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WO2022194237A1 - Quinoline derivative and application thereof in preparation of autoimmune drug - Google Patents

Quinoline derivative and application thereof in preparation of autoimmune drug Download PDF

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Publication number
WO2022194237A1
WO2022194237A1 PCT/CN2022/081400 CN2022081400W WO2022194237A1 WO 2022194237 A1 WO2022194237 A1 WO 2022194237A1 CN 2022081400 W CN2022081400 W CN 2022081400W WO 2022194237 A1 WO2022194237 A1 WO 2022194237A1
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Prior art keywords
azabicyclo
mmol
trifluoromethyl
hexane
cyanoquinolin
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Ceased
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PCT/CN2022/081400
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French (fr)
Chinese (zh)
Inventor
袁永海
魏用刚
楚洪柱
李强
卞红丽
孙毅
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Chengdu Baiyu Pharmaceutical Co Ltd
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Chengdu Baiyu Pharmaceutical Co Ltd
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Publication of WO2022194237A1 publication Critical patent/WO2022194237A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to quinoline derivatives or their stereoisomers or pharmaceutically acceptable salts, and their application in medicine.
  • TLRs Toll-like receptors
  • PAMPs pathogen-associated molecular patterns
  • DAMPs damage-associated molecular patterns
  • TLRs belong to type I transmembrane proteins. So far, 13 members of the TLR family have been found, of which 10 are present in humans.
  • TLR1, TLR2, TLR4, TLR5, TLR6, TLR10 and TLR11 are located on the cell membrane and can recognize lipids of microorganisms , lipoprotein and other substances; while TLR3, TLR7, TLR8 and TLR9 are located in intracellular vesicle structures (such as lysosomes, endosomes and endoplasmic reticulum, etc.), and recognize nucleic acids of microorganisms.
  • TLR7 and TLR8 are the most similar in sequence and function, and numerous studies have shown that activation of TLR7/8 can trigger type I interferon responses and various inflammatory responses, and in the context of autoimmune disorders such as systemic lupus erythematosus (SLE), Abnormal persistent activation of TLR7/8 leads to exacerbation of disease state. Therefore, the development of compounds with selective and potent inhibitory activity to inhibit the over-activated immune response by antagonizing TLR7/8 is expected to be a new approach for the treatment of autoimmune diseases.
  • SLE systemic lupus erythematosus
  • R 1 is C 1-6 alkyl optionally further substituted with 1 or more halogens
  • R 2 is -CN or C 1-6 alkyl optionally further substituted with 1 or more halogens;
  • R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;
  • R a is -(R a1 ) m -(R a2 ) n , said R a is optionally further 1 or more selected from D, -OH, halogen, -NR b R c , C 1-6 alkanes base, C 1-6 alkoxy, D substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-10 cycloalkyl, C 3 Substituent substitution of -10 heterocycloalkyl and C 1-6 alkyl-C 3-10 cycloalkyl;
  • R a2 is H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, The C 1-6 alkyl group is optionally further substituted by 1 or more D;
  • R b and R c are each independently H or C 1-6 alkyl
  • n 1, 2 or 3;
  • n 0, 1, 2, 3 or 4.
  • X is C or N
  • R 1 is -CF 3 or -CH 3 ;
  • R 2 is -CN or -CF 3 ;
  • R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;
  • R a2 is H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, The C 1-6 alkyl group is optionally further substituted by 1 or more D;
  • R 1 is -CF 3 or -CH 3 ;
  • X is C or N
  • R 1 is -CF 3 or -CH 3 ;
  • X is C or N
  • R a is -NH 2 , -OH, piperidinyl, And R a is further optionally substituted with 1 to 2 C 1-6 alkyl groups.
  • R 2 is -CN or C 1-6 alkyl, and said C 1-6 alkyl is optionally further substituted by 1 or more halogens;
  • R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;
  • R a is -(R a1 ) m -(R a2 ) n ;
  • R a1 is each independently -O-, -NH-, -OCO-, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, The C 1-6 alkyl is optionally further substituted with 1 or more D;
  • R a2 is each independently H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycle alkyl, the C 1-6 alkyl is optionally further substituted with 1 or more D;
  • R b and R c are each independently H or C 1-6 alkyl
  • n 1, 2 or 3;
  • n 0, 1, 2, 3 or 4.
  • Ra is selected from -NH 2 , piperidinyl, and R a is optionally further substituted with 1 or 2 C 1-6 alkyl groups.
  • One or more embodiments of the present application provide a compound of general formula (II'), or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof:
  • R is selected from -COOH, -NH 2 , -CONH 2 or -COR a ;
  • R a is selected from -NH 2 or piperidinyl, and the piperidinyl is optionally further substituted with 1 to 2 selected from C 1-6 alkyl.
  • One or more embodiments of the present application provide the following compounds or stereoisomers, deuterated compounds or pharmaceutically acceptable salts thereof, wherein the compound is:
  • One or more embodiments of the present application provide the use of a compound of the present application or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application in the preparation of a medicament for the treatment of autoimmune diseases.
  • One or more embodiments of the present application provide a compound of the present application, or a stereoisomer, deuterated product or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, prepared for use in the treatment of TLR7, TLR8 or TLR9-related use in disease.
  • One or more embodiments of the present application provide the use of a compound of the present application or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application in the preparation of an IL-6 inhibitor.
  • One or more embodiments of the present application provide a compound of the present application, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, for use as a medicament.
  • One or more embodiments of the present application provide a compound of the present application, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, for use in the treatment of TLR7, TLR8 or TLR9-related disease.
  • One or more embodiments of the present application provide a compound of the present application, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, for use as an IL-6 inhibitor.
  • One or more embodiments of the present application provide a method of treating a disease associated with TLR7, TLR8 or TLR9, comprising adding a compound of the present application or a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof or a medicament of the present application
  • the composition is administered to a subject in need thereof.
  • One or more embodiments of the present application provide methods of inhibiting IL-6, comprising administering a compound of the present application, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application in need thereof Object.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy 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.
  • isotopes of carbon include 12 C, 13 C
  • Alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (eg 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms , more preferably an alkyl group of 1 to 6 carbon atoms, further preferably an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and Various branched chain isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.
  • Alkoxy refers to a group formed by substituting 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-pentoxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.
  • the definition of alkyl is the same as the definition of "alkyl" described above.
  • Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-2-yl En-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecene -3-base.
  • the alkenyl group may be optionally further substituted with one or more substituents.
  • Alkynyl means a carbon-carbon triple bond containing 1 to 10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Linear or branched unsaturated aliphatic hydrocarbon groups, preferably alkynyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably 2 An alkynyl group of to 8 carbon atoms, more preferably an alkynyl group of 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 , octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl.
  • the alkynyl group may optionally be further substituted with one or more substituents.
  • Heteroaryl refers to a substituted or unsubstituted aromatic ring, which may be a 3 to 8 membered (eg 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (eg 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (eg 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5- to 8-membered heteroaryl, 1 to 4 (eg 1, 2) optionally substituted in the ring of heteroaryl , 3, 4) N, S can be oxidized into various oxidation states.
  • N, S can be oxidized into various oxidation states.
  • Heteroaryl can be attached to a heteroatom or a carbon atom. Heteroaryl can be bridged or spiro, non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. Heteroaryl groups are optionally further substituted with one or more substituents.
  • Carbocyclyl or “carbocycle” refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, it is as defined above for “aryl”; when non-aromatic, it may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, 4 to 12 membered (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) membered) tricyclic ring system, which may be bridged or spiro, 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, cyclohexy
  • Optionally substituted 1 to 4 (eg 1, 2, 3, 4) N, S in the ring of “heterocyclyl” or “heterocycle” can be oxidized to various oxidation states; “heterocyclyl” or A “heterocycle” can be attached to a heteroatom or a carbon atom; a “heterocyclyl” or “heterocycle” can be a bridged ring or a spirocyclic ring.
  • heterocyclyl or “heterocycle” include oxiranyl, glycidyl, azetidinyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen nitrogen Heterozoyl, diazepinyl, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazine base, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thio
  • Cycloalkyl refers to a saturated cyclic hydrocarbon group, the ring of which may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (eg 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) and more
  • the ring carbon atoms are preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms.
  • Non-limiting examples of "cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene group, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl, etc.
  • cycloalkyl When cycloalkyl is substituted, it may be optionally further substituted with one or more substituents.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be a (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring systems, including 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
  • heterocycloalkyl can be oxidized to various oxidation states; “heterocycloalkyl” can be attached to a heteroatom or carbon atom; “heterocycloalkyl” Alkyl” can be bridged or spiro.
  • heterocycloalkyl include oxiranyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxoyl Pentacyclyl, 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, oxatri Cyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
  • Halogens include F, Cl, Br and I.
  • “Pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
  • “Pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders and disintegrants.
  • Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • heterocyclyl optionally substituted with an alkyl group means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group happening.
  • trimethyl sulfoxide (3.5 g , 15.8 mmol) was dissolved in 10 mL of dimethyl sulfoxide, and sodium hydride (633.6 mg, 15.8 mmol) in dimethyl sulfoxide was added in portions under ice bath The solution (5 mL) was stirred at room temperature for 30 minutes. Subsequently, a solution of 1c (4.3 g, 14.4 mmol) in dimethyl sulfoxide (5 mL) was added dropwise, and the reaction was carried out at 60° C. for 5 h.
  • reaction solution was added to 15 mL of water, extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine (15 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a silica gel column layer was used.
  • the intermediate tert-butyl(1-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl ) azetidin-3-yl) carbamate 25b was dissolved in 2 mL of dioxane, followed by adding 2 mL of hydrochloric acid dioxane solution in an ice bath, and stirred at room temperature for 1 h.
  • Compound 29-A, 29-B, 29-C and 29-D were prepared by resolving compound 29 by chiral preparative high performance liquid chromatography. Analysis method: chiral column OD-3, mobile phase is ethanol + 0.2% diethylamine, flow rate is 1mL/min, compound 29-A retention time is 3.297min, compound 29-B retention time is 3.620min, compound 29-C The retention time was 4.456 min, and the retention time of compound 29-D was 4.561 min.
  • Compound 33-A and compound 33-B were prepared by resolving compound 33 by chiral preparative high performance liquid chromatography. Analysis method: chiral column Ig-3, mobile phase is ethanol + 0.2% diethylamine, flow rate is 1 mL/min, compound 33-A retention time is 2.746min, compound 33-B retention time is 3.514min.
  • 51a (10 g , 60 mmol) was dissolved in 30 mL of dichloromethane, a solution of 51b (14.4 g, 60 mmol) in dichloromethane (10 mL) was added dropwise under ice bath, followed by dropwise addition of trifluoroacetic acid (684 mg, 6 mmol) in dichloromethane (10 mL) and stirred at room temperature for 2 h.
  • the product 1-benzyl-4-methyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester 51c (yellow oily liquid, 7.1 g, 50.4% yield) was used directly in the next step.
  • trimethyl sulfoxide (3.5 g , 15.8 mmol) was dissolved in 10 mL of dimethyl sulfoxide, and sodium hydride (633.6 mg, 15.8 mmol) in dimethyl sulfoxide was added in portions under ice bath The solution (5 mL) was stirred at room temperature for 30 min. Then, a solution of 51c (4.3 g, 14.4 mmol) in dimethyl sulfoxide (5 mL) was added dropwise, and the reaction was carried out at 60° C. for 5 h.
  • Compound 53 was resolved by chiral preparative high performance liquid chromatography to obtain chiral compounds 53-A, 53-B, 53-C and 53-D.
  • Analysis method chiral column OD-3, mobile phase is ethanol + 0.2% diethylamine, flow rate is 1mL/min, compound 53-A retention time is 3.554min, compound 53-B retention time is 3.963min, compound 53-C The retention time was 4.200 min, and the retention time of compound 53-D was 4.822 min.

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Abstract

Provided are a quinoline derivative represented by general formula (I) and an application thereof in the preparation of an autoimmune drug.

Description

[根据细则37.2由ISA制定的发明名称]　喹啉衍生物及其在制备自身免疫药物上的应用[Title of invention formulated by ISA pursuant to Rule 37.2] Quinoline derivatives and their use in the preparation of autoimmune drugs 技术领域technical field

本发明涉及喹啉衍生物或者其立体异构体或药物可接受的盐，及其在医药上的应用。The present invention relates to quinoline derivatives or their stereoisomers or pharmaceutically acceptable salts, and their application in medicine.

背景技术Background technique

Toll样受体(Toll-like receptors，TLR)是一类分子模式识别受体，广泛分布于不同的组织中，监视识别不同的病原体相关分子模式(PAMP)和损伤相关分子模式(DAMP)，在先天免疫和获得性免疫中均扮演着重要的角色。Toll-like receptors (TLRs) are a class of molecular pattern recognition receptors that are widely distributed in different tissues and monitor and recognize different pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Both innate and acquired immunity play important roles.

TLR属于I型跨膜蛋白，到目前为止已发现13个TLR家族成员，其中10个存在于人类中，TLR1、TLR2、TLR4、TLR5、TLR6、TLR10和TLR11位于细胞膜上，可以识别微生物的脂类、脂蛋白等物质；而TLR3、TLR7、TLR8和TLR9位于胞内囊泡结构(如溶酶体、内涵体和内质网等)，识别微生物的核酸。TLRs belong to type I transmembrane proteins. So far, 13 members of the TLR family have been found, of which 10 are present in humans. TLR1, TLR2, TLR4, TLR5, TLR6, TLR10 and TLR11 are located on the cell membrane and can recognize lipids of microorganisms , lipoprotein and other substances; while TLR3, TLR7, TLR8 and TLR9 are located in intracellular vesicle structures (such as lysosomes, endosomes and endoplasmic reticulum, etc.), and recognize nucleic acids of microorganisms.

TLR7和TLR8在序列和功能上最相似，大量研究表明，TLR7/8的激活可以引发I型干扰素应答及多种炎症反应，在自身免疫性障碍如系统性红斑狼疮(SLE)的情况下，TLR7/8的异常持续激活导致疾病状态的恶化。因此，开发具有选择性和强效抑制活性化合物，通过拮抗TLR7/8抑制过度激活的免疫反应有望成为治疗自身免疫性疾病的新方法。TLR7 and TLR8 are the most similar in sequence and function, and numerous studies have shown that activation of TLR7/8 can trigger type I interferon responses and various inflammatory responses, and in the context of autoimmune disorders such as systemic lupus erythematosus (SLE), Abnormal persistent activation of TLR7/8 leads to exacerbation of disease state. Therefore, the development of compounds with selective and potent inhibitory activity to inhibit the over-activated immune response by antagonizing TLR7/8 is expected to be a new approach for the treatment of autoimmune diseases.

发明内容SUMMARY OF THE INVENTION

本申请的目的是提供新的喹啉衍生物或者其立体异构体、其药物组合物或药物可接受的盐以及其在制备自身免疫疾病药物中的应用。The purpose of this application is to provide novel quinoline derivatives or stereoisomers thereof, pharmaceutical compositions or pharmaceutically acceptable salts thereof, and applications thereof in the preparation of medicines for autoimmune diseases.

本申请的一个或多个实施方式提供通式(I)所示的化合物，或者其立体异构体、氘代物或药物可接受的盐：One or more embodiments of the present application provide a compound represented by general formula (I), or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof:

Figure PCTCN2022081400-appb-000001
Figure PCTCN2022081400-appb-000001

其中：in:

X为C或N；X is C or N;

R 1为C 1-6烷基，所述C 1-6烷基任选地进一步被1个或多个卤素取代； R 1 is C 1-6 alkyl optionally further substituted with 1 or more halogens;

R 2为-CN或C 1-6烷基，所述C 1-6烷基任选地进一步被1个或多个卤素取代； R 2 is -CN or C 1-6 alkyl optionally further substituted with 1 or more halogens;

R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;

R a为-(R a1) m-(R a2) n，所述R a任选地进一步被1个或多个选自D、-OH、卤素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、C 3-10环烷基、C 3-10杂环烷基和C 1-6烷基-C 3-10环烷基的取代基取代； R a is -(R a1 ) m -(R a2 ) n , said R a is optionally further 1 or more selected from D, -OH, halogen, -NR b R c , C 1-6 alkanes base, C 1-6 alkoxy, D substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-10 cycloalkyl, C 3 Substituent substitution of -10 heterocycloalkyl and C 1-6 alkyl-C 3-10 cycloalkyl;

R a1各自独立地选自-O-、-NH-、-OCO-、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基或者C 3- 10杂环烷基，所述C 1-6烷基任选地进一步被1个或多个D取代； R a1 is each independently selected from -O-, -NH-, -OCO-, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , the C 1-6 alkyl is optionally further substituted by 1 or more D;

R a2为H、D、-OH、卤素、-NR bR c、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基，所述的C 1-6烷基任选地进一步被1个或多个D取代； R a2 is H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, The C 1-6 alkyl group is optionally further substituted by 1 or more D;

R b、R c各自独立地为H或C 1-6烷基； R b and R c are each independently H or C 1-6 alkyl;

m为1、2或3；m is 1, 2 or 3;

n为0、1、2、3或4。n is 0, 1, 2, 3 or 4.

在一个或多个实施方式中：In one or more embodiments:

X为C或N；X is C or N;

R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ;

R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ;

R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;

R a为-(R a1) m-(R a2) n，所述R a任选地进一步被1个或多个选自D、-OH、卤素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、C 3-10环烷基、C 3-10杂环烷基和C 1-6烷基-C 3-10环烷基的取代基取代； R a is -(R a1 ) m -(R a2 ) n , said R a is optionally further 1 or more selected from D, -OH, halogen, -NR b R c , C 1-6 alkanes base, C 1-6 alkoxy, D substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-10 cycloalkyl, C 3 Substituent substitution of -10 heterocycloalkyl and C 1-6 alkyl-C 3-10 cycloalkyl;

R a1为-O-、-NH-、-OCO-、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基或C 3-10杂环烷基，所述C 1-6烷基任选地进一步被1个或多个D取代； R a1 is -O-, -NH-, -OCO-, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, the C 1-6 alkyl is optionally further substituted with 1 or more D;

R a2为H、D、-OH、卤素、-NR bR c、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基，所述的C 1-6烷基任选地进一步被1个或多个D取代； R a2 is H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, The C 1-6 alkyl group is optionally further substituted by 1 or more D;

R b、R c各自独立地为H或C 1-6烷基； R b and R c are each independently H or C 1-6 alkyl;

m为1、2或3；m is 1, 2 or 3;

n为0、1、2、3或4。n is 0, 1, 2, 3 or 4.

在一个或多个实施方式中：In one or more embodiments:

X为C或N；X is C or N;

R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ;

R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ;

R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;

R a为-NH 2、-OH、哌啶基、C 1-6烷基、

Figure PCTCN2022081400-appb-000002
Figure PCTCN2022081400-appb-000003
Figure PCTCN2022081400-appb-000004
且R a任选地进一步被1至多个选自D、-OH、卤素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、C 3-10环烷基、C 3-10杂环烷基和C 1-6烷基-C 3-10环烷基的取代基取代； R a is -NH 2 , -OH, piperidinyl, C 1-6 alkyl,
Figure PCTCN2022081400-appb-000002
Figure PCTCN2022081400-appb-000003
Figure PCTCN2022081400-appb-000004
and R a is optionally further C 1-6 alkyl substituted by 1 to more selected from D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, D substituted , hydroxy substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 alkyl-C 3-10 ring Substituent substitution of alkyl;

R b、R c各自独立地为H或C 1-6烷基。 R b and R c are each independently H or C 1-6 alkyl.

在一个或多个实施方式中：In one or more embodiments:

X为C或N；X is C or N;

R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ;

R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ;

R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;

R a为-NH 2、-OH、哌啶基、

Figure PCTCN2022081400-appb-000005
Figure PCTCN2022081400-appb-000006
Figure PCTCN2022081400-appb-000007
且R a任选地进一步被1个或2个C 1-6烷基取代。 R a is -NH 2 , -OH, piperidinyl,
Figure PCTCN2022081400-appb-000005
Figure PCTCN2022081400-appb-000006
Figure PCTCN2022081400-appb-000007
and R a is optionally further substituted with 1 or 2 C 1-6 alkyl groups.

在一个或多个实施方式中：In one or more embodiments:

X、R 1、R 2、R定义与上述的定义相同； The definitions of X, R 1 , R 2 and R are the same as the above definitions;

R a选自-NH 2、-OH、哌啶基、

Figure PCTCN2022081400-appb-000008
Figure PCTCN2022081400-appb-000009
Figure PCTCN2022081400-appb-000010
且R a任选地进一步被1个或2个C 1-6烷基取代。 Ra is selected from -NH 2 , -OH, piperidinyl,
Figure PCTCN2022081400-appb-000008
Figure PCTCN2022081400-appb-000009
Figure PCTCN2022081400-appb-000010
and R a is optionally further substituted with 1 or 2 C 1-6 alkyl groups.

在一个或多个实施方式中：In one or more embodiments:

X、R 1、R 2、R定义与上述的定义相同； The definitions of X, R 1 , R 2 and R are the same as the above definitions;

R a为-NH 2、-OH、哌啶基、

Figure PCTCN2022081400-appb-000011
Figure PCTCN2022081400-appb-000012
Figure PCTCN2022081400-appb-000013
且R a任选地进一步被1个或2个C 1-6烷基取代。 R a is -NH 2 , -OH, piperidinyl,
Figure PCTCN2022081400-appb-000011
Figure PCTCN2022081400-appb-000012
Figure PCTCN2022081400-appb-000013
and R a is optionally further substituted with 1 or 2 C 1-6 alkyl groups.

在一个或多个实施方式中：In one or more embodiments:

X选自C或N；X is selected from C or N;

R 1选自-CF 3或-CH 3； R 1 is selected from -CF 3 or -CH 3 ;

R 2选自-CN或-CF 3； R 2 is selected from -CN or -CF 3 ;

R为-CONHR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -CONHR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;

R a选自

Figure PCTCN2022081400-appb-000014
Figure PCTCN2022081400-appb-000015
Figure PCTCN2022081400-appb-000016
且R a任选地进一步被1个或2个C 1-6烷基取代。 Ra is selected from
Figure PCTCN2022081400-appb-000014
Figure PCTCN2022081400-appb-000015
Figure PCTCN2022081400-appb-000016
and R a is optionally further substituted with 1 or 2 C 1-6 alkyl groups.

在一个或多个实施方式中：In one or more embodiments:

X为C或N；X is C or N;

R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ;

R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ;

R为-CONHR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -CONHR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;

R a为

Figure PCTCN2022081400-appb-000017
Figure PCTCN2022081400-appb-000018
且R a任选地进一步被1个或2个C 1-6烷基取代。 Ra is
Figure PCTCN2022081400-appb-000017
Figure PCTCN2022081400-appb-000018
and R a is optionally further substituted with 1 or 2 C 1-6 alkyl groups.

在一个或多个实施方式中：In one or more embodiments:

X为C或N；X is C or N;

R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ;

R 2为-CN； R 2 is -CN;

R为-CONHR a、-COOR a或-NHCOR a； R is -CONHR a , -COOR a or -NHCOR a ;

R a为

Figure PCTCN2022081400-appb-000019
Figure PCTCN2022081400-appb-000020
且R a任选地进一步被1个2个C 1-6烷基取代。 Ra is
Figure PCTCN2022081400-appb-000019
Figure PCTCN2022081400-appb-000020
and R a is optionally further substituted with 1 2 C 1-6 alkyl.

本申请的一个或多个实施方式提供了通式(I’)所示的化合物，或者其立体异构体、氘代物或其药物可接受的盐：One or more embodiments of the present application provide a compound represented by the general formula (I'), or a stereoisomer, a deuterated compound or a pharmaceutically acceptable salt thereof:

Figure PCTCN2022081400-appb-000021
Figure PCTCN2022081400-appb-000021

其中：in:

X为C或N；X is C or N;

R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ;

R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ;

R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;

R a为-NH 2、-OH、哌啶基、

Figure PCTCN2022081400-appb-000022
Figure PCTCN2022081400-appb-000023
Figure PCTCN2022081400-appb-000024
且R a进一步任选地被1至2个C 1-6烷基取代。 R a is -NH 2 , -OH, piperidinyl,
Figure PCTCN2022081400-appb-000022
Figure PCTCN2022081400-appb-000023
Figure PCTCN2022081400-appb-000024
And R a is further optionally substituted with 1 to 2 C 1-6 alkyl groups.

本申请的一个或多个实施方式提供了通式(I”)所示的化合物，或者其立体异构体、氘代物或其药物可接受的盐：One or more embodiments of the present application provide a compound represented by the general formula (I"), or a stereoisomer, a deuterated compound or a pharmaceutically acceptable salt thereof:

Figure PCTCN2022081400-appb-000025
Figure PCTCN2022081400-appb-000025

其中：in:

X为C或N；X is C or N;

R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ;

R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ;

R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;

R a为-NH 2、-OH、哌啶基、

Figure PCTCN2022081400-appb-000026
Figure PCTCN2022081400-appb-000027
Figure PCTCN2022081400-appb-000028
且R a进一步任选地被1至2个C 1-6烷基取代。 R a is -NH 2 , -OH, piperidinyl,
Figure PCTCN2022081400-appb-000026
Figure PCTCN2022081400-appb-000027
Figure PCTCN2022081400-appb-000028
And R a is further optionally substituted with 1 to 2 C 1-6 alkyl groups.

本申请的一个或多个实施方式提供了通式(I”’)所示的化合物，或者其立体异构体、氘代物或其药物可接受的盐：One or more embodiments of the present application provide a compound represented by the general formula (I"'), or a stereoisomer, a deuterated compound or a pharmaceutically acceptable salt thereof:

Figure PCTCN2022081400-appb-000029
Figure PCTCN2022081400-appb-000029

其中：in:

X为C或N；X is C or N;

R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ;

R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ;

R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;

R a为-NH 2、-OH、哌啶基、

Figure PCTCN2022081400-appb-000030
Figure PCTCN2022081400-appb-000031
Figure PCTCN2022081400-appb-000032
且R a进一步任选地被1至2个C 1-6烷基取代。 R a is -NH 2 , -OH, piperidinyl,
Figure PCTCN2022081400-appb-000030
Figure PCTCN2022081400-appb-000031
Figure PCTCN2022081400-appb-000032
And R a is further optionally substituted with 1 to 2 C 1-6 alkyl groups.

本申请的一个或多个实施方式提供了通式(I””)所示的化合物，或者其立体异构体、氘代物或其药物可接受的盐：One or more embodiments of the present application provide a compound represented by the general formula (I""), or a stereoisomer, a deuterated compound or a pharmaceutically acceptable salt thereof:

Figure PCTCN2022081400-appb-000033
Figure PCTCN2022081400-appb-000033

其中：in:

X为C或N；X is C or N;

R 1为C 1-6烷基，所述的C 1-6烷基任选地进一步被1个或多个卤素取代； R 1 is C 1-6 alkyl, and said C 1-6 alkyl is optionally further substituted by one or more halogens;

R 2为-CN或C 1-6烷基，所述的C 1-6烷基任选地进一步被1个或多个卤素取代； R 2 is -CN or C 1-6 alkyl, and said C 1-6 alkyl is optionally further substituted by 1 or more halogens;

R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ;

R a为-(R a1) m-(R a2) n； R a is -(R a1 ) m -(R a2 ) n ;

R a1各自独立地为-O-、-NH-、-OCO-、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基或C 3-10杂环烷基，所述C 1-6烷基任选地进一步被1个或多个D取代； R a1 is each independently -O-, -NH-, -OCO-, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, The C 1-6 alkyl is optionally further substituted with 1 or more D;

R a2各自独立地为H、D、-OH、卤素、-NR bR c、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基，所述C 1-6烷基任选地进一步被1个或多个D取代； R a2 is each independently H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycle alkyl, the C 1-6 alkyl is optionally further substituted with 1 or more D;

R b、R c各自独立地为H或C 1-6烷基； R b and R c are each independently H or C 1-6 alkyl;

m为1、2或3；m is 1, 2 or 3;

n为0、1、2、3或4。n is 0, 1, 2, 3 or 4.

在本申请的一个或多个实施方式中，R a选自-NH 2、-OH、哌啶基、

Figure PCTCN2022081400-appb-000034
Figure PCTCN2022081400-appb-000035
Figure PCTCN2022081400-appb-000036
且R a进一步被1至2个的C 1-6烷基取代。 In one or more embodiments of the present application, R a is selected from -NH 2 , -OH, piperidinyl,
Figure PCTCN2022081400-appb-000034
Figure PCTCN2022081400-appb-000035
Figure PCTCN2022081400-appb-000036
And R a is further substituted with 1 to 2 C 1-6 alkyl groups.

本申请的一个或多个实施方式提供了通式(II)所示的化合物，或者其立体异构体、氘代物或其药物可接受的盐：One or more embodiments of the present application provide a compound represented by general formula (II), or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof:

Figure PCTCN2022081400-appb-000037
Figure PCTCN2022081400-appb-000037

其中：in:

R选自-COOH、-NH 2、-CONH 2、-COR a或-COOR a； R is selected from -COOH, -NH 2 , -CONH 2 , -COR a or -COOR a ;

R a选自-NH 2、哌啶基、

Figure PCTCN2022081400-appb-000038
Figure PCTCN2022081400-appb-000039
Figure PCTCN2022081400-appb-000040
且R a任选地进一步被1个或2个C 1-6烷基取代。 Ra is selected from -NH 2 , piperidinyl,
Figure PCTCN2022081400-appb-000038
Figure PCTCN2022081400-appb-000039
Figure PCTCN2022081400-appb-000040
and R a is optionally further substituted with 1 or 2 C 1-6 alkyl groups.

本申请的一个或多个实施方式提供了通式(II’)化合物，或者其立体异构体、氘代物或药物可接受的盐：One or more embodiments of the present application provide a compound of general formula (II'), or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof:

Figure PCTCN2022081400-appb-000041
Figure PCTCN2022081400-appb-000041

R选自-COOH、-NH 2、-CONH 2或-COR a； R is selected from -COOH, -NH 2 , -CONH 2 or -COR a ;

R a选自-NH 2或哌啶基，且所述哌啶基任选地进一步被1至2个选自C 1-6烷基取代。 R a is selected from -NH 2 or piperidinyl, and the piperidinyl is optionally further substituted with 1 to 2 selected from C 1-6 alkyl.

本申请的一个或多个实施方式提供了如下化合物或者其立体异构体、氘代物或药物可接受的盐，其中该化合物为：One or more embodiments of the present application provide the following compounds or stereoisomers, deuterated compounds or pharmaceutically acceptable salts thereof, wherein the compound is:

Figure PCTCN2022081400-appb-000042
Figure PCTCN2022081400-appb-000042

Figure PCTCN2022081400-appb-000043
Figure PCTCN2022081400-appb-000043

Figure PCTCN2022081400-appb-000044
Figure PCTCN2022081400-appb-000044

本申请的一个或多个实施方式提供制备本申请化合物的中间体或其立体异构体、氘代物或药物可接受的盐，所述中间体为：One or more embodiments of the present application provide intermediates or stereoisomers, deuterated compounds or pharmaceutically acceptable salts thereof for the preparation of compounds of the present application, the intermediates being:

Figure PCTCN2022081400-appb-000045
Figure PCTCN2022081400-appb-000045

Figure PCTCN2022081400-appb-000046
Figure PCTCN2022081400-appb-000046

Figure PCTCN2022081400-appb-000047
Figure PCTCN2022081400-appb-000047

本申请的一个或多个实施方式提供药物组合物，所述药物组合物包含：One or more embodiments of the present application provide a pharmaceutical composition comprising:

(1)本申请的化合物或者其立体异构体、氘代物或药物可接受的盐；(1) the compound of the present application or its stereoisomer, deuterated product or pharmaceutically acceptable salt;

(2)任选的一种或者多种其他活性成分；以及(2) optionally one or more other active ingredients; and

(3)药学上可接受的载体和/或赋形剂。(3) A pharmaceutically acceptable carrier and/or excipient.

本申请的一个或多个实施方式提供本申请的化合物或者其立体异构体、氘代物或药物可接受的盐，或者本申请的药物组合物制备用于治疗自身免疫疾病的药物中的用途。One or more embodiments of the present application provide the use of a compound of the present application or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application in the preparation of a medicament for the treatment of autoimmune diseases.

本申请的一个或多个实施方式提供本申请的化合物或者其立体异构体、氘代物或药物可接受的盐，或者本申请的药物组合物在制备用于治疗与TLR7、TLR8或TLR9相关的疾病中的用途。One or more embodiments of the present application provide a compound of the present application, or a stereoisomer, deuterated product or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, prepared for use in the treatment of TLR7, TLR8 or TLR9-related use in disease.

本申请的一个或多个实施方式提供本申请的化合物或者其立体异构体、氘代物或药物可接受的盐，或者本申请的药物组合物在制备IL-6抑制剂中的用途。One or more embodiments of the present application provide the use of a compound of the present application or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application in the preparation of an IL-6 inhibitor.

本申请的一个或多个实施方式提供本申请的化合物或者其立体异构体、氘代物或药物可接受的盐，或者本申请的药物组合物，其用作药物。One or more embodiments of the present application provide a compound of the present application, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, for use as a medicament.

本申请的一个或多个实施方式提供本申请的化合物或者其立体异构体、氘代物或药物可接受的盐，或者本申请的药物组合物，其用于治疗自身免疫疾病的方法。One or more embodiments of the present application provide a compound of the present application, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, for use in a method of treating an autoimmune disease.

本申请的一个或多个实施方式提供本申请的化合物或者其立体异构体、氘代物或药物可接受的盐，或者本申请的药物组合物，其用于治疗与TLR7、TLR8或TLR9相关的疾病。One or more embodiments of the present application provide a compound of the present application, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, for use in the treatment of TLR7, TLR8 or TLR9-related disease.

本申请的一个或多个实施方式提供本申请的化合物或者其立体异构体、氘代物或药物可接受的盐，或者本申请的药物组合物，其用作IL-6抑制剂。One or more embodiments of the present application provide a compound of the present application, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, for use as an IL-6 inhibitor.

本申请的一个或多个实施方式提供治疗自身免疫疾病的方法，其包括将本申请的化合物或者其立体异构体、氘代物或药物可接受的盐或者本申请的药物组合物给予有此需要的对象。One or more embodiments of the present application provide a method of treating an autoimmune disease comprising administering a compound of the present application, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application in need thereof Object.

本申请的一个或多个实施方式提供治疗与TLR7、TLR8或TLR9相关的疾病的方法，其包括将本申请的化合物或者其立体异构体、氘代物或药物可接受的盐或者本申请的药物组合物给予有此需要的对象。One or more embodiments of the present application provide a method of treating a disease associated with TLR7, TLR8 or TLR9, comprising adding a compound of the present application or a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof or a medicament of the present application The composition is administered to a subject in need thereof.

本申请的一个或多个实施方式提供抑制IL-6的方法，其包括将本申请的化合物或者其立体异构体、氘代物或药物可接受的盐或者本申请的药物组合物给予有此需要的对象。One or more embodiments of the present application provide methods of inhibiting IL-6, comprising administering a compound of the present application, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application in need thereof Object.

除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.

本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选 进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，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 of the present invention all include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy 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个碳原子的直链或支链饱和脂肪族烃基，优选为1至8个(例如1、2、3、4、5、6、7、8个)碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；当烷基被取代基时，可以任选进一步被1个或者多个取代基所取代。"Alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (eg 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms , more preferably an alkyl group of 1 to 6 carbon atoms, further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and Various branched chain isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.

“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。"Alkoxy" refers to a group formed by substituting 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-pentoxy, n-hexyloxy, cyclopropoxy and cyclobutoxy. The definition of alkyl is the same as the definition of "alkyl" described above.

“烯基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基，更优选2至8个碳原子的烯基，进一步优选2至6个碳原子的烯基。非限制性实例包括乙烯基、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。所述的烯基可以任选进一步被1个或者多个取代基所取代。"Alkenyl" means a straight chain consisting of 2 to 20 carbon atoms containing 1 to 10 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds Chain or branched unsaturated aliphatic hydrocarbon groups, preferably alkenyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 An alkenyl group of 8 carbon atoms, more preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-2-yl En-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecene -3-base. The alkenyl group may be optionally further substituted with one or more substituents.

“炔基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、或10个)碳-碳叁键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基，更优选2至8个碳原子的炔基，进一步优选2至6个碳原子的炔基。非限制性实例包括乙炔基、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。所述的炔基可以任选进一步被一至多个取代基所取代。"Alkynyl" means a carbon-carbon triple bond containing 1 to 10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Linear or branched unsaturated aliphatic hydrocarbon groups, preferably alkynyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably 2 An alkynyl group of to 8 carbon atoms, more preferably an alkynyl group of 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 , octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl. The alkynyl group may optionally be further substituted with one or more substituents.

“芳基”是指是指取代的或未取代的芳香环，其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，其可以是桥环或者螺环，非限制性实例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。"Aryl" means a substituted or unsubstituted aromatic ring, which may be a 5- to 8-membered (eg, 5, 6, 7, 8) , 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which may be bridged or spirocyclic, non-limiting examples Including phenyl, naphthyl. The aryl group may optionally be further substituted with one or more substituents.

“杂芳基”是指取代的或未取代的芳香环，其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子，优选5至8元杂芳基，杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态。杂芳基可以连接在杂原子或者碳原子上，杂芳基可以是桥环或者螺环，非限制性实例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。"Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which may be a 3 to 8 membered (eg 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (eg 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (eg 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5- to 8-membered heteroaryl, 1 to 4 (eg 1, 2) optionally substituted in the ring of heteroaryl , 3, 4) N, S can be oxidized into various oxidation states. Heteroaryl can be attached to a heteroatom or a carbon atom. Heteroaryl can be bridged or spiro, non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. Heteroaryl groups are optionally further substituted with one or more substituents.

“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时，其定义与上文“芳基”的定义相同；当为非芳香环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，可以是桥环或者螺环，非限制性实例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、 环辛基、环壬基、环癸基、环十一烷基、环十二烷基、

Figure PCTCN2022081400-appb-000048
所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。 "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, it is as defined above for "aryl"; when non-aromatic, it may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, 4 to 12 membered (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) membered) tricyclic ring system, which may be bridged or spiro, 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, cycloheptyl cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,
Figure PCTCN2022081400-appb-000048
Said "carbocyclyl" or "carbocycle" is optionally further substituted with one or more substituents.

“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环，当为芳香性杂环时，其定义与上文“杂芳基”定义相同；当为非芳香性杂环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子，优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态；“杂环基”或“杂环”可以连接在杂原子或者碳原子上；“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、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、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”可以任选进一步被1个或者多个取代基所取代。"Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle, and when it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above; when When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (eg 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, 4- to 12-membered (eg 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group. Optionally substituted 1 to 4 (eg 1, 2, 3, 4) N, S in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or A "heterocycle" can be attached to a heteroatom or a carbon atom; a "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocyclic ring. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxiranyl, glycidyl, azetidinyl, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen nitrogen Heterozoyl, diazepinyl, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazine base, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl , dithiopenyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzoyl Imidazolyl, benzopyridyl, pyrrolopyridyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, indoline, 2H-pyranyl, 4H-pyranyl, Dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiazolinyl, dihydrothienyl, pyrazolidine, imidazolinyl, imidazolidinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H -Indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonane oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl. Said "heterocyclyl" or "heterocycle" may be optionally further substituted with one or more substituents.

“环烷基”是指饱和的环烃基，其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如10、11、12、13、14、15、16、17、18、19、20元)多环体系，环碳原子优选3至10个碳原子，进一步优选3至8个碳原子。“环烷基”非限制性实例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时，可以任选进一步被1个或者多个取代基所取代。"Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (eg 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) and more In the ring system, the ring carbon atoms are preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene group, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl, etc. When cycloalkyl is substituted, it may be optionally further substituted with one or more substituents.

“杂环烷基”是指取代的或未取代的饱和非芳香环基，其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1、2或3个选自N、O或S的杂原子，优选3至8元杂环基。“杂环烷基”的环中选择性取代的1、2或3个N、S可被氧化成各种氧化态；“杂环烷基”可以连接在杂原子或者碳原子上；“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be a (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring systems, including 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group. Optionally substituted 1, 2 or 3 N, S in the ring of "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" can be attached to a heteroatom or carbon atom; "heterocycloalkyl" Alkyl" can be bridged or spiro. Non-limiting examples of "heterocycloalkyl" include oxiranyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxoyl Pentacyclyl, 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, oxatri Cyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.

当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时，可以选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C 1-6烷基氨基、＝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环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基、-C(＝O)OC 6-10芳基、-OC(＝O)C 6-10芳基、-OC(＝O)C 5-10杂芳基、-C(＝O)OC 5-10杂芳基、-OC(＝O)C 3-8杂环烷基、-C(＝O)OC 3-8杂环烷基、-OC(＝O)C 3-8环烷基、-C(＝O)OC 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8环烷基、-NHC(＝O)C 3-8杂环烷基、-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环烷基、C 3-8杂环烷基、C 6-10芳基、C 5-10杂芳基、-NHC(＝O)C 6-10芳基、-NHC(＝O)C 5-10杂芳基、-NHC(＝O)C 3-8杂环烷基或者-NHC(＝O)C 3-8环烷基任选进一步被1至3个选自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选自C 1-6烷基、C 1-6烷氧基或者C 6-10芳基；R q2、R q3选自H或者C 1-6烷基；其中，R q4、R q5选自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烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C 1-6烷基、C 1-6烷氧基、C 6-10芳基、C 5-10杂芳基、C 3-8环烷基或者C 3-8杂环烷基的取代基所取代；或者R q4与R q5及N原子形成一个3至8元杂环，所述杂环可以含有1个或者多个选自N、O或者S的杂原子。 When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocycle", " When "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" is substituted, it may be further selected by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 alkylamino, =O, C 1-6 alkyl, C 1 -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, - NR q4 R q5 , =NR q6 , -C(=O)OC 1-6 alkyl, -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 Aryl, -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 hetero Aryl, -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 substituents, and wherein the substituents 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 is optionally further selected from 1 to 3 groups selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, -NR q4 R q5 or a substituent of =O; 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; wherein, 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 said C 1-6 alkyl Optionally further selected by one or more selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 5-10 hetero substituted by substituents of aryl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; or R q4 , R q5 and N atom form a 3- to 8-membered heterocycle, which may contain 1 one or more heteroatoms selected from N, O or S.

卤素包括F、Cl、Br和I。Halogens include F, Cl, Br and I.

“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"Pharmaceutically acceptable salt" or "a pharmaceutically acceptable salt thereof" means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.

“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.

“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"Carrier" refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.

“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders and disintegrants.

“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.

“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。"Optional" or "optionally" or "selective" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not occur what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group Happening.

具体实施方式Detailed ways

以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但不限于此。The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.

实施例1Example 1

(1R,5S)和(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸 化合物1-A和化合物1-B(1R,5S) and (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Carboxylic Acid Compound 1-A and Compound 1-B

3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

Figure PCTCN2022081400-appb-000049
Figure PCTCN2022081400-appb-000049

第一步：first step:

1-苄基-4-(三氟甲基)-2,5-二氢-1H-吡咯-3-羧酸乙酯 1c1-Benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate ethyl ester 1c

ethyl 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylateethyl 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate

N 2氛围下，将1a(10g，60mmol)溶于30mL二氯甲烷(DCM)中，冰浴下滴加1b(14.4g，60mmol)的二氯甲烷溶液(10mL)，随后缓慢滴加三氟乙酸(684mg，6mmol)的二氯甲烷溶液(10mL),室温搅拌2h。将反应液加入30mL水中，DCM萃取三次，有机相用饱和食盐水30mL洗，无水硫酸钠干燥，旋干，硅胶柱层析纯化(乙酸乙酯:石油醚＝1:10)，得到目标产物1-苄基-4-(三氟甲基)-2,5-二氢-1H-吡咯-3-羧酸乙酯1c(黄色油状液体，15.5g，产率86％)，直接用于下一步反应。 Under N atmosphere, 1a (10 g , 60 mmol) was dissolved in 30 mL of dichloromethane (DCM), and a solution of 1b (14.4 g, 60 mmol) in dichloromethane (10 mL) was added dropwise under an ice bath, followed by the slow dropwise addition of trifluoromethane A solution of acetic acid (684 mg, 6 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 h. The reaction solution was added to 30 mL of water, 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 the target product 1-Benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate ethyl ester 1c (yellow oily liquid, 15.5 g, 86% yield) was used directly in the following one-step reaction.

1H NMR(400MHz,DMSO-d 6)δ7.34-7.24(m,5H),4.19(q,2H),3.79-3.78(m,4H),1.20(t,3H)。 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]。LC-MS m/z (ESI) = 300.1 [M+1].

第二步：Step 2:

3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯 1dEthyl 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 1d

ethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylateethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

N 2氛围下，将三甲基碘化亚砜(3.5g，15.8mmol)溶于10mL二甲亚砜中，冰浴下分批次加入氢化钠(633.6mg，15.8mmol)的二甲亚砜溶液(5mL)，室温搅拌30分钟。随后滴加1c(4.3g，14.4mmol)的二甲亚砜溶液(5mL),60℃反应5h。饱和氯化铵淬灭反应，DCM 30mL萃取，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，硅胶柱层析纯化(乙酸乙酯:石油醚＝1:10)，得到目标产物3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯 1d(无色油状液体，3.5g,产率78％)，直接用于下一步反应。 Under N atmosphere, trimethyl sulfoxide (3.5 g , 15.8 mmol) was dissolved in 10 mL of dimethyl sulfoxide, and sodium hydride (633.6 mg, 15.8 mmol) in dimethyl sulfoxide was added in portions under ice bath The solution (5 mL) was stirred at room temperature for 30 minutes. Subsequently, a solution of 1c (4.3 g, 14.4 mmol) in dimethyl sulfoxide (5 mL) was added dropwise, and the reaction was carried out at 60° C. for 5 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain the target The product, ethyl 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 1d (colorless oily liquid, 3.5 g, 78% yield), used directly in the next reaction.

1H NMR(400MHz,DMSO-d 6)δ7.34-7.24(m,5H),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)。 1 H NMR (400MHz, DMSO-d 6 ) δ 7.34-7.24(m, 5H), 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]。LC-MS m/z (ESI) = 314.1 [M+1].

第三步：third step:

5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯 1eEthyl 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 1e

ethyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylateethyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

将1d(1g，3.2mmol)溶于乙醇50mL中，随后加入Pd/C(681mg，0.64mmol)，反应体系用1atm H 2置换两次，升温至60℃反应3h。硅藻土过滤，旋干溶剂，得到目标产物5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯 1e(无色油状液体，1g，产率88％)，直接用于下一步。 1d (1 g, 3.2 mmol) was dissolved in 50 mL of ethanol, then Pd/C (681 mg, 0.64 mmol) was added, the reaction system was replaced with 1 atm H 2 twice, and the temperature was raised to 60 °C for 3 h. Filter through celite, spin dry the solvent to obtain the target product, ethyl 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 1e (colorless oily liquid, 1 g, produced rate 88%), which was directly used in the next step.

1H NMR(400MHz,DMSO-d 6)δ4.11(q,2H),3.20-2.75(m,5H),1.75(d,1H),1.48-1.47(m,1H),1.16(t,3H)。 1 H NMR (400MHz, 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]。LC-MS m/z (ESI) = 224.1 [M+1].

第四步：the fourth step:

(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯1g(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate ethyl ester 1 g

3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

N 2氛围下，将5-溴喹啉-8-甲腈1f(654mg，2.9mmol)溶于1,4-二氧六环30mL中，随后加入1e(804mg，3.5mmol)，N 2置换气三次，依次加入碳酸铯(4.3g，13.05mmol)和RuPhosPdG3(486mg，0.58mmol),N 2置换气三次,升温至90℃反应2h。旋干溶剂，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，旋干溶剂，粗产物1g直接投下一步。 Under N atmosphere, 5 -bromoquinoline-8-carbonitrile 1f (654 mg, 2.9 mmol) was dissolved in 1,4-dioxane 30 mL, followed by the addition of 1e (804 mg, 3.5 mmol), N 2 replacement gas Three times, cesium carbonate (4.3 g, 13.05 mmol) and RuPhosPdG3 (486 mg, 0.58 mmol) were successively added, N 2 was replaced three times, and the temperature was raised to 90 °C for 2 h. The solvent was spin-dried, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried, and 1 g of the crude product was directly put into the next step.

LC-MS m/z(ESI)＝376.1[M+1],398.1[M+23]。LC-MS m/z (ESI) = 376.1 [M+1], 398.1 [M+23].

第五步：the fifth step:

3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸 化合物13-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Compound 1

3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

将1g的粗产品(2.02g，5.39mmol)溶于四氢呋喃溶液10mL中，将无水氢氧化锂(1.29g，53.9mmol)的水溶液10mL滴入反应液中，室温搅拌过夜。待反应结束，旋干四氢呋喃，乙酸乙酯萃取，保留水相，用2M盐酸水溶液将水相PH调至3-4，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，真空除去溶剂。MPLC分离(乙腈:水＝47：53)，得到目标产物3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸化合物1(黄色固体，387mg，21％)。1 g of the crude product (2.02 g, 5.39 mmol) was dissolved in 10 mL of tetrahydrofuran solution, and 10 mL of an aqueous solution of anhydrous lithium hydroxide (1.29 g, 53.9 mmol) was added dropwise to the reaction solution, and stirred at room temperature overnight. After the reaction is over, spin dry tetrahydrofuran, extract with ethyl acetate, keep the aqueous phase, adjust the pH of the aqueous phase to 3-4 with 2M aqueous hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and vacuum Remove the 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 1 (yellow solid, 387 mg, 21%).

1H NMR(400MHz,DMSO-d 6)δ13.26(s,1H),9.02-9.00(m,1H),8.64-8.62(m,1H),8.16(d,J＝8.0Hz,1H),7.61(dd,1H),7.25(d,1H),4.05-3.77(m,4H),2.07-1.86(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ 13.26(s, 1H), 9.02-9.00(m, 1H), 8.64-8.62(m, 1H), 8.16(d, J=8.0Hz, 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]。LC-MS m/z (ESI) = 348.1 [M+1], 370.1 [M+23].

第六步：Step 6:

3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸 化合物1-A和化合物1-B3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Compound 1-A and Compound 1-B

3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

通过手性制备高效液相色谱(chiral prep-HPLC)拆分化合物1制备得到化合物1-A和化合物1-B。分析方法：手性柱Ig-3，甲醇作为流动相，流速1mL/min,化合物1-A保留时间为3.619min，化合物1-B保留时间为4.741min。Compound 1-A and compound 1-B were prepared by resolving compound 1 by chiral prep-HPLC. Analysis method: chiral column Ig-3, methanol as mobile phase, flow rate 1mL/min, retention time of compound 1-A is 3.619min, compound 1-B retention time is 4.741min.

实施例2Example 2

3-(8-氰基喹啉-5-基)-N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧 酰胺 化合物2-A和化合物2-B3-(8-Cyanoquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxamide compound 2-A and compound 2-B

3-(8-cyanoquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000050
Figure PCTCN2022081400-appb-000050

第一步：first step:

3-(8-氰基喹啉-5-基)-N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物23-(8-Cyanoquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxamide Compound 2

3-(8-cyanoquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1(40mg，0.12mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入4-氨基-1-甲基哌啶2a(26.32mg，0.24mmol)，室温搅拌1h。原料反应完全，TLC分离(二氯甲烷:甲醇＝10:1)，得到目标产物3-(8-氰基喹啉-5-基)-N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物2(黄色固体，30mg，56％)。Compound 1 (40 mg, 0.12 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding 4- Amino-1-methylpiperidine 2a (26.32 mg, 0.24 mmol) was stirred at room temperature for 1 h. The reaction of the raw materials was completed, and TLC separation (dichloromethane: methanol = 10: 1) was performed to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(1-methylpiperidin-4-yl) -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 2 (yellow solid, 30 mg, 56%).

