5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds,compositions and methods of use thereof

Abstract

Compounds of Formula (00A) and methods of use as Janus kinase inhibitors are described herein.

What is claimed is: 
     
         1 . A compound of Formula (00A): 
       
         
           
           
               
               
           
         
         and stereoisomers and salts thereof, wherein: R 00  is H or CH 3 ; R 01  is H or NH 2 ; R 0  is H or NH 2 ; and Ring Q is either (i) or (ii): 
       
       
         
           
           
               
               
           
         
         wherein: t 1  and t 2  are each independently 0 or 1; X A  and X B  are independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 4  alkenyl, —NR a R b , C 2 -C 5  alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10 membered heteroaryl; wherein when either of X A  and X B  are independently C 1 -C 6  alkyl, C 2 -C 4  alkenyl, C 2 -C 5  alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10 membered heteroaryl, each of X A  and X B  is independently optionally substituted by Y 1 , wherein Y 1  is selected from:
 (a) C 1 -C 6  alkyl optionally substituted by T 1 , wherein T 1  is selected from the group consisting of OH, halo, CN, imino, 3-6 membered cycloalkyl, 3-11 membered heterocycloalkyl, 3-11 membered heterocycloalkenyl, 5-10 membered heteroaryl, —O—(C 1 -C 6  alkyl), C(O)OH, oxetan-3-ylmethyl, —C(O)O—(C 1 -C 6  alkyl), —S—(C 1 -C 6  alkyl), —SO 2 —(C 1 -C 6  alkyl), —NR a R b , —N(+)R a R b R c  wherein R c  is methyl, —C(O)NR a R b , −(2-oxoindolin-1-yl), —OC(O)-3-6 membered cycloalkyl, and phenyl, wherein each alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, and phenyl of T 1  is optionally substituted by OH, —C(O)O—(C 1 -C 6  alkyl), C 1 -C 6  alkyl, halo, CN, oxo, —(C 1 -C 6  alkyl)CONR a R b , —NR a R b , phenyl, or —O—(C 1 -C 6  alkyl) optionally substituted by OH; 
 (b) 3-11 membered heterocycloalkyl, —(C 1 -C 6  alkylene)-3-11 membered heterocycloalkyl, —C(O)-3-11 membered heterocycloalkyl, —(C 1 -C 6  alkylene)C(O)-3-11 membered heterocycloalkyl, or —OC(O)-4-6 membered heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted by OH, halo, CN, C 1 -C 6  alkyl, —(C 1 -C 6  alkylene)-CF 3 , oxo, —C(O)—(C 1 -C 6  alkyl), —C(O)O—(C 1 -C 6  alkyl), —C(O)O—(C 1 -C 6  alkylene)-phenyl, —SO 2 —(C 1 -C 6  alkyl), —C(O)NR a R b , —NR a R b , —(C 1 -C 6  alkylene)-phenyl, or —C(O)-4-6 membered heterocycloalkyl optionally substituted by —NR a R b ; 
 (c) N(+)(AA) 3 , wherein each AA is independently C 1 -C 6  alkyl optionally substituted by phenyl; 
 (d) 3-6 membered cycloalkyl optionally substituted by OH, halo, NR a R b , or CN; 
 (e) CN, halo, or oxo; 
 (f) —C(O)—(C 1 -C 6  alkyl), —C(O)OH, —C(O)O—(C 1 -C 6  alkylene)-phenyl, —SO 2 —(C 1 -C 6  alkyl), —C(O)NR a R b , or —C(O)-4-6 membered heterocycloalkyl optionally substituted by —(C 1 -C 6  alkyl) or —NR a R b , or —C(O)O—(C 1 -C 6  alkyl) optionally substituted by OH, NR a R b , or 3-11 membered heterocycloalkyl wherein said heterocycloalkyl is optionally substituted by C 1 -C 6  alkyl; 
 (g) OH, —O-phenyl, or —O—(C 1 -C 6  alkyl), wherein the alkyl is optionally substituted by OH or —NR a R b ; 
 (h) phenyl optionally substituted by OH, halo, C 1 -C 6  alkyl, CF 3 , or CN; 
 (i) 5-6 membered heteroaryl optionally substituted by OH, halo, C 1 -C 6  alkyl, CF 3 , CN, or 3-11 membered heterocycloalkyl optionally substituted by C 1 -C 6  alkyl or 3-11 membered heterocycloalkyl; 
 (j) isoindolin-2-yl optionally substituted by halo; 
 (k) —NR a R b , and 
 (l) —O—CH 2 C(O)-3-11 membered heterocycloalkyl; 
 wherein R a  and R b  are independently selected from:
 (a) H, 
 (b) C 1 -C 6  alkyl optionally substituted by OH, halo, CN, —C(O)OH, —C(O)O—(C 1 -C 6 alkyl), —C(O)O-(3-11 membered heterocycloalkyl), —C(O)O—(C 1 -C 6  alkyl)-S—(C 1 -C 6  alkyl), —S—(C 1 -C 6  alkyl), naphthylenyl, —NR az R bz , —C(O)NR az R bz , oxo, —O—(C 1 -C 6  alkyl), 5-6 membered heteroaryl optionally substituted by C 1 -C 6  alkyl or halo, or benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl optionally substituted by oxo; 
 (c) —(C 1 -C 6  alkylene)-3-6 membered cycloalkyl wherein the alkylene is optionally substituted by OH, halo, or CN; 
 (d) —(C 1 -C 6  alkylene)-phenyl wherein alkylene is optionally substituted by halo and the phenyl is optionally substituted by OH, halo, CF 3 , C 1 -C 6  alkyl, —O—(C 1 -C 6  alkyl), —S—(C 1 -C 6  alkyl, or —O-phenyl; 
 (e) —(C 1 -C 6  alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by halo, oxo, or C 1 -C 6  alkyl; 
 (f) —(C 1 -C 6  alkylene)-O-phenyl wherein the phenyl is optionally substituted by halo, C 1 -C 6  alkyl, or —O-phenyl; 
 (g) —(C 1 -C 6  alkyl)3-6 membered cycloalkyl optionally substituted by OH, halo, CN, or C 1 -C 6  alkyl optionally substituted by OH or CN; 
 (h) C 2 -C 5  alkenyl; 
 (i) 4-6 membered heterocycloalkyl optionally substituted by halo, 
 (j) —(C 1 -C 6  alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl, 
 (k) phenyl, 
 (l) —C(O)(C 1 -C 6  alkyl), 
 (m) —C(O)O(C 1 -C 6  alkyl), 
 (n) —C(O)O(3-6 membered cycloalkyl), and 
 (o) —C(O)-phenyl, 
 
