TW202348602A - Pyrrolidine derivative, and pharmaceutical composition thereof and application thereof in medicine - Google Patents

Pyrrolidine derivative, and pharmaceutical composition thereof and application thereof in medicine Download PDF

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TW202348602A
TW202348602A TW112121743A TW112121743A TW202348602A TW 202348602 A TW202348602 A TW 202348602A TW 112121743 A TW112121743 A TW 112121743A TW 112121743 A TW112121743 A TW 112121743A TW 202348602 A TW202348602 A TW 202348602A
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cycloalkyl
alkyl
compound
trifluoromethyl
azabicyclo
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TW112121743A
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Chinese (zh)
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袁永海
魏用剛
賈志龍
楚洪柱
葉飛
蘇桂轉
孫毅
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大陸商成都百裕製藥股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

A pyrrolidine derivative and an application thereof in medicine, specifically relating to the pyrrolidine derivative represented by general formula (I-0) or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, a pharmaceutical composition containing same, and a use of the compound or composition in the preparation of a drug for autoimmune diseases.

Description

吡咯烷衍生物、藥物組合物及其在醫藥上的應用Pyrrolidine derivatives, pharmaceutical compositions and their applications in medicine

本發明涉及一種吡咯烷衍生物、藥物組合物及其在醫藥上的應用。The present invention relates to a pyrrolidine derivative, a pharmaceutical composition and its application in medicine.

類鐸受體(Toll-like Recepto RS，TL R)是一類分子模式識別受體，廣泛分佈於不同的組織中，監視識別不同的病原體相關分子模式(PAMP)和損傷相關分子模式(DAMP)，在先天免疫和後天免疫中均扮演著重要的角色。 Toll-like Recepto RS (TL R ) is a type of molecular pattern recognition receptor that is widely distributed in different tissues and monitors and recognizes different pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). , plays an important role in both innate immunity and acquired immunity.

TL R屬於I型跨膜蛋白，到目前為止已發現13個TLR家族成員，其中10個存在於人類中，TL R1、TL R2、TL R4、TL R5、TL R6、TL R10和TL R11位於細胞膜上，可以識別微生物的脂類、脂蛋白等物質；而TL R3、TL R7、TL R8和TL R9位於胞內囊泡結構(如溶酶體、包涵體和內質網等)，識別微生物的核酸。 TL R is a type I transmembrane protein. So far, 13 TLR family members have been discovered, 10 of which exist in humans, TL R 1, TL R 2, TL R 4, TL R 5, TL R 6, TL R 10 and TL R 11 are located on the cell membrane and can recognize microbial lipids, lipoproteins and other substances; while TL R 3, TL R 7, TL R 8 and TL R 9 are located in intracellular vesicle structures (such as lysosomes, inclusion body and endoplasmic reticulum, etc.) and recognize the nucleic acids of microorganisms.

TL R7和TL R8在序列和功能上最相似，大量研究表明，TL R7/8的活化可以引發I型干擾素反應及多種發炎反應，在自體免疫性障礙如系統性紅斑狼瘡(SLE)的情況下，TL R7/8的異常持續活化導致疾病狀態的惡化。因此，開發具有選擇性和強效抑制活性化合物，通過拮抗TL R7/8抑制過度活化的免疫反應有望成為治療自體免疫性疾病的新方法。 TL R 7 and TL R 8 are the most similar in sequence and function. A large number of studies have shown that activation of TL R 7/8 can trigger type I interferon responses and various inflammatory reactions, which can be seen in autoimmune disorders such as systemic lupus erythematosus ( In the case of SLE), abnormal sustained activation of TL R 7/8 leads to the worsening of the disease state. Therefore, the development of compounds with selective and potent inhibitory activity to inhibit over-activated immune responses by antagonizing TL R 7/8 is expected to become a new method for the treatment of autoimmune diseases.

本發明的目的是提供新的吡咯烷衍生物或者立體異構物、其藥物組合物以及其在製備自體免疫疾病藥物中的應用。The object of the present invention is to provide new pyrrolidine derivatives or stereoisomers, their pharmaceutical compositions and their applications in the preparation of drugs for autoimmune diseases.

本發明的一個或多個實施方式提供通式(I-0)所示的化合物，其所有的立體異構物、藥學上可接受的鹽或者氘代物： (I-0) 其中： R 1為 ； A為C 6-12芳基或5至12元雜芳基，5至12元雜芳基包含1、2、3或4個獨立地選自O、N和S的雜原子； B為C 3-10環烷基或3至10元雜環烷基，3至10元雜環烷基包含1、2、3或4個獨立地選自O、N和S的雜原子； R 4選自H、D、鹵素、C 1-6烷基或C 3-6環烷基，所述C 1-6烷基或C 3-6環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 5選自H、D、鹵素、C 1-6烷基或C 3-6環烷基，所述C 1-6烷基或C 3-6環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 2選自C 1-6烷基，所述烷基任選地進一步被1至多個鹵素取代； R 3選自 、 、 、 、 、 、 、 、 、 ； m為0、1、2或者3； n為0、1、2、3或者4。 One or more embodiments of the present invention provide a compound represented by general formula (I-0), all stereoisomers, pharmaceutically acceptable salts or deuterated products thereof: (I-0) where: R 1 is ; A is C 6-12 aryl or 5 to 12 membered heteroaryl, and the 5 to 12 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; B is C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl, 3 to 10 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; R 4 is selected from H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, the C 1-6 alkyl or C 3-6 cycloalkyl is further substituted by 1 to more substituents selected from the following: H , D, halogen or C 3-6 cycloalkyl; R 5 is selected from H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, the C 1-6 alkyl or C 3- 6 cycloalkyl is further substituted by 1 to more substituents selected from: H, D, halogen or C 3-6 cycloalkyl; R 2 is selected from C 1-6 alkyl, the alkyl is optionally further substituted by 1 to multiple halogen substitutions; R 3 is selected from , , , , , , , , , ; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4.

進一步地，本發明的一個或多個實施方式中，R 4選自H或D。 Further, in one or more embodiments of the present invention, R 4 is selected from H or D.

進一步地，本發明的一個或多個實施方式中，R 3進一步可以被H、D、鹵素、C 1-6烷基或C 3-6環烷基中的一個或多個取代，所述C 1-6烷基或C 3-6環烷基可以進一步被1至多個選自以下的取代基取代：H、D、鹵素或C 3-6環烷基。 Further, in one or more embodiments of the present invention, R 3 may be further substituted by one or more of H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, and the C 1-6 alkyl or C 3-6 cycloalkyl may be further substituted by 1 to more substituents selected from: H, D, halogen or C 3-6 cycloalkyl.

進一步地，本發明的一個或多個實施方式中，A為5至12元雜芳基，5至12元雜芳基包含1-3個獨立地選自O、N和S的雜原子； B為3至10元雜環烷基，3至10元雜環烷基包含1或2個獨立地選自O、N和S的雜原子。 Further, in one or more embodiments of the present invention, A is a 5- to 12-membered heteroaryl group, and the 5- to 12-membered heteroaryl group contains 1-3 heteroatoms independently selected from O, N and S; B is a 3- to 10-membered heterocycloalkyl group, and the 3- to 10-membered heterocycloalkyl group contains 1 or 2 heteroatoms independently selected from O, N, and S.

本發明的一個或多個實施方式提供通式(I)所示的化合物、其所有的立體異構物、藥學上可接受的鹽或氘代物： (I) 其中： R 1選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 ； R 2選自CF 3； R 3選自 、 、 、 、 、 、 、 、 、 。 One or more embodiments of the present invention provide compounds represented by general formula (I), all stereoisomers, pharmaceutically acceptable salts or deuterated products thereof: (I) where: R 1 is selected from , , , , , , , , , , , , , , , , , , , , or ; R 2 is selected from CF 3 ; R 3 is selected from , , , , , , , , , .

本發明的一個或多個實施方式提供通式(I)所示的化合物、其所有的立體異構物、藥學上可接受的鹽或氘代物，所述化合物為以下結構之一： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 One or more embodiments of the present invention provide a compound represented by general formula (I), all stereoisomers, pharmaceutically acceptable salts or deuterated products thereof, and the compound is one of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

本發明還提供一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，所述的中間體選自通式(I-A)所示的化合物： (I-A) R 1為H、Boc、或者 ； B為C 3-10環烷基或3至10元雜環烷基，3至10元雜環烷基包含1、2、3或4個獨立地選自O、N和S的雜原子； R 5選自Boc、H、D、鹵素、C 1-6烷基或C 3-10環烷基，所述C 1-6烷基或C 3-10環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 2選自C 1-6烷基，所述烷基任選地進一步被1至多個鹵素取代； R 3選自H、 、 、 、 、 、 、 、 、 、 或者胺基保護基，優選地所述胺基保護基為： 、Bn、Cbz、Boc、Fmoc、Tos、Alloc、 Tfa、Dmb或PMB； n為0、1、2、3或者4。 The present invention also provides an intermediate for preparing the compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterated product, pharmaceutically acceptable salt or co-crystal , the intermediate is selected from the compounds represented by the general formula (IA): (IA) R 1 is H, Boc, or ; B is C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl, and the 3 to 10 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; R 5 is selected from Boc, H, D, halogen, C 1-6 alkyl or C 3-10 cycloalkyl, and the C 1-6 alkyl or C 3-10 cycloalkyl is further selected from 1 to more The following substituents are substituted: H, D, halogen or C 3-6 cycloalkyl; R 2 is selected from C 1-6 alkyl, the alkyl is optionally further substituted by 1 to more halogens; R 3 is selected from H , , , , , , , , , , Or an amino protecting group, preferably the amino protecting group is: , Bn, Cbz, Boc, Fmoc, Tos, Alloc, Tfa, Dmb or PMB; n is 0, 1, 2, 3 or 4.

本發明還提供一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中該中間體選自以下結構之一： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 The present invention also provides an intermediate for preparing the compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterated product, pharmaceutically acceptable salt or co-crystal , where the intermediate is selected from one of the following structures: , , , , , , , , , , , , , , or .

本發明還提供一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，所述的中間體選自通式(I-B)所示的化合物： (I-B) R 1為 ； B為C 3-10環烷基或3至10元雜環烷基，3至10元雜環烷基包含1、2、3或4個獨立地選自O、N和S的雜原子； R 5選自H、D、鹵素、C 1-6烷基或C 3-6環烷基，所述C 1-6烷基或C 3-6環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 2選自C 1-6烷基，所述烷基任選地進一步被1至多個鹵素取代； R 3選自H、 、 、 、 、 、 、 、 、 、 或胺基保護基，優選地所述胺基保護基為： 、Cbz、Boc、Fmoc、Tos、Alloc、Tfa、Dmb 或PMB； n為0、1、2、3或者4。 The present invention also provides an intermediate for preparing the compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterated product, pharmaceutically acceptable salt or co-crystal , the intermediate is selected from the compounds represented by the general formula (IB): (IB) R 1 is ; B is C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl, and the 3 to 10 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; R 5 is selected from H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, the C 1-6 alkyl or C 3-6 cycloalkyl is further substituted by 1 to more selected from the following Base substitution: H, D, halogen or C 3-6 cycloalkyl; R 2 is selected from C 1-6 alkyl, the alkyl is optionally further substituted by 1 to more halogens; R 3 is selected from H, , , , , , , , , , Or an amino protecting group, preferably the amino protecting group is: , Cbz, Boc, Fmoc, Tos, Alloc, Tfa, Dmb or PMB; n is 0, 1, 2, 3 or 4.

本發明還提供一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中該中間體選自以下結構之一： 。 The present invention also provides an intermediate for preparing the compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterated product, pharmaceutically acceptable salt or co-crystal , where the intermediate is selected from one of the following structures: .

本發明還提供一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，所述的中間體選自通式(I-C)所示的化合物： (I-C) R 1為 ； A為C 6-12芳基或5至12元雜芳基，5至12元雜芳基包含1、2、3或4個獨立地選自O、N和S的雜原子； B為3至10元雜環烷基，所述3至10元雜環烷基包含1、2、3或4個獨立地選自O、N和S的雜原子； R 4選自H或D； R 5選自H、D、鹵素、C 1-6烷基或C 3-6環烷基，所述C 1-6烷基或C 3-6環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 6為胺基保護基，優選地所述胺基保護基為：Cbz、Boc、Fmoc、Tos、Alloc、Tfa、Dmb或PMB； R 2選自C 1-6烷基，所述烷基任選地進一步被1至多個鹵素取代； R 3選自H、 、 、 、 、 、 、 、 、 、 、胺基保護基，優選地所述胺基保護基為： 、Cbz、Boc、Fmoc、Tos、Alloc、Tfa、Dmb 或PMB； m為0、1、2或者3； n為0、1、2、3或者4。 The present invention also provides an intermediate for preparing the compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterated product, pharmaceutically acceptable salt or co-crystal , the intermediate is selected from the compounds represented by the general formula (IC): (IC) R 1 is ; A is C 6-12 aryl or 5 to 12 membered heteroaryl, and the 5 to 12 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; B is 3 To a 10-membered heterocycloalkyl group, the 3 to 10-membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; R 4 is selected from H or D; R 5 Selected from H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, the C 1-6 alkyl or C 3-6 cycloalkyl is further substituted by 1 to more substituents selected from the following : H, D, halogen or C 3-6 cycloalkyl; R 6 is an amino protecting group, preferably the amino protecting group is: Cbz, Boc, Fmoc, Tos, Alloc, Tfa, Dmb or PMB; R 2 is selected from C 1-6 alkyl, which is optionally further substituted by 1 to more halogens; R 3 is selected from H, , , , , , , , , , , amino protecting group, preferably the amino protecting group is: , Cbz, Boc, Fmoc, Tos, Alloc, Tfa, Dmb or PMB; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4.

本發明還提供一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中該中間體選自以下結構之一： 、 或 。 The present invention also provides an intermediate for preparing the compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterated product, pharmaceutically acceptable salt or co-crystal , where the intermediate is selected from one of the following structures: , or .

本發明還提供一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，所述的中間體選自通式(I-D)所示的化合物： (I-D) 其中： R 1為 ； A為C 6-12芳基或5至12元雜芳基，5至12元雜芳基包含1、2、3或4個獨立地選自O、N和S的雜原子； B為C 3-10環烷基或3至10元雜環烷基，3至10元雜環烷基包含1、2、3或4個獨立地選自O、N和S的雜原子； R 4選自H或D； R 5選自H、D、鹵素、C 1-6烷基或C 3-6環烷基，所述C 1-6烷基或C 3-6環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 2選自C 1-6烷基，所述烷基任選地進一步被1至多個鹵素取代； R 3選自H或胺基保護基，優選地所述胺基保護基為： 、Cbz、Boc、Fmoc、Tos、Alloc、Tfa、Dmb或PMB； m為0、1、2或者3； n為0、1、2、3或者4。 The present invention also provides an intermediate for preparing the compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterated product, pharmaceutically acceptable salt or co-crystal , the intermediate is selected from the compounds represented by the general formula (ID): (ID) where: R 1 is ; A is C 6-12 aryl or 5 to 12 membered heteroaryl, and the 5 to 12 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; B is C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl, 3 to 10 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; R 4 is selected from H or D; R 5 is selected from H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, the C 1-6 alkyl or C 3-6 cycloalkyl is further replaced by 1 to more Selected from the following substituents: H, D, halogen or C 3-6 cycloalkyl; R 2 is selected from C 1-6 alkyl, the alkyl is optionally further substituted by 1 to more halogens; R 3 is selected From H or amino protecting group, preferably the amino protecting group is: , Cbz, Boc, Fmoc, Tos, Alloc, Tfa, Dmb or PMB; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4.

本發明還提供一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中該中間體選自以下結構之一： 、 、 、 、 或者 。 The present invention also provides an intermediate for preparing the compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterated product, pharmaceutically acceptable salt or co-crystal , where the intermediate is selected from one of the following structures: , , , , or .

本發明的一個或多個實施方式提供藥物組合物，所述藥物組合物包括： 通式(I-0)所示的化合物、其所有的立體異構物、藥學上可接受的鹽或氘代物； 任選的一種或者多種其他活性成分；以及 藥學上可接受的載體和/或賦形劑。 One or more embodiments of the invention provide a pharmaceutical composition comprising: Compounds represented by general formula (I-0), all stereoisomers, pharmaceutically acceptable salts or deuterated products thereof; optionally one or more other active ingredients; and Pharmaceutically acceptable carriers and/or excipients.

本發明的一個或多個實施方式提供上述藥物組合物、通式(I-0)化合物、其所有的立體異構物、藥學上可接受的鹽或氘代物在製備自體免疫疾病藥物中的用途。One or more embodiments of the present invention provide the use of the above-mentioned pharmaceutical composition, the compound of general formula (I-0), all stereoisomers, pharmaceutically acceptable salts or deuterated products thereof in the preparation of drugs for autoimmune diseases. use.

除非有相反的陳述，在說明書和請求項中使用的術語具有下述含義。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

本發明所述基團和化合物中所涉及的碳、氫、氧、硫、氮或F、Cl、Br、I均包括它們的同位素情況，及本發明所述基團和化合物中所涉及的碳、氫、氧、硫或氮任選進一步被一個或多個它們對應的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氫的同位素包括氕(H)、氘(D，又叫重氫)、氚(T，又叫超重氫)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, (also called heavy hydrogen), tritium (T, also called superheavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.

「烷基」是指1至20個碳原子的直鏈或支鏈飽和脂肪族烴基，優選為1至8個(例如1、2、3、4、5、6、7、8個)碳原子的烷基，更優選為1至6個碳原子的烷基，進一步優選為1至4個碳原子的烷基。非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、異戊基、新戊基、正己基及其各種支鏈異構物；當烷基被取代基時，可以任選進一步被1個或者多個取代基所取代。「烷氧基」是指烷基中至少1個碳原子被氧原子取代所形成的基團。非限制性實施例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、環丙氧基和環丁氧基。所述的烷基定義與上文所述的「烷基」定義相同。"Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (such as 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms. The alkyl group is more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched chain isomers; when the alkyl group is substituted, it can be optionally further substituted by one or more substituents. "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy. The definition of alkyl is the same as the definition of "alkyl" mentioned above.

「烯基」是指含有1至10個(例如1、2、3、4、5、6、7、8、9、10個)碳-碳雙鍵，由2至20個碳原子組成的直鏈或者支鏈不飽和脂肪族烴基，優選2至12個(例如2、3、4、5、6、7、8、9、10、11、12個)碳原子的烯基，更優選2至8個碳原子的烯基，進一步優選2至6個碳原子的烯基。非限制性實施例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任選進一步被1個或者多個取代基所取代。"Alkenyl" refers to a straight group containing 1 to 10 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds and composed of 2 to 20 carbon atoms. Chain or branched unsaturated aliphatic hydrocarbon group, preferably an alkenyl group with 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 carbon atoms. An alkenyl group of 8 carbon atoms is further preferred, and an alkenyl group of 2 to 6 carbon atoms is further preferred. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, Hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decene-4-yl, and undecayl En-3-yl. The alkenyl group may be optionally further substituted by one or more substituents.

「炔基」是指含有1至10個(例如1、2、3、4、5、6、7、8、9、或10個)碳-碳三鍵，由2至20個碳原子組成的直鏈或者支鏈不飽和脂肪族烴基，優選2至12個(例如2、3、4、5、6、7、8、9、10、11或12個)碳原子的炔基，更優選2至8個碳原子的炔基，進一步優選2至6個碳原子的炔基。非限制性實施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任選進一步被一至多個取代基所取代。"Alkynyl" refers to a group containing 1 to 10 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds and composed of 2 to 20 carbon atoms. Straight chain or branched unsaturated aliphatic hydrocarbon group, preferably an alkynyl group with 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably 2 an alkynyl group having to 8 carbon atoms, more preferably an alkynyl group having 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl Base, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl. The alkynyl group may be optionally further substituted by one or more substituents.

「芳基」是指是指取代的或未取代的芳香環，其可以是5至8元(例如5、6、7、8元)的單環、5至12元(例如5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系，其可以是橋環或者螺環，非限制性實施例包括苯基、萘基。所述的芳基可以任選進一步被1個或者多個取代基所取代。"Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a monocyclic ring with 5 to 8 members (such as 5, 6, 7, 8 members), a monocyclic ring with 5 to 12 members (such as 5, 6, 7 , 8, 9, 10, 11, 12-membered) bicyclic ring or 10 to 15-membered (such as 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which can be a bridged ring or spiro ring, non-limiting implementation Examples include phenyl and naphthyl. The aryl group may be optionally further substituted by one or more substituents.

「雜芳基」是指取代的或未取代的芳香環，其可以是3至8元(例如3、4、5、6、7、8元)的單環、5至12元(例如5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系，且包含1至6個(例如1、2、3、4、5、6個)選自N、O或S的雜原子，優選5至8元雜芳基，雜芳基的環中選擇性取代的1至4個(例如1、2、3、4個)N、S可被氧化成各種氧化態。雜芳基可以連接在雜原子或者碳原子上，雜芳基可以是橋環或者螺環，非限制性實施例包括環吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡𠯤基、嗒𠯤基、咪唑基、哌啶基苯並咪唑基、苯並吡啶基、吡咯並吡啶基。雜芳基任選進一步被1個或多個取代基所取代。"Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring or 10 to 15-membered (such as 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 6 (such as 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5 to 8-membered heteroaryl, 1 to 4 optionally substituted in the ring of the heteroaryl (for example, 1, 2 , 3, 4) N, S can be oxidized into various oxidation states. The heteroaryl group can be connected to a heteroatom or a carbon atom, and the heteroaryl group can be a bridged ring or a spiro ring. Non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, Pyridyl, pyrrolidyl, imidazolyl, piperidylbenzimidazolyl, benzopyridinyl, pyrrolopyridinyl. Heteroaryl groups are optionally further substituted with one or more substituents.

「碳環基」或「碳環」是指飽和或者不飽和的芳香環或者非芳香環。當為芳香環時，其定義與上文「芳基」的定義相同；當為非芳香環時，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系，可以是橋環或者螺環，非限制性實施例包括環丙基、環丁基、環戊基、1-環戊基-1-烯基、1-環戊基-2-烯基、1-環戊基-3-烯基、環己基、1-環己基-2-烯基、1-環己基-3-烯基、環己烯基、環己二烯基、環庚基、環辛基、環 壬基、環癸基、環十一烷基、環十二烷基、 、 、 、 。 所述的「碳環基」或「碳環」任選進一步被1個或者多個取代基所取代。 "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl"above; when it is a non-aromatic ring, it can be 3 to 10 members (such as 3, 4, 5, 6, 7, 8, 9, 10 single ring of 4 to 12 members (such as 4, 5, 6, 7, 8, 9, 10, 11, 12 members) or double ring of 10 to 15 members (such as 10, 11, 12, 13, 14, 15 (1-membered) tricyclic system, which can be a bridged ring or a spiro ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2 -Alkenyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cyclohexyl Heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, , , , . The "carbocyclic group" or "carbocyclic ring" is optionally further substituted by one or more substituents.

