Claims for Patent: 9,714,258

Summary for Patent: 9,714,258

Title:	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.
Inventor(s):	Cui Jingrong Jean, Li Yishan, Rogers Evan W., Zhai Dayong
Assignee:	TP Therapeutics, Inc.
Application Number:	US15113583
Patent Claims:	2. The compound of claim 1 , wherein p′ is 1 claim 1 , and R is selected from the group consisting of deuterium claim 1 , halogen claim 1 , —OR claim 1 , —OC(O)R claim 1 , —OC(O)NRR claim 1 , —OC(═N)NRR claim 1 , —OS(O)R claim 1 , —OS(O)R claim 1 , —OS(O)NRR claim 1 , —OS(O)NRR claim 1 , —SR claim 1 , —S(O)R claim 1 , —S(O)R claim 1 , —S(O)NRR claim 1 , —S(O)NRR claim 1 , —NRR claim 1 , —NRC(O)R claim 1 , —NRC(O)OR claim 1 , —NRC(O)NRR claim 1 , —NRC(═N)NRR claim 1 , —NRS(O)R claim 1 , —NRS(O)R claim 1 , —NRS(O)NRR claim 1 , —NRS(O)NRR claim 1 , —C(O)R claim 1 , —C(O)OR claim 1 , —C(O)NRR claim 1 , —C(═N)NRR claim 1 , —PRR claim 1 , —P(O)RR claim 1 , —P(O)RR claim 1 , —P(O)NRR claim 1 , —P(O)NRR claim 1 , —P(O)OR claim 1 , —P(O)OR claim 1 , —CN claim 1 , —NO claim 1 , Calkyl claim 1 , Calkenyl claim 1 , Calkynyl claim 1 , Ccycloalkyl claim 1 , 3- to 7-membered heterocycloalkyl claim 1 , Caryl claim 1 , and mono- or bicyclic heteroaryl claim 1 , wherein each hydrogen atom in Calkyl claim 1 , Calkenyl claim 1 , Calkynyl claim 1 , Ccycloalkyl claim 1 , 3- to 7-membered heterocycloalkyl claim 1 , Caryl claim 1 , mono- or bicyclic heteroaryl Ccycloalkyl or a 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium claim 1 , halogen claim 1 , Calkyl claim 1 , Chaloalkyl claim 1 , —OR claim 1 , —OC(O)R claim 1 , —OC(O)NRR claim 1 , —OS(O)R claim 1 , —OS(O)R claim 1 , —OS(O)NRR claim 1 , —OS(O)NRR claim 1 , —SR claim 1 , —S(O)R claim 1 , —S(O)R claim 1 , —S(O)NRR claim 1 , —S(O)NRR claim 1 , —NRR claim 1 , —NRC(O)R claim 1 , —NRC(O)OR claim 1 , —NRC(O)NRR claim 1 , —NRS(O)R claim 1 , —NRS(O)R claim 1 , —NRS(O)NRR claim 1 , —NRS(O)NRR claim 1 , —C(O)R claim 1 , —C(O)OR claim 1 , —C(O)NRR claim 1 , —PRR claim 1 , —P(O)RR claim 1 , —P(O)RR claim 1 , —P(O)NRR claim 1 , —P(O)NRR claim 1 , —P(O)OR claim 1 , —P(O)OR claim 1 , —CN claim 1 , or —NO claim 1 , or a pharmaceutically acceptable salt thereof.3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein R is fluoro claim 2 , chloro claim 2 , bromo claim 2 , methyl claim 2 , ethyl claim 2 , propyl claim 2 , isopropyl claim 2 , methoxy claim 2 , ethoxy claim 2 , isopropoxy claim 2 , —CN claim 2 , or —CF.5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof claim 4 , wherein R is H claim 4 , or R is methyl or ethyl claim 4 , each unsubstituted or substituted with halogen claim 4 , —OH claim 4 , —OCalkyl claim 4 , —NH claim 4 , —NH(Calkyl) claim 4 , —N(Calkyl) claim 4 , —COH claim 4 , —COCalkyl claim 4 , —CONH claim 4 , Ccycloalkyl claim 4 , or monocyclic heterocycloalkyl.6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof claim 5 , wherein each R is independently H claim 5 , methyl claim 5 , ethyl claim 5 , propyl claim 5 , isopropyl claim 5 , or cyclopropyl.7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof claim 6 , wherein -(L)- is —CHCH— claim 6 , —CH—S— claim 6 , —CH—SO— claim 6 , —SO—N(Calkyl)- claim 6 , —SO—NH— claim 6 , —CH—O— claim 6 , —CH(Calkyl)-O— claim 6 , —CH(CHF)—O— claim 6 , —CH(Ccycloalkyl)-O—; —CHNH— claim 6 , —CH(Calkyl)-NH— claim 6 , —CH(CalkylOH)—NH— claim 6 , —CH(Calkyl-Ccycloalkyl)-NH— claim 6 , —CH—N(Calkyl)- claim 6 , —CH—N(Ccycloalkyl)- claim 6 , —CH—N(CalkylOH)— claim 6 , —CH(Calkyl)-N(Calkyl) claim 6 , —CH(COCalkyl)-NH— claim 6 , —CH(C(O)NH)—NH— claim 6 , —CH(COCalkyl)-N(Calkyl) claim 6 , —CH(C(O)NH)—N(Calkyl)- claim 6 , —CH(C(O)NH(Calkyl))-NH— claim 6 , —CH(C(O)NH(Calkyl))-N(Calkyl)- claim 6 , —CH(C(O)N(Calkyl))-NH— claim 6 , or —CH(C(O)N(Calkyl))-N(Calkyl)-.8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof claim 7 , wherein -(L)- is —O—(C(R)(R))— claim 7 , —O—(C(R)(R))— claim 7 , —O—(CH)— claim 7 , —O—(CH)— claim 7 , —N(R)—(C(R)(R))— claim 7 , —N(R)—(C(R)(R))— claim 7 , —S—(C(R)(R))— claim 7 , —S—(C(R)(R))— claim 7 , —SO—(C(R)(R))— claim 7 , —SO—(C(R)(R))— claim 7 , —SO—(C(R)(R))— claim 7 , —SO—N(R)—(C(R)(R))— or —(C(R)(R))—.9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein m′ is 3.10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein n′ is 2.11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein p′ is 1.12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein q′ is 0.16. The compound of selected from the group consisting