Claims
- 1. A compound of formula I: or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;ring D is a membered aromatic system containing from 0-2 heteroatoms selected from the group N, and O; ring D, when present, is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom; E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, substituted with 0-1 R; R is selected from Cl, F, Br, I, OH, C1-3 alkoxy, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), and CH2CH2N(C1-3 alkyl)2; M is attached to ring B or ring D, when present, and is selected from the group: Ja is NH or NR1a; Z is —CONH R1a and R1b are independently absent or selected from —(CH2)r—R1′, —CH═CH—R1′, NCH2R1″, OCH2R1″, SCH2R1″, NH(CH2)2(CH2)tR′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2)tR1′; alternatively, R1a and R1b, when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4 and which contains from 0-2 heteroatoms selected from the group consisting of N, O and S; alternatively, when Z is C(O)NH and R1a is attached to a ring carbon adjacent to Z, then R1a is a C(O) bound to Z by replacing the amide hydrogen of Z to form a cyclic imide; R1′ is selected from H, C1-3 alkyl, F, Cl, Br, I, —CN, —CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, CH(═NR2c)NR2R2a, NR2c(O)R2b, NR2c(O)NHR2b, NR2c(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4a, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a; R1″ is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a; R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, phenethyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl; R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl; R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl; R3C, at each occurrence, is selected from C1-4 alkyl, and phenyl; R3d, at each occurrence, is selected from H, OH, and C1-3 alkyl; R3e, at each occurrence, is selected from H and CH3; A is selected from: C3-10 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4; X-Y combine to form a group selected from: C(R3dR3e)C(R3dR3e), C(R3dR3e)C(R3dR3e)C(R3dR3e), NR4cC(R3dR3e), NR4cC(═O), NR4cC(═NH), NR4cC(R3dR3e)C(R3dR3e), NR4cC(R3dR3e)NR4cC, NR4cC(O)NR4c, NR4cC(═O)C(R3dR3e), C(R3dR3e)NR4c, C(R3dR3e)NR4cC(R3dR3e), C(R3dR3e)C(R3dR3e)NR4c, NR4c, NR4c, NR4cNR4cC(R3dR3e), and C(R3dR3e)NR4cNR4c; R4, at each occurrence, is selected from H, ═O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2c(O)R2b, C(O)NR2R2a, NR2c(O)NR2R2a, CH(═NR2)NR2R2a, CH(═NS(O)2R5)NR2R2a, NHC(═NR2)NR2R2a, C(O)NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NCH2R1″, OCH2R1″, SCH2R1″, N(CH2)2(CH2)tR1′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2)tR1′; alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; R4a is selected from H, ═O, (CH2)rOR2, (CH2)rF, (CH2)r—Br, (CH2)r—Cl, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rNR2R2b, (CH2)rC(O)R2c, NR2c(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2c(O)NR2R2a, CH(═NR2)NR2R2a, NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, C(O)NHSO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3; R4b, at each occurrence, is selected from H, ═O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)0R3c, NR3c(O)R3a, C(O)NR3R3a, NR3c(O)NR3R3a, CH(═NR3)NR3R3a, NH3c(═NR3)NR3R3a, SO2NR3R3a, NR3 SO2NR3R3a, NR3 SO2—C1-4 alkyl, NR3 SO2CF3, NR3 SO2— phenyl, S(O)pCF3, S(O)p—C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3; R4C, at each occurrence, is selected from H, C1-4 alkyl, CH2—CN, (CH2)2—CN, CH2—NR2R2a, (CH2)2NR2R2a, CH2C(O)R2c, (CH2)2C(O)R2c, CH2—C(O)NR2R2a, (CH2)2C(O)NR2R2a, phenyl, and benzyl; R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; R6, at each occurrence, is selected from H, OH, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, CH(═NH)NH2, NHC(═NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2—C1-4 alkyl; R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl; R8, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl; alternatively, R7 and R8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl; n is selected from 0, 1, 2, and 3; m is selected from 0, 1, and 2; p is selected from 0, 1, and 2; r is selected from 0, 1, 2, and 3; s is selected from 0, 1, and 2; and, t is selected from 0 and 1.
