N-biphenyl(substituted methyl) aminocycloalkane-carboxamide derivatives
View Patent ↗N-Biphenyl(substituted methyl)aminocycloalkanecarboxamide 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 or a pharmaceutically acceptable salt thereof:
wherein
R 1 and R 2 are independently selected from
(1) hydrogen and
(2) C 1-4 alkyl;
R 3a is selected from
(1) hydrogen and
(2) C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms;
R 3b is 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 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 tetrabydrofliranyl, 5-oxotetrahydrofuranyl, 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-dibydro-oxazolyl and 4,5-dihydro-1,2,4-oxadiazolyl, and wherein said substituent is 1 to 3 groups independently selected from C 1-4 alicyl 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 R 3a is hydrogen and R 3b is C 1-4 alkyl.
4. 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.
5. A compound of claim 1 wherein R 4a and R 4b are each hydrogen.
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 , and 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 5 halogen atoms, or a group selected from cyano, hydroxy, C 1-4 alkoxy and C 1-4 alkoxycarbonyl.
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 (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.
12. 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-oxidopyndinyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, thiazolyl, 5-oxotetrahydrofuranyl, 2-oxo-2H-pyranyl, 6-oxo-1,6-dihydro-pyridazinyl, oxazolyl, pyridazinyl, pyrimidinyl and quinoxalinyl.
13. A compound of claim 1 wherein R 5 is selected from 5-isoxazolyl, 5-pyrimidinyl, 5-bromo-3-pyridyl and N-oxide thereof, and 5-trifluoromethyl-3-pyridyl.
14. A compound of claim 1 wherein R 5 is selected from isoxazolyl optionally substituted with C 1-4 alkyl, pyrimidinyl, pyridinyl optionally substituted with C 1-4 alkyl and N-oxides thereof.
15. A compound of claim 1 having the formula I(1):
wherein m, R 1 , R 2 , R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 6c and R 7a are as defined in claim 1 .
16. A compound of claim 15 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 .
17. A compound of claim 15 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 .
18. A compound of claim 15 wherein R 6b is selected from hydrogen, halogen and CO 2 R a .
19. A compound of claim 15 wherein R 6b is hydrogen or halogen.
20. A compound of claim 15 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 ; R 6b is selected from hydrogen, fluorine and chlorine; and R 6c is hydrogen.
21. A compound of claim 15 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.
22. A compound of claim 1 having the formula I(2):
wherein m, R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 6c and R 7a are as defined in claim 1 .
23. A compound of claim 22 wherein R 3b is methyl.
24. A compound of claim 22 wherein R 6b is hydrogen or halogen.
25. A compound of claim 22 wherein R 6b is hydrogen.
26. A compound of claim 22 wherein R 6b is fluorine or chlorine.
27. A compound of claim 22 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 22 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 22 wherein R 6a is selected from CO 2 R a , methyltetrazolyl and methyloxadiazolyl.
30. A compound of claim 22 wherein R 6c is hydgrogen.
31. A compound of claim 22 wherein R 7a is hydrogen or halogen.
