Diaryl macrocycles as modulators of protein kinases

Abstract

The present invention relates to certain diaryl macrocyclic compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

1 .- 56 . (canceled) 
     
     
         57 . A compound of the following Formula (I-A): 
       
         
           
           
               
               
           
         
         wherein
 Ring A′ and Ring B′ are each independently a monocyclic or bicyclic aryl or heteroaryl; wherein one of Ring A′ and Ring B′ is a monocyclic aryl or heteroaryl and the other is a bicyclic heteroaryl; and at least one of Ring A′ and Ring B′ comprises at least one nitrogen ring member; provided that B′ is not of the formula 
 
       
       
         
           
           
               
               
           
         
         
           each L 1  and L 2  is independently —C(R 1′ )(R 2′ )—, —O—, —N(R k′ )—, —S—, —S(O)— or —S(O) 2 —; 
           each R 1′  and R 2′  are independently H, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl, —OR a′ , —OC(O)R a′ , —OC(O)NR a′ R b′ , —OS(O)R a′ , —OS(O) 2 R a′ , —SR a′ , —S(O)R a′ , —S(O) 2 R a′ , —S(O)NR a′ R b′ , —S(O) 2 NR a′ R b′ , —OS(O)NR a′ R b′ , —OS(O) 2 NR a′ R b′ , —NR a′ R b′ , —NR a′ C(O)R b′ , —NR a′ C(O)OR b′ , —NR a′ C(O)NR a′ R b′ , —NR a′ S(O)R b′ , —NR a′ S(O) 2 R b′ , —NR a′ S(O)NR a′ R b′ , —NR a′ S(O) 2 NR a′ R b′ , —C(O)R a′ , —C(O)OR a′ , —C(O)NR a′ R b′ , —PR a′ R b′ , —P(O)R a′ R b′ , —P(O) 2 R a′ R b′ , —P(O)NR a′ R b′ , —P(O) 2 NR a′ R b′ , —P(O)OR a′ , —P(O) 2 OR a′ , —CN, or —NO 2 , or R 1′  and R 2′  taken together with the carbon or carbons to which they are attached form a C 3-6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, mono- or bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR e′ , —OC(O)R e′ , —OC(O)NR e′ R f′ , —OS(O)R e′ , —OS(O) 2 R e′ , —OS(O)NR e′ R f′ , —OS(O) 2 NR e′ R f′ , —SR e′ , —S(O)R e′ , —S(O) 2 R e′ , —S(O)NR e′ R f′ , —S(O) 2 NR e′ R f′ , —NR e′ R f′ , —NR e′ C(O)R f′ , —NR e′ C(O)OR f′ , —NR e′ C(O)NR e′ R f′ , —NR e′ S(O)R f′ , —NR e′ S(O) 2 R f′ , —NR e′ S(O)NR e′ R f′ , —NR e′ S(O) 2 NR e′ R f′ , —C(O)R e′ , —C(O)OR e′ , —C(O)NR e′ R f′ , —PR e′ R f′ , —P(O)R e′ R f′ , —P(O) 2 R e′ R f′ , —P(O)NR e′ R f′ , —P(O) 2 NR e′ R f′ , —P(O)OR e′ , —P(O) 2 OR e′ , —CN, or —NO 2 ; 
           each R k′  is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR e′ , —OC(O)R e′ , —OC(O)NR e′ R f′ , —OS(O)R e′ , —OS(O) 2 R e′ , —OS(O)NR e′ R f′ , —OS(O) 2 NR e′ R f′ , —SR e′ , —S(O)R e′ , —S(O) 2 R e′ , —S(O)NR e′ R f′ , —S(O) 2 NR e′ R f′ , —NR e′ R f′ , —NR e′ C(O)R f′ , —NR e′ C(O)OR f′ , —NR e′ C(O)NR e′ R f′ , —NR e′ S(O)R f′ , —NR e′ S(O) 2 R f′ , —NR e′ S(O)NR e′ R f′ , —NR e′ S(O) 2 NR e′ R f′ , —C(O)R e′ , —C(O)OR e′ , —C(O)NR e′ R f′ , —PR e′ R f′ , —P(O)R e′ R f′ , —P(O) 2 R e′ R f′ , —P(O)NR e′ R f′ , —P(O) 2 NR e′ R f′ , —P(O)OR e′ , —P(O) 2 OR e′ , —CN, or —NO 2 ; 
