible provided a basic group, such as pyridyl, constitutes part of the
structure.
[0046] The neutral forms of the compounds may be regenerated by contacting the
salt with
a base or acid and isolating the parent compound in the conventional manner.
The parent
form of the compound differs from the various salt forms in certain physical
properties, such
as solubility in polar solvents, but otherwise the salts are equivalent to the
parent form of the
compound for the purposes of the present embodiments.
[0047] Certain compounds disclosed herein possess asymmetric carbon atoms
(optical
centers) or double bonds; the racemates, diastereomers, geometric isomers and
individual
isomers are all intended to be encompassed within the scope of the present
embodiments.
[0048] "Hydrate" refers to a compound that is complexed to at least one water
molecule.
The compounds disclosed herein can be complexed with from 1 to 10 water
molecules.
[0049] "Composition" as used herein is intended to encompass a product
comprising the
specified ingredients in the specified amounts, as well as any product, which
results, directly
or indirectly, from combination of the specified ingredients in the specified
amounts. By
"pharmaceutically acceptable" it is meant the carrier, diluent or excipient
must be compatible
with the other ingredients of the formulation and deleterious to the recipient
thereof
[0050] "Pharmaceutically acceptable excipient" refers to a substance that aids
the
administration of an active agent to and absorption by a subject.
Pharmaceutical excipients
useful in the present embodiments include, but are not limited to, binders,
fillers,
disintegrants, lubricants, coatings, sweeteners, flavors and colors. One of
skill in the art will
recognize that other pharmaceutical excipients are useful in the present
embodiments.
13
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[0051] "Treat", "treating" and "treatment" refers to any indicia of success in
the treatment
or amelioration of an injury, pathology, condition, or symptom (e.g., pain),
including any
objective or subjective parameter such as abatement; remission; diminishing of
symptoms or
making the symptom, injury, pathology or condition more tolerable to the
patient; decreasing
the frequency or duration of the symptom or condition; or, in some situations,
preventing the
onset of the symptom. The treatment or amelioration of symptoms can be based
on any
objective or subjective parameter; including, e.g., the result of a physical
examination.
[0052] "Administering" refers to oral administration, administration as a
suppository,
topical contact, parenteral, intravenous, intraperitoneal, intramuscular,
intralesional,
intranasal or subcutaneous administration, intrathecal administration, or the
implantation of a
slow-release device e.g., a mini-osmotic pump, to the subject.
[0053] "Therapeutically effective amount or dose" or "therapeutically
sufficient amount or
dose" or "effective or sufficient amount or dose" refer to a dose that
produces therapeutic
effects for which it is administered. The exact dose will depend on the
purpose of the
treatment, and will be ascertainable by one skilled in the art using known
techniques (see,
e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The
Art, Science
and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage
Calculations
(1999); and Remington: The Science and Practice of Pharmacy, 20th Edition,
2003, Gennaro,
Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically
effective dose
can often be lower than the conventional therapeutically effective dose for
non-sensitized
cells.
[0054] "Subject" refers to animals such as mammals, including, but not limited
to, primates
(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice
and the like. In
certain embodiments, the subject is a human.
14
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III. COMPOUNDS
100551 The present embodiments provide compounds, and pharmaceutically
acceptable
salts thereof, of Formula (I):
Ll
R7
N
R5
N0
)--R6 s
Y
R3 P R2)
m (I)
wherein
m is 1 or 2;
pis 1 or 2;
Ll is
CN }(R1)k
wherein k is an integer from 0 to 4; and each R1 is independently selected
from
methyl, and cyanomethyl, C2-C4 alkyl, cyano, cycloalkyl, halo, haloalkyl,
trifluoromethyl, and
alkoxy; or any two Rl combine to form a fused ring, bridge or spirocycle
structure optionally
comprising a heteroatom in the bridge or spirocycle selected from S, SO2, 0 or
N, and
wherein the bridge or spirocycle structure is optionally substituted with oxo;
R2 is is selected from the group consisting of alkyl, N-alkylamino, N, N-
dialkylamino, alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl,
arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl, alkoxy,
alkoxyalkyl,
cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halogen, haloalk-yl, aryl, aralkyl,
heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, any of which are
optionally substituted;
or when m is 2, two R2 combine to form a spirocyclic 3-6-membered ring
optionally
containing 1 to 3 heteroatoms selected from N, 0, or S;
R3, R4, R5, and R6 are independently selected from halogen, hydrogen,
hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino, C-amide (-CONRR'), N-
amides (-
SUBSTITUTE SHEET (RULE 26)
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NHCOR), urea (-NHCONHR), ether (-OR), sulfonamide (-NHSO2R or -SO2NHR), and
CF3;
wherein each R and R' is independently hydrogen, alkyl, or cycloalkyl; or
any two adjacent R3, R4, R5, or R6 form an optionally substituted fused 5- or
6-
membered ring comprising 0 to 3 heteroatoms selected from N, 0 or S;
provided that one of R3, R4, R5, or R6 is a bond to the 2-
quinazolinone; and
R7 is alkyl, cyano, cycloalkyl, halogen, haloalkyl, trifluoromethyl, and
alkoxy.
[0056] In embodiments, provided herein are compounds having Formula (Ha) a
pharmaceutically acceptable salt thereof:
.k,(N
F3C
N
No
Sx4
Arl (ha)
wherein AO is a C-linked aryl, heteroaryl, heterocycle, or carbocycle;
n is an integer from 0 to 3: and,
each Rth is independently selected from alkyl, amino, cyano halogen,
trifluoromethyl,
heterocyclyl, or two Rth combine to form a bicyclic fused heterocyle.
[0057] In embodiments, provided herein are compounds having Formula (llb), or
a
pharmaceutically acceptable salt thereof:
F3C
J. N
N0
)
S \
Ar2 (Hb)
wherein Ar2 is an N-linked heteroaryl or heterocycle;
16
SUBSTITUTE SHEET (RULE 26)
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n is an integer from 0 to 3; and,
each IV is independently selected from alkyl, amino, cyano halogen,
trifluoromethyl,
heterocyclyl, or two IV combine to form a bicyclic fused heterocyle.
[0058] In embodiments, provided herein are compounds having Formula (IIc), or
a
pharmaceutically acceptable salt thereof:
F3C
N
NL0
O-Ar3 (IIc)
wherein Ar3 is aryl or heteroaryl;
n is an integer from 0 to 3; and,
each IV is independently selected from alkyl, amino, cyano halogen,
trifluoromethyl,
heterocyclyl, or two IV combine to form a bicyclic fused heterocyle.
[0059] In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.
In
embodiments, n is 4.
[0060] In embodiments, p is 1. In embodiments, p is 2.
[0061] In embodiments, Ll selected from:
Jvw
Me....(NyMe NcN) (NMe (NMe NC,,.(Nj
N) Me's. N
vv vv vw JVW
I N ,NCJ Me
(N)
17
SUBSTITUTE SHEET (RULE 26)
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F
\
1-N N-I 1-N NA 1-1-\1-1
\
1-----F\ N-
--\
1-N N-1 1 N NI 1-N NA
OH OH
____________________________________ \ 1 1- /--i / \NA
N\ ____________ I 7N N\ \ i
oµ
1¨N7 \N __________________ 1¨N/
\/
F
OH
1-N N-I 1-N 1r1
OH
0
rR\--OH
1-N NA ___________________ N N-1 1-N NI
0 0
OH-S --NFI2
1--N \N-I 1-N/ N
18
SUBSTITUTE SHEET (RULE 26)
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F3C
N N
CN NC
/
N\ N
N\ / ___________________________________
222c N"--", 1--NOON
11711,- Pricri
'VNZN) ¨2N),
µ2, _______ N
NA
, wherein is attached through either of the two nitrogen atoms
of If
[0062] In embodiments, R2 is selected from methoxy, amino, MeOCH2-. EtOCH2-,
ccsf N
O
__________________________________________ (N)
MeO(CH2)2NH-, V , V F F 0 Me
A
(N) c) N
N , NI N , 1\1 ,
A A 'O-cycloalkyl
19
SUBSTITUTE SHEET (RULE 26)
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,
\
0
ck ----NRR'
0-heteroaryl , and o ,C-linked aryl or heteroaryl, N-linked heteroaryl or
heterocyclyl, wherein R and R' are independently selected from hydrogen,
alkyl, and
cycloalkyl.
[0063] In embodiments, R3, R4, R5, and R6 define a fused thiophene selected
from:
x, ),` \
--\--j T
s ,and S .
,
wherein each W, X, Y, and Z are independently selected from C=0, NH, 0, S,
CH, C-Q, where Q is amino, halogen, methyl, -0-alkyl, -0-cycloalkyl, or
trifluoromethyl.
[0064] In embodiments, R3, R4, R5, and R6 define a thiophene selected from:
H2N
a NH2 0,. ,NH2
0---NH
X-e\ S \ S \ S \ S ,wherein X is hydrogen,
chloro, methyl, or CF3,
H 0 H 0
N¨' N-4' H2N ......
HNN )_....NH
\ µ N \ \ \r:t('Izz. H2NN,._ A
'=====
\ S , \ S , \ S , \ S , sti ,
_S) H2N
H 0
H2N¨n S-:¨ H2N H2N "=-NH
NH z 1 µ 0 fr''2z. \N
HO 1-1
\S"¨j
0
H 0 0 H
,\:....j, NH H2N Nh N H2N L
HN /.
):),2. I )2y22.
1 HN / 1
I
S S S S ,and s
, , ,.
SUBSTITUTE SHEET (RULE 26)
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[0065] In embodiments, compounds disclosed herein include the following
compounds or
pharmaceutically acceptable salt thereof:
0 0
(:)
Iklj, Me.1/4(N),,Me 44ndo
N N N
F3C F3C F3C
N N
N N NN
N0 N0
---. N 0
CI CI
\ S S \ S S ) \ S s....)..,1\
bMe
0 Cyl 0
%..(1\1j.= Me.....(NMe ( N
)
N N N
F3C F3C F3C
N N NN NN
N0 N0 NO ci CI µ
\ S SI-Ni \ S S\
(21, 8 \ s s\_8,
cl
, ,
0 0 0
(N .4,,Clx= Me.,(NyMe
\S/P
F3C F3C F3C
N N N N F N N
--... N,0 / N0
CI CI / 1 N 0 1
\ S Sj,0 S S S9,OMeNL 1 SjO ,
0 0
0
Me.,..(NyMe
Me..,(1\1)õMe
LN) Me4,(NyMe
N LN)
F3C F3C
N N N N F3C
N0 NN
/ 1 N 0 s ----
I
S SOMe ' S0Me FsC N0 \
S SNvc,
Me Me OMe
,
21
SUBSTITUTE SHEET (RULE 26)
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C:1
Me.1/4(NyMe
(:)
0
N E
F3C Mea,C).,Me
Me NI Me
1\1
N0 N N
CI \ F3C
` S S CI N.) F3C 1\1
N
/
NL0
0 N0 i
/ I SOMe
S
N , S Sj,0Me CF3
, ,
1
(:)v
Me.....(Nfe
0 Me.,(1\1)0Me
Me N Me N N
H2N
)__NF3C N F3C
N
N
N
No
ii NOF3C \
N / 1
NC
NL0 S SH \ S SH
SON
\ s sOMe OMe OMe ,
Ovl
I 0.7
(:)NV. Me N'
L Me 4,..(N NyMe Me.h.(1\H"Me
N)
N F3C
1\1
F3C F3C
N N
S -... N L0
I CI
N0 / 1 N 0 \ S S\ (S)) Me H2N \
S SH S SvH
.--0-0/
OMe , N-C) OMe ,
,
22
SUBSTITUTE SHEET (RULE 26)
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1 07.
(:) (y
Me.,...(Nj "Me MeNMe
,%.(Nyo N
N N
F3C
F3C
F3C I\I
N N
N,L N0 NL0
CI 0 CI CI .
\ S S )
\ S S\ ________ / ) \ S S ) \ __ /
\ ___________________________________ /
N¨
N \\1> =- N
.--0¨(
N' N¨
.
N N
F3C F3C
1\1 1\1 N
NL0 F3C 1\1
CI N 0 ci --....
\ S S\ j
CI
0 V 0 \ S S )
---f -N \ __ /
r4 N
-N I lalp
1 . µN
,
0
0
.(1\ixok
MeNyMe
L
N N) 0
F3C N
MeN).õMe
I\J
CI No F3C
N N
\ S S\ ________ / ) CI 0 F3C
N I\J
"S S\ )
-,/
NL
1\1õ) 0_0 CI 0
\
/
N N , \ S S7LMe
, ,
23
SUBSTITUTE SHEET (RULE 26)
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1 I
0 0 1C)
Me NT Me
T
N N N
F3C F3C F3C
N N N N
N0 N0NOCI CI CI
\ S S ) \ S S 2 \ S S\ )
\ \
"
0
--0¨ .-o¨µ N¨N '-o¨cjN
N
,
1 I
0 0
Me.,..(NTMe Meõ1/4(NTMe 0
N N Me N Me
F3C F3C )"
1\1 N
----. N0 N0 N
F3C
CI CI N
S S\ )
N0
Br
\
0 S SJNI
OMe ,
1 I
0 0 0
MeTNTMe MeND,Me MeNyMe
N N N
F3C F3C F3C
N N 1\1
CI CI
N0 N0 N0
\ S S ) \ S S \ S S
\
\ _________________________________________________________
24
SUBSTITUTE SHEET (RULE 26)
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1
0 (:)
017
Me4,..(NMe MeNTMe
Me4õ..(N).,Me
N N
F3C N
N F3C
1\1 F3C
N0 CI N O 1\1
CI -...
NO
\ S S\) \ S S Br
\ S S\)
b N
N') , b-0
N ,
,
1 I
o7. 07
Me NDr Me MeNTMe N.(r),==
'C
N N N
F3C F3C F3C
N 1\1 1\1
N0 N0
\ S S\) \ S S \ S Si
1\1 N N j
1
0 0 0
MeN),,Me Me4,..(NyMe Me4,..(N)0Me
N N N
F3C F3C F3C
1\1 1\1
1\1
N0 N0
\
C NO CI CI S S
I
\ S S\ j \ S S )
\ \
F ;
--N /-- \
NJ ¨N , ¨N ,
SUBSTITUTE SHEET (RULE 26)
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0 o.7
MeNyMe MeTNTMe 07'
N N
Me.,(N)õMe
S
F3C F3C
N N
N0 N7L0 N
CI CI \s s\--
S F3C 1\1
\ S ,)No \
CI
\ S )
QN N \ __ /
F F >
0 0
0
M
MeN Me eNj.õMe Me Me
TN N
N F3C F3C
1\1 1µ1
F3C
1\1
N N0
CI 0 CI
CI N 0 \ S S\ j \ S S
\ S S\
Sa \ __ S
F F
0 0 V C ) V
N N Me NT Me
( ) C )
N N N
F3C F3C F3C
1\1 1\1 1\1
'"---
` S S \ S S\ ) \ S S\ )
:
Ni \ 0 j----
N N
26
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _ PCT/US2022/030829
0 07
IC)
Me.,.(NMe N
(N ) N
(N )
N
F3C F3C F3C
N 1\1 1\1
CI CI\
NL0 N'L0
----
\ S S ) S S ) \ S S )
N O ci
\ \ \
F
0
N- , -1\1 0
0 C)
4%,(N),, %n..,=
N N
F3C F3C
N N
NL0 NL0
CI \ CI
S S\ )
\
---Me 0--Me
'IV , or 'NI .
[0066] In embodiments, compounds disclosed herein include the following
further
compounds, or pharmaceutically acceptable salt thereof:
27
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 -
PCT/US2022/030829
0,, .....-õ,>. f=-= ,....
I 'I
t
, ..... i
" ...p. , , = ..A.,...... ' ..1., t.s=-= e - ¨
N''''
e'r 1-. 7 .....,.,,..k.õ.,............m, ....t)
Ci''=====r*,.. 1 1 7 - clõ, / -7- y 0
'.='\ t 1 1
.....-8 S =.\\ 0
= 1,,,, ......' s \ :\:====.$ S e,sk 0
====== \ .C3 $ "P
et
0.>c,...,...-= ,., 0,, ,4.-;,....,.. 0 \õ.4..,,
(1 iff( 1.
k\)Ne t
11..,N
\--A
s,,/,\,,,---- \.)-= N f:õ} S:õ,./ky's kN'i'
.....' µN.' -'0 Sõ,......,1-'=kr, 1, N' NO
4 ,. t ., µ,-.4
.z..........,.., ....), .A....õ...,....õ..,,..,
N^...". ve. ...., N.w..... I a
s.,....,,., ..."..A1. ..õ....
1
3 r 1
=N' ..-
NM. õ EztC=v::::;`.N;rA N HA 7
ta.
Ve.N\.1:1 ' -\\
3.: t 1õ)
=
-µ-' $.\)\..,..,..0- h .,. \s,-':'
Sk.,,...0,, \ II 6 1 0
S- ',N.,-
\,....-= N.,
4\''.".\e"
[
;
1,... i
ilf)
'W.". .0e-N-)
=I.=N
k f:Z=C -= ...4' \ \ ("Ls 1, r v.,,,,..1.1.,,,7
...õ1,,,k,,,
S,µõkõoõ
,,i s.,,,A.õ-0,õ
28
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _ PCT/US2022/030829
Oy.....,,k......, 0 ...,
.
= ;
EX,. " ),, FIC ..=., ...-k F =,,,C N. ....::::N, ..--
L, , õ ...õ=I ,...,N siy
, õ,,,...... ,.....: ...,......,,,, ...... , ....
...,õ
1..,-.St S',.,,,,,\H.,,µ ',1.::...,,S S. 1,. ,....--.... =
. - twS e L 1-0
.,,, = /
... .....,
t.,....0,..,
0
sy ..õ..)
( I
r=
1
.14., ' N = ,,,Nõ
4\\\ ....-µ,N F3C ,=:,,,, ....e.LN
=-y-,.., ri= raC.,..= ....r.P.y.LN
ik ,
.),, .3.k. = ...L...
.....,...,,,,,,,, N.---;..=0 ss,,, "Lyk. "k\o's,
N. 1
\µµ,....., s.1 L ....,. ....,=S k µõõs t
/-0
-..õ.., ..\\ s sõ - ==.. \\,"
N...¨.....,s,...t.)
k 1
1
= ...."
t\ Xr"?
\ 0
0.= 0"N., . 0 .." a,,,,..s=¨=,"='=.\.,
"s4" '==== ..,-., =-=...c,
: 1 '
'...N,
:
Fle., ..",. ,&N P.,zcs. ...e, .A.... F...,$.C...
,.......,, õ1,. .
. IT I - ==== -y- vtst
1: 4 1.
l'.... 1 1
...k. A\..,
µ,¨.S t ', =\ =
N.:õ....S S. ,,,,,, ...... ,,,,,.,i >,=,,:'
,.. i, =,¨Ø
= N...õõõ..a,..? \ \s---1' 0 .........-1.-- ' \.
µ 0
s \ '0' k. õ,=,'
0
Qy ...µ.., 0 ;=,...../=\\\
1 \\
N
(N.....1.===µ'
1 ,.....f,,, .., vN R=C õt
, -.,õ ====,. = ,..?.N
i L 1
\\. ..k.
."-- "A` ." = = -
..,.,,,...,. ...= ,,,.., ...,,,...- \µ.,::,..,
My 1=-' ,,,,k,r
'
\:====S = ..\\,..,111 ,,,,,,_,Ls
kõ
.\0.." .0' 1.......11õ,
29
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _
PCT/US2022/030829
()=\.),""\ 0, ......N
1Z11 e N.1..,
"Y N
. ,
. ,
HA F.-C-- .....,-;=-ts:N. õ..-4k-N H.2=N - -z 1......,y
',';Iki
-"r-'" i IL 4: 8 t.....\...õõ==
k............õ,,,v, =,-,,0 4 ..õ=;,.õ....,- sk,......?. .N.A.1õ0
1,...2,,,,,,N.....,. ki:õ.= ,N,- õso
"-= i , --i- 1
.1 A =====.$ $ L \ie,-' t 1 tµ'-t)
"N. ...."
\'1.........74: Z. . . 3 = . . ,., . L., ...." \''' N'e"..
0 \'µ..õõisie \-*
\e,b
k i
''0."...
0 ====,.
0,:v.--....\õ.., ."\)"'''<- 0.1.,,,=====,õk
*,,, .õ:=No, '%*)=.'14%\k" +4,,,,..N.,,,,o.
F.kC ,,,, I., F.47,' = ..i.
1-6N -1- IP. ==== =.":p4
i
ii:N F3hrice*I4
I 1 , - ),.........N, 1 - :-.-.1%.,Jsk ' 1 = ;
,r, .õ,x, ,,....- v. ,,.. \\N--.0 4õ,.ex-yf ' \*" . NA'O
4.,..p=-=,;õ--' k\y"' \ N Ab
\J .,õõõõ.......-..Ø.... \ 4 4 Ã
\ .(} k =r
===== 0,,,
Oky,enk,k, 0,, AN.,
N
(N) N
r.., -...,
.. ......, ..,N......
) H-N
' F1C .....\õ. k to
- I. ..,,, ........õ,õ J.,.
,,,,krii ' '`Yo'NY <4'4 ...),,,.....<.,, ... -....õ.5õ. ..,...,=-===<*i
...p..õ...õ.N y..= ...N
N .%. ...1 tk. ), Ns 'sk s.-,, N' 1,. ( vi
't, Ak.i.- 'N,--- 'N' xb, ,,,,..,.......,/.........:,f-=
r, NA ,0 \y,:,....., ..,õ, sk...õ..:,..."\Nõ,/ 1,4 , NZto
s'NS, czA i µ.,--i ,, 1, - ====S $ ` i.--
\ "¨ '''' '''''',.......:::=(="\ . .. "'NV"' \
,,,,..........>4( \
..."
k... ,.....= . --1
<:zz,""k-ks =======,,
Y ' \ 0:h .==='-`,\
krril 1)
(,.1)
ksN,)
),..,...x.Nt Aisõ,,..,õ==;-õ,.\,,õ===&=,õ,..N ,),,,,,..k.14 3
NT5=;...ezykl, ' .):,.,.;1` klak.,,, õ.õ--.µõ,,,õ..A.õ1/
,z,.4....,,,,,,,,......1.1..e-\.",,,0
fi
/0
-b ¨
¨s
).
\ sa \....1)......)
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _
PCT/US2022/030829
01,/ 0
0
c), cr\l)/
N N N
F3C
NH2 F3C H2N F3C
`N
`N
0
H2N
N,L0 c,"-NH
1\10
.õ.
N-
0 \ S S4 Cs S\ j \S sq
OMe bMe OMe
0
0 0
N N
N
F3C F3C
`N F3C
`N
H o
NO H21\1 N0
\ S
OMe OMe OMe
0 0 0
=(), ,,cklj. cl\ljr
N
N N
NH2
H2N N>iJ õ... r
F3C
`N F3C F3C 41.1.t. ,
N
N,k0
HN =-- s\4 HN .-. s\ j 0 \ S SN4
\ S \ S
OMe \OMe NHCH2CF3
0 0-% 0
N N N
F3C H2N F3C F3C
`N
`N r& N0
H2N 0
N,1/40 ds-NH .. tW
\ S4
S Cs S4
\ S S4
NHCH2CF3 NHCH2CF3 NHCH2CF3
01,. 0.% 01..%
N N N
F3C C N H2N N F3 F3C 0 `N `N 'NI 0-NH
N 1\1-0
1 S4 S ==== s4 HN === s4
\ S \ S \ S
NHCH2CF3 NHCH2CF3 NHCH2CF3
01,
N
F3C & ,N
H2NN
W N 0
HN ==== s4
\ S
NHCH2CF3
31
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _
PCT/US2022/030829
0 0=
01,=
N N N
,F3C ==N H211. F3C N.N
NH2 "L H2N "" ,µ 0 NH
N 0 N 0 NO
0-
OA*1:)r-% 01,,
N N N
F3C =,N F3C ..,N F3C ,N
ICI 0 M 0
,L N NO H2N)'N
\ N 0 % N-0
\ S S \ s
b-<
o
N
N N
F3C ,N F3C ,N F3C ,N
NH2
1-NH H2N N
NrµO
HN µ,. s\__e HN =-= s\ j 0 \ S
\ S \ S
O-Q bA
0 Oy=% 0
N N N
H
F3C ,N H2N F3C ,N F3C õN 0
H2N ."-NIH
110 0 N'60 \ 1\10
\' Sq.
S
N N N
F3C .,N F3C ,,N
M 0
N N'O H2N1---N r\i3O S 1-NH
N(60
% ...,. HN =%, s\__.
\ S S ' S\__.
\ S \ S
0
crµl)
N
F3C ,,N
H2NJLJ
),__N
NO
HN -, s\__.
\ S
32
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _ PCT/US2022/030829
(:) 0-%
N N N
F3C 1i7F3C H2N F3C
'NI
NH2 ,... 1 H2N
N/k0 (:).-NH
N,µ0
NO=-.
0 \ S S\4
\ S s\¨? \ S sq
0 ( (00
(
CONH2 CONH2 CONH2
01,/-
i(1\1),, cl\)/ (1\1),=
N N
N
H
F3C F3C ' F3C
N
1\1 'N
kl 1 H2Nµ_N
N,k0 o -N \
"L = r---
N'O
S --.
\ S S\4 \ S s\)
\ s s\4
o p o
( (
CONH2 CONH2 CONH2
,:),,= o c
N
N N
F3C F3C F3C
' N
'N
01¨NH It NH2
N(:)
N0 H2N
N
HN .-. 0 \ S Sq
\ S Sq
\ s s\4 O
o
(o
(o
c0NH2 c0NH2
33
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _
PCT/US2022/030829
C) (:) 0
N N N
F3C H2N F3C F3C
' N
`N ' N H 0
H2N
N0
1\10 \ Sq .,,
.... =,.
\ S \ S Sq \ S S\4
z40 0 r_40
N N N
C) C ()
N N
N
F3C F3C
'N F3C ' N
H 0 "N H2N
N,µ0 01--NH
N,1/40
N 1\10 N
% =-- S '' HN --.
\ S Sq \ S Sq
\ S Sq
O 0 1_40
0 ei 0
N N N
0
N
F3C `NJ
H211..._N
N 0
HN Sq\ S
r__40
0 N
34
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _
PCT/US2022/030829
(:) IC 0
N N N
F3C N F3C H2N F3C
11\1 H2N 0 'N 'N
H2
NO I\10 N"LO
S\
0 "S S\_ -...
\ S \ S
11 II-s 11'0
0 0
0
(:) (:)),/ 01
(1\1j, =,(1µ1)? %,(1\1)/
N N
N
F3C F3C F3C
N
`N 'N 0 -N _k Fi2NN
\ N 0 1\1\11 :
N- S --, s\_(27N,L 0
II II II
0 0 0
O 0 01
)?
N
N N
F3C
F3C F3C 'N
'N
0--NH \....N Nj NF
H2N
N'O r NO VLO
\ S \ S
44.--.0 Szzo
Il Il 1)
0 0
O (: 0
N N N
F3C H2N F3C F3C
'N
'N
H2N 0
NO C*-NH
"'N 'O \
--. S\__I
\ S "S \ S
0 0 0
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _
PCT/US2022/030829
0 1C) 0
N N N
F3C ` F3C F3C
11 0 N 'NI `N
N,k0 N.
H2NN N,k0 01¨NH
N,k0
s\-- S
\ S \ S \ S
0 0 0
0
(1\1)?
N
F3C `I\1
H2N\rN
N"L0
HN
\ S
0
0 0 (:)
N N N
F3C `
F3C H2N F3C
N 0 `I\1 `N
NiL(L i H2N
N,L0 0'NH
N,µ0
0 S s\4
S S
OMe OMe OMe
0 0 10
N N
N
F3C F3C F3C
H
'N ' N 0 `1\1
H2N,r_N
N,µ0
Nil N 0
\ N 0 µ
i Sq
S S
S
OMe OMe OMe
36
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 -
PCT/US2022/030829
0
(211 0
N
N N
F3C F3C F3C)N
`
`N `N
0--NH H2NN NH2
N/µ0
N-0 N 0 / 1
S\4 ,
q 0 s S4 HN / i HN /1 s
S S OMe OMe NHCH2CF3
C:) (:)1 (:)
N
N N
F3C `N H2N F3C F3C
`N
IC) `N m 0
H2N
µ N0
N/0 -NH
N/ 0 \
/ i
S
S S
NHCH2CF3 NHCH2CF3 NHCH2CF3
(: (:) 0
=,( N ji, c)/ ),o
N N N
F3C F3C F3c
A 0 -N ' N "N
01--NH
N
NO H2Nv__N /L0 N0 r
i S\4 I I S4
S S S
NHCH2CF3 NHCH2CF3 NHCH2CF3
(:)
N
F3C
' N
H2N.__N
,L
N 0
i
S
NHCH2CF3
37
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _
PCT/US2022/030829
0
N N N
F3C itik -
'NI / H N F3C 'NI H211 F3C I.1 '1\1
NH2 I, -µ rµo 0 NH NA)
/ 2 r\ N 0
0 s s/ i S4
Sz
o-.<
o ci (:)
c1\1), =t\lj/
N (1\1)r
N
H r1F3C N,N ti oF3C ,N _ F3C
"2N 16 A
N ' -k NN'1\1 N 0
LW
\ N 0 ,
= S4 / i s4 S /1 s4
S S S
0-1 0-1 0-<
0
N
N N
F3C diti, ,N F3C ,N F3C iiik ,N
N-0 NH2
/
ir Nr.60 H2Nr_N
HN /1 s,__e HN / 1 s4 0 S
S
0- S
<1 OA
0 01,- 0
N N N
,F3C ,N H2N H2N F3C i ,N1 FN1 oF3C 'N
u
N-µ0 eNH IW Niko \ N-k0
/ 1 S\__. 'I S\__ s\__.
S S S
0 0 0
N N N
H 0F3C -NI F3C ral?,t, ..N 0 F3C As,,,.. ,N
NN Ni-c) H2N)---N W N-c) 1-NH I. N-(:)
S / / Sµi HN / / Sµ__.
S S S
0
N
F3C
H2N N 1.I
r-- N0
HN /
S
38
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 -
PCT/US2022/030829
0 0 0
1.
N N N
F3C F3C H2N F3C
-y 0 -N -N
NH2 H2N
/ i NO N 0 1\10
1 S\
0 S 1
4
S S
OCH200NH2 OCH2CONH2
OCH2CONH2
0 (:
0
(1\1)? =x1\1),0
N (1\1)?
N
N
F3C F3C
F3C
0 N
H2N y
H 0 -N
,µ N. is(µO N I"
I Sq
/ i Sq S I Sq
S
S OCH2CONH2 OCH2CONH2
OCH2CONH2
I: CD
N
N N
F3C
F3C
F3C 'N
"N "N
0--=NH 1 H2N
N,0 NH2
N"L0
NO / f
S S 1_40
OCH2CONH2 OCH2CONH2
C_IIN
0 0
N N
N
F3C F3C 'N
'N H2N F3C
'N H 0
S Nµ
HN
/ 1
q(:)
S S
1_40 S 0
0
D
N 0
N (---) N
39
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _
PCT/US2022/030829
00 (:),. 0
N N N
F3C F3C F3C
Icl 0 -N 1\1 1\1
01-NH
N N0 N,k0 N,k0 . H2N):-_=N
/ i
I Sq
S S S
N N N
1C)
=,(N)?
N
F3C
'N
H2N)....N
N/0
I SqS
0
0 N '
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _
PCT/US2022/030829
0 0 0
7
7
=t\l),/ (1\1),
(1\1)/
N N N
F3C F3C H2N F3C 'N
'N 0 'N
NH2 H2N 0'''1\1H
/ i NO NAO I\10
'IS
S S
IIS-'="0
0 0
0
() (D (:
7
7
N N
N
F3C F3C 'N F3C
'N
H 0 'N
N. N 0 N 0 H2N)T.-..N
N'O
/ I /i S , S\__L2.7
S S S
Szzo Sz---0 S-=-0
II II II
0 0 0
01,/ (: (:
N N N
F3C 3
'N
F3C 'N F3C AI õ
N
01¨NH H2
I\rµO N \r_-N
1\10 CI I\1'0
S S\4S S
OMe
11 11
0 0
C)
7
N
F3C
N
CI 1\l'LO
\ S S\4
NHCH2CF3
41
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _
PCT/US2022/030829
(:=
(:
13
N N N
F3C S
N F3C 'N F3C
N
,L
CI NI 0 CI
\ N 0 CI ''' N 0
\ S Sq S S \ S Sq
0¨.< 0¨(
0
(:)
(J
=,cNlj/ (1\1),o
N
N
N
F3C ' N F3C 'N F3C & ,N
N/L0 ,=L
N0 CI N 0
CI \ S S\_14 CI \
\ S Sq
0+ Ldr--0
II 0
0
C (:
(:),.
(1\1)/ =,(N),o
N N
F3C 0 .,
N F3C 0 1 N
N0 F3C
' N
CI \ CI N 0
N0 S Sq \ S
\ S Sq
0--\
----NH2 ¨C F3
0
Oy
(1\1)/
N
F3C
- y
ci I\10
\ S S\_8
42
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 -
PCT/US2022/030829
0 0 0
N N N
CI F3C AI ,,N F3C , m
1 01 0 1 C I F3C 1101 NI
/ 1 IW N= O / 1 N1:O / 1 N 0
S Sq S 1 S4 S S\__
OMe NHCH2CF3 0-<1
0 0 0
)/
N N
N
CI F3C lai ,
N CI F3C riki .,
N CI F3C AI õ
N
= ,µ ,µ
IW N 0
/ 1 W N 0 / 1 W N 0 / 1
S S S S\__? S sq
0-( 0*
0 0 0
N N
N
F3C F3C raiii %,
N F3C `1\1 CI 110 `N
N,µO CI
I, i\j/0 CI Ir µ
N, 0
/ 1
S S\_L S S S Sq
0-0
0
0 0 0
7
(1\1)/
N
N N
F3C
N F3C A, t i õ
N CI F3C
N
CI
CI
= 0 / 1 IW N 0
s s<)s s I s s,
0¨\
-NH2 N
\-CF3
0
43
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 _
PCT/US2022/030829
0 (:) 0
I\J)/ I\J), (1\1j=
N N N
F3C
F3C H2N F3C
` N 0 ` N ` N
H2N N _
" L H2N
Nk0 0
N,0
0 \ S S\_74 \ S
1\c N N
F3C>
F3C) )
F3C
0 1C) C11
(1\1)/ clNy =,(N)/
N
F3C N
F3C N
F3c
` N
N,k0
\ /k
N 0 NI N,k0 r
S
S S\-L
N N N
>
F3C) )
F3C
F3C
(:) 00 (2
icy =,(N),= cl\J),
N N N
F3C F3C F3C
N 0 ` N
H2N
NO .,:..-N
N" N,k0
HN H2N)HN
\ S S\¨ \
S
N N Y
F3C) )
F)
F3C 3C
44
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
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(3 0 (21/%
N F3C N
F3C N
H2N F3C & N H 0 (? \ NI
-N
--NH
N,µ0
IW 0 % /
/ I S\_L27
I S\
S S S
N N N
F3C) F3C r,)
F3C)
C) (:) (:)
N N N
0 F3C F3C ,N
`N ' N
NH 1 O 0 H2 F3C
N):-_.N
N,L0 y-NH ir N,0
\ N'S /I S\__L2 HN /
S S S
L-14 N N
\¨CF3 \¨CF3 \¨CF3
(:)
1\1j,o
N
F3C 'N
H2NsrN
/1/4
N 0
S
N
\¨C F3
C) (:) 0
=µ(N)? =1\1),* (1\1)?
N N N
F3C 'N F3C H2N F3C & N H2NJLL 1 H2N ,µ 0 NH
N-0 N 0 IW N'µO
0 \ S S\4 \ s sq \5 sq
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
WO 2022/251296 -
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(:) (:), (:)
)?
N
F3C N
F3C N
H 0 -N ki 0 F3c N
N H2N,_N ` \ µ
NO N, 0 NI S
\ s S4 \ S S\4 \ S S\--?
0 _ JO 0
---"c A ---c
0 0"
0
N N F3C
HN N
F3C F3C
01--NH `N
1110 r _k H2N
N" N,c,
\ s S\-- HN oq
\ S
S
\ ---c 7c
0" 0" 0"
N F3C N
F3C N
H2N F3C
NH is 1\11_ H 0 N
-N
0 N0 N,µ0
/ I Sq 1 s\4
s 7c 1 sq
s s
o
A 7c
0" 0" 0"
N N N
H2N
0 F3C `Nt N F3C `1\1 F3C `1\1
NH L '-
NHN#µ0
\ NO 1\1#0
01 /
/ I s S / q
s I S HN4
s I Sq
s
_A p o o
7c 7c
46
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
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0
N
F3C iti .,
N
H2NN
,µ
T' N 0
HN
S
_____p
A
o o 0
N F3C N N
F3C H2N F3C
r)J
N `N
H2N
N0 H2N
N,0
N,µ0
0 \ S S\_6 \ S S\--8 \ S S\-6
0 0 0
F3C N F3C N N
H 0 ' N H 0 F3C
' N
N
N0 NN N'NIL0
\ % S
S S\_8, \ S S\_8,
0 0 0
(1\1)?
N N
F3C N
F3C F3C
01-NH NI_ H2N ' N 0 ' N
1\10 r I, H2N
N'O N,µ0
HN HN
\ S S\--6 \ S S\--6
S
47
SUBSTITUTE SHEET (RULE 26)
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0 0-%
0
N F3C N F3C N
H2N F3C & N 0
--1\1H N N
0 ,k N,k0
\ / N 0 1\1\ /
/ I S\ S\_8,
S S S
NH
0 0 C
N N N
0 F3C F3C `N `N 0y-NH `N
NH
N,k0 H2N).-,..-N
F3C
N,k0 N"L0
\ S / HN /
/ I S I s\_8, I
S S S
CD
cl\lj/
N
F3C `11
H211rN
N,µ0
S
48
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
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1C) CD C)
N N N
F3C
F3C F3C H N
H2N)___N ` N ` N 2 )z...,N
` N
S N,L0 H2N\r_.-N
\
I I S SS S S-CCS S SS
0 (:) CD
(1\1)?
N N N
H2N F3C F3C,J
H2N F3C
NçI ):--N ` N H2NMII` N
N/L0
\ S SS \ S S -COS S SCS
(:) 0 0
N N N
H2N F3C H2N F3C F3C
NI ` N
NI N H2N
)---
S N0
i \ S S \ S S
S SS S -CCS
(:),. 0 CD
N N N
CN) (N) (N)
F3C H N F3C H2N F3C
H2N\rN `N 5_,..,N
`N ).,..._N
N
N"L0 N
N,0 S / 1 N
I %
S S - C OS S S - C OS \ S
49
SUBSTITUTE SHEET (RULE 26)
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0 C) 0
Ak,(11x0 N rN o%
N N
F3C F3C F3C
1\1 1\1 1\1
=--- N /0 CI N LCD CI =-=... N
CI \ \
S
0 Oy= 0
N N
F3C 1\1 F3C F3C
N H2N).õ....,N 1\1
H2N)-_-_-N H2N),-._-N
S "--. N'.0
\ S S \ S SN) \ S SN.vl
Oy 0 0
Akk(N),0 N ri\J so%
N N
F3C F3C F3C N
N 2N 1\1
H2N)-.7-_N H H2N)-L-...-N
S / N LCD
S I s/c S I S I S
Oy= (:) 0
N N
H2N H2N H2N
N )......NF3C
N N
S I s)\ S I N s7 s I SNvc
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
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0 C) 0
Ak,(1\1x0 N rN ,0
N N
F3C F3C F30
1\1 1\1 1\1
'-.. N /0 CI N LCD
CI \ \
S .7.7
0 Oy= 0
N N
F3C 1\1 F3C F3C
N H2N)õ..._,N 1\1
H2N)-_-_-N H2N)-::_-N
S "--. N'.0
\ S S \ S SN)v \ S SN.v
Oy 0 0
N N
F3C F3C F3C N
N 2 1\1
H2N)-;-_N HN H2N)-_=:-._-N
S / N LCD
S I S7c.7 S I S I S
Oy= (:) (::)
N N
H2N H2N H2N
S I s/ S I N Sj s I SNviv
51
SUBSTITUTE SHEET (RULE 26)
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O 0 0
N N N
F3C 1\1 F3C F3C
1\1 N
N,L0 NL0 N0
CI \ CI CI \
' S Sycv
O () C)
i\cN)/0 N KN sso
N N
F3C F3C F3C
S )-
H2N N 1\1 H2 N
N H2N)....õ__N 1\1 ---S
N,0
S N,0
\ S Svly \ S S7 \ S SN)
C) CD C)
4N,Cljoo N ,0µ
N N
F3C
N F3C 1\1 F3C
N H2N)-z-_N
NL0 H2N H2
N0 N).- L
N0
S I sj\7 S I S s I SN.rl
O (: 0
(
=,(1\1j,00
N N
H2N I-12N H2N
)--NF3C N ).___NF3C 1\1 )--NF3C
1\1
N1 / N'L0 N
S I
52
SUBSTITUTE SHEET (RULE 26)
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O 0 0
( ) oeLN)
N N
F3C F3C F3C
1\1 1\1 1\1
N LC:) 1\10 CI \ N 0
CI \ CI \
SH7 \ S S.71)7i
Cy= Oy= 0
N N
F3C F3C F3C
H2N \......N 1\1 H2NI N H2N 1\1
N/LO
\ S S1)7r \ S Sjr, \ S
SN.vcr
(:) Oy- 0
N N
F3C F3C F3C N
1\1 1\1 2
H2N)--.....-N H2N HN
N
I I I
S SH7 S SH7
S S.v1)7,
O 0
(:)
N N
H2N H2N I H2N
)--NIF3C N )---11F3C N )--1\IF3C 1\1
N N N
N
S
I I SH7 S SH7
S S
53
SUBSTITUTE SHEET (RULE 26)
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[0067] The compounds disclosed herein can exist as salts. The present
embodiments include
such salts, which can be pharmaceutically acceptable salts. Examples of
applicable salt
forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates,
nitrates, maleates,
acetates, citrates, fumarates, tartrates (eg (+)-tartrates, (-)-tartrates or
mixtures thereof
including racemic mixtures, succinates, benzoates and salts with amino acids
such as
glutamic acid. These salts may be prepared by methods known to those skilled
in art. Also
included are base addition salts such as sodium, potassium, calcium, ammonium,
organic
amino, or magnesium salt, or a similar salt. When compounds disclosed herein
contain
relatively basic functionalities, acid addition salts can be obtained by
contacting the neutral
form of such compounds with a sufficient amount of the desired acid, either
neat or in a
suitable inert solvent. Examples of acceptable acid addition salts include
those derived from
inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,
monohydrogencarbonic,
phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as
the salts
derived organic acids like acetic, propionic, isobutyric, maleic, malonic,
benzoic, succinic,
suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-
tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino acids such as
arginate and the
like, and salts of organic acids like glucuronic or galactunoric acids and the
like. Certain
specific compounds disclosed herein contain both basic and acidic
functionalities that allow
the compounds to be converted into either base or acid addition salts.
[0068] Other salts include acid or base salts of the compounds used in the
methods of the
present embodiments. Illustrative examples of pharmaceutically acceptable
salts are mineral
acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like)
salts, organic acid
(acetic acid, propionic acid, glutamic acid, citric acid and the like) salts,
and quaternary
ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood
that the
pharmaceutically acceptable salts are non-toxic. Additional information on
suitable
pharmaceutically acceptable salts can be found in Remington's Pharmaceutical
Sciences, 17th
ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein
by reference.
[0069] Pharmaceutically acceptable salts includes salts of the active
compounds which are
prepared with relatively nontoxic acids or bases, depending on the particular
substituents
found on the compounds described herein. When compounds disclosed herein
contain
relatively acidic functionalities, base addition salts can be obtained by
contacting the neutral
54
SUBSTITUTE SHEET (RULE 26)
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form of such compounds with a sufficient amount of the desired base, either
neat or in a
suitable inert solvent. Examples of pharmaceutically acceptable base addition
salts include
sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a
similar salt.
When compounds disclosed herein contain relatively basic functionalities, acid
addition salts
can be obtained by contacting the neutral form of such compounds with a
sufficient amount
of the desired acid, either neat or in a suitable inert solvent. Examples of
pharmaceutically
acceptable acid addition salts include those derived from inorganic acids like
hydrochloric,
hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric,
hydriodic, or phosphorous acids and the like, as well as the salts derived
from relatively
nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic,
benzoic, succinic,
suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-
tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino acids such as
arginate and the
like, and salts of organic acids like glucuronic or galactunoric acids and the
like (see, for
example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical
Science, 1977, 66,
1-19). Certain specific compounds disclosed herein contain both basic and
acidic
functionalities that allow the compounds to be converted into either base or
acid addition
salts.
[0070] The neutral forms of the compounds are preferably regenerated by
contacting the
salt with a base or acid and isolating the parent compound in the conventional
manner. The
parent form of the compound differs from the various salt forms in certain
physical
properties, such as solubility in polar solvents.
[0071] Certain compounds disclosed herein can exist in unsolvated forms as
well as
solvated forms, including hydrated forms. In general, the solvated forms are
equivalent to
unsolvated forms and are encompassed within the scope of the present
embodiments. Certain
compounds disclosed herein may exist in multiple crystalline or amorphous
forms. In
general, all physical forms are equivalent for the uses contemplated by the
present
embodiments and are intended to be within the scope of the present
embodiments.
