Guanidine mimics factor Xa inhibitors
View Patent ↗The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula I: or pharmaceutically acceptable salt forms thereof, wherein rings D-E represent guanidine mimics, which are useful as inhibitors of factor Xa.
1. A compound of formula I:
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
D-E is selected from the group 3-aminobenzisoxazol-5-yl and 3-hydroxybenzisoxazol-5-yl
M is
Z is selected from a bond, C 1-4 alkylene, (CH 2 ) r O(CH 2 ) r , (CH 2 ) r NR 3 (CH 2 ) r , (CH 2 ) r C(O)(CH 2 ) r , (CH 2 ) r C(O)O(CH 2 ) r , (CH 2 ) r OC(O)(CH 2 ) r , (CH 2 ) r C(O)NR 3 (CH 2 ) r , (CH 2 ) r NR 3 C(O)(CH 2 ) r , (CH 2 ) r OC(O)O(CH 2 ) r , (CH 2 ) r OC(O)NR 3 (CH 2 ) r , (CH 2 ) r NR 3 C(O)O(CH 2 ) r , (CH 2 ) r NR 3 C(O)NR 3 (CH 2 ) r , (CH 2 ) r S(O) p (CH 2 ) r , (CH 2 ) r SO 2 NR 3 (CH 2 ) r , (CH 2 ) r NR 3 SO 2 (CH 2 ) r , and (CH 2 ) r NR 3 SO 2 NR 3 (CH 2 ) r , provided that Z does not form a N—N, N—O, N—S, NCH 2 N, NCH 2 O, or NCH 2 S bond with ring M or group A;
R 1a and R 1b are independently H or selected from —(CH 2 ) r —R 1′ , —CH═CH—R 1′ , NHCH 2 R 1″ , OCH 2 R 1″ , SCH 2 R 1″ , NH(CH 2 ) 2 (CH 2 ) t R 1′ , O(CH 2 ) 2 (CH 2 ) t R 1′ , and S(CH 2 ) 2 (CH 2 ) t R 1′ ;
R 1′ is selected from H, C 1-3 alkyl, F, Cl, Br, I, —CN, —CHO, (CF 2 ) r CF 3 , (CH 2 ) r OR 2 , NR 2 R 2a , C(O)R 2c , OC(O)R 2 , (CF 2 ) r CO 2 R 2c , S(O) p R 2b , NR 2 (CH 2 ) r OR 2 , C(═NR 2c )NR 2 R 2a , NR 2 C(O)R 2b , NR 2 C(O)NHR 2b , NR 2 C(O) 2 R 2a , OC(O)NR 2a R 2b , C(O)NR 2 R 2a , C(O)NR 2 (CH 2 ) r OR 2 , SO 2 NR 2 R 2a , NR 2 SO 2 R 2b , C 3-6 carbocyclic group substituted with 0-2 R 4 , 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 R 4 , provided that if R 1′ is substituted with R 4 then R 4 is other than NH(CH 2 ) 2 (CH 2 ) t R 1′ , O(CH 2 ) 2 (CH 2 ) t R 1′ , and S(CH 2 ) 2 (CH 2 ) t R 1′ ;
R 1″ is selected from H, CH(CH 2 OR 2 ) 2 , C(O)R 2c , C(O)NR 2 R 2a , S(O)R 2b , S(O) 2 R 2b , and SO 2 NR 2 R 2a ;
R 2 , at each occurrence, is selected from H, CF 3 , C 1-6 alkyl, benzyl, C 3-6 carbocyclic group substituted with 0-2 R 4b , 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 R 4b ;
R 2a , at each occurrence, is selected from H, CF 3 , C 1-6 alkyl, benzyl, phenethyl, C 3-6 carbocyclic group substituted with 0-2 R 4b , 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 R 4b ;
R 2b , at each occurrence, is selected from CF 3 , C 1-4 alkoxy, C 1-6 alkyl, benzyl, C 3-6 carbocyclic group substituted with 0-2 R 4b , 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 R 4b ;
R 2c , at each occurrence, is selected from CF 3 , OH, C 1-4 alkoxy, C 1-6 alkyl, benzyl, C 3-6 carbocyclic group substituted with 0-2 R 4b , 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 R 4b ;
R 3 , at each occurrence, is selected from H, C 1-4 alkyl, and phenyl;
