Note: Descriptions are shown in the official language in which they were submitted.
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HETEROCYCLIC INHIBITORS OR PHOSPHATASES,
COMPOSITIONS AND USES THEREOF
TECHNICAL FIELD OF THE INVENTION
[0001]The present invention relates to compounds that
inhibit phosphatases, compositions thereof, and methods
of using those compounds and compositions for treating
diseases.
BACKGROUND OF THE INVENTION
[0002] Many biologically important functions are
regulated by the transfer of a phosphate group. Often,
the active or inactive form of a compound is determined
by the presence or absence of a phosphate group bound to
that compound. Accordingly, many biological enzymes are
involved in regulating this phosphate group transfer.
For example, kinase enzymes catalyze transfer of a
phosphate group from a nucleoside triphosphate to a
protein receptor. In contrast, phosphatase enzymes
remove a phosphate group from a substrate by hydrolysis.
[0003]SHP-2 (src homology 2-containing protein
tyrosine phosphatase) is a 68 kDa phosphatase protein and
is also known as SHPTP2, Syp, PTP1D and PTP2C. Lu et
al., Molecular Cell (2001) 8, 759. The enzyme is
expressed in the cytoplasm of every tissue. SHP-2 is an
important signaling enzyme, and the biological functions
of SHP-2 have been extensively reviewed. Feng, Exp. Cell
Res. (1999) 253, 45; Neel and Tonks, Curr. Opin. Cell
Biol. (1997) 9, 193; Tonks, Adv. Pharmacol. (1996) 36,
91. The enzyme is activated through interactions with a
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variety of ligands including growth factors, cytokine
receptor tyrosine kinases, and adhesion molecules and is
most notably recognized as a positive regulator of cell
proliferation. SHP-2 also plays an important function in
immune signaling. 'Huyer and Alexander, Curr. Biol.
(1999) 9, R129; Cohen et al., Cell (1995) 80, 237. The
SHP-2 enzyme is required for activation of the Ras-MAP
kinase cascade, although its precise role in the pathway
is unclear. Van Vactor et al., Curr. Opin. Genet. Dev.
(1998) 8, 112. SHP-2 has recently been identified as an
intracellular target of Helicobacter pylori. Higashi et
al., Science (2002) 295, 683. Due to the critical role
SHP-2 plays in various biological pathways, development
of inhibitors against the enzyme would provide useful
treatments for cancer and other autoimmune diseases.
'[0004] Development of new chemical entities that
modulate phosphatase enzymes such as SHP-2 would be an
important advance and could lead to the development of
novel treatments for diseases in which phosphatase
enzymes play a critical role. The development of
phosphatase modulators is an active area of research and
has been extensively reviewed. Ripka, Annual Rev. Med.
Chem. 2000, 35, Chapter 21 and references cited therein.
[0005] More recent work has focused on the
development of new heterocyclic groups that can mimic a
phosphate moiety, i.e. the development of phosphate
isosteres. A successful phosphate isostere will ideally
be both nonhydrolyzable and bioavailable. Successful
phosphate mimicry will also depend on the shape and
ionization state of the mimic. Examples of new
heterocyclic groups designed to mimic a phosphate moiety
include tetronic acid derivatives investigated against
Cdc25b, Sodeoka et al., J. Med. Chem. (2001) 44(20),
3216, and the azoledinedione class of inhibitors that
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have been investigated against protein tyrosine
phosphatase 1B (PTB1B). Malamas et al., J. Med. Chem.
(2000) 43, 995. However, the efficacy of these mimics is
still being investigated.
[0006] There is still a great need to develop potent
modulators of phosphatase enzymes and other enzymes that
are involved in regulating the transfer of a phosphate
group.
SUMMARY OF THE INVENTION
.[0007] The present invention relates to compounds
of formula (I):
0 R1
R3\
N Ra
A
R4 N O
1
R2 (I) ;
wherein:
ring A is an aryl or heteroaryl ring;
Ra is -COOH, a salt or an ester thereof, or a
bioisostere thereof;
n is 1-3;
R1 is H, hydroxyaliphatic, aminoaliphatic, aliphatic-
COOH, aliphatic-CONH2, or arylaliphatic;
R2 is aliphatic, arylaliphatic, cycloaliphatic-
aliphatic, heteroarylaliphatic, or heterocyclylaliphatic;
3 4
R and R are independently selected from R11, R12, R14 or
R15;
wherein:
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each R11 is independently selected from 1,2-
methylenedioxy, 1,2-ethylenedioxy, R6 or (CH2)m Y;
wherein m is 0, 1 or 2; and
Y is selected from halogen, CN, N02, CF3, OCF3,
OH, SR6, S(O)R6, S02R6, NH2, NHR6, N(R6)2, NR6R8, COOH,
COOR6 or OR6;
each R12 is independently selected from (C1-C6)-
straight or branched alkyl, or (C2-C6)-straight or
branched alkenyl or alkynyl; and each R12 optionally
comprises up to 2 substituents, wherein:
the first of said substituents, if present, is
selected from R11, R14 and R15, and
the second of said substituents, if present, is
R11;
each R14 is independently selected from OR15,
OC(O)R6, OC(O)R15, OC(O)OR6, OC(O)OR15, OC(O)N(R6)2,
OP(O)(OR6)2, SR6, SR15, S(O)R6, S(O)R15, S02R6, S02R15,
S02N(R6)2, S02NR15R6, S03R6, C(O)R15, C(O)OR15, C(O)R6,
C(O)0R6, NC(O)C(O)R6, NC (O) C (O) R15, NC(O)C(O)0R6,
NC(O)C(O)N(R6)2, C(O)N(R6)2, C(O)N(OR6)R6, C(O)N(OR6)R15,
C(NOR6)R6, C(NOR6)R15, N(R6)2, NR6C(O)R11, NR6C(O)R6,
NR6C(O)R15, NR6C(O)OR6, NR6C(O)OR15, NR6C(O)N(R6)2,
NR6C(O)NR15R6, NR6SO2R6, NR6S02R15, NR6S02N(R6)2,
NR6S02NR15R6, N(OR6)R6, N(OR6)R15, P(O)(OR6)N(R6)2, and
P(O) (OR6)2;
each R15 is a cycloaliphatic, aryl, heterocyclyl, or
heteroaromatic; and each R15 optionally comprises up to 3
substituents, each of which, if present, is R11;
each R6 is independently selected from H, (C1-C6)-
straight or branched alkyl, or (C2-C6) straight or
branched alkenyl; and each R6 optionally comprises a
substituent that is R7;
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R7 is a cycloaliphatic, aryl, heterocyclyl, or heteroaromatic; and each R7
optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-
straight or branched alkyl, (C2-C6) straight or branched alkenyl, 1,2-
methylenedioxy,
1,2-ethylenedioxy, or (CH2)p-Z;
5 wherein p is 0, 1 or 2; and
Z is selected from halogen, CN, NO2, CF3, OCF3, OH, S(C,-C6)-alkyl,
SO(C1-C6)-alkyl, SO2(C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((Ci-C6)-alkyl)2,
N((C1-C6)-
alkyl)R8, COOH, C(O)O(CI-CO-alkyl or OP-CO-alkyl; and
R8 is an amino protecting group;
provided that:
R3 and R4 are not simultaneously hydrogen;
when R3 is H, then R4 is not chloro; and
when R4 is H, then R3 is not -SCH3 or -NH-C(O)CH3.
[0007a] More particularly, there is provided a compound having formula (I):
0 RI
R3
N n Ra
A
R4 N O
1
R2 (I);
wherein:
ring A is an aryl ring;
Ra is -COOH;
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n is 1;
R1 is a hydroxyaliphatic, aminoaliphatic, aliphatic-COON, aliphatic-
CONH2, or arylaliphatic wherein said hydroxyaliphatic, aminoaliphatic,
aliphatic-
COOH, aliphatic-CONH2, or arylaliphatic is either unsubstituted or substituted
with
one or more substituents selected from halogen, -R , -OR , -SR , 1,2-methylene-
dioxy, 1,2-ethylenedioxy; unsubstituted phenyl (Ph), unsubstituted -O(Ph),
unsubstituted -CH2(Ph), unsubstituted -CH2CH2(Ph) or (Ph), -O(Ph), -CH2(Ph),
or
-CH2CH2(Ph) substituted with one or more -R groups; -NO2, -CN, -N(R )2,
-NR C(O)R , -NR C(O)N(R )2, -NR C02R , -NR NR C(O)R , -NR NR C(O)N(R )2,
-NR NR C02R , -C(O)C(O)R , -C(O)CH2C(O)R , -C02R , -C(O)R , -C(O)N(R )2,
-OC(O)N(R )2, -S(0)2R , -S02N(R )2, -S(O)R , -NR S02N(R )2, -NR S02R ,
-C(=S)N(R )2, -C(=NH)-N(R )2, or -(CH2)gNHC(O)R ; wherein:
q is 0-2; and wherein:
each R is independently selected from hydrogen, a C1_6 aliphatic,
wherein said C1_6 aliphatic group is either unsubstituted or substituted with
one or
more substituents selected from =O, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*,
=NNHCO2(alkyl), =NNHSO2(alkyl), =NR*NH2, NH(C1_4 aliphatic), N(C1_4
aliphatic)2,
halogen, C1-4 aliphatic, OH, O(C14 aliphatic), NO2, CN, CO2H, CO2(C14
aliphatic),
O(halo C1_4 aliphatic), or halo C1_4 aliphatic; an unsubstituted 5-6 membered
heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH2(Ph), or wherein two
occurrences of R , on the same substituent or different substituents, taken
together,
form a 5-8-membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; wherein:
each R* is independently selected from hydrogen or a C1-6 aliphatic
group wherein said aliphatic group of R* is either unsubstituted or
substituted with
one or more substituents selected from NH2, NH(C14 aliphatic), N(C14
aliphatic)2,
halogen, C1_4 aliphatic, OH, O(C14 aliphatic), NO2, CN, CO2H, C02(C1_4
aliphatic),
O(halo C1-4 aliphatic), or halo(C14 aliphatic);
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the nitrogen of any non-aromatic heterocyclic ring is either
unsubstituted or substituted with one or more groups selected from -R+, -
N(R+)2,
-C(O)R+, -OR+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2,
-C(=S)N(R+)2, -C(=NH)-N(R+)2, or -NR+SO2R+; wherein:
R+ is hydrogen, an unsubstituted 5-6 membered heteroaryl or
heterocyclic ring, an unsubstituted C1_6 aliphatic, unsubstituted phenyl (Ph),
unsubstituted -O(Ph), unsubstituted -CH2(Ph), unsubstituted -CH2CH2(Ph); or
C1_6
aliphatic, phenyl(Ph), -O(Ph), -CH2(Ph), or -CH2CH2(Ph) substituted with one
or more
groups selected from NH2, NH(C1-4 aliphatic), N(C1-4 aliphatic)2, halogen, C1-
4
aliphatic, OH, O(C1-4 aliphatic), NO2, CN, CO2H, CO2(C1_4 aliphatic), O(halo
C1_4
aliphatic), or halo(C1-4 aliphatic) or wherein two occurrences of R+, on the
same
substituent or different substituents, taken together, form a 5-8-membered
heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected
from
nitrogen, oxygen, or sulfur;
R2 is an unsubstituted aliphatic, or a cycloaliphatic-aliphatic, or
heteroarylaliphatic, wherein said cycloaliphatic-aliphatic or
heteroarylaliphatic is either
unsubstituted or substituted with one or more substituents selected from
halogen,
-R , -OR , -SR , 1,2-methylene-dioxy, 1,2-ethylenedioxy; unsubstituted phenyl
(Ph),
unsubstituted -O(Ph), unsubstituted -CH2(Ph), unsubstituted -CH2CH2(Ph) or
(Ph),
-O(Ph), -CH2(Ph), or -CH2CH2(Ph) substituted with one or more -R groups; -
NO2,
-CN, -N(R )2, -NR C(O)R , -NR C(O)N(R )2, -NR C02R , -NR NR C(O)R ,
-NR NR C(O)N(R )2, -NR NR C02R , -C(O)C(O)R , -C(O)CH2C(O)R , -C02R ,
-C(O)R , -C(O)N(R )2, -OC(O)N(R )2, -S(O)2R , -S02N(R )2, -S(O)R ,
-NR S02N(R )2, -NR S02R , -C(=S)N(R )2, -C(=NH)-N(R )2, or -(CH2)gNHC(O)R ;
wherein q, R , R* and R+ are as previously defined;
R3 and R4 are independently selected from R11, R12, R14 or R15;
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wherein:
each R" is independently selected from 1,2-methylenedioxy,
1,2-ethylenedioxy, R6 or (CH2)m-Y;
wherein m is 0, 1 or 2; and
Y is selected from halogen, CN, NO2, CF3, OCF3, OH, SR6, S(O)R6,
S02R6, NH2, NHR6, N(R6)2, NR6R8, COOH, COOR6 or OR6;
each R12 is independently selected from (C1-C6)-straight or branched
alkyl, or (C2-C6)-straight or branched alkenyl or alkynyl; and each R12
optionally
comprises up to 2 substituents, wherein:
the first of said substituents, if present, is selected from R11 R14 and
R15, and
the second of said substituents, if present, is R11;
each R14 is independently selected from OR15, OC(O)R6, OC(O)R15
OC(O)OR6, OC(O)OR15, OC(O)N(R6)2, OP(O)(OR6)2, SR6, SR15, S(O)R6, S(O)R15,
SO2R6, SO2R15, SO2N(R6)2, S02NR15R6, SO3R6, C(O)R15, C(O)OR15, C(O)R6,
C(O)OR6, NC(O)C(O)R6, NC(O)C(O)R15, NC(O)C(O)OR6, NC(O)C(O)N(R6)2,
C(O)N(R6)2, C(O)N(OR6)R6, C(O)N(OR6)R15, C(NOR6)R6, C(NOR6)R15, N(R6)2,
NR6C(O)R11, NR6C(O)R6, NR6C(O)R15, NR6C(O)OR6, NR6C(O)OR15,
NR6C(O)N(R6)2, NR6C(O)NR15R6, NR6SO2R6, NR6SO2R15, NR6SO2N(R6)2,
NR6SO2NR15R6, N(OR6)R6, N(OR6)R15, P(O)(OR6)N(R6)2, and P(O)(OR6)2;
each R15 is a cycloaliphatic, aryl, heterocyclyl, or heteroaromatic; and
each R15 optionally comprises up to 3 substituents, each of which, if present,
is R11;
each R6 is independently selected from H, (C1-C6)-straight or branched
alkyl, or (C2-C6) straight or branched alkenyl; and each R6 optionally
comprises a
substituent that is R7;
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R7 is a cycloaliphatic, aryl, heterocyclyl, or heteroaromatic; and each R7
optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-
straight or branched alkyl, (C2-C6) straight or branched alkenyl, 1,2-
methylenedioxy,
1,2-ethylenedioxy, or (CH2)p-Z;
wherein p is 0, 1 or 2; and
Z is selected from halogen, CN, NO2, CF3, OCF3, OH, S(C1-C6)-alkyl,
SO(C1-C6)-alkyl, SO2(C1-C6)-alkyl, NH2, NH(Ci-C6)-alkyl, N((Ci-C6)-alkyl)2,
N((C1-C6)-
alkyl)R8, COOH, C(O)O(C1-C6)-alkyl or O(C1-C6)-alkyl; and
R8 is -C(O)CH3, -C(O)Ph, or -SO2Ph;
wherein the term aryl means monocyclic, bicyclic and tricyclic ring systems
having a
total of five to fourteen ring members, wherein at least one ring in the
system is
aromatic and wherein each ring in the system contains 3 to 7 ring members, the
term
aliphatic means a straight-chain or branched, substituted or unsubstituted
hydrocarbon chain that is completely saturated (alkyl) or is unsaturated
(alkenyl or
alkynyl), the term cycloaliphatic means a 3-8 membered monocyclic hydrocarbon
ring
or a 8-12 membered bicyclic hydrocarbon ring that is completely saturated
(e.g.,
cycloalkyl) or that contains one or more units of unsaturation (e.g.,
cycloalkenyl), but
which is not aromatic, and has a single point of attachment to the rest of the
molecule, the term heterocycle means non-aromatic, monocyclic, bicyclic or
tricyclic
ring systems having in total 5 to 14 ring members in which one or more ring
members
is a heteroatom, wherein each ring in the system contains 3 to 7 ring members,
and
the term heteroaryl means monocyclic, bicyclic and tricyclic ring systems,
wherein at
least one ring in the system is aromatic, at least one ring in the system
contains one
or more heteroatoms,
provided that:
R3 and R4 are not simultaneously hydrogen;
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when R3 is H, then R4 is not chloro; and
when R4 is H, then R3 is not -SCH3 or -NH-C(O)CH3.
