WO2021027729A1 - 一种免疫调节剂 - Google Patents

一种免疫调节剂 Download PDF

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WO2021027729A1
WO2021027729A1 PCT/CN2020/107845 CN2020107845W WO2021027729A1 WO 2021027729 A1 WO2021027729 A1 WO 2021027729A1 CN 2020107845 W CN2020107845 W CN 2020107845W WO 2021027729 A1 WO2021027729 A1 WO 2021027729A1
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alkylene
alkyl
membered
ring
halogen
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PCT/CN2020/107845
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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
刘利
周贤思
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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Publication of WO2021027729A1 publication Critical patent/WO2021027729A1/zh

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Definitions

  • the invention belongs to the field of pharmacy, 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), but patients usually do not respond or respond poorly to currently available drugs (Al-Ramli et al. J Allergy Clin Immunol, 2009, 123:1185-1187).
  • COPD chronic obstructive pulmonary disease
  • IL-17A levels may lead to 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 intraperitoneal abscess
  • intraperitoneal abscess inflammatory bowel disease
  • allograft rejection psoriasis
  • atherosclerosis asthma And multiple sclerosis
  • IL-17A neutralizing antibody therapy can reduce the disease incidence and severity of autoimmune encephalomyelitis ( 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 a variety of IL-17A antibodies currently exist, there are few reports on specific small molecule IL-17 inhibitors with oral bioavailability. Considering the high cost of producing antibodies and the limitation of the route of administration, the development of new IL-17A small molecule inhibitors is of great significance for the development of drugs for the treatment of IL-17A-mediated diseases.
  • the purpose of the present invention is to provide a new compound and its use in preparing IL-17A inhibitors and preparing drugs for treating IL-17A-mediated diseases.
  • the present invention provides a compound represented by Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • 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 cycloalkyl, heterocycloalkyl, 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, 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);
  • R 3 and R 4 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 group-(3 ⁇ 10 membered heterocycloalkyl group), -O(C 1 ⁇ 10 alkyl group), -O(C 0 ⁇ 4 alkylene group) (3 ⁇ 10 membered cycloalkyl group) , -O(C 0-4 alkylene) (3-10 membered heterocycloalkyl); or, wherein the alkyl, cycloalkyl, and heterocycloalkyl are further substituted with one, two or three R 31 ;
  • R 3 and R 4 are connected to form a 3-10 membered cycloalkyl group or a 3-10 membered heterocycloalkyl group; or, wherein the cycloalkyl group and the heterocycloalkyl group are further substituted by one, two or three R 31 ;
  • Each R 31 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl), -O(C 0 ⁇ 4 alkylene) (3 ⁇ 10 membered cycloalkyl), -O(C 0 ⁇ 4 alkylene) (3 ⁇ 10 membered heterocycloalkyl);
  • Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring; or, among them, cycloalkyl, heterocycloalkyl, aromatic ring ,
  • the aromatic heterocycle is further substituted by one, two or three 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 member heterocycloalkyl), -C 0 ⁇ 4 alkylene-(5 ⁇
  • Each R A4 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 ;
  • R A2 and R A3 are each independently selected from hydrogen and -C 1-10 alkyl
  • X 1 is selected from CR x1 or N;
  • R x1 , R x3 , and R x4 are each independently selected from hydrogen, halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O(C 1-10 alkyl);
  • R x2 is selected from hydrogen, -C 1-10 alkyl, -C(O) (C 1-10 alkyl);
  • L 1 is selected from -C 1-10 alkylene-
  • R 5 is selected from -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl;
  • R 6 is selected from hydrogen, -C 1-10 alkyl, and halogen-substituted -C 1-10 alkyl;
  • L 2 is selected from -C 0 ⁇ 4 alkylene-C(O)NR L21 -, -C 0 ⁇ 4 alkylene-NR L21 C(O)-, -C 0 ⁇ 4 alkylene-S(O )NR L21 -, -C 0 ⁇ 4 alkylene-S(O) 2 NR L21 -, -C 0 ⁇ 4 alkylene-NR L21 S(O)-, -C 0 ⁇ 4 alkylene-NR L21 S(O) 2 -, -C 0 ⁇ 4 alkylene-P(O)(OH)NR L21 -, -C 0 ⁇ 4 alkylene-NR L21 P(O)(OH)-, -C 0 ⁇ 4 alkylene-C(O)-, -C 0 ⁇ 4 alkylene-NR L21 -;
  • R L21 is selected from hydrogen, -C 1-10 alkyl
  • R is selected from -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 heterocycle), -C 0 ⁇ 4 alkylene-(5 ⁇ 12 membered spiro ring), -C 0 ⁇ 4 alkylene-(5 ⁇ 12 membered spiro heterocycle), -C 0 ⁇ 4 alkylene-(5 ⁇ 12 member bridged ring), -C 0 ⁇ 4 alkylene-(5 ⁇ 12 member bridge hetero ring), wherein C ring is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring; or wherein alkylene, cycl
  • R a, R a ' are each independently selected from hydrogen, -C 1 ⁇ 10 alkyl, halogen-substituted -C 1 ⁇ 10 alkyl, -C 0 ⁇ 4 alkylene group - (3 to 10-membered cycloalkyl group), -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 heterocycle), -C 0 ⁇ 4 alkylene-(5-12 membered bridged ring), -C 0 ⁇ 4 alkylene-(5-12 membered bridged heterocyclic ring), -O(C 1 ⁇ 10 alkyl), -O (C 0-4 alkylene) (3-10 membered cycloalkyl), -O (C 0-4 alkylene) (3-10 membered heterocycloalkyl
  • R a and R a' are connected to form a 3-10 membered cycloalkyl group or a 3-10 membered heterocycloalkyl group; or, wherein the cycloalkyl group and the heterocycloalkyl group are further substituted by one, two or three Ra1 ;
  • Each R a1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl);
  • R b and R c 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 ⁇ 10 member aromatic ring), -C 0 ⁇ 4 alkylene-(5 ⁇ 10 Membered aromatic heterocycle); or, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and aromatic heterocyclic ring are further substituted with one, two or three R b1 ;
  • R a and R b are connected to form 3-10 membered heterocycloalkyl, 5-10 membered aromatic heterocycle, 5-12 membered spiro heterocycle, 5-12 membered bridged heterocycle; or, wherein heterocycloalkyl, aromatic
  • the heterocycle, spiro heterocycle, and bridged heterocycle are further substituted with one, two or three Rd ;
  • Each R b1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -OH, -O (C 1-10 alkyl);
  • Each R d is independently selected from halogen, cyano, carbonyl, nitro, -C 1-10 alkyl, halogen-substituted -C 1-10 alkyl, -C 0-4 alkylene -OR d1 , -C 0 ⁇ 4 alkylene-OC(O)R d1 , -C 0 ⁇ 4 alkylene-C(O)R d1 , -C 0 ⁇ 4 alkylene-C(O)OR d1 , -C 0 ⁇ 4 alkylene-C(O)NR d1 R d2 , -C 0 ⁇ 4 alkylene-NR d1 R d2 , -C 0 ⁇ 4 alkylene-NR d1 C(O)R d2 ;
  • R d1 and R d2 are each independently selected from hydrogen, -C 1-10 alkyl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl.
  • 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 cycloalkyl, heterocycloalkyl, 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, 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);
  • R 3 and R 4 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), -O(C 1 ⁇ 6 alkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered cycloalkyl) , -O(C 0-2 alkylene) (3-6 membered heterocycloalkyl); or, wherein the alkyl, cycloalkyl, and heterocycloalkyl are further substituted with one, two or three R 31 ;
  • R 3 and R 4 are connected to form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group; or, wherein the cycloalkyl group and the heterocycloalkyl group are further substituted by one, two or three R 31 ;
  • Each R 31 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered cycloalkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered heterocycloalkyl);
  • Ring A is selected from 5 to 6 membered aromatic rings, 5 to 6 membered aromatic heterocycles, 3 to 6 membered cycloalkyls, 3 to 6 membered heterocycloalkyls; or, among them, aromatic rings, aromatic heterocycles, 3 to 6 membered Cycloalkyl and 3-6 membered heterocycloalkyl are further substituted with one, two or three 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-(
  • Each R A4 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 ;
  • R A2 and R A3 are each independently selected from hydrogen and -C 1-6 alkyl
  • X 1 is selected from CR x1 or N;
  • R x1 , R x3 , and R x4 are independently selected from hydrogen, halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O(C 1-6 alkyl);
  • R x2 is selected from hydrogen, -C 1-6 alkyl, -C(O) (C 1-6 alkyl);
  • L 1 is selected from -C 1-6 alkylene-
  • R 5 is selected from -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl;
  • R 6 is selected from hydrogen, -C 1-6 alkyl, and halogen-substituted -C 1-6 alkyl;
  • L 2 is selected from -C 0 ⁇ 2 alkylene-C(O)NR L21 -, -C 0 ⁇ 2 alkylene-NR L21 C(O)-, -C 0 ⁇ 2 alkylene-C(O )-, -C 0 ⁇ 2 alkylene-NR L21 -;
  • R L21 is selected from hydrogen, -C 1-6 alkyl
  • R is selected from -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), -C 0 ⁇ 2 alkylene-(6 ⁇ 11 membered spiro ring), -C 0 ⁇ 2 alkylene-(6 ⁇ 11 membered spiro heterocycle), -C 0 ⁇ 2 alkylene-(5 ⁇ 10 member bridged ring), -C 0 ⁇ 2 alkylene-(5 ⁇ 10 member bridge hetero ring), Wherein C ring is selected from 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, 5 to 6 membered aromatic ring, 5 to 6 membered aromatic heterocyclic ring; or where
  • R a, R a ' are each independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen-substituted -C 1 ⁇ 6 alkyl, -C 0 ⁇ 2 alkylene group - (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), -O(C 1 ⁇ 6 alkyl), -O (C 0-2 alkylene) (3-6 membered cycloalkyl), -O (C 0-2 alkylene) (3-6 membered heterocycloalkyl);
  • R a and R a' are connected to form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group; or, wherein the cycloalkyl group and the heterocycloalkyl group are further substituted by one, two or three Ra1 ;
  • Each R a1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);
  • R b and R c 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-(5 ⁇ 6 member aromatic ring), -C 0 ⁇ 2 alkylene-(5 ⁇ 6 Membered aromatic heterocycle); or, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and aromatic heterocyclic ring are further substituted with one, two or three R b1 ;
  • R a and R b are connected to form 3-10 membered heterocycloalkyl, 5-10 membered aromatic heterocycle, 5-12 membered spiro heterocycle, 5-12 membered bridged heterocycle; or, wherein heterocycloalkyl, aromatic
  • the heterocycle, spiro heterocycle, and bridged heterocycle are further substituted with one, two or three Rd ;
  • Each R b1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);
  • Each R d is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -C 0-2 alkylene -OR d1 , -C 0 ⁇ 2 alkylene-OC(O)R d1 , -C 0 ⁇ 2 alkylene-C(O)R d1 , -C 0 ⁇ 2 alkylene-C(O)OR d1 , -C 0 ⁇ 2 alkylene-C(O)NR d1 R d2 , -C 0 ⁇ 2 alkylene-NR d1 R d2 , -C 0 ⁇ 2 alkylene-NR d1 C(O)R d2 ;
  • R d1 and R d2 are each independently selected from hydrogen, -C 1-6 alkyl, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl.
  • 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 cycloalkyl, heterocycloalkyl, 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, 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);
  • R 3 and R 4 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), -O(C 1 ⁇ 6 alkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered cycloalkyl) , -O(C 0-2 alkylene) (3-6 membered heterocycloalkyl); or, wherein the alkyl, cycloalkyl, and heterocycloalkyl are further substituted with one, two or three R 31 ;
  • R 3 and R 4 are connected to form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group; or, wherein the cycloalkyl group and the heterocycloalkyl group are further substituted by one, two or three R 31 ;
  • Each R 31 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered cycloalkyl), -O(C 0 ⁇ 2 alkylene) (3 ⁇ 6 membered heterocycloalkyl);
  • Ring A is selected from 5 to 6 membered aromatic rings, 5 to 6 membered aromatic heterocycles, 3 to 6 membered cycloalkyls, 3 to 6 membered heterocycloalkyls; or, among which aromatic rings, aromatic heterocycles, 3 to 6 membered Cycloalkyl and 3-6 membered heterocycloalkyl are further substituted with one, two or three 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-(
  • Each R A4 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 ;
  • R A2 and R A3 are each independently selected from hydrogen and -C 1-6 alkyl
  • L 1 is selected from -C 1-6 alkylene-
  • R 5 is selected from -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl;
  • R 6 is selected from hydrogen, -C 1-6 alkyl, and halogen-substituted -C 1-6 alkyl;
  • R a is selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen-substituted -C 1 ⁇ 6 alkyl, -C 0 ⁇ 2 alkylene group - (3-6 membered cycloalkyl), - C 0 ⁇ 2 alkylene Alkyl-(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 group-(5 ⁇ 10 membered bridged ring), -C 0 ⁇ 2 alkylene group-(5 ⁇ 10 membered bridged heterocyclic ring), -O(C 1 ⁇ 6 alkyl group),- O(C 0 ⁇ 2 alkylene group) (3 ⁇ 6 membered cycloalkyl group), -O(C 0 ⁇ 2 alkylene group)
  • Each R a1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl);
  • R b and R c 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 member heterocycloalkyl)-C 0 ⁇ 2 alkylene-(5 ⁇ 6 member aromatic ring), -C 0 ⁇ 2 alkylene-(5 ⁇ 6 member Aromatic heterocycle); or, wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle are further substituted with one, two or three R b1 ;
  • R a and R b are connected to form 3-10 membered heterocycloalkyl, 5-10 membered aromatic heterocycle, 5-12 membered spiro heterocycle, 5-12 membered bridged heterocycle; or, wherein heterocycloalkyl, aromatic
  • the heterocycle, spiro heterocycle, and bridged heterocycle are further substituted with one, two or three Rd ;
  • Each R b1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl).
  • R 1 is selected from -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocyclic ring, -NR 11 R 12 , -OR 11 ; or, wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring are further substituted with one, two or three independent R 13 ;
  • R 11 and R 12 are each independently selected from hydrogen, -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
  • 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 Halogenated or non-halogenated C 1-3 alkyl, halogenated or non-halogenated C 1-3 alkoxy
  • R 13 is selected from methyl and ethyl
  • R 1a and R 1b are each independently selected from hydrogen, C 1-2 alkyl, C 1-2 alkoxy
  • the C 1-3 alkyl group is selected from methyl, ethyl
  • the halogen is selected from fluorine, chlorine, and bromine.
  • R 3 and R 4 are each independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -O( C 1-6 alkyl), -O (3-6 membered cycloalkyl); or, wherein the alkyl, cycloalkyl, and heterocycloalkyl are further substituted with one, two or three R 31 ;
  • Each R 31 is independently selected from halogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl), -O (3--6 membered ring alkyl).
  • At least one of R 3 and R 4 is hydrogen; preferably, one of R 3 and R 4 is hydrogen, and the other is selected from the following groups substituted by halogen or methyl: C 1-3 alkyl, C 1-3 alkoxy base, More preferably, the C 1-3 alkyl group is selected from methyl, ethyl, The halogen is selected from fluorine, chlorine, and bromine.
  • Ring A is selected from a 5- to 6-membered aromatic ring, a 5- to 6-membered aromatic heterocyclic ring, and a 4- to 6-membered saturated cycloalkyl group; Two or three R A1 substitutions;
  • Each R A1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR A2 , -OC(O)R A2 ,- C(O)R A2 , -C(O)OR A2 , -C(O)NR A2 R A3 , -NR A2 R A3 , -NR A2 C(O)R A3 , 3 to 6 membered cycloalkyl, 3 ⁇ 6-membered heterocycloalkyl, 5 to 6-membered aromatic ring, 5 to 6-membered aromatic heterocyclic ring; or, wherein cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring are further divided by one, two or three R A4 replaced;
  • Each R A4 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OR A2 , -OC(O)R A2 ,- C(O)R A2 , -C(O)OR A2 , -C(O)NR A2 R A3 , -NR A2 R A3 , -NR A2 C(O)R A3 ;
  • R A2 and R A3 are each independently selected from hydrogen and -C 1-6 alkyl
  • the A ring is selected from a benzene ring, a 4-6 membered saturated cycloalkyl group, or wherein the benzene ring, a 4-6 membered saturated cycloalkyl group is further substituted by one, two or three R A1 , each R A1 Each is independently selected from halogen, and the halogen is preferably fluorine, chlorine, or bromine.
  • L 1 is selected from -C 1-4 alkylene-; R 5 is selected from -C 1-4 alkyl; R 6 is selected from hydrogen, -C 1-4 alkyl.
  • L 1 is selected from methylene, ethylene, n-propyl, isopropylidene; R 5 is selected from methyl, ethyl, n-propyl, isopropyl; R 6 is selected from hydrogen, methyl, ethyl Group, n-propyl, isopropyl.
  • R a is selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-11 membered spiro ring, 6 ⁇ 11 membered spiro heterocyclic ring, 5-10 membered bridged ring, 5-10 membered bridged heterocyclic ring, -O(C 1-6 alkyl), -O(3-6 membered cycloalkyl), -O(3 ⁇ 6-membered heterocycloalkyl); or, wherein the alkyl, cycloalkyl, heterocycloalkyl, spiro ring, spiro heterocyclic ring, bridged ring, and bridged heterocyclic ring are further substituted with one, two or three R a1 ; preferably , The spiro ring is The bridge ring is The bridge ring is
  • Each Ra1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl).
  • R a is selected from Or where It is further substituted by one, two or three methyl groups, halogens, or methoxy groups, and the halogens are preferably fluorine, chlorine, or bromine.
  • R b and R c 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, wherein the alkyl, cycloalkyl, and heterocycloalkyl are further substituted with one, two or three R b1 ;
  • Each R b1 is independently selected from halogen, cyano, carbonyl, nitro, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl, -OH, -O (C 1-6 alkyl).
  • At least one of R b and R c is hydrogen; preferably, one of R b and R c is hydrogen, and the other is L c R c1 ; L c is selected from C 0-2 alkylene, preferably none, methylene , Ethylene; R c1 is selected from C 1-2 alkyl Or, where C 1-2 alkyl, Further substituted by one, two or three substituents R b1, R b1 each independently selected from halogen, hydroxy, C 1 ⁇ 2 alkyl, C 1 ⁇ 2 alkoxy; the halogen is selected from fluoro, chloro, bromo.
  • R a and R b are connected to form a 5-12 membered spiro heterocyclic ring, further, the spiro heterocyclic ring is
  • R 2 is hydrogen
  • R 2 is hydrogen
  • R 3 , R 4 are as described above;
  • the A ring is as described above;
  • R 5 , R 6 , and L 1 are as described above;
  • n is an integer of 0 to 3, preferably an integer of 0 to 1;
  • R f is selected from hydrogen, L 0 R f1 ; where L 0 is C 0-3 alkylene, preferably none or methylene; R f1 is selected from amino, hydroxyl, C 1-3 alkyl, C 1 ⁇ alkoxy, COOCH 3;
  • R e is selected from substituted or unsubstituted 4-6 membered saturated cycloalkyl groups, preferably substituted or unsubstituted
  • the substituent is selected from halogen, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, and the halogen is preferably fluorine.
  • the compound is selected from:
  • the present invention also provides the use of the aforementioned compounds, or stereoisomers, or pharmaceutically acceptable salts thereof in the preparation of drugs for treating IL-17A-mediated diseases.
  • the IL-17A-mediated disease is one or more of diseases related to inflammation, autoimmune disease, infectious disease, cancer, and precancerous syndrome; preferably rheumatoid arthritis, Bone erosion, intraperitoneal abscess, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma, or multiple sclerosis.
  • the present invention also provides the use of the aforementioned compounds, or stereoisomers, or pharmaceutically acceptable salts thereof in the preparation of IL-17A inhibitors.
