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HK1174629B - Benzoxazepin pi3k inhibitor compounds and methods of use - Google Patents

Benzoxazepin pi3k inhibitor compounds and methods of use Download PDF

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Publication number
HK1174629B
HK1174629B HK13101739.9A HK13101739A HK1174629B HK 1174629 B HK1174629 B HK 1174629B HK 13101739 A HK13101739 A HK 13101739A HK 1174629 B HK1174629 B HK 1174629B
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HK
Hong Kong
Prior art keywords
triazol
oxazazepine
isopropyl
dihydrobenzo
imidazo
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HK13101739.9A
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Chinese (zh)
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HK1174629A1 (en
Inventor
Nicole Blaquiere
Steven Do
Danette Dudley
Adrian J. Folkes
Robert Heald
Timothy Heffron
Mark Jones
Aleksandr Kolesnikov
Chudi Ndubaku
Alan G. Olivero
Stephen Price
Steven Staben
Lan Wang
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霍夫曼-拉罗奇有限公司
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Priority claimed from PCT/EP2010/064208 external-priority patent/WO2011036280A1/en
Publication of HK1174629A1 publication Critical patent/HK1174629A1/en
Publication of HK1174629B publication Critical patent/HK1174629B/en

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Benzoxazepine PI3K inhibitor compounds and methods of use
The present invention relates generally to compounds having anti-cancer activity and more specifically to compounds that inhibit PI3 kinase activity. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells or associated pathological conditions.
The present invention provides benzoxaazanesCompounds and pharmaceutical formulations thereof, which are potentially useful for treating diseases, conditions and/or disorders modulated by PI3 kinase.
In one aspect, the present invention provides compounds of formula I, including stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof:
wherein Z1Is CR1Or N; z2Is CR2Or N; z3Is CR3Or N; z4Is CR4Or N; and B is a group with benzoxaazaneA ring-fused pyrazolyl, imidazolyl or triazolyl ring. Each substituent is as defined herein.
More specifically, the present invention provides compounds of formula I or stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof:
wherein
Z1Is CR1Or N;
Z2is CR2Or N;
Z3is CR3Or N;
Z4is CR4Or N;
b is a radical of a heterocyclic oxygen with a benzoxaneA ring fused pyrazolyl, imidazolyl, or triazolyl ring and selected from the following structures:
R1、R2、R3and R4Independently selected from H, F, Cl, Br, I, -CN, -COR10、-CO2R10、-C(＝O)N(R10)OR11、-C(＝NR10)NR10R11、-C(＝O)NR10R11、-NO2、-NR10R11、-NR12C(＝O)R10、-NR12C(＝O)OR11、-NR12C(＝O)NR10R11、-NR12C(＝O)(C1-C12Alkylene) NR10R11、-NR12(C1-C12Alkylene) NR10R11、-NR12(C1-C12Alkylene) OR10、-NR12(C1-C12Alkylene) C (═ O) NR10R11、-OR10、-S(O)2R10、-C(＝O)NR10(C1-C12Alkylene) NR10R11、-C(＝O)NR10(C1-C12Alkylene) NR10C(＝O)OR11、-C(＝O)NR10(C1-C12Alkylene) NR10C(＝O)R11、-C(＝O)NR10(C1-C12Alkylene) R10、C1-C12Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C12Carbocyclyl, C2-C20Heterocyclic group, C6-C20Aryl radical, C1-C20Heteroaryl, - (C)3-C12Carbocyclyl) - (C1-C12Alkyl), - (C)2-C20Heterocyclyl) - (C) 1-C12Alkyl), - (C)6-C20Aryl group) - (C1-C12Alkyl), - (C)1-C20Heteroaryl) - (C)1-C12Alkyl), - (C)1-C12Alkylene group) - (C3-C12Carbocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)3-C12Carbocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) -C (═ O) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C1-C20Heteroaryl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)1-C12Alkyl), - (C)1-C12Alkylene group) - (C6-C20Aryl group) - (C1-C12Alkyl), - (C)1-C12Alkylene group) - (C1-C20Heteroaryl) - (C)1-C12Alkyl), - (C)1-C12Alkylene) -C (═ O) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene) C (═ O) OR10、-(C1-C12Alkylene) -NR10R11、-(C1-C12Alkylene) NR12C(＝O)R10、-(C1-C12Alkylene) OR10、-(C1-C12Alkylene) -NR10-(C1-C12Alkylene group) - (C1-C20Heteroaryl), - (C)1-C12Alkylene) -NR10-(C1-C12Alkylene group) - (C1-C20Heterocyclyl), - (C)1-C12Alkylene) -NR10-(C1-C12Alkylene) -NHC (═ O) - (C)1-C20Heteroaryl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) -NR10R11And- (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)1-C12Alkyl) -NR10R11，
Wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, R10、-SR10、-S(O)2R10、-S(O)2NR10R11、-NR10R11、-NR12C(O)R10、-CO2R10、-C(O)R10、-CONR10R11Oxo and-OR10；
A is selected from-C (═ O) NR5R6、-NR5R6、C6-C20Aryl radical, C2-C20Heterocyclyl and C1-C20Heteroaryl, wherein said aryl, heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CN, -COR 10、-CO2R10、-C(＝O)N(R10)OR11、-C(＝NR10)NR10R11、-C(＝O)NR10R11、-NO2、-NR10R11、-NR12C(＝O)R10、-NR12C(＝O)OR11、-NR12C(＝O)NR10R11、-NR12C(＝O)(C1-C12Alkylene) NR10R11、-NR12(C1-C12Alkylene) NR10R11、-NR12(C1-C12Alkylene) OR10、-NR12(C1-C12Alkylene) C (═ O) NR10R11、-OR10、-S(O)2R10、-C(＝O)NR10(C1-C12Alkylene) NR10R11、-C(＝O)NR10(C1-C12Alkylene) NR10C(＝O)OR11、-C(＝O)NR10(C1-C12Alkylene) NR10C(＝O)R11、-C(＝O)NR10(C1-C12Alkylene) R10、C1-C12Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C12Carbocyclyl, C2-C20Heterocyclic group, C6-C20Aryl radical, C1-C20Heteroaryl, - (C)3-C12Carbocyclyl) - (C1-C12Alkyl), - (C)2-C20Heterocyclyl) - (C)1-C12Alkyl), - (C)6-C20Aryl group) - (C1-C12Alkyl), - (C)1-C20Heteroaryl) - (C)1-C12Alkyl), - (C)1-C12Alkylene group) - (C3-C12Carbocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)3-C12Carbocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) -C (═ O) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C1-C20Heteroaryl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)1-C12Alkyl), - (C)1-C12Alkylene group) - (C6-C20Aryl group) - (C1-C12Alkyl), - (C)1-C12Alkylene group) - (C1-C20Heteroaryl) - (C)1-C12Alkyl), - (C)1-C12Alkylene) -C (═ O) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene) C (═ O) OR10、-(C1-C12Alkylene) -NR10R11、-(C1-C12Alkylene) NR12C(＝O)R10、-(C1-C12Alkylene) OR10、-(C1-C12Alkylene) -NR10-(C1-C12Alkylene group) - (C1-C20Heteroaryl), - (C)1-C12Alkylene) -NR10-(C1-C12Alkylene group) - (C1-C20Heterocyclyl), - (C)1-C12Alkylene) -NR10-(C1-C12Alkylene) -NHC (═ O) - (C)1-C20Heteroaryl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) -NR10R11And- (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)1-C12Alkyl) -NR10R11，
Wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, R 10、-SR10、-S(O)2R10、-NR10R11、-NR12C(O)R10、-CO2R10、-C(O)R10、-CONR10R11and-OR10；
R5Selected from H and C1-C12Alkyl optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CN, -CO2H、-CONH2、-CONHCH3、-NH2、-NO2、-N(CH3)2、-NHCOCH3、-NHS(O)2CH3、-OH、-OCH3、-OCH2CH3、-S(O)2NH2and-S (O)2CH3；
R6Is selected from C1-C12Alkyl radical, C3-C12Carbocyclyl, C2-C20Heterocyclic group, C1-C20Heteroaryl and C6-C20Aryl, each of which is optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH3、-CH2OH、-CH2C6H5(i.e., benzyl), -CN, -CF3、-CO2H、-C(O)CH3、-NH2、-NO2、-N(CH3)2、-NHCOCH3、-NHS(O)2CH3-OH, oxo, -OCH3、-OCH2CH3、-S(O)2NH2、-S(O)2CH3、-C(＝O)NR10(C1-C12Alkylene) NR10R11Phenyl, pyridyl, tetrahydro-furan-2-yl, 2, 3-dihydro-benzofuran-2-yl, 1-isopropyl-pyrrolidin-3-ylmethyl, morpholin-4-yl, piperidin-1-yl, piperazinyl, 2-oxo-piperazin-4-yl, 3-oxo-piperazin-4-yl, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, -C ≡ CR13、-CH＝CHR13and-C (═ O) NR10R11(ii) a Or
R5And R6Together with the nitrogen atom to which they are attached form C2-C20Heterocyclyl or C1-C20Heteroaryl, optionally substituted with one or more groups selected from: F. cl, Br, I, CH3、C(CH3)3、-CH2OH、-CH2CH2OH、-CH2C6H5Pyridin-2-yl, 6-methyl-pyridin-2-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-2-yl, pyrazin-2-yl, tetrahydrofuran-carbonyl, 2-methoxy-phenyl, benzoyl, cyclopropylmethyl, (tetrahydrofuran-2-yl) methyl, 2, 6-dimethyl-morpholin-4-yl, 4-methyl-piperazin-carbonyl, pyrrolidine-1-carbonyl, cyclopropanecarbonyl, 2, 4-difluoro-phenyl, pyridin-2-ylmethyl, morpholin-4-yl, -CN, -CF 3、-CO2H、-CONH2、-CONHCH3、-CON(CH3)2、-COCF3、-COCH3、-COCH(CH3)2、-NO2、NHCH3、-N(CH3)2、-N(CH2CH3)2、-NHCOCH3、-NCH3COCH3、-NHS(O)2CH3、-OH、-OCH3、-OCH2CH3、-CH2OCH3、-CH2CH2OCH3、-CH2S(O)2NHCH3、-CH2S(O)2CH2CH3、-S(O)2NHCH3、-S(O)2CH2CH3、-S(O)2NH2、-S(O)2N(CH3)2and-S (O)2CH3；
R10、R11And R12Independently selected from H, C1-C12Alkyl, - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C6-C20Aryl), - (C)1-C12Alkylene group) - (C3-C12Carbocyclyl), C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C12Carbocyclyl, C2-C20Heterocyclic group, C6-C20Aryl radicalsAnd C1-C20Heteroaryl, each of which is optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH3、-CH2CH3、-CH(CH3)2、-CH2OH、-CH2OCH3、-CH2CH2OH、-C(CH3)2OH、-CH2C(CH3)2OH、-CH2CH(CH3)OH、-CH2CO2H、-CH2CO2CH3、-CH2NH2、-(CH2)2N(CH3)2、-CH2C6H5、-CN、-CF3、-CO2H、-C(O)CH3、-C(O)CH(OH)CH3、-CO2CH3、-CONH2、-CONHCH3、-CON(CH3)2、-C(CH3)2CONH2、-NH2、-NO2、-N(CH3)2、-N(CH3)C(CH3)2CONH2、-N(CH3)CH2CH2S(O)2CH3、-NHCOCH3、-NHS(O)2CH3O (oxo), -OH, -OCH3、-OCH2CH3、-OCH2CH2OH、-OP(O)(OH)2、-SCH3、-S(O)2CH3、-S(O)2NH2、-S(O)2N(CH3)2、-CH2S(O)2NHCH3、-CH2S(O)2CH2CH3、-S(O)2NHCH3、-S(O)2CH2CH3Pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, cyclopropyl, cyclopentyl, oxetanyl, 4-methylpiperazin-1-yl and morpholin-4-yl; or
R10And R11When attached to a nitrogen atom, together with the nitrogen atom to which they are attached form C2-C20Heterocyclyl ring or C1-C20Heteroaryl rings, each of which is optionally substituted with one or more independent substituentsA group selected from: F. cl, Br, I, -CH3、-CH2OH、-CH2C6H5、-CN、-CF3、-CO2H、-CONH2、-CONHCH3、-NO2、-N(CH3)2、-NHCOCH3、-NHS(O)2CH3-OH, oxo, -OCH3、-OCH2CH3、-S(O)2NH2、-S(O)2CH3、-CH(CH3)2、-CH2CF3、-CH2CH2OH and-C (CH)3)2OH; and is
R13Selected from H, F, Cl, Br, I, -CH3、-CH2CH3、-CN、-CF3、-CH2N(CH3)2、-CH2OH、-CO2H、-CONH2、-CON(CH3)2、-NO2and-S (O)2CH3。
More specifically, the present invention provides compounds of formula I or stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof:
wherein
Z1Is CR1Or N;
Z2is CR2Or N;
Z3is CR3Or N;
Z4is CR4Or N;
b is a radical of a heterocyclic oxygen with a benzoxaneA ring fused pyrazolyl, imidazolyl, or triazolyl ring and selected from the following structures:
R1、R2、R3And R4Independently selected from H, F, Cl, Br, I, -CN, -COR10、-CO2R10、-C(＝O)N(R10)OR11、-C(＝NR10)NR10R11、-C(＝O)NR10R11、-NO2、-NR10R11、-NR12C(＝O)R10、-NR12C(＝O)OR11、-NR12C(＝O)NR10R11、-NR12C(＝O)(C1-C12Alkylene) NR10R11、-NR12(C1-C12Alkylene) NR10R11、-NR12(C1-C12Alkylene) OR10、-NR12(C1-C12Alkylene) C (═ O) NR10R11、-OR10、-S(O)2R10、-C(＝O)NR10(C1-C12Alkylene) NR10R11、-C(＝O)NR10(C1-C12Alkylene) NR10C(＝O)OR11、-C(＝O)NR10(C1-C12Alkylene) NR10C(＝O)R11、-C(＝O)NR10(C1-C12Alkylene) R10、C1-C12Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C12Carbocyclyl, C2-C20Heterocyclic group, C6-C20Aryl radical, C1-C20Heteroaryl, - (C)3-C12Carbocyclyl) - (C1-C12Alkyl), - (C)2-C20Heterocyclyl) - (C)1-C12Alkyl), - (C)6-C20Aryl group) - (C1-C12Alkyl), - (C)1-C20Heteroaryl) - (C)1-C12Alkyl), - (C)1-C12Alkylene group) - (C3-C12Carbocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)3-C12Carbocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) -C (═ O) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C1-C20Heteroaryl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)1-C12Alkyl), - (C)1-C12Alkylene group) - (C6-C20Aryl group) - (C1-C12Alkyl), - (C)1-C12Alkylene group) - (C1-C20Heteroaryl) - (C)1-C12Alkyl), - (C)1-C12Alkylene) -C (═ O) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene) C (═ O) OR10、-(C1-C12Alkylene) -NR10R11、-(C1-C12Alkylene) NR12C(＝O)R10、-(C1-C12Alkylene) OR10、-(C1-C12Alkylene) -NR10-(C1-C12Alkylene group) - (C1-C20Heteroaryl), - (C)1-C12Alkylene) -NR10-(C1-C12Alkylene group) - (C1-C20Heterocyclyl), - (C)1-C12Alkylene) -NR10-(C1-C12Alkylene) -NHC (═ O) - (C)1-C20Heteroaryl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) -NR10R11And- (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)1-C12Alkyl) -NR 10R11，
Wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, R10、-SR10、-S(O)2R10、-S(O)2NR10R11、-NR10R11、-NR12C(O)R10、-CO2R10、-C(O)R10、-CONR10R11Oxo and-OR10；
A is selected from-C (═ O) NR5R6、-NR5R6、C6-C20Aryl radical, C2-C20Heterocyclyl and C1-C20Heteroaryl, wherein said aryl, heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CN, -COR10、-CO2R10、-C(＝O)N(R10)OR11、-C(＝NR10)NR10R11、-C(＝O)NR10R11、-NO2、-NR10R11、-NR12C(＝O)R10、-NR12C(＝O)OR11、-NR12C(＝O)NR10R11、-NR12C(＝O)(C1-C12Alkylene) NR10R11、-NR12(C1-C12Alkylene) NR10R11、-NR12(C1-C12Alkylene) OR10、-NR12(C1-C12Alkylene) C (═ O) NR10R11、-OR10、-S(O)2R10、-C(＝O)NR10(C1-C12Alkylene) NR10R11、-C(＝O)NR10(C1-C12Alkylene) NR10C(＝O)OR11、-C(＝O)NR10(C1-C12Alkylene) NR10C(＝O)R11、-C(＝O)NR10(C1-C12Alkylene) R10、C1-C12Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C12Carbocyclyl, C2-C20Heterocyclic group, C6-C20Aryl radical, C1-C20Heteroaryl, - (C)3-C12Carbocyclyl) - (C1-C12Alkyl), - (C)2-C20Heterocyclyl) - (C)1-C12Alkyl), - (C)6-C20Aryl group) - (C1-C12Alkyl), - (C)1-C20Heteroaryl) - (C)1-C12Alkyl), - (C)1-C12Alkylene group) - (C3-C12Carbocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)3-C12Carbocyclyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) -C (═ O) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C1-C20Heteroaryl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)1-C12Alkyl), - (C)1-C12Alkylene group) - (C6-C20Aryl group) - (C1-C12Alkyl), - (C)1-C12Alkylene group) - (C1-C20Heteroaryl) - (C) 1-C12Alkyl), - (C)1-C12Alkylene) -C (═ O) - (C)2-C20Heterocyclyl), - (C)1-C12Alkylene) C (═ O) OR10、-(C1-C12Alkylene) -NR10R11、-(C1-C12Alkylene) NR12C(＝O)R10、-(C1-C12Alkylene) OR10、-(C1-C12Alkylene) -NR10-(C1-C12Alkylene group) - (C1-C20Heteroaryl), - (C)1-C12Alkylene) -NR10-(C1-C12Alkylene group) - (C1-C20Heterocyclyl), - (C)1-C12Alkylene) -NR10-(C1-C12Alkylene) -NHC (═ O) - (C)1-C20Heteroaryl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) -NR10R11And- (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) - (C)1-C12Alkyl) -NR10R11，
Wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, Br, I, R10、-SR10、-S(O)2R10、-NR10R11、-NR12C(O)R10、-CO2R10、-C(O)R10、-CONR10R11and-OR10；
R5Selected from H and C1-C12Alkyl optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CN, -CO2H、-CONH2、-CONHCH3、-NH2、-NO2、-N(CH3)2、-NHCOCH3、-NHS(O)2CH3、-OH、-OCH3、-OCH2CH3、-S(O)2NH2and-S (O)2CH3；
R6Is selected from C1-C12Alkyl radical, C3-C12Carbocyclyl, C2-C20Heterocyclic group, C1-C20Heteroaryl and C6-C20Aryl, each of which is optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH3、-CH2OH、-CH2C6H5、-CN、-CF3、-CO2H、-C(O)CH3、-NH2、-NO2、-N(CH3)2、-NHCOCH3、-NHS(O)2CH3-OH, oxo, -OCH3、-OCH2CH3、-S(O)2NH2、-S(O)2CH3、-C(＝O)NR10(C1-C12Alkylene) NR10R11Phenyl, pyridyl, tetrahydro-furan-2-yl, 2, 3-dihydro-benzofuran-2-yl, 1-isopropyl-pyrrolidin-3-ylmethyl, morpholin-4-yl, piperidin-1-yl, piperazinyl, 2-oxo-piperazin-4-yl, 3-oxo-piperazin-4-yl, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, -C ≡ CR 13、-CH＝CHR13and-C (═ O) NR10R11(ii) a Or
R5And R6Together with the nitrogen atom to which they are attached form C2-C20Heterocyclyl or C1-C20Heteroaryl, optionally substituted with one or more groups selected from: F. cl, Br, I, CH3、C(CH3)3、-CH2OH、-CH2CH2OH、-CH2C6H5Pyridin-2-yl, 6-methyl-pyridin-2-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-2-yl, pyrazin-2-yl, tetrahydrofuran-carbonyl, 2-methoxy-phenyl, benzoyl, cyclopropylmethyl, (tetrahydrofuran-2-yl) methyl, 2, 6-dimethyl-morpholin-4-yl, 4-methyl-piperazin-carbonyl, pyrrolidine-1-carbonyl, cyclopropanecarbonyl, 2, 4-difluoro-phenyl, pyridin-2-ylmethyl, morpholin-4-yl, -CN, -CF3、-CO2H、-CONH2、-CONHCH3、-CON(CH3)2、-COCF3、-COCH3、-COCH(CH3)2、-NO2、NHCH3、-N(CH3)2、-N(CH2CH3)2、-NHCOCH3、-NCH3COCH3、-NHS(O)2CH3、-OH、-OCH3、-OCH2CH3、-CH2OCH3、-CH2CH2OCH3、-CH2S(O)2NHCH3、-CH2S(O)2CH2CH3、-S(O)2NHCH3、-S(O)2CH2CH3、-S(O)2NH2、-S(O)2N(CH3)2and-S (O)2CH3；
R10、R11And R12Independently selected from H, C1-C12Alkyl, - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C6-C20Aryl), - (C)1-C12Alkylene group) - (C3-C12Carbocyclyl), C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C12Carbocyclyl, C2-C20Heterocyclic group, C6-C20Aryl and C1-C20Heteroaryl, each of which is optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH3、-CH2CH3、-CH(CH3)2、-CH2OH、-CH2OCH3、-CH2CH2OH、-C(CH3)2OH、-CH2C(CH3)2OH、-CH2CH(CH3)OH、-CH2CO2H、-CH2CO2CH3、-CH2NH2、-(CH2)2N(CH3)2、-CH2C6H5、-CN、-CF3、-CO2H、-C(O)CH3、-C(O)CH(OH)CH3、-CO2CH3、-CONH2、-CONHCH3、-CON(CH3)2、-C(CH3)2CONH2、-NH2、-NO2、-N(CH3)2、-N(CH3)C(CH3)2CONH2、-N(CH3)CH2CH2S(O)2CH3、-NHCOCH3、-NHS(O)2CH3O (oxo), -OH, -OCH3、-OCH2CH3、-OCH2CH2OH、-OP(O)(OH)2、-SCH3、-S(O)2CH3、-S(O)2NH2、-S(O)2N(CH3)2、-CH2S(O)2NHCH3、-CH2S(O)2CH2CH3、-S(O)2NHCH3、-S(O)2CH2CH3Pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, cyclopropyl, cyclopentyl, oxetanyl, 4-methylpiperazin-1-yl and morpholin-4-yl; or
R10And R11Together with the nitrogen atom to which they are attached form C 2-C20Heterocyclyl ring or C1-C20A heteroaryl ring, each of which is optionally substituted with one or more groups independently selected from: F. cl, Br, I, -CH3、-CH2OH、-CH2C6H5、-CN、-CF3、-CO2H、-CONH2、-CONHCH3、-NO2、-N(CH3)2、-NHCOCH3、-NHS(O)2CH3-OH, oxo, -OCH3、-OCH2CH3、-S(O)2NH2、-S(O)2CH3、-CH(CH3)2、-CH2CF3、-CH2CH2OH and-C (CH)3)2OH; and is
R13Selected from H, F, Cl, Br, I, -CH3、-CH2CH3、-CN、-CF3、-CH2N(CH3)2、-CH2OH、-CO2H、-CONH2、-CON(CH3)2、-NO2and-S (O)2CH3。
Reference will now be made in detail to some embodiments of the invention, examples of which are illustrated in the accompanying structural formulae and chemical formulae. While the invention will be described in conjunction with the listed embodiments, it will be understood that they are not intended to limit the invention to these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize a variety of methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. If one or more of the incorporated documents, patents, and similar materials differ or contradict the present application (including but not limited to defined terms, usage of terms, described techniques, etc.), the present application controls.
The term "alkyl" as used herein refers to a compound having 1 to 12 carbon atoms (C) 1-C12) Wherein the alkyl group may be optionally independently substituted with one or more of the following substituents. In another embodiment, the alkyl group has one to eight carbon atoms (C)1-C8) Or one to six carbon atoms (C)1-C6). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) Propan-1-yl (n-Pr, n-propyl, -CH)2CH2CH3) Propan-2-yl (i-Pr, isopropyl, -CH (CH)3)2) But-1-yl (n-Bu, n-butyl, -CH)2CH2CH2CH3) 2-methylpropan-1-yl (i-Bu, isobutyl, -CH)2CH(CH3)2) But-2-yl (s-Bu, sec-butyl, -CH (CH)3)CH2CH3) 2-methylpropan-2-yl (t-Bu, tert-butyl, -C (CH)3)3) Pentan-1-yl (n-pentyl, -CH)2CH2CH2CH2CH3) Pentan-2-yl (-CH (CH)3)CH2CH2CH3) Pentan-3-yl (-CH (CH)2CH3)2) 2-methylbut-2-yl (-C (CH)3)2CH2CH3) 3-methylbut-2-yl (-CH (CH)3)CH(CH3)2) 3-methylbut-1-yl (-CH)2CH2CH(CH3)2) 2-methylbut-1-yl (-CH)2CH(CH3)CH2CH3) Hex-1-yl (-CH)2CH2CH2CH2CH2CH3) Hex-2-yl (-CH (CH)3)CH2CH2CH2CH3) Hex-3-yl (-CH (CH)2CH3)(CH2CH2CH3) 2-methylpent-2-yl (-C (CH))3)2CH2CH2CH3) 3-methylpent-2-yl (-CH (CH)3)CH(CH3)CH2CH3) 4-methylpent-2-yl (-CH (CH)3)CH2CH(CH3)2) 3-methylpent-3-yl (-C (CH)3)(CH2CH3)2) 2-methylpent-3-yl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethylbut-2-yl (-C (CH)3)2CH(CH3)2) 3, 3-dimethylbut-2-yl (-CH (CH)3)C(CH3)3Hept-1-yl, oct-1-yl, and the like.
The term "alkylene" as used herein refers to a group having 1 to 12 carbon atoms (C) 1-C12) Wherein the alkylene group may be optionally independently substituted with one or more of the following substituents. In another embodiment, the alkylene has one to eight carbon atoms (C)1-C8) Or one to six carbon atoms (C)1-C6). Examples of alkylene groups include, but are not limited to, methylene (-CH)2-) ethylene (-CH2CH2-) propylene (-CH)2CH2CH2-) and the like.
The term "alkenyl" refers to a group having 2 to 8 carbon atoms (C)2-C8) And having at least one site of unsaturation, i.e., a carbon-carbon sp2A double bond, wherein said alkenyl group may be optionally independently substituted with one or more substituents described herein and includes having "cis" and "trans" orientations (or "E" and "Z" orientations)) A group of (1). Examples include, but are not limited to, ethenyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) And the like.
The term "alkenylene" refers to a compound having 2-8 carbon atoms (C)2-C8) And having at least one site of unsaturation, i.e., a carbon-carbon sp2A double bond, wherein said alkenyl group may be optionally substituted and includes groups having "cis" and "trans" orientations (or "E" and "Z" orientations). Examples include, but are not limited to, ethenylene (-CH-), allylene (-CH) 2CH-) and the like.
The term "alkynyl" refers to a compound having 2-8 carbon atoms (C)2-C8) And a straight or branched monovalent hydrocarbon group having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein said alkynyl group may be optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C ≡ CH), propynyl (propargyl, -CH)2C.ident.CH) and the like.
The term "alkynylene" refers to a compound having 2-8 carbon atoms (C)2-C8) And a straight or branched chain divalent hydrocarbon radical having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein said alkynyl radical may be optionally substituted. Examples include, but are not limited to, ethynylene (-C ≡ C-), propynyl (propargylene, -CH)2C.ident.C-), and the like.
The terms "carbocycle", "carbocyclyl", "carbocycle", and cycloalkyl "refer to a compound having 3 to 12 carbon atoms (C)3-C12) Monovalent non-aromatic saturated or partially unsaturated rings in the form of a single ring or in the form of a ring having 7 to 12 carbon atoms. Bicyclic carbocycles having 7 to 12 atoms may be arranged, for example, as bicyclo [4, 5 ]]System, bicyclo [5, 5 ]]System, bicyclo [5, 6 ]]Systems or bicyclo [6, 6 ]]Bicyclic carbocycles of a system and having 9 or 10 ring atoms may be arranged as a bicyclo [5, 6 ] ]Systems or bicyclo [6, 6 ]]Systems or arrangements for bridging systems such as bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane and bicyclo [3.2.2]Nonane. Examples of monocyclic carbocycles include, but are not limited toIn cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-1-en-1-yl, cyclopent-2-en-1-yl, cyclopent-3-en-1-yl, cyclohexyl, cyclohex-1-en-1-yl, cyclohex-2-en-1-yl, cyclohex-3-en-1-yl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like.
"aryl" means having 6 to 20 carbon atoms (C)6-C20) A monovalent aromatic hydrocarbon group of (a), which is obtained by: one hydrogen atom is removed from one carbon atom in the parent aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ar". Aryl includes bicyclic groups containing an aromatic ring fused to a saturated, partially unsaturated, or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, biphenyl (biphenyl), indene (indenyl), indan (indanyl), 1, 2-dihydronaphthalene, 1, 2, 3, 4-tetrahydronaphthalene (1, 2, 3, 4-tetrahydronaphthyl), and the like. Aryl groups may be optionally substituted independently with one or more substituents described herein.
"arylene" means having 6 to 20 carbon atoms (C)6-C20) A divalent aromatic hydrocarbon group of (a), which is obtained by: two hydrogen atoms are removed from two carbon atoms in the parent aromatic ring system. Some arylene groups are represented as "Ar" in the exemplary structures. Arylene includes bicyclic groups containing an aromatic ring fused to a saturated, partially unsaturated, or aromatic carbocyclic ring. Typical arylene groups include, but are not limited to, groups derived from benzene (phenylene), substituted benzenes, naphthalene, anthracene, biphenyl (biphenylene), indene (indenylene), indane (indanylene), 1, 2-dihydronaphthalene, 1, 2, 3, 4-tetrahydronaphthalene (1, 2, 3, 4-tetrahydronaphthalene subunit), and the like. The arylene group may be optionally substituted.
The terms "heterocycle" (heterocyclic), "heterocyclyl" and "heterocyclic" are used interchangeably herein and refer to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds in the ring) carbocyclic group having from 3 to about 20 ring atoms, at least one of which is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remainder of which are ring atomsAnd is C, wherein one or more ring atoms are optionally independently substituted with one or more substituents described below. The heterocycle may be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or a bicyclic ring (e.g., bicyclo [4, 5 ] having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S) ]System, bicyclo [5, 5 ]]System, bicyclo [5, 6 ]]Systems or bicyclo [6, 6 ]]A system). Heterocycles are described in Paquette, Leo a.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968) (in particular chapters 1, 3, 4, 6, 7 and 9); "The chemistry company, A series of monograms" (John Wiley&Sons, new york, 1950to present) (especially volumes 13, 14, 16, 19 and 28); and j.am.chem.soc. (1960) 82: 5566. "Heterocyclyl" also includes groups in which a heterocyclyl group is fused to a saturated ring, a partially unsaturated ring, an aromatic carbocyclic ring, or an aromatic heterocyclic ring. Examples of heterocycles include, but are not limited to, morpholin-4-yl, piperidin-1-yl, piperazinyl, 2-oxo-piperazin-4-yl, 3-oxo-piperazin-4-yl, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azetidin-1-yl, octahydropyrido [1, 2-a ] group]Pyrazin-2-yl, [1, 4 ]]Diazepan-1-yl, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thiexocyclohexyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxaazazepanyl Radical diazaThio-aza radical2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranylDioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithiacyclohexyl, dithiocyclopentyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0]Hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo [2.2.2]Hexyl, 3H-indolyl, quinolizinyl and N-pyridylurea groups. Spirocyclic moieties are also included within the scope of this definition. Examples of heterocyclyl groups in which 2 ring atoms are substituted with an oxo (═ O) moiety are pyrimidinone groups and 1, 1-dioxo-thiomorpholinyl groups. The heterocyclyl groups of the present application are optionally independently substituted with one or more substituents described herein.
The term "heteroaryl" refers to a monovalent aromatic group in the form of a 5, 6 or 7 membered ring containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur and includes fused ring systems (wherein at least one ring is aromatic) having 5 to 20 atoms. Examples of heteroaryl groups are pyridyl (including, for example, 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionally independently substituted with one or more substituents described herein.
The heterocyclyl or heteroaryl group may be attached via carbon or via nitrogen, where applicable. For example, and without limitation, a carbon-linked heterocyclyl or heteroaryl group is attached at the following positions: 2, 3, 4, 5 or 6 position of pyridine; the 3, 4, 5 or 6 position of pyridazine; 2, 4, 5 or 6 positions of pyrimidine; 2, 3, 5 or 6 position of pyrazine; 2, 3, 4 or 5 positions of furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole; 2, 4 or 5 position of oxazole, imidazole or thiazole; the 3, 4 or 5 position of isoxazole, pyrazole or isothiazole; 2 or 3 position of aziridine; the 2, 3 or 4 position of azetidine; 2, 3, 4, 5, 6, 7 or 8 positions of quinoline; or 1, 3, 4, 5, 6, 7 or 8 positions of isoquinoline.
For example, but not limited to, a nitrogen-linked heterocyclyl or heteroaryl group is attached at the following positions: aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, or 1H-indazole at the 1-position; 2-position of isoindoline or isoindoline; 4-position of morpholine; and the 9-position of carbazole or β -carboline.
The term "treatment" refers to both therapeutic treatment and prophylactic measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e., not worsening) of the disease state, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "treatment" may also mean an extended survival compared to the expected survival without treatment. Those in need of treatment include those already with the condition or disorder as well as those susceptible to the condition or disorder or those in which the condition or disorder is to be prevented.
The phrase "therapeutically effective amount" means (i) the amount of a compound of the present invention that treats or prevents the particular disease, condition, or disorder described herein; (ii) an amount of a compound of the invention that attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder described herein; or (iii) an amount of a compound of the invention that prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. For cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or relieve to some extent one or more symptoms associated with cancer. The drug may be cytostatic and/or cytotoxic if it can prevent the growth of cancer cells and/or kill existing cancer cells. For cancer treatment, efficacy can be measured, for example, by assessing time to disease progression (TTP) and/or determining Response Rate (RR).
The term "cancer" refers to or describes the physiological state in mammals that is typically characterized by dysregulated cell growth. A "tumor" includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of the above cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma); lung cancer, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung, and squamous carcinoma of the lung; peritoneal cancer; hepatocellular carcinoma; gastric or gastric cancer, including gastrointestinal cancer; pancreatic cancer; a glioblastoma; cervical cancer; ovarian cancer; liver cancer; bladder cancer; liver cancer; breast cancer; colon cancer; rectal cancer; colorectal cancer; endometrial or uterine cancer; salivary gland cancer; kidney cancer or renal cancer; prostate cancer; vulvar cancer; thyroid cancer; liver cancer; anal cancer; penile cancer; and head and neck cancer.
A "chemotherapeutic agent" is a compound useful in the treatment of cancer, regardless of the mechanism of action. Classes of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, spindle toxic plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy. Examples of chemotherapeutic agents include erlotinib (Tarceva)Genentech/OSI Pharm.), docetaxel (docetaxel) (TAXOTERE)Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CASNO.51-21-8), gemcitabine (Gemcitabine) (GEMZAR)Lilly), PD-0325901(CAS No.391210-10-9, Pfizer), cisplatin (cisclinin) (cis-diamineplatinum (II) dichloride, CAS No.15663-27-1), carboplatin (CAS No.41575-94-4), paclitaxel (paclitaxel) (TAXOL)Bristol-Myers Squibb Oncology, Princeton, N.J.), trastuzumab (trastuzumab) (HERCEPTINGenentech), temozolomide (temozolomide) (4-methyl-5-oxo-2, 3, 4, 6, 8-pentaazabicyclo [4.3.0 ]]Nonane-2, 7, 9-triene-9-carboxamide, CAS No.85622-93-1, TEMODAR ，TEMODALSchering Plough), tamoxifen (tamoxifen) ((Z) -2- [4- (1, 2-diphenylbut-1-enyl) phenoxy]-N, N-dimethylethylamine, NOLVADEX，ISTUBAL，VALODEX) Doxorubicin (doxorubicin) (ADRIAMYCIN)) Akti-1/2, HPPD and LeiPatulin (rapamycin).
Other examples of chemotherapeutic agents include oxaliplatin (oxaliplatin) (ELOXATIN)Sanofi), bortezomib (Bortezomib) (VELCADE)Millennium Pharm.), SUNITINIB (sutentib)SU 11248, Pfizer), letrozole (FEMARA)Novartis), imatinib mesylate (GLEEVEC)Novartis), XL-518(MEK inhibitor, Exelixis, WO 2007/044515), ARRY-886(MEK inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126(PI3K inhibitor, SemaforPharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147(PI3K inhibitor, Exelixis), PTK787/ZK 222584(Novartis), fulvestrant (fulvestrant) (FASLODEX)AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus), rapamycin (rapamycin)Wyeth), lapatinib (TYKERB)，GSK572016，GlaxoSmith Kline)、lonafarnib(SARASARTMSCH 66336, Schering Plough), Sorafenib (Nexavar) BAY43-9006, Bayer Labs), gefitinib (IRESSA)AstraZeneca), irinotecan (CAMPTOSAR)，CPT-11，Pfizer)、tipifarnib(ZARNESTRATM，Johnson & Johnson)、ABRAXANETM(without Cremophor), albumin engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Il), vandetanib (rINN, ZD6474, ZACTIMA)AstraZeneca), chlorambucil (chlorambucil), AG 1478, AG 1571(SU 5271; sugen), temsirolimus (Torisel)，Wyeth)、pazopanib(Glaxo SmithKline)、canfosfamide(TELCYTATelik), thiotepa and cyclophosphamide (cycloxan)，NEOSAR) (ii) a Alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines (ethylenimine) and methylaminoacridines (methyamelamines) including hexamethylmelamine (altretamine), triimizine (triethyleneamine), triethylenephosphoramide (triethylenephosphoramide), triethylenephosphoramide (triethylenesulfide)thiophosphoramide) and trimethymemimine; annonaceous acetogenins (especially bullatacin and bullatacin); camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin (adozelesin), carvelesin (carzelesin), and bizelesin (bizelesin) synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin (dolastatin); duocarmycins (including the synthetic analogs KW-2189 and CB1-TM 1); eiscosahol (eleutherobin); pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil (chlorambucil), chlorambucil (chlorenaphazine), chlorophosphamide (chlorophosphamide), estramustine (estramustine), ifosfamide (ifosfamide), mechlorethamine (mechlorethamine), mechlorethamine hydrochloride (mechlorethamine), melphalan (melphalan), neomustard (novembichin), benzene mustard cholesterol (phenyleneterester), prednimustine (prednimustine), trofosfamide (trofosfamide) and uramustine (uracil mustard); nitroureas such as carmustine (carmustine), chlorouretocin (chlorozotocin), fotemustine (fotemustine), lomustine (lomustine), nimustine (nimustine) and ramustine (ranirnustine); antibiotics, such as enediyne (endidiyne) antibiotics (e.g., calicheamicin, including calicheamicin γ 1I and calicheamicin ω I1(Angew chem. intel. ed. engl. (1994) 33: 183-186); dynemicin, including dynemicin a; bisphosphonates, such as clodronate (clodronate); esperamicin (esperamicin); the neooncostatin chromophore (neocarzinostatin chromophore) and related chromoprotein enediyne antibiotic chromophores (relatedchromoproteine endinic chromophores), the classes of aclacinomyins, actinomycins (actinomycins), aurramycins, azaserines (azaserines), bleomycin (bleomycin), actinomycin C (cactinomycin), carabicins, carminomycins (carminomycins), carcinostatins (carzinophilins), tryptomycin (chromomycins), actinomycin D (dactinomycins), daunorubicins (daunorubicins), ditorelbirubicins (detonbucins), 6-diazo-5-oxo-L-norleucine (6-diaza-5-oxo-L-norleu. cine), morpholino-doxorubicin (morpholino-doxorubicin), cyanomorpholino-doxorubicin (cyanomorpholo-doxorubicin), 2-pyrrolidino-doxorubicin (2-pyrrolino-doxorubicin), deoxydoxorubicin (deoxydoxorubicin), epirubicin (epirubicin), esorubicin (esorubicin), idarubicin (idarubicin), nemorubicin (nemorubicin), mariomycin (marcellomamycin), mitomycin (mitomycin) classes such as mitomycin C (mitomycin C), mycophenolic acid (mycophenolic acid), noramycin (nogalamycin), olivomycin (olivomycin), pelomomycin (peplomycin), poisomycin (porfiromycin), puromycin (puromycin), triiron doxorubicin (quelamycin), rodobicin (rodorubicin), streptomycin (streptonigrin), streptozocin (streptozocin), tubercidin (tubicidin), ubenimex (ubenimex), zinostatin (zinostatin), and zorubicin; antimetabolites such as methotrexate (methotrexate) and 5-fluorouracil (5-fluorouracil) (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin and trimetrexate; purine analogs such as fludarabine (fludarabine), 6-mercaptopurine (6-mercaptopurine), thiamiprine (thiamiprine), and thioguanine (thioguanine); pyrimidine analogs such as ancitabine (ancitabine), azacitidine (azacitidine), 6-azauridine (6-azauridine), carmofur (carmofur), cytarabine (cytarabine), dideoxyuridine (dideoxyuridine), doxifluridine (doxifluridine), enocitabine (enocitabine), and floxuridine (floxuridine); androgens such as carposterone (calusterone), methyl androsterone propionate (dromostanolone propionate), epitioandrostanol (epitiostanol), mepiquitane (mepiquitane), and testolactone (testolactone); anti-adrenergic agents (anti-adrenals), such as aminoglutethimide, mitotane and trilostane; folic acid supplements such as folinic acid (frilic acid); acetoglucurolactone (acegultone); an aldophosphamide glycoside (aldophosphamide glycoside); aminolevulinic acid (aminolevulinic acid); eniluracil (eniluracil); amsacrine (amsacrine); bestrabuucil; bisantrene; idazot (edatraxate); diphosphamide (def) ofamine); colchicine (demecolcine); diazaquinone (diaziqutone); elfornitine; ammonium etitanium acetate; epothilone (epothilone); etoglut (etoglucid); gallium nitrate (gallium nitrate); hydroxyurea (hydroxyurea); lentinan (lentinan); lonidamine (lonidainine); maytansinol (maytansinoid) classes such as maytansinoid (maytansine) and ansamitocins (ansamitocins); mitoguazone (mitoguzone); mitoxantrone (mitoxantrone); mopidanmol; rhizobia (nitrarine); pentostatin (pentostatin); methionine mustard (phenamett); pirarubicin (pirarubicin); losoxantrone (losoxantrone); podophyllinic acid (podophyllic acid); 2-ethylhydrazine (2-ethylhydrazine); procarbazine (procarbazine); PSKPolysaccharide complex (PSK)polysaccharide complex) (JHS Natural Products, Eugene, OR); razoxane (rizoxane); rhizomycin (rhizoxin); sizofuran (sizofiran); germanium spiroamines (spirogyranium); tenuazonic acid (tenuazonic acid); triimine quinone (triaziquone); 2, 2 ', 2 "-trichlorotriethylamine (2, 2', 2" -trichlorotriethylamine); trichothecenes (trichothecenes) (especially T-2 toxin, veracurin A, bacillocin A (roridin A) and anguidine); urethane (urethan); vindesine (vindesine); dacarbazine (dacarbazine); mannomustine (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactol); pipobromane (pipobroman); a polycytidysine; cytarabine (arabine) ("Ara-C"); cyclophosphamide; thiotepa; 6-thioguanine (6-thioguanine); mercaptopurine (mercaptoprine); methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine (vinblastine); etoposide (VP-16); ifosfamide; mitoxantrone (mitoxantrone); vincristine (vincristine); vinorelbine (vinorelbine) (NAVELBINE) ) (ii) a Norfloxacin (novantrone); teniposide (teniposide); idazocide (edatrexate); daunorubicin (daunomycin); aminopterin (aminopterin); capecitabine (XELODA)Roche); ibandronate (ibandronate); CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids (retinoids), such as retinoic acid (retinic acid); and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.
The following are also included in the definition of "chemotherapeutic agents": (i) anti-hormonal agents such as anti-estrogens (anti-estrogen) and Selective Estrogen Receptor Modulators (SERMs) including, for example, tamoxifen (including NOLVADEX) for modulating or inhibiting the effects of hormones on tumors(ii) a Tamoxifen citrate), raloxifene (raloxifene), droloxifene (droloxifene), 4-hydroxytamoxifen (4-hydroxytamoxifen), trioxifene (trioxifene), raloxifene (ketoxifene), LY117018, onapristone (onapristone), and FARESTON(toremifene citrate); (ii) aromatase inhibitors which inhibit aromatase (aromatase regulates estrogen production in the adrenal gland), such as 4(5) -imidazoles, aminoglutethimide, MEGASE Megestrol acetate (megestrol acetate), AROMASIN(exemestane (Pfizer), formestanie, fadrozole, and rivistor)(Volvo chlorine)Oxazole (vorozole)), FEMARA(letrozole; Novartis) and ARIMIDEX(anastrozole; AstraZeneca); (iii) anti-androgens (anti-androgens), such as flutamide (flutamide), nilutamide (nilutamide), bicalutamide (bicalutamide), leuprolide (leuprolide), and goserelin (goserelin), and troxacitabine (troxacitabine) (1, 3-dioxolane nucleoside cytosine analogues)); (iv) protein kinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) a lipid kinase inhibitor; (vi) antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, e.g., PKC- α, Ralf, and H-Ras, such as oblimersen (GENASENSE)Genta Inc.); (vii) ribozymes, such as VEGF expression inhibitors (e.g., ANGIOZYME)) And inhibitors of HER2 expression; (viii) vaccines, such as gene therapy vaccines, e.g. ALLOVECTIN、LEUVECTINAnd VAXID；PROLEUKINrIL-2; topoisomerase 1 inhibitors, such as lutotecan (ii) a And ABARELIXrmRH; (ix) anti-angiogenic agents, such as bevacizumab (AVASTIN)Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.
Therapeutic antibodies are also included in the definition of "chemotherapeutic agents", such as alemtuzumab (Campath), bevacizumab (AVASTIN)Genentech); cetuximab (ERBITUX)Imclone); palmazumab (Vectibix)Amgen), Rituximab (RITUXAN)Genentech/Biogen Idec), pertuzumab (OMNITARG)TM2C4, Genentech), trastuzumab (HERCEPTIN)Genentech), tositumomab (tositumomab) (Bexxar, Corixia) and the antibody drug conjugate ogitumomab ozogamicin (MYLOTARG) (myootrg)，Wyeth)。
Humanized monoclonal antibodies having therapeutic potential as chemotherapeutic agents for use in combination with the PI3K inhibitors of the invention include alemtuzumab (alemtuzumab), aprezumab (apilizumab), alemtuzumab (aselizumab), atlizumab (atlizumab), bapineuzumab, bevacizumab, mabuzumab (bivatuzumab), moccantuzumab (canazumab mertansine), cetilizumab (cedelizumab), cetuximab (cetuzumab), ciduzumab (ciduzumab), daclizumab (daclizumab), eculizumab (eculizumab), efalizumab (epratuzumab), epratuzumab (epuzumab), linumumab (erlitumumab), panlizumab (fevinuzumab), rituzumab (rituximab), poluzumab (olanzumab), tumumab (otelizumab), tumumab (tumumab), linuzumab (tamuzumab), rituzumab (tamuzumab), rituximab (netuzumab), rituximab (rituximab), rituximab (rituximab, Palivizumab (palivizumab), paclobuzumab (paclobuzumab), pecluzumab (pecluzumab), pertuzumab (petuzumab), pevizumab (pexelizumab), ralvizumab (ranibizumab), rayleigh mab (relivizumab), resyvizumab (roveluzumab), lulitumumab (ruplizumab), sibutrumab (sibutrumab), sibirizumab (sibilizumab), solurizumab (soluzumab), tatuzumab (tacatuzumab), taduzumab (taltuzumab tetraxetan), talucizumab (taluzumab), teluzumab (tebazumab), tuzumab (tocuzumab), tositumumab (tollizumab), tralizumab (toralizumab), trolizumab (taclizumab), trastuzumab (toralizumab), paclobuzumab (tuzumab), and wuxizumab (wuxituzumab).
A "metabolite" is a product produced by the in vivo metabolism of a particular compound or salt thereof. Metabolites of compounds can be identified using conventional techniques known in the art and their activity can be determined using the assays described herein. Such products may be derived, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolite thereof.
The term "package insert" refers to instructions typically included in commercial packages of therapeutic products that contain information regarding the indications, usage, dosage, administration, contraindications, and/or precautions relating to the use of the therapeutic products described above.
The term "chiral" refers to a molecule that has a mirror image partner (mirror image partner) non-superimposability, while the term "achiral" refers to a molecule that can be superimposed with its mirror image partner.
The term "stereoisomers" refers to compounds having the same chemical composition but differing in the spatial arrangement of the atoms or groups.
"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography.
"enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.
The stereochemical definitions and general knowledge used herein generally correspond to those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. The present invention is intended to include all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers), and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active form, i.e. they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) designate the symbols by which the compound rotates plane polarized light, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers and mixtures of the above isomers are often referred to as mixtures of enantiomers. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when a chemical reaction or process is not stereoselective or stereospecific. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, which are not optically active.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert through a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.
The phrase "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1' -methylene-bis (2-hydroxynaphthalene-3-formate)). A pharmaceutically acceptable salt may involve the introduction of another molecule such as an acetate, succinate or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the parent compound charge. In addition, pharmaceutically acceptable salts may have more than one charged atom in their structure. When multiple charged atoms are present in the pharmaceutically acceptable salt, the pharmaceutically acceptable salt can have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.
If the compounds of the invention are bases, the desired pharmaceutically acceptable salts can be prepared by any suitable method known in the art, for example by treatment of the free base with an inorganic (such as hydrochloric, hydrobromic, sulfuric, nitric, methanesulfonic, phosphoric, and the like) or organic acid (such as acetic, trifluoroacetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, oxalic, glycolic, salicylic, pyranosyl, such as glucuronic or galacturonic, alpha-hydroxy, such as citric or tartaric acid, amino acid, such as aspartic or glutamic acid, aromatic acid, such as benzoic or cinnamic acid, sulfonic acid, such as p-toluenesulfonic or ethanesulfonic acid, and the like).
If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from: amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine; and inorganic salts obtained from: sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
The phrase "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith.
"solvate" refers to an association or complex of one or more solvent molecules with a compound of the invention. Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
The terms "compounds of the invention" and "compounds of formula I" include compounds of formula I and stereoisomers, geometric isomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof.
Any formula or structural formula given herein, including the compounds of formula I, is also intended to represent hydrates, solvates, and polymorphs of the above compounds, and mixtures thereof.
Any formulae or structural formulae given herein, including compounds of formula I, are also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically-labeled compounds have the structure depicted in the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to 2H (deuterium, D),3H (tritium),11C、13C、14C、15N、18F、31P、32P、35S、36Cl and125I. the invention includes various isotopically-labeled compounds of the invention, e.g., radioactive isotopes such as3H、13C and14those compounds of the present invention into which C is introduced. The isotopically labeled compounds described above are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays or in the treatment of patients with radioactivity. Therapeutic compounds of the invention labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetics) properties, including absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements). Warp beam18Conversion of F-tagThe compounds are useful in PET or SPECT studies. Isotopically-labeled compounds of the present invention and prodrugs thereof can generally be prepared as follows: the procedures disclosed in the schemes or examples and preparations below were performed and the non-isotopically labeled reagents were replaced with readily available isotopically labeled reagents. In addition, with heavier isotopes, especially deuterium (i.e. deuterium) 2H or D) may result in some therapeutic advantages (e.g. increased in vivo half-life or reduced dosage requirements or improved therapeutic index) due to better metabolic stability. It is to be understood that deuterium in the present application is considered as a substituent in the compounds of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. Any atom in the compounds of the present invention that is not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a location is specifically designated as "H" or "hydrogen," it is understood that the location has a concentration of hydrogen that is the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) is intended to represent deuterium.
BenzoxazepinesCompound (I)
Exemplary embodiments of the compounds of formula I include those wherein Z is1Is CR1；Z2Is CR2；Z3Is CR3(ii) a And Z is4Is CR4。
Exemplary embodiments of the compounds of formula I include those wherein Z is1Is N; z2Is CR2；Z3Is CR3(ii) a And Z is4Is CR4。
Exemplary embodiments of the compounds of formula I include those wherein Z is 1Is CR1；Z2Is N; z3Is CR3(ii) a And Z is4Is CR4。
Exemplary embodiments of the compounds of formula I include those wherein Z is1Is CR1；Z2Is CR2；Z3Is N; and Z is4Is CR4。
Exemplary embodiments of the compounds of formula I include those wherein Z is1Is CR1；Z2Is CR2；Z3Is CR3(ii) a And Z is4Is N.
An exemplary embodiment of the compounds of formula I are those wherein B is a structure of formula (a).
An exemplary embodiment of the compounds of formula I are those wherein B is a structure of formula (B).
An exemplary embodiment of the compounds of formula I are those wherein B is a structure of formula (c).
An exemplary embodiment of the compounds of formula I are those wherein B is a structure of formula (d).
An exemplary embodiment of the compounds of formula I are those wherein B is a structure of formula (e).
An exemplary embodiment of the compounds of formula I are those wherein B is a structure of formula (f).
An exemplary embodiment of the compounds of formula I are those wherein B is a structure of formula (g).
Exemplary embodiments of the compounds of formula I include those wherein Z is1Is CR1；Z2Is CR2；Z3Is CR3；Z4Is CR4(ii) a And B is a structure of formula (a), (B), (d), (e), (f) or (g).
Exemplary embodiments of the compounds of formula I include those wherein Z is 1Is CR1；Z2Is CR2；Z3Is CR3；Z4Is CR4(ii) a And B is a structure of formula (a), (B), (d) or (g).
Exemplary embodiments of the compounds of formula I include those wherein Z is1Is CR1；Z2Is CR2；Z3Is CR3；Z4Is CR4(ii) a And B is a structure of formula (a) or (d).
Exemplary embodiments of compounds of formula I include those wherein a is-C (═ O) NR5R6。
Exemplary embodiments of the compounds of formula I include those wherein R is5Is CH3。
Exemplary embodiments of the compounds of formula I include those wherein R is6Is phenyl substituted with one or more groups independently selected from: F. cl, Br, I, -CH2OH、-CH2C6H5、-CN、-CF3、-CO2H、-CONH2、-CONHCH3、-NO2、-N(CH3)2、-NHCOCH3、-NHS(O)2CH3、-OH、-OCH3、-OCH2CH3、-S(O)2NH2、-S(O)2CH3Morpholin-4-yl, piperidin-1-yl, piperazinyl, 2-oxo-piperazin-4-yl, 3-oxo-piperazin-4-yl, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, -C ≡ CR13and-CH ═ CHR13。
Exemplary embodiments of the compounds of formula I include those wherein R is5And R6Together with the nitrogen atom to which they are attached form morpholin-4-yl, piperidin-1-yl, piperazinyl, 2-oxo-piperazin-4-yl, 3-oxo-piperazin-4-yl, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azocin-1-yl, azetidin-1-yl, octahydropyrido [1, 2-a ] group ]Pyrazin-2-yl, [1, 4 ]]Diazepan-1-yl or indolinyl.
Exemplary embodiments of compounds of formula I include those wherein a is-C (═ O) NR5R6Wherein R is5Is CH3And R is6Is phenyl substituted with one or more groups independently selected from: F. cl, Br, I, -CH2OH、-CH2C6H5、-CN、-CF3、-CO2H、-CONH2、-CONHCH3、-NO2、-N(CH3)2、-NHCOCH3、-NHS(O)2CH3、-OH、-OCH3、-OCH2CH3、-S(O)2NH2、-S(O)2CH3Morpholin-4-yl, piperidin-1-yl, piperazinyl, 2-oxo-piperazin-4-yl, 3-oxo-piperazin-4-yl, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, -C ≡ CR13and-CH ═ CHR13。
Exemplary embodiments of compounds of formula I include those wherein a is-C (═ O) NR5R6Wherein R is5Is CH3And R is6Is phenyl, said phenyl being substituted with one or more F.
Exemplary embodiments of the compounds of formula I include those wherein A is C2-C20Heterocyclyl or C1-C20Heteroaryl substituted with-CH2OH、-CH2CO2H、-CH(CH3)CH2OCH3、-CH3、-CH(CH3)2、-CH2CH(CH3)2、-CH2CF3、-C(＝O)CH3、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-CO2H、-CO2CH3、-CH2CO2CH3、-NH2、-NHC(＝O)CH3、-OH、-OCH3、-S(O)2CH31-methylpiperidin-4-yl, 4-methylpiperazin-1-yl, morpholin-4-yl, (4-methylpiperazin-1-yl) carboxamide group, -CH2(1H-1, 2, 4-triazol-5-yl), cyclopropyl, cyclopropylmethyl or cyclobutyl.
A compound of formula IExemplary embodiments include compounds wherein A is C1-C20Heteroaryl selected from the group consisting of pyridyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, 1, 3, 4-oxadiazol-2 (3H) -one radical, furyl, thienyl, 1, 2, 3-triazolyl, 1, 2, 4-triazol-5 (4H) -one radical, 4, 5-dihydro-1, 2, 4-triazin-6 (1H) -one radical, tetrazolyl, pyrrolo [2, 3-b ] pyrrole ]Pyridyl, indazolyl, 3, 4-dihydroquinolinyl and benzo [ d]A thiazolyl group.
Exemplary embodiments of compounds of formula I include compounds wherein a is selected from the following structures:
wherein R is9Independently selected from H, F, Cl, Br, I, -CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH2OH、-CH2CO2H、-CH(CH3)CH2OCH3、-CN、-CF3、-CH2CF3、-CH2NH2、-CH2CH2NH2、-C(＝O)CH3、-CH2C(＝O)NHCH3、-C(＝O)NHCH3、-CO2H、-CH2CO2CH3、-NH2、-OH、-OCH3、-SCH3、-S(O)2CH3Cyclopropyl, cyclopropylmethyl, 1-methylpiperidin-4-yl, 4-methylpiperazin-1-yl, morpholin-4-yl-ethyl, benzyl and phenyl, wherein the benzyl and phenyl are optionally substituted with one or more groups selected from: F. cl, Br, I, -CH2OH、-CH2CO2H、-CN、-CH2NH2、-CH3、-C(＝O)CH3、-C(＝O)NHCH3、-CO2H、-CH2CO2CH3、-NH2、-OCH3、-S(O)2CH31-methylpiperidin-4-yl, 4-methylpiperazin-1-yl and morpholin-4-yl; and wherein the wavy line represents the connection site.
Exemplary embodiments of compounds of formula I include those wherein A is a group of formula (I):
wherein R is9Independently selected from H, F, Cl, Br, I, -CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH2OH、-CH2CO2H、-CH(CH3)CH2OCH3、-CN、-CF3、-CH2CF3、-CH2NH2、-CH2CH2NH2、-C(＝O)CH3、-CH2C(＝O)NHCH3、-C(＝O)NHCH3、-CO2H、-CH2CO2CH3、-NH2、-OH、-OCH3、-SCH3、-S(O)2CH3Cyclopropyl, cyclopropylmethyl, 1-methylpiperidin-4-yl, 4-methylpiperazin-1-yl, morpholin-4-yl-ethyl, benzyl and phenyl, wherein the benzyl and phenyl are optionally substituted with one or more groups selected from: F. cl, Br, I, -CH2OH、-CH2CO2H、-CN、-CH2NH2、-CH3、-C(＝O)CH3、-C(＝O)NHCH3、-CO2H、-CH2CO2CH3、-NH2、-OCH3、-S(O)2CH31-methylpiperidin-4-yl, 4-methylpiperazin-1-yl and morpholin-4-yl; and wherein the wavy line represents the connection site.
Of the compound of formula I Exemplary embodiments include compounds wherein A is a group of formula (i), wherein R9Is independently selected from-CH3、-CH(CH3)2、-NH2And a phenyl group, wherein the phenyl group is optionally substituted with one or more groups selected from: f and Cl.
Exemplary embodiments of compounds of formula I include compounds wherein a is selected from the following structures:
wherein the wavy line indicates the connection site.
Exemplary embodiments of compounds of formula I include compounds wherein A is a group of formula (ii), (iii), (iv), (v), or (vi):
exemplary embodiments of compounds of formula I include those wherein A is a group of formula (ii) or (vi).
Exemplary embodiments of the compounds of formula I include those wherein Z is1Is CR1；Z2Is CR2；Z3Is CR3；Z4Is CR4(ii) a B is a structure of formula (a) or (d); and A is a group of formula (ii) or (vi).
Exemplary embodiments of the compounds of formula I include those wherein Z is1Is CR1；Z2Is CR2；Z3Is CR3；Z4Is CR4(ii) a B is a knot of formula (a)Structuring; and A is a group of formula (vi).
Exemplary embodiments of the compounds of formula I include those wherein Z is1Is CR1；Z2Is CR2；Z3Is CR3；Z4Is CR4(ii) a B is a structure of formula (d); and A is a group of formula (vi).
Exemplary embodiments of compounds of formula I include compounds of formula Ih:
Wherein R is1、R2、R3、R4And a has the meaning as defined above for the compounds of formula I.
Exemplary embodiments of compounds of formula Ih include those wherein R is1、R2、R3And R4Independently selected from H, Br, -C (═ O) NR10R11、C2-C20Heterocyclyl or- (C)2-C20Heterocyclyl) - (C)1-C12Alkyl), wherein the alkyl is optionally substituted with-S (O)2R10(ii) a A is selected from C1-C20Heteroaryl, wherein the heteroaryl is optionally substituted with one or more- (C)6-C20Aryl groups); wherein said aryl group is optionally substituted with one or more groups independently selected from: f and Cl; and R is10And R11Independently selected from hydrogen and C1-C12An alkyl group.
Exemplary embodiments of compounds of formula Ih include those wherein R is1Is hydrogen, R2Is hydrogen, Br, -C (O) NH2Or 1- (2-methanesulfonyl-ethyl) -azetidin-3-yl, R3Is hydrogen or piperidin-4-yl, R4Is hydrogen and A is 2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl or 2- (2-chloro-phenyl) -2H- [1, 2, 4]Triazol-3-yl.
Exemplary embodiments of the compounds of formula I include compounds of formula Ii:
wherein R is1、R2、R3、R4And a has the meaning as defined above for the compounds of formula I.
An exemplary embodiment of a compound of formula Ii is a compound wherein R is1、R2、R3And R4Independently selected from H, F, -C (═ O) NR10R11、-(C2-C20Heterocyclyl) - (C)1-C12Alkyl) or- (C) 1-C20Heteroaryl) - (C)1-C12Alkyl), wherein the alkyl is optionally substituted with one or more groups independently selected from: -NR10R11Oxo and-OR10(ii) a A is C1-C20Heteroaryl, wherein the heteroaryl is optionally substituted with one or more groups independently selected from: -NR10R11、C1-C12Alkyl and C6-C20An aryl group; wherein said aryl is optionally substituted with one or more Cl; and R is10And R11Independently selected from H and C1-C12An alkyl group.
An exemplary embodiment of a compound of formula Ii is a compound wherein
R1Is hydrogen;
R2is hydrogen, F or a group of the formula:
R3is hydrogen or-C (O) NH2；
R4Is hydrogen(ii) a And is
A is 1-isopropyl-1H- [1, 2, 4] triazol-5-yl, 1-isopropyl-3-methyl-1H- [1, 2, 4] triazol-5-yl, 1-isopropyl-3-amino-1H- [1, 2, 4] triazol-5-yl or 1- (2-chlorophenyl) -1H- [1, 2, 4] triazol-5-yl.
Exemplary embodiments of compounds of formula I include compounds of formula Ij:
wherein R is1、R2、R3、R4And a has the meaning as defined above for the compounds of formula I.
An exemplary embodiment of the compounds of formula Ij is a compound wherein R is1、R2、R3And R4Independently selected from H and- (C)2-C20Heterocyclyl) - (C)1-C12Alkyl groups); wherein said heterocyclyl is optionally substituted with one OR more-OR10(ii) a A is selected from-C (═ O) NR5R6And C1-C20Heteroaryl, wherein said heteroaryl is optionally substituted with one or more C 1-C12An alkyl group; r5Is C1-C12An alkyl group; r6Is C6-C20Aryl optionally substituted with one or more F; and R is10Is H.
An exemplary embodiment of the compounds of formula Ij is a compound wherein
R1Is hydrogen;
R2is hydrogen;
R3is hydrogen or a group of the formula:
R4is hydrogen; and is
A is a group of the formula:
exemplary embodiments of compounds of formula I include compounds of formula Ik:
exemplary embodiments of compounds of formula I include compounds of formula Im:
exemplary embodiments of the compounds of formula I include compounds of formula In:
exemplary embodiments of the compounds of formula I include compounds of formula Ip:
exemplary embodiments of compounds of formula I include compounds of formula Iq:
exemplary embodiments of compounds of formula I include compounds of formula Ir:
wherein A has the meaning as described above for the compounds of the formula I.
An exemplary embodiment of compounds of formula Ir are those wherein A is C1-C20Heteroaryl, wherein the heteroaryl is optionally substituted with one or more groups independently selected from: c1-C12Alkyl, for example a is a group of the formula:
the present invention relates generally to benzoxaazanes of formula I having anti-cancer activity and more specifically PI3 kinase inhibitory activityA compound is provided. Some hyperproliferative disorders are characterized by modulation of PI3 kinase function, for example due to mutation or overexpression of the protein. Thus, the compounds of the present invention are useful for the treatment of hyperproliferative disorders such as cancer. The compounds can inhibit tumor growth in mammals and are useful for treating human cancer patients.
The invention also relates to the use of benzoxaazanes of formula IMethods of in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions with compounds.
Another aspect of the invention provides methods of inhibiting PI3 kinase activity comprising contacting PI3 kinase with an effective inhibitory amount of a compound of formula I.
The PI3 kinase activity of the compounds of formula I can be determined by a variety of direct and indirect assays. P110 α and other isoforms PI3K binding activity (example 901) and in vitro anti-tumor cell activity (example 902) were determined for some of the exemplary compounds described herein. Some exemplary compounds of the invention have a PI3K binding activity IC of less than 10nM50The value is obtained. Some compounds of the invention have a tumor cell-based activity EC of less than 100nM50The value is obtained.
In one aspect, the present invention provides a method for inhibiting or modulating the activity of a lipid kinase, comprising contacting said lipid kinase with an effective inhibitory amount of a compound as defined herein. In one aspect, the present invention provides a method for inhibiting or modulating PI3K activity, comprising contacting said PI3K with an effective inhibitory amount of a compound as defined herein. In one aspect, the present invention provides a method for inhibiting or modulating the activity of the PI3K p110 a subunit, comprising contacting said PI3K p110 a subunit with an effective inhibitory amount of a compound as defined herein.
In one aspect, the present invention provides a method for inhibiting or modulating lipid kinase activity, e.g. PI3K activity, in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound as defined herein.
The cytotoxic or cytostatic activity of exemplary compounds of formula I is measured as follows: proliferative mammalian tumor cell lines were established in cell culture medium, compounds of formula I were added, cells were cultured for about 6 hours to about 5 days and cell viability was measured (example 902). Cell-based in vitro assays for measuring viability, i.e., proliferation (IC)50) Cytotoxicity (EC)50) And induction of apoptosis (caspase activation).
In vitro potency of exemplary Compounds of formula I by cell proliferation assay CellTiter-GloViability assay of luminogenic cells (from Pro)mega corp., Madison, WI) (example 902). The homogeneous assay method is based on recombinant expression of coleopteran luciferase (Coleoptera luciferase) (US 5583024; US 5674713; US 5700670) and the number of cells surviving in the culture medium is determined by quantifying the ATP present (an indicator of metabolically active cells) (Crouch et al (1993) J.Immunol.meth.160: 81-88; US 6602677). CellTiter-Glo Assays were performed in 96 or 384 well plates, making them suitable for automated High Throughput Screening (HTS) (Cree et al (1995) AntiCancer Drugs 6: 398-404). The homogeneous assay procedure involves a single reagent (CellTiter-Glo)Reagents) were added directly to the cells cultured in medium supplemented with serum. There is no need for washing the cells, removing the medium and multiple pipetting steps. After adding the reagents and mixing, the system only needs to detect 15 cells/well in 384-well plates in 10 minutes.
The homogeneous "add-mix-measure" plate lyses the cells and produces a luminescent signal proportional to the amount of ATP present. The amount of ATP is directly proportional to the number of cells present in the medium. CellTiter-GloThe assay produces a "glow-type" luminescent signal due to the luciferase reaction, which has a half-life of typically more than five hours, depending on the cell type and the medium used. Surviving cells are reflected in Relative Luminescence Units (RLU). The substrate luciferin is oxidatively decarboxylated by recombinant firefly luciferase, with conversion of ATP to AMP and production of photons. The extended half-life eliminates the need for using a reagent syringe and provides flexibility for continuous or batch mode processing of multiple plates. The cell proliferation assay can be used with a variety of multi-well plates, such as 96 or 384 well plates. Data may be recorded by a luminometer or a CCD camera imaging device. The luminous output is recorded Is the Relative Light Unit (RLU) measured over time.
Antiproliferative effects of exemplary compounds of formula I on several tumor cell lines were measured by CellTiter-GloDetermined (example 902) to measure. Determination of the potency EC of a test Compound50The value is obtained. The in vitro cell potency activity ranges from about 100nM to about 10. mu.M. Some test compounds had an EC of less than 1 micromolar (1. mu.M) in stopping proliferation of some tumor cell lines50The value is obtained.
Some ADME properties of some exemplary compounds are measured by assays that include Caco-2 permeability (example 903), hepatocyte clearance (example 904), cytochrome P450 inhibition (example 905), cytochrome P450 induction (example 906), plasma protein binding (example 907), and hERG channel blocking (example 908).
The efficacy of some exemplary compounds was tested in a dose escalation study by administering (example 909) to a tumor xenograft Taconic nude mouse model. Some exemplary compounds of formula I and vehicle (MCT, negative control) were administered to a mouse model of the breast cancer cell line MDA-MB-361.1. Tumor growth delay was measured when orally administered at 50 and 100mg/kg daily for 21 days. The change of body weight with the course of treatment was measured as a safety index. Treatment of a mouse model of MDA-MB-361.1 with some of the exemplified compounds of formula I resulted in tumor growth arrest, inhibition, or reversal when administered orally daily for 21 days.
Exemplary compounds of formula I identified in Table 1 as 101-294, Table 2 as 295-533 and Table 3 as 534-570 were prepared, characterized and tested for inhibition of PI3K alpha (IC) according to the methods of the present invention50p110 α is less than 1 micromolar (μ M)) and selectivity and these compounds have the following structure and corresponding name (ChemDraw Ultra, version 9.0.1, cambridge soft corp. For example, compound 101 has an IC of 0.77 micromolar50(ii) a Compound 102 has a concentration of 0.003 micromolarIC of degree50(ii) a Compound 103 has an IC of 0.058 micromolar50(ii) a Compound 154 IC with 0.00091 micromolar concentration50(ii) a Compound 170 has an IC of 0.022 micromolar concentration50(ii) a Compound 171 has an IC of 0.00066 micromolar50(ii) a Compound 180 has an IC of 0.00018 micromolar50(ii) a Compound 200 has an IC of 0.0020 micromolar50(ii) a Compound 248 IC with 0.00037 micromolar concentration50(ii) a Compound 251 has an IC of 0.0014 micromolar50(ii) a Compound 253 has an IC of 0.0044 micromolar50(ii) a And compound 280 has an IC of 0.20 micromolar50。
TABLE 1
TABLE 2
TABLE 3
The compounds of formula I of the present invention may be administered by any route suitable for the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. For local immunosuppressive therapy, the compound may be administered by administration to the injury area (including perfusion or contacting the graft with an inhibitor prior to transplantation). It will be appreciated that the preferred route may vary, for example, with the condition of the receptor. When the compound is administered orally, it may be formulated with a pharmaceutically acceptable carrier or excipient into pills, capsules, tablets, and the like. When the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle and into unit dosage injectable forms, as described below.
The dose for treating a human patient may be from about 10mg to about 1000mg of a compound of formula I. A typical dose may be from about 100mg to about 300mg of the compound. The dose may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties of the particular compound, including absorption, distribution, metabolism, and excretion. In addition, toxicity factors can affect dosage and dosing regimens. When administered orally, the pills, capsules or tablets may be taken daily or less frequently for a prescribed period of time. The dosing regimen may be repeated for a number of treatment cycles.
Another aspect of the invention provides a method of preventing or treating a hyperproliferative disease or disorder modulated by PI3 kinase, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I. Examples of such hyperproliferative diseases or disorders include, but are not limited to, cancer.
Another aspect of the invention provides a method of preventing or treating a hyperproliferative disorder comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I alone or in combination with one or more other compounds that are anti-hyperproliferative.
In another aspect, the invention provides methods of treating a hyperproliferative disease or disorder modulated by PI3 kinase in a mammal using the compounds of the invention.
Another aspect of the invention is the use of a compound of the invention for the treatment of cancer modulated by PI3 kinase in a mammal.
The compounds of formula I of the present invention are useful for treating hyperproliferative diseases, conditions and/or disorders, including but not limited to those characterized by the overexpression of a lipid kinase, such as PI3 kinase. Accordingly, another aspect of the invention includes methods of treating or preventing a disease or condition that can be treated or prevented by inhibiting a lipid kinase, including PI 3. In one embodiment, the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I, or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, a human patient is treated with a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the compound of formula I is present in an amount that detectably inhibits PI3 kinase activity.
The compounds of formula I are also useful in the treatment of protein kinases such as PIM (I) Proviral Insertion，Moloney) (e.g., the genes Pim-1, Pim-2 and Pim-3 involved in lymphoma and solid tumor development) are characterized by hyperproliferative diseases characterized by overexpression of those protein kinases (Cuypers et al (1984) Cell, vol.37(1) pp.141-50; selten et al (1985) EMBO J.vol.4(7) pp.1793-8; van der Lugt et al (1995) EMBO J.vol.14(11) pp.2536-44; mikkers et al (2002) Nature Genetics, vol.32(1) pp.153-9; van Lohuizen et al (1991) Cell, vol.65(5) pp.737-52).
Cancers that may be treated according to the methods of the invention include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, myeloid disorders, lymphoid disorders, hairy cell cancer, oral and pharyngeal (oral) cancer, lip cancer, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain cancer, and central nervous system cancer, and Hodgkin's disease (Hodgkin's) and leukemia.
The compounds of formula I are useful for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions such as systemic and local inflammation, immunoinflammatory diseases such as rheumatoid arthritis, immunosuppression, organ transplant rejection, allergy, ulcerative colitis, Crohn's disease, dermatitis, asthma, systemic lupus erythematosus, sjogren's syndrome (j: (r) (r))Syndrome), multiple sclerosis, sclerodermaDisease/systemic sclerosis, Idiopathic Thrombocytopenic Purpura (ITP), anti-neutrophilic cytoplasmic antibody (ANCA) vasculitis, Chronic Obstructive Pulmonary Disease (COPD), and psoriasis.
The compounds of formula I are useful in the treatment of disorders of the brain and central nervous system that require crossing the blood-brain barrier. Some compounds of formula I have advantageous properties with respect to delivery to the brain. Brain disorders that can be effectively treated with the compounds of formula I include metastatic and primary brain tumors, such as glioblastoma and melanoma.
The compounds of formula I may be used to treat ocular disorders by topical delivery to the eye. Some compounds of formula I have advantageous properties for delivery to the eye.
Another aspect of the invention provides a compound of the invention for use in treating a disease or condition described herein in a mammal, such as a human, suffering from such a disease or condition. The invention also provides the use of a compound of the invention in the manufacture of a medicament for use in the treatment of diseases and conditions described herein in a warm-blooded animal such as a mammal, e.g. a human, suffering from such diseases and conditions.
For the therapeutic treatment (including prophylactic treatment) of mammals (including humans) using compounds of formula I, they are generally formulated in accordance with standard pharmaceutical practice as pharmaceutical compositions. This aspect of the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.
In another aspect of the invention, pharmaceutical compositions are provided comprising benzoxaazanes of formula IA compound and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise one or more other therapeutic agents.
Typical formulations are prepared by mixing a compound of formula I with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include the following: such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc. The particular carrier, diluent or excipient employed will depend upon the mode and purpose for which the compounds of the present invention are to be employed. Solvents are generally selected based on the solvents (GRAS) that one skilled in the art would consider safe for administration to mammals. Generally, the safe solvent is a non-toxic aqueous solvent such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), and the like, and mixtures thereof. The formulation may further comprise one or more of the following: buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, and other known additives to impart a superior appearance to a drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the preparation of a pharmaceutical product (i.e., a drug).
The formulations may be prepared using conventional dissolution and mixing operations. For example, a quantity of the drug substance, i.e., a stabilized form of a compound of the invention or a compound of formula I (e.g., a complex with a cyclodextrin derivative or other known complexing agent), is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide easily controllable dosages of the drug and to enable patient compliance with prescribed dosing regimens.
Pharmaceutical compositions (or formulations) for administration can be packaged in a variety of ways, depending on the method of administration. Typically, the articles for dispensing comprise a container having disposed therein a pharmaceutical formulation in a suitable form. Suitable containers are well known to those skilled in the art and include the following: such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-resistant assembly that prevents inadvertent access to the contents of the package. In addition, the container has disposed thereon a label describing the contents of the container. The label may also include appropriate precautions.
Pharmaceutical formulations of the compounds of the present invention may be prepared for a variety of routes and types of administration. For example, a compound of formula I having the desired purity may optionally be admixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1980)16th edition, Osol, A.Ed.) in the form of a lyophilized formulation, a finely divided powder or an aqueous solution. The formulation can be carried out as follows: mixed at ambient temperature and at a suitable pH in the desired purity with a physiologically acceptable carrier, i.e. a carrier which is non-toxic to the recipient at the dosages and concentrations used. The pH of the formulation depends primarily on the particular use and concentration of the compound, but can range from about 3 to about 8. A formulation with a pH of 5 in acetate buffer is a suitable embodiment.
The compounds of the invention for use in the present application are preferably sterile. In particular, formulations for in vivo administration must be sterile. The above-mentioned sterilization is easily accomplished by filtration with a sterile filtration membrane.
The compounds can generally be stored in the form of solid compositions, lyophilized formulations or aqueous solutions.
The pharmaceutical compositions of the present invention comprising the compounds of formula I will be formulated, dosed and administered in a manner consistent with good medical practice, i.e., in amounts, concentrations, schedules, procedures, vehicles and routes of administration. Factors considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the drug, the method of administration, the timing of administration, and other factors known to medical practitioners. The "therapeutically effective amount" of the compound to be administered will depend on the above factors considered and is the minimum amount required to prevent, ameliorate or treat the disorder mediated by the coagulation factor. The above amount is preferably lower than an amount that is toxic to the host or renders the host significantly more susceptible to bleeding.
As a general proposition, the initial pharmaceutically effective amount of a compound of formula I administered parenterally will be about 0.01-100mg/kg, i.e., about 0.1 to 20mg/kg, patient body weight/day in each dose, with a typical initial range of 0.3 to 15 mg/kg/day for the compound used.
Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; chlorhexidine di-ammonium; benzalkonium chloride, benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; penta-3-ol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants, such as TWEEN TM、PLURONICSTMOr polyethylene glycol (PEG). The active pharmaceutical ingredient may also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. See Remington's pharmaceutical Sciences 16th edition, Osol, A.Ed. (1980).
Sustained release formulations of the compounds of formula I can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound of formula I, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl methacrylate) or poly (vinyl alcohol)), polylactides (U.S. Pat. Nos. 3, 7)73,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOTTM(microspheres for injection composed of lactic acid-glycolic acid copolymer and leuprorelin acetate) and poly D- (-) -3-hydroxybutyric acid.
Such formulations include those suitable for the routes of administration described herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). The above method comprises the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Typically, the formulations are prepared as follows: the active ingredient is mixed homogeneously and intimately with liquid carriers or finely divided solid carriers or with both carriers, and the product is then shaped as required.
Formulations of a compound of formula I suitable for oral administration may be prepared as discrete units, such as pills, capsules, cachets, or tablets each containing a predetermined amount of a compound of formula I.
Compressed tablets may be prepared as follows: the active ingredient is compressed with a suitable machine in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets may be prepared as follows: the mixture of powdered active ingredient moistened with an inert liquid diluent is moulded with a suitable machine. The tablets may optionally be coated or scored and optionally formulated to provide slow or controlled release of the active ingredient from the tablet.
Can be made into oral tablet, buccal tablet, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule such as gelatin capsule, syrup or elixir. Formulations of compounds of formula I intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic physiologically acceptable excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
For the treatment of the eye or other external tissues such as the mouth and skin, the formulations may be applied in the form of a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredient may be employed with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream together with an oil-in-water cream base.
When desired, the aqueous phase in the cream base may include polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol, and polyethylene glycols (including PEG 400) and mixtures thereof. Topical formulations may desirably include compounds that promote absorption or permeation of the active ingredient through the skin or other affected area. Examples of the above-mentioned skin permeation enhancers include dimethyl sulfoxide and the like.