「雜環基」或「雜環」是指飽和或不飽和的芳香性雜環或者非芳香性雜環，當為芳香性雜環時，其定義與上文「雜芳基」定義相同；當為非芳香性雜環時，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系，且包含1至4個(例如1、2、3、4個)選自N、O或S的雜原子，優選3至8元雜環基。「雜環基」或「雜環」的環中選擇性取代的1至4個(例如1、2、3、4個)N、S可被氧化成各種氧化態；「雜環基」或「雜環」可以連接在雜原子或者碳原子上；「雜環基」或「雜環」可以為橋環或者螺環。「雜環基」或「雜環」的非限制性實施例包括環氧乙基、環氧丙基、氮雜環丙基、氧雜環丁基、氮雜環丁基、硫雜環丁基、1,3-二氧戊環基、1,4-二氧戊環基、1,3-二氧六環基、氮雜環庚基、氧雜環庚基、硫雜環庚基、氧氮雜卓基、二氮雜卓基、硫氮雜卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡𠯤基、嗒𠯤基、哌𠯤基、高哌𠯤基、咪唑基、哌啶基、嗎啉基、硫代嗎啉基、噻噁烷基、1,3-二噻烷基、二氫呋喃基、二噻戊環基、四氫呋喃基、四氫噻吩基、四氫吡喃基、四氫噻喃基、四氫吡咯基、四氫咪唑基、四氫噻唑基、四氫吡喃基、苯並咪唑基、苯並吡啶基、吡咯並吡啶基、苯並二氫呋喃基、2-吡咯啉基、3-吡咯啉基、二氫吲哚基、2H-吡喃基、4H-吡喃基、二氧雜環己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氫噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氫異喹啉基、3-氮雜雙環[3.1.0]己基、3-氮雜雙環[4.1.0]庚基、氮雜雙環[2.2.2]己基、3H-吲哚基喹𠯤基、N-吡啶基尿素、1,1-二氧硫代嗎啉基、氮雜二環[3.2.1]辛烷基、氮雜二環[5.2.0]壬烷基、氧雜三環[5.3.1.1]十二烷基、氮雜金剛烷基和氧雜螺[3.3]庚烷基。所述的「雜環基」或「雜環」可以任選進一步被1個或者多個取代基所取代。"Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above; when When it is a non-aromatic heterocyclic ring, it can be a 3- to 10-membered (for example, 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4 to 12-membered (for example, 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring system or 10 to 15-membered (such as 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 4 (such as 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably 3 to 8-membered heterocyclic groups. The optionally substituted 1 to 4 (such as 1, 2, 3, 4) N and S in the ring of "heterocyclyl" or "heterocycle" can be oxidized into various oxidation states; "heterocyclyl" or "heterocyclyl" or "heterocyclyl" "Heterocycle" can be connected to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spiro ring. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxiethyl, glycidyl, aziridyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolanyl, 1,4-dioxanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen Azazoyl, diazazoyl, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyridyl 𠯤yl, pyridyl, piperidyl, homopiperyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuran base, dithiopentyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzene Imidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolyl, 2H-pyranyl, 4H-pyranyl , dioxanyl, 1,3-dioxopentyl, pyrazolinyl, dithialkyl, dithiazolinyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinoyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl Alkyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted by one or more substituents.

「環烷基」是指飽和的環烴基，其環可以為3至10元(例如3、4、5、6、7、8、9、10元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至20元(例如10、11、12、13、14、15、16、17、18、19、20元)多環體系，環碳原子優選3至10個碳原子，進一步優選3至8個碳原子。“環烷基”非限制性實施例包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環丙烯基、環丁烯基、環戊烯基、環己烯基、環庚烯基、1,5-環辛二烯基、1,4-環己二烯基和環庚三烯基等。當環烷基被取代時，可以任選進一步被1個或者多個取代基所取代。"Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which can be a monocyclic ring with 3 to 10 members (such as 3, 4, 5, 6, 7, 8, 9, 10 members), or a 4 to 12 member (such as 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or more than 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) In the ring system, the ring carbon atoms are preferably 3 to 10 carbon atoms, and further preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptadienyl, etc. When the cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.

「雜環烷基」是指取代的或未取代的飽和非芳香環基，其可以是3至8元(例如3、4、5、6、7、8元)的單環、4至12元(例如4、5、6、7、8、9、10、11、12元)雙環或者10至15元(例如10、11、12、13、14、15元)三環體系，且包含1、2或3個選自N、O或S的雜原子，優選3至8元雜環基。「雜環烷基」的環中選擇性取代的1、2或3個N、S可被氧化成各種氧化態；「雜環烷基」可以連接在雜原子或者碳原子上；「雜環烷基」可以為橋環或者螺環。「雜環烷基」非限制性實施例包括環氧乙基、氮雜環丙基、氧雜環丁基、氮雜環丁基、1,3-二氧戊環基、1,4-二氧戊環基、1,3-二氧六環基、氮雜環庚基、哌啶基、哌叮基、嗎啉基、硫代嗎啉基、1,3-二噻烷基、四氫呋喃基、四氫吡咯基、四氫咪唑基、四氫噻唑基、四氫吡喃基、氮雜二環[3.2.1]辛烷基、氮雜二環[5.2.0]壬烷基、氧雜三環[5.3.1.1]十二烷基、氮雜金剛烷基和氧雜螺[3.3]庚烷基。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be a 3- to 8-membered (such as 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 4- to 12-membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring system or 10 to 15-membered (e.g. 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1, 2 or 3 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclic groups. The optionally substituted 1, 2 or 3 N and S atoms in the ring of "heterocycloalkyl" can be oxidized into various oxidation states; "heterocycloalkyl" can be connected to heteroatoms or carbon atoms; "heterocycloalkyl" "Base" can be a bridged ring or a spiro ring. Non-limiting examples of "heterocycloalkyl" include oxetyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-di Oxopentyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxa Tricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.

當上文所述的「烷基」、「烷氧基」、「烯基」、「炔基」、「芳基」、「雜芳基」、「碳環基」、「碳環」、「雜環基」、「雜環」、「環烷基」、「雜環烷基」或者「雜環基」被取代時，可以選進一步被0、1、2、3、4、5、6、7、8、9或者10個選自F、Cl、Br、I、羥基、巰基、硝基、氰基、胺基、C 1-6烷基胺基、=O、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-NR q4R q5、=NR q6、-C(=O)OC 1-6烷基、-OC(=O)C 1-6烷基、-C(=O)NR q4R q5、C 3-8環烷基、C 3-8雜環烷基、C 6-10芳基、C 5-10雜芳基、-C(=O)OC 6-10芳基、-OC(=O)C 6-10芳基、-OC(=O)C 5-10雜芳基、-C(=O)OC 5-10雜芳基、-OC(=O)C 3-8雜環烷基、-C(=O)OC 3-8雜環烷基、-OC(=O)C 3-8環烷基、-C(=O)OC 3-8環烷基、-NHC(=O)C 3-8雜環烷基、-NHC(=O)C 6-10芳基、-NHC(=O)C 5-10雜芳基、-NHC(=O)C 3-8環烷基、-NHC(=O)C 3-8雜環烷基、-NHC(=O)C 2-6烯基或者-NHC(=O)C 2-6炔基的取代基所取代，且其中所述的取代基C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8環烷基、C 3-8雜環烷基、C 6-10芳基、C 5-10雜芳基、-NHC(=O)C 6-10芳基、-NHC(=O)C 5-10雜芳基、-NHC(=O)C 3-8雜環烷基或者-NHC(=O)C 3-8環烷基任選進一步被1至3個選自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、-NR q4R q5或者=O的取代基所取代；R q1選自C 1-6烷基、C 1-6烷氧基或者C 6-10芳基；R q2、R q3選自H或者C 1-6烷基；其中，R q4、R q5選自H、C 1-6烷基、-NH(C=NR q1)NR q2R q3、-S(=O) 2NR q2R q3、-C(=O)R q1或者-C(=O)NR q2R q3，其中所述的C 1-6烷基任選進一步被1個或者多個選自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 5-10雜芳基、C 3-8環烷基或者C 3-8雜環烷基的取代基所取代；或者R q4與R q5及N原子形成一個3至8元雜環，所述雜環可以含有1個或者多個選自N、O或者S的雜原子。 When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocyclic", " When "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" is substituted, it can be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 are selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkylamino, =O, C 1-6 alkyl, C 1-6 alkoxy group, C 2-6 alkenyl group, C 2-6 alkynyl group, -NR q4 R q5 , =NR q6 , -C(=O)OC 1-6 alkyl group, -OC(=O )C 1-6 alkyl, -C(=O)NR q4 R q5 , C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl , -C(=O)OC 6-10 aryl, -OC(=O)C 6-10 aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5- 10 Heteroaryl, -OC(=O)C 3-8 heterocycloalkyl, -C(=O)OC 3-8 heterocycloalkyl, -OC(=O)C 3-8 cycloalkyl, - C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5- 10 Heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 2-6 alkenyl or -NHC( =O) C 2-6 alkynyl substituent substituted, and wherein the substituent C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl , C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 aryl, -NHC(= O)C 5-10 heteroaryl, -NHC(=O)C 3-8 heterocycloalkyl or -NHC(=O)C 3-8 cycloalkyl are optionally further selected from 1 to 3 OH, Substituted by F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, -NR q4 R q5 or =O substituent; R q1 is selected from C 1-6 alkyl, C 1 -6 alkoxy or C 6-10 aryl; R q2 and R q3 are selected from H or C 1-6 alkyl; among them, R q4 and R q5 are selected from H, C 1-6 alkyl, -NH ( C=NR q1 )NR q2 R q3 , -S(=O) 2 NR q2 R q3 , -C(=O)R q1 or -C(=O)NR q2 R q3 , wherein C 1-6 The alkyl group is optionally further substituted by 1 or more members selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 5-10 hetero Substituted with aryl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl substituents; or R q4 , R q5 and N atoms form a 3 to 8-membered heterocyclic ring, which may contain 1 One or more heteroatoms selected from N, O or S.

「藥學上可接受的鹽」或者「其藥學上可接受的鹽」是指本發明化合物保持游離酸或者游離鹼的生物有效性和特性，且所述的游離酸通過與無毒的無機鹼或者有機鹼，所述的游離鹼通過與無毒的無機酸或者有機酸反應獲得的鹽。"Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts thereof" means that the compounds of the present invention retain the biological effectiveness and properties of free acids or free bases, and the free acids are combined with non-toxic inorganic bases or organic Base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.

「藥物組合物」是指一種或多種本發明所述化合物、其藥學上可接受的鹽或前藥和其它化學組分形成的混合物，其中，「其它化學組分」是指藥學上可接受的載體、賦形劑和/或一種或多種其它治療劑。"Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, where "other chemical components" refers to pharmaceutically acceptable carrier, excipient, and/or one or more other therapeutic agents.

「載體」是指不會對生物體產生明顯刺激且不會消除所給予化合物的生物活性和特性的材料。"Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to be administered.

「賦形劑」是指加入到藥物組合物中以促進化合物給藥的惰性物質。非限制性實施例包括碳酸鈣、磷酸鈣、糖、澱粉、纖維素衍生物(包括微晶纖維素)、明膠、植物油、聚乙二醇類、稀釋劑、成粒劑、潤滑劑、粘合劑和崩解劑。"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.

「前藥」是指可經體內代謝轉化為具有生物活性的本發明化合物。本發明的前藥通過修飾本發明化合物中的胺基或者羧基來製備，該修飾可以通過常規的操作或者在體內被除去，而得到母體化合物。當本發明的前藥被施予哺乳動物個體時，前藥被割裂形成游離的胺基或者羧基。"Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body. The prodrugs of the present invention are prepared by modifying the amine group or carboxyl group in the compound of the present invention. The modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amine or carboxyl group.

「共晶」是指活性藥物成分(API)和共晶形成物(CCF)在氫鍵或其他非共價鍵的作用下結合而成的晶體，其中API和CCF的純態在室溫下均為固體，並且各組分間存在固定的化學計量比。共晶是一種多組分晶體，既包含兩種中性固體之間形成的二元共晶，也包含中性固體與鹽或溶劑化物形成的多元共晶。"Co-crystal" refers to a crystal in which an active pharmaceutical ingredient (API) and a co-crystal form (CCF) are combined under the action of hydrogen bonds or other non-covalent bonds. The pure states of API and CCF are homogeneous at room temperature. It is a solid and has a fixed stoichiometric ratio between its components. A eutectic is a multicomponent crystal that includes both a binary eutectic formed between two neutral solids and a multicomponent eutectic formed between a neutral solid and a salt or solvate.

「立體異構物」是指由分子中原子在空間上排列方式不同所產生的異構物，包括順反異構物、對映異構物和構型異構物。"Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in molecules, including cis-trans isomers, enantiomers and configurational isomers.

「任選」或「任選地」或「選擇性的」或「選擇性地」是指隨後所述的事件或狀況可以但未必發生，該描述包括其中發生該事件或狀況的情況及其中未發生的情況。例如，「任選地被烷基取代的雜環基」是指該烷基可以但未必存在，該描述包括其中雜環基被烷基取代的情況，及其中雜環基未被烷基取代的情況。"Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or condition may but may not occur, and the description includes the circumstances in which the event or condition occurs and the circumstances in which it does not occur. What happened. For example, "heterocyclyl optionally substituted by alkyl" means that the alkyl group may but need not be present, and this description includes the case where the heterocyclyl is substituted by an alkyl group, and the case where the heterocyclyl is not substituted by an alkyl group. condition.

以下實施例詳細說明本發明的技術方案，但本發明的保護範圍包括但不限於此。 DMSO：二甲基亞碸； HATU：2-(7-偶氮苯並三氮唑)- N,N,N',N'-四甲基脲六氟磷酸酯； DIPEA： N,N-二異丙基乙胺。 The following examples illustrate the technical solution of the present invention in detail, but the protection scope of the present invention includes but is not limited to these. DMSO: dimethylsulfoxide; HATU: 2-(7-azobenzotriazole)-N ,N,N',N' -tetramethylurea hexafluorophosphate; DIPEA: N,N -di Isopropylethylamine.

中間體A (3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 ethyl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate Intermediate A (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester ethyl-3 -(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

第一步： 1-苄基-4-(三氟甲基)-2,5-二氫-1 H-吡咯-3-羧酸乙酯 A-1.3 ethyl-1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1 H-pyrrole-3-carboxylate Step 1: 1-Benzyl-4-(trifluoromethyl)-2,5-dihydro- 1H -pyrrole-3-carboxylic acid ethyl ester A-1.3 ethyl-1-benzyl-4-(trifluoromethyl) -2,5-dihydro-1 H -pyrrole-3-carboxylate

N 2氛圍下，將A-1.1 (10 g，60 mmol) 溶於30 mL二氯甲烷(DCM)中，冰浴下滴加A-1.2 (14.4 g，60 mmol) 的二氯甲烷溶液 (10 mL)，隨後緩慢滴加三氟乙酸 (684 mg，6 mmol) 的二氯甲烷溶液 (10 mL)，室溫攪拌2 h。將反應液加入30 mL水中，DCM萃取三次，有機相用飽和食鹽水30 mL洗，無水硫酸鈉乾燥，旋乾，矽膠管柱層析純化 (乙酸乙酯:石油醚 = 1:10)，得到目標產物1-苄基-4-(三氟甲基)-2,5-二氫-1 H-吡咯-3-羧酸乙酯 A-1.3 (黃色油狀液體，15.5 g，產率86%)，直接用於下一步反應。 1H NMR (400 MHz, DMSO- d 6) δ 7.34-7.24 (m, 5H), 4.19 (q, 2H), 3.79-3.78 (m, 4H), 1.20 (t, 3H). LC-MS m/z (ESI)= 300.1 [M+1]。 Under N2 atmosphere, A-1.1 (10 g, 60 mmol) was dissolved in 30 mL dichloromethane (DCM), and A-1.2 (14.4 g, 60 mmol) dichloromethane solution (10 mL), then a dichloromethane solution (10 mL) of trifluoroacetic acid (684 mg, 6 mmol) was slowly added dropwise, and stirred at room temperature for 2 h. The reaction solution was added to 30 mL of water, and extracted three times with DCM. The organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain Target product 1-benzyl-4-(trifluoromethyl)-2,5-dihydro- 1H -pyrrole-3-carboxylic acid ethyl ester A-1.3 (yellow oily liquid, 15.5 g, yield 86% ), used directly for the next reaction. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.34-7.24 (m, 5H), 4.19 (q, 2H), 3.79-3.78 (m, 4H), 1.20 (t, 3H). LC-MS m/ z(ESI)= 300.1 [M+1].

第二步： 3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 A-1.4 ethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate Step two: 3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester A-1.4 ethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

N 2氛圍下，將三甲基碘化亞碸 (3.5 g，15.8 mmol) 溶於10 mL二甲亞碸中，冰浴下分批次加入氫化鈉 (633.6 mg，15.8 mmol) 的二甲亞碸溶液 (5 mL)，室溫攪拌30分鐘。隨後滴加A-1.3 (4.3 g，14.4 mmol)的二甲亞碸溶液 (5 mL)，60 ℃反應5 h。飽和氯化銨淬滅反應，DCM 30 mL萃取，飽和食鹽水30 mL洗，有機相用無水硫酸鈉乾燥，旋乾，矽膠管柱層析純化 (乙酸乙酯:石油醚 = 1:10)，得到目標產物3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯A-1.4 (無色油狀液體，3.5 g，產率78%)，直接用於下一步反應。 1H NMR (400 MHz, DMSO- d 6) δ 7.34-7.24 (m, 5 H), 4.11 (q, 2H), 3.66 (s, 2H), 3.08-3.01(m, 2H), 2.86-2.82 (m, 1H), 2.65-2.62 (m, 1H), 1.82-1.79 (m, 2H), 1.15 (t, 3H). LC-MS m/z (ESI)= 314.1 [M+1]。 Dissolve trimethylstyrene iodide (3.5 g, 15.8 mmol) in 10 mL dimethylstyrene under N2 atmosphere, and add sodium hydride (633.6 mg, 15.8 mmol) in dimethylstyrene in batches under ice bath. The solution (5 mL) was stirred at room temperature for 30 minutes. Then, a solution of A-1.3 (4.3 g, 14.4 mmol) in dimethylsulfoxide (5 mL) was added dropwise, and the reaction was carried out at 60 °C for 5 h. Quench the reaction with saturated ammonium chloride, extract with 30 mL of DCM, wash with 30 mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, spin dry, and purify by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10). Obtain the target product 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester A-1.4 (colorless oily liquid, 3.5 g, yield 78%), directly used in the next reaction. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.34-7.24 (m, 5 H), 4.11 (q, 2H), 3.66 (s, 2H), 3.08-3.01(m, 2H), 2.86-2.82 ( m, 1H), 2.65-2.62 (m, 1H), 1.82-1.79 (m, 2H), 1.15 (t, 3H). LC-MS m/z (ESI)= 314.1 [M+1].

第三步： 5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 A-1.5 ethyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate third step: 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester A-1.5 ethyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

將A-1.4 (1 g，3.2 mmol) 溶於乙醇50 mL中，隨後加入Pd/C (681 mg，0.64 mmol)，反應體系用1atm H 2置換兩次，升溫至60 ℃反應3 h。矽藻土過濾，旋乾溶劑，得到目標產物5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 A-1.5 (無色油狀液體，1 g，產率88%)，直接用於下一步。 1H NMR (400 MHz, DMSO- d 6) δ 4.11 (q, 2H), 3.20-2.75(m, 5H), 1.75 (d, 1H), 1.48-1.47 (m, 1H), 1.16 (t, 3H). LC-MS m/z (ESI)= 224.1 [M+1]。 A-1.4 (1 g, 3.2 mmol) was dissolved in 50 mL of ethanol, and then Pd/C (681 mg, 0.64 mmol) was added. The reaction system was replaced twice with 1 atm H 2 and the temperature was raised to 60 °C for 3 h. Filter through diatomaceous earth and spin the solvent dry to obtain the target product 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester A-1.5 (colorless oily liquid, 1 g, yield 88%), was used directly in the next step. 1 H NMR (400 MHz, DMSO- d 6 ) δ 4.11 (q, 2H), 3.20-2.75(m, 5H), 1.75 (d, 1H), 1.48-1.47 (m, 1H), 1.16 (t, 3H ). LC-MS m/z (ESI)= 224.1 [M+1].

第四步： (3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸乙酯 A ethyl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate the fourth step: (3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester A ethyl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

N 2氛圍下，將5-溴喹啉-8-甲腈A-1.6 (654 mg，2.9 mmol) 溶於1,4-二氧六環30 mL中，隨後加入A-1.5 (804 mg，3.5 mmol)，N 2置換氣三次，依序加入碳酸銫 (4.3 g，13.05 mmol) 和RuPhosPdG3 (486 mg，0.58 mmol)，N 2置換氣三次，升溫至90 ℃反應2 h。旋乾溶劑，乙酸乙酯萃取，飽和食鹽水洗，無水硫酸鈉乾燥，過濾，旋乾溶劑，粗產物A直接投下一步。 LC-MS m/z (ESI)= 376.1 [M+1], 398.1 [M+23]. Under N2 atmosphere, 5-bromoquinoline-8-carbonitrile A-1.6 (654 mg, 2.9 mmol) was dissolved in 30 mL of 1,4-dioxane, and then A-1.5 (804 mg, 3.5 mmol), N 2 was substituted three times, cesium carbonate (4.3 g, 13.05 mmol) and RuPhosPdG3 (486 mg, 0.58 mmol) were added in sequence, N 2 was substituted three times, and the temperature was raised to 90 ℃ for 2 h. The solvent was spun dry, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spun dry. The crude product A was directly added to the next step. LC-MS m/z (ESI)= 376.1 [M+1], 398.1 [M+23].

