IP Library › Patent Application 16797866

Patent Application

App. No. 16/797,866

DIARYL MACROCYCLES AS MODULATORS OF PROTEIN KINASES

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App. No.: 16/797,866

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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.

Claims (93)

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;

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′ )—;

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;

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;

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′)—;

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;

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.