- 2. A compound of claim 1, wherein the compound is of formula Ia: wherein in formula Ia, rings D-E represent a bicycle selected from the group: 3-aminoindazol-5-yl; 3-hydroxyindazol-5-yl; 3-aminobenzisoxazol-5-yl; 3-hydroxybenzisoxazol-5-yl; and, 1-aminoisoindol-6-yl;M is selected from the group: R3d, at each occurrence, is selected from H and CH3; A is selected from: C5-6 carbocyclic residue substituted with 0-2 R4, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4; X-Y combine to form a group selected from: C(R3dR3e)C(R3dR3e), C(R3dR3e)C(R3dR3e)C(R3dR3e), NR4cC(R3dR3e), NR4cC(═O), NR4cC(R3dR3e)C(R3dR3e), NR4cC(R3dR3e)NR4c, NR4cC(═O)NR4c, NR4cC(═O)C(R3dR3e), C(R3dR3b)NR4c, C(R3dR3e)NR4cC(R3dR3e), and C(R3dR3e)C(R3dR3e)NR4c; and, R4c, at each occurrence, is selected from H, C1-4 alkyl, CH2—CN, (CH2)2—CN, CH2—NR2R2a, (CH2)2NR2R2a, CH2C(O)R2c, and (CH2)2C(O)R2c.
- 3. A compound of claim 2, wherein the compound is of formula Ia, wherein;rings D-E represent a bicycle selected from the group: 3-aminobenzisoxazol-5-yl, and 1-aminoisoindol-6-yl; M is selected from the group: A is selected from: C5-6 carbocyclic residue substituted with 0-2 R4, and 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4; X-Y combine to form a group selected from: CH2CH2, NR4cCH2, NR4cC(═O), and CH2NR4c; and, R4c, at each occurrence, is selected from H, CH2—CN, (CH2)2—CN, CH2—NR2R2a, and (CH2)2NR2R2a.
- 4. A compound of claim 3, wherein;rings D-E represent a bicycle selected from the group: 3-aminobenzisoxazol-5-yl, and, 1-aminoisoindol-6-yl; M is R1a is absent or is —(CH2)r—R1′; R1′ is selected from H, C1-3 alkyl, F, Cl, —CN, CF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, S(O)pR2b, NR2 C(O)R2b, C(O)NR2R2a, SO2NR2R2a, C3-6 carbocyclic residue substituted with 0-2 R4a, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a; A is selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, and pyrazinyl and is substituted with 0-2 R4; X-Y combine to form NR4cCH2; R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, phenethyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; alternatively, R2 and R2b, together with the atom to which they are attached, combine to form a ring selected from imidazolyl, morpholino, piperazinyl, pyridyl, and pyrrolidinyl, substituted with 0-2 R4b; R4, at each occurrence, is selected from H, ═O, OR2, CH20R2, F, Cl, C1-4 alkyl, NR2R2a, CH2NR2R2a, C(O)R2c, CH2C(O)R2c, C(O)NR2R2a, SO2NR2R2a, NR2SO2—C1-4 alkyl, S(O)2R5, and CF3 R4a, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, C1-4 alkyl, NR2R2a, CH2NR2R2a, NR2R2b, CH2NR2R2b, (CH2)rC(O)R2c, NR2c(O)R2b, C(O)NR2R2a, NR2c(O)NR2R2a, SO2NR2R2a, S(O)2R5, and CF3; R4b, at each occurrence, is selected from H, ═O, (CH2)rOR3, F, Cl, C1-4 alkyl, NR3R3a, CH2NR3R3a, C(O)R3, CH2C(O)R3, C(O)0R3c, C(O)NR3R3a, SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2-phenyl, S(O)2—C1-4 alkyl, S(O)2-phenyl, and CF3; and, R4c, at each occurrence, is selected from H, CH2—CN, (CH2)2—CN, CH2—NH2, and (CH2)2NH2.
- 5. A compound of claim 1, wherein the compound is selected from:1-(3-(amino-1,2-benzisoxazol-5-yl)-N-[4-(2,3-dihydro-2-methyl-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; 1-(3-(amino-1,2-benzisoxazol-5-yl)-N-[4-[2-[2-(diethylamino)ethyl]-2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and 1-(3-(amino-1,2-benzisoxazol-5-yl)-N-[4-(2,3-dihydro-1,1-dioxido-benzo[b]thiophen-7-yl))phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; or a pharmaceutically acceptable salt form thereof.
- 6. A compound of claim 1, wherein rings D-E combine to form a bicyclic moiety selected from the group:
- 7. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof.
- 8. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof.
- 9. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof.
- 10. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof.
- 11. Apharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof.
- 12. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 6 or a pharmaceutically acceptable salt form thereof.
- 13. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof.
- 14. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof.
- 15. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof.
- 16. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof.
- 17. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof.
- 18. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional application of U.S. application Ser. No. 09/540,467, filed Mar. 31, 2000, now U.S. Pat. No. 6,399,644, which claims the priority benefit of U.S. Provisional Application No. 60/127,624, filed Apr. 2, 1999, which is expressly incorporated fully herein by reference.
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