The oily phase of the emulsions of the invention may be constituted by known ingredients in a known manner. Although the phase may comprise only emulsifiers, it is desirable that it comprises a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, the hydrophilic emulsifier and the lipophilic emulsifier as a stabilizer include Together. It is also preferred to include both oil and fat. The emulsifier(s), with or without stabilizer(s), together constitute the so-called emulsifying wax and the wax together with the oil and fat constitutes the so-called emulsifying ointment base which forms the oily dispersed phase in the cream. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween60、Span80. Stearyl/cetyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
Aqueous suspensions of the compounds of formula I contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents such as naturally occurring phosphatides (e.g. lecithin), condensation products of an alkylene oxide with fatty acids (e.g. polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g. heptadecaethyleneoxyethanoyl hexadecanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (partial esters) (e.g. polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Pharmaceutical compositions of the compounds of formula I may be in the form of sterile injectable aqueous or oleaginous suspensions, such as sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the methods known in the art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in butane-1, 3-diol or as a lyophilized powder. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a timed release formulation intended for oral administration to humans may contain from about 1 to 1000mg of the active substance and a suitable and convenient amount of carrier material which may comprise from about 5 to about 95% (weight: weight) of the total composition. Pharmaceutical compositions can be prepared to provide an easily measurable amount of the drug to be administered. For example, aqueous solutions intended for intravenous infusion may contain from about 3 to 500 μ g of active ingredient per mL of solution, so that an appropriate volume of infusion at a rate of about 30mL/hr may be performed.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The concentration of the active ingredient present in the above formulations is preferably from about 0.5 to 20% w/w, for example from about 0.5 to 10% w/w, for example about 1.5% w/w.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; lozenges comprising the active ingredient in an inert base (such as gelatin and glycerol or sucrose and acacia); and mouth washes comprising the active ingredient in a suitable liquid carrier.
Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
Formulations suitable for intrapulmonary or nasal administration have, for example, a particle size in the range of 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns and in increments of microns such as 0.5, 1, 30, 35 microns, etc.), which are administered by rapid or oral inhalation through the nasal passages to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as compounds heretofore used to treat or prevent the disorders described below.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules or vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water, for injections, immediately prior to use. Ready-to-use injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind described above. Preferred unit dosage formulations are those containing the active ingredient in a daily dose or unit daily sub-dose, or suitable fraction thereof, as herein described.
The invention also provides a veterinary composition, which therefore contains at least one active ingredient as described above and a veterinary carrier. Veterinary carriers are substances useful for the purpose of administering the composition and can be solid, liquid or gaseous substances which are either inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
The compounds of formula I may be used alone or in combination with other therapeutic agents to treat diseases or disorders described herein, such as hyperproliferative disorders (e.g., cancer). In some embodiments, a compound of formula I is combined in a pharmaceutical combination preparation or in a dosing regimen that is a combination therapy with a second compound that is anti-hyperproliferative or useful for treating a hyperproliferative disorder (e.g., cancer). The second compound in the pharmaceutical combination formulation or dosing regimen preferably has complementary activity towards the compound of formula I such that they do not adversely affect each other. The amount of the above-mentioned compounds present in the combination is suitably an amount effective for the intended purpose. In one embodiment, the compositions of the present invention comprise a compound of formula I in combination with a chemotherapeutic agent as described herein.
The combination therapy may be administered on a simultaneous or sequential dosing schedule. When administered sequentially, the combination may be administered in two or more administrations. Co-administration includes simultaneous administration and sequential administration in any order using separate formulations or a single pharmaceutical formulation, wherein preferably both (or all) active agents exert their biological activities simultaneously over a period of time.
Suitable dosages for any of the above co-administered drugs are those currently used and may be reduced by the combined effect (synergy) of the newly identified drug and other chemotherapeutic agents or treatments.
Combination therapy may provide a "synergistic effect" and is demonstrated to be "synergistic", i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects obtained with each of these compounds. When the active ingredients (1) are co-formulated and administered or delivered simultaneously in the combined unit dosage formulation; (2) alternatively or in parallel in separate formulations; or (3) when administered by some other dosing regimen, a synergistic effect may be achieved. When delivered in alternation therapy, synergy may be achieved when the compounds are administered or delivered sequentially, e.g., by different injections in different syringes, separate pills or capsules, or separate infusions. Typically, an effective dose of each active ingredient is administered sequentially (i.e., sequentially) during alternation therapy, while in combination therapy, effective doses of two or more active ingredients are administered together.
In particular embodiments of anticancer therapy, the compounds of formula I, or stereoisomers, geometric isomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, can be used in combination with other chemotherapeutic agents, hormonal agents, or antibody agents (such as those described herein), as well as in combination with surgical therapy and radiation therapy. Accordingly, the combination therapies of the present invention include the administration of at least one compound of formula I, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and the use of at least one other cancer treatment method. The amount and relative timing of administration of the compound of formula I (or compounds of formula I) and the other pharmaceutically active chemotherapeutic agent (or agents) will be selected to achieve the desired combination therapeutic effect.
In vivo metabolites of formula I as described herein are also within the scope of the present invention. Such products may be derived, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound. Accordingly, the present invention includes metabolites of the compounds of formula I, including compounds produced by a method comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolite thereof.
Metabolites are typically identified as follows: preparation of the Compounds of the invention radiolabeled (e.g.14C or3H) Isotopes, which are administered parenterally to an animal such as rat, mouse, guinea pig, monkey, or human at detectable doses (e.g., greater than about 0.5mg/kg), allowed a sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and then their conversion products isolated from urine, blood or other biological samples. These products are easily isolated because they are labeled (other products)Isolated by using antibodies that bind to epitopes of antigens that survive metabolism). The structure of the metabolite is determined in a conventional manner, for example by MS, LC/MS or NMR analysis. Typically, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites, so long as they are not otherwise present in the body, can be used in diagnostic assays for therapeutic administration of the compounds of the invention.
Another embodiment of the present invention provides an article of manufacture or "kit" comprising materials useful for the treatment of the diseases and disorders described above. The kit comprises a container comprising a compound of formula I. The kit may further comprise a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions typically included in commercial packages of therapeutic products containing information regarding the indications, usage, dosage, administration, contraindications and/or precautions relating to the use of the therapeutic products described above. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container may contain a compound of formula I or II or a formulation thereof effective to treat the condition and may have a sterile outlet (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of formula I. The label or package insert indicates that the composition can be used to treat a selected condition, such as cancer. In addition, the label or package insert may indicate that the patient to be treated is a patient suffering from a disorder such as a hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine or a neurotrauma disease or event. In one embodiment, the label or package insert indicates that compositions comprising a compound of formula I are useful for treating disorders resulting from abnormal cell growth. The label or package insert may also indicate that the composition may be used to treat other disorders. Alternatively or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. It may also contain other substances as desired from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.
The kit may further comprise instructions for administering the compound of formula I and the second pharmaceutical formulation (if present). For example, if a kit comprises a first composition comprising a compound of formula I and a second pharmaceutical formulation, the kit may further comprise instructions for administering the first and second pharmaceutical compositions to a patient in need thereof simultaneously, sequentially or separately.
In another embodiment, the kit is suitable for delivering a solid oral form of a compound of formula I or II, such as a tablet or capsule. The kit preferably comprises a plurality of unit doses. The kit may comprise a card with a method of administration for its intended use. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dose forms. When desired, a memory aid may be provided, for example in the form of a number, letter or other indicia or with a calendar insert indicating those days in the treatment schedule on which administration may be performed.
According to one embodiment, a kit may comprise (a) a first container having a compound of formula I contained therein; and optionally (b) a second container having a second pharmaceutical formulation therein, wherein the second pharmaceutical formulation comprises a second compound having anti-hyperproliferative activity. Alternatively or additionally, the kit may further comprise a third container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. It may also contain other substances as desired from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.
In some other embodiments where the kit comprises a composition of formula I and a second therapeutic agent, the kit may comprise containers for holding separate compositions, such as separate bottles or separate foil packets, however, separate compositions may also be held in a single, undivided container. Typically, the kit contains instructions for administering the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) or at different dosage intervals or when increasing the dosage of each of the components of the combination as desired by the prescribing physician.
Another aspect of the invention includes a kit comprising a compound of formula I, a container, and optionally a package insert or label indicating treatment.
Benzoxazepines of the formula IThe compounds may be synthesized by synthetic routes including methods analogous to those well known in the chemical arts, particularly in accordance with the description herein. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for organic Synthesis, v.1-23, Wiley, N.Y. (1967. and 2006ed.) or Beilsteins Handbuch der organischen Chemie, 4, Aust. ed. spring-Verlag, Berlin (including appendix) (also available from the Beilstein on-line database)).
In some embodiments, the compounds of formula I may be used to prepare benzoxasCompounds (Sekhar et al (1989) sulfurur Letters 9 (6): 271-277; Katsura et al (2000J. Med. chem.43: 3315-3321; Rueeger et al (2004) Biorganic 3321)& Med.Chem.Letters14：2451-2457；Reiter et al(2007)Biorganic &Med, chem, letters 17: 5447-5454; banaszak et al (2006) Tetrahedron Letters 47: 6235-6238) and other heterocycles, see Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g. volume 3; liebigs AnnalenderChemie，(9)：1910-16，(1985)；Helvetica Chimica Acta，41：1052-60，(1958)；Arzneimittel-Forschung，40(12)：1328-31，(1990)。
The compounds of formula I can be prepared individually or as libraries comprising at least 2, e.g. 5 to 1,000 or 10 to 100 compounds. Libraries of compounds of formula I can be prepared by procedures known to those skilled in the art using solution phase or solid phase chemistry by combinatorial 'split and mix' approaches or by multiple parallel syntheses. Accordingly, another aspect of the present invention provides a library of compounds comprising at least 2 compounds or pharmaceutically acceptable salts thereof.
For illustrative purposes, the general procedure shows a general procedure for the preparation of the compounds of formula I and key intermediates. The schemes and examples section contains more detailed descriptions about the individual reaction steps. It will be appreciated by those skilled in the art that other synthetic routes may be used to synthesize the compounds of the invention. Although some starting materials and routes are described in the schemes, general procedures, and examples, other similar starting materials and routes can be substituted to provide a variety of derivatives and/or reaction conditions. In addition, the various compounds prepared by the methods described below can be further modified according to the present application using conventional chemical methods well known to those skilled in the art.
When preparing compounds of formula I, it may be desirable to protect terminal functional groups (e.g., primary or secondary amines) in the intermediates. The need for such protection will vary with the nature of the terminal functional group and the conditions of the preparation process. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and fluoren-9-ylmethyl oxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting Groups and their use see t.w. greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
In the process for preparing the compounds of the invention, it may be advantageous to separate the reaction products from each other and/or from the starting materials. The desired product in each step or steps is isolated and/or purified (hereinafter referred to as isolated) by techniques common in the art to the desired degree of homogeneity. Typically, such separation involves heterogeneous extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any number of methods including, for example, reverse-phase and normal-phase, size exclusion, ion exchange, high, medium and low pressure liquid chromatography and apparatus, small scale analysis, Simulated Moving Bed (SMB) and preparative thin or thick layer chromatography, and small scale thin layer and flash chromatography techniques.
Another type of separation method involves treating the mixture with reagents selected to combine or isolate the desired product, unreacted starting materials, reaction by-products, etc. Such agents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, and the like. Alternatively, the reagent may be an acid (in the case of a basic substance), a base (in the case of an acidic substance), a binding agent such as an antibody, a binding protein, a selective chelating agent such as a crown ether, a liquid/liquid ion extraction agent (LIX), or the like.
The choice of a suitable separation method depends on the nature of the substances involved, such as boiling point and molecular weight (in distillation and sublimation), presence or absence of polar functional groups (in chromatography), stability of the substances in acidic and basic media (in heterogeneous extraction), etc. Those skilled in the art will use techniques that are most likely to achieve the desired separation.
Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physical-chemical differences by methods well known to those skilled in the art, such as chromatography and/or fractional crystallization. Enantiomers can be separated as follows: mixtures of enantiomers are converted to mixtures of diastereomers by reaction with an optically active suitable compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), the diastereomers are separated, and the individual diastereomers are then converted (e.g., hydrolyzed) to the corresponding pure enantiomers. Additionally, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered to be part of the present invention. Enantiomers can also be separated by using a chiral HPLC column.
Individual stereoisomers, for example enantiomers substantially free of their stereoisomers, can be obtained by resolution of racemic mixtures using, for example, optically active resolving agents to form diastereomers (Eliel, E.and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H., (1975) J.Chromatogr., 113 (3): 283-302). Racemic mixtures of chiral compounds of the invention can be separated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other method; (2) forming a diastereomeric compound with a chiral derivatizing agent, separating the diastereomers and converting them to pure stereoisomers; and (3) direct separation of the substantially pure or enriched stereoisomers under chiral conditions. See "Drug Stereochemistry, Analytical Methods and Pharmacology", Irving w.wainer, ed., Marcel Dekker, inc., New York (1993).
In process (1), diastereomeric salts may be formed as follows: enantiomerically pure chiral bases such as strychnine, quinine, ephedrine, brucine, alpha-methyl-beta-phenylethylamine (amphetamine), and the like are reacted with asymmetric compounds having acidic functional groups such as carboxylic and sulfonic acids. Separation of diastereomeric salts can be achieved by fractional crystallization or ion chromatography. To separate the optical isomers of the amino compounds, chiral carboxylic or sulfonic acids such as camphorsulfonic, tartaric, mandelic or lactic acids are added, which can lead to the formation of diastereomeric salts.
Alternatively, the substrate to be resolved is reacted with one enantiomer of a chiral compound by method (2) to form a diastereomer pair (Eliel, E.and Wilen, S. "stereoschemistry of organic Compounds", John Wiley& Sons，Inc., 1994, p.322). Diastereomeric compounds can be formed as follows: asymmetric compounds are reacted with enantiomerically pure chiral derivatizing agents such as menthyl derivatives, followed by separation and hydrolysis of the diastereomers to yield pure or enriched enantiomers. Methods for determining optical purity involve the preparation of chiral esters of racemic mixtures [ such as the preparation of menthyl esters such as (-) -menthyl chloroformate or the preparation of Mosher esters, i.e., alpha-methoxy-alpha- (trifluoromethyl) phenyl acetate (Jacob III.J.org.chem. (1982) 47: 4165)]And are related to the presence of two atropisomeric enantiomers or diastereomers1H NMR spectrum was analyzed. The stable diastereoisomers of atropisomeric compounds can be separated by normal and reverse phase chromatography according to the method for separating atropisomeric naphthyl-isoquinoline compounds (WO 1996/15111). In method (3), racemic mixtures of the two enantiomers can be separated by chromatography using a Chiral stationary phase ("Chiral Liquid chromograph" (1989) W.J.Lough, Ed., Chapman and Hall, New York; Okamoto, J.Chromatogr., (1990) 513: 375-378). Enriched or purified enantiomers can be distinguished by methods for distinguishing other chiral molecules with asymmetric carbon atoms, such as optical rotation or circular dichroism.
The following scheme illustrates possible routes for preparing the compounds of the present invention.
Another aspect of the invention includes processes for the preparation, isolation and purification of compounds of formula I.
Another aspect of the invention includes novel intermediates useful in the preparation of compounds of formula I.
Examples
The chemical reactions described in the examples can be readily adapted to prepare a variety of other PI3K inhibitors of the invention and other methods of preparing the compounds of the invention are considered to be within the scope of the invention. For example, compounds not exemplified in the present invention can be successfully synthesized by variations that will be apparent to those skilled in the art, for example, by appropriate protection of interfering groups, by use of other suitable reagents known in the art other than those described, and/or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability to the preparation of other compounds of the invention.
In the following examples, all temperatures are given in degrees celsius unless otherwise indicated. Unless otherwise indicated, reagents were purchased from commercial suppliers such as Sigma Aldrich Chemical Company and used without further purification. The reactions described below are typically carried out under a positive pressure of nitrogen or argon or in anhydrous solvents using a dry tube (unless otherwise indicated) and the reaction flask is typically equipped with a rubber septum for introducing substrates and reagents via syringe. The glassware is dried and/or heat dried. Column chromatography tool Biotage system with silica gel column (Dyax Corporation) or silica gel SEP PAKColumn (Waters). In deuterated CDCl3、d6-DMSO、CH3OD or d6Obtained at 400MHz in acetone solution1H NMR spectrum (reported in ppm) using chloroform as reference standard (7.25 ppm). When reporting the multiplicity of peaks, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in hertz (Hz).
Liquid chromatography-mass spectrometry (LCMS) experiments were performed to determine Retention Time (RT) and associated mass spectrometry ions using a variety of methods familiar to those skilled in the art of methods of organic compound analysis.
Chemical structures are named according to vendor assignment, IUPAC rules, ChemDraw Ultra, version 9.0.1, Cambridge soft corp, Cambridge MA or Autonom 2000 Name, MDL Inc. It will be understood by those skilled in the art that a compound may have more than one name due to different rules.
The following abbreviations are used: DCM: dichloromethane; DMF: n, N-dimethylformamide; DMSO, DMSO: dimethyl sulfoxide; EtOAc: ethyl acetate; HATU: n, N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorosulfate; hr: hours; IPA: isopropyl alcohol; min: the method comprises the following steps of (1) taking minutes; NIS: n-iodosuccinimide; pd (PPh) 3)4: tetrakis (triphenylphosphine) palladium (0); PPA: polyphosphoric acid; RT: room temperature; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; IMS: industrial methanol denatured alcohol.
Example 1: 8-bromo-3, 4-dihydrobenzo [ b ]]Oxygen oxide-5(2H) -one 1
Step 1: 4- (3-bromophenoxy) butanoic acid ethyl ester
Solid 3-bromophenol (10.0g, 58mmol) was added portionwise to K at room temperature2CO3In a stirred suspension in acetone (100 mL). Sodium iodide (NaI, 1.0g) was added followed by ethyl 4-bromobutyrate (9.2mL, 64 mmol). The reaction mixture was heated at 80 ℃ overnight, cooled to room temperature, diluted with water and extracted with ethyl acetate to give ethyl 4- (3-bromophenoxy) butyrate 6.
Step 2: 4- (3-bromophenoxy) butanoic acid
Ethyl 4- (3-bromophenoxy) butanoate 6 was taken up in 100mL THF and 50mL water and treated with lithium hydroxide LiOH (hydrate, 4.9 g). The whole was heated at 50 ℃ for 2 days. The mixture was cooled to room temperature and acidified to pH 1 with 2N HCl. The aqueous phase was extracted with ethyl acetate. The combined organics were washed with brine and dried over sodium sulfate to give crude 4- (3-bromophenoxy) butanoic acid as a viscous solid.1HNMR(DMSO-d6，500MHz)7.24(m，1H)，7.13(m，1H)，7.11(m，1H)，6.95(m，1H)，3.99(m，2H)，2.37(m，2H)，1.94(m，2H)。
And step 3: to PPA (about 60g) and Celite(Celite) (about 40g) to a stirred suspension in 100mL of toluene was added crude 4- (3-bromophenoxy) butanoic acid 7 (about 58mmol) in one portion, rinsing with 10mL of toluene. The resulting suspension was heated at 110 ℃ for 5 hours. The toluene was decanted with a celite plug and the residual slurry was washed repeatedly with toluene and ethyl acetate. The eluate was concentrated and purified by flash column chromatography (4: 1 hexanes: EtOAc) to give 1(7g, about 50% yield). 1H NMR(DMSO-d6，500MHz)7.55(d，J＝8.5Hz，1H)，7.37(d，J＝1.5Hz，1H)，7.35(dd，J＝8.5，1.5Hz，1H)，4.24(t，J＝6.5Hz，2H)，2.79(t，J＝7.0Hz，2H)，2.14(m，2H)。
Example 2: (Z) -8-bromo-5-chloro-2, 3-dihydrobenzo [ b ]]Oxygen oxide-4-Formaldehyde 2
Phosphorus oxychloride POCl at 0 deg.C3(1.88mL, 20.8mmol) was added dropwise to DMF (5 mL). After 30 minutes, a solution of 1(2.0g, 8.3mmol) (example 1) in 8mL DMF was added dropwise. The reaction mixture was allowed to reach room temperature and stirred for 2 hours, then slowly poured into rapidly stirred ice water. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with brine, dried over sodium sulfate and concentrated to give 2.
Example 3: 7-bromo-3, 4-dihydrobenzo [ b ]]Oxygen oxide-5(2H) -one 3
To a slurry of NaH (60% dispersion in mineral oil) (1.48g, 37.1mmol) in THF (. about.50 mL) was added 1- (5-bromo-2- (2-bromoethoxy) phenyl) ethanone (8.07g, 25.1mmol) at room temperature. The reaction mixture was slowly heated to reflux and stirred for 20 hours. The solvent was removed in vacuo and the concentrated residue was adsorbed onto silica gel and purified by column chromatography (4: 1 EtOAc/petroleum ether). After removal of the solvent, the product was obtained as a yellow oil, yielding 4.22g (70%) of 3.1H NMR(CDCl3)7.87(d，J＝2.6Hz，1H)，7.50(dd，J＝2.6，8.1Hz，1H)，6.97(d，J＝8.8Hz，2H)，4.24(t，J＝6.6Hz，2H)，2.89(t，J＝7.0Hz，2H)，2.15-2.29(m，2H)。
Example 4: 4, 7-dibromo-3, 4-dihydrobenzo [ b ]]Oxygen oxide-5(2H) -one 4
To a solution of 3(3g, 12mmol) in diethyl ether (110mL) was added bromine (0.7)mL, 14mmol) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by ISCO chromatography (hexanes to 20% hexanes/EtOAc over 45 minutes). The fractions were collected and concentrated to yield 4(3.53g, 89%). 1HNMR(500MHz，CDCl3)7.86(d，J＝2.5，1H)，7.52(dt，J＝28.5，14.2，1H)，6.97(d，J＝8.7，1H)，4.95(dd，J＝7.6，6.8，1H)，4.53-4.36(m，1H)，4.17(ddd，J＝12.8，9.9，4.4，1H)，3.04-2.84(m，1H)，2.52(ddt，J＝14.7，7.8，4.5，1H)。
Example 5: 3-isopropyl-1-methyl-1H-1, 2, 4-triazol-5 (4H) -one 5
Step 1: 1-methylhydrazinecarboxamide
Methyl hydrazine and trimethylsilyl isocyanate were reacted in THF at 0 ℃, then quenched and hydrolyzed with methanol to give 1-methylhydrazinecarboxamide.
Step 2: 2-isobutyryl-1-methylhydrazinecarboxamide
Acylation of 1-methylhydrazinecarboxamide with isobutyryl chloride in TEA and DCM gave 2-isobutyryl-1-methylhydrazinecarboxamide.
And step 3:
cyclization of 2-isobutyryl-1-methylhydrazinecarboxamide with camphor-10-sulfonic acid in ethyl acetate under reflux gave 5.
Example 6: 1, 3-dimethyl-1H-1, 2, 4-triazol-5 (4H) -one 6a and 1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5 (4H) -one 6b
Acetamide and ethyl chloroformate were mixed at 45 ℃ to give ethyl imidoacetate hydrochloride, which was further reacted with ethyl chloroformate, diisopropylethylamine and DCM at 0 ℃ to give ethyl N-ethoxycarbonylimidoacetate, which was reacted with methylhydrazine or isopropylhydrazine hydrochloride in TEA and toluene to give 6a and 6 b.
Example 7: 4-isopropyl-1- (4-methoxybenzyl) -1H-imidazol-2 (3H) -one 7
Bromination of 3-methylbutan-2-one with bromine in methanol gives 1-bromo-3-methylbutan-2-one, which is reacted with 4-methoxybenzylamine and cyclized with sodium cyanate to give 7.
Example 8: 6, 7-dihydroimidazo [1, 2-d]Pyrido [3, 2-b][1，4]Oxazazepine-3-Carboxylic acid methyl ester 8
Step 1: 2-methyl-1-trityl-1H-imidazoles
A triphenylmethyl groupChlorine (16.0g, 57.5mmol) was added portionwise to a solution of 2-methylimidazole (4.10g, 50.0mmol) and TEA (9.02mL, 64.7mmol) in 20mL of N, N-dimethylformamide. The mixture was stirred for 18 h, mixed with 300mL water and extracted with 1000mL EtOAc. The organic extracts were washed with 1L water and brine, MgSO4Dried and concentrated in vacuo to a volume of 50 mL. The precipitate was collected, washed with EtOAc and dried under high vacuum for 18 h. The weight was 15.0g (92.5%).1H NMR(400MHz，CDCl3)7.34-7.29(m，9H)，7.16-7.11(m，6H)，6.90(d，J＝1.5，1H)，6.71(d，J＝1.5，1H)，1.65(s，3H)。
Step 2: 2- (1-trityl-1H-imidazol-2-yl) acetaldehyde
A solution of 1.6M n-butyllithium in hexane (7.5mL) was added dropwise to a solution of 2-methyl-1-trityl-1H-imidazole (3.244g, 10.00mmol) in THF (100.0mL, 1233mmol) at-76 ℃. The dark red mixture was stirred for 45 minutes. Ethyl formate (4.039mL, 50.00mmol) was added quickly and the mixture (turning yellow) was stirred for 20 minutes. 6mL of 5% aqueous citric acid was added and the mixture was mixed with 60mL of aqueous citric acid and extracted with EtOAc. The organic layer was washed with water and brine, MgSO 4Dried and concentrated in vacuo. The pale yellow semi-solid material (2.025g, 57.5%) was used in the next step without further purification.
And step 3: 2- (1-trityl-1H-imidazol-2-yl) ethanol
Crude 2- (1-trityl-1H-imidazol-2-yl) acetaldehyde (2.025g, 5.75mmol) was dissolved in MeOH/THF (1: 1, 40mL) and NaBH4(0.435g, 11.5mmol) was added portionwise to the above mixture. The mixture was stirred for 18 hours, diluted with 100mL of water and extracted with 2 x DCM. The combined organic extracts were washed with water and brine, washed with Na2SO4Dried and concentrated in vacuo. The weight of the residue was 1.915g (94%).1H NMR(500MHz，CDCl3)7.35-7.31(m，9H)，7.12(dd，J＝6.7，2.7，6H)，6.93(d，J＝1.0，1H)，6.74(d，J＝1.0，1H)，5.04(br，1H)，3.46(t，J＝5.4，2H)，2.00(t，J＝5.4，2H)。
And 4, step 4: 6-iodo-5- (2- (1-trityl-1H-imidazol-2-yl) ethoxy) pyridine-3-carboxylic acid methyl ester
Diisopropyl azodicarboxylate (1160. mu.L, 5.90mmol) was added dropwise to a mixture of 2- (1-trityl-1H-imidazol-2-yl) ethanol (1900mg, 5.4mmol), methyl 5-hydroxy-6-iodopyridine-3-carboxylate (1570mg, 5.63mmol), and triphenylphosphine (1550mg, 5.90mmol) in THF (45.0mL, 555mmol) at 0 ℃. After stirring for 3 hours, the mixture was mixed with water and extracted with EtOAc. The organic layer was washed with water and brine, MgSO4Dried and concentrated in vacuo. The residue was purified on a 40g silica gel column (eluted with 50% EtOAc/DCM) to give 1.45g (44%) of methyl 6-iodo-5- (2- (1-trityl-1H-imidazol-2-yl) ethoxy) pyridine-3-carboxylate. MS (ESI +): 616.0. 1H NMR(400MHz，CDCl3)8.52(d，J＝1.9，1H)，7.40-7.28(m，10H)，7.20-7.16(m，6H)，6.99(d，J＝1.5，1H)，6.81(d，J＝1.5，1H)，3.98-3.91(m，5H)，2.46(t，J＝7.3，2H)。
And 5: 5- (2- (1H-imidazol-2-yl) ethoxy) -6-iodopyridine-3-carboxylic acid methyl ester
Triethylsilane (0.160mL, 1.00mmol) was added to a solution of 1.45g (2.36mmol) of methyl 6-iodo-5- (2- (1-trityl-1H-imidazol-2-yl) ethoxy) pyridine-3-carboxylate in TFA (30.0mL, 389 mmol). The mixture was stirred for 4 hours, concentrated in vacuo and triturated with 50mL of anhydrous ether. The solid material was collected, washed with several portions of diethyl ether and partitioned between 1M aqueous sodium carbonate and EtOAc. The organic extracts were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give a residue (0.55g, 62%) of methyl 5- (2- (1H-imidazol-2-yl) ethoxy) -6-iodopyridine-3-carboxylate. MS (ESI +): 374.0.
step 6: a mixture of methyl 5- (2- (1H-imidazol-2-yl) ethoxy) -6-iodopyridine-3-carboxylate (373mg, 1.00mmol), copper (I) oxide (14.3mg, 0.10mmol), ninhydrin (35.6mg, 0.20mmol) and potassium carbonate (290mg, 2.10mmol) in DMSO (10.0mL) was heated at 110 ℃ for 2 hours. The mixture was poured into 20mL water and extracted with EtOAc (3X 15 mL). Water for organic extract(3X 15mL) and brine, MgSO4Dried and concentrated. The residue (0.220g, 90%) was used in the next step without further purification. MS (ESI +): 246.0. 1H NMR(500MHz，CDCl3)8.77(d，J＝1.9，1H)，8.10(s，1H)，8.04(d，J＝1.9，1H)，7.08(s，1H)，4.47(t，J＝5.1，2H)，3.97(s，3H)，3.46(t，J＝5.1，2H)。
Example 9: 9, 10-diiodo-6, 7-dihydroimidazo [1, 2-d]Pyrido [3, 2-b][1，4]Oxazazepine-3-Carboxylic acid methyl ester 9
N-iodosuccinimide (394mg, 1.75mmol) was added to a solution of methyl 5- (2- (1H-imidazol-2-yl) ethoxy) -6-iodopyridine-3-carboxylate (220mg, 0.90mmol) in DMF (8.0mL, 100 mmol). The mixture was stirred at room temperature for 6 hours and at 60 ℃ for 18 hours. The mixture was concentrated in vacuo and the residue was taken up in EtOAc and 1M Na2CO3The aqueous solution was partitioned. The organic layer was washed with water and brine, and Na2SO4Dried and concentrated. The residue was purified with a 4g silica gel column (eluted with 40% EtOAc/heptane). The weight was 130 mg. MS (ESI +): 497.9.1H NMR(500MHz，CDCl3)9.02(d，J＝1.9，1H)，8.21(d，J＝1.9，1H)，4.65(t，J＝6.4，2H)，4.00(s，3H)，3.14(t，J＝6.4，2H)。
example 10: 10-iodo-6, 7-dihydroimidazo [1, 2-d]Pyrido [3, 2-b][1，4]Oxazazepine-3-Carboxylic acid methyl ester 10
A solution of ethyl magnesium bromide in diethyl ether (3.0M, 0.104mL) was added dropwise to a suspension of 9(130mg, 0.26mmol) in THF (5.0mL, 62mmol) at-15 deg.C. The mixture was stirred for 15-20 minutes (reaction was monitored by LCMS)Not complete), 20mL of saturated NH is poured in4Aqueous Cl and extracted with EtOAc. The organic extracts were washed with water (2X 20mL) and brine, over MgSO4Dried and concentrated in vacuo. Weight 92mg (94%). MS (ESI +): 372.0.
Example 11: 9- (1-isopropyl-1H-pyrazol-5-yl) -6, 7-dihydroimidazo [1, 2-d]Pyrido [3, 2-b][1，4]Oxazazepine-3-Carboxylic acid methyl ester 11
P-1-isopropyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (117.1mg, 0.4958mmol), 10(92.0mg, 0.248mmol), [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride [ Complex with DCM (1: 1)]A mixture of (20.24mg, 0.02479mmol) and 1.0M potassium acetate/water (0.49mL) in 1, 2-dimethoxyethane (5.0mL, 48mmol) was degassed. The reaction mixture was irradiated with microwaves at 140 ℃ and 200 watts for 40 minutes. The reaction mixture was filtered, washed with DME, mixed with water and extracted with EtOAc. The combined organic extracts were washed with 1% aqueous NaOH to remove phenolic by-products, then 5% aqueous citric acid, water and brine, and Na2SO4Dried and concentrated in vacuo. The residue was purified with a 4g silica gel column (eluted with 60-70% EtOAc/heptane). The yield thereof was found to be 21 mg. MS (ESI +): 354.2.
example 12: 9- (1-isopropyl-1H-pyrazol-5-yl) -6, 7-dihydroimidazo [1, 2-d]Pyrido [3, 2-b][1，4]Oxazazepine-3-carboxylic acid 12
A mixture of 21mg (0.06mmol) of 11 and 1.0mL of 1N aqueous LiOH in 4mL of methanol and 4mL of THF was stirred for 6 hours. The mixture was acidified to pH 3 by addition of 1N HCl and concentrated in vacuo. The residue was taken up in EtOAc and water Partitioned between, the organic layer washed with brine and Na2SO4Dried and concentrated. The yield was 17 mg. MS (ESI +): 340.1.
example 13: 2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-Carboxylic acid methyl ester 13
P-26 (370.1mg, 1.000mmol), 1-isopropyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (354mg, 1.50mmol), [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride [ Complex with DCM (1: 1)]A mixture of (40.8mg, 0.0500mmol) and 2.0M potassium acetate/water (1.00mL) in acetonitrile (12mL, 230mmol) was degassed. The reaction mixture was irradiated with microwaves at 200 watts for 30 minutes at 140 ℃. The reaction mixture was partitioned between water and EtOAc, filtered, and the organic layer was washed with water and brine, over MgSO4Dried and concentrated in vacuo. The residue was purified with a 12g silica gel column (eluted with 35-40% EtOAc/heptane). Yield 119mg (34%). MS (ESI +): 353.1.
example 14: 2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxylic acid 14
Hydrolysis of 13 according to example 10 gave 14. MS (ESI +): 339.4.
Example 15: 2- (4-cyano-1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 15
Step 1: 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile
Sodium methoxide (2.139g, 39.60mmol) was added to a solution of ethoxymethylenemalononitrile (2.198g, 18.00mmol) and isopropylhydrazine hydrochloride (2.212g, 20.00mmol) in ethanol (50mL, 800 mmol). The mixture was heated to reflux for 18 hours. The solvent was removed in vacuo and the residue partitioned between EtOAc and water. The organic layer was washed with water and brine, and Na2SO4Dried, concentrated in vacuo and purified with a 25g silica gel column (eluted with 25-30% EtOAc/heptane) to give 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (yield 1.77g, 65%). MS (ESI +): 151.2.1HNMR(400MHz，CDCl3)7.51(d，J＝6.4，1H)，4.23(ddd，J＝19.8，16.6，9.8，3H)，1.46(d，J＝6.6，7H)。
step 2: 5-iodo-1-isopropyl-1H-pyrazole-4-carbonitrile
Amyl nitrite (13.00g, 111.0mmol) was added to a suspension of 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (1.77g, 11.8mmol) in diiodomethane (56.0mL, 695mmol) at-10 ℃ over 30 min. The mixture was stirred at room temperature for 30 minutes and then heated at 100 ℃ for 2 hours. The mixture was then cooled and concentrated in high vacuum to give a residue which was taken up in EtOAc and 5% Na 2S2O5Are distributed among the devices. The organic layer was washed with water, 0.1% aqueous HCl, water and brine, dried and concentrated in vacuo. The residue was purified on a silica gel column (eluted with 20-30% EtOAc/heptane). The yield was 1.68g (55%). MS (ESI +): 262.2.
and step 3: 2- (Tributylstannyl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester
A solution of isopropyl magnesium chloride in THF (2.0M, 1.5mL, 3.00mmol) was added dropwise to 40(740mg, 2.00mmol) in THF (12mL, 150mmol) at room temperatureIn the solution of (1). The mixture was stirred for 2.5 hours. Tributyltin chloride (0.8138mL, 3.000mmol) was added and the mixture was stirred for 18 hours. Mixing the mixture with saturated NH4Aqueous Cl solution was mixed and extracted with ethyl acetate. The organic layer was washed with brine, washed with Na2SO4Dried and purified with a 25g silica gel column (eluted with 15-20% EtOAc/heptane). Yield 160mg (15%). MS (ESI +): 535.2.
and 4, step 4: reacting 2- (tributylstannyl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester (155mg, 0.291mmol), 5-iodo-1-isopropyl-1H-pyrazole-4-carbonitrile (133mg, 0.509mmol) and Pd (PPh)3)4A mixture of (16.8mg, 0.0145mmol) in toluene (6.0mL, 56mmol) was heated for 18 hours. The mixture was concentrated in vacuo and the residue was purified on a 4g silica gel column (eluted with 30% EtOAc/heptane). Yield 65mg (59%). MS (ESI +): 378.2.
Example 16: 2- (4-cyano-1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxylic acid 16
Hydrolysis of 15 was carried out as in example 10 to give 16. MS (ESI +): 364.3.
example 17: 10-chloro-5, 6-dihydroimidazo [1, 2-d]Pyrido [4, 3-f][1，4]Oxazazepine17
Step 1: 2-chloro-5- (methoxymethoxy) pyridine
Sodium hydride (60% in mineral oil)Dispersion, 3: 2 sodium hydride: mineral oil, 2.32g) was added portionwise to a solution of 6-chloro-pyridin-3-ol (5.00g, 38.6mmol) in a mixture of THF (10.0mL, 123mmol) and DMF (20.0mL, 258 mmol). The resulting mixture was stirred for 15 min and chloromethyl methyl ether (3.66mL, 48.2mmol) was added dropwise. The mixture was stirred for 6 hours (monitored by LCMS), poured into water and extracted with EtOAc. The organic extracts were washed with water and brine, over MgSO4Dried and concentrated in vacuo. Purification on a 40g silica gel column (eluted with 10-40% EtOAc/heptane) afforded 6.33g 2-chloro-5- (methoxymethoxy) pyridine.
Step 2: 2-chloro-5- (methoxymethoxy) pyridine-4-carbaldehyde
A solution of tert-butyllithium in pentane (1.7M, 19.0mL) was added dropwise to a solution of 2-chloro-5- (methoxymethoxy) pyridine (4.880g, 28.11mmol) in 100mL of diethyl ether at-76 ℃. Some precipitates appeared. The mixture was kept at-76 ℃ for 20 min, then DMF (2.938mL, 37.95mmol) was added dropwise. The mixture was stirred at-76 ℃ for 10 minutes, then warmed to 0 ℃ and held for 1 hour. Adding 10% NH 4Aqueous Cl and the mixture was extracted with EtOAc. The organic solution was washed with water and brine and Na2SO4And (5) drying. After concentration in vacuo, the yield of crude 2-chloro-5- (methoxymethoxy) pyridine-4-carbaldehyde was 5.49 g. MS: 202.0, 172.0. It was used in the next step without further purification.
And step 3: 2-chloro-4- (1H-imidazol-2-yl) -5- (methoxymethoxy) pyridine
Crude 2-chloro-5- (methoxymethoxy) pyridine-4-carbaldehyde (5.20g, 25.87mmol) was dissolved in 60mL of methanol and mixed with 40% aqueous glyoxal solution (16.31g, 112.4mmol) and aqueous ammonia (19.15g, 337.3 mmol). The mixture was stirred for 3 hours, concentrated in vacuo and acidified to pH < 1 with 60mL of 1N aqueous HCl solution. The aqueous solution was extracted with EtOAc (3X 30 mL). The organic extract was discarded while adding saturated NaHCO3The aqueous phase is basified. The mixture was extracted with EtOAc (3 × 30mL), and the combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The residue (crude 4.185g) was applied to a 40g silica gel column (washed with 60-70% EtOAc/heptane)Removing) and purifying. The yield was 2.06g (33%). MS (ESI +): 208 (loss of HOMe).1HNMR(500MHz，CDCl3)10.56(s，1H)，8.35(s，1H)，8.23(s，1H)，7.30(s，1H)，7.22(s，1H)，5.43(s，2H)，3.54(d，J＝14.0，3H)。
And 4, step 4: 6-chloro-4- (1H-imidazol-2-yl) pyridin-3-ol
A solution of hydrogen chloride in dioxane (4M, 40mL) was added dropwise to a solution of 2.06g (8.60mmol) 2-chloro-4- (1H-imidazol-2-yl) -5- (methoxymethoxy) pyridine in DCM (40mL, 600 mmol). The suspension was stirred for 2 hours and filtered. The solid was washed with DCM and ether and dried in vacuo. The yield of 6-chloro-4- (1H-imidazol-2-yl) pyridin-3-ol dihydrochloride was 2.31g (100%). MS (ESI +): 196.2. 1H NMR(400MHz，DMSO)13.20(s，1H)，8.14(s，1H)，7.96(s，1H)，7.42(s，2H)。
And 5: a mixture of 2.30g (8.55mmol) 6-chloro-4- (1H-imidazol-2-yl) pyridin-3-ol dihydrochloride, 1, 2-dibromoethane (1.842mL, 21.37mmol) and cesium carbonate (19.46g, 59.74mmol) in 120mL DMF was heated at 90 ℃ for 3H. The mixture was filtered and concentrated in high vacuum to give 17. The weight was 1.88g (99%). MS (ESI +): 222.2.1H NMR(400MHz，CDCl3)8.37(s，1H)，8.17(s，1H)，7.24(d，J＝1.0，1H)，7.10(d，J＝0.9，1H)，4.51-4.45(m，4H)。
example 18: 10-chloro-2, 3-diiodo-5, 6-dihydroimidazo [1, 2-d]Pyrido [4, 3-f][1，4]Oxazazepine18
NIS (5.771g, 25.65mmol) was added to a solution of 1.89g (8.55mmol)17 in DMF (28mL, 360mmol) and the mixture was heated at 80 ℃ for 48 h. The precipitate was collected, washed with DMF and ether and air dried, then dried under high vacuum. The weight was 2.85g (70%). MS: 473.9.1HNMR(500MHz，CDCl3)8.33(s，1H)，8.19(s，1H)，4.53-4.46(m，2H)，4.45-4.38(m，2H)。
example 19: 10-chloro-2-iodo-5, 6-dihydroimidazo [1, 2-d]Pyrido [4, 3-f][1，4]Oxazazepine19
A solution of isopropyl magnesium chloride in THF (2.0M, 3.311mL) was added dropwise to a solution of 18(2.850g, 6.020mmol) in 110mL of THF at-10 ℃. The mixture was warmed to 10 ℃ over 45 minutes and then mixed with 250mL of cold 10% NH4And mixing with Cl. The organic layer was washed with brine and Na2SO4And (5) drying. Concentration in vacuo gave 2.06g (98.5%). MS: 348.0.1H NMR(500MHz，CDCl3)8.33(d，J＝10.1，1H)，8.18(s，1H)，7.18(s，1H)，4.46(q，J＝5.8，4H)。
example 20: 10-chloro-5, 6-dihydroimidazo [1, 2-d ]Pyrido [4, 3-f][1，4]Oxazazepine-2-carboxamide 20
A mixture of 19(2056mg, 5.916mmol), bis (triphenylphosphine) palladium (II) dichloride (0.00210mg, 0.300mmol) and bis (trimethylsilyl) azane (7.488mL, 35.50mmol) in 60mL DMF was carbonylated at 1atm with CO from a balloon. The reaction mixture was heated at 70 ℃ for 1 hour. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and 1M aqueous sodium carbonate. The organic extracts were washed with water and brine, dried over magnesium sulfate, concentrated in vacuo and purified with a 12g silica gel column (eluted with 0-5% MeOH/DCM) to give 1300mg (83%). MS (ESI +): 265.0.1HNMR(500MHz，DMSO)8.37(s，1H)，8.22(s，1H)，7.93(s，1H)，7.70(s，1H)，7.25(s，1H)，4.56(s，4H)。
example 21: 10-chloro-N- ((dimethylamino) methylene) -5, 6-dihydroimidazo [1, 2-d]Pyrido [4, 3-f][1，4]Oxazazepine-2-carboxamide 21
A mixture of 20(1.290g, 4.875mmol) and 1, 1-dimethoxy-N, N-dimethylmethylamine (3.238mL, 24.37mmol) in 70mL of toluene was heated at reflux for 1 hour. After cooling, the product precipitated from the reaction mixture, collected, washed with ether and air dried. The weight was 0.705g (85%). MS (ESI +): 320.1.
example 22: 10-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ]Pyrido [4, 3-f][1，4]Oxazazepine22
A mixture of 660mg (2.06mmol) of 21 and isopropylhydrazine hydrochloride (0.332g, 3.00mmol) in 44mL of acetic acid was heated at 85 ℃ for 3 hours. The mixture was cooled, filtered and mixed with 15mL of water. The precipitate is filtered off, washed with water and dried under high vacuum. The solid was triturated with 10mL EtOAc, filtered off, washed with EtOAc and ether and air dried. The yield was 0.710 g. MS: 331.2.1H NMR(500MHz，DMSO)8.26(s，1H)，8.20(s，1H)，8.11(s，1H)，7.96(s，1H)，5.76(dt，J＝13.1，6.6，1H)，4.62(q，J＝5.6，4H)，1.50(d，J＝6.6，6H)。
example 23: 4-hydroxy-3- (1H-imidazol-2-yl) benzoic acid methyl ester 23
Methyl 3-formyl-4-hydroxybenzoate was coupled with acetaldehyde and ammonia as in example 22 to give 23. The yield thereof was found to be 78%. MS (ESI +): 219.1.
example 24: 5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-Carboxylic acid methyl ester 24
Reaction of 23 with 1, 2-dibromoethane followed the procedure in example 17 gave 24. The yield thereof was found to be 76%. MS (ESI +): 245.0.1H NMR(400MHz，CDCl3)9.21(d，J＝2.2，1H)，7.91(dd，J＝8.6，2.2，1H)，7.20(t，J＝4.8，1H)，7.05(d，J＝8.6，1H)，7.00(d，J＝0.8，1H)，4.53-4.48(m，2H)，4.43-4.39(m，2H)，3.91(d，J＝5.9，3H)。
example 25: 2, 3-diiodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-Carboxylic acid methyl ester 25
A mixture of 24(2670mg, 9.29mmol) and NIS (5230mg, 23.2mmol) in 100mL DMF was heated at 80 ℃ for 3 hours. The mixture was mixed with 300mL of water and extracted with 3X 120mL of DCM. The combined organic extracts were washed with 5% aqueous sodium bicarbonate, 2X 50mL of 10% aqueous sodium thiosulfate, water, and brine, over MgSO 4Dried and concentrated in vacuo to a small volume. The precipitate was filtered, washed with DCM and dried in vacuo. The yield was 3.86g (84%). MS 497.0.1H NMR(500MHz，CDCl3)9.12(d，J＝2.0，1H)，7.93(dd，J＝8.6，2.1，1H)，7.05(d，J＝8.6，1H)，4.55-4.46(m，2H)，4.38(dd，J＝5.0，2.9，2H)，3.92(s，3H)。
Example 26: 2-iodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-Carboxylic acid methyl ester 26
Conversion of 25 to 26 was carried out as in example 19. The yield thereof was found to be 95%. MS (ESI +): 370.9.1H NMR(400MHz，CDCl3)9.15(d，J＝2.1，1H)，7.92(dd，J＝8.6，2.2，1H)，7.08(s，1H)，7.04(t，J＝7.9，1H)，4.48(dd，J＝9.5，5.5，2H)，4.40(dd，J＝9.4，5.5，2H)，3.92(s，3H)。
example 27: 2-cyano-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-Carboxylic acid methyl ester 27
2-iodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineMethyl-10-carboxylate (370.1mg, 1.0mmol) and cuprous cyanide (268.6mg, 3.000mmol) were combined in 8mL DMF. The reaction mixture was irradiated with microwaves at 150 ℃ for 40 minutes at 200 watts. The reaction mixture was partitioned between 25mL of 5% ammonia and 25mL of EtOAc. The aqueous layer was extracted with 3X 20mL of EtOAc and the combined extracts were washed with water and brine and MgSO4Drying gave 225mg 27. The yield thereof was found to be 81%. MS: 270.0.
example 28: 2-carbamoyl-5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-Carboxylic acid methyl ester 28
27(220mg, 0.82mmol) was dissolved in 4.0mL DMSO and treated with a solution of potassium carbonate (136mg, 0.980mmol) in water (1.60mL, 88.8 mmol). After cooling at 0 deg.C, hydrogen peroxide (0.751mL, 9.80mmol) was added slowly. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with 20mL of water and extracted with EtOAc (3X 20 mL). Is provided with The organic extract is extracted by 5 percent sodium thiosulfate and saturated NaHCO3And brine, dried over sodium sulfate and concentrated to give 180mg (77%) of crude 28. MS (ESI +): 288.0.
example 29: 2- ((dimethylamino) methylenecarbamoyl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-Carboxylic acid methyl ester 29
28 was converted to 29 according to the procedure in example 21. The yield thereof was found to be 82%. MS (ESI +): 343.1.
example 30: 2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-Carboxylic acid methyl ester 30
Coupling of 29 with 2-chlorophenylhydrazine hydrochloride as in example 22 gave 30. The yield thereof was found to be 59%. MS (ESI +): 422.1.
example 31: 2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxylic acid 31
Hydrolysis of 30 was carried out as in example 12 to give 31. The yield thereof was found to be 75%. MS (ESI +): 408.1.
example 33: 9-bromo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-Formaldehyde 33
A solution of ethylmagnesium bromide in diethyl ether (3.0M, 3.472mL) was added dropwise to 9-bromo-2-iodo-5, 6-dihydrobenzo [ f ] at-30 deg.C]Imidazo [1, 2-d ] s ][1，4]Oxazazepine(1173mg, 3.000mmol) in 20mL THF. The mixture was stirred at this temperature for 20 minutes and warmed to 15 ℃. The mixture was cooled again to-25 ℃ and DMF (929.2 μ L, 12.00mmol) was added. The mixture was allowed to stand for 18 hours. Saturated NH for the mixture4Aqueous Cl was quenched and extracted with EtOAc. The organic extracts were washed with water and brine, over MgSO4Dried and concentrated in vacuo. The yield was 0.92 g. MS: 293.1.
example 34: 9-bromo-2- (4-methyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine34
Aqueous ammonia (16.0M, 0.819mL) was added to a solution of 33(640mg, 2.2mmol) and methylglyoxal (0.787g, 4.37mmol) in methanol (17mL, 420mmol) and THF (6mL, 70 mmol). After 1 hour, the same amount of methylglyoxal and 16.0M aqueous ammonia was added. The mixture was stirred for 2 hours, concentrated in vacuo and the residue partitioned between EtOAc and water. The organic extracts were washed with water and brine, over MgSO4Dried and concentrated. The residue was purified over a 4g silica gel column (using a gradient of EtOAc/DCM). The weight was 0.417 g. MS: 344.9.
example 35: 9-bromo-2- (1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine35
Glyoxal (0.689mL, 6.01mmol) and 16.0M aqueous ammonia (1.50mL) were added to a solution of 33(550mg, 1.5mmol) in methanol (30.0mL, 742 mmol). After 1 hour, glyoxal and ammonia were added and the mixture was stirred for 4 hours. The mixture was then concentrated in vacuo and partitioned between 0.5N HCl and EtOAc. The organic extract was discarded by careful addition of saturated NaHCO 3The acidic aqueous solution is basified. The mixture was extracted with EtOAc and the organic extracts were washed with water and brine, dried and concentrated. The residue was triturated with DCM to give a precipitate which was collected, washed with cold DCM and dried to give 35. MS (ESI +), 331.2.
Example 36: 9-bromo-2- (1-isopropyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine36
To a solution of 35(0.237g, 0.716mmol) and cesium carbonate (0.280g, 0.859mmol) in DMF (4.74mL, 61.2mmol) was added isopropyl iodide (0.0859mL, 0.859 mmol). The reaction mixture was stirred at 50 ℃ for 18 hours. The reaction mixture was quenched with water and then extracted with EtOAc (2 ×). The crude product was purified to give 36. MS (ESI +) ═ 373.1.
Example 37: 3-hydroxy-4- (1H-imidazol-2-yl) benzoic acid methyl ester 37
4-formyl-3-hydroxybenzoic acid (5g, 30mmol) was suspended in methanol (70mL) and treated dropwise with thionyl chloride (3.29mL 45 mmol). The mixture was heated to reflux overnight. Concentrate to dryness and add 50mL of toluene and concentrate again. The residue was recrystallized from EtOAc-hexanes. A total of 4.8g (85%) of methyl 4-formyl-3-hydroxybenzoate were obtained.
Methyl 4-formyl-3-hydroxybenzoate (4.8g, 27mmol), 40% glyoxal aqueous solution (11.6g, 79.93mmol) and 5 A mixture of 0% aqueous ammonia (6.8g, 399mmol) in methanol (50mL) was stirred for 2 hours or more until the reaction was complete. The solvent was removed by rotary evaporation and the residue was partitioned between EtOAc and water. The mixture was filtered to remove the precipitate. The pH was adjusted to 5-6 by careful addition of 1N HCl. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water and brine and MgSO4And (5) drying. The residue was purified by flash chromatography to give 37 as a yellow solid (4g, 71%).
Example 38: 5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 38
A mixture of 37(2.2g, 10mmol), 1, 2-dibromoethane (3.12mL, 36mmol) and cesium carbonate (13.14g, 40mmol) in DMF (100mL) was heated at 90 ℃ for 12 h. The mixture was filtered, the mother liquor was concentrated in vacuo and the residue was partitioned between water and EtOAc. The suspension was filtered and the solid was a pure by-product. The organic layer was washed with water and brine and MgSO4Dried and concentrated to give crude 38(2g, 80%).
Example 38 a: 10-bromo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine38a
To 10-bromo-2-iodo-5, 6-dihydrobenzo [ f ] at-20 deg.C]Imidazo [1, 2-d ] s][1，4]Oxazazepine(9g, 20mmol) in THF (40mL) was added a solution of ethylmagnesium bromide in ether (22 mL). The mixture was warmed to room temperature and LCMS showed the reaction was complete in 1.5 hours. The reaction mixture was poured into 10% NH 4Cl and extracted with EtOAc.The organic layer was washed with brine, over MgSO4Dried and concentrated. The crude product was purified by ISCO chromatography to afford 38 a. LC/MS (ESI +): m/z 265(M + H).
Example 38 b: 10- (2-fluoropyridin-3-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine38b
To a solution of 38a (140mg, 0.53mmol) in DMF (20mL) and water (2mL) was added 2-fluoropyridine-3-boronic acid (89mg, 0.632mmL), potassium acetate (207mg, 2.11mmol) and tetrakis (triphenylphosphine) palladium (30mg, 0.0264 mmol). The reaction mixture was degassed for 5 minutes and heated at 100 ℃ overnight. LCMS showed the desired product peak. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through a thin plug of celite. The filtrate was washed with water and brine, then MgSO4Dried and concentrated. The crude residue was purified by preparative HPLC to give 38 b. LC/MS (ESI +): m/z 282(M + H).
Example 38 c: 3- (5, 6-dihydrobenzo [ f ]]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) pyridin-2 (1H) -one 38c
To a solution of 38b (100mg, 0.4mmol) in DME (4mL) was added 10% aqueous HCl (4 mL). The reaction mixture was stirred and heated at 80 ℃ overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 38 c. LC/MS (ESI +): m/z280(M + H). 1H NMR(500MHz，DMSO)11.73(s，1H)，8.71(d，J＝2.3，1H)，7.72-7.50(m，1H)，7.47-7.21(m，1H)，7.15-6.86(m，2H)，6.29(t，J＝6.6，1H)，4.44(d，J＝6.1，4H)。
Example 38 d: 4- (5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) pyridin-2 (1H) -one 38d
38d were prepared according to the methods in examples 38 a-c. LC/MS (ESI +): m/z 280(M + H).1H NMR(500MHz，DMSO)8.70(d，J＝2.5，1H)，7.59(dd，J＝8.5，2.5，1H)，7.45(d，J＝6.8，1H)，7.35(s，1H)，7.09(dd，J＝16.9，4.7，2H)，6.57-6.36(m，2H)，4.47(dd，J＝11.6，5.6，4H)。
Example 38 e: 5- (5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) pyridin-2 (1H) -one 38e
38e were prepared according to the methods in examples 38 a-c. LC/MS (ESI +): m/z 280(M + H).1HNMR(500MHz，DMSO)8.48(s，1H)，8.03(s，1H)，7.94(s，1H)，7.83(d，J＝10.8，1H)，7.77(d，J＝8.7，1H)，7.21(d，J＝8.7，2H)，6.46(d，J＝9.8，1H)，4.65(dd，J＝24.3，4.8，4H)。
Example 39: 2, 3-diiodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 39
A mixture of 38(2g, 8mmol) and NIS (9.2g, 41mmol) in DMF was heated at 80 ℃ overnight. The mixture was diluted with EtOAc and water. The thick suspension was filtered through a glass filter. The solid was washed with EtOAc, then diluted with THF and MgSO4And (5) drying. LCMS showed the solution contained pure product. The brown solution was washed with 10% sodium thiosulfate, water, and brine, and with MgSO4Dried and concentrated to small volume. The precipitate was filtered and dried to give 39(3.4g, 81% yield).
Example 40: 2-iodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 40
A fresh solution of ethyl magnesium bromide in ether (3.0M, 1.1mL) was added dropwise to a suspension of 39(1.1g, 2.2mmol) in THF at-15 deg.C. The mixture was stirred and monitored using LC/MS. After 1 hour, no starting material remained and the reaction mixture was poured into saturated NH 4Cl and extracted with EtOAc. The organic extracts were washed with water and brine, over MgSO4Dried and concentrated. After completion of this operation, 0.7g (80%) of 40 are obtained.
Example 41: 2-cyano-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 41
40(740, 2.3mmol) and cuprous cyanide (537mg, 6.9mmol) were combined in DMF (8 mL). The reaction mixture was irradiated with microwaves at 150 ℃ for 40 minutes at 200 watts. The reaction mixture was partitioned between 15% aqueous ammonia and EtOAc. The aqueous layer was extracted three times with EtOAc, and the combined organic extracts were washed with water and brine and MgSO4Drying gave 0.46g (74% yield) of 41.
Example 42: 2-carbamoyl-5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 42
41(0.46g, 1.7mmol) was stirred with potassium carbonate (469mg, 3.4mmmol), water (1.2mL) and hydrogen peroxide (408mg, 6mmol) in DMSO (7mL) for 4 hours. The mixture was diluted with 70mL of water and extracted with EtOAc. EtOAc solution was water, 5% Na2S2O3Water and brine, over MgSO4Dried and concentrated in vacuo to give 42(0.37 g).
Example 43: 9-bromo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-carboxamide 43
Step 1: 5-bromo-2- (1H-imidazol-2-yl) phenol
A solution of 4-bromo-2-hydroxybenzaldehyde (1.0g, 5mmol), 40% aqueous glyoxal (3.6g, 24.87mmol), and 50% aqueous ammonia (2.5g) in methanol (20mL) was stirred for 2 hours or more until the reaction was complete. The solvent was concentrated by rotary evaporation and the residue was partitioned between EtOAc and water. The mixture was filtered to remove the precipitate. The pH was adjusted to 5-6 by careful addition of 1N HCl. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water and brine and MgSO4And (5) drying. Purification by ISCO chromatography (30% EtOAc/DCM) gave 5-bromo-2- (1H-imidazol-2-yl) phenol as a yellow solid (0.9 g).
Step 2: 9-bromo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine
A mixture of 5-bromo-2- (1H-imidazol-2-yl) phenol (0.9g, 4mmol), 1, 2-dibromoethane (1.3mL, 15mmol) and cesium carbonate (4.9g, 15mmol) in DMF (20mL) was heated to 90 ℃ and held for 12 hours. The mixture was partitioned between water and EtOAc. The organic layer was washed with water and brine and MgSO4Drying and concentrating to obtain 9-bromo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxa nitrogenHetero compound(0.8g)。
And step 3: 9-bromo-2, 3-diiodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine
Reacting 9-bromo-5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]OxazazepineA mixture of (0.8g, 3mmol) and NIS (1.87g, 8.3mmol) in DMF was stirred at room temperature for 48 h. The mixture was diluted with EtOAc, washed with 5% sodium bicarbonate, 10% sodium thiosulfate, water, and brine and the organic layer was MgSO4Dried and concentrated to a solid residue. Purification by ISCO chromatography (30% EtOAc/heptane) afforded 9-bromo-2, 3-diiodo-5, 6-dihydrobenzo [ f []Imidazo [1, 2-d ] s][1，4]Oxazazepine(1.2g)。
And 4, step 4: 9-bromo-2-iodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine
A solution of 3.0M ethyl magnesium bromide in diethyl ether (1.1mL) was added dropwise to 9-bromo-2, 3-diiodo-5, 6-dihydrobenzo [ f ] f at-15 deg.C]Imidazo [1, 2-d ] s][1，4]Oxazazepine(1.1g, 2.2mmol) in THF. The mixture was stirred and monitored by LC/MS. After 1 hour, no starting material remained and the reaction mixture was poured into saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with water and brine, over MgSO4Dried and concentrated. Crude residue is passed throughPurifying by flash column chromatography to obtain 9-bromo-2-iodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineIt was a white solid (0.7 g).
And 5: reacting 9-bromo-2-iodo-5, 6-dihydrobenzo [ f ]Imidazo [1, 2-d ] s][1，4]Oxazazepine(1.5g, 3.8mmol), bis (triphenylphosphine) palladium (II) dichloride (142mg, 0.202mmol), DMF (45mL) and bis (trimethylsilyl) azane (4.34mL, 20.6mmol) were combined. All solutions were purged with a CO balloon and sealed with a CO balloon attached. The reaction flask was heated at 70 ℃ for 2 hours. LC/MS indicated complete conversion. Cooled to room temperature and poured into 1N HCl (30 mL). Stir 5 min and use saturated NaHCO3Neutralizing with water solution. Extracted three times with EtOAc and then MgSO4Dried, filtered and concentrated in vacuo. Triturate with IPA and collect the solid after filtration and washing with EtOAc. 734mg (62% yield) 43 was obtained as a brown solid. LC/MS (ESI +): m/z 310(M + H).1H NMR(400MHz，CDCl3)8.36(d，J＝8.5，1H)，7.63(s，1H)，7.24(dd，J＝7.2，4.2，1H)，7.09-6.99(m，1H)，4.51-4.36(m，4H)。
Example 44: 9-bromo-N-formyl-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-carboxamide 44
Reacting 9-bromo-2-iodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(10g, 25.6mmol) in a solution containing Pd (dppf) Cl2(0.94g, 1.28mmol) and DMAP (3.13g, 25.6mmol) in formamide (200mL) heated under a CO balloon at 70 deg.C2.5 hours. The mixture was cooled to rt, diluted with EtOAc and filtered. The resulting precipitate was dried to yield 44(6.7g, 78%). 1H NMR(DMSO-d6，400MHz)：11.10(d，J＝9.6Hz，1H)，9.21(d，J＝9.6Hz，1H)，8.53(d，J＝8.8Hz，1H)，8.24(s，1H)，7.34-7.28(m，2H)，4.53-4.50(m，4H)。LC-MS(ESI，m/z)＝336[M+H]+。
Example 46: 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ E ] azulene-2-carboxylic acid [ 1-dimethylamino-eth- (E) -ylidene ] -amide 46
To a solution of 51(0.280g, 0.000909mol) in toluene (5mL) was added dimethylacetamide dimethyl acetal (0.405mL, 0.00273 mol). The solution was stirred at 95 ℃ for 4 hours. The toluene was removed in vacuo to give 46. MS (ESI +) 377.1/379.1.
Example 47: [5- (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulen-2-yl) -1-isopropyl-1H- [1, 2, 4] triazol-3-yl ] -carbamic acid tert-butyl ester 47
Step 1: 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene-2-carboxylic acid methyl ester
8-bromo-2-iodo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene (6.000g, 0.01534mol), palladium diacetate (0.1722g, 0.0007672mol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (0.8879g, 0.001534mol) were added successively to a dry flask filled with nitrogen. Degassed TEA (180mL, 1.3mol) and methanol (60mL) were added and the reaction mixture was thoroughly washed with carbon monoxide balloon for about 3 minutes. Two carbon monoxide balloons were fixed to the flask and the reaction mixture was heated to 50 ℃ and held for 3 hours. The reaction mixture was purged with nitrogen, concentrated in vacuo and loaded onto silica gel in a dry process. The crude product was purified by flash chromatography (40-100% EtOAc/hexanes followed by 5-15% MeOH/DCM) to give methyl 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene-2-carboxylate (4.242g) as a light brown solid. MS (ESI +) 323.0/325.0.
Step 2: 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene-2-carboxylic acid
To a solution of methyl 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene-2-carboxylate (1.000g, 0.003095mol) in THF (7.50mL) and water (4.5mL) was added lithium hydroxide (0.2964g, 0.01238 mol). The reaction mixture was stirred at 45 ℃ for 2 hours. The mixture was acidified with 2N HCl to pH 1. The resulting precipitate was filtered and rinsed with cold water to give 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene-2-carboxylic acid (860mg) as an off-white solid. MS (ESI +) 309.0/311.0.
Alternatively, 8-bromo-2-iodo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] is reacted at-78 deg.C]To a solution of azulene (10g, 25.6mmol) in THF (120mL) was added nBuLi (n-butyllithium) (19.2mL, 1.6M in hexane, 30.7mmol) at a rate such that T was addedmax< -73 ℃. During the addition, the purple faded and a brown precipitate formed. The reaction mixture was stirred at-78 ℃ for 20 minutes. Passing CO produced from dry ice and through dry silica gel2Bubble through the reaction mixture for 30 minutes. The temperature was raised to-55 ℃ and then lowered to-78 ℃. After adding CO2In the process of (3), a thick precipitate is formed rapidly. The reaction mixture was stirred at-78 ℃ for 1 hour. The reaction mixture was quenched by pouring into 20mL of water (careful effervescence). The mixture was warmed to room temperature. By adding saturated NaHCO 3The pH of the mixture was adjusted to-pH 8 with aqueous solution and the aqueous layer was washed with EtOAc. The aqueous phase was collected and the pH was adjusted to-pH 4 by addition of AcOH. The precipitate formed was collected by filtration, washed with water and dried under vacuum to give 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulene-2-carboxylic acid as a beige solid (4.38g, 55%).1HNMR(400MHz，d6-DMSO)8.31(1H, d, J ═ 8.5Hz), 7.98(1H, s), 7.32(1H, dd, J ═ 8.5, 2.2Hz), 7.27(1H, d, J ═ 2.2Hz), 4.51-4.47(4H, m). LCMS: RT 3.67 min, M + H+＝309/311(40％)，M+Na+＝323/325(100％)。1H NMR showed the product to contain-5% 8-iodo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulene-2-carboxylic acid.
And step 3: { [ (E) -8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ E ] azulene-2-carbonylimino ] -methylsulfanylmethyl } -carbamic acid tert-butyl ester
To a solution of 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene-2-carboxylic acid (0.839g, 0.00271mol) and oxalyl chloride (2M in DCM, 1.36mL, 0.002714mol) in DCM (16.70mL) was added 1 drop DMF under a nitrogen atmosphere. The solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the acid chloride was redissolved in DCM (9.0 mL). The solution was added dropwise to a solution of N-tert-butoxycarbonyl-S-methylpseudothiourea (0.5164g, 0.002714mol) and TEA (1.173mL, 0.008414mol) in DCM (9.0 mL). The reaction mixture was stirred at room temperature for 1.5 hours. DCM and water were added and the mixture was extracted three times with DCM. Saturated sodium carbonate was then added and the mixture was extracted with chloroform. The organic layers were combined and concentrated. The product was redissolved in DCM and methanol and filtered. The filtrate was collected, concentrated and loaded onto silica gel as dry method and purified by flash chromatography (0-15% MeOH/DCM) to give { [ (E) -8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ E ] azulene-2-carbonylimino ] -methylsulfanylmethyl } -carbamic acid tert-butyl ester (658mg) as an off-white solid. MS (ESI +) 481.0/483.0.
And 4, step 4: to { [ (E) -8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ E ]]Azulene-2-carbonylimino]-Methylthiomethyl } -carbamic acid tert-butyl ester (0.658g, 0.00137mol) in DMF (7.50mL) was added N, N-diisopropylethylamine (0.9524mL, 0.005468mol) followed by isopropylhydrazine hydrochloride (0.2267g, 0.002050 mol). The reaction mixture was stirred at room temperature for 4 hours. Water and DCM were added and the mixture was extracted three times with DCM. The organic layers were combined and MgSO4Dried and concentrated. The crude product was purified by flash chromatography (0-10% MeOH/DCM) to give 47(642mg) as a viscous pale yellow solid. This material was used without further purification. MS (ESI +) 489.1/491.1.
Example 48: 8-bromo-2- (2-isopropyl-5-methyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene 48
To a solution of 46(0.340g, 0.000901mol) in acetic acid (3.0mL, 0.053mol) was added isopropylhydrazine hydrochloride (0.1196g, 0.001082 mol). The reaction mixture was heated to 95 ℃ and held for 3 hours. The acetic acid was removed in vacuo and the product was loaded onto silica gel as a solid and purified by flash chromatography (0-10% MeOH/DCM) to give 48(293mg) as an orange solid. MS (ESI +) 388.1/390.1.
Alternatively, 48 is prepared as follows: a mixture of 4-bromo-2-fluoro-benzamidine hydrochloride (5.67g, 22.3mmol), potassium bicarbonate (8.95g, 89.4mmol), THF (45mL), and water (10mL) was heated to reflux and a solution of 91(5.5g, 22.3mmol) in THF (15mL) was added dropwise. The reaction mixture was heated to reflux for 18 hours, then the volatile solvent was removed in vacuo. The resulting suspension was filtered and the residue was triturated in hot ether to give 5- [2- (4-bromo-2-fluoro-phenyl) -1H-imidazol-4-yl]-1-isopropyl-3-methyl-1H- [1, 2, 4]Triazole as an off-white solid (6.4g, 79%).1H NMR 400MHz(DMSO-d6): 7.97(1H, t, J ═ 8.30Hz), 7.81(1H, s), 7.76(1H, dd, J ═ 10.68, 1.92Hz), 7.58(1H, dd, J ═ 8.42, 1.93Hz), 5.79(1H, broad multiplet), 2.26(3H, s), 1.44(6H, d, J ═ 6.60 Hz).
5- [2- (4-bromo-2-fluoro-phenyl) -1H-imidazol-4-yl]-1-isopropyl-3-methyl-1H- [1, 2, 4]A suspension of triazole (2.9g, 7.96mmol) in toluene (50mL) was treated with ethylene carbonate (25mL) and heated at reflux for 5 h. The cooled reaction mixture was diluted with DCM and passed through a plug of silica gel (eluting with DCM followed by 20% methanol in DCM). The methanol containing fractions were combined and concentrated in vacuo to give a light brown solid. Trituration of the solid in ether afforded 2- [2- (4-bromo-2-fluoro-phenyl) -4- (2-isopropyl-5-methyl-2H- [1, 2, 4) ]Triazol-3-yl) -imidazol-1-yl]Ethanol, as a white solid (2.3g, 71%).LCMS: RT 2.85 min, [ M + H]+＝408/410。1H NMR400MHz(CDCl3)：8.16(1H，s)，7.67-7.20(3H，m)，5.83(1H，m)，4.05(2H，t，J＝5.10Hz)，3.92(2H，t，J＝5.10Hz)，2.44(3H，s)，1.50(6H，d，J＝6.65Hz)。
2- [2- (4-bromo-2-fluoro-phenyl) -4- (2-isopropyl-5-methyl-2H- [1, 2, 4]Triazol-3-yl) -imidazol-1-yl]A suspension of ethanol (2.3g, 5.6mmol) in DMF (50mL) was treated portionwise with sodium hydride (60% dispersion, 247mg, 6.2mmol) over 5 min and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by slow addition of water (200 mL). The precipitate formed was filtered off and washed with water to give 48 as a white solid (1.64g, 53%). LCMS: RT 3.43 min, [ M + H]+＝388/390。1HNMR 400MHz(CDCl3)：8.37(1H，d，J＝8.61Hz)，7.70(1H，s)，7.26-7.25(2H，m)，5.87-5.86(1H，m)，4.50-4.48(2H，m)，4.46-4.42(2H，m)，2.42(3H，s)，1.57(6H，d，J＝6.64Hz)。
Example 49: 9-bromo-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene 49
Step 1: 7-bromo-3, 4-dihydro-2H-benzo [ b ]]Oxygen oxide-5-ketones
To a stirred solution of 5 '-bromo-2' -hydroxyacetophenone (10g, 46.5mmol) in methyl ethyl ketone (100mL) was added K2CO3(13.5g, 97.7mmol) followed by 1, 2-dibromoethane (20mL, 232.5 mmol). The reaction mixture was heated at moderate reflux temperature for 16 hours and then cooled to room temperature. The reaction mixture was filtered and then concentrated in vacuo. The resulting residue was dissolved in ether/EtOAc (4: 1, 500mL) and the precipitated solid was removed by filtration. The filtrate was washed with 2N NaOH (100mL) and the organic portion was Na 2SO4Drying and concentrating in vacuo to give 1- [ 5-bromo-2- (2-bromo-ethoxy) -phenyl]-ethanones(8.07g, 55%) which was used in the next step without further purification.
To a slurry of NaH (60% dispersion in mineral oil) (1.48g, 37.1mmol) in THF (50mL) at room temperature was added 1- [ 5-bromo-2- (2-bromo-ethoxy) -phenyl]Ethanone (8.07g, 25.1 mmol). The reaction mixture was slowly heated to reflux and stirred for 20 hours. The solvent was removed in vacuo and the residue was flash chromatographed (SiO)24: 1 EtOAc/petroleum ether) to give 7-bromo-3, 4-dihydro-2H-benzo [ b ]]Oxygen oxide-5-ketone as a yellow oil (4.22g, 70%).1H NMR(CDCl3)2.15-2.29(2H，m)，2.89(2H，t，J＝7.0Hz)，4.24(2H，t，J＝6.6Hz)，6.97(1H，d，J＝8.8Hz)，7.50(1H，dd，J＝2.6，8.1Hz)，7.87(1H，d，J＝2.6Hz)。
Step 2: 7-bromo-4- [ 1-dimethylamino-methyl- (E) -ylidene]-3, 4-dihydro-2H-benzo [ b]Oxygen oxide-5-ketones
Reacting 7-bromo-3, 4-dihydro-2H-benzo [ b ]]Oxygen oxideA solution of-5-ketone (10.0g, 41.5mmol) in dimethylformamide dimethyl acetal (100mL) was heated at 110 ℃ for 18 hours. The reaction mixture was cooled to room temperature and cyclohexane (100mL) was added. The resulting solid precipitate was collected by filtration, washed with cyclohexane and then dried under vacuum at 40 ℃ to give 7-bromo-4- [ 1-dimethylamino-methyl- (E) -ylidene]-3, 4-dihydro-2H-benzo [ b]Oxygen oxide-5-ketone as yellow crystals (8.19g, 67%). 1H NMR (ppm)(CDCl3)：7.83(1H，d，J＝2.59Hz)，7.74(1H，s)，7.46(1H，dd，J＝8.51，2.58Hz)，6.88(1H，d，J＝8.52Hz)，4.27-4.19(2H，m)，3.14(6H，s)，2.76-2.69(2H，m)。
And step 3: to 7-bromo-4- [ 1-dimethylamino-methyl- (E) -ylidene at room temperature]-3, 4-dihydro-2H-benzo [ b]Oxygen oxideTo a suspension of-5-ketone (8.19g, 27.7mmol) in ethanol (100mL) was added hydrazine dihydrochloride powder (5.81g, 55.3mmol) and the mixture was stirred for 3 hours. The reaction mixture was concentrated to near dryness in vacuo and isopropanol (200mL) and water (100mL) were added. The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The mixture was concentrated in vacuo to remove volatile solvents, then diluted to 400mL with water. The resulting solid precipitate was collected by filtration, washed with water and dried under vacuum at 40 ℃ to give 49 as a pale yellow solid (7.8g, 106%).1H NMR (ppm)(CDCl3)：8.27(1H，d，J＝2.45Hz)，7.59(1H，s)，7.32(1H，dd，J＝8.64，2.41Hz)，6.94(1H，d，J＝8.64Hz)，4.34-4.28(2H，m)，3.15-3.09(2H，m)。
Example 50: 8-bromo-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene 50
Step 1: 8-bromo-4- [ 1-dimethylamino-methyl- (E) -ylidene]-3, 4-dihydro-2H-benzo [ b]Oxygen oxide-5-ketones
Reacting 8-bromo-3, 4-dihydro-2H-benzo [ b ]]Oxygen oxideA solution of-5-ketone (5.0g, 20.7mmol) in dimethylformamide dimethyl acetal (15mL) was heated at 110 ℃ for 18 h. The reaction mixture was cooled to room temperature and cyclohexane (20mL) was added. The resulting solid precipitate was collected by filtration, washed with cyclohexane and then dried under vacuum at 40 ℃ to give 8-bromo-4- [ 1-dimethylamino-methyl- (E) -ylidene ]-3, 4-dihydro-2H-benzo [ b]Oxygen oxide-5-ketone as yellow crystals (5.32g, 86%).1H NMR(ppm)(CDCl3)：7.73(1H，s)，7.61(1H，d，J＝8.29Hz)，7.29(1H，dd，J＝8.29，1.94Hz)，7.18(1H，d，J＝1.91Hz)，4.28-4.21(2H，m)，3.14(6H，s)，2.77-2.70(2H，m)。
Step 2: to 8-bromo-4- [ 1-dimethylamino-methyl- (E) -ylidene at room temperature]-3, 4-dihydro-2H-benzo [ b]Oxygen oxideTo a suspension of-5-ketone (5.32g, 17.9mmol) in isopropanol (50mL) was added hydrazine dihydrochloride powder (3.77g, 35.9mmol), and the mixture was stirred for 2 hours. The reaction mixture was diluted with water (20mL), then heated at 100 ℃ for 2 hours, and then cooled to room temperature. The reaction mixture was concentrated in vacuo to remove volatile solvents. The resulting suspension was filtered and the filtrate was washed with water and dried in vacuo at 40 ℃ to give 50 as a pale yellow solid (4.28g, 90%).1H NMR(ppm)(DMSO-d6)：8.07(1H，d，J＝8.52Hz)，7.64(1H，s)，7.30-7.24(1H，m)，7.21(1H，d，J＝2.07Hz)，4.24(2H，dd，J＝5.63，4.50Hz)，3.00(2H，t，J＝5.09Hz)。
Example 51: 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene-2-carboxamide 51
To 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]To a solution of azulene-2-carboxylic acid (8.27g, 26.7mmol), EDCI (6.66g, 34.8mmol), HOBt (4.69g, 34.8mmol) and ammonium chloride (4.29g, 80.2mmol) in DMF (80mL) was added TEA (7.49mL, 53.5mmol) and the reaction mixture was stirred at 45 ℃ for 1.5 h. The reaction mixture was concentrated in vacuo and the residue triturated with water (250 mL). The precipitated product was collected by filtration and dried under vacuum at 45 ℃ for 16 h to give 51 as a beige solid (7.67g, 93%). 1H NMR(400MHz，d6-DMSO)8.40(1H, d, J ═ 8.7Hz), 7.80(1H, s), 7.42(1H, broad singlet), 7.32(1H, dd, J ═ 8.7, 2.0Hz), 7.27(1H, d, J ═ 2.1Hz), 7.15(1H, broad singlet), 4.50-4.46(4H, m). LCMS: RT 3.07 min, M + H+＝308/310。1H NMR showed the product to contain 5% 8-iodo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulene-2-carboxamide.
Alternatively, 8-bromo-2-iodo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]A solution of azulene (10.00g, 0.02558mol) in DMF (250mL) was degassed well with nitrogen. Bis (triphenylphosphine) palladium (II) dichloride (0.807g, 0.00115mol) was added followed by bis (trimethylsilyl) azane (21.58mL, 0.1023 mol). The solution was flushed with CO for 2 minutes and then sealed with a CO balloon attached. The reaction mixture was heated to 70 ℃ and held for 2.5 hours. DCM and saturated NH were added4Cl and the mixture was extracted 4 times with DCM. The organic phases were combined and MgSO4Dried and concentrated. A small amount of isopropanol was added and the mixture was triturated overnight. The mixture was filtered to give 5.97g (76% yield) 51 as a fine brown powder. MS (ESI +) 308.0/310.0.
Example 52: 8-bromo-2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene 52
Step 1: 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene-2-carboxylic acid 1-dimethylamino-m- (Z) -ylideneamide
To a suspension of 51(7.67g, 24.9mmol) in dioxane (150mL) was added DMF-DMA (9.92mL, 74.7mmol) and the reaction mixture was heated at 100 ℃ for 1 hour. During the reaction, the solid dissolved to give a brown solution. The reaction mixture was concentrated in vacuo and the solid residue was triturated with ether (-150 mL). The product was collected by filtration and dried under vacuum at 45 ℃ for 3 hours to give 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulene-2-carboxylic acid 1-dimethylamino-methyl- (Z) -ylideneamide as an off-white solid (8.52g, 94%).1H NMR(400MHz，d6-DMSO)8.56(1H，s)，8.34(1H，d，J＝8.6Hz)，7.96(1H，s)，7.32(1H，dd，J＝8.6，2.0Hz)，7.26(1H，d，J＝2.1Hz)，4.51-4.46(4H，m)，3.16(3H，s)，3.08(3H，s)。1H NMR showed the product to contain 5% 8-iodo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulene-2-carboxylic acid 1-dimethylamino-methyl- (Z) -ylideneamide.
Step 2: to a solution of 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene-2-carboxylic acid 1-dimethylamino-m- (Z) -ylideneamide in acetic acid was added isopropylhydrazine hydrochloride. The reaction mixture was heated to 95 ℃ and held for 3 hours. Acetic acid was removed in vacuo and the product was loaded onto silica gel as a solid and purified by flash chromatography (0-10% MeOH/DCM) to give 8-bromo-2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene.
Example 53: 1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -4- (tributylstannyl) -1H-imidazole 53a and 1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -5- (tributylstannyl) -1H-imidazole 53b
A solution of isopropyl magnesium chloride (iPrMgCl-LiCl, 4.3mL of 1.3M) in THF was added dropwise to a solution of 4-iodo-1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-imidazole (1.50g, 4.66mmol, mixture of regioisomers) in THF (20mL, 0.3mol) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 1 hour. Tributyltin chloride (1.64mL, 6.05mmol) was added and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was rotary evaporated and quenched with water, diluted with DCM and filtered over celite. The aqueous layer was extracted and the concentrated crude organics were purified by flash column chromatography (50-100% ethyl acetate/hexanes). NMR showed 53a and 53b in a 2: 1 ratio (confirmed by similar imidazole substitution in the reference). Regioisomers were not separated.