  • the present invention also provides a pharmaceutical composition, which is a preparation prepared by using the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt as the active ingredient, plus pharmaceutically acceptable auxiliary materials.
  • 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.
  • Groups of the compounds of the present invention "or, wherein cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic ring further substituted with one, two or three independent substituents R 13" refers to cycloalkyl, heterocycloalkyl
  • the group, aromatic ring, and aromatic heterocyclic ring may be unsubstituted or substituted by one, two or three independent R 13 .
  • 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 to C 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.
  • Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) Base) and hexyl.
  • the alkyl group may also be part of another group, such as a C 1 to C 6 alkoxy group.
  • Alkylene refers to a divalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms and in some embodiments 1 to 6 carbon atoms.
  • (C a -C b ) alkylene group refers to an alkylene group having a to b carbon atoms.
  • Alkylene groups include branched and straight chain hydrocarbyl groups.
  • (C 1 -C 6 )alkylene is meant to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene and the like.
  • the term "propylene” can be exemplified by the following structure:
  • the term “dimethyl butylene” can be exemplified by any of the following structures, for example:
  • the term "(C 1 -C 6 )alkylene” is intended to include such branched hydrocarbon groups, such as cyclopropylmethylene, which can be exemplified by the following structure:
  • 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-Cb)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.
  • Alkenylene refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond, and two unsaturated chemical valences.
  • 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 -C 6 )alkynyl is meant to include ethynyl, propynyl, and the like.
  • Alkynylene refers to a divalent hydrocarbon chain having 2 to 10 carbon atoms and at least one triple bond.
  • 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.
  • a C 1-4 halogen alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which a hydrogen atom is replaced by one or more halogen 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 stereoisomers, with a certain amount of acid or base as appropriate (e.g. 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 compounds provided by the present invention have good IL-17A inhibitory activity, and can be used to prepare IL-17A inhibitors and prevent and/or treat IL-17A-mediated diseases (such as inflammation, autoimmune diseases, infectious diseases).
  • IL-17A-mediated diseases such as inflammation, autoimmune diseases, infectious diseases.
  • Drugs for diseases, cancer, precancerous syndrome, etc. provide a new medicinal possibility for clinical treatment of diseases related to abnormal IL-17A activity.
  • the raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.
  • 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 magnetic instrument, 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
  • 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.
  • Supercritical fluid chromatography SFC
  • reaction temperature is room temperature.
  • M is mole per liter. Room temperature is the most suitable reaction temperature, which is 20 to 30°C.
  • the (2S, 3S) configuration has a specific rotation of 78.18° (25°C, 0.089g/100ml methanol solution, wavelength 589nm), and the (2R, 3R) configuration has a specific rotation of -72.60° (25°C, 0.098g) /100ml methanol solution, wavelength 589nm).
  • the diastereoisomer mixture intermediate 2-4 (a mixture of four chiral isomers) of Example 2 was separated and purified by silica gel column chromatography (petroleum ether/methyl tert-butyl ether 100:1) to obtain the intermediate Enantiomers of form 2-4 (a mixture of enantiomers of 2-4a and 2-4b, a mixture of (2S, 3S) and (2R, 3R) configurations, the enantiomer on TLC plate chromatography
  • the mixture is less polar
  • take the enantiomer (1.7g, 4.62 mmol)
  • dissolve it in 20ml of dry DCM under nitrogen protection cool the internal temperature to -40°C, add ZnEt 2 (1M tetrahydrofuran solution) , 27.73mL), stir the reaction at -30°C for 1 hour and then add diiodomethane (9.90g, 36.97mmol) dropwise.
  • Intermediate 3-2 (a mixture of enantiomers) can be separated and prepared by SFC chiral column to obtain single chiral isomers 3-3a (2R, 3R) and 3-3b (2S, 3S).
  • the retention time of (2S, 3S) configuration is 5.904 min, and the retention time of (2R, 3R) configuration is 3.306 min ( AD-3150*3mm, 5um, isocratic 5% ethanol 1mL/min).
  • the specific rotation of the (2S, 3S) configuration is 48.755° (25°C, 0.1g/100ml in Methanol, wavelength 589nm), and the specific rotation of the (2R, 3R) configuration is -40.695° (25°C, 0.1g/100ml in Methanol, wavelength 589nm).
  • Example 1-1 it was prepared from 2-chloro-6-fluoro-benzaldehyde and ethyl nitroacetate.
  • Example 1-1 it was prepared from 2-chloro-3-fluoro-benzaldehyde and ethyl nitroacetate.
  • 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.
  • Example 7 Refer to the method of Example 7, obtained by condensing Boc-D-(3,3-difluorocyclobutyl)glycine with methylamine hydrochloride and then removing Boc, MS m/z: 179[M+1] + .
  • Example 7 Refer to the method of Example 7, which was obtained by condensation of Boc-D-cyclobutylglycine and methylamine hydrochloride, followed by de-Boc, MS m/z: 143[M+1] + .
  • Example 7 Refer to the method in Example 7, obtained by condensation of Boc-D-cyclobutylglycine and cyclopropylamine, followed by de-Boc, MS m/z: 169[M+1] + .
  • Example 7 Refer to the method in Example 7, obtained by condensation of Boc-D-cyclobutylglycine and cyclopropylmethylamine, followed by de-Boc, MS m/z: 183[M+1] + .
  • Example 7 Refer to the method in Example 7, obtained by condensing Boc-D-cyclobutylglycine and 1-aminomethyl-1-cyclopropanol, followed by de-Boc, MS m/z: 199[M+1] + .
  • Example 7 Refer to the method of Example 7, which was obtained by condensing Boc-D-cyclobutylglycine with (1-methoxycyclopropyl)methylamine, followed by de-Boc, MS m/z: 213[M+1] + .
  • Example 7 Refer to the method of Example 7, obtained by condensing Boc-D-cyclobutylglycine and (1-fluorocyclopropyl)methylamine, followed by de-Boc, MS m/z: 201[M+1] + .
  • Example 7 Refer to the method in Example 7, which was obtained by condensing Boc-D-cyclobutylglycine with 2,2-difluoroethylamine and then removing Boc, MS m/z: 193[M+1] + .
  • Example 7 Refer to the method in Example 7, which was obtained by the condensation of Boc-D-cyclobutylglycine and 2-fluoroethylamine, followed by Boc removal, MS m/z: 175[M+1] + .
  • Example 7 Refer to the method of Example 7, which was obtained by condensing Boc-D-cyclopentylglycine with ethylamine hydrochloride and then removing Boc, MS m/z: 171[M+1] + .
  • Example 7 Refer to the method of Example 7, obtained by condensing Boc-D-(tetrahydrofuran-2-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 173[M+1] + .
  • Example 7 Refer to the method in Example 7, obtained by condensing Boc-D-(tetrahydropyran-4-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 187[M+1] + .
  • Example 7 Refer to the method in Example 7, which was obtained by condensing Boc-D-cyclohexylglycine with ethylamine hydrochloride and then removing Boc, MS m/z: 285[M+1] + .
  • Example 7 Refer to the method in Example 7, obtained by condensing Boc-D-cyclohexylglycine and cis-2-fluoro-cyclopropylamine, followed by de-Boc, MS m/z: 187[M+1] + .
  • Example 7 Refer to the method of Example 7, obtained by condensation of Boc-D-cyclohexylglycine and trans-2-fluoro-cyclopropylamine, followed by de-Boc, MS m/z: 187[M+1] + .
  • Example 7 Refer to the method in Example 7, which was obtained by condensing Boc-D-(3-fluorocyclobutyl)glycine with ethylamine hydrochloride and then removing Boc, MS m/z: 175[M+1] + .
  • Example 7 Refer to the method of Example 7, obtained by condensing Boc-D-(3,3-difluorocyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 193[M+1] + .
  • Example 7 Refer to the method of Example 7, obtained by condensing Boc-D-(3-methylcyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 171[M+1] + .
  • Example 7 Refer to the method of Example 7, obtained by condensing Boc-D-(3-methoxycyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 187[M+1] + .
  • Example 7 Refer to the method of Example 7, obtained by condensing Boc-D-(1-methylcyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 171[M+1] + .
  • Example 7 Refer to the method in Example 7, obtained by condensing Boc-(S)-(1-fluorocyclobutyl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 175[M+1] + .
  • Example 7 Refer to the method of Example 7, obtained by condensing Boc-D-(3-methyl-3-fluorocyclobutyl)glycine with ethylamine hydrochloride and then removing Boc, MS m/z: 189[M+1] + .
  • Example 7 Refer to the method of Example 7, obtained by condensing Boc-D-(spiro[2,3]hexane-5-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 183[M+1] + .
  • Example 7 Refer to the method of Example 7, obtained by condensing Boc-D-(bicyclo[1.1.1]pentan-1-yl)glycine with ethylamine hydrochloride and then removing Boc, MS m/z:169[M+1] + .
  • Example 7 With reference to the method in Example 7, it was obtained by condensing Boc-D-(3-(methyl)bicyclo[1.1.1]pentan-1-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 183[M+1] + .
  • Example 7 Refer to the method in Example 7, obtained by condensing Boc-D-(3-(fluoro)bicyclo[1.1.1]pentan-1-yl)glycine with ethylamine hydrochloride, followed by de-Boc, MS m/z: 187 [M+1] + .
  • the single-configuration intermediate 1-5b (614.57 mg, 1.80 mmol, SFC chiral resolution to obtain a single chiral isomer) in step 5 of Example 1, EDCI (412.08 mg, 2.16 mmol), DIPEA (697.08 mg) , 5.39mmol, 939.46uL), HOAt (293.42mg, 2.16mmol) and the single-configuration intermediate 6-6b (0.45g, 1.80mmol) in step 6 of Example 6 were added to DCM (10mL), and reacted at room temperature for 3 After hours, quench with water, remove most of the organic solvents under reduced pressure, extract with ethyl acetate (20ml*3), combine the organic phases, wash with saturated ammonium chloride and saturated brine, dry with anhydrous sodium sulfate, and spin-dry under reduced pressure.
  • HBTU 134.35mg, 353.56 ⁇ mol
  • DIPEA 114.23mg, 883.89 ⁇ mol, 153.95uL
  • 1-methyl-1H-pyrazole-5-carboxylic acid (112.01mg, 888.21 ⁇ mol) in DCM (5mL )
  • the intermediate 34-4 160mg, 294.63 ⁇ mol
  • step 3 react at room temperature for 2h, quench with water, extract with ethyl acetate (20ml*3), combine the organic phases, and then respectively saturated with ammonium chloride Wash with saturated brine, dry with anhydrous sodium sulfate, and spin dry under reduced pressure.
  • HBTU 357.2mg, 942.5 ⁇ mol
  • DIPEA 146mg, 1131 ⁇ mol, 187uL
  • step 5 intermediate 34-6 202mg, 376.85 ⁇ mol
  • DCM 5mL
  • Example 7 Intermediate 7-2 (71mg, 452.4 ⁇ mol)
  • react at room temperature for 1h add 10mL of water to quench, remove most of the organic solvents under reduced pressure, extract with ethyl acetate (10ml*3), combine the organic phases, and saturate them with ammonium chloride Wash with saturated brine, dry with anhydrous sodium sulfate, and spin-dry under reduced pressure.
  • step 6 of Example 34 Refer to the method for preparing 34-b in step 6 of Example 34, using intermediate 34-6 as a raw material, and condensing with intermediate 9 of Example 9 to obtain compound 35-b.
  • step 5 intermediate another configuration of 34-6 in the preparation of another configuration 34-a is used as a raw material, and the compound 35-a can be obtained by condensing with the intermediate 9 of Example 9.
  • step 6 of Example 34 Refer to the method for preparing 34-b in step 6 of Example 34, using intermediate 34-6 as a raw material, and condensing with intermediate 10 of Example 10 to obtain compound 36-b. Similarly, the step 5 intermediate (another configuration of 34-6) in the preparation of another configuration 34-a is used as a raw material, and the compound 36-a can be obtained by condensation with the intermediate 10 of Example 10. MS m/z: 688 (M+1) + .
  • step 6 of Example 34 Refer to the method for preparing 34-b in step 6 of Example 34, using intermediate 34-6 as a raw material, and condensing with intermediate 11 of Example 11 to obtain compound 37-b.
  • step 5 intermediate (another configuration of 34-6) in the preparation of another configuration 34-a is used as a raw material, and the compound 37-a can be obtained by condensation with the intermediate 11 of Example 11.
  • step 6 of Example 34 Refer to the method of preparing 34-b in step 6 of Example 34, using intermediate 34-6 as the raw material, and condensing with the intermediate 18 of Example 18 to obtain compound 44-b; similarly, the step of preparing another configuration 34-a 5 Intermediate (another configuration of 34-6) is a raw material, and compound 44-a can be obtained by condensation with Example 18 Intermediate 18, MS m/z: 692(M+1) + .
  • step 6 of Example 34 Refer to the method of preparing 34-b in step 6 of Example 34, using intermediate 34-6 as the raw material, and condensing with the intermediate 22 of Example 22 to obtain compound 48-b; similarly, the step of preparing another configuration 34-a 5 Intermediate (another configuration of 34-6) is a raw material, and compound 48-a can be obtained by condensation with Intermediate 22 of Example 22, MS m/z: 706(M+1) + .
  • step 6 of Example 34 Refer to the method of preparing 34-b in step 6 of Example 34, using intermediate 34-6 as the raw material, and condensing with the intermediate 25 of Example 25 to obtain compound 51-b; similarly, the step of preparing another configuration 34-a 5 Intermediate (another configuration of 34-6) is a raw material, and compound 51-a can be obtained by condensation with Example 25 Intermediate 25, MS m/z: 690(M+1) + .
  • step 6 of Example 34 Refer to the method of preparing 34-b in step 6 of Example 34, using intermediate 34-6 as the raw material, and condensing with the intermediate 26 of Example 26 to obtain compound 52-b; similarly, the step of preparing another configuration 34-a 5 Intermediate (another configuration of 34-6) is a raw material, and compound 52-a can be obtained by condensing with Intermediate 26 of Example 26, MS m/z: 706(M+1) + .
  • step 6 of Example 34 Refer to the method for preparing 34-b in step 6 of Example 34, using intermediate 34-6 as the raw material, and condensing with the intermediate 27 of Example 27 to obtain compound 53-b; similarly, the step of preparing another configuration 34-a 5 Intermediate (the other configuration of 34-6) is the raw material, and the compound 53-a can be obtained by condensing with the intermediate 27 of Example 27, MS m/z: 690(M+1) + .
  • step 6 of Example 34 Refer to the method of preparing 34-b in step 6 of Example 34, using intermediate 34-6 as the raw material, and condensing with the intermediate 28 of Example 28 to obtain compound 54-b; similarly, the step of preparing another configuration 34-a 5 Intermediate (the other configuration of 34-6) is the raw material, and the condensation with the intermediate 28 of Example 28 can give compound 54-a, MS m/z: 694(M+1) + .
  • step 6 of Example 34 Refer to the method of preparing 34-b in step 6 of Example 34, using intermediate 34-6 as the raw material, and condensing with the intermediate 32 of Example 32 to obtain compound 58-b; similarly, the step of preparing another configuration 34-a 5 Intermediate (another configuration of 34-6) is a raw material, and compound 58-a can be obtained by condensing with the intermediate 32 of Example 32, MS m/z: 702(M+1) + .
  • step 6 of Example 34 Refer to the method of preparing 34-b in step 6 of Example 34, using intermediate 34-6 as the raw material, and condensing with the intermediate 33 of Example 33 to obtain compound 59-b; similarly, the step of preparing another configuration 34-a 5 Intermediate (another configuration of 34-6) is a raw material, and compound 59-a can be obtained by condensation with the intermediate 33 of Example 33, MS m/z: 706(M+1) + .
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 9 Intermediate 9, and then chiral resolution by SFC to prepare compound 60-a, 60-b ,60-c,60-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 7 Intermediate 7-2, and then chiral resolution by SFC to prepare compound 61-a,61 -b,61-c,61-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 10 Intermediate 10, and then chiral resolution by SFC to prepare compound 62-a, 62-b ,62-c,62-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 11 Intermediate 11, and then chiral resolution by SFC to prepare compound 63-a, 63-b ,63-c,63-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 12 Intermediate 12, and then chiral resolution by SFC to prepare compound 64-a, 64-b ,64-c,64-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 13 Intermediate 13, and then chiral resolution by SFC to prepare compound 65-a, 65-b ,65-c,65-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 14 Intermediate 14, and then chiral resolution by SFC to prepare compound 66-a, 66-b ,66-c,66-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 15 Intermediate 15, and then chiral resolution by SFC to prepare compound 67-a, 67-b ,67-c,67-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 16 Intermediate 16, and then chiral resolution by SFC to prepare compound 68-a, 68-b ,68-c,68-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 17 Intermediate 17, and then chiral resolution by SFC to prepare compound 69-a, 69-b ,69-c,69-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 18 Intermediate 18, and then chiral resolution by SFC to prepare compound 70-a, 70-b ,70c,70-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 19 Intermediate 19, and then chiral resolution by SFC to prepare compound 71-a, 71-b ,71-c,71-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 20 Intermediate 20, and then chiral resolution by SFC to prepare compound 72-a, 72-b ,72-c,72-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 21 Intermediate 21, and then chiral resolution by SFC to prepare compound 73-a, 73-b ,73-c,73-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 22 Intermediate 22, and then chiral resolution by SFC to prepare compound 74-a, 74-b ,74-c,74-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 23 Intermediate 23, and then chiral resolution by SFC to prepare compound 75-a, 75b, 75 -c,75-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 24 Intermediate 24, and then chiral resolution by SFC to prepare compound 76-a, 76b, 76 -c,76-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 25 Intermediate 25, and then chiral resolution by SFC to prepare compound 77-a, 77b, 77 -c,77-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 26 Intermediate 26, and then chiral resolution by SFC to prepare compound 78-a, 78b, 78 -c,78-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 27 Intermediate 27, and then chiral resolution by SFC to prepare compound 79-a, 79b, 79 -c,79-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 28 Intermediate 28, and then chiral resolution by SFC to prepare compound 80-a, 80-b ,80-c,80-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 29 Intermediate 29, and then chiral resolution by SFC to prepare compound 81-a, 81-b ,81-c,81-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 30 Intermediate 30, and then chiral resolution by SFC to prepare compound 82-a, 82-b ,82-c,82-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 31 of Example 31, and then chiral resolution by SFC to prepare compound 83-a, 83-b ,83-c,83-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 32 Intermediate 32, and then chiral resolution by SFC to prepare compound 84-a, 84-b ,84-c,84-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 33 Intermediate 33, and then chiral resolution by SFC to prepare compound 85-a, 85-b ,85-c,85-d.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 9 of Example 9 to obtain compound 86-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 86-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 7 Intermediate 7-2 to obtain compound 87-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 10 Intermediate 10 to obtain compound 88-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 88-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 11 of Example 11 to obtain compound 89-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection. , Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing and condensing compound 89-a. MS m/z: 714(M+1) + .
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 12 of Example 12 to obtain compound 90-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 13 Intermediate 13 to obtain compound 91-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection. , Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing and condensing to obtain compound 91-a. MS m/z: 744(M+1) + .
