US 2011/0257100 A1 · Inhibitors of Protein Tyrosine Kinase Activity

Abstract

This invention relates to compounds that inhibit protein tyrosine kinase activity. In particular the invention relates to compounds that inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling, for example, the inhibition of VEGF receptor signaling. The invention also provides compounds, compositions and methods for treating cell proliferative diseases and conditions and ophthalmic diseases, disorders and conditions.

A compound having the Formula (I):

including N-oxides, hydrates, solvates, tautomers, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein,
D is selected from the group consisting of an aromatic, heteroaromatic, cycloalkyl or heterocyclic ring system, C1-C6alkyl-heterocyclyl-C(O)—, C1-C6alkyl-heterocyclyl-C1-C6alkyl-N(R6)—C(O)—, (R6)(R6)N—C(O)—O-heterocyclyl-C(O)—, heterocyclyl-C(O)—, PivO-heterocyclyl-C(O)—, C1-C6alkyl-O—C(O)-heterocyclyl-C(O)—, C1-C6alkyl-C(O)—N(R6)— heterocyclyl-C(O)—, (C1-C6alkyl)(Box)N-heterocyclyl-C(O)—, HO-heterocyclyl-C(O)—, HO—C(O)-heterocyclyl-C(O)—, C1-C6alkyl-C(O)—O-heterocyclyl-C(O)—, (R6)(R6)N—C1-C6alky-N(R6)—C(O)-heterocyclyl-C(O)—, C1-C6alkyl-heterocyclyl-C(O)-heterocyclyl-C(O)— and (R6)(R6)N-heterocyclyl-C(O)—, wherein each of the aromatic, heteroaromatic, cycloalkyl and heterocyclic groups is optionally substituted with 1 or more independently selected R38;
M is an optionally substituted fused heterocyclic moiety;
Z is selected from the group consisting of —O—, —S(O)0-2- and —NR5—, wherein R5 is selected from the group consisting of H, optionally substituted C1-C5alkyl, an optionally substituted (C1-C5)acyl and C1-C6 alkyl-O—C(O), wherein C1-C6 alkyl is optionally substituted:
Ar is a group of the formula C,
wherein,
A4, A5, A6 and A7 are independently selected from the group consisting of N and —CH—, with the proviso that no more than two of A4, A5, A6 and A7 can be N, wherein Ar is optionally substituted;
and
G is a group B-L-T, wherein
B is selected from the group consisting of a covalent bond, —N(R13)—, —N(SO2R13)—, —O—, —S(O)0-2 and —C(═O)—;
L is selected from the group consisting of a covalent bond, —C(═S)N(R13)—, —C(═NR14)N(R13)—, —SO2N(R13)—, —SO2—, —C(═O)N(R13)—, —N(R13)—, —C(═O)C1-2alkyl-N(R13)—, —N(R13)C1-2alkyl-C(═O)—, —C(═O)C0-1alkyl-C(═O)N(R13)—, —C0-4alkylene, —C(═O)C0-1alkyl-C(═O)OR3—, —C(═NR14)—C0-1 alkyl-C(═O)—, —C(═O)—, —C(═O)C0-1alkyl-C(═O)— and an optionally substituted four to six-membered heterocyclyl containing between one and three annular heteroatoms including at least one nitrogen, wherein the alkyl and alkylene are optionally substituted;
and
T is selected from the group consisting of —H, —R13, —C0-4alkyl, —C0-4alkyl-Q, —O—C0-4alkyl-Q, —C0-4alkyl-O-Q, —N(R13)C0-4alkyl-Q, —SO2C0-4alkyl-Q, —C(═O)C0-4alkyl-Q, —C0-4alkyl-N(R13)Q and —C(═O)N(R13)—C0-4alkyl-Q, wherein each C0-4alkyl is optionally substituted;
