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WO2025082467A1 - 一种免疫调节剂 - Google Patents

一种免疫调节剂 Download PDF

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Publication number
WO2025082467A1
WO2025082467A1 PCT/CN2024/125698 CN2024125698W WO2025082467A1 WO 2025082467 A1 WO2025082467 A1 WO 2025082467A1 CN 2024125698 W CN2024125698 W CN 2024125698W WO 2025082467 A1 WO2025082467 A1 WO 2025082467A1
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alkylene
alkyl
membered
substituted
deuterium
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French (fr)
Inventor
李进
白晓光
洪新福
龚义
邓宁
张培
瞿庆喜
黄晓东
张瑞
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Hitgen Inc
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Hitgen Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the invention relates to an immunomodulator and use thereof in preparing medicines.
  • IL-17 (interleukin-17) is a proinflammatory cytokine that plays a role in inducing other inflammatory cytokines, chemokines and adhesion factors.
  • the IL-17 family consists of cytokines involved in acute and chronic inflammatory responses, including IL-17A (CTLA-8), IL-17B, IL-17C, IL-17D, IL-17E (IL-25) and IL-17F.
  • IL-17A is expressed by TH17 cells, which are involved in the pathogenesis of inflammatory and autoimmune diseases.
  • Human IL-17A is a glycoprotein with a molecular weight of approximately 17,000 Daltons.
  • IL-17A transmits signals into cells through the IL-17 receptor complex (IL-17RA and IL-17RC) (Wright, et al. Journal of immunology, 2008, 181: 2799-2805).
  • the main function of IL-17A is to coordinate local tissue inflammation through the upregulation of proinflammatory and neutrophil migratory cytokines and chemokines (including IL-6, G-CSF, TNF- ⁇ , IL-1, CXCL1, CCL2, CXCL2), as well as matrix metalloproteinases to allow activated T cells to penetrate the extracellular matrix.
  • IL-17A plays an important role in severe asthma and chronic obstructive pulmonary disease (COPD), and those patients are usually unresponsive or poorly responsive to currently available drugs (Al-Ramli et al. J Allergy Clin Immunol, 2009, 123: 1185-1187). Upregulated IL-17A levels are involved in many diseases, including rheumatoid arthritis (RA), bone erosion, intraperitoneal abscesses, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma and multiple sclerosis (Gaffen, SL et al. Arthritis Research & Therapy, 2004, 6:240-247).
  • IL-17A is a recognized proinflammatory cytokine that plays a key role in chronic inflammation and is a major driver of tissue damage. IL-17A induces normal immune and inflammatory responses to pathogens, but can also contribute to chronic autoimmune diseases, including psoriasis, spondyloarthritis, rheumatoid arthritis, and multiple sclerosis. Therefore, targeting the combination of IL-17A and IL-17R is an effective strategy for treating IL-17A-mediated autoimmune inflammatory diseases.
  • IL-17A Treatment of animals with IL-17A neutralizing antibodies reduced disease incidence and severity in autoimmune encephalomyelitis ( Komiyama Y et al. J. Immunol., 2006, 177: 566-573). Clinical trials of IL-17A antibodies have shown good results in IL-17A-mediated inflammatory diseases (including asthma, psoriasis, rheumatoid arthritis, ankylosing spondylitis and multiple sclerosis). IL-17A antibody (Novartis's Cosentyx/secukinumab) was approved by the FDA for the treatment of psoriasis in January 2015.
  • IL-17A antibodies Although several IL-17A antibodies have been marketed, there are relatively few known IL-17A small molecule regulators, especially Therefore, the development of IL-17A small molecule regulators has important clinical therapeutic significance.
  • the present invention first provides a compound represented by formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • X1 is selected from C or N;
  • X 2 and X 3 are independently selected from O, N, NR X or CR X ;
  • X 4 and X 5 are independently selected from C or N;
  • Each RX is independently selected from hydrogen, deuterium, halogen, cyano, -C1-6 alkyl, -OC1-6 alkyl, -C0-2 alkylene-(3-10 membered cycloalkyl), -O(3-10 membered cycloalkyl), -C0-2 alkylene-(4-10 membered heterocycloalkyl), -O(4-10 membered heterocycloalkyl), deuterium-substituted -C1-6 alkyl, halogen-substituted -C1-6 alkyl;
  • Y 1 , Y 2 , and Y 3 are independently selected from N or CR Y ;
  • Each RY is independently selected from hydrogen, deuterium, halogen, cyano, -C 1-6 alkyl, deuterium-substituted -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene-(4-10 membered heterocycloalkyl), -C 0-2 alkylene-OC 1-6 alkyl, -C 0-2 alkylene-O(halogen-substituted C 1-6 alkyl), -C 0-2 alkylene-O(3-10 membered cycloalkyl), -C 0-2 alkylene-O(4-10 membered heterocycloalkyl);
  • Z is selected from C(O), S(O) or S(O) 2 ;
  • R 1 is selected from -C 1-6 alkyl, deuterium-substituted C 1-6 alkyl, halogen-substituted C 1-6 alkyl, -C 2-6 alkenyl, halogen-substituted C 2-6 alkenyl, -C 2-6 alkynyl, halogen-substituted C 2-6 alkynyl , -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene-(4-10 membered heterocycloalkyl), -C 0-2 alkylene-(5-10 membered aromatic ring), -C 0-2 alkylene-(5-10 membered aromatic heterocycle), -C 0-2 alkylene- OR 11 , -C 0-2 alkylene-NR 11 R 12 ; wherein alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
  • R 11 and R 12 are independently selected from hydrogen, deuterium, C 1-6 alkyl, deuterium-substituted -C 1-6 alkyl, halogen-substituted C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene-(4-10 membered heterocycloalkyl), -C 0-2 alkylene-(5-10 membered aromatic ring), -C 0-2 alkylene-(5-10 membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two or three independent R 1a ;
  • two R 1a s connected to the same carbon atom together form a 3- to 10-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group; wherein the cycloalkyl group or the heterocycloalkyl group may be optionally substituted by one, two or three independent R 1e s;
  • R2 is selected from -C0 ⁇ 2 alkylene-(3 ⁇ 10 membered cycloalkyl), -C0 ⁇ 2 alkylene-(4 ⁇ 10 membered heterocycloalkyl), -C0 ⁇ 2 alkylene-(5 ⁇ 12 membered bridged cycloalkyl), -C0 ⁇ 2 alkylene-(5 ⁇ 12 membered bridged heterocycloalkyl), -C0 ⁇ 2 alkylene-(5 ⁇ 12 membered spirocycloalkyl), -C0 ⁇ 2 alkylene-(5 ⁇ 12 membered spiroheterocycloalkyl), -C0 ⁇ 2 alkylene-(5 ⁇ 12 membered aromatic ring), -C0 ⁇ 2 alkylene-(5 ⁇ 10 membered aromatic heterocycle), -C0 ⁇ 2 alkylene- OR21 , -C0 ⁇ 2 alkylene- NR21R22 , -C0 ⁇ 2 0 to 2
  • R 21 and R 22 are independently selected from hydrogen, deuterium, -C 1-6 alkyl, -C 1-6 alkyl substituted with deuterium, -C 1-6 alkyl substituted with halogen, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene-(4-10 membered heterocycloalkyl), -C 0-2 alkylene-(5-10 membered aromatic ring), -C 0-2 alkylene-(5-10 membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted with One, two or three independent R 2a substitutions;
  • R 2a connected to the same carbon atom together with the carbon atom to which they are connected form a 3- to 10-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group;
  • R 2b and R 2c are independently selected from hydrogen, deuterium, -C 1-6 alkyl, -C 1-6 alkyl substituted with deuterium, -C 1-6 alkyl substituted with halogen, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene-(4-10 membered heterocycloalkyl), -C 0-2 alkylene-(5-10 membered aromatic ring), -C 0-2 alkylene-(5-10 membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted by one, two or three independent R 2d ;
  • R 3 is selected from hydrogen, deuterium, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkyl substituted with deuterium, -C 1-6 alkyl substituted with halogen, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene-(4-10 membered heterocycloalkyl), -C 0-2 alkylene-(5-10 membered aromatic ring), -C 0-2 alkylene-(5-10 membered aromatic heterocycle), -C 0-2 alkylene-OR 31 , -C 0-2 alkylene-NR 31 R 32 ; wherein the alkylene, cycloalkyl, heterocycloalkyl , aromatic ring, aromatic heterocycle is optionally substituted by one, two or three independent R 3a ;
  • R 31 and R 32 are independently selected from hydrogen, deuterium, C 1-6 alkyl, deuterium-substituted -C 1-6 alkyl, halogen-substituted C 1-6 alkyl, -C 0-2 alkylene-(3-10 membered cycloalkyl), -C 0-2 alkylene-(4-10 membered heterocycloalkyl), -C 0-2 alkylene-(5-10 membered aromatic ring), -C 0-2 alkylene-(5-10 membered aromatic heterocycle);
  • L is selected from C 2-6 alkylene and C 2-6 alkenylene; wherein,
  • One or more methylene groups in the alkylene group and the alkenylene group may be optionally replaced by O, NR L1 , C(O), S(O) or S(O) 2 exchange; and/or
  • Alkylene and alkenylene are optionally substituted by one, two, three or four independent RLs ;
  • Each RL1 is selected from hydrogen, deuterium, -C1-6 alkyl, -C1-6 alkyl substituted with deuterium, C1-6 alkyl substituted with halogen, -C0-2 alkylene-OC1-6 alkyl , -C0-2 alkylene-CN, -C0-2 alkylene-C(O)( C1-6 alkyl), -C0-2 alkylene-O(3-10 membered cycloalkyl), -C0-2 alkylene-O(4-10 membered heterocycloalkyl), -C0-2 alkylene-(3-10 membered cycloalkyl), -C0-2 alkylene-(3-10 membered heterocycloalkyl), -C0-2 alkylene-(5-10 membered aromatic ring), -C0-2 alkylene-(5-10 membered aromatic heterocycle), -C0-4 alkylene-N( C1-6 alkyl)(C0-2 1-6 alkyl); wherein the alky
  • Two RLs connected to the same carbon atom together with the carbon atom to which they are connected form a 3- to 10-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group.
  • the compound represented by formula I is represented by formula II:
  • R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , Z, L, X 1 , X 2 , X 3 , X 4 and X 5 are as defined above.
  • the ring composed of X 1 , X 2 , X 3 , X 4 and X 5 is an aromatic heterocycle, and X 4 and X 5 are not N at the same time.
  • X1 is C
  • X2 is NRX
  • X3 is N
  • X4 is C
  • X5 is C
  • X1 is C
  • X2 is N
  • X3 is N
  • X4 is C
  • X5 is N
  • X1 is C
  • X2 is N
  • X3 is CR X
  • X4 is N
  • X5 is C
  • X1 is N
  • X2 is N
  • X3 is CR X
  • X4 is C
  • X5 is C
  • X1 is C
  • X2 is O
  • X3 is N
  • X4 is C
  • X5 is C.
  • R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , Z and L are as defined above.
  • R 4 , R 5 , and R 6 are independently selected from hydrogen, deuterium, halogen, cyano, -C 1-6 alkyl, deuterium-substituted -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-4 alkylene-OR 1b , -C 0-4 alkylene-SR 1b , -C 0-2 alkylene-C(O)R 1b , -C 0-2 alkylene -C(O)NR 1b R 1c , -C 0 ⁇ 4 alkylene-NR 1b R 1c , -C 0 ⁇ 2 alkylene-NR 1b C(O)R 1c , -C 0 ⁇ 4 alkylene-S(O) 2 R 1b , -C 0 ⁇ 4 alkylene-NHS(O) 2 R 1b , -C 0 ⁇ 4 alkylene-S(O)R 1b , -C
  • R 5 , R 6 and the carbon atom to which they are directly connected together form a 3- to 10-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group; wherein the cycloalkyl group or the heterocycloalkyl group is optionally substituted by one, two or three independent R 1e groups;
  • R 2 , R 3 , Y 1 , Y 2 , Y 3 , and L are as defined in claim 1.
  • R 4 is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 1-3 alkyl substituted with deuterium, -C 1-3 alkyl substituted with halogen;
  • R 5 and R 6 are independently selected from hydrogen, deuterium, halogen, -C 1-3 alkyl, -C 1-3 alkyl substituted with deuterium, -C 1-3 alkyl substituted with halogen, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 6-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle; wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle are optionally substituted with one, two or three independent R 1d ;
  • R 1d is independently selected from hydrogen, deuterium, -C 1-6 alkyl, deuterium-substituted -C 1-6 alkyl, halogen-substituted C 1-6 alkyl, halogen, and cyano;
  • R 5 , R 6 and the atoms directly connected thereto together form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one, two or three independent R 1e .
  • Y 1 , Y 2 , and Y 3 are independently selected from N or CR Y ;
  • Each RY is independently selected from hydrogen, deuterium, halogen, cyano, -C1-3 alkyl, 3-6 membered cycloalkyl, deuterium-substituted -C1-3 alkyl, halogen-substituted -C1-3 alkyl, -C0-2 alkylene- OC1-3 alkyl, -C0-2 alkylene-O(halogen-substituted C1-3 alkyl).
  • Y 1 , Y 2 , and Y 3 are independently selected from N or CR Y ;
  • Each RY is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy.
  • Y 1 and Y 3 are independently selected from N, CH or CF; Y 2 is selected from N or CR Y ;
  • Each RY is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy.
  • Z is selected from C(O) or S(O) 2 .
  • R3 is selected from methyl, deuterated methyl, ethyl, perdeuterated ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxymethyl, methoxymethyl, deuterated methoxymethyl, amino, methylamino, dimethylamino, deuterated methylamino.
  • R 1 is selected from a benzene ring, a 5-membered aromatic heterocycle, and a 6-membered aromatic heterocycle; wherein the benzene ring and the aromatic heterocycle are optionally substituted by one, two or three independent R 1a .
  • R 1 is selected from -methylene-benzene ring, -methylene-5-membered aromatic heterocycle, -methylene-6-membered aromatic heterocycle, -methylene-9-membered aromatic heterocycle; wherein the methylene group, benzene ring, aromatic heterocycle are optionally substituted by one, two or three independent R 1a .
  • R 1 is selected from -difluoromethylene-benzene ring, -difluoromethylene-5-membered aromatic heterocycle, -difluoromethylene-6-membered aromatic heterocycle, -difluoromethylene-9-membered aromatic heterocycle; wherein the benzene ring and the aromatic heterocycle are optionally substituted by one R 1a .
  • R 1 is selected from 8-membered fused heterocycloalkyl, 9-membered fused heterocycloalkyl, 10-membered fused heterocycloalkyl, 9-membered fused aromatic heterocycle, 10-membered fused aromatic heterocycle; wherein the fused heterocycloalkyl and fused aromatic heterocycle are optionally substituted by one, two or three independent R 1a .
  • R 1 is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one, two or three independent R 1a .
  • R 1 is selected from -methylene-3-membered cycloalkyl, -methylene-4-membered cycloalkyl, -methylene-5-membered cycloalkyl, -methylene-6-membered cycloalkyl, -methylene-4-membered heterocycloalkyl, -methylene-5-membered heterocycloalkyl, -methylene-6-membered heterocycloalkyl, -methylene-9-membered heterocycloalkyl; wherein the methylene, cycloalkyl, and heterocycloalkyl are optionally substituted by one, two, or three independent R 1a .
  • R1 is selected from -difluoromethylene-3-membered cycloalkyl, -difluoromethylene-4-membered Cycloalkyl, -difluoromethylene-5-membered cycloalkyl, -difluoromethylene-6-membered cycloalkyl, -difluoromethylene-4-membered heterocycloalkyl, -difluoromethylene-5-membered heterocycloalkyl, -difluoromethylene-6-membered heterocycloalkyl, -difluoromethylene-9-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one R 1a .
  • R 11 and R 12 are independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, deuterium substituted methyl, deuterium substituted ethyl, deuterium substituted n-propyl, deuterium substituted isopropyl, halogen substituted methyl, halogen substituted ethyl, halogen substituted n-propyl, halogen substituted isopropyl.
  • R 11 and R 12 are independently selected from -C 0 ⁇ 2 alkylene-(3-membered cycloalkyl), -C 0 ⁇ 2 alkylene-(4-membered cycloalkyl), -C 0 ⁇ 2 alkylene-(5-membered cycloalkyl), -C 0 ⁇ 2 alkylene-(6-membered cycloalkyl), -C 0 ⁇ 2 alkylene-(4-membered heterocycloalkyl), -C 0 ⁇ 2 alkylene-(5-membered heterocycloalkyl), -C 0 ⁇ 2 alkylene-(6-membered heterocycloalkyl); wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted by one, two or three independent R 1a .
  • each R 1a is independently selected from -C 0 ⁇ 2 alkylene-(3-membered cycloalkyl), -C 0 ⁇ 2 alkylene-(4-membered cycloalkyl), -C 0 ⁇ 2 alkylene-(5-membered cycloalkyl), -C 0 ⁇ 2 alkylene-(6-membered cycloalkyl), -C 0 ⁇ 2 alkylene-(4-membered heterocycloalkyl), -C 0 ⁇ 2 alkylene-(5-membered heterocycloalkyl), -C 0 ⁇ 3 alkylene-(6-membered heterocycloalkyl), -(6-membered aromatic ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring are optionally substituted by one, two or three independent R 1d ;
  • each R 1a is independently selected from -C 0 ⁇ 4 alkylene-OR 1b , -C 0 ⁇ 4 alkylene-SR 1b , -C 0 ⁇ 4 alkylene-S(O) 2 R 1b , -C 0 ⁇ 4 alkylene-S(O)R 1b , -NHS(O) 2 R 1b , -C 0 ⁇ 3 alkylene-NR 1b R 1c ; wherein the alkylene group is optionally substituted by one, two or three independent R 1d ;
  • two R 1a s connected to the same carbon atom together form a 3-membered cycloalkyl group, a 4-membered cycloalkyl group, a 5-membered cycloalkyl group, a 6-membered cycloalkyl group, a 5-membered heterocycloalkyl group, or a 6-membered heterocycloalkyl group; wherein the cycloalkyl group or the heterocycloalkyl group may be optionally substituted by one, two or three independent R 1e groups;
  • R 1e are each independently selected from hydrogen, deuterium, -C 1-3 alkyl, deuterium-substituted -C 1-3 alkyl, halogen-substituted -C 1-3 alkyl, and halogen.
  • the R 1 is selected from
  • R 2 is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl; wherein the cycloalkyl is optionally substituted with one, two, three or four independent R 2a .
  • R2 is selected from -C1 alkylene-(3-membered cycloalkyl), -C1 alkylene-(4-membered cycloalkyl), -C1 alkylene-(5-membered cycloalkyl), -C1 alkylene-(6-membered cycloalkyl), -C1 alkylene-(7-membered cycloalkyl), -C1 alkylene-(8-membered cycloalkyl), -C1 alkylene-(phenyl ring), -C1 alkylene- (aromatic heterocycle); wherein the alkylene, cycloalkyl, benzene ring, and aromatic heterocycle are optionally substituted by one, two, three, or four independent R2a .
  • R 2 is selected from Wherein ring V is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, and 4-membered heterocycloalkyl; wherein the cycloalkyl is optionally substituted by one, two or three independent R 2a ; R 2a' is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, and 4-membered heterocycloalkyl; wherein the cycloalkyl is optionally substituted by one, two or three independent R 2d .
  • R 2 is selected from 6-membered fused cycloalkyl, 9-membered fused cycloalkyl, 10-membered fused cycloalkyl, 11-membered fused cycloalkyl, 9-membered fused heterocycloalkyl, 10-membered fused heterocycloalkyl, 12-membered fused heterocycloalkyl, 8-membered spirocycloalkyl; wherein the fused cycloalkyl, fused heterocycloalkyl, spirocycloalkyl are optionally substituted by one, two, three or four independent R 2a .
  • R2 is selected from 5-membered bridged cycloalkyl, 6-membered bridged cycloalkyl, 7-membered bridged cycloalkyl, 8-membered bridged cycloalkyl, 9-membered bridged cycloalkyl, 10-membered bridged cycloalkyl, -C1 alkylene-(5-membered bridged cycloalkyl), -C1 alkylene-(6-membered bridged cycloalkyl), -C1 alkylene-(7-membered bridged cycloalkyl), -C1 alkylene-(8-membered bridged cycloalkyl), -C1 alkylene-(9-membered bridged cycloalkyl), -C1 alkylene-(10-membered bridged cycloalkyl).
  • R 21 and R 22 are independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, butyl, deuterium substituted methyl, deuterium substituted ethyl, deuterium substituted n-propyl, deuterium substituted isopropyl, halogen substituted methyl, halogen substituted ethyl, halogen substituted n-propyl, halogen substituted isopropyl, halogen substituted butyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, -C 1 alkylene-(3-membered cycloalkyl), -C 1 alkylene-(4-membered cycloalkyl), -C 1 alkylene-(5-membered
  • each R 2a is independently selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, -C 1 alkylene-(3-membered cycloalkyl), -C 1 alkylene-(4-membered cycloalkyl), -C 1 alkylene-(5-membered cycloalkyl), -C 1 alkylene-(6-membered cycloalkyl), -C 1 alkylene-(7-membered cycloalkyl); wherein alkylene, cycloalkyl, heterocycloalkyl is optionally substituted by one, two or three independent R 2d ;
  • R 2a connected to the same carbon atom together with the carbon atom to which they are connected form a 3- to 10-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group;
  • R 2b and R 2c are independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, deuterium-substituted methyl, deuterium-substituted ethyl, deuterium-substituted n-propyl, deuterium-substituted isopropyl, halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, halogen-substituted isopropyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, -C 1 alkylene-(3-membered cycloalkyl), -C 1 alkylene-(4-membered
  • said R 2 is selected from
  • L is selected from C3 alkylene, C4 alkylene, C5 alkylene, C6 alkylene, C3 alkenylene, C4 alkenylene, C5 alkenylene, C6 alkenylene; wherein,
  • One, two or three methylene groups in the alkylene or alkenylene groups may be optionally replaced by O, NR L1 , C(O), S(O) or S(O) 2 ; and/or
  • alkylene and alkenylene groups are optionally substituted with one, two, three or four independent RL groups.
  • Each RL1 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, methyl substituted by halogen, ethyl substituted by halogen, n-propyl substituted by halogen, isopropyl substituted by halogen, -C0 ⁇ 2 alkylene-CN, -C0 ⁇ 2 alkylene-C(O)(C1 ⁇ 6 alkyl), -C0 ⁇ 2 alkylene-(3-membered cycloalkyl), -C0 ⁇ 2 alkylene-(4-membered cycloalkyl), -C0 ⁇ 2 alkylene-(6-membered cycloalkyl), -C0 ⁇ 2 alkylene-(6-membered heterocycloalkyl), -C0 ⁇ 2 alkylene-(6-membered aromatic ring), -C0 ⁇ 2 alkylene-OC1 ⁇ 6 alkyl,
  • Two RLs connected to the same carbon atom together with the carbon atom to which they are connected form a 3-membered cycloalkyl group, a 4-membered cycloalkyl group, a 5-membered cycloalkyl group, or a 6-membered cycloalkyl group.
  • L is selected from
  • the aa end is connected to X 4.
  • the compound is specifically:
  • the present invention also provides the use of any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof in the preparation of drugs for treating IL-17-mediated diseases.
  • the IL-17-mediated disease is one or more of diseases associated with inflammation, autoimmune diseases, infectious diseases, cancer, and precancerous syndrome.
  • the present invention also provides a pharmaceutical composition, which is a preparation prepared by adding any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, to pharmaceutically acceptable excipients.
  • the present invention also provides any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, for use in treating diseases or conditions of psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, suppurative hidradenitis, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma and/or COPD.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention also provides the use of the aforementioned compound, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite in the preparation of a drug for treating IL-17-mediated diseases.
  • the present invention also provides a method for treating psoriasis, comprising administering an effective amount of any one of the above compounds or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • the present invention also provides any one of the above compounds or a pharmaceutically acceptable salt thereof for use in therapy.
  • the present invention also provides a method for treating or preventing inflammation, cancer or autoimmune diseases in a patient, comprising administering a therapeutically effective amount of any of the above compounds to a patient in need thereof.
  • the present invention also provides any of the above compounds or pharmaceutically acceptable salts thereof for use in treating psoriasis.
  • the present invention also provides use of any of the above compounds or pharmaceutically acceptable salts thereof in preparing a medicament for treating psoriasis.
  • the IL-17-mediated diseases defined in the present invention are diseases in which IL-17 plays an important role in the pathogenesis of the disease.
  • the main function of IL-17 is to coordinate local tissue inflammation, thereby playing a role in various diseases.
  • IL-17-mediated diseases include inflammation One or more of the following diseases: autoimmune diseases, infectious diseases, cancer, and precancerous syndrome-related diseases.
  • Cancer refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other parts of the body (i.e., metastasis), and any of a number of characteristic structural and/or molecular features.
  • Cancer cells refer to cells in the early, middle, or late stages of multi-step tumor progression. Cancers include sarcomas, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer, and prostate cancer.
  • the compound of Formula I is used to treat a cancer selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma.
  • cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer.
  • the cancer treated is a metastatic cancer.
  • autoimmune diseases are caused by the body's immune response to substances and tissues that are normally present in the body.
  • autoimmune diseases include myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type 1 diabetes, Grave's disease, celiac disease, Crohn's disease, autoimmune neutropenia, juvenile arthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barré syndrome, multiple sclerosis, and autoimmune retinopathy.
  • Some embodiments of the invention relate to treating autoimmune diseases such as psoriasis or multiple sclerosis.
  • Inflammatory diseases include a variety of conditions characterized by histopathological inflammation.
  • inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, airway inflammation caused by house dust mites, and interstitial cystitis.
  • inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, airway inflammation caused by house dust mites, and interstitial cystitis.
  • inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rhe
  • substitution means that the hydrogen atom in a molecule is replaced by another different atom or group; or the lone pair of electrons in an atom in a molecule is replaced by another atom or group.
  • the lone pair of electrons on the S atom can be replaced by an O atom to form
  • C a-b alkyl indicates any alkyl group containing from “a” to "b” carbon atoms.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms.
  • Alkyl refers to a saturated hydrocarbon chain with a specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. Alkyl groups can also be part of other groups, such as -O(C 1-6 alkyl).
  • Alkylene refers to a divalent saturated aliphatic hydrocarbon radical having a specified number of member atoms.
  • C a-b alkylene refers to an alkylene group having from a to b carbon atoms.
  • Alkylene groups include branched and straight chain hydrocarbon groups.
  • the term “propylene” can be exemplified by the following structure:
  • the term “dimethylbutylene” can be exemplified, for example, by any of the following structures:
  • -C0 ⁇ 2 alkylene can be C0 alkylene, C1 alkylene (e.g., -CH2- ), C2 alkylene (e.g. , -CH2CH2- , etc.);
  • C0 alkylene means that the group here does not exist and is connected in the form of a chemical bond, such as A0 alkylene-B means AB, that is, the A group and the B group are directly connected by a chemical bond.
  • Cycloalkyl and “cycloalkane” as described in the present invention refer to saturated or partially saturated cyclic groups having carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including condensed, bridged).
  • the terms “cycloalkyl” and “cycloalkane” include cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl.
  • cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, etc.
  • Two such bicycloalkyl polycyclic structures are exemplified and named below: Biscyclohexyl and
  • the term "cycloalkyl” or “cycloalkane” also includes a partially saturated cyclic group formed by condensing an aromatic ring with a non-aromatic ring, and the attachment point can be located at a non-aromatic carbon atom or an aromatic carbon atom, examples of which include 1,2,3,4-tetrahydronaphthalene-5-yl and 5,6,7,8-tetrahydronaphthalene-5-yl.
  • the unsaturated mentioned in the present invention refers to the presence of carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc. in the group or molecule; the unsaturated carbocyclic group of the present invention may or may not include aromatic ring groups, and the unsaturated heterocyclic group may or may not include heteroaryl groups, which can be freely selected by those skilled in the art.
  • C ab alkenyl refers to an alkenyl group having a to b carbon atoms and is meant to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.
  • Alkynyl refers to a straight chain monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond.
  • alkynyl is also intended to include those hydrocarbon groups having one triple bond and one double bond.
  • C2-6 alkynyl is intended to include ethynyl, propynyl, etc.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Halogen alkyl and halogen-substituted alkyl refer to alkyl groups in which hydrogen atoms may be substituted by one or more halogen atoms.
  • halogen-substituted C 1-4 alkyl refers to alkyl groups containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms; other examples include monofluoromethyl, difluoromethyl, and trifluoromethyl.
  • Heterocycloalkyl refers to a saturated or non-aromatic partially saturated ring having a single ring or multiple rings (fused, bridged) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It usually refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with multiple ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon.
  • Bicyclic means composed of two rings with two ring atoms in common, that is, the bridge separating the two rings is a single bond or a chain of one or two ring atoms.
  • monocyclic saturated heterocycloalkyl are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,1-dioxo-thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazazepanyl.
  • bicyclic saturated heterocycloalkyls are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl.
  • partially unsaturated heterocycloalkyls are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.
  • heterocycloalkyl also includes partially saturated cyclic groups formed by fusion of an aromatic ring containing at least one heteroatom with a non-aromatic ring, and the site of attachment can be located at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom, examples include
  • Aromatic ring group refers to an aromatic hydrocarbon group having multiple carbon atoms.
  • Aryl groups are typically monocyclic, bicyclic or tricyclic aromatic groups having multiple carbon atoms.
  • aryl refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
  • aromatic heterocyclic group and “aromatic heterocycle” described in the present invention refer to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It is usually an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, wherein one or more ring atoms are selected from O, N, and S heteroatoms. Preferably there are one to three heteroatoms.
  • Heterocyclic aromatic groups for example, represent: pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzothiophenyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl 1-Hydroxy, ...
  • Steps include enantiomers and diastereomers
  • the oxygen atom in "-C(O)R", “-S(O) 2 R” and the like described in the present invention is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the carbon atom or sulfur atom by a single bond.
  • the "deuterated compound” of the present invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.
  • pharmaceutically acceptable means that a carrier, vehicle, diluent, excipient, and/or formed salt is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form and physiologically compatible with the receptor.
  • salts and “pharmaceutically acceptable salt” refer to acidic and/or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compound. It can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent).
  • the salt described in the present invention can be a sodium salt, potassium salt, hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
  • one or more compounds of the present invention may be used in combination with each other. It is also possible to select the compounds of the present invention and any other active agent for use in combination to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately or sequentially.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR measurements were performed using (Bruker AvanceIII 400MHz and Bruker Avance NEO 600 MHz) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • LC-MS determination uses Shimadzu LC-MS2020 (ESI) instrument.
  • HPLC determination uses Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).
  • MPLC medium pressure preparative chromatography
  • Gilson GX-281 reverse phase preparative chromatograph Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, and the specifications used for thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200 ⁇ 300 mesh silica gel as the carrier.
  • Supercritical fluid chromatography (SFC) analysis and preparation use SHIMADZU SFC-30A instrument.
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.
  • the reaction is carried out under a nitrogen atmosphere.
  • the solution refers to an aqueous solution.
  • the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, which is 20°C to 30°C. Unless otherwise specified in the examples, M is moles per liter.
  • intermediate B-2-1 To a solution of intermediate B-2-1 (5g, 18.24mmol) in methanol/glacial acetic acid/water (72mL/3mL/18mL), add reduced iron powder (5.09g, 91.22mmol) in batches under stirring. After the addition is complete, heat to reflux and stir to react for 3 hours. After monitoring the reaction, filter with hot diatomaceous earth and wash the filter cake with ethyl acetate.
  • intermediate B-1 methyl 4-amino-2-bromo-4-chlorobenzoate was used instead of intermediate B-1-1.
  • the other reagents and operations were the same to obtain intermediate B-4.
  • MS (ESI) m/z 312 [M+1] + .
  • reaction solution was cooled to room temperature, quenched with 30% NH 4 Cl aqueous solution, extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product, which was separated and purified by vacuum distillation to obtain a clear oily intermediate C-1-1 (279g, 74.2% yield).
  • oxalyl chloride (COCl) 2 (1365.2 g 10.75 mol) was added dropwise to a mixed solution of intermediate C-2-2 (1505 g 7.16 mol) in DCM (10 L) / DMF (50 mL). The mixture was stirred at zero degrees for 3 hours, then cooled to -10°C, AlCl 3 (1904.56 g, 14.32 mol) was added in batches, and the reaction solution was slowly heated to room temperature and stirred for another hour.
  • reaction solution was slowly poured into ice water, the organic phase was separated, the aqueous phase was extracted 3 times with DCM, the organic phases were combined, washed 3 times with water, washed with saturated sodium bicarbonate solution until weakly alkaline, washed 2 times with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude intermediate C-2-3 (1200 g, 6.25 mol, 85.3% yield), which was directly used in the next reaction without purification.
  • intermediate D-48-1 (5.7 g, 19.55 mmol) and DMF (50 mL) to a single-mouth bottle, then add sodium azide (1.29 g, 19.80 mmol). After the addition is complete, heat to 90 ° C and stir to react for 12 hours. After the reaction is completed, cool, add sodium bicarbonate aqueous solution to quench the reaction, and extract with ethyl acetate. The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain intermediate D-48-2 (2.95 g, 16.65 mmol, 84.07% yield).
  • intermediate D-48-4 is used in place of intermediate D-47-2 in step 2.
  • MS (ESI) m/z 222 [M+1] + .
  • intermediate D-48-5 is used in place of intermediate D-1-1 in step 2.
  • MS (ESI) m/z 208 [M+1] + .
  • step 4 methylamine hydrochloride is replaced by the corresponding amine in the table below, and the remaining reagents and operations are the same to obtain the corresponding intermediate.
  • intermediate E-16 Referring to the synthesis method of intermediate E-16, the corresponding macrocyclic amide in the table below is used to replace intermediate E-1. The remaining reagents and operations are the same to obtain the corresponding intermediate.
  • intermediate E-29-2 is used to replace intermediate A-3 in step 7, and intermediate B-3 is used to replace intermediate E-1-5.
  • MS (ESI) m/z 405 [M+1] + .
  • step 4 the corresponding amine in the table below is used instead of cyclopropylamine, and the remaining reagents and operations are the same to obtain the corresponding intermediate.
  • intermediate E-16 Referring to the synthesis method of intermediate E-16, the corresponding pyridine macrocyclic amide in the table below is used to replace intermediate E-1. The remaining reagents and operations are the same to obtain the corresponding intermediate.
  • intermediate E-45 was used to replace intermediate E-37.
  • the remaining reagents and operations were the same to obtain intermediate E-46-2.
  • MS (ESI) m/z 477 [M+1] + .
  • intermediate C-4 was used in place of intermediate C-1 in step 5
  • 1-ethylpyrazole-5-carboxylic acid was used in place of 1-isopropylpyrazole-5-carboxylic acid in step 7.
  • the remaining reagents and operations were the same.
  • intermediate 12-2 was used instead of intermediate 1-1, and the other reagents and operations were the same to obtain intermediate 12-5.
  • MS (ESI) m/z 361 [M+1] + .
  • intermediate 13-1 (741 mg, 2.12 mmol), intermediate B-2 (1.60 g, 4.24 mmol) and Cs 2 CO 3 (1.38 g, 4.24 mmol) of 1,4-dioxane (20 mL)/water (4 mL) mixed solvent, add Pd(dppf)Cl 2 (77.61 mg, 106.07 ⁇ mol), after addition, evacuate and replace with nitrogen three times, stir and react at 80°C for 12 hours, cool after reaction, add water and ethyl acetate for extraction, wash the organic layer with brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure.
  • the crude product is purified by silica gel column chromatography to obtain intermediate 13-2 (332 mg, 638.68 ⁇ mol, 30.11% yield).
  • MS (ESI) m/z 520 [M + 1] + .
  • Methylamine hydrochloride (30 g, 217.38 mmol) was added to a solution of 2-bromo-5-nitrobenzaldehyde (25 g, 108.69 mmol) in methanol (500 mL). After the addition, the mixture was stirred at room temperature for 1 hour, cooled to 0°C in an ice-water bath, and sodium borohydride (8.22 g, 217.38 mmol) was added in batches.
  • LiAlH 4 (62.63 mg, 1.65 mmol, 1M THF solution) was added dropwise to the intermediate 22-6 (638 mg, 825.22 ⁇ mol) in dry THF (20 mL) at -78°C. After the addition, the temperature was raised to room temperature for reaction for 1 hour. After the reaction, ice water (0.08 mL), 15% NaOH aqueous solution (0.08 mL) and water (0.24 mL) were added in sequence at -10°C to quench the reaction and stirred for 10 minutes.
  • step 4 the corresponding pyrazole carboxylic acid in the table below is used instead of 1-isopropylpyrazole-5-carboxylic acid, and the remaining reagents and operations are the same to obtain the corresponding structural example compounds in the table.
  • intermediate B-4 was used in place of intermediate B-1 in step 1, and the remaining reagents and operations were the same to obtain intermediate 29-4.
  • MS (ESI) m/z 394 [M+1] + .
  • Triethylamine (9.57 mg, 94.57 ⁇ mol, 13.19 ⁇ L) was added to a solution of cyclopropanol (6.59 mg, 113.48 ⁇ mol) and N,N'-disuccinimidyl carbonate (29.07 mg, 113.48 ⁇ mol) in acetonitrile (1 mL) at room temperature. After addition, the mixture was stirred at room temperature for 2 hours. Then, a solution of intermediate 15-6 (50 mg, 94.57 ⁇ mol) in DMF (0.5 mL) was added. After addition, the mixture was stirred at room temperature overnight.
  • step 1 intermediate 15-4 was used instead of intermediate 1-4, and the other reagents and operations were the same.
  • intermediate 15-4 was used in place of intermediate 1-4 in step 1
  • 1-isopropylpyrazole-5-carboxylic acid was used in place of 1-ethylpyrazole-5-carboxylic acid in step 3.
  • the remaining reagents and operations were the same.
  • step 1 intermediate D-1 was used instead of 3-ethylisoxazole-4-carboxylic acid, and the other reagents and operations were the same.
  • MS (ESI) m/z 571[M+1] + .
  • Example 40a Preparation of Example 40a, Example 40b to Example 39a, Example 39b
  • Example 39b Referring to the synthetic routes of Example 39a and Example 39b, the intermediate pyrazolecarboxylic acid shown in the following table is used instead of the intermediate D-1 in step 1, and the remaining reagents and operations are the same to obtain the corresponding example compounds.
  • Example 39a Referring to Example 39a and the synthetic route of Example 39a, intermediate D-51 was used instead of intermediate D-1 in step 1, and the other reagents and operations were the same.
  • MS (ESI) m/z 597[M+1] + .
  • intermediate C-5 was used instead of intermediate C-1 in step 5, and the other reagents and operations were the same.
  • step 5 the intermediate C-1 is replaced by the corresponding intermediate carboxylic acid in the table below, and in step 7, 1-isopropylpyrazole-5-carboxylic acid is replaced by the corresponding pyrazole carboxylic acid in the table below or the same, and the remaining reagents and operations are the same to obtain the corresponding example compounds.
  • step 7 1-isopropylpyrazole-5-carboxylic acid is replaced by the corresponding pyrazole carboxylic acid in the table below, and the remaining reagents and operations are the same to obtain the corresponding example compounds.
  • step 8 1-isopropylpyrazole-5-carboxylic acid is replaced by the corresponding pyrazole carboxylic acid in the following table, and the remaining reagents and operations are the same to obtain the corresponding example compounds.
  • step 7 1-isopropylpyrazole-5-carboxylic acid is replaced by the corresponding pyrazole carboxylic acid in the table below, and the remaining reagents and operations are the same to obtain the corresponding example compounds.
  • step 2 the corresponding pyrazole carboxylic acid in the table below is used to replace the intermediate D-46, and the remaining reagents and operations are the same to obtain the corresponding example compound.
  • Methylmagnesium bromide (110.10 mmol, 37 mL) was added dropwise to a solution of intermediate A-2 (10 g, 27.52 mmol) in dry THF (100 mL) in an ice-water bath at 0°C under nitrogen protection. After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was completed, the reaction solution was poured into an iced aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • intermediate 116-1 (3.8 g, 10.46 mmol), intermediate B-3 (3.39 g, 11.50 mmol), Pd 2 (dba) 3 (478.82 mg, 522.89 ⁇ mol), Rac-BI-DIME (345.48 mg, 1.05 mmol) and 1,4-dioxane/water (38 mL/7.6 mL) were added, and CS 2 CO 3 (10.96 g, 20.92 mmol) was added under stirring, and the mixture was evacuated and replaced with nitrogen three times. The mixture was heated to 100°C and stirred for 12 hours.
  • Methylmagnesium bromide (76.46mmol, 26mL) was added dropwise to a solution of intermediate 118-2 (15g, 38.23mmol) in dry THF (150mL) in an ice-water bath at 0°C under nitrogen protection. After the addition was completed, the mixture was heated to room temperature and stirred for 2 hours. After the reaction was completed, the reaction solution was poured into an iced aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • intermediate 118-4 was used instead of intermediate 116-1, and the other reagents and operations were the same.
  • Example 118 ethylpyrazole-5-carboxylic acid was used instead of isopropylpyrazole-5-carboxylic acid in step 11, and the other reagents and operations were the same.
  • step 1 intermediate D-8 was used instead of 3-ethylisoxazole-4-carboxylic acid, and the other reagents and operations were the same.
  • MS (ESI) m/z 549[M+1] + .
  • intermediate 129-6 (1.32 g, 3.49 mmol), intermediate 129-2 (1.27 g, 3.84 mmol), dioxane and water (10 mL/2 mL) were added, and Pd 2 (dba) 3 (79.86 mg, 87.21 ⁇ mol), rac-BI-DIME (57.56 mg, 174.42 ⁇ mol) and potassium phosphate (1.48 g, 6.98 mmol) were added at room temperature. The vacuum was replaced with nitrogen three times, and the temperature was gradually raised to 100 ° C. and stirred to react overnight. After the reaction was completed, water was added to quench the reaction, and ethyl acetate was used for extraction.
  • intermediate 129-9 was used in place of intermediate 1-4 in step 5, and BOC-L-2-amino-3,3-dicyclopropylpropionic acid was used in place of intermediate C-1.
  • the palladium carbon debenzyloxycarbonyl was replaced by 4M HCl ethyl acetate solution to remove Boc.
  • the de-Boc method was based on the synthetic method of intermediate 129-9.
  • the remaining two synthetic methods were based on the synthetic route of Example 1. The remaining reagents and operations were the same, and Example 129 was obtained.
  • MS (ESI) m/z 531 [M + 1] + .
  • intermediate 131-2 (7.7 g, 18.63 mmol) and 33% methylamine methanol solution (60 mL) into a sealed tube, heat to 60°C and stir to react for 2.5 hours. After the reaction, cool in an ice-water bath and concentrate to dryness under reduced pressure to obtain intermediate 131-3 (6.29 g, 18.06 mmol, 96.94% yield), which is used directly in the next step without purification.
  • MS (ESI) m/z 348 [M+1] + .
  • step 5 intermediate 1-4 is replaced by the corresponding macrocyclic amine intermediate in the table below, and in step 7, 1-isopropylpyrazole-5-carboxylic acid is the same or the corresponding pyrazolecarboxylic acid in the table below is used to replace 1-isopropylpyrazole-5-carboxylic acid, and the remaining reagents and operations are the same to obtain the corresponding structural example compounds in the table.
  • step 1 the corresponding macrocyclic amine intermediate in the table below is used to replace the intermediate E-31, and the remaining reagents and operations are the same to obtain the corresponding structural example compounds in the table.
  • step 8 intermediate D-40 was used instead of 1-isopropylpyrazole-5-carboxylic acid, and the other reagents and operations were the same.
  • Example 190a Preparation of Example 190a and Example 190b
  • step 8 intermediate D-1 was used instead of 1-isopropylpyrazole-5-carboxylic acid, and the other reagents and operations were the same.
  • step 6 the corresponding macrocyclic amine intermediate in the table below is used instead of intermediate 12-5, and the remaining reagents and operations are the same to obtain the corresponding structural example compounds in the table.
  • step 6 the corresponding macrocyclic amine intermediate in the table below is used instead of intermediate 12-5, and in step 8, the corresponding carboxylic acid in the table below is used instead of 1-isopropylpyrazole-5-carboxylic acid.
  • step 8 the corresponding macrocyclic amine intermediate in the table below is used instead of intermediate 12-5, and in step 8, the corresponding carboxylic acid in the table below is used instead of 1-isopropylpyrazole-5-carboxylic acid.
  • the remaining reagents and operations are the same to obtain the corresponding structural example compounds in the table.
  • step 8 1-isopropylpyrazole-5-carboxylic acid is replaced by the corresponding carboxylic acid in the table below, and the remaining reagents and operations are the same to obtain the corresponding structural example compounds in the table.
  • step 6 the corresponding macrocyclic amine intermediate in the table below is used instead of intermediate 12-5, and in step 8, the corresponding carboxylic acid in the table below is used instead of 1-isopropylpyrazole-5-carboxylic acid.
  • step 8 the corresponding macrocyclic amine intermediate in the table below is used instead of intermediate 12-5, and in step 8, the corresponding carboxylic acid in the table below is used instead of 1-isopropylpyrazole-5-carboxylic acid.
  • the remaining reagents and operations are the same to obtain the corresponding structural example compounds in the table.
  • Test Example 1 IL-17A enzyme-linked immunosorbent assay (ELISA) experiment
  • IL-17A enzyme-linked immunosorbent assay (ELISA) experiment are as follows: (1) Coating of human IL17A (Sino Biological lnc.Cat#12047-H07B): dilute human IL-17A into coating solution (50mM PBS, pH7.4) to obtain 0.2 ⁇ g/ml IL17A, and incubate in a 96-well plate at 37 degrees for 30 minutes with 100 ⁇ l per well. Note that the blank group is replaced with 100 ⁇ l of coating solution. (2) Elution: Wash the plate 4 times with 10mM PBST (PBS, pH 7.4, 0.05% Tween-20), 200 ⁇ l per well each time, and pat dry on absorbent paper after the last wash.
  • PBST PBS, pH 7.4, 0.05% Tween-20
  • Blocking Prepare fresh 5% (w/v) skim milk solution before the experiment. Prepare the corresponding volume according to the experimental needs. For example, dissolve 5 grams of skim milk (Bio-Rad, 170-6404) in 100 mL of 10mM PBST. Add 200 ⁇ l of 5% (w/v) skim milk solution to each well and incubate on a shaker at 25 degrees for 30 minutes.
  • Preparation of 100X test compound Prepare the test compound solution during the blocking period. Dissolve the powdered compound in DMSO to a storage concentration of 10mM. Use DMSO to dilute the compound 4 times to 9 concentrations, ranging from 0.61 ⁇ M to 4000 ⁇ M. (5) Elution: Repeat step (2).
  • IL17A Pre-incubation of IL17A with compounds: Add 89 ⁇ l PBST and 1 ⁇ l 100X concentration of the test compound to the well, mix well and pre-incubate at 25 degrees for 10 minutes. Note: 1 ⁇ l DMSO was added to the blank group and the control group instead of the compound.
  • Incubation of human IL17Ra Add 10 ⁇ l 16nM human IL-17R (Sino Biological lnc., Cat#10895-H03H) and incubate on a shaker at 25 degrees for 30 minutes. The buffer is 10 mM PBST. (8) Elution, repeat step (2).
  • HRP antibody incubation Add 100 ⁇ l mouse anti-Fc tag HRP-conjugated antibody (Sino Biological lnc., Cat#10702-MM01T-H) and incubate on a shaker at 25 degrees for 30 minutes. Mouse anti-Fc tag HRP-conjugated antibody and 5% (w/v) skim milk solution are prepared at a volume ratio of 1:5000. (10) Elution, repeat step (2). (11) Add 100 ⁇ l TMB Incubate the substrate (BD, Cat#555214, substrate A and substrate B are freshly prepared in a volume ratio of 1:1) solution at 25 degrees in the dark for 5 to 15 minutes. When the room temperature is low, the incubation time needs to be appropriately extended.
  • Termination Add 2.5M HCl to terminate the color reaction, and use a microplate reader BMG PHERStar to detect the light absorption value at a wavelength of 450nm.
  • IC50 calculation Calculate the relative percentage of residual activity of each concentration of the compound according to equation 1, and calculate the IC50 of the test compound according to equation 2 of log (inhibitor) vs. normalized response--Variable slope in Graphpad6.
  • the compounds prepared in the examples were tested for IL-17A inhibitory activity according to the above method.
  • the test results are shown in Table 1, wherein the IC 50 of each compound was determined and classified as follows.
  • Test Example 2 IL17AF enzyme-linked immunosorbent assay (ELISA) experiment
  • IL17AF enzyme-linked immunosorbent assay (ELISA) experiment are as follows: (1) Coating of human IL17AF (Sino Biological lnc.Cat#CT047-H08H): dilute human IL17AF into coating solution (50mM PBS, pH7.4) to obtain 0.625 ⁇ g/ml IL17AF, and incubate in a 96-well plate at 37 degrees for 30 minutes with 100 ⁇ l per well. Note that the blank group is replaced with 100 ⁇ l of coating solution. (2) Elution: Wash the plate 4 times with 10mM PBST (PBS, pH 7.4, 0.05% Tween-20), 200 ⁇ l per well each time, and pat dry on absorbent paper after the last wash.
  • PBST PBS, pH 7.4, 0.05% Tween-20
  • Blocking Prepare fresh 5% (w/v) skim milk solution before the experiment. Prepare the corresponding volume according to the experimental needs. For example, dissolve 5 g skim milk (Bio-Rad, 170-6404) in water. Dissolve in 100mL of 10mM PBST, add 200 ⁇ l of 5% (w/v) skim milk to each well and incubate on a shaker at 25 degrees for 30 minutes.
  • Preparation of 100X test compound Prepare the test compound solution during the blocking period, dissolve the powdered compound in DMSO to a storage concentration of 10mM, and use DMSO to dilute the compound 4-fold to 9 concentrations, from 0.61 ⁇ M to 4000 ⁇ M. (5) Elution, repeat step (2).
  • Pre-incubation of IL17AF with compound Add 89 ⁇ l PBST and 1 ⁇ l of 100X concentration of test compound to the well, mix well, and pre-incubate at 25 degrees for 10 minutes. Note: 1 ⁇ l DMSO is added to the blank group and the control group instead of the compound.
  • Human IL17Ra incubation Add 10 ⁇ l 100 nM human IL-17R (Sino Biological lnc., Cat#10895-H03H) and incubate on a shaker at 25 degrees for 30 minutes. The buffer is 10 mM PBST.
  • Elution, repeat step (2) is described incubation of IL17AF with compound.
  • HRP antibody incubation Add 100 ⁇ l mouse anti-Fc tag HRP-conjugated antibody (Sino Biological lnc., Cat#10702-MM01T-H) and incubate on a shaker at 25 degrees for 30 minutes.
  • the mouse anti-Fc tag HRP-conjugated antibody is prepared with 5% (w/v) skim milk at a volume ratio of 1:5000.
  • Elution, repeat step (2) (11) Add 100 ⁇ l TMB substrate (BD, Cat#555214, substrate A and substrate B are freshly prepared in a volume ratio of 1:1) solution and incubate at 25 degrees in the dark for 5 to 15 minutes. If the room temperature is low, the incubation time needs to be appropriately extended.
  • Termination Add 2.5M HCl to terminate the color reaction, and use a microplate reader BMG PHERStar to detect the light absorption value at a wavelength of 450nm.
  • IC50 calculation Calculate the relative percentage of residual activity of each concentration of the compound according to equation 1, and calculate the IC50 of the test compound according to equation 2 of log (inhibitor) vs. normalized response--Variable slope in Graphpad6.
  • the IL17AF inhibitory activity of the compounds prepared in the examples was tested according to the above method.
  • the test results are shown in Table 2, wherein the IC 50 of each compound was determined and classified as follows.
  • “++” indicates that the IC 50 determination value is less than or equal to 500 nM and greater than 100 nM;
  • “++” indicates that the IC 50 determination value is less than or equal to 500 nM and greater than 100 nM;
  • the experiment shows that the compound of the embodiment of the present invention has good human IL-17A inhibitory activity and can be effectively used for the treatment of diseases with abnormal hIL-17A activity.