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 14 Intermediate 14 to obtain compound 92-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 92-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 15 Intermediate 15 to obtain compound 93-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 93-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 16 of Example 16 to obtain compound 94-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection. , Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing and condensing to obtain compound 94-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 17 Intermediate 17 to obtain compound 95-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection. , Introduce 1-methyl-1H-pyrazole-5-acyl group, hydrolyze and condense to obtain compound 95-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 18 Intermediate 18 to obtain compound 96-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 96-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 19 Intermediate 19 to obtain compound 97-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection. , Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing and condensing compound 97-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 20 of Example 20 to obtain compound 98-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection. , Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing and condensing compound 98-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 21 of Example 21 to obtain compound 99-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection. , Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing and condensing to obtain compound 99-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 22 of Example 22 to obtain compound 100-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 100-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 23 Intermediate 23 to obtain compound 101-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 101-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 24 of Example 24 to obtain compound 102-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 102-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 25 of Example 25 to obtain compound 103-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection. , Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing and condensing to obtain compound 103-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 26 of Example 26 to obtain compound 104-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 104-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 27 Intermediate 27 to obtain compound 105-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 105-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 28 Intermediate 28 to obtain compound 106-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 106-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 29 Intermediate 29 to obtain compound 107-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 107-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 30 Intermediate 30 to obtain compound 108-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 108-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 31 of Example 31 to obtain compound 109-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 109-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 32 of Example 32 to obtain compound 110-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-methyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 110-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 33 of Example 33 to obtain compound 111-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection. , Introducing 1-methyl-1H-pyrazole-5-acyl group, hydrolyzing and condensing to obtain compound 111-a.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 9 Intermediate 9, and then chiral resolution by SFC to prepare compound 112-a, 112-b ,112-c,112-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 7 Intermediate 7-2, and then chiral resolution by SFC to prepare compound 113-a,113 -b,113-c,113-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 10 Intermediate 10, and then chiral resolution by SFC to prepare compounds 114-a, 114-b ,114-c,114-d.
  • the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 11 Intermediate 11, and then chiral resolution by SFC to prepare compounds 115-a, 115-b ,115-c,115-d.
  • the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 12 of Example 12, and then chiral resolution by SFC to prepare compounds 116-a, 116-b ,116-c,116-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 13 Intermediate 13, and then chiral resolution by SFC to prepare compounds 117-a, 117-b ,117-c,117-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 14 Intermediate 14, and then chiral resolution by SFC to prepare compound 118-a, 118-b ,118-c,118-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 15 Intermediate 15, and then chiral resolution by SFC to prepare compound 119-a, 119-b ,119-c,119-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 16 Intermediate 16, and then chiral resolution by SFC to prepare compounds 120-a, 120-b ,120-c,120-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 17 Intermediate 17, and then chiral resolution by SFC to prepare compounds 121-a, 121-b ,121-c,121-d.
  • Example 122 Preparation of compound 122-a, 122-b, 122-c, 122-d, 122-e, 122-f, 122-g, 122-h
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 18 Intermediate 18, and then chiral resolution by SFC to prepare compound 122-a, 122-b ,122-c,122-d.
  • the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 19 Intermediate 19, and then chiral resolution by SFC to prepare compound 123-a, 123-b ,123-c,123-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 20 Intermediate 20, and then chiral resolution by SFC to prepare compound 124-a, 124-b ,124-c,124-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 21 Intermediate 21, and then chiral resolution by SFC to prepare compounds 125-a, 125-b ,125-c,125-d.
  • the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 22 Intermediate 22, and then chiral resolution by SFC to prepare compound 126-a, 126-b ,126-c,126-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 23 Intermediate 23, and then chiral resolution by SFC to prepare compound 127-a, 127-b ,127-c,127-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 24 Intermediate 24, and then chiral resolution by SFC to prepare compound 128-a, 128-b ,128-c,128-d.
  • the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 25 Intermediate 25, and then chiral resolution by SFC to prepare compound 129-a, 129-b ,129-c,129-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 26 Intermediate 26, and then chiral resolution by SFC to prepare compound 130-a, 130-b ,130-c,130-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 27 Intermediate 27, and then chiral resolution by SFC to prepare compound 131-a, 131-b ,131-c,131-d.
  • Example 132 Preparation of compound 132-a, 132-b, 132-c, 132-d, 132-e, 132-f, 132-g, 132-h
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 28 Intermediate 28, and then chiral resolution by SFC to prepare compound 132-a, 132-b ,132-c,132-d.
  • Example 133 Preparation of compound 133-a, 133-b, 133-c, 133-d, 133-e, 133-f, 133-g, 133-h
  • the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 29 Intermediate 29, and then chiral resolution by SFC to prepare compound 133-a, 133-b ,133-c,133-d.
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 30 Intermediate 30, and then chiral resolution by SFC to prepare compound 134-a, 134-b ,134-c,134-d.
  • the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 31 of Example 31, and then chiral resolution by SFC to prepare compounds 135-a, 135-b ,135-c,135-d.
  • Example 136 Preparation of compound 136-a, 136-b, 136-c, 136-d, 136-e, 136-f, 136-g, 136-h
  • the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 32 intermediate 32, and then chiral resolution by SFC to prepare compound 136-a, 136-b ,136-c,136-d.
  • Example 137 Preparation of compound 137-a, 137-b, 137-c, 137-d, 137-e, 137-f, 137-g, 137-h
  • Example 34 Referring to the method of steps 1 to 6 in Example 34, the intermediate 4-5 in step 5 in Example 4 and the step 66-6b in Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 33 Intermediate 33, and then chiral resolution by SFC to prepare compounds 137-a, 137-b ,137-c,137-d.
  • Example 138 Preparation of compound 138-a, 138-b, 138-c, 138-d, 138-e, 138-f, 138-g, 138-h
  • Example 9 the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 9 Intermediate 9, and then chiral resolution by SFC to prepare compound 138-a, 138-b ,138-c,138-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiralized by SFC to prepare compound 138-e, 138-f, 138-g, 138-h.
  • Example 139 Preparation of compound 139-a, 139-b, 139-c, 139-d, 139-e, 139-f, 139-g, 139-h
  • Example 34 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 7 Intermediate 7-2, and then chiral resolution by SFC to prepare compound 139-a,139 -b,139-c,139-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiralized by SFC to prepare compound 139-e,139-f,139-g,139-h.
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 10 Intermediate 10, and then chiral resolution by SFC to prepare compound 140-a, 140-b ,140-c,140-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 140-e, 140-f, 140-g, 140-h.
  • Example 141 Preparation of compound 141-a, 141-b, 141-c, 141-d, 141-e, 141-f, 141-g, 141-h
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 11 Intermediate 11, and then chiral resolution by SFC to prepare compound 141-a, 141-b ,141-c,141-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 141-e, 141-f, 141-g, 141-h.
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 12 of Example 12, and then chiral resolution by SFC to prepare compound 142-a, 142-b ,142-c,142-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 142-e,142-f,142-g,142-h.
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 13 Intermediate 13, and then chiral resolution by SFC to prepare compound 143-a, 143-b ,143-c,143-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl group was hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 143-e,143-f,143-g,143-h.
  • Example 34 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 14 Intermediate 14, and then chiral resolution by SFC to prepare compound 144-a, 144-b ,144-c,144-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 144-e, 144-f, 144-g, 144-h.
  • Example 145 Preparation of compound 145-a, 145-b, 145-c, 145-d, 145-e, 145-f, 145-g, 145-h
  • Example 15 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 15 Intermediate 15, and then chiral resolution by SFC to prepare compound 145-a, 145-b ,145-c,145-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl group, hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 145-e, 145-f, 145-g, 145-h.
  • Example 34 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 16 Intermediate 16, and then chiral resolution by SFC to prepare compound 146-a, 146-b ,146-c,146-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiralized by SFC to prepare compound 146-e,146-f,146-g,146-h. MS m/z: 712 (M+1) + .
  • Example 34 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 17 Intermediate 17, and then chiral resolution by SFC to prepare compound 147-a, 147-b ,147-c,147-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl group, hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 147-e, 147-f, 147-g, 147-h.
  • Example 34 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 18 Intermediate 18, and then chiral resolution by SFC to prepare compound 148-a, 148-b ,148-c,148-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl group was hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 148-e, 148-f, 148-g, 148-h.
  • Example 19 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 19 Intermediate 19, then chiral resolution by SFC to prepare compound 149-a, 149-b ,149-c,149-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl group was hydrolyzed, condensed, and then chiralized by SFC to prepare compound 149-e, 149-f, 149-g, 149-h.
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 20 of Example 20, and then chiral resolution by SFC to prepare compounds 150-a, 150-b ,150-c,150-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 150-e, 150-f, 150-g, 150-h.
  • Example 151 Preparation of compound 151-a, 151-b, 151-c, 151-d, 151-e, 151-f, 151-g, 151-h
  • Example 34 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 21 Intermediate 21, and then chiral resolution by SFC to prepare compound 151-1a, 151-b ,151-c,151-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl group was hydrolyzed, condensed, and then chiralized by SFC to prepare compound 151-1, 151-5, 151-1, 151-3.
  • Example 152 Preparation of compound 152-a, 152-b, 152-c, 152-d, 152-e, 152-f, 152-g, 152-h
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with the intermediate 22 of Example 22, and then chiral resolution by SFC to prepare compound 152-a, 152-b ,152-c,152-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl group, hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 152-e, 152-f, 152-g, 152-h.
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 23 Intermediate 23, and then chiral resolution by SFC to prepare compound 153-a, 153-b ,153-c,153-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl group was hydrolyzed, condensed, and then chiralized by SFC to prepare compound 153-e, 153-f, 153-g, 153-h.
  • Example 34 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 24 Intermediate 24, and then chiral resolution by SFC to prepare compound 154-a, 154-b ,154-c,154-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 154-e, 154-f, 154-g, 154-h.
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 25 Intermediate 25, and then chiral resolution by SFC to prepare compound 155-a, 155-b ,155-c,155-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiralized by SFC to prepare compound 155-e, 155-f, 155-g, 155-h.
  • Example 34 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 26 Intermediate 26, and then chiral resolution by SFC to prepare compound 156-a, 156-b ,156-c,156-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiralized by SFC to prepare compound 156-e, 156-f, 156-g, 156-h.
  • Example 34 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 27 Intermediate 27, and then chiral resolution by SFC to prepare compound 157-a, 157-b ,157-c,157-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl group was hydrolyzed, condensed, and then chiral resolution by SFC to prepare compound 157-e,157-f,157-g,157-h. MS m/z: 708 (M+1) + .
  • Example 158 Preparation of compound 158-a, 158-b, 158-c, 158-d, 158-e, 158-f, 158-g, 158-h
  • Example 34 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 28 Intermediate 28, and then chiral resolution by SFC to prepare compound 158-a, 158-b ,158-c,158-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl group was hydrolyzed, condensed, and then chiralized by SFC to prepare compound 158-e,158-f,158-g,158-h. MS m/z: 712 (M+1) + .
  • Example 159 Preparation of compound 159-a, 159-b, 159-c, 159-d, 159-e, 159-f, 159-g, 159-h
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 29 Intermediate 29, and then chiral resolution by SFC to prepare compound 159-a, 159-b ,159-c,159-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiralized by SFC to prepare compound 159-e, 159-f, 159-g, 159-h.
  • Example 34 Referring to the method of steps 1 to 6 of Example 34, the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 30 Intermediate 30, and then chiral resolution by SFC to prepare compound 160-a, 160-b ,160-c,160-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiralized by SFC to prepare compound 160-e, 160-f, 160-g, 160-h.
  • Example 161 Preparation of compound 161-a, 161-b, 161-c, 161-d, 161-e, 161-f, 161-g, 161-h
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 31 Intermediate 31, and then chiral resolution by SFC to prepare compound 161-1a, 161-b ,161-c,161-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl group was hydrolyzed, condensed, and then chiral resolution by SFC was used to prepare compound 161-e, 161-f, 161-g, and 161-h.
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 32 Intermediate 32, and then chiral resolution by SFC to prepare compound 162-a, 162-b ,162-c,162-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiralized by SFC to prepare compound 162-e,162-f,162-g,162-h.
  • the intermediate 5-5 of step 5 in Example 5 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-methyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 33 Intermediate 33, and then chiral resolution by SFC to prepare compound 163-a, 163-b ,163-c,163-d.
  • step 5 in Example 5 and the 6-6a of step 6 in Example 6 are condensed, ring closed, deprotected, and introduced 1-Methyl-1H-pyrazole-5-acyl, hydrolyzed, condensed, and then chiralized by SFC to prepare compound 163-e,163-f,163-g,163-h.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 7 intermediate 7-2 to obtain compound 164-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce 1-ethyl-1H-pyrazole-5-acyl group hydrolyze and condense to obtain compound 164-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with Example 7 Intermediate 7-2 to obtain compound 165-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce propionyl group hydrolyze and condense to obtain compound 165-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of isobutyryl group, hydrolysis, and finally condensation with Example 7 Intermediate 7-2 to obtain compound 166-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection. , Introduction of isobutyryl group, hydrolysis and condensation to obtain compound 166-a. MS m/z: 650 (M+1) + .
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with Example 7 Intermediate 7-2 to obtain compound 167-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with the intermediate 7-2 of Example 7 to obtain compound 168-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of methylaminocarbonyl, hydrolysis, and finally condensation with the intermediate 7-2 of Example 7 to obtain compound 169-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of N-methyl-N'-ethylcarbonyl, hydrolysis, and finally condensation with the intermediate 7-2 of Example 7 to obtain compound 170-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 were condensed, Ring closure, deprotection, introduction of N-ethylcarbonyl, hydrolysis, and finally condensation with Example 7 Intermediate 7-2 to obtain compound 171-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 were used for condensation, ring closure, and deprotection.
  • Introduce N-ethylcarbonyl hydrolyze and condense to obtain compound 171-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of N,N-diethylcarbonyl, hydrolysis, and finally condensation with the intermediate 7-2 of Example 7 to obtain compound 172-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection.
  • Introduce N,N-diethylcarbonyl hydrolyze and condense to obtain compound 172-a.
  • the intermediate 3-3b of step 3 in Example 3 and step 66-6b of Example 6 (prepared by SFC chiral resolution to obtain a single configuration) were condensed, Ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally condensation with Example 7 Intermediate 7-2 to obtain compound 173-b.
  • the intermediate 3-3b of step 3 in Example 3 and the 6-6a of step 6 in Example 6 (another single configuration prepared by SFC chiral resolution) were used for condensation, ring closure, and deprotection. , Introducing N-methyl-N'-cyclopropylcarbonyl, hydrolyzing and condensing to obtain compound 173-a.
  • the intermediate 1-5 (S, S enantiomer obtained by SFC chiral resolution) of step 5 in Example 1 and the intermediate of step 6 in Example 6 6-6b (SFC chiral resolution to obtain a single configuration) reaction, after condensation, ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with Example 7 Intermediate 7-2 to obtain compound 175-b.
  • the intermediate 1-5 (S, S enantiomer obtained by SFC chiral resolution) of step 5 in Example 1 and the intermediate of step 6 in Example 6 6-6b (SFC chiral resolution to obtain a single configuration) reaction, through condensation, ring closure, deprotection, introduction of isopropionyl group, hydrolysis, and finally condensation with Example 7 Intermediate 7-2 to obtain compound 176-b .
  • the intermediate 1-5 (S, S enantiomer obtained by SFC chiral resolution) of step 5 in Example 1 and the intermediate of step 6 in Example 6 6-6b (SFC chiral resolution to obtain a single configuration) reaction, after condensation, ring closure, deprotection, introduction of pyrrolidinyl carbonyl, hydrolysis, and finally condensation with Example 7 Intermediate 7-2 to obtain compound 177- b.
  • the intermediate 1-5 (S, S enantiomer obtained by SFC chiral resolution) in step 5 in Example 1 and the intermediate in step 6 in Example 6 6-6b (SFC chiral resolution to obtain a single configuration) reaction, through condensation, ring closure, deprotection, introduction of methylamine carbonyl, hydrolysis, and finally condensation with Example 7 Intermediate 7-2 to obtain compound 179-b .
  • the intermediate 1-5 (S, S enantiomer obtained by SFC chiral resolution) of step 5 in Example 1 and the intermediate of step 6 in Example 6 6-6b (SFC chiral resolution to obtain a single configuration) reaction, through condensation, ring closure, deprotection, introduction of ethylaminocarbonyl, hydrolysis, and finally condensation with Example 7 Intermediate 7-2 to obtain compound 181-b .
  • the intermediate 1-5 (S, S enantiomer obtained by SFC chiral resolution) of step 5 in Example 1 and the intermediate of step 6 in Example 6 6-6b (SFC chiral resolution to obtain a single configuration) reaction, after condensation, ring closure, deprotection, introduction of N-methyl-N'-cyclopropylcarbonyl, hydrolysis, and finally the intermediate of Example 7 7-2 condensation gives compound 183-b.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of 1-ethyl-1H-pyrazole-5-acyl group, hydrolysis, and finally condensation with Example 7 Intermediate 7-2, and then chiral resolution by SFC to prepare compound 184-a,184 -b,184-c,184-d.
  • step 6 in Example 6 using 6-6a (prepared by SFC chiral resolution to obtain a single configuration) of step 6 in Example 6, after condensation, ring closure, and deprotection, 1-ethyl-1H-pyrazole-5-acyl group was introduced , Hydrolysis, condensation, and then chiral resolution by SFC to prepare compound 184-e, 184-f, 184-g, 184-h. MS m/z: 708 (M+1) + .
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of propionyl group, hydrolysis, and finally condensation with Example 7 Intermediate 7-2, and then chiral resolution by SFC to prepare compound 185-a, 185-b, 185-c, 185-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of isopropionyl group, hydrolysis, and finally condensation with Example 7 Intermediate 7-2, and then chiral resolution by SFC to prepare compound 186-a, 186-b, 186-c, 186-d .
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of N-pyrrolidinylcarbonyl, hydrolysis, and finally condensation with Example 7 Intermediate 7-2, and then chiral resolution by SFC to prepare compound 187-a,187-b,187-c, 187-d.
  • the intermediate 2-6 in step 5 in Example 2 and step 66-6b in Example 6 were condensed, Ring closure, deprotection, introduction of N,N-dimethylcarbonyl, hydrolysis, and finally condensation with the intermediate 7-2 of Example 7, and then chiral resolution by SFC to prepare compound 188-a,188-b,188- c,188-d.