Example 54: 1- (4-bromo-1H-imidazol-1-yl) -2-methylpropan-2-ol and 1- (5-bromo-1H-imidazol-1-yl) -2-methylpropan-2-ol 54
To a suspension of 4-bromo-1H-imidazole (1.0g, 6.8mmol) and 2, 2-dimethyloxirane (0.665mL, 7.48mmol) in methanol (0.331mL, 8.16mmol) was added cesium carbonate (0.63g, 1.9 mmol). The reaction mixture was carefully heated in a sealed vessel at 110 ℃ for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with ether and washed twice with water. The organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a white solid which was flash purified with 100% EtOAc to give two different intermediates. The major regioisomer was 1- (4-bromo-1H-imidazol-1-yl) -2-methylpropan-2-ol (0.8g, 54% yield, M +1 was 220) and the minor regioisomer was 1- (5-bromo-1H-imidazol-1-yl) -2-methylpropan-2-ol (0.32g, 21% yield, M +1 was 220).
Example 55: n, N-diethyl-2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethanamine 55
To a solution of 4, 4, 5, 5-tetramethyl-2- (1H-pyrazol-4-yl) -1, 3, 2-dioxaborolan (250mg, 1.29mmol) and sodium hydride (61.8mg, 2.58mmol) in THF was added 2-bromo-N, N-diethylethylamine (558mg, 2.58mmol) at 0 deg.C. The reaction mixture was warmed to room temperature and monitored by LCMS. After 90 minutes, no reaction had taken place and potassium iodide (1.71g, 10.3mmol) was added and the reaction mixture was heated at 50 ℃ overnight. The reaction mixture was diluted with large volume of EtOAc and water and partitioned. The organic layer containing the product was washed with brine and concentrated in vacuo to give a clear thick oil which was 100% pure 55 by LCMS (340mg, 90% yield, M +1 294.2).
Example 56: 1- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -4- (trimethylstannanyl) -1H-imidazole 56
Step 1: 2, 4, 5-triiodo-1H-imidazoles
To a mixture of 1H-imidazole (50g, 0.73mol) in DMF (200mL) was added NIS (328g, 1.46mol) in portions and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into saturated Na 2CO3The solution was filtered, and the residue was washed with water and dried to obtain 150g of 2, 4, 5-triiodo-1H-imidazole (yield: 46%).
Step 2: 4-iodo-1H-imidazoles
Reacting 2, 4, 5-triiodo-1H-imidazole with Na2SO3The reaction was taken up in DMF (250mL) and stirred overnight at 110 ℃ under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated and poured into water, then extracted with EtOAc, the organics were washed with water, and Na was added2SO4Dried, concentrated and purified by silica gel column to give 4-iodo-1H-imidazole (yield ═ 55%). LC-MS: 195[ M + H ] M/z]+。
And step 3: 1- (4-iodo-1H-imidazol-1-yl) -2-methylpropan-2-ol
4-iodo-1H-imidazole and 0.5 equivalent Cs2CO3The mixture in 2, 2-dimethyloxirane was stirred at 120 ℃ for 20 minutes under microwave irradiation. The reaction mixture was concentrated and purified to give 1- (4-iodo-1H-imidazol-1-yl) -2-methylpropan-2-ol (yield 71%). LC-MS: 266[ M + H ] M/z]+。1HNMR(CDCl3，400MHz)：7.36(s，1H)，7.06(s，1H)，3.84(s，2H)，1.22(s，6H)。
And 4, step 4: 1- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -4-iodo-1H-imidazole
1- (4-iodo-1H-imidazol-1-yl) -2-methylpropan-2-ol was dissolved in DCM and 2, 6-lutidine was added dropwise at 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes, and tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) was then added dropwise. The mixture was warmed to room temperature and allowed to stand for about 1 hour, then quenched with 30% acetic acid, extracted with ethyl acetate, dried and concentrated to give 1- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -4- iodo-1H-imidazole (yield 74%). LC-MS: 381[ M + H ] M/z]+。
And 5: to a mixture of 1- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -4-iodo-1H-imidazole in DCM was added ethylmagnesium bromide (1.5 eq) at-78 ℃. The temperature of the mixture was slowly warmed to about 10 ℃ and cooled again. Trimethyltin chloride (1.6 equivalents) was added dropwise at-78 ℃. After the addition was complete, the temperature was slowly warmed to room temperature. The reaction mixture was poured into saturated NH4Cl solution, then extracted with DCM. The organic phase was washed twice with water and anhydrous Na2SO4Dried and concentrated to give 56 (yield 74%). LC-MS: m/z 419[ M + H ]]+。1H NMR(CDCl3，400MHz)：7.63(s，1H)，7.00(s，1H)，3.79(s，2H)，1.22-1.19(s，6H)，0.86(s，9H)，0.27(s，6H)，0.02(s，6H)。
Example 57: 2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine57
Step 1: 9-bromo-2- (1-isopropyl-4-methyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine
Isopropyl iodide (165. mu.L, 1.65mmol) was added to a mixture of 417mg (1.21mmol)34 and cesium carbonate (538mg, 1.65mmol) in 3mL DMF. The reaction mixture was stirred at rt for 18 h, mixed with water and extracted with EtOAc. The organic extracts were washed with water and brine, over MgSO 4Dried, concentrated and purified with 4g silica gel column (eluted with 4-5% methanol/DCM) to give 210mg of 9-bromo-2- (1-isopropyl-4-methyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f [ -f)]An imidazo [1 ] compound having a structure of,2-d][1，4]oxazazepineMS：387.1。
Step 2: 9-bromo-2- (1-isopropyl-4-methyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineA solution of (1.00g, 0.00258mol) and potassium acetate (0.758g, 0.00773mol) in DMSO (8.5mL, 0.12mol) was thoroughly purged with nitrogen in a round bottom flask equipped with a magnetic stir bar. Dipinopinacol diboron (0.719g, 0.00283mol) and [1, 1' -bis (diphenylphosphino) ferrocene were added]Palladium (II) dichloride [ Complex with DCM (1: 1)](0.210g, 0.258mmol) and the reaction mixture was heated to 85 ℃ under an inert atmosphere. The reaction was monitored by LC/MS and was complete after 6 hours. The mixture was partitioned between water and DCM and the mixture was extracted three times with DCM. The organic phases were combined and MgSO4Dried and concentrated. The entire material was loaded onto silica gel and purified by flash chromatography (0-10% MeOH/DCM followed by 100% EtOAC) to give 57(488mg) as a beige solid. MS (ESI +) 436.2.
Example 58: 9-bromo-2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene 58
58 and 8-bromo-2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Analogously to azulene from 49(450mg, 1.7mmol) and 5-chloro-1-isopropyl-1H- [1, 2, 4]Triazole (369mg, 2.55mmol) was prepared as a white solid (375mg, 59%). LCMS: RT 5.05 min, M + H+＝374/376。
Example 59: 9-bromo-2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene 59
59 and 8-bromo-2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]From 5-chloro-1- (2, 4-difluoro-phenyl) -1H- [1, 2, 4]Triazole (1.33g, 6.16mmol) and 49(1.36g, 5.13mmol) and flash chromatography (SiO) of the crude product2Gradient 0 to 35% EtOAc/cyclohexane) to give 59(1.42g, 62%). LCMS: RT ═ 4.80, M + H+＝444/446。
Example 60: 9-bromo-2- [2- (2-chloro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene 60
As for 1- (2, 4-difluoro-phenyl) -1H- [1, 2, 4]Triazole (example 103) procedure 2, 4-dichlorophenylhydrazine hydrochloride was reacted with formamide to give 1- (2-chloro-phenyl) -1H- [1, 2, 4 ]Triazole, which is an off-white solid.1H NMR(ppm)(CDCl3)：8.54(1H，s)，8.14(1H，s)，7.61-7.54(2H，m)，7.46-7.39(2H，m)。
As for 5-chloro-1- (2, 4-difluoro-phenyl) -1H- [1, 2, 4]Method for triazole (example 103) Synthesis of 1- (2-chloro-phenyl) -1H- [1, 2, 4]Triazole reacts with n-butyllithium and hexachloroethane to obtain 5-chloro-1- (2-chloro-phenyl) -1H- [1, 2, 4]Triazole, which is a white solid.1H NMR(ppm)(CDCl3)：8.05(1H，s)，7.61-7.58(1H，m)，7.55-7.48(1H，m)，7.46-7.43(2H，m)。
60 and 8-bromo-2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]From 5-chloro-1- (2-chloro-phenyl) -1H- [1, 2, 4]Triazole (2.25g, 10.5mmol) and 49(1.9g, 7mmol) and flash chromatography (SiO) of the crude product2Gradient 0 to 60% DCM (+ 10% EtOAc)/cyclohexane) to give 60(1.3g, 33%). LCMS: RT 4.82, M + H+＝442/444。
Example 61: 9-bromo-2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulene 61
Step 1: 4-bromo-1- (but-3-ynyloxy) -2-nitro-benzene 61_1
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (20.0g, 90mmol), 3-butyn-1-ol (7.0g, 99.8mmol) and potassium carbonate (13.8g, 99.8mmol) in anhydrous DMF (20mL) was reacted withThe molecular sieves were heated together for 43 hours. The mixture was cooled, diluted to about 500mL with water and extracted three times with EtOAc. The combined organic extracts were washed with water and then brine, dried and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO) 2Gradient 5 to 10% EtOAc/cyclohexane) to give 61 — 1 as a yellow solid (17.35g, 71%). NMR showed impurities (19%) which were not removed at this stage. LCMS: RT 4.41 min, [ M + Na]+＝292/294。
Step 2: 5-bromo-2- (but-3-ynyloxy) -phenylamine 61_2
4-bromo-1- (but-3-ynyloxy) -2-nitro-benzene (82% pure, 4.22g, 12.5mmol) was heated in a mixture of IMS (40mL) and glacial acetic acid (2mL) at about 50 ℃ until a solution formed. Iron powder (5.05g, 89.8mmol) and iron (III) trichloride hexahydrate (0.56g, 1.56mmol) were added and the mixture was heated at reflux for 18 h. The cooled mixture was filtered through celite and washed thoroughly with EtOAc. The filtrate was washed with water followed by brine and dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 10 to 20% EtOAc/cyclohexane) to give 61 — 2 as an orange oil (2.68g, 89%). LCMS: RT ═ 4.10 min, M + H+＝240/242。
And step 3: chloro- (5-bromo-2- (but-3-ynyloxy) phenylhydrazono) acetic acid ethyl ester 61_3
Ethyl 2-chloro-3-oxo-butyrate (1.94g, 11).2mmol) and sodium acetate (1.45g, 17.8mmol) were stirred in IMS (100mL) to give a clear solution which was then cooled to 0 deg.C. Additionally, a solution of 5-bromo-2- (but-3-ynyloxy) -phenylamine (2.68g, 11.2mmol) in 6M hydrochloric acid (6.8mL) was cooled to 0 ℃ and a solution of sodium nitrite (0.77g, 11.2mmol) in water (11.2mL) was added dropwise with stirring, maintaining the temperature below 5 ℃. The above acidic aqueous solution was added to the above IMS solution and washed with a small amount of water, wherein the temperature was kept below 5 ℃. After 1 hour at 0-5 ℃, the mixture was diluted with water and extracted several times with EtOAc. The combined organic extracts were washed with water and dried (Na) 2SO4) Filtered and concentrated in vacuo to give 61_3 as a light brown solid (3.96g, 95%). LCMS: RT ═ 4.97 min, [ M + Na-]+＝395/397/399。
And 4, step 4: 9-bromo-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulene-2-carboxylic acid ethyl ester 61_4
A mixture of chloro- (5-bromo-2- (but-3-ynyloxy) phenylhydrazono) acetic acid ethyl ester (3.28g, 8.78mmol) and TEA (12.2mL, 88mmol) in dry toluene (900mL) was heated slightly to reflux (120 ℃ C.) for 54 hours. The cooled mixture was filtered, the residue was washed with EtOAc and the filtrate was concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO 2)，Gradient 10 to 15% EtOAc/cyclohexane) to give 61 — 4 as a yellow solid (2.52g, 85%). LCMS: RT 4.52 min, M + H+＝337/339，[M+Na]+＝359/361。
And 5: 9-bromo-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulene-2-carboxamide 61_5
Reacting 9-bromo-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]A solution of azulene-2-carboxylic acid ethyl ester (1.51g, 4.48mmol) in 2M ammonia/methanol solution (70mL) was heated at about 120 deg.C (external temperature) in a pressure resistant tank for 30 hours and then cooled. The mixture was filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 50 to 100% EtOAc/cyclohexane) to give 61 — 5 as a pale yellow solid (1.11g, 80%). LCMS: RT 4.00 min, M + H +＝308/310，[M+Na]+＝330/332。
Step 6: 9-bromo-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulene-2-carboxylic acid 1-dimethylaminomethyleneamide 61_6
Reacting 9-bromo-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]A mixture of azulene-2-carboxamide (1.11g, 3.60mmol) and dimethylformamide dimethyl acetal (1.44mL, 10.8mmol) in dry 1, 4-dioxane (25mL) was heated at 100 ℃ for 2 h and then concentrated in vacuo. The resulting residue was triturated in ether to give 61 — 6 as a yellow solid (1.27g, 97%). LCMS: RT 3.27 min, M + H+＝363/365。
And 7: reacting 9-bromo-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]A mixture of azulene-2-carboxylic acid 1-dimethylaminomethylenamide (1.27g, 3.5mmol), isopropylhydrazine hydrochloride (0.48g, 4.37mmol) and glacial acetic acid (6mL) was heated at 110 ℃ for 6.5 h, then cooled and concentrated in vacuo. The resulting residue was dissolved in aqueous sodium bicarbonate and DCM and the phases were separated. The aqueous phase was extracted several times with DCM and the combined organic extracts were dried (MgSO)4) And concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 30 to 70% EtOAc/cyclohexane) to give 61(0.99g, 76%). LCMS: RT 5.07 min, M + H +＝374/376。1H NMR(ppm)(CDCl3)：8.07(1H，d，J＝2.41Hz)，7.96(1H，s)，7.39(1H，dd，J＝8.63，2.43Hz)，7.08(1H，d，J＝8.63Hz)，6.91(1H，s)，5.73-5.65(1H，m)，4.53(2H，t，J＝5.91Hz)，3.18(2H，t，J＝5.91Hz)，1.60(6H，d，J＝6.62Hz)。
Example 62: 9-bromo-2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulene 62
Reacting 9-bromo-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] according to the procedure used for 61]Azulene-2-carboxylic acid 1-dimethylaminomethylenamide with trifluoroethylhydrazine (70%Aqueous solution) to give 62 as a white solid. LCMS: RT 4.49 min, M + H+＝414/416。
Example 63: 8- (azetidin-3-yl) -2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene hydrochloride 63
Step 1: 1-tert-Butoxycarbonyl-azetidin-3-yl zinc iodide 63_1
To a sealed flask, zinc powder (276mg, 4.22mmol) and Celpure P65 filter (60mg) were added and the mixture was heated under vacuum at 300 ℃ for 10 minutes. The flask was purged with argon and cooled to room temperature. DMA (2.4mL) was added to the mixture, followed by the dropwise addition of a mixture of chlorotrimethylsilane (TMSCl) and 1, 2-dibromoethane (84. mu.L, 7: 5 v: v), which caused a slight exotherm and a small amount of effervescence. The reaction mixture was allowed to stand at room temperature for 15 minutes, then a solution of tert-butyl 3-iodo-azetidine-1-carboxylate (0.96g, 3.38mmol) in DMA (2mL) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours, then filtered to give 63_1 as a colorless DMA solution.
Step 2: 3- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl } -azetidine-1-carboxylic acid tert-butyl ester 63_2
8-bromo-2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene (1g, 2.25mmol) and [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride [ complexes with DCM]A solution of (183mg, 0.22mmol) and copper (I) iodide (56mg, 0.29mmol) in DMA (10mL) was degassed as follows: a vacuum purge was performed and then argon was bubbled through the mixture (× 3). To the dark red mixture was added a solution of 1-tert-butoxycarbonyl-azetidin-3-yl zinc iodide (3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide) (1.17g, 3.38mmol) in DMA (4.4mL) and the mixture was heated at 85 ℃ for 2 hours. During the reaction, the mixture changesGreen, then light orange, and finally black. The reaction mixture was diluted with water (20mL) and EtOAc (20mL) and the mixture was filtered through celite. The organic portion of the filtrate was separated and the aqueous phase was extracted with EtOAc (2X 20 mL). The combined organic fractions were washed with brine (100mL) and dried (MgSO) 4) And then concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 100% EtOAc/cyclohexane) to give 63_2 as a yellow oil (1.1g, 94%). LCMS: RT 4.81 min, M + H+＝521(100％)，M+H+-OtBu＝465(60％)，M+H+-Boc＝421(20％)。
And step 3: mixing 3- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulen-8-yl } -azetidine-1-carboxylic acid tert-butyl ester (1.1g, 2.11mmol) was dissolved in hydrochloric acid/dioxane (10mL, 4N) and the reaction mixture was stirred at room temperature for 1 hour. After about 5 minutes, a thick white precipitate formed. The reaction mixture was concentrated in vacuo to afford 63 as a yellow solid (1.0g, 100%). LCMS: RT 3.00 min, M + H+＝421。
Example 64: 8- (azetidin-3-yl) -2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene hydrochloride 64
Step 1: 3- [2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl ] -azetidine-1-carboxylic acid tert-butyl ester
3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester with 3- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4 ]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulen-8-yl } -azetidine-1-carboxylic acid tert-butyl ester was prepared analogously from 8-bromo-2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene and 1-tert-butoxycarbonylAlkyl-azetidin-3-yl zinc iodide. LCMS: RT 4.85 min, M + H+＝451(40％)，M+H+-OtBu＝395(100％)，M+H+-Boc＝351(10％)。
Step 2: 64 and 63 are similar to each other and consist of 3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester. LCMS: RT 2.86 min, M + H+＝351(20％)，M+H+-iPr＝308(100％)。
Example 65: 8- (azetidin-3-yl) -2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene hydrochloride 65
Step 1: 3- [2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulen-8-yl ] -azetidine-1-carboxylic acid tert-butyl ester
3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester with 3- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ]Azulen-8-yl } -azetidine-1-carboxylic acid tert-butyl ester was prepared analogously from 52 and 1-tert-butoxycarbonyl-azetidin-3-yl zinc iodide. LCMS: RT 4.61 min, M + H+＝451。
Step 2: 65 and 63 are similar to each other and consist of 3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester. LCMS: RT 2.44 min, M + H+＝351。
Example 66: 2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene trifluoroacetate 66
Step 1: 4- [2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulen-8-yl ] -piperidine-1-carboxylic acid tert-butyl ester 66_1
4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester with 3- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulen-8-yl } -azetidine-1-carboxylic acid tert-butyl ester was prepared analogously to 52(3.0g, 8.0mmol) and 1-tert-butoxycarbonyl-piperidin-4-yl zinc iodide (4-piperidine-1-carboxylic acid tert-butyl ester zinc iodide) (12mmol), prepared analogously to 1-tert-butoxycarbonyl-azetidin-3-yl zinc iodide, to yield 66 — 1(1.2g, 31%). LCMS: RT 5.06 min, M + H +＝479。
Step 2: to 4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]To a solution of tert-butyl piperidine-1-carboxylate (1.2g, 2.51mmol) in DCM (12mL) was added TFA (8mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the residue triturated in ether to give 66 as a grey solid (1.34g, 100%). LCMS: RT 2.88 min, M + H+＝379。
Alternatively, 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene hydrochloride was prepared as follows: 52(2.1g, 5.4mmol), 3, 6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (2.59g, 8.3mmol) and potassium carbonate (1.92g, 13.9mmol) were combined with DMF (13mL) and purged with argon. Adding PdCl2dppf-DCM (310mg, 0.42mmol), washing was repeated and the mixture was heated to 80 ℃ and held for 18 hours. After cooling, the reaction mixture was filtered through celite, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water, the organic layer was separated and dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO) 2Gradient of0 to 2% methanol/EtOAc) to give 4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.56g, 96%). LCMS: RT ═ 4.79, [ M + H]+＝477。1H NMR 400MHz(CDCl3)：8.45(1H，d，J＝8.46Hz)，7.89(1H，s)，7.73(1H，s)，7.19(1H，dd，J＝8.37，1.80Hz)，7.04(1H，d，J＝1.87Hz)，6.15(1H，s)，6.04-5.96(1H，m)，4.51-4.43(4H，m)，4.09(2H，d，J＝3.68Hz)，3.64(2H，t，J＝5.64Hz)，2.52(2H，s)，1.59(6H，d，J＝6.63Hz)，1.49(9H，s)。
4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Treating tert-butyl (3, 6-dihydro-2H-pyridine-1-carboxylate) with hydrochloric acid to obtain 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene hydrochloride.1H NMR 400MHz(DMSO-d6)：9.08(2H，s)，8.37(1H，d，J＝8.30Hz)，8.18(1H，s)，8.07(1H，s)，7.06(1H，dd，J＝8.35，1.80Hz)，6.91(1H，d，J＝1.80Hz)，5.85(1H，m)，4.53(4H，m)，3.35(2H，d，J＝12.46Hz)，2.98(2H，m)，2.87(1H，m)，1.93(4H，m)，1.50(6H，d，J＝6.57Hz)。
Example 67: 2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -9- (piperidin-4-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene hydrochloride 67
Step 1: 4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 67_1
4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester with 4- {2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4 ]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was prepared analogously to 59(1.55mg, 1.13mmol) to give 67_1 as a colourless gum (1.47g, 77%). LCMS: RT 5.01 min, M + H+＝547。
Step 2: 2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-9- (piperidin-4-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene hydrochloride with 9- (piperidin-4-yl) -2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]The azulene is prepared from 4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.06g, 3.77mmol) was prepared to give 67 as a white solid (1.15g, 62%). LCMS: RT 3.04 min, M + H+＝449。
Example 68: (4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -piperidin-4-yl) -methanol hydrochloride 68
Step 1: 4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -piperidine-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester 68_1
To a solution of dicyclohexylamine (291. mu.L, 1.463mmol) in anhydrous toluene (3mL) was added dropwise a 2.5M solution of n-butyllithium in hexane (563. mu.L, 1.575mmol) at room temperature under nitrogen. After the addition was complete, the mixture was stirred at room temperature for 10 minutes, then N-Boc-piperidine-4-carboxylic acid ethyl ester (305. mu.L, 1.24mmol) was added dropwise at room temperature and the mixture was stirred for 30 minutes. The mixture was added to 59(500mg, 1.13mmol), bis (dibenzylideneacetone) palladium (35mg, 0.06mmol) and tri-tert-butylphosphonium tetrafluoroborate (17.4mg, 0.06mmol) at room temperature under nitrogen, and then heated to 100 ℃. After heating for 17 hours, the mixture was cooled to room temperature and flash chromatography (SiO) was performed2Gradient 0 to 50% EtOAc/cyclohexane) to yield 68_1(200mg, 29%). LCMS: RT 4.93 min, M + H+＝621。
Step 2: 4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4 ] at 0 ℃ under nitrogen]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]To a solution of azulen-9-yl } -piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (200mg, 0.323mmol) in anhydrous THF (10mL) was added dropwise a 1M solution of lithium aluminum hydride in THF (485. mu.L, 0.485 mmol). The mixture was stirred at 0 ℃ for 15 minutes and then warmed to room temperature. After 60 minutes, a further 1M solution of lithium aluminum hydride in THF (485. mu.L, 0.485mmol) was added and stirring was continued. After 2 hours, the mixture was cooled to 0 ℃ and saturated NH 4The Cl solution was carefully quenched. The mixture was extracted with DCM and the organic layer was washed with water followed by brine, dried (Na)2SO4) And the solvent was removed in vacuo. The resulting residue was dissolved in DCM (10mL) and treated with a solution of 4NHCl in dioxane (2mL) at room temperature. After stirring for 5 hours, the solvent was removed in vacuo, the solid was triturated with ether and collected by filtration to give 68(97mg, 58%). LCMS: RT 2.84 min, M + H+＝479。
Example 69: 2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulene-9-carbaldehyde 69
Step 1: 2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulene-9-carboxylic acid methyl ester
P-62 (2.18g, 5.28mmol), molybdenum hexacarbonyl (696mg, 2.64mmol), trans-bis (. mu. -acetoxy) bis [ o- (di-o-tolylphosphino) benzyl]Dipalladium (II) [ trans-di (mu-acetato) bis [ o- (di-o-tolylphosphino) benzyl]dipalladium(II)]A suspension of (240mg, 0.24mmol), tri-tert-butylphosphonium tetrafluoroborate (156mg, 0.52mmol) and DBU (792 μ L, 5.28mmol) in methanol (15mL) and dioxane (15mL) was degassed and then heated using microwave radiation at 150 ℃ for 30 min. Inverse direction The mixture was diluted with EtOAc (20mL), filtered and the filtrate was concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 30 to 60% EtOAc/cyclohexane) to give the title compound (1.02g, 49%).1H NMR (ppm)(CDCl3)：8.69(1H，d，J＝2.12Hz)，8.03(1H，s)，7.96(1H，dd，J＝8.48，2.12Hz)，7.22(1H，d，J＝8.50Hz)，6.94(1H，s)，5.57(2H，dd，J＝16.24，8.12Hz)，4.62-4.56(2H，m)，3.94(3H，s)，3.29-3.23(2H，m)。
Step 2: 2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulene-9-carboxylic acid
To 2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]To a solution of azulene-9-carboxylic acid methyl ester (553mg, 1.4mmol) in dioxane (12.5mL) and water (12.5mL) was added lithium hydroxide (67mg, 2.8mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to remove dioxane and the resulting solution was acidified to pH 1 by addition of HCl (12N). The precipitate formed was collected by filtration, washed with water and dried under vacuum at 40 ℃ to give the title compound (519mg, 98%). LCMS: RT 4.04 min, M + H+＝380。
And step 3: {2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulen-9-yl } -methanol
To 2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4] at-70 deg.C ]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]DIBAL (3mL, 1M in toluene, 3mmol) was added to a solution of azulene-9-carboxylic acid methyl ester (393mg, 1mmol) in THF (10mL) and the reaction mixture was stirred at 0 ℃ for 1 h. The reaction mixture was diluted with methanol (5mL) and then with saturated aqueous sodium potassium tartrate solution. The resulting mixture was extracted with EtOAc (3X 20mL) and the combined organic fractions were dried (MgSO)4) And concentrated in vacuo to give the title compound (370mg, 100%).
And 4, step 4: to {2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]To a solution of azulen-9-yl } -methanol (370mg, 1mmol) in DCM (20mL) was added Dess-Martin (Dess-Martin) iodophor (467mg, 1.1mmol) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM (20mL) and the solution was washed with sodium hydroxide solution (1M, aq). The organic layer was separated and dried (MgSO)4) And then concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 90% EtOAc/cyclohexane) to give 69 as a white solid (253mg, 70%). LCMS: RT ═ 4.10, M + H +＝364。
Example 70: 2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulene-9-carboxylic acid 70
Step 1: 2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulene-9-carboxylic acid methyl ester
2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulene-9-carboxylic acid methyl ester with 2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Methyl azulene-9-carboxylate was prepared analogously from 61(0.99g, 2.65 mmol). The reaction mixture was diluted with EtOAc (20mL), filtered and the filtrate concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 50 to 100% EtOAc/cyclohexane) to give the title compound (0.32g, 34%). LCMS: RT 4.73, M + H+＝354。
Step 2: [2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulen-9-yl ] -methanol
[2- (2-isopropyl-2H- [1, 2, 4]]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulen-9-yl]Methanol is reacted with {2- [2- (2,2-trifluoro-ethyl) -2H- [1, 2, 4 ]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulen-9-yl } -methanol was prepared analogously from 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulene-9-carboxylic acid methyl ester (0.50g, 1.42mmol) to give the title compound (360mg, 78%). LCMS: RT ═ 3.81, M + H+＝326。
And step 3: 2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulene-9-carbaldehyde
2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulene-9-carbaldehyde was synthesized from [2- (2-isopropyl-2H- [1, 2, 4] similarly to 69]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulen-9-yl]Methanol (360mg, 1.11 mmol). The reaction mixture was diluted with DCM (20mL) and the solution was washed with sodium hydroxide solution (1M, aq). The organic layer was separated and dried (MgSO)4) And concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2100% EtOAc) to give the title compound as a white solid (410mg, 114%). LCMS: RT ═ 4.15, M + H+＝324。
And 4, step 4: 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ]Azulene-9-carboxylic acid and 2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulene-9-carboxylic acid is prepared from 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulene-9-carboxylic acid methyl ester (720mg, 2.04 mmol). The reaction mixture was concentrated in vacuo to remove dioxane and the resulting solution was acidified to pH 1 by addition of HCl (12N). The precipitate formed was collected by filtration, washed with water and dried under vacuum at 50 ℃ to give 70(584mg, 84%). LCMS: RT 4.61 min, M + H+＝340。
Example 72: 2- (1- (2-chlorophenyl) -1H-imidazol-2-yl) -5,6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxylic acid 72
Step 1: 2- (1- (2-chlorophenyl) -1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-Carboxylic acid methyl ester
To a solution of 1- (2-chlorophenyl) -1H-imidazole (0.133g, 0.743mmol) in THF (5.43mL, 66.9mmol) was added dropwise a 1.60M solution of n-butyllithium in hexane (0.464mL) at-78 ℃. The reaction mixture was stirred at-78 ℃ for 1 hour, then a 0.50M solution of zinc dichloride in THF (1.48mL) was added. The reaction mixture was warmed to room temperature and held for 30 minutes, then Pd (PPh) was added 3)4(0.0780g, 0.0675mmol) and 26(0.250g, 0.675mmol) in 2mL THF. The reaction mixture was refluxed for 2 hours, then treated with a 0.50M solution of zinc dichloride in THF (2.2mL) and refluxed for 3 hours. The mixture was diluted with EtOAc and then saturated Na2CO3And a brine wash. Na for organic layer2SO4Drying and vacuum concentrating. Crude product 2- (1- (2-chlorophenyl) -1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-Carboxylic acid methyl ester was purified by chromatography.
MS(ESI+)＝421.2。
Step 2: to 2- (1- (2-chlorophenyl) -1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineTo a solution of methyl (0.100g, 0.238mmol) 10-carboxylate in THF (5.56mL, 68.5mmol) and water (5.56mL, 308mmol) was added lithium hydroxide monohydrate (0.0399g, 0.950 mmol). Will reactThe mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The reaction mixture was acidified with 1M HCl and then extracted with DCM (3 ×). The combined organics were washed with Na2SO4Dried, filtered and concentrated to give 72. MS (ESI +) -407.2.
Example 74: 10-bromo-2- (1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine74
Step 1: 10-bromo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s ][1，4]Oxazazepine-2-carboxaldehyde
P-10-bromo-2-iodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineFormylation to obtain 10-bromo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-formaldehyde. The yield thereof was found to be 84%. MS: 293.1.
step 2: reacting 10-bromo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineCoupling of-2-carboxaldehyde with glyoxal in the presence of ammonia gives 74. The yield thereof was found to be 37%. MS: 331.0.
example 82: 1- (2-Bromoethoxy) -2-nitrobenzene 82
To 2-nitrophenol (25.0g, 0.180mol) in hydrogen at 107 ℃ in a 500mL flask with reflux condenserTo a solution of sodium oxide (14.4g, 359mmol) and water (6.0mL, 330mmol) was added 1, 2-dibromoethane (61.9mL, 719mmol) and the flask was heated at 107 ℃ for three days (scheme 18). The product was then extracted twice with 100mL DCM, washed with 2M NaOH and brine, dried over sodium sulfate and concentrated. Silica gel chromatography (eluting with hexanes and EtOAc) afforded bromide 82 in 63% yield.1H NMR(500MHz，CDCl3)7.83(dd, J ═ 8.4, 1.6Hz, 1H), 7.53(td, J ═ 8.1, 1.6Hz, 1H), 7.12-7.01(m, 2H), 4.45-4.34(m, 2H), 3.67(t, J ═ 6.5Hz, 2H) (see WO 2002076926).
Example 83: 3- (2-Nitrophenoxy) propionitrile 83
To a solution of sodium cyanide (0.398g, 8.13mmol) in DMSO (29.0mL, 409mmol) was added bromide 82(2.00g, 8.13mmol) in one portion at 45 ℃ and the reaction mixture was stirred at 70 ℃ for 4 h (scheme 18). The reaction mixture was then extracted with EtOAc and the organic layer was dried over sodium sulfate and concentrated. Chromatography on silica gel (eluting with hexanes and EtOAc) afforded nitrile 83 in 43% yield.1HNMR(400MHz，CDCl3)7.89(dd, J ═ 8.1, 1.7Hz, 1H), 7.62-7.55(m, 1H), 7.19-7.13(m, 1H), 7.11(dd, J ═ 8.4, 0.8Hz, 1H), 4.36(t, J ═ 6.6Hz, 2H), 2.94(t, J ═ 6.6Hz, 2H) (compliant with Vitale et al (1994) Anales de la isociacion quiica argentata 82 (1): 19-23).
Example 84: 3- (2-Aminophenoxy) propionitrile 84
In a 50mL flask with stir bar to palladium (0.00748g, 0.0702mmol) under nitrogen was added EtOAc (11.7g, 133mmol) followed by nitrile 83(0.675g, 3.51mmol) (scheme 18). The flask was equipped with a balloon containing hydrogen and the nitrogen inlet was removed. The reaction mixture was stirred vigorously for 4 hours, then filtered through celite, washing with EtOAc. Product 84 was not further purified (98% yield).1HNMR(500MHz，CDCl3)6.85-6.77(m，1H)，6.74-6.62(m，3H)，4.08(t，J＝6.1Hz，2H)，3.94-3.74(m，2H)，2.72(t，J＝6.1Hz，2H)。LRMS m/z C9H10N2Calculated O is 162.07931, found 163.1[ M +1 ] ]。
Example 85: (E/Z) -2-chloro-2- (2- (2- (2-cyanoethoxy) phenyl) hydrazono) acetic acid methyl ester 85
To a solution of aniline 84(1.65g, 10.2mmol) in acetic acid (6.80mL, 120mmol) was added a solution of 2M hydrogen chloride in water (13.59mL) followed by sodium nitrite (1.0290g, 14.914mmol) at 0 deg.C under vigorous stirring (scheme 18). After 20 min, methyl 2-chloroacetoacetate (1.5317g, 10.173mmol) was added dropwise via syringe and the mixture was warmed to room temperature over 5 h. The organic layer was then extracted twice with 100mL of diethyl ether and dried over sodium sulfate and concentrated. The crude product 85 was used in the next step. LRMSm/z C12H12ClN3O3Calculated value is 281.05672, found 282.1[ M +1 ]]。
Example 86: 4, 5-dihydrobenzo [ b ]][1，2，4]Triazolo [1, 5-d][1，4]Oxazazepine-2-Carboxylic acid methyl ester 86
To the chlorophydrazone 85(2.87g, 10.2mmol) in a 200mL flask under nitrogen was added 1, 4-dioxane (100mL) and silver carbonate (4.22g, 15.3mmol) (scheme 18). The flask was equipped with a reflux condenser and wrapped with tin foil (to protect from light). The reaction mixture was then refluxed with stirring for 4 hours. The reaction mixture was then filtered, concentrated and purified by silica gel chromatography to give ester 86 in 7% yield over two steps.1HNMR(500MHz，CDCl3)8.19(dd，J＝8.2，1.4Hz，1H)，7.31(td，J＝8.0，1.6Hz，1H)，7.25-7.20(m，1H)，7.18(dd，J＝8.1，1.3Hz，1H)，4.50(t，J＝5.7Hz，2H)，4.03(s，3H)，3.50(t，J＝5.7Hz，2H)。LRMS m/z C12H11N3O3Calculated value is 245.08004, found 246.1[ M +1 ] ]。
Example 87: 4, 5-dihydrobenzo [ b ]][1，2，4]Triazolo [1, 5-d][1，4]Oxazazepine-2-carboxamide 87
Ester 86(0.166g, 0.677mmol) was dissolved in 3: 2: 1 THF: MeOH: H2O (31.2mL), treated with 4N aqueous lithium hydroxide (1.32mL) and the mixture stirred at 25 ℃ for 30 min (scheme 18). The reaction mixture was quenched with 1N aqueous HCl (20mL) and the solution was extracted three times with 20mL EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated to give crude 4, 5-dihydrobenzo [ b ]][1，2，4]Triazolo [1, 5-d][1，4]Oxazazepine-2-carboxylic acid, which is used in the next step. LRMS m/z C12H9N3O3Calculated value is 231.06439, found 232.1[ M +1 ]]。
To crude 4, 5-dihydrobenzo [ b ]][1，2，4]Triazolo [1, 5-d][1，4]OxazazepineTo a solution of-2-carboxylic acid (0.177g) in DMF (1.55mL, 20.0mmol) was added N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (0.761g, 2.00mmol) and 6-chloro-1-hydroxybenzotriazole (0.339g, 2.00mmol) (scheme 18). The reaction mixture was stirred vigorously and ammonium chloride (0.285g, 5.34mmol) was added to the reaction mixture. After 10 min, N-diisopropylethylamine (0.465mL, 2.67mmol) was added. After 3 hours, the reaction mixture was dried. Preparative HPLC (acetonitrile/water) gave amide 87(0.0485 g, 31% (two steps)). 1H NMR(500MHz，CDCl3)8.22(d，J＝8.2Hz，1H)，7.30(t，J＝7.7Hz，1H)，7.22(t，J＝7.7Hz，1H)，7.18(d，J＝8.0Hz，1H)，6.97(s，1H)，5.75(s，1H)，4.49(t，J＝5.7Hz，2H)，3.48(t，J＝4.0Hz，2H)。LRMS m/z C12H10N4O2Calculated value is 230.08038, found 231.08[ M +1 ]]。
Example 89: 5- (9-fluoro-5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-ylcarbamic acid tert-butyl ester 89
Step 1: 4-fluoro-2-hydroxybenzaldehyde (1.918g, 0.01369mol), glyoxal (1.884mL, 0.04107mol), a solution of 14.8M ammonium hydroxide in water (14mL, 0.21mol), and methanol (34mL, 0.84mol) were mixed in a round bottom flask and the reaction mixture was stirred at room temperature overnight. LCMS showed reaction completion. Concentrate in vacuo and dissolve the crude solid in 1M HCl until pH paper shows a pH of-8. The product was extracted with EtOAc, washed with brine, dried over magnesium sulfate and concentrated again in vacuo. Purification by flash chromatography (ISCO, 0% to 50% EtOAc/heptane) and concentration in vacuo afforded 5-fluoro-2- (1H-imidazol-2-yl) phenol (0.92g, 37.7% yield).
Step 2: 5-fluoro-2- (1H-imidazol-2-yl) phenol (0.90g, 5.0mmol) was dissolved in DMF (40mL, 500 mmol). Cesium carbonate (6.6g, 20mmol) was added followed by 1, 2-dibromoethane (1.7mL, 20mmol) and heating at 90 ℃ for 3 hours with attached Vigreux (Vigreux) condensation column. LCMS showed reaction completion. Diluted with water and extracted with EtOAc. The aqueous layer was acidified to pH 5 with HCl and extracted with EtOAc. The combined organics were concentrated in vacuo and purified by flash chromatography (ISCO, 0-50% EtOAc/hexanes) and concentrated in vacuo to give 9-fluoro-5, 6-dihydrobenzo [ f [ ]Imidazo [1, 2-d ] s][1，4]Oxazazepine(0.69g, 67% yield).
And step 3:reacting 9-fluoro-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(0.69g, 3.4mmol), NIS (2.83g, 12.6mmol) and DMF were stirred in a round bottom flask for 4 days. Diluted with EtOAc and partitioned with saturated sodium bicarbonate and water (50/50). The aqueous layer was extracted once more with EtOAc and the combined organics were dried over magnesium sulfate and concentrated in vacuo and purified by flash chromatography (ISCO, 0-40% EtOAc/hexanes) to give 9-fluoro-2, 3-diiodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(1.25g, 81% yield).
And 4, step 4: reacting 9-fluoro-2, 3-diiodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(1.24g, 2.74mmol) was dissolved in THF (25mL, 310mmol) and cooled to-78 ℃ in a dry ice/acetone bath. A solution of 3.0M ethyl magnesium bromide in ether (1.37mL) was added and the reaction mixture was warmed to-40 ℃ and stirred for 4 hours. LCMS showed reaction completion. Diluted with 100mL of saturated ammonium chloride and extracted with EtOAc. Drying over magnesium sulfate, concentration in vacuo and purification by flash chromatography (ISCO, 0-40% EtOAc/hexanes) afforded 9-fluoro-2-iodo-5, 6-dihydrobenzo [ f [ -f []Imidazo [1, 2-d ] s][1，4]Oxazazepine (0.794g, 88% yield).
And 5: containing 9-fluoro-2-iodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(0.794g, 2.40mmol) of the round-bottom flask was thoroughly purged with nitrogen. Palladium (II) diacetate (27mg, 0.12mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (139mg, 0.24 mm) were added successively with continued washingol). Methanol (10mL, 200mmol) and TEA (30mL, 200mmol) purged with nitrogen were added and the reaction mixture was purged with carbon monoxide for 5 minutes. Two carbon monoxide balloons were attached and the reaction mixture was heated at 50 ℃ for 4.5 hours. LCMS confirmed complete formation of the methyl ester. The reaction mixture was purged with nitrogen and concentrated in vacuo. The ester was purified by flash chromatography (ISCO, 0 to 50% EtOAc/heptane) and concentrated in vacuo. The ester was dissolved in THF (20mL, 200mmol) and 1M lithium hydroxide (7.22mL) was added and the reaction mixture was stirred for three days. LCMS showed hydrolysis complete. Adjusted to pH-5 with 1M HCl and the product extracted with DCM and 5% methanol to give 9-fluoro-5, 6-dihydrobenzo [ f []Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-carboxylic acid (0.386g, 64.6% yield).
Step 6: reacting 9-fluoro-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-carboxylic acid (0.65g, 2.6mmol) was suspended in DCM (15mL, 230mmol) and a solution of 2.0M oxalyl chloride in DCM (2.0mL) was added followed by DMF (81 μ L) and since the reaction mixture was still undissolved toluene (15mL, 140mmol) was added and the mixture was heated with a heat gun until about half dissolved. Stirred for 30 min and concentrated in vacuo to afford the acid chloride. It was dissolved in 20mL DCM and a solution of the above intermediate (0.50g, 2.6mmol) and TEA (1.1mL, 7.8mmol) in DCM (50mL, 800mmol) was added. The reaction mixture was stirred for 3 hours and LCMS showed the reaction was mostly complete. Water was added and extracted three times with DCM. Washed with brine, dried over magnesium sulfate and concentrated in vacuo and purified by flash chromatography (ISCO, 0-50% EtOAc/heptane) to give the acylthiourea intermediate (0.20g, 18% yield).
And 7: the acylthiourea intermediate (200mg, 0.4mmol) was dissolved in DMF (10mL, 100mmol) and N, N-diisopropylamine (0.29mL, 1.662mmol) was added followed by isopropylhydrazine hydrochloride (68.92mg, 0.62 mmol). The reaction mixture was stirred at room temperature overnight. LCMS confirmed reaction completion. Dilute with water and extract 3 times with DCM. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified by flash chromatography (ISCO, 0 to 10% methanol in DCM) to give 89(200mg, 100% yield).
Example 90: 10-fluoro-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-carboxamide 90
Step 1: 4-fluoro-2- (1H-imidazol-2-yl) phenol
5-fluoro-2-hydroxybenzaldehyde (5.0g, 36mmol), glyoxal (4.912mL, 107mmol), a solution of 14.8M ammonium hydroxide in water (40mL, 600mmol), and methanol (90mL, 2000mmol) were combined in a round bottom flask and stirred at room temperature overnight. LCMS confirmed reaction completion. Concentrate in vacuo and add 1M HCl until pH 8. Extracted with EtOAc, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (0 to 50% EtOAc/heptane) afforded 4-fluoro-2- (1H-imidazol-2-yl) phenol (2.24g, 35% yield).
Step 2: 4-fluoro-2- (1H-imidazol-2-yl) phenol was converted to 90.
Example 91: 2-bromo-1- (2-isopropyl-5-methyl-2H- [1, 2, 4] triazol-3-yl) -ethanone 91
Step 1: acetylhydrazine (100g, 1.35mol) was suspended in acetone (991mL, 13.5mol) and cyclohexane (1.5L). The reaction mixture was heated at 55 ℃ for 16 h, during which time the solid dissolved to give a colorless solution. The reaction mixture was concentrated in vacuo to afford isopropylidene acetate hydrazide as a white solid (153g, 100%).1H NMR 400MHz(CDCl3): 8.25(1H, broad singlet), 2.26(3H, s), 2.00(3H, s), 1.83(3H, s).
Step 2: to isopropylidene hydrazide acetate (153g, 1.35mol)) Platinum oxide (0.66g) was added to the solution in IMS (1.5L) and the reaction mixture was stirred at room temperature under a hydrogen atmosphere until1H NMR showed complete consumption (. about.48H) of isopropylidene acetate hydrazide. The reaction mixture was filtered through a plug of celite and the filtrate was concentrated in vacuo to give acetic acid N' -isopropyl hydrazide as a colorless oil that crystallized on standing (154.6 g).1H NMR 400MHz(CDCl3): 3.12(1H, heptad, J ═ 6.3Hz), 1.96(3H, s), 1.04(6H, d, J ═ 6.3 Hz).
And step 3: to a solution of ethyl thioaluminate (29.6g, 0.22mol) in DCM (260mL) was added trimethyloxonium tetrafluoroborate (34.5g, 0.23mol) at room temperature and the mixture was stirred at room temperature for 2 hours. During this time the yellow color faded and a thick white precipitate formed. A solution of acetic acid N' -isopropyl hydrazide (27.1g, 0.23mol) and TEA (30.9mL, 0.22mol) in DCM (75mL) was added, which dissolved the precipitate. The reaction mixture was stirred at reflux for 5 hours and then at room temperature for 10 hours. The reaction mixture was washed with water and the aqueous layer was extracted with DCM (2X 50 mL). The combined organic extracts were washed with brine and dried (MgSO) 4) And concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0-100% EtOAc/cyclohexane) to give 2-isopropyl-5-methyl-2H- [1, 2, 4]Triazole-3-carboxylic acid ethyl ester as a pale yellow oil which crystallised on standing (15.6g, 32%).1HNMR 400MHz(CDCl3): 5.49(1H, heptad, J ═ 6.7Hz), 4.45(2H, t, J ═ 7.2Hz), 2.43(3H, s), 1.50(6H, d, J ═ 6.7Hz), 1.44(3H, t, J ═ 7.2 Hz).
And 4, step 4: to 2-isopropyl-5-methyl-2H- [1, 2, 4 ] at-78 deg.C]To a solution of triazole-3-carboxylic acid ethyl ester (12.09g, 61.3mmol) and dibromomethane (8.63mL, 122.6mmol) in THF (500mL) was added methyllithium (40.9mL, 122.6mmol, 3M in diethoxymethane) dropwise. The reaction mixture was stirred at-78 ℃ for 15 minutes. Acetic acid (3mL) was added and the reaction mixture was warmed to room temperature. The reaction mixture was diluted with water and extracted with EtOAc (3X 30 mL). The combined organic extracts were washed with brine and dried (MgSO4) And concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0-100% EtOAc/cyclohexane) to give 91 as a colorless oil that crystallized on standing (11.26g, 75%).1H NMR 400MHz(CDCl3): 5.41(1H, heptad, J ═ 6.6Hz), 4.67(2H, s), 2.44(3H, s), 1.49(6H, d, J ═ 6.6 Hz).
Example 92: 2- (2-isopropyl-5-methyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene-8-ol 92
Step 1: 4-chloro-5-iodo-pyridin-2-ylamine
To a solution of 2-amino-4-chloropyridine (150g, 0.78mol) in DMF (1.5L) was added NIS (341g, 1.52mol) and the reaction mixture was stirred at room temperature for 18 h, then concentrated in vacuo to a volume of 300 mL. The resulting residue was poured into 10% aqueous sodium thiosulfate (1.2L), stirred for 15 minutes and the precipitate formed was collected by filtration, washed with water, and then dried under vacuum at 35 ℃ to give the title compound as a light brown solid (185g, 62%).1H NMR 400MHz(CDCl3)：8.33(1H，s)，6.68(1H，s)，4.52(2H，s)。
Step 2: 4-chloro-5-iodo-2-methoxy-pyridine
To a solution of 4-chloro-5-iodo-pyridin-2-ylamine (64.2g, 0.25mol) in methanol (1.1L) and TFA (93.7mL, 1.26mol) was added tert-butyl nitrite (150mL, 1.26mol) and the temperature was maintained below 3 ℃. The resulting mixture was stirred at room temperature for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched by careful addition of water and then concentrated to 1/4 volume in vacuo. The resulting residue was treated with water (1L) and the precipitate formed was collected by filtration and dried under vacuum at 35 ℃ to give the title compound (62.3g, 92%). Contains 16% of impurities. 1H NMR 400MHz(DMSO-d6)：8.56(1H，s)，7.20(1H，s)，3.86(3H，s)。
And step 3: 4-chloro-6-methoxy-pyridine-3-carbonitrile
Para-4-chloro-5-iodo-2-methoxy-pyridine (30.5g, 0.11mol), zinc (II) cyanide (7.97g, 68mmol), Pd (PPh)3)4A suspension of (6.56g, 5.66mmol) and DMF (450mL) was degassed and then heated at 120 ℃ for 1 hour before concentration in vacuo. The resulting residue was treated with water, then extracted with DCM and the organic extracts were dried (MgSO)4) Filtered and then concentrated in vacuo. The resulting residue was crystallized from DCM to give the title compound (10.1g, 54%). The mother liquor was concentrated in vacuo and the residue was subjected to flash chromatography (SiO)2Gradient 0 to 100% EtOAc/cyclohexane) and then crystallized from cyclohexane to give the title compound (5.16g, 28%, 82% overall yield).1H NMR 400MHz(CDCl3)：8.45(1H，s)，6.90(1H，s)，4.01(3H，s)。
And 4, step 4: 4-chloro-6-methoxy-pyridine-3-carboxamidine hydrochloride
To a solution of 4-chloro-6-methoxy-pyridine-3-carbonitrile (10.1g, 59.7mmol) in THF (300mL) was added LiHMDS (lithium bis (trimethylsilyl) amide) (65.7mL) dropwise at-78 ℃ and the reaction mixture was stirred for 30 min, then warmed to room temperature and stirred for an additional 1 h. The reaction mixture was quenched by addition of 1n hcl (to pH-1) and then extracted three times with EtOAc. The aqueous layer was concentrated in vacuo to give a brown solid, which was azeotroped with toluene to give the title compound as a brown solid. A mixture with ammonium chloride containing 72% by weight of the title compound (15.2g, 83%). 1H NMR400MHz(DMSO-d6)：9.68(4H，d，J＝15.79Hz)，8.46(1H，s)，7.47(5H，t，J＝50.66Hz)，7.27(1H，s)，3.95(3H，s)。
And 5: 4-chloro-5- [4- (2-isopropyl-5-methyl-2H- [1, 2, 4] triazol-3-yl) -1H-imidazol-2-yl ] -2-methoxy-pyridine
A suspension of 4-chloro-6-methoxy-pyridine-3-carboxamidine hydrochloride (18.4mmol) and potassium bicarbonate (7.37g, 73.6mmol) in THF (42mL) and water (8.5mL) was heated back toFlow and treat dropwise with a solution of 91(4.53g, 18.4mmol) in THF (14 mL). The reaction mixture was heated to reflux for 18 hours, then the volatile solvent was removed in vacuo. The resulting suspension was filtered and the residue was washed with water and then dried to give the title compound as a brown solid (5.91g, 97%). LCMS: RT 2.68 min, [ M + H]+＝333/335。1H NMR 400MHz(CDCl3)：10.41(1H，s)，9.02(1H，s)，7.81(1H，s)，6.87(1H，s)，5.91(1H，m)，4.00(3H，s)，2.41(3H，s)，1.55(6H，d，J＝6.71Hz)。
Step 6: 2- [2- (4-chloro-6-methoxy-pyridin-3-yl) -4- (2-isopropyl-5-methyl-2H- [1, 2, 4] triazol-3-yl) -imidazol-1-yl ] -ethanol
4-chloro-5- [4- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -1H-imidazol-2-yl]A suspension of-2-methoxy-pyridine (5.9g, 17.7mmol) in toluene (20mL) was treated with ethylene carbonate (50mL) and heated at 130 ℃ for 2.5 h. The cooled reaction mixture was concentrated in vacuo, then diluted with DCM and passed through a plug of silica gel (eluting with DCM followed by 20% methanol in DCM). The methanol containing fractions were combined and concentrated in vacuo and the resulting residue was recrystallized from acetonitrile to give the title compound as a light brown solid (2.27g, 34%). LCMS: RT 2.53 min, [ M + H ]+＝377/379。1H NMR400MHz(CDCl3)：8.25(1H，s)，8.05(1H，s)，6.92(1H，s)，5.82-5.80(1H，m)，4.00(3H，s)，3.97(2H，t，J＝4.92Hz)，3.88(2H，t，J＝4.92Hz)，2.38(3H，s)，1.48(6H，d，J＝6.63Hz)。
And 7: 2- (2-isopropyl-5-methyl-2H- [1, 2, 4] triazol-3-yl) -8-methoxy-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene
2- [2- (4-chloro-6-methoxy-pyridin-3-yl) -4- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -imidazol-1-yl]A solution of ethanol (2.25g, 5.97mmol) in DMF (30mL) was cooled to 0 ℃ and treated with sodium hydride (239mg, 5.97mmol), the reaction mixture was stirred at 0 ℃ for 30 min, then warmed to room temperature and stirred for 2 h. Will be reversedThe mixture was again cooled to 0 ℃ and treated with water (400mL), the precipitated product was filtered off and washed with water, then dried in vacuo to give the title compound as a white solid (1.02g, 50%). LCMS: RT 2.68 min, [ M + H]+＝341。1H NMR400MHz(DMSO-d6)：9.15(1H，s)，7.87(1H，s)，6.42(1H，s)，5.84(1H，m)，4.57-4.56(4H，m)，3.89(3H，s)，2.25(3H，s)，1.46(6H，d，J＝6.60Hz)。
And 8: 2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -8-methoxy-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]A solution of azulene (1.0g, 2.97mmol) in 48% aqueous HBr (5mL) and acetic acid (5mL) was heated at 80 ℃ for 7.5 h and then concentrated in vacuo. The resulting residue was suspended in water (10mL) and the pH was adjusted to-6 using 5N aqueous NaOH. The precipitate formed was filtered off, washed with water, then dried in vacuo to give 92 as a white solid (1.01g, 100%). LCMS: RT 2.01 min, [ M + H ]+＝327。1H NMR 400MHz(DMSO-d6)：8.42(1H，s)，7.85(1H，s)，5.85(1H，s)，5.69-5.65(1H，m)，4.55-4.54(2H，m)，4.50-4.46(2H，m)，2.27(3H，s)，1.44(6H，d，J＝6.59Hz)。
Example 93: 2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulen-8-ol 93
Step 1: 4-chloro-5- [4- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -1H-imidazol-2-yl ] -2-methoxy-pyridine
A suspension of 4-chloro-6-methoxy-pyridine-3-carboxamidine hydrochloride (50.9mmol) and potassium bicarbonate (20.4g, 202.5mmol) in THF (128mL) and water (21mL) was heated to reflux and treated with 2-chloro-1- (2-isopropyl-2H- [1, 2, 4] methyl acetate]A solution of triazol-3-yl) -ethanone (9.55g, 50.9mmol) in THF (25mL) was treated dropwise. The reaction mixture was heated to reflux for 24 hours, then the volatile solvent was removed in vacuo. The resulting residue was diluted with water and extracted with EtOAc. Drying the combined extractsDry (Na)2SO4) Treated with charcoal (15g), filtered and concentrated in vacuo to give a solid. The solid was triturated with a 10% solution of diethyl ether in pentane then dried under vacuum at 50 ℃ to give the title compound as a light brown solid (8.74g, 54%). LCMS: RT 2.86 min, [ M + H]+＝319/321。1H NMR 400MHz(CDCl3)：9.03(1H，s)，7.89(1H，s)，7.83(1H，s)，7.26(1H，s)6.88(1H，s)，4.01(3H，s)，1.58(6H，d，J＝6.63Hz)。
Step 2: 2- [2- (4-chloro-6-methoxy-pyridin-3-yl) -4- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -imidazol-1-yl ] -ethanol
To warm ethylene carbonate (34g) was added 4-chloro-5- [4- (2-isopropyl-2H- [1, 2, 4] ]Triazol-3-yl) -1H-imidazol-2-yl]-2-methoxy-pyridine (8.74g, 27.4mmol) and the mixture was heated at 130 ℃ for 3 hours. The cooled reaction mixture was diluted with DCM and loaded onto silica gel (150 g). The silica gel was washed with DCM and then 5% methanol/DCM. The methanol containing fractions were combined and concentrated in vacuo to give the title compound as a brown foam (7.52g, 75%). LCMS: RT 2.65, [ M + H]+＝363/365。1HNMR 400MHz(CDCl3)：8.27(1H，s)，8.02(1H，s)，7.85(1H，s)，6.93(1H，s)，5.98-5.82(1H，m)，4.00(5H，m)，3.88(2H，t，J＝5.11Hz)，1.51(6H，d，J＝6.62Hz)。
And step 3: 2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -8-methoxy-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene
2- [2- (4-chloro-6-methoxy-pyridin-3-yl) -4- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -imidazol-1-yl]A solution of ethanol (7.52g, 20.7mmol) in DMF (100mL) was cooled to 0 ℃ and treated with sodium hydride (804mg, 20.1mmol), the reaction mixture was stirred at 0 ℃ for 10 min, then warmed to room temperature and stirred for 72 h. Additional sodium hydride (150mg) was added and stirring was continued until no more starting material remained, then the solvent was removed in vacuo. The residue was dissolved in EtOAc and the resulting solution was washed three times with saturated brine and then dried (Na)2SO4) Filtered and concentrated in vacuo. The resulting residue was triturated in pentane/diethyl ether (5: 1) to give the title compound as a brown solid (5.38g, 79%). LCMS: RT 2.86, [ M + H ]+＝327。1H NMR 400MHz(CDCl3)：9.35(1H，s)，7.87(1H，s)，7.63(1H，s)，6.37(1H，s)，6.03-6.02(1H，m)，4.54-4.53(2H，m)，4.53-4.33(2H，m)，3.99(3H，s)，1.57(6H，d，J＝6.63Hz)。
And 4, step 4: 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8-methoxy-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]A solution of azulene (1.0g, 2.97mmol) in acetic acid (40mL) was treated with 48% aqueous HBr (37.7mL) and heated at 80 ℃ for 5 h before being concentrated in vacuo. The resulting residue was suspended in water (60mL) and the pH was adjusted to-6 using 5N aqueous NaOH. The precipitate formed is filtered off, washed with water and then dried in vacuo. The resulting solid was triturated in acetone to give 93 as a beige solid (3.58g, 69%). LCMS: RT 2.04 min, [ M + H]+＝313。1H NMR400MHz(DMSO-d6)：8.42(1H，s)，7.90(1H，s)，7.83(1H，s)，5.84(1H，s)，5.78(1H，m)，4.71-4.30(4H，m)，1.45(6H，d，J＝6.60Hz)。
Example 94: 2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene hydrochloride 94
Step 1: trifluoromethanesulfonic acid 2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulen-8-yl ester
93(238mg, 0.76mmol) in DMF (2.2mL) was treated with sodium hydride (65% dispersion in mineral oil, 34mg, 0.91mmol) and the reaction mixture was heated at 40 ℃ for 1.5 h and then cooled to room temperature. Benzenebis (trifluoromethane) sulfonamide (327mg, 0.91mmol) was added and the reaction mixture was stirred at room temperature for 24 h, then diluted with EtOAc (60mL) and washed with brine (4X 20 mL). Will be described The resulting solution was dried (MgSO)4) Filtered and concentrated in vacuo to give a solid which is triturated in ether to give trifluoromethanesulfonic acid 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]Azulen-8-yl ester as a white solid (44 mg). The mother liquor from trituration was concentrated in vacuo and the resulting residue was recrystallized from methanol to afford the compound (39mg, 25% overall yield). LCMS: RT 3.27 min, [ M + H]+＝445。1H NMR 400MHz(DMSO-d6)：9.32(1H，s)，8.04(1H，s)，7.93(1H，s)，7.36(1H，s)，5.89(1H，m)，4.74(2H，m)，4.63(2H，m)，1.48(6H，d，J＝6.58Hz)。
Step 2: to trifluoromethanesulfonic acid 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]To a mixture of azulen-8-yl ester (83mg, 0.19mmol) and 2N aqueous sodium carbonate (600. mu.L) in DMF (1.2mL) were added palladium bis (dibenzylideneacetone) (6mg, 0.01mmol), triphenylphosphine (4mg, 0.015mmol) and 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2-tetramethyl- [1]Dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (75mg, 0.24 mmol). The reaction mixture was degassed and then heated at 90 ℃ under an argon atmosphere for 2 hours, then concentrated in vacuo. The resulting residue was partitioned between EtOAc and water, the aqueous phase was extracted with EtOAc (× 3) and the combined organic extracts were dried (MgSO) 4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 10% methanol/EtOAc) to obtain 4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]Azulen-8-yl]-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a white solid (41mg, 45%). LCMS (*) RT 3.24 min, [ M + H]+＝478。1H NMR400MHz(CDCl3)：9.65(1H，s)，7.94(1H，s)，7.89(1H，s)，7.00(1H，s)，6.84(1H，s)，4.60(2H，s)，4.50(2H，s)，4.18(2H，s)，3.67(2H，s)，2.62(2H，s)，1.59(6H，d，J＝6.62Hz)，1.50(9H，s)。
And step 3: 4- [2- (2-isopropyl-2H- [1,2，4]triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]Azulen-8-yl]A mixture of tert-butyl-3, 6-dihydro-2H-pyridine-1-carboxylate (89mg, 0.19mmol) in IMS (10mL) was treated with platinum oxide (10mg), the reaction mixture was degassed and stirred at room temperature under a hydrogen atmosphere for 72H. Platinum oxide (10mg) was added further and stirring was continued at room temperature for 18 h, then filtered through celite and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 5% methanol/DCM) to give 4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]Azulen-8-yl]Tert-butyl piperidine-1-carboxylate (58g, 64%). LCMS (*)RT＝2.72，[M+H]+＝480。
And 4, step 4: 4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ]Azulen-8-yl]A solution of tert-butyl-piperidine-1-carboxylate (58mg, 0.12mmol) in DCM (0.5mL) and methanol (0.3mL) was treated with a solution of 4M HCl in dioxane (0.8mL) and the reaction mixture was stirred at room temperature for 1.5 h, then concentrated in vacuo. The resulting residue was triturated with ether to give 94(66mg, 100%). LCMS: RT 1.68 min, [ M + H]+＝380。
Example 102: 2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxamide 102
A solution of oxalyl chloride in DCM (2.00M, 3.0mL) was added to a suspension of 31(112mg, 0.178mmol) in 30mL of DCM. A catalytic amount of DMF (1.0. mu.L, 0.013mmol) was added and the mixture was stirred for 2 hours. The mixture was filtered, the filtrate was concentrated in vacuo and the residue was dried under high vacuum for 1 hour. The above residue was dissolved in N, N-dimethylacetamide (3.0mL, 32mmol) and saturated with ammonia gas. The mixture was stirred for 20 minutes, concentrated in vacuo, dissolved in aqueous methanol and RP HP was performedAnd (5) LC purification. Yield 18.5mg (26%), MS: 407.1.1H NMR(400MHz，DMSO)8.26(d，J＝2.2，1H)，8.20(s，1H)，7.80(s，1H)，7.72-7.51(m，6H)，7.29(s，1H)，7.00(d，J＝8.5，1H)。
example 103: 2- (1- (2, 4-difluorophenyl) -1H-1, 2, 4-triazol-5-yl) -8-bromo-4, 5-dihydrobenzo-2H-oxaAnd [4, 5-d ] ]Pyrazole 103
A solution of 2, 4-difluorophenylhydrazine (20g, 0.14mol) in formamide (60mL) was heated at 120 ℃ for 18 hours. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate and EtOAc to form an emulsion. The emulsion was filtered through celite and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na)2SO4) Filtered and concentrated in vacuo and the resulting solid subjected to flash chromatography (SiO)2Gradient 0 to 100% EtOAc/cyclohexane) to give 1- (2, 4-difluoro-phenyl) -1H- [1, 2, 4]Triazole as a white solid (15.7g, 62%).1H NMR(ppm)(CDCl3)：8.60(1H，d，J＝2.83Hz)，8.12(1H，s)，7.91-7.83(1H，m)，7.10-7.04(2H，m)。
1- (2, 4-difluoro-phenyl) -1H- [1, 2, 4]A solution of triazole (15.7g, 86.7mmol) in THF (300mL) was treated dropwise with n-butyllithium (38mL, 2.5M, 95.3mmol) at-78 deg.C under a nitrogen atmosphere. After stirring for 1.5 h, a solution of hexachloroethane (22.6g, 95.3mmol) in THF (30mL) was added dropwise. The resulting reaction mixture was stirred for 1.5 hours, then warmed to room temperature and quenched with water. The resulting mixture was diluted with water and extracted with EtOAc, and the combined organic extracts were dried (Na)2SO4) Filtered and concentrated in vacuo to give an oil which crystallizes on standing. The solid was recrystallized from cyclohexane to give 5-chloro-1- (2, 4-difluoro-phenyl) -1H- [1, 2, 4 ]Triazole (12.4g, 66%).1H NMR(ppm)(CDCl3)：8.04(1H，s)，7.51-7.43(1H，m)，7.10-7.04(2H，m)。
To a mixture of 50(2.12g, 7.99mmol) and 5-chloro-1- (2, 4-difluoro-phenyl) -1H- [1, 2, 4%]To a solution of triazole (2.58g, 12.0mmol) in THF (10mL) was added cesium carbonate (3.9g, 12.0mmol) and the reaction mixture was heated using microwave radiation at 180 ℃ for 60 minutes. The cooled reaction mixture was diluted with water and extracted with EtOAc, and the combined organic extracts were washed with brine and then dried (MgSO)4) Filtered and concentrated in vacuo. The resulting residue was triturated in hot cyclohexane to give 103(1.62g, 46%).1HNMR(DMSO-d6，400MHz)：8.45(s，1H)；8.30(s，1H)；7.84-7.77(m，1H)；7.66-7.58(m，1H)；7.37-7.30(m，1H)；7.27(d，J＝8.6Hz，1H)；7.22(d，J＝2.0Hz，1H)；7.13(dd，J＝8.6，2.1Hz，1H)；4.26(t，J＝5.0Hz，2H)；3.06(t，J＝5.0Hz，2H)。
Example 104: 2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 104
2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] according to the procedure used for 243]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-9-carboxylic acid, ammonium chloride, HATU, diisopropylethylamine and DMF gave 104. The yield thereof was found to be 51%. MS: 407.0.1H NMR(400MHz，DMSO)8.21(s，1H)，7.99(s，1H)，7.95(s，1H)，7.74(d，J＝7.0，1H)，7.69-7.54(m，4H)，7.47(s，1H)，7.44-7.36(m，2H)，4.48(d，J＝7.6，4H)。
example 105: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -8- (pyrazol-4-yl) -4, 5-dihydrobenzo-2H-oxaAnd [4, 5-d ]]Pyrazole 105
In a reaction bottle, 8-bromo-2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ]Azulene (53mg, 0.14mmol), 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxaborolan-2-yl) -1H-pyrazole (36mg, 0.18mmol), tris (dibenzylideneacetone) dipalladium (0) (2.2mg, 1.7 mol%), 2, 4 ', 6 ' -diisopropyl-1, 1 ' -biphenyl-2-yl dicyclohexylphosphine (5.3mg, 9 mol%) and K3PO4(89mg, 0.42mmol) were mixed, evacuated and back-filled with nitrogen. Dioxane (1mL) and water (0.1mL) were added and the reaction mixture was heated to reflux for 18 hours. Then adding 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ]]Dioxaborolan-2-yl) -1H-pyrazole (36mg, 0.18mmol), tris (dibenzylideneacetone) dipalladium (0) (2.2mg, 1.7 mol%) and 2, 4 ', 6 ' -diisopropyl-1, 1 ' -biphenyl-2-yl dicyclohexylphosphine (5.3mg, 9 mol%) and heating was continued for a further 18 hours. The reaction mixture was diluted with EtOAc, decanted, and then concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 10 to 60% EtOAc/cyclohexane) to give 105 as a white solid (12mg, 24%).1H NMR(CDCl3400 MHz): 8.28(d, J ═ 8.2Hz, 1H); 8.08(s, 1H); 7.90(s, 2H); 7.80(s, 1H); 7.30(dd, J ═ 8.2, 1.8Hz, 1H); 7.23(d, J ═ 1.8Hz, 1H); 5.73-5.59(m, 1H); 4.42-4.35(m, 2H); 3.20-3.13(m, 2H); 1.62(d, J ═ 6.6Hz, 6H). No 1 exchangeable proton was observed. LCMS (method D) *): RT 9.48 min, M + H+＝362。
Example 106: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -8-bromo-4, 5-dihydrobenzo-2H-oxaAnd [4, 5-d ]]Pyrazole 106
Step 1: 1-isopropyl-1H- [1, 2, 4] triazole
A solution of isopropylhydrazine hydrochloride (60g, 0.54mmol) in formamide (270mL) was heated at 130 ℃ for 3 days. The cooled solution was diluted with saturated brine (700mL) and extracted with EtOAc (4X 1L). The combined organics were dried (Na)2SO4) Filtered and concentrated in vacuo to give an oil. The oil was distilled under reduced pressure (25mbar, bp 85-90 ℃) to give 1-isopropyl-1H- [1, 2, 4 ℃]Triazole as a colorless oil (54g, 90%).1H NMR (ppm)(CDCl3)：8.10(1H，s)，7.95(1H，s)，4.63-4.50(1H，m)，1.56(6H，d，J＝6.69Hz)。
Step 2: 5-chloro-1-isopropyl-1H- [1, 2, 4] triazole
1-isopropyl-1H- [1, 2, 4]A solution of triazole (19mmol) in THF (50mL) was treated dropwise with n-butyllithium (11.4mL, 2.5M, 28.5mmol) at-78 deg.C under a nitrogen atmosphere to give a milky yellow suspension. After 1 hour, n-butyllithium (3.8mL, 2.5M, 9.5mmol) was added and stirring was continued for an additional 1.5 hours. 1, 1, 2-trichlorotrifluoroethane (4.57mL, 38mmol) was added dropwise to give a dark brown solution. The resulting reaction mixture was stirred for 15 minutes and then purified by addition of saturated NaHCO3Aqueous solution (20mL) was quenched and then warmed to room temperature. The resulting mixture was extracted twice with diethyl ether and the combined organic extracts were dried (Na) 2SO4) Filtering and vacuum concentrating to obtain 5-chloro-1-isopropyl-1H- [1, 2, 4]Triazole, as a dark oil (3.9g) which was used in the next step without further purification.1H NMR(ppm)(CDCl3)：7.85(1H，s)，4.73-4.63(1H，m)，1.54-1.46(6H，m)。
Treatment of an ice-cooled sodium hydride suspension (60% dispersion, 1.09g, 38mmol) with 50(3.6g, 13.6mmol) portions gave a dark red suspension. Adding 5-chloro-1-isopropyl-1H- [1, 2, 4%]Triazole (19mmol) and the mixture was heated at 80 ℃ under nitrogen for 72 h. The cooled reaction mixture was quenched with water and extracted twice with EtOAc. The combined organic extracts were dried (Na)2SO4) Filtered and then concentrated in vacuo.The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 15% EtOAc/cyclohexane). The appropriate fractions were combined and recrystallized from methanol and cyclohexane/EtOAc to give 106 as a brown solid (789mg, 16%).1H NMR(CDCl3，400MHz)：8.15-8.11(m，1H)；8.08(s，1H)；7.80(s，1H)；7.28-7.23(m，2H)；5.65-5.53(m，1H)；4.38-4.31(m，2H)；3.18-3.10(m，2H)；1.60(d，J＝6.6Hz，6H)。
Example 107: 2- (1- (2, 4-difluorophenyl) -1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo-2H-oxa-lAnd [4, 5-d ]]Pyrazole-8-carboxamides 107
To 8-bromo-2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene (80mg, 0.18mmol), hydroxylamine hydrochloride (25mg, 0.36mmol), molybdenum hexacarbonyl (24mg, 0.09mmol), tri-tert-butylphosphine tetrafluoroborate (5mg, 10 mol%) and trans-bis (μ -acetoxy) bis [2- (di-o-tolylphosphino) benzyl ]To a suspension of dipalladium (II) (8.4mg, 5 mol%) in dioxane (4mL) was added 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (27. mu.L, 0.18mmol) and DIPEA (62. mu.L, 0.36 mmol). The reaction mixture was heated at 150 ℃ under microwave irradiation for 30 min and diluted with EtOAc. The organic layer was washed with water, saturated aqueous sodium bicarbonate and brine, dried (Na)2SO4) And concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)220 to 90% EtOAc/cyclohexane) to give a solid which was recrystallized from methanol to give 107 as a white solid (17mg, 23%).1H NMR(DMSO-d6400MHz)8.48(s, 1H); 8.31(s, 1H); 7.98(s, 1H); 7.87-7.79(m, 1H); 7.69-7.61(m, 1H); 7.49(d, J ═ 1.7Hz, 1H); 7.43(dd, J ═ 8.3, 1.8Hz, 1H); 7.40-7.32(m, 3H); 4.27(t, J ═ 5.0Hz, 2H); 3.09(t, J ═ 5.0Hz, 2H). LCMS (method D)*): RT 8.72 min, M + H+＝409。
Example 108: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (pyrazol-4-yl) -4, 5-dihydrobenzo-2H-oxaAnd [4, 5-d ]]Pyrazole 108
A suspension of 58(78mg, 0.21mmol), 4, 5, 5-tetramethyl-2- (1H-pyrazol-4-yl) -1, 3, 2-dioxaborolan (61mg, 0.31mmol), tetrakis (triphenylphosphine) palladium (0) (24mg, 0.021mmol) and sodium carbonate (45mg, 0.42mmol) in acetonitrile (6mL) and water (3mL) was heated at 140 ℃ under nitrogen for 25 minutes using microwave radiation. The reaction mixture was diluted with EtOAc and water, the organic layer was separated and washed with brine, dried (Na) 2SO4) And (4) concentrating in vacuum. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 50% EtOAc/cyclohexane) then recrystallized from acetonitrile and triturated in pentane to give 108 as an off-white solid (16mg, 20%) (67261).1H NMR(DMSO-d6400 MHz): 12.91(s, 1H); 8.38(d, J ═ 2.3Hz, 1H); 8.32(s, 1H); 8.03(s, 1H); 7.97(s, 2H); 7.52(dd, J ═ 8.4, 2.3Hz, 1H); 7.05(d, J ═ 8.4Hz, 1H); 5.41-5.26(m, 1H); 4.35-4.26(m, 2H); 3.17-3.08(m, 2H); 1.55(d, J ═ 6.6Hz, 6H). LCMS: RT 9.38 min, M + H+＝362。
Example 109: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxamide 109
2- (1-isopropyl-1H-1, 2, 4-triazole-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxylic acid (0.170g, 0.000501mol) was dissolved in DMF (7.84mL, 0.101mol) and treated with N, N-diisopropylethylamine (0.524mL, 0.00300mol), ammonium chloride (0.107g, 0.00200mol) and N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (0.228g, 0.000601mol) sequentially. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated sodium bicarbonate and then extracted with EtOAc (3 ×). The organic layer was dried (Na) 2SO4) And concentrated in vacuo to afford 109, which was purified by reverse phase HPLC. MS (ESI +) ═ 339.1.1H NMR(400MHz，DMSO)8.93(d，J＝2.2Hz，1H)，7.95(s，2H)，7.92(s，1H)，7.79(dd，J＝8.5，2.2Hz，1H)，7.10(d，J＝8.5Hz，1H)，5.82(dt，J＝13.2，6.6Hz，1H)，4.56(s，4H)，1.49(d，J＝6.6Hz，6H)。
Example 110: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N-methyl-4, 5-dihydrobenzo-2H-oxaAnd [4, 5-d ]]Pyrazole-9-carboxamides 110
Reaction of 58 with N, O-dimethylhydroxylamine hydrochloride gave 110 as a white solid (29mg, 31%).1H NMR(DMSO-d6400 MHz): 8.75(d, J ═ 2.3Hz, 1H); 8.44-8.38(m, 1H); 8.33(s, 1H); 8.05(d, J ═ 0.6Hz, 1H); 7.73(dd, J ═ 8.5, 2.3Hz, 1H); 7.10(d, J ═ 8.5Hz, 1H); (ii) a 5.31-5.21(m, 1H); 4.35(t, J ═ 5.0Hz, 2H); 3.13(t, J ═ 5.0Hz, 2H); 2.78(d, J ═ 4.5Hz, 3H); 1.51(d, J ═ 6.6Hz, 6H). LCMS (method D)*): RT 8.24 min, M + H+＝353。
Example 111: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N- (2-hydroxyethyl) -4, 5-dihydrobenzo-2H-oxaAnd [4, 5-d ]]Pyrazole-9-carboxamides 111
Reaction of 58 with ethanolamine as for 107 gave 111 as a white solid (23mg, 22%).1H NMR(400MHz，DMSO-d6): 8.71(d, J ═ 2.29Hz, 1H); 8.35(t, J ═ 5.57Hz, 1H); 8.29(s, 1H); 8.00(d, J ═ 0.60Hz, 1H); 7.71(dd, J ═ 8.51, 2.33Hz, 1H); 7.06(d, J ═ 8.49Hz, 1H); 5.29-5.21(m, 1H); 4.65(t, J ═ 5.60Hz, 1H); 4.30(t, J ═ 4.98Hz, 2H); 3.47(q, J ═ 5.99Hz, 2H); 3.28(t, J ═ 4.93Hz, 2H); 3.09(t, J ═ 4.98Hz, 2H); 1.46(d, J ═ 6.59Hz, 6H). LCMS: RT 7.41 min, M + H +＝383。
Example 112: (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) (S, S-dioxothiomorpholino) methanone 112
2- (2-isopropyl-2H- [1, 2, 4) according to the procedure used for 116]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene-9-carboxylic acid with thiomorpholine dioxide gives 112.1HNMR(DMSO-d6400 MHz): 8.06(d, J ═ 2.1Hz, 1H); 8.04(d, J ═ 0.6Hz, 1H); 7.50(dd, J ═ 8.3, 2.1Hz, 1H); 7.34(d, J ═ 8.3Hz, 1H); 6.92(s, 1H); 5.67-5.54(m, 1H); 4.57(t, J ═ 5.9Hz, 2H); 3.35-3.26 (broad multiplet, 8H); 3.24(t, J ═ 6.0Hz, 2H); 1.48(d, J ═ 6.6Hz, 6H). LCMS: RT 8.24 min, M + H+＝457。
Example 113: (4- (2-hydroxypropan-2-yl) piperidin-1-yl) (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) methanone 113
