Triazolopyridine compounds, compositions and methods of use thereof

Abstract

Compounds of Formula 0, Formula I and Formula II and methods of use as Janus kinase inhibitors are described herein.

1 . A compound of Formula 0: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Ar 1  is phenylene or 3-11 membered heteroarylene, wherein Ar 1  is optionally substituted; 
 X is —O— or —N(R 1b )—(CR x1 RY 1y ) p —, wherein R x1  and R y1  are each independently hydrogen or C 1 -C 6  alkyl and p is 0 to 6, and wherein the —N(R 1b )— portion of —N(R 1b )—(CR x1 R y1 ) p — is bound to the carbonyl carbon of Formula 0; 
 R 1a  is hydrogen, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, or 3-11 membered heterocyclyl and R 1a  is optionally substituted by R 9 ; 
 R 1b  is hydrogen, C 1 -C 6  alkyl, or C 3 -C 8  cycloalkyl, and wherein one or more alkylene units of said alkyl group is optionally substituted by —O— and wherein any alkyl or cycloalkyl group is optionally substituted by OH, or
 when p is 0 and X is —N(R 1b )—, R 1a  and R 1b  may be joined together with the nitrogen atom to which R 1a  and R 1b  is attached to form a 3-11 membered heterocyclyl optionally substituted by R 9 ; 
 
 R 2  is a 3-11 membered heterocyclyl containing at least 1 nitrogen, selected from groups (a)-(e) and (h)-(j), or a C 5 -C 8  cycloalkenyl ring (f), or a —O—(CR x R y ) q —Ar 2  group (g) where R x  and R y  are independently hydrogen or C 1 -C 6  alkyl, q is 0 to 3 and Ar 2  is optionally substituted C 6 -C 10  aryl or optionally substituted 5-11 membered heteroaryl: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 3 , R 4  and R 5  are each independently selected from the group consisting of hydrogen, CH 3 , CH 2 CH 3 , OCH 3 , CF 3 , F and Cl; 
         R 6  and R 7  are independently selected from the group consisting of hydrogen, halogen, OH, CN, phenyl, C 1 -C 6  alkyl, (C 0 -C 6  alkylene)C 3 -C 8  cycloalkyl, (C 0 -C 6  alkylene) 3-11 membered heterocyclyl, (C 0 -C 6  alkylene)C(O)NR a R b , (C 0 -C 6  alkylene)NR a C(O)(C 1 -C 6  alkyl), (C 0 -C 6  alkylene)NR a C(O)(phenyl), (C 0 -C 6  alkylene)C(O)R 8a , (C 0 -C 6  alkylene)C(O)OR 8a , C 1 -C 6  alkoxy, —O—(C 3 -C 6  cycloalkyl), —O—(C 0 -C 6  alkylene)C(O)NR a R b , —C═N—O—(C 1 -C 6  alkyl), —O—(C 1 -C 6  alkyl) 3- membered heterocyclyl, (C 0 -C 6  alkylene)NR a SO 2 (C 1 -C 6  alkyl), (C 0 -C 6  alkylene)NR a SO 2 (phenyl), and —O— (3-11 membered heterocyclyl); wherein said alkyl, alkylene, alkoxy, cycloalkyl, phenyl and heterocyclyl are each independently optionally substituted, 
         or R 6  and R 7  together form an optionally substituted phenyl or optionally substituted 3-11 membered heterocyclyl; 
         R 8  is H, C 1 -C 6  alkyl, (C 0 -C 6  alkylene)phenyl, (C 0 -C 6  alkylene) C 3 -C 8  cycloalkyl, (C 0 -C 6  alkylene) 3-11 membered heterocyclyl, C(O)NR a R b , SO 2 NR a R b , (C 1 -C 6  alkylene)C(O)OR 8a  or C(O)R 8a , wherein said alkyl, alkylene, heterocyclyl and phenyl are each independently optionally substituted; 
         R 8a  is H, NR a R b , C 1 -C 6  alkyl, (C 0 -C 6  alkylene)C 3 -C 8  cycloalkyl, (C 0 -C 6  alkylene)phenyl, or (C 0 -C 6  alkylene) 3-11 membered heterocyclyl, wherein said alkyl, alkylene, cycloalkyl, phenyl and heterocyclyl are each independently optionally substituted; 
         R 8aa  is H, C 1 -C 6  alkyl optionally substituted by OH, or C(O)NR a R b ; or 
         or R 8  and R 8aa  together form an optionally substituted 3-11 membered heterocyclyl; 
         R 9 , independently at each occurrence, is OH, halogen, C 1 -C 6  alkyl, (C 0 -C 6  alkylene) C 3 -C 8  cycloalkyl, (C 0 -C 6  alkylene)phenyl, (C 0 -C 6  alkylene) 3-11 membered heterocyclyl, (C 0 -C 6  alkylene) C(O)NR a R b , (C 0 -C 6  alkylene) NR a R b , or C(O)(C 1 -C 6  alkyl), wherein said alkyl, alkylene, cycloalkyl, phenyl and heterocyclyl are each independently optionally substituted; 
         R a  and R b , independently at each occurrence, are selected from the group consisting of hydrogen, C 1 -C 6  alkyl optionally substituted by halogen or CN, (C 0 -C 6  alkylene) C 3 -C 8  cycloalkyl, or (C 0 -C 6  alkylene)phenyl, and wherein one or more alkylene units of any alkyl group is independently optionally substituted by —O—, or alternatively R a  and R b  may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3-11 membered heterocyclyl; 
         m 1 , m 2 , m 3  and m 4  are each independently 0, 1 or 2; and 
         n is 0 or 1. 
       