中間體A-1.6 5-溴喹啉-8-甲腈 5-bromoquinoline-8-carbonitrile Intermediate A-1.6 5-bromoquinoline-8-carbonitrile5-bromoquinoline-8-carbonitrile

將原料A-1.6a (1.0 g, 0.005 mol)、A-1.6b (1.6g, 0.012 mol)依序加入到反應瓶中，然後加入30 mL的1M稀鹽酸，升溫至110度回流，攪拌2小時，通過LCMS監測反應完全，加二氯甲烷20毫升萃取3次，飽和鹽水洗一次，無水硫酸鈉乾燥，濃縮，過矽膠管柱(石油醚：乙酸乙酯=20:1)得到目標化合物(白色固體，350 mg，產率：30%)。 1H NMR (400 MHz, DMSO- d 6) δ 9.18 (dd, 1H), 8.66 (dt, 1H), 8.33 (d, 1H), 8.18 (d, 1H), 7.90 (dd, 1H). LC-MS m/z (ESI)= 233.0 [M+1] Add raw materials A-1.6a (1.0 g, 0.005 mol) and A-1.6b (1.6g, 0.012 mol) into the reaction bottle in sequence, then add 30 mL of 1M dilute hydrochloric acid, raise the temperature to 110 degrees and reflux, stir for 2 hours, monitor the reaction is complete by LCMS, add 20 ml of dichloromethane for extraction three times, wash with saturated brine once, dry with anhydrous sodium sulfate, concentrate, and pass through a silica gel column (petroleum ether: ethyl acetate = 20:1) to obtain the target compound ( White solid, 350 mg, yield: 30%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.18 (dd, 1H), 8.66 (dt, 1H), 8.33 (d, 1H), 8.18 (d, 1H), 7.90 (dd, 1H). LC- MS m/z (ESI)= 233.0 [M+1]

中間體B-1：(1S,5R)--3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 中間體B-2：(1R,5S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 (1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Intermediate B-1: (1S,5R)--3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxylic acid (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Intermediate B-2: (1R ,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (1R,5S) -3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

第一步： 3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 B 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid first step: 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid B 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

將A的粗產品 (2.02 g，5.39 mmol) 溶於四氫呋喃溶液10 mL中，將無水氫氧化鋰 (1.29 g，53.9 mmol)的水溶液10 mL滴入反應液中，室溫攪拌過夜。待反應結束，旋乾四氫呋喃，乙酸乙酯萃取，保留水相，用2M鹽酸水溶液將水相pH調至3-4，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，真空除去溶劑。MPLC分離 (乙腈:水= 47：53)，得到目標產物3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸化合物B (黃色固體，387 mg，21%)。 1H NMR (400 MHz, DMSO- d 6) δ 13.26 (s, 1H), 9.02-9.00 (m, 1H), 8.64-8.62 (m, 1H), 8.16 (d, J= 8.0 Hz, 1H), 7.61 (dd, 1H), 7.25 (d, 1H), 4.05-3.77 (m, 4H), 2.07-1.86 (m, 2H). LC-MS m/z (ESI)= 348.1 [M+1], 370.1 [M+23]. Dissolve the crude product A (2.02 g, 5.39 mmol) in 10 mL of tetrahydrofuran solution, add 10 mL of anhydrous lithium hydroxide (1.29 g, 53.9 mmol) aqueous solution dropwise into the reaction solution, and stir at room temperature overnight. After the reaction is completed, spin dry tetrahydrofuran, extract with ethyl acetate, retain the aqueous phase, adjust the pH of the aqueous phase to 3-4 with 2M hydrochloric acid aqueous solution, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and remove in vacuum Solvent. MPLC separation (acetonitrile: water = 47:53), the target product 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane was obtained Alkane-1-carboxylic acid compound B (yellow solid, 387 mg, 21%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.26 (s, 1H), 9.02-9.00 (m, 1H), 8.64-8.62 (m, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.61 (dd, 1H), 7.25 (d, 1H), 4.05-3.77 (m, 4H), 2.07-1.86 (m, 2H). LC-MS m/z (ESI)= 348.1 [M+1], 370.1 [M+23].

第六步： (1S,5R)--3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 中間體B-1 (1R,5S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸 (1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 中間體B-2 化合物B-1和化合物B-2通過chiral prep-HPLC拆分。分析方法：手性柱Ig-3，甲醇作為流動相，流速1 mL/min，中間體B-1保留時間為3.619 min，中間體B-2保留時間為4.741min。 Step 6: (1S,5R)--3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Intermediate B-1 (1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Intermediate B-2 Compound B-1 and Compound B-2 were resolved by chiral prep-HPLC. Analysis method: Chiral column Ig-3, methanol as mobile phase, flow rate 1 mL/min, retention time of intermediate B-1 is 3.619 min, and retention time of intermediate B-2 is 4.741 min.

中間體C 2-(1-甲基哌啶-4-基)-5-((1 S,5 R)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)-1,3,4-口咢二唑 中間體C 2-(1-methylpiperidin-4-yl)-5-((1 S,5 R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Intermediate C 2-(1-methylpiperidin-4-yl)-5-((1 S ,5 R )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-yl)-1,3,4-azabicyclo intermediate C 2-(1-methylpiperidin-4-yl)-5-((1 S ,5 R )-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexan-1-yl)-1,3,4-oxadiazole

第一步： (1 S,5 R)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼 C-1.1(1 S,5 R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide Step 1: (1 S ,5 R )-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide C-1.1 (1 S ,5 R )-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

將化合物A-1.4 (5.0 g，0.0167 mol) 溶於50 mL乙醇溶液，隨後加入水合肼 (8.36 g，0.167 mol)，70 ℃條件下反應4 h，旋乾溶劑，得到目標產物(1 S,5 R)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼化合物B-1.1直接用於下一步。 LC-MS m/z (ESI)= 300.3 [M+1]。 Compound A-1.4 (5.0 g, 0.0167 mol) was dissolved in 50 mL of ethanol solution, then hydrazine hydrate (8.36 g, 0.167 mol) was added, the reaction was carried out at 70 °C for 4 h, and the solvent was spin-dried to obtain the target product (1 S , 5 R )-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide compound B-1.1 was used directly in the next step. LC-MS m/z (ESI)= 300.3 [M+1].

第二步： (1 S,5 R)-3-苄基- N'-(1-甲基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼 化合物C-1.3 (1 S,5 R)-3-benzyl- N'-(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide Second step: (1 S ,5 R )-3-benzyl- N' -(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]Hexane-1-carbohydrazide compound C-1.3 (1 S ,5 R )-3-benzyl- N' -(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]hexane-1-carbohydrazide

將化合物1-甲基哌啶-4-羧酸C-1.2 (2.08 g, 0.0147 mol) 溶於20 mL二氯甲烷中，0 ℃條件下緩慢加入二氯亞碸 (4.96 mL, 0.067 mol)，隨後反應體系升溫至40 ℃，繼續反應2 h，後濃縮溶劑，再用10 mL二氯甲烷溶解，加入化合物(1 S,5 R)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼 化合物C-1.1 (4.00 g, 0.0134 mol)，室溫攪拌1 h。TLC監測反應完畢，加水淬滅，加入二氯甲烷萃取，合併有機相用飽和食鹽水洗滌，有機相用無水硫酸鈉乾燥，減壓濃縮，矽膠管柱層析純化，即可得到目標產物(1 S,5 R)-3-苄基- N'-(1-甲基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼C-1.3(黃色液體，5.1 g，產率: 90.0%)。 LC-MS m/z (ESI)= 425.2 [M+1]。 Dissolve compound 1-methylpiperidine-4-carboxylic acid C-1.2 (2.08 g, 0.0147 mol) in 20 mL of dichloromethane, and slowly add trisene dichloride (4.96 mL, 0.067 mol) at 0 °C. Then the temperature of the reaction system was raised to 40 °C, and the reaction was continued for 2 h. The solvent was then concentrated, dissolved in 10 mL of dichloromethane, and compound (1 S ,5 R )-3-benzyl-5-(trifluoromethyl)- was added. 3-Azabicyclo[3.1.0]hexane-1-carbohydrazide compound C-1.1 (4.00 g, 0.0134 mol), stirred at room temperature for 1 h. TLC monitors the completion of the reaction, adds water to quench, and adds methylene chloride for extraction. The combined organic phases are washed with saturated brine, the organic phases are dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the target product (1 S ,5 R )-3-benzyl- N' -(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 -Carbohydrazide C-1.3 (yellow liquid, 5.1 g, yield: 90.0%). LC-MS m/z (ESI)= 425.2 [M+1].

第三步： 2-((1 S,5 R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole 2-((1 S,5 R)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0] 己烷-1-基)-5-(1-甲基哌啶-4-基)-1,3,4-口咢二唑 化合物C-1.4 Step 3: 2-((1 S ,5 R )-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl )-1,3,4-oxadiazole 2-((1 S ,5 R )-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl )-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole compound C-1.4

將(1 S,5 R)-3-苄基- N'-(1-甲基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼化合物C-1.3 (5.1 g, 0.012 mol) 溶於20 mL二氯甲烷中，隨後加入三乙胺 (12.0 g, 0.12 mol)，對甲苯磺醯氯 (6.8 g, 0.036 mol)，室溫攪拌5小時，TLC監測反應完畢，濃縮反應液，矽膠管柱層析純化，即可得到目標產物2-((1 S,5 R)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0] 己烷-1-基)-5-(1-甲基哌啶-4-基)-1,3,4-口咢二唑 化合物C-1.4 (黃色液體，4.2 g，產率: 85%)。 LC-MS m/z (ESI)= 407.2 [M+1]. (1 S ,5 R )-3-benzyl- N' -(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carbohydrazide compound C-1.3 (5.1 g, 0.012 mol) was dissolved in 20 mL of methylene chloride, and then triethylamine (12.0 g, 0.12 mol) and p-toluenesulfonyl chloride (6.8 g, 0.036 were added mol), stir at room temperature for 5 hours, TLC monitors the reaction to completion, concentrate the reaction solution, and purify by silica gel column chromatography to obtain the target product 2-((1 S ,5 R )-3-benzyl-5-(tri Fluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole compound C -1.4 (yellow liquid, 4.2 g, yield: 85%). LC-MS m/z (ESI)= 407.2 [M+1].

第四步： 2-(1-甲基哌啶-4-基)-5-((1 S,5 R)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)-1,3,4-口咢二唑 中間體C 2-(1-methylpiperidin-4-yl)-5-((1 S,5 R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Step 4: 2-(1-methylpiperidin-4-yl)-5-((1 S ,5 R )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-yl)-1,3,4-piperidinazole intermediate C 2-(1-methylpiperidin-4-yl)-5-((1 S ,5 R )-5-(trifluoromethyl)-3- azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

將2-((1 S,5 R)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0] 己烷-1-基)-5-(1-甲基哌啶-4-基)-1,3,4-口咢二唑 化合物C-1.4 (1.0 g, 2.5 mmol) 溶於5 mL甲醇，依序加入氫氧化鈀 (35 mg, 0. 25 mmol)，甲酸銨(464 mg, 3.69 mol)，加熱回流6 h，TLC監測反應完畢，濃縮反應液，矽膠管柱層析純化，即可得到目標產物2-(1-甲基哌啶-4-基)-5-((1 S,5 R)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)-1,3,4-口咢二唑 中間體C (黃色液體，600 mg，產率: 76%) LC-MS m/z (ESI)= 317.2 [M+1]. 2-((1 S ,5 R )-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methyl Piperidin-4-yl)-1,3,4-oxadiazole compound C-1.4 (1.0 g, 2.5 mmol) was dissolved in 5 mL methanol, and palladium hydroxide (35 mg, 0. 25 mmol) was added sequentially. ), ammonium formate (464 mg, 3.69 mol), heated to reflux for 6 h, TLC monitored the reaction to completion, concentrated the reaction solution, and purified by silicone column chromatography to obtain the target product 2-(1-methylpiperidine-4- base)-5-((1 S ,5 R )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-1-yl)-1,3,4-oxadiazole Intermediate C (yellow liquid, 600 mg, yield: 76%) LC-MS m/z (ESI)= 317.2 [M+1].

實施例1 5-(1 S，5 R)-1-(5-(1-甲基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物1 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 1 5-(1 S , 5 R )-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 1 5-((1S,5R)-1-(5-(1-methylpiperidin) -4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

第一步： (1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼 化合物1-1 (1 S, 5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo-[3.1.0]hexane-1-carbohydrazide Step 1: (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 -Carbohydrazide compound 1-1 (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo-[3.1.0]hexane-1-carbohydrazide

將乙基(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸鹽 (1 S, 5 R)-A (1 g, 2.6 mmol)溶於5 ml 乙醇中，隨後加入水合肼5ml，升溫至85℃攪拌3小時，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化(鹼法)，得到(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼1-1 (淡黃色固體，800 mg，93%)。 LC-MS m/z (E SI)= 362.20 [M+1]. Ethyl (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Carboxylate (1 S , 5 R )-A (1 g, 2.6 mmol) was dissolved in 5 ml of ethanol, then 5 ml of hydrazine hydrate was added, the temperature was raised to 85°C and stirred for 3 hours. After the TLC reaction was completed, the reaction solution was directly concentrated and reversed. Phase C18 column chromatography purification (alkaline method) gave (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carbohydrazide 1-1 (light yellow solid, 800 mg, 93%). LC-MS m/z ( ESI )= 362.20 [M+1].

第二步： (1 S，5 R)-3-(8-氰基喹啉-5-基)- N'-(1-甲基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼 1-3 (1 S, 5 R)-3-(8-cyanoquinolin-5-yl)- N'-(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide Step 2: (1 S , 5 R )-3-(8-cyanoquinolin-5-yl) -N' -(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl )-3-Azabicyclo[3.1.0]hexane-1-carbohydrazide 1-3 (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)- N' -(1-methylpiperidine -4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

將1-甲基哌啶-4-羧酸 1-2 (119 mg, 83 mmol)溶於 N,N-二甲基甲醯胺10ml中，隨後冰浴加入HATU(378 mg, 0.99 mmol)，DIPEA(321 mg, 2.49 mmol)低溫攪拌5分鐘，然後加入(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼1-1 (300 mg, 0.83 mmol)攪拌半小時，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化(鹼法)，得到目標產物(1 S，5 R)-3-(8-氰基喹啉-5-基)- N'-(1-甲基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼1-3(淡黃色固體，380 mg，89%)。 LC-MS m/z (ESI)= 487.20 [M+1]. Dissolve 1-methylpiperidine-4-carboxylic acid 1-2 (119 mg, 83 mmol) in 10 ml of N,N -dimethylformamide, then add HATU (378 mg, 0.99 mmol) in an ice bath. DIPEA (321 mg, 2.49 mmol) was stirred at low temperature for 5 minutes, then (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-nitrogen was added Heterobicyclo[3.1.0]hexane-1-carbohydrazide 1-1 (300 mg, 0.83 mmol) was stirred for half an hour. The TLC reaction was completed. The reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkali method). Obtain the target product (1 S , 5 R )-3-(8-cyanoquinolin-5-yl) -N' -(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carbohydrazide 1-3 (light yellow solid, 380 mg, 89%). LC-MS m/z (ESI)= 487.20 [M+1].

第三步： 5-(1 S，5 R)-1-(5-(1-甲基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物1 5-((1 S, 5 R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Step 3: 5-(1 S , 5 R )-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 1 5-((1 S , 5 R )-1-(5-( 1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

將(1 S，5 R)-3-(8-氰基喹啉-5-基)- N'-(1-甲基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼1-3(115 mg，0.23 mmol)溶於6 ml 1,2-二氯乙烷中，隨後加入三乙胺(47 mg，0.46mmol)，對甲苯磺醯氯(66 mg，0.345mmol)，常溫攪拌15小時，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化(鹼法)，得到目標化合物(5-(1 S，5 R)-1-(5-(1-甲基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈化合物1 (淡黃色固體，70 mg，46%)。 1H NMR (400 MHz, DM SO- d 6) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.19 (d, 1H), 4.07 (dd, 2H), 3.92 (d, 1H), 2.97 (td, 1H), 2.77 (d, 2H), 2.24 (d, 2H), 2.21 ( S, 3H), 2.12 ( S, 2H), 2.03 – 1.93 (m, 2H), 1.81 – 1.65 (m, 2H). 19F NMR (376 MHz, DM SO- d 6) δ -64.08. LC-MS m/z (E S I)= 469.20 [M+1]. (1 S ,5 R )-3-(8-cyanoquinolin-5-yl) -N' -(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carbohydrazide 1-3 (115 mg, 0.23 mmol) was dissolved in 6 ml of 1,2-dichloroethane, followed by addition of triethylamine (47 mg, 0.46mmol), p-toluenesulfonyl chloride (66 mg, 0.345mmol), stir at room temperature for 15 hours, the TLC reaction is completed, the reaction solution is directly concentrated, and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target compound (5-( 1 S , 5 R )-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 1 (light yellow solid, 70 mg, 46%). 1 H NMR (400 MHz, DM S O- d 6 ) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.19 (d, 1H), 4.07 (dd, 2H), 3.92 (d, 1H), 2.97 (td, 1H), 2.77 (d, 2H), 2.24 (d, 2H), 2.21 ( S , 3H), 2.12 ( S , 2H), 2.03 – 1.93 (m, 2H), 1.81 – 1.65 (m, 2H). 19 F NMR (376 MHz, DM S O- d 6 ) δ -64.08. LC-MS m/z (E S I)= 469.20 [M+1].

實施例2 5-(1 S，5 R)-1-(5-( S)-4-甲基嗎啉-2-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物2 5-((1 S,5 R)-1-(5-(( S)-4-methylmorpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 2 5-(1 S , 5 R )-1-(5-( S )-4-methylmorpholin-2-yl)-1,3,4-oxadiazol-2-yl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 2 5-((1 S ,5 R )-1-(5 -(( S )-4-methylmorpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline- 8-carbonitrile

第一步： 叔丁基-( S)-5-(2-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼-1-羰基)嗎啉-4-羧酸鹽 2-2 tert-butyl-( S)-5-(2-((1 S,5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)morpholine-4-carboxylate Step 1: tert-Butyl-( S )-5-(2-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)morpholine-4-carboxylate 2-2 tert-butyl-( S )-5-(2-((1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)morpholine-4-carboxylate

將( S)-4-(叔丁氧羰基)嗎啉-2-羧酸 2-1 (32 mg，0.13 mmol)溶於 N,N-二甲基甲醯胺5 ml中，隨後冰浴加入HATU (59 mg, 0.15 mmol)，DIPEA(50 mg，0.39 mmol)低溫攪拌5分鐘，然後加入(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼1-1 (50 mg，0.13 mmol)攪拌半小時，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化(鹼法)，得到目標產物叔丁基-( S)-5-(2-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼-1-羰基)嗎啉-4-羧酸鹽2-2 (淡黃色固體，82 mg，95%)。 LC-MS m/z (ESI)= 575.20 [M+1]. Dissolve ( S )-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid 2-1 (32 mg, 0.13 mmol) in 5 ml of N,N -dimethylformamide, then add in ice bath HATU (59 mg, 0.15 mmol), DIPEA (50 mg, 0.39 mmol) were stirred at low temperature for 5 minutes, then (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 1-1 (50 mg, 0.13 mmol) was stirred for half an hour. After the TLC reaction was completed, the reaction solution was concentrated directly and reversed phase C18 Column chromatography purification (alkali method) gave the target product tert-butyl-( S )-5-(2-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)morpholine-4-carboxylate 2-2 (light yellow solid, 82 mg, 95 %). LC-MS m/z (ESI)= 575.20 [M+1].

第二步： 叔丁基-( S)-2-(5-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-1,3,4-口咢二唑-2-基)嗎啉-4-羧酸鹽 2-3 tert-butyl-( S)-2-(5-((1 S,5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)morpholine-4-carboxylate Step 2: tert-butyl-( S )-2-(5-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)morpholine-4-carboxylate 2-3 tert-butyl-( S ) -2-(5-((1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1, 3,4-oxadiazol-2-yl)morpholine-4-carboxylate

將叔丁基-( S)-5-(2-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼-1-羰基)嗎啉-4-羧酸鹽 2-2 (82 mg, 0.14 mmol)溶於65ml 1,2-二氯乙烷中，隨後加入三乙胺(28 mg，0.28mmol)，對甲苯磺醯氯(40 mg，0.21mmol)，常溫攪拌5小時，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化(鹼法)，得到目標化合物叔丁基-( S)-2-(5-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-1,3,4-口咢二唑-2-基)嗎啉-4-羧酸鹽 2-3 (淡黃色固體，40 mg，43%)。 LC-MS m/z (ESI)= 557.20 [M+1]. Tert-butyl-( S )-5-(2-(1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)morpholine-4-carboxylate 2-2 (82 mg, 0.14 mmol) was dissolved in 65 ml of 1,2-dichloroethane, Then, triethylamine (28 mg, 0.28mmol) and p-toluenesulfonyl chloride (40 mg, 0.21mmol) were added, and the mixture was stirred at room temperature for 5 hours. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkali method ), the target compound tert-butyl-( S )-2-(5-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)morpholine-4-carboxylate 2-3 (light yellow solid, 40 mg, 43%). LC-MS m/z (ESI)= 557.20 [M+1].

第三步： 5-(1 S，5 R)-1-(5-( S)-嗎啉-2-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 2-4 5-((1 S, 5 R)-1-(5-(( S)-morpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile The third step: 5-(1 S , 5 R )-1-(5-( S )-morpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 2-4 5-((1 S , 5 R )-1-(5-( ( S )-morpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

將叔丁基-( S)-2-(5-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-1,3,4-口咢二唑-2-基)嗎啉-4-羧酸鹽 2-3 粗品溶於1 mL二氧六環中，隨後冰浴加入鹽酸二氧六環溶液3mL，室溫攪拌2h。TLC反應完畢，反應液直接濃縮，得到目標產物5-(1 S，5 R)-1-(5-( S)-嗎啉-2-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈化合物2-4 (淡黃色固體)。 LC-M Sm/z (ESI)= 457.20 [M+1]. Tert-butyl-( S )-2-(5-(1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-aza The crude product of bicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)morpholine-4-carboxylate 2-3 was dissolved in 1 mL of dioxane , then add 3 mL of dioxane hydrochloride solution in an ice bath, and stir at room temperature for 2 h. After the TLC reaction is completed, the reaction solution is directly concentrated to obtain the target product 5-(1 S , 5 R )-1-(5-( S )-morpholin-2-yl)-1,3,4-oroxadiazole- 2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 2-4 (light yellow solid). LC-M S m/z (ESI)= 457.20 [M+1].

第四步： 5-(1 S，5 R)-1-(5-( S)-4-甲基嗎啉-2-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物2 5-((1 S,5 R)-1-(5-(( S)-4-methylmorpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluo Romethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Step 4: 5-(1 S , 5 R )-1-(5-( S )-4-methylmorpholin-2-yl)-1,3,4-oxadiazol-2-yl) -5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 2 5-((1 S ,5 R )-1-( 5-(( S )-4-methylmorpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-( trifluomethyl )-3-azabicyclo[3.1.0]hexan-3-yl )quinoline-8-carbonitrile

將5-(1 S，5 R)-1-(5-( S)-嗎啉-2-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 2-4 (63 mg，0.14 mmol)，溶於5 mL甲醇中，隨後加入三乙胺20 ul，多聚甲醛(50 mg，0.56 mmol)，氰基硼氫化鈉(42 mg，1.12 mmol)升溫至80度攪拌3小時，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化(鹼法)，得到目標產物5-(1 S，5 R)-1-(5-( S)-4-甲基嗎啉-2-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物2 (淡黃色固體，22 mg，71%)。 1H NMR (400 MHz, DMSO- d 6) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 5.32 (t, 1H),4.91 (s, 1H), 4.20 (d, 1H), 4.08 (dd, 2H), 3.94 (d, 2H), 3.73 (s, 1H), 2.67 (m, 1H), 2.33 (m, 1H), 2.25 (s, 3H), 1.99 (q, 1H), 1.41(d,1H) ,0.85 (t, 1H). LC-MS m/z (ESI)= 471.10[M+1]. 5-(1 S , 5 R )-1-(5-( S )-morpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl (63 mg, 0.14 mmol), dissolved in 5 mL of methanol, then added triethylamine 20 ul, paraformaldehyde (50 mg, 0.56 mmol), sodium cyanoborohydride (42 mg, 1.12 mmol) was heated to 80 degrees and stirred for 3 hours. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reversed-phase C18 column chromatography. (Alkali method), the target product 5-(1 S , 5 R )-1-(5-( S )-4-methylmorpholin-2-yl)-1,3,4-oroxadiazole- 2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 2 (light yellow solid, 22 mg, 71% ). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 5.32 ( t, 1H), 4.91 (s, 1H), 4.20 (d, 1H), 4.08 (dd, 2H), 3.94 (d, 2H), 3.73 (s, 1H), 2.67 (m, 1H), 2.33 (m , 1H), 2.25 (s, 3H), 1.99 (q, 1H), 1.41(d,1H) ,0.85 (t, 1H). LC-MS m/z (ESI)= 471.10[M+1].

