Sulfonyl substituted n-(biarylmethyl) aminocyclopropanecarboxamides

1. A compound of formula I and pharmaceutically acceptable salts thereof:

wherein

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 hydrogen, halogen, and 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; (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-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 OSO 2 R 8 ;

R 6b , R 6c , and R 6d are independently selected from (1) hydrogen, (2) halogen, (3) OSO 2 R 8 , (4) C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms, (5) cyano, (6) nitro, (7) OR a , and (8) CO 2 R a , or

when attached to adjacent carbon atoms R 6c and R 6d together with the carbon atoms to which they are attached form a 5- to 8-membered saturated or unsaturated ring;

R 7 is 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 , and (8) C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms,

R 8 is selected from (1) C 1-4 alkyl optionally substituted with 1 to 5 halogen atoms, (2) (CH 2 ) k -aryl optionally substituted with 1 to 3 groups independently selected from halogen, nitro, cyano, NR a C(O)R a , OR a , SR a , CO 2 R a , C 1-4 alkyl, C 1-3 haloalkyl and NR b R c , (3) NR b R c , and (4) hydrogen;

R a , R b and R c are independently 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 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, (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, and (4) hydrogen;

X is selected from CH and N;

Y is selected from C and S═O; and

k is selected from 0, 1, and 2.

2. A compound of claim 1 wherein R 5 is selected from pyrimidinyl and C 1-6 alkyl optionally substituted with 1 to 5 groups independently selected from halogen.

3. A compound of claim 1 wherein Y is C.

4. A compound of claim 1 R 8 is selected from 2,2,2,-trifluoromethyl, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, and dimethylamino.

5. A compound of claim 1 wherein R 6b is selected from hydrogen, fluorine, and chlorine.

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

wherein X is N or CH, R 3a is H or C 1-4 alkyl, R 7 is hydrogen or halogen, and R 5 , R 6a , R 6b and R 6c have the same definitions as provided in claim 1 .

7. A compound of claim 6 wherein R 6a is OSO 2 R 8 ; R 8 is selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, benzyl, dimethylamino, 2,2,2-trifluoroethyl, and phenyl; R 6b is hydrogen or halogen, and R 6c is hydrogen or halogen.

8. A compound of claim 6 wherein R5 is pyrimidinyl or C 1-4 alkyl optionally substituted with 1 to 5 groups independently selected from halogen.

9. A compound selected from

3,3′-difluoro-4′-{[({1-[(pyrimidin-5-ylcarbonyl)amino]cyclopropyl}carbonyl)amino]methyl}-1,1′-biphenyl-2-yl trifluoromethanesulfonate,

3,3′-difluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-yl trifluoromethanesulfonate,

3,3′-difluoro-4′-((1R)-1-{[(1-{[(trifluoromethyl)sulfonyl]amino}cyclopropyl)carbonyl]amino}-ethyl)-1,1′-biphenyl-2-yl trifluoromethanesulfonate,

1-({[(1R)-1-(3,3′-difluoro-2′-{[(trifluoromethyl)sulfonyl]oxy}-1,1′-biphenyl-4-yl)ethyl]amino}-carbonyl)cyclopropanaminium trifluoroacetate,

3,3′-difluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-yl methanesulfonate,

5-chloro-3,3′-difluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]-ethyl}-1,1′-biphenyl-2-yl trifluoromethanesulfonate,

3,3′-difluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-yl methanesulfonate,

3,3′-difluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-yl propane-1-sulfonate

3,3′-difluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-yl propane-2-sulfonate,

3,3′-difluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-yl benzenesulfonate,

3,3′-difluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-yl phenylmethanesulfonate

3,3′-difluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-yl dimethylsulfamate,

3,3′-difluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-yl 2,2,2-trifluoroethanesulfonate,

3-chloro-3′-fluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-yl trifluoromethanesulfonate,

3′-fluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-2-{[(trifluoromethyl)sulfonyl]oxy}-1,1′-biphenyl-3-yl trifluoromethanesulfonate,

N-(1-{[((1R)-1-{3,3′-difluoro-2′-[methyl(methylsulfonyl)amino]-1,1′-biphenyl-4-yl}ethyl)amino]-carbonyl)cyclopropyl}pyrimidine-5-carboxamide,

N-(1-{[({3,3′-difluoro-2′-[(methylsulfonyl)amino]-1,1′-biphenyl-4-yl}methyl)amino]carbonyl}-cyclopropyl)pyrimidine-5-carboxamide,

N-{1-[({[2′-(1,1-dioxido-1,2-thiazinan-2-yl)-3,3′-difluoro-1,1′-biphenyl-4-yl]methyl}amino)carbonyl]-cyclopropyl}pyrimidine-5-carboxamide,

N-[(1R)-1-(3,3′-difluoro-2-{[(trifluoromethyl)sulfonyl]methyl}-1,1′-biphenyl-4-yl)ethyl]-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide,

N-[(1R)-1-(3,3′-difluoro-2′-{[(trifluoromethyl)sulfonyl]amino}-1,1′-biphenyl-4-yl)ethyl]-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide, and

N-(1-{[((1R)-1-{3,3′-difluoro-2′-[(methylsulfonyl)amino]-1,1′-biphenyl-4-yl}ethyl)amino]-carbonyl}-cyclopropyl)pyrimidine-5-carboxamide.

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

11. The compound N-[(1R)-1-(2-fluoro-4-{1-[(trifluoromethyl)sulfonyl]-1,2,3,4-tetrahydroquinolin-8-yl}phenyl)ethyl]-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide.