WO2021027724A1 - 一种免疫调节剂 - Google Patents

一种免疫调节剂 Download PDF

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WO2021027724A1
WO2021027724A1 PCT/CN2020/107802 CN2020107802W WO2021027724A1 WO 2021027724 A1 WO2021027724 A1 WO 2021027724A1 CN 2020107802 W CN2020107802 W CN 2020107802W WO 2021027724 A1 WO2021027724 A1 WO 2021027724A1
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alkylene
alkyl
membered
halogen
group
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French (fr)
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李进
张登友
白晓光
尚巳耘
洪新福
钟猛
周贤思
龚义
杨丹梅
黄昊岚
林燕萍
陈欣
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成都先导药物开发股份有限公司
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    • 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
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
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    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to an immunomodulator and its use in preparing medicines.
  • IL-17 Interleukin-17
  • CTLA-8 IL-17A
  • IL-17B IL-17C
  • IL-17D IL-17D
  • IL-17E IL-25
  • IL-17F IL-17A
  • IL-17A is expressed by TH17 cells and is involved in the pathogenesis of inflammation and autoimmune diseases.
  • Human IL-17A is a glycoprotein with a molecular weight of approximately 17,000 Daltons.
  • IL-17A transmits signals to the cell via the IL-17 receptor complex (IL-17RA and IL-17RC) (Wright, et al.
  • IL-17A plays an important role in severe asthma and chronic obstructive pulmonary disease (COPD). Those patients usually do not respond or respond poorly to currently available drugs (Al-Ramli et al. J Allergy Clin Immunol, 2009, 123:1185-1187).
  • IL-17A levels involves many diseases, including rheumatoid arthritis (RA), bone erosion, intraperitoneal abscess, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma, and multiple Sclerosis (Gaffen, SL et al. Arthritis Research & Therapy, 2004, 6: 240-247).
  • RA rheumatoid arthritis
  • bone erosion rheumatoid arthritis
  • intraperitoneal abscess inflammatory bowel disease
  • allograft rejection psoriasis
  • atherosclerosis asthma
  • multiple Sclerosis multiple Sclerosis
  • IL-17A IL-17A-mediated autoimmune inflammatory diseases.
  • the IL-17A neutralizing antibody can treat autoimmune encephalomyelitis and reduce the incidence and severity of the disease ( Komiyama Y et al. J. Immunol., 2006, 177: 566-573).
  • the clinical trials of IL-17A antibody have shown good results on IL-7A-mediated inflammatory diseases (including asthma, psoriasis, rheumatoid arthritis, ankylosing spondylitis and multiple sclerosis).
  • the IL-17A antibody (Cosentyx/secukinumab from Novartis) was approved by the FDA for the treatment of psoriasis in January 2015.
  • IL-17A antibodies Although there are a variety of IL-17A antibodies, few studies have been conducted on small-molecule specific inhibitors of IL-17 with oral bioavailability. In view of the cost considerations of producing antibodies and the limitation of the route of administration, the development of IL-17A small molecule inhibitor drugs has a good research and development prospect.
  • the purpose of the present invention is to provide an immunomodulator.
  • the present invention provides a compound represented by formula I, or its stereoisomer, or its salt, or its solvate, or its prodrug, or its metabolite:
  • R 1 is selected from hydrogen, -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkane Group), -C 0 ⁇ 4 alkylene-(5-10 membered aromatic ring), -C 0 ⁇ 4 alkylene-(5-10 membered aromatic heterocyclic ring), -NR 11 R 12 , -OR 11 ; Or, wherein the alkyl group, alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and aromatic heterocyclic ring are further substituted by one, two or three independent R 13 ;
  • R 11 and R 12 are each independently selected from hydrogen, -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3 ⁇ 10-membered heterocycloalkyl), -C 0-4 alkylene-(5-10 membered aromatic ring), -C 0-4 alkylene-(5-10 membered aromatic heterocyclic ring); or, where cycloalkane Group, alkylene, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring are further substituted by one, two or three independent R 13 ;
  • Each R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl), -NH 2 , -NH (C 1-10 alkyl), -N (C 1-10 alkyl) (C 1-10 alkyl);
  • R 2 is selected from hydrogen, -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkane base);
  • Ring A is selected from 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl; or, wherein cycloalkyl and heterocycloalkyl are further substituted by one, two or three independent R A1 ;
  • Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene -OR A2 , -C 0 ⁇ 4 alkylene-OC(O)R A2 , -C 0 ⁇ 4 alkylene-C(O)R A2 , -C 0 ⁇ 4 alkylene-C(O)OR A2 , -C 0 ⁇ 4 alkylene-C(O)NR A2 R A3 , -C 0 ⁇ 4 alkylene-NR A2 R A3 , -C 0 ⁇ 4 alkylene-NR A2 C(O)R A3 , -C 0 ⁇ 4 -alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkyl), -C 0-4 alkylene-(5-10 member
  • R A2 and R A3 are each independently selected from hydrogen, -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3 ⁇ 10-membered heterocycloalkyl);
  • Y 1 , Y 2 , and Y 3 are each independently selected from N or CR Y1 ;
  • Each R Y1 is independently selected from hydrogen, halogen, cyano, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl), -NH 2 , -NH (C 1-10 alkyl), -N (C 1-10 alkyl) (C 1-10 alkyl);
  • R 5 and R 6 are each independently selected from hydrogen, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl),- C 0 ⁇ 4 alkylene-(3 ⁇ 10 membered heterocycloalkyl), -(C 0 ⁇ 4 alkylene)O(C 1 ⁇ 10 alkyl), -(C 0 ⁇ 4 alkylene)O (C 0 ⁇ 4 alkylene) (3 ⁇ 10 membered cycloalkyl), -(C 0 ⁇ 4 alkylene) O(C 0 ⁇ 4 alkylene) (3 ⁇ 10 membered heterocycloalkyl);
  • R 5 and R 6 are connected to form a 3-10 membered cycloalkyl group or a 3-10 membered heterocycloalkyl group; or, wherein the alkyl group, alkylene group, cycloalkyl group, and heterocycloalkyl group are further
  • Each R 51 is independently selected from halogen, -C 1-10 alkyl, and halogen-substituted -C 1-10 alkyl;
  • R 7 is selected from hydrogen, -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl), -C 0-4 alkylene-(3-10 membered heterocycloalkane base);
  • R 8 and R 9 are each independently selected from hydrogen, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl),- C 0 ⁇ 4 alkylene-(3 ⁇ 10 membered heterocycloalkyl), -C 0 ⁇ 4 alkylene-(5 ⁇ 12 membered spiro ring), -C 0 ⁇ 4 alkylene-(5 ⁇ 12 Membered spiro heterocyclic ring), -C 0 ⁇ 4 alkylene-(5-12 membered bridged ring), -C 0 ⁇ 4 alkylene-(5-12 membered bridged heterocyclic ring), -(C 0 ⁇ 4 Alkyl) O (C 1 ⁇ 10 alkyl), -(C 0 ⁇ 4 alkylene) O(C 0 ⁇ 4 alkylene) (3 ⁇ 10 member cycloalkyl), -(C 0 ⁇ 4 alkylene)
  • Each R 81 is independently selected from halogen, -C 1-10 alkyl, and halogen-substituted -C 1-10 alkyl;
  • R 10 and R 11 are each independently selected from hydrogen, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene-(3-10 membered cycloalkyl),- C 0-4 alkylene-(3-10 membered heterocycloalkyl); or R 10 and R 11 are connected to form 3-10 membered heterocycloalkyl; or, where alkyl, alkylene, cycloalkyl, The heterocycloalkyl group is further substituted with one, two or three R 101 ;
  • Each R 101 is independently selected from halogen, -C 1-10 alkyl, and halogen-substituted -C 1-10 alkyl.
  • R 1 is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3-6 membered heterocycloalkane) Group), -C 0 ⁇ 2 alkylene-(5-6 membered aromatic ring), -C 0 ⁇ 2 alkylene-(5-6 membered aromatic heterocyclic ring), -NR 11 R 12 , -OR 11 ; Or, wherein the alkyl group, alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and aromatic heterocyclic ring are further substituted by one, two or three independent R 13 ;
  • R 11 and R 12 are each independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3 ⁇ 6-membered heterocycloalkyl), -C 0-2 alkylene-(5-6 membered aromatic ring), -C 0-2 alkylene-(5-6 membered aromatic heterocyclic ring); or, where cycloalkane Group, alkylene, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring are further substituted by one, two or three independent R 13 ;
  • Each R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl);
  • R 2 is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3-6 membered heterocycloalkane base);
  • Ring A is selected from 5 to 10 membered cycloalkyl and 5 to 9 membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl may be further substituted by one, two or three independent R A1 ;
  • Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene -OR A2 , -C 0 ⁇ 2 alkylene-OC(O)R A2 , -C 0 ⁇ 2 alkylene-C(O)R A2 , -C 0 ⁇ 2 alkylene-C(O)OR A2 , -C 0 ⁇ 2 alkylene-C(O)NR A2 R A3 , -C 0 ⁇ 2 alkylene-NR A2 R A3 , -C 0 ⁇ 2 alkylene-NR A2 C(O)R A3 , -C 0 ⁇ 2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3-6 membered heterocycloalkyl), -C 0-2 alkylene-(5-6 membered aromatic Ring
  • R A2 and R A3 are each independently selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3 ⁇ 6-membered heterocycloalkyl);
  • Y 1 , Y 2 , and Y 3 are each independently selected from N or CR Y1 ;
  • Each R Y1 is independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl);
  • R 5 and R 6 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl), -(C 0 ⁇ 2 alkylene)O(C 1-6 alkyl), -(C 0 ⁇ 2 alkylene)O (C 0-2 alkylene) (3-6 membered cycloalkyl), -(C 0-2 alkylene) O(C 0-2 alkylene) (3-6 membered heterocycloalkyl);
  • R 5 and R 6 are connected to form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group; or, wherein the alkyl group, alkylene group, cycloalkyl group and heterocycloalkyl group are further divided by one or two Or three independent
  • Each R 51 is independently selected from halogen, -C 1-6 alkyl, and halogen-substituted -C 1-6 alkyl;
  • R 7 is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3-6 membered heterocycloalkane base);
  • R 8 and R 9 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl), -C 0 ⁇ 2 alkylene-(6 ⁇ 11 membered spiro ring), -C 0 ⁇ 2 alkylene-(6 ⁇ 11 Membered spiro heterocycle), -C 0 ⁇ 2 alkylene-(5 ⁇ 10 membered bridged ring), -C 0 ⁇ 2 alkylene-(5 ⁇ 10 membered bridged heterocycle), -(C 0 ⁇ 2 Alkyl) O (C 1 ⁇ 6 alkyl), -(C 0 ⁇ 2 alkylene) O(C 0 ⁇ 2 alkylene) (3-6 membered cycloalkyl), -(C 0 ⁇ 2 alkylene) Alkyl)
  • Each R 81 is independently selected from halogen, -C 1-6 alkyl, and halogen-substituted -C 1-6 alkyl;
  • R 10 and R 11 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0-2 alkylene-(3-6 membered heterocycloalkyl); or R 10 and R 11 are connected to form 3-6 membered heterocycloalkyl; or, where alkyl, alkylene, cycloalkyl, The heterocycloalkyl group is further substituted with one, two or three R 101 ;
  • Each R 101 is independently selected from halogen, -C 1-6 alkyl, and halogen-substituted -C 1-6 alkyl.
  • R 1 is selected from -C 1-6 alkyl, -OR 11 , 5-6 membered aromatic ring, 5-6 membered aromatic heterocyclic ring; or, wherein the aromatic ring and aromatic heterocyclic ring are further separated by one, two or three independent ⁇ R 13 substitution;
  • R 11 is selected from hydrogen, -C 1-6 alkyl
  • Each R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl).
  • R 1 is selected from -OCH 3 , -CH 3 ;
  • R 13 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, and halogen-substituted -C 1-6 alkyl.