實施例3 5-(1 S，5 R)-1-(3-(1-甲基哌啶-4-基)-1,2,4-口咢二唑-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物3 5-((1 S,5 R)-1-(3-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 3 5-(1 S , 5 R )-1-(3-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 3 5-((1 S ,5 R )-1-(3-(1 -methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

第一步： (Z)- N'-羥基-1-甲基哌啶-4-羧醯胺 3-2 (Z)- N'-hydroxy-1-methylpiperidine-4-carboximidamide Step 1: (Z)- N' -hydroxy-1-methylpiperidine-4-carboximidamide 3-2 (Z)- N' -hydroxy-1-methylpiperidine-4-carboximidamide

將1-甲基哌啶-4-甲腈 3-1 (500 mg，4 mmol)溶於10mL 乙醇中，隨後加入DIPEA(1.2 g，8 mmol)，鹽酸羥胺(420 mg，6 mmol)，升溫至80 ℃攪拌6小時，TLC反應完畢，反應液直接濃縮，甲醇打漿得到目標產物(Z)- N'-羥基-1-甲基哌啶-4-羧醯胺 3-2 (白色固體，470 mg，76%)。 LC-MS m/z (ESI)= 158.10 [M+1]. Dissolve 1-methylpiperidine-4-carbonitrile 3-1 (500 mg, 4 mmol) in 10 mL ethanol, then add DIPEA (1.2 g, 8 mmol), hydroxylamine hydrochloride (420 mg, 6 mmol), and raise the temperature Stir for 6 hours at 80°C. After the TLC reaction is completed, the reaction solution is directly concentrated and slurried with methanol to obtain the target product (Z) -N' -hydroxy-1-methylpiperidine-4-carboxamide 3-2 (white solid, 470 mg, 76%). LC-MS m/z (ESI)= 158.10 [M+1].

第二步： (1 S，5 R)-3-(8-氰基喹啉-5-基)- N-(Z)-(羥基亞胺基)(1-甲基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 3-3 (1 S, 5 R)-3-(8-cyanoquinolin-5-yl)- N-((Z)-(hydroxyimino)(1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Second step: (1 S , 5 R )-3-(8-cyanoquinolin-5-yl) -N- (Z)-(hydroxyimino)(1-methylpiperidin-4-yl) )methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-methamide 3-3 (1 S , 5 R )-3-(8-cyanoquinolin- 5-yl)- N -((Z)-(hydroxyimino)(1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

將(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羧酸  B-1(100 mg, 0.28 mmol)溶於5 ML N,N-二甲基甲醯胺中，隨後冰浴加入HATU (127 mg, 0.33 mmol)，DIPEA(108 mg, 0.84 mmol)低溫攪拌1分鐘，然後加入(Z)- N'-羥基-1-甲基哌啶-4-羧醯胺 (49.7 mg，0.31 mmol)，攪拌半小時，TLC反應完畢，反應液直接濃縮，反相C18柱層析純化(鹼法)，得到目標產物((1 S，5 R)-3-(8-氰基喹啉-5-基)- N-(Z)-(羥基亞胺基)(1-甲基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 3-3 (淡黃色固體，106 mg，83%)。 LC-MS m/z (ESI)= 487.20 [M+1]. (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid B-1 (100 mg, 0.28 mmol) was dissolved in 5 ML N,N -dimethylformamide, then HATU (127 mg, 0.33 mmol) and DIPEA (108 mg, 0.84 mmol) were added in ice bath and stirred at low temperature 1 minutes, then add (Z) -N' -hydroxy-1-methylpiperidine-4-carboxamide (49.7 mg, 0.31 mmol) and stir for half an hour. After the TLC reaction is completed, the reaction solution is directly concentrated and placed on a reversed-phase C18 column. Chromatography purification (alkali method) gave the target product ((1 S , 5 R )-3-(8-cyanoquinolin-5-yl) -N- (Z)-(hydroxyimino)(1- Methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-methamide 3-3 (light yellow solid, 106 mg , 83%). LC-MS m/z (ESI)= 487.20 [M+1].

第三步： 5-(1 S，5 R)-1-(3-(1-甲基哌啶-4-基)-1,2,4-口咢二唑-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物3 5-((1 S,5 R)-1-(3-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Step 3: 5-(1 S , 5 R )-1-(3-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 3 5-((1 S ,5 R )-1-(3-( 1-methylpiperidin-4-yl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

將((1 S，5 R)-3-(8-氰基喹啉-5-基)- N-(Z)-(羥基亞胺基)(1-甲基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲醯胺 3-3(106 mg, 0.21 mmol)溶於5 mL N,N-二甲基甲醯胺中，升溫至130 ℃ 攪拌4小時。TLC反應完畢，反應液直接濃縮，反相C18柱層析純化(鹼法)，得到目標產物5-(1 S，5 R)-1-(3-(1-甲基哌啶-4-基)-1,2,4-口咢二唑-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物3(淡黃色固體，76 mg，78%)。 1H NMR (400 MHz, DMSO- d 6) δ 9.02 (dd, 1H), 8.68 – 8.66 (m, 1H), 8.20 (d, 1H), 7.62 (dd, 1H), 7.34 (d, 1H), 4.23 (d, 1H), 4.12 – 4.07 (m, 2H), 3.93 (d, 1H), 2.80-2.73 (m, 3H), 2.32 (d, 1H), 2.26-2.22 (m, 1H), 2.80(s, 3H), 2.01 – 2.00 (m, 2H), 1.89 – 1.88 (m, 2H), 1.73 – 1.63 (m, 2H). 19F NMR (376 MHz, DMSO- d 6) δ -63.77. LC-MS m/z (ESI)= 469.20 [M+1]. ((1 S ,5 R )-3-(8-cyanoquinolin-5-yl) -N- (Z)-(hydroxyimino)(1-methylpiperidin-4-yl)methyl ( 106 mg, 0.21 mmol) was dissolved in 5 mL N,N -dimethyl in methylformamide, raise the temperature to 130°C and stir for 4 hours. After the TLC reaction is completed, the reaction solution is directly concentrated and purified by reverse-phase C18 column chromatography (alkali method) to obtain the target product 5-(1 S , 5 R )-1-(3-(1-methylpiperidin-4-yl) )-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-methyl Nitrile compound 3 (light yellow solid, 76 mg, 78%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (dd, 1H), 8.68 – 8.66 (m, 1H), 8.20 (d, 1H), 7.62 (dd, 1H), 7.34 (d, 1H), 4.23 (d, 1H), 4.12 – 4.07 (m, 2H), 3.93 (d, 1H), 2.80-2.73 (m, 3H), 2.32 (d, 1H), 2.26-2.22 (m, 1H), 2.80( s, 3H), 2.01 – 2.00 (m, 2H), 1.89 – 1.88 (m, 2H), 1.73 – 1.63 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -63.77. LC- MS m/z (ESI)= 469.20 [M+1].

實施例4 5-(1 S，5 R)-1-(5-(哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物4 5-((1 S, 5 R)-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 4 5-(1 S , 5 R )-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl )-3-Azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 4 5-((1 S , 5 R )-1-(5-(piperidin-4-yl )-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

第一步： 4-(2-((1S，5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼-1叔丁基-羰基)哌啶-1-羧酸鹽 4-2 tert-butyl 4-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)piperidine-1-carboxylate first step: 4-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 -Carbonyl)hydrazine-1tert-butyl-Carbonyl)piperidine-1-carboxylate 4-2 tert-butyl 4-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1 -carbonyl)piperidine-1-carboxylate

將1-(叔丁氧羰基)哌啶-4-羧酸4-1 (1.27 g，5.5 mmol)溶於 N,N-二甲基甲醯胺15 ml中，隨後冰浴加入HATU (2.5 g，6.6 mmol)，DIPEA(2.1 g，16.5 mmol)低溫攪拌5分鐘，然後加入(1S，5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼1-1 (2 g, 5.5 mmol)攪拌1小時，TLC反應完畢，反應液直接濃縮，過矽膠管柱(二氯甲烷：甲醇=80:1到30:1)得到目標產物叔丁基-4-(2-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼基)哌啶-1-羧酸酯4-2 (淡黃色固體，2.5 g，89%)。 LC-MS m/z (ESI)= 573.20 [M+1]. Dissolve 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid 4-1 (1.27 g, 5.5 mmol) in 15 ml of N,N -dimethylformamide, and then add HATU (2.5 g , 6.6 mmol), DIPEA (2.1 g, 16.5 mmol) was stirred at low temperature for 5 minutes, then (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)- was added 3-Azabicyclo[3.1.0]hexane-1-carbohydrazide 1-1 (2 g, 5.5 mmol) was stirred for 1 hour. After the TLC reaction was completed, the reaction solution was directly concentrated and passed through a silica gel column (dichloromethane: Methanol=80:1 to 30:1) to obtain the target product tert-butyl-4-(2-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazino)piperidine-1-carboxylate 4-2 (light yellow solid, 2.5 g, 89%). LC-MS m/z (ESI)= 573.20 [M+1].

第二步： 叔丁基-4-(5-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-1,3,4-口咢二唑-2-基)哌啶-1-羧酸酯 4-3 tert-butyl-4-(5-((1 S,5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate Step 2: tert-Butyl-4-(5-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate 4-3 tert-butyl-4-(5-(( 1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2- yl)piperidine-1-carboxylate

將叔丁基-4-(2-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼基)哌啶-1-羧酸酯4-2 (2.3 g，4 mmol)溶於20ml 1,2-二氯乙烷中，隨後加入三乙胺(3.2 g，32 mmol)，對甲苯磺醯氯(1.5 g，8 mmol)，常溫攪拌5小時，TLC反應完畢，反應液直接濃縮，過矽膠管柱(石油醚：乙酸乙酯=3:1到1:1)得到目標化合物叔丁基-4-(5-(1S，5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-1,3,4-口咢二唑-2-基)哌啶-1-羧酸酯4-3 (淡黃色固體，1.7 g，56%)。 LC-MS m/z (ESI)= 555.10 [M+1]. Add tert-butyl-4-(2-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1. 0]Hexane-1-carbonyl)hydrazino)piperidine-1-carboxylate 4-2 (2.3 g, 4 mmol) was dissolved in 20 ml 1,2-dichloroethane, and then triethylamine (3.2 g, 32 mmol), p-toluenesulfonyl chloride (1.5 g, 8 mmol), stir at room temperature for 5 hours, the TLC reaction is completed, the reaction solution is concentrated directly, and passed through a silica gel column (petroleum ether: ethyl acetate = 3:1 to 1 :1) Obtain the target compound tert-butyl-4-(5-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]Hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate 4-3 (light yellow solid, 1.7 g, 56%) . LC-MS m/z (ESI)= 555.10 [M+1].

第三步： 5-(1 S，5 R)-1-(5-(哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物4 5-((1 S, 5 R)-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Step 3: 5-(1 S , 5 R )-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl base)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 4 5-((1 S , 5 R )-1-(5-(piperidin-4- yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

將叔丁基-4-(5-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-1,3,4-口咢二唑-2-基)哌啶-1-羧酸酯 4-3 (200 mg，0.36 mmol)溶於1 mL二氧六環中，隨後冰浴加入鹽酸二氧六環溶液3mL，室溫攪拌2h。TLC反應完畢，反應液直接濃縮，反相C18柱層析純化(鹼法)，得到目標產物5-(1S，5R)-1-(5-(哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物4 (淡黃色固體，150 mg，92%)。 1H NMR (400 MHz, DMSO- d 6) δ 9.02 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.33 (d, 1H), 4.19 (d, 1H), 4.07 (dd, 2H), 3.93 (d, 1H), 3.10 (ddd, 1H), 3.04 – 2.94 (m, 2H), 2.65 (td, 2H), 2.22 (s, 2H), 1.93 (dd, 2H), 1.88 (s, 1H), 1.70 – 1.56 (m, 2H). 19F NMR (376 MHz, DMSO- d 6) δ -64.11. LC-MS m/z (ESI)= 455.10 [M+1]. Add tert-butyl-4-(5-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1. 0]hexane-1-yl)-1,3,4-ethyl)piperidine-1-carboxylate 4-3 (200 mg, 0.36 mmol) was dissolved in 1 mL dioxane ring, then add 3 mL of dioxane hydrochloride solution in an ice bath, and stir at room temperature for 2 h. After the TLC reaction is completed, the reaction solution is directly concentrated and purified by reverse-phase C18 column chromatography (alkali method) to obtain the target product 5-(1S, 5R)-1-(5-(piperidin-4-yl)-1,3, 4-Aminodiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 4 (light yellow solid, 150 mg, 92%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.33 (d, 1H), 4.19 ( d, 1H), 4.07 (dd, 2H), 3.93 (d, 1H), 3.10 (ddd, 1H), 3.04 – 2.94 (m, 2H), 2.65 (td, 2H), 2.22 (s, 2H), 1.93 (dd, 2H), 1.88 (s, 1H), 1.70 – 1.56 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -64.11. LC-MS m/z (ESI)= 455.10 [ M+1].

實施例5 5-(1 S，5 R)-1-(5-(1-(甲基- d 3 )哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物5 5-((1 S, 5 R)-1-(5-(1-(methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 5 5-(1 S , 5 R )-1-(5-(1-(methyl- d 3 )piperidin-4-yl)-1,3,4-oxadiazol-2-yl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 5 5-((1 S , 5 R )-1- (5-(1-(methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl )quinoline-8-carbonitrile

將5-(1 S，5 R)-1-(5-(哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物4 (163 mg，0.36 mmol)，溶於5 mL N,N-二甲基甲醯胺中，隨後加入碳酸鉀(149 mg，1.08mmol)，冰浴降溫，隨後氘代碘甲烷(50 mg，0.9 mmol)，用1ml N,N-二甲基甲醯胺稀釋並滴加入反應液中，低溫攪拌3小時，TLC反應完畢，反應液直接濃縮，通過Pre-TLC，得到目標產物5-(1 S，5 R)-1-(5-(1-(甲基- d 3 )哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物5 (淡黃色固體，60 mg，34%)。 1H NMR (400 MHz, DMSO- d 6) δ 9.02 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.19 (d, 1H), 4.07 (dd, 2H), 3.92 (d, 1H), 2.95 (ddt, 1H), 2.74 (d,2H), 2.22 (q, 2H), 2.07 (t, 2H), 2.01 – 1.90 (m, 2H), 1.81 – 1.66 (m, 2H). 19F NMR (376 MHz, DMSO- d 6) δ -64.08. LC-MS m/z (ESI)= 472.20 [M+1]. 5-(1 S , 5 R )-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 4 (163 mg, 0.36 mmol), dissolved in 5 mL N,N -dimethylformamide, Then potassium carbonate (149 mg, 1.08 mmol) was added, cooled in an ice bath, and then deuterated methyl iodide (50 mg, 0.9 mmol) was diluted with 1 ml N,N -dimethylformamide and added dropwise to the reaction solution at low temperature. After stirring for 3 hours, the TLC reaction was completed. The reaction solution was directly concentrated and passed through Pre-TLC to obtain the target product 5-(1 S , 5 R )-1-(5-(1-(methyl- d 3 ) piperidine-4). -yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8 -Conitrile compound 5 (light yellow solid, 60 mg, 34%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.19 ( d, 1H), 4.07 (dd, 2H), 3.92 (d, 1H), 2.95 (ddt, 1H), 2.74 (d,2H), 2.22 (q, 2H), 2.07 (t, 2H), 2.01 – 1.90 (m, 2H), 1.81 – 1.66 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -64.08. LC-MS m/z (ESI)= 472.20 [M+1].

實施例6 5-(1 S，5 R)-1-(5-(1-(環丙基甲基)哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物6 5-((1 S, 5 R)-1-(5-(1-(cyclopropylmethyl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 6 5-(1 S , 5 R )-1-(5-(1-(cyclopropylmethyl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 6 5-((1 S , 5 R )-1- (5-(1-(cyclopropylmethyl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline -8-carbonitrile

將5-(1 S，5 R)-1-(5-(哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物4 (100 mg，0.22 mmol)溶於 N,N-二甲基甲醯胺5 ml中，隨後加入三乙胺(66 mg，0.66 mmol)，(溴甲基)環丙烷(44.6 mg，0.33 mmol)，升溫至55℃攪拌15小時，TLC反應轉化60%，反應液直接濃縮，過Pre-TLC得到目標產物5-(1 S，5 R)-1-(5-(1-(環丙基甲基)哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈化合物6 (淡黃色固體，23 mg，21%)。 1H NMR (400 MHz, DMSO- d 6) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.20 (d, 1H), 4.07 (dd, 2H), 3.93 (d, 1H), 3.32 (s, 2H), 2.97 (d, 2H), 2.23 (q, 5H), 1.98 (dd, 2H), 1.76 (t, 2H), 0.84 (q, 1H), 0.46 (dt, 2H), 0.08 (q, 2H). 19F NMR (376 MHz, DMSO- d 6) δ -64.07. LC-MS m/z (ESI)= 509.20 [M+1]. 5-(1 S , 5 R )-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 4 (100 mg, 0.22 mmol) was dissolved in 5 ml of N,N -dimethylformamide, and then Add triethylamine (66 mg, 0.66 mmol) and (bromomethyl)cyclopropane (44.6 mg, 0.33 mmol), raise the temperature to 55°C and stir for 15 hours. The TLC reaction conversion is 60%. The reaction solution is directly concentrated and subjected to Pre-TLC. The target product 5-(1 S , 5 R )-1-(5-(1-(cyclopropylmethyl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl was obtained )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 6 (light yellow solid, 23 mg, 21%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.20 ( d, 1H), 4.07 (dd, 2H), 3.93 (d, 1H), 3.32 (s, 2H), 2.97 (d, 2H), 2.23 (q, 5H), 1.98 (dd, 2H), 1.76 (t , 2H), 0.84 (q, 1H), 0.46 (dt, 2H), 0.08 (q, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -64.07. LC-MS m/z (ESI) = 509.20 [M+1].

實施例7 5-(1 S，5 R)-1-(5-(4-氟-1-甲基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物7 5-((1 S, 5 R)-1-(5-(4-fluoro-1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 7 5-(1 S , 5 R )-1-(5-(4-fluoro-1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl) -5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 7 5-((1 S , 5 R )-1-( 5-(4-fluoro-1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline -8-carbonitrile

第一步： 叔丁基4-(2-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼基-1-羰基)-4-氟哌啶-1-羧酸酯 7-2 tert-butyl 4-(2-((1 S,5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazineyl-1-carbonyl)-4-fluoropiperidine-1-carboxylate The first step: tert-butyl 4-(2-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0]Hexane-1-carbonyl)hydrazino-1-carbonyl)-4-fluoropiperidine-1-carboxylate 7-2 tert-butyl 4-(2-((1 S ,5 R )- 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazineyl-1-carbonyl)-4-fluoropiperidine-1-carboxylate

將1-(叔丁氧羰基)-4-氟哌啶-4-羧酸 7-1 (342 mg，1.38 mmol)溶於 N,N-二甲基甲醯胺10 ml中，隨後冰浴加入HATU (629 mg，1.65 mmol)，DIPEA (534 mg，4.1 mmol)低溫攪拌5分鐘，然後加入(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼 1-1 (500 mg，1.38 mmol)攪拌1小時，TLC反應完畢，反應液直接濃縮，過矽膠管柱 (石油醚：乙酸乙酯= 3:1 到 1:1) 得到目標產物叔丁基-4-(2-(1S，5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼基)-4-氟哌啶-1-羧酸酯 7-2 (淡黃色固體，900 mg，86%)。 LC-MS m/z (ESI)= 591.20[M+1]. Dissolve 1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid 7-1 (342 mg, 1.38 mmol) in 10 ml of N,N -dimethylformamide, then add in ice bath HATU (629 mg, 1.65 mmol), DIPEA (534 mg, 4.1 mmol) were stirred at low temperature for 5 minutes, then (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazine 1-1 (500 mg, 1.38 mmol) was stirred for 1 hour. After the TLC reaction was completed, the reaction solution was concentrated directly and passed through a silicone tube. Column (petroleum ether: ethyl acetate = 3:1 to 1:1) to obtain the target product tert-butyl-4-(2-(1S, 5R)-3-(8-cyanoquinolin-5-yl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazino)-4-fluoropiperidine-1-carboxylate 7-2 (light yellow solid, 900 mg, 86%). LC-MS m/z (ESI)= 591.20[M+1].

第二步： 叔丁基-4-(5-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-1,3,4-口咢二唑-2-基)-4-氟哌啶-1-羧酸酯 7-3 tert-butyl-4-(5-((1 S,5 R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-4-fluoropiperidine-1-carboxylate Step 2: tert-Butyl-4-(5-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]Hexan-1-yl)-1,3,4-ethyl-oxadiazol-2-yl)-4-fluoropiperidine-1-carboxylate 7-3 tert-butyl-4-( 5-((1 S ,5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4- oxadiazol-2-yl)-4-fluoropiperidine-1-carboxylate

將叔丁基-4-(2-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼基)-4-氟哌啶-1-羧酸酯 7-2 (800 mg，1.35 mmol)溶於10ml 1,2-二氯乙烷中，隨後加入三乙胺(1.09 g，10.8 mmol)，對甲苯磺醯氯(517 mg，2.7 mmol)，常溫攪拌5小時，TLC反應完畢，反應液直接濃縮，過矽膠管柱(石油醚：乙酸乙酯=3:1到2:1)得到目標化合物叔丁基-4-(5-(1S，5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-1,3,4-口咢二唑-2-基)-4-氟哌啶-1-羧酸酯 7-3 (淡黃色固體，600 mg，61%)。 LC-MS m/z (ESI)= 573.20 [M+1]. Add tert-butyl-4-(2-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1. 0]Hexane-1-carbonyl)hydrazino)-4-fluoropiperidine-1-carboxylate 7-2 (800 mg, 1.35 mmol) was dissolved in 10 ml of 1,2-dichloroethane, then tris Ethylamine (1.09 g, 10.8 mmol), p-toluenesulfonyl chloride (517 mg, 2.7 mmol), stir at room temperature for 5 hours, the TLC reaction is completed, the reaction solution is concentrated directly, and passed through a silica gel column (petroleum ether: ethyl acetate = 3 :1 to 2:1) to obtain the target compound tert-butyl-4-(5-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-4-fluoropiperidine-1-carboxylate 7-3 (light yellow solid, 600 mg, 61%). LC-MS m/z (ESI)= 573.20 [M+1].