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Abstract

本发明公开了一种免疫调节剂，具体涉及一类抑制IL-17A的化合物及其作为免疫调节剂在制备药物中的用途。本发明公开了式（I）所示的化合物、或其立体异构体在制备抑制IL-17A类药物中的用途，为临床上筛选和/或制备与IL-17A活性相关的疾病的药物提供了一种新的选择。

Description

一种免疫调节剂 技术领域
本发明涉及一种免疫调节剂及其在制备药物中的用途。
背景技术
IL-17(白细胞介素-17)是促炎性细胞因子，在诱导其他炎性细胞因子、趋化因子和粘附因子中发挥作用。IL-17家族由参与急性和慢性炎症反应的细胞因子组成，包括IL-17A(CTLA-8)、IL-17B、IL-17C、IL-17D、IL-17E(IL-25)和IL-17F。IL-17A由TH17细胞表达，其参与炎症和自身免疫性疾病的病理发生。人类IL-17A是分子量约为17000道尔顿的糖蛋白。IL-17A通过IL-17受体复合物(IL-17RA和IL-17RC)将信号传送至细胞内(Wright,et al.Journal of immunology,2008,181:2799-2805)。IL-17A的主要功能是通过促炎和嗜中性粒细胞迁移细胞因子和趋化因子(包括IL-6，G-CSF，TNF-α，IL-1，CXCL1，CCL2，CXCL2)的上调来协调局部组织炎症，以及基质金属蛋白酶来允许活化的T细胞穿透细胞外基质。有研究表明IL-17A在严重哮喘和慢性阻塞性肺疾病(COPD)中发挥重要作用，那些患者通常对目前可用的药物无响应或响应不良(Al-Ramli et al.J Allergy Clin Immunol,2009,123:1185-1187)。IL-17A水平上调涉及许多疾病，包括类风湿性关节炎(RA)、骨侵蚀、腹膜内脓肿、炎性肠病、同种异体移植物排斥反应、牛皮癣、动脉粥样硬化、哮喘和多发性硬化症(Gaffen,SL et al.Arthritis Research&Therapy,2004,6:240-247)。
免疫功能对于维持体内平衡和对疾病的有效应答是关键的，并且异常免疫应答是自身免疫性疾病的病理生理学已确定贡献因素。在某些疾病状态中，已经发现导致这些异常自身免疫应答的一些关键途径是治疗干预的有效方法。IL-17A是公认的促炎细胞因子，其在慢性炎症中起关键作用，并且是组织损伤的主要驱动因素。IL-17A诱导对病原体的正常免疫和炎性应答，但也可以促成慢性自身免疫疾病，包括银屑病、脊柱关节炎、类风湿性关节炎和多发性硬化。因此，靶向IL-17A与IL-17R的结合是治疗IL-17A介导的自身免疫性炎性疾病的有效策略。通过IL-17A中和抗体治疗动物在自身免疫性脑脊髓炎中降低疾病发病率和严重性(Komiyama Y et al.J.Immunol.,2006,177:566-573)。已有IL-17A抗体的临床试验在IL-17A介导的炎性疾病(包括哮喘、牛皮癣、类风湿性关节炎、强直性脊柱炎和多发性硬化症)上显示出良好的结果。IL-17A抗体(Novartis的Cosentyx/secukinumab)在2015年1月已被FDA批准用于牛皮癣的治疗。
尽管已有多个IL-17A抗体上市，但已知的IL-17A小分子调节剂还相对较少，尤其是改 进的和/或可口服的IL-17A小分子调节剂，因此，开发IL-17A小分子调节剂具有重要的临床治疗意义。
发明内容
本发明首先提供了一种式I所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐：
其中，
表示单键或双键；
X1选自C或N；
X2、X3分别独立选自O、N、NRX或CRX；
X4、X5分别独立选自C或N；
每个RX分别独立选自氢、氘、卤素、氰基、-C1～6烷基、-OC1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-O(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-O(4～10元杂环烷基)、氘取代的-C1～6烷基、卤素取代的-C1～6烷基；
Y1、Y2、Y3分别独立选自N或CRY；
每个RY分别独立选自氢、氘、卤素、氰基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-OC1～6烷基、-C0～2亚烷基-O(卤素取代的C1～6烷基)、-C0～2亚烷基-O(3～10元环烷基)、-C0～2亚烷基-O(4～10元杂环烷基)；
Z选自C(O)、S(O)或S(O)2；
R1选自-C1～6烷基、氘取代的C1～6烷基、卤素取代的C1～6烷基、-C2～6烯基、卤素取代的C2～6烯基、-C2～6炔基、卤素取代的C2～6炔基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)、-C0～2亚烷基-OR11、-C0～2亚烷基-NR11R12；其中亚烷基、烷基、烯基、炔基、环烷基、杂环烷基、芳环、芳杂环 任选被一个、两个或三个独立的R1a取代；
R11、R12分别独立选自氢、氘、C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R1a取代；
每个R1a分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基、-C0～4亚烷基-OR1b、-C0～4亚烷基-SR1b、-C0～2亚烷基-C(O)R1b、-C0～2亚烷基-C(O)NR1bR1c、-C0～2亚烷基-NR1bR1c、-C0～2亚烷基-NR1bC(O)R1c、-C0～4亚烷基-S(O)2R1b、-C0～4亚烷基-NHS(O)2R1b、-C0～4亚烷基-S(O)R1b、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(5～10元芳环)、-C0～4亚烷基-(5～10元芳杂环)；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R1d取代；
R1b、R1c、R1d分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、卤素、氰基、＝O、＝S、硝基、-OH、-SH、-S(C1～6烷基)、-C0～2亚烷基-O(C1～6烷基)、-C(O)NH2、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6烷基)、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；
或者，两个连接在同一个碳原子上的R1a，与其相连的碳原子共同形成3～10元环烷基、4～10元杂环烷基；其中环烷基、杂环烷基任选被一个、两个或三个独立的R1e取代；
R1e分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、卤素、氰基、＝O、＝S、硝基、-OH、-SH、-S(C1～6烷基)、-C0～2亚烷基-O(C1～6烷基)、-C(O)NH2、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6烷基)、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(6～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；
R2选自-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～12元桥环烷基)、-C0～2亚烷基-(5～12元桥杂环烷基)、-C0～2亚烷基-(5～12元螺环烷基)、-C0～2亚烷基-(5～12元螺杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)、-C0～2亚烷基-OR21、-C0～2亚烷基-NR21R22、-C0～2亚烷基-CN；其中亚烷基、环烷基、杂环烷基、桥环烷基、桥杂环烷基、螺环烷基、螺杂环烷基、芳环、芳杂环任选被一个、两个、三个或四个独立的R2a取代；
R21、R22分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被 一个、两个或三个独立的R2a取代；
每个R2a分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基、-C0～2亚烷基-OR2b、-C0～2亚烷基-C(O)R2b、-C0～2亚烷基-C(O)NR2bR2c、-C0～2亚烷基-NR2bR2c、-C0～2亚烷基-NR2bC(O)R2c、-C0～4亚烷基-S(O)2R2b、-C0～4亚烷基-CN、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～12元桥环烷基)、-C0～2亚烷基-(5～12元桥杂环烷基)、-C0～2亚烷基-(5～12元螺环烷基)、-C0～2亚烷基-(5～12元螺杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；其中烷基、亚烷基、环烷基、杂环烷基、桥环烷基、桥杂环烷基、螺环烷基、螺杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R2d取代；
或者，
两个连接在同一个碳原子上的R2a，与其相连的碳原子共同形成3～10元环烷基、4～10元杂环烷基；
R2b、R2c分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R2d取代；
每个R2d分别独立选自氢、氘、C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、卤素、氰基、＝O、＝S、硝基、-OH、-O(C1～6烷基)、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6烷基)；
R3选自氢、氘、卤素、氰基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)、-C0～2亚烷基-OR31、-C0～2亚烷基-NR31R32；其中亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R3a取代；
R31、R32分别独立选自氢、氘、C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；
每个R3a分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基；
L选自C2～6的亚烷基、C2～6的亚烯基；其中，
1)亚烷基、亚烯基中的一个或多个亚甲基可以任选被O、NRL1、C(O)、S(O)或S(O)2替 换；和/或
2)亚烷基、亚烯基任选被一个、两个、三个或四个独立的RL取代；
每个RL1选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、-C0～2亚烷基-OC1～6烷基、-C0～2亚烷基-CN、-C0～2亚烷基-C(O)(C1～6烷基)、-C0～2亚烷基-O(3～10元环烷基)、-C0～2亚烷基-O(4～10元杂环烷基)、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(3～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)、-C0～4亚烷基-N(C1～6烷基)(C1～6烷基)；；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的RL2取代；
每个RL2分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基；
每个RL分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基、-C0～2亚烷基-OC1～6烷基、-C0～2亚烷基-O(3～10元环烷基)、-C0～2亚烷基-O(4～10元杂环烷基)；
或者，
两个连接在同一个碳原子上的RL，与其相连的碳原子共同形成3～10元环烷基、4～10元杂环烷基。
在本发明的一些实施方案中，式I所示的化合物如式II所示：
其中，R1、R2、R3、Y1、Y2、Y3、Z、L、X1、X2、X3、X4、X5定义如前所述。
在本发明的一些实施方案中，X1、X2、X3、X4、X5组成的环为芳杂环，且X4、X5不同时为N。
在本发明的一些实施方案中，
X1为C，X2为NRX，X3为N，X4为C，X5为C；
或者，X1为C，X2为N，X3为N，X4为C，X5为N；
或者，X1为C，X2为N，X3为CRX，X4为N，X5为C；
或者，X1为N，X2为N，X3为CRX，X4为C，X5为C；
或者，X1为C，X2为O，X3为N，X4为C，X5为C。
在本发明的一些实施方案中，进一步地，式I所示的化合物如下式所示：
其中，R1、R2、R3、Y1、Y2、Y3、Z、L定义如前所述。
在本发明的一些实施方案中，进一步地，式I所示的化合物如下式所示：
其中，
R4、R5、R6分别独立选自氢、氘、卤素、氰基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基、-C0～4亚烷基-OR1b、-C0～4亚烷基-SR1b、-C0～2亚烷基-C(O)R1b、-C0～2亚烷基 -C(O)NR1bR1c、-C0～4亚烷基-NR1bR1c、-C0～2亚烷基-NR1bC(O)R1c、-C0～4亚烷基-S(O)2R1b、-C0～4亚烷基-NHS(O)2R1b、-C0～4亚烷基-S(O)R1b、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元芳杂环)；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R1d取代；
R1b、R1c、R1d分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、卤素、氰基、＝O、＝S、硝基、-OH、-SH、-S(C1～6烷基)、-C0～2亚烷基-O(C1～6烷基)、-C(O)NH2、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6烷基)、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(6～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；
或者，R5、R6与其直接相连的碳原子共同形成3～10元环烷基、4～10元杂环烷基；其中环烷基、杂环烷基任选被一个、两个或三个独立的R1e取代；
R1e分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、卤素、氰基、＝O、＝S、硝基、-OH、-SH、-S(C1～6烷基)、-C0～2亚烷基-O(C1～6烷基)、-C(O)NH2、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6烷基)、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(6～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；
R2、R3、Y1、Y2、Y3、L定义如权利要求1所述。
作为优选：所述R4选自氢、氘、卤素、-C1～3烷基、氘取代的-C1～3烷基、卤素取代的-C1～3烷基；
R5、R6分别独立选自氢、氘、卤素、-C1～3烷基、氘取代的-C1～3烷基、卤素取代的-C1～3烷基、3元环烷基、4元环烷基、5元环烷基、6元环烷基、5元杂环烷基、6元杂环烷基、6元芳环、5元芳杂环、6元芳杂环；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R1d取代；
R1d分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、卤素、氰基；
或者，R5、R6与其直接相连的原子共同形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、5元杂环烷基、6元杂环烷基；其中环烷基、杂环烷基任选被一个、两个或三个独立的R1e取代。
在本发明的一些实施方案中，
Y1、Y2、Y3分别独立选自N或CRY；
每个RY分别独立选自氢、氘、卤素、氰基、-C1～3烷基、3～6元环烷基、氘取代的-C1～3烷基、卤素取代的-C1～3烷基、-C0～2亚烷基-OC1～3烷基、-C0～2亚烷基-O(卤素取代的C1～3烷基)。
优选地，
Y1、Y2、Y3分别独立选自N或CRY；
每个RY分别独立选自氢、氘、氟、氯、溴、氰基、甲基、乙基、正丙基、异丙基、环丙基、三氟甲基、甲氧基、乙氧基、三氟甲氧基。
在本发明的一些优选实施方案中，
Y1、Y3分别独立选自N或CH或CF；Y2选自N或CRY；
每个RY分别独立选自氢、氘、氟、氯、溴、氰基、甲基、乙基、正丙基、异丙基、环丙基、三氟甲基、甲氧基、乙氧基、三氟甲氧基。
优选地，Z选自C(O)或S(O)2。
优选地，
R3选自甲基、氘代甲基、乙基、全氘代乙基、正丙基、异丙基、三氟甲基、环丙基、环丁基、羟甲基、甲氧甲基、氘代甲氧甲基、氨基、甲胺基、二甲胺基、氘代甲胺基。
在本发明的一些实施方案中，R1选自苯环、5元芳杂环、6元芳杂环；其中，苯环、芳杂环任选被一个、两个或三个独立的R1a取代。
或者，在本发明的一些实施方案中，R1选自-亚甲基-苯环、-亚甲基-5元芳杂环、-亚甲基-6元芳杂环、-亚甲基-9元芳杂环；其中，亚甲基、苯环、芳杂环任选被一个、两个或三个独立的R1a取代。
或者，在本发明的一些实施方案中，R1选自-二氟亚甲基-苯环、-二氟亚甲基-5元芳杂环、-二氟亚甲基-6元芳杂环、-二氟亚甲基-9元芳杂环；其中，苯环、芳杂环任选被一个R1a取代。
或者，在本发明的一些实施方案中，R1选自8元稠杂环烷基、9元稠杂环烷基、10元稠杂环烷基、9元稠芳杂环、10元稠芳杂环；其中，稠杂环烷基、稠芳杂环任选被一个、两个或三个独立的R1a取代。
或者，在本发明的一些实施方案中，R1选自3元环烷基、4元环烷基、5元环烷基、6元环烷基、4元杂环烷基、5元杂环烷基、6元杂环烷基；其中环烷基、杂环烷基任选被一个、两个或三个独立的R1a取代。
或者，在本发明的一些实施方案中，R1选自-亚甲基-3元环烷基、-亚甲基-4元环烷基、-亚甲基-5元环烷基、-亚甲基-6元环烷基、-亚甲基-4元杂环烷基、-亚甲基-5元杂环烷基、-亚甲基-6元杂环烷基、-亚甲基-9元杂环烷基；其中，亚甲基、环烷基、杂环烷基任选被一个、两个或三个独立的R1a取代。
或者，在本发明的一些实施方案中，R1选自-二氟亚甲基-3元环烷基、-二氟亚甲基-4元 环烷基、-二氟亚甲基-5元环烷基、-二氟亚甲基-6元环烷基、-二氟亚甲基-4元杂环烷基、-二氟亚甲基-5元杂环烷基、-二氟亚甲基-6元杂环烷基、-二氟亚甲基-9元杂环烷基；其中，环烷基、杂环烷基任选被一个R1a取代。
或者，在本发明的一些实施方案中，R1选自甲基、二氟甲基、三氟甲基、乙基、一氟乙基、二氟乙基、丙基、丁基、-C0～2亚烷基-OR11、-C0～2亚烷基-NR11R12、乙烯基、丙烯基、丁烯基、戊烯基、己烯基；其中甲基、乙基、丙基、丁基、乙烯基、丙烯基、丁烯基、戊烯基、己烯基任选被一个、两个或三个独立的R1a取代。
在本发明的一些实施方案中，R11、R12分别独立选自氢、氘、甲基、乙基、正丙基、异丙基、氘取代的甲基、氘取代的乙基、氘取代的正丙基、氘取代的异丙基、卤素取代的甲基、卤素取代的乙基、卤素取代的正丙基、卤素取代的异丙基。
或者，在本发明的一些实施方案中，R11、R12分别独立选自-C0～2亚烷基-(3元环烷基)、-C0～2亚烷基-(4元环烷基)、-C0～2亚烷基-(5元环烷基)、-C0～2亚烷基-(6元环烷基)、-C0～2亚烷基-(4元杂环烷基)、-C0～2亚烷基-(5元杂环烷基)、-C0～2亚烷基-(6元杂环烷基)；其中烷基、亚烷基、环烷基、杂环烷基任选被一个、两个或三个独立的R1a取代。
在本发明的一些实施方案中，每个R1a分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、甲基、乙基、正丙基、异丙基、丁基、氘取代的甲基、氘取代的乙基、氘取代的正丙基、氘取代的异丙基、卤素取代的甲基、卤素取代的乙基、卤素取代的正丙基、卤素取代的异丙基、卤素取代的丁基；其中，甲基、乙基、正丙基、异丙基、丁基任选被一个、两个或三个独立的R1d取代；
或者，在本发明的一些实施方案中，每个R1a分别独立选自-C0～2亚烷基-(3元环烷基)、-C0～2亚烷基-(4元环烷基)、-C0～2亚烷基-(5元环烷基)、-C0～2亚烷基-(6元环烷基)、-C0～2亚烷基-(4元杂环烷基)、-C0～2亚烷基-(5元杂环烷基)、-C0～3亚烷基-(6元杂环烷基)、-(6元芳环)；其中亚烷基、环烷基、杂环烷基、芳环任选被一个、两个或三个独立的R1d取代；
或者，在本发明的一些实施方案中，每个R1a分别独立选自-C0～4亚烷基-OR1b、-C0～4亚烷基-SR1b、-C0～4亚烷基-S(O)2R1b、-C0～4亚烷基-S(O)R1b、-NHS(O)2R1b、-C0～3亚烷基-NR1bR1c、；其中亚烷基任选被一个、两个或三个独立的R1d取代；
在本发明的一些实施方案中，R1b、R1c、R1d分别独立选自氢、氘、甲基、乙基、正丙基、异丙基、丁基、氘取代的甲基、氘取代的乙基、氘取代的正丙基、氘取代的异丙基、卤素取代的甲基、卤素取代的乙基、卤素取代的正丙基、卤素取代的异丙基、卤素、氰基、＝O、＝S、硝基、-OH、-O(C1～6烷基)、-CH2-O(C1～6烷基)、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6 烷基)、-(3元环烷基)、-(4元环烷基)、-(5元环烷基)、-(6元环烷基)、-C(O)NH2。
或者，两个连接在同一个碳原子上的R1a，与其相连的碳原子共同形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、5元杂环烷基、6元杂环烷基；其中环烷基、杂环烷基任选被一个、两个或三个独立的R1e取代；
R1e分别独立选自氢、氘、-C1～3烷基、氘取代的-C1～3烷基、卤素取代的C1～3烷基、卤素。
优选地，所述R1选自



