Pyrazolopyrimidine jak inhibitor compounds and methods

Abstract

The invention provides JAK kinase inhibitors of Formula Ia, enantiomers, diasteriomers or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 7 and Z are defined herein, a pharmaceutical composition that includes a compound of Formula Ia and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a JAK kinase activity in a patient.

What is claimed is: 
     
         1 . A compound of Formula Ia: 
       
         
           
           
               
               
           
         
         enantiomers, diastereomers or pharmaceutically acceptable salts thereof, wherein: 
         R 1  is H; 
         R 2  is —OR 4 , —NR 3 R 4 , —NR 3 NR 12 R 4 , —NR 3 S(O)R 4  or —NR 3 S(O) 2 R 4 ; 
         R 3  is H or C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, F, OR a  or NR a R b ; 
         R 4  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —(C 0 -C 5  alkyl)(C 1 -C 9  heterocyclyl), —(C 0 -C 5  alkyl)(C 3 -C 6  cycloalkyl), —(C 0 -C 5  alkyl)(C 1 -C 9  heteroaryl), —(C 0 -C 5  alkyl)(C 6 -C 10  aryl), wherein said alkyl, alkenyl and alkynyl are optionally substituted by R 8 , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by R 9 ; or 
         R 3  and R 4  are taken together with the nitrogen to which they are attached to form a C 1 -C 9  heterocyclyl optionally substituted by R 13 ; 
         Z is —OR 6  or —NR 5 R 6 ; 
         R 5  is H or C 1 -C 3  alkyl; 
         R 6  is H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, —(C 0 -C 5  alkyl)(C 1 -C 9  heterocyclyl), —(C 0 -C 5  alkyl)(C 3 -C 8  cycloalkyl), —(C 0 -C 5  alkyl)(C 1 -C 9  heteroaryl), —(C 0 -C 5  alkyl)(C 6 -C 9  aryl), wherein said alkyl, alkenyl and alkynyl are optionally substituted by R 10 , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by R 1 ; 
         R 7  is H, halo, C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl or —O(C 1 -C 3  alkyl); 
         R 8  is independently oxo, halo, OR a  or NR a R b ; 
         R 9  is independently oxo, —CN, —CF 3 , halo, —C(O)C 1 -C 6  alkyl, —C(O)OR a , —C(O)NR a R b , —(C 0 -C 5  alkyl)NR a R b , —(C 0 -C 5  alkyl)OR a , —(C 0 -C 5  alkyl)SR a , —O[C(R a ) 2 ] 1-3 O—, C 1 -C 3  alkyl optionally substituted by oxo or F, —(C 0 -C 5  alkyl)(C 3 -C 6  cycloalkyl) optionally substituted by oxo or F, —(C 0 -C 5  alkyl)C 1 -C 9  heterocyclyl optionally substituted by halo, oxo, C 1 -C 3  alkyl or C(O)C 1 -C 3  alkyl, —(C 0 -C 5  alkyl)C 6  aryl optionally substituted by halo or C 1 -C 3  alkyl —O(C 1 -C 3  alkyl), or —(C 0 -C 5  alkyl)C 1 -C 9  heteroaryl optionally substituted by halo or C 1 -C 3  alkyl; 
         R 10  is independently oxo, halo, OR a  or NR a R b ; 
         R 11  is independently oxo, —CN, —CF 3 , halo, —O[C(R a ) 2 ] 1-3 O—, —C(O)C 1 -C 6  alkyl, —C(O)OR a , —C(O)NR a R b , —(C 0 -C 5  alkyl)NR a R b , —(C 0 -C 5  alkyl)OR a , C 1 -C 6  alkyl optionally substituted by oxo or F, —(C 0 -C 5  alkyl)C 1 -C 9  heterocyclyl optionally substituted by halo, oxo, C 1 -C 3  alkyl or C(O)C 1 -C 3  alkyl, —(C 0 -C 5  alkyl)C 1 -C 9  heteroaryl optionally substituted by halo or C 1 -C 3  alkyl, —(C 0 -C 5  alkyl)phenyl optionally substituted by C 1 -C 4  alkyl, C 1 -C 4  alkenyl, C 1 -C 4  alkynyl, C 3 -C 6  cycloalkyl, —CF 3 , halo, —CN, —OR a  or —NR a R b , or —(C 0 -C 5  alkyl)C 3 -C 6  cycloalkyl optionally substituted by oxo, —NR c R d , C 1 -C 3  alkyl or F; 
         R 12  is H or C 1 -C 3  alkyl; 
         R 13  is oxo, halo, C 1 -C 3  alkyl, —C(O)C 1 -C 6  alkyl, —C(O)OR a , C 6  aryl, C 3 -C 6  cycloalkyl, C 1 -C 5  heteroaryl or C 4 -C 5  heterocyclyl; wherein said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by C 1 -C 4  alkyl, —(C 0 -C 3  alkyl)OR c , oxo, halo or NR c R d ; 
         R a  and R b  are independently H, —CF 3 , —CHF 2 , —CH 2 F, C 1 -C 6  alkyl, C 6  aryl, C 3 -C 6  cycloalkyl or C 4 -C 5  heterocyclyl; wherein said alkyl, aryl and cycloalkyl are optionally substituted by C 1 -C 4  alkyl, —(C 0 -C 3  alkyl)OR c , oxo, halo, NR c R d  or C 4 -C 5  heterocyclyl; or 
         R a  and R b  together with the atom to which they are attached form a C 1 -C 5  heterocyclyl optionally substituted by oxo, F, C 1 -C 3  alkyl, —C(O)C 1 -C 6  alkyl or —C(O)OR a ; and 
         R c  and R d  are independently H, C 1 -C 3  alkyl, C 3 -C 6  cycloalkyl or phenyl, wherein said alkyl, cycloalkyl and phenyl are optionally substituted by halo, CH 3 OH, NH 2 , C(O)O(C 1 -C 6  alkyl) or C(O)NH(C 1 -C 6  alkyl). 
       