第三步： 5-(1 S，5 R)-1-(5-(4-氟哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 7-4 5-((1 S, 5 R)-1-(5-(4-fluoropiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile The third step: 5-(1 S , 5 R )-1-(5-(4-fluoropiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 7-4 5-((1 S , 5 R )-1-(5-( 4-fluoropiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

將叔丁基-4-(5-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-基)-1,3,4-口咢二唑-2-基)-4-氟哌啶-1-羧酸酯 7-3 (600 mg，1.04 mmol)溶於3 mL二氧六環中，隨後冰浴加入鹽酸二氧六環溶液5mL，室溫攪拌2h。TLC反應完畢，反應液直接濃縮，得到目標產物5-(1 S，5 R)-1-(5-(4-氟哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 7-4 (淡黃色固體，粗品)。 LC-MS m/z (ESI)= 473.10 [M+1]. Add tert-butyl-4-(5-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1. 0]Hexane-1-yl)-1,3,4-ethyl)-4-fluoropiperidine-1-carboxylate 7-3 (600 mg, 1.04 mmol) was dissolved in 3 mL of dioxane, then add 5 mL of dioxane hydrochloride solution in an ice bath, and stir at room temperature for 2 h. After the TLC reaction is completed, the reaction solution is directly concentrated to obtain the target product 5-(1 S , 5 R )-1-(5-(4-fluoropiperidin-4-yl)-1,3,4-orodiazole- 2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 7-4 (light yellow solid, crude product). LC-MS m/z (ESI)= 473.10 [M+1].

第四步： 5-(1 S，5 R)-1-(5-(4-氟-1-甲基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物7 5-((1S,5R)-1-(5-(4-fluoro-1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Step 4: 5-(1 S , 5 R )-1-(5-(4-fluoro-1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 7 5-((1S,5R)-1-(5 -(4-fluoro-1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline- 8-carbonitrile

將5-(1 S，5 R)-1-(5-(4-氟哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 7-4 (490 mg，1.04 mmol)，溶於5 mL甲醇中，隨後加入多聚甲醛(187 mg，2.08 mmol)，氰基硼氫化鈉 (158 mg，4.16 mmol)常溫攪拌3小時，TLC反應完畢，反應液直接濃縮，通過Pre-TLC，得到目標產物5-(1 S，5 R)-1-(5-(4-氟-1-甲基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物7 (淡黃色固體，71 mg，13%)。 1H NMR (400 MHz, DMSO- d 6) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.35 (d, 1H), 4.23 (d, 1H), 4.09 (dd, 2H), 3.94 (d, 1H), 3.32 (s, 3H), 2.37 (d, 2H), 2.31 (d, 1H), 2.29 – 2.22 (m, 3H), 2.20 (s, 4H). 19F NMR (376 MHz, DMSO- d 6) δ -64.10. LC-MS m/z (ESI)= 487.10 [M+1]. 5-(1 S , 5 R )-1-(5-(4-fluoropiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl (490 mg, 1.04 mmol), dissolved in 5 mL of methanol, then added paraformaldehyde (187 mg, 2.08 mmol), sodium cyanoborohydride (158 mg, 4.16 mmol) was stirred at room temperature for 3 hours. After the TLC reaction was completed, the reaction solution was directly concentrated and passed through Pre-TLC to obtain the target product 5-(1 S , 5 R )-1-(5-(4-fluoro-1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 7 (light yellow solid, 71 mg, 13%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.35 (d, 1H), 4.23 ( d, 1H), 4.09 (dd, 2H), 3.94 (d, 1H), 3.32 (s, 3H), 2.37 (d, 2H), 2.31 (d, 1H), 2.29 – 2.22 (m, 3H), 2.20 (s, 4H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -64.10. LC-MS m/z (ESI)= 487.10 [M+1].

實施例8 5-((1 S，5 R)-1-(5-(1-異丙基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈 化合物8 5-((1 S, 5 R)-1-(5-(1-isopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 8 5-((1 S , 5 R )-1-(5-(1-isopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile compound 8 5-((1 S , 5 R )-1-(5- (1-isopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

第一步： (1 S，5 R)-3-(8-氰基喹啉-5-基)- N'-(1-異丙基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-碳醯肼 8-2 (1S,5R)-3-(8-cyanoquinolin-5-yl)-N'-(1-isopropylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide Step 1: (1 S , 5 R )-3-(8-cyanoquinolin-5-yl) -N' -(1-isopropylpiperidine-4-carbonyl)-5-(trifluoromethyl yl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 8-2 (1S,5R)-3-(8-cyanoquinolin-5-yl)-N'-(1-isopropylpiperidine -4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

將1-異丙基哌啶-4-羧酸8-1 (48 mg，0.27 mmol)溶於 N,N-二甲基甲醯胺5 ml中，隨後冰浴加入HATU (123 mg，0.32 mmol)，DIPEA(104 mg，0.81 mmol)低溫攪拌一分鐘，然後加入(1S，5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼1-1 (100 mg，0.27 mmol) 攪拌一小時，TLC監測反應完畢，反應液直接濃縮，反相純化得到目標產物(1S，5R)-3-(8-氰基喹啉-5-基)-N'-(1-異丙基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-碳醯肼8-2 (淡黃色固體，100 mg，82%)。 LC-MS m/z (ESI)= 515.20 [M+1]. 1-Isopropylpiperidine-4-carboxylic acid 8-1 (48 mg, 0.27 mmol) was dissolved in 5 ml of N,N -dimethylformamide, and then HATU (123 mg, 0.32 mmol) was added in ice bath ), DIPEA (104 mg, 0.81 mmol) was stirred at low temperature for one minute, then (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-nitrogen was added Heterobicyclo[3.1.0]hexane-1-carbohydrazide 1-1 (100 mg, 0.27 mmol) was stirred for one hour. TLC monitored the completion of the reaction. The reaction solution was directly concentrated and reversed phase purified to obtain the target product (1S, 5R). -3-(8-cyanoquinolin-5-yl)-N'-(1-isopropylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]Hexane-1-carbohydrazide 8-2 (light yellow solid, 100 mg, 82%). LC-MS m/z (ESI)= 515.20 [M+1].

第二步： 5-((1 S，5 R)-1-(5-(1-異丙基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈 化合物8 5-((1 S, 5 R)-1-(5-(1-isopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Second step: 5-((1 S , 5 R )-1-(5-(1-isopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile compound 8 5-((1 S , 5 R )-1-(5 -(1-isopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

將(1 S，5 R)-3-(8-氰基喹啉-5-基)- N'-(1-異丙基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-碳醯肼8-2 (100 mg，0.19 mmol)溶於5ml 1,2-二氯乙烷中，隨後加入三乙胺(153 mg，1.52 mmol)，對甲苯磺醯氯(74 mg，0.38 mmol)，常溫攪拌5小時，TLC監測反應完畢，反應液直接濃縮，反相純化得到目標化合物5-((1S，5R)-1-(5-(1-異丙基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈化合物8 (淡黃色固體，32 mg，42%)。 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.19 (d, 1H), 4.07 (t, 2H), 3.92 (d, 1H), 3.00 – 2.90 (m, 1H), 2.82 – 2.65 (m, 3H), 2.25-2.23 (m, 4H), 1.96 (d, 2H), 1.70-1.68 (m, 2H), 0.96 (d, 6H). 19F NMR (376 MHz, DMSO-d6) δ -64.09. LC-MS m/z (ESI)= 497.20 [M+1]. (1 S ,5 R )-3-(8-cyanoquinolin-5-yl) -N '-(1-isopropylpiperidine-4-carbonyl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexane-1-carbohydrazide 8-2 (100 mg, 0.19 mmol) was dissolved in 5 ml of 1,2-dichloroethane, then triethylamine (153 mg , 1.52 mmol), p-toluenesulfonyl chloride (74 mg, 0.38 mmol), stir at room temperature for 5 hours, TLC monitors the reaction completion, the reaction solution is directly concentrated, and reversed phase purification is performed to obtain the target compound 5-((1S, 5R)-1- (5-(1-isopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]Hexyl-3-yl)quinoline-8-carbonitrile compound 8 (light yellow solid, 32 mg, 42%). 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.19 (d , 1H), 4.07 (t, 2H), 3.92 (d, 1H), 3.00 – 2.90 (m, 1H), 2.82 – 2.65 (m, 3H), 2.25-2.23 (m, 4H), 1.96 (d, 2H ), 1.70-1.68 (m, 2H), 0.96 (d, 6H). 19 F NMR (376 MHz, DMSO-d6) δ -64.09. LC-MS m/z (ESI)= 497.20 [M+1].

實施例9 5-((1 S，5 R)-1-(5-(1-乙基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈 化合物9 5-((1 S, 5 R)-1-(5-(1-ethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 9 5-((1 S , 5 R )-1-(5-(1-ethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile compound 9 5-((1 S , 5 R )-1-(5-( 1-ethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

第一步： (1 S，5 R)-3-(8-氰基喹啉-5-基)-N'-(1-乙基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-碳醯肼 9-2(1 S, 5 R)-3-(8-cyanoquinolin-5-yl)-N'-(1-ethylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide Step 1: (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-N'-(1-ethylpiperidine-4-carbonyl)-5-(trifluoromethyl )-3-Azabicyclo[3.1.0]hexane-1-carbohydrazide 9-2 (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-N'-(1- ethylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

將1-乙基哌啶-4-羧酸9-1 (100 mg，0.51 mmol)溶於 N,N-二甲基甲醯胺5 ml中，隨後冰浴加入HATU (235 mg，0.62 mmol)，DIPEA(197 mg，1.53 mmol)低溫攪拌一分鐘，然後加入(1S，5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼1-1 (186 mg, 0.51 mmol)攪拌一小時，TLC監測反應完畢，反應液直接濃縮，反相純化得到目標產物(1 S，5 R)-3-(8-氰基喹啉-5-基)- N'-(1-乙基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-碳醯肼9-2 (淡黃色固體，160 mg，86%)。 LC-MS m/z (ESI)= 501.20 [M+1]. Dissolve 1-ethylpiperidine-4-carboxylic acid 9-1 (100 mg, 0.51 mmol) in 5 ml of N,N -dimethylformamide, and then add HATU (235 mg, 0.62 mmol) in an ice bath. , DIPEA (197 mg, 1.53 mmol) was stirred at low temperature for one minute, then (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-aza was added Bicyclo[3.1.0]hexane-1-carbohydrazide 1-1 (186 mg, 0.51 mmol) was stirred for one hour. TLC monitored the completion of the reaction. The reaction solution was directly concentrated and purified by reverse phase to obtain the target product (1 S , 5 R )-3-(8-cyanoquinolin-5-yl) -N' -(1-ethylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]Hexane-1-carbohydrazide 9-2 (light yellow solid, 160 mg, 86%). LC-MS m/z (ESI)= 501.20 [M+1].

第二步： 5-((1 S，5 R)-1-(5-(1-乙基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈 化合物9 5-((1 S, 5 R)-1-(5-(1-ethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Step 2: 5-((1 S , 5 R )-1-(5-(1-ethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile compound 9 5-((1 S , 5 R )-1-(5- (1-ethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

將(1 S，5 R)-3-(8-氰基喹啉-5-基)- N'-(1-乙基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-碳醯肼9-2 (160 mg，0.32 mmol)溶於5ml 1,2-二氯乙烷中，隨後加入三乙胺(258 mg，2.56 mmol)，對甲苯磺醯氯(122 mg，0.64 mmol)，常溫攪拌5小時，TLC監測反應完畢，反應液直接濃縮，反相純化得到目標化合物5-((1S，5R)-1-(5-(1-乙基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈化合物9 (淡黃色固體，97 mg，48%)。 1H NMR (400 MHz, DMSO-d6) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.20 (d, 1H), 4.07 (dd, 2H), 3.92 (d, 1H), 2.97 (t, 1H), 2.82 (d, 2H), 2.33 (q, 2H), 2.23 (t, 2H), 2.06 (t, 2H), 1.97 (d, 2H), 1.72 (t, 2H), 0.99 (t, 3H). 19F NMR (376 MHz, DMSO-d6) δ -64.08. LC-MS m/z (ESI)= 483.20 [M+1]. (1 S ,5 R )-3-(8-cyanoquinolin-5-yl) -N' -(1-ethylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carbohydrazide 9-2 (160 mg, 0.32 mmol) was dissolved in 5 ml of 1,2-dichloroethane, followed by addition of triethylamine (258 mg, 2.56 mmol), p-toluenesulfonyl chloride (122 mg, 0.64 mmol), stir at room temperature for 5 hours, TLC monitors the completion of the reaction, the reaction solution is directly concentrated, and reversed phase purification gives the target compound 5-((1S, 5R)-1-( 5-(1-ethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]hexyl-3-yl)quinoline-8-carbonitrile compound 9 (light yellow solid, 97 mg, 48%). 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.20 (d , 1H), 4.07 (dd, 2H), 3.92 (d, 1H), 2.97 (t, 1H), 2.82 (d, 2H), 2.33 (q, 2H), 2.23 (t, 2H), 2.06 (t, 2H), 1.97 (d, 2H), 1.72 (t, 2H), 0.99 (t, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -64.08. LC-MS m/z (ESI)= 483.20 [M+1].

實施例10 5-((1 S，5 R)-1-(5-(1-環丙基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈 化合物10 5-((1S,5R)-1-(5-(1-cyclopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 10 5-((1 S , 5 R )-1-(5-(1-cyclopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile compound 10 5-((1S,5R)-1-(5-(1 -cyclopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

第一步： (1 S，5 R)-3-(8-氰基喹啉-5-基)- N'-(1-環丙基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-碳醯肼10-2 (1 S, 5 R)-3-(8-cyanoquinolin-5-yl)- N'-(1-cyclopropylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide Step 1: (1 S , 5 R )-3-(8-cyanoquinolin-5-yl) -N' -(1-cyclopropylpiperidine-4-carbonyl)-5-(trifluoromethyl (1 S , 5 R )-3-(8-cyanoquinolin-5-yl)- N' -(1 -cyclopropylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

將1-環丙基哌啶-4-羧酸10-1 (150 mg，0.88 mmol)溶於 N,N-二甲基甲醯胺5 ml中，隨後冰浴加入HATU (400 mg，1.05 mmol)，DIPEA(340 mg，2.6 mmol)低溫攪拌1分鐘，然後加入(1S，5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼1-1 (319 mg，0.88 mmol)攪拌1小時，TLC監測反應完畢，反應液直接濃縮，反相純化得到目標產物(1S，5R)-3-(8-氰基喹啉-5-基)- N'-(1-環丙基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-碳醯肼10-2 (淡黃色固體，287 mg，87%)。 LC-MS m/z (ESI)= 513.20 [M+1]. Dissolve 1-cyclopropylpiperidine-4-carboxylic acid 10-1 (150 mg, 0.88 mmol) in 5 ml of N,N -dimethylformamide, then add HATU (400 mg, 1.05 mmol) in ice bath ), DIPEA (340 mg, 2.6 mmol) was stirred at low temperature for 1 minute, then (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-nitrogen was added Heterobicyclo[3.1.0]hexane-1-carbohydrazide 1-1 (319 mg, 0.88 mmol) was stirred for 1 hour. TLC monitored the completion of the reaction. The reaction solution was directly concentrated and reversed phase purified to obtain the target product (1S, 5R). -3-(8-cyanoquinolin-5-yl) -N' -(1-cyclopropylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]Hexane-1-carbohydrazide 10-2 (light yellow solid, 287 mg, 87%). LC-MS m/z (ESI)= 513.20 [M+1].

第二步： 5-((1 S，5 R)-1-(5-(1-環丙基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈 化合物10 5-((1 S, 5 R)-1-(5-(1-cyclopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Second step: 5-((1 S , 5 R )-1-(5-(1-cyclopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile compound 10 5-((1 S , 5 R )-1-(5 -(1-cyclopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

將(1S，5R)-3-(8-氰基喹啉-5-基)- N'-(1-環丙基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-碳醯肼10-2 (287 mg，0.56 mmol)溶於10ml 1,2-二氯乙烷中，隨後加入三乙胺(452 mg，4.48 mmol)，對甲苯磺醯氯(214 mg，1.12 mmol)，常溫攪拌5小時，TLC監測反應完畢，反應液直接濃縮，TLC純化得到目標化合物5-((1S，5R)-1-(5-(1-環丙基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈 化合物10 (淡黃色固體，180 mg，52%)。 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.62 (dd, 1H), 7.33 (d, 1H), 4.19 (d, 1H), 4.07 (dd, 2H), 3.92 (d, 1H), 3.00-2.94 (m, 1H), 2.90 (d, 2H), 2.37 – 2.27 (m, 2H), 2.22 (q, 2H), 1.94 (d, 2H), 1.71 – 1.55 (m, 3H), 0.40 (dt, 2H), 0.32 – 0.24 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -64.08. LC-MS m/z (ESI)= 495.20 [M+1]. (1S,5R)-3-(8-cyanoquinolin-5-yl) -N' -(1-cyclopropylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carbohydrazide 10-2 (287 mg, 0.56 mmol) was dissolved in 10 ml of 1,2-dichloroethane, and then triethylamine (452 mg, 4.48 mmol), p-toluenesulfonyl chloride (214 mg, 1.12 mmol), stir at room temperature for 5 hours, TLC monitors the completion of the reaction, the reaction solution is directly concentrated, and TLC purifies to obtain the target compound 5-((1S, 5R)-1-(5- (1-cyclopropylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexyl-3-yl)quinoline-8-carbonitrile compound 10 (light yellow solid, 180 mg, 52%). 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.62 (dd, 1H), 7.33 (d, 1H), 4.19 (d , 1H), 4.07 (dd, 2H), 3.92 (d, 1H), 3.00-2.94 (m, 1H), 2.90 (d, 2H), 2.37 – 2.27 (m, 2H), 2.22 (q, 2H), 1.94 (d, 2H), 1.71 – 1.55 (m, 3H), 0.40 (dt, 2H), 0.32 – 0.24 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -64.08. LC-MS m/z (ESI)= 495.20 [M+1].

實施例11 1-甲基-4-((1 S,5 R)-1-(5-(1-甲基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)-1,8-萘啶-2(1H)-酮 化合物11 1-methyl-4-((1 S,5 R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,8-naphthyridin-2(1H)-one Example 11 1-methyl-4-((1 S ,5 R )-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole-2- base)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,8-naphthyridin-2(1H)-one compound 11 1-methyl-4 -((1 S ,5 R )-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]hexan-3-yl)-1,8-naphthyridin-2(1H)-one

N 2氛圍下，將2-(1-甲基哌啶-4-基)-5-((1 S,5 R)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)-1,3,4-口咢二唑 中間體C (60 mg，0.19 mmol) 溶於DMSO (2 mL) 中，依序加入4-氯-1-甲基-1,8-萘啶-2(1H)-酮 化合物11-1 (44 mg，0.227 mmol)和氟化銫 (58 mg，0.38 mmol)，升溫至120 ℃反應5 h。TLC監測反應完畢，濃縮反應液，矽膠管柱層析純化，即可得到目標產物1-甲基-4-((1 S,5 R)-1-(5-(1-甲基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)-1,8-萘啶-2(1H)-酮 化合物11 (淡黃色固體，30 mg，產率：33%)。 1H NMR (400 MHz, DMSO- d 6) δ8.62 (dd, 1H), 8.36 (dd, 1H), 7.26 (dd, 1H), 6.14 (s, 1H), 4.13 (d, 1H), 4.01 (d, 1H), 3.91 (d, 1H), 3.80 (d, 1H), 3.61 (s, 3H), 3.02 – 2.94 (m, 1H), 2.79 (s, 2H), 2.24 (s, 3H), 2.21 (d, 2H), 2.14 (d, 2H), 1.99 (d, 2H), 1.80 – 1.69 (m, 2H). LC-MS m/z (ESI)= 475.2 [M+1]. Under N 2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1 S ,5 R )-5-(trifluoromethyl)-3-azabicyclo [3.1.0 ]Hexan-1-yl)-1,3,4-triazole intermediate C (60 mg, 0.19 mmol) was dissolved in DMSO (2 mL), and 4-chloro-1-methyl-1 was added sequentially , 8-naphthyridin-2(1H)-one compound 11-1 (44 mg, 0.227 mmol) and cesium fluoride (58 mg, 0.38 mmol) were heated to 120 ℃ for 5 h. After TLC monitoring of the reaction is completed, the reaction solution is concentrated and purified by silica gel column chromatography to obtain the target product 1-methyl-4-((1 S ,5 R )-1-(5-(1-methylpiperidine- 4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1, 8-Naphthyridin-2(1H)-one compound 11 (light yellow solid, 30 mg, yield: 33%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.62 (dd, 1H), 8.36 (dd, 1H), 7.26 (dd, 1H), 6.14 (s, 1H), 4.13 (d, 1H), 4.01 ( d, 1H), 3.91 (d, 1H), 3.80 (d, 1H), 3.61 (s, 3H), 3.02 – 2.94 (m, 1H), 2.79 (s, 2H), 2.24 (s, 3H), 2.21 (d, 2H), 2.14 (d, 2H), 1.99 (d, 2H), 1.80 – 1.69 (m, 2H). LC-MS m/z (ESI)= 475.2 [M+1].