2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the procedure used for 109]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxylic acid is reacted with 2- (piperidin-4-yl) propan-2-ol to give 113. MS (ESI +) -465.2.1H NMR(400MHz，DMSO)8.40(d，J＝1.6Hz，1H)，7.96(s，1H)，7.92(s，1H)，7.35(dd，J＝8.4，1.9Hz，1H)，7.11(d，J＝8.4Hz，1H)，5.87-5.69(m，1H)，4.6(s，4H)，4.15(s，1H)，1.75(s，2H)，1.48(d，J＝6.6Hz，7H)，1.19(dd，J＝23.3，11.1Hz，2H)，1.05(s，7H)。
Example 114: 9- (1-isopropyl-1H-pyrazol-5-yl) -6, 7-dihydroimidazo [1, 2-d ]Pyrido [3, 2-b][1，4]Oxazazepine-3-carboxamide 114
A mixture of 17mg (0.05mmol) of 12, 30mg (0.061mmol) of HATU and 0.022mL (0.155mmol) of TEA in 2mL of DMF was stirred for 10 minutes. Ammonia gas was bubbled through the mixture for 5 minutes. The mixture was stirred for 1 hour, concentrated in vacuo and partitioned between EtOAc and 0.01N aqueous HCl. The organic layer was concentrated and the residue was purified on a 4g silica gel column (eluted with 7-8% methanol in DCM) to give 114. The yield was 2.4 mg. MS (ESI +) 339.2.1H NMR(400MHz，CH3OH+D2O)8.70(d，J＝1.8，1H)，8.33(s，1H)，8.05(d，J＝1.8，1H)，7.52(s，1H)，6.48(d，J＝1.6，1H)，5.16(dd，J＝13.2，6.6，1H)，4.56(t，J＝5.1，2H)，3.52-3.45(m，2H)，1.49(d，J＝6.6，6H)。
Example 115: 2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxamide 115
Coupling of 14 with ammonia as in example 51 gave 115. MS (ESI +): 338.1.1HNMR(400MHz，DMSO)8.94(d，J＝2.2，1H)，7.94(s，1H)，7.77(dd，J＝8.5，2.2，1H)，7.69(s，1H)，7.44(d，J＝1.4，1H)，7.25(s，1H)，7.08(d，J＝8.5，1H)，6.40(d，J＝1.7，1H)，5.34(dt，J＝13.0，6.4，1H)，4.52(dd，J＝11.0，5.6，4H)，1.44(d，J＝6.6，6H)。
example 116: n- (2-hydroxy-2-methylpropyl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-carboxamide 116
2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulene-9-carboxylic acid (0.2g, 0.59mmol) was suspended in DMF (5mL) and DIPEA (0.21mL, 1.2mmol) was added. The resulting solution was treated with HATU (0.23g, 0.6mmol) and HOBT (81mg, 0.6mmol), followed by addition of 1-amino-2-methyl-propan-2-ol (52.5mg, 0.59mmol) and stirring at room temperature for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue partitioned between DCM and water. The aqueous layer was extracted three times with DCM and the combined organic extracts were washed with water and dried (Na) 2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 10% MeOH/EtOAc) and recrystallization from EtOAc gave 116(163mg, 67%).1H NMR(CDCl3，400MHz)：8.46(d，J＝2.2Hz，1H)；7.94(s，1H)；7.72(dd，J＝8.4，2.2Hz，1H)；7.22(d，J＝8.4Hz，1H)；6.86(s，1H)；6.66(s，1H)；5.74-5.61(m，1H)；4.57(t，J＝5.7Hz，2H)；3.50(d，J＝5.9Hz，2H)；3.22(t，J＝5.7Hz，2H)；2.18(s，1H)；1.59(d，J＝6.6Hz，6H)；1.31(s，6H) In that respect LCMS: RT 9.53 min, M + H+＝411。
Example 117: (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) (S, S-dioxothiomorpholino) methanone 117
Reacting 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene-9-carboxylic acid with thiomorpholine dioxide gave 117.1HNMR(DMSO-d6400 MHz): 8.06(d, J ═ 2.1Hz, 1H); 8.04(d, J ═ 0.6Hz, 1H); 7.50(dd, J ═ 8.3, 2.1Hz, 1H); 7.34(d, J ═ 8.3Hz, 1H); 6.92(s, 1H); 5.67-5.54(m, 1H); 4.57(t, J ═ 5.9Hz, 2H); 3.35-3.26 (broad multiplet, 8H); 3.24(t, J ═ 6.0Hz, 2H); 1.48(d, J ═ 6.6Hz, 6H). LCMS: RT 8.24 min, M + H+＝457。
Example 118: (4-hydroxypiperidin-1-yl) (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) methanone 118
2- (2-isopropyl-2H- [1, 2, 4) according to the procedure used for 116]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ]Reaction of azulene-9-carboxylic acid with 4-hydroxypiperidine gives 118 as a white solid.1H NMR(CDCl3400 MHz): 8.02(d, J ═ 2.1Hz, 1H); 7.94(s, 1H); 7.35(dd, J ═ 8.3, 2.1Hz, 1H); 7.23(d, J ═ 8.3Hz, 1H); 6.88(s, 1H); 5.76-5.62(m, 1H); 4.58(t, J ═ 5.8Hz, 2H); 4.19 (broad singlet, 1H); 4.07-3.98(m, 1H); 3.82 (broad singlet, 1H); 3.37 (broad singlet, 2H); 3.20(t, J ═ 5.8Hz, 2H); 1.95 (broad singlet, 2)H) (ii) a 1.70(d, J ═ 3.9Hz, 1H); 1.67-1.54(d, J ═ 6.6Hz, 8H). LCMS: RT 8.77 min, M + H+＝423。
Example 119: n- (2- (methylsulfonyl) ethyl) -2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxamide 119
2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the procedure used for 109]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-10-carboxylic acid with 2- (methylsulfonyl) ethylamine gave 119. MS (ESI +) -485.1.1H NMR(400MHz，DMSO)8.93(d，J＝2.1Hz，1H)，8.72(t，J＝5.4Hz，1H)，8.10(s，2H)，7.78(dd，J＝8.6，2.2Hz，1H)，7.14(d，J＝8.5Hz，1H)，5.94(q，J＝8.9Hz，2H)，4.58(s，4H)，3.69(dd，J＝12.7，6.5Hz，2H)，3.38(t，J＝6.8Hz，2H)，3.04(s，3H)。
Example 120: (4-Isopropylpiperazin-1-yl) (2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) methanone 120
2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the procedure used for 109]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-10-carboxylic acid with 1-isopropylpiperazine gives 120. MS (ESI+)＝490.2。1H NMR(400MHz，DMSO)8.38(d，J＝2.0Hz，1H)，8.10(d，J＝5.4Hz，2H)，7.37(dd，J＝8.4，2.1Hz，1H)，7.12(d，J＝8.4Hz，1H)，5.87(q，J＝8.8Hz，2H)，4.57(s，4H)，3.49(s，4H)，2.68(dt，J＝13.0，6.6Hz，1H)，2.45(s，4H)，0.97(d，J＝6.5Hz，6H)。
Example 121: n- (1-hydroxy-2-methylpropan-2-yl) -2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxamide 121
2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the procedure used for 109]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxylic acid is reacted with 2-amino-2-methylpropan-1-ol to give 121. MS (ESI +) ═ 451.1.1H NMR(400MHz，DMSO)8.82(d，J＝2.2Hz，1H)，8.09(d，J＝2.9Hz，2H)，7.74(dd，J＝8.6，2.3Hz，1H)，7.58(s，1H)，7.10(d，J＝8.5Hz，1H)，5.94(q，J＝8.9Hz，2H)，4.91(t，J＝5.9Hz，1H)，4.57(dd，J＝10.9，5.6Hz，4H)，3.51(d，J＝5.9Hz，2H)，1.32(s，6H)。
Example 122: (4- (2-hydroxyethyl) piperazin-1-yl) (2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) methanone 122
2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the procedure used for 109]An imidazo [1 ] compound having a structure of,2-d][1，4]oxazazepineReaction of-10-carboxylic acid with 2- (piperazin-1-yl) ethanol gives 122. MS (ESI +) ═ 492.2.1H NMR(400MHz，DMSO)8.39(d，J＝2.0Hz，1H)，8.10(d，J＝5.4Hz，2H)，7.38(dd，J＝8.4，2.1Hz，1H)，7.13(d，J＝8.4Hz，1H)，5.89(q，J＝8.7Hz，2H)，4.57(s，4H)，4.40(t，J＝5.4Hz，1H)，4.06(q，J＝5.3Hz，1H)，3.51(dd，J＝11.6，6.0Hz，4H)，3.17(d，J＝5.2Hz，1H)，2.46-2.39(m，5H)。
Example 123: morpholino (2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) methanone 123
2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the procedure used for 109]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-10-carboxylic acid with morpholine gives 123. MS (ESI +) ═ 449.1.1H NMR(400MHz，DMSO)8.42(d，J＝2.0Hz，1H)，8.10(d，J＝5.6Hz，2H)，7.40(dt，J＝21.4，10.7Hz，1H)，7.13(d，J＝8.4Hz，1H)，5.89(q，J＝8.8Hz，2H)，4.57(s，4H)，3.61(s，4H)，3.52(s，4H)。
Example 124: (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) (4- (2, 2, 2-trifluoroethyl) piperazin-1-yl) methanone 124
2- (2-isopropyl-2H- [1, 2, 4) according to the procedure used for 116]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene-9-carboxylic acid with 1- (2, 2, 2-trifluoroethyl) piperazine dihydrochloride yielded 124 as a white solid.1H NMR(CDCl3400 MHz): 8.02(d, J ═ 2.1Hz, 1H); 7.95(s, 1H); 7.35(dd, J ═ 8.3, 2.1Hz, 1H); 7.23(d, J ═ 8.3Hz, 1H); 6.88(s, 1H); 5.73-5.60(m, 1H); 4.58(t, J ═ 5.8Hz, 2H); 3.94-3.44 (broad multiplet, 4H); 3.20(t, J ═ 5.8Hz, 2H); 3.04(q, J ═ 9.4Hz, 2H); 2.74 (broad singlet, 4H); 1.58(d, J ═ 6.6Hz, 6H). LCMS: RT 10.93 min, M + H+＝490。
Example 125: n- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b ]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-carboxamide 125
Reacting 2- (2-isopropyl-2H- [1, 2, 4 ] according to the method used for 126]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene-9-carboxylic acid with 4-amino-1- (2-hydroxyethyl) pyrazole gave 125 as a white solid.1H NMR(CDCl3400 MHz): 8.50(d, J ═ 2.2Hz, 1H); 8.38(s, 1H); 8.10(s, 1H); 7.96(s, 1H); 7.78-7.73(m, 1H); 7.56(s, 1H); 7.22(d, J ═ 8.4Hz, 1H); 6.81(s, 1H); 5.60-5.47(m, 1H); 4.57(t, J ═ 5.7Hz, 2H); 4.23(t, J ═ 4.8Hz, 2H); 4.01(t, J ═ 4.8Hz, 2H); 3.20(t, J ═ 5.7Hz, 2H); 1.57(d, J ═ 6.6Hz, 6H). No 1 exchangeable proton was observed. LCMS: RT 9.27 min, M + H+＝449。
Example 126: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N- (isoxazol-3-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-carboxamide 126
To 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]To an ice-cooled suspension of azulene-9-carboxylic acid (0.15g, 0.44mmol) in DCM (3.5mL) was added oxalyl chloride (79. mu.L, 0.93mmol) and DMF (25. mu.L) and the mixture was stirred at room temperature for 2 h. 3-amino-isoxazole (185mg, 2.2mmol) and TEA (0.12mL, 0.88mmol) were added and the mixture was stirred at room temperature for 18 h, then saturated aqueous sodium bicarbonate was added. The resulting mixture was extracted with DCM followed by 5% MeOH/DCM and the combined extracts were dried (Na) 2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 10% MeOH/DCM) then triturated in ether to give 126 as a white solid.1H NMR(CDCl3400 MHz): 9.49(s, 1H); 8.65(d, J ═ 2.3Hz, 1H); 8.30(d, J ═ 1.8Hz, 1H); 7.96(d, J ═ 0.7Hz, 1H); 7.86(dd, J ═ 8.5, 2.3Hz, 1H); 7.30(d, J ═ 8.5Hz, 1H); 7.23(d, J ═ 1.8Hz, 1H); 6.88(s, 1H); 5.72-5.59(m, 1H); 4.61(t, J ═ 5.6Hz, 2H); 3.25(t, J ═ 5.6Hz, 2H); 1.58(d, J ═ 6.6Hz, 6H). LCMS: RT 10.24 min, M + H+＝406。
Example 127: n- (1H-pyrazol-4-yl) -2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-carboxamide 127
Reacting 2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4 ] according to the procedure used for 126]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulene-9-carboxylic acid was reacted with 4-amino-pyrazole-1-carboxylic acid tert-butyl ester. Intermediate carboxylic acid tert-butyl ester was dissolved in DCM (5mL) and treated with TFA (2mL), then the reaction mixture was placed in a chamberStir for 2 hours at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was triturated in water to give 127 as a white solid. 1H NMR(DMSO-d6400 MHz): 10.53(s, 1H); 8.51(d, J ═ 2.2Hz, 1H); 8.23(s, 1H); 7.96(dd, J ═ 8.5, 2.2Hz, 1H); 7.84(s, 2H); 7.39(d, J ═ 8.5Hz, 1H); 7.02(s, 1H); 5.77(q, J ═ 8.7Hz, 2H); 4.59(t, J ═ 5.8Hz, 2H). 3 protons are masked by the water peak. LCMS: RT 9.11 min, M + H+＝445。
Example 128: 2- (4- ((2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) methyl) piperazin-1-yl) ethanol 128
69(175mg, 0.48mmol) and piperazine ethanol in DCE (15mL) was treated with sodium triacetoxyborohydride (153mg, 0.72mmol) and a catalytic amount of acetic acid, then stirred at room temperature for 72 hours. The resulting mixture was diluted with DCM and washed with saturated aqueous sodium bicarbonate solution, then dried (Na)2SO4) Filtered and concentrated in vacuo to give a colorless gum which was flash chromatographed (SiO)2Gradient 0-10% MeOH/DCM). The appropriate fractions were combined, concentrated in vacuo and the resulting residue was dissolved in diethyl ether and treated with a solution of 1M HCl in diethyl ether (2mL, 2 mmol). The resulting precipitate was filtered off, washed with diethyl ether and dried in vacuo to give 128 as a white solid. 1HNMR(DMSO-d6+ deuterated TFA, 400 MHz): 8.22(s, 1H); 8.16-8.12(m, 1H); 7.66-7.60(m, 1H); 7.39(d, J ═ 8.3Hz, 1H); 7.02(s, 1H); 5.75(q, J ═ 8.7Hz, 2H); 4.57(t, J ═ 5.9Hz, 2H); 4.52(s, 2H); 3.76(t, J ═ 5.0Hz, 2H); 3.61 (broad singlet, 8H); 3.32(s, 2H); 3.24(t, J ═ 5.9Hz, 2H). No 1 exchangeable proton was observed. LCMS: RT 6.56 min, M + H+＝478。
Example 129: (4-hydroxypiperidin-1-yl) (2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) methanone 129
2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the procedure used for 109]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-10-carboxylic acid with 4-hydroxypiperidine gives 129. MS (ESI +) ═ 463.1.1H NMR(400MHz，DMSO)8.39(d，J＝2.0Hz，1H)，8.09(d，J＝4.4Hz，2H)，7.37(dd，J＝8.4，2.1Hz，1H)，7.12(d，J＝8.4Hz，1H)，5.87(q，J＝8.5Hz，2H)，4.76(d，J＝3.8Hz，1H)，4.57(s，4H)，3.76(d，J＝3.6Hz，2H)，1.74(s，2H)，1.39(s，2H)。
Example 130: 9- (piperidin-4-yl) -2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1, 5-d][1，4]Oxazazepine130
Step 1: 4- {2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
62(207mg, 0.5mmol), 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ]]Dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (232mg, 0.75mmol), [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride DCM (10 mol%) and potassium carbonate (138mg, 1.0mmol) were added to the reaction flask, the air was evacuated and back-filled with nitrogen. Adding intoDMF (1mL), degassing was repeated and the mixture was heated at 80 ℃ for 18 hours. The cooled reaction mixture was diluted with EtOAc and washed with water, then dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 20 to 60% EtOAc/cyclohexane) to give 4- {2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a white crystalline solid (232mg, 90%). LCMS: RT 4.87 min, M + H+＝517。
Step 2: 4- {2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]A solution of azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (232mg, 0.41mmol) in IMS (10mL) was treated with a slurry of Pd/C (170mg, 10 wt% palladium on charcoal, 50% water) in IMS. The mixture was degassed, then evacuated and backfilled with hydrogen, then stirred at room temperature for 18 hours. The reaction mixture was filtered through celite, washing with EtOAc and the filtrate was concentrated in vacuo. The resulting residue was dissolved in methanol (5mL), treated with a solution of 1M HCl in ether (2mL, 2mmol) and the mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was triturated in ether to give 130 as a pale yellow solid (127mg, 74%). 1HNMR(DMSO-d6400 MHz): 9.08-8.97 (broad multiplet, 1H); 8.96-8.81 (broad multiplet, 1H); 8.22(s, 1H); 7.69(s, 1H); 7.31-7.23(m, 2H); 6.99(s, 1H); 5.72(q, J ═ 8.8Hz, 2H); 4.51(t, J ═ 6.1Hz, 2H); 3.42-3.32(m, 2H); 3.22-3.15(m, 2H); 3.08-2.88(m, 3H); 2.04-1.95(m, 2H); 1.94-1.80(m, 2H). LCMS: RT 6.75 min, M + H+＝419.2。
Example 131: n- ((2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) methyl) pyrazin-2-amine 131
Following the procedure for 128, but without using a solution of HCl in ether, 69 was reacted with 2-aminopyrazine to give 131 as a white solid.1H NMR(CDCl3400 MHz): 8.03-7.99(m, 3H); 7.87(d, J ═ 2.6Hz, 1H); 7.84(d, J ═ 2.2Hz, 1H); 7.31(dd, J ═ 8.3, 2.2Hz, 1H); 7.20(d, J ═ 8.3Hz, 1H); 6.92(s, 1H); 5.49(q, J ═ 8.2Hz, 2H); 5.42 (broad singlet, 1H); 4.66(d, J ═ 5.4Hz, 2H); 4.55(t, J ═ 6.0Hz, 2H); 3.16(t, J ═ 6.0Hz, 2H). LCMS: RT 9.93 min, M + H+＝443。
Example 132: 2-hydroxy-1- (4- ((2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b) ]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) methyl) piperazin-1-yl) ethanone 132
2- (2-isopropyl-2H- [1, 2, 4 ] according to the procedure for 128, but without using HCl in ether]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene-9-carbaldehyde with 2-hydroxy-1- (piperazin-1-yl) -ethanone gave 132 as a white solid.1H NMR(CDCl3400 MHz): 7.95(s, 1H); 7.86(d, J ═ 2.0Hz, 1H); 7.28-7.23(m, 1H); 7.17(d, J ═ 8.2Hz, 1H); 6.86(s, 1H); 5.73-5.60(m, 1H); 4.55(t, J ═ 6.0Hz, 2H); 4.15(s, 2H); 3.69(t, J ═ 4.8Hz, 2H); 3.64-3.55(m, 3H); 3.29(t, J ═ 4.8Hz, 2H); 3.16(t, J ═ 6.0Hz, 2H); 2.55-2.46(m, 4H); 1.58(d, J ═ 6.6Hz, 6H). LCMS: RT 5.70 min, M + H+＝452。
Example 133: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N- (2- (methylsulfonyl) ethyl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 133
P-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineSaponification of the methyl (E) -9-carboxylate 184 to give the corresponding acid 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -E ]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxylic acid (30mg, 0.09mmol), dissolved in DMF (0.5mL) and treated with diisopropylethylamine (0.077mL, 0.44mmol), 2- (methylsulfonyl) ethylamine (22mg, 0.18mmol) and HATU (67mg, 0.18mmol) successively. The resulting mixture was stirred at ambient temperature for 12 hours. With EtOAc and H2Diluted O, aqueous layer extracted with EtOAc (2X) and the combined organic phases washed with brine, MgSO4Dried, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 133. LC/MS (ESI +): m/z462(M + H).1H NMR(400MHz，DMSO)8.76(t，J＝5.1，1H)，8.48(d，J＝8.4，1H)，7.99(s，1H)，7.92(s，1H)，7.59(d，J＝8.4，1H)，7.53(s，1H)，5.86(dt，J＝13.0，6.6，1H)，4.56(d，J＝1.9，4H)，3.69(dd，J＝12.7，6.5，2H)，3.39(t，J＝6.7，2H)，3.05(d，J＝9.0，3H)，1.49(d，J＝6.6，5H)。
Example 134: 2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -N- (2- (methylsulfonyl) ethyl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 134
Reacting 2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-9-carboxylic acid (40mg, 0.1mmol) with 2- (methylsulfonyl) ethylamine gave 134. LC/MS (ESI +): m/z 514(M + H).1H NMR(400MHz，DMSO)8.72(s，1H)，8.56(s，0H)，8.20(s，1H)，7.94(s，1H)，7.73(d，J＝7.0，1H)，7.71-7.52(m，3H)，7.43(s，1H)，7.36(d，J＝8.9，1H)，4.48(d，J＝6.6，3H)，3.73-3.58(m，2H)，3.02(s，3H)。
Example 135: 2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -N- (1-hydroxy-2-methylpropan-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxamide 135
Reaction of 72 with 2-amino-2-methylpropan-1-ol as per procedure used for 109 gave 135. MS (ESI +) -479.1. 1HNMR(400MHz，DMSO)8.19(s，1H)，8.11(d，J＝2.2Hz，1H)，7.78(s，1H)，7.71-7.66(m，1H)，7.63(dd，J＝7.2，2.1Hz，1H)，7.60-7.50(m，3H)，7.37(s，1H)，6.98(d，J＝8.5Hz，1H)，4.99(t，J＝5.9Hz，1H)，4.46(d，J＝3.7Hz，4H)，3.54(d，J＝5.9Hz，2H)，1.36(s，6H)。
Example 136: (2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) (4-isopropylpiperazin-1-yl) methanone 136
Reaction of 72 with 4-isopropylpiperazine following the procedure used for 109 gave 136. MS (ESI +) -518.2.1H NMR(400MHz，DMSO)8.20(s，1H)，7.84(s，1H)，7.70(s，2H)，7.64(d，J＝7.4Hz，1H)，7.62-7.51(m，2H)，7.36(d，J＝8.5Hz，1H)，7.06(d，J＝8.5Hz，1H)，4.48(s，4H)，3.57(s，2H)，3.04(s，2H)，1.29(d，J＝6.5Hz，6H)。
Example 137: 2- (1- (2, 4-difluorophenyl) -1H-1, 2, 4-triazol-5-yl) -N- (1-hydroxy-2-methylpropan-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxamide 137
2- (1- (2, 4-difluorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the procedure used for 109]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxylic acid is reacted with 2-amino-2-methylpropan-1-ol to give 137. MS (ESI +) ═ 481.1.1H NMR(400MHz，DMSO)8.26(d，J＝2.2Hz，1H)，8.21(s，1H)，7.94(s，1H)，7.73-7.65(m，1H)，7.62(dd，J＝8.5，2.3Hz，1H)，7.51-7.42(m，1H)，7.39(s，1H)，7.25(t，J＝7.7Hz，1H)，7.00(d，J＝8.5Hz，1H)，4.96(t，J＝6.0Hz，1H)，4.49(d，J＝6.1Hz，4H)，3.52(d，J＝5.8Hz，2H)，1.35(s，6H)。
Example 138: 2- (4-cyano-1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 138
Coupling of 16 with ammonia as in example 51 gave 138. Yield 27.8mg (44%). MS (ESI): 363.1.1H NMR(400MHz，DMSO)8.46(d，J＝8.4，1H)，8.11(s，1H)，8.00(d，J＝4.7，2H)，7.62(dd，J＝8.4，1.5，1H)，7.57(d，J＝1.4，1H)，7.44(s，1H)，5.46(dt，J＝13.1，6.5，1H)，4.59(dd，J＝17.5，4.8，4H)，1.48(d，J＝6.6，6H)。
example 139: 2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -N-methyl-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 139
2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the same method as 133 ]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-9-carboxylic acid (40mg, 0.1mmol) with methylamine (2M, 0.2mL) in THF gave 139. LC/MS (ESI +): m/z 422(M + H).1H NMR(400MHz，DMSO)8.43(d，J＝4.5，1H)，8.19(s，1H)，7.93(s，1H)，7.72(t，J＝10.9，1H)，7.68-7.51(m，4H)，7.47-7.28(m，2H)，4.50(t，J＝15.6，4H)，2.76(d，J＝4.5，3H)。
Example 140: n- (2-hydroxyethyl) -N-isopropyl-4, 5-dihydrobenzo [ b ]]Pyrazolo [1, 5-d][1，4]Oxazazepine-2-carboxamide 140
Reacting 8-bromo-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ] according to the procedure used for 116]Azulene-2-carboxylic acid was reacted with 2-isopropylamino-ethanol. The intermediate formed (145mg, 0.37mmol) was dissolved in IMS (10mL) and TEA (50. mu.L, 0.37mmol) and 10% Pd/C (20mg) was added, and the reaction mixture was stirred under hydrogen (1 atmosphere) for 2.75 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The resulting residue was partitioned between DCM and water, the aqueous layer was separated and extracted with DCM. Combining the organic extractsExtract drying (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is dissolved in diethyl ether and the solution is washed with water and dried (Na)2SO4) Filtered and then concentrated in vacuo to give 140(79mg, 68%).1H NMR(DMSO-d6400 MHz): 7.83(dd, J ═ 8.0, 1.6Hz, 1H); 7.30(td, J ═ 7.6, 1.8Hz, 1H); 7.26-7.16(m, 2H); 6.54(s, 1H); 4.67-4.53(m, 1H); 4.46(t, J ═ 6.0Hz, 2H); 4.35-4.27(m, 1H); 3.64-3.56(m, 2H); 3.55-3.46(m, 2H); 3.13(t, J ═ 6.0Hz, 2H); 1.22(d, J ═ 6.8Hz, 6H). LCMS: RT 9.00 min, M + H +＝316。
Example 141: 4- ((2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) methyl) piperazin-2-one 141
2- (2-isopropyl-2H- [1, 2, 4 ] according to the procedure for 128, but without using HCl in ether]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene-9-carbaldehyde with 2-hydroxy-1- (piperazin-1-yl) -ethanone gave 141 as a white solid.1H NMR (MeOD, 400 MHz): 8.00(s, 1H); 7.92(d, J ═ 2.1Hz, 1H); 7.34(dd, J ═ 8.3, 2.1Hz, 1H); 7.22(d, J ═ 8.3Hz, 1H); 6.88(s, 1H); 5.80-5.67(m, 1H); 4.54(t, J ═ 6.1Hz, 2H); 3.69(s, 2H); 3.36-3.28(m, 2H); 3.19(t, J ═ 6.1Hz, 2H); 3.13(s, 2H); 2.76-2.70(m, 2H); 1.56(d, J ═ 6.6Hz, 6H). No 1 exchangeable proton was observed. LCMS: RT 7.45 min, M + H+＝408。
Example 142: 2- (4- (2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) piperidin-1-yl) ethanol 142
Mixing 9- (piperidine-4-yl) -2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e ]A mixture of azulene (180mg, 0.43mmol) in DMF (1mL), potassium carbonate (89mg, 0.65mmol) and 2- (2-bromo-ethoxy) -tetrahydropyran (97 μ L, 0.65mmol) was heated at 50 ℃ for 18 h. The cooled reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc and the combined organic extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 10% MeOH (+2M NH)3) DCM) to give a colorless oil. The oil was dissolved in methanol and treated with a 1M solution of HCl in methanol (2mL, 2mmol) and the reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The resulting residue was triturated in a mixture of ether and methanol to give 142 as a pale yellow solid (115mg, 54%).1HNMR(DMSO-d6400 MHz): 9.81 (broad singlet, 1H); 8.22(s, 1H); 7.70(s, 1H); 7.32-7.24(m, 2H); 6.99(s, 1H); 5.72(q, J ═ 8.7Hz, 2H); 5.36 (broad singlet, 1H); 4.51(t, J ═ 6.0Hz, 2H); 3.80(t, J ═ 4.9Hz, 2H); 3.67-3.57(m, 2H); 3.22-3.06(m, 6H); 2.97-2.85(m, 1H); 2.10-2.00(m, 4H). LCMS: RT 6.62 min, M + H+＝463.1。
Example 143: 2- (4- (2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b) ]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) piperidin-1-yl) acetamide 143
9- (piperidin-4-yl) -2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]A mixture of azulene (180mg, 0.43mmol) in DMF (1mL) was purified with potassium carbonate (89mg,0.65mmol) and bromoacetamide (77mg, 0.56mmol), and then stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc and the combined organic extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The resulting residue was triturated in ether to give 143 as a pale yellow solid (115mg, 54%).1H NMR(DMSO-d6400 MHz): 8.21(s, 1H); 7.75(d, J ═ 2.2Hz, 1H); 7.28(dd, J ═ 8.4, 2.2Hz, 1H); 7.20(d, J ═ 8.3Hz, 1H); 7.15(s, 2H); 6.97(s, 1H); 5.73(q, J ═ 8.8Hz, 2H); 4.49(t, J ═ 6.0Hz, 2H); 3.20(t, J ═ 6.0Hz, 2H); 2.96-2.85(m, 4H); 2.62-2.52(m, 1H); 2.24-2.14(m, 2H); 1.84-1.66(m, 4H). LCMS: RT 6.55 min, M + H+＝476。
Example 144: 9- (azetidin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1, 5-d ][1，4]Oxazazepine144
Reaction of 61(0.52g, 1.40mmol) with 1-tert-butoxycarbonyl-azetidin-3-ylzinc iodide (2.0mmol) gave 3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulen-9-yl]-azetidine-1-carboxylic acid tert-butyl ester (0.47g, 49%). LCMS: RT 4.70M + H+＝451。
9- (azetidin-3-yl) -2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulene (0.41g, 0.76mmol) was treated with acid to give the crude hydrochloride salt, which was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution and extracted three times with DCM. The combined extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient of 0 to 10% [2M NH ]3(in MeOH)]DCM), 144(162mg, 31%).1HNMR(400MHz，CDCl3): 7.97-7.93(m, 1H); 7.82(d, J ═ 2.19Hz, 1H); 7.29(dd, J ═ 8.36, 2.25Hz, 1H); 7.19(d, J ═ 8.32Hz, 1H); 6.87(s, 1H); 5.74-5.66(m, 1H); 4.57-4.50(m, 2H); 4.12-4.02(m, 1H); 4.00(t, J ═ 7.46Hz, 2H); 3.87(t, J ═ 7.27Hz, 2H); 3.16(t, J ═ 6.02Hz, 2H); 1.62(d, 6H). LCMS: RT ═ 6.01 min, M + H +＝351。
Example 145: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (piperazine-1-carboxy) -4, 5-dihydrobenzo-2H-oxaAnd [4, 5-d ]]Pyrazole 145
N-Boc piperazine (101mg, 0.54mmol), 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]A mixture of azulene-9-carboxylic acid (180mg, 0.53mmol), EDCI (151mg, 0.79mmol), HOBt (107mg, 0.795mmol) and TEA (216. mu.L, 1.54mmol) in DMF (2mL) was stirred at room temperature for 20 h. The mixture was diluted with ethyl acetate and washed (water, saturated aqueous sodium bicarbonate and brine in succession), dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 10% MeOH/DCM) to give 4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene-9-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (258mg, 96%). Intermediate carboxylic acid tert-butyl ester was dissolved in DCM (20mL) and treated with a solution of 4N HCl in dioxane (4mL) and stirred at rt for 3 h, then diethyl ether (20mL) was added. The resulting precipitate was collected by filtration and washed with diethyl ether to give 145 as a white solid (209mg, 93%). 1H NMR(400MHz，DMSO-d6)：9.32(s，2H)；8.37(s，1H)；8.31(d，J＝2.20Hz，1H)；8.06(s，1H)；7.44(dd，J＝8.37，2.21Hz，1H)；7.15(d，J＝8.37Hz，1H)；5.32-5.23(m，1H)；4.37(t，J＝4.98Hz，2H)；3.77(s，4H)；3.15(t，J＝6.94Hz，6H)；1.51(d，J＝6.59Hz, 6H). LCMS: RT 6.02 min, M + H+＝408。
Example 146: 2- (4-isopropyl-4H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo-2H-oxaAnd [4, 5-d ]]Pyrazole 146
Step 1: 4-isopropyl-3-methylsulfanyl-4H- [1, 2, 4] triazole
To a solution of 4-isopropyl-3-thiosemicarbazide (4-isopropyl-3-thioSemicarbazide) (7.0g, 52.54mmol) in dioxane (50mL) was added DMF-DMA (14.1mL, 105.08mmol) and the mixture was heated to 100 ℃. After 3 hours, DMF-DMA (52.54mmol) was added and heating continued. After 18 hours, the mixture was cooled to room temperature and the solvent was removed in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 100% EtOAc/cyclohexane) to give 4-isopropyl-3-methylsulfanyl-4H- [1, 2, 4]Triazole (4.05g, 49%). LCMS: RT 2.55 min, M + H+＝158。
Step 2: 4-isopropyl-3-methanesulfonyl-4H- [1, 2, 4] triazole
To 4-isopropyl-3-methylsulfanyl-4H- [1, 2, 4]To a solution of triazole (3.05g, 19.43mmol) in DCM (30mL) was added formic acid (2.9mL, 76.36mmol) and ammonium molybdate tetrahydrate (56mg, 0.047 mmol). To the rapidly stirred mixture was carefully added portionwise a hydrogen peroxide solution (50% by weight in H)28mL in O, 116.58mmol) to avoid an uncontrolled exotherm. After the addition was complete, the mixture was stirred at room temperature for 18 hours. The mixture was cooled in an ice bath and carefully quenched with saturated sodium sulfite solution, then extracted with DCM (3 × 100 mL). The organic extracts were combined and dried (Na) 2SO4) Filtering and vacuum concentrating to obtain 4-isopropyl-3-methylsulfonyl-4H- [1, 2, 4%]Triazole (3.29g, 90%). LCMS: RT 2.02 min, M + H+＝190。
And step 3: 9-bromo-2- (4-isopropyl-4H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene
49(200mg, 0.755mmol), 4-isopropyl-3-methanesulfonyl-4H- [1, 2, 4] are added to a microwave bottle]Triazole (143mg, 0.755mmol), cesium carbonate (246mg, 0.755mmol), and THF (2 mL). The reaction mixture was heated to 150 ℃ and held for 2 hours, then extracted with EtOAc (20mL), washed with water (20mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 100% EtOAc/cyclohexane) to give 9-bromo-2- (4-isopropyl-4H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene (122mg, 43%). LCMS: RT 4.34 min, M + H+＝374/376。
And 4, step 4: 2- (4-isopropyl-4H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene
To the 9-bromo-2- (4-isopropyl-4H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Degassed solution of azulene (122mg, 0.326mmol) in IMS (10mL) was added TEA (51. mu.L, 0.359mmol) and 10% Pd/C (15 mg). The mixture was stirred under hydrogen (1 atm) for 60 min, then filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in DCM (20mL) and washed with water (20mL), the organic layer was dried (Na) 2SO4) Filtered and concentrated in vacuo. The resulting residue was lyophilized with acetonitrile and water to give 146(54mg, 56%). LCMS: RT 10.29 min, M + H+＝296。
Alternatively, to 8-bromo-2- (4-isopropyl-4H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]To a degassed solution of azulene (122mg, 0.326mmol) in IMS (10mL) was added 10% Pd/C (15mg), the reaction mixture was stirred under an atmosphere of hydrogen for 1 hour, then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in DCM and the solution was washed with water, the organic layer was dried (Na)2SO4) Filtered and concentrated in vacuo to give a residue. Will be provided withThe residue was dissolved in acetonitrile and water and the solution was freeze-dried to give 2- (4-isopropyl-4H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene as a white solid (54mg, 56%).1HNMR(400MHz，CDCl3): 8.27-8.23(m, 2H); 8.12(t, J ═ 1.02Hz, 1H); 7.30-7.24(m, 1H); 7.14-7.06(m, 2H); 5.38-5.29(m, 1H); 4.36(t, J ═ 5.10Hz, 2H); 3.16(td, J ═ 5.10, 1.06Hz, 2H); 1.63-1.54(d, J ═ 6.59Hz, 6H). LCMS: RT 10.29 min, M + H+＝296。
Example 147: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -4, 5-dihydrobenzo-2H-oxa And [4, 5-d ]]Pyrazole-9-carboxamides 147
2- (2-isopropyl-2H- [1, 2, 4) according to the procedure used for 116]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Reaction of azulene-9-carboxylic acid with 4-amino-1- (2-hydroxyethyl) pyrazole gave 147 as a white solid.1H NMR(400MHz，DMSO-d6): 10.45(s, 1H); 8.85(d, J ═ 2.32Hz, 1H); 8.36(s, 1H); 8.08-8.05(m, 2H); 7.87(dd, J ═ 8.53, 2.35Hz, 1H); 7.58(d, J ═ 0.69Hz, 1H); 7.18(d, J ═ 8.50Hz, 1H); 5.36-5.28(m, 1H); 4.88(t, J ═ 5.31Hz, 1H); 4.39(t, J ═ 4.97Hz, 2H); 4.13(t, J ═ 5.61Hz, 2H); 3.73(q, J ═ 5.51Hz, 2H); 3.16(t, J ═ 4.96Hz, 2H); 1.53(d, J ═ 6.59Hz, 6H). LCMS: RT 9.63 min, M + H+＝449。
Example 148: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (methylsulfonyl) azetidin-3-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1, 5-d][1，4]Oxazazepine148
9- (azetidin-3-yl) -2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]An ice-cooled solution of azulene (0.16g, 0.46mmol) in DCM (5mL) was treated with TEA (0.14mL, 1.0mmol) followed by methanesulfonyl chloride (40. mu.L, 0.51mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was washed with water and the aqueous layer was extracted with DCM, the organic extracts were combined and dried (Na) 2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 50 to 100% EtOAc/cyclohexane) to give 148 as a white solid (126mg, 64%).1H NMR(400MHz，CDCl3): 7.95(d, J ═ 2.49Hz, 2H); 7.31(dd, J ═ 8.35, 2.29Hz, 1H); 1.21(d, J ═ 8.32Hz, 1H); 6.89(s, 1H); 5.75-5.66(m, 1H); 4.56(t, J ═ 5.89Hz, 2H); 4.32(t, J ═ 8.24Hz, 2H); 4.12(t, J ═ 7.34Hz, 2H); 3.92-3.82(m, 1H); 3.20(t, J ═ 5.89Hz, 2H); 2.93(s, 3H); 1.62(d, 6H). LCMS: RT 9.68 min, M + H+＝429。
Example 149: 1- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) azetidin-1-yl) ethanone 149
Reacting 9- (azetidin-3-yl) -2- (2-isopropyl-2H- [1, 2, 4) according to the procedure used for 148]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene with acetic anhydride gave 149 as a white solid.1H NMR(400MHz，CDCl3)：7.93(s，1H)；7.85(d，J＝2.17Hz，1H)；7.27-7.20(m，1H)；7.19(d，J＝8.32Hz，1H)；6.85(s，1H)；5.68-5.59(m，1H)；4.59-4.50(m，3H)；4.44(t，J＝9.38Hz，1H)；4.18-4.11(m，1H)；4.13-4.05(m，1H)；3.89-3.80(m，1H)；3.16(t，J＝5.93Hz，2H)；1.91(s，3H)；1.57(d，J＝6.62Hz, 6H). LCMS: RT 9.50 min, M + H+＝393。
Example 150: 2-hydroxy-1- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) azetidin-1-yl) ethanone 150
Reacting 9- (azetidin-3-yl) -2- (2-isopropyl-2H- [1, 2, 4) according to the procedure used for 116]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene with glycolic acid gave 150 as a white solid.1H NMR(400MHz，CDCl3): 7.95(s, 1H); 7.87(d, J ═ 2.09Hz, 1H); 7.28-7.21(m, 1H); 7.24-7.19(m, 1H); 6.87(s, 1H); 5.68-5.59(m, 1H); 4.60-4.48(m, 4H); 4.20(dd, J ═ 9.89, 6.11Hz, 1H); 4.16-4.07(m, 1H); 4.05(d, J ═ 3.28Hz, 2H); 4.03-3.96(m, 1H); 3.18(t, J ═ 5.91Hz, 2H); 1.58(d, J ═ 6.62Hz, 6H). No 1 exchangeable proton was observed. LCMS: RT 8.95 min, M + H+＝409。
Example 151: 2-hydroxy-1- (4- (2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b ]]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) piperidin-1-yl) ethanone 151
9- (piperidin-4-yl) -2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4 ] according to the procedure used for 116]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene with glycolic acid gave 151 as a white solid.1HNMR(400MHz，DMSO-d6)：8.21(s，1H)；7.73(d，J＝2.16Hz，1H)；7.29(dd，J＝8.37，2.17Hz，1H)；7.21(d，J＝8.32Hz，1H)；6.97(s，1H)；572(q, J ═ 8.78Hz, 2H); 4.55-4.43(m, 4H); 4.13-4.05(m, 2H); 3.79(d, J ═ 13.44Hz, 1H); 3.23-3.15(m, 3H); 3.09(t, J ═ 12.91Hz, 1H); 2.91-2.82(m, 1H); 2.77-2.65(m, 1H); 1.86(d, J ═ 12.87Hz, 2H). LCMS: RT 9.76 min, M + H +＝477。
Example 152: 9- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1, 5-d][1，4]Oxazazepine152
9- (piperidin-4-yl) -2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]A mixture of azulene (90mg, 0.22mmol), TEA (150. mu.L) and IMS (0.6mL) was treated with vinyl sulfone (48mL, 0.54mmol), then diluted with DCM and stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue was triturated in ether to give a solid which was subjected to flash chromatography (SiO)2Gradient 0 to 5% MeOH/DCM) to give 152 as a white solid (96mg, 85%).1H NMR(400MHz，CDCl3): 8.01(s, 1H); 7.69(s, 1H); 7.19-7.08(m, 2H); 6.92(s, 1H); 5.53(q, J ═ 8.15Hz, 2H); 4.54(t, J ═ 6.01Hz, 2H); 3.21-3.12(m, 4H); 3.21-2.92(m, 5H); 2.93(t, J ═ 6.33Hz, 2H); 2.63-2.54(m, 1H); 2.21(t, J ═ 11.57Hz, 2H); 1.94(d, J ═ 12.96Hz, 2H); 1.81-1.66(m, 2H). LCMS: RT 6.57 min, M + H+＝525。
Example 153: ((3S, 5R) -3, 5-dimethylpiperazin-1-yl) (2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) methanone 153
2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the procedure used for 109]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-10-carboxylic acid with 3S, 5R-dimethylpiperazine gives 153. MS (ESI +) ═ 476.1.1H NMR(400MHz，DMSO)8.39(d，J＝2.0Hz，1H)，8.10(d，J＝4.9Hz，2H)，7.37(dd，J＝8.4，2.1Hz，1H)，7.12(d，J＝8.4Hz，1H)，5.88(s，2H)，4.57(s，4H)，4.06(q，J＝5.3Hz，2H)，3.17(d，J＝5.2Hz，2H)，2.67(s，2H)，0.92(s，6H)。
Example 154: 2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -9- (piperidin-4-yl) -4, 5-dihydrobenzo-2H-oxaAnd [4, 5-d ]]Pyrazole 154
Step 1: 4- {2- [2- (2-chloro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
4- {2- [2- (2-chloro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester with 4- {2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was prepared analogously to 60(500mg, 1.13mmol) to give 4- {2- [2- (2-chloro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a colourless gum (490mg, 80%). LCMS: RT 5.14 min, M + Na +＝567。
Step 2: 2- [2- (2-chloro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -9- (piperidin-4-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene
2- [2- (2-chloro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-9- (piperidin-4-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Reaction of azulene with 9- (piperidin-4-yl) -2- [2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]The azulene is prepared from 4- {2- [2- (2-chloro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulen-9-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (490mg, 0.9mmo [). The crude salt was partitioned between DCM and saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with DCM. The combined organic extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained was subjected to reverse phase HPLC (Gemini C)18Column, gradient MeOH/H2O+0.1％HCO2H) To give 154(80mg, 18%) as the mono-formate salt.1H NMR(400MHz，DMSO-d6): 8.44(s, 1H); 8.39(s, 1H); 8.27(s, 1H); 7.81-7.68(m, 3H); 7.64(td, J ═ 7.60, 1.51Hz, 1H); 7.09-7.03(m, 2H); 6.90(d, J ═ 8.28Hz, 1H); 4.19(t, J ═ 5.06Hz, 2H); 3.32(d, J ═ 12.42Hz, 2H); 3.04(t, J ═ 5.01Hz, 2H); 2.89(dd, J ═ 13.45, 11.09Hz, 2H); 2.54-2.56(m, 1H); 1.69(d, J ═ 13.20Hz, 2H); 1.58-1.45(m, 2H). LCMS: RT 7.99 min, M + H +＝447。
Example 155: 2- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) azetidin-1-yl) acetamide 155
Reacting 9- (azetidin-3-yl) -2- (2-isopropyl-2H- [1, 2, 4) according to the procedure used for 143]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene with bromoacetamide and purification of the crude productPerforming flash chromatography (SiO)2Gradient 0 to 10% MeOH/DCM) to give 155 as a white solid.1H NMR(400MHz，CDCl3): 7.95(s, 1H); 7.83(d, J ═ 2.18Hz, 1H); 7.24(d, J ═ 2.21Hz, 1H); 7.18(d, J ═ 8.31Hz, 1H); 6.86(s, 1H); 5.71-5.63(m, 1H); 5.45(s, 1H); 4.54(t, J ═ 5.98Hz, 2H); 3.87(t, J ═ 7.28Hz, 2H); 3.81-3.72(m, 1H); 3.38(t, J ═ 6.84Hz, 2H); 3.22(s, 2H); 3.16(t, J ═ 5.99Hz, 2H); 1.59(d, J ═ 6.62Hz, 6H). No 1 exchangeable proton was observed. LCMS: RT 5.84 min, M + H+＝408。
Example 156: n- (azetidin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-carboxamide 156
Reacting 2- (2-isopropyl-2H- [1, 2, 4 ] according to the method used for 126 ]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulene-9-carboxylic acid was reacted with 3-aminoazetidine-1-carboxylic acid 1, 1-dimethylethyl ester and the crude product was then suspended in DCM and treated with MP carbonate resin and stirred for 1.5 h. The mixture was filtered, the filtrate was concentrated in vacuo and the resulting residue was triturated in ether to give 156 as a white solid.1H NMR(400MHz，DMSO-d6): 9.11(d, J ═ 6.84Hz, 1H); 8.46(d, J ═ 2.18Hz, 1H); 8.05(t, J ═ 0.64Hz, 1H); 7.90-7.85(m, 1H); 7.37-7.30(m, 1H); 6.92(s, 1H); 5.62-5.53(m, 1H); 4.82-4.73(m, 1H); 4.57(t, J ═ 5.76Hz, 2H); 3.95-3.81(m, 4H); 3.25(t, J ═ 5.78Hz, 2H); 1.50(d, J ═ 6.58Hz, 6H). LCMS: RT 6.45 min, M + H+＝394。
Example 157: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (methylsulfonyl) ethyl) azetidine-3-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1, 5-d][1，4]Oxazazepine157
Reacting 9- (azetidin-3-yl) -2- (2-isopropyl-2H- [1, 2, 4) according to the procedure used for 152]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene with vinyl sulfone gave 157 as a white solid. 1H NMR(400MHz，DMSO-d6): 8.01(d, J ═ 0.64Hz, 1H); 7.84(d, J ═ 2.19Hz, 1H); 7.36(dd, J ═ 8.32, 2.21Hz, 1H); 7.21(d, J ═ 8.30Hz, 1H); 6.87(s, 1H); 5.60-5.51(m, 1H); 4.48(t, J ═ 6.03Hz, 2H); 3.67(s, 3H); 3.20-3.10(m, 6H); 3.03(s, 3H); 2.83(t, J ═ 6.83Hz, 2H); 1.48(d, J ═ 6.58Hz, 6H). LCMS: RT 5.99 min, M + H+＝457。
Example 158: n-methyl-2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 158
2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] was reacted according to the same method as 133]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-9-carboxylic acid (60mg, 0.1mmol) with 2M methylamine (0.26mL) in THF gave 158. LC/MS (ESI +): m/z 393(M + H).1HNMR(400MHz，DMSO)8.49(d，J＝4.2，1H)，8.42(s，1H)，8.11(d，J＝9.8，1H)，7.60(dd，J＝8.4，1.6，1H)，7.52(d，J＝1.4，1H)，5.90(q，J＝8.8，2H)，4.57(dd，J＝11.5，5.4，4H)，2.79(d，J＝4.5，3H)。
Example 159: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N-methyl-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 159
2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] was reacted according to the same method as 133]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-9-carboxylic acid (100mg, 0.3mmol) with 2M methylamine (0.59mL) in THF gave 159. LC/MS (ESI +): m/z 353(M + H). 1H NMR(400MHz，DMSO)8.54-8.39(m，1H)，7.93(dd，J＝18.0，11.2，1H)，7.67-7.46(m，-1H)，6.47(d，J＝33.7，-2H)，5.94-5.78(m，-2H)，4.68-4.47(m，-4H)，3.52-3.55(s，-3H)，2.90-2.68(m，1H)，1.47(t，J＝13.6，6H)。
Example 160: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -10- (1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine160
10-bromo-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted as in example 182]Imidazo [1, 2-d ] s][1，4]OxazazepineCoupling of 187 with tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate gave 160. MS: 362.3.1HNMR(400MHz，DMSO)8.57(t，J＝4.0，1H)，7.99-7.94(m，4H)，7.56(dt，J＝11.2，5.6，1H)，7.06(t，J＝8.6，1H)，5.81(p，J＝6.6，1H)，4.53(d，J＝9.5，4H)，1.53(d，J＝6.6，7H)。
example 161: 2- (1- (2-chlorophenyl) -1H-imidazol-2-yl) -N- (1-hydroxy-2-methylpropan-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxamide 161
Reaction of 72 with 2-amino-2-methylpropan-1-ol as per the procedure used for 109 gave 161. MS (ESI +) -478.1.1H NMR(400MHz，DMSO)8.12(d，J＝2.1Hz，1H)，7.63(dd，J＝6.0，3.4Hz，1H)，7.53(dd，J＝6.1，3.2Hz，2H)，7.50-7.44(m，3H)，7.36(s，1H)，7.28(d，J＝1.1Hz，1H)，7.12(s，1H)，6.96(d，J＝8.4Hz，1H)，5.00(s，1H)，4.41(s，4H)，3.55(d，J＝5.1Hz，2H)，1.36(s，6H)。
Example 162: (2- (1- (2, 4-difluorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) (4- (2-hydroxyethyl) piperazin-1-yl) methanone 162
2- (1- (2, 4-difluorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the procedure used for 109]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-10-carboxylic acid with 2- (piperazin-1-yl) ethanol to give 162. MS (ESI +) -522.2.
Example 163: n- (1-hydroxy-2-methylpropan-2-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 163
2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] was reacted according to the same method as 133]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid (20mg, 0.06mmol) was reacted with 2-amino-2-methylpropan-1-ol (11mg, 0.12mmol) in THF to give 163. LC/MS (ESI +): m/z 411(M + H).1H NMR(400MHz，DMSO)8.45(d，J＝8.4，1H)，7.95(d，J＝22.3，2H)，7.64-7.45(m，3H)，5.86(dt，J＝13.1，6.5，1H)，4.88(t，J＝6.0，1H)，4.63-4.44(m，4H)，3.58-3.45(m，3H)，1.49(d，J＝6.6，6H)，1.32(s，6H)。
Example 164: n- (1-hydroxy-2-methylpropan-2-yl) -2- (1- (S, S-dioxo-tetrahydrothiophen-3-yl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxamide 164
2- (1- (S, S-dioxo-tetrahydrothiophen-3-yl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carboxylic acid is reacted with 2-amino-2-methylpropan-1-ol to give 164. MS (ESI +) ═ 487.1.
Example 165: 2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -N- (1-hydroxy-2-methylpropan-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 165
2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the same method as 133 ]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-9-carboxylic acid (20mg, 0.06mmol) with 2-amino-2-methylpropan-1-ol (11mg, 0.12mmol) in THF gave 165. LC/MS (ESI +): m/z480(M + H).1H NMR(400MHz，DMSO)8.19(s，1H)，7.93(s，1H)，7.78-7.48(m，6H)，7.43-7.26(m，2H)，4.85(t，J＝6.1，1H)，4.47(d，J＝9.0，4H)，3.49(d，J＝6.0，2H)，1.29(s，6H)。
Example 166: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (pyridin-4-ylmethyl) azetidin-3-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1, 5-d][1，4]Oxazazepine166
Reacting 9- (azetidin-3-yl) -2- (2-isopropyl-2H- [1, 2, 4) according to the procedure for 128]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene with pyridine-4-carbaldehyde and flash chromatography (SiO) of the crude product2Gradient 0 to 20% MeOH/EtOAc), then triturated in cyclohexane to give 166 as a white solid.1H NMR(400MHz，CDCl3): 8.55(d, J ═ 5.20Hz, 2H); 7.95(s, 1H); 7.86(d, J ═ 2.20Hz, 1H); 7.30-7.24(m, 3H); 7.21-7.12(m, 1H); 6.88-6.83(m, 1H); 5.73-5.65(m, 1H); 4.54(t, J ═ 5.99Hz, 2H); 3.89-3.74(m, 3H); 3.71(s, 2H); 3.30(s, 2H); 3.16(t, J ═ 5.99Hz, 2H); 1.58(d, J ═ 6.62Hz, 6H). LCMS (method F): RT 6.07 min, M + H+＝442。
Example 167: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N- (1-isopropyl-azetidin-3-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-carboxamide 167
2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]A solution of azulene-9-carboxylic acid azetidin-3-ylamide (0.15g, 0.38mmol), acetone (84. mu.L, 1.14mmol), acetic acid (22. mu.L), methanol (1mL) and DCM (1mL) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (0.2g, 0.95mmol) was added and the resulting mixture was stirred at room temperature for 72 hours. Acetone (84. mu.L) andmolecular sieves were then stirred for an additional 1 hour, followed by addition of sodium triacetoxyborohydride (0.2g, 0.95 mmol). The reaction mixture was stirred at room temperature for 18 hours, and then saturated aqueous sodium bicarbonate solution was added. The resulting mixture was extracted with 10% MeOH/DCM. The combined extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 10% MeOH/DCM), then triturated in ether and recrystallized with EtOAc to give 167 as a white solid.1H NMR(400MHz，CDCl3): 8.47(d, J ═ 2.22Hz, 1H); 7.95(s, 1H); 7.71(dd, J ═ 8.44, 2.24Hz, 1H); 7.23(d, J ═ 8.43Hz, 1H); 6.87(s, 1H); 5.72-5.64(m, 1H); 4.74-4.67(m, 1H); 4.58(t, J ═ 5.67Hz, 2H); 3.68(t, J ═ 7.42Hz, 2H); 3.22(t, J ═ 5.69Hz, 2H); 3.12(s, 2H); 2.38(t, J ═ 7.02Hz, 1H); 1.61(d, J ═ 6.61Hz, 6H); 0.98(d, J ═ 6.21Hz, 6H). LCMS (method F): RT 6.82 min, M + H +＝436。
Example 168: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N-methoxy-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 168
2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] was reacted according to the same method as 133]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-9-carboxylic acid (20mg, 0.06mmol) with methoxylamine hydrochloride (9.8mg, 0.12mmol) in THF gave 168. LC/MS (ESI +): m/z 369(M + H).1H NMR(400MHz，DMSO)8.45(t，J＝16.8，1H)，7.95(d，J＝26.9，2H)，7.49(dd，J＝20.1，18.6，2H)，5.86(dt，J＝13.1，6.4，1H)，4.56(d，J＝2.8，4H)，3.72(s，2H)，1.61-1.32(m，5H)。
Example 169: 2- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) azetidin-1-yl) ethanol 169
Reacting 9- (azetidin-3-yl) -2- (2-isopropyl-2H- [1, 2, 4) according to the procedure for 142]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Reaction of azulene with 2- (2-bromo-ethoxy) -tetrahydropyran gave 169 as a white solid.1H NMR(400MHz，DMSO-d6): 8.03(s, 1H); 7.88(d, J ═ 2.22Hz, 1H); 7.42(dd, J ═ 8.35, 2.22Hz, 1H); 7.26(d, J ═ 8.32Hz, 1H); 6.89(s, 1H); 5.62-5.54(m, 1H); 4.83(s, 1H); 4.50(t, J ═ 6.03Hz, 2H); 4.06(s, 2H); 3.94(t, J ═ 8.52Hz, 1H); 3.70(s, 2H); 3.51(s, 3H); 3.18(t, J ═ 6.05Hz, 2H); 2.94(s, 2H); 1.49(d, J ═ 6.58Hz, 6H). LCMS (method F): RT 6.01 min, M + H395 min.
Example 170: 2- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo[b]Pyrazolo [1, 5-d][1，4]Oxazazepine-9-yl) azetidin-1-yl) -2-methylpropan-1-ol 170
Reacting 9- (azetidin-3-yl) -2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]A mixture of azulene (200mg, 0.55mmol), methyl 2-bromo-2-methylpropionate (71. mu.L, 0.55mmol) and TEA (75. mu.L, 0.55mmol) in DMF was heated at 55 ℃ for 30 h and then concentrated in vacuo. The residue was partitioned between 10% MeOH/DCM and water, the aqueous phase was extracted with 10% MeOH/DCM and the combined organic extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 10% MeOH/DCM) to give 2- {3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulen-9-yl]-azetidin-1-yl } -2-methyl-propionic acid methyl ester (56mg, 23%). To 2- {3- [2- (2-isopropyl-2H- [1, 2, 4 ] at-78 deg.C]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 10 b-diaza-benzo [ e]Azulen-9-yl]-azetidin-1-yl } -2-methyl-propionic acid methyl ester (56mg, 0.12mmol) in THF (1.5mL) was added DIBAL (1.5M solution in toluene, 0.24mL, 0.36mmol) and the mixture was warmed to room temperature over 18 hours. The mixture was cooled to 0 ℃, DIBAL (0.12mL, 0.18mmol) was added dropwise and stirring was continued for 45 min. The reaction mixture was quenched by the addition of MeOH (0.5mL) followed by saturated aqueous Rochelle's (Rochelle's) salt solution (0.5mL), then diluted with EtOAc and filtered over Celite, with washing with EtOAc. The filtrate was concentrated in vacuo and the residue was subjected to flash chromatography (SiO) 2Gradient 0 to 5% MeOH (+2M NH)3) DCM) to give 170 as a white solid (27mg, 53%).1H NMR(400MHz，CDCl3)：7.95(s，1H)；7.85(d，J＝2.18Hz，1H)；7.23(d，J＝2.23Hz，1H)；7.17(d，J＝8.29Hz，1H)；6.87(s，1H)；5.74-5.66(m，1H)；4.55(t，J＝6.02Hz，2H)；3.71(s，3H)；3.43(s，2H)；3.28(s，2H)；3.16(t，J＝6.03Hz，2H)；1.59(d，J＝6.62Hz，6H)；1.04(s, 6H). No 1 exchangeable proton was observed. LCMS (method F): RT 6.43 min, M + H+＝423。
Example 171: 2- (1- (2, 4-difluorophenyl) -1H-1, 2, 4-triazol-5-yl) -8- (1- (2- (methylsulfonyl) ethyl) azetidin-3-yl) -4, 5-dihydrobenzo-2H-oxa-lAnd [4, 5-d ]]Pyrazole 171
63 was reacted with vinyl sulfone following the procedure used for 152. The crude product was subjected to reverse phase HPLC (Gemini C)6-phenyl column, gradient 40 to 90% methanol/water + 0.1% HCO2H) Yield 171 as a white solid.1H NMR(400MHz，DMSO-d6): 8.42(s, 1H); 8.29(s, 1H); 8.14(s, 1H); 7.81(td, J ═ 8.75, 5.92Hz, 1H); 7.64(ddd, J ═ 10.33, 9.02, 2.80Hz, 1H); 7.38-7.32(m, 1H); 7.29(d, J ═ 8.17Hz, 1H); 6.96(d, J ═ 1.71Hz, 1H); 6.91(dd, J ═ 8.25, 1.80Hz, 1H); 4.23(t, J ═ 5.01Hz, 2H); 3.66(t, J ═ 7.11Hz, 2H); 3.76-3.41(m, 1H); 3.16(t, J ═ 7.36Hz, 5H); 3.05(s, 4H); 2.88(t, J ═ 6.91Hz, 2H). LCMS (method F): RT 7.25 min, M + H+＝527。
Example 172: 2- (3- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl } -azetidin-1-yl) -acetamide 172
The crude product was flash chromatographed (SiO) by reacting 63 with bromoacetamide as described for 1432Gradient 0 to 10% MeOH/DCM) to give 172 as a white solid.1H NMR(400MHz，DMSO-d6)：8.42(s，1H)；8.28(s，1H)；7.81(td，J＝8.75，5.92Hz，1H)；7.63(ddd，J＝10.33，9.01，2.79Hz，1H)；7.39-7.27(m，2H)；7.11(s，1H)；7.03(s，1H)；6.96-6.89(m，2H)；4.23(t, J ═ 5.01Hz, 2H); 3.66(t, J ═ 7.02Hz, 2H); 3.62-3.52(m, 1H); 3.16(t, J ═ 6.65Hz, 2H); 3.10-2.98(m, 4H). LCMS (method F): RT 7.00 min, M + H+＝478。
Example 173: n-hydroxy-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 173
2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] was reacted according to the same method as 133]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-9-carboxylic acid (20mg, 0.06mmol) with hydroxylamine hydrochloride (8mg, 0.1mmol) in THF gave 173. LC/MS (ESI +): m/z 355(M + H).
Example 174: 2- (1- (2, 4-difluorophenyl) -1H-1, 2, 4-triazol-5-yl) -N-methyl-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 174
2- (1- (2, 4-difluorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] was reacted according to the same manner as 133]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-9-carboxylic acid (30mg, 0.07mmol) with 2M methylamine (0.06mL) in THF gave 174. LC/MS (ESI +): m/z 422(M + H). 1HNMR(400MHz，DMSO)8.52(t，J＝9.7，1H)，8.23(s，1H)，8.03(s，1H)，7.80-7.67(m，2H)，7.67-7.55(m，1H)，7.47-7.38(m，2H)，7.33(t，J＝8.4，1H)，4.50(d，J＝7.7，3H)，2.74(t，J＝17.2，3H)。
Example 175: 2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -9- [1- (2-methanesulfonyl-ethyl) -piperidin-4-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene 175
Reacting 2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] according to the method used for 152]Triazol-3-yl]-9- (piperidin-4-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Reacting azulene hydrochloride with vinyl sulfone. The crude product was dissolved in DCM and treated with 4N HCl. After stirring for 10 min, diethyl ether was added and the solid precipitate was collected by filtration to give 175 as a white solid.1H NMR(400MHz，DMSO-d6): 10.63(s, 1H); 8.45(s, 1H); 8.30(s, 1H); 7.85(td, J ═ 8.75, 5.90Hz, 1H); 7.72(t, J ═ 9.62Hz, 1H); 7.42(t, J ═ 8.57Hz, 1H); 7.22(d, J ═ 2.33Hz, 1H); 7.11(dd, J ═ 8.45, 2.37Hz, 1H); 6.97(d, J ═ 8.34Hz, 1H); 4.22(t, J ═ 5.02Hz, 2H); 3.82(t, J ═ 7.50Hz, 2H); 3.76-3.63(m, 2H); 3.59(d, J ═ 9.30Hz, 2H); 3.16(s, 3H); 3.14(m, 2H); 3.06(t, J ═ 5.04Hz, 2H); 2.66(s, 1H); 1.96-1.76(m, 4H). LCMS (method F): RT 7.54 min, M + H+＝555。
Example 176: 2- {4- [2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl ] -pyrazol-1-yl } -ethanol 176
Reacting 8-bromo-2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene (160mg, 0.43mmol), 1- [2- (tetrahydropyran-2-yloxy) -ethyl]-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxaborolan-2-yl) -1H-pyrazole (165mg, 0.51mmol), cesium carbonate (279mg, 0.85mmol) and 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) DCM (17mg, 5 mol%) were mixed in a reaction flask, evacuated of air and backfilled with nitrogen. THF (5mL) and water (1mL) were added and the solution was stirredThe reaction mixture was heated at 85 ℃ for 4 hours. The reaction mixture was diluted with EtOAc and water, the organic layer was separated and dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 30% EtOAc/cyclohexane) to give 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8- {1- [2- (tetrahydropyran-2-yloxy) -ethyl]-1H-pyrazol-4-yl } -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene (134mg, 64%).
2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8- {1- [2- (tetrahydropyran-2-yloxy) -ethyl]-1H-pyrazol-4-yl } -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene (134mg, 0.27mmol) was dissolved in diethyl ether (5mL) and treated with a solution of 1M HCl in diethyl ether (1mL) followed by methanol (5 mL). After 30 min, the reaction mixture was concentrated to dryness and the resulting residue was triturated in ether to give 176 as a pale cream solid (105mg, 86%). 1H NMR(400MHz，DMSO-d6): 8.32(s, 1H); 8.23(s, 1H); 8.19(d, J ═ 8.23Hz, 1H); 8.03(s, 1H); 7.96(s, 1H); 7.39(dd, J ═ 8.24, 1.74Hz, 1H); 7.29(d, J ═ 1.68Hz, 1H); 5.46-5.36(m, 1H); 4.34(t, 2H); 4.17(t, J ═ 5.61Hz, 2H); 3.78(t, J ═ 5.58Hz, 2H); 3.13(t, J ═ 4.91Hz, 2H); 1.52(d, J ═ 6.57Hz, 6H). No 1 exchangeable proton was observed. LCMS (method F): RT 10.68 min, M + H+＝406。
Example 177: 1- (4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -piperidin-1-yl) -2-methyl-propan-2-ol 177
2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-9- (piperidin-4-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]A mixture of azulene hydrochloride (100mg, 0.21mmol), lithium perchlorate (22mg, 0.21mmol) and DIPEA (72. mu.L, 0.41mmol) in THF (3mL) was treated with 2, 2-dimethyl-ethylene oxide (183. mu.L, 2.06mmol) followed by water (150. mu.L). The reaction mixture was allowed to stand at room temperatureStirred for 18 hours and then concentrated in vacuo. The resulting residue was partitioned between DCM and water, the organic layer was separated and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO) 2Gradient 40 to 100% EtOAc/cyclohexane) then triturated in a mixture of MeOH and water to give 177 as a white solid (58mg, 54%).1H NMR(400MHz，DMSO-d6): 8.44(s, 1H); 8.28(s, 1H); 7.85(td, J ═ 8.76, 5.90Hz, 1H); 7.61(ddd, J ═ 10.27, 8.88, 2.78Hz, 1H); 7.36-7.30(m, 1H); 7.22(d, J ═ 2.31Hz, 1H); 7.08(dd, J ═ 8.38, 2.35Hz, 1H); 6.89(d, J ═ 8.34Hz, 1H); 4.21(t, J ═ 5.02Hz, 2H); 4.06(s, 1H); 3.12-3.02(m, 4H); 2.31-2.19(m, 5H); 1.60-1.48(m, 4H); 1.15(s, 6H). LCMS (method F): RT 7.75 min, M + H+＝521。
Example 178: 2- (4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -piperidin-1-yl) -acetamide 178
2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] according to the procedure used for 143]Triazol-3-yl]-9- (piperidin-4-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Reacting azulene hydrochloride with bromoacetamide. Flash chromatography (SiO) of the crude product2Gradient 50 to 100% EtOAc/cyclohexane). The pure fractions were combined and concentrated in vacuo and the resulting residue was dissolved in DCM and treated with 4M HCl in dioxane followed by diethyl ether. The resulting precipitate was collected by filtration to give 178 as a white solid. 1H NMR(400MHz，DMSO-d6)：9.86(s，1H)；8.48-8.43(m，1H)；8.30(s，1H)；8.05(s，1H)；7.85(td，J＝8.75，5.93Hz，1H)；7.74-7.63(m，2H)；7.41-7.34(m，1H)；7.22(d，J＝2.30Hz，1H)；7.10(dd，J＝8.45，2.35Hz，1H)；6.97(d，J＝8.39Hz，1H)；4.22(t，J＝5.00Hz，2H)；3.98(d，J＝4.37Hz，2H)；3.60(t，J＝12.26Hz，2H)；3.24-3.13(m，2H)；3.06(t，J＝4.95Hz，2H)；2.69-2.61(m，1H)；1.87(s，4H)。LCMS (method F): RT 7.46 min, M + H+＝506。
Example 179: 2- (4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -piperidin-1-yl) -ethanol 179
Reacting 2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] according to the method used for 142]Triazol-3-yl]-9- (piperidin-4-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene hydrochloride was reacted with 2- (2-bromo-ethoxy) -tetrahydropyran to give 179 as a white solid.1H NMR(400MHz，DMSO-d6): 9.86(s, 1H); 8.44(s, 1H); 8.29(s, 1H); 7.84(td, J ═ 8.75, 5.94Hz, 1H); 7.72(td, J ═ 9.64, 2.83Hz, 1H); 7.43-7.37(m, 1H); 7.21(d, J ═ 2.28Hz, 1H); 7.09(dd, J ═ 8.45, 2.36Hz, 1H); 6.96(d, J ═ 8.40Hz, 1H); 5.37(t, J ═ 4.89Hz, 1H); 4.21(t, J ═ 5.01Hz, 2H); 3.83(d, J ═ 5.48Hz, 2H); 3.65(d, J ═ 12.04Hz, 2H); 3.23(m, 2H); 3.10(m, 4H); 2.69-2.60(m, 1H); 2.01-1.80(m, 4H). LCMS (method F): RT 7.55 min, M + H+＝493。
Example 180: 1- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol 180
52(7.84g, 20.95mmol), 2-methyl-1- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ] methyl-1- [ 4] methyl-2-carboxylate by evacuation/bubbling with argon (. times.3) according to the method used for 182]Dioxaborolan-2-yl) -pyrazol-1-yl]A solution of-propan-2-ol (11.15g, 41.90mmol) and cesium carbonate (20.47g, 62.8mmol) in dioxane (380mL) and water (38mL) was degassed. 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride DCM (1.71g, 2.09mmol) was added and the reaction mixture was heatedReflux for 2 hours. The reaction mixture was diluted with water (250mL) and extracted with EtOAc (3X 100 mL). The combined organic fractions were washed with brine (100mL) and dried (MgSO)4) And concentrated in vacuo to give a dark brown slurry. The slurry was triturated with hot IPA (. about.50 mL), cooled to room temperature and filtered. The solid was washed with cold IPA (. about.30 mL) and dried in vacuo to give 180 as an off-white solid (6.6g, 73%). LS/MS (ESI +): m/z 434(M + H).1H NMR(400MHz，DMSO)8.37(d，J＝8.4，1H)，8.16(s，1H)，7.95(s，1H)，7.91(s，2H)，7.39(dd，J＝8.4，1.7，1H)，7.28(d，J＝1.7，1H)，5.90(dt，J＝13.0，6.5，1H)，4.72(s，1H)，4.52(q，J＝6.2，4H)，4.04(s，2H)，1.49(d，J＝6.6，6H)，1.10(s，6H)。
Example 181: 2- {3- [2- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl ] -azetidin-1-yl } -acetamide 181
64 was reacted with bromoacetamide according to the procedure for 143, and the crude product was subjected to reverse phase HPLC (Gemini C) 18Column, gradient 10 to 90% MeOH/water + 0.1% HCO2H) To give 181 as a white solid.1HNMR(400MHz，DMSO-d6): 8.33(s, 1H); 8.21-8.14(m, 2H); 8.04(s, 1H); 7.21(dd, J ═ 8.42, 1.92Hz, 2H); 7.12-7.02(m, 2H); 5.44-5.36(m, 1H); 4.32(t, J ═ 5.05Hz, 2H); 3.80-3.61(m, 3H); 3.30(t, J ═ 7.44Hz, 2H); 3.16-3.09(m, 4H); 1.52(d, J ═ 6.59Hz, 6H). LCMS (method F): RT 6.49 min, M + H+＝408。
Example 182: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol 182
To 10mL microwave bottle was charged with 194(0.210g, 0.56mmol), potassium acetate (0.17g, 1.68mmol), MeCN (1mL) and water (2 mL). The mixture was thoroughly purged with nitrogen. A solution of 1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.271g, 0.84mmol) in MeCN (1mL) was added, followed by tetrakis (triphenylphosphine) palladium (65mg, 0.056mmol) and the vial was immediately sealed. The mixture was irradiated with microwaves at 150 ℃ for 20 minutes. LC/MS indicated complete conversion (small amount of THP-depleted product was observed). The reaction mixture was diluted with EtOAc and water and extracted three times with EtOAc. The organic phases were combined and MgSO 4Dried and concentrated. The residue was purified using ISCO chromatography (using 10% MeOH/EtOAc) to give 170mg (0.35mmol, 62%) of a white foamy solid as the product, which was immediately dissolved in DCM (2mL) and treated with a solution of 4M hydrogen chloride in 1, 4-dioxane (0.35 mL). During the addition, a white precipitate formed. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and in DMF/H2Dissolving in O. The mixture was purified by RP-HPLC to give 105mg (74% yield) 182 as a white partially crystalline solid. LS/MS (ESI +): m/z 406(M + H).1H NMR(400MHz，DMSO)8.37(d，J＝8.4，1H)，8.22(s，1H)，7.95(s，1H)，7.91(s，2H)，7.38(dd，J＝8.4，1.8，1H)，7.27(d，J＝1.7，1H)，5.91(dq，J＝13.3，6.7，1H)，4.91(t，J＝5.3，1H)，4.58-4.44(m，4H)，4.16(t，J＝5.6，2H)，3.77(q，J＝5.4，2H)，1.49(d，J＝6.6，6H)。
Example 183: 1- (3- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl } -azetidin-1-yl) -2-methyl-propan-2-ol 183
Reaction of 63 with 2, 2-dimethyl-oxirane as per procedure for 177 gave 183 as a white solid.1H NMR(400MHz，DMSO-d6)：8.45(s，1H)；8.31(s，1H)；8.17(s，1H)；7.84(td，J＝8.75，5.92Hz，1H)；7.66(ddd，J＝10.33，9.02，2.79Hz, 1H); 7.40-7.34(m, 1H); 7.31(d, J ═ 8.17Hz, 1H); 7.00(d, J ═ 1.69Hz, 1H); 6.93(dd, J ═ 8.25, 1.78Hz, 1H); 4.26(t, J ═ 5.06Hz, 2H); 3.79(t, J ═ 7.52Hz, 2H); 3.64(t, J ═ 7.75Hz, 1H); 3.35(t, 2H); 3.08(t, J ═ 5.05Hz, 2H); 2.35(t, 2H); 1.10(s, 6H). LCMS (method F): RT 7.45 min, M + H +＝493。
Example 184: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 184
To 40(1.0g, 2.7mmol), 1-isopropyl-1H-1, 2, 4-triazole (0.30g, 2.7mmol), CuI (1.5g, 8.1mmol), Pd (OAc)2To (0.061g, 0.27mmol) and cesium carbonate (2.2g, 6.8mmol) was added DMF (26 mL). The reaction mixture was stirred in a sealed vial and heated at 100 ℃ for 24 hours. The reaction mixture was cooled to room temperature and poured into a mixture of ammonium hydroxide/water (1: 2) and EtOAc and filtered through a plug of silica gel. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with ammonium hydroxide (1: 2), water and brine, MgSO4Dried and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with EtOAc) to give 184(0.270g, 28%).1H NMR(400MHz，DMSO)8.54(d，J＝8.4，1H)，7.97(d，J＝35.2，2H)，7.70(dd，J＝8.4，1.7，1H)，7.57(d，J＝1.7，1H)，5.99-5.70(m，1H)，4.57(q，J＝5.9，4H)，3.87(s，3H)，1.49(d，J＝6.6，6H)。MS(ESI(+))：m/z 354.1(M+H)。
Alternatively, a solution of 42(370mg, 1.3mmol) in dimethoxyethane (3mL) was treated with 1, 1-dimethoxy-N, N-dimethylmethylamine (1mL, 7.5mmol) and heated to 90 ℃ and held for 0.5 h. LC/MS showed the major desired product. After cooling, the reaction mixture was concentrated to give the crude acylamidine which was then suspended in acetic acid (2.3mL) and treated with isopropylhydrazine hydrochloride (0.29g, 2) 5 mmol). The mixture was heated at 75 ℃ for 30 minutes, cooled to room temperature and concentrated. Purification by ISCO (using 100% EtOAc) gave 184(0.32g, 70% yield).1H NMR(400MHz，DMSO)8.54(d，J＝8.4，1H)，8.02(s，1H)，7.93(s，1H)，7.70(dd，J＝8.4，1.7，1H)，7.57(d，J＝1.7，1H)，5.85(dq，J＝13.3，6.6，1H)，4.57(q，J＝6.0，4H)，3.87(s，3H)，1.49(d，J＝6.6，6H)。
Example 185: 2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 185
40 was reacted with trifluoroethyltriazole (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazole) according to the method used for 184. The product was precipitated from EtOAc and collected by filtration to give 185(393mg, 40%).1H NMR(400MHz，DMSO)8.51(d，J＝8.4，1H)，8.15(s，1H)，8.10(s，1H)，7.71(dd，J＝8.4，1.7，1H)，7.58(d，J＝1.6，1H)，5.89(q，J＝8.8，2H)，4.64-4.49(m，4H)，3.87(s，3H)。MS(ESI(+))：m/z 394.0(M+H)。
Alternatively, 42 was reacted with 1, 1-dimethoxy-N, N-dimethylmethylamine as for 184 and then treated with a solution of trifluoroethylhydrazine hydrochloride in acetic acid to give 185 (65% yield).1H NMR(400MHz，DMSO)8.51(d，J＝8.4，1H)，8.15(s，1H)，8.10(s，1H)，7.71(dd，J＝8.4，1.7，1H)，7.58(d，J＝1.6，1H)，5.89(q，J＝8.8，2H)，4.65-4.45(m，5H)，3.87(s，3H)，3.58-3.37(m，7H)。
Example 186: 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol 186
9-bromo-2- (1-isopropyl-4-methyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the same method as 182]Imidazo [1, 2-d ] s][1，4]OxazazepineSuzuki reaction with 1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole gave 186 as a white crystalline solid (72% yield) after removal of the THP group with acid. LS/MS (ESI +): m/z 420(M + H). 1H NMR(400MHz，DMSO)8.36(d，J＝8.4，1H)，8.22(s，1H)，7.95(s，1H)，7.87(s，1H)，7.38(dd，J＝8.4，1.7，1H)，7.27(d，J＝1.7，1H)，5.83(dt，J＝13.2，6.6，1H)，4.91(t，J＝5.3，1H)，4.51(s，4H)，4.16(t，J＝5.6，2H)，3.77(q，J＝5.6，2H)，1.48(t，J＝9.0，6H)。
Example 187: 10-bromo-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine187
To 10-bromo-2-iodo-5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(1.5g, 3.8mmol), 1-isopropyl-1H-1, 2, 4-triazole (0.40g, 3.0mmol), CuI (1.8g, 9.5mmol), Pd (OAc)2To (0.071g, 0.32mmol) and cesium carbonate (2.6g, 7.9mmol) was added DMF (20 mL). The reaction mixture was stirred in a sealed vial and heated at 100 ℃ for 24 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered over celite. The filtrate was concentrated under reduced pressure. To the crude residue was added EtOAc and a solidCollected by filtration. The filtrate was concentrated and the crude product was dissolved in DMF and purified by reverse phase HPLC to give 187(64mg, 5%).1H NMR(400MHz，DMSO)8.43(dd，J＝47.5，31.0，1H)，7.97(s，1H)，7.92(s，1H)，7.60-7.39(m，1H)，7.04(d，J＝8.7，1H)，5.74(dt，J＝13.2，6.6，1H)，4.76-4.33(m，4H)，1.49(d，J＝6.6，6H)。MS(ESI(+))：m/z 374.0(M+H)。
Example 188: [4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -1- (2-methanesulfonyl-ethyl) -piperidin-4-yl ] -methanol 188
To a stirred mixture of 68(97mg, 0.1873mmol) in IMS (3mL) at room temperature was added DIPEA (165. mu.L, 0.94mmol) followed by vinyl sulfone (18. mu.L, 0.206 mmol). After 3 hours, the solvent was removed in vacuo and the residue was subjected to HPLC (Gemini C) 6A phenyl column, gradient from 10 to 60% over 20 min, yielding 188(63mg, 53%).1H NMR (ppm)(DMSO-d6): 8.42-8.39(1H, m), 8.23(1H, s), 8.19(1H, s), 7.80(1H, td, J ═ 8.77, 5.87Hz), 7.53(1H, ddd, J ═ 10.34, 8.85, 2.77Hz), 7.36(1H, d, J ═ 2.40Hz), 7.33-7.27(1H, m), 7.12(1H, dd, J ═ 8.59, 2.48Hz), 6.85(1H, dd, J ═ 8.55, 4.83Hz), 4.17(2H, t, J ═ 5.04Hz), 3.22-3.14(6H, m), 3.02(2H, t, J ═ 5.09), 2.98(3H, s), 2.02(2H, s), 2.72H, s) (1H, 4.72 Hz). 2 protons are masked by the water peak. LCMS (method F): RT 6.57 min, M + H+＝585。
Example 189: 2- (4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -piperidin-1-yl) -2-methyl-propan-1-ol 189
Reacting 2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-9- (piperidin-4-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulene hydrochloride(250mg, 0.52mmol) was dissolved in DMF (3mL) and treated with cesium carbonate (336mg, 1.03mmol) and methyl 2-bromo-2-methylpropionate (333 μ L, 2.58mmol) and then heated at 80 ℃ for 20 h. The cooled reaction mixture was diluted with EtOAc and washed with water and brine, dried (Na) 2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 20 to 70% EtOAc/cyclohexane) to give 2- (4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e]Azulen-9-yl } -piperidin-1-yl) -2-methyl-propionic acid methyl ester. Intermediate 2-methyl-propionic acid methyl ester (195mg, 0.355mmol) was dissolved in THF (5mL) and the solution was cooled to 0 ℃. Lithium aluminum hydride (0.533mL, 1M in THF) was added dropwise and the reaction mixture was stirred at 0 ℃ for 15 minutes, then at room temperature for 90 minutes. The reaction mixture was cooled to 0 ℃ and water was added, the mixture was extracted with EtOAc and the organic extract was washed with brine, dried (Na)2SO4) Filtered and then concentrated in vacuo. The residue obtained was subjected to reverse phase HPLC (Gemini C)6-phenyl column, gradient 30 to 60% methanol/water + 0.1% HCO2H) Yield 189 as a white solid (123mg, 70%).1H NMR (ppm)(DMSO-d6): 8.40(1H, s), 8.24(1H, s), 8.17(1H, s), 7.79(1H, td, J ═ 8.76, 5.90Hz), 7.64-7.57(1H, m), 7.34-7.28(1H, m), 7.18(1H, d, J ═ 2.29Hz), 7.03(1H, dd, J ═ 8.38, 2.33Hz), 6.84(1H, d, J ═ 8.33Hz), 4.16(2H, t, J ═ 5.02Hz), 3.35(2H, s), 3.14(3H, d, J ═ 11.68Hz), 3.00(2H, t, J ═ 5.05Hz), 2.38-2.23(3H, m), 1.63(2H, d, J ═ 11.68Hz), 1.00 (2H, t, J ═ 5.05Hz), 2.38-2.23(3H, m), 1.63(2H, 12H, J ═ 1.53, 1H, 39.53, 6H, s). LCMS (method F): RT 7.89 min, M + H +＝521。
Example 190: 1- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol 190
9-bromo-2- (1-isopropyl-4-methyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the same method as 182]Imidazo [1, 2-d ] s][1，4]OxazazepineSuzuki reaction with 2-methyl-1- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propan-2-ol gave 190. LS/MS (ESI +): m/z 448(M + H).1H NMR(400MHz，DMSO)8.36(d，J＝8.4，1H)，8.16(s，1H)，7.94(s，1H)，7.87(s，1H)，7.39(dd，J＝8.4，1.8，1H)，7.27(d，J＝1.7，1H)，5.90-5.70(m，1H)，4.72(s，1H)，4.51(s，4H)，4.04(s，2H)，2.25(s，3H)，1.47(d，J＝6.6，6H)，1.10(s，6H)。
Example 191: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (methylsulfonyl) ethyl) azetidin-3-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine191
65 was reacted with vinyl sulfone following the procedure used for 152 to give 191 as a white solid.1H NMR (ppm)(CDCl3): 8.44(1H, d, J ═ 8.28Hz), 7.84(1H, s), 7.60(1H, s), 7.05(1H, dd, J ═ 8.32, 1.83Hz), 6.94(1H, d, J ═ 1.78Hz), 5.99-5.89(1H, m), 4.48-4.39(4H, m), 3.78-3.70(2H, m), 3.71-3.62(1H, m), 3.25-3.18(2H, m), 3.04(3H, s), 3.02-2.95(4H, m), 1.56(6H, d, J ═ 6.64 Hz). LCMS (method F): RT 5.58 min, M + H +＝457。
Example 192: 2- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) azetidin-1-yl) acetamide 192
65 was reacted with bromoacetamide according to the procedure for 143. Flash chromatography (SiO) of the crude product2Gradient 0 to 10% MeOH/DCM) then triturated in ether to give 192 as a white solid.1H NMR(ppm)(CDCl3): 8.46(1H, d, J ═ 8.28Hz), 7.84(1H, s), 7.61(1H, s), 7.07(1H, dd, J ═ 8.32, 1.84Hz), 6.95(1H, d, J ═ 1.79Hz), 6.89(1H, s), 5.99-5.90(1H, m), 5.44(1H, s), 4.48-4.45(2H, m), 4.43-4.40(2H, m), 3.86-3.78(2H, m), 3.73-3.63(1H, m), 3.38-3.31(2H, m), 3.20(2H, s), 1.56(6H, d, J ═ 6.64 Hz). LCMS (method F): RT 5.45 min, M + H+＝408。
Example 193: (1-Aminocyclopropyl) (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) azetidin-1-yl) methanone 193
65 was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid according to the method for 127. The crude product was subjected to reverse phase HPLC (Gemini C)18Column, gradient 20 to 95% MeOH/H2O+0.1％HCO2H) To give 193 as a white solid. 1H NMR(ppm)(DMSO-d6): 8.36(1H, d, J ═ 8.28Hz), 8.09(1H, s), 7.88 to 7.86(2H, m), 7.14(1H, dd, J ═ 8.35, 1.82Hz), 7.01(1H, d, J ═ 1.78Hz), 5.88 to 5.80(1H, m), 4.50 to 4.44(4H, m), 3.83 to 3.71(2H, m), 1.44(6H, d, J ═ 6.60Hz), 1.05(2H, d, J ═ 4.13Hz), 0.67(2H, d, J ═ 4.01 Hz). No 2 exchangeable protons were observed. The 4 protons are masked by the water peak. LCMS (method F): RT 6.73 min, M + H+＝434。
Example 194: 9-bromo-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine194
43(4.93g, 16.0mmol) was taken up in 1, 1-dimethoxy-N, N-dimethylmethylamine (25mL, 0.18mol) and 1, 2-dimethoxyethane (66.5mL, 0.640 mol). The heterogeneous mixture was stirred very vigorously and heated at 65 ℃ for 1 hour. LC/MS then showed complete consumption of starting material. The reaction mixture was concentrated in vacuo and used for the subsequent reaction without further purification. The crude product from the previous reaction (5.8g, 16.0mmol) was suspended in glacial acetic acid (53.2mL) and isopropylhydrazine hydrochloride (4.36g, 39.4mmol) was added. The mixture was heated at 100 ℃ for 2 hours. The reaction vessel was cooled to room temperature and the solvent was removed in vacuo. The resulting residue was loaded onto silica gel in a dry process and purified by ISCO chromatography (120g column, 100% EtOAc). The two steps were combined and isolated to 2.3g (39% yield) 194. LC/MS (ESI +): m/z376(M + H, with halogen isotope). 1H NMR(400MHz，DMSO)8.34(d，J＝8.6，1H)，7.95(s，1H)，7.91(s，1H)，7.36(dd，J＝8.7，2.0，1H)，7.30(d，J＝2.0，1H)，5.85(dt，J＝13.3，6.6，1H)，4.55(d，J＝15.5，4H)，1.48(d，J＝6.6，6H)。
Alternatively to 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]To a suspension of azulene-2-carboxylic acid 1-dimethylamino-methyl- (Z) -ylideneamide (8.52g, 23.5mmol) in acetic acid (50mL) was added isopropylhydrazine hydrochloride (3.37g, 30.5mmol) and the reaction mixture was heated at 100 ℃ for 1 h. The reaction mixture was cooled to room temperature and poured into water (500mL), which precipitated the product as an off-white solid. The product was collected by filtration, washed with water (-200 mL) and dried under vacuum at 45 ℃ for 16 h to give 194 as an off-white solid (7.88g, 86%).1H NMR(400MHz，d6-DMSO)8.43(1H，d，J＝8.6Hz)，7.97(1H，s)，7.92(1H，d，J＝0.6Hz)，7.36(1H，dd，J＝8.6，20Hz), 7.30(1H, d, J ═ 2.0Hz), 5.86(1H, heptad, J ═ 6.6Hz), 4.56 to 4.52(4H, m), 1.48(6H, d, J ═ 6.6 Hz). LCMS: RT 4.69 min, M + H+＝374/376。1H NMR showed the product to contain 5% 8-iodo-2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]And (2) azulene.