1H NMR(400MHz,DMSO-d 6)δ9.01-9.00(m,1H),8.63(dd,1H),8.17(d,1H),8.04(d,1H),7.60(dd,1H),7.22(d,1H),4.02-3.80(m,4H),3.61-3.53(m,1H),2.75-2.66(m,2H),2.15(s,3H),2.00-1.88(m,3H),1.67-1.62(m,3H),1.50-1.40(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01-9.00(m,1H), 8.63(dd,1H), 8.17(d,1H), 8.04(d,1H), 7.60(dd,1H), 7.22(d, 1H), 4.02-3.80(m, 4H), 3.61-3.53(m, 1H), 2.75-2.66(m, 2H), 2.15(s, 3H), 2.00-1.88(m, 3H), 1.67-1.62 (m, 3H), 1.50-1.40 (m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-64.85. 19 F NMR (376MHz, DMSO-d 6 ) δ-64.85.

LC-MS m/z(ESI)＝444.2[M+1],466.2[M+23]。LC-MS m/z (ESI) = 444.2 [M+1], 466.2 [M+23].

第二步：Step 2:

3-(8-氰基喹啉-5-基)-N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物2-A和化合物2-B3-(8-Cyanoquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxamide compound 2-A and compound 2-B

3-(8-cyanoquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

通过手性制备高效液相色谱拆分化合物2制备得到化合物2-A和化合物2-B。分析方法：手性柱Ig-3，流动相为乙醇:乙腈＝1:1+0.2％二乙胺，流速1mL/min，化合物2-A保 留时间为3.619min，化合物2-B保留时间为4.741min。Compound 2-A and compound 2-B were prepared by resolving compound 2 by chiral preparative high performance liquid chromatography. Analysis method: chiral column Ig-3, mobile phase is ethanol:acetonitrile=1:1+0.2% diethylamine, flow rate 1mL/min, compound 2-A retention time is 3.619min, compound 2-B retention time is 4.741 min.

实施例3Example 3

3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物33-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 3

3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000051
Figure PCTCN2022081400-appb-000051

将化合物1(100mg，0.29mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(166.3mg，0.44mmol)和DIPEA(56.9mg，0.44mmol)，室温搅拌10min，加入碳酸氢铵(45.9mg，0.58mmol)，室温搅拌5.5h。原料反应完全，TLC分离(二氯甲烷：甲醇＝10：1)，得到目标产物3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物3(黄色固体，52mg，52％)。Compound 1 (100 mg, 0.29 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (166.3 mg, 0.44 mmol) and DIPEA (56.9 mg, 0.44 mmol), stirring at room temperature for 10 min, adding hydrogen carbonate Ammonium (45.9 mg, 0.58 mmol), stirred at room temperature for 5.5 h. The reaction of the raw materials was completed, and the TLC separation (dichloromethane:methanol=10:1) was performed to obtain the target product 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0] Hexane-1-carboxamide Compound 3 (yellow solid, 52 mg, 52%).

1H NMR(400MHz,DMSO-d 6)δ9.01-9.00(m,1H),8.65-8.62(m,1H),8.17(d,1H),7.70(s,1H),7.61(dd,1H),7.44(s,1H),7.22(d,1H),4.01-3.93(m,3H),3.78(d,1H),2.0-1.98(m,1H),1.64-1.62(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01-9.00(m,1H), 8.65-8.62(m,1H), 8.17(d,1H), 7.70(s,1H), 7.61(dd,1H) ), 7.44(s, 1H), 7.22(d, 1H), 4.01-3.93(m, 3H), 3.78(d, 1H), 2.0-1.98(m, 1H), 1.64-1.62(m, 1H).

LC-MS m/z(ESI)＝347.1[M+1]。LC-MS m/z (ESI) = 347.1 [M+1].

实施例4Example 4

5-[1-氨基-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基]喹啉-8-腈 化合物45-[1-Amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl]quinoline-8-carbonitrile Compound 4

5-[1-amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl]quinoline-8-carbonitrile5-[1-amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl]quinoline-8-carbonitrile

Figure PCTCN2022081400-appb-000052
Figure PCTCN2022081400-appb-000052

第一步：first step:

叔丁基-N-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂二环[3.1.0]己烷-1-基]氨基甲酸 叔丁酯 4atert-Butyl-N-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl]amino tert-Butyl formate 4a

tert-butyl N-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]carbamatetert-butyl N-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]carbamate

将化合物1(60mg，0.173mmol)溶于叔丁醇5mL中，随后加入DPPA(71.6mg，0.26mmol)和三乙胺(70mg，0.69mmol)，升温至95℃反应4.5h，待原料消失，二氯甲烷萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，旋干溶剂，粗产物4a直接投下一步反应。Compound 1 (60 mg, 0.173 mmol) was dissolved in 5 mL of tert-butanol, then DPPA (71.6 mg, 0.26 mmol) and triethylamine (70 mg, 0.69 mmol) were added, the temperature was raised to 95 °C and the reaction was performed for 4.5 h. After the raw materials disappeared, Extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried the solvent, and the crude product 4a was directly put into the next reaction.

LC-MS m/z(ESI)＝419.1[M+1],441.1[M+23]。LC-MS m/z (ESI) = 419.1 [M+1], 441.1 [M+23].

第二步：Step 2:

5-[1-氨基-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基]喹啉-8-腈 化合物45-[1-Amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl]quinoline-8-carbonitrile Compound 4

5-[1-amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl]quinoline-8-carbonitrile5-[1-amino-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl]quinoline-8-carbonitrile

将粗产物4a溶于氯化氢-二氧六环溶液10mL中,室温搅拌4h，加入三乙胺碱化，旋干溶剂，MPLC分离(乙腈:水＝30:70)，得到5-[1-氨基-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基]喹啉-8-腈 化合物4(黄色固体，30mg，55％)。The crude product 4a was dissolved in 10 mL of hydrogen chloride-dioxane solution, stirred at room temperature for 4 h, basified by adding triethylamine, spin-dried the solvent, and separated by MPLC (acetonitrile:water=30:70) to obtain 5-[1-amino -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl]quinoline-8-carbonitrile Compound 4 (yellow solid, 30 mg, 55%).

1H NMR(400MHz,DMSO-d 6)δ8.99(dd,1H),8.63(dd,1H),8.12(d,1H),7.59(dd,1H),7.12(d,1H),3.89-3.76(m,3H),3.54(d,1H),2.39-2.32(m,2H),1.48-1.45(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.99(dd,1H), 8.63(dd,1H), 8.12(d,1H), 7.59(dd,1H), 7.12(d,1H), 3.89- 3.76 (m, 3H), 3.54 (d, 1H), 2.39-2.32 (m, 2H), 1.48-1.45 (m, 2H).

LC-MS m/z(ESI)＝319.1[M+1],341.1[M+23]。LC-MS m/z (ESI) = 319.1 [M+1], 341.1 [M+23].

实施例5Example 5

3-(4-氰基萘-1-基)-N-(8-甲基-8-氮杂二环[3.2.1]辛-3-基)-5-(三氟甲基)-3-氮杂二环[3.1.0]己烷-1-甲酰胺 化合物5-A、5-B、5-C、5-D3-(4-Cyanonaphthalen-1-yl)-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carboxamide Compounds 5-A, 5-B, 5-C, 5-D

3-(4-cyanonaphthalen-1-yl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(4-cyanonaphthalen-1-yl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

Figure PCTCN2022081400-appb-000053
Figure PCTCN2022081400-appb-000053

Figure PCTCN2022081400-appb-000054
Figure PCTCN2022081400-appb-000054

将化合物1(100mg，0.28mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(165mg，0.44mmol)和DIPEA(56mg，0.44mmol)，室温搅拌10min，加入3-氨基托烷5a(81mg，0.58mmol)，室温搅拌3h。原料反应完全，TLC分离(二氯甲烷:甲醇＝5:1)，得到目标产物3-(4-氰基萘-1-基)-N-(8-甲基-8-氮杂二环[3.2.1]辛-3-基)-5-(三氟甲基)-3-氮杂二环[3.1.0]己烷-1-甲酰胺 化合物5(黄色液体，80mg，61％)。Compound 1 (100 mg, 0.28 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (165 mg, 0.44 mmol) and DIPEA (56 mg, 0.44 mmol), stirring at room temperature for 10 min, and adding 3-aminotropin Alkane 5a (81 mg, 0.58 mmol) was stirred at room temperature for 3 h. The reaction of the raw materials was completed, and TLC separation (dichloromethane:methanol=5:1) was performed to obtain the target product 3-(4-cyanonaphthalen-1-yl)-N-(8-methyl-8-azabicyclo[ 3.2.1]Oct-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 5 (yellow liquid, 80 mg, 61%).

1H NMR(600MHz,DMSO-d 6)δ9.02-9.00(m,1H),8.63(dd,1H),8.19-8.16(m,1H),7.99(s,1H),7.62-7.59(m,1H),7.23(t,1H),3.99–3.92(m,4H),3.87-3.85(m,1H),2.22(s,3H),1.98-1.91(m,3H),1.64-1.57(m,6H),1.28-1.15(m,3H)。 1 H NMR (600MHz, DMSO-d 6 )δ9.02-9.00(m,1H), 8.63(dd,1H), 8.19-8.16(m,1H), 7.99(s,1H), 7.62-7.59(m) ,1H),7.23(t,1H),3.99-3.92(m,4H),3.87-3.85(m,1H),2.22(s,3H),1.98-1.91(m,3H),1.64-1.57(m , 6H), 1.28-1.15 (m, 3H).

19F NMR(565MHz,DMSO-d 6)δ-63.57 19 F NMR (565MHz, DMSO-d 6 ) δ-63.57

LC-MS m/z(ESI)＝470.2[M+1]。LC-MS m/z (ESI) = 470.2 [M+1].

第二步：Step 2:

3-(4-氰基萘-1-基)-N-(8-甲基-8-氮杂二环[3.2.1]辛-3-基)-5-(三氟甲基)-3-氮杂二环[3.1.0]己烷-1-甲酰胺 化合物5-A、5-B、5-C、5-D3-(4-Cyanonaphthalen-1-yl)-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-5-(trifluoromethyl)-3 -Azabicyclo[3.1.0]hexane-1-carboxamide Compounds 5-A, 5-B, 5-C, 5-D

3-(4-cyanonaphthalen-1-yl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(4-cyanonaphthalen-1-yl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

通过手性制备高效液相色谱拆分化合物5得到化合物5-A、5-B、5-C和5-D。分析方法：手性柱IG-3，流动相为乙醇+0.2％二乙胺，流速1mL/min，化合物5-A保留时间为2.997min，化合物5-B保留时间为3.376min,化合物5-C保留时间为4.809min，化合物5-D保留时间为5.385min。Compound 5 was resolved by chiral preparative high performance liquid chromatography to yield compounds 5-A, 5-B, 5-C and 5-D. Analysis method: chiral column IG-3, mobile phase is ethanol + 0.2% diethylamine, flow rate is 1mL/min, compound 5-A retention time is 2.997min, compound 5-B retention time is 3.376min, compound 5-C The retention time was 4.809 min, and the retention time of compound 5-D was 5.385 min.

实施例6Example 6

3-(8-氰基喹啉-5-基)-N-[(3R)-1-甲基吡咯烷-3-基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物63-(8-Cyanoquinolin-5-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 6

3-(8-cyanoquinolin-5-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000055
Figure PCTCN2022081400-appb-000055

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入(3S)-(9CI)1-甲基-3-吡咯烷胺6a(29mg，0.29mmol)，室温搅拌3h。原料反应完全，TLC分离(二氯甲烷:甲醇＝8:1)，得到目标产物3-(8-氰基喹啉-5-基)-N-[(3R)-1-甲基吡咯烷-3-基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物6(黄色固体，55mg，89％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, adding (3S) -(9CI)1-methyl-3-pyrrolidinamine 6a (29 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials was completed, and the TLC separation (dichloromethane:methanol=8:1) was performed to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-[(3R)-1-methylpyrrolidine- 3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 6 (yellow solid, 55 mg, 89%).

1H NMR(600MHz,DMSO-d 6)δ9.01(d,1H),8.64(d,1H),8.36(d,1H),8.18(d,1H),7.61(dd,1H),7.23(dd,1H),4.26(s,1H),4.03-4.00(m,1H),3.98-3.91(m,2H),3.83-3.81(m,1H),2.73-2.69(m,2H),2.32(s,3H),2.13-2.11(m,1H),2.00-1.97(m,1H),1.64-1.63(m,2H),1.30-1.22(m,2H)。 1 H NMR (600MHz, DMSO-d 6 )δ9.01(d,1H), 8.64(d,1H), 8.36(d,1H), 8.18(d,1H), 7.61(dd,1H), 7.23( dd,1H),4.26(s,1H),4.03-4.00(m,1H),3.98-3.91(m,2H),3.83-3.81(m,1H),2.73-2.69(m,2H),2.32( s, 3H), 2.13-2.11 (m, 1H), 2.00-1.97 (m, 1H), 1.64-1.63 (m, 2H), 1.30-1.22 (m, 2H).

19F NMR(565MHz,DMSO-d 6)δ-63.55,-69.49,-70.74 19 F NMR (565MHz, DMSO-d 6 )δ-63.55,-69.49,-70.74

LC-MS m/z(ESI)＝430.2[M+23]。LC-MS m/z (ESI) = 430.2 [M+23].

实施例7Example 7

3-(8-氰基喹啉-5-基)-N-[(3S)-1-甲基吡咯烷-3-基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物73-(8-Cyanoquinolin-5-yl)-N-[(3S)-1-methylpyrrolidin-3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 7

3-(8-cyanoquinolin-5-yl)-N-[(3S)-1-methylpyrrolidin-3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-[(3S)-1-methylpyrrolidin-3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000056
Figure PCTCN2022081400-appb-000056

Figure PCTCN2022081400-appb-000057
Figure PCTCN2022081400-appb-000057

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入3S-1-甲基-3-吡咯烷胺7a(29mg，0.29mmol)，室温搅拌3h。原料反应完全，TLC分离(二氯甲烷:甲醇＝8:1)，得到目标产物3-(8-氰基喹啉-5-基)-N-[(3S)-1-甲基吡咯烷-3-基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物7(黄色固体,42mg,68％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, and adding 3S-1 -Methyl-3-pyrrolidinamine 7a (29 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials was completed, and the TLC separation (dichloromethane:methanol=8:1) gave the target product 3-(8-cyanoquinolin-5-yl)-N-[(3S)-1-methylpyrrolidine- 3-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 7 (yellow solid, 42 mg, 68%).

1H NMR(600MHz,DMSO-d 6)δ9.02-9.01(m,1H),8.64(dd,1H),8.36(d,1H),8.18(d,1H),7.61(dd,1H),7.23(dd,1H),4.27-4.23(m,1H),4.01(t,1H),3.96-3.93(m,2H),3.82(dd,1H),2.79-2.68(m,2H),2.33(s,3H),2.13-2.10(m,1H),2.00-1.97(m,1H),1.67-1.63(m,2H),1.28-1.22(m,2H)。 1 H NMR (600MHz, DMSO-d 6 )δ9.02-9.01(m,1H), 8.64(dd,1H), 8.36(d,1H), 8.18(d,1H), 7.61(dd,1H), 7.23(dd,1H),4.27-4.23(m,1H),4.01(t,1H),3.96-3.93(m,2H),3.82(dd,1H),2.79-2.68(m,2H),2.33( s, 3H), 2.13-2.10 (m, 1H), 2.00-1.97 (m, 1H), 1.67-1.63 (m, 2H), 1.28-1.22 (m, 2H).

19F NMR(565MHz,DMSO-d 6)δ-63.53,-69.49,-70.74 19 F NMR (565MHz, DMSO-d 6 )δ-63.53,-69.49,-70.74

LC-MS m/z(ESI)＝430.1[M+1]。LC-MS m/z (ESI) = 430.1 [M+1].

实施例8Example 8

3-(8-氰基喹啉-5-基)-N-(氧杂-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物83-(8-Cyanoquinolin-5-yl)-N-(oxa-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Carboxamide Compound 8

3-(8-cyanoquinolin-5-yl)-N-(oxepan-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(oxepan-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000058
Figure PCTCN2022081400-appb-000058

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入4-氨基四氢吡喃8a(29mg，0.29mmol)，室温搅拌3h。原料反应完全，TLC分离(二氯甲烷:甲醇＝5:1)，得到目标产物3-(8-氰基喹啉-5-基)-N-(氧杂-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物8(黄色固体，50mg，81％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, and adding 4-amino Tetrahydropyran 8a (29 mg, 0.29 mmol) was stirred at room temperature for 3 h. The reaction of the raw materials is complete, and TLC separation (dichloromethane:methanol=5:1) is performed to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(oxa-4-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 8 (yellow solid, 50 mg, 81%).

1H NMR(600MHz,DMSO-d 6)δ9.01-9.00(m,1H),8.64(dd,1H),8.17(d,1H),8.11(d,1H),7.61(dd,1H),7.23(d,1H),4.02(d,1H),3.96-3.94(m,2H),3.87-3.82(m,4H),3.35-3.31(m,1H),2.69(s,1H),2.00(d,1H),1.67-1.60(m,3H),1.48-1.40(m,2H)。 1 H NMR (600MHz, DMSO-d 6 )δ9.01-9.00(m,1H), 8.64(dd,1H), 8.17(d,1H), 8.11(d,1H), 7.61(dd,1H), 7.23(d,1H),4.02(d,1H),3.96-3.94(m,2H),3.87-3.82(m,4H),3.35-3.31(m,1H),2.69(s,1H),2.00( d, 1H), 1.67-1.60 (m, 3H), 1.48-1.40 (m, 2H).

19F NMR(565MHz,DMSO-d 6)δ-63.58 19 F NMR (565MHz, DMSO-d 6 ) δ-63.58

LC-MS m/z(ESI)＝453.1[M+23]。LC-MS m/z (ESI) = 453.1 [M+23].

实施例9Example 9

N-(8-氮杂双环[3.2.1]辛烷-外-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物9N-(8-Azabicyclo[3.2.1]octane-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide Compound 9

N-(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamide

Figure PCTCN2022081400-appb-000059
Figure PCTCN2022081400-appb-000059

第一步：first step:

N-叔丁氧羰基-(8-氮杂双环[3.2.1]辛烷-外-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 9bN-tert-Butoxycarbonyl-(8-azabicyclo[3.2.1]octane-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide 9b

N-Boc-(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-Boc-(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg,0.22mmol)和DIPEA(27.9mg,0.22mmol)，室温搅拌10min，加入N-Boc-exo-3-氨基托烷9a(65.6mg，0.29mmol)，室温搅拌3h。原料反应完全，加水淬灭反应，旋干溶剂，直接投一步反应。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, and adding N-Boc -exo-3-aminotropane 9a (65.6 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials is complete, the reaction is quenched by adding water, the solvent is spin-dried, and the one-step reaction is directly added.

第二步：Step 2:

N-(8-氮杂双环[3.2.1]辛烷-外-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物9N-(8-Azabicyclo[3.2.1]octane-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide Compound 9

N-(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-(8-azabicyclo[3.2.1]octan-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamide

将上述粗产物9a溶于氯化氢二氧六环溶液中，室温搅拌3h，原料反应完全，MPLC分离(乙腈:水＝43:57)，得到目标产物N-(8-氮杂双环[3.2.1]辛烷-外-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物9(黄色固体，58mg，91％)。The above crude product 9a was dissolved in a hydrogen chloride dioxane solution, stirred at room temperature for 3h, the reaction of the raw materials was complete, and MPLC separation (acetonitrile:water=43:57) was performed to obtain the target product N-(8-azabicyclo[3.2.1] ]octane-exo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-methyl Amide Compound 9 (yellow solid, 58 mg, 91%).

1H NMR(600MHz,DMSO-d 6)δ9.01-9.00(m,1H),8.63(dd,1H),8.36-8.34(m,1H),8.17(d,1H),7.61(dd,1H),7.22(d,1H),3.97-3.79(m,5H),2.01-1.90(m,3H),1.86-1.81(m, 2H),1.77-1.72(m,5H),1.34-0.97(m,3H)。 1 H NMR (600MHz, DMSO-d 6 )δ9.01-9.00(m,1H), 8.63(dd,1H), 8.36-8.34(m,1H), 8.17(d,1H), 7.61(dd,1H) ), 7.22(d, 1H), 3.97-3.79(m, 5H), 2.01-1.90(m, 3H), 1.86-1.81(m, 2H), 1.77-1.72(m, 5H), 1.34-0.97(m , 3H).

19F NMR(565MHz,DMSO-d 6)δ-63.61 19 F NMR (565MHz, DMSO-d 6 ) δ-63.61

LC-MS m/z(ESI)＝456.2[M+1],478.2[M+23]。LC-MS m/z (ESI) = 456.2 [M+1], 478.2 [M+23].

实施例10Example 10

氮-(8-氮杂双环[3.2.1]辛烷-内-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物10Aza-(8-azabicyclo[3.2.1]octane-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide Compound 10

N-(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamide

Figure PCTCN2022081400-appb-000060
Figure PCTCN2022081400-appb-000060

第一步：first step:

N-叔丁氧羰基-(8-氮杂双环[3.2.1]辛烷-内-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 10bN-tert-Butoxycarbonyl-(8-azabicyclo[3.2.1]octane-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide 10b

N-Boc-(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-Boc-(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入N-Boc-exo-3-氨基托烷10a(65.6mg，0.29mmol)，室温搅拌3h。原料反应完全，加水淬灭反应，旋干溶剂，直接投一步反应。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, and adding N-Boc -exo-3-aminotropane 10a (65.6 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials is complete, the reaction is quenched by adding water, the solvent is spin-dried, and the one-step reaction is directly added.

第二步：Step 2:

N-(8-氮杂双环[3.2.1]辛烷-内-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物10N-(8-Azabicyclo[3.2.1]octane-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide Compound 10

N-(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-(8-azabicyclo[3.2.1]octan-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamide

将上述粗产物10a溶于氯化氢二氧六环溶液中，室温搅拌3h，原料反应完全，MPLC分离(乙腈:水＝43:57)，得到目标产物N-(8-氮杂双环[3.2.1]辛烷-内-3-基)-3-(4-氰基萘-1-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物10(黄色固体，58mg，91％)。The above crude product 10a was dissolved in a hydrogen chloride dioxane solution, stirred at room temperature for 3h, the reaction of the raw materials was complete, and MPLC separation (acetonitrile:water=43:57) was performed to obtain the target product N-(8-azabicyclo[3.2.1] ]octane-endo-3-yl)-3-(4-cyanonaphthalen-1-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-methyl Amide Compound 10 (yellow solid, 58 mg, 91%).

1H NMR(600MHz,DMSO-d 6)δ9.01(d,1H),8.63(d,1H),8.17(d,1H),8.03(s,1H),7.60(dd,1H),7.23(d,1H),4.01-3.61(m,5H),2.23-2.18(m,2H),1.99(d,1H),1.71-1.23(m,7H),0.43-0.22(m,3H)。 1 H NMR (600MHz, DMSO-d 6 )δ9.01(d,1H), 8.63(d,1H), 8.17(d,1H), 8.03(s,1H), 7.60(dd,1H), 7.23( d, 1H), 4.01-3.61 (m, 5H), 2.23-2.18 (m, 2H), 1.99 (d, 1H), 1.71-1.23 (m, 7H), 0.43-0.22 (m, 3H).

19F NMR(565MHz,DMSO-d 6)δ-63.64 19 F NMR (565MHz, DMSO-d 6 ) δ-63.64

LC-MS m/z(ESI)＝456.2[M+1]。LC-MS m/z (ESI) = 456.2 [M+1].

实施例11Example 11

3-(8-氰基喹啉-5-基)-N-(1-环丙基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物113-(8-Cyanoquinolin-5-yl)-N-(1-cyclopropylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxamide Compound 11

3-(8-cyanoquinolin-5-yl)-N-(1-cyclopropylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-cyclopropylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000061
Figure PCTCN2022081400-appb-000061

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入4-氨基-1-环丙基哌啶11a(40.7mg，0.29mmol)，室温搅拌3h。原料反应完全，依次用N,N-二甲基甲酰胺、水、甲醇、丙酮打浆，过滤，得到目标产物3-(8-氰基喹啉-5-基)-氮-(1-环丙基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物11(黄色固体，19mg，29％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, and adding 4-amino -1-Cyclopropylpiperidine 11a (40.7 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials is complete, and successively beats with N,N-dimethylformamide, water, methanol, and acetone, and filters to obtain the target product 3-(8-cyanoquinolin-5-yl)-nitrogen-(1-cyclopropane) ylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 11 (yellow solid, 19 mg, 29%).

1H NMR(600MHz,DMSO-d 6)δ9.01(d,1H),8.64(d,1H),8.17(d,1H),8.06-7.98(m,1H),7.60(dd,1H),7.22(d,1H),4.01-3.82(m,4H),2.93-2.84(m,1H),2.23-2.12(m,3H),1.99(d,2H),1.74-1.53(m,5H),1.47-1.23(m,2H),0.40-0.20(m,3H)。 1 H NMR (600MHz, DMSO-d 6 )δ9.01(d,1H), 8.64(d,1H), 8.17(d,1H), 8.06-7.98(m,1H), 7.60(dd,1H), 7.22(d,1H), 4.01-3.82(m,4H), 2.93-2.84(m,1H), 2.23-2.12(m,3H), 1.99(d,2H), 1.74-1.53(m,5H), 1.47-1.23 (m, 2H), 0.40-0.20 (m, 3H).

19F NMR(565MHz,DMSO-d 6)δ-63.61 19 F NMR (565MHz, DMSO-d 6 ) δ-63.61

LC-MS m/z(ESI)＝470.2[M+1],492.2[M+23]。LC-MS m/z (ESI) = 470.2 [M+1], 492.2 [M+23].

实施例12Example 12

3-(4-氰基萘-1-基)-N-(2-(二乙氨基)乙基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物123-(4-Cyanonaphthalen-1-yl)-N-(2-(diethylamino)ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-Carboxamide Compound 12

3-(4-cyanonaphthalen-1-yl)-N-(2-(diethylamino)ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(4-cyanonaphthalen-1-yl)-N-(2-(diethylamino)ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000062
Figure PCTCN2022081400-appb-000062

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入N,N-二乙基乙二胺12a(34mg，0.29mmol)，室温搅拌3h。原料反应完全，MPLC分离(乙腈:水＝25％:75％)，得到目标产物3-(4-氰基萘-1-基)-N-(2-(二乙氨基)乙基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物12(黄色油状液体，42mg，67％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, adding N,N - Diethylethylenediamine 12a (34 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 25%: 75%) was performed to obtain the target product 3-(4-cyanonaphthalen-1-yl)-N-(2-(diethylamino)ethyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 12 (yellow oily liquid, 42 mg, 67%).

1H NMR(400MHz,DMSO-d 6)δ9.02(dd,1H),8.64-8.62(m,1H),8.58-8.47(m,1H),8.19(d,1H),7.62(dd,1H),7.24(d,1H),3.98-3.79(m,4H),3.21-3.04(m,4H),2.73-2.67(m,2H),2.33-2.32(m,2H),1.99-1.98(m,1H),1.75-1.70(m,1H),1.28-1.13(m,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.02(dd,1H), 8.64-8.62(m,1H), 8.58-8.47(m,1H), 8.19(d,1H), 7.62(dd,1H) ), 7.24(d, 1H), 3.98-3.79(m, 4H), 3.21-3.04(m, 4H), 2.73-2.67(m, 2H), 2.33-2.32(m, 2H), 1.99-1.98(m , 1H), 1.75-1.70 (m, 1H), 1.28-1.13 (m, 6H).

19F NMR(376MHz,DMSO-d 6)δ-73.51 19 F NMR (376MHz, DMSO-d 6 ) δ-73.51

LC-MS m/z(ESI)＝446.2[M+1],468.1[M+23]。LC-MS m/z (ESI) = 446.2 [M+1], 468.1 [M+23].

实施例13Example 13

3-(8-氰基喹啉-5-基)-N-[(1R,5S)-1,5-二氢-3-氮杂双环[3.1.0]己-6-基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物133-(8-Cyanoquinolin-5-yl)-N-[(1R,5S)-1,5-dihydro-3-azabicyclo[3.1.0]hex-6-yl]-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 13

3-(8-cyanoquinolin-5-yl)-N-[(1R,5S)-1,5-dihydrogenio-3-azabicyclo[3.1.0]hexan-6-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-[(1R,5S)-1,5-dihydrogenio-3-azabicyclo[3.1.0]hexan-6-yl]-5-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000063
Figure PCTCN2022081400-appb-000063

第一步：first step:

叔丁基-6-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-酰胺]-1,5-二 氢-3-氮杂双环[3.1.0]-3-羧酸己酯 13atert-Butyl-6-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amide]-1 ,5-Dihydro-3-azabicyclo[3.1.0]-3-carboxylate hexyl ester 13a

tert-butyl-6-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido]-1,5-dihydrogenio-3-azabicyclo[3.1.0]hexane-3-carboxylatetert-butyl-6-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido]-1,5-dihydrogenio-3-azabicyclo[ 3.1.0]hexane-3-carboxylate

将化合物1(50mg,0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入(1R,5S,6S)-6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(57.5mg，0.29mmol)，室温搅拌3h。原料反应完全，加水淬灭反应，MPLC纯化(乙腈:水＝75％:25％)，得到黄色固体，直接投下一步反应。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, adding (1R, 5S,6S)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (57.5 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials was completed, and the reaction was quenched by adding water, and purified by MPLC (acetonitrile:water=75%:25%) to obtain a yellow solid, which was directly used in the next reaction.

第二步：Step 2:

3-(8-氰基喹啉-5-基)-N-[(1R,5S)-1,5-二氢-3-氮杂双环[3.1.0]己-6-基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物133-(8-Cyanoquinolin-5-yl)-N-[(1R,5S)-1,5-dihydro-3-azabicyclo[3.1.0]hex-6-yl]-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 13

3-(8-cyanoquinolin-5-yl)-N-[(1R,5S)-1,5-dihydrogenio-3-azabicyclo[3.1.0]hexan-6-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-[(1R,5S)-1,5-dihydrogenio-3-azabicyclo[3.1.0]hexan-6-yl]-5-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane-1-carboxamide

将13a溶解于氯化氢二氧六环溶液中，室温搅拌3h。待原料反应完，旋干溶剂，MPLC纯化(乙腈:水＝45％:55％)，3-(8-氰基喹啉-5-基)-N-[(1R,5S)-1,5-二氢-3-氮杂双环[3.1.0]己-6-基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物13(淡黄色固体，33mg，55％)。13a was dissolved in hydrogen chloride dioxane solution and stirred at room temperature for 3h. After the reaction of the raw materials, the solvent was spin-dried and purified by MPLC (acetonitrile: water = 45%: 55%), 3-(8-cyanoquinolin-5-yl)-N-[(1R,5S)-1,5 -Dihydro-3-azabicyclo[3.1.0]hex-6-yl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 13 ( pale yellow solid, 33 mg, 55%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.62(dd,1H),8.19-8.16(m,2H),7.60(dd,1H),7.21(d,1H),3.98-3.78(m,4H),2.99(d,2H),2.77(d,2H),2.67-2.66(m,1H),2.34-2.32(m,1H),1.95(d,1H),1.62(d,1H),1.51(d,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.01 (dd, 1H), 8.62 (dd, 1H), 8.19-8.16 (m, 2H), 7.60 (dd, 1H), 7.21 (d, 1H), 3.98-3.78(m, 4H), 2.99(d, 2H), 2.77(d, 2H), 2.67-2.66(m, 1H), 2.34-2.32(m, 1H), 1.95(d, 1H), 1.62( d, 1H), 1.51 (d, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.58 19 F NMR (376MHz, DMSO-d 6 ) δ-63.58

LC-MS m/z(ESI)＝428.2[M+1],450.2[M+23]。LC-MS m/z (ESI) = 428.2 [M+1], 450.2 [M+23].

实施例14Example 14

N-[(3aR,6aR)-3a,6a-二氢-八氢环戊[c]吡咯-5-基]-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物14N-[(3aR,6aR)-3a,6a-dihydro-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 14

N-[(3aR,6aR)-3a,6a-dihydrogenio-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-[(3aR,6aR)-3a,6a-dihydrogenio-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000064
Figure PCTCN2022081400-appb-000064

第一步：first step:

叔丁基(3aR,6aR)-5-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-酰 胺]-3a,6a-二氢-八氢环戊[c]吡咯-2-羧酸酯14atert-Butyl(3aR,6aR)-5-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 -Amide]-3a,6a-dihydro-octahydrocyclopenta[c]pyrrole-2-carboxylate 14a

tert-butyl(3aR,6aR)-5-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido]-3a,6a-dihydrogenio-octahydrocyclopenta[c]pyrrole-2-carboxylatetert-butyl(3aR,6aR)-5-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido]-3a,6a-dihydrogenio -octahydrocyclopenta[c]pyrrole-2-carboxylate

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入反式-5-氨基-2-BOC-六氢-环戊二烯并[C]吡咯盐酸盐(76.2mg，0.29mmol)，室温搅拌3h。原料反应完全，加水淬灭反应，MPLC纯化(乙腈:水＝65％:35％)，得到黄色固体14a，直接投下一步反应。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, adding trans- 5-Amino-2-BOC-hexahydro-cyclopentadieno[C]pyrrole hydrochloride (76.2 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials was completed, and the reaction was quenched by adding water, and purified by MPLC (acetonitrile:water=65%:35%) to obtain a yellow solid 14a, which was directly used in the next reaction.

第二步：Step 2:

N-[(3aR,6aR)-3a,6a-二氢-八氢环戊[c]吡咯-5-基]-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物14N-[(3aR,6aR)-3a,6a-dihydro-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 14

N-[(3aR,6aR)-3a,6a-dihydrogenio-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-[(3aR,6aR)-3a,6a-dihydrogenio-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]hexane-1-carboxamide

将14a溶解于氯化氢二氧六环溶液中，室温搅拌3h。待原料反应完，旋干溶剂，MPLC纯化(乙腈:水＝45％:55％)，N-[(3aR,6aR)-3a,6a-二氢-八氢环戊[c]吡咯-5-基]-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物14(淡黄色固体，22mg，35％)。14a was dissolved in hydrogen chloride dioxane solution and stirred at room temperature for 3h. After the reaction of the raw materials, the solvent was spin-dried and purified by MPLC (acetonitrile: water = 45%: 55%), N-[(3aR,6aR)-3a,6a-dihydro-octahydrocyclopenta[c]pyrrole-5- base]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 14 (pale yellow solid , 22mg, 35%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.63(dd,1H),8.17(d,1H),8.03-8.01(m,1H),7.60(dd,1H),7.22(d,1H),4.21-3.80(m,6H),3.06-3.0(m,2H),2.68-2.66(m,1H),2.34-2.32(m,2H),2.00-1.95(m,1H),1.75-1.56(m,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.63(dd,1H), 8.17(d,1H), 8.03-8.01(m,1H), 7.60(dd,1H), 7.22(d,1H), 4.21-3.80(m,6H), 3.06-3.0(m,2H), 2.68-2.66(m,1H), 2.34-2.32(m,2H), 2.00-1.95(m,1H) ), 1.75-1.56 (m, 6H).

19F NMR(376MHz,DMSO-d 6)δ-63.70 19 F NMR (376MHz, DMSO-d 6 ) δ-63.70

LC-MS m/z(ESI)＝456.2[M+1],478.2[M+23]。LC-MS m/z (ESI) = 456.2 [M+1], 478.2 [M+23].

实施例15Example 15

N-[(3aR,6aR)-3a,6a-二氢-2-甲基-八氢环戊[c]吡咯-5-基]-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物15N-[(3aR,6aR)-3a,6a-dihydro-2-methyl-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 15

N-[(3aR,6aR)-3a,6a-dihydrogenio-2-methyl-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-[(3aR,6aR)-3a,6a-dihydrogenio-2-methyl-octahydrocyclopenta[c]pyrrol-5-yl]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000065
Figure PCTCN2022081400-appb-000065

将化合物14(100mg，0.22mmol)溶解于甲醇5mL中，随后加入多聚甲醛(139mg，1.54mmol)和氰基硼氢化钠(25mg，0.66mmol)，加热回流3h。原料反应完全，水淬 灭反应。MPLC分离(乙腈:水＝45％:55％)，得到目标产物N-[(3aR,6aR)-3a,6a-二氢-2-甲基-八氢环戊[c]吡咯-5-基]-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物15(黄色固体，25mg，24％)。Compound 14 (100 mg, 0.22 mmol) was dissolved in 5 mL of methanol, followed by adding paraformaldehyde (139 mg, 1.54 mmol) and sodium cyanoborohydride (25 mg, 0.66 mmol), and heating under reflux for 3 h. The reaction of the starting material was complete, and the reaction was quenched with water. MPLC separation (acetonitrile:water=45%:55%), the target product N-[(3aR,6aR)-3a,6a-dihydro-2-methyl-octahydrocyclopenta[c]pyrrol-5-yl was obtained ]-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 15 (yellow solid, 25 mg ,twenty four%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,J＝4.1,1.4Hz,1H),8.63(dd,J＝8.7,1.4Hz,1H),8.16(d,J＝8.2Hz,1H),7.98(d,J＝7.5Hz,1H),7.60(dd,J＝8.7,4.2Hz,1H),7.21(d,J＝8.3Hz,1H),4.31-4.21(m,1H),4.01-3.80(m,4H),2.64-2.60(m,2H),2.32-2.25(m,6H),1.97(d,J＝4.0Hz,1H),1.62-1.59(m,5H),1.23(s,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.00 (dd, J=4.1, 1.4Hz, 1H), 8.63 (dd, J=8.7, 1.4Hz, 1H), 8.16 (d, J=8.2Hz, 1H), 7.98(d, J＝7.5Hz, 1H), 7.60(dd, J＝8.7, 4.2Hz, 1H), 7.21(d, J＝8.3Hz, 1H), 4.31-4.21(m, 1H), 4.01-3.80(m, 4H), 2.64-2.60(m, 2H), 2.32-2.25(m, 6H), 1.97(d, J=4.0Hz, 1H), 1.62-1.59(m, 5H), 1.23( s, 1H).

19F NMR(376MHz,DMSO-d 6)δ-63.70 19 F NMR (376MHz, DMSO-d 6 ) δ-63.70

LC-MS m/z(ESI)＝470.2[M+1],492.2[M+23]。LC-MS m/z (ESI) = 470.2 [M+1], 492.2 [M+23].

实施例16Example 16

3-(8-三氟甲基喹啉-5-基)-N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物163-(8-Trifluoromethylquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ] Hexane-1-carboxamide Compound 16

3-(8-trifluoromethylquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-trifluoromethylquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000066
Figure PCTCN2022081400-appb-000066

第一步：first step:

3-(8-三氟甲基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯16bEthyl 3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 16b

3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

N 2氛围下，将1e(193mg，0.84mmol)溶于1,4-二氧六环10mL中，随后加入16a(250mg，0.9mmol)，N 2置换气三次，依次加入碳酸铯(1.23g，3.8mmol)和Ruphos Pdg3(70mg，0.084mmol),N 2置换气三次,升温至90℃反应2.5h。硅藻土过滤，旋干溶剂，粗产物16b直接投下一步。 Under N 2 atmosphere, 1e (193 mg, 0.84 mmol) was dissolved in 1,4-dioxane 10 mL, then 16a (250 mg, 0.9 mmol) was added, N 2 was replaced three times, and cesium carbonate (1.23 g, 0.9 mmol) was added successively. 3.8 mmol) and Ruphos Pdg3 (70 mg, 0.084 mmol), N 2 replaced the gas three times, and the temperature was raised to 90 ° C for 2.5 h. Celite was filtered, the solvent was spin-dried, and the crude product 16b was directly put into the next step.

LC-MS m/z(ESI)＝419.1[M+1],441.1[M+23]。LC-MS m/z (ESI) = 419.1 [M+1], 441.1 [M+23].

第二步：Step 2:

3-(8-三氟甲基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸16c3-(8-Trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 16c

3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

将16b的粗产品(351mg，0.84mmol)溶于四氢呋喃溶液10mL中，将无水氢氧化 锂(201mg，8.4mmol)的水溶液10mL滴入反应液中，室温搅拌过夜。待反应结束，旋干四氢呋喃，乙酸乙酯萃取，保留水相，用2M盐酸水溶液将水相PH调至3-4，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，真空除去溶剂。MPLC分离(乙腈:水＝47:53)，得到目标产物3-(8-三氟甲基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸 16c(黄色固体，271mg，83％)。The crude product of 16b (351 mg, 0.84 mmol) was dissolved in 10 mL of tetrahydrofuran solution, and 10 mL of an aqueous solution of anhydrous lithium hydroxide (201 mg, 8.4 mmol) was added dropwise to the reaction solution, and stirred at room temperature overnight. After the reaction is over, spin dry tetrahydrofuran, extract with ethyl acetate, keep the aqueous phase, adjust the pH of the aqueous phase to 3-4 with 2M aqueous hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and vacuum Remove the solvent. MPLC separation (acetonitrile:water=47:53), the target product 3-(8-trifluoromethylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]hexane-1-carboxylic acid 16c (yellow solid, 271 mg, 83%).

1H NMR(400MHz,DMSO-d 6)δ13.26(s,1H),9.00(dd,J＝4.1,1.6Hz,1H),8.60(dd,J＝8.7,1.7Hz,1H),8.02(d,J＝8.1Hz,1H),7.62(dd,J＝8.6,4.1Hz,1H),7.30(d,J＝8.2Hz,1H),3.89-3.53(m,4H),2.04-2.00(m,2H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.26 (s, 1H), 9.00 (dd, J=4.1, 1.6 Hz, 1H), 8.60 (dd, J=8.7, 1.7 Hz, 1H), 8.02 ( d, J＝8.1Hz, 1H), 7.62(dd, J＝8.6, 4.1Hz, 1H), 7.30(d, J＝8.2Hz, 1H), 3.89-3.53(m, 4H), 2.04-2.00(m , 2H).

19F NMR(376MHz,DMSO-d 6)δ-58.04,-61.99 19 F NMR (376MHz, DMSO-d 6 )δ-58.04,-61.99

LC-MS m/z(ESI)＝391.1[M+1],413.0[M+23]。LC-MS m/z (ESI) = 391.1 [M+1], 413.0 [M+23].

第三步：third step:

3-(8-三氟甲基喹啉-5-基)-N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物163-(8-Trifluoromethylquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ] Hexane-1-carboxamide Compound 16

3-(8-trifluoromethylquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-trifluoromethylquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将16c(50mg，0.13mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(76.5mg，0.2mmol)和DIPEA(26mg，0.2mmol)，室温搅拌10min，加入4-氨基-1-甲基哌啶(30mg，0.26mmol)，室温搅拌3h。原料反应完全，加水淬灭，MPLC纯化，得到目标产物3-(8-三氟甲基喹啉-5-基)-N-(1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物16(白色固体，17mg，27％)。16c (50 mg, 0.13 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (76.5 mg, 0.2 mmol) and DIPEA (26 mg, 0.2 mmol), stirring at room temperature for 10 min, adding 4-amino- 1-Methylpiperidine (30 mg, 0.26 mmol) was stirred at room temperature for 3 h. The reaction of the raw materials was complete, quenched by adding water, and purified by MPLC to obtain the target product 3-(8-trifluoromethylquinolin-5-yl)-N-(1-methylpiperidin-4-yl)-5-(trifluoromethylquinolin-5-yl)-5-(trifluoromethylquinolin-5-yl)- Fluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 16 (white solid, 17 mg, 27%).

1H NMR(400MHz,DMSO-d 6)δ9.00-8.99(m,1H),8.58(dd,J＝8.5,1.6Hz,1H),8.04-8.02(m,2H),7.61(dd,J＝8.6,4.0Hz,1H),7.29(d,J＝8.7Hz,1H),3.93-3.69(m,4H),2.78-2.66(m,3H),2.33-2.32(m,2H),2.16-2.13(m,3H),1.98(d,J＝6.1Hz,1H),1.78-1.75(m,1H),1.70-1.39(m,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.00-8.99 (m, 1H), 8.58 (dd, J=8.5, 1.6 Hz, 1H), 8.04-8.02 (m, 2H), 7.61 (dd, J =8.6,4.0Hz,1H),7.29(d,J=8.7Hz,1H),3.93-3.69(m,4H),2.78-2.66(m,3H),2.33-2.32(m,2H),2.16- 2.13 (m, 3H), 1.98 (d, J=6.1 Hz, 1H), 1.78-1.75 (m, 1H), 1.70-1.39 (m, 4H).

19F NMR(376MHz,DMSO-d 6)δ-57.99,-63.49 19 F NMR (376MHz, DMSO-d 6 )δ-57.99,-63.49

LC-MS m/z(ESI)＝487.2[M+1],509.2[M+23]。LC-MS m/z (ESI) = 487.2 [M+1], 509.2 [M+23].

实施例17Example 17

5-(1-[(4-(吗啉-4-基)哌啶-1-基)甲基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基)喹啉-8-甲腈 化合物175-(1-[(4-(Morpholin-4-yl)piperidin-1-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3 -yl)quinoline-8-carbonitrile Compound 17

5-(1-[(4-(morpholin-4-yl)piperidin-1-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-[(4-(morpholin-4-yl)piperidin-1-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure PCTCN2022081400-appb-000067
Figure PCTCN2022081400-appb-000067

将化合物17a(100mg，0.21mmol，制备方法见实施例56、57)溶解于N,N-二甲基甲酰胺2mL中，随后加入4-(4-哌啶基)吗啉(53mg，0.31mmol)，碳酸钾(58mg，0.42 mmol)和碘化钠(32mg，0.21mmol)，100℃避光搅拌3h。原料反应完全，MPLC分离(乙腈:水＝45％:55％)，得到目标产物5-(1-[(4-(吗啉-4-基)哌啶-1-基)甲基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基)喹啉-8-甲腈 化合物17(黄色固体，50mg，49％)。Compound 17a (100 mg, 0.21 mmol, see Examples 56 and 57 for the preparation method) was dissolved in N,N-dimethylformamide 2 mL, followed by the addition of 4-(4-piperidinyl)morpholine (53 mg, 0.31 mmol). ), potassium carbonate (58 mg, 0.42 mmol) and sodium iodide (32 mg, 0.21 mmol), and stirred at 100 °C for 3 h in the dark. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 45%: 55%) was performed to obtain the target product 5-(1-[(4-(morpholin-4-yl)piperidin-1-yl)methyl]-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile Compound 17 (yellow solid, 50 mg, 49%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,J＝4.1,1.4Hz,1H),8.72-8.56(m,1H),8.13(d,J＝8.2Hz,1H),7.61(dd,J＝8.7,4.2Hz,1H),7.18(d,J＝8.3Hz,1H),3.97(dd，J＝8.0Hz,1H),3.81-3.73(m,2H),3.59-3.54(m,5H),2.21-2.11(m,1H),2.97-2.83(m,2H),2.44-2.40(m,4H),2.33-2.20(m,1H),2.17-1.94(m,2H),1.88-1.65(m,3H),1.61-1.57(m,1H),1.44-1.32(m,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.00 (dd, J=4.1, 1.4Hz, 1H), 8.72-8.56 (m, 1H), 8.13 (d, J=8.2Hz, 1H), 7.61 ( dd,J=8.7,4.2Hz,1H),7.18(d,J=8.3Hz,1H),3.97(dd,J=8.0Hz,1H),3.81-3.73(m,2H),3.59-3.54(m ,5H),2.21-2.11(m,1H),2.97-2.83(m,2H),2.44-2.40(m,4H),2.33-2.20(m,1H),2.17-1.94(m,2H),1.88 -1.65(m, 3H), 1.61-1.57(m, 1H), 1.44-1.32(m, 3H).

19F NMR(376MHz,DMSO-d 6)δ-61.86 19 F NMR (376MHz, DMSO-d 6 ) δ-61.86

LC-MS m/z(ESI)＝486.2[M+1],508.2[M+23]。LC-MS m/z (ESI) = 486.2 [M+1], 508.2 [M+23].

实施例18Example 18

3-(8-氰基喹啉-5-基)-N-(1-(丙-2-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物18-A和化合物18-B3-(8-Cyanoquinolin-5-yl)-N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compound 18-A and Compound 18-B

3-(8-cyanoquinolin-5-yl)-N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000068
Figure PCTCN2022081400-appb-000068

第一步：first step:

3-(8-氰基喹啉-5-基)-N-(1-(丙-2-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物183-(8-Cyanoquinolin-5-yl)-N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compound 18

3-(8-cyanoquinolin-5-yl)-N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入1-异丙基-4-哌啶胺18a(41mg，0.29mmol)，室温搅拌3h。原料反应完全，MPLC分离(乙腈:水＝45％:55％)，得到目标产物3-(8-氰基喹啉-5-基)-N-(1-(丙-2-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物18(黄色固体，60mg，91％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, and adding 1-iso Propyl-4-piperidinamine 18a (41 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 45%: 55%) was performed to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(1-(propan-2-yl)piperidine -4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 18 (yellow solid, 60 mg, 91%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.63(dd,1H),8.16(d,1H),8.09(d,8.0Hz,1H),7.60(dd,1H),7.22(d,1H),4.03-3.81(m,4H),2.90-2.73(m,4H),2.29(s,2H),1.99(d,1H),1.75-1.46(m,5H),0.99(d,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.00(dd,1H), 8.63(dd,1H), 8.16(d,1H), 8.09(d,8.0Hz,1H), 7.60(dd,1H) ,7.22(d,1H),4.03-3.81(m,4H),2.90-2.73(m,4H),2.29(s,2H),1.99(d,1H),1.75-1.46(m,5H),0.99 (d, 6H).

19F NMR(565MHz,DMSO-d 6)δ-63.61 19 F NMR (565MHz, DMSO-d 6 ) δ-63.61

LC-MS m/z(ESI)＝472.2[M+1],494.2[M+23]。LC-MS m/z (ESI) = 472.2 [M+1], 494.2 [M+23].

第二步：Step 2:

3-(8-氰基喹啉-5-基)-N-(1-(丙-2-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物18-A和化合物18-B3-(8-Cyanoquinolin-5-yl)-N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compound 18-A and Compound 18-B

3-(8-cyanoquinolin-5-yl)-N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-(propan-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

通过手性制备高效液相色谱拆分化合物18制备得到化合物18-A和化合物18-B。分析方法：手性柱AD-3，流动相为乙醇+0.2％二乙胺，流速1mL/min,化合物18-A保留时间为3.101min，化合物18-B保留时间为5.757min。Compound 18-A and compound 18-B were prepared by resolving compound 18 by chiral preparative high performance liquid chromatography. Analysis method: chiral column AD-3, mobile phase is ethanol + 0.2% diethylamine, flow rate is 1 mL/min, retention time of compound 18-A is 3.101 min, and retention time of compound 18-B is 5.757 min.