[0072] Certain compounds disclosed herein possess asymmetric carbon atoms
(optical
centers) or double bonds; the enantiomers, racemates, diastereomers,
tautomers, geometric
isomers, stereoisometric forms that may be defined, in terms of absolute
stereochemistry, as
(R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are
encompassed within
SUBSTITUTE SHEET (RULE 26)
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the scope of the present embodiments. The compounds disclosed herein do not
include those
which are known in art to be too unstable to synthesize and/or isolate. The
present
embodiments are meant to include compounds in racemic and optically pure
forms. Optically
active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral
synthons or chiral
reagents, or resolved using conventional techniques. The compounds disclosed
herein can be
provided as a mixture of atropisomers or can be pure atropisomers.
[0073] Isomers include compounds having the same number and kind of atoms, and
hence
the same molecular weight, but differing in respect to the structural
arrangement or
configuration of the atoms.
[0074] Unless otherwise stated, structures depicted herein are also meant to
include all
stereochemical forms of the structure; i.e., the R and S configurations for
each asymmetric
center. Therefore, single stereochemical isomers as well as enantiomeric and
diastereomeric
mixtures of the present compounds are within the scope of the embodiments.
[0075] Unless otherwise stated, the compounds disclosed herein may also
contain unnatural
proportions of atomic isotopes at one or more of the atoms that constitute
such compounds.
For example, the compounds disclosed herein may be labeled with radioactive or
stable
isotopes, such as for example deuterium (2H), tritium (3H), iodine-125 (1251),
fluorine-18
(18F), nitrogen-15 (15N), oxygen-17 (170), oxygen-18 (180), carbon-13 (13C),
or carbon-14
(14c.
) All isotopic variations of the compounds disclosed herein, whether
radioactive or not,
are encompassed within the scope of the present embodiments.
[0076] In addition to salt forms, the present embodiments provide compounds,
which are in
a prodrug form. Prodrugs of the compounds described herein are those compounds
that
readily undergo chemical changes under physiological conditions to provide the
compounds
disclosed herein. Additionally, prodrugs can be converted to the compounds
disclosed herein
by chemical or biochemical methods in an ex vivo environment. For example,
prodrugs can
be slowly converted to the compounds disclosed herein when placed in a
transdermal patch
reservoir with a suitable enzyme or chemical reagent.
[0077] Compounds disclosed herein can be made by a variety of methods depicted
in the
illustrative synthetic reaction schemes shown and described below. The
starting materials and
reagents used in preparing these compounds generally are either available from
commercial
suppliers, such as Aldrich Chemical Co., or are prepared by methods known to
those skilled
in the art following procedures set forth in references such as Fieser and
Fieser's Reagents for
56
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Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R. C. LaRock,
Comprehensive
Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive
Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford,
1991;
Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.)
Pergamon,
Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R.
Katritzky and C. W.
Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley &
Sons: New
York, 1991, vol. 1-40. The following synthetic reaction schemes are merely
illustrative of
some methods by which the compounds disclosed herein can be synthesized, and
various
modifications to these synthetic reaction schemes can be made and will be
suggested to one
skilled in the art having referred to the disclosure contained herein.
[0078] For illustrative purposes, reaction Schemes below provide routes for
synthesizing
the compounds disclosed herein as well as key intermediates, For a more
detailed description
of the individual reaction steps, see the Examples section below. Those
skilled in the art will
appreciate that other synthetic routes may be used. Although some specific
starting materials
and reagents are depicted in the Schemes and discussed below, other starting
materials and
reagents can be substituted to provide a variety of derivatives or reaction
conditions. In
addition, many of the compounds prepared by the methods described below can be
further
modified in light of this disclosure using conventional chemistry well known
to those skilled
in the art.
[0079] The starting materials and the intermediates of the synthetic reaction
schemes can
be isolated and purified if desired using conventional techniques, including
but not limited to,
filtration, distillation, crystallization, chromatography, and the like. Such
materials can be
characterized using conventional means, including physical constants and
spectral data.
[0080] Unless specified to the contrary, the reactions described herein
preferably are
conducted under an inert atmosphere at atmospheric pressure at a reaction
temperature range
of from about ¨78 C to about 150 C, more preferably from about 0 C to about
125 C, and
most preferably and conveniently at about room (or ambient) temperature, or,
about 20 C.
[0081] Some compounds in following schemes are depicted with generalized
substituents;
however, one skilled in the art will immediately appreciate that the nature of
the substituents
can varied to afford the various compounds contemplated in the present
embodiments.
Moreover, the reaction conditions are exemplary and alternative conditions are
well known.
57
SUBSTITUTE SHEET (RULE 26)
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The reaction sequences in the following examples are not meant to limit the
scope of the
embodiments as set forth in the claims.
IV. PHARMACEUTICAL FORMULATIONS
[0082] In some embodiments, pharmaceutical compositions comprise a compound of
any
one of the compounds disclosed herein and a pharmaceutically acceptable
excipient.
[0083] In some embodiments, there is provided a pharmaceutical composition
comprising a
pharmaceutically effective amount of a compound of Formula (I), or a
pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0084] In some embodiments, the pharmaceutical composition further comprises
an
additional therapeutic agent.
[0085] In some embodiments, the additional therapeutic agent is a
chemotherapeutic agent.
In some embodiments, the chemotherapeutic agent is an anti-microtubule agent,
a platinum
coordination complex, a alkylating agent, an antibiotic agent, a topoisomerase
II inhibitor, a
antimetabolite, a topoisomerase I inhibitor, a hormone or hormonal analogue, a
signal
transduction pathway inhibitor, a non-receptor tyrosine kinase angiogenesis
inhibitor, a
immunotherapeutic agent, a proapoptotic agent, an inhibitor of LDH-A, an
inhibitor of fatty
acid biosynthesis, a cell cycle signalling inhibitor, a HDAC inhibitor, a
proteasome inhibitor,
or an inhibitor of cancer metabolism. In some embodiments, the
chemotherapeutic agent is
cisplatin, carboplatin, doxorubicin, ionizing radiation, docetaxel or
paclitaxel.
[0086] The compounds disclosed herein can be prepared and administered in a
wide variety
of oral, parenteral and topical dosage forms. Oral preparations include
tablets, pills, powder,
dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions,
etc., suitable for
ingestion by the patient. The compounds disclosed herein can also be
administered by
injection, that is, intravenously, intramuscularly, intracutaneously,
subcutaneously,
intraduodenally, or intraperitoneally. Also, the compounds described herein
can be
administered by inhalation, for example, intranasally. Additionally, the
compounds disclosed
herein can be administered transdermally. The compounds disclosed herein can
also be
administered by in intraocular, intravaginal, and intrarectal routes including
suppositories,
insufflation, powders and aerosol formulations (for examples of steroid
inhalants, see
Rohatagi, I Cl/n. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma
Immunol.
75:107-111, 1995). Accordingly, the present embodiments also provide
pharmaceutical
compositions including one or more pharmaceutically acceptable carriers and/or
excipients
58
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and either a compound of Formula I, or a pharmaceutically acceptable salt of a
compound of
Formula I.
[0087] For preparing pharmaceutical compositions from the compounds disclosed
herein,
pharmaceutically acceptable carriers can be either solid or liquid. Solid form
preparations
include powders, tablets, pills, capsules, cachets, suppositories, and
dispersible granules. A
solid carrier can be one or more substances, which may also act as diluents,
flavoring agents,
surfactants, binders, preservatives, tablet disintegrating agents, or an
encapsulating material.
Details on techniques for formulation and administration are well described in
the scientific
and patent literature, see, e.g., the latest edition of Remington's
Pharmaceutical Sciences,
Maack Publishing Co, Easton PA ("Remington's").
[0088] In powders, the carrier is a finely divided solid, which is in a
mixture with the finely
divided active component. In tablets, the active component is mixed with the
carrier having
the necessary binding properties and additional excipients as required in
suitable proportions
and compacted in the shape and size desired.
[0089] The powders, capsules and tablets preferably contain from 5% or 10% to
70% of the
active compound. Suitable carriers are magnesium carbonate, magnesium
stearate, talc,
sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The
term
"preparation" is intended to include the formulation of the active compound
with
encapsulating material as a carrier providing a capsule in which the active
component with or
without other exceipients, is surrounded by a carrier, which is thus in
association with it.
Similarly, cachets and lozenges are included. Tablets, powders, capsules,
pills, cachets, and
lozenges can be used as solid dosage forms suitable for oral administration.
[0090] Suitable solid excipients are carbohydrate or protein fillers
including, but not
limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch
from corn, wheat,
rice, potato, or other plants; cellulose such as methyl cellulose,
hydroxypropylmethyl-
cellulose, or sodium carboxymethylcellulose; and gums including arabic and
tragacanth; as
well as proteins such as gelatin and collagen. If desired, disintegrating or
solubilizing agents
may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic
acid, or a salt
thereof, such as sodium alginate.
[0091] Dragee cores are provided with suitable coatings such as concentrated
sugar
solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone,
carbopol gel,
59
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polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable
organic solvents
or solvent mixtures. Dyestuffs or pigments may be added to the tablets or
dragee coatings for
product identification or to characterize the quantity of active compound
(i.e., dosage).
Pharmaceutical preparations can also be used orally using, for example, push-
fit capsules
made of gelatin, as well as soft, sealed capsules made of gelatin and a
coating such as
glycerol or sorbitol. Push-fit capsules can contain the compounds disclosed
herein mixed
with a filler or binders such as lactose or starches, lubricants such as talc
or magnesium
stearate, and, optionally, stabilizers. In soft capsules, the compounds
disclosed herein may be
dissolved or suspended in suitable liquids, such as fatty oils, liquid
paraffin, or liquid
polyethylene glycol with or without stabilizers.
[0092] For preparing suppositories, a low melting wax, such as a mixture of
fatty acid
glycerides or cocoa butter, is first melted and the active component is
dispersed
homogeneously therein, as by stirring. The molten homogeneous mixture is then
poured into
convenient sized molds, allowed to cool, and thereby to solidify.
[0093] Liquid form preparations include solutions, suspensions, and emulsions,
for
example, water or water/propylene glycol solutions. For parenteral injection,
liquid
preparations can be formulated in solution in aqueous polyethylene glycol
solution.
[0094] Aqueous solutions suitable for oral use can be prepared by dissolving
the active
component in water and adding suitable colorants, flavors, stabilizers, and
thickening agents
as desired. Aqueous suspensions suitable for oral use can be made by
dispersing the finely
divided active component in water with viscous material, such as natural or
synthetic gums,
resins, methylcellulose, sodium carboxymethylcellulose,
hydroxypropylmethylcellulose,
sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and
dispersing or
wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a
condensation
product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene
stearate), a condensation
product of ethylene oxide with along chain aliphatic alcohol (e.g.,
heptadecaethylene
oxycetanol), a condensation product of ethylene oxide with a partial ester
derived from a fatty
acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a
condensation product of
ethylene oxide with a partial ester derived from fatty acid and a hexitol
anhydride (e.g.,
polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain
one or
more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more
coloring
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agents, one or more flavoring agents and one or more sweetening agents, such
as sucrose,
aspartame or saccharin. Formulations can be adjusted for osmolarity.
[0095] Also included are solid form preparations, which are intended to be
converted,
shortly before use, to liquid form preparations for oral administration. Such
liquid forms
include solutions, suspensions, and emulsions. These preparations may contain,
in addition
to the active component, colorants, flavors, stabilizers, buffers, artificial
and natural
sweeteners, dispersants, thickeners, solubilizing agents, and the like.
[0096] Oil suspensions can be formulated by suspending the compounds disclosed
herein
in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil,
or in a mineral oil
such as liquid paraffin; or a mixture of these. The oil suspensions can
contain a thickening
agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can
be added to
provide a palatable oral preparation, such as glycerol, sorbitol or sucrose.
These formulations
can be preserved by the addition of an antioxidant such as ascorbic acid. As
an example of
an injectable oil vehicle, see Minto, I Pharmacol. Exp. Ther. 281:93-102,
1997. The
pharmaceutical formulations can also be in the form of oil-in-water emulsions.
The oily
phase can be a vegetable oil or a mineral oil, described above, or a mixture
of these. Suitable
emulsifying agents include naturally-occurring gums, such as gum acacia and
gum
tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters
or partial esters
derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate,
and
condensation products of these partial esters with ethylene oxide, such as
polyoxyethylene
sorbitan mono-oleate. The emulsion can also contain sweetening agents and
flavoring agents,
as in the formulation of syrups and elixirs. Such formulations can also
contain a demulcent, a
preservative, or a coloring agent.
[0097] The compounds disclosed herein can be delivered by transdermally, by a
topical
route, formulated as applicator sticks, solutions, suspensions, emulsions,
gels, creams,
ointments, pastes, jellies, paints, powders, and aerosols.
[0098] The compounds disclosed herein can also be delivered as microspheres
for slow
release in the body. For example, microspheres can be administered via
intradermal injection
of drug -containing microspheres, which slowly release subcutaneously (see
Rao, J. Biomater
Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel
formulations (see, e.g.,
Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration
(see, e.g.,
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Eyles, I Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal
routes
afford constant delivery for weeks or months.
[0099] The pharmaceutical formulations of the compounds disclosed herein can
be
provided as a salt and can be formed with many acids, including but not
limited to
hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts
tend to be more
soluble in aqueous or other protonic solvents that are the corresponding free
base forms. In
other cases, the preparation may be a lyophilized powder in 1 mM-50 mM
histidine, 0.1%-
2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with
buffer prior
to use.
101001 The pharmaceutical formulations of the compounds disclosed herein can
be
provided as a salt and can be formed with bases, namely cationic salts such as
alkali and
alkaline earth metal salts, such as sodium, lithium, potassium, calcium,
magnesium, as well
as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and
tris-(hydroxymethyl)-methyl-ammonium salts.
101011 In some embodiments, the formulations of the compounds disclosed herein
can be
delivered by the use of liposomes which fuse with the cellular membrane or are
endocytosed,
i.e., by employing ligands attached to the liposome, or attached directly to
the
oligonucleotide, that bind to surface membrane protein receptors of the cell
resulting in
endocytosis. By using liposomes, particularly where the liposome surface
carries ligands
specific for target cells, or are otherwise preferentially directed to a
specific organ, one can
focus the delivery of the GR modulator into the target cells in vivo. (See,
e.g., Al-
Muhammed, I Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol.
6:698-
708, 1995; Ostro, Am. I Hosp. Pharm, 46:1576-1587, 1989).
[0102] The pharmaceutical preparation is preferably in unit dosage form. In
such form the
preparation is subdivided into unit doses containing appropriate quantities of
the active
component. The unit dosage form can be a packaged preparation, the package
containing
discrete quantities of preparation, such as packeted tablets, capsules, and
powders in vials or
ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or
lozenge itself, or it
can be the appropriate number of any of these in packaged form.
[0103] The quantity of active component in a unit dose preparation may be
varied or
adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most
typically 10 mg
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to 500 mg, according to the particular application and the potency of the
active component.
The composition can, if desired, also contain other compatible therapeutic
agents.
[0104] The dosage regimen also takes into consideration pharmacokinetics
parameters well
known in the art, i.e., the rate of absorption, bioavailability, metabolism,
clearance, and the
like (see, e.g., Hidalgo-Aragones (1996)1. Steroid Biochem. Mol. Biol. 58:611-
617; Groning
(1996) Pharmazie 51:337 -341; Fotherby (1996) Contraception 54:59-69; Johnson
(1995)1
Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983)
Eur.
Chn. Pharmacol. 24:103-108; the latest Remington's, supra). The state of the
art allows the
clinician to determine the dosage regimen for each individual patient, GR and
/or MR
modulator and disease or condition treated.
[0105] Single or multiple administrations of the compounds disclosed herein
formulations
can be administered depending on the dosage and frequency as required and
tolerated by the
patient. The formulations should provide a sufficient quantity of active agent
to effectively
treat the disease state. Thus, in one embodiment, the pharmaceutical
formulations for oral
administration of the compounds disclosed herein is in a daily amount of
between about 0.5
to about 30 mg per kilogram of body weight per day. In an alternative
embodiment, dosages
are from about 1 mg to about 20 mg per kg of body weight per patient per day
are used.
Lower dosages can be used, particularly when the drug is administered to an
anatomically
secluded site, such as the cerebral spinal fluid (C SF) space, in contrast to
administration
orally, into the blood stream, into a body cavity or into a lumen of an organ.
Substantially
higher dosages can be used in topical administration. Actual methods for
preparing
formulations including the compounds disclosed herein for parenteral
administration are
known or apparent to those skilled in the art and are described in more detail
in such
publications as Remington's, supra. See also Nieman, In "Receptor Mediated
Antisteroid
Action," Agarwal, et al., eds., De Gruyter, New York (1987).
[0106] The compounds described herein can be used in combination with one
another, with
other active agents known to be useful in modulating a glucocorticoid
receptor, or with
adjunctive agents that may not be effective alone, but may contribute to the
efficacy of the
active agent.
[0107] In some embodiments, co-administration includes administering one
active agent
within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active
agent. Co-
administration includes administering two active agents simultaneously,
approximately
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simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each
other), or
sequentially in any order. In some embodiments, co-administration can be
accomplished by
co-formulation, i.e., preparing a single pharmaceutical composition including
both active
agents. In some embodiments, the active agents can be formulated separately.
In some
embodiments, the active and/or adjunctive agents may be linked or conjugated
to one
another.
[0108] After a pharmaceutical composition including a compound disclosed
herein has
been formulated in one or more acceptable carriers, it can be placed in an
appropriate
container and labeled for treatment of an indicated condition. For
administration of the
compounds of Formula I, such labeling would include, e.g., instructions
concerning the
amount, frequency and method of administration.
[0109] In some embodiments, the compositions disclosed herein are useful for
parenteral
administration, such as intravenous (IV) administration or administration into
a body cavity
or lumen of an organ. The formulations for administration will commonly
comprise a
solution of the compositions disclosed herein dissolved in one or more
pharmaceutically
acceptable carriers. Among the acceptable vehicles and solvents that can be
employed are
water and Ringer's solution, an isotonic sodium chloride. In addition, sterile
fixed oils can
conventionally be employed as a solvent or suspending medium. For this purpose
any bland
fixed oil can be employed including synthetic mono- or diglycerides. In
addition, fatty acids
such as oleic acid can likewise be used in the preparation of injectables.
These solutions are
sterile and generally free of undesirable matter. These formulations may be
sterilized by
conventional, well known sterilization techniques. The formulations may
contain
pharmaceutically acceptable auxiliary substances as required to approximate
physiological
conditions such as pH adjusting and buffering agents, tonicity adjusting
agents, e.g., sodium
acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate
and the like.
The concentration of the compositions in these formulations can vary widely,
and will be
selected primarily based on fluid volumes, viscosities, body weight, and the
like, in
accordance with the particular mode of administration selected and the
patient's needs. For
IV administration, the formulation can be a sterile injectable preparation,
such as a sterile
injectable aqueous or oleaginous suspension. This suspension can be formulated
according to
the known art using those suitable dispersing or wetting agents and suspending
agents. The
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sterile injectable preparation can also be a sterile injectable solution or
suspension in a
nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-
butanediol.
[0110] In some embodiments, the formulations of the compositions disclosed
herein can be
delivered by the use of liposomes which fuse with the cellular membrane or are
endocytosed,
i.e., by employing ligands attached to the liposome, or attached directly to
the
oligonucleotide, that bind to surface membrane protein receptors of the cell
resulting in
endocytosis. By using liposomes, particularly where the liposome surface
carries ligands
specific for target cells, or are otherwise preferentially directed to a
specific organ, one can
focus the delivery of the compositions disclosed herein into the target cells
in vivo. (See,
e.g., Al-Muhammed, I Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin.
Biotechnol.
6:698-708, 1995; Ostro, Arn. I Hosp. Phann. 46:1576-1587, 1989).
V. METHODS
[0111] In some embodiments, there is provided a method of treating a disorder
or condition
in a subject, the method comprising administering to the human a
therapeutically effective
amount of a compound disclosed herein, or a pharmaceutically acceptable salt
thereof, or a
pharmaceutical composition as disclosed herein.
[0112] In some embodiments, there is provided a method for inhibiting KRAS
G12C
activity in a cell, comprising contacting the cell in which inhibition of KRAS
G12C activity
is desired with an effective amount of a compound disclosed herein or a
pharmaceutically
acceptable salt thereof.
[0113] In some embodiments, there is provided a method for inhibiting KRAS
G12C
activity in a cell, comprising contacting the cell in which inhibition of KRAS
G12C activity
is desired with the pharmaceutical composition disclosed herein.
[0114] In some embodiments, there is provided a method for treating a KRAS
G12C-
associated cancer comprising administering to a patient in need thereof a
therapeutically
effective amount of a compound disclosed herein, or a pharmaceutically
acceptable salt
thereof
[0115] In some embodiments, there is provided a method for treating a KRAS
G12C-
associated cancer comprising administering to a patient in need thereof the
pharmaceutical
composition disclosed herein.
[0116] In some embodiments, there is provided a method of treating a subject
having
cancer, the cancer characterized by the presence of a KRAS G12C mutation, the
method
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comprising administering to the human a therapeutically effective amount of a
compound of
any one of Formula (I) or Formula (II), or a pharmaceutically acceptable salt
thereof, or a a
pharmaceutical composition as disclosed herein.
[0117] In some embodiments, there is provided a method for manufacturing a
medicament
for treating a subject having cancer, the cancer characterized by the presence
of a KRAS
G12C mutation, the compound comprising Formula (I) or Formula (II), or a
pharmaceutically
acceptable salt thereof, or a pharmaceutical composition.
[0118] In some embodiments, there is provided a use of a compound of Formula
(I) or
Formula (II), or a pharmaceutically acceptable salt thereof, or a a
pharmaceutical composition
as disclosed herein, for the manufacture of a medicament for the treatment in
a human having
cancer, the cancer characterized by the presence of a KRAS G12C mutation.
[0119] In some embodiments, there are provided compounds of Formula (I) or
Formula
(II), or a pharmaceutically acceptable salt thereof, or a a pharmaceutical
composition as
disclosed herein, for use in the treatment of a subject having cancer, the
cancer characterized
by the presence of a KRAS G12C mutation.
[0120] In some embodiments, there is provided a method for treating cancer in
a patient in
need thereof, the method comprising (a) determining that the cancer is
associated with a
KRAS G12C mutation (e.g., a KRAS G12C- associated cancer); and (b)
administering to the
patient a therapeutically effective amount of a compound disclosed herein.
[0121] In some embodiments, there is provided a method for treating cancer in
a patient in
need thereof, the method comprising (a) determining that the cancer is
associated with a
KRas G12C mutation (e.g., a KRAS G12C- associated cancer); and (b)
administering to the
patient the pharmaceutical composition disclosed herein.
[0122] In some embodiments, the cancer is Cardiac: sarcoma (angiosarcoma,
fibrosarcoma,
rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and
teratoma;
Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell,
undifferentiated
large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial
adenoma, sarcoma,
lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus
(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach
(carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,
insulinoma,
glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel
(adenocarcinoma,
lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,
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neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous
adenoma,
hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's
tumor
(nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell
carcinoma,
transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma,
sarcoma), testis
(seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma,
sarcoma,
interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,
lipoma); Liver:
hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,
angiosarcoma,
hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma,
ampullary
carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma),
fibrosarcoma,
malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant
lymphoma
(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor
chordoma,
osteochronfroma (osteocartilaginous exostoses), benign chondroma,
chondroblastoma,
chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system:
skull
(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges
(meningioma,
meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma,
ependymoma,
germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma,
retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma,
glioma,
sarcoma); Gynecological: uterus (endometrial 'carcinoma (serous
cystadenocarcinoma,
mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell
tumors,
Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous
cell
carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),
vagina
(clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal
rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid
leukemia
(acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic
leukemia,
myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome),
Hodgkin's
disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant
melanoma, basal
cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic
nevi, lipoma,
angioma, dermatofibroma, keloids, psoriasis; or Adrenal glands: neuroblastoma.
[0123] In some embodiments, the cancer is non-small cell lung cancer, small
cell lung
cancer, colorectal cancer, rectal cancer, or pancreatic cancer.
[0124] In certain embodiments, treatment may be administered after one or more
symptoms
have developed. In other embodiments, treatment may be administered in the
absence of
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symptoms. For example, treatment may be administered to a susceptible
individual prior to
the onset of symptoms (e.g., in light of a history of symptoms and/or in light
of genetic or
other susceptibility factors). Treatment may also be continued after symptoms
have resolved,
for example to prevent or delay their recurrence.
[0125] The compounds of Formula (I) or Formula (II), or a pharmaceutically
acceptable
salt thereof, can be inhibitors of KRAS G12C. For example, the inhibition
constant (Ki) of
the compounds disclosed herein can be less than about 50[1M, or less than
about 40, 30, 20,
10, 9, 8, 7, 6, 5, 4, 3, 2, or less than about 1 M. The inhibition constant
(Ki) of the
compounds disclosed herein can be less than about 1,000 nM, or less than about
900, 800,
700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8,
7, 6, 5, 4, 3, 2, or
less than about 1 nM. The inhibition constant (Ki) of the compounds disclosed
herein can be
less than about 1 nM, or less than about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3,
0.2, or less than about
0.1 nM.
[0126] The compounds of Formula (I) or Formula (II), or a pharmaceutically
acceptable
salt thereof, can be selective inhibitors of KRAS G12C. For example, KRAS G12C
inhibition constant (IC50) of the compounds disclosed herein can be at least 2-
fold less than
the inhibition constant of one or more of KRAS wild-type, or NRAS, or HRAS, or
at least 3,
4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100-fold less. The
KRAS G12C inhibition
constant (Ki) of the compounds disclosed herein can also be at least 100-fold
less than the
inhibition constant of one or more of KRAS wild-type, or NRAS, or HRAS, or at
least 200,
300, 400, 500, 600, 700, 800, 900, 1000, or 10,000-fold less.
A. Cancer Combination Therapies
[0127] The compounds disclosed herein or salts thereof may be employed alone
or in
combination with other agents for treatment. For example, the second agent of
the
pharmaceutical combination formulation or dosing regimen may have
complementary
activities to the compounds disclosed herein such that they do not adversely
affect each other.
The compounds may be administered together in a unitary pharmaceutical
composition or
separately. In one embodiment a compound or a pharmaceutically acceptable salt
can be co-
administered with a cytotoxic agent to treat proliferative diseases and
cancer.
[0128] The term "co-administering" refers to either simultaneous
administration, or any
manner of separate sequential administration, of a compound disclosed herein
or a salt
thereof, and a further active pharmaceutical ingredient or ingredients,
including cytotoxic
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agents and radiation treatment. If the administration is not simultaneous, the
compounds are
administered in a close time proximity to each other. Furthermore, it does not
matter if the
compounds are administered in the same dosage form, e.g. one compound may be
administered topically and another compound may be administered orally.
[0129] Those additional agents may be administered separately from an
inventive
compound-containing composition, as part of a multiple dosage regimen.
Alternatively,
those agents may be part of a single dosage form, mixed together with a
compound disclosed
herein, in a single composition. If administered as part of a multiple dosage
regime, the two
active agents may be submitted simultaneously, sequentially or within a period
of time from
one another normally within five hours from one another.
[0130] As used herein, the term "combination," "combined," and related terms
refers to the
simultaneous or sequential administration of therapeutic agents in accordance
with
embodiments herein. For example, a compound disclosed herein may be
administered with
another therapeutic agent simultaneously or sequentially in separate unit
dosage forms or
together in a single unit dosage form. Accordingly, the present embodiments
provide a single
unit dosage form comprising a compound of Formula!, an additional therapeutic
agent, and a
pharmaceutically acceptable carrier, adjuvant, or vehicle.
[0131] The amount of both an inventive compound and additional therapeutic
agent (in
those compositions which comprise an additional therapeutic agent as described
above) that
may be combined with the carrier materials to produce a single dosage form
will vary
depending upon the host treated and the particular mode of administration. In
certain
embodiments, compositions disclosed herein are formulated such that a dosage
of between
0.01 - 100 mg/kg body weight/day of an inventive can be administered.
[0132] Typically, any agent that has activity against a disease or condition
being treated
may be co-administered. Examples of such agents can be found in Cancer
Principles and
Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition
(February 15,
2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in
the art would
be able to discern which combinations of agents would be useful based on the
particular
characteristics of the drugs and the disease involved.
[0133] In one embodiment, the treatment method includes the co-administration
of a
compound disclosed herein or a pharmaceutically acceptable salt thereof and at
least one
cytotoxic agent. The term "cytotoxic agent" as used herein refers to a
substance that inhibits
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or prevents a cellular function and/or causes cell death or destruction.
Cytotoxic agents
include, but are not limited to, radioactive isotopes (e.g., At', 1131, 1125,
y90. Re186, Re188,
sm153, Bi212, p32, pb212 and radioactive isotopes of Lu); chemotherapeutic
agents; growth
inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes;
and toxins
such as small molecule toxins or enzymatically active toxins of bacterial,
fungal, plant or
animal origin, including fragments and/or variants thereof
[0134] Exemplary cytotoxic agents can be selected from anti-microtubule
agents, platinum
coordination complexes, alkylating agents, antibiotic agents, topoisomerase II
inhibitors,
antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues,
signal
transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis
inhibitors,
immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors
of fatty acid
biosynthesis; cell cycle signalling inhibitors; HDAC inhibitors, proteasome
inhibitors; and
inhibitors of cancer metabolism.
[0135] "Chemotherapeutic agent" includes chemical compounds useful in the
treatment of
cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA ,
Genentech/OSI
Pharm.), bortezomib (VELCADE, Millennium Pharm.), disulfiram ,
epigallocatechin gallate
, salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate
dehydrogenase
A (LDH-A), fulvestrant (FASLODEX , AstraZeneca), sunitib (SUTENT ,
Pfizer/Sugen),
letrozole (FEMARA , Novartis), imatinib mesylate (GLEEVEC ., Novartis),
finasunate
(VATALANIB , Novartis), oxaliplatin (ELOXATIN Sanofi), 5-FU (5-fluorouracil),
leucovorin, Rapamycin (Sirolimus, RAPAMTJNE , Wyeth), Lapatinib (TYKERB ,
GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR ,
Bayer
Labs), gefitinib (IRESSA , AstraZeneca), AG1478, alkylating agents such as
thiotepa and
CYTOXAN cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and
piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa;
ethylenimines and methylamelamines including altretamine, triethylenemelamine,
triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine;
acetogenins (especially bullatacin and bullatacinone); a camptothecin
(including topotecan
and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin,
carzelesin and
bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and
cryptophycin 8);
adrenocorticosteroids (including prednisone and prednisolone); cyproterone
acetate; 5a-
reductases including finasteride and dutasteride); vorinostat, romidepsin,
panobinostat,
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valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin
(including the synthetic
analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin;
spongistatin;
nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide,
estramustine,
ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,
novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;
nitrosoureas such as
carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and
ranimnustine: antibiotics
such as the enediyne antibiotics (e.g., calicheamicin, especially
calicheamicin yl I and
calicheamicin o.)1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicin,
including
dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as
neocarzinostatin chromophore and related chromoprotein enediyne antibiotic
chromophores),
aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin,
carabicin,
caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin,
detorubicin, 6-
diazo-5-oxo-L-norleucine, ADRIAMYCIN (doxorubicin), morpholino-doxorubicin,
cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin),
epirubicin,
esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C,
mycophenolic acid,
nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin,
rodorubicin,
streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-
metabolites such
as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as
denopterin,
methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-
mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as
ancitabine, azacitidine,
6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine,
enocitabine, floxuridine;
androgens such as calusterone, dromostanolone propionate, epitiostanol,
mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane;
folic acid
replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside;
aminolevulinic
acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;
demecolcine;
diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;
gallium nitrate;
hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and
ansamitocins;
mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet;
pirarubicin;
losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK
polysaccharide
complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran;
spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine;
trichothecenes
(especially T-2 toxin, verracurin A, roridin A and anguidine); urethan;
vindesine;
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dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;
arabinoside
("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel;
Bristol-Myers
Squibb Oncology, Princeton, N.J.), ABRAXANE (Cremophor-free), albumin-
engineered
nanoparticle formulations of paclitaxel (American Pharmaceutical Partners,
Schaumberg,
Ill.), and TAXOTERE (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil;
GEMZAR
(gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs
such as
cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide;
mitoxantrone;
vincristine; NAVELBINE (vinorelbine); novantrone; teniposide; edatrexate;
daunomycin;
aminopterin; capecitabine (XELODA'); ibandronate; CPT-11; topoisomerase
inhibitor RFS
2000; difluoromethylomithine (DMF0); retinoids such as retinoic acid; and
pharmaceutically
acceptable salts, acids and derivatives of any of the above.
[0136] Chemotherapeutic agent also includes (i) anti-hormonal agents that act
to regulate
or inhibit hormone action on tumors such as anti-estrogens and selective
estrogen receptor
modulators (SERMs), including, for example, tamoxifen (including NOLVADEX ;
tamoxifen citrate), raloxifene, droloxifene, iodoxyfene , 4-hydroxytamoxifen,
trioxifene,
keoxifene, LY117018, onapristone, and FARESTON (toremifine citrate); (ii)
aromatase
inhibitors that inhibit the enzyme aromatase, which regulates estrogen
production in the
adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide,
MEGASE
(megestrol acetate), AROMASIN (exemestane; Pfizer), formestanie, fadrozole,
RI VISOR
(vorozole), FEMARA (letrozole; Novartis), and ARIMIDEX (anastrozole;
AstraZeneca);
(iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide
and goserelin;
buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol,
premarin,
fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine
(a 1,3-dioxolane
nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase
inhibitors; (vi)
antisense oligonucleotides, particularly those which inhibit expression of
genes in signaling
pathways implicated in aberrant cell proliferation, such as, for example, PKC-
alpha, Ralf and
H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME )
and
HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for
example,
ALLOVECTIN , LEUVECTIN , and VAXID ; PROLEUKIN , rIL-2; a topoisomerase 1
inhibitor such as LURTOTECAN ; ABARELIX rmRH; and (ix) pharmaceutically
acceptable salts, acids and derivatives of any of the above.
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[0137] Chemotherapeutic agent also includes antibodies such as alemtuzumab
(Campath),
bevacizumab (AVASTINO, Genentech); cetuximab (ERBITUXO, Imclone); panitumumab
(VECTIBIX , Amgen), rituximab (RITUXANk, Genentech/Biogen Idec), pertuzumab
(OMNITARGt, 2C4, Genentech), trastuzumab (HERCEPTINk, Genentech), tositumomab
(Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin
(MYLOTARGO, Wyeth). Additional humanized monoclonal antibodies with
therapeutic
potential as agents in combination with the compounds disclosed herein
include: apolizumab,
aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab
mertansine,
cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab,
eculizumab,
efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab
ozogamicin,
inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab,
mepolizumab,
motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab,
ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab,
pectuzumab,
pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab,
rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab
tetraxetan,
tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab
celmoleukin,
tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the
anti¨
interleukin-12 (ABT-874/.1695, Wyeth Research and Abbott Laboratories) which
is a
recombinant exclusively human-sequence, full-length IgGi 2\, antibody
genetically modified
to recognize interleukin-12 p40 protein.
[0138] Chemotherapeutic agent also includes "EGFR inhibitors," which refers to
compounds that bind to or otherwise interact directly with EGFR and prevent or
reduce its
signaling activity, and is alternatively referred to as an "EGFR antagonist."
Examples of
such agents include antibodies and small molecules that bind to EGFR. Examples
of
antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455
(ATCC
CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent
No. 4,943, 533, Mendelsohn et al.) and variants thereof, such as chimerized
225 (C225 or
Cetuximab; ERBUTIX ) and reshaped human 225 (H225) (see, WO 96/40210, Imclone
Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone);
antibodies that
bind type II mutant EGFR (US Patent No. 5,212,290); humanized and chimeric
antibodies
that bind EGFR as described in US Patent No. 5,891,996; and human antibodies
that bind
EGFR, such as ABX-EGF or Panitumumab (see W098/50433, Abgenix/Amgen); EMD
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55900 (Stragliotto etal. Fur. J Cancer 32A:636-640 (1996)); EMD7200
(matuzumab) a
humanized EGFR antibody directed against EGFR that competes with both EGF and
TGF-
alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab);
fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and
E7.6. 3 and
described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb
806
(Johns etal., I Biol. Chem. 279(29):30375-30384 (2004)). The anti-EGFR
antibody may be
conjugated with a cytotoxic agent, thus generating an immunoconjugate (see,
e.g.,
EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such
as
compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001,
5,654,307,
5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484,
5,770,599,
6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455,
5,760,041,
6,002,008, and 5,747,498, as well as the following PCT publications:
W098/14451,
W098/50038, W099/09016, and W099/24037. Particular small molecule EGFR
antagonists
include OSI-774 (CP-358774, erlotinib, TARCEVA Genentech/OSI
Pharmaceuticals); PD
183805 (CI 1033, 2-propenamide, N44-[(3-chloro-4-fluorophenyl)aminol-743-(4-
morpholinyl)propoxyl-6-quinazolinyll-, dihydrochloride, Pfizer Inc.); ZD1839,
gefitinib
(IRES SAO) 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-
morpholinopropoxy)quinazoline,
AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline,
Zeneca);
BIBX-1382 (N8-(3-chloro-4-fluoro-pheny1)-N2-(1-methyl-piperidin-4-y1)-
pyrimido[5,4-
dlpyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-444-[(1-
phenylethyl)amino]-1H-pyrrolo[2,3-dlpyrimidin-6-yll-phenol); (R)-6-(4-
hydroxypheny1)-4-
[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N44-[(3-
bromophenyl)amino]-6-quinazolinyll-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-
fluorophenyl)aminol-3-cyano-7-ethoxy-6-quinolinyll-4-(dimethylamino)-2-
butenamide)
(Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine
kinase
inhibitors such as lapatinib (TYKERBO, GSK572016 or N-[3-chloro-4-[(3
fluorophenyl)methoxylpheny1]-6[5[[[2methylsulfonyl)ethyllamino]methy1]-2-
furany1]-4-
quinazolinamine).
[0139] Chemotherapeutic agents also include "tyrosine kinase inhibitors"
including the
EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2
tyrosine
kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral
selective
inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER
inhibitors such as
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EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits
both HER2
and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-
SmithKline),
an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from
Novartis); pan-
HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such
as antisense
agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1
signaling; non-
HER targeted TK inhibitors such as imatinib mesylate (GLEEVECO, available from
Glaxo
SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib
(SUTENT ,
available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as
vatalanib
(PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular
regulated
kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as
PD 153035,4-
(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines;
pyrrolopyrimidines,
such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-
(phenylamino)-7H-
pyrrolo[2,3-dl pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-
fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties;
PD-0183805
(Warner-Lamber); antisense molecules (e.g. those that bind to HER-encoding
nucleic acid);
quinoxalines (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396);
ZD6474
(Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-
1033
(Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVECO); PM
166
(Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth);
Semaxinib
(Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11
(Imclone),
rapamycin (sirolimus, RAPAMUNE0); or as described in any of the following
patent
publications: US Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO
1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378
(Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc);
WO
1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).
[0140] Chemotherapeutic agents also include dexamethasone, interferons,
colchicine,
metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab,
alitretinoin, allopurinol,
amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene,
cladribine,
clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa,
elotinib, filgrastim,
histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b,
lenalidomide,
levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab,
oprelvekin,
palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed
disodium,
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plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim,
temozolomide, VM-26,
6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic
acid, and
pharmaceutically acceptable salts thereof
[0141] Chemotherapeutic agents also include hydrocortisone, hydrocortisone
acetate,
cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone
alcohol,
mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone
acetonide,
betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone
sodium
phosphate; fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-
valerate;
aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate,
prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate,
fluocortolone caproate,
fluocortolone pivalate and fluprednidene acetate; immune selective anti-
inflammatory
peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-
isomeric form
(feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as
azathioprine,
ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine,
leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFa)
blockers such as
etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab
pegol
(Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra
(Kineret), T
cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6)
blockers such as
tocilizumab (ACTEMERA0); Interleukin 13 (IL-13) blockers such as lebrikizumab;
Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers
such as
rhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secreted
homotrimeric LTa3
and membrane bound heterotrimer LTa1/32 blockers such as Anti-lymphotoxin
alpha (LTa);
radioactive isotopes (e.g., At211, 1131, 1125, y90, Re186, Re188, sm153,
Bi212, 1332, pb212 and
radioactive isotopes of Lu); miscellaneous investigational agents such as
thioplatin, PS-341,
phenylbutyrate, ET-18- OCH3, or farnesyl transferase inhibitors (L-739749, L-
744832);
polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine
gallate, theaflavins,
flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy
inhibitors such as
chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOLO); beta-
lapachone;
lapachol; colchicines; betulinic acid; acetylcamptothecin; scopolectin, and
9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL0); bexarotene
(TARGRETINO); bisphosphonates such as clodronate (for example, BONEFOSO or
OSTACO), etidronate (DIDROCALO). NE-58095, zoledronic acid/zoledronate
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(ZOMETAO), alendronate (FOSAMAXO), pamidronate (AREDIAO), tiludronate
(SKELIDO), or risedronate (ACTONEL0); and epidermal growth factor receptor
(EGF-R);
vaccines such as THERATOPE vaccine; perifosine, COX-2 inhibitor (e.g.
celecoxib or
etoricoxib), proteosome inhibitor (e.g. P5341); CCI-779; tipifarnib (R11577);
orafenib,
ABT510; Bc1-2 inhibitor such as oblimersen sodium (GENASENSE ); pixantrone;
farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASARTm); and
pharmaceutically acceptable salts, acids or derivatives of any of the above;
as well as
combinations of two or more of the above such as CHOP, an abbreviation for a
combined
therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and
FOLFOX, an
abbreviation for a treatment regimen with oxaliplatin (ELOXATINTm) combined
with 5-FU
and leucovorin.
[0142] Chemotherapeutic agents also include non-steroidal anti-inflammatory
drugs with
analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-
selective
inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include
aspirin,
propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen,
flurbiprofen, oxaprozin
and naproxen, acetic acid derivatives such as indomethacin, sulindac,
etodolac, diclofenac,
enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam,
lomoxicam and
isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid,
flufenamic
acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib,
lumiracoxib,
parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for
the
symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis,
inflammatory
arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome,
acute gout,
dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative
pain, mild-to-
moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal
colic.
[0143] In certain embodiments, chemotherapeutic agents include, but are not
limited to,
doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil,
topotecan,
interferons, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel),
vinca alkaloids (e.g.,
vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g.,
etoposide),
cisplatin, an mTOR inhibitor (e.g., a rapamycin), methotrexate, actinomycin D,
dolastatin 10,
colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide,
amphotericin,
alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin,
cisplatin,
metronidazole, and imatinib mesylate, among others. In other embodiments, a
compound
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disclosed herein is administered in combination with a biologic agent, such as
bevacizumab
or panitumumab.
[0144] In certain embodiments, compounds disclosed herein, or a
pharmaceutically
acceptable composition thereof, are administered in combination with an
antiproliferative or
chemotherapeutic agent selected from any one or more of abarelix, aldesleukin,
alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole,
arsenic trioxide,
asparaginase, azacitidine, BCG live, bevacuzimab, fluorouracil, bexarotene,
bleomycin,
bortezomib, busulfan, calusterone, capecitabine, camptothecin, carboplatin,
carmustine,
cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide,
cytarabine,
dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane,
docetaxel,
doxorubicin (neutral), doxorubicin hydrochloride, dromostanolone propionate,
epirubicin,
epoetin alfa, elotinib, estramustine, etoposide phosphate, etoposide,
exemestane, filgrastim,
floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab,
goserelin acetate,
histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib
mesylate,
interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole,
leucovorin,
leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan,
mercaptopurine, 6-
MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,
nandrolone,
nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin,
pamidronate,
pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,
pipobroman,
plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab,
sargramostim,
sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide,
teniposide, VM-26,
testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab,
trastuzumab,
tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine,
vinorelbine, zoledronate,
or zoledronic acid.
[0145] Chemotherapeutic agents also include treatments for Alzheimer's Disease
such as
donepezil hydrochloride and rivastigmine; treatments for Parkinson's Disease
such as L-
DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide,
trihexephendyl, and amantadine; agents for treating multiple sclerosis (MS)
such as beta
interferon (e.g., Avonex and Rebir), glatiramer acetate, and mitoxantrone;
treatments for
asthma such as albuterol and montelukast sodium; agents for treating
schizophrenia such as
zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such
as
corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and
sulfasalazine;
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immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus,
rapamycin, mycophenolate mofetil, interferons, corticosteroids,
cyclophophamide,
azathioprine, and sulfasalazine; neurotrophic factors such as
acetylcholinesterase inhibitors,
MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole,
and anti-
Parkinsonian agents; agents for treating cardiovascular disease such as beta-
blockers, ACE
inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents
for treating liver
disease such as corticosteroids, cholestyramine, interferons, and anti-viral
agents; agents for
treating blood disorders such as corticosteroids, anti-leukemic agents, and
growth factors; and
agents for treating immunodeficiency disorders such as gamma globulin.
[0146] Additionally, chemotherapeutic agents include pharmaceutically
acceptable salts,
acids or derivatives of any of chemotherapeutic agents, described herein, as
well as
combinations of two or more of them.
VI. EXAMPLES
[0147] Synthetic Procedures
General Procedure
[0148] The compounds of Formula I may be prepared from commercially available
reagents
using the synthetic methods and reaction schemes herein, or using other
reagents and
conventional methods well known to those skilled in the art. For instance,
compounds of the
present invention may be prepared according to the general reactions in Scheme
I and II
utilizing conventional cross-coupling chemistry:
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SCHEME I
Compounds of Formula (I)
o o
0
R7 R7 R7
= OMe OMe
OMe
R5 R5
0,B _._ _._
R41.4
NH2NH2
)--R6
R3
R3 S S
1 /
Oy
0
L1
R7
R7 NH
N R5
NL0
RyL77N LO H
S R3
S
R3
m
SCHEME II
I
oyo oyo Ov
L1
Li _ Li
R7 R7 N _._ `N 1 N R5 R7
N,0
NL0
R s
R5
N0 `tL
X R4r ,---R6 µj
S trP 2
\(IR )
R3 S y P ) R3 m
P (µR2)
m 'OR2 m
In Scheme II X is halogen or pseudo-halogen such as mesylate, triflate or the
like.
