N-biarylmethyl aminocycloalkanecarboxamide derivatives
View Patent ↗N-Biarylmethylaminocycloalkanecarboxamide derivatives are bradykinin B1 antagonists or inverse agonists useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin B1 pathway.
1. A compound of formula I and pharmaceutically acceptable salts thereof:
wherein
Het is pyrimidinyl or pyridyl, or N-oxide thereof;
R 1 and R 2 are independently selected from hydrogen and C 1-4 alkyl;
R 3a and R 3b are independently selected from hydrogen and C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms;
R 4a and R 4b are independently selected form (1) hydrogen, (2) halogen, and (3) C 1-4 alkyl optionally substituted with 1 to 4 groups selected from halogen, OR a , OC(O)R a , S(O) k R d , OS(O) 2 R d , and NR 1 R 2 , or
R 4a and R 4b together with the carbon atom to which they are both attached form an exo-cyclic methylene optionally substituted with 1 to 2 groups selected from C 1-4 alkyl optionally substituted with 1–5 halogen atoms and C 1-4 alkyloxy;
R 5 is selected from (1) C 1-6 alkyl optionally substituted with 1 to 5 groups independently selected from halogen, nitro, cyano, OR a , SR a , COR a , SO 2 R d , CO 2 R a , OC(O)R a , NR b R c , NR b C(O)R a , NR b C(O) 2 R a , C(O)NR b R c , C 3-8 cycloalkyl, (2) C 3-8 cycloalkyl optionally substituted with 1 to 5 groups independently selected from halogen, nitro, cyano and phenyl, (3) C 3-6 alkynyl, (4) C 2-6 alkenyl optionally substituted with hydroxyethyl, (5) (CH 2 ) k -aryl optionally substituted with 1 to 3 groups independently selected from halogen, nitro, cyano, OR a , SR a , C(O) 2 R a , C 1-4 alkyl and C 1-3 haloalkyl, wherein aryl is selected from phenyl, 3,4-methylenedioxyphenyl and naphthyl, (6) (CH 2 ) k -heterocycle optionally substituted with 1 to 3 groups independently selected from halogen, nitro, cyano, OR a , SR a , C 1-4 alkyl and C 1-3 halo-alkyl wherein said heterocycle is selected from (a) a 5-membered heteroaromatic ring having a ring heteroatom selected from N, O and S, and optionally having up to 3 additional ring nitrogen atoms wherein said ring is optionally benzo-fused; (b) a 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms and N-oxides thereof, wherein said ring is optionally benzo-fused; and (c) a 5- or 6-membered non-aromatic heterocyclic ring selected from tetrahydrofuranyl, 5-oxotetrahydrofuranyl, 2-oxo-2H-pyranyl, and 6-oxo-1,6 -dihydropyridazinyl, (7) C(O) 2 R a , (8) C(O)NR b R c , and (9) NR b CO 2 R a ;
R 6a is selected from (1) C 1-8 alkyl optionally substituted with 1–5 groups independently selected from halogen, nitro, cyano, COR a , CO 2 R a , C(O)NR b R c , OR a , OC(O)R a , SR a , SO 2 R d , S(O)R d , NR b R c , NR b C(O)R a , NR b SO 2 R d , NR b CO 2 R a , (2) C 3-8 cycloalkyl, (3) C 2-8 alkenyl optionally substituted with CO 2 R a , (4) halogen, (5) cyano, (6) nitro, (7) NR b R c , (8) NR b C(O)R a , (9) NR b CO 2 R a , (10) NR b C(O)NR b R c , (11) NR b C(O)NR b CO 2 R a , (12) NR b SO 2 R d , (13) CO 2 R a , (14) COR a , (15) C(O)NR b R c , (16) C(O)NHOR a , (17) C(═NOR a )R a , (18) C(═NOR a )NR b R c , (19) OR a , (20) OC(O) k R a , (21) S(O) k R d , (22) SO 2 NR b R c , and (23) optionally substituted heterocycle where the heterocycle is selected from (a) a 5-membered heteroaromatic ring having a ring heteroatom selected from N, O and S, and optionally having up to 3 additional ring nitrogen atoms, (b) 4,5-dihydro-oxazolyl, and (3) 4,5-dihydro-1,2,4-oxadiazolyl, and wherein said substituent is 1 to 3 groups independently selected from C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms, OR a or OC(O)R a ,
R 6b and R 6c are independently selected from hydrogen, and a group from R 6a ; with the proviso that not more than one of R 6a , R 6b , and R 6c is a heterocycle;
R 7a and R 7b are independently selected from hydrogen, halogen, cyano, nitro, OR a , CO 2 R a , C(O)NR b R c , SO 2 R d , NR b R c , and C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms;
R a is selected from (1) hydrogen, (2) C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms, (3) phenyl optionally substituted with 1 to 3 groups independently selected from halogen, cyano, nitro, OH, C 1-4 alkyloxy, C 3-6 cycloalkyl and C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms, (4) C 3-6 cycloalkyl, and (5) pyridyl;
R b and R c are independently selected from (1) hydrogen, (2) C 1-4 alkyl optionally substituted with 1 to 5 groups independently selected from halogen, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino, and SO 2 R d , (3) (CH 2 )k-phenyl optionally substituted with 1 to 3 groups selected from halogen, cyano, nitro, OH, C 1-4 alkyloxy, C 3-6 cycloalkyl and C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms, and (4) C 3-6 cycloalkyl, or
R b and R c together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered ring optionally containing an additional heteroatom selected from N, O, and S; or
R b and R c together with the nitrogen atom to which they are attached form a cyclic imide;
R d is selected from (1) C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms, (2) C 1-4 alkyloxy, and (3) phenyl optionally substituted with 1 to 3 groups selected from halogen, cyano, nitro, OH, C 1-4 alkyloxy, C 3-6 cycloalkyl and C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms;
k is 0, 1 or 2; and
m is 0, 1, 2 or 3.