实施例19Example 19

3-(8-氰基喹啉-5-基)-氮-(反式-4-甲氧基环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物193-(8-Cyanoquinolin-5-yl)-nitrogen-(trans-4-methoxycyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxamide Compound 19

3-(8-cyanoquinolin-5-yl)-N-(trans-4-methoxycyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(trans-4-methoxycyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000069
Figure PCTCN2022081400-appb-000069

将化合物1(55mg，0.16mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入反式-4-甲氧基环己胺 19a(31.0mg，0.24mmol)，室温搅拌1h。TLC监测反应完毕，将反应液加入15mL水中，加入乙酸乙酯萃取两次，合并有机相用饱和食盐水洗两遍(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物3-(8-氰基喹啉-5-基)-氮-(反式-4-甲氧基环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物19(黄色固体，65mg，88.7％)。Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding trans-form -4-Methoxycyclohexylamine 19a (31.0 mg, 0.24 mmol), stirred at room temperature for 1 h. The completion of the reaction was monitored by TLC, the reaction solution was added to 15 mL of water, extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and filtered through a silica gel column. Purified by chromatography (dichloromethane:methanol=10:1) to obtain the target product 3-(8-cyanoquinolin-5-yl)-nitrogen-(trans-4-methoxycyclohexyl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 19 (yellow solid, 65 mg, 88.7%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.64(dd,1H),8.17(d,1H),8.00(d,1H),7.60(dd,1H),7.22(d,1H),4.00(d,1H),3.94(dd,2H),3.82(d,1H),3.63-3.55(m,1H),3.22(s,3H),3.11-3.04(m,1H),1.98(d,3H),1.79-1.68(m,2H),1.62(d,1H),1.30-1.21(m,2H),1.20-1.11(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.64(dd,1H), 8.17(d,1H), 8.00(d,1H), 7.60(dd,1H), 7.22( d, 1H), 4.00(d, 1H), 3.94(dd, 2H), 3.82(d, 1H), 3.63-3.55(m, 1H), 3.22(s, 3H), 3.11-3.04(m, 1H) , 1.98(d, 3H), 1.79-1.68(m, 2H), 1.62(d, 1H), 1.30-1.21(m, 2H), 1.20-1.11(m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.58 19 F NMR (376MHz, DMSO-d 6 ) δ-63.58

LC-MS m/z(ESI)＝459.2[M+1]。LC-MS m/z (ESI) = 459.2 [M+1].

实施例20Example 20

3-(8-氰基喹啉-5-基)-N-(反式-4-甲基环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物203-(8-Cyanoquinolin-5-yl)-N-(trans-4-methylcyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxamide Compound 20

3-(8-cyanoquinolin-5-yl)-N-(trans-4-methylcyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(trans-4-methylcyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000070
Figure PCTCN2022081400-appb-000070

将化合物1(55mg，0.16mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入反式4-甲基环己胺盐酸盐 20a(35.9mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中，加入乙酸乙酯萃取两次，合并有机相用饱和食盐水洗两遍(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物3-(8-氰基喹啉-5-基)-N-(反式-4-甲基环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物20(黄色固体，64mg，91.9％)。Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding trans-form 4-Methylcyclohexylamine hydrochloride 20a (35.9 mg, 0.24 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a silica gel column layer was used. analytical purification (dichloromethane: methanol = 10: 1) to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(trans-4-methylcyclohexyl)-5-(tri Fluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 20 (yellow solid, 64 mg, 91.9%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.64(dd,1H),8.17(d,1H),7.98(d,1H),7.60(dd,1H),7.22(d,1H),4.01(d,1H),3.93(dd,2H),3.81(d,1H),3.60-3.50(m,1H),1.99(d,1H),1.81-1.64(m,4H),1.61(d,1H),1.39-1.26(m,1H),1.25-1.15(m,2H),0.99-0.90(m,2H),0.86(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.64(dd,1H), 8.17(d,1H), 7.98(d,1H), 7.60(dd,1H), 7.22( d,1H),4.01(d,1H),3.93(dd,2H),3.81(d,1H),3.60-3.50(m,1H),1.99(d,1H),1.81-1.64(m,4H) , 1.61(d, 1H), 1.39-1.26(m, 1H), 1.25-1.15(m, 2H), 0.99-0.90(m, 2H), 0.86(d, 3H).

19F NMR(376MHz,DMSO-d 6)δ-63.53 19 F NMR (376MHz, DMSO-d 6 ) δ-63.53

LC-MS m/z(ESI)＝443.2[M+1]。LC-MS m/z (ESI) = 443.2 [M+1].

实施例21Example 21

(8-氰基喹啉-5-基)-N-(反式-4-(二甲基氨基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物21(8-Cyanoquinolin-5-yl)-N-(trans-4-(dimethylamino)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxamide Compound 21

(8-cyanoquinolin-5-yl)-N-(trans-4-(dimethylamino)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(8-cyanoquinolin-5-yl)-N-(trans-4-(dimethylamino)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000071
Figure PCTCN2022081400-appb-000071

Figure PCTCN2022081400-appb-000072
Figure PCTCN2022081400-appb-000072

将化合物1(55mg，0.16mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入反式N,N-二甲基环己烷-1,4-二胺盐酸盐21a(42.9mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中，加入乙酸乙酯萃取两次，合并有机相用饱和食盐水洗两遍(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物(8-氰基喹啉-5-基)-N-(反式-4-(二甲基氨基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物21(淡黄色固体，65mg，86.7％)。Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding trans-form N,N-Dimethylcyclohexane-1,4-diamine hydrochloride 21a (42.9 mg, 0.24 mmol) was stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a silica gel column layer was used. analytical purification (dichloromethane:methanol=10:1) to obtain the target product (8-cyanoquinolin-5-yl)-N-(trans-4-(dimethylamino)cyclohexyl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 21 (pale yellow solid, 65 mg, 86.7%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.63(dd,1H),8.16(d,1H),8.01(d,1H),7.60(dd,1H),7.22(d,1H),4.01(d,1H),3.93(d,2H),3.81(d,1H),3.55(d,1H),2.52(s,1H),2.23(s,6H),1.99(d,1H),1.80(s,4H),1.61(d,1H),1.29-1.14(m,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.00(dd,1H), 8.63(dd,1H), 8.16(d,1H), 8.01(d,1H), 7.60(dd,1H), 7.22( d, 1H), 4.01(d, 1H), 3.93(d, 2H), 3.81(d, 1H), 3.55(d, 1H), 2.52(s, 1H), 2.23(s, 6H), 1.99(d , 1H), 1.80 (s, 4H), 1.61 (d, 1H), 1.29-1.14 (m, 4H).

19F NMR(376MHz,DMSO-d 6)δ-63.52 19 F NMR (376MHz, DMSO-d 6 ) δ-63.52

LC-MS m/z(ESI)＝472.2[M+1]。LC-MS m/z (ESI) = 472.2 [M+1].

实施例22Example 22

3-(8-氰基喹啉-5-基)-N-(1-甲基氮杂环丁烷-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物223-(8-Cyanoquinolin-5-yl)-N-(1-methylazetidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] Hexane-1-carboxamide Compound 22

3-(8-cyanoquinolin-5-yl)-N-(1-methylazetidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-methylazetidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000073
Figure PCTCN2022081400-appb-000073

将化合物1(55mg，0.16mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入1-甲基氮杂啶-3-胺 22a(20.7mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中，加入乙酸乙酯萃取两次，合并有机相用饱和食盐水洗两遍(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物3-(8-氰基喹啉-5-基)-N-(1-甲基氮杂环丁烷-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物22(黄色固体，65mg，98.5％)。Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding 1- Methylazidine-3-amine 22a (20.7 mg, 0.24 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a silica gel column layer was used. analytical purification (dichloromethane:methanol=10:1) to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(1-methylazetidin-3-yl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 22 (yellow solid, 65 mg, 98.5%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.77-8.55(m,2H),8.18(d,1H),7.61(dd,1H),7.23(d,1H),4.28(q,1H),4.01(d,1H),3.95(d,2H),3.81(d,1H),3.53(q,2H),3.07-2.90(m,2H),2.26(s,3H),2.00(d,1H),1.66(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.77-8.55(m,2H), 8.18(d,1H), 7.61(dd,1H), 7.23(d,1H), 4.28(q, 1H), 4.01(d, 1H), 3.95(d, 2H), 3.81(d, 1H), 3.53(q, 2H), 3.07-2.90(m, 2H), 2.26(s, 3H) , 2.00(d, 1H), 1.66(d, 1H).

19F NMR(376MHz,DMSO-d 6)δ-63.56 19 F NMR (376MHz, DMSO-d 6 ) δ-63.56

LC-MS m/z(ESI)＝416.1[M+1]。LC-MS m/z (ESI) = 416.1 [M+1].

实施例23Example 23

3-(8-氰基喹啉-5-基)-N-((1R,5S)-9-甲基-9-氮杂双环[3.3.1]壬基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物233-(8-Cyanoquinolin-5-yl)-N-((1R,5S)-9-methyl-9-azabicyclo[3.3.1]nonyl)-5-(trifluoromethyl) )-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 23

3-(8-cyanoquinolin-5-yl)-N-((1R,5S)-9-methyl-9-azabicyclo[3.3.1]nonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-((1R,5S)-9-methyl-9-azabicyclo[3.3.1]nonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] hexane-1-carboxamide

Figure PCTCN2022081400-appb-000074
Figure PCTCN2022081400-appb-000074

将化合物1(55mg，0.16mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入外向-3-氨基-9-甲基-9-氮杂双环[3,3,1]壬烷 23a(40.1mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中，加入乙酸乙酯萃取两次，合并有机相用饱和食盐水洗两遍(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(二氯甲烷:甲＝10:1)，得到目标产物3-(8-氰基喹啉-5-基)-N-(1R,5S)-9-甲基-9-氮杂双环[3.3.1]壬基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物23(黄色固体，70mg，90.9％)。Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding exogenous- 3-Amino-9-methyl-9-azabicyclo[3,3,1]nonane 23a (40.1 mg, 0.24 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a silica gel column layer was used. analytical purification (dichloromethane:formaldehyde=10:1) to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(1R,5S)-9-methyl-9-azabicyclo [3.3.1]Nonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 23 (yellow solid, 70 mg, 90.9%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.67-8.60(m,1H),8.31-8.04(m,2H),7.73-7.54(m,1H),7.23(dd,1H),4.54(s,1H),4.11-3.94(m,3H),3.83(dd,1H),3.56(d,2H),2.88(dd,3H),2.10(s,1H),2.07(d,1H),2.04(d,1H),1.99(d,2H),1.92(d,1H),1.84(s,1H),1.80(d,1H),1.72(d,1H),1.69-1.64(m,2H),1.35-1.21(m,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.01 (dd, 1H), 8.67-8.60 (m, 1H), 8.31-8.04 (m, 2H), 7.73-7.54 (m, 1H), 7.23 (dd ,1H),4.54(s,1H),4.11-3.94(m,3H),3.83(dd,1H),3.56(d,2H),2.88(dd,3H),2.10(s,1H),2.07( d, 1H), 2.04(d, 1H), 1.99(d, 2H), 1.92(d, 1H), 1.84(s, 1H), 1.80(d, 1H), 1.72(d, 1H), 1.69-1.64 (m, 2H), 1.35-1.21 (m, 1H).

19F NMR(376MHz,DMSO-d 6)δ-63.49,-73.77 19 F NMR (376MHz, DMSO-d 6 ) δ-63.49, -73.77

LC-MS m/z(ESI)＝484.2[M+1]。LC-MS m/z (ESI) = 484.2 [M+1].

实施例24Example 24

3-(8-氰基喹啉-5-基)-N-(((1R,3R,5S)-9-甲基-9-氮杂双环[3.3.1]壬南-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物243-(8-Cyanoquinolin-5-yl)-N-(((1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 24

3-(8-cyanoquinolin-5-yl)-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-5-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000075
Figure PCTCN2022081400-appb-000075

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺4mL中，随后加入HATU(65.7mg，0.17mmol)和DIPEA(37.15mg，0.29mmol)，冰浴下搅拌活化10min，加入(1R,3S,4R)-4-甲基奎宁环丁-3-胺化合物24a(26mg，0.17mmol)，室温搅拌1h。原料反应完全，加水淬灭，用二氯甲烷萃取两遍，反相C18柱层析纯化(碱法)，得到目标产物3-(8-氰基喹啉-5-基)-N-(((1R,3r,5S)-9-甲基-9-氮杂双环[3.3.1]壬南-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺化合物24(黄色固体，51mg，75.4％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 4 mL of N,N-dimethylformamide, followed by adding HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol), stirring and activating under ice bath for 10 min, (1R,3S,4R)-4-methylquinuclidin-3-amine compound 24a (26 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction of the raw materials was complete, quenched by adding water, extracted twice with dichloromethane, and purified by reverse-phase C18 column chromatography (alkali method) to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(( (1R,3r,5S)-9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxamide compound 24 (yellow solid, 51 mg, 75.4%).

1H NMR(400MHz,DMSO-d6)δ9.01(dd,1H),8.64(dd,1H),8.17(d,1H),7.90(d,1H),7.68-7.52(m,1H),7.23(d,1H),4.14(d,1H),3.98(dd,3H),3.81(dd,1H),3.17(d,1H),2.99(s,2H),2.41(s,2H),2.15-1.96(m,3H),1.96-1.80(m,3H),1.63(d,2H),1.43(d,1H),1.32(s,2H),0.93(s,1H)。 1 H NMR (400MHz, DMSO-d6)δ9.01(dd,1H), 8.64(dd,1H), 8.17(d,1H), 7.90(d,1H), 7.68-7.52(m,1H), 7.23 (d,1H),4.14(d,1H),3.98(dd,3H),3.81(dd,1H),3.17(d,1H),2.99(s,2H),2.41(s,2H),2.15- 1.96(m, 3H), 1.96-1.80(m, 3H), 1.63(d, 2H), 1.43(d, 1H), 1.32(s, 2H), 0.93(s, 1H).

LC-MS m/z(ESI)＝484.2[M+1]LC-MS m/z(ESI)=484.2[M+1]

实施例25Example 25

5-(1-(3-氨基氮杂环丁烷-1-羰基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基)喹啉-8-腈 化合物255-(1-(3-Aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8- Nitrile Compound 25

5-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure PCTCN2022081400-appb-000076
Figure PCTCN2022081400-appb-000076

第一步：first step:

叔丁基(1-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基)氮杂丁-3-基)氨基甲酸酯 25btert-Butyl(1-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)aza Butan-3-yl)carbamate 25b

tert-butyl(1-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)azetidin-3-yl)carbamatetert-butyl(1-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)azetidin-3-yl)carbamate

将化合物1(55mg，0.16mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入3-氮-叔丁氧羰基胺基环丁胺 25a(41.3mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中，加入乙酸乙酯萃取两次，合并有机相用饱和食盐水洗两遍(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(二氯甲烷:甲＝10:1)，得到中间体叔丁基(1-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基)氮杂丁-3-基)氨基甲酸酯 25b粗品(黄色固体，66mg)。Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding 3- Nitrogen-tert-butoxycarbonylaminocyclobutylamine 25a (41.3 mg, 0.24 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a silica gel column layer was used. analytical purification (dichloromethane:methane=10:1) to obtain the intermediate tert-butyl(1-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carbonyl)azetidin-3-yl)carbamate 25b crude (yellow solid, 66 mg).

第二步：Step 2:

5-(1-(3-氨基氮杂环丁烷-1-羰基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基)喹啉-8-腈 化合物255-(1-(3-Aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8- Nitrile Compound 25

5-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

将中间体叔丁基(1-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基)氮杂丁-3-基)氨基甲酸酯 25b溶于2mL二氧六环中，随后冰浴加入盐酸二氧六环溶液2mL，室温搅拌1h。TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物5-(1-(3-氨基氮杂环丁烷-1-羰基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基)喹啉-8-腈 化合物25(淡黄色固体，47mg，73.4％)。The intermediate tert-butyl(1-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl ) azetidin-3-yl) carbamate 25b was dissolved in 2 mL of dioxane, followed by adding 2 mL of hydrochloric acid dioxane solution in an ice bath, and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target product 5-(1-(3-aminoazetidine-1-carbonyl)-5-(trifluoromethane). yl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile Compound 25 (pale yellow solid, 47 mg, 73.4%).

1H NMR(400MHz,DMSO-d 6)δ9.01(d,1H),8.77-8.55(m,1H),8.15(dd,1H),7.63-7.58(m,1H),7.24(dd,1H),4.50(q,1H),4.26-4.02(m,2H),3.97(s,2H),3.87-3.77(m,2H),3.75-3.69(m,1H),3.60-3.49(m,1H),1.70(dd,1H),1.63(d,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.01 (d, 1H), 8.77-8.55 (m, 1H), 8.15 (dd, 1H), 7.63-7.58 (m, 1H), 7.24 (dd, 1H) ), 4.50(q, 1H), 4.26-4.02(m, 2H), 3.97(s, 2H), 3.87-3.77(m, 2H), 3.75-3.69(m, 1H), 3.60-3.49(m, 1H ), 1.70(dd, 1H), 1.63(d, 1H).

19F NMR(376MHz,DMSO-d 6)δ-63.51 19 F NMR (376MHz, DMSO-d 6 ) δ-63.51

LC-MS m/z(ESI)＝402.2[M+1]。LC-MS m/z (ESI) = 402.2 [M+1].

实施例26Example 26

N-(氮杂环丁烷-3-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物26N-(azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxamide Compound 26

N-(azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-(azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000077
Figure PCTCN2022081400-appb-000077

Figure PCTCN2022081400-appb-000078
Figure PCTCN2022081400-appb-000078

第一步：first step:

3-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)氮杂环丁烷-1-羧酸叔丁酯26b3-(3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide)azetidine -1-Carboxylic acid tert-butyl ester 26b

tert-butyl 3-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)azetidine-1-carboxylatetert-butyl 3-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)azetidine-1-carboxylate

将化合物1(55mg，0.16mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入1-叔丁氧羰基-3-胺基环丁胺26a(41.3mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中，加入乙酸乙酯萃取两次，合并有机相用饱和食盐水洗两遍(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到中间体3-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)氮杂环丁烷-1-羧酸叔丁酯26b粗品(黄色固体，70mg)。Compound 1 (55 mg, 0.16 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding 1- tert-Butoxycarbonyl-3-aminocyclobutylamine 26a (41.3 mg, 0.24 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a silica gel column layer was used. analytical purification (dichloromethane: methanol = 10: 1) to obtain the intermediate 3-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide) tert-butyl azetidine-1-carboxylate 26b crude product (yellow solid, 70 mg).

第二步：Step 2:

N-(氮杂环丁烷-3-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物26N-(azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxamide Compound 26

N-(azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-(azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将中间体3-((3-(8-氰基喹啉-5-基)-3-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)氮杂环丁-1-甲酸叔丁酯26b溶于2mL二氧六环中，随后冰浴加入盐酸二氧六环溶液2mL，室温搅拌1h。TLC反应完毕，反应液直接浓缩，MPLC纯化(碱法)，得到目标产物N-(氮杂环丁烷-3-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物26(淡黄色固体，40mg，62.5％)。The intermediate 3-((3-(8-cyanoquinolin-5-yl)-3-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide) nitrogen Heterocyclobutane-1-carboxylate tert-butyl ester 26b was dissolved in 2 mL of dioxane, followed by adding 2 mL of hydrochloric acid dioxane solution in an ice bath, and stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was directly concentrated, and purified by MPLC (alkali method). ) to obtain the target product N-(azetidin-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 26 (pale yellow solid, 40 mg, 62.5%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.77(d,1H),8.63(dd,,1H),8.17(d,1H),7.61(dd,1H),7.23(d,1H),4.54(d,1H),3.98(dd,4H),3.80(d,1H),3.65(d,2H),3.52(s,1H),2.02(d,1H),1.67(s,1H),1.23(s,1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.01 (dd, 1H), 8.77 (d, 1H), 8.63 (dd, 1H), 8.17 (d, 1H), 7.61 (dd, 1H), 7.23 (d,1H),4.54(d,1H),3.98(dd,4H),3.80(d,1H),3.65(d,2H),3.52(s,1H),2.02(d,1H),1.67( s, 1H), 1.23 (s, 1H).

19F NMR(376MHz,DMSO-d 6)δ-63.55 19 F NMR (376MHz, DMSO-d 6 ) δ-63.55

LC-MS m/z(ESI)＝402.2[M+1]。LC-MS m/z (ESI) = 402.2 [M+1].

实施例27Example 27

1-甲基哌啶-4-基-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-1-羧酸酯 化合物27-A、27-B1-Methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-1-carboxy Ester Compounds 27-A, 27-B

1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

Figure PCTCN2022081400-appb-000079
Figure PCTCN2022081400-appb-000079

第一步：first step:

3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基氯27a3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 27a

3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride

将化合物1(100mg，0.29mmol)溶解于DCM 5mL中，随后加入二氯亚砜(1mL)和DMF(1滴)，回流搅拌2h。TLC反应完毕，直接浓缩反应液，得到中间体3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基氯27a粗品(黄色油状物，110mg)。Compound 1 (100 mg, 0.29 mmol) was dissolved in DCM 5 mL, followed by addition of thionyl chloride (1 mL) and DMF (1 drop), and stirring at reflux for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Crude carbonyl chloride 27a (yellow oil, 110 mg).

第二步：Step 2:

1-甲基哌啶-4-基-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-1-羧酸酯 化合物271-Methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-1-carboxy Ester Compound 27

1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

将中间体3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基氯26a溶于2mL DCM中，随后冰浴滴加1-甲基-4-哌啶醇(40.0mg，0.35mmol)、三乙胺(58.7mg，0.58mmol)的DCM溶液，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中，加入乙酸乙酯萃取两次，合并有机相用饱和食盐水洗两遍(15mL×2)，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物1-甲基哌啶-4-基-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-1-羧酸酯 化合物27(淡黄色固体，74mg，57.8％)。The intermediate 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 26a was dissolved in 2 mL of DCM Then, 1-methyl-4-piperidinol (40.0 mg, 0.35 mmol) and triethylamine (58.7 mg, 0.58 mmol) in DCM were added dropwise in an ice bath, and the mixture was stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water, extracted twice with ethyl acetate, the combined organic phases were washed twice with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a silica gel column layer was used. analytical purification (dichloromethane:methanol=10:1) to obtain the target product 1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl) )-3-azabicyclo[3.1.0]hexan-1-carboxylate Compound 27 (pale yellow solid, 74 mg, 57.8%).

1H NMR(400MHz,DMSO-d 6)δ9.02(dd,1H),8.63(dd,1H),8.18(d,1H),7.62(dd,1H),7.28(d,1H),4.85-4.73(m,1H),4.03(d,1H),3.95(d,1H),3.89(d,1H),3.82(d,1H),2.51(s,1H),2.20(s,1H),2.17(s,3H),2.09(d,1H),2.01-1.93(m,1H),1.82(d,2H),1.65-1.57 (m,2H),1.22(d,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.02(dd,1H), 8.63(dd,1H), 8.18(d,1H), 7.62(dd,1H), 7.28(d,1H), 4.85- 4.73(m, 1H), 4.03(d, 1H), 3.95(d, 1H), 3.89(d, 1H), 3.82(d, 1H), 2.51(s, 1H), 2.20(s, 1H), 2.17 (s, 3H), 2.09 (d, 1H), 2.01-1.93 (m, 1H), 1.82 (d, 2H), 1.65-1.57 (m, 2H), 1.22 (d, 2H).

19F NMR(376MHz,DMSO-d 6)δ-62.08 19 F NMR (376MHz, DMSO-d 6 ) δ-62.08

LC-MS m/z(ESI)＝445.2[M+1]。LC-MS m/z (ESI) = 445.2 [M+1].

第三步：third step:

1-甲基哌啶-4-基-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-1-羧酸酯 化合物27-A、27-B1-Methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-1-carboxy Ester Compounds 27-A, 27-B

1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate1-methylpiperidin-4-yl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

通过手性制备高效液相色谱拆分化合物27制备得到化合物27-A和27-B。分析方法：手性柱AD-3，流动相为乙醇+0.2％二乙胺，流速1mL/min，化合物27-A保留时间为3.002min，化合物27-B保留时间为5.152min。Compound 27-A and 27-B were prepared by resolving compound 27 by chiral preparative high performance liquid chromatography. Analysis method: chiral column AD-3, mobile phase is ethanol + 0.2% diethylamine, flow rate is 1 mL/min, retention time of compound 27-A is 3.002 min, and retention time of compound 27-B is 5.152 min.

实施例28Example 28

3-(8-氰基喹啉-5-基)-N-(哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物283-(8-Cyanoquinolin-5-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Carboxamide Compound 28

3-(8-cyanoquinolin-5-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000080
Figure PCTCN2022081400-appb-000080

第一步：first step:

4-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺基)哌啶-1-羧酸叔丁酯28b4-(3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)piperidine-1 - tert-butyl carboxylate 28b

tert-butyl 4-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)piperidine-1-carboxylatetert-butyl 4-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)piperidine-1-carboxylate

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(65.7mg，0.17mmol)和DIPEA(37.15mg，0.29mmol)，冰浴下搅拌活化10min，加入4-氨基哌啶-1-羧酸叔丁酯28a(34.6mg，0.17mmol)，室温搅拌1h。原料反应完全，加水淬灭后，用二氯甲烷萃取两遍，合并有机相并旋干得到28b粗品，直接投下一步。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol), stirring and activating for 10 min under ice bath, 4-Aminopiperidine-1-carboxylate tert-butyl ester 28a (34.6 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction of the raw materials is complete, after adding water to quench, extract twice with dichloromethane, combine the organic phases and spin dry to obtain the crude product 28b, which is directly put into the next step.

第二步：Step 2:

3-(8-氰基喹啉-5-基)-N-(哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物283-(8-Cyanoquinolin-5-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Carboxamide Compound 28

3-(8-cyanoquinolin-5-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

中间体28b溶于3mL盐酸二氧六环溶液室温搅拌20min，得到目标产物3-(8-氰基喹 啉-5-基)-N-(哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物28(黄色固体，16mg，26.6％)。Intermediate 28b was dissolved in 3 mL of dioxane hydrochloride solution and stirred at room temperature for 20 min to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(piperidin-4-yl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 28 (yellow solid, 16 mg, 26.6%).

1H NMR(600MHz,DMSO-d 6)δ9.01(dd,1H),8.64(dd,1H),8.39(d,1H),8.18(d,1H),7.61(dd,1H),7.24(d,1H),4.04(s,1H),4.00-3.93(m,2H),3.84(s,1H),3.25(d,2H),2.94(td,2H),2.48(s,1H),1.87-1.79(m,2H),1.70(t,2H),0.99(t,2H)。 1 H NMR (600MHz, DMSO-d 6 )δ9.01(dd,1H), 8.64(dd,1H), 8.39(d,1H), 8.18(d,1H), 7.61(dd,1H), 7.24( d,1H),4.04(s,1H),4.00-3.93(m,2H),3.84(s,1H),3.25(d,2H),2.94(td,2H),2.48(s,1H),1.87 -1.79(m, 2H), 1.70(t, 2H), 0.99(t, 2H).

LC-MS m/z(ESI)＝430.2[M+1],452.2[M+23]。LC-MS m/z (ESI) = 430.2 [M+1], 452.2 [M+23].

实施例29Example 29

3-(8-氰基喹啉-5-基)-N-((4-甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物29-A、29-B、29-C和29-D3-(8-Cyanoquinolin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compounds 29-A, 29-B, 29-C and 29-D

3-(8-cyanoquinolin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000081
Figure PCTCN2022081400-appb-000081

第一步：first step:

3-(8-氰基喹啉-5-基)-N-((4-甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物293-(8-Cyanoquinolin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 29

3-(8-cyanoquinolin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(65.7mg，0.17mmol)和DIPEA(37.15mg，0.29mmol)，冰浴下搅拌活化10min，加入(4-甲基吗啉-2-基)甲胺29a(23mg，0.17mmol)，室温搅拌1h。原料反应完全，加水淬灭，用二氯甲烷萃取两遍，MPLC纯化(碱法)，得到目标产物3-(8-氰基喹啉-5-基)-氮-((4-甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物29(黄色固体，24mg，37.3％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol), stirring and activating for 10 min under ice bath, (4-Methylmorpholin-2-yl)methanamine 29a (23 mg, 0.17 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw materials was completed, quenched by adding water, extracted twice with dichloromethane, and purified by MPLC (alkali method) to obtain the target product 3-(8-cyanoquinolin-5-yl)-nitrogen-((4-methylamine) olin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 29 (yellow solid, 24 mg, 37.3%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.63(dd,1H),8.35(d,1H),8.17(d,1H),7.60(dd,1H),7.23(dd,1H),4.03-3.90(m,3H),3.94(d,1H),3.82(d,1H),3.75(dd,1H),3.45-3.39(m,2H),3.21-3.06(m,2H),2.63(d,1H),2.14(s,3H),1.99-1.95(m,1H),1.70-1.55(m, 2H),1.05(t,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.63(dd,1H), 8.35(d,1H), 8.17(d,1H), 7.60(dd,1H), 7.23( dd,1H),4.03-3.90(m,3H),3.94(d,1H),3.82(d,1H),3.75(dd,1H),3.45-3.39(m,2H),3.21-3.06(m, 2H), 2.63(d, 1H), 2.14(s, 3H), 1.99-1.95(m, 1H), 1.70-1.55(m, 2H), 1.05(t, 1H).

LC-MS m/z(ESI)＝460.2[M+1],482.2[M+23]。LC-MS m/z (ESI) = 460.2 [M+1], 482.2 [M+23].

第二步：Step 2:

3-(8-氰基喹啉-5-基)-N-((4-甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物29-A、29-B、29-C和29-D3-(8-Cyanoquinolin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compounds 29-A, 29-B, 29-C and 29-D

3-(8-cyanoquinolin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

A,通过手性制备高效液相色谱拆分化合物29制备得到化合物29-A、29-B、29-C和29-D。分析方法：手性柱OD-3，流动相为乙醇+0.2％二乙胺，流速1mL/min,化合物29-A保留时间为3.297min，化合物29-B保留时间为3.620min，化合物29-C保留时间为4.456min，化合物29-D保留时间为4.561min。A, Compound 29-A, 29-B, 29-C and 29-D were prepared by resolving compound 29 by chiral preparative high performance liquid chromatography. Analysis method: chiral column OD-3, mobile phase is ethanol + 0.2% diethylamine, flow rate is 1mL/min, compound 29-A retention time is 3.297min, compound 29-B retention time is 3.620min, compound 29-C The retention time was 4.456 min, and the retention time of compound 29-D was 4.561 min.

实施例30Example 30

3-(8-氰基喹啉-5-基)-N-(((1R,3S,4R)-奎宁环丁-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物303-(8-Cyanoquinolin-5-yl)-N-(((1R,3S,4R)-quinuclidin-3-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide Compound 30

3-(8-cyanoquinolin-5-yl)-N-((1R,3S,4R)-quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-((1R,3S,4R)-quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000082
Figure PCTCN2022081400-appb-000082

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(65.7mg，0.17mmol)和DIPEA(37.15mg，0.29mmol)，冰浴下搅拌活化10min，加入(1S,4s)-奎尼丁-3-胺30a(34.5mg，0.17mmol)，室温搅拌1h。原料反应完全，加水淬灭，用二氯甲烷萃取两遍，MPLC纯化(碱法)，得到目标产物3-(8-氰基喹啉-5-基)-N-(((1R,3S,4R)-奎宁环丁-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物30(黄色固体，16mg，25.1％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol), stirring and activating for 10 min under ice bath, (1S,4s)-quinidine-3-amine 30a (34.5 mg, 0.17 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw materials was completed, quenched by adding water, extracted twice with dichloromethane, and purified by MPLC (alkali method) to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-((((1R,3S, 4R)-quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 30 (yellow solid, 16 mg, 25.1%) .

1H NMR(600MHz,DMSO-d 6)δ9.02(d,1H),8.64(dd,1H),8.55(dd,1H),8.22-8.14(m,1H),8.07(s,0H),7.62(dd,1H),7.30-7.21(m,1H),5.28-5.22(m,1H),4.33-4.25(m,1H),4.03-3.95(m,2H),3.55-3.43(m,2H),3.29-3.22(m,1H),2.61(t,1H),2.38(t,1H),2.15-2.07(m,2H),2.05-1.97(m,2H),1.92-1.84(m,1H),1.75-1.72(m,1H),1.28-1.19(m,2H),0.85(t,1H)。 1 H NMR (600MHz, DMSO-d 6 )δ9.02(d,1H), 8.64(dd,1H), 8.55(dd,1H), 8.22-8.14(m,1H), 8.07(s,0H), 7.62(dd,1H),7.30-7.21(m,1H),5.28-5.22(m,1H),4.33-4.25(m,1H),4.03-3.95(m,2H),3.55-3.43(m,2H ),3.29-3.22(m,1H),2.61(t,1H),2.38(t,1H),2.15-2.07(m,2H),2.05-1.97(m,2H),1.92-1.84(m,1H) ), 1.75-1.72 (m, 1H), 1.28-1.19 (m, 2H), 0.85 (t, 1H).

LC-MS m/z(ESI)＝456.2[M+1],478.2[M+23]。LC-MS m/z (ESI) = 456.2 [M+1], 478.2 [M+23].

实施例31Example 31

3-(8-氰基喹啉-5-基)-N-(((1S,3R,4S)-奎宁环丁-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物313-(8-Cyanoquinolin-5-yl)-N-(((1S,3R,4S)-quinuclidin-3-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide Compound 31

3-(8-cyanoquinolin-5-yl)-N-((1S,3R,4S)-quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-((1S,3R,4S)-quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000083
Figure PCTCN2022081400-appb-000083

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(65.7mg，0.17mmol)和DIPEA(37.15mg，0.29mmol)，冰浴下搅拌活化10min，加入(1R,3S,4R)-4-甲基奎宁环丁-3-胺31a(34.5mg，0.17mmol)室温搅拌1h。原料反应完全，加水淬灭，用二氯甲烷萃取两遍，MPLC纯化(碱法)，得到目标产物3-(8-氰基喹啉-5-基)-N-(((1S,3R,4S)-奎宁环丁-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物31(黄色固体，32mg，50.2％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol), stirring and activating for 10 min under ice bath, (1R,3S,4R)-4-methylquinuclidin-3-amine 31a (34.5 mg, 0.17 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw materials was completed, quenched by adding water, extracted twice with dichloromethane, and purified by MPLC (alkali method) to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(((1S,3R, 4S)-quinuclidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 31 (yellow solid, 32 mg, 50.2%) .

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.65(ddd,1H),8.19(ddd,2H),7.61(dd,4.2Hz,1H),7.23(dd,1H),4.10-4.03(m,1H),4.03-3.93(m,2H),3.86(q,2H),3.19(d,1H),2.97-2.70(m,4H),2.70-2.58(m,1H),1.98(dd,1H),1.85-1.70(m,2H),1.70-1.52(m,3H),1.39(t,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.01 (dd, 1H), 8.65 (ddd, 1H), 8.19 (ddd, 2H), 7.61 (dd, 4.2Hz, 1H), 7.23 (dd, 1H) ,4.10-4.03(m,1H),4.03-3.93(m,2H),3.86(q,2H),3.19(d,1H),2.97-2.70(m,4H),2.70-2.58(m,1H) , 1.98 (dd, 1H), 1.85-1.70 (m, 2H), 1.70-1.52 (m, 3H), 1.39 (t, 1H).

LC-MS m/z(ESI)＝456.2[M+1],478.2[M+23]。LC-MS m/z (ESI) = 456.2 [M+1], 478.2 [M+23].

实施例32Example 32

N-(9-氮杂双环[3.3.1]壬南-3-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双[3.1.0]己烷-1-甲酰胺 化合物32N-(9-azabicyclo[3.3.1]nonan-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabi [3.1.0] Hexane-1-carboxamide Compound 32

N-(9-azabicyclo[3.3.1]nonan-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-(9-azabicyclo[3.3.1]nonan-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000084
Figure PCTCN2022081400-appb-000084

Figure PCTCN2022081400-appb-000085
Figure PCTCN2022081400-appb-000085

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(65.7mg，0.17mmol)和DIPEA(37.15mg，0.29mmol)，冰浴下搅拌活化10min，加入3-氨基-9-氮杂双环[3.3.1]壬烷-9-羧酸叔丁酯32a(41mg，0.17mmol)，室温搅拌1h。加水淬灭后，用二氯甲烷萃取两遍，合并有机相并旋干得到32b，加入3mL盐酸二氧六环溶液室温搅拌20min原料反应完全，体系旋干用三乙胺碱化，MPLC纯化(碱法)，得到目标产物N-(9-氮杂双环[3.3.1]壬南-3-基)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双[3.1.0]己烷-1-甲酰胺 化合物32(黄色固体，51mg，77.7％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (65.7 mg, 0.17 mmol) and DIPEA (37.15 mg, 0.29 mmol), stirring and activating for 10 min under ice bath, 3-Amino-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl ester 32a (41 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 1 h. After adding water to quench, extract twice with dichloromethane, combine the organic phases and spin dry to obtain 32b, add 3mL hydrochloric acid dioxane solution and stir at room temperature for 20min. Alkaline method) to obtain the target product N-(9-azabicyclo[3.3.1]nonan-3-yl)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl) )-3-azabis[3.1.0]hexane-1-carboxamide Compound 32 (yellow solid, 51 mg, 77.7%).

1H NMR(400MHz,DMSO-d 6)δ9.01(d,1H),8.77-8.55(m,1H),8.17(dd,1H),8.02(dd,1H),7.60(dd,1H),7.22(dd,1H),4.56(s,1H),4.01(d,1H),3.94(dd,2H),3.82(dd,1H),3.16(s,1H),2.05-1.93(m,2H),1.92-1.80(m,3H),1.70(s,2H),1.65-1.55(m,3H),1.49-1.40(m,1H),1.39-1.19(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(d,1H), 8.77-8.55(m,1H), 8.17(dd,1H), 8.02(dd,1H), 7.60(dd,1H), 7.22(dd,1H),4.56(s,1H),4.01(d,1H),3.94(dd,2H),3.82(dd,1H),3.16(s,1H),2.05-1.93(m,2H) , 1.92-1.80(m, 3H), 1.70(s, 2H), 1.65-1.55(m, 3H), 1.49-1.40(m, 1H), 1.39-1.19(m, 2H).

LC-MS m/z(ESI)＝470.2[M+1],LC-MS m/z(ESI)=470.2[M+1],

实施例33Example 33

N-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基]-1-甲基哌啶-4-甲酰胺 化合物33-A和化合物33-BN-[3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl]-1-methylpiperidine Pyridin-4-carboxamide Compound 33-A and Compound 33-B

N-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]-1-methylpiperidine-4-carboxamideN-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]-1-methylpiperidine-4-carboxamide

Figure PCTCN2022081400-appb-000086
Figure PCTCN2022081400-appb-000086

第一步：first step:

N-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基]-1-甲基哌啶-4-甲酰胺 化合物33N-[3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl]-1-methylpiperidine Pyridin-4-carboxamide Compound 33

N-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]-1-methylpiperidine-4-carboxamideN-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]-1-methylpiperidine-4-carboxamide

将1-甲基哌啶-4-甲酸33a(118mg，1.03mmol)溶解于N,N-二甲基甲酰胺5mL中，随后加入HATU(573mg，1.5mmol)和DIPEA(193mg,1.5mmol)，室温搅拌10min，加入化合物4(330mg，1.03mmol)，室温搅拌2h。原料反应完全，MPLC分离(乙腈:水＝35％：65％)，得到目标产物N-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基]-1-甲基哌啶-4-甲酰胺 化合物33(黄色固体，47mg，11％)。1-Methylpiperidine-4-carboxylic acid 33a (118 mg, 1.03 mmol) was dissolved in N,N-dimethylformamide 5 mL, followed by the addition of HATU (573 mg, 1.5 mmol) and DIPEA (193 mg, 1.5 mmol), Stir at room temperature for 10 min, add compound 4 (330 mg, 1.03 mmol), and stir at room temperature for 2 h. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 35%: 65%) was performed to obtain the target product N-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-yl]-1-methylpiperidine-4-carboxamide Compound 33 (yellow solid, 47 mg, 11%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,J＝4.1,1.2Hz,1H),8.66-8.63(m,2H),8.13(d,J＝8.3Hz,1H),7.59(dd,J＝8.7,4.2Hz,1H),7.15(d,J＝8.4Hz,1H),3.95-3.89(m,3H),3.81-3.79(m,1H),3.19-3.10(m,3H),2.5(s,3H),2.33-2.24(m,2H),1.78-1.59(m,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.00 (dd, J=4.1, 1.2 Hz, 1H), 8.66-8.63 (m, 2H), 8.13 (d, J=8.3 Hz, 1H), 7.59 ( dd,J=8.7,4.2Hz,1H),7.15(d,J=8.4Hz,1H),3.95-3.89(m,3H),3.81-3.79(m,1H),3.19-3.10(m,3H) , 2.5(s, 3H), 2.33-2.24(m, 2H), 1.78-1.59(m, 6H).

19F NMR(376MHz,DMSO-d 6)δ-63.53,-69.19,-71.08 19 F NMR (376MHz, DMSO-d 6 )δ-63.53,-69.19,-71.08

LC-MS m/z(ESI)＝444.2[M+1]。LC-MS m/z (ESI) = 444.2 [M+1].

第二步：Step 2:

N-[3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基]-1-甲基哌啶-4-甲酰胺 化合物33-A和化合物33-BN-[3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl]-1-methylpiperidine Pyridin-4-carboxamide Compound 33-A and Compound 33-B

N-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]-1-methylpiperidine-4-carboxamideN-[3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl]-1-methylpiperidine-4-carboxamide

通过手性制备高效液相色谱拆分化合物33制备得到化合物33-A和化合物33-B。分析方法：手性柱Ig-3，流动相为乙醇+0.2％二乙胺，流速1mL/min,化合物33-A保留时间为2.746min，化合物33-B保留时间为3.514min。Compound 33-A and compound 33-B were prepared by resolving compound 33 by chiral preparative high performance liquid chromatography. Analysis method: chiral column Ig-3, mobile phase is ethanol + 0.2% diethylamine, flow rate is 1 mL/min, compound 33-A retention time is 2.746min, compound 33-B retention time is 3.514min.

实施例34Example 34

3-(8-氰基喹啉-5-基)-N-{[(3R)-4-甲基吗啉-3-基]甲基}-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物343-(8-Cyanoquinolin-5-yl)-N-{[(3R)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 34

3-(8-cyanoquinolin-5-yl)-N-{[(3R)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-{[(3R)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000087
Figure PCTCN2022081400-appb-000087

第一步：first step:

叔丁基(3R)-3-{(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-1-基)甲酰胺]甲基}吗啉-4-羧酸盐 34atert-Butyl(3R)-3-{(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-1-yl ) formamide]methyl}morpholine-4-carboxylate 34a

tert-butyl(3R)-3-{[(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)formamido]methyl}morpholine-4-carboxylatetert-butyl(3R)-3-{[(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)formamido]methyl}morpholine- 4-carboxylate

将化合物1(200mg，0.56mmol)溶解于N,N-二甲基甲酰胺5mL中，随后加入HATU(330mg，0.88mmol)和DIPEA(117mg，0.88mmol)，室温搅拌10min，加入(R)-3-(氨基甲基)吗啉-4-羧酸叔丁酯(250mg，1.16mmol)，室温搅拌3h。原料反应完 全。MPLC纯化(乙腈:水＝65％:35％)，得到34a黄色固体，直接投下一步反应。Compound 1 (200 mg, 0.56 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by adding HATU (330 mg, 0.88 mmol) and DIPEA (117 mg, 0.88 mmol), stirring at room temperature for 10 min, adding (R)- 3-(Aminomethyl)morpholine-4-carboxylic acid tert-butyl ester (250 mg, 1.16 mmol), stirred at room temperature for 3 h. The reaction of the starting materials is complete. MPLC purification (acetonitrile:water=65%:35%) gave 34a yellow solid, which was directly used in the next reaction.

第二步：Step 2:

3-(8-氰基喹啉-5-基)-N-{[(3R)-吗啉-3-基]甲基}-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 34b3-(8-Cyanoquinolin-5-yl)-N-{[(3R)-morpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]Hexane-1-carboxamide 34b

3-(8-cyanoquinolin-5-yl)-N-{[(3R)-morpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-{[(3R)-morpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将34a溶解于氯化氢二氧六环溶液中，室温搅拌过夜。待原料反应完，旋干溶剂，MPLC纯化(乙腈:水＝35％:65％)，3-(8-氰基喹啉-5-基)-N-{[(3R)-吗啉-3-基]甲基}-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 34b(淡黄色固体，195mg，78％)。34a was dissolved in a solution of hydrogen chloride in dioxane and stirred at room temperature overnight. After the reaction of the raw materials, the solvent was spin-dried and purified by MPLC (acetonitrile: water = 35%: 65%), 3-(8-cyanoquinolin-5-yl)-N-{[(3R)-morpholine-3 -yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 34b (pale yellow solid, 195 mg, 78%).

LC-MS m/z(ESI)＝446.2[M+1],468.2[M+23]。LC-MS m/z (ESI) = 446.2 [M+1], 468.2 [M+23].

第三步：third step:

3-(8-氰基喹啉-5-基)-N-{[(3R)-4-甲基吗啉-3-基]甲基}-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物343-(8-Cyanoquinolin-5-yl)-N-{[(3R)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 34

3-(8-cyanoquinolin-5-yl)-N-{[(3R)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-{[(3R)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物34b(100mg，0.23mmol)溶解于甲醇5mL中，随后加入多聚甲醛(141mg，1.57mmol)和氰基硼氢化钠(26mg,0.69mmol)，加热回流3h。原料反应完全，水淬灭反应。MPLC分离(乙腈:水＝45％:55％)，得到目标产物3-(8-氰基喹啉-5-基)-N-{[(3R)-4-甲基吗啉-3-基]甲基}-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物34(黄色固体，60mg，57％)。Compound 34b (100 mg, 0.23 mmol) was dissolved in 5 mL of methanol, followed by adding paraformaldehyde (141 mg, 1.57 mmol) and sodium cyanoborohydride (26 mg, 0.69 mmol), and heating under reflux for 3 h. The reaction of the starting material was complete, and the reaction was quenched with water. MPLC separation (acetonitrile:water=45%:55%), the target product 3-(8-cyanoquinolin-5-yl)-N-{[(3R)-4-methylmorpholin-3-yl was obtained ]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 34 (yellow solid, 60 mg, 57%).

1H NMR(400MHz,DMSO-d 6) 1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.63(d,1H),8.23-8.16(m,2H),7.60(dd,1H),7.23(d,1H),4.01-3.92(m,3H),3.83-3.80(m,1H),3.65-3.62(m,2H),3.47-3.40(m,2H),3.13-3.11(m,1H),2.96-2.90(m,1H),2.62-2.59(m,1H),2.23(s,3H),2.17-2.05(m,2H),1.93(d,1H),1.63(d,1H)。 1 H NMR (400MHz, DMSO-d 6 ) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.00 (dd, 1H), 8.63 (d, 1H), 8.23-8.16 (m, 2H), 7.60 (dd ,1H),7.23(d,1H),4.01-3.92(m,3H),3.83-3.80(m,1H),3.65-3.62(m,2H),3.47-3.40(m,2H),3.13-3.11 (m,1H),2.96-2.90(m,1H),2.62-2.59(m,1H),2.23(s,3H),2.17-2.05(m,2H),1.93(d,1H),1.63(d , 1H).

19F NMR(376MHz,DMSO-d 6)δ-63.55 19 F NMR (376MHz, DMSO-d 6 ) δ-63.55

LC-MS m/z(ESI)＝460.2[M+1],482.2[M+23]。LC-MS m/z (ESI) = 460.2 [M+1], 482.2 [M+23].

实施例35Example 35

3-(8-氰基喹啉-5-基)-N-{[(3S)-4-甲基吗啉-3-基]甲基}-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物353-(8-Cyanoquinolin-5-yl)-N-{[(3S)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 35

3-(8-cyanoquinolin-5-yl)-N-{[(3S)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-{[(3S)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000088
Figure PCTCN2022081400-appb-000088

第一步：first step:

叔丁基(3S)-3-{(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-1-基)甲酰胺]甲基}吗啉-4-羧酸盐35atert-Butyl(3S)-3-{(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-1-yl ) formamide]methyl}morpholine-4-carboxylate 35a

tert-butyl(3S)-3-{[(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)formamido]methyl}morpholine-4-carboxylatetert-butyl(3S)-3-{[(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)formamido]methyl}morpholine- 4-carboxylate

将化合物1(200mg，0.56mmol)溶解于N,N-二甲基甲酰胺5mL中，随后加入HATU(330mg，0.88mmol)和DIPEA(117mg，0.88mmol)，室温搅拌10min，加入(S)-3-(氨基甲基)吗啉-4-羧酸叔丁酯(250mg，1.16mmol)，室温搅拌3h。原料反应完全。MPLC纯化(乙腈:水＝65％:35％)，得到黄色固体，直接投下一步反应。Compound 1 (200 mg, 0.56 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by adding HATU (330 mg, 0.88 mmol) and DIPEA (117 mg, 0.88 mmol), stirring at room temperature for 10 min, adding (S)- 3-(Aminomethyl)morpholine-4-carboxylic acid tert-butyl ester (250 mg, 1.16 mmol), stirred at room temperature for 3 h. The raw materials reacted completely. MPLC purification (acetonitrile:water=65%:35%) gave a yellow solid, which was directly used in the next reaction.

第二步：Step 2:

3-(8-氰基喹啉-5-基)-N-{[(3S)-吗啉-3-基]甲基}-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物35b3-(8-Cyanoquinolin-5-yl)-N-{[(3S)-morpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 35b

3-(8-cyanoquinolin-5-yl)-N-{[(3S)-morpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-{[(3S)-morpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将35a溶解于氯化氢二氧六环溶液中，室温搅拌过夜。待原料反应完，旋干溶剂，MPLC纯化(乙腈:水＝35％:65％)，3-(8-氰基喹啉-5-基)-N-{[(3S)-吗啉-3-基]甲基}-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物35b(淡黄色固体，206mg，83％)。35a was dissolved in a solution of hydrogen chloride in dioxane and stirred at room temperature overnight. After the reaction of the raw materials, the solvent was spin-dried and purified by MPLC (acetonitrile: water = 35%: 65%), 3-(8-cyanoquinolin-5-yl)-N-{[(3S)-morpholine-3 -yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 35b (pale yellow solid, 206 mg, 83%).

LC-MS m/z(ESI)＝446.2[M+1],468.22[M+23]。LC-MS m/z (ESI) = 446.2 [M+1], 468.22 [M+23].

第三步：third step:

3-(8-氰基喹啉-5-基)-N-{[(3S)-4-甲基吗啉-3-基]甲基}-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物353-(8-Cyanoquinolin-5-yl)-N-{[(3S)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 35

3-(8-cyanoquinolin-5-yl)-N-{[(3S)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-{[(3S)-4-methylmorpholin-3-yl]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物35b(100mg，0.23mmol)溶解于甲醇5mL中，随后加入多聚甲醛(141mg,1.57mmol)和氰基硼氢化钠(26mg,0.69mmol)，加热回流3h。原料反应完全，水淬灭反应。MPLC分离(乙腈:水＝45％:55％)，得到目标产物3-(8-氰基喹啉-5-基)-N-{[(3S)-4-甲基吗啉-3-基]甲基}-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物35(黄色固体，66mg，63％)。Compound 35b (100 mg, 0.23 mmol) was dissolved in 5 mL of methanol, followed by adding paraformaldehyde (141 mg, 1.57 mmol) and sodium cyanoborohydride (26 mg, 0.69 mmol), and heating under reflux for 3 h. The reaction of the starting material was complete, and the reaction was quenched with water. MPLC separation (acetonitrile:water=45%:55%), the target product 3-(8-cyanoquinolin-5-yl)-N-{[(3S)-4-methylmorpholin-3-yl was obtained ]methyl}-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 35 (yellow solid, 66 mg, 63%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.63(d,1H),8.23-8.15(m,2H),7.60(dd,1H),7.23(d,1H),4.01-3.92(m,3H),3.83-3.80(m,1H),3.65-3.62(m,2H),3.47-3.40(m,2H),3.16-3.11(m,1H),2.96-2.90(m,1H),2.61-2.59(m,1H),2.23(s,3H),2.17-2.07(m,2H),1.94(d,J＝4.0Hz,1H),1.65(d,J＝4.0Hz,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.00(dd,1H), 8.63(d,1H), 8.23-8.15(m,2H), 7.60(dd,1H), 7.23(d,1H), 4.01-3.92(m, 3H), 3.83-3.80(m, 1H), 3.65-3.62(m, 2H), 3.47-3.40(m, 2H), 3.16-3.11(m, 1H), 2.96-2.90(m ,1H),2.61-2.59(m,1H),2.23(s,3H),2.17-2.07(m,2H),1.94(d,J＝4.0Hz,1H),1.65(d,J＝4.0Hz, 1H).