Example 1: (S)-84(3S,5R)-4-acrvloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
chlorothiophen-
2-y1)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-11,41thiazepino12,3,4-
ill a uinazolin-6-one (El).
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oY
F3C
N
N 0
\ S\
CI
OMe (El)
[0149] Over a solution of (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-
dimethylpiperazin-
l-y1)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H41,4lthiazepino [2,3,4-
ijl quinazolin-6-one (0.095 mmol) in dichloromethane (1 mL), triethylamine
(0.57 mmol) and
acryloyl chloride (0.19 mmol) were added at 0 'C. The reaction mixture was
stirred at room
temperature for two hours. The solvent was removed in vacuo to afford a
residue that was
purified by preparative HPLC to afford the title compound in 39% yield as a
yellow solid
m/z (ESI, +ve)= 599.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 6 8.00 (s, 111), 7.88
(s,
1H), 7.15 (s, 1H), 6.81 (dd, J = 16.0, 8.0 Hz, 1H), 6.19 (dd, J = 16.0, 4.0
Hz, 1H), 5.74 (dd, J
= 8.0, 4.0 Hz, 1H), 4.66 ¨ 4.45 (m, 3H), 4.05 - 3.94 (m. 2H), 3.89¨ 3.81 (m,
1H), 3.32 (s,
5H), 3.28 - 3.24 (m, 2H), 3.17 (s, 1H), L39 (s, 6H).
Step 1: (3-chlorothiophen-2-yl)triisopropylsilane
[0150] Over a solution of 3-chlorothiophene (73.4 mmol) in THF (50 mL) at -78
C, LDA
(73.4 mmol) was added and after one hour at -78 C, chlorotriisopropylsilane
was added. The
mixture was stirred at room temperature for 16 hours, quenched with aqueous
saturated
ammonium chloride solution and extracted with ethyl acetate. The organic phase
was dried
over sodium sulfate, filtered and concentrated under reduced pressure. The
residue was
purified by silica gel chromatography to afford the title compound in 90%
yield.
Step 2: (3-chloro-5-iodothiophen-2-yl)triisopropylsilane
[0151] To a solution of (3-chlorothiophen-2-yl)triisopropylsilane (8.4 mmol)
in THF (20 mL)
at -78 C was added LDA (10.08 mol). The reaction mixture was stirred at -78 C
for 2 hours.
A solution of iodine (10.92 mmol) in THF (5 mL) was added and the reaction
mixture was
stirred at room temperature for 16 hours. The reaction was diluted with water
and extracted
with ethylacetate three times. The combined organic layers were washed with
saturated
aqueous Na2S203 three times, dried over sodium sulfate and concentrated to
afford a residue
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that was purified by silica gel chromatography to afford the title compound in
91% yield as a
colorless oil.
Step 3: methyl 2-amino-4-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-5-
(trifluoromethyl)benzoate
[0152] A mixture of methyl 2-amino-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
y1)-5-
(trifluoromethyl)benzoate (0.14 mol), (3-chloro-5-iodothiophen-2-
yl)triisopropylsilane (0.11
mol), Pd(dppf)C12 (24.5 mmol) and K3PO4 (0.37 mol) in 1,4-dioxane:H20 (300
mL:30 mL)
was stirred at 100 C for 16 hours. The mixture was cooled to room temperature
and the
solids filtered. The filtrate was concentrated to afford a residue that was
purified by silica gel
chromatography to afford the title compound in 63% yield as a yellow solid;
m/z (ESI, +ve)=
492.1 [M+H]+.
Step 4: methyl 2-amino-4-(4-chlorothiophen-2-y1)-5-(trifluoromethyl)benzoate
[0153] TBAF (14.7 mmol) was a added over a solution of methyl 2-amino-4-(4-
chloro-5-
(triisopropylsilyl)thiophen-2-y1)-5-(trifluoromethyl)benzoate (4.9 mmol) in
THF (30 mL).
The mixture was stirred at room temperature for three hours, diluted with
water and extracted
with ethyl acetate three times. The combined organic layers were dried over
sodium sulfate
and the volatiles removed under reduced pressure to afford a residue that was
purified by
silica gel chromatography to afford the title compound in 97% yield as a white
solid; m/z
(ESI, +ve)= 336.0 [M+H]+.
Step 5: methyl 2-amino-4-(4-chlorothiophen-2-y1)-3-iodo-5-
(trifluoromethyObenzoate
[0154] To a mixture of methyl 2-amino-4-(4-chlorothiophen-2-y1)-5-
(trifluoromethyl)benzoate (27.1 mmol) in AcOH (100 mL) was added N-
iodosuccinamide
(44.4 mol). The reaction was stirred at room temperature for 36 hours and the
volatiles
removed under reduced pressure. The resulting residue was redissolved in ethyl
acetate and
sequentially washed with saturated aqueous Na2S203, water and brine. The
organic layer was
dried over sodium sulfate and concentrated to afford a residue that was
purified by silica gel
chromatography (0-15% ethyl acetate in hexanes) affording the title compound
in 35% yield
as a white solid; m/z (ESI, +ve)= 461.9 [M+H]+.
Step 6: 2-amino-4-(4-chlorothiophen-2-y1)-3-iodo-5-(trifluoromethyl)benzoic
acid
[0155] To a mixture of methyl
2-amino-4-(4-chlorothiophen-2-y1)-3-iodo-5-
(trifluoromethyl)benzoate (23.8 mmol) in MeOH:THF(30 mL:30 mL) was added
aqueous
0.01M NaOH (0.238 mol) and the reaction was stirred at room temperature for 30
minutes. The
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pH of the mixture was adjusted to 5 by the addition of 6M HC1 and the solution
was extracted
with ethyl acetate three times. The combined organic layers were washed with
water, brine,
dried over sodium sulfate and concentrated to afford the title compound in 96%
yield as a
yellow solid; m/z (ESI, +ve)= 447.9 [M+H]+.
Step 7: 7-(4-chlorothiophen-2-y1)-8-iodo-6-(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione
[0156] A mixture of 2-amino-4-(4-chlorothiophen-2-y1)-3-iodo-5-
(trifluoromethyObenzoic
acid (20.4 mmol) and urea (1.67 mol) was heated at 200 C for 2 hours. The
reaction was
cooled down to 90 C and diluted with 600 mL of methanol:ethyl acetate (1:1).
The mixture
was allowed to cool down to room temperature slowly and stirred for another 3
hours. After
filtration, the volatiles were removed under reduced pressure and the crude
material purified
by reverse phase silica gel chromatography to afford the title compound as a
white solid in
50% yield: m/z (EST, +ve)= 472.8 [M+1-11+,
Step 8: (S)-7-(4-chlorothiophen-2-y1)-8-((3-hydroxy-2-methoxypropyl)thio)-6-
(trifluoromethyl)quinazoline-2,4(1H,3H)-dione
[0157] To a solution of 7-(4-chlorothiophen-2-y1)-8-iodo-6-
(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione (0.0124 mol), Cuprous iodide (470 mg, 0.0024 mol) and
Potassium carbonate (5.14 g, 00.0372 mol) in isopropyl acohol (30 ml) and
ethylene
glycol (60 ml) was added (S)-3-mercapto-2- methoxypropan-1-ol (0.0372 mol).The
reaction
mixture was stirred at 85 C for 36 hours. The mixture was concentrated under
reduced
pressure and the crude material purified by reverse column to afford the title
compound in
39% yield as a white solid; m/z (ESI, +ve)= 467.0 [M+H]+.
Step 9: (S)-11-(4-chlorothiophen-2-y1)-3-methoxy-10-(trifluoromethyl)-3,4-
dihydro-2H,6H-
11,41thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione
[0158] To a solution of triphenylphosphine (6.4 mmol) in THF (10 ml) cooled
to 0 C was added N,N-diisopropylethylamine (6.4 mmol) and the mixture was
stirred for 30
minutes. (S)-7-(4-chlorothiophen-2-y1)-8-((3-hydroxy-2-methoxypropyl)thio)-6-
(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (6.4 mmol) was added and stirred
at 0 C for
1 hour. The mixture was concentrated under reduced pressure and the residue
purified by
reverse column chromatography to afford the title compound in 77% yield as a
white solid;
m/z (ESI, +ve)= 449.0 [M+H]+.
Step 10: (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-
3-methoxy-
10-(trifluoromethyl)-3,4-dihydro-2H,6H41,4]thiazepino[2.3,4-ij]quinazolin-6-
one
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[0159] To a solution of (S)-11-(4-chlorothiophen-2-y1)-3-methoxy-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H41,41thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione (0.05 mmol) in
toluene (1
mL) were added /V,N-diisopropylethylamine (1.0 mmol) and P0C13 (1 mL). The
reaction mixture was stirred at 120 C for 1.5 hours, cooled down to room
temperature and
concentrated to afford a residue that was dissolved in dichloroethane (1 mL)
and added to
a solution of (2R,6S)-2,6-dimethylpiperazine (0.35 mmol) and
N,Ndiisopropylethylamine
(1.0 mmol) in dichloroethane (1 mL). The reaction mixture was stirred at room
temperature
for 1 hour, concentrated and the resulting solid purified by silica gel
chromatography to
afford the title compound in 51% yield as a yellow solid; m/z (ESI, +ve)=
545.1 [M+H]+.
Example 2: (S)-74(3S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-10-(4-
chlorothiophen-
2-y1)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-l1,41thiazino[2,3,4-
iil uinazolin-5-one (E2)
(Nj,
F3C
N
N
\ I s7H
CI OMe (E2)
[0160] To a 0 C solution of (125)-8-(4-chloro-2-thieny1)-4-[(38,5R)-3,5-
dimethylpiperazin-
1-y11-12-(methoxymethyl)-7-(trifluoromethyl)-10-thia-1,3-diazatricyclo
[7.3.1.05,13] trideca-
3,5(13),6,8-tetraen-2-one;2,2,2-trifluoroacetic acid (0.05 mmol) in
acetonitrile (2mL) was
added diisopropylethylamine (0.46 mmol) followed by acryloyl chloride (0.14
mmol). The
reaction was stirred at 0 C for 20 minutes, diluted with ethyl acetate and
washed with water.
The organic layer was dried over sodium sulfate and concentrated under reduced
pressure to
afford a residue that was purified by HPLC. The title compound was isolated as
a white solid
in 36% yield. MS (ESI) m/z: 599.1 [M+I-11+. 1H NMR (400 MHz, Me0D) 6 8.02 (s,
1H), 7.50
(s, 1H), 6.90 (broad singlet, 1H), 6.74 (dd, J = 16.7, 10.6 Hz, 1H), 6.19 (d,
J = 16.7, 2.0 Hz,
1H), 5.71 (d. J= 10.6, 2.0 Hz, 1H), 5.25 (s, 1H), 4.69-4.47 (m, 2H), 4.24 (d,
16 Hz, 1H), 4.15
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(d, 16 Hz, 1H), 3.67-3.62 (m, 1H), 3.54-3.50 (m, 1H), 3.40 (m, 1H), 3.36-3.23
(m, 5H), 3.02
(dd, J= 14, 3.0 Hz, 1H), 1.47 (d, J= 6.9 Hz, 6H), 1.31 (d, J= 6.9 Hz, 3H).
Step 1: Methyl 2-acetamido-4-chloro-5-iodobenzoate
[0161] To a mixture of methyl 2-amino-4-chloro-5-iodobenzoate (161 mmol) in
AcOH
(500 mL) was added Ac20 (193 mmol). The mixture was stirred at 100 C for 16
hours,
cooled to room temperature, filtered and washed with hexanes to afford the
title compound in
62% yield as a white solid. MS (ESI) m/z: 353.9 [M+H]t.
Step 2: Methyl 2-acetamido-4-chloro-5-(trifluoromethyl)benzoate
[0162] To a mixture of methyl 2-acetamido-4-chloro-5-iodobenzoate (99 mmol) in
DMF
(350 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (396 mmol),
HMPA (396
mmol) and CuI (79 mmol). The mixture was stirred at 90 C for 16 hours, poured
into water
and extracted with ethyl acetate three times, The combined organic layers were
washed with
brine, dried over sodium sulfate, filtered and concentrated under reduced
pressure. The
resulting residue was purified by silica gel chromatography (1-5% ethyl
acetate in hexanes)
to afford the title compound in 84% yield as white solid. MS (ESI) m/z: 296.0
[M+I-11+.
Step 3: Methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate
[0163] A mixture of methyl 2-acetamido-4-chloro-5-(trifluoromethyl)benzoate
(68 mmol)
in HC1/Me0H (200 mL) was stirred at 70 C for 2 hours. The mixture was
concentrated and
the residue treated with a saturated aqueous solution of NaHCO3 (100 mL). The
resulting
mixture was extracted with ethyl acetate three times and the combined organic
layers were
washed with brine and dried over sodium sulfate. Evaporation of volatiles
under reduced
pressure afforded the title compound as a yellow solid in quantitative yield.
MS (ESI) m/z:
254.0 [M+111+
Step 4: Methyl 2-amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoate
[0164] To a solution of methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate
(110 mmol)
in acetic acid (280 mL) was added N-iodosuccinimide (143 mmol). The mixture
was stirred
at 50 C for 16 hours. The reaction mixture was poured into water, extracted
with ethyl
acetate three times and the combined organic layers were washed with brine,
dried over
sodium sulfate, filtered and concentrated. The resulting residue was washed
with hexanes to
afford the title compound as a white solid in quantitative yield. MS (ESI)
m/z: 379.9 [M+Hr
Step 5: 2-Amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoic acid
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[0165] To a solution of methyl 2-amino-4-chloro-3-iodo-5-
(trifluoromethyl)benzoate (66
mmol) in dioxane (200 mL) and water (200 mL) was added solid sodium hydroxide
(132
mmol). The mixture was stirred at 90 C for 3 hours. After completion, the
solution was
poured into water and the pH adjusted to 4-5. The mixture was extracted with
ethyl acetate
three times and the combined organic layers were washed with brine, dried over
sodium
sulfate, filtered and concentrated to afford the title compound as a yellow
solid in 95% yield.
MS (ESI) m/z: 365.9 [M+H]
Step 6: 7-Chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione
[0166] A mixture of 2-amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoic acid
(14 mmol)
and urea (274 mmol) was stirred at 200 C for 5 hours, cooled to 80 C and
treated with water
(100 mL). The mixture was stirred for another additional hour, cooled down to
room
temperature and extracted with ethyl acetate three times. The combined organic
layers were
washed with brine, dried over sodium sulfate, filtered and concentrated. The
resulting residue
was purified by silica gel chromatography (20% ethyl acetate in hexanes) to
afford the title
compound as a white solid in 33% yield. MS (ESI) m/z: 388.8 [M-H]-
Step 7: (R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-
(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione
[0167] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione
(51.2 mmol) in dioxane (800 mL), potassium carbonate (153.6 mmol), (R)-1-
mercapto-3-
methoxypropan-2-ol (92.1 mmol), 4,5-Bis(diphenyl- phosphino)-9,9-
dimethylxanthene
(10.24 mmol) and tris(dibenzylideneacetone) dipalladium (5.1 mmol) were added.
The
mixture was stirred at 55 C for 18 hours. After completion, the insoluble
materials were
filtered off, the filtrate was concentrated and the pH adjusted to 4 with
acetic acid, extracted
with ethyl acetate and washed with brine. Evaporation of volatiles afforded a
residue that was
crystallized dichloromethane/ methanol = 1/10) to afford the title compound as
a white solid
in 73% yield. MS (ESI) m/z: 385.0 [M+H]+.
Step 8: (S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-
2H41,4]thiazino[2,3,4-
ijjquinazoline-5,7(3H,6H)-dione
[0168] To a mixture of (R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-
(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (89.5 mmol) and
triphenylphosphoranylidene
(134.3 mmol) in tetrahydrofuran (500 mL) was added diethyl azodicarboxylate
(134.3 mmol)
at 0 C. The mixture was stirred at 0 C for 45 min. After completion, the
mixture was poured
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into ice-water (300 mL) and extracted with ethyl acetate three times. After
concentration, the
residue was recrystallized (dichloromethane/ methanol = 1/10) to afford the
title compound as
a white solid in 73% yield. MS (ESI): m/z 367.0 [M+Hr.
Step 9: (2S,6R)-tert-butyl 4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-
(trifluoromethyl)-
3,5-dihydro-2H41,41thiazino[2,3,4-ij]quinazolin-7-y1)-2,6-dimethylpiperazine-1-
carboxylate
[0169] To a mixture of (5)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-
[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (27.32 mmol) and potassium
carbonate
(273.2 mmol) in acetonitrile (500 mL) was added 4-methylbenzenesulfonic
anhydride (40.98
mmol) at 0 C. The mixture was stirred at 0 C for 30 mm and at 30 C for 4
hours, after that
time (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (54.64 mmol) was
added and
the resulting mixture stirred at 0 C for 2 additional hours. The mixture was
filtered through a
Celite pad, and the filtrate concentrated. The residue was purified by silica
gel
chromatography (1-3 % methanol in dichloromethane) to afford the title
compound as a white
solid in quantitative yield. This material was used in the next step without
further
purification. MS (ESI) m/z 563.5[M+H]t
Step 10: tert-butyl (2S,6R)-4-(0-10-(4-chlorothiophen-2-y1)-3-(methoxymethyl)-
5-oxo-9-
(trifluoromethyl)-2,3-dihydro-5H41,4]thiazino[2,3,4-ij]quinazolin-7-y1)-2,6-
dimethylpiperazine-1-carboxylate
[0170] tert-butyl (2S,6R)-4-[(119-8-chloro-12-(methoxymethyl)-2-oxo-7-
(trifl uoromethyl)-10-thi a-1,3-di azatri cy cl o [7. 3.1. 05,13] tri deca-3,5
(13),6,8-tetraen-4-yll -2,6-
dimethyl-piperazine-1-carboxylate (0.07 mmol), RuPhos G4 (0.01 mmol),
potassium
phosphate (0.22 mmol) and (4-chloro-2-thienyl)boronic acid (0.22 mmol) were
dissolved in
dioxane (2 mL) and water (0.5 mL) and the mixture degassed for 2 minutes with
nitrogen.
The reaction was stirred at 80 C for 1 hour, cooled down to room temperature,
diluted with
ethyl acetate and washed with water and brine. The organic layer was dried
with sodium
sulfate and concentrated to afford a residue that was purified by HPLC to
afford the title
compound in 62% yield as a tan solid.
Step 11: (S)-10-(4-chlorothiophen-2-y1)-74(3S,5R)-3,5-dimethylpiperazin-l-y1)-
3-
(methoxymethyl)-9-(trifluoromethyl)-2.3-dihydro-5H-[1.4]thiazino[2,3,4-
ij]quinazolin-5-one
[0171] To a stirred solution of tert-butyl (2S,6R)-4-[(12S)-8-(4-chloro-2-
thieny1)-12-
(methoxymethyl)-2-methylene-7-(trifluoromethyl)-10-thia-1,3-
diazatricy clo [7.3105,13] trideca-3,5(13),6,8-tetraen-4-yll -2,6-dimethyl-pip
erazine-1-
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carboxylate (0.05 mmol) in dichloromethane (3mL) was added TFA (0.3mL) and the
reaction
was stirred for 45 minutes at room temperature. The volatiles were removed
under reduced
pressure to afford an orange residue that was used in the next step without
further
purification.
Example 3: (S)-7-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-1-y1)-3-
(methoxymethyl)-
10-(5-methylthiophen-2-y1)-9-(trifluoromethyl)-2H-ilslithiazino[2,3,4-
iilquinazolin-
5(3H)-one (E3)
NT"TµB
F3C
N
0
O
S SJN1
(E3)
Reaction Scheme 1
0
F30 0
NH
NH
CI N
0 (TMS)2S/TBAF HS F3C I 3 H CI N0 PPh3/DEAD
THF/O C XantPhos/(dba)3Pd THF/0 C
1 2
K2CO3/dioxane/55 C
'OH 4
OH
0 Boc
irB-OH
F3c Ts2 0, K2 C 03
NH
ACN/r.t
CI 0 Boc RuPhos-Pd-G2
then
F3CN K3 P 04/d ioxane
N CI
6
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0
Boc
4R)9".
1)1\1(.5# '(R)9"/
TFA
F3C o o
F3C 1\1 F3C
SO
1\1
0
DCM/r.t
NL0 N 0 S
S S
8 Ex. 3
7
(R)-1-mercapto-3-methoxypropan-2-ol (2)
[0172] To a mixture of (S)-2-(methoxymethyl)oxirane (50 g, 568.2 mmol) in
tetrahydrofuran (800 mL) was added 1,1,1,3,3,3-hexamethyldisilathiane (119.4
g, 681.8
mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 170.6 mL,
170.5 mmol)
at 0 C. The mixture was stirred at room temperature for 2 hours. After
completion, the
mixture was poured into water (3000 mL), extracted with ethyl acetate (3 x800
mL). The
combined organic phases were washed with brine (800 mL) and dried over
anhydrous sodium
sulfate. After filtration and concentration, the residue was purified by
silica gel column with
petroleum ether/ethyl acetate=3/1 to afford (R)-1-mercapto-3-methoxypropan-2-
ol (70.0 g,
crude) as a colorless oil. 11-1NMR (300 MHz, CDC13) 6 3.86-3.82 (m, 1H), 3.49-
3.46 (m,
1H), 3.41-3.37 (m, 4H), 2.71-2.64 (m, 1H), 1.55-1.50 (m, 1H).
(R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-
(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione (4)
[0173] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione
(3) (20 g, 51.2 mmol) in dioxane (800 mL), potassium carbonate (21.2 g, 153.6
mmol), (R)-1-
mercapto-3-methoxypropan-2-ol (11.26 g, 92.1 mmol), 4,5-Bis(diphenyl-
phosphino)-9,9-
dimethylxanthene (5.93 g, 10.24 mmol) and Tris(dibenzylideneacetone)
dipalladium (4.7 g,
5.1 mmol) were added. The mixture was stirred at 55 C under nitrogen
atmosphere for 18
hours. After completion, the insoluble was filtered out. Then the filtrate was
concentrated, the
residue was adjusted to pH = 4 with acetic acid and extracted with ethyl
acetate (1000 mL),
washed with brine (500 mL). The organic phase was concentrated and
recrystallized
(dichloromethane/ methanol = 1/10). The mixture was filtered and collected
filter cake to
89
SUBSTITUTE SHEET (RULE 26)
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afford (R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-
(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione (4) (14 g, yield: 71 %) as a white solid. MS (ESI) nilz 385.0
[M+Hlf.
(S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-11,41thiazino[2,3,4-
ij]quinazoline-5,7(3H,6H)-dione (5)
[0174] To a mixture of (R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-
(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (4) (34.4 g, 89.5 mmol) and
triphenylphosphoranylidene (35.2 g, 134.3 mmol) in tetrahydrofuran (500 mL)
was added
diethyl azodicarboxylate (23.3 g, 134.3 mmol) at 0 C. The mixture was stirred
at 0 C for 45
min. After completion, the mixture was poured into ice-water (300 mL) and
extracted with
ethyl acetate (3 x 500 mL). After concentration, the residue was
recrystallized
(dichloromethane/ methanol = 1/10), the mixture was filtered and collected
filter cake to
afford (5)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-
[1,41thiazino[2,3,4-
ijlquinazoline-5,7(3H,6H)-dione (24.0 g, 73% yield) as a white solid. MS
(ESI): m/z 367.0
[M+H[+.
(2S,6R)-tert-butyl 4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-
(trifluoromethyl)-3,5-
dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-y1)-2,6-dimethylpiperazine-1-
carboxylate
(6)
[0175] To a mixture of (S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-
[1,41thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (10 g, 27.32 mmol) and
potassium
carbonate (37.7 g, 273.2 mmol) in acetonitrile (500 mL) was added 4-
methylbenzenesulfonic
anhydride (13.4 g, 40.98 mmol) at 0 C. The mixture was stirred at 0 C for 30
min and at
30 C for 4 hours. After completion, (25,6R)-tert-butyl 2,6-dimethylpiperazine-
1-carboxylate
(11.7 g, 54.64 mmol) was added into the reaction solution. The reaction
mixture was stirred
at 0 C for 2 hours. After completion, the mixture was filtered through a
Celite pad, and the
filtrate concentrated. The residue was purified by chromatography column
(dichloromethane/methanol = 100/1 to 30/1) to afford (25,6R)-tert-butyl 4-((S)-
10-chloro-3-
(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,41thiazino[2,3,4-
ijlquinazolin-7-y1)-2,6-dimethylpiperazine-1-carboxylate (15 g, crude) as a
pale-white solid.
MS (ESI) m/z 563.5[M+Hr.
(2S,6R)-tert-butyl 4-4S)-3-(methoxymethyl)-10-(5-methylthiophen-2-y1)-5-oxo-9-
(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-y1)-2,6-
dimethylpiperazine-1-carboxylate (7)
SUBSTITUTE SHEET (RULE 26)
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[0176] To a mixture of (2S,6R)-tert-butyl 4-((S)-10-chloro-3-(methoxymethy1)-5-
oxo-9-
(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-
dimethylpiperazine-1-carboxylate (6) (200 mg, 0.35 mmol) in a solution of 1,4-
dioxane (6
mL) and water (1 mL), tripotassium phosphate (780 mg, 3.5 mmol), (5-
methylthiophen-2-
yl)boronic acid (497 mg, 3.5 mmol), and Chloro(2-dicyclohexylphosphino-2', 6'-
diisopropoxy-1,1'-bipheny1)[2-(2'-amino-1,1'-biphenyelpalladium(II) (41 mg,
0.52mmo1)
were added. The mixture was stirred at 85 C under nitrogen atmosphere for 4
hours. After
completion, the mixture was concentrated. The residue was purified by silica
gel column
chromatography (dichloromethane/methanol = 100/1 to 30/1) to afford (28,6R)-
tert-butyl 4-
((S)-3-(methoxymethyl)-10-(5-methylthiophen-2-y1)-5-oxo-9-(trifluoromethyl)-
3,5-dihydro-
2H41,41thiazino[2,3,4-ij[quinazolin-7-y1)-2,6-dimethylpiperazine-1-carboxylate
(7) (200
mg, crude) as yellow solid. MS (ESI) m/z 625.5[M+Hr
(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-(methoxymethyl)-10-(5-
methylthiophen-2-
y1)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (8)
[0177] To a mixture of (2S,6R)-tert-butyl 4-4S)-3-(methoxymethyl)-10-(5-
methylthiophen-2-y1)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-
[1,41thiazino[2,3,4-
ij[quinazolin-7-y1)-2,6-dimethylpiperazine-1-carboxylate (200 mg, 0.32 mmol)
in
dichloromethane (3 ml) was added trifluoroacetic acid (1 mL) at 0 C. The
reaction solution
was stirred at room temperature for 30 minutes. After completion, the mixture
was
concentrated. The resiue was redissolved in dichloromethane and dried over
Na2SO4. After
concentration, the residue was purified by column (dichloromethane/methanol =
15:1) to
afford (S)-7-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-(methoxymethyl)-10-(5-
methylthiophen-
2-y1)-9-(trifluoromethyl)-2H41,4[thiazino[2,3,4-ijlquinazolin-5(3H)-one (8)
(150 mg, yield:
89%) as a yellow solid. MS (ESI) m/z 525.3[M+Hr
(S)-7-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-1-y1)-3-(methoxymethyl)-10-(5-
methylthiophen-2-y1)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-
5(3H)-one
(Example 3)
[0178] To a mixture of (S)-7-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-
(methoxymethyl)-10-
(5-methylthiophen-2-y1)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-
ij[quinazolin-5(3H)-one
(100 mg, 0.19 mmol) and triethyl amine (28 mg, 0.28 mmol) in dichloromethane
(3 ml) was
added acrylic anhydride (36 mg, 0.28 mmol) at 0 C. The mixture was stirred at
0 C for 30
minutes. After completion, the mixture was poured into ice-water (1 mL) and
extracted with
91
SUBSTITUTE SHEET (RULE 26)
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ethyl acetate (3 x 5 mL). After concentration, the residue was purified by
chromatography
column (dichloromethane/methanol = 60/1 to 30/1) to afford (S)-7-((3S,5R)-4-
acryloy1-3,5-
dimethylpiperazin-1-y1)-3-(methoxymethyl)-10-(5-methylthiophen-2-y1)-9-
(trifluoromethyl)-
2H41,4]thiazino[2,3,4-ijlquinazolin-5(3H)-one (Example 3) (48 mg yield: 44%)
as a white
powder. MS (ESI) m/z 579.3 [M+H]+; 1H NMR (400 MHz, CDC13) 68.03 (s, 1H), 6.82
(s,
2H), 6.62 (dd, J= 10.4 Hz, J= 16.4 Hz, 1H), 6.40 (dd, J = 1.6 Hz, J = 16.4 Hz,
1H), 5.77 (dd,
J = 1.6 Hz, J= 10.4 Hz, 1H), 5.42-5.38 (m, 1H), 4.78-4.54 (m, 2H), 4.20-4.15
(m, 2H), 3.72-
3.62 (m ,2H), 3.40 (s, 3H), 3.38-3.28 (m, 3H), 2.96 (dd, J = 2.8 Hz, J= 13.6
Hz, 1H), 2.57 (s,
3H), 1.61 (d, J = 6.8 Hz, 3H), 1.46 (d, J = 6.8 Hz, 3H).
Example 4: (S)-7-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-1-y1)-10-(5-
chlorothiophen-
2-y1)-3-(methoxymethyl)-9-(trifluoromethyl)-2H- 11,41thiazino 12,3,4-ill
uinazolin-5 (3H)-
one (E4)
144µt)(y 6
F3C
N
S S
CI (E4)
9H yoc
=R4).õ( N yos)
0(N)1) p'B'OH N
N CI S
F3C ,N F3 ,N TEA F3C ,N F3C
RuPhos-Pd-G2
N
CI I\10 0 DCM/r t NO TEA/DCM/
S(>1
K3PO4/dioxane \ s sço sS6>C,C) 0 C SCI
H20/85 C CI CI 4 o,
1 2 3
(2S,6R)-tert-butyl 44(S)-10-(5-chlorothiophen-2-y1)-3-(methoxymethyl)-5-oxo-9-
(trifluoromethyl)-3,5-dihydro-2H- [1,4] thiazino [2,3,4-ij] quinazolin-7-y1)-
2,6-
dimethylpiperazine-1-carboxylate (2)
[0179] To a mixture of (2S,6R)-tert-butyl 4-((S)-10-chloro-3-(methoxymethyl)-5-
oxo-9-
(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-y1)-2,6-
92
SUBSTITUTE SHEET (RULE 26)
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dimethylpiperazine-1-carboxylate (400 mg, 0.71 mmol) in a solution of 1,4-
dioxane (15 mL)
and water (2 mL), tripotassium phosphate (1.5 g, 7.1 mmol), (5-chlorothiophen-
2-yOboronic
acid (497 mg, 3.5 mmol), and Chloro(2-dicyclohexylphosphino-2', 6'-
diisopropoxy-1,1'-
bipheny1)[2-(2'-amino-1,1'-biphenyOlpalladium(II) (83 mg, 0.1 mmol) were
added. The
mixture was stirred at 85 C under nitrogen atmosphere for 4 hours. After
completion, the
mixture was concentrated. The residue was purified by silica gel column
chromatography
(dichloromethane/methanol = 100/1 to 30/1) to afford (2S,6R)-tert-butyl 4-((S)-
10-(5-
chlorothiophen-2-y1)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-
2H-
[1,41thiazino[2,3,4-ij]quinazolin-7-y1)-2,6-dimethylpiperazine-1-carboxylate
(2) (450 mg,
crude) as yellow solid. MS (ESI) m/z 645.5[M+H1+.
(S)-10-(5-chlorothiophen-2-y1)-7-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-
(methoxymethyl)-9-(trifluoromethyl)-2H-I1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-
one (3)
[0180] To a mixture of (2S,6R)-tert-butyl 4-((S)-10-(5-chlorothiophen-2-y1)-3-
(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,41thiazino[2,3,4-
ij]quinazolin-7-y1)-2,6-dimethylpiperazine-1-carboxylate (2) (450 mg, 0.69
mmol) in
dichloromethane (3 ml) was added trifluoroacetic acid (1 mL) at 0 C. The
reaction solution
was stirred at room temperature for 30 minutes. After completion, the mixture
was
concentrated, the residue was purified by column (dichloromethane/methanol =
15:1) to
afford (S)-10-(5-chlorothiophen-2-y1)-7-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-
(methoxymethyl)-9-(trifluoromethyl)-2H41,41thiazino[2,3,4-ij]quinazolin-5(3H)-
one (3)
(350 mg, Ccrude ) as a yellow solid. MS (ESI) nilz 544.9[M+Hr
(S)-7-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-10-(5-chlorothiophen-2-
y1)-3-
(methoxymethyl)-9-(trifluoromethyl)-2H-11,4]thiazino12,3,4-ij]quinazolin-5(3H)-
one (4)
[0181] To a mixture of (S)-10-(5-chlorothiophen-2-y1)-7-((3S,5R)-3,5-
dimethylpiperazin-
l-y1)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,41thiazino[2,3,4-
ij]quinazolin-5(3H)-one
(350 mg, 0.64 mmol) and triethyl amine (97 mg, 0.96 mmol) in dichloromethane
(3 ml) was
added acrylic anhydride (121 mg, 0.96 mmol) at 0 C. The mixture was stirred
at 0 C for 30
minutes. After completion, the mixture was poured into ice-water (1 mL) and
extracted with
ethyl acetate (3 x 5 mL). The organic layer was dried over Na2So4 and
concentrated. The
residue was purified by chromatography column (dichloromethane/methanol = 60/1
to 30/1)
to afford (5)-10-(5-chlorothiophen-2-y1)-7-((3S,5R)-3,5-dimethylpiperazin-l-
y1)-3-
(methoxymethyl)-9-(trifluoromethyl)-2H41,41thiazino[2,3,4-ij]quinazolin-5(3H)-
one (4) (88
93
SUBSTITUTE SHEET (RULE 26)
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mg yield: 24%) as yellow powder. MS (ESI) m/z 599.9 [M+H]+; 1H NMR (400 MHz,
CDC13) 5 8.03 (s, 1H), 6.98 (d, J = 4.0 Hz, 1H), 6.81 (d, J = 3.2 Hz, 1H),
6.61 (dd, J = 10.8
Hz, J = 16.8 Hz, 1H), 6.40 (dd, J = 2.0 Hz, J = 16.8 Hz, 1H), 5.77 (dd, J =
2.0 Hz, J = 10.4
Hz, 1H), 5.46-5.41 (m, 1H), 4.82-4.48 (m, 2H), 4.17 (t, J = 13.6 Hz, 2H), 3.70-
3.62 (m ,2H),
3.40-3.28 (m, 6H), 2.96 (dd, J = 2.8 Hz, J = 13.2 Hz, 1H), 1.61 (d, J = 6.8
Hz, 3H), 1.46 (d, J
= 7.2 Hz, 3H).
Example 23: (S)-8-((3S,5R)-4-aeryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
ehlorothiophen-2-y1)-3-(pvrimidin-2-vloxv)-10-(trifluoromethvl)-3,4-dihvdro-
2H,6H-
11,41thiazepino[2,3,4-illquinazolin-6-one
0
Me4,1/4(NTMe
F3C
CI
S Sv,$))
NJ
Step 1: tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-
y1)-6-oxo-3-
(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
Boc
Me N Me
F3C
1,11
CI N
õo4=>
TIPS
NJ
[0182] A mixture of tert-butyl (25,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-
yloxy)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate (0.32 mmol), (4-chloro-5-
(triisopropylsilyl)thiophen-2-
94
SUBSTITUTE SHEET (RULE 26)
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yl)boronic acid (1.28 mmol), potassium phosphate (0.96 mmol) and Ruphos Pd G4
(0.03
mmol) in dioxane (5 mL) and water (0.1 mL) was degassed and purged with
nitrogen three
times. The mixture was stirred at 80 C for 30 minutes and the volatiles were
removed under
reduced pressure to afford a residue that was purified by preparative TLC (65%
ethyl acetate
in hexanes). The title compound was isolated in 63% yield as a white solid. MS
(ESI) m/z:
865.3 [M+11+.
Step 2: tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-
(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-dihydro-2H.6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate
Boc
F3C
N
N
CI 0
S S\ (S))
= N_
b -µ
[0183] To a solution of tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-
(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H41,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
1-
carboxylate (0.20 mmol) in tetrahydrofuran (5 mL) was added a 1M solution of
tetrabutylammonium fluoride in THF (0.3 mL). The mixture was stirred at room
temperature
for 30 minutes, the volatiles were removed under reduced pressure and the
resulting residue
was purified by preparative TLC (60% ethyl acetate in hexanes) to afford the
title compound
in 72% yield as a colorless semisolid. MS (ESI) m/z: 709.2 [M+11+
Step 3: (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-
3-(pyrimidin-
2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-
ij]quinazolin-6-one
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
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F3C
N
CI \
S S\ (S)
.b4=>
[0184] Trifluoroacetic acid (2 mL) was added over a solution of tert-butyl
(25,6R)-44(S)-
11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-
3,4-dihydro-
2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate (0.14
mmol) in dichloromethane (6 mL). After 30 minutes, the volatiles were removed
under
reduced pressure to afford the title compound in 99% yield as a yellow oil.
This material was
used in the next step without further purification. MS (ESI) m/z: 609.2
[M+11+.
Step 4: (S)-8-((35,5R)-4-acrylov1-3,5-dimethylpiperazin-1-y1)-11-(4-
chlorothiophen-2-y1)-3-
(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H41,41thiazepino[2,3,4-
1j]quinazolin-6-one
Oj
MeNj.õMe
F3C
CI N /0
S S
VS)) N
0
[0185] Triethylamine (0.43 mmol) and prop-2-enoyl chloride (0.21 mmol) were
added to a
solution of (5)-11-(4-chlorothiophen-2-y1)-84(3S,5R)-3,5-dimethylpiperazin-l-
y1)-3-
(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1,41thiazepino[2,3,4-
ijlquinazolin-6-one (0.14 mmol) in dichloromethane (2 mL). After 30 minutes,
the volatiles
were removed under reduced pressure to afford a residue that was purified by
preparative
TLC (100% ethyl acetate in hexanes). The title compound was isolated in 67%
yield as a
white solid. MS (ESI) m/z: 663.4 [M+11+. 1H NMR (400 MHz, CDC13) 6 8.52 (d, J
= 4.8
96
SUBSTITUTE SHEET (RULE 26)
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Hz, 2H), 8.06 (s, 1H), 7.34 (s, 1H), 7.00 (t, J = 4.8 Hz, 1H), 6.92 (s, 1H),
6.63 (dd, J = 10.4,
16.4 Hz, 1H), 6.47 - 6.37 (m, 1H), 5.84 - 5.69 (m, 2H), 4.95 - 4.53 (m, 4H),
4.21 (d, J = 13.2
Hz, 2H), 3.60 (dd, J = 2.8, 13.6 Hz, 1H), 3.45 -3.32 (m, 2H), 3.19- 3.06 (m,
1H), 1.64 - 1.60
(m, 3H), 1.48 (d, J = 6.4 Hz, 3H)
Example 24: (S)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
chlorothiophen-2-y1)-3-(1H-pyrazolo13,4-bipyridin-l-y1)-10-(trifluoromethyl)-
3,4-
dihydro-2H,6H-11,41thiazepino12,3,4-ijlquinazolin-6-one
0.7
N
F3C
N
CI 0
\ S S-..õ L-1(s)
N N,
,;,,
Reaction Scheme
OH
F3C 0
N
CI eLOH
,
OH
0-...,P \-a-A TFA/Et3SiH Q7\NI I
Bna,..).õ..STrt -)111.- N N'N -)101" - N. - -0-
(R) PPh3/DEAD BnO, jN,STrt Bn0SH
Pd2(dba)3,
(s) Xantphos)
1 2 3
OH loc
OH OH ?IjI
F3C 0 "NI
F3C
,L TFA, so 1 pph3/ F3C Ali ,N
N
CI N OH 80 C , DEAD ir kir, H
-II, CI N OH CI i v µ../ _lw-
o
S
S S\Lsj
Nl ,OBn
i' N ks0H =N 6 NJ,
N:j....) -- 4
\ /N
97
SUBSTITUTE SHEET (RULE 26)
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yoc
yoc yoc
N
CI
N TIPS1¨ S $._B4OH )/
N
OH F3C 101
F3C 41,,sh, , N 1, TBAFfTHF F3C ,1
.." 0
1\1
CI NO CI N 0
S S
RuPhos Pd G2 \ N j CI \
S. j = S S\))
= 3N k PO4, TIPS 'N...).
9
-NJ) dioxanefH20 8
7 N, / 80 C
0,%/
H
(N)/
,O, .(N),,
N 11 11 N
TFA/DCM F3C so
`N 0 0 F3C
,µ
¨Y.¨
0
CI , N TEA, DCM CI \' NO
1 S S\2) s S s\z)
' N
N \ /50 11 = \
(S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-y1)-1H-pyrazolo[3,4-b]pyridine (2)
[0186] To a mixture of (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (30 g,
68.18 mmol),
1H-pyrazolo[3,4-blpyridine (9.74 g, 81.85 mmol) and triphenylphosphine (53.6
g, 204.6
mmol) in tetrahydrofuran (340 mL) was added (E)-diethyl diazene-1,2-
dicarboxylate (35.6 g,
204.6 mmol) at 0 C. The mixture was stirred at room temperature for 12 hours
under
nitrogen atmosphere. After completion, the mixture was quenched with water
(300 mL) and
extracted with dichloromethane (100 mLx3). The organic phase were concentrated
under
reduced pressure. The residue was purified by silica gel column with petroleum
ether/ethyl
acetate = 10/1 to afford (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-y1)-1H-
pyrazolo[3,4-
b]pyridine (2) (23.36 g, 63% yield) as a colorless oil. 1H NMR (400 MHz,
CDC13) 6 8.51-
8.49 (m, 1H), 8.02-8.00 (m, 2H), 7.43-7.32 (m, 6H), 7.24-6.99 (m, 15H), 4.36-
4.26 (m, 3H),
3.79-3.64 (m, 2H), 3.20-3.15 (m, 1H), 2.72-2.68 (m, 1H).
(S)-3-(benzyloxy)-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)propane-1-thiol (3)
[0187] To a mixture of (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-y1)-1H-
pyrazolo[3,4-
blpyridine (2) (23.36 g, 43.18 mmol) in dichloromethane (90 mL) and 2,2,2-
trifluoroacetic
acid (30 mL) was added triethylsilane (15 g, 129.3 mmol) at 0 C under
nitrogen atmosphere.
The mixture was stirred at 0 C for 10 mm. After completion, the mixture was
concentrated
under reduced pressure and adjusted to PH = 8 with NH3.Me0H. Then the mixture
was
98
SUBSTITUTE SHEET (RULE 26)
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extracted with ethyl acetate (60 mL x 3). After concentration, the residue was
purified by
silica gel column with petroleum ether/ethyl acetate = 10/1 to afford to
afford (S)-3-
(benzyloxy)-2-(1H-pyrazolo[3,4-blpyridin-l-y0propane-1-thiol (3) (11 g, 85%
yield) as a
yellow oil. 1H NMR (400 MHz, CDC13)6 8.56-8.64 (m, 1H), 8.08-8.05 (m, 2H),
7.29-7.12
(m, 6H), 5.39-5.35 (m, 1H), 4.53-4.45 (m, 2H), 4.01-3.93 (m, 2H), 3.35-3.13
(m, 2H), 1.27-
1.22 (m, 1H).
(S)-8-((3-(benzyloxy)-2-(1H-pyrazolo13,4-b[pyridin-1-y1)propyl)thio)-7-chloro-
6-
(trifluoromethyl)quinazoline-2,4-diol (4)
[0188] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-
diol (3) (8 g,
20.51 mmol) in 1,4-dioxane (100 mL) were added potassium carbonate (8.5 g,
61.59 mmol),
(S)-3-(benzyloxy)-2-(1H-pyrazolo[3,4-blpyridin-l-y0propane-1-thiol (11 g,
36.79 mmol),
4,5-Bis(diphenyl- phosphino)-9,9-dimethylxanthene (1.78 g, 3.08 mmol) and
Tris(dibenzylideneacetone) dipalladium (1.87 g, 2.04 mmol). The mixture was
stirred at 60
C under nitrogen atmosphere for 18 hours. After completion, the mixture was
concentrated
under reduced pressure, the residue was purified by silica gel column
chromatography
(dichloromethane/methanol = 50/1) to afford (S)-8-((3-(benzyloxy)-2-(1H-
pyrazolo[3,4-
b]pyridin-1-yl)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol
(4) (15 g, crude)
as a red oil. MS (ESI): m/z 563 EM-H]-.
(S)-7-chloro-8-((3-hydroxy-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)thio)-6-
(trifluoromethyl)quinazoline-2,4-diol (5)
[0189] A solution of (S)-8-03-(benzyloxy)-2-(1H-pyrazolo[3,4-b[pyridin-1-
yl)propypthio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (4) (15 g,
26.69 mmol) in
trifluoroacetic acid (120 mL). The mixture was stirred at 80 C for 18 hours.
After
completion, the mixture was concentrated and adjusted to PH = 7-8 at 0 C.
After
concentration, the residue was purified by silica gel column with
dichloromethane/methanol
= 40/1 to afford (S)-7-chloro-8-((3-hydroxy-2-(1H-pyrazolo[3,4-b]pyridin-l-
yl)propyl)thio)-
6-(trifluoromethyl)quinazoline-2,4-diol (5) (7.67 g, 26% yield for two steps)
as a yellow
solid. MS (ESI): m/z 472 [M-H]-.