R 3a , at each occurrence, is selected from H, C 1-4 alkyl, and phenyl;
R 3c , at each occurrence, is selected from C 1-4 alkyl, and phenyl;
A is C 3-10 carbocyclic group substituted with 0-2 R 4 ;
B is Y;
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4a ;
phenyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, beuzofuran, benzimidazole, benzoxazole, indazole, and benzisoxazole;
R 4 , at each occurrence, is selected from H, ═O, (CH 2 ) r OR 2 , F, Cl, Br, I, C 1-4 alkyl, —CN, NO 2 , (CH 2 ) r NR 2 R 2a , (CH 2 ) r C(O)R 2c , NR 2 C(O)R 2b , C(O)NR 2 R 2a , NR 2 C(O)NR 2 R 2a , C(═NR 2 )NR 2 R 2a , C(═NS(O) 2 R 5 )NR 2 R 2a , NHC(═NR 2 )NR 2 R 2a , C(O)NHC(═NR 2 )NR 2 R 2a , SO 2 NR 2 R 2a , NR 2 SO 2 NR 2 R 2a , NR 2 SO 2 —C 1-4 alkyl, NR 2 SO 2 R 5 , S(O) p R 5 , (CF 2 ) r CF 3 , NHCH 2 R 1″ , OCH 2 R 1″ , SCH 2 R 1″ , NH(CH 2 ) 2 (CH 2 ) t R 1″ , O(CH 2 ) 2 (CH 2 ) t R 1′ , and S(CH 2 ) 2 (CH 2 ) t R 1′ ;
R 4a , at each occurrence, is selected from H, ═O, (CH 2 ) r OR 2 , (CH 2 ) r —F, (CH 2 ) r —Br, (CH 2 ) r —Cl, I, C 1-4 alkyl, —CN, NO 2 , (CH 2 ) r NR 2 R 2a , (CH 2 ) r NR 2 R 2b , (CH 2 ) r C(O)R 2c , NR 2 C(O)R 2b , C(O)NR 2 R 2a , C(O)NH(CH 2 ) 2 NR 2 R 2a , NR 2 C(O)NR 2 R 2a , C(═NR 2 )NR 2 R 2a , NHC(═NR 2 )NR 2 R 2a , SO 2 NR 2 R 2a , NR 2 SO 2 NR 2 R 2a , NR 2 SO 2 —C 1-4 alkyl, C(O)NHSO 2 —C 1-4 alkyl, NR 2 SO 2 R 5 , S(O) p R 5 , and (CF 2 ) r CF 3 ;
R 4b , at each occurrence, is selected from H, ═O, (CH 2 ) r OR 3 , F, Cl, Br, I, C 1-4 alkyl, —CN, NO 2 , (CH 2 ) r NR 3 R 3a , (CH 2 ) r C(O)R 3 , (CH 2 ) r C(O)OR 3c , NR 3 C(O)R 3a , C(O)NR 3 R 3a , NR 3 C(O)NR 3 R 3a , C(═NR 3 )NR 3 R 3a , NR 3 C(═NR 3 )NR 3 R 3a , SO 2 NR 3 R 3a , NR 3 SO 2 NR 3 R 3a , NR 3 SO 2 —C 1-4 alkyl, NR 3 SO 2 CF 3 , NR 3 SO 2 -phenyl, S(O) p CF 3 , S(O) p —C 1-4 alkyl, S(O) p -phenyl, and (CF 2 ) r CF 3 ;
R 5 , at each occurrence, is selected from CF 3 , C 1-6 alkyl, phenyl substituted with 0-2 R 6 , and benzyl substituted with 0-2 R 6 ;
R 6 , at each occurrence, is selected from H, OH, (CH 2 ) r OR 2 , F, Cl, Br, I, C 1-4 alkyl, CN, NO 2 , (CH 2 ) r NR 2 R 2a , (CH 2 ) r C(O)R 2b , NR 2 C(O)R 2b , NR 2 C(O)NR 2 R 2a , C(═NH)NH 2 , NHC(═NH)NH 2 , SO 2 NR 2 R 2a , NR 2 SO 2 NR 2 R 2a , and NR 2 SO 2 —C 1-4 alkyl;
p is selected from 0, 1, and 2;
r is selected from 0, 1, 2, and 3; and,
t is selected from 0 and 1.
2. A compound according to claim 1 , wherein:
M is
3. A compound according to claim 1 , wherein:
D-E is 3-aminobenzisoxazol-5-yl.
4. A compound according to claim 1 , wherein:
Z is selected from (CH 2 ) r C(O)(CH 2 ) r , (CH 2 ) r C(O)O(CH 2 ) r , (CH 2 ) r C(O)NR 3 (CH 2 ) r , (CH 2 ) r S(O) p (CH 2 ) r , and (CH 2 ) r SO 2 NR 3 (CH 2 ) r .
5. A compound according to claim 1 , wherein:
Z is selected from (CH 2 ) r C(O)(CH 2 ) r and (CH 2 ) r C(O)NR 3 (CH 2 ) r .
6. A compound according to claim 1 , wherein:
Z is (CH 2 ) r C(O)NR 3 (CH 2 ) r .