  • Ring A is selected from 5 to 10 membered cycloalkyl and 5 to 9 membered heterocycloalkyl; or, wherein the cycloalkyl and heterocycloalkyl are further substituted by one, two or three independent R A1 ;
  • Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-OR A2 ;
  • R A2 is selected from hydrogen, -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl), -C 0-2 alkylene-(3-6 membered heterocycloalkane base).
  • a ring is
  • R A1 may be none; or R A1 is selected from halogen, cyano, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl.
  • R 5 and R 6 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl), -(C 0 ⁇ 2 alkylene)O(C 1-6 alkyl), -(C 0 ⁇ 2 alkylene)O (C 0-2 alkylene) (3-6 membered cycloalkyl), -(C 0-2 alkylene) O(C 0-2 alkylene) (3-6 membered heterocycloalkyl);
  • R 5 and R 6 are connected to form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group; or, wherein the alkyl group, alkylene group, cycloalkyl group and heterocycloalkyl group are further divided by one or two Or three independent
  • Each R 51 is independently selected from halogen, -C 1-6 alkyl, and halogen-substituted -C 1-6 alkyl.
  • R 5 and R 6 are independently selected from hydrogen, -CH 3 , -CH 2 OCH 3 ; or R 5 and R 6 are connected to form
  • R 8 and R 9 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene-(3-6 membered cycloalkyl),- C 0 ⁇ 2 alkylene-(3 ⁇ 6 membered heterocycloalkyl), -C 0 ⁇ 2 alkylene-(6 ⁇ 11 membered spiro ring), -C 0 ⁇ 2 alkylene-(6 ⁇ 11 Membered spiro heterocyclic ring), -C 0-2 alkylene-(5-10 membered bridged ring), -C 0-2 alkylene-(5-10 membered bridged heterocyclic ring); or, where alkyl, alkylene Alkyl, cycloalkyl, heterocycloalkyl, spiro ring, spiro heterocyclic ring, bridged ring, bridged heterocyclic ring are further substituted with one, two or three R 81
  • Each R 81 is independently selected from halogen, -C 1-6 alkyl, and halogen-substituted -C 1-6 alkyl.
  • R 8 and R 9 are each independently selected from hydrogen, -C 1-6 alkyl
  • R 81 is none, or is selected from halogen, -C 1-6 alkyl, and halogen-substituted -C 1-6 alkyl.
  • the present invention also provides the use of the aforementioned compound, or its stereoisomer, or its salt, or its solvate, or its prodrug, or its metabolite in the preparation of IL-17A inhibitors.
  • the present invention also provides the use of the aforementioned compound, or its stereoisomer, or its salt, or its solvate, or its prodrug, or its metabolite in the preparation of drugs for the treatment of IL-17A-mediated diseases use.
  • the IL-17A-mediated disease is one or more of diseases related to inflammation, autoimmune disease, infectious disease, cancer, and precancerous syndrome.
  • the present invention also provides a drug, which uses the aforementioned compound, or its stereoisomer, or its salt, or its solvate, or its prodrug, or its metabolite as the active ingredient, plus the pharmaceutical Preparations prepared from acceptable excipients.
  • the IL-17A-mediated disease defined in the present invention is a disease in which IL-17A plays an important role in the pathogenesis of the disease.
  • the main function of IL-17A is to coordinate local tissue inflammation, thereby playing a role in various diseases.
  • IL-17A-mediated diseases include one or more of inflammation, autoimmune diseases, infectious diseases, cancer, and diseases related to precancerous syndrome.
  • Cancer or “malignant tumor” refers to any of a variety of diseases characterized by uncontrolled abnormal cell proliferation, and the ability of affected cells to spread to other locations locally or through the bloodstream and lymphatic system The body (i.e. metastasis) and any of many characteristic structural and/or molecular characteristics.
  • Cancer cells refer to cells that undergo multiple stages of tumor progression in the early, middle or late stages. Cancers include sarcoma, 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.
  • the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer.
  • the cancer being treated is a metastatic cancer.
  • autoimmune diseases are caused by the body's immune response to substances and tissues that normally exist 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 type Arthritis, rheumatoid arthritis, fibromyalgia, Guillambali syndrome, multiple sclerosis and autoimmune retinopathy.
  • Some embodiments of the invention relate to the treatment of 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 and interstitial cystitis caused by house dust mites.
  • 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 and interstitial cystitis caused by house dust mites.
  • inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheuma
  • the compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.
  • substitution refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.
  • the minimum and maximum content of carbon atoms in a hydrocarbon group are indicated by prefixes.
  • the prefix Ca to b alkyl indicates any alkyl group containing "a" to "b” carbon atoms.
  • C 1-4 alkyl refers to an alkyl group containing 1 to 4 carbon atoms.
  • Alkyl refers to a saturated hydrocarbon chain having the specified number of member atoms.
  • a C 1-6 alkyl group refers to an alkyl group having 1 to 6 member atoms, for example, 1 to 4 member atoms.
  • Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein.
  • C 1-6 alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isoamyl) And neopentyl) and hexyl.
  • the alkyl group may also be part of another group, such as a C 1-6 alkoxy group.
  • Cycloalkyl refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, and spiro ring systems).
  • cycloalkyl e.g. 5,6,7,8,-tetra Hydronaphthalene-5-yl.
  • cycloalkyl includes cycloalkenyl groups such as cyclohexenyl.
  • cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
  • cycloalkyl groups including multiple bicycloalkyl ring systems are dicyclohexyl, dicyclopentyl, bicyclooctyl and the like. The following examples and names two such bicyclic alkyl polycyclic structures: Dicyclohexyl and Bicyclohexyl.
  • the straight or branched chain hydrocarbon group for example, ( Ca ⁇ b )alkenyl refers to an alkenyl group having a to b carbon atoms and is intended 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 chain monovalent hydrocarbon group containing at least one triple bond.
  • alkynyl is also meant to include those hydrocarbyl groups that have one triple bond and one double bond.
  • (C 2-6 )alkynyl is meant to include ethynyl, propynyl and the like.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Halogenalkyl means that the hydrogen atom in the alkyl group can be replaced by one or more halogen atoms.
  • halo C 1-4 alkyl group whose hydrogen atom is substituted with one or more halogen atoms, an alkyl group having 1 to 4 carbon atoms.
  • Heterocycle and “heterocycloalkyl” refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;
  • Aromatic heterocyclic ring refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, and a sulfur atom;
  • Steps include enantiomers and diastereomers.
  • pharmaceutically acceptable refers to a certain carrier, carrier, diluent, excipient, and/or the salt formed is usually chemically or physically compatible with other ingredients constituting a pharmaceutical dosage form, and physiologically Compatible with the receptor.
  • salts and “pharmaceutically acceptable salts” refer to the above-mentioned compounds or their stereoisomers, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (internal Salt), also including quaternary ammonium salts, such as alkyl ammonium salts. These salts can be directly obtained in the final isolation 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 (for example, equivalent).
  • salts may form a precipitate in the solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by freeze-drying after reaction in an aqueous medium.
  • the salt in the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butane Acid salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • one or more compounds of the present invention may be used in combination with each other.
  • the compound of the present invention can be used in combination with any other active agent to prepare drugs or pharmaceutical compositions for regulating cell function or treating diseases. If a group of compounds are used, these compounds can be administered to the subject simultaneously, separately or sequentially.
  • the compound of the present invention exhibits good IL-17A inhibitory activity and can be used to prepare IL-17A inhibitors for the treatment of diseases related to abnormal IL-17A activity, and provides a way for clinical treatment of diseases related to abnormal IL-17A activity New medicinal possibilities.
  • the structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
  • NMR is measured with (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetometer, and the solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD3OD), internal standard It is tetramethylsilane (TMS).
  • the LC-MS measurement uses Shimadzu LC-MS 2020 (ESI). Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A) was used for HPLC measurement. MPLC (Medium Pressure Preparative Chromatography) uses Gilson GX-281 reverse phase preparative chromatograph.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications 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.
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.
  • Cs 2 CO 3 (290.82g, 894.85mmol) was added to the dry DMF (700mL) solution of ethyl p-nitrophenylacetate (156g, 745.71mmol), warmed to room temperature and stirred for 1 hour Then it was reduced to 0°C and methyl iodide (116.43g, 820.28mmol) was slowly added dropwise. After dripping, the reaction was carried out overnight, and then filtered with suction.
  • trans-(2S)-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid (compound 1-1) and compound 2-1 (refer to published patents) CN110511213A) as the raw material, after condensation, closing the imidazole ring, de-Boc, condensation introduction of 1-methyl-1H-pyrazole-5-acyl, ester hydrolysis, and finally with (R)-2-amino-2-cyclobutyl -Acetylethylamine condensation can give compound 2, MS m/z: 576[M+1] + .
  • trans-(2S)-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid 1-1 and 3-(3,4-diaminophenyl)oxy Ethylene-3-carboxylic acid ethyl ester 3-1 is used as the raw material, and the 1-methyl-1H-pyrazole-5-acyl group is introduced through condensation, imidazole ring removal, de-Boc, condensation, ester hydrolysis, and finally with (R )-2-amino-2-cyclobutyl-acetylethylamine condensation can give compound 3, MS m/z: 590[M+1] + .
  • trans-(2S)-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid 1-1 and compound 4-1 were used as raw materials.
  • the imidazole ring Boc removal, introduction of 1-methyl-1H-pyrazole-5-acyl group by condensation, ester hydrolysis, and finally condensation with (R)-2-amino-2-cyclobutyl-acetylethylamine to obtain compound 4, MS m/z:604[M+1] + .
  • the intermediate 5-1c was deacetylated to obtain the intermediate 5-1d with a yield of 96%. MS m/z: 295[M+1] + .
  • trans-(2S)-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid 1-1 and compound 5-1 were used as raw materials.
  • the imidazole ring De-Boc, introduction of 1-methyl-1H-pyrazole-5-acyl group by condensation, ester hydrolysis, and finally condensation with (R)-2-amino-2-cyclobutyl-acetylethylamine to obtain compound 5, MS m/z:618[M+1] + .
  • trans-(2S)-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid 1-1 and compound 7-1 were used as raw materials.
  • the imidazole ring De-Boc, introduction of 1-methyl-1H-pyrazole-5-acyl group by condensation, ester hydrolysis, and finally condensation with (R)-2-amino-2-cyclobutyl-acetylethylamine to obtain compound 7, MS m/z:618[M+1] + .
  • trans-(2S)-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid 1-1 and compound 8-1 prepared with reference to published patent CN110511213A
  • the 1-methyl-1H-pyrazole-5-acyl group is introduced through condensation, off the imidazole ring, de-Boc, and condensation, and the ester is hydrolyzed.
  • Amine condensation can give compound 8, MS m/z: 562[M+1] + .
  • Example 1 using trans-(2S)-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid 1-1 and compound 9-1 as raw materials, the imidazole ring was condensed , De-Boc, introduction of 1-methyl-1H-pyrazole-5-acyl group by condensation, ester hydrolysis, and finally condensation with (R)-2-amino-2-cyclobutyl-acetylethylamine to obtain compound 9, MS m/z:548[M+1] + .
  • Example 1 Refer to the method of Example 1, taking (2S)-(tert-butoxycarbonylamino)-2-cyclooctyl-acetic acid 10-0 and compound 1-2 as raw materials, and introducing 1 through condensation, closing the imidazole ring, de-Boc, and condensation. -Methyl-1H-pyrazole-5-acyl, ester is hydrolyzed, and finally condensed with (R)-2-amino-2-cyclobutyl-acetylethylamine to obtain compound 10, MS m/z: 620[M +1] + .
  • Example 1 Refer to the method of Example 1, taking (2S)-(tert-butoxycarbonylamino)-2-cyclooctyl-acetic acid 10-0 and compound 2-1 as raw materials, and introducing 1 through condensation, imidazole ring, de-Boc, and condensation. -Methyl-1H-pyrazole-5-acyl, ester is hydrolyzed, and finally condensed with (R)-2-amino-2-cyclobutyl-acetylethylamine to obtain compound 11, MS m/z: 590[M +1] + .
