Pyrazolochlorophenyl compounds, compositions and methods of use thereof

Abstract

Compounds of Formula I and methods of use as Janus kinase inhibitors are described herein.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —(C 0 -C 3 alkyl)CN, —(C 0 -C 3 alkyl)OR a , —(C 0 -C 3 alkyl)R a , —(C 0 -C 3 alkyl)SR a , —(C 0 -C 3 alkyl)NR a R b , —(C 0 -C 3 alkyl)OCF 3 , —(C 0 -C 3 alkyl)CF 3 , —(C 0 -C 3 alkyl)NO 2 , —(C 0 -C 3 alkyl)C(O)R a , —(C 0 -C 3 alkyl)C(O)OR a , —(C 0 -C 3 alkyl)C(O)NR a R b , —(C 0 -C 3 alkyl)NR a C(O)R b , —(C 0 -C 3 alkyl)S(O) 1-2 R a , —(C 0 -C 3 alkyl)NR a S(O) 1-2 R b , —(C 0 -C 3 alkyl)S(O) 1 2 NR a R b , —(C 0 -C 3 alkyl)(5-6-membered heteroaryl) or —(C 0 -C 3 alkyl)phenyl, wherein R 1  is optionally substituted by halogen, C 1 -C 3 alkyl, oxo, —CF 3 , —(C 0 -C 3 alkyl)OR c  or —(C 0 -C 3 alkyl)NR c R d ; 
 each R a  is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6  cycloalkyl, 3-10 membered heterocyclyl, 5-6 membered heteroaryl, —C(O)R c , —C(O)OR c , —C(O)NR c R d , —NR c C(O)R d , —S(O) 1-2 R c , —NR c S(O) 1-2 R d  and —S(O) 1-2 NR c R d , wherein any C 3 -C 6  cycloalkyl, 3-10 membered heterocyclyl, and 5-6 membered heteroaryl of R a  is optionally substituted with R e ; 
 each R b  is independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl, wherein said alkyl is optionally substituted halogen or oxo; 
 each R c  and R d  is independently selected from the group consisting of hydrogen, 3-6 membered heterocyclyl, C 3 -C 6  cycloalkyl, and C 1 -C 3 alkyl, wherein any 3-6 membered heterocyclyl, C 3 -C 6  cycloalkyl, and C 1 -C 3 alkyl of R c  and R d  is optionally substituted by halogen or oxo; or R c  and R d  are taken together with the atom to which they are attached to form a 3-6-membered heterocyclyl, optionally substituted by halogen, oxo, —CF 3  or C 1 -C 3 alkyl; 
 each R e  is independently selected from the group consisting of oxo, OR f , NR f R g , halogen, 3-10 membered heterocyclyl, C 3 -C 6  cycloalkyl, and C 1 -C 6 alkyl, wherein any C 3 -C 6  cycloalkyl and C 1 -C 6 alkyl of R e  is optionally substituted by OR f , NR f R g , halogen, 3-10 membered heterocyclyl, oxo, or cyano, and wherein any 3-10 membered heterocyclyl of R e  is optionally substituted by halogen, oxo, cyano, —CF 3 , NR h R k , 3-6 membered heterocyclyl, or C 1 -C 3 alkyl that is optionally substituted by halogen, oxo, OR f , or NR h R k ; 
 each R f  and R g  is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, 3-6 membered heterocyclyl, and C 3 -C 6  cycloalkyl, wherein any C 1 -C 6 alkyl, 3-6 membered heterocyclyl, and C 3 -C 6  cycloalkyl of R f  and R g  is optionally substituted by R m ; 
 each R h  and R k  is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl that is optionally substituted by halogen, cyano, 3-6 membered heterocyclyl, or oxo; or R h  and R k  are taken together with the atom to which they are attached to form a 3-6-membered heterocyclyl that is optionally substituted by halogen, cyano, oxo, —CF 3  or C 1 -C 3 alkyl that is optionally substituted by halogen or oxo; 
 each R m  is independently selected from the group consisting of halogen, cyano, oxo, C 3 -C 6 cycloalkyl, hydroxy, and NR h R k , wherein any C 3 -C 6 cycloalkyl of R m  is optionally substituted with halogen, oxo, cyano, or C 1 -C 3 alkyl; 
 R 2  is phenyl, 5-6 membered heteroaryl, C 3 -C 6  cycloalkyl or 3-10 membered heterocyclyl, wherein R 2  is optionally substituted by 1-5 R n ; 
 each R n  is independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, oxo, halogen, —(C 0 -C 3  alkyl)CN, —(C 0 -C 3  alkyl)OR o , —(C 0 -C 3  alkyl)SR o , —(C 0 -C 3  alkyl)NR o R p , —(C 0 -C 3  alkyl)OCF 3 , —(C 0 -C 3  alkyl)CF 3 , —(C 0 -C 3  alkyl)NO 2 , —(C 0 -C 3  alkyl)C(O)R o , —(C 0 -C 3  alkyl)C(O)OR o , —(C 0 -C 3  alkyl)C(O)NR o R p , —(C 0 -C 3  alkyl)NR o C(O)R p , —(C 0 -C 3  alkyl)S(O) 1-2 R o , —(C 0 -C 3  alkyl)NR o S(O) 1-2 R p , —(C 0 -C 3  alkyl)S(O) 1-2 NR o R p , —(C 0 -C 3  alkyl)(C 3 -C 6  cycloalkyl), —(C 0 -C 3  alkyl)(3-6-membered heterocyclyl), —(C 0 -C 3  alkyl)C(O)(3-6-membered heterocyclyl), —(C 0 -C 3  alkyl)(5-6-membered heteroaryl) and —(C 0 -C 3  alkyl)phenyl, wherein each R n  is independently optionally substituted with halogen, C 1 -C 3  alkyl, oxo, —CF 3 , —(C 0 -C 3  alkyl)OR r  or —(C 0 -C 3  alkyl)NR r R s ; or two R n  are taken together to form —O(CH 2 ) 1-3 O—; 
 each R o  is independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, 3-6 membered heterocyclyl, —C(O)R r , —C(O)OR r , 
 —C(O)NR r R s , —NR r C(O)R s , —S(O) 1-2 R r , —NR r S(O) 1-2 R s  and —S(O) 1-2 NR r R s , wherein said alkyl, cycloalkyl and heterocyclyl are independently optionally substituted by oxo, C 1 -C 3  alkyl, OR r , NR r R s  or halogen; and each RP is independently selected from the group consisting of hydrogen and C 1 -C 3  alkyl, wherein said alkyl is independently optionally substituted by halogen or oxo; or R o  and RP are taken together with the atom to which they are attached to form a 3-6-membered heterocyclyl, optionally substituted by halogen, oxo, —CF 3  or C 1 -C 3  alkyl; 
 each R r  and R s  is independently selected from the group consisting of hydrogen and C 1 -C 3  alkyl optionally substituted by halogen or oxo; or R r  and R s  are taken together with the atom to which they are attached to form a 3-6-membered heterocyclyl, optionally substituted by halogen, oxo, —CF 3  or C 1 -C 3  alkyl; and 
 X is a 9-10 membered bicyclic heteroaryl that comprises 2 or 3 atoms each independently selected from the group consisting of O, S, and N, wherein the 9-10 membered bicyclic heteroaryl is optionally substituted with R u ; provided X is not, 
 