在本发明的一些实施方案中，R2选自3元环烷基、4元环烷基、5元环烷基、6元环烷基、7元环烷基、8元环烷基；其中环烷基任选被一个、两个、三个或四个独立的R2a取代。
或者，在本发明的一些实施方案中，R2选自-C1亚烷基-(3元环烷基)、-C1亚烷基-(4元环烷基)、-C1亚烷基-(5元环烷基)、-C1亚烷基-(6元环烷基)、-C1亚烷基-(7元环烷基)、-C1亚烷基-(8元环烷基)、-C1亚烷基-(苯环)、-C1亚烷基-(芳杂环)；其中亚烷基、环烷基、苯环、芳杂环任选被一个、两个、三个或四个独立的R2a取代。
在本发明的一些实施方案中，优选地，R2选自其中环V选自3元环烷基、4元环烷基、5元环烷基、6元环烷基、7元环烷基、4元杂环烷基；其中环烷基任选被一个、两个或三个独立的R2a取代；R2a‘选自3元环烷基、4元环烷基、5元环烷基、6元环烷基、7元环烷基、4元杂环烷基；其中环烷基任选被一个、两个或三个独立的R2d取代。
或者，在本发明的一些实施方案中，R2选自6元稠环烷基、9元稠环烷基、10元稠环烷基、11元稠环烷基、9元稠杂环烷基、10元稠杂环烷基、12元稠杂环烷基、8元螺环烷基；其中稠环烷基、稠杂环烷基、螺环烷基任选被一个、两个、三个或四个独立的R2a取代。
或者，在本发明的一些实施方案中，R2选自5元桥环烷基、6元桥环烷基、7元桥环烷基、8元桥环烷基、9元桥环烷基、10元桥环烷基、-C1亚烷基-(5元桥环烷基)、-C1亚烷基-(6元桥环烷基)、-C1亚烷基-(7元桥环烷基)、-C1亚烷基-(8元桥环烷基)、-C1亚烷基-(9元桥环烷基)、-C1亚烷基-(10元桥环烷基)。
在本发明的一些实施方案中，R21、R22分别独立选自氢、氘、甲基、乙基、正丙基、异丙基、丁基、氘取代的甲基、氘取代的乙基、氘取代的正丙基、氘取代的异丙基、卤素取代的甲基、卤素取代的乙基、卤素取代的正丙基、卤素取代的异丙基、卤素取代的丁基、3元环烷基、4元环烷基、5元环烷基、6元环烷基、7元环烷基、-C1亚烷基-(3元环烷基)、-C1亚烷基-(4元环烷基)、-C1亚烷基-(5元环烷基)、-C1亚烷基-(6元环烷基)、-C1亚烷基-(7元环烷基)；其中亚烷基、环烷基、杂环烷基任选被一个、两个或三个独立的R2a取代。
在本发明的一些实施方案中，每个R2a分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、甲基、乙基、正丙基、异丙基、氘取代的甲基、氘取代的乙基、氘取代的正丙基、氘取代的异丙基、卤素取代的甲基、卤素取代的乙基、卤素取代的正丙基、卤素取代的异丙基、-S(O)2R2b、-OR2b。
或者，在本发明的一些实施方案中，每个R2a分别独立选自3元环烷基、4元环烷基、5元环烷基、6元环烷基、7元环烷基、-C1亚烷基-(3元环烷基)、-C1亚烷基-(4元环烷基)、-C1亚烷基-(5元环烷基)、-C1亚烷基-(6元环烷基)、-C1亚烷基-(7元环烷基)；其中亚烷基、环烷基、杂环烷基任选被一个、两个或三个独立的R2d取代；
或者，
两个连接在同一个碳原子上的R2a，与其相连的碳原子共同形成3～10元环烷基、4～10元杂环烷基；
在本发明的一些实施方案中，R2b、R2c分别独立选自氢、氘、甲基、乙基、正丙基、异丙基、氘取代的甲基、氘取代的乙基、氘取代的正丙基、氘取代的异丙基、卤素取代的甲基、卤素取代的乙基、卤素取代的正丙基、卤素取代的异丙基、3元环烷基、4元环烷基、5元环烷基、6元环烷基、7元环烷基、-C1亚烷基-(3元环烷基)、-C1亚烷基-(4元环烷基)、-C1亚烷基-(5元环烷基)、-C1亚烷基-(6元环烷基)、-C1亚烷基-(7元环烷基)；其中烷基、亚烷基、环烷基、杂环烷基任选被一个、两个或三个独立的R2d取代；
在本发明的一些实施方案中，每个R2d分别独立选自氢、氘、甲基、乙基、正丙基、异丙基、氘取代的甲基、氘取代的乙基、氘取代的正丙基、氘取代的异丙基、卤素取代的甲基、卤素取代的乙基、卤素取代的正丙基、卤素取代的异丙基、卤素、氰基、＝O、＝S、硝基、-OH、 -O(C1～6烷基)、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6烷基)。
优选地，所述R2选自

在本发明的一些实施方案中，L选自C3亚烷基、C4亚烷基、C5亚烷基、C6亚烷基、C3亚烯基、C4亚烯基、C5亚烯基、C6亚烯基；其中，
1)亚烷基、亚烯基中的一个、两个或三个亚甲基可以任选被O、NRL1、C(O)、S(O)或S(O)2替换；和/或
2)亚烷基、亚烯基任选被一个、两个、三个或四个独立的RL取代。
每个RL1选自氢、氘、甲基、乙基、正丙基、异丙基、卤素取代的甲基、卤素取代的乙基、卤素取代的正丙基、卤素取代的异丙基、-C0～2亚烷基-CN、-C0～2亚烷基-C(O)(C1～6烷基)、-C0～2亚烷基-(3元环烷基)、-C0～2亚烷基-(4元环烷基)、-C0～2亚烷基-(6元环烷基)、-C0～2亚烷基-(6元杂环烷基)、-C0～2亚烷基-(6元芳环)、-C0～2亚烷基-OC1～6烷基、-C0～4亚烷基-N(C1～6烷基)(C1～6烷基)；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的RL2取代；
每个RL2分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基；
每个RL分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、甲基、乙基、正丙基、异丙基、氘取代的甲基、氘取代的乙基、氘取代的正丙基、氘取代的异丙基、卤素取代的甲基、卤素取代的乙基、卤素取代的正丙基、卤素取代的异丙基；
或者，
两个连接在同一个碳原子上的RL，与其相连的碳原子共同形成3元环烷基、4元环烷基、5元环烷基、6元环烷基。
优选地，L选自

