Therapeutic compounds

Abstract

Compounds of formula (I) or salts thereof are disclosed. Also disclosed are pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for treating a Retroviridae viral infection including an infection caused by the HIV virus.

1 - 54 . (canceled) 
     
     
         55 . A process for preparing a compound of formula A11: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein,
 A is a 6-membered monocyclic-heteroaryl with one or two nitrogen atoms, wherein the 
 6-membered monocyclic-heteroaryl is substituted with one Z 1  group, one Z 2  group, and optionally substituted with one or more (e.g., 1 or 2) Z 3  groups; 
 R 1  is 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 membered heterocycle, 
 wherein any 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 membered heterocycle of R 1  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 4  groups; R 2  is phenyl, 5-membered monocyclic-heteroaryl, 6-membered monocyclic-heteroaryl or (C 3 -C 7 )carbocycle, wherein any phenyl, 5-membered monocyclic-heteroaryl, 6-membered monocyclic-heteroaryl or (C 3 -C 7 )carbocycle of R 2  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 5  groups; 
 each R 3a  and R 3b  is independently selected from H, halogen, (C 1 -C 3 )alkyl and (C 1 -C 3 )haloalkyl, or R 3a  is selected from H, (C 1 -C 3 )alkyl and (C 1 -C 3 )haloalkyl and R 3b  is selected from —OH and —CN; 
 Z 1  is selected from 6-12 membered aryl, 5-14 membered heteroaryl and 3-14 membered heterocycle, wherein any 6-12 membered aryl, 5-14 membered heteroaryl and 3-14 membered heterocycle of Z 1  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1a  or Z 1b ; 
 each Z 1a  is independently selected from (C 3 -C 7 )carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, —CN, —OR n1 , —OC(O)R p1 , —OC(O)NR q1 R r1 , —SR n1 , —S(O)R p1 , —S(O) 2 OH, —S(O) 2 R p1 , —S(O) 2 NR q1 R r1 , —NR q1 R r1 , —NR n1 COR p1 , —NR n1 CO 2 R p1 , —NR n1 CONR q1 R r1 , —NR n1 S(O) 2 R p1 , —NR n1 S(O) 2 OR p1 , —NR n1 S(O) 2 NR q1 R r1 , NO 2 , —C(O)R n1 , —C(O)OR n1 , —C(O)NR q1 R r1  and —S(O) 2 NR n1 COR p1 , wherein any (C 3 -C 7 )carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl and 3-12 membered heterocycle of Z 1a  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c  or Z 1d  groups; 
 each Z 1b  is independently selected from (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl, wherein any (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl of Z 1b  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c  groups; 
 each Z 1c  is independently selected from (C 3 -C 7 )carbocycle, phenyl, 5-6 membered monocyclic-heteroaryl, 3-7 membered heterocycle, halogen, —CN, —OR n2 , —OC(O)R p2 , —OC(O)NR q2 R r2 , —SR n2 , —S(O)R p2 , —S(O) 2 H, —S(O) 2 R p2 , —S(O) 2 NR q2 R r2 , —NR q2 R r2 , —NR n2 COR p2 , —NR n2 CO 2 R p2 , —NR n2 CONR q2 R r2 , —NR n2 S(O) 2 R p2 , —NR n2 S(O) 2 OR p2 , —NR n2 S(O 2 NR q2 R r2 , NO 2 , —C(O)R n2 , —C(O)OR n2 , —C(O)NR q2 R r2 , halophenyl, 5-6 membered haloheteroaryl, 3-7 membered haloheterocycle and (C 1 -C 8 )heteroalkyl; 
 each Z 1d  is independently selected from (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl and (C 1 -C 8 )haloalkyl; 
 each R n1  is independently selected from H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein any (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl and phenyl of R n1  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c  or Z 1d  groups, and wherein any (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl of R n1  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c  groups; 
 each R p1  is independently selected from (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein any (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl and phenyl of R p1  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c  or Z 1d  groups, and wherein any (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl of R p1  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c  groups; 
 R q1  and R r1  are each independently selected from H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein any (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl and phenyl of R q1  or R r1  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c  or Z 1d  groups, and wherein any (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl of R q1  or R r1  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c  groups, or R q1  and R r1  together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or 7-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c  or Z 1d  groups; 
 each R 2  is independently selected from H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic-haloheteroaryl, 3-7 membered haloheterocycle, (C 1 -C 8 )haloalkyl and (C 1 -C 8 )heteroalkyl; 
 each R p2  is independently selected from (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic-haloheteroaryl, 3-7 membered haloheterocycle, (C 1 -C 8 )haloalkyl and (C 1 -C 8 )heteroalkyl; 
 R q2  and R r2  are each independently selected from H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic-haloheteroaryl, 3-7 membered haloheterocycle, (C 1 -C 8 )haloalkyl and (C 1 -C 8 )heteroalkyl, or R q2  and R r2  together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle; 