(S)-11-chloro-8-hydroxy-3-0B-pyrazolo13,4-b[pyridin-1-y1)-10-(trifluoromethyl)-
3,4-
dihydro-11,4]thiazepino[2,3,4-q[quinazolin-6(2H)-one (6)
[0190] To a mixture of (S)-7-chloro-8-43-hydroxy-2-(1H-pyrazolo[3,4-b[pyridin-
l-
yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (5) (7.57 g, 16.07
mmol) and
99
SUBSTITUTE SHEET (RULE 26)
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triphenylphosphine (12.6 g, 48.09 mmol) in tetrahydrofuran (300 mL) was added
diethyl
azodicarboxylate (8.4 g, 48.28 mmol) at 0 C. The mixture was stirred at 0 C
for 45 min.
After completion, the mixture was poured into ice-water (100 mL) and extracted
with ethyl
acetate (100 mL x 3). After concentration, the residue was purified by C18
with 30-95%
acetonitrile in water to afford (S)-11-chloro-8-hydroxy-3-(1H-pyrazolo[3,4-
blpyridin-l-y1)-
10-(trifluoromethyl)-3,4-dihydro-[1,41thiazepino[2,3,4-ij]quinazolin-6(2H)-one
(6) (6 g, 82%
yield) as a white solid. 1F1 NMR (400 MHz, CDC13) 6 12.12 (s, 1H), 8.61-8.60
(m, 1H), 8.32-
8.23 (m, 2H), 8.09 (s, 1H), 7.32-7.29 (m, 1H), 5,69-5,63 (m, 1H), 5.14-4.22
(m, 3H), 3.59 (s,
1H).
(2S,6R)-tert-butyl 44(S)-11-chloro-6-oxo-3-(1H-pyrazolo13,4-b]pyridin-l-y1)-10-
(trifluoromethyl)-2,3,4,6-tetrahydro-11,41thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate (7)
[0191] To a mixture of (5)-11-chloro-8-hydroxy-3-(1H-pyrazolo[3,4-blpyridin-l-
y1)-10-
(trifluoromethyl)-3,4-dihydro-[1,41thiazepino[2,3,4-ij]quinazolin-6(2H)-one
(6) (3 g, 6.62
mmol) and potassium carbonate (9.2 g, 66.7 mmol) in acetonitrile (120 mL) and
dichloromethane (80 mL) was added 2,4,6-triisopropylphenyl 4-
methylbenzenesulfonate (4 g,
13.2 mmol). The mixture was stirred at 35 C for 5 hours. After completion,
(2S,6R)-tert-
butyl 2,6-dimethylpiperazine-1-carboxylate (2.2 g, 10.3 mmol) was added into
the reaction
solution. The reaction mixture was stirred at 35 C for 1 hour. After
completion, the mixture
was poured into ice-water (200 mL) and extracted with ethyl acetate (100 mL x
3). After
concentration, the residue was purified by C18 column with 20-95% acetonitrile
in water to
afford (2S,6R)-tert-butyl 4-((S)-11-chloro-6-oxo-3-(1H-pyrazolo[3,4-blpyridin-
l-y1)-10-
(trifluoromethyl)-2,3,4,6-tetrahydro-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate (7) (3.92 g, 91% yield) as a yellow solid. MS
(ESI) m/z
650 [M+Hr
(2S,6R)- tert-butyl 4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-
oxo-3-(1H-
pyrazolo[3,4-b]pyridin-1-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
11,4]thiazepino12,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
(8)
[0192] To a solution of (25,6R)-tert-butyl 4-((S)-11-chloro-6-oxo-3-(1H-
pyrazolo[3,4-
blpyridin-1-y1)-10-(trifluoromethyl)-2,3,4,6-tetrahydro41,41thiazepino[2,3,4-
ijlquinazolin-8-
y1)-2,6-dimethylpiperazine-1-carboxylate (7) (400 mg, 0.615 mmol) in 1,4-
dioxane (10 mL)
and water (1 mL) were added tripotassium phosphate (491 mg, 1.85 mmol), (4-
chloro-5-
100
SUBSTITUTE SHEET (RULE 26)
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(triisopropylsilyl)thiophen-2-yl)boronic acid (586 mg, 1.84 mmol), and
Chloro(2-
dicyclohexylphosphino-2', 6'- diisopropoxy-1,1'-bipheny1)[2-(2'-amino-1,1'-
biphenyOlpalladium(II) (49 mg, 0.062 mmol). The mixture was stirred at 80 C
under
nitrogen atmosphere for 2 hours. After completion, the mixture was
concentrated under
reduced pressure, the residue was purified by silica gel column chromatography
(dichloromethane/methanol = 60/1) to afford (2S,6R)- tert-butyl 4-((S)-11-(4-
chloro-5-
(triisopropylsilyl)thiophen-2-y1)-6-ox0-3-(1H-pyrazolo[3,4-b]pyridin-l-y1)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate (8) (200 mg, 37% yield) as a yellow solid. MS
(ESI) nilz
888.2 [M+I-11+.
(2S,6R)- tert-butyl 4-((S)-11-(4-ehlorothiophen-2-y1)-6-oxo-3-(1H-pyrazolo13,4-
b]pyridin-1-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-11,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-earboxylate (9)
[0193] To a mixture of (25,6R)- tert-butyl 4-((S)-11-(4-chloro-5-
(triisopropylsilyl)thiophen-2-y1)-6-ox0-3-(1H-pyrazolo[3,4-blpyridin-1-y1)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate (8) (200 mg, 0.23 mmol) in tetrahydrofuran (5
mL) was
added tetrabutylammonium fluoride (0.35 mL, 1.0 M solution in tetrahydrofuran)
at 0 C.
The reaction solution was stirred at 0 C for 1 hour. After completion, the
mixture was
concentrated and extracted with ethyl acetate (50 mL x 3). The organic phase
was
concentrated and the residue was purified by C18 column with 20%-95%
acetonitrile in water
to afford (25,6R)- tert-butyl 4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(1H-
pyrazolo[3,4-
blpyridin-1-y1)-10-(trifluoromethyl)-3,4-dihydro-
2H,61141,41thiazepino[2,3,44j1quinazolin-
8-y1)-2,6-dimethylpiperazine-1-carboxylate (9) (130 mg, 77 % yield) as a pale
yellow solid.
MS (ESI) miz 732.2 [M+I-11+.
(S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-(1H-
pyrazolo[3,4-b]pyridin-1-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
11,4]thiazepino12,3,4-ij]quinazolin-6-one (10)
[0194] To a mixture of (25,6R)- tert-butyl 4-((S)-11-(4-chlorothiophen-2-y1)-6-
oxo-3-(1H-
pyrazolo[3,4-blpyridin-1-y1)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H41,41thiazepino[2,3,4-
ijiquinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (9) (130 mg, 0.178
mmol) in
dichloromethane (5 ml) was added trifluoroacetic acid (2 mL) at 0 C. The
mixture was
101
SUBSTITUTE SHEET (RULE 26)
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stirred at room temperature for 1 hour. After completion, the mixture was
concentrated and
adjusted to pH = 7-8 at 0 C. After concentration, the residue was purified by
silica gel
column with dichloromethane/methanol = 30/1 to afford (S)-11-(4-chlorothiophen-
2-y1)-8-
((3 S,5R)-3,5-dimethylpiperazin-l-y1)-3 -(1H-pyrazol o [3,4-b] pyri din-1 -y1)-
10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-
one (10) (92 mg,
82% yield) as a yellow oil. MS (ESI) nilz 632.2 [M+Hr
(S)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-chlorothiophen-2-
y1)-3-(1H-
pyrazolo13,4-b]pyridin-1-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
11,4]thiazepino12,3,4-ij]quinazolin-6-one (11)
[0195] To a mixture of (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-
dimethylpiperazin-
l-y1)-3-(1H-pyrazolo [3,4-b] pyri din-l-y1)-10-(trifluoromethyl)-3 ,4-dihy dro-
2H,6H-
[1,4]thiazepino [2,3,4-ij quinazolin-6-one (10) (92 mg, 0.146 mmol) and
triethyl amine (29
mg, 0.292 mmol) in dichloromethane (2 ml) was added acrylic anhydride (27 mg,
0.219
mmol) at 0 C. The mixture was stirred at 0 C for 1 hour. After completion,
the mixture was
poured into ice-water (30 mL) and extracted with dichloromethane (10 mL x 3).
Concentrated
and the residue was purified by preparative High Performance Liquid
Chromatography (20%
to 95% acetonitrile in water) to afford (S)-8-((3S,5R)-4-acryloy1-3.5-
dimethylpiperazin-1-y1)-
11 -(4-chl orothi ophen-2-y1)-3 -(1H-pyrazol o[3,4-b] pyri din-l-y1)-10-(trifl
uoromethyl)-3,4-
dihy dro-2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-6-one (11) (28 mg, 28%
yield) as a white
solid. MS (ESI) nilz 686.1 [M+H]+. 1H NMR (400 MHz, CDC13) 6 8.53 (d, J= 4.0
Hz, 1H),
8.10-8.04 (m, 3H), 7.34 (s, 1H), 7.18-7.15 (dd, J= 8.0 Hz, 4.4 Hz, 1H), 7.02-
6.88 (m, 1H),
6.67-6.60 (m, 1H), 6.42 (dd, J= 16.8 Hz, 2.0 Hz, 1H), 5.78 (dd, J= 10.4 Hz,
2.0 Hz, 2H),
5.54-5.28 (m, 111), 5.10 (d, J= 13.6 Hz, 1H), 4.80-4.44 (m, 2H), 4.17 (d. J=
13.2 Hz, 2H),
3.91-3.57 (m, 1H), 3.40-3.33 (m, 3H), 1.59-1.58 (m, 6H).
Example 25: (S)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
chlorothiophen-2-y1)-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-y1)-10-
(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one
102
SUBSTITUTE SHEET (RULE 26)
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o
N
N
P
F3C 1\1
CI x
\ S S \ (S)
= 0
N---f
N\ I \ N
;
Reaction Scheme
0
r)
Oss1-1(NH
0 OH
KF N'u,0
Bn0,./L _il..- BnO.A.,../..STr
( (R) Bn0,./STr
s) TrSH
1 2 PPh3, DEAD, THF P 3
OH OH
rµ F3C 1011 F3C
I
: OH
:10H ,L
0 rN
TFA/Et3SiH N. I S TFA
_),... N 0 _______________ S. 80 C
Bn0,..,SH
(s) Pd2(dba)3, XantPhos e,N.Nis)./0 OBn
4
K2CO3, dioxane N0 5
_
yoc
y oc
OH OH (1\1)/
F3C *I
`N F3C
N
CI N*LOH PPh3/DEAD F3C 0
`N
_10.- S\ j H -VP" CI N0
THF '-Ki 0
N ,OH ;.=""f Ts20, K2CO3 S\,d
_I IT NACN % 0
CNA 6 7 N-1
_ 0 0 8 No
103
SUBSTITUTE SHEET (RULE 26)
CA 03221390 2023-11-23
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Boo Boo
(N)/
CI \s 6(01-1)2
F3C F3C rai
TIPS TBAF/THF
CI N-"0 ¨10.- CI N 0
RuPhos Pd G2 S
k3PO4, dioxane/H20 TIPS = 0 N¨f
80 C
Nµ N
9 N 10
(N)/
F3C 401 F30
TFA/DCM
?.L
¨)10- CI k.**- NO 00 CI NO
S S\isj TEA, DCM S S\/2)
-1. 0
N--f
11 N \ N 12 NI. N
(R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (2)
[0196] To a mixture of (S)-2-((benzyloxy)methyl)oxirane (25 g, 152.4 mmol) and
potassium fluoride (17.7 g, 304.8 mmol) in methonal (250 mL) was added
triphenylmethanethiol (42 g, 152.4 mmol). The mixture was stirred at room
temperature for
18 hours. After completion, the mixture was concentrated under reduced
pressure and
purified by silica gel column with petroleum ether/ethyl acetate = 5/1 to
afford (R)-1-
(benzyloxy)-3-(tritylthio)propan-2-ol (2) (60 g, 90% yield) as a colorless
oil. 1H NMR (400
MHz, CDC13) 6 7.44-7.38 (m, 6H), 7.35-7.18 (m, 14H), 4.46 (s, 2H), 3.58-3.48
(m, 1H),
3.37-3.26 (m, 2H), 2.45-2.35 (m, 2H).
(S)-2-(1-(benzyloxy)-3-(tritylthio)propan-2-y1)-[1,2,4]triazolo[4,3-a] pyridin-
3(2H)-one
(3)
[0197] To a mixture of [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (5.5 g, 41
mmol) and
triphenylphosphine (13.4 g, 51 mmol) in tetrahydrofuran (400 mL) was added
diethyl
azodicarboxylate (8.8 g, 51 mmol) at 0 C under nitrogen atmosphere. The
mixture was
104
SUBSTITUTE SHEET (RULE 26)
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stirred at room temperature for 10 min, then was added (R)-1-(benzyloxy)-3-
(tritylthio)propan-2-ol (2) (15 g, 34 mmol). The mixture was stirred for 2
hours. After
completion, the mixture was poured into ice-water (300 mL) and extracted with
ethyl acetate
(150 mL x 3). After concentration, the residue was purified by silica gel
column with
petroleum ether/ethyl acetate = 50/1 to afford to afford crude (S)-2-(1-
(benzyloxy)-3-
(tritylthio)propan-2-041,2,41triazolo[4,3-alpyridin-3(2H)-one (3) (16.5 g,
crude) as a white
soid. MS (ESI): m/z 558.2 [M+H]t
(S)-2-(1-(benzyloxy)-3-mercaptopropan-2-y1)-11,2,4]triazolo14,3-a]pyridin-
3(2H)-one (4)
[0198] To a mixture of (S)-2-0-(benzyloxy)-3-(tritylthio)propan-2-
y1)41,2,41triaz010[4,3-
alpyridin-3(2H)-one (3) (165 g, 30 mmol) and triethylsilane (17.4 g, 150 mmol)
in
dichloromethane (300 mL) was added trifluoroacetic acid (30 mL). The mixture
was stirred
at room temperature for 2 hours. After completion, the mixture was
concentrated and
adjusted pH = 7-8 at 0 C. After concentration, the residue was purified by
silica gel column
with petroleum ether/ethyl acetate = 2/1 to afford (S)-2-(1-(benzyloxy)-3-
mercaptopropan-2-
y1)41,2,41triazolo[4,3-alpyridin-3(2H)-one (4) (7.9 g, 85% yield) MS (ESI):
m/z
316.1[M+Hr
(S)-2-(1-(benzyloxy)-3-07-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-
yl)thio)propan-2-y1)-11,2,4]triazolo[4,3-a]pyridin-3(2H)-one (5)
[0199] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-
diol (4.5g, 11
mmol) in 1,4-dioxane (200 mL), potassium carbonate (4.6 g, 33 mmol), (S)-2-(1-
(benzyloxy)-3-mercaptopropan-2-y1)41,2,41triaz010[4,3-a]pyridin-3(2H)-one (4)
(55 g, 17
mmol), 4,5-Bis(diphenyl- phosphino)-9,9-dimethylxanthene (1.2g, 1.03 mmol) and
Tris(dibenzylideneacetone) dipalladium (0.92g, 1.0 mmol) were added. The
mixture was
stirred at 60 C under nitrogen atmosphere for 18 hours. After completion, the
mixture was
concentrated under reduced pressure, the residue was purified by silica gel
column
chromatography (dichloromethane/methanol= 20/1) to afford (S)-2-(1-(benzyloxy)-
3-((7-
chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)propan-2-y1)-
[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (5) (6.2 g, 93% yield) as pale yellow
solid MS (ESI):
m/z 578.1[M+H]+.
(S)-2-(1-47-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)-3-
hydroxypropan-2-y1)-11,2,4]triazolo[4,3-a]pyridin-3(2H)-one (6)
105
SUBSTITUTE SHEET (RULE 26)
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[0200] A solution of (S)-2-(1-(benzyloxy)-347-chloro-2,4-dihydroxy-6-
(trifluoromethyl)quinazolin-8-yl)thio)propan-2-y1)41,2,41triaz010[4,3-
a]pyridin-3(2H)-one
(5) (6.2 g, 10 mmol) in trifluoroacetic acid (50 mL). The mixture was stirred
at 80 C for 18
hours. After completion, the mixture was concentrated and adjusted pH = 7-8 at
0 C. After
concentration, the residue was purified by silica gel column with
dichloromethane/methanol
= 10/1 to afford (S)-2-(1-((7-chloro-2,4-dihydroxy-6-
(trifluoromethyl)quinazolin-8-yl)thio)-
3-hydroxypropan-2-041,2,4]triazolo[4,3-a]pyridin-3(2H)-one (6) (3.6 g, 69%
yield) as a
yellow solid. MS (ESI): m/z 488.1 [M+H]t
(S)-11-chloro-8-hydroxy-3-(3-oxo-11,2,41triazolo[4,3-a]pyridin-2(3H)-y1)-10-
(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one
(7)
[0201] To a mixture of (S)-2-(147-chloro-2,4-dihydroxy-6-
(trifluoromethyl)quinazolin-8-
yOthio)-3-hydroxypropan-2-y1)41,2,41triazolo[4,3-alpyridin-3(2H)-one (6) (3.5
g, 7.1 mmol)
and triphenylphosphine (7.5 g, 28.6 mmol) in tetrahydrofuran (130 mL) was
added diethyl
azodicarboxylate(4.9 g, 28.6 mmol) at 0 C under nitrogen atmosphere. The
mixture was
stirred at room temperature for 3 hours. After completion, the mixture was
poured into ice-
water (100 mL) and extracted with ethyl acetate (100 mL x 3). Concentrated and
the residue
was purified by C18 with 30-95% acetonitrile in water to afford (S)-11-chloro-
3-(4-
fluorophenoxy)-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-
2H,6H41,4]thiazepino[2,3,4-
ijlquinazolin-6-one (7) (2.6 g, 78% yield) as a yellow solid. MS (ESI): m/z
470. [M+Hr.
(2S,6R)-tert-butyl 44(S)-11-chloro-6-oxo-3-(3-oxo-11,2,4]triazolo[4,3-
a]pyridin-2(3H)-
y1)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate (8)
[0202] To a mixture of ((5)-11-chloro-3-(4-fluorophenoxy)-8-hydroxy-10-
(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4lthiazepino[2,3,4-ij[quinazolin-6-one
(7) (2.4 g, 5.1
mmol) and potassium carbonate (7.0 g, 51 mmol) in acetonitrile (100 mL) was
added 4-
methylbenzenesulfonic anhydride (4.9 g, 15.3 mmol). The mixture was stirred at
35 C for 8
hours. After completion, (25,6R)-tert-butyl 2,6-dimethylpiperazine-1-
carboxylate (3.8 g, 17.8
mmol) was added into the reaction solution. The reaction mixture was stirred
at 35 C
overnight. After completion, the mixture was poured into ice-water (200 mL)
and extracted
with ethyl acetate (100 mL x 3). Concentrated and the residue was purified by
C18 column
with 20-95% acetonitrile in water to afford (25.6R)-tert-butyl 4-((S)-11-
chloro-6-oxo-3-(3-
oxo-[1,2,41triazolo[4,3-a]pyridin-2(3H)-y1)-10-(trifluoromethyl)-2,3,4,6-
tetrahydro-
106
SUBSTITUTE SHEET (RULE 26)
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[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
(8) (2.3 g,
72% yield) as a pale yellow solid. MS (ESI) m/z 666.2 [M+Hr.
(2S,6R)-tert-butyl 44(S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-
oxo-3-(3-oxo-
11,2,4] triazolo [4,3-a] pyridin-2(3H)-y1)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
11,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
(9)
[0203] To a solution of (2S,6R)-tert-butyl 4-((S)-11-chloro-6-oxo-3-(3-oxo-
[1,2,4]triazolo[4,3-a]pyridin-2(3H)-y1)-10-(trifluoromethyl)-2,3,4,6-
tetrahydro-
[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
(8) (350 mg,
0.53 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) were added tripotassium
phosphate
(337 mg, 1.59 mmol), (4-chloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid
(507 mg, 1.59
mmol), and Chloro(2-dicyclohexylphosphino-2', 6'- diisopropoxy-1,1'-
bipheny1)[2-(2'-amino-
1,1'-biphenyl)]palladium(II) (41 mg, 0.053 mmol). The mixture was stirred at
80 C under
nitrogen atmosphere for 1 hour. After completion, the mixture was concentrated
under
reduced pressure, the residue was purified by silica gel column chromatography
(dichloromethane/methanol = 60/1) to afford (2S,6R)-tert-butyl 4-((S)-11-(4-
chloro-5-
(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-(3-oxo-[1,2,41triazolo[4,3-alpyridin-
2(3H)-y1)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate (9) (250 mg, crude) as a yellow solid. MS
(ESI) m/z 904.1
[M+H]+.
(2S,6R)- tert-butyl 4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(3-oxo-
11,2,41triazolo14,3-
a]pyridin-2(3H)-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1,41thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (10)
[0204] To a mixture of (2S,6R)-tert-butyl 44(S)-11-(4-chloro-5-
(triisopropylsilyethiophen-
2-y1)-6-oxo-3-(3-oxo-[1,2,41triazolo[4,3-alpyridin-2(3H)-y1)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
1-
carboxylate (9) (250 mg, 0.28 mmol) in tetrahydrofuran (5 mL) was added
tetrabutylammonium fluoride (0.34 mL, 1.0 M solution in tetrahydrofuran) at 0
C. The
reaction solution was stirred at 0 C for 1 hour. After completion, the
mixture was
concentrated and extracted with ethyl acetate (50 mL x 3). Concentrated and
the residue was
purified by C18 column with 20%-95% acetonitrile in water to afford (2S,6R)-
tert-butyl 4-
((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(3-oxo-[1,2,4]triazolo[4,3-alpyridin-
2(3H)-y1)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-
y1)-2,6-
107
SUBSTITUTE SHEET (RULE 26)
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dimethylpiperazine-1-carboxylate (10) (150 mg, 38 % yield for two steps) as a
pale yellow
solid. MS (ESI) m/z 748.2 [M+H1+.
(S)-11-(4-chlorothiop hen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-(3-
oxo-
[1,2,4] triazolo [4,3-a] pyridin-2 (3H)-y1)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
[1,4] thiazepino [2,3,4-ij] quinazolin-6-one (11)
[0205] To a mixture of (2S,6R)- tert-butyl 4-((S)-11-(4-chlorothiophen-2-y1)-6-
oxo-3-(3-
oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-y1)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
(10) (150 mg,
0.20 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL) at
25 C. The
mixture was stirred at 25 C for 1 hour. After completion, the mixture was
concentrated and
adjusted PH to 8 with ammonia in methanol at 0 C. The mixture was
concentrated and
purified by silica gel column chromatography (dichloromethane/ methanol =
30/1) to afford
(S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-(3-oxo-
[1,2,4]triazolo[4,3-a]pyridin-2(3H)-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (11) (80 mg, 62% yield) as yellow
solid. MS (ESI)
m/z 648.2 [M+1-1]+.
(S)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-chlorothiophen-2-
y1)-3-(3-
oxo- [1,2,4] triazolo[4,3-a] pyridin-2(3H)-y1)-10-(trifluo romethyl)-3,4-
dihydro-2H,6H-
[1,4] thiazepino12,3,4-ij] quinazolin-6-one (12)
[0206] To a mixture of (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-
dimethylpiperazin-
l-y1)-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-y1)-10-(trifluoromethyl)-
3,4-dihydro-
2H,6H41,41thiazepino[2,3,4-ij]quinazolin-6-one (11) (80 mg, 0.12 mmol) in
dichloromethane (6 mL) was added triethylamine (24 mg, 0.24 mmol) and acrylic
anhydride
(23 mg, 0.18 mmol) at 0 C. The mixture was stirred at 25 C for 1 hour. After
completion,
the mixture was added methanol at 25 C and concentrated. The mixture was
purified by
preparative high performance liquid chromatography (20% to 95% acetonitrile in
water) to
afford (S)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-1-y1)-11-(4-
chlorothiophen-2-y1)-3-
(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-y1)-10-(trifluoromethyl)-3,4-
dihydro-2H,6H-
[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (12) (24 mg, 0.034 mmol, 28% yield)
as a pale
yellow powder. MS (ESI) m/z 702.3 [M+H]. 1H NMR (400 MHz, CDC13) 6 8.09 (s,
1H),
7.75 (d, J = 7.2 Hz, 1H), 7.34 (s, 1H), 7.10-7.00 (m, 2H), 6.96-6.95 (m, 1H),
6.65-6.59 (m,
1H), 6.49 (t, J= 7.2 Hz, 1H), 6.41 (dd, J= 16.8 Hz, 2.0 Hz, 1H), 5.78 (dd, J =
10.4 Hz, 2.0
108
SUBSTITUTE SHEET (RULE 26)
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Hz, 1H), 5.35-5.27 (m, 1H), 5.25-5.08 (m, 1H), 5.02-4.90 (m, 1H), 4.90-4.50
(m, 2H), 4.15
(d, J = 13.2 Hz, 2H), 3.85-3,00 (m, 4H), 1.60-1,40 (m, 6H),
Example 26: (S)-843S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
chlorothiophen-2-y1)-3-(1-oxoisoindolin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
11,4]thiazepino[2,3,4-ij]quinazolin-6-one
r464..e
N
F3C (E)
N
N0
CI ,
\ S S\ (S)
% 0
N
140
Reaction Scheme
CI b LDA, TIPSCI CI...b LDA, B(OCH3)3 CI
\
...b....
/
S TIPS S TIPS s B(OH)2
1 2 3
0
A
101 NH
0 OH 0 0
KF 0 N
BnO,L1 _),.. BnOSTrt _________________________ II' BnOSTrt
(S) (R) TrSH PPh3, DEAD, THE (S)
4 5 6
OH
OH
4/ F3C
# %NL F3C `N
CI N OH #
CI 1.I NL OH TFA
Zn/AcOH 0
U I -Jo,-
Bn0,..,SH S 80 C
100 C (s)
Pd2(dba)3, XantPhos .. NoIQ, OBn
7 K2003, dioxane #
0 8
109
SUBSTITUTE SHEET (RULE 26)
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Boc
Boc N
OH OH N
F3C r" N F3C
N,µO N N OH PPh3/DEAD CI IW H
F3C
N
S (s)) _ill._
0 CI N,0
W
THF
N'ks),OH N POCI3, Toulene
#120 C . 0 0 9 10 io N
1 1 0
Boc Boc
N N
__ZT)...
13(01-02 F3C &
I NI TBAF/THF F3C
TIPS s r& ,
N
1 TFA/DCM
-)1"- CI .--- N 0
\ S SN j k N S S\ 2)
RuPhos Pd G2 P
n TIPS = 0 =1. 0
k3PO4, dioxane,../1_4 2.- 1\1 N
80 C
12 * 13
*
H OW
(1\1)?
cN)
N
F3C Ai . = . .
N
-µ 0 0 F3C la ,
N
CI W N 0
\ S kid TEA, DCM IP'CI \**-- W 1\10
S S\E)
:N 0
=-N 0
14 * 15
1101
(3-chlorothiophen-2-yl)triisopropylsilane (2)
[0207] Lithium diisopropylamide (221.37 mL, 442.74 mmol, 2.0 M solution in
tetrahydrofuran/n-heptane) was slowly added to a solution of 3-chlorothiophene
(50 g, 421.66
mmol) in tetrahydrofuran (1.05 L) at -78 C under nitrogen atmosphere. The
mixture was
stirred at -78 C for 1 hour, then triisopropylsilyl chloride (85.36 g, 442.74
mmol) was added.
The mixture was slowly warmed to room temperature and stirred overnight. After
completion, aqueous saturated ammonium chloride solution (800 mL) was slowly
added and
extracted with ethyl acetate (1L x 3). After concentration, the residue was
purified by silica
gel column (with petroleum ether/ethyl acetate = 500/1) to afford to afford (3-
chlorothiophen-
110
SUBSTITUTE SHEET (RULE 26)
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2-yl)triisopropylsilane (2) (57 g, 49% yield) as a colorless oil. 11-1NMR (400
MHz, CDC13) 6
7.52 (d, J= 4.8 Hz, 1H), 7.04 (d, J= 4.8 Hz, 1H), 1.57-1.51 (m, 3H), 1.12 (d,
J= 8.0 Hz,
18H).
(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (3)
Lithium diisopropylamide (10.91 mL, 21.83 mmol, 2.0 M solution in
tetrahydrofuran/n-
heptane) was slowly added to a solution of (3-chlorothiophen-2-
yl)triisopropylsilane (2) (5 g,
18.19 mmol) in tetrahydrofuran (90 mL) at -78 C under nitrogen atmosphere.
The mixture was
stirred at -78 C for 1 hour, then trimethyl borate (2.27 g, 21.83 mmol) was
added. The mixture
was slowly warmed to room temperature and stirred for 1 hour. After
completion, aqueous
saturated ammonium chloride solution (10 mL) was slowly added. After
concentration, the
residue was purified by silica gel column (with dichloromethane/methanol =
50/1) to afford to
afford (4-chloro-5-(triisopropylsily0thiophen-2-yl)boronic acid (3) (3.5 g,
60% yield) as a pale
yellow oil. 1H NMR (400 MHz, CD30D) 6 7.53 (s, 1H), 1.59-1.52 (m, 3H), 1.13
(d, J= 8.0
Hz, 18H).
(R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (5)
[0208] To a mixture of (S)-2-((benzyloxy)methyl)oxirane (25 g, 152.4 mmol) and
potassium fluoride (17.7 g, 304.8 mmol) in methonal (250 mL) was added
triphenylmethanethiol (42 g, 152.4 mmol). The mixture was stirred at room
temperature for
18 hours. After completion, the mixture was concentrated under reduced
pressure and
purified by silica gel column with petroleum ether/ethyl acetate = 5/1 to
afford (R)-1-
(benzyloxy)-3-(tritylthio)propan-2-ol (5) (60 g, 90% yield) as a colorless
oi1.1H NMR (400
MHz, CDC13) 6 7.44-7.38 (m, 6H), 7.35-7.18 (m, 14H), 4.46 (s, 2H), 3.58-3.48
(m, 1H),
3.37-3.26 (m, 2H), 2.45-2.35 (m, 2H).
(S)-2-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)isoindoline-1,3-dione (6)
[0209] To a mixture of isoindoline-1,3-dione (6.0 g, 40.9 mmol) and
triphenylphosphine
(13.3 g, 51.1 mmol) in tetrahydrofuran (400 mL) was added diethyl
azodicarboxylate (8.9 g,
51.1 mmol) at 0 C under nitrogen atmosphere. The mixture was stirred at room
temperature
for 10 min, then (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (5) (15 g, 34.1
mmol) was
added. The mixture was stirred for 2 hours. After completion, the mixture was
poured into
ice-water (300 mL) and extracted with ethyl acetate (150 mL x 3). After
concentration, the
residue was purified by silica gel column with petroleum ether/ethyl acetate =
50/1 to afford
111
SUBSTITUTE SHEET (RULE 26)
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to afford crude (S)-2-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)isoindoline-1,3-
dione (6) (19.0
g, crude) as a colorless oil. MS (ESI) nilz 570.2 [M+Hr.
(S)-2-(1-(benzyloxy)-3-mercaptopropan-2-yl)isoindolin-1-one (7)
[0210] To a solution of (S)-2-(1-(benzyloxy)-3-(tritylthio)propan-2-
yeisoindoline-1,3-
dione (6) (18.0 g, 31.66 mmol) in acetic acid (250 mL) was added zinc (30.8 g,
474 mmol) at
0 C. The mixture was stirred at 100 C for 4 hours. After completion, the
mixture was
concentrated and adjusted pH = 7-8 at 0 C and extracted with dichloroethane .
After
concentration, the residue was purified by silica gel column with petroleum
ether/ethyl
acetate = 3/1 to afford (S)-2-(1-(benzyloxy)-3-mercaptopropan-2-yl)isoindolin-
1-one (7) (3.7
g, 37% yield) as a yellow oil. MS (ESI) m/z 314.1 [M+Hr.
(S)-2-(1-(benzyloxy)-3-47-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-
yl)thio)propan-2-ypisoindolin-1-one (8)
[0211] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-
diol (4.6 g, 12
mmol) in 1,4-dioxane (200 mL) were added potassium carbonate (11.8 g, 36
mmol), (S)-2-(1-
(benzyloxy)-3-mercaptopropan-2-yl)isoindolin-1-one (7) (4.7 g, 15 mmol), 4,5-
Bis(diphenyl-
phosphino)-9,9-dimethylxanthene (1.4 g, 1.6 mmol) and
Tris(dibenzylideneacetone)
dipalladium (1.1 g, 1.2 mmol). The mixture was stirred at 60 C under nitrogen
atmosphere
for 18 hours. After completion, the mixture was concentrated under reduced
pressure, the
residue was purified by silica gel column chromatography
(dichloromethane/ethyl acetate =
3/1) to afford (S)-2-(1-(benzyloxy)-3-((7-chloro-2,4-dihydroxy-6-
(trifluoromethyl)quinazolin-8-yl)thio)propan-2-yl)isoindolin-1-one (8) (4.6 g,
66% yield) as
pale yellow solid. MS (ESI) m/z 576.1 [M+Hr.
(S)-2-(1-47-chloro-2,4-dihydroxy-6-(trifluoromethyDquinazolin-8-yl)thio)-3-
hydroxypropan-2-ypisoindolin-1-one (9)
[0212] A solution of (S)-2-(1-(benzyloxy)-3-((7-chloro-2,4-dihydroxy-6-
(trifluoromethyl)quinazolin-8-yl)thio)propan-2-yl)isoindolin-1-one (8) (4.5 g,
7.8 mmol) in
trifluoroacetic acid (100 mL). The mixture was stirred at 80 C for 18 hrs.
After completion,
the mixture was concentrated and adjusted pH = 7-8 at 0 C. After
concentration, the residue
was purified by silica gel column with dichloromethane/ethyl acetate = 1/2 to
afford (S)-2-(1-
47-chloro-2,4-dihydroxy-6-(trifluoromethyDquinazolin-8-yethio)-3-hydroxypropan-
2-
yDisoindolin-l-one (9) (2.8 g, 75% yield) as a yellow solid. MS (ESI): m/z
486.1 [M+Hr.
112
SUBSTITUTE SHEET (RULE 26)
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(S)-11-chloro-8-hydroxy-3-(1-oxois oindolin-2-y1)-10-(trifluoromethyl)-3,4-
dihydro-
11,4]thiazepino12,3,4-ij]quinazolin-6(2H)-one (10)
[0213] To a mixture of (S)-2-(1-((7-chloro-2,4-dihydroxy-6-
(trifluoromethyl)quinazolin-8-
yl)thio)-3-hydroxypropan-2-yl)isoindolin-1-one (9) (2.6 g, 5.3 mmol) and
triphenylphosphine
(5.6 g, 21.4 mmol) in tetrahydrofuran (100 mL) was added diethyl
azodicarboxylate(3.7 g,
21.4 mmol) at 0 C under nitrogen atmosphere. The mixture was stirred at room
temperature
for 3 hours. After completion, the mixture was poured into ice-water (100 mL)
and extracted
with ethyl acetate (100 mL x 3). Concentrated and the residue was purified by
C18 with 30-
95% acetonitrile in water to afford (S)-11-chloro-8-hydroxy-3-(1-oxoisoindolin-
2-y1)-10-
(trifluoromethyl)-3,4-dihydro-[1,41thiazepino[2,3,4-ij]quinazolin-6(2H)-one
(10) (2.0 g, 83%
yield) as a yellow solid. MS (ESI) m/z 468.2 [M+Hr
(2S,6R)-tert-buty1-4-4S)-11-chloro-6-oxo-3-(1-oxoisoindolin-2-y1)-10-
(trifluoromethyl)-
2, 3,4,6-
tetrahydro-[1,4]thiazepino12,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate (11)
[0214] To a mixture of (S)-11-chloro-8-hydroxy-3-(1-oxoisoindolin-2-y1)-10-
(trifluoromethyl)-3,4-dihydro-[1,41thiazepino[2,3,4-ij]quinazolin-6(2H)-one
(10) (500 mg,
1.06 mmol) and DIEA (690.38 mg, 5.34 mmol) in toulene (20 mL) was added
phosphoryl
trichloride (1.31 g, 8.547 mmol). The mixture was stirred at 120 C for 4
hours. After
completion, the mixture was concentrated and the residue was added to on
solution. The
reaction mixture was stirred at 35 C for 1 hour. After completion, the
mixture was poured
into ice-water (100 mL) and extracted with ethyl acetate (50 mL x 3).
Concentrated and the
residue was purified by C18 column with 20-95% acetonitrile in water to afford
(2S,6R)-tert-
butyl 4-((S)-11-chloro-6-oxo-3-(1-oxoisoindolin-2-y1)-10-(trifluoromethyl)-
2,3,4,6-
tetrahydro-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate
(11) (532 mg, 75 % yield) as a pale yellow solid. MS (ESI) m/z 664.1 [M+Hr
(2S,6R)-tert-butyl 44(S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-
oxo-3-(1-
oxoisoindolin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
11,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (12)
[0215] To a solution of (2S,6R)-tert-butyl 4-((S)-11-chloro-6-oxo-3-(1-
oxoisoindolin-2-y1)-
10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,41thiazepino[2,3,4-ij ] quinazolin-
8-y1)-2,6-
dimethylpiperazine-1-carboxylate (11) (350 mg, 0.53 mmol) in 1,4-dioxane (5
mL) and water
(0.5 mL) were added tripotassium phosphate (337 mg, 1.59 mmol), (4-chloro-5-
113
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(triisopropylsilyl)thiophen-2-yl)boronic acid (507 mg, 1.59 mmol), and
Chloro(2-
dicyclohexylphosphino-2', 6'- diisopropoxy-1,1'-bipheny1)[2-(2'-amino-1,1'-
biphenyOlpalladium(II) (41 mg, 0.053 mmol). The mixture was stirred at 80 C
under
nitrogen atmosphere for 1 hour. After completion, the mixture was concentrated
under
reduced pressure, the residue was purified by silica gel column chromatography
(dichloromethane/methanol = 60/1) to afford (2S,6R)-tert-butyl 4-((S)-11-(4-
chloro-5-
(triisopropylsilypthiophen-2-y1)-6-oxo-3-(1-oxoisoindolin-2-y1)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H41,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
1-
carboxylate (12) (190 mg, 40% yield) as a yellow solid. MS (ESI) nilz 902.1
[114+Hr.
(28,6R)-tert-butyl 4-48)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(1-oxoisoindolin-2-
y1)-10-
(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate (13)
[0216] To a mixture of (2S,6R)-tert-butyl 44(S)-11-(4-chloro-5-
(triisopropylsilyethiophen-
2-y1)-6-oxo-3 -(1-oxoi s oindolin-2-y1)-10-(tri fluoromethyl)-3,4-dihy dro-2H,
6H-
[1,41thiazepino [2,3,4-ij ] quinazolin-8-y1)-2,6-dimethylpiperazine-1 -
carboxylate (12) (190 mg,
0.21 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride
(0.23 mL, 1.0
M solution in tetrahydrofuran) at 0 C. The reaction solution was stirred at 0
C for 1 hour.
After completion, the mixture was concentrated and extracted with ethyl
acetate (100 mL
3). Concentrated and the residue was purified by C18 column with 20%-95%
acetonitrile in
water to afford (25,6R)-tert-butyl 4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-
(1-
oxoisoindolin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1,41thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (13) (110 mg, 70%
yield) as a pale
yellow solid. MS (ESI) nilz 746.2 [M+I-11+.
(S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-(1-
oxoisoindolin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
11,4]thiazepino[2,3,4-
ij]quinazolin-6-one (14)
[0217] To a mixture of (25,6R)-tert-butyl 4-((S)-11-(4-chlorothiophen-2-y1)-6-
oxo-3-(1-
oxoisoindolin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1,4]thiazepino[2,3,4-
iflquinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (13) (110 mg, 0.15
mmol) in
dichloromethane (6 mL) was added trifluoroacetic acid (2 mL) at 0 C. The
reaction solution
was stirred at room temperature for 1 hour. After completion, the mixture was
concentrated
and the residue was purified by silica gel column chromatography
114
SUBSTITUTE SHEET (RULE 26)
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(dichloromethane/methanol = 15/1) to afford (S)-11-(4-chlorothiophen-2-y1)-8-
((3S,5R)-3,5-
dimethylpiperazin-1-y1)-3-(1-oxoisoindolin-2-y1)-10-(trifluoromethyl)-3,4-
dihydro-2H,6H-
[1,41thiazepino[2,3,4-ijlquinazolin-6-one (14) (62 mg, 64% yield) as a pale
yellow solid. MS
(ESI) m/z 646.2 [M+I-11+.
(S)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-chlorothiophen-2-
y1)-3-(1-
oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
11,4]thiazepino[2,3,4-
inquinazolin-6-one (15)
[0218] To a mixture of (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-
dimethylpiperazin-
l-y1)-3-(1-oxoisoindolin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1,41thiazepino[2,3,4-ijlquinazolin-6-one (14) (62 mg, 0.096 mmol) and
triethyl amine (19
mg, 0.192 mmol) in dichloromethane (3 ml) was added acrylic anhydride (18 mg,
0.144
mmol) at 0 C. The mixture was stirred at 0 C for 1 hour. After completion,
the mixture was
poured into ice-water (10 mL) and extracted with dichloromethane (10 mL x 3).
Concentrated
and the residue was purified by preparative High Performance Liquid
Chromatography (20 %
to 95 % acetonitrile in water) to afford (S)-8-((3S,5R)-4-acryloy1-3,5-
dimethylpiperazin-1-
y1)-11-(4-chlorothiophen-2-y1)-3-(1-oxoisoindolin-2-y1)-10-(trifluoromethyl)-
3,4-dihydro-
2H,6H41,41thiazepino[2,3,4-ij quinazolin-6-one (15) (20 mg, 30% yield) as a
white solid.
MS (ESI) m/z 700.3 [M+H]t 1H NMR (400 MHz, CDC13) 6 8.09 (s, 1H), 7.86 (d, J=
7.6 Hz,
1H), 7.57-7.52 (m, 1H), 7.47 (t, J= 7.6 Hz, 2H), 7.36 (s, 1H), 7.00-6.93 (m,
1H), 6.66-6.60
(m, 1H), 6.44-6.40 (m, 1H), 5.79 (dd, J= 10.4 Hz, 2.0 Hz, 1H), 5.20-4.15 (m,
10H), 3.43-
3.37 (m, 3H), 1.57-1.56 (m, 6H).
Example 27: (S)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-3-(1H-
benzoldlimidazol-1-y1)-11-(4-chlorothiophen-2-y1)-10-(trifluoromethyl)-3,4-
dihydro-
11,41thiazepino12,3,4-illquinazolin-6(2H)-one
CF3 N
CI NO
S S\ (S)
Reaction Scheme
115
SUBSTITUTE SHEET (RULE 26)
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H110
N gt N,I
0 OH N
Bn0
,/A _)....KF
BnOSTrt -10- BnOSTrt
(s) R (s)
TrSH PPh3, DEAD, THE
1 2 3
OH OH
* Ni F3C Fil
`N
A F3C &
`N
A
TFA/Et3SiH N CI W N OH CI IW N OH
-).- BnOSH I
THF (s)
OBn
4 Pd2(dba)3, XantPhos N's
/..
K2CO3, dioxane
* 5
OH
OH Boc
F3C io
NN
F3C E) AI s, N
*L
CI N OH
N0 ?1)
TFA S PPh3/DEAD CI W N
H
Q
s 6\1) )., -)0.
80 C N " 4.....õ,µ= OH THF :
N
µ IP POCI3, Toulene
6 7 N 120 C
Boc
Boc )?
1
(1\1)/
CI N(E)
N(E) ,b.... F3C rill ....
N
TIPS s B(OH)2 ir N'µo TBAF/THF
F3C so
`N CI
0 _)111õ... = S S\i) -IP-
CI N S. )
RuPhos Pd G2 TIPS
k3PO4, dioxane/H20
8 11 *
µN 80 C u N
Boc H
)/
N
N(E) N(E) rolr (E)
F3C ip
`N
L TFA/DCM F3C 110
' N 0 0
' F3C 0 -...N
N 0 -)1.'
NO CI \
S SNE) \S S\ (s)) --- N0
CI C CI TEA, DCM
' S S\29
-N Al
s
11 µN Mr 12
N
116
SUBSTITUTE SHEET (RULE 26)
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(R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (2)
[0219] To a mixture of (S)-2-((benzyloxy)methyl)oxirane (25 g, 152.4 mmol) and
potassium fluoride (17.7 g, 304.8 mmol) in methonal (250 mL) was added
triphenylmethanethiol (42 g, 152.4 mmol). The mixture was stirred at room
temperature for
18 hours. After completion, the mixture was concentrated under reduced
pressure and
purified by silica gel column with petroleum ether/ethyl acetate = 5/1 to
afford (R)-1-
(benzyloxy)-3-(tritylthio)propan-2-ol (2) (60 g, 90% yield) as a colorless
oil. 1H NMR (400
MHz, CDC13) 6 7.44-7.38 (m, 6H), 7.35-7.18 (m, 14H), 4.46 (s, 2H), 3.58-3.48
(m, 1H),
3.37-3.26 (m, 2H), 2.45-2.35 (m, 2H).
(S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-y1)-1H-benzo[d]imidazole (3)
[0220] To a mixture of 1H-benzo[dlimidazole (8.45 g, 71.59 mmol) and
triphenylphosphine (25.0 g, 95.46 mmol) in tetrahydrofuran (470 mL) was added
diethyl
azodicarboxylate (16.6 g, 95.46 mmol) at 0 C under nitrogen atmosphere. The
mixture was
stirred at room temperature for 10 min, then (R)-1-(benzyloxy)-3-
(tritylthio)propan-2-ol (2)
(21 g, 47.73 mmol) was added. The mixture was stirred for 2 hours. After
completion, the
mixture was poured into ice-water (300 mL) and extracted with ethyl acetate
(150 mL x 3).