  • Example 2 Refer to the method of Example 1, taking (2S)-(tert-butoxycarbonylamino)-2-cyclooctyl-acetic acid 10-0 and compound 3-1 as raw materials, and introducing 1 through condensation, closing the imidazole ring, de-Boc, and condensation. -Methyl-1H-pyrazole-5-acyl, ester is hydrolyzed, and finally condensed with (R)-2-amino-2-cyclobutyl-acetylethylamine to obtain compound 12, MS m/z: 604[M +1] + .
  • Example 1 Refer to the method of Example 1, taking (2S)-(tert-butoxycarbonylamino)-2-cyclooctyl-acetic acid 10-0 and compound 4-1 as raw materials, and introducing 1 through condensation, imidazole ring, de-Boc, and condensation. -Methyl-1H-pyrazole-5-acyl, ester is hydrolyzed, and finally condensed with (R)-2-amino-2-cyclobutyl-acetylethylamine to obtain compound 13, MS m/z:618[M +1] + .
  • Example 1 Refer to the method of Example 1, taking (2S)-(tert-butoxycarbonylamino)-2-cyclooctyl-acetic acid 10-0 and compound 5-1 as raw materials, and introducing 1 through condensation, closing the imidazole ring, de-Boc, and condensation. -Methyl-1H-pyrazole-5-acyl, ester hydrolysis, and finally (R)-2-amino-2-cyclobutyl-acetylethylamine condensation to obtain compound 14, MS m/z:632[M +1] + .
  • Example 1 Refer to the method of Example 1, taking (2S)-(tert-butoxycarbonylamino)-2-cyclooctyl-acetic acid 10-0 and compound 8-1 as raw materials, and introducing 1 through condensation, off imidazole ring, de-Boc, and condensation. -Methyl-1H-pyrazole-5-acyl, ester is hydrolyzed, and finally condensed with (R)-2-amino-2-cyclobutyl-acetylethylamine to obtain compound 15, MS m/z: 576[M +1] + .
  • Example 1 Refer to the method of Example 1, taking (2S)-(tert-butoxycarbonylamino)-2-cyclooctyl-acetic acid 10-0 and compound 9-1 as raw materials, and introducing 1 through condensation, off-imidazole ring, de-Boc, and condensation. -Methyl-1H-pyrazole-5-acyl, ester is hydrolyzed, and finally condensed with (R)-2-amino-2-cyclobutyl-acetylethylamine to obtain compound 16, MS m/z:562[M +1] + .
  • Example 1 With reference to the method of Example 1, the intermediates 1-3 of Example 1 were used as raw materials, followed by ester hydrolysis, condensation of (R)-2-amino-2-cyclobutyl-acetylethylamine, de-Boc, and finally with chlorine The reaction of methyl formate gave compound 17, MS m/z: 556.0 [M+1] + .
  • Example 1 Take 2-(1-adamantyl)-2-(tert-butoxycarbonylamino)acetic acid 18-1 and compound 1-2 as raw materials, and introduce through condensation, imidazole ring, de-Boc, and condensation 1-Methyl-1H-pyrazole-5-acyl, ester is hydrolyzed, and finally condensed with (R)-2-amino-2-cyclobutyl-acetylethylamine to obtain compound 18, MS m/z: 644.0[ M+1] + .
  • Example 18 With reference to the method of Example 1, the intermediate 18-2 in Example 18 was used as a raw material. After ester hydrolysis, (R)-2-amino-2-cyclobutyl-acetylethylamine was condensed, Boc was removed, and finally, it was combined with chloroformic acid. The methyl ester was reacted to obtain compound 19, MS m/z: 594.0 [M+1] + .
  • Example 2 Take 2-(1-adamantyl)-2-(tert-butoxycarbonylamino)acetic acid 18-1 and compound 4-1 as raw materials, and introduce through condensation, imidazole ring, de-Boc, and condensation Hydrolysis of 1-methyl-1H-pyrazole-5-acyl and ester, and finally condensation with (R)-2-amino-2-(1-methylcyclobutyl)-acetylethylamine (Intermediate 20-6) Compound 21 can be obtained, MS m/z: 656.0 [M+1] + .
  • Example 2 using trans-(2S)-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acetic acid 1-1 and compound 23-1 as raw materials, and then condense the imidazole ring , Boc removal, introduction of 1-methyl-1H-pyrazole-5-acyl group by condensation, ester hydrolysis, and finally with (R)-2-amino-2-(1-methylcyclobutyl)-acetylethylamine (middle Compound 20-6) can be condensed to obtain compound 23, MS m/z: 636.0[M+1] + .
  • Example 22 With reference to the method of Example 1, the intermediate 22-2 in Example 22 was used as the raw material, and the acetyl group was introduced by de-Boc, condensation, ester hydrolysis, and finally with (R)-2-amino-2-(1-methyl ring). Butyl)-acetylethylamine (Intermediate 20-6) can be condensed to obtain compound 25, MS m/z: 580.0[M+1] + .
  • Example 22 With reference to the method of Example 1, the intermediate 22-2 in Example 22 was used as a raw material, and (R)-2-amino-2-(1-methylcyclobutyl)-acetylethylamine (middle Body 20-6), de-Boc, and finally react with methyl chloroformate to obtain compound 26, MS m/z: 596.0 [M+1] + .
  • Test Example 1 IL-17 enzyme-linked immunosorbent assay (ELISA) experiment
  • IL-17A inhibitors The inhibition of receptor-ligand binding by IL-17A inhibitors was quantitatively detected by competitive ELISA.
  • the IL-17A inhibitory activity of the compounds prepared in the examples were tested according to the above method, and the test results are shown in Table 1.
  • the IC 50 of each compound is classified according to the instructions, in Table 1:
  • Example IC 50 Example IC 50 Example IC 50 Example IC 50 Example IC 50 1 +++ 2 ++ 4 +++ 9 ++ 10 ++ 11 ++ 13 ++ 17 +++
  • test results show that the compound of the present invention has good IL-17A inhibitory activity and can be used to prepare IL-17A inhibitors for the treatment of diseases with abnormal IL-17A activity.
  • the compounds of the present invention exhibit good IL-17A inhibitory activity and can be used to prepare IL-17A inhibitors for the treatment of diseases related to abnormal IL-17A activity, and provide clinical treatment for diseases related to abnormal IL-17A activity A new medicinal possibility.

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Abstract

本发明提供了一种免疫调节剂，属于医药化学领域。该免疫调节剂是式I所示的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物。本发明化合物表现出良好的IL-17A抑制活性，可用于制备IL-17A抑制剂，用于与IL-17A活性异常疾病的治疗，为临床治疗与IL-17A活性异常相关的疾病提供了一种新的药用可能。

Description

一种免疫调节剂 技术领域
本发明属于医药化学领域，具体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进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，以及促进基质金属蛋白酶表达来允许活化的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)。
靶向IL-17A与IL-17RA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，治疗自身免疫性脑脊髓炎，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-7A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。
尽管存在多种IL-17A抗体，但很少有对具有口服生物利用度的IL-17的小分子特异性抑制剂进行研究。鉴于产生抗体的成本考虑和给药途径的限制，开发IL-17A小分子抑制剂药物具有良好的研发前景。
发明内容
本发明的目的是提供一种免疫调节剂。
本发明提供了式I所示的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物：
Figure PCTCN2020107802-appb-000001
其中，
R 1选自氢、-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)、-C 0～4亚烷基-(5～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)、-NR 11R 12、-OR 11；或者，其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个独立的R 13取代；
R 11、R 12分别独立选自氢、-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)、-C 0～4亚烷基-(5～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；或者，其中环烷基、亚烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个独立的R 13取代；
每个R 13独立选自卤素、氰基、羰基、硝基、-C 1～10烷基、卤素取代的-C 1～10烷基、-OH、-O(C 1～10烷基)、-NH 2、-NH(C 1～10烷基)、-N(C 1～10烷基)(C 1～10烷基)；
R 2选自氢、-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)；
A环选自5～10元环烷基、5～10元杂环烷基；或者，其中环烷基、杂环烷基进一步被一个、两个或三个独立的R A1取代；
每个R A1独立选自卤素、氰基、羰基、硝基、-C 1～10烷基、卤素取代的-C 1～10烷基、-C 0～4亚烷基-OR A2、-C 0～4亚烷基-OC(O)R A2、-C 0～4亚烷基-C(O)R A2、-C 0～4亚烷基-C(O)OR A2、-C 0～4亚烷基-C(O)NR A2R A3、-C 0～4亚烷基-NR A2R A3、-C 0～4亚烷基-NR A2C(O)R A3、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)、-C 0～4亚烷基-(5～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；
R A2、R A3分别独立选自氢、-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)；
Y 1、Y 2、Y 3分别独立选自N或CR Y1；
每个R Y1独立选自氢、卤素、氰基、硝基、-C 1～10烷基、卤素取代的-C 1～10烷基、-OH、-O(C 1～10烷基)、-NH 2、-NH(C 1～10烷基)、-N(C 1～10烷基)(C 1～10烷基)；
R 5、R 6分别独立选自氢、-C 1～10烷基、卤素取代的-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)、-(C 0～4亚烷基)O(C 1～10烷基)、-(C 0～4亚烷基)O(C 0～4亚烷基)(3～10元环烷基)、-(C 0～4亚烷基)O(C 0～4亚烷基)(3～10元杂环烷基)；或者，R 5、R 6相连形成3～10元环烷基、3～10元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基进一步被一个、两 个或三个独立的R 51取代；
每个R 51独立选自卤素、-C 1～10烷基、卤素取代的-C 1～10烷基；
R 7选自氢、-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)；
R 8、R 9分别独立选自氢、-C 1～10烷基、卤素取代的-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)、-C 0～4亚烷基-(5～12元螺环)、-C 0～4亚烷基-(5～12元螺杂环)、-C 0～4亚烷基-(5～12元桥环)、-C 0～4亚烷基-(5～12元桥杂环)、-(C 0～4亚烷基)O(C 1～10烷基)、-(C 0～4亚烷基)O(C 0～4亚烷基)(3～10元环烷基)、-(C 0～4亚烷基)O(C 0～4亚烷基)(3～10元杂环烷基)；或者，R 8、R 9相连形成3～10元环烷基、3～10元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基、螺环、螺杂环、桥环、桥杂环进一步被一个、两个或三个R 81取代；
每个R 81独立选自卤素、-C 1～10烷基、卤素取代的-C 1～10烷基；
R 10、R 11分别独立选自氢、-C 1～10烷基、卤素取代的-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)；或者R 10、R 11相连形成3～10元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基进一步被一个、两个或三个R 101取代；
每个R 101独立选自卤素、-C 1～10烷基、卤素取代的-C 1～10烷基。
进一步地，
R 1选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-C 0～2亚烷基-(5～6元芳环)、-C 0～2亚烷基-(5～6元芳杂环)、-NR 11R 12、-OR 11；或者，其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个独立的R 13取代；
