US 6,635,626 B1Granted

Imidazoquinoxaline protein tyrosine kinase inhibitors

AssigneeBristol-Myers Squibb Company

InventorsJoel C. Barrish, Steven H. Spergel

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Abstract

Novel imidazoquinoxalines and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic disorders.

Claims16

Dependent claims

A method for the treatment of T-cell mediated disorders, comprising the step of administering to a subject in need thereof an effective amount of an Lck inhibitor of the following formula I or a pharmaceutically acceptable salt thereof:

where
p is 0, 1, 2, 3 or 4;
each R1, and R2 are independently selected from:
(1) hydrogen or R6,
where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or more groups Z3;
(2) —OH or —OR6;
(3) —SH or —SR6;
(4) —C(O)qH, —C(O)qR6, or —O—C(O)qR6, where q is 1 or 2;
(5) —SO3H or —S(O)qR6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NR7R6;
(10) —Z4—N(R9)—Z5—NR10R11;
(11) —Z4—N(R12)—Z5—R6;
(12) —SiR13R14R15;
(13) —P(O)(OR6)2;
(14) —CH═N—OR6;
(15) any two groups R1 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the carbon atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(16) any two groups R1 may, together with the carbons to which they are attached, form a heterocyclo group, which group is unsubstituted or substituted with Z1, Z2 and Z3;
R3 is
(1) hydrogen or R6,
where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or groups Z3;
(2) —OH or —OR6;
(3) —SH or —SR6;
(4) —C(O)H, —C(O)R6, or —C(O)R6;
(5) —SO3H or —S(O)qR6 where q is 1 or 2;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NR7R8;
(10) —Z4—N(R9)—Z5—NR10R11;
(11) —Z4—N(R12)—Z5—R6;
(12) —SiR13R14R15;
(13) —P(O)(OR6)2;
or
(14) —CH═N—OR6;
R4 is oxygen, or sulfur;
R5 is alkenyl, aryl, or aromatic heterocyclo, each of which is unsubstituted or substituted with Z1, Z2 and one or more groups Z3;
R7, R8, R9, R10, R11 and R12:
(1) are each independently hydrogen or R6;
(2) R7 and R8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(3) any two of R9, R10 and R11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
R13, R14 and R15 are each independently:
(1) alkyl;
or
(2) phenyl;
Z1, Z2 and Z3 are each independently:
(1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z1, Z2 and Z3;
(2) —OH or —OZ6;
(3) —SH or —SZ6;
(4) —C(O)qH, —C(O)qZ5, or —O—C(O)qZ6;
(5) —SO3H or —S(O)qZ6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NZ7Z8;
(10) —Z4—N(Z9)—Z5—NZ7Z8;
(11) —Z4—N(Z10)—Z5—Z6;
(12) —Z4—N(Z10)—Z5—H;
(13) oxo;
(14) —O—C(O)—Z6;
(15) any two of Z1, Z2, and Z3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
or
(16) any two of Z1, Z2, and Z3 may together be —O—(CH2)q—O—;
Z4 and Z5 are each independently:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12—;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12—;
or
(8) —Z11—C(O)—O—Z12—;
Z7, Z8, Z9 and Z10:
(1) are each independently hydrogen or Z6;
(2) Z7 and Z8, or Z6 and Z10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
and
Z11 and Z12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene;
or
(4) alkynylene;
wherein the term “heterocyclo” refers to fully saturated or unsaturated, including aromatic or nonaromatic cyclic groups, selected from 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring where each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized and wherein the heterocyclic group may be attached at any available heteroatom or carbon atom of the ring or ring system.

89 more elements

where
p is 0, 1, 2, 3 or 4;
each R1, and R2 are independently selected from:
(1) hydrogen or R6,
where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or more groups Z3;
(2) —OH or —OR6;
(3) —SH or —SR6;
(4) —C(O)qH, —C(O)qR6, or —O—C(O)qR6, where q is 1 or 2;
(5) —SO3H or —S(O)qR6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NR7R6;
(10) —Z4—N(R9)—Z5—NR10R11;
(11) —Z4—N(R12)—Z5—R6;
(12) —SiR13R14R15;
(13) —P(O)(OR6)2;
(14) —CH═N—OR6;
(15) any two groups R1 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the carbon atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(16) any two groups R1 may, together with the carbons to which they are attached, form a heterocyclo group, which group is unsubstituted or substituted with Z1, Z2 and Z3;
R3 is
(1) hydrogen or R6,
where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or groups Z3;
(2) —OH or —OR6;
(3) —SH or —SR6;
(4) —C(O)H, —C(O)R6, or —O—C(O)R6;
(5) —SO3H or —S(O)qR6 where q is 1 or 2;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NR7R8;
(10) —Z4—N(R9)—Z5—NR10R11;
(11) —Z4—N(R12)—Z5—R6;
(12) —SiR13R14R15;
or
(13) —P(O)(OR6)2;
R4 is oxygen, sulfur, or a single bond;
R5 is aryl, or heterocyclo, each of which is unsubstituted or substituted with Z1, Z2 and one or more groups Z3;
R7, R8, R9, R10, R11 and R12:
(1) are each independently hydrogen or R6;
(2) R7 and R8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(3) any two of R9, R10 and R11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
R13, R14 and R15 are each independently:
(1) alkyl;
or
(2) phenyl;
Z1, Z2 and Z3 are each independently:
(1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z1, Z2 and Z3;
(2) —OH or —OZ6;
(3) —SH or —SZ6;
(4) —C(O)qH, —C(O)qZ6, or —O—C(O)qZ6;
(5) —SO3H or —S(O)qZ6;
(6) halo;
(7) cyano;
(8) nitro;
(9) —Z4—NZ7Z8;
(10) —Z4—N(Z9)—Z5—NZ7Z8;
(11) —Z4—N(Z10)—Z5—Z6;
(12) —Z4—N(Z10)—Z5—H;
(13) oxo;
(14)—O—C(O)—Z6;
(15) any two of Z1, Z2, and Z3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
or
(16) any two of Z1, Z2, and Z3 may together be —O—(CH2)q—O—;
Z4 and Z5 are each independently:
(1) a single bond;
(2) —Z11—S(O)q—Z12—;
(3) —Z11—C(O)—Z12—;
(4) —Z11—C(S)—Z12—;
(5) —Z11—O—Z12—;
(6) —Z11—S—Z12—;
(7) —Z11—O—C(O)—Z12—;
or
(8) —Z11—C(O)—O—Z12—;
Z7, Z8, Z9 and Z10:
(1) are each independently hydrogen or Z6;
(2) Z7 and Z8, or Z6 and Z10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
or
(3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
and
Z11 and Z12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene;
or
(4) alkynylene;
wherein the term “heterocyclo” refers to fully saturated or unsaturated, including aromatic or nonaromatic cyclic groups, selected from 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring where each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized and wherein the heterocyclic group may be attached at any available heteroatom or carbon atom of the ring or ring system.

88 more elements

Dependencies are inferred from the claim text.

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