After concentration, the residue was purified by silica gel column with
petroleum ether/ethyl
acetate = 30/1 to afford to afford (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-
y1)-1H-
benzo[dlimidazole (3) (12.4 g, 48% yield) as a yellow oil. MS (ESI) m/z 541.0
[M+H]t
(S)-2-(1H-benzo[d]imidazol-1-y1)-3-(benzyloxy)propane-1-thiol (4)
[0221] To a mixture of (5)-1-0-(benzyloxy)-3-(tritylthio)propan-2-y1)-1H-
benzo[dlimidazole (3) (12.47 g, 23.1 mmol) and triethylsilane (6.7 g, 57.7
mmol) in
dichloromethane (230 mL) was added trifluoroacetic acid (26.3 g, 231 mmol).
The mixture
was stirred at room temperature for 3 hours. After completion, the mixture was
concentrated
and adjusted pH = 7-8 at 0 C . After concentration, the residue was purified
by silica gel
column with petroleum ether/ethyl acetate = 10/1 to afford (S)-2-(1H-
benzo[dlimidazol-1-
y1)-3-(benzyloxy)propane-1-thiol (4) (3.95 g, 57% yield) as a yellow oil. MS
(ESI) in/z 299.2
[M+H]+.
(S)-8-((2-(1H-benzo [d]imidazol-1-y1)-3-(benzyloxy)propyl)thio)-7-chloro-6-
(trifluoromethyl)quinazoline-2,4-diol (5)
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[0222] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-
diol (2.87 g,
7.36 mmol) in 1,4-dioxane (73 mL) were added potassium carbonate (3.0 g, 22.08
mmol),
(S)-2-(1H-benzo[dlimidazol-1-y1)-3-(benzyloxy)propane-1-thiol (4) (3.95 g,
13.26 mmol),
4,5-Bis(diphenyl- phosphino)-9,9-dimethylxanthene (639 mg, 1.10 mmol) and
Tris(dibenzylideneacetone) dipalladium (674 mg, 0.736 mmol). The mixture was
stirred at 60
C under nitrogen atmosphere for 18 hours. After completion, the mixture was
concentrated
under reduced pressure, the residue was purified by silica gel column
chromatography
(dichloromethane/ethyl acetate = 3/1) to afford (S)-8-((2-(1H-benzo[dlimidazol-
1-y1)-3-
(benzyloxy)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (5)
(3.8 g, 93%
yield) as pale yellow solid. MS (ESI)m/z 561 [M+H1+.
(S)-8-((2-(1H-benzo[d]imidazol-1-y1)-3-hydroxypropyl)thio)-7-chloro-6-
(trifluoromethyl)quinazoline-2,4-diol (6)
[0223] A solution of (S)-842-(1H-benzo[dlimidazol-1-y1)-3-
(benzyloxy)propyl)thio)-7-
chloro-6-(trifluoromethyl)quinazoline-2,4-diol (5) (3.8 g, 6.78 mmol) in
trifluoroacetic acid
(55 mL). The mixture was stirred at 80 C for 18 hours. After completion, the
mixture was
concentrated and adjusted pH = 7-8 at 0 C . After concentration, the residue
was purified by
silica gel column with dichloromethane/ethyl acetate = 1/2 to afford (S)-8-((2-
(1H-
benzo [d]imidazol-1 -y1)-3 -hy droxypropyl)thio)-7-chloro-6-
(trifluoromethyl)quinazoline-2,4-
diol (6) (2.5 g, 78% yield) as a yellow solid. MS (ESI): m/z 471.0 [M+Hr.
(S)-3-(1H-benzo[d]imidazol-1-y1)-11-chloro-8-hydroxy-10-(trifluoromethyl)-3,4-
dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (7)
[0224] To a mixture of (S)-8-((2-(1H-benzo[d]imidazol-1-y1)-3-
hydroxypropyl)thio)-7-
chloro-6-(trifluoromethyl)quinazoline-2,4-diol (6) (2.56 g, 5.45 mmol) and
triphenylphosphine (5.7 g, 21.78 mmol) in tetrahydrofuran (750 mL) was added
diethyl
azodicarboxylate(3.79 g, 21.78 mmol) at 0 C. The mixture was stirred at 0 C
for 45 min.
After completion, the mixture was poured into ice-water (100 mL) and extracted
with ethyl
acetate (100 mL x 3). Concentrated and the residue was purified by C18 with 30-
95%
acetonitrile in water to afford (S)-3-(1H-benzo[d]imidazol-1-y1)-11-chloro-8-
hydroxy-10-
(trifluoromethyl)-3,4-dihydro-[1,41thiazepino[2,3,4-ri]quinazolin-6(2H)-one
(7) (840 mg,
34% yield) as a yellow solid. MS (ESI) m/z 451.3 [M-HI.
118
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(2S,6R)-tert-butyl 44(S)-3-(1H-benzo[d]imidazol-1-y1)-11-chloro-6-oxo-10-
(trifluoromethyl)-2,3,4,6-tetrahydro-11,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate (8)
[0225] To a mixture of (S)-3-(1H-benzo[dlimidazol-1-y1)-11-chloro-8-hydroxy-10-
(trifluoromethyl)-3,4-dihydro-[1,41thiazepino[2,3,4-ij[quinazolin-6(2H)-one
(7) (680 mg, 1.5
mmol) and potassium carbonate (2.07 g, 15.0 mmol) in acetonitrile (50 mL) was
added 2,4,6-
Triisopropylbenzenesulfonyl chloride (908 mg, 3.0 mmol). The mixture was
stirred at 35 C
for 4 hours. After completion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-
carboxylate (802
mg, 3.75 mmol) was added into the reaction solution. The reaction mixture was
stirred at
35 C for 1 hour. After completion, the mixture was poured into ice-water (200
mL) and
extracted with ethyl acetate (100 mL x 3). Concentrated and the residue was
purified by C18
column with 20-95% acetonitrile in water to afford (2S,6R)-tert-butyl 4-((S)-3-
(1H-
benzo[dlimidazol-1-y1)-11-chloro-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-
[1,41thiazepino[2,3,4-ij[quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
(8) (486 mg,
50% yield) as a pale yellow solid. MS (ESI) m/z 649.2 [M+Hr.
(2S,6R)-tert-butyl 44(S)-3-(1H-benzo[d]imidazol-1-y1)-11-(4-chloro-5-
(triisopropylsilyl)thiophen-2-y1)-6-oxo-10-(trifluoromethyl)-2,3,4,6-
tetrahydro-
11,41thiazepino12,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
(9)
[0226] To a solution of (2S,6R)-tert-butyl 44(S)-3-(1H-benzo[d]imidazol-1-y1)-
11-chloro-
6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,41thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate (8) (350 mg, 0.54 mmol) in 1,4-dioxane (5 mL)
and water
(0.5 mL) were added tripotassium phosphate (343 mg, 1.62 mmol), (4-chloro-5-
(triisopropylsilyl)thiophen-2-yl)boronic acid (515 mg, 1.62 mmol), and
Chloro(2-
dicyclohexylphosphino-2', 6'- diisopropoxy-1,1'-bipheny1)[2-(2'-amino-1,1'-
biphenyl)Thalladium(II) (42 mg, 0.054 mmol). The mixture was stirred at 80 C
under
nitrogen atmosphere for 1 hour. After completion, the mixture was concentrated
under
reduced pressure, the residue was purified by silica gel column chromatography
(dichloromethane/methanol = 60/1) to afford (2S,6R)-tert-butyl 4-((S)-3-(1H-
benzo[dlimidazol-1-y1)-11-(4-chloro-5-(triisopropylsily1)thiophen-2-y1)-6-oxo-
10-
(trifluoromethyl)-2,3,4,6-tetrahydro-[1,41 thi azepino[2,3,4-ij]quinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate (9) (197 mg, 41% yield) as a yellow solid. MS
(ESI) nilz
888 [M+Hr.
119
SUBSTITUTE SHEET (RULE 26)
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(2S,6R)-tert-butyl 4-((S)-3-(1H-benzo[d]imidazol-1-y1)-11-(4-chlorothiophen-2-
y1)-6-
oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-
ijIquinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate (10)
[0227] To a mixture of (2S,6R)-tert-butyl 4-((S)-3-(1H-benzo[dlimidazol-1-y1)-
11-(4-
chloro-5-(triisopropylsily0thiophen-2-y1)-6-oxo-10-(trifluoromethyl)-2,3,4,6-
tetrahydro-
[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
(9) (197 mg,
0.22 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride
(0.24 mL) at
0 C. The reaction solution was stirred at 0 C for 1 hour. After completion,
the mixture was
concentrated and extracted with ethyl acetate (100 mL x 3). Concentrated and
the residue was
purified by C18 column with 20%-95% acetonitrile in water to afford (2S,6R)-
tert-butyl 4-
((S)-3-(1H-benzo[d]imidazol-1 -y1)-11-(4-chlorothiophen-2-y1)-6-oxo-10-
(trifluoromethyl)-
2,3,4,6-tetrahy dro-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-
dimethylpiperazine-1-
carboxylate (10) (81 mg, 50 % yield) as a pale yellow solid. MS (ESI)nilz
731.2 [M+H]t
(S)-3-(1H-benzo[d]imidazol-1-y1)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-
dimethylpiperazin-1-y1)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-
ij]quinazolin-6(2H)-one (11)
[0228] To a mixture of (2S,6R)-tert-butyl 4-((S)-3-(1H-benzo[dlimidazol-1-y1)-
11-(4-
chlorothiophen-2-y1)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-
[1,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (10) (81 mg, 0.11
mmol) in
dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 0 C. The
reaction solution
was stirred at room temperature for 1 hour. After completion, the mixture was
concentrated
and the residue was purified by silica gel column chromatography
(dichloromethane/methanol = 20/1) to afford (S)-3-(1H-benzo[dlimidazol-1-y1)-
11-(4-
chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-10-
(trifluoromethyl)-3,4-
dihydro41,41thiazepino[2,3,4-ijlquinazolin-6(2H)-one (11) (60 mg, crude) as a
pale yellow
solid. MS (ESI) nilz 631.2 [M+H1+.
(S)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-1-y1)-3-(1H-benzo[d]imidazol-1-
y1)-11-
(4-chlorothiophen-2-y1)-10-(trifluoromethyl)-3,4-dihydro-11,4]thiazepino12,3,4-
ij]quinazolin-6(2H)-one (12)
[0229] To a mixture of (S)-3-(1H-benzo[d]imidazol-1-y1)-11-(4-chlorothiophen-2-
y1)-8-
((3 S,5R)-3,5-dimethylpiperazin-l-y1)-10-(tri fluoromethyl)-3,4-dihy dro-
[1,41thi azepino [2,3,4-
ijlquinazolin-6(2H)-one (11) (60 mg, crude) and triethyl amine (56 mg, 0.55
mmol) in
120
SUBSTITUTE SHEET (RULE 26)
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dichloromethane (5 ml) was added acrylic anhydride (42 mg, 0.33 mmol) at 0 C.
The
mixture was stirred at 0 C for 1 hour, After completion, the mixture was
poured into ice-
water (30 mL) and extracted with dichloromethane (30 mL x 3). Concentrated and
the residue
was purified by preparative High Performance Liquid Chromatography (20 % to 95
%
acetonitrile in water) to afford (S)-8-((3S,5R)-4-acryloy1-3,5-
dimethylpiperazin-1-y1)-3-(1H-
benzo[dlimidazol-1-y1)-11-(4-chlorothiophen-2-y1)-10-(trifluoromethyl)-3,4-
dihydro-
[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (12) (2.5 mg, 3% yield) as a
white solid. MS
(ESI) m/z 685.8 [M+H1+. NMR (400 MHz, CDC13) 6 8.21 (s, 1H), 8.13 (s, 1H),
7.83-7.79
(m, 1H), 7.60-7.54 (m, 1H), 7.40-7.32 (m, 4H), 6.66-6.59 (m, 1H), 6.43 (dd, J=
16.4 Hz, 1.6
Hz, 1H), 5.81 (dd, J= 10.8 Hz, 1.6 Hz, 1H), 5.39-5.32 (m, 4H), 5.12-4.95 (m,
3H), 4.76-4.61
(m, 2H), 4.24-4.17 (m, 2H), 2.01-2.00 (m, 6H).
Example 28: (S)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
chlorothiophen-2-y1)-3-(1H-1,2,3-triazol-1-y1)-10-(trifluoromethyl)-3,4-
dihydro-
11,41thiazepino12,3,4-illquinazolin-6(2H)-one
or
F3C
N
0
CI N
\ S Ss )
Reaction Scheme
121
SUBSTITUTE SHEET (RULE 26)
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X
OH DPPA N3 TMS-0 TMS NI¨
. TBAF
Bn0STrt -IR- Bn0,1-3) .,STrt )1- BnOSTrt
THF
(R) toluene
PPh3/DEAD 2 100 C 3
1
OH
OH
\JN, r¨N
F3C F3C
i , 0 N
N TFA/Et3SiH N CI N*LOH CI N OH
Bn0 (rs Slit -0,- BnOSH )11.-
4 5 Pd2(dba)3, XantPhos N,
.14,0Bn
K2003, dioxane NJ 6
OH OH Boc Boc
F3C ...N F3C ati .....
E)
N (Ki)/ cl\ljo
Ir *L
CI N OH PPh3/DEAD CI IW N0 N N(E)
TFA H
_)õ... S _ _),.. F3C * -y
80 C ,1\1.4p 7 0H ACN
THF S\j,$)
N
TPSCI. K2CO3, ci I\10
-
N.,..j S\hs)
8 --3
N 9 -N--,
i\fõ 3
N
13oc Boc
TIPS-)5_B(OH)2 N N
F3C .1 'N F3C * `N
CI
___________ v
CI N,µ0 TBAF TFA i.
¨).- 0
S S\j,) THF S SN.4) -IN-
\ s \ ,s
RuPhos Pd G2
TIPS '-, =.,
k3PO4, dioxane/H20 P---A N---A
80 C 10 N,,N) ii r\LN
(:),
H
N(E) .....---yo N(E)
F3C 0 4,
N 00 F3C 0 `N
_____________________________ 0.-
N 0 TEA N0
CI , DCM CI
\ S \ S Svs)
=-
,N1--1, -N--11
12 Nõ ) 13 IV,.
N N
(S)-(2-azido-3-(benzyloxy)propyl)(trityl)sulfane (2)
[0230] To a mixture of (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (1) (20 g,
45.45 mmol)
and triphenylphosphine (30 g, 113.6 mmol) in tetrahydrofuran (400 mL) was
added diethyl
azodicarboxylate (30 mL, 113.6 mmol) at 0 C under nitrogen atmosphere. The
mixture was
122
SUBSTITUTE SHEET (RULE 26)
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stirred at room temperature for 10 min, then DPPA (11 mL, 47.73 mmol) was
added. The
mixture was stirred for 2 hours. After completion, the mixture was poured into
ice-water (300
mL) and extracted with ethyl acetate (150 mL x 3). After concentration, the
residue was
purified by silica gel column with petroleum ether/ethyl acetate = 20/1 to
afford to afford
crude (S)-(3-(benzyloxy)-2-(4-fluorophenoxy)propyl)(trityl)sulfane (2) (16.5
g, crude) as a
yellow oil. 1H NMR (400 MHz, CDC13) 6 7.43-7.19 (m, 20H), 4.52-4.49 (m, 1H),
4.45 (s,
2H), 3.39-3.35 (m, 2H), 2.41-2.36 (m, 2H).
(S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-y1)-5-(trimethylsily1)-1H-1,2,3-
triazole (3)
[0231] To a solution of (S)-(2-azido-3-(benzyloxy)propyl)(trityl)sulfane (2)
(16.5 g, 35.48
mmol) in toluene (70 mL) was added ethynyltrimethylsilane (13 mL, 88.71 mmol).
The
mixture was stirred at 100 C for 16 hours. After completion, the mixture was
concentrated
and purified by silica gel column with petroleum ether/ethyl acetate = 15/1 to
afford the
product (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-y1)-5-(trimethylsily1)-1H-
1,2,3-triazole
(3) (14.1 g, 55% yield for two steps) as colorless oil. 1H NMR (400 MHz,
CDC13) 6 7.40-7.19
(m, 20H), 7.12-7.09 (m, 1H), 4.43 (s, 2H), 4.13-4.09 (m, 1H), 3.70-3.59 (m,
2H), 2.87-2.83
(m, 2H), 1.26 (s, 9H).
(S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-y1)-1H-1,2,3-triazole (4)
[0232] To a solution of (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-y1)-5-
(trimethylsily1)-
1H-1,2,3-triazole (3) (14.1 g 24.87 mmol) in tetrahydrofuran (70 mL) was added
Tetrabutylammonium fluoride (9.2 g, 35mmo1). The mixture was stirred at 40 C
for 2 hours.
After completion, the mixture was poured into ice-water (100 mL) and extracted
with ethyl
acetate (100 mL x 3). After concentration, the residue was purified by silica
gel column with
petroleum ether/ethyl acetate = 10/1 to afford to afford (S)-1-(1-(benzyloxy)-
3-
(tritylthio)propan-2-y1)-1H-1,2,3-triazole (4) (12 g, 98% yield). 1H NMR (400
MHz, CDC13)
6 7.61 (s, 1H), 7.40-7.19 (m, 20H), 7.13-7.11 (m, 1H), 4.35 (s, 2H), 4.15-4.01
(m, 1H), 3.75-
3.57 (m, 2H), 2.87-2.84 (m, 2H).
(S)-3-(benzyloxy)-2-(1H-1,2,3-triazol-1-yl)propane-1-thiol (5)
[0233] To a mixture of (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-y1)-1H-
1,2,3-triazole
(4) (12g, 24.87 mmol) and triethylsilane (2.9 g, 24.87 mmol) in
dichloromethane (40 mL)
was added trifluoroacetic acid (40 mL). The mixture was stirred at room
temperature for 2
hours. After completion, the mixture was concentrated and adjusted pH = 7-8 at
0 C. After
concentration, the residue was purified by silica gel column with petroleum
ether/ethyl
123
SUBSTITUTE SHEET (RULE 26)
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acetate = 5/1 to afford (S)-3-(benzyloxy)-2-(1H-1,2,3-triazol-1-y1) propane-l-
thiol (5) (5 g,
83% yield) as a yellow oil. 1I-1 NMR (400 MHz, CDC13) 67.73-7.71 (m, 2H), 7.38-
7.28 (m,
4H), 7.25-7.23 (m, 1H), 4.82-4.80 (m, 1H), 4.55-4.47 (m, 2H), 3.99-3.86 (m,
2H), 3.17-3.09
(m, 2H), 2.05 (s, 1H).
(S)-8-03-(benzyloxy)-2-(1H-1,2,3-triazol-1-yl)propypthio)-7-chloro-6-
(trifluoromethyl)quinazoline-2,4-diol (6)
[0234] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-
diol (5.3 g,
13.39 mmol) in 1,4-dioxane (100 mL) were added potassium carbonate (5.5 g,
40.17 mmol),
(S)-3-(benzyloxy)-2-(1H-1,2,3-triazol-1-y1) propane-l-thiol (5) (5 g, 20.08
mmol), 4,5-
Bis(diphenyl- phosphino)-9,9-dimethylxanthene (1.17 g, 2.01 mmol) and
Tris(dibenzylideneacetone) dipalladium (1.23 g, 1.34 mmol). The mixture was
stirred at 60
C under nitrogen atmosphere for 18 hours. After completion, the mixture was
concentrated
under reduced pressure, the residue was purified by silica gel column
chromatography
(dichloromethane/ethyl acetate = 4/1) to afford (S)-8-((3-(benzyloxy)-2-(1H-
1,2,3-triazol-1-
yl)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (6) (6.8 g,
97% yield) as
pale yellow solid. MS (ESI) m/z 512.0 [M+Hr.
(S)-7-chloro-8-03-hydroxy-2-(1H-1,2,3-triazol-1-yl)propyl)thio)-6-
(trifluoromethyl)quinazoline-2,4-diol (7)
[0235] A solution of (S)-8-((3-(benzyloxy)-2-(1H-1,2,3-triazol-1-
yl)propyl)thio)-7-chloro-
6-(trifluoromethyl)quinazoline-2,4-diol (6) (6.8 g, 13.70 mmol) in
trifluoroacetic acid (12
mL). The mixture was stirred at 80 C for 18 hours. After completion, the
mixture was
concentrated and adjusted pH = 7-8 at 0 C. After concentration, the residue
was purified by
silica gel column with dichloromethane/ethyl acetate = 1/2 to afford (S)-7-
chloro-8-((3-
hydroxy-2-(1H-1,2,3-triazol-1-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-
2,4-diol (7)
(6.0 g, crude) as a yellow solid. MS (ESI): miz 422.1 [M+1-11f.
(S)-11-chloro-8-hydroxy-3-(1H-1,2,3-triazol-1-y1)-10-(trifluoromethyl)-3,4-
dihydro-
[1,41thiazepino[2,3,4-ij]quinazolin-6(2H)-one (8)
[0236] To a mixture of (S)-7-chloro-8-((3-hydroxy-2-(1H-1,2,3-triazol-1-
yl)propyl)thio)-6-
(trifluoromethyl)quinazoline-2,4-diol (7) (6.0 g, 13.54 mmol) and
triphenylphosphine (11.0 g,
40.62 mmol) in tetrahydrofuran (400 mL) was added diethyl azodicarboxylate (11
mL,
40.62mmo1) at 0 C. The mixture was stirred at 0 C for 45 min. After
completion, the
mixture was poured into ice-water (100 mL) and extracted with ethyl acetate
(100 mL x 3).
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The organic phase was concentrated and the residue was purified by C18 with 30-
95%
acetonitrile in water to afford (S)-11-chloro-8-hydroxy-3-(1H-1,2,3-triazol-1-
y1)-10-
(trifluoromethyl)-3,4-dihydro-[1,41thiazepino[2,3,4-ij]quinazolin-6(2H)-one
(8) (4.2 g, 76%
yield for two steps) as a yellow solid. MS (ESI) m/z 402.0 [M-H]t.
(2S,6R)-tert-butyl 4-0S)-11-chloro-6-oxo-3-(1H-1,2,3-triazol-1-y1)-10-
(trifluoromethyl)-
2,3,4,6-tetrahydro-11,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-
dimethylpiperazine-1-
carboxylate (9)
[0237] To a mixture of (S)-11-chloro-8-hydroxy-3-(1H-1,2,3-triazol-1-y1)-10-
(trifluoromethyl)-3,4-dihydro-[1,41thiazepino[2,3,4-ij[quinazolin-6(2H)-one
(8) (2.4 g, 5.96
mmol) and potassium carbonate (8.23 g, 59.6 mmol) in acetonitrile (50 mL) was
added 2,4,6-
Tris(prop-2-yObenzenesulphonyl chloride (7.22 g, 23.82 mmol). The mixture was
stirred at
35 C for 4 hours. After completion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-
1-carboxylate
(5.1 g, 23.82 mmol) was added into the reaction solution. The reaction mixture
was stirred at
35 C for 1 hour. After completion, the mixture was poured into ice-water (200
mL) and
extracted with ethyl acetate (100 mL x 3). Concentrated and the residue was
purified by C18
column with 20-95% acetonitrile in water to afford (25,6R)-tert-butyl 4-((S)-
11-chloro-6-
oxo-3-(1H-1,2,3-triazol-1-y1)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-
[1,4[thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (9) (1.5 g, 43%
yield) as a pale
yellow solid. MS (ESI) miz 600.3[M+I-11+.
(2S,6R)-tert-butyl 44(S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-
oxo-3-(1H-
1,2,3-triazol-1-y1)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-
11,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (10)
[0238] To a solution of (25,6R)-tert-butyl 4-((S)-11-chloro-6-oxo-3-(1H-1,2,3-
triazol-1-
y1)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,41thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate (9) (200 mg, 0.33 mmol) in 1,4-dioxane (3 mL)
and water
(0.5 mL) were added tripotassium phosphate (270 mg, 1.0 mmol), (4-chloro-5-
(triisopropylsilyl)thiophen-2-yl)boronic acid (430 mg, 1.34 mmol), and
chloro(2-
dicyclohexylphosphino-2', 6'- diisopropoxy-1,1'-bipheny1)[2-(2'-amino-1,1'-
biphenyl)Ipalladium(II) (40 mg, 0.05 mmol). The mixture was stirred at 80 C
under nitrogen
atmosphere for 1 hour. After completion, the mixture was concentrated under
reduced
pressure, the residue was purified by silica gel column chromatography
(dichloromethane/methanol = 20/1) to afford (25,6R)-tert-butyl 4-((S)-11-(4-
chloro-5-
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SUBSTITUTE SHEET (RULE 26)
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(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-(1H-1,2,3-triazol-1-y1)-10-
(trifluoromethyl)-2,3,4,6-
tetrahydro-[1,41thiazepino[2,3,4-ijlquinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate
(10) (175 mg, 63% yield) as a yellow solid. MS (ESI) m/z 838.0 [M+Hr.
(2S,6R)-tert-butyl 44(S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(1H-1,2,3-triazol-
1-y1)-10-
(trifluoromethyl)-2,3,4,6-tetrahydro-11,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate (11)
[0239] To a solution of (2S,6R)-tert-butyl 4-((S)-11-(4-chloro-5-
(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-(1H-1,2,3-triazol-1-y1)-10-
(trifluoromethyl)-2,3,4,6-
tetrahydro-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate
(10) (150 mg, 0.2 mmol) in tetrahydrofuran (1 mL) was added Tetrabutylammonium
fluoride
(130 mg, 0.5 mmol). The mixture was stirred at 40 C for 2 hours. After
completion, the
mixture was poured into ice-water (5 mL) and extracted with ethyl acetate (10
mL x 3). After
concentration, the residue was purified by silica gel column with
dichloromethane/methanol
= 80/1 to afford to afford (2S,6R)-tert-butyl 4-((S)-11-(4-chlorothiophen-2-
y1)-6-oxo-3-(1H-
1,2,3-triazol-1-y1)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,41thiazepino
[2,3,4-
iii quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (11) (150 mg, crude)
as a yellow
solid. MS (ESI) nilz 682.2 [M+H1+.
(S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-(1H-
1,2,3-
triazol-1-y1)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-
ijIquinazolin-6(2H)-
one (12)
[0240] To a mixture of (2S,6R)-tert-butyl 4-((S)-11-(4-chlorothiophen-2-y1)-6-
oxo-3-(1H-
1,2,3-triazol-1-y1)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-
[1,41thiazepino[2,3,4-
ijiquinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (11) (150 mg, crude)
in
dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at 0 C. The
reaction solution
was stirred at room temperature for 1 hour. After completion, the mixture was
concentrated
and the residue was purified by silica gel column chromatography
(dichloromethane/methanol = 15/1) to afford (5)-11-(4-chlorothiophen-2-y1)-8-
((3S,5R)-3,5-
dimethyl pip erazin-l-y1)-3-(1H-1,2,3-tri azol- 1-y1)-10-(trifl uoromethyl)-
3,4-dihy dro-
[1,4]thiazepino [2,3,4-ij quinazolin-6(2H)-one (12) (80 mg, 69% yield for two
steps) as a pale
yellow solid. MS (ESI) miz 582.3[M+H1+.
126
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(S)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-chlorothiophen-2-
y1)-3-(1H-
1,2,3-triazol-1-y1)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-
ij]quinazolin-
6(2H)-one (13)
[0241] To a mixture of (5)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-
dimethylpiperazin-
1-y1)-3-(1H-1,2,3-tri azol-1-y1)-10-(trifluoromethyl)-3,4-dihy dro-[1,41
thiazepino [2,3,4-
ijlquinazolin-6(2H)-one (12) (80 mg, 0.138 mmol) and triethyl amine (28 mg,
0.275 mmol)
in dichloromethane (2 ml) was added acrylic anhydride (26 mg, 0.207 mmol) at 0
C. The
mixture was stirred at 0 C for 1 hour. After completion, the mixture was
poured into ice-
water (10 mL) and extracted with dichloromethane (10 mL x 3). Concentrated and
the residue
was purified by preparative High Performance Liquid Chromatography (20 % to 95
%
acetonitrile in water) to afford (S)-8-((3S,5R)-4-acryloy1-3,5-
dimethylpiperazin-1-y1)-11-(4-
chlorothiophen-2-y1)-3 -(1H-1,2,3 -triazol-1 -y1)-10-(trifluoromethyl)-3,4-
dihy dro-
[1,41thiazepino[2,3,4-ij quinazolin-6(2H)-one (13) (12 mg, 14% yield) as a
white solid. MS
(ESI) m/z 636.2 [M+1-11+. NMR (400
MHz, CDC13) 58.11 (s, 1H), 7.87-7.77 (m, 2H), 7.36
(s, 1H), 6.98 (s, 1H), 6.67-6.59 (m, 1H), 6.42 (dd, J= 16.4 Hz, 2.0 Hz, 1H),
5.79 (dd, J=
10.4 Hz, 1.6 Hz 1H), 5.64-5.42 (m, 1H), 5.29-5.17 (m, 1H), 5.11-4.95 (m, 1H),
4.79-4.64 (m,
2H), 4.21-4.18 (m, 2H), 3.80-3.67 (m, 1H), 3.41-3.38 (m, 3H), 1.55-1.54 (m,
6H).
Example 29: (S)-8-((3S,5R)-4-acrylov1-3,5-dimethylpiperazin-1-y1)-11-(4-
chlorothiophen-2-y1)-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
11,41thiazepino[2,3,4-iilquinazolin-6-one
MecN,Me
F3C
CI \ s
N 0
4=N
0 \
127
SUBSTITUTE SHEET (RULE 26)
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Step 1: (S)-2-((1-((tert-butyldiphenylsily0oxy)-3-(tritylthio)propan-2-
yl)oxy)pyrazine
P
Ph Ph
PhS7N(sOTBDPS
N
[0242] Sodium hydride (42 mmol) was added to a 0 C solution of (S)-1-((tert-
butyldiphenylsily0oxy)-3-(tritylthio)propan-2-ol (17 mmol) in THF (100 mL).
After 30
minutes, 2-fluoropyrazine (25.5 mmol) was added and the mixture was stirred at
room
temperature for 16 hours. The reaction was diluted with water, extracted with
ethyl acetate
and the combined organic layers were dried over anhydrous sodium sulfate,
filtered and
concentrated under reduced pressure to afford the title compound in 93% yield
as white solid.
MS (ESI) m/z: 667.0 [M+1]+.
Step 2: (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyrazin-2-yloxy)propane-1-
thiol
HSOTBDPS
[0243] Triethylsilane (37 mmol) was added to a 0 C solution of (S)-2-((1-
((tert-
butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyrazine (19 mmol) in
TFA (30 mL)
and dichloromethane (90 mL). The reaction was allowed to reach room
temperature over 60
minutes and at that time water was added. The mixture was extracted with
dichloromethane
three times and the combined organic layers were washed with brine, dried over
anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to afford a
residue that was
purified by silica gel chromatography (0-10% methanol in dichloromethane) to
afford the title
compound in 90% yield as yellow oil. MS (ESI) miz: 425.0 [M+11+.
128
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Step 3: (S)-8-03-((tert-butyldiphenylsily0oxy)-2-(pyrazin-2-yloxy)propyl)thio)-
7-chloro-6-
(trifluoromethyl)quinazoline-2,4(1H,3H)-dione
0
F3C
NH
Nc)
CI
t.1 0'
N)) OTBDPS
[0244] A mixture of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-
dione
(6.10 mmol), (S)-3-((tert-butyldiphenylsily0oxy)-2-(pyrazin-2-yloxy)propane-1-
thiol (9.1
mmol), Xantphos (1.2 mmol), diisopropylethylamine (24.4 mmol) and Pd2(dba)3
(0.06
mmol) in dioxane (20 mL) was stirred at 100 C for two hours. The reaction was
allowed to
cool down to room temperature and the volatiles were removed under reduced
pressure to
afford a residue that was purified by reverse phase chromatography (0-100%
acetonitrile in
water). The title compound was isolated in 93% yield as a yellow solid. MS
(ESI) m/z: 681.0
[M+11+.
Step 4: (S)-7-chloro-8-43-hydroxy-2-(pyrazin-2-yloxy)propyl)thio)-6-
(trifluoromethyl)quinazoline-2,4(1H,3H)-dione
0
F3C
NH
0 CI
NH OH
[0245] A 1M solution of TBAF in THF (15 mL) was added to a solution of (S)-
84(3-((tert-
butyldiphenylsilypoxy)-2-(pyrazin-2-yloxy)propyl)thio)-7-chloro-6-
(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (5.0 mmol) in THF (1 mL). After
one hour,
the reaction mixture was diluted with water, extracted with ethyl acetate and
the combined
organic layers were dried over anhydrous sodium sulfate, filtered and
concentrated under
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reduced pressure to afford the title compound in 44% yield as a brown solid.
MS (EST) m/z:
449.0 [M+11+,
Step 5: (S)-11-chloro-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione
0
F3C
NH
L0 CI N
=b_(=N/\
N¨/
[0246] A 0 C solution of DIAD (3.81 mmol) in THF (5 mL) was added to a 0 C
solution
of triphenylphoshine (3.61 mmol) in THF (5 mL). After 10 minutes, a 0.2 M THF
solution of
(S)-7-chloro-8-03-hydroxy-2-(pyrazin-2-yloxy)propyl)thio)-6-
(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione (10 mL) was added and the mixture was stirred at room
temperature for 16
hours. The volatiles were removed under reduced pressure to afford a residue
that was
purified by reverse phase chromatography (0-100% acetonitrile in water). The
title compound
was isolated in 44% yield as a white solid. MS (ESI) m/z: 431.0 [M+1]+.
Step 6: tert-butyl (25,6R)-4-((S)-11-chloro-6-oxo-3-(pyrazin-2-yloxy)-10-
(trifluoromethyl)-
3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-
dimethylpiperazine-1-
carboxylate
Boc
F3C
N
0 CI
SJ
=_o_cN\
[0247] A solution of (S)-11-chloro-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-
3,4-dihydro-
2H,6H41,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione (0.77 mmol), N,N'-
diisopropylethylamine (7.66 mmol) and P0C13 (4 mL) in toluene (4 mL) was
stirred at 120
C for 90 minutes. The volatiles were removed under reduced pressure and the
residue was
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redissolved in dichloroethane (5 mL). This solution was added to a 0 C
solution of tert-butyl
(2R,65)-2,6-dimethylpiperazine-1-carboxylate (3.10 mmol) and N,N'-
diisopropylethylamine
(7.66 mmol) in dichloroethane and the mixture was stirred at room temperature
for one
additional hour. The volatiles were removed under reduced pressure to afford a
residue that
was purified by silica gel chromatography. The title compound was isolated in
51% yield as a
yellow solid. MS (ESI) m/z: 627.0 [M+11+.
Step 7: tert-butyl (25,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-
v1)-6-oxo-3-
(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H41,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
Boc
F3C
N
NL0
CI
S S
TIPS
[0248] The title compound was prepared analogously to Example 23, step 1,
where tert-
butyl (25,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
1-
carboxylate was replaced with tert-butyl (25,6R)-4-((S)-11-chloro-6-oxo-3-
(pyrazin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ijlquinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate. The title compound was isolated in 88% yield
as a brown
solid. MS (ESI) m/z= 865.0 [M+H]+.
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Step 8: (S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-8-((3S,5R)-3,5-
dimethylpiperazin-l-y1)-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
[1,4]thiazepino[2,3,4-ij]quinazolin-6-one
Me4h.(NyMe
F3C
0/
CI N
\ S
N/\
TIPS
[0249] The title compound was prepared analogously to Example 23, step 3 where
tert-
butyl (25,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ijIquinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (25,6R)-4-((S)-
11-(4-chloro-
5-(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-(pyrazin-2-yloxy)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H41,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
1-
carboxylate. The title compound was isolated in 80% yield as a yellow oil. MS
(ESI) m/z=
765.0 [M+H]+.
Step 9: (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-
3-(pyrazin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-
ij]quinazolin-6-one
Me N Me
F3C
N
CI
\ S S
=b4=N\
[0250] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-
(pyrimidin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ijlquinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with (S)-11-(4-chloro-5-
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(triisopropylsilyl)thiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-
(pyrazin-2-yloxy)-
10-(trifluoromethyl)-3,4-dihydro-2H,6H41,41thiazepino[2,3,4-ij[quinazolin-6-
one. The title
compound was isolated in 83% yield as a yellow oil. MS (ESI) m/z= 609.0
[M+H]+.
Step 10: (S)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-1-y1)-11-(4-
chlorothiophen-2-y1)-
3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H41,41thiazepino[2,3,4-
ij[quinazolin-6-one
Me N Me
F3C
[0251] The title compound was prepared analogously to Example 23, step 4 where
(S)-11-
(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-(pyrimidin-2-
yloxy)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ij[quinazolin-6-
one was replaced
with (5)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-
(pyrazin-2-
yloxy)-10-(trifluoromethy1)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ij[quinazolin-6-one.
The title compound was isolated in 10% yield as a white solid. MS (ESI) m/z=
663.0
[M+H]+. 1H NMR (400 MHz, CDC13) 6 8.27 - 8.22 (m, 1H), 8.20 - 8.15 (m, 1H),
8.09- 8.06
(m, 2H), 7.36 - 7.35 (m, 1H), 7.00 - 6.87 (m, 1H), 6.67 - 6.57 (m, 1H), 6.45 -
6.38 (m, 1H),
5.82 - 5.58 (m, 2H), 5.01 - 4.78 (m, 1H), 4.71 - 4.58 (m, 2H), 4.27 - 4.09 (m,
2H), 3.70 - 3.26
(m, 4H), 3.19 - 3.02 (m, 1H), 1.64 - 1.50 (m, 6H).
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Example 31: (S)-843S,5R)-4-acryloy1-3,5-dimethylpiperazin- 1-y1)-11-(4-
chlorothiophen-2-y1)-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
11,41thiazepino12,3,4-ij] quinazolin-6-one
0
Me N Me
LN)
F3C
N
CI 0
S S
\_22
b-0
Step 1: (S)-3-(Tritylthio)propane-1,2-diol
P
Ph Ph
Ph S OH
OH
[0252] Potassium tert-butoxide (498 mmol) was added to a 0 C solution of
triphenylmethanethiol (452 mmol) in DMF (800 mL). After 30 minutes, a solution
of (2S)-3-
chloropropane-1,2-diol (452 mmol) in DMF (200 mL) was added and the mixture
was
allowed to reach room temperature slowly and stirred overnight. The reaction
mixture was
diluted with water, extracted with ethyl acetate and the combined organic
layers were dried
over anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to afford a
residue that was purified by silica gel chromatography (10% ethyl acetate in
hexanes) to
afford the title compound in 97% yield as yellow oil. MS (EST) miz= 351.1
[M+H]+.
Step 2: (S)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol
Ph
Ph
Ph S . OTBDPS
OH
[0253] Imidazole (228 mmol) was added to a 0 C solution of (S)-3-
(tritylthio)propane-1,2-
diol (143 mmol) in dichloroemthane (500 mL). After 30 minutes, tert-
butyldiphenyl
chlorosilane (171 mmol) was added and the reaction stirred at room temperature
overnight.
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The reaction was filtered and the volatiles were removed under reduced
pressure to afford a
residue that was purified by silica gel chromatography (0-10% ethyl acetate in
hexanes) to
afford the title compound in 58% yield as colorless oil. MS (ESI) m/z= 589.3
[M+H]+.
Step 3: (S)-2-((1-((tert-butyldiphenylsily0oxy)-3-(tritylthio)propan-2-
yl)oxy)pyridine
Ph
Ph
PI-SOTBDPS
N
[0254] The title compound was prepared analogously to Example 29, step 1 where
2-
fluoropyrazine was replaced with 2-fluoropyridine. The title compound was
isolated in 75%
yield as a colorless oil. MS (ESI) m/z= 666.3 [M+H]+.
Step 4: (S)-2-(Pyridin-2-yloxy)-3-(tritylthio)propan-1-ol
P
Ph Ph
Ph' S(s0H
z
N
[0255] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (25,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilypthiophen-2-y1)-6-oxo-3-
(pyrimidin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-
ijlquinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with (S)-2-((1-((tert-
butyldiphenylsilyl)oxy)-
3-(tritylthio)propan-2-yl)oxy)pyridine. The title compound was isolated in 82%
yield as a
colorless oil. MS (ESI) m/z= 428.2 [M+H]+.
Step 5: (S)-3-mercapto-2-(pyridin-2-yloxy)propan-1-ol
(sy=
HS - OH
bY
N
[0256] The title compound was prepared analogously to Example 29, step 2 where
(S)-2-
41-((tert-butyldiphenylsilypoxy)-3-(tritylthio)propan-2-yl)oxy)pyrazine was
replaced with
(S)-2-(Pyridin-2-yloxy)-3-(tritylthio)propan-1-ol. The title compound was
isolated in
quantitative yield as a white solid.
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Step 6: (S)-7-chloro-843-hydroxy-2-(pyridin-2-vloxy)propyl)thio)-6-
(trifluoromethyl)quinazoline-2,4(1H,3H)-dione
0
F3C
NH
CI N 0
(s)
rON
OH
[0257] The title compound was prepared analogously to Example 29, step 3 where
(S)-3-
((tert-butyldiphenylsilyl)oxy)-2-(pyrazin-2-yloxy)propane-1-thiol was replaced
with (S)-3-
mercapto-2-(pyridin-2-yloxy)propan-1-ol. The title compound was isolated in
42% yield as a
pale green solid. MS (ESI) m/z= 447.9 [M+H]+.
Step 7: (S)-11-chloro-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
11,41thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione
0
F3C fah
NH
CI N 0
S\ (s)
[0258] The title compound was prepared analogously to Example 29, step 5 where
(S)-7-
chloro-8-((3-hydroxy-2-(pyrazin-2-yloxy)propyl)thio)-6-
(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione was replaced with (S)-7-chloro-8-((3-hydroxy-2-(pyridin-2-
yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione. The title
compound
was isolated in 28% yield as a white solid. MS (ESI) m/z= 430.0 [M+H]+.
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Step 8: tert-butyl (25,6R)-4-((S)-11-ch1oro-6-oxo-3-(pyridin-2-y1oxy)-10-
(trifluoromethy1)-
3,4-dihydro-2H,6H41,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-
dimethylpiperazine-1-
carboxylate
yoc
F3CN
CI N 0
S\ (s)
[0259] The title compound was prepared analogously to Example 29, step 6 where
(S)-11-
chloro-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1,4]thiazepino[2,3,4-
ij]quinazoline-6,8(7H)-dione was replaced with (S)-11-chloro-3-(pyridin-2-
yloxy)-10-
(trifluoromethyl)-3,4-dihydro-2K6H-[1,4]thiazepino[2,3,4-ij]quinazoline-
6,8(7H)-dione. The
title compound was isolated in 78% yield as a pale yellow solid. MS (ESI) m/z=
626.2
[M+H]+.
Step 9: tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-
y1)-6-oxo-3-
(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H41,4]thiazepino[2,3,4-
jj]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
Boc
Me N Me
F3C
1,11
NO
CI
S S
\ (s)
TIPS
0-0
[0260] The title compound was prepared analogously to Example 23, step 1,
where tert-
butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-
dihydro-211,611-[1,4]thiazepino[2,3,4-ij]quinazo1in-8-y1)-2,6-
dimethy1piperazine-l-
carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-
(pyridin-2-yloxy)-
137
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10-(trifluoromethyl)-3,4-dihydro-2H,6H41,41thiazepino[2,3,4-ijlquinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate. The title compound was isolated in 36% yield
as a yellow
oil. MS (ESI) m/z= 865.6 [M+H]+.
Step 10: tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyridin-
2-yloxy)-10-
(trifluoromethyl)-3,4-dihydro-2H.6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate
Boc
MeN)õMe
F3C
N
CI O
S S\ (S)
[0261] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-
(pyrimidin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-
11-(4-chloro-
5-(tri i sopropyl silyl)thiophen-2-y1)-6-oxo-3-(pyri din-2-y' oxy)-10-(tri
fluoromethyl)-3,4-
dihy dro-2H,6H41,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
1-
carboxylate. The title compound was isolated in 87% yield as a white solid. MS
(ESI) m/z=
708.2 [M+H]+.
Step 11: (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-
3-(pyridin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ij]quinazolin-6-one
Me4,(Nfe
F3C
N
CI O
S S\ (S)
b-0
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[0262] The title compound was prepared analogously to Example 23, step 3 where
tert-
butyl (25,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethy1)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (25,6R)-4-((S)-
11-(4-
chlorothiophen-2-y1)-6-oxo-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-
dihydro-2H,6H-
[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate. The title
compound was isolated in 87% yield as a white solid. MS (ESI) m/z= 608.2
[M+H]+.
Step 12: (S)-8-((3S,5R)-4-acrvloy1-3,5-dimethylpiperazin-1-y1)-11-(4-
chlorothiophen-2-y1)-
3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H41,4]thiazepino[2,3,4-
ij]quinazolin-6-one
Me N Me
F3C
N 0
CI
S S\ (S))
[0263] The title compound was prepared analogously to Example 23, step 4 where
(S)-11-
(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-(pyrimidin-2-
yloxy)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-
one was replaced
with (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-
(pyridin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-
ij]quinazolin-6-one.
The title compound was isolated in 13% yield as a white solid. MS (ESI) m/z=
662.2
[M+H]+. 1H NMR (400MHz, CDC13) 6 8.14 - 8.05 (m, 2H), 7.59 (ddd, J = 2.0, 7.2,
8.4 Hz,
1H), 7.34 (s, 1H), 7.01 - 6.86 (m, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.63 (dd, J
= 10.4, 16.8 Hz,
1H), 6.42 (dd, J = 1.6, 16.8 Hz, 1H), 5.84 - 5.70 (m, 2H), 5.00 - 4.57 (m,
4H), 4.20 - 4.10 (m,
2H), 3.52 - 3.33 (m, 4H), 1.55 (br s, 6H).