32. A compound of claim 22 wherein R 7a is hydrogen or fluorine.
33. A compound of claim 22 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 1 having the formula I(3):
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 3b is C 1-4 alkyl; 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, particularly trifluoromethyl, difluoromethyl, chlorodifluromethyl; and R 7a is hydrogen or fluorine.
35. A compound selected from:
R 3a is H unless otherwise specified
m
R 5
R 6a
R 6b
R 6c
R 7a
*
0
CH 2 CF 3
CO 2 CH 3
F
H
H
R
0
CH 2 CF 3
CONHOCH 3
F
H
H
R
0
CF 3
CO 2 CH 3
F
H
H
§
0
CF 3
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
R
0
CF 3
CO 2 CH 3
Cl
H
F
R
0
CF 3
2-CH 3 -tetrazol-5-yl
F
H
F
R
0
CH 2 CN
CO 2 CH 3
F
H
H
R
0
CH 2 CN
CO 2 CH 3
Cl
H
H
R
0
CH 2 CF 3
CO 2 CH 3
Cl
H
H
R
0
CH 2 CF 3
CO 2 CH 3
F
H
F
(±)
0
isoxazol-5-yl
CO 2 CH 3
F
H
F
(±)
0
CH 2 CN
CO 2 CH 3
F
H
F
(±)
0
pyrimidin-5-yl
CO 2 CH 3
F
H
H
R
0
CH 2 CF 3
CO 2 CH 3
F
H
F
S
0
CH 2 CF 3
CO 2 CH 3
F
H
F
R
0
pyrimidin-5-yl
CO 2 CH 3
F
H
F
(±)
0
isoxazol-5-yl
CO 2 CH 3
F
H
F
R
0
CF 3
CO 2 CH 3
F
H
F
R
0
pyrimidin-5-yl
CO 2 CH 3
F
H
F
R
0
isoxazol-5-yl
CO 2 CH 3
F
H
F
S
0
CF 3
CO 2 CH 3
F
H
F
S
0
pyrimidin-5-yl
CO 2 CH 3
F
H
F
S
0
CH 3
CO 2 CH 3
F
H
F
R
0
5-Br-pyridin-3-yl
CO 2 CH 3
F
H
F
R
0
5-Br-1-oxido-pyridin-3-yl
CO 2 CH 3
F
H
F
R
0
CF 3
CO 2 CH 3
H
H
F
R
0
pyrimidin-5-yl
CO 2 CH 3
H
H
F
R
0
CClF 2
CO 2 CH 3
F
H
F
R
0
5-(CF 3 )pyridin-3-yl
CO 2 CH 3
F
H
F
R
0
CClF 2
CO 2 CH 3
Cl
H
F
R
0
CHF 2
CO 2 CH 3
F
H
F
R
0
CF 2 CF 3
CO 2 CH 3
F
H
F
R
0
CHF 2
CO 2 CH 3
Cl
H
F
R
0
CH 3
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
H
R
0
CH 2 CN
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
H
R
0
CH 2 CF 3
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
H
R
0
isoxazol-5-yl
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
H
R
0
CH 2 CF 3
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
S
0
CH 2 CF 3
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
R
0
CH 2 CN
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
(±)
0
CH 2 CF 3
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
(±)
0
pyrimidin-5-yl
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
(±)
0
CClF 2
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
R
0
pyrimidin-5-yl
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
R
0
CHF 2
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
R
0
CH 2 CN
2-CH 3 -tetrazol-5-yl
F
H
H
R
0
CH 2 CF 3
2-CH 3 -tetrazol-5-yl
F
H
H
R
0
CH 2 CN
1-CH 3 -tetrazol-5-yl
F
H
H
R
0
CH 2 CF 3
1-CH 3 -tetrazol-5-yl
F
H
H
R
0
CH 3
1-CH 3 -tetrazol-5-yl
F
H
H
R
0
isoxazol-5-yl
2-CH 3 -tetrazol-5-yl
F
H
F
(±)
0
CH 2 CF 3
2-CH 3 -tetrazol-5-yl
F
H
F
(±)
0
pyrimidin-5-yl
2-CH 3 -tetrazol-5-yl
F
H
F
(±)
0
CF 3
2-CH 3 -tetrazol-5-yl
F
H
F
S
0
CClF 2
2-CH 3 -tetrazol-5-yl
F
H
F
R
0
CHF 2
2-CH 3 -tetrazol-5-yl
F
H
F
R
0
CH 2 CF 3
cyano
F
H
H
R
0
CH 2 CF 3
difluoromethoxy
H
H
H
R
0
CH 2 CF 3
trifluoromethoxy
H
H
H
R
0
CH 2 CF 3
trifluoromethyl
F
H
H
R
0
CH 2 CF 3
Cl
Cl
H
H
R
0
isoxazol-5-yl
trifluoromethyl
F
H
H
R
0
CH 2 CN
trifluoromethyl
F
H
H
R
0
isoxazol-5-yl
Cl
Cl
H
H
R
0
CH 2 CN
Cl
Cl
H
H
R
0
CH 2 CN
F
CO 2 Me
H
H
R
0
cyclopropyl
cyano
F
H
H
R
0
CH 2 CF 3
CON(CH 3 ) 2
F
H
H
R
0
pyrimidin-5-yl
NHCO 2 CH 3
F
H
H
R
0
pyrimidin-5-yl
NHCONHCH 3
F
H
H
R
0
CF 3
CONHCH 3
F
H
H
R
0
CF 3
CONHCH 3
Cl
H
H
R
0
CH 2 CF 3
CONHCH 3
F
H
H
R
0
isoxazol-5-yl
CONHOCH 3
F
H
H
R
0
CH 2 CF 3