wherein
R38 is selected from the group consisting of
C2-C6alkynyl-heterocyclyl,
H(O)C— and C1-C6alkyl-C(O)—O—C1-C6alkyl-C(O)—,
R37O—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-,
R37O—(CH2)1-6—N(A)-(CH2)1-4—,
C1-C6alkyl-S(O)2—(CH2)2—N(A)-CH2—,
R37O—(CH2)j—[(CH2)iO]x—(CH2)i1—N(A)-(CH2)j1—,
R37O—C(O)—C0-C6alkyl-heterocyclyl-CH2—,
R37O—(CH2)j—[(CH2)iO]x—(CH2)i1—N(R39)—C(O)—,
R37—O—C(O)—C1-C6alkyl-heterocyclyl-C(O)—,
HOOC—C1-C6alkyl-N(A)-CH2—,
(HOOC)(NR9R10)—C1-C6alkyl-N(A)-CH2—,
R37O—C(O)—C1-C6alkyl-C(O)—,
(R9)(R10)N—C1-C6alkyl-C(O)-heterocyclyl-CH2—,
cycloalkyl-N(R39)—C(O)—O—C1-C6alkyl-,
R37—O—C1-C6alkyl-O—C1-C6alkyl-C(O)—,
(R9)(R10)N—C(O)—C1-C6alkyl-heterocyclyl-CH2—,
(R9)(R10)N—C1-C6alkyl-C(O)—O—C1-C6alkyl-heterocyclyl-CH2—,
NC—C1-C6alkyl-heterocyclyl-CH2—,
F3C—C1-C6alkyl-heterocyclyl-CH2—,
C1-C6alkyl-C(O)—O—C1-C6alkyl-C(O)-(5 to 10-membered heterocyclyl)-C1-C6alkyl-,
(optionally substituted 8- to 10-membered fused heterocyclyl)-C1-C6alkyl-,
F-heterocyclyl-C1-C6alkyl-,
heteroaryl-C1-C6alkyl-heterocyclyl-C1-C6alkyl-,
R37—C1-C6alkyl-O—C1-C6alkyl-heterocyclyl-C1-C6alkyl-,
R37O—C(O)—C1-C6alkyl-O-heterocyclyl-C1-C6alkyl-,
R37O—C(O)—C1-C6alkyl-heterocyclyl-C1-C6alkyl-,
heterocyclyl-C1-C6alkyl-O-aryl-N(R6)—C1-C6alkyl-,
(heteroaryl substituted with one or more C1-C6alkyl)-N(R6)—C1-C6alkyl-,
(C1-C6alkyl)2N—C1-C6alkyl-aryl-N(R6)—C1-C6alkyl-,
(C1-C6alkyl)2N—C1-C6alkyl-C(O)-aryl —N(R6)—C1-C6alkyl-,
heterocyclyl-C1-C6alkyl-O-aryl-N(R6)—C1-C6alkyl-,
(R6)2N-heterocyclyl-C1-C6alkyl-,
C1-C6alkyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-,
C1-C6alkylC(O)—O—C1-C6alkyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-,
R37O—C1-C6alkyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-,
heteroaryl-C1-C6alkyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-,
C1-C6alkyl-S(O)2—N(R6)-heterocyclyl-C1-C6alkyl-,
C1-C6alkyl-O—C(O)—N(R6)-heterocyclyl-C1-C6alkyl-,
C1-C6alkyl-N(R6)—C(O)—N(R6)-heterocyclyl-C1-C6alkyl-,
C1-C6alkyl-heterocyclyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-,
R37O—C1-C6alkyl-N(R6)—C(O)—N(R6)-heterocyclyl)-C1-C6alkyl-,
(heterocyclyl optionally substituted with one or more C1-C6alkyl)-C1-C6alkyl-,
(C1-C6alkyl)2N—C1-C6alkyl-,
C1-C6alkyl-heterocyclyl-C(O)—C1-C6alkyl-,
heterocyclyl-C(O)—C1-C6alkyl-,
C1-C6alkyl-O—C(O)—C1-C6alkyl-,
C1-C6alkyl —O—C(O)—C1-C6alkyl-heteroaryl-N(R6)—C(O)—C1-C6alkyl-,
(C1-C6alkyl)2N-heterocyclyl-C(O)—C1-C6alkyl-,
heteroaryl-C1-C6alkyl-N(R6)—C(O)—C1-C6alkyl-,
(Boc)(H)N-heterocyclyl-C(O)—C1-C6alkyl-,
C1-C6alkyl-O—C(O)-heterocyclyl-C(O)—C1-C6alkyl-,
Boc-heterocyclyl-C(O)—C1-C6alkyl-,
Ac—O—C1-C6alkyl-C(O)-heterocyclyl-C(O)—C1-C6alkyl-,
R37O—C1-C6alkyl-C(O)-heterocyclyl-C(O)—C1-C6alkyl-,
(Boc)(H)N—C1-C6alkyl —C(O)-heterocyclyl-C(O)—C1-C6alkyl-,
NH2—C1-C6alkyl-C(O)-heterocyclyl-C(O)—C1-C6alkyl-,
(C1-C6alkyl)(H)N—C(O)-heterocyclyl-C(O)—C1-C6alkyl-,
NH2-heterocyclyl-C(O)—C1-C6alkyl-,
