US2022213111A1PendingUtilityA1

Substituted heterocycles as cyclic trex1 inhibitors

61
Assignee: VENENUM BIODESIGN LLCPriority: Apr 8, 2019Filed: Mar 8, 2022Published: Jul 7, 2022
Est. expiryApr 8, 2039(~12.7 yrs left)· nominal 20-yr term from priority
Inventors:Jeffrey J. LetourneauKiruthika Selvarangan ElamparuthiChia-Yu HuangVenugopalareddy Bommireddy Venkata
C07D 487/04A61K 31/5517A61P 35/00C07D 243/08A61K 45/06C07D 471/04
61
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Claims

Abstract

The present invention provides compounds of Formula I: wherein {circle around (A)}, X, R 1 , R 2 , R 3 and R 4 are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are effective at modulating the TREX1 protein and thus can be used as medicaments for treating or preventing disorders affected by the inhibition of TREX1.

Claims

exact text as granted — not AI-modified
1 .- 9 . (canceled) 
     
     
         10 . A method of treating a disorder, disease, syndrome, or condition, wherein said disease, syndrome, or condition is affected by the inhibition of TREX1, comprising administering to a subject in need thereof a therapeutically effective amount of the compound, stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: 
       
         
           
           
               
               
           
         
         X is —C 1 -C 6  alkylene-NR S C(O)—, —C 1 -C 6  alkylene-NR 5 S(O) 2 —, —C(O)NR 5 —, —C(O)NR 5 S(O) 2 —, or a 5-membered heteroarylene, wherein the 5-membered heteroarylene contains at least 1 nitrogen heteroatom; 
         R 1  is C 1 -C 6  alkylene-NR 5 R 6  or NR 5 R 6 ; 
         R 2  is C 1 -C 6  alkyl, C 1 -C 6  alkylene-O-C 6 -C 10  aryl, C 1 -C 6  alkylene-O-5- to 10-membered heteroaryl, C 1 -C 6  alkylene-S—C 6 -C 10  aryl, C 1 -C 6  alkylene-S-5- to 10-membered heteroaryl, C 1 -C 6  alkylene-S(O)—C 6 -C 10  aryl, C 1 -C 6  alkylene-S(O)-5- to 10-membered heteroaryl, C 1 -C 6  alkylene-S(O) 2 -C 6 -C 10  aryl, C 1 -C 6  alkylene-S(O) 2 — 5- to 10-membered heteroaryl, C 1 -C 6  alkylene-C 6 -C 10  aryl, or C 1 -C 6  alkylene-5- to 10-membered heteroaryl, wherein any C 6 -C 10  aryl or 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl; 
         R 3  is C 1 -C 6  alkyl, C 1 -C 6  alkylene-C 3 -C 6  cycloalkyl, C 1 -C 6  alkylene-C 6 -C 10  aryl, C 1 -C 6  alkylene-5- to 10-membered heteroaryl, or C 6 -C 10  aryl, wherein any C 3 -C 6  cycloalkyl, C 6 -C 10  aryl, or 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 6  haloalkyl; 
         R 4  is C 1 -C 6  alkyl, wherein the C 1 -C 6  alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR 8 R 9 , C(O)NR 8 S(O) 2 R 9 , C(O)NR 8 S(O) 2 NR 28 R 29 , C(O)OH, NR 8 R 9 , NR 28 C(O)NR 8 R 9 , NR 28 C(O)NR 8 S(O) 2 R 9 , NR 8 S(O) 2 R 9 , OH, ONR 8 R 9 , SR 9 , S(O)R 9 , S(O) 2 R 9 , S(O) 2 NR 8 R 9 , S(O) 2 OH, C 6 -C 10  aryl, and a 5- to 10-membered heteroaryl,wherein the 5- to 10-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C 6 -C 10  aryl or 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, ═O, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl; 
         each R 5  is independently H, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
         each R 6  is independently H, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C(O)R 7 ; 
         each R 7  is independently C 1 -C 6  alkyl or OC 1 -C 6  alkyl; 
         each R 8  is independently H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C(O)C 1 -C 4  alkyl, OC 1 -C 4  alkyl, or OC 1 -C 4  haloalkyl; 
         each R 9  is independently H, C 1 -C 4  alkyl, OH, OC 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, or C 6 -C 10  aryl, wherein each C 1 -C 4  alkyl, OC 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, and C 6 -C 10  aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, ═O, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl; 
         each R 28  is independently H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OC 1 -C 4  alkyl, or OC 1 -C 4  haloalkyl; and 
         each R 29  is independently H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OC 1 -C 4  alkyl, or OC 1 -C 4  haloalkyl. 
       