of(13R)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;2-[(13R)-12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide;2-[12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide;(13R)-12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13S)-11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-6-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-7-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one;11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(13R)-12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; and12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;or a pharmaceutically acceptable salt thereof.17. The compound of selected from the group consisting of 12-chloro-11-fluoro-14-methyl-6 claim 1 ,7 claim 1 ,13 claim 1 ,14-tetrahydro-1 claim 1 ,15-ethenopyrazolo[4 claim 1 ,3-f][1 claim 1 ,4 claim 1 ,8 claim 1 ,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-3,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;14-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-propyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;14-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-t][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-(2-hydroxyethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(13R)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-chloro-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide;11-fluoro-7-(hydroxymethyl)-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-13-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide;11-fluoro-7-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide;11-fluoro-7-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;methyl 11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxylate;11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxamide;13-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one;11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one 14,14-dioxide;6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][10,1,4,8]benzoxathiadiazacyclotridecin-4(5H)-one;14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one;13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one;11-fluoro-6,7-dihydro-5H-1,15-ethenopyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one 13,13-dioxide;11-fluoro-14-methyl-6,7-dihydro-5H-1,15-ethenopyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one 13,13-dioxide;12-fluoro-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;(14R)-12-fluoro-14-methyl-5,6,7,8,14,15-hex ahydro-4H-1,16-ethenop yrazolo [4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;11-chloro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;13-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;13-cyclobutyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;{'sup': '2', 'sub': '4', '11-fluoro-14-methyl(6,6,7,7-H)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;'}11-fluoro-13-phenyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;13-(cyclopropylmethyl)-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7R,14R)-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;(7S,14R)-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;(7R,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7R)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(6R)-11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-fluoro-7-hydroxy-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;(7S)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-13-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-fluoro-14-(hydroxymethyl)-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one;11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-(2-hydroxy-2-methylpropyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;12-fluoro-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9]benzoxadiazacyclotetradecin-4-one;11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one;11-fluoro-14-(1-methylpyrrolidin-3-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one 8-oxide;11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one 8,8-dioxide;(7S)-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8]benzoxadiazacyclotridecin-4(5H)-one;(6S,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(6R,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one;(7S,13S)-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; and11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one; or a pharmaceutically acceptable salt thereof.20. A pharmaceutical composition comprising (a) at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and (b) a pharmaceutically acceptable excipient.