19F NMR(376MHz,DMSO-d 6)δ-63.53 19 F NMR (376MHz, DMSO-d 6 ) δ-63.53

LC-MS m/z(ESI)＝460.2[M+1],482.2[M+23]。LC-MS m/z (ESI) = 460.2 [M+1], 482.2 [M+23].

实施例36Example 36

3-(8-氰基喹啉-5-基)-N-(1-(2-羟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物363-(8-Cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compound 36

3-(8-cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000089
Figure PCTCN2022081400-appb-000089

Figure PCTCN2022081400-appb-000090
Figure PCTCN2022081400-appb-000090

将化合物1(55mg，0.16mmol)溶解于DMF 2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入2-(4-氨基-1-哌啶)乙醇36a(41.8mg，0.29mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物3-(8-氰基喹啉-5-基)-N-(1-(2-羟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物36(黄色固体，55mg，83.3％)。Compound 1 (55 mg, 0.16 mmol) was dissolved in DMF 2 mL, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding 2-(4-amino-1-piperidine) pyridine)ethanol 36a (41.8 mg, 0.29 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3 -(8-Cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 36 (yellow solid, 55 mg, 83.3%).

1H NMR(400MHz,DMSO-d 6)δ9.02-8.98(m,1H),8.65-8.61(m,1H),8.16(d,1H),8.03(d,1H),7.63-7.59(m,1H),7.22(d,1H),4.35(s,1H),4.01(d,1H),3.96-3.89(m,2H),3.82(d,1H),3.67-3.55(m,1H),3.46(d,2H),2.88-2.72(m,2H),2.35(t,2H),2.11-1.91(m,2H),1.63(t,2H),1.46-1.41(m,2H),0.97(d,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.02-8.98(m,1H), 8.65-8.61(m,1H), 8.16(d,1H), 8.03(d,1H), 7.63-7.59(m) ,1H),7.22(d,1H),4.35(s,1H),4.01(d,1H),3.96-3.89(m,2H),3.82(d,1H),3.67-3.55(m,1H), 3.46(d,2H),2.88-2.72(m,2H),2.35(t,2H),2.11-1.91(m,2H),1.63(t,2H),1.46-1.41(m,2H),0.97( d, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.60 19 F NMR (376MHz, DMSO-d 6 ) δ-63.60

LC-MS m/z(ESI)＝474.2[M+1]。LC-MS m/z (ESI) = 474.2 [M+1].

实施例37Example 37

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(2-羟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物37(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 37

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000091
Figure PCTCN2022081400-appb-000091

将化合物1-A(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入 HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入2-(4-氨基-1-哌啶)乙醇(42mg，0.29mmol)，室温搅拌3h。原料反应完全，MPLC分离(乙腈:水＝35％:65％)，得到目标产物(1R,5S)-3-(8-氰基喹啉-5-基)-N-(1-(2-羟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物37(黄色固体，16mg，26％)。Compound 1-A (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, adding 2 -(4-Amino-1-piperidine)ethanol (42 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 35%: 65%) was performed to obtain the target product (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(2- Hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 37 (yellow solid, 16 mg, 26%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.63(dd,1H),8.16(d,1H),8.03(d,1H),7.60(dd,1H),7.22(d,1H),4.35(t,1H),4.02-3.81(m,4H),3.65-3.52(m,1H),3.48-3.44(m,2H),2.84-2.80(m,2H),2.35-2.33(m,2H),2.00-1.95(m,3H),1.68-1.61(m,3H),1.47-1.35(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.00(dd,1H), 8.63(dd,1H), 8.16(d,1H), 8.03(d,1H), 7.60(dd,1H), 7.22( d, 1H), 4.35(t, 1H), 4.02-3.81(m, 4H), 3.65-3.52(m, 1H), 3.48-3.44(m, 2H), 2.84-2.80(m, 2H), 2.35- 2.33 (m, 2H), 2.00-1.95 (m, 3H), 1.68-1.61 (m, 3H), 1.47-1.35 (m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.59 19 F NMR (376MHz, DMSO-d 6 ) δ-63.59

LC-MS m/z(ESI)＝474.20[M+1],496.20[M+23]。LC-MS m/z (ESI) = 474.20 [M+1], 496.20 [M+23].

实施例38Example 38

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(1-(2-羟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物38(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 38

(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000092
Figure PCTCN2022081400-appb-000092

将化合物1-B(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入2-(4-氨基-1-哌啶)乙醇(42mg,0.29mmol)，室温搅拌3h。原料反应完全，MPLC分离(乙腈:水＝35％:65％)，得到目标产物(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(2-羟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物38(黄色固体，44mg，71.6％)。Compound 1-B (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol), stirring at room temperature for 10 min, adding 2 -(4-Amino-1-piperidine)ethanol (42 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 35%: 65%) was performed to obtain the target product (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2- Hydroxyethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 38 (yellow solid, 44 mg, 71.6%).

1H NMR(400MHz,DMSO-d 6)δ9.06-8.91(m,1H),8.73-8.55(m,1H),8.16(d,1H),8.03(d,1H),7.60(dd,1H),7.22(d,1H),4.35(t,1H),4.02-3.81(m,4H),3.61-3.54(m,1H), 3.48-3.44(m,2H),2.83-2.80(m,2H),2.37-2.33(m,2H),2.00-1.95(m,3H),1.67-1.61(m,3H),1.46-1.38(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.06-8.91(m,1H), 8.73-8.55(m,1H), 8.16(d,1H), 8.03(d,1H), 7.60(dd,1H) ), 7.22(d, 1H), 4.35(t, 1H), 4.02-3.81(m, 4H), 3.61-3.54(m, 1H), 3.48-3.44(m, 2H), 2.83-2.80(m, 2H ), 2.37-2.33(m, 2H), 2.00-1.95(m, 3H), 1.67-1.61(m, 3H), 1.46-1.38(m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.59 19 F NMR (376MHz, DMSO-d 6 ) δ-63.59

LC-MS m/z(ESI)＝474.20[M+1],496.20[M+23]。LC-MS m/z (ESI) = 474.20 [M+1], 496.20 [M+23].

实施例39Example 39

3-(8-氰基喹啉-5-基)-N-反式-(4-(4-(环丙基甲基)哌嗪-1-基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物393-(8-Cyanoquinolin-5-yl)-N-trans-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl) base)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 39

3-(8-cyanoquinolin-5-yl)-N-trans-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-trans-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

Figure PCTCN2022081400-appb-000093
Figure PCTCN2022081400-appb-000093

将化合物1(50mg，0.15mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(60mg，0.16mmol)和DIPEA(130ul，0.74mmol)，冰浴下搅拌活化10min，加入4-(4-(环丙基甲基)哌嗪-1-基)环己胺39a(56mg，0.16mmol)，室温搅拌1h。原料反应完全，加水淬灭后旋干，过MPLC，得到目标产物(1R,5S)-3-(8-氰基喹啉-5-基)-N-反式-(4-(4-(环丙基甲基)哌嗪-1-基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物39(黄色固体，21mg，25.2％)。Compound 1 (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (60 mg, 0.16 mmol) and DIPEA (130 ul, 0.74 mmol), stirring and activating under ice bath for 10 min, adding 4 -(4-(Cyclopropylmethyl)piperazin-1-yl)cyclohexylamine 39a (56 mg, 0.16 mmol), stirred at room temperature for 1 h. The reaction of the raw materials is complete, quenched with water, spin-dried, and passed through MPLC to obtain the target product (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-trans-(4-(4-( Cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 39 (yellow solid, 21 mg , 25.2%).

1H NMR(400MHz,DMSO-d 6)δ9.04–8.96(m,1H),8.66–8.60(m,1H),8.17(dd,1H),8.00(d,1H),7.66–7.57(m,1H),7.24(dd,1H),4.09–3.89(m,3H),3.85–3.70(m,2H),2.24–2.05(m,3H),2.03-1.90(dd,3H),1.86-1.70(s,3H),1.61(d,1H),1.45(s,1H),1.35-1.2(m,9H),0.91–0.72(m,2H),0.43(dd,2H),0.07-0.02(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.04-8.96(m,1H), 8.66-8.60(m,1H), 8.17(dd,1H), 8.00(d,1H), 7.66-7.57(m) ,1H),7.24(dd,1H),4.09-3.89(m,3H),3.85-3.70(m,2H),2.24-2.05(m,3H),2.03-1.90(dd,3H),1.86-1.70 (s,3H),1.61(d,1H),1.45(s,1H),1.35-1.2(m,9H),0.91-0.72(m,2H),0.43(dd,2H),0.07-0.02(m , 2H).

LC-MS m/z(ESI)＝567.3[M+1],589.3[M+23]。LC-MS m/z (ESI) = 567.3 [M+1], 589.3 [M+23].

实施例40Example 40

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-(4-(环丙基甲基)哌嗪-1-基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物40(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-(4-(cyclopropylmethyl)piperazin-1-yl)ring Hexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 40

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)- 3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000094
Figure PCTCN2022081400-appb-000094

将化合物1-A(50mg,0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(112mg，0.88mmol)，室温搅拌10min，加入4-[4-(环丙基甲基)-1-哌嗪基]-环己胺三盐酸盐40a(101mg，0.29mmol)，室温搅拌3h。原料反应完全，MPLC分离(乙腈:水＝40％:60％)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-(4-(环丙基甲基)哌嗪-1-基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物40(黄色固体，40mg，54％)。Compound 1-A (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (112 mg, 0.88 mmol), stirring at room temperature for 10 min, adding 4- [4-(Cyclopropylmethyl)-1-piperazinyl]-cyclohexylamine trihydrochloride 40a (101 mg, 0.29 mmol) was stirred at room temperature for 3 h. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 40%: 60%) was performed to obtain the target product (1R, 5S) or (1S, 5R)-3-(8-cyanoquinolin-5-yl)-N- (4-(4-(Cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 40 (yellow solid, 40 mg, 54%).

1H NMR(400MHz,DMSO-d 6)δ9.01(m,1H),8.63(dd,1H),8.17(dd,1H),8.00(d,1H),7.61(m,1H),7.24(dd,1H),4.03-3.72(m,6H),3.66-3.34(m,9H),2.23-2.05(m,2H),2.02-1.90(m,2H),1.86-1.72(m,2H),1.50-1.02(m,7H),0.86-0.74(m,1H),0.46-0.39(m,1H),0.07-0.05(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(m,1H), 8.63(dd,1H), 8.17(dd,1H), 8.00(d,1H), 7.61(m,1H), 7.24( dd,1H),4.03-3.72(m,6H),3.66-3.34(m,9H),2.23-2.05(m,2H),2.02-1.90(m,2H),1.86-1.72(m,2H), 1.50-1.02 (m, 7H), 0.86-0.74 (m, 1H), 0.46-0.39 (m, 1H), 0.07-0.05 (m, 1H).

19F NMR(376MHz,DMSO-d 6)δ-63.61 19 F NMR (376MHz, DMSO-d 6 ) δ-63.61

LC-MS m/z(ESI)＝567.30[M+1],589.30[M+23]。LC-MS m/z (ESI) = 567.30 [M+1], 589.30 [M+23].

实施例41Example 41

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(4-(4-(环丙基甲基)哌嗪-1-基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物41(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(4-(4-(cyclopropylmethyl)piperazin-1-yl)ring Hexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 41

(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)- 3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000095
Figure PCTCN2022081400-appb-000095

将化合物1-b(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(112mg，0.88mmol)，室温搅拌10min，加入4-[4-(环丙基甲基)-1-哌嗪基]-环己胺三盐酸盐41a(101mg，0.29mmol)，室温搅拌3h。原料反应完全，MPLC分离(乙腈:水＝40％:60％)，得到目标产物(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(4-(4-(环丙基甲基)哌嗪-1-基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物41(黄色固体，40mg，54％)。Compound 1-b (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (83 mg, 0.22 mmol) and DIPEA (112 mg, 0.88 mmol), stirring at room temperature for 10 min, adding 4- [4-(Cyclopropylmethyl)-1-piperazinyl]-cyclohexylamine trihydrochloride 41a (101 mg, 0.29 mmol) was stirred at room temperature for 3 h. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 40%: 60%) was performed to obtain the target product (1S, 5R) or (1R, 5S)-3-(8-cyanoquinolin-5-yl)-N- (4-(4-(Cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 41 (yellow solid, 40 mg, 54%).

1H NMR(400MHz,DMSO-d 6)δ9.01(td,1H),8.63(dd,1H),8.17(dd,1H),8.00(d,1H),7.61(m,1H),7.24(dd,1H),4.03-3.72(m,6H),3.65-3.35(m,9H),2.17-2.07(m,2H),2.02-1.95(m,2H),1.82-1.75(m,2H),1.25-1.20(m,7H),0.87-0.73(m,1H),0.45-0.39(m,1H),0.06-0.02(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(td,1H), 8.63(dd,1H), 8.17(dd,1H), 8.00(d,1H), 7.61(m,1H), 7.24( dd,1H),4.03-3.72(m,6H),3.65-3.35(m,9H),2.17-2.07(m,2H),2.02-1.95(m,2H),1.82-1.75(m,2H), 1.25-1.20 (m, 7H), 0.87-0.73 (m, 1H), 0.45-0.39 (m, 1H), 0.06-0.02 (m, 1H).

19F NMR(376MHz,DMSO-d 6)δ-63.61 19 F NMR (376MHz, DMSO-d 6 ) δ-63.61

LC-MS m/z(ESI)＝567.30[M+1]。LC-MS m/z (ESI) = 567.30 [M+1].

实施例42Example 42

3-(8-氰基喹啉-5-基)-N-(1-(环丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物423-(8-Cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compound 42

3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000096
Figure PCTCN2022081400-appb-000096

Figure PCTCN2022081400-appb-000097
Figure PCTCN2022081400-appb-000097

第一步：first step:

(1-(环丙基甲基)哌啶-4-基)氨基甲酸叔丁酯42c(1-(Cyclopropylmethyl)piperidin-4-yl)carbamic acid tert-butyl ester 42c

tert-butyl(1-(cyclopropylmethyl)piperidin-4-yl)carbamatetert-butyl(1-(cyclopropylmethyl)piperidin-4-yl)carbamate

50mL圆底烧瓶中，将42a(1g，5mmol)溶于30mL乙腈中，冰浴下加入42b(877mg，6.5mmol)和DIPEA(1.65mL，10mmol)，80℃搅拌5h。将反应液加入30mL水中，DCM萃取三次，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，得到目标产物(1-(环丙基甲基)哌啶-4-基)氨基甲酸叔丁酯42c(黄色油状液体，1.5g，粗品)，直接用于下一步。In a 50 mL round-bottomed flask, dissolve 42a (1 g, 5 mmol) in 30 mL of acetonitrile, add 42b (877 mg, 6.5 mmol) and DIPEA (1.65 mL, 10 mmol) under ice bath, and stir at 80°C for 5 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the target product (1-(cyclopropylmethyl)piperidin-4-yl)amino tert-Butyl formate 42c (yellow oily liquid, 1.5 g, crude) was used directly in the next step.

LC-MS m/z(ESI)＝255.2[M+1]。LC-MS m/z (ESI) = 255.2 [M+1].

第二步：Step 2:

1-(环丙基甲基)哌啶-4-胺 42d1-(Cyclopropylmethyl)piperidin-4-amine 42d

1-(cyclopropylmethyl)piperidin-4-amine1-(cyclopropylmethyl)piperidin-4-amine

50mL圆底烧瓶中，将42c(100mg，5mmol)溶于10mL二氯甲烷中，随后加入三氟乙酸(1mL)，室温反应2h。饱和氯化铵淬灭反应，DCM 30mL萃取，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，得到目标产物1-(环丙基甲基)哌啶-4-胺 42d(无色油状液体，100mg，粗品)，直接用于下一步。In a 50 mL round-bottomed flask, 42c (100 mg, 5 mmol) was dissolved in 10 mL of dichloromethane, then trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain the target product 1-(cyclopropylmethyl)piperidin-4-amine 42d ( Colorless oily liquid, 100 mg, crude), used directly in the next step.

LC-MS m/z(ESI)＝155.2[M+1]。LC-MS m/z (ESI) = 155.2 [M+1].

第三步：third step:

3-(8-氰基喹啉-5-基)-N-(1-(环丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物423-(8-Cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compound 42

3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入42d(37.0mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物3-(8-氰基喹啉-5-基)-N-(1-(环丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物42(黄色固体，26mg，38.5％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding 42d ( 37.0 mg, 0.24 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3 -(8-Cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 42 (yellow solid, 26 mg, 38.5%).

1H NMR(400MHz,DMSO-d 6)δ9.03-8.97(m,1H),8.66-8.61(m,1H),8.16(d,1H),8.05(d,1H),7.62-7.58(m,1H),7.22(d,1H),4.01(d,1H),3.97-3.91(m,2H),3.82(d,1H),3.59(d,1H),2.94(d,2H),2.18(d,2H),1.99(d,3H),1.73-1.58(m,3H),1.48-1.42(m,2H),0.87-0.75(m,1H),0.52-0.38(m,2H),0.06(d,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.03-8.97(m,1H), 8.66-8.61(m,1H), 8.16(d,1H), 8.05(d,1H), 7.62-7.58(m) ,1H),7.22(d,1H),4.01(d,1H),3.97-3.91(m,2H),3.82(d,1H),3.59(d,1H),2.94(d,2H),2.18( d,2H),1.99(d,3H),1.73-1.58(m,3H),1.48-1.42(m,2H),0.87-0.75(m,1H),0.52-0.38(m,2H),0.06( d, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.48 19 F NMR (376MHz, DMSO-d 6 ) δ-63.48

LC-MS m/z(ESI)＝484.2[M+1]。LC-MS m/z (ESI) = 484.2 [M+1].

实施例43Example 43

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(环丙基甲基)哌啶-4-基)-5-(三氟甲基)-3- 氮杂双环[3.1.0]己烷-1-甲酰胺 化合物43(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 43

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000098
Figure PCTCN2022081400-appb-000098

将化合物1-A(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入43d(37.0mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(环丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物43(黄色固体，30mg，47.8％)。Compound 1-A (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, and adding 43d (37.0 mg, 0.24 mmol) was stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product ( 1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(tri Fluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 43 (yellow solid, 30 mg, 47.8%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.64(dd,1H),8.17(d,1H),8.03(d,1H),7.60(dd,1H),7.22(d,1H),4.03-3.81(m,4H),3.67-3.50(m,1H),2.98-2.85(m,2H),2.14(d,J＝8.2,2H),2.00-1.90(m,3H),1.71-1.62(m,3H),1.50-1.36(m,2H),0.81-0.76(m,1H),0.45-0.41(m,2H),0.05-0.03(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.00(dd,1H), 8.64(dd,1H), 8.17(d,1H), 8.03(d,1H), 7.60(dd,1H), 7.22( d, 1H), 4.03-3.81(m, 4H), 3.67-3.50(m, 1H), 2.98-2.85(m, 2H), 2.14(d, J=8.2, 2H), 2.00-1.90(m, 3H) ), 1.71-1.62(m, 3H), 1.50-1.36(m, 2H), 0.81-0.76(m, 1H), 0.45-0.41(m, 2H), 0.05-0.03(m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.58 19 F NMR (376MHz, DMSO-d 6 ) δ-63.58

LC-MS m/z(ESI)＝484.20[M+1]，506.20[M+Na]。LC-MS m/z (ESI) = 484.20 [M+1], 506.20 [M+Na].

实施例44Example 44

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(1-(环丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物44(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 44

(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000099
Figure PCTCN2022081400-appb-000099

Figure PCTCN2022081400-appb-000100
Figure PCTCN2022081400-appb-000100

将化合物1-B(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入44d(37.0mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(1-(环丙基甲基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物44(黄色固体，30mg，47.8％)。Compound 1-B (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, and adding 44d (37.0 mg, 0.24 mmol) was stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product ( 1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(cyclopropylmethyl)piperidin-4-yl)-5-(tri Fluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 44 (yellow solid, 30 mg, 47.8%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.64(dd,1H),8.17(d,1H),8.03(d,1H),7.60(dd,1H),7.22(d,1H),4.03-3.81(m,4H),3.61-3.54(m,1H),2.94-2.90(m,2H),2.14(d,J＝8.2,2H),2.00-1.90(m,3H),1.69-1.62(m,3H),1.49-1.39(m,2H),0.83-0.76(m,1H),0.45-0.42(m,2H),0.06-0.02(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.00(dd,1H), 8.64(dd,1H), 8.17(d,1H), 8.03(d,1H), 7.60(dd,1H), 7.22( d, 1H), 4.03-3.81(m, 4H), 3.61-3.54(m, 1H), 2.94-2.90(m, 2H), 2.14(d, J=8.2, 2H), 2.00-1.90(m, 3H) ), 1.69-1.62(m, 3H), 1.49-1.39(m, 2H), 0.83-0.76(m, 1H), 0.45-0.42(m, 2H), 0.06-0.02(m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.58 19 F NMR (376MHz, DMSO-d 6 ) δ-63.58

LC-MS m/z(ESI)＝484.20[M+1]，506.20[M+Na]。LC-MS m/z (ESI) = 484.20 [M+1], 506.20 [M+Na].

实施例45Example 45

3-(8-氰基喹啉-5-基)-N-(1-(氧杂环丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物453-(8-Cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compound 45

3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000101
Figure PCTCN2022081400-appb-000101

第一步：first step:

(1-(氧杂环丁烷-3-基)哌啶-4-基)氨基甲酸叔丁酯 45ctert-Butyl (1-(oxetan-3-yl)piperidin-4-yl)carbamate 45c

tert-butyl(1-(oxetan-3-yl)piperidin-4-yl)carbamatetert-butyl(1-(oxetan-3-yl)piperidin-4-yl)carbamate

50mL圆底烧瓶中，将45a(1g，5mmol)溶于30mL二氯甲烷中，冰浴下加入45b (720mg，10mmol)和三乙酰氧基氰基硼氢化钠(4.24g，20mmol)，加入冰醋酸调节pH至4-5，室温搅拌2h。将反应液加入30mL水中，DCM萃取三次，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，得到目标产物(1-(氧杂环丁烷-3-基)哌啶-4-基)氨基甲酸叔丁酯 45c(黄色油状液体，1.5g，粗品)，直接用于下一步。In a 50 mL round-bottomed flask, dissolve 45a (1 g, 5 mmol) in 30 mL of dichloromethane, add 45b (720 mg, 10 mmol) and sodium triacetoxycyanoborohydride (4.24 g, 20 mmol) under ice bath, add ice The pH was adjusted to 4-5 with acetic acid, and the mixture was stirred at room temperature for 2 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the target product (1-(oxetan-3-yl)piperidine-4 -yl) tert-butyl carbamate 45c (yellow oily liquid, 1.5 g, crude), used directly in the next step.

LC-MS m/z(ESI)＝257.2[M+1]。LC-MS m/z (ESI) = 257.2 [M+1].

第二步：Step 2:

1-(氧杂环丁烷-3-基)哌啶-4-胺 45d1-(oxetan-3-yl)piperidin-4-amine 45d

1-(oxetan-3-yl)piperidin-4-amine1-(oxetan-3-yl)piperidin-4-amine

50mL圆底烧瓶中，将45c(100mg，5mmol)溶于10mL二氯甲烷中，随后加入三氟乙酸(1mL)，室温反应2h。饱和氯化铵淬灭反应，DCM 30mL萃取，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，得到目标产物1-(氧杂环丁烷-3-基)哌啶-4-胺 45d(无色油状液体，100mg，粗品)，直接用于下一步。In a 50 mL round-bottomed flask, 45c (100 mg, 5 mmol) was dissolved in 10 mL of dichloromethane, then trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain the target product 1-(oxetan-3-yl)piperidine-4 - Amine 45d (colorless oily liquid, 100 mg, crude), used directly in the next step.

LC-MS m/z(ESI)＝157.1[M+1]。LC-MS m/z (ESI) = 157.1 [M+1].

第三步：third step:

3-(8-氰基喹啉-5-基)-N-(1-(氧杂环丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物453-(8-Cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compound 45

3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1(50mg，0.17mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入45d(37.0mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物3-(8-氰基喹啉-5-基)-N-(1-(氧杂环丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物45(黄色固体，32mg，47.1％)。Compound 1 (50 mg, 0.17 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding 45d ( 37.0 mg, 0.24 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3 -(8-Cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 45 (yellow solid, 32 mg, 47.1%).

1H NMR(400MHz,DMSO-d 6)δ9.02-8.99(m,1H),8.65-8.60(m,1H),8.16(d,1H),8.07(d,1H),7.63-7.59(m,1H),7.22(d,1H),4.51(t,2H),4.39(t,2H),4.01(d,1H),3.97-3.92(m,2H),3.82(d,1H),3.68-3.56(m,1H),3.37(s,1H),2.72-2.60(m,2H),1.99(d,1H),1.79(t,2H),1.73-1.61(m,2H),1.53-1.39(m,2H),1.06(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.02-8.99(m,1H), 8.65-8.60(m,1H), 8.16(d,1H), 8.07(d,1H), 7.63-7.59(m) ,1H),7.22(d,1H),4.51(t,2H),4.39(t,2H),4.01(d,1H),3.97-3.92(m,2H),3.82(d,1H),3.68- 3.56(m, 1H), 3.37(s, 1H), 2.72-2.60(m, 2H), 1.99(d, 1H), 1.79(t, 2H), 1.73-1.61(m, 2H), 1.53-1.39( m, 2H), 1.06 (s, 1H).

19F NMR(376MHz,DMSO-d 6)δ-63.58 19 F NMR (376MHz, DMSO-d 6 ) δ-63.58

LC-MS m/z(ESI)＝486.2[M+1]。LC-MS m/z (ESI) = 486.2 [M+1].

实施例46Example 46

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(氧杂环丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物46(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl) -5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 46

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3 -azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000102
Figure PCTCN2022081400-appb-000102

Figure PCTCN2022081400-appb-000103
Figure PCTCN2022081400-appb-000103

将化合物1-A(50mg，0.17mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入46d(37.0mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(氧杂环丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物46(黄色固体，30mg，47.6％)。Compound 1-A (50 mg, 0.17 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, and adding 46d (37.0 mg, 0.24 mmol) was stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product ( 1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 46 (yellow solid, 30 mg, 47.6%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.64(dd,1H),8.17(d,1H),8.12-7.95(m,1H),7.60(dd,1H),7.23(d,1H),4.52-4.38(m,4H),4.02-3.75(m,4H),3.64-3.51(m,1H),2.68-2.62(m,2H),2.35-2.30(m,1H),2.01-1.98(m,1H),1.84-1.62(m,5H),1.50-1.40(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.64(dd,1H), 8.17(d,1H), 8.12-7.95(m,1H), 7.60(dd,1H), 7.23(d,1H), 4.52-4.38(m,4H), 4.02-3.75(m,4H), 3.64-3.51(m,1H), 2.68-2.62(m,2H), 2.35-2.30(m,1H) ), 2.01-1.98 (m, 1H), 1.84-1.62 (m, 5H), 1.50-1.40 (m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.60 19 F NMR (376MHz, DMSO-d 6 ) δ-63.60

LC-MS m/z(ESI)＝486.20[M+1]，508.20[M+Na]。LC-MS m/z (ESI) = 486.20 [M+1], 508.20 [M+Na].

实施例47Example 47

(1S,5R)或·(1R,5S)-3-(8-氰基喹啉-5-基)-N-(1-(氧杂环丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物47(1S,5R) or · (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 47

(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-3 -azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000104
Figure PCTCN2022081400-appb-000104

Figure PCTCN2022081400-appb-000105
Figure PCTCN2022081400-appb-000105

将化合物1-b(50mg，0.17mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入47d(37.0mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物(1R,5S)-3-(8-氰基喹啉-5-基)-N-(1-(氧杂环丁烷-3-基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物47(黄色固体，30mg，47.6％)。Compound 1-b (50 mg, 0.17 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, and adding 47d (37.0 mg, 0.24 mmol) was stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product ( 1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl) yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 47 (yellow solid, 30 mg, 47.6%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,J＝4.1,1.4Hz,1H),8.64(dd,J＝8.9,1.6Hz,1H),8.17(d,J＝8.2Hz,1H),8.06(d,J＝8.4Hz,1H),7.60(dd,J＝8.3,4.3Hz,1H),7.23(d,J＝8.5Hz,1H),4.52-4.38(m,4H),4.03-3.81(m,4H),3.68-3.54(m,1H),2.72-2.61(m,2H),2.33-2.32(m,1H),2.01-1.97(m,1H),1.83-1.60(m,5H),1.49-1.37(m,2H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.01 (dd, J=4.1, 1.4 Hz, 1H), 8.64 (dd, J=8.9, 1.6 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 8.06(d, J＝8.4Hz, 1H), 7.60(dd, J＝8.3, 4.3Hz, 1H), 7.23(d, J＝8.5Hz, 1H), 4.52-4.38(m, 4H), 4.03-3.81(m, 4H), 3.68-3.54(m, 1H), 2.72-2.61(m, 2H), 2.33-2.32(m, 1H), 2.01-1.97(m, 1H), 1.83-1.60(m , 5H), 1.49-1.37 (m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.60 19 F NMR (376MHz, DMSO-d 6 ) δ-63.60

LC-MS m/z(ESI)＝486.20[M+1]，508.20[M+Na]。LC-MS m/z (ESI) = 486.20 [M+1], 508.20 [M+Na].

实施例48Example 48

3-(8-氰基喹啉-5-基)-N-[(1-甲基吡咯烷-2-基)甲基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物48-A、48-B、48-C和48-D3-(8-Cyanoquinolin-5-yl)-N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compounds 48-A, 48-B, 48-C and 48-D

3-(8-cyanoquinolin-5-yl)-N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000106
Figure PCTCN2022081400-appb-000106

Figure PCTCN2022081400-appb-000107
Figure PCTCN2022081400-appb-000107

第一步：first step:

3-(8-氰基喹啉-5-基)-N-[(1-甲基吡咯烷-2-基)甲基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物483-(8-Cyanoquinolin-5-yl)-N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 48

3-(8-cyanoquinolin-5-yl)-N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1(200mg，0.56mmol)溶解于N,N-二甲基甲酰胺4mL中，随后加入HATU(330mg，0.88mmol)和DIPEA(114mg，0.88mmol)，冰浴下搅拌活化10min，加入(1-甲基吡咯烷-2-基)甲胺化合物48a(140ul，1.12mmol)，室温搅拌1h。原料反应完全，加水淬灭后旋干，过MPLC，得到目标产物3-(8-氰基喹啉-5-基)-N-[(1-甲基吡咯烷-2-基)甲基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物48(黄色固体，252mg，57％)。Compound 1 (200 mg, 0.56 mmol) was dissolved in 4 mL of N,N-dimethylformamide, followed by adding HATU (330 mg, 0.88 mmol) and DIPEA (114 mg, 0.88 mmol), stirring and activating under ice bath for 10 min, adding ( 1-Methylpyrrolidin-2-yl)methanamine compound 48a (140ul, 1.12mmol), stirred at room temperature for 1h. The reaction of the raw materials is complete, quenched by adding water, spin-dried, and subjected to MPLC to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-[(1-methylpyrrolidin-2-yl)methyl] -5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 48 (yellow solid, 252 mg, 57%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.63(m,1H),8.18(dd,2H),7.60(dd,1H),7.22(d,1H)，4.03-3.81(m,4H),2.95-2.89(m,2H),2.28-2.20(m,4H),2.13-2.06(m,1H),1.94-1.91(m,1H),1.82-1.41(m,6H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.00 (dd, 1H), 8.63 (m, 1H), 8.18 (dd, 2H), 7.60 (dd, 1H), 7.22 (d, 1H), 4.03- 3.81(m,4H), 2.95-2.89(m,2H), 2.28-2.20(m,4H), 2.13-2.06(m,1H), 1.94-1.91(m,1H), 1.82-1.41(m,6H) ).

LC-MS m/z(ESI)＝444.2[M+1],466.2[M+23]。LC-MS m/z (ESI) = 444.2 [M+1], 466.2 [M+23].

第二步：Step 2:

3-(8-氰基喹啉-5-基)-N-[(1-甲基吡咯烷-2-基)甲基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物48-A、48-B、48-C和48-D3-(8-Cyanoquinolin-5-yl)-N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compounds 48-A, 48-B, 48-C and 48-D

3-(8-cyanoquinolin-5-yl)-N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-[(1-methylpyrrolidin-2-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

A,通过手性制备高效液相色谱拆分化合物48制备得到化合物48-A、48-B、48-C和48-D。分析方法：手性柱Ig-3，流动相为乙醇+0.2％二乙胺，流速1mL/min,化合物48-A保留时间为5.156min，化合物48-B保留时间为5.784min，化合物48-C保留时间为6.234min，化合物48-D保留时间为7.314min。A, Compounds 48-A, 48-B, 48-C and 48-D were prepared by resolving compound 48 by chiral preparative high performance liquid chromatography. Analysis method: chiral column Ig-3, mobile phase is ethanol + 0.2% diethylamine, flow rate 1mL/min, compound 48-A retention time is 5.156min, compound 48-B retention time is 5.784min, compound 48-C The retention time was 6.234 min, and the retention time of compound 48-D was 7.314 min.

实施例49Example 49

3-(8-氰基喹啉-5-基)-N-(2-吗啉乙基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺  化合物493-(8-Cyanoquinolin-5-yl)-N-(2-morpholinoethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Formamide Compound 49

3-(8-cyanoquinolin-5-yl)-N-(2-morpholinoethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(2-morpholinoethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000108
Figure PCTCN2022081400-appb-000108

将化合物1(50mg，0.15mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(65mg，0.17mmol)和DIPEA(52ul，0.29mmol)，冰浴下搅拌活化10min，加入2-吗啉代乙胺化合物49a(23mg，0.17mmol)，室温搅拌1h。原料反应完全，加水淬灭后旋干，过MPLC，得到目标产物(1R,5S)-3-(8-氰基喹啉-5-基)-N-(2-吗啉乙基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物49(黄色固体，62mg，91.8％)。Compound 1 (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (65 mg, 0.17 mmol) and DIPEA (52 ul, 0.29 mmol), stirring and activating under ice bath for 10 min, adding 2 - Morpholinoethylamine compound 49a (23 mg, 0.17 mmol), stirred at room temperature for 1 h. The reaction of the raw materials was complete, quenched with water, spin-dried, and passed through MPLC to obtain the target product (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(2-morpholinoethyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 49 (yellow solid, 62 mg, 91.8%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.63(dd,1H),8.20(t,1H),8.17(d,1H),7.60(dd,1H),7.22(d,1H),4.05-3.89(m,3H),3.81(d,1H),3.55(t,4H),3.23(q,2H),2.45-2.26(m,6H),1.95(d,1H),1.64(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.63(dd,1H), 8.20(t,1H), 8.17(d,1H), 7.60(dd,1H), 7.22( d, 1H), 4.05-3.89(m, 3H), 3.81(d, 1H), 3.55(t, 4H), 3.23(q, 2H), 2.45-2.26(m, 6H), 1.95(d, 1H) , 1.64(d,1H).

LC-MS m/z(ESI)＝460.2[M+1],482.2[M+23]。LC-MS m/z (ESI) = 460.2 [M+1], 482.2 [M+23].

实施例50Example 50

(1R,5S)-3-(8-氰基喹啉-5-基)-N-(2-(吡咯烷-1-基)乙基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物50(1R,5S)-3-(8-Cyanoquinolin-5-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 50

(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 -carboxamide

Figure PCTCN2022081400-appb-000109
Figure PCTCN2022081400-appb-000109

Figure PCTCN2022081400-appb-000110
Figure PCTCN2022081400-appb-000110

将化合物1(50mg，0.15mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(65mg，0.17mmol)和DIPEA(52ul，0.29mmol)，冰浴下搅拌活化10min，加入2-吗啉代乙胺50a(20mg，0.17mmol)，室温搅拌1h。原料反应完全，加水淬灭后旋干，过MPLC，得到目标产物(1R,5S)-3-(8-氰基喹啉-5-基)-N-(2-(吡咯烷-1-基)乙基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物50(黄色固体，32mg，50.1％)。Compound 1 (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (65 mg, 0.17 mmol) and DIPEA (52 ul, 0.29 mmol), stirring and activating under ice bath for 10 min, adding 2 - Morpholinoethylamine 50a (20 mg, 0.17 mmol), stirred at room temperature for 1 h. The reaction of the raw materials is complete, quenched with water, spin-dried, and passed through MPLC to obtain the target product (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(2-(pyrrolidin-1-yl) )ethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 50 (yellow solid, 32 mg, 50.1%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.63(dd,1H),8.23(t,1H),8.17(d,1H),7.60(dd,1H),7.22(d,1H),4.00(d,1H),3.94(d,2H),3.80(d,1H),3.21(q,2H),2.44(m,6H),1.95(d,1H),1.65(m,5H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.00(dd,1H), 8.63(dd,1H), 8.23(t,1H), 8.17(d,1H), 7.60(dd,1H), 7.22( d, 1H), 4.00(d, 1H), 3.94(d, 2H), 3.80(d, 1H), 3.21(q, 2H), 2.44(m, 6H), 1.95(d, 1H), 1.65(m , 5H).

LC-MS m/z(ESI)＝444.2[M+1],466.2[M+23]。LC-MS m/z (ESI) = 444.2 [M+1], 466.2 [M+23].

实施例51Example 51

3-(8-氰基喹啉-5-基)-5-甲基-N-(1-甲基哌啶-4-基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物513-(8-Cyanoquinolin-5-yl)-5-methyl-N-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1- Formamide Compound 51

3-(8-cyanoquinolin-5-yl)-5-methyl-N-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-5-methyl-N-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000111
Figure PCTCN2022081400-appb-000111

第一步：first step:

1-苄基-4-甲基-2,5-二氢-1H-吡咯-3-羧酸乙酯 51c1-Benzyl-4-methyl-2,5-dihydro-1H-pyrrole-3-carboxylate ethyl ester 51c

ethyl 1-benzyl-4-methyl-2,5-dihydro-1H-pyrrole-3-carboxylateethyl 1-benzyl-4-methyl-2,5-dihydro-1H-pyrrole-3-carboxylate

N 2氛围下，将51a(10g，60mmol)溶于30mL二氯甲烷中，冰浴下滴加51b(14.4g，60mmol)的二氯甲烷溶液(10mL)，随后滴加三氟乙酸(684mg，6mmol)的二氯甲烷溶液(10mL)，室温搅拌2h。将反应液加入30mL水中，DCM萃取三次，饱和食盐水30 mL洗，有机相用无水硫酸钠干燥，旋干，硅胶柱层析纯化(乙酸乙酯:石油醚＝1:10)，得到目标产物1-苄基-4-甲基-2,5-二氢-1H-吡咯-3-羧酸乙酯51c(黄色油状液体，7.1g，产率50.4％)，直接用于下一步。 Under N atmosphere, 51a (10 g , 60 mmol) was dissolved in 30 mL of dichloromethane, a solution of 51b (14.4 g, 60 mmol) in dichloromethane (10 mL) was added dropwise under ice bath, followed by dropwise addition of trifluoroacetic acid (684 mg, 6 mmol) in dichloromethane (10 mL) and stirred at room temperature for 2 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain the target The product 1-benzyl-4-methyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester 51c (yellow oily liquid, 7.1 g, 50.4% yield) was used directly in the next step.

第二步：Step 2:

3-苄基-5-甲基-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯 51d3-Benzyl-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate ethyl ester 51d

ethyl-3-benzyl-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylateethyl-3-benzyl-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate

N 2氛围下，将三甲基碘化亚砜(3.5g，15.8mmol)溶于10mL二甲亚砜中，冰浴下分批次加入氢化钠(633.6mg，15.8mmol)的二甲亚砜溶液(5mL)，室温搅拌30min。随后滴加51c(4.3g，14.4mmol)的二甲亚砜溶液(5mL)，60℃反应5h。饱和氯化铵淬灭反应，DCM 30mL萃取，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，硅胶柱层析纯化(乙酸乙酯:石油醚＝1:10)，得到目标产物3-苄基-5-甲基-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯51d(无色油状液体，3.2g，产率78.9％)，直接用于下一步。 Under N atmosphere, trimethyl sulfoxide (3.5 g , 15.8 mmol) was dissolved in 10 mL of dimethyl sulfoxide, and sodium hydride (633.6 mg, 15.8 mmol) in dimethyl sulfoxide was added in portions under ice bath The solution (5 mL) was stirred at room temperature for 30 min. Then, a solution of 51c (4.3 g, 14.4 mmol) in dimethyl sulfoxide (5 mL) was added dropwise, and the reaction was carried out at 60° C. for 5 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain the target The product, ethyl 3-benzyl-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate 51d (colorless oily liquid, 3.2 g, 78.9% yield), was used directly in the following step.

LC-MS m/z(ESI)＝260.1[M+1]。LC-MS m/z (ESI) = 260.1 [M+1].

第三步：third step:

5-甲基-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯51e5-Methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate ethyl ester 51e

ethyl-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylateethyl-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate

H 2氛围下，将51d(1g，3.2mmol)溶于乙醇50mL中，随后加入Pd/C(681mg，0.64mmol)，升温至60℃反应3h。硅藻土过滤，旋干溶剂，得到目标产物5-甲基-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯51e(无色油状液体，487mg，产率90.1％)，直接用于下一步。 Under H 2 atmosphere, 51d (1 g, 3.2 mmol) was dissolved in 50 mL of ethanol, then Pd/C (681 mg, 0.64 mmol) was added, and the temperature was raised to 60 °C for reaction for 3 h. The celite was filtered, and the solvent was spin-dried to obtain the target product, ethyl 5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate 51e (colorless oily liquid, 487 mg, yield 90.1%) , used directly in the next step.

LC-MS m/z(ESI)＝170.1[M+1]。LC-MS m/z (ESI) = 170.1 [M+1].

第四步：the fourth step:

(3-(8-氰基喹啉-5-基)-5-甲基-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯51g(3-(8-cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate ethyl ester 51g

3-(8-cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate3-(8-cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylate

N 2氛围下，将51f(654mg，2.9mmol)溶于1,4-二氧六环30mL中，随后加入51e(487mg，2.9mmol)，N 2置换气三次，依次加入碳酸钾(1.8g，13.05mmol)和Ruphos Pdg3(486mg，0.58mmol)，N 2置换气三次，升温至90℃反应24h。旋干溶剂，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，旋干溶剂，粗产物51g直接投下一步。 Under N 2 atmosphere, 51f (654 mg, 2.9 mmol) was dissolved in 30 mL of 1,4-dioxane, then 51e (487 mg, 2.9 mmol) was added, and N 2 was replaced three times, followed by adding potassium carbonate (1.8 g, 13.05 mmol) and Ruphos Pdg3 (486 mg, 0.58 mmol), replaced by N 2 three times, and the temperature was raised to 90 °C for 24 h. The solvent was spin-dried, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried, and 51 g of the crude product was directly put into the next step.

LC-MS m/z(ESI)＝322.1[M+1]。LC-MS m/z (ESI) = 322.1 [M+1].

第五步：the fifth step:

3-(8-氰基喹啉-5-基)-5-甲基-3-氮杂双环[3.1.0]己烷-1-羧酸 51h3-(8-Cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 51h

3-(8-cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid3-(8-cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

将51g的粗产品(1.0g，2.9mmol)溶于四氢呋喃溶液10mL中，将无水氢氧化锂(243mg，5.8mmol)的水溶液10mL滴入反应液中，室温搅拌过夜。待反应结束，旋干四氢呋喃，乙酸乙酯萃取，保留水相，用2M盐酸水溶液将水相PH调至3-4，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，真空除去溶剂。MPLC分离(乙腈:水＝47:53)，得到目标产物3-(8-氰基喹啉-5-基)-5-甲基-3-氮杂双环[3.1.0]己烷-1-羧酸51h(黄色固体，333mg，39.2％)。51 g of crude product (1.0 g, 2.9 mmol) was dissolved in 10 mL of tetrahydrofuran solution, 10 mL of anhydrous lithium hydroxide (243 mg, 5.8 mmol) aqueous solution was added dropwise to the reaction solution, and the mixture was stirred at room temperature overnight. After the reaction is over, spin dry tetrahydrofuran, extract with ethyl acetate, keep the aqueous phase, adjust the pH of the aqueous phase to 3-4 with 2M aqueous hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and vacuum Remove the solvent. MPLC separation (acetonitrile:water=47:53), the target product 3-(8-cyanoquinolin-5-yl)-5-methyl-3-azabicyclo[3.1.0]hexane-1- Carboxylic acid 51h (yellow solid, 333 mg, 39.2%).

1H NMR(400MHz,DMSO-d 6)δ12.61(s,1H),9.01-8.95(m,1H),8.66-8.60(m,1H),8.09(d,1H),7.58-7.53(m,1H),7.06(d,1H),3.87(s,3H),3.43(d,1H),1.38(s,3H),1.36-1.31(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.61(s,1H), 9.01-8.95(m,1H), 8.66-8.60(m,1H), 8.09(d,1H), 7.58-7.53(m , 1H), 7.06(d, 1H), 3.87(s, 3H), 3.43(d, 1H), 1.38(s, 3H), 1.36-1.31(m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.55 19 F NMR (376MHz, DMSO-d 6 ) δ-63.55

LC-MS m/z(ESI)＝294.1[M+1]。LC-MS m/z (ESI) = 294.1 [M+1].

第六步：Step 6:

3-(8-氰基喹啉-5-基)-5-甲基-N-(1-甲基哌啶-4-基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物513-(8-Cyanoquinolin-5-yl)-5-methyl-N-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1- Formamide Compound 51

3-(8-cyanoquinolin-5-yl)-5-methyl-N-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-5-methyl-N-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物51h(50mg，0.16mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(68.8mg，0.18mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入4-氨基-1-甲基哌啶51i(31.0mg，0.24mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物3-(8-氰基喹啉-5-基)-5-甲基-N-(1-甲基哌啶-4-基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物51(黄色固体，67mg，84.1％)。Compound 51h (50 mg, 0.16 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by adding HATU (68.8 mg, 0.18 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding 4- Amino-1-methylpiperidine 51i (31.0 mg, 0.24 mmol) was stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3 -(8-Cyanoquinolin-5-yl)-5-methyl-N-(1-methylpiperidin-4-yl)-3-azabicyclo[3.1.0]hexane-1-methyl Amide Compound 51 (yellow solid, 67 mg, 84.1%).

1H NMR(400MHz,DMSO-d 6)δ9.01-8.95(m,1H),8.67-8.61(m,1H),8.11(d,1H),7.57-7.53(m,2H),7.05(d,1H),3.98(d,1H),3.87-3.81(m,2H),3.69-3.61(m,1H),3.40(d,1H),2.83(d,2H),2.22(s,3H),2.06(s,2H),1.69(d,2H),1.59-1.47(m,2H),1.39(d,1H),1.25(s,3H),1.12(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01-8.95(m,1H), 8.67-8.61(m,1H), 8.11(d,1H), 7.57-7.53(m,2H), 7.05(d ,1H),3.98(d,1H),3.87-3.81(m,2H),3.69-3.61(m,1H),3.40(d,1H),2.83(d,2H),2.22(s,3H), 2.06(s, 2H), 1.69(d, 2H), 1.59-1.47(m, 2H), 1.39(d, 1H), 1.25(s, 3H), 1.12(d, 1H).

19F NMR(376MHz,DMSO-d 6)δ-63.60 19 F NMR (376MHz, DMSO-d 6 ) δ-63.60

LC-MS m/z(ESI)＝390.2[M+1]。LC-MS m/z (ESI) = 390.2 [M+1].

实施例52Example 52

2-(二乙氨基)乙基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸酯 化合物522-(Diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Ester Compound 52

2-(diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate2-(diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

Figure PCTCN2022081400-appb-000112
Figure PCTCN2022081400-appb-000112

第一步：first step:

3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基氯 化合物52a3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride Compound 52a

3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride

将化合物1(100mg，0.29mmol)溶解于DCM 5mL中，随后加入二氯亚砜(1mL)和DMF(1滴)，回流搅拌2h。TLC反应完毕，直接浓缩反应液，得到中间体3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基氯52a粗品(黄色油状物，110mg)。Compound 1 (100 mg, 0.29 mmol) was dissolved in DCM 5 mL, followed by addition of thionyl chloride (1 mL) and DMF (1 drop), and stirring at reflux for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Crude carbonyl chloride 52a (yellow oil, 110 mg).

第二步：Step 2:

2-(二乙氨基)乙基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸酯 化合物522-(Diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Ester Compound 52

2-(diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate2-(diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

将中间体3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基氯52a溶于2mL DCM中，随后冰浴滴加二乙氨基乙醇52b(42.0mg，0.36mmol)、三乙胺(58.7mg，0.58mmol)的DCM溶液，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物2-(二乙氨基)乙基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸酯 化合物52(淡黄色固体，79mg，61.2％)。The intermediate 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 52a was dissolved in 2 mL of DCM Then, the DCM solution of diethylaminoethanol 52b (42.0 mg, 0.36 mmol) and triethylamine (58.7 mg, 0.58 mmol) was added dropwise in an ice bath, and the mixture was stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water and washed with 15 mL of saturated brine. The organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 2 -(Diethylamino)ethyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate Compound 52 (pale yellow solid, 79 mg, 61.2%).

1H NMR(400MHz,DMSO-d 6)δ9.05-9.00(m,1H),8.66-8.61(m,1H),8.18(d,1H),7.65-7.59(m,1H),7.26(d,1H),4.25–4.11(m,2H),4.02-3.97(m,2H),3.90(d,1H),3.79(d,1H),2.65(t,2H),2.51(s,4H),2.07(d,1H),1.99–1.93(m,1H),0.94(t,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.05-9.00(m,1H), 8.66-8.61(m,1H), 8.18(d,1H), 7.65-7.59(m,1H), 7.26(d ,1H),4.25-4.11(m,2H),4.02-3.97(m,2H),3.90(d,1H),3.79(d,1H),2.65(t,2H),2.51(s,4H), 2.07 (d, 1H), 1.99–1.93 (m, 1H), 0.94 (t, 6H).

19F NMR(376MHz,DMSO-d 6)δ-62.28 19 F NMR (376MHz, DMSO-d 6 ) δ-62.28

LC-MS m/z(ESI)＝447.2[M+1]。LC-MS m/z (ESI) = 447.2 [M+1].

实施例53Example 53

3-(8-氰基喹喔啉-5-基)-N-((4-甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物53-A、53-B、53-C和53-D3-(8-Cyanoquinoxalin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compounds 53-A, 53-B, 53-C and 53-D

3-(8-cyanoquinoxalin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinoxalin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000113
Figure PCTCN2022081400-appb-000113

第一步：first step:

3-(8-氰基喹喔啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸乙酯53bEthyl 3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 53b

ethyl 3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylateethyl 3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

N 2氛围下，将1e(700mg，3.2mmol)溶于1,4-二氧六环30mL中，随后加入53a(499mg，2.1mmol)，N 2置换气三次，依次加入碳酸钾(1.8g，13.05mmol)和Ruphos Pdg3(486mg，0.58mmol)，N 2置换气三次，升温至90℃反应2h。旋干溶剂，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，旋干溶剂，粗产物53b直接投下一步。 Under N atmosphere, 1e (700 mg, 3.2 mmol) was dissolved in 1,4-dioxane 30 mL, then 53a (499 mg, 2.1 mmol) was added, N 2 was replaced three times, potassium carbonate (1.8 g, 13.05 mmol) and Ruphos Pdg3 (486 mg, 0.58 mmol), N 2 replaced the gas three times, and the temperature was raised to 90 °C for 2 h. The solvent was spin-dried, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried, and the crude product 53b was directly put into the next step.

