N-biphenylmethyl aminocycloalkanecarboxamide derivatives

1. A compound of formula I

wherein

R 1 and R 2 are independently selected from

(1) hydrogen and

(2) C 1-4 alkyl;

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 halogens 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 haloalkyl 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-oxo-tetrahydrofuranyl, 2-oxo-2H-pyranyl, 6-oxo-1,6-dihydropyridazinyl,

(7) C(O) 2 R a , and

(8) C(O)NR b R c ;

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)R a ,

(21) S(O) k R d ,

(22) SO 2 NR b R c , and

(23) optionally substituted heterocycle where the heterocycle is 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, 4,5-dihydro-oxazolyl and 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

(1) hydrogen, and

(2) 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

(1) hydrogen,

(2) halogen,

(3) cyano,

(4) nitro,

(5) OR a ,

(6) CO 2 R a ,

(7) C(O)NR b R c .

(8) C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms,

(9) NR b R c , and

(10) S(O) k R d ;

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 optionally substituted with 1 to 3 groups independently selected from halogen and C 1-4 alkyl;

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 or 1.

2. A compound of claim 1 wherein R 1 and R 2 are each hydrogen.

3. A compound of claim 1 wherein one of R 4a and R 4b is hydrogen and the other is selected from hydrogen, halogen and C 1-4 alkyl optionally substituted with a group 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.

4. A compound of claim 1 wherein R 4a and R 4b are each hydrogen.

5. A compound of claim 1 wherein R 4a is hydrogen and R 4b is selected from CH 2 -halogen, CH 2 —OR a , CH 2 —OC(O)R a , CH 2 —S(O) k R d , CH 2 —OS(O) 2 R d , and CH 2 —NR 1 R 2 .

6. A compound of claim 1 wherein R 5 is 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 C 3-8 cycloalkyl.

7. A compound of claim 1 wherein R 5 is selected from C 1-5 alkyl and C 1-3 alkyl substituted with 1 to 3 groups selected from halogen, cyano, hydroxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl.

8. A compound of claim 1 wherein R 5 is selected from C 1-3 alkyl substituted with 1 to 3 groups selected from chloro, fluoro and cyano.

9. A compound of claim 1 wherein R 5 is C 3-6 cycloalkyl optionally substituted with 1 to 3 groups independently selected from halogen, nitro, cyano and phenyl.

10. A compound of claim 1 wherein R 5 is (CH 2 ) k -aryl 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 haloalkyl, wherein aryl is selected from phenyl, 3,4-methylenedioxyphenyl and naphthyl.

11. A compound of claim 1 wherein R 5 is phenyl optionally substituted with 1 to 2 groups selected from methyl, trifluoromethyl, halogen, cyano, nitro and methoxy.

12. A compound of claim 1 wherein (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 haloalkyl 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; and (b) a 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms wherein said ring is optionally benzo-fused.

13. A compound of claim 1 wherein R 5 is (CH 2 ) k -heterocycle optionally substituted with 1 to 2 groups independently selected from halogen, nitro, cyano, OR a , SR a , C 1-4 alkyl and C 1-3 haloalkyl wherein said heterocycle is selected from isoxazolyl, thienyl, pyridinyl, benzothienyl, furyl, oxadiazolyl, 1-oxidopyridinyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, thiazolyl, 5-oxotetrahydrofuranyl, 2-oxo-2H-pyranyl, 6-oxo-1,6-dihydropyridazinyl, oxazolyl, pyridazinyl, pyrimidinyl and quinoxalinyl.

14. A compound of claim 1 wherein R 5 is selected from isoxazolyl optionally substituted with 1 or 2 C 1-4 alkyl, thienyl, pyridinyl optionally substituted with hydroxy or halogen, benzothienyl, furyl, tetrahydrofuranyl, oxadiazolyl optionally substituted with C 1-4 alkyl, 1-oxidopyridinyl optionally substituted with C 1-4 alkyl, pyrazolyl optionally substituted with C 1-4 alkyl, imidazolyl optionally substituted with C 1-4 alkyl, 1,2,4-triazolyl optionally substituted with C 1-4 alkyl, thiazolyl optionally substituted with C 1-4 alkyl, 5-oxotetrahydrofuranyl, 2-oxo-2H-pyranyl, 6-oxo-1,6-dihydropyridazinyl, oxazolyl, pyridazinyl, pyrimidinyl and quinoxalinyl.