實施例12 2-(1-甲基哌啶-4-基)-5-((1 S,5 R)-5-(三氟甲基)-3-(8-(三氟甲基)喹啉-5-基)-3-氮雜雙環[3.1.0] 己烷-1-基)-1,3,4-口咢二唑 化合物12 2-(1-methylpiperidin-4-yl)-5-((1 S,5 R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Example 12 2-(1-methylpiperidin-4-yl)-5-((1 S ,5 R )-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quine Phin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxazole compound 12 2-(1-methylpiperidin-4-yl)-5 -((1 S ,5 R )-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3, 4-oxadiazole

N 2氛圍下，將2-(1-甲基哌啶-4-基)-5-((1 S,5 R)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)-1,3,4-口咢二唑 中間體C (80 mg，0.25 mmol)溶於1,4-二氧六環(3 mL)中，隨後依序加入5-溴-8-(三氟甲基)喹啉 化合物12-1 (90 mg，0.33 mmol)、碳酸銫 (525.8 mg，1.0 mmol) 和RuPhosPdG3 (42 mg，0.058 mmol)，N 2置換氣三次，升溫至90 ℃反應2 h。旋乾溶劑，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，過濾，旋乾溶劑，矽膠管柱層析純化，即可得到目標產物2-(1-甲基哌啶-4-基)-5-((1 S,5 R)-5-(三氟甲基)-3-(8-(三氟甲基)喹啉-5-基)-3-氮雜雙環[3.1.0] 己烷-1-基)-1,3,4-口咢二唑 化合物12 (淡黃色固體，43 mg，產率：33%)。 1H NMR (400 MHz, DMSO- d 6) δ = 9.02 (dd, 1H), 8.66 (dd, 1H), 8.05 (d, 1H), 7.63 (dd, 1H), 7.38 (d, 1H), 4.09 (d, 1H), 3.98 (t, 2H), 3.83 (d, 1H), 2.99 – 2.91 (m, 1H), 2.75 (d, 2H), 2.34 (d, 1H), 2.23 (d, 1H), 2.08 (t, 2H), 2.19 (s, 3H), 1.97 (d, 2H), 1.80 – 1.68 (m, 2H). LC-MS m/z (ESI)= 512.2 [M+1] Under N 2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1 S ,5 R )-5-(trifluoromethyl)-3-azabicyclo [3.1.0 ]Hexan-1-yl)-1,3,4-triazole intermediate C (80 mg, 0.25 mmol) was dissolved in 1,4-dioxane (3 mL), and then 5- Bromo-8-(trifluoromethyl)quinoline compound 12-1 (90 mg, 0.33 mmol), cesium carbonate (525.8 mg, 1.0 mmol) and RuPhosPdG3 (42 mg, 0.058 mmol), N2 replacement gas three times, heating React at 90°C for 2 hours. Spin the solvent dry, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, spin the solvent dry, and purify by silica column chromatography to obtain the target product 2-(1-methylpiperidine-4) -yl)-5-((1 S ,5 R )-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1 .0] Hexan-1-yl)-1,3,4-triazole compound 12 (light yellow solid, 43 mg, yield: 33%). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.02 (dd, 1H), 8.66 (dd, 1H), 8.05 (d, 1H), 7.63 (dd, 1H), 7.38 (d, 1H), 4.09 (d, 1H), 3.98 (t, 2H), 3.83 (d, 1H), 2.99 – 2.91 (m, 1H), 2.75 (d, 2H), 2.34 (d, 1H), 2.23 (d, 1H), 2.08 (t, 2H), 2.19 (s, 3H), 1.97 (d, 2H), 1.80 – 1.68 (m, 2H). LC-MS m/z (ESI)= 512.2 [M+1]

實施例13 8-((1 S,5 R)-1-(5-(1-甲基哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹口咢啉-5-甲腈 化合物13 8-((1 S,5 R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-5-carbonitrile Example 13 8-((1 S ,5 R )-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinorin-5-carbonitrile compound 13 8-((1 S ,5 R )-1-(5 -(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-5-carbonitrile

N 2氛圍下，將2-(1-甲基哌啶-4-基)-5-((1 S,5 R)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)-1,3,4-口咢二唑 中間體C (100 mg，0.315 mmol) 溶於1,4-二氧六環(3 mL)中，依序加入8-溴喹口咢啉-5-甲腈 化合物13-1 (96 mg，0.41 mmol)、碳酸銫 (410 mg，1.26 mmol) 和RuPhosPdG3 (53 mg，0.063 mmol)，N 2置換氣三次，升溫至90 ℃反應2 h。旋乾溶劑，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，過濾，旋乾溶劑，矽膠管柱層析純化，即可得到目標產物2-(1-甲基哌啶-4-基)-5-((1 S,5 R)-5-(三氟甲基)-3-(8-(三氟甲基)喹啉-5-基)-3-氮雜雙環[3.1.0] 己烷-1-基)-1,3,4-口咢二唑 化合物13 (淡黃色固體，60 mg，產率：41%)。 1H NMR (400 MHz, DMSO- d 6) δ= 9.03 (d, 1H), 8.93 (d, 1H), 8.17 (d, 1H), 7.03 (d, 1H), 4.87 (t, 2H), 4.37 (d, 1H), 4.23 (d, 1H), 3.10 – 2.90 (m, 1H), 2.73 (d, 2H), 2.31 (d, 1H), 2.17 (s, 3H), 2.08 – 1.89 (m, 5H), 1.79 – 1.67 (m, 2H). LC-MS m/z (ESI)= 470.2 [M+1]. Under N 2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1 S ,5 R )-5-(trifluoromethyl)-3-azabicyclo [3.1.0 ]Hexan-1-yl)-1,3,4-oxazole intermediate C (100 mg, 0.315 mmol) was dissolved in 1,4-dioxane (3 mL), and 8-bromo was added sequentially Quinosoline-5-carbonitrile compound 13-1 (96 mg, 0.41 mmol), cesium carbonate (410 mg, 1.26 mmol) and RuPhosPdG3 (53 mg, 0.063 mmol), N 2 replacement gas three times, and the temperature was raised to 90 ℃ Reaction 2 h. Spin the solvent dry, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, spin the solvent dry, and purify by silica column chromatography to obtain the target product 2-(1-methylpiperidine-4) -yl)-5-((1 S ,5 R )-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1 .0] Hexan-1-yl)-1,3,4-oxadiazole compound 13 (light yellow solid, 60 mg, yield: 41%). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.03 (d, 1H), 8.93 (d, 1H), 8.17 (d, 1H), 7.03 (d, 1H), 4.87 (t, 2H), 4.37 (d, 1H), 4.23 (d, 1H), 3.10 – 2.90 (m, 1H), 2.73 (d, 2H), 2.31 (d, 1H), 2.17 (s, 3H), 2.08 – 1.89 (m, 5H ), 1.79 – 1.67 (m, 2H). LC-MS m/z (ESI)= 470.2 [M+1].

實施例14 5-((1 R，5 S)-1-(5-(1-(甲基-d3)哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-腈 化合物14 5-((1 R, 5 S)-1-(5-(1-(methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 14 5-((1 R ,5 S )-1-(5-(1-(methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-nitrile compound 14 5-((1 R , 5 S )-1-(5 -(1-(methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline -8-carbonitrile

第一步： 2-((1 R，5 S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼-1-羧酸叔丁酯14-1 tert-butyl 2-((1 R,5 S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylate The first step: 2-((1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alk-1-carbonyl)hydrazine-1-carboxylic acid tert-butyl ester 14-1 tert-butyl 2-((1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)- 3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylate

將(1 R，5 S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-甲酸B-2 (1 g，2.8 mmol)溶於N,N二甲基甲醯胺5 ml中，隨後冰浴加入HATU (1.27 g，3.3 mmol)，DIPEA(1 g，8.4 mmol)低溫攪拌1分鐘，然後加入Boc-肼 (418 mg，3.1 mmol)攪拌1小時，TLC反應完畢，反應液直接濃縮，過反相得到目標產物2-((1R，5S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼-1-羧酸叔丁酯14-1 (淡黃色固體，1.1g，76%)。 LC-MS m/z (ESI)= 462.20 [M+1]. (1 R , 5 S )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid B -2 (1 g, 2.8 mmol) was dissolved in 5 ml of N,N dimethylformamide, then HATU (1.27 g, 3.3 mmol) was added in ice bath, and DIPEA (1 g, 8.4 mmol) was stirred at low temperature for 1 minute. Then Boc-hydrazine (418 mg, 3.1 mmol) was added and stirred for 1 hour. The TLC reaction was completed. The reaction solution was directly concentrated and passed through reversed phase to obtain the target product 2-((1R,5S)-3-(8-cyanoquinoline- 5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylic acid tert-butyl ester 14-1 (light yellow solid, 1.1g , 76%). LC-MS m/z (ESI)= 462.20 [M+1].

第二步： (1 R，5 S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼14-2 (1 R,5 S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide Step 2: (1 R , 5 S )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 -Carbohydrazide 14-2 (1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

將2-((1 R，5 S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-羰基)肼-1-羧酸叔丁酯14-1 (1.1 g，2.3 mmol)溶於5ml 1,2-二氯乙烷中，隨後加入鹽酸二氧六環10 ml，常溫攪1小時，TLC反應完畢，反應液直接濃縮，得到目標化合物(1 R，5 S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼化合物14-2 (淡黃色固體，738 mg，73%)。 LC-MS m/z (ESI)= 362.20 [M+1]. 2-((1 R ,5 S )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 -Carbonyl)hydrazine-1-carboxylic acid tert-butyl ester 14-1 (1.1 g, 2.3 mmol) was dissolved in 5 ml of 1,2-dichloroethane, then 10 ml of dioxane hydrochloride was added, and stirred at room temperature for 1 hour. After the TLC reaction is completed, the reaction solution is directly concentrated to obtain the target compound (1 R , 5 S )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carbohydrazide compound 14-2 (light yellow solid, 738 mg, 73%). LC-MS m/z (ESI)= 362.20 [M+1].

第三步： (1 R，5 S)-3-(8-氰基喹啉-5-基)-N'-(1-(甲基-d3)哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-碳醯肼14-4 (1 R, 5 S)-3-(8-cyanoquinolin-5-yl)-N'-(1-(methyl-d3)piperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide Step 3: (1 R , 5 S )-3-(8-cyanoquinolin-5-yl)-N'-(1-(methyl-d3)piperidine-4-carbonyl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-carbohydrazine 14-4 (1 R , 5 S )-3-(8-cyanoquinolin-5-yl)-N'-( 1-(methyl-d3)piperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

將1-(甲基-d3)哌啶-4-羧酸14-3 (298 mg, 2 mmol)溶於N,N二甲基甲醯胺5 ml中，隨後冰浴加入HATU (932 mg，2.4 mmol)，DIPEA (774 mg，6 mmol)低溫攪拌1分鐘，然後加入(1R，5S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼3 (738 mg, 2 mmol)攪拌1小時，TLC反應完畢，反應液直接濃縮，過反相得到目標產物(1R，5S)-3-(8-氰基喹啉-5-基)-N'-(1-(甲基-d3)哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-碳醯肼14-4 (淡黃色固體，794 mg，83%)。 LC-MS m/z (ESI)= 490.20 [M+1]. 1-(Methyl-d3)piperidine-4-carboxylic acid 14-3 (298 mg, 2 mmol) was dissolved in 5 ml of N,N dimethylformamide, and then HATU (932 mg, 932 mg, 2.4 mmol), DIPEA (774 mg, 6 mmol) was stirred at low temperature for 1 minute, then (1R, 5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3 was added -Azabicyclo[3.1.0]hexane-1-carbohydrazide 3 (738 mg, 2 mmol) was stirred for 1 hour. After the TLC reaction was completed, the reaction solution was directly concentrated and passed through reversed phase to obtain the target product (1R, 5S)- 3-(8-cyanoquinolin-5-yl)-N'-(1-(methyl-d3)piperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexan-1-carbohydrazide 14-4 (light yellow solid, 794 mg, 83%). LC-MS m/z (ESI)= 490.20 [M+1].

第四步： 5-((1 R，5 S)-1-(5-(1-(甲基-d3)哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-腈 化合物14 5-((1 R, 5 S)-1-(5-(1-(methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Step 4: 5-((1 R , 5 S )-1-(5-(1-(methyl-d3)piperidin-4-yl)-1,3,4-oxadiazole-2- base)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-nitrile compound 14 5-((1 R , 5 S )-1-( 5-(1-(methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl) quinoline-8-carbonitrile

將(1 R，5 S)-3-(8-氰基喹啉-5-基)-N'-(1-(甲基-d3)哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-碳醯肼4 (794 mg，1.6 mmol)溶於20ml 1,2-二氯乙烷中，隨後加入三乙胺(969 mg，9.6 mmol)，對甲苯磺醯氯(619 mg，3.2 mmol)，常溫攪拌5小時，TLC反應完畢，反應液直接濃縮，過矽膠管柱(二氯甲烷：甲醇=30:1到10:1)得到目標化合物5-((1R，5S)-1-(5-(1-(甲基-d3)哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-3-基)喹啉-8-腈化合物14 (淡黃色固體，628 mg，42%)。 LC-MS m/z (ESI)= 472.20 [M+1]. 1H NMR (400 MHz, DMSO- d 6) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.20 (d, 1H), 4.07 (dd, 2H), 3.93 (d, 1H), 2.94 (tt, 1H), 2.73 (d, 2H), 2.23 (t, 2H), 2.12 – 2.00 (m, 2H), 1.96 (dq, 2H), 1.81 – 1.65 (m, 2H). 19F NMR (376 MHz, DMSO- d 6) δ -64.08. (1 R , 5 S )-3-(8-cyanoquinolin-5-yl)-N'-(1-(methyl-d3)piperidine-4-carbonyl)-5-(trifluoromethyl (794 mg, 1.6 mmol) was dissolved in 20 ml of 1,2-dichloroethane, and then triethylamine (969 mg, 9.6 mmol), p-toluenesulfonyl chloride (619 mg, 3.2 mmol), stir at room temperature for 5 hours, the TLC reaction is completed, the reaction solution is concentrated directly, and passed through a silica gel column (dichloromethane: methanol = 30:1 to 10:1) The target compound 5-((1R,5S)-1-(5-(1-(methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-nitrile compound 14 (light yellow solid, 628 mg, 42%). LC-MS m/z (ESI)= 472.20 [M+1]. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.03 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H) , 7.63 (dd, 1H), 7.34 (d, 1H), 4.20 (d, 1H), 4.07 (dd, 2H), 3.93 (d, 1H), 2.94 (tt, 1H), 2.73 (d, 2H), 2.23 (t, 2H), 2.12 – 2.00 (m, 2H), 1.96 (dq, 2H), 1.81 – 1.65 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -64.08.

實施例15 8-((1 S,5 R)-1-(5-(1-甲基-d3)哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹口咢啉-5-甲腈 化合物15 8-((1 S,5 R)-1-(5-(1-methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-5-carbonitrile Example 15 8-((1 S ,5 R )-1-(5-(1-methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl) -5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoroline-5-carbonitrile compound 15 8-((1 S ,5 R )-1 -(5-(1-methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl )quinoxaline-5-carbonitrile

第一步： (1 S,5 R)-3-苄基-N'-(1-甲基-d3)哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼 15-1 (1 S,5 R)-3-benzyl-N'-(1-(methyl-d3)piperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide Step 1: (1 S ,5 R )-3-benzyl-N'-(1-methyl-d3)piperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]Hexane-1-carbohydrazine 15-1 (1 S ,5 R )-3-benzyl-N'-(1-(methyl-d3)piperidine-4-carbonyl)-5-(trifluoromethyl )-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

將化合物1-(甲基-d3)哌啶-4-羧酸14-3 (4.23 g，0.029 mol) 溶於20 mL二氯甲烷中，0 ℃條件下緩慢加入二氯亞碸 (4.21 mL, 0.058 mol)，隨後反應體系升溫至40 ℃，繼續反應2 h，後濃縮溶劑，再用10 mL二氯甲烷溶解，加入上步所得的化合物(1S,5R)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼 C-1.1 (8.67 g，0.029 mol)，室溫攪拌1 h。TLC監測反應完畢，加水淬滅，加入二氯甲烷萃取，合併有機相用飽和食鹽水洗滌，有機相用無水硫酸鈉乾燥，減壓濃縮，矽膠管柱層析純化，即可得到目標產物(1S,5R)-3-苄基-N'-(1-甲基-d3)哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼化合物15-1 (白色固體，6.6 g，產率：53.3%)。 LC-MS m/z (ESI)= 428.2 [M+1]。 Compound 1-(methyl-d3)piperidine-4-carboxylic acid 14-3 (4.23 g, 0.029 mol) was dissolved in 20 mL of methylene chloride, and dichloromethane (4.21 mL, 4.21 mL, 0.058 mol), then the reaction system was heated to 40°C, and the reaction was continued for 2 h. The solvent was concentrated, and then dissolved in 10 mL of dichloromethane. The compound (1S,5R)-3-benzyl-5-( obtained in the previous step was added Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide C-1.1 (8.67 g, 0.029 mol), stirred at room temperature for 1 h. TLC monitors the completion of the reaction, adds water to quench, and adds methylene chloride for extraction. The combined organic phases are washed with saturated brine, the organic phases are dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the target product (1S ,5R)-3-benzyl-N'-(1-methyl-d3)piperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-Carbohydrazide compound 15-1 (white solid, 6.6 g, yield: 53.3%). LC-MS m/z (ESI)= 428.2 [M+1].

第二步： 2-((1 S,5 R)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0] 己烷-1-基)-5-(1-甲基-d3)哌啶-4-基)-1,3,4-口咢二唑15-2 2-((1 S, 5 R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-(methyl-d3)piperidin-4-yl)-1,3,4-oxadiazole Second step: 2-((1 S ,5 R )-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-( 1-Methyl-d3)piperidin-4-yl)-1,3,4-oxadiazole 15-2 2-((1 S , 5 R )-3-benzyl-5-(trifluoromethyl)-3 -azabicyclo[3.1.0]hexan-1-yl)-5-(1-(methyl-d3)piperidin-4-yl)-1,3,4-oxadiazole

(1 S,5 R)-3-苄基-N'-(1-甲基-d3)哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼 15-1 (2.0 g，0.0047 mol) 溶於20 mL二氯甲烷中，隨後加入三乙胺 (3.2 mL，0.024 mol)，對甲苯磺醯氯 (1.78 g，0.0094 mol)，室溫攪拌5小時，TLC反應完畢，濃縮反應液，矽膠管柱層析純化，即可得到目標產物2-((1S,5R)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0] 己烷-1-基)-5-(1-甲基-d3)哌啶-4-基)-1,3,4-口咢二唑化合物15-2 (黃色液體，1.2 g，產率：55%)。 LC-MS m/z (ESI)= 410.2 [M+1]. (1 S ,5 R )-3-benzyl-N'-(1-methyl-d3)piperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]Hexane-1-carbohydrazide 15-1 (2.0 g, 0.0047 mol) was dissolved in 20 mL dichloromethane, then triethylamine (3.2 mL, 0.024 mol), p-toluenesulfonyl chloride (1.78 g, 0.0094 mol), stir at room temperature for 5 hours, the TLC reaction is completed, the reaction solution is concentrated, and purified by silica gel column chromatography to obtain the target product 2-((1S,5R)-3-benzyl-5-(trifluoromethyl) base)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methyl-d3)piperidin-4-yl)-1,3,4-oxadiazole compound 15-2 (yellow liquid, 1.2 g, yield: 55%). LC-MS m/z (ESI)= 410.2 [M+1].

第三步： 2-((1-甲基-d 3)哌啶-4-基)-5-((1 S,5 R)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)-1,3,4-口咢二唑15-3 2-((methyl-d 3)piperidin-4-yl)-5-((1 S,5 R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole The third step: 2-((1-methyl-d 3 )piperidin-4-yl)-5-((1 S ,5 R )-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0]Hex-1-yl)-1,3,4-piperidin-15-3 2-((methyl-d 3 )piperidin-4-yl)-5-((1 S ,5 R ) -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

將2-((1 S,5 R)-3-苄基-5-(三氟甲基)-3-氮雜雙環[3.1.0] 己烷-1-基)-5-(1-甲基-d 3)哌啶-4-基)-1,3,4-口咢二唑 化合物15-2 (500.0 mg，1.22 mmol) 溶於5 mL甲醇，依序加入氫氧化鈀 (17.0 mg，0. 12 mmol)，甲酸銨(770.0 mg，10.2 mmol)，加熱回流6 h，TLC監測反應完畢，濃縮反應液，矽膠管柱層析純化，即可得到目標產物2-((1-甲基-d3)哌啶-4-基)-5-((1S,5R)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)-1,3,4-口咢二唑 化合物15-3 (黃色液體，300 mg，產率：77%)。 LC-MS m/z (ESI)= 320.2 [M+1]. 2-((1 S ,5 R )-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methyl Base-d 3 )piperidin-4-yl)-1,3,4-oxadiazole compound 15-2 (500.0 mg, 1.22 mmol) was dissolved in 5 mL methanol, and palladium hydroxide (17.0 mg, 17.0 mg, 0.12 mmol), ammonium formate (770.0 mg, 10.2 mmol), heat to reflux for 6 h, TLC monitors the reaction is completed, concentrate the reaction solution, and purify by silica gel column chromatography to obtain the target product 2-((1-methyl -d3)piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-1-yl)-1,3, 4-Aminodiazole compound 15-3 (yellow liquid, 300 mg, yield: 77%). LC-MS m/z (ESI)= 320.2 [M+1].

第四步： 8-((1S,5R)-1-(5-(1-甲基-d3)哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0 ]己烷-3-基)喹口咢啉-5-甲腈 化合物15 8-((1S,5R)-1-(5-(1-methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-5-carbonitrile the fourth step: 8-((1S,5R)-1-(5-(1-methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(tri Fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinorin-5-carbonitrile compound 15 8-((1S,5R)-1-(5-(1-methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexan-3-yl)quinoxaline-5-carbonitrile

N 2氛圍下，將2-((1-甲基-d3)哌啶-4-基)-5-((1S,5R)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己-1-基)-1,3,4-口咢二唑 化合物15-3 (300 mg，0.94 mmol) 溶於1,4-二氧六環(20 mL)中，隨後依序加入8-溴喹口咢啉-5-甲腈 化合物15-4 (220 mg，0.94 mmol)，依序加入碳酸銫 (1.2 g，3.76 mmol) 和RuPhosPdG3 (78 mg，0.094 mmol)，N2置換氣三次，升溫至100 ℃反應2 h。旋乾溶劑，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，過濾，旋乾溶劑，矽膠管柱層析純化，即可得到目標產物8-((1S,5R)-1-(5-(1-甲基-d3)哌啶-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0 ]己烷-3-基)喹口咢啉-5-甲腈 化合物15 (淡黃色固體，398 mg，產率：90%)。 1H NMR (400 MHz, DMSO- d 6) δ = 9.04 (d, 1H), 8.93 (d, 1H), 8.18 (d, 1H), 7.03 (d, 1H), 4.91 (d, 1H), 4.84 (d, 1H), 4.38 (d, 1H), 4.23 (d, 1H), 3.46 – 3.28 (m, 2H), 3.28 – 3.16 (m, 2H), 2.94 – 2.72 (m, 2H), 2.32 (d, 1H), 2.22 – 2.10 (m, 2H), 1.97 – 1.86 (m, 2H), LC-MS m/z (ESI)= 473.2 [M+1]. Under N2 atmosphere, 2-((1-methyl-d3)piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]Hexan-1-yl)-1,3,4-oxazole compound 15-3 (300 mg, 0.94 mmol) was dissolved in 1,4-dioxane (20 mL), followed by Add 8-bromoquinoroline-5-carbonitrile compound 15-4 (220 mg, 0.94 mmol), followed by cesium carbonate (1.2 g, 3.76 mmol) and RuPhosPdG3 (78 mg, 0.094 mmol), and replace the gas with N2 Three times, the temperature was raised to 100°C for 2 h. The solvent was spun dry, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was spun dry, and purified by silica gel column chromatography to obtain the target product 8-((1S,5R)-1- (5-(1-methyl-d3)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0]Hexan-3-yl)quinosorine-5-carbonitrile compound 15 (light yellow solid, 398 mg, yield: 90%). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.04 (d, 1H), 8.93 (d, 1H), 8.18 (d, 1H), 7.03 (d, 1H), 4.91 (d, 1H), 4.84 (d, 1H), 4.38 (d, 1H), 4.23 (d, 1H), 3.46 – 3.28 (m, 2H), 3.28 – 3.16 (m, 2H), 2.94 – 2.72 (m, 2H), 2.32 (d , 1H), 2.22 – 2.10 (m, 2H), 1.97 – 1.86 (m, 2H), LC-MS m/z (ESI)= 473.2 [M+1].