     
     
         11 . The method of  claim 10 , wherein said disorder, disease, syndrome, or condition is cancer. 
     
     
         12 . A method of treating a disorder, disease, syndrome, or condition selected from the group consisting of viral infection, melanoma, colon cancer, breast cancer, prostate cancer, lung cancer, bladder cancer and fibrosarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim  8 . 
     
     
         13 . A method of treating a disorder, disease, syndrome, or condition selected from the group consisting of viral infection, melanoma, colon cancer, breast cancer, prostate cancer, lung cancer, bladder cancer and fibrosarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim  9 . 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 10 , wherein:
 X is —C 1 -C 6  alkylene-NR 5 C(O)—, —C(O)NR 5 —, —C(O)NR 5 S(O) 2 —, or a 5-membered heteroarylene, wherein the 5-membered heteroarylene contains at least 1 nitrogen heteroatom;   R 2  is C 1 -C 6  alkyl, C 1 -C 6  alkylene-O—C 6 -C 10  aryl, C 1 -C 6  alkylene-S(O)—C 6 -C 10  aryl, C 1 -C 6  alkylene- S(O)—C 6 -C 10  aryl, C 1 -C 6  alkylene-S(O) 2 —C 6 -C 10  aryl, or C 1 -C 6  alkylene-C 6 -C 10  aryl, wherein any C 6 -C 10  aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl;   R 3  is C 1 -C 6  alkyl, C 1 -C 6  alkylene-C 6 -C 10  aryl, C 1 -C 6  alkylene-5- to 10-membered heteroaryl, or C 6 -C 10  aryl, wherein any C 6 -C 10  aryl or the 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 6  haloalkyl;   R 4  is C 1 -C 6  alkyl, wherein the C 1 -C 6  alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR 8 R 9 , C(O)OH, OH, C 6 -C 10  aryl, and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C 6 -C 10  aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, ═O, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl;   each R 8  is independently H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or OC 1 -C 4  alkyl; and   each R 9  is independently H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or OC 1 -C 4  alkyl.   
     
     
         17 . The method of  claim 10 , wherein:
 X is —C 1 -C 6  alkylene-NR 5 C(O)—, —C(O)NR 5 —, or a 5-membered heteroarylene, wherein the 5-membered heteroarylene contains at least 1 nitrogen heteroatom;   R 2  is C 1 -C 6  alkyl, C 1 -C 6  alkylene-O-C 6 -C 10  aryl, C 1 -C 6  alkylene-S-C 6 -C 10  aryl, or C 1 -C 6  alkylene-C 6 -C 10  aryl, wherein any C 6 -C 10  aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl;   R 3  is C 1 -C 6  alkyl, C 1 -C 6  alkylene-C 6 -C 10  aryl, C 1 -C 6  alkylene-5-membered heteroaryl, or C 6 -C 10  aryl, wherein any C 6 -C 10  aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 6  haloalkyl;   R 4  is C 1 -C 6  alkyl, wherein the C 1 -C 6  alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR 8 R 9 , C(O)OH, OH, C 6 -C 10  aryl, and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C 6 -C 10  aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, ═O, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl;   each R 8  is independently H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or OC 1 -C 4  alkyl; and   each R 9  is independently H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or OC 1 -C 4  alkyl.   
     