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Abstract

本发明公开了一种免疫调节剂，具体涉及一类式I所示的化合物、或其立体异构体、或其药学上可接受的盐。实验证明，该化合物具有良好的IL-17A抑制活性，可以用来制备IL-17A抑制剂以及预防和/或治疗IL-17A介导的疾病(比如炎症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征等)的药物，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
本发明属于制药领域，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，但是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水平上调可能导致多种许多疾病，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)。
研究发现，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，可以降低自身免疫性脑脊髓炎的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。
尽管目前已经存在多种IL-17A抗体，但很少有关于具有口服生物利用度的IL-17小分子特异性抑制剂的报道。考虑到产生抗体的成本较高以及给药途径的限制，开发新的IL-17A小分子抑制剂对研发治疗IL-17A介导的疾病的药物具有非常重要的意义。
发明内容
本发明的目的是提供一种新的化合物及其在制备IL-17A抑制剂、制备治疗IL-17A介导的疾病的药物中的用途。
本发明提供了式I所示的化合物、或其立体异构体、或其药学上可接受 的盐：
Figure PCTCN2020107845-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、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)；
R 3、R 4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)、-O(C 1～10烷基)、-O(C 0～4亚烷基)(3～10元环烷基)、-O(C 0～4亚烷基)(3～10元杂环烷基)；或者，其中烷基、环烷基、杂环烷基进一步被一个、两个或三个R 31取代；
或者R 3、R 4相连形成3～10元环烷基、3～10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R 31取代；
每个R 31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)、-O(C 0～4亚烷基)(3～10元环烷基)、-O(C 0～4亚烷基)(3～10元杂环烷基)；
A环选自3～10元环烷基、3～10元杂环烷基、5～10元芳环、5～10元芳杂环；或者，其中环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R A1取代；
每个R A1分别独立选自卤素、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)；或者，其中环烷基、杂环烷基、芳环、芳杂环进一步被一个、两 个或三个R A4取代；
每个R A4分别独立选自卤素、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；
R A2、R A3分别独立选自氢、-C 1～10烷基；
X 1选自CR x1或N；
X 2选自NR x2、O、S或-(CR x3＝CR x4)-；
R x1、R x3、R x4分别独立选自氢、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)；
R x2选自氢、-C 1～10烷基、-C(O)(C 1～10烷基)；
L 1选自-C 1～10亚烷基-；
R 5选自-C 1～10烷基、卤素取代的-C 1～10烷基；
R 6选自氢、-C 1～10烷基、卤素取代的-C 1～10烷基；
L 2选自-C 0～4亚烷基-C(O)NR L21-、-C 0～4亚烷基-NR L21C(O)-、-C 0～4亚烷基-S(O)NR L21-、-C 0～4亚烷基-S(O) 2NR L21-、-C 0～4亚烷基-NR L21S(O)-、-C 0～4亚烷基-NR L21S(O) 2-、-C 0～4亚烷基-P(O)(OH)NR L21-、-C 0～4亚烷基-NR L21P(O)(OH)-、-C 0～4亚烷基-C(O)-、-C 0～4亚烷基-NR L21-；
R L21选自氢、-C 1～10烷基；
R选自-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)、-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)、
Figure PCTCN2020107845-appb-000002
其中C环选自3～10元环烷基、3～10元杂环烷基、5～10元芳环、5～10元芳杂环；或者，其中亚烷基、环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环进一步被被一个、两个或三个R d取代；
R a、R a’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)、-O(C 1～10烷基)、-O(C 0～4亚烷基)(3～10元环烷基)、-O(C 0～4亚烷基)(3～10元杂环烷基)；或者，其中烷基、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 a1取代；
或者R a、R a’相连形成3～10元环烷基、3～10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、-OH、-O(C 1～10烷基)；
R b、R c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-(5～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；或者，其中烷基、环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R b1取代；
或者R a、R b相连形成3～10元杂环烷基、5～10元芳杂环、5～12元螺杂环、5～12元桥杂环；或者，其中杂环烷基、芳杂环、螺杂环、桥杂环进一步被一个、两个或三个R d取代；
每个R b1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)；
每个R d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 d1、-C 0～4亚烷基-OC(O)R d1、-C 0～4亚烷基-C(O)R d1、-C 0～4亚烷基-C(O)OR d1、-C 0～4亚烷基-C(O)NR d1R d2、-C 0～4亚烷基-NR d1R d2、-C 0～4亚烷基-NR d1C(O)R d2；
R d1、R d2分别独立选自氢、-C 1～10烷基、3～10元环烷基、3～10元杂环烷基。
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、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)；
R 3、R 4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)、-O(C 1～6烷基)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；或者，其中烷基、环烷基、杂环烷基进一步被一个、两个或三个R 31取代；
或者R 3、R 4相连形成3～6元环烷基、3～6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R 31取代；
每个R 31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)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；
A环选自5～6元芳环、5～6元芳杂环、3～6元环烷基、3～6元杂环烷基；或者，其中芳环、芳杂环、3～6元环烷基、3～6元杂环烷基进一步被一个、 两个或三个R A1取代；
每个R A1分别独立选自卤素、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)；或者，其中环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R A4取代；
每个R A4分别独立选自卤素、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；
R A2、R A3分别独立选自氢、-C 1～6烷基；
X 1选自CR x1或N；
X 2选自NR x2、O、S或-(CR x3＝CR x4)-；
R x1、R x3、R x4分别独立选自氢、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)；
R x2选自氢、-C 1～6烷基、-C(O)(C 1～6烷基)；
L 1选自-C 1～6亚烷基-；
R 5选自-C 1～6烷基、卤素取代的-C 1～6烷基；
R 6选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
L 2选自-C 0～2亚烷基-C(O)NR L21-、-C 0～2亚烷基-NR L21C(O)-、-C 0～2亚烷基-C(O)-、-C 0～2亚烷基-NR L21-；
R L21选自氢、-C 1～6烷基；
R选自-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)、-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)、
Figure PCTCN2020107845-appb-000003
其中C环选自3～6元环烷基、3～6元杂环烷基、5～6元芳环、5～6元芳杂环；或者，其中亚烷基、环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环进一步被被一个、两个或三个R d取代；
R a、R a’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)、-O(C 1～6烷基)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；或者，其中烷基、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 a1取代；
或者R a、R a’相连形成3～6元环烷基、3～6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、-OH、-O(C 1～6烷基)；
R b、R c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-(5～6元芳环)、-C 0～2亚烷基-(5～6元芳杂环)；或者，其中烷基、环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R b1取代；
或者R a、R b相连形成3～10元杂环烷基、5～10元芳杂环、5～12元螺杂环、5～12元桥杂环；或者，其中杂环烷基、芳杂环、螺杂环、桥杂环进一步被一个、两个或三个R d取代；
每个R b1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)；
每个R d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 d1、-C 0～2亚烷基-OC(O)R d1、-C 0～2亚烷基-C(O)R d1、-C 0～2亚烷基-C(O)OR d1、-C 0～2亚烷基-C(O)NR d1R d2、-C 0～2亚烷基-NR d1R d2、-C 0～2亚烷基-NR d1C(O)R d2；
R d1、R d2分别独立选自氢、-C 1～6烷基、3～6元环烷基、3～6元杂环烷基。
进一步地，
所述式I的化合物如式II所示：
Figure PCTCN2020107845-appb-000004
其中，
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、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)；
R 3、R 4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)、-O(C 1～6烷基)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；或者，其中烷基、环烷基、杂环烷基进一步被一个、两个或三个R 31取代；
或者R 3、R 4相连形成3～6元环烷基、3～6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R 31取代；
每个R 31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)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；
A环选自5～6元芳环、5～6元芳杂环、3～6元环烷基、3～6元杂环烷基；或者，其中芳环、芳杂环、3～6元环烷基、3～6元杂环烷基进一步被一个、两个或三个R A1取代；
每个R A1分别独立选自卤素、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)；或者，其中环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R A4取代；
每个R A4分别独立选自卤素、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；
R A2、R A3分别独立选自氢、-C 1～6烷基；
L 1选自-C 1～6亚烷基-；
R 5选自-C 1～6烷基、卤素取代的-C 1～6烷基；
R 6选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
R a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)、-O(C 1～6烷基)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；或者，其中烷基、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 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、-OH、-O(C 1～6烷基)；
R b、R c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-(5～6元芳环)、 -C 0～2亚烷基-(5～6元芳杂环)；或者，其中烷基、环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R b1取代；
或者R a、R b相连形成3～10元杂环烷基、5～10元芳杂环、5～12元螺杂环、5～12元桥杂环；或者，其中杂环烷基、芳杂环、螺杂环、桥杂环进一步被一个、两个或三个R d取代；
每个R b1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)。
进一步地，
R 1选自-C 1～6烷基、3～6元环烷基、3～6元杂环烷基、5～6元芳环、5～6元芳杂环、-NR 11R 12、-OR 11；或者，其中环烷基、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、3～6元环烷基、3～6元杂环烷基；
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 PCTCN2020107845-appb-000005
卤代或未卤代的C 1～3烷基、卤代或未卤代的C 1～3烷氧基、
Figure PCTCN2020107845-appb-000006
R 13选自甲基、乙基，R 1a、R 1b分别独立选自氢、C 1～2烷基、C 1～2烷氧基、
Figure PCTCN2020107845-appb-000007
优选的，所述C 1～3烷基选自甲基、乙基、
Figure PCTCN2020107845-appb-000008
所述卤素选自氟、氯、溴。
进一步地，
R 3、R 4分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、3～6元环烷基、3～6元杂环烷基、-O(C 1～6烷基)、-O(3～6元环烷基)；或者，其中烷基、环烷基、杂环烷基进一步被一个、两个或三个R 31取代；
每个R 31独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基、-OH、-O(C 1～6烷基)、-O(3～6元环烷基)。
进一步地，
R 3、R 4至少有一个为氢；优选的，R 3、R 4一个为氢，另一个选自卤素或甲基取代的以下基团：C 1～3烷基、C 1～3烷氧基、
Figure PCTCN2020107845-appb-000009
更优选的，所述C 1～3烷基选自甲基、乙基、
Figure PCTCN2020107845-appb-000010
所述卤素选自氟、氯、溴。
进一步地，
A环选自5～6元芳环、5～6元芳杂环、4～6元饱和环烷基；或者，其中 芳环、芳杂环、4～6元饱和环烷基进一步被一个、两个或三个R A1取代；
每个R A1分别独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR A2、-OC(O)R A2、-C(O)R A2、-C(O)OR A2、-C(O)NR A2R A3、-NR A2R A3、-NR A2C(O)R A3、3～6元环烷基、3～6元杂环烷基、5～6元芳环、5～6元芳杂环；或者，其中环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R A4取代；
每个R A4分别独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR A2、-OC(O)R A2、-C(O)R A2、-C(O)OR A2、-C(O)NR A2R A3、-NR A2R A3、-NR A2C(O)R A3；
R A2、R A3分别独立选自氢、-C 1～6烷基；
优选的，A环选自苯环、4～6元饱和环烷基，或者，其中苯环、4～6元饱和环烷基进一步被一个、两个或三个R A1取代，每个R A1分别独立选自卤素，所述卤素优选为氟、氯、溴。
进一步地，
L 1选自-C 1～4亚烷基-；R 5选自-C 1～4烷基；R 6选自氢、-C 1～4烷基。
进一步地，
L 1选自亚甲基、亚乙基、亚正丙基、亚异丙基；R 5选自甲基、乙基、正丙基、异丙基；R 6选自氢、甲基、乙基、正丙基、异丙基。
进一步地，
R a选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、3～6元环烷基、3～6元杂环烷基、6～11元螺环、6～11元螺杂环、5～10元桥环、5～10元桥杂环、-O(C 1～6烷基)、-O(3～6元环烷基)、-O(3～6元杂环烷基)；或者，其中烷基、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 a1取代；优选的，所述螺环为
Figure PCTCN2020107845-appb-000011
所述桥环为
Figure PCTCN2020107845-appb-000012
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、-OH、-O(C 1～6烷基)。
进一步地，
R a选自
Figure PCTCN2020107845-appb-000013
或者，其中
Figure PCTCN2020107845-appb-000014
进一步被一个、两个或三个甲基、卤素、甲氧基取代，所述卤素优选为氟、氯、溴。
进一步地，
R b、R c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，其中烷基、环烷基、杂环烷基进一步被一个、两个或三个R b1取代；
每个R b1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)。
进一步地，
R b、R c至少有一个为氢；优选的，R b、R c一个为氢，另一个为L cR c1；L c选自C 0～2亚烷基，优选为无、亚甲基、亚乙基；R c1选自C 1～2烷基、
Figure PCTCN2020107845-appb-000015
或者，其中C 1～2烷基、
Figure PCTCN2020107845-appb-000016
进一步被一个、两个或三个R b1取代，每个R b1独立选自卤素、羟基、C 1～2烷基、C 1～2烷氧基；所述卤素选自氟、氯、溴。
进一步地，
R a、R b相连形成5～12元螺杂环，进一步地，所述螺杂环为
Figure PCTCN2020107845-appb-000017
进一步地，
R 2为氢。
进一步地，
所述化合物的结构如式III所示：
Figure PCTCN2020107845-appb-000018
其中，R 1如上所述；
R 2为氢；
R 3、R 4如上所述；
A环如上所述；
R 5、R 6、L 1如上所述；
n为0～3的整数，优选为0～1的整数；
R f选自氢、L 0R f1；其中，L 0为C 0～3亚烷基，优选为无或亚甲基；R f1选自氨基、羟基、C 1～3烷基、C 1～3烷氧基、COOCH 3；
R e选自取代或未取代的4～6元饱和环烷基，优选为取代或未取代的
Figure PCTCN2020107845-appb-000019
所述取代基选自卤素、羟基、C 1～3烷基、C 1～3烷氧基，所述卤素优选为氟。
进一步地，所述化合物选自：
Figure PCTCN2020107845-appb-000020
Figure PCTCN2020107845-appb-000021
Figure PCTCN2020107845-appb-000022
Figure PCTCN2020107845-appb-000023
Figure PCTCN2020107845-appb-000024
Figure PCTCN2020107845-appb-000025
Figure PCTCN2020107845-appb-000026
Figure PCTCN2020107845-appb-000027
Figure PCTCN2020107845-appb-000028
Figure PCTCN2020107845-appb-000029
Figure PCTCN2020107845-appb-000030
Figure PCTCN2020107845-appb-000031
Figure PCTCN2020107845-appb-000032
Figure PCTCN2020107845-appb-000033
Figure PCTCN2020107845-appb-000034
Figure PCTCN2020107845-appb-000035
Figure PCTCN2020107845-appb-000036
Figure PCTCN2020107845-appb-000037
Figure PCTCN2020107845-appb-000038
Figure PCTCN2020107845-appb-000039
Figure PCTCN2020107845-appb-000040
Figure PCTCN2020107845-appb-000041
Figure PCTCN2020107845-appb-000042
Figure PCTCN2020107845-appb-000043
本发明还提供了前述化合物、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。
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；优选为类风湿性关节炎、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、哮喘或多发性硬化症。
本发明还提供了前述化合物、或其立体异构体、或其药学上可接受的盐在制备IL-17A抑制剂中的用途。
本发明还提供了一种药物组合物，它是以前述化合物、或其立体异构体、或其药学上可接受的盐为活性成分，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。
本发明的化合物中，
Figure PCTCN2020107845-appb-000044
表示
Figure PCTCN2020107845-appb-000045
或
Figure PCTCN2020107845-appb-000046
或二者任意比例的混合物。
本发明化合物的基团中，“或者，其中环烷基、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。
“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～C 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。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～C 6烷氧基。
“亚烷基”是指具有1至10个碳原子和在一些实施方案中1至6个碳原子的二价饱和脂族烃基。“(C a～C 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，“(C 1～C 6)亚烷基”意在包括亚甲基、亚乙基、亚丙基、2-甲基亚丙基、二甲基亚乙基、亚戊基等等。因此，术语“亚丙基”可以通过下列结构例举：
Figure PCTCN2020107845-appb-000047
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：
Figure PCTCN2020107845-appb-000048
此 外，术语“(C 1～C 6)亚烷基”意在包括此类支链烃基基团，诸如环丙基亚甲基，其可以通过下列结构例举：
Figure PCTCN2020107845-appb-000049
“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 PCTCN2020107845-appb-000050
双环己基和
Figure PCTCN2020107845-appb-000051
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，(Ca-Cb)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。
“亚烯基”是指具有2至10个碳原子、至少一个双键和两个不饱和化学价的烃链。例如，(C 3-C 6)亚烯基包括>C＝CH-CH 2-、-CH-CH＝CH-CH 2-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-C 6)炔基意在包括乙炔基、丙炔基等。
“亚炔基”是指具有2至10个碳原子和至少一个三键的二价烃链。
“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；
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。
实验证明，本发明提供的化合物具有良好的IL-17A抑制活性，可以用来制备IL-17A抑制剂以及预防和/或治疗IL-17A介导的疾病(比如炎症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征等)的药物，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
本发明所用原料与设备均为已知产品，通过购买市售产品所得。
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。超临界流体色谱(SFC)。
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。实施例中无特殊说明，M是摩尔每升。室温为最适宜的反应温度，为20℃～30℃。
实施例1 中间体1-5a,1-5b的制备
Figure PCTCN2020107845-appb-000052
步骤1 中间体1-1的制备
Figure PCTCN2020107845-appb-000053
向配备有机械搅拌和氮气保护的10L三口烧瓶中加入THF(3500mL)，依次加入邻氯苯甲醛(341g,2.43mol)和硝基乙酸乙酯(323g,2.43mol)，随后冰盐浴冷却至內温-10℃，机械搅拌下缓慢滴加TiCl 4(920g,4.85mol)，滴加时控制內温不超过0℃，滴毕，维持0℃继续反应0.5h，随后逐滴加入N-甲基吗啉(981.51g,9.70mol)，滴加时控制內温不超过15℃，滴毕，允许升至室温并搅拌1h，最后加入饱和氯化铵500mL淬灭，乙酸乙酯(1000mL×3)萃取，经饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，经硅胶柱层析分离(石油醚/乙酸乙酯100:1)得中间体1-1(580g,2.27mol,93.52％产率)。
步骤2 中间体1-2的制备
Figure PCTCN2020107845-appb-000054
向配备有机械搅拌和氮气保护的10L三口烧瓶中加入1M的氯化锌四氢呋喃溶液(5.5mol，5.5L)，冰浴降温至0℃，缓慢滴加2M的异丙基氯化镁四氢呋喃溶液(5.5mol，2.75L)，控制内温低于5℃，滴毕，0-5℃继续反应30分钟。随后，缓慢滴加中间体1-1(702g,2.75mol)的无水THF(500mL)溶液，滴加时控制内温低于5℃，滴毕，0-5℃继续反应1小时。反应完毕，取500g氯化铵配置成饱和水溶液，缓慢加入上述反应液中淬灭反应，乙酸乙酯(5L×2)萃取，合并有机相并水洗，饱和氯化钠水洗，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析分离(石油醚/乙酸乙酯50:1)，得到中间体1-2(377g,1.26mol,45.80％产率)。
步骤3 中间体1-3的制备
Figure PCTCN2020107845-appb-000055
向配备有机械搅拌的10L三口烧瓶加入中间体1-2(730g,2.44mol)和冰醋酸(6L)，冰浴降温至0℃，机械搅拌下分批加入锌粉(796.24g,12.18mol)，加入时控制內温低于60℃。加毕，继续搅拌反应1小时，反应完毕，抽滤，乙酸乙酯100mL淋洗滤饼，滤液减压浓缩除去冰醋酸，粗品经硅胶柱层析分离纯化(石油醚/乙酸乙酯50:1～10:1)得非对映体之一中间体1-3(对映异构体(2S,3S)和(2R,3R)构型混合物，TLC极性较小的点)，黄色粘稠状液体(280g,1.04mol,42.65％产率)，MS m/z:270(M+1) +。
步骤4 中间体1-4的制备
Figure PCTCN2020107845-appb-000056
向中间体1-3(60g,222.41mmol)的四氢呋喃(200mL)和水(100mL)的悬浊液中依次加入碳酸氢钠(37.37g,444.83mmol)和Boc-酸酐(53.34g,244.66mmol)，加毕，室温搅拌过夜。反应完毕，加水300mL，乙酸乙酯(300mL×2)萃取，合并有机相，饱和氯化钠水洗，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析分离纯化(石油醚/乙酸乙酯100:1～50:1)，得到中间体1-4(39.4g,106.52mmol,47.89％产率)，MS m/z:270[M-99] +，314[M-55] +。
步骤5 中间体1-5a,1-5b的制备
Figure PCTCN2020107845-appb-000057
向中间体1-4(20.00g,54.07mmol)的甲醇(100mL)和水(10mL)的混悬液中加入NaOH(6.49g,162.21mmol)，升温至50℃反应3小时，反应完毕，将反应液浓缩，加水100mL，乙酸乙酯(100mL)萃取一次，水相降温至0～5℃，用1M的HCl调pH＝3-4，然后乙酸乙酯(100mL)萃取，有机相减压浓缩，得到中间体1-5的一对对映异构体形式(17.8g,52.07mmol,96.30％产率)，黄色油状物，该对映异构体经超临界流体色谱(SFC)手性拆分分离制备后分别得到单一手性异构体1-5a(2R,3R),1-5b(2S,3S)，分别6.5g，MS m/z:242[M-99] +，286[M-55] +。 1H NMR(400MHz,Chloroform-d)δ7.41–7.35(m,1H),7.27–7.23(m,2H),7.21–7.15(m,1H),4.90–4.82(m,1H),4.82–4.74 (m,1H),3.68–3.56(m,1H),2.19–2.03(m,1H),1.41(s,9H),1.17(d,J＝6.4Hz,3H),0.75(d,J＝6.7Hz,3H)。其中，(2S,3S)构型的保留时间为2.59min，(2R,3R)构型的保留时间为3.06min(
Figure PCTCN2020107845-appb-000058
AD-3 150*3mm,5um,等梯度5％乙醇1mL/min)。(2S,3S)构型的比旋光度为78.18°(25℃,0.089g/100ml甲醇溶液,波长589nm)，(2R,3R)构型的比旋光度为-72.60°(25℃,0.098g/100ml甲醇溶液,波长589nm)。
实施例2 中间体2-6的制备
Figure PCTCN2020107845-appb-000059
步骤1 中间体2-2的制备
Figure PCTCN2020107845-appb-000060
参照实施例1中间体1-2的制备方法，由中间体1-1与异丙烯基溴化镁反应制备得到，收率37％，MS m/z:298(M+1) +。
步骤2 中间体2-3的制备
Figure PCTCN2020107845-appb-000061
参照实施例1中间体1-3的制备方法，由锌粉-醋酸体系还原2-2的硝基得到，收率85％，MS m/z:268(M+1) +。其四个手性异构体未拆分直接用于下一步。
步骤3 中间体2-4的制备
Figure PCTCN2020107845-appb-000062
参照实施例1中间体1-4的制备方法，由Boc酸酐保护2-3的氨基得到，MS m/z:368[M+1] +，312[M-55] +。
步骤4 中间体2-5的制备
Figure PCTCN2020107845-appb-000063
将九水合硝酸铁(439.29mg,1.09mmol)溶解于10ml水中，于0℃下超声脱气10min并氮气保护，随后依次加入10ml乙腈和selectflour(384.92mg,1.09mmol)，0℃下再分别将中间体2-4(100mg,271.84μmol)的10ml乙腈溶液和NaBH 4(66.84mg,1.77mmol)加至反应液中，2min后，补加NaBH 4(66.84mg,1.77mmol)，于0℃下继续搅拌30min，反应完毕，加1ml氨水淬灭反应，DCM萃取，有机相用硫酸钠干燥，减压浓缩旋干，粗品经硅胶柱分离纯化(石油醚/乙酸乙酯100:1～50:1)得中间体2-5，(84.2mg,217.6μmol,80.0％产率),MS m/z:388[M+1] +。
步骤5 中间体2-6的制备
Figure PCTCN2020107845-appb-000064
参照实施例1中间体1-5的制备方法，由氢氧化钠水解2-5得到，MS m/z:360[M+1] +。
实施例3 中间体手性环丙甲基氨基酸3-3a,3-3b的制备
Figure PCTCN2020107845-appb-000065
步骤1 中间体3-1的制备
Figure PCTCN2020107845-appb-000066
实施例2的非对映异构体混合物中间体2-4(四个手性异构体的混合物)经硅胶柱层析分离纯化(石油醚/甲基叔丁基醚100:1)得中间体2-4的一对映异构体(2-4a与2-4b的对映体混合物，(2S,3S)和(2R,3R)构型混合物，在TLC板层析上该对映体混合物极性较小)，取该对映异构体(1.7g,4.62 mmol)，氮气保护下，溶于20ml干燥的DCM中，冷却內温至-40℃，加入ZnEt 2(1M的四氢呋喃溶液,27.73mL)，-30℃搅拌反应1小时后滴加二碘甲烷(9.90g,36.97mmol)，滴加时维持內温不高于-20℃，滴毕，允许内温缓慢升至室温并搅拌过夜，LC-MS显示有约30％的起始原料2-4的脱Boc后的副产物，加水5ml淬灭反应，有机相减压浓缩至干，得粗品1g，粗品此时为3-1的脱Boc形式和起始原料2-4的脱Boc后的混合物，将其混合物溶于10mL的THF中，依次加入TEA(897.78mg,8.87mmol,1.24mL)和(Boc) 2O(1.16g,5.32mmol)，于室温搅拌过夜，减压浓缩至干，粗品经硅胶柱分离纯化(石油醚/甲基叔丁基醚100:3)得Boc保护的环丙甲基乙酯3-1粗品和前一步未反应完的中间体2-4的混合物0.5g，将该粗品溶于四氢呋喃(5mL)和乙腈(5mL)及5mL水的混合液中，加入二水合锇酸钾(44.3mg,0.12mmol)和N-甲基-N-氧化吗啉(111mg,0.96mmol)，通过双键双羟化除去未反应的2-4，室温搅拌过夜，LC-MS监测显示已无未反应的中间体2-4，减压浓缩除去大部分有机溶剂，乙酸乙酯15ml萃取，有机相浓缩，粗品经硅胶柱层析分离纯化(石油醚/乙酸乙酯20:1)得中间体3-1(0.5g,1.31mmol,28％产率)，MS m/z:382[M+1] +.