實施例16 5-((1 S，5 R)-1-(5-(奎寧-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈 化合物16 5-((1S,5R)-1-(5-(quinuclidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 16 5-((1 S , 5 R )-1-(5-(quinin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl base)-3-azabicyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile compound 16 5-((1S,5R)-1-(5-(quinuclidin-4-yl) -1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

第一步： 氮-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-羰基)奎寧-4-碳酸肼16-2 N-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)quinuclidine-4-carbohydrazide Step 1: Nitrogen-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alk-1-carbonyl)quinine-4-hydrazine carbonate 16-2 N-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]hexane-1-carbonyl)quinuclidine-4-carbohydrazide

將奎寧-4-羧酸16-1 (360 mg，1.8 mmol)溶於 N,N-二甲基甲醯胺30 ml中，隨後冰浴加入HATU ( 822 mg，2.16 mmol)，DIPEA (930 mg，7.2 mmol)低溫攪拌一分鐘，然後加入(1S，5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼1-1 (600 mg，1.8 mmol)攪拌一小時，TLC監測反應完畢，反應液直接濃縮，反相純化得到目標產物氮-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-羰基)奎寧-4-碳酸肼16-2 (淡黃色固體，710 mg，86%)。 LC-MS m/z (ESI)= 499.20 [M+1]. Quinine-4-carboxylic acid 16-1 (360 mg, 1.8 mmol) was dissolved in 30 ml of N,N -dimethylformamide, and then HATU (822 mg, 2.16 mmol), DIPEA (930 mg, 7.2 mmol) and stir at low temperature for one minute, then add (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] Hexane-1-carbohydrazide 1-1 (600 mg, 1.8 mmol) was stirred for one hour. TLC monitored the reaction to completion. The reaction solution was directly concentrated and purified by reverse phase to obtain the target product nitrogen-(1 S , 5 R )- 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)quinine-4-hydrazine carbonate 16 -2 (light yellow solid, 710 mg, 86%). LC-MS m/z (ESI)= 499.20 [M+1].

第二步： 5-((1 S，5 R)-1-(5-(奎寧-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈 化合物16 5-((1S,5R)-1-(5-(quinuclidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Second step: 5-((1 S , 5 R )-1-(5-(quinin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile compound 16 5-((1S,5R)-1-(5-(quinuclidin-4-yl )-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

氮-(1 S，5 R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己烷-1-羰基)奎寧-4-碳酸肼16-2 (710 mg，1.4 mmol)溶於5ml 1,2-二氯乙烷中，隨後加入三乙胺(848 mg，8.4 mmol)，對甲苯磺醯氯(543 mg，2.85 mmol)，常溫攪拌5小時，TLC監測反應完畢，反應液直接濃縮，反相純化得到目標化合物5-((1 S，5 R)-1-(5-(奎寧-4-基)-1,3,4-口咢二唑-2-基)-5-(三氟甲基)-3-氮雜二環[3.1.0]己基-3-基)喹啉-8-碳腈 化合物16 (淡黃色固體，179 mg，25%)。 1H NMR (400 MHz, DMSO-d6) δ 9.03 (dd, 1H), 8.70 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.21 (d, 1H), 4.07 (dd, 2H), 3.92 (d, 1H), 2.91-2.74 (m, 6H), 2.29-2.16 (m, 2H), 1.82-1.64 (m, 6H). 19F NMR (376 MHz, DMSO-d6) δ -64.15. LC-MS m/z (ESI)= 481.20 [M+1]. Nitrogen-(1 S , 5 R )-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Carbonyl)quinine-4-hydrazine carbonate 16-2 (710 mg, 1.4 mmol) was dissolved in 5 ml of 1,2-dichloroethane, then triethylamine (848 mg, 8.4 mmol), p-toluenesulfonyl chloride was added (543 mg, 2.85 mmol), stirred at room temperature for 5 hours, TLC monitored the reaction to completion, the reaction solution was directly concentrated, and reverse-phase purified to obtain the target compound 5-((1 S , 5 R )-1-(5-(quinine-4) -yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexyl-3-yl)quinoline-8 -Carbonitrile compound 16 (light yellow solid, 179 mg, 25%). 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (dd, 1H), 8.70 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.21 (d , 1H), 4.07 (dd, 2H), 3.92 (d, 1H), 2.91-2.74 (m, 6H), 2.29-2.16 (m, 2H), 1.82-1.64 (m, 6H). 19 F NMR (376 MHz, DMSO-d6) δ -64.15. LC-MS m/z (ESI)= 481.20 [M+1].

實施例17 5-(1 S，5 R)-1-(5-(1-甲基哌啶-4-基)-1,3,4-噻二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈 化合物17 5-((1 S, 5 R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-thiadiazole-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Example 17 5-(1 S , 5 R )-1-(5-(1-methylpiperidin-4-yl)-1,3,4-thiadiazol-2-yl)-5-(tri Fluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 17 5-((1 S , 5 R )-1-(5-(1- methylpiperidin-4-yl)-1,3,4-thiadiazole-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

將(1 S，5 R)-3-(8-氰基喹啉-5-基)- N'-(1-甲基哌啶-4-羰基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-1-碳醯肼1-3 (115 mg，0.23 mmol)溶於6 ml 甲苯中，隨後加入4-甲氧基苯基硫代磷環二(硫代酸酐) (278 mg，0.69 mmol)，升溫至120℃攪拌3小時，TLC反應完畢，反應液直接濃縮，TLC純化(DCM:MeOH=5：1)，得到目標化合物(5-(1 S，5 R)-1-(5-(1-甲基哌啶-4-基)-1,3,4-噻二唑-2-基)-5-(三氟甲基)-3-氮雜雙環[3.1.0]己烷-3-基)喹啉-8-甲腈化合物17 (淡黃色固體，20 mg，15%)。 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, 1H), 8.69 (d, 1H), 8.19 (d, 1H), 7.65-7.57 (m, 1H), 7.33 (d, 1H), 4.28(d, 1H), 4.10-4.02 (m, 2H), 3.98 (d, 1H), 3.16 (d, 1H), 2.85 (d, 2H), 2.32-2.28 (m, 1H), 2.26-2.16 (m, 4H), 2.14-2.00 (m, 4H), 1.81-1.67 (m, 2H). LC-MS m/z (ESI)= 485.20 [M+1]. (1 S ,5 R )-3-(8-cyanoquinolin-5-yl) -N' -(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carbohydrazide 1-3 (115 mg, 0.23 mmol) was dissolved in 6 ml of toluene, followed by the addition of 4-methoxyphenylphosphorothioate acid anhydride) (278 mg, 0.69 mmol), raise the temperature to 120°C and stir for 3 hours. The TLC reaction is completed. The reaction solution is directly concentrated and purified by TLC (DCM:MeOH=5:1) to obtain the target compound (5-(1 S , 5 R )-1-(5-(1-methylpiperidin-4-yl)-1,3,4-thiadiazol-2-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 17 (light yellow solid, 20 mg, 15%). 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, 1H), 8.69 (d, 1H), 8.19 (d, 1H), 7.65-7.57 (m, 1H), 7.33 (d, 1H), 4.28 (d, 1H), 4.10-4.02 (m, 2H), 3.98 (d, 1H), 3.16 (d, 1H), 2.85 (d, 2H), 2.32-2.28 (m, 1H), 2.26-2.16 (m , 4H), 2.14-2.00 (m, 4H), 1.81-1.67 (m, 2H). LC-MS m/z (ESI)= 485.20 [M+1].

生物測試biological testing

HEK-Blue-hTLR7/8/9細胞抑制實驗 HEK-Blue-hTLR7/8/9 cell inhibition assay

1、將HEK-Blue-hTL R7/8細胞 (1×10 4個/孔)、HEK-Blue-hTL R9細胞(1.5×10 4個/孔)接種於384孔細胞培養盤中，每孔體積為30 µL。置於37 °C，5% CO 2培養箱培養4 h。 1. Inoculate HEK-Blue-hTL R 7/8 cells (1×10 4 cells/well) and HEK-Blue-hTL R 9 cells (1.5×10 4 cells/well) into a 384-well cell culture plate. Well volume is 30 µL. Place in a 37°C, 5% CO2 incubator for 4 hours.

2、將化合物用DM SO配製，用DMEM培養基稀釋10個濃度 (1:3稀釋)，終濃度分別為10000，3333.3，1111.1，370.4，123.5，41.2，13.7，4.6，1.5，0.5 nM； R848使用DM SO配製，用DMEM培養基稀釋，終濃度為0.8 μM(HEK-Blue-hTL R7)、3 μM(HEK-Blue-hTL R8)；ODN2006使用無內毒素水配製，用DMEM培養基稀釋，終濃度為1 μM。 2. Prepare the compound with DMSO and dilute it to 10 concentrations (1:3 dilution) with DMEM medium. The final concentrations are 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, 1.5, 0.5 nM respectively; R 848 is prepared with DM S O and diluted with DMEM medium. The final concentration is 0.8 μM (HEK-Blue-hTL R 7) and 3 μM (HEK-Blue-hTL R 8); ODN2006 is prepared with endotoxin-free water and used DMEM medium. Dilute to a final concentration of 1 μM.

3、以DM SO處理的細胞為空白對照組，同時設立單獨用 Re Siquimod ( R848)處理的細胞為HEK-Blue-hTL R7/8的陽性對照組，單獨用ODN2006處理的細胞為HEK-Blue-hTL R9的陽性對照組。以受試化合物與 R848或ODN2006處理的細胞為測試組。每組設2個平行孔，放入置於37 °C，5% CO 2培養箱培養。 3. Use DMSO- treated cells as the blank control group, and set up cells treated with R e S iquimod ( R 848) alone as the positive control group of HEK-Blue-hTL R 7/8, and cells treated with ODN2006 alone. It is the positive control group of HEK-Blue-hTL R 9. Cells treated with the test compound and R 848 or ODN2006 were used as the test group. Set up 2 parallel wells in each group and place them in a 37°C, 5% CO2 incubator for culture.

4、培養4 h後，從培養箱中取出HEK-Blue-hTL R7/8的384孔盤，每孔單獨加入 R848或者同時加入 R848和稀釋後的化合物。置於37 °C，5% CO 2培養箱培養16 h；從培養箱中取出HEK-Blue-hTL R9的384孔盤，每孔單獨加入ODN2006或者同時加入ODN2006和稀釋後的化合物。置於37 °C，5% CO 2培養箱培養16 h。 4. After 4 hours of culture, take out the 384-well plate of HEK-Blue-hTL R 7/8 from the incubator, and add R 848 to each well alone or add R 848 and the diluted compound at the same time. Place it in a 37 °C, 5% CO 2 incubator for 16 hours; take out the 384-well plate of HEK-Blue-hTL R 9 from the incubator, and add ODN2006 to each well alone or add ODN2006 and the diluted compound at the same time. Place in a 37°C, 5% CO2 incubator for 16 h.

5、培養16 h後，從培養箱中取出384孔盤，1000 Rpm離心1分鐘，使用多功能微量盤檢測儀讀取每個孔在620nm處的吸光值。 5. After 16 hours of culture, take out the 384-well plate from the incubator, centrifuge at 1000 Rpm for 1 minute, and use a multifunctional microplate detector to read the absorbance value of each well at 620 nm.

6、計算細胞抑制率 = (1-(OD620測試組-OD620空白組)/(OD620陽性組-OD620空白組))×100%，通過曲線模擬計算半抑制濃度 (half maximal inhibitory concentration，IC 50)。 表1：本發明化合物在HEK-Blue-hTLR7/8/9細胞測定中的活性 化合物 TLR7 IC 50(nM) TLR8 IC 50(nM) TLR9 IC 50(nM) 化合物1 ＜10 ＜10 ＞5000 化合物2 ＜100 ＜100 ＞10000 化合物3 ＜10 ＜10 ＞1000 化合物4 ＜10 ＜10 ＞1000 化合物5 ＜10 ＜10 ＞1000 化合物6 ＜10 ＜10 ＞1000 化合物7 ＜10 ＜20 ＞1000 化合物8 ＜10 ＜10 ＞1000 化合物9 ＜10 ＜10 ＞1000 化合物10 ＜10 ＜10 ＞1000 化合物11 ＜100 - ＞10000 化合物12 ＜10 ＜10 ＞1000 化合物13 ＜10 ＜10 ＞1000 6. Calculate the cell inhibition rate = (1-(OD620 test group-OD620 blank group)/(OD620 positive group-OD620 blank group)) × 100%, and calculate the half max inhibitory concentration (IC 50 ) through curve simulation. . Table 1: Activity of compounds of the present invention in HEK-Blue-hTLR7/8/9 cell assay compound TLR7 IC 50 (nM) TLR8 IC 50 (nM) TLR9 IC 50 (nM) Compound 1 <10 <10 ＞5000 Compound 2 <100 <100 ＞10000 Compound 3 <10 <10 >1000 Compound 4 <10 <10 >1000 Compound 5 <10 <10 >1000 Compound 6 <10 <10 >1000 Compound 7 <10 <20 >1000 Compound 8 <10 <10 >1000 Compound 9 <10 <10 >1000 Compound 10 <10 <10 >1000 Compound 11 <100 - ＞10000 Compound 12 <10 <10 >1000 Compound 13 <10 <10 >1000

結論：本發明化合物對HEK-Blue-hTL R7/8細胞拮抗活性IC50小於100nM，有明顯拮抗作用，同時對HEK-Blue-hTL R9細胞無明顯拮抗作用。 Conclusion: The compound of the present invention has an antagonistic activity IC50 of less than 100 nM on HEK-Blue-hTL R 7/8 cells and has obvious antagonistic effect. At the same time, it has no obvious antagonistic effect on HEK-Blue-hTL R 9 cells.

IL-6的體內抑制實驗 實驗材料：化合物溶液的配製：R848用純水配製 (滅菌)，最終濃度25µg/100µL；受試化合物用pH=3的檸檬酸鈉緩衝液配製，最終濃度0.1 mg/mL。 實驗動物：C57BL/6雌鼠，購自集萃藥康，6-8周齡。 實驗方法：C57BL/6雌鼠隨機分為空白組、對照組和實驗組，每組8隻。 空白組：小鼠禁食12 h後取血。 對照組：小鼠禁食12 h後灌胃PH=3的檸檬酸鈉緩衝液，其餘操作與實驗組一致； 實驗組：小鼠禁食12 h後灌胃給予受試化合物 (1 mg/kg)，1 h後腹腔注射25 µg R848 (購自MCE)，2 h後摘眼球取血，血清室溫靜置30 min，接著離心10 min (3000 rpm)，取上清液，用IL-6 ELISA試劑盒測量血清IL-6濃度，通過對照組和實驗組IL-6血清濃度，計算IL-6抑制率。計算公式：抑制率=(C2-C3)/(C2-C1)×100%。 C1：空白組血清IL-6濃度； C2: 對照組血清IL-6濃度； C3: 實驗組血清IL-6濃度。 In vivo inhibition assay of IL-6 Experimental materials: Preparation of compound solution: R848 is prepared with pure water (sterilized), with a final concentration of 25µg/100µL; the test compound is prepared with sodium citrate buffer at pH=3, with a final concentration of 0.1 mg/mL. Experimental animals: C57BL/6 female mice, purchased from Jicui Yaokang, 6-8 weeks old. Experimental method: C57BL/6 female mice were randomly divided into blank group, control group and experimental group, with 8 mice in each group. Blank group: mice were fasted for 12 hours and then blood was collected. Control group: The mice were fasted for 12 hours and then intragastrically administered sodium citrate buffer with pH=3. The other operations were consistent with the experimental group; Experimental group: After fasting for 12 hours, the mice were intragastrically administered the test compound (1 mg/kg). 1 hour later, they were intraperitoneally injected with 25 µg R848 (purchased from MCE). After 2 hours, the eyeballs were removed to collect blood. The serum was left at room temperature. 30 min, then centrifuge for 10 min (3000 rpm), take the supernatant, and use the IL-6 ELISA kit to measure the serum IL-6 concentration. Calculate the IL-6 inhibition rate based on the IL-6 serum concentration of the control group and the experimental group. Calculation formula: Inhibition rate = (C2-C3)/(C2-C1)×100%. C1: Serum IL-6 concentration in blank group; C2: Serum IL-6 concentration in control group; C3: Serum IL-6 concentration in the experimental group.

按照上述實驗步驟再分別進行四組實驗，四組實驗與上述實驗的區別分別在於：「4h後腹腔注射25 µg R848 (購自MCE)」、「8h後腹腔注射25 µg R848 (購自MCE)」、「16h後腹腔注射25 µg R848 (購自MCE)」、「24h後腹腔注射25 µg R848 (購自MCE)」。 表2：IL-6的體內抑制實驗 化合物 IL-6抑制率(1h後腹腔注射) 化合物1 96% 化合物2 95% 化合物3 97% 化合物4 86% 化合物5 97% 化合物6 98% 化合物7 96% 化合物13 99% 化合物14 88% 化合物15 99% 化合物16 96% Follow the above experimental steps and conduct four groups of experiments respectively. The differences between the four groups of experiments and the above experiments are: "Intraperitoneal injection of 25 µg R848 (purchased from MCE) after 4 hours", "Intraperitoneal injection of 25 µg R848 (purchased from MCE) after 8 hours" ”, “Intraperitoneal injection of 25 µg R848 (purchased from MCE) after 16 hours”, “Intraperitoneal injection of 25 µg R848 (purchased from MCE) after 24 hours”. Table 2: In vivo inhibition experiment of IL-6 compound IL-6 inhibition rate (intraperitoneal injection after 1 hour) Compound 1 96% Compound 2 95% Compound 3 97% Compound 4 86% Compound 5 97% Compound 6 98% Compound 7 96% Compound 13 99% Compound 14 88% Compound 15 99% Compound 16 96%

結論：本發明化合物對IL-6有明顯的抑制作用，且在不同的實驗方案中(不同腹腔注射時間點)，測試結果均表明本發明化合物對IL-6有良好的抑制作用。Conclusion: The compound of the present invention has a significant inhibitory effect on IL-6, and in different experimental protocols (different intraperitoneal injection time points), the test results show that the compound of the present invention has a good inhibitory effect on IL-6.

犬藥物代謝動力學測定Canine Pharmacokinetics Assay

實驗方案： (1)健康雄性比格犬 (購自成都達碩實驗動物有限公司，6-8kg)，每個化合物6隻犬，分成2組(iv和po組，每組3隻)。 (2) 禁食過夜 (自由飲水)後，以10% DMSO、90%的 30% HP-β-CD (v: v)為iv溶媒，0.5% MC作為po溶媒對本發明化合物進行溶解(或形成混懸液)。分別經靜脈(iv，1 mg/kg)、灌胃(po，3mg/kg)給藥。 (3) iv組分別於給藥後 5min、15 min、0.5h、1h、2h、4h、8h、12h、24h 由前肢靜脈採血0.5mL，由EDTA-K 2抗凝，4℃離心 5min 分離血漿，於-20℃保存待測。po組分別於給藥前及給藥後15min、0.5h、1h、2h、4h、6h、8h、12h、24h由前肢靜脈採血0.5 mL，處理方法同靜脈組。 (4) 採用LC-MS/MS 法測定血漿的本發明化合物的濃度。 (5) 使用Certara公司的 WinNonlin軟體進行結果計算和模擬。 Experimental protocol: (1) Healthy male beagle dogs (purchased from Chengdu Dashuo Experimental Animal Co., Ltd., 6-8kg), 6 dogs for each compound, divided into 2 groups (IV and PO groups, 3 dogs in each group). (2) After fasting overnight (free drinking water), use 10% DMSO, 90% of 30% HP-β-CD (v: v) as the iv solvent, and 0.5% MC as the po solvent to dissolve (or form suspension). It was administered via intravenous (iv, 1 mg/kg) and intragastric administration (po, 3 mg/kg) respectively. (3) In the iv group, 0.5 mL of blood was collected from the forelimb vein at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h after administration, anticoagulated with EDTA-K 2 , and centrifuged at 4°C for 5 min to separate the plasma. , stored at -20°C until testing. In the po group, 0.5 mL of blood was collected from the forelimb vein before administration and at 15min, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration. The processing method was the same as that of the intravenous group. (4) Determine the concentration of the compound of the present invention in plasma using LC-MS/MS method. (5) Use Certara's WinNonlin software for result calculation and simulation.

結果表明，本申請的化合物具有良好的藥物代謝動力學特性。The results show that the compound of the present application has good pharmacokinetic properties.

小鼠藥物代謝動力學測定Mouse pharmacokinetic assay

實驗方案： (1) 準備健康雄性ICR 小鼠 (購自北京維通利華實驗動物技術有限公司，18-22g)，每個化合物用6隻，分成2組(iv和po組)，每組3隻，每個時間點對小鼠進行微量採血(50μL)。 (2) 禁食過夜 (自由飲水)後，以10% DMSO、90%的 30% HP-β-CD (v: v)為iv溶媒，0.5% MC作為po溶媒對本發明化合物進行溶解 (或形成混懸液)。分別經靜脈 (iv，1 mg/kg)、灌胃(po，10mg/kg)給藥。 (3) iv組分別於給藥後 5min、15 min、0.5h、1h、2h、4h、8h、12h、24h 由眼眶採血，由EDTA-K 2抗凝，4℃離心5min 分離血漿，於-20℃保存待測。po組分別於給藥前及給藥後15min、0.5h、1h、2h、4h、6h、8h、12h、24h由眼眶採血，處理方法同靜脈給藥組。 (4) 採用LC-MS/MS 法測定血漿中本發明化合物的濃度。 (5) 使用Certara公司的 WinNonlin軟體進行結果計算和模擬。 Experimental protocol: (1) Prepare healthy male ICR mice (purchased from Beijing Vitong Lihua Experimental Animal Technology Co., Ltd., 18-22g), use 6 mice for each compound, and divide them into 2 groups (iv and po groups), 3 in each group Only, microblood collection (50 μL) was performed on mice at each time point. (2) After fasting overnight (free drinking water), use 10% DMSO, 90% of 30% HP-β-CD (v: v) as the iv solvent, and 0.5% MC as the po solvent to dissolve (or form suspension). It was administered via intravenous (iv, 1 mg/kg) and intragastric administration (po, 10 mg/kg) respectively. (3) In the iv group, blood was collected from the orbit at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h after administration, anticoagulated with EDTA-K 2 , and centrifuged at 4°C for 5 min to separate the plasma. Store at 20°C until testing. In the po group, blood was collected from the orbit before administration and at 15min, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration. The treatment methods were the same as those in the intravenous administration group. (4) Determine the concentration of the compound of the present invention in plasma using LC-MS/MS method. (5) Use Certara's WinNonlin software for result calculation and simulation.