 
         wherein R az  and R bz  are each independently selected from
 (a) H, 
 (b) C 1 -C 6  alkyl optionally substituted by OH, halo, CN, —C(O)OH, —C(O)O—(C 1 -C 6 alkyl), —C(O)O-(3-11 membered heterocycloalkyl), —C(O)O—(C 1 -C 6  alkyl)-S—(C 1 -C 6  alkyl), —S—(C 1 -C 6  alkyl), naphthylenyl, -oxo, —O—(C 1 -C 6  alkyl), 5-6 membered heteroaryl optionally substituted by C 1 -C 6  alkyl or halo, or benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl optionally substituted by oxo; 
 (c) —(C 1 -C 6  alkylene)-3-6 membered cycloalkyl wherein the alkylene is optionally substituted by OH, halo, or CN; 
 (d) —(C 1 -C 6  alkylene)-phenyl wherein alkylene is optionally substituted by halo and the phenyl is optionally substituted by OH, halo, CF 3 , C 1 -C 6  alkyl, —O—(C 1 -C 6  alkyl), —S—(C 1 -C 6  alkyl, or —O-phenyl; 
 (e) —(C 1 -C 6  alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by halo, oxo, or C 1 -C 6  alkyl; 
 (f) —(C 1 -C 6  alkylene)-O-phenyl wherein the phenyl is optionally substituted by halo, C 1 -C 6  alkyl, or —O-phenyl; 
 (g) —(C 1 -C 6  alkyl)3-6 membered cycloalkyl optionally substituted by OH, halo, CN, or C 1 -C 6  alkyl optionally substituted by OH or CN; 
 (h) C 2 -C 5  alkenyl; 
 (i) 4-6 membered heterocycloalkyl optionally substituted by halo, 
 (j) —(C 1 -C 6  alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl, 
 (k) phenyl, 
 (l) —C(O)(C 1 -C 6  alkyl), 
 (m) —C(O)O(C 1 -C 6  alkyl), 
 (n) —C(O)O(3-6 membered cycloalkyl), and 
 (o) —C(O)-phenyl, 
 
         with the following provisos: when R 0 , R 00 , and R 01  are each H and Ring Q is 
       
       
         
           
           
               
               
           
         
       
       where t 1  is 0, then X A  is not methyl, 2-methylpropan-2-ol, or tetrahydropyranyl. 
     
