Claims
- 1. A compound of formula I: or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:one of W, W1, W2, and W3 is C—D and the remaining are C—R1; D is selected from C(═NR7)NR8R9 and NR8R9; Q is CO; J, Ja and Jb together are N(Z—A—B) (CRaRb)aQNRd; a is 0; Rd is selected from H, OH, NH2, C1-2 alkyl, and C1-2 alkyl-OH, Z is selected from C1-4 alkylene, (CH2)rO(CH2)r, (CH2)rNR3 (CH2)r, (CH2)rC(O) (CH2)r, (CH2)rC(O)O(CH2)r, (CH2)rOC(O) (CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)rNR3C(O) (CH2)r, (CH2)rOC(O)O(CH2)r, (CH2)rOC(O)NR3(CH2)r, (CH2)rNR3C(O)O(CH2)r, (CH2)rNR3C(O)NR3 (CH2)r, (CH2)rS(O)p(CH2)r, (CH2)rSO2NR3(CH2)r, (CH2)rNR3SO2(CH2)r, and (CH2)rNR3SO2NR3(CH2)r, provided that Z does not form a N—N, N—O, N—S, NCH2N, NCH2O, or NCH2S bond with the groups to which it is attached; R1, at each occurrence, is selected from H, F, Cl, Br, I, (CH2)rCF3, OR2, NR2R2a, C(O)R2b, (CF2)rCO2R2, S(O)2R2b, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, C3-6 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 and substituted with 0-2 R4; R1′, at each occurrence, 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, C(═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 R4b, 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 R4b; R1″, at each occurrence, 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, S and substituted with 0-2 R4b; R2a, 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 form 1-4 heteroatoms selected from the group consisting of N, O, and S and 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; R2b 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 and 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; 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; A is selected from: C3-10 carbocyclic residue substituted with 0-2 R4b, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R4; B is selected from: Y and X—Y; X is selected from C1-4 alkylene, —CR2(CR2R2b) (CH2)t—, —C(O)—, —C(═NR1″)—, —CR2(NR1″R2)—, —CR2(OR2)—, —CR2(SR2)—, —C(O)CR2R2a—, —CR2R2aC(O), —S(O)p—, —S(O)pCR2R2a—, —CR2R2aS(O)p—, —S(O)2NR2—, —NR2S(O)2—, —NR2S(O)2CR2R2a—, —CR2R2aS(O)2NR2—, —NR2S(O)2NR2—, —C(O)NR2—, —NR2C(O)—, —C(O)NR2CR2R2a—, —NR2C(O)CR2R2a, —CR2R2aC(O)NR2—, —CR2R2aNR2C(O)—, —NR2C(O)O—, —OC(O)NR2—, —NR2C(O)NR2—, —NR2—, —NR2CR2R2a—, —CR2R2aNR—, O, —CR2R2aO—, and —OCR2R2a—; Y is selected from: (CH2)rNR2R2a, provided that X—Y do not form an N—N, O—N, or S—N bond, C3-10 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; 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, C(═NR2)NR2R2a, C(═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, at each occurrence, is selected from H, ═O, (CH2)rOR2, (CH2)r—F, (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, C(═NR2)NR2R2a, NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, C(O)NHSO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3; alternatively, one R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; 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)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, C(═NR3)NR3R3a, NH3C(═NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)p—C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3; 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, C(═NH)NH2, NHC(═NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl; R7, at each occurrence, is selected form H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, 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; R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl; n, at each occurrence, is selected from 0, 1, 2, and 3; p, at each occurrence, is selected from 0, 1, and 2; r, at each occurrence, is selected from 0, 1, and 2; and, t, at each occurrence, is selected from 0 and 1; provided that A—B is other than benzyl-thiazolidin-2-4-dione.
- 2. A compound according to claim 1, wherein;B is selected from: Y, X—Y, and NR2R2a; Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole; Y may also be selected from the following bicyclic heteroaryl ring systems: K is selected from O, S, NH, and N.
- 3. A compound according to claim 2, wherein the compound is of formula Ia; or a stereoisomer or pharmaceutically acceptable salt thereof, wherein; D is C(═NR7)NR8R9; A is selected from: piperidinyl, piperazinyl, C5-6 carbocyclic residue substituted with 0-2 R4, and 5-6 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R4; and, B is selected from: Y and X—Y.
