Diaryl macrocycles as modulators of protein kinases
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. A compound of the formula
wherein
Ring A′ is a monocyclic or bicyclic aryl or a heteroaryl; Ring B′ is 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′ is 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′ , —C(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.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A′ is monocyclic aryl or heteroaryl and Ring B′ is bicyclic heteroaryl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A′ is phenyl or pyridyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B′ is
5. The compound of claim 1 , 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 .
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein each R 3′ is fluoro or chloro.
7. The compound of claim 1 , 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.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R k′ is independently H, methyl, ethyl, propyl, isopropyl, or cyclopropyl.
9. The compound of claim 1 , 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)-.
10. The compound of claim 9 , 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 —.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m′ is 3, 4, or 5.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein n′ is 2, 3 or 4.
13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein p′ is 0, 1 or 2.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein q′ is 0, 1 or 2.
15. A compound of the formula
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 1-6 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;
Z 3 is N, Z 7 is NH, and Z 1 , Z 2 , Z 4 , Z 5 , and Z 6 are each independently 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 ; and
m′ is 2 or 3;
or a pharmaceutically acceptable salt thereof.
16. A compound of the formula
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;
Z 3 is N, Z 7 is NH, and Z 1 , Z 2 , Z 4 , Z 5 , and Z 6 are each independently 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 ; and
m′ is 2 or 3;
or a pharmaceutically acceptable salt thereof.
17. 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;
Z 3 is N, Z 7 is NH, and Z 1 , Z 2 , Z 4 , Z 5 , and Z 6 are each independently 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 ; and
m′ is 2 or 3;
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of
(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(azenometheno)pyrrolo[3,4-f][1,10,4]benzodioxazacyclotridecin-4(5H)-one;
12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(azenometheno)pyrrolo[3,4-f][1,10,4]benzodioxazacyclotridecin-4(5H)-one; and
12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-2H-1,15-(azenometheno)pyrrolo[3,4-f][1,4,10]benzoxadiazacyclotridecin-4(5H)-one.
19. A pharmaceutical composition comprising (a) at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and (b) at least one pharmaceutically acceptable excipient.