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Example 32: (S)-843S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
chlorothiophen-2-y1)-3-(pyridazin-3-yloxy)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
11,41thiazepino12,3,4-ijlquinazolin-6-one
0
Me N Me
F3C
N /
CI 0 \
S S\ (S))
N-N
[0264] The title compound was prepared analogously to Example 29, where 2-
fluoropyrazine was replaced with 2-chloropyridazine in step 1. The title
compound was
isolated as a white solid. MS (ESI) m/z: 663.0 [M+H]+. 1H NMR (400 MHz, CDC13)
6 8.93
(d, J = 4.0 Hz, 1H), 8.09 (s, 1H), 7.66 - 7.56 (m, 1H), 7.35 (d, J = 1.2 Hz,
1H), 7.21 (d, J = 8.4
Hz, 1H), 7.03 - 6.87 (m, 1H), 6.68 - 6.58 (m, 1H), 6.42 (dd, J = 2.0, 16.6 Hz,
1H), 5.89 - 5.76
(m, 2H), 4.97 -4.89 (m, 1H), 4.83 (s, 2H), 4.75 -4.70 (m, 1H), 4.27 - 4.15 (m,
2H), 3.48 -
3.39 (m, 2H), 3.38 - 3.31 (m, 1H), 3.17 (dd. J = 2.4, 13.6 Hz, 1H), 1.61 (d, J
= 7.2 Hz, 3H),
1.50 (d, J = 7.2 Hz, 3H).
Example 33: (S)-843S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
chlorothiophen-2-y1)-3-(pyrimidin-4-yloxy)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
11,41thiazepino[2,3,4-illquinazolin-6-one
oY
Me41/4cNxMe
F3C
N
CI
S S
b-rN
N J/
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[0265] The title compound was prepared analogously to Example 29, where 2-
fluoropyrazine was replaced with 4-chloropyrimidine in step 1. The title
compound was
isolated as a yellow oil. MS (ESI) m/z: 690.0 [M+Na]+.
Example 35: (S)-843S,5R)-4-acrylov1-3,5-dimethylpiperazin-l-v1)-11-(4-
chlorothiorthen-2-y1)-3-(pyridin-4-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
11,41thiazeroino[2,3,4-illquinazolin-6-one
F3C
N
CI
S N 0
S \ (s))
Step 1: 2,4,7-Trichloro-8-iodo-6-(trifluoromethyl)quinazoline
CI
F3CN
CI N CI
[0266] To a mixture of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione
(5.1 mmol) in N,N-diisopropylethylamine (17.9 mmol) was added phosphoryl
trichloride (12
mL). The mixture was stirred at 110 C for 12 hours and the reaction mixture
was
concentrated under reduced pressure to afford a residue that was taken up in
cold water and
extracted with ethyl acetate three times. The combined organic layers were
washed with
brine, dried over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure.
The resulting crude material was purified by silica gel chromatography (0-15%
ethyl acetate
in petroleum ether) to afford the title compound in 44% yield as a white
solid. MS (ESI) m/z:
427.0 [M+11+.
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Step 2: tert-Butyl (2S,6R)-4-(2,7-dichloro-8-iodo-6-
(trifluoromethyl)quinazolin-4-y1)-2,6-
dimethylpiperazine-1-carboxylate
Boc
(N/
F3C
N N
CI N CI
[0267] To a solution of 2,4,7-trichloro-8-iodo-6-(trifluoromethyl)quinazoline
(2.04 mmol)
and triethylamine (6.11 mmol) in dichloromethane (10 mL) was added tert-butyl
(2S,6R)-2,6-
dimethylpiperazine-1-carboxylate (1.83 mmol) at 0 C. The mixture was stirred
at room
temperature for 1 hour and the volatiles were removed under reduced pressure.
The residue
was purified by silica gel column chromatography (5-15% ethyl acetate in
hexanes) to afford
the title compound in 82% yield as white solid. MS (EST) m/z: 605.2 [M+H]+.
Step 3: tert-Butyl (2S,6R)-4-(7-chloro-8-iodo-2-oxo-6-(trifluoromethyl)-1,2-
dihydroquinazolin-4-y1)-2,6-dimethylpiperazine-1-carboxylate
Boc
MerNMe
LN
F3C
CI N 0
[0268] To a solution of tert-butyl (2S,6R)-4-(2,7-dichloro-8-iodo-6-
(trifluoromethyl)quinazolin-4-y1)-2,6-dimethylpiperazine-l-carboxylate (1.73
mmol) in
acetonitrile (50 mL) was added 2-(methylsulfonyl)ethan-1-ol (3.47 mmol),
cesium carbonate
(3.47 mmol) and 1,4-diazabicyclo[2.2.2loctane (0.17 mmol). The mixture was
stirred at 80
C for 2 hours and the volatiles were removed under reduced pressure to afford
a solid that
was redissolved in dichloromethane, washed with water, dried over sodium
sulfate, filtered
and concentrated under reduced pressure. The resulting residue was triturated
with 60 mL of
a 10:1 mixture of tert-butylmethylether and ethyl acetate to afford a yellow
solid that was
filtered and dried to afford the title compound in 88% yield. MS (ESI) m/z:
587.2 [M+H]+.
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Step 4: 2-(Pyridin-4-yl)propane-1,3-diol
H070H
[0269] A mixture of 4-methylpyridine (430 mmol) in 37% formaldehyde (1.72 mol)
was
stirred at 100 C for 12 hours. The reaction mixture was concentrated under
reduced pressure
to afford a residue that was purified by silica gel chromatography (1-10%
methanol in ethyl
acetate). The title compound was isolated in 88% yield as a colorless oil. 1H
NMR (400
MHz, methanol-d4) 6 ppm 2.99 (q, J = 6.4 Hz, 1H) 3.77-3.91 (m, 4 H) 7.29-7.47
(m, 2 H)
8.33-8.54 (m, 2 H).
Step 5: 3-Hydroxy-2-(pyridin-4-yl)propyl 4-methylbenzenesulfonate
HOOTos
[0270] To a 0 C solution of 2-(pyridin-4-yl)propane-1,3-diol (65.3 mmol) in
dichloromethane (100 mL) was added p-toluensulfonyl chloride (65.3 mmol), N,N'-
dimethylaminopyridine (6.53 mmol) and pyridine (65.3 mmol). The mixture was
stirred at
room temperature for 3 hours, quenched with water and extracted with ethyl
acetate three
times. The organic layers were combined and dried over anhydrous sodium
sulfate, filtered
and concentrated under reduced pressure to afford a residue that was used in
the next step
without further purification.
Step 6: S-(3-Hydroxy-2-(pyridin-4-yl)propyl) ethanethioate
0
HOS)Me
[0271] To a solution of 3-hydroxy-2-(pyridin-4-yl)propyl 4-
methylbenzenesulfonate (55.3
mmol) in dimethyl formamide (150 mL) was added potassium thioacetate (81.9
mmol). The
mixture was stirred at 50 C for 2 hours, quenched with water and extracted
with ethyl
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acetate three times. The combined organic layers were dried over anhydrous
sodium sulfate,
filtered and concentrated under reduced pressure to afford a residue that was
purified by silica
gel chromatography (50-100 % ethyl acetate in hexanes). The title compound was
isolated in
15% yield as a yellow oil. 1H NMR (400 MHz, CDC13) 6 ppm 2.35 (s, 3 H) 2.99
(quin, J=
6.4 Hz, 1 H) 3.15-3.24 (m, 1 H), 3.37 (dd, J= 14.0, 7.2 Hz, 1H) 3.79-3.90 (m,
2 H) 7.14-7.24
(m, 2 H), 8.48-8.59 (m, 2H).
Step 7: tert-butyl (25,6R)-4-(7-chloro-8-03-hydroxy-2-(pyridin-4-
yl)propyl)thio)-2-oxo-6-
(trifluoromethyl)-1,2-dihydroquinazolin-4-v1)-2,6-dimethylpiperazine-1-
carboxylate
Boc
MeN)(Me
F3C
N
0 CI
ri
OH
[0272] To a solution of S-(3-hydroxy-2-(pyridin-4-yl)propyl) ethanethioate
(0.95 mmol)
and tert-butyl (2S,6R)-4-(7-chloro-8-iodo-2-oxo-6-(trifluoromethyl)-1,2-
dihydroquinazolin-
4-y1)-2,6-dimethylpiperazine-1-carboxylate (1.42 mmol) in 1,2-ethanediol (2
mL) and
isopropanol (2 mL), was added potassium carbonate (2.84 mmol) and cuprous
iodide (0.47
mmol). The mixture was stirred at 85 C for 2 hours, quenched with water and
extracted with
ethyl acetate three times. The combined organic layers were dried over
anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to afford a residue
that was purified
by preparative TLC. The title compound was isolated in 65% yield as a yellow
solid. MS
(ESI) m/z: 627.9 [M+11+.
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Step 8: tert-Butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-4-y1)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H41,41thiazepino[2,3.4-ij]quinazolin-8-y1)-2.6-dimethylpiperazine-
1-
carboxylate (Int-la) and tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-
4-y1)-10-
(trifluoromethyl)-3,4-dihydro-2H.6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-l-carboxylate (Int-lb)
Boc Boc
F3C F3C
CI N 0 CI 0
S (R)
(s)
/ e
It-la It-lb
[0273] To a 0 C solution of tert-butyl (2S,6R)-4-(7-chloro-8-03-hydroxy-2-
(pyridin-4-
yl)propypthio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-y1)-2,6-
dimethylpiperazine-1-carboxylate (2.11 mmol) in tetrahydrofuran (100 mL) was
added
triphenylphosphine (10.6 mmol). The mixture was stirred at 0 C for 30 minutes
and diethyl
azodicarboxylate (10.6 mmol) was added. After 12 hours, the volatiles were
removed under
reduced pressure to afford a residue that was purified by silica gel
chromatography (0-10 %
methanol in ethyl acetate). Compounds Int-la and Int-lb were isolated as a 1:1
mixture of
diastereomers in 65% yield. Pure diastereomers Int-la and Int-lb were obtained
by
purification of the mixture of diastereomers by semi-preparative reverse phase-
HPLC
(column= Daicel Chiracel OD 250mm*30mm,10um; mobile phase B= methanol;
gradient=
50% for 6.4 minutes runtime) and characterized by SFC (Column= Chiracel OD-3,
50x4.6
mm I.D., 3 um stabilized at 35 C with a back pressure of 100 bar. Mobile
phase A= CO2 and
mobile phase B= methanol containing 0.05% diethylamine; gradient= 40%; flow
rate= 3
mL/min. Detector= Photodiode-array). Int-la: SFC Rt= 1.03 min; MS (ESI) m/z:
609.9
[M+1]+. Int-lb: SFC Rt= 1.40 min; MS (EST) m/z: 609.9 [M+1]+
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Step 9: tert-butyl (25,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-
y1)-6-oxo-3-
(pyridin-4-y1)-10-(tri fluoromethyl)-3,4-dihy dro-2H,6H-[1,41 thi azepino
[2,3,4-ij I quinazolin-8-
y1)-2,6-dimethylpiperazine-1-carboxylate
Boc
Me N Me
F3C
N
CI
S S\ (S)
TIPS
¨N
[0274] The title compound was prepared analogously to Example 23, step 1,
where tert-
butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
1-
carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-
(pyridin-4-y1)-10-
(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate. The title compound was isolated in 38% yield
as a yellow
solid. MS (ESI) m/z: 848.1 [M+H]+.
Step 10: tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyridin-
4-y1)-10-
(trifluoromethyl)-3,4-dihydro-2H.6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate
Boc
Me.1/4cN y Me
F3C
CI N
\
S
¨N
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[0275] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-
(pyrimidin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-
11-(4-chloro-
5-(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-(pyridin-4-y1)-10-
(trifluoromethyl)-3,4-dihydro-
2H,6H41,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate. The
title compound was isolated in 98% yield as a white solid. MS (ESI) m/z: 692.2
[M+H]+.
Step 11: (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-
3-(pyridin-4-
y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1.4]thiazepino[2,3,4-ij]quinazolin-
6-one
Mei.(N),11/le
F3C
CI \
S Sx_d
\=N
[0276] The title compound was prepared analogously to Example 23, step 3 where
tert-
butyl (25,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-
11-(4-
chlorothiophen-2-y1)-6-oxo-3-(pyridin-4-y1)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate. The title
compound was isolated in 99% yield as a yellow solid. MS (ESI) m/z: 592.2 [M+1-
11+,
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Step 12: (S)-8-((3S,5R)-4-acrvloy1-3,5-dimethylpiperazin-1-y1)-11-(4-
chlorothiophen-2-y1)-
3-(pyridin-4-y1)-10-(trifluoromethyl)-3,4-dihvdro-2H,6H-[1,41thiazepino [2,3,4-
ij I quinazolin-
6-one
F3C
NL
CI 0
S S\ (S)
\=N
[0277] The title compound was prepared analogously to Example 23, step 4 where
(S)-11-
(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-(pyrimidin-2-
yloxy)-10-
(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-6-one
was replaced
with (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-
(pyridin-4-y1)-
104trifluoromethyl)-3,4-dihydro-211,6H41,41thiazepino[2,3,4-ijlquinazolin-6-
one. The title
compound was isolated in 33% yield as a white solid. MS (ESI) m/z: 646.2
[M+H]+.1H NMR
(400 MHz, CDC13-d) = 8.62 (d, J= 5.6 Hz, 2H), 8.13 (s, 1H), 7.39 - 7.32 (m,
3H), 7.12 -
6.89 (m, 1H), 6.70 - 6.61 (m, 1H), 6.44 (dd. J= 1.6, 16.8 Hz, 1H), 5.83 - 5.79
(m, 1H), 4.88 -
4.61 (m, 4H), 4.19 (br dd, J= 9.2, 11.4 Hz, 2H), 3.83 -3.66 (m, 2H), 3.46-
3.37 (m. 2H),
3.22 - 3.09 (m, 1H), 1.61 (br d, J= 6.8 Hz, 3H), L54 (br d, J= 7.2 Hz, 3H).
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Example 37: (R)-8438,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
chlorothiophen-2-y1)-3-(pyridin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
11,41thiazepino12,3,4-ijlquinazolin-6-one
Me N Me
F3C
CI
S S\ (R)
N
Step 1: tert-butyl (25,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-2-y1)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H41,4]thiazepino[2,3.4-ij]quinazolin-8-y1)-2.6-dimethylpiperazine-
1-
carboxylate (Int-2a) and tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-
2-y1)-10-
(trifluoromethyl)-3,4-dihydro-2R6H-[1,41thiazepino[2,3,4-ijlquinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate (Int-2b)
Boc Boc
Me N Me Me N Me
F3C F3c 100
CI N 0 CI N 0
))S\ S\ (R
N
Int-2a
Int-2b \-7
[0278] The title compounds were prepared as a 1:1 mixture of diastereomers
analogously to
Example 35, steps 1-8, where 2-(pyridin-4-yl)propane-1,3-diol was replaced
with 2-(pyridin-
2-yl)propane-1,3-diol in step 4. Int-2a and Int-2b were obtained as single
diastereomers by
purification of the aforementioned mixture by semi-preparative reverse phase-
HPLC
(column: Diacel Chiracel OD 250mmx30mm, 10um; mobile phase B: methanol;
gradient=
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50% for 6.4 minutes runtime) and characterized by SFC (Column: Chiracel OD-3,
50x4.6
mm, I.D.=3 um stabilized at 35 C with a back pressure of 100 bar. Mobile
phase B= 40%
methanol containing 0.05% diethylamine; gradient= 40%, flow rate= 3 mL/min.
Detector:
Photodiode-array) SFC Rt=
1.39 min; MS (ESI) m/z: 610.2 [M+H]+. Int-lb: SFC Rt=
2.25 min; MS (ESI) m/z: 610.2 [M+H]+.
Step 2: tert-butyl (25,6R)-4-((R)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-
y1)-6-oxo-3-
(pyridin-2-y1)-10-(trifluoromethyl)-3,4-dihy dro-2H,6H41,4] thiazepino [2,3,4-
ij quinazolin-8-
y1)-2,6-dimethylpiperazine-1-carboxylate
'cc
Me,1/4(N),,Me
F3C
y
O
CI N
(IR)
TIPS N
[0279] The title compound was prepared analogously to Example 23, step 1,
where tert-
butyl (2 S,6R)-4-((S)-11 -chl oro-6-oxo-3-(pyrimi din-2-y' oxy)-10-
(trifluoromethyl)-3 ,4-
dihy dro-2H,6H-11,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-
dimethylpiperazine-1-
carboxylate was replaced with tert-butyl (25,6R)-4-((R)-11-chloro-6-oxo-3-
(pyridin-2-y1)-10-
(trifluoromethyl)-3,4-dihydro-211,6H-[1,41thiazepin0[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate. The title compound was isolated in 72% yield
as a yellow
solid. MS (ESI) m/z: 848.3 [M+H]+.
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Step 3: tert-butyl (25,6R)-4-((R)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyridin-
2-y1)-10-
(trifluoromethyl)-3,4-dihydro-2H.6H-[1,41thiazepino[2,3,4-ij I quinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate
yoc
Me41/4(NMe
F3C
NO
CI
S S\ (R)
(N)
[0280] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-ox0-3-
(pyrimidin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ijlquinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((R)-
11-(4-chloro-
5-(triisopropylsilyl)thiophen-2-y1)-6-ox0-3-(pyridin-2-y1)-10-
(trifluoromethyl)-3,4-dihydro-
2H,6H41,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate. The
title compound was isolated in 95% yield as a yellow solid. MS (ESI) m/z:
692.2 [M+H]+.
Step 4: (R)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-
3-(pyridin-2-
y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1.4]thiazepino[2,3,4-ij ]
quinazolin-6-one
Me N Me
F3C
JN
CI S S\ (R)
(N)
[0281] The title compound was prepared analogously to Example 23, step 3 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyrimidin-2-yloxy)-10-
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(trifluoromethyl)-3,4-dihydro-2K6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (25,6R)-4-((R)-
11-(4-
chlorothiophen-2-y1)-6-oxo-3-(pyridin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate. The title
compound was isolated in 99% yield as a yellow solid. MS (ESI) m/z: 592.2
[M+H]+.
Step 5: (R)-8-((3 S,5R)-4-acryloy1-3,5-dimethylpiperazin-1-y1)-11-(4-
chlorothiophen-2-y1)-3-
(pyridin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H41,4]thiazepino[2,3,4-
ijjquinazolin-6-
one
F3C
CI N
,
S S\21)
(N)
[0282] The title compound was prepared analogously to Example 23, step 4 where
(S)-11-
(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-(pyrimidin-2-
yloxy)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ij]quinazolin-6-
one was replaced
with (R)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-
(pyridin-2-
y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-
6-one. The
title compound was isolated in 33% yield as a yellow solid. MS (ESI) m/z:
616.2 [M+H]+.
1H NMR (400 MHz, CDC13) 5, 8.54 - 8.45 (m, 1H), 8.01 (s, 1H), 7.70 - 7.56 (m,
111), 7.30 -
7.22 (m, 2H), 7.10 (s, 1H), 6.98 - 6.78 (m, 1H), 6.62 - 6.50 (m, 1H), 6.35
(dd, J = 2.0, 16.8
Hz, 1H), 5.71 (dd, J = 2.0, 10.4 Hz, 1H), 5.02 - 4.85 (m, 2H), 4.72 - 4.45 (m,
2H), 4.20 - 4.03
(m, 2H), 3.96 - 3.74 (m, 1H), 3.63 -3.41 (m, 2H), 3.34- 3.19 (m, 2H), 1.51 (br
s, 3H), 1.46 -
1.38 (m, 3H).
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Example 43: (S)-843S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
chlorothiophen-2-y1)-3-(pyridin-3-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
11,41thiazepino12,3,4-ijlquinazolin-6-one
Me N y Me
LN)
F3C
N
CI
S S\ (S)
¨/
Step 1: 2-(pyridin-3-yl)prop-2-en-1-ol
70H
[0283] A mixture of pyridin-3-ylboronic acid (41 mmol), 2-bromoprop-2-en-1-ol
(49
mmol), potassium phosphate (122 mmol) and XPhosPd G2 (1.0 mmol) in THF (50mL)
and
water (50 mL) was stirred at 60 C for 12 hours. The reaction mixture was
diluted with water,
extracted with ethyl acetate three times and the combined organic layers were
dried over
anhydrous sodium sulfate, filtered and concentrated under reduced pressure to
afford a
residue that was purified by silica gel chromatography (35-80% ethyl acetate
in hexanes).
The title compound was isolated in 53% yield as colorless oil. MS (ESI) miz:
136.1 [M+H]+.
Step 2: 2-(pyridin-3-yl)propane-1,3-diol
HO"-""OH
[0284] A 10M solution of borane dimethyl sulfide complex in THF (8.6 mL) was
added
over a 0 C solution of 2-(pyridin-3-yl)prop-2-en-1-ol (22 mmol) in THF (30
mL).After 5
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minutes, a 1M aqueous solution of NaOH (6.5 mL) was added dropwise, followed
by a 35%
aqueous solution of hydrogen peroxide (86 mmol). After 2 hours, methanol (50
mL) was
added and the resulting reaction was stirred at 70 C for 12 hours. The
reaction mixture was
diluted with water, extracted with ethyl acetate three times and the combined
organic layers
were dried over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure
to afford a residue that was purified by silica gel chromatography (0-20%
methanol in ethyl
acetate). The title compound was isolated in 73% yield as colorless oil. 1H
NMR (400 MHz,
CDC13) 6 8.58 - 8.48 (m, 2H), 7.68 -7.59 (m, 1H), 7.32 - 7.28 (m, 1H), 4.10 -
3.96 (m, 4H),
3.16 - 3.07 (m, 1H).
Step 3: 3-((tert-butyldiphenylsilypoxy)-2-(pyridin-3-yl)propan-1-ol
TBDPSOOH
[0285] The title compound was prepared analogously to Example 31, step 1,
where (S)-3-
(tritylthio)propane-1,2-diol was replaced with 2-(pyridin-3-yl)propane-1,3-
diol. The title
compound was isolated in 47% yield as a colorless oil. 1H NMR (400 MHz, CDC13)
6 8.49
(d, J = 4.4 Hz, 1H), 8.45 (s, 1H), 7.61 (dd, J = 7.6, 11.2 Hz, 4H), 7.54 (d, J
= 8.0 Hz, 1H),
7.49 - 7.33 (m, 6H), 7.21 (dd, J = 4.8, 7.6 Hz, 1H), 4.11 - 4.05 (m, 1H), 3.99
- 3.89 (m, 3H),
3.08 (quin, J = 6.0 Hz, 1H), 2.14 (s, 1H), 1.05 (s, 9H).
Step 4: S-(3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl)
ethanethioate
TBDPSOSAc
N
[0286] A solution of triphenylphosphine (8.20 mmol) and DIAD (8.17 mmol) in
THF (50
mL) was stirred at 0 C for 30 minutes. 3-((tert-butyldiphenylsilyl)oxy)-2-
(pyridin-3-
yl)propan-1-ol (4.09 mmol) and ethanethioic S-acid (9.81 mmol) were added and
the mixture
was stirred at room temperature for one hour. Evaporation of volatiles under
reduced pressure
afforded a residue that was purified by silica gel chromatography (10-25%
ethyl acetate in
hexanes). The title compound was isolated in 98% yield as a colorless oil. MS
(EST) miz:
450.1 [M+H]+.
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Step 5: tert-butyl (2S,6R)-4-(8-43-((tert-butyldiphenylsily0oxv)-2-(pyridin-3-
y0propyl)thio)-
7-chloro-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-y1)-2,6-
dimethylpiperazine-1-
carboxylate
Boc
MeN..(Nja,,Me
F3C ithh
N
CI N 0
TBDPSON
[0287] The title compound was prepared analogously to example 35, step7, where
S-(3-
hydroxy-2-(pyridin-4-yl)propyl) ethanethioate was replaced with S-(3-((tert-
butyldiphenylsily0oxy)-2-(pyridin-3-yppropyl) ethanethioate. The title
compound was
isolated in 97% yield as a brown solid. MS (ESI) m/z: 866.3 [M+H]+.
Step 6: tert-butyl (2S,6R)-4-(7-chloro-8-03-hydroxy-2-(pyridin-3-
yppropyl)thio)-2-oxo-6-
(trifluoromethyl)-1,2-dihydroquinazolin-4-v1)-2,6-dimethylpiperazine-1-
carboxylate
Boc
Me N Me
F3C 1,6N
CI N 0
HON
[0288] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilypthiophen-2-y1)-6-oxo-3-
(pyrimidin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ijlquinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-(8-03-
((tert-
butyldiphenylsily0oxy)-2-(pyridin-3-yppropyl)thio)-7-chloro-2-oxo-6-
(trifluoromethyl)-1,2-
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dihydroquinazolin-4-y1)-2,6-dimethylpiperazine-1-carboxylate. The title
compound was
isolated in 80% yield as a brown solid. MS (ESI) m/z: 628.2 [M+1-11+,
Step 7: tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-3-y1)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H41,4]thiazepino[2,3.4-ij]quinazolin-8-y1)-2.6-dimethylpiperazine-
1-
carboxylate (int-3a) and tert-butyl (2S,6R)-44R)-11-chloro-6-oxo-3-(pyridin-3-
y1)-10-
(trifluoromethyl)-3,4-dihydro-2H.6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate (int-3b)
Boc Boc
MeNxMe
MeNXMe
F3C F3
CI N 0 CI N 0
S\ (s)) s\
int-3a CN int-3b \ N
¨/ ¨/
[0289] The title compounds were isolated as a 1:1 mixture of diastereomers
analogously to
Example 29, step 5, where (S)-7-chloro-8-((3-hydroxy-2-(pyrazin-2-
yloxy)propyl)thio)-6-
(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was replaced with tert-butyl
(2S,6R)-4-(7-
chloro-8-43-hydroxy-2-(pyridin-3-yepropyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-
dihydroquinazolin-4-y1)-2,6-dimethylpiperazine-1-carboxylate. Int-3a and Int-
3b were
obtained as single diastereomers by purification of the aforementioned mixture
by semi-
preparative reverse phase-HPLC (column: Daicel Chiralcel OD 250 mm x 30 mm,10
um);
mobile phase B= methanol; gradient= 50% for 6.4 minutes runtime) and
characterized by
SFC (Column= Chiracel OD-3, 50x4.6 mm, I.D.= 3 um stabilized at 35 C with a
back
pressure of 100 bar. Mobile phase B= methanol containing 0.05% diethylamine;
gradient=
40%, flow rate= 3 mL/min. Detector: Photodiode-array). Int-3a: SFC Rt= 1.94
min; MS (ESI)
m/z: 610.1 [M+H]+. Int-3b: SFC Rt= 2.42 min; MS (ESI) m/z: 610.1 [M+1-11+,
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Step 8: tert-butyl (25,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-
y1)-6-oxo-3-
(pyridin-3-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H41,41thiazepino[2,3,4-
ijlquinazolin-8-
y1)-2,6-dimethylpiperazine-1-carboxylate
Boc
Me N Me
F3C
CI N
S\ (S)
TIPS
¨/
[0290] The title compound was prepared analogously to Example 23, step 1,
where tert-
butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
l-
carboxylate was replaced with tert-butyl (25,6R)-4-((S)-11-chloro-6-oxo-3-
(pyridin-3-y1)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate. The title compound was isolated in 72% yield
as a yellow
oil. MS (ESI) m/z: 848.2 [M+H]+.
Step 9: tert-butyl (25,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyridin-
3-y1)-10-
(trifluoromethyl)-3,4-dihydro-2H.6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate
Boc
F3C
N
CI O
S S )
(s)/
CN
[0291] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-
(pyrimidin-2-
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yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ijlquinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-
11-(4-chloro-
5-(triisopropylsilypthiophen-2-y1)-6-oxo-3-(pyridin-3-y1)-10-(trifluoromethyl)-
3,4-dihydro-
2H,6H41,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate. The
title compound was isolated in 92% yield as a white semisolid. MS (ESI) m/z:
692.2
[M+H]+.
Step 10: (S)-11-(4-chlorothiophen-2-y1)-8-((35,5R)-3,5-dimethylpiperazin-1-y1)-
3-(pyridin-3-
y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1.4]thiazepino[2,3,4-ij]quinazolin-
6-one
Me N Me
F3C
%
CI N"
\ S S\21)
¨/
[0292] The title compound was prepared analogously to Example 23, step 3 where
tert-
butyl (25,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-
11-(4-
chlorothiophen-2-y1)-6-oxo-3-(pyridin-3-y1)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate. The title
compound was isolated in 94% yield as a yellow solid. MS (ESI) m/z: 592.3
[M+H]+.
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Step 11: (S)-8-((3 S,5R)-4-acrvloy1-3,5-dimethylpiperazin-1-y1)-11-(4-
chlorothiophen-2-y1)-
3-(pyri din-3 -y1)-1O-(tri fluoromethyl)-3,4-dihv dro-2H,6H- [1,41thiazepino
[2,3,4-ij I quinazolin-
6-one
Me.,(N)õMe
F3C
1\11
CI ,
S S\ (S)
Ci\N
[0293] The title compound was prepared analogously to Example 23, step 4 where
(S)-11-
(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-(pyrimidin-2-
yloxy)-10-
(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-6-one
was replaced
with (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-
(pyridin-3-y1)-
10-(trifluoromethyl)-3,4-dihydro-2H,6H41,41thiazepino[2,3,4-ijlquinazolin-6-
one. The title
compound was isolated in 41% yield as a white solid. MS (ESI) m/z: 646.1
[M+H]+. 1H
NMR (400 MHz, DMSO-d6) 6 8.58 (s, 1H), 8.48 (d, J = 4.4 Hz, 1H), 8.06 (s, 1H),
7.88 (s,
1H), 7.84 - 7.68 (m, 1H), 7.37 (s, 1H), 7.33 - 6.98 (m, 1H), 6.82 (dd, J =
10.4, 16.4 Hz, 1H),
6.20 (dd. J = 2.4, 16.4 Hz, 1H), 5.78 - 5.71 (m, 1H), 4.86 - 4.47 (m, 4H),
4.08 (d, J = 13.2 Hz,
2H), 3.97 - 3.68 (m, 1H), 3.67 - 3.35 (m, 2H), 3.29 - 3.22 (m, 2H), 1.40 (s,
6H).
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Example 45 and Example 46: (S)-84(3S,5R)-4-aeryloy1-3,5-dimethylpiperazin-l-
y1)-11-
(4-ehlorothiophen-2-y1)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
11,41thiazepino12,3,4-ijlquinazolin-6-one and (R)-8-((3S,5R)-4-acryloy1-3,5-
dimethylpiperazin-l-y1)-11-(4-chlorothiophen-2-v1)-3-(pyrimidin-2-0)-10-
(trifluoromethyl)-3,4-dihydro-2H,6H-11,41thiazepino[2,3,4-illquinazolin-6-one
o
Me N Me Me N Me
F3C F3C
N
CI
0 CI
S S (s) S S\ (R)0
N
example 45 N example 46 N'
\_ \_/
Step 1: dimethyl 2-(pyrimidin-2-yl)malonate
0 0
Me0 yOMe
N N
[0294] A mixture of 2-chloropyrimidine (87.0 mmol), 1,3-diethyl propanedioate
(175
mmol), copper(I) iodide (17 mmol), cesium carbonate (262 mmol) and picolinic
acid (35
mmol) in dioxane (300 mL) was stirred at 100 C for 16 hours. The reaction
mixture was
diluted with water, extracted with ethyl acetate three times and the combined
organic layers
were dried over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure
to afford a residue that was purified by silica gel chromatography (0-30%
ethyl acetate in
hexanes). The title compound was isolated in 25% yield as yellow solid. Mass
Spectrum
(ESI) m/z = 211.0 (M+H)+.
Step 2: 2-(pyrimidin-2-yl)propane-1,3-diol
HOOH
N
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[0295] A 1M solution of DIBALH in THF (380 mL) was added to a -40 C solution
of 1,3-
dimethyl 2-(pyrimidin-2-yl)propanedioate (95.2 mmol) in THF (200 mL). After 1
hour, the
reaction was quenched with sodium sulfate decahydrate, diluted with water and
extracted
with ethyl acetate three times. The combined organic layers were dried over
anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to afford the
title compound
as yellow oil. MS (ESI) m/z = 155.1 (M+H)+.
Step 3: 3-((tert-butyldiphenylsily0oxy)-2-(pyrimidin-2-yl)propan-1-ol
TBDPSOOH
N
[0296] The title compound was prepared analogously to Example 31, step 2,
where (S)-3-
(tritylthio)propane-1,2-diol was replaced with 2-(pyrimidin-2-yl)propane-1,3-
diol. The title
compound was isolated in 55% yield as a yellow solid. MS (ESI) m/z = 393.0
(M+H) +.
Step 4: S-(3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-y1)propyl)
ethanethioate
TBDPSOSAc
N
[0297] The title compound was prepared analogously to Example 43, step 4 where
3-((tert-
butyldiphenylsily0oxy)-2-(pyridin-3-yl)propan-1-ol was replaced with 3-((tert-
butyldiphenylsily0oxy)-2-(pyrimidin-2-yl)propan-1-ol. The title compound was
isolated in
99% yield as a yellow oil. MS (ESI) m/z = 451.2 (M+H)+.
Step 5: 3-((tert-butyldiphenylsily0oxy)-2-(pyrimidin-2-yl)propane-1-thiol
TBDPSOSH
N
[0298] A solution of S-(3-((tert-butyldiphenylsilypoxy)-2-(pyrimidin-2-
y0propyl)
ethanethioate (48.8 mmol) in hydrazine monohydrate (60 mL), THF (90 mL) and
methanol
(90 mL) was stirred at room temperature for 1 hour. The mixture was diluted
with water and
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most volatiles were removed under reduced pressure. The resulting aqueous
solution was
extracted with ethyl acetate and concentrated to afford a residue that was
purified by silica
gel chromatography (0-15% ethyl acetate in hexanes). The title compound was
isolated in
67% yield as a colorless oil. MS (ESI) m/z = 409.2 [M+H]+.
Step 6: 8-43-((tert-butyldiphenylsily0oxy)-2-(pyrimidin-2-y1)propyl)thio)-7-
chloro-6-
(trifluoromethyl)quinazoline-2,4(1H,3H)-dione
0
F3C
NH
CI N 0
s\_cOTBDPS
N\
[0299] The title compound was prepared analogously to Example 29, step 3 where
(S)-3-
((tert-butyldiphenylsilyl)oxy)-2-(pyrazin-2-yloxy)propane-1-thiol was replaced
with 3-((tert-
butyldiphenylsilypoxy)-2-(pyrimidin-2-yl)propane-1-thiol. The title compound
was isolated
in 86% yield as a white solid. MS (ESI) m/z = 671.0 [M+H]+.
Step 7: 7-chloro-8-((3-hydroxy-2-(pyrimidin-2-yl)propyl)thio)-6-
(trifluoromethyl)quinazoline-2,4(1H,3H)-dione
0
F3C
NH
CI N 0
s\ ______ C-OH
)-N
N\
[0300] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-
(pyrimidin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-
ijlquinazolin-8-0-2,6-
dimethylpiperazine-1-carboxylate was replaced with 8-((3-((tert-
butyldiphenylsilypoxy)-2-
(pyrimidin-2-yl)propypthio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-
dione. The
title compound was isolated in 92% yield as a white solid. MS (ESI) m/z: 433.0
[M+H]+.
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Step 8: 11-chloro-3-(pyrimidin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
11,41thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione
0
F3C
NH
CI N 0
N\_)
[0301] The title compound was prepared analogously to Example 29, step 5 where
(S)-7-
chloro-8-((3-hydroxy-2-(pyrazin-2-yloxy)propyl)thio)-6-
(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione was replaced with 7-chloro-8-((3-hydroxy-2-(pyrimidin-2-
yl)propyl)thio)-
6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione. The title compound was
isolated in 55%
yield as a yellow solid. MS (ESI) m/z: 415.0 [M+H]+.
Step 9: tert-butyl (2S,6R)-4-(11-chloro-6-oxo-3-(pyrimidin-2-y1)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-[1,4]thiazepino[2,3.4-ij]quinazolin-8-y1)-2.6-dimethylpiperazine-
1-
carboxylate
Boc
F3C N
CI N 0
N \_)
[0302] The title compound was prepared analogously to Example 29, step 6 where
(S)-11-
chloro-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
]1,4]thiazepino[2,3,4-
ij]quinazoline-6,8(7H)-dione was replaced with 11-chloro-3-(pyrimidin-2-y1)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,4]thiazepino[2,3,44j]quinazoline-
6,8(7H)-dione. The
title compound was isolated in 61% yield as a yellow solid, MS (ESI) m/z:
611.2 [M+1-11+,
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Step 10: tert-butyl (25,6R)-4-(11-(4-chloro-5-(triisopropvlsilyl)thiophen-2-
y1)-6-oxo-3-
(pyrimidin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1.4]thiazepino[2,3,4-
ij]quinazolin-
8-y1)-2,6-dimethylpiperazine-1-carboxylate
Boc
Me N Me
F3C
N 0
CI
S S
TIPS
N"
\-
103031 The title compound was prepared analogously to Example 23, step 1,
where tert-
butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
l-
carboxylate was replaced with tert-butyl (2S,6R)-4-(11-chloro-6-oxo-3-
(pyrimidin-2-y1)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate. The title compound was isolated in 45% yield
as a brown
solid. MS (ESI) m/z: 849.2 [M+H]+.
Step 11: 11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-8-((3S,5R)-3.5-
dimethylpiperazin-1-
y1)-3-(pyrimidin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1,41thiazepino[2,3,4-
ij]quinazolin-6-one
Me N Me
F3C
NO
CI \
S S
TIPS
N
\-
103041 The title compound was prepared analogously to Example 23, step 3 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyrimidin-2-yloxy)-10-
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(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-
y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (25,6R)-4-(11-(4-
chloro-5-
(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-(pyrimidin-2-y1)-10-
(trifluoromethyl)-3,4-dihydro-
2H,6H41,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate. The
title compound was isolated in 95% yield as a yellow oil. MS (ESI) m/z: 749.2
[M+H]+.
Step 12: 11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-
(pyrimidin-2-
y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1.4]thiazepino[2,3,4-ij ]
quinazolin-6-one
Me N Me
F3C
N
CI ,
S S
N'\_)
[0305] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (25,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilypthiophen-2-y1)-6-oxo-3-
(pyrimidin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ijlquinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with 11-(4-chloro-5-
(triisopropylsilyl)thiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-
(pyrimidin-2-y1)-
10-(trifluoromethyl)-3,4-dihydro-2H,6H41,41thiazepino[2,3,4-ijlquinazolin-6-
one. The title
compound was isolated in 95% yield as a yellow solid. MS (ESI) m/z: 593.1
[M+H]+.
Step 13: (S)-8-((3 S,5R)-4 -acryl oy1-3,5 -dimethylpiperazin-1 -y1)-11 -(4-chl
orothi ophen-2 -y1)-
3-(pyrimi din-2-y1)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H41,4]thiazepino[2,3,4-
ij ] quinazolin-6-one and (R)-8-((3S,5R)-4-acryloy1-3,5-dimethylpiperazin-1-
y1)-11-(4-
chlorothiophen-2-y1)-3-(pyrimidin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
11,41thiazepino[2,3,4-ijlquinazolin-6-one
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oY
Me N Me Me N Me
F3C F3C
ci N C I N
S S (S) S S\ (R)
2N
example 45 N example 46 N'
\¨ \¨/
[0306] The title compounds were prepared analogously to Example 23, step 4
where (S)-
11-(4-ch1orothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-(pyrimidin-
2-yloxy)-
10-(trifluoromethyl)-3,4-dihydro-2H,6H41,41thiazepino[2,3,4-ij]quinazolin-6-
one was
replaced with 11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-
y1)-3-
(pyrimidin-2-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-
ij]quinazolin-
6-one. The title compounds were isolated in 34% yield as a 1:1 mixture of
diastereomers.
Example 45 and Example 46 were obtained as single diastereomers by
purification of the
mixture by SFC (column= Daicel Chiralpak AS 250mmx30mm,10um; phase A: 60%
ethanol
in acetonitrile, phase B: CO2; gradient: 60% A in B for 3 minutes runtime) and
characterized
by SFC (Column: Chirappak AS-3, 50x4.6 mm, I.D. 3 um, stabilized at 35 C with
a back
pressure of 100 bar. Mobile phase B: methanol containing 0.05% diethylamine;
gradient= 5-
40% B in A, flow rate= 3 mL/min. Detector: Photodiode-array).
[0307] Example 45: SFC Rt= 1.95 min; MS (ESI) m/z: 647.1 [M+H]+.1H NMR (400
MHz, CDC13) 6 8.72 (s, 2H), 8.09 (s, 1H), 7.32 (m, 1H), 7.20 (m, 1H), 6.93 (m,
1H), 6.65 (m,
1H), 6.43 (m, 1H), 5.81 (m, 1H), 5.32 ¨ 4.43 (m, 4H), 4.25 ¨3.65 (m, 4H), 3.50
¨3.10 (m,
3H), 1.47 - 1.45 (m, 6H).
[0308] Example 46: SFC Rt= 2.36 min; MS (ESI) m/z: 647.1 [M+H]+. 1H NMR (400
MHz, CDC13) 6 8.73 (s, 2H), 8.10 (s, 1H), 7.32 (m, 1H), 7.24 (m, IH), 6.92 (m,
1H), 6.66 (m,
1H), 6.45 (m, 1H), 5.82 (m, 1H), 5.34 ¨ 4.45 (m, 4H), 4.26 ¨ 3.66 (m, 4H),
3.52 ¨ 3.12 (m,
3H), 1.50 - 1.47 (m, 6H).
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Example 49: (S)-843S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
chlorothiophen-2-y1)-3-(5-fluoropyridin-3-y1)-10-(trifluoromethyl)-3,4-dihydro-
2H,6H-
11,41thiazepino12,3,4-ijlquinazolin-6-one
Me N Me
F3C
N
CI o \
S S\ (S)
cN
Step 1: tert-butyl (25,6R)-4-((R)-11-chloro-3-(5-fluoropyridin-3-y1)-6-oxo-10-
(trifluoromethyl)-3,4-dihydro-2H.6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate (int-4a) and tert-butyl (25,6R)-4-((S)-11-
chloro-3-(5-
fluoropyridin-3-y1)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-
2H,6H41,4]thiazepino[2,3,4-
ijiquinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (int-4b)
Boc Boc
Me N Me Me N Me
F3C (00 F3C 401N
CI NO CI N 0
S (R) s\ (S)
int-4a / \ N int-4b çN
[0309] The title compounds were prepared analogously to Example 43, steps 1-7,
where
pyridin-3-ylboronic acid was replaced with (5-fluoropyridin-3-yl)boronic acid
in step 1. The
title compounds were isolated as a 1:1 mixture of diastereomers. Int-4a and
Int-4b were
obtained as single diastereomers by purification of the mixture by SFC
(column= Daicel
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Chiralpak IC 250mmx30mm, 10um; phase A: ethanol, phase B: CO2; gradient: 65% A
in B
for 7.45 minutes runtime) and characterized by SFC (Column: Chiralpak IC-3,
50x4.6 mm,
I.D.= 3 urn, stabilized at 35 C with a back pressure of 100 bar. Mobile
phase: 60% ethanol
containing 0.05% diethylamine in CO2, flow rate= 3 mL/min. Detector:
Photodiode-array).
Int-4a: SFC Rt= 1.58 min; MS (ESI) m/z: 628.2 [M+H]+. Int-4b: SFC Rt= 2.87
min; MS
(ESI) m/z: 628.2 [M+H]+.
Step 2: tert-butyl (25,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-
y1)-3-(5-
fluoropyridin-3-y1)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-
2H,6H41,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
Boc
Me N Me
F3C
N
CI ,
S S\ (S)
TIPS
cN
[0310] The title compound was prepared analogously to Example 23, step 1,
where tert-
butyl (25,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
1-
carboxylate was replaced with tert-butyl (25,6R)-4-((S)-11-chloro-3-(5-
fluoropyridin-3-y1)-6-
oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H41,4]thiazepino[2,3,4-ij]quinazolin-
8-y1)-2,6-
dimethylpiperazine-1-carboxylate. The title compound was isolated in 72% yield
as a yellow
oil. MS (ESI) m/z: 866.1 [M+H]+.
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Step 3: tert-butyl (25,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-3-(5-
fluoropyridin-3-y1)-6-oxo-
10-(trifluoromethyl)-3,4-dihy dro-2H,6H-[1,41thi azepino [2.3,4-ij]quinazolin-
8-y1)-2,6-
dimethylpiperazine-l-carboxylate
Boc
Me.,..(N)õMe
F3C
N /0
CI
S S\22)
[0311] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilypthiophen-2-y1)-6-oxo-3-
(pyrimidin-2-
yloxy)-10-(trifluoromethy1)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ijlquinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-
11-(4-chloro-
5-(triisopropylsilypthiophen-2-y1)-3-(5-fluoropyridin-3-y1)-6-oxo-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H41,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
1-
carboxylate. The title compound was isolated in 73% yield as a colorless oil.
MS (ESI) m/z:
710.0 [M+H]+.
Step 4: (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-
3-(5-
fluoropyridin-3-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1,4]thiazepino[2,3,4-
ij]quinazolin-6-one
Me N Me
F3C
N "0
CI ) ,
S S
\ (Sy
¨/
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[0312] The title compound was prepared analogously to Example 23, step 3 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-
11-(4-
chlorothiophen-2-y1)-3-(5-fluoropyridin-3-y1)-6-oxo-10-(trifluoromethyl)-3,4-
dihydro-
2H,6H41,4]thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate. The
title compound was isolated in 97% yield as a yellow oil. MS (ESI) m/z: 609.9
[M+H]+.
