CXCR4 Receptor Antagonists

Abstract

The compounds of formula (I) are antagonists of the CXCR4 receptor Wherein R 1 , X, Y and R 2 are as defined in the claims.

1 - 20 . (canceled) 
     
     
         21 . A compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from hydrogen, C 1-4 -alkyl, cyano, —COR 3 , —CONR 3 R 4 , and heteroaryl, wherein
 (a) the heteroaryl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 1-4 -alkoxy, fluoro-C 1-6 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy-C 1-4 -alkyl, C 6-10 -aryl, heteroaryl, —NR 5A R 5B , —C 1-4 -alkyl-NR 5A R 5B , —NR 4 C(O)O—C 1-4 -alkyl, —NR 4 C(O)—C 1-4 -alkyl, —NR 4 C(O)O-fluoro-C 1-4 -alkyl, —NR 4 C(O)-fluoro-C 1-4 -alkyl, —NR 4 C(O)NR 5A R 5B , C(O)NR 5A R 5B , —C(O)R 4 , —C(O)OR 4 , —NR 4 S(O) 2 —C 1-4 -alkyl, and —NR 4 S(O) 2 -fluoro-C 1-4 -alkyl, and 
 (b) the C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy; 
 
         X is selected from radicals of formulae (A)-(F) inclusive, any of which being optionally substituted with one more substituents independently selected from halogen, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to R 1  and the bond marked ** is attached to Y; 
       
       
         
           
           
               
               
           
         
         Y is a radical of formula (L), which is optionally substituted with one more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to X and the bond marked ** is attached to R 2   
       
       
         
           
           
               
               
           
         
         and n is 1 or 2, and R 20  is hydrogen or C 1-4 -alkyl; 
         R 2  is selected from radicals of formulae (N)-(S) inclusive, any of which is optionally substituted with one more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to Y 
       
       
         
           
           
               
               
           
         
         and o and p are each independently 1 or 2, and W is O or NR 9 ; 
         R 3  is selected from hydrogen, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl, heteroaryl, C 6-10 -aryl-C 1-4 -alkyl, and heteroaryl-C 1-4 -alkyl, wherein
 (i) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl, the C 1-4 -alkyl part of the heterocyclyl-C 1-4 -alkyl, the C 6-10 -aryl-C 1-4 -alkyl, or the heteroaryl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxy, cyano, C 1-4 -alkoxy, and —NR 5A R 5B , and 
 (ii) the C 6-10 -aryl, the heteroaryl, the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl or the heteroaryl part of the heteroaryl-C 1-4 -alkyl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy-C 1-4 -alkyl, —NR 5A R 5B , —C 1-4 -alkyl-NR 5A R 5B , —NR 4 C(O)O—C 1-4 alkyl, —NR 4 C(O)—C 1-4 alkyl, —NR 4 C(O)O-fluoro-C 1-4 alkyl, —NR 4 C(O)-fluoro-C 1-4 alkyl, —NR 4 C(O)NR 5A R 5B , —C(O)NR 5A R 5B , —C(O)R 4 , —C(O)OR 4 , —NR 4 S(O) 2 —C 1-4 alkyl, and —NR 4 S(O) 2 -fluoro-C 1-4 alkyl; 
 
         R 4 , R 5A , and R 5B  are each independently selected from hydrogen, C 1-4 -alkyl, and fluoro-C 1-4 -alkyl, 
         or 
         R 5A  and R 5B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, the ring being optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy, 
         or 
         R 3  and R 4 , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, the ring being optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy; and 
         R 6  is selected from C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl-C 1-4 -alkyl, and C 6-10 -aryl, wherein
 (iii) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, or the C 1-4 -alkyl part of the heterocyclyl-C 1-4 -alkyl or the C 6-10 -aryl-C 1-4 -alkyl, or the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, and 
 (iv) the C 6-10 -aryl or the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy-C 1-4 -alkyl; 
 
         R 7  is selected from C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl-C 1-4 -alkyl, C 6-10 -aryl, and —NR 10A R 10B , wherein
 (v) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, the C 1-4 -alkyl part of the heterocyclyl-C 1-4 -alkyl or the C 6-10 -aryl-C 1-4 -alkyl, or the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, and 
 (vi) the C 6-10 -aryl or the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy-C 1-4 -alkyl; 
 