步骤2 中间体3-2的制备
Figure PCTCN2020107845-appb-000067
参照实施例1中间体1-5的制备方法，由3-1经氢氧化钠水解得到，MS m/z:298[M-55] +。
步骤3 中间体3-3a,3-3b的制备
Figure PCTCN2020107845-appb-000068
中间体3-2(一对映体混合物)经SFC手性柱拆分分离制备后可分别得到单一手性异构体3-3a(2R,3R),3-3b(2S,3S)。其中(2S,3S)构型的保留时间为5.904min，(2R,3R)构型的保留时间为3.306min(
Figure PCTCN2020107845-appb-000069
AD-3150*3mm,5um,等梯度5％乙醇1mL/min)。(2S,3S)构型的的比旋光度为48.755°(25℃,0.1g/100ml in Methanol,波长589nm)，(2R,3R)构型的的比旋光度为-40.695°(25℃,0.1g/100ml in Methanol,波长589nm)。
实施例4 中间体氨基酸4-5的制备
Figure PCTCN2020107845-appb-000070
步骤1 中间体4-1的制备
Figure PCTCN2020107845-appb-000071
参照实施例1中间体1-1制备方法，由2-氯-6-氟-苯甲醛与硝基乙酸乙酯制备得到。
步骤2 中间体4-2的制备
Figure PCTCN2020107845-appb-000072
参照实施例1中间体1-2制备方法，由中间体4-1与异丙基氯化镁反应制备得到。
步骤3 中间体4-3的制备
Figure PCTCN2020107845-appb-000073
参照实施例1中间体1-3制备方法，由中间体4-2经硝基锌粉-醋酸体系还原硝基制备得到，MS m/z:288[M+1] +。
步骤4 中间体4-4的制备
Figure PCTCN2020107845-appb-000074
参照实施例1中间体1-4制备方法，由中间体4-3氨基上Boc保护得到，MS m/z:388[M+1] +，332[M-55] +。
步骤5 中间体4-5的制备
Figure PCTCN2020107845-appb-000075
参照实施例1中间体1-5制备方法，由中间体4-4经NaOH水解得到，MS m/z:360[M+1] +。
实施例5 中间体氨基酸5-5的制备
Figure PCTCN2020107845-appb-000076
步骤1 中间体5-1的制备
Figure PCTCN2020107845-appb-000077
参照实施例1中间体1-1制备方法，由2-氯-3-氟-苯甲醛与硝基乙酸乙酯制备得到。
步骤2 中间体5-2的制备
Figure PCTCN2020107845-appb-000078
参照实施例1中间体1-2制备方法，由中间体5-1与异丙基氯化镁反应制备得到。
步骤3 中间体5-3的制备
Figure PCTCN2020107845-appb-000079
参照实施例1中间体1-3制备方法，由中间体5-2经硝基锌粉-醋酸体系还原制备得到，MS m/z:288[M+1] +。
步骤4 中间体5-4的制备
Figure PCTCN2020107845-appb-000080
参照实施例1中间体1-4制备方法，由中间体5-3氨基上Boc保护得到，MS m/z:388[M+1] +，332[M-55] +。
步骤5 中间体5-5的制备
Figure PCTCN2020107845-appb-000081
参照实施例1中间体1-5制备方法，由中间体5-4经NaOH水解得到，MS m/z:360[M+1] +。
实施例6 中间体6-6a,6-6b的制备
Figure PCTCN2020107845-appb-000082
步骤1 中间体6-1的制备
Figure PCTCN2020107845-appb-000083
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6-1(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6-2的制备
Figure PCTCN2020107845-appb-000084
氮气保护和-10℃下，将中间体6-1(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℃，滴加氯甲基氯甲醚(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)得到中间体6-2(45g,168.36mmol,42.23％产率)，MS m/z:268[M+1] +.
步骤3 中间体6-3的制备
Figure PCTCN2020107845-appb-000085
将中间体6-2(45g,168.36mmol)溶于EtOH(100mL)中，氮气置换后，加入10％Pd/C(8g)，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6-3(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6-4的制备
Figure PCTCN2020107845-appb-000086
将中间体6-3(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6-4粗品(17g,52.42mmol,78.23％产率)，MS m/z:325[M+1] +。
步骤5 中间体6-5的制备
Figure PCTCN2020107845-appb-000087
将中间体6-4(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6-5粗品(8g,28.34mmol,42.29％产率)，MS m/z:283[M+1] +。
步骤6 中间体6-6a,6-6b的制备
Figure PCTCN2020107845-appb-000088
将中间体6-5(21g,74.2mmol)溶于甲醇中，氮气氛下加入10％Pd/C(5g)，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反相柱纯化得到消旋体，再经SFC手性柱拆分分离，得单一构型6-6a(7.5g，淡棕色半固体，40％产率，手性柱保留时间5.755min，CHIRALPAK AY-H(AYH0CE-VC001)0.46cm I.D.*25cm L,流动相：正己烷/乙醇80/20(V/V),35℃,流速：1mL/min)和另一单一构型6-6b(7.5g，淡棕色半固体，40％产率，手性柱保留时间6.805min，CHIRALPAK AY-H(AYH0CE-VC001)0.46cm I.D.*25cm L,流动相：正己烷/乙醇80/20(V/V),35℃,流速：1mL/min)，MS m/z:253[M+1] +.
实施例7 中间体7-2的制备
Figure PCTCN2020107845-appb-000089
步骤1 中间体7-1的制备
Figure PCTCN2020107845-appb-000090
将Boc-D-环丁基甘氨酸(800mg,3.49mmol)溶于DCM(8mL)，冷却至0℃，依次加入HBTU(1.06g,4.19mmol)，DIEA(2.25g,17.45mmol)和乙胺盐酸盐(284mg,3.49mmol)，15min后转至室温反应1.5小时，LC-MS显示原料消失，经饱和氯化铵洗(10ml×3)，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纯化(石油醚/乙酸乙酯3:1)得中间体7-1，白色固体(822mg,3.21mmol,92％产率)，MS m/z:257[M+1] +.
步骤2 中间体7-2的制备
Figure PCTCN2020107845-appb-000091
将7-1(822mg,3.21mmol)溶于DCM(3mL)中，冰浴下，缓慢加入TFA(1.5mL)，冰浴下搅拌1.5小时，原料消失，减压浓缩至干，得无色半粘稠状固体7-2的TFA盐(820mg,100％)，MS m/z:157[M+1] +，该粗品未经纯化直接用于下一步。
实施例8 中间体R-环丁基甘氨酰胺8的制备
Figure PCTCN2020107845-appb-000092
参考实施例7方法，由Boc-D-(3,3-二氟环丁基)甘氨酸与甲胺盐酸盐缩合，随后脱Boc得到，MS m/z:179[M+1] +.
实施例9 中间体9的制备
Figure PCTCN2020107845-appb-000093
参考实施例7方法，由Boc-D-环丁基甘氨酸与甲胺盐酸盐缩合，随后脱Boc得到，MS m/z:143[M+1] +.
实施例10 中间体10的制备
Figure PCTCN2020107845-appb-000094
参考实施例7方法，由Boc-D-环丁基甘氨酸与环丙胺缩合，随后脱Boc得到，MS m/z:169[M+1] +.
实施例11 中间体11的制备
Figure PCTCN2020107845-appb-000095
参考实施例7方法，由Boc-D-环丁基甘氨酸与环丙甲胺缩合，随后脱Boc得到，MS m/z:183[M+1] +.
实施例12 中间体12的制备
Figure PCTCN2020107845-appb-000096
参考实施例7方法，由Boc-D-环丁基甘氨酸与1-氨甲基-1-环丙醇缩合，随后脱Boc得到，MS m/z:199[M+1] +.
实施例13 中间体13的制备
Figure PCTCN2020107845-appb-000097
参考实施例7方法，由Boc-D-环丁基甘氨酸与(1-甲氧基环丙基)甲胺缩合，随后脱Boc得到，MS m/z:213[M+1] +.
实施例14 中间体14的制备
Figure PCTCN2020107845-appb-000098
参考实施例7方法，由Boc-D-环丁基甘氨酸与(1-氟环丙基)甲胺缩合，随后脱Boc得到，MS m/z:201[M+1] +.
实施例15 中间体15的制备
Figure PCTCN2020107845-appb-000099
参考实施例7方法，由Boc-D-环丁基甘氨酸与2,2-二氟乙胺缩合，随后脱Boc得到，MS m/z:193[M+1] +.
实施例16 中间体16的制备
Figure PCTCN2020107845-appb-000100
参考实施例7方法，由Boc-D-环丁基甘氨酸与2-氟乙胺缩合，随后脱Boc得到，MS m/z:175[M+1] +.
实施例17 中间体17的制备
Figure PCTCN2020107845-appb-000101
参考实施例7方法，由Boc-D-环戊基甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:171[M+1] +.
实施例18 中间体18的制备
Figure PCTCN2020107845-appb-000102
参考实施例7方法，由Boc-D-(四氢呋喃-2-基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:173[M+1] +.
实施例19 中间体19的制备
Figure PCTCN2020107845-appb-000103
参考实施例7方法，由Boc-D-(四氢吡喃-4-基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:187[M+1] +.
实施例20 中间体20的制备
Figure PCTCN2020107845-appb-000104
参考实施例7方法，由Boc-D-环己基甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:285[M+1] +.
实施例21 中间体21的制备
Figure PCTCN2020107845-appb-000105
参考实施例7方法，由Boc-D-环己基甘氨酸与顺式-2-氟-环丙胺缩合，随后脱Boc得到，MS m/z:187[M+1] +.
实施例22 中间体22的制备
Figure PCTCN2020107845-appb-000106
参考实施例7方法，由Boc-D-环己基甘氨酸与反式-2-氟-环丙胺缩合，随后脱Boc得到，MS m/z:187[M+1] +.
实施例23 中间体23的制备
Figure PCTCN2020107845-appb-000107
参考实施例7方法，由Boc-D-(3-氟环丁基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:175[M+1] +.
实施例24 中间体24的制备
Figure PCTCN2020107845-appb-000108
参考实施例7方法，由Boc-D-(3,3-二氟环丁基)甘氨酸与乙胺盐酸盐缩 合，随后脱Boc得到，MS m/z:193[M+1] +.
实施例25 中间体25的制备
Figure PCTCN2020107845-appb-000109
参考实施例7方法，由Boc-D-(3-甲基环丁基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:171[M+1] +.
实施例26 中间体26的制备
Figure PCTCN2020107845-appb-000110
参考实施例7方法，由Boc-D-(3-甲氧基环丁基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:187[M+1] +.
实施例27 中间体27的制备
Figure PCTCN2020107845-appb-000111
参考实施例7方法，由Boc-D-(1-甲基环丁基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:171[M+1] +.
实施例28 中间体28的制备
Figure PCTCN2020107845-appb-000112
参考实施例7方法，由Boc-(S)-(1-氟环丁基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:175[M+1] +.
实施例29 中间体29的制备
Figure PCTCN2020107845-appb-000113
参考实施例7方法，由Boc-D-(3-甲基-3-氟环丁基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:189[M+1] +.
实施例30 中间体30的制备
Figure PCTCN2020107845-appb-000114
参考实施例7方法，由Boc-D-(螺[2,3]己烷-5-基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:183[M+1] +.
实施例31 中间体31的制备
Figure PCTCN2020107845-appb-000115
参考实施例7方法，由Boc-D-(双环[1.1.1]戊烷-1-基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:169[M+1] +.
实施例32 中间体32的制备
Figure PCTCN2020107845-appb-000116
参考实施例7方法，由Boc-D-(3-(甲基)双环[1.1.1]戊烷-1-基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:183[M+1] +.
实施例33 中间体33的制备
Figure PCTCN2020107845-appb-000117
参考实施例7方法，由Boc-D-(3-(氟)双环[1.1.1]戊烷-1-基)甘氨酸与乙胺盐酸盐缩合，随后脱Boc得到，MS m/z:187[M+1] +.
实施例34 化合物34-a，34-b的制备
Figure PCTCN2020107845-appb-000118
步骤1 中间体34-1，34-2的制备(结构异构体混合物形式)
Figure PCTCN2020107845-appb-000119
将实施例1中步骤5单一构型中间体1-5b(614.57mg,1.80mmol，SFC手性拆分得到一单一手性异构体)，EDCI(412.08mg,2.16mmol)，DIPEA(697.08mg,5.39mmol,939.46uL)，HOAt(293.42mg,2.16mmol)及实施例6中步骤6单一构型中间体6-6b(0.45g,1.80mmol)依次加入到DCM(10mL)中，室温反应3小时，加水淬灭，减压除去大部分有机溶剂，乙酸乙酯(20ml*3)萃取，合并有机相，再分别饱和氯化铵和饱和食盐水洗，无水硫酸钠干燥，减压旋干，粗品经硅胶柱层析纯化分离(石油醚/乙酸乙酯5:1)即可得到中间体34-1和34-2的结构异构体混合物(0.4g,696μmol,39％产率)，MS m/z:576(M+1) +，二者不用分离并用于下一步。
步骤2 中间体34-3的制备
Figure PCTCN2020107845-appb-000120
将步骤2所得中间体34-1，34-2混合物(0.4g,696μmol)加至AcOH(2mL)中，55℃反应12h，减压浓缩旋干，硅胶柱层析分离纯化(石油醚/乙酸乙酯1:1)得到中间体34-3(330mg,534.08μmol,76.66％产率)，MS m/z：558(M+1) +。
步骤3 中间体34-4的制备
Figure PCTCN2020107845-appb-000121
将步骤2所得中间体34-3(0.33g,593.43μmol)溶于DCM(3mL)中，冰浴下滴加TFA(1mL)，冰浴下继续搅拌反应2h，旋干即可得到中间体34-4的粗品(250mg,493.45μmol,83.15％产率)，MS m/z：458(M+1) +，未经纯化直接用于下一步反应。
步骤4 中间体34-5的制备
Figure PCTCN2020107845-appb-000122
将HBTU(134.35mg,353.56μmol)，DIPEA(114.23mg,883.89μmol,153.95uL)，依次加至1-甲基-1H-吡唑-5-羧酸(112.01mg,888.21μmol)的DCM(5mL)溶液中，15min后加入步骤3所得中间体34-4(160mg,294.63μmol)，室温反应2h，加水淬灭，乙酸乙酯(20ml*3)萃取，合并有机相，再分别饱和氯化铵和饱和食盐水洗，无水硫酸钠干燥，减压旋干，粗品经硅胶柱层析纯化分离(石油醚/乙酸乙酯3:1)即可得到中间体34-5(301mg,480.26μmol,81.11％产率)，MS m/z：566(M+1) +。
步骤5 中间体34-6的制备
Figure PCTCN2020107845-appb-000123
向中间体34-5(301mg,533.62μmol)的EtOH(3mL)和水(1mL)的混合液中加入NaOH(64.03mg,1.60mmol)，于75℃反应12小时，LC-MS显示原料已反应完毕，经1N HCl调pH～4，EA(10ml*3)萃取，合并有机相，经饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得到中间体34-6的粗品(202mg,376.85μmol,70.62％产率)，MS m/z:538[M+1] +，未经纯化直接用于下一步反应。
步骤6 化合物34-a，34-b的制备
步骤6-1 化合物34-b的制备：
Figure PCTCN2020107845-appb-000124
将HBTU(357.2mg,942.5μmol)，DIPEA(146mg,1131μmol,187uL)，依次加至步骤5中间体34-6(202mg,376.85μmol)的DCM(5mL)溶液中，15min后加入实施例7的中间体7-2(71mg,452.4μmol)，室温反应1h，加10mL水淬灭，减压除去大部分有机溶剂，乙酸乙酯(10ml*3)萃取，合并有机相，再分别饱和氯化铵和饱和食盐水洗，无水硫酸钠干燥，减压旋干，粗品经MPLC反相C18柱层析纯化分离(乙腈/0.05％水0～60％)即可得到中间体34-b(204mg,309μmol,82％产率)，MS m/z：676(M+1) +。 1HNMR(400MHz,MeOD):δ7.94(t,J＝5.6Hz,1H),7.60(d,J＝1.8Hz,1H),7.57–7.53(m,1H),7.53–7.49(m,1H),7.43(d,J＝8.0Hz,1H),7.40–7.32(m,3H),7.29(dd,J＝8.6,1.8Hz,1H),7.26–7.21(m,1H),6.51(d,J＝2.2Hz,1H),6.00(d,J＝9.3Hz,1H),4.37(t,J＝8.3Hz,1H),4.19(t,J＝7.8Hz,1H),4.01(d,J＝9.6Hz,1H),3.93(s,3H),3.74(d,J＝9.6Hz,1H),3.63(q,J＝7.0Hz,1H),3.44(s,3H),3.26–3.12(m,2H),2.64–2.52(m,1H),2.01–1.72(m,7H),1.59(s,3H),1.20(t,J＝7.0Hz,1H),1.10(t,J＝7.2Hz,3H),0.99(d,J＝6.7Hz,3H),0.86(d,J＝6.8Hz,3H).