 Z 2  is selected from (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, 6-12 membered aryl, 5-12 membered C-linked-heteroaryl, 3-12 membered C-linked-heterocycle, —C(O)R n3  and —C(O)NR q3 R r3 , wherein any 6-12 membered aryl, 5-12 membered C-linked-heteroaryl and 3-12 membered C-linked-heterocycle of Z 2  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2b  or Z 2c  groups, and wherein any (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl of Z 2  is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) Z 2c  groups; 
 each Z 2a  is independently selected from (C 3 -C 7 )carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, —CN, —OR n4 , —OC(O)R p4 , —OC(O)NR q4 R r4 , —SR n4 , —S(O)R p4 , —S(O) 2 OH, —S(O) 2 R p4 , —S(O) 2 NR q4 R r4 , —NR q4 R r4 , —NR n4 COR p4 , —NR n4 CO 2 R p4 , —NR n4 CONR q4 R r4 , —NR n4 S(O) 2 R p4 , —NR n4 S(O) 2 OR p4 , —NR n4 S(O) 2 NR q4 R r4 , NO 2 , —C(O)R n4 , —C(O)OR n4  and —C(O)NR q4 R r4 , wherein any (C 3 -C 7 )carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl and 3-12 membered heterocycle of Z 2a  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2b  or Z 2c  groups; 
 each Z 2b  is independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl and (C 1 -C 4 )haloalkyl; 
 each Z 2c  is independently selected from halogen, —CN, —OR n4 , —OC(O)R p4 , —OC(O)NR q4 R r4 , —SR n4 , —S(O)R p4 , —S(O) 2 OH, —S(O) 2 R p4 , —S(O) 2 NR q4 R r4 , —NR q4 R r4 , —NR n4 COR p4 , —NR n4 CO 2 R p4 , —NR n4 CONR q4 R r4 , —NR n4 S(O) 2 R p4 , —NR n4 S(O) 2 OR p4 , —NR n4 S(O) 2 NR q4 R r4 , NO 2 , —C(O)R n4 , —C(O)OR n4  and —C(O)NR q4 R r4 ; 
 each R n3  is independently selected from H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 3 -C 7 )carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl and 6-12 membered aryl, wherein any (C 3 -C 7 )carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl and 6-12 membered aryl of R n3  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2b  or Z 2c  groups, and wherein any (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl and (C 2 -C 4 )alkynyl of R n3  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2a  groups; 
 R q3  and R r3  are each independently selected from H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 3 -C 7 )carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl and 6-12 membered aryl, wherein any (C 3 -C 7 )carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl and 6-12 membered aryl of R q3  or R r3  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2b  or Z 2c  groups, and wherein any (C 1 -C 4 )alkyl and (C 2 -C 4 )alkenyl of R q3  or R r3  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2a  groups, or R q3  and R r3  together with the nitrogen to which they are attached form a heterocycle or heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2b  or Z 2c  groups; 
 each R n4  is independently selected from H, (C 1 -C 4 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )haloalkyl and (C 1 -C 4 )heteroalkyl; 
 each R p4  is independently selected from (C 1 -C 8 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )haloalkyl and (C 1 -C 4 )heteroalkyl; 
 R q4  and R r4  are each independently selected from H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 4 )haloalkyl and (C 1 -C 4 )heteroalkyl; 
 each Z 3  is independently selected from halogen, (C 1 -C 4 )alkyl, —OH, —CN, (C 1 -C 4 )heteroalkyl and (C 1 -C 4 )haloalkyl; 
 each Z 4  is independently selected from (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n5 , —OC(O)R p5 , —OC(O)NR q5 R r5 , —SR n5 , —S(O)R p5 , —S(O) 2 OH, —S(O) 2 R p5 , —S(O) 2 NR q5 R r5 , —NR q5 R r5 , —NR n5 COR p5 , —NR n5 CO 2 R p5 , —NR n5 CONR q5 R r5 , —NR n5 S(O) 2 R p5 , —NR n5 S(O) 2 OR p5 , —NR n5 S(O) 2 NR q5 R r5 , NO 2 , —C(O)R n5 , —C(O)OR n5  and —C(O)NR q5 R r5 , wherein any (C 3 -C 7 )carbocycle, of Z 4  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 4a  or Z 4b  groups, and wherein any (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl of Z 4  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 4a  groups; 
 each Z 4a  is independently selected from halogen, —CN, —OR n6 , —OC(O)R p6 , —OC(O)NR q6 R r6 , —SR n6 , —S(O)R p6 , —S(O) 2 OH, —S(O) 2 R p6 , —S(O) 2 NR q6 R r6 , —NR q6 R r6 , —NR n6 COR p6 , —NR n6 CO 2 R p6 , —NR n6 CONR q6 R r6 , —NR n6 S(O) 2 R p6 , —NR n6 S(O) 2 OR p6 , —NR n6 S(O) 2 NR q6 R r6 , NO 2 , —C(O)R n6 , —C(O)OR n6  and —C(O)NR q6 R r6 ; 
 each Z 4b  is independently selected from (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl (C 2 -C 4 )alkynyl and (C 1 -C 4 )haloalkyl; 
 each R n5  is independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )heteroalkyl, (C 2 -C 4 )alkenyl and (C 2 -C 4 )alkynyl; 
 each R p5  is independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )heteroalkyl, (C 2 -C 4 )alkenyl and (C 2 -C 4 )alkynyl; 
 R q5  and R r5  are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )heteroalkyl, (C 2 -C 4 )alkenyl and (C 2 -C 4 )alkynyl; 
 each R n6  is independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )heteroalkyl, (C 2 -C 4 )alkenyl and (C 2 -C 4 )alkynyl; 
 each R p6  is independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )heteroalkyl, (C 2 -C 4 )alkenyl and (C 2 -C 4 )alkynyl; 
 R q6  and R r6  are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )heteroalkyl, (C 2 -C 4 )alkenyl and (C 2 -C 4 )alkynyl; 
 each Z 5  is independently selected from (C 1 -C 6 )alkyl, halogen, —CN and —OR n7 , wherein any (C 1 -C 6 )alkyl of Z 5  is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) halogen; and 
 each R 7  is independently selected from H, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl and (C 3 -C 7 )carbocycle; 
 