     
     
         2 . A compound of  claim 1 , selected from Formula I: 
       
         
           
           
               
               
           
         
         enantiomers, diastereomers or pharmaceutically acceptable salts thereof, wherein: 
         R 1  is H; 
         R 2  is —OR 4  or —NR 3 R 4 ; 
         R 3  is H or C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, F, OR a  or NR a R b ; 
         R 4  is H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —(C 0 -C 5  alkyl)(C 1 -C 9  heterocyclyl), —(C 0 -C 5  alkyl)(C 3 -C 6  cycloalkyl), —(C 0 -C 5  alkyl)(C 1 -C 9  heteroaryl), —(C 0 -C 5  alkyl)(C 6 -C 9  aryl), wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, F, OR a  or NR a R b , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by
 oxo, —CN, —CF 3 , halo, —C(O)C 1 -C 6  alkyl, —C(O)OR a , —C(O)NR a R b , —(C 0 -C 5  alkyl)NR a R b , —(C 0 -C 5  alkyl)OR a , —O[C(R a ) 2 ] 1-3 O—C 1 -C 3  alkyl optionally substituted by oxo or F, 
 —(C 0 -C 5  alkyl)C 1 -C 9  heterocyclyl optionally substituted by halo, oxo, C 1 -C 3  alkyl or C(O)C 1 -C 3  alkyl, or 
 —(C 0 -C 5  alkyl)C 1 -C 9  heteroaryl optionally substituted by halo or C 1 -C 3  alkyl; or 
 