[0008] The present invention also relates to compositions thereof, and
methods of treating diseases using such compounds and compositions.
DETAILED DESCRIPTION OF THE INVENTION
[0009] The present invention relates to compounds of formula (I):
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0
R1
R3
N n Ra
R
4
R2 (I);
wherein:
ring A is an optionally substituted aryl or
heteroaryl ring;
Ra is -COOH;
n is 0-4;
R1 is H, or an optionally substituted
hydroxyaliphatic, aminoaliphatic, aliphatic-COOH,
aliphatic-CONH2, or arylaliphatic;
R2 is an optionally substituted aliphatic,
arylaliphatic, cycloaliphatic-aliphatic,
heteroarylaliphatic, or heterocyclylaliphatic;
3 4
R and R are independently selected from R11, R12, R14 or
R15;
wherein:
each R11 is independently selected from 1,2-
methylenedioxy, 1,2-ethylenedioxy, R6 or (CH2)m-Y;
wherein m is 0, 1 or 2; and
Y is selected from halogen, CN, N02, CF3, OCF3,
OH, SR6, S(O)R6, S02R6, NH2, NHR6, N(R6)2, NR6R8, COOH,
COOR6 or OR6;
each R12 is independently selected from (C1-C6)-
straight or branched alkyl, or (C2-C6)-straight or
branched alkenyl or alkynyl; and each R12 optionally
comprises up to 2 substituents, wherein:
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the first of said substituents, if present, is
selected from R11, R14 and R15, and
the second of said substituents, if present, is
R11;
each R14 is independently selected from OR15,
OC(O)R6, OC(0)R15, OC(0)OR6, OC(0)OR15, OC(O)N(R6)2,
OP(0)(OR6)2, SR6, SR15, S(O)R6, S(0)R15, S02R6, S02R15,
S02N(R6)2, S02NR15R6, S03R6, C(O)R-5, C(0)OR15, C(O)R6,
C(O)OR6, NC(O)C(O)R6, NC(O)C(0)R15, NC(O)C(0)0R6,
NC(0)C(0)N(R6)2, C(0)N(R6)2, C(0)N(OR6)R6, C(0)N(OR6)R-5,
C(NOR6)R6, C(NOR6)R15, N(R6)2, NR6C(0)R11, NR6C(O)R6,
NR6C(O)R15, NR6C(0)OR6, NR6C(O)OR15, NR6C(O)N(R6)2,
NR6C(O)NR15R6, NR6S02R6, NR6S02R15, NR6S02N(R6)2,
NR6S02NR15R6, N(OR6)R6, N(OR6)R15, P(0)(OR6)N(R6)2, and
P(O) (OR6)2;
each R15 is a cycloaliphatic, aryl, heterocyclyl, or
heteroaromatic; and each R15 optionally comprises up to 3
substituents, each of which, if present, is R11;
each R6 is independently selected from H, (C1-C6)-
straight or branched alkyl, or (C2-C6) straight or
branched alkenyl; and each R6 optionally comprises a
substituent that is R7;
R7 is a cycloaliphatic, aryl, h.eterocyclyl, or
heteroaromatic; and each R7 optionally comprises up to 2
substituents independently chosen from H, (C1-C6)-
straight or branched alkyl, (C2-C6) straight or branched
alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or
(CH2)p-Z;
wherein p is 0, 1 or 2; and
Z is selected from halogen, CN, N02, CF3, OCF3, OH,
S(C1-C6)-alkyl, SO(C1-C6)-alkyl, S02(C1-C6)-alkyl, NH2,
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NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, N((C1-C6)-alkyl)R8,
COON, C(O)O(C1-C6)-alkyl or O(C1-C6)-alkyl; and
R8 is an amino protecting group;
provided that:
R3 and R4 are not simultaneously hydrogen;
when R3 is H, then R4 is not chloro; and
when R4 is H, then R3 is not -SCH3 or -NH-C (0)CH3.
[0010] As used herein, the following definitions
shall apply unless otherwise indicated.
[0011] The phrase "optionally substituted" is
used interchangeably with the phrase "substituted or
unsubstituted." Unless otherwise indicated, an
optionally substituted group may have a substituent at
each substitutable position of the group, and each
substitution is independent of the other.
[0012] The term "aliphatic" or "aliphatic group",
as used herein, means a straight-chain or branched,
substituted or unsubstituted hydrocarbon chain that is
completely saturated (alkyl) or is unsaturated (alkenyl
or alkynyl). Unless otherwise specified, an aliphatic
group has 1 to 12 carbon atoms. Preferably, an aliphatic
group has 1-6 carbon atoms. Up to two -CH2- in said
aliphatic may be replaced with 0, S, or'-NR,-.
[0013] The term "cycloaliphatic" means a 3-8
membered monocyclic hydrocarbon ring or a 8-12 membered
bicyclic hydrocarbon ring that is completely saturated
(e.g., cycloalkyl) or that contains one or more units of
unsaturation (e.g., cycloalkenyl), but which is not
aromatic, and has a single point of attachment to the
rest of the molecule.
[0014] The term "heteroatom" unless otherwise
specified means nitrogen, oxygen, or sulfur and includes
any oxidized form of nitrogen and sulfur, and the
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quaternized form of any basic nitrogen. Also the term
"nitrogen" includes a substitutable nitrogen of a
heterocyclic ring. As an'example, in a saturated or
partially unsaturated ring having 0-3 heteroatoms
selected from oxygen, sulfur or nitrogen, the nitrogen
may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in
pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl).
[0015] The term "unsaturated", as used herein,
means a double bond or a triple bond. Each such bond
constitutes one unit of unsaturation.
[0016] The term "aryl" used alone or as part of a
larger moiety as in "aralkyl", "aralkoxy", or
"aryloxyalkyl", refers to monocyclic, bicyclic and
tricyclic ring systems having a total of five to fourteen
ring members, wherein at least one ring in the system is
aromatic and wherein each ring in the system contains 3
to 7 ring members. The term "aryl" may be used
interchangeably with the term "aryl ring". Phenyl is an
example of aryl.
[0017] The term "heterocycle", "heterocyclyl",
"heterocycloaliphatic", or "heterocyclic" as used herein
means non-aromatic, monocyclic, bicyclic or tricyclic
ring systems having in total 5 to 14 ring members in
which one or more ring members is a heteroatom, wherein
each ring in the system contains 3 to 7 ring members.
[0018] The term "heteroaryl", used alone or as
part of a larger moiety as in "heteroaralkyl" or
"heteroarylalkoxy", refers to monocyclic, bicyclic and
tricyclic ring systems, wherein at least one ring in the
system is aromatic, at least one ring in the system
contains one or more heteroatoms. Unless otherwise
specified, such ring systems have a total of 5 to 15 ring
members, wherein each ring in the system contains 3 to 7
ring members. The term "heteroaryl" may be used
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interchangeably with the term "heteroaryl ring" or the
term "heteroaromatic".
[0019] An aryl (including aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl (including
heteroaralkyl and heteroarylalkoxy and the like) group
may contain one or more substituents. Suitable
substituents on the unsaturated carbon atom of an aryl,
heteroaryl, aralkyl, or heteroaralkyl group include
halogen, -R , -OR , -SR , 1,2-methylene-dioxy, 1,2-
ethylenedioxy, phenyl (Ph) optionally substituted with R ,
-0(Ph) optionally substituted with R , -CH2(Ph) optionally
substituted with R , -CH2CH2(Ph),optionally substituted
with R , -NO2, -CN, -N (R ) 2 , -NR C (0) R , -NR C (0) N (R ) 2 ,
-NR C02R , -NR NR C (0) R , -NR NR C (O) N (R ) 2 , -NR NR C02R ,
-C(O)C(O)R , -C (0) CH2C (0) R , -C02R , -C(O)R , -C (0) N (R ) 2,
-OC (0) N (R ) 2, -S(O)2R , -S02N (R ) 2, -S(O)R , -NR S02N (R ) 2,
-NR S02R , -C(=S)N(R )2, -C(=NH)-N(R )2, or -(CH2)gNHC(0)R
wherein q is 0-2, and wherein each R is independently
selected from hydrogen, optionally substituted C1-C6
aliphatic, an unsubstituted 5-6 membered heteroaryl or
heterocyclic ring, phenyl, -O(Ph), or -CH2(Ph), or
wherein two occurrences of R , on the same substituent or
different substituents, taken together, form a 5-8-
membered heterocyclyl or heteroaryl ring having 1-3
heteroatoms independently selected from nitrogen, oxygen,
or sulfur. Optional substituents on the aliphatic group
of R are selected from NH2, NH (C1-4 aliphatic), N(C1-4
aliphatic) 2, halogen, C1-4 aliphatic, OH, O (C1-4 aliphatic),
NO2, CN, C02H, CO2 (C1-4 aliphatic), O (halo C1_4 aliphatic),
or halo C1-4 aliphatic.
[0020] An aliphatic group or a non-aromatic
heterocyclic ring may contain one or more substituents.
Suitable substituents on the saturated carbon of an
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aliphatic group or of a non-aromatic heterocyclic ring
include those listed above for the unsaturated carbon of
an aryl or heteroaryl group and the following: =0, =S,
=NNHR*, =NN (R*) 2, =NNHC (0) R*, =NNHCO2 (alkyl) ,
=NNHS02 (alkyl) , or =NR*, where each R* is independently
selected from hydrogen or an optionally substituted C1-6
aliphatic. Optional substituents on the aliphatic group
of R* are selected from NH2, NH (Cl-4 aliphatic) , N (C1_4
aliphatic) 2, halogen, C1_4 aliphatic, OH, 0 (C1-4 aliphatic),
N02, CN, C02H, C02 (C1_4 aliphatic) , 0 (halo C1_4 aliphatic) ,
or halo (C1-4 aliphatic).