Alternatively:
step 1: 4-bromo-2-fluoro-iminobenzoic acid ethyl ester hydrochloride
A suspension of 4-bromo-2-fluorobenzonitrile (25.0g, 125mmol) in IMS (88mL) was treated dropwise with acetyl chloride (71mL, 1mol) at 0-5 deg.C, maintaining the temperature below 10 deg.C. The reaction vessel was sealed and the mixture was stirred at room temperature for 18 hours, then concentrated in vacuo. The resulting residue was triturated in ether to give 4-bromo-2-fluoro-iminobenzoic acid ethyl ester hydrochloride as a white solid (20.3g, 57%). 1HNMR(ppm)(DMSO-d6)：7.93-7.88(1H，m)，7.85-7.76(1H，m)，7.72-7.64(1H，m)，4.60(2H，q，J＝7.02Hz)，1.47-1.38(3H，m)。
Step 2: 4-bromo-2-fluoro-benzamidine hydrochloride
A mixture of 4-bromo-2-fluoro-iminobenzoic acid ethyl ester hydrochloride (20.3g, 72mmol) in IMS (250mL) at 0-5 deg.C with NH3Saturated (gaseous) and the flask was sealed, then warmed to room temperature and stirred for 18 hours. The solvent was removed in vacuo and the residue was triturated in ether to give 4-bromo-2-fluoro-benzamidine hydrochloride as a white solid (18.1g, 100%).1H NMR (ppm)(DMSO-d6)：9.26(4H，s)，7.92-7.87(1H，m)，7.71-7.62(2H，m)。
And step 3: 1- (2-isopropyl-2H- [1, 2, 4] triazol-3-yl) -ethanone
1-isopropyl-1H- [1, 2, 4] at-10 ℃ for 45 minutes]To a solution of triazole (33g, 300mmol) in THF was added n-butyllithium (145mL, 2.5M, 360mmol) dropwise, and the mixture was stirred at 0 deg.C for 30 min. DMA (35mL) was added and the mixture was warmed to room temperatureWarm and stir for 1 hour. The resulting suspension was treated with saturated aqueous ammonium chloride (300 mL). The aqueous phase was extracted with EtOAc and the combined organic extracts were dried (Na)2SO4) Filtering and vacuum concentrating to obtain 1- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -ethanone as a light orange oil (40.1g, 87%).1H NMR (ppm)(CDCl3): 7.93(1H, s), 5.58-5.46(1H, m), 2.72(3H, d, J ═ 0.78Hz), 1.49(6H, dd, J ═ 6.61, 0.78 Hz). And 4, step 4: 2-bromo-1- (2-isopropyl-2H- [1, 2, 4) ]Triazol-3-yl) -ethanones
1- (2-isopropyl-2H- [1, 2, 4] over 20 minutes]To a solution of triazol-3-yl) -ethanone (10g, 65.3mmol) in acetic acid (1mL) and THF (100mL) was added a solution of PTT (phenyltrimethylammonium tribromide, 24.5g, 65.3mmol) in THF (100 mL). The reaction mixture was heated at 75 ℃ and then cooled to room temperature. The resulting mixture was concentrated in vacuo and the product was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was separated and dried (Na)2SO4) Filtered and concentrated in vacuo to give a residue which is subjected to flash chromatography (SiO)2Gradient 0 to 20% EtOAc/cyclohexane) to give 2-bromo-1- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -ethanone as an oil (5.4g, 36%).1H NMR(ppm)(CDCl3)：7.98(1H，s)，5.53-5.42(1H，m)，4.69(2H，s)，1.52(6H，d，J＝6.63Hz)。
And 5: 5- [2- (4-bromo-2-fluoro-phenyl) -1H-imidazol-4-yl ] -1-isopropyl-1H- [1, 2, 4] triazole
To a rapidly stirred mixture of 4-bromo-2-fluoro-benzamidine hydrochloride (9.84g, 38.8mmol), potassium bicarbonate (15.6g, 154.8mmol), THF (98mL) and water (16mL) was added 2-bromo-1- (2-isopropyl-2H- [1, 2, 4] under reflux over 15 minutes]Triazol-3-yl) -ethanone (9.0g, 38.8mmol) in THF (19 mL). The resulting mixture was stirred at reflux for 18 hours and then concentrated in vacuo. The resulting residue was treated with water and the solid formed was collected by filtration, washed (water, 1: 1 ether: cyclohexane and ether in this order) to give 5-, [2 ], [ 2- (4-bromo-2-fluoro-phenyl) -1H-imidazol-4-yl]-1-isopropyl-1H- [1, 2, 4]Triazole as a brown solid (10.1g, 74%).1H NMR (ppm)(CDCl3): 8.21-8.14(1H, m), 7.90(1H, s), 7.80(1H, s), 7.47-7.38(2H, m), 7.26(1H, s), 5.91(1H, broad singlet), 1.59(6H, d, J ═ 6.63 Hz).
5- [2- (4-bromo-2-fluoro-phenyl) -1H-imidazol-4-yl]-1-isopropyl-1H- [1, 2, 4]A solution of triazole (10.0g, 28.6mmol) in DMF (100mL) was treated with ethylene carbonate (5.3g, 60.1mmol) and cesium carbonate (13.9g, 42.5mmol) and then heated at 100 ℃ for 72 h. Additional cesium carbonate (9.0g, 27.5mmol) and water (0.5mL) were added and heating was continued for 24 hours, then the reaction mixture was concentrated in vacuo. The resulting residue was partitioned between DCM and water, the organic layer was separated, washed with water and brine, dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)21% MeOH/DCM) to give 194 as an off-white solid (5.78g, 58%).1H NMR(ppm)(CDCl3)：8.04(1H，s)，7.83(1H，s)，7.50-7.38(3H，m)，5.93-5.84(1H，m)，4.07-4.02(2H，m)，3.93-3.88(2H，m)，1.53-1.46(6H，m)。
Example 195: 1- (4- (2- (1-isopropyl-4-methyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol 195
9-bromo-2- (1-isopropyl-4-methyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f ] according to the procedure in example 182 ]Imidazo [1, 2-d ] s][1，4]OxazazepineCoupling with 2-methyl-1- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propan-2-ol gave 195. The yield thereof was found to be 22%.MS(ESI+)：447.1。1H NMR(400MHz，DMSO)8.34(d，J＝8.4，1H)，8.14(s，1H)，7.93(s，1H)，7.63(s，1H)，7.36(dd，J＝8.4，1.7，1H)，7.25(d，J＝1.7，1H)，7.00(d，J＝0.6，1H)，5.68-5.57(m，1H)，4.72(s，1H)，4.48(s，4H)，4.03(s，2H)，2.10(s，3H)，2.07(s，1H)，1.42(d，J＝6.7，6H)，1.09(s，6H)。
Example 196: 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropanamide 196
Prepared from 9-bromo-2- (1-isopropyl-4-methyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f using an analogous method to that described for preparation 215]Imidazo [1, 2-d ] s][1，4]OxazazepineTo prepare 196 as a white crystalline solid (72% overall yield). LS/MS (ESI +): m/z 461(M + H).1H NMR(400MHz，DMSO)8.40(s，1H)，8.36(d，J＝8.4，1H)，8.01(s，1H)，7.87(s，1H)，7.45(dd，J＝8.41.8，1H)，7.35(d，J＝1.7，1H)，7.17(s，1H)，6.81(s，1H)，5.82(dt，J＝13.3，6.6，1H)，4.52(s，4H)，2.25(s，3H)，1.74(s，6H)，1.47(d，J＝6.6，6H)。
Example 197: 2- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) azetidin-1-yl) -N, N-dimethylethanesulfonamide 197
65 with N, N-Dimethylethenesulfonamide following the procedure for 152197 was obtained as a white solid.1H NMR (ppm)(CDCl3): 8.44(1H, d, J ═ 8.28Hz), 7.84(1H, d, J ═ 0.67Hz), 7.61(1H, s), 7.05(1H, dd, J ═ 8.32, 1.83Hz), 6.95(1H, d, J ═ 1.78Hz), 6.00-5.90(1H, m), 4.48-4.39(4H, m), 3.80-3.72(2H, m), 3.72-3.64(1H, m), 3.27-3.19(2H, m), 3.02-2.89(4H, m), 2.87(6H, s), 1.56(6H, d, J ═ 6.63 Hz). LCMS (method F): RT ═ 6.35 min, M + H +＝486。
Example 198: 2- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) azetidin-1-yl) -N, N-dimethylacetamide 198
The crude product was flash chromatographed (SiO) by reacting 65 with 2-chloro-N, N-dimethylacetamide according to the method used for 1432Gradient 0 to 6% MeOH/DCM) to give 198 as a white solid.1H NMR (ppm)(CDCl3): 8.44(1H, d, J ═ 8.28Hz), 7.84(1H, d, J ═ 0.71Hz), 7.60(1H, s), 7.10(1H, dd, J ═ 8.33, 1.81Hz), 6.97(1H, d, J ═ 1.72Hz), 6.01-5.91(1H, m), 4.48-4.39(4H, m), 3.99-3.90(2H, m), 3.86-3.77(1H, m), 3.46-3.38(4H, m), 3.00(3H, s), 2.93(3H, s), 1.56(6H, d, J ═ 6.63 Hz). LCMS (method F): RT 5.87 min, M + H+＝436。
Example 199: 9- (4, 4-dimethyl-4, 5-dihydrooxazol-2-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine199
2-amino-2-methylpropan-1-ol (0.20g, 2.3mmol) in THF (2.2mL)NaH (60% in mineral oil, 0.0942g) was dissolved and added. The resulting mixture was stirred at room temperature for 1 hour. To this mixture was added 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1, 2-d ] s][1，4]OxazazepineA solution of methyl-9-carboxylate 184(0.40g, 1.1mmol) in THF/DMF (1: 1, 10 mL). The entire reaction mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with water and diluted with EtOAc. Extracting with MgSO 24Dried, filtered and concentrated. Dissolved in DCM (10mL, 200mmol) and cooled to 0 ℃ and treated dropwise with thionyl chloride (0.314mL, 4.30 mmol). After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 3 hours. Concentration in vacuo and purification by reverse phase HPLC gave 199(209mg, 48% yield). LC/MS (ESI +): m/z 393(M + H).1HNMR(400MHz，DMSO)8.47(d，J＝8.4，1H)，7.99(s，1H)，7.92(d，J＝3.5，1H)，7.59(dd，J＝8.4，1.6，1H)，7.45(d，J＝1.6，1H)，5.85(dt，J＝13.2，6.6，1H)，4.55(dd，J＝10.6，6.4，4H)，4.12(s，2H)，1.49(d，J＝6.6，6H)，1.30(s，6H)。
Example 200: n-isopropyl-2- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) azetidin-1-yl) acetamide 200
65 was reacted with 2-chloro-N-isopropylacetamide according to the procedure used for 143. The crude product was subjected to reverse phase HPLC (Gemini C)18Column, gradient 0 to 70% MeOH/H2O+0.1％HCO2H) To give 200 as a white solid.1H NMR (ppm)(CDCl3)：8.46(1H，d，J＝8.28Hz)，7.85(1H，s)，7.63(1H，s)，7.05(1H，dd，J＝8.32，1.82Hz)，6.94-6.92(1H，m)，6.00-5.90(1H，m)，4.49-4.40(4H，m)，4.12-4.02(1H, m), 3.88(2H, t, J ═ 7.51Hz), 3.82-3.71(1H, m), 3.41(2H, t, J ═ 7.23Hz), 3.23(2H, s), 1.56(6H, d, J ═ 6.63Hz), 1.16(6H, d, J ═ 6.57 Hz). No 1 exchangeable proton was observed. LCMS (method F): RT 6.8 min, M + H +＝450。
Example 201: 2- (3- {2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl } -azetidin-1-yl) -ethanol 201
63 was reacted with 2- (2-bromo-ethoxy) -tetrahydropyran according to the procedure for 142, and the crude product was subjected to reverse phase HPLC (Gemini C)18Column, gradient 10 to 90% MeOH/water + 0.1% HCO2H) To give 201 as a white solid.1H NMR(400MHz，DMSO-d6): 8.41(s, 1H); 8.28(s, 1H); 8.16(s, 1H); 7.80(td, J ═ 8.75, 5.92Hz, 1H); 7.62(ddd, J ═ 10.34, 9.02, 2.81Hz, 1H); 7.37-7.31(m, 1H); 7.28(d, J ═ 8.17Hz, 1H); 6.95(d, J ═ 1.73Hz, 1H); 6.89(dd, J ═ 8.25, 1.81Hz, 1H); 4.22(t, J ═ 5.03Hz, 2H); 3.69(t, J ═ 7.37Hz, 2H); 3.60(dt, J ═ 15.08, 7.40Hz, 1H); 3.39(t, J ═ 6.62Hz, 1H); 3.23(t, J ═ 7.74Hz, 2H); 3.14(s, 2H); 3.05(t, J ═ 5.14Hz, 2H); 2.61(t, J ═ 5.95Hz, 2H). LCMS (method F): RT 7.11 min, M + H+＝465。
Example 202: 1- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-imidazol-1-yl) -2-methylpropan-2-ol 202
To a microwave vial containing 194(402mg, 1.07mmol) was added potassium acetate (316mg, 3.22mmol) and DMSO (8mL, 100 mmol). The reaction mixture was thoroughly purged with nitrogen and dipioronate dipinacol ester (310 m) was addedg, 3.22mmol), then [1, 1' -bis (diphenylphosphino) ferrocene ] is added]Palladium (II) dichloride [ Complex with DCM (1: 1)](87.7mg, 0.107mmol) and the vial sealed. The vial was heated in an oil bath for 24 hours. LCMS showed complete conversion. Filter through celite (8/2 DCM/methanol) and concentrate in vacuo. Flash chromatography (0 to 5% methanol in DCM) was performed. Concentration in vacuo afforded 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(117mg, 26% yield).
2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(113mg, 0.268mmol), 54(88.14mg, 0.40mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (21.90mg, 0.027mmol), 1, 2-dimethoxyethane (3.0mL, 29mmol) and a solution of 1M cesium carbonate in water (0.54mL, 0.5mmol) were mixed in a microwave bottle and irradiated with microwaves at 140 ℃ for 15 minutes. LCMS showed reaction completion. Filtering with filter paper and silica gel filler. Concentrate in vacuo and purify by HPLC to give 202(13.7mg, 12% yield).
Alternatively, 224(300mg, 0.75mmol) and Cs were mixed under nitrogen2CO3(733mg, 2.25mmol) to a mixture in DMF (15mL) was added 2, 2-dimethyl-oxirane (2mL, 22.4 mmol). The reaction mixture was heated at 80 ℃ for 8 hours. Cool to room temperature, pour the resulting mixture into water and extract with EtOAc. The organics were dried over sodium sulfate and purified by preparative TLC (DCM/MeOH ═ 10: 1) to give 202 as a white solid (75.3mg, 23% yield).1HNMR(DMSO-d6，400MHz)：8.37(d，J＝8.4Hz，1H)，7.92(s，2H)，7.67(s，1H)，7.64(s 1H)，7.53(dd，J1＝1.6Hz，J2＝8.4Hz，1H)，7.42(d，J＝1.6Hz，1H)，5.94-5.88(m，1H)，4.79(s，1H)，4.54-4.50(m，4H)，3.89(s，2H)，1.49(d，J＝6.4Hz，6H)，1.09(s，6H)。MS(ESI，m/z)＝434[M+H]+。
Example 203: 3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) pyridin-2 (1H) -one 203
Reacting 10-bromo-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine187(0.057g, 0.15mmol), 2-fluoropyridin-3-ylboronic acid (0.026g, 0.183mmol), potassium acetate (0.059g, 0.609mmol), Pd (PPh)3)4(8.8mg, 0.007mmol), DMF (6mL) and water (0.6mL) were combined. Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was stirred and heated at 105 ℃ for 24 hours, then cooled, diluted with EtOAc and filtered over a celite plug. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The solution was washed with water followed by brine and then MgSO 4Dried and concentrated under reduced pressure. The crude product was dissolved in DMF and purified by reverse phase HPLC to give 10- (2-fluoropyridin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(47mg，80％)。MS(ESI(+))：m/z 391.1(M+H)。
To 10- (2-fluoropyridin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(0.047g, 0.12mmol) in DME (2mL) was added 10% aqueous HCl (2 mL). The reaction mixture was stirred and heated at 80 ℃ for 18 hours, then cooled and concentrated under reduced pressure. The crude product was dissolved in DMF and purified by reverse phase HPLC to give 203(25mg, 55%).1H NMR(400MHz，DMSO)11.82(s，1H)，8.88(d，J＝2.3，1H)，7.92(d，J＝6.7，2H)，7.67(ddd，J＝9.0，7.7，2.2，2H)，7.38(d，J＝4.8，1H)，7.07(d，J＝8.6，1H)，6.31(t，J＝6.7，1H)，5.81(dt，J＝13.2，6.6，1H)，4.54(q，J＝5.8，4H)，1.48(d，J＝6.6，6H)。MS(ESI(+))：m/z 389.1(M+H)。
Example 204: 9- (1- (2- (3-fluoroazetidin-1-yl) ethylsulfonyl) azetidin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine204
65(200mg, 0.517mmol) was stirred in DCM (2mL) containing TEA (145. mu.L, 1.04mmol) for 1h, then 2-chloroethanesulfonyl chloride (84mg, 0.52mmol) was added. After stirring for 1 hour, more TEA (73. mu.L, 0.52mmol) was added and the mixture was stirred for 18 hours, then diluted with DCM and washed with water and brine. The resulting solution was concentrated in vacuo to give a brown oil, which was used in the next step without purification. A portion of the brown oil (81mg, 0.18mmol) was stirred in 3mL IMS with 3-fluoro-azetidine hydrochloride (22mg, 0.22mmol) and TEA (56 μ L, 0.4mmol) at room temperature for 18 h, then concentrated in vacuo. The resulting residue was dissolved in DCM and the solution washed with water and brine, dried (Na) 2SO4) Filtered and concentrated in vacuo. Flash chromatography (SiO) of the resulting light brown oil2Gradient 0 to 2% MeOH/DCM) to give 204 as a white solid (37mg, 40%).1H NMR (ppm)(CDCl3)：8.49(1H，d，J＝8.30Hz)，7.84(1H，d，J＝0.64Hz)，7.62(1H，s)，7.12(1HDd, J ═ 8.34, 1.88Hz), 7.00(1H, d, J ═ 1.83Hz), 5.99-5.91(1H, m), 5.19-5.13(0.5H, m), 5.05-4.99(0.5H, m), 4.49-4.46(2H, m), 4.45-4.41(2H, m), 4.26(2H, t, J ═ 8.24Hz), 4.06(2H, t, J ═ 7.28Hz), 3.80-3.63(3H, m), 3.27-3.22(1H, m), 3.21-3.16(1H, m), 3.06-3.00(2H, m), 2.97-2.90(2H, m), 1.60-1.54(6H, m). LCMS: RT 2.94 min, M + H+＝516。
Example 205: 2- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) azetidin-1-yl) -2-methylpropanamide 205
A suspension of 65(0.23g, 0.6mmol) in water (2.5mL) was treated with sodium cyanide (49.5mg, 0.6mmol) followed by a solution of acetone (60mg, 0.91mmol) in water (0.25mL) and the mixture was stirred at room temperature for 18 h. The mixture was extracted four times with DCM and the combined extracts were dried (Na)2SO4) Filtered and concentrated in vacuo to give 2- {3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]Azulen-8-yl]-azetidin-1-yl } -2-methyl-propionitrile (0.19g, 76%). LCMS: RT 3.76 min, M + H+＝418。
2- {3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Azetidin-1-yl } -2-methyl-propionitrile (0.17g, 0.41mmol) in concentrated H2SO4(2mL) and the mixture was left to stand at room temperature for 3.25 hours, then added to ice. The obtained solution was treated with Na2CO3Basified, water added and the mixture extracted with 10% MeOH in DCM. The combined extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 10% MeOH/DCM) to give 205 as a white solid (97 mg)，54％)。1H NMR(ppm)(CDCl3): 8.46(1H, d, J ═ 8.29Hz), 7.84(1H, s), 7.61(1H, s), 7.13(1H, s), 7.08(1H, d, J ═ 8.39Hz), 6.95(1H, s), 6.01-5.91(1H, m), 5.27(1H, s), 4.50-4.40(4H, m), 3.62(3H, s), 3.33(2H, s), 1.56(6H, d, J ═ 6.63Hz), 1.23(6H, s). LCMS: RT 2.53 min, M + H+＝436。
Example 206: 2- (4- (2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol 206
9-bromo-2-iodo-5, 6-dihydrobenzo [ f ] according to the procedure used for 184]Imidazo [1, 2-d ] s][1，4]OxazazepineReacting with 1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazole to obtain 9-bromo-2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(0.109g，10％)。1H NMR(400MHz，DMSO)8.28(t，J＝21.9，1H)，8.11(t，J＝7.9，2H)，7.51-7.35(m，1H)，7.32(d，J＝2.0，1H)，5.88(q，J＝8.8，2H)，4.76-4.29(m，4H)。MS(ESI(+))：m/z 413.9(M+H)。
9-bromo-2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the procedure used for 182]Imidazo [1, 2-d ] s][1，4]OxazazepineAnd 1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1HPyrazole reaction to give 206(0.056g, 48%).1H NMR(400MHz，DMSO)8.33(d，J＝8.4，1H)，8.24(s，1H)，8.07(d，J＝11.7，2H)，7.95(d，J＝8.9，1H)，7.41(dd，J＝8.4，1.7，1H)，7.28(d，J＝1.7，1H)，5.91(q，J＝8.8，2H)，4.91(t，J＝5.3，1H)，4.54(dd，J＝10.8，5.6，4H)，4.16(t，J＝5.6，2H)，3.87-3.69(m，2H)。MS(ESI(+))：m/z 446.1(M+H)。
Example 207: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-imidazol-1-yl) ethanol 207
Pd (PPh)3)4(84.0mg 0.0727mmol) was added to a degassed solution of 194(272mg, 0.727mmol) and the regioisomers 53a and 53b (600mg, 1mmol) in acetonitrile (5mL, 100 mmol). The reaction mixture was heated in CEM microwaves at 140 ℃ for 30 minutes, where LCMS showed complete conversion. Concentrate in vacuo and purify by flash chromatography (0 to 100% methanol in DCM). The product tube was concentrated in vacuo to give 270mg of the regioisomer 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-imidazol-4-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1, 2-d ] s][1，4]OxazazepineAnd 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-imidazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineThese inseparable compounds were dissolved in a solution of 4N HCl in dioxane (10mL) and the solution was stirred at room temperature for 30 minutes. LCMS confirmed complete deprotection to give the final compound, which was purified by SFC to isolate regioisomer 207 (15)9.8mg, 54% yield, 406.1 for M + 1).
Alternatively, 224(300mg, 0.75mmol) and Cs were mixed under nitrogen2CO3(733mg, 2.25mmol) to a mixture in DMF (15mL) was added 2- (2-bromo-ethoxy) -tetrahydropyran (0.68mL, 4.52 mmol). The reaction mixture was heated at 80 ℃ for 5 hours. Cool to room temperature, pour the resulting mixture into water and extract with EtOAc. The organics were dried over sodium sulfate and purified by preparative TLC (DCM/MeOH ═ 10: 1) to give 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-imidazol-4-yl) -5, 6-dihydrobenzo [ f ═ f]Imidazo [1, 2-d ] s][1，4]OxazazepineIt was a yellow oil (250mg, 68% yield). LCMS (ESI, M/z) ═ 490[ M + H [ ] ]+。
To 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-imidazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(250mg, 0.51mmol) in EtOH (15mL) was added a solution of hydrogen chloride in dioxane (1.28mL, 5.1 mmol). The mixture was refluxed for 2 hours, cooled to room temperature and concentrated. The resulting precipitate was washed with EtOAc to give 207 as a yellow solid (115.2mg, 56% yield).1H NMR (methane-d)4，400MHz)：9.12(d，J＝1.2Hz，1H)，8.78(s，1H)，8.65(d，J＝8.4Hz，1H)，8.28(s，1H)，8.17(d，J＝1.2Hz，1H)，7.58-7.53(m，2H)，5.85-5.78(m，1H)，4.71-4.63(m，4H)，4.41(t，J＝5.2Hz，2H)，3.96(t，J＝5.2Hz，2H)，1.66(d，J＝6.8Hz，6H)。MS(ESI，m/z)＝406[M+H]+。
Example 208: 2- (5- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-imidazol-1-yl) ethanol 208
Pd (PPh)3)4(84.0mg 0.0727mmol) was added to a degassed solution of 194(272mg, 0.727mmol) and the regioisomers 53a and 53b (600mg, 1mmol) in acetonitrile (5mL, 100 mmol). The reaction mixture was heated in CEM microwaves at 140 ℃ for 30 minutes, where LCMS showed complete conversion. Concentrate in vacuo and purify by flash chromatography (0 to 100% methanol in DCM). The product tube was concentrated in vacuo to give 270mg of the regioisomer 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-imidazol-4-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1, 2-d ] s][1，4]OxazazepineAnd 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-imidazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineThese inseparable compounds were dissolved in a solution of 4N HCl in dioxane (10mL) and the solution was stirred at room temperature for 30 minutes. LCMS confirmed complete deprotection to give the final compound, which was purified by SFC, isolating the regioisomer 208(27mg, 9% yield, 406.1 for M + 1).
Example 209: 2- (1- (2-morpholinoethyl) -1H-imidazol-2-yl) -10- (1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine209
35 alkylation with 4- (2-chloroethyl) morpholine to give 9-bromo-2- [1- (2-morpholinoethyl) -1H-imidazol-2-yl]-5, 6-dihydrobenzo [ f]Imidazo[1，2-d][1，4]Oxazazepine(yield 51%, MS: 444.2) which was coupled under Suzuki palladium coupling conditions with tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate to give 209. The yield thereof was found to be 24%. MS: 432.1.1H NMR(400MHz，DMSO)12.95(s，1H)，8.56(d，J＝2.3，1H)，8.09(s，1H)，7.87(s，1H)，7.72(s，1H)，7.51(dd，J＝8.4，2.3，1H)，7.21(d，J＝1.0，1H)，7.04(d，J＝8.4，1H)，6.89(d，J＝1.0，1H)，4.72(t，J＝7.1，2H)，4.50(q，J＝5.6，4H)，3.48-3.40(m，4H)，2.73(t，J＝7.1，2H)，2.46-2.36(m，4H)。
example 210: 2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2-morpholinoethyl) -1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1, 2-d ] s][1，4]Oxazazepine210
In analogy to the procedure described in general procedure C, 48 was reacted with 4- (2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethyl) morpholine. The crude reaction mixture was purified by reverse phase HPLC to afford 210. LCMS: 489.2.
example 211: 2- (4- (2- (3-amino-1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol 211
Adding 5- (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] to a microwave bottle]Azulen-2-yl) -1-isopropyl-1H- [1, 2, 4]Triazol-3-ylamine (0.180g, 0.000)462mol) and potassium carbonate (0.1917g, 0.001387mol) in acetonitrile (2.0mL, 0.038mol) and water (2.0mL, 0.11 mol). The reaction mixture was degassed thoroughly and purged with nitrogen for 5 minutes. Adding Pd (PPh)3)4(0.05344g, 0.00004624mol) and acetic acid 2- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxaborolan-2-yl) -pyrazol-1-yl]Ethyl ester (0.1554g, 0.0005549mol) and the vial was immediately sealed. The reaction mixture was heated to 140 ℃ in a microwave and held for 20 minutes. The mixture was diluted with DCM and filtered over celite. Adding saturated NH 4Cl and the mixture was extracted three times with DCM. The organic layers were combined and MgSO4Dried and concentrated. The crude product was purified by reverse phase HPLC to give 211(34.6mg) as a colourless solid. MS (ESI +) 421.1.1H NMR(400MHz，DMSO)8.35(d，J＝8.4，1H)，8.22(s，1H)，7.95(s，1H)，7.73(s，1H)，7.38(dd，J＝8.4，1.8，1H)，7.27(d，J＝1.7，1H)，5.84-5.69(m，1H)，5.19(s，2H)，4.93(t，J＝5.3，1H)，4.50(s，4H)，4.16(t，J＝5.6，2H)，3.77(q，J＝5.6，2H)，1.42(d，J＝6.6，6H)。
Example 212: 2- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) azetidin-1-yl) -N-methylacetamide 212
A solution of 65(70mg, 0.2mmol) in NMP (2mL) was treated with sodium phosphate (85mg, 0.6mmol) followed by a solution of N-methyl-2-chloroacetamide (24mg, 0.22mmol) in NMP (0.2mL) and the mixture was stirred at room temperature for 18 h. Loading the mixture into IsoluteSCX-2 column (MeOH followed by 2M NH)3MeOH elution). The appropriate fractions were combined and concentrated in vacuo and the residue obtained was subjected to flash chromatography (SiO)2Gradient 0 to 10% MeOH/DCM) to give 212(24 m)g，29％)。1HNMR (ppm)(CDCl3): 8.50(1H, d, J ═ 8.29Hz), 7.89(1H, s), 7.68(1H, s), 7.22(1H, s), 7.10(1H, dd, J ═ 8.33, 1.81Hz), 6.99-6.96(1H, m), 6.03-5.94(1H, m), 4.53-4.49(2H, m), 4.48-4.44(2H, m), 3.96(2H, t, J ═ 7.77Hz), 3.81(1H, t, J ═ 7.74Hz), 3.54(2H, t, J ═ 7.43Hz), 3.35(2H, s), 2.86(3H, d, J ═ 4.93Hz), 1.60(6H, d, J ═ 6.63 ═ 6H, 63). LCMS: RT 2.53 min, M + H +＝422。
Example 213: 1- (4- (2- (3-amino-1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol 213
Adding 5- (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] to a microwave bottle]Azulen-2-yl) -1-isopropyl-1H- [1, 2, 4]Solution of triazol-3-ylamine (0.180g, 0.000462mol) and potassium acetate (0.1362g, 0.001387mol) in acetonitrile (2.0mL, 0.038mol) and water (2.0mL, 0.11 mol). The reaction mixture was degassed thoroughly and purged with nitrogen for 5 minutes. Adding Pd (PPh)3)4(0.05344g, 0.00004624mol) and 2-methyl-1- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxaborolan-2-yl) -pyrazol-1-yl]Propan-2-ol (0.1477g, 0.0005549mol) and the vial was immediately sealed. The reaction mixture was heated to 140 ℃ in a microwave and held for 20 minutes. The mixture was diluted with DCM and filtered over celite. Adding saturated NH4Cl and the mixture was extracted three times with DCM. The organic layers were combined and MgSO4Dried and concentrated. The crude product was purified by reverse phase HPLC to give 213(68.2mg) as a colourless solid. MS (ESI +) 449.2.1H NMR(400MHz，DMSO)8.35(d，J＝8.4，1H)，8.16(s，1H)，7.95(s，1H)，7.73(s，1H)，7.38(dd，J＝8.4，1.7，1H)，7.27(d，J＝1.7，1H)，5.82-5.68(m，1H)，5.19(s，2H)，4.74(s，1H)，4.50(br，4H)，4.04(s，2H)，1.42(d，J＝6.6，6H)，1.09(s，6H)。
Example 214: 1- (4- (2- (1-isopropyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol 214
36(157mg, 0.421mmol), 2-methyl-1- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propan-2-ol (139.9mg, 0.5258mmol) and Pd (PPh)3)4(68.05mg, 0.05889mmol) was dissolved in acetonitrile (2.66mL, 50.9mmol) and a 2.00M solution of potassium carbonate in water (0.421mL) was added. The reaction mixture is degassed. The reaction mixture was irradiated with microwaves at 150 watts for 10 minutes at 140 ℃. The reaction mixture was cooled to rt and extracted with EtOAc to give the crude product, which was purified by rphplc to give 214. MS (ESI +) ═ 433.2.1HNMR(400MHz，DMSO)8.36(d，J＝8.4Hz，1H)，8.15(s，1H)，7.94(s，1H)，7.68(s，1H)，7.42-7.31(m，2H)，7.26(d，J＝1.7Hz，1H)，6.94(s，1H)，5.66(dt，J＝13.5，6.7Hz，1H)，4.74(s，1H)，4.50(s，4H)，4.03(s，2H)，1.46(d，J＝6.7Hz，6H)，1.09(s，6H)。
Example 215: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropanamide 215
194 was reacted with 2-methyl-2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propionamide in the same manner as 182. To obtain an intermediate ester 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropanoic acid methyl ester (and corresponding acid) (62% yield). LS/MS (ESI +): m/z388(M + H).
A mixture containing the above ester and the corresponding acid (100mg, 0.22mmol) was treated with a solution of 1M lithium hydroxide in water (2mL) and methanol (0.37 mL). The reaction mixture was stirred at room temperature for 12 hours. Acidified to pH 5 with 10% aqueous citric acid and extracted twice with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The resulting carboxylic acid was used without further purification.1H NMR(400MHz，DMSO)8.44(s，1H)，8.39(s，0H)，8.37(s，1H)，7.98(s，1H)，7.92(s，2H)，7.45(dd，J＝8.4，1.8，1H)，7.36(d，J＝1.7，1H)，5.90(dt，J＝13.2，6.6，1H)，4.53(q，J＝6.0，4H)，1.72(d，J＝42.8，6H)，1.50(d，J＝6.6，6H)。
The carboxylic acid product from the above transformation (100mg, 0.22mmol) was dissolved in DMF (1mL) and treated with N, N-diisopropylethylamine (0.3mL, 2.0mmol), ammonium chloride (50mg, 0.9mmol) and N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (200mg, 0.6mmol) sequentially. The resulting mixture was stirred at room temperature overnight. Saturated sodium bicarbonate was added and the mixture was extracted with EtOAc. The combined organics were dried over sodium sulfate and concentrated. Purification by RP-HPLC afforded 53mg (54% yield) 215. LC/MS (ESI +): m/z 447(M + H).1H NMR (400MHz, DMSO)8.41(s, 1H), 8.39(s, 0H), 8.37(s, 1H), 8.02(s, 1H), 7.46(dd, J ═ 8.4, 1.7, 1H), 7.35(t, J ═ 7.2, 1H), 7.20(s, 1H), 6.85(s, 1H), 5.90 (heptad, J ═ 6.6, 1H), 4.53(q, J ═ 5.9, 4H), 1.74(s, 6H), 1.50(d, J ═ 6.6, 6H).
Example 216: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropionic acid 216
Reacting 194 with ethyl 2-methyl-2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propionate in Suchu Palladium conditions (Pd (dppf) Cl2，Cs2CO3) Then reacting to obtain 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazole-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropionic acid ethyl ester. LC/MS (ESI +): m/z 476(M + H). 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]OxazazepineTreatment of ethyl-9-yl) -1H-pyrazol-1-yl) -2-methylpropionate with a solution of lithium hydroxide in water gave 216. LC/MS (ESI +): m/z 448(M + H).1H NMR(400MHz，DMSO)8.44(s，1H)，8.38(d，J＝8.4，1H)，7.98(s，1H)，7.92(s，2H)，7.45(dd，J＝8.4，1.8，1H)，7.36(d，J＝1.7，1H)，5.90(dt，J＝13.2，6.6，1H)，4.53(q，J＝6.0，4H)，1.77(s，6H)，1.50(d，J＝6.6，6H)。
Example 217: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine217
194 was reacted with 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in the same manner as 182 to give 217 (78% yield). LS/MS (ESI +): m/z 362(M + H). 1H NMR(400MHz，DMSO)13.02(s，1H)，8.37(d，J＝8.4，1H)，8.29(s，1H)，8.00(s，1H)，7.54-7.38(m，1H)，7.30(t，J＝12.5，1H)，5.91(dt，J＝13.2，6.6，1H)，4.57-4.46(m，4H)，1.50(d，J＝6.6，6H)。
Example 218: 3- (2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) pyridin-2 (1H) -one 218
Step 1: reacting 10-bromo-2-iodo-5, 6-dihydrobenzo [ f ] according to the procedure used for 187]Imidazo [1, 2-d ] s][1，4]OxazazepineWith trifluoroethyltriazole (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazole). The crude mixture was purified by silica gel column chromatography (eluted with EtOAc), then concentrated under reduced pressure, dissolved in DMF and purified by reverse phase HPLC to give 10-bromo-2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(0.027g，2％)。1HNMR(400MHz，DMSO)8.48(d，J＝2.6，1H)，8.10(d，J＝5.5，2H)，7.49(dd，J＝8.7，2.6，1H)，7.04(t，J＝7.5，1H)，5.86(q，J＝8.8，2H)，4.54(dt，J＝7.4，3.7，4H)。MS(ESI(+))：m/z 413.9(M+H)。
Step 2: 10-bromo-2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted according to the method used for 203]Imidazo [1, 2-d ] s][1，4]OxazazepineReacting with 2-fluoropyridin-3-ylboronic acid to give 10- (2-fluoropyridin-3-yl) -2- (1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(0.108g，55％)。1H NMR (400MHz, DMSO)8.71(t, J ═ 2.0, 1H), 8.57-7.83(m, 4H), 7.80-7.39(m, 2H), 7.22(d, J ═ 8.5, 1H), 5.88(q, J ═ 8.8, 2H), 4.79-4.38(m, 4H). MS (ESI (+): m/z 431.1(M + H). It was hydrolyzed with HCl to give 218(0.072g, 72%). 1H NMR(400MHz，DMSO)11.85(s，1H)，8.78(d，J＝2.3，1H)，8.09(d，J＝2.8，2H)，7.69(ddd，J＝8.9，7.7，2.2，2H)，7.36(t，J＝23.8，1H)，7.08(d，J＝8.6，1H)，6.30(t，J＝6.7，1H)，5.91(q，J＝8.8，2H)，4.56(dd，J＝13.5，5.5，4H)。MS(ESI(+))：m/z 429.1(M+H)。
Example 219: 5- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyridin-2-amine 219
Reaction of 194 with 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine followed the same way as 182 gave 219 (62% yield). LS/MS (ESI +): m/z 388(M + H).1H NMR(400MHz，DMSO)8.42(d，J＝8.4，1H)，8.33(d，J＝2.4，1H)，7.93(d，J＝6.5，2H)，7.77(dd，J＝8.7，2.5，1H)，7.41(dd，J＝8.5，1.9，1H)，7.26(d，J＝1.8，1H)，6.53(d，J＝8.6，1H)，6.16(s，2H)，5.92(dt，J＝13.2，6.6，1H)，4.60-4.44(m，4H)，1.50(d，J＝6.6，6H)。
Example 220: 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-imidazol-1-yl) ethanol 220
1- [2- (tetrahydropyran-2-yloxy) -ethyl]-4-Tributylstannyl-1H-imidazole (0.690g, 0.00142mol) was added to a solution of 48(0.293g, 0.000755mol) in acetonitrile (4.5mL, 0.086 mol). The mixture was degassed thoroughly with nitrogen and Pd (PPh) was added3)4(0.0872g, 0.0000755 mol). The vial was sealed and heated to 140 ℃ in a microwave and held for 30 minutes. DCM and water were added and the mixture was filtered over celite. The aqueous phase was extracted three times with DCM. The organic phases were combined and MgSO4Dried and concentrated.
The crude product was redissolved in DCM (8.0mL, 0.12 mol). Hydrogen chloride (4N in dioxane, 0.47mL, 0.00189mol) was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. DCM and saturated sodium carbonate were added, which precipitated the product in the aqueous phase. The aqueous phase was filtered and the solid was purified by reverse phase HPLC to give 220(42mg) as a colourless solid. MS (ESI +) 420.2.
Example 221: 2- (2- (9- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1H-imidazol-1-yl) -N-methylacetamide 221
Reacting 2- (2- (9-bromo-5, 6-dihydrobenzo [ f ] according to the procedure used for 214]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1H-imidazol-1-yl) -N-methylacetamide was reacted with 2-methyl-1- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propan-2-ol under suzuki conditions to give 221. MS (ESI +) ═ 462.2.1H NMR(400MHz，DMSO)8.38(d，J＝8.4Hz，1H)，8.18(s，1H)，8.06-7.99(m，1H)，7.96(s，1H)，7.69(s，1H)，7.33(dd，J＝8.4，1.8Hz，1H)，7.26(d，J＝1.7Hz，1H)，7.11(d，J＝1.1Hz，1H)，6.90(d，J＝1.1Hz，1H)，5.18(s，2H)，4.76(s，1H)，4.49(s，4H)，4.04(s，2H)，2.65(d，J＝4.6Hz，3H)，1.10(s，6H)。
Example 222: n, N-diethyl-2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethylamine 222
To a 5mL microwave vial were added 194(347mg, 0.928mmol), 55(340mg, 1.16mmol), a 2M solution of potassium carbonate in water (0.9mL, 2mmol) and acetonitrile (1.52g, 37.1mmol) and 1, 1-bis (diphenylphosphino) ferrocene dichloropalladium (II) (45.4mg, 0.056mmol), then the vial was sealed. The reaction mixture was irradiated with microwaves at 140 ℃ for 10 minutes. The cooled reaction mixture was diluted with EtOAc and water and partitioned. The organic layer was washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by HPLC to give 222(140mg, 33% yield, M +1 of 461.6).
Example 223: 5- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyrimidin-2-amine 223
Reaction of 194 with 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-amine according to the same method as 182 gave 223 (73% yield). LS/MS (ESI +): m/z 389(M + H).1HNMR (400MHz, DMSO)8.66(s, 1H), 8.45(d, J ═ 8.4, 1H), 7.93(d, J ═ 9.7, 2H), 7.46(dd, J ═ 8.5, 1.9, 1H), 7.35(d, J ═ 1.8, 1H), 6.86(s, 1H), 5.91 (septematic peak, J ═ 6.4, 1H), 4.61-4.44(m, 4H), 1.50(d, J ═ 8＝6.6，6H)。
Example 224: 9- (1H-imidazol-5-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine224
To a solution of 242(120mg, 0.27mmol) in dioxane (4mL) was added a solution of hydrogen chloride in dioxane (0.34mL, 1.35 mmol). The whole was heated at 60 ℃ for 2 hours, cooled to room temperature and concentrated. To the mixture was added saturated sodium bicarbonate and extracted with EtOAc. The organics were dried over sodium sulfate and the concentrated residue was purified by preparative TLC (DCM/MeOH ═ 8: 1) to give 224 as a yellow solid (36mg, 37% yield). 1H NMR(DMSO-d6400 MHz): 12.29(s, 1H), 8.37(d, J ═ 8.4Hz, 1H), 7.91(s, 2H), 7.75(s, 1H), 7.69(s, 1H), 7.55(d, J ═ 8.0Hz, 1H), 7.45(s, 1H), 5.94-5.88(m, 1H), 4.53 (broad singlet, 4H), 1.49(d, J ═ 6.4Hz, 6H). MS (ESI, M/z) ═ 362[ M + H ]]+。
Example 225: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine225
Reaction of 66 with vinyl sulfone following the procedure used for 152 gave 225 as a white solid.1H NMR (ppm)(DMSO-d6)：8.27(1H，d，J＝8.29Hz)，7.86-7.84(2H，m)，7.00(1H，dd，J＝8.37，1.76Hz)，6.85(1H，d，J＝1.70Hz)，5.88-5.78(1H，m)，4.44(4H，q，J＝5.99Hz)，3.26(3H，m)，3.00(3H，s)，2.95(2H，d，J＝11.00Hz)，2.68(2H，t，J＝6.79Hz)，2.02(2H，t，J＝11.39Hz)，1.72(2H，d, J-12.62 Hz), 1.57(2H, qd, J-12.27, 3.58Hz), 1.42(6H, d, J-6.60 Hz). LCMS: RT 2.68 min, M + H+＝485。
Example 226: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) acetamide 226
Reaction of 66 with 2-bromoacetamide following the procedure used for 143 gave 226 as a white solid.1H NMR (ppm)(DMSO-d6): 8.27(1H, d, J ═ 8.27Hz), 7.84(2H, d, J ═ 2.70Hz), 7.15(1H, s), 7.06(1H, s), 7.01(1H, d, J ═ 8.43Hz), 6.87(1H, s), 5.87-5.78(1H, m), 4.44(4H, d, J ═ 6.92Hz), 2.90-2.78(4H, m), 2.15-2.06(2H, m), 1.68(5H, s), 1.42(6H, d, J ═ 6.59 Hz). LCMS (method F): RT 2.57 min, M + H +＝436。
Example 227: 2-hydroxy-1- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropan-1-one 227
A solution of 66(350mg, 0.71mmol), 2-hydroxyisobutyric acid (111mg, 1.07mmol), EDCI (327mg, 1.7mmol), HOBt (230mg, 1.7mmol) and DIPEA (0.36mL, 2.13mmol) was stirred at room temperature for 5 hours, then saturated aqueous sodium bicarbonate was added. The resulting mixture was extracted with DCM (2 × 30mL), and the combined extracts were washed with brine and then dried (MgSO)4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 5% MeOH/DCM) then freeze dried to give 227 as a white solid (141mg, 43%).1H NMR (ppm)(DMSO-d6): 8.31(1H, d, J ═ 8.29Hz), 7.82(1H, s), 7.78(1H, s), 7.03(1H, d, J ═ 8.38Hz), 6.90(1H, s), 5.85-5.77(1H, m), 4.69(2H, d, J ═ 13.25Hz), 4.48(4H, t, J ═ 7.99Hz), 2.91-2.74(4H, m), 1.85(2H, d, J ═ 13.04Hz), 1.63-1.49(2H, m), 1.49(6H, d, J ═ 6.64Hz), 1.37(6H, s). LCMS: RT 3.92 min, M + H+＝465。
Example 228: (2S) -2-hydroxy-1- (3- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) azetidin-1-yl) propan-1-one 228
Reaction of 48 with 3- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -pyrazol-1-yl ] -azetidine-1-carboxylic acid tert-butyl ester under suzuki conditions catalysed by palladium gave 3- {4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulen-8-yl ] -pyrazol-1-yl } -azetidine-1-carboxylic acid tert-butyl ester. MS (ESI +) 531.2.
Reacting 3- {4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulen-8-yl ] -pyrazol-1-yl } -azetidine-1-carboxylic acid tert-butyl ester with an acid to give 8- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -2- (2-isopropyl-5-methyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene. MS (ESI +) 431.2.
Reacting 8- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -2- (2-isopropyl-5-methyl-2H- [1, 2, 4-]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Coupling of azulene with DIPEA, HATU and L-lactic acid gave 228. MS (ESI +) 503.2. 1H NMR(400MHz，DMSO)8.45(d，J＝1.7，1H)，8.37(d，J＝8.4，1H)，8.12(s，1H)，7.89(s，1H)，7.42(dd，J＝8.4，1.7，1H)，7.32(d，J＝1.7，1H)，5.92-5.74(m，1H)，5.34-5.25(m，1H)，5.21(t，J＝5.5，1H)，4.84-4.66(m，1H)，4.60-4.53(m，1H)，4.52(s，4H)，4.40-4.31(m，1H)，4.26-4.09(m，2H)，2.25(s，3H)，1.47(d，J＝6.6，6H)，1.22(d，J＝6.7，3H)。
Example 229: 2- (4- (2- (3-amino-1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-imidazol-1-yl) ethanol 229
After reaction of 5- (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulen-2-yl) -1-isopropyl-1H- [1, 2, 4] triazol-3-ylamine with 53a, removal of THP with aqueous HCl and purification by reverse phase HPLC, 229(49mg) was obtained. LCMS: 421.2.
example 230: 2- (3- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) azetidin-1-yl) ethanol 230
To 8- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]To a solution of azulene in DCM was added (tert-butyl-dimethyl-silyloxy) -acetaldehyde and acetic acid followed by sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for about 5 hours and quenched with 1N NaOH. DCM was added and the mixture was extracted three times with DCM. The organic phases were combined and MgSO4Dried and concentrated. The mixture was purified by flash chromatography (0-10% MeOH/DCM) to afford 8- (1- {1- [2- (tert-butyl-dimethyl-silyl) Oxy) -ethyl]-azetidin-3-yl } -1H-pyrazol-4-yl) -2- (2-isopropyl-5-methyl-2H- [1, 2, 4]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene, MS (ESI +)589.3, which was treated with acid to give 230.1H NMR (400MHz, DMSO)8.45(s, 1H), 8.36(d, J ═ 8.4, 1H), 8.03(s, 1H), 7.88(s, 1H), 7.41(d, J ═ 8.3, 1H), 7.32(d, J ═ 1.6, 1H), 5.90-5.78(m, 1H), 4.97 (quintuple, J ═ 6.9, 1H), 4.52(s, 4H), 4.47(t, J ═ 5.4, 1H), 3.73(t, J ═ 7.6, 2H), 3.47-3.37(m, 4H), 2.58(t, J ═ 7.7, 2H), 2.25(s, 3H), 1.47(d, J ═ 6, 6H).
Example 231: 5- (5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine 231
Hydrogenation of 5- (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulen-2-yl) -1-isopropyl-1H- [1, 2, 4] triazol-3-ylamine in the presence of 10% palladium on charcoal gave 231 after purification by reverse phase HPLC. LCMS: 311.2.
example 232: 2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine232
To a 25mL round bottom flask under nitrogen was added 9-bromo-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1, 2-d ] s][1，4]Oxazazepine411(1.0g, 2.6mmol), dipicolinate (0.719g, 2.83mmol), potassium acetate (0.76g, 7.7mmol) and [1, 1'Di (diphenylphosphino) ferrocene]Palladium (II) dichloride [ Complex with DCM (1: 1)](0.21g, 0.26 mmol). The combined mixture was diluted with dimethyl sulfoxide (8.5mL) and heated at 85 ℃ for 12 hours. The reaction mixture was then cooled to room temperature and diluted with water and DCM. The phases were partitioned and the aqueous phase was extracted three times with DCM. The organic layers were combined and MgSO4Dried, filtered and concentrated. The residue was purified by flash column chromatography to give 232 as an acid-dehalogenated by-product (66mg, 7% yield). MS (ESI +) M/z 310.2(M + H)+) Calculated value is 310.4.1HNMR(500MHz，DMSO)8.41(dd，J＝8.0，1.6Hz，1H)，7.89(s，1H)，7.33(dd，J＝11.0，4.3Hz，1H)，7.16(t，J＝7.6Hz，1H)，7.07(d，J＝8.1Hz，1H)，5.83(dt，J＝13.0，6.6Hz，1H)，4.51(q，J＝5.6Hz，4H)，2.26(s，3H)，1.46(d，J＝6.6Hz，6H)。
Example 233: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [4, 3-f][1，4]Oxazazepine233
A mixture of 22(82.7mg, 0.250mmol), 10% palladium on charcoal (0.1: 0.9, palladium: carbon black, 83mg) and TEA (0.104mL, 0.750mmol) in 5.0mL ethanol and 5.0mL THF (5.0mL, 62mmol) was hydrogenated at 1atm for 3 hours. The catalyst was filtered off, the filtrate was concentrated and the residue was purified by RP HPLC (acetonitrile gradient) to give 233. Yield 32mg (43%). MS (ESI +): 297.2. 1HNMR(500MHz，DMSO)8.40(s，1H)，8.30(d，J＝5.2，1H)，8.25(d，J＝5.2，1H)，8.08(s，1H)，7.94(s，1H)，5.87(dt，J＝13.0，6.6，1H)，4.60(dd，J＝13.1，5.5，4H)，1.49(d，J＝6.6，6H)。
Example 234: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -10- (4-methylpiperazin-1-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [4, 3-f][1，4]Oxazazepine234
P-22 (132mg, 0.400mmol), 1-methyl-piperazine (88.7. mu.L, 0.800mmol), palladium diacetate (44.9mg, 0.200mmol), 2, 8, 9-triisobutyl-2, 5, 8, 9-tetraaza-1-phosphabicyclo [ 3.3.3%]A mixture of undecane (71.0 μ L, 0.200mmol) and sodium tert-butoxide (38.4mg, 0.400mmol) in 1, 4-dioxane (8.0mL) was degassed. The reaction mixture was irradiated with microwaves at 120 ℃ for 30 minutes at 200 watts. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between water and EtOAc. The organic extracts were washed with water and brine and MgSO4Dried and concentrated in vacuo. The residue was purified on a 4g silica gel column (using a gradient of 5-10% (methanol with 1% ammonia)/DCM) to give 234. The yield was 50mg (30%). MS: 395.2.1H NMR(500MHz，DMSO)8.04(s，1H)，8.03(s，1H)，7.94(s，1H)，7.63(s，1H)，5.69(dt，J＝13.3，6.6，1H)，4.61-4.53(m，2H)，4.49-4.41(m，2H)，3.41(s，4H)，2.45(s，4H)，2.23(s，3H)，1.50(d，J＝6.6，6H)。
example 235: 2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (pyrimidin-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine235
Reacting 48 under Suzu-based conditions catalyzed by palladium with 5- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxaborolan-2-yl) -pyrimidine to give 235. MS (ESI +) 388.2. 1H NMR(500MHz，DMSO)9.24-9.20(m，3H)，8.54(d，J＝8.4，1H)，7.96(s，1H)，7.65(dd，J＝8.4，1.4，1H)，7.58(d，J＝1.2，1H)，5.96-5.71(m，1H)，4.57(s，4H)，2.26(s，3H)，1.48(d，J＝6.6，6H)。
Example 236: 9- (5-Fluoropyridin-3-yl) -2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine236
Reacting 48 under Suzu-based conditions catalyzed by palladium with 3-fluoro-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxaborolan-2-yl) -pyridine to give 236. MS (ESI +) 405.2.1H NMR(500MHz，DMSO)8.89(s，1H)，8.61(d，J＝2.6，1H)，8.52(d，J＝8.4，1H)，8.19-8.14(m，1H)，7.96(s，1H)，7.63(dd，J＝8.3，1.3，1H)，7.54(d，J＝1.4，1H)，5.89-5.80(m，1H)，4.57(s，4H)，2.26(s，3H)，1.48(d，J＝6.6，6H)。
Example 237: 2- (3-amino-1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carbonitrile 237
Reaction of 5- (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulen-2-yl) -1-isopropyl-1H- [1, 2, 4] triazol-3-ylamine with zinc cyanide gave 237 after purification by reverse phase HPLC. LCMS: 336.
example 238: n- (5- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyridin-2-yl) acetamide 238
Reacting 48 under Suzu-based conditions catalyzed by palladium with N- [5- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ]]Dioxaborolan-2-yl) -pyridin-2-yl]-acetamide reaction to give238。MS(ESI+)444.2。1HNMR(500MHz，DMSO)10.63(s，1H)，8.72(s，1H)，8.48(d，J＝8.4，1H)，8.17(s，2H)，7.93(s，1H)，7.55(dd，J＝8.4，1.4，1H)，7.43(d，J＝1.4，1H)，5.89-5.80(m，1H)，4.55(s，4H)，2.26(s，3H)，2.12(s，3H)，1.47(d，J＝6.6，6H)。
Example 239: 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f][1，2，4]Triazolo [1, 5-d ][1，4]Oxazazepine239
Step 1: 9-chloro-5, 6-dihydrobenzo [ f][1，2，4]Triazolo [1, 5-d][1，4]Oxazazepine-2-Carboxylic acid methyl ester
To a solution of methyl 1- (2- (2-bromo-5-chlorophenoxy) ethyl) -1H-1, 2, 4-triazole-3-carboxylate in acetonitrile (10.00mL, 191.5mmol) in a microwave flask with a stir bar was added cesium carbonate (0.9036g, 2.773 mmol). The mixture was degassed by bubbling nitrogen through the syringe. Tetraethylammonium chloride (0.2298g, 1.387mmol), palladium diacetate (0.1556g, 0.6933mmol) and copper (I) iodide (0.02641g, 0.1387mmol) were added separately and the vessel was sealed by crimping. The flask was then heated to 165 ℃ in a microwave with stirring and held for 18 minutes. After cooling the reaction mixture to room temperature, the crude product was filtered through celite, concentrated and purified by silica gel chromatography to give 9-chloro-5, 6-dihydrobenzo [ f][1，2，4]Triazolo [1, 5-d][1，4]Oxazazepine-2-carboxylic acid methyl ester (15% yield).1H NMR(400MHz，CDCl3)8.59(d，J＝2.6Hz，1H)，7.34(dd，J＝8.8，2.7Hz，1H)，7.04(d，J＝8.8Hz，1H)，4.75(m，2H)，4.53(m，2H)，4.05(s，3H)。LRMS m/z C12H10ClN3O3Calculated value is 279.04107, found 280.0[ M +1 ]]。
Step 2: reacting 9-chloro-5, 6-dihydrobenzo [ f)][1，2，4]Triazolo [1, 5-d][1，4]OxazazepineMethyl (0.144g, 0.515mmol) of (E) -2-carboxylate in 3: 2: 1 THF: MeOH: H2O (5.0mL) and treated with 4NLiOH in water (0.644 mL). The mixture was stirred at 25 ℃ for 30 minutes. The reaction mixture was quenched with 1N aqueous HCl (10mL) and the solution was extracted with EtOAc (3X 20 mL). The combined organic extracts were extracted with Na 2SO4Drying and vacuum concentrating to obtain 9-chloro-5, 6-dihydrobenzo [ f][1，2，4]Triazolo [1, 5-d][1，4]Oxazazepine-2-carboxylic acid (89% yield).
And step 3: to 9-chloro-5, 6-dihydrobenzo [ f)][1，2，4]Triazolo [1, 5-d][1，4]OxazazepineTo a solution of (E) -2-carboxylic acid (0.137g, 0.515mmol) in DMF (1.20mL, 15.4mmol) were added N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (0.587g, 1.54mmol) and 6-chloro-1-hydroxybenzotriazole (0.262g, 1.54 mmol). The mixture was stirred vigorously and NH was added4Cl (0.220g, 4.12 mmol). After 10 min, N-diisopropylethylamine (0.359mL, 2.06mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated, dried and washed with water. The crude product was purified by packing on silica gel (eluting with DCM/MeOH) and then by reverse phase HPLC to give 9-chloro-5, 6-dihydrobenzo [ f ]][1，2，4]Triazolo [1, 5-d][1，4]Oxazazepine-2-carboxamide (5.3% yield).
And 4, step 4: to 9-chloro-5, 6-dihydrobenzo [ f)][1，2，4]Triazolo [1, 5-d][1，4]OxazazepineTo a solution of-2-carboxamide (0.0053g, 0.020mmol) in toluene (0.160mL, 1.50mmol) was added 1, 1-dimethoxy-N, N-dimethylmethylamine (0.0150mL, 0.113mmol) and the mixture was heated to 102 ℃ in a sealed flask with stirring and held for 2 hours. The reaction mixture was then cooled and concentrated to dryness and isopropylhydrazine hydrochloride (0.00376g, 0.0340mmol) and acetic acid (0.0938g, 1.56mmol) were added and the reaction mixture was sealed and heated to 102 ℃ overnight with stirring. The reaction mixture was then concentrated to dryness and taken up in DMF and purified by reverse phase HPLC to give 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ][1，2，4]Triazolo [1, 5-d][1，4]Oxazazepine(98% yield).1H NMR(500MHz，CDCl3)8.56(d，J＝2.6Hz，1H)，8.02(s，1H)，7.35(dd，J＝8.8，2.6Hz，1H)，7.06(d，J＝8.8Hz，1H)，5.84-5.66(m，1H)，4.84-4.70(m，2H)，4.62-4.47(m，2H)，1.61(s，6H)。LRMS m/z C15H15ClN6O calculated as 330.09959, found 331.1[ M +1 ]]。
Example 241: 5- (9- (5-Fluoropyridin-3-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine 241
Reacting 5- (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulen-2-yl) -1-isopropyl-1H- [1, 2, 4] triazol-3-ylamine with 3-fluoro-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine under suzuki palladium coupling conditions. The crude product was purified by reverse phase HPLC to afford 241. LCMS: 406.2.
example 242: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (tetrahydro-2H-pyran-2-yl) -1H-imidazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine242
1- (tetrahydro-2H-pyran-2-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-imidazole was prepared as follows: palladium reduction of 2-chloro-1- (tetrahydro-2H-pyran-2-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-imidazole with hydrogen.
To a mixture of 194(250mg, 0.67mmol) and 1- (tetrahydro-2H-pyran-2-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-imidazole (204mg, 0.73mmol) in anhydrous DMF (2.5mL) under nitrogen was added CsF (254mg, 1.68mmol), CuI (13mg, 0.067mmol) and Pd (PPh) 3)4(39mg, 0.034 mmol). The reaction mixture was heated in a microwave at 130 ℃ for 40 minutes. Cool to room temperature, pour the resulting mixture into water and extract with EtOAc. The organics were dried over sodium sulfate and purified by preparative TLC (100% EtOAc) to give 242 as a yellow solid (49.3mg, 17% yield).1H NMR(DMSO-d6，400MHz)：8.49(d，J＝8.4Hz，1H)，8.11(s，1H)，7.97(s，1H)，7.92(s 1H)，7.28(dd，J1＝1.6Hz，J2＝8.4Hz，1H)，7.18(d，J＝6.8Hz，2H)，5.92-5.89(m，1H)，5.19(d，J＝9.2Hz，1H)，4.55-4.52(m，4H)，4.04(d，J＝11.2Hz，1H)，3.60-3.56(m，1H)，2.29-1.90(m，3H)，1.58-1.48(m，9H)。MS(ESI，m/z)＝446[M+H]+。
Example 243: 3- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]An imidazo [1 ] compound having a structure of,2-d][1，4]oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropanamide 243
Reacting 9-bromo-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine411 in Suzuki Palladium coupling conditions (Pd (dppf) Cl2，Cs2CO3) Reaction with ethyl 2-methyl-3- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propionate to give 3- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropionic acid ethyl ester, LC/MS (ESI +): m/z 490(M + H), which was hydrolyzed with lithium hydroxide in water, then the corresponding acid was treated with ammonium chloride, HATU, diisopropylethylamine and DMF to give 243. LC/MS (ESI +): m/z 461(M + H). 1H NMR(500MHz，DMSO)8.35(d，J＝8.4，1H)，8.15(s，1H)，7.95(s，1H)，7.86(s，1H)，7.36(dd，J＝8.4，1.7，2H)，7.25(d，J＝1.7，1H)，6.83(s，1H)，5.82(dt，J＝13.2，6.6，1H)，4.51(s，4H)，4.30(dd，J＝13.5，7.6，1H)，4.02(dd，J＝13.5，7.0，1H)，2.91(dd，J＝14.3，7.1，1H)，2.25(s，3H)，1.47(d，J＝6.6，5H)，1.01(d，J＝7.0，3H)。
Example 244: 2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (pyridin-3-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine244
Reaction of 48 with 3- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -pyridine affords 244. MS (ESI +) 387.2.
Example 245: 5- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -N, N-dimethylpyrimidin-2-amine 245
Reaction of 48 with dimethyl- [5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -pyrimidin-2-yl ] -amine affords 245. MS (ESI +) 431.2.
Example 246: 5- (5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1-isopropyl-N-methyl-1H-1, 2, 4-triazol-3-amine 246
Para-5- (9-bromo-5, 6-dihydrobenzo [ f ] in the presence of 10% palladium on charcoal]Imidazo [1, 2-d ] s][1，4]OxazazepineHydrogenation of-2-yl) -1-isopropyl-N-methyl-1H-1, 2, 4-triazol-3-amine gave 246 after purification by reverse phase HPLC. LCMS: 325.2.
example 247: n-isopropyl-2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine -9-yl) piperidin-1-yl) acetamide 247
To 66(350mg, 0.71mmol) at THTo the suspension in F was added potassium carbonate (245mg, 1.78mmol), then N-isopropyl-2-chloroacetamide (106mg, 0.78mmol) and the reaction mixture was stirred at room temperature for 18 hours, then heated at 50 ℃ for 2 hours. The resulting mixture was concentrated in vacuo and the residue was subjected to flash chromatography (SiO)2Gradient 0 to 5% MeOH/DCM) to give 247 as a white solid (180mg, 53%).1H NMR (ppm)(DMSO-d6): 8.28(1H, d, J ═ 8.28Hz), 7.86(1H, d, J ═ 0.63Hz), 7.85(1H, s), 7.40(1H, d, J ═ 8.18Hz), 7.03(1H, dd, J ═ 8.36, 1.77Hz), 6.89(1H, d, J ═ 1.72Hz), 5.88-5.79(1H, m), 4.48-4.41(4H, m), 3.89-3.83(1H, m), 2.89-2.79(4H, m), 2.13(2H, td, J ═ 10.70, 4.11Hz), 1.74-1.64(4H, m), 1.43(6H, d, J ═ 6.60Hz), 1.04(6H, J ═ 59 Hz). 1 proton is masked by the solvent peak. LCMS: RT 2.94 min, M + H+＝478。
Example 248: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -N, 2-dimethylpropanamide 248
A biphasic mixture of 50% aqueous sodium hydroxide (2mL) and DCM (2.5mL) was treated with a solution of 2-bromo-2, N-dimethyl-propionamide (121mg, 0.67mmol), tetrabutylammonium bromide (118mg, 0.37mmol) and 66(300mg, 0.61mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 3 hours, then tetrabutylammonium bromide (118mg, 0.37mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM and washed with water. The combined aqueous extracts were washed with DCM and the combined organic extracts were dried (MgSO) 4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 5% MeOH/DCM) then triturated in ether to give 248 as an opalescent solid (120mg, 41%).1H NMR(ppm)(DMSO-d6)：8.27(1H，d，J＝8.26Hz), 7.86(1H, d, J ═ 0.63Hz), 7.85(1H, s), 7.64(1H, m), 7.02(1H, dd, J ═ 8.34, 1.75Hz), 6.91(1H, d, J ═ 1.70Hz), 5.88-5.78(1H, m), 4.48-4.42(4H, m), 2.74(2H, d, J ═ 10.86Hz), 2.59(3H, d, J ═ 4.75Hz), 2.17-2.08(2H, m), 1.75-1.69(4H, m), 1.43(6H, d, J ═ 6.60Hz), 1.05(6H, s). 1 proton is masked by the solvent peak. LCMS: RT 2.78 min, M + H+＝478。
Example 249: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -N, N-dimethylethanesulfonamide 249
Reaction of 66 with N, N-dimethylvinylsulfonamide gave 249 as a white solid.1H NMR(ppm)(DMSO-d6): 8.28(1H, d, J ═ 8.29Hz), 7.86(1H, d, J ═ 0.63Hz), 7.85(1H, s), 7.01(1H, dd, J ═ 8.37, 1.77Hz), 6.85(1H, d, J ═ 1.72Hz), 5.88-5.80(1H, m), 4.48-4.42(4H, m), 3.23-3.15(2H, m), 2.95(2H, d, J ═ 11.09Hz), 2.74(6H, s), 2.68-2.60(2H, m), 2.09-1.98(2H, m), 1.73(2H, d, J ═ 12.61Hz), 1.64-1.55(2H, m), 1.43(6H, d, J ═ 6.61 Hz). 1 proton is masked by the solvent peak. LCMS: RT 2.90, M + H +＝513。
Example 250: 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) acetamide 250
4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4 ]]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl esterPrepared from 52(500mg, 1.12mmol) and 1-tert-butoxycarbonyl-piperidin-4-ylzinc iodide (1.68mmol) to give 4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (569mg, 100%). LCMS: RT 4.79 min, M + H+＝493。
To 4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]To a solution of tert-butyl-piperidine-1-carboxylate (569mg, 1.16mmol) in dioxane (15mL) and methanol (5mL) was added a solution of 4M HCl in dioxane (15mL) and the reaction mixture was stirred at room temperature for 20 hours, then concentrated in vacuo. The residue obtained is triturated in a mixture of diethyl ether and methanol to give 2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]Azulene hydrochloride as a brown solid (212mg, 43%). LCMS: RT 2.34/2.66 min, M + H+＝393。
2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]A mixture of azulene hydrochloride (120mg, 0.28mmol) in DMF (1.5mL) was treated with potassium carbonate (97mg, 0.7mmol) followed by bromoacetamide (43mg, 0.336mmol) and stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc/methanol and washed with water and the organic layer was dried (Na)2SO4) Filtered and concentrated in vacuo. The resulting solid residue was recrystallized from methanol to give 250 as a white solid (51mg, 41%).1H NMR (ppm)(DMSO-d6): 8.27(1H, d, J ═ 8.28Hz), 7.81(1H, s), 7.16(1H, s), 7.07(1H, s), 7.01(1H, dd, J ═ 8.36, 1.78Hz), 6.87(1H, d, J ═ 1.72Hz), 5.81-5.73(1H, m), 4.45-4.41(4H, m), 2.89-2.82(2H, m), 2.83(2H, s), 2.20(3H, s), 2.16-2.07(2H, m), 1.72-1.66(4H, m), 1.40(6H, d, J ═ 6.61 Hz). 1 proton is masked by the solvent peak. LCMS: RT ═ 2.97, [ M + H]+＝450。
Example 251: 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s ][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropanoic acid 251
To a solution of 4, 4, 5, 5-tetramethyl-2- (1H-pyrazol-4-yl) -1, 3, 2-dioxaborolane (5g, 0.03mol) and cesium carbonate (10g, 0.03mol) in DMF (50mL) was added ethyl 2-bromoisobutyrate (4.2mL, 0.03 mol). The reaction mixture was heated to 110 ℃ and stirred overnight. The reaction mixture was cooled to room temperature and washed with H2Diluted O, aqueous layer extracted with EtOAc (2X) and the combined organic phases washed with brine, MgSO4Dried, filtered and concentrated in vacuo. The crude product was a mixture of the two isomers which was then separated by trituration with hexane to give the desired product ethyl 2-methyl-2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propionate. LC/MS (ESI +): m/z309(M + H).1H NMR(400MHz，CDCl3)7.89(d，J＝4.1，1H)，7.84(s，1H)，4.22-4.08(m，2H)，1.85(d，J＝7.6，6H)，1.36-1.31(m，12H)，1.20(td，J＝7.1，2.8，3H)。
Reacting 9-bromo-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine411 was coupled with ethyl 2-methyl-2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propionate under suzuki conditions to give 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -f ]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropionic acid ethyl ester. LC/MS (ESI +): m/z 490(M + H).
2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropionic acid ethyl ester (750mg, 0.0015mol) with 1M LiOH/H2O (1.6mL) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified by 10% aqueous citric acid until pH 5, extracted twice with EtOAc, and MgSO4Dried and concentrated in vacuo. The crude product was purified by preparative HPLC to afford 251. LC/MS (ESI +): m/z 462(M + H).1H NMR(500MHz，DMSO)8.44(s，1H)，8.36(d，J＝8.4，1H)，7.97(s，1H)，7.86(s，1H)，7.44(dd，J＝8.4，1.7，1H)，7.35(d，J＝1.7，1H)，5.82(dt，J＝13.1，6.6，1H)，4.52(s，3H)，2.25(s，2H)，1.78(s，4H)，1.45(t，J＝13.9，4H)。
Example 252: 1- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-imidazol-1-yl) -2-methylpropan-2-ol 252
Reaction of 2- (2-isopropyl-5-methyl-2H- [1, 2, 4] triazol-3-yl) -8- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene with 1- (4-bromo-imidazol-1-yl) -2-methyl-propan-2-ol gave 252. MS (ESI +) 448.3.
Example 253: 5- (9-fluoro-5, 6-dihydrobenzo [ f) ]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1-isopropyl-1H-1,2, 4-triazol-3-amines 253
89(0.200mg, 0.47mmol) was dissolved in 1, 2-dichloroethane (3mL, 40mmol) and TFA (3mL, 40mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. LCMS confirmed the reaction was complete and the reaction mixture was concentrated in vacuo. The crude solid was purified by HPLC to give 253(18.3mg, 12% yield).
Example 254: 2- (4- (2- (3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol 254
8-bromo-2- (5-methyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene is reacted with 1- [2- (tetrahydropyran-2-yloxy) -ethyl ] -4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -1H-pyrazole under microwave conditions to give 254. MS (ESI +) 378.2.
Example 255: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -2-methyl-1H-imidazol-1-yl) ethanol 255
Compound 256(90mg, 0.18mmol) was dissolved in 3mL of methanol and HCl-methanol (3mL, 4M) was added dropwise at 0 ℃. The mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours, concentrated. The residue was washed with EtOAc to give 65mg 255 as the hydrochloride salt. The yield was 82%. 1H NMR(CDCl3，400MHz)：8.65-8.61(m，2H)，8.17(s，1H)，8.00(s，1H)，7.52-7.48(m，2H)，5.81-5.78(m，1H)，4.68-4.60(m，4H)，4.31-4.29(m，2H)，3.95-3.92(m，2H)，2.74(s，3H)，1.65(d，J＝1.2Hz，6H)。LC-MS：m/z＝404[M+H]+。
Example 256: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (2-methyl-1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-imidazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine256
4-iodo-2-methyl-1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-imidazole was prepared as follows: 4-iodo-2-methyl-1H-imidazole, Cs2CO3And 2- (2-bromo-ethoxy) -tetrahydropyran in DMF. To a mixture of 4-iodo-2-methyl-1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-imidazole (500mg, 1.9mmol) in DCM (10mL) was added ethylmagnesium bromide (0.7mL, 3mol/L, 2.2mmol) at-78 ℃. The temperature of the mixture was slowly warmed to about 10 ℃ and cooled again. Trimethyltin chloride (2.2mL, 1mol/l, 2.2mmol) was added dropwise at-78 ℃. After the addition was complete, the temperature was slowly warmed to room temperature. The reaction mixture was poured into saturated NH4Cl solution, then extracted with DCM. The organic was washed twice with water and anhydrous Na2SO4Drying and concentration gave 0.44g of 2-methyl-1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -4- (trimethylstannanyl) -1H-imidazole. The yield was 63%.1H NMR(CDCl3，400MHz)：7.04(s，1H，ArH)，3.71(s，2H)，2.43(s，3H)，1.24-1.20(m，6H)，0.88(s，9H)，0.29(s，6H)，0.06(s，9H)。LC-MS：m/z＝375[M+H]+。
194(300mg，0.8mmol)、Pd(PPh3)4A mixture of (93mg, 0.08mmol) and 2-methyl-1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -4- (trimethylstannanyl) -1H-imidazole (600mg, 1.6mmol) in dioxane (2mL) was bubbled with nitrogen for about 2 minutes, then stirred under microwave irradiation at 120 ℃ for 35 minutes. Filtration, concentration and purification by preparative tlc (etoac) gave 130mg 256. The yield was 32%. 1H NMR(CDCl3，400MHz)：8.44-8.42(m，1H，ArH)，7.81(s，1H)，7.58(s，1H)，7.48-7.46(m，1H)，7.42(d，J＝1.6Hz，1H)，7.19(s，1H)，4.51-4.95(m，1H)，4.45-4.44(t，1H)，4.39-4.38(m，2H)，4.38-4.37(m，2H)，4.07-4.04(m，2H)，4.00-4.97(m，1H)，3.63-3.54(m，2H)，3.40-3.36(m，1H)，2.49(s，3H)，1.76-1.60(m，4H)，1.48-1.47(m，2H)。LC-MS：m/z＝504[M+H]+。
Example 257: 5- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyrimidin-2-amine 257
Reaction of 48 with 5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -pyrimidin-2-ylamine gave 257. MS (ESI +) 403.2.