R 11、R 12分别独立选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-C 0～2亚烷基-(5～6元芳环)、-C 0～2亚烷基-(5～6元芳杂环)；或者，其中环烷基、亚烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个独立的R 13取代；
每个R 13独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OH、-O(C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)；
R 2选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)；
A环选自5～10元环烷基、5～9元杂环烷基；其中环烷基、杂环烷基可进一步被一个、两个或三个独立的R A1取代；
每个R A1独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-OR A2、-C 0～2亚烷基-OC(O)R A2、-C 0～2亚烷基-C(O)R A2、-C 0～2亚烷基-C(O)OR A2、-C 0～2亚烷基-C(O)NR A2R A3、-C 0～2亚烷基-NR A2R A3、-C 0～2亚烷基-NR A2C(O)R A3、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-C 0～2亚烷基-(5～6元芳环)、-C 0～2亚烷基-(5～6元芳杂环)；
R A2、R A3分别独立选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2 亚烷基-(3～6元杂环烷基)；
Y 1、Y 2、Y 3分别独立选自N或CR Y1；
每个R Y1独立选自氢、卤素、氰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OH、-O(C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)；
R 5、R 6分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-(C 0～2亚烷基)O(C 1～6烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元环烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元杂环烷基)；或者，R 5、R 6相连形成3～6元环烷基、3～6元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基进一步被一个、两个或三个独立的R 51取代；
每个R 51独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基；
R 7选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)；
R 8、R 9分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-C 0～2亚烷基-(6～11元螺环)、-C 0～2亚烷基-(6～11元螺杂环)、-C 0～2亚烷基-(5～10元桥环)、-C 0～2亚烷基-(5～10元桥杂环)、-(C 0～2亚烷基)O(C 1～6烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元环烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元杂环烷基)；或者，R 8、R 9相连形成3～6元环烷基、3～6元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基、螺环、螺杂环、桥环、桥杂环进一步被一个、两个或三个R 81取代；
每个R 81独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基；
R 10、R 11分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)；或者R 10、R 11相连形成3～6元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基进一步被一个、两个或三个R 101取代；
每个R 101独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基。
进一步地，
R 1选自-C 1～6烷基、-OR 11、5～6元芳环、5～6元芳杂环；或者，其中芳环、芳杂环进一步被一个、两个或三个独立的R 13取代；
R 11选自氢、-C 1～6烷基；
每个R 13独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OH、-O(C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)。
进一步地，
R 1选自
Figure PCTCN2020107802-appb-000002
-OCH 3、-CH 3；
R 13独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基。
进一步地，
A环选自5～10元环烷基、5～9元杂环烷基；或者，其中环烷基、杂环烷基进一步被一个、两个或三个独立的R A1取代；
每个R A1独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-OR A2；
R A2选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)。
进一步地，
A环为
Figure PCTCN2020107802-appb-000003
R A1可为无；或者R A1选自卤素、氰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基。
进一步地，
R 5、R 6分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-(C 0～2亚烷基)O(C 1～6烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元环烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元杂环烷基)；或者，R 5、R 6相连形成3～6元环烷基、3～6元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基进一步被一个、两个或三个独立的R 51取代；
每个R 51独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基。
进一步地，
R 5、R 6分别独立选自氢、-CH 3、-CH 2OCH 3；或者R 5、R 6相连形成
Figure PCTCN2020107802-appb-000004
Figure PCTCN2020107802-appb-000005
进一步地，
R 8、R 9分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-C 0～2亚烷基-(6～11元螺环)、-C 0～2亚烷基-(6～11元螺杂环)、-C 0～2亚烷基-(5～10元桥环)、-C 0～2亚烷基-(5～10元桥杂环)；或者，其中烷基、亚烷基、环烷基、杂环烷基、螺环、螺杂环、桥环、桥杂环进一步被一个、两个或三个R 81取代；
每个R 81独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基。
进一步地，
R 8、R 9分别独立选自氢、-C 1～6烷基、
Figure PCTCN2020107802-appb-000006
R 81为无，或者选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基。
进一步地，式I所示的化合物具体为：
Figure PCTCN2020107802-appb-000007
Figure PCTCN2020107802-appb-000008
Figure PCTCN2020107802-appb-000009
本发明还提供了前述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物在制备IL-17A抑制剂中的用途。
本发明还提供了前述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗IL-17A介导的疾病的药物中的用途。
进一步地，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。
本发明还提供了一种药物，它是以前述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物为活性成分，加上药学上可接受的辅料制备而成的制剂。
本发明所定义的IL-17A介导的疾病是IL-17A在该疾病的病理发生中起重要作用的疾病。IL-17A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-17A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分子所替换。
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C a～ b烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，“C 1～4烷基”是指包含1～4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。例如，C 1～6烷基是指具有1至6个成员原子，例如1至4个成员原子的烷基基团。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。C 1～6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C 1～6烷氧基。
“环烷基”是指具有3至14个碳原子且没有环杂原子且具有单个环或多个环(包括稠合、桥连和螺环体系)的饱和或部分饱和的环状基团。对于具有不含环杂原子的芳族和非芳族环的多环体系，当连接点位于非芳族碳原子时，适用术语“环烷基”(例如5,6,7,8,-四氢化萘-5-基)。术语“环烷基”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：
Figure PCTCN2020107802-appb-000010
双环己基和
Figure PCTCN2020107802-appb-000011
双环己基。
“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，(C a～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，(C 2-6)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”指烷基中的氢原子可被一个或多个卤素原子取代。例如C 1～ 4卤素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。
“杂环”、“杂环烷基”指包含至少一个杂原子的饱和环或非芳香性的不饱和环；其中杂原子指氮原子、氧原子、硫原子；
“芳杂环”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；
“立体异构体”包括对映异构体和非对映异构体。
本发明化合物的基团中，“或者，其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个独立的R 13取代”是指环烷基、杂环烷基、芳环、芳杂环可以不被取代，也可以被一个、两个或三个独立的R 13取代。
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。
本发明化合物表现出良好的IL-17A抑制活性，可用于制备IL-17A抑制剂，用于与IL-17A活性异常疾病的治疗，为临床治疗与IL-17A活性异常相关的疾病提供了一种新的药用可能。
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
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 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl 3)，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-MS 2020(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。
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(25±5℃)。实施例中无特殊说明，反应过夜为反应12±2h。实施例中无特殊说明，M是摩尔每升。
实施例1、化合物1的制备
1、中间体1-2的制备
Figure PCTCN2020107802-appb-000012
步骤1：中间体1-2a的制备
氮气保护和0℃下，向对硝基苯乙酸乙酯(156g,745.71mmol)的干燥的DMF(700mL)溶液中加入Cs 2CO 3(290.82g,894.85mmol)，升至室温并搅拌 1小时，随后降至0℃并缓慢滴加碘甲烷(116.43g,820.28mmol)，滴毕，反应过夜，抽滤，滤液用2L乙酸乙酯稀释，饱和食盐水洗涤(3*1.5L)，有机相无水硫酸钠干燥，过滤，浓缩即可得到中间体1-2a(165g,739.16mmol,99.12％产率)，MS m/z:224[M+1] +，粗品直接用于下一步。
步骤2：中间体1-2b的制备
氮气保护和-10℃下，将中间体1-2a(11.48g,478.44mmol)的DMF(300mL)溶液缓慢滴加至干燥的0.3L的DMF和NaH(11.48g,478.44mmol)的混合溶液中，30min后，降温至-50℃，滴加氯甲基甲醚(48.15g,598.05mmol)，30min滴毕，反应液于-50℃～-10℃继续搅拌3小时，反应完毕，冷的饱和氯化铵淬灭反应，乙酸乙酯(2*400ml)萃取，合并有机相，经饱和食盐水(400ml*2)洗，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱层析分离(石油醚/乙酸乙酯100：1～50：1，v/v)得到中间体1-2b(45g,168.36mmol,42.23％产率)，MS m/z:268[M+1] +。
步骤3：中间体1-2c的制备
将中间体1-2b(45g,168.36mmol)溶于EtOH(100mL)中，氮气置换后，加入10％Pd/C(8g)，随后氢气置换，并常压氢气氛下搅拌反应过夜，原料消失后，经硅藻土抽滤，乙醇洗涤，滤液减压浓缩至干，得到中间体1-2c(34.6g,145.81mmol,86.60％产率)，MS m/z:260[M+1+22] +，产物未经纯化直接用于下一步反应。
步骤4：中间体1-2d的制备
将中间体1-2c(15.9g,67.01mmol)溶于醋酐(136mL)中，冷却至0℃，并搅拌15min，缓慢滴加HNO 3(9.31g,100.51mmol,68％质量分数)，滴毕，反应继续搅拌30min，原料消失，将反应液倾入冰水中，乙酸乙酯(2*100mL)萃取，合并有机相，经饱和碳酸钠洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得到中间体1-2d粗品(17g,52.42mmol,78.23％产率)，MS m/z:325[M+1] +。
步骤5：中间体1-2e的制备
将中间体1-2d(21.73g,67.01mmol)溶于100ml乙醇中，加入NaOH(1.61g,40.20mmol)，加热至50℃搅拌0.5小时，TLC显示原料消失，反应液减压浓缩至干，加入H 2O(150mL)，用6N HCl调pH值～7，水相再经CH 2Cl 2(2*100mL)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩至干，得到中间体1-2e粗品(8g,28.34mmol,42.29％产率)，MS m/z:283[M+1] +。
步骤6：中间体1-2的制备
将中间体1-2e(21g,74.2mmol)溶于甲醇中，氮气氛下加入10％Pd/C(5g)，随后氢气置换，并常压氢化反应过夜，原料消失后，经硅藻土抽滤，滤 液减压浓缩至干，MPLC C18反相柱纯化得到中间体1-2(15g，淡棕色半固体，70％产率)，MS m/z:253[M+1] +。
2、化合物1的制备
Figure PCTCN2020107802-appb-000013
步骤1：中间体1-3的制备
Figure PCTCN2020107802-appb-000014
向100mL单口瓶中加入中间体1-1(反式-(2S)-(叔丁氧羰基氨基)-2-(4-甲基环己基)乙酸(263mg,0.969mmol)和中间体1-2(293mg,1.162mmol)，加入DCM(10mL)，得淡棕色澄清溶液。搅拌下依次加入DIPEA(0.51mL,2.907mmol)，HOAt(158mg,1.162mmol)和EDCI(223mg,1.162mmol)，室温下搅拌3小时，LCMS显示酰化完成。反应液用水(20mL)洗，干燥后旋干，残余物柱层析纯化(硅胶：100-200目，PE:EA＝2:1,v/v)，得430mg固体，将此中间体溶于冰醋酸(5mL)中，60℃下搅拌过夜。LCMS显示关环反应完成，旋去冰醋酸，残余物加饱和NaHCO 3(aq)和EA(20mL)溶解，分出EA层后，水层继续用EA(20mL)萃取2次，合并EA层干燥后旋干，得淡黄色固体1-3(368mg,yield:78％)，直接用于下一步反应。MS m/z:488[M+1] +.
步骤2：中间体1-4的制备
Figure PCTCN2020107802-appb-000015
向100mL单口瓶中加入中间体1-3(368mg,0755mmol)，加入DCM(2 mL)溶解。冰浴下加入三氟乙酸(2ml)，搅拌反应3小时。LCMS显示反应完成，减压浓缩得粗品1-4(293mg,yield:100％)，直接用于下一步反应。MS m/z:388[M+1] +.
步骤3：中间体1-5的制备
Figure PCTCN2020107802-appb-000016
向100mL单口瓶中加入中间体1-4(293mg,0.755mmol)，加入DCM(10mL)，搅拌得淡棕色澄清溶液，搅拌下依次加入1-甲基-5-吡唑甲酸(96mg,0.758mmol)，DIPEA(0.4mL,2.274mmol)和HBTU(373mg,0.985mmol)，氮气保护于室温下反应过夜。LCMS显示反应完成，向反应液中加水(20mL)洗，分出DCM层，干燥后旋干，残余物柱层析纯化(硅胶：100-200目，PE:EA＝1:1，v/v)，得淡黄色油1-5(243mg,yield:65％)。MS m/z:496[M+1] +.
步骤4：中间体1-6的制备
Figure PCTCN2020107802-appb-000017
向100mL单口瓶中加入中间体1-5(243mg,0.49mmol)，加入乙醇(5mL)和水(1mL)，搅拌得淡黄色溶液。加入NaOH(340mg,8.52mmol)，升温到60℃下反应过夜。LCMS显示反应完成，旋去溶剂，残余固体加1M HCl和EA(20mL)溶解，分出EA层后，水层继续用EA(20mL)萃取2次，合并EA层，干燥后旋干，得淡黄色固体1-6(183mg,yield:80％)，直接用于下一步反应。MS m/z:468[M+1] +.