LC-MS m/z(ESI)＝377.1[M+1]。LC-MS m/z (ESI) = 377.1 [M+1].

第二步：Step 2:

3-(8-氰基喹喔啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸 53c3-(8-Cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 53c

3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

将53b的粗产品(1.0g，3.2mmol)溶于四氢呋喃溶液10mL中，将无水氢氧化锂(243mg，5.8mmol)的水溶液10mL滴入反应液中，室温搅拌过夜。待反应结束，旋干四氢呋喃，乙酸乙酯萃取，保留水相，用2M盐酸水溶液将水相PH调至3-4，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，真空除去溶剂。MPLC分离(乙腈:水＝47:53)，得到目标产物3-(8-氰基喹喔啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸53c(黄色固体，448mg，40.3％)。The crude product of 53b (1.0 g, 3.2 mmol) was dissolved in 10 mL of tetrahydrofuran solution, 10 mL of anhydrous lithium hydroxide (243 mg, 5.8 mmol) aqueous solution was added dropwise to the reaction solution, and stirred at room temperature overnight. After the reaction is over, spin dry tetrahydrofuran, extract with ethyl acetate, keep the aqueous phase, adjust the pH of the aqueous phase to 3-4 with 2M aqueous hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and vacuum Remove the solvent. MPLC separation (acetonitrile:water=47:53), the target product 3-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] was obtained Hexane-1-carboxylic acid 53c (yellow solid, 448 mg, 40.3%).

1H NMR(400MHz,DMSO-d 6)δ13.36(s,1H),9.01(s,1H),8.93(d,H),8.13(d,1H),6.97(d,1H),4.80(d,1H),4.62(d,1H),4.24(d,1H),4.10(d,1H),2.11(d,1H),1.58-1.51(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ13.36(s,1H), 9.01(s,1H), 8.93(d,H), 8.13(d,1H), 6.97(d,1H), 4.80( d, 1H), 4.62 (d, 1H), 4.24 (d, 1H), 4.10 (d, 1H), 2.11 (d, 1H), 1.58-1.51 (m, 1H).

19F NMR(376MHz,DMSO-d 6)δ-62.48 19 F NMR (376MHz, DMSO-d 6 ) δ-62.48

LC-MS m/z(ESI)＝349.1[M+1]。LC-MS m/z (ESI) = 349.1 [M+1].

第三步：third step:

3-(8-氰基喹喔啉-5-基)-N-((4-甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物533-(8-Cyanoquinoxalin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compound 53

3-(8-cyanoquinoxalin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinoxalin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物53c(200mg，0.57mmol)溶解于N,N-二甲基甲酰胺5mL中，随后加入HATU(218.5mg，0.57mmol)和DIPEA(0.2mL，1.15mmol)，室温搅拌10min，加入4-甲基吗啉-2-甲胺53d(89.8mg，0.69mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物3-(8-氰基喹喔啉-5-基)-N-((4-甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物53(黄色固体，184mg，70.2％)。Compound 53c (200 mg, 0.57 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by adding HATU (218.5 mg, 0.57 mmol) and DIPEA (0.2 mL, 1.15 mmol), stirring at room temperature for 10 min, adding 4- Methylmorpholine-2-methylamine 53d (89.8 mg, 0.69 mmol), stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3 -(8-Cyanoquinoxalin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide Compound 53 (yellow solid, 184 mg, 70.2%).

1H NMR(400MHz,DMSO-d 6)δ9.01(d,1H),8.92(d,1H),8.48(q,1H),8.13(d,1H),6.95(d,1H),4.69(d,1H),4.54(d,1H),4.25(d,1H),4.14(d,1H),3.76(d,1H),3.47-3.42(m,2H),3.23-3.07(m,2H),2.64(d,1H),2.56(d,1H),2.15(s,3H),2.03(d,1H),1.96-1.87(m,1H),1.65(t,1H),1.33(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(d,1H), 8.92(d,1H), 8.48(q,1H), 8.13(d,1H), 6.95(d,1H), 4.69( d, 1H), 4.54(d, 1H), 4.25(d, 1H), 4.14(d, 1H), 3.76(d, 1H), 3.47-3.42(m, 2H), 3.23-3.07(m, 2H) ,2.64(d,1H),2.56(d,1H),2.15(s,3H),2.03(d,1H),1.96-1.87(m,1H),1.65(t,1H),1.33(d,1H) ).

19F NMR(376MHz,DMSO-d 6)δ-64.30 19 F NMR (376MHz, DMSO-d 6 ) δ-64.30

LC-MS m/z(ESI)＝461.2[M+1]。LC-MS m/z (ESI) = 461.2 [M+1].

第四步：the fourth step:

3-(8-氰基喹喔啉-5-基)-N-((4-甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物53-A、53-B、53-C和53-D3-(8-Cyanoquinoxalin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide Compounds 53-A, 53-B, 53-C and 53-D

3-(8-cyanoquinoxalin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinoxalin-5-yl)-N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

经手性制备高效液相色谱拆分化合物53，得到手性化合物53-A、53-B、53-C、53- D。分析方法：手性柱OD-3，流动相为乙醇+0.2％二乙胺，流速1mL/min,化合物53-A保留时间为3.554min，化合物53-B保留时间为3.963min，化合物53-C保留时间为4.200min，化合物53-D保留时间为4.822min。Compound 53 was resolved by chiral preparative high performance liquid chromatography to obtain chiral compounds 53-A, 53-B, 53-C and 53-D. Analysis method: chiral column OD-3, mobile phase is ethanol + 0.2% diethylamine, flow rate is 1mL/min, compound 53-A retention time is 3.554min, compound 53-B retention time is 3.963min, compound 53-C The retention time was 4.200 min, and the retention time of compound 53-D was 4.822 min.

实施例54Example 54

5-(1-(氨基甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物545-(1-(Aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 54

5-(1-(aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-(aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure PCTCN2022081400-appb-000114
Figure PCTCN2022081400-appb-000114

第一步：first step:

(1R,5S)-3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸 54a(1R,5S)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 54a

(1R,5S)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid(1R,5S)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

在500mL单口瓶中将化合物1d(粗品5.5g)溶于甲醇(150mL)，另外将无水氢氧化锂(2.2g，52.7mmol)溶解到100mL水中，溶解完后室温下缓慢加入之前的甲醇溶液中，40℃反应1.5h。原料水解完全，旋干甲醇后用乙酸乙酯和水酸碱洗倒置除杂，得到目标产物(1R,5S)-3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸 54a(3.1g)，直接用于下一步。Compound 1d (crude product 5.5g) was dissolved in methanol (150mL) in a 500mL single-neck flask, and anhydrous lithium hydroxide (2.2g, 52.7mmol) was dissolved in 100mL of water, and the methanol solution before was slowly added at room temperature after dissolving in the reaction at 40°C for 1.5h. The raw material was completely hydrolyzed, spin-dried with methanol, washed with ethyl acetate and water with acid and alkali, and then inverted to remove impurities to obtain the target product (1R,5S)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxylic acid 54a (3.1 g) was used directly in the next step.

LC-MS m/z(ESI)＝286.1[M+1],308.1[M+23]。LC-MS m/z (ESI) = 286.1 [M+1], 308.1 [M+23].

第二步：Step 2:

3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 54b3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 54b

3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物54a(100mg，0.35mmol)溶解于N,N-二甲基甲酰胺10mL中，随后加入HATU(160mg，0.42mmol)和DIPEA(124uL，0.7mmol)，冰浴下搅拌活化10min，加入碳酸氢铵(55.3mg，0.7mmol)，室温搅拌1h。原料反应完全，加水淬灭后旋干，萃取3次，得到目标粗产物(1R,5S)-3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺54b(粗产品1.1g)，直接用于下一步。Compound 54a (100 mg, 0.35 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by adding HATU (160 mg, 0.42 mmol) and DIPEA (124 uL, 0.7 mmol), stirring and activating under ice bath for 10 min, adding carbonic acid Ammonium hydrogen (55.3 mg, 0.7 mmol) was stirred at room temperature for 1 h. The reaction of the raw materials was completed, quenched by adding water, spin-dried, and extracted 3 times to obtain the target crude product (1R,5S)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxamide 54b (crude 1.1 g) was used directly in the next step.

LC-MS m/z(ESI)＝285.1[M+1],307.1[M+23]。LC-MS m/z (ESI) = 285.1 [M+1], 307.1 [M+23].

第三步：third step:

3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1)-甲胺 54c3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1)-methylamine 54c

3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanam-ine3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanam-ine

将54b(粗产品1.1g)溶解于四氢呋喃20mL中，加入硼烷四氢呋喃络合物50mL，60℃下搅拌3h，原料反应完全。冰浴下缓慢滴加甲醇淬灭反应，直到无气泡产生后缓慢滴加水，直至淬灭完全。旋干有机溶剂后用乙酸乙酯/水和二氯甲烷/水萃取多次后旋干有机相。拿到目标粗产物((1S,5S)-3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1)-甲胺54c(粗产品780mg)。54b (1.1 g of crude product) was dissolved in 20 mL of tetrahydrofuran, 50 mL of borane tetrahydrofuran complex was added, and the mixture was stirred at 60° C. for 3 h, and the reaction of the raw materials was completed. Methanol was slowly added dropwise under an ice bath to quench the reaction until no bubbles were formed, and then water was slowly added dropwise until the quenching was complete. After spin drying of the organic solvent, after several extractions with ethyl acetate/water and dichloromethane/water, the organic phase was spin dried. The target crude product ((1S,5S)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1)-methylamine 54c (crude product 780 mg) was obtained .

LC-MS m/z(ESI)＝271.1[M+1],293.1[M+23]。LC-MS m/z (ESI) = 271.1 [M+1], 293.1 [M+23].

第四步：the fourth step:

((3-苄基-5-(三氟甲基)-3氮杂双环[3.1.0]己-1-基)甲基)氨基甲酸叔丁酯 54dtert-Butyl ((3-benzyl-5-(trifluoromethyl)-3azabicyclo[3.1.0]hex-1-yl)methyl)carbamate 54d

tert-butyl((3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamatetert-butyl((3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate

将54c(粗产品780mg)溶于四氢呋喃50mL中，加入Boc酸酐(792.8uL，3.4mmol)，三乙胺(805.6uL，5.8mmol)和4-二甲氨基吡啶(38.4mg，0.3mmol)。室温反应2h，原料反应完全，旋干后用甲醇溶解反相纯化，得到目标产物(((1S,5S)-3-苄基-5-(三氟甲基)-3氮杂双环[3.1.0]己-1-基)甲基)氨基甲酸叔丁酯 54d(530mg，粗产品)，直接用于下一步。54c (780 mg of crude product) was dissolved in 50 mL of tetrahydrofuran, Boc anhydride (792.8 uL, 3.4 mmol), triethylamine (805.6 uL, 5.8 mmol) and 4-dimethylaminopyridine (38.4 mg, 0.3 mmol) were added. The reaction was carried out at room temperature for 2 h, and the reaction of the raw materials was complete. After spin-drying, it was dissolved in methanol for reverse-phase purification to obtain the target product (((1S,5S)-3-benzyl-5-(trifluoromethyl)-3azabicyclo[3.1. 0] Hex-1-yl)methyl)carbamate tert-butyl ester 54d (530 mg, crude), used directly in the next step.

LC-MS m/z(ESI)＝371.1[M+1],393.1[M+23]。LC-MS m/z (ESI) = 371.1 [M+1], 393.1 [M+23].

第五步：the fifth step:

叔丁基((5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲基)氨基甲酸酯54etert-Butyl((5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl)carbamate 54e

tert-butyl((5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamatetert-butyl((5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate

H 2氛围下，将54d(530mg，1.4mmol)溶于乙醇50mL中，随后加入Pd/C(681mg，0.64mmol)，升温至60℃反应3h。硅藻土过滤，旋干溶剂，得到目标产物叔丁基((5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲基)氨基甲酸酯54e(无色油状液体，352mg，产率90.1％)，直接用于下一步。 Under H 2 atmosphere, 54d (530 mg, 1.4 mmol) was dissolved in 50 mL of ethanol, then Pd/C (681 mg, 0.64 mmol) was added, and the temperature was raised to 60 °C for 3 h. Filter through celite, spin dry the solvent to obtain the target product tert-butyl((5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl)carbamate 54e (colorless oily liquid, 352 mg, 90.1% yield) was used directly in the next step.

LC-MS m/z(ESI)＝281.1[M+1]。LC-MS m/z (ESI) = 281.1 [M+1].

第六步：Step 6:

叔丁基((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲基)氨基甲酸酯54ftert-Butyl((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl)amino Formate 54f

tert-butyl((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamatetert-butyl((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)carbamate

N 2氛围下，将54e(352mg，1.4mmol)溶于1,4-二氧六环30mL中，随后加入5-溴喹啉-8-甲腈(396.4mg，1.72mmol)，依次加入碳酸铯(2.1g，6.4mmol)和Ruphos Pdg3(119.7mg，0.14mmol)，N 2置换气三次，升温至90℃反应24h。旋干溶剂，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，旋干溶剂，粗产物54f直接投下一步。 Under N atmosphere, 54e (352 mg , 1.4 mmol) was dissolved in 1,4-dioxane 30 mL, followed by 5-bromoquinoline-8-carbonitrile (396.4 mg, 1.72 mmol), followed by cesium carbonate (2.1 g, 6.4 mmol) and Ruphos Pdg3 (119.7 mg, 0.14 mmol), replaced by N 2 three times, and the temperature was raised to 90 °C for 24 h. The solvent was spin-dried, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried, and the crude product 54f was directly put into the next step.

LC-MS m/z(ESI)＝433.2[M+1]。LC-MS m/z (ESI) = 433.2 [M+1].

第七步：Step 7:

5-(1-(氨基甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物545-(1-(Aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 54

5-(1-(aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-(aminomethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

50mL圆底烧瓶中，将54f(粗产品，1.43mmol)溶于10mL二氯甲烷中，随后加入三氟乙酸(1mL)，室温反应2h。饱和氯化铵淬灭反应，DCM 30mL萃取，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，反相纯化得到目标产物5-(1-(氨基甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物54(40mg，淡黄色固体) 。In a 50 mL round-bottomed flask, 54f (crude product, 1.43 mmol) was dissolved in 10 mL of dichloromethane, then trifluoroacetic acid (1 mL) was added, and the reaction was performed at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by reverse phase to obtain the target product 5-(1-(aminomethyl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 54 (40 mg, pale yellow solid).

1H NMR(400MHz,DMSO-d 6)δ9.02-8.97(m,1H),8.68-8.62(m,1H),8.13(d,1H),7.63-7.57(m,1H),7.13(d,1H),3.97-3.92(m,2H),3.78(d,1H),3.70(d,1H),2.87(q,2H),1.71(s,2H),1.39(d,1H),1.32(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.02-8.97(m,1H), 8.68-8.62(m,1H), 8.13(d,1H), 7.63-7.57(m,1H), 7.13(d ,1H),3.97-3.92(m,2H),3.78(d,1H),3.70(d,1H),2.87(q,2H),1.71(s,2H),1.39(d,1H),1.32( d, 1H).

19F NMR(376MHz,DMSO-d 6)δ-62.27 19 F NMR (376MHz, DMSO-d 6 ) δ-62.27

LC-MS m/z(ESI)＝333.1[M+1]。LC-MS m/z (ESI) = 333.1 [M+1].

实施例55Example 55

5-(1-((1-甲基哌啶-4-基)氨基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物555-(1-((1-Methylpiperidin-4-yl)amino)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl) Quinoline-8-carbonitrile Compound 55

5-(1-(((1-methylpiperidin-4-yl)amino)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-(((1-methylpiperidin-4-yl)amino)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure PCTCN2022081400-appb-000115
Figure PCTCN2022081400-appb-000115

50mL圆底烧瓶中，将化合物54(30mg，0.09mmol)溶于30mL二氯甲烷中，冰浴下加入55a(20.4mg，0.18mmol)和三乙酰氧基氰基硼氢化钠(76.3mg，0.36mmol)，加入冰醋酸调节pH至4-5，室温搅拌2h。将反应液加入30mL水中，DCM萃取三次，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，得到目标产物(1-(氧杂环丁烷-3-基)哌啶-4-基)氨基甲酸叔丁酯 化合物55(黄色固体，23mg，59.6％)。In a 50 mL round-bottomed flask, compound 54 (30 mg, 0.09 mmol) was dissolved in 30 mL of dichloromethane, and 55a (20.4 mg, 0.18 mmol) and sodium triacetoxycyanoborohydride (76.3 mg, 0.36 mmol) were added under ice bath. mmol), glacial acetic acid was added to adjust the pH to 4-5, and the mixture was stirred at room temperature for 2 h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the target product (1-(oxetan-3-yl)piperidine-4 -yl) tert-butyl carbamate Compound 55 (yellow solid, 23 mg, 59.6%).

1H NMR(400MHz,DMSO-d 6)δ9.08-9.03(m,1H),8.72-8.67(m,1H),8.19(d,1H),7.68-7.64(m,1H),7.35(d,1H),7.20(d,1H),4.03-3.98(m,2H),3.84(s,1H),3.68(d,1H),3.07(s,1H),3.04(s,2H),2.84(d,1H),2.64(s,1H),2.45(s,3H),1.92(s,2H),1.50-1.46(m,4H),1.28(s,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.08-9.03(m,1H), 8.72-8.67(m,1H), 8.19(d,1H), 7.68-7.64(m,1H), 7.35(d ,1H),7.20(d,1H),4.03-3.98(m,2H),3.84(s,1H),3.68(d,1H),3.07(s,1H),3.04(s,2H),2.84( d, 1H), 2.64 (s, 1H), 2.45 (s, 3H), 1.92 (s, 2H), 1.50-1.46 (m, 4H), 1.28 (s, 2H).

19F NMR(376MHz,DMSO-d 6)δ-62.45 19 F NMR (376MHz, DMSO-d 6 ) δ-62.45

LC-MS m/z(ESI)＝430.2[M+1]。LC-MS m/z (ESI) = 430.2 [M+1].

实施例56Example 56

5-(1-(羟甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物565-(1-(Hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 56

5-(1-(hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-(hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure PCTCN2022081400-appb-000116
Figure PCTCN2022081400-appb-000116

Figure PCTCN2022081400-appb-000117
Figure PCTCN2022081400-appb-000117

第一步：first step:

(3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己-1-基)甲醇 56a(3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-1-yl)methanol 56a

(3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol(3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol

50mL圆底烧瓶中，将化合物1d(500mg，1.6mmol)溶于20mL四氢呋喃中，冰浴下加入四氢锂铝(61.0mg，1.6mmol)，缓慢升至室温搅拌2h。将反应淬灭，DCM萃取三次，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，得到目标产物(3-苄基-5-(三氟甲基)-3-氮杂双环[3.1.0]己-1-基)甲醇 56a(无色油状，446mg，粗产品)。In a 50 mL round-bottomed flask, compound 1d (500 mg, 1.6 mmol) was dissolved in 20 mL of tetrahydrofuran, lithium aluminum tetrahydrogen (61.0 mg, 1.6 mmol) was added under ice bath, and the mixture was slowly warmed to room temperature and stirred for 2 h. The reaction was quenched, extracted with DCM for three times, washed with 30 mL of saturated brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the target product (3-benzyl-5-(trifluoromethyl)-3-azabicyclo) [3.1.0]Hex-1-yl)methanol 56a (colorless oil, 446 mg, crude product).

LC-MS m/z(ESI)＝272.2[M+1]。LC-MS m/z (ESI) = 272.2 [M+1].

第二步：Step 2:

(5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲醇 56b(5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methanol 56b

(5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol(5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol

H 2氛围下，将56a(446mg，1.6mmol)溶于乙醇50mL中，随后加入Pd/C(681mg，0.64mmol)，升温至60℃反应3h。硅藻土过滤，旋干溶剂，得到目标产物(5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲醇 56b(无色油状液体，300mg，粗产物)，直接用于下一步。 Under H 2 atmosphere, 56a (446 mg, 1.6 mmol) was dissolved in 50 mL of ethanol, then Pd/C (681 mg, 0.64 mmol) was added, and the temperature was raised to 60 °C for 3 h. Filter through celite, spin dry the solvent to obtain the target product (5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methanol 56b (colorless oily liquid, 300 mg, crude product), used directly in the next step.

LC-MS m/z(ESI)＝182.1[M+1]。LC-MS m/z (ESI) = 182.1 [M+1].

第三步：third step:

5-(1-(羟甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物565-(1-(Hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 56

5-(1-(hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-(hydroxymethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

N 2氛围下，将56b(300mg，1.6mmol)溶于1,4-二氧六环30mL中，随后加入5-溴喹啉-8-甲腈(443.5mg，1.92mmol)，依次加入碳酸铯(2.3g，7.2mmol)和Ruphos Pdg3(134mg，0.16mmol)，N 2置换气三次，升温至90℃反应4h。旋干溶剂，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，旋干溶剂，反相纯化得产物 化合物56(60mg，黄色固体)。 Under N atmosphere, 56b (300 mg , 1.6 mmol) was dissolved in 1,4-dioxane 30 mL, followed by 5-bromoquinoline-8-carbonitrile (443.5 mg, 1.92 mmol), followed by cesium carbonate (2.3 g, 7.2 mmol) and Ruphos Pdg3 (134 mg, 0.16 mmol), replaced by N 2 three times, and heated to 90 °C for 4 h. The solvent was spin-dried, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried the solvent, and purified by reverse phase to obtain the product compound 56 (60 mg, yellow solid).

1H NMR(400MHz,DMSO-d 6)δ9.01-8.98(m,1H),8.68-8.60(m,1H),8.13(d,1H),7.62-7.56(m,1H),7.14(d,1H),5.04(t,1H),3.93(t,2H),3.78(d,2H),3.71-3.61(m,2H),1.46(d,1H),1.35(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01-8.98(m,1H), 8.68-8.60(m,1H), 8.13(d,1H), 7.62-7.56(m,1H), 7.14(d , 1H), 5.04(t, 1H), 3.93(t, 2H), 3.78(d, 2H), 3.71-3.61(m, 2H), 1.46(d, 1H), 1.35(d, 1H).

19F NMR(376MHz,DMSO-d 6)δ-62.56 19 F NMR (376MHz, DMSO-d 6 ) δ-62.56

LC-MS m/z(ESI)＝334.1[M+1]。LC-MS m/z (ESI) = 334.1 [M+1].

实施例57Example 57

5-(1-((1-甲基哌啶-4-基)氧基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基)喹啉-8-碳腈 化合物575-(1-((1-Methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl) Quinoline-8-carbonitrile Compound 57

5-(1-(((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-(((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure PCTCN2022081400-appb-000118
Figure PCTCN2022081400-appb-000118

第一步：first step:

(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲基4-甲基苯磺酸盐 57a(3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl 4-methylbenzenesulfonate Acid 57a

(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 4-methylbenzenesulfonate(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 4-methylbenzenesulfonate

将化合物56(60mg，0.18mmol)溶于20mL DCM中，随后加入DMAP(44.0mg，0.36mmol)、三乙胺(36.1mg，0.36mmol)，45℃回流搅拌2h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:丙酮＝20:1)，得到目标产物(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲基4-甲基苯磺酸盐 57a(淡黄色固体，74mg，84.4％)，直接用于下一步。Compound 56 (60 mg, 0.18 mmol) was dissolved in 20 mL of DCM, followed by adding DMAP (44.0 mg, 0.36 mmol), triethylamine (36.1 mg, 0.36 mmol), and stirring at 45 °C for 2 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:acetone=20:1) to obtain the target product ( 3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl 4-methylbenzenesulfonic acid Salt 57a (pale yellow solid, 74 mg, 84.4%) was used directly in the next step.

LC-MS m/z(ESI)＝488.1[M+1]。LC-MS m/z (ESI) = 488.1 [M+1].

第二步：Step 2:

5-(1-((1-甲基哌啶-4-基)氧基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基)喹啉-8-碳腈 化合物575-(1-((1-Methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl) Quinoline-8-carbonitrile Compound 57

5-(1-(((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-(((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

将57a(37mg，0.07mmol)溶于2mL乙腈中，加入1-甲基-4-哌啶醇57b(10.5mg，0.09mmol)、碘化钠(11.4mg，0.07mmol)和碳酸钾(21.0mg，0.15mmol)，80℃搅拌反应2h。待反应结束，浓缩，乙酸乙酯萃取，无水硫酸钠干燥，真空除去溶剂。MPLC分离(乙腈:水＝47:53)，得到目标产物5-(1-((1-甲基哌啶-4-基)氧基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基)喹啉-8-碳腈 化合物57(黄色固体，16mg，53.3％)。57a (37 mg, 0.07 mmol) was dissolved in 2 mL of acetonitrile, 1-methyl-4-piperidinol 57b (10.5 mg, 0.09 mmol), sodium iodide (11.4 mg, 0.07 mmol) and potassium carbonate (21.0 mg were added) , 0.15mmol), and the reaction was stirred at 80°C for 2h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. MPLC separation (acetonitrile:water=47:53), the target product 5-(1-((1-methylpiperidin-4-yl)oxy)methyl)-5-(trifluoromethyl)-3 was obtained - azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile Compound 57 (yellow solid, 16 mg, 53.3%).

1H NMR(400MHz,DMSO-d 6)δ9.03(d,1H),8.75-8.69(m,1H),8.21(d,1H),7.69-7.60(m,1H),7.35(d,1H),4.31-4.19(m,2H),4.02-3.95(m,1H),3.77-3.71(m,4H),3.63-3.42(m,4H),3.20(s,3H),2.10(d,1H),1.97(d,1H),1.89(d,2H),1.87-1.65(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.03(d,1H), 8.75-8.69(m,1H), 8.21(d,1H), 7.69-7.60(m,1H), 7.35(d,1H) ), 4.31-4.19(m, 2H), 4.02-3.95(m, 1H), 3.77-3.71(m, 4H), 3.63-3.42(m, 4H), 3.20(s, 3H), 2.10(d, 1H ), 1.97(d, 1H), 1.89(d, 2H), 1.87-1.65(m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-62.63 19 F NMR (376MHz, DMSO-d 6 ) δ-62.63

LC-MS m/z(ESI)＝431.2[M+1]。LC-MS m/z (ESI) = 431.2 [M+1].

实施例58Example 58

5-(1-(哌嗪-1-基甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物585-(1-(Piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 58

5-(1-(piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-(piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure PCTCN2022081400-appb-000119
Figure PCTCN2022081400-appb-000119

第一步：first step:

4-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲基)哌嗪-1-羧酸叔丁酯 58b4-((3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl)piperazine -1-Carboxylic acid tert-butyl ester 58b

tert-butyl 4-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)piperazine-1-carboxylatetert-butyl 4-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl)piperazine-1-carboxylate

将57a(50mg，0.1mmol)溶于2mL乙腈中，加入1-叔丁氧羰基哌嗪(28.7mg，0.15mmol)、碘化钠(15.4mg，0.1mmol)和碳酸钾(28.4mg，0.21mmol)，80℃搅拌反应2h。待反应结束，浓缩，乙酸乙酯萃取，无水硫酸钠干燥，真空除去溶剂。MPLC分离(乙腈:水＝47:53)，得到目标产物4-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲基)哌嗪-1-羧酸叔丁酯 58b(黄色固体，20mg，粗产品)，直接用于下一步。57a (50 mg, 0.1 mmol) was dissolved in 2 mL of acetonitrile, 1-tert-butoxycarbonylpiperazine (28.7 mg, 0.15 mmol), sodium iodide (15.4 mg, 0.1 mmol) and potassium carbonate (28.4 mg, 0.21 mmol) were added ), and the reaction was stirred at 80 °C for 2 h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. MPLC separation (acetonitrile:water=47:53), the target product 4-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0]hexane-1-yl)methyl)piperazine-1-carboxylate tert-butyl ester 58b (yellow solid, 20 mg, crude), used directly in the next step.

LC-MS m/z(ESI)＝502.3[M+1]。LC-MS m/z (ESI) = 502.3 [M+1].

第二步：Step 2:

5-(1-(哌嗪-1-基甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物585-(1-(Piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 58

5-(1-(piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-(piperazin-1-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

50mL圆底烧瓶中，将58b(20mg，0.1mmol)溶于10mL二氯甲烷中，随后加入三氟乙酸(1mL)，室温反应2h。饱和氯化铵淬灭反应，DCM 30mL萃取，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，反相纯化得到目标产物5-(1-(哌嗪-1-基甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-3-基)喹啉-8-碳腈 化合物58(16mg)。In a 50 mL round-bottomed flask, 58b (20 mg, 0.1 mmol) was dissolved in 10 mL of dichloromethane, then trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of DCM, washed with 30 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by reverse phase to obtain the target product 5-(1-(piperazin-1-ylmethyl) )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 58 (16 mg).

1H NMR(400MHz,DMSO-d 6)δ9.03-8.98(m,1H),8.66-8.62(m,1H),8.17-8.10(m,1H),7.65-7.58(m,1H),7.21-7.17(m,1H),4.00(d,1H),3.84(d,1H),3.76(d,1H),3.58(d,1H),3.09-2.93(m,4H),2.66(s,2H),2.47-2.42(m,2H),2.31(d,1H),2.19-1.93(m,1H),1.75(s,1H),1.59(d,1H),1.45-1.30(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.03-8.98(m,1H), 8.66-8.62(m,1H), 8.17-8.10(m,1H), 7.65-7.58(m,1H), 7.21 -7.17(m, 1H), 4.00(d, 1H), 3.84(d, 1H), 3.76(d, 1H), 3.58(d, 1H), 3.09-2.93(m, 4H), 2.66(s, 2H) ), 2.47-2.42(m, 2H), 2.31(d, 1H), 2.19-1.93(m, 1H), 1.75(s, 1H), 1.59(d, 1H), 1.45-1.30(m, 1H).

19F NMR(376MHz,DMSO-d 6)δ-62.58 19 F NMR (376MHz, DMSO-d 6 ) δ-62.58

LC-MS m/z(ESI)＝402.2[M+1]。LC-MS m/z (ESI) = 402.2 [M+1].

实施例59Example 59

(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲基1-甲基哌啶-4-羧酸酯 化合物59(3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl 1-methylpiperidine -4-Carboxylate Compound 59

(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 1-methylpiperidine-4-carboxylate(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 1-methylpiperidine-4-carboxylate

Figure PCTCN2022081400-appb-000120
Figure PCTCN2022081400-appb-000120

第一步：first step:

1-甲基哌啶-4-羰基氯59b1-Methylpiperidine-4-carbonyl chloride 59b

1-methylpiperidine-4-carbonyl chloride1-methylpiperidine-4-carbonyl chloride

将化合物59a(25.8mg，0.18mmol)溶解于DCM 5mL中，随后加入二氯亚砜(1mL)和DMF(1滴)，回流搅拌2h。TLC反应完毕，直接浓缩反应液，得到1-甲基哌啶-4-羰基氯59b(无色油状物，30mg)。Compound 59a (25.8 mg, 0.18 mmol) was dissolved in DCM 5 mL, then thionyl chloride (1 mL) and DMF (1 drop) were added, and the mixture was stirred at reflux for 2 h. After completion of the TLC reaction, the reaction solution was directly concentrated to obtain 1-methylpiperidine-4-carbonyl chloride 59b (colorless oil, 30 mg).

第二步：Step 2:

(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲基1-甲基哌啶-4-羧酸酯 化合物59(3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl 1-methylpiperidine -4-Carboxylate Compound 59

(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 1-methylpiperidine-4-carboxylate(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methyl 1-methylpiperidine-4-carboxylate

将59b溶于2mL DCM中，随后冰浴滴加化合物56(50.0mg，0.15mmol)、三乙胺(58.7mg，0.58mmol)的DCM溶液，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)甲基1-甲基哌啶-4-羧酸酯 化合物59(13mg)。59b was dissolved in 2 mL of DCM, followed by dropwise addition of compound 56 (50.0 mg, 0.15 mmol) and triethylamine (58.7 mg, 0.58 mmol) in DCM in an ice bath, and stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product ( 3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)methyl 1-methylpiperidine- 4-carboxylate compound 59 (13 mg).

1H NMR(400MHz,DMSO-d 6)δ9.08–8.95(m,1H),8.64(d,1H),8.14(t,1H),7.60(d,1H),7.19(d,1H),4.55(d,1H),4.18(d,1H),3.97-3.91(m,2H),3.77-3.73(m,2H),3.70-3.59(m,2H),2.77-2.73(m,2H),2.36-2.30(m,1H),2.19(d,3H),1.79(d,2H),1.65-1.52(m,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.08-8.95(m,1H), 8.64(d,1H), 8.14(t,1H), 7.60(d,1H), 7.19(d,1H), 4.55(d,1H), 4.18(d,1H), 3.97-3.91(m,2H), 3.77-3.73(m,2H), 3.70-3.59(m,2H), 2.77-2.73(m,2H), 2.36-2.30 (m, 1H), 2.19 (d, 3H), 1.79 (d, 2H), 1.65-1.52 (m, 4H).

19F NMR(376MHz,DMSO-d 6)δ-62.67 19 F NMR (376MHz, DMSO-d 6 ) δ-62.67

LC-MS m/z(ESI)＝459.2[M+1]。LC-MS m/z (ESI) = 459.2 [M+1].

实施例60Example 60

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(顺式-4-(4-(环丙基甲基)哌嗪-1-基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物60(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(cis-4-(4-(cyclopropylmethyl)piperazine-1- (yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 60

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-[cis-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-[cis-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl]-5-(trifluoromethyl) )-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000121
Figure PCTCN2022081400-appb-000121

将化合物1-A(50mg，0.15mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(65mg，0.17mmol)和DIPEA(52ul，0.29mmol)，冰浴下搅拌活化10min，加入顺式-4-[4-(环丙基甲基)-1-哌嗪]-环己烷60a(50mg，0.21mmol)，室温搅拌1h。原料反应完全，加水淬灭后旋干，过MPLC，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(顺式-4-(4-(环丙基甲基)哌嗪-1-基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物60(黄色固体，55mg，75％)。Compound 1-A (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N-dimethylformamide, then HATU (65 mg, 0.17 mmol) and DIPEA (52 ul, 0.29 mmol) were added, and the mixture was stirred and activated under ice bath for 10 min. cis-4-[4-(cyclopropylmethyl)-1-piperazine]-cyclohexane 60a (50 mg, 0.21 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw materials is complete, quenched with water, spin-dried, and passed through MPLC to obtain the target product (1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(cis- 4-(4-(Cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 60 (yellow solid, 55 mg, 75%).

1H NMR(400MHz,DMSO-d 6)δ9.03–8.99(m,1H),8.65–8.60(m,1H),8.17(dd,1H),8.00(d,1H),7.64–7.57(m,1H),7.24(dd,1H),4.08–3.89(m,3H),3.84–3.70(m,2H),2.24–2.05(m,3H),2.03-1.90(dd,3H),1.85-1.70(s,3H),1.61(d,1H),1.45(s,1H),1.23(s,9H),0.90–0.73(m,2H),0.44(dd,2H),0.07-0.02(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.03-8.99(m,1H), 8.65-8.60(m,1H), 8.17(dd,1H), 8.00(d,1H), 7.64-7.57(m) ,1H),7.24(dd,1H),4.08-3.89(m,3H),3.84-3.70(m,2H),2.24-2.05(m,3H),2.03-1.90(dd,3H),1.85-1.70 (s,3H), 1.61(d,1H), 1.45(s,1H), 1.23(s,9H), 0.90–0.73(m,2H), 0.44(dd,2H), 0.07-0.02(m,2H) ).

19F NMR(376MHz,DMSO-d 6)δ-63.68 19 F NMR (376MHz, DMSO-d 6 ) δ-63.68

LC-MS m/z(ESI)＝567.30[M+1],589.30[M+23]。LC-MS m/z (ESI) = 567.30 [M+1], 589.30 [M+23].

实施例61Example 61

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(顺式-4-(4-(环丙基甲基)哌嗪-1-基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物61(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(cis-4-(4-(cyclopropylmethyl)piperazine-1- (yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 61

(1S,5R)或(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-[cis-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-[cis-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl]-5-(trifluoromethyl) )-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000122
Figure PCTCN2022081400-appb-000122

Figure PCTCN2022081400-appb-000123
Figure PCTCN2022081400-appb-000123

将化合物1-B(50mg，0.15mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(65mg，0.17mmol)和DIPEA(52ul，0.29mmol)，冰浴下搅拌活化10min，加入顺式-4-[4-(环丙基甲基)-1-哌嗪]-环己烷61a(50mg，0.21mmol)，室温搅拌1h。原料反应完全，加水淬灭后旋干，过MPLC，得到目标产物(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(顺式-4-(4-(环丙基甲基)哌嗪-1-基)环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物61(黄色固体，45mg，61％)。Compound 1-B (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N-dimethylformamide, then HATU (65 mg, 0.17 mmol) and DIPEA (52 ul, 0.29 mmol) were added, and the mixture was stirred and activated under ice bath for 10 min. cis-4-[4-(cyclopropylmethyl)-1-piperazine]-cyclohexane 61a (50 mg, 0.21 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw materials is complete, quenched with water, spin-dried, and passed through MPLC to obtain the target product (1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(cis- 4-(4-(Cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 61 (yellow solid, 45 mg, 61%).

1H NMR(400MHz,DMSO-d 6)δ9.04–8.96(m,1H),8.66–8.58(m,1H),8.17(dd,1H),7.99(d,1H),7.66–7.56(m,1H),7.24(dd,1H),4.09–3.88(m,3H),3.85–3.69(m,2H),2.24–2.04(m,3H),2.00(dd,3H),1.78(s,3H),1.61(d,1H),1.45(s,1H),1.23(s,9H),0.91–0.72(m,2H),0.43(dd,2H),0.07-0.02(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.04-8.96(m,1H), 8.66-8.58(m,1H), 8.17(dd,1H), 7.99(d,1H), 7.66-7.56(m) ,1H),7.24(dd,1H),4.09–3.88(m,3H),3.85–3.69(m,2H),2.24–2.04(m,3H),2.00(dd,3H),1.78(s,3H) ), 1.61 (d, 1H), 1.45 (s, 1H), 1.23 (s, 9H), 0.91–0.72 (m, 2H), 0.43 (dd, 2H), 0.07–0.02 (m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.68 19 F NMR (376MHz, DMSO-d 6 ) δ-63.68

LC-MS m/z(ESI)＝567.30[M+1],589.30[M+23]。LC-MS m/z (ESI) = 567.30 [M+1], 589.30 [M+23].

实施例62Example 62

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-[反式-4-(二甲氨基)环己基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物62(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl) base)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 62

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000124
Figure PCTCN2022081400-appb-000124

将化合物1-A(50mg，0.15mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(65mg，0.17mmol)和DIPEA(52μl，0.29mmol)，冰浴下搅拌活化10min，加入顺式-4-[4-(环丙基甲基)-1-哌嗪]-环己烷62a(23mg，0.15mmol)，室温搅拌1h。原料反应完全，加水淬灭后旋干，过MPLC，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-[反式-4-(二甲氨基)环己基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化 合物62(黄色固体，17mg，28％)。Compound 1-A (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by the addition of HATU (65 mg, 0.17 mmol) and DIPEA (52 μl, 0.29 mmol), stirring and activation under ice bath for 10 min, cis-4-[4-(cyclopropylmethyl)-1-piperazine]-cyclohexane 62a (23 mg, 0.15 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw materials is complete, quenched with water, spin-dried, and passed through MPLC to obtain the target product (1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-[trans- 4-(Dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 62 (yellow solid, 17 mg, 28%).

1H NMR(400MHz,DMSO-d 6)δ9.01(d,1H),8.63(d,J＝9.3Hz,1H),8.17(d,1H),8.02(d,1H),7.60(dd,1H),7.22(d,1H)，4.01-3.80(m,4H),2.37-2.26(m,6H),2.00-1.97(m,2H),1.87-1.74(m,3H),1.63-1.61(m,1H),1.23(s,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.01 (d, 1H), 8.63 (d, J=9.3 Hz, 1H), 8.17 (d, 1H), 8.02 (d, 1H), 7.60 (dd, 1H), 7.22(d, 1H), 4.01-3.80(m, 4H), 2.37-2.26(m, 6H), 2.00-1.97(m, 2H), 1.87-1.74(m, 3H), 1.63-1.61( m, 1H), 1.23 (s, 6H).

19F NMR(376MHz,DMSO-d 6)δ-63.58 19 F NMR (376MHz, DMSO-d 6 ) δ-63.58

LC-MS m/z(ESI)＝472.20[M+1],494.20[M+23]。LC-MS m/z (ESI) = 472.20 [M+1], 494.20 [M+23].

实施例63Example 63

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-[反式-4-(二甲氨基)环己基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物63(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl) base)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 63

(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-[trans-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000125
Figure PCTCN2022081400-appb-000125

将化合物1-B(50mg，0.15mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(65mg，0.17mmol)和DIPEA(52ul，0.29mmol)，冰浴下搅拌活化10min，加入顺式-4-[4-(环丙基甲基)-1-哌嗪]-环己烷63a(23mg，0.15mmol)，室温搅拌1h。原料反应完全，加水淬灭后旋干，过MPLC，得到目标产物(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-[(1s,4s)-4-(二甲氨基)环己基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物63(黄色固体，16mg，28％)。Compound 1-B (50 mg, 0.15 mmol) was dissolved in 2 mL of N,N-dimethylformamide, then HATU (65 mg, 0.17 mmol) and DIPEA (52 ul, 0.29 mmol) were added, and the mixture was stirred and activated under ice bath for 10 min. cis-4-[4-(cyclopropylmethyl)-1-piperazine]-cyclohexane 63a (23 mg, 0.15 mmol) was added and stirred at room temperature for 1 h. The reaction of the raw materials was completed, quenched by adding water, spin-dried, and passed through MPLC to obtain the target product (1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-[(1s, 4s)-4-(dimethylamino)cyclohexyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 63 (yellow solid, 16 mg, 28% ).

1H NMR(400MHz,DMSO-d 6)δ9.01(d,J＝3.9Hz,1H),8.63(d,J＝9.3Hz,1H),8.17(d,J＝8.2Hz,1H),8.02(d,J＝7.2Hz,1H),7.60(dd,J＝8.5,4.1Hz,1H),7.22(d,J＝8.2Hz,1H)，4.02-3.80(m,4H),2.36-2.26(m,6H),2.02-1.98(m,2H),1.87-1.72(m,3H),1.63-1.61(m,1H),1.23(s,6H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.01 (d, J=3.9 Hz, 1H), 8.63 (d, J=9.3 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 8.02 (d, J=7.2Hz, 1H), 7.60 (dd, J=8.5, 4.1Hz, 1H), 7.22 (d, J=8.2Hz, 1H), 4.02-3.80 (m, 4H), 2.36-2.26 ( m, 6H), 2.02-1.98 (m, 2H), 1.87-1.72 (m, 3H), 1.63-1.61 (m, 1H), 1.23 (s, 6H).

19F NMR(376MHz,DMSO-d 6)δ-63.58. 19 F NMR (376MHz, DMSO-d 6 ) δ-63.58.

LC-MS m/z(ESI)＝472.20[M+1],494.20[M+23]。LC-MS m/z (ESI) = 472.20 [M+1], 494.20 [M+23].

实施例64Example 64

(4-甲基吗啉-2-基)甲基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸酯 化合物64(4-Methylmorpholin-2-yl)methyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxylate Compound 64

(4-methylmorpholin-2-yl)methyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate(4-methylmorpholin-2-yl)methyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

Figure PCTCN2022081400-appb-000126
Figure PCTCN2022081400-appb-000126

第一步：first step:

3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基氯64b3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 64b

3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride

将化合物1(100mg，0.29mmol)溶解于DCM 5mL中，随后加入二氯亚砜(1mL)和DMF(1滴)，回流搅拌2h。TLC反应完毕，直接浓缩反应液，得到中间体3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基氯 64b粗品(黄色油状物，110mg)。Compound 1 (100 mg, 0.29 mmol) was dissolved in DCM 5 mL, followed by addition of thionyl chloride (1 mL) and DMF (1 drop), and stirring at reflux for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Crude carbonyl chloride 64b (yellow oil, 110 mg).

第二步：Step 2:

(4-甲基吗啉-2-基)甲基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸酯 化合物64(4-Methylmorpholin-2-yl)methyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxylate Compound 64

(4-methylmorpholin-2-yl)methyl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate(4-methylmorpholin-2-yl)methyl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

将中间体3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羰基氯64b溶于2mL DMF中，随后冰浴滴加4-甲基-2-吗啉甲醇(45.6mg，0.35mmol)、三乙胺(58.7mg，0.58mmol)的DCM溶液，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物(4-甲基吗啉-2-基)甲基3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸酯 化合物64(淡黄色固体，35mg，26.3％)。The intermediate 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl chloride 64b was dissolved in 2 mL of DMF Then, 4-methyl-2-morpholinemethanol (45.6 mg, 0.35 mmol) and triethylamine (58.7 mg, 0.58 mmol) in DCM were added dropwise in an ice bath, and the mixture was stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product ( 4-Methylmorpholin-2-yl)methyl 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-Carboxylate Compound 64 (pale yellow solid, 35 mg, 26.3%).

1H NMR(400MHz,DMSO-d 6)δ9.05-9.00(m,1H),8.72-8.45(m,1H),8.18(d,1H),7.64-7.69(m,1H),7.28(d,1H),4.22-4.08(m,2H),4.02-3.97(m,2H),3.88-3.84(m,2H),3.79-3.70(m,2H),3.64(s,1H),3.53-3.42(m,2H),2.63-2.58(m,2H),2.16(s,3H),2.00-1.90(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.05-9.00(m,1H), 8.72-8.45(m,1H), 8.18(d,1H), 7.64-7.69(m,1H), 7.28(d ,1H),4.22-4.08(m,2H),4.02-3.97(m,2H),3.88-3.84(m,2H),3.79-3.70(m,2H),3.64(s,1H),3.53-3.42 (m, 2H), 2.63-2.58 (m, 2H), 2.16 (s, 3H), 2.00-1.90 (m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-62.35. 19 F NMR (376MHz, DMSO-d 6 ) δ-62.35.

LC-MS m/z(ESI)＝461.2[M+1]。LC-MS m/z (ESI) = 461.2 [M+1].

实施例65Example 65

N-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)-2-(4-甲基吗啉-2-基)乙酰胺 化合物65N-(3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-2-(4- Methylmorpholin-2-yl)acetamide Compound 65

N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-(4-methylmorpholin-2-yl)acetamideN-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-(4-methylmorpholin-2-yl)acetamide

Figure PCTCN2022081400-appb-000127
Figure PCTCN2022081400-appb-000127

第一步：first step:

叔丁基2-(2-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)氨基)-2-氧乙基)吗啉-4-羧酸酯65ctert-Butyl 2-(2-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl) Amino)-2-oxoethyl)morpholine-4-carboxylate 65c

tert-butyl 2-(2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)amino)-2-oxoethyl)morpholine-4-carboxylatetert-butyl 2-(2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)amino)-2-oxoethyl)morpholine -4-carboxylate

将化合物65a(46.3mg，0.19mmol)溶解于DMF 5mL中，随后加入HATU(71.7mg，0.19mmol)和DIPEA(41.3mg，0.32mmol)，室温搅拌10min，加入化合物4(50mg，0.16mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物叔丁基2-(2-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)氨基)-2-氧乙基)吗啉-4-羧酸酯65c(黄色固体，55mg)。直接用于下一步。Compound 65a (46.3 mg, 0.19 mmol) was dissolved in DMF 5 mL, followed by adding HATU (71.7 mg, 0.19 mmol) and DIPEA (41.3 mg, 0.32 mmol), stirring at room temperature for 10 min, adding compound 4 (50 mg, 0.16 mmol), Stir at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product tertiary Butyl 2-(2-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)amino )-2-Oxoethyl)morpholine-4-carboxylate 65c (yellow solid, 55 mg). used directly in the next step.

LC-MS m/z(ESI)＝546.2[M+1]。LC-MS m/z (ESI) = 546.2 [M+1].

第二步：Step 2:

N-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)-2-(吗啉-2-基)乙酰胺65dN-(3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-2-(morpholine -2-yl)acetamide 65d

N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-(morpholin-2-yl)acetamideN-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-(morpholin-2-yl)acetamide

将65c的粗产品(55mg，0.16mmol)溶于二氯甲烷10mL中，加入三氟乙酸(6.2mg，0.06mmol)，室温搅拌过夜。待反应结束，旋干。MPLC分离(乙腈:水＝47:53)，得到目标产物N-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)-2-(吗啉-2-基)乙酰胺 65d(黄色油状，45mg)。直接用于下一步。The crude product of 65c (55 mg, 0.16 mmol) was dissolved in 10 mL of dichloromethane, trifluoroacetic acid (6.2 mg, 0.06 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction is over, spin dry. MPLC separation (acetonitrile:water=47:53), the target product N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] Hexan-1-yl)-2-(morpholin-2-yl)acetamide 65d (yellow oil, 45 mg). used directly in the next step.

LC-MS m/z(ESI)＝446.2[M+1]。LC-MS m/z (ESI) = 446.2 [M+1].

第三步：third step:

N-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)-2-(4-甲基吗啉-2-基)乙酰胺 化合物65N-(3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-2-(4- Methylmorpholin-2-yl)acetamide Compound 65

N-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-(4-methylmorpholin-2-yl)acetamideN-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2-(4-methylmorpholin-2-yl)acetamide

50mL圆底烧瓶中，将化合物65d(45mg，0.16mmol)溶于20mL二氯甲烷中，冰浴下加入多聚甲醛(14.4mg，0.16mmol)和三乙酰氧基氰基硼氢化钠(76.3mg，0.36mmol)，加入冰醋酸调节pH至4-5，室温搅拌2h。将反应液加入30mL水中，DCM萃取三次，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，得到目标产物N-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-基)-2-(4-甲基吗啉-2-基)乙酰胺 化合物65(黄色固体，52mg，71.2％)。In a 50 mL round-bottomed flask, compound 65d (45 mg, 0.16 mmol) was dissolved in 20 mL of dichloromethane, and paraformaldehyde (14.4 mg, 0.16 mmol) and sodium triacetoxycyanoborohydride (76.3 mg) were added under ice bath. , 0.36mmol), add glacial acetic acid to adjust the pH to 4-5, and stir at room temperature for 2h. The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the target product N-(3-(8-cyanoquinolin-5-yl)- 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-2-(4-methylmorpholin-2-yl)acetamide Compound 65 (yellow solid, 52 mg , 71.2%).

1H NMR(400MHz,DMSO-d 6)δ9.01-8.97(m,1H),8.67-8.63(m,2H),8.13(d,1H),7.62-7.58(m,1H),7.19-7.13(m,1H),3.93(d,1H),3.91(s,1H),3.87-3.83(m,1H),3.81(d,1H),3.74-3.69(m,2H),3.48-3.41(m,1H),2.70-2.67(m,1H),2.57(d,1H),2.34-2.29(m,2H),2.15(s,3H),1.99-1.95(m,1H),1.74-1.68(m,2H),1.62-1.57(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01-8.97(m,1H), 8.67-8.63(m,2H), 8.13(d,1H), 7.62-7.58(m,1H), 7.19-7.13 (m, 1H), 3.93(d, 1H), 3.91(s, 1H), 3.87-3.83(m, 1H), 3.81(d, 1H), 3.74-3.69(m, 2H), 3.48-3.41(m ,1H),2.70-2.67(m,1H),2.57(d,1H),2.34-2.29(m,2H),2.15(s,3H),1.99-1.95(m,1H),1.74-1.68(m , 2H), 1.62-1.57 (m, 1H).