- 4. A compound according to claim 3, wherein;Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazole, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, and 1,3,4-triazole.
- 5. A compound according to claim 1, wherein the compound is selected from:1N-(2′-Aminosulfonyl-[1,1′]biphenylamino)carbonylmethyl-6-amidinobenzimidazolinone; 1N-(2′-Aminosulfonyl-[1,1′]biphenylamino)-carbonylmethyl-5-amidinobenzimidazolinone; 1N-[4′-(p-chlorophenyl)thiazolyl-2′-amino)carbonylmethyl-6-amidinobenzimidazolinone; 5-Amidino-1N-(1′N-(4′-benzylpiperidino)carbonylmethyl)benzimidazolinone; 1N-(2′-Aminosulfonyl-[1,1′]biphenylamino)carbonylmethyl-3N-β-hydroxyethylene-6-amidinobenzimidazolinone; 1-([1,1′]-Biphenylcarbonyl)ethyl-6-amidino-3N-methylbenzimidazolinone; and, 1-([1,1′]-biphenylcarbonyl)ethyl-6-amidinobenzimidazolinone.
- 6. A compound according to claim 1, wherein the compound is of formula b: or stereoisomer or pharmaceutically acceptable salt form thereof.
- 7. A compound according to claim 6, wherein;B is selected from: Y, X—Y, and NR2R2a; Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole; Y may also be selected from the following bicyclic heteroaryl ring systems: K is selected from O, S, NH, and N.
- 8. A compound according to claim 7, wherein;A is selected from: piperidinyl, piperazinyl, C5-6 carbocyclic residue substituted with 0-2 R4, and 5-6 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-2 R4; and, B is selected from: Y and X—Y.
- 9. A compound according to claim 8, wherein;Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazole, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, and 1,3,4-triazole.
- 10. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
- 11. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
- 12. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
- 13. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt thereof.
- 14. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 5 or a pharmaceutically acceptable salt thereof.
- 15. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 6 or a pharmaceutically acceptable salt thereof.
- 16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 7 or a pharmaceutically acceptable salt thereof.
- 17. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 8 or a pharmaceutically acceptable salt thereof.
- 18. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 9 or a pharmaceutically acceptable salt thereof.
- 19. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
- 20. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
- 21. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
- 22. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt thereof.
- 23. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 5 or a pharmaceutically acceptable salt thereof.
- 24. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 6 or a pharmaceutically acceptable salt thereof.
- 25. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 7 or a pharmaceutically acceptable salt thereof.
- 26. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 8 or a pharmaceutically acceptable salt thereof.
- 27. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 9 or a pharmaceutically acceptable salt thereof.
Parent Case Info
This application is a Divisional of Ser. No. 09/149,826 filed Sep. 8, 1998 now U.S. Pat. No. 6,207,697 which claims the benefit of Provisional application No. 60/058,288 filed Sep. 9, 1997.
US Referenced Citations (5)
Number |
Name |
Date |
Kind |
4110465 |
Holmes |
Aug 1978 |
A |
4985448 |
Zilch et al. |
Jan 1991 |
A |
5317103 |
Baker et al. |
May 1994 |
A |
5886191 |
Dominguez et al. |
Mar 1999 |
A |
5998463 |
Hulin et al. |
Dec 1999 |
A |
Foreign Referenced Citations (5)
Number |
Date |
Country |
2626128 |
Dec 1977 |
DE |
0540051 |
May 1993 |
EP |
0787727 |
Aug 1997 |
EP |
6227971 |
Aug 1994 |
JP |
9402477 |
Feb 1994 |
WO |
Non-Patent Literature Citations (7)
Entry |
Agrawal et al., Chem. Abstract 95:132750, 1981.* |
Henning et al., Chem. Abstract 106:196346, 1987.* |
Yamakawa et al., Chem. Abstract 112:45524, 1990.* |
Devivar et al., Chem. Abstract 119:139675, 1993.* |
Gruda, Chemical Abstract No. 68:114341 (1968). |
Bolotov et al., Chemical Abstract No. 86:121089. |
Hoelck et al., Chemical Abstract No. 104:207267 (1986). |
Provisional Applications (1)
|
Number |
Date |
Country |
|
60/058288 |
Sep 1997 |
US |