其中，aa端与X4相连。在本发明的一些具体实施方案中，所述的化合物具体为：






















本发明还提供了任一上述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐在制备治疗IL-17介导的疾病的药物中的用途。
进一步地，所述IL-17介导的疾病是与炎症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。
本发明还提供了一种药物组合物，它是以任一上述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐，加上药学上可接受的辅料制备而成的制剂。
本发明还提供了上述任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其用于治疗银屑病、类风湿性关节炎、脊柱关节炎、多发性硬化、银屑病关节炎、中轴型脊柱关节炎、强直性脊椎炎、化脓性汗腺炎、系统性红斑狼疮、掌跖脓疱病(PPP)、特应性皮炎、哮喘和/或COPD的疾病或病症。
本发明提供了一种药物组合物，其包含任一上述化合物或其药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂。
本发明还提供了前述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗IL-17介导的疾病的药物中的用途。
本发明还提供了一种治疗银屑病的方法，所述方法包括向有需要的患者施用有效量的上述任一化合物或其药学上可接受的盐。
本发明还提供了上述任一的化合物或其药学上可接受的盐，其用于治疗法。
本发明还提供了一种治疗或预防患者的炎症、癌症或自身免疫性疾病的方法，其包括向有需要的患者施用治疗有效量的上述任一所述的化合物。
本发明还提供了上述任一所述的化合物或其药学上可接受的盐，其用于治疗银屑病。
本发明还提供了上述任一的化合物或其药学上可接受的盐在制备用于治疗银屑病的药物中的用途。
本发明所定义的IL-17介导的疾病是IL-17在该疾病的病理发生中起重要作用的疾病。IL-17的主要功能是协调局部组织炎症，从而在各种疾病中起作用。IL-17介导的疾病包括炎 症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。。
“癌症”或“恶性肿瘤”是指以不受控制的细胞异常增殖为特征的多种疾病中的任何一种，受影响的细胞在局部或通过血流和淋巴系统扩散到其他部位的能力的身体(即转移)以及许多特征结构和/或分子特征中的任何一个。“癌细胞”是指经历多步骤肿瘤进展的早期，中期或晚期阶段的细胞。癌症包括肉瘤、乳腺癌、肺癌、脑癌、骨癌、肝癌、肾癌、结肠癌和前列腺癌。在一些实施方案中，式I的化合物用于治疗选自结肠癌、脑癌、乳腺癌、纤维肉瘤和鳞状细胞癌的癌症。在一些实施方案中，癌症选自黑素瘤、乳腺癌、结肠癌、肺癌和卵巢癌。在一些实施方案中，所治疗的癌症是转移性癌症。
自身免疫性疾病是由身体对体内正常存在的物质和组织的免疫反应引起的。自身免疫疾病的例子包括心肌炎、狼疮性肾炎、原发性胆汁性肝硬化、牛皮癣、1型糖尿病、格雷夫氏病、腹腔疾病、克罗恩病、自身免疫性中性白细胞减少症、幼年型关节炎、类风湿性关节炎、纤维肌痛、吉兰巴利综合征、多发性硬化症和自身免疫性视网膜病变。本发明的一些实施方案涉及治疗自身免疫疾病如牛皮癣或多发性硬化症。
炎症疾病包括以组织病理性炎症为特征的多种病症。炎性疾病的例子包括寻常性痤疮、哮喘、腹腔疾病、慢性前列腺炎、肾小球性肾炎、炎症性肠病、盆腔炎、再灌注损伤、类风湿性关节炎、结节病、血管炎、房尘螨引起的气道炎症和间质性膀胱炎。炎性疾病与自身免疫性疾病之间存在显著重叠。本发明的一些实施方案涉及炎性疾病哮喘的治疗。免疫系统通常涉及炎症性疾病，在过敏反应和一些肌病中都有表现，许多免疫系统疾病导致异常炎症。IL-17A介导的疾病也包括自身免疫性炎症性疾病。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或基团所替换；或者是分子中原子的孤对电子被其它的原子或基团替换，例如S原子上的孤对电子可被O原子取代形成
“可任选被取代”是指“取代”可以但不必须发生，该说明包括发生或不发生的情形。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca～b烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，“C1～6烷基”是指包含1～6个碳原子的烷基。
“烷基”是指具有指定数目的成员原子的饱和烃链。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分，所述其他基团为例如-O(C1～6烷基)。
“亚烷基”是指具有指定数目的成员原子的二价饱和脂族烃基。Ca～b亚烷基是指具有a至b个碳原子的亚烷基基团。亚烷基基团包括支链和直链烃基基团。例如，术语“亚丙基”可以通过下列结构例举：同样地，术语“二甲基亚丁基”可以例如通过下列结构的任一种例举：
本发明中-C0～2亚烷基可以为C0的亚烷基、C1的亚烷基(例如-CH2-)、C2的亚烷基(例如-CH2CH2-等)；C0亚烷基指的是此处的基团不存在，以化学键的形式连接，如A-C0亚烷基-B指的是A-B，即A基团与B基团直接通过化学键连接。
本发明中所述的“环烷基”、“环烷烃”是指具有碳原子且没有环杂原子且具有单个环或多个环(包括稠合、桥连)的饱和或部分饱和的环状基团。术语“环烷基”、“环烷烃”包括环烯基基团，诸如环己烯基。环烷基基团的实例包括例如，金刚烷基、环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。包括多双环烷基环体系的环烷基基团的实例是双环己基、双环戊基、双环辛基等。下面例举并命名两种此类双环烷基多环结构：双环己基和双环己基。术语“环烷基”、“环烷烃”还包括芳香环与非芳香环稠合形成的部分饱和环状基团的情形，其连接位点可以位于非芳族碳原子或芳族碳原子，实例包括1,2,3,4-四氢化萘-5-基、5,6,7,8-四氢化萘-5-基。
本发明中所述的不饱和是指基团或者分子中含有碳碳双键、碳碳三键、碳氧双键、碳硫双键、碳氮三键等；本发明的不饱和的碳环基包括或不包括芳环基，不饱和的杂环基包括不包括杂芳基，本领域的技术人员可以自由选择。
“烯基”是指具有2至10个碳原子和在一些实施方案中2至6个碳原子或2至4个碳原子且具有至少1个乙烯基不饱和位点(>C＝C<)的直链或支链烃基基团。例如，Ca-b烯基是指具有a至b个碳原子的烯基基团并且意在包括例如乙烯基、丙烯基、异丙烯基、1,3-丁二烯基等。
“炔基”是指含有至少一个三键的直链一价烃基或支链一价烃基。术语“炔基”还意在包括具有一个三键和一个双键的那些烃基基团。例如，C2-6炔基意在包括乙炔基、丙炔基等。
“卤素”为氟、氯、溴或碘。
“卤素烷基”、“卤素取代的烷基”指烷基中的氢原子可被一个或多个卤素原子取代。例如卤素取代的C1～4烷基指氢原子被一个或多个卤素原子取代的包含1～4个碳原子的烷基；还例如单氟甲基、双氟甲基、三氟甲基。
“杂环烷基”、“杂环”、“杂环烷烃”是指包含至少一个杂原子的且具有单个环或多个环(稠合、桥连)的饱和环或非芳香性的部分饱和环；其中杂原子指氮原子、氧原子、硫原子等。通常表示多个环原子的一价饱和或部分不饱和单环或二环环系统，其包含1、2或3个选自N、O和S的环杂原子，其余的环原子是碳。二环表示由共有两个环原子的两个环组成的，即将两个环分开的桥是单键或是一个或两个环原子的链。单环饱和杂环烷基的实例是氧杂环丁基、氮杂环丁基、吡咯烷基、2-氧代-吡咯烷-3-基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、硫代吗啉基、1，1-二氧代-硫代吗啉-4-基、氮杂环庚基、二氮杂环庚基、高哌嗪基或氧杂氮杂环庚基。二环饱和杂环烷基的实例是8-氮杂-二环[3.2.1]辛基、奎宁环基、8-氧杂-3-氮杂-二环[3.2.1]辛基、9-氮杂-二环[3.3.1]壬基。部分不饱和杂环烷基的实例是二氢呋喃基、咪唑啉基、四氢-吡啶基或二氢吡喃基。术语“杂环烷基”还包括包含至少一个杂原子的芳香环与非芳香环稠合形成的部分饱和环状基团的情形，其连接位点可以位于非芳族碳原子、芳族碳原子或杂原子，实例包括
“芳环基”、“芳环”是指具有多个碳原子的芳烃基团。芳基通常是具有多个碳原子的单环、二环或三环芳基。此外，本文所用的术语“芳基”是指可以是单个芳环或稠合在一起的多个芳环的芳族取代基。非限制性实例包括苯基、萘基或四氢萘基。
本发明中所述的“芳杂环基”、“芳杂环”是指包含至少一个杂原子的芳香性不饱和环；其中杂原子指氮原子、氧原子、硫原子等。通常包含多个环原子的、其中一个或多个环原子选自O、N、S的杂原子的芳族单环或双环烃。优选地有一到三个杂原子。杂环芳基例如代表：吡啶基、吲哚基、喹噁啉基、喹啉基、异喹啉基、苯并噻吩基、苯并呋喃基、苯并噻吩基、苯并吡喃基、苯并噻吡喃基、呋喃基、吡咯基、噻唑基、噁唑基、异噁唑基、三唑基、四唑 基、吡唑基、咪唑基、噻吩基、噁二唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基。
“立体异构体”包括对映异构体和非对映异构体；
本发明中所述的“-OR”、“-NRR”等是指R基团与氧原子或氮原子以单键相连。
本发明中所述的“-C(O)R”、“-S(O)2R”等中的氧原子是与碳原子或硫原子以双键相连，R基团与碳原子或硫原子以单键相连。
本发明中所述的“＝O”、“＝S”是指氧原子、硫原子通过双键连接到取代位置。
本发明基团描述中的是用来描述基团取代的位置。
本发明的“氘代化合物”是指分子或基团中的1个或多个氢原子被氘原子取代，其中氘原子的占比大于氘在自然界中的丰度。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的钠盐、钾盐、盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
在某些实施方式中，本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用，用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物，则可将这些化合物同时、分别或有序地对受试对象进行给药。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但 不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker AvanceIII 400MHz和Bruker Avance NEO 600 MHz)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
LC-MS的测定使用岛津液质联用仪(Shimadzu LC-MS2020(ESI))。HPLC的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。MPLC(中压制备色谱)使用Gilson GX-281反相制备色谱仪。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。超临界流体色谱(SFC)分析与制备使用仪器为SHIMADZU SFC-30A。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于安耐吉化学、成都科龙化工、韶远化学科技、百灵威科技等公司。
实施例中无特殊说明，反应在氮气氛围下进行。实施例中无特殊说明，溶液是指水溶液。实施例中无特殊说明，反应的温度为室温。室温为最适宜的反应温度，为20℃～30℃。实施例中无特殊说明，M是摩尔每升。
实施例中所述试剂缩写如下：DMF：N,N-二甲基甲酰胺；DCM：二氯甲烷；TFA：三氟醋酸；MeOH：甲醇；Cs2CO3：碳酸铯；DIPEA：N,N-二异丙基乙胺；HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；SEM-Cl：2-(三甲基硅烷基)乙氧甲基氯；LiAlH4：四氢铝锂；TBS-Cl：叔丁基二甲基氯硅烷；THF：四氢呋喃；NBS：N-溴代丁二酰亚胺；(Boc)2O：二碳酸二叔丁酯；Na2CO3:碳酸钠；B2pin2：联硼酸频那醇酯；AcOK：醋酸钾；Pd(dppf)2Cl2：1,1‘-双(二苯基膦)二茂铁二氯化钯；n-BuLi：正丁基锂；MgSO4：硫酸镁；CsF：氟化铯；TMSCN:三甲基氰硅烷：EA/HCl：氯化氢乙酸乙酯溶液；Cbz-Osu：苄基-N-琥珀酰亚胺基碳酸酯；K2CO3：碳酸钾；H2O2：双氧水；DMSO：二甲基亚砜；NMP:N-甲基吡咯烷酮：LiOH.H2O：一水合氢氧化锂；Pd(PPh3)4：四三苯基磷钯；SOCl2：二氯亚砜；t-BuOK：叔丁醇钾；t-BuOH：叔丁醇；Pd/C：钯碳；HCOONH4：甲酸胺；(COCl)2：草酰氯；EDCI：1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；DIAD：偶氮二甲酸二异丙酯；PPh3：三苯基磷；Zn：锌粉；NH4Cl：氯化铵；Ti(OEt)4：钛酸四异丙酯；Raney Ni：雷尼镍；Pd2(dba)3：三(二亚苄基丙酮)二钯；Pd(amphos)Cl2：二氯二叔丁基-(4-二甲基氨基苯基)膦钯(II)；Pd(OAc)2：醋酸钯；Pd(OH)2：氢氧化钯；CyJohnphos：2-(二环己基膦基)联苯；rac-BI-DIME：3-(叔丁基)-4-(2,6- 二甲氧基苯基)-2,3-二氢苯并[D][1,3]氧,膦戊轭；CbzCl：氯甲酸苄酯；NaBH(OAc)3：三乙酰氧基硼氢化钠；K3PO4：磷酸钾；Py：吡啶；selectfluor：1-氯甲基-4-氟-1，4二氮杂双环【2.2.2】辛烷二(四氟硼酸盐)。
中间体A-1的制备
0℃下往原料2-(5-甲基-1H-吡唑-3-基)乙酸甲酯(2.83g,18.36mmol)和DIPEA(11.86g,91.78mmol,15.99mL)的DMF(60mL)溶液中，滴加SEM-Cl(3.67g,22.03mmol)。加完后升温到室温反应过夜，反应完后加入水和乙酸乙酯萃取，有机层用盐水洗，浓缩干，经硅胶柱层析纯化得中间体A-1-1(4.6g,88％收率)。MS(ESI)m/z＝285[M+1]+。
-78℃往中间体A-1-1(4.3g,15.12mmol)的THF(150mL)溶液中分批加入LiAlH4(1.15g,30.24mmol)，加料完后升温到室温反应1小时。反应完后降温至-10℃依次滴加水(2mL)、15％的NaOH水溶液(2mL)和水(6mL)淬灭反应，滴毕，室温搅拌10分钟，过滤，滤饼用乙酸乙酯淋洗，滤液浓缩干得中间体A-1-2(3.8g,98％收率)，粗品未经纯化直接用于下一步。MS(ESI)m/z＝257[M+1]+。
于0℃往中间体A-1-2(3.8g,14.82mmol)的THF(50mL)溶液中加入TBSCl(4.47g,29.64mmol)和咪唑(2.02g,29.64mmol)，室温搅拌反应2小时。反应完后加入水和乙酸乙酯萃取，有机层饱和食盐水洗，有机层浓缩至干，粗品经硅胶柱层析纯化得中间体A-1-3(4.77g,87％收率)，粗品未经纯化直接用于下一步。MS(ESI)m/z＝371[M+1]+。
往中间体A-1-3(4.77g,12.87mmol)的DCM(60mL)溶液中，加入NBS(2.7g,15.17mmol)，室温搅拌反应1小时。反应完后加入碳酸氢钠水溶液淬灭反应，加入DCM萃取，有机层用盐水洗，有机层浓缩至干，粗品经硅胶柱层析纯化得中间体A-1(5.5g，95％收率)。MS(ESI)m/z＝449[M+1]+。
中间体A-2的制备
于50mL单口瓶中加入中间体A-1-1(206mg,724.27μmol)和DCM(7mL)，再室温加入NBS(141.80mg,796.69μmol)，室温搅拌反应过夜。反应完后加入碳酸氢钠水溶液淬灭反应，加入DCM萃取，有机层盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱层析纯化(PE/EA10:1to 5/1)得中间体A-2(150mg,412.86μmol,57.0％收率)。MS(ESI)m/z＝363[M+1]+。
中间体A-3的制备
往中间体A-2(600g,1.65mol)的1,4二氧六环(6L)溶液中，依次加入频那醇硼烷(570.63,g,4.46mol)、Pd(OAc)2(11.22g,49.54mmol),CyJohnphos(34.73g,99.09mmol)和三乙胺(250.66g,2.48mol,345.50mL)，加毕，抽真空氮气置换三次，氮气保护下升温到90℃搅拌反应过夜。反应完后加入水淬灭反应，乙酸乙酯萃取，有机相盐水洗，无水硫酸钠干燥，过滤，减压浓缩干，粗品经硅胶柱层析纯化得中间体A-3(540.6g,1.32mol,79.77％收率)。MS(ESI)m/z＝411[M+1]+。
中间体B-1的制备
往原料2-溴-5-氨基苯甲酸甲酯(11.5g,49.99mmol)的MeOH(150mL)溶液中加入(Boc)2O(24.00g,109.97mmol)和Na2CO3(15.89g,149.96mmol)，室温搅拌反应过夜。原料反应完后加入水和乙酸乙酯萃取，有机层盐水洗。有机层浓缩干，经硅胶柱层析纯化得中间体B-1-1(13.9g,84％收率)。MS(ESI)m/z＝330[M+1]+。
往中间体B-1-1(6.6g,19.99mmol)的1,4二氧六环(70mL)溶液中，依次加入B2pin2 (5.58g,21.99mmol)、AcOK(3.92g,39.98mmol)和Pd(dppf)Cl2(731.31mg,999.47μmol)，加毕，抽真空氮气置换三次，氮气保护下升温到80℃搅拌反应过夜。反应完后加入水和乙酸乙酯萃取，有机层盐水洗，无水硫酸钠干燥，过滤，减压浓缩干，粗品经硅胶柱层析纯化得中间体B-1(6.7g,89％收率)。MS(ESI)m/z＝378[M+1]+。
中间体B-2的制备
往2-溴苯乙酸甲酯(10g,43.65mmol)的浓硫酸(42mL)溶液中，冰水浴滴加入浓硝酸(5.50g,87.31mmol)，滴毕，维持0℃搅拌反应30分钟。反应完后慢慢倾倒入冰水中，乙酸乙酯萃取。合并有机相，依次水洗，盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱层析纯化得中间体B-2-1(9.8g,35.76mmol,81.91％收率)。MS(ESI)m/z＝272[M-1]-。
往中间体B-2-1(5g,18.24mmol)的甲醇/冰乙酸/水(72mL/3mL/18mL)溶液中，搅拌状态下分批加入还原铁粉(5.09g,91.22mmol)，加毕，升温至回流搅拌反应3小时。监控反应完后，趁热硅藻土过滤，滤饼用乙酸乙酯洗涤。滤液减压浓缩至干，残留物用乙酸乙酯溶解，依次水，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩干，粗品经硅胶柱层析纯化得中间体B-2-2(3.95g,16.19mmol,88.73％收率)。MS(ESI)m/z＝244[M+1]+。
往中间体B-2-2(3.95g,16.19mmol)的四氢呋喃(80mL)溶液中，室温下加入甲醇(726.08mg,22.66mmol)和硼氢化锂(916.89mg,42.09mmol)，加毕，升温至60℃搅拌反应2小时。反应完后倾倒入冰水中淬灭反应，乙酸乙酯萃取。合并有机相，依次水洗，盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干得粗品中间体B-2-3(3.58g,14.89mmol,92.02％收率)。MS(ESI)m/z＝216[M+1]+。
往中间体B-2-3(3.58g,16.55mmol)的四氢呋喃(80mL)溶液中，冰水浴下加入咪唑(2.25g,33.10mmol)和TBSCl(4.99g,33.10mmol)，加毕，升至室温搅拌反应2小时。反应完后倾倒入饱和氯化铵溶液中淬灭反应，乙酸乙酯萃取。合并有机相，依次水洗，盐水洗， 无水硫酸钠干燥，过滤，减压浓缩至干。粗品经硅胶柱层析纯化得中间体B-2-4(4.58g,13.87mmol,83.81％收率)。MS(ESI)m/z＝330[M+1]+。
于250mL单口瓶中加入中间体B-2-4(3g,9.08mmol)，联硼酸频哪醇酯(2.54g,9.99mmol)，醋酸钾(1.71g,18.16mmol)和二氧六环(50mL)，搅拌状态下抽真空氮气置换三次，升温至90℃搅拌反应过夜。反应完后冷却，直接拌样经硅胶柱层析纯化得中间体B-2(2.12g,5.60mmol,61.71％收率)。MS(ESI)m/z＝378[M+1]+。
中间体B-3的制备
于250mL单口瓶中加入2-溴-4氟-5-硝基苯甲酸(5g,18.94mmol)和甲醇(100mL)，于冰水浴滴加入二氯亚砜(6.76g,56.82mmol,4.13mL)，滴毕，升温至60℃搅拌反应过夜。反应完后冷却至室温，减压浓缩至干，残留物加入乙酸乙酯溶解，依次用碳酸氢钠水溶液，饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，减压浓缩至干得中间体B-3-1(5.03g,18.10mmol,95.58％收率)。MS(ESI)m/z＝276[M-1]-。
于250mL单口瓶中加入中间体B-3-1(5g,17.98mmol)和乙醇/冰乙酸/水(120mL/5mL/30mL)，室温搅拌状态下分批加入还原铁粉5.02g,89.92mmol)，加毕，升温至回流反应2小时。稍微冷却趁热硅藻土过滤，乙酸乙酯洗涤，滤液减压浓缩至干，残留物加入乙酸乙酯溶解，依次用碳酸氢钠水溶液，饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，减压浓缩至干。粗品经硅胶柱层析纯化得中间体B-3-2(4.3g,17.34mmol,96.40％收率)。MS(ESI)m/z＝248[M+1]+。
于250mL单口瓶中加入中间体B-3-2(3.97g,16.00mmol)，联硼酸频哪醇酯(4.47g,17.61mmol)，醋酸钾(3.01g,32.01mmol)和二氧六环(100mL)，再加入Pd(dppf)Cl2(585.54mg,0.800mmol)，搅拌状态下抽真空氮气置换三次，升温至85℃搅拌反应过夜。反应完后冷却，减压浓缩至干，粗品经硅胶柱层析纯化得中间体B-3(4.83g,13.59mmol,84.89％收率)。MS(ESI)m/z＝296[M+1]+。
中间体B-4的制备
参照中间体B-1合成方法，用4-氨基-2-溴-4-氯苯甲酸甲酯代替中间体B-1-1，其余试剂和操作相同，可得中间体B-4，MS(ESI)m/z＝312[M+1]+。
中间体C-1的制备
冰水浴且氮气保护下，向(甲氧基甲基)三苯基氯化磷(300g,4.09mol)的干燥THF(2.4L)溶液中滴加入n-BuLi(2.5M的己烷溶液,4.09mol,1.63L)，滴毕，混合液0℃下搅拌1hr，反应液逐渐转变为深棕色，然后逐滴滴加入二环丙基酮(300g,2.72mol)的THF(0.6L)溶液。滴毕，反应混合液升温至60℃并搅拌反应4hrs。反应完成后，反应液冷却至室温，加30％ NH4Cl水溶液淬灭，用乙酸乙酯萃取，合并的有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得粗品,经减压蒸馏分离纯化，得澄清油状物中间体C-1-1(279g,74.2％收率)。
在冰水浴条件下向中间体C-1-1(279g,2.02mol)的干燥THF(1.7L)溶液中加入6MHCl(1.7L)，反应液升温至60℃并在此温度下搅拌反应5hrs。反应完成后，加乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩至干得油状物粗品中间体C-1-2(239.6g)，未经进一步纯化直接用于下一步反应。
于5L三口瓶中加入中间体C-1-2(239g,1.92mol,按100％纯度计)和DCM(2.5L)，再依次加入(S)-(+)-对甲基苯亚磺酰胺(299g,1.92mol)，无水硫酸镁(697g,5.79mol)和四氢吡咯(13.73g,0.193mol)。加毕，反应液室温搅拌过夜，过滤，滤液40℃减压浓缩至干，加入石油醚打浆得到滤液，滤液浓缩后，分离纯化，得中间体C-1-3(217g,43％收率)。MS(ESI)m/z＝262[M+1]+。
向中间体C-1-3(217g,0.83mol)的正己烷(2L)溶液中，搅拌状态下加入CsF(252g,1.66mol)，氮气保护下冷却至0℃，然后滴加入TMSCN(165g,1.66mol)。反应液升至室温，搅拌反应过夜。反应完成后，浓缩干，再加入正己烷打浆过滤2次，将固体减压浓缩干得中间体C-1-4(168g,70％收率)。MS(ESI)m/z＝289[M+1]+。
取中间体C-1-4(84g,2.92mol)溶于MeOH(840mL)溶液中，冰水浴下加入HCl/EA(4M,146ml,0.583mol)，搅拌反应2hrs。反应完成后，反应液减压浓缩至干，粗品用石油醚打浆洗涤几次，过滤，滤饼干燥后得中间体C-1-5(54.4g)，未经纯化直接用于下一步反应。MS(ESI)m/z＝151[M+1]+。
冰水浴下，向中间体C-1-5(54.4g,0.363mol，按100％纯度计)的THF(300mL)/H2O(300mL)混合液中加入K2CO3(100.74g,0.73mol)，CbzOsu(90.39g,0.363mol)，25℃搅拌反应2小时。反应完成后，加入乙酸乙酯萃取，合并的有机相无水硫酸钠干燥，过滤，减压浓缩至干。粗品经正相柱分离纯化得白色固体中间体C-1-6(93.6g,0.330mol,90.8％收率)。MS(ESI)m/z＝285[M+1]+。
向中间体C-1-6(75.4g,0.264mol)的DMSO(750mL)溶液中加入K2CO3(54.9mg,0.398mol)，降温至10℃下，然后滴加入H2O2(90g,0.79mol,30％含量)，反应液25℃搅拌反应过夜。反应完成后，加水稀释，乙酸乙酯萃取，合并的有机相无水硫酸钠干燥，过滤，减压浓缩至干后得到中间体C-1-7(73.5g,0.242mol,91.6％收率)，未经纯化直接用于下一步反应。MS(ESI)m/z＝303[M+1]+。
-78℃且氮气保护下，向中间体C-1-7(73.5g,0.242mol)的干燥THF(500mL)/NMP(150mL)混合液中滴加入n-BuLi(204mL,0.5mol,2.5M的己烷溶液)。滴毕，维持在-78℃搅拌反应1小时。然后加入(Boc)2O(57.5mg,0.26mol)的THF(250mL)溶液，继续搅拌反应1小时。反应完成后，小心缓慢加入冷的30％NH4Cl水溶液淬灭反应，加乙酸乙酯萃取。合并有机相，依次水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干得粗品中间体C-1-8(86g,0.214mol)，未经进一步纯化直接用于下一步反应。MS(ESI)m/z＝403[M+1]+。
向中间体C-1-8(86g,0.214mol)的四氢呋喃(800mL)和H2O(200mL)混合溶液中加 入LiOH.H2O(17.89g,0.426mol)，升至40℃并在此温度下搅拌反应过夜，反应完成后，减压蒸馏除去溶剂，粗品溶解在水中，加乙酸乙酯萃取出杂质，冰水浴降温，用6M HCl调pH至2～3，再用乙酸乙酯萃取，浓缩后得粗品，经柱层析分离纯化得中间体C-1(48g,0.158mol,74.07％收率)。MS(ESI)m/z＝304[M+1]+。
中间体C-2的制备
零度下，向3-氟苯酚(1063g，9.49mol)，乙基1-(羟甲基)环丙烷羧酸酯(1435g，9.96mol)和PPh3(2741g，10.46mol)的THF(15L)混合溶液中滴入DIAD(2099g 10.39mol)。控制温度在0℃以下，滴毕，自然升至室温反应过夜。LCMS显示反应完，反应液浓缩至干，加入PE:EA＝15:1的溶液12升，搅拌30分钟析出大量固体，过短硅胶柱，并用PE:EA＝15:1的溶液15升淋洗硅胶层，滤液浓缩至干得中间体C-2-1，以100％计直接用于下一步反应。MS(ESI)m/z＝239[M+1]+。
向中间体C-2-1(9.49mol，以上一步100％计)的95％ EtOH(8L)/H2O(1.6L)混合液中加入LiOH(988.4g，23.72mol)，反应混合液常温搅拌反应12小时。反应完成后，浓缩混合液，粗品加水稀释，滴加浓HCl调节pH至3-4，然后用DCM萃取，合并有机相，分别用水，饱和食盐水洗3次，硫酸钠干燥，过滤，浓缩至干，加入石油醚3升搅30分钟，过滤，并用石油醚洗涤固体，固体干燥得中间体C-2-2(1495g,7.12mol,两步75％产率)，未经纯化直接用于下一步反应。MS(ESI)m/z＝211[M+1]+。
零度且氮气保护下，向中间体C-2-2(1505g 7.16mol)的DCM(10L)/DMF(50mL)混合溶液中逐滴加入草酰氯(COCl)2(1365.2g 10.75mol)，混合液零度下搅拌反应3小时，然后降温至-10℃，分批加入AlCl3(1904.56g，14.32mol)，反应液缓慢升至室温再搅拌反应1小时。 将反应液缓慢倒入冰水中，分出有机相，水相用DCM萃取3次，合并有机相，用水洗3次，用饱和碳酸氢钠溶液洗至弱碱性，用饱和食盐水洗2次，无水硫酸钠干燥，过滤浓缩后得中间体C-2-3粗品(1200g,6.25mol,85.3％产率)，未经纯化直接用于下一步反应。
冰浴且氮气保护下，向(甲氧基甲基)三苯基氯化磷(0.677mol,232.1g)的无水THF(1000mL)溶液中滴加n-BuLi(2.5M的己烷溶液,0.677mol，271ml)，滴毕，混合液0℃下搅拌1小时，混合液转为深棕色，然后逐滴滴加中间体C-2-3(100g，0.521mol)的THF溶液。滴毕，反应混合液升温至60℃并搅拌反应4h。反应完成后，混合液冷却至室温，加30％ NH4Cl水溶液淬灭，用乙酸乙酯萃取，合并的有机相经无水硫酸钠干燥，过滤，滤液浓缩后得粗品，经硅胶柱(0～10％,PE/EA)分离纯化，得到C-2-4(114.74g,0.521mol,100％产率)澄清油状物。
将中间体C-2-4(114g,0.518mmol)的THF(570mL)溶液降温至0℃，控温10℃以下缓慢滴入6M HCl(570mL)，混合液升温至60℃并在此温度下搅拌反应5小时。反应完成后，加乙酸乙酯萃取，合并有机相用10％碳酸氢钠水溶液洗涤1次，饱和氯化钠洗涤1次，经无水硫酸钠干燥后浓缩得中间体C-2-5(106.8g,0.518mol,100％产率)，油状物，未经进一步纯化直接用于下一步反应。
将中间体C-2-5(106.8g,0.518mol),(S)-(+)-叔丁基亚磺酰胺(62.78g,0.518mol)，无水THF(1000mL)和(EtO)4Ti(236.3g,1.036mol)混溶于2000mL单口瓶，氮气保护下，升温至60℃，并搅拌反应5小时，冷却至室温，加水和乙酸乙酯，滤除不溶物，滤液分层，水层用乙酸乙酯萃取2次，合并分离的有机相，浓缩后得到棕色油状物，经硅胶柱(洗脱剂：PE/EA0～50％)分离纯化，得中间体C-2-6(128g,0.414mol,80％产率)浅黄色固体，MS(ESI)m/z＝310[M+1]+。
向中间体C-2-6(128g,0.414mol)的MTBE(2560mL)溶液中，加入CsF(125.78g,0.828mol)，常温加入TMSCN(82.1g,0.828mol)。反应混合液20～25℃搅拌反应过夜。反应完成后，析出大量固体，过滤得到固体，加水，加乙酸乙酯将固体溶解，分层取有机相，水相用乙酸乙酯萃取2次，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干，得到粗品，粗品加入MTBE(5v/m)升温至回流打浆1小时，再逐渐降温至室温搅拌2小时，过滤，得到固体中间体C-2-7(37.6g,0.112mol,27％产率)，类白色固体。MS(ESI)m/z＝337[M+1]+。
向中间体C-2-7(37.6g,0.112mol)的MeOH(376mL)溶液中滴加入HCl/EA(4M，56ml,0.224mol)，室温搅拌反应2h，反应完成后。浓缩反应液，粗品用甲基叔丁基醚打浆洗涤1次，过滤干燥后得中间体C-2-8(25.52g,0.110mol,98％收率)未经纯化直接用于下一步反应。 MS(ESI)m/z＝233[M+1]+。
室温下，向中间体C-2-8(25.52g,0.110mol)的THF(153mL)/H2O(77mL)混合液中加入K2CO3(45.6g,0.330mol)，Cbz-Osu(54.82g,0.220mol)，40℃搅拌反应过夜，反应完成后。加乙酸乙酯萃取，合并的有机相浓缩后得粗品经MPLC分离纯化，得中间体C-2-9(38.66g,0.106mol,96.02％产率)油状物。MS(ESI)m/z＝367[M+1]+。
向中间体C-2-9(38.66g,0.106mol)的DMSO(387mL)溶液中加入K2CO3(14.65g,0.106mol)，然后滴加入H2O2(24g,30％,0.212mol)，反应混合液25℃搅拌2小时。反应完成后，加大量水稀释，析出大量白色固体，将固体过滤，并用水充分淋洗滤饼，滤饼再用适量乙酸乙酯溶解，水洗1次后用饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤液浓缩后得到中间体C-2-10(39.93g,0.104mol,98％产率)固体。MS(ESI)m/z＝385[M+1]+。
-78℃且氮气保护下，向中间体C-2-10(39.93g,0.104mol)的无水THF(400mL)/NMP(80mL)混合液中滴加n-BuLi(96ml,0.239mol，2.5M in hexane)。滴毕，维持在-78℃搅拌反应1小时。然后加入(Boc)2O(29.06g,0.135mol)的THF溶液，继续搅拌1小时。反应完成后，小心缓慢加入冷的30％NH4Cl水溶液淬灭反应，加乙酸乙酯萃取，浓缩萃取得到中间体C-2-11(50.4g,0.104mol,100.00％产率)，未经进一步纯化直接用于下一步反应。MS(ESI)m/z＝485[M+1]+。
向中间体C-2-11(50.4g,0.104mol)的THF(806mL)/H2O(201mL)混合液中加入LiOH一水合物(8.67g,0.208mol)，升温至40℃并在此温度下搅拌过夜，反应完成后，用2M HCl调节水层pH＝3～4，分层，水层再用乙酸乙酯萃取2次，合并有机层，用饱和食盐水洗涤1次，无水硫酸钠干燥，过滤后减压蒸馏除去溶剂得到粗品，粗品溶解在乙酸乙酯中，常温搅拌滴入二异丙胺(12.6g，0.125mol)，滴完继续搅拌2小时，过滤得白色固体，将固体溶于适量水和乙酸乙酯，用2M HCl调节水层pH＝3～4，分层取有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤后有机相浓缩至干得纯品中间体C-2(27g,70mmol,67.3％两步收率)，MS(ESI)m/z＝386[M+1]+。1H NMR(400MHz,Methanol-d4)δ7.30(q,J＝7.7,6.6Hz,5H),7.02(dd,J＝8.5,6.6Hz,1H),6.52(dd,J＝10.6,2.6Hz,1H),6.44(td,J＝8.5,2.7Hz,1H),5.06(d,J＝12.5Hz,1H),4.96(d,J＝12.6Hz,1H),4.68(dd,J＝11.3,2.0Hz,1H),4.54(d,J＝7.6Hz,1H),3.27(d,J＝1.8Hz,1H),2.38(d,J＝7.5Hz,1H),0.94–0.79(m,2H),0.75–0.64(m,1H),0.63–0.53(m,2H),0.46–0.35(m,1H)。旋光数据：测试温度25℃，样品浓度0.002g/100mL，溶剂甲醇，比旋光度-132.8°，手性纯度98％。
中间体C-3的制备
合成方法：参照专利UCB-WO2020/11731,2020,A1里面的合成方法，可得中间体C-3，MS(ESI)m/z＝306[M+1]+。
中间体C-4的制备
合成方法：参照专利WO2020/146194,2020,A1里面的合成方法，只是中间一步双键还原采用了Pd/C还原，其余试剂和操作相同，可得中间体C-4，MS(ESI)m/z＝328[M+1]+。
中间体C-5的制备
于三口瓶中加入(S)-(-)-N-Z-氮杂环丙烷-2-羧酸甲酯(10g,42.55mmol)，2-三氟甲基-2-丙醇(27.23g,212.77mmol)和二氯甲烷(90mL)，抽真空氮气置换三次，反应混合液降温至0℃，滴加入三氟化硼乙醚溶液(4mL)。加毕，升至室温搅拌反应6小时。反应完成后，冰水浴降温，用甲醇淬灭反应，反应液减压浓缩至干。粗品经硅胶柱层析纯化得中间体C-5-1(400mg,1.10mmol,2.59％收率)。MS(ESI)m/z＝364[M+1]+。
于单口瓶中加入中间体C-5-1(400mg,1.10mmol)和四氢呋喃/甲醇(10mL/10mL)，冰水浴降温，加入氢氧化钠(79.27mg,1.98mmol)的水溶液(10mL)。加毕，升至室温搅拌反应1小时。反应完成后，用6N盐酸调PH值至弱碱性，与0℃减压浓缩除去有机溶液，加水稀释，用乙酸乙酯萃取两遍，弃去，水相再用6N盐酸调PH值至4，乙酸乙酯萃取，有机相无水硫酸钠干燥，过滤，减压浓缩至干得中间体C-5(298mg,853.13μmol,86.10％收率)。MS (ESI)m/z＝350[M+1]+。
中间体D-1的制备
于三口瓶中加入1H-3-吡唑羧酸甲酯(1.31g,10.41mmol)，三苯基磷(3.28g,12.49mmol)和干燥四氢呋喃(80mL)，抽真空氮气置换三次，然后经注射器加入1,1-二氟-2-丙醇(1g,10.41mmol)，反应混合液降温至-5℃，滴加入DIAD(2.52g,12.49mmol)。加毕，升至室温搅拌反应过夜。反应完成后，直接硅胶柱层析纯化得到中间体D-1-1(1.5g,3.82mmol,36.70％收率,52％纯度，第一个极性较小的点，另一个位置异构体极性较大，因这一步不纯，故在下一步水解后NOE确认结构)。MS(ESI)m/z＝205[M+1]+。
于单口瓶中加入中间体D-1-1(1.5g,3.82mmol,52％纯度)和四氢呋喃/甲醇(12mL/12mL)，冰水浴降温，加入氢氧化钠(305.62mg,7.64mmol)的水溶液(12mL)。加毕，升至室温搅拌反应1小时。反应完成后，减压浓缩除去有机溶液，加水稀释，用乙酸乙酯萃取两遍，弃去，水相再用6N盐酸调pH值至4，析出大量白色固体，减压过滤，水洗，干燥得到中间体D-1(0.56g,2.39mmol,62.44％收率,81％纯度,NOE确认结构)。MS(ESI)m/z＝191[M+1]+。1H NMR(400MHz,DMSO-d6)δ13.58(s,1H),7.66(t,J＝2.3Hz,1H),6.89(d,J＝2.0Hz,1H),6.27(tdd,J＝55.6,5.0,2.4Hz,1H),5.85–5.67(m,1H),1.54(dd,J＝7.0,1.2Hz,3H).中间体D-2至中间体D-43的制备
参照中间体D-1的合成路线，步骤1中用下表中相应的醇代替1,1-二氟-2-丙醇，其余试剂和操作相同，可得下表中相应的中间体。





中间体D-44的制备
参照中间体D-1的合成路线，步骤1中用(R)-(-)-1-苄氧基-2-丙醇代替1,1-二氟-2-丙醇，其余试剂和操作相同，可得中间体D-44-2，MS(ESI)m/z＝261[M+1]+。
于单口瓶中加入中间体D-44-2(2g,7.68mmol)和甲醇(100mL)，再加入Pd/C(200mg,w/w 10％)。加毕，抽真空氢气置换三次，于氢气球环境下室温搅拌反应过夜。反应完成后，硅藻土过滤，甲醇洗涤，滤液减压浓缩至干得中间体D-44(1.30g,7.64mmol,99.43％收率)。MS(ESI)m/z＝171[M+1]+。
中间体D-45的制备
参照中间体D-44的合成路线，步骤1中用3-苄氧基-1-丙醇代替(R)-(-)-1-苄氧基-2-丙醇，其余试剂和操作相同，可得中间体D-45，MS(ESI)m/z＝171[M+1]+。
中间体D-46的制备
于三口瓶中加入1-H-吡唑-5-羧酸甲酯(30g,237.88mmol)和干燥四氢呋喃(300mL)，抽真空氮气置换三次，冰水浴降温至0℃，再分批加入氢化钠(14.27g,356.82mmol)。加毕，抽真空氢气置换三次，保温0℃搅拌反应30分钟。然后于0℃滴加入SEMCl(47.59g,285.46mmol)，滴毕，升至室温搅拌反应3小时。冰水浴降温至0℃，反应液慢慢倾倒入冰的氯化铵溶液中淬灭反应，用乙酸乙酯萃取两次，合并有机相，有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩至干，粗品经硅胶柱层析纯化得中间体D-46-1(55g,214.53mmol,90.18％收率)。MS(ESI)m/z＝257[M+1]+。
于单口瓶中加入中间体D-46-1(60g,234.03mmol)和四氢呋喃/甲醇(100mL/300mL)，冰水浴降温，加入氢氧化锂(29.46g,702.10mmol)的水溶液(200mL)。加毕，升至室温搅拌反应2小时。反应完成后，减压浓缩除去有机溶液，加水稀释，用乙酸乙酯萃取两遍，弃去，水相再用6N盐酸调pH值至4，析出大量白色固体，减压过滤，水洗，干燥得到中间体D-46-2(50g,206.32mmol,88.16％收率)。MS(ESI)m/z＝243[M+1]+。
于单口瓶中加入中间体D-46-2(62g,255.83mmol)和DMF(1000mL)，冰水浴降温，加入碳酸钾(45.96g,332.58mmol)，升至室温搅拌30分钟，然后冰水浴降温，滴加入苄溴(113.77g,665.16mmol)。加毕，升至室温搅拌反应过夜。反应完成后，倒入冰水中，用乙酸乙酯萃取两遍，有机相饱和食盐水洗涤三遍，无水硫酸钠干燥，过滤，滤液减压浓缩至干。粗品经硅胶柱层析纯化得中间体D-46-3(60g,180.47mmol,70.54％收率)。MS(ESI)m/z＝333[M+1]+。
于单口瓶中加入中间体D-46-3(20g,60.24mmol)和二氯甲烷(150mL)，冰水浴降温， 加三氟乙酸(150mL)，加毕，升至室温搅拌反应1小时，然后减压浓缩至干。粗品用二氯甲烷溶解，搅拌状态下用碳酸氢钠溶液调pH至8，分出有机相，有机相饱和食盐水洗涤两遍，无水硫酸钠干燥，过滤，滤液减压浓缩至干得中间体D-46-4(10.98g,54.34mmol,90.20％收率)。MS(ESI)m/z＝203[M+1]+。
参照中间体D-1的合成路线，步骤1中用N-叔丁基-3-羟基氮杂环丁烷代替1,1-二氟-2-丙醇，其余试剂和操作相同，可得中间体D-46-5，MS(ESI)m/z＝314[M+1]+。
于单口瓶中加入中间体D-46-5(300mg,957.26μmol)和甲醇(10mL)，再加入Pd/C(45mg,w/w 15％)和Pd(OH)2(45mg,w/w 15％)。加毕，抽真空氢气置换三次，于氢气球环境下室温搅拌反应3小时。反应完成后，硅藻土过滤，甲醇洗涤，滤液减压浓缩至干得中间体D-46(190mg,850.98μmol,88.90％收率)。MS(ESI)m/z＝224[M+1]+。
中间体D-47的制备
参照中间体D-44的合成路线，步骤1中用2-苄氧基-1-乙醇代替(R)-(-)-1-苄氧基-2-丙醇，其余试剂和操作相同，可得中间体D-47-1，MS(ESI)m/z＝157[M+1]+。
参照中间体D-46的合成路线，步骤3中用中间体D-47-1代替中间体D-46-2，其余试剂和操作相同，可得中间体D-47-2，MS(ESI)m/z＝247[M+1]+。
于单口瓶中加入中间体D-47-2(498.98mg,2.80mmol)和乙腈(20mL)，再加入碘化亚铜(88.94mg,466.98μmol)，将2-氟磺酰基二氟乙酸(498.98mg,2.80mmol)溶解于乙腈(5mL)中，滴加入上述溶液，加毕，升至50℃搅拌反应2小时。反应完成后，用碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取。有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经硅胶柱层析纯化得中间体D-47-3(145mg,489.42μmol,26.20％收率)，MS(ESI)m/z＝ 297[M+1]+。
参照中间体D-46的合成路线，步骤6中用中间体D-47-3代替中间体D-46-5，其余试剂和操作相同，可得中间体D-47，MS(ESI)m/z＝207[M+1]+。
中间体D-48的制备
于三口瓶中加入苄氧乙醇(3g,19.71mmol)，二氯甲烷(100mL)和三乙胺(7.98g,78.85mmol,11.00mL)，冰水浴降温至0℃，滴加入甲基磺酰氯(4.52g,39.42mmol)，滴毕，升至室温搅拌反应2小时。反应完成后，加水淬灭反应，乙酸乙酯萃取。合并后的有机相用碳酸氢钠水溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得中间体D-48-1(5.7g,19.55mmol,99.20％收率)。
于单口瓶中加入中间体D-48-1(5.7g,19.55mmol)和DMF(50mL)，再加入叠氮化钠(1.29g,19.80mmol)，加毕，升温至90℃搅拌反应12小时。反应完成后，冷却，加入碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取。合并后的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得中间体D-48-2(2.95g,16.65mmol,84.07％收率)。
于单口瓶中加入中间体D-48-2(2.95g,16.65mmol)和甲苯(40mL)，再加入丙炔酸甲酯(1.40g,16.65mmol)，加毕，升温至100℃搅拌反应12小时。反应完成后，冷却，减压浓缩至干。粗品经硅胶柱层析纯化，收集极性小的产品点，经H-NMR和NOE验证得中间体D-48-3(749mg,2.87mmol,17.22％收率)。MS(ESI)m/z＝262[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.15(s,1H),7.29–7.19(m,3H),7.17–7.12(m,2H),4.96(t,J＝5.3Hz,2H),4.43(s,2H),3.87(t,J＝5.3Hz,2H),3.83(s,3H).
于单口瓶中加入中间体D-48-3(749mg,2.87mmol)和甲醇(20mL)，再加入Pd/C(150mg,w/w 20％)和Pd(OH)2(150mg,w/w 20％)。加毕，抽真空氢气置换三次，于氢气球环境下室温搅拌反应12小时。反应完成后，硅藻土过滤，甲醇洗涤，滤液减压浓缩至干得中间体D-48-4(541mg,2.84mmol,99.24％收率)。MS(ESI)m/z＝172[M+1]+。
参照中间体D-47步骤2的合成路线，步骤2中用中间体D-48-4代替中间体D-47-2，其余试剂和操作相同，可得中间体D-48-5，MS(ESI)m/z＝222[M+1]+。
参照中间体D-1步骤2的合成路线，步骤2中用中间体D-48-5代替中间体D-1-1，其余试剂和操作相同，可得中间体D-48，MS(ESI)m/z＝208[M+1]+。
中间体D-49的制备
于单口瓶中加入中间体D-43-1(189mg,943.78μmol)和二氯甲烷(6mL)，降温至0℃再加入m-CPBA(210.77mg,1.04mmol)。加毕，升至室温搅拌反应3小时。反应完成后，降温至0℃，加入饱和亚硫酸钠溶液淬灭反应，二氯甲烷萃取。有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经硅胶柱层析纯化得中间体D-49-1(190mg,818.06μmol,86.68％收率)。MS(ESI)m/z＝233[M+1]+。
于单口瓶中加入中间体D-49-1(730mg,3.14mmol)和四氢呋喃/甲醇(5mL/5mL)，冰水浴降温，加入氢氧化锂一水合物(395.68mg,9.43mmol)的水溶液(5mL)。加毕，升至室温搅拌反应2小时。反应完成后，减压浓缩除去有机溶液，加水稀释，用乙酸乙酯萃取两遍，弃去，水相再用6N盐酸调pH值至4，析出大量白色固体，减压过滤，水洗，干燥得到中间体D-49(650mg,2.98mmol,94.76％收率)。MS(ESI)m/z＝219[M+1]+。
中间体D-50的制备
于单口瓶中加入中间体D-45(2g,11.76mmol)和DMF(39mL)，冰水浴降温，加入碳酸钾(3.25g,23.52mmol)，升至室温搅拌30分钟，然后冰水浴降温，滴加入碘甲烷(1.84g,12.94mmol)。加毕，升至室温搅拌反应过夜。反应完成后，倒入冰水中，用乙酸乙酯萃取两遍，有机相饱和食盐水洗涤三遍，无水硫酸钠干燥，过滤，滤液减压浓缩至干。粗品经硅胶柱层析纯化得中间体D-50-1(2.09g,11.36mmol,96.64％收率)。MS(ESI)m/z＝185[M+1]+。
于三口瓶中加入草酰氯(206.73mg,1.63mmol)和DCM(4mL)，干冰乙醇浴降温至-60℃，滴加入DMSO(254.52mg,3.26mmol)，保温搅拌反应30分钟，然后滴加入中间体D-50-1(100mg,542.91μmol)的二氯甲烷溶液。加毕，保温搅拌反应1小时。然后滴加入三乙胺(329.62mg,3.26mmol)，加毕，逐渐升温至0℃并搅拌反应30分钟。反应完成后，倒入冰水中，用二氯甲烷萃取两遍，有机相饱和食盐水洗涤三遍，无水硫酸钠干燥，过滤，滤液减压浓缩至干得粗品中间体D-50-2(100mg,542.91μmol)。
于单口瓶中加入中间体D-50-2(100mg,542.91μmol)和四氢呋喃(2mL)，再加入氟化铯(4.17mg,27.45μmol)和三氟甲基三甲基硅烷(85.86mg,603.81μmol)。加毕，室温搅拌反应2小时。反应完成后，加水淬灭反应，用乙酸乙酯萃取两遍，有机相饱和食盐水洗涤三遍，无水硫酸钠干燥，过滤，滤液减压浓缩至干。粗品经硅胶柱层析纯化得中间体D-50-3(40mg,158.61μmol,28.90％收率)。MS(ESI)m/z＝253[M+1]+。
于单口瓶中加入中间体D-50-3(40mg,158.61μmol)和四氢呋喃/甲醇(1mL/1mL)，冰水浴降温，加入氢氧化锂一水合物(19.97mg,475.83μmol)的水溶液(1mL)。加毕，升至室温搅拌反应2小时。反应完成后，减压浓缩除去有机溶液，加水稀释，用乙酸乙酯萃取两遍，弃去，水相再用6N盐酸调pH值至4，用乙酸乙酯萃取两遍，有机相饱和食盐水洗涤两遍，无水硫酸钠干燥，过滤，滤液减压浓缩至干得中间体D-50(25mg,104.97μmol,66.18％收率)。MS(ESI)m/z＝239[M+1]+。
中间体D-51的制备
于单口瓶中加入中间体D-39-1(280mg,1.31mmol)和二氯甲烷(6mL)，降温至0℃再加入m-CPBA(247.55mg,1.44mmol)。加毕，升至室温搅拌反应3小时。反应完成后，降温至0℃，加入饱和亚硫酸钠溶液淬灭反应，二氯甲烷萃取。有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经硅胶柱层析纯化得中间体D-51-1(248.39mg,1.08mmol,82.54％收率)。MS(ESI)m/z＝231[M+1]+。
于单口瓶中加入中间体D-51-1(200mg,868.49μmol)和THF/MeOH/H2O(3mL/3mL/3mL)，加入水合氢氧化锂(3.25g,23.52mmol)，室温搅拌反应2小时。反应完成后，有机溶剂减压浓缩，加入适当水稀释，用6N HCl调PH值至4，乙酸乙酯萃取两遍，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干得粗品中间体D-51(120mg,554.90μmol,63.89％收率)，MS(ESI)m/z＝217[M+1]+，不经纯化直接用于下一步。
中间体D-52的制备
于三口瓶中加入2-氟-2-磷酰基乙酸三乙酯(1g,4.13mmol)和干燥THF(10mL)，抽真空氮气置换三次，干冰乙醇浴降温至-60℃，滴加入正丁基锂(1.65mL,4.13mmol)，滴毕，保持此温度继续搅拌反应10分钟，然后滴加入异丁醛(238.19mg,3.30mmol)。滴毕，逐渐升至室温并搅拌反应1小时，反应完成后，倾倒入饱和氯化铵溶液中淬灭反应，二氯甲烷萃取。有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干得粗品中间体D-52-1(436mg,2.72mmol,65.92％收率)，不经纯化直接用于下一步。
于单口瓶中加入中间体D-52-1(436mg,2.72mmol)和THF/EtOH/H2O(8mL/0.8mL/3mL)，加入水合氢氧化锂(125.75mg,2.99mmol)，室温搅拌反应2小时。反应完成后，冰水浴条件下用6N HCl调PH值至4，二氯甲烷萃取两遍，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干得粗品中间体D-52(337mg,2.55mmol,93.70％收率)，MS(ESI) m/z＝131[M-1]+，不经纯化直接用于下一步。
中间体D-53的制备
参照中间体D-52的合成路线，步骤1中用环丙甲醛代替异丁醛，其余试剂和操作相同，可得中间体D-53，MS(ESI)m/z＝129[M-1]+，不经纯化直接用于下一步。
中间体D-54的制备
参照中间体D-52的合成路线，步骤1中用丙酮代替异丁醛，其余试剂和操作相同，可得中间体D-54，MS(ESI)m/z＝117[M-1]+，不经纯化直接用于下一步。
中间体D-55的制备
于单口瓶中加入5-溴-1-甲基-1H-吡咯-2-羧酸甲酯(1g,4.59mmol)和DMF(15mL)，再加入氰化锌(807.76mg,6.88mmol)和四三苯基磷(264.85mg,229.31μmol)，抽真空氮气置换三次，升温至95℃搅拌反应16小时。反应完成后，加水淬灭反应，乙酸乙酯萃取两遍，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱层析纯化得中间体D-55-1(680mg,4.14mmol,90.32％收率)。
1H NMR(600MHz,Chloroform-d)δ6.89(d,J＝4.3Hz,1H),6.74(d,J＝4.3Hz,1H),4.07(s,3H),3.87(s,3H).
于单口瓶中加入中间体D-55-1(630mg,3.84mmol)和THF//H2O(6mL/6mL)，加入水合氢氧化锂(319.76mg,7.68mmol)，室温搅拌反应2小时。反应完成后，有机溶剂减压浓缩，加入适当水稀释，用6N HCl调PH值至4，析出大量白色固体，过滤，水洗，固体干燥得中间体D-55(527mg,3.51mmol,91.47％收率)，MS(ESI)m/z＝151[M+1]+。
中间体D-56的制备
于单口瓶中加入3-吡唑羧酸甲酯(1.40g,11.09mmol)和乙腈(50mL)，搅拌状态下再加入碳酸铯(3.62g,11.09mmol)，冰水浴条件下滴加入三氟甲磺酸乙酯(1.97g,11.09mmol)，滴毕，室温搅拌反应2小时。反应完成后，硅藻土过滤，滤液减压浓缩至干，粗品经硅胶柱层析纯化得中间体D-56-1(1.94g,9.34mmol,84.21％收率)，MS(ESI)m/z＝209[M+1]+。
参照中间体D-1的合成路线，步骤2中用中间体D-56-1代替中间体D-1-1，其余试剂和操作相同，可得中间体D-56，MS(ESI)m/z＝195[M+1]+。
中间体D-57的制备
于30mL微波管中加入1-异丙基-1H-吡唑-5-羧酸乙酯(500mg,2.74mmol)和乙腈/冰乙酸(6.9mL/2.3mL)，然后加入selectfluor(1.46g,4.12mmol)，加毕，氮气鼓泡1分钟，至于微波反应器中，升温至100℃搅拌反应6小时。液质和TLC显示只反应了一半，加水淬灭反应，用碳酸钾溶液调pH值至8，二氯甲烷萃取。有机相无水硫酸钠干燥，过滤，滤液减压浓缩至干，粗品经硅胶柱层析纯化得中间体D-57-1(0.2g,998.95μmol,36.41％收率)，MS(ESI)m/z＝201[M+1]+。
参照中间体D-1的合成路线，步骤2中用中间体D-57-1代替中间体D-1-1，其余试剂和操作相同，可得中间体D-57，MS(ESI)m/z＝173[M+1]+。
中间体D-58的制备
参照中间体D-1的合成路线，步骤1中用1,2,4-三氮唑-3-羧酸甲酯代替1H-3-吡唑羧酸甲酯，同时用异丙醇代替1,1-二氟-2-丙醇，其余试剂和操作相同，D-58-1经氢谱和NOE确认， 可得中间体D-58，MS(ESI)m/z＝156[M+1]+。D-58-1：1H NMR(600MHz,Methanol-d4)δ8.05(s,1H),5.55(p,J＝6.6Hz,1H),3.99(s,3H),1.51(d,J＝6.6Hz,6H)。
中间体D-59的制备
参照中间体D-46步骤5和步骤6的合成路线，步骤5中用氧杂环丁烷-3-甲醇代替N-叔丁基-3-羟基氮杂环丁烷，其余试剂和操作相同，可得中间体D-59，MS(ESI)m/z＝183[M+1]+。
中间体E-1的制备
于单口瓶中加入中间体B-3-2(247g,995.77mmol)和DCM(2L)，室温加入DMAP(24.4g,199.72mmol)，然后冰水浴条件下加入Boc酸酐(24.4g,199.72mmol)。加毕，室温搅拌反 应过夜。反应完后，反应液减压浓缩至干，粗品经硅胶柱纯化得中间体E-1-1A(280.8g,626.39mmol,62.91％收率)，MS(ESI)m/z＝448[M+1]+和中间体E-1-1B(79.5g,228.34mmol,22.93％收率，MS(ESI)m/z＝348[M+1]+。
于单口瓶中加入中间体E-1-1A(280.8g,626.39mmol)和四氢呋喃(2L)，室温加入甲醇(28g,873.91mmol)和硼氢化锂(41g,1.88mol)。加毕，升温至60℃搅拌反应1小时。反应完后，冷却，加饱和氯化铵淬灭反应，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体E-1-2(153.7g,480.08mmol,76.64％收率)，MS(ESI)m/z＝320[M+1]+.
于单口瓶中加入中间体E-1-2(13.56g,42.35mmol)和二氯甲烷(140mL)，冰水浴条件下分批加入DMP(21.56g,50.83mmol)。加毕，室温搅拌反应2小时。反应完后，加入1M Na2S2O3溶液和1M NaHCO3溶液淬灭反应，并搅拌30分钟，二氯甲烷萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体E-1-3(12g,37.72mmol,89.06％收率)，MS(ESI)m/z＝318[M+1]+.
于单口瓶中加入中间体E-1-3(4.42g,13.89mmol)和甲醇(50mL)，室温加入甲胺盐酸盐(862.97mg,27.79mmol)，室温搅拌反应1小时，冰水浴降温至0℃，分批加入硼氢化钠(1.05g,27.79mmol)，加毕，升至室温搅拌反应2小时。反应完后，冷却，加饱和氯化铵淬灭反应，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得粗品中间体E-1-4(4.62g,13.87mmol,99.80％收率)，MS(ESI)m/z＝333[M+1]+，不经纯化直接用于一下步。
于单口瓶中加入中间体E-1-4(4.28g,12.85mmol)和四氢呋喃/水(40mL/20mL)，室温加入碳酸氢钠(2.16g,25.69mmol)，然后加入Boc酸酐(4.21g,19.27mmol)，室温搅拌反应2小时。反应完后，加水稀释，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体E-1-5(5.33g,12.30mmol,95.76％收率)，MS(ESI)m/z＝433[M+1]+。
于单口瓶中加入中间体E-1-5(5.0g,11.57mmol)，中间体A-3(4.75g,11.57mmol)，二氧六环和水(100mL/20mL)，室温下加入Pd2(dba)3(264.76mg,289.25μmol)，rac-BI-DIME(190.97mg,578.50μmol)和磷酸钾(4.91g,23.14mmol)，抽真空氮气置换三次，逐渐升至100℃搅拌反应过夜。反应完后，加入水淬灭反应，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体E-1-6(4.32g,6.78mmol,58.64％收率)，MS(ESI)m/z＝637[M+1]+.
于单口瓶中加入中间体E-1-6(4.0g,6.29mmol)和乙酸乙酯(15mL)，冰水浴条件下加入4M HCl乙酸乙酯溶液(142mL)，逐渐升至室温搅拌反应1小时。反应完后，冰水浴冷却，慢慢倾倒入饱和碳酸氢钠溶液中，始终保持溶液pH值偏碱性，然后乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体E-1-7(1.51g,3.47mmol,55.15％收率)，MS(ESI)m/z＝437[M+1]+.
于单口瓶中加入中间体E-1-7(1.51g,3.47mmol)和四氢呋喃/水(10mL/10mL)，室温加入氢氧化锂水合物(0.29g,6.93mmol)，室温搅拌反应2小时。反应完后，冰水浴条件下用2M HCl调pH值至中性，减压浓缩至干得粗品中间体E-1-8(1.46g,3.47mmol,按理论百分百收率计算)，MS(ESI)m/z＝423[M+1]+。
于单口瓶中加入中间体E-1-8(1.46g,3.47mmol)和DMF(18mL)，再加入HATU(1.58g,4.16mmol)和DIPEA(1.34g,10.41mmol)，室温搅拌反应2小时。反应完后，加入水淬灭反应，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化中间体E-1(0.99g,2.45mmol,70.58％收率)，MS(ESI)m/z＝405[M+1]+。
中间体E-2至中间体E-15的制备
参照中间体E-1的合成路线，步骤4中用下表中相应的胺代替甲胺盐酸盐，其余试剂和操作相同，可得相应中间体。