步骤5：化合物1的制备
Figure PCTCN2020107802-appb-000018
向50mL单口瓶中加入中间体1-6(46mg,0.10mmol)，加入DCM(5mL)溶解，得淡黄色溶液。搅拌下依次加入(R)-2-氨基-2-环丁基-乙酰乙胺(19mg,0.12mmol)，DIPEA(0.05mL,0.30mmol)和HBTU(46mg,0.12mmol)，室温下反应过夜。LCMS显示反应完成，旋去溶剂，残余物加DMF溶解后用prep-HPLC纯化(MeCN/0.05％HCOOH,在45％MeCN时出峰)，得白色固体1(27mg,yield:44％)。MS m/z:606[M+1] +。核磁谱图： 1H NMR(400MHz,Methanol-d 4)δ7.65–7.54(m,2H),7.53–7.41(m,2H),7.34(dd,J＝8.6,1.8Hz,1H),6.98(d,J＝2.2Hz,1H),5.12(d,J＝8.5Hz,1H),5.01(s,1H),4.36(t,J＝8.3Hz,1H),4.07(s,3H),3.98(d,J＝9.5Hz,1H),3.73(d,J＝9.6Hz,1H),3.42(s,3H),3.29–3.01(m,3H),2.63–2.50(m,1H),2.17–1.96(m,2H),1.93(s,1H),2.00–1.77(m,3H),1.81–1.67(m,2H),1.58(s,3H),1.52–1.38(m,1H),1.42–1.24(m,13H),1.29–1.13(m,2H),1.16–0.96(m,6H),1.01–0.85(m,9H).
实施例2、化合物2的制备
Figure PCTCN2020107802-appb-000019
参考实施例1方法，以反式-(2S)-(叔丁氧羰基氨基)-2-(4-甲基环己基)乙酸(化合物1-1)和化合物2-1(可参照已公开专利CN110511213A制备)为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物2，MS m/z:576[M+1] +.
化合物2的结构式如下：
Figure PCTCN2020107802-appb-000020
实施例3、化合物3的制备
1、中间体3-1的制备
Figure PCTCN2020107802-appb-000021
步骤1：中间体3-1a的制备
向对溴苯乙酸(48.6g,199.92mmol)的DMF(500mL)溶液中加入NaOEt(2.72g,39.98mmol)和多聚甲醛(18.01g,599.76mmol)。反应混合液室温搅拌过夜，反应完成后，加水淬灭，加乙酸乙酯萃取。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，旋干后得粗品用硅胶柱分离纯化(PE:EA＝10:1-2:1，v/v)得到3-1a(32g,105.56mmol,52.80％yield)，MS m/z:303/305[M+1] +。
步骤2：中间体3-1b的制备
室温下，向LiAlH 4(7.51g,197.92mmol)的THF(300mL)溶液中逐滴滴加中间体3-1a(30g,98.96mmol)的THF(100mL)溶液。混合液室温搅拌20min，然后加热至60℃搅拌2小时。冷却至室温后，反应液加冰水淬灭，然后加aq.HC1(2N)调节pH至2-3，混合液用正丁醇萃取，合并的有机相浓缩，粗品用硅胶柱分离纯化(DCM:MeOH＝10:1，v/v)得到3-1b(22g,84.26mmol,85.14％yield)，MS m/z:259/261[M+1] +。
步骤3：中间体3-1c的制备
向3-1b(22g,84.26mmol)和碳酸乙二酯(10.95g,92.68mmol)的混合物中加入EtOH(2mL)和KOH(141.82mg,2.53mmol)。反应混合液加热至110℃搅拌1小时，蒸馏去除乙醇后，混合液升温至190℃搅拌3小时。冷却至室温，混合物用硅胶柱分离纯化(PE/EA＝1/1，v/v)得到3-1c(3.5g,14.40mmol,17.09％yield)，黄色油状物。
步骤4：中间体3-1d的制备
向3-1c(1.5g,6.17mmol)的ACN(15mL)溶液中加入TEMPO(96.41mg,617.04μmol)，加入次氯酸钠(2.23g,24.68mmol)和亚氯酸钠(367.47mg,4.94mmol)的水溶液(5mL)，混合液室温下搅拌3小时。反应完成后，反应液用2M NaOH调节pH至10，加入10％硫代硫酸钠(10mL)。反应液被分散到乙酸乙酯层和水层，水层用柠檬酸调节成酸性，并用乙酸乙酯萃取，有机相无水硫酸镁干燥，过滤后浓缩，得3-1d粗品(1.22g,4.75mmol,76.91％yield)。
步骤5：中间体3-1e的制备
向3-1d(1.2g,4.67mmol)的DMF(12mL)中加入K 2CO 3(4.67mmol)，碘乙烷(2.18g,14.00mmol)，反应混合液室温搅拌5小时。反应完成后，混合液加水稀释加乙酸乙酯萃取，合并的有机相用无水硫酸钠干燥，旋干后得3-1e (1.12g,3.93mmol,84.15％yield)，未经进一步纯化直接用于下一步反应。MS m/z:285/287[M+1] +。
步骤6：中间体3-1f的制备
向3-1e(1g,3.51mmol)和乙酰胺(258.94mg,4.38mmol)的1,4-dioxane(20mL)混合液中加入Cs 2CO 3(1.71g,5.26mmol),Xantphos(304.39mg,526.07μmol)和Pd 2(dba) 3(160.58mg,175.36μmol)，反应混合液氮气置换后，在氮气保护下升温至100℃并搅拌3小时，反应完成后，旋除溶剂，粗品用硅胶柱分离纯化(PE/EA＝4/1，v/v)得到3-1f(640mg,2.43mmol,69.31％yield)，白色固体。MS m/z:264[M+1] +。
步骤7：中间体3-1g的制备
零度下，向3-1f(0.64g,2.43mmol)的乙酐(5mL)溶液中加入硝酸(153.17mg,2.43mmol)，混合液在0℃搅拌1小时，然后加入25ml水，混合液用EA萃取，合并的有机相用Na 2CO 3水溶液洗涤后，旋干溶剂，粗品用硅胶柱分离纯化(EA/PE＝1/20，v/v)得3-1g(0.42g,1.36mmol,56.05％yield)黄色油状物。MS m/z:309[M+1] +。
步骤8：中间体3-1h的制备
向3-1g(420mg,1.36mmol)的EtOH(1mL)的溶液中加入NaOH(59.94mg,1.50mmol)水溶液(1mL)，混合液室温搅拌5小时，然后旋除溶剂，粗品用反相柱分离纯化得3-1h(120mg,450.71umol,33.08％yield)。MS m/z:267[M+1] +。
步骤9：中间体3-1的制备
向3-1h(120mg,450.71umol)的MeOH(1mL)溶液中加入Pd/C(20mg,450.71μmol)，混合液室温搅拌16小时，反应完成后，滤除催化剂，滤液旋干得3-1g，未经纯化直接用于下一步反应。MS m/z:237[M+1] +。
2、化合物3的制备
Figure PCTCN2020107802-appb-000022
参考实施例1方法，以反式-(2S)-(叔丁氧羰基氨基)-2-(4-甲基环己基)乙酸1-1和3-(3,4-二氨基苯基)氧杂环丁烷-3-羧酸乙酯3-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物3，MS m/z:590[M+1] +.
化合物3的结构式如下：
Figure PCTCN2020107802-appb-000023
实施例4、化合物4的制备
1、中间体4-1的制备
Figure PCTCN2020107802-appb-000024
步骤1：中间体4-1a的制备
室温下，向对硝基苯乙酸(300g,1.66mol)的乙醇(1L)溶液中加入催化量的浓H 2SO 4(1.66mol,2mL)，升温至80℃并搅拌16小时，原料消失后，减压浓缩至干，溶于2L的乙酸乙酯，碳酸氢钠水溶液洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩即可得到中间体4-1a(330g,1.58mol,95.25％产率),MS m/z:210[M+1] +.
步骤2：中间体4-1b的制备
氮气保护下，将中间体4-1a对硝基苯乙酸乙酯(29.4g,140.54mmol)溶于干燥的1.2L的N,N-二甲基乙酰胺中，干冰-乙醇浴冷却至內温-40℃，加入碳酸铯(114.54g,351.34mmol)，-40℃搅拌15min，2-氯乙基氯甲基醚(19.94g,154.59mmol)缓慢滴加至反应液中，滴毕，允许反应恢复至室温，并搅拌过夜，待原料消失后，加入3L的冰水淬灭反应，乙酸乙酯(2L*2)萃取，有机相经饱和食盐水(2L*2)洗，无水硫酸钠干燥，过滤，减压浓缩至干，粗品经硅胶柱层析分离得到中间体4-1b(6.5g,24.50mmol,17.44％产率)，MS m/z:266[M+1] +.
步骤3：中间体4-1c的制备
将中间体4-1b(15g,56.55mmol)溶于EtOH(100mL)中，氮气置换后，加入10％Pd/C(3g)，常压氢气氛下搅拌反应过夜，原料消失后，经硅藻土抽滤，乙醇洗涤，滤液减压浓缩至干，得到中间体4-1c(12.7g,53.98mmol,95.46％产率)，MS m/z:236[M+1] +，产物未经纯化直接用于下一步反应。
步骤4：中间体4-1d的制备
将中间体4-1c(16g,68.00mmol)溶于醋酐(136mL)中，冷却至0℃，并搅拌15min，缓慢滴加HNO 3(9.45g,102.01mmol,68％质量分数)，滴毕，反应继续搅拌30min，原料消失，将反应液倾入冰水中，乙酸乙酯(2*300mL)萃取，有机相经饱和碳酸钠洗涤，无水硫酸钠干燥，过滤，减压浓缩至干得到中间体4-1d粗品(21g,65.15mmol,95.81％产率)，MS m/z:323[M+1] +，产物未经纯化直接用于下一步反应。
步骤5：中间体4-1e的制备
将中间体4-1d(21g,65.15mmol)溶于150ml乙醇中，加入SOCl 2(23.25g,195.46mmol,14.18mL)，加热至50℃搅拌1小时，LC-MS显示原料消失，反应液减压浓缩至干，加入CH 2Cl 2(150mL)和H 2O(150mL)，用饱和NaHCO 3调pH值～8，水相再经CH 2Cl 2(2*150mL)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩至干，得到中间体4-1e粗品(18g,64.22mmol,98.57％产率)，MS m/z:281[M+1] +，产物未经纯化直接用于下一步反应。
步骤6：中间体4-1的制备
将中间体4-1e(19g,67.79mmol)溶于甲醇中，氮气氛下加入Pd/C(5.7g)，常压氢化反应过夜，原料消失后，经硅藻土抽滤，滤液减压浓缩至干，MPLCC18反相柱纯化得到4-1(15.0g，淡棕色半固体，88％产率)，MS m/z:251[M+1] +.
2、化合物4的制备
Figure PCTCN2020107802-appb-000025
参考实施例1方法，以反式-(2S)-(叔丁氧羰基氨基)-2-(4-甲基环己基)乙酸1-1和化合物4-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物4，MS m/z:604[M+1] +.
化合物4的结构式如下：
Figure PCTCN2020107802-appb-000026
实施例5、化合物5的制备
1、中间体5-1的制备
Figure PCTCN2020107802-appb-000027
步骤1：中间体5-1a的制备
参照实施例4中间体4-1的制备步骤2，对硝基苯乙酸乙酯在无水DMF中与2,2'-二溴二乙醚以碳酸铯为傅酸剂反应得到中间体5-1a，收率60％，MS m/z:280[M+1] +.
步骤2：中间体5-1b的制备
参照实施例4中间体4-1的制备步骤3，中间体5-1a经锌粉-醋酸体系还原得到中间体5-1b，收率95％，MS m/z:250[M+1] +.
步骤3：中间体5-1c的制备
参照实施例4中间体4-1的制备步骤4，中间体5-1b在醋酐中硝化得到中间体5-1c，收率74％，MS m/z:337[M+1] +.
步骤4：中间体5-1d的制备
参照实施例4中间体4-1的制备步骤5，中间体5-1c脱乙酰基得到中间体5-1d，收率96％，MS m/z:295[M+1] +.
步骤5：中间体5-1的制备
参照实施例4中间体4-1的制备步骤6，中间体5-1d经氢化还原得到中间体5-1，收率90％，MS m/z:265[M+1] +.
2、化合物5的制备
Figure PCTCN2020107802-appb-000028
参考实施例1方法，以反式-(2S)-(叔丁氧羰基氨基)-2-(4-甲基环己基)乙酸1-1和化合物5-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物5，MS m/z:618[M+1] +.
化合物5的结构式如下：
Figure PCTCN2020107802-appb-000029
实施例6、化合物6的制备
Figure PCTCN2020107802-appb-000030
参考实施例1方法，以反式-(2S)-(叔丁氧羰基氨基)-2-(4-甲基环己基)乙酸1-1和化合物6-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物6，MS m/z:604[M+1] +.