         R 3  and R 4  are taken together with the nitrogen to which they are attached to form a C 1 -C 5  heterocyclyl optionally substituted by oxo, F, C 1 -C 3  alkyl, —C(O)C 1 -C 6  alkyl or —C(O)OR a ; 
         Z is —OR 6  or —NR 5 R 6 ; 
         R 5  is H or C 1 -C 3  alkyl; 
         R 6  is H, C 1 -C 10 alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, —(C 0 -C 5  alkyl)(C 1 -C 9  heterocyclyl), —(C 0 -C 5  alkyl)(C 3 -C 8  cycloalkyl), —(C 0 -C 5  alkyl)(C 1 -C 9  heteroaryl), —(C 0 -C 5  alkyl)(C 6 -C 9  aryl), wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, F, OR a  or NR a R b , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by
 oxo, —CN, —CF 3 , halo, —O[C(R a ) 2 ] 1-3 O—, —C(O)C 1 -C 6  alkyl, —C(O)OR a , —C(O)NR a R b , —(C 0 -C 5  alkyl)NR a R b , —(C 0 -C 5  alkyl)OR a , 
 C 1 -C 6  alkyl optionally substituted by oxo or F, 
 —(C 0 -C 5  alkyl)C 1 -C 9  heterocyclyl optionally substituted by halo, oxo, C 1 -C 3  alkyl or C(O)C 1 -C 3  alkyl, 
 —(C 0 -C 5  alkyl)C 1 -C 9  heteroaryl optionally substituted by halo or C 1 -C 3  alkyl, 
 —(C 0 -C 5  alkyl)phenyl optionally substituted by C 1 -C 3  alkyl, —CF 3 , halo, —CN, —OR a  or —NR a R b , or 
 —(C 0 -C 5  alkyl)C 3 -C 6  cycloalkyl optionally substituted by oxo, —NR c R d , C 1 -C 3  alkyl or F; 
 
         R a  and R b  are independently H, —CF 3 , —CHF 2 , —CH 2 F, C 1 -C 6  alkyl, C 6  aryl, C 3 -C 6  cycloalkyl or C 4 -C 5  heterocyclyl; wherein said alkyl, aryl and cycloalkyl are optionally substituted by C 1 -C 4  alkyl, —(C 0 -C 3  alkyl)OR c , oxo, halo, NR c R d  or C 4 -C 5  heterocyclyl; or 
         R a  and R b  together with the atom to which they are attached form a C 1 -C 5  heterocyclyl optionally substituted by oxo, F, C 1 -C 3  alkyl, —C(O)C 1 -C 6  alkyl or —C(O)OR a ; and 
         R c  and R d  are independently H, C 1 -C 3  alkyl, C 3 -C 6  cycloalkyl or phenyl, wherein said alkyl, cycloalkyl and phenyl are optionally substituted by halo, CH 3 OH, NH 2 , C(O)O(C 1 -C 6  alkyl) or C(O)NH(C 1 -C 6  alkyl). 
       
     
     
         3 . The compound of  claim 1 , wherein R 2  is —NHR 4 . 
     
     
         4 . The compound of  claim 3 , wherein R 2  is —NH 2 . 
     
     
         5 . The compound of  claim 3 , wherein R 4  is C 1 -C 6  alkyl, —(C 0 -C 5  alkyl)(C 1 -C 9  heterocyclyl), —(C 0 -C 5  alkyl)(C 3 -C 6  cycloalkyl), —(C 0 -C 5  alkyl)(C 1 -C 9  heteroaryl), —(C 0 -C 5  alkyl)(C 6 -C 10  aryl), wherein said alkyl is optionally substituted by R 8 , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by R 9 . 
     
     
         6 . The compound of  claim 1 , wherein R 3  and R 4  are taken together with the nitrogen to which they are attached to form a C 1 -C 9  heterocyclyl optionally substituted by R 13 . 
     
     
         7 . The compound of  claim 1 , wherein R 2  is —NHS(O) 2 R 4 . 
     
     
         8 . The compound of  claim 7 , wherein R 4  is —(C 6 -C 10  aryl) optionally substituted by R 9 . 
     
     
         9 . The compound of  claim 1 , wherein Z is —NHR 6 . 
     
     
         10 . The compound of  claim 1 , wherein R 6  is C 1 -C 10  alkyl, —(C 0 -C 5  alkyl)(C 1 -C 9  heterocyclyl), —(C 0 -C 5  alkyl)(C 3 -C 8  cycloalkyl), —(C 0 -C 5  alkyl)(C 1 -C 9  heteroaryl), —(C 0 -C 5  alkyl)(C 6 -C 9  aryl), wherein said alkyl is optionally substituted by R 10 , and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by R 11 . 
     
     
         11 . The compound of  claim 1 , wherein R 7  is H; R 2  is —NR 3 S(O) 2 R 4 ; R 3  is H; and R 4  is phenyl optionally substituted by 1-3 substituents selected from C 1 -C 3  alkyl, —CF 3  and halo; Z is —NR 5 R 6 ; R 5  is H; and R 6  is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and wherein R 6  is optionally substituted by 1 to 3 substituents selected from oxo, halo and C 1 -C 6  alkyl. 
     
