Certain heterocycles, compositions thereof, and methods for their use

Abstract

Provided are compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Z 1 , Z 2 , Z 3 , Z 4 and m are as defined herein. Also provided is a pharmaceutically acceptable composition comprising sing a compound of Formula I, or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula I, or a pharmaceutically acceptable salt thereof.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 X is selected from the group consisting of a bond, —(CH 2 ) p —, —(CH 2 ) p C(O)(CH 2 ) q —, —(CH 2 ) p O(CH 2 ) q —, —(CH 2 ) p S(CH 2 ) q —, —(CH 2 ) p NR d (CH 2 ) q —, —(CH 2 ) p C(O)O(CH 2 ) q —, —(CH 2 ) p OC(O)(CH 2 ) q —, —(CH 2 ) p NR d C(O)(CH 2 ) q —, —(CH 2 ) p C(O)NR d (CH 2 ) q —, —(CH 2 ) p NR d C(O)NR d (CH 2 ) q —, —(CH 2 ) p NR d SO 2 (CH 2 ) q —, and —(CH 2 ) p SO 2 NR d (CH 2 ) q —;
 Z 1  is selected from the group consisting of O, N, NR 8  and CR 9 ; 
 Z 2  is selected from the group consisting of N and C; 
 Z 3  is selected from the group consisting of O, N, NR 10  and CR 11 ; 
 Z 4  is selected from the group consisting of O, N, NR 12  and CR 13 ; 
 R 1  is selected from the group consisting of C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, 5-10 membered heteroaryl and NR b R c , wherein each of the C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, (CH 2 ) n OR a , (CH 2 ) n OC(O)R a , (CH 2 ) n OC(O)OR a , (CH 2 ) n OC(O)NR b R c , (CH 2 ) n NR b R c , (CH 2 ) n NR d C(O)R a , (CH 2 ) n NR d C(O)OR a , (CH 2 ) n NR d C(O)NR b R c , (CH 2 ) n NR d C(O)C(O)NR b R c , (CH 2 ) n NR d C(S)R a , (CH 2 ) n NR d C(S)OR a , (CH 2 ) n NR d C(S)NR b R c , (CH 2 ) n NR d C(NR e )NR b R c , (CH 2 ) n NR d S(O)R a , (CH 2 ) n NR d SO 2 R a , (CH 2 ) n NR d SO 2 NR b R c , (CH 2 ) n C(O)R a , (CH 2 ) n C(O)OR a , (CH 2 ) n C(O)NR b R c , (CH 2 ) n C(S)R a , (CH 2 ) n C(S)OR a , (CH 2 ) n C(S)NR b R c , (CH 2 ) n C(NR e )NR b R c , (CH 2 ) n SR a , (CH 2 ) n S(O)R a , (CH 2 ) n SO 2 R a , (CH 2 ) n SO 2 NR b R c , C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, (CH 2 ) n C 3-8  cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n C 6-10  aryl and (CH 2 ) n 5-10 membered heteroaryl, wherein each of the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, (CH 2 ) n C 3-8  cycloalkyl, (CN 2 ) n 3-8 membered heterocycloalkyl, (CN 2 ) n C 6-10  aryl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R f  substituents; 
 R 2  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C(O)R a , C(O)OR a , C(O)NR b R c  and SO 2 R a ; 
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, halogen, C 1-6  alkyl and C 1-6  haloalkyl; 
 or alternatively, R 3  and R 4  together with the carbon atom to which they are bound form C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6  alkyl and C 1-6  haloalkyl; 
 R 5  is selected from the group consisting of C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl and 5-10 membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , OC(O)NR b R c , NR b R c , NR d C(O)R a , NR d C(O)OR a , NR d C(O)NR b R c , NR d C(O)C(O)NR b R c , NR d C(S)R a , NR d C(S)OR a , NR d C(S)NR b R c , NR d C(NR e )NR b R c , NR d S(O)R a , NR d SO 2 R a , NR d SO 2 NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , C(S)R a , C(S)OR a , C(S)NR b R c , C(NR e )NR b R c , SR a , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl, and 5-10 membered heteroaryl, wherein each of the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R f  substituents; 
 R 6  and R 7 , at each occurrence, are each independently selected from the group consisting of hydrogen, halogen and C 1-6  alkyl; 
 R 8 , R 10 , and R 12  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C(O)R a , C(O)OR a , C(O)NR b R c  and SO 2 R a ; 