Step 5: (S)-8-((35,5R)-4-acrylov1-3,5-dimethylpiperazin-1-y1)-11-(4-
chlorothiophen-2-y1)-3-
(5-fluoropyridin-3-y1)-10-(trifluoromethyl)-3.4-dihydro-
2H,6H41,4]thiazepino[2,3,4-
1j]quinazolin-6-one
MeNyMe
F3C
CI N
\
\ S S\21)
¨/
[0313] The title compound was prepared analogously to Example 23, step 4 where
(S)-11-
(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-(pyrimidin-2-
yloxy)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-
one was replaced
with (S)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-
(5-
fluoropyridin-3-y1)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1,4]thiazepino[2,3,4-
ijlquinazolin-6-one. The title compound was isolated in 69% yield as a white
solid. MS (ESI)
m/z: 664.0 [M+H]+. 1H NMR (400 MHz, CDC13) 6 8.50 (s, 1H), 8.44 (d, J = 2.4
Hz, 1H),
8.12 (s, 1H), 7.54 - 7.45 (m, 1H), 7.43 - 7.31 (m, 1H), 7.08 - 6.85 (m, 1H),
6.69 - 6.59 (m,
1H), 6.43 (dd, J = 2.0, 16.8 Hz, 1H), 5.83 - 5.76 (m, 1H), 4.96 - 4.52 (m,
4H), 4.22 -4.15 (m,
2H), 3.97 - 3.62 (m, 2H), 3.46 -3.36 (m, 2H), 3.19 - 3.00 (m, 1H), 1.58 - 1.49
(m, 6H).
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Example 53: (S)-843S,5R)-4-acryloy1-3,5-dimethylpiperazin-l-y1)-11-(4-
chlorothiophen-2-y1)-3-(4-fluorothiophen-2-y1)-10-(trifluoromethyl)-3,4-
dihydro-2H,6H-
11,41thiazepino12,3,4-ij] quinazolin-6-one
Me4
õõ(N)0Me
F3C N
NL0
CI \
S S\ (s)
SF
Step 1: methyl 3-fluoro-5-iodothiophene-2-carboxylate
0
[0314] A 1M solution of chloro-(2,2,6,6-tetramethy1-1-piperidyl)magnesium-
lithium
chloride complex (18.7 mL) was added dropwise to a -40 C solution of methyl 3-
fluorothiophene-2-carboxylate (19 mmol) in THF (30 mL). After 30 minutes, the
mixture was
cooled down to -70 C and iodine (19.7 mmol) in THF (10 mL) was added. The
reaction was
stirred at room temperature for one hour and quenched with water. The mixture
was extracted
with ethyl acetate twice, the combined organic layers were washed with brine,
dried over
anhydrous sodium sulfate, filtered and concentrated under reduced pressure to
afford a
residue that was purified by silica gel chromatography (4% ethyl acetate in
hexanes). The
title compound was isolated in 75% yield as a white solid.
Step 2: 3-fluoro-5-iodothiophene-2-carboxylic acid
0
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[0315] Sodium hydroxide (42 mmol) was added to a solution of methyl 3-fluoro-5-
iodothiophene-2-carboxylate (14.0 mmol) in THF (10 mL) and the mixture was
stirred at
room temperature for four hours. Most volatiles were removed under reduced
pressure and
the resulting aqueous solution was treated with a 1M aqueous solution of HC1
(10 mL) to
induce the precipitation of the title compound which was filtered and dried.
The title
compound was isolated in 79% yield as a white solid.
Step 3: 4-fluoro-2-iodothiophene
I
[0316] A solution of 3-fluoro-5-iodothiophene-2-carboxylic acid (11.0 mmol) in
(methylsulfinyl)methane (30 mL) was treated with silver carbonate (1.10 mmol)
and acetic
acid (13.2 mmol) and the mixture was heated at 120 C for 3 hours. The mixture
was cooled
down to room temperature and diluted with water, extracted with ethyl acetate
three times
and the combined organic layers were dried over anhydrous sodium sulfate,
filtered and
concentrated under reduced pressure to afford the title compound in 99% yield
as yellow oil.
1H NMR (400 MHz, CDC13) 6 ppm 6.72 - 6.74 (m, 1 H) 6.99 - 7.00 (m, 1 H).
Step 4: tert-butyldimethyl((2-(4,4,5.5-tetramethy1-1,3,2-dioxaborolan-2-
yl)allypoxy)silane
0
0 OTBS
[0317] To a solution of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (52.8
mmol), N,N'-
bis(2-benzothiazoly1)-2,6-pyridinedicarboxamide (58.1 mmol) , Copper chloride
(5.28 mmol)
and sodium tert-butoxide (7.93 mmol) in toluene (90 mL) was added tri-tert-
butylphosphane
(5.28 mmol) under nitrogen. Methanol (4.28 mL) was added and the mixture
stirred at room
temperature for 12 hours. The volatiles were removed under reduced pressure
and the
resulting residue was purified by silica gel chromatography (0-5% ethyl
acetate in hexanes)
to afford the title compound as a colorless oil in 76% yield. 1H NMR (400 MHz,
CDC13) 6
ppm 0.93 (s, 9 H) 1.27 (s, 12 H) 4.29 ¨ 4.30 (m, 2 H) 5.87 ¨ 5.89 (m, 1 H)
5.97 (s, 1 H).
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Step 5: tert-butyl((2-(4-fluorothiophen-2-yOallypoxy)dimethylsilane
OTBS
[0318] To a solution of 4-fluoro-2-iodothiophene (11.0 mmol) and tert-
butyldimethyl((2-
(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)allypoxy)silane (12.1 mmol) in
dioxane (10
mL) and water (5 mL) was added potassium phosphate (32.9 mmol) and )(Phos Pd
G3 (0.22
mmol). The suspension was stirred at 60 C for 2 hours and the volatiles were
removed under
reduced pressure to afford a residue that was purified by silica gel
chromatography (4% ethyl
acetate in hexanes). The title compound was isolated in 54% yield as a yellow
oil.
Step 6: 3-((tert-butyldimethylsily0oxv)-2-(4-fluorothiophen-2-y0propan-1-ol
HOWOTBS
[0319] The title compound was prepared analogously to Example 43, step 2 where
2-
(pyridin-3-yl)prop-2-en-1-ol was replaced with tert-butyl((2-(4-fluorothiophen-
2-
yOallypoxy)dimethylsilane. The title compound was isolated in 35% yield as a
yellow oil. 1H
NMR (400 MHz, CDC13) 6 ppm 0.08 (s, 6 H) 0.91 (s, 9 H) 2.30 - 2.52 (m, 1 H)
3.20 (t, J=5.6
Hz, 1 H) 3.85 -3.97 (m, 4 H) 6.55 (s, 1 H) 6.69(s, 1 H).
Step 7: S-(3-((tert-butyldimethylsilyl)oxy)-2-(4-fluorothiophen-2-y1)propyl)
ethanethioate
TBSOSAc
[0320] The title compound was prepared analogously to Example 43, step 4 where
3-((tert-
butyldiphenylsily0oxy)-2-(pyridin-3-yl)propan-1-ol was replaced with 3-((tert-
butyldimethylsily0oxy)-2-(4-fluorothiophen-2-y0propan-1-ol. The title compound
was
isolated in 97% yield as a yellow oil. 111 NMR (400 MHz, methanol-d4) 6 ppm
0.05 (s, 6 H)
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0.91 (s, 9 H) 2.33 (s, 3 H) 3.12 - 3.15 (m, 2 H) 3.31 - 3.35 (m, 1 H) 3.73 -
3.77 (m, 1 H) 3.84
¨ 3.86 (m, 1 H) 6.53 ¨ 6.54 (m, 1 H) 6.67 ¨ 6.68 (m, 1 H).
Step 8: tert-butyl (25,6R)-4-(843-((tert-butyldimethylsilyl)oxy)-2-(4-
fluorothiophen-2-
yl)propyl)thio)-7-chloro-2-oxo-6-(trifluoromethyl)-1.2-dihydroquinazolin-4-y1)-
2,6-
dimethylpiperazine-1-carboxylate
Boc
Me N Me
CI NO
F
TBSO S
[0321] The title compound was prepared analogously to Example 35, step 7 where
S-(3-
Hydroxy-2-(pyridin-4-yl)propyl) ethanethioate was replaced with S-(3-((tert-
butyldimethylsily0oxy)-2-(4-fluorothiophen-2-y0propyl) ethanethioate. The
title compound
was isolated in 76% yield as a yellow solid. MS (ESI) m/z: 765.1 [M+H]+.
Step 9: tert-butyl (25,6R)-4-(7-chloro-8-((2-(4-fluorothiophen-2-y1)-3-
hydroxypropyl)thio)-2-
oxo-6-(trifluoromethyl)-1.2-dihydroquinazolin-4-y1)-2,6-dimethylpiperazine-1-
carboxylate
Boc
MeN),,Me
F3C
CI N 0
F
OH S
[0322] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (25,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-
(pyrimidin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ijlquinazolin-8-y1)-2,6-
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dimethylpiperazine-l-carboxylate was replaced with tert-butyl (2S,6R)-4-(8-03-
((tert-
butyldimethylsily0oxy)-2-(4-fluorothiophen-2-y0propyl)thio)-7-chloro-2-oxo-6-
(trifluoromethyl)-1,2-dihydroquinazolin-4-y1)-2,6-dimethylpiperazine-1-
carboxylate. The
title compound was isolated in 47% yield as a yellow oil. MS (ESI) m/z: 651.1
[M+H]+
Step 10: tert-butyl (25,6R)-44(S)-11-chloro-3-(4-fluorothiophen-2-y1)-6-oxo-10-
(trifluoromethyl)-3,4-dihydro-2H.6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate (it-5a) and tert-butyl (25,6R)-4-((R)-11-
chloro-3-(4-
fluorothiophen-2-y1)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-
2H,6H41,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate (int-5b)
Boc Boc
Me.,..(N)Me Meikk(N)Me
F3CN F3CN
CI N CI N
S ) S (R)
int-5a int-5b s
[0323] The title compounds were prepared analogously to Example 29, step 5
where (S)-7-
chloro-8-((3-hydroxy-2-(pyrazin-2-yloxy)propyl)thio)-6-
(trifluoromethyl)quinazoline-
2,4(1H,3H)-dione was replaced with tert-butyl (25,6R)-4-(7-chloro-842-(4-
fluorothiophen-
2-y1)-3-hydroxypropyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-
y1)-2,6-
dimethylpiperazine-l-carboxylate. The title compounds were isolated as a 1:1
mixture of
diastereomers. Int-5a and Int-5b were obtained as single diastereomers by
purification of the
aforementioned mixture by SFC (column: Daicel Chiralpak IC (250mm*30mm,10um);
phase
A: 55% methanol in acetonitrile, phase B:CO2) and characterized by SFC
(Column: Chirapak
IC-3, 50x4.6 mm, I.D.= 3 urn, stabilized at 35 C with a back pressure of 100
bar. Mobile
phase A: CO2 and mobile phase B: 40% methanol in acetonitrile containing 0.05%
diethylamine, flow rate= 3 mL/min. Detector: Photodiode-array).
[0324] Int-5a: SFC Rt= 1.18 mm; MS (EST) m/z: 633.2 [M+H]+. 1H NMR (400 MHz,
CDC13) 6 ppm 1.51 (s, 9 H) 1.37- 1.50 (m, 6H) 3.18 -3.36 (m, 3 H) 3.68- 3.83
(m, 1 H)
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3.98 -4.18 (m, 3 H) 4.31 - 4.45 (m, 2 H) 4.53 -4.72 (m, 1 H) 4.83 (dd, J=13.2,
4.4 Hz, 1 H)
6.64 (s, 1 H) 6.89 (s, 1 H) 8.04 (s, 1 H).
[0325] Int-5b: SFC Rt= 2.23 mm; MS (ESI) m/z: 633.2 [M+H]+. 1H NMR (400 MHz,
CDC13) 6 ppm 1.51 (s, 9 H) 1.55 (s, 6 H) 3.16 - 3.34 (m, 3 H) 3.68 -3.80 (m, 1
H) 3.97 - 4.17
(m, 3 H) 4.31 - 4.44 (m, 2 H) 4.53 -4.71 (m, 1 H) 4.83 (dd, J=13.6, 4.8 Hz, 1
H) 6.65 (s, 1 H)
6.89 (s, 1 H) 8.04 (s, 1 H).
Step 11: tert-butyl (25,6R)-44(S)-11-(4-chloro-5-(triisopropylsily1)thiophen-2-
y1)-3-(4-
fluorothiophen-2-y1)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-
2H,6H41,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-carboxylate
Boc
F3C
N
CI ,
S S\ (s)
TIPS
[0326] The title compound was prepared analogously to Example 23, step 1,
where ten-
butyl (25,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
1-
carboxylate was replaced with tert-butyl (25,6R)-4-((S)-11-chloro-3-(4-
fluorothiophen-2-y1)-
6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H41,4]thiazepino[2,3,4-
ij]quinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate. The title compound was isolated in 94% yield
as a white
solid. MS (ESI) m/z: 871.1 [M+H]+.
Step 12: tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-3-(4-
fluorothiophen-2-y1)-6-
oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H41,4]thiazepino[2,3,4-ij]quinazolin-
8-y1)-2,6-
dimethylpiperazine-1-carboxylate
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Boc
Meiµ.(N)Me
F3C
N 0
CI
SF
[0327] The title compound was prepared analogously to Example 23, step 2 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-y1)-6-oxo-3-
(pyrimidin-2-
yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-
ijlquinazolin-8-y1)-2,6-
dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-
11-(4-chloro-
5-(triisopropylsilypthiophen-2-y1)-3-(4-fluorothiophen-2-y1)-6-oxo-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H41,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-
1-
carboxylate. The title compound was isolated in 61% yield as a white solid. MS
(ESI) m/z:
715.0 [M+H]+.
Step 13: (5)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-
3-(4-
fluorothiophen-2-y1)-10-(trifluoromethyl)-3.4-dihy dro-2H,6H-[1,4]thiazepino
[2,3,4-
ij]quinazolin-6-one
Me N Me
F3C
ci
S S )
(s)/
SF
[0328] The title compound was prepared analogously to Example 23, step 3 where
tert-
butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-y1)-6-oxo-3-(pyrimidin-2-yloxy)-10-
(trifluoromethy1)-3,4-dihydro-2H,6H-[1,41thiazepino[2,3,4-ij]quinazolin-8-y1)-
2,6-
dimethylpiperazine-1-carboxylate was replaced with: tert-butyl (2S,6R)-4-((S)-
11-(4-
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chlorothiophen-2-y1)-3-(4-fluorothiophen-2-y1)-6-oxo-10-(trifluoromethyl)-3,4-
dihydro-
2H,6H41,41thiazepino[2,3,4-ij]quinazolin-8-y1)-2,6-dimethylpiperazine-1-
carboxylate. The
title compound was isolated in 87% yield as a yellow solid. MS (ESI) m/z:
615.0 [M+H]+.
Step 14: (S)-8-((3S,5R)-4-acrvloy1-3,5-dimethylpiperazin-1-y1)-11-(4-
chlorothiophen-2-y1)-
3-(4-fluorothiophen-2-y1)-10-(trifluoromethyl)-3,4-dihvdro-2H,6H-
[1,41thiazepino[2,3,4-
1j]quinazolin-6-one
Meih.(NMe
F3C
NO
CI
S S\ (S)
[0329] The title compound was prepared analogously to Example 23, step 4 where
(S)-11-
(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-1-y1)-3-(pyrimidin-2-
yloxy)-10-
(trifluoromethyl)-3,4-dihydro-21-1,6H-[1,41thiazepino[2,3,4-ij]quinazolin-6-
one was replaced
with (5)-11-(4-chlorothiophen-2-y1)-8-((3S,5R)-3,5-dimethylpiperazin-l-y1)-3-
(4-
fluorothiophen-2-y1)-10-(trifluoromethyl)-3,4-dihydro-
211,61141,41thiazepino[2,3,4-
ijlquinazolin-6-one. The title compound was isolated in 42% yield as a white
solid. MS (ESI)
m/z: 669.0 [M+H]+. 1H NMR (400 MHz, CDC13) 6 ppm 1.51 - 1.61 (m, 6 H) 2.99 -
3.21 (m,
1 H) 3.29 - 3.46 (m, 2 H) 3.55 - 3.74 (m, 1 H) 3.86 - 4.05 (m, 1 H) 4.17 (t,
J=11.2 Hz, 2 H)
4.43 - 5.00 (m, 4 H) 5.76 - 5.83 (m, 1 H) 6.43 (dd, J=16.8, 2.0 Hz, 1 H) 6.54 -
6.73 (m, 2 H)
6.82 (s, 1 H) 6.86 - 7.10 (m, 1 H) 7.37 (s, 1 H) 8.09 (s, 1 H).
[0330] Compounds of the application that are synthesized according to any one
of the
above procedures include:
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Table 1
Ex. Structure IUPAC
El (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
M e N Me
11-(4-chlorothiophen-2-y1)-
3-methoxy-10-
N
(trifluoromethyl)-3,4-
F3C
N dihy dro-2H,6H-
NLo [1,4] thiazepino [2,3,4-
\ I s ij quinazolin-6-one
\ /
CI
bMe
E2 (S)-7-(4-acryloyl pip erazin-
1-y1)-10-(4-chl orothi ophen-
2-y1)-3 -(methoxymethyl)-9-
(trifluoromethyl)-2,3-
dihydro-5H-
F3C N [1,4] thi azino [2,3,4-
S
No ijlquinazolin-5 -one
\ I S
CI
OMe
E3 (S)-7-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Njo.
3-(methoxymethyl)-10-(5 -
methylthi ophen-2-y1)-9-
(trifluoromethyl)-2,3-
F3C
dihy dro-5H-
N [1,41thiazino [2,3,4-
ijlquinazolin-5 -one
S )=.1
0
E4 (S)-7-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
( N
10-(5-chl orothi ophen-2-y1)-
3-(methoxymethyl)-9-
F3C
(trifluoromethyl)-2H-
N 0
N [1,4] thi azino [2,3,4-
ij]quinazolin-5(3H)-one
S
CI ()
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Ex. Structure IUPAC
5I '-((3S,5R)-4-acryloy1-3,5-
0 dimethylpiperazin- 1 -y1)-1 1-
Me N Me (4-chlorothiophen-2-y1)-10'-
'C D" (trifluoromethyl)-
2'H,4'H,6'H-
spiro[cyclobutane-1,3'-
F3C
N [1,4] thiazepino [2,3,4-
0 ij] quinazolin] -6-one
CI ,
6 8'-(4-acryloylpiperazin-l-
y1)-11'-(4-chlorothiophen-2-
N
y1)-10'-(trifluoromethyl)-
2'H,4'H,6'H-
spiro[cyclobutane-
F3C
N CI [1,4] thiazepino [2,3,4-
NO ij[quinazolin] -6-one
\ S s,
7 1C1 (3S)-7-(4-acryloy1-6,6-
dioxidohexahydrothieno [3,4-
hi pyrazin-1(2H)-y1)-10-(4-
-0 chlorothiophen-2-y1)-3 -
F3C
(methoxymethyl)-9-
N (trifluoromethyl)-2,3-
dihy dro-5H-
CI N 0 [1,4] thiazino [2,3,4-
\ S ijlquinazolin-5 -one
8 (S)-7-((3S,5R)-4-acryloy1-
3,5-dimethylpiperazin-l-y1)-
( N1.
10-(5-chlorothiophen-3-y1)-
3-(methoxymethyl)-9-
F3C
(trifluoromethyl)-2,3-
N dihydro-5H-
N0 [1,4] thiazino [2,3,4-
CI / ijlquinazolin-5 -one
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Ex. Structure IUPAC
9 Oy= (S)-7-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me 10-(4-fluorothiophen-3-y1)-
3-(methoxymethyl)-9-
(trifluoromethyl)-2,3-
F3C dihy dro-5H-
0 [1,4] thi azino [2,3,4-
/ ij quinazolin-5 -one
0 (S)-7-((3S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me
3-(methoxymethyl)-10-(2-
methylthi ophen-3-y1)-9-
(trifluoromethyl)-2,3-
F3C
dihydro-5H-
N0 [1,4] thi azino [2,3,4-
/ ij quinazolin-5 -one
S j.N.,0 Me
Me
11 () (S)-7-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
MeNyMe
3-(methoxymethyl)-10-(4-
methylthi ophen-3-y1)-9-
(trifluoromethyl)-2,3-
F3C
dihydro-5H-
N0 [1,4] thi azino [2,3,4-
S ijlquinazolin-5 -one
S ).N4.,0Me
Me
12 (S)-7-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
MeNyMe
3-(methoxymethyl)-9-
(trifluoromethyl)-10-(4-
F3C
N (trifluoromethyl)thiophen-2-
y1)-2,3 -dihy dro-5H-
N0 [1,4] thi azino
F3s, iiiquinazolin-5 -one
S SOMe
181
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Ex. Structure IUPAC
13 (S)-7-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me
10-(4-chlorothiophen-2-y1)-
3-((pyridin-4-yloxy)methyl)-
N 9-(trifluoromethyl)-2,3-
F3C
N dihy dro-5H-
N [1,41thiazino [2,3,4-
CI ij quinazolin-5 -one
S S
0
14 (S)-7-((3S,5R)-4-acryloyl-
o
3,5-dimethyl pip erazin-l-y1)-
Me N Me
'C 10-(4-chlorothiophen-3-y1)-
3-(methoxymethyl)-9-
(trifluoromethyl)-2,3-
F3C Idihy dro-5H-
CI N
N,L0 [1,41thiazino [2,3,4-
/ ij quinazolin-5 -one
SOMe
15 (S)-7-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
MeNyMe 3-(methoxymethyl)-9-
(trifluoromethyl)-10-(2-
N (trifluoromethyl)thiophen-3-
F3C
y1)-2,3 -dihy dro-5H-
N,L0 [1,4] thi azino [2,3,4-
ijlquinazolin-5 -one
SOMe
C F3
16 (S)-7-((3 S,5R)-4-acryloyl-
Me N
3,5-dimethyl pip erazin-l-y1)-
N Me
3-(methoxymethyl)-10-(4-
thiomorpholinothiophen-2-
y1)-9-(trifluoromethyl)-2,3-
F3C
dihydro-5H-
r
0 [1,4] thi azino [2,3,4-
S¨\ ij quinazolin-5 -one
s S OMe
182
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Ex. Structure IUPAC
17 I (S)-7-((3R,5 S)-4-acryloyl-
07 3,5-dimethylpip erazin-l-y1)-
Me N Me
T 10-(2-aminothi eno [3,2-
d] pyrimi din-7-y1)-3-
(methoxymethyl)-9-
N
H2N F3C (trifluoromethyl)-2,3-
)-------N
N dihy dro-5H-
N
1 [1,4] thiazino [2,3,4-
/ 1 N 0
S Sv ijlquinazolin-5 -one
OMe
18 0 5-((S)-7-((3 S,5R)-4-
acryloy1-3,5 -
Me N Me
T dimethylpiperazin-l-y1)-3-
(methoxymethyl)-5-oxo-9-
N
(trifluoromethyl)-2,3-
F3C
N N dihy dro-5H-
[1,4] thiazino [2,3,4-
NC ijlquinazolth-10-
\ S S yl)thi ophene-3 -c arb onitril e
OMe
19 07 (S)-7-((3S,5R)-4-acryloy1-
3,5-dimethylpiperazin-l-y1)-
Me N Me
'C T 3-(methoxymethyl)-10-
(thieno[3,2-bithiophen-3-y1)-
F3C
N
9-(trifluoromethyl)-2,3-
N N dihy dro-5H-
S
I
NLO [1,4] thiazino [2,3,4-
/
iiiIiL 1 ijlquinazolin-5 -one
S
OMe
20 I (S)-8-((3 S,5R)-4-acryloyl-
07 3,5-dimethylpip erazin-l-y1)-
Me N Me 11-(4-chlorothiophen-2-y1)-
T 3-((5-methyl is oxazol-3 -
yl)oxy)-10-
N
(trifluoromethyl)-3,4-
F3C
N dihydro-2H,6H-
--, N0 [1,4] thiazepino [23 A-
\
C I ijlquinazolin-6-one S S\ (s) Me
-- ¨CN-0
183
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Ex. Structure IUPAC
21 (S)-7-((3 S,5R)-4-acryloyl-
3,5-dimethylpip erazin-l-y1)-
Me N Me
10-(4-aminothiophen-2-y1)-
3-(methoxymethyl)-9-
F3C
(trifluoromethyl)-2,3-
N dihy dro-5H-
N0 [1,4] thiazino [2,3,4-
2 H N ijlquinazolin-5 -one
S S7H
OM e
22 I (S)-8-((3S,5R)-4-acryloy1-
0 3,5-dimethylpip erazin-l-y1)-
Me N ,Me 11-(4-chl orothi ophen-2-y1)-
j3-(i sothiazol-3-yloxy)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-
F3C
N [1,4] thiazepino [2,3,4-
N0 iji quinazolin-6-one
CI
S S \
23 (S)-8-((3S,5R)-4-acryloy1-
0 3,5-dimethylpip erazin-l-y1)-
Me N Me 11-(4-chlorothiophen-2-y1)-
3-(pyrimidin-2-yloxy)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-
F3C
N [1,4] thiazepino [23 A-
CI NL0 ijlquinazolin-6-one
S
. ND
24 C) (S)-8-((3S,5R)-4-acryloy1-
3,5-dimethylpiperazin-l-y1)-
NT=
11-(4-chlorothiophen-2-y1)-
3-(1H-pyrazolo[3,4-
1)] pyridin-1 -y1)-10-
F3C
N (trifluoromethyl)-3,4-
0 dihy dro-2H,6H-
CI [1,4] thiazepino [2,3,4-
S S ij]quinazolin-6-one
N
/
:N
N
184
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Ex. Structure IUPAC
25 C) (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
N
11-(4-chl orothi ophen-2-y1)-
3-(3-oxo-[1,2,41 triazolo [4,3-
F3C
N a] pyridin-2(3H)-y1)-10-
N (trifluoromethyl)-3,4-
NL0 dihy dro-2H,6H-
CI [1,4] thiazepino [2,3,4-
s S
ij quinazolin-6-one
0
26 C) (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
11-(4-chlorothiophen-2-y1)-
3-(1-oxoisoindolin-2-y1)-10-
N
(trifluoromethyl)-3,4-
F3C
N dihy dro-2H,6H-
0 [1,4] thiazepino [2,3,4-
CI S ijlquinazolin-6-one
S
= 0
27 (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Njoo
3-(1H-benzo [d] imidazol-1-
y1)-11-(4-chl orothi ophen-2-
y1)-10-(trifluoromethyl)-3,4-
F3C
N dihydro-2H,6H-
N0 [1,4] thiazepino [2,3 A-
CI S ijlquinazolin-6-one
S
= *
185
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Ex. Structure IUPAC
28 101 (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
NTot
11-(4-chl orothi ophen-2-y1)-
3-(1H-1,2,3-triazol-1 -y1)-10-
(trifluoromethyl)-3,4-
F3C dihy dro-2H,6H-
NL0 [1,41thiazepino [2,3,4-
\
CI
s ijlquinazolin-6-one S
Nõ
29 (S)-8-((3 S,5R)-4-acryloy1-
3,5-dimethyl pip erazin-l-y1)-
Me N Me
11-(4-chlorothiophen-2-y1)-
3-(pyrazin-2-yloxy)-10-
F3C
N (trifluoromethyl)-3,4-
dihy dro-2H,6H-
N /L0 [1,4] thiazepino [2,3,4-
CI ijlquinazolin-6-one
\ S
= /=N
30 (S)-7-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me
10-(4-chlorothiophen-2-y1)-
3-ethy1-9-(trifluoromethyl)-
2,3-dihydro-5H-
F3C [1,4] thi azino [2,3,4-
N 0
ijlquinazolin-5 -one
CI \
S SN)N,,Me
31 I (S)-8-((3 S,5R)-4-acryloyl-
(:)7 3,5-dimethyl pip erazin-l-y1)-
Me., N Me 11-(4-chl orothi ophen-2-y1)-
c ).õ,,
3-(pyridin-2-yloxy)-10-
N (trifluoromethyl)-3,4-
F3CJN
dihydro-2H,6H-
[1,41thiazepino[2,3,4-
CI N0 ijlquinazolin-6-one
\ S S
¨0
186
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Ex. Structure IUPAC
32 I (S)-8-((3 S,5R)-4-acryloyl-
07 3,5-dimethylpiperazin-l-y1)-
Nj.,A 11-(4-chlorothiophen-2-y1)-
3-(pyridazin-3-yloxy)-10-
N (trifluoromethyl)-3,4-
dihydro-2H,6H-
F3C
N [1,4] thiazepino [2,3,4-
ij] quinazolin-6-one
\ S S\)
b
. 4\
N¨N
33 0 (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethylpip erazin-l-y1)-
Me N Me
T 11-(4-chlorothiophen-2-y1)-
3-(pyrimidin-4-yloxy)-10-
N
(trifluoromethyl)-3,4-
F3C N dihydro-2H,6H-
---.. N'L0 [1,4] thiazepino [23 ,4-
)
CI ijlquinazolin-6-one
\ S S
\
b-cN
N-1/
34 I (R)-8-((3S,5R)-4-acryloy1-
0 3,5-dimethylpip erazin-l-y1)-
Me N Me 11-(4-chlorothiophen-2-y1)-
'C D" 3-(pyridin-4-y1)-10-
(trifluoromethyl)-3,4-
F3C
N
dihydro-2H,6H-
N [1,4] thiazepino [2,3,4-
ijlquinazolin-6-one
CI
¨N
187
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Ex. Structure IUPAC
35I (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me D 11-(4-chlorothiophen-2-y1)-
" 3-(pyridin-4-y1)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-
F3C N [1,4] thiazepino [2,3,4-
iii quinazolin-6-one
CI N 0
S S
36 (S)-7-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me
10-(4-bromothiophen-2-y1)-
3-(methoxymethyl)-9-
F3C
(trifluoromethyl)-2,3-
N dihydro-5H-
-, NL0 [1,41thiazino [2,3,4-
Br S ijlquinazolin-5 -one
S
0 Me
37 (R)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me NMe
11-(4-chl orothi ophen-2-y1)-
3-(pyridin-2-y1)-10-
N (trifluoromethyl)-3,4-
dihydro-2H,6H-
F3C
[1,4] thiazepino [2,3,4-
0 ij] quinazolin-6-one
CI
S \
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Ex. Structure IUPAC
38 I (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethylpiperazin-l-y1)-
Me N Me
D" 11-(4-chlorothiophen-2-y1)-
3-(pyridin-2-y1)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-
F3C
N [1,41thiazepino [2,3,4-
N0 ij] quinazolin-6-one
CI
S S
39 8-((3S,5R)-4-acryloy1-3,5-
dimethylpiperazin- 1 -y1)-11-
Me.1/4(N),õMe
(4-chlorothiophen-2-y1)-3-
(pyridin-2-y1)-10-
N
(trifluoromethyl)-3,4-
F3C N dihydro-2H,6H-
NL0 [1,41thiazepino [2,3,4-
CI ijlquinazolin-6-one
S S
40 I (S)-8-((3S,5R)-4-acryloy1-
0 3,5-dimethylpiperazin-l-y1)-
Me Me
11-(4-chl orothiophen-2-y1)-
N
3-cyclopropoxy-10-
N (trifluoromethyl)-3,4-
dihydro-2H,6H-
F3C
N [1,41thiazepino[2,3,4-
N0 ijlquinazolin-6-one
CI
S
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Ex. Structure IUPAC
41 8-((3S,5R)-4-acryloy1-3,5-
dimethylpiperazin- 1 -y1)-11-
Me N Me
(4-chlorothiophen-2-y1)-3-
(pyrimidin-2-y1)-10-
N (trifluoromethyl)-3,4-
F3C
N
[1,41thiazepino [2,3,4-
C I \ ijlquinazolin-6-one
S S
N
42 (S)-8-((3S,5R)-4-acry1oy1-
3,5-dimethylpiperazin-l-y1)-
Me N Me
11-(4-bromothiophen-2-y1)-
3-(pyridin-2-yloxy)-10-
F3C
N (trifluoromethyl)-3,4-
N
N,L0 [1,41thiazepino [2,3,4-
Br ijlquinazolin-6-one
S
N)
43I (S)-8-((3S,5R)-4-acryloy1-
0 3,5-dimethylpip erazin-l-y1)-
Me N Me 11-(4-chl orothiophen-2-y1)-
3-(pyridin-3-y1)-10-
(trifluoromethyl)-3,4-
F3C
dihydro-2H,6H-
N [1,4] thiazepino [2,3,4-
N ijlquinazolin-6-one
CI
s S\ )
1\1
¨/
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Ex. Structure IUPAC
44 0 (R)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me
T 11-(4-chlorothiophen-2-y1)-
3-(pyridin-3-y1)-10-
N (trifluoromethyl)-3,4-
F3C N dihydro-2H,6H-
[1,41thiazepino [2,3,4-
"S S\
CI ij1qui11az01in-6-0ne
45 I (S)-8-((3S,5R)-4-acry1oy1-
0 3,5-dimethyl pip erazin-l-y1)-
NJ/.
11-(4-chl orothi ophen-2-y1)-
4(
3-(pyrimidin-2-y1)-10-
(trifluoromethyl)-3 ,4-
N
dihydro-2H,6H-
F3C
N [1,4] thiazepino [2,3,4-
iji quinazolin-6-one
\ S S\______
N
N j
46 I (R)-8-((3S,5R)-4-acryloy1-
0 3,5-dimethyl pip erazin-l-y1)-
Me N Me 11-(4-chlorothiophen-2-y1)-
'C T 3-(pyrimidin-2-y1)-10-
(trifluoromethyl)-3 ,4-
N
dihydro-2H,6H-
F3C
N [1,4] thiazepino [2,3,4-
ij ] quinazolin-6-one
---.. N 0
CI
\ S S\/)
:
-----N
N3
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Ex. Structure IUPAC
47 (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me
11-(4-chlorothiophen-2-y1)-
3-(3-fluoropyridin-4-y1)-10-
N (trifluoromethyl)-3,4-
F3C N
NLio [1,4] thiazepino [2,3,4-
CI S ijlquinazolin-6-one
S
= F
\
48 (R)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me
11-(4-chlorothiophen-2-y1)-
3-(3-fluoropyridin-4-y1)-10-
N (trifluoromethyl)-3,4-
F3C
N
NL0 [1,4] thiazepino [2,3,4-
CI ijlquinazolin-6-one
S S
49 (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me
11-(4-chlorothiophen-2-y1)-
3-(5-fluoropyridin-3-y1)-10-
N (trifluoromethyl)-3,4-
F3C
N dihydro-2H,6H-
N0 [1,4] thiazepino [2,3,4-
CI iii quinazolin-6-one
S S
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Ex. Structure IUPAC
50 (R)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me
'C 11-(4-chlorothiophen-2-y1)-
3-(5-fluoropyridin-3-y1)-10-
N (trifluoromethyl)-3,4-
F3C
N dihydro-2H,6H-
-, No [1,4] thiazepino [2,3,4-
CI ijlquinazolin-6-one
51 121 (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me.1/4(N), Me
11-(4-chlorothiophen-2-y1)-
3-cyclopropy1-10-
N
(trifluoromethyl)-3,4-
F3C
N dihydro-2H,6H-
N0 [1,4] thiazepino [2,3 A-
CI S ijlquinazolin-6-one
S
52 (R)-8-((3 S,5R)-4-acryloyl-
3,5-dimethyl pip erazin-l-y1)-
Me N Me
11-(4-chlorothiophen-2-y1)-
3-cyclopropy1-10-
N
(trifluoromethyl)-3,4-
F3C
N dihy dro-2H,6H-
N0 [1,4] thiazepino [2,3,4-
CI ijlquinazolin-6-one
S
193
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Ex. Structure IUPAC
53 (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethylpip erazin-l-y1)-
Me N Me
11-(4-chlorothiophen-2-y1)-
3-(4-fluorothiophen-2-y1)-
N 10-(trifluoromethyl)-3,4-
F3C
N
No [1,4] thiazepino [2,3,4-
CI S ij1quinaz01in-6-0ne
S
S
54 121 (R)-8-((3S,5R)-4-acryloy1-
3,5-dimethylpiperazin-l-y1)-
Me.1/4(NTMe
11-(4-chlorothiophen-2-y1)-
3-(4-fluorothiophen-2-y1)-
N 10-(trifluoromethyl)-3,4-
F3C
N dihydro-2H,6H-
[1,41thiazepino [2,3,4-
CI \ N 0 ijlquinazolin-6-one
S
S
55 (S)-8-(4-acryloylpiperazin-
l-y1)-11-(4-chlorothiophen-
N
2-y1)-3-(pyridin-2-y1)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-
F3C
N [1,4] thiazepino [2,3,4-
NLO ijlquinazolin-6-one
CI
S S
N \
194
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Ex. Structure IUPAC
56 (R)-8-(4-acryloylpiperazin-
l-y1)-11-(4-chlorothiophen-
N
2-y1)-3-(pyridin-2-y1)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-
F3C N [1,4] thiazepino [2,3,4-
NL0 ij] quinazolin-6-one
CI
S S\/'
57 (R)-8-((3 S,5R)-4-acryloyl-
3,5-dimethylpip erazin-l-y1)-
Me N Me
11-(4-chlorothiophen-2-y1)-
3-(pyrazin-2-y1)-10-
N
(trifluoromethyl)-3,4-
F3C dihydro-2H,6H-
-, N,L0 [1,4] thiazepino [23,4-
C ijlquinazolin-6-one
S
N N
58 (S)-8-((3 S,5R)-4-acryloyl-
3,5-dimethylpip erazin-l-y1)-
Me N Me
11-(4-chlorothiophen-2-y1)-
3-(4-fluoropyridin-3-y1)-10-
N (trifluoromethyl)-3,4-
F3C N dihy dro-2H,6H-
N0 [1,4] thiazepino [2.3.4-
CI
S ijlquinazolin-6-one
S
= F
\
N-
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Ex. Structure IUPAC
59 (S)-8-(4-acry1oy1piperazin-
l-y1)-11-(4-chlorothiophen-
N
2-y1)-3-(3-fluoropyridin-4-
y1)-10-(trifluoromethyl)-3,4-
N dihydro-2H,6H-
F3C
N [1,4]thiazepino [2,3,4-
No ij] quinazolin-6-one
CI \
s S
F
60 (S)-8-(4-acry1oy1piperazin-
l-y1)-11-(4-chlorothiophen-
N
2-y1)-3-(pyridin-4-y1)-10-
(trifluoromethyl)-3,4-
dihydro-2H,6H-
F3C
N [1,4]thiazepino[2,3,4-
--.. NL0 ij] quinazolin-6-one
CI
S S
61 (R)-8-((3S,5R)-4-acryloy1-
3,5-dimethylpiperazin-l-y1)-
Nj,==
11-(4-chlorothiophen-2-y1)-
3-(2-methylpyridin-4-y1)-10-
F3C
N (trifluoromethyl)-3,4-
N dihydro-2H,6H-
N0 [1,41thiazepino [2,3,4-
CI \ iii quinazolin-6-one
S S
Me
¨N
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Ex. Structure IUPAC
62 (S)-8-((3S,5R)-4-acryloyl-
3,5-di methyl pip erazin-l-y1)-
(N
11-(4-chlorothiophen-2-y1)-
3-(2-methylpyridin-4-y1)-10-
N (trifluoromethyl)-3,4-
F3C
N dihydro-2H,6H-
No [1,41thiazepino[2,3,4-
CI ij]quinazolin-6-one
S S
0--Me
¨N
A. Assays & Activity Data
[0331] KRAS G12C covalent binding assays are carried out as follows:
KRAS G12C Covalent Adduct Formation (CAF) Assay
[0332] This Example provides a protocol for assessing covalent adduct
formation (CAF)
between the compounds of Formula (I) and KRAS.
[0333] In vitro covalent adduct formation assay: Covalent adduct formation
(CAF)
reactions between Cys12 of the KRAS 4B Gl2C protein and the compounds
disclosed herein
are measured in vitro using liquid chromatography-mass spectrometry (LC-MS).
[0334] Recombinant Human KRAS 4B protein containing the G12C mutation is used
in
compound screening experiments. This protein contained 188 amino acids in
total, including
an N-terminal 6-Histidine tag, followed by a Tobacco Etch Virus (TEV) tag,
followed by
residues 1-169 of the native KRAS 4B sequence. The exact mass of the protein
is 21,310 Da
as determined by mass spectrometry. The full amino acid sequence is shown
below:
MAHHHHHHAG GAENLYFQSM TEYKLVVVGA CGVGKSALTI
QLIQNHFVDE YDPTIEDSYR KQVVIDGETC LLDILDTAGQ
EEYSAMRDQY MRTGEGFLCV FAINNTKSFE DIHHYREQIK
RVKDSEDVPM VLVGNKCDLP SRTVDTKQAQ DLARSYGIPF
IETSAKTRQG VDDAFYTLVR EIRKHKEK (SEQ ID NO: 1)
[0335] In an alternative screen, the assay can be conducted using a KRAS 4b
G12C protein
having 170 amino acids, a mass of 19,336 Da, and the amino acid sequence
SMTEYKLVVVGA CGVGKSALTI QLIQNHFVDE YDPTIEDSYR KQVVIDGETC
LLDILDTAGQ EEYSAMRDQY MRTGEGFLCV FAINNTKSFE DIHHYREQIK
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RVKDSEDVPM VLVGNKCDLP SRTVDTKQAQ DLARSYGIPF IETSAKTRQG
VDDAFYTLVR EIRKHKEK (SEQ ID NO: 2).
[0336] The recombinant protein is expressed in E. coil BL21 cells and purified
using
affinity chromatography via a Ni-NTA column. Protein stocks are nucleotide-
exchanged to
>95 % GDP, concentrated to 4 mg/mL, and stored at -80 C in storage buffer (50
mM
HEPES pH 7.4, 50 mM NaCl, 5 mM MgCl2, 1 mM DTT). Pure KRAS 4B G12C protein is
diluted to a concentration of 5 M in Tris Buffered Saline, pH 7.4. The
compounds are
dissolved in DMSO and added to the diluted protein to make a 10 jtM
concentration. The
total DMSO concentration in the reaction is 4%. The reaction is mixed by
pipetting and
incubated at 22 C for one hour. Aliquots of the reaction are taken over time
and diluted 2:1
in 0.1% formic acid. The intact mass of the protein samples is measured by LC-
MS using a
QExactive+ mass spectrometer (Thermo Scientific). An amount of 500 ng total
protein is
injected onto a C8 reverse phase column, eluted with a seven-minute gradient
of 30%-90%
acetonitrile/0.1% formic acid, and analyzed for intact mass by the mass
spectrometer.
Adducts identified are confirmed to be within 1 Dalton of the expected mass,
and the relative
ratios of free: adduct protein were used to quantify the percentage of protein
bound by the
compound. CAF reactions are run in duplicate, with a typical variability of +
5%.
[0337] Examples El -E4 were evaluated in the above CAF assay at 60 minutes.
Table 2
Example number % CAF A': 60 min
El 95
E2 95
E3 95
E4 94
[0338] Inhibition of KRAS G12C-mediated phospho-ERK1/2 inhibition by Exemplary
Compounds of Formula (I)
[0339] This Example illustrates that exemplary compounds of the present
disclosure inhibit
KRAS G12C as measured by the downstream inhibition of the phosphorylation of
ERK.
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[0340] KRAS G12C mutant cell lines, NCI H358 (ATCC, CRL-5807), and Ras
Initiative
(RI) KRAS G12C were cultured according to published protocols and maintained
at 37 C in
5% CO2. The phospho-ERK HTRF assay was executed following provider's protocol
(CisBio
#64AERPEH). NCI-H358 or RI KRAS G12C cells were plated at a density of 50,000
cells
per well in a 96-well plate (Corning #3903) in respective medias (for NCI-
H358, RPMI +
10% FBS + 1% Pen/Strep, and for RI KRAS G12C, DMEM + 10% FBS + 1% Pen/Strep +
4ug/m1Blasticidin) and maintained at 37 C in 5% CO2. Cells were allowed to
adhere
overnight and treated the following day with a Tecan D300e Digital Dispenser
(Tecan Group
Ltd., Switzerland) using an 11-point dose response starting at 2,500 nM of
exemplified
compounds followed by sequential 1:3 dilutions for either 4 hours or 16 hours.
Following
compound treatment, the cells were washed once with ice-cold PBS. Cells were
lysed by
adding 501A1 of lysis buffer (1x) supplemented with lx Pierce Halt Protease
and Phosphatase
inhibitor and incubated for 30 minutes at 4 C with shaking. After lysis, 16
IAL of cell lysate
from the 96-well cell-culture plate was transferred to a 384-well plate
(Perkin Elmer
#6007290). The premixed antibody solution was prepared by mixing (vol/vol)
advanced
phospho-ERK1/2 d2 antibody and advanced phospho-ERK1/2 Eu Cryptate antibody.
The
premixed antibody solution (4 [it) was added to the detection plate containing
cell
lysate. The detection plate was incubated overnight at 4 C, the HTRF signal
was read the
next day by using either a Spectramax M5 or Spectrarnax i3 microplate reader
(Molecular
Devices, San Jose, CA, USA), and data was processed according to
manufacturer's protocol.
[0341] Further compounds were characterized for inhibition of p-ERK as
described below.
Results are summarized in Table 3.