.[0021] Optional substituents on the nitrogen of a
non-aromatic heterocyclic ring include -R+, -N(R+)2, -
C (O) R+, -OR +, -C02R+, -C (0) C (0) R+, -C (0) CH2C (O) R+, -S02R+,
-S02N(R+) 2, -C(=S)N(R+) 2, -C (=NH) -N (R+) 2, or -NR+S02R+;
wherein R+ is hydrogen, an optionally substituted C1-6
aliphatic, optionally substituted phenyl, optionally
.substituted -O(Ph), optionally substituted -CH2(Ph),
optionally substituted -CH2CH2(Ph), or an unsubstituted 5-
6 membered heteroaryl or heterocyclic ring, or wherein
two occurrences of R+, on the same substituent or
different substituents, taken together, form a 5-8-
membered heterocyclyl or heteroaryl ring having 1-3
heteroatoms independently selected from nitrogen, oxygen,
or sulfur. Optional substituents on the aliphatic group
or the phenyl ring of R+ are selected from NH2, NH (CI-4
aliphatic) , N(C1-4 aliphatic) 2, halogen, C1-4 aliphatic, OH,
0 (C1_4 aliphatic), NO2, CN, C02H, C02 (C1-4 aliphatic),
O (halo C1-4 aliphatic), or halo (C1_4 aliphatic).
[0022] The term "alkylidene chain" refers to a
straight or branched carbon chain that may be fully
saturated or have one or more units of unsaturation and
has two points of attachment to the rest of the molecule.
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[0023] A combination of substituents or variables
is permissible only if such a combination results in a
stable or chemically feasible compound. A stable
compound or chemically feasible compound is one that is
not substantially altered when kept at a temperature of
40 C or less, in the absence of moisture or other
chemically reactive conditions, for at least a week.
[0024] It will be apparent to one skilled in the
art that certain compounds of this invention may exist in
tautomeric forms, all such tautomeric forms of the
compounds being within the scope.of the invention.
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 invention. Unless otherwise stated, structures
depicted herein are also meant to include compounds that
differ only in the presence of one or more isotopically
enriched atoms. For example, compounds having the
present structures except for the replacement of a
hydrogen by a deuterium or tritium, or the replacement of
a carbon by a 13C- or 14C-enriched carbon are within the
scope of this invention. Such compounds are useful, for
example, as analytical tools or probes in biological
assays.
[0025] According to a preferred embodiment, ' ring
A is an optionally substituted 5 or 6 membered aryl or
heteroaryl ring, wherein said heteroaryl ring contains up
to 2 ring heteroatoms independently selected from 0, S,
or NR+.
[0026] According to another preferred embodiment,
ring A is phenyl.
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[0027] According to another preferred embodiment,
R 1 is hydrogen, -(CH 2)q-X, wherein q is 1-4, and X is OH,
NH21 COOH or CONH2, (C1-C6)-alkyl, or benzyl.
[0028] According to another preferred embodiment,
1
R is hydrogen, hydroxymethyl, methyl, -CH2COOH,
-CH2CONH2, aminobutyl, methyl, or isopentyl.
[0029] According to another preferred embodiment,
2
R is selected from butyl, isobutyl, methoxypropyl,
cyclopentyl, cyclohexylmethyl, phenyl, trifluorophenyl,
benzyl, fluorobenzyl, methylenedioxybenzyl,
pyridylmethyl, furanylmethyl, tetrahydrofuranylmethyl, N-
morpholinylmethyl, thienylmethyl, 2-oxo-
pyrrolodinylpropyl, phenylethyl, chlorophenylethyl,
methoxyphenylethyl, or dimethoxyphenylethyl.
[0030] According to another preferred embodiment,
2
R is selected from 2-furanylmethyl or methyl.
[0031] According to another preferred embodiment,
3 4
R and R are independently selected from hydrogen, halo,
acetamido, allyloxy, thiophenyl, sulfoxyalkyl, or
sulfoxyphenyl.
[0032] The term "amino protecting group" refers
to a suitable chemical group that may be attached to a
nitrogen atom. The term "protected" refers to when the
designated functional group is attached to a suitable
chemical group (protecting group). Examples of suitable
amino protecting groups and protecting groups are
described in T.W. Greene and P.G.M. Wuts, Protective
Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons
(1991); L. Fieser and M. Fieser, Fieser and Fieser's
Reagents for Organic Synthesis, John Wiley and Sons
(1994); L. Paquette, ed. Encyclopedia of Reagents for
Organic Synthesis, John Wiley and Sons (1995) and are
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14
exemplified in certain of the specific compounds used in
this invention.
[0033] According to an alternate embodiment, the
present invention provides compounds of formula (II):
(A)q Rx
/NARY
X
N
Rz COOH ( II) ;
wherein:
X is -(CH2)n-, or -C(O)-;
n is 1-3;
Y is 0, S, NH, or N(C1-C6 aliphatic);
Z is H or C1-C6 aliphatic;
=Q is 0 or 1;
A, Rx, RY, and RZ are independently selected from R11,
R12, R14 or p,15;
wherein:
each R11 is independently selected from 1,2-
methylenedioxy, 1,2-ethylenedioxy, R6 or (CH2)m Y;
wherein m is 0, 1 or 2; and
Y is selected from halogen, CN, N02, CF3, OCF3,
OH, SR6, S(O)R6, S02R6, NH2, NHR6, N(R6)2, NR6R8, COOH,
COOR6 or OR6;
each R12 is independently selected from (C1-C6)-
straight or branched alkyl, or (C2-C6)-straight or
branched alkenyl or alkynyl; and each R12 optionally
comprises up to 2 substituents, wherein:
the first of said substituents, if present, is
selected from R11, R14 and p,15, and
the second of said substituents, if present, is
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R11;
each R14 is independently selected from OR15,
OC(O)R6, OC(0)R15, OC(0)OR6, OC(0)OR15, OC(0)N(R6)2,
OP(O)(OR6)2, SR6, SR15, S(O)R6, S(0)R15, S02R6, S02R15,
S02N (R6) 2, S02NR15R6, S03R6, C(O)R15, C(O)0R15, C(O)R6,
C(O)0R6, NC(O)C(O)R6, NC (0) C (0) R15, NC(O)C(O)0R6,
NC(0)C(0)N(R6)2, C(0)N(R6)2, C(O)N(OR6)R6, C(O)N(OR6)R15,
C(NOR6)R6, C(NOR6)R15, N(R6)2, NR6C(O)R11, NR6C(O)R6,
NR6C(0)R15, NR6C(O)OR6, NR6C(0)OR15, NR6C(O)N(R6)2,
NR6C(O)NR15R6, NR6S02R6, NR6S02R1-5, NR6S02N(R6)2,
NR6S02NR15R6, N(OR6)R6, N(OR6)R15, p(O) (OR6)N(R6)2, and
P(O) (OR'6)2;
each R15 is a cycloaliphatic, aryl, heterocyclyl, or
heteroaromatic; and each R15 optionally comprises up to 3
substituents, each of which, if present, is R11;
each R6 is independently selected from H, (C1-C6)-
straight or branched alkyl, or (C2-C6) straight or
branched alkenyl; and each R6 optionally comprises a
substituent that is R7;
R7 is a cycloaliphatic, aryl, heterocyclyl, or
heteroaromatic; and each R7 optionally comprises up to 2
substituents independently chosen from H, (C1-C6)-
straight or branched alkyl, (C2-C6) straight or branched
alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or
(CH2)p-Z;
wherein p is 0, 1 or 2; and
Z is selected from halogen, CN, N02, CF3, OCF3, OH,
S(C1-C6)-alkyl, SO(C1-C6)-alkyl, S02(C1-C6)-alkyl, NH2,
NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, N((C1-C6)-alkyl)R8,
COOH, C(0)O(C1-C6)-alkyl or O(C1-C6)-alkyl; and
R8 is an amino protecting group;
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or RX and R , taken together, form an optionally
substituted heterocyclic ring having up to 3
substituents.
[0034] The scope of the present invention includes
within its scope pharmaceutically acceptable prodrugs of
the compounds of the present invention. A
"pharmaceutically acceptable prodrug" means any
pharmaceutically acceptable salt, ester, salt of an
ester, or other derivative of a compound of the present
invention that, upon administration to a recipient, is
capable of providing (directly or indirectly) a compound
of this invention or an active metabolite or residue
thereof. Preferred prodrugs are those that increase the
bioavailability of the compounds of this invention when
such compounds are administered to a mammal or which
enhance delivery of the parent compound to a biological
compartment (e.g., the brain or lymphatic system)
relative to the parent species.
[0035] The compounds of the present invention may be
readily prepared using methods known in the art. One
such synthetic route is illustrated below in Scheme 1.
One of skill in the art will recognize that this
synthetic route can be readily exploited for other
embodiments of formula M.
[0036] Scheme 1
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17
' C02Me C02Me C02H
R3 R3 T R3 l`~ O
" NH2 lv NH N~
I O
R III R
0 R O Rl'
IJIC02Me, Cott-Bu
R3 H 0 R3 C02H
N-< O NIO
IV ` R 1 R2
[0037] Preparation of compounds of formula (I) is
carried out following the generalized procedures outlined
in Scheme 1. The preparation of quinazolinediones
involves 4 basic steps-i) reductive alkylation, ii)
loading to resin, iii) peptide coupling and iv)
cyclization and release from the resin.
[0038] Step 1. Reductive alkylation of Anthranilic
Acids
An anthranilic acid and aldehyde (4 eq) was
dissolved in DCE at room temperature in the presence of
acetic acid. After 15 minutes, sodium
triacetoxyborohydride (4 eq) was added, and the solution
stirred at room temperature (4-12 hrs. depending on the
aldehyde used). The reaction was quenched with excess IN
NaOH and stirred for 20 minutes. The reaction was
extracted several times with ethyl acetate, washed with
brine, dried over sodium sulfate, filtered and
concentrated. Purification was carried out via silica
gel column chromatography using ethyl acetate/hexanes.
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[0039] Saponification of the anthranilate esters was
carried out by dissolving the ester in THF/MeOH and
treated with 1 N lithium hydroxide at room temperature
for 12 hrs. The reaction was concentrated to 1/3 the
original volume, and poured into 10% NaOH. The solution
was extracted with ether to remove unreacted material.
The aqueous layer was collected and carefully acidified
with iN HC1. In most cases the anthranilic acids
precipitated from solution and were collected by
filtration. In the event that precipitation did not
occur, the aqueous solution was diluted with brine
solution and extracted several times with ethyl acetate.
The organics were dried over sodium sulfate, filtered and
concentrated to provide the desired anthranilic acids.
[0040] Step 2. Loading of Substituted Anthranilic
acids to Resin
CAUTION: The following procedure involves the use of
phosgene and should only be carried out by an experienced
technician in a well-vented chemical hood.
eq. 2.5 M Phosgene in toluene o
Eq. 1 HOb Cif
THF, A 0
Preparation of chloroformate resin
grams of hydroxymethyl polystyrene (1.2mmol/g
loading) was weighed into a tared 250 ml peptide flask.
The resin was washed with 100 ml dry THE and finally
suspended in an additional 100 ml dry THF. To the resin
suspension was added 25 ml (5.0 eq., 2.54 M) of a
phosgene solution in toluene. The flask was sealed
tightly and swirled on an orbital shaker for 2-3 hours.
The peptide flasks were drained under positive pressure,
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19
collecting the mother liquor into a flask containing
concentrated (20%) aqueous sodium hydroxide/methanol
solution.
R2 CI O R2
Eq.2 NH O DIEA NYO
DCM, rt 0
R1 CO2H R CO2H
The chloroformate resin was subsequently washed 2x
100 ml dry THF, 2x 100 ml dry DCM using positive pressure
to drain the vessel. A 100 ml DCM solution containing
the anthranilic acid (3eq) and DIEA (10 eq) was added
quickly to the freshly prepared chloroformate resin and
the flasks resealed and swirled on the orbital shaker for
an additional 3 1/2 hours. The resins were drained, washed
and washed extensively. The resins were dried under high
vacuum overnight. The approximate loading was determined
by weight gain. Typical loadings of 0.7-0.9 mmol/g were
routinely obtainable using this method.
[0041]
Step 3. Coupling of Amino Acids to anthranilic acid
functionalized resin
1-methyl-2-pyrrolidinone (NMP) solutions of HOBT
(1M), HBTU (0.5 M), amino acid ester (1M) and Hunigs base
(2M) were made freshly prior to carrying out the coupling
reactions. The resin was suspended in NMP and a
solution of HOST (5 eq) was added followed by the
addition of HBTU (5.0 eq). The reaction was sealed and
shaken for 15 minutes. The vessel was unsealed and the
reaction block placed on the Packard for addition of the
remaining reagents. After 15 minutes, the solution of
amino ester (4 eq) was added followed by the addition of
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diisopropyl ethylamine (5 eq). The reaction vessel was
resealed and shaken for 18 hours at room temperature,
after which the resin was subsequently washed
extensively.
[0042]
Step 4. Product formation and Isolation
OYOb R2
\ _rO
\ N'Rz 10 % Et3N N
Eq. 3 o ~~ N,
R Meox, 60 c R1 Rs
1 O
R3~NH
Cleavage of the products from the resins and
isolation of the quinazoline-2,4-diones was carried out
as follows. A solution of 10% triethylamine in methanol
was added to the resin and the reaction vessel heated for
20 hours at 60-65 C. After the desired time, the reaction
was cooled slightly and the mother liquor collected. The
resin was washed 2x with methanol and the washings
combined with the mother liquor. Concentration of the
solution using a rotovaporator provided the desired
quinazolinediones.