Example 258: 5- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) pyridin-2 (1H) -one 258
Reacting 10-bromo-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineReacting with 6-fluoropyridin-3-ylboronic acid to give 10- (6-fluoropyridin-3-yl) -2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(0.121g，39％)。1H NMR(500MHz，DMSO)8.67(d，J＝2.4，1H)，8.52(d，J＝2.6，1H)，8.25(td，J＝8.2，2.7，1H)，7.92(s，1H)，7.68(dd，J＝8.5，2.5，1H)，7.31(dd，J＝8.4，2.8，1H)，7.19(d，J＝8.5，1H)，5.69(dt，J＝13.3，6.6，1H)，4.56(s，4H)，2.26(s，3H)，1.47(d，J＝6.6，6H)。MS(ESI(+))：m/z 405.2(M+H)。
10- (6-Fluoropyridin-3-yl) -2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineHydrolysis with HCl gave 258(0.028g, 25%).1HNMR(500MHz，DMSO)11.76(s，1H)，8.50(d，J＝2.4，1H)，7.90(s，1H)，7.78(dd，J＝9.5，2.8，1H)，7.64(s，1H)，7.52(dd，J＝8.5，2.5，1H)，7.10(d，J＝8.5，1H)，6.47(d，J＝9.5，1H)，5.70(dt，J＝13.2，6.5，1H)，4.52(q，J＝5.8，4H)，2.26(s，3H)，1.48(d，J＝6.6，6H)。MS(ESI(+))：m/z 403.2(M+H)。
Example 261: n- (azetidin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [4, 3-f][1，4]Oxazazepine-10-amine 261
A solution of 22(90.0mg, 0.272mmol), tert-butyl 3-aminoazetidine-1-carboxylate (46.9mg, 0.272mmol), palladium diacetate (6.11mg, 0.0272mmol), XPhos (13.0mg, 0.0272mmol) and sodium tert-butoxide (52.3mg, 0.544mmol) in 1, 4-dioxane (1.50mL, 19.2mmol) was heated in a microwave at 115 ℃ for 20 minutes. The reaction mixture was filtered through celite, then rinsed with EtOAc. The filtrate was washed with water and brine. Na for organic layer2SO4Drying and concentrating to obtain crude intermediate 3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [4, 3-f][1，4]Oxazazepine-10-ylamino) azetidine-1-carboxylic acid tert-butyl ester, which was dissolved in DCM (10.0 mL). TFA (0.419mL, 5.44mmol) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated and subjected to rphplc purification to afford 261. MS (ESI +) ═ 367.2.1H NMR(500MHz，DMSO)8.29(s，1H)，8.23(s，1H)，7.98(s，1H)，7.79(s，1H)，5.74(dt，J＝13.1，6.5Hz，2H)，4.73-4.60(m，3H)，4.58-4.51(m，2H)，4.43(dd，J＝12.7，6.9Hz，2H)，4.24(dt，J＝15.9，5.6Hz，1H)，2.77(m，J＝34.8，13.1，5.3Hz，2H)，1.50(d，J＝6.6，2.9Hz，6H)。
Example 262: 3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [4, 3-f][1，4]Oxazazepine-10-ylamino) propane-1, 2-diol 262
A solution of 22(90.0mg, 0.272mmol), (2, 2-dimethyl-1, 3-dioxolan-4-yl) methylamine (0.0353mL, 0.272mmol), palladium diacetate (6.11mg, 0.0272mmol), XPhos (13.0mg, 0.0272mmol) and sodium tert-butoxide (52.3mg, 0.544mmol) in 1, 4-dioxane (1.50mL, 19.2mmol) was heated in a microwave at 115 ℃ for 20 minutes. The reaction mixture was filtered through celite, then rinsed with EtOAc. The filtrate was washed with water and brine. Na for organic layer 2SO4Drying and concentrating to obtain intermediate N- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [4, 3-f][1，4]Oxazazepine-10-amine, to which was added a 4.00M solution of hydrogen chloride in dioxane (5.00 mL). The reaction mixture was stirred for 3 hours. The reaction mixture was concentrated and purified by HPLC to afford 262. MS (ESI +)386.2。1HNMR(500MHz，DMSO)7.99(s，1H)，7.92(s，1H)，7.85(s，1H)，7.44(s，1H)，6.36(s，1H)，5.86(dt，J＝13.2，6.6Hz，1H)，4.78(d，J＝4.8Hz，1H)，4.61-4.46(m，3H)，4.46-4.33(m，2H)，3.64(dd，J＝11.4，5.3Hz，1H)，3.47-3.34(m，3H)，3.21-3.10(m，1H)，1.49(d，J＝6.6Hz，6H)。
Example 263: 3- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) pyridin-2 (1H) -one 263
Preparation of 10- (2-Fluoropyridin-3-yl) -2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] according to the procedure used for 203]Imidazo [1, 2-d ] s][1，4]Oxazazepine(0.756g，62％)。1H NMR(500MHz，DMSO)8.73(s，1H)，8.24(d，J＝4.7，1H)，8.20-8.10(m，1H)，7.91(s，1H)，7.60(d，J＝9.4，1H)，7.55-7.45(m，1H)，7.20(d，J＝8.5，1H)，5.70(dt，J＝13.2，6.6，1H)，4.57(s，4H)，2.26(s，3H)，1.45(d，J＝6.6，6H)。MS(ESI(+))：m/z 405.2(M+H)。
10- (2-Fluoropyridin-3-yl) -2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineHydrolysis with HCl gave 263(0.412g, 70% yield).1H NMR(500MHz，DMSO)11.80(s，1H)，8.86(d，J＝2.3，1H)，7.88(s，1H)，7.66(ddd，J＝9.0，7.7，2.2，2H)，7.37(d，J＝5.0，1H)，7.06(d，J＝8.5，1H)，6.31(t，J＝6.6，1H)，5.73(dt，J＝13.2，6.6，1H)，4.61-4.47(m，4H)，2.25(s，3H)，1.45(d，J＝6.6，6H)。MS(ESI(+))：m/z 403.2(M+H)。
Example 265: 1- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -2-methyl-1H-imidazol-1-yl) -2-methylpropan-2-ol 265
1- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -4-iodo-2-methyl-1H-imidazole was prepared as follows: 1- (4-iodo-2-methyl-1H-imidazol-1-yl) -2-methylpropan-2-ol, 2, 6-lutidine, and tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) were reacted in DCM.
To a mixture of 1- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -4-iodo-2-methyl-1H-imidazole (1.5g, 3.8mmol) in DCM (15mL) was added ethylmagnesium bromide (1.9mL, 3mol/L, 5.7mmol) at-78 ℃. The temperature of the mixture was slowly warmed to about 10 ℃ and cooled again. Trimethyltin chloride (6.5mL, 1mol/L, 6.5mmol) was added dropwise at-78 ℃. After the addition was complete, the temperature was slowly warmed to room temperature. The reaction mixture was poured into saturated NH4Cl solution, then extracted with DCM. The organic was washed twice with water and anhydrous Na2SO4Drying and concentration gave 0.44g of 1- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -2-methyl-4- (trimethylstannanyl) -1H-imidazole. The yield was 63%.1HNMR(CDCl3，400MHz)：7.04(s，1H，ArH)，3.74(s，2H)，2.43(s，3H)，1.24-1.20(m，6H)，0.88(s，9H)，0.29(s，6H)，0.03(s，8H)。LC-MS：m/z＝375[M+H]+。
194(300mg，0.8mmol)、Pd(PPh3)4A mixture of (93mg, 0.08mmol) and 1- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -2-methyl-4- (trimethylstannyl) -1H-imidazole (690mg, 1.6mmol) in dioxane (2mL) was bubbled with nitrogen for about 2 minutes, then irradiated under microwave radiation Stirred at 120 ℃ for 35 minutes. Filtration, concentration and purification by preparative TLC (pure EtOAc) afforded 160mg of 9- (1- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -2-methyl-1H-imidazol-4-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineThe yield was 46%. LC-MS: 548[ M + H ] M/z]+。
Reacting 9- (1- (2- (tert-butyldimethylsilyloxy) -2-methylpropyl) -2-methyl-1H-imidazol-4-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine(110mg, 0.196mmol) was dissolved in 5mL THF and tetrabutylammonium fluoride (102mg, 0.392mmol) was added at 0 deg.C. The temperature was slowly warmed to room temperature and stirred at room temperature overnight. Concentrate and partition the residue between EtOAc and water to give 30mg 265. The yield was 36%.1H NMR(CDCl3，400MHz)：8.48(d，J＝8.0Hz，1H)，7.87(s，1H)，7.64(s，1H)，7.51-7.47(m，2H)，7.26(s，1H)，6.03-5.99(m，1H)，4.51-4.43(m，4H)，3.85(s，1H)，2.47(s，3H)，1.65-1.56(m，6H)，1.28-1.26(m，6H)。LC-MS：m/z＝433[M+H]+。
Example 269: 3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [4, 3-f][1，4]Oxazazepine-10-yl) pyridin-2 (1H) -one 269
To 10- (2-fluoropyridin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [4, 3-f][1，4]Oxazazepine(0.087g, 0.22mmol) in 1, 2-dimethoxyethane (3.00mL, 28.9mmol) was added 10% aqueous HCl (3 mL). The reaction mixture was stirred and heated at 80 ℃ overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 269, which was analyzed by rphplc. MS (ESI +) -390.2. 1H NMR(500MHz，DMSO)9.76(s，1H)，8.45-8.39(m，2H)，8.04(s，1H)，7.93(s，1H)，7.47(dd，J＝6.1，2.1Hz，1H)，6.37(t，J＝6.7Hz，1H)，5.91(dt，J＝13.3，6.7Hz，2H)，5.91(dt，J＝13.3，6.7Hz，1H)，4.61(dd，J＝13.1，5.5Hz，4H)，1.52(d，J＝6.6Hz，6H)。
Example 270: 2- (5- (9-cyclopropyl-5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -3-methyl-1H-1, 2, 4-triazol-1-yl) propan-1-ol 270
Adding 2- [5- (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] to a microwave bottle]Azulen-2-yl) -3-methyl- [1, 2, 4]Triazol-1-yl]-a solution of propan-1-ol (0.140g, 0.000346mol) and potassium phosphate (0.220g, 0.00104mol) in THF (2.0mL) and water (2.0 mL). The mixture was thoroughly purged with nitrogen. 2-cyclopropyl-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (0.189mL, 0.00104mol) and Pd (PPh) were added3)4(0.0400g, 0.0000346mol) and the vial was immediately sealed. The reaction mixture was heated to 120 ℃ in a microwave and held for 20 minutes. The reaction mixture was diluted with DCM and filtered over celite. Adding saturated NH4Cl and the mixture was extracted three times with DCM. The organic layers were combined and MgSO4Dried and concentrated. The crude product was purified by reverse phase HPLC to give 35mg 270 as a white solid. MS (ESI +) 366.2.1H NMR(500MHz，DMSO)8.26(d，J＝8.3Hz，1H)，7.82(s，1H)，6.86(dd，J＝8.4，1.7Hz，1H)，6.75(d，J＝1.7Hz，1H)，5.73-5.57(m，1H)，4.85(t，J＝5.4Hz，1H)，4.50-4.43(m，4H)，3.76(ddd，J＝10.7，7.5，6.0Hz，1H)，3.68-3.62(m，1H)，2.24(s，3H)，1.97-1.85(m，1H)，1.39(d，J＝6.7Hz，3H)，1.02-0.93(m，2H)，0.75-0.67(m，2H)。
Example 271: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (2-methyl-1H-imidazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine271
Reaction of 194 with a mixture of the regioisomers 2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -4- (trimethylstannyl) -1H-imidazole and 2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -5- (trimethylstannyl) -1H-imidazole according to the method used for 265 gives 9- (1- ((2- (tert-butyldimethylsilyl) ethoxy) methyl) -2-methyl-1H-imidazol-4-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1, 2-d ] s][1，4]OxazazepineThis (360mg, 0.71mmol) was dissolved in ethanol (3 mL). HCl-methanol (3mL, 4mol/L) was added dropwise to the mixture at 0 ℃. After 30 minutes, the temperature was warmed to 70 ℃ and stirred overnight. Concentration and basification of the residue with TEA followed by purification by preparative TLC yielded 240mg 271. The yield was 91%.1HNMR(MeOD，400MHz)：8.72(s，1H)，8.60(d，J＝4.4Hz，1H)，8.19(s，1H)，7.87(s，1H)，7.51(d，J＝2.0Hz，1H)，7.46(s，1H)，5.72-5.72(m，1H)，4.65-4.64(m，2H)，4.60-4.59(m，2H)，2.68(s，3H)，1.63-1.62(d，J＝6.8Hz，6H)。LC-MS：m/z＝376[M+H]+。
Example 272: 1- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1-methyl-1H-imidazol-2-yl) -2-methylpropan-2-ol 272
To a mixture of 194(500mg, 1.336mmol) and 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -bis (1, 3, 2-dioxaborolane) (509mg, 2.004mmol) in anhydrous DMF (4mL) under nitrogen was added KOAc (393mg, 4.01mmol) and Pd (dppf) Cl2(50mg, 0.067 mmol). The reaction mixture was heated in a microwave at 120 ℃ for 20 minutes. Cooled to room temperature and concentrated, and the crude product purified by column chromatography (hexane/EtOAc ═ 3: 1 to 1: 2) to give 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s ][1，4]OxazazepineIt was a yellow solid (275mg, 49% yield). LCMS (ESI, M/z) ═ 422[ M + H]+。
To 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydrobenzo [ f ] n under nitrogen]Imidazo [1, 2-d ] s][1，4]Oxazazepine(200mg, 0.48mmol) and 1- (4-bromo-1-methyl-1H-imidazol-2-yl) -2-methyl-propan-2-ol (166mg, 0.71mmol) in anhydrous DMF (2mL) CsF (180mg, 1.19mmol), CuI (9mg, 0.048mmol) and Pd (PPh)3)4(27mg, 0.024 mmol). The reaction mixture was heated in a microwave at 130 ℃ for 40 minutes. Cool to room temperature, pour the resulting mixture into water and extract with EtOAc. The organics were dried over sodium sulfate and purified by preparative HPLC to give 272 as a white solid (34.9mg, 16% yield).1H NMR(DMSO-d6，400MHz)：8.51(s，1H)，7.90(s，1H)，7.86(s，1H)，7.23-7.11(m，3H)，5.93-5.89(m，1H)，4.54-4.52(m，4H)，3.74-3.66(m，5H)，1.46(dd，J＝6.4Hz6H), 1.24 (broad singlet, 6H). MS (ESI, M/z) ═ 448[ M + H]+。
Example 274: n-tert-butyl-2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) acetamide 274
To a suspension of 66(300mg, 0.61mmol) in THF (5mL) was added potassium carbonate (295mg, 2.13mmol) and N-tert-butyl-2-chloro-acetamide (100mg, 0.67 mmol). The mixture was stirred for 5 days, then diluted with DCM and washed with water (2 × 30 mL). The organic phase was dried (MgSO) 4) And concentrated in vacuo. The resulting residue was triturated in ether to give 274 as an opalescent solid (169mg, 0.34mmol, 56%). LCMS: RT 3.12 min, [ M + H]+＝492。1H NMR (ppm)(DMSO-d6): 8.29(1H, d, J ═ 8.29Hz), 7.86(1H, d, J ═ 0.63Hz), 7.85(1H, s), 7.15(1H, s), 7.03(1H, dd, J ═ 8.36, 1.77Hz), 6.89(1H, d, J ═ 1.71Hz), 5.90-5.80(1H, m), 4.48-4.41(4H, m), 2.85(2H, d, J ═ 11.24Hz), 2.81(2H, s), 2.20-2.09(2H, m), 1.78-1.67(2H, m), 1.70-1.58(2H, m), 1.44(6H, d, J ═ 6.60Hz), 1.25(9H, s). 1H is masked by the solvent.
Example 275: 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -N-methylacetamide 275
For 48(1.2g, 3.09mmol), 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.8g, 5.82mmol), PdCl2dppf·DCM(339mg，0.46mmol) and potassium carbonate (1.9g, 13.9mmol) in DMF (10mL) were degassed and then heated at 90 ℃ under a nitrogen atmosphere for 1.5 hours. The cooled reaction mixture was diluted with EtOAc and water, the aqueous phase was extracted with EtOAc and the combined organic extracts were dried (Na) 2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 100% EtOAc/cyclohexane, 1% TEA in final eluent) to give 4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as brown foam (1.5g, 99%). LCMS: RT 3.77 min, [ M + H]+＝491。
P-4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]A solution of tert-butyl-3, 6-dihydro-2H-pyridine-1-carboxylate (1.5g, 3.06mmol) in IMS (15mL) was degassed then treated with palladium on carbon (10% palladium, 50% water, 450mg) and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 18H, then at 40 ℃ for 8H, then at room temperature for 18H. Additional palladium on charcoal (10% palladium, 50% water, 450mg) was added and stirring continued at 40 ℃ for 8 hours, then filtered through a plug of celite and the solvent removed in vacuo. The resulting residue was dissolved in methanol (5mL) and treated with a solution of 3M HCl in methanol (10mL) and stirred at room temperature for 1.5 hours, then concentrated in vacuo. The residue obtained is triturated in diethyl ether to give 2- (2-isopropyl-5-methyl-2H- [1, 2, 4) ]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene hydrochloride as yellow solid (1.26g, 79%).1H NMR 400MHz(DMSO-d6)：9.03(2H，s)，8.37(1H，d，J＝8.31Hz)，8.17(1H，s)，7.06(1H，dd，J＝8.37，1.7Hz)，6.92(1H，d，J＝1.7Hz)，5.78(1H，m)，4.54(4H，d，J＝17.19Hz)，3.35(2H，d，J＝12.43Hz)，2.98(2H，m)，2.87(1H，m)，2.38(2H，s)，2.08-1.78(4H，m)，1.49(6H，d，J＝6.57Hz)。
To 2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]To a suspension of azulene hydrochloride (150mg, 0.35mmol) was added TEA (107. mu.L, 0.77mmol) followed by 2-chloro-N-methyl-acetamide (41mg, 0.38 mmol). The resulting mixture was stirred overnight, then tetrabutylammonium iodide (13mg, 0.04mmol) was added and the reaction mixture was stirred for 24 hours. The mixture was washed with water and then extracted with 10% MeOH/DCM (. times.5). The combined organic layers were dried (MgSO)4) Concentrated in vacuo and purified by flash column chromatography (SiO)2Gradient 0-10% MeOH/DCM) to give 275(23mg, 0.05mmol, 14%). LCMS: RT 2.63 min, [ M + H]+＝464。1H NMR(ppm)(CDCl3): 8.42(1H, d, J ═ 8.30Hz), 7.59(1H, s), 7.00(1H, dd, J ═ 8.35, 1.83Hz), 6.88(1H, d, J ═ 1.79Hz), 5.91-5.81(1H, m), 4.48-4.44(2H, m), 4.42-4.36(2H, m), 3.13-2.91(4H, m), 2.85(3H, d, J ═ 4.98Hz), 2.56-2.48(1H, m), 2.39(3H, s), 2.33(2H, s), 1.87(2H, s), 1.78(2H, s), 1.54(6H, d, J ═ 6.65 Hz). No NH was observed.
Alternatively, to a suspension of 66(300mg, 0.61mmol) in THF (5mL) was added TEA (291. mu.L, 2.10mmol) and 2-bromo-N-methyl-acetamide (102mg, 0.67 mmol). The mixture was stirred for 2 hours, then potassium carbonate (169mg, 1.22mmol) was added, followed by stirring for an additional 2 hours. The reaction mixture was diluted with DCM and washed with water (2X 20mL), dried (MgSO)4) And concentrated in vacuo. The resulting residue was triturated with ether to give 275 as an opalescent solid (156mg, 0.35mmol, 57%). LCMS: RT 2.62 min, [ M + H]+＝450。1H NMR (ppm)(DMSO-d6): 8.29(1H, d, J ═ 8.27Hz), 7.86(1H, s), 7.85(1H, s), 7.66(1H, s), 7.02(1H, dd, J ═ 8.33, 1.76Hz), 6.88(1H, d, J ═ 1.71Hz), 5.89-5.79(1H, m), 4.49-4.42(4H, m), 2.88(2H, s), 2.84(2H, d, J ═ 10.90Hz), 2.59(3H, d, J ═ 4.73Hz), 2.13(2H, s), 1.77-1.67(4H, m), 1.44(6H, d, J ═ 6.60 Hz). 1H is masked by the solvent.
Example 276: N-Ethyl-2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) acetamide 276
To 2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]To a suspension of azulene hydrochloride (150mg, 0.35mmol) in DCM (2mL) was added TEA (107. mu.L, 0.77 mmol). The resulting mixture was stirred for 10 min, then 2-chloro-N-ethyl-acetamide (46mg, 0.38mmol) and tetrabutylammonium iodide (13mg, 0.04mmol) were added. The reaction mixture was stirred at room temperature for 4 days, and then the reaction mixture was washed with a sodium hydrogencarbonate solution (saturated aqueous solution). The aqueous phase was extracted with 10% MeOH/DCM (. times.3) and the combined organic layers were dried (Na)2SO4) And then concentrated in vacuo. The residue obtained is subjected to flash column chromatography (SiO)2Gradient 0-10% MeOH/DCM) to give 276(91mg, 0.19mmol, 55%). LCMS: RT 2.75 min, [ M + H]+＝478。1H NMR (ppm)(CDCl3)：8.43(1H，d，J＝8.29Hz)，7.59(1H，s)，7.16(1H，s)，7.00(1H，dd，J＝8.34，1.81Hz)，6.88(1H，d，J＝1.76Hz)，5.91-5.80(1H，m)，4.48-4.44(2H，m)，4.42-4.37(2H，m)，3.37-3.26(2H，m)，3.06-2.88(4H，m)，2.57-2.47(1H，m)，2.38(3H，s)，2.30(2H，s)，1.87(2H，d，J＝12.74Hz)，1.76(2H，s)，1.54(6H，d，J＝6.65Hz)，1.15(3H，t，J＝7.26Hz)。
Example 277: n-isopropyl-2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) acetamide 277
To 2- (2-iso)propyl-5-methyl-2H- [1, 2, 4]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]To a suspension of azulene hydrochloride (150mg, 0.35mmol) in DCM (2mL) was added TEA (107. mu.L, 0.77 mmol). The resulting mixture was stirred for 10 min, then 2-chloro-N-isopropyl-acetamide (52mg, 0.38mmol) and tetrabutylammonium iodide (13mg, 0.04mmol) were added. The reaction mixture was stirred at room temperature for 4 days, and then the reaction mixture was washed with a sodium hydrogencarbonate solution (saturated aqueous solution). The aqueous phase was extracted with 10% MeOH/DCM (. times.3) and the combined organic layers were dried (Na) 2SO4) And then concentrated in vacuo. The residue obtained is subjected to flash column chromatography (SiO)2Gradient 0-10% MeOH/DCM) to yield 277(88mg, 0.18mmol, 51%). LCMS: RT 2.85 min, [ M + H]+＝492。1H NMR (ppm)(CDCl3)：8.43(1H，d，J＝8.29Hz)，7.59(1H，s)，7.01(1H，dd，J＝8.34，1.82Hz)，6.97(1H，s)，6.89(1H，d，J＝1.76Hz)，5.92-5.82(1H，m)，4.48-4.44(2H，m)，4.42-4.38(2H，m)，4.13-4.02(1H，m)，3.10-2.85(4H，m)，2.58-2.46(1H，m)，2.38(3H，s)，2.35-2.20(2H，m)，1.94-1.84(2H，s)，1.81-1.68(2H，m)，1.54(6H，d，J＝6.64Hz)，1.16(6H，d，J＝6.55Hz)。
Example 278: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -N, N-dimethylacetamide 278
To a suspension of 66(300mg, 0.61mmol) in THF (5mL) was added potassium carbonate (295mg, 2.13mmol) and 2-chloro-N, N-dimethyl-acetamide (82mg, 0.67 mmol). The reaction mixture was stirred for 4 hours, then diluted with DCM and the mixture washed with water (2 × 30mL), dried (MgSO)4) And concentrated in vacuo. The residue obtained is subjected to flash column chromatography (SiO)2Gradient 0-5% MeOH/DCM). The obtained material was used successively with diethyl etherAnd trituration with petroleum ether gave 278 as a white solid (85mg, 0.17mmol, 29%). LCMS: RT 2.72 min, [ M + H]+＝464。1H NMR(ppm)(DMSO-d6): 8.28(1H, d, J ═ 8.29Hz), 7.86(1H, d, J ═ 0.64Hz), 7.85(1H, s), 7.01(1H, dd, J ═ 8.35, 1.78Hz), 6.86(1H, d, J ═ 1.73Hz), 5.89-5.79(1H, m), 4.48-4.41(4H, m), 3.10(2H, s), 3.00(3H, s), 2.89(2H, d, J ═ 10.79Hz), 2.77(3H, s), 2.11(2H, dd, J ═ 12.35, 10.20Hz), 1.71(2H, d, J ═ 12.52Hz), 1.61(2H, td, 12.15, J ═ 12.73, 6.44, 6H, 60 Hz). 1H is masked by the solvent.
Alternatively, a solution of 94(66mg, 0.12mmol) in DCM (1mL), methanol (1mL) and TEA (0.07mL) was treated with N, N-dimethyl-2-chloroacetamide (17mg, 0.14mmol) and TBAI (5mg), then stirred at room temperature for 48 hours, then at 30 ℃ for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and water. The aqueous layer was extracted three times with DCM and 10% methanol/DCM and the combined organic extracts were dried using a phase separation column and then concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 10% methanol/DCM) to give 278 as a white solid (34mg, 61%). LCMS: RT 2.26 min, [ M + H]+465。1H NMR 400MHz(DMSO-d6)：9.43(1H，s)，7.96(1H，s)，7.92(1H，s)，6.91(1H，s)，5.91-5.90(1H，m)，4.60-4.58(4H，m)，3.15(2H，s)，3.06(3H，s)，2.93(2H，d，J＝11.06Hz)，2.82(3H，s)，2.63(1H，m)，2.15-2.14(2H，m)，1.82-1.69(4H，m)，1.50(6H，d，J＝6.60Hz)。
Example 280: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b][1，2，4]Triazolo [1, 5-d][1，4]Oxazazepine88 (Compound 280 of Table 1)
To a solution of amide 87(0.0485g, 0.211mmol) in toluene(1.68mL, 15.8mmol) to the solution was added 1, 1-dimethoxy-N, N-dimethylmethylamine (0.158mL, 1.19mmol) and the mixture was heated to 102 ℃ in a sealed flask with stirring and held for 2 hours (scheme 18). The reaction mixture was then cooled and concentrated to dryness and isopropylhydrazine hydrochloride (0.0396g, 0.358mmol) and acetic acid (0.934mL, 16.4mmol) were added and the reaction mixture was sealed and heated to 102 ℃ overnight with stirring. The reaction mixture was then concentrated to dryness and taken up in DMF and purified by preparative HPLC (acetonitrile/water) to give triazole 88 (42% yield). 1H NMR(500MHz，CDCl3)8.23(d，J＝8.2Hz，1H)，8.02(s，1H)，7.30(dd，J＝15.6，7.8Hz，2H)，7.23(d，J＝7.4Hz，1H)，7.20(d，J＝7.9Hz，1H)，5.77-5.69(m，1H)，4.51(t，J＝5.6Hz，2H)，3.56(t，J＝5.6Hz，2H)，1.60(d，J＝6.6Hz，6H)。LRMS m/z C12H16N6Calculated O is 296.13856, found 297.1[ M +1 ]]。
Example 281: 10-fluoro-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine281
90(0.2g, 0.81mmol), dimethylacetamide dimethyl acetal (0.36mL, 2.4mmol) and toluene (10mL, 90mmol) were combined in a round bottom flask with a Vigreux condensation column attached. Heated at 95 ℃ for > 24 h and concentrated in vacuo. The residue was dissolved in acetic acid and isopropylhydrazine hydrochloride (0.11g, 0.97mmol) was added and heated at 95 ℃ for four hours with a vigreux condensation column attached. LCMS showed reaction completion. Concentration in vacuo and purification by HPLC gave 281(67.7mg, 26% yield, M + 1: 328.1).
Example 282: 9- (1, 2-dimethyl-1H-imidazol-4-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo[1，2-d][1，4]Oxazazepine282
To a 100mL round bottom flask containing NaH (12mg, 0.5mmol) was added DMF (6mL) dropwise followed by 271(100mg, 0.25 mmol). After stirring for about 1 hour, a solution of methyl iodide (48mg, 0.33mmol) in THF was added dropwise at 0 deg.C. The mixture was then slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into water, extracted with EtOAc and the organic phase was taken up with anhydrous Na 2SO4Drying, concentration, and purification by preparative TLC (EtOAc) provide 50mg (52% yield) of 282[ alpha ], [ beta ]1HNMR(CDCl3，400MHz)：8.48(d，J＝8.0Hz，1H)，7.87(s，1H)，7.64(s，1H)，7.48-7.44(m，2H)，7.14(s，1H)，6.04-5.98(m，1H)，4.51-4.43(m，4H)，3.62(s，3H)，2.45(s，3H)，1.60(d，J＝6.8Hz，6H)]And 15mg (16% yield) of the regioisomer 9- (1, 2-dimethyl-1H-imidazol-5-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine291[1H NMR(CDCl3，400MHz)：8.57(d，J＝8.0Hz，1H)，7.87(s，1H)，7.87(s，1H)，7.69(s，1H)，7.16(d，J＝6.8Hz，1H)，7.06-7.04(m，2H)，6.02-5.96(m，1H)，4.54-4.52(m，2H)，4.48-4.47(m，2H)，3.59(s，3H)，2.46(s，3H)，1.60(d，J＝6.8Hz，6H)]。LC-MS：m/z＝389[M+H]+
Example 285: 2- (4- (2- (1, 3-dimethyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol 285
Reaction of 51 with dimethylacetamide dimethyl acetal in toluene followed by dissolution in acetic acid and treatment with methylhydrazine hydrochloride yielded 8-bromo-2- (2, 5-dimethyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene. MS (ESI +) 360.0/362.0.
Adding 8-bromo-2- (2, 5-dimethyl-2H- [1, 2, 4] into a microwave bottle]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Solutions of azulene (0.150g, 0.000416mol) and potassium acetate (0.123g, 0.00125mol) in acetonitrile (2.0mL) and water (2.0 mL). The solution was thoroughly purged with nitrogen. Adding 1- [2- (tetrahydropyran-2-yloxy) -ethyl]-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxaborolan-2-yl) -1H-pyrazole (0.148g, 0.000458mol) and Pd (PPh) 3)4(0.0481g, 0.0000416mol) and the vial was immediately sealed. The reaction mixture was heated to 140 ℃ in a microwave and held for 20 minutes. The mixture is saturated with NH4Partitioned between Cl and DCM and extracted three times with DCM. The organic phases were combined and MgSO4Dried and concentrated. The crude product was dissolved in DCM (5.0mL) and hydrogen chloride (0.00125mol, 4N in dioxane, 0.31mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and partitioned between saturated sodium bicarbonate and DCM and extracted three times with DCM. Most of the product precipitated in the aqueous phase, the mixture was filtered and subjected to reverse phase HPLC, then recrystallized from EtOH/MeOH to give 24mg 285 as a white solid. MS (ESI +) 392.2.1H NMR(500MHz，DMSO)8.40(d，J＝8.4Hz，1H)，8.22(s，1H)，7.94(s，1H)，7.88(s，1H)，7.36(dd，J＝8.4，1.7Hz，1H)，7.27(d，J＝1.7Hz，1H)，4.90(t，J＝5.3Hz，1H)，4.54-4.48(m，4H)，4.21(s，3H)，4.16(t，J＝5.7Hz，2H)，3.77(q，J＝5.6Hz，2H)，2.24(s，3H)。
Example 286: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2-methoxyethyl) piperidin-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine286
To a solution of 66(300mg, 0.61mmol) in DMF (3.5mL) was added potassium carbonate (290mg, 2.10mmol) and 1-bromo-2-methoxy-ethane (93mg, 0.67 mmol). The resulting reaction mixture was stirred at 60 ℃ for 4 hours, then cooled to room temperature and diluted with DCM. The mixture was washed with sodium bicarbonate solution (saturated aqueous solution), water and brine, and then dried (MgSO) 4) And concentrated in vacuo. The residue obtained is subjected to flash column chromatography (SiO)2Gradient 0-8% MeOH/DCM) and trituration with petroleum ether gave 286 as a white solid (127mg, 0.29mmol, 48%). LCMS: RT 3.02 min, [ M + H]+＝437。1H NMR (ppm)(DMSO-d6): 8.28(1H, d, J ═ 8.28Hz), 7.86(1H, d, J ═ 0.62Hz), 7.85(1H, s), 7.01(1H, dd, J ═ 8.36, 1.77Hz), 6.85(1H, d, J ═ 1.72Hz), 5.90-5.80(1H, m), 4.45(4H, m), 3.40(2H, t, J ═ 5.89Hz), 3.20(3H, s), 2.93(2H, d, J ═ 11.11Hz), 2.01(2H, dd, J ═ 12.41, 10.21Hz), 1.70(2H, d, J ═ 12.52Hz), 1.58(2H, dd, J ═ 24.42, 12.21, 3.61, 3.44, 6H, 6.44 Hz). 3H are masked by the solvent.
Example 287: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropanamide 287
To 2- {4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Piperidin-1-yl } -2-methyl-propionitrile (312mg, 0.70mmol) was added concentrated sulfuric acid (3.5 mL). The resulting mixture was stirred at room temperature for 3.5 hours, then poured into ice and basified with sodium carbonate. The aqueous mixture was extracted with 10% MeOH/DCM (. times.5). The combined organic layers were dried (Na) 2SO4) And concentrated in vacuo. The residue obtained is subjected to flash column chromatography (SiO)2Gradient 0-10% MeOH/DCM), then trituration with ether (. times.3)Yield 287(196mg, 0.42mmol, 60%). LCMS: RT 2.67 min, [ M + H]+＝464。1H NMR (ppm)(DMSO-d6): 8.27(1H, d, J ═ 8.27Hz), 7.86(1H, d, J ═ 0.63Hz), 7.85(1H, s), 7.17(1H, d, J ═ 3.55Hz), 7.03(1H, dd, J ═ 8.34, 1.74Hz), 6.91-6.89(2H, m), 5.89-5.79(1H, m), 4.48-4.41(4H, m), 2.80(2H, d, J ═ 10.82Hz), 2.17-2.09(2H, m), 1.77-1.60(4H, m), 1.44(6H, d, J ═ 6.60Hz), 1.05(6H, s). 1H is masked by the solvent.
Example 288: 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) ethanol 288
To 2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]To a suspension of azulene hydrochloride (100mg, 0.23mmol) in DMF (2mL) was added disodium hydrogen phosphate (107mg, 0.75mmol), TEA (2 drops) and 2- (2-bromo-ethoxy) -tetrahydropyran (38 μ L, 0.25 mmol). The resulting mixture was stirred at room temperature overnight, then TEA (100. mu.L) was added. The reaction mixture was stirred at 50 ℃ for 5 hours and then allowed to stand at room temperature over the weekend. The reaction mixture was heated to 50 ℃ and stirred overnight, then 2- (2-bromo-ethoxy) -tetrahydropyran (38 μ L, 0.25mmol) and potassium iodide (10mg, 0.06mmol) were added, followed by stirring at 55 ℃ overnight. The solution was cooled and loaded onto a SCX-2 column, washed with MeOH, then 2M NH 3The solution in MeOH eluted. The residue obtained is subjected to flash column chromatography (SiO)2Gradient 0-10% MeOH/DCM) to yield 288(31mg, 0.07mmol, 31%). LCMS: RT 2.59 min, [ M + H]+437。1H NMR (ppm)(CDCl3)：8.42(1H，d，J＝8.30Hz)，7.58(1H，s)，7.00(1H，dd，J＝8.34，1.83Hz)，6.88(1H，d，J＝1.78Hz)，5.93-5.83(1H，m)，4.46-4.43(2H，m)，4.41-4.37(2H, m), 3.70(2H, t, J ═ 5.19Hz), 3.17(2H, d, J ═ 11.24Hz), 2.68(2H, t, J ═ 5.17Hz), 2.62 to 2.50(1H, m), 2.38(3H, s), 2.36 to 2.27(2H, m), 2.05 to 1.85(4H, m), 1.54(6H, d, J ═ 6.65 Hz). No OH was observed.
Example 289: 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropanamide 289
To 2- {4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4 ]]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Piperidin-1-yl } -2-methyl-propionitrile (140mg, 0.31mmol) was added concentrated sulfuric acid (1.75 mL). The mixture was stirred at room temperature for 3.5 hours, then the reaction mixture was diluted with ice and neutralized with sodium carbonate. The aqueous mixture was extracted with 10% MeOH/DCM (. times.5), and the organic phase was dried (MgSO 5)4) And concentrated in vacuo. The residue obtained is subjected to flash column chromatography (SiO)2Gradient 0-10% MeOH/DCM). The material was triturated with ether and then subjected to reverse phase HPLC (C18, gradient 20-70% MeOH/[ 0.1% formic acid/water) ]0.1% formic acid). The resulting residue was taken up in MeOH (1.2mL) and treated with a 0.2M HCl in ether solution. The solution was concentrated in vacuo to give 289(14mg, 0.03mmol, 9%). LCMS: RT 2.65 min, [ M + H]+＝478。1H NMR(ppm)(DMSO-d6): 9.50(1H, m), 8.33(1H, d, J ═ 8.29Hz), 7.97(1H, s), 7.93(1H, s), 7.86(1H, s), 7.02(1H, dd, J ═ 8.36, 1.75Hz), 6.87(1H, d, J ═ 1.71Hz), 5.78-5.71(1H, m), 4.50-4.44(4H, m), 3.19-3.04(2H, m), 2.91-2.80(1H, m), 2.25(3H, s), 2.12(2H, d, J ═ 13.49Hz), 1.98(2H, d, J ═ 13.54Hz), 1.51(6H, s), 1.43(6H, d, J ═ 6.59 Hz). 2H are masked by the solvent.
Example 292: 1- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropan-2-ol 292
To 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]To a stirred suspension of azulene trifluoroacetate (300mg, 0.61mmol) in THF (8mL) was added lithium perchlorate (65mg, 0.61mmol) and DIPEA (0.21mL, 1.21mmol), followed by 1, 2-epoxy-2-methylpropane (0.54mL, 0.81mmol) and the mixture stirred at room temperature for 5h, followed by water (2.5 mL). After stirring for a further 18 hours, DIPEA (0.16mL, 0.92mmol) was added and the mixture was heated at 45 ℃ for 5 hours and then held at room temperature for 72 hours. The reaction mixture was diluted with DCM and washed with water, then dried (MgSO) 4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Pretreated with 25% TEA/DCM, gradient 0 to 5% methanol/DCM), then lyophilized with methanol/water and triturated in petroleum ether to give 292 as an opalescent solid (92mg, 34%). LCMS: RT 2.76 min, [ M + H]+＝451。1H NMR 400MHz(DMSO-d6)：8.32(1H，d，J＝8.28Hz)，7.90(2H，d，J＝2.80Hz)，7.05(1H，dd，J＝8.35，1.77Hz)，6.90(1H，d，J＝1.70Hz)，7.27-4.48(1H，m)，4.49(4H，q，J＝5.87Hz)，4.03(1H，s)，3.04(2H，d，J＝10.80Hz)，2.46(1H，s)，2.23(4H，s)，1.70(4H，s)，1.48(6H，d，J＝6.59Hz)，1.10(6H，s)。
Example 293: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) ethanol 293
To 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]To a stirred suspension of azulene trifluoroacetate (300mg, 0.61mmol) in DMF (3.5mL) were added potassium carbonate (290mg, 2.1mmol) and 2- (2-bromoethoxy) tetrahydro-2H-pyran and the mixture was heated at 60 ℃ for 18H before dilution with DCM. The resulting solution was washed with saturated aqueous sodium bicarbonate, water, and brine, then dried (MgSO)4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 8% methanol/DCM) to give 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8- {1- [2- (tetrahydropyran-2-yloxy) -ethyl ]-piperidin-4-yl } -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e)]Azulene as an opalescent solid (147mg, 48%).1H NMR400MHz(CDCl3)：8.44(1H，d，J＝8.29Hz)，7.87(1H，s)，7.63(1H，s)，7.04(1H，dd，J＝8.33，1.81Hz)，6.92(1H，d，J＝1.75Hz)，6.01-6.00(1H，m)，4.63(1H，t，J＝3.54Hz)，4.46-4.45(4H，m)，3.92-3.91(2H，m)，3.65(1H，m)，3.57-3.49(1H，m)，3.15(2H，m)，2.73(2H，m)，2.53(1H，m)，2.25(2H，m)，1.87(5H，m)，1.73-1.69(3H，m)，1.60(8H，m)。
2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8- {1- [2- (tetrahydropyran-2-yloxy) -ethyl]-piperidin-4-yl } -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e)]A solution of azulene (371mg, 0.73mmol) in methanol (3.5mL) was treated with a solution of 4N HCl in dioxane (3.5mL) and the mixture was stirred for 45 minutes then concentrated in vacuo. The resulting residue was again subjected to the above reaction conditions and stirred at room temperature for 1 hour, then concentrated in vacuo. The resulting residue was partitioned between DCM and saturated aqueous sodium bicarbonate, the aqueous phase was extracted twice with DCM and the combined organic extracts were washed with brine and then dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2The column was pretreated with 1% TEA/DCM, gradient 0 to 7% methanol/DCM) to give 293 as a yellow foam (94mg, 30%). LCMS: RT 2.61 min, [ M + H]+＝423。1H NMR400MHz(DMSO-d6)：8.32(1H，d，J＝8.28Hz)，7.89(2H，d，J＝1.96Hz)，7.05(1H，dd，J＝8.31，1.76Hz)，6.89(1H，d，J＝1.71Hz)，5.88-5.87(1H，m)，4.49(4H，q，J＝5.91Hz)，3.53(2H，t，J＝7.21Hz)，3.03(2H，d，J＝11.27Hz)，2.52(3H，m)，2.16(2H，t，J＝11.38Hz)，1.76(2H，d，J＝12.61Hz)，1.67(2H，d，J＝12.75Hz)，1.47(6H，d，J＝6.60Hz)。
Example 294: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (tetrahydro-2H-pyran-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine294
3, 6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (125mg, 0.54mmol) and 8- (5, 5-dimethyl- [1, 3, 2 ] methyl ester ]Dioxaborolan-2-yl) -2- (2-isopropyl-2H- [1, 2, 4]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene (200mg, 0.491mmol), PdCl2A mixture of dppf DCM (41mg, 0.05mmol, 10 mol%), cesium carbonate (400mg, 1.23mmol), DME (2mL) and water (0.2mL) was heated at 80 deg.C for 90 min. The cooled reaction mixture was diluted with DCM, filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 100% EtOAc/cyclohexane) to give 8- (3, 6-dihydro-2H-pyran-4-yl) -2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene (73mg, 39%). LCMS: RT ═ 4.36, [ M + H]+＝378。
P-8- (3, 6-dihydro-2H-pyran-4-yl) -2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]A mixture of azulene (73mg, 0.19mmol), 20% palladium hydroxide on charcoal (50mg) and EtOAc (10mL) was degassed and then stirred at room temperature for 72 h under a hydrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was triturated in cyclohexane to give 294 as a white solid (51mg, 71%). LCMS: RT ═ 4.30 min, [ M + H ]+＝380。1H NMR400MHz(DMSO-d6)：8.34(1H，d，J＝8.29Hz)，7.91(2H，d，J＝1.36Hz)，7.08(1H，dd，J＝8.34，1.79Hz)，6.92(1H，d，J＝1.73Hz)，5.90-5.89(1H，m)，4.50(4H，q，J＝5.58Hz)，3.96-3.95(2H，m)，3.44(2H，td，J＝11.21，3.01Hz)，2.77-2.76(1H，m)，1.73-1.66(4H，m)，1.49(6H，d，J＝6.60Hz)。
Example 295: 2- (2-ethoxyphenyl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 295
A solution of 40(80mg, 1 equivalent), 2-ethoxyphenylboronic acid (66mg, 1.75 equivalents), and tetrakis (triphenylphosphine) palladium (10mg, 0.05 equivalents) in 1.0M aqueous sodium carbonate (1.0mL) and acetonitrile (1.0mL) was heated to 140 ℃ in a sealed microwave reactor and held for 10 minutes. The crude reaction mixture was concentrated and purified using reverse phase HPLC to give 295(9 mg). ESI-MS: 365.1(M)+。
Example 296: 2- (3-isopropylphenyl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 296
A solution of 40(80mg, 1 equivalent), 3-isopropylphenylboronic acid (65mg, 1.75 equivalents), and tetrakis (triphenylphosphine) palladium (10mg, 0.05 equivalents) in 1.0M aqueous sodium carbonate (1.0mL) and acetonitrile (1.0mL) was heated to 140 ℃ in a sealed microwave reactor and held for 10 minutes. The crude reaction mixture was concentrated and purified using reverse phase HPLC to give 296(4 mg). ESI-MS: 363.1(M)+。
Example 297: 2- (2-ethylphenyl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 297
A solution of 40(80mg, 1 equivalent), 2-ethylphenylboronic acid (60mg, 1.75 equivalents), and tetrakis (triphenylphosphine) palladium (10mg, 0.05 equivalents) in 1.0M aqueous sodium carbonate (1.0mL) and acetonitrile (1.0mL) was heated to 140 ℃ in a sealed microwave reactor and held for 10 minutes. The crude reaction mixture was concentrated and purified using reverse phase HPLC to give 297(11 mg). ESI-MS: 349.1(M) +。
Example 298: 2- (2-isopropylphenyl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 298
A solution of 40(80mg, 1 equivalent), 2-isopropylphenylboronic acid (65mg, 1.75 equivalents), and tetrakis (triphenylphosphine) palladium (10mg, 0.05 equivalents) in 1.0M aqueous sodium carbonate (1.0mL) and acetonitrile (1.0mL) was heated to 140 ℃ in a sealed microwave reactor and held for 10 minutes. The crude reaction mixture was concentrated and purified using reverse phase HPLC to give 298(23 mg). ESI-MS: 363.1(M)+。
Example 299: 2- (3- (trifluoromethyl) phenyl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-Carboxylic acid methyl ester 299
A solution of 40(80mg, 1 equivalent), 3- (trifluoromethyl) phenylboronic acid (76mg, 1.75 equivalents) and tetrakis (triphenylphosphine) palladium (10mg, 0.05 equivalents) in 1.0M aqueous sodium carbonate (1.0mL) and acetonitrile (1.0mL) was placed in a sealed microwave reactorMedium heated to 140 ℃ and held for 10 minutes. The crude reaction mixture was concentrated and purified using reverse phase HPLC to give 299(34 mg). ESI-MS: 389.1(M)+。
Example 300: 2- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) acetamide 300
To 194mg (0.500mmol) of 9-bromo-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1, 2-d ] s][1，4]Oxazazepine411. A mixture of 0.436mL (2.00mmol) of 1- (tert-butyldimethylsilyloxy) -1-methoxyethylene, 19.6mg (0.025mmol) of bis (tri-o-tolylphosphine) palladium (II) dichloride (19.6mg, 0.0250mmol) and 309mg (1.00mmol) of tributyltin fluoride (309mg, 1.00mmol) in 3.0mL of THF was degassed and then heated at 80 ℃ for 18 hours. The mixture was filtered through celite, the filtrate was mixed with 10mL of water, the mixture was acidified to pH 2 and extracted with EtOAc. The organic phases were combined and MgSO4Dried and concentrated. The residue was purified by flash chromatography (gradient 0-5% methanol in DCM) to give 98mg of 2- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f/] -5]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) acetic acid methyl ester (51%). m/z 382.2, calculated 381.18.
98mg (0.257mmol) of 2- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) acetic acid methyl ester and 2.0mL 1.0A mixture of aqueous M lithium hydroxide in a methanol/THF (1: 1) mixture (6mL) was stirred at 50 ℃ for 3 hours. The mixture was concentrated and acidified to pH 3 by careful addition of 1N aqueous hydrogen chloride. The precipitate was collected and dried under high vacuum for 18 hours to give 2- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -f [ ] ]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) acetic acid. The yield was 58 mg. m/z 368.2, calculated 367.16.
58mg (0.158mmol) of 2- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineA mixture of-9-yl) acetic acid, 76mg (0.20mmol) N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate, 16mg (0.30mmol) ammonium chloride and 28. mu.L (0.200mmol) TEA in 3.0mL of N, N-dimethylformamide was stirred for 40 min. The mixture was concentrated in vacuo and triturated with 10mL of water. The solid was collected and purified by RP HPLC (acetonitrile gradient) to give 300. The yield was 8.1 mg. m/z 367.2, calculated 366.18.1HNMR(500MHz，DMSO)8.30(d，J＝8.2，1H)，7.86(s，1H)，7.44(s，1H)，7.04(d，J＝8.3，1H)，6.96(s，1H)，6.88(s，1H)，5.80(dt，J＝13.1，6.5，1H)，4.49(q，J＝6.2，4H)，3.38(s，2H)，2.25(s，3H)，1.45(d，J＝6.6，6H)。
Example 302: 1- (4- (2- (1-isopropyl-3- (methoxymethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol 302
Step 1: to 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-dinitrogen at 0 DEG CHetero-benzo [ e)]To a mixture of azulene-2-carboxylic acid (1.92g, 6.2mmol) and tert-butyl N' -isopropyl-hydrazinecarboxylate (1.30g, 7.5mmol) in DMF (20mL) were added DIPEA (2.70mL, 15.5mmol) and HATU (3.54g, 9.3 mmol). The reaction mixture was stirred at room temperature for 7 hours, then DMF (40mL) was added and stirred overnight. The reaction mixture was concentrated in vacuo and the resulting residue partitioned between DCM and water. The aqueous phase was extracted with DCM (× 2), and the combined organic extracts were washed with 10% citric acid solution, saturated sodium bicarbonate solution and brine, dried (Na) 2SO4) And concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0-90% EtOAc/cyclohexane) to yield N' - (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Tert-butyl azulene-2-carbonyl) -N' -isopropyl-hydrazinecarboxylate as white solid (3.02g, quantitative yield). LCMS: RT 4.76 min, [ M + H]+＝465/467。1H NMR400MHz(DMSO-d6)：8.62(1H，s)，8.40(1H，d，J＝8.59Hz)，7.69(1H，s)，7.23-7.22(2H，m)，4.81(1H，s)，4.44(4H，s)，1.32(9H，s)，1.13(6H，d，J＝6.64Hz)。
Step 2: n' - (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e)]A solution of tert-butyl azulene-2-carbonyl) -N' -isopropyl-hydrazinecarboxylate (2.71g, 5.83mmol) in methanol (52mL) was treated with a solution of 4N HCl in dioxane (5.83mL, 23.3 mmol). The reaction mixture was stirred at 50 ℃ overnight, then the reaction mixture was concentrated in vacuo and the resulting residue was triturated with ether to give 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulene-2-carboxylic acid N-isopropyl-hydrazide dihydrochloride as a pale yellow foam (2.69g, quantitative yield). LCMS: RT 4.17 min, [ M + H]+＝365/367。
And step 3: 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e)]A suspension of azulene-2-carboxylic acid N-isopropyl-hydrazide dihydrochloride (2.69g, 6.1mmol) in DCM (61mL) was treated with TEA (3.84mL, 27.6 mmol). The resulting solution was cooled to 0 ℃, then methoxyacetyl chloride (1.12mL, 12.3mmol) was added dropwise and the reaction mixture was stirred at 0 ℃ for 1.75 hours. Saturated carbonic acid for reaction mixture The sodium hydrogen solution was quenched and the phases separated. The aqueous phase was extracted with DCM (× 2) and the combined organic phases were washed with 10% citric acid solution, saturated sodium bicarbonate solution and then brine. The organic solution was dried (Na)2SO4) Concentrated in vacuo and the resulting solid triturated with ether to give 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulene-2-carboxylic acid N-isopropyl-N' - (2-methoxy-acetyl) -hydrazide as an off-white solid (2.29g, 5.24mmol, 86%). LCMS: RT 4.29 min, [ M + H]+＝437/439。1H NMR400MHz(DMSO-d6)：9.61(1H，s)，8.29(1H，d，J＝8.63Hz)，7.71(1H，s)，7.27(1H，dd，J＝8.64，2.06Hz)，7.21(1H，d，J＝2.06Hz)，4.84(1H，t，J＝6.91Hz)，4.45(4H，s)，3.92(2H，s)，3.33(3H，s)，1.15(6H，d，J＝6.66Hz)。
And 4, step 4: reacting 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene-2-carboxylic acid N-isopropyl-N' - (2-methoxy-acetyl) -hydrazide (1.00g, 2.29mmol) was suspended in phosphorous (V) acid chloride (23mL) and then stirred at 100 ℃ for 18 h. The reaction mixture was concentrated in vacuo, then the residue was azeotroped with toluene (× 3) to afford a brown solid. To the brown solid was added acetic acid (23mL) and ammonium chloride (1.76g, 22.9mmol), the resulting mixture was stirred at 125 ℃ for 2.5 hours, then ammonium chloride (0.88g, 11.4mmol) was added, and the reaction mixture was stirred at 125 ℃ for 1 hour, then concentrated in vacuo. The resulting residue was treated with water and extracted with DCM (× 3). The combined organic extracts were washed with saturated aqueous sodium bicarbonate, then brine, and dried (Na) 2SO4) And concentrated in vacuo. The resulting solid was triturated with ether to give 8-bromo-2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene as light brown solid (0.73g, 1.74mmol, 76%). LCMS: RT 4.95 min, [ M + H]+＝418/420。1H NMR 400MHz(DMSO-d6)：8.29(1H，d，J＝8.65Hz)，7.93(1H，s)，7.31(1H，dd，J＝8.66，2.05Hz)，7.25(1H，d，J＝2.05Hz)，5.79-5.78(1H，m)，4.49(4H，s)，4.33(2H，s)，3.27(3H，s)，1.43(6H，d，J＝6.60Hz)。
And 5: para 8-bromo-2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene (100mg, 0.24mmol), 2-methyl-1- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Dioxaborolan-2-yl) -pyrazol-1-yl]-propan-2-ol (127mg, 0.48mmol), PdCl2A mixture of (dppf). DCM (9.8mg, 0.012mmol), cesium carbonate (234mg, 0.72mmol), DME (1.6mL), water (0.27mL) and IMS (0.5mL) was degassed and then heated at 140 ℃ for 20 minutes using microwave radiation. The reaction mixture was partitioned between DCM and water, the aqueous phase was extracted twice with DCM and the combined organic extracts were washed with brine and then dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to RP HPLC (C18 column, gradient 5 to 95% methanol/water + 0.1% HCO2H) Yield 302 as a white solid (40mg, 35%). LCMS: RT 3.77 min, [ M + H ]+478。1H NMR 400MHz(DMSO-d6)：8.37(1H，d，J＝8.38Hz)，8.17(1H，s)，7.94(2H，d，J＝7.28Hz)，7.40(1H，dd，J＝8.37，1.80Hz)，7.28(1H，d，J＝1.77Hz)，5.89-5.88(1H，m)，4.74(1H，s)，4.53(4H，m)，4.38(2H，s)，4.04(2H，s)，3.32(3H，s)，1.49(6H，d，J＝6.60Hz)，1.10(6H，s)。
Example 303: (3R, 4R) -4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-3-ol 303
4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Tert-butyl-3, 6-dihydro-2H-pyridine-1-carboxylate (1.05g, 2.21mmol) was partially dissolved in anhydrous diethylene glycol dimethyl ether (25mL) and borane/THF complex solution (1M in THF, 13.2mL, 13.2mmol) was added dropwise. After stirring briefly at room temperature, the mixture was left to stand for 16 hoursThen (c) is performed. The mixture was then cooled in ice and water (2mL), 2M sodium hydroxide (6.5mL) and 35% hydrogen peroxide (1.7mL, 16.24mmol) were added dropwise. The mixture was heated at 50 ℃ for 6 hours, then cooled, diluted with water (about 45mL) and extracted three times with EtOAc. The combined organic extracts were dried (Na)2SO4) And concentrated. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0-8.5% methanol/DCM) to give the title compound (0.78g, 71%) which contained about 20% of the 4-hydroxypiperidine isomer. This material was recrystallized twice from EtOAc/methanol to give rac-trans-3-hydroxy-4- [2- (2-isopropyl-2H- [1, 2, 4) ]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Tert-butyl piperidine-1-carboxylate, which contains < 5% of the cis isomer (0.38 g). LCMS: RT ═ 4.44, [ M + H]+＝495。1H NMR 400MHz(DMSO-d6)：8.39(1H，d，J＝8.25Hz)，7.89(1H，s)，7.47(1H，d，J＝2.62Hz)，7.03(1H，dd，J＝8.29，1.80Hz)，6.77(1H，s)，6.07-5.99(1H，m)，4.37-4.37(6H，m)，4.19-4.18(1H，m)，3.73-3.73(1H，m)，2.66-2.66(3H，m)，1.81-1.81(1H，m)，1.61(6H，d，J＝6.01Hz)，1.50(9H，s)。
Trans-racemic-3-hydroxy-4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]To a solution of tert-butyl-piperidine-1-carboxylate (180mg, 0.36mmol) in DCM (1mL) and methanol (0.6mL) was slowly added a solution of 4M HCl in dioxane (1.6mL) and the reaction mixture was stirred at room temperature for 2.5 h, then concentrated in vacuo. The resulting residue was triturated in ether to give 4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-3-ol, which was resolved to give (3R, 4R) enantiomer 303 as a white solid (172mg, quantitative). LCMS: RT 2.41 min, [ M + H]+395。1H NMR 400MHz(DMSO-d6): 9.30(1H, broad singlet), 9.10(1H, broad singlet), 8.36(1H, d)J ═ 8.28Hz), 8.10(1H, broad singlet), 8.06(1H, s), 7.04(1H, d, J ═ 8.38Hz), 6.91(1H, s), 5.87(1H, m), 4.53(4H, d, J ═ 8.12Hz), 3.90(1H, broad multiplet), 3.25(2H, m), 2.78(1H, m), 2.52(2H, m), 1.80(2H, m), 1.50(1H, d, J ═ 6.58 Hz).
Example 305: 2- (5- (9-bromo-5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-yl) acetamide 305
8-bromo-2-iodo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] according to example 420]Azulene was reacted with 2-carbamimidoyl-acetamide hydrochloride and isopropylhydrazine hydrochloride. The crude product was purified by reverse phase HPLC to give 305 (yield 29 mg). LCMS: 433.0.1H NMR(500MHz，DMSO)8.33(d，J＝8.6Hz，1H)，7.95(s，1H)，7.39(s，1H)，7.35(dd，J＝8.7，2.0Hz，1H)，7.29(d，J＝2.0Hz，1H)，6.97(s，1H)，5.79(dt，J＝13.2，6.6Hz，1H)，4.53(s，4H)，3.45(s 2H)，1.47(d，J＝6.6Hz，6H)。
example 306: 5- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [4, 3-f][1，4]Oxazazepine-10-yl) pyridin-2 (1H) -one 306
22(85.0mg, 0.257mmol) was dissolved in acetonitrile (2mL, 50mmol) and water (2mL, 100mmol) in which potassium acetate (85.5mg, 0.871mmol) was dissolved. Degassing was performed by bubbling nitrogen for 5 minutes. 2-Fluoropyridine-5-boronic acid (47.1mg, 0.334mmol) was added followed by Pd (PPh)3)4(40mg, 0.035 mmol). The reaction mixture was irradiated with microwaves at 145 ℃ for 35 minutes. Cooled to rt and extracted with EtOAc. Concentrating the combined organic matterTo obtain a fluorine intermediate 10- (6-fluoropyridin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [4, 3-f][1，4]OxazazepineThis was dissolved in 1, 2-dimethoxyethane (3.00mL, 28.9 mmol). 10% aqueous HCl (3mL) was added. The reaction mixture was stirred and heated at 80 ℃ overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 306, which was analyzed by rphplc. MS (ESI +) -390.1.
Example 307: 4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [4, 3-f][1，4]Oxazazepine-10-yl) piperazin-2-one 307
A solution of 22(80.0mg, 0.242mmol), piperazin-2-one (48.4mg, 0.484mmol), XPhos (23.0mg, 0.0484mmol) and sodium tert-butoxide (46.5mg, 0.484mmol) was heated in a microwave at 125 ℃ for 30 minutes. The reaction mixture was filtered through celite, then rinsed with EtOAc. The filtrate was washed with water and brine. The organic layer was dried (Na)2SO4) Concentrated to give 307, which is analyzed by rHPLC. MS (ESI +) ═ 395.2.1H NMR(500MHz，DMSO)8.06(s，1H)，8.03(d，J＝5.7Hz，2H)，7.93(s，1H)，7.59(s，1H)，5.72(dt，J＝13.1，6.6Hz，1H)，4.62-4.52(m，2H)，4.51-4.39(m，2H)，3.94(s，2H)，3.73-3.62(m，2H)，3.37-3.30(m，2H)，1.51(d，J＝6.6Hz，6H)。
Example 308: 2- (4- (2- (1-isopropyl-3- (methoxymethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperazinePyridin-1-yl) acetamide 308
Step 1: reacting 8-bromo-2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene (250mg, 0.60mmol), 3, 6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (370mg, 1.20mmol), cesium carbonate (585mg, 1.79mmol) and 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride DCM (24mg, 0.03mmol) were suspended in DME (4.0mL), IMS (1.3mL) and water (0.68mL) and the reaction mixture was purged with argon. The reaction mixture was heated in a sealed tube using microwave radiation at 140 ℃ for 20 minutes. The reaction mixture was washed with water, extracted with DCM (2 × 15mL) and the combined organics washed with brine, dried (Na) 2SO4) And then concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Eluting with 5% methanol/DCM) to obtain 4- [2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as brown foam (224mg, 72%). LCMS: RT ═ 5.08 min, [ M + H]+＝521。
Step 2: to 4- [2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4 ]]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]To a solution of tert-butyl-3, 6-dihydro-2H-pyridine-1-carboxylate (224mg, 0.43mmol) in IMS (3mL) was added a catalytic amount of palladium on carbon (10 wt%) and the reaction mixture was stirred under a hydrogen atmosphere at 50 ℃ for 16H. The reaction mixture was filtered and the solid was washed with IMS (10 mL). The filtrate was concentrated in vacuo and the resulting residue was subjected to flash chromatography (SiO)2Eluting with 2% MeOH/DCM) to give 4- [2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Tert-butyl piperidine-1-carboxylate as a yellow oil (162mg, 72%). LCMS: RT 5.05 min, [ M + H ]+＝523。
And step 3: to 4- [2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4 ]]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-piperazineTo a solution of tert-butyl pyridine-1-carboxylate (158mg, 0.30mmol) in DCM (1.5mL) was added TFA (1.5mL, 20.2mmol) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo and the residue was azeotroped with diethyl ether. The resulting oil was triturated with ether to give 2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene trifluoroacetate salt as solid which was collected by filtration (103mg, 64%). LCMS: RT 3.03 min, [ M + H]+＝423。1H NMR400MHz(DMSO-d6)：8.56(1H，s)，8.33(1H，d，J＝8.33Hz)，7.90(1H，s)，7.00(1H，dd，J＝8.38，1.78Hz)，6.85(1H，d，J＝1.73Hz)，5.81-5.80(1H，m)，4.46(4H，d，J＝2.51Hz)，4.33(2H，s)，3.34(2H，d，J＝12.58Hz)，3.27(3H，s)，2.98-2.95(2H，m)，2.82(1H，t，J＝11.91Hz)，1.93(2H，d，J＝13.66Hz)，1.75(2H，t，J＝12.95Hz)，1.44(6H，d，J＝6.60Hz)。
And 4, step 4: 2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]A suspension of azulene trifluoroacetate (99mg, 0.18mmol) in THF (1.8mL) was treated with 2-bromoacetamide (109mg, 0.2mmol) followed by potassium carbonate (56mg, 0.41mmol) and the reaction mixture was stirred at room temperature before dilution with DCM and water. The aqueous layer was extracted twice with DCM and the combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine, then dried (Na) 2SO4) Filtered and concentrated in vacuo. The resulting residue was dissolved in methanol, the solution was cooled to 0 ℃ and treated with water to give a precipitate which was filtered off and washed with cold methanol/water to give a white solid. The solid was azeotroped with methanol then ether to afford 308 as a white solid (38mg, 43%). LCMS: RT 2.66 min, [ M + H]+＝480。1H NMR 400MHz(DMSO-d6)：8.39(1H，d，J＝8.32Hz)，8.16(1H，s)，7.09-7.08(1H，m)，6.97(1H，s)，5.76-5.74(1H，m)，4.58(4H，d，J＝14.42Hz)，4.51(2H，s)，3.96(2H，s)，3.60(2H，d，J＝11.71Hz)，3.37(3H，s)，3.20(2H，m)，2.86(1H，m)，2.03(4H，m)，1.53(6H，d，J＝6.57Hz)。
Example 309: 2- (1-isopropyl-3- (methoxymethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine309
Step 1: reacting 9-bromo-2-iodo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]A mixture of azulene (2.00g, 5.1mmol), 2-methoxy-acetamidine hydrochloride (0.76g, 6.1mmol) and TEA (5.00mL, 35.9mmol) in DMF (38mL) was evacuated and backfilled with nitrogen (. times.3). The reaction mixture was treated with Xantphos (0.15g, 0.26mmol) and palladium (II) diacetate (57mg, 0.26mmol), then the reaction mixture was washed with carbon monoxide gas and the reaction mixture was stirred at 60 ℃ for 3.5 hours. The reaction mixture was cooled to room temperature, purged with nitrogen, and then treated with isopropyl-hydrazine hydrochloride (1.70g, 15.0mmol) and acetic acid (19 mL). After stirring at 60 ℃ for 1.5 h, the reaction mixture was diluted with EtOAc (350 mL). The solution was washed with 1N NaOH (2X 50mL) followed by brine (50mL) and then dried (Na) 2SO4) And concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0-3% methanol/DCM), then triturated with ether to give 9-bromo-2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene as a light pink solid (0.85g, 2.0mmol, 40%). LCMS: RT 4.95 min, [ M + H]+＝418/420。1H NMR 400MHz(DMSO-d6)：8.44(1H，d，J＝2.57Hz)，7.94(1H，s)，7.43(1H，dd，J＝8.74，2.58Hz)，6.99(1H，d，J＝8.74Hz)，5.72-5.63(1H，m)，4.49(4H，d，J＝3.06Hz)，4.33(2H，s)，3.27(3H，s)，1.44(6H，d，J＝6.60Hz)。
Step 2: to the 9-bromo-2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4 ]]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene (0.8)5g, 2.0mmol) in IMS (20mL) DCM (6mL) was added. The mixture was degassed with nitrogen and then treated with palladium on charcoal (10% palladium, 50% water, 350 mg). The vessel was evacuated and backfilled with hydrogen and stirred at room temperature for 18 hours, then the catalyst was added and the reaction mixture stirred for 72 hours. The reaction mixture was filtered and then concentrated in vacuo to give 309 as a pale yellow solid (0.73g, quantitative yield). LCMS: RT 4.55 min, [ M + H]+＝340。1H NMR400MHz(DMSO-d6)：8.37(2H，dd，J＝9.88，1.75Hz)，7.30(1H，ddd，J＝7.93，7.18，1.70Hz)，7.12-7.12(1H，m)，7.03(1H，dd，J＝8.19，1.22Hz)，5.83-5.74(1H，m)，4.48-4.47(4H，m)，4.36(2H，s)，3.28(3H，s)，1.45(6H，d，J＝6.60Hz)。
Example 313: 9-bromo-2- (3-cyclopropyl-1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine313
8-bromo-2-iodo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] according to example 420 ]Reacting azulene with cyclopropane formamidine hydrochloride and isopropylhydrazine hydrochloride. The crude product was purified by reverse phase HPLC to give 313 (to 75 mg). LCMS: 414.0.1H NMR(400MHz，DMSO)8.30(m，H)，7.90(s，1H)，7.35(dd，J＝8.7，2.0Hz，1H)，7.29(d，J＝2.0Hz，1H)，5.75(dt，J＝13.2，6.6Hz，1H)，4.51(m.4H)，2.02-1.91(m，1H)，1.45(d，J＝6.6Hz，6H)，0.93-0.85(m，2H)，0.84-0.77(m，12H)。
example 314: 9- (1-ethylpiperidin-4-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine314
To 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]To a stirred suspension of azulene trifluoroacetate (189mg, 0.37mmol) in DCE (3mL) were added acetic acid (3 drops, catalytic amount), acetaldehyde (0.023mL, 0.41mmol) and sodium triacetoxyborohydride (94mg, 0.44 mmol). After stirring at room temperature for 2 hours, DCM was added and the mixture was washed with saturated aqueous sodium bicarbonate solution, water and brine, then dried (MgSO)4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 20% methanol/DCM), then lyophilized with methanol/water and triturated in petroleum ether to give 314 as a brown solid (18mg, 12%). LCMS: RT 2.73 min, [ M + H]+＝407。1H NMR 400MHz(DMSO-d6)：8.32(1H，d，J＝8.29Hz)，7.90(2H，d，J＝2.38Hz)，7.06(1H，d，J＝8.41Hz)，6.90(1H，s)，5.90-5.89(1H，m)，4.49(4H，d，J＝7.47Hz)，2.97(2H，d，J＝10.98Hz)，2.34(2H，q，J＝7.20Hz)，1.95(2H，t，J＝11.47Hz)，1.76(2H，d，J＝12.54Hz)，1.72-1.54(3H，m)，1.48(6H，d，J＝6.59Hz)，1.02(3H，t，J＝7.20Hz)。
Example 315: (5- (5, 6-dihydrobenzo [ f ]]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-yl) methanol 315
Reacting 8-bromo-2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]A solution of azulene 309(280mg, 0.67mmol) in 48% aqueous HBr (4.19mL) was heated at 100 ℃ for 4 h and then cooled to room temperature. The solution was neutralized by addition of 1M aqueous sodium carbonate solution, then extracted with DCM, the organic layer washed with water and then dried (Na)2SO4) Filtered and concentrated in vacuo to give [5- (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulen-2-yl) -1-isopropyl-1H- [1, 2, 4]Triazol-3-yl]Methanol, as an opalescent solid (162mg, 60%). LCMS: RT 4.74 min, [ M + H]+＝404。1H NMR 400MHz(DMSO-d6)：8.30(1H，d，J＝8.65Hz)，7.91(1H，s)，7.33(1H，dd，J＝8.65，2.06Hz)，7.27(1H，d，J＝2.03Hz)，5.82-5.75(1H，m)，5.18(1H，t，J＝6.03Hz)，4.51(4H，s)，4.40(2H，d，J＝5.99Hz)，1.44(6H，d，J＝6.60Hz)。
Para [5- (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulen-2-yl) -1-isopropyl-1H- [1, 2, 4]Triazol-3-yl]A solution of methanol (67mg, 0.17mmol) in IMS was degassed and then treated with Pd/C (10 wt%, 120mg) and then stirred at room temperature under a hydrogen atmosphere for 18 h. The reaction mixture was filtered through celite, washed with DCM and the filtrate was concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 7% methanol/DCM) to give 315 as a white solid (13mg, 24%). LCMS: RT 3.79 min, [ M + H ]+＝326。1H NMR400MHz(DMSO-d6)：8.42(1H，dd，J＝8.03，1.74Hz)，7.91(1H，s)，7.33(1H，ddd，J＝8.16，7.12，1.77Hz)，7.16-7.16(1H，m)，7.06(1H，dd，J＝8.18，1.21Hz)，5.86(1H，t，J＝6.61Hz)，5.21(1H，t，J＝6.03Hz)，4.52(4H，q，J＝5.81Hz)，4.42(2H，d，J＝6.00Hz)，1.48(6H，d，J＝6.61Hz)。
Example 316: 3- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) propanamide 316
A mixture of 0.194g (0.500mmol)194, 0.180mL (2.00mmol) methyl acrylate, 22.4mg (0.0999mmol) palladium diacetate, 122mg (0.400mmol) tri-o-tolylphosphine, and 0.278mL (2.00mmol) TEA in 4.0mL DMF was heated at 100 deg.C for 6 hours. The mixture was concentrated in vacuo and partitioned between EtOAc and waterAnd (4) preparing. The organic extracts were washed with dilute aqueous HCl, water and brine, Na2SO4Dried and concentrated in vacuo. The residue was purified on a 4g silica gel column (eluted with a heptane-EtOAc gradient) to give (E) -3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) acrylic acid methyl ester. The yield was 0.11 g. m/z 380.2, calculated 379.16.
0.11g (0.28mmol) of (E) -3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]OxazazepineA solution of methyl-9-yl) acrylate in a THF/ethanol mixture (5mL) was hydrogenated with 100mg of 10% Pd/C for 4 hours. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to give 3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) propionic acid methyl ester. The yield thereof was found to be 96 mg. m/z 382.2, calculated 381.18. Which is treated with lithium hydroxide to give 3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -1-methyl-1H-1, 2, 4-triazol-5-yl)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) propionic acid. m/z 368.2, calculated 367.16.
3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is synthesized according to the procedure in example 300]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) propionic acid to 316. m/z 367.1, calculated 366.18.1H NMR(400MHz，DMSO)8.29(d，J＝8.2，1H)，7.85(s，1H)，7.28(s，1H)，7.00(d，J＝8.3，1H)，6.89(s，1H)，6.75(s，1H)，5.81(dt，J＝13.1，6.4，1H)，4.48(s，4H)，2.80(t，J＝7.5，2H)，2.36(dd，J＝16.8，9.2，2H)，2.25(s，3H)，1.45(d，J＝6.5，6H)。
Example 317: 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine(264)317
Reacting 9-chloro-5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]OxazazepineA mixture of-2-carboxamide (0.520g, 1.96mmol) and 1, 1-dimethoxy-N, N-dimethylmethylamine (1.305mL, 9.824mmol) in toluene (28.2mL, 265mmol) was heated at reflux for 1 h. LCMS showed no starting material and the main peak was m/z 320.1. After cooling, the intermediate was concentrated. A mixture of intermediate and isopropylhydrazine hydrochloride (0.4345g, 3.929mmol) in acetic acid (18mL, 320mmol) was heated at 85 ℃ for 3 hours. The mixture was cooled and insoluble impurities were filtered off. The mother liquor was concentrated in vacuo. The residue was diluted with EtOAc, then washed with water and brine. The organic layer was dried (Na) 2SO4) Filtered and concentrated to give 317. MS (ESI +) ═ 331.0.1H NMR(400MHz，DMSO)9.29(s，1H)，7.97(d，J＝24.4Hz，1H)，7.94(s，1H)，7.31-7.19(m，1H)，5.85(dq，J＝13.0，6.4Hz，1H)，4.66(dd，J＝5.2，2.5Hz，2H)，4.63-4.54(m，2H)，1.48(d，J＝6.6Hz，6H)。
Example 318: 1- (5- (5, 6-dihydrobenzo [ f ]]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazole-3-yl) -N, N-dimethylmethylamine 318
[5- (8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulen-2-yl) -1-isopropyl-1H- [1, 2, 4]Triazol-3-yl]A suspension of methanol 315(166mg, 0.51mmol) in DCM (5mL) was treated with dess-martin iodophor (DMP, 238mg, 0.56mmol) and the resulting solution was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction mixture was quenched by the addition of sodium thiosulfate (620mg in 1mL of water), then water was added and extracted twice with DCM. The combined organic extracts were washed with water and then dried (Na)2SO4) Filtered and concentrated in vacuo to give 5- (4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulen-2-yl) -1-isopropyl-1H- [1, 2, 4]Triazole-3-carbaldehyde as an opalescent solid (170mg, quantitative). LCMS: RT ═ 4.30 min, [ M + H]+324。1H NMR 400MHz(DMSO-d6)：9.91(1H，s)，8.43(1H，dd，J＝8.06，1.78Hz)，8.11(1H，s)，7.34-7.34(1H，m)，7.17-7.17(1H，m)，7.07(1H，dd，J＝8.17，1.23Hz)，6.03(1H，m)，4.57-4.48(4H，m)，1.55(6H，d，J＝6.60Hz)。
Reacting 5- (4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e)]Azulen-2-yl) -1-isopropyl-1H- [1, 2, 4]Triazole-3-carbaldehyde (85mg, 0.26mmol), acetic acid (catalytic amount, 2 drops),A mixture of molecular sieves and dimethylamine hydrochloride (24mg, 0.29mmol) in THF (5mL) was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (66mg, 0.31mmol) was added. After stirring at room temperature for a further 18 h, the reaction mixture was diluted with DCM and the organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, then dried (Na) 2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to RP HPLC (C18 column, gradient 5 to 98% methanol/water + 0.1% HCO2H) Yield 318 as a white solid (13mg, 14%). LCMS: RT 3.18 min, [ M + H]+353。1H NMR 400MHz(DMSO-d6)：8.45(1H，dd，J＝8.02，1.76Hz)，7.97(1H，s)，7.39-7.32(1H，m)，7.19-7.19(1H，m)，7.09(1H，dd，J＝8.15，1.25Hz)，5.89(1H，m)，4.54(4H，d，J＝2.46Hz)，3.47(2H，s)，2.24(6H，s)，1.51(6H，d，J＝6.59Hz)。
Example 319: rac-cis-2- (3-hydroxy-4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -N, N-dimethylacetamide 319
Step 1: rac-trans-3-hydroxy-4- [2- (2-isopropyl-2H- [1, 2, 4 ] from example 328]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Tert-butyl-piperidine-1-carboxylate (containing about 24% of the 4-hydroxypiperidine isomer, 0.32g, 0.65mmol) was dissolved in DCM (15mL) and cooled in an ice bath. Dorse-Martin iodophor (0.3M in DCM, 4.33mL, 1.3mmol) was added dropwise and the mixture was stirred at 0-10 ℃ for 7 h, then frozen for 16 h. Aqueous sodium hydrogen sulfate and aqueous sodium bicarbonate (10 mL each) were added and the mixture was stirred at room temperature for 15 minutes. The phases were separated and the aqueous phase was extracted twice with DCM. The combined organic extracts were washed with brine and dried (Na)2SO4) And concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO) 2Gradient 0-5% methanol/DCM), then trituration with ether afforded 4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (86 mg). Additional product (59mg) was recovered from the slurry. The overall yield was 145mg (45%). LCMS: RT ═ 3.53, [ M + H]+＝493，[M+H+MeOH]+＝525。
Step 2: 4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]A solution of tert-butyl (145mg, 0.29mmol) 3-oxo-piperidine-1-carboxylate in anhydrous THF (10mL) was cooled to-78 deg.C and tri-sec-butylboron was added dropwiseSolution of lithium hydride in THF (L-Selectride)1M, 0.30mL, 0.30 mmol). The mixture was stirred at-78 ℃ for 1 hour, and then an aqueous sodium bicarbonate solution was added dropwise. After warming to rt, the mixture was extracted three times with EtOAc. The combined organic extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0-5% methanol/DCM) to give rac-cis-3-hydroxy-4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Tert-butyl piperidine-1-carboxylate (92mg, 64%). LCMS: RT ═ 3.39, [ M + H ]+＝495。
And step 3: to rac-cis-3-hydroxy-4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]To a solution of tert-butyl-piperidine-1-carboxylate (92mg, 0.186mmol) in DCM (0.5mL) and methanol (0.3mL) was slowly added a solution of hydrogen chloride in dioxane (4M, 0.8 mL). The mixture was stirred at room temperature for 2 hours 20 minutes, then concentrated in vacuo. The resulting residue was triturated with ether twice and dried under vacuum to give rac-cis-4- [2- (2-isopropyl-2H- [1, 2, 4 ]]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Piperidin-3-ol hydrochloride (86mg, 108%). LCMS: RT ═ 1.93, [ M + H]+＝395。
And 4, step 4: reacting cis-rac-4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Reaction of piperidin-3-ol hydrochloride (86mg, 0.19mmol) with N, N-dimethyl-2-chloroacetamide (26mg, 0.21mmol) gave 319(51mg, 57%). LCMS: RT 2.58 min, [ M + H]+＝480。1H NMR 400MHz(DMSO-d6)：8.29(1H，d，J＝8.29Hz)，7.90-7.90(2H，m)，7.08(1H，dd，J＝8.37，1.72Hz)，6.98(1H，d，J＝1.65Hz)，5.89-5.88(1H，m)，4.56-4.41(4H，m)，4.08(1H，br)，3.79(1H，br)，3.17(2H，m)，3.06(3H，s)，2.88(2H，m)，2.82(3H，s)，2.62(1H，m)，2.39(1H，m)，2.22(2H，m)，1.53(1H，m)，1.48(6H，d，J＝6.61Hz)。
Example 320: rac-trans-2- (3-hydroxy-4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine -9-yl) piperidin-1-yl) -N, N-dimethylacetamide 320
Reacting trans-racemic-4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Piperidine-3-ol hydrochloride (0.15g, 0.35mmol) was reacted with N, N-dimethyl-2-chloroacetamide (46mg, 0.38mmol) to give 320(135mg, 80%). LCMS: RT 2.50 min, [ M + H]+＝480。1H NMR 400MHz(CDCl3): 8.40(1H, d, J ═ 8.26Hz), 7.86(1H, s), 7.43(1H, s), 7.08-7.03(1H, m), 6.82(1H, d, J ═ 1.72Hz), 6.02(1H, m), 4.38(4H, m), 4.10(1H, broad multiplet), 3.38(2H, m), 3.31(2H, m), 3.09(3H, s), 3.00(1H, m), 2.98(3H, s), 2.47(2H, m), 1.86(2H, m), 1.60(6H, dd, J ═ 6.59, 2.76 Hz).