           each R 3′  and R 4′  is independently deuterium, halogen, —OR c′ , —OC(O)R c′ , —OC(O)NR c′ R d′ , —OC(═N)NR c′ R d′ , —OS(O)R c′ , —OS(O) 2 R c′ , —OS(O)NR c′ R d′ , —OS(O) 2 NR c′ R d′ , —SR c′ , —S(O)R c′ , —S(O) 2 R c′ , —S(O)NR c′ R d′ , —S(O) 2 NR c′ R d′ , —NR c′ R d′ , —NR c′ C(O)R d′ , —NR c′ C(O)OR d′ , —NR c′ C(O)NR c′ R d′ , —NR c′ C(═N)NR c′ R d′ , —NR c′ S(O)R d′ , —NR c′ S(O) 2 R d′ , —NR c′ S(O)NR c′ R d′ , —NR c′ S(O) 2 NR c′ R d′ , —(O)R c′ , —C(O)OR c′ , —C(O)NR c′ R d′ , —C(N)NR c′ R d′ , —PR c′ R d′ , —P(O)R c′ R d′ , —P(O) 2 R c′ R d′ , —P(O)NR c′ R d′ , —P(O) 2 NR c′ R d′ , —P(O)OR c′ , —P(O) 2 OR c′ , —CN, —NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl, or any two R 3′  groups or any two R 4′  groups taken together with the ring to which they are attached form a C 5-8 cycloalkyl or a 5- to 8-membered heterocycloalkyl, wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, mono- or bicyclic heteroaryl C 5-8 cycloalkyl or a 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR e′ , —OC(O)R e′ , —OC(O)NR e′ R f′ , —OS(O)R e′ , —OS(O) 2 R e′ , —OS(O)NR e′ R f′ , —OS(O) 2 NR e′ R f′ , —SR e′ , —S(O)R e′ , —S(O) 2 R e′ , —S(O)NR e′ R f′ , —S(O) 2 NR e′ R f′ , —NR e′ R f′ , —NR e′ C(O)R f′ , —NR e′ C(O)OR f′ , —NR e′ C(O)NR e′ R f′ , —NR e′ S(O)R f′ , —NR e′ S(O) 2 R f′ , —NR e′ S(O)NR e′ R f′ , —NR e′ S(O) 2 NR e′ R f′ , —C(O)R e′ , —C(O)OR e′ , —C(O)NR e′ R f′ , —PR e′ R f′ , —P(O)R e′ R f′ , —P(O) 2 R e′ R f′ , —P(O)NR e′ R f′ , —P(O) 2 NR e′ R f′ , —P(O)OR e′ , —P(O) 2 OR e′ , —CN, or —NO 2 ; 
           R 7′  is H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, —OR i′ , —OC(O)R i′ , —OC(O)NR i′ R j′ , —OS(O)R i′ , —OS(O) 2 R i′ , —OS(O)NR i′ R j′ , —OS(O) 2 NR i′ R j′ , —SR i′ , —S(O)R i′ , —S(O) 2 R i′ , —S(O)NR i′ R j′ , —S(O) 2 NR i′ R j′ , —NR i′ R j′ , —NR i′ C(O)R j′ , —NR i′ C(O)OR j′ , —NR i′ C(O)NR i′ R j′ , —NR i′ S(O)R j′ , —NR i′ S(O) 2 R j′ , —NR i′ S(O)NR i′ R j′ , —NR i′ S(O) 2 NR i′ R j′ , —C(O)R i′ , —C(O)OR i′ , —C(O)NR i′ R j′ , —PR i′ R j′ , —P(O)R i′ R j′ , —P(O) 2 R i′ R j′ , —P(O)NR i′ R j′ , —P(O) 2 NR i′ R j′ , —P(O)OR i′ , —P(O) 2 OR i′ , —CN, or —NO 2 ; 
           each R a′ , R b′ , R c′ , R d′ , R e′ , R f , R i′  and R j′  is independently selected from the group consisting of H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, and heteroaryl; 
           m′ is 2, 3, 4, or 5; 
           n′ is 2, 3, or 4; 
           p′ is 0, 1, 2, 3, or 4; and 
           q′ is 0, 1, 2, 3, or 4; 
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         58 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein Ring A′ is monocyclic aryl or heteroaryl. 
     
     
         59 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein Ring A′ is phenyl or pyridyl. 
     