中间体E-16的制备
于三口瓶中加入中间体E-1(0.5g,1.24mmol)和干燥四氢呋喃(20mL)，抽真空氮气置换三次，经注射器加入硼烷四氢呋喃溶液(7.44mL,7.44mmoL)，逐渐升温至60℃搅拌反应6小时。反应液冷却，冰水浴条件滴加入甲醇淬灭反应，减压浓缩至干得，粗品经硅胶柱层析纯化得中间体E-16(0.28g,0.72mmol,58.0％收率)，MS(ESI)m/z＝391[M+1]+。
中间体E-17至中间体E-15的制备
参照中间体E-16的合成方法，用下表中相应的大环酰胺代替中间体E-1，其余试剂和操作相同，可得相应中间体。



中间体E-29的制备
于单口瓶中加入中间体118-3(5.6g,16.12mmol)和甲醇(50mL)，室温加入乙酸铵(6.21g,80.62mmol)，然后升温至50℃搅拌反应3小时。冷却，分批加入氰基硼氢化钠(2.03g,32.25mmol)，然后室温搅拌反应2小时。用碳酸氢钠溶液淬灭反应，乙酸乙酯萃取。有机相饱和 食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经MPLC纯化得中间体E-29-1(5.2g,14.93mmol,92.58％收率)，MS(ESI)m/z＝348[M+1]+。
于单口瓶中加入中间体E-29-1(250mg,717.66μmol)和DCM(8L)，室温加入三乙胺(145.24g,1.44mmol)和Boc酸酐(187.95mg,861.19μmol)。加毕，室温搅拌反应3小时。反应完后，加水淬灭反应，二氯甲烷萃取。有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经硅胶柱纯化得中间体E-29-2(180mg,401.37μmol,55.93％收率)，MS(ESI)m/z＝448[M+1]+。
参照中间体E-1的合成路线，步骤7中用中间体E-29-2代替中间体A-3，同时用中间体B-3代替中间体E-1-5，其余试剂和操作相同，可得中间体E-29，MS(ESI)m/z＝405[M+1]+。
中间体E-30的制备
参照中间体E-1的合成路线，步骤1中用2-氨基-5-溴异烟酸甲酯代替中间体B-3-2，其余试剂和操作相同，可得中间体E-30-2，MS(ESI)m/z＝303[M+1]+。
于单口瓶中加入中间体E-30-2(18.2g,60.04mmol)和二氯甲烷(300mL)，室温加入三乙胺(12.15g,120.07mmol,16.75mL)，然后冰水浴条件下滴加入甲基磺酰氯(7.56g,66.04mmol)，滴毕，室温搅拌反应3小时。反应完后，加水稀释，二氯甲烷萃取。有机相依次用碳酸氢钠溶液、饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得粗品中间体E-30-3(18.8g,49.31mmol,82.14％收率)，MS(ESI)m/z＝381[M+1]+，不经纯化直接用于下一步。
于单口瓶中加入中间体E-30-3(10g,26.32mmol)和DMF(130mL)，室温加入环丙胺(18g,31.58mmol)，然后加入碳酸钠(5.58g,52.64mmol)和碘化钠(3.95g,26.32mmol)，加毕，室温搅拌反应过夜。反应完后，加水淬灭反应，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经硅胶柱层析纯化得中间体E-30-4(7.69g,22.55mmol,85.68％收率)，MS(ESI)m/z＝342[M+1]+。
于单口瓶中加入中间体E-30-4(1.98g,5.78mmol)和四氢呋喃/水(15mL/15mL)，室温加入碳酸钠(1.84g,17.35mmol)和氯甲酸苄酯(1.48g,8.67mmol)，加毕，室温搅拌反应2小时。反应完后，加水稀释，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经硅胶柱层析纯化得中间体E-30-5(2.2g,4.62mmol,79.87％收率)，MS(ESI)m/z＝476[M+1]+。
参照中间体E-1的合成路线，步骤6中用中间体E-30-5代替中间体E-1-5，其余试剂和操作相同，可得中间体E-30-6，MS(ESI)m/z＝680[M+1]+。
于单口瓶中加入中间体E-30-6(1.57g,2.31mmol)和甲醇(30mL)，室温加入钯碳(471mg,w/w 30％)，加毕，抽真空氢气置换三次，室温搅拌反应3小时。反应完后，硅藻土过滤，甲醇洗涤，滤液减压浓缩至干得粗品中间体E-30-7(966mg,1.77mmol,76.65％收率)，MS(ESI)m/z＝546[M+1]+。
参照中间体E-1的合成路线，步骤7中用中间体E-30-7代替中间体E-1-6，其余试剂和操作相同，可得中间体E-30，MS(ESI)m/z＝414[M+1]+。
中间体E-31至中间体E-36的制备
参照中间体E-30的合成方法，步骤4中用下表中相应的胺代替环丙基胺，其余试剂和操作相同，可得相应中间体。

中间体E-37至中间体E-42的制备
参照中间体E-16的合成方法，用下表中相应的吡啶大环酰胺代替中间体E-1，其余试剂和操作相同，可得相应中间体。

中间体E-43的制备
参照中间体E-1的合成路线，步骤1中用中间体E-37代替中间体B-3-2，其余试剂和操作相同，可得中间体E-43-1，MS(ESI)m/z＝550[M+1]+。
于单口瓶中加入中间体E-43-1(500mg,0.91mmol)和甲醇(9mL)，室温加入钯碳(150mg,w/w 30％)和氢氧化钯(150mg,w/w 30％)，加毕，抽真空氢气置换三次，室温搅拌反应6小时。反应完后，硅藻土过滤，甲醇洗涤，滤液减压浓缩至干得粗品中间体E-43-2(384.59mg,0.84mmol,92％收率)，MS(ESI)m/z＝460[M+1]+。
于单口瓶中加入中间体E-43-2(384.59mg,0.84mmol)和二氯甲烷(8mL)，室温加入三乙胺(93.32mg,0.92mmol)和乙酸酐(85.68mg,0.84mmol)，加毕，室温搅拌反应2小时。反应完后，滤液减压浓缩至干，粗品经反相MPLC纯化得中间体E-43-3(331.71mg,0.66mmol,78.82％收率)，MS(ESI)m/z＝502[M+1]+。
参照中间体E-1的合成路线，步骤7中用中间体E-43-3代替中间体E-1-6，其余试剂和操作相同，可得中间体E-43，MS(ESI)m/z＝402[M+1]+。
中间体E-44的制备
参照中间体E-1的合成路线，步骤4中用苄胺代替甲胺盐酸盐，其余试剂和操作相同，可得中间体E-44，MS(ESI)m/z＝481[M+1]+。
中间体E-45的制备
参照中间体E-16的合成方法，用中间体E-44代替中间体E-1，其余试剂和操作相同，可得中间体E-45，MS(ESI)m/z＝467[M+1]+。
中间体E-46的制备
参照中间体E-43的合成方法，用中间体E-45代替中间体E-37，其余试剂和操作相同，可得中间体E-46-2，MS(ESI)m/z＝477[M+1]+。
于单口瓶中加入中间体E-46-2(400mg,0.84mmol)和二氯甲烷(8mL)，室温加入DIPEA(271mg,2.10mmol)和溴乙腈(109.96mg,0.92mmol)，加毕，室温搅拌反应过夜。反应完后，滤液减压浓缩至干，粗品经反相MPLC纯化得中间体E-46-3(297.15mg,0.58mmol,68.69％收率)，MS(ESI)m/z＝516[M+1]+。
于单口瓶中加入中间体E-46-3(297.15mg,0.58mmol)和二氯甲烷(5mL)，冰水浴条件下加入TFA(0.5mL)，加完后室温反应3小时，反应完后倒入碳酸氢钠水溶液中，二氯甲烷萃取，有机相无水硫酸钠干燥，过滤，减压浓缩至干，粗品经反相MPLC纯化得中间体E-46，MS(ESI)m/z＝416[M+1]+。
中间体E-47的制备
于单口瓶中加入中间体118-3(1.0g,2.89mmol)和DCE(20mL)，再加入2’2-二氟乙胺(0.35g,4.34mmol)，然后40℃搅拌反应过夜，冷却至室温，分批加入三乙酰氧基硼氢化钠(1.53g,7.23mmol)，然后再继续室温搅拌反应过夜。加入水淬灭反应，二氯甲烷萃取，有机相无水硫酸钠干燥，过滤，减压浓缩至干，粗品经反相MPLC纯化得中间体E-47-1(800.33mg,1.95mmol,67.38％收率)，MS(ESI)m/z＝412[M+1]+。
于单口瓶中加入中间体E-47-1(3g,4.36mmol)和THF/H2O(20mL/20mL)，再加入碳酸氢钠(733.35mg,8.73mmol)和CbzOsu(1.09g,4.36mmol)，室温搅拌反应过夜。加入水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体E-47-2(0.93g,1.70mmol,38.99％收率)，MS(ESI)m/z＝546[M+1]+。
于单口瓶中加入E-47-2(900mg,1.65mmol)、中间体B-3(487.16g,1.65mmol)、Cs2CO3(1.08g,3.30mmol)和1,4二氧六环(15mL)/水(3mL)，再加入Pd(dppf)Cl2(120.88mg,165.14μmol)，加毕，抽真空氮气置换三次，于90℃搅拌反应过夜，反应完后冷却，加入水和乙酸乙酯萃取，有机层用盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干,粗品经硅胶柱层析纯化得中间体E-47-3(738.74mg,1.17mmol,70.56％收率)。MS(ESI)m/z＝635[M+1]+。
于单口瓶中加入中间体E-47-3(738.74mg,1.17mmol)和甲醇(10mL)，室温加入钯碳(221mg,w/w 30％)，加毕，抽真空氢气置换三次，室温搅拌反应4小时。反应完后，硅藻土过滤，甲醇洗涤，滤液减压浓缩至干得粗品中间体E-47-4(530.2mg,1.06mmol,91％收率)， MS(ESI)m/z＝501[M+1]+。
参照实施例1步骤2至步骤4的合成方法，步骤2中用中间体E-47-4代替中间体1-1，其余试剂和操作相同，可得中间体E-47，MS(ESI)m/z＝455[M+1]+。
中间体E-48的制备
参照中间体E-30的合成方法，步骤4中用1-三氟甲基乙胺代替环丙基胺，其余试剂和操作相同，可得中间体E-48，MS(ESI)m/z＝470[M+1]+。
中间体E-49的制备
参照中间体E-16的合成方法，用中间体E-48代替中间体E-1，其余试剂和操作相同，可得中间体E-49，MS(ESI)m/z＝456[M+1]+。
中间体E-50的制备
参照中间体E-16的合成方法，用中间体E-34代替中间体E-1，其余试剂和操作相同，可得中间体E-50，MS(ESI)m/z＝450[M+1]+。
中间体E-51的制备
参照中间体E-30的合成方法，步骤4中用2,2,2-三氟-1,1-二甲基乙胺代替环丙基胺，其余试剂和操作相同，可得中间体E-51，MS(ESI)m/z＝484[M+1]+。
中间体E-52的制备
参照中间体E-30的合成方法，步骤4中用1-(三氟甲基)环丙胺代替环丙基胺，其余试剂和操作相同，可得中间体E-52，MS(ESI)m/z＝482[M+1]+。
中间体E-53的制备
参照中间体E-16的合成方法，用中间体E-51代替中间体E-1，其余试剂和操作相同，可得中间体E-53，MS(ESI)m/z＝470[M+1]+。
中间体E-54的制备
参照中间体E-16的合成方法，用中间体E-52代替中间体E-1，其余试剂和操作相同，可得中间体E-54，MS(ESI)m/z＝468[M+1]+。
中间体E-55的制备
参照中间体E-1的合成路线，步骤4中用2,2,2-三氟-1,1-二甲基乙胺代替甲胺盐酸盐，其余试剂和操作相同，可得中间体E-55，MS(ESI)m/z＝501[M+1]+。
中间体E-56的制备
参照中间体E-16的合成方法，用中间体E-55代替中间体E-1，其余试剂和操作相同，可得中间体E-56，MS(ESI)m/z＝487[M+1]+。
中间体E-57的制备
参照中间体E-1的合成路线，步骤4中用1-(三氟甲基)环丙胺代替甲胺盐酸盐，其余试剂和操作相同，可得中间体E-57，MS(ESI)m/z＝499[M+1]+。
中间体E-58的制备
参照中间体E-16的合成方法，用中间体E-57代替中间体E-1，其余试剂和操作相同，可得中间体E-58，MS(ESI)m/z＝485[M+1]+。
实施例1的制备
往中间体B-1(4g,8.90mmol)、中间体A-1(4.03g,10.68mmol)和Cs2CO3(5.80g,17.79mmol)的1,4二氧六环(40mL)/水(8mL)混和溶剂中，加入Pd(PPh3)4(1.03g,889.73μmol)，氮气鼓泡除氧，于120℃微波反应1小时，反应完后加入水和乙酸乙酯萃取，有机层用盐水洗，浓缩至干,经硅胶柱层析纯化得中间体1-1(2.5g,45％收率)。MS(ESI)m/z＝620[M+1]+。
-78℃下往中间体1-1(2.5g,4.03mmol)的干燥THF(50mL)中，滴加LiAlH4(382.60mg,10.08mmol,1M的THF溶液)，滴加完后升温到室温反应2小时。反应完后于-10℃依次加入冰水(0.7mL),15％ NaOH水溶液(0.7mL)和水(2.1mL)淬灭反应。反应液过滤，滤饼用乙酸乙酯洗，滤液浓缩至干到中间体1-2(1.5g,63％收率)，粗品未经纯化直接用于下一步。MS(ESI)m/z＝592[M+1]+。
0℃下往中间体1-2(1.5g,2.53mmol)的DCM(60mL)溶液中，滴加二氯亚砜(2.7g,15.17mmol)，滴完后保温反应1小时。反应完后加入碳酸氢钠水溶液淬灭，加入乙酸乙酯萃取，有机层用盐水洗，浓缩干得到中间体1-3(189mg,19％收率)，粗品未经纯化直接用于下一步。MS(ESI)m/z＝396[M+1]+。
往中间体1-3(189mg,477.28μmol)的t-BuOH(4mL)溶液中，加入t-BuOK(58.91mg,525.00μmol)。升温到80℃反应1小时。反应完浓缩干加入水和乙酸乙酯萃取，有机层用盐水洗，有机浓缩干纯化得到中间体1-4(159mg,93％收率)，粗品未经纯化直接用于下一步。MS(ESI)m/z＝360[M+1]+。
往中间体C-1(125mg,412.06μmol)和DIPEA(176.86mg,1.37mmol,238.35μL)的DMF(4mL)溶液中，加入HATU(169mg,444.47μmol)。室温搅拌5分钟后加入中间体1-4(123mg，342.11μmol)，加毕，室温搅拌反应3小时。反应完后加入水和乙酸乙酯萃取，有机层用盐水洗，浓缩干，经硅胶柱层析纯化得中间体1-5(215mg,97％收率)。MS(ESI)m/z＝645[M+1]+。
往中间体1-5(51mg,79.09μmol)和甲酸胺(49.87mg,790.85μmol)的MeOH(1mL)溶液中，加入Pd/C(20mg,w/w10％)。室温搅拌反应1小时，反应液硅藻土过滤，甲醇洗涤，滤液减压浓缩至干，粗品加入乙酸乙酯溶解，碳酸氢钠水溶液洗涤，有机层用盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干得中间体1-6(40mg,99％收率)，粗品未经纯化直接用于下一步。MS(ESI)m/z＝511[M+1]+。
往2-异丙基-3-吡唑羧酸(16mg,103.78μmol)和DIPEA(40.49mg,313.27μmol,54.56μL)的DMF(1mL)溶液中，加入HATU(42mg,110.46μmol)。室温搅拌5分钟后加入中间体1-6(40mg,78.32μmol)，加毕，室温搅拌反应1小时。反应完后加入水和乙酸乙酯萃取，有机层用盐水洗，浓缩干经MPLC纯化得中间体1-7(50mg,99％收率)。MS(ESI)m/z＝647 [M+1]+。
往中间体1-7(50mg,77.29μmol))的DCM(0.8mL)溶液中，加入TFA(0.8mL)。加完后室温反应3小时，反应完后浓缩干经MPLC制备纯化得实施例1(15mg,38％收率)。MS(ESI)m/z＝517[M+1]+。1H NMR(400MHz,Methanol-d4)δ7.72–7.64(m,2H),7.52(d,J＝2.0Hz,1H),7.41–7.27(m,1H),6.80(d,J＝2.1Hz,1H),5.41(hept,J＝6.7Hz,1H),4.91(d,J＝7.5Hz,1H),4.33(m,2H),3.72(s,2H),2.69(s,2H),2.26(s,3H),1.45(dd,J＝6.7,5.5Hz,6H),0.97–0.73(m,3H),0.61–0.21(m,8H)。
实施例2至实施例7的制备
参照实施例1的合成路线，用下表中相应的羧酸中间体代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得表中相应结构实施例化合物。

实施例8至实施例10的制备
参照实施例1的合成路线，步骤5中用下表中相应的氨基酸代替中间体C-1，同时步骤7中用1-乙基吡唑-5-羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得表中相应结构实施例化合物。

实施例11的制备
参照实施例1的合成路线，步骤5中用中间体C-4代替中间体C-1，同时步骤7中用1-乙基吡唑-5-羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，最后一步脱SEM经MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化后再经SFC拆分(手性柱型号：Daicel CHIRALPAK AD-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-乙醇，A/B＝70/30：流速:1mL/min；柱温:40℃)可得实施例11a(P1，SFC tR＝3.054)，MS(ESI)m/z＝527[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.87–7.64(m,2H),7.50(d,J＝2.1Hz,1H),7.36(d,J＝8.3Hz,1H),6.89(d,J＝2.2Hz,1H),4.59–4.48(m,3H),4.38(d,J＝57.2Hz,2H),3.96–3.57(m,2H),2.74(t,J＝49.5Hz,2H),2.30(s,3H),2.14–2.02(m,3H),2.02–1.95(m,1H),1.91–1.74(m,3H),1.63–1.44(m,2H),1.37(t,J＝7.2Hz,3H).实施例11b(P2，SFC tR＝4.824)，MS(ESI)m/z＝527[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.75–7.66(m,2H),7.50(d,J＝2.1Hz,1H),7.35(d,J＝8.3Hz,1H),6.89(d,J＝2.1Hz,1H),4.59–4.48(m,3H),4.34(s,2H),3.90–3.57(m,2H),2.89–2.54(m,2H),2.29(s,3H),2.10(tt,J＝16.5,10.3Hz,3H),1.99(d,J＝13.8Hz,1H),1.80(dt,J＝31.7,13.3Hz,3H),1.63–1.43(m,2H),1.37(t,J＝7.1Hz,3H).
实施例12的制备
于500mL三口瓶中加入中间体A-1(11g,24.47mmol)和干燥四氢呋喃(150mL)，抽真空氮气置换三次，降温至-70℃，滴加入正丁基锂(24.47mmol,9.7mL)，保温搅拌反应1小时。滴加入异丙醇频哪醇硼酸酯(9.10g,48.94mmol)的干燥四氢呋喃(80mL)溶液，滴毕，升至室温搅拌反应1小时。反应完后倾倒入饱和氯化铵溶液中淬灭反应，加入乙酸乙酯萃取。有机相盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱层析纯化得中间体12-1(8.28g,11.66mmol,47.67％收率)。MS(ESI)m/z＝497[M+1]+。
往中间体12-1(5.00g,10.07mmol)、2-氨基-5-溴异烟酸甲酯(1.94g,8.39mmol)和Cs2CO3(5.47g,16.78mmol)的1,4二氧六环(80mL)/水(20mL)混和溶剂中，加入Pd(PPh3)4(484.82mg,419.40μmol)，加毕，抽真空氮气置换三次，于100℃搅拌反应6小时，反应完后冷却，加入水和乙酸乙酯萃取，有机层用盐水洗，浓缩至干,粗品经硅胶柱层析纯化得中间体12-2(1.40g,1.88mmol,22.47％收率)。MS(ESI)m/z＝521[M+1]+。
参照实施例1步骤2至步骤4的合成方法，用中间体12-2代替中间体1-1，其余试剂和操作相同，可得中间体12-5。MS(ESI)m/z＝361[M+1]+。
往中间体12-5(80mg,221.90μmol)和中间体C-1(134.63mg,443.80μmol)的吡啶(2 mL)溶液中加入EDCI(127.61mg,665.70μmol)，加毕，60℃搅拌反应2小时，反应完后冷却，减压浓缩至干,粗品经MPLC(H2O/CH3CN,0.05％ TFA)纯化得中间体12-6(30mg,46.45μmol,20.93％收率)。MS(ESI)m/z＝646[M+1]+。
参照实施例1步骤6至步骤8的合成方法，用中间体12-6代替中间体1-5，其余试剂和操作相同，可得实施例12，MS(ESI)m/z＝518[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.30(s,1H),8.22(s,1H),7.53(d,J＝2.0Hz,1H),6.81(d,J＝2.1Hz,1H),5.45–5.35(m,1H),4.98(d,J＝7.3Hz,1H),4.66–4.13(m,2H),3.92–3.57(m,2H),2.88–2.58(m,2H),2.31(s,3H),1.45(dd,J＝8.5,6.6Hz,6H),0.96–0.79(m,3H),0.59–0.42(m,3H),0.42–0.32(m,2H),0.32–0.28(m,2H),0.28–0.22(m,1H).
实施例13的制备
于250mL单口茄型瓶中加入5-甲基-1-(2-三甲基硅乙氧甲基)吡唑-3-羧酸甲酯(3.47g,12.83mmol)和DCM(70mL)，再室温加入NBS(4.57g,25.67mmol)，室温搅拌反应过夜。反应完后加入碳酸氢钠水溶液淬灭反应，加入DCM萃取，有机层盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱层析纯化得中间体13-1(791mg,2.26mmol,17.65％收率)。MS(ESI)m/z＝349[M+1]+。
往中间体13-1(741mg,2.12mmol)、中间体B-2(1.60g,4.24mmol)和Cs2CO3(1.38g,4.24 mmol)的1,4二氧六环(20mL)/水(4mL)混和溶剂中，加入Pd(dppf)Cl2(77.61mg,106.07μmol)，加毕，抽真空氮气置换三次，于80℃搅拌反应12小时，反应完后冷却，加入水和乙酸乙酯萃取，有机层用盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干,粗品经硅胶柱层析纯化得中间体13-2(332mg,638.68μmol,30.11％收率)。MS(ESI)m/z＝520[M+1]+。
参照实施例1的合成路线，步骤2中用中间体13-2代替中间体1-1，其余试剂和操作相同，可得实施例13，MS(ESI)m/z＝517[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.64–7.49(m,3H),7.28(s,1H),6.82(d,J＝2.0Hz,1H),4.92(d,J＝7.7Hz,1H),4.23(d,J＝72.7Hz,1H),3.64(s,1H),3.25–3.20(m,1H),2.77(t,J＝5.1Hz,2H),2.31(s,3H),1.48(dd,J＝8.0,6.6Hz,6H),1.33(t,J＝7.3Hz,2H),1.00–0.74(m,3H),0.62–0.36(m,5H),0.35–0.24(m,3H).
实施例14的制备
参照实施例13的合成路线，步骤8中用1-乙基吡唑-5-羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得实施例14，MS(ESI)m/z＝503[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.63–7.48(m,3H),7.35–7.24(m,1H),6.89(d,J＝2.2Hz,1H),4.92(d,J＝7.6Hz,1H),4.80–4.50(m,3H),4.17(s,2H),3.82–3.51(m,1H),2.77(t,J＝5.1Hz,2H),2.31(s,3H),1.41(t,J＝7.2Hz,3H),0.97–0.76(m,3H),0.58(tt,J＝8.5,4.6Hz,1H),0.55–0.46(m,2H),0.45–0.36(m,2H),0.35–0.24(m,3H).
实施例15的制备
参照实施例1的合成路线，步骤1中用中间体B-3代替中间体B-1，其余试剂和操作相同，可得实施例15，MS(ESI)m/z＝535[M+1]+。1H NMR(400MHz,Methanol-d4)δ8.04(d,J＝8.0Hz,1H),7.53(d,J＝2.0Hz,1H),7.19(d,J＝11.2Hz,1H),6.80(d,J＝2.1Hz,1H),5.48–5.33(m,1H),5.01(d,J＝7.1Hz,1H),4.31(s,2H),3.72(s,2H),2.70(s,2H),2.28(s,3H),1.46(dd,J＝6.7,4.8Hz,6H),1.02–0.79(m,3H),0.61–0.53(m,1H),0.53–0.41(m,3H),0.41–0.35(m,1H),0.35–0.21(m,3H).
实施例16至实施例21的制备
参照实施例15的合成路线，步骤7中用下表中相应的羧酸中间体代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得表中相应结构实施例化合物。