步骤6-2 化合物34-a的制备：
Figure PCTCN2020107845-appb-000125
参照实施例34的步骤1～6制备34-b的方法，以实施例1中步骤5的单一构型中间体1-5b和实施例6中步骤6的单一构型中间体6-6a反应，经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，与实施例7中间体酰胺7-2缩合等步骤得到34-a，MS m/z：676(M+1) +。
实施例35 化合物35-a,35-b的制备
Figure PCTCN2020107845-appb-000126
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例9中间体9缩合得到化合物35-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例9中间体9缩合可得到化合物35-a。MS m/z：662(M+1) +。
实施例36 化合物36-a,36-b的制备
Figure PCTCN2020107845-appb-000127
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例10中间体10缩合得到化合物36-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例10中间体10缩合可得到化合物36-a。MS m/z：688(M+1) +。
实施例37 化合物37-a,37-b的制备
Figure PCTCN2020107845-appb-000128
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例11中间体11缩合得到化合物37-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例11中间体11缩合可得到化合物37-a。MS m/z：702(M+1) +。37-b的核磁氢谱： 1HNMR(400MHz,DMSO-d 6):δ12.52(s,1H),8.72(dd,J＝16.2,9.7Hz,1H),7.84–7.75(m,1H),7.62–7.54(m,1H),7.47–7.37(m,3H),7.35–7.27(m,2H),7.26–7.10(m,3H),6.49(s,1H),5.94–5.84(m,1H),4.38–4.30(m,1H),4.30–4.22(m,1H), 3.91(d,J＝9.9Hz,1H),3.83(s,2H),3.64(d,J＝9.4Hz,1H),3.31–3.27(m,3H),3.00–2.93(m,1H),2.89–2.81(m,1H),2.69–2.66(m,1H),2.35–2.31(m,1H),1.87–1.64(m,6H),1.49(s,2H),0.81–0.73(m,4H),0.38–0.31(m,2H),0.11–0.05(m,2H).
实施例38 化合物38-a,38-b的制备
Figure PCTCN2020107845-appb-000129
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例12中间体12缩合得到化合物38-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例12中间体12缩合可得到化合物38-a，MS m/z：718(M+1) +。
实施例39 化合物39-a,39-b的制备
Figure PCTCN2020107845-appb-000130
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例13中间体13缩合得到化合物39-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例13中间体13缩合可得到化合物39-a，MS m/z：732(M+1) +。化合物39-b的核磁氢谱为： 1HNMR(400MHz,DMSO-d 6):δ8.72(s,1H),7.92–7.82(m,1H),7.70–7.63(m,1H),7.63–7.58(m,1H),7.51–7.46(m,1H),7.42–7.23(m,7H),6.65(s,1H),6.01(s,1H),4.40–4.33(m,1H),4.23–4.16(m,1H),3.93–3.88(m,1H),3.86(s,3H),3.70–3.64(m,2H),3.29(s,3H),1.89–1.63(m,8H),1.50(s,3H),1.30–1.23(m,3H),0.91–0.84(m,3H),0.80–0.75(m,3H),0.50–0.44(m,2H),0.41–0.35(m,2H).
实施例40 化合物40-a,40-b的制备
Figure PCTCN2020107845-appb-000131
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例14中间体14缩合得到化合物40-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例14中间体14缩合可得到化合物40-a，MS m/z：720(M+1) +。40-b的核磁氢谱： 1HNMR(400MHz,DMSO-d 6):δ8.76(dd,J＝16.5,9.3Hz,2H),8.18(t,J＝5.9Hz,2H),7.63–7.52(m,2H),7.50–7.36(m,4H),7.31(dd,J＝6.8,4.9Hz,2H),7.22(dd,J＝15.0,7.5Hz,2H),7.18–7.07(m,2H),6.55(s,1H),6.49(s,2H),5.97–5.80(m,2H),4.40(t,J＝7.2Hz,2H),4.31–4.22(m,2H),3.91(dd,J＝9.4,3.4Hz,2H),3.82(s,3H),3.63(d,J＝9.5Hz,2H),1.94–1.61(m,9H),1.49(s,4H),1.24(s,2H),0.91(d,J＝18.7Hz,3H),0.77(t,J＝6.2Hz,6H),0.64(d,J＝7.9Hz,3H).
实施例41 化合物41-a,41-b的制备
Figure PCTCN2020107845-appb-000132
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例15中间体15缩合得到化合物41-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例15中间体15缩合可得到化合物41-a，MS m/z：712(M+1) +。41-b的核磁氢谱： 1HNMR(400MHz,MeOD):δ7.63–7.49(m,4H),7.46(d,J＝8.0Hz,1H),7.38(dd,J＝9.3,4.0Hz,4H),7.32–7.21(m,3H),6.51(s,2H),6.00(d,J＝9.2Hz,2H),4.48(t,J＝4.9Hz,1H),4.46–4.39(m,2H),4.37(t,J＝4.9Hz,1H),4.19(s,2H),4.02(d,J＝9.6Hz,2H),3.94(s,3H),3.74(d,J＝9.5Hz,2H),3.44(s,3H),2.60(dd,J＝15.8,7.9Hz,3H),1.90(ddd,J＝21.8,11.1,5.6Hz,6H),1.79(d,J＝20.1Hz,3H),1.56(d,J＝23.0Hz,4H),1.44–1.35(m,2H),0.99(d,J＝6.1Hz,4H),0.86(d,J＝6.8Hz,4H).
实施例42 化合物42-a,42-b的制备
Figure PCTCN2020107845-appb-000133
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例16中间体16缩合得到化合物42-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例16中间体16缩合可得到化合物42-a，MS m/z：694(M+1) +。42-b的核磁氢谱： 1HNMR(400MHz,MeOD):δ7.63–7.49(m,4H),7.46(d,J＝8.0Hz,1H),7.38(dd,J＝9.3,4.0Hz,4H),7.32–7.21(m,3H),6.51(s,2H),6.00(d,J＝9.2Hz,2H),4.48(t,J＝4.9Hz,1H),4.46–4.39(m,2H),4.37(t,J＝4.9Hz,1H),4.19(s,2H),4.02(d,J＝9.6Hz,2H),3.94(s,3H),3.74(d,J＝9.5Hz,2H),3.44(s,3H),2.60(dd,J＝15.8,7.9Hz,3H),1.90(ddd,J＝21.8,11.1,5.6Hz,6H),1.79(d,J＝20.1Hz,3H),1.56(d,J＝23.0Hz,4H),1.44–1.35(m,2H),0.99(d,J＝6.1Hz,4H),0.86(d,J＝6.8Hz,4H).
实施例43 化合物43-a,43-b的制备
Figure PCTCN2020107845-appb-000134
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例17中间体17缩合得到化合物43-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例17中间体17缩合可得到化合物43-a，MS m/z：690(M+1) +。
实施例44 化合物44-a,44-b的制备
Figure PCTCN2020107845-appb-000135
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施 例18中间体18缩合得到化合物44-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例18中间体18缩合可得到化合物44-a，MS m/z：692(M+1) +。
实施例45 化合物45-a,45-b的制备
Figure PCTCN2020107845-appb-000136
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例19中间体19缩合得到化合物45-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例19中间体19缩合可得到化合物45-a，MS m/z：706(M+1) +。
实施例46 化合物46-a,46-b的制备
Figure PCTCN2020107845-appb-000137
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例20中间体20缩合得到化合物46-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例20中间体20缩合可得到化合物46-a，MS m/z：704(M+1) +。
实施例47 化合物47-a,47-b的制备
Figure PCTCN2020107845-appb-000138
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例21中间体21缩合得到化合物47-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例21中间体21缩合可得到化 合物47-a，MS m/z：706(M+1) +。
实施例48 化合物48-a,48-b的制备
Figure PCTCN2020107845-appb-000139
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例22中间体22缩合得到化合物48-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例22中间体22缩合可得到化合物48-a，MS m/z：706(M+1) +。
实施例49 化合物49-a,49-b的制备
Figure PCTCN2020107845-appb-000140
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例23中间体23缩合得到化合物49-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例23中间体23缩合可得到化合物49-a，MS m/z：694(M+1) +。
实施例50 化合物50-a,50-b的制备
Figure PCTCN2020107845-appb-000141
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例24中间体24缩合得到化合物50-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例24中间体24缩合可得到化合物50-a，MS m/z：712(M+1) +。
实施例51 化合物51-a,51-b的制备
Figure PCTCN2020107845-appb-000142
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例25中间体25缩合得到化合物51-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例25中间体25缩合可得到化合物51-a，MS m/z：690(M+1) +。
实施例52 化合物52-a,52-b的制备
Figure PCTCN2020107845-appb-000143
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例26中间体26缩合得到化合物52-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例26中间体26缩合可得到化合物52-a，MS m/z：706(M+1) +。
实施例53 化合物53a,53-b的制备
Figure PCTCN2020107845-appb-000144
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例27中间体27缩合得到化合物53-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例27中间体27缩合可得到化合物53-a，MS m/z：690(M+1) +。化合物53-b的核磁氢谱为： 1H NMR(400MHz,MeOD)δ8.03(t,J＝4.2Hz,1H),7.64(d,J＝1.2Hz,1H),7.59(d,J＝8.8Hz,1H),7.55(d,J＝8.4Hz,2H),7.42–7.36(m,4H),7.28–7.24(m,1H),6.57(s,1H),6.04(d,J＝8.8Hz,1H),4.41(d,J＝8.8Hz,1H),4.17–4.11(m,1H),4.01(d,J＝10.0Hz,1H),3.96(s,3H),3.75(d,J＝10.0Hz,1H),3.46(s,3H),3.29–3.14(m,2H),2.27-2.20(m,1H),2.17-1.87(m,3H),1.78–1.66(m, 1H),1.62–1.52(m,5H),1.13(d,J＝7.2Hz,2H),1.10(d,J＝3.6Hz,4H),1.05(d,J＝6.4Hz,3H),0.86(d,J＝6.8Hz,3H).
实施例54 化合物54-a,54-b的制备
Figure PCTCN2020107845-appb-000145
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例28中间体28缩合得到化合物54-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例28中间体28缩合可得到化合物54-a，MS m/z：694(M+1) +。
实施例55 化合物55-a,55-b的制备
Figure PCTCN2020107845-appb-000146
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例29中间体29缩合得到化合物55-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例29中间体29缩合可得到化合物55-a，MS m/z：708(M+1) +。
实施例56 化合物56-a,56-b的制备
Figure PCTCN2020107845-appb-000147
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例30中间体30缩合得到化合物56-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例30中间体30缩合可得到化合物56-a，MS m/z：702(M+1) +。
实施例57 化合物57-a,57-b的制备
Figure PCTCN2020107845-appb-000148
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例31中间体31缩合得到化合物57-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例31中间体31缩合可得到化合物57-a，MS m/z：688(M+1) +。化合物57-b的核磁： 1H NMR(400MHz,Methanol-d 4)δ7.68(s,2H),7.58(d,J＝7.2Hz,1H),7.48(d,J＝7.2Hz,1H),7.35-7.32(m,3H),7.27-7.23(m,1H),6.33(d,J＝2.0Hz,1H),6.03(d,J＝12.0Hz,1H),4.76(d,J＝8.8Hz,1H),4.69(s,1H),4.07–3.97(m,3H),3.87(s,3H),3.76(d,J＝12.0Hz,1H),3.26–3.08(m,2H),2.93–2.87(m,1H),2.64-2.57(m,1H),1.77–1.72(m,6H),1.12–1.07(m,6H),0.79-0.74(m,1H),0.02–-0.02(m,1H),-0.14(t,J＝7.6Hz,2H).
实施例58 化合物58-a,58-b的制备
Figure PCTCN2020107845-appb-000149
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例32中间体32缩合得到化合物58-b；类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与实施例32中间体32缩合可得到化合物58-a，MS m/z：702(M+1) +。
实施例59 化合物59a,59-b的制备
Figure PCTCN2020107845-appb-000150
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与实施例33中间体33缩合得到化合物59-b；类似地，以制备另一构型34-a的步骤 5中间体(34-6的另一构型)为原料，与实施例33中间体33缩合可得到化合物59-a，MS m/z：706(M+1) +。
实施例60 化合物60-a,60-b,60-c,60-d,60-e,60-f,60-g,60-h的制备
Figure PCTCN2020107845-appb-000151
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例9中间体9缩合，再经SFC手性拆分制备得到化合物60-a,60-b,60-c,60-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物60-e,60-f,60-g,60-h。MS m/z：680(M+1) +。
实施例61 化合物61-a,61-b,61-c,61-d,61-e,61-f,61-g,61-h的制备
Figure PCTCN2020107845-appb-000152
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物61-a,61-b,61-c,61-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物61-e,61-f,61-g,61-h。MS m/z：694(M+1) +。
实施例62 化合物62-a,62-b,62-c,62-d,62-e,62-f,62-g,62-h的制备
Figure PCTCN2020107845-appb-000153
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例10中间体10缩合，再经SFC手性拆分制备得到化合物62-a,62-b,62-c,62-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物62-e,62-f,62-g,62-h。MS m/z：706(M+1) +。
实施例63 化合物63-a,63-b,63-c,63-d,63-e,63-f,63-g,63-h的制备
Figure PCTCN2020107845-appb-000154
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例11中间体11缩合，再经SFC手性拆分制备得到化合物63-a,63-b,63-c,63-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物63-e,63-f,63-g,63-h。MS m/z：720(M+1) +。
实施例64 化合物64-a,64-b,64-c,64-d,64-e,64-f,64-g,64-h的制备
Figure PCTCN2020107845-appb-000155
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例12中间体12缩合，再经SFC手性拆分制备得到化合物64-a,64-b,64-c,64-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物64-e,64-f,64-g,64-h。MS m/z：736(M+1) +。
实施例65 化合物65-a,65-b,65-c,65-d,65-e,65-f,65-g,65-h的制备
Figure PCTCN2020107845-appb-000156
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例13中间体13缩合，再经SFC手性拆分制备得到化合物65-a,65-b,65-c,65-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物65-e,65-f,65-g,65-h。MS m/z：750(M+1) +。
实施例66 化合物66-a,66-b,66-c,66-d,66-e,66-f,66-g,66-h的制备
Figure PCTCN2020107845-appb-000157
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例14中间体14缩合，再经SFC手性拆分制备得到化合物66-a,66-b,66-c,66-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物66-e,66-f,66-g,66-h。MS m/z：738(M+1) +。
实施例67 化合物67-a,67-b,67-c,67-d,67-e,67-f,67-g,67-h的制备
Figure PCTCN2020107845-appb-000158
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例15中间体15缩合，再经SFC手性拆分制备得到化合物67-a,67-b,67-c,67-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物67-e,67-f,67-g,67-h。MS m/z：730(M+1) +。
实施例68 化合物68-a,68-b,68-c,68-d,68-e,68-f,68-g,68-h的制备
Figure PCTCN2020107845-appb-000159
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例16中间体16缩合，再经SFC手性拆分制备得到化合物68-a,68-b,68-c,68-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物68-e,68-f,68-g,68-h。MS m/z：712(M+1) +。
实施例69 化合物69-a,69-b,69-c,69-d,69-e,69-f,69-g,69-h的制备
Figure PCTCN2020107845-appb-000160
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例17中间体17缩合，再经SFC手性拆分制备得到化合物69-a,69-b,69-c,69-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物69-e,69-f,69-g,69-h。MS m/z：708(M+1) +。
实施例70 化合物70-a,70-b,70c,70-d,70-e,70-f,70-g,70-h的制备
Figure PCTCN2020107845-appb-000161
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例18中间体18缩合，再经SFC手性拆分制备得到化合物70-a,70-b,70c,70-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物70-e,70-f,70-g,70-h。MS m/z：710(M+1) +。
实施例71 化合物71-a,71-b,71-c,71-d,71-e,71-f,71-g,71-h的制备
Figure PCTCN2020107845-appb-000162
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例19中间体19缩合，再经SFC手性拆分制备得到化合物71-a,71-b,71-c,71-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物71-e,71-f,71-g,71-h。MS m/z：724(M+1) +。
实施例72 化合物72-a,72-b,72-c,72-d,72-e,72-f,72-g,72-h的制备
Figure PCTCN2020107845-appb-000163
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例20中间体20缩合，再经SFC手性拆分制备得到化合物72-a,72-b,72-c,72-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物72-e,72-f,72-g,72-h。MS m/z：722(M+1) +。
实施例73 化合物73-a,73-b,73-c,73-d,73-e,73-f,73-g,73-h的制备
Figure PCTCN2020107845-appb-000164
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例21中间体21缩合，再经SFC手性拆分制备得到化合物73-a,73-b,73-c,73-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物73-e,73-f,73-g,73-h。MS m/z：724(M+1) +。
实施例74 化合物74-a,74-b,74-c,74-d,74-e,74-f,74-g,74-h的制备
Figure PCTCN2020107845-appb-000165
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例22中间体22缩合，再经SFC手性拆分制备得到化合物74-a,74-b,74-c,74-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物74-e,74-f,74-g,74-h。MS m/z：724(M+1) +。
实施例75 化合物75-a,75b,75-c,75-d,75-e,75-f,75-g,75-h的制备
Figure PCTCN2020107845-appb-000166
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例23中间体23缩合，再经SFC手性拆分制备得到化合物75-a,75b,75-c,75-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物75-e,75-f,75-g,75-h。MS m/z：712(M+1) +。
实施例76 化合物76-a,76b,76-c,76-d,76-e,76-f,76-g,76-h的制备
Figure PCTCN2020107845-appb-000167
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例24中间体24缩合，再经SFC手性拆分制备得到化合物76-a,76b,76-c,76-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物76-e,76-f,76-g,76-h。MS m/z：730(M+1) +。
实施例77 化合物77-a,77b,77-c,77-d,77-e,77-f,77-g,77-h的制备
Figure PCTCN2020107845-appb-000168
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例25中间体25缩合，再经SFC手性拆分制备得到化合物77-a,77b,77-c,77-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物77-e,77-f,77-g,77-h。MS m/z：708(M+1) +。
实施例78 化合物78-a,78b,78-c,78-d,78-e,78-f,78-g,78-h的制备
Figure PCTCN2020107845-appb-000169
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例26中间体26缩合，再经SFC手性拆分制备得到化合物78-a,78b,78-c,78-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物78-e,78-f,78-g,78-h。MS m/z：724(M+1) +。
实施例79 化合物79-a,79-b,79-c,79-d,79-e,79-f,79-g,79-h的制备
Figure PCTCN2020107845-appb-000170
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例27中间体27缩合，再经SFC手性拆分制备得到化合物79-a,79b,79-c,79-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物79-e,79-f,79-g,79-h。MS m/z：708(M+1) +。
实施例80 化合物80-a,80-b,80-c,80-d,80-e,80-f,80-g,80-h的制备
Figure PCTCN2020107845-appb-000171
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例28中间体28缩合，再经SFC手性拆分制备得到化合物80-a,80-b,80-c,80-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物80-e,80-f,80-g,80-h。MS m/z：712(M+1) +。
实施例81 化合物81-a,81-b,81-c,81-d,81-e,81-f,81-g,81-h的制备
Figure PCTCN2020107845-appb-000172
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例29中间体29缩合，再经SFC手性拆分制备得到化合物81-a,81-b,81-c,81-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物81-e,81-f,81-g,81-h。MS m/z：726(M+1) +。
实施例82 化合物82-a,82-b,82-c,82-d,82-e,82-f,82-g,82-h的制备
Figure PCTCN2020107845-appb-000173
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例30中间体30缩合，再经SFC手性拆分制备得到化合物82-a,82-b,82-c,82-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物82-e,82-f,82-g,82-h。MS m/z：720(M+1) +。
实施例83 化合物83-a,83-b,83-c,83-d,83-e,83-f,83-g,83-h的制备
Figure PCTCN2020107845-appb-000174
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例31中间体31缩合，再经SFC手性拆分制备得到化合物83-a,83-b,83-c,83-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物83-e,83-f,83-g,83-h。MS m/z：706(M+1) +。
实施例84 化合物84-a,84-b,84-c,84-d,84-e,84-f,84-g,84-h的制备
Figure PCTCN2020107845-appb-000175
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例32中间体32缩合，再经SFC手性拆分制备得到化合物84-a,84-b,84-c,84-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物84-e,84-f,84-g,84-h。MS m/z：720(M+1) +。
实施例85 化合物85-a,85-b,85-c,85-d,85-e,85-f,85-g,85-h的制备
Figure PCTCN2020107845-appb-000176
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例33中间体33缩合，再经SFC手性拆分制备得到化合物85-a,85-b,85-c,85-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物85-e,85-f,85-g,85-h。MS m/z：724(M+1) +。
实施例86 化合物86-a,86-b的制备
Figure PCTCN2020107845-appb-000177
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例9中间体9缩合得到化合物86-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物86-a。MS m/z：674(M+1) +。核磁谱图： 1H NMR(400MHz,Methanol-d 4)δ7.66(s,1H),7.59(dd,J＝12.6,8.2Hz,2H),7.47(d,J＝8.0Hz,2H),7.37–7.28(m,3H),7.24(t,J＝7.6Hz,1H),6.32(s,1H),6.03(d,J＝11.9Hz,1H),4.38(t,J＝8.2Hz,1H),4.04(d,J＝9.5Hz,1H),3.85(s,3H),3.76(d,J＝10.5Hz,2H),3.45(s,3H),2.73(d,J＝3.8Hz,3H),2.66–2.53(m,1H),2.02–1.81(m,4H),1.81–1.67(m,2H),1.60(s,3H),1.12(s,3H),0.82–0.74(m,1H),0.06–-0.01(m,1H),-0.12(t,J＝7.5Hz,2H).