 R 9 , R 11  and R 13  are each independently selected from the group consisting of hydrogen, halogen, CN, C 1-6  alkyl, C 1-6  haloalkyl, C(O)OR a , C(O)NR b R c , OR a , NR b R c , C 6-10  aryl and 5-10 membered heteroaryl; 
 R a , at each occurrence, is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl 3-8 , cycloalkyl, cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl and 5-10 membered heteroaryl, wherein each of the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R f  substituents; 
 R b  and R c , at each occurrence, are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl, 5-10 membered heteroaryl, C(O)R g , C(O)OR g , C(O)NR i R j  and SO 2 R g , wherein each of the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R f  substituents; 
 R d , at each occurrence, is independently selected from the group consisting of hydrogen and C 1-6  alkyl; 
 R e , at each occurrence, is independently selected from the group consisting of hydrogen, CN, OH, C 1-6  alkoxy, C 1-6  alkyl and C 1-6  haloalkyl; 
 R f , at each occurrence, is independently selected from the group consisting of halogen, CN, OR h , OC(O)R h , OC(O)OR h , OC(O)NR i R j , NR i R j , NR d C(O)R h , NR d C(O)OR h , NR d C(O)NR i R j , NR d C(O)C(O)NR i R j , NR d C(S)R h , NR d C(S)OR h , NR d C(S)NR i R j , NR d C(NR e )NR i R j , NR d S(O)R h , NR d SO 2 R h , NR d SO 2 NR i R j , C(O)R h , C(O)OR h , C(O)NR i R j , C(S)R h , C(S)OR h , C(S)NR i R j , C(NR e )NR i R j , SR h , S(O)R h , SO 2 R h , SO 2 NR i R j , C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl and 5-10 membered heteroaryl, wherein each of the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R k  substituents; 
 or two R f  substituents bound to a single carbon atom, together with the carbon atom to which they are both bound, form a group selected from the group consisting of carbonyl, C 3-8  cycloalkyl and 3-8 membered heterocycloalkyl; 
 R g , at each occurrence, is independently selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, phenyl, naphthyl, and C 7-11  aralkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, OH, C 1-6  alkoxy, C 1-6  alkyl and C 1-6  haloalkyl; 
 R h , at each occurrence, is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl and 5-10 membered heteroaryl, wherein each of the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R k  substituents; 
 R i  and R j , at each occurrence, are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl, 5-10 membered heteroaryl, C(O)R g , and C(O)OR g , wherein each of the C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, OH, C 1-6  alkoxy, C 1-6  alkyl and C 1-6  haloalkyl; 
 R k , at each occurrence, is independently selected from the group consisting of halogen, CN, OH, C 1-6  alkoxy, NH 2 , NH(C 1-6  alkyl), N(C 1-6  alkyl) 2 , NHC(O)C 1-6  alkyl, NHC(O)C 7-11  aralkyl, NHC(O)OC 1-6  alkyl, NHC(O)OC 7-11  aralkyl, OO(O)C 1-6  alkyl, OO(O)C 7-11  aralkyl, OC(O)OC 1-6  alkyl, OC(O)OC 7-11  aralkyl, O(O)C 1-6  alkyl, C(O)C 7-11  aralkyl, C(O)OC 1-6  alkyl, C(O)OC 7-11  aralkyl, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl, wherein each C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 7-11  aralkyl substituent is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of OH, C 1-6  alkoxy, NH 2 , NH(C 1-6  alkyl), N(C 1-6  alkyl) 2 , NHC(O)C 1-6  alkyl, NHC(O)C 7-11  aralkyl, NHC(O)OC 1-6  alkyl, and NHC(O)OC 7-11  aralkyl; 
 or two R k  substituents bound to a single carbon atom, together with the carbon atom to which they are both bound, form a carbonyl group; 
 m is 0, 1 or 2; 
 n, at each occurrence, independently is 0, 1 or 2; 
 p is 0, 1 or 2; and 
 q is 0, 1 or 2. 
 