[0043] Subsequent removal of the butyl protecting
groups was carried out by adding 1.5 mL of 95:3:2
TFA:water:triisopropyl silane to the crude
quinazolinediones for 3 hrs at room temperature. The TFA
solution was removed under vacuum and the compounds
purified by C18 chromatography.
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21
[0044] Preparation of compounds of formula (II) is
carried out following the generalized procedures outlined
in Scheme 2 below:
\ O 1) BBr3 1) MsCI \ \
\ 2) TBS-CI JD:) 2) NaN3 /
~O H 3) LAH TBSO H OH 3) H2, Pd/c TBSO H NH2
V VI
1) Cbz-CI
2) TBAF
1) Coupling 1) XCH((dC/02Et)R2
0 H HN-X 2) Nom O N NH2 2 I N NHCbz
Ri H HO H
R2 CO2H R2 2CO2Et
X = CO, S02, CONH VIII VII
IX
[0045] The term "pharmaceutically acceptable
carrier, adjuvant, or.vehicle" refers to a non-toxic
carrier, adjuvant, or vehicle that does not destroy the
pharmacological activity of the compound with which it is
formulated. Pharmaceutically acceptable carriers,
adjuvants or vehicles that may be used in the
compositions of this invention include, but are not
limited to, ion exchangers, alumina, aluminum stearate,
lecithin, serum proteins, such as human serum albumin,
buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of
saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium
hydrogen phosphate, potassium hydrogen phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium
carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.
[0046] Pharmaceutically acceptable salts of the
compounds of this invention include those derived from
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22
pharmaceutically acceptable inorganic and organic acids
and bases. Examples of suitable acid salts include
acetate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, citrate,
camphorate, camphorsulfonate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, formate,
fumarate, glucoheptanoate, glycerophosphate, glycolate,
hemisulfate, heptanoate, hexanoate, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, malonate, methanesulfonate, 2-
naphthalenesulfonate, nicotinate, nitrate, oxalate,
palmoate, pectinate, persulfate, 3-phenylpropionate,
phosphate, picrate, pivalate, propionate, salicylate,
succinate, sulfate, tartrate, thiocyanate, tosylate and
undecanoate. Other acids, such as oxalic, while not in
themselves pharmaceutically acceptable, may be employed
in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their
pharmaceutically acceptable acid addition salts.
[0047] Salts derived from appropriate bases include
alkali metal (e.g., sodium and potassium), alkaline earth
metal (e.g., magnesium), ammonium and N+(C1-4 alkyl)4
salts. This invention also envisions the quaternization
of any basic nitrogen-containing groups of the compounds
disclosed herein. Water or oil-soluble or dispersible
products may be obtained by such quaternization.
[0048] The compositions of the present invention may
be administered orally, parenterally, by inhalation
spray, topically, rectally, nasally, buccally, vaginally
or via an implanted reservoir. The term "parenteral" as
used herein includes subcutaneous, intravenous,
intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional
and intracranial injection or infusion techniques.
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Preferably, the compositions are administered orally,
intraperitoneally or intravenously. Sterile injectable
forms of the compositions of this invention may be
aqueous or oleaginous suspension. These suspensions may
be formulated according to techniques known in the art
using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension
in a non-toxic parenterally-acceptable diluent or
solvent, for example as a solution in 1,3-butanediol.
Among the acceptable vehicles and solvents that may be
employed are water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending
medium.
[0049] For this purpose, any bland fixed oil may be
employed including synthetic mono- or di-glycerides.
Fatty acids, such as oleic acid and its glyceride
derivatives are useful in the preparation of injectables,
as are natural pharmaceutically-acceptable oils, such as
olive oil or castor oil, especially in their
polyoxyethylated versions. These oil solutions or
suspensions may also contain a long-chain alcohol diluent
or dispersant, such as carboxymethyl cellulose or similar
dispersing agents that are commonly used in the
formulation of pharmaceutically acceptable dosage forms
including emulsions and suspensions. Other commonly used
surfactants, such as Tweens, Spans and other emulsifying
agents or bioavailability enhancers which are commonly
used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for
the purposes of formulation.
[0050] The pharmaceutically acceptable compositions
of this invention may be orally administered in any
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24
orally acceptable dosage form including, but not limited
to, capsules, tablets, aqueous suspensions or solutions.
In the case of tablets for oral use, carriers commonly
used include lactose and corn starch. Lubricating
agents, such as magnesium stearate, are also typically
added. For oral administration in a capsule form, useful
diluents include lactose and dried cornstarch. When
aqueous suspensions are required for oral use, the active
ingredient is combined with emulsifying and suspending
agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
,[0051] Alternatively, the pharmaceutically
acceptable compositions of this invention may be
administered in the form of suppositories for rectal
administration. These can be prepared by mixing the
agent with a suitable non-irritating excipient that is
solid at room temperature but liquid at rectal
temperature and therefore will melt in the rectum to
release the drug. Such materials include cocoa butter,
beeswax and polyethylene glycols.
1[0052] The pharmaceutically acceptable compositions
of this invention may also be administered topically,
especially when the target of treatment includes areas or
organs readily accessible by topical application,
including diseases of the eye, the skin, or the lower
intestinal tract. Suitable topical formulations are
readily prepared for each of these areas or organs.
[0053] Topical application for the lower intestinal
tract can be effected in a rectal suppository formulation
(see above) or in a suitable enema formulation.
Topically-transdermal patches may also be used.
[0054] For topical applications, the
pharmaceutically acceptable compositions may be
formulated in a suitable ointment containing the active
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component suspended or dissolved in one or more carriers.
Carriers for topical administration of the compounds of
this invention include, but are not limited to, mineral
oil, liquid petrolatum, white petrolatum, propylene
glycol, polyoxyethylene, polyoxypropylene compound,
emulsifying wax and water. Alternatively, the
pharmaceutically acceptable compositions can be
formulated in a suitable lotion or cream containing the
active components suspended or dissolved in one or more
pharmaceutically acceptable carriers. Suitable carriers
include, but are not limited to, mineral oil, sorbitan
monostearate, polysorbate 60, cetyl esters wax, cetearyl
alcohol, 2-octyldodecanol, benzyl alcohol and water.
.[0055] For ophthalmic use, the pharmaceutically
acceptable compositions may be formulated as micronized
suspensions in isotonic, pH adjusted sterile saline, or,
preferably, as solutions in isotonic, pH adjusted sterile
saline, either with or without a preservative such as
benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutically acceptable compositions may be
formulated in an ointment such as petrolatum.
[0056] The pharmaceutically acceptable compositions
of this invention may also be administered by nasal
aerosol or inhalation. Such compositions are prepared
according to techniques well-known in the art of
pharmaceutical formulation and may be prepared as
solutions in saline, employing benzyl alcohol or other
suitable preservatives, absorption promoters to enhance
bioavailability, fluorocarbons, and/or other conventional
solubilizing or dispersing agents.
[0057] Most preferably, the pharmaceutically
acceptable compositions of this invention are formulated
for oral administration.
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26
[0058] The amount of the compounds of the present
invention that may be combined with the carrier materials
to produce a composition in a single dosage form will
vary depending upon the host treated, the particular mode
of administration. Preferably, the compositions should
be formulated so that a dosage of between 0.01-100 mg/kg
body weight/day of the inhibitor can be administered to a
patient receiving these compositions.
'[0059] It should also be understood that a specific
dosage and treatment regimen for any particular patient
will depend upon a variety of factors, including the
activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and
the judgment of the treating physician and the severity
of the particular disease being treated. The amount of a
compound of the present invention in the composition will
also depend upon the particular compound in the
composition.
[0060] Depending upon the particular condition, or
disease, to be treated or prevented, additional
therapeutic agents, which are normally administered to
treat or prevent that condition, may also be present in
the compositions of this invention. As used herein,
additional therapeutic agents that are normally
administered to treat or prevent a particular disease, or
condition, are known as "appropriate for the disease, or
condition, being treated."
[0061] For example, chemotherapeutic agents or other
anti-proliferative agents may be combined with the
compounds of this invention to treat cancer and
proliferative diseases. Examples of known
chemotherapeutic agents include, but are not limited to,
GleevecTM, adriamycin, dexamethasone, vincristine,
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27
cyclophosphamide, fluorouracil, topotecan, taxol,
interferons, and platinum derivatives.
[0062] Other examples of agents with which the
compounds of this invention may be combined include,
without limitation, anti-inflammatory agents such as
corticosteroids, TNF blockers, IL-1 RA, azathioprine,
cyclophosphamide, and sulfasalazine; 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; agents for treating diabetes such as insulin,
insulin analogues, alpha glucosidase inhibitors,
biguanides, and insulin sensitizers; and agents for
treating immunodeficiency disorders such as gamma
globulin.
[0063] The amount of additional therapeutic agent
present in the compositions of this invention will be no
more than the amount that would normally be administered
in a composition comprising that therapeutic agent as the
only active agent. Preferably the amount of additional
therapeutic agent in the presently disclosed compositions
will range from about 50% to 100% of the amount normally
present in a composition comprising that agent as the
only therapeutically active agent.
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[0064] According to another embodiment, the
invention relates to a method of inhibiting SHP-2
phosphatase activity in a biological sample comprising
the step of contacting said biological sample with a
compound of this invention, or a composition comprising
said compound.
[0065] The term "biological sample", as used herein,
includes, without limitation, cell cultures or extracts
thereof; biopsied material obtained from a mammal or
extracts thereof; and blood, saliva, urine, feces, semen,
tears, or other body fluids or extracts thereof.
[0066] Inhibition of SHP-2 phosphatase activity in a
biological sample is useful for a variety of purposes
that are known to one of skill in the art. Examples of
such purposes include, but are not limited to, blood
transfusion, organ-transplantation, biological specimen
storage, and biological assays.
[0067] According to another embodiment, the
invention provides a method for treating or lessening the
severity of a disease selected from autoimmune diseases,
proliferative diseases, angiogenic disorders, and
cancers.
[0068] According to a preferred embodiment, the
invention provides a method for treating or lessening the
severity of a SHP-2-mediated disease or condition in a
patient comprising the step of administering to said
patient a composition according to the present invention.
[0069] The term "SHP-2-mediated disease," as used
herein means any disease or other deleterious condition
in which SHP-2 is known to play a role. Such conditions
include, without limitation, autoimmune diseases,
proliferative diseases, angiogenic disorders, and
cancers.
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[0070] Autoimmune diseases which may be treated or
prevented by the compounds of this invention include, but
are not limited to, glomerulonephritis, rheumatoid
arthritis, systemic lupus erythematosus, scleroderma,
chronic thyroiditis, Graves' disease, autoimmune
gastritis, diabetes, autoimmune hemolytic anemia,
autoimmune neutropenia, thrombocytopenia, atopic
dermatitis, chronic active hepatitis, myasthenia gravis,
multiple sclerosis, inflammatory bowel disease,
ulcerative colitis, Crohn's disease, psoriasis, or graft
vs. host disease.
;[0071] Proliferative diseases which may be treated
or prevented by the compounds of this invention include,
but are not limited to, acute myelogenous leukemia,
chronic myelogenous leukemia, metastatic melanoma,
Kaposi's sarcoma, multiple myeloma and HTLV-1-mediated
tumorigenesis.
[0072] Angiogenic disorders that may be treated or
prevented by the compounds of this invention include
solid tumors, ocular neovasculization, infantile
haemangiomas.
[0073] Cancers that may be treated or prevented by
the compounds of this invention include, without
limitation, colon, breast, stomach, and ovarian cancers.
[0074] In another embodiment, the methods of this
invention that utilize compositions that do not contain
an additional therapeutic agent, comprise the additional
step of separately administering to said patient an
additional therapeutic agent. When these additional
therapeutic agents are administered separately, they may
be administered to the patient prior to, sequentially
with or following administration of the compositions of
this invention.
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[0075] The compounds of this invention or
pharmaceutical compositions thereof may also be
incorporated into compositions for coating an implantable
medical device, such as prostheses, artificial valves,
vascular grafts, stents and catheters. Vascular stents,
for example, have been used to overcome restenosis (re-
narrowing of the vessel wall after injury). However,
patients using stents or other implantable devices risk
clot formation or platelet activation. These unwanted
effects may be prevented or mitigated by pre-coating the
device with a pharmaceutically acceptable composition
comprising a kinase inhibitor. Suitable coatings and the
general preparation of coated implantable devices are
described in US Patents 6,099,562; 5,886,026; and
5,304,121. The coatings are typically biocompatible
polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene
glycol, polylactic acid, ethylene vinyl acetate, and
mixtures thereof. The coatings may be further covered by
a suitable topcoat of fluorosilicone, polysaccarides,
polyethylene glycol, phospholipids or combinations
thereof to impart controlled-release characteristics in
the composition. Implantable devices coated with a
compound of this invention are another embodiment of the
present invention.
[0076] In order that the invention described herein
may be more fully understood, the following examples are
set forth. It should be understood that these examples
are for illustrative purposes only and are not to be
construed as limiting this invention in any manner.