         R 8A , R 8B  and R 9  are each independently selected from hydrogen, C 3-5 -cycloalkyl, C 1-6 -alkyl, and C 6-10 -aryl-C 1-4 -alkyl wherein any alkyl residue or cycloalkyl or C 6-10 -aryl ring system is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, and C 1-4 -alkoxy, 
         or 
         R 8A  and R 8B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring which is optionally fused to a C 6-10 -aryl or heteroaryl ring system, the 4- to 7-membered saturated heterocyclic ring or the C 6-10 -aryl or heteroaryl ring systems being optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy; and 
         R 10A  and R 10B  are each independently selected from hydrogen and C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, 
         or 
         R 10A  and R 10B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy. 
       
     
     
         22 . A compound of  claim 21 , wherein R 1  is CONR 3 R 4  or heteroaryl. 
     
     
         23 . A compound of  claim 22 , wherein R 1  is heteroaryl optionally substituted with one more substituents independently selected from halogen, cyano, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 1-4 -alkoxy, fluoro-C 1-6 -alkyl, fluoro-C 1-4 -alkoxy, and heteroaryl. 
     
     
         24 . A compound of  claim 22 , wherein the heteroaryl is selected from benzoxazolyl, indlyl, azaindolyl, imidazolyl, benzimidazolyl, oxazolyl, oxadiazolyl, and tetrazolyl, any of which being optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 1-4 -alkoxy, fluoro-C 1-6 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy-C 1-4 -alkyl, C 6-10 -aryl, heteroaryl, —NR 5A R 5B , —C 1-4 -alkyl-NR 5A R 5B , —NR 4 C(O)O—C 1-4 -alkyl, —NR 4 C(O)—C 1-4 -alkyl, —NR 4 C(O)O-fluoro-C 1-4 -alkyl, —NR 4 C(O)-fluoro-C 1-4 -alkyl, —NR 4 C(O)NR 5A R 5B , —C(O)NR 5A R 5B , —C(O)R 4 , —C(O)OR 4 , —NR 4 S(O) 2 —C 1-4 -alkyl, and —NR 4 S(O) 2 -fluoro-C 1-4 -alkyl. 
     
     
         25 . A compound of  claim 22 , wherein R 4  is hydrogen or methyl. 
     
     
         26 . A compound of  claim 22 , wherein R 3  is tetrahydropyranyl, isopropylmethyl, tetrahydropyranylmethyl, imidazolylethyl, methoxyethyl, N-methylimidazolylmethyl, tetrahydrofuranylmethyl, 1-fluorothyl, oxazolylmethyl, pyridylmethyl, 2,2-difluoromethyl, tetrahydrofuranyl, methyl, ethyl, n- or iso-propyl, n-sec- or tert-butyl, cyclopropyl, hydroxyethyl, cyanoethyl, phenyl, chlorophenyl, methoxyphenyl, methylphenyl, hydroxyphenyl, thiazoloylmethyl, indolyl, methoxypropyl, tetrahydroisoquinolinyl, furylmethylpyridylethyl, thiazolyl, or cyclopropylmethyl. 
     
     
         27 . A compound of  claim 22 , wherein R 3  is pyridyl optionally substituted with one or more substituents selected from halogen, C 1-4 -alkyl, C 1-4 -alkoxy, and fluoro-C 1-4 -alkyl. 
     
     
         28 . A compound of  claim 27 , where R 3  is 4-pyridyl optionally substituted with one or more methyl groups. 
     
     
         29 . A compound of  claim 21 , wherein X is formula (A). 
     
     
         30 . A compound of  claim 21 , wherein R 6  is hydrogen, halogen, C 1-6 -alkyl, C 1-6  fluoroalkyl, C 1-4 -alkoxy, C 1-2 -alkoxy-C 1-4 alkyl, C 3-5  cycloalkyl, C 3-5  fluorocycloalkyl, benzyl, alpha methyl-benzyl, wherein each of benzyl and alpha methyl-benzyl is optionally ring-substituted by one or two substituents selected from halogen, C 1-4 -alkyl, and C 1-4 -alkoxy. 
     