     
         2 . The compound of  claim 1 , further defined as a compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein:
 w is 0 or 1; 
 R 0b  is H or NH 2 ; 
 R 1b  is selected from the group consisting of
 a. H, 
 b. C 1 -C 6  alkyl optionally substituted by OH, halo, CN, —O—(C 1 -C 6  alkyl), naphthylenyl, 5-6 membered heteroaryl, or —C(O)NR v R w , wherein R v  and R w  are independently H or C 1 -C 6  alkyl optionally substituted by halo, 
 c. —(C 1 -C 6  alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl is optionally substituted by CN, 
 d. —(C 1 -C 6  alkylene)-phenyl wherein the alkyl is optionally substituted by halo and wherein the phenyl is optionally substituted by OH, halo, CF 3 , C 1 -C 6  alkyl, —O—(C 1 -C 6  alkyl) or —O-phenyl, 
 e. —(C 1 -C 6  alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by halo or C 1 -C 6  alkyl, 
 f. —(C 1 -C 6  alkylene)-O-phenyl wherein the phenyl is optionally substituted by halo or C 1 -C 6  alkyl, or 
 g. 3-6 membered cycloalkyl; 
 
 R 2b  is selected from the group consisting of H, C 1 -C 6  alkyl optionally substituted by halo, or C 2 -C 5  alkenyl; 
 or R 1b  and R 2b  together form a 3-11 membered heterocycloalkyl optionally substituted by OH; 
 R 3b  is absent or methyl, wherein when R 3b  is methyl, the nitrogen to which it is attached is N+ and w is 1; 
 R 4b  is a bond or C 1 -C 6  alkylene; 
 R 5b  is selected from the group consisting of H, OH, and phenyl; and 
 Ring F is a 3-7 membered heterocycloalkyl wherein p 1b  is 0, 1 or 2 and p 2b  is 0, 1 or 2; 
 wherein w is equal to 1 only when R 3b  is methyl. 
 
       
     
     
         3 . The compound of  claim 1 , further defined as a compound of Formula (Ia) or Formula (Ib): 
       
         
           
           
               
               
           
         
         wherein:
 R 0a  is H or NH2; 
 R 1a  is bound to a nitrogen atom of Ring A in (Ia) or is bound to a carbon atom of Ring B in (Ib), and is selected from the group consisting of:
 a. H, 
 b. C 1 -C 6  alkyl optionally substituted by OH, halo, —O—(C 1 -C 6  alkyl), —SO 2 —(C 1 -C 6  alkyl), −(2-oxoindolin-1-yl), —OC(O)-3-6 membered cycloalkyl, —OC(O)-4-6 membered heterocycloalkyl, or phenyl; 
 c. —(C 1 -C 6  alkylene)-O—(C 1 -C 6  alkylene)-phenyl wherein the phenyl is optionally substituted by halo; 
 d. —(C 1 -C 6  alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl is optionally substituted by halo, OH, or CN; 
 e. —(C 1 -C 6  alkylene)-4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by oxo, C 1 -C 6  alkyl, —C(O)—(C 1 -C 6  alkyl), —C(O)O—(C 1 -C 6  alkyl), —SO 2 —(C 1 -C 6  alkyl), —C(O)-4-6 membered heterocycloalkyl, or —C(O)N(C 1 -C 6  alkyl)(C 1 -C 6  alkyl); 
 f. —C(O)O—(C 1 -C 6  alkylene)-OH; and 
 g. —C(O)O—(C 1 -C 6  alkylene)-phenyl; 
 h. —NR a R b , wherein R a  and R b  are independently selected from the group consisting of H and C 1 -C 6  alkyl optionally substituted by OH, halo, CN, phenyl, and 3-7 membered heterocycloalkyl; 
 
 R 2a  is selected from the group consisting of H, C 1 -C 6  alkyl optionally substituted by OH, and phenyl; 
 R 3a  is selected from the group consisting of H, C 1 -C 6  alkyl optionally substituted by OH, and phenyl; 
 Ring A is a 3-7 membered heterocycloalkyl; and 
 Ring B is a 3-7 membered heterocycloalkyl or a 3-7 membered heterocyclyalkenyl, wherein p 1a  is 0, 1 or 2 and p 2a  is 0, 1 or 2, 
 provided that Ring A and Ring B together form a 6-11 membered bicyclic heterocycloalkyl. 
 