R37O—C1-C6alkyl-O—C1-C6alkyl-heterocyclyl-C(O)—,
C1-C6alkyl-O—C(O)—N(R6)-heterocyclyl-C(O)—,
(R6)(R6)N-heterocyclyl-C(O)—,
(R6)(R6)N-heterocyclyl-C1-C6alkyl-,
heterocyclyl-O—C1-C6alkyl-,
C1-C6alkyl-N(R6)—C(O)—N(R6)-heterocyclyl-C(O)—,
(R6)(R6)N—C(O)-heterocyclyl-O—C1-C6alkyl-,
C2-C6alkenyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-,
R37O—C1-C6alkyl-C(O)-heterocyclyl-O—C1-C6alkyl-,
R37O—C1-C6alkyl-N(R6)-heterocylcyl-C1-C6alkyl-,
R37O—(CH2)j—[(CH2)iO]x—C1-C6alkyl-N(R6)-heterocyclyl-C1-C6alkyl-,
halo-C1-C6alkyl-heterocyclyl-C1-C6alkyl-,
halo-C1-C6alkyl-N(R6)-heterocyclyl-C1-C6alkyl-,
R37O—C(O)—C1-C6alkyl-N(R6)-heterocyclyl-C1-C6alkyl-,
R37—O—C(O)—C1-C6alkyl-N(R6)—C(O)—N(R6)-heterocyclyl-C1-C6alkyl-,
(C1-C6alkyl)(H)N—C(O)-heterocyclyl-N[C1-C6alkyl-C(O)—OH]—C1-C6alkyl-,
C1-C6alkyl-O—C(O)-heterocylcyl-C1-C6alkyl-,
HO—C(O)-heterocyclyl-C1-C6alkyl-,
C1-C6alkyl-heterocyclyl-C(O)-heterocyclyl-C1-C6alkyl-,
R37O—C1-C6alkyl-N(R6)—C(O)-heterocyclyl-C1-C6alkyl-,
(R6)(R6)N—C1-C6alkyl-N(R6)—CO)-heterocyclyl-C1-C6alkyl-,
(C1-C6alkyl)(C1-C6alkyl)N-heterocycl yl-C1-C6alkyl-,
R37O—C1-C6alkyl —C(O)—[(C1-C6alkyl)(C1-C6alkyl)heterocyclyl]-C1-C6alkyl-,
C2-C6alkenyl-C(O)—[(C1-C6alkyl)(C1-C6alkyl)heterocyclyl]-C1-C6alkyl-,
R37—O—C1-C6alkyl-[(C1-C6alkyl)(C1-C6alkyl)heterocyclyl]-C1-C6alkyl-,
C1-C6alkyl-O—C1-C6alkyl-NR(6)—C1-C6alkyl-,
C1-C6alkyl-O—C1-C6alkyl-N[C(O)—NH—C1-C6alkyl]-C1-C6alkyl-,
C1-C6alkyl-O—C1-C6alkyl-N[C(O)—C1-C6alkyl]-C1-C6alkyl-,
C1-C6alkyl-O—C1-C6alkyl-[C(O)—C1-C6alkyl-OH]-C1-C6alkyl-,
R37O—C(O)—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-,
R37O—C(O)—C1-C6alkyl-heterocyclyl-C1-C6alkyl-,
spiro-heterocyclyl-C1-C6alkyl-,
R37O—C1-C6alkyl-C(O)-spiro-heterocyclyl-C1-C6alkyl-,
R37O—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-,
C1-C6alkyl-heterocyclyl-C1-C6alkyl-,
C1-C6alkyl-C(O)—O—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-,
heterocyclyl-C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-,
(R6)(R6)N—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-,
heterocyclyl-C(O)-heterocyclyl-C1-C6alkyl-,
(R6)(R6)N—C2-C6alkenyl-C(O)-heterocyclyl-C1-C6alkyl-,
heterocyclyl-C2-C8alkenyl-C(O)-heterocyclyl-C1-C6alkyl-,
(R6)(R6)N—C1-C6alkyl-N(R6)—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-,
heterocyclyl-C(O)—,
(R6)(R6)N—C(O)-heterocyclyl-C1-C6alkyl-,
R37O—C(O)—C1-C6alkyl-N(R6)—C(O)-heterocyclyl-C1-C6alkyl-,
C2-C6alkenyl-C(O)—O—C1-C6alkyl-N(R6)—C(O)-heterocyclyl-C1-C6alkyl-,
(R6)(R6)N—C(O)-heterocyclyl-C(O)—,
R37O—C1-C6alkyl-N(R6)—C(O)-heterocyclyl-C1-C6alkyl-,
R37O—C1-C6alkyl-heterocyclyl-C1-C6alkyl-(heterocyclyl)-,
R37O—C(O)—C1-C6alkyl-heterocyclyl-C(O)—,
R37O—C1-C6alkyl-heterocyclyl-C(O)—,
R37O—C1-C6alkyl-C(O)-heterocyclyl-C(O)—,
C1-C6alkyl-O—C(O)—N(R6)—C1-C6alkyl-C(O)—O—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-
R37O—(CH2)n[(CH2)iO]x—C1-C6alkyl-N(R6)—C(O)-heterocyclyl-C1-C6alkyl-,