     
     
         2 . The compound of  claim 1 , further defined as a compound of Formula Ia: 
       
         
           
           
               
               
           
         
       
       wherein Ar 1 , X, R 1a , R 3 -R 7 , m 1 , m 2  and n are as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m 1  is 1 and m 2  is 1, or m 1  is 2 and m 2  is 1. 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 R 6  and R 7  are attached to the ring at the same carbon atom; or   R 6  is C 1 -C 6  alkyl or C 1 -C 6 -alkoxy, and R 7  is optionally substituted phenyl; or   R 6  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl or optionally substituted phenyl and R 7  is OH, (C 0 -C 6  alkylene) C(O)NR a R b , (C 0 -C 6  alkylene) CN or —O— (C 0 -C 6  alkyl)CN; or   R 6  is hydrogen and R 7  is selected from (C 0 -C 6  alkylene) C(O)NR a R b , (C 0 -C 6  alkylene) CN, C 1 -C 6 -alkoxy, —O—(C 3 -C 6  cycloalkyl), —O—(C 0 -C 6  alkylene)C(O)NR a R b , and —O—(C 1 -C 6  alkylene)CN; or   R 6  and R 7  together form a 3-11 membered heterocycloalkyl optionally substituted by oxo.   
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
       
       is selected from 
       
         
           
           
               
               
           
         
       
       wherein R 7a  is selected from hydrogen, halogen, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl and —CN. 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein one or both of R 6  and R 7  is located at the para position of the ring. 
     
     
         7 . The compound of  claim 1 , further defined as a compound of Formula Ib: 
       
         
           
           
               
               
           
         
       
       wherein Ar 1 , X, R 1a , R 3 -R 7 , m 1 , m 2  and n are as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m 1  is 1 and m 2  is 2, or m 1  is 2 and m 2  is 1, or m 1  is 1 and m 2  is 1. 
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6  is H and R 7  and is substituted phenyl. 
     
     
         10 . The compound of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
       
       is selected from 
       
         
           
           
               
               
           
         
       
       wherein R 7a  is selected from hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl and CN. 
     
     
         11 . The compound of  claim 1 , further defined as a compound of Formula Ic: 
       
         
           
           
               
               
           
         
       
       wherein Ar 1 , X, R 1a , R 3 -R 5 , R 8 , m 3 , m 4  and n are as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The compound of  claim 11 , or a pharmaceutically acceptable salt thereof, wherein m 3  is 1 and m 4  is 1, or m 3  is 1 and m 4  is 2, or m 3  is 1 and m 4  is 0. 
     