     
         60 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein Ring B′ is: 
       
         
           
           
               
               
           
         
       
     
     
         61 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein each R 3′  is independently fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF 3 . 
     
     
         62 . The compound of  claim 61 , or a pharmaceutically acceptable salt thereof, wherein each R 3′  is fluoro or chloro. 
     
     
         63 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 7′  is H or is methyl or ethyl, each unsubstituted or substituted with halogen, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , cycloalkyl, or monocyclic heterocycloalkyl. 
     
     
         64 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein each R k′  is independently H, methyl, ethyl, propyl, isopropyl, or cyclopropyl. 
     
     
         65 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein -(L 1 ) n′ - is —CH 2 CH 2 —, —CH 2 —S—, —CH 2 —SO 2 —, —SO 2 —N(C 1-4 alkyl)-, —SO 2 —NH—, —CH 2 —O—, —CH(C 1-4 alkyl)-O—, —CH(CH 2 F)—O—, —CH(C 3-6 cycloalkyl)-O—; —CH 2 NH—, —CH(C 1-4 alkyl)-NH—, —CH(C 1-4 alkylOH)—NH—,—CH(C 1-4 alkyl-C 3-6 cycloalkyl)-NH—, —CH 2 —N(C 1-4 alkyl)-, —CH 2 —N(C 3-6 cycloalkyl)-, —CH 2 —N(C 1-4 -alkylOH)—, —CH(C 1-4 alkyl)-N(C 1-4 alkyl)-, —CH(CO 2 C 1-4 alkyl)-NH—, —CH(C(O)NH 2 )—NH—, —CH(CO 2 C 1-4 alkyl)-N(C 1-4 alkyl), —CH(C(O)NH 2 )—N(C 1-4 alkyl)-, —CH(C(O)NH(C 1-4 alkyl))-NH—, —CH(C(O)NH(C 1-4 alkyl))-N(C 1-4 alkyl)-, —CH(C(O)N(C 1-4 alkyl) 2 )—NH—, or —CH(C(O)N(C 1-4 alkyl) 2 )—N(C 1-4 alkyl)-. 
     
     
         66 . The compound of  claim 65 , or a pharmaceutically acceptable salt thereof, wherein -(L 2 ) m′  is —O—(C(R 1′ )(R 2′ )) 2 —, —O—(C(R 1′ )(R 2′ )) 3 —, —O—(CH 2 ) 2 —, —O—(CH 2 ) 3 —, —N(R k′ )—(C(R 1′ )(R 2′ )) 2 —, —N(R k′ )—(C(R 1′ )(R 2′ )) 3 —, —S—(C(R 1′ )(R 2′ )) 2 —, —S—(C(R 1′ )(R 2′ )) 3 —, —SO—(C(R 1′ )(R 2′ )) 2 —, —SO 2 —(C(R 1′ )(R 2′ )) 2 —, —SO 2 —(C(R 1′ )(R 2′ )) 3 —, —SO 2 —N(R k′ )—(C(R 1′ )(R 2′ )) 2 — or —(C(R 1′ )(R 2′ )) 3 —. 
     
     
         67 . The compound of  claim 66 , or a pharmaceutically acceptable salt thereof, wherein m′ is 3; or 4; or 5. 
     
     
         68 . The compound of  claim 67 , or a pharmaceutically acceptable salt thereof, wherein n′ is 2, 3 or 4. 
     
     
         69 . The compound of  claim 68 , or a pharmaceutically acceptable salt thereof, wherein p′ is 0, 1 or 2. 
     
     
         70 . The compound of  claim 69 , or a pharmaceutically acceptable salt thereof, wherein q′ is 0, 1 or 2. 
     
     
         71 . A compound of the Formula (IV): 
       
         
           
           
               
               
           