实施例87 化合物87-a,87-b的制备
Figure PCTCN2020107845-appb-000178
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合得到化合物87-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合得到化合物87-a。MS m/z：688(M+1) +；87b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.99–7.91(m,1H),7.69–7.64(m,1H),7.64–7.54(m,2H),7.51–7.44(m,2H),7.37–7.31(m,3H),7.29–7.21(m,1H),6.34(d,J＝2.1Hz,1H),6.01(d,J＝11.9Hz,1H),4.38(t,J＝8.3Hz,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.77(d,J＝1.5Hz,1H),3.74(d,J＝3.8Hz,1H),3.45(s,3H),3.24–3.12(m,2H),2.66–2.52(m,1H),1.98–1.75(m,6H),1.61(s,3H),1.36– 1.29(m,1H),1.15–1.07(m,6H),0.82–0.72(m,1H),0.05–-0.02(m,1H),-0.07–-0.18(m,2H).87a的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ8.01(s,1H),7.66(s,1H),7.61-7.56(m,2H),7.48(dd,J＝8.0,1.2Hz,1H),7.41(d,J＝7.6Hz,1H),7.35–7.31(m,3H),7.25(td,J＝8.0,1.6Hz,1H),6.33(d,J＝2.0Hz,1H),6.01(d,J＝12.0Hz,1H),4.37(t,J＝8.0Hz,1H),4.00(d,J＝9.6Hz,1H),3.87(s,3H),3.74(t,J＝10.2Hz,2H),3.43(s,3H),3.24–3.14(m,2H),2.64-2.58(m,1H),1.97–1.83(m,7H),1.64(s,3H),1.13-1.08(m,6H),0.79–0.74(m,1H),-0.04--0.01(m,1H),-0.09–-0.15(m,2H).
实施例88 化合物88-a,88-b的制备
Figure PCTCN2020107845-appb-000179
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例10中间体10缩合得到化合物88-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物88-a。MS m/z：688(M+1) +.88b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ8.08(s,1H),7.70–7.53(m,3H),7.51–7.42(m,2H),7.37–7.29(m,3H),7.25(td,J＝7.7,1.6Hz,1H),6.34(d,J＝2.1Hz,1H),6.01(d,J＝11.9Hz,1H),4.34(t,J＝8.3Hz,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.76(d,J＝1.8Hz,1H),3.74(s,1H),3.46(s,3H),2.66–2.51(m,2H),1.98–1.70(m,6H),1.61(s,3H),1.13(s,3H),0.81–0.67(m,3H),0.46(dd,J＝8.6,3.8Hz,2H),0.02(dt,J＝10.4,5.1Hz,1H),-0.08–-0.18(m,2H).
实施例89 化合物89-a,89-b的制备
Figure PCTCN2020107845-appb-000180
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环， 脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例11中间体11缩合得到化合物89-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物89-a。MS m/z：714(M+1) +.
实施例90 化合物90-a,90-b的制备
Figure PCTCN2020107845-appb-000181
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例12中间体12缩合得到化合物90-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物90-a。MS m/z：730(M+1) +.
实施例91 化合物91-a,91-b的制备
Figure PCTCN2020107845-appb-000182
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例13中间体13缩合得到化合物91-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物91-a。MS m/z：744(M+1) +.
实施例92 化合物92-a,92-b的制备
Figure PCTCN2020107845-appb-000183
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例14中间体14缩合得到化合物92-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物92-a。MS m/z：732(M+1) +.
实施例93 化合物93-a,93-b的制备
Figure PCTCN2020107845-appb-000184
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例15中间体15缩合得到化合物93-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物93-a。MS m/z：724(M+1) +.
实施例94 化合物94-a,94-b的制备
Figure PCTCN2020107845-appb-000185
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例16中间体16缩合得到化合物94-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物94-a。MS m/z：706(M+1) +.化合物94-b的核磁： 1H NMR(400MHz,Methanol-d 4)δ7.71–7.53(m,3H),7.52–7.42(m,2H),7.38–7.30(m,3H),7.29–7.20(m,1H),6.33(d,J＝2.2Hz,1H),6.01(d,J＝12.0Hz,1H),4.52–4.34(m,3H),4.08–4.01(m,1H),3.87(s,3H),3.81–3.68(m,2H),3.59–3.37(m,5H),2.73–2.49(m,1H),2.01–1.73(m,6H),1.61(s,3H),1.13(s,3H),0.85–0.67(m,1H),0.01(dt,J＝10.1,5.2Hz,1H),-0.13(tt,J＝7.6,4.8Hz,2H).
实施例95 化合物95-a,95-b的制备
Figure PCTCN2020107845-appb-000186
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例17中间体17缩合得到化合物95-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物95-a。MS m/z：702(M+1) +.化合物95-b的核磁： 1H NMR(400MHz,Methanol-d 4)δ8.03(t,J＝5.2,Hz,1H),7.65-7.57(m,3H),7.48(d,J＝8.0Hz,1H),7.40(d,J＝8.0Hz,1H),7.37-7.29(m,3H),7.27-7.23(m,1H),6.33(d,J＝1.2Hz,1H),6.01(d,J＝12.0Hz,1H),4.27(t,J＝8.0Hz,1H),4.03(d,J＝9.2Hz,1H),3.87(s,3H),3.80-3.70(m,2H),3.45(s,3H),3.29-3.06(m,2H),2.27-2.03(m,1H),1.76-1.44(m,9H),1.42-1.16(m,3H),1.13-1.10(m,,6H),0.79-0.74(m,1H),0.04-0.0(m,1H),-0.11--0.14(m,2H).
实施例96 化合物96-a,96-b的制备
Figure PCTCN2020107845-appb-000187
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例18中间体18缩合得到化合物96-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物96-a。MS m/z：704(M+1) +.化合物96-b再经SFC拆分得两个组分峰，组分之一96-b1的核磁为： 1H NMR(400MHz,Methanol-d 4)δ7.65(s,1H),7.63–7.55(m,2H),7.48(dd,1H),7.36–7.29(m,3H),7.28–7.21(m,1H),6.33(d,J＝2.1Hz,1H),6.02(d,J＝12.0Hz,1H),4.47(d,J＝7.3Hz,1H),4.03(q,J＝9.5Hz,2H),3.87(s,3H),3.86–3.81(m,1H),3.79–3.67(m,3H),3.45(s,3H),3.22(q,J＝7.3Hz,2H),1.95–1.71(m,4H),1.60(s,3H),1.13(q,6H),0.81–0.72(m,1H),0.05–-0.03(m,1H),-0.08–-0.17(m,2H)；组分之一96-b2的核磁为： 1H NMR(400MHz,Methanol-d 4)δ7.77–7.05(m,10H),6.33(d,J＝2.2Hz,1H),6.01(d,J＝12.0Hz,1H),4.47–4.42(m,1H),4.28–4.23(m,1H),4.11(d,J＝9.6Hz,1H),3.92–3.71(m,5H),3.53(s,3H),3.28–3.19(m,2H),1.81–1.65(m,1H),1.60(s,3H),1.58–1.49(m,2H),1.41(d,J＝11.0Hz,1H),1.37–1.24(m,4H),1.16–1.08(m,6H),0.81–0.75(m,1H),-0.08–-0.17(m,2H).
实施例97 化合物97-a,97-b的制备
Figure PCTCN2020107845-appb-000188
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例19中间体19缩合得到化合物97-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物97-a。MS m/z： 718(M+1) +.97-b的核磁为： 1H NMR(400MHz,Methanol-d 4)δ7.73–7.62(m,1H),7.62–7.52(m,2H),7.51–7.45(m,1H),7.37–7.28(m,3H),7.28–7.22(m,1H),6.34(s,1H),6.01(d,J＝11.9Hz,1H),4.32–4.26(m,1H),4.05(d,J＝9.6Hz,1H),3.87(s,5H),3.74(d,J＝9.5Hz,2H),3.45(s,3H),3.21(s,2H),1.92(dt,J＝7.8,3.9Hz,1H),1.65–1.56(m,3H),1.54–1.19(m,6H),1.16–1.07(m,6H),0.83–0.72(m,1H),0.02(m,1H),-0.13(m,2H).
实施例98 化合物98-a,98-b的制备
Figure PCTCN2020107845-appb-000189
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例20中间体20缩合得到化合物98-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物98-a。MS m/z：716(M+1) +.98b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ8.07–7.99(m,1H),7.70–7.54(m,3H),7.51–7.45(m,1H),7.38–7.20(m,5H),6.37–6.27(m,1H),6.01(d,J＝11.9Hz,1H),4.28–4.22(m,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.79–3.72(m,2H),3.46(s,3H),3.26–3.17(m,2H),1.82–1.51(m,10H),1.36–1.27(m,1H),1.15–1.11(m,6H),1.10(s,1H),0.06–-0.02(m,1H),-0.06–-0.22(m,2H).
实施例99 化合物99-a,99-b的制备
Figure PCTCN2020107845-appb-000190
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例21中间体21缩合得到化合物99-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱 保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物99-a。MS m/z：718(M+1) +.99b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.72–7.55(m,3H),7.53(d,J＝7.9Hz,1H),7.48(dd,J＝8.0,1.4Hz,1H),7.33(dt,J＝7.3,1.7Hz,3H),7.25(td,J＝7.7,1.6Hz,1H),6.34(d,J＝2.1Hz,1H),6.01(d,J＝11.9Hz,1H),4.69(td,J＝5.7,3.1Hz,0H),4.53(td,J＝5.7,3.1Hz,0H),4.45(t,J＝8.2Hz,1H),4.03(d,J＝9.6Hz,1H),3.87(s,3H),3.76(s,1H),3.74(d,J＝2.3Hz,1H),3.46(s,3H),2.73–2.65(m,1H),2.64–2.53(m,1H),2.00–1.69(m,6H),1.61(s,3H),1.13(s,3H),0.92(dddd,J＝24.6,8.4,5.9,3.1Hz,1H),0.81–0.72(m,1H),0.05–-0.03(m,1H),-0.13(ddd,J＝9.0,6.0,2.2Hz,2H).
实施例100 化合物100-a,100-b的制备
Figure PCTCN2020107845-appb-000191
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例22中间体22缩合得到化合物100-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物100-a。MS m/z：718(M+1) +.化合物100-b再经SFC拆分得两个组分峰(氟代三元环顺反异构)，组分之一100-b1的核磁为： 1H NMR(400MHz,Methanol-d 4)δ7.69–7.54(m,3H),7.52–7.44(m,2H),7.37–7.29(m,3H),7.25(td,J＝7.6,1.6Hz,1H),6.33(d,J＝2.0Hz,1H),6.01(d,J＝12Hz,1H),4.60-4.57(m,0.5H),4.48-4.40(m,0.5H),4.31(t,J＝8.2Hz,1H),4.17–4.08(m,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.79–3.71(m,2H),3.46(s,3H),3.04–2.91(m,1H),2.60-2.55(m,1H),1.99–1.71(m,6H),1.60(s,3H),1.41–1.29(m,1H),1.13(s,3H),0.97–0.85(m,1H),0.79-0.74(m,1H),0.06–-0.04(m,1H),-0.10--0.14(m,2H)；组分之二100-b2的核磁为： 1H NMR(400MHz,Methanol-d 4)δ7.73–7.51(m,3H),7.48(dd,J＝8.0,1.2Hz,1H),7.37–7.29(m,3H),7.25(td,J＝7.6,1.6Hz,1H),6.33(d,J＝2.0Hz,1H),6.01(d,J＝12.0Hz,1H),4.62-4.60(m,0.5H),4.45-4.44(m,0.5H),4.33-4.29(m,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.79–3.70(m,2H),3.46(s,3H),2.99-2.92(m,1H),2.62–2.50(m,1H),1.99–1.69(m,6H),1.36–1.20(m,1H),1.12(s,3H),0.93-0.85(m,1H),0.78-0.74(m,1H),0.07–-0.04(m,1H),-0.11--0.14(m,1H).
实施例101 化合物101-a,101-b的制备
Figure PCTCN2020107845-appb-000192
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例23中间体23缩合得到化合物101-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物101-a。MS m/z：706(M+1) +.化合物101-b的核磁为： 1H NMR(400MHz,Methanol-d 4)δ7.65(s,1H),7.63–7.55(m,2H),7.50–7.45(m,1H),7.37–7.30(m,3H),7.28–7.21(m,1H),6.37–6.28(m,1H),6.02(d,J＝11.9Hz,1H),4.79–4.67(m,1H),4.61(s,0H),4.48–4.40(m,1H),4.05(d,J＝9.6Hz,1H),3.86(s,3H),3.80–3.70(m,2H),3.46(s,3H),3.26–3.13(m,2H),2.34(ddq,J＝23.3,11.8,6.0Hz,2H),2.13–1.99(m,2H),1.99–1.84(m,1H),1.62(s,3H),1.15–1.07(m,6H),0.82–0.71(m,1H),0.06–-0.03(m,1H),-0.07–-0.17(m,2H).
实施例102 化合物102-a,102-b的制备
Figure PCTCN2020107845-appb-000193
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例24中间体24缩合得到化合物102-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物102-a。MS m/z：724(M+1) +.化合物102-b的核磁为： 1H NMR(400MHz,Methanol-d 4)δ7.67–7.53(m,4H),7.45(dd,J＝8.0,1.2Hz,1H),7.33–7.26(m,3H),7.23(td,J＝7.6,1.6Hz,1H),6.31(d,J＝2.0Hz,1H),5.99(d,J＝12.0Hz,1H),4.48(t,J＝7.6Hz,1H),4.06(d,J＝9.6Hz,1H),3.84(s,3H),3.76-3.71(m,2H),3.44(s,3H),3.24–3.11(m,2H),2.64–2.25(m,6H),1.61(s,3H),1.11-1.06(m,6H),0.81–0.71(m,1H),0.02--0.03(m,1H),-0.09–-0.21(m,2H).
实施例103 化合物103-a,103-b的制备
Figure PCTCN2020107845-appb-000194
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例25中间体25缩合得到化合物103-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物103-a。MS m/z：702(M+1) +.化合物103-b再经SFC拆分得两个组分峰(为3-甲基环丁基的顺反结构)，组分之一103-b1的核磁为： 1H NMR(400MHz,Methanol-d 4)δ7.74-7.52(m,3H),7.46(d,J＝8.0Hz,1H),7.37-7.28(m,3H),7.25(t,J＝7.6Hz,1H),6.33(d,J＝2.0Hz,1H),6.01(d,J＝12.0Hz,1H),4.31(d,5.6Hz,1H),4.05(d,J＝9.6Hz,1H),3.76(dd,J＝12.0Hz,4.0Hz,2H),3.46(s,3H),3.28-3.09(m,2H),2.41-2.34(m,,1H),2.24-1.95(m,3H),1.60(s 3H),1.47-1.39(m,1H),1.33-1.21(m,1H),1.15-1.04(m,6H),0.93(d,J＝6.4Hz,3H),0.81-0.72(m,1H),0.03--0.01(m,1H),-0.08--0.16(m,2H)；组分之二103-b2的核磁为： 1H NMR(400MHz,Methanol-d 4)δ7.72-7.52(m,3H),7.51-7.45(m,1H),7.36-7.29(m,3H),7.28-7.21(m,1H),6.34(d,J＝2.0Hz,1H),6.01(d,J＝12.0Hz,1H),4.44-4.40(m,1H),4.05(d,J＝9.6Hz,1H),3.87(s,3H),3.77-3.73(m,2H),3.45(s,3H),3.25-3.11(m,2H),2.65-2.52(m,1H),2.34-2.21(m,1H),2.10-2.04(m,1H),1.96-1.89(m,1H),1.68-1.52(m,5H),1.15-1.04(m,9H),0.83-0.70(m,1H),0.06--0.03(m,1H),-0.08--0.18(m,2H).
实施例104 化合物104-a,104-b的制备
Figure PCTCN2020107845-appb-000195
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例26中间体26缩 合得到化合物104-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物104-a。MS m/z：718(M+1) +.化合物104-b再经SFC拆分得两个组分峰(为3-甲氧基环丁基的顺反结构).组分之一104-b1；组分之二104-b2。
实施例105 化合物105-a,105-b的制备
Figure PCTCN2020107845-appb-000196
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例27中间体27缩合得到化合物105-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物105-a。MS m/z：702(M+1) +.105-b的核磁为： 1H NMR(400MHz,Methanol-d 4)δ7.72(s,1H),7.69–7.60(m,2H),7.60–7.52(m,3H),7.52–7.43(m,3H),7.33(dd,J＝8.8,4.2Hz,8H),7.29–7.16(m,2H),6.34(s,3H),6.01(d,J＝11.9Hz,3H),4.48–4.32(m,3H),4.04(d,J＝9.7Hz,3H),3.87(s,8H),3.82–3.68(m,5H),3.54–3.49(m,1H),3.17–3.13(m,1H),2.28–2.17(m,3H),2.14–2.02(m,3H),1.97–1.86(m,2H),1.82–1.67(m,3H),1.55(s,4H),1.17–1.02(m,25H),0.81–0.69(m,2H),0.06–-0.04(m,3H),-0.07–-0.22(m,6H).
