Azabenzothiazole compounds, compositions and methods of use

Abstract

Provided are compounds of Formula I, stereoisomers, tautomers, solvates, prodrugs and pharmaceutically acceptable salts thereof, wherein A, X, R 1 , R 2 , R 4 and R 5 are defined herein, a pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle, methods of using the compound or composition in therapy, and methods of manufacturing a compound of Formula I.

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         stereoisomers, tautomers, solvates, prodrugs and pharmaceutically acceptable salts thereof, wherein: 
         A is CR 3  or N; 
         X is CR 15  or N; 
         R 1  is independently hydrogen, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, —CF 3 , —OR 6 , —SR 6 , —OCF 3 , —CN, —NO 2 , —C(O)R 6 , —C(O)OR 6 , —C(O)NR 6 R 7 , —S(O) 1-2 R 6 , —S(O) 1-2 NR 6 R 7 , —NR 6 S(O) 1-2 R 7 , —NR 6 SO 2 NR 6 R 7 , —NR 6 C(O)R 7 , —NR 6 C(O)OR 7 , —NR 6 C(O)NR 6 R 7 , —OC(O)NR 6 R 7  or —NR 6 R 7 , wherein both R 1  cannot be hydrogen at the same time, and wherein said alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted by halogen, oxo, —CN, OR 6 , —NR 6 R 7 , C 3 -C 6  cycloalkyl, 3-6 membered heterocyclyl or phenyl and said cycloalkyl, heterocyclyl and phenyl are independently optionally substituted by R 10 ; 
         R 2  and R 3  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —(C 0 -C 3  alkylene)CN, —(C 0 -C 3  alkylene)OR 8 , —(C 0 -C 3  alkylene)SR 8 , —(C 0 -C 3  alkylene)NR 8 R 9 , —(C 0 -C 3  alkylene)CF 3 , —O(C 0 -C 3  alkylene)CF 3 , —(C 0 -C 3  alkylene)NO 2 , —(C 0 -C 3  alkylene)C(O)R 8 , —(C 0 -C 3  alkylene)C(O)OR 8 , —(C 0 -C 3  alkylene)C(O)NR 8 R 9 , —(C 0 -C 3  alkylene)NR 8 C(O)R 9 , —(C 0 -C 3  alkylene)S(O) 1-2 R 8 , —(C 0 -C 3  alkylene)NR 8 S(O) 1-2 R 9 , —(C 0 -C 3  alkylene)S(O) 1-2 NR 8 R 9 , —(C 0 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 0 -C 3  alkylene)(3-10-membered heterocyclyl), —(C 0 -C 3  alkylene)(5-10-membered heteroaryl) or —(C 0 -C 3  alkylene)phenyl, wherein R 2  and R 3  are each independently optionally substituted by R 10 ; 
         R 4  is hydrogen, —NR 6 —, —NR 6 R 7 , —NR 6 C(O)—, —NR 6 C(O)O—, —NR 6 C(O)NR 7 —, NR 6 S(O) 1-2 — or —NR 6 S(O) 1-2 NR 7 —; 
         R 5  is absent, hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl, wherein R 5  is optionally substituted by R 10 ; 
         R 6  and R 7  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or C 3 -C 6  cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, C 1 -C 6  alkyl, oxo, —CN, —OR 11  or —NR 11 R 12 ; or 
         R 6  and R 7  are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 11 , —NR 11 R 12  or C 1 -C 6  alkyl optionally substituted by halogen; 
         R 8  and R 9  are each independently hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, phenyl, 3-6-membered heterocyclyl or 5-6-membered heteroaryl, wherein said alkyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl are independently optionally substituted by R 10 ; or 
         R 8  and R 9  are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —NR 11 R 12  or C 1 -C 6  alkyl; 