化合物6的结构式如下：
Figure PCTCN2020107802-appb-000031
实施例7、化合物7的制备
Figure PCTCN2020107802-appb-000032
参考实施例1方法，以反式-(2S)-(叔丁氧羰基氨基)-2-(4-甲基环己基)乙酸1-1和化合物7-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物7，MS m/z:618[M+1] +.
化合物7的结构式如下：
Figure PCTCN2020107802-appb-000033
实施例8、化合物8的制备
Figure PCTCN2020107802-appb-000034
参考实施例1方法，以反式-(2S)-(叔丁氧羰基氨基)-2-(4-甲基环己基)乙酸1-1和化合物8-1(可参照已公开专利CN110511213A制备)为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物8，MS m/z:562[M+1] +.
化合物8的结构式如下：
Figure PCTCN2020107802-appb-000035
实施例9、化合物9的制备
Figure PCTCN2020107802-appb-000036
参考实施例1方法，以反式-(2S)-(叔丁氧羰基氨基)-2-(4-甲基环己基)乙酸1-1和化合物9-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物9，MS m/z:548[M+1] +.
化合物9的结构式如下：
Figure PCTCN2020107802-appb-000037
实施例10、化合物10的制备
Figure PCTCN2020107802-appb-000038
参考实施例1方法，以(2S)-(叔丁氧羰基氨基)-2-环辛基-乙酸10-0和化合物1-2为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物10，MS m/z:620[M+1] +.
化合物10的结构式如下：
Figure PCTCN2020107802-appb-000039
实施例11、化合物11的制备
Figure PCTCN2020107802-appb-000040
参考实施例1方法，以(2S)-(叔丁氧羰基氨基)-2-环辛基-乙酸10-0和化合物2-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物11，MS m/z:590[M+1] +.
化合物11结构式如下：
Figure PCTCN2020107802-appb-000041
实施例12、合物12的制备
Figure PCTCN2020107802-appb-000042
参考实施例1方法，以(2S)-(叔丁氧羰基氨基)-2-环辛基-乙酸10-0和化合物3-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物12，MS m/z:604[M+1] +.
化合物12结构式如下：
Figure PCTCN2020107802-appb-000043
实施例13、化合物13的制备
Figure PCTCN2020107802-appb-000044
参考实施例1方法，以(2S)-(叔丁氧羰基氨基)-2-环辛基-乙酸10-0和化 合物4-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物13，MS m/z:618[M+1] +.
化合物13结构式如下：
Figure PCTCN2020107802-appb-000045
实施例14、化合物14的制备
Figure PCTCN2020107802-appb-000046
参考实施例1方法，以(2S)-(叔丁氧羰基氨基)-2-环辛基-乙酸10-0和化合物5-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物14，MS m/z:632[M+1] +.
化合物14结构式如下：
Figure PCTCN2020107802-appb-000047
实施例15、化合物15的制备
Figure PCTCN2020107802-appb-000048
参考实施例1方法，以(2S)-(叔丁氧羰基氨基)-2-环辛基-乙酸10-0和化合物8-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物15，MS m/z:576[M+1] +.
化合物15结构式如下：
Figure PCTCN2020107802-appb-000049
实施例16、化合物16的制备
Figure PCTCN2020107802-appb-000050
参考实施例1方法，以(2S)-(叔丁氧羰基氨基)-2-环辛基-乙酸10-0和化合物9-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物16，MS m/z:562[M+1] +.
化合物16结构式如下：
Figure PCTCN2020107802-appb-000051
实施例17、化合物17的制备
Figure PCTCN2020107802-appb-000052
参考实施例1的方法，以实施例1的中间体1-3为原料，依次经酯水解，缩合(R)-2-氨基-2-环丁基-乙酰乙胺，脱Boc，最后与氯甲酸甲酯反应得化合物17，MS m/z:556.0[M+1] +。核磁谱图： 1H NMR(400MHz,Methanol-d 4)δ7.60–7.48(m,2H),7.46–7.33(m,2H),7.26(dd,J＝8.6,1.8Hz,1H),4.93(s,7H),4.69(d,J＝7.6Hz,1H),4.62(s,1H),4.41–4.31(m,1H),4.00(d,J＝9.5Hz,1H),3.76–3.61(m,5H),3.43(s,3H),3.35(s,1H),3.27–3.10(m,2H),2.57(dq,J＝16.3,8.0Hz,1H),2.00–1.65(m,6H),1.58(s,3H),1.48–1.40(m,1H),1.44–1.25(m,7H),1.24–0.96(m,5H),0.99–0.86(m,5H).
化合物17结构式如下：
Figure PCTCN2020107802-appb-000053
实施例18、化合物18的制备
Figure PCTCN2020107802-appb-000054
参考实施例1方法，以2-(1-金刚烷基)-2-(叔丁氧羰基氨基)乙酸18-1和化合物1-2为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-环丁基-乙酰乙胺缩合即可得到化合物18，MS m/z:644.0[M+1] +.核磁谱图： 1H NMR(400MHz,Methanol-d 4)δ7.94(t,J＝5.5Hz,1H),7.63–7.50(m,3H),7.42(d,J＝8.0Hz,1H),7.28(dd,J＝8.6,1.8Hz,1H),7.01(d,J＝2.1Hz,1H),5.14(s,1H),4.41–4.27(m,1H),4.09(s,3H),4.01(d,J＝9.5Hz,1H),3.73(d,J＝9.5Hz,1H),3.44(s,3H),3.27–3.09(m,2H),2.58(h,J＝8.3,7.7Hz,1H),2.05–1.98(m,3H),1.99–1.88(m,1H),1.92(s,2H),1.92–1.71(m,7H),1.69–1.56(m,9H),1.10(td,J＝7.3,2.9Hz,3H).
化合物18结构式如下：
Figure PCTCN2020107802-appb-000055
实施例19、化合物19的制备
Figure PCTCN2020107802-appb-000056
参考实施例1方法，以实施例18中的中间体18-2为原料，经酯水解，缩合(R)-2-氨基-2-环丁基-乙酰乙胺，脱Boc，最后与氯甲酸甲酯反应得化合 物19，MS m/z:594.0[M+1] +。核磁谱图： 1H NMR(400MHz,Methanol-d 4)δ7.60–7.49(m,2H),7.26(dd,J＝8.5,1.8Hz,1H),4.60(s,1H),4.41–4.32(m,1H),4.01(d,J＝9.6Hz,1H),3.77–3.63(m,5H),3.44(s,3H),3.27–3.10(m,2H),2.57(p,J＝8.1Hz,1H),2.03–1.93(m,4H),1.91(s,4H),1.97–1.80(m,2H),1.84–1.70(m,10H),1.62(d,J＝26.9Hz,10H),1.10(t,J＝7.3Hz,3H).
化合物19结构式如下：
Figure PCTCN2020107802-appb-000057
实施例20、化合物20的制备
1、中间体20-6的制备
Figure PCTCN2020107802-appb-000058
步骤1：20-A1的制备
冰盐浴下，向环丁基甲酸(20g,199.77mmol)的THF(200mL)溶液中加入逐滴LDA(53.50g,499.42mmol,188mL)，滴加耗时约30分钟。混合液0℃下搅拌30mins，然后逐滴加入CH 3I(31.19g,219.75mmol)，滴加完毕后，反应液室温搅拌过夜。反应完成后，加水(200mL)淬灭反应，用6N HCl调节pH至4，然后用EA(200mL*2)萃取混合液，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤旋干后得20-A1(21g,183.98mmol,92.10％yield)，MS m/z:115[M+1] +。
步骤2：20-A2的制备
零度且氮气保护下，向20-A1(20g,175.22mmol)的DCM(500mL)溶液中加入4,5,6,7-四氯-2-羟基-异吲哚啉-1,3-二酮(58.58g,175.22mmol)、DMAP(2.14g,17.52mmol)和DIC(26.54g,210.26mmol)，混合液室温搅拌3小时，反应完成后，混合液在低于30度的水浴中减压蒸馏得到20-A2(69g,173.79mmol,99.18％yield)，粗品未经纯化直接用于下一步反应。MS m/z:396[M+1] +。
步骤3：20-A3的制备
零度下，向20-A2(84g,211.57mmol)的NMP(600mL)溶液中加入甲基(2Z)-2-[(R)-(2,4,6-三甲基苯基]亚磺酰基]亚氨基乙酸酯(69.67g,275.04mmol)和Ni(OAc) 2.4H 2O(13.17g,52.89mmol)，分批次加入Zn(41.51g,634.70mmol)，控制反应液温度在20℃以下，加完后氮气保护，常温搅拌反应过夜。反应完成后，加饱和食盐水淬灭，加入EA稀释，过滤除去固体残渣，滤液分液，下层水相用EA再萃取2次，合并EA，旋干，得蓝黑色液体，过柱纯化，PE/EA＝2/1(v/v)，收集产物20-A3(52g,154.09mmol,72.83％yield)。MS m/z:338[M+1] +。
步骤4：20-A4的制备
零度下，向20-A3(100g,296.32mmol)的MeOH(1L)溶液中加入TFA(67.57g,592.64mmol,43.88mL)。然后反应混合液室温搅拌1小时，反应混合液减压浓缩，粗品用300mL水稀释，用CH 2Cl 2(300mL*2)萃取，分离得到的水相用饱和K 2CO 3溶液调节pH至8.0，然后用CH 2Cl 2萃取，合并的有机相用无水硫酸钠干燥，过滤然后减压浓缩得到20-A4(50.7g,296.08mmol,99.92％yield)，MS m/z:172[M+1] +。
步骤5：20-A5的制备
室温下，向20-A4(17.4g,101.61mmol)的THF(100mL)溶液中缓慢加入NaOH(8.13g,203.23mmol)的H 2O(20mL)溶液，混合液升温至50℃搅拌反应2h，反应完成后，反应液降至室温，用6N的HCl调节pH至7左右，未经进一步处理直接用于下一步反应。
步骤6：20-A6的制备
向上一步反应液中依次加入NaHCO 3(25.70g,305.90mmol)和Fmoc-Osu(37.83g,112.16mmol)，反应混合液室温搅拌1小时。反应完成后，用6M HCl溶液调节pH至4～5，加EA萃取，合并的有机相旋干，粗品经柱色谱分离纯化(DCM/MeOH＝20/1,v/v)得20-A6(20g,54.73mmol,53.68％yield)，MS m/z:366[M+1] +。
步骤7：20-A7的制备
向20-A6(3.0g,8.21mmol)的DCM(50mL)溶液中加入TEA(2.49g,24.63mmol,3.44mL)和HBTU(2.50g,9.85mmol)，然后加入乙二胺盐酸盐(370.12mg,4.54mmol,CL)，反应混合液室温搅拌1小时。反应完成后，加水淬灭，加DCM萃取，合并的有机相用无水硫酸钠干燥，旋干后粗品用硅胶柱分离纯化得到20-A7(3.0g,7.64mmol,93.10％yield)，MS m/z:393[M+1] +。
步骤8：中间体20-6的制备
向20-A7(3.1g,7.90mmol)的THF(35mL)/MeOH(0.01mL)混合液中 加入LiOH.H2O(398.07mg,9.48mmol)的H 2O(7mL)溶液，该混合液室温搅拌1小时。反应完成后，加入1N HCl调节pH至中性，减压浓缩混合液，粗品用石油醚洗涤几次，然后干燥得20-6(1.25g,7.34mmol,92.96％yield)。MS m/z:171[M+1] +。
2、化合物20的制备
Figure PCTCN2020107802-appb-000059
参考实施例1方法，以(S)-2-((叔丁氧羰基)-2-((1s,4R)-4-甲基环己基)乙酸20-1和化合物4-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-1-甲基环丁基-乙酰乙胺(中间体20-6)缩合即可得到化合物20，MS m/z:618.0[M+1] +。核磁谱图： 1H NMR(400MHz,Methanol-d 4)δ7.65–7.55(m,2H),7.49(d,J＝2.2Hz,1H),7.25(dd,J＝8.5,1.8Hz,1H),6.95(d,J＝2.2Hz,1H),5.11(d,J＝8.6Hz,1H),4.68(d,J＝8.6Hz,1H),4.34(s,1H),4.08(s,3H),4.05–3.97(m,3H),3.24–3.04(m,2H),2.88–2.81(m,1H),2.62–2.50(m,1H),2.10–1.89(m,4H),1.87–1.61(m,4H),1.60–1.40(m,4H),1.24–1.10(m,3H),1.05(t,J＝7.3Hz,3H),0.99(s,3H),0.90(d,J＝6.5Hz,3H).