EXAMPLES
Example 1
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Preparation of 2-(7-Acetylamino-l-furan-2-ylmethyl-2,4-
dioxo-1,4-dihydro-2H-quinazolin-3-yl)-succinic acid
(Compound 1)
\ CO2H 0 \ C02H
"ro
, ~c
H2N I NO2 H NH
DIOX
4-Acetylamino-2-[(furan-2-ylmethyl)-amino]-benzoic acid
The 4-amino-2-nitrobenzoic acid (3g) was suspended
in 20 ml 4:1 THF/MeOH, cooled to 0 C. TMS-diazomethane
(5.6 g, 49 mmol, 3 eq, 2M in hex) was added dropwise and
the solution stirred at room temperature for 2 hrs. The
reaction was quenched with IN acetic acid and the
organics removed under vacuum. The aqueous layer poured
into ethyl acetate, neutralized with sodium bicarbonate,
dried over sodium sulfate, filtered and concentrated to a
yellow oil. The ester was purified by flash column
chromatography using 30% Acetone/hex. Isolated the
nitroester as a bright yellow solid (92% yield).
The ester (1.0 g, 5.1 mmol) was dissolved in 20 ml
DCM at room temperature. DIEA (0.98g, 7.6mmol, 1.5 eq)
was added followed by the addition of acetyl chloride
(0.48g, 6.1 mmol, 1.2 eq). Reaction was stirred at room
temperature for 4 hrs. Reaction was poured into 1M HC1,
dried over sodium sulfate, filtered and concentrated to a
yellow oil/solid. The crude reaction was taken up in -20
ml MeOH, saturated NH4C1 was added followed by the
addition of excess Zn powder. Reaction was stirred at
room temperature for 45 minutes when TLC showed complete
reduction. The reaction was filtered to remove the Zn
particulates, extracted with ethyl acetate. The aqueous
layer was extracted 2X with ethyl aceate and the organics
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32
combined. Dried over sodium sulfate, filtered, and
concentrated to a yellow film. The product was taken up
in small amount of acetone and purified using 10-30%
Acetone/2% MeOH/Hex as a gradient. Isolated the desired
aniline compound as a light yellow solid (positive APCI,
M+1= 208.9)
Reductive amination was carried out by dissolving
the anthranilate (2.3g, llmmol, leq), 2-furylaldehyde
(3.2g, 33 mmol, 3 eq) and 1 ml acetic acid in 50 ml DCE
at room temperature. After 15 minutes sodium
triacetoxyborohydride (9.4g, 44 mmol, 4 eq) was added and
the solution stirred at room temperature for 4 hrs. The
reaction was quenched by addition of excess IN NaOH.
After stirring for 20 minutes, the suspension was
extracted 3X with ethyl acetate. Washed the organics
with brine, dried over sodium sulfate, filtered and
concentrated to a brown oil. The product was isolated by
flash column using 10-30% acetone/hex. The desired
anilide was obtained a light yellow solid.
The ester was taken up in THE and IN LiOH (1.5 eq)
was added and stirred at 60 C for 12 hrs. Reaction was
cooled, concentrated to remove organics and diluted with
water. The solution was washed with ether and the
aqueous layer acidified with 1M HC1. A thick white
precipitate formed and was collected by filtration to
afford the desired compound.
NMR (DMSO-D6) 5 = 10.0 (s, 1H), 8.2 (bs, 1H), 7.66 (1H,
D, J= 8.6 Hz), 7.54 (1H, d, J= 3.1 Hz), 7.18 (1H, D,
J=2.3 Hz), 6.73 (1H, dd, J= 1.5, 8.6 Hz), 6.36 (1H, dd,
J= 3.1, 2.3 Hz), 6.32 (1H, dd, J= 1.5, 3.1 Hz), 4.3 (2H,
s), 2.00 (3H, s).
MS m/e= 273.1 (m-1) corresponds to C14H14N204, Mw=274.27.
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33
CO2H
aIC02H O IN 1 NH H N O
DIO/
H DIO//
4 g of hydroxymethyl PS resin (1.2mmol/g) was placed
in a tared 100ml peptide flask. The resin was washed 2x
with dry THE and the resin suspended in a minimal amount
of dry THF. A 2.5 M solution of phosgene in toluene
(20m1) was added and the flask agitated for several
hours. The reaction was filtered using postive nitrogen
pressure, and the resin washed several times with DCM. A
solution of 4-Acetylamino-2-[(furan-2-ylmethyl)-amino]
benzoic acid (compound 1, 3 eq) and DIEA (4 eq) in DCM
was added to the resin and agitated for 3 hrs. The resin
was filtered, washed several times with DMF, McOH and DCM
and dried under vacuum. Loading of the resin was
calculated to be 0.9 mmol/g based on weight gain.
O CO2H
CO2H
INI COZH
O I/ 00/ 0 &",--0
)H N)LN I) H
I /
0~
CIO)/
2-(7-Acetylamino-l-furan-2-ylmethyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-yl)-succinic acid (Compound 1)
The resin (400mg) was suspended in NMP and treated
with HBTU (4eq). HOBT (4eq) for fifteen minutes before
adding aspartic acid dit-butyl ester hydrochloride (3eq.)
and finally DIEA (4eq). The reaction was agitated for 12
hours before filtering and washing extensively with NMP,
DMF, MeOH. The resin was resuspended in 8m1 of 10%
TEA/MeOH and heated to 600C for 18 hrs. The mother
liquor was collected, and concentrated solutions to
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34
dryness. The crude quinazolinedione was deprotected
using 50% TFA/DCM for 2 hrs. The reaction was
concentrated under vacuum and the residue taken up in
small amount of MeCN, and purified by C18 using
MeCN/Water. Isolated a light-colored foam from azetrope
with acetonitrile.
NMR (400 mHz, MeOH-D4) 5 = 8.19 (1H, d, J= 2.3 Hz), 8.03
(1H, d, J= 8.6 Hz), 7.42 (d, J=3.1 Hz), 7.29 (1H, dd, J=
1.5, 8.6 Hz), 6.45 (1H, d, J= 3.1Hz), 6.34 (1H, dd, J=
2.3, 3.1 Hz), 6.07 (1 H, m), 5.32 (2H, s), 3.40 (1H, dd,
J= 7.8 16.4 Hz), 2.81 (1H, dd, J= 6.3, 16.4 Hz), 2.15
(3H, s).
MS m/e= 414 (m-1) corresponds to C19H17N308, Mw= 415.35
Example 2
Preparation of 2-[6-Chloro-l-(5-methyl-furan-2-ylmethyl)-
2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-succinic acid
(Compound 2)
CICOZH
CI~C02Me
NH
NH2
5-Chloro-2-,E(5-methyl-furan-2-ylmethyl)-amino]-benzoic
acid 911-71
Reductive amination of 5-chloro-2-amino-
methylanthranilate carried out as described for compound
1 using 5-methyl furaldehyde in DCE for 4 hrs. After
workup, the product was isolated by FC using 10-30%
acetone/hexanes to afford a light yellow solid. The
ester was subsequently taken up in THE and saponified
using IN at 60 C for 12 hrs. The solution was cooled,
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acidified and the product collected as an off-white
solid.
C
CI C02H CI \ CO2Ho
NH I / NOQ
/ I /
4.51 g of hydroxymethyl PS resin (1.2mmol/g) was
placed in a tared 100ml peptide flask (tare=112.8423g).
The resin was washed 2x with THE and the resin suspended
in a minimal amount of THF. A 2.5 M solution of phosgene
in toluene (20m1) was added and the flask agitated for
several hours. Reaction was filtered under postive
pressure, washed several times with DCM. A solution of
the anthranilic acid and DIEA in DCM was added and the
reaction agitated for 2 hrs. Reaction filtered, washed
several times with DMF, MeOH and DCM. Dried under
vacuum. Loading was calculated to be 0.96 mmol/g.
O CO2H
OI \ COzH
/ CI I \ N Co2H
N O / N,
I ~
2
2-[6-Chloro-l-(5-methyl-furan-2-ylmethyl)-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-yl]-succinic acid (Compound 2)
Dispensed 500 mg of resin into Quest 210 tubes.
Added a solution of HOBT (2m1, 1.OM in NMP, 4eq) )
followed by the addition of HBTU in NMP (4ml, 0.5 M,
4eq). The resin was agitated for 15 minutes before
adding an NMP solution of amine (4ml, 5 eq) and DIEA
(5eq). The reaction was agitated for 18 hrs. The
resins were filtered, washed extensively with DMF, MeOH
and DCM, finally washing 3x with methanol.
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36
The resin was taken up in 8 ml of 10% TEA/MeOH and heated
to 60 C for 20 hrs. The mother liquour was collected and
concentrated to dryness. Compounds with protecting
groups were deprotected using standard conditions and
purified by FC using C18 and water/acetonitrile gradient
to afford an off-white colored foam.
NMR (400 mHz, DMSO-D6) 5 = 7.99 (1H, d, J= 2.3 Hz), 7.84
(1H, dd, J= 2.3, 8.6 Hz), 7.65 (1H, d, J= 8.6 Hz), 6.25
(1H, D, j= 3.1 Hz), 5.98 (1H, d, J= 3.1 Hz), 5.85 (1H,
dd, J= 4.6, 8.6 Hz), 5.27 (2H, s), 3.31 (3H, s), 3.18
(1H, dd, J= 8.6, 16.4 Hz), 2.69 (1H, dd, J= 4.6 17.2Hz).
MS: m/e= 405 (m-1) corresponds to Cl8H15C1N207 Mw= 406.77
Example 3
Preparation of 2-(1-Furan-2-ylmethyl-6-methanesulfonyl
2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-succinic acid
(Compound 3)
H3CS CO2H
H3CS CO2H lo~
NH
~ CI O
2-[(Furan-2-ylmethyl)-amino]-5-methylsulfanyl-benzoic
acid.
2-Chloro-5-(methylthio)benzoic acid (15.5 g, 76.5
mmol) was dissolved in DMF (20 mL). Potassium carbonate
(10.6 g, 76.7 mmol) was added, and the solution stirred
for 5 min (until effervescence subsides). Furfurylamine
(8.8 mL, 99 mmol) was then added followed by copper(I)
bromide (1 g, 7 mmol). The reaction was heated to 150 C
overnight in a sealed tube, then (while still hot) poured
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37
intol0% NH4OH (300 mL) . The mixture was acidified to pH
4-5 (by pH paper) with glacial AcOH and the crude product
was collected by filtration. The collected solids were
then dissolved in IN NaOH and the insoluble black
particulates were filtered off. The filtrate was then
acidified with 6N AcOH and the product (an olive solid,
11.64 g, 58%) was collected by filtration and dried under
high vacuum for 2 days to remove most of the residual
water. 1H NMR (400 MHz, DMSO) 5 7.70 (d, J = 2.3 Hz, 1H),
7.60 (d, J = 1.6 Hz, 1H), 7.39 (dd, j = 8.6, 2.3 Hz, 1H),
6.86 (d, J = 8.6 Hz, 1H), 6.40 (dd, J = 3.1, 1.6 Hz, 1H),
6.33 (d, J = 3.1 Hz, 1H), 4.46 (s, 2H), 2.37 (s, 3H). MS
(LR-APCI) calcd. for C13H14N03S (M+H) 264.07; found 263.9. llzz~ H3CS I NH
CO2H H3CS CO2H
I/N 0
D/~
Hydroxymethyl polystyrene (HM-PS) resin (5.988 g,
1.29 mmol/g) was taken up in THE and phosgene (15 mL of a
-2.5 M solution in toluene) was added. The reaction was
shaken for 3 h, and the phosgene solution was then
drained (use caution)) and washed successively with DCM
(4x). A solution of 2-[(Furan-2-ylmethyl)-amino]-5-
methylsulfanyl-benzoic acid (3.07 g, 1.5 equiv) in DCM
was then added to the resin along with DIEA (6.6 mL, 5
equiv) and the reaction shaken for another 3 h. The
resin was then rinsed successively with DCM (3x), MeOH
(3x), DCM (3x), MeOH (3x) and Et20 (2x) and dried under
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38
high vacuum. Yield of resin = 8.811 g (estimated loading
by weight gain substitution = 1.10 mmol/g).
O CO2H
H3CS CO2H H CO S "(
s 2 N CO2H
N O
/ N O
0-k-0 3
2-(1-Furan-2-ylmethyl-6-methanesulfonyl-2,4-dioxo-l,4-
dihydro-2H-quinazolin-3-yl)-succinic acid (Compound 3).
The PS resin was taken up in NMP and HOBT=H20 (4
equiv in NMP) and HBTU (4 equiv in NMP) were added.
After shaking for -5 min, L-aspartic acid ^,^-di-t-butyl
ester hydrochloride (4 equiv in NMP) and DIEA (5 equiv)
were added to the mixture. After shaking overnight, the
solution was drained, and the resin washed successively
with NMP (2X), DCM (3X), and MeOH (3x) and dried under
high vacuum. The resin was heated to 60 C overnight in
10% Et3N/MeOH solution in order to affect cyclative
cleavage of the compound from resin. The crude product
was then purified by chromatography (Si02, Rf = 0.29 in
20% EtOAc/hexanes). The 6-methylsulfanyl-quinazoline-
2,4-dione was then taken up in CHC13 and cooled in an ice
bath. MCPBA (-77%, -2 equiv) was then added and the
reaction monitored by TLC for conversion to the sulfone.
Once satisfactory conversion is achieved, IN NaOH was
added and the layers separated. The organic layer was
dried (MgSO4) and the sulfone was purified by
chromatography (Si02, Rf = 0.39 in 60% EtOAc/hexanes).