     
         13 . The compound as in  claim 11 , or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
       
       is selected from 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , further defined as a compound of Formula Id: 
       
         
           
           
               
               
           
         
       
       wherein Ar 1 , R 1a , R 1b , R 3 -R 5 , R 8 , m 3 , m 4  and n are as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound of  claim 14 , or a pharmaceutically acceptable salt thereof, wherein m 3  is 1 and m 4  is 1, m 3  is 1 and m 4  is 1, or m 3  is 1 and m 4  is 2. 
     
     
         16 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8  is substituted phenyl, C(O)NR a R b  or C(O)R 8a . 
     
     
         17 . The compound of  claim 1 , further defined as a compound of Formula Ie: 
       
         
           
           
               
               
           
         
       
       wherein Ar 1 , R 1a , R 1b , R 3 -R 6 , R 8 , m 3 , m 4  and n are as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound of  claim 17 , or a pharmaceutically acceptable salt thereof, wherein m 3  is 0 and m 4  is 1 or m 3  is 1 and m 4  is 1. 
     
     
         19 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8  is C(O)NR a R b . 
     
     
         20 . The compound of  claim 1 , further defined as a compound Formula If: 
       
         
           
           
               
               
           
         
       
       wherein Ar 1 , R 1a , R 1b , R 3 -R 7 , m 3 , m 4  and n are as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The compound of  claim 20 , or a pharmaceutically acceptable salt thereof, wherein m 3  is 1 and m 4  is 1. 
     
     
         22 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7  is OH or C 1 -C 6 -alkoxy. 
     
     
         23 . The compound of  claim 1 , further defined as a compound of Formula Ig: 
       
         
           
           
               
               
           
         
       
       wherein Ar 1 , R 1a , R 1b , R 3 -R 5 , R 7a  and n are as defined in  claim 1 , R 7a  is selected from hydrogen, OH, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, (C 1 -C 6  alkyl)phenyl, C 1 -C 6  haloalkyl, oxo and CN, and q is either 0 or 1, and when q is 1, then R x  and R y  are hydrogen or a pharmaceutically acceptable salt thereof. 
     
     
         24 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4  and R 5  are each hydrogen. 
     
     
         25 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 1  is phenylene or pyrazolylene. 
     
     
         26 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the moiety 
       
         
           
           
               
               
           
         
       
       is further defined as 
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein —X—R 1a  is —N(R 1b )—(CR x1 R y1 ) p —R 1a . 
     
     
         28 . The compound of  claim 27 , or a pharmaceutically acceptable salt thereof, wherein:
 (1) R 1b  is C 1 -C 6  alkyl optionally substituted by C 1 -C 6  alkoxy, p is 0-3, R x1  and R y1  are each independently hydrogen or C 1 -C 6  alkyl, R 1a  is C 1 -C 6  alkyl and R 9  is NR a R b ; or   (2) R 1b  is C 1 -C 6  alkyl optionally substituted by C 1 -C 6  alkoxy, p is 0-3, R x1  and R y1  are each independently hydrogen or C 1 -C 6  alkyl, and R 1a  is 3-11 membered heterocyclyl optionally substituted by R 9 ; or   (3) p is 0 and R 1a  and R 1b  are joined to form a 3-11 membered heterocyclyl optionally substituted by R 9 .   
     
     
         29 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9  is optionally substituted C 1 -C 6  alkyl or optionally substituted 3-11 membered heterocyclyl. 
     
     
         30 . The compound of  claim 27 , or a pharmaceutically acceptable salt thereof, wherein the optional substituents of said optionally substituted C 1 -C 6  alkyl of R 9  or optionally substituted 3-11 membered heterocyclyl of R 9  are selected from OH; halogen; CN; NR a R b ; C 1 -C 6  alkyl optionally substituted by halogen; C 3 -C 8  cycloalkyl; C 1 -C 6  alkoxy; phenyl; 3-11 membered heterocyclyl optionally substituted by C 1 -C 6  alkyl or NR a R b ; C(O)C 1 -C 6  alkyl; and C(O)— 3-11 membered heterocyclyl optionally substituted by C 1 -C 6  alkyl. 
     