19F NMR(376MHz,DMSO-d 6)δ-64.28. 19 F NMR (376MHz, DMSO-d 6 ) δ-64.28.

LC-MS m/z(ESI)＝460.2[M+1]。LC-MS m/z (ESI) = 460.2 [M+1].

实施例66Example 66

N-((4-甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-(8-(三氟甲基)喹啉-5-基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物66N-((4-Methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 66

N-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamideN-((4-methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000128
Figure PCTCN2022081400-appb-000128

第一步：first step:

将化合物16c(100mg，0.26mmol)溶解于DMF 2mL中，随后加入HATU(97.5mg，0.26mmol)和DIPEA(23.3mg，0.18mmol)，室温搅拌10min，加入化合物66a(40.1mg，0.31mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物N-((4-甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-(8-(三氟甲基)喹啉-5-基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物66(白色固体，91mg，69.7％)。Compound 16c (100 mg, 0.26 mmol) was dissolved in DMF 2 mL, followed by adding HATU (97.5 mg, 0.26 mmol) and DIPEA (23.3 mg, 0.18 mmol), stirring at room temperature for 10 min, adding compound 66a (40.1 mg, 0.31 mmol), Stir at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product N -((4-Methylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide Compound 66 (white solid, 91 mg, 69.7%).

1H NMR(400MHz,DMSO-d 6)δ9.03-8.98(m,1H),8.61-8.57(m,1H),8.36-8.31(m,1H),8.03(d,1H),7.63-7.58(m,1H),7.29(d,1H),3.91(d,1H),3.84-3.80(m,2H),3.75-3.69(m,2H),3.49-3.37(m,2H),3.16-3.12(m,2H),2.63(d,1H),2.55(d,1H),2.14(s,3H),2.01-1.88(m,2H),1.78(d,1H),1.68-1.60(m,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.03-8.98(m,1H), 8.61-8.57(m,1H), 8.36-8.31(m,1H), 8.03(d,1H), 7.63-7.58 (m,1H),7.29(d,1H),3.91(d,1H),3.84-3.80(m,2H),3.75-3.69(m,2H),3.49-3.37(m,2H),3.16-3.12 (m, 2H), 2.63(d, 1H), 2.55(d, 1H), 2.14(s, 3H), 2.01-1.88(m, 2H), 1.78(d, 1H), 1.68-1.60(m, 1H) ).

LC-MS m/z(ESI)＝503.2[M+1]。LC-MS m/z (ESI) = 503.2 [M+1].

实施例67Example 67

3-(8-氰基喹啉-5-基)-5-甲基-N-((4-甲基吗啉-2-基)甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物673-(8-Cyanoquinolin-5-yl)-5-methyl-N-((4-methylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane Alkane-1-carboxamide Compound 67

3-(8-cyanoquinolin-5-yl)-5-methyl-N-((4-methylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-5-methyl-N-((4-methylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000129
Figure PCTCN2022081400-appb-000129

将化合物51h(200mg，0.68mmol)溶解于DMF 5mL中，随后加入HATU(259.4mg，0.68mmol)和DIPEA(175.4mg，1.36mmol)，室温搅拌10min，加入化合物67a(106.6mg，0.82mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物3-(8-氰基喹啉-5-基)-5-甲基-N-((4-甲基吗啉-2-基)甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物67(黄色固体，245mg，89.1％)。Compound 51h (200 mg, 0.68 mmol) was dissolved in DMF 5 mL, followed by adding HATU (259.4 mg, 0.68 mmol) and DIPEA (175.4 mg, 1.36 mmol), stirring at room temperature for 10 min, adding compound 67a (106.6 mg, 0.82 mmol), Stir at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product 3 -(8-Cyanoquinolin-5-yl)-5-methyl-N-((4-methylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane -1-Carboxamide Compound 67 (yellow solid, 245 mg, 89.1%).

1H NMR(400MHz,DMSO-d 6)δ8.99-8.94(m,1H),8.65(d,1H),8.11(d,1H),7.84(t,1H),7.58-7.52(m,1H),7.04(d,1H),4.01(s,1H),3.87-3.84(m,2H),3.76(d,1H),3.53-3.44(m,2H),3.41(d,1H),3.18-3.12(m,2H),2.67(d,1H),2.57(d,1H),2.16(s,3H),1.97-1.93(m,1H),1.73-1.63(m,1H),1.39(d,1H),1.27(s,3H),1.14(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.99-8.94(m,1H), 8.65(d,1H), 8.11(d,1H), 7.84(t,1H), 7.58-7.52(m,1H) ), 7.04(d, 1H), 4.01(s, 1H), 3.87-3.84(m, 2H), 3.76(d, 1H), 3.53-3.44(m, 2H), 3.41(d, 1H), 3.18- 3.12(m, 2H), 2.67(d, 1H), 2.57(d, 1H), 2.16(s, 3H), 1.97-1.93(m, 1H), 1.73-1.63(m, 1H), 1.39(d, 1H), 1.27(s, 3H), 1.14(d, 1H).

LC-MS m/z(ESI)＝406.2[M+1]。LC-MS m/z (ESI) = 406.2 [M+1].

实施例68Example 68

3-(8-氰基喹啉-5-基)-N-((4-(甲基-d3)吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物68-A3-(8-Cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 68-A

3-(8-cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamide

Figure PCTCN2022081400-appb-000130
Figure PCTCN2022081400-appb-000130

2-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)-4,4-双(甲基-d3)吗啉-4-碘 化合物68-B2-((3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide)methyl)- 4,4-Bis(methyl-d3)morpholine-4-iodo compound 68-B

2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)-4,4-bis(methyl-d3)morpholin-4-ium2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)-4,4-bis(methyl-d3)morpholin -4-ium

Figure PCTCN2022081400-appb-000131
Figure PCTCN2022081400-appb-000131

第一步：first step:

叔丁基2-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)吗啉-4-羧酸酯68ctert-Butyl 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide)methane yl)morpholine-4-carboxylate 68c

tert-butyl 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)morpholine-4-carboxylatetert-butyl 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)morpholine-4-carboxylate

将化合物1(100mg，0.29mmol)溶解于DMF 5mL中，随后加入HATU(110.3mg，0.29mmol)和DIPEA(74mg，0.58mmol)，室温搅拌10min，加入化合物68b(74.8mg，0.58mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物叔丁基2-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)吗啉-4-羧酸酯 化合物68c(黄色固体，105mg)。直接用于下一步。Compound 1 (100 mg, 0.29 mmol) was dissolved in DMF 5 mL, followed by adding HATU (110.3 mg, 0.29 mmol) and DIPEA (74 mg, 0.58 mmol), stirring at room temperature for 10 min, adding compound 68b (74.8 mg, 0.58 mmol), room temperature Stir for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product tertiary Butyl 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide)methyl ) morpholine-4-carboxylate Compound 68c (yellow solid, 105 mg). used directly in the next step.

LC-MS m/z(ESI)＝546.2[M+1]。LC-MS m/z (ESI) = 546.2 [M+1].

第二步：Step 2:

3-(8-氰基喹啉-5-基)-N-(吗啉-2-基甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺68d3-(8-Cyanoquinolin-5-yl)-N-(morpholin-2-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-Carboxamide 68d

3-(8-cyanoquinolin-5-yl)-N-(morpholin-2-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(morpholin-2-ylmethyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将68c的粗产品(105mg，0.29mmol)溶于二氯甲烷10mL中，加入三氟乙酸(30.0mg，0.29mmol)，室温搅拌过夜。待反应结束，旋干。MPLC分离(乙腈:水＝47:53)，得到目标产物3-(8-氰基喹啉-5-基)-N-(吗啉-2-基甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺68d(黄色油状，85mg)。直接用于下一步。The crude product of 68c (105 mg, 0.29 mmol) was dissolved in 10 mL of dichloromethane, trifluoroacetic acid (30.0 mg, 0.29 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction is over, spin dry. MPLC separation (acetonitrile:water=47:53), the target product 3-(8-cyanoquinolin-5-yl)-N-(morpholin-2-ylmethyl)-5-(trifluoromethyl) was obtained )-3-azabicyclo[3.1.0]hexane-1-carboxamide 68d (yellow oil, 85 mg). used directly in the next step.

LC-MS m/z(ESI)＝446.2[M+1]。LC-MS m/z (ESI) = 446.2 [M+1].

第三步：third step:

3-(8-氰基喹啉-5-基)-N-((4-(甲基-d3)吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0] 己烷-1-甲酰胺 化合物68-A3-(8-Cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide Compound 68-A

3-(8-cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-((4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- carboxamide

2-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)-4,4-双(甲基-d3)吗啉-4-碘 化合物68-B2-((3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide)methyl)- 4,4-Bis(methyl-d3)morpholine-4-iodo compound 68-B

2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)-4,4-bis(methyl-d3)morpholin-4-ium2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)-4,4-bis(methyl-d3)morpholin -4-ium

50mL圆底烧瓶中，将化合物68d(50mg，0.11mmol)溶于5mL DMF中，冰浴下加入碳酸钠(23.3mg，0.21mmol)和氘代碘甲烷(18mg，0.12mmol)，室温搅拌0.5h。将反应液加入30mL水中，DCM萃取三次，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，MPLC纯化，得到目标产物3-(8-氰基喹啉-5-基)-N-((4-(甲基-d3)吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物68-A(黄色固体，12mg)；2-((3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)-4,4-双(甲基-d3)吗啉-4-碘 化合物68-B(黄色固体，23mg)。In a 50 mL round-bottomed flask, compound 68d (50 mg, 0.11 mmol) was dissolved in 5 mL of DMF, sodium carbonate (23.3 mg, 0.21 mmol) and deuterated iodomethane (18 mg, 0.12 mmol) were added under ice bath, and the mixture was stirred at room temperature for 0.5 h . The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by MPLC to obtain the target product 3-(8-cyanoquinolin-5-yl)- N-((4-(Methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 68-A (yellow solid, 12 mg); 2-((3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxamide)methyl)-4,4-bis(methyl-d3)morpholine-4-iodo compound 68-B (yellow solid, 23 mg).

化合物68-A：Compound 68-A:

1H NMR(400MHz,DMSO-d 6)δ9.03-8.98(m,1H),8.68-8.62(m,1H),8.35(t,1H),8.17(d,1H),7.63-7.58(m,1H),7.23(d,1H),4.01(d,1H),3.97-3.90(m,2H),3.82(d,1H),3.77-3.72(m,1H),3.47-3.40(m,2H),3.16-3.12(m,2H),2.62-2.58(m,2H),2.15-1.83(m,3H),1.64(d,2H),1.54-1.37(m,1H),1.28(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.03-8.98(m,1H), 8.68-8.62(m,1H), 8.35(t,1H), 8.17(d,1H), 7.63-7.58(m) ,1H),7.23(d,1H),4.01(d,1H),3.97-3.90(m,2H),3.82(d,1H),3.77-3.72(m,1H),3.47-3.40(m,2H) ), 3.16-3.12(m, 2H), 2.62-2.58(m, 2H), 2.15-1.83(m, 3H), 1.64(d, 2H), 1.54-1.37(m, 1H), 1.28(s, 1H) ).

19F NMR(376MHz,DMSO-d 6)δ-64.32. 19 F NMR (376MHz, DMSO-d 6 ) δ-64.32.

LC-MS m/z(ESI)＝463.2[M+1]。LC-MS m/z (ESI) = 463.2 [M+1].

化合物68-B：Compound 68-B:

1H NMR(400MHz,DMSO-d 6)δ9.02(d,1H),8.72-8.54(m,2H),8.21-8.15(m,1H),7.65-7.60(m,1H),7.25(d,1H),3.97(s,5H),3.82(d,1H),3.43(d,2H),3.14(s,2H),3.07(t,1H),2.08-1.93(m,2H),1.70(s,1H),1.43(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.02(d,1H), 8.72-8.54(m,2H), 8.21-8.15(m,1H), 7.65-7.60(m,1H), 7.25(d ,1H),3.97(s,5H),3.82(d,1H),3.43(d,2H),3.14(s,2H),3.07(t,1H),2.08-1.93(m,2H),1.70( s, 1H), 1.43(d, 1H).

19F NMR(376MHz,DMSO-d 6)δ-64.36. 19 F NMR (376MHz, DMSO-d 6 ) δ-64.36.

LC-MS m/z(ESI)＝480.2[M]。LC-MS m/z (ESI) = 480.2 [M].

实施例69Example 69

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(反式-4-吗啉环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物69(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 69

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

Figure PCTCN2022081400-appb-000132
Figure PCTCN2022081400-appb-000132

将化合物1-A(50mg，0.14mmol)溶解于DMF 5mL中，随后加入HATU(53mg，0.14mmol)和DIPEA(36.1mg，0.28mmol)，室温搅拌10min，加入化合物69b(29.2mg，0.16mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(反式-4-吗啉环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物69(黄色固体，47mg，65.5％)。Compound 1-A (50 mg, 0.14 mmol) was dissolved in DMF 5 mL, followed by adding HATU (53 mg, 0.14 mmol) and DIPEA (36.1 mg, 0.28 mmol), stirring at room temperature for 10 min, adding compound 69b (29.2 mg, 0.16 mmol) , and stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product ( 1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3 - Azabicyclo[3.1.0]hexane-1-carboxamide Compound 69 (yellow solid, 47 mg, 65.5%).

1H NMR(400MHz,DMSO-d 6)δ9.02-8.97(m,1H),8.65-8.62(m,1H),8.16(d,1H),7.99(d,1H),7.63-7.59(m,1H),7.22(d,1H),4.00(d,1H),3.94(s,2H),3.81(d,1H),3.53(d,5H),2.44(t,4H),2.13(s,1H),1.98(d,1H),1.80(s,4H),1.61(d,1H),1.23(s,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.02-8.97(m,1H), 8.65-8.62(m,1H), 8.16(d,1H), 7.99(d,1H), 7.63-7.59(m) ,1H),7.22(d,1H),4.00(d,1H),3.94(s,2H),3.81(d,1H),3.53(d,5H),2.44(t,4H),2.13(s, 1H), 1.98 (d, 1H), 1.80 (s, 4H), 1.61 (d, 1H), 1.23 (s, 4H).

19F NMR(376MHz,DMSO-d 6)δ-63.58. 19 F NMR (376MHz, DMSO-d 6 ) δ-63.58.

LC-MS m/z(ESI)＝514.2[M+1]。LC-MS m/z (ESI) = 514.2 [M+1].

实施例70Example 70

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(反式-4-吗啉环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物70(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)- 3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 70

(1S,5R)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

Figure PCTCN2022081400-appb-000133
Figure PCTCN2022081400-appb-000133

将化合物1-B(50mg，0.14mmol)溶解于DMF 5mL中，随后加入HATU(53mg，0.14mmol)和DIPEA(36.1mg，0.28mmol)，室温搅拌10min，加入化合物 70b(29.2mg，0.16mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(反式-4-吗啉环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物70(黄色固体，46mg，64.1％)。Compound 1-B (50 mg, 0.14 mmol) was dissolved in DMF 5 mL, followed by adding HATU (53 mg, 0.14 mmol) and DIPEA (36.1 mg, 0.28 mmol), stirring at room temperature for 10 min, adding compound 70b (29.2 mg, 0.16 mmol) , and stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product ( 1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3 - Azabicyclo[3.1.0]hexane-1-carboxamide Compound 70 (yellow solid, 46 mg, 64.1%).

1H NMR(400MHz,DMSO-d 6)δ9.05-8.96(m,1H),8.67-8.60(m,1H),8.16(d,1H),7.99(d,1H),7.63-7.57(m,1H),7.22(d,1H),4.00(d,1H),3.93(d,2H),3.81(d,1H),3.53(d,5H),2.44(t,4H),2.12(s,1H),1.98(d,1H),1.79(s,4H),1.61(d,1H),1.23(s,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.05-8.96(m,1H), 8.67-8.60(m,1H), 8.16(d,1H), 7.99(d,1H), 7.63-7.57(m) ,1H),7.22(d,1H),4.00(d,1H),3.93(d,2H),3.81(d,1H),3.53(d,5H),2.44(t,4H),2.12(s, 1H), 1.98 (d, 1H), 1.79 (s, 4H), 1.61 (d, 1H), 1.23 (s, 4H).

19F NMR(376MHz,DMSO-d 6)δ-63.58. 19 F NMR (376MHz, DMSO-d 6 ) δ-63.58.

LC-MS m/z(ESI)＝514.2[M+1]。LC-MS m/z (ESI) = 514.2 [M+1].

实施例71Example 71

3-(8-氰基喹啉-5-基)-N-(3,3-二氟-1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物713-(8-Cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide Compound 71

3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000134
Figure PCTCN2022081400-appb-000134

第一步：first step:

4-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-酰胺基)-3,3-二氟哌啶-1-羧酸叔丁酯 71c4-(3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido)-3,3- tert-Butyl difluoropiperidine-1-carboxylate 71c

5-tert-butyl-4-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido)-3,3-difluoropiperidine-1-carboxylate5-tert-butyl-4-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amido)-3,3-difluoropiperidine-1- carboxylate

将化合物1(300mg，0.87mmol)溶解于DMF 5mL中，随后加入HATU(115mg，1.3mmol)和DIPEA(168mg，1.3mmol)，室温搅拌10min，加入化合物71b(411mg，1.74mmol)，室温搅拌2h。原料反应完毕，加入15mL水中淬灭，体系用乙酸乙酯萃取三遍，合并有机相并用饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，MPLC(乙腈:水＝60:40)分离纯化，得到目标产物4-(3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-酰胺基)-3,3-二氟哌啶-1-羧酸叔丁酯71c(黄色固体，490mg)。直接用于下一步。Compound 1 (300 mg, 0.87 mmol) was dissolved in 5 mL of DMF, followed by adding HATU (115 mg, 1.3 mmol) and DIPEA (168 mg, 1.3 mmol), stirring at room temperature for 10 min, adding compound 71b (411 mg, 1.74 mmol), stirring at room temperature for 2 h . The reaction of the raw materials was completed, 15 mL of water was added to quench, the system was extracted three times with ethyl acetate, the organic phases were combined and washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, MPLC (acetonitrile:water=60:40) Separation and purification to obtain the target product 4-(3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-amide )-3,3-difluoropiperidine-1-carboxylate tert-butyl ester 71c (yellow solid, 490 mg). used directly in the next step.

LC-MS m/z(ESI)＝566.2[M+1]。LC-MS m/z (ESI) = 566.2 [M+1].

第二步：Step 2:

3-(8-氰基喹啉-5-基)-N-(3,3-二氟哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 71d3-(8-Cyanoquinolin-5-yl)-N-(3,3-difluoropiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0 ]hexane-1-carboxamide 71d

3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoropiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoropiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将71c(490mg，0.87mmol)溶于氯化氢二氧六环溶液(10mL)中，室温搅拌过夜。待反应结束，旋干。MPLC分离(乙腈:水＝40:60)，得到目标产物3-(8-氰基喹啉-5-基)-N-(3,3-二氟哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺71d(黄色固体，404mg)。直接用于下一步。71c (490 mg, 0.87 mmol) was dissolved in a solution of hydrogen chloride in dioxane (10 mL) and stirred at room temperature overnight. After the reaction is over, spin dry. MPLC separation (acetonitrile:water=40:60), the target product 3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoropiperidin-4-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 71d (yellow solid, 404 mg). used directly in the next step.

LC-MS m/z(ESI)＝466.1[M+1]。LC-MS m/z (ESI) = 466.1 [M+1].

第三步：third step:

3-(8-氰基喹啉-5-基)-N-(3,3-二氟-1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物713-(8-Cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide Compound 71

3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

50mL圆底烧瓶中，将化合物71d(404mg，0.87mmol)溶于15mL无水甲醇中，随后加入多聚甲醛(549mg，6.09mmol)和氰基硼氢化钠(987mg,2.61mmol)，加热回流3h。将反应液加入30mL水中，DCM萃取三次，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，MPLC纯化(乙腈:水＝45:55)，得到目标产物3-(8-氰基喹啉-5-基)-N-(3,3-二氟-1-甲基哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物71(黄色固体，145mg，35％)。In a 50 mL round-bottomed flask, compound 71d (404 mg, 0.87 mmol) was dissolved in 15 mL of anhydrous methanol, followed by adding paraformaldehyde (549 mg, 6.09 mmol) and sodium cyanoborohydride (987 mg, 2.61 mmol), heating to reflux for 3 h . The reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by MPLC (acetonitrile:water=45:55) to obtain the target product 3-(8-cyanide). quinolin-5-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxamide Compound 71 (yellow solid, 145 mg, 35%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,J＝4.1,1.3Hz,1H),8.64(dd,J＝8.6,1.5Hz,1H),8.40(d,J＝8.9Hz,1H),8.18(d,J＝8.2Hz,1H),7.61(dd,J＝8.7,4.2Hz,1H),7.24(d,J＝8.3Hz,1H)。4.25-3.85(m,5H),3.05-2.98(m,1H),2.79-2.67(m,1H),2.36-2.26(m,1H),2.22(s,3H),2.14-2.04(m,1H),1.98(d,J＝8.0Hz,1H),1.75-1.59(m,3H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.01 (dd, J=4.1, 1.3 Hz, 1H), 8.64 (dd, J=8.6, 1.5 Hz, 1H), 8.40 (d, J=8.9 Hz, 1H), 8.18 (d, J=8.2Hz, 1H), 7.61 (dd, J=8.7, 4.2Hz, 1H), 7.24 (d, J=8.3Hz, 1H). 4.25-3.85(m, 5H), 3.05-2.98(m, 1H), 2.79-2.67(m, 1H), 2.36-2.26(m, 1H), 2.22(s, 3H), 2.14-2.04(m, 1H) ), 1.98 (d, J=8.0 Hz, 1H), 1.75-1.59 (m, 3H).

19F NMR(376MHz,DMSO-d 6)δ-63.71,-63.93. 19 F NMR (376MHz, DMSO-d 6 )δ-63.71,-63.93.

LC-MS m/z(ESI)＝480.2[M+1]。LC-MS m/z (ESI) = 480.2 [M+1].

实施例72Example 72

3-(8-氰基喹啉-5-基)-N-(9-甲基-3-氧杂-9-氮杂双环[3.3.1]壬南-7-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物723-(8-Cyanoquinolin-5-yl)-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-(tri Fluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 72

3-(8-cyanoquinolin-5-yl)-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide3-(8-cyanoquinolin-5-yl)-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000135
Figure PCTCN2022081400-appb-000135

将化合物1(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg，0.22mmol)，室温搅拌10min，加入内-7-氨基-9-甲基-3-氧杂-9-氮杂双环[3.3.1]壬烷二盐酸盐72b(66mg，0.29mmol)，室温搅拌3h。原料反应完全，MPLC分离(乙腈:水＝45％:55％)，得到目标产物3-(8-氰基喹啉-5-基)-N-(9-甲基-3-氧杂-9-氮杂双环[3.3.1]壬南-7-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物72(淡黄色固体，27mg，40％)。Compound 1 (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol) were added, and the mixture was stirred at room temperature for 10 min. -Amino-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane dihydrochloride 72b (66 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 45%: 55%) was performed to obtain the target product 3-(8-cyanoquinolin-5-yl)-N-(9-methyl-3-oxa-9 -azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 72 (pale yellow solid, 27 mg, 40%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.64(dd,1H),8.50(d,1H),8.17(d,1H),7.61(dd,1H),7.24(d,1H),4.29-4.23(m,1H),4.03-3.81(m,6H),3.59(dd,2H),2.58(s,2H),2.40(s,3H),2.31-2.25(m,2H),1.75-1.69(m,2H),1.22(dd,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.64(dd,1H), 8.50(d,1H), 8.17(d,1H), 7.61(dd,1H), 7.24( d,1H),4.29-4.23(m,1H),4.03-3.81(m,6H),3.59(dd,2H),2.58(s,2H),2.40(s,3H),2.31-2.25(m, 2H), 1.75-1.69 (m, 2H), 1.22 (dd, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.48. 19 F NMR (376MHz, DMSO-d 6 ) δ-63.48.

LC-MS m/z(ESI)＝486.2[M+1],508.2[M+23]。LC-MS m/z (ESI) = 486.2 [M+1], 508.2 [M+23].

实施例73Example 73

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(9-甲基-3-氧杂-9-氮杂双环[3.3.1]壬南-7-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物73(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1] Nonann-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 73

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)- 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000136
Figure PCTCN2022081400-appb-000136

将化合物1-A(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg,0.22mmol)，室温搅拌10min，加入内-7-氨基-9-甲基-3-氧杂-9-氮杂双环[3.3.1]壬烷二盐酸盐(66mg，0.29mmol)，室温搅拌3h。原料反应完全，MPLC分离(乙腈:水＝45％:55％)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(9-甲基-3-氧杂-9-氮杂双环[3.3.1]壬南-7-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物73(淡黄色固体，40mg，63％)。Compound 1-A (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol) were added, and the mixture was stirred at room temperature for 10 min. -7-Amino-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane dihydrochloride (66 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 45%: 55%) was performed to obtain the target product (1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N- (9-Methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxamide Compound 73 (pale yellow solid, 40 mg, 63%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.64(dd,1H),8.50(d,1H),8.17(d,1H),7.61(dd,1H),7.24(d,1H),4.29-4.23(m,1H),4.03-3.81(m,6H),3.59(dd,2H),2.58(s,2H),2.40(s,3H),2.31-2.25(m,2H),1.75-1.69(m,2H),1.22(dd,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.64(dd,1H), 8.50(d,1H), 8.17(d,1H), 7.61(dd,1H), 7.24( d,1H),4.29-4.23(m,1H),4.03-3.81(m,6H),3.59(dd,2H),2.58(s,2H),2.40(s,3H),2.31-2.25(m, 2H), 1.75-1.69 (m, 2H), 1.22 (dd, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.48. 19 F NMR (376MHz, DMSO-d 6 ) δ-63.48.

LC-MS m/z(ESI)＝486.2[M+1]。LC-MS m/z (ESI) = 486.2 [M+1].

实施例74Example 74

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(9-甲基-3-氧杂-9-氮杂双环[3.3.1]壬南-7-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物74(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1] Nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 74

(1S,5R)或(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)- 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000137
Figure PCTCN2022081400-appb-000137

将化合物1-B(50mg，0.14mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入HATU(83mg，0.22mmol)和DIPEA(27.9mg,0.22mmol)，室温搅拌10min，加入内-7-氨基-9-甲基-3-氧杂-9-氮杂双环[3.3.1]壬烷二盐酸盐(66mg，0.29mmol)，室温搅拌3h。原料反应完全，MPLC分离(乙腈:水＝45％:55％)，得到目标产物(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(9-甲基-3-氧杂-9-氮杂双环[3.3.1]壬南-7-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酰胺 化合物74(淡黄色固体，40mg，66％)。Compound 1-B (50 mg, 0.14 mmol) was dissolved in 2 mL of N,N-dimethylformamide, then HATU (83 mg, 0.22 mmol) and DIPEA (27.9 mg, 0.22 mmol) were added, and the mixture was stirred at room temperature for 10 min. -7-Amino-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane dihydrochloride (66 mg, 0.29 mmol), stirred at room temperature for 3 h. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 45%: 55%) was performed to obtain the target product (1S, 5R) or (1R, 5S)-3-(8-cyanoquinolin-5-yl)-N- (9-Methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-Carboxamide Compound 74 (pale yellow solid, 40 mg, 66%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.64(dd,1H),8.50(d,1H),8.17(d,1H),7.61(dd,1H),7.24(d,1H),4.29-4.23(m,1H),4.03-3.81(m,6H),3.59(dd,2H),2.58(s,2H),2.40(s,3H),2.31-2.25(m,2H),1.75-1.69(m,2H),1.22(dd,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.64(dd,1H), 8.50(d,1H), 8.17(d,1H), 7.61(dd,1H), 7.24( d,1H),4.29-4.23(m,1H),4.03-3.81(m,6H),3.59(dd,2H),2.58(s,2H),2.40(s,3H),2.31-2.25(m, 2H), 1.75-1.69 (m, 2H), 1.22 (dd, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.48 19 F NMR (376MHz, DMSO-d 6 ) δ-63.48

LC-MS m/z(ESI)＝486.2[M+1]LC-MS m/z(ESI)=486.2[M+1]

实施例75Example 75

5-(1-[(吗啉-4-基)甲基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基)喹啉-8-甲腈 化合物755-(1-[(Morpholin-4-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile Compound 75

5-(1-[(morpholin-4-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile5-(1-[(morpholin-4-yl)methyl]-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

Figure PCTCN2022081400-appb-000138
Figure PCTCN2022081400-appb-000138

将化合物75a(100mg，0.21mmol)溶解于N,N-二甲基甲酰胺2mL中，随后加入吗啉(27mg，0.31mmol)，碳酸钾(58mg，0.42mmol)，碘化钠(32mg，0.21mmol)，100℃避光搅拌3h。原料反应完全，MPLC分离(乙腈:水＝40％:60％)，得到目标产物5-(1-[(吗啉-4-基)甲基]-5-(三氟甲基)-3-氮杂双环[3.1.0]己-3-基)喹啉-8-甲腈 化合物76(淡黄色固体，40mg，99％)。Compound 75a (100 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide 2 mL, followed by the addition of morpholine (27 mg, 0.31 mmol), potassium carbonate (58 mg, 0.42 mmol), sodium iodide (32 mg, 0.21 mmol) mmol), and stirred at 100 °C for 3 h in the dark. The reaction of the raw materials was completed, and MPLC separation (acetonitrile: water = 40%: 60%) was performed to obtain the target product 5-(1-[(morpholin-4-yl)methyl]-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile Compound 76 (pale yellow solid, 40 mg, 99%).

1H NMR(400MHz,DMSO-d 6)δ9.02(dd,J＝4.1,1.3Hz,1H),8.77-8.57(m,1H),8.19(d,J＝8.2Hz,1H),7.63(dd,J＝8.7,4.2Hz,1H),7.21(d,J＝8.2Hz,1H),4.14-3.58(m,12H),3.23-3.04(m,2H),1.83-1.62(m,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.02 (dd, J=4.1, 1.3 Hz, 1H), 8.77-8.57 (m, 1H), 8.19 (d, J=8.2 Hz, 1H), 7.63 ( dd,J=8.7,4.2Hz,1H),7.21(d,J=8.2Hz,1H),4.14-3.58(m,12H),3.23-3.04(m,2H),1.83-1.62(m,2H) .

19F NMR(376MHz,DMSO-d 6)δ-61.72 19 F NMR (376MHz, DMSO-d 6 ) δ-61.72

LC-MS m/z(ESI)＝403.2[M+1]LC-MS m/z(ESI)=403.2[M+1]

实施例76Example 76

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(反式-3-吗啉代环丁基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物76(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl) )-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 76

(1R,5S)或(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

Figure PCTCN2022081400-appb-000139
Figure PCTCN2022081400-appb-000139

第一步：first step:

顺式-3-((叔丁氧基羰基)氨基)环丁基4-甲基苯磺酸盐76bcis-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate 76b

cis-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonatecis-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate

将化合物76a(3.0g，16mmol)溶于20mL DCM中，随后加入DMAP(3.9g，32mmol)、三乙胺(4.4mL，32mmol)、对甲苯磺酰氯(3.0g，16mmol)，45℃回流搅拌2h。TLC反应完毕，将反应液加入50mL水中水洗，饱和食盐水50mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(乙酸乙酯:石油醚＝10:1)，得到目标产物反式-3-((叔丁氧基羰基)氨基)环丁基4-甲基苯磺酸盐76b(白色固体，5.3g，98.1％)。Compound 76a (3.0 g, 16 mmol) was dissolved in 20 mL of DCM, followed by adding DMAP (3.9 g, 32 mmol), triethylamine (4.4 mL, 32 mmol), p-toluenesulfonyl chloride (3.0 g, 16 mmol), and stirring at 45°C under reflux 2h. After the TLC reaction was completed, the reaction solution was washed with 50 mL of water, washed with 50 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=10:1) to obtain the target product trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate 76b (white solid, 5.3 g, 98.1%).

LC-MS m/z(ESI)＝342.2[M+1]。LC-MS m/z (ESI) = 342.2 [M+1].

第二步：Step 2:

(反式-3-吗啉代环丁基)氨基甲酸叔丁酯76c(trans-3-morpholinocyclobutyl) tert-butyl carbamate 76c

tert-butyl(trans-3-morpholinocyclobutyl)carbamatetert-butyl(trans-3-morpholinocyclobutyl)carbamate

将76b(1.0g，2.93mmol)溶于10mL DMF中，加入吗啉(306.6mg，3.52mmol)、碘化钠(88.0mg，0.58mmol)和碳酸钾(808.0mg，5.86mmol)，90℃搅拌反应2h。待反应结束，浓缩，乙酸乙酯萃取，无水硫酸钠干燥，真空除去溶剂。硅胶柱层析纯化(乙酸乙酯:石油醚＝1:1)，得到目标产物(反式-3-吗啉代环丁基)氨基甲酸叔丁酯76c(无色油状，350mg，46.7％)。直接用于下一步。76b (1.0 g, 2.93 mmol) was dissolved in 10 mL of DMF, morpholine (306.6 mg, 3.52 mmol), sodium iodide (88.0 mg, 0.58 mmol) and potassium carbonate (808.0 mg, 5.86 mmol) were added, and stirred at 90 °C The reaction was carried out for 2h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain the target product (trans-3-morpholinocyclobutyl)carbamate tert-butyl ester 76c (colorless oil, 350 mg, 46.7%) . used directly in the next step.

LC-MS m/z(ESI)＝257.2[M+1]。LC-MS m/z (ESI) = 257.2 [M+1].

第三步：third step:

(反式-3-吗啉代环丁基)氨基76d(trans-3-morpholinocyclobutyl)amino 76d

trans-3-morpholinocyclobutan-1-aminetrans-3-morpholinocyclobutan-1-amine

将76c(256mg，1.0mmol)溶于二氯甲烷10mL中，加入三氟乙酸(114.0mg，1.0mmol)，室温搅拌过夜。待反应结束，旋干。得((1R,3R)-3-吗啉代环丁基)氨基76d粗产品(无色油状，200mg)。直接用于下一步。76c (256 mg, 1.0 mmol) was dissolved in 10 mL of dichloromethane, trifluoroacetic acid (114.0 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction is over, spin dry. The crude product of ((1R,3R)-3-morpholinocyclobutyl)amino 76d was obtained (colorless oil, 200 mg). used directly in the next step.

LC-MS m/z(ESI)＝157.2[M+1]。LC-MS m/z (ESI) = 157.2 [M+1].

第四步：the fourth step:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((1R,3R)-3-吗啉代环丁基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物76(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((1R,3R)-3-morpholinocyclobutyl)-5-(tri Fluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 76

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((1R,3R)-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((1R,3R)-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]hexane-1-carboxamide

将化合物1-A(173.5mg，0.5mmol)溶解于DMF 2mL中，随后加入HATU(190.1mg，0.5mmol)和DIPEA(129.1mg，1.0mmol)，室温搅拌10min，加入化合物76d(78.0mg，0.5mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，MPLC纯化，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(反式-3-吗啉代环丁基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物76(白色固体，100mg，41.3％)。Compound 1-A (173.5 mg, 0.5 mmol) was dissolved in DMF 2 mL, followed by adding HATU (190.1 mg, 0.5 mmol) and DIPEA (129.1 mg, 1.0 mmol), stirring at room temperature for 10 min, adding compound 76d (78.0 mg, 0.5 mmol), and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1R,5S) or (1S,5R)-3-( 8-Cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-Carboxamide Compound 76 (white solid, 100 mg, 41.3%).

1H NMR(400MHz,DMSO-d6)δ9.01(d,1H),8.67-8.61(m,1H),8.41-8.38(m,1H),8.19-8.14(m,1H),7.63-7.60(m,1H),7.26-7.21(m,1H),4.17-4.08(m,1H),4.04-3.98(m,2H),3.98-3.92(m,1H),3.80(t,1H),3.59-3.54(m,4H),2.86-2.65(m,1H),2.46-2.28(m,2H),2.18(d,4H),1.99-1.95(m,2H),1.75(d,1H),1.63(t,1H)。 1 H NMR (400MHz, DMSO-d6)δ9.01(d,1H), 8.67-8.61(m,1H), 8.41-8.38(m,1H), 8.19-8.14(m,1H), 7.63-7.60( m,1H),7.26-7.21(m,1H),4.17-4.08(m,1H),4.04-3.98(m,2H),3.98-3.92(m,1H),3.80(t,1H),3.59- 3.54(m, 4H), 2.86-2.65(m, 1H), 2.46-2.28(m, 2H), 2.18(d, 4H), 1.99-1.95(m, 2H), 1.75(d, 1H), 1.63( t,1H).

19F NMR(376MHz,DMSO-d6)δ-63.61. 19 F NMR (376MHz, DMSO-d6) δ-63.61.

LC-MS m/z(ESI)＝486.2[M+1]。LC-MS m/z (ESI) = 486.2 [M+1].

实施例77Example 77

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(反式-3-吗啉环丁基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物77(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 77

(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

Figure PCTCN2022081400-appb-000140
Figure PCTCN2022081400-appb-000140

Figure PCTCN2022081400-appb-000141
Figure PCTCN2022081400-appb-000141

将化合物1-B(173.5mg，0.5mmol)溶解于DMF 2mL中，随后加入HATU(190.1mg，0.5mmol)和DIPEA(129.1mg，1.0mmol)，室温搅拌10min，加入化合物76d(78.0mg，0.5mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，MPLC纯化，得到目标产物(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(反式-3-吗啉环丁基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物77(白色固体，102mg，42.1％)。Compound 1-B (173.5 mg, 0.5 mmol) was dissolved in 2 mL of DMF, followed by adding HATU (190.1 mg, 0.5 mmol) and DIPEA (129.1 mg, 1.0 mmol), stirring at room temperature for 10 min, adding compound 76d (78.0 mg, 0.5 mmol), and stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1S,5R) or (1R,5S)-3-( 8-Cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Formamide Compound 77 (white solid, 102 mg, 42.1%).

1H NMR(400MHz,DMSO-d6)δ9.01(d,1H),8.70-8.59(m,1H),8.41-8.37(m,1H),8.19-8.16(m,1H),7.64-7.58(m,1H),7.26-7.22(m,1H),4.15(d,1H),4.08-3.98(m,1H),3.97-3.92(m,2H),3.80(t,1H),3.56(d,4H),2.77(q,1H),2.44-2.30(m,2H),2.18(d,4H),1.99-1.96(m,2H),1.75(q,1H),1.63(t,1H)。 1 H NMR (400MHz, DMSO-d6)δ9.01(d,1H), 8.70-8.59(m,1H), 8.41-8.37(m,1H), 8.19-8.16(m,1H), 7.64-7.58( m, 1H), 7.26-7.22(m, 1H), 4.15(d, 1H), 4.08-3.98(m, 1H), 3.97-3.92(m, 2H), 3.80(t, 1H), 3.56(d, 4H), 2.77(q,1H), 2.44-2.30(m,2H), 2.18(d,4H), 1.99-1.96(m,2H), 1.75(q,1H), 1.63(t,1H).

19F NMR(376MHz,DMSO-d6)δ-63.67. 19 F NMR (376MHz, DMSO-d6) δ-63.67.

LC-MS m/z(ESI)＝486.2[M+1]。LC-MS m/z (ESI) = 486.2 [M+1].

实施例78Example 78

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(顺式-3-吗啉代环丁基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物78(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(cis-3-morpholinocyclobutyl)-5-(trifluoromethyl) )-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 78

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(cis-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(cis-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

Figure PCTCN2022081400-appb-000142
Figure PCTCN2022081400-appb-000142

第一步：first step:

反式-3-((叔丁氧基羰基)氨基)环丁基4-甲基苯磺酸盐78btrans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate 78b

trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonatetrans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate

将化合物78a(3.7g，20mmol)溶于20mL DCM中，随后加入DMAP(4.9g，40mmol)、三乙胺(4.0g，40mmol)、对甲苯磺酰氯(3.7g，20mmol)，45℃回流搅拌2h。TLC反应完毕，将反应液加入50mL水中水洗，饱和食盐水50mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(乙酸乙酯:石油醚＝10:1)，得到目标产物反式-3-((叔丁氧基羰基)氨基)环丁基4-甲基苯磺酸盐78b(白色固体，4.9g，72.1％)。Compound 78a (3.7 g, 20 mmol) was dissolved in 20 mL of DCM, followed by adding DMAP (4.9 g, 40 mmol), triethylamine (4.0 g, 40 mmol), p-toluenesulfonyl chloride (3.7 g, 20 mmol), and stirring at 45°C under reflux 2h. After the TLC reaction was completed, the reaction solution was washed with 50 mL of water, washed with 50 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=10:1) to obtain the target product trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate 78b (white solid, 4.9 g, 72.1%).

LC-MS m/z(ESI)＝342.1[M+1]。LC-MS m/z (ESI) = 342.1 [M+1].

第二步：Step 2:

顺式-3-吗啉代环丁基)氨基甲酸叔丁酯78ccis-3-Morpholinocyclobutyl) tert-butyl carbamate 78c

tert-butyl(cis-3-morpholinocyclobutyl)carbamatetert-butyl(cis-3-morpholinocyclobutyl)carbamate

将78b(1.0g，3.0mmol)溶于10mL DMF中，加入吗啉(522.7mg，6.0mmol)、碘化钠(150.0mg，3.0mmol)和碳酸钾(828.0mg，6.0mmol)，90℃搅拌反应2h。待反应结束，浓缩，乙酸乙酯萃取，无水硫酸钠干燥，真空除去溶剂。硅胶柱层析纯化(乙酸乙酯:石油醚＝1:1)，得到目标产物(顺式-3-吗啉代环丁基)氨基甲酸叔丁酯78c(无色油状，550mg，72.3％)。直接用于下一步。78b (1.0 g, 3.0 mmol) was dissolved in 10 mL of DMF, morpholine (522.7 mg, 6.0 mmol), sodium iodide (150.0 mg, 3.0 mmol) and potassium carbonate (828.0 mg, 6.0 mmol) were added, and stirred at 90 °C The reaction was carried out for 2h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain the target product (cis-3-morpholinocyclobutyl)carbamate tert-butyl ester 78c (colorless oil, 550 mg, 72.3%) . used directly in the next step.

LC-MS m/z(ESI)＝257.2[M+1]。LC-MS m/z (ESI) = 257.2 [M+1].

第三步：third step:

(顺式-3-吗啉代环丁基)氨基78d(cis-3-morpholinocyclobutyl)amino 78d

cis-3-morpholinocyclobutan-1-aminecis-3-morpholinocyclobutan-1-amine

将78c(256.0mg，1.0mmol)溶于二氯甲烷10mL中，加入三氟乙酸(114.0mg，1.0mmol)，室温搅拌过夜。待反应结束，旋干。得到(顺式-3-吗啉代环丁基)氨基78d粗产品(无色油状，200mg)。直接用于下一步。78c (256.0 mg, 1.0 mmol) was dissolved in 10 mL of dichloromethane, trifluoroacetic acid (114.0 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction is over, spin dry. The crude product of (cis-3-morpholinocyclobutyl)amino 78d was obtained (colorless oil, 200 mg). used directly in the next step.

LC-MS m/z(ESI)＝157.2[M+1]。LC-MS m/z (ESI) = 157.2 [M+1].

第四步：the fourth step:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(反式-3-吗啉代环丁基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物78(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl) )-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 78

(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(trans-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1-A(100.0mg，0.3mmol)溶解于DMF 2mL中，随后加入HATU(109.5mg，0.3mmol)和DIPEA(77.4mg，0.6mmol)，室温搅拌10min，加入化合物 78d(67.0mg，0.4mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，MPLC纯化，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(顺式-3-吗啉代环丁基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物78(白色固体，102mg，70.3％)。Compound 1-A (100.0 mg, 0.3 mmol) was dissolved in DMF 2 mL, followed by adding HATU (109.5 mg, 0.3 mmol) and DIPEA (77.4 mg, 0.6 mmol), stirring at room temperature for 10 min, adding compound 78d (67.0 mg, 0.4 mmol), and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1R,5S) or (1S,5R)-3-( 8-Cyanoquinolin-5-yl)-N-(cis-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-Carboxamide Compound 78 (white solid, 102 mg, 70.3%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.63(dd,1H),8.34(d,1H),8.16(d,1H),7.60(dd,1H),7.22(d,1H),4.02(d,2H),3.95-3.89(m,2H),3.79(d,1H),3.54(t,4H),2.46-2.36(m,1H),2.35-2.28(m,2H),2.22(s,4H),2.00(d,1H),1.74(dd,2H),1.62(d,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.00(dd,1H), 8.63(dd,1H), 8.34(d,1H), 8.16(d,1H), 7.60(dd,1H), 7.22( d, 1H), 4.02(d, 2H), 3.95-3.89(m, 2H), 3.79(d, 1H), 3.54(t, 4H), 2.46-2.36(m, 1H), 2.35-2.28(m, 2H), 2.22(s, 4H), 2.00(d, 1H), 1.74(dd, 2H), 1.62(d, 1H).

19F NMR(376MHz,DMSO-d6)δ-63.57. 19 F NMR (376MHz, DMSO-d6) δ-63.57.

LC-MS m/z(ESI)＝486.2[M+1]。LC-MS m/z (ESI) = 486.2 [M+1].

实施例79Example 79

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(顺式-3-吗啉环丁基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物79(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(cis-3-morpholinocyclobutyl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 79

(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(cis-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(cis-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

Figure PCTCN2022081400-appb-000143
Figure PCTCN2022081400-appb-000143

将化合物1-B(100.0mg，0.3mmol)溶解于DMF 2mL中，随后加入HATU(109.5mg，0.3mmol)和DIPEA(77.4mg，0.6mmol)，室温搅拌10min，加入化合物 78d(67.0mg，0.4mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，MPLC纯化，得到目标产物(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(顺式-3-吗啉环丁基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物79(白色固体，108mg，74.0％)。Compound 1-B (100.0 mg, 0.3 mmol) was dissolved in 2 mL of DMF, followed by adding HATU (109.5 mg, 0.3 mmol) and DIPEA (77.4 mg, 0.6 mmol), stirring at room temperature for 10 min, adding compound 78d (67.0 mg, 0.4 mmol), and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1S,5R) or (1R,5S)-3-( 8-Cyanoquinolin-5-yl)-N-(cis-3-morpholinocyclobutyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Formamide Compound 79 (white solid, 108 mg, 74.0%).

1H NMR(400MHz,DMSO-d6)δ9.00(dd,1H),8.63(dd,1H),8.35(d,1H),8.17(d,1H),7.60(dd,1H),7.22(d,1H),4.00(d,2H),3.96-3.89(m,2H),3.79(d,1H),3.54(t,4H),2.44-2.36(m,1H),2.35-2.28(m,2H),2.22(s,4H),2.00(d,1H),1.79-1.73(m,2H),1.62(d,1H)。 1 H NMR (400MHz, DMSO-d6)δ9.00(dd,1H), 8.63(dd,1H), 8.35(d,1H), 8.17(d,1H), 7.60(dd,1H), 7.22(d ,1H),4.00(d,2H),3.96-3.89(m,2H),3.79(d,1H),3.54(t,4H),2.44-2.36(m,1H),2.35-2.28(m,2H) ), 2.22(s, 4H), 2.00(d, 1H), 1.79-1.73(m, 2H), 1.62(d, 1H).

19F NMR(376MHz,DMSO-d6)δ-63.63. 19 F NMR (376MHz, DMSO-d6) δ-63.63.

LC-MS m/z(ESI)＝486.2[M+1]。LC-MS m/z (ESI) = 486.2 [M+1].

实施例80Example 80

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(顺式-4-吗啉代环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物80(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 80

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

Figure PCTCN2022081400-appb-000144
Figure PCTCN2022081400-appb-000144

Figure PCTCN2022081400-appb-000145
Figure PCTCN2022081400-appb-000145

第一步：first step:

反式-4-((叔丁氧羰基)氨基)环己基4-甲基苯磺酸盐80btrans-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate 80b

trans-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonatetrans-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate

将化合物80a(4.3g，20mmol)溶于20mL DCM中，随后加入DMAP(4.9g，40mmol)、三乙胺(4.0g，40mmol)、对甲苯磺酰氯(3.8g，20mmol)，45℃回流搅拌2h。TLC反应完毕，将反应液加入50mL水中水洗，饱和食盐水50mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(乙酸乙酯:石油醚＝10:1)，得到目标产物反式-4-((叔丁氧羰基)氨基)环己基4-甲基苯磺酸盐80b(白色固体，5.4g，73.0％)。Compound 80a (4.3 g, 20 mmol) was dissolved in 20 mL of DCM, followed by adding DMAP (4.9 g, 40 mmol), triethylamine (4.0 g, 40 mmol), p-toluenesulfonyl chloride (3.8 g, 20 mmol), and stirring at 45°C under reflux 2h. After the TLC reaction was completed, the reaction solution was washed with 50 mL of water, washed with 50 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=10:1) to obtain the target product trans-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate 80b (white solid, 5.4 g, 73.0%).

LC-MS m/z(ESI)＝370.1[M+1]。LC-MS m/z (ESI) = 370.1 [M+1].

第二步：Step 2:

顺式-4-吗啉代环己基)氨基甲酸叔丁酯80ccis-4-Morpholinocyclohexyl) tert-butyl carbamate 80c

tert-butyl(cis-4-morpholinocyclohexyl)carbamatetert-butyl(cis-4-morpholinocyclohexyl)carbamate

将80b(1.1g，3.0mmol)溶于10mL DMF中，加入吗啉(522.7mg，6.0mmol)、碘化钠(150.0mg，3.0mmol)和碳酸钾(828.0mg，6.0mmol)，90℃搅拌反应2h。待反应结束，浓缩，乙酸乙酯萃取，无水硫酸钠干燥，真空除去溶剂。硅胶柱层析纯化(乙酸乙酯:石油醚＝1:1)，得到目标产物((cis-4-吗啉代环丁基)氨基甲酸叔丁酯80c(无色油状，283mg，33.2％)。直接用于下一步。Dissolve 80b (1.1 g, 3.0 mmol) in 10 mL of DMF, add morpholine (522.7 mg, 6.0 mmol), sodium iodide (150.0 mg, 3.0 mmol) and potassium carbonate (828.0 mg, 6.0 mmol), stir at 90 °C The reaction was carried out for 2h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain the target product ((cis-4-morpholinocyclobutyl)carbamate tert-butyl ester 80c (colorless oil, 283 mg, 33.2%) .Used directly in the next step.

LC-MS m/z(ESI)＝285.3[M+1]。LC-MS m/z (ESI) = 285.3 [M+1].

第三步：third step:

(顺式-4-吗啉代环丁基)氨基80d(cis-4-morpholinocyclobutyl)amino 80d

cis-4-morpholinocyclohexan-1-aminecis-4-morpholinocyclohexan-1-amine

将80c(283.0mg，1.0mmol)溶于二氯甲烷10mL中，加入三氟乙酸(114.0mg，1.0mmol)，室温搅拌过夜。待反应结束，旋干。得(顺式-4-吗啉代环丁基)氨基80d粗产品(无色油状，220mg)。直接用于下一步。80c (283.0 mg, 1.0 mmol) was dissolved in 10 mL of dichloromethane, trifluoroacetic acid (114.0 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction is over, spin dry. The crude product of (cis-4-morpholinocyclobutyl)amino 80d was obtained (colorless oil, 220 mg). used directly in the next step.