     
         31 . A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from hydrogen, C 1-4 -alkyl, cyano, —COR 3 , —CONR 3 R 4 , and heteroaryl, wherein
 (a) the heteroaryl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 1-4 -alkoxy, fluoro-C 1-6 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy-C 1-4 -alkyl, C 6-10 -aryl, heteroaryl, —NR 5A R 5B , —C 1-4 -alkyl-NR 5A R 5B , —NR 4 C(O)O—C 1-4 -alkyl, —NR 4 C(O)—C 1-4 -alkyl, —NR 4 C(O)O-fluoro-C 1-4 -alkyl, —NR 4 C(O)-fluoro-C 1-4 -alkyl, —NR 4 C(O)NR 5A R 5B , C(O)NR 5A R 5B , —C(O)R 4 , —C(O)OR 4 , —NR 4 S(O) 2 —C 1-4 -alkyl, and —NR 4 S(O) 2 -fluoro-C 1-4 -alkyl, and 
 (b) the C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy; 
 
         X is selected from radicals of formulae (A)-(F) inclusive, any of which being optionally substituted with one more substituents independently selected from halogen, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to R 1  and the bond marked ** is attached to Y 
       
       
         
           
           
               
               
           
         
         Y is a radical of formula (L) which is optionally substituted with one more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to X and the bond marked ** is attached to R 2   
       
       
         
           
           
               
               
           
         
         and n is 1 or 2, and R 20  is hydrogen or C 1-4 -alkyl; 
         R 2  is selected from radicals of formulae (N)-(S) inclusive, any of which is optionally substituted with one more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to Y 
       
       
         
           
           
               
               
           
         
         and o and p are each independently 1 or 2, and W is O or NR 9 ; 
         R 3  is selected from hydrogen, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl, heteroaryl, C 6-10 -aryl-C 1-4 -alkyl, and heteroaryl-C 1-4 -alkyl, wherein
 (i) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl, the C 1-4 -alkyl part of the heterocyclyl-C 1-4 -alkyl, the C 6-10 -aryl-C 1-4 -alkyl, or the heteroaryl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxy, cyano, C 1-4 -alkoxy and —NR 5A R 5B , and 
 (ii) the C 6-10 -aryl, the heteroaryl, the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl or the heteroaryl part of the heteroaryl-C 1-4 -alkyl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy-C 1-4 -alkyl, —NR 5A R 5B , —C 1-4 -alkyl-NR 5A R 5B , —NR 4 C(O)O—C 1-4 alkyl, —NR 4 C(O)—C 1-4 alkyl, —NR 4 C(O)O-fluoro-C 1-4 alkyl, —NR 4 C(O)-fluoro-C 1-4 alkyl, —NR 4 C(O)NR 5A R 5B , —C(O)NR 5A R 5B , —C(O)R 4 , —C(O)OR 4 , —NR 4 S(O) 2 —C 1-4 alkyl, and —NR 4 S(O) 2 -fluoro-C 1-4 alkyl; 
 
         R 4 , R 5A  and R 5B  are each independently selected from hydrogen, C 1-4 -alkyl, and fluoro-C 1-4 -alkyl, 
         or 
         R 5A  and R 5B  together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, the ring being optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy, 
         or 
         R 3  and R 4 , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, the ring being optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy; and 
         R 6  is selected from C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl-C 1-4 -alkyl, and C 6-10 -aryl, wherein
 (iii) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, or the C 1-6 -alkyl part of the heterocyclyl-C 1-4 -alkyl or the C 6-10 -aryl-C 1-4 -alkyl, or the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, and 
 (iv) the C 6-10 -aryl or the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy-C 1-4 -alkyl; 
 
         R 7  is selected from C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl-C 1-4 -alkyl, C 6-10 -aryl, and —NR 10A R 10B , wherein
 (v) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, the C 1-6 -alkyl part of the heterocyclyl-C 1-4 -alkyl or the C 6-10 -aryl-C 1-4 -alkyl, or the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, and 
 (vi) the C 6-10 -aryl or the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy-C 1-4 -alkyl; 
 