CONH-cyclopropyl
F
H
H
R
0
CH 2 CF 3
CONH-cyclobutyl
F
H
H
R
0
CH 2 CF 3
5-CH 3 -1,2,4-oxadiazol-3-yl
F
H
H
R
0
isoxazol-5-l
5-CH 3 -1,2,4-oxadiazol-3-yl
F
H
H
R
0
pyrimidin-5-yl
5-CH 3 -1,2,4-oxadiazol-3-yl
H
H
F
R
0
CF 3
5-CH 3 -1,2,4-oxadiazol-3-yl
H
H
F
R
0
pynmidin-5-yl
5-CH 3 -1,2,4-oxadiazol-3-yl
H
5-Cl
F
R
0
CF 3
5-CH 3 -1,2,4-oxadiazol-3-yl
H
5-Cl
F
R
0
pyrimidin-5-yl
5-CH 3 -1,2,4-oxadiazol-3-yl
H
5-CH3
F
R
0
CF 3
5-CH 3 -1,2,4-oxadiazol-3-yl
H
5-CH3
F
R
0
pyrimidin-5-yl
5-CH 3 -1,2,4-oxadiazol-3-yl
H
5-F
F
R
0
CF 3
5-CH 3 -1,2,4-oxadiazol-3-yl
H
5-F
F
R
0
pyrimidin-5-yl
methoxy
F
5-F
H
R
0
CF 3
methoxy
F
5-F
H
R
0
pyrimidin-5-yl
2-CH 3 -2H-tetrazol-5-yl
H
5-F
F
R
0
CF 3
2-CH 3 -2H-tetrazol-5-yl
H
5-F
F
R
0
CF 3
CO 2 CH 3
H
5-Cl
F
R
0
CClF 2
CO 2 CH 3
H
5-Cl
F
R
0
CF 3
CO 2 CH 3
H
5-CH 3
F
R
0
CClF 2
CO 2 CH 3
H
5-CH 3
F
R
0
CF 3
3-CH 3 -1,2,4-oxadiazol-5-yl
H
5-F
F
R
0
CF 3
3-CH 3 -1,2,4-oxadiazol-5-yl
H
5-Cl
F
R
0
CClF 2
3-CH 3 -1,2,4-oxadiazol-5-yl
H
5-Cl
F
R
0
CF 3
3-CH 3 -1,2,4-oxadiazol-5-yl
H
5-CH 3
F
R
0
CClF 2
3-CH 3 -1,2,4-oxadiazol-5-yl
H
5-CH 3
F
R
0
CF 3
CO 2 CH 3
H
5-F
F
R
0
CClF 2
CO 2 CH 3
H
5-F
F
R
0
pyrimidin-5-yl
2-CH 3 -2H-tetrazol-5-yl
H
5-Cl
F
R
0
CF 3
2-CH 3 -2H-tetrazol-5-yl
H
5-Cl
F
R
0
pyrimidin-5-yl
2-CH 3 -2H-tetrazol-5-yl
H
5-CH 3
F
R
0
CF 3
2-CH 3 -2H-tetrazol-5-yl
H
5-CH3
F
R
0
CF 3
CONHCH 3
Cl
H
F
R
0
CF 3
NHCO 2 CH 3
Cl
H
F
R
0
CF 3
NHCO 2 CH(CH 3 ) 2
Cl
H
F
R
0
pyrimidin-5-yl
NHCO 2 CH(CH 3 ) 2
Cl
H
F
R
0
CF 3
NHCO 2 CH 3
F
H
F
R
0
CF 3
2-methoxy-2-oxoethyl
F
H
F
R
0
CF 3
CONHCH 3
F
H
F
R
0
CF 3
CH 2 OCH 3
Cl
H
F
R
0
CF 3
hydroxy
Cl
5-Cl
H
R
0
pyrimidin-5-yl
NHCO 2 CH 3
F
H
F
R
0
pyrimidin-5-yl
NHCO 2 CH 3
Cl
H
F
R
0
CF 3
CO 2 CH 3
H
6-CH 3
F
R
0
CClF 2
CO 2 CH 3
H
6-CH 3
F
R
0
CF 3
CO 2 CH 3
Cl
H
F
R
0
CF 3
CO 2 CH 3
CH3
H
F
R
0
CClF 2
CO 2 CH 3
CH3
H
F
R
1
pyrimidin-5-yl
CO 2 CH 3
F
H
H
§
1
CF 3
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
R
1
CClF 2
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
R
1
pynmidin-5-yl
3-CH 3 -1,2,4-oxadiazol-5-yl
F
H
F
R
1
CF 3
CO 2 CH 3
F
H
F
R
1
CClF 2
CO 2 CH 3
F
H
F
R
1
pyrimidin-5-yl
CO 2 CH 3
F
H
F
R
1
pyrimidin-5-yl
CO 2 CH 3
F
H
H
R
1
pyrimidin-5-yl
2-CH 3 -2H-tetrazol-5-yl
F
H
F
R
1
CF 3
CO 2 CH 3
Cl
H
F
R
1
CClF 2
CO 2 CH 3
Cl
H
F
R
1
CHF 2
CO 2 CH 3
Cl
H
F
R
*stereoconfiguration at the indicated carbon, § R 3a is CH 3 ; or a pharmaceutically acceptable salt thereof.
36. The compound methyl 3-chloro-3′-fluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-carboxylate.
37. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and pharmaceutically acceptable excipients.
38. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 36 and pharmaceutically acceptable excipients.
39. A method of treatment of osteoarthritis, repetitive motion pain, dental pain, cancer pain, myofascial pain, muscular injury pain, fibromyalgia pain, perioperative pain comprising a step of administering, to a subject in need of such treatment, an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
40. A method of treatment of diabetic vasculopathy, post capillary resistance, diabetic symptoms associated with insulitis, psoriasis, eczema, spasms of the gastrointestinal tract or uterus, Crohn's disease, ulcerative colitis, or pancreatitis comprising a step of administering, to a subject in need of such treatment, an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.