Sulfonamide compounds as cysteine protease inhibitors

1. A compound of Formula (I):

R 1 and R 2 taken together with the carbon atom to which R 1 and R 2 are attached form cyclopropylene optionally substituted with one to four fluoro;

R 3 is -alkylene-SO 2 NR 5 R 6 where:

R 5 is hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, -(alkylene)-NR 7 R 8 [where R 7 is hydrogen, alkyl, acyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkylalkyl and R 8 is haloalkyl, acyl, cycloalkylcarbonyl, 4-membered heterocyloalkylcarbonyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl alkoxycarbonylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonyl, aminosulfonyl, —C(O)OR 9 (where R 9 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, 4- or heterocycloalkyl) provided that R 7 is not hydrogen, alkyl, or —COR (where R is alkyl) when R 8 is aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl), or —SO 2 R 10 (where R 10 is alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl)], acylalkyl, or heterocycloalkylaminocarbonyl; and

R 6 is hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; or

R 5 and R 6 together with the nitrogen atom to which they are attached form heterocycloamino or bridged azabicyclic ring;

wherein the aromatic or alicyclic ring in R 5 and R 6 and the heterocycloamino and bridged azabicyclic rings formed by R 5 and R 6 are optionally substituted with one, two, or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy or cyano; or optionally substituted with one or two R b independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one R c selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, cycloalkylcarbonyl, 4-membered heterocycloalkylcarbonyl, acylalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, 4-heterocycloalkyloxycarbonyl, heterocycloalkylalkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, cycloalkylaminocarbonyl, aminosulfonyl, or —SO 2 R 11 (where R 11 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in R c is optionally substituted with one, two, or three R d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, cyano, —CONH 2 , alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyl, alkylsulfonyl, or alkylsulfonylamino;

R 4 is hydrogen, alkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl attached via a carbon ring atom, wherein the aromatic or alicyclic ring in R 4 is optionally substituted by one, two, or three R f independently selected from alkyl, halo, hydroxy, alkoxy, alkoxyalkyloxy, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, cyano, alkylcarbonyl, alkylsulfonyl, or alkylsulfonylamino;

R 4a is —CHF 2 , —CF 3 , —CF 2 CF 3 , —CCl 3 , —CFCl 2 , —CF 2 Cl, —CCl 2 CF 3 , —CF 2 CHF 2 , —CF 2 CF 2 CF 3 , or —CF 2 CF 2 CHF 2 ; and

R 4b is hydrogen or haloalkyl; or

a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 4 is hydrogen and R 4b is hydrogen.

3. The compound of claim 1 wherein R 4 is hydrogen and R 4b is haloalkyl.

4. The compound of claim 1 wherein R 4 is alkyl and R 4b is hydrogen.

5. The compound of claim 1 wherein R 4 is alkyl and R 4b is haloalkyl.

6. The compound of claim 1 wherein R 4 is aryl optionally substituted with one, two or three R f and R 4b is hydrogen.

7. The compound of claim 1 wherein R 4 is aryl optionally substituted with one, two or three R f and R 4b is haloalkyl.

8. The compound of claim 1 wherein R 4 is heteroaryl optionally substituted with one, two or three R f and R 4b is hydrogen.

9. The compound of claim 1 wherein R 4 is heteroaryl optionally substituted with one, two or three R f and R 4b is haloalkyl.

10. The compound of claim 1 wherein R 3 is -alkylene-SO 2 NR 5 R 6 where:

R 5 is hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, -(alkylene)-NR 7 R 8 [where R 7 is hydrogen, alkyl, acyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkylalkyl and R 8 is haloalkyl, acyl, cycloalkylcarbonyl, 4-membered heterocyloalkylcarbonyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl alkoxycarbonylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, 4-heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonyl, aminosulfonyl, —C(O)OR 9 (where R 9 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl) provided that R 7 is not hydrogen, alkyl, or —COR (where R is alkyl) when R 8 is aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl), or —SO 2 R 10 (where R 10 is alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl)], acylalkyl, or heterocycloalkylaminocarbonyl; and

R 6 is hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; or

R 5 and R 6 together with the nitrogen atom to which they are attached form heterocycloamino or bridged azabicyclic ring;

wherein the aromatic or alicyclic ring in R 5 and R 6 and the heterocycloamino and bridged azabicyclic rings formed by R 5 and R 6 are optionally substituted with one, two, or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy or cyano; or optionally substituted with one or two R b independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one R c selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, cycloalkylcarbonyl, 4-membered heterocycloalkylcarbonyl, acylalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, heterocycloalkyloxycarbonyl, heterocycloalkylalkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, cycloalkylaminocarbonyl, aminosulfonyl, or —SO 2 R 11 (where R 11 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in R c is optionally substituted with one, two, or three R d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, cyano, —CONH 2 , alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyl, alkylsulfonyl, or alkylsulfonylamino; provided that:

(i) when R 5 is hydrogen, alkyl, acyl, or haloalkyl, then R 6 is not hydrogen or alkyl;

(ii) when R 5 is hydrogen, alkyl, or acyl and R 6 is aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, then the aromatic or alicylic ring in these groups has to be substituted with an R c provided that: (a) R c is not alkoxycarbonyl or an acyl group that does not contain a substituted aromatic or alicyclic ring and (b) when R c is aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl then the aromatic or alicyclic ring in these groups is substituted with at least an R d ; and

(iii) when R 5 and R 6 together with the nitrogen atom to which they are attached form heterocycloamino the heterocycloamino ring has to be substituted with an R c provided that: (a) R c is not alkoxycarbonyl or an acyl group that does not contain a substituted aromatic or alicyclic ring and (b) when R c is aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl then the aromatic or alicyclic ring in these groups is substituted with at least an R d .