     
         12 . The compound of  claim 1 , wherein R 7  is H; R 2  is —NR 3 R 4 ; R 3  is H; R 5  is H; R 6  is pyrazolyl substituted by phenyl and further optionally substituted by methyl, and wherein said phenyl is optionally substituted by one or two substituents selected from methyl, halo, methoxy, cyano, trifluoromethyl, hydroxy and trifluoromethoxy. 
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier, adjuvant or vehicle. 
     
     
         14 . A method of treating or lessening the severity of a disease or condition responsive to the inhibition of a JAK kinase activity in a patient, comprising administering to said patient a therapeutically effective amount of a compound of  claim 1 . 
     
     
         15 . The method of  claim 14 , wherein said disease is and immunological disorder. 
     
     
         16 . The method of  claim 15 , wherein said disease is asthma, rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions, lupus or multiple sclerosis. 
     
     
         17 . A method of manufacturing a compound of  claim 1 , comprising contacting a compound of formula i: 
       
         
           
           
               
               
           
         
       
       wherein R is independently halogen, with a compound of formula NHR 3 R 4 , under conditions sufficient to form the compound of  claim 1 . 
     
     
         18 . The method of  claim 15 , wherein R is Cl. 
     
     
         19 . The compound of  claim 1 , wherein R 4  is phenyl, —(CH 2 )phenyl, —(CH 2 CH 2 )phenyl, —CH(CH 3 )phenyl, —CH(CH 2 CH 3 )phenyl, —(R)—CH(CH 3 )phenyl, —(S)—CH(CH 3 )phenyl, —(R)—CH(CH 2 CH 3 )phenyl, —(S)—CH(CH 2 CH 3 )phenyl or —C(CH 3 ) 2 phenyl, wherein said phenyl is optionally substituted by R 9 . 
     
     
         20 . The compound of  claim 1 , wherein R 9  is independently selected from methyl, ethyl, i-propyl, cyclopropyl, F, Cl, —OCH 2 O—, —OCH 2 CH 2 O—, —OCH 2 CH 2 CH 2 O—, —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 NMe 2 , —O(CH 2 ) 1-3 (C 4 -C 5  heterocyclyl), C 3 -C 5  heteroaryl, —(CH 2 ) 0-3 C 3 -C 5  heterocyclyl optionally substituted by C 1 -C 3  alkyl or halo, —OH, —OCH 3 , —OCH 2 CH 3 , —SH, —SCH 3 , —SCH 2 CH 3 , —N(CH 3 ) 2 —N(CH 2 CH 3 ) 2 , —CN, —CF 3 , —OCF 3 , —OCHF 2  and C(O)O(C 1 -C 3  alkyl). 
     
     
         21 . The compound of  claim 1 , wherein R 4  is selected from: H, methyl, ethyl, i-propyl, —CH 2 CH 2 OH, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein the wavy lines represent the point of attachment of R 4 . 
     
     
         22 . The compound of  claim 9 , wherein R 6  is
 —(C 0 -C 1  alkyl)(C 6 -C 8  cycloalkyl) optionally substituted by oxo, —CN, —CF 3 , halo, —C(O)C 1 -C 6  alkyl, —C(O)OR a , —C(O)NR a R b , —(C 0 -C 5  alkyl)NR a R b , —(C 0 -C 5  alkyl)OR a  or C 1 -C 6  alkyl optionally substituted by oxo or F,   —(C 0 -C 2  alkyl)C 4 -C 5  heterocyclyl optionally substituted by halo, oxo, C 1 -C 3  alkyl or C(O)C 1 -C 3  alkyl,   —(C 0 -C 2  alkyl)C 3 -C 5  heteroaryl optionally substituted by halo, C 1 -C 3  alkyl or phenyl, wherein said phenyl is optionally substituted by C 1 -C 3  alkyl, —CF 3 , halo, —CN, —OR a  or —NR a R b ,   —(C 0 -C 2  alkyl)phenyl optionally substituted by halo, —CN, —OR a  or —NR a R b , or   —(C 0 -C 2  alkyl)C 6 -C 7  cycloalkyl optionally substituted by oxo, C 1 -C 3  alkyl or F.