         R 10  is independently hydrogen, oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —(C 0 -C 3  alkylene)CN, —(C 0 -C 3  alkylene)OR 11 , —(C 0 -C 3  alkylene)SR 11 , —(C 0 -C 3  alkylene)NR 11 R 12 , —(C 0 -C 3  alkylene)CF 3 , —(C 0 -C 3  alkylene)NO 2 , —C═NH(OR 11 ), —(C 0 -C 3  alkylene)C(O)R 11 , —(C 0 -C 3  alkylene)C(O)OR 11 , —(C 0 -C 3  alkylene)C(O)NR 11 R 12 , —(C 0 -C 3  alkylene)NR 11 C(O)R 12 , —(C 0 -C 3  alkylene)S(O) 1-2 R 11 , —(C 0 -C 3  alkylene)NR 11 S(O) 1-2 R 12 , —(C 0 -C 3  alkylene)S(O) 1-2 NR 11 R 12 , —(C 0 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 0 -C 3  alkylene)(3-10-membered heterocyclyl), —(C 0 -C 3  alkylene)C(O)(3-10-membered heterocyclyl), —(C 0 -C 3  alkylene)(5-10-membered heteroaryl) or —(C 0 -C 3  alkylene)phenyl, wherein R 10  is independently optionally substituted by halogen, oxo, —CF 3 , —(C 0 -C 3  alkylene)OR 13 , —(C 0 -C 3  alkylene)NR 13 R 14 , —(C 0 -C 3  alkylene)C(O)R 13 , —(C 0 -C 3  alkylene)S(O) 1-2 R 13  or C 1 -C 6  alkyl optionally substituted by oxo, —CN or halogen; 
         R 11  and R 12  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, —CN, —OR 16 , —NR 16 R 17  or C 1 -C 6  alkyl optionally substituted by halogen, —CN or oxo; or 
         R 11  and R 12  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 16 , —NR 16 R 17  or C 1 -C 6  alkyl optionally substituted by halogen, oxo or OH; 
         R 13  and R 14  are each independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen or oxo; or 
         R 13  and R 14  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6  alkyl optionally substituted by halogen or oxo; 
         R 15  is hydrogen, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —(C 0 -C 3  alkylene)CN, —(C 0 -C 3  alkylene)OR 18 , —(C 0 -C 3  alkylene)SR 18 , —(C 0 -C 3  alkylene)NR 18 R 19 , —(C 0 -C 3  alkylene)CF 3 , —O(C 0 -C 3  alkylene)CF 3 , —(C 0 -C 3  alkylene)NO 2 , —(C 0 -C 3  alkylene)C(O)R 18 , —(C 0 -C 3  alkylene)C(O)OR 18 , —(C 0 -C 3  alkylene)C(O)NR 18 R 19 , —(C 0 -C 3  alkylene)NR 18 C(O)R 19 , —(C 0 -C 3  alkylene)S(O) 1-2 R 18 , —(C 0 -C 3  alkylene)NR 18 S(O) 1-2 R 19 , —(C 0 -C 3  alkylene)S(O) 1-2 NR 18 R 19 , —(C 0 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 0 -C 3  alkylene)(3-6-membered heterocyclyl), —(C 0 -C 3  alkylene)(5-6-membered heteroaryl) or —(C 0 -C 3  alkylene)phenyl; 
         R 16  and R 17  are each independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen or oxo; or 
         R 16  and R 17  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6  alkyl optionally substituted by oxo or halogen; and 
         R 18  and R 19  are each independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen or oxo; 
         other than 2-(2-chlorophenyl)thiazolo[5,4-c]pyridine, 2-(thiazolo[5,4-c]pyridin-2-yl)aniline, 2-phenoxy-N-(2-thiazolo[5,4-c]pyridin-2-yl-phenyl)-propanamide, N-(2-thiazolo[5,4-c]pyridin-2-ylphenyl)-benzenepropanamide, 2-(2-methylphenyl)-thiazolo[5,4-c]pyridine, 2-[2-methoxy-4-(methylthio)phenyl]-thiazolo[5,4-c]pyridine and 2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine. 
       