Treatment of the 6-methanesulfonyl-quinazoline-2,4-dione
with TFA/DCM (1:1) overnight afforded the crude final
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39
product, which was purified by reverse phase C18
chromatography. 1H NMR (400 MHz, CD3CN) 5 8.60 (s, 1H),
8.21 (d, J = 9.4 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.48
(s, 1H), 6.46-6.41 (m, 2H), 6.02 (t, J = 7.0 Hz, 1H),
5.38 (s, 2H), 3.35 (dd, J = 17.2, 7.8 Hz, 1H), 3.12 (s,
3H), 2.80 (dd, J = 17.2, 5.5 Hz, 1 H). MS (LR-APCI)
calcd. for C18H15N209S (M-H) 435.05; found 435Ø
The following additional derivatives were prepared using
the same chemical transformation as previously described.
0
OH
OH
\ O
- N ~O
O
O=II N~
O
Example 4
2-(6-Benzenesulfonyl-l-furan-2-ylmethyl-2,4-dioxo-l,4-
dihydro-2H-quinazolin-3-yl)-succinic acid
1H NMR (400 MHz, DMSO-d6) 5 7.83 (s, 1H) , 7.41 (d, J = 9.4
Hz, 1H), 7.16 (d, J = 7.8 Hz, 2H), 6.96 (d, J = 8.6 Hz,
1H), 6.83 (t, j = 7.8 Hz, 1H), 6.77 (t, J = 7.3 Hz, 2H),
6.60 (s, 1H), 5.57 (d, J = 3.2 Hz, 1H), 5.52 (app s, 1H),
5.24 (t, J = 7.4 Hz, 1H), 4.57 (s, 2H), 2.56 (dd, J =
18.0, 7.8 Hz, 1H), 2.03 (dd, J = 16.4, 6.3 Hz, 1 H). MS'
(LR-APCI) calcd. for C23H17N209S (M-H) 497.07; found 496.9.
0
0 OH
\ OH
p I N
0)NNLO H 0
O
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Example 5
2-(7-Benzoylamino-1-furan-2-ylmethyl-2,4-dioxo-l,4-
dihydro-2H-quinazolin-3-yl)-succinic acid
1H NMR (400 MHz, CD3CN) 5 9.13 (s, 1H) , 8.27 (d, J = 1.6
Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 7.0 Hz,
1H), 7.65 (app t, J = 7.4 Hz, 1H), 7.57 (app t, J = 7.4
Hz, 4H), 7.48 (d, J = 2.3 Hz, 1H), 6.52 (d, J = 3.1 Hz,
1H), 6.41 (app t, J = 2.6 Hz, 1H), 6.04 (dd, J = 8.2, 5.1
Hz, 1H), 5.33 (d, J = 2.3 Hz, 2H), 3.34 (dd, J = 16.8,
8.2 Hz, 1H), 2.78 (dd, J = 16.4, 5.5 Hz, 1 H). MS (LR-
APCI) calcd. for C24H18N308 (M-H) 476.11; found 476Ø
0
0 OH
OH
N
0
HN & N O
1 - 0 0 /
0 // - 01-~' Example 6
2-(7-Benzenesulfonylamino-l-furan-2-ylmethyl-2,4-dioxo-
1,4-dihydro-2H-quinazolin-3-yl)-succinic acid
1H NMR (400 MHz, CD3CN) 5 8.58 (s, 1H), 7.98 (d, LT= 8.6
Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.64 (app t, J = 7.0
Hz, 1H), 7.53 (app t, J = 7.8 Hz, 2H), 7.48 (s, 1H), 7.30
(s, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.45-6.43 (m, 1H),
6.38 (d, J = 3.1 Hz, 1H), 5.98 (dd, J = 7.8, 5.5 Hz, 1H),
5.23 (d, J = 3.9 Hz, 2H), 3.29 (dd, J = 16.4, 7.8 Hz,
1H), 2.73 (dd, J = 17.2, 5.5 Hz, 1 H). MS (LR-APCI)
calcd. for C23H18N309S (M-H) 512.08; found 512.1.
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41
0
1 O OH
0 N OH
O
O
Example 7
2-(6-Allyloxy-l-furan-2-ylmethyl-2,4-dioxo-l,4-dihydro-
2H-quinazolin-3-yl)-succinic acid
1H NMR (400 MHz, CD3CN) 5 7.61 (d, J = 3.1 Hz, 1H) , 7.48-
7.43 (m, 2H), 7.35 (dd, J = 8.6, 3.1 Hz, 1H), 6.40-6.35
(m, 2H), 6.12-6.01 (m, 2H), 5.45-5.27 (m, 4H), 4.64 (d, J
= 4.7 Hz, 2H), 3.32 (dd, J = 16.4, 7.8 Hz, 1H), 2.78 (dd,
J = 16.4, 5.5 Hz, 1H). MS (LR-APCI) calcd. for C20H17N208
(M-H) 413.10; found 413Ø
CI
O
O OH
O 11 N OH
O I /
N~O O
O
OIX
Example 8
2-[6-(4-Chloro-benzenesulfonyl)-1-furan-2-ylmethyl-2,4-
dioxo-1,4-dihydro-2H-quinazolin-3-yl]-succinic acid
1H NMR (400 MHz, CD3CN) 6 8.59 (d, J= 2.3 Hz, 1H), 8.18
(dd, J = 9.4, 2.3 Hz, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.69
(d, J = 8. 6 Hz, 2H) , 7.60 (d, J = 8. 6 Hz, 2H), 7.43 (s,
1H), 6.40-6.37 (m, 2H), 6.00 (dd, J = 7.8, 5.5 Hz, 1H),
5.32 (d, J = 3.1 Hz, 2H), 3.31 (dd, J = 17.2, 7.8 Hz,
1H), 2.77 (dd, J = 17.2, 5.5 Hz, 1H). MS (LR-APCI)
calcd. for C23H16C1N209S (M-H) 531.03; found 530.8.
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O
0 OH
N OH
N~O O
O
I
Example 9
2-(1-Furan-2-ylmethyl-6-methyl-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-y1)-succinic acid
1H NMR (400 MHz, DMSO-d6) 6 7.87 (s, 1H), 7.63-7.59 (m,
2H), 7.53 (d, J = 8.6 Hz, 1H), 6.41 (s, 2H), 5.90 (dd, J
= 8.6, 4.7 Hz, 1H), 5.34 (s, 2H), 3.21 (dd, J = 16.4, 8.6
Hz, 1H), 2.70 (dd, J = 16.4, 4.7 Hz, 1H), 2.37 (s, 3H).
MS (LR-APCI) calcd. for C18H15N207 (M-H) 371.09; found
371Ø
O
9 O OH
S OH
Nk-O0
O
1-11
Example 10
2-(1-Furan-2-ylmethyl-2,4-dioxo-6-phenylsulfanyl-l,4-
dihydro-2H-quinazolin-3-yl)-succinic acid. 1H NMR (400
MHz, CD3CN) 6 8.01 (s, 1H), 7.67 (dd, J = 8.6, 2.3 Hz,
1H), 7.49 (d, J = 8.6 Hz, 1H), 7.44 (s, 1H), 7.42-7.37
(m, 5H), 6.38 (s, 2H), 5.99 (dd, J = 7.8, 5.5 Hz, 1H),
5.30 (s, 2H), 3.30 (dd, J = 17.2, 8.6 Hz, 1H), 2.75 (dd,
J = 17.2, 5.5 Hz, 1H) . MS (LR-APCI) calcd. for C23H17N207S
(M-H) 465.08; found 465Ø
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CI
0
O OH
S OH
N--~O 0
Example 11
2-[6-(4-Chloro-benzenesulfinyl)-1-furan-2-yimethyl-2,4-
dioxo-1,4-dihydro-2H-quinazolin-3-yl]-succinic acid. 1H
NMR (400 MHz, CD3CN) 5 8.41 (d, J = 2.3 Hz, 1H), 7.94 (dd,
J = 10.2, 1.6 Hz, 1H), 7.71 (d, j = 7.8 Hz, 2H), 7.65 (d,
J = 8. 6 Hz, 2H) , 7 .55 (d, J = 8. 6 Hz, 2H) , 7.43 (s, 1H) ,
6.39 (s, 2H), 6.02 (dd, J = 7.8, 5.5 Hz, 1H), 5.32 (t, J
= 3.1 Hz, 2H), 3.32 (dd, J = 17.2, 7.8 Hz, 1H), 2.78 (dd,
J = 17.2, 5.5 Hz, 1H). MS (LR-APCI) calcd. for
C23H16C1N208S (M-H) 515.03; found 515.3.
O
0
CI OH
N OH
N-
-'--0 0
O
X
Example 12
2-(6-Chloro-l-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-yl)-succinic acid
1H NMR (Acetone-D6) 5 = 8.07 (1H, d, J=2.3 Hz), 7.89 (1H,
dd, J= 1.5, 8.6 Hz), 7.69 (1H, d, J= 8.6 Hz), 7.5 (1H,
s), 6.44 (1H, d, J= 3.1 Hz), 6.39 (1H, d, J= 2.3 Hz),
6.15 (1H, dd, J= 4.6, 8.6 Hz) , 5.43 (2H, s) , 3.49 (1H,
dd, J= 8.6, 16.4 Hz), 2.87 (1H, dd, J= 4.6, 16.4 Hz)
MS (negative APCI) m/e= 391 (m-1) corresponds to
C17H13C1N207 Mol. Wt.: 392.75
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9oo
O OH
/ N 0
O
Example 13
2-(1-Furan-2-ylmethyl-6-(naphthalen-2-yloxy)-2,4-dioxo-
1,4-dihydro-2H-quinazolin-3-yl]-3-phenyl-propionic acid
1H NMR (400 MHz, CD3CN) 5 7.95 (d, J = 8.6 Hz, 1H), 7.92
(d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.59 (s,
1H), 7.54-7.41 (m, 5H), 7.38 (s, 1H), 7.27 (d, J = 7.8
Hz, 1H), 7.13 (s, 5H), 6.40 (s, 1H), 6.25 (s, 1H), 5.89
(dd, J = 11.0, 5.5 Hz, 1 H) , 5.27 (s, 2H) , 3.50 (dd, J =
14.1, 5.5 Hz, 1H), 3.42 (dd, J = 14.1, 11.0, 1H). MS
(LR-APCI) calcd. for C32H23N206 (M-H) 531.16; found 531Ø
o
0 OH
O N OH
0
Example 14
2-[6-(Biphenyl-4-yloxy)-1-furan-2-ylmethyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-yl]-succinic acid. 1H NMR (400
MHz, CD3CN) 5 7.70-7.64 (m, 5H) 7.57 (d, J = 8.6 Hz, 1H),
7.50-7.44 (m, 4H), 7.37 (t, J = 7.4 Hz, 1H), 7.13 (d, J =
8.6 Hz, 2H), 6.40 (s, 2H), 6.01 (dd, J = 7.8, 5.5 Hz,
1H), 5.33 (s, 2H), 3.32 (dd, J = 16.4, 7.8 Hz, 1H), 2.78
(dd, J = 16.4, 5.5 Hz, 1H) . MS (LR-APCI) calcd. for
C29H21N208 (M-H) 525.13; found 525.8.
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0
0 OH
o S I N OH
O
N
Example 15
2-(1-Furan-2-ylmethyl-6-methanesulfinyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-yl)-succinic acid. 1H NMR (400
MHz, CD3CN) 5 8.38 (d, J = 2.3 Hz, 1H), 8.00 (dd, J = 8.6,
2.3 Hz, 1H), 7.72 (d, j = 8.6 Hz, 1H), 7.46 (d, J = 2.3
Hz, 1H), 6.44-6.40 (m, 2H), 6.04 (dd, J = 7.8, 5.5 Hz,
1H) , 5.37 (s, 2H) , 3.33 (dd, J = 16.4, 7.8 Hz, 1H) , 2.81
(dd, J = 16.4, 5.5 Hz, 1H), 2.74 (s, 3H) . MS (LR-APCI)
calcd. for C18H15N208S (M-H) 419.05; found 418.9.