化合物20结构式如下：
Figure PCTCN2020107802-appb-000060
实施例21、化合物21的制备
Figure PCTCN2020107802-appb-000061
参考实施例1方法，以2-(1-金刚烷基)-2-(叔丁氧羰基氨基)乙酸18-1和化合物4-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-(1-甲基环丁基)-乙酰乙胺(中间体20-6)缩合即可得到化合物21，MS m/z:656.0[M+1] +。
化合物21结构式如下：
Figure PCTCN2020107802-appb-000062
实施例22、化合物22的制备
Figure PCTCN2020107802-appb-000063
参考实施例1方法，以2-(叔丁氧羰基)氨基)-2-(2,2,4-三甲基环己基)乙酸22-1和化合物4-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-(1-甲基环丁基)-乙酰乙胺(中间体20-6)缩合即可得到化合物22，MS m/z:646.0[M+1] +。核磁谱图： 1H NMR(400MHz,CDCl 3)δ8.05(s,1H),7.70(d,J＝6.6Hz,2H),7.53(s,1H),7.48(d,J＝8.7Hz,1H),6.95(s,1H),6.88(d,J＝8.7Hz,1H),6.00(s,1H),4.65(d,J＝8.8Hz,1H),4.36(d,J＝8.3Hz,1H),4.14(s,3H),4.03(dd,J＝17.7,9.2Hz,4H),3.20(s,1H),3.11(s,1H),2.96–2.83(m,1H),2.51(d,J＝10.2Hz,1H),2.10(t, J＝11.3Hz,2H),1.84(t,J＝13.1Hz,2H),1.68(dd,J＝27.7,14.9Hz,4H),1.48(dd,J＝37.9,12.6Hz,5H),1.31(s,1H),1.07(d,J＝6.9Hz,6H),1.02(d,J＝4.3Hz,6H),0.90(d,J＝6.4Hz,3H).
化合物22结构式如下：
Figure PCTCN2020107802-appb-000064
实施例23、化合物23的制备
1、中间体23-1的制备
Figure PCTCN2020107802-appb-000065
步骤1：中间体23-1a的制备
在反应瓶中加入4-溴-3氟-2硝基苯胺(10g,42.55mmol)的二氧六环(200mL)和水(20mL)溶液中，依次加入3,6-二氢-2H-吡喃-4-硼酸频哪醇酯(8.94g,42.55mmol)、Pd(dppf)Cl 2(1.55g,2.12mmol)和K 2CO 3(17.60g,127.54mmol)，混合均匀后，抽真空氮气保护，升温到100℃反应3小时，反应完后降温到室温，过滤，滤液加入乙酸乙酯和盐水分层，浓缩干得到粗品23-1a(9.69g,40.68mmol,95.60％收率)，MS m/z：239.0(M+1) +
步骤2：中间体23-1b的制备
向23-1a(700mg,2.94mmol)的醋酸(7mL)溶液中加入Ac 2O(484mg,4.74mmol)，混合液加热到90℃反应2小时，反应完后滴加到35ml水中，过滤浓缩干后得23-1b(618mg,2.21mmol,75.04％收率)。MS m/z：281.0(M+1) +
步骤3：中间体23-1c的制备
向23-1b(200mg,713.65umol)的二氯甲烷溶液中加入m-CPBA(246.31mg,1.43mmol)，混合液室温搅拌过夜，原料1/3剩余，反应液升温至40℃继续反应4h后，加碳酸钠水溶液和乙酸乙酯萃取，有机层用亚硫酸钠水溶液 洗涤，分离的有机层经浓缩后得到中间体23-1c(205mg,691.98umol,96.96％收率)，MS m/z：297.0(M+1) +
步骤4：中间体23-1d的制备
冰浴下，向23-1c(1.9g,6.41mmol)的二氯甲烷(50mL)溶液中加入BF 3.OEt(2.74g,19.28mmol)，逐步升至室温并搅拌2小时,反应完后用碳酸钠淬灭，乙酸乙酯萃取，旋干有机相后得粗品，用正向硅胶柱分离纯化，(洗脱剂，二氯甲烷/乙酸乙酯＝10：1～5：1，v/v)得到23-1d(1.37g,4.62mmol,72.11％收率)产品。MS m/z：297.0(M+1) +
步骤5：中间体23-1e的制备
在反应瓶中加入NaClO 2(1.31g,12.95mmol)和NaH 2PO 4(1.59g,10.17mmol)，混匀后降温到0℃，滴加23-1d(1.37g,4.62mmol)的叔丁醇(12mL)和水(9mL)的混合溶液，保温搅拌1小时，反应完后调酸到pH＝5-6，乙酸乙酯萃取后浓缩有机相得到23-1e(1.38g,4.42mmol,95.57％收率)。MS m/z：297.0(M+1) +
步骤6：中间体23-1f的制备
向23-1e(600mg,1.92mmol)的EtOH(12mL)溶液中滴加SOCl 2(685.82mg,5.76mmol,418.18uL)，滴加完毕后升温到60℃反应12小时。冷却至室温，反应液倒入碳酸氢钠溶液中，然后用乙酸乙酯萃取，浓缩得到粗品23-1f(434mg,1.46mmol,75.72％收率)，MS m/z：299.0(M+1) +
步骤7：中间体23-1的制备
向23-1f(434mg,1.61mmol)的乙醇(8mL)溶液中加入钯碳，氢气球置换后在室温下搅拌12小时，反应完后过滤掉钯碳，滤液浓缩，用正向硅胶柱(二氯甲烷/甲醇＝50/1，v/v)纯化得到中间体23-1(187mg,697.02umol,43.40％收率)，MS m/z：269.0(M+1) +。
2、化合物23的制备
Figure PCTCN2020107802-appb-000066
参考实施例1方法，以反式-(2S)-(叔丁氧羰基氨基)-2-(4-甲基环己基)乙 酸1-1和化合物23-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-(1-甲基环丁基)-乙酰乙胺(中间体20-6)缩合即可得到化合物23，MS m/z:636.0[M+1] +.核磁谱图： 1H NMR(400MHz,Methanol-d 4)δ7.50(d,J＝2.2Hz,1H),7.39(d,J＝8.5Hz,1H),7.33(t,J＝7.5Hz,1H),6.96(d,J＝2.1Hz,1H),5.13–5.05(m,1H),4.63–4.52(m,1H),4.33(s,1H),4.17–4.11(m,1H),4.08(d,J＝1.6Hz,3H),4.02–3.92(m,1H),3.23–3.14(m,1H),3.14–3.05(m,1H),3.04–2.95(m,1H),2.52–2.40(m,1H),2.12–1.90(m,4H),1.86–1.76(m,2H),1.70(d,J＝13.0Hz,1H),1.46–1.29(m,5H),1.25–1.10(m,2H),1.09–1.04(m,3H),1.00(s,3H),0.90(d,J＝6.5Hz,3H).
化合物23结构式如下：
Figure PCTCN2020107802-appb-000067
实施例24、化合物24的制备
Figure PCTCN2020107802-appb-000068
参考实施例1方法，以2-((叔丁氧羰基)氨基)-2-(2,4-二甲基环己基)乙酸25-1和苯二胺4-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-(1-甲基环丁基)-乙酰乙胺(中间体20-6)缩合即可得到化合物25，MS m/z:632.0[M+1] +。核磁谱图： 1H NMR(400MHz,Methanol-d 4)δ7.59(d,J＝15.2Hz,2H),7.46(dd,J＝4.4,2.1Hz,1H),7.25(dd,J＝8.4,1.8Hz,1H),6.83(dd,J＝11.6,2.2Hz,1H),5.66–5.50(m,1H),4.70(t,J＝7.7Hz,1H),4.38-4.32(m,1H),4.08(s,3H),4.16–4.02(m,1H),4.06–3.93(m,4H),3.25–3.02(m,2H),2.90–2.77(m,1H),2.70(dq,J＝11.1,3.7Hz,1H),2.57(dt,J＝12.6,8.0Hz,1H),2.13–1.98(m,2H),2.02–1.86(m,2H),1.90–1.68(m,2H),1.67–1.49(m,4H),1.54–1.35(m,2H),1.37–1.27(m,2H),1.31–1.08(m,2H),1.09–0.81(m,11H),0.45(d,J＝7.3Hz,3H).
化合物24结构式如下：
Figure PCTCN2020107802-appb-000069
实施例25、化合物25的制备
Figure PCTCN2020107802-appb-000070
参考实施例1方法，以实施例22中的中间体22-2为原料，经脱Boc、缩合引入乙酰基、酯水解，最后与(R)-2-氨基-2-(1-甲基环丁基)-乙酰乙胺(中间体20-6)缩合即可得到化合物25，MS m/z:580.0[M+1] +。核磁谱图： 1H NMR(400MHz,Methanol-d 4)δ7.61–7.55(m,2H),7.25(dd,J＝8.4,1.7Hz,1H),5.69(d,J＝3.0Hz,1H),4.69(d,J＝8.5Hz,1H),4.34(s,1H),4.06–3.98(m,3H),3.26–3.15(m,1H),3.15–3.05(m,1H),2.90–2.79(m,1H),2.62–2.51(m,1H),2.10(s,3H),2.08–1.99(m,2H),1.97–1.88(m,1H),1.86–1.78(m,1H),1.78–1.72(m,1H),1.67–1.61(m,1H),1.61–1.51(m,2H),1.48–1.43(m,1H),1.42–1.39(m,1H),1.39–1.32(m,2H),1.10–1.04(m,6H),1.03–0.95(m,7H),0.95–0.89(m,1H),0.89–0.80(m,4H).
化合物25结构式如下：
Figure PCTCN2020107802-appb-000071
实施例26、化合物26的制备
Figure PCTCN2020107802-appb-000072
参考实施例1方法，以实施例22中的中间体22-2为原料，经酯水解，缩合(R)-2-氨基-2-(1-甲基环丁基)-乙酰乙胺(中间体20-6)，脱Boc，最后与氯甲酸甲酯反应得化合物26，MS m/z:596.0[M+1] +。核磁谱图： 1H NMR(400MHz,Methanol-d 4)δ7.55(s,2H),7.22(dd,J＝8.5,1.8Hz,1H),5.38(d,J＝3.0Hz,1H),4.67(d,J＝8.6Hz,1H),4.32(s,1H),4.04–3.94(m,3H),3.70(s,3H),3.22–3.03(m,2H),2.82(dt,J＝12.5,6.1Hz,1H),2.54(dt,J＝12.7,8.0Hz,1H),2.07–1.86(m,3H),1.85–1.67(m,2H),1.60–1.47(m,3H),1.46–1.32(m,5H),1.07(s,3H),1.04(t,J＝7.3Hz,3H),0.98(d,J＝3.7Hz,3H),0.96(s,3H),0.84(d,J＝6.4Hz,3H).
化合物26结构式如下：
Figure PCTCN2020107802-appb-000073
实施例27、化合物27的制备
Figure PCTCN2020107802-appb-000074
参考实施例1方法，以2-((叔丁氧羰基)胺基)-2-(7-螺[2.5]辛基-4-甲基)乙酸27-1和化合物4-1为原料，经缩合、关咪唑环、脱Boc、缩合引入1-甲基-1H-吡唑-5-酰基、酯水解，最后与(R)-2-氨基-2-(1-甲基环丁基)-乙酰乙胺 (中间体20-6)缩合即可得到化合物27，MS m/z:644.0[M+1] +。核磁谱图： 1H NMR(400MHz,Methanol-d 4)δ7.81–7.71(m,3H),7.53–7.47(m,2H),7.06–6.87(m,2H),6.86(d,J＝2.2Hz,1H),5.96(d,J＝11.4Hz,1H),4.64(d,J＝8.9Hz,1H),4.37(d,J＝8.7Hz,1H),4.10(s,3H),4.08–3.98(m,5H),3.26–3.17(m,2H),3.17–3.05(m,2H),2.95–2.82(m,2H),2.57–2.45(m,2H),2.16–2.03(m,2H),2.05–1.93(m,2H),1.91–1.75(m,5H),1.74–1.56(m,2H),1.55–1.38(m,3H),1.37–1.22(m,2H),1.10–1.01(m,8H),1.01–0.92(m,5H),0.90–0.80(m,1H),0.76–0.65(m,2H),0.53–0.41(m,2H),0.40–0.26(m,2H).