     
         31 . The compound of  claim 27 , or a pharmaceutically acceptable salt thereof, wherein —N(R 1b )—(CR x1 R y1 ) p —R 1a  is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 27 , or a pharmaceutically acceptable salt thereof, wherein R 1b  is hydrogen or CH 3 . 
     
     
         33 . The compound of  claim 27 , or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3. 
     
     
         34 . A compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Q 1  is a 3-11 membered heterocyclyl containing at least 1 nitrogen, selected from groups (a)-(e) and (h)-(j), or a C 5 -C 8  cycloalkenyl ring (f), or a —O—(CR x R y ) q —Ar 2  group (g) where R x  and R y  are independently hydrogen or C 1 -C 6  alkyl, q is 0 to 3 and Ar 2  is optionally substituted C 6 -C 10  aryl or optionally substituted 3-11 membered heteroaryl: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 6  and R 7  are independently selected from the group consisting of hydrogen, halogen, OH, CN, phenyl, C 1 -C 6  alkyl, (C 0 -C 6  alkylene) C 3 -C 8  cycloalkyl, (C 0 -C 6  alkylene) 3-11 membered heterocyclyl, (C 0 -C 6  alkylene) C(O)NR a R b , (C 0 -C 6  alkylene) NR a C(O)(C 1 -C 6  alkyl), (C 0 -C 6  alkylene)C(O)R 8a , (C 0 -C 6  alkylene) C(O)OR 8a , C 1 -C 6  alkoxy, —O—(C 3 -C 6  cycloalkyl), —O—(C 0 -C 6  alkylene)C(O)NR a R b , and —O— (3-11 membered heterocyclyl); wherein said alkyl, alkylene, alkoxy, cycloalkyl, phenyl and heterocyclyl are each independently optionally substituted, 
         or R 6  and R 7  together form an optionally substituted phenyl or optionally substituted 3-11 membered heterocyclyl; 
         R 8  is C 1 -C 6  alkyl, (C 0 -C 6  alkylene)phenyl, C(O)NR a R b , SO 2 NR a R b , C(O)OR 8a  or C(O)R 8a , wherein said alkyl, alkylene and phenyl are each independently optionally substituted; 
         R 8a  is C 1 -C 6  alkyl, (C 0 -C 6  alkylene)C 3 -C 8  cycloalkyl, (C 0 -C 6  alkylene)phenyl, or (C 0 -C 6  alkylene) 3-11 membered heterocyclyl, wherein said alkyl, alkylene, cycloalkyl, phenyl and heterocyclyl are each independently optionally substituted; 
         R 8aa  is H; or 
         or R 8  and R 8aa  together form an optionally substituted 3-11 membered heterocyclyl; 
         R 9 , independently at each occurrence, is OH, halogen, C 1 -C 6  alkyl, (C 0 -C 6  alkylene)C 3 -C 8  cycloalkyl, (C 0 -C 6  alkylene)phenyl, (C 0 -C 6  alkylene) 3-11 membered heterocyclyl, (C 0 -C 6  alkylene)C(O)NR a R b , (C 0 -C 6  alkylene)NR a R b , or C(O)(C 1 -C 6  alkyl), wherein said alkyl, cycloalkyl, phenyl and heterocyclyl are each independently optionally substituted; 
         R a  and R b  are independently at each occurrence hydrogen, C 1 -C 6  alkyl, (C 0 -C 6  alkylene) C 3 -C 8  cycloalkyl, or (C 0  -C 6  alkylene)phenyl, and wherein one or more alkylene units of any alkyl group is independently optionally substituted by —O—, or alternatively R a  and R b  may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3-11 membered heterocyclyl; 
         m 1 , m 2 , m 3  and m 4  are each independently 0, 1 or 2; and 
         Q 2  is C 3 -C 8  cycloalkyl optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  heteroalkyl, F, Cl, Br, I, OH, SH, NH 2 , CN or N 3 . 
       
     
     
         35 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         36 . 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.