         
         wherein
 M is CH or N; 
 X 1  and X 1′  are independently —C(R 1a )(R 2a )—, —S—, —S(O)—, —S(O) 2 —, —O— or —N(R k′ )—; 
 each R 1a  and R 2a  is independently H, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10  aryl, —C(O)OR a′ , —C(O)NR a′ R b′ , —NR a′ R b′ , —SR a′ , —S(O)R a′ , —S(O)NR a′ , —S(O) 2 R a′ , —S(O) 2 NR a′  or —OR a′  wherein each hydrogen atom in C 1-6 alkyl is independently optionally substituted by deuterium, halogen, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , NHC(O)C 1-4 alkyl, —N(C 1-4 alkyl)C(O)C 1-4 alkyl, —NHC(O)NHC 1-4 alkyl, —N(C 1-4 alkyl)C(O)NHC 1-4 alkyl, —NHC(O)N(C 1-4 alkyl) 2 , —N(C 1-4 alkyl)C(O)N(C 1-4 alkyl) 2 , —NHC(O)OC 1-4 alkyl, —N(C 1-4 alkyl)C(O)OC 1-4 alkyl, —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —SC 1-4 alkyl, —S(O)C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —S(O)NH(C 1-4 alkyl), —S(O) 2 NH(C 1-4 alkyl), —S(O)N(C 1-4 alkyl) 2 , —S(O) 2 N(C 1-4 alkyl) 2 , C 3-6 cycloalkyl, or 3- to 7-membered heterocycloalkyl; 
 R 3a  and R 3b  are each independently H, deuterium, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF 3 ; 
 R 7a  is H, C 1-6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C 1-6 alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, —CN, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , cycloalkyl, or monocyclic heterocycloalkyl; 
 each R k′  is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl in R k′  is independently optionally substituted by deuterium, halogen, C 1-6 alkyl, C 1-4 haloalkyl or —OR a′ ; 
 wherein each R a′  and R b′  is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or heteroaryl; 
 each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6  or Z 7  is independently N, NH, or C(R x ), wherein each RX when present is independently H, deuterium, halogen, C 1-4 alkyl, —O—C 1-4 alkyl, —OH, —NH 2 , —NH(C 1-4 alkyl), —NH(phenyl), —NH(heteroaryl), CN, or —CF 3 , provided that at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6  or Z 7  is N or NH, provided that the compound does not comprise a moiety of the formula 
 
       
       
         
           
           
               
               
           
         
       
       and
   m′ is 2 or 3;   
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         72 . A compound of the Formula (V): 
       
         
           
           
               
               
           
         
         wherein
 M is CH or N; 
 X 1  and X 1′  are independently —C(R 1a )(R 2a )—, —S—, —S(O)—, —S(O) 2 —, —O— or —N(R k′ )—; 
 each R 1a  and R 2a  is independently H, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10  aryl, —C(O)OR a′ , —C(O)NR a′ R b′ , —NR a′ R b′ , —SR a′ , —S(O)R a′ , —S(O)NR a′ , —S(O) 2 R a′ , —S(O) 2 NR a′  or —OR a′  wherein each hydrogen atom in C 1-6 alkyl is independently optionally substituted by deuterium, halogen, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , NHC(O)C 1-4 alkyl, —N(C 1-4 alkyl)C(O)C 1-4 alkyl, —NHC(O)NHC 1-4 alkyl, —N(C 1-4 alkyl)C(O)NHC 1-4 alkyl, —NHC(O)N(C 1-4 alkyl) 2 , —N(C 1-4 alkyl)C(O)N(C 1-4 alkyl) 2 , —NHC(O)OC 1-4 alkyl, —N(C 1-4 alkyl)C(O)OC 1-4 alkyl, —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —SC 1-4 alkyl, —S(O)C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —S(O)NH(C 1-4 alkyl), —S(O) 2 NH(C 1-4 alkyl), —S(O)N(C 1-4 alkyl) 2 , —S(O) 2 N(C 1-4 alkyl) 2 , C 3-6 cycloalkyl, or 3- to 7-membered heterocycloalkyl; 
 R 3a  and R 3b  are each independently H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF 3 ; 
 R 7a  is H, C 1-6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C 1-6 alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , cycloalkyl, or monocyclic heterocycloalkyl; 
 each R k′  is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl in R k′  is independently optionally substituted by deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl or —OR a′ ; 
 wherein each R a′  and R b′  is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or heteroaryl; 
 each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6  or Z 7  is independently N, NH, or C(R x ), wherein each RX when present is independently H, deuterium, halogen, C 1-4 alkyl, —O—C 1-4 alkyl, —OH, —NH 2 , —NH(C 1-4 alkyl), —NH(phenyl), —NH(heteroaryl), CN, or —CF 3 , provided that at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6  or Z 7  is N or NH, provided that the compound does not comprise a moiety of the formula 
 
       
       
         
           
           
               
               
           