         comprising
 (a) forming a compound of formula A9 by coupling a compound of formula A7: 
 
       
       
         
           
           
               
               
           
         
         
           wherein X is NH 2 , SH, or halogen, and the compound of formula A9 is represented by: 
         
       
       
         
           
           
               
               
           
         
       
     
     
         56 . The process of  claim 55 , wherein the forming of a compound of formula A9 in step (a) is carried out in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA) and dimethylformamide (DMF). 
     
     
         57 . The process of  claim 55 , further comprising:
 (b) converting a compound of formula A5:   
       
         
           
           
               
               
           
         
       
       to a compound of formula A7 in the presence of hydrochloric acid (HC). 
     
     
         58 . The process of  claim 55 , further comprising:
 (c) reacting a compound of formula A4:   
       
         
           
           
               
               
           
         
       
       with a Grignard reagent 
       
         
           
           
               
               
           
         
       
       wherein X is Br, to form a compound of formula A5. 
     
     
         59 . The process of  claim 55 , further comprising:
 (d) reacting a compound of formula A3:   
       
         
           
           
               
               
           
         
       
       with 
       
         
           
           
               
               
           
         
       
       to form a compound of formula A4. 
     
     
         60 . The process of  claim 59 , wherein the reacting of a compound of formula A3 with 
       
         
           
           
               
               
           
         
         in step (d) is carried out in the presence of copper sulfate (CuSO 4 ) and dichloromethane (DCM). 
       
     
     
         61 . The process of  claim 55 , further comprising:
 (e) reacting a compound of formula A2:   
       
         
           
           
               
               
           
         
       
       with diisobutylaluminum hydride (DIBAL-H) to form a compound of formula A3. 
     
     
         62 . The process of  claim 55 , further comprising:
 (f) reacting a compound of formula A1:   
       
         
           
           
               
               
           
         
       
       with 
       
         
           
           
               
               
           
         
       
       to form a compound of formula A2. 
     
     
         63 . The process of  claim 62 , wherein the reacting of a compound of formula A1 with 
       
         
           
           
               
               
           
         
         in step (f) is carried out in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA) and dimethylformamide (DMF).