1o
O C NN~OH
~O O
IO
Example 16
(6-Allyloxy-1-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-yl)-acetic acid. 1H NMR (400 MHz, CD3CN) S
7.62 (d, J = 3.1 Hz, 1H), 7.49 (d, J = 9.4 Hz, 1H), 7.45
(s, 1H), 7.36 (dd, J = 9.4, 3.1 Hz, 1H), 6.40-6.37 (m,
2H), 6.14-6.04 (m, 1H), 5.44 (d, J = 18.0 Hz, 1H), 5.33
(s, 2H), 5.30 (d, J = 11.7 Hz, 1H), 4.75 (s, 2H), 4.65
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(d, J = 4.7 Hz, 2H) . MS (LR-APCI) calcd. for C18H15N206
o
O N OH
N1111O O
(M-H) 355.09; found 355.1
Example 17
2-[6-(Biphenyl-4-yloxy)-1-furan-2-ylmethyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-yl]-3-phenyl-propionic acid. 1H
NMR (400 MHz, CD3CN 5 7.38 (app t, J= 9.0 Hz, 4H), 7.28
(s, 1H), 7.22-7.07 (m, 6H), 6.86-6.81 (m, 7H), 6.12 (s,
1H), 5.96 (s, 1H), 5.61 (dd, J = 11.0, 5.5 Hz, 1H), 4.99
(s, 2H), 3.23 (dd, J = 13.7, 5.5 Hz, 1H), 3.15 (dd, J =
13 7, 11.0 Hz, 1H). MS (LR-APCI) calcd. for C34H25N206 (M-
H) 557.17; found 557Ø
NH
CI
N OH
N-I_-O O
O
I
Example 18
2-(6-Chloro-l-furan-2-ylmethyl-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-yl)-3-(1H-indol-3-yl)-propionic acid
1H NMR (MeOH-D4) 6 = 10.08 (1H, bs), 7.88 (1H, bs), 7.60
(1H, dd, J= 3.1, 9.4 Hz), 7.41 (2H, d, J= 9.4 Hz), 7.36
(1H, d, J= 7.8 Hz), 7.19 (1H, d, J= 8.6 Hz), 6.95 (1H, d,
J= 7.8 Hz), 6.92 (2H, s), 6.75 (1H, trp, J= 7.8 Hz), 6.31
(1H, bs), 5.89 (1H, dd, J= 5.4, 10.9 Hz), 5.21 (2H, s),
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3.73 (1H, dd, j= 10.9, 14.8 Hz), 3.63 (1H, dd, J= 5.4,
15.6 Hz)
MS (negative APCI) m/e= 461.9 (m-1) corresponds to
C24H18C1N305 Mol. Wt.: 463.87
CI
S OH
O 0
N
11O
Example 19
2-[6-(4-Chloro-phenylsulfanyl)-1-furan-2-ylmethyl-2,4-
dioxo-1,4-dihydro-2H-quinazolin-3-yl]-3-phenyl-propionic
acid. 1H NMR (400 MHz, DMSO-d6) 5 7.82 (s, 1H) , 7.72 (dd,
J = 8. 6, 2. 3 Hz, 1H) , 7.63 (d, J = 7. 8 Hz, 2H) , 7 .45 (d,
J = '8.6 Hz, 2H) , 7.33 (d, J = 8.6 Hz, 2H) , 7.14-7. 07 (m,
5H) , 6.42 (s, 1H) , 6.30 (s, 1H) , 5.76 (dd, J = 10.2, 6.3
Hz, 1H), 5.30 (s, 2H), 3.49-3.30 (m, 2H). MS (LR-APCI)
calcd. for C28H2OC1N205S (M-H) 531.08; found 531Ø
O
O N^ OH
N~O 0
~Co)
Example 20
[6-(Biphenyl-4-yloxy)-1-furan-2-ylmethyl-2,4-dioxo-l,4-
dihydro-2H-quinazolin-3-y1]-acetic acid. 1H NMR (400 MHz,
DMSO-d6) 5 7.76-7.60 (m, 7H), 7.56 (d, J = 3.1 Hz, 1H),
7.46 (t, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.16
(d, J = 8.6 Hz, 2H), 6.48 (d, J = 3.1 Hz, 1H), 6.44-6.42
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(m, 1H), 5.40 (s, 2H), 4.62 (s, 2H). MS (LR-APCI) calcd.
for C27H19N206 (M-H) 467.12; found 466.9.
NH
S J N OH
N--~O
I / .
Example 21
2--[6-(4-Chloro-phenylsulfanyl)-1-furan-2-ylmethyl-2,4-
dioxo-1,4-dihydro-2H-quinazolin-3-yl]-3-(1H-indol-3-yl)-
propionic acid. 1H NMR (400 MHz, CD3CN) 5 8.87 (s, 1H),
7.80 (s, 1H), 7.51 (dd, J = 8.6, 2.3 Hz, 1H), 7.34-7.30
(m, 2H), 7.29-7.25 (m, 3H), 7.20-7.16 (m, 3H), 6.92 (t, J
=7.0 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.73 (t, J = 7.8
Hz, 1H), 6.27 (s, 1H), 5.93 (s, 1H), 5.77 (dd, J = 9.4,
7.0 Hz, 1H), 5.10 (app d, J = 7.8 Hz, 2H), 3.52-3.47 (m,
2H) . MS (LR-APCI) calcd. for C3oH21C1N305S (M-H) 570.09;
found 569.9.
0
O OH
N OH
OSO I N O
N~O
O
Example 21
2-(6-Benzenesulfonylamino-l-furan-2-ylmethyl-2,4-dioxo-
1,4-dihydro-2H-quinazolin-3-yl)-succinic acid. 1H NMR
(400 MHz, DMSO-d6) 5 10.57 (s, 1 H), 7.75-7.47 (m, 9 H),
6.40-6.37 (m, 2 H), 5.82-5.72 (m, 1 H), 5.24 (s, 2 H),
3.22-3.14 (m, 1 H), 2.65-2.56 (m, 1 H). MS (LR-APCI)
calcd. for C23H18N309S (M-H) 512.08; found 512Ø
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NH
0
S N OH
/ NIkIO 0
Example 22
2-(1-Furan-2-ylmethyl-6-methylsulfanyl-2,4-dioxo-l,4-
dihydro-2H-quinazolin-3-yl)-3-(1H-indol-3-yl)-propionic
acid. 1H NMR (400 MHz, CD3CN) 5 8.86 (s, 1H), 7.71 (s,
1H), 7.46 (dd, J = 8.6, 2.3 Hz, 1H), 7.36 (d, J = 7.8 Hz,
1H), 7.31 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.19 (d, J =
7.8 Hz, 1H), 6.92 (t, J =7.0 Hz, 1H), 6.85 (s, 1H), 6.77
(t, J = 7.4 Hz, 1H), 6.25 (s, 1H), 5.90 (s, 1H), 5.81
(dd, J = 9.4, 6.3 Hz, 1H), 5.10 (app d, J = 7.0 Hz, 2H),
3.54-3.49 (m, 2H), 2.38 (s, 3H). MS (LR-APCI) calcd. for
C25H20N305S (M-H) 474.11; found 473.9.
Example 23
O CO2H
N CO2H
PhOCHN N~O
O
2-(7-Benzoylamino-l-furan-2-ylmethyl-2,4-dioxo-1,4-
dihydro-2H-quinazolin-3-yl)-succinic acid. 1H NMR (400
MHz, CD3CN) 5 9.13 (s, 1H) , 8.27 (d, J = 1.6 Hz, 1H), 8.12
(d, J = 8.6 Hz, 1H), 7.98 (d, J = 7.0 Hz, 1H), 7.65 (app
t, j = 7.4 Hz, 1H), 7.57 (app t, J = 7.4 Hz, 4H), 7.48
(d, J = 2.3 Hz, 1H), 6.52 (d, J = 3.1 Hz, 1H), 6.41 (app
t, j = 2.6 Hz, 1H), 6.04 (dd, J = 8.2, 5.1 Hz, 1H), 5.33
(d, J = 2.3 Hz, 2H), 3.34 (dd, J = 16.8, 8.2 Hz, 1H),
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2.78 (dd, J = 16.4, 5.5 Hz, 1 H) MS (LR-APCI) calcd.
for C24H18N308 (M-H) 476.11; found 476Ø
Example 24
2-[2-(Benzenesulfonylamino-methyl)-1H-indol-6-yloxy]-malonic
acid
O
~ \ NH-S=0
O I / NH I \
HO2C = CO2H
Step A: 6-(tert-Butyl-dimethyl-silanyloxy)-1H-indole-2-
carboxylic acid
6-Hydroxy-1H-indole-2-carboxylic acid (5'.40 g, 30.48 mmol) is
dissolved in THF (100 ml) and imidazole (10.38, 152.4 mmol) is
added. The mixture is stirred for 5 minutes, TBDMS-C1 (13.78
g, 91.44 mmol) is added. The reaction is stirred at room
temperature for 1 hour. The mixture is filtered into water
(200 ml). The solid is washed with THF (50 ml). The filtrate
is concentrated to remove THF. The product is extracted with
ethyl acetate (100 ml) three times. The organic is dried
(MgSO4), filtered, and concentrated to provide 6-(tert-Butyl-
dimethyl-silanyloxy)-1H-indole-2-carboxylic acid (8.0 g, 90%
yield). ''H NMR (400 MHz, DMSO-d6): 5 12.73 (s, 1H), 11.43 (s,
1H), 7.49 (d, 1H), 7.00 (s, 1H), 6.84 (s, 1H), 6,63 (m, 1H),
0.97 (s, 9H), 0.20 (s, 6H).
Step B: [6-(tert-Butyl-dimethyl-silanyloxy)-1H-indol-2-yl]-
methanol
1M LAH in THF (103 ml) is cooled to 0 C. A solution of 6-
(tert-Butyl-dimethyl-silanyloxy)-1H-indole-2-carboxylic acid
(6.0 g, 20.60 mmol) in THF (30 ml) is added slowly. The
reaction is stirred at room temperature for two days, quenched
with water (10 ml), iN NaOH (10 ml) and water (20 ml). To
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the mixture MgSO4 is added. The mixture is filtered, washed
with 10% methanol in ethyl acetate (200 ml). The filtrate is
concentrated to oil. The crude is purified by column
chromatography (20% ethyl acetate in hexanes) to provide [6-
(tert-Butyl-dimethyl-silanyloxy)-1H-indol-2-yl]-methanol (2.30
g, 40% yield) . 1H NMR (400 MHz, DMSO-d6) : 5 10.72 (s, 1H), 7.28
(d, 1H), 6.76 (s, 1H), 6.50 (m, 1H), 6.16 (s, 1H), 5.13 (t,
1H), 4.52 (d, 2H), 0.96 (s, 9H), 0.17 (s, 6H).
Step C: 2-Azidomethyl-6-(tert-butyl-dimethyl-silanyloxy)-1H-
indole
[6-(tert-Butyl-dimethyl-silanyloxy)-1H-indol-2-yl]-methanol
(2.0-g, 7.21 mmol) is dissolved in DMF (950 ml), cooled to 0 C.
TEA (2.01 ml, 14.42 mmol) and MsCl (0.83 g, 7.21 mmol) are
added. The mixture is stirred at room temperature for 1 hour.
NaN3 (2.34 g, 34 mmol) is added. The reaction is stirred at
room temperature for 1 hour and then 80 C overnight. The
mixture is cooled to room temperature, concentrated. The
residue is purified by column chromatography (10% ethyl
acetate in hexanes) to give 2-Azidomethyl-6-(tert-butyl-
dimethyl-silanyloxy)-1H-indole (1.40g, 64%). 1H NMR (400 MHz,
DMSO-d6): 6 11.08 (s, 1H), 7.38 (d, 1H), 6.80 (s, 1H), 6.58
(m, 1H), 6.40 (s, 1H), 4.53 (d, 2H), 0.96 (s, 9H), 0.17 (s,
6H).
Step D: [6-(tert-Butyl-dimethyl-silanyloxy)-1H-indol-2-yl]-
methylamine
2-Azidomethyl-6-(tert-butyl-dimethyl-silanyloxy)-1H-indole
(0.70 g, 2.31 mmol), is dissolved in ethanol (10 ml). 100 mg
of 10% Pd/C is added. The mixture is hydrogenated at 40 psi
of hydrogen overnight to give [6-(tert-Butyl-dimethyl-
silanyloxy)-1H-indol-2-yl]-methylamine.
Step E: [6-(tart-Butyl-dimethyl-silanyloxy)-lH-indol-2
ylmethyl]-carbamic acid benzyl ester
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[6-(tert-Butyl-dimethyl-silanyloxy)-1H-indol-2-yl]-methylamine
(0.70 g, 1.01 mmol) is dissolved in DCM (10 ml), cooled to 0 C.
DIEA (0.35 ml, 2.02 mmol) and Cbz-Cl (0.17 g, 1.01 mmol) are
added. The mixture is stirred for 1 hour at room temperature.
The reaction mixture is concentrated and the residue is
.purified by column chromatography (10% ethyl acetate in
hexanes) to provide [6-(tert-Butyl-dimethyl-silanyloxy)-1H-
indol-2-ylmethyl]-carbamic acid benzyl ester.
Step F: (6-Hydroxy-lH-indol-2-ylmethyl)-carbamic acid benzyl
ester
[6-(tert-Butyl-dimethyl-silanyloxy)-1H-indol-2-ylmethyl]-
carbamic acid benzyl ester (0.80 g, 1.95 mmol) is dissolved in
THE (2 ml) . Cooled to -78 C. 1 M TBAF solution in THE (3.90
ml) is added. The reaction mixture is concentrated and the
residue is purified by column chromatography (30% ethyl
acetate in hexanes) to obtain (6-Hydroxy-lH-indol-2-ylmethyl)-
carbamic acid benzyl ester.
Step G: 2-(2-Aminomethyl-lH-indol-6-yloxy)-malonic acid
diethyl ester
(6-Hydroxy-lH-indol-2-ylmethyl)-carbamic acid benzyl ester was
dissolved in 10 ml acetone, Cs2CO3 and diethyl chloromalonate
were added. The reaction is stirred overnight. HPLC and TLC
indicated the reaction is done. The mixture was diluted with
ethyl acetate and filtered through silica gel plug. The
filtrate is concentrated and redissolved in ethanol,
hydrogenated for 3 hours at 40 psi of hydrogen. The mixture
is filtered, washed with ethyl acetate. The filtrate is
concentrated to give 2-(2-Aminomethyl-lH-indol-6-yloxy)-
malonic acid diethyl ester.
Step H: 2-[2-(Benzenesulfonylamino-methyl)-1H-indol-6-yloxy]-
malonic acid diethyl ester
2-(2-Aminomethyl-lH-indol-6-yloxy)-malonic acid diethyl ester
(80 mg, 0.2
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mmol) is dissolved in DCM (2 ml). DIEA (87 ^l, 0.50 mmol) is
added. To the solution, benzenesulfonyl chloride (44 mg, 0.25
mmol) is added. The reaction is stirred at room temperature
for two hours. The reaction mixture is concentrated and the
residue is purified by chromatography (30% ethyl acetate in
hexanes) to give the title compound.