实施例22的制备
往2-溴-5-硝基苯甲醛(25g,108.69mmol))的甲醇(500mL)溶液中，加入甲胺盐酸盐(30g,217.38mmol)。加完后室温搅拌反应1小时，冰水浴降温至0℃，分批加入硼氢化钠(8.22g,217.38mmol)。加毕，升至室温搅拌反应2小时，降温至0℃加入30％氯化铵溶液淬灭反应，并搅拌10分钟，减压浓缩至适量，加入乙酸乙酯，依次水洗，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，硅胶柱层析纯化得中间体22-1(23g,93.85mmol,86.35％收率)。MS(ESI)m/z＝245[M+1]+。
往中间体22-1(23g,93.85mmol)的THF/H2O(230mL/100mL)溶液中，加入碳酸氢钠(15.77g,187.70mmol)和(Boc)2O(30.72g,140.77mmol)。加完后室温搅拌反应过夜，加入水(100mL)，乙酸乙酯萃取。合并有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，硅胶柱层析纯化得中间体22-2(32.3g,93.57mmol,99.70％收率)。MS(ESI)m/z＝345[M+1]+。
往中间体22-2(32g,92.70mmol)的EtOH/H2O(640mL/128mL)溶液中，加入氯化铵(39.67g,741.62mmol)，然后冰水浴条件下分批加入锌粉(30.72g,140.77mmol)。加完后室温搅拌反应过夜，硅藻土过滤，乙酸乙酯洗涤。滤液减压浓缩至干。加入水和乙酸乙酯，萃取，合并有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经硅胶柱层析纯化得中间体22-3(20g,63.45mmol,68.45％收率)。MS(ESI)m/z＝315[M+1]+。
于500mL单口瓶中加入中间体22-3(23g,72.97mmol)，联硼酸频哪醇酯(22.24g,87.56mmol)，醋酸钾(14.32g,145.94mmol)，Pd(dppf)Cl2(5.34g,7.30mmol)和二氧六环(230mL)，搅拌状态下抽真空氮气置换三次，升温至100℃搅拌反应过夜。反应完后冷却，浓缩至适量，加入乙酸乙酯，水洗。有机相无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱层析纯化得中间体22-4(22.9g,63.21mmol,86.63％收率)。MS(ESI)m/z＝363[M+1]+。
于500mL单口瓶中加入中间体22-4(22.43g,61.93mmol)，中间体A-2(15g,42.19mmol)，碳酸钠(8.5g,82.57mmol)，Pd(dppf)Cl2(1.51g,2.06mmol)和二氧六环/水(230mL/50mL)，搅拌状态下抽真空氮气置换三次，升温至100℃搅拌反应过夜。反应完后冷却，浓缩至适量，加入乙酸乙酯，水洗。有机相无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱层析纯化得中间体22-5(12.41g,23.95mmol,58％收率)。MS(ESI)m/z＝519[M+1]+。
往中间体22-5(2g,3.86mmol))的DCM(100mL)溶液中，冰水浴条件下加入TFA(10mL)。加完后室温搅拌至反应完全，反应完后浓缩干经MPLC制备(H2O/CH3CN，0.05％NH4HCO3)纯化得中间体22-6(1.53g,3.66mmol,94.98％收率)。MS(ESI)m/z＝419[M+1]+。
往50mL玻璃风管中加入中间体22-6(649mg,1.55mmol))，甲醇(10mL)和三甲基乙 酸。加完后，升温至90℃搅拌反应12小时，有部分原料未反应完全，直接减压浓缩至干，残留物用二氯甲烷溶解，依次经饱和碳酸氢钠溶液，水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经硅胶柱层析纯化得中间体22-7(688mg,889.90μmol,57.40％收率,50％purity)。MS(ESI)m/z＝387[M+1]+。
参照实施例1的合成路线，步骤5中用中间体22-7代替中间体1-4，其余试剂和操作相同，可得实施例22，MS(ESI)m/z＝544[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.78(d,J＝2.4Hz,1H),7.61(dd,J＝8.5,2.3Hz,1H),7.54(d,J＝2.1Hz,1H),7.44(s,1H),6.83(d,J＝2.0Hz,1H),5.48–5.38(m,1H),4.93(d,J＝7.7Hz,1H),4.51(q,J＝14.7Hz,2H),4.02(d,J＝41.7Hz,2H),2.95(s,3H),2.35(s,3H),1.47(dd,J＝9.1,6.7Hz,6H),0.98–0.78(m,3H),0.62–0.45(m,3H),0.44–0.37(m,2H),0.35–0.23(m,3H).
实施例23的制备
参照实施例22的合成路线，步骤9中用1-乙基吡唑-5-羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得实施例23，MS(ESI)m/z＝530[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.77–7.69(m,1H),7.58(s,1H),7.44(d,J＝62.0Hz,2H),6.86(t,J＝3.5Hz,1H),4.90(d,J＝7.6Hz,1H),4.58–4.40(m,4H),3.99(d,J＝67.6Hz,2H),2.91(s,3H),2.32(s,3H),1.44–1.30(m,3H),0.95–0.73(m,3H),0.59–0.52(m,1H),0.52–0.41(m,2H),0.41–0.33(m,2H),0.33–0.20(m,3H).
实施例24的制备
-78℃下往中间体22-6(638mg,825.22μmol)的干燥THF(20mL)中，滴加LiAlH4(62.63mg,1.65mmol,1M的THF溶液)，滴加完后升温到室温反应1小时。反应完后于-10℃依次加入冰水(0.08mL),15％ NaOH水溶液(0.08mL)和水(0.24mL)淬灭反应并搅拌10分钟。反应液硅藻土过滤，滤饼用乙酸乙酯洗，滤液浓缩至干得中间体24-1(235mg,630.74μmol,76.43％收率)，粗品未经纯化直接用于下一步。MS(ESI)m/z＝373[M+1]+。
参照实施例1的合成路线，步骤5中用中间体24-1代替中间体1-4，其余试剂和操作相同，可得实施例24，MS(ESI)m/z＝530[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.76–7.61(m,2H),7.56–7.50(m,1H),7.34(s,1H),6.82(d,J＝2.1Hz,1H),5.43(hept,J＝6.8Hz,1H),4.92(d,J＝7.6Hz,1H),3.67(s,2H),3.07–2.56(m,4H),2.45(s,3H),2.25(s,3H),1.48(dd,J＝7.8,6.7Hz,6H),0.97–0.77(m,3H),0.64–0.35(m,5H),0.33–0.24(m,3H).
实施例25和实施例26的制备
参照实施例24的合成路线，步骤4中用下表中相应的吡唑羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得表中相应结构实施例化合物。
实施例27的制备
参照实施例22步骤4至步骤5的合成方法，步骤4中用5-氨基-2-溴苯腈代替中间体22-3，其余试剂和操作相同，可得中间体27-2，MS(ESI)m/z＝401[M+1]+。
于50mL单口瓶中加入中间体27-2(300mg,748.98μmol)和甲醇(6mL)中，加入Raney镍(60mg,748.98μmol)，抽真空氢气置换三次，室温搅拌反应过夜。反应液硅藻土过滤，滤饼用甲醇洗涤，滤液浓缩至干得中间体27-3(218mg,538.83μmol,71.94％收率)，粗品未经纯化直接用于下一步。MS(ESI)m/z＝405[M+1]+。
参照实施例22步骤7至步骤11的合成方法，步骤7中用中间体27-3代替中间体22-6，其余试剂和操作相同，可得实施例27，MS(ESI)m/z＝530[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.80(d,J＝2.3Hz,1H),7.63(d,J＝8.3Hz,1H),7.54(d,J＝2.0Hz,1H),7.37(d,J＝8.3Hz,1H),6.81(d,J＝2.0Hz,1H),5.48–5.35(m,1H),4.91(d,J＝7.7Hz,1H),4.05(s,2H),3.55(s,2H),2.32(s,3H),1.47(dd,J＝8.8,6.7Hz,6H),0.98–0.75(m,3H),0.62–0.35(m,5H),0.34–0.23(m,3H).
实施例28的制备
参照实施例27的合成路线，步骤7中用1-乙基吡唑-5-羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得实施例28，MS(ESI)m/z＝516[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.80(d,J＝2.3Hz,1H),7.63(d,J＝8.3Hz,1H),7.52(d,J＝2.1Hz,1H),7.37(d,J＝7.4Hz,1H),6.88(d,J＝2.1Hz,1H),4.92(d,J＝7.6Hz,1H),4.56(qd,J＝7.1,2.5Hz,2H),4.05(s,2H),3.55(s,2H),2.32(s,3H),1.40(t,J＝7.2Hz,3H),0.98–0.76(m,3H),0.65–0.35(m,5H),0.35–0.23(m,3H).
实施例29的制备
参照实施例1合成路线步骤1至步骤4的合成方法，步骤1中用中间体B-4代替中间体B-1，其余试剂和操作相同，可得中间体29-4。MS(ESI)m/z＝394[M+1]+。
往中间体29-4(600mg,1.53mmol)和中间体C-1(601.37,1.98mmol)的吡啶(16mL)溶液中加入EDCI(1.18g,6.12mmol)，加毕，室温搅拌反应过夜，减压浓缩至干,粗品用乙酸乙酯溶解，依次经水，饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，减压浓缩至干。粗品经MPLC(H2O/CH3CN,0.05％ NH4HCON3)纯化得中间体29-5(902mg,1.33mmol,86.98％收率)。MS(ESI)m/z＝679[M+1]+。
往中间体29-5(800mg,1.18mmol)的二氯甲烷(11mL)溶液中加入三乙胺(83.42mg, 0.83mmol)和PdCl2(41.44mg,0.24mmol)，加毕，冰水浴降温至0℃，滴加入三乙基硅烷(684.40mg,5.90mmol)的二氯甲烷(3mL)溶液，滴毕，氮气保护，0℃搅拌至反应完全。反应液硅藻土过滤，二氯甲烷洗涤，滤液减压浓缩至干。粗品经MPLC(H2O/CH3CN,0.05％NH4HCON3)纯化得中间体29-6(464.62mg,0.85mmol,72.38％收率)。MS(ESI)m/z＝545[M+1]+。
参照实施例1合成路线步骤7至步骤8的合成方法，步骤7中用中间体29-6代替中间体1-6，其余试剂和操作相同，可得实施例29。MS(ESI)m/z＝551[M+1]+。1H NMR(600MHz,DMSO-d6)δ12.47(d,J＝28.7Hz,1H),9.68(s,1H),8.44(d,J＝8.7Hz,1H),7.81(s,1H),7.55–7.36(m,2H),6.90(d,J＝1.9Hz,1H),5.51–5.28(m,1H),4.93(t,J＝8.8,7.2Hz,1H),4.20(s,2H),3.60(s,2H),2.72–2.52(m,2H),2.18(d,J＝35.6Hz,3H),1.36(dd,J＝16.6,6.6Hz,6H),1.02–0.78(m,3H),0.51–0.45(m,1H),0.43–0.28(m,4H),0.28–0.17(m,3H).
实施例30至实施例31的制备
参照实施例29的合成路线，步骤7中用以下列表中相应的吡唑羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得相应实施例化合物。
实施例32的制备
于室温往环丙醇(6.59mg,113.48μmol)和N,N'-二琥珀酰亚胺基碳酸酯(29.07mg,113.48μmol)的乙腈(1mL)溶液中加入三乙胺(9.57mg,94.57μmol,13.19μL)，加毕，室温搅拌反应2小时，然后加入中间体15-6(50mg,94.57μmol)的DMF(0.5mL)溶液，加毕，室温搅拌反应过夜。反应液直接经MPLC(H2O/CH3CN,0.05％ TFA)纯化得中间体32-1(14mg,22.85μmol,24.16％收率)。MS(ESI)m/z＝613[M+1]+。
往中间体32-1(14mg,22.85μmol)的DCM(1mL)溶液中，加入TFA(1mL)。加完后室温反应3小时，反应完后浓缩干经MPLC制备纯化得实施例32(5mg,8.38μmol,36.69％收率)。MS(ESI)m/z＝483[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.02(d,J＝7.9Hz,1H),7.21(d,J＝11.4Hz,1H),4.56(d,J＝6.0Hz,1H),4.34(s,2H),4.10–3.99(m,1H),3.73(s,2H),2.72(s,2H),2.30(s,3H),0.90–0.80(m,2H),0.75–0.62(m,J＝3.8Hz,5H),0.61–0.52(m,1H),0.51–0.46(m,1H),0.46–0.39(m,2H),0.32–0.21(m,4H).
实施例33的制备
往3-乙基异噁唑-4-甲酸(16.01mg,113.48μmol)和DIPEA(44.00mg,340.44μmol,59.30μL)的DMF(1mL)溶液中，加入HATU(51.75mg,136.17μmol)和中间体15-6，加毕，室温搅拌反应1小时。反应完后加入水(3mL)，析出大量白色固体，过滤，水洗，干燥得中间体33-1(30mg,46.02μmol,40.56％收率)。MS(ESI)m/z＝652[M+1]+。
往中间体33-1(30mg,46.02μmol)的DCM(1mL)溶液中，加入TFA(1mL)。加完后室温搅拌反应1小时，反应完后减压浓缩干经MPLC制备纯化得实施例33(13mg,20.40μmol,44.33％收率)。MS(ESI)m/z＝522[M+1]+。1H NMR(600MHz,Methanol-d4)δ9.13(s,1H),8.05(d,J＝7.9Hz,1H),7.22(d,J＝11.3Hz,1H),5.01(dd,J＝7.3,1.5Hz,1H),4.33(s,2H),3.78(s,2H),2.93(q,J＝7.5Hz,2H),2.73(s,2H),2.31(s,3H),1.28(t,J＝7.6,1.5Hz,3H),0.98–0.84(m,2H),0.83–0.76(m,1H),0.61–0.54(m,1H),0.54–0.40(m,3H),0.39–0.23(m,4H).
实施例34至实施例36的制备
参照实施例33的合成路线，步骤1中用以下列表中相应的异噁唑羧酸代替3-乙基异噁唑-4-甲酸，其余试剂和操作相同，可得相应实施例化合物。
实施例37a和实施例37b的制备
参照实施例11a&11b的合成路线，步骤1中用中间体15-4代替中间体1-4，其余试剂和操作相同，最后一步脱SEM经MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化后再经SFC拆分(手性柱型号：Daicel CHIRALPAK AD-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-异丙醇，A/B＝75/25：流速:1mL/min；柱温:40℃)可得实施例37a(P1，SFC tR＝2.114)，MS(ESI)m/z＝545[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.98(d,J＝7.9Hz,1H),7.50(d,J＝2.1Hz,1H),7.19(d,J＝11.2Hz,1H),6.88(d,J＝2.2Hz,1H),4.67(d,J＝8.7Hz,1H),4.59–4.50(m,2H),4.32(s,2H),3.86–3.53(m,2H),2.70(s,2H),2.27(s,3H),2.16–2.05(m,3H),2.02–1.96(m,1H),1.91(d,J＝13.6Hz,1H),1.88–1.74(m,2H),1.62–1.45(m,2H),1.38(t,J＝7.2Hz,3H).实施例37b(P2，SFC tR＝5.415)，MS(ESI)m/z＝545[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.98(d,J＝7.9Hz,1H),7.50(d,J＝2.1Hz,1H),7.19(d,J＝11.1Hz,1H),6.88(d,J＝2.1Hz,1H),4.68(dd,J＝8.7,1.3Hz,1H),4.54(q,J＝7.2Hz,2H),4.31(s,2H),3.71(s,2H),2.69(s,2H),2.27(s,3H),2.15–2.04(m,3H),2.02–1.96(m,1H),1.93–1.88(m,1H),1.80(ddd,J＝33.2,14.1,8.3Hz,2H),1.63–1.45(m,2H),1.38(t,J＝7.2Hz,3H).
实施例38a和实施例38b的制备
参照实施例11a&11b的合成路线，步骤1中用中间体15-4代替中间体1-4，同时步骤3中用1-异丙基吡唑-5-羧酸代替1-乙基吡唑-5-羧酸，其余试剂和操作相同，最后一步脱SEM经MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化后再经SFC拆分(手性柱型号：Daicel  CHIRALPAK AD-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-异丙醇，A/B＝75/25：流速:1mL/min；柱温:40℃)可得实施例38a(P1，SFC tR＝1.771)，MS(ESI)m/z＝559[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.98(d,J＝7.9Hz,1H),7.51(d,J＝2.0Hz,1H),7.19(d,J＝11.3Hz,1H),6.81(d,J＝2.0Hz,1H),5.45–5.35(m,1H),4.67(dd,J＝8.6,1.4Hz,1H),4.30(s,2H),3.72(s,2H),2.69(s,2H),2.27(s,3H),2.16–2.04(m,3H),1.99(d,J＝13.6Hz,1H),1.91(d,J＝13.2Hz,1H),1.88–1.75(m,2H),1.63–1.49(m,2H),1.45(t,J＝6.7Hz,6H).实施例38b(P2，SFC tR＝4.932)，MS(ESI)m/z＝559[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.98(d,J＝7.9Hz,1H),7.51(d,J＝2.0Hz,1H),7.19(d,J＝11.3Hz,1H),6.81(d,J＝2.1Hz,1H),5.45–5.35(m,1H),4.68(dd,J＝8.5,1.1Hz,1H),4.30(s,2H),3.92–3.52(m,2H),2.69(s,2H),2.27(s,3H),2.16–2.04(m,3H),2.02–1.96(m,1H),1.91(d,J＝13.5Hz,1H),1.81(d,J＝32.3Hz,2H),1.63–1.49(m,2H),1.45(t,J＝6.9Hz,6H).
实施例39a和实施例39b的制备
参照实施例33的合成路线，步骤1中用中间体D-1代替3-乙基异噁唑-4-甲酸，其余试剂和操作相同，最后一步经碱法MPLC纯化后再经SFC拆分(手性柱型号：Daicel CHIRALPAK AD-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-乙醇，A/B＝77/23：流速:1mL/min；柱温:40℃)可得实施例39a(P1，SFC tR＝2.467)，MS(ESI)m/z＝571[M+1]+。1H NMR(600MHz,DMSO-d6)δ12.47(d,J＝24.5Hz,1H),10.02(s,1H),8.63(d,J＝8.8Hz,1H),7.93(d,J＝8.2Hz,1H),7.64(d,J＝2.0Hz,1H),7.25(s,1H),7.11(d,J＝2.0Hz,1H),6.24(td,J＝55.8,5.2Hz,1H),5.83–5.72(m,1H),4.99(t,1H),4.34(s,2H),3.61(s,2H),2.61(s,2H),2.21(s,3H),1.53(d,J＝6.9Hz,3H),0.97–0.83(m,2H),0.79(td,J＝9.4,7.8Hz,1H),0.54–0.45(m,1H),0.43–0.36(m,2H),0.36–0.28(m,2H),0.28–0.15(m,3H).实施例39b(P2，SFC tR＝3.450)，MS(ESI)m/z＝571[M+1]+。1H NMR(600MHz,DMSO-d6)δ12.40(s,1H),9.99(s,1H),8.53(d,J＝8.7Hz,1H),7.90(d,J＝8.2Hz,1H),7.60(d,J＝2.0Hz,1H),7.21(d,J＝11.6Hz,1H),7.09(d,J＝2.0Hz,1H),6.23(td,J＝55.9,5.0Hz,1H),5.82–5.70(m,1H),4.95(t,J＝8.2Hz,1H),4.17(s,2H),3.57(s,2H),2.58(s,2H),2.17(s,3H),1.48(d,J＝7.0Hz,3H),0.93–0.80(m,2H),0.76(q,J＝8.9Hz,1H),0.49–0.41(m,1H),0.38–0.23(m,4H),0.24–0.11(m,3H).
实施例40a、实施例40b至实施例39a、实施例39b的制备
参照实施例39a和实施例39b的合成路线，步骤1中用下表中间体吡唑羧酸代替中间体D-1，其余试剂和操作相同，可得相应实施例化合物。


实施例43a、实施例43b和实施例43c的制备
参照实施例39a和实施例39a的合成路线，步骤1中用中间体D-51代替中间体D-1，其余试剂和操作相同，最后一步经碱法MPLC纯化后再经SFC拆分(手性柱型号：Daicel CHIRALCEL OX-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-乙醇，A/B＝65/35：流速:1mL/min；柱温:40℃)可得实施例43a(P1，SFC tR＝2.467)，MS(ESI)m/z＝597[M+1]+。1H NMR(600MHz,Methanol-d4)δ7.98(d,J＝7.9Hz,1H),7.60(d,J＝2.0Hz,1H),7.17(d,J＝10.7Hz,1H),6.83(d,J＝2.0Hz,1H),5.90–5.78(m,1H),5.03(d,J＝6.1Hz,1H),4.31(s,2H),3.71(s,2H),3.59(dd,J＝13.3,10.6Hz,1H),3.16(dd,J＝13.3,4.2Hz,1H),2.84–2.62(m,2H),2.57(s,3H),2.28(s,3H),1.63(d,J＝6.7Hz,3H),0.96–0.84(m,3H),0.61–0.42(m,4H),0.37(dq,J＝9.8,5.0Hz,1H),0.29(dtq,J＝23.4,9.4,4.7Hz,3H).实施例43b(P2，mix,SFC tR＝3.110)，MS(ESI)m/z＝597[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.02(dd,J＝13.4,7.9Hz,1H),7.59(s,1H),7.19(s,1H),6.86(dd,J＝15.8,2.0Hz,1H),5.88–5.80(m,1H),5.00(d,J＝7.1Hz,1H),4.32(s,2H),3.70(d,J＝25.4Hz,2H),3.56–3.46(m,1H),3.41–3.32(m,1H),2.63(d,J＝44.0Hz,5H),2.27(d,J＝17.0Hz,3H),1.62(dd,J＝17.1,6.7Hz,3H),0.97–0.78(m,3H),0.59–0.42(m,4H),0.38(dq,J＝9.6,5.0Hz,1H),0.29(ddq,J＝22.2,9.3,4.8Hz,3H).实施例43c(P3，SFC tR＝3.762)，MS(ESI)m/z＝597[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.04(d,J＝8.0Hz,1H),7.58(d,J＝2.0Hz,1H),7.19(d,J＝11.3Hz,1H),6.89(d,J＝2.0Hz,1H),5.90–5.83(m,1H),5.01(d,J＝7.2Hz,1H),4.31(s,2H),3.68(dd,J＝13.3,10.5Hz,3H),3.15(dd,J＝13.4,4.0Hz,1H),2.89–2.62(m,2H),2.58(s,3H),2.28(s,3H),1.60(d,J＝6.7Hz,3H),0.96–0.82(m,3H),0.58–0.43(m,4H),0.37(tdd,J＝5.3,3.6,1.9Hz,1H),0.32–0.25(m,3H).
实施例44a和实施例44b的制备
参照实施例15的合成路线，步骤5中用中间体C-5代替中间体C-1，其余试剂和操作相同，最后一步经碱法MPLC纯化后再经SFC拆分(手性柱型号：Daicel CHIRALPAK AD-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-乙醇，A/B＝80/20：流速:1mL/min；柱温:40℃)可得实施例44a(P1，SFC tR＝3.283)，MS(ESI)m/z＝581[M+1]+，1H NMR(600MHz,Methanol-d4)δ8.04(d,J＝7.9Hz,1H),7.52(d,J＝2.1Hz,1H),7.18(s,1H),6.80(d,J＝2.0Hz,1H),5.43(h,J＝6.7Hz,1H),4.94(t,J＝6.0Hz,1H),4.56–4.10(m,2H),4.04–3.95(m,2H),3.87–3.57(m,2H),2.70(s,2H),2.27(d,J＝25.3Hz,3H),1.49–1.44(m,6H),1.42(s,6H)；实施例44b(P2，SFC tR＝5.063)，MS(ESI)m/z＝581[M+1]+，1H NMR(600MHz,Methanol-d4)δ8.04(d,J＝7.9Hz,1H),7.52(d,J＝2.1Hz,1H),7.19(s,1H),6.80(d,J＝2.0Hz,1H),5.47–5.40(m,1H),4.94(t,J＝6.0Hz,1H),4.30(s,2H),4.04–3.95(m,2H),3.84–3.56(m,2H),2.70(s,2H),2.29(s,3H),1.46(dd,J＝6.6,4.2Hz,6H),1.42(s,6H).
实施例45至实施例50的制备
参照实施例15的合成路线，步骤5中用下表中相应的中间体羧酸代替中间体C-1，同时步骤7中用下表中相应的吡唑羧酸代替1-异丙基吡唑-5-羧酸或相同，其余试剂和操作相同，可得相应实施例化合物。


实施例51和实施例52的制备
参照实施例1的合成路线，步骤7中用下表中相应的吡唑羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得相应实施例化合物。
实施例52和实施例53的制备
参照实施例12的合成路线，步骤8中用下表中相应的吡唑羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得相应实施例化合物。
实施例55至实施例109的制备
参照实施例15的合成路线，步骤7中用下表中相应的吡唑羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得相应实施例化合物。














实施例110的制备
于冰水浴条件下往中间体15-6(1.0g,1.89mmol)的DCM(5mL)溶液中，加入TFA(5mL)。加完后室温搅拌反应2小时，反应完后减压浓缩干，粗品经MPLC纯化(CH3CN/H2O,0.05％NH4HCO3)得中间体110-1(534.36mg,1.34mmol,70.89％收率)。MS(ESI)m/z＝399[M+1]+。
往中间体D-46(30.82mg,138.19μmol)和中间体110-1(50mg,125.63μmol)的DMF(1mL)溶液中，加入DIPEA(40.49mg,313.27μmol,54.56μL)和HATU(42mg,110.46μmol)。加毕，室温搅拌反应1小时。反应完毕，经MPLC制备纯化得实施例110(38.12mg,63.23μmol,50.33％收率)。MS(ESI)m/z＝604[M+1]+。1H NMR(400MHz,Methanol-d4)δ8.03(d,J＝8.1Hz,1H),7.71(dd,J＝16.7,2.0Hz,1H),7.20(d,J＝11.5Hz,1H),7.02(dd,J＝12.6,2.0Hz,1H),6.07(p,J＝8.0Hz,1H),4.98(d,J＝6.8Hz,1H),4.83–4.70(m,2H),4.61(s,1H),4.51–4.15(m,3H),3.72(s,2H),2.70(s,2H),2.28(s,3H),1.38(d,J＝2.6Hz,9H),1.01–0.79(m,3H),0.63–0.22(m,8H).
实施例111至实施例115的制备
参照实施例110的合成路线，步骤2中用下表中相应的吡唑羧酸代替中间体D-46，其余试剂和操作相同，可得相应实施例化合物。