       
     
     
         4 . The compound of  claim 1 , further defined as a compound of Formula (III): 
       
         
           
           
               
               
           
         
         wherein:
 R 0C  is H or NH 2 ; 
 R 3  is (i) or (ii): 
 
       
       
         
           
           
               
               
           
         
         wherein:
 R 1c  is selected from the group consisting of H, C 1 -C 6  alkyl, —(C 1 -C 6  alkyl)-phenyl, —C(O)—(C 1 -C 6  alkyl), —C(O)-phenyl, and 4-6 membered heterocycloalkyl; 
 R 2c  is H or C 1 -C 6  alkyl; and 
 R 3c  is a bond or C 1 -C 6  alkylene optionally substituted by oxo; or 
 R 1c  and R 2c  together form a 3-11 membered heterocycloalkyl optionally substituted by C 1 -C 6  alkyl, oxo, or —(C 1 -C 6  alkylene)-phenyl; or 
 R 1c  and R 3c  together form a 3-7 membered heterocycloalkyl; 
 
         (ii) H; C 1 -C 6  alkyl optionally substituted by OH, —SO 2 —(C 1 -C 6  alkyl), phenyl, or —O—(C 1 -C 6  alkylene)-phenyl; —(C 1 -C 6  alkylene)-C(O)O(C 1 -C 6  alkyl); or 4-6 membered heterocycloalkyl optionally substituted by —C(O)(C 1 -C 6  alkyl); and 
         Ring G is a 3-7 membered heterocycloalkyl wherein p 1 C is 0, 1 or 2 and p 2 C is 0, 1 or 2. 
       
     
     
         5 . The compound of  claim 1 , further defined as a compound of Formula (IV): 
       
         
           
           
               
               
           
         
         wherein:
 R 0d  is H or NH 2 ; 
 R 1d  is 3-11 membered heterocycloalkyl or —C(O)-3-11 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted C 1 -C 6  alkyl, CF 3 , or fluoro, or R 1d  is —(C 1 -C 6  alkylene)-NR v R w , wherein R v  and R w  are independently H or C 1 -C 6  alkyl optionally substituted by halo. 
 
       
     
     
         6 . The compound of  claim 1 , further defined as a compound of Formula (V): 
       
         
           
           
               
               
           
         
         wherein:
 R 0e  is H or NH 2 ; 
 R 1e  is selected from the group consisting of
 a. H, 
 b. C 1 -C 6  alkyl optionally substituted by halo, CN, or phenyl, 
 c. —(C 1 -C 6  alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl is optionally substituted by CN, 
 d. —(C 1 -C 6  alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by C 1 -C 6  alkyl; 
 
 R 2e  is H or C 1 -C 6  alkyl; 
 or R 1e  and R 2e  together form a 3-11 membered heterocycloalkyl optionally substituted by halo or —NR v R w , wherein R v  and R w  are independently H or C 1 -C 6  alkyl optionally substituted by halo; 
 R 3e  is a bond or C 1 -C 6  alkylene optionally substituted by oxo; and 
 Ring H is a 3-7 membered heterocycloalkyl wherein p 1e  is 0, 1 or 2 and p 2e  is 0, 1 or 2. 
 
       
     
     
         7 . The compound of  claim 1 , further defined as a compound of Formula (VI): 
       
         
           
           
               
               
           
         
         wherein:
 R 0f  is H or NH 2 ; 
 R 1f  is selected from the group consisting of C 1 -C 6  alkyl optionally substituted by halo, 3-6 membered cycloalkyl, or phenyl; and 
 Ring J is a 6-7 membered heterocycloalkyl wherein p 1f  is 1 or 2 and p 2f  is 1 or 2. 
 
       
     
     
         8 . The compound of  claim 1 , further defined as a compound of Formula (VII): 
       
         
           
           
               
               
           
         
         wherein:
 R 0g  is H or NH2; 
 R 1g  is selected from the group consisting of C 1 -C 6  alkyl; 
 R 2g  is selected from the group consisting of C 1 -C 6  alkyl. 
 
       
     
     
         9 . The compound of  claim 1 , further defined as a compound of Formula (VIII): 
       
         
           
           
               
               
           
         
         wherein:
 R 0h  is H or NH 2 ; 
 R 1h  is selected from the group consisting of H and C 1 -C 6  alkyl optionally substituted by CN, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkylene-C(O)O—(C 1 -C 6  alkylene)-phenyl; 
 Ring C is 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; and 
 Ring D is a 3-7 membered heterocycloalkyl substituted at the sole nitrogen by R 1h ; and 
 provided Rings C and D together form a 3-11 membered spiro heterocycloalkyl. 
 