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Table 3
MS
Ex. Structure (ES!) PERK
1H-NMR (RI)
m/s
4h
[M+H]
'FINMR (400
MHz, DMSO-d6)
6 7.99 (s, 1H),
7.87 (d, J = 1.2
Hz, 1H), 7.15 (s,
1H), 6.81 (dd, J =
16.0, 8.0 Hz, 1H),
Me N Me 6.19 (dd, J = 16.0,
D" 4.0 Hz, 1H), 5.74
(dd, J = 16.0, 4.0
F3C 609 Hz, 1H), 5.11 (s, ++
N 1H), 4.62-4.54
(m, 2H), 4.10-
N 0
CI
S s\_6 3.95 (m, 2H),
3.29-3.16 (m,
3H), 1.95-1.70
(m, 4H), 1.45-
1.30 (m, 4H),
1.00-0.98 (m,
3H), 0.98-0.97
(m, 3H).
1H NMR (400
MHz, CDC13) 6
7.76 (s, 1H), 7.34
ON J = 1.2 Hz,
1H), 6.92 (s, 1H),
6.59 (dd, J 16.0,
C 8.0 Hz, 1H), 6.37
(dd, J = 16.0, 4.0
6 F3C 581 Hz, 1H), 5.79 (dd, ++
N
NL0 J = 16.0, 4.0 Hz,
1H), 4.30-3.52
CI
S S\_8, (m, 8H), 3.25-
3.00 (m, 2H),
2.10-1.75 (m,
5H), 1.54-1.39
(m, 2H), 1.25 (s,
1H).
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MS
Ex. Structure (ES!) PERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, DMSO-d6)
8.01-7.90 (m,
2H), 7.24-7.06
(m, 1H), 6.84-
6.72 (m, 1H),
6.23 (dd, J = 16.0,
01
4.0 Hz, 1H), 5.80
r
, (dd, J = 16.0, 4.0 N 0
Hz, 1H), 5.44-
0 5.12 (m, 2H),
7 660.8
F3C 4.89-4.79 (m,
CI
N
NO 1H), 4.18-3.95
(m, 2H), 3.88-
S>c,0 3.79 (m, 2H),
3.73-3.56 (m,
4H), 3.51-3.45
(m, 1H), 3.43-
3.35 (m, 2H),
3.32-3.25 (m,
3H), 3.12-3.00
(m, 1H).
1H NMR (400
MHz, CDC13) 5
8.03 (s, 1H),
7.10-7.02 (m,
1H), 6.91-6.81
(m, 1H), 6.65-
6.58 (m, 1H),
6.45-6.37 (m,
1H), 5.81-5.74
(m, 1H), 5.44 (t,
8 599.1 J=4.0 Hz, 1H), +++
F3C
N 4.85-4.45 (m,
2H),4.23-4.11
0 (m, 2H), 3.72-
SO
3.57 (m, 2H),
3.41 (d, J= 4.0
Hz, 3H), 3.40-
3.27 (m, 3H),
3.01-2.93 (m,
1H), 1.61 (d,
J=4.0 Hz, 3H),
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MS
Ex. Structure (ES!) PERK
1H-NMR (RI)
m/s
4h
[M+H]
1.50-1.40 (m,
3H).
1H NMR (400
MHz, CDC13)
8.05 (s, 1H), 7.20
(m, 1H), 6.90 (d,
J = 4.0 Hz, 1H),
6.62 (dd, J = 16.0,
0
12.0 Hz, 1H),
Me N Me
6.41 (dd, J = 16.0,
4.0 Hz, 1H), 5.78
(dd, J = 12.0, 4.0
9 583 ++++
Hz, 1H), 5.53 ¨
F3C
5.39 (m, 1H),
NO 4.65 (m, 2H),
/
S=Ne.,0Me 4.19 (m, 2H),
j
3,74¨ 3.56 (m,
2H), 3.44 ¨ 3.27
(m, 6H), 3.03 (m,
1H), 1.62 (m,
3H), 1.47 (m,
3H).
1H NMR (400
MHz, CDC13) 6
8.05 (s,1H), 7.24-
7.22(m, 1H),
6.79-6.78 (m,
1H), 6.66-6.60
(m, 1H), 6.43-
Me N Me
6.39 (m, 1H),
5.79-5.77 (m,
1H), 5.46 (s, 1H),
579.1 ++++
F3C 4.46 (s, 3H), 4.19
N (s, 2H), 3.68-3.61
()
/ (m, 2H), 3.40-
s-1\S,OMe 3.30 (m, 5H),
Me 3.05-3.01 (m,
1H), 2.22-2.20
(m, 3H), 1.65-
1.62 (m, 3H),
1.49-1.46 (m,
3H).
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MS
Ex. Structure (ES!) PERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, CDC13) 6
8.06 (s, 1H), 7.17
(dd, J = 8.0, 5.2
Hz, 1H), 7.10 (m,
1H), 6.63 (dd, J =
16.8, 10.4 Hz,
1H), 6.41 (dd, J =
Me N Me 14.8, 2.0 Hz, 1H),
5.78 (dd, J = 10.4,
2.0 Hz, 1H), 5.53
11 579.2 +++
F3C ¨5.39 (m, 1H),
4.66 (s, 2H), 4.25
¨ 4.12 (m, 2H),
SOMe 3.64 (m, 2H),
Me 3.39 (s, 3H), 3.32
(m, 2H), 3.01 (m,
1H), 2.00 (d, J =
12.4 Hz, 3H),
1.65 (s, 1H), 1.62
(m, 3H), 1.53 ¨
1.42 (m, 3H).
1H NMR (400
MHz, CDC13) 6
8.05 (s, 1H), 7.95
(s, 1H), 7.23-7.08
(m, 1H), 6.63 (dd,
C) J = 16.0, 8.0 Hz,
1H), 6.42 (dd, J =
Me N Me
D" 16.0, 4.0 Hz, 1H),
5.78 (dd, J = 16.0,
12 633 4.0 Hz, 1H), 5.58- +++
r, F3C N 5.30 (m, 1H),
0 4.85-4.42 (m,
2H), 4.25-4.07
SI,OMe (m, 2H), 3.75-
3.62 (m, 2H),
3.42-3.25 (m,
5H), 3.02-2.79
(m, 2H), 1.52-
1.38 (m, 6H).
203
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) PERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, CDC13) 6
8.05 (s, 1H), 7.95
(s, 1H), 7.23-7.08
(m, 1H), 6.63 (dd,
Me41/4(N),,Me J= 16.0, 8.0 Hz,
1H), 6.42 (dd, J =
16.0, 4.0 Hz, 1H),
F3C 5.78 (dd, J = 16.0,
N
0 633 4.0 Hz, 1H), 5.58- ++
13 CI
5.30 (m, 1H),
\ S 4.85-4.42 (m,
2H), 4.25-4.07
(m, 2H), 3.75-
I N 3.62 (m, 2H),
3.42-3.25 (m,
5H), 3.02-2.79
(m, 2H), 1.52-
1.38 (m, 6H).
1H NMR (400
MHz, CDC13) 6
8.06 (s, 1H), 7.31
(m, 2H), 6.63 (dd,
J = 16.0, 12.0 Hz,
1H), 6.41 (d, J =
Me N Me 16.0 Hz, 1H),
5.77 (d, J = 12.0
14 599 Hz, 1H), 5.45 (m, ++
F3C
CI N 1H), 4.66 (m,
NL0 2H), 4.27 ¨ 4.10
/ (m, 2H), 3.67 (m,
SjNvOMe 2H), 3.41 ¨ 3.28
(m, 6H), 3.05 (d,
J = 12.0 Hz, 1H),
1.62 (m, 3H),
1.47 (m, 3H).
204
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, CDC13) 6
8.05 (s, 1H),
7.53-7.45 (m,1H),
7.07-6.94 (m,
1H), 6.62 (dd,
J=16.0, 8.0 Hz,
Me N Me
1H), 6.45-6.37
(m, 1H), 5.81-
5.75 (m, 1H),
15 633.1 5.49-5.36(m,
F3C 1\1 1H), 4.75-4.45
(m, 2H), 4.17 (t,
/ N 0
J=12.0 Hz, 2H),
CF3 3.71-3.60 (m,
1H), 3.38-3.22
(m, 6H), 2.95-
2.88 (m, 1H),
1.55 (d, J=8.0 Hz,
1H), 1.40 (d,
J=8.0, 1H)
1H NMR (400
MHz, CDC13) 6
Me N Me
8.03 (s, 1H), 6.86
(bs, 1H), 6.59 (m,
2H), 6.40 (d, 1H),
16 666.1
F3C 5.76 (d, 1H), 4.72
(m, 4H), 4.10 (m,
SON N 0
\ S SOMe 11H), 2.84 (m,
3H), 3.5-3.0 (m,
4H), 1.5 (bs, 6H)
1H NMR (400
07 MHz, CDC13) 6
8.95 (d, J = 8.0
Me N Me Hz, 1H), 8.12 (s,
1H), 7.90 (d, J =
28 Hz, 1H), 7.28
17 H2N F3C N
632.1 +++
(s, 2H), 6.64-6.62
NL0 (m, 1H), 6.43 (d,
\
/ I J = 16.0 Hz, 1H),
S7H 5.80 (d, J = 10.4
Hz, 1H), 5.71 ¨0Me
5.29 (m, 2H),
205
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
5.28¨ 5.05 (m,
1H), 4.93 ¨ 4.46
(m, 2H), 4.41 ¨
4.06 (m, 2H),
3.92¨ 3.57 (m,
2H), 3.50 ¨ 3.37
(m, 3H), 3.36 ¨
3.26 (m, 1H),
3.17 ¨ 2.97 (m,
1H), 1.65 (d, J =
6.8 Hz, 3H), 1.50
(d, J = 6.8 Hz,
3H).
1H NMR (400
MHz, CDC13) 6
8.14 (s, 1H), 8.06
(s, 1H), 7.24-7.11
(m, 1H), 6.62 (dd,
J=16.0, 8.0, 1H),
Me N Me
6.42 (dd, J=16.0,
4.0, 1H), 5.79
(dd, J=16.0, 4.0,
18 F3C 590.1 ++++
N 1H), 4.93-4.34
(m, 4H), 4.23-
NC N 0 3.86 (m, 3H),
S SH 3.56-3.44 (m,
OMe 3H), 3.40-3.20
(m, 3H), 3.16-
3.04 (m, 1H),
1.58-1.43 (m,
6H).
1H NMR (400
MHz, CDC13) 6
8.09 (s, 1H), 7.45
MeN)0,Me
¨7.31 (m, 2H),
6.63 (dd, J = 16.0,
12.0 Hz. 1H)
19 F3C +++
N 621.1 6.42 (dd, J = '16.0,
N0 4.0 Hz, 1H), 5.78
/ (dd, J = 12.0, 4.0
SH Hz, 1H), 5.52 ¨
0Me 5.39 (m, 1H),
4.67 (m, 2H),
206
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
4.22 (m, 2H),
3.73 - 3.58 (m,
2H), 3.48 -3.19
(m, 6H), 3.00 (m,
1H), 1.63 (m,
3H), 1.48 (m,
3H).
1H NMR (400
MHz, DMSO-d6)
6, 1H NMR (400
MHz,
CHLOROFORM-
d) 6 = 8.07 (s,
1H), 7.37 (d, J =
1.6 Hz, 1H), 7.00
Oy
- 6.91 (m, 1H),
Me....(NxMe 6.65 (dd, J = 10.6,
16.8 Hz, 1H),
6.48 - 6.39 (m,
20 F3C
N 666.1 1H), 5.84 - 5.78 +++
No (m, 1H), 5.75
5.63 (m, 2H),
CI
S S 4.62 - 4.44 (m,
Me 3H), 4.28 - 4.26
(m, 1H), 4.28 -
N-u
4.19 (m, 1H),
3.50 - 3.30 (m,
4H), 3.11 (dd, J=
2.4, 14.0 Hz, 1H),
2.34 (s, 3H), 1.50
(br d, J = 6.4 Hz,
6H)
0 1H NMR (400
MHz, CDC13) 6
Me N Me 8.02 (s, 1H), 6.62
(dd, J = 16.0, 12.0
Hz, 1H), 6.51 (d,
21 F3C 580.1 J = 4.0 Hz, 1H), ++++
6.40 (dd, J = 16.0,
N 0 4.0 Hz, 1H), 5.77
H2N S SN) (dd, J = 12.0, 4.0
Hz, 1H), 5.42 (s,
OMe 1H), 4.64 (m,
207
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
2H), 4.17 (m,
2H), 3.75 - 3.60
(m, 2H), 3.44 -
3.24 (m, 6H),
2.96 (dd, J = 12.0,
4.0 Hz, 1H), 1.61
(d, J = 8.0 Hz,
3H), 1.46 (d, J =
8.0 Hz, 3H).
1H NMR (400
MHz,
CHLOROFORM-
d)5: 8.47 (d, J =
4.8 Hz, 1H), 8.07
(s, 1H), 7.37 (d, J
Ov = 1.2 Hz, 1H),
Me N Me 6.95 (br d. J = 2.4
()
Hz, 1H), 6.71 -
N 6.59 (m, 2H),
22 688.2
6.44 (dd, J = 1.6,
F3C
N
16.4 Hz, 1H), ++++
NL0 5.85 - 5.69 (m,
CI
S S 2H), 4.69 - 4.64
(m, 2H), 4.26 -
b-0 4.17 (m, 2H),
N-S 3.48 - 3.30 (m,
3H), 3.13 (dd, J =
2.8, 13.6 Hz, 1H),
1.63 (br d. J = 6.8
Hz, 6H), 1.51 (br
d, J = 6.8 Hz, 2H)
1H NMR (400
Ov MHz, CDC13) 6
Me N Me 8.52 (d, J = 4.8
Hz, 2H), 8.06 (s,
1H), 7.34 (s, 1H),
23 F3C 663.4
7.00 (t, J = 4.8
Hz, 1H), 6.92 (s, ++++
N0 1H), 6.63 (dd, J =
CI
S S\10.4, 16.4 Hz,
N 1H), 6.47 - 6.37
"o-¨µ (m, 1H), 5.84 -
N 5.69 (m, 2H),
208
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
4.95 - 4.53 (m,
4H), 4.21 (d, J =
13.2 Hz, 2H),
3.60 (dd, J = 2.8,
13.6 Hz, 1H),
3.45 - 3.32 (m,
2H), 3.19 - 3.06
(m, 1H), 1.64 -
1.60 (m, 3H),
1.48 (d, J = 6.4
Hz, 3H)
1H NMR (400
MHz, CDC13) 6
8.53 (d, J= 4.0
Hz, 1H), 8.10-
8.04 (m, 3H),
7.34 (s, 1H),
7.18-7.15 (dd, J=
8.0 Hz, 4.4 Hz,
1H), 7.02-6.88
4k,( N (m, 1H), 6.67-
6.60 (m, 1H),
6.42 (dd, J= 16.8
F3C Hz, 2.0 Hz, 1H),
24 N 686.1 ++++
NL0 5.78 (dd, J= 10.4
CI Hz, 2.0 Hz, 2H),
S S 5.54-5.28 (m,
N 1H), 5.10 (d, J=
N ' ) 13.6 Hz, 1H),
4.80-4.44 (m,
2H), 4.17 (d, J=
13.2 Hz, 2H),
3.91-3.57 (m,
1H), 3.40-3.33
(m, 3H), 1.59-
1.58 (m, 6H).
209
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, CDC13) 6
8.09 (s, 1H), 7.75
(d, J= 7.2 Hz,
1H), 7.34 (s, 1H),
7.10-7.00 (m,
2H), 6.96-6.95
(m, 1H), 6.65-
6.59 (m, 1H),
6.49 (t, J= 7.2
Hz, 1H), 6.41 (dd,
F3C N N J= 16.8 Hz, 2.0
NL0 701.3 Hz, 1H), 5.78 (dd, ++++
CI S S J= 10.4 Hz, 2.0
Hz, 1H), 5.35-
-- 0
5.27 (m, 1H),
N 5.25-5.08 (m,
1H), 5.02-4.90
(m, 1H), 4.90-
4.50 (m, 2H),
4.15 (d, J=13.2
Hz, 2H), 3.85-
3.00 (m, 4H),
1.60-1.40 (m,
6H).
114 NMR (400
MHz, CDC13) 6
8.09 (s, 1H), 7.86
(d, i= 7.6 Hz,
*(Nj.? 1H), 7.57-7.52
(m, 1H), 7.47 (t. J
= 7.6 Hz, 2H),
F3C 7.36 (s, 1H),
N
0 699.14 7.00-6.93 (m,
26 CI
++++
1H), 6.66-6.60
\
\ S S (m, 1H), 6.44-
\ 6.40 (m, 1H),
5.79 (dd, J= 10.4
= Hz, 2.0 Hz, 1H),
5.20-4.15 (m,
10H), 3.43-3.37
(m, 3H), 1.57-
1.56 (m, 6H).
210
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, CDC13) 6
8.21 (s, 1H), 8.13
(s, 1H), 7.83-7.79
(m, 1H), 7.60-
7.54 (m, 1H),
(Njµ.
7.40-7.32 (m,
4H), 6.66-6.59
(m, 1H), 6.43 (dd,
F3C
N J= 1.6 Hz, 16.4
N A0
Hz, 1H), 5.81 (dd,
27 685.1 ++
ci J= 1.6 Hz, 10.8
\ S S Hz, 1H), 5.39-
\
5.32 (m, 4H),
5.12-4.95 (m,
3H), 4.76-4.61
(m, 2H), 4.24-
4.17 (m, 2H),
2.01-2.00 (m,
6H).
11-1NMR (400
MHz, CDC13) 6
8.11 (s, 1H),
7.87-7.77 (m,
2H), 7.36 (s, 1H),
6.98 (s, 1H),
6.67-6.59 (m,
4( N joo
1H), 6.42 (dd, J=
16.4 Hz, 2.0 Hz,
F3C 1H), 5.79 (dd, J=
N 10.4 Hz, 1.6 Hz
28
0 636.2
1H), 5.64-5.42 ++++
CI S S (m, 1H), 5.29-
\
5.17 (m, 1H),
5.11-4.95(m,
1H), 4.79-4.64
(m, 2H), 4.21-
4.18 (m, 2H),
3.80-3.67 (m,
1H), 3.41-3.38
(m, 3H), 1.55-
1.54 (m, 6H).
211
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, CDC13) 6
8.27 - 8.22 (m,
1H), 8.20 - 8.15
(m, 1H), 8.09 8.06 (m, 2H),
7.36 - 7.35 (m,
Me N Me
1H), 7.00 - 6.87
(m, 1H), 6.67 -
N
6.57 (m, 1H),
F3C
29 N 663 6.45 - 6.38 (m, ++++
0 1H), 5.82 - 5.58
CI
\ (m, 2H), 5.01 -
\ S S 4.78 (m, 1H),
b = _rN
4.71 - 4.58 (m,
2H), 4.27 - 4.09
(m, 2H), 3.70 -
3.26 (m, 4H),
3.19 - 3.02 (m,
1H), 1.64 - 1.50
(m, 6H).
1H NMR (400
MHz, CDCL3-d)
5, 8.06 (s, 1H),
7.37 (d, J = 1.6
Hz, 1H), 7.07 -
6.83 (m, 1H),
6.63 (dd, J = 10.4,
16.8 Hz, 1H),
Me N Me 6.42 (dd, J = 2.0,
16.8 Hz, 1H),
5.78 (dd, J = 1.9,
30 785 +++
F3C N 10.4 Hz, 1H),
N0 5.29 - 5.17 (m,
1H), 4.72 - 4.60
CI
S (m, 1H), 4.22 -
4.11 (m, 2H),
3.39 - 3.27 (m,
2H), 3.14 - 3.01
(m, 2H), 2.98 -
2.87 (m, 1H),
1.98 - 1.76 (m,
2H), 1.62 (br d, J
212
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
= 6.8 Hz, 3H),
1.49 (br d. J = 6.8
Hz, 3H), 0.99 (t, J
= 7.6 Hz, 3H)
1H NMR
(400MHz,
CDC13) 6 8.14 -
8.05 (m, 2H),
7.59 (ddd, J = 2.0,
7.2, 8.4 Hz, 1H),
Me N Me 7.34 (s, 1H), 7.01
-6.86 (m, 2H),
6.77 (d, J = 8.4
Hz, 1H), 6.63 (dd,
31 F3C
662.2
J= 10.4, 16.8 Hz, ++++
0 1H), 6.42 (dd, J =
CI 1.6, 16.8 Hz, 1H),
S S
5.84 - 5.70 (m,
2H), 5.00 - 4.57
(m, 4H), 4.20 -
4.10 (m, 2H),
3.52 - 3.33 (m,
4H), 1.55 (br s,
6H).
1H NMR (400
MHz, CDC13) 6
8.93 (d, J = 4.0
Hz, 1H), 8.09 (s,
O 1H), 7.66 - 7.56
y
(m, 1H), 7.35 (d,
4.(N
7.21 (d, J = 8.4
Hz, 1H), 7.03 -
32 F3C
N 663 6.87 (m, 1H), ++++
6.68 - 6.58 (m,
N 0 1H), 6.42 (dd, J =
CI
S S 2.0, 16.6 Hz, 1H),
5.89 - 5.76 (m,
2H), 4.97 - 4.89
N-N
(m, 1H), 4.83 (s,
2H), 4.75 - 4.70
(m, 1H), 4.27 -
4.15 (m, 2H),
213
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
3.48 - 3.39 (m,
2H), 3.38 - 3.31
(m, 1H), 3.17 (dd,
J = 2.4, 13.6 Hz,
1H), 1.61 (d, J =
7.2 Hz, 3H), 1.50
(d, J = 7.2 Hz,
3H)
1H NMR (400
MHz, cdc13) 6
8.86 (s, 1H), 8.50
(d, J = 4.0 Hz,
1H), 8.16 - 8.07
(m, 1H), 7.33 (d,
J = 12.0 Hz, 1H),
6.89 - 6.88 (m, J
= 6.1 Hz, 2H),
Me N Me
6.62 (dd, J = 16.0,
12.0 Hz, 1H),
6.42 (dd, J = 16.0,
F3C
33 N 663 4.0 Hz, 1H), 5.79 ++++
N,L0 (dd, J = 12.0, 4.0
CI Hz, 1H), 5.77 -
\ S )
5.74 (m, 1H),
o-
',N 4.76 - 4.69 (m,
3H), 4.22 - 4.18
(m, 2H), 3.46 -
3.34 (m, 4H),
3.17 - 3.13 (m,
1H), 1.61 (d, J =
8.0 Hz, 3H), 1.47
(d, J = 8.0 Hz,
3H).
214
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, CDC13-d) 6
,8.64 (d, J = 5.8
Hz, 2H), 8.13 (s,
1H), 7.39 (br d, J
ro =4.8 Hz, 3H),
7.08 - 6.88 (m,
Me N Me 1H), 6.65 (dd, J =
10.8, 16.8 Hz,
1H), 6.44 (dd, J =
F3C 1.6, 16.8 Hz, 1H),
34 663.4 ++++
0 5.81 (dd, J = 1.6,
10.4 Hz, 1H),
CI \
S 4.93 - 4.44 (m,
4H), 4.27 - 4.12
(m, 2H), 3.89 -
3.63 (m, 2H),
-N
3.42 (ddd, J = 4.8,
13.6, 17.6 Hz,
2H), 3.24 - 3.10
(m, 1H), 1.62 -
1.52 (m, 6H)
1H NMR (400
MHz, CDC13-d) 5
= 8.62 (d, J = 5.6
Hz, 2H), 8.13 (s,
1H), 7.39 - 7.32
(m, 3H), 7.12 -
MeNMe 6.89 (m, 1H),
6.70 - 6.61 (m,
1H), 6.44 (dd, J =
F3C 1.6, 16.8 Hz, 1H),
35 646.2 ++++
5.83 - 5.79 (m,
CIO
1H), 4.88 - 4.61
S S (m, 4H), 4.19 (br
dd, J = 9.2, 11.4
Hz, 2H), 3.83 -
3.66 (m, 2H),
N=Ni 3.46 - 3.37 (m,
2H), 3.22 - 3.09
(m, 1H), 1.61 (br
d, J = 6.8 Hz,
215
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) PERK
1H-NMR (RI)
m/s
4h
[M+H]
3H), 1.54 (br d, J
= 7.2 Hz, 3H)
1H NMR (400
MHz, CDC13) 6
8.05 (s, 1 H), 7.48
(d, J = 1.2 Hz, 1
H), 6.98 (s, 1 H),
6.66 - 6.60 (m, 1
H), 6.42 (dd, J =
16.4, 1.6 Hz, 1
H), 5.78 (dd, J =
10.4, 1.6 Hz, 1
Me N Me
H), 5.45 - 5.44
(m, 1 H), 4.66 -
N 4.63 (m, 2 H),
36 F3C 645 4.21 - 4.18 (m, 2 +++
N
Br\ NLo H), 3.69 - 3.66
(m, 2 H), 3.42 (s,
S 3 H), 3.40 (d, J =
3.2 Hz, 1 H), 3.36
OMe (d. J = 3.2 Hz, 1
H), 3.32 (dd, J =
13.6, 4.4 Hz,
H), 2.98 (dd, J =
13.2, 2.8 Hz,
H), 1.62 (d, J=
6.8 Hz, 3 H), 1.48
(d, J = 6.8 Hz, 3
H).
1H NMR (400
Jo MHz,
CHLOROFORM-
Me N" (m, 1H), Me d) 6, 8.54 - 8.45
D 8.01 (s,
1H), 7.70 - 7.56
F3C (m, 1H), 7.30 -
37 N 616.2 ++++
7.22 (m, 2H),
N0
7.10 (s, 1H), 6.98
CI
S S - 6.78 (m, 1H),
6.62 - 6.50 (m,
N 1H), 6.35 (dd, J =
2.0, 16.8 Hz, 1H),
5.71 (dd, J = 2.0,
216
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) PERK
1H-NMR (RI)
m/s
4h
[M+H]
10.4 Hz, 1H),
5.02 - 4.85 (m,
2H), 4.72 - 4.45
(m, 2H), 4.20 -
4.03 (m, 2H),
3.96 - 3.74 (m,
1H), 3.63 - 3.41
(m, 2H), 3.34 -
3.19 (m, 2H),
1.51 (br s, 3H),
1.46- 1.38(m,
3H).
1H NMR (400
MHz, CDC13) 6,
8.54 - 8.45 (m,
1H), 8.01 (s, 1H),
7.70 - 7.56 (m,
1H), 7.30 - 7.22
(m, 2H), 7.10 (s,
1H), 6.98 - 6.78
(m, 1H), 6.62 -
Me N Me
6.50 (m, 1H),
6.35 (dd, J = 2.0,
16.8 Hz, 1H),
C
F3
38 616.2 5.71 (dd, J = 2.0, ++++
10.4 Hz, 1H),
CI \ N 0 5.02 - 4.85 (m,
S 2H), 4.72 - 4.45
(m, 2H), 4.20 -
4.03 (m, 2H),
3.96 - 3.74 (m,
1H), 3.63 - 3.41
(m, 2H), 3.34 -
3.19 (m, 2H),
1.51 (br s, 3H),
1.46- 1.38(m,
3H)
217
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, CDC13) 6 =
8.60 - 8.54 (m,
1H), 8.08 - 8.06
(m, 1H), 7.69 (s,
1H), 7.32 - 7.29
(m, 2H), 7.23 -
Me.1/4(Nj,õMe 7.17 (m, 1H),
6.96 (s, 1H), 6.63
(dd, J = 16.0, 12.0
F3C Hz, 1H), 6.42 (dd,
N N
39
NLo 646.1 J = 16.0, 4.0 Hz, ++++
1H), 5.78 (dd, J =
CI \
S 12.0, 4.0 Hz, 1H),
5.01 (s, 2H), 4.80
- 4.55 (m, 2H),
4.20 - 4.14 (m,
2H), 4.00 - 3.85
(m, 1H), 3.65 -
3.48 (m, 2H),
3.38 - 3.30 (m,
2H), 1.58- 1.40
(m, 6H).
1H NMR (400
MHz, DMSO-d6)
6: 8.01 (s, 1H),
7.89 (s, 1H), 7.38
- 7.01 (m, 1H),
6.82 (dd, J = 10,4,
Me N Me
16.4 Hz, 1H),
6.20 (dd, J = 2.0,
16.8 Hz, 1H),
F3C
40 N 625.2 5.84 - 5.69 (m, +++
1H), 4.70 - 4.47
N
CI 0
S (m, 3H), 4.06 (br
S
d, J = 7.2 Hz,
o 3H), 3.65 - 3.52
(m, 1H), 3.32 -
3.16 (m, 5H),
1.40 (br d. J= 1.2
Hz, 6H), 0.60 -
0.43 (m, 4H)
218
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) PERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, CDC13) 6=
8.78 (s, 2H), 8.09
(s, 1H), 7.33 (s,
1H), 6.93 (s, 1H),
Me N Me 6.62 (dd, J = 16.0,
12.0 Hz, 1H),
6.42 (dd, J = 16.0,
F3C N 4.0 Hz, 1H), 5.77
41 647.1 (dd, J = 12.0, 4.0 ++++
N0 Hz, 1H), 5.24 -
--..
CI \
S S 5.22 (m, 1H),
4.99 - 4.95 (m,
1H), 4.80 - 4.45
N
\- (m, 2H), 4.15 -
4.12 (m, 3H),
3.69 - 3.23 (m,
4H), 1.73 - 1.42
(m, 6H).
1H NMR (400
MHz, CDC13) 6
8.12 (dd, J = 4.8,
1.2 Hz, 1 H), 8.08
(s, 1 H), 7.59 (t, J
=7.6 Hz, 1 H),
7.47 (s, 1 H), 7.07
- 6.95 (m, 1H),
Me N Me
6.90 (dd, J = 6.4,
5.2 Hz, 1 H), 6.77
(d, J = 8.4 Hz, 1
F3C
42 707.9 H), 6.64 (dd, J = ++
N'Lo 16.4, 10.4 Hz, 1
Br H), 6.43 (dd, J =
S S
16.4, 2.0 Hz, 1
H), 5.81 - 5.78
(m, 2 H), 4.92 -
4.88 (m, 4 H),
4.21 -4.17 (m, 2
H), 3.49 - 3.41
(m, 1 H), 3.41 -
3.32 (m, 3 H),
1.56 (s, 6 H).
219
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, DMSO-d6)
6 8.58 (s, 1H),
8.48 (d, J = 4.4
Hz, 1H), 8.06 (s,
0 1H), 7.88 (s, 1H),
7.84 - 7.68 (m,
Me N Me
)' 1H), 7.37 (s, 1H),
7.33 - 6.98 (m,
N 1H), 6.82 (dd, J =
F3C 10.4, 16.4 Hz,
43 N 646.1 ++++
1H), 6.20 (dd, J =
N0
2.4, 16.4 Hz, 1H),
CI
\ S S ) 5.78 - 5.71 (m,
\ 1H), 4.86 - 4.47
.---
(m, 4H), 4.08 (d,
IN J = 13.2 Hz, 2H),
\¨/
3.97 - 3.68 (m,
1H), 3.67 - 3.35
(m, 2H), 3.29 -
3.22 (m, 2H),
1.40 (s, 611)
1H NMR (400
MHz, DMSO-d6)
6 8.59 (s, 1H),
8.48 (d, J = 4.0
0 Hz, 1H), 8.06 (s,
1H), 7.89 (s, 1H),
Me N Me
)' 7.79 (d, J = 6.8
Hz, 1H), 7.38 (s,
N 1H), 7.32 - 6.94
F3C
N (m, 1H), 6.82 (dd,
44
N0 646
J = 10.4, 16.4 Hz, ++++
CI 1H), 6.20 (dd, J =
2.4, 16.4 Hz, 11-I),
5.82 - 5.68 (m,
1H), 4.89 - 4.34
N
¨ (m, 4H), 4.08 (d,
J = 13.6 Hz, 2H),
4.03 - 3.71 (m,
1H), 3.70 - 3.35
(m, 2H), 3.26 -
220
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
2.96 (m, 2H),
1.40 (s, 6H)
1H NMR (400
MHz, CDC13)
07 8.72 (s, 2H), 8.09
(s, 1H), 7.32 (m,
=%,.(NjA
1H), 7.20 (m,
1H), 6.93 (m,
F3C 1H), 6.65 (m,
45 647.2 1H), 6.43 (m, +++
CI 0 1H), 5.81 (m,
1H), 5.32 ¨ 4.43
S (m, 4H), 4.25 ¨
3.65 (m, 4H),
N 3.50 ¨ 3.10 (m,
3H), 1.47- 1.45
(m, 6H)
1H NMR (400
MHz, CDC13) 6
07 8.73 (s, 2H), 8.10
(s, 1H), 7.32 (m,
MeTN,Me
1H), 7.24 (m,
1H), 6.92 (m,
1H), 6.66 (m,
F3C
46 647.2 1H), 6.45 (m, ++++
1H), 5.82 (m,
N 0
CI 1H), 5.34 ¨ 4.45
S S
(m, 4H), 4.26 ¨
3.66 (m, 4H),
N 3.52 ¨ 3.12 (m,
3H), 1.50 - 1.47
(m, 6H)
221
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz,
CHLOROFORM-
d) 5 ppm 1.50
O 1.62 (m, 6 H)
2.98 - 3.30 (m, 1
Me N Me H) 3.35 - 3.46 (m,
2 H) 3.52 - 3.83
(m, 1 H) 4.05 -
F3C N 4.29 (m, 3 H)
47
CI
No 664 4.45 - 5.09 (m, 4 ++++
H) 5.80 (dd, J =
\ S S 10.4, 2.0 Hz, 1 H)
F 6.43 (dd, J = 16.8,
\ 2.0 Hz, 1H) 6.58
- 6.70 (m, 1H)
6.82 - 7.08 (m, 1
H) 7.28 - 7.39 (m,
2H) 8.11 (s, 1 H)
8.35 - 8.55 (m, 2
H).
1H NMR (400
MHz,
CHLOROFORM-
d) 6 ppm 1.45 -
1.61 (m, 6 H)
2.98 - 3.28 (m, 1
H) 3.35 - 3.47 (m,
Me N Me
2 H) 3.51 - 3.82
(m, 1 H) 4.06 -
N
4.30 (m, 3 H)
F3C
N 4.45 - 5.04 (m, 4
48
No 664.2
+++
H) 5.80 (dd, J =
CI 10.4, 2.0 Hz, 1 H)
S S \ 6.43 (dd, J = 16.8,
2.0 Hz, 1 H) 6.64
(dd, J = 16.8, 10.4
-N Hz, 1 H) 6.82 -
7.06 (m, 1H)
7.27 - 7.40 (m, 2
H) 8.11 (s, 1 H)
8.34 - 8.56 (m, 2
H).
222
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, CDC13)
8.50 (s, 1H), 8.44
(d, J = 2.4 Hz,
1H), 8.12 (s, 1H),
7.54 - 7.45 (m,
Me41/4(N),,Me 1H), 7.43 - 7.31
(m, 1H), 7.08 -
N 6.85 (m, 1H),
F3C 6.69 - 6.59 (m,
N 1H), 6.43 (dd, J =
49 664 ++++
N 0 2.0, 16.8 Hz, 1H),
CI
S S 5.83 - 5.76 (m,
1H), 4.96 - 4.52
(m, 4H), 4.22 -
QN 4.15 (m, 2H),
3.97 - 3.62 (m,
2H), 3.46 - 3.36
(m, 2H), 3.19 -
3.00 (m, 1H),
1.58 - 1.49 (m,
6H)
1H NMR (400
MHz, CDC13) 5
8.50 (s, 1H), 8.46
- 8.40 (m, 1H),
8.12 (s, 1H), 7.53
- 7.43 (m, 1H),
Me N Me
D" 7.38 (s, 1H), 7.11
-6.82 (m, 1H),
F3C 6.64 (dd, J = 10.4,
N 16.4 Hz, 1H),
N0 664 6.43 (dd, J = 2.0, ++++
CI 16.4 Hz, 1H),
S N 5.82 - 5.77 (m,
1H), 4.91 - 4.50
(m, 4H), 4.22 -
4.15 (m, 2H),
3.93 - 3.64 (m,
2H), 3.41 (ddd, J
= 4.8, 13.2, 17.6
Hz, 2H), 3.17 -
3.00 (m, 1H),
223
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1.58 (d, J = 6.8
Hz, 3H), L52 (d,
J = 6.8 Hz, 3H)
1H NMR (400
MHz, CDC13) 6
8.05 (s, 1H), 7.35
(s, 1H), 7.00 -
6.91 (m, 1H),
6.62 (dd, J = 16.0,
10.0 Hz, 1H),
6.41 (dd, J = 16.0,
MeN)õMe
4.0 Hz, 1H), 5.77
(dd, J = 12.0, 4.0
Hz, 111), 4.72 -
F3C
51 N 609.2 4.47 (m, 4H), ++
4.21 - 4.08 (m,
0
CI N 2H), 3.46 - 3.20
S S
(m, 4H), 3.01
2.98 (m, 1H),
1.59 - 1.57 (m,
6H), 0.89 - 0.83
(m, 1H), 0.68 -
0.58 (m, 1H),
0.51 - 0.40 (m,
2H), 0.16 - 0.13
(m, 1H).
1H NMR (400
MHz, CDC13) 6
8.05 (s, 1H), 7.35
(s, 1H), 7.00 -
6.91 (m, 1H),
Me N Me
6.61 (dd, J = 16.0,
10.0 Hz, 1H),
6.41 (dd, J = 16.0,
F3C
52 N 609.2 4.0 Hz, 1H), 5.77 +++
N0 (dd, J = 12.0, 4.0
CI Hz, 1H), 4.77 -
\ S 4.32 (m, 4H),
4.21 - 4.08 (m,
2H), 3.41 - 3.25
(m, 3H), 3.01 -
2.98 (m, 1H),
1.59- 1.57(m,
224
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
6H), 1.28 - 1.24
(m, 1H), 0.89 -
0.83 (m, 1H),
0.68 - 0.58 (m,
1H), 0.51 - 0.40
(m, 2H), 0.16 -
0.13 (m, 1H).
1H NMR (400
MHz, CDC13) 6
ppm 1.51 - 1.61
(m, 6 H) 2.99 -10).
3.21 (m, 1 H)
Me N Me 3.29 - 3.46 (m, 2
D" H) 3.55 - 3.74 (m,
1 H) 3.86 - 4.05
F3C (m, 1 H) 4.17 (t.
N
53
CI NO 669 J=11.2 Hz, 2 H) ++++
4.43 - 5.00 (m, 4
S S H) 5.76- 5.83 (m,
1 H) 6.43 (dd,
J=16.8, 2.0 Hz, 1
S H) 6.54 - 6.73 (m,
2 H) 6.82 (s, 1 H)
6.86 - 7.10 (m, 1
H) 7.37 (s, 1H)
8.09(s, 1H)
1H NMR (400
MHz, CDC13) 6
ppm 1.51 - 1.61
O (m, 6 H) 2.99 -
Me N Me 3.21 (m, 1 H)
3.29 - 3.46 (m, 2
H) 3.55 - 3.74 (m,
F3C 1 H) 3.86 - 4.05
N
54 669 (m, 1 H) 4.17 (t, +++
N0
J=11.2 Hz, 2H)
CI \
S 4.43 - 5.00 (m, 4
H) 5.76 - 5.83 (m,
1 H) 6.43 (dd,
S\1 J=16.8, 2.0 Hz, 1
H) 6.54 - 6.73 (m,
2 H) 6.82 (s, 1 H)
6.86 - 7.10 (m, 1
225
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
H) 7.37 (s, 1H)
8.09(s, 1H)
1H NMR (400
MHz, CDC13) =
O 8.61 (s, 1H), 7.84
- 7.63 (m, 2H),
7.33 (s, 1H), 7.02
- 6.98 (m, 3H),
F3C N 6.59 (dd, J = 16.0,
N0 619.1 10.0 Hz, 1H), +++
6.36 (dd, J = 16.0,
CI
S S 4.0 Hz, 1H), 5.78
(dd, J = 12.0, 4.0
Hz, 111), 5.09 -
N \ 4.84 (m, 2H),
4.16- 3.45 (m,
11H).
1H NMR (400
MHz, CDC13) 6 =
8.60 - 8.54 (m,
1H), 7.81 (s, 1H),
7.71 (s, 1H), 7.46
- 7.27 (m, 3H),
6.99 - 6.86 (m,
F3C
N 1H), 6.60 (dd, J =
N0
16.0, 10.0 Hz,
56 619.1 ++++
CI 1H), 6.37 (dd, J=
s S 16.0, 4.0 Hz, 1H),
5.79 (dd, J = 12.0,
NO 4.0 Hz, 1H), 5.07
- 4.90 (m, 2H),
4.01 - 3.47 (m,
11H).
226
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1H NMR (400
MHz, CDC13-d)
6, 8.57 (s, 1H),
8.48 - 8.40 (m,
2H), 8.02 (s, 1H),
7.26 (s, 1H), 6.87
Me N Me (br s, 1H), 6.59 -
6.52 (m, 1H),
6.35 (dd, J = 1.6,
F3C 16.8 Hz, 1H),
N
57 647.2 5.72 (dd, J = 1.6, ++++
N 0 10.4 Hz, 1H),
CI
S S 4.94 (br s, 2H),
4.75 - 4.46 (m,
2H), 4.09 (br d, J
N N = 12.8 Hz, 2H),
4.01 - 3.82 (m,
1H), 3.61 - 3.34
(m, 2H), 3.33 -
3.26 (m, 2H),
1.46 (br s, 6H)
1H NMR (400
MHz, DMSO-d6)
8.73 - 8.59 (m,
1H), 8.55 (t, J =
5.6 Hz, 1H), 8.07
(s, 1H), 7.90 (d, J
= 1.2 Hz, 1H),
Me.,(N).,Me
7.35 (dd, J = 5.2,
10.4 Hz, 1H),
7.30 - 7.02 (m,
F3C
N 1H), 6.82 (dd, J =
58 664.1 ++++
N0 9.6, 16.6 Hz, 1H),
CI 6.20 (dd, J = 2.4,
S S\__) 16.6 Hz, 1H),
F
5.80 - 5.68 (m,
1H), 4.85 (dd, J =
N¨ 8.8, 13.2 Hz, 1H),
4.66 - 4.53 (m,
2H), 4.09 (d, J =
12.4 Hz, 2H),
3.94 - 3.81 (m,
1H), 3.33 - 3.21
227
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
(m, 5H), 1.42 (d,
J = 2.4 Hz, 6H)
1H NMR (400
MHz,
CHLOROFORM-
d) 6 ppm 2.91 -
3.30 (m, 1 H)
3.59 - 4.25 (m, 10
H) 4.90 (d, J =
1.2 Hz, 2 H) 5.80
F3C
N (dd, J = 10.4, 1.6
59
N0 636.2
Hz, 1 H) 6.39 (dd, ++++
CI J = 16.8, 1.6 Hz,
S S
F 1 H) 6.60 (dd, J =
=
16.8, 10.4 Hz, 1
\ H) 6.84 - 7.06 (m,
-N 1 H) 7.29 - 7.41
(m, 2 H) 7.86 (s,
1 H) 8.33 - 8.57
(m, 2 H).
1H NMR (400
MHz, DMSO-d6)
6=8.54 (rd,J=
4.8 Hz, 2H), 7.90
(d, J = 15.1 Hz,
2H), 7.39 (d, J =
F3C 5.8 Hz, 3H), 6.83
N
N 618.3 (d. J = 10.4, 16.7 +++
60 CI
Hz, 1H), 6.18 (d,
S S J = 2.4, 16.8 Hz,
1H), 5.79 - 5.70
(m, 1H), 4.80 -
4.59 (m, 2H),
-N 3.94 - 3.54 (m,
11H)
228
SUBSTITUTE SHEET (RULE 26)
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MS
Ex. Structure (ES!) pERK
1H-NMR (RI)
m/s
4h
[M+H]
1HNMR (400
MHz, CDC13) 6
8.48 (d, J = 5.2
Hz, 1H), 8.11 (s,
1H), 7.37 (s, 2H),
7.20 - 7.08 (m,
(N 2H), 6.72 - 6.57
(m, 1H), 6.51 -
N 6.37 (m, 1H),
F3C 5.86 - 5.72 (m,
N
N0 660.4 1H), 4.86 - 4.56
+++
61 CI
(m, 4H), 4.21 -
S 4.14 (m, 2H),
3.77 - 3.62 (m,
2H), 3.43 - 3.34
Me (m, 2H), 3.21 -
¨N 3.04 (m, 1H),
2.57 (s, 3H), 1.60
(d, J = 6.8 Hz,
3H), 1.52 (d, J =
6.8 Hz, 3H)
1H NMR (400
MHz, CDC13) 6
8.48 (d, J = 5.4
Hz, 1H), 8.11 (s,
1H), 7.38 (s, 2H),
7.18 - 7.10 (m,
2H), 6.64 (d, J =
4,(N j,o
10.4, 16,4 Hz,
1H), 6.43 (d, J =
F3C 2.0, 16.8 Hz, 1H),
N 5.85 - 5.74 (m,
62
N0 660.4
1H), 4.90 - 4.60 ++++
CI S S (m, 4H), 4.22 -
\
4.14 (m, 2H),
3.79 - 3.59 (m,
O¨Me 2H), 3.44 - 3.34
¨N (m, 2H), 3.23 -
3.04 (m, 1H),
2.57 (s, 3H), 1.60
(d, J = 6.8 Hz,
3H), 1.52 (r d, J =
6.4 Hz, 3H)
229
SUBSTITUTE SHEET (RULE 26)
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+ = >500 nM; ++ = 200 to 500 nM; +++ = 50 to <200 nM; ++++ = 0.1 nM to < 50
nM.
[0342] Although the foregoing embodiments have been described in some detail
by way of
illustration and Example for purposes of clarity of understanding, one of
skill in the art will
appreciate that certain changes and modifications may be practiced within the
scope of the
appended claims. In addition, each reference provided herein is incorporated
by reference in
its entirety to the same extent as if each reference was individually
incorporated by reference.
Where a conflict exists between the instant application and a reference
provided herein, the
instant application shall dominate.
230
SUBSTITUTE SHEET (RULE 26)