     
     
         2 . The compound of  claim 1 , wherein A is CR 3  and X is CR 5 . 
     
     
         3 . The compound of  claim 2 , wherein one R 1  is halogen and the other R 1  is hydrogen, halogen, C 1 -C 3  alkyl, C 3 -C 4  cycloalkyl, —CF 3 , —OH, —O(C 1 -C 3  alkyl), —SH, —S(C 1 -C 3  alkyl), —OCF 3 , —CN, —NO 2 , —NHSO 2 CH 3 , —NHC(O)R 7  or —NR 6 R 7 , wherein said alkyl and cycloalkyl are optionally substituted by halogen, OR 6 , —NR 6 R 7  or phenyl. 
     
     
         4 . The compound of  claim 3 , wherein R 1  is Cl. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein R 3  is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —CN, —NR 8 R 9 , —NR C(O)R 9 , —C(O)R 8  or —S(O) 1-2 (C 1 -C 3  alkyl), wherein said alkyl, alkenyl and alkynyl are independently optionally substituted by halogen, oxo, —OR 11  or —NR 11 R 12 . 
     
     
         7 . The compound of  claim 6 , wherein R 3  is hydrogen or —CN. 
     
     
         8 . The compound of  claim 1 , wherein the portion of Formula I having the structure: 
       
         
           
           
               
               
           
         
         is selected from: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the wavy lines represent the point of attachment in Formula I. 
       
     
     
         9 . The compound of  claim 1 , wherein R 4  is hydrogen, —NR 6 —, —NR 6 C(O)—, —NR 6 C(O)O— or —NR 6 C(O)NR 7 —. 
     
     
         10 . The compound of  claim 1 , wherein R 5  is C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, phenyl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl, wherein R 5  is optionally substituted by R 10 . 
     
     
         11 . The compound of  claim 10 , wherein R 5  is selected from methyl, ethyl, isopropyl, tert-butyl, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CN, —CH 2 NH 2 , —CH 2 N(CH 3 ) 2  or —CH 2 CH 2 NH 2  phenyl, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the wavy line represents the point of attachment of R 5  in Formula I. 
       
     
     
         12 . The compound of  claim 1 , wherein R 10  is selected from F, —CN, methyl, ethyl, isopropy, —CH 2 OH, —CH 2 CH 2 OH, —CH(OH)CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CF 3 , —OH, —OCH 3 , —NH 2 , —NHCH 3 , —NHC(O)CH 3 , —N(CH 3 ) 2 , —N(CH 2 CH 2 OH) 2 , —NHCH 2 CH 2 OH, —N(CH 3 )CH 2 CH 2 OH, —NHCH 2 C(CH 3 ) 2 OH, —N(CH 3 )CH 2 C(CH 3 ) 2 OH, —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , —CH 2 thiomorpholinyl dioxide, —CH 2 -morpholinyl, —CH 2 cyclopropyl, —CH(OH)CH 3 , —CH(NH 2 )CH 3 , (R)—CH(OH)CH 3 , (R)—CH(NH 2 )CH 3 , (S)—CH(OH)CH 3 , (S)—CH(NH 2 )CH 3 , 
       
         
           
           
               
               
           
         
         wherein the wavy line represents the point of attachment in Formula I. 
       
     
     
         13 . A pharmaceutical composition comprising a compound of Formula I 
       
         
           
           
               