結果表明，本申請的化合物具有良好的藥物代謝動力學特性。The results show that the compound of the present application has good pharmacokinetic properties.

大鼠藥物代謝動力學測定Rat pharmacokinetics assay

實驗方案： (1) 準備健康雄性SD大鼠 (購自北京維通利華實驗動物技術有限公司，190-220g)，每個化合物用6 隻，分成2組(iv和po組)，每組3隻，每個時間點對大鼠進行微量採血(100μL)。 (2) 禁食過夜 (自由飲水)後，以10% DMSO、90%的 30% HP-β-CD (v: v)為iv溶媒，0.5% MC作為po溶媒對本發明化合物進行溶解 (或形成混懸液)。分別經靜脈 (iv，1 mg/kg)、灌胃(po，5mg/kg)給藥。 (3) iv組分別於給藥後 5min、15 min、0.5h、1h、2h、4h、8h、12h、24h 由頸靜脈採血，由EDTA-K 2抗凝，4℃離心5min 分離血漿，於-20℃保存待測。po組分別於給藥前及給藥後15min、0.5h、1h、2h、4h、6h、8h、12h、24h由頸靜脈採血，處理方法同靜脈組。 (4) 採用LC-MS/MS 法測定血漿中本發明化合物的濃度。 (5) 使用Certara公司的 WinNonlin軟體進行結果計算和模擬。 Experimental protocol: (1) Prepare healthy male SD rats (purchased from Beijing Vitong Lihua Experimental Animal Technology Co., Ltd., 190-220g), use 6 rats for each compound, and divide them into 2 groups (IV and PO groups), each group has 3 rats. Only, micro-volume blood collection (100 μL) was performed on rats at each time point. (2) After fasting overnight (free drinking water), use 10% DMSO, 90% of 30% HP-β-CD (v: v) as the iv solvent, and 0.5% MC as the po solvent to dissolve (or form suspension). Administer via intravenous (iv, 1 mg/kg) and intragastric administration (po, 5 mg/kg) respectively. (3) In the iv group, blood was collected from the jugular vein at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h after administration, anticoagulated with EDTA-K 2 , and centrifuged at 4°C for 5 min to separate the plasma. Store at -20℃ until testing. In the po group, blood was collected from the jugular vein before administration and at 15min, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration, and the treatment methods were the same as those in the intravenous group. (4) Determine the concentration of the compound of the present invention in plasma using LC-MS/MS method. (5) Use Certara's WinNonlin software for result calculation and simulation.

結果表明，本申請的化合物具有良好的藥物代謝動力學特性。The results show that the compound of the present application has good pharmacokinetic properties.

化合物抑制PBMC釋放IL6Compounds inhibit IL6 release from PBMCs

獲取健康志願者捐獻的10ml 新鮮抗凝血，恢復至室溫。取一離心管加入等體積PBS，向管內加入血液，輕輕混勻。在另一離心管中加入10mL細胞分離液(HISTOPAQUE®-1077，SIGMA)，將血液混合液加入分離液之上；隨後室溫下400g離心30分鐘。將第二層環狀乳白色淋巴細胞層倒到一支含10ml PBS(含0.3% FBS)的新離心管中。4℃，250g，離心10min；棄上清液；重複兩次。用RPMI 1640培養基(含10% FBS，1% PS)重懸浮hPBMC，置於37℃、5% CO 2細胞培養箱中培養過夜。第二天1000 rpm離心5min去掉舊培養基，加入2 mL新鮮培養基重懸浮計數。鋪96孔盤，10 5個/孔，每孔80μL。每孔加入10 μL梯度稀釋的化合物，10 μM起始，1:5稀釋。1h後，每孔加入10 μL 10 μM R848刺激TLR7/8。繼續培養過夜後，1500 rpm離心檢測盤2 min，收集上清液。用Elisa方法(IL-6 human Uncoated ELISA Kit，Thermofisher)檢測上清液中IL-6表達。檢測分析結果如表3所示： 表3：化合物抑制PBMC釋放IL6結果 化合物 IC 50(nM) 化合物1 72.23 M5049 199 Obtain 10 ml of fresh anticoagulated blood donated by healthy volunteers and return to room temperature. Take a centrifuge tube and add an equal volume of PBS, add blood into the tube and mix gently. Add 10 mL of cell separation solution (HISTOPAQUE®-1077, SIGMA) to another centrifuge tube, and add the blood mixture on top of the separation solution; then centrifuge at 400 g for 30 minutes at room temperature. Pour the second layer of ring-shaped milky white lymphocytes into a new centrifuge tube containing 10 ml PBS (containing 0.3% FBS). Centrifuge at 250g for 10 minutes at 4°C; discard the supernatant; repeat twice. Resuspend hPBMC in RPMI 1640 medium (containing 10% FBS, 1% PS) and culture in a 37°C, 5% CO2 cell culture incubator overnight. The next day, centrifuge at 1000 rpm for 5 minutes to remove the old culture medium, and add 2 mL of fresh culture medium to resuspend and count. Plate a 96-well plate, 10 5 cells/well, 80 μL per well. Add 10 μL of gradient diluted compound to each well, starting at 10 μM and diluting 1:5. After 1 hour, 10 μL of 10 μM R848 was added to each well to stimulate TLR7/8. After continuing to culture overnight, centrifuge the detection plate at 1500 rpm for 2 minutes and collect the supernatant. Elisa method (IL-6 human Uncoated ELISA Kit, Thermofisher) was used to detect IL-6 expression in the supernatant. The detection and analysis results are shown in Table 3: Table 3: Results of compounds inhibiting the release of IL6 from PBMC compound IC 50 (nM) Compound 1 72.23 M5049 199

結果表明：本申請化合物對IL6的釋放有良好的抑制作用。The results show that the compound of the present application has a good inhibitory effect on the release of IL6.

化合物抑制PBMC釋放TNFαCompounds inhibit TNFα release from PBMCs

獲取健康志願者捐獻的10ml 新鮮抗凝血，恢復至室溫。取一離心管加入等體積PBS，向管內加入血液，輕輕混勻。在另一離心管中加入10mL細胞分離液(HISTOPAQUE®-1077，SIGMA)，將血液混合液加入分離液之上；隨後室溫下400g離心30分鐘。將第二層環狀乳白色淋巴細胞層倒到一支含10ml PBS(含0.3% FBS)的新離心管中。4℃，250g，離心10min；棄上清液；重複兩次。用RPMI 1640培養基(含10% FBS，1% PS)重懸浮hPBMC，置於37℃、5% CO 2細胞培養箱中培養過夜。第二天1000 rpm離心5min去掉舊培養基，加入2 mL新鮮培養基重懸浮計數。鋪96孔盤，10 5個/孔，每孔80μL。每孔加入10 μL梯度稀釋的化合物，10 μM起始，1:5稀釋。1h後，每孔加入10 μL 10 μM R848刺激TLR7/8。繼續培養過夜後，1500 rpm離心檢測盤2 min，收集上清液。用Elisa檢測試劑盒(BD OptELA TMSet Human TNF,BD)檢測上清液中TNF-α表達。檢測分析結果如下表4所示： 表4：化合物抑制PBMC釋放TNFα結果 化合物  IC 50(nM) 化合物1 20.0 M5049 62.8 Obtain 10 ml of fresh anticoagulated blood donated by healthy volunteers and return to room temperature. Take a centrifuge tube and add an equal volume of PBS, add blood into the tube and mix gently. Add 10 mL of cell separation solution (HISTOPAQUE®-1077, SIGMA) to another centrifuge tube, and add the blood mixture on top of the separation solution; then centrifuge at 400 g for 30 minutes at room temperature. Pour the second layer of ring-shaped milky white lymphocytes into a new centrifuge tube containing 10 ml PBS (containing 0.3% FBS). Centrifuge at 250g for 10 minutes at 4°C; discard the supernatant; repeat twice. Resuspend hPBMC in RPMI 1640 medium (containing 10% FBS, 1% PS) and culture in a 37°C, 5% CO2 cell culture incubator overnight. The next day, centrifuge at 1000 rpm for 5 minutes to remove the old culture medium, and add 2 mL of fresh culture medium to resuspend and count. Plate a 96-well plate, 10 5 cells/well, 80 μL per well. Add 10 μL of gradient diluted compound to each well, starting at 10 μM and diluting 1:5. After 1 hour, 10 μL of 10 μM R848 was added to each well to stimulate TLR7/8. After continuing to culture overnight, centrifuge the detection plate at 1500 rpm for 2 minutes and collect the supernatant. Elisa detection kit (BD OptELA TM Set Human TNF, BD) was used to detect TNF-α expression in the supernatant. The detection and analysis results are shown in Table 4 below: Table 4: Results of compounds inhibiting the release of TNFα from PBMC compound IC 50 (nM) Compound 1 20.0 M5049 62.8

結果表明：本申請化合物對TNFα的釋放有良好的抑制作用。The results show that the compound of the present application has a good inhibitory effect on the release of TNFα.

本發明說明書對具體實施方案進行了詳細描述，本領域技術人員應認識到，上述實施方案是例示性的，不能理解為對本發明的限制，對於所屬技術領域的通常知識者來說，在不脫離本發明原理的前提下，通過對本發明進行若干改進和修飾，這些改進和修飾獲得技術方案也落在本發明的請求項的保護範圍內。The specification of the present invention describes specific embodiments in detail. Those skilled in the art should realize that the above embodiments are illustrative and cannot be construed as limitations of the present invention. For those of ordinary skill in the technical field, without departing from the On the premise of the principles of the present invention, several improvements and modifications are made to the present invention, and the technical solutions obtained through these improvements and modifications also fall within the protection scope of the claims of the present invention.

無without

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Claims (16)

通式(I-0)所示的化合物，其所有的立體異構物、藥學上可接受的鹽或者氘代物： (I-0) 其中： R 1為 ； A為C 6-12芳基或5至12元雜芳基，5至12元雜芳基包含1、2、3或4個獨立地選自O、N和S的雜原子； B為C 3-10環烷基或3至10元雜環烷基，所述3至10元雜環烷基包含1、2、3或4個獨立地選自O、N和S的雜原子； R 4選自H、D、鹵素、C 1-6烷基或C 3-6環烷基，所述C 1-6烷基或C 3-6環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 5選自H、D、鹵素、C 1-6烷基或C 3-6環烷基，所述C 1-6烷基或C 3-6環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 2選自C 1-6烷基，所述烷基任選地進一步被1至多個鹵素取代； R 3選自 、 、 、 、 、 、 、 、 、 ； m為0、1、2或者3； n為0、1、2、3或者4。 Compounds represented by general formula (I-0), all stereoisomers, pharmaceutically acceptable salts or deuterated products thereof: (I-0) where: R 1 is ; A is C 6-12 aryl or 5 to 12 membered heteroaryl, and the 5 to 12 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; B is C R 4 Selected from H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, the C 1-6 alkyl or C 3-6 cycloalkyl is further substituted by 1 to more substituents selected from the following : H, D, halogen or C 3-6 cycloalkyl; R 5 is selected from H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, the C 1-6 alkyl or C 3-6 cycloalkyl is further substituted by 1 to more substituents selected from: H, D, halogen or C 3-6 cycloalkyl; R 2 is selected from C 1-6 alkyl, the alkyl is optionally further substituted by 1 to more halogens; R 3 is selected from , , , , , , , , , ; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4. 如請求項1所述之化合物或者其立體異構物、藥學上可接受的鹽或氘代物，其中： R 4選自H或D。 The compound of claim 1 or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein: R 4 is selected from H or D. 如請求項1所述之化合物或者其立體異構物、藥學上可接受的鹽或氘代物，其中： R 3進一步被H、D、鹵素、C 1-6烷基或C 3-6環烷基中的一個或多個取代，所述C 1-6烷基或C 3-6環烷基進一步被1至多個選自以下的取代基取代：H、D、鹵素或C 3-6環烷基。 The compound as described in claim 1 or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein: R 3 is further replaced by H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl One or more substituted groups, the C 1-6 alkyl or C 3-6 cycloalkyl group is further substituted by 1 to more substituents selected from the following: H, D, halogen or C 3-6 cycloalkyl base. 如請求項2所述之化合物或者其立體異構物、藥學上可接受的鹽或氘代物，其中： A為5至12元雜芳基，5至12元雜芳基包含1-3個獨立地選自O、N和S的雜原子； B為3至10元雜環烷基，3至10元雜環烷基包含1或2個獨立地選自O、N和S的雜原子。 The compound described in claim 2 or its stereoisomer, pharmaceutically acceptable salt or deuterated product, wherein: A is a 5- to 12-membered heteroaryl group, and the 5- to 12-membered heteroaryl group contains 1-3 heteroatoms independently selected from O, N and S; B is a 3- to 10-membered heterocycloalkyl group, and the 3- to 10-membered heterocycloalkyl group contains 1 or 2 heteroatoms independently selected from O, N, and S. 如請求項2所述之化合物或者其立體異構物、藥學上可接受的鹽或氘代物，所述化合物或者其立體異構物，藥學上可接受的鹽或氘代物具有式(I)所示的結構： (I) 其中： R 1選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 ； R 2選自CF 3。 The compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product as described in claim 2, said compound or its stereoisomer, pharmaceutically acceptable salt or deuterated product having the formula (I) The structure shown: (I) where: R 1 is selected from , , , , , , , , , , , , , , , , , , , , or ; R 2 is selected from CF 3 . 如請求項1至5中任一項所述之化合物、其所有的立體異構物、藥學上可接受的鹽或氘代物，所述化合物為以下結構之一： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 The compound described in any one of claims 1 to 5, all stereoisomers, pharmaceutically acceptable salts or deuterated products thereof, said compound is one of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . 一種藥物組合物，所述藥物組合物包括： 請求項1至6所述的化合物、其所有的立體異構物、藥學上可接受的鹽或氘代物； 任選的一種或者多種其他活性成分；以及 藥學上可接受的載體和/或賦形劑。 A pharmaceutical composition comprising: The compounds described in claims 1 to 6, all stereoisomers, pharmaceutically acceptable salts or deuterated products thereof; optionally one or more other active ingredients; and Pharmaceutically acceptable carriers and/or excipients. 請求項1至6所述的化合物、其所有的立體異構物、藥學上可接受的鹽或氘代物、請求項7所述的藥物組合物在製備自體免疫疾病藥物中的用途。 Use of the compounds described in claims 1 to 6, all stereoisomers, pharmaceutically acceptable salts or deuterated products thereof, and the pharmaceutical composition described in claim 7 in the preparation of drugs for autoimmune diseases. 一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中，所述的中間體選自通式(I-A)所示的化合物： (I-A) R 1為H、Boc、或者 ； B為C 3-10環烷基或3至10元雜環烷基，3至10元雜環烷基包含1、2、3或4個獨立地選自O、N和S的雜原子； R 5選自Boc、H、D、鹵素、C 1-6烷基或C 3-10環烷基，所述C 1-6烷基或C 3-10環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 2選自C 1-6烷基，所述烷基任選地進一步被1至多個鹵素取代； R 3選自H、 、 、 、 、 、 、 、 、 、 或者胺基保護基，優選地所述胺基保護基為： 、Bn、Cbz、Boc、Fmoc、Tos、 Alloc、Tfa、Dmb或PMB； n為0、1、2、3或者4。 An intermediate for preparing a compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterate, pharmaceutically acceptable salt or co-crystal, wherein, The above-mentioned intermediate is selected from the compounds represented by the general formula (IA): (IA) R 1 is H, Boc, or ; B is C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl, and the 3 to 10 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; R 5 is selected from Boc, H, D, halogen, C 1-6 alkyl or C 3-10 cycloalkyl, and the C 1-6 alkyl or C 3-10 cycloalkyl is further selected from 1 to more The following substituents are substituted: H, D, halogen or C 3-6 cycloalkyl; R 2 is selected from C 1-6 alkyl, the alkyl is optionally further substituted by 1 to more halogens; R 3 is selected from H , , , , , , , , , , Or an amino protecting group, preferably the amino protecting group is: , Bn, Cbz, Boc, Fmoc, Tos, Alloc, Tfa, Dmb or PMB; n is 0, 1, 2, 3 or 4. 如請求項9所述的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中，所述中間體選自以下結構之一： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。 The intermediate as described in claim 9, or its stereoisomer, solvate, metabolite, prodrug, deuterate, pharmaceutically acceptable salt or co-crystal, wherein the intermediate is selected from the following structures one: , , , , , , , , , , , , , , or . 一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中，所述中間體選自通式(I-B)所示的化合物： (I-B) R 1為 ； B為C 3-10環烷基或3至10元雜環烷基，3至10元雜環烷基包含1、2、3或4個獨立地選自O、N和S的雜原子； R 5選自H、D、鹵素、C 1-6烷基或C 3-6環烷基，所述C 1-6烷基或C 3-6環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 2選自C 1-6烷基，所述烷基任選地進一步被1至多個鹵素取代； R 3選自H、 、 、 、 、 、 、 、 、 、 或胺基保護基，優選地所述胺基保護基為： 、Cbz、Boc、Fmoc、Tos、 Alloc、Tfa、Dmb或PMB； n為0、1、2、3或者4。 An intermediate for preparing a compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterate, pharmaceutically acceptable salt or co-crystal, wherein, The intermediates are selected from compounds represented by general formula (IB): (IB) R 1 is ; B is C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl, and the 3 to 10 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; R 5 is selected from H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, the C 1-6 alkyl or C 3-6 cycloalkyl is further substituted by 1 to more selected from the following Base substitution: H, D, halogen or C 3-6 cycloalkyl; R 2 is selected from C 1-6 alkyl, the alkyl is optionally further substituted by 1 to more halogens; R 3 is selected from H, , , , , , , , , , Or an amino protecting group, preferably the amino protecting group is: , Cbz, Boc, Fmoc, Tos, Alloc, Tfa, Dmb or PMB; n is 0, 1, 2, 3 or 4. 如請求項11所述的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中，所述中間體選自以下結構： The intermediate as described in claim 11, or its stereoisomer, solvate, metabolite, prodrug, deuterate, pharmaceutically acceptable salt or co-crystal, wherein the intermediate is selected from the following structures: 一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中，所述中間體選自通式(I-C)所示的化合物： (I-C) R 1為 ； A為C 6-12芳基或5至12元雜芳基，5至12元雜芳基包含1、2、3或4個獨立地選自O、N和S的雜原子； B為3至10元雜環烷基，所述3至10元雜環烷基包含1、2、3或4個獨立地選自O、N和S的雜原子； R 4選自H或D； R 5選自H、D、鹵素、C 1-6烷基或C 3-6環烷基，所述C 1-6烷基或C 3-6環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 6為胺基保護基，優選地所述胺基保護基為：Cbz、Boc、Fmoc、Tos、Alloc、Tfa、Dmb或PMB； R 2選自C 1-6烷基，所述烷基任選地進一步被1至多個鹵素取代； R 3選自H、 、 、 、 、 、 、 、 、 、 、胺基保護基，優選地所述胺基保護基為： 、Bn、Cbz、Boc、Fmoc、 Tos、Alloc、Tfa、Dmb或PMB； m為0、1、2或者3； n為0、1、2、3或者4。 An intermediate for preparing a compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterate, pharmaceutically acceptable salt or co-crystal, wherein, The above-mentioned intermediate is selected from the compounds represented by the general formula (IC): (IC) R 1 is ; A is C 6-12 aryl or 5 to 12 membered heteroaryl, and the 5 to 12 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; B is 3 To a 10-membered heterocycloalkyl group, the 3 to 10-membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; R 4 is selected from H or D; R 5 Selected from H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, the C 1-6 alkyl or C 3-6 cycloalkyl is further substituted by 1 to more substituents selected from the following : H, D, halogen or C 3-6 cycloalkyl; R 6 is an amino protecting group, preferably the amino protecting group is: Cbz, Boc, Fmoc, Tos, Alloc, Tfa, Dmb or PMB; R 2 is selected from C 1-6 alkyl, which is optionally further substituted by 1 to more halogens; R 3 is selected from H, , , , , , , , , , , amino protecting group, preferably the amino protecting group is: , Bn, Cbz, Boc, Fmoc, Tos, Alloc, Tfa, Dmb or PMB; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4. 如請求項13所述的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中，所述中間體選自以下結構： 、 或 。 The intermediate as described in claim 13, or its stereoisomer, solvate, metabolite, prodrug, deuterate, pharmaceutically acceptable salt or co-crystal, wherein the intermediate is selected from the following structures: , or . 一種製備通式(I-0)或(I)化合物的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中，所述中間體選自通式(I-D)所示的化合物： (I-D) 其中： R 1為 ； A為C 6-12芳基或5至12元雜芳基，所述5至12元雜芳基包含1、2、3或4個獨立地選自O、N和S的雜原子； B為C 3-10環烷基或3至10元雜環烷基，所述3至10元雜環烷基包含1、2、3或4個獨立地選自O、N和S的雜原子； R 4選自H或D； R 5選自H、D、鹵素、C 1-6烷基或C 3-6環烷基，所述C 1-6烷基或C 3-6環烷基進一步被1至多個選自以下取代基取代：H、D、鹵素或C 3-6環烷基； R 2選自C 1-6烷基，所述烷基任選地進一步被1至多個鹵素取代； R 3選自H或胺基保護基，優選地所述胺基保護基為： 、Cbz、 Bn、Boc、Fmoc、Tos、Alloc、Tfa、Dmb或PMB； m為0、1、2或者3； n為0、1、2、3或者4。 An intermediate for preparing a compound of general formula (I-0) or (I), or its stereoisomer, solvate, metabolite, prodrug, deuterate, pharmaceutically acceptable salt or co-crystal, wherein, The intermediates are selected from compounds represented by the general formula (ID): (ID) where: R 1 is ; A is a C 6-12 aryl group or a 5- to 12-membered heteroaryl group, and the 5- to 12-membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; B Is C 3-10 cycloalkyl or 3 to 10 membered heterocycloalkyl, the 3 to 10 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from O, N and S; R 4 is selected from H or D; R 5 is selected from H, D, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, the C 1-6 alkyl or C 3-6 cycloalkyl further Substituted by 1 to more substituents selected from the following: H, D, halogen or C 3-6 cycloalkyl; R 2 is selected from C 1-6 alkyl, the alkyl is optionally further substituted by 1 to more halogens ; R 3 is selected from H or an amino protecting group. Preferably, the amino protecting group is: , Cbz, Bn, Boc, Fmoc, Tos, Alloc, Tfa, Dmb or PMB; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4. 如請求項15所述的中間體，或者其立體異構物、溶劑化物、代謝產物、前藥、氘代物、藥學上可接受的鹽或共晶，其中，所述中間體選自以下結構： 、 、 、 、 或者 。 The intermediate as described in claim 15, or its stereoisomer, solvate, metabolite, prodrug, deuterate, pharmaceutically acceptable salt or co-crystal, wherein the intermediate is selected from the following structures: , , , , or .
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