Example 321: 2- ((1R, 3R, 5S) -3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -8-azabicyclo [3.2.1]Oct-8-yl) acetamide 321
Step 1: to the vessel were added 52(1.00g, 2.67mmol), bis (neopentylglycol) diboron (905mg, 4.01mmol), potassium acetate (918mg, 9.35mmol) and dioxane (12mL), then the vessel was sealed and degassed with nitrogen for 10 minutes. Adding PdCl to the reaction mixture 2dppf-DCM (109mg, 0.13mmol, 5 mol%) and the reaction mixture was purged with nitrogen and then stirred at 90 ℃ for 65 h. The reaction mixture was cooled to room temperature, then diluted with DCM (200mL) and treated with charcoal. The mixture was filtered and the filtrate was washed with water, dried (Na)2SO4) And vacuum concentrating to obtain 8- (5, 5-dimethyl- [1, 3, 2)]Dioxaborolan-2-yl) -2- (2-isopropyl-2H- [1, 2, 4]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene (1.00g, 2.46mmol, 92%). LCMS: RT 3.79 min, [ M-HCC (CH)3)2CH+H]+＝340。
Step 2: to 3-oxo-8-aza-bicyclo [3.2.1 ] at-78 deg.C]To a solution of tert-butyl octane-8-carboxylate (500mg, 2.22mmol) in THF (5mL) was added dropwise a 1M solution of LiHMDS in THF (2.44mL, 2.44 mmol). The resulting mixture was stirred at-78 ℃ for 1 hour, then a solution of N-phenylbis (trifluoromethanesulfonimide) (872mg, 2.44mmol) in THF (5mL) was added dropwise. The reaction mixture was stirred at-78 ℃ for 4 hours and then quenched with saturated sodium bicarbonate solution. The mixture was extracted with EtOAc and dried (MgSO)4) And concentrated in vacuo, then flash chromatographed (SiO)2Gradient 0-40% EtOAc/cyclohexane). The residue obtained is further purified by flash chromatography (SiO) 2Gradient 0-100% DCM/cyclohexane) to give 3-trifluoromethanesulfonyloxy-8-aza-bicyclo [3.2.1]Tert-butyl oct-2-ene-8-carboxylate (402mg, 0.56mmol, 25%).1H NMR 400MHz(CDCl3)：6.11(1H，s)，4.48(2H，m)，3.02(1H，m)，2.26(1H，m)，2.13(1H，m)，2.09(1H，m)，2.04(1H，m)，2.03(1H，s)，1.48(9H，s)。
And step 3: adding 8- (5, 5-dimethyl- [1, 3, 2 ] into a container]Dioxaborolan-2-yl) -2- (2-isopropyl-2H- [1, 2, 4]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene (237mg, 0.56mmol), PdCl2dppf-DCM (46mg, 0.06mmol, 10 mol%) and cesium carbonate (456mg, 1.40mmol), then evacuated and backfilled with nitrogen. To the resulting mixture was added 3-trifluoromethanesulfonyloxy-8-aza-bicyclo [3.2.1]Oct-2-ene-8-carboxylic acidA solution of tert-butyl ester (402mg, 0.56mmol) in DME (2mL) followed by water (0.2 mL). The reaction mixture was evacuated and backfilled with nitrogen and then stirred at 110 ℃ for 1.5 hours. The reaction mixture was partitioned between EtOAc and water, the organic phase was separated and dried (MgSO4) And concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0-100% EtOAc/cyclohexane) to give 3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-8-aza-bicyclo [3.2.1 ]Tert-butyl oct-2-ene-8-carboxylate as a colorless oil (177mg, 0.35mmol, 63%). LCMS: RT 4.84 min, [ M + H]+＝503。
And 4, step 4: to 3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-8-aza-bicyclo [3.2.1]To a degassed solution of tert-butyl oct-2-ene-8-carboxylate (176mg, 0.35mmol) in acetic acid (7mL) was added palladium hydroxide on charcoal (20% palladium, 50% water, 62 mg). The vessel was evacuated and backfilled with hydrogen (× 3) and the reaction mixture was stirred at room temperature for 100 hours. The reaction mixture was filtered through a plug of celite, washed with EtOAc and the filtrate was concentrated in vacuo to provide endo/exo-3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-8-aza-bicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester mixture as a black gum (177mg, 0.35mmol, quantitative yield). LCMS: RT 4.83 min, [ M + H]+505。
And 5: to 3- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-8-aza-bicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate (177mg, 0.35mmol) in dioxane (10mL) was added a solution of 4M HCl in dioxane (5mL) and methanol (5 mL). The resulting mixture was stirred at room temperature for 18 hours, then concentrated in vacuo. The resulting residue was taken up in methanol and loaded onto an SCX-2 column (with methanol followed by 2M NH 3Methanol elution). Concentrating the alkaline fraction in vacuo to obtain endo/exo-8- (8-aza-bicyclo [ 3.2.1%]Oct-3-yl) -2- (2-isopropyl-2H- [1, 2, 4]Triazole-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Mixture of azulenes as brown glass (91mg, 0.22mmol, 64%). LCMS: RT 2.77 min and 2.91 min, [ M + H]+＝405。
Step 6: endo/exo-8- (8-aza-bicyclo [ 3.2.1)]Oct-3-yl) -2- (2-isopropyl-2H- [1, 2, 4]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]A solution of azulene (91mg, 0.22mmol) in DCM (1mL) was treated with TEA (38. mu.L, 0.27mmol) followed by bromoacetamide (37mg, 0.27mmol) and the reaction mixture was stirred at room temperature for 22 h and then concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 7% (2M NH)3methanol)/DCM) and the endo/exo isomer was passed through RPHPLC (C6-phenyl column, gradient 5 to 25% acetonitrile/water + 0.1% HCO over 20 min2H) To give the title compound as a white solid (3 mg and 13mg of the first and second eluting isomers, respectively). The first eluting isomer was 321. LCMS: RT 2.64 min, [ M + H]+＝462。1H NMR 400MHz(CDCl3)：8.45(1H，d，J＝8.40Hz)，8.10(1H，br)，7.97(1H，br)，7.89(1H，s)，7.67(1H，s)，7.14(1H，d，J＝8.52Hz)，7.02(1H，s)，5.99(1H，m)，5.81(1H，br)，4.49-4.47(4H，m)，3.49(2H，s)，3.19(3H，m)，2.66-2.56(2H，m)，2.04-1.96(4H，m)，1.66(2H，m)，1.59(6H，d，J＝6.63Hz)。
Example 322: 2- ((1R, 3S, 5S) -3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) -8-azabicyclo [3.2.1]Oct-8-yl) acetamide 322
Following the procedure in example 321, the second eluting isomer was 322. LCMS: RT 2.70 min, [ M + H]+＝462。1H NMR 400MHz(CDCl3)：8.45(1H，d，J＝8.31Hz)，8.02(1H，br)，7.88(1H，d，J＝0.67Hz)，7.74(1H，br)，7.66(1H，s)，7.06(1H，dd，J＝8.35，1.82Hz)，6.93(1H，d，J＝1.77Hz)，5.99-5.98(1H，m)，5.75(1H，br)，4.47-4.46(4H，m)，3.42(2H，m)，3.16(2H，s)，2.92-2.90(1H，m)，2.10-2.08(2H，m)，2.00(2H，t，J＝12.82Hz)，1.82-1.81(4H，m)，1.59(6H，d，J＝6.63Hz)。
Example 323: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (4-methylpiperazin-1-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 2-f][1，4]Oxazazepine323
Mixing 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 2-f][1，4]OxazazepineA solution of (66.0mg, 0.200mmol), 1-methyl-piperazine (88.5. mu.L, 0.798mmol) and TEA (167. mu.L, 1.20mmol) in N, N-dimethylacetamide (3.00mL, 32.3mmol) was heated in a microwave at 160 ℃ for 20 minutes. The reaction mixture was filtered through celite, then rinsed with EtOAc. The filtrate was washed with water and brine. Na for organic layer2SO4Drying and concentrating. The crude product was purified by rlhplc to afford 323. MS (ESI +) ═ 395.2.1H NMR(400MHz，DMSO)8.50(d，J＝8.7Hz，1H)，7.88(s，1H)，7.80(s，1H)，6.72(d，J＝8.8Hz，1H)，5.88(dt，J＝13.2，6.7Hz，1H)，4.49(m，4H)，3.61-3.48(m，4H)，2.42-2.34(m，4H)，2.21(s，3H)，1.47(d，J＝6.6Hz，6H)。
Example 324: 4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 2-f][1，4]Oxazazepine-9-yl) piperazin-2-one 324
9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ] according to the procedure in example 323 ]Pyrido [3, 2-f][1，4]OxazazepineReaction with piperazin-2-one affords 324. MS (ESI +) ═ 395.1.1H NMR(400MHz，DMSO)8.55(d，J＝8.7Hz，1H)，8.10(s，1H)，7.88(s，1H)，7.81(s，1H)，6.70(d，J＝8.8Hz，1H)，5.88(dt，J＝13.2，6.6Hz，1H)，4.60-4.40(m，4H)，4.06(s，J＝8.0Hz，2H)，3.84-3.68(m，2H)，1.47(d，J＝6.6Hz，6H)。
Example 325: 4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) piperazin-2-one 325
Mixing 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine264(55.0mg, 0.166mmol), piperazin-2-one (0.110g, 1.10mmol) and TEA (0.275mL, 1.97mmol) in N-methylpyrrolidone (3.00mL, 31.1mmol) were heated at 150 ℃ for 2 days. The reaction mixture was filtered through celite, then rinsed with EtOAc. The filtrate was washed with water and brine. Na for organic layer2SO4Dried and concentrated to give 325, which was analyzed by rHPLC. MS (ESI +) ═ 395.1.1H NMR(400MHz，DMSO)8.55(d，J＝8.7Hz，1H)，8.10(s，1H)，7.88(s，1H)，7.81(s，1H)，6.70(d，J＝8.8Hz，1H)，5.88(dt，J＝13.2，6.6Hz，1H)，4.63-4.30(m，4H)，4.06(d，J＝8.0Hz，2H)，3.81-3.63(m，2H)，1.47(d，J＝6.6Hz，6H)。
Example 327, the following: 4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-yl) pyridin-2 (1H) -one 327
Prepared according to the method for 203 by replacing 2-fluoropyridin-3-ylboronic acid with 2-fluoropyridin-4-ylboronic acid to give 10- (2-fluoropyridin-4-yl) -2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1, 2-d ] s][1，4]Oxazazepine(0.242g, 24%), MS (ESI (+): m/z404.9(M + H), which was treated with 10% aqueous HCl to give 327(0.141g, 59%).1HNMR(400MHz，DMSO)11.53(s，1H)，8.72(d，J＝2.2，1H)，7.93(s，1H)，7.67(dd，J＝8.5，2.3，1H)，7.49(d，J＝6.9，1H)，7.15(d，J＝8.6，1H)，6.55(s，1H)，6.48(d，J＝6.2，1H)，5.70(dt，J＝13.2，6.7，1H)，4.56(s，4H)，2.26(s，3H)，1.49(d，J＝6.6，6H)。MS(ESI(+))：m/z 403.1(M+H)。
Example 328: (3R, 4S) -4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-3-ol 328
Step 1: 4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Tert-butyl-3, 6-dihydro-2H-pyridine-1-carboxylate (0.60g, 1.22mmol) was partially dissolved in anhydrous diethylene glycol dimethyl ether (14mL) and borane/THF complex solution (1M in THF, 7.29mL, 7.29mmol) was added dropwise. Stirring briefly at room temperatureAfter stirring, the mixture was left to stand for 16 hours. The mixture was then cooled in ice and water (1.1mL), 2M sodium hydroxide (3.6mL) and 35% hydrogen peroxide (0.94mL, 8.98mmol) were added dropwise. The mixture was heated at 50 ℃ for 8 h, then cooled, diluted with water (ca. 30mL) and extracted three times with EtOAc. The combined organic extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0-10% methanol/DCM) to give rac-trans-3-hydroxy-4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4) ]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.46g, 74%) containing about 20% of the 4-hydroxypiperidine isomer. LCMS: RT ═ 4.48, [ M + H]+＝509。
Step 2: mixing racemic-trans-3-hydroxy-4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Tert-butyl-piperidine-1-carboxylate (0.215g, 0.42mmol) was suspended in anhydrous THF (10mL) and triphenylphosphine (0.22g, 0.85mmol) and chloroacetic acid (82mg, 0.85mmol) were added. Diethyl azodicarboxylate (0.133mL, 0.85mmol) was added dropwise and the mixture was stirred at room temperature for 24 hours. The mixture was concentrated and the residue obtained was subjected to flash chromatography (SiO)2Gradient 0-10% methanol/DCM). The resulting impurity was dissolved in anhydrous DCM (5mL) and triphenylphosphine, chloroacetic acid and diethyl azodicarboxylate (amounts as described above) were added. The mixture was stirred at room temperature for 16 h, then concentrated in vacuo, the crude product triturated with ether and the liquid concentrated. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0-5% methanol/DCM) to give impure rac-cis-3- (2-chloro-acetoxy) -4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4) ]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Tert-butyl piperidine-1-carboxylate (0.297g), which was used in the next step without further purification. LCMS: RT ═ 4.61, [ M + H]+＝585/587。
And step 3: mixing impure rac-cis-3- (2-chloro-acetoxy) -4- [2- (2-isopropyl-5-methyl-2H- [1, 2)，4]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]A solution of tert-butyl-piperidine-1-carboxylate (0.297g) in dioxane (5mL) was stirred with aqueous sodium hydroxide (1M, 4.2mL) at room temperature for 16 hours, then heated at 50 ℃ for about 24 hours. The cooled mixture was extracted three times with EtOAc and the combined organic extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0-5% methanol/DCM) to give rac-cis-3-hydroxy-4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Tert-butyl piperidine-1-carboxylate (17 mg). LCMS: RT ═ 4.50, [ M + H]+509。
To cis-rac-3-hydroxy-4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]Azulen-8-yl]To a solution of tert-butyl-piperidine-1-carboxylate (17mg, 0.36mmol) in DCM (1mL) and methanol (0.6mL) was slowly added a solution of 4M HCl in dioxane (1.5mL) and the reaction mixture was stirred at room temperature for 2.5 h, then concentrated in vacuo. The resulting residue was triturated in ether to give rac-cis-4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-3-ol, which was resolved to give (3R, 4S) enantiomer 328 as a white solid (10mg, 67%). MS RT 2.47, [ M + H]+＝409。1H NMR(DMSO-d6): 8.92(1H, broad doublet), 8.33(1H, d, J ═ 8.30Hz), 7.97(1H, s), 7.08(1H, d, J ═ 8.36Hz), 6.96(1H, d, J ═ 1.66Hz), 5.79(1H, t, J ═ 6.59Hz), 4.50(4H, d, J ═ 7.99Hz), 4.06(1H, s), 3.27(2H, m), 3.17(2H, m), 2.97(2H, d, J ═ 14.58Hz), 2.32-2.27(1H, m), 2.29(3H, s), 1.74(1H, d, J ═ 13.43Hz), 1.46(6H, d, J ═ 6.59 Hz).
Example 329: 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -N, N-dimethylacetamide 329
P-2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]A suspension of azulene hydrochloride (310mg, 0.72mmol) in DCM (6mL) and TEA (0.3mL, 2.16mmol) was sonicated and stirred, then N, N-dimethyl-2-chloroacetamide (98mg, 0.8mmol) and TBAI (28mg, 0.072mmol) were added and the reaction mixture was stirred at room temperature for 72 h then concentrated in vacuo. The resulting residue was partitioned between water and DCM and the aqueous phase was extracted five times with DCM, the combined organic extracts were dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 10% methanol/DCM) then trituration in ether afforded 329 as a white solid (129mg, 38%). LCMS: RT 2.71 min, [ M + H]+＝478。1H NMR 400MHz(CDCl3)：8.44(1H，d，J＝8.30Hz)，7.61(1H，s)，7.04(1H，d，J＝8.43Hz)，6.91(1H，s)，5.91(1H，t，J＝6.63Hz)，4.45(4H，d，J＝14.92Hz)，3.39(2H，m)，3.11(2H，m)，3.10(3H，s)，2.99(1H，m)，2.98(3H，s)，2.54(2H，m)，2.41(3H，s)，1.90(4H，s)，1.57(6H，d，J＝6.65Hz)。
Example 330: 2- (3-hydroxy-4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -N, 2-dimethylpropanamide 330
Trans-racemic-4- [2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]A mixture of piperidin-3-ol hydrochloride (199mg, 0.46mmol), 2-bromo-2-methyl-N-methylpropanamide (83mg, 0.46mmol), NaOH (2mL, 50% aq), TBAB (16mg, 0.05mmol), and DCM (2.5mL) was stirred vigorously at room temperature for 7.5 hours. The phases were separated and the aqueous layer was extracted three times with 10% methanol/DCM and the combined organic extracts were washed with brine and then dried (Na) 2SO4) Filtered and concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 10% methanol/DCM) to give 330(84mg, 37%). LCMS: RT 2.54 min, [ M + H]+＝494。1H NMR 400MHz(CDCl3)：8.44(1H，d，J＝8.23Hz)，7.87(1H，s)，7.48(1H，s)，7.17(1H，br)，7.08(1H，m)，6.86(1H，s)，6.03-6.01(1H，m)，4.77-4.07(4H，m)，3.82(1H，br)，3.17(1H，m)，2.86(3H，d，J＝4.98Hz)，2.85(2H，m)，2.46(1H，m)，2.27(1H，m)，2.18(1H，m)，1.90(1H，m)，1.70(1H，m)，1.61(6H，m)，1.27(6H，d，J＝10.69Hz)。
Example 331: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) piperazin-1-yl) -N, N-dimethylacetamide 331
Mixing 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]OxazazepineA solution of 264(80.0mg, 0.242mmol), ethyl 2- (piperazin-1-yl) acetate (0.275g, 1.60mmol) and TEA (0.400mL, 2.87mmol) in N-methylpyrrolidone (4.36mL, 45.2mmol) was heated at 150 ℃ for 2 days. The reaction mixture was filtered through celite, then rinsed with EtOAc. The filtrate was washed with water and brine. Na for organic layer2SO4Drying and concentrating. Is coarseTo a solution of the ethyl ester intermediate in THF (3.00mL, 37.0mmol) and water (3.00mL, 166mmol) was added lithium hydroxide hydrate (0.0406g, 0.967 mmol). The reaction mixture was stirred at room temperature. The reaction mixture was quenched with water and then washed with EtOAc. Concentrating the aqueous layer to obtain 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ] ]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) piperazin-1-yl) acetic acid, which is used for the next reaction. MS (ESI +) ═ 439.2.
2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazole-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) piperazin-1-yl) acetic acid (0.050g, 0.00011mol) was dissolved in DMF (1.79mL, 0.0231mol) and treated sequentially with N, N-diisopropylethylamine (0.119mL, 0.000686mol), dimethylamine hydrochloride (0.0373g, 0.000457mol) and N, N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (0.0521g, 0.000137 mol). Stir at room temperature for 2 hours. Saturated sodium bicarbonate was added and extracted with EtOAc. The organic phase was dried over sodium sulfate and concentrated to give 331 which was analyzed by rHPLC. MS (ESI +) ═ 466.2.1H NMR(400MHz，DMSO)9.10(s，1H)，7.89(s，1H)，7.84(s，1H)，6.34(s，1H)，6.01-5.79(m，1H)，4.50(d，J＝10.0Hz，4H)，3.53(s，4H)，3.18(s，2H)，3.03(s，3H)，2.82(s，3H)，1.47(d，J＝6.5Hz，6H)。
Example 332: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) piperazin-1-yl) acetamide 332
Will be from fruitExample 331 of 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ]]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) piperazin-1-yl) acetic acid (0.050g, 0.11mmol) was dissolved in DMF (1.79mL, 0.0231mol) and treated with N, N-diisopropylethylamine (0.119mL, 0.686mmol), ammonium chloride (0.0244g, 0.457mmol) and N, N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (0.0521g, 0.137mmol) in succession. Stir at room temperature for 2 hours. Saturated sodium bicarbonate was added and extracted with EtOAc. The organic phase was dried over sodium sulfate and concentrated to give 332, which was analyzed by rHPLC. MS (ESI +) ═ 466.2. 1H NMR(400MHz，DMSO)9.11(s，1H)，7.89(s，1H)，7.85(s，1H)，7.20(s，2H)，6.35(s，1H)，5.93(dt，J＝13.7，7.0Hz，1H)，4.50(d，J＝10.4Hz，4H)，3.57(s，5H)，2.91(s，2H)，1.47(d，J＝6.5Hz，6H)。
Example 333: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 2-f][1，4]Oxazazepine-9(8H) -one 333 reacting 9-chloro-5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 2-f][1，4]OxazazepineA solution of-2-carboxamide (55.0mg, 0.166mmol) in sulfuric acid (0.70mL, 13mmol) and water (0.70mL, 39mmol) was heated at 125 ℃ for 2 hours. The reaction mixture was diluted with water, neutralized with 1M NaOH, and then extracted with EtOAc. Na for organic layer2SO4Drying, concentration and rHPLC purification gave 333. MS (ESI +) ═ 313.0.
Example 334: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo[1，2-d]Pyrido [3, 2-f][1，4]Oxazazepine-9-yl) piperazin-1-yl) -N-methylacetamide 334
Mixing 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 2-f][1，4]OxazazepineA solution of (150.0mg, 0.4535mmol), ethyl 2- (piperazin-1-yl) acetate (0.275g, 1.60mmol) and TEA (0.400mL, 2.87mmol) in N-methylpyrrolidone (4.36mL, 45.2mmol) was heated at 150 ℃ for 2 days. The reaction mixture was diluted with EtOAc, then washed with water and brine. Na for organic layer2SO4Drying and concentration gave the intermediate ethyl ester, which was dissolved in THF (8.00mL, 98.6mmol) and water (8.00mL, 444 mmol). Lithium hydroxide hydrate (0.07612g, 1.814mmol) was added. The reaction mixture was stirred at rt, then quenched with water and washed with EtOAc. Concentrating the aqueous layer to obtain 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ] ]Pyrido [3, 2-f][1，4]Oxazazepine-9-yl) piperazin-1-yl) acetic acid. MS (ESI +) ═ 439.4.
2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazole-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 2-f][1，4]Oxazazepine-9-yl) piperazin-1-yl) acetic acid (0.050g, 0.00011mol) was dissolved in DMF (1.79mL, 0.0231mol) and treated sequentially with N, N-diisopropylethylamine (0.119mL, 0.000686mol), a 2.00M solution of methylamine in THF (0.228mL), and N, N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (0.0521g, 0.000137 mol). Stir at room temperature for 2 hours. Saturated sodium bicarbonate was added and extracted with EtOAc. The organic phase is dried over sodium sulfate andconcentration afforded 334, which was analyzed by rHPLC. MS (ESI +) = 452.2.
Example 335: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 2-f][1，4]Oxazazepine-9-yl) piperazin-1-yl) -N, N-dimethylacetamide 335
2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ] from example 334]Pyrido [3, 2-f][1，4]Oxazazepine-9-yl) piperazin-1-yl) acetic acid (0.050g, 0.00011mol) was dissolved in DMF (1.79mL, 0.0231mol) and treated sequentially with N, N-diisopropylethylamine (0.119mL, 0.000686mol), dimethylamine hydrochloride (0.0373g, 0.000457mol) and N, N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (0.0521g, 0.000137 mol). Stir at room temperature for 2 hours. Saturated sodium bicarbonate was added and extracted with EtOAc. The organic phase was dried over sodium sulfate and concentrated to give 335, which was analyzed by rHPLC. MS (ESI +) ═ 466.3.
Example 337: 1- ((2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) methyl) urea 337
40(0.6g, 2.0mmol) prepared according to example 40, 1-isopropyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.477mmol, 2.02mmol) and bis (triphenylphosphine) palladium (II) dichloride (0.059g, 0.084mmol) were combined in a 35mL microwave vessel. Potassium carbonate (1.0M in water, 5mL) and acetonitrile (5mL) were then added. However, the device is not suitable for use in a kitchenThe post-reaction vessel was irradiated with microwaves at 140 ℃ for 20 minutes. The mixture was further diluted with EtOAc and the product was isolated by acid-base extraction to give 0.3g (50% yield) of 2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxylic acid.
2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxylic acid (0.3g, 0.9mmol) was dissolved in THF (3mL) and ammonium chloride (0.19g, 3.6mmol) and N, N-diisopropylethylamine (0.31mL, 1.8mmol) were added followed by HATU (0.37g, 0.98mmol) and the resulting mixture stirred at ambient temperature for 2 h. LCMS analysis indicated the reaction was complete. The reaction mixture was then diluted with saturated aqueous sodium bicarbonate and extracted twice with EtOAc. The combined organic layers were washed once with brine and with Na 2SO4And (5) drying. The liquid was filtered and concentrated to dryness. The crude residue was used in the next reaction without further purification. 0.3g (quantitative) of 2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f ] are obtained]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carboxamide 346. MS (ESI +) M/z338.1(M + H)+Calculated value is 338.4.
Lithium tetrahydroaluminate (0.047g, 1.3mmol) was suspended in THF (8mL) and cooled to 0 ℃. A solution of 346(0.3g, 0.9mmol) in THF (2mL) was added and the reaction mixture was stirred at cold temperature for 10 min. The flask was gradually brought to room temperature and stirred for 16 hours. The reaction mixture was quenched by pouring into a mixture of diethyl ether and saturated aqueous Rochelle's salt (1: 1). The mixture containing the significant emulsion was stirred very vigorously until the phases separated (about 2 hours). The phases were partitioned and the aqueous layer was extracted several times with EtOAc. The combined organic layers were over MgSO4Drying, filtering and concentrating to obtain(0.15g, 0.46mmol) (2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) methylamine 347(MS (ESI +) M/z 323.1(M + H)+) Calculated 323.4) was dissolved in glacial acetic acid (0.8mL) and water (5 mL). A solution of potassium cyanate (0.114g, 1.41mmol) in water was added dropwise. DMF (3mL) was added to aid dissolution. The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then heated at 50 ℃ for 3 hours. The mixture was cooled to room temperature and filtered to give 0.02g (10% yield) 337. MS (ESI +) M/z 367.1(M + H) +Calculated value is 367.4.1H NMR(400MHz，DMSO)8.53(s，5H)，8.33(d，J＝8.2Hz，1H)，7.61(d，J＝3.7Hz，1H)，7.43(s，1H)，7.01(d，J＝8.7Hz，1H)，6.91(s，1H)，6.63(s，1H)，6.38(s，1H)，5.62(s，2H)，5.42(s，7H)，4.47(s，3H)，4.17(d，J＝5.8Hz，2H)，1.44(d，J＝6.4Hz，6H)。
Example 338: (2S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 338
93 was reacted with L-prolinamide according to the method in example 339 and the crude product was subjected to flash chromatography (SiO)2Gradient 0 to 8% methanol/DCM) then recrystallised from methanol gave 338 as a white solid (115mg, 44%). LCMS: RT 2.48 min, [ M + H]+409。1H NMR400MHz(DMSO-d6)：9.06(1H，s)，7.88(1H，s)，7.83(1H，s)，7.33(1H，br)，6.92(1H，br)，5.97-5.96(1H，m)，5.94(1H，s)，4.53-4.45(4H，m)，4.30(1H，d，J＝8.51Hz)，3.59(1H，s)，3.37(1H，d，J＝9.93Hz)，2.18(1H，m)，1.95(3H，m)，1.47(6H，dd，J＝6.59，3.43Hz)。
Example 339: 1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) piperidine-4-carboxamide 339
93 with sodium hydride (1.2 equivalents) and the reaction mixture stirred at room temperature or 40 ℃ for 15 minutes to 1.25 hours, then the benzenebis (trifluoromethane) sulfonamide [ bezenebis (trifluoromethane) sulfonamide ] sulfonamide was added](1.2 equiv.). Stirring was continued at room temperature until complete consumption of pyridone was observed (TLC or LCMS), then piperidine-4-carboxamide (1 to 2.5 equivalents) was added and the reaction mixture was heated at 70 to 100 ℃ until no further reaction was observed. The crude product was isolated by removal of the solvent in vacuo, precipitated from the reaction mixture by addition of water, added water and extracted with EtOAc or DCM or purified by using an Isolute SCX-2 column and recrystallized from methanol to give 339 as a white solid (161mg, 60%). LCMS: RT 2.41 min, [ M + H ]+423。1H NMR400MHz(DMSO-d6)：9.10(1H，s)，7.88(1H，d，J＝0.65Hz)，7.83(1H，s)，7.27(1H，s)，6.76(1H，s)，6.34(1H，s)，5.93-5.92(1H，m)，4.51-4.49(4H，m)，4.31(2H，d，J＝13.19Hz)，2.94-2.81(2H，m)，2.38-2.35(1H，m)，1.73(2H，m)，1.53(2H，dd，J＝12.25，3.87Hz)，1.47(6H，d，J＝6.60Hz)。
Example 340: 1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) piperidin-4-ol 340
93 was reacted with 4-hydroxypiperidine according to the method in example 339, and the crude product was recrystallized from methanol to give 340 which is whiteA colored solid (106mg, 42%). LCMS: RT 2.48 min, [ M + H]+＝396。1H NMR 400MHz(DMSO-d6)：9.09(1H，s)，7.88(1H，d，J＝0.64Hz)，7.83(1H，s)，6.33(1H，s)，5.97-5.88(1H，m)，4.69(1H，d，J＝4.26Hz)，4.49-4.48(4H，m)，4.03-3.99(2H，m)，3.75-3.67(1H，m)，3.14-3.13(2H，m)，1.80-1.71(2H，m)，1.47(6H，d，J＝6.60Hz)，1.34-1.33(2H，m)
Example 341: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9-morpholino-5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine341
93 was reacted with morpholine as in example 339 and the crude product was recrystallized from methanol to give 341 as a white solid (107mg, 44%). LCMS: RT 3.12 min, [ M + H]+382。1H NMR400MHz(DMSO-d6)：9.14(1H，s)，7.90(1H，d，J＝0.63Hz)，7.86(1H，s)，6.36(1H，s)，5.93-5.92(1H，m)，4.57-4.48(4H，m)，3.70(4H，t，J＝4.74Hz)，3.50(4H，t，J＝4.74Hz)，1.49(6H，d，J＝6.60Hz)。
Example 342: n-isopropyl-2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) piperazin-1-yl) acetamide 342
342 were prepared according to the method in example 331. MS (ESI +) ═ 480.2.
Example 343: 1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyridine compoundAnd [3, 2-f ]][1，4]Oxazazepine-9-yl) azetidine-3-carboxamide 343
Reacting 9-chloro-5, 6-dihydroimidazo [1, 2-d ]Pyrido [3, 2-f][1，4]OxazazepineA solution of-2-carboxamide (45.0mg, 0.136mmol), azetidine-3-carboxylic acid (30.0mg, 0.297mmol) and TEA (0.300mL, 2.15mmol) in isopropanol (1.00mL, 13.1mmol) was heated at 150 ℃ for 2 days. The reaction mixture was diluted with water and then washed with EtOAc. The aqueous layer was acidified and then extracted with EtOAc. Na for organic layer2SO4Drying and concentrating to obtain the carboxylic acid intermediate 1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 2-f][1，4]Oxazazepine-9-yl) azetidine-3-carboxylic acid (MS: (ESI +)396.1) dissolved in DMF (2.37mL, 0.0306mol) and treated with N, N-diisopropylethylamine (0.158mL, 0.000910mol), ammonium chloride (0.0325g, 0.000607mol) and N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (0.0692g, 0.000182mol) one after the other. Stir at room temperature for 2 hours. Saturated sodium bicarbonate was added and extracted with EtOAc. The organic phase was dried over sodium sulfate and concentrated to give 343, which was analyzed by rHPLC. MS (ESI +) ═ 395.1.1H NMR(400MHz，DMSO)8.50(d，J＝8.5Hz，1H)，7.88(s，1H)，7.80(s，1H)，7.50(s，1H)，7.04(s，1H)，6.28(d，J＝8.5Hz，1H)，5.96-5.76(m，1H)，4.48(d，J＝10.2Hz，4H)，4.09(t，J＝8.3Hz，2H)，3.98(t，J＝6.9Hz，2H)，3.44(dd，J＝14.5，7.4Hz，1H)，1.46(d，J＝6.5Hz，6H)。
Example 345: 2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo[f]Imidazo [1, 2-d ] s ][1，4]Oxazazepine-9-yl) propionamide 345
A degassed mixture of 187mg (0.500mmol)194, 320.6mg (2.000mmol) (1-trimethylsilyloxy) -1-methoxyprop-1-ene, 19.4mg (0.025mmol) bromo (tri-tert-butylphosphine) palladium dimer and 154.5mg (0.500mmol) tributyltin fluoride in 4.0mL 1, 4-dioxane was heated at 105 ℃ for 18 h. After work-up, a mixture of saturated and unsaturated esters was separated from the debrominated product by column chromatography (eluting with a gradient of 1-4% methanol in DCM). A solution of 98mg of the above mixture and 100mg of 10% palladium on charcoal in 12mL of ethanol was hydrogenated at 1atm for 3 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give 80mg of pure 2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -f ]]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) propionic acid methyl ester. m/z 382.1, calculated 381.18.
Reacting 2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]OxazazepineReacting methyl (E) -9-yl) propionate with lithium hydroxide to obtain 2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) propionic acid. m/z 368.2, calculated 367.16, which was converted to 345. m/z 367.1, calculated 366.18. 1HNMR(400MHz，DMSO)8.32(d，J＝8.3，1H)，7.90(s，2H)，7.41(s，1H)，7.10(d，J＝8.5，1H)，7.00(s，1H)，6.87(s，1H)，5.88(dt，J＝12.5，6.2，1H)，4.50(d，J＝4.7，4H)，3.57(q，J＝6.9，1H)，1.48(d，J＝6.5，6H)，1.31(d，J＝6.9，3H)。
Example 348: 2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (oxetan-3-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine348
Production of boric acid: 2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxaborolan-2-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]A solution of azulene (example 57, 0.495g, 0.00114mol) and sodium periodate (0.730g, 0.00341mol) in a 4: 1 mixture of THF (7.38mL) and water (1.84mL) was stirred at room temperature for 30 minutes. Aqueous hydrogen chloride (0.000796mol, 1N, 0.8mL) was added and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted three times with DCM. The organic layers were combined and MgSO4Dried and concentrated. The crude product was used without further purification.
To a CEM microwave vial was added a solution of crude boric acid (0.154g, 0.437mmol), nickel (II) diiodide (0.0186g, 0.0596mmol), trans-2-aminocyclohexanol hydrochloride (0.00904g, 0.0596mmol) and sodium bis (trimethylsilyl) amide (0.477mmol, 2M in THF, 0.24mL) in degassed isopropanol (0.91mL) and DMSO (1.5 mL). The mixture was continuously purged with nitrogen. A solution of 3-iodooxetane (0.0731g, 0.398mmol) in isopropanol (0.21mL) was added and the vial was capped immediately. The reaction mixture was heated to 85 ℃ in a microwave and held for 25 minutes. LC/MS indicated about 50% conversion to product, acid boronation was also observed (protoboronation). The mixture was diluted with DCM and filtered over celite. Water was added and the mixture was extracted three times with DCM. The crude product was loaded onto silica gel as a solid and purified by flash chromatography (50% EtOAc/hexanes) and re-purified by reverse phase HPLC to give 25.8mg 348 as a white solid. MS (ESI +) 366.1. 1H NMR(400MHz，DMSO)8.40(d，J＝8.2Hz，1H)，7.89(s，1H)，7.22(d，J＝8.3Hz，1H)，7.06(s，1H)，5.93-5.73(m，1H)，4.94(t，J＝7.0Hz，2H)，4.63(t，J＝6.2Hz，2H)，4.55-4.46(m，4H)，4.33-4.18(m，1H)，2.25(s，3H)，1.46(d，J＝6.4Hz，6H)。
Example 352: n-hydroxy-2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) acetamide 352
2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] is reacted by the method in example 316]Imidazo [1, 2-d ] s][1，4]OxazazepineReaction of-9-yl) acetic acid 336 with hydroxylamine affords 352. m/z 369.1, calculated 368.16.1H NMR(400MHz，DMSO)10.69(s，1H)，8.88(s，1H)，8.32(d，J＝8.2，1H)，7.92(d，J＝2.9，2H)，7.04(d，J＝8.2，1H)，6.97(s，1H)，5.95-5.81(m，1H)，4.50(d，J＝5.7，4H)，3.29(s，2H)，1.48(d，J＝6.6，6H)。
Example 354: 1- ((2- (1- (2, 4-difluorophenyl) -3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) methyl) urea 354
Reacting C- {2- [2- (2, 4-difluoro-phenyl) -5-methyl-2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]A solution of azulen-8-yl } -methylamine in acetic acid and water was reacted with a solution of potassium cyanate in water to afford 354. MS (ESI +) 452.1.1H NMR(400MHz，DMSO)7.89(s，1H)，7.68(td，J＝8.7，6.2Hz，1H)，7.62-7.54(m，2H)，7.32-7.25(m，1H)，6.87-6.80(m，2H)，6.44(t，J＝6.1Hz，1H)，5.57(br，2H)，4.49-4.38(m，4H)，4.12(d，J＝6.1Hz，2H)，2.35(s，3H)。
Example 355: (2- (1- (2, 4-difluorophenyl) -3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) methylamine 355
To a solution of 51(5.00g, 0.0162mol) in toluene (85mL) was added dimethylacetamide dimethyl acetal (7.23mL, 0.0487 mol). The reaction mixture was stirred at 95 ℃ for 4 hours. The toluene was removed in vacuo and the crude 46 was used without further purification. MS (ESI +) 377.1/379.1.
46(0.0162mol) was dissolved in acetic acid (50 mL). 2, 4-difluorophenylhydrazine hydrochloride (3.52g, 0.0195mol) was added and the reaction mixture was stirred at 95 ℃ overnight. The acetic acid was removed in vacuo. The crude product was loaded onto silica gel as a solid and purified by flash chromatography (4-10% methanol/DCM) to give 3.662g of 8-bromo-2- [2- (2, 4-difluoro-phenyl) -5-methyl-2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene as an orange solid. MS (ESI +) 458.0/460.0.
Subjecting 8-bromo-2- [2- (2, 4-difluoro-phenyl) -5-methyl-2H- [1, 2, 4] to microwave irradiation at 60W]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene with Zinc cyanide and Pd (PPh)3)4Reaction in DMF for 30 min (T)max175 ℃) to give 2- [2- (2, 4-difluoro-phenyl) -5-methyl-2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene-8-carbonitrile. MS (ESI +) 405.1.
To 2- [2- (2, 4-difluoro-phenyl) -5-methyl-2H- [1, 2, 4] at 0 deg.C]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Lithium tetrahydroaluminate (1M in THF) was added dropwise to a solution of azulene-8-carbonitrile in THF. The reaction mixture was stirred for 2 hours and saturated with water Na2SO4Quenching until no more hydrogen gas is evolved. Adding MgSO4And the whole was diluted with copious amounts of DCM, filtered through celite and concentrated in vacuo. The crude product was purified by flash chromatography (1-15% MeOH/DCM containing Et3N)) to yield 355. MS (ESI +) 409.1.1H NMR(400MHz，DMSO)7.89(s，1H)，7.68(td，J＝8.7，6.2Hz，1H)，7.64-7.52(m，2H)，7.32-7.25(m，1H)，6.95(s，1H)，6.91(dd，J＝8.2，1.2Hz，1H)，4.48-4.38(m，4H)，3.66(s，2H)，2.35(s，3H)。
Example 356: 9- (1- (2- (dimethylamino) -2-oxoethyl) piperidin-4-yl) -N- (2-hydroxyethyl) -N-isopropyl-5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-carboxamide 356
Step 1: containing 8-bromo-2-iodo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]A sealed flask containing azulene (500mg, 1.28mmol), palladium (II) dichloride (6mg, 0.03mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (15mg, 0.03mmol) was rinsed with CO. A solution of 2-isopropylaminoethanol (172mg, 1.67mmol) and TEA (0.53mL, 3.8mmol) in toluene (2.5mL) was added and the reaction mixture was heated at 100 ℃ for 3.5 h. The reaction mixture was washed with water and extracted with EtOAc (2X 30 mL). The combined organic extracts were washed with brine and dried (Na)2SO4) And concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 2-3% methanol/DCM) to give 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]Azulene-2-carboxylic acid (2-hydroxy-ethyl) -isopropyl-amide (123mg, 23%). LCMS: RT 3.11 min, [ M + H ]+＝394/396。
Step 2: reacting 8-bromo-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene-2-carboxylic acid (2-hydroxy-ethyl) -isopropyl-amide (114mg, 0.28mmol), 3, 6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (129mg, 0.62mmol), potassium carbonate (96mg, 0).69mmol) and PdCl2dppf-DCM (20mg, 0.02mmol) was suspended in DMF (1.5mL) and the reaction mixture was purged with argon. The reaction mixture was heated at 100 ℃ for 3 hours. The reaction mixture was washed with water, extracted with EtOAc (2X 15mL) and the combined organic extracts were washed with brine, dried (Na)2SO4) And concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0-2% MeOH/DCM) to give 4- {2- [ (2-hydroxy-ethyl) -isopropyl-carbamoyl]-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (115mg, 80%). LCMS: RT 3.48 min, [ M + H]+＝497。
And step 3: 8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] azulene-2-carboxylic acid (2-hydroxy-ethyl) -isopropyl-amide hydrochloride
To 4- {2- [ (2-hydroxy-ethyl) -isopropyl-carbamoyl]-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]To a solution of azulen-8-yl } -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (112mg, 0.23mmol) in IMS (3mL) were added hydrochloric acid (2mL, 2M, 4.0mmol) and palladium on charcoal (20mg, 10 wt%). The reaction mixture was stirred at 50 ℃ for 4.5 hours under a hydrogen atmosphere. The reaction mixture was filtered and the solid was washed with IMS (10 mL). The filtrate was concentrated in vacuo and azeotroped with acetonitrile to give 8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ] ]Azulene-2-carboxylic acid (2-hydroxy-ethyl) -isopropyl-amide hydrochloride as a thick oil (110 mg). LCMS: RT 0.32 min, [ M + H]+＝399。
To 8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e ]]To a stirred mixture of azulene-2-carboxylic acid (2-hydroxy-ethyl) -isopropyl-amide hydrochloride (127mg, 0.23mmol) in DMF (2mL) was added potassium carbonate (127mg, 0.92mmol), N-dimethyl-2-chloroacetamide (36mg, 0.3mmol) and KI (catalytic amount) and stirring continued at room temperature for 72 h, then concentrated in vacuo. The resulting residue was diluted with EtOAc and washed with water and brine, then dried (Na)2SO4) Filtered and concentrated in vacuo. The residue obtained is passed through Isolute SCX-2 column (successively with DCM/methanol and 2M NH)3Methanol elution). The basic fractions were combined and concentrated in vacuo, and the residue subjected to RP HPLC (C18 column, gradient 5 to 95% CH)3CN/Water + 0.1% HCO2H) Yield 356 as a colorless glass (22mg, 20%). LCMS: RT 1.90 min, [ M + H]+＝484。1H NMR 400MHz(CDCl3): 8.42(2H, s), 8.20(1H, broad singlet), 8.34(1H, d, J ═ 8.32Hz), 7.81(1H, s), 7.04(1H, dd, J ═ 8.40, 1.77Hz), 6.90(1H, d, J ═ 1.69Hz), 4.63(2H, m), 4.45-4.44(4H, m), 3.38(3H, m), 3.32(2H, m), 3.16(2H, d, J ═ 11.21Hz), 3.11(3H, s), 2.99(3H, s), 2.56(1H, m), 2.48(2H, m), 1.87(4H, m), 1.42(6H, d, J ═ 6.46 Hz).
Example 357: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1-isopropylpiperidin-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine357
To 2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]To a suspension of azulene trifluoroacetate (250mg, 0.51mmol) in DCE (5mL) were added acetone (0.06mL, 0.77mmol) andmolecular sieves and stirred under an argon atmosphere for 10 min, then sodium triacetoxyborohydride (216mg, 1.02mmol) was added and stirred at room temperature for 18 h. Acetone (0.06mL) and sodium triacetoxyborohydride (216mg) were added again and stirring was continued for an additional 24 hours. The reaction mixture was diluted with DCM and saturated aqueous sodium bicarbonate and the organic layer was washed with water and brine, then dried (MgSO)4) Filtered and concentrated in vacuo. The resulting solid was subjected to RP HPLC (gradient 20 to 70% methanol/water + 0.1% HCO)2H) Yield 357 as a yellow solid (17mg, 8%). LCMS: RT 2.81 min, [ M + H]+＝421。1H NMR 400MHz(DMSO-d6)：8.37-8.26(1H，m)，7.90-7.89(2H，m)，7.05(1H，dd，J＝8.33，1.81Hz)，6.89(1H，d，J＝1.73Hz)，5.89-5.88(1H，m)，4.49-4.48(4H，m)，2.91(2H，d，J＝10.95Hz)，2.76-2.75(1H，m)，2.46(1H，s)，2.26(2H，t，J＝11.38Hz)，1.78(2H，d，J＝12.43Hz)，1.64(2H，td，J＝12.20，3.68Hz)，1.48(6H，d，J＝6.60Hz)，1.01(6H，d，J＝6.57Hz)。
Example 358: 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropan-1-ol 358
2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]A mixture of azulene hydrochloride (100mg, 0.255mmol), ethyl 2-bromo-2-methyl-propionate (45. mu.L, 0.31mmol), cesium carbonate (187mg, 0.57mmol) and DMF (0.5mL) was heated at 70 ℃ for 3 h, then stirred at room temperature for 18 h, then heated at 70 ℃ for 4 h, then concentrated in vacuo. The residue obtained is subjected to flash chromatography (SiO)2Gradient 0 to 5% methanol/DCM) to give 2- {4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]Piperidin-1-yl } -2-methyl-propionic acid ethyl ester (47mg, 36%). LCMS: RT 2.24, [ M + H]+＝507。
2- {4- [2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl]A solution of piperidin-1-yl } -2-methyl-propionic acid ethyl ester (47mg, 0.092mmol) in anhydrous THF (3mL) was cooled to 0 ℃ and treated with lithium aluminum hydride (1M solution in THF, 0.3mL, 0.3mmol), the mixture was stirred and warmed to room temperature, then quenched by addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with EtOAc Extracted twice and the combined organic extracts dried (Na)2SO4) Filtered and concentrated in vacuo. The resulting residue was subjected to RP HPLC (C18 column, gradient 0 to 60% methanol/water + 0.1% formic acid) to give 358 as a white solid (20mg, 47%). LCMS: RT 2.74 min, [ M + H]+＝465。1H NMR 400MHz(DMSO-d6)：8.33(1H，d，J＝8.28Hz)，8.26(1H，s)，7.87(1H，s)，7.05(1H，dd，J＝8.35，1.77Hz)，6.90(1H，d，J＝1.71Hz)，5.82-5.81(1H，m)，4.49(4H，m)，3.38(2H，s)，3.21(2H，d，J＝11.33Hz)，2.58(1H，t，J＝11.87Hz)，2.47(2H，d，J＝11.47Hz)，2.26(3H，s)，1.85(2H，d，J＝12.54Hz)，1.72(2H，m)，1.46(6H，d，J＝6.60Hz)，1.07(6H，s)。
Example 359: 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropan-1-ol 359
2- (2-isopropyl-2H- [1, 2, 4 ] as in example 358]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulene trifluoroacetate (103mg) was converted to 359 as a white solid (6.6mg, 2% overall yield). LCMS: RT 2.73 min, [ M + H]+＝451。1H NMR400MHz(DMSO-d6): 8.33(1H, d, J ═ 8.28Hz), 7.91(2H, d, J ═ 2.06Hz), 7.06(1H, dd, J ═ 8.35, 1.76Hz), 6.90(1H, d, J ═ 1.71Hz), 5.90(1H, t, J ═ 6.60Hz), 4.50(4H, dd, J ═ 11.70, 5.85Hz), 3.34(2H, broad multiplet), 3-13(2H, d, J ═ 11.26Hz), 2.55(1H, m), 2.35(2H, t, J ═ 11.38Hz), 1.81(2H, d, J ═ 12.50Hz), 1.64(2H, d, J ═ 12.44Hz), 1.49(6H, J ═ 6.50 Hz), 1.02 (2H, d, J ═ 12.44 Hz).
Example 360: 4- (2- (1-isopropyl) benzeneradical-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyrazolidine-3, 5-dione 360
A mixture of 194(1410mg (3.77mmol), diethyl malonate (2.00mL, 13.2mmol), palladium (II) diacetate (42.3mg, 0.188mmol), 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (148mg, 0.377mmol), and potassium phosphate (2.80g, 13.2mmol) in 6.0mL 1, 4-dioxane was degassed and heated at 100 ℃ for 24 hours, the mixture was concentrated in vacuo and the residue was purified with a 24g silica gel column (eluted with 1% MeOH/EtOAc) to give 2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f/] f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) malonic acid diethyl ester. The yield was 974 mg. m/z 454.3, calculated 453.20.
181mg (0.40mmol) of 2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]OxazazepineA mixture of diethyl-9-yl) malonate and 0.314mL (10.0mmol) hydrazine in 4.0mL ethanol was heated at 75 deg.C for 18 hours. The mixture was concentrated and the residue was triturated with acetic acid. The precipitate was filtered off, washed with acetic acid and diethyl ether and recrystallized from a diethyl ether/ethanol mixture to yield 360. The yield was 59mg (37.5%). m/z 394.1, calculated 393.15. 1H NMR(400MHz，DMSO)10.20(s，2H)，8.29(d，J＝8.6，1H)，7.89(d，J＝12.9，2H)，7.70(d，J＝8.5，1H)，7.63(s，1H)，5.93(dt，J＝13.1，6.7，1H)，4.48(d，J＝7.2，4H)，1.49(d，J＝6.6，6H)。
Example 361: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2, 2, 2-trifluoroethyl)) Piperidin-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine361
2- (2-isopropyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (piperidin-4-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]A suspension of azulene trifluoroacetate (250mg, 0.51mmol) in THF (5mL) was treated with TEA and the mixture was flushed with argon. 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (0.15mL, 1.02mmol) was added and the mixture was stirred at room temperature for 72 h. The reaction mixture was partitioned between DCM and water, the organic layer was washed with saturated aqueous sodium bicarbonate solution and then brine, then dried (MgSO)4) Filtered and concentrated in vacuo. The resulting residue was dissolved in 1.25M HCl/methanol and then concentrated in vacuo to give a solid which was triturated in IPA followed by ether. The solid obtained is subjected to RPHPLC (C18 column, gradient 10 to 98% methanol/water + 0.1% HCO2H) Yield 361 as a white solid (49mg, 23%). LCMS: RT 4.59 min, [ M + H]+＝461。1H NMR400MHz(DMSO-d6)：8.33(1H，d，J＝8.29Hz)，7.91-7.91(2H，m)，7.08(1H，dd，J＝8.36，1.79Hz)，6.92(1H，m)，5.91-5.90(1H，m)，4.51(4H，q，J＝5.90Hz)，3.21(2H，q，J＝10.30Hz)，3.03(2H，d，J＝11.25Hz)，2.45(3H，m)，1.76(2H，m)，1.69-1.67(2H，m)，1.49(6H，d，J＝6.60Hz)。
Example 363: 1- ((2- (1- (2, 4-difluorophenyl) -3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s ][1，4]Oxazazepine-9-yl) methylamino) -2-methylpropan-2-ol 363
To C- {2- [2- (2, 4-difluoro-phenyl) -5-methyl-2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Azulen-8-yl } -methylamine (0.150g, 0.000 g)367mol) and cesium carbonate (0.0335g, 0.000103mol) in methanol (0.5mL) was added 2, 2-dimethyloxirane (isobutenyleneoxide) (0.0359mL, 0.000404 mol). The flask was sealed and heated to 70 ℃ and held for 2 hours. The mixture was diluted with ether and water was added. The mixture was extracted three times with diethyl ether. The organic phases were combined and MgSO4Drying and concentration gave 11.2mg 363 as a white solid (6.4% yield). MS (ESI +) 481.2.1H NMR(400MHz，DMSO)7.89(s，1H)，7.68(td，J＝8.6，6.0Hz，1H)，7.63-7.51(m，2H)，7.29(td，J＝8.2，1.5Hz，1H)，6.94(s，1H)，6.90(dd，J＝8.3，1.3Hz，1H)，4.47-4.38(m，4H)，4.20(s，1H)，3.67(s，2H)，2.35(s，3H)，2.33(s，2H)，1.08(s，6H)。
Example 364: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine364
To 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine264(35.0mg, 0.106mmol) in methanol (1.91mL, 47.1mmol) were added TEA (0.0147mL, 0.106mmol) and palladium (0.0113g, 0.0106 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite. Concentrate the solute then dilute with EtOAc and use H 2And O washing. Na for organic layer2SO4Drying and concentrating. The crude product was purified by ISCO column to afford 364. MS (ESI +) -297.1.1H NMR(400MHz，DMSO)9.49(s，1H)，8.36(d，J＝5.7Hz，1H)，7.99(s，1H)，7.92(s，1H)，7.05(d，J＝5.7Hz，1H)，5.90(dt，J＝13.2，6.5Hz，1H)，4.59(dt，J＝26.2，13.1Hz，4H)，1.50(d，J＝6.6Hz，6H)。
Example 365: (2R) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 365
Mixing 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine264(25.0mg, 0.0756mmol), R-prolinamide (0.0570g, 0.499mmol) and TEA (0.125mL, 0.897mmol) in N-methylpyrrolidone (1.36mL, 14.1mmol) were heated at 150 ℃ for 2 days. The reaction mixture was filtered through celite, then rinsed with EtOAc. The filtrate was washed with water and brine. Na for organic layer2SO4Drying and concentration gave 365, which was analyzed by rHPLC. MS (ESI +) 409.2.
Example 366: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (pyrrolidin-1-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine366
366 was prepared according to the method in example 365. MS (ESI +) ═ 366.2.1H NMR(400MHz，DMSO)9.08(s，1H)，7.88(s，1H)，7.82(s，1H)，5.94(dd，J＝13.6，6.9Hz，1H)，4.61-4.32(m，4H)，3.40(d，J＝6.3Hz，4H)，1.95(t，J＝6.5Hz，4H)，1.48(d，J＝6.6Hz，6H)。
Example 367: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N-methyl-5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 2-f ][1，4]Oxazazepine-9-amine 367
A mixture of 1.936g (11.00mmol) of 2, 6-dichloropyridine-3-carbaldehyde, 6.384g (44.00mmol) of aqueous glyoxal solution and ammonia (4.996g, 88.00mmol) in 60mL of methanol was stirred for 3 hours. The mixture was concentrated in vacuo and acidified to pH < 1 with 200mL of 0.5N aqueous HCl. The aqueous solution was extracted with EtOAc (3X 30 mL). The organic extract was discarded while the aqueous phase was purified by addition of saturated NaHCO3To be alkalized. The mixture was extracted with EtOAc (3 × 30mL), and the combined organic extracts were washed with water and brine, dried and concentrated in vacuo to give 2, 6-dichloro-3- (1H-imidazol-2-yl) pyridine (crude 0.85g, 36% yield). m/z 214.0, calculated 212.99.1H NMR(500MHz，DMSO)12.51(s，1H)，8.31(d，J＝8.1，1H)，7.74-7.63(m，1H)，7.26(s，2H)。
A mixture of 0.856g (4.00mmol)2, 6-dichloro-3- (1H-imidazol-2-yl) pyridine, 704mg (8.00mmol) ethylene carbonate and 2930mg (9.00mmol) cesium carbonate in 25.0mL DMF was heated at 90 ℃ for 13H. The mixture was filtered, the filtrate was concentrated in high vacuum and the residue was purified on a 10g silica gel column (eluted with 80% EtOAc/heptane) to give 9-chloro-5, 6-dihydroimidazo [1, 2-d ]]Pyrido [3, 2-f][1，4]OxazazepineThe yield was 0.359g (41%). m/z 222.0, calculated 221.04.1HNMR(500MHz，CDCl3)8.84(d，J＝8.2，1H)，7.18(s，1H)，7.15(d，J＝8.2，1H)，7.02(s，1H)，4.63-4.57(m，2H)，4.47-4.41(m，2H)。
0.359g (1.62mmol) of 9-chloro-5, 6-dihydroimidazo [1, 2-d ]Pyrido [3, 2-f][1，4]OxazazepineAnd a mixture of 0.913g (4.06mmol) of N-iodosuccinimide in 20.0mL of DMF was heated at 80 ℃ for 60 hours. The mixture was concentrated in vacuo and the residue was removedThe reaction mixture was washed with EtOAc (40mL) and 0.1M Na2CO3The aqueous solution was partitioned. The organic extract was extracted with 5% Na2S2O5Aqueous solution, water and brine, washed with Na2SO4Drying and vacuum concentrating to obtain 9-chloro-2, 3-diiodo-5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 2-f][1，4]OxazazepineThe yield was 0.644 (84%). m/z 473.9, calculated 472.83.1HNMR(500MHz，CDCl3)8.85(d，J＝8.2，1H)，7.19(s，1H)，7.16(d，J＝8.2，1H)，7.03(s，1H)，4.60(dd，J＝9.9，5.8，2H)，4.47-4.42(m，2H)。
A solution of 2.0M isopropyl magnesium chloride in THF (0.782mL) was added dropwise to 0.644g (1.36mmol) of 9-chloro-2, 3-diiodo-5, 6-dihydroimidazo [1, 2-d ] at-10 deg.C]Pyrido [3, 2-f][1，4]OxazazepineIn a solution of 12mL THF. The mixture was warmed to 15 ℃. The mixture was then purified by adding 20mL of saturated NH4Aqueous Cl and extracted with EtOAc. The organic extracts were washed with water and brine, washed with Na2SO4Drying and concentrating to obtain 9-chloro-2-iodo-5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 2-f][1，4]OxazazepineThe yield was 448mg (98%). m/z 348.2, calculated 346.93.1HNMR(400MHz，CDCl3)8.83(d，J＝8.2，1H)，7.16(dd，J＝14.0，5.9，1H)，7.10(s，1H)，4.61-4.54(m，2H)，4.41(dd，J＝5.0，2.9，2H)。
9-chloro-2-iodo-5, 6-dihydroimidazo [1, 2-d ] was reacted according to the procedure in the examples herein, including examples 20-22 ]Pyrido [3, 2-f][1，4]OxazazepineTransformation ofIs 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 2-f][1，4]Oxazazepine
110mg (0.33mmol) 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 2-f][1，4]OxazazepineA mixture of 87mg (1.3mmol) of methylammonium chloride and 0.23mL (1.3mmol) of N, N-diisopropylethylamine in 3.0mL of N-methylpyrrolidone was irradiated with microwaves at 170 ℃ for 90 minutes. NMP was removed under high vacuum and the residue was taken up in 1M Na2CO3Basified and partitioned between EtOAc and water. The organic extracts were washed with 5% aqueous citric acid, water and brine, MgSO4Dried and concentrated. The residue was purified by RP HPLC (acetonitrile gradient) to afford 367. The yield was 12 mg. m/z 326.3, calculated 325.17.1H NMR(400MHz，DMSO)8.37(d，J＝8.6，1H)，7.88(s，1H)，7.77(s，1H)，6.96(s，1H)，6.34(d，J＝8.6，1H)，5.88(dt，J＝13.0，6.5，1H)，4.46(d，J＝9.2，4H)，2.78(d，J＝2.9，3H)，1.46(d，J＝6.6，6H)。
Example 368: (2S, 4R) -4-hydroxy-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 368
Reaction of 92 with 4-trans-hydroxy-L-prolinamide and recrystallization of the crude product from IMS as in example 339 gave 368 as a white solid (86mg, 53%). LCMS: RT 2.19 min, [ M + H ]+439。1H NMR 400MHz(DMSO-d6)：9.02(1H，s)，7.77(1H，s)，7.40(1H，br)，6.90(1H，br)，5.90(1H，s)，5.87-5.85(1H，m)，5.05(1H，d，J＝3.93Hz)，4.52-4.41(4H，m)，4.39(1H，m)，4.31(1H，m)，3.66(1H，dd，J＝10.60，4.98Hz)，2.22(3H，s)，2.16-2.10(1H，m)，2.00-1.99(1H，m)，1.43(6H，dd，J＝6.59，2.86Hz)。
Example 369: (2S) -1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 369
Reaction of 92 with L-prolinamide and recrystallization of the crude product from IMS as in example 339 gave 369 as a white solid (130mg, 67%). LCMS: RT 2.48 min, [ M + H]+＝423。1H NMR 400MHz(DMSO-d6)：9.06(1H，s)，7.80(1H，s)，7.35(1H，br)，6.94(1H，br)，5.96(1H，s)，5.90-5.88(1H，m)，4.50(4H，d，J＝17.28Hz)，4.32(1H，m)，3.61(1H，m)，3.45(1H，m))，2.26(2H，s)，2.24-2.15(1H，m)，1.98-1.97(3H，m)，1.47(6H，dd，J＝6.59，3.27Hz)。
Example 370: 1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) azetidin-3-ol 370
93 was reacted with 3-hydroxyazetidine hydrochloride charged with DIPEA (2.2 equiv.) and the crude product was flash chromatographed (SiO)2Gradient 0 to 8% methanol/DCM) and then recrystallised from IMS to give 370 as pale green crystals (16mg, 14%). LCMS: RT 2.26 min, [ M + H]+368。1H NMR 400MHz(DMSO-d6)：9.09(1H，s)，7.90(1H，d，J＝0.63Hz)，7.84(1H，s)，5.95-5.94(1H，m)，5.91(1H，s)，5.70(1H，d，J＝6.40Hz)，4.59(1H，s)，4.55-4.47(4H，m)，4.18(2H，t，J＝7.66Hz)，3.70(2H，dd，J＝8.85，4.66Hz)，1.48(6H，d，J＝6.60Hz)。
Example 371: (3R) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidin-3-ol 371
93 was reacted with (R) -prolinol hydrochloride with DIPEA (2.2 equiv.) added and the crude product was recrystallized from methanol as in example 339 to give 371 as a green solid (46mg, 34%). LCMS: RT 2.26 min, [ M + H ]+＝382。1H NMR 400MHz(DMSO-d6)：9.09(1H，s)，7.88(1H，d，J＝0.63Hz)，7.82(1H，s)，5.97-5.96(1H，m)，5.94(1H，s)，4.97(1H，d，J＝3.62Hz)，4.49-4.48(4H，m)，4.39(1H，s)，3.53-3.42(3H，m)，2.02-2.00(1H，m)，1.90-1.87(1H，m)，1.48(6H，d，J＝6.60Hz)。
Example 372: (1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) piperidin-4-yl) methanol 372
93 was reacted with piperidine-4-methanol as in example 339 and the crude product was subjected to flash chromatography (SiO)2Gradient 0 to 8% methanol/DCM) then recrystallised from methanol gave 372 as a white solid (69mg, 48%). LCMS: RT 2.57 min, [ M + H]+＝410。1H NMR400MHz(DMSO-d6)：9.10(1H，s)，7.90(1H，s)，7.84(1H，s)，6.32(1H，s)，5.99-5.90(1H，m)，4.54-4.44(5H，m)，4.34(2H，d，J＝13.11Hz)，3.28(2H，t，J＝5.64Hz)，2.84(2H，t，J＝12.55Hz)，1.71(2H，d，J＝13.74Hz)，1.65(1H，m)，1.49(6H，d，J＝6.60Hz)，1.13(2H，t，J＝12.33Hz)。
Example 373: (2S, 4S) -4-fluoro-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 373
93 was reacted with 4-cis-fluoro-L-prolinamide hydrochloride with DIPEA (2.2 equiv.) added and the crude product was recrystallized from IMS as in example 339 to give 373 as a white solid (56mg, 22%). LCMS: RT 2.59 min, [ M + H]+＝427。1H NMR 400MHz(DMSO-d6)：9.05(1H，s)，7.84(1H，d，J＝0.63Hz)，7.80(1H，s)，7.11(1H，s)，6.92(1H，s)，5.93-5.91(2H，m)，5.42(1H，s)，5.29(1H，s)，4.46-4.44(5H，m)，3.83-3.54(2H，m)，2.28(1H，dd，J＝20.28，14.80Hz)，1.43(6H，dd，J＝6.59，3.60Hz)。
Example 374: (2S, 4R) -4-hydroxy-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 374
93 was reacted with 4-trans-hydroxy-L-prolinamide according to the method in example 339 and the crude product was subjected to flash chromatography (SiO) 2Gradient 0 to 10% methanol/DCM) to give 374 as a white solid (56mg, 27%). LCMS: RT 2.16 min，[M+H]+＝425。1H NMR400MHz(DMSO-d6)：9.05(1H，s)，7.88(1H，s)，7.83(1H，s)，7.42(1H，br)，6.92(1H，br)，5.95(1H，m)，5.92(1H，s)，5.07(1H，d，J＝3.93Hz)，4.50-4.49(4H，m)，4.40(1H，m)，4.32(1H，m)，3.67(1H，t，J＝5.33Hz)，2.16(1H，m)，2.04(1H，m)，1.47(6H，dd，J＝6.59，3.01Hz)。
Example 375: (2S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 375
A degassed mixture of 374mg (1.00mmol)194, 342.5mg (2.000mmol) L-proline tert-butyl ester, 26mg (0.050mmol) bis (tri-tert-butylphosphine) palladium and 192mg (2.00mmol) sodium tert-butoxide in toluene (10.0mL, 93.9mmol) was heated at 95 ℃ for 24 h. The same amounts of tert-butyl L-proline, sodium tert-butoxide and catalyst were added and the mixture was heated at 115 ℃ for 6 hours until no starting bromide remained in the reaction mixture. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and 5% aqueous citric acid. Organic extracts were washed with water, saturated NaHCO3Water and brine, over MgSO4Dried and purified with a 12g silica gel column (eluted with 4% methanol/DCM) to give (S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxylic acid tert-butyl ester. The yield was 153mg (purity 55-60% and product contaminated with debrominated by-products). m/z 465.2, calculated 464.25.
3mL of TFA was added to 153mg of (S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxylic acid tert-butyl ester and 0.2mL triethylsilane in 5mL DCM. The reaction mixture was stirred for 3 hours. The mixture was concentrated and the residue was taken up in 1M Na2CO3Partition between aqueous solution and ether. The aqueous layer was extracted twice more with EtOAc. The organic layer was discarded and the aqueous solution was neutralized to pH 6. The precipitate was collected, washed with water and dried under high vacuum for 36 hours to give (S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxylic acid. The yield was 55 mg. m/z 409.3, calculated 408.19.
55mg (0.135mmol) of (S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]OxazazepineA mixture of-9-yl) pyrrolidine-2-carboxylic acid, N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (57.0mg, 0.150mmol), N, N-diisopropylethylamine (52.2. mu.L, 0.300mmol) and ammonium chloride (8.02mg, 0.150mmol) in N, N-dimethylacetamide (3.0mL, 32mmol) was stirred for 1 hour. The mixture was concentrated in vacuo and the residue triturated with water, 0.01N aqueous HCl and water, dried in vacuo and subjected to RP HPLC, followed by chiral purification to afford 375. The yield was 12 mg. m/z 408.2, calculated 407.21. 1H NMR(400MHz，DMSO)8.19(d，J＝8.9，1H)，7.87(s，1H)，7.77(s，1H)，7.40(s，1H)，7.04(s，1H)，6.36(dd，J＝9.0，2.4，1H)，6.07(d，J＝2.4，1H)，5.91(dq，J＝13.3，6.5，1H)，4.44(d，J＝6.5，4H)，4.01-3.93(m，1H)，3.57(t，J＝7.0，1H)，3.24(d，J＝9.0，1H)，2.23(dd，J＝12.1，6.9，1H)，1.98(dd，J＝14.8，11.3，3H)，1.47(dd，J＝6.6，3.3，6H)。
Example 376: (2R) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 376
194 was reacted with 1- (tert-butyldimethylsilyloxy) -1-methoxyethylene according to the method in example 316 to give 2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) acetic acid methyl ester. m/z 368.2, calculated 367.16. Reacting 2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) acetic acid methyl ester is reacted with lithium hydroxide to give 2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -1-isopropyl-1H-1, 2, 4-triazol-5-yl)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) acetic acid 336. m/z354.1, calculated 353.15.
336 was reacted with ammonia to give 376. m/z 353.1, calculated 352.16.1H NMR(400MHz，DMSO)8.32(d，J＝8.3，1H)，7.91(s，2H)，7.48(s，1H)，7.04(d，J＝8.2，1H)，6.97(s，1H)，6.92(s，1H)，5.95-5.81(m，1H)，4.50(d，J＝5.8，4H)，3.38(s，2H)1.48(d，J＝6.5，6H)。
Example 377: (2S) -1- (2- (1-isopropyl-1H-imidazol-2-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 377
Ethyl magnesium bromide (3.0M in Et) at-20 deg.C2O, 100mmol, 33.3mL) was added dropwise to 9-chloro-2-iodo-5, 6-dihydroimidazo [1, 2-d ] ]Pyrido [3, 4-f][1，4]Oxazazepine(10.0g, 28.8mmol) in THF (173 mL). The mixture was held at this temperature for 20 minutes, then warmed to ambient temperature and held for 1 hour. The reaction mixture was then cooled again to-20 ℃ and DMF (8.9mL, 115mmol) was added to the mixture. Stirring was continued for 16 h, then quenched with saturated aqueous ammonium chloride (220mL) and further diluted with EtOAc (250 mL). The phases were separated and the aqueous layer was extracted twice with EtOAc. The combined organic phases were washed once with brine, over MgSO4Dried, filtered and concentrated in vacuo. 7.08g (98% yield) of 9-chloro-5, 6-dihydroimidazo [1, 2-d are obtained]Pyrido [3, 4-f][1，4]Oxazazepine-2-carboxaldehyde as a yellow solid with > 95% purity as determined by analytical HPLC. MS (ESI +): m/z 249.8(M + H)+Calculated value is 249.65.
To a 100mL round bottom flask was added 9-chloro-5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-2-carboxaldehyde (1.1g, 4.4mmol), 40% aqueous glyoxal (2.1mL, 18.0mmol), ammonium hydroxide (2.55mL, 65.5mmol) and methanol (10.5 mL). The resulting reaction mixture was stirred together at room temperature for 6 hours. The mixture was then evaporated to dryness and the oily residue was purified by flash column chromatography (slow gradient of 0-100% EtOAc/DCM) to give 1.13g (86% yield) of 9-chloro-2- (1H-imidazol-2-yl) -5, 6-dihydroimidazo [1, 2-d ]Pyrido [3, 4-f][1，4]Oxazazepine
To 9-chloro-2- (1H-imidazol-2-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine(0.402g, 1.4mmol) in DMF (9.6mL) was added Cs2CO3(0.6g, 2.0mmol) followed by isopropyl iodide (0.2mL, 2 mmol). The reaction mixture was heated at 50 ℃ for 20 hours. The mixture was then cooled to room temperature and diluted with water and EtOAc. The mixture was extracted twice with EtOAc and over MgSO4Dried, filtered and concentrated. The resulting residue was purified by flash column chromatography (0-10% MeOH/DCM). 0.22g (48% yield) 9-chloro-2- (1-isopropyl-1H-imidazol-2-yl) -5, 6-dihydroimidazo [1, 2-d is obtained]Pyrido [3, 4-f][1，4]OxazazepineThis was mixed with L-prolinamide (0.152g, 1.33mmol) in N, N-dimethylacetamide (6.7mL) and sealed in a pressure resistant vessel. The mixture was heated at 150 ℃ for 40 h, then L-prolinamide (0.152g, 1.33mmol) was added and the heating of the mixture was continued for 12 h. Then only 50% conversion was observed and heating was stopped and the material was passed through RP-HPLC (with 0.1% NH)4OH/acetonitrile elution) to yield 19.8mg (8% yield) 377. MS (ESI +) M/z 408.2(M + H)+Calculated value was 408.5.1H NMR(400MHz，DMSO)9.03(s，1H)，7.58(s，1H)，7.43-7.26(m，2H)，6.89(d，J＝1.0Hz，2H)，5.94(s，1H)，5.72(dt，J＝13.6，6.8Hz，1H)，4.56-4.38(m，4H)，4.29(d，J＝8.0Hz，1H)，3.59(s，1H)，2.17(d，J＝8.9Hz，1H)，1.98(dd，J＝31.1，24.1Hz，4H)，1.44(d，J＝4.2Hz，6H)。
Example 378: (2S) -1- (2- (1- (2, 4-difluorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 378
To a solution of 8-chloro-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene-2-carboxamide (2.40g, 0.00907mol) in toluene (40mL) was added 1, 1-dimethoxy-N, N-dimethylmethylamine (4.82mL, 0.0363 mol). The flask was sealed and heated to 95 ℃ and held for 8 hours. TLC indicated the reaction was complete. The solvent was removed in vacuo to give 8-chloro-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene-2-carboxylic acid 1-dimethylamino-methyleneamide, which was used in crude form. MS (ESI +) 320.1.
Reacting 8-chloro-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]Azulene-2-carboxylic acid 1-dimethylamino-methylene amide (0.00907mol) was dissolved in acetic acid (36 mL). 2, 4-difluorophenylhydrazine hydrochloride (1.965g, 0.01088mol) was added and the reaction mixture was stirred at 95 ℃ for 2.5 hours. AcOH was removed in vacuo. The crude product was triturated in iPrOH to give 2.828g (78% yield in two steps) of 8-chloro-2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4%]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]Azulene, which is a light brown powder,1h NMR indicated it was pure. MS (ESI +) 401.1.
Reacting 8-chloro-2- [2- (2, 4-difluoro-phenyl) -2H- [1, 2, 4 ] under nitrogen]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]A solution of azulene (0.200g, 0.499mmol), L-prolinamide (0.171g, 0.00150mol) and TEA (0.417mL, 0.00299mol) in N-methylpyrrolidone (5mL) was heated to 150 ℃ overnight. The mixture was diluted with DCM. Adding saturated NH4Cl and the mixture was extracted three times with DCM. The organic phases were combined with Na2SO4Dried and concentrated. The crude product is purified by reverse phase HPLC to give 94mg (39% yield) 378 as a pale pink solid. MS (ESI +) 479.2.1H NMR(400MHz，DMSO)8.35(s，1H)，8.18(s，1H)，7.86(s，1H)，7.69(td，J＝8.7，6.0Hz，1H)，7.62-7.53(m，1H)，7.35-7.26(m，2H)，6.92(br，1H)，5.84(s，1H)，4.47-4.36(m，4H)，4.24(d，J＝7.4Hz，1H)，3.62-3.53(m，1H)，3.42-3.32(m，1H)，2.24-2.08(m，1H)，2.02-1.83(m，3H)。
Example 379: (2R) -2- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyrrolidine-1-carboxamide 379 and (2S) -2- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) pyrrolidine-1-carboxamide 380
To a solution of N- (tert-butoxycarbonyl) pyrrolidine (1.02mL, 0.00584mol) and N, N, N ', N' -tetramethylethylenediamine (0.881mL, 0.00584mol) in anhydrous 2-methoxy-2-methylpropane (12mL) was added sec-butyllithium (0.00584mol, 1.4M in cyclohexane, 4.17mL) at-78 ℃. The reaction mixture was stirred at-78 ℃ for 3 hours. A solution of zinc dichloride (0.00350mol, 0.5M in THF, 7.0mL) was added dropwise with rapid stirring and stirred at-78 ℃ for 30 minutes. The reaction mixture was then warmed to room temperature and stirred for an additional 30 minutes. To a flask charged with nitrogen containing 48(0.900g, 0.00232mol), palladium diacetate (0.0260g, 0.000116mol) and tri-tert-butylphosphonium tetrafluoroborate (0.0420g, 0.000145mol) was added a zinc chloride pyrrolidine solution (1.25 equivalents, 0.243M, 11.9 mL). The reaction mixture was heated to 90 ℃ overnight. LC/MS indicated incomplete conversion to product. The mixture was diluted with DCM and filtered over celite. Adding saturated NH 4Cl and the mixture was extracted three times with DCM. The organic layers were combined and washed with Na2SO4Dried and concentrated. The crude product was redissolved in DCM (4.5 mL). TFA (5.5mL) was added and the reaction mixture was stirred at room temperature for 30 min, then concentrated. The crude product was purified by reverse phase HPLC and the enantiomers were separated by chiral SFC to give 2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (pyrrolidin-2-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]Each enantiomer of azulene (10 mg each) was obtained as a white solid. MS (ESI +) 379.2.
To 2- (2-isopropyl-5-methyl-2H- [1, 2, 4)]Triazol-3-yl) -8- (pyrrolidin-2-yl) -4, 5-dihydro-6-oxa-1, 3 a-diaza-benzo [ e]To a solution of azulene (0.009g, 0.00002mol) in acetic acid (4.06 μ L, 0.0000713mol) and water (0.13mL) was added dropwise a solution of potassium cyanate (0.00579g, 0.0000713mol) in water (0.13 mL). DMF (0.13mL, 0.0017mol) was added to dissolve the reagents. The reaction mixture was stirred at 50 ℃ overnight, cooled, filtered and rinsed with cold water. The crude product was purified by precipitation in MeOH/water to give each enantiomer 379 and 380 (10 mg each). MS (ESI +) 422.2.1HNMR(400MHz，DMSO)8.32(d，J＝8.3Hz，1H)，7.85(s，1H)，6.95(dd，J＝8.3，1.6Hz，1H)，6.79(d，J＝1.3Hz，1H)，5.90-5.76(m，1H)，5.69(br，2H)，4.89(dd，J＝7.9，1.3Hz，1H)，4.53-4.44(m，4H)，3.58-3.49(m，1H)，3.42-3.34(m，1H)，2.25(s，3H)，2.25-2.17(m，1H)，1.92-1.65(m，3H)，1.45(dd，J＝6.6，3.9Hz，6H)。
Example 381: (2S) -4, 4-difluoro-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 381
93 was reacted with 4, 4-difluoro-L-prolinamide hydrochloride added DIPEA (2.2 equiv.) and the crude product was subjected to RP HPLC (C18 column, gradient 5 to 95% acetonitrile/water + 0.1% HCO) as in example 3392H) Then recrystallized from IMS to give 381 as a white solid (24mg, 11%). LCMS: RT 3.21 min, [ M + H]+＝445。1H NMR 400MHz(DMSO-d6)：9.11(1H，s)，7.90(1H，d，J＝0.64Hz)，7.87(1H，s)，7.53(1H，br)，7.14(1H，br)，6.08(1H，s)，5.99-5.91(1H，m)，4.61(1H，dd，J＝9.53，4.24Hz)，4.58-4.49(4H，m)，4.00-3.98(2H，m)，2.91-2.90(1H，m)，2.45(1H，dd，J＝13.51，4.18Hz)，1.49(6H，dd，J＝6.59，3.35Hz)。
Example 382: (2S, 4S) -4-fluoro-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 382
92 was reacted with 4-cis-fluoro-L-prolinamide hydrochloride with TEA (2.5 equivalents) added and the crude product was recrystallized from IMS/DCM as in example 339 to give 382 as a white solid (68mg, 42%). LCMS: RT 2.58 min, [ M + H]+441。1H NMR400MHz(DMSO-d6)：9.04(1H，s)，7.76(1H，s)，7.10(1H，s)，6.91(1H，s)，5.95(1H，s)，5.87-5.80(1H，m)，5.42(1H，s)，5.29(1H，s)，4.49-4.36(5H，m)，3.74-3.73(2H，m)，2.46-2.45(1H，m)，2.20(3H，s)，1.40(6H，dd，J＝6.59，3.37Hz)。
Example 383: (2S) -4, 4-difluoro-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 383
92 was reacted with TEA (2.5 equivalents) added 4, 4-difluoro-L-prolinamide hydrochloride as in example 339 and the crude product was flash chromatographed (SiO) 2Gradient 0 to 5% methanol/DCM) to give 383 as a white solid (29mg, 17%). LCMS: RT 3.14 min, [ M + H]+＝459。1H NMR 400MHz(DMSO-d6)：9.09(1H，s)，7.85(1H，d，J＝0.64Hz)，7.55(1H，br)，7.15(1H，br)，6.05(1H，s)，5.93-5.81(1H，m)，4.61(1H，dd，J＝9.53，4.24Hz)，4.58-4.49(4H，m)，4.00-3.98(2H，m)，2.91-2.90(1H，m)，2.45(1H，dd，J＝13.51，4.18Hz)，2.25(3H，s)，1.49(6H，dd，J＝6.59，3.35Hz)。
Example 384: (2S, 4S) -4-hydroxy-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 384
93 was reacted with 4-cis-hydroxy-L-prolinamide as in example 339 and the crude product recrystallized from IMS to give 384 as a white solid (75mg, 28%). LCMS: RT 2.32 min, [ M + H]+425。1H NMR 400MHz(DMSO-d6)：9.08(1H，s)，7.90(1H，d，J＝0.63Hz)，7.85(1H，s)，7.47(1H，br)，7.13(1H，br)，6.00(1H，s)，5.95-5.94(1H，m)，5.28(1H，d，J＝6.27Hz)，4.51(4H，d，J＝11.64Hz)，4.32(2H，m)，3.60(1H，m)，3.50(1H，m)，2.42(1H，t，J＝4.54Hz)，1.94(1H，d，J＝13.24Hz)，1.49(6H，dd，J＝6.59，2.75Hz)。
Example 385: (2S, 4S) -4-hydroxy-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 385
Reaction of 92 with 4-cis-hydroxy-L-prolinamide and recrystallization of the crude product from IMS as in example 339 gave 385 as a white solid (74mg, 46%). LCMS: RT 2.34 min, [ M + H]+439。1H NMR 400MHz(DMSO-d6)：9.05(1H，s)，7.79(1H，s)，7.45(1H，br)，7.11(1H，br)，5.98(1H，s)，5.90-5.84(1H，m)，5.27(1H，d，J＝6.27Hz)，4.48(4H，m)，4.31-4.28(2H，m)，3.59(1H，dd，J＝10.61，4.77Hz)，3.48(1H，d，J＝10.45Hz)，2.40-2.38(1H，m)，2.24(3H，s)，1.93(1H，d，J＝13.06Hz)，1.45(6H，dd，J＝6.59，2.55Hz)。
Example 386: 2- (1-isopropyl-1H-imidazol-2-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine386
9-chloro-2- (1-isopropyl-1H-imidazol-2-yl) -5, 6-dihydroimidazo [1, 2-d ] prepared according to example 377 ]Pyrido [3, 4-f][1，4]Oxazazepine(0.044g, 0.13mmol) was taken up in ethanol (5mL) and 20% palladium hydroxide on charcoal (19mg, 0.03mmol) and glacial acetic acid (0.2mL) were added. The mixture was evacuated under reduced pressure and circulated with a hydrogen atmosphere. This operation was repeated twice. Finally the reaction mixture was placed under a hydrogen atmosphere and stirred at ambient temperature for 2 hours. The mixture was then filtered through a pad of celite and concentrated in vacuo. The residue was purified by RP-HPLC (0.1% NH)4OH/acetonitrile) to yield 13mg (39% yield) 386. MS (ESI +) M/z 296.1(M + H)+Calculated value is 295.3.1H NMR(400MHz，DMSO)9.47(s，1H)，8.33(d，J＝5.6Hz，1H)，7.74(s，1H)，7.33(d，J＝1.1Hz，1H)，7.03(d，J＝5.6Hz，1H)，6.92(d，J＝0.9Hz，1H)，5.66(dq，J＝13.3，6.6Hz，1H)，4.57(td，J＝7.9，3.5Hz，4H)，1.38(d，J＝6.6Hz，6H)。
Example 387: (5- (9-chloro-5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-2-yl) -1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-3-yl) methanol 387
Reacting 8-chloro-2- [ 5-methoxymethyl-2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]A suspension of azulene (500mg, 1.20mmol) in 48% aqueous HBr (2.1mL) was sealed and heated at 100 ℃ for 3 h while being carefully monitored by LCMS. The mixture was cooled to room temperature and poured into a cold 10% KOH solution. The solid was collected by filtration (LCMS and1h NMR analysis showed purity of-90%). The solid was used in the next step without purification. A small amount of solid was purified by HPLC to give 17mg 387. LCMS: 401.0. 1H NMR(400MHz，DMSO)9.27(s，1H)，8.11(s，1H)，7.24(s，1H)，5.81(q，J＝8.9Hz，2H)，5.34(t，J＝6.0Hz，1H)，4.71-4.57(m，4H)，4.46(d，J＝6.0Hz，2H)。
Example 388: (2R) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) -2, 5-dihydro-1H-pyrrole-2-carboxamide 388
2.64g (8.00mmol) of 9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine264 in 250mL glacial acetic acid was placed in a 350mL glass pressure vessel. The vessel was sealed and the mixture was heated at 155 ℃ for 64 hours. The mixture was cooled to room temperature. White precipitates appeared. The mixture was concentrated in vacuo to a volume of 50mL, the solid material was filtered off, washed with acetic acid and diethyl ether and air dried. The weight was 1.68 g. The product was taken up with 15mL of saturated NaHCO3Stirred together for 1h, filtered off, washed with 2X 10mL of water and dissolved in a THF/water (10: 1) mixtureAnd concentrated. The residue was dried under high vacuum for 18 hours to give 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9(10H) -one. The yield was 1.12g (45%). m/z 313.1, calculated 312.13.1H NMR(400MHz，DMSO)11.79(s，1H)，8.41(s，1H)，7.89(s，1H)，7.82(s，1H)，5.84(s，1H)，5.78(dt，J＝13.2，6.6，1H)，4.57-4.51(m，2H)，4.50-4.45(m，2H)，1.45(d，J＝6.6，6H)。
Sodium hydride (192mg (4.80mmol) of a 60% suspension in mineral oil) was added to 600mg (1.92mmol) of 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ]Pyrido [3, 4-f][1，4]Oxazazepine-9(10H) -ketone in 5.0mL dimethylformamide and the mixture was heated at 45 ℃ for 1 hour. N-phenyl bis (trifluoromethanesulfonimide) (1373mg, 3.842mmol) was added and the reaction mixture was heated at 45 ℃ for 20 h. The mixture was partitioned between EtOAc and 5% citric acid and the organic extracts were washed with water (. times.2) and brine, MgSO4Dried and concentrated. The residue was purified on a 12g silica gel column eluting with 4% MeOH/DCM trifluoromethanesulfonic acid 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ]]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl ester. Yield 560mg (66%). m/z 445.2, calculated 444.08.