               
           
         
         stereoisomers, tautomers, solvates, prodrugs or pharmaceutically acceptable salts thereof, wherein: 
         A is CR 3  or N; 
         X is CR 15  or N; 
         R 1  is independently hydrogen, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, —CF 3 , —OR 6 , —SR 6 , —OCF 3 , —CN, —NO 2 , —C(O)R 6 , —C(O)OR 6 , —C(O)NR 6 R 7 , —S(O) 1-2 R 6 , —S(O) 1-2 NR 6 R 7 , —NR 6 S(O) 1-2 R 7 , —NR 6 SO 2 NR 6 R 7 , —NR 6 C(O)R 7 , —NR 6 C(O)OR 7 , —NR 6 C(O)NR 6 R 7 , —OC(O)NR 6 R 7  or —NR 6 R 7 , wherein both R 1  cannot be hydrogen at the same time, and wherein said alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted by halogen, oxo, —CN, OR 6 , —NR 6 R 7 , C 3 -C 6  cycloalkyl, 3-6 membered heterocyclyl or phenyl and said cycloalkyl, heterocyclyl and phenyl are independently optionally substituted by R 10 ; 
         R 2  and R 3  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —(C 0 -C 3  alkylene)CN, —(C 0 -C 3  alkylene)OR 8 , —(C 0 -C 3  alkylene)SR 8 , —(C 0 -C 3  alkylene)NR 8 R 9 , —(C 0 -C 3  alkylene)CF 3 , —O(C 0 -C 3  alkylene)CF 3 , —(C 0 -C 3  alkylene)NO 2 , —(C 0 -C 3  alkylene)C(O)R 8 , —(C 0 -C 3  alkylene)C(O)OR 8 , —(C 0 -C 3  alkylene)C(O)NR 8 R 9 , —(C 0 -C 3  alkylene)NR 8 C(O)R 9 , —(C 0 -C 3  alkylene)S(O) 1-2 R 8 , —(C 0 -C 3  alkylene)NR 8 S(O) 1-2 R 9 , —(C 0 -C 3  alkylene)S(O) 1-2 NR 8 R 9 , —(C 0 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 0 -C 3  alkylene)(3-10-membered heterocyclyl), —(C 0 -C 3  alkylene)(5-10-membered heteroaryl) or —(C 0 -C 3  alkylene)phenyl, wherein R 2  and R 3  are each independently optionally substituted by R 10 ; 
         R 4  is hydrogen, —NR 6 —, —NR 6 R 7 , —NR 6 C(O)—, —NR 6 C(O)O—, —NR 6 C(O)NR 7 —, —NR 6 S(O) 1-2 — or —NR 6 S(O) 1-2 NR 7 —; 
         R 5  is absent, hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl, wherein R 5  is optionally substituted by R 10 ; 
         R 6  and R 7  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or C 3 -C 6  cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, C 1 -C 6  alkyl, oxo, —CN, —OR 11  or —NR 11 R 12 ; or 
         R 6  and R 7  are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 11 , —NR 11 R 12  or C 1 -C 6  alkyl optionally substituted by halogen; 
         R 8  and R 9  are each independently hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, phenyl, 3-6-membered heterocyclyl or 5-6-membered heteroaryl, wherein said alkyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl are independently optionally substituted by R 10 ; or 
         R 8  and R 9  are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —NR 11 R 12  or C 1 -C 6  alkyl; 