Step I:2-[2-(Benzenesulfonylamino-methyl)-1H-indol-6-yloxy]-
malonic acid
2-[2-(Benzenesulfonylamino-methyl)-1H-indol-6-yloxy]-malonic
acid diethyl is dissolved in ethanol (3 ml). 1M NaOH (2 ml) is
added. The mixture is stirred for 1 hour. The mixture was
acidified with 1M HCl to pH = 2 and purified by C18 column
chromatography (15% atetonitrile in water). 1H NMR (400 MHz,
DMSO-d6): 5 10.76 (s, 1H), 8.04 (t, 1H), 7.82 (d, 2H), 7.54-
7.64 (m, 3H), 7.23 (d, 1H), 6.72 (s, 1H), 6.57 (d, 1H), 6.06
(s, 1H), 5.07 (s, 1H), 4.01 (d, 2H); MS (ES-) m/z 403 (M-1).
The following compounds can be prepared using similar
chemistry to that which is described above:
Example 24
2-(2-(Phenylmethanesulfonylamino-methyl)-1H-indol-6-yloxy]-
malonic acid
XHN+O
H02CCO2H
1H NMR (400 MHz, DMSO-d6): 5 10.89 (s, 1H), 7.60 (t, 1H), 7.30-
7.38 (m, 6H), 6.88 (s, 1H), 6.67 (m, 1H), 6.27 (s, 1H), 5.25
(s, 1H), 4.31 (s, 2H); 4.18 (d, 2H); MS (ES-) m/z 417 (M-1).
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Example 25
2-{2-[(4-Acetylamino-benzenesulfonylamino)-methyl]-1H-indol-6-
yloxy}-malonic acid
0 _
11
HN-S \ / NH O
0
C,!~~nN
O H
H02CIIIC02H
1H NMR (400 MHz, DMSO-d6): 5 10.71 (s, 1H), 10.26 (s, 1H), 7.85
(t, 1H), 7.68 (m, 4H), 7.20 (d, 1H), 7.00 (d, 1H), 6.69 (s,
1H), 6.55 (d, 1H), 6.05 (s, 1H), 5.04 (s, 1H), 3.96 (d, 2H);
2.03 (s, 3H); MS (ES-) m/z 460 (M-1).
Example 26
2-{2-[(Biphenyl-4-sulfonylamino)-methyl]-1H-indol-6-yloxy}-
malonic acid
0
11
HN-S=0
O
/ H \
HO2CCO2H
1H NMR (400 MHz, DMSO-d6): 5 10.91 (s, 1H), 8.14 (t, 1H), 7.44-
7.91 (m, 9H), 7.30 (d, 1H), 6.84 (s, 1H), 6.64 (m, 1H), 6.14
(s, 1H), 5.22 (s, 1H), 4.10 (d, 2H); MS (ES-) m/z 479 (M-i).
Example 27
2-(2-{[(1-Acetyl-piperidine-4-carbonyl)-amino]-methyl}-1H-
indol-6-yloxy)-malonic acid
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O
NH
O NH
HO2C CO2H
O
1H NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.20 (t, 1H), 7.21
(d, 1H), 6.66 (s, 1H), 6.52 (m, 1H), 4.94 (s, 1H), 4.29 (m,
2H), 3.78 (d, 1H), 3.40 (m, 1H), 2.97 (m, 1H), 2.34-2.53 (m,
2H), 1.95 (s, 3H), 1.69 (m, 2H), 1.50 (m, 1H), 1.35 (m, 1H);
MS (ES-) m/z 416 (M-1).
Example 28
2-[2-(Methanesulfonylamino-methyl)-1H-indol-6-yloxy]-malonic
acid
o' H HN 11=O
O
HO2C CO2H
1H NMR (400 MHz, DMSO-d6): 5 10.88 (s, 1H), 7.60 (t, 1H), 7.30-
7.38 (m, 6H), 6.97 (s, 2H), 6.80 (s, 1H), 6.65 (m, 1H), 6.28
(s, 1H), 5.39 (s, 1H), 4.24 (d, 2H); 2.85 (s, 3H); MS (ES-)
m/z 341 (M-1).
Example 29
2-{2-[(3,5-Bis-trifluoromethyl-phenylmethanesulfonylamino)-
methyl]-1H-indol-6-yloxy}-malonic acid
0
n
NH-S=0
CF3
0 NH
HO2C CO2H
CF3
lH NMR (400 MHz, DMSO-d6): 5 10.65 (s, 1H), 8.17 (t, 1H), 8.15
(s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.16 (d, 1H), 6.58 (s,
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1H), 6.49 (m, 1H), 6.05 (s, 1H), 5.04 (m, 2H), 4.84 (s, 1H),
4.19 (s, 2H); MS (ES-) m/z 553 (M-1).
Example 30
2-{2-[(3,5-Dichloro-phenylmethanesulfonylamino)-methyl]-1H-
indol-6-yloxy}-malonic acid
0
11
\ \ NH-S=0
Cl
O NH
HO2C CO2H
CI
1H NMR (400 MHz, DMSO-d6): 6 10.75 (s, 1H), 7.66 (t, 1H), 7.15-
7.52 (m, 4H), 6.93 (d, 1H), 6.56 (m, 1H), 6.27 (s, 1H), 5.25
(s, 1H), 4.31 (s, 2H); 4.18 (d, 2H); MS (ES-) m/z 485 (M-1).
Example 31
2-{2-'[(2,2-Diphenyl-ethanesulfonylamino)-methyl]-1H-indol-6-
yloxy}-malonic acid
\
H HIN
O
H02 CO2H
1H NMR (400 MHz, DMSO-d6): 6 10.77 (s, 1H), 7.47 (t, 1H), 7.12-
7.32 (m, 11H), 6.76 (s, 1H), 6.62 (m, 1H), 6.17 (s, 1H), 5.07
(s, 1H), 4.46 (m, 1H); 4.14 (d, 2H), 3.82 (d, 2H), MS (ES-)
m/z 507 (M-1).
Example 32
2-{2-[(4'-Methyl-biphenyl-4-sulfonylamino)-methyl]-1H-indol-6-
yloxy}-malonic acid
0
11
\ HN-S=0
O I / N
H
H02CIII CO2H
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1H NMR (400 MHz, DMSO-d6): 5 10.88 (s, 1H), 8.11 (t, 1H), 7.82-
7.88 (m, 4H), 7.62 (d, 2H), 7.32 (d, 2H), 7.29 (d, 1H), 6.82
(s, 1H), 6.64 (m, 1H), 6.14 (s, 1H), 5.19 (s, 1H), 4.08 (d,
2H); 2.40 (s, 3H), MS (ES-) m/z 493 (M-1).
Example 33
2-{2-[(4'-Chloro-biphenyl-4-sulfonylamino)-methyl]-1H-indol-6-
yloxy}-malonic acid
0
11
\ HN-S=0
O H N \
HO2CCO2H
Cl
1H NMR (400 MHz, DMSO-d6): 5 10.80 (s, 1H), 8.06 (t, 1H), 7.77-
7.83 (m, 4H), 7.66 (d, 2H), 7.49 (d, 2H), 7.21 (d, 1H), 6.76
(s, 1H), 6.56 (m, 1H), 6.06 (s, 1H), 5.14 (s, 1H), 4.02 (d,
2H); MS (ES-) m/z 513 (M-1).
Example 34
2-(2-Benzylcarbamoyl-lH-indol-6-yloxy)-malonic acid
~M\ HN
0 JC H O
H02C~CO2H
1H NMR (400 MHz, DMSO-d6): 6 11.44 (s, 1H), 8.89 (t, 1H), 7.50
(d, 1H), 7.31 (m, 4H), 7.22 (m, 1H), 7.09 (d, 1H), 6.88 (d,
1H), 6.73 (m, 1H), 5.24 (s, 1H), 4.47 (d, 2H); MS (ES-) m/z
367 (M-1).
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Example 35
2-(2-Phenethylcarbamoyl-lH-indol-6-yloxy)-malonic acid
HN
I N O
H02C'j-1 CO2H
1H NMR (400 MHz, DMSO-d6): 5 11.39 (s, 1H), 8.43 (t, 1H), 7.50
(d, 1H), 7.15-7.29 (m, 5H), 7.00 (s, 1H), 6.86 (s, 1H), 6.73
(m, 1H), 5.24 (s, 1H), 3.49 (m, 2H), 2.85 (m, 2H); MS (ES-)
m/z 381 (M-1).
Example 36
2-[2-(4-Phenyl-butylcarbamoyl)-1H-indol-5-yloxy]-malonic acid
HO2Cy0 I \ 7 N 5
CO2H N O
H
1H NMR (400 MHz, DMSO-d6): 5 11.42 (s, 1H), 8.40 (t, 1H), 7..30
(d, 1H), 7.10-7.29 (m, 5H), 7.05 (s, 1H), 6.98 (s, 1H), 6.90
(s, 1H), 5.24 (s, 1H), 3.30 (m, 2H); 2.65 (m, 2H), 1.60 (m,
4H), MS (ES-) m/z 409 (M-1).
Example 37
2-{2-[(Benzyl-phenylmethanesulfonyl-amino)-methyl]-1H-indol-6-
yloxy}-malonic acid
n\N
0
11
N
O
0 / H
-s-b
H02C1111 CO2H
'H NMR (400 MHz, DMSO-d6): 6 10.92 (s, 1H), 7.33 (d, 1H), 7.12-
7.28 (m, 1OH), 6.84 (s, 1H), 6.63 (m, 1H), 6.24 (s, 1H), 5.20
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(s, 1H), 4.28 (s, 2H); 4.23 (s, 2H), 4.15 (s, 2H), 2.65 (s,
3H); MS (ES-) m/z 507 (M-1).
Example 38
2-(2-{[(4-Phenyl-butyl)-phenylmethanesulfonyl-amino]-methyl}-
1H-indol-6-yloxy)-malonic acid
5c?
N-S
0 I ~ N O b
H
HO2CCO2H
2-[2-(Phenylmethanesulfonylamino-methyl)-1H-indol-6-yloxy]-
malonic acid diethyl ester (20 mg 0.042 mmol) of is dissolved
in THE (1 ml) . Ph3P (17 mg, 0.063 mmol) and DIAD (128 mg,
0.063 mmol) are added. The mixture is stirred for 2 minutes
and phenbutanol is added. The reaction is stirred overnight.
The reaction mixture is concentrated and the residue is
purified by column chromatography (15% ethyl acetate in
hexanes) to obtain 14 mg of ester. The ester is dissolved in
methanol (2 ml). IN NaOH aqueous solution (0.40 ml) is added.
The reaction is stirred for 1 hour and acidified with IN HC1.
The product was purified by C18 column (40% acetonitrile in
water) .1H NMR (400 MHz, DMSO-d6) : 5 10.81 (s, 1H), 7.29-7.36
(m, 6H), 7.18 (d, 2H), 7.12 (d, 1h), 7.03 (d, 2H), 6.874 (s,
1H), 6.65 (m, 1H), 6.28 (s, 1H), 5.16 (s, 1H), 4.36 (s, 2H);
4.31 (s, 2H), 3.04 (m, 2H), 2.39 (m, 2H), 1.20-1.35 (m, 4H);
MS (ES-) m/z 549 (M-1).
Example 39
2-[3-Acetyl-2-(phenylmethanesulfonylamino-methyl)-1H-indol-6-
yloxy]-malonic acid
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O
C-0
O H HN-S=O
11
HO2CIII CO2H 0
1H NMR (400 MHz, DMSO-d6): 5 11.67 (s, 1H), 7.74 (d, 2H),
7.58 (d, 2H) , 7.35 (br s, 4 H), 6.76-6.85 (m, 3 H) , 5.05 (s,
1H), 4.52 (d, 2H), 4.39 (br s, 2H), 2.50 (s, 3H); MS (ES-) m/z
415 (M-C02H).
Example 40
2-[3-Benzoyl-2-(phenylmethanesulfonylamino-methyl)-1H-indol-6-
yloxy]-malonic,acid
O
HN-S=0
0 H
HO2CCO2H
1H NMR (400 MHz, DMSO-d6): 5 11.83 (s, 1H), 7.61 (m, 3 H),
7.53 (m, 3H), 7.29 (m, 5H), 6.87-7.01 (m, 2H), 6.66 (d, 1 H),
5.18 (s, 1H), 4.36 (d, 2H), 4.33 (s, 1H); MS (ES-) m/z 477 (M-
C02H).
Example 41
SHP-2 Assay Conditions
N-terminal 6 His-tagged, catalytic domain of SHP-2
(250-527) is expressed in E. coli and protein is purified
by conventional methods. SHP-2's activity was assessed
by measuring the fluorescent signal generated by the
dephosphorylation of fluorescein diphosphate (FDP). The
assay is carried out in 96-well polypropylene black
plate. The final assay volume is 100 L and comprises of
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61
25 mM NaOAc, pH 6, 0.02% Triton X-100, 10 MM DTT and 2 nM
SHP-2. Inhibitors are suspended in DMSO, and all
reactions, including controls are performed at a final
concentration of 3% DMSO. Reactions are initiated by the
addition of 3 gM FDP and incubated at ambient temperature
for 25 minutes. Plates were read using a Molecular
Devices Gemini plate reader, Ex 485, Em 538, Cutoff 530.