实施例116的制备
于冰水浴0℃氮气保护下往中间体A-2(10g,27.52mmol)的干燥THF(100mL)溶液中滴加入甲基溴化镁(110.10mmol,37mL)，滴毕，升至室温搅拌反应3小时。反应完后，将反应液倒入冰的氯化铵水溶液中，乙酸乙酯萃取。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经反相MPLC(CH3CN/H2O,0.05％TFA)纯化得中间体116-1(5.3g,14.59mmol,52.99％收率)。MS(ESI)m/z＝363[M+1]+。
往单口茄型瓶中加入中间体116-1(3.8g,10.46mmol)、中间体B-3(3.39g,11.50mmol)、Pd2(dba)3(478.82mg,522.89μmol)、Rac-BI-DIME(345.48mg,1.05mmol)和1,4二氧六环/水(38mL/7.6mL)，在搅拌状态下加入CS2CO3(10.96g,20.92mmol)，抽真空，氮气置换三次，升温至100℃搅拌反应12小时。反应完后，趁热硅藻土过滤，滤液减压浓缩干，粗品经硅胶柱层析纯化得中间体116-2(913mg,2.02mmol,19.29％收率)。MS(ESI)m/z＝452[M+1]+。
于冰水浴0℃下往中间体116-2(913mg,2.02mmol,19.29％)的干燥THF(10mL)中，滴加LiAlH4(6.07mmol,6mL,1M in THF)，滴加完后升温到室温反应2小时。反应完后于-10℃依次加入冰水(0.23mL),15％ NaOH水溶液(0.23mL)和水(0.69mL)淬灭反应。反应液无水硫酸钠干燥，过滤，滤饼用乙酸乙酯洗涤，滤液减压浓缩至干得中间体116-3(570mg,1.35mmol,66.56％收率)，粗品未经纯化直接用于下一步。MS(ESI)m/z＝424[M+1]+。
参照实施例1的合成路线，用中间体116-3代替中间体1-2，其余试剂和操作相同，可得中间体116-5，MS(ESI)m/z＝406[M+1]+。
于茄型瓶中加入中间体116-5(58mg,143.00μmol)，中间体C-1(43.38mg,143.00μmol)，EDCI(82.37mg,429.01μmol)和吡啶(2.5mL)，室温搅拌反应过夜。反应完后，将反应液减压浓缩至干。粗品经反相MPLC(CH3CN/H2O,0.05％TFA)纯化得中间体116-6(57mg,82.50μmol,57.69％收率)。MS(ESI)m/z＝691[M+1]+。
参照实施例1的合成路线，用中间体116-6代替中间体1-5，其余试剂和操作相同，可得实施例116，MS(ESI)m/z＝563[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.03(d,J＝7.9Hz,1H),7.52(d,J＝2.0Hz,1H),7.16(s,1H),6.79(d,J＝2.0Hz,1H),5.41(p,J＝6.6Hz,1H),5.01(d,J＝7.3Hz,1H),4.26(s,2H),2.59(s,2H),2.29(s,3H),1.46(t,J＝7.0Hz,6H),1.23(d,J＝3.0Hz,6H),0.95–0.80(m,3H),0.60–0.43(m,4H),0.42–0.35(m,1H),0.34–0.24(m,3H).
实施例117的制备
参照实施例116的合成路线，步骤8中用乙基吡唑-5-羧酸代替异丙基吡唑-5-羧酸，其余试剂和操作相同，可得实施例117，MS(ESI)m/z＝549[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.03(d,J＝8.0Hz,1H),7.51(d,J＝2.1Hz,1H),7.16(d,J＝11.2Hz,1H),6.87(d,J＝2.1Hz,1H),5.01(d,J＝7.2Hz,1H),4.55(q,J＝7.2Hz,2H),4.26(s,2H),2.59(s,2H),2.29(s,3H),1.40(t,J＝7.2Hz,3H),1.23(d,J＝2.9Hz,6H),0.95–0.81(m,3H),0.61–0.43(m,4H),0.42–0.36(m,1H),0.35–0.25(m,3H).
实施例118a和实施例118b的制备
于单口瓶中加入中间体A-2(30g,82.57mmol)和甲醇(240mL)，冰水浴条件下加入NaOH(4.95g,123.86mmol)的水(80mL)溶液，加毕，室温搅拌反应1小时。反应完后降温到0℃，用6N盐酸调PH值至4，乙酸乙酯萃取。有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得中间体118-1(28.7g,82.17mmol,99.51％收率)。MS(ESI)m/z＝349[M+1]+。
于单口瓶中加入中间体118-1(28.7g,82.17mmol)、二甲羟胺盐酸盐(6.52g,106.82mmol)和DMF(280mL)，冰水浴条件下加入HATU(46.86g,123.25mmol)和DIPEA(31.86g,246.50mmol,42.93mL)，加毕，室温搅拌反应2小时。反应完后，倒入冰水中，乙酸乙酯萃取。有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经反相MPLC纯化得中间体118-2(20g,50.97mmol,62.04％收率)。MS(ESI)m/z＝392[M+1]+。
于冰水浴0℃氮气保护下往中间体118-2(15g,38.23mmol)的干燥THF(150mL)溶液中滴加入甲基溴化镁(76.46mmol,26mL)，滴毕，升至室温搅拌反应2小时。反应完后，将反应液倒入冰的氯化铵水溶液中，乙酸乙酯萃取。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经反相MPLC(CH3CN/H2O,0.05％TFA)纯化得中间体118-3(6.3g,18.14mmol,47.45％收率)。MS(ESI)m/z＝347[M+1]+。
于单口瓶中加入中间体118-3(4g,11.52mmol)和乙醇(40mL)，冰水浴条件下分批加入硼氢化钠(653.51mg,17.28mmol)，加毕，保温搅拌反应1小时。反应完后，倒入冰的氯化铵水溶液中淬灭反应，乙酸乙酯萃取。有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得粗品中间体118-4(4.02g,11.51mmol,100.00％收率)。MS(ESI)m/z＝349[M+1]+。
参照实施例116的合成路线，用中间体118-4代替中间体116-1，其余试剂和操作相同，最后一步脱SEM经MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化后再经SFC拆分(手性柱型号：Daicel CHIRALPAK AD-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-乙醇，A/B＝70/30：流速:1mL/min；柱温:40℃)可得实施例118a(P1，SFC tR＝1.760)，MS(ESI)m/z＝549[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.04(d,J＝7.9Hz,1H),7.53(d,J＝2.0Hz,1H),7.18(s,1H),6.80(d,J＝2.0Hz,1H),5.41(hept,J＝6.7Hz,1H),5.01(d,J＝7.3Hz,1H),4.67(d,J＝12.5Hz,1H),4.01(d,J＝12.7Hz,1H),3.64(s,1H),2.86(d,J＝15.0Hz,1H),2.28(s,4H),1.46(t,J＝6.8Hz,6H),1.26(d,J＝6.3Hz,3H),0.95–0.85(m,2H),0.82(td,J＝9.3,7.4Hz,1H),0.63–0.54(m,1H),0.54–0.42(m,3H),0.38(dq,J＝9.7,4.9Hz,1H),0.30(ddt,J＝10.7,8.8,5.2Hz,3H).实施例118b(P2，SFC tR＝1.880)，MS(ESI)m/z＝549[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.02(d,J＝7.9Hz,1H),7.53(d,J＝2.0Hz,1H),7.18(s,1H),6.80(d,J＝2.0Hz,1H),5.41(hept,J＝6.7Hz,1H),5.00(d,J＝7.3Hz,1H),4.67(d,J＝12.7Hz,1H),4.02(d,J＝12.8Hz,1H),3.64(s,1H),2.85(d,J＝14.9Hz,1H),2.28(s,4H),1.46(t,J＝7.0Hz,6H),1.25(d,J＝6.3Hz,3H),0.97–0.85(m,2H),0.82 (td,J＝9.2,7.2Hz,1H),0.57(tq,J＝8.3,4.0Hz,1H),0.54–0.41(m,3H),0.38(dq,J＝9.7,4.9Hz,1H),0.29(ddp,J＝18.3,9.3,4.7Hz,3H).
实施例119a和实施例119b的制备
参照实施例118的合成路线，步骤11中用乙基吡唑-5-羧酸代替异丙基吡唑-5-羧酸，其余试剂和操作相同，最后一步脱SEM经MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化后再经SFC拆分(手性柱型号：Daicel CHIRALPAK AD-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-乙醇，A/B＝70/30：流速:1mL/min；柱温:40℃)可得实施例119a(P1,SFC tR＝1.902)，MS(ESI)m/z＝535[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.05(d,J＝7.9Hz,1H),7.53(d,J＝2.1Hz,1H),7.20(s,1H),6.89(d,J＝2.1Hz,1H),5.03(d,J＝7.3Hz,1H),4.69(d,J＝12.4Hz,1H),4.57(q,J＝7.2Hz,2H),4.03(d,J＝12.7Hz,1H),3.66(s,1H),2.88(d,J＝15.0Hz,1H),2.30(s,4H),1.42(t,J＝7.2Hz,3H),1.28(d,J＝6.3Hz,3H),1.01–0.87(m,2H),0.84(td,J＝9.2,7.3Hz,1H),0.59(tdd,J＝8.0,4.9,3.6Hz,1H),0.56–0.43(m,3H),0.40(dq,J＝9.7,4.9Hz,1H),0.36–0.22(m,3H).实施例119b(P2,SFC tR＝2.145)，MS(ESI)m/z＝535[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.01(d,J＝7.9Hz,1H),7.51(d,J＝2.0Hz,1H),7.18(s,1H),6.87(d,J＝2.1Hz,1H),5.00(d,J＝7.1Hz,1H),4.67(d,J＝12.7Hz,1H),4.56(q,J＝7.1Hz,2H),4.02(d,J＝12.7Hz,1H),3.64(s,1H),2.85(d,J＝15.0Hz,1H),2.28(s,4H),1.40(t,J＝7.2Hz,3H),1.25(d,J＝6.3Hz,3H),0.95–0.85(m,2H),0.83(td,J＝9.3,7.2Hz,1H),0.57(tq,J＝8.2,4.0Hz,1H),0.54–0.41(m,3H),0.38(dq,J＝9.7,4.9Hz,1H),0.29(ddt,J＝12.2,9.0,5.1Hz,3H).
实施例120a和实施例120b的制备
参照实施例118的合成路线，步骤3中用乙基溴化镁代替甲基溴化镁，其余试剂和操作相同，最后一步脱SEM经MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化后再经SFC拆分(手性柱型号：Daicel CHIRALPAK AS-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-乙醇，A/B＝80/20：流速:1mL/min；柱温:40℃)可得实施例120a(P1,SFC tR＝1.749)，MS (ESI)m/z＝563[M+1]+。1H NMR(400MHz,Methanol-d4)δ8.04(d,J＝8.0Hz,1H),7.52(d,J＝2.1Hz,1H),7.18(d,J＝11.4Hz,1H),6.80(d,J＝2.0Hz,1H),5.41(p,J＝6.7Hz,1H),5.01(d,J＝7.1Hz,1H),4.69(d,J＝12.5Hz,1H),4.00(d,J＝12.5Hz,1H),3.34(s,1H),2.88(d,J＝14.9Hz,1H),2.27(s,4H),1.65–1.52(m,2H),1.46(dd,J＝6.7,4.8Hz,6H),1.01(t,J＝7.4Hz,3H),0.96–0.77(m,3H),0.62–0.53(m,1H),0.48(qdd,J＝9.0,5.7,3.1Hz,3H),0.38(dt,J＝9.4,4.2Hz,1H),0.35–0.21(m,3H).实施例120b(P2,SFC tR＝1.974)，MS(ESI)m/z＝563[M+1]+。1H NMR(400MHz,Methanol-d4)δ8.03(d,J＝8.0Hz,1H),7.52(d,J＝2.1Hz,1H),7.18(d,J＝11.4Hz,1H),6.80(d,J＝2.0Hz,1H),5.50–5.31(m,1H),5.01(d,J＝7.0Hz,1H),4.68(d,J＝12.6Hz,1H),4.00(d,J＝12.6Hz,1H),3.32(s,1H),2.87(d,J＝14.8Hz,1H),2.27(s,4H),1.63–1.52(m,2H),1.46(dd,J＝6.7,4.9Hz,6H),1.01(d,J＝7.4Hz,3H),0.96–0.79(m,3H),0.61–0.53(m,1H),0.48(ddtd,J＝13.2,9.3,4.6,4.2,2.8Hz,3H),0.42–0.35(m,1H),0.35–0.25(m,3H).
实施例121的制备
于单口瓶中加入中间体15-6(50mg,94.57μmol)和干燥二氯甲烷(20mL)，再加入DIPEA(24.44mg,189.13μmol,32.94μL)，冰水浴条件下滴加入氯甲酸甲酯(9.83mg,104.02μmol)，然后升至室温搅拌反应30分钟。反应完后，加水淬灭反应，二氯甲烷萃取。有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得中间体121-1(52mg,88.62μmol,93.71％收率)。MS(ESI)m/z＝587[M+1]+。
往中间体121-1(52mg,88.62μmol)的DCM(1mL)溶液中，加入TFA(1mL)。加完后室温反应2小时，反应完后浓缩干，用二氯甲烷溶解，冰水条件下用三乙胺调PH值至8，减压浓缩干。粗品经反相MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化得实施例121(17mg,37.24μmol,42.02％收率)。MS(ESI)m/z＝457[M+1]+。1H NMR(600MHz,DMSO-d6)δ12.43(d,J＝29.0Hz,1H),9.74(s,1H),7.86(d,J＝8.1Hz,1H),7.31(d,J＝9.0Hz,1H),7.19(s,1H),4.45(dd,J＝9.0,6.4Hz,1H),4.32–3.93(m,2H),3.71–3.55(m,2H),3.54(s,3H),2.76–2.49(m,2H),2.17(s,3H),0.94–0.84(m,1H),0.81–0.73(m,1H),0.61–0.53(m,1H),0.47–0.38(m,1H),0.37–0.29(m,1H),0.29–0.21(m,2H),0.21–0.11(m,4H).
实施例122的制备
参照实施例15的合成路线，步骤7中用1-氟环丙烷羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得实施例122，MS(ESI)m/z＝485[M+1]+。
实施例123a和实施例123b的制备
参照实施例33的合成路线，步骤1中用中间体D-8代替3-乙基异噁唑-4-甲酸，其余试剂和操作相同，最后一步经碱法MPLC纯化后再经SFC拆分(手性柱型号：Daicel CHIRALPAK IG；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-乙醇，A/B＝75/25：流速:1mL/min；柱温:40℃)可得实施例123a(P1，SFC tR＝3.993)，MS(ESI)m/z＝549[M+1]+。1H NMR(400MHz,Methanol-d4)δ8.04(d,J＝8.0Hz,1H),7.55(d,J＝2.1Hz,1H),7.19(d,J＝11.4Hz,1H),6.78(d,J＝2.0Hz,1H),5.19(dp,J＝9.1,6.5Hz,1H),5.00(d,J＝7.1Hz,1H),4.31(s,2H),3.71(s,2H),2.70(s,2H),2.27(s,3H),1.93(ddq,J＝14.6,9.1,7.4Hz,1H),1.81–1.70(m,1H),1.47(d,J＝6.7Hz,3H),0.92–0.81(m,3H),0.72(t,J＝7.4Hz,3H),0.60–0.36(m,5H),0.34–0.23(m,3H).实施例123b(P2，SFC tR＝4.966)，MS(ESI)m/z＝549[M+1]+。1H NMR(400MHz,Methanol-d4)δ8.04(d,J＝8.0Hz,1H),7.55(d,J＝2.0Hz,1H),7.19(d,J＝11.5Hz,1H),6.81(d,J＝2.0Hz,1H),5.22(dp,J＝9.1,6.6Hz,1H),5.01(d,J＝6.8Hz,1H),4.31(s,2H),3.72(s,2H),2.70(s,2H),2.28(s,3H),1.96(ddq,J＝14.7,9.1,7.4Hz,1H),1.84–1.71(m,1H),1.46(d,J＝6.6Hz,3H),0.97–0.81(m,3H),0.74(t,J＝7.4Hz,3H),0.61–0.34(m,5H),0.34–0.23(m,3H).
实施例124的制备
参照实施例12的合成路线，步骤8中用中间体D-21代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得实施例124，MS(ESI)m/z＝536[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.33(s,1H),8.18(s,1H),7.53(d,J＝2.1Hz,1H),6.91(d,J＝2.1Hz,1H),4.98(d,J＝6.6Hz,1H),4.65(td,J＝6.9,2.1Hz,2H),4.45(td,J＝6.0,1.6Hz,1H),4.37(td,J＝5.9,1.3Hz,1H),4.27(s,2H),3.76(s,2H),2.72(s,2H),2.30(s,3H),2.24–2.14(m,2H),0.98–0.81(m,3H),0.59–0.53(m,1H),0.52–0.42(m,2H),0.41–0.32(m,2H),0.33–0.27(m,2H),0.26–0.21(m,1H).
实施例125的制备
参照实施例12的合成路线，步骤8中用中间体D-35代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得实施例125，MS(ESI)m/z＝548[M+1]+。1H NMR(400MHz,Methanol-d4)δ8.33(s,1H),8.21(s,1H),7.54(dd,J＝2.2,1.0Hz,1H),6.93(t,J＝1.9Hz,1H),5.03–4.95(m,1H),4.61(dddt,J＝64.0,8.7,6.3,2.3Hz,1H),4.49–4.07(m,4H),3.75(s,2H),2.71(s,2H),2.30(s,3H),1.88–1.65(m,1H),1.06–0.80(m,4H),0.71(dq,J＝10.4,6.7Hz,1H),0.61–0.20(m,8H).
实施例126和实施例127的制备
于单口瓶中加入6-溴-5-氟-2-吡啶甲酸(23.71g,107.77mmol)和甲醇(380mL)，室温再滴加入浓硫酸(71mL)，然后室温搅拌反应过夜。反应完后，倒入冰水中淬灭反应，二氯甲烷萃取。有机相用碳酸氢钠溶液调PH值至8，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得中间体126-1(24.58g,105.03mmol,97.46％收率)。MS(ESI)m/z＝234[M+1]+。
于单口瓶中加入中间体126-1(10g,42.73mmol)、氨基Boc(6.01g,51.28mmol)、Cs2CO3(27.84g,85.46mmol),Pd2(dba)3(1.96g,2.14mmol),Xantphos(2.47g,4.27mmol)和甲苯(150mL)，搅拌状态下抽真空氮气置换三次，升温至90℃搅拌反应过夜。反应完后，趁热硅藻土过滤，滤液减压浓缩至干，粗品经柱层析纯化得中间体126-2(2.13g,12.52mmol,29.30％收率)。MS(ESI)m/z＝171[M+1]+。
于单口瓶中加入中间体126-2(1.97g,11.58mmol)、冰乙酸(69.54mg,1.16mmol)和乙腈(40mL)，室温加入NBS(2.27g,12.74mmol)，室温搅拌反应2小时。反应完后，加水中淬灭 反应，乙酸乙酯萃取。有机相依次用酸氢钠溶液，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体126-3(2.42g,9.73mmol,84.06％收率)。MS(ESI)m/z＝249[M+1]+。1H NMR(400MHz,DMSO-d6)δ7.82(d,J＝10.2Hz,1H),6.84(s,2H),3.82(s,3H).
于单口瓶中加入中间体126-3(2.36g,9.48mmol)、中间体A-3(4.28g,10.42mmol)、CsF(2.88g,18.95mmol),Pd(amphos)Cl2(336.46mg,473.83μmol)和二氧六环/水(50mL/10mL)，搅拌状态下抽真空氮气置换三次，升温至100℃搅拌反应过夜。反应完后，趁热硅藻土过滤，滤液减压浓缩至干，粗品经柱层析纯化得中间体126-4(3.06g,6.76mmol,71.35％收率)。MS(ESI)m/z＝453[M+1]+。
参照实施例1的合成路线，用中间体126-4代替中间体1-1，其余试剂和操作相同，只是中间体126-8经钯碳和甲酸铵氢化时，有约1/3的原料掉氟，然后分别往后走，得实施例126，MS(ESI)m/z＝536[M+1]+。1H NMR(400MHz,Methanol-d4)δ7.69(d,J＝10.1Hz,1H),7.52(d,J＝2.0Hz,1H),6.79(d,J＝2.0Hz,1H),5.41(p,J＝6.7Hz,1H),5.07(s,1H),4.50(d,J＝62.6Hz,2H),3.75(s,2H),2.79(d,J＝51.4Hz,2H),2.30(s,3H),1.46(dd,J＝6.6,4.4Hz,6H),0.90(qd,J＝8.9,8.3,4.3Hz,3H),0.64–0.41(m,5H),0.36–0.27(m,3H).实施例127，MS(ESI)m/z＝518[M+1]+。1H NMR(400MHz,Methanol-d4)δ8.19(d,J＝8.4Hz,1H),7.80(d,J＝8.3Hz,1H),7.53(d,J＝2.0Hz,1H),6.82(d,J＝2.1Hz,1H),5.40(p,J＝6.6Hz,1H),4.96(d,J＝6.7Hz,1H),4.40(s,2H),3.75(s,2H),2.79(d,J＝58.1Hz,2H),2.28(s,3H),1.46(dd,J＝6.6,5.5Hz,6H),1.02–0.76(m,3H),0.61–0.42(m,3H),0.42–0.21(m,5H).
实施例128的制备
于单口瓶中加入2-氯-3-氟异烟酸甲酯(9g,47.48mmol)、氨基Boc(8.34g,71.21mmol)、Cs2CO3(30.94g,94.95mmol),Pd(OAc)2(532.94mg,2.37mmol),Xantphos(2.75g,4.75mmol)和二氧六环(100mL)，搅拌状态下抽真空氮气置换三次，升温至100℃搅拌反应16小时。反应完后，趁热硅藻土过滤，滤液减压浓缩至干，粗品经柱层析纯化得中间体128-1(1.6g,9.40mmol,19.81％收率)。MS(ESI)m/z＝171[M+1]+。1H NMR(600MHz,Chloroform-d)δ7.92(d,J＝5.2Hz,1H),7.03(t,J＝4.9Hz,1H),3.95(s,3H).
于单口瓶中加入中间体128-1(1.6g,9.40mmol)和DMF(40mL)，室温加入NBS(1.84g,10.34mmol)，室温搅拌反应2小时。反应完后，加水中淬灭反应，乙酸乙酯萃取。有机相依次用碳酸氢钠溶液，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体128-2(1.5g,6.02mmol,64.05％收率)，MS(ESI)m/z＝249[M+1]+。1H NMR(600MHz,Chloroform-d)δ8.01(s,1H),3.99(s,3H).
参照实施例126的合成路线，用中间体128-2代替中间体126-3，其余试剂和操作相同，可得实施例128，MS(ESI)m/z＝536[M+1]+。1H NMR(600MHz,Chloroform-d)δ8.61(s,1H),8.25(s,1H),7.52(d,J＝2.0Hz,1H),7.26(s,1H),7.18(d,J＝8.3Hz,1H),6.58(d,J＝2.1Hz,1H),5.49(p,J＝6.7Hz,1H),5.04 (s,1H),3.65(d,J＝191.7Hz,5H),2.81(s,1H),2.37(s,3H),1.50(dd,J＝12.9,6.6Hz,6H),0.98–0.87(m,3H),0.70–0.50(m,4H),0.46–0.21(m,4H).
实施例129的制备
于单口瓶中加入中间体E-1-2(5.7g,17.80mmol)和二氯甲烷(50mL)，室温加入三苯基磷(7.00g,26.71mmol)和四溴化碳(7.68g,23.15mmol)。加毕，室温搅拌反应过夜。反应完后，加水淬灭反应，二氯甲烷萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体129-1(4.26g,11.12mmol,62.47％收率)，MS(ESI)m/z＝382[M+1]+.
于三口瓶中加入中间体129-1(3.26g,8.51mmol)和甲苯(30mL)，室温下加入碘化亚铜(162.08mg,851.06μmol)和2,2'-二联吡啶(132.92mg,851.06μmol)，抽真空氮气置换三次。降温至-70℃，滴加入乙烯基溴化镁(3.35g,25.53mmol)，加毕，逐渐升至室温搅拌反应过夜。 反应完后，加入饱和氯化铵淬灭反应，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体129-2(1.5g,4.54mmol,53.38％收率)，MS(ESI)m/z＝328[M-1]+.
于三口瓶中加入3-溴-5-甲基-1H-吡唑(20g,124.22mmol)和四氢呋喃(200mL)，冰水浴降温至0℃，分批加入钠氢(5.96g,248.45mmol)。加毕，保温搅拌反应1小时，然后滴加入2-(三甲基硅烷基)乙氧甲基氯(24.85g,149.07mmol)。滴毕，升至室温搅拌反应过夜，反应完后，加饱和氯化铵溶液淬灭反应，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体129-3(30g,103.00mmol,82.92％收率)，MS(ESI)m/z＝291[M+1]+.
于单口瓶中加入中间体129-3(6g,20.60mmol)，二氧六环和水(40mL/8mL)，再加入烯丙基硼酸频哪醇酯(9.52g,61.80mmol)，碳酸钾(8.53g,61.80mmol)and Pd(dppf)Cl2(753.66mg,1.03mmol)，抽真空氮气置换三次，升温至100℃搅拌反应过夜。反应完后，冷却，加水稀释，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体129-4(4.67g,18.50mmol,89.81％收率)，MS(ESI)m/z＝253[M+1]+.
于单口瓶中加入中间体129-4(4.5g,17.83mmol)和二氯甲烷(40mL)，再加入N-溴代丁二酰亚胺(3.49g,19.61mmol)，反应液室温搅拌反应1小时。反应完后，加水淬灭反应，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体129-5(5.2g,15.69mmol,88.04％收率)，MS(ESI)m/z＝331[M+1]+.
于三口瓶中加入中间体129-5(4.4g,13.28mmol)和二氧六环(60mL)，室温下加入三乙胺(2.02g,19.92mmol,2.78mL)，Pd(OAc)2(90.25mg,398.40μmol)和CyJohnphos(279.26mg,796.81μmol)，抽真空氮气置换三次。经注射器加入频那醇硼烷(4.59g,35.86mmol)，加毕，逐渐升至80℃搅拌反应过夜。反应完后，加入水淬灭反应，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体129-6(5.2g,15.69mmol,88.04％收率)，MS(ESI)m/z＝379[M+1]+.
于单口瓶中加入中间体129-6(1.32g,3.49mmol)，中间体129-2(1.27g,3.84mmol)，二氧六环和水(10mL/2mL)，室温下加入Pd2(dba)3(79.86mg,87.21μmol)，rac-BI-DIME(57.56mg,174.42μmol)和磷酸钾(1.48g,6.98mmol)，抽真空氮气置换三次，逐渐升至100℃搅拌反应过夜。反应完后，加入水淬灭反应，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体129-7(1.38g,2.74mmol,78.56％ 收率)，MS(ESI)m/z＝502[M+1]+.
于单口瓶中加入中间体129-7(1.38g,2.74mmol)和二氯甲烷(200mL)，室温下加入Grubbs二代催化剂(116.34mg,137.03μmol)，抽真空氮气置换三次，逐渐升至45℃搅拌反应48小时。反应完后，加入水淬灭反应，分层，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体129-8(605mg,1.28mmol,46.61％收率)，MS(ESI)m/z＝474[M+1]+.
于单口瓶中加入中间体129-8(200mg,422.25μmol)和乙酸乙酯(1mL)，冰水浴条件下加入4M HCl乙酸乙酯溶液(16.89mg,4.22mmol)，逐渐升至室温搅拌反应1小时。反应完后，冰水浴冷却，用三乙胺调PH值至8，减压浓缩至干，粗品经MPLC(CH3CN/H2O,0.05％NH4HCO3)纯化得中间体129-9(60mg,160.63μmol,38.04％收率)，MS(ESI)m/z＝374[M+1]+.
参照实施例1的合成路线，步骤5中用中间体129-9代替中间体1-4，同时用BOC-L-2-氨基-3,3-二环丙基丙酸代替中间体C-1，钯碳脱苄氧碳基改为用4M HCl乙酸乙酯溶液脱Boc，此脱Boc方法参照中间体129-9的合成方法，剩余两步合成方法均参照实施例1的合成路线，其余试剂和操作相同，可得实施例129，MS(ESI)m/z＝531[M+1]+.
实施例130的制备
于单口瓶中加入实施例129(12mg,22.61μmol)和甲醇(2mL)，加入钯碳(4.2mg,w/w30％)，抽真空氢气置换三次，于室温搅拌反应2小时。反应完后，过滤，滤液减压浓缩至干，粗品经MPLC纯化得实施例130(240.00μg,4.51e-1μmol,1.99％收率)。MS(ESI)m/z＝533[M+1]+。
实施例131的制备
于单口瓶中加入中间体A-2(10.9g,30.00mmol)、甲醇(1.35g,42.00mmol)和四氢呋喃(110mL)，室温加入硼氢化锂(1.7g,78.05mmol)，然后升温至60℃搅拌反应1小时。反应完后，冰水浴冷去，饱和氯化铵溶液淬灭反应，乙酸乙酯萃取。有机相依次用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体131-1(8.6g,25.65mmol,85.49％收率)。MS(ESI)m/z＝335[M+1]+。
于三口瓶中加入中间体131-1(6.6g,19.68mmol)和二氯甲烷(60mL)，室温加入三乙胺(3.98g,39.37mmol,5.49mL)，然后冰水浴下滴加入甲基磺酰氯(2.71g,23.62mmol)。滴毕，室温搅拌反应1小时。反应完后，加水淬灭反应，二氯甲烷萃取。有机相依次用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得中间体131-2(7.7g,18.63mmol,94.63％收率)。MS(ESI)m/z＝413[M+1]+。
于封管中加入中间体131-2(7.7g,18.63mmol)和33％甲胺甲醇溶液(60mL)，升温至60℃搅拌反应2.5小时。反应完后，冰水浴冷却，减压浓缩至干得中间体131-3(6.29g,18.06mmol,96.94％收率)，不经纯化直接用于下一步反应。MS(ESI)m/z＝348[M+1]+。
于单口瓶中加入中间体131-3(5.25g,15.07mmol)，四氢呋喃和水(50mL/25mL)，室温加入碳酸氢钠(3.95g,18.09mmol)和(Boc)2O(3.95g,18.09mmol)。加毕，室温搅拌反应2 小时。反应完后，加水稀释，乙酸乙酯萃取。有机相依次用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干。粗品经硅胶柱层析得中间体131-4(5.57g,12.42mmol,82.41％收率)。MS(ESI)m/z＝448[M+1]+。
往中间体B-3(3.99g,13.52mmol)、中间体131-4(6.67g,14.87mmol)和Cs2CO3(8.81g,27.03mmol)的1,4二氧六环(80mL)/水(16mL)混和溶剂中，加入Pd(dtppf)Cl2(881.18mg,1.35mmol)，氮气鼓泡除氧，于80℃搅拌反应过夜，反应完后冷却，加入水和乙酸乙酯萃取，有机层用盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干,经硅胶柱层析纯化得中间体131-5(4.1g,7.64mmol,56.50％收率)。MS(ESI)m/z＝537[M+1]+。
于单口瓶中加入中间体131-5(196mg,365.19μmol)，四氢呋喃/甲醇和水(2mL/2mL/2mL)，室温加入氢氧化钠(70.04mg,1.83mmol)。加毕，升温至60℃搅拌反应1小时。反应完后，冰水浴降温，用1N HCl盐酸调pH值至7，然后减压浓缩至干得粗品中间体131-6(190mg,363.51μmol)。MS(ESI)m/z＝523[M+1]+。
于单口瓶中加入中间体131-6(190mg,363.51μmol)和二氯甲烷(3mL)，冰水浴条件下加入三氟乙酸(414.47mg,3.64mmol)。加毕，室温搅拌反应30分钟。反应完后，冰水浴降温，用饱和碳酸氢钠溶液调pH值至7，然后减压浓缩至干得粗品中间体131-7(153mg,362.07μmol)。MS(ESI)m/z＝423[M+1]+。
于单口瓶中加入中间体131-7(153mg,362.07μmol)和DMF(4mL)，再依次加入DIPEA(187.18mg,1.45mmol,252.26μL)和HATU(178.97mg,470.69μmol)。加毕，室温搅拌反应1小时，加入水淬灭反应，乙酸乙酯萃取，有机层用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱纯化得中间体131-8(121mg,299.10μmol,82.61％收率)。MS(ESI)m/z＝405[M+1]+。
于单口瓶中加入中间体131-8(121mg,299.10μmol)和吡啶(1.5mL)，再加入中间体C-1(108.88mg,358.92μmol)和EDCI(172.01mg,897.29μmol)，室温搅拌反应过夜。反应完后，将反应液减压浓缩至干。粗品经反相MPLC(CH3CN/H2O,0.05％TFA)纯化得中间体131-9(128mg,185.54μmol,62.03％收率)。MS(ESI)m/z＝690[M+1]+。
参照实施例1步骤6至步骤8的合成方法，用中间体131-9代替中间体1-5，其余试剂和操作相同，可得实施例131，MS(ESI)m/z＝562[M+1]+。1H NMR(400MHz,Methanol-d4)δ8.09(dd,J＝14.7,7.8Hz,1H),7.51(t,J＝2.6Hz,1H),7.18–7.10(m,1H),6.78(dd,J＝3.8,2.1Hz,1H),5.40(pd,J＝6.7,2.3Hz,1H),5.01(dd,J＝9.5,7.1Hz,1H),4.01(tt,J＝14.3,4.7Hz,1H),3.40(dt,J＝14.4,5.5Hz,1H),3.35-3.24(m,1H),3.01(s,3H),2.92–2.78(m,1H),2.17(s,3H),1.45(td,J＝6.8,3.0Hz,6H),0.98–0.75(m,3H),0.63–0.16(m,8H).
实施例132至实施例181的制备
参照实施例1的合成路线，步骤5中用下表中相应大环胺中间体代替中间体1-4，同时步骤7中1-异丙基吡唑-5-羧酸相同或者用下表中相应的吡唑羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得表中相应结构实施例化合物。