15. A compound of claim 1 wherein R 5 is selected from isoxazolyl optionally substituted with C 1-4 alkyl, pyrimidinyl, pyridinyl optionally substituted with halogen or C 1-4 alkyl and N-oxides thereof.

16. A compound of claim 1 wherein R 5 is selected from C 1-3 alkyl substituted with 1 to 3 halogen atoms, 5-isoxazole and 5-pyrimidinyl.

17. A compound of claim 1 having the formula I(1):

wherein m, R 1 , R 4a , R 4b , R 5 , R 6a , R 6b , R 6c and R 7a are as defined in claim 1 .

18. A compound of claim 17 wherein R 6a is selected from (1) CO 2 R a , (2) C(O)NHOR a , (3) cyano, (4) halogen, (5) OR a , (6) C 1-8 alkyl optionally substituted with 1–5 halogen atoms, or a group selected from CO 2 R a , C(O)NR b R c and OR a , (7) C(O)NR b R c , (8) NR b C(O)NR b R c , (9) NR b C(O)OR a , and (10) optionally substituted heterocycle where the heterocycle is selected from oxadiazolyl and tetrazolyl 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 .

19. A compound of claim 17 wherein R 6a is selected from CO 2 R a , C(O)NHOR a , methyltetrazolyl, methyloxadiazolyl, NR b C(O)NR b R c , and NR b C(O)OR a .

20. A compound of claim 17 wherein R 6b is selected from hydrogen, halogen and CO 2 R a .

21. A compound of claim 17 wherein R 6b is hydrogen, chloro or fluoro.

22. A compound of claim 17 wherein R 5 is selected from C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms or a cyano group, C 3-6 cycloalkyl, isoxazolyl, pyrimidinyl and pyridinyl (and N-oxide thereof) optionally substituted with halogen.

23. A compound of claim 1 having the formula I(2):

wherein m, R 5 , R 6a , R 6b and R 7a are as defined in claim 1 .

24. A compound of claim 23 wherein R 6b is hydrogen or halogen.

25. A compound of claim 23 wherein R 6b is hydrogen.

26. A compound of claim 23 wherein R 6b is fluorine or chlorine.

27. A compound of claim 23 wherein R 6a is selected from (1) CO 2 R a , (2) C(O)NHOR a , (3) cyano, (4) halogen, (5) OR a , (6) C 1-8 alkyl optionally substituted with 1–5 halogen atoms, or a group selected from CO 2 R a , C(O)NR b R c and OR a , (7) C(O)NR b R c , (8) NR b C(O)NR b R c , (9) NR b C(O)OR a , and (10) optionally substituted heterocycle where the heterocycle is selected from oxadiazolyl and tetrazolyl 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 .

28. A compound of claim 23 wherein R 6a is selected from CO 2 R a , C(O)NHOR a , methyltetrazolyl, methyloxadiazolyl, NR b C(O)NR b R c , and NR b C(O)OR a .

29. A compound of claim 23 wherein R 6a is selected from CO 2 R a , methyltetrazolyl and methyloxadiazolyl.

30. A compound of claim 23 wherein in another embodiment R 7a is hydrogen or halogen.

31. A compound of claim 23 wherein R 7a is hydrogen.

32. A compound of claim 23 wherein R 7a is fluorine.

33. A compound of claim 23 wherein R 5 is selected from C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms or a cyano group, C 3-6 cycloalkyl, isoxazolyl, pyrimidinyl and pyridinyl (and N-oxide thereof) optionally substituted with halogen.

34. A compound of claim 23 wherein m is 0 or 1, R 6a is 2-methyl-2H-tetrazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, CO 2 R a or C(O)NHOR a wherein R a is C 1-4 alkyl; R 6b is hydrogen, fluorine or chlorine; R 5 is selected from C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms or a cyano group, C 3-6 cycloalkyl, isoxazolyl, pyrimidinyl and pyridinyl (and N-oxide thereof) optionally substituted with halogen or trifluoromethyl; and R 7a is hydrogen or fluorine.

35. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and pharmaceutically acceptable excipients.