         R 10  is independently hydrogen, oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —(C 0 -C 3  alkylene)CN, —(C 0 -C 3  alkylene)OR 11 , —(C 0 -C 3  alkylene)SR 11 , —(C 0 -C 3  alkylene)NR 11 R 12 , —(C 0 -C 3  alkylene)CF 3 , —(C 0 -C 3  alkylene)NO 2 , —C═NH(OR 11 ), —(C 0 -C 3  alkylene)C(O)R 11 , —(C 0 -C 3  alkylene)C(O)OR 11 , —(C 0 -C 3  alkylene)C(O)NR 11 R 12 , —(C 0 -C 3  alkylene)NR 11 C(O)R 12 , —(C 0 -C 3  alkylene)S(O) 1-2 R 11 , —(C 0 -C 3  alkylene)NR 11 S(O) 1-2 R 12 , —(C 0 -C 3  alkylene)S(O) 1-2 NR 11 R 12 , —(C 0 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 0 -C 3  alkylene)(3-10-membered heterocyclyl), —(C 0 -C 3  alkylene)C(O)(3-10-membered heterocyclyl), —(C 0 -C 3  alkylene)(5-10-membered heteroaryl) or —(C 0 -C 3  alkylene)phenyl, wherein R 10  is independently optionally substituted by halogen, oxo, —CF 3 , —(C 0 -C 3  alkylene)OR 13 , —(C 0 -C 3  alkylene)NR 13 R 14 , —(C 0 -C 3  alkylene)C(O)R 13 , —(C 0 -C 3  alkylene)S(O) 1-2 R 13  or C 1 -C 6  alkyl optionally substituted by oxo, —CN or halogen; 
         R 11  and R 12  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, —CN, —OR 16 , —NR 16 R 17  or C 1 -C 6  alkyl optionally substituted by halogen, —CN or oxo; or 
         R 11  and R 12  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 16 , —NR 16 R 17  or C 1 -C 6  alkyl optionally substituted by halogen, oxo or OH; 
         R 13  and R 14  are each independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen or oxo; or 
         R 13  and R 14  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6  alkyl optionally substituted by halogen or oxo; 
         R 15  is hydrogen, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —(C 0 -C 3  alkylene)CN, —(C 0 -C 3  alkylene)OR 18 , —(C 0 -C 3  alkylene)SR 18 , —(C 0 -C 3  alkylene)NR 18 R 19 , —(C 0 -C 3  alkylene)CF 3 , —O(C 0 -C 3  alkylene)CF 3 , —(C 0 -C 3  alkylene)NO 2 , —(C 0 -C 3  alkylene)C(O)R 18 , —(C 0 -C 3  alkylene)C(O)OR 18 , —(C 0 -C 3  alkylene)C(O)NR 18 R 19 , —(C 0 -C 3  alkylene)NR 18 C(O)R 19 , —(C 0 -C 3  alkylene)S(O) 1-2 R 18 , —(C 0 -C 3  alkylene)NR 18 S(O) 1-2 R 19 , —(C 0 -C 3  alkylene)S(O) 1-2 NR 18 R 19 , —(C 0 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 0 -C 3  alkylene)(3-6-membered heterocyclyl), —(C 0 -C 3  alkylene)(5-6-membered heteroaryl) or —(C 0 -C 3  alkylene)phenyl; 
         R 16  and R 17  are each independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen or oxo; or 
         R 16  and R 17  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6  alkyl optionally substituted by oxo or halogen; and 
         R 18  and R 19  are each independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen or oxo. 
       