         
       
       and
   m′ is 2 or 3;   
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         73 . A compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein
 M is CH or N; 
 X 1  and X 1′  are independently —C(R 1a )(R 2a )—, —S—, —S(O)—, —S(O) 2 —, —O— or —N(R k′)—;    
 each R 1a  and R 2a  is independently H, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10  aryl, —C(O)OR a′ , —C(O)NR a′ R b′ , —NR a′ R b′ , —SR a′ , —S(O)R a′ , —S(O)NR a′ , —S(O) 2 R a′ , —S(O) 2 NR a′  or —OR a′ wherein each hydrogen atom in C   1-6 alkyl is independently optionally substituted by deuterium, halogen, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , NHC(O)C 1-4 alkyl, —N(C 1-4 alkyl)C(O)C 1-4 alkyl, —NHC(O)NHC 1-4 alkyl, —N(C 1-4 alkyl)C(O)NHC 1-4 alkyl, —NHC(O)N(C 1-4 alkyl) 2 , —N(C 1-4 alkyl)C(O)N(C 1-4 alkyl) 2 , —NHC(O)OC 1-4 alkyl, —N(C 1-4 alkyl)C(O)OC 1-4 alkyl, —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —SC 1-4 alkyl, —S(O)C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —S(O)NH(C 1-4 alkyl), —S(O) 2 NH(C 1-4 alkyl), —S(O)N(C 1-4 alkyl) 2 , —S(O) 2 N(C 1-4 alkyl) 2 , C 3-6 cycloalkyl, or 3- to 7-membered heterocycloalkyl; 
 R 3a  and R 3b  are each independently H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, —CN, or —CF 3 ; 
 R 7a  is H, C 1-6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C 1-6 alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, —OH, —OC 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 H, —CO 2 C 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , cycloalkyl, or monocyclic heterocycloalkyl; 
 each R k′  is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or mono- or bicyclic heteroaryl in R k′  is independently optionally substituted by deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl or —OR a′ ; 
 wherein each R a′  and R b′  is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6-10  aryl, or heteroaryl; 
 each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6  or Z 7  is independently N, NH, or C(R x ), wherein each R x  when present is independently H, deuterium, halogen, C 1-4 alkyl, —O—C 1-4 alkyl, —OH, —NH 2 , —NH(C 1-4 alkyl), —NH(phenyl), —NH(heteroaryl), CN, or —CF 3 , provided that at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6  or Z 7  is N or NH, provided that the compound does not comprise a moiety of the formula 
 
       
       
         
           
           
               
               
           
         
       
       and
   m′ is 2 or 3;   
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         74 . The compound of claim  1 , selected from the group consisting of (7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;
 8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;   (5R)-3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazacyclotridecin-12(13H)-one;   3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazacyclotridecin-12(13H)-one;   (5R)-3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazacyclotridecin-12(10H)-one;   3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenometheno)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazacyclotridecin-12(10H)-one;   (7R)-8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrazolo[3,4-f][1,10,4]benzodioxazacyclotridecin-16(13H)-one;   8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrazolo[3,4-f][1,10,4]benzodioxazacyclotridecin-16(13H)-one;   12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-15,1-(azenometheno)pyrazolo[4,3-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one;   12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-15,1-(azenometheno)pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;   12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(azenometheno)pyrrolo[3,2-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;   12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(azenometheno)pyrrolo[3,2-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one;   9-chloro-1-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)imidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one;   9-chloro-1-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)imidazo[5,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;   9-chloro-1-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenometheno)pyrrolo[2,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;   9-chloro-1-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenometheno)imidazo[2,1-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;   9-chloro-1-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-etheno[1,2,4]triazolo[3,4-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)-one;   9-chloro-1-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenometheno)[1,2,4]triazolo[3,4-f][1,4,7,10]benzoxatriazacyclotridecin-17(14H)-one;   8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrrolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one;   8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrazolo[3,4-f][1,4,8,10]benzoxatriazacyclotridecin-16(13H)-one;   8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(azenometheno)pyrazolo[3,4-f][1,4,10]benzoxadiazacyclotridecin-16(13H)-one;   (7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one; and   9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenometheno)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16(13H)-one;   or a pharmaceutically acceptable salt thereof.   
     
     
         75 . A pharmaceutical composition comprising (a) at least one compound according to  claim 57 , or a pharmaceutically acceptable salt thereof, and (b) at least one pharmaceutically acceptable excipient. 
     
     
         76 . A method of treating cancer, pain, a neurological disease, an autoimmune disease, or inflammation, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to  claim 57 , or a pharmaceutically acceptable salt thereof.