11. The compound of claim 1 wherein R 3 is -alkylene-SO 2 NR 5 R 6 where:

R 5 is alkoxyalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, -(alkylene)NR 7 R 8 [where R 7 is hydrogen, alkyl, acyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkylalkyl and R 8 is hydroxyalkyl, alkoxyalkyl, carboxyalkyl alkoxycarbonylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonyl, aminosulfonyl, —C(O)OR 9 (where R 9 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl) provided that R 7 is not hydrogen, alkyl, or —COR (where R is alkyl) when R 8 is aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl], acylalkyl, or heterocycloalkylaminocarbonyl, and

R 6 is hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;

wherein the aromatic or alicyclic ring in R 5 and R 6 are optionally substituted with one, two, or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo; or optionally substituted with one or two R b independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one R c selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, acyl, acylalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, heterocycloalkylalkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or —SO 2 R 11 (where R 11 is alkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in R c is optionally substituted with one, two, or three R d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo.

12. The compound of claim 1 wherein R 3 is -alkylene-SO 2 NR 5 R 6 where R 5 and R 6 together with the nitrogen atom to which they are attached form heterocycloamino substituted one, two, or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy or cyano; or optionally substituted with one or two R b independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one R c selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, cycloalkylcarbonyl, 4-membered heterocycloalkylcarbonyl, acylalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, -heterocycloalkyloxycarbonyl, heterocycloalkylalkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, cycloalkylaminocarbonyl, aminosulfonyl, or —SO 2 R 11 (where R 11 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in R c is optionally substituted with one, two, or three R d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, cyano, —CONH 2 , alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyl, alkylsulfonyl, or alkylsulfonylamino; provided that heterocycloamino ring is substituted with at least an R c provided that (a) R c is not an acyl group that does not contain a substituted aromatic or alicyclic ring and (b) when R c is aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl then the aromatic or alicyclic ring in these groups is substituted with at least an R d .

13. The compound of claim 1 wherein R 3 is -alkylene-SO 2 NR 5 R 6 where R 5 and R 6 together with the nitrogen atom to which they are attached form a bridged azabicyclic ring optionally substituted with one, two, or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo; or optionally substituted with one or two R b independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one R c selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, acyl, acylalkyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, heterocycloalkyloxycarbonyl, heterocycloalkylalkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or —SO 2 R 11 (where R 11 is alkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in R c is optionally substituted with one, two, or three R d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo; provided that the bridged azabicyclic ring is substituted with at least an R c provided that (a) R c is not an acyl group that does not contain a substituted aromatic or alicyclic ring and (b) when R c is aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl then the aromatic or alicyclic ring in these groups is substituted with at least an R d .

14. The compound of claim 1 wherein R 3 is -alkylene-SO 2 NR 5 R 6 where R 5 and R 6 together with the nitrogen atom to which they are attached form piperazinyl or piperidin-1-yl substituted one, two, or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy or cyano; or optionally substituted with one or two R b independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one R c selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, 4-heterocycloalkyl, heterocycloalkylalkyl, acyl, cycloalkylcarbonyl, 4-membered heterocycloalkylcarbonyl, acylalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, heterocycloalkyloxycarbonyl, heterocycloalkylalkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, cycloalkylaminocarbonyl, aminosulfonyl, or —SO 2 R 11 (where R 11 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in R c is optionally substituted with one, two, or three R d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, cyano, —CONH 2 , alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyl, alkylsulfonyl, or alkylsulfonylamino; provided that heterocycloamino ring is substituted with at least an R c provided that (a) R c is not an acyl group that does not contain a substituted aromatic or alicyclic ring and (b) when R c is aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl then the aromatic or alicyclic ring in these groups is substituted with at least an R d .

15. The compound of claim 1 wherein R 3 is -alkylene-SO 2 NR 5 , R 6 where R 5 and R 6 together with the nitrogen atom to which they are attached form piperazinyl or piperidin-1-yl substituted at least at the 4-position of the ring with one, two, or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy or cyano; or optionally substituted with one or two R b independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one R c selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, 4-heterocycloalkylalkyl, acyl, cycloalkylcarbonyl, 4-membered heterocycloalkylcarbonyl, acylalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, heterocycloalkyloxycarbonyl, heterocycloalkylalkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkylalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, cycloalkylaminocarbonyl, aminosulfonyl, or —SO 2 R 11 (where R 11 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in R c is optionally substituted with one, two, or three R d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, cyano, —CONH 2 , alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyl, alkylsulfonyl, or alkylsulfonylamino; provided that heterocycloamino ring is substituted with at least an R c provided that (a) R c is not an acyl group that does not contain a substituted aromatic or alicyclic ring and (b) when R c is aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, or cycloalkylalkyl then the aromatic or alicyclic ring in these groups is substituted with at least an R d .

16. The compound of claim 1 wherein R 4a is —CF 3 or —CHF 2 .

17. A pharmaceutical composition comprising a compound of claim 1 in admixture with one or more suitable excipients.

18. A method for ameliorating a disease in an animal mediated by Cathepsin S which method comprises administering to the animal a pharmaceutical composition comprising a compound of claim 1 in admixture with one or more suitable excipients; wherein the disease is rheumatoid arthritis.