HO-heterocyclyl-C1-C6alkyl-,
R37O-cycloalkyl-C(O)-heterocyclyl-C1-C6alkyl-
and
R37O—(CH2)n[(CH2)iO]x—C1-C6alkyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-;
A is selected from the group consisting of —C(O)—C1-C6alkyl-N(R39)—C(O)—C1-C6alkyl-N(R9)(R10), —C(O)—N(R39)—C1-C6alkyl, —C(═NR37)—C1-C6alkyl, —C(O)—(CH2)n—S(O)2—C1-C6alkyl, —C(O)—N(R39)-cycloalkyl, —C(O)—N(R9)(R10), (R37O)(R37aO)P(O)O—C1-C6alkyl-C(O)—, —C(═NR37)—H and —C1-C6alkyl-CF3;
each R6 is independently H or C1-C6alkyl;
R37 is selected from the group consisting of H, C1-C6alkyl and C3-C10cycloalkyl:
R37a is selected from the group consisting of H, C1-C6alkyl and C3-C10cycloalkyl;
j is an integer ranging from 0 to 4, alternatively 0 to 2;
i is 2 or 3;
x is an integer ranging from 0 to 6, alternatively 2 or 3;
i1 is 2 or 3;
j1 is an integer ranging from 0 to 4, alternatively 1 or 2;
n is an integer ranging from 0 to 4;
R39 is selected from the group consisting of H, —OH, C1-C6 alkyl, C3-C10 cycloalkyl, —(CH2)n2(C6-C10 aryl), —(CH2)n2(C5-C10 heteroaryl), —(CH2)n2(5-10 membered heterocyclyl), —(CH2)n2—O—(CH2)i2OR37 and —(CH2)n2OR37, wherein the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing R39 groups are optionally substituted;
R9 is selected from the group consisting of H, —OH, C1-C6 alkyl, C3-C10 cycloalkyl, —(CH2)n3(C6-C10 aryl), —(CH2)n3(C5-C10 heteroaryl), —(CH2)n3(5-10 membered heterocyclyl), —(CH2)n3O(CH2)i3OR37 and —(CH2)n3OR37, wherein the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing R9 groups are optionally substituted;
R10 is selected from the group consisting of H, —OH, C1-C6 alkyl, C3-C10 cycloalkyl, —(CH2)n4(C6-C10 aryl), —(CH2)n4(C5-C10 heteroaryl), —(CH2)n4(5-10 membered heterocyclyl), —(CH2)n4—O—(CH2)i4OR37 and —(CH2)n4OR37, wherein the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing R10 groups are optionally substituted;
n2 is an integer ranging from 0 to 6;
i2 is an integer ranging from 2 to 6;
n3 is an integer ranging from 0 to 6;
i3 is an integer ranging from 2 to 6;
n4 is an integer ranging from 0 to 6;
i4 is an integer ranging from 2 to 6;
R2 at each occurrence is independently selected from the group consisting of —H, halogen, trihalomethyl, —CN, —NO2, —NH2, —OR3, —NR3R4, —S(O)0-2R3, —S(O)2NR3R3, —C(O)OR3, —C(O)NR3R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —C(O)R3, C1-C4 alkoxy, C1-C4 alkylthio, —O(CH2)naryl, —O(CH2)nheteroaryl, —(CH2)0-5(aryl), —(CH2)0-5(heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —CH2(CH2)0-4-T2, wherein T2 is selected from the group consisting of —OH, —OMe, —OEt, —NH2, —NHMe, —NMe2, —NHEt and —NEt2, and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
and
q is an integer from 0 to 4;
