Carm1 inhibitors and uses thereof

Abstract

Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X, R 1 , R 2a , R 2b , R 2c , R 2d , are as defined herein, and Ring HET is a 6-membered monocyclic heteroaryl ring system of formula: wherein L 2 , R 13 , G 8 , G 10 , G 11 , and G 12 are as defined herein. Compounds of the present invention are useful for inhibiting CARM1 activity. Methods of using the compounds for treating CARM1-mediated disorders are also described.

1 - 25 . (canceled) 
     
     
         26 . A method of treating a CARM1-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof: 
         wherein:
 X is —O—, —S—, or —CH 2 —; 
 R 1  is hydrogen or optionally substituted C 1-4  aliphatic; 
 each of R 2a , R 2b , R 2c , and R 2d  is independently hydrogen, halogen, —CN, —NO 2 , —C(═O)R A2 , —C(═O)OR A2 , —C(═O)N(R A2 ) 2 , —OR A2 , —SR A , —N(R A2 ) 2 , —S(═O)R A2 , —S(═O) 2 R A2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl, wherein each instance of R A2  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R A2  groups attached to the same nitrogen atom are joined to form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring; 
 Ring HET is a 6-membered monocyclic heteroaryl ring system of the formula: 
 
       
       
         
           
           
               
               
           
         
         
           each instance of R 8 , R 10 , R 11 , and R 12  is independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , —C(═O)R′, —C(═O)OR′, —C(═O)N(R′) 2 , optionally substituted alkyl, and -L 1 -R 3 ; 
           each instance of R′ is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R′ groups attached to the same nitrogen are joined to form an optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; 
           each instance of L 1  and L 2  is independently a bond, —O—, —N(R L )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R L )—, —C(O)N(R L )N(R L )—, —OC(O)—, —OC(O)N(R L )—, —NR L C(O)—, —NR L C(O)N(R L )—, —NR L C(O)N(R L )N(R L )—, —NR L C(O)O—, —SC(O)—, —C(═NR L )—, —C(═NNR L )—, —C(═NOR L )—, —C(═NR L )N(R L )—, —NR L C(═NR L )—, —C(S)—, —C(S)N(R L )—, —NR L C(S)—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —SO 2 —, —N(R L )SO 7 —, —SO 2 N(R L )—, —N(R L )SO 2 N(R L )—, an optionally substituted C 1-10  saturated or unsaturated hydrocarbon chain, wherein one or more moieties selected from the group consisting of —O—, —N(R L )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R L )—, —C(O)N(R L )N(R L )—, —OC(O)—, —OC(O)N(R L )—, —NR L C(O)—, —NR L C(O)N(R L )—, —NR L C(O)N(R L )N(R L )—, —NR L C(O)O—, —SC(O)—, —C(═NR L )—, —C(═NNR L )—, —C(═NOR L )—, —C(═NR L )N(R L )—, —NR L C(═NR L )—, —C(S)—, —C(S)N(R L )—, —NR L C(S)—, —S(O)—, —OS(O)—, —S(O) 2 O—, —SO 2 —, —N(R L )SO 2 —, —SO 2 N(R L )—, and —N(R L )SO 2 N(R L )— is optionally and independently present between two carbon atoms of the hydrocarbon chain, and optionally and independently present at one or both ends of the hydrocarbon chain; 
           each R L  is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group, or R L  and R 3  taken together form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or R L  and R 13  taken together form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring; 
           R 3  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, provided when R 3  is hydrogen, then L is not a bond; and 
           R 13  is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. 
         
       
     
     
         27 . The method of  claim 26 , wherein the disorder is a proliferative disorder. 
     
     
         28 . The method of  claim 26 , wherein the disorder is cancer. 
     
     
         29 . The method of  claim 28 , wherein the cancer is associated with E2F1 upregulation. 
     
     
         30 . The method of  claim 28 , wherein the cancer is associated with aberrant CARM1 activity. 
     
     
         31 . The method of  claim 28 , wherein the cancer is breast cancer, prostate cancer, or colorectal cancer. 
     
     
         32 . The method of  claim 28 , wherein the cancer is ERα-dependent breast cancer. 
     
     
         33 . The method of  claim 28 , wherein the cancer is castration-resistant prostate cancer. 
     
     
         34 . The method of  claim 28 , wherein the cancer is colorectal cancer associated with dysregulated WNT/β-catenin signaling. 
     
     
         35 . The method of  claim 26 , wherein the disorder is a metabolic disorder. 
     
     
         36 . The method of  claim 28 , wherein the cancer is leukemia, lymphoma, or multiple myeloma. 
     
     
         37 . The method of  claim 36 , wherein the cancer is leukemia. 
     
     
         38 . The method of  claim 36 , wherein the cancer is lymphoma. 
     
     
         39 . The method of  claim 36 , wherein the cancer is multiple myeloma. 
     