LC-MS m/z(ESI)＝185.2[M+1]。LC-MS m/z (ESI) = 185.2 [M+1].

第四步：the fourth step:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(顺式-4-吗啉代环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物80(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 80

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

将化合物1-A(100.0mg，0.3mmol)溶解于DMF 2mL中，随后加入HATU(109.5 mg，0.3mmol)和DIPEA(77.4mg，0.6mmol)，室温搅拌10min，加入化合物80d(67.0mg，0.4mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，MPLC纯化，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(cis-4-吗啉代环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物80(白色固体，98mg，63.7％)。Compound 1-A (100.0 mg, 0.3 mmol) was dissolved in DMF 2 mL, followed by adding HATU (109.5 mg, 0.3 mmol) and DIPEA (77.4 mg, 0.6 mmol), stirring at room temperature for 10 min, adding compound 80d (67.0 mg, 0.4 mmol), and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1R,5S) or (1S,5R)-3-( 8-Cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Formamide compound 80 (white solid, 98 mg, 63.7%).

1H NMR(400MHz,DMSO-d6)δ9.00(dd,1H),8.64(dd,1H),8.16(d,1H),8.00(d,1H),7.60(dd,1H),7.22(d,1H),4.03(dd,1H),3.98-3.90(m,2H),3.89-3.72(m,2H),3.59-3.52(m,4H),2.45-2.35(m,4H),2.09-1.92(m,2H),1.77(d,3H),1.60(t,2H),1.43(dd,3H),1.23(s,1H)。 1 H NMR (400MHz, DMSO-d6)δ9.00(dd,1H), 8.64(dd,1H), 8.16(d,1H), 8.00(d,1H), 7.60(dd,1H), 7.22(d ,1H),4.03(dd,1H),3.98-3.90(m,2H),3.89-3.72(m,2H),3.59-3.52(m,4H),2.45-2.35(m,4H),2.09-1.92 (m, 2H), 1.77 (d, 3H), 1.60 (t, 2H), 1.43 (dd, 3H), 1.23 (s, 1H).

19F NMR(376MHz,DMSO-d6)δ-63.61. 19 F NMR (376MHz, DMSO-d6) δ-63.61.

LC-MS m/z(ESI)＝514.3[M+1]。LC-MS m/z (ESI) = 514.3 [M+1].

实施例81Example 81

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(顺式-4-吗啉代环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物81(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl)-5-(trifluoromethyl) -3-Azabicyclo[3.1.0]hexane-1-carboxamide Compound 81

(1S,5R)或(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(cis-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

Figure PCTCN2022081400-appb-000146
Figure PCTCN2022081400-appb-000146

将化合物1-B(100.0mg，0.3mmol)溶解于DMF 2mL中，随后加入HATU(109.5mg，0.3mmol)和DIPEA(77.4mg，0.6mmol)，室温搅拌10min，加入化合物80d(67.0mg，0.4mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，MPLC纯化，得到目标产物(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(反式-4-吗啉代环己基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物81(白色固体，100mg，65.4％)。Compound 1-B (100.0 mg, 0.3 mmol) was dissolved in 2 mL of DMF, followed by adding HATU (109.5 mg, 0.3 mmol) and DIPEA (77.4 mg, 0.6 mmol), stirring at room temperature for 10 min, adding compound 80d (67.0 mg, 0.4 mmol), and stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate and spin-dried, and purified by MPLC to obtain the target product (1S,5R) or (1R,5S)-3-( 8-Cyanoquinolin-5-yl)-N-(trans-4-morpholinocyclohexyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 - Formamide Compound 81 (white solid, 100 mg, 65.4%).

1H NMR(400MHz,DMSO-d6)δ9.00(dd,1H),8.64(dd,1H),8.16(d,1H),8.00(d,1H),7.60(dd,1H),7.22(d,1H),4.03(dd,1H),3.96-3.91(m,2H),3.88-3.73(m,2H),3.55(d,4H),2.41(d,4H),2.04(s,1H),1.97(d,1H),1.77(d,3H),1.60(t,2H),1.43(dd,3H),1.23(s,1H)。 1 H NMR (400MHz, DMSO-d6)δ9.00(dd,1H), 8.64(dd,1H), 8.16(d,1H), 8.00(d,1H), 7.60(dd,1H), 7.22(d ,1H),4.03(dd,1H),3.96-3.91(m,2H),3.88-3.73(m,2H),3.55(d,4H),2.41(d,4H),2.04(s,1H), 1.97(d,1H), 1.77(d,3H), 1.60(t,2H), 1.43(dd,3H), 1.23(s,1H).

19F NMR(376MHz,DMSO-d6)δ-63.67. 19 F NMR (376MHz, DMSO-d6) δ-63.67.

LC-MS m/z(ESI)＝514.3[M+1]。LC-MS m/z (ESI) = 514.3 [M+1].

实施例82Example 82

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((R)-吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物82(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((R)-morpholin-2-yl)methyl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 82

(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(((R)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(((R)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-carboxamide

Figure PCTCN2022081400-appb-000147
Figure PCTCN2022081400-appb-000147

第一步：first step:

(R)-2-((甲苯氧基)甲基)吗啉-4-羧酸叔丁酯 82b(R)-2-((Tolyloxy)methyl)morpholine-4-carboxylate tert-butyl ester 82b

tert-butyl(R)-2-((tosyloxy)methyl)morpholine-4-carboxylatetert-butyl(R)-2-((tosyloxy)methyl)morpholine-4-carboxylate

将化合物82a(500mg，2.3mmol)溶于20mL DCM中，随后加入对甲苯磺酰氯(526.5.0mg，2.76mmol)、DMAP(562.0mg，4.6mmol)、三乙胺(465.5mg，4.6mmol)，45℃回流搅拌2h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷：丙酮＝20：1)，得到目标产物(R)-2-((甲苯氧基)甲基)吗啉-4-羧酸叔丁酯82b(白色固体，743mg，87.1％)，直接用于下一步。Compound 82a (500 mg, 2.3 mmol) was dissolved in 20 mL of DCM, followed by the addition of p-toluenesulfonyl chloride (526.5.0 mg, 2.76 mmol), DMAP (562.0 mg, 4.6 mmol), triethylamine (465.5 mg, 4.6 mmol), 45 ℃ of reflux stirring for 2h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:acetone=20:1) to obtain the target product ( R)-tert-butyl 2-((tolyloxy)methyl)morpholine-4-carboxylate 82b (white solid, 743 mg, 87.1%) was used directly in the next step.

LC-MS m/z(ESI)＝394.1[M+23]。LC-MS m/z (ESI) = 394.1 [M+23].

第二步：Step 2:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 82c(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 -Formamide 82c

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1-A(500mg，1.44mmol)溶解于DMF 5mL中，随后加入HATU(547.9mg，1.44mmol)和DIPEA(0.5mL，2.88mmol)，室温搅拌10min，加入氯化铵(92.4mg，1.73 mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，硅胶柱层析纯化(二氯甲烷：甲醇＝10：1)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 82c(淡黄色固体，423mg)。直接用于下一步。Compound 1-A (500 mg, 1.44 mmol) was dissolved in DMF 5 mL, followed by adding HATU (547.9 mg, 1.44 mmol) and DIPEA (0.5 mL, 2.88 mmol), stirring at room temperature for 10 min, adding ammonium chloride (92.4 mg, 1.73 mmol) mmol), and stirred at room temperature for 1 h. The TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the target product ( 1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1- Formamide 82c (pale yellow solid, 423 mg). used directly in the next step.

LC-MS m/z(ESI)＝347.1[M+1]。LC-MS m/z (ESI) = 347.1 [M+1].

第三步：third step:

叔丁基(S)-2-((1R,5S)或(1R,5S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)吗啉-4-羧酸酯 82dtert-Butyl (S)-2-((1R,5S) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide)methyl)morpholine-4-carboxylate 82d

tert-butyl(S)-2-(((1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)morpholine-4-carboxylatetert-butyl(S)-2-(((1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-carboxamido)methyl)morpholine-4-carboxylate

将化合物82b(430.0mg，1.16mmol)溶于5mL乙腈中，加入化合物82c(200.0mg，0.58mmol)和氢氧化钾(65.0mg，1.16mmol)，100℃搅拌反应2h。待反应结束，浓缩，乙酸乙酯萃取，无水硫酸钠干燥，真空除去溶剂。得到粗产物叔丁基(S)-2-((1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)吗啉-4-羧酸酯 82d。直接用于下一步。Compound 82b (430.0 mg, 1.16 mmol) was dissolved in 5 mL of acetonitrile, compound 82c (200.0 mg, 0.58 mmol) and potassium hydroxide (65.0 mg, 1.16 mmol) were added, and the reaction was stirred at 100 °C for 2 h. After the reaction was completed, it was concentrated, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. The crude product tert-butyl (S)-2-((1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3 was obtained - azabicyclo[3.1.0]hexane-1-carboxamide)methyl)morpholine-4-carboxylate 82d. used directly in the next step.

LC-MS m/z(ESI)＝546.3[M+1]。LC-MS m/z (ESI) = 546.3 [M+1].

第四步：the fourth step:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((R)-吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物82(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((R)-morpholin-2-yl)methyl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 82

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((R)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((R)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexane-1-carboxamide

将82d的粗产品(316.0mg，0.58mmol)溶于二氯甲烷10mL中，加入三氟乙酸(126.0mg，1.16mmol)，室温搅拌2h。待反应结束，旋干。MPLC分离(乙腈：水＝47：53)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((R)-吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物82(黄色固体，141mg，54.6％)。The crude product of 82d (316.0 mg, 0.58 mmol) was dissolved in 10 mL of dichloromethane, trifluoroacetic acid (126.0 mg, 1.16 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction is over, spin dry. MPLC separation (acetonitrile:water=47:53) gave the target product (1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((R)- olin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 82 (yellow solid, 141 mg, 54.6%).

1H NMR(400MHz,DMSO-d6)δ9.06-8.98(m,1H),8.92(s,1H),8.64(d,1H),8.51(t,1H),8.18(d,1H),7.61-7.59(m,1H),7.23(d,1H),4.03–3.91(m,4H),3.82(d,1H),3.72-3.59(m,1H),3.66-3.59(m,1H),3.26-3.19(m,4H),2.96(d,1H),2.73(d,1H),1.98(d,1H),1.68(d,1H)。 19F NMR(376MHz,DMSO-d6)δ64.54. 1 H NMR (400MHz, DMSO-d6)δ9.06-8.98(m,1H), 8.92(s,1H), 8.64(d,1H), 8.51(t,1H), 8.18(d,1H), 7.61 -7.59(m, 1H), 7.23(d, 1H), 4.03-3.91(m, 4H), 3.82(d, 1H), 3.72-3.59(m, 1H), 3.66-3.59(m, 1H), 3.26 -3.19(m, 4H), 2.96(d, 1H), 2.73(d, 1H), 1.98(d, 1H), 1.68(d, 1H). 19 F NMR (376MHz, DMSO-d6) δ 64.54.

LC-MS m/z(ESI)＝446.1[M+1]。LC-MS m/z (ESI) = 446.1 [M+1].

实施例83Example 83

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-((R)-吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物83(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-((R)-morpholin-2-yl)methyl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 83

(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(((R)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(((R)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000148
Figure PCTCN2022081400-appb-000148

操作同化合物82，得到黄色固体化合物83。The same operation as compound 82 gave compound 83 as a yellow solid.

1H NMR(400MHz,DMSO-d6)δ9.06-8.98(m,1H),8.95(s,1H),8.65-8.59(m,1H),8.50(t,1H),8.18(d,1H),7.63-7.55(m,1H),7.23(d,1H),4.01–3.90(m,4H),3.81(d,1H), 3.73-3.69(m,1H),3.63-3.58(m,1H),3.27–3.08(m,4H),2.95(d,1H),2.74(t,1H),1.98(d,1H),1.68(d,1H)。 19F NMR(376MHz,DMSO-d6)δ64.59. 1 H NMR(400MHz,DMSO-d6)δ9.06-8.98(m,1H),8.95(s,1H),8.65-8.59(m,1H),8.50(t,1H),8.18(d,1H) ,7.63-7.55(m,1H),7.23(d,1H),4.01-3.90(m,4H),3.81(d,1H), 3.73-3.69(m,1H),3.63-3.58(m,1H) , 3.27–3.08 (m, 4H), 2.95 (d, 1H), 2.74 (t, 1H), 1.98 (d, 1H), 1.68 (d, 1H). 19 F NMR (376MHz, DMSO-d6) δ64.59.

LC-MS m/z(ESI)＝446.1[M+1]。LC-MS m/z (ESI) = 446.1 [M+1].

实施例84Example 84

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物84(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-morpholin-2-yl)methyl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 84

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000149
Figure PCTCN2022081400-appb-000149

操作同化合物82，得到黄色固体化合物84。The same operation as compound 82 gave compound 84 as a yellow solid.

1H NMR(400MHz,DMSO-d6)δ9.09-8.99(m,1H),8.96(s,1H),8.66-8.59(m,1H),8.50(t,1H),8.18(d,1H),7.66-7.56(m,1H),7.23(d,1H),4.01–3.93(m,4H),3.81(d,1H),3.77-3.66(m,1H),3.66–3.55(m,1H),3.31-3.09(m,4H),2.96(s,1H),2.84-2.67(m,1H),1.98(d,1H),1.68(d,1H)。 19F NMR(376MHz,DMSO-d6)δ64.57. 1 H NMR(400MHz,DMSO-d6)δ9.09-8.99(m,1H),8.96(s,1H),8.66-8.59(m,1H),8.50(t,1H),8.18(d,1H) ,7.66-7.56(m,1H),7.23(d,1H),4.01-3.93(m,4H),3.81(d,1H),3.77-3.66(m,1H),3.66-3.55(m,1H) , 3.31-3.09(m, 4H), 2.96(s, 1H), 2.84-2.67(m, 1H), 1.98(d, 1H), 1.68(d, 1H). 19 F NMR (376MHz, DMSO-d6) δ 64.57.

LC-MS m/z(ESI)＝446.1[M+1]。LC-MS m/z (ESI) = 446.1 [M+1].

实施例85Example 85

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-((S)-吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物85(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-((S)-morpholin-2-yl)methyl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 85

(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(((S)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(((S)-morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000150
Figure PCTCN2022081400-appb-000150

操作同化合物82，得到黄色固体化合物85。The same operation as compound 82 gave compound 85 as a yellow solid.

1H NMR(400MHz,DMSO-d6)δ9.04-8.98(m,1H),8.94(s,1H),8.66-8.59(m,1H),8.51(t,1H),8.18(d,1H),7.64-7.57(m,1H),7.23(d,1H),4.07–3.92(m,4H),3.82(d,1H),3.74–3.67(m,1H),3.64–3.57(m,1H),3.31–3.13(m,4H),2.96(d,1H),2.80-2.64(m,1H),1.98(d,1H),1.68(d,1H)。 19F NMR(376MHz,DMSO-d6)δ64.55. 1 H NMR(400MHz,DMSO-d6)δ9.04-8.98(m,1H),8.94(s,1H),8.66-8.59(m,1H),8.51(t,1H),8.18(d,1H) ,7.64-7.57(m,1H),7.23(d,1H),4.07-3.92(m,4H),3.82(d,1H),3.74-3.67(m,1H),3.64-3.57(m,1H) , 3.31–3.13 (m, 4H), 2.96 (d, 1H), 2.80–2.64 (m, 1H), 1.98 (d, 1H), 1.68 (d, 1H). 19 F NMR (376MHz, DMSO-d6) δ 64.55.

LC-MS m/z(ESI)＝446.1[M+1]。LC-MS m/z (ESI) = 446.1 [M+1].

实施例86Example 86

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-N-((S)-4,6,6-三甲基吗啉-2-基)甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物86(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-((S)-4,6,6-tris Methylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 86

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-(((S)-4,6,6-trimethylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-(((S)-4,6,6-trimethylmorpholin-2-yl) methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000151
Figure PCTCN2022081400-appb-000151

第一步：first step:

叔丁基(S)-6-((1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)-2,2-二甲基吗啉-4-羧酸酯 86btert-Butyl (S)-6-((1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide)methyl)-2,2-dimethylmorpholine-4-carboxylate 86b

tert-butyl(S)-6-(((1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)methyl)-2,2-dimethylmorpholine-4-carboxylatetert-butyl(S)-6-(((1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane -1-carboxamido)methyl)-2,2-dimethylmorpholine-4-carboxylate

将化合物1-A(347.0mg，1.0mmol)溶解于DMF 5mL中，随后加入HATU(380.0mg，1.0mmol)和DIPEA(258.0mg，2.0mmol)，室温搅拌10min，加入化合物86a(334.4mg，1.0mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干，得到粗产品叔丁基(S)-6-((1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)-2,2-二甲基吗啉-4-羧酸酯 86b(黄色油状)。直接用于下一步。Compound 1-A (347.0 mg, 1.0 mmol) was dissolved in DMF 5 mL, followed by adding HATU (380.0 mg, 1.0 mmol) and DIPEA (258.0 mg, 2.0 mmol), stirring at room temperature for 10 min, adding compound 86a (334.4 mg, 1.0 mmol) mmol), and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was added to 15 mL of water and washed with 15 mL of saturated brine. The organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a crude product of tert-butyl (S)-6-((1R,5S) or (1S). ,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide)methyl)- 2,2-Dimethylmorpholine-4-carboxylate 86b (yellow oil). used directly in the next step.

LC-MS m/z(ESI)＝574.3[M+1]。LC-MS m/z (ESI) = 574.3 [M+1].

第二步：Step 2:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((R)-6,6-二甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 86c(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((R)-6,6-dimethylmorpholin-2-yl)methyl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 86c

(1R,5S)或(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((R)-6,6-dimethylmorpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((R)-6,6-dimethylmorpholin-2-yl)methyl)-5-(trifluoromethyl) -3-azabicyclo[3.1.0]hexane-1-carboxamide

将86b的粗产品溶于二氯甲烷10mL中，加入三氟乙酸(180.0mg，2.0mmol)，室温搅拌2h。待反应结束，旋干。MPLC分离(乙腈：水＝47：53)，得到目标产物(1R,5S)-3-(8-氰基喹啉-5-基)-N-((R)-6,6-二甲基吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰 86c(黄色油状，420mg，88.8％)。直接用于下一步。The crude product of 86b was dissolved in 10 mL of dichloromethane, trifluoroacetic acid (180.0 mg, 2.0 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction is over, spin dry. MPLC separation (acetonitrile: water = 47:53) to obtain the target product (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-((R)-6,6-dimethyl Morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxyl 86c (yellow oil, 420 mg, 88.8%). used directly in the next step.

LC-MS m/z(ESI)＝474.3[M+1]。LC-MS m/z (ESI) = 474.3 [M+1].

第三步：third step:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-N-((S)-4,6,6-三甲基吗啉-2-基)甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物86(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-((S)-4,6,6-tris Methylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 86

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-(((S)-4,6,6-trimethylmorpholin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-(((S)-4,6,6-trimethylmorpholin-2-yl) methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

50mL圆底烧瓶中，将化合物86c(420.0mg，0.89mmol)溶于5mL甲醇中，室温下加入多聚甲醛(159.9mg，1.77mmol)和氰基硼氢化钠(223.7mg，3.56mmol)，室温搅拌0.5h。TLC检测反应完毕后，将反应液加入30mL水中，DCM萃取三次，饱和食盐水30mL洗，有机相用无水硫酸钠干燥，旋干，MPLC纯化，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-N-((S)-4,6,6-三甲基吗啉-2-基)甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物86(黄色固体，272mg，55.9％)。In a 50 mL round-bottomed flask, compound 86c (420.0 mg, 0.89 mmol) was dissolved in 5 mL of methanol, and paraformaldehyde (159.9 mg, 1.77 mmol) and sodium cyanoborohydride (223.7 mg, 3.56 mmol) were added at room temperature. Stir for 0.5h. After TLC detection, the reaction solution was added to 30 mL of water, extracted three times with DCM, washed with 30 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by MPLC to obtain the target product (1R, 5S) or (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-N-((S)-4,6,6-trimethylmorpholin-2-yl) Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 86 (yellow solid, 272 mg, 55.9%).

1H NMR(400MHz,DMSO-d6)δ9.02-8.99(m,1H),8.66-8.60(m,1H),8.35(t,1H),8.17(d,1H),7.64-7.56(m,1H),7.23(d,1H),4.02(d,1H),3.96-3.90(m,2H),3.82(d,1H),3.72-3.65(m,1H),3.21-3.09(m,1H),3.03-2.98(m,1H),2.65(d,1H),2.49-2.42(m,1H),2.10(s,3H),1.94(d,1H),1.69-1.58(m,2H),1.43(t,1H),1.20(s,3H),1.08(s,3H)。 19F NMR(376MHz,DMSO-d6)δ64.42. 1 H NMR(400MHz,DMSO-d6)δ9.02-8.99(m,1H),8.66-8.60(m,1H),8.35(t,1H),8.17(d,1H),7.64-7.56(m, 1H), 7.23(d, 1H), 4.02(d, 1H), 3.96-3.90(m, 2H), 3.82(d, 1H), 3.72-3.65(m, 1H), 3.21-3.09(m, 1H) ,3.03-2.98(m,1H),2.65(d,1H),2.49-2.42(m,1H),2.10(s,3H),1.94(d,1H),1.69-1.58(m,2H),1.43 (t, 1H), 1.20 (s, 3H), 1.08 (s, 3H). 19 F NMR (376MHz, DMSO-d6) δ 64.42.

LC-MS m/z(ESI)＝488.3[M+1]。LC-MS m/z (ESI) = 488.3 [M+1].

实施例87Example 87

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(2-氟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物87(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2-fluoroethyl)piperidin-4-yl)-5-( Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 87

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2-fluoroethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2-fluoroethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo [3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000152
Figure PCTCN2022081400-appb-000152

将化合物1-A(50.0mg，0.14mmol)溶解于DMF 2mL中，随后加入HATU(54.8mg，0.14mmol)和DIPEA(74.5mg，0.57mmol)，室温搅拌10min，加入化合物87a(31.6mg，0.14mmol)，室温搅拌1h。TLC反应完毕，将反应液加入15mL水中水洗，饱和食盐水15mL洗，有机相用无水硫酸钠干燥旋干MPLC纯化，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(2-氟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物87(白色固体，22mg，33.1％)。Compound 1-A (50.0 mg, 0.14 mmol) was dissolved in DMF 2 mL, followed by adding HATU (54.8 mg, 0.14 mmol) and DIPEA (74.5 mg, 0.57 mmol), stirring at room temperature for 10 min, adding compound 87a (31.6 mg, 0.14 mmol) mmol), and stirred at room temperature for 1 h. After the TLC reaction was completed, the reaction solution was washed with 15 mL of water, washed with 15 mL of saturated brine, and the organic phase was dried with anhydrous sodium sulfate and spin-dried for MPLC purification to obtain the target product (1R,5S) or (1S,5R)-3-(8 -Cyanoquinolin-5-yl)-N-(1-(2-fluoroethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxamide Compound 87 (white solid, 22 mg, 33.1%).

1H NMR(400MHz,DMSO-d6)δ9.04-8.96(m,1H),8.68-8.60(m,1H),8.17(d,1H),8.05(d,1H),7.64-7.55(m,1H),7.22(d,1H),4.56(t,1H),4.44(t,1H),4.01(d,1H),3.97-3.91(m,2H),3.82(d,1H),3.65-3.53(m,1H),2.94-2.81(m,2H),2.62-2.56(m,2H),2.10-1.91(m,3H),1.73-1.56(m,3H),1.51-1.34(m,2H),1.00(s,1H)。 19F NMR(376MHz,DMSO-d6)δ64.49. 1 H NMR(400MHz,DMSO-d6)δ9.04-8.96(m,1H),8.68-8.60(m,1H),8.17(d,1H),8.05(d,1H),7.64-7.55(m, 1H), 7.22(d, 1H), 4.56(t, 1H), 4.44(t, 1H), 4.01(d, 1H), 3.97-3.91(m, 2H), 3.82(d, 1H), 3.65-3.53 (m,1H),2.94-2.81(m,2H),2.62-2.56(m,2H),2.10-1.91(m,3H),1.73-1.56(m,3H),1.51-1.34(m,2H) ,1.00(s,1H). 19 F NMR (376MHz, DMSO-d6) δ64.49.

LC-MS m/z(ESI)＝476.3[M+1]。LC-MS m/z (ESI) = 476.3 [M+1].

实施例88Example 88

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4-(甲基-d3)吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物88(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4-(methyl-d3)morpholin-2-yl)methan base)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 88

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(methyl-d3)morpholin-2- yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(methyl-d3)morpholin-2-yl)methyl)-5- (trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000153
Figure PCTCN2022081400-appb-000153

第一步：first step:

(R)-(4-(甲基-d3)吗啉-2-基)甲基4-甲基苯磺酸 88b(R)-(4-(Methyl-d3)morpholin-2-yl)methyl 4-methylbenzenesulfonic acid 88b

(R)-(4-(methyl-d3)morpholin-2-yl)methyl 4-methylbenzenesulfonate(R)-(4-(methyl-d3)morpholin-2-yl)methyl 4-methylbenzenesulfonate

将化合物88a(1g，3.7mmol)溶解于乙腈20mL中，随后加入碳酸钠(1.5g，14.8mmol)，冰浴降温，低温搅拌5min，缓慢滴加氘带碘甲烷(642mg，4.4mmol)，低温搅拌1h。TLC检测反应完毕，将硅胶加入反应液中，减压浓缩，硅胶柱层析纯化(石油醚：乙酸乙酯＝100：1)，得到中间体(R)-(4-(甲基-d3)吗啉-2-基)甲基4-甲基苯磺酸 88b(白色固体，200mg)。Compound 88a (1 g, 3.7 mmol) was dissolved in 20 mL of acetonitrile, then sodium carbonate (1.5 g, 14.8 mmol) was added, cooled in an ice bath, stirred at low temperature for 5 min, slowly added dropwise with deuterium band iodomethane (642 mg, 4.4 mmol), low temperature Stir for 1 h. TLC detected the completion of the reaction, silica gel was added to the reaction solution, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1) to obtain intermediate (R)-(4-(methyl-d3) Morpholin-2-yl)methyl 4-methylbenzenesulfonic acid 88b (white solid, 200 mg).

1H NMR(400MHz,DMSO-d 6)δ7.78(d,2H),7.48(d,2H),4.08–3.91(m,2H),3.73-3.68(m,1H),3.62-3.56(m,1H),3.44-3.33(m,1H),2.56(d,2H),2.42(s,3H),1.96-1.89(m,1H),1.73(t,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 7.78(d, 2H), 7.48(d, 2H), 4.08-3.91(m, 2H), 3.73-3.68(m, 1H), 3.62-3.56(m , 1H), 3.44-3.33(m, 1H), 2.56(d, 2H), 2.42(s, 3H), 1.96-1.89(m, 1H), 1.73(t, 1H).

LC-MS m/z(ESI)＝289.2[M+1]。LC-MS m/z (ESI) = 289.2 [M+1].

第二步：Step 2:

双叔丁基(S)-(4-(甲基-D 3)吗啉-2-基)甲基)氨基甲酸酯 88c Bis-tert-butyl (S)-(4-(methyl- D3 )morpholin-2-yl)methyl)carbamate 88c

Di tert-butyl(S)-(4-(methyl-D 3)morpholine-2-yl)methyl)carbamate Di tert-butyl(S)-(4-(methyl-D 3 )morpholine-2-yl)methyl)carbamate

将中间体(R)-(4-(甲基-d3)吗啉-2-基)甲基4-甲基苯磺酸88b(200mg,0.69mmol)溶于N,N-二甲基甲酰胺(20ml)中，随后加入碳酸铯(674mg，2.07mmol)，碘化钠(20mg，0.13mmol)，双(叔丁氧羰基)胺(181mg，0.83mmol)，缓慢升温至90℃，搅拌2h。TLC反应完毕，反应液直接浓缩，硅胶柱层析纯化(乙酸乙酯)，得到中间体双叔丁基(S)-(4-(甲基-d3)吗啉-2-基)甲基)氨基甲酸酯88c(白色固体，157mg)。Intermediate (R)-(4-(methyl-d3)morpholin-2-yl)methyl 4-methylbenzenesulfonic acid 88b (200 mg, 0.69 mmol) was dissolved in N,N-dimethylformamide (20ml), followed by adding cesium carbonate (674mg, 2.07mmol), sodium iodide (20mg, 0.13mmol), bis(tert-butoxycarbonyl)amine (181mg, 0.83mmol), slowly warming to 90°C, stirring for 2h. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain the intermediate bis-tert-butyl (S)-(4-(methyl-d3)morpholin-2-yl)methyl) Carbamate 88c (white solid, 157 mg).

LC-MS m/z(ESI)＝334.2[M+1]。LC-MS m/z (ESI) = 334.2 [M+1].

第三步：third step:

(S)-(4-(甲基-D 3)吗啉-2-基)甲酰胺盐酸盐 88d (S)-(4-(Methyl- D3 )morpholin-2-yl)carboxamide hydrochloride 88d

(S)-(4-(methyl-d3)morpholine-2-yl)formamide hydrochloride(S)-(4-(methyl-d3)morpholine-2-yl)formamide hydrochloride

将双叔丁基(S)-(4-(甲基-D 3)吗啉-2-基)甲基)氨基甲酸酯88c(218mg,0.65mmol)加入5ml二氧六环氯化氢溶液中，缓慢升温至55℃，搅拌2h。TLC反应完毕，反应液直接浓缩，得到中间体(S)-(4-(甲基-d3)吗啉-2-基)甲酰胺盐酸盐88d(白色固体，157mg)。 Di-tert-butyl (S)-(4-(methyl- D3 )morpholin-2-yl)methyl)carbamate 88c (218 mg, 0.65 mmol) was added to 5 ml dioxane hydrogen chloride solution, The temperature was slowly raised to 55 °C and stirred for 2 h. After completion of the TLC reaction, the reaction solution was directly concentrated to obtain the intermediate (S)-(4-(methyl-d3)morpholin-2-yl)carboxamide hydrochloride 88d (white solid, 157 mg).

LC-MS m/z(ESI)＝134.2[M+1]。LC-MS m/z (ESI) = 134.2 [M+1].

第四步：the fourth step:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4-(甲基-d3)吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物88(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4-(methyl-d3)morpholin-2-yl)methan base)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 88

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(methyl-d3)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(methyl-d3)morpholin-2-yl)methyl)-5- (trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1-A(200mg,0.59mmol)溶于6mL二氧六环中，随后冰浴加入HATU(87mg,0.65mmol)，DIPEA(304mg,0.78mmol)低温搅拌5min，然后加入(S)-(4-(甲基-d3)吗啉-2-基甲酰胺盐酸盐 88d，搅拌0.5h，TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4-(甲基-d3)吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物88(淡黄色固体，173mg，72.6％)。Compound 1-A (200 mg, 0.59 mmol) was dissolved in 6 mL of dioxane, then HATU (87 mg, 0.65 mmol) was added in an ice bath, DIPEA (304 mg, 0.78 mmol) was stirred at low temperature for 5 min, and then (S)-( 4-(methyl-d3)morpholin-2-ylcarboxamide hydrochloride 88d, stirred for 0.5h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse phase C18 column chromatography (alkali method) to obtain the target product ( 1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4-(methyl-d3)morpholin-2-yl)methyl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 88 (pale yellow solid, 173 mg, 72.6%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.63(dd,1H),8.48(s,1H),8.18(d,1H),7.61(dd,1H),7.24(d,1H),4.05–3.87(m,4H),3.82(d,1H),3.57(d,2H),3.24-3.15(m,2H),3.15–3.04(m,3H),1.98(d,1H),1.72–1.64(m,1H),1.23(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.63(dd,1H), 8.48(s,1H), 8.18(d,1H), 7.61(dd,1H), 7.24( d, 1H), 4.05-3.87(m, 4H), 3.82(d, 1H), 3.57(d, 2H), 3.24-3.15(m, 2H), 3.15-3.04(m, 3H), 1.98(d, 1H), 1.72–1.64 (m, 1H), 1.23 (s, 1H).

LC-MS m/z(ESI)＝463.2[M+1]。LC-MS m/z (ESI) = 463.2 [M+1].

实施例89Example 89

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4-(甲基-d3)吗啉-2-基)甲基-d2)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物89(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4-(methyl-d3)morpholin-2-yl)methan Base-d2)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 89

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(methyl-d3)morpholin-2-yl)methyl-d2)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(methyl-d3)morpholin-2-yl)methyl-d2)- 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000154
Figure PCTCN2022081400-appb-000154

第一步：first step:

4-(叔丁基)2-甲基(R)-吗啉-2,4-二甲酸酯 89b4-(tert-Butyl) 2-methyl(R)-morpholine-2,4-dicarboxylate 89b

4-(tert-butyl)2-methyl(R)-morpholine-2,4-dicarboxylate4-(tert-butyl)2-methyl(R)-morpholine-2,4-dicarboxylate

将化合物89a(1g，5.5mmol)溶解于二氯甲烷20mL中，随后加入三乙胺(2.2g，22mmol)，冰浴降温，然后加入二碳酸二叔丁酯(1.4g，6.6mmol)，常温搅拌3h。TLC检测反应完毕，将硅胶加入反应液中，减压浓缩，硅胶柱层析纯化(二氯甲烷：甲醇＝140：1)，得到中间体4-(叔丁基)2-甲基(R)-吗啉-2,4-二甲酸酯89b(白色固体，1.2g)。Compound 89a (1 g, 5.5 mmol) was dissolved in 20 mL of dichloromethane, then triethylamine (2.2 g, 22 mmol) was added, cooled in an ice bath, and then di-tert-butyl dicarbonate (1.4 g, 6.6 mmol) was added at room temperature. Stir for 3h. TLC detected the completion of the reaction, silica gel was added to the reaction solution, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol=140:1) to obtain the intermediate 4-(tert-butyl)2-methyl (R) - Morpholine-2,4-dicarboxylate 89b (white solid, 1.2 g).

LC-MS m/z(ESI)＝246.20[M+1]。LC-MS m/z (ESI) = 246.20 [M+1].

第二步：Step 2:

(R)-(4-(甲基-D 3)吗啉-2-基)甲烷-D 2-醇化合物 89c (R)-(4-(Methyl- D3 )morpholin- 2 -yl)methane-D2-ol compound 89c

(R)-(4-(methyl-D 3)morpholin-2-yl)methan-D 2-ol (R)-(4-(methyl-D 3 )morpholin-2-yl)methan-D 2 -ol

将中间体4-(叔丁基)2-甲基(R)-吗啉-2,4-二甲酸酯89b(1.2g,4.9mmol)溶于10ml四氢呋喃中，随后加入氘带铝锂氢(823mg,19.6mmol)，缓慢升温至60℃，搅拌1h。TLC反应完毕，随后加入500ml水，1ml 10％氢氧化钠水溶液，1.5ml水搅拌，有固体析出，用硅藻土过滤，滤液浓缩至干得到中间体(R)-(4-(甲基-d3)吗啉-2-基)甲烷-D 2-醇89c(黄色固体，642mg)。 The intermediate 4-(tert-butyl)2-methyl(R)-morpholine-2,4-dicarboxylate 89b (1.2 g, 4.9 mmol) was dissolved in 10 ml of tetrahydrofuran, followed by the addition of deuterium with aluminum lithium hydride (823 mg, 19.6 mmol), slowly warmed to 60° C. and stirred for 1 h. After the TLC reaction was completed, 500 ml of water, 1 ml of 10% aqueous sodium hydroxide solution, and 1.5 ml of water were added to stir, and a solid was precipitated, which was filtered through celite, and the filtrate was concentrated to dryness to obtain intermediate (R)-(4-(methyl- d3) Morpholin- 2 -yl)methane-D2-ol 89c (yellow solid, 642 mg).

1H NMR(400MHz,DMSO-D 6)δ4.61(s,1H),3.73(ddd,1H),3.45(td,1H),3.38(dd,1H),2.68(m,1H),2.55(m,1H),1.91(m,1H),1.66(dd,1H)。 1 H NMR (400MHz, DMSO-D 6 )δ4.61(s,1H), 3.73(ddd,1H), 3.45(td,1H), 3.38(dd,1H), 2.68(m,1H), 2.55( m, 1H), 1.91 (m, 1H), 1.66 (dd, 1H).

LC-MS m/z(ESI)＝137[M+1]。LC-MS m/z (ESI) = 137 [M+1].

第三步：third step:

(R)-(4-(甲基-D 3)吗啉-2-基)甲基-D 2 4-甲基苯磺酸盐 89d (R)-(4-(Methyl- D3 )morpholin- 2 -yl)methyl-D24-methylbenzenesulfonate 89d

(R)-(4-(methyl-d3)morpholin-2-yl)methyl-d2 4-methylbenzenesulfonate(R)-(4-(methyl-d3)morpholin-2-yl)methyl-d2 4-methylbenzenesulfonate

将89c加入6ml二氯甲烷中，然后加入三乙胺(949mg,9.4mmol)，对甲苯磺酰氯(1g,5.6mmol)，N,N-二甲基吡啶(57mg,0.47mmol)常温搅拌2h。TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物得到中间体(R)-(4-(甲基-D 3)吗啉-2-基)甲基-D 2 4-甲基苯磺酸盐 89d(白色固体，900mg)。 89c was added to 6 ml of dichloromethane, then triethylamine (949 mg, 9.4 mmol), p-toluenesulfonyl chloride (1 g, 5.6 mmol), and N,N-lutidine (57 mg, 0.47 mmol) were added and stirred at room temperature for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target product to obtain the intermediate (R)-(4-(methyl-D 3 )morpholin-2-yl)methyl -D 2 4-methylbenzenesulfonate 89d (white solid, 900 mg).

1H NMR(400MHz,DMSO-d 6)δ7.81–7.75(m,2H),7.48(d,2H),3.69(ddd,1H),3.58(dd,1H),3.41(td,1H),2.58–2.51(m,1H),2.50(s,1H),2.42(s,3H),1.90(td,1H),1.69(dd,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ7.81-7.75(m,2H), 7.48(d,2H), 3.69(ddd,1H), 3.58(dd,1H), 3.41(td,1H), 2.58–2.51 (m, 1H), 2.50 (s, 1H), 2.42 (s, 3H), 1.90 (td, 1H), 1.69 (dd, 1H).

LC-MS m/z(ESI)＝291.2[M+1]。LC-MS m/z (ESI) = 291.2 [M+1].

第四步：the fourth step:

叔丁基(S)-(4-(甲基-D 3)吗啉-2-基)甲基-D 2)氨基甲酸酯 89e tert-Butyl (S)-(4-(methyl- D3 )morpholin- 2 -yl)methyl-D2)carbamate 89e

tert-butyl(S)-(4-(methyl-d3)morpholine-2-yl)methyl-d2)carbamatetert-butyl(S)-(4-(methyl-d3)morpholine-2-yl)methyl-d2)carbamate

将89d(900mg,3.1mmol)溶于6ml N,N-二甲基甲酰胺中，随后加入碳酸铯(3g，9.3mmol)，碘化钠(93mg,0.62mmol)，双(叔丁氧羰基)胺(808mg,3.7mmol)，缓慢升温至90℃，搅拌4h。TLC反应完毕，反应液直接浓缩，硅胶柱层析纯化(二氯甲烷：甲醇＝100:1～20:1)，得到中间体双叔丁基(S)-(4-(甲基-D 3)吗啉-2-基)甲基-D 2)氨基甲酸酯 89e(白色固体，370mg)。 89d (900 mg, 3.1 mmol) was dissolved in 6 ml of N,N-dimethylformamide, followed by the addition of cesium carbonate (3 g, 9.3 mmol), sodium iodide (93 mg, 0.62 mmol), bis(tert-butoxycarbonyl) Amine (808 mg, 3.7 mmol), slowly warmed to 90 °C and stirred for 4 h. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by silica gel column chromatography (dichloromethane:methanol=100:1～20:1) to obtain the intermediate bis-tert-butyl (S)-(4-(methyl-D 3 ). )morpholin- 2 -yl)methyl-D2)carbamate 89e (white solid, 370 mg).

1H NMR(400MHz,DMSO-d 6)δ6.83(s,1H),3.73(ddd,1H),3.48–3.34(m,2H),2.58(m,2H),1.91(td,1H),1.61(t,1H),1.37(s,9H)。 1 H NMR (400MHz, DMSO-d 6 )δ6.83(s,1H), 3.73(ddd,1H), 3.48-3.34(m,2H), 2.58(m,2H), 1.91(td,1H), 1.61(t, 1H), 1.37(s, 9H).

LC-MS m/z(ESI)＝236.2[M+1]。LC-MS m/z (ESI) = 236.2 [M+1].

第五步：the fifth step:

(S)-(4-(甲基-D 3)吗啉-2-基)甲烷-D 2-胺 89f (S)-(4-(Methyl- D3 )morpholin- 2 -yl)methane-D2-amine 89f

(S)-(4-(methyl-D 3)morpholin-2-yl)methan-d2-amine (S)-(4-(methyl-D 3 )morpholin-2-yl)methan-d2-amine

将双叔丁基(S)-(4-(甲基-D 3)吗啉-2-基)甲基-D 2)氨基甲酸酯89e(370mg,1.1mmol)加入6ml二氧六环氯化氢溶液中，缓慢升温至55℃，搅拌2h。TLC反应完毕，反应液直接浓缩，得到中间体(S)-(4-(甲基-D 3)吗啉-2-基)甲烷-D 2-胺89f(白色固体，粗品)。 Di-tert-butyl (S)-(4-(methyl- D3 )morpholin- 2 -yl)methyl-D2)carbamate 89e (370 mg, 1.1 mmol) was added to 6 ml dioxane hydrogen chloride In the solution, the temperature was slowly raised to 55 °C and stirred for 2 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate (S)-(4-(methyl-D 3 )morpholin-2-yl)methane-D 2 -amine 89f (white solid, crude product).

1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.24(s,3H),4.16(dd,1H),4.06(dd,1H),3.88(td,1H),3.43–3.34(m,2H),3.04(d,1H),2.92–2.80(m,1H)。 1 H NMR (400MHz, DMSO-d6) δ 11.86(s,1H), 8.24(s,3H), 4.16(dd,1H), 4.06(dd,1H), 3.88(td,1H), 3.43–3.34 (m, 2H), 3.04 (d, 1H), 2.92–2.80 (m, 1H).

LC-MS m/z(ESI)＝136.2[M+1]。LC-MS m/z (ESI) = 136.2 [M+1].

第六步：Step 6:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4-(甲基-d3)吗啉-2-基)甲基-d2)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物89(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4-(methyl-d3)morpholin-2-yl)methan Base-d2)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 89

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(methyl-d3)morpholin-2-yl)methyl-d2)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(methyl-d3)morpholin-2-yl)methyl-d2)- 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1-A(200mg,0.5mmol)溶于6mL二氧六环中，随后冰浴加入HATU(269mg,0.63mmol)，DIPEA(304mg,0.78mmol)低温搅拌5min，然后加入(S)-(4-(甲基-D 3)吗啉-2-基)甲烷-D 2-胺89f(85mg,0.63mmol)，搅拌0.5h，TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4-(甲基-d3)吗啉-2-基)甲基-d2)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物89(淡黄色固体，60mg，43.2％)。 Compound 1-A (200 mg, 0.5 mmol) was dissolved in 6 mL of dioxane, then HATU (269 mg, 0.63 mmol) was added in an ice bath, DIPEA (304 mg, 0.78 mmol) was stirred at low temperature for 5 min, and (S)-( 4-(Methyl-D 3 )morpholin-2-yl)methane-D 2 -amine 89f (85mg, 0.63mmol), stirred for 0.5h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse-phase C18 column chromatography (Alkaline method) to obtain the target product (1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4-(methyl-d3) Morpholin-2-yl)methyl-d2)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 89 (pale yellow solid, 60 mg, 43.2% ).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.63(dd,1H),8.35(s,1H),8.17(d,1H),7.60(dd,1H),7.23(d,1H),4.04–3.88(m,3H),3.81(d,1H),3.75(ddd,1H),3.44(ddd,2.4Hz,2H),2.63(dt,1H),2.60–2.52(m,1H),2.01–1.87(m,2H),1.70–1.59(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.00(dd,1H), 8.63(dd,1H), 8.35(s,1H), 8.17(d,1H), 7.60(dd,1H), 7.23( d, 1H), 4.04–3.88 (m, 3H), 3.81 (d, 1H), 3.75 (ddd, 1H), 3.44 (ddd, 2.4Hz, 2H), 2.63 (dt, 1H), 2.60–2.52 (m , 1H), 2.01–1.87 (m, 2H), 1.70–1.59 (m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.50 19 F NMR (376MHz, DMSO-d 6 ) δ-63.50

LC-MS m/z(ESI)＝465.3[M+1]。LC-MS m/z (ESI) = 465.3 [M+1].

实施例90Example 90

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(2,2,2-三氟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物90(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl )-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 90

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-5-(trifluoromethyl) -3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000155
Figure PCTCN2022081400-appb-000155

将(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸 化合物1-A(100mg,0.28mmol)溶于6mL二氧六环中，随后冰浴加入HATU(127mg,0.31 mmol)，DIPEA(144mg,1.12mmol)低温搅拌5min，然后加入1-(2,2,2-三氟乙基)哌啶-4-胺90a(57.6mg,0.3mmol)，搅拌0.5h，TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(1-(2,2,2-三氟乙基)哌啶-4-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺化合物90(淡黄色固体，50mg，47.8％)。(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-Carboxylic acid Compound 1-A (100 mg, 0.28 mmol) was dissolved in 6 mL of dioxane, then HATU (127 mg, 0.31 mmol) was added in an ice bath, DIPEA (144 mg, 1.12 mmol) was stirred at low temperature for 5 min, and then 1- (2,2,2-trifluoroethyl)piperidin-4-amine 90a (57.6mg, 0.3mmol), stirred for 0.5h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse-phase C18 column chromatography (alkali method ) to obtain the target product (1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(1-(2,2,2-trifluoroethyl)piperidine Iridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 90 (pale yellow solid, 50 mg, 47.8%).

1H NMR(400MHz,DMSO)δ9.00(dd,1H),8.63(dd,1H),8.17(d,1H),8.04(d,1H),7.60(dd,1H),7.22(d,1H),4.04–3.89(m,3H),3.82(d,1H),3.68–3.55(m,1H),3.14(q,2H),2.93–2.83(m,2H),2.44–2.32(m,2H),1.99(d,1H),1.65(dd,3H),1.50-1.39(m,2H)。 1 H NMR (400MHz, DMSO)δ9.00(dd,1H), 8.63(dd,1H), 8.17(d,1H), 8.04(d,1H), 7.60(dd,1H), 7.22(d,1H) ), 4.04–3.89 (m, 3H), 3.82 (d, 1H), 3.68–3.55 (m, 1H), 3.14 (q, 2H), 2.93–2.83 (m, 2H), 2.44–2.32 (m, 2H ), 1.99 (d, 1H), 1.65 (dd, 3H), 1.50-1.39 (m, 2H).

19F NMR(376MHz,DMSO-d 6)δ-63.60,-68.14. 19 F NMR (376MHz, DMSO-d 6 )δ-63.60,-68.14.

LC-MS m/z(ESI)＝512.3[M+1]。LC-MS m/z (ESI) = 512.3 [M+1].

实施例91Example 91

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-氟-1-甲基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物91(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-fluoro-1-methylpiperidin-4-yl)methyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 91

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3 -azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000156
Figure PCTCN2022081400-appb-000156

第一步：first step:

叔丁基4-((1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)-4-氟哌啶-1-羧酸酯 91btert-Butyl 4-((1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] Hexane-1-carboxamide)methyl)-4-fluoropiperidine-1-carboxylate 91b

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3 -azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1-A(150mg,0.43mmol)溶于6mL二氧六环中，随后冰浴加入HATU(196mg,0.51mmol)，DIPEA(166mg,1.29mmol)低温搅拌5min，然后加入4-(氨基甲基)-4-氟哌啶-1-羧酸叔丁酯91a(110mg,0.647mmol)，搅拌0.5h，TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物叔丁基4-((1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)-4-氟哌啶-1-羧酸酯 91b(淡黄色固体，250mg，87％)。Compound 1-A (150 mg, 0.43 mmol) was dissolved in 6 mL of dioxane, then HATU (196 mg, 0.51 mmol) was added in an ice bath, DIPEA (166 mg, 1.29 mmol) was stirred at low temperature for 5 min, and then 4-(aminomethyl) was added. (base)-4-fluoropiperidine-1-carboxylate tert-butyl ester 91a (110 mg, 0.647 mmol), stirred for 0.5 h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse-phase C18 column chromatography (alkaline method) to obtain The target product tert-butyl 4-((1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[ 3.1.0] Hexane-1-carboxamide)methyl)-4-fluoropiperidine-1-carboxylate 91b (pale yellow solid, 250 mg, 87%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.64(dd,1H),8.47(t,1H),8.17(d,1H),7.61(dd,1H),7.24(d,1H),4.05–3.90(m,3H),3.84(d,1H),3.73(d,2H),3.41–3.35(m,1H),2.93(d,2H),1.97(d,2H),1.71–1.48(m,5H),1.38(s,9H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.64(dd,1H), 8.47(t,1H), 8.17(d,1H), 7.61(dd,1H), 7.24( d, 1H), 4.05–3.90 (m, 3H), 3.84 (d, 1H), 3.73 (d, 2H), 3.41–3.35 (m, 1H), 2.93 (d, 2H), 1.97 (d, 2H) , 1.71–1.48 (m, 5H), 1.38 (s, 9H).

LC-MS m/z(ESI)＝562.2[M+1]。LC-MS m/z (ESI) = 562.2 [M+1].

第二步：Step 2:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-氟哌啶-4-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺盐酸盐 91c(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-fluoropiperidin-4-yl)methyl)-5-(trifluoromethyl) base)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 91c

(1R,5S)/(1S,5R)-3-(8-cyanoquinoline-5-yl)-N-(4-fluoropiperidine-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide hydrochloride(1R,5S)/(1S,5R)-3-(8-cyanoquinoline-5-yl)-N-(4-fluoropiperidine-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]hexane-1-formamide hydrochloride

将叔丁基4-((1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)-4-氟哌啶-1-羧酸酯91b(250mg,0.44mmol)加入10ml二氧六环氯化氢溶液中，缓慢升温至55℃，搅拌1h。TLC反应完毕，反应液直接浓缩，得到中间体(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-氟哌啶-4-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺盐酸盐91c(白色固体，110mg)。The tert-butyl 4-((1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1 .0] Hexane-1-carboxamide)methyl)-4-fluoropiperidine-1-carboxylate 91b (250mg, 0.44mmol) was added to 10ml of dioxane hydrogen chloride solution, the temperature was slowly raised to 55°C, and stirred. 1h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate (1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-fluoropiperidine-4- yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 91c (white solid, 110 mg).

LC-MS m/z(ESI)＝462.20[M+1]。LC-MS m/z (ESI) = 462.20 [M+1].