       
       
         
           
           
               
               
           
         
         optionally substituted with R u ;
 each R u  is independently selected from the group consisting of hydrogen, halo, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, 3-6 membered heterocyclyl, —OR v , —C(O)R v , —C(O)OR v , —C(O)NR v R w , —NR v R w , —NR v C(O)R w , —S(O) 1-2 R, —NR v S(O) 1-2 R w  and —S(O) 1-2 NR v R w , wherein said alkyl, cycloalkyl and heterocyclyl are independently optionally substituted by oxo, C 1 -C 3  alkyl, —OR v , —NR v R w  or halogen; and 
 each R v  and R w  is independently selected from the group consisting of hydrogen and C 1 -C 3  alkyl optionally substituted by halogen or oxo; or R v  and R w  are taken together with the atom to which they are attached to form a 3-6-membered heterocyclyl, optionally substituted by halogen, oxo, —CF 3  or C 1 -C 3  alkyl; 
 provided the compound or pharmaceutically acceptable salt is not: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1  wherein R 1  is —(C 0 -C 3 alkyl)C(O)R a , or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein R 1  is H, methyl, 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 1  is H or methyl. 
     
     
         5 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 2  is phenyl that is optionally substituted by 1-5 R n . 
     
     
         6 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 2  is phenyl that is optionally substituted by 1-2 R n . 
     
     
         7 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 2  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein X selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and is optionally substituted with R u . 
       
     
     
         10 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein X selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein X is not selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein X selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and is optionally substituted with R u . 
       
     
     
         13 . A compound of  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein:
 R u1  is H or methyl; 
 R u2  is methyl or difluoromethyl; and 
 R u3  is methyl, methoxy, halo, or NH 2 ; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         14 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 R u1  is H or methyl; and 
 R U2  is methyl or difluoromethyl; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         15 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         17 . A method of preventing, treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method of  claim 17 , wherein the disease or condition is asthma. 
     
     
         19 . The method of  claim 17 , wherein the Janus kinase is JAK1.