2. A compound of claim 1 wherein R 5 is (1) C 1-6 alkyl optionally substituted with 1 to 5 groups independently selected from halogen, nitro, cyano, OR a , SR a , COR a , SO 2 R d , CO 2 R a , OC(O)R a , NR b R c , NR b C(O)R a , C(O)NR b R c , and C 3-8 cycloalkyl, (2) 1,2,5-thiadiazolyl, (3) isoxazolyl, (4) isothiazolyl or (5) pyrimidinyl.
3. A compound of claim 1 wherein R 5 is C 1-3 alkyl optionally substituted with 1 to 5 halogen atoms wherein said halogen is chloro or fluoro.
4. A compound of claim 1 wherein R 5 is selected from difluoromethyl, dichloromethyl, chlorodifluoromethyl, trifluoromethyl, 1,1-dichloroethyl and 2,2,2-trifluoroethyl.
5. A compound of claim 1 wherein R 5 is pyrimidinyl.
6. A compound of claim 1 wherein R 5 is 1,2,5-thiadiazolyl, isoxazolyl or isothiazolyl.
7. A compound of claim 1 wherein R 6a is OR a , CO 2 R a or tetrazolyl optionally substituted with C 1-4 alkyl.
8. A compound of claim 1 wherein R 6a is OR a , CO 2 R a or tetrazolyl optionally substituted with C 1-4 alkyl, R 6b is hydrogen or halogen, and R 6c is hydrogen or halogen.
9. A compound of claim 1 wherein R 6a is methoxycarbonyl, ethoxycarbonyl, C 1-4 alkoxy optionally substituted with 1 to 5 halogen atoms, or 2-methyl-2H-tetrazol-5-yl, R 6b is fluoro or chloro, and R 6c is hydrogen, chloro or fluoro.
10. A compound of claim 1 wherein Het is 2,5-pyridinediyl and R 7a and R 7b are independently hydrogen or halogen.
11. A compound of claim 10 wherein one of R 7a and R 7b is hydrogen and the other is fluoro or chloro.
12. A compound of claim 1 wherein m is 0 or 1.
13. A compound of claim 1 having formula Ia:
wherein X is carbon or nitrogen, and all other variables are as defined claim 1 .
14. A compound of claim 13 wherein m is 0 or 1 and one of R 3a and R 3b is hydrogen and the other is hydrogen or C 1-3 alkyl.
15. A compound of claim 13 wherein X is carbon, R 7a is hydrogen or chloro or fluoro, and R 7b is hydrogen.
16. A compound of claim 13 wherein X is nitrogen and R 7a and R 7b are each hydrogen.
17. A compound of claim 1 having formula Ib:
wherein m is 0 or 1, R 3a is hydrogen or methyl, R 6b and R 6c are independently hydrogen, chloro or fluoro, R 7a is hydrogen, chloro or fluoro, and the other variables are as defined in claim 1 .
18. A compound of claim 17 wherein R 3a is hydrogen, and R 6b and R 7a are each indepedently chloro or fluoro.
19. A compound of claim 17 wherein R 3a is hydrogen, R 6b and R 7a are each indepedently chloro or fluoro, R 5 is selected from isoxazolyl, thiazolyl, 1,2,5-thiadiazolyl, 5-pyrimidinyl and C 1-2 alkyl substituted with 1 to 3 halogen atoms selected from chloro and fluoro, and R 6a is OR a , CO 2 R a or 2-methyl-5-tetrazolyl.
20. A compound of claim 1 having the formula Ic:
wherein R 5 , R 6a , R 6b , R 6c and R 7a are as defined in claim 1 .
21. A compound of claim 20 wherein R 6b is halogen, and R 6c and R 7a are independently hydrogen or halogen.
22. A compound of claim 20 wherein R 5 is selected from isoxazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 5-pyriridinyl and C 1-2 alkyl substituted with 1 to 5 halogen atoms.
23. A compound of claim 21 wherein R 5 is selected from isoxazolyl, isothiazolyl, 1,2,5-thiadiazolyl, 5-pyrimidinyl and C 1-2 alkyl substituted with 1 to 5 halogen atoms.
24. A compound of claim 20 wherein R 6a is selected from CO 2 C 1-4 alkyl, C 1-4 alkoxy optionally substituted with 1 to 5 halogen atoms and 2-methyl-5-tetrazolyl.
25. A compound of claim 23 wherein R 6a is selected from CO 2 C 1-4 alkyl, C 1-4 alkoxy optionally substituted with 1 to 5 halogen atoms and 2-methyl-5-tetrazolyl.
26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and pharmaceutically acceptable excipients.