     
         40 . A method of treating a CARM1-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 X is —O—, —S—, or —CH 2 —; 
 R 1  is hydrogen or optionally substituted C 1-4  aliphatic; 
 each of R 2a , R 2b , R 2c , and R 2d  is independently hydrogen, halogen, —CN, —NO 2 , —C(═O)R A2 , —C(═O)OR A2 , —C(═O)N(R A2 ) 2 , —OR A2 , —SR A2 , —N(R A2 ) 2 , —S(═O)R A2 , —S(═O) 2 R A2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl, wherein each instance of R A2  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R A2  groups attached to the same nitrogen atom are joined to form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring; 
 Ring HET is a 6-membered monocyclic heteroaryl ring system of the formula: 
 
       
       
         
           
           
               
               
           
         
         wherein:
 G 8  is C—R 8  or N; 
 G 10  is C—R 10  or N; 
 G 11  is C—R 11  or N; 
 G 12  is C—R 12  or N; 
 provided at least one instance of G 8 , G 10 , G 11 , or G 12  is N; 
 each instance of R 8 , R 10 , R 11 , and R 12  is independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , —C(═O)R′, —C(═O)OR′, —C(═O)N(R′) 2 , optionally substituted alkyl, and -L 1 -R 3 ; 
 each instance of R′ is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R′ groups attached to the same nitrogen are joined to form an optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; 
 each instance of L 1  and L 2  is independently a bond, —O—, —N(R L )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R L )—, —C(O)N(R L )N(R L )—, —OC(O)—, —OC(O)N(R L )—, —NR L C(O)—, —NR L C(O)N(R L )—, —NR L C(O)N(R L )N(R L )—, —NR L C(O)O—, —SC(O)—, —C(═NR L) —, —C(═NNR L )—, —C(═NOR L )—, —C(═NR L )N(R L )—, —NR L C(═NR L )—, —C(S)—, —C(S)N(R L )—, —NR L C(S)—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —SO 2 —, —N(R L )SO 2 —, —SO 2 N(R L )—, —N(R L )SO 2 N(R L )—, an optionally substituted C 10  saturated or unsaturated hydrocarbon chain, wherein one or more moieties selected from the group consisting of —O—, —N(R L )—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(R L )—, —C(O)N(R L )N(R L )—, —OC(O)—, —OC(O)N(R L )—, —NR L C(O)—, —NR L C(O)N(R L )—, —NR L C(O)N(R L )N(R L )—, —NR L C(O)O—, —SC(O)—, —C(═NR L )—, —C(═NNR L )—, —C(═NOR L )—, —C(═NR L )N(R L )—, —NR L C(═NR L )—, —C(S)—, —C(S)N(R L )—, —NR L C(S)—, —S(O)—, —OS(O) 2 —, —S(O) 2 O—, —SO 2 —, —N(R L )SO 2 —, —SO 2 N(R L )—, and —N(R L )SO 2 N(R L )— is optionally and independently present between two carbon atoms of the hydrocarbon chain, and optionally and independently present at one or both ends of the hydrocarbon chain; 
 each R L  is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group, or R L  and R 3  taken together form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring, or R L  and R 13  taken together form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring; 
 R 3  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or aryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NO 2 , —N 3 , —SO 2 H, SO 3 H, —OH, —OR aa , —N(R bb ) 2 , —SH, —SR aa , —C(═O)R aa , —CO 2 H, —CHO, —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , C 1  alkyl, C 1  perhaloalkyl, C 2-4  alkenyl, and C 2-4  alkynyl, provided when R 3  is hydrogen, then L 1  is not a bond; and 
 R 13  is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or aryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —NO 2 , —N 3 , —SO 2 H, SO 3 H, —OH, —OR aa , —N(R bb ) 2 , —SH, —SR aa , —C(═O)R aa , —CO 2 H, —CHO, —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , C 1  alkyl, Ci perhaloalkyl, C 2-4  alkenyl, and C 2-4  alkynyl; 
 wherein: 
 each instance of R aa  is, independently, Ci alkyl; and 
 each instance of R bb  is, independently, hydrogen or Ci alkyl, or two R bb  groups are joined to form a 3-6 membered heterocyclyl or 5-6 membered heteroaryl ring. 
 
       
     
     
         41 . The method of  claim 40 , wherein the disorder is a metabolic disorder. 
     
     
         42 . The method of  claim 40 , wherein the disorder is a proliferative disorder. 
     
     
         43 . The method of  claim 40 , wherein the disorder is cancer. 
     
     
         44 . The method of  claim 43 , wherein the cancer is associated with E2F1 upregulation. 
     
     
         45 . The method of  claim 43 , wherein the cancer is associated with aberrant CARM1 activity. 
     
     
         46 . The method of  claim 43 , wherein the cancer is breast cancer, prostate cancer, or colorectal cancer. 
     
     
         47 . The method of  claim 43 , wherein the cancer is ERα-dependent breast cancer. 
     
     
         48 . The method of  claim 43 , wherein the cancer is castration-resistant prostate cancer. 
     
     
         49 . The method of  claim 43 , wherein the cancer is colorectal cancer associated with dysregulated WNT/β-catenin signaling. 
     
     
         50 . The method of  claim 43 , wherein the cancer is leukemia, lymphoma, or multiple myeloma. 
     
     
         51 . The method of  claim 50 , wherein the cancer is leukemia. 
     
     
         52 . The method of  claim 50 , wherein the cancer is lymphoma. 
     
     
         53 . The method of  claim 50 , wherein the cancer is multiple myeloma.