R13 is selected from the group consisting of —H, —CN, —NO2, —NH2, —OR3, —NR3R4, —S(O)0-2R3, —S(O)2NR3R3, —C(O)OR3, —C(O)NR3R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —C(O)R3, —C(O)SR3, C1-C4 alkoxy, C1-C4 alkylthio, —O(CH2)n5aryl, —O(CH2)n5heteroaryl, —(CH2)n5(aryl), —(CH2)n5(heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —CH2(CH2)0-4-T2, an optionally substituted C1-4 alkylcarbonyl, and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of —OH, —OMe, —OEt, —NH2, —NHMe, —NMe2, —NHEt and —NEt2, and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
two R13, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, wherein the heteroalicyclic can have up to four annular heteroatoms, and the heteroalicyclic can have an aryl or heteroaryl fused thereto, in which case the aryl or heteroaryl is optionally substituted with an additional one to four of R60;
n5 is an integer ranging from 0 to 6
R60 is selected from the group consisting of —H, halogen, trihalomethyl, —CN, —NO2, —NH2, —OR3, —NR3R4, —S(O)0-2R3, —SO2NR3R3, —CO2R3, —C(O)NR3R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —C(O)R3, an optionally substituted (C1-C6)alkyl, an optionally substituted aryl, an optionally substituted heteroarylalkyl and an optionally substituted arylalkyl;
two R60, when attached to a non-aromatic carbon, can be oxo;
each R3 is independently selected from the group consisting of —H and R4;
R4 is selected from the group consisting of a (C1-C6)alkyl, an aryl, a lower arylalkyl, a heterocyclyl and a lower heterocyclyl-alkyl, each of which is optionally substituted, or
R3 and R4, taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, the optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from the group consisting of N, O, S and P;
R14 is selected from the group —H, —NO2, —NH2, —N(R3)R4, —CN, —OR3, an optionally substituted (C1-C6)alkyl, an optionally substituted heteroalicyclyl-alkyl, an optionally substituted aryl, an optionally substituted arylalkyl and an optionally substituted heteroalicyclic,
Q is a three- to ten-membered ring system, optionally substituted with zero, one or more of R20;
R20 is selected from the group consisting of —H, halogen, trihalomethyl, —CN, —NO2, —NH2, —OR3, —OCF3, —NR3R4, —S(O)0-2R3, —S(O)2NR3R3, —C(O)OR3, —C(O)NR3R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)C(O)OR3, —C(O)R3, —C(O)SR3, C1-C4 alkoxy, C1-C4 alkylthio, —O(CH2)n6aryl, —O(CH2)n6heteroaryl, —(CH2)n6(aryl), —(CH2)n6(heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —CH2(CH2)0-4-T2, an optionally substituted C1-4 alkylcarbonyl, C1-4 alkoxy, an amino optionally substituted by C1-4 alkyl optionally substituted by C1-4 alkoxy, —(CH2)n6P(═O)(C1-C6alkyl)2, a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, —SiMe3 and —SbF5;
and
n6 is an integer ranging from 0 to 6.

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Inhibitors of Protein Tyrosine Kinase Activity

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Inhibitors of Protein Tyrosine Kinase Activity

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Abstract

Claims69