 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0. 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1. 
     
     
         4 . The compound of  claim 3 , wherein R 6  and R 7  are each hydrogen. 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  and R 4  are each C 1-6  alkyl. 
     
     
         6 . The compound of  claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3  and R 4  are each methyl. 
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  and R 4  together with the carbon atom to which they are bound form a group selected from the group consisting of C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl and 3-8 membered heterocycloalkenyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6  alkyl and C 1-6  haloalkyl. 
     
     
         8 - 11 . (canceled) 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  and R 4  together with the carbon atom to which they are bound form a group selected from the group consisting of cyclobutyl, 3-fluorocyclobutyl and 3,3-difluorocyclobutyl. 
     
     
         13 - 30 . (canceled) 
     
     
         31 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is phenyl or pyridyl, optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR a , OC(O)R a , OC(O)OR a , OC(O)NR b R c , NR b R c , NR d C(O)R a , NR d C(O)OR a , NR d C(O)NR b R c , NR d C(O)C(O)NR b R c , NR d C(S)R a , NR d C(S)OR a , NR d C(S)NR b R c , NR d C(NR e )NR b R c , NR d S(O)R a , NR d SO 2 R a , NR d SO 2 NR b R c , C(O)R a , C(O)OR a , C(O)NR b R c , C(S)R a , C(S)OR a , C(S)NR b R c , C(NR e )NR b R c , SR a , S(O)R a , SO 2 R a , SO 2 NR b R c , C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl, and 5-10 membered heteroaryl, wherein each of the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C 6-10  aryl, C 7-11  aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R f  substituents. 
     
     
         32 - 34 . (canceled) 
     
     
         35 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is a bond. 
     
     
         36 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is phenyl, pyridyl, or pyrrolyl, optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, (CH 2 ) n OR a , (CH 2 ) n OC(O)R a , (CH 2 ) n OC(O)OR a , (CH 2 ) n OC(O)NR b R c , (CH 2 ) n NR b R c , (CH 2 ) n NR d C(O)R a , (CH 2 ) n NR d C(O)OR a , (CH 2 ) n NR d C(O)NR b R c , (CH 2 ) n NR d C(O)C(O)NR b R c , (CH 2 ) n NR d C(S)R a , (CH 2 ) n NR d C(S)OR a , (CH 2 ) n NR d C(S)NR b R c , (CH 2 ) n NR d C(NR e )NR b R c , (CH 2 ) n NR d S(O)R a , (CH 2 ) n NR d SO 2 R a , (CH 2 ) n NR d SO 2 NR b R c , (CH 2 ) n C(O)R a , (CH 2 ) n C(O)OR a , (CH 2 ) n C(O)NR b R c , (CH 2 ) n C(S)R a , (CH 2 ) n C(S)OR a , (CH 2 ) n C(S)NR b R c , (CH 2 ) n C(NR e )NR b R c , (CH 2 ) n SR a , (CH 2 ) n S(O)R a , (CH 2 ) n SO 2 R a , (CH 2 ) n SO 2 NR b R c , C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, (CH 2 ) n C 3-8  cycloalkyl, (CH 2 ) n 3-8 membered heterocycloalkyl, (CH 2 ) n C 6-10  aryl and (CH 2 ) n 5-10 membered heteroaryl, wherein each of the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, (CH 2 ) n C 3-8  cycloalkyl, (CN 2 ) n 3-8 membered heterocycloalkyl, (CN 2 ) n C 6-10  aryl and (CH 2 ) n 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R f  substituents. 
     
     
         37 - 43 . (canceled) 
     
     
         44 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen. 
     
     
         45 - 47 . (canceled) 
     
     
         48 . A compound selected from the group consisting of compounds in Table 5, or a pharmaceutically acceptable salt thereof. 
     
     
         49 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         50 . The pharmaceutical composition of  claim 49 , wherein the pharmaceutical composition is formulated for oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. 
     
     
         51 . (canceled) 
     
     
         52 . A pharmaceutical composition comprising a compound of  claim 48 , or a pharmaceutically acceptable salt thereof. 
     
     
         53 . The pharmaceutical composition of  claim 52 , wherein the pharmaceutical composition is formulated for oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. 
     
     
         54 . A method of treating a disease or condition responsive to modulation of the contractility of the skeletal sarcomere in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of  claim 1 . 
     
     
         55 . The method of  claim 54 , wherein the disease or condition is selected from the group consisting of neuromuscular disorders, conditions of muscle wasting, muscular myopathies, rehabilitation-related deficits, peripheral vascular disease, peripheral arterial disease, muscle atrophy and fatigue, metabolic syndrome, chronic fatigue syndrome, and obesity. 
     
     
         56 . The method of  claim 54 , wherein the disease or condition is selected from the group consisting of Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), myasthenia gravis, chronic obstructive pulmonary disease (COPD), heart failure, peripheral vascular disease, peripheral arterial disease, and frailty.