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US 2002/0058677 A1Published application
Isoquinolone inhibitors of factor Xa
AssigneeMillennium Pharmaceuticals, Inc.
InventorsCharles K. Marlowe, Wenhao Li, Ting Su, Robert M. Scarborough
Life of this patent
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Abstract
Novel compounds of formula I: 1 including its pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives having activity against mammalian factor Xa is described. Compositions containing such compounds are also described. The compounds and compositions are useful in vitro or in vivo for preventing or treating conditions in mammals characterized by undesired thrombosis.
Claims16
A compound represented by the formula:
- 129
- wherein:
- A is a member selected from the group consisting of:
- R2, —NR3R4,
- 130
- where R2, R3, R4, R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
- where R6 taken with either of R7 and R8, and/or R7 taken with R8, can each form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
- m is an integer from 0-3;
- Z is a member selected from the group consisting of a direct link, C1-6alkyl, C3-8cycloalkyl,C1-6alkenyl, aryl, or a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
- n is an integer from 0-3;
- D is a member selected from the group consisting of a direct link, —O—, —NR, —C(═O)—, —S—, —SO2—, —SO2—NR2, —NR2—SO2, —OCO—, —C(═O)NR2, and —NR2—C(═O)—, where R2 is as set forth above;
- R1 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl—C(═O)OH, C0-8alkyl—C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl—OH, C0-8alkyl—SH, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono- or di-substituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, C0-8alkyl—C(═O)OH and C0-8alkyl—C(═O)O—C1-8alkyl, where R2 is as set forth above;
- q is an integer from 0-3;
- X is —NR12— or —CHR12—;
- R11 and R12 are independently a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, C1-6alkylaryl, C1-6alkyl—C3-8cycloalkyl, —O—R2, —O—C(═O)R2, —C1-8alkyl—O—R —C1-8alkyl—O—C(═O)R10, —C1-8alkyl—O—C(═O)OR10, —C1-8alkyl—C(═O)NR10OR10, —C1-8alkyl—NR10R10, —C1-8alkyl—NR10C(═O)R10, and —SR10, wherein R10 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, and wherein when two R10 groups are present they may be taken together to form a saturated or unsaturated ring with the atom to which they are both attached;
- p is an integer from 0-3;
- E is a member selected from the group consisting of a direct link, —O—, —NR11—, —(CH2)0-3—C(═O)—NH—(CH2)0-3—, —CH(CO2R11)(CH2)0-3—, —CH(CONR11)(CH2)0-3—, where R11 is as described above, phenylene, a 5 to 12 membered bivalent heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered non-aromatic heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, wherein said heteroaryl and said non-aromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups;
- R14 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl—C(═O)OH, C0-8alkyl—C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl—OH, C0-8alkyl—SH, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono- or di-substituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, C0-8alkyl—C(═O)OH and C0-8alkyl—C(═O)O—C1-8alkyl, where R2 is as set forth above;
- J is a member selected from the group consisting of a direct link, C3-8cycloalkyl, phenylene, naphthalene, a 5 to 12 membered bivalent heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered non-aromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S wherein said heteroaryl and said non-aromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups where each R14 group is as set forth above;
- G is a member selected from the group consisting of:
- H, —CN, —OR17,
- 131
- wherein
- t is an integer from 0 to 6;
- u is the integer 0 or 1;
- and
- R17, R18, R19, R20, R21, R22, R23, R24, R25, and R26 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
- where R18 taken with R19, R22 taken with either of R24 and R25, and R24 taken with R25, can each independently form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
- with the proviso that when G is H, —CN, or —OR17, either E or J must contain at least one N atom;
- and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
27 more elements
A compound according to formula II:
- 134
- wherein:
- A is a member selected from the group consisting of:
- R2, —NR3R4,
- 135
- where R2, R3, R4, R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
- where R6 taken with either of R7 and R8, and/or R7 taken with R8, can each form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
- m is an integer from 0-3;
- Z is a member selected from the group consisting of a direct link, C1-8alkyl, C3-8cycloalkyl, C2-8alkenyl, C2-8alkynyl, C1-8carbocyclic aryl, or a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
- n is an integer from 0-3;
- D is a member selected from the group consisting of:
- —O—, —NR2, —C(═O)—, —S—, —SO2—, —SO2—NR2, —NR2—SO2, —OCO—, —C(═O)NR2, and —NR2—C(═O) —, where R2 is as set forth above;
- R1 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl-C(═O)OH, C0-8alkyl—C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl—OH, C0-8alkyl—SH, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono- or di-substituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, C0-8alkyl—C(═O)OH and C0-8alkyl—C(═O)O—C1-8alkyl, where R2 is as set forth above;
- q is an integer from 0-3;