第三步：third step:

叔丁基4-((1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)-4-氟哌啶-1-羧酸酯 化合物91tert-Butyl 4-((1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0] Hexane-1-carboxamide) methyl)-4-fluoropiperidine-1-carboxylate Compound 91

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3 -azabicyclo[3.1.0]hexane-1-carboxamide

将(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-氟哌啶-4-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺盐酸盐91c(25mg,0.26mmol)，溶于6mL甲醇中，随后加入三乙胺100μL，多聚甲醛(64mg,0.78mmol),氰基硼氢化钠(20mg,0.52mmol)逐步升温至65℃搅拌4h，TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物叔丁基4-((1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)甲基)-4-氟哌啶-1-羧酸酯化合物91(淡黄色固体，47mg，76％)。(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-fluoropiperidin-4-yl)methyl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 91c (25 mg, 0.26 mmol), dissolved in 6 mL of methanol, followed by the addition of triethylamine 100 μL, paraformaldehyde (64 mg) , 0.78mmol), sodium cyanoborohydride (20mg, 0.52mmol) was gradually warmed to 65 ° C and stirred for 4h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse phase C18 column chromatography (alkali method) to obtain the target product tert-butyl base 4-((1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0] Hexane-1-carboxamide)methyl)-4-fluoropiperidine-1-carboxylate compound 91 (pale yellow solid, 47 mg, 76%).

1H NMR(400MHz,DMSO-d6)δ9.01(dd,1H),8.64(dd,1H),8.43(t,1H),8.17(d,1H),7.60(dd,1H),7.24(d,1H),4.00(q,2H),3.92(d,1H),3.84(d,1H),3.42–3.36(m,1H),3.31(d,1H),2.56–2.50(m,2H),2.15(s,3H),2.09(t,2H),1.97(d,1H),1.72–1.61(m,4H),1.60–1.50(m,1H)。 1 H NMR (400MHz, DMSO-d6)δ9.01(dd,1H), 8.64(dd,1H), 8.43(t,1H), 8.17(d,1H), 7.60(dd,1H), 7.24(d , 1H), 4.00(q, 2H), 3.92(d, 1H), 3.84(d, 1H), 3.42–3.36(m, 1H), 3.31(d, 1H), 2.56–2.50(m, 2H), 2.15 (s, 3H), 2.09 (t, 2H), 1.97 (d, 1H), 1.72–1.61 (m, 4H), 1.60–1.50 (m, 1H).

19F NMR(376MHz,DMSO-d6)δ-63.51 19 F NMR (376MHz, DMSO-d6) δ-63.51

LC-MS m/z(ESI)＝476.20[M+1]。LC-MS m/z (ESI) = 476.20 [M+1].

实施例92Example 92

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4,4-二氟-1-甲基哌啶-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物92(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoro-1-methylpiperidine-3- base)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 92

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoro-1-methylpiperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoro-1-methylpiperidin-3-yl)-5-(trifluoromethyl) )-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000157
Figure PCTCN2022081400-appb-000157

Figure PCTCN2022081400-appb-000158
Figure PCTCN2022081400-appb-000158

第一步：first step:

叔丁基(S)-3-((1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)-4,4-二氟哌啶-1-羧酸盐 92btert-Butyl (S)-3-((1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-aza Bicyclo[3.1.0]hexane-1-carboxamide)-4,4-difluoropiperidine-1-carboxylate 92b

tert-butyl(S)-3-((1R,5S)或(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamido)-4,4-difluoropiperidine-1-carboxylatetert-butyl(S)-3-((1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamido)-4,4-difluoropiperidine-1-carboxylate

将(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸 化合物1-A(150mg,0.43mmol)溶于6mL二氧六环中，随后冰浴加入HATU(196mg,0.51mmol)，DIPEA(166mg,1.29mmol)低温搅拌5min，然后加入(S)-3-氨基-4,4-二氟哌啶-1-羧酸叔丁酯92a(110mg,0.647mmol)，搅拌0.5h，TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物叔丁基(S)-3-((1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)-4,4-二氟哌啶-1-羧酸盐92b(淡黄色固体，250mg，87％)。(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-Carboxylic acid Compound 1-A (150mg, 0.43mmol) was dissolved in 6mL of dioxane, then HATU (196mg, 0.51mmol) was added in an ice bath, DIPEA (166mg, 1.29mmol) was stirred at low temperature for 5min, then (S )-3-amino-4,4-difluoropiperidine-1-carboxylic acid tert-butyl ester 92a (110 mg, 0.647 mmol), stirred for 0.5 h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse-phase C18 column chromatography (Alkaline method) to obtain the target product tert-butyl (S)-3-((1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide)-4,4-difluoropiperidine-1-carboxylate 92b (pale yellow solid, 250 mg, 87%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.65(dd,1H),8.40(d,1H),8.17(d,1H),7.62-7.58(m,1H),7.24(d,1H),4.24(s,1H),4.112-4.10(m,1H),4.03-3.98(m,2H),3.96–3.85(m,2H),3.70(s,1H),3.16(d,2H),2.18(d,1H),2.07–1.90(m,2H),1.69(d,1H),1.36(s,9H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.65(dd,1H), 8.40(d,1H), 8.17(d,1H), 7.62-7.58(m,1H), 7.24(d, 1H), 4.24(s, 1H), 4.112-4.10(m, 1H), 4.03-3.98(m, 2H), 3.96-3.85(m, 2H), 3.70(s, 1H), 3.16( d, 2H), 2.18 (d, 1H), 2.07–1.90 (m, 2H), 1.69 (d, 1H), 1.36 (s, 9H).

LC-MS m/z(ESI)＝566.2[M+1]。LC-MS m/z (ESI) = 566.2 [M+1].

第二步：Step 2:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4,4-二氟哌啶-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺盐酸盐 92c(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoropiperidin-3-yl)-5- (Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 92c

(1R,5S)/(1S,5R)-3-(8-cyanoquinoline-5-yl)-N-((s)-4,4-difluoropyridine-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide hydrochloride(1R,5S)/(1S,5R)-3-(8-cyanoquinoline-5-yl)-N-((s)-4,4-difluoropyridine-3-yl)-5-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane-1-formamide hydrochloride

将叔丁基(S)-3-((1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺)-4,4-二氟哌啶-1-羧酸盐92b(194mg,0.43mmol)加入10ml二氧六环氯化氢溶液中，缓慢升温至55℃，搅拌1h。TLC反应完毕，反应液直接浓缩，得到中间体(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4,4-二氟哌啶-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺盐酸盐92c(白色固体，110mg)。tert-Butyl (S)-3-((1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-nitrogen Heterobicyclo[3.1.0]hexane-1-carboxamide)-4,4-difluoropiperidine-1-carboxylate 92b (194 mg, 0.43 mmol) was added to 10 ml of dioxane hydrogen chloride solution, and the temperature was slowly raised to 55°C, stirred for 1 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate (1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4- Difluoropiperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 92c (white solid, 110 mg).

LC-MS m/z(ESI)＝466.20[M+1]。LC-MS m/z (ESI) = 466.20 [M+1].

第三步：third step:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4,4-二氟-1-甲基哌啶-3-基)-5-(三氟甲 基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物92(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoro-1-methylpiperidine-3- base)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 92

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoro-1-methylpiperidin-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoro-1-methylpiperidin-3-yl)-5-(trifluoromethyl) )-3-azabicyclo[3.1.0]hexane-1-carboxamide

将(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4,4-二氟哌啶-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺盐酸盐92c(150mg,0.32mmol)，溶于6mL甲醇中，随后加入三乙胺100μL，多聚甲醛(60mg,0.64mmol),氰基硼氢化钠(50mg,1.28mmol)逐步升温至65℃搅拌4h，TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4,4-二氟-1-甲基哌啶-3-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物92(淡黄色固体，44mg，34％)。(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoropiperidin-3-yl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 92c (150 mg, 0.32 mmol) was dissolved in 6 mL of methanol, followed by adding triethylamine 100 μL, more Polyoxymethylene (60mg, 0.64mmol), sodium cyanoborohydride (50mg, 1.28mmol) were gradually heated to 65°C and stirred for 4h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse phase C18 column chromatography (alkali method) to obtain The target product (1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4,4-difluoro-1-methylpiperidine- 3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 92 (pale yellow solid, 44 mg, 34%).

1H NMR(400MHz,DMSO-d6)δ9.00(dd,1H),8.64(dd,1H),8.38(d,1H),8.17(d,1H),7.60(dd,1H),7.23(d,1H),4.31(m,1H),4.05(d,1H),4.01–3.84(m,3H),2.71–2.55(m,2H),2.21(s,3H),2.20–1.92(m,5H),1.65(d,1H)。 1 H NMR (400MHz, DMSO-d6)δ9.00(dd,1H), 8.64(dd,1H), 8.38(d,1H), 8.17(d,1H), 7.60(dd,1H), 7.23(d ,1H),4.31(m,1H),4.05(d,1H),4.01–3.84(m,3H),2.71–2.55(m,2H),2.21(s,3H),2.20–1.92(m,5H) ), 1.65(d, 1H).

19F NMR(376MHz,DMSO-d6)δ-63.95,-102.84,-103.46 19 F NMR (376MHz, DMSO-d6) δ-63.95, -102.84, -103.46

LC-MS m/z(ESI)＝480.30[M+1]。LC-MS m/z (ESI) = 480.30 [M+1].

实施例93Example 93

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-(4-羟基-1-甲基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物93(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(4-hydroxy-1-methylpiperidin-4-yl)methyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 93

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((4-hydroxy-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((4-hydroxy-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3 -azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000159
Figure PCTCN2022081400-appb-000159

第一步：first step:

(1-(叔丁氧羰基)-4-羟基哌啶-4-基)甲基(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸酯 93b(1-(tert-Butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 93b

(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3- azabicyclo[3.1.0]hexane-1-carboxylate

将(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸 化合物1-A(150mg,0.43mmol)溶于6mL二氧六环中，随后冰浴加入HATU(196mg,0.51mmol)，DIPEA(166mg,1.29mmol)低温搅拌5分钟，然后加入4-(氨基甲基)-4-羟基哌啶- 1-羧酸叔丁酯93a(109mg,0.47mmol)，搅拌0.5h，TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物(1-(叔丁氧羰基)-4-羟基哌啶-4-基)甲基(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-羧酸酯93b(淡黄色固体，130mg，76％)。(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane- 1-Carboxylic acid Compound 1-A (150 mg, 0.43 mmol) was dissolved in 6 mL of dioxane, then HATU (196 mg, 0.51 mmol) was added in an ice bath, DIPEA (166 mg, 1.29 mmol) was stirred at low temperature for 5 minutes, and then 4 -(Aminomethyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester 93a (109mg, 0.47mmol), stirred for 0.5h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse-phase C18 column chromatography (alkali method) to obtain the target product (1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)methyl (1S,5R) or (1R,5S)-3-(8-cyanoquinoline- 5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate 93b (pale yellow solid, 130 mg, 76%).

LC-MS m/z(ESI)＝560.2[M+1]。LC-MS m/z (ESI) = 560.2 [M+1].

第二步：Step 2:

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(4-羟基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 盐酸盐 93c(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(4-hydroxypiperidin-4-yl)methyl)-5-(trifluoromethyl) base)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 93c

(1S,5R)/(1R,5S)-3-(8-cyanoquinoline-5-yl)-N-(4-hydroxypiperidine-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formamide hydrochloride(1S,5R)/(1R,5S)-3-(8-cyanoquinoline-5-yl)-N-(4-hydroxypiperidine-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]hexane-1-formamide hydrochloride

将93b(130mg,0.23mmol)加入10ml二氧六环氯化氢溶液中，缓慢升温至55℃，搅拌1h。TLC反应完毕，反应液直接浓缩，得到中间体(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(4-羟基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺盐酸盐93c(白色固体，197mg)。93b (130 mg, 0.23 mmol) was added to 10 ml of dioxane hydrogen chloride solution, the temperature was slowly raised to 55° C., and stirred for 1 h. After the TLC reaction was completed, the reaction solution was directly concentrated to obtain the intermediate (1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(4-hydroxypiperidine-4- yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 93c (white solid, 197 mg).

LC-MS m/z(ESI)＝460.20[M+1]。LC-MS m/z (ESI) = 460.20 [M+1].

第三步：third step:

(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(4-羟基-1-甲基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物93(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(4-hydroxy-1-methylpiperidin-4-yl)methyl)-5 -(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 93

(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-((4-hydroxy-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1S,5R)/(1R,5S)-3-(8-cyanoquinolin-5-yl)-N-((4-hydroxy-1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3 -azabicyclo[3.1.0]hexane-1-carboxamide

将(1S,5R)或(1R,5S)-3-(8-氰基喹啉-5-基)-N-(4-羟基哌啶-4-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺盐酸盐93c(197mg,0.43mmol)，溶于6mL甲醇中，随后加入三乙胺100μL，多聚甲醛(58mg,0.64mmol),氰基硼氢化钠(49mg,1.29mmol)逐步升温至65℃搅拌4h，TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物化合物93(淡黄色固体，80mg，73％)。(1S,5R) or (1R,5S)-3-(8-cyanoquinolin-5-yl)-N-(4-hydroxypiperidin-4-yl)methyl)-5-(trifluoro Methyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide hydrochloride 93c (197 mg, 0.43 mmol) was dissolved in 6 mL of methanol, followed by the addition of triethylamine 100 μL, paraformaldehyde (58 mg , 0.64mmol), sodium cyanoborohydride (49mg, 1.29mmol) was gradually warmed to 65 ° C and stirred for 4h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target product compound 93 (pale yellow solid, 80 mg, 73%).

1H NMR(400MHz,DMSO-d 6)δ9.01(dd,1H),8.64(dd,1H),8.17(d,1H),8.07(t,1H),7.61(dd,1H),7.24(d,1H),4.30(s,1H),3.99(s,2H),3.92(d,1H),3.84(d,1H),3.12(t,2H),2.42–2.29(m,2H),2.20(m,2H),1.94(d,1H),1.64(d,1H),1.54–1.32(m,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.01(dd,1H), 8.64(dd,1H), 8.17(d,1H), 8.07(t,1H), 7.61(dd,1H), 7.24( d, 1H), 4.30(s, 1H), 3.99(s, 2H), 3.92(d, 1H), 3.84(d, 1H), 3.12(t, 2H), 2.42–2.29(m, 2H), 2.20 (m, 2H), 1.94 (d, 1H), 1.64 (d, 1H), 1.54–1.32 (m, 4H).

19F NMR(376MHz,DMSO-d 6)δ-63.45. 19 F NMR (376MHz, DMSO-d 6 ) δ-63.45.

LC-MS m/z(ESI)＝474.20[M+1]。LC-MS m/z (ESI) = 474.20 [M+1].

实施例94Example 94

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-氮-((S)-4-(环丙基甲基)吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物94(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-nitrogen-((S)-4-(cyclopropylmethyl)morpholin-2-yl) Methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 94

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(cyclopropylmethyl)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(cyclopropylmethyl)morpholin-2-yl)methyl)-5-(trifluoromethyl) )-3-azabicyclo[3.1.0]hexane-1-carboxamide

Figure PCTCN2022081400-appb-000160
Figure PCTCN2022081400-appb-000160

Figure PCTCN2022081400-appb-000161
Figure PCTCN2022081400-appb-000161

第一步：first step:

(R)-吗啉-2-基甲醇 盐酸盐 94b(R)-Morpholin-2-ylmethanol hydrochloride 94b

(R)-morpholine-2-yl methanol hydrochloride(R)-morpholine-2-yl methanol hydrochloride

将(R)-2-(羟甲基)吗啉-4-羧酸叔丁酯 94a(2g,9.2mmol)溶于20mL盐酸二氧六环中，缓慢升温至55℃，搅拌1h。TLC反应完毕，反应液直接浓缩，得到中间体(R)-吗啉-2-基甲醇盐酸盐94b(白色固体，110mg)。(R)-2-(hydroxymethyl)morpholine-4-carboxylate tert-butyl ester 94a (2 g, 9.2 mmol) was dissolved in 20 mL of dioxane hydrochloric acid, slowly heated to 55 °C, and stirred for 1 h. After completion of the TLC reaction, the reaction solution was directly concentrated to obtain the intermediate (R)-morpholin-2-ylmethanol hydrochloride 94b (white solid, 110 mg).

LC-MS m/z(ESI)＝118.20[M+1]。LC-MS m/z (ESI) = 118.20 [M+1].

第二步：Step 2:

叔丁基(R)-2-(羟甲基)吗啉-4-羧酸酯(R)-(4-(环丙基甲基)吗啉-2-基)甲醇 94ctert-Butyl(R)-2-(hydroxymethyl)morpholine-4-carboxylate (R)-(4-(cyclopropylmethyl)morpholin-2-yl)methanol 94c

(R)-(4-(cyclopropylmethyl)morpholin-2-yl)methanol(R)-(4-(cyclopropylmethyl)morpholin-2-yl)methanol

将化合物94b(500mg，4.2mmol)溶解于N,N-二甲基甲酰胺20mL中，随后加入三乙胺(1.27g，12.6mmol)，然后加入环丙甲基溴(692mg,5.1mmol)，缓慢升温至55℃搅拌3h。TLC检测反应完毕，减压浓缩，得到中间体叔丁基(R)-2-(羟甲基)吗啉-4-羧酸酯(R)-(4-(环丙基甲基)吗啉-2-基)甲醇94c(无色油状物，510mg)。Compound 94b (500 mg, 4.2 mmol) was dissolved in N,N-dimethylformamide 20 mL, followed by triethylamine (1.27 g, 12.6 mmol), followed by cyclopropylmethyl bromide (692 mg, 5.1 mmol), The temperature was slowly raised to 55°C and stirred for 3h. TLC detected the completion of the reaction, and concentrated under reduced pressure to obtain the intermediate tert-butyl (R)-2-(hydroxymethyl)morpholine-4-carboxylate (R)-(4-(cyclopropylmethyl)morpholine) -2-yl)methanol 94c (colorless oil, 510 mg).

LC-MS m/z(ESI)＝172.2[M+1]。LC-MS m/z (ESI) = 172.2 [M+1].

第三步：third step:

(R)-(4-(环丙基甲基)吗啉-2-基)甲基4-甲基苯磺酸盐 94d(R)-(4-(Cyclopropylmethyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate 94d

(R)-(4-(cyclopropylmethyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate(R)-(4-(cyclopropylmethyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate

将化合物94c(510g，2.9mmol)溶解于N,N-二甲基甲酰胺20mL中，随后加入三乙胺(602mg，5.8mmol)，4-二甲氨基吡啶(35mg,0.29mmol)，缓慢加入对甲苯磺酰氯(608mg，3.19mmol)，室温搅拌1h。TLC监测反应完毕，减压浓缩，得到中间体(R)-(4-(环丙基甲基)吗啉-2-基)甲基4-甲基苯磺酸盐94d(白色固体，640mg)。Compound 94c (510 g, 2.9 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by adding triethylamine (602 mg, 5.8 mmol), 4-dimethylaminopyridine (35 mg, 0.29 mmol), slowly adding p-Toluenesulfonyl chloride (608 mg, 3.19 mmol) was stirred at room temperature for 1 h. The completion of the reaction was monitored by TLC, and concentrated under reduced pressure to obtain the intermediate (R)-(4-(cyclopropylmethyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate 94d (white solid, 640 mg) .

LC-MS m/z(ESI)＝326.2[M+1]。LC-MS m/z (ESI) = 326.2 [M+1].

第四步：the fourth step:

双叔丁基(S)-(4-(环丙基甲基)吗啉-2-基)甲基)氨基甲酸酯94eBis-tert-butyl (S)-(4-(cyclopropylmethyl)morpholin-2-yl)methyl)carbamate 94e

Di tert-butyl(S)-(4-(cyclopropylmethyl)morpholine-2-yl)methyl)carbamateDi tert-butyl(S)-(4-(cyclopropylmethyl)morpholine-2-yl)methyl)carbamate

将中间体(R)-(4-(环丙基甲基)吗啉-2-基)甲基4-甲基苯磺酸盐94d(640mg,1.9mmol)溶于60ml N,N-二甲基甲酰胺中，随后加入碳酸铯(1.9g，5.9mmol)，碘化钠(60mg,0.39mmol)，双BOC胺(413mg,2.3mmol)，缓慢升温至90℃，搅拌2h。TLC监测反应完毕，反应液直接浓缩，硅胶柱层析纯化(乙酸乙酯：石油醚＝1:3)，得到中间体双叔丁基(S)-(4-(环丙基甲基)吗啉-2-基)甲基)氨基甲酸酯94e(白色固体，400mg)。Intermediate (R)-(4-(cyclopropylmethyl)morpholin-2-yl)methyl 4-methylbenzenesulfonate 94d (640 mg, 1.9 mmol) was dissolved in 60 ml of N,N-dimethyl In the base formamide, cesium carbonate (1.9 g, 5.9 mmol), sodium iodide (60 mg, 0.39 mmol), bis-BOC amine (413 mg, 2.3 mmol) were then added, the temperature was slowly raised to 90 °C, and stirred for 2 h. TLC monitoring the completion of the reaction, the reaction solution was directly concentrated and purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:3) to obtain the intermediate bis-tert-butyl (S)-(4-(cyclopropylmethyl)? olin-2-yl)methyl)carbamate 94e (white solid, 400 mg).

LC-MS m/z(ESI)＝371.2[M+1]。LC-MS m/z (ESI) = 371.2 [M+1].

第五步：the fifth step:

(S)-(4-(环丙基甲基)吗啉-2-基)甲酰胺 盐酸盐 94f(S)-(4-(Cyclopropylmethyl)morpholin-2-yl)carboxamide hydrochloride 94f

(S)-(4-(cyclopropylmethyl)morpholine-2-yl)formamide hydrochloride(S)-(4-(cyclopropylmethyl)morpholine-2-yl)formamide hydrochloride

将双叔丁基(S)-(4-(环丙基甲基)吗啉-2-基)甲基)氨基甲酸酯94e(400mg,1.08mmol)加入5ml二氧六环氯化氢溶液中，缓慢升温至55℃，搅拌1h。TLC监测反应完毕，反应液直接浓缩，得到中间体(S)-(4-(环丙基甲基)吗啉-2-基)甲酰胺盐酸盐94f(白色固体，460mg)。Di-tert-butyl (S)-(4-(cyclopropylmethyl)morpholin-2-yl)methyl)carbamate 94e (400 mg, 1.08 mmol) was added to 5 ml of dioxane hydrogen chloride solution, The temperature was slowly raised to 55 °C and stirred for 1 h. The completion of the reaction was monitored by TLC, and the reaction solution was directly concentrated to obtain the intermediate (S)-(4-(cyclopropylmethyl)morpholin-2-yl)carboxamide hydrochloride 94f (white solid, 460 mg).

LC-MS m/z(ESI)＝171.2[M+1]。LC-MS m/z (ESI) = 171.2 [M+1].

第六步：Step 6:

(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4-(环丙基甲基)吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物94(1R,5S) or (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((S)-4-(cyclopropylmethyl)morpholin-2-yl) Methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 94

(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(cyclopropylmethyl)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide(1R,5S)/(1S,5R)-3-(8-cyanoquinolin-5-yl)-N-(((S)-4-(cyclopropylmethyl)morpholin-2-yl)methyl)-5-(trifluoromethyl) )-3-azabicyclo[3.1.0]hexane-1-carboxamide

将化合物1-A(100mg,0.28mmol)溶于N,N二甲基甲酰胺6ml中，随后冰浴加入HATU(127mg,0.33mmol)，DIPEA(108mg,0.84mmol)低温搅拌5分钟，然后加入94f(75mg,0.3mmol)搅拌0.5h，TLC反应完毕，反应液直接浓缩，反相C18柱层析纯化(碱法)，得到目标产物(1R,5S)或(1S,5R)-3-(8-氰基喹啉-5-基)-N-((S)-4-(环丙基甲基)吗啉-2-基)甲基)-5-(三氟甲基)-3-氮杂双环[3.1.0]己烷-1-甲酰胺 化合物94(淡黄色固体,80mg,78％)。Compound 1-A (100 mg, 0.28 mmol) was dissolved in 6 ml of N,N dimethylformamide, then HATU (127 mg, 0.33 mmol) was added in an ice bath, DIPEA (108 mg, 0.84 mmol) was stirred at low temperature for 5 minutes, and then added 94f (75mg, 0.3mmol) was stirred for 0.5h, the TLC reaction was completed, the reaction solution was directly concentrated, and purified by reverse-phase C18 column chromatography (alkali method) to obtain the target product (1R, 5S) or (1S, 5R)-3-( 8-Cyanoquinolin-5-yl)-N-((S)-4-(cyclopropylmethyl)morpholin-2-yl)methyl)-5-(trifluoromethyl)-3- Azabicyclo[3.1.0]hexane-1-carboxamide Compound 94 (pale yellow solid, 80 mg, 78%).

1H NMR(400MHz,DMSO-d 6)δ9.00(dd,1H),8.63(dd,1H),8.40(t,1H),8.17(d,1H),7.60(dd,1H),7.23(d,1H),4.01(d,1H),3.98–3.90(m,2H),3.80(dd,2H),3.54–3.40(m,2H),3.14(m,2H),2.92–2.65(m,2H),2.15(s,2H),1.98(t,2H),1.66(t,2H),0.82(d,1H),0.44(d,2H),0.11–0.01(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ9.00(dd,1H), 8.63(dd,1H), 8.40(t,1H), 8.17(d,1H), 7.60(dd,1H), 7.23( d, 1H), 4.01 (d, 1H), 3.98–3.90 (m, 2H), 3.80 (dd, 2H), 3.54–3.40 (m, 2H), 3.14 (m, 2H), 2.92–2.65 (m, 2H), 2.15(s, 2H), 1.98(t, 2H), 1.66(t, 2H), 0.82(d, 1H), 0.44(d, 2H), 0.11–0.01(m, 2H).

19F NMR(376MHz,DMSO-d6)δ-63.52 19 F NMR (376MHz, DMSO-d6) δ-63.52

LC-MS m/z(ESI)＝500.20[M+1]。LC-MS m/z (ESI) = 500.20 [M+1].

生物测试biological test

HEK-Blue-hTLR7/8/9细胞抑制实验HEK-Blue-hTLR7/8/9 cell inhibition assay

1、将HEK-Blue-hTLR7/8细胞(1×10 4个/孔)、HEK-Blue-hTLR9细胞(1.5×10 4个/孔)接种于384孔细胞培养板中，每孔体积为30μL。置于37℃，5％CO 2培养箱培养4h。 1. Inoculate HEK-Blue-hTLR7/8 cells (1×10 4 cells/well) and HEK-Blue-hTLR9 cells (1.5×10 4 cells/well) in a 384-well cell culture plate, the volume of each well is 30 μL . Placed at 37°C, 5% CO2 incubator for 4h.

2、将化合物用DMSO配制，用DMEM培养基稀释10个浓度(1:3稀释)，终浓度分别为10000，3333.3，1111.1，370.4，123.5，41.2，13.7，4.6，1.5，0.5nM；R848使用DMSO配制，用DMEM培养基稀释，终浓度为0.8μM(HEK-Blue-hTLR7)、3μM(HEK-Blue-hTLR8)；ODN2006使用无内毒素水配制，用DMEM培养基稀释，终浓度为1μM。2. Compounds were prepared with DMSO, diluted with DMEM medium at 10 concentrations (1:3 dilution), the final concentrations were 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, 1.5, 0.5nM; R848 was used Prepared in DMSO and diluted with DMEM medium to a final concentration of 0.8 μM (HEK-Blue-hTLR7) and 3 μM (HEK-Blue-hTLR8); ODN2006 was prepared with endotoxin-free water and diluted with DMEM medium to a final concentration of 1 μM.

3、以DMSO处理的细胞为空白对照组，同时设立单独用Resiquimod(R848)处理的细胞为HEK-Blue-hTLR7/8的阳性对照组，单独用ODN2006处理的细胞为HEK-Blue-hTLR9的阳性对照组。以受试化合物与R848或ODN2006处理的细胞为测试组。每组设2个平行孔，放入置于37℃，5％CO 2培养箱培养。 3. The cells treated with DMSO were used as the blank control group, and the cells treated with Resiquimod (R848) alone were established as the positive control group for HEK-Blue-hTLR7/8, and the cells treated with ODN2006 alone were established as the positive control group for HEK-Blue-hTLR9. control group. The cells treated with the test compound and R848 or ODN2006 were used as the test group. Two parallel wells were set in each group, and were placed in a 37°C, 5% CO 2 incubator for culture.

4、培养4h后，从培养箱中取出HEK-Blue-hTLR7/8的384孔板，每孔单独加入R848 或者同时加入R848和稀释后的化合物。置于37℃，5％CO 2培养箱培养16h；从培养箱中取出HEK-Blue-hTLR9的384孔板，每孔单独加入ODN2006或者同时加入ODN2006和稀释后的化合物。置于37℃，5％CO 2培养箱培养16h。 4. After culturing for 4 hours, take out the 384-well plate of HEK-Blue-hTLR7/8 from the incubator, and add R848 to each well or add R848 and the diluted compound at the same time. Incubate at 37°C in a 5% CO 2 incubator for 16h; remove the HEK-Blue-hTLR9 384-well plate from the incubator, add ODN2006 to each well or add ODN2006 and the diluted compound at the same time. Placed at 37°C, 5% CO2 incubator for 16h.

5、培养16h后，从培养箱中取出384孔板，1000rpm离心1分钟，使用多功能酶标仪读取每个孔在620nm处的光密度值。5. After culturing for 16 hours, the 384-well plate was taken out from the incubator, centrifuged at 1000 rpm for 1 minute, and the optical density value of each well at 620 nm was read using a multi-function microplate reader.

6、计算细胞抑制率＝(1-(OD620测试组-OD620空白组)/(OD620阳性组-OD620空白组))×100％，通过曲线拟合计算半数抑制浓度(half maximal inhibitory concentration,IC 50)。 6. Calculate the cell inhibition rate=(1-(OD620 test group-OD620 blank group)/(OD620 positive group-OD620 blank group))×100%, and calculate the half maximal inhibitory concentration (IC 50 ) by curve fitting ).

表1：本发明化合物在HEK-Blue-hTLR7/8/9细胞测定中的活性Table 1: Activity of compounds of the invention in HEK-Blue-hTLR7/8/9 cell assay

化合物compound TLR7 IC 50(nM) TLR7 IC50 (nM) TLR8 IC 50(nM) TLR8 IC 50 (nM) TLR9 IC 50(nM) TLR9 IC 50 (nM) 化合物2Compound 2 5.15.1 14.314.3 44544454 化合物2-ACompound 2-A 3.43.4 1515 55665566 化合物2-BCompound 2-B 16.316.3 9.39.3 63376337 化合物5Compound 5 44 2828 22922292 化合物5-ACompound 5-A 13.813.8 52.752.7 29592959 化合物5-BCompound 5-B 6.16.1 -- 53795379 化合物5-CCompound 5-C 1.71.7 31.831.8 13191319 化合物5-DCompound 5-D 3.43.4 34.134.1 10991099 化合物6Compound 6 6.26.2 60.560.5 >10000>10000 化合物7Compound 7 7.17.1 -- >10000>10000 化合物10Compound 10 -- -- >10000>10000 化合物11Compound 11 4.34.3 8.98.9 >10000>10000 化合物12Compound 12 2727 -- >10000>10000 化合物15Compound 15 2.12.1 21twenty one 42424242 化合物16Compound 16 25.525.5 22twenty two >10000>10000 化合物18Compound 18 8.58.5 1313 64806480 化合物18-ACompound 18-A 8.88.8 5.75.7 37793779 化合物18-BCompound 18-B 3.63.6 19.419.4 45324532 化合物20Compound 20 46.146.1 -- >10000>10000 化合物21Compound 21 10.610.6 36.636.6 56015601 化合物22Compound 22 13.713.7 -- 69456945 化合物23Compound 23 4.64.6 4747 11931193 化合物24Compound 24 4.94.9 4848 27332733 化合物27Compound 27 5.65.6 2.92.9 36153615 化合物27-ACompound 27-A 4.94.9 1.31.3 11211121

化合物27-BCompound 27-B 1.81.8 2.92.9 13391339 化合物29Compound 29 10.810.8 41.241.2 >10000>10000 化合物29-ACompound 29-A 17.217.2 6868 >10000>10000 化合物29-BCompound 29-B 21twenty one -- >10000>10000 化合物29-CCompound 29-C 59.759.7 -- >10000>10000 化合物29-DCompound 29-D 6565 47.647.6 >10000>10000 化合物30Compound 30 11.911.9 80.580.5 677.2677.2 化合物32Compound 32 28.228.2 -- 11361136 化合物33Compound 33 14.414.4 24.224.2 >10000>10000 化合物33-ACompound 33-A 4.94.9 7.37.3 59665966 化合物33-BCompound 33-B 40.740.7 33.733.7 >10000>10000 化合物34Compound 34 5757 -- >10000>10000 化合物35Compound 35 51.951.9 -- >10000>10000 化合物36Compound 36 15.215.2 37.637.6 30353035 化合物37Compound 37 12.212.2 41.641.6 27682768 化合物38Compound 38 65.465.4 23.323.3 36543654 化合物39Compound 39 3.13.1 6.26.2 10711071 化合物40Compound 40 3.43.4 5.85.8 22232223 化合物41Compound 41 11.211.2 7.47.4 15061506 化合物42Compound 42 4.24.2 6.36.3 33783378 化合物43Compound 43 3.13.1 88 28362836 化合物44Compound 44 9.79.7 3.33.3 29012901 化合物45Compound 45 59.459.4 -- >10000>10000 化合物46Compound 46 71.571.5 >10000>10000 >10000>10000 化合物48Compound 48 3.23.2 84.284.2 53775377 化合物48-ACompound 48-A 6.16.1 47.547.5 45324532 化合物48-BCompound 48-B 8.18.1 29.629.6 49174917 化合物48-CCompound 48-C 2.92.9 5858 53015301 化合物48-DCompound 48-D 22 48.448.4 55505550 化合物49Compound 49 71.471.4 -- >10000>10000 化合物50Compound 50 5.15.1 -- 53475347 化合物51Compound 51 2.52.5 7.17.1 23472347

化合物53-ACompound 53-A 3.63.6 9.69.6 >10000>10000 化合物53-BCompound 53-B 5.45.4 21.221.2 >10000>10000 化合物53-CCompound 53-C 7.17.1 35.735.7 >10000>10000 化合物53-DCompound 53-D 3.23.2 12.512.5 >10000>10000 化合物54Compound 54 46.946.9 -- 38593859 化合物55Compound 55 70.970.9 39.339.3 424.8424.8 化合物58Compound 58 15.815.8 6.56.5 46274627 化合物59Compound 59 19.619.6 18.218.2 56455645 化合物60Compound 60 1.31.3 8.58.5 11661166 化合物61Compound 61 4.94.9 11.911.9 10681068 化合物62Compound 62 4.24.2 30.630.6 >10000>10000 化合物63Compound 63 18.418.4 6363 >10000>10000 化合物64Compound 64 32.532.5 13.613.6 >10000>10000 化合物65Compound 65 34.634.6 55.655.6 >10000>10000 化合物66Compound 66 23.323.3 54.854.8 >10000>10000 化合物67Compound 67 33.433.4 35.535.5 >10000>10000 化合物68-ACompound 68-A 23.623.6 92.292.2 >10000>10000 化合物69Compound 69 29.629.6 53.953.9 >10000>10000 化合物70Compound 70 1.91.9 7.27.2 44234423 化合物74Compound 74 7.67.6 -- >10000>10000 化合物76Compound 76 <100<100 -- >10000>10000 化合物77Compound 77 -- <100<100 >10000>10000 化合物82Compound 82 1616 9191 76267626 化合物83Compound 83 4242 -- 54455445 化合物84Compound 84 99 -- 80578057 化合物85Compound 85 1212 2626 28792879 化合物86Compound 86 1818 -- >10000>10000 化合物87Compound 87 99 7070 >10000>10000 化合物88Compound 88 1111 6060 >10000>10000 化合物89Compound 89 1414 9797 >10000>10000 化合物90Compound 90 22twenty two -- >10000>10000 化合物91Compound 91 22 24twenty four 48394839

化合物92Compound 92 4343 -- >10000>10000 化合物93Compound 93 7777 -- 27632763 化合物94Compound 94 1010 2929 74407440

结论：本发明化合物对HEK-Blue-hTLR7/8细胞有明显拮抗作用，同时对HEK-Blue-hTLR9细胞无明显拮抗作用。Conclusion: The compounds of the present invention have obvious antagonistic effect on HEK-Blue-hTLR7/8 cells, but have no obvious antagonistic effect on HEK-Blue-hTLR9 cells.

IL-6的体内抑制实验In vivo inhibition experiment of IL-6

实验材料：化合物溶液的配制：R848用纯水配制(灭菌)，最终浓度25μg/100μL；受试化合物用pH＝3的柠檬酸钠缓冲液配制，最终浓度0.1mg/mL。Experimental materials: Preparation of compound solution: R848 was prepared with pure water (sterilized) with a final concentration of 25 μg/100 μL; the test compound was prepared with pH=3 sodium citrate buffer with a final concentration of 0.1 mg/mL.

实验动物：C57BL/6雌鼠，购自集萃药康，6-8周龄。Experimental animals: C57BL/6 female mice, purchased from Jicuiyaokang, 6-8 weeks old.

实验方法：C57BL/6雌鼠随机分为空白组、对照组和实验组，每组8只。Experimental method: C57BL/6 female mice were randomly divided into blank group, control group and experimental group, with 8 mice in each group.

空白组：小鼠禁食12h后取血。Blank group: mice were fasted for 12 hours and then blood was collected.

对照组：小鼠禁食12h后灌胃PH＝3的柠檬酸钠缓冲液，其余操作与实验组一致；Control group: mice were given sodium citrate buffer with pH=3 after fasting for 12 hours, and other operations were consistent with the experimental group;

实验组：小鼠禁食12h后灌胃给予受试化合物(1mg/kg)，1h后腹腔注射25μg R848(购自MCE)，2h后摘眼球取血，血清室温静置30min，接着离心10min(3000rpm)，取上清液，用IL-6ELISA试剂盒测量血清IL-6浓度，通过对照组和实验组IL-6血清浓度，计算IL-6抑制率。计算公式：抑制率＝(C2-C3)/(C2-C1)×100％。Experimental group: mice were fasted for 12 hours and then given the test compound (1 mg/kg) by gavage. After 1 hour, they were intraperitoneally injected with 25 μg R848 (purchased from MCE). After 2 hours, the eyeballs were removed and blood was collected. 3000rpm), take the supernatant, measure the serum IL-6 concentration with IL-6 ELISA kit, and calculate the IL-6 inhibition rate according to the IL-6 serum concentration in the control group and the experimental group. Calculation formula: inhibition rate=(C2-C3)/(C2-C1)×100%.

C1：空白组血清IL-6浓度；C1: serum IL-6 concentration of blank group;

C2:对照组血清IL-6浓度；C2: serum IL-6 concentration of control group;

C3:实验组血清IL-6浓度。C3: Serum IL-6 concentration in experimental group.

表2：IL-6的体内抑制实验Table 2: In vivo inhibition experiments of IL-6

化合物compound IL-6抑制率IL-6 inhibition rate 化合物27-ACompound 27-A 97.1％97.1% 化合物27-BCompound 27-B 99.8％99.8% 化合物29-ACompound 29-A 98％98% 化合物29-BCompound 29-B 99.7％99.7% 化合物29-CCompound 29-C 90.5％90.5% 化合物29-DCompound 29-D 90％90% 化合物43Compound 43 93.8％93.8% 化合物44Compound 44 90％90% 化合物53-ACompound 53-A 97.2％97.2% 化合物53-BCompound 53-B 99.3％99.3% 化合物53-CCompound 53-C 100％100% 化合物53-DCompound 53-D 97.8％97.8% 化合物69Compound 69 68.9％68.9% 化合物73Compound 73 94.4％94.4% 化合物74Compound 74 92.2％92.2%

结论：本发明化合物对IL-6有明显的抑制作用。Conclusion: The compound of the present invention has obvious inhibitory effect on IL-6.

本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。The specification of the present invention describes the specific embodiments in detail. Those skilled in the art should realize that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention Under the premise, by carrying out several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (15)

通式(I)所示的化合物，或者其立体异构体、氘代物或药物可接受的盐：The compound represented by general formula (I), or its stereoisomer, deuterated product or pharmaceutically acceptable salt:
Figure PCTCN2022081400-appb-100001
Figure PCTCN2022081400-appb-100001
 其中：in: X为C或N；X is C or N; R 1为C 1-6烷基，所述C 1-6烷基任选地进一步被1个或多个卤素取代； R 1 is C 1-6 alkyl optionally further substituted with 1 or more halogens; R 2为-CN或C 1-6烷基，所述C 1-6烷基任选地进一步被1个或多个卤素取代； R 2 is -CN or C 1-6 alkyl optionally further substituted with 1 or more halogens; R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a为-(R a1) m-(R a2) n，所述R a任选地进一步被1个或多个选自D、-OH、卤素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、C 3-10环烷基、C 3-10杂环烷基和C 1-6烷基-C 3-10环烷基的取代基取代； R a is -(R a1 ) m -(R a2 ) n , said R a is optionally further 1 or more selected from D, -OH, halogen, -NR b R c , C 1-6 alkanes base, C 1-6 alkoxy, D substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-10 cycloalkyl, C 3 Substituent substitution of -10 heterocycloalkyl and C 1-6 alkyl-C 3-10 cycloalkyl; R a1为-O-、-NH-、-OCO-、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基或C 3-10杂环烷基，所述C 1-6烷基任选地进一步被1个或多个D取代； R a1 is -O-, -NH-, -OCO-, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, the C 1-6 alkyl is optionally further substituted with 1 or more D; R a2为H、D、-OH、卤素、-NR bR c、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基或C 3-10杂环烷基，所述C 1-6烷基任选地进一步被1个或多个D取代； R a2 is H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, The C 1-6 alkyl is optionally further substituted with 1 or more D; R b、R c各自独立地为H或C 1-6烷基； R b and R c are each independently H or C 1-6 alkyl; m为1、2或3；m is 1, 2 or 3; n为0、1、2、3或4。n is 0, 1, 2, 3 or 4. 根据权利要求1所述的化合物，或者其立体异构体、氘代物或药物可接受的盐：The compound according to claim 1, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof: 其中：in: X为C或N；X is C or N; R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ; R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ; R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a为-(R a1) m-(R a2) n，所述R a任选地进一步被1个或多个选自D、-OH、卤素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、C 3-10环烷基、C 3-10杂环烷基和C 1-6烷基-C 3-10环烷基的取代基取代； R a is -(R a1 ) m -(R a2 ) n , said R a is optionally further 1 or more selected from D, -OH, halogen, -NR b R c , C 1-6 alkanes base, C 1-6 alkoxy, D substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-10 cycloalkyl, C 3 Substituent substitution of -10 heterocycloalkyl and C 1-6 alkyl-C 3-10 cycloalkyl; R a1为-O-、-NH-、-OCO-、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基或C 3-10杂环烷基，所述C 1-6烷基任选地进一步被1个或多个D取代； R a1 is -O-, -NH-, -OCO-, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, the C 1-6 alkyl is optionally further substituted with 1 or more D; R a2为H、D、-OH、卤素、-NR bR c、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基或C 3-8杂环烷基，所述C 1-6烷基任选地进一步被1个或多个D取代； R a2 is H, D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, The C 1-6 alkyl is optionally further substituted with 1 or more D; R b、R c各自独立地为H或C 1-6烷基； R b and R c are each independently H or C 1-6 alkyl; m为1、2或3；m is 1, 2 or 3; n为0、1、2、3或4。n is 0, 1, 2, 3 or 4. 根据权利要求1或2所述的化合物，或者其立体异构体、氘代物或药物可接受的 盐：The compound according to claim 1 or 2, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof: 其中：in: X为C或N；X is C or N; R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ; R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ; R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a为-NH 2、-OH、哌啶基、C 1-6烷基、
Figure PCTCN2022081400-appb-100002
Figure PCTCN2022081400-appb-100003
Figure PCTCN2022081400-appb-100004
且R a任选地进一步被1至多个选自D、-OH、卤素、-NR bR c、C 1-6烷基、C 1-6烷氧基、D取代的C 1-6烷基、羟基取代的C 1-6烷基、卤素取代的C 1-6烷基、C 3-10环烷基、C 3-10杂环烷基和C 1-6烷基-C 3-10环烷基的取代基取代； R a is -NH 2 , -OH, piperidinyl, C 1-6 alkyl,
Figure PCTCN2022081400-appb-100002
Figure PCTCN2022081400-appb-100003
Figure PCTCN2022081400-appb-100004
And R a is optionally further C 1-6 alkyl substituted by 1 to more selected from D, -OH, halogen, -NR b R c , C 1-6 alkyl, C 1-6 alkoxy, D substituted , hydroxy substituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl and C 1-6 alkyl-C 3-10 ring Substituent substitution of alkyl; R b、R c各自独立地为H或C 1-6烷基。 R b and R c are each independently H or C 1-6 alkyl. 根据权利要求1至3中任一项所述的化合物，或者其立体异构体、氘代物或药物可接受的盐：A compound according to any one of claims 1 to 3, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof: 其中：in: X为C或N；X is C or N; R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ; R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ; R为-COOH、-NH 2、-CONH 2、-CONHR a、-COR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -COOH, -NH 2 , -CONH 2 , -CONHR a , -COR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a为-NH 2、-OH、哌啶基、
Figure PCTCN2022081400-appb-100005
Figure PCTCN2022081400-appb-100006
R a is -NH 2 , -OH, piperidinyl,
Figure PCTCN2022081400-appb-100005
Figure PCTCN2022081400-appb-100006
Figure PCTCN2022081400-appb-100007
Figure PCTCN2022081400-appb-100008
且R a任选地进一步被1个或2个C 1-6烷基取代。
Figure PCTCN2022081400-appb-100007
Figure PCTCN2022081400-appb-100008
and R a is optionally further substituted with 1 or 2 C 1-6 alkyl groups. 根据权利要求1至4中任一项所述的化合物，或者其立体异构体、氘代物或药物可接受的盐：A compound according to any one of claims 1 to 4, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof: 其中：in: X为C或N；X is C or N; R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ; R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ; R为-CONHR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -CONHR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a为
Figure PCTCN2022081400-appb-100009
Figure PCTCN2022081400-appb-100010
Figure PCTCN2022081400-appb-100011
且R a进一步被1个或2个C 1-6烷基取代。 Ra is
Figure PCTCN2022081400-appb-100009
Figure PCTCN2022081400-appb-100010
Figure PCTCN2022081400-appb-100011
And R a is further substituted with 1 or 2 C 1-6 alkyl groups. 根据权利要求1至5任一项所述的化合物，或者其立体异构体、氘代物或药物可接受的盐：A compound according to any one of claims 1 to 5, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof: 其中：in: X为C或N；X is C or N; R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ; R 2为-CN或-CF 3； R 2 is -CN or -CF 3 ; R为-CONHR a、-COOR a、-NHCOR a或-C 1-6烷基-R a； R is -CONHR a , -COOR a , -NHCOR a or -C 1-6 alkyl-R a ; R a为
Figure PCTCN2022081400-appb-100012
Figure PCTCN2022081400-appb-100013
且R a任选地进一步被1个或2个C 1-6烷基取代。 Ra is
Figure PCTCN2022081400-appb-100012
Figure PCTCN2022081400-appb-100013
and R a is optionally further substituted with 1 or 2 C 1-6 alkyl groups. 根据权利要求1至6任一项所述的化合物，或者其立体异构体、氘代物或药物可接受的盐：A compound according to any one of claims 1 to 6, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof: 其中：in: X为C或N；X is C or N; R 1为-CF 3或-CH 3； R 1 is -CF 3 or -CH 3 ; R 2为-CN； R 2 is -CN; R为-CONHR a、-COOR a或-NHCOR a； R is -CONHR a , -COOR a or -NHCOR a ; R a为
Figure PCTCN2022081400-appb-100014
Figure PCTCN2022081400-appb-100015
且R a任选地进一步被1个或2个C 1-6烷基取代。 Ra is
Figure PCTCN2022081400-appb-100014
Figure PCTCN2022081400-appb-100015
and R a is optionally further substituted with 1 or 2 C 1-6 alkyl groups. 根据权利要求1-7中任一项所述的化合物或者其立体异构体、氘代物或药物可接受的盐，其中所述卤素为F。The compound of any one of claims 1-7, or a stereoisomer, deuterated or pharmaceutically acceptable salt thereof, wherein the halogen is F. 通式(II)所示的化合物，或者其立体异构体、氘代物或药物可接受的盐：The compound represented by general formula (II), or its stereoisomer, deuterated product or pharmaceutically acceptable salt:
Figure PCTCN2022081400-appb-100016
Figure PCTCN2022081400-appb-100016
 其中：in: R为-COOH、-NH 2、-CONH 2、-COR a或-COOR a； R is -COOH, -NH 2 , -CONH 2 , -COR a or -COOR a ; R a为-NH 2、哌啶基、
Figure PCTCN2022081400-appb-100017
Figure PCTCN2022081400-appb-100018
Figure PCTCN2022081400-appb-100019
且R a任选地进一步被1个或2个C 1-6烷基取代。 R a is -NH 2 , piperidinyl,
Figure PCTCN2022081400-appb-100017
Figure PCTCN2022081400-appb-100018
Figure PCTCN2022081400-appb-100019
and R a is optionally further substituted with 1 or 2 C 1-6 alkyl groups. 根据权利要求1至9中任一项所述的化合物或者其立体异构体、氘代物或药物可接受的盐，所述化合物为：The compound according to any one of claims 1 to 9, or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof, which is:
Figure PCTCN2022081400-appb-100020
Figure PCTCN2022081400-appb-100020
Figure PCTCN2022081400-appb-100021
Figure PCTCN2022081400-appb-100021
Figure PCTCN2022081400-appb-100022
Figure PCTCN2022081400-appb-100022
Figure PCTCN2022081400-appb-100023
Figure PCTCN2022081400-appb-100023
 制备权利要求1至10中任一项所述的化合物的中间体或者其立体异构体、氘代物或药物可接受的盐，所述中间体为：An intermediate for the preparation of a compound according to any one of claims 1 to 10, or a stereoisomer, deuterated substance or a pharmaceutically acceptable salt thereof, the intermediate is:
Figure PCTCN2022081400-appb-100024
Figure PCTCN2022081400-appb-100024
Figure PCTCN2022081400-appb-100025
Figure PCTCN2022081400-appb-100025
 药物组合物，所述药物组合物包含：A pharmaceutical composition comprising: (1)权利要求1至10中任一项所述的化合物或者其立体异构体、氘代物或药物可接受 的盐；(1) The compound of any one of claims 1 to 10, or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof; (2)任选的一种或者多种其他活性成分；以及(2) optional one or more other active ingredients; and (3)药学上可接受的载体和/或赋形剂。(3) A pharmaceutically acceptable carrier and/or excipient. 权利要求1至10中任一项所述的化合物或者其立体异构体、氘代物或药物可接受的盐，或者权利要求12所述的药物组合物在制备用于治疗自身免疫疾病的药物中的用途。The compound of any one of claims 1 to 10, or a stereoisomer, deuterated substance or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12 in the manufacture of a medicament for the treatment of autoimmune diseases the use of. 权利要求1至10中任一项所述的化合物或者其立体异构体、氘代物或药物可接受的盐，或者权利要求12所述的药物组合物在制备用于治疗与TLR7、TLR8或TLR9相关的疾病中的用途。The compound of any one of claims 1 to 10, or a stereoisomer, deuterated substance or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12 is prepared for the treatment of TLR7, TLR8 or TLR9 Use in related diseases. 权利要求1至10中任一项所述的化合物或者其立体异构体、氘代物或药物可接受的盐，或者权利要求12所述的药物组合物在制备IL-6抑制剂中的用途。Use of the compound of any one of claims 1 to 10, or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12 in the preparation of an IL-6 inhibitor.
PCT/CN2022/081400 2021-03-18 2022-03-17 Quinoline derivative and application thereof in preparation of autoimmune drug Ceased WO2022194237A1 (en)

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