134mg (0.30mmol) of trifluoromethanesulfonic acid 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl ester, (S) -2, 5-dihydro-1H-pyrrole-2-carboxamideA mixture of (84.1mg, 0.750mmol) and N, N-diisopropylethylamine (61.0. mu.L, 0.350mmol) in N, N-dimethylacetamide (3.0mL, 32mmol) was heated at 80 ℃ for 18 h. The mixture was concentrated under high vacuum and the residue was triturated with 5% aqueous citric acid. The precipitate was filtered off, washed with aqueous citric acid and water, dried in vacuo and purified by RP HPLC (acetonitrile gradient) to give 388. The yield was 28 mg. m/z 407.2, calculated 406.19. 1H NMR(400MHz，DMSO)9.08(s，1H)，7.88(s，1H)，7.84(s，1H)，7.38(s，1H)，6.98(s，1H)，6.13(dd，J＝6.2，1.9，1H)，6.02-5.88(m，3H)，4.97(s，1H)，4.52(dd，J＝9.3，7.1，4H)，4.39-4.18(m，2H)，1.48(dd，J＝6.6，2.5，6H)。
Example 390: (5- (9- (pyrrolidin-1-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-2-yl) -1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-3-yl) methanol 390
Reacting (5- (9-chloro-5, 6-dihydroimidazo [1, 2-d ]]Pyrido [3, 4-f][1，4]Oxazazepine-2-yl) -1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-3-yl) methanol 387 was reacted with pyrrolidine to give 390(13mg) as a colorless solid. LCMS: 436.1.1H NMR(400MHz，DMSO)9.05(s，1H)，7.93(s，1H)，5.95(s，1H)，5.84(q，J＝8.9Hz，2H)，5.32(t，J＝6.1Hz，1H)，4.50(m，4H)，4.45(d，J＝6.0Hz，2H)，3.41(m，4H)，1.95(m，4H)。
example 391: (2S) -1- (2- (1- (3, 5-difluorophenyl) -3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 391
(S) -1- (2-iodo-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] was reacted as in example 420]Azulen-8-yl) -pyrrolidine-2-carboxamide is reacted with acetamidine hydrochloride and 3, 5-difluorophenylhydrazine hydrochloride. The crude product was purified by reverse phase HPLC to give 391(13mg, 11% yield). LCMS: 493.2.1HNMR(400MHz，DMSO)8.58(s，1H)，7.82(s，1H)，7.45(m，3H)，7.32(s，1H)，6.91(s，1H)，5.87(s，1H)，4.45(m，4H)，4.25(d，J＝7.8Hz，1H)，3.59(m，1H)，3.42-3.31(m，1H)，2.34(s，3H)，2.22-2.09(m，1H)，2.00-1.86(m，3H)。
example 392: (2S) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-ylamino) propionamide 392
9-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ] prepared according to example 377 ]Pyrido [3, 4-f][1，4]Oxazazepine264(0.1g, 0.3mmol) and L-alaninamide hydrochloride (0.15g, 1.21mmol) in N, N-dimethylacetamide (1mL) were heated at 90 ℃ for 16 h. The crude reaction mixture was directly purified by RP-HPLC to give 8mg (7% yield) 392. MS (ESI +) M/z 383.1(M + H)+Calculated value is 383.2.1H NMR(400MHz，DMSO)8.99(s，1H)，7.88(s，1H)，7.81(s，1H)，7.30(s，1H)，6.90(s，1H)，6.81(d，J＝7.4Hz，1H)，6.12(s，1H)，5.92(dt，J＝13.1，6.5Hz，1H)，4.47(q，J＝5.8Hz，4H)，4.37-4.21(m，1H)，1.47(dd，J＝6.6Hz，6H)，1.25(d，J＝7.0Hz，3H)。
Example 393: (2S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) -3, 3-dimethylpyrrolidine-2-carboxamide 393
Trifluoromethanesulfonic acid 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ] according to the procedure in example 388]Pyrido [3, 4-f][1，4]OxazazepineReaction of the-9-yl ester with (S) -3, 3-dimethylpyrrolidine-2-carboxamide affords 393. m/z 437.2, calculated 436.23.1HNMR(400MHz，DMSO)9.05(s，1H)，7.88(s，1H)，7.82(s，1H)，7.40(s，1H)，6.97(s，1H)，5.95(dd，J＝14.5，7.9，2H)，4.49(dd，J＝14.6，5.6，4H)，3.90(s，1H)，3.63(t，J＝8.5，1H)，3.43(d，J＝7.8，1H)，1.96(dd，J＝21.1，9.3，1H)，1.68(dd，J＝11.9，5.8，1H)，1.48(dd，J＝6.6，3.6，6H)，1.08(d，J＝6.9，6H)。
Example 394: (5- (9- (dimethylamino) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-2-yl) -1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-3-yl) methanol 394
Reacting (5- (9-chloro-5, 6-dihydroimidazo [1, 2-d ]]Pyrido [3, 4-f][1，4]Oxazazepine-2-yl) -1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-3-yl) methanol 387 was reacted with dimethylamine hydrochloride to give 394(11mg) as a colorless solid. LCMS: 410.1. 1H NMR(400MHz，DMSO)9.06(s，1H)，7.94(s，1H)，6.13(s，1H)，5.84(q，J＝8.9Hz，2H)，5.32(t，J＝6.1Hz，1H)，4.50(m，4H)，4.45(d，J＝6.0Hz，2H)，3.05(s，6H)。
Example 395: (2S, 3S) -3-hydroxy-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 395
Reaction of 92 with 3-trans-hydroxy-L-prolinamide and recrystallization of the crude product from IMS as in example 339 gave 395 as a white solid (63mg, 39%). LCMS: RT 2.23 min, [ M + H]+439。1H NMR 400MHz(DMSO-d6)：9.07(1H，s)，7.80(1H，s)，7.38(1H，br)，7.02(1H，br)，5.97(1H，s)，5.91-5.90(1H，m)，5.27(1H，d，J＝3.77Hz)，4.50(5H，m)，4.35(1H，t，J＝5.08Hz)，4.27(2H，m)，3.65(1H，m)，2.25(3H，s)，2.07(1H，m)，1.89(1H，m)，1.46(6H，dd，J＝6.60，3.78Hz)。
Example 396: (2S, 3R) -3-hydroxy-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 396
Reaction of 92 with 3-cis-hydroxy-L-prolinamide as in example 339 and recrystallization of the crude product from IMS followed by trituration in hot IMS gave 396 as a white solid (37mg, 23%). LCMS: RT 2.29 min, [ M + H]+439。1HNMR 400MHz(DMSO-d6)：9.04(1H，s)，7.78(1H，s)，7.17(1H，br)，6.91(1H，br)，5.91(1H，s)，5.88(1H，m)，5.22(1H，d，J＝4.70Hz)，4.47(4H，m)，4.24(1H，m)，3.64(1H，m)，3.37(1H，m)，2.24(3H，s)，2.07(2H，m)，2.02(1H，m)，1.44(6H，dd，J＝6.59，3.11Hz)。
Example 397: (2S, 3R) -3-hydroxy-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 397
93 was reacted with 3-cis-hydroxy-L-prolinamide as in example 339 and the crude product was subjected to RPHPLC (C18 column, gradient 15 to 55% methanol/water + 0.1% HCO 2H) Yield 397 as a white powder (11mg, 6%). LCMS: RT 2.28 min, [ M + H]+425。1H NMR400MHz(DMSO-d6)：9.08(1H，s)，7.91(1H，d，J＝0.63Hz)，7.85(1H，s)，7.20(1H，br)，6.94(1H，br)，6.00-5.98(1H，m)，5.94(1H，s)，5.25(1H，d，J＝4.81Hz)，4.51-4.50(4H，m)，4.47(1H，m)，4.27(1H，m)，3.68(1H，m)，3.41(1H，m)，2.09-2.08(1H，m)，2.04-2.01(1H，m)，1.50(6H，dd，J＝6.59，3.26Hz)。
Example 398: (2S, 3S) -3-hydroxy-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 398
93 was reacted with 3-trans-hydroxy-L-prolinamide as in example 339 and the crude product was subjected to RPHPLC (C18 column, gradient 15 to 55% methanol/water + 0.1% HCO2H) Yield 398 as a white powder (63mg, 39%). LCMS: RT 2.20 min, [ M + H]+425。1H NMR400MHz(DMSO-d6)：9.09(1H，s)，7.91(1H，d，J＝0.63Hz)，7.86(1H，s)，7.40(1H，br)，7.04(1H，br)，5.99(1H，m)，5.89(1H，s)，5.29(1H，d，J＝3.76Hz)，4.53(4H，m)，4.29(1H，m)，4.21(1H，br)，3.66(1H，d，J＝m)3.50(1H，m)，2.13-2.02(1H，m)，1.91(1H，dd，J＝12.83，6.39Hz)，1.50(6H，dd，J＝6.59，3.95Hz)。
Example 399: (2S) -1- (2- (3-methyl-1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 399
8-chloro-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene-2-carboxylic acid 1-dimethylamino-methyleneamide was reacted with trifluoroethylhydrazine according to the method in example 378 to give 8-chloro-2- [ 5-methyl-2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4] triazol-3-yl ] -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene (MS (ESI +)385.1/387.1) which was reacted with L-prolinamide to give 399.
MS(ESI+)463.2。1H NMR(400MHz，DMSO)9.02(s，1H)，7.92(s，1H)，7.33(s，1H)，6.91(s，1H)，5.94(s，1H)，5.86-5.72(m，2H)，4.55-4.54(m，4H)，4.35-4.26(m，1H)，3.65-3.56(m，1H)，3.43-3.35(m，1H)，2.28(s，3H)，2.22-2.10(m，1H)，2.04-1.90(m，3H)。
Example 400: (2S, 4R) -4-fluoro-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 400
Reaction of 92 with 4-trans-fluoro-L-prolinamide and recrystallization of the crude product from IMS as in example 339 gave 400 as a white solid (53mg, 33%). LCMS: RT 2.77 min, [ M + H]+441。1H NMR 400MHz(DMSO-d6)：9.01(1H，s)，7.75(1H，s)，7.51(1H，s)，7.00(1H，s)，5.96(1H，s)，6.00-5.66(1H，m)，5.46(1H，s)，5.33(1H，s)，4.45-4.44(4H，m)，4.34(1H，t，J＝8.00Hz)，3.86(1H，s)，3.71(1H，ddd，J＝36.66，12.73，3.36Hz)，2.53-2.52(1H，m)，2.20(3H，s)，1.40(6H，dd，J＝6.59，2.53Hz)。
Example 401: (2S, 4R) -4-fluoro-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 401
93 was reacted with 4-trans-fluoro-L-prolinamide as in example 339 and the crude product was recrystallized from IMS to give a white solid. The mother liquor was concentrated in vacuo and the residue was subjected to flash chromatography (SiO)2Gradient 0 to 10% methanol/DCM) and the pure products were combined to give 401 as a white solid (45mg, 28%). LCMS: RT 2.80 min, [ M + H]+＝427。1H NMR 400MHz(DMSO-d6)：9.02(1H，s)，7.84(1H，d，J＝0.63Hz)，7.80(1H，s)，7.51(1H，s)，7.00(1H，s)，5.97(1H，s)，5.90-5.89(1H，m)，5.46(1H，s)，5.33(1H，s)，4.50-4.43(4H，m)，4.34(1H，t，J＝8.09Hz)，3.73-3.72(1H，m)，2.53-2.52(1H，m)，2.13-2.12(1H，m)，1.43(6H，dd，J＝6.59，2.68Hz)。
Example 405: (2S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) -N-methylpyrrolidine-2-carboxamide 405
Trifluoromethanesulfonic acid 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ] according to the procedure in example 388 ]Pyrido [3, 4-f][1，4]OxazazepineReaction of the-9-yl ester with (S) -N-methylpyrrolidine-2-carboxamide gave 405. m/z 423.2, calculated 422.22.1HNMR(400MHz，DMSO)9.06(s，1H)，7.88(s，1H)，7.83(s，1H)，7.74(d，J＝4.3，1H)，5.95(p，J＝6.7，2H)，4.58-4.41(m，4H)，4.35(d，J＝8.5，1H)，3.67-3.57(m，1H)，3.41-3.33(m，1H)，2.57(d，J＝4.6，3H)，2.15(dd，J＝10.8，7.7，1H)，1.94(d，J＝6.6，3H)，1.47(dd，J＝6.6，2.4，6H)。
Example 406: (2S, 3S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) -3-methylpyrrolidine-2-carboxamide 406
Trifluoromethanesulfonic acid 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d ] according to the procedure in example 388]Pyrido [3, 4-f][1，4]OxazazepineReaction of the-9-yl ester with (2S, 3S) -3-methylpyrrolidine-2-carboxamide affords 406. m/z 432.2, calculated 422.22.1HNMR(400MHz，DMSO)9.05(s，1H)，7.88(s，1H)，7.82(s，1H)，7.36(s，1H)，6.91(s，1H)，6.57(s，1H)，6.01-5.88(m，2H)，4.49(d，J＝8.8，4H)，3.88(s，1H)，3.55(t，J＝6.7，2H)，2.32(dd，J＝10.3，6.4，1H)，2.18-2.09(m，1H)，1.59(dd，J＝12.0，5.7，1H)，1.48(dd，J＝6.6，2.9，6H)，1.10(d，J＝6.9，3H)。
Example 409: (2S) -1- (2- (1-cyclohexyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 409
8-chloro-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene-2-carboxylic acid 1-dimethylamino-methyleneamide was reacted with cyclohexylhydrazine hydrochloride according to the method in example 378 to give 8-chloro-2- (2-cyclohexyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene (MS (ESI +) 371/373.2) which was reacted with L-prolinamide to give 409. MS (ESI +) 449.2.
Example 410: (2S) -1- (2- (1- (2-chlorophenyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide 410
8-chloro-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] was reacted according to the procedure in example 378]Reacting azulene-2-carboxylic acid 1-dimethylamino-methylene amide with 2-chlorophenylhydrazine hydrochloride to obtain 8-chloro-2- [2- (2-chloro-phenyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]Azulene (MS (ESI +)399.1/401.1) was reacted with L-prolinamide to give 410. MS (ESI +) 477.1.1H NMR(400MHz，DMSO)8.26(s，1H)，8.15(s，1H)，7.79(s，1H)，7.72(dd，J＝8.0，1.1Hz，1H)，7.66-7.52(m，3H)，7.29(br，1H)，6.91(br，1H)，5.83(s，1H)，4.45-4.38(m，4H)，4.23(d，J＝7.7Hz，1H)，3.61-3.53(s，1H)，3.40-3.32(m，1H)，2.23-2.06(m，1H)，2.02-1.84(m，3H)。
Example 413: (5- (9- (dimethylamino) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-yl) methanol 413
8-chloro-2-iodo-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene was reacted with 2-methoxyethamidine hydrochloride and isopropylhydrazine hydrochloride according to example 420 to give 8-chloro-2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4] triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulene (1.42g, 66% yield) after collection by filtration.
Reacting 8-chloro-2- (2-isopropyl-5-methoxymethyl-2H- [1, 2, 4) ]Triazol-3-yl) -4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]Reaction of azulene with 48% aqueous HBr by FCC (CH)2Cl2MeOH) to afford [5- (8-chloro-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ]]Azulen-2-yl) -1-isopropyl-1H- [1, 2, 4]Triazol-3-yl]Methanol (29% isolated yield).
Reacting [5- (8-chloro-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ]]Azulen-2-yl) -1-isopropyl-1H- [1, 2, 4]Triazol-3-yl]Methanol with dimethylamine hydrochloride to give 413(10mg) as a colourless solid. LCMS: 370.2.1H NMR(400MHz，DMSO)9.09(s，1H)，7.80(s，1H)，6.13(s，1H)，5.98-5.85(m，1H)，5.18(t，J＝6.0Hz，1H)，4.56-4.44(m，4H)，4.41(d，J＝6.0Hz，2H)，3.05(s，6H)，1.47(d，J＝6.6Hz，6H)。
example 417: (5- (9- (3, 3-difluoroazetidin-1-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3, 4-f][1，4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-yl) methanol 417
Reacting [5- (8-chloro-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ]]Azulen-2-yl) -1-isopropyl-1H- [1, 2, 4]Triazol-3-yl]Reaction of methanol with 3, 3-difluoroazetidine hydrochloride gave 417(23mg) as a colourless solid. LCMS: 418.1.1h NMR (400MHz, DMSO)9.14(s, 1H), 7.85(s, 1H), 6.16(s, 1H), 5.87(dt, J ═ 13.2, 6.6Hz, 1H), 5.18(t, J ═ 6.0Hz, 1H), 4.60-4.47(m, 4H), 4.41 (overlapping multiplet, 6H), 1.47(d, J ═ 6.6Hz, 6H).
Example 420: 2- (3-methyl-1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -9- (2- (2-methylbenzyl) pyrrolidin-1-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][l，4]Oxazazepine420
8-chloro-2-iodo-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]Azulene (2.00g, 0.58mmol) and acetamidine hydrochloride (0.653g, 0.69mmol) in DMF (20mL) and Et3A solution in N (4.0mL) was treated under nitrogen with 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos, 0.166g, 0.029mmol) and Pd (OAc)2(0.0646g, 0.029 mmol). The flask was equipped with a carbon monoxide balloon and the reaction mixture was heated at 65 ℃ for 2 hours. After cooling to room temperature, trifluoroethylhydrazine (70 wt% in H) was added2O, 1.12g, 0.69mmol) in acetic acid (5 mL). After 3 hours at 65 ℃, the mixture was cooled and diluted with water. 8-chloro-2- [ 5-methyl-2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]The azulenes were collected by filtration, washed with water and hexane and dried in vacuo (1.74g, 78% yield).1H NMR(400MHz，DMSO)9.26(s，1H)，8.10(s，1H)，7.24(s，1H)，5.76(q，J＝8.8Hz，2H)，4.71-4.53(m，4H)，2.29(s，3H)。
To a 10mL microwave bottle was added 8-chloro-2- [ 5-methyl-2- (2, 2, 2-trifluoro-ethyl) -2H- [1, 2, 4 ]Triazol-3-yl]-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e]Azulene (85mg, 0.22mmol) and 2- (2-methyl-benzyl) -pyrrolidine (231mg, 6 equivalents). 0.5mL NMP and 0.5mL TEA were added. The vial was sealed and heated at 160 ℃ for 24 hours. After cooling to room temperature, the solution was directly subjected to reverse phase HPLC (0.1% NH)4OH/ACN). The isolated solid was further purified by chiral SFC (AD column, 35% MeOH isocratic elution) to give 27mg of one enantiomer and 29mg of 420 (48% overall yield). LCMS: 524.2.1h NMR (400MHz, DMSO)9.08(s, 1H), 7.92(s, 1H), 7.27-7.06(m, 4H), 5.99(s, 1H), 5.80(q, J ═ 8.9Hz, 2H), 4.50(m, 4H), 4.38 (broad singlet, 1H), 3.49(t, J ═ 8.6Hz, 1H), 3.15(d, J ═ 10.0Hz, 1H), 2.60-2.53(m, 1H), 2.42(s, 3H), 2.28(s, 3H), 2.10-1.89(m, 2H), 1.81-1.71(m, 2H).
Example 421: 2- (3-methyl-1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -9- (2- (piperidin-1-ylmethyl) pyrrolidin-1-yl) -5, 6-dihydroimidazo [1, 2-d]Pyrido [3, 4-f][1，4]Oxazazepine421
Reaction of [5- (8-chloro-4, 5-dihydro-6-oxa-1, 3a, 9-triaza-benzo [ e ] azulen-2-yl) -1-isopropyl-1H- [1, 2, 4] triazol-3-yl ] -methanol with 1- (pyrrolidin-2-yl) methyl-piperidine gave 421(67mg) after purification by reverse phase HPLC. LCMS: 542.2.
Example 423: 2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (1-methyl-1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine423
Adding 9-bromo-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] to a microwave bottle]Imidazo [1, 2-d ] s][1，4]Oxazazepine411(0.239mg, 0.617mmol) in 3.0mL of water. To the suspension were added potassium acetate (182mg, 1.85mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (154mg, 740 mmol). The reaction suspension was degassed by bubbling nitrogen through the stirred mixture via syringe. After a few minutes, the syringe was removed and Pd (PPh) was added3)4(57mg, 56mmol) and the reaction flask was quickly sealed. The sealed vial was rapidly heated in a microwave at 150 ℃ for 30 minutes. The cooled reaction mixture was diluted with EtOAc and the organic solution was washed with water × 1 and brine × 1 and dried (Na)2SO4) And then concentrated in vacuo. The crude residue is purified by preparative RP-HPLC to yield 132mg 423 (55% of th.).1H NMR(400MHz，DMSO)8.36(d，J＝8.4Hz，1H)，8.20(s，1H)，7.90(d，J＝23.3Hz，2H)，7.36(dd，J＝8.4，1.6Hz，1H)，7.25(d，J＝1.6Hz，1H)，5.83(dt，J＝13.3，6.6Hz，1H)，4.51(s，4H)，3.87(s，3H)，2.25(s，3H)，1.47(d，J＝6.6Hz，6H)。
Example 424: 2- (3-amino-1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-10-carbonitrile 424
2- (10-bromo-5, 6-dihydrobenzo [ f ] is treated as in example 425]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1- (2,2-trifluoroethyl) -1H-imidazol-4-amine (150mg, 0.350mmol) is converted into 31mg 424 (24% of th.).1H NMR(400MHz，DMSO)8.72(d，J＝2.1Hz，1H)，7.94(s，1H)，7.76(dd，J＝8.5，2.1Hz，1H)，7.24(d，J＝8.6Hz，1H)，5.58(q，J＝8.8Hz，2H)，5.48(d，J＝12.2Hz，2H)，4.60(d，J＝9.0Hz，4H)。
Example 425: 2- (3-amino-1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carbonitrile 425
Adding 2- (9-bromo-5, 6-dihydrobenzo [ f ] in a microwave bottle]Imidazo [1, 2-d ] s][1，4]OxazazepineA solution of (2-yl) -1- (2, 2, 2-trifluoroethyl) -1H-imidazol-4-amine (0.200mg, 0.466mmol) in 1.0mL DMF. To this solution was added zinc cyanide (160mg, 1.4 mmol). The reaction mixture was degassed by bubbling nitrogen through the stirred mixture via a syringe. After a few minutes, the syringe was removed and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (66mg, 0.093mmol) was added and the reaction vial was quickly sealed. The sealed vial was rapidly heated in a microwave at 125 ℃ for 30 minutes. The cooled reaction mixture was diluted with EtOAc and the organic solution was washed with water × 1 and brine × 1 and dried (Na)2SO4) And then concentrated in vacuo. The crude residue is purified by preparative RP-HPLC to yield 81mg 425 (38% of th.). 1H NMR(400MHz，DMSO)8.51(dd，J＝11.8，5.7Hz，1H)，8.07(d，J＝75.8Hz，1H)，7.78-7.40(m，2H)，5.58(q，J＝8.9Hz，2H)，5.50(s，2H)。
Example 431: 5- (9-cyclopropyl-5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine 431
Adding 5- (9-bromo-5, 6-dihydrobenzo [ f ] to a microwave bottle]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine (100mg, 0.200mmol) in 0.500mL THF and 0.300mL water. To the solution were added potassium phosphate (164mg, 0.770mol) and cyclopropylboronic acid pinacol ester (308mg, 1.48 mol). The reaction suspension was degassed by bubbling nitrogen through the stirred mixture via syringe. After a few minutes, the syringe was removed and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (20mg, 0.026mmol) was added and the reaction vial was quickly sealed. The sealed vial was rapidly heated in a microwave at 130 ℃ for 30 minutes. The cooled reaction mixture was diluted with EtOAc and the organic solution was washed with water × 1 and brine × 1 and dried (Na)2SO4) And then concentrated in vacuo. The crude residue is purified by preparative RP-HPLC to yield 16.7mg 431 (14% of th.).1H NMR(400MHz，DMSO)8.24(d，J＝8.3Hz，1H)，7.69(s，1H)，6.85(d，J＝8.4Hz，1H)，6.74(s，1H)，5.73(dt，J＝13.3，6.8Hz，1H)，5.15(s，2H)，4.46(d，J＝2.3Hz，4H)，2.04-1.86(m，1H)，1.40(d，J＝6.6Hz，6H)，1.11-0.88(m，2H)，0.72(q，J＝4.9Hz，2H)。
Example 442: 5- (10-cyclopropyl-5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-3-amine 442
5- (10-bromo-5, 6-dihydrobenzo [ f ] a]Imidazo [1, 2-d ] s][1，4]Oxazazepine-2-yl) -1- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazol-3-amine (150mg, 0.350mmol) was converted to 8.4mg 442 (6.4% of th.).1H NMR(400MHz，DMSO)8.72(d，J＝2.1Hz，1H)，7.94(s，1H)，7.76(dd，J＝8.5，2.1Hz，1H)，7.24(d，J＝8.6Hz，1H)，5.73(dt，J＝13.3，6.8Hz，1H)，5.15(s，2H)，4.46(d，J＝2.3Hz，4H)，2.04-1.86(m，1H)，1.40(d，J＝6.6Hz，6H)，1.11-0.88(m，2H)，0.72(q，J＝4.9Hz，2H)。
Example 443: 2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-carbonitrile 443
Adding 9-bromo-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] to a microwave bottle]Imidazo [1, 2-d ] s][1，4]Oxazazepine411(0.300mg, 0.699mmol) in 2.0mL DMF. To this solution was added zinc cyanide (250mg, 2.1 mmol). The reaction mixture was degassed by bubbling nitrogen through the stirred mixture via a syringe. After a few minutes, the syringe was removed and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (100mg, 0.140mmol) was added and the reaction vial was quickly sealed. The sealed vial was rapidly heated in a microwave at 125 ℃ for 30 minutes. The cooled reaction mixture was diluted with EtOAc and the organic solution was washed with water × 1 and brine × 1 and dried (Na)2SO4) And then concentrated in vacuo. The crude residue was purified by preparative RP-HPLC to give 156mg 443 (59% of th.) in yield. 1H NMR(400MHz，DMSO)8.55(d，J＝8.2Hz，1H)，8.02(s，1H)，7.74-7.46(m，2H)，5.79(dt，J＝13.1，6.6Hz，1H)，4.57(s，4H)，2.29(d，J＝28.5Hz，3H)，1.46(d，J＝6.6Hz，6H)。
Example 475: 2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (2- (methylsulfonyl) phenyl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine475
52194A solution of 0.050g (0.13 mmol) and finely divided potassium phosphate (0.0851g, 0.401mmol) in DMF (0.5mL) was degassed thoroughly with nitrogen. 2-Methylsulfonylphenylboronic acid (0.053g, 0.27mmol), palladium diacetate (0.0015g, 0.0067mmol) and S-Phos (0.00686g, 0.0167mmol) were added and the mixture was heated in a microwave at 180 ℃ for 30 minutes. The reaction mixture was diluted with DCM and filtered over celite. Adding saturated NH4Cl and the mixture was extracted three times with DCM. The organic layers were combined and washed with Na2SO4Dried and concentrated. The crude product was purified by reverse phase HPLC to give 8.1mg 475 as a white solid. MS (ESI +) 450.1.1H NMR (400MHz, DMSO)8.47(d, J ═ 8.3Hz, 1H), 8.11(dd, J ═ 8.0, 1.1Hz, 1H), 7.98(s, 1H), 7.92(s, 1H), 7.79(td, J ═ 7.5, 1.3Hz, 1H), 7.70(td, J ═ 7.8, 1.3Hz, 1H), 7.45(dd, J ═ 7.5, 1.1Hz, 1H), 7.21(dd, J ═ 8.3, 1.8Hz, 1H), 7.12(d, J ═ 1.7Hz, 1H), 5.93 (heptad, J ═ 6.2Hz, 1H), 4.57(q, J ═ 5.7, 4H), 2.93(s, 3H), 6.6H, 6H).
Example 476: 2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) benzamide 476
52194 is reacted with (2-aminocarbonylphenyl) boronic acid according to the procedure in example 475 to give 476. MS (ESI +) 415.2.1H NMR(400MHz，DMSO)8.42(dJ ═ 8.3Hz, 1H), 7.95(s, 1H), 7.91(s, 1H), 7.70(s, 1H), 7.54-7.39(m, 4H), 7.34(s, 1H), 7.22(dd, J ═ 8.3, 1.7Hz, 1H), 7.12(d, J ═ 1.7Hz, 1H), 5.93 (heptad, J ═ 6.2Hz, 1H), 4.55(q, J ═ 5.7Hz, 4H), 1.50(d, J ═ 6.6Hz, 6H).
Example 477: 9- (2-ethylphenyl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1, 2-d ] s][1，4]Oxazazepine477
52194 was reacted with 2-ethylphenylboronic acid according to the procedure for example 475 to give 477. MS (ESI +) 400.2.1H NMR (400MHz, DMSO)8.47(d, J ═ 8.2Hz, 1H), 7.95(s, 1H), 7.92(s, 1H), 7.38-7.31(m, 2H), 7.30-7.23(m, 1H), 7.20(d, J ═ 7.3Hz, 1H), 7.12(dd, J ═ 8.2, 1.7Hz, 1H), 6.97(d, J ═ 1.6Hz, 1H), 5.93 (heptad, J ═ 6.2Hz, 1H), 4.65-4.41(m, 4H), 2.61(q, J ═ 7.6Hz, 2H), 1.50(d, J ═ 6.6Hz, 6H), 1.07(t, J ═ 7.5, 3H).
Example 478: (2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1, 2-d ] s][1，4]Oxazazepine-9-yl) phenyl) methanol 478
Reaction of 52 with 2- (hydroxymethyl) phenylboronic acid was carried out in accordance with example 475 to give 478. MS (ESI +) 402.1.1H NMR(400MHz，DMSO)8.46(d，J＝8.3Hz，1H)，7.96(s，1H)，7.92(s，1H)，7.58(d，J＝7.7Hz，1H)，7.41(td，J＝7.4，1.1Hz，1H)，7.38-7.32(m，1H)，7.28(d，J＝7.4Hz，1H)，7.20(dd，J＝8.3，1.6Hz，1H)，7.09(d，J＝1.5Hz，1H)，6.02-5.83(m，1H)，5.16(t，J＝5.3Hz，1H)，4.56(q，J＝6.1Hz，4H)，4.45(d，J＝5.3Hz，2H)，1.50(d，J＝6.6Hz，6H)。
Example 901: p 110. alpha. PI3K binding assay
Binding assay: initial polarization experiments were performed with analysis HT 96-384(Molecular Devices Corp, Sunnyvale, Calif.). The samples for fluorescence polarization affinity measurements were prepared as follows: a1: 3 serial dilution of p 110. alpha. PI3K (Upstate Cell Signaling Solutions, Charlottesville, Va.) was prepared in a polarizing buffer (10mM Tris pH 7.5, 50mM NaCl, 4mM MgCl. sub.10 mM) from 20. mu.g/ml20.05% Chaps and 1mM DTT)) to a final concentration of 10mM PIP2(Echelon-Inc., Salt Lake City, UT.). After incubation for 30 min at room temperature, the reaction was stopped by adding GRP-1 and PIP3-TAMRA probes (Echelon-Inc., Salt Lake City, UT.) (final concentrations of 100nM and 5nM, respectively). Rhodamine fluorophores were read with standard cut-off filters in 384-well black low-volume Proxi plates (PerkinElmer, wellelsley, MA.) (λ) ex＝530nm；λem590 nm). Fluorescence polarization values were plotted as a function of protein concentration and EC50The values are obtained as follows: data were fit to a four parameter equation using KaleidaGraph software (Synergy software, Reading, PA). This experiment also determined the protein concentration suitable for the following inhibitor competition experiments.
Inhibitor IC50The values were determined as follows: 0.04 mg/ml p110 α PI3K (final concentration) was added along with PIP2(10mM final concentration) to wells containing 1: 3 serial dilutions of the antagonist in Cell Signaling Technology, Inc., Danvers, MA)/polarizing buffer at a final concentration of 25 mM. After incubation for 30 min at room temperature, the reaction was stopped by adding GRP-1 and PIP3-TAMRA probes (Echelon-Inc., Salt Lake City, UT.) (final concentrations of 100nM and 5nM, respectively). Rhodamine fluorophores were read with standard cut-off filters in 384-well black low-volume Proxi plates (PerkinElmer, wellelsley, MA.) (λ)ex＝530nm；λem590 nm). Polarization value of fluorescencePlotted as a function of antagonist concentration and IC50The values are obtained as follows: the data were fit to a four parameter equation using the Assay Explorer software (MDL, San Ramon, CA.).
Alternatively, inhibition of PI3K was determined in a radioactive assay using purified recombinase and ATP at a concentration of 1 μ M. Compounds of formula I were serially diluted in 100% DMSO. The kinase reaction mixture was incubated at room temperature for 1h and the reaction was stopped by adding PBS. Then IC 50Values were determined using a sigmoidal dose response curve fit (variable slope).
Example 902: in vitro cell proliferation assay
The potency of the compound of formula I was measured by a cell proliferation assay using the following protocol (Promega Corp. technical Bulletin TB 288; Mendoza et al (2002) Cancer Res.62: 5485-5488):
1. 100. mu.l of an aliquot of the cell culture (containing about 10 of the culture medium)4Individual cells (PC3, Detroit562 or MDAMB361.1)) were placed in each well of a 384-well opaque plate.
2. Control wells containing media but no cells were prepared.
3. Compounds were added to the experimental wells and incubated for 3-5 days.
4. The plate was equilibrated to room temperature and held for about 30 minutes.
5. CellTiter-Glo reagent was added at the same volume as the volume of cell culture medium present in each well.
6. The contents were mixed with an orbital shaker for 2 minutes to lyse the cells.
7. The plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal.
8. Luminescence signals were recorded and reported in graph form as RLU ═ relative luminescence units.
Alternatively,cells were seeded in 96-well plates at optimal density and incubated for 4 days in the presence of test compounds. Then Alamar BlueTMAdded to the assay medium and the cells incubated for 6h, then read with excitation wavelength 544nm and emission wavelength 590 nm. EC (EC) 50Values were calculated using sigmoidal dose response curve fitting. Term EC50Refers to the half maximal effective concentration and is the concentration at which the drug elicits a response after a certain exposure time that is the midpoint between the baseline response and the maximal response. It is commonly used to measure the efficacy of drugs.
Antiproliferative effects of exemplary compounds of formula I on various tumor cell lines were measured by CellTiter-GloAssay to measure, comprising the following:
example 903: permeability of Caco-2
Caco-2 cells were cultured at 1X 105Individual cell/cm2Inoculated onto Millipore Multiscreen plates and incubated for 20 days. The permeability of the compound was then evaluated. Compounds were applied to the apical surface (a) of the cell monolayer and the compounds permeated into the basolateral (B) compartment were measured. This was reversed (B-A) to investigate active transport. The permeability coefficient value P of each compound was calculatedappI.e. a measure of the transmission of a compound through the membrane. Compounds are classified into groups of low absorption potential (P) by comparison with control compounds for which human absorption has been determinedapp＜/＝1.0×106cm/s) or high absorption potential group (P)app＞/＝1.0×106cm/s)。
To evaluate the ability of a compound to undergo active efflux, the ratio of transport from the bottom side (B) to the top side (a) to transport from a to B was determined. The value of B-a/a-B >/═ 1.0 indicates the occurrence of active cell efflux.
Example 904: clearance rate of liver cells
A suspension of cryopreserved human hepatocytes was used. At a compound concentration of 1mM or 3. mu.M and 0.5X 106The incubation was performed at a cell density of individual viable cells/ml. The final concentration of DMSO in the incubation was about 0.25%. Control incubations were also performed in the absence of cells to show any non-enzymatic degradation. Samples (50 μ L) were removed from the incubation mixture in duplicate at 0, 5, 10, 20, 40 and 60 minutes (control samples at only 60 minutes) and added to MeOH with internal standard (100 μ L) to stop the reaction. Tolbutamide (tolbutamide), 7-hydroxycoumarin (7-hydroxycoumarin) and testosterone (testosterone) can be used as control compounds. The samples were centrifuged and the supernatants collected at each time point were used for analysis by LC-MSMS. Intrinsic Clearance (CL) by plotting the natural logarithm of the peak area ratio (parent compound peak area/internal standard peak area) versus timeint) The following calculations were made: CLint(μ l/min/million cells) ═ V × k, where k is the elimination rate constant, obtained from the gradient of the natural logarithm of the concentration plotted against time; v is the volume term derived from the incubation volume and is expressed as μ L106Individual cell-1。
Example 905: cytochrome P450 inhibition
Compounds of formula I can be screened in duplicate at about 10 concentrations (maximum concentration of about 100 μ M) against CYP450 targets (1a2, 2C9, 2C19, 2D6, 3a 4). Standard inhibitors (furafylline), sulfaphenazole (sulfaphenazole), tranylcypromine (tranylcyclopromine), quinidine (quinidine), ketoconazole (ketoconazole)) may be used as controls. Plates can be read in fluorescence mode using bmglab technologies polaristar.
Example 906: cytochrome P450 Induction
Freshly isolated human hepatocytes from a single donor may be incubated for about 48h, then the compound of formula I added at three concentrations and incubated for 72 h. Probe substrates for CYP3a4 and CYP1a2 were added 30 minutes and 1h before the end of incubation. At 72h, cells and medium were removed and the degree of metabolism of each probe substrate was quantified by LC-MS/MS. The experiment was controlled by using the inducer of the corresponding P450 (incubated in triplicate at one concentration).
Example 907: plasma protein binding
A solution of the compound of formula I (5. mu.M, final concentration of DMSO 0.5%) was prepared in buffer and 10% plasma (v/v in buffer). The 96-well HT dialysis plates were assembled such that each well was bisected by a cellulose semipermeable membrane. Adding a buffer solution to one side of the membrane and a plasma solution to the other side; then incubated at 37 ℃ for 2h in triplicate. Cells were then emptied and solutions of each batch of compound were combined into two groups (plasma-free and plasma-containing) and then analyzed by LC-MSMS using two sets of calibration standards for the plasma-free solution (6 points) and for the plasma-containing solution (7 points). Calculate the unbound fraction value of the compound.
Example 908: hERG channel blockade
The ability of compounds of formula I to modulate rubidium efflux from HEK-294 cells stably expressing the hERG potassium channel was evaluated using established efflux methodologies. Cells were prepared in RbCl-containing medium, plated into 96-well plates and grown overnight to form monolayers. The efflux experiment was started as follows: the medium was aspirated at room temperature and each well was pre-incubated with 3X 100. mu.L of pre-incubation buffer (containing low [ K ]+]) And (6) washing. After the last aspiration, 50 μ L of compound working stock (2 ×) was added to each well and incubated for 10 min at room temperature. Then 50. mu.L of stimulation was slowed downFlushing liquid (containing high [ K ]+]) Add to each well to give the final test compound concentration. The cell plates were then incubated at room temperature for an additional 10 minutes. Then 80 μ Ι _ of supernatant from each well was transferred to the corresponding well of a 96-well plate and analyzed by atomic emission spectroscopy. Duplicate IC at 10 dots50Compounds were screened for the curve (n-2, maximum concentration 100 μ M).
Example 909: in vivo tumor xenografts
Animals suitable for transgenic experiments can be obtained from standard commercial sources. Groups of Taconic nude mice were implanted with MDA-MB-361.1(PI3K mutant) breast cancer cells subcutaneously in the posterior costal region. The mouse xenografts were given drug or vehicle daily and maintained for 21 days. Tumor size was recorded twice weekly during the study. Mouse body weights were also recorded twice weekly and mice were observed regularly. Tumor volumes were measured in two dimensions (length and width) using an Ultra Cal-IV caliper (Model 54-10-111; Fred v. fowler co., inc.; Newton, MA) and analyzed using Excel v.11.2(Microsoft Corporation; Redmond, WA). The tumor suppression graph was plotted using KaleidaGraph (version 3.6, Synergy Software; Reading, Pa.). Tumor volume was calculated using the formula: tumor size (mm) 3) Two (longer measurement x shorter measurement)2)×0.5。
Animal body weights were measured using Adventurera Pro AV812 Scale (Ohaus Corporation; PineBrook, NJ). Graphs were generated using KaleidaGraph (version 3.6). The weight percent change was calculated using the formula: group weight change percentage ═ 1- (initial weight/latest weight)) × 100.
According to the rule guidance, the tumor volume exceeds 2000mm3Or mice with a weight loss of > 20% of their initial weight were immediately euthanized.
Percent tumor growth inhibition (% INH) at the end of the study (EOS) was calculated using the formula: % INH is 100 × (mean volume of tumor EOS in vehicle-mean volume of tumor EOS in drug-administered animals)/mean volume of tumor EOS in vehicle-administered animals.
Tumor Incidence (TI) was determined based on the number of measurable tumors remaining in each group at the end of the study. Partial Response (PR) was defined as > 50% but < 100% reduction in tumor volume observed on any day of the study compared to the initial tumor volume. Complete Response (CR) was defined as the 100% reduction in tumor volume observed on any day of the study compared to the initial tumor volume. The data were analyzed using Dunnett's test [ JMP statistical software (version 5.1.2, SAS Institute; Cary, NC) ] and the p-value determined. Individual tumor volumes and mean tumor volumes at the end of the study ± SEM values were calculated using JMP statistical software (version 5.1.2). The body weight data were plotted as a graph based on mean percent change from initial body weight ± SEM.
Example 910: phosphoakt induction assay
Cells were treated at 5X 105Individual cells/well were seeded overnight in 6-well tissue culture plates. The concentration for the cells is EC80Treatment of a compound of formula I. After treatment, cells were washed once with cold PBS and lysed in 1 × cell extraction buffer (Biosource, Carlsbad, CA) supplemented with protease inhibitors (Roche, Mannheim, Germany), 1mM PMSF, and phosphatase inhibitor cocktail 1 and 2(Sigma, st. Protein concentration was determined using Pierce BCA protein assay kit (Rockford, IL). pAkt (Ser)473) Levels and total Akt levels were assessed using a bead kit (Biosource, Carlsbad, Calif.) and a Luminex Bio-Plex System (Bio-Rad, Hercules, Calif.).
When the words "comprise" and "comprising" are used in this specification and the appended claims, they are intended to specify the presence of stated features, integers, components or steps, but do not preclude the presence or addition of one or more other features, integers, components, steps or groups thereof.

Claims (15)

1. A compound of formula I:
wherein
Z1Is CR1Or N;
Z2is CR2Or N;
Z3is CR3Or N;
Z4is CR4Or N;
b is a radical of a heterocyclic oxygen with a benzoxaneA ring fused pyrazolyl or imidazolyl ring and selected from the following structures:
R1、R2、R3and R4Independently selected from H, F, Cl, Br, -CN, -CO2R10、-C(＝O)N(R10)OR11、-C(＝O)NR10R11、-NR10R11、-NR12(C1-C12Alkylene) NR10R11、-NR12(C1-C12Alkylene) OR10、-NR12(C1-C12Alkylene) C (═ O) NR10R11、-OR10、C1-C12Alkyl radical, C3-C12Carbocyclyl, C2-C20Heterocyclic group, C6-C20Aryl radical, C1-C20Heteroaryl, - (C)3-C12Carbocyclyl) - (C1-C12Alkyl), - (C)2-C20Heterocyclyl) - (C)1-C12Alkyl), - (C)6-C20Aryl group) - (C1-C12Alkyl), - (C)1-C20Heteroaryl) - (C)1-C12Alkyl), - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) and- (C)1-C12Alkylene) -NR10R11，
Wherein the alkyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, R10、-S(O)2R10、-S(O)2NR10R11、-NR10R11、-NR12C(O)R10、-CO2R10、-C(O)R10、-CONR10R11Oxo and-OR10；
A is selected from-C (═ O) NR5R6And C1-C20Heteroaryl, wherein the heteroaryl is optionally substituted with one or more groups independently selected from: -CN, -NR10R11、-OR10、C1-C12Alkyl radical, C3-C12Carbocyclyl, C6-C20Aryl, - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl) and- (C)1-C12Alkylene) OR10，
Wherein the alkyl, alkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from: F. cl, R10、-SR10、-NR10R11、-CONR10R11and-OR10；
R5Selected from H and C 1-C12Alkyl optionally substituted with one or more groups independently selected from: -OH;
R6is selected from C1-C12Alkyl and C6-C20Aryl, each of which is optionally substituted with one or more groups independently selected from: F. -CH3、-CH2OH and-OH; or
R10、R11And R12Independently selected from H, C1-C12Alkyl, - (C)1-C12Alkylene group) - (C2-C20Heterocyclyl), - (C)1-C12Alkylene group) - (C6-C20Aryl group), C3-C12Carbocyclyl, C2-C20Heterocyclic group, C6-C20Aryl and C1-C20Heteroaryl, each of which is optionally substituted with one or more groups independently selected from: F. -CH3、-CH2CH3、-CH(CH3)2、-CH2OH、-CH2OCH3、-CH2CH2OH、-C(CH3)2OH、-CF3、-CO2H、-C(O)CH(OH)CH3、-CONH2、-NH2O (oxo), -OH, -OCH3、-S(O)2CH3And morpholin-4-yl; or
R10And R11When attached to a nitrogen atom, together with the nitrogen atom to which they are attached form C2-C20Heterocyclyl ring or C1-C20A heteroaryl ring, each of which is optionally substituted with one or more groups independently selected from: -CH3、-CF3、-CONH2-OH, oxo, -CH (CH)3)2、-CH2CF3、-CH2CH2OH and-C (CH)3)2OH。
2. The compound of claim 1, wherein Z1Is CR1；Z2Is CR2；Z3Is CR3(ii) a And Z is4Is CR4。
3. A compound according to claim 1 or 2, wherein a is-C (═ O) NR5R6Or a group of formula ii, iii, iv, v or vi, wherein R5Is CH3And R is6Is phenyl substituted with one or more F, said group of formula ii, iii, iv, v or vi being:
4. the compound of claim 3, wherein Z1Is CR1；Z2Is CR2；Z3Is CR3；Z4Is CR4(ii) a B is a structure of formula a or d; and A is a group of formula ii or vi.
5. The compound of claim 1, having formula Ih or Ii:
wherein R is1、R2、R3、R4And A is as defined in claim 1.
6. The compound of claim 5, having formula Ih, wherein R1Is hydrogen, R2Is hydrogen, Br, -C (O) NH2Or 1- (2-methanesulfonyl-ethyl) -azetidin-3-yl, R3Is hydrogen or piperidin-4-yl, R4Is hydrogen and A is 2- [2- (2, 4-difluoro-phenyl) -2H- [1,2,4]Triazol-3-yl or 2-chlorophenyl) -2H- [1,2,4]Triazol-3-yl; or the compound has the formula Ii, wherein R1Is hydrogen, R2Is hydrogen, F or a group of the formula:
R3is hydrogen or-C (O) NH2，R4Is hydrogen and A is 1-isopropyl-1H- [1,2,4]Triazol-5-yl, 1-isopropyl-3-methyl-1H- [1,2,4 ]]Triazol-5-yl, 1-isopropyl-3-amino-1H- [1,2,4]Triazol-5-yl or 1- (2-chlorophenyl) -1H- [1,2,4]Triazol-5-yl.
7. A compound selected from the group consisting of:
101N- (2, 4-difluorophenyl) -N-methyl-4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine-2-carboxamides
1022- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-AAmides of carboxylic acids
1032- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -8-bromo-4, 5-dihydrobenzo-2H-oxa-lAnd [4,5-d ]]Pyrazoles
1042- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
1052- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -8- (pyrazol-4-yl) -4, 5-dihydrobenzo-2H-oxaAnd [4,5-d ]]Pyrazoles
1062- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -8-bromo-4, 5-dihydrobenzo-2H-oxaAnd [4,5-d ]]Pyrazoles
1072- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -4, 5-dihydrobenzo-2H-oxa-lAnd [4,5-d ]]Pyrazole-8-carboxamides
1082- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (pyrazol-4-yl) -4, 5-dihydrobenzo-2H-oxaAnd [4,5-d ]]Pyrazoles
1092- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-carboxamides
1102- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N-methyl-4, 5-bishydrobenzo-2H-oxaAnd [4,5-d ]]Pyrazole-9-carboxamides
1112- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N- (2-hydroxyethyl) -4, 5-dihydrobenzo-2H-oxaAnd [4,5-d ]]Pyrazole-9-carboxamides
112 (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) (S, S-dioxothiomorpholino) methanone
113 (4- (2-hydroxypropan-2-yl) piperidin-1-yl) (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -f)]Imidazo [1,2-d ] s ][1,4]Oxazazepine-10-yl) methanone
1149- (1-isopropyl-1H-pyrazol-5-yl) -6, 7-dihydroimidazo [1,2-d]Pyrido [3,2-b][1,4]Oxazazepine-3-carboxamides
1152- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-carboxamides
116N- (2-hydroxy-2-methylpropyl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine-9-carboxamides
117 (2- (1-isopropyl-1H)-1,2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) (S, S-dioxothiomorpholino) methanone
118 (4-hydroxypiperidin-1-yl) (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) methanones
119N- (2- (methylsulfonyl) ethyl) -2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-carboxamides
120 (4-isopropylpiperazin-1-yl) (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) methanone
121N- (1-hydroxy-2-methylpropan-2-yl) -2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s ][1,4]Oxazazepine-10-carboxamides
122 (4- (2-hydroxyethyl) piperazin-1-yl) (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) methanone
123 morpholino (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) methanone
124 (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) (4- (2,2, 2-trifluoroethyl) piperazin-1-yl) methanone
125N- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine-9-carboxamides
1262- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N- (isoxazol-3-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine-9-carboxamides
127N- (1H-pyrazol-4-yl) -2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine-9-carboxamides
1282- (4- ((2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) methyl) piperazin-1-yl) ethanol
129 (4-hydroxypiperidin-1-yl) (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) methanone
1309- (piperidin-4-yl) -2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine
131N- ((2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) methyl) pyrazin-2-amine
1322-hydroxy-1- (4- ((2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) methyl) piperazin-1-yl) ethanone
1332- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N- (2- (methylsulfonyl) ethyl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
1342- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -N- (2- (methylsulfonyl) ethyl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
1352- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -N- (1-hydroxy-2-methylpropan-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-carboxamides
136 (2- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) (4-isopropylpiperazin-1-yl) methanone
1372- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -N- (1-hydroxy-2-methylpropan-2-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-carboxamides
1382- (4-cyano-1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
1392- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -N-methyl-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
140N- (2-hydroxyethyl) -N-isopropyl-4, 5-dihydrobenzo [ b ]]Pyrazolo [1,5-d][1,4]Oxazazepine-2-carboxamides
1414- ((2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b)]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) methyl) piperazin-2-one
1422- (4- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b ]]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) piperidin-1-yl) ethanol
1432- (4- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b ]]PyrazolesAnd [1,5-d ]][1,4]Oxazazepine-9-yl) piperidin-1-yl) acetamide
1449- (azetidin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine
1452- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (piperazine-1-carbonyl) -4, 5-dihydrobenzo-2H-oxaAnd [4,5-d ]]Pyrazoles
1462- (4-isopropyl-4H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo-2H-oxa And [4,5-d ]]Pyrazoles
1472- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) -4, 5-dihydrobenzo-2H-oxaAnd [4,5-d ]]Pyrazole-9-carboxamides
1482- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (methylsulfonyl) azetidin-3-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine
1491- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b ]]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) azetidin-1-yl) ethanones
1502-hydroxy-1- (3- (2- (1-isopropyl) ethyl acetate-1H-1,2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) azetidin-1-yl) ethanones
1512-hydroxy-1- (4- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b ]]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) piperidin-1-yl) ethanones
1529- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine
153 ((3S,5R) -3, 5-dimethylpiperazin-1-yl) (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) methanone
1542- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -9- (piperidin-4-yl) -4, 5-dihydrobenzo-2H-oxa And [4,5-d ]]Pyrazoles
1552- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b ]]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) azetidin-1-yl) acetamide
156N- (azetidin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine-9-carboxamides
1572- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (methylsulfonyl) ethyl) azetidin-3-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine
158N-methyl-2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
1592- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N-methyl-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
1602- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -10- (1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
1612- (1- (2-chlorophenyl) -1H-imidazol-2-yl) -N- (1-hydroxy-2-methylpropan-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-carboxamides
162 (2- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) (4- (2-hydroxyethyl) piperazin-1-yl) methanone
163N- (1-hydroxy-2-methylpropan-2-yl) -2- (1-isopropyl-1H-1, 2, 4-trisAzol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
164N- (1-hydroxy-2-methylpropan-2-yl) -2- (1- (S, S-dioxo-tetrahydrothiophen-3-yl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-carboxamides
1652- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -N- (1-hydroxy-2-methylpropan-2-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
1662- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (pyridin-4-ylmethyl) azetidin-3-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine
1672- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N- (1-isopropyl azetidin-3-yl) -4, 5-dihydrobenzo [ b]Pyrazolo [1,5-d][1,4]Oxazazepine-9-carboxamides
1682- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N-methoxy-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
1692- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b ]]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) azetidin-1-yl) ethanol
1702- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b ] ]Pyrazolo [1,5-d][1,4]Oxazazepine-9-yl) azetidin-1-yl) -2-methylpropan-1-ol
1712- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -8- (1- (2- (methylsulfonyl) ethyl) azetidin-3-yl) -4, 5-dihydrobenzo-2H-oxa-lAnd [4,5-d ]]Pyrazoles
1722- (3- {2- [2- (2, 4-difluoro-phenyl) -2H- [1,2,4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl } -azetidin-1-yl) -acetamide
173N-hydroxy-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
1742- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -N-methyl-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
1752- [2- (2, 4-difluoro-phenyl) -2H- [1,2,4] triazol-3-yl ] -9- [1- (2-methanesulfonyl-ethyl) -piperidin-4-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulene
1762- {4- [2- (2-isopropyl-2H- [1,2,4] triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl ] -pyrazol-1-yl } -ethanol
1771- (4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1,2,4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -piperidin-1-yl) -2-methyl-propan-2-ol
1782- (4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1,2,4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -piperidin-1-yl) -acetamide
1792- (4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1,2,4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -piperidin-1-yl) -ethanol
1801- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
1812- {3- [2- (2-isopropyl-2H- [1,2,4] triazol-3-yl) -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl ] -azetidin-1-yl } -acetamide
1822- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol
1831- (3- {2- [2- (2, 4-difluoro-phenyl) -2H- [1,2,4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl } -azetidin-1-yl) -2-methyl-propan-2-ol
1842- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-Carboxylic acid methyl ester
1852- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-Carboxylic acid methyl ester
1862- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol
18710-bromo-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
188 [4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1,2,4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -1- (2-methanesulfonyl-ethyl) -piperidin-4-yl ] -methanol
1892- (4- {2- [2- (2, 4-difluoro-phenyl) -2H- [1,2,4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-9-yl } -piperidin-1-yl) -2-methyl-propan-1-ol
1901- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
1912- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (methylsulfonyl) ethyl) azetidin-3-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
1922- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) azetidin-1-yl) acetamide
193 (1-aminocyclopropyl) (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) azetidin-1-yl) methanones
1949-bromo-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
1951- (4- (2- (1-isopropyl-4-methyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
1962- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropanamide
1972- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) azetidin-1-yl) -N, N-dimethylethanesulfonamide
1982- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) azetidin-1-yl) -N, N-dimethylacetamide
1999- (4, 4-dimethyl-4, 5-dihydrooxazol-2-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
200N-isopropyl-2- (3- (2- (1-isopropyl-1H)-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) azetidin-1-yl) acetamide
2012- (3- {2- [2- (2, 4-difluoro-phenyl) -2H- [1,2,4] triazol-3-yl ] -4, 5-dihydro-2H-6-oxa-1, 2-diaza-benzo [ e ] azulen-8-yl } -azetidin-1-yl) -ethanol
2021- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-imidazol-1-yl) -2-methylpropan-2-ol
2033- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) pyridin-2 (1H) -one
2049- (1- (2- (3-fluoroazetidin-1-yl) ethylsulfonyl) azetidin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2052- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) azetidin-1-yl) -2-methylpropanamide
2062- (4- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol
2072- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-imidazol-1-yl) ethanol
2082- (5- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-imidazol-1-yl) ethanol
2092- (1- (2-morpholinoethyl) -1H-imidazol-2-yl) -10- (1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f [ -f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2102- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2-morpholinoethyl) -1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f [ -f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2112- (4- (2- (3-amino-1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol
2122- (3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) azetidin-1-yl) -N-methylacetamide
2131- (4- (2- (3-amino-1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
2141- (4- (2- (1-isopropyl-1H-imidazol-2-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
2152- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropanamide
2162- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropionic acid
2172- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2183- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -F ]]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) pyridin-2 (1H) -one
2195- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) pyridin-2-amine
2202- (4- (2- (1-isopropyl) benzene3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-imidazol-1-yl) ethanol
2212- (2- (9- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1H-imidazol-1-yl) -N-methylacetamide
222N, N-diethyl-2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethylamine
2235- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) pyrimidin-2-amine
2249- (1H-imidazol-5-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine
2252- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2262- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) acetamide
2272-hydroxy-1- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropan-1-one
228 (2S) -2-hydroxy-1- (3- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) azetidin-1-yl) propan-1-one
2292- (4- (2- (3-amino-1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-imidazol-1-yl) ethanol
2302- (3- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) azetidin-1-yl) ethanol
2315- (5, 6-dihydrobenzo [ f ]]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine
2322- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine
2332- (1-isopropyl-1H-1, 2, 4-triazole-5)-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [4,3-f][1,4]Oxazazepine
2342- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -10- (4-methylpiperazin-1-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [4,3-f][1,4]Oxazazepine
2352- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (pyrimidin-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2369- (5-Fluoropyridin-3-yl) -2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2372- (3-amino-1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carbonitrile
238N- (5- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) pyridin-2-yl) acetamide
2399-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f][1,2,4]Triazolo [1,5-d][1,4]Oxazazepine
2409-bromo-2-(1-isopropyl-3- (methylthio) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2415- (9- (5-Fluoropyridin-3-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine -2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine
2422- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (tetrahydro-2H-pyran-2-yl) -1H-imidazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2433- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropanamide
2442- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (pyridin-3-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2455- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -N, N-dimethylpyrimidin-2-amine
2465- (5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1-isopropyl-N-methyl-1H-1, 2, 4-triazol-3-amine
247N-isopropyl-2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) acetamide
2482- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -N, 2-dimethylpropionamide
2492- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -N, N-dimethylethanesulfonamide
2502- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) acetamide
2512- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropionic acid
2521- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-imidazol-1-yl) -2-methylpropan-2-ol
2535- (9-fluoro-5, 6-dihydrobenzo [ f)]ImidazoleAnd [1,2-d ]][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine
2542- (4- (2- (3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol
2552- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -2-methyl-1H-imidazol-1-yl) ethanol
2562- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (2-methyl-1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-imidazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2575- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) pyrimidin-2-amine
2585- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) pyridin-2 (1H) -one
261N- (azetidin-3-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [4,3-f][1,4]Oxazazepine-10-amine
2623- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [4,3-f][1,4]Oxazazepine-10-ylamino) propane-1, 2-diol
2633- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) pyridin-2 (1H) -one
2651- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -2-methyl-1H-imidazol-1-yl) -2-methylpropan-2-ol
2683- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) pyridin-2 (1H) -one
2693- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [4,3-f][1,4]Oxazazepine-10-yl) pyridin-2 (1H) -one
2702- (5- (9-cyclopropyl-5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -3-methyl-1H-1, 2, 4-triazol-1-yl) propan-1-ol
2712- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (2-methyl-1H-imidazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo[1,2-d][1,4]Oxazazepine
2721- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1-methyl-1H-imidazol-2-yl) -2-methylpropan-2-ol
2731- (4- (2- (3- (hydroxymethyl) -1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
274N-tert-butyl-2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) acetamide
2752- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -N-methylacetamide
276N-Ethyl-2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ [ f ]]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) acetamide
277N-isopropyl-2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) acetamide
2782- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -N, N-dimethylacetamide
2792- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -N-methylacetamide
2802- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -4, 5-dihydrobenzo [ b][1,2,4]Triazolo [1,5-d][1,4]Oxazazepine
28110-fluoro-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2829- (1, 2-dimethyl-1H-imidazol-4-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2835- (10-fluoro-5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine
2849, 10-difluoro-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2852- (4- (2- (1, 3-dimethyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol
2862- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2-methoxyethyl) piperidin-4-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine
2872- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropanamide
2882- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) ethanol
2892- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropanamide
2901- (5- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-imidazol-2-yl) -2-methylpropan-2-ol
291 9-(1, 2-dimethyl-1H-imidazol-5-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
2921- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropan-2-ol
2932- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) ethanol
2942- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (tetrahydro-2H-pyran-4-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine
2952- (2-ethoxyphenyl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-Carboxylic acid methyl ester
2962- (3-isopropylphenyl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-Carboxylic acid methyl ester
2972- (2-ethylphenyl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-Carboxylic acid methyl ester
2982- (2-isopropylphenyl)) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-Carboxylic acid methyl ester
2992- (3- (trifluoromethyl) phenyl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-Carboxylic acid methyl ester
3002- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) acetamide
3012- (5- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -2-methyl-1H-imidazol-1-yl) ethanol
3021- (4- (2- (1-isopropyl-3- (methoxymethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
303 (3R,4R) -4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-3-ol
304 rac-cis/trans-2- (3-hydroxy-4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -N, N-dimethylacetamide
3052- (5- (9-bromo-5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-yl) acetamide
3065- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [4,3-f][1,4]Oxazazepine-10-yl) pyridin-2 (1H) -one
3074- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [4,3-f][1,4]Oxazazepine-10-yl) piperazin-2-one
3082- (4- (2- (1-isopropyl-3- (methoxymethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) acetamide
3092- (1-isopropyl-3- (methoxymethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
3102- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9-methoxy-5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine
3119-fluoro-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
3125- (9, 10-difluoro-5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine
3139-bromo-2- (3-cyclopropyl-1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
3149- (1-ethylpiperidin-4-yl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
315 (5- (5, 6-dihydrobenzo [ f ]]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-yl) methanol
3163- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) propanamide
3179-chloro-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine
3181- (5- (5, 6-dihydrobenzo [ f ]]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-yl) -N, N-dimethylmethylamine
319 rac-cis-2- (3-hydroxy-4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -N, N-dimethylacetamide
320 rac-trans-2- (3-hydroxy-4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s ][1,4]Oxazazepine-9-yl) piperidin-1-yl) -N, N-dimethylacetamide
3212- ((1R,3R,5S) -3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -8-azabicyclo [3.2.1]Octanyl-8-yl) acetamide
3222- ((1R,3S,5S) -3- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -8-azabicyclo [3.2.1]Octanyl-8-yl) acetamide
3232- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (4-methylpiperazin-1-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,2-f][1,4]Oxazazepine
3244- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,2-f][1,4]Oxazazepine-9-yl) piperazin-2-one
3254- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) piperazin-2-one
3274- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-yl) pyridin-2 (1H) -one
328 (3R,4S) -4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-3-ol
3292- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -N, N-dimethylacetamide
3302- (3-hydroxy-4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -N, 2-dimethylpropionamide
3312- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) piperazin-1-yl) -N, N-dimethylacetamide
3322- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) piperazin-1-yl) acetamide
3332- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,2-f][1,4]Oxazazepine-9(8H) -one
3342- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,2-f][1,4]Oxazazepine-9-yl) piperazin-1-yl) -N-methylacetamide
3352- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,2-f][1,4]Oxazazepine-9-yl) piperazin-1-yl) -N, N-dimethylacetamide
3362- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) acetic acid
3371- ((2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) methyl) urea
338 (2S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
3391- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) piperidine-4-carboxamide
3401- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) piperidin-4-ol
3412- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9-morpholino-5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine
342N-isopropyl-2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) piperazin-1-yl) acetamide
3431- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,2-f][1,4]Oxazazepine-9-yl) azetidine-3-carboxamides
344 (2S) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) propanamide
345 (2R) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine -9-yl) propanamide
3462- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carboxamides
347 (2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) methylamine
3482- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (oxetan-3-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
3512- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) acetamide
352N-hydroxy-2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) acetamide
3541- ((2- (1- (2, 4-difluorophenyl) -3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) methyl) urea
355 (2- (1- (2, 4-difluorophenyl) -3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) methylamine
3569- (1- (2- (dimethylamino) -2-oxoethyl) piperidin-4-yl) -N- (2-hydroxyethyl) -N-isopropyl-5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-carboxamides
3572- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1-isopropylpiperidin-4-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine
3582- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropan-1-ol
3592- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -2-methylpropan-1-ol
3604- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) pyrazolidine-3, 5-dione
3612- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
3622- (3-hydroxy-4- (2- (1-isopropyl-1H-1, 2, 4-tri)Azol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidin-1-yl) -N, N-dimethylacetamide
3631- ((2- (1- (2, 4-difluorophenyl) -3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) methylamino) -2-methylpropan-2-ol
3642- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine
365 (2R) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d ]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
3662- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (pyrrolidin-1-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine
3672- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N-methyl-5, 6-dihydroimidazo [1,2-d]Pyrido [3,2-f][1,4]Oxazazepine-9-amine
368 (2S,4R) -4-hydroxy-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
369 (2S) -1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
3701- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) azetidin-3-ol
371 (3R) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d ]]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidin-3-ol
372 (1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) piperidin-4-yl) methanol
373 (2S,4S) -4-fluoro-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d) ]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
374 (2S,4R) -4-hydroxy-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
375 (2S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzeneAnd [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
376 (2R) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
377 (2S) -1- (2- (1-isopropyl-1H-imidazol-2-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
378 (2S) -1- (2- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
379 (2R) -2- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) pyrrolidine-1-carboxamide
380 (2S) -2- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) pyrrolidine-1-carboxamide
381 (2S) -4, 4-difluoro-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d ]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
382 (2S,4S) -4-fluoro-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
383 (2S) -4, 4-difluoro-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
384 (2S,4S) -4-hydroxy-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
385 (2S,4S) -4-hydroxy-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
3862- (1-isopropyl-1H-imidazol-2-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine
387 (5- (9-chloro-5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-2-yl) -1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-yl) methanol
388 (2R) -1- (2- (1-isopropyl-1H-1, 2, 4-trisAzol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) -2, 5-dihydro-1H-pyrrole-2-carboxamide
389 (2S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) -2, 5-dihydro-1H-pyrrole-2-carboxamide
390 (5- (9- (pyrrolidin-1-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-2-yl) -1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-yl) methanol
391 (2S) -1- (2- (1- (3, 5-difluorophenyl) -3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
392 (2S) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-ylamino) propanamide
393 (2S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) -3, 3-dimethylpyrrolidine-2-carboxamide
394 (5- (9- (dimethylamino) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-2-yl) -1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-yl) methanol
395 (2S,3S) -3-hydroxy-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
396 (2S,3R) -3-hydroxy-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d ]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
397 (2S,3R) -3-hydroxy-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
398 (2S,3S) -3-hydroxy-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
399 (2S) -1- (2- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
400 (2S,4R) -4-fluoro-1- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
401 (2S,4R) -4-fluoro-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
402 (2S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) -2-methylpyrrolidine-2-carboxamide
4031-isopropyl-4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidine-3-carboxamide
4042- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-ylamino) acetamide
405 (2S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d ]]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) -N-methylpyrrolidine-2-carboxamide
406 (2S,3S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) -3-methylpyrrolidine-2-carboxamide
407 (2S,4R)-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) -4-methoxypyrrolidine-2-carboxamide
408 (2S,3S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) -3-methoxypyrrolidine-2-carboxamide
409 (2S) -1- (2- (1-cyclohexyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
410 (2S) -1- (2- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
4119-bromo-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
4122- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropionic acid ethyl ester
413 (5- (9- (dimethylamino) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-yl) methanol
4144- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1-methyl-1, 2,5, 6-tetrahydropyridine-3-carboxamide
4154- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1-methyl-1, 2,3, 6-tetrahydropyridine-3-carboxamide
4162- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -N-methyl-5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
417 (5- (9- (3, 3-difluoroazetidin-1-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-yl) methanol
4189-chloro-2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f ][1,4]Oxazazepine
4192- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -9- (2- (1-methylpiperidin-2-yl) pyrrolidin-1-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine
4202- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -9- (2- (2-methylbenzyl) pyrrolidin-1-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine
4212- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -9- (2- (piperidin-1-ylmethyl) pyrrolidin-1-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine
4222- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -N, N-dimethyl-5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
4232- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (1-methyl-1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
4242- (3-amino-1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-carbonitrile
4252- (3-amino-1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carbonitrile
426 (2S) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d ]Pyrido [3,4-f][1,4]Oxazazepine-9-yloxy) propanamide
4272- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yloxy) acetamide
4282- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) acetamide
4292- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yloxy) -2-methylpropanamide
4315- (9-cyclopropyl-5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine
4325- (10-fluoro-5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-amine
433 (2S) -1- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
434 (2S) -1- (2- (1-isopropyl-1H-pyrazol-5-yl) -5, 6-dihydroimidazo[1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
4353- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -2-methylpropionamide
436 (2S) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propanamide
438N- ((1H-pyrazol-5-yl) methyl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
4392- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-ylamino) propan-1-ol
4402- (1-isopropyl-3- (methoxymethyl) -1H-1,2, 4-triazol-5-yl) -9-methyl-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
441N- (3, 4-Dimethoxybenzyl) -2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
4425- (10-cyclopropyl-5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-amine
4432- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-carbonitrile
4442- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-ylamino) acetamide
4452- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) ethanesulfonamide
446 (R) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-yloxy) propanamide
4479- (difluoromethyl) -2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
4484- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1-methyl-1, 2,3, 6-tetrahydropyridine-3-carboxamide
4494- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1-methyl-1, 2,3, 6-tetrahydropyridine-3-carboxamide
4502- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-ylamino) -1- (1-methyl-1H-imidazol-2-yl) ethanol
4512- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
4522- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yloxy) -3-methylbutanamide
4532- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d ]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
4542- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -10- (1-methyl-1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
4552- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-10-carbonitrile
4562- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -N- (2- (methylsulfonyl) benzyl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
4571- (2- (2- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-ylamino) ethyl) pyrrolidin-2-one
4582- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-ylamino) acetamide
4591- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidine-2-carboxamide
4602- ((2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) (methyl) amino) acetamide
461N- (3- (1H-imidazol-1-yl) propyl) -2- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d ]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
462N- ((1H-imidazol-2-yl) methyl) -2- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
4632- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
4641- (2,2, 2-trifluoroethyl) -5- (10- (trifluoromethyl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1H-1,2, 4-triazol-3-amine
4652- (2- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-ylamino) -1- (1-methyl-1H-imidazol-2-yl) ethanol
4668- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1, 2-d)]Pyrido [3,4-f][1,4]Oxazazepine-9-yl) -3, 8-diazabicyclo [3.2.1]Octan-2-ones
4673-methyl-2- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) butanamide
4682- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo[f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-alcohols
469 (2S) -1- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
470 (2S) -1- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidine-2-carboxamide
471 (3S) -4- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) morpholine-3-carboxamide
4722-methyl-2- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propanamide
473 (2R) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-ylamino) propanamide
4742- (2- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-ylamino) acetamide
4752- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (2- (methylsulfonyl) phenyl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
4762- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) benzamides
4779- (2-ethylphenyl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine
478 (2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) phenyl) methanol
4792- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-amine
4802- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-amine
4812- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -10-methyl-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
4822- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9-methyl-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
48310- (difluoromethyl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [4,3-f][1,4]Oxazazepine
4841-isopropyl-5- (10- (trifluoromethyl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1H-1,2, 4-triazol-3-amine
485 (2R) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propanamide
486 (2S) -2- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine -9-yloxy) propanamide
487 (2R) -2- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propanamide
488N- (3, 4-dimethoxybenzyl) -2- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
4892- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-amine
4902- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-alcohols
4912- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d ]]Pyrido [3,4-f][1,4]Oxazazepine-9-ylamino) acetic acid
4929- (Difluoromethoxy) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
4932- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-amine
494 (2S) -2- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) butanamide
495 (2R) -2- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) butanamide
4962- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d]Pyrido [3,4-f][1,4]Oxazazepine-9-ylamino) acetamide
4973- ((2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) methyl) oxetan-3-amine
4981- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidine-2-carboxamide
4999-Ethyl-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5001- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperidine-2-carboxamide
501 (2S) -3-methyl-2- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) butanamide
502 (2R) -3-methyl-2- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) butanamide
5033- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f) ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropionic acid ethyl ester
5043- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropanoic acid methyl ester
5052- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (1H-pyrazol-4-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5063- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropionic acid
5079-isopropoxy-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5082- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropanoic acid methyl ester
5092- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (oxetan-3-yloxy) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5109-ETHOXY-2- (1-ISOPROPYL-1H-1, 2, 4-TRIAZOL-5-YL) -5, 6-DIHYDROBENZO [ F]Imidazo [1,2-d ] s][1,4]Oxazazepine
5112- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9- (2,2, 2-trifluoroethoxy) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine
512 (2S) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propionic acid
513 (2S) -3-hydroxy-2- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propanamide
514 (2S) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) butanamide
5152- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9-methoxy-5, 6-bisHydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine
5162- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -9-methoxy-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5179-ethoxy-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5189-Isopropoxy-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5192- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (2,2, 2-trifluoroethoxy) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5202- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -9- (oxetan-3-yloxy) -5, 6-dihydrobenzo [ f [ -f [ ] ]Imidazo [1,2-d ] s][1,4]Oxazazepine
5219 Cyclopropoxy-2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5229 Cyclobutoxy-2- (1-isopropyl-1H-1, 2, 4-triazole-5)-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5239 Cyclobutoxy-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
524N- ((3-Aminooxetan-3-yl) methyl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-amine
525 (3-amino-1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) azetidin-3-yl) methanol
5262- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-ylamino) acetamide
5271- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) cyclopropanecarboxamides
5282- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) cyclopropanecarboxamides
529 (2S) -2- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-ylamino) propanamide
531 (2S) -3-hydroxy-2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propanamide
5322- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) pentanamide
5332- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) -4-methylpentanamide
5349 Cyclopropoxy-2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5352- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) -3-methylbutanamide
538 (2S) -1- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) azetidine-2-carboxamides
539 (2S) -2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-ylamino) propanamide
540 (2S) -2- (2- (1-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propanamide
541 (2S) -4-hydroxy-2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) butanamide
542 (2S) -3-methoxy-2- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-ylamino) propanamide
543 (2S) -1- (2- (1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) piperazine-2-carboxamide
544 (2S) -2- (2- (1-ethyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propanamide
545 (2S) -2- (2- (1-tert-butyl-1H-1, 2, 4-triazole-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propanamide
546 (2S) -2- (2- (1- (2, 4-difluorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propanamide
547 carbamic acid (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) methyl ester
548 (2S) -1- (2- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) pyrrolidine-2-carboxamide
5492-cyclopropyl-2- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f [ -I]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) acetamide
550 (2S) -2- ((2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) (methyl) amino) propionamide
551 (2S) -1- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) azetidine-2-carboxamides
5521- ((2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) methyl) -1-methylurea
553 (2S) -1- (2- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) azetidine-2-carboxamides
554 (2S) -2- (2- (1-cyclopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yloxy) propanamide
5552- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -10-phenyl-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5561-isopropyl-5- (10-phenyl-5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine -2-yl) -1H-1,2, 4-triazol-3-amine
5572- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -10- (pyrimidin-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5581-isopropyl-5- (10- (pyrimidin-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1H-1,2, 4-triazol-3-amine
5591- (2-chlorophenyl) -5- (10- (pyrimidin-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1H-1,2, 4-triazol-3-amine
56010- (4-chlorophenyl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5615- (10- (4-chlorophenyl) -5, 6-dihydrobenzo [ f ]]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine
56210- (4-chlorophenyl) -2- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5632- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -10-phenyl-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5641- (2-chlorophenyl) -5- (10-phenyl-5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1H-1,2, 4-triazol-3-amine
5652- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -10- (pyrimidin-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s ][1,4]Oxazazepine
5661- (2-chlorophenyl) -5- (10- (4-chlorophenyl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1H-1,2, 4-triazol-3-amine
5679- (4-chlorophenyl) -2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5689- (4-chlorophenyl) -2- (1- (2-chlorophenyl) -1H-1,2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
5695- (9- (4-chlorophenyl) -5, 6-dihydrobenzo [ f ]]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1-isopropyl-1H-1, 2, 4-triazol-3-amine
5701- (2-chlorophenyl) -5- (9- (4-chlorophenyl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-2-yl) -1H-1,2, 4-triazol-3-amine.
8. A compound which is 1- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol.
9. Compound (I)Which is 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) ethanol.
10. A compound which is 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-pyrazol-1-yl) -2-methylpropanamide.
11. A compound which is 2- (4- (2- (1-isopropyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine-9-yl) -1H-imidazol-1-yl) ethanol.
12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient, optionally further comprising an additional therapeutic agent selected from: chemotherapeutic agents, anti-inflammatory agents, immunomodulators, neurotrophic factors, agents for treating cardiovascular disease, agents for treating liver disease, antiviral agents, agents for treating blood disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders.
13. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the prophylactic or therapeutic treatment of cancer.
14. A compound according to any one of claims 1 to 11 for use in the prophylactic or therapeutic treatment of cancer.
15. A kit for treating a condition mediated by PI3K, comprising: a first pharmaceutical composition comprising a compound of any one of claims 1 to 11; and b instructions for use.
HK13101739.9A 2009-09-28 2010-09-27 Benzoxazepin pi3k inhibitor compounds and methods of use HK1174629B (en)

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