- R11 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, C1-6alkylaryl, C1-6alkyl-C3-8cycloalkyl, —O—R2, —O-13 C(═O)R2, —C1-8alkyl—O—R10, —C1-6alkyl—O—C(═O)R10, —C1-8alkyl—O—C(═O)OR10, —C1-8alkyl-C(═O)NR10OR10, —C1-8alkyl—NR10R10, —C1-8alkyl—NR10C(═O)R10, —SR10, where R2 is as set forth above and R10 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, and wherein when two R10 groups are present they may be taken together to form a saturated or unsaturated ring with the atom to which they are both attached;
- p is an integer from 0-3;
- E is a member selected from the group consisting of a direct link, —O—, —NR11—, —(CH2)0-3—C(═O)—NH—(CH2)0-3—, —CH(CO2R11)(CH2)0-3—, —CH(CONR11)(CH2)0-3—,where R11 is as set forth above, phenylene, a bivalent 5 to 12 membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered non-aromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, wherein said heteroaryl and said non-aromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups and each R14 group is independently defined the same as the substituents set forth above for the R1 group;
- J is a member selected from the group consisting of a direct link, a bivalent C3-8cycloalkyl group, phenylene, naphthalene, a 5 to 12 membered bivalent heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered non-aromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S wherein said heteroaryl and said non-aromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups;
- R14 group is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl—C(═O)OH, C0-8alkyl—C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl—OH, CO8alkyl—SH, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono- or di-substituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, C0-8alkyl—C(═O)OH and C0-8alkyl—C(═O)O—C1-8alkyl, where R2 is as set forth above;
- G is a member selected from the group consisting of:
- H, —CN, —OR17,
- 136
- wherein
- t is an integer from 0 to 6;
- u is the integer 0 or 1;
- and
- R17, R18, R19, R20, R21, R22, R23, R24, R25 and R26 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
- where R18 taken with R19, R22 taken with either of R24 and R25, and R24 taken with R25, can each independently form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
- with the proviso that when G is H, —CN, or —OR17 , either E or J must contain at least one N atom;
- and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
27 more elements
A compound according to 5, wherein:
- A is a member selected from the group consisting of:
- 140
- CH3—H—, NH2—, (CH3—)2NCO—,
- 141
- Z is a member selected from the group consisting of:
- 142
- n is an integer from 0-2;
- D is a member selected from the group consisting of:
- —O—, —N(CH3)—, and —CH2—;
- q is 0;
- and
- G is
- 143
10 more elements
A compound according to formula III:
- 145
- wherein:
- R8 is selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
- R1 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl—C(═O)OH, C0-8alkyl—C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl—OH, C0-8alkyl—SH, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono- or di-substituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, C0-8alkyl—C(═O)OH and C0-8alkyl—C(═O)O—C1-8alkyl;
- q is an integer from 0-3;
- R11 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, C1-6alkylaryl, C1-6alkyl—C3-8cycloalkyl, —O—R2, —O—C(═O)R2, —C1-8alkyl—O—R10, —C1-8alkyl—O—C(═O)R10, —C1-8alkyl—O—C(═O)OR10, —C1-8alkyl—C(═O)NR10R10, —C1-8alkyl—NR10R10, —C1-8alkyl—NR10C(═O)R10, —SR10, wherein R10 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, and wherein when two R10 groups are present they may be taken together to form a saturated or unsaturated ring with the atom to which they are both attached;
- p is an integer from 0-3;
- E is a member selected from the group consisting of a direct link, —O—, —NR11, —(CH2)0-3—C(═O)—NH—(CH2)0-3—, —CH(CO2R11)(CH2)0-3—, —CH(CONR11)(CH2)0-3—, where R11 is as described above, phenylene, a bivalent 5 to 12 membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered non-aromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, wherein said heteroaryl and said non-aromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups and each R14 group is independently defined the same as the substituents set forth above for the R1 group;
- J is a member selected from the group consisting of a direct link, a bivalent C3-8cycloalkyl group, phenylene, naphthalene, a 5 to 12 membered bivalent heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered non-aromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S wherein said heteroaryl and said non-aromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups and each R14 group is independently defined the same as the substituents set forth above for the R1 group;
- G is a member selected from the group consisting of:
- H, —CN, —OR17,
- 146
- wherein:
- t is an integer from 0 to 6;
- u is the integer 0 or 1;
- and
- R17, R18, R19, R20, R21, R22, R23, R24, R25 and R26 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
- where R18 taken with R19, R22 taken with either of R24 and R25, and R24 taken with R25, can each independently form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
- with the proviso that when G is H, —CN, or —OR17, either E or J must contain at least one N atom;
- and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
17 more elements
Dependencies are inferred from the claim text.