化合物27结构式如下：
Figure PCTCN2020107802-appb-000075
以下通过具体的试验例证明本发明的有益效果。
试验例1、IL-17酶联免疫吸附测定(ELISA)实验
通过竞争性ELISA对IL-17A抑制剂对受体-配体结合的抑制情况进行了定量检测。将0.2μg/mL IL-17A(Sino Biological lnc.Cat#12047-H07B)以100μL(50mM磷酸盐缓冲液，pH 7.4)每孔在96孔板中37度孵育30分钟。用PBST(PBS，0.05％Tween-20)洗板4次，每次200μL每孔，加入200μL 5％脱脂牛奶于25度摇床上孵育30分钟。准备100X浓度待测化合物，终浓度从0.0002μM到30μM。用PBST(PBS，0.05％Tween-20)洗板4次后加入89μL PBST和1μL 100X浓度待测化合物混匀后于25度预孵育10分钟。加入10μL 16nM IL-17R(Sino Biological lnc.Cat#10895-H03H)于25度摇床上孵育30分钟。洗板4次后，加入100μL抗Fc标签HRP偶联抗体(Sino Biological lnc.Cat#10702-T16-H-50)于25度摇床上孵育30分钟。洗板4次后，加入100μL TMB底物溶液25度避光孵育。加入100μL 2.5M HCl后，采用酶标仪于450nm波长检测光吸收值。
按照上述方法对实施例制备的化合物进行IL-17A抑制活性检测，试验结果见表1。其中测定各化合物的IC 50按照说明分类，表1中：
“+”表示IC 50测定值小于100μM大于1μM；
“++”表示IC 50测定值小于1μM大于100nM；
“+++”表示IC 50测定值小于100nM。
表1.本发明化合物对IL-17A的抑制活性
实施例 IC 50 实施例 IC 50 实施例 IC 50 实施例 IC 50
1 +++ 2 ++ 4 +++ 9 ++
10 ++ 11 ++ 13 ++ 17 +++
18 +++ 19 +++ 20 ++ 21 +++
22 +++ 23 +++ 24 +++ 25 ++
26 +++ 27 +++        
试验结果表明：本发明化合物具有良好的IL-17A抑制活性，可用于制备IL-17A抑制剂，用于与IL-17A活性异常疾病的治疗。
综上，本发明化合物表现出良好的IL-17A抑制活性，可用于制备IL-17A抑制剂，用于与IL-17A活性异常疾病的治疗，为临床治疗与IL-17A活性异常相关的疾病提供了一种新的药用可能。

Claims (15)

  1. 式I所示的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物：
    Figure PCTCN2020107802-appb-100001
    其中，
    R 1选自氢、-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)、-C 0～4亚烷基-(5～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)、-NR 11R 12、-OR 11；或者，其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个独立的R 13取代；
    R 11、R 12分别独立选自氢、-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)、-C 0～4亚烷基-(5～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；或者，其中环烷基、亚烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个独立的R 13取代；
    每个R 13独立选自卤素、氰基、羰基、硝基、-C 1～10烷基、卤素取代的-C 1～10烷基、-OH、-O(C 1～10烷基)、-NH 2、-NH(C 1～10烷基)、-N(C 1～10烷基)(C 1～10烷基)；
    R 2选自氢、-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)；
    A环选自5～10元环烷基、5～10元杂环烷基；或者，其中环烷基、杂环烷基进一步被一个、两个或三个独立的R A1取代；
    每个R A1独立选自卤素、氰基、羰基、硝基、-C 1～10烷基、卤素取代的-C 1～10烷基、-C 0～4亚烷基-OR A2、-C 0～4亚烷基-OC(O)R A2、-C 0～4亚烷基-C(O)R A2、-C 0～4亚烷基-C(O)OR A2、-C 0～4亚烷基-C(O)NR A2R A3、-C 0～4亚烷基-NR A2R A3、-C 0～4亚烷基-NR A2C(O)R A3、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)、-C 0～4亚烷基-(5～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；
    R A2、R A3分别独立选自氢、-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)；
    Y 1、Y 2、Y 3分别独立选自N或CR Y1；
    每个R Y1独立选自氢、卤素、氰基、硝基、-C 1～10烷基、卤素取代的-C 1～10烷基、-OH、-O(C 1～10烷基)、-NH 2、-NH(C 1～10烷基)、-N(C 1～10烷基)(C 1～10烷基)；
    R 5、R 6分别独立选自氢、-C 1～10烷基、卤素取代的-C 1～10烷基、-C 0～4亚烷 基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)、-(C 0～4亚烷基)O(C 1～10烷基)、-(C 0～4亚烷基)O(C 0～4亚烷基)(3～10元环烷基)、-(C 0～4亚烷基)O(C 0～4亚烷基)(3～10元杂环烷基)；或者，R 5、R 6相连形成3～10元环烷基、3～10元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基进一步被一个、两个或三个独立的R 51取代；
    每个R 51独立选自卤素、-C 1～10烷基、卤素取代的-C 1～10烷基；
    R 7选自氢、-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)；
    R 8、R 9分别独立选自氢、-C 1～10烷基、卤素取代的-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)、-C 0～4亚烷基-(5～12元螺环)、-C 0～4亚烷基-(5～12元螺杂环)、-C 0～4亚烷基-(5～12元桥环)、-C 0～4亚烷基-(5～12元桥杂环)、-(C 0～4亚烷基)O(C 1～10烷基)、-(C 0～4亚烷基)O(C 0～4亚烷基)(3～10元环烷基)、-(C 0～4亚烷基)O(C 0～4亚烷基)(3～10元杂环烷基)；或者，R 8、R 9相连形成3～10元环烷基、3～10元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基、螺环、螺杂环、桥环、桥杂环进一步被一个、两个或三个R 81取代；
    每个R 81独立选自卤素、-C 1～10烷基、卤素取代的-C 1～10烷基；
    R 10、R 11分别独立选自氢、-C 1～10烷基、卤素取代的-C 1～10烷基、-C 0～4亚烷基-(3～10元环烷基)、-C 0～4亚烷基-(3～10元杂环烷基)；或者R 10、R 11相连形成3～10元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基进一步被一个、两个或三个R 101取代；
    每个R 101独立选自卤素、-C 1～10烷基、卤素取代的-C 1～10烷基。
  2. 根据权利要求1所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 1选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-C 0～2亚烷基-(5～6元芳环)、-C 0～2亚烷基-(5～6元芳杂环)、-NR 11R 12、-OR 11；或者，其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个独立的R 13取代；
    R 11、R 12分别独立选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-C 0～2亚烷基-(5～6元芳环)、-C 0～2亚烷基-(5～6元芳杂环)；或者，其中环烷基、亚烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个独立的R 13取代；
    每个R 13独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OH、-O(C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)；
    R 2选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)；
    A环选自5～10元环烷基、5～9元杂环烷基；其中环烷基、杂环烷基可进一步被一个、两个或三个独立的R A1取代；
    每个R A1独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6 烷基、-C 0～2亚烷基-OR A2、-C 0～2亚烷基-OC(O)R A2、-C 0～2亚烷基-C(O)R A2、-C 0～2亚烷基-C(O)OR A2、-C 0～2亚烷基-C(O)NR A2R A3、-C 0～2亚烷基-NR A2R A3、-C 0～2亚烷基-NR A2C(O)R A3、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-C 0～2亚烷基-(5～6元芳环)、-C 0～2亚烷基-(5～6元芳杂环)；
    R A2、R A3分别独立选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)；
    Y 1、Y 2、Y 3分别独立选自N或CR Y1；
    每个R Y1独立选自氢、卤素、氰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OH、-O(C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)；
    R 5、R 6分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-(C 0～2亚烷基)O(C 1～6烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元环烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元杂环烷基)；或者，R 5、R 6相连形成3～6元环烷基、3～6元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基进一步被一个、两个或三个独立的R 51取代；
    每个R 51独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基；
    R 7选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)；
    R 8、R 9分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-C 0～2亚烷基-(6～11元螺环)、-C 0～2亚烷基-(6～11元螺杂环)、-C 0～2亚烷基-(5～10元桥环)、-C 0～2亚烷基-(5～10元桥杂环)、-(C 0～2亚烷基)O(C 1～6烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元环烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元杂环烷基)；或者，R 8、R 9相连形成3～6元环烷基、3～6元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基、螺环、螺杂环、桥环、桥杂环进一步被一个、两个或三个R 81取代；
    每个R 81独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基；
    R 10、R 11分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)；或者R 10、R 11相连形成3～6元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基进一步被一个、两个或三个R 101取代；
    每个R 101独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基。
  3. 根据权利要求1所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 1选自-C 1～6烷基、-OR 11、5～6元芳环、5～6元芳杂环；或者，其中芳环、芳杂环进一步被一个、两个或三个独立的R 13取代；
    R 11选自氢、-C 1～6烷基；
    每个R 13独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OH、-O(C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)。
  4. 根据权利要求3所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 1选自
    Figure PCTCN2020107802-appb-100002
    -OCH 3、-CH 3；
    R 13独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基。
  5. 根据权利要求1所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    A环选自5～10元环烷基、5～9元杂环烷基；或者，其中环烷基、杂环烷基进一步被一个、两个或三个独立的R A1取代；
    每个R A1独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-OR A2；
    R A2选自氢、-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)。
  6. 根据权利要求5所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    A环为
    Figure PCTCN2020107802-appb-100003
    R A1可为无；或者R A1选自卤素、氰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基。
  7. 根据权利要求1所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 5、R 6分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-(C 0～2亚烷基)O(C 1～6烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元环烷基)、-(C 0～2亚烷基)O(C 0～2亚烷基)(3～6元杂环烷基)；或者，R 5、R 6相连形成3～6元环烷基、3～6元杂环烷基；或者，其中烷基、亚烷基、环烷基、杂环烷基进一步被一个、两个或三个独立的R 51取代；
    每个R 51独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基。
  8. 根据权利要求7所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 5、R 6分别独立选自氢、-CH 3、-CH 2OCH 3；或者R 5、R 6相连形成
    Figure PCTCN2020107802-appb-100004
    Figure PCTCN2020107802-appb-100005
  9. 根据权利要求1所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 8、R 9分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～2亚烷基-(3～6元环烷基)、-C 0～2亚烷基-(3～6元杂环烷基)、-C 0～2亚烷基-(6～11元螺环)、-C 0～2亚烷基-(6～11元螺杂环)、-C 0～2亚烷基-(5～10元桥环)、-C 0～2亚烷基-(5～10元桥杂环)；或者，其中烷基、亚烷基、环烷基、杂环烷基、螺环、螺杂环、桥环、桥杂环进一步被一个、两个或三个R 81取代；
    每个R 81独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基。
  10. 根据权利要求9所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：
    R 8、R 9分别独立选自氢、-C 1～6烷基、
    Figure PCTCN2020107802-appb-100006
    R 81为无，或者选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基。
  11. 根据权利要求1所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物，其特征在于：式I所示的化合物具体为：
    Figure PCTCN2020107802-appb-100007
    Figure PCTCN2020107802-appb-100008
    Figure PCTCN2020107802-appb-100009
  12. 权利要求1～11任一项所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物在制备IL-17A抑制剂中的用途。
  13. 权利要求1～11任一项所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗IL-17A介导的疾病的药物中的用途。
  14. 根据权利要求13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。
  15. 一种药物，其特征在于：它是以权利要求1～11任一项所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其前体药物、或其代谢产物为活性成分，加上药学上可接受的辅料制备而成的制剂。
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