实施例182的制备
参照实施例12的合成路线，步骤6中用中间体E-31代替中间体12-5，其余试剂和操作相同，可得中间体182-1，MS(ESI)m/z＝749[M+1]+。
于单口瓶中加入中间体182-1(300mg,401.07μmol)和二氯甲烷(4mL)，再加入二氯化钯(14.12mg,80.21μmol)和三乙胺(8.53g,280.75μmol)，冰水浴条件下滴加入三乙基硅烷(232.62mg,2.01mmol)，升至室温搅拌反应1小时。反应完后，硅藻土过滤，滤液减压浓缩至干，粗品经反相MPLC纯化得中间体182-2(210.87mg,343.44μmol,85.63％收率)，MS(ESI)m/z＝615[M+1]+。
参照实施例12的合成路线，步骤8中用中间体182-2代替中间体12-7，其余试剂和操作相同，可得中间体实施例182，MS(ESI)m/z＝621[M+1]+。
实施例183至实施例185的制备
参照实施例182的合成路线，步骤1中用下表中相应大环胺中间体代替中间体E-31，其余试剂和操作相同，可得表中相应结构实施例化合物。

实施例186a和实施例186b的制备
参照实施例118的合成路线，步骤9中用中间体E-11代替中间体118-8，其余试剂和操作相同，最后一步脱SEM经MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化后再经SFC拆分(手 性柱型号：Daicel CHIRALPAK AD-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-0.1％DEA/乙醇，A/B＝75/25：流速:1mL/min；柱温:40℃)可得实施例186a(P1,SFC tR＝2.533)，MS(ESI)m/z＝644[M+1]+，1H NMR(600MHz,Methanol-d4)δ8.24(d,J＝7.7Hz,1H),7.52(d,J＝2.0Hz,1H),7.25(d,J＝10.8Hz,1H),6.79(d,J＝2.0Hz,1H),5.53(d,J＝8.1Hz,1H),5.40(hept,J＝6.6Hz,1H),5.00(d,J＝7.4Hz,1H),4.21(t,J＝12.8Hz,2H),3.72–3.51(m,2H),2.36(s,3H),1.53(d,J＝7.2Hz,3H),1.46(dd,J＝11.3,6.6Hz,6H),0.96–0.86(m,2H),0.82(td,J＝9.3,7.4Hz,1H),0.61–0.55(m,1H),0.54–0.41(m,3H),0.37(dt,J＝9.6,4.7Hz,1H),0.30(dhept,J＝18.4,4.8Hz,3H)；实施例186b(P2,SFC tR＝4.165)，MS(ESI)m/z＝644[M+1]+，1H NMR(600MHz,Methanol-d4)δ8.23(d,J＝7.7Hz,1H),7.53(d,J＝2.0Hz,1H),7.25(d,J＝10.9Hz,1H),6.80(d,J＝2.0Hz,1H),5.53(s,1H),5.41(hept,J＝6.7Hz,1H),4.99(d,J＝7.4Hz,1H),4.35–4.15(m,2H),3.76–3.49(m,2H),2.36(s,3H),1.54(d,J＝7.2Hz,3H),1.46(dd,J＝10.4,6.7Hz,6H),0.90(dddt,J＝22.6,13.0,8.0,5.0Hz,2H),0.81(td,J＝9.3,7.4Hz,1H),0.57(tt,J＝9.0,4.3Hz,1H),0.54–0.40(m,3H),0.37(dq,J＝9.7,4.9Hz,1H),0.31(ttd,J＝7.2,5.0,2.6Hz,2H),0.25(dq,J＝9.6,4.9Hz,1H).
实施例187a和实施例187b的制备
参照实施例118的合成路线，步骤9中用中间体E-29代替中间体118-8，其余试剂和操作相同，最后一步脱SEM经MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化后再经SFC拆分(手性柱型号：Daicel CHIRALPAK AD-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-乙醇，A/B＝75/25：流速:1mL/min；柱温:40℃)可得实施例187a(P1,SFC tR＝2.677)，MS(ESI)m/z＝562[M+1]+，1H NMR(600MHz,DMSO-d6)δ12.22(d,J＝109.0Hz,1H),9.86(s,1H),8.21(d,J＝8.6Hz,1H),7.86–7.58(m,2H),7.28(d,J＝2.0Hz,1H),6.95(d,J＝11.8Hz,1H),6.69(d,J＝2.0Hz,1H),5.17(p,J＝6.6Hz,1H),4.74(t,J＝8.2Hz,1H),3.51(dddd,J＝13.0,10.1,6.4,3.9Hz,1H),2.64(d,J＝32.0Hz,1H),2.47(dd,J＝16.4,12.5Hz,1H),1.85(s,3H),1.14(dd,J＝15.3,6.6Hz,6H),0.93(d,J＝6.5Hz,3H),0.76–0.69(m,1H),0.68–0.62(m,1H),0.55(td,J＝9.4,7.8Hz,1H),0.30–0.22(m,1H),0.19–-0.03(m,6H),-0.04–-0.09(m,1H)；实施例187b(P2,SFC tR＝4.627)，MS(ESI)m/z＝562[M+1]+，1H NMR(600MHz,DMSO-d6)δ12.45(d,J＝102.7Hz,1H),10.03(s,1H),8.45(d,J＝8.6Hz,1H),7.88(t,J＝11.6Hz,2H),7.51(d,J＝1.9Hz,1H),7.17(d,J＝11.7Hz,1H),6.90(d,J＝2.0Hz,1H),5.39(p,J＝6.6Hz,1H),5.02–4.86(m,1H),3.74(dtd,J＝9.1,6.3,2.6Hz,1H),2.85(s,1H),2.69(dd,J＝16.3,12.4Hz,1H),2.08(s,3H),1.37(dd,J＝19.7,6.6Hz,6H),1.16(d,J＝6.5Hz,3H),0.97–0.83(m,2H),0.79(td,J＝9.4,7.6Hz,1H),0.49(dt,J＝13.2,6.4Hz,1H),0.42–0.15(m,7H).
实施例188a和实施例188b的制备
参照实施例12的合成路线，步骤8中用中间体D-41代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，最后一步脱SEM经MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化后再经SFC拆分(手性柱型号：Daicel CHIRALPAK AD-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-0.1％DEA/乙醇，A/B＝60/40：流速:1mL/min；柱温:40℃)可得实施例188a(P1,SFC tR＝2.850)，MS(ESI)m/z＝544[M+1]+，1H NMR(600MHz,Methanol-d4)δ8.32(s,1H),8.22(s,1H),7.56(d,J＝2.0Hz,1H),6.80(d,J＝2.0Hz,1H),4.93(d,J＝7.1Hz,1H),4.52(dq,J＝9.6,6.7Hz,3H),3.68(d,J＝96.4Hz,2H),2.68(d,J＝35.9Hz,2H),2.30(s,3H),1.58(d,J＝6.8Hz,3H),1.33(dddd,J＝12.9,9.7,8.0,4.9Hz,1H),0.94–0.80(m,3H),0.62–0.53(m,2H),0.53–0.43(m,2H),0.40–0.32(m,3H),0.32–0.27(m,4H),0.24(dt,J＝9.2,4.7Hz,1H)；实施例188b(P2,SFC tR＝5.574)，MS(ESI)m/z＝544[M+1]+，1H NMR(600MHz,Methanol-d4)δ8.31(s,1H),8.22(s,1H),7.56(d,J＝2.0Hz,1H),6.84(d,J＝2.1Hz,1H),4.94(d,J＝6.7Hz,1H),4.58(dq,J＝9.5,6.7Hz,1H),4.35(s,2H),3.75(s,2H),2.71(s,2H),2.30(s,3H),1.56(d,J＝6.8Hz,3H),1.38(dddd,J＝12.8,9.8,8.0,4.9Hz,1H),0.92(dtd,J＝13.2,8.3,4.9Hz,1H),0.88–0.82(m,2H),0.62(tdd,J＝8.8,5.4,3.6Hz,1H),0.56(dq,J＝8.1,3.6Hz,1H),0.52–0.43(m,2H),0.36(dddd,J＝21.3,10.7,5.2,3.5Hz,4H),0.30(dt,J＝9.2,4.9Hz,3H),0.24(dt,J＝9.3,4.8Hz,1H).
实施例189a和实施例189b的制备
参照实施例12的合成路线，步骤8中用中间体D-40代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，最后一步脱SEM经MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化后再经SFC拆分(手性柱型号：Daicel CHIRALCEL OX-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-乙醇，A/B＝80/20：流速:1mL/min；柱温:40℃)可得实施例189a(P1,SFC tR＝3.813)， MS(ESI)m/z＝536[M+1]+，1H NMR(600MHz,Methanol-d4)δ8.33(d,J＝29.6Hz,1H),8.22(s,1H),7.58(d,J＝2.0Hz,1H),6.86(d,J＝2.1Hz,1H),5.64(dddd,J＝13.1,8.0,6.7,4.6Hz,1H),4.98(d,J＝7.1Hz,1H),4.69(ddd,J＝47.7,9.4,8.1Hz,1H),4.61–4.59(m,0.5H),4.52(dd,J＝9.4,4.7Hz,0.5H),4.35(s,2H),3.69(d,J＝72.1Hz,2H),2.74(d,J＝35.5Hz,2H),2.31(s,3H),1.48(dd,J＝6.9,1.6Hz,3H),0.94–0.81(m,3H),0.58–0.43(m,3H),0.41–0.33(m,2H),0.30(dqt,J＝9.3,4.7,2.9Hz,2H),0.24(dq,J＝9.4,4.9Hz,1H).；实施例189b(P2,SFC tR＝4.502)，MS(ESI)m/z＝536[M+1]+，1H NMR(600MHz,Methanol-d4)δ8.32(s,1H),8.23(s,1H),7.57(d,J＝2.0Hz,1H),6.88(d,J＝2.0Hz,1H),5.66(dddd,J＝13.2,8.2,6.8,4.6Hz,1H),5.00(d,J＝7.1Hz,1H),4.70(ddd,J＝47.8,9.4,8.1Hz,1H),4.61(dd,J＝9.3,4.6Hz,0.5H),4.53(dd,J＝9.4,4.6Hz,0.5H),4.35(s,2H),3.94–3.57(m,2H),2.65(s,2H),2.30(s,3H),1.46(dd,J＝6.9,1.6Hz,3H),0.94–0.81(m,3H),0.55(tq,J＝8.7,4.1Hz,1H),0.51–0.42(m,2H),0.37(dddd,J＝9.3,7.5,5.2,4.0Hz,1H),0.34–0.22(m,4H).
实施例190a和实施例190b的制备
参照实施例12的合成路线，步骤8中用中间体D-1代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，最后一步脱SEM经MPLC(H2O/CH3CN,0.05％ NH4HCO3)纯化后再经SFC拆分(手性柱型号：Daicel CHIRALPAK AD-3；规格：3μm,150mm*3mm；流动相:A-CO2，流动相：B-乙醇，A/B＝80/20：流速:1mL/min；柱温:40℃)可得实施例190a(P1,SFC tR＝2.647)，MS(ESI)m/z＝554[M+1]+，1H NMR(600MHz,Methanol-d4)δ8.35(d,J＝33.5Hz,1H),8.23(s,1H),7.62(d,J＝2.0Hz,1H),6.95(d,J＝2.0Hz,1H),6.10(td,J＝56.2,5.3Hz,1H),5.70(ddd,J＝10.6,5.3,1.7Hz,1H),5.01(d,J＝7.2Hz,1H),4.36(s,2H),3.77(s,2H),2.70(d,J＝32.6Hz,2H),2.33(s,3H),1.62(dd,J＝7.1,1.2Hz,3H),0.96–0.82(m,3H),0.60–0.54(m,1H),0.54–0.49(m,1H),0.49–0.44(m,1H),0.42–0.34(m,2H),0.34–0.29(m,2H),0.26(dq,J＝9.3,4.9Hz,1H)；实施例190b(P2,SFC tR＝5.788)，MS(ESI)m/z＝554[M+1]+，1HNMR(600MHz,Methanol-d4)δ8.33(s,1H),8.24(s,1H),7.62(d,J＝2.0Hz,1H),6.97(d,J＝2.0Hz,1H),6.10(td,J＝56.4,5.4Hz,1H),5.71(dd,J＝7.1,5.4Hz,1H),5.02(d,J＝7.1Hz,1H),4.36(s,2H),3.77(s,2H),2.73(s,2H),2.32(s,3H),1.61(dd,J＝7.0,1.2Hz,3H),0.96–0.83(m,3H),0.57(tq,J＝8.8,5.2,4.6Hz,1H),0.53–0.43(m,2H),0.42–0.36(m,1H),0.30(dddt,J＝26.5,22.1,9.2,4.4Hz,4H).
实施例191和实施例213的制备
参照实施例12步骤6至步骤9的合成路线，步骤6中用下表中相应大环胺中间体代替中间体12-5，其余试剂和操作相同，可得表中相应结构实施例化合物。




实施例214和实施例233的制备
参照实施例12步骤6至步骤9的合成方法，步骤6中用下表中相应大环胺中间体代替中间体12-5，同时步骤8中用下表中相应羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得表中相应结构实施例化合物。





实施例234和实施例245的制备
参照实施例12的合成方法，步骤8中用下表中相应羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得表中相应结构实施例化合物。



实施例246的制备
参照实施例12步骤6和步骤7的合成方法，步骤6中用中间体E-38代替中间体12-5，其余试剂和操作相同，可得中间体246-2，MS(ESI)m/z＝551[M+1]+。
参照实施例32的合成路线，步骤1中用环丁醇代替环丙醇，同时用中间体246-2代替中间体15-6，其余试剂和操作相同，可得实施例246，MS(ESI)m/z＝519[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.45(d,J＝34.0Hz,2H),4.92(d,J＝7.6Hz,2H),4.65–4.14(m,3H),3.55(s,2H),3.17–2.84(m,2H),2.33(s,5H),2.11(dq,J＝19.2,9.4Hz,2H),1.79(q,J＝9.8,8.9Hz,1H),1.63(dtd,J＝18.3,10.3,7.9Hz,1H),1.17(dt,J＝20.8,4.5Hz,4H),0.93–0.82(m,2H),0.69(td,J＝9.5,6.0Hz,1H),0.56(tt,J＝9.0,4.7Hz,1H),0.49(tt,J＝8.9,4.7Hz,1H),0.44–0.34(m,2H),0.25(dddt,J＝38.0,14.0,9.2,4.7Hz,4H).
实施例247的制备
参照实施例32的合成路线，步骤1中用环丁醇代替环丙醇，同时用中间体12-7代替中间体15-6，其余试剂和操作相同，可得实施例247，MS(ESI)m/z＝480[M+1]+。1H NMR(600MHz,Methanol-d4)δ8.34(s,1H),8.06(s,1H),4.96–4.89(m,1H),4.59–4.15(m,3H),3.78(s,2H),2.80(d,J＝66.9Hz,2H),2.32(s,5H),2.11(p,J＝9.8Hz,2H),1.79(q,J＝10.6Hz,1H),1.63(h,J＝9.8Hz,1H),0.85(dddd,J＝13.2,9.9,8.1,4.9Hz,2H),0.70(q,J＝8.9Hz,1H),0.57(dq,J＝13.6,8.6,6.9Hz,1H),0.49(tt,J＝8.6,4.6Hz,1H),0.39(dtd,J＝17.8,8.7,4.4Hz,2H),0.30(dq,J＝9.9,5.0Hz,1H),0.24(dp,J＝14.4,4.6Hz,3H).
实施例248和实施例257的制备
参照实施例12步骤6至步骤9的合成方法，步骤6中用下表中相应大环胺中间体代替中间体12-5，同时步骤8中用下表中相应羧酸代替1-异丙基吡唑-5-羧酸，其余试剂和操作相同，可得表中相应结构实施例化合物。



为了说明本发明的有益效果，本发明提供以下试验例
试验例1、IL-17A酶联免疫吸附测定(ELISA)实验
通过竞争性ELISA对人IL17A抑制剂对受体-配体结合的抑制情况进行定量检测。
IL-17A酶联免疫吸附测定(ELISA)实验具体步骤如下：(1)包被人IL17A(Sino Biological lnc.Cat#12047-H07B):将人IL-17A稀释至包被液(50mM PBS，PH7.4)中得到0.2μg/ml IL17A,以100μl每孔在96孔板中37度孵育30分钟，注意，其中空白组用100μl包被液代替。(2)洗脱：用10mM PBST(PBS，pH 7.4,0.05％ Tween-20)洗板4次，每次200μl每孔，且最后一次至于后吸水纸上拍干。(3)封闭：在实验开始前提前准备好新鲜的5％(w/v)脱脂牛奶液，根据实验需要配制相应体积，例如将5克脱脂牛奶(Bio-Rad,170-6404)充分溶解在100mL的10mM PBST中，每孔加入200μl 5％(w/v)脱脂牛奶液并于25度摇床上孵育30分钟。(4)100X待测化合物准备，在封闭期间开始准备待测化合物溶液，将粉末化合物溶解到DMSO，使其存储浓度为10mM,使用DMSO将化合物进行4倍梯度稀释，9个浓度，浓度从0.61μM到4000μM。(5)洗脱，重复步骤(2)。(6)IL17A与化合物预孵育：向孔中加入89μl PBST和1μl 100X浓度待测化合物混匀后于25度预孵育10分钟，注：空白组和对照组均加入1μlDMSO代替化合物。(7)人IL17Ra孵育：加入10μl 16nM人IL-17R(Sino Biological lnc.，Cat#10895-H03H)于25度摇床上孵育30分钟，配制缓冲液为10mM PBST。(8)洗脱，重复步骤(2)。(9)HRP抗体孵育：加入100μl鼠抗Fc标签HRP偶联抗体(Sino Biological lnc.,Cat#10702-MM01T-H)于25度摇床上孵育30分钟，鼠抗Fc标签HRP偶联抗体与5％(w/v)脱脂牛奶液按体积比为1：5000进行配制。(10)洗脱，重复步骤(2)。(11)加入100μl TMB 底物(BD,Cat#555214，底物A和底物B按照体积比1：1进行新鲜配制)溶液25度避光孵育孵育5～15分钟，室温偏低时需要适当延长孵育时间，此时可孵育至对照组出现显著颜色变化时。(12)终止：加入2.5M HCl进行终止显色反应，采用酶标仪BMG PHERStar于450nm波长检测光吸收值。(13)IC50计算:按照方程1计算化合物每个浓度相对百分剩余活性％，根据Graphpad6中log(inhibitor)vs.normalized response--Variable slope的方程2计算出待测化合物的IC50。
方程1：相对百分剩余活性％＝(样品吸光值-空白组吸光值)/(对照组吸光值-空白吸光值)％
方程2：Y＝100/(1+10^((LogIC50-X)*HillSlope))
按照上述方法对实施例制备的化合物进行IL-17A抑制活性测试，试验结果见表1，其中测定各化合物的IC50按照说明分类如下。
“+”表示IC50测定值小于等于1μM大于150nM；
“++”表示IC50测定值小于等于150nM大于50nM；
“+++”表示IC50测定值小于等于50nM。
表1、化合物对人IL-17A的抑制活性




试验例2、IL17AF酶联免疫吸附测定(ELISA)实验
通过竞争性ELISA对人IL17AF抑制剂对受体-配体结合的抑制情况进行定量检测。
IL17AF酶联免疫吸附测定(ELISA)实验具体步骤如下：(1)包被人IL17AF(Sino Biological lnc.Cat#CT047-H08H):将人IL17AF稀释至包被液(50mM PBS，PH7.4)中得到0.625μg/ml IL17AF,以100μl每孔在96孔板中37度孵育30分钟，注意，其中空白组用100μl包被液代替。(2)洗脱：用10mM PBST(PBS，pH 7.4,0.05％ Tween-20)洗板4次，每次200μl每孔，且最后一次至于后吸水纸上拍干。(3)封闭：在实验开始前提前准备好新鲜的5％(w/v)脱脂牛奶液，根据实验需要配制相应体积，例如将5克脱脂牛奶(Bio-Rad,170-6404)充分溶 解在100mL的10mM PBST中，每孔加入200μl 5％(w/v)脱脂牛奶液并于25度摇床上孵育30分钟。(4)100X待测化合物准备，在封闭期间开始准备待测化合物溶液，将粉末化合物溶解到DMSO，使其存储浓度为10mM,使用DMSO将化合物进行4倍梯度稀释，9个浓度，浓度从0.61μM到4000μM。(5)洗脱，重复步骤(2)。(6)IL17AF与化合物预孵育：向孔中加入89μl PBST和1μl 100X浓度待测化合物混匀后于25度预孵育10分钟，注：空白组和对照组均加入1μl DMSO代替化合物。(7)人IL17Ra孵育：加入10μl 100nM人IL-17R(Sino Biological lnc.，Cat#10895-H03H)于25度摇床上孵育30分钟，配制缓冲液为10mM PBST。(8)洗脱，重复步骤(2)。(9)HRP抗体孵育：加入100μl鼠抗Fc标签HRP偶联抗体(Sino Biological lnc.,Cat#10702-MM01T-H)于25度摇床上孵育30分钟，鼠抗Fc标签HRP偶联抗体与5％(w/v)脱脂牛奶液按体积比为1：5000进行配制。(10)洗脱，重复步骤(2)。(11)加入100μl TMB底物(BD,Cat#555214，底物A和底物B按照体积比1：1进行新鲜配制)溶液25度避光孵育孵育5～15分钟，室温偏低时需要适当延长孵育时间，此时可孵育至对照组出现显著颜色变化时。(12)终止：加入2.5M HCl进行终止显色反应，采用酶标仪BMG PHERStar于450nm波长检测光吸收值。(13)IC50计算:按照方程1计算化合物每个浓度相对百分剩余活性％，根据Graphpad6中log(inhibitor)vs.normalized response--Variable slope的方程2计算出待测化合物的IC50。
方程1：相对百分剩余活性％＝(样品吸光值-空白组吸光值)/(对照组吸光值-空白吸光值)％
方程2：Y＝100/(1+10^((LogIC50-X)*HillSlope))
按照上述方法对实施例制备的化合物进行IL17AF抑制活性测试，试验结果见表2，其中测定各化合物的IC50按照说明分类如下。
“+”表示IC50测定值小于等于1μM大于500nM；
“++”表示IC50测定值小于等于500nM大于100nM；
“+++”表示IC50测定值小于等于100nM。
表2、化合物对人IL17AF的抑制活性



试验例3、化合物抑制人IL17A蛋白诱导HT-29细胞产生趋化因子GROα/CXCL1实验
将5x 104个/孔的人结直肠癌上皮细胞HT-29(成都中源共创科技有限公司)加入96孔板中，在37℃培养箱培养过夜。将30ng/mL的人IL17A蛋白(R&D,#317-ILB)与梯度浓度的IL17A小分子抑制剂或与0.3μg/mL阳性对照IL17A抗体(R&D,#AF-317-NA)的混合物在37℃温育1小时后加入到上述96孔板中，与HT-29细胞在37℃共温育48小时，然后用GROα的ELISA试剂盒(Cisbio,#62HCXC1PEG)检测细胞培养上清中的GROα的水平。
按照上述试验例1和2的方法对实施例制备的化合物进行抑制人IL17A蛋白诱导HT-29细胞产生趋化因子GROα/CXCL1实验。结果见表3，各化合物的抑制HT-29细胞GROα/CXCL1的IC50抑制活性。其中测定各化合物的IC50按照说明分类如下。
“+”表示IC50测定值小于等于1μM大于500nM；
“++”表示IC50测定值小于等于500nM大于100nM；
“+++”表示IC50测定值小于等于100nM。
表3、化合物抑制HT-29细胞GROα/CXCL1的抑制IC50



试验表明，本发明实施例的化合物具有良好的人IL-17A抑制活性，可以有效用于与hIL-17A活性异常疾病的治疗。

Claims (13)

  1. 式I所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐：
    其中，
    表示单键或双键；
    X1选自C或N；
    X2、X3分别独立选自O、N、NRX或CRX；
    X4、X5分别独立选自C或N；
    每个RX分别独立选自氢、氘、卤素、氰基、-C1～6烷基、-OC1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-O(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-O(4～10元杂环烷基)、氘取代的-C1～6烷基、卤素取代的-C1～6烷基；
    Y1、Y2、Y3分别独立选自N或CRY；
    每个RY分别独立选自氢、氘、卤素、氰基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-OC1～6烷基、-C0～2亚烷基-O(卤素取代的C1～6烷基)、-C0～2亚烷基-O(3～10元环烷基)、-C0～2亚烷基-O(4～10元杂环烷基)；
    Z选自C(O)、S(O)或S(O)2；
    R1选自-C1～6烷基、氘取代的C1～6烷基、卤素取代的C1～6烷基、-C2～6烯基、卤素取代的C2～6烯基、-C2～6炔基、卤素取代的C2～6炔基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)、-C0～2亚烷基-OR11、-C0～2亚烷基-NR11R12；其中亚烷基、烷基、烯基、炔基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R1a取代；
    R11、R12分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、 -C0～2亚烷基-(5～10元芳杂环)；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R1a取代；
    每个R1a分别独立选自氢、氘、卤素、氰基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基、-C0～4亚烷基-OR1b、-C0～4亚烷基-SR1b、-C0～2亚烷基-C(O)R1b、-C0～2亚烷基-C(O)NR1bR1c、-C0～4亚烷基-NR1bR1c、-C0～2亚烷基-NR1bC(O)R1c、-C0～4亚烷基-S(O)2R1b、-C0～4亚烷基-NHS(O)2R1b、-C0～4亚烷基-S(O)R1b、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(5～10元芳环)、-C0～4亚烷基-(5～10元芳杂环)；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R1d取代；
    R1b、R1c、R1d分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、卤素、氰基、＝O、＝S、硝基、-OH、-SH、-S(C1～6烷基)、-C0～2亚烷基-O(C1～6烷基)、-C(O)NH2、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6烷基)、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；
    或者，两个连接在同一个碳原子上的R1a，与其相连的碳原子共同形成3～10元环烷基、4～10元杂环烷基；其中环烷基、杂环烷基任选被一个、两个或三个独立的R1e取代；
    R1e分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、卤素、氰基、＝O、＝S、硝基、-OH、-SH、-S(C1～6烷基)、-C0～2亚烷基-O(C1～6烷基)、-C(O)NH2、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6烷基)、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(6～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；
    R2选自-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～12元桥环烷基)、-C0～2亚烷基-(5～12元桥杂环烷基)、-C0～2亚烷基-(5～12元螺环烷基)、-C0～2亚烷基-(5～12元螺杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)、-C0～2亚烷基-OR21、-C0～2亚烷基-NR21R22、-C0～2亚烷基-CN；其中亚烷基、环烷基、杂环烷基、桥环烷基、桥杂环烷基、螺环烷基、螺杂环烷基、芳环、芳杂环任选被一个、两个、三个或四个独立的R2a取代；
    R21、R22分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R2a取代；
    每个R2a分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基、-C0～2亚烷基-OR2b、-C0～2亚烷基-C(O)R2b、-C0～2亚烷基 -C(O)NR2bR2c、-C0～2亚烷基-NR2bR2c、-C0～2亚烷基-NR2bC(O)R2c、-C0～4亚烷基-S(O)2R2b、-C0～4亚烷基-CN、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～12元桥环烷基)、-C0～2亚烷基-(5～12元桥杂环烷基)、-C0～2亚烷基-(5～12元螺环烷基)、-C0～2亚烷基-(5～12元螺杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；其中烷基、亚烷基、环烷基、杂环烷基、桥环烷基、桥杂环烷基、螺环烷基、螺杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R2d取代；
    或者，
    两个连接在同一个碳原子上的R2a，与其相连的碳原子共同形成3～10元环烷基、4～10元杂环烷基；
    R2b、R2c分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R2d取代；
    每个R2d分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、卤素、氰基、＝O、＝S、硝基、-OH、-O(C1～6烷基)、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6烷基)；
    R3选自氢、氘、卤素、氰基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)、-C0～2亚烷基-OR31、-C0～2亚烷基-NR31R32；其中亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的R3a取代；
    R31、R32分别独立选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(4～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)；
    每个R3a分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基；
    L选自C2～6的亚烷基、C2～6的亚烯基；其中，
    1)亚烷基、亚烯基中的一个、两个或三个亚甲基可以任选被O、NRL1、C(O)、S(O)或S(O)2替换；和/或
    2)亚烷基、亚烯基任选被一个、两个、三个或四个独立的RL取代；
    每个RL1选自氢、氘、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的C1～6烷基、-C0～2亚烷 基-OC1～6烷基、-C0～2亚烷基-CN、-C0～2亚烷基-C(O)(C1～6烷基)、-C0～2亚烷基-O(3～10元环烷基)、-C0～2亚烷基-O(4～10元杂环烷基)、-C0～2亚烷基-(3～10元环烷基)、-C0～2亚烷基-(3～10元杂环烷基)、-C0～2亚烷基-(5～10元芳环)、-C0～2亚烷基-(5～10元芳杂环)、-C0～4亚烷基-N(C1～6烷基)(C1～6烷基)；其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环任选被一个、两个或三个独立的RL2取代；
    每个RL2分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基；
    每个RL分别独立选自氢、氘、卤素、氰基、＝O、＝S、硝基、-C1～6烷基、氘取代的-C1～6烷基、卤素取代的-C1～6烷基、-C0～2亚烷基-OC1～6烷基、-C0～2亚烷基-O(3～10元环烷基)、-C0～2亚烷基-O(4～10元杂环烷基)；
    或者，
    两个连接在同一个碳原子上的RL，与其相连的碳原子共同形成3～10元环烷基、4～10元杂环烷基。
  2. 根据权利要求1所述的化合物，其特征在于：
    X1为C，X2为NRX，X3为N，X4为C，X5为C；
    或者，X1为C，X2为N，X3为N，X4为C，X5为N；
    或者，X1为C，X2为N，X3为CRX，X4为N，X5为C；
    或者，X1为N，X2为N，X3为CRX，X4为C，X5为C；
    或者，X1为C，X2为O，X3为N，X4为C，X5为C。
  3. 根据权利要求1～2任一项所述的化合物，其特征在于：式I所示的化合物如下式所示：

    其中，R1、R2、R3、Y1、Y2、Y3、Z、L定义如权利要求1所述。
  4. 根据权利要求1～3任一项所述的化合物，其特征在于：
    Y1、Y2、Y3分别独立选自N或CRY；
    每个RY分别独立选自氢、氘、氟、氯、溴、氰基、甲基、乙基、正丙基、异丙基、环丙基、三氟甲基、甲氧基、乙氧基、三氟甲氧基；
    Z选自C(O)或S(O)2。
  5. 根据权利要求1～4任一所述的化合物，其特征在于：
    R3选自甲基、氘代甲基、乙基、全氘代乙基、正丙基、异丙基、三氟甲基、环丙基、环丁基、羟甲基、甲氧甲基、氘代甲氧甲基、氨基、甲胺基、二甲胺基、氘代甲胺基。
  6. 根据权利要求1～5任一项所述的化合物，其特征在于：所述R1选自



  7. 根据权利要求1～6任一项所述的化合物，其特征在于：所述R2选自

  8. 根据权利要求1～7任一项所述的化合物，其特征在于：L选自

    其中，aa端与X4相连。
  9. 根据权利要求1～8任一项所述的化合物，其特征在于：所述的化合物具体为：






















  10. 权利要求1-9任一项所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐在制备治疗IL-17A介导的疾病的药物中的用途。
  11. 权利要求10所述的用途，其特征在于：所述IL-17A介导的疾病是与炎症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。
  12. 一种药物组合物，其特征在于：它是以权利要求1～9任一项所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐，加上药学上可接受的辅料制备而成的制剂。
  13. 权利要求1-9任一项所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其用于治疗银屑病、类风湿性关节炎、脊柱关节炎、多发性硬化、银屑病关节炎、中轴型脊柱关节炎、强直性脊椎炎、化脓性汗腺炎、系统性红斑狼疮、掌跖脓疱病(PPP)、特应性皮炎、哮喘和/或COPD的疾病或病症。
PCT/CN2024/125698 2023-10-19 2024-10-18 一种免疫调节剂 Pending WO2025082467A1 (zh)

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