7. A compound according to claim 1 , wherein:
Z is C(O)NH.
8. A compound according to claim 1 , wherein:
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4a ;
phenyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, and benzimidazolyl.
9. A compound according to claim 1 , wherein:
Y is imidazolyl substituted with 0-2 R 4a .
10. A compound according to claim 1 , wherein:
A is C 5-6 carbocyclic group substituted with 0-2 R 4 ; and,
R 4 , at each occurrence, is selected from H, ═O, OR 2 , CH 2 OR 2 , F, Cl, C 1-4 alkyl, NR 2 R 2a , CH 2 NR 2 R 2a , C(O)R 2c , CH 2 C(O)R 2c , C(O)NR 2 R 2a , C(═NR 2 )NR 2 R 2a , C(═NS(O) 2 R 5 )NR 2 R 2a , SO 2 NR 2 R 2a , NR 2 SO 2 —C 1-4 alkyl, S(O) 2 R 5 , and CF 3 .
11. A compound according to claim 1 , wherein:
A is phenyl substituted with R 4 ; and,
R 4 is F.
12. A compound according to claim 1 , wherein:
R 1a is —(CH 2 ) r —R 1′ ; and,
R 1′ is selected from H, C 1-3 alkyl, F, Cl, Br, I, CF 3 , (CH 2 ) r OR 2 , NR 2 R 2a , C(O)R 2c , S(O) p R 2b , and NR 2 SO 2 R 2b .
13. A compound according to claim 1 , wherein:
R 1a is selected from H, C 1-3 alkyl, F, Cl, Br, CF 3 , CH 2 OR 2 , C(O)R 2c , S(O) p R 2b , and NR 2 SO 2 R 2b .
14. A compound according to claim 1 , wherein:
R 1a is CF 3 .
15. A compound according to claim 1 , wherein:
R 4a , at each occurrence, is selected from H, ═O, (CH 2 ) r OR 2 , F, Cl, C 1-4 alkyl, NR 2 R 2a , CH 2 NR 2 R 2a , NR 2 R 2b , CH 2 NR 2 R 2b , (CH 2 ) r C(O)R 2c , NR 2 C(O)R 2b , C(O)NR 2 R 2a , C(O)NH(CH 2 ) 2 NR 2 R 2a , NR 2 C(O)NR 2 R 2a , SO 2 NR 2 R 2a , S(O) 2 R 5 , and CF 3 .
16. A compound according to claim 1 , wherein:
R 4a , at each occurrence, is selected from CH 2 OR 2 and CH 2 NR 2 R 2a .
17. A compound according to claim 1 , wherein:
R 2 , at each occurrence, is selected from H and C 1-6 alkyl;
R 2a , at each occurrence, is selected from H and C 1-6 alkyl;
R 2b , at each occurrence, is selected from C 1-4 alkoxy and C 1-6 alkyl; and,
R 2c , at each occurrence, is selected from OH, C 1-4 alkoxy, and C 1-6 alkyl.
18. A compound according to claim 1 , wherein:
R 2 , at each occurrence, is selected from H and CH 3 ; and,
R 2a , at each occurrence, is selected from H and CH 3 .
19. 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.
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 1 or a pharmaceutically acceptable salt thereof.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 10 or a pharmaceutically acceptable salt thereof.
30. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 11 or a pharmaceutically acceptable salt thereof.
31. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 12 or a pharmaceutically acceptable salt thereof.
32. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 13 or a pharmaceutically acceptable salt thereof.
33. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 14 or a pharmaceutically acceptable salt thereof.
34. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 15 or a pharmaceutically acceptable salt thereof.
35. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 16 or a pharmaceutically acceptable salt thereof.
36. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 17 or a pharmaceutically acceptable salt thereof.
37. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 18 or a pharmaceutically acceptable salt thereof.
38. 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.
39. 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.
40. 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.
41. 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.
42. 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.
43. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeuticaliy effective amount of a compound according to claim 7 or a pharmaceutically acceptable salt thereof.
44. 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.
45. 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.
46. 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 10 or a pharmaceutically acceptable salt thereof.
47. A method for treating a thromboembolie disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 11 or a pharmaceutically acceptable salt thereof.
48. 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 12 or a pharmaceutically acceptable salt thereof.
49. 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 13 or a pharmaceutically acceptable salt thereof.
50. 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 14 or a pharmaceutically acceptable salt thereof.
51. 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 15 or a pharmaceutically acceptable salt thereof.
52. 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 16 or a pharmaceutically acceptable salt thereof.
53. 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 17 or a pharmaceutically acceptable salt thereof.
54. 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 18 or a pharmaceutically acceptable salt thereof.