     
         18 . The method of  claim 17 , wherein::
 X is —C(O)NR 5 —;   R 1  is NR 5 R 6 ;   R 2  is C 1 -C 6  alkylene-C 6 -C 10  aryl, wherein the C 6 -C 10  aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, OH, and OC 1 -C 4  haloalkyl;   R 3  is C 1 -C 6  alkylene-C 6 -C 10  aryl, wherein the C 6 -C 10  aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and OH;   R 4  is C 1 -C 6  alkyl, wherein the C 1 -C 6  alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of C(O)OH, OH, C 6 -C 10  aryl, and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C 6 -C 10  aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, ═O, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl;   each R 5  is independently H or CH 3 ; and   R 6  is H or C 1 -C 6  alkyl.   
     
     
         19 . The method of  claim 10 , wherein: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 19 , wherein: R 4  is C 1 -C 6  alkyl, wherein the C 1 -C 6  alkyl is substituted with 1 substituent selected from the group consisting of C(O)OH and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein the 5-membered heteroaryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, ═O, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl. 
     
     
         21 . The method of  claim 10 , wherein:
 X is —C 1 -C 6  alkylene-NR 5 C(O)— or —C(O)NR 5 —;   R 2  is C 1 -C 6  alkyl, C 1 -C 6  alkylene-O—C 6 -C 10  aryl, or C 1 -C 6  alkylene-C 6 -C 10  aryl, wherein any C 6 -C 10  aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl;   R 3  is C 1 -C 6  alkyl, C 1 -C 6  alkylene-C 6 -C 10  aryl, or C 6 -C 10  aryl, wherein any C 6 -C 10  aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 6  haloalkyl;   R 4  is C1-C6 alkyl, wherein the C 1 -C 6  alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR 8 R 9 , C(O)OH, OH, and C 6 -C 10  aryl, wherein any C 6 -C 10  aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl;   each R 8  is independently H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or OC 1 -C 4  alkyl; and   each R 9  is independently H, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or OC 1 -C 4  alkyl.   
     
     
         22 . The method of  claim 10 , wherein:
 X is —C 1 -C 6  alkylene-NR 5 C(O)— or —C(O)NR 5 —;   R 2  is C 1 -C 6  alkyl or C 1 -C 6  alkylene-C 6 -C 10  aryl, wherein the C 6 -C 10  aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl;   R 3  is C 1 -C 6  alkyl, C 1 -C 6  alkylene-C 6 -C 10  aryl, or C 6 -C 10  aryl, wherein any C 6 -C 10  aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 6  haloalkyl;   R 4  is C 1 -C 6  alkyl, wherein the C 1 -C 6  alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR 8 R 9 , C(O)OH, OH, and C 6 -C 10  aryl, wherein any C 6 -C 10  aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, OH, OC 1 -C 4  alkyl, and OC 1 -C 4  haloalkyl;   each R 8  is independently H, C 1 -C 4  alkyl, or C 1 -C 4  haloalkyl; and   each R 9  is independently H, C 1 -C 4  alkyl, or C 1 -C 4  haloalkyl.   
     
     
         23 . The method of  claim 10 , wherein:
 X is —C(O)NR 5 —;   R 1  is NR 5 R 6 ;   R 2  is C 1 -C 6  alkyl or C 1 -C 6  alkylene-C 6 -C 10  aryl, wherein the C 6 -C 10  aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and OH;   R 3  is C 1 -C 6  alkyl, C 1 -C 6  alkylene-C 6 -C 10  aryl, or C 6 -C 10  aryl, wherein the C 6 -C 10  aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and OH;   R 4  is C 1 -C 6  alkyl, wherein the C 1 -C 6  alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of C(O)OH, OH, and C 6 -C 10  aryl, wherein any C 6 -C 10  aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and OH;   each R 5  is independently H or C 1 -C 6  alkyl;   R 6  is H, C 1 -C 6  alkyl, or C(O)R 7 ;. and   R 7  is C 1 -C 6  alkyl or OC 1 -C 6  alkyl.   
     
     
         24 . The method of  claim 20 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 10 , wherein the compound is selected from the group consisting of:

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