       
     
     
         10 . The compound of  claim 1 , further defined as a compound of Formula (IX): 
       
         
           
           
               
               
           
         
         wherein:
 R 0j  is H or NH 2 ; 
 R 3j  is selected from the group consisting of H and C 1 -C 6  alkyl optionally substituted by OH, 3-6 membered cycloalkyl, —O—(C 1 -C 6  alkyl), —O—(C 1 -C 6  alkyl)-OH, —SO 2 —(C 1 -C 6  alkyl) and phenyl, wherein the phenyl is optionally substituted by CN; 
 R 4j  is selected from the group consisting of H and C 1 -C 6  alkyl optionally substituted by OH; 
 or R 3  and R 4  together form a 4-6-membered heterocycloalkyl; 
 R 5j  is selected from the group consisting of H and C 1 -C 6  alkyl; and 
 Ring K is a 6-7 membered heterocycloalkyl wherein p 1j  is 1 or 2 and p 2j  is 1 or 2. 
 
       
     
     
         11 . The compound of  claim 1 , further defined as a compound of Formula (X): 
       
         
           
           
               
               
           
         
         wherein:
 R 0k  is H or NH 2 ; 
 R 1k  is selected from the group consisting of
 a. H, 
 b. C 1 -C 6  alkyl optionally substituted by halo, CN, or phenyl, 
 c. —(C 1 -C 6  alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl is optionally substituted by CN, 
 d. —(C 1 -C 6  alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by C 1 -C 6  alkyl; 
 
 R 2k  is selected from the group consisting of H and C 1 -C 6  alkyl; 
 or R 1k  and R 2k  together form a 3-11 membered heterocycloalkyl optionally substituted by halo; C 1 -C 6  alkyl optionally substituted by OH; or —NR v R w , wherein R v  and R w  are independently H or C 1 -C 6  alkyl optionally substituted by halo; and 
 R 3k  is a bond, methylene, or —C(═O)—. 
 
       
     
     
         12 . The compound of  claim 1 , wherein X A  and X B  are independently selected from the group consisting of 3-6-membered cycloalkyl, 6-10 membered aryl, 5-6 membered heterocycloalkenyl, and 5-10 membered heteroaryl, wherein each of X A  and X B  are independently optionally substituted by Y 1 . 
     
     
         13 . The compound of  claim 1 , wherein either X A  or X B  is a 3-11 membered heterocycloalkyl optionally substituted by Y 1 . 
     
     
         14 . The compound of  claim 1 , wherein Ring Q is (i). 
     
     
         15 . The compound of  claim 1 , wherein t 1  is 0. 
     
     
         16 . The compound of  claim 1 , wherein t 1  is 1. 
     
     
         17 . The compound of  claim 1 , wherein Ring Q is (ii). 
     
     
         18 . The compound of  claim 1 , wherein t 2  is 0. 
     
     
         19 . The compound of  claim 1 , wherein t 2  is 1. 
     
     
         20 . The compound of  claim 1 , wherein R 0 , R 00  and R 01  are each H. 
     
     
         21 . The compound of  claim 1 , wherein R 0  is NH 2 . 
     
     
         22 . The compound of  claim 1 , wherein Ring Q is (i), t 1  is 0 or 1, and R 0 , R 00  and R 01  are each H. 
     
     
         23 . The compound of  claim 1 , wherein Ring Q is (i), t 1  is 1, and X A  is NR a R b , wherein R a  and R b  are each independently H, C 1 -C 6  alkyl optionally substituted with 5-6 membered heteroaryl, or 3-6 membered cycloalkyl optionally substituted by OH, halo, CN, or C 1 -C 6  alkyl optionally substituted by OH. 
     
     
         24 . The compound of  claim 1 , wherein Ring Q is (i), t 1  is 0, and X A  is C 1 -C 6  alkyl or 3-6 membered cycloalkyl, wherein X A  is optionally substituted by —NR a R b , wherein R a  and R b  are independently H or C 1 -C 6  alkyl. 
     
     
         25 . The compound of  claim 1 , selected from Table 1. 
     
     
         26 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         27 . 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 . 
     
     
         28 . The method of  claim 27 , wherein the disease or condition is asthma. 
     
     
         29 . The method of  claim 27 , wherein the Janus kinase is JAK1.