     
     
         14 . The composition of  claim 13 , further comprising a pharmaceutically acceptable carrier, adjuvant or vehicle. 
     
     
         15 . A method of treating a disease responsive to the inhibition of TYK2 kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition of  claim 13 . 
     
     
         16 . The method of  claim 15 , wherein said disease is an inflammatory disease. 
     
     
         17 . The method of  claim 16 , wherein said disease is asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, allergic rhinitis, atopic dermatitis, contact dermatitis, delayed hypersensitivity reactions, lupus or multiple sclerosis. 
     
     
         18 . The method of  claim 15 , further comprising administering a second therapeutic agent. 
     
     
         19 . A method of manufacturing a compound of  claim 1 , comprising:
 (a) reacting a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein Lv is a leaving group, with a compound of the formula H—R 4 —R 5  under conditions sufficient to form a compound of Formula I. 
       
     
     
         20 . A compound of formula (i) 
       
         
           
           
               
               
           
         
         wherein 
         Lv is a leaving group; 
         A is CR 3  or N; 
         X is CR 15  or N; 
         R 1  is independently hydrogen, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, —CF 3 , —OR 6 , —SR 6 , —OCF 3 , —CN, —NO 2 , —C(O)R 6 , —C(O)OR 6 , —C(O)NR 6 R 7 , —S(O) 1-2 R 6 , —S(O) 1-2 NR 6 R 7 , —NR 6 S(O) 1-2 R 7 , —NR 6 SO 2 NR 6 R 7 , —NR 6 C(O)R 7 , —NR 6 C(O)OR 7 , —NR 6 C(O)NR 6 R 7 , —OC(O)NR 6 R 7  or —NR 6 R 7 , wherein both R 1  cannot be hydrogen at the same time, and wherein said alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted by halogen, oxo, —CN, OR 6 , —NR 6 R 7 , C 3 -C 6  cycloalkyl, 3-6 membered heterocyclyl or phenyl and said cycloalkyl, heterocyclyl and phenyl are independently optionally substituted by R 10 ; 
         R 2  and R 3  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —(C 0 -C 3  alkylene)CN, —(C 0 -C 3  alkylene)OR 8 , —(C 0 -C 3  alkylene)SR 8 , —(C 0 -C 3  alkylene)NR 8 R 9 , —(C 0 -C 3  alkylene)CF 3 , —O(C 0 -C 3  alkylene)CF 3 , —(C 0 -C 3  alkylene)NO 2 , —(C 0 -C 3  alkylene)C(O)R 8 , —(C 0 -C 3  alkylene)C(O)OR 8 , —(C 0 -C 3  alkylene)C(O)NR 8 R 9 , —(C 0 -C 3  alkylene)NR 8 C(O)R 9 , —(C 0 -C 3  alkylene)S(O) 1-2 R 8 , —(C 0 -C 3  alkylene)NR 8 S(O) 1-2 R 9 , —(C 0 -C 3  alkylene)S(O) 1-2 NR 8 R 9 , —(C 0 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 0 -C 3  alkylene)(3-10-membered heterocyclyl), —(C 0 -C 3  alkylene)(5-10-membered heteroaryl) or —(C 0 -C 3  alkylene)phenyl, wherein R 2  and R 3  are each independently optionally substituted by R 10 ; 
         R 4  is hydrogen, —NR 6 —, —NR 6 R 7 , —NR 6 C(O)—, —NR 6 C(O)O—, —NR 6 C(O)NR 7 —, NR 6 S(O) 1-2 — or —NR 6 S(O) 1-2 NR 7 —; 
         R 5  is absent, hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, 3-10-membered heterocyclyl or 5-10-membered heteroaryl, wherein R 5  is optionally substituted by R 10 ; 
         R 6  and R 7  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or C 3 -C 6  cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, C 1 -C 6  alkyl, oxo, —CN, —OR 11  or —NR 11 R 12 ; or 
         R 6  and R 7  are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 11 , —NR 11 R 12  or C 1 -C 6  alkyl optionally substituted by halogen; 
         R 8  and R 9  are each independently hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, phenyl, 3-6-membered heterocyclyl or 5-6-membered heteroaryl, wherein said alkyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl are independently optionally substituted by R 10 ; or 
         R 8  and R 9  are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —NR 11 R 12  or C 1 -C 6  alkyl; 