         R 8A , R 8B  and R 9  are each independently selected from hydrogen, C 3-5 -cycloalkyl, C 1-6 -alkyl, and C 6-10 -aryl-C 1-4 -alkyl, wherein any alkyl residue or cycloalkyl or C 6-10 -aryl ring system is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, and C 1-4 -alkoxy, 
         or 
         R 8A  and R 8B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring which is optionally fused to a C 6-10 -aryl or heteroaryl ring system, the 4- to 7-membered saturated heterocyclic ring or the C 6-10 -aryl or heteroaryl ring systems being optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy; and 
         R 10A  and R 10B  are each independently selected from hydrogen and C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, 
         or 
         R 10A  and R 10B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy; and 
         a pharmaceutically acceptable carrier and/or excipient. 
       
     
     
         32 . A pharmaceutical composition of  claim 31 , wherein R 1  is CONR 3 R 4  or heteroaryl. 
     
     
         33 . A pharmaceutical composition of  claim 32 , wherein R 1  is heteroaryl optionally substituted with one more substituents independently selected from halogen, cyano, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 1-4 -alkoxy, fluoro-C 1-6 -alkyl, fluoro-C 1-4 -alkoxy, and heteroaryl. 
     
     
         34 . A pharmaceutical composition of  claim 32 , wherein R 1  is heteroaryl selected from benzoxazolyl, indlyl, azaindolyl, imidazolyl, benzimidazolyl, oxazolyl, oxadiazolyl, and tetrazolyl, any of which being optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 1-4 -alkoxy, fluoro-C 1-6 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy-C 1-4 -alkyl, C 6-10 -aryl, heteroaryl, —NR 5A R 5B , —C 1-4 -alkyl-NR 5A R 5B , —NR 4 C(O)O—C 1-4 -alkyl, —NR 4 C(O)—C 1-4 -alkyl, —NR 4 C(O)O-fluoro-C 1-4 -alkyl, —NR 4 C(O)-fluoro-C 1-4 -alkyl, —NR 4 C(O)NR 5A R 5B , —C(O)NR 5A R 5B , —C(O)R 4 , —C(O)OR 4 , —NR 4 S(O) 2 —C 1-4 -alkyl, and —NR 4 S(O) 2 -fluoro-C 1-4 -alkyl. 
     
     
         35 . A pharmaceutical composition of  claim 32 , wherein R 4  is hydrogen or methyl. 
     
     
         36 . A pharmaceutical composition of  claim 32 , wherein R 3  is tetrahydropyranyl, isopropylmethyl, tetrahydropyranylmethyl, imidazolylethyl, methoxyethyl, N-methylimidazolylmethyl, tetrahydrofuranylmethyl, 1-fluorothyl, oxazolylmethyl, pyridylmethyl, 2,2-difluoromethyl, tetrahydrofuranyl, methyl, ethyl, n- or iso-propyl, n-sec- or tert-butyl, cyclopropyl, hydroxyethyl, cyanoethyl, phenyl, chlorophenyl, methoxyphenyl, methylphenyl, hydroxyphenyl, thiazoloylmethyl, indolyl, methoxypropyl, tetrahydroisoquinolinyl, furylmethylpyridylethyl, thiazolyl, or cyclopropylmethyl. 
     
     
         37 . A pharmaceutical composition of  claim 31 , wherein R 3  is pyridyl optionally substituted with one or more substituents selected from halogen, C 1-4 -alkyl, C 1-4 -alkoxy, and fluoro-C 1-4 -alkyl. 
     
     
         38 . A pharmaceutical composition of  claim 32 , where R 3  is 4-pyridyl optionally substituted with one or more methyl groups. 
     
     
         39 . A pharmaceutical composition of  claim 31 , wherein X is formula (A). 
     
     
         40 . A pharmaceutical composition of  claim 31 , wherein R 6  is hydrogen, halogen, C 1-6 -alkyl, C 1-6  fluoroalkyl, C 1-4 -alkoxy, C 1-2 -alkoxy-C 1-4 alkyl, C 3-5  cycloalkyl, C 3-5  fluorocycloalkyl, benzyl, alpha methyl-benzyl, and benzyl or alpha methyl-benzyl either of which being optionally ring-substituted by one or two substituents selected from halogen, C 1-4 -alkyl, and C 1-4 -alkoxy.