         R 10  is independently hydrogen, oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, —(C 0 -C 3  alkylene)CN, —(C 0 -C 3  alkylene)OR 11 , —(C 0 -C 3  alkylene)SR 11 , —(C 0 -C 3  alkylene)NR 11 R 12 , —(C 0 -C 3  alkylene)CF 3 , —(C 0 -C 3  alkylene)NO 2 , —C═NH(OR 11 ), —(C 0 -C 3  alkylene)C(O)R 11 , —(C 0 -C 3  alkylene)C(O)OR 11 , —(C 0 -C 3  alkylene)C(O)NR 11 R 12 , —(C 0 -C 3  alkylene)NR 11 C(O)R 12 , —(C 0 -C 3  alkylene)S(O) 1-2 R 11 , —(C 0 -C 3  alkylene)NR 11 S(O) 1-2 R 12 , —(C 0 -C 3  alkylene)S(O) 1-2 NR 11 R 12 , —(C 0 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 0 -C 3  alkylene)(3-10-membered heterocyclyl), —(C 0 -C 3  alkylene)C(O)(3-10-membered heterocyclyl), —(C 0 -C 3  alkylene)(5-10-membered heteroaryl) or —(C 0 -C 3  alkylene)phenyl, wherein R 10  is independently optionally substituted by halogen, oxo, —CF 3 , —(C 0 -C 3  alkylene)OR 13 , —(C 0 -C 3  alkylene)NR 13 R 14 , —(C 0 -C 3  alkylene)C(O)R 3 , —(C 0 -C 3  alkylene)S(O) 1-2 R 13  or C 1 -C 6  alkyl optionally substituted by oxo, —CN or halogen; 
         R 11  and R 12  are each independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl and heterocyclyl are independently optionally substituted by halogen, oxo, —CN, —OR 16 , —NR 16 R 17  or C 1 -C 6  alkyl optionally substituted by halogen, —CN or oxo; or 
         R 11  and R 12  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 16 , —NR 16 R 17  or C 1 -C 6  alkyl optionally substituted by halogen, oxo or OH; 
         R 13  and R 14  are each independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen or oxo; or 
         R 13  and R 14  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6  alkyl optionally substituted by halogen or oxo; 
         R 15  is hydrogen, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —(C 0 -C 3  alkylene)CN, —(C 0 -C 3  alkylene)OR 18 , —(C 0 -C 3  alkylene)SR 18 , —(C 0 -C 3  alkylene)NR 18 R 19 , —(C 0 -C 3  alkylene)CF 3 , —O(C 0 -C 3  alkylene)CF 3 , —(C 0 -C 3  alkylene)NO 2 , —(C 0 -C 3  alkylene)C(O)R 18 , —(C 0 -C 3  alkylene)C(O)OR 18 , —(C 0 -C 3  alkylene)C(O)NR 18 R 19 , —(C 0 -C 3  alkylene)NR 18 C(O)R 19 , —(C 0 -C 3  alkylene)S(O) 1-2 R 18 , —(C 0 -C 3  alkylene)NR 18 S(O) 1-2 R 19 , —(C 0 -C 3  alkylene)S(O) 1-2 NR 18 R 19 , —(C 0 -C 3  alkylene)(C 3 -C 6  cycloalkyl), —(C 0 -C 3  alkylene)(3-6-membered heterocyclyl), —(C 0 -C 3  alkylene)(5-6-membered heteroaryl) or —(C 0 -C 3  alkylene)phenyl; 
         R 16  and R 17  are each independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen or oxo; or 
         R 16  and R 17  are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6  alkyl optionally substituted by oxo or halogen; and 
         R 18  and R 19  are each independently hydrogen or C 1 -C 6  alkyl optionally substituted by halogen or oxo; 
         other than 4-chloro-2-(2,3-difluorophenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2,3-dimethylphenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2-methoxyphenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-o-tolylthiazolo[5,4-c]pyridine, 4-chloro-2-(2-(difluoromethoxy)phenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2-fluorophenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2,3-dichlorophenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2,4-dichlorophenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2,4-dimethylphenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2-chlorophenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2,6-dimethylphenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2,5-dichlorophenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine, 2-(2-bromophenyl)-4-chlorothiazolo[5,4-c]pyridine, 4-chloro-2-(2,6-difluorophenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2,5-difluorophenyl)thiazolo[5,4-c]pyridine, 4-chloro-2-(2,4-difluorophenyl)thiazolo[5,4-c]pyridine or 4-chloro-2-(2,5-dimethyl)thiazolo[5,4-c]pyridine. 
       
     
     
         21 . The compound of  claim 20 , wherein -Lv is a halogen, —OR or —OS(O) 1-2 R, wherein R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independently optionally substituted. 
     
     
         22 . The compound of  claim 21 , wherein -Lv is a halogen. 
     
     
         23 . A kit comprising a pharmaceutical composition of  claim 13  and instructions for use.