实施例106 化合物106-a,106-b的制备
Figure PCTCN2020107845-appb-000197
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例28中间体28缩合得到化合物106-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物106-a。MS m/z： 706(M+1) +.
实施例107 化合物107-a,107-b的制备
Figure PCTCN2020107845-appb-000198
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例29中间体29缩合得到化合物107-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物107-a。MS m/z：720(M+1) +.
实施例108 化合物108-a,108-b的制备
Figure PCTCN2020107845-appb-000199
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例30中间体30缩合得到化合物108-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物108-a。MS m/z：714(M+1) +.
实施例109 化合物109-a,109-b的制备
Figure PCTCN2020107845-appb-000200
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例31中间体31缩合得到化合物109-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物109-a。MS m/z：700(M+1) +.化合物109-b的核磁为：1H NMR(400MHz,Methanol-d4)δ7.68(s,1H),7.65–7.54(m,2H),7.48(dd,J＝7.9,1.4Hz,1H),7.39–7.29(m,3H),7.25(td,J＝7.6,1.6Hz,1H),6.34(d,J＝2.2Hz,1H),6.02(d,J＝11.9Hz,1H),4.42(t,J＝2.6Hz,1H),4.01(d,J＝9.7Hz,1H),3.87(s,3H),3.76(t,2H),3.47(s,3H),3.29–3.11(m,2H),2.44(s,1H),1.75–1.63(m,6H),1.60(s,3H),1.12(t,6H),0.81–0.71(m,1H),0.06–-0.04(m,1H),-0.08–-0.18(m,2H).
实施例110 化合物110-a,110-b的制备
Figure PCTCN2020107845-appb-000201
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例32中间体32缩合得到化合物110-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物110-a。MS m/z：714(M+1) +.化合物110-b的核磁为： 1H NMR(400MHz,Methanol-d 4)δ7.78–7.51(m,3H),7.48(dd,J＝8.0,1.4Hz,1H),7.41(d,J＝7.7Hz,1H),7.38–7.29(m,3H),7.25(td,J＝7.7,1.6Hz,1H),6.34(d,J＝2.1Hz,1H),6.02(d,J＝12.0Hz,1H),4.43(d,1H),4.01(d,J＝9.7Hz,1H),3.87(s,3H),3.76(t,2H),3.47(s,3H),3.30–3.10(m,2H),1.59(s,3H),1.55–1.45(m,6H),1.17–1.07(m,9H),0.81–0.72(m,1H),0.05–-0.03(m,1H),-0.13(ddd,J＝8.8,6.1,2.1Hz,2H).
实施例111 化合物111-a,111-b的制备
Figure PCTCN2020107845-appb-000202
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例33中间体33缩合得到化合物111-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合得到化合物111-a。MS m/z：718(M+1) +.化合物111-b的核磁为： 1H NMR(400MHz,Methanol-d 4)δ8.16(s,1H),7.68(s,1H),7.65–7.60(m,1H),7.60–7.55(m,2H),7.50–7.45(m,1H),7.38–7.30(m,3H),7.29–7.22(m,1H),6.40–6.26(m,1H),6.02(d,J＝11.6Hz,1H),4.74(d,J＝7.7Hz,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.81–3.71(m,2H),3.47(s,3H),3.29–3.10(m,2H),1.97–1.85(m,6H),1.60(s,3H),1.17–1.09(m,6H),0.82–0.73(m,1H),0.07–-0.03(m,1H),-0.12(t,J＝7.5Hz,2H).
实施例112 化合物112-a,112-b,112-c,112-d,112-e,112-f,112-g,112-h的制备
Figure PCTCN2020107845-appb-000203
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例9中间体9缩合，再经SFC手性拆分制备得到化合物112-a,112-b,112-c,112-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物112-e,112-f,112-g,112-h。MS m/z：680(M+1) +。
实施例113 化合物113-a,113-b,113-c,113-d,113-e,113-f,113-g,113-h的制备
Figure PCTCN2020107845-appb-000204
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物113-a,113-b,113-c,113-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物113-e,113-f,113-g,113-h。MS m/z：694(M+1) +。113-b核磁氢谱： 1H NMR(400MHz,MeOD):δ＝7.97(t,J＝4.4Hz,1H),7.58(s,1H),7.53(d,J＝8.4Hz,1H),7.46(d,J＝8.0Hz,1H),7.41(d,J＝2.0Hz,1H),7.30-7.24(m,2H),7.21(d,J＝7.2Hz,1H),7.16-7.11(m,1H),6.56(d,J＝2.4Hz,1H),6.11(d,J＝8.8Hz,1H),4.36(t,J＝8.8Hz,1H),4.17(t,J＝8.4Hz,1H),4.00(t,J＝9.6Hz,1H),3.97(s,3H),3.73(d,J＝9.6Hz,1H),3.43(s,3H),3.25-3.13(m,2H),2.61-2.55(m,1H),2.30-2.25(m,1H),1.96-1.74(m,6H),1.58(s,3H),1.10(t,J＝7.2Hz,3H),0.94(d,J＝6.4Hz,3H),0.84(dd,d1＝1.6Hz,d2＝6.8Hz,1H).
实施例114 化合物114-a,114-b,114-c,114-d,114-e,114-f,114-g,114-h的制备
Figure PCTCN2020107845-appb-000205
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例10中间体10缩合，再经SFC手性拆分制备得到化合物114-a,114-b,114-c,114-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物114-e,114-f,114-g,114-h。MS m/z：706(M+1) +。
实施例115 化合物115-a,115-b,115-c,115-d,115-e,115-f,115-g,115-h的制备
Figure PCTCN2020107845-appb-000206
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例11中间体11缩合，再经SFC手性拆分制备得到化合物115-a,115-b,115-c,115-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物115-e,115-f,115-g,115-h。MS m/z：720(M+1) +。
实施例116 化合物116-a,116-b,116-c,116-d,116-e,116-f,116-g,116-h的制备
Figure PCTCN2020107845-appb-000207
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例12中间体12缩合，再经SFC手性拆分制备得到化合物116-a,116-b,116-c,116-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物116-e,116-f,116-g,116-h。MS m/z：736(M+1) +。
实施例117 化合物117-a,117-b,117-c,117-d,117-e,117-f,117-g,117-h的制备
Figure PCTCN2020107845-appb-000208
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例13中间体13缩合，再经SFC手性拆分制备得到化合物117-a,117-b,117-c,117-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物117-e,117-f,117-g,117-h。MS m/z：750(M+1) +。
实施例118 化合物118-a,118-b,118-c,118-d,118-e,118-f,118-g,118-h的制备
Figure PCTCN2020107845-appb-000209
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例14中间体14缩合，再经SFC手性拆分制备得到化合物118-a,118-b,118-c,118-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物118-e,118-f,118-g,118-h。MS m/z：738(M+1) +。
实施例119 化合物119-a,119-b,119-c,119-d,119-e,119-f,119-g,119-h的制备
Figure PCTCN2020107845-appb-000210
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例15中间体15缩合，再经SFC手性拆分制备得到化合物119-a,119-b,119-c,119-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物119-e,119-f,119-g,119-h。MS m/z：730(M+1) +。
实施例120 化合物120-a,120-b,120-c,120-d,120-e,120-f,120-g,120-h的制备
Figure PCTCN2020107845-appb-000211
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例16中间体16缩合，再经SFC手性拆分制备得到化合物120-a,120-b,120-c,120-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物120-e,120-f,120-g,120-h。MS m/z：712(M+1) +。
实施例121 化合物121-a,121-b,121-c,121-d,121-e,121-f,121-g,121-h的制备
Figure PCTCN2020107845-appb-000212
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例17中间体17缩合，再经SFC手性拆分制备得到化合物121-a,121-b,121-c,121-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物121-e,121-f,121-g,121-h。MS m/z：708(M+1) +。
实施例122 化合物122-a,122-b,122-c,122-d,122-e,122-f,122-g,122-h的制备
Figure PCTCN2020107845-appb-000213
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例18中间体18缩合，再经SFC手性拆分制备得到化合物122-a,122-b,122-c,122-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物122-e,122-f,122-g,122-h。MS m/z：710(M+1) +。
实施例123 化合物123-a,123-b,123-c,123-d,123-e,123-f,123-g,123-h的制备
Figure PCTCN2020107845-appb-000214
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例19中间体19缩合，再经SFC手性拆分制备得到化合物123-a,123-b,123-c,123-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物123-e,123-f,123-g,123-h。MS m/z：724(M+1) +。
实施例124 化合物124-a,124-b,124-c,124-d,124-e,124-f,124-g,124-h的制备
Figure PCTCN2020107845-appb-000215
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例20中间体20缩合，再经SFC手性拆分制备得到化合物124-a,124-b,124-c,124-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物124-e,124-f,124-g,124-h。MS m/z：722(M+1) +。
实施例125 化合物125-a,125-b,125-c,125-d,125-e,125-f,125-g,125-h的制备
Figure PCTCN2020107845-appb-000216
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例21中间体21缩合，再经SFC手性拆分制备得到化合物125-a,125-b,125-c,125-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物125-e,125-f,125-g,125-h。MS m/z：724(M+1) +。
实施例126 化合物126-a,126-b,126-c,126-d,126-e,126-f,126-g,126-h的制备
Figure PCTCN2020107845-appb-000217
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例22中间体22缩合，再经SFC手性拆分制备得到化合物126-a,126-b,126-c,126-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物126-e,126-f,126-g,126-h。MS m/z：724(M+1) +。
实施例127 化合物127-a,127-b,127-c,127-d,127-e,127-f,127-g,127-h的制备
Figure PCTCN2020107845-appb-000218
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例23中间体23缩合，再经SFC手性拆分制备得到化合物127-a,127-b,127-c,127-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物127-e,127-f,127-g,127-h。MS m/z：712(M+1) +。
实施例128 化合物128-a,128-b,128-c,128-d,128-e,128-f,128-g,128-h的制备
Figure PCTCN2020107845-appb-000219
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例24中间体24缩合，再经SFC手性拆分制备得到化合物128-a,128-b,128-c,128-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物128-e,128-f,128-g,128-h。MS m/z：730(M+1) +。
实施例129 化合物129-a,129-b,129-c,129-d,129-e,129-f,129-g,129-h的制备
Figure PCTCN2020107845-appb-000220
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例25中间体25缩合，再经SFC手性拆分制备得到化合物129-a,129-b,129-c,129-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物129-e,129-f,129-g,129-h。MS m/z：708(M+1) +。
实施例130 化合物130-a,130-b,130-c,130-d,130-e,130-f,130-g,130-h的制备
Figure PCTCN2020107845-appb-000221
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例26中间体26缩合，再经SFC手性拆分制备得到化合物130-a,130-b,130-c,130-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物130-e,130-f,130-g,130-h。MS m/z：724(M+1) +。
实施例131 化合物131-a,131-b,131-c,131-d,131-e,131-f,131-g,131-h的制备
Figure PCTCN2020107845-appb-000222
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例27中间体27缩合，再经SFC手性拆分制备得到化合物131-a,131-b,131-c,131-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物131-e,131-f,131-g,131-h。MS m/z：708(M+1) +。
实施例132 化合物132-a,132-b,132-c,132-d,132-e,132-f,132-g,132-h的制备
Figure PCTCN2020107845-appb-000223
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例28中间体28缩合，再经SFC手性拆分制备得到化合物132-a,132-b,132-c,132-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物132-e,132-f,132-g,132-h。MS m/z：712(M+1) +。
实施例133 化合物133-a,133-b,133-c,133-d,133-e,133-f,133-g,133-h的制备
Figure PCTCN2020107845-appb-000224
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例29中间体29缩合，再经SFC手性拆分制备得到化合物133-a,133-b,133-c,133-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物133-e,133-f,133-g,133-h。MS m/z：726(M+1) +。
实施例134 化合物134-a,134-b,134-c,134-d,134-e,134-f,134-g,134-h的制备
Figure PCTCN2020107845-appb-000225
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例30中间体30缩合，再经SFC手性拆分制备得到化合物134-a,134-b,134-c,134-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物134-e,134-f,134-g,134-h。MS m/z：720(M+1) +。
实施例135 化合物135-a,135-b,135-c,135-d,135-e,135-f,135-g,135-h的制备
Figure PCTCN2020107845-appb-000226
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例31中间体31缩合，再经SFC手性拆分制备得到化合物135-a,135-b,135-c,135-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物135-e,135-f,135-g,135-h。MS m/z：706(M+1) +。
实施例136 化合物136-a,136-b,136-c,136-d,136-e,136-f,136-g,136-h的制备
Figure PCTCN2020107845-appb-000227
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例32中间体32缩合，再经SFC手性拆分制备得到化合物136-a,136-b,136-c,136-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物136-e,136-f,136-g,136-h。MS m/z：720(M+1) +。
实施例137 化合物137-a,137-b,137-c,137-d,137-e,137-f,137-g,137-h的制备
Figure PCTCN2020107845-appb-000228
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例33中间体33缩合，再经SFC手性拆分制备得到化合物137-a,137-b,137-c,137-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物137-e,137-f,137-g,137-h。MS m/z：724(M+1) +。
实施例138 化合物138-a,138-b,138-c,138-d,138-e,138-f,138-g,138-h的制备
Figure PCTCN2020107845-appb-000229
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例9中间体9缩合，再经SFC手性拆分制备得到化合物138-a,138-b,138-c,138-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物138-e,138-f,138-g,138-h。MS m/z：680(M+1) +。
实施例139 化合物139-a,139-b,139-c,139-d,139-e,139-f,139-g,139-h的制备
Figure PCTCN2020107845-appb-000230
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物139-a,139-b,139-c,139-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物139-e,139-f,139-g,139-h。MS m/z：680(M+1) +。
实施例140 化合物140-a,140-b,140-c,140-d,140-e,140-f,140-g,140-h的制备
Figure PCTCN2020107845-appb-000231
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例10中间体10缩合，再经SFC手性拆分制备得到化合物140-a,140-b,140-c,140-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物140-e,140-f,140-g,140-h。MS m/z：706(M+1) +。
实施例141 化合物141-a,141-b,141-c,141-d,141-e,141-f,141-g,141-h的制备
Figure PCTCN2020107845-appb-000232
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例11中间体11缩合，再经SFC手性拆分制备得到化合物141-a,141-b,141-c,141-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物141-e,141-f,141-g,141-h。MS m/z：720(M+1) +。
实施例142 化合物142-a,142-b,142-c,142-d,142-e,142-f,142-g,142-h的制备
Figure PCTCN2020107845-appb-000233
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例12中间体12缩合，再经SFC手性拆分制备得到化合物142-a,142-b,142-c,142-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物142-e,142-f,142-g,142-h。MS m/z：736(M+1) +。
实施例143 化合物143-a,143-b,143-c,143-d,143-e,143-f,143-g,143-h的制备
Figure PCTCN2020107845-appb-000234
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例13中间体13缩合，再经SFC手性拆分制备得到化合物143-a,143-b,143-c,143-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物143-e,143-f,143-g,143-h。MS m/z：750(M+1) +。
实施例144 化合物144-a,144-b,144-c,144-d,144-e,144-f,144-g,144-h的制备
Figure PCTCN2020107845-appb-000235
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例14中间体14缩合，再经SFC手性拆分制备得到化合物144-a,144-b,144-c,144-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物144-e,144-f,144-g,144-h。MS m/z：738(M+1) +。
实施例145 化合物145-a,145-b,145-c,145-d,145-e,145-f,145-g,145-h的制备
Figure PCTCN2020107845-appb-000236
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例15中间体15缩合，再经SFC手性拆分制备得到化合物145-a,145-b,145-c,145-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物145-e,145-f,145-g,145-h。MS m/z：730(M+1) +。
实施例146 化合物146-a,146-b,146-c,146-d,146-e,146-f,146-g,146-h的制备
Figure PCTCN2020107845-appb-000237
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例16中间体16缩合，再经SFC手性拆分制备得到化合物146-a,146-b,146-c,146-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物146-e,146-f,146-g,146-h。MS m/z：712(M+1) +。
实施例147 化合物147-a,147-b,147-c,147-d,147-e,147-f,147-g,147-h的制备
Figure PCTCN2020107845-appb-000238
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例17中间体17缩合，再经SFC手性拆分制备得到化合物147-a,147-b,147-c,147-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物147-e,147-f,147-g,147-h。MS m/z：708(M+1) +。
实施例148 化合物148-a,148-b,148-c,148-d,148-e,148-f,148-g,148-h的制备
Figure PCTCN2020107845-appb-000239
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例18中间体18缩合，再经SFC手性拆分制备得到化合物148-a,148-b,148-c,148-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物148-e,148-f,148-g,148-h。MS m/z：710(M+1) +。
实施例149 化合物149-a,149-b,149-c,149-d,149-e,149-f,149-g,149-h的制备
Figure PCTCN2020107845-appb-000240
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例19中间体19缩合，再经SFC手性拆分制备得到化合物149-a,149-b,149-c,149-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物149-e,149-f,149-g,149-h。MS m/z：724(M+1) +。
实施例150 化合物150-a,150-b,150-c,150-d,150-e,150-f,150-g,150-h的制备
Figure PCTCN2020107845-appb-000241
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例20中间体20缩合，再经SFC手性拆分制备得到化合物150-a,150-b,150-c,150-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物150-e,150-f,150-g,150-h。MS m/z：722(M+1) +。
实施例151 化合物151-a,151-b,151-c,151-d,151-e,151-f,151-g,151-h的制备
Figure PCTCN2020107845-appb-000242
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例21中间体21缩合，再经SFC手性拆分制备得到化合物151-a,151-b,151-c,151-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物151-e,151-f,151-g,151-h。MS m/z：724(M+1) +。
实施例152 化合物152-a,152-b,152-c,152-d,152-e,152-f,152-g,152-h的制备
Figure PCTCN2020107845-appb-000243
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例22中间体22缩合，再经SFC手性拆分制备得到化合物152-a,152-b,152-c,152-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物152-e,152-f,152-g,152-h。MS m/z：724(M+1) +。
实施例153 化合物153-a,153-b,153-c,153-d,153-e,153-f,153-g,153-h的制备
Figure PCTCN2020107845-appb-000244
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例23中间体23缩合，再经SFC手性拆分制备得到化合物153-a,153-b,153-c,153-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物153-e,153-f,153-g,153-h。MS m/z：712(M+1) +。
实施例154 化合物154-a,154-b,154-c,154-d,154-e,154-f,154-g,154-h的制备
Figure PCTCN2020107845-appb-000245
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例24中间体24缩合，再经SFC手性拆分制备得到化合物154-a,154-b,154-c,154-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物154-e,154-f,154-g,154-h。MS m/z：730(M+1) +。
实施例155 化合物155-a,155-b,155-c,155-d,155-e,155-f,155-g,155-h的制备
Figure PCTCN2020107845-appb-000246
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例25中间体25缩合，再经SFC手性拆分制备得到化合物155-a,155-b,155-c,155-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物155-e,155-f,155-g,155-h。MS m/z：708(M+1) +。
实施例156 化合物156-a,156-b,156-c,156-d,156-e,156-f,156-g,156-h的制备
Figure PCTCN2020107845-appb-000247
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例26中间体26缩合，再经SFC手性拆分制备得到化合物156-a,156-b,156-c,156-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物156-e,156-f,156-g,156-h。MS m/z：724(M+1) +。
实施例157 化合物157-a,157-b,157-c,157-d,157-e,157-f,157-g,157-h的制备
Figure PCTCN2020107845-appb-000248
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例27中间体27缩合，再经SFC手性拆分制备得到化合物157-a,157-b,157-c,157-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物157-e,157-f,157-g,157-h。MS m/z：708(M+1) +。
实施例158 化合物158-a,158-b,158-c,158-d,158-e,158-f,158-g,158-h的制备
Figure PCTCN2020107845-appb-000249
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例28中间体28缩合，再经SFC手性拆分制备得到化合物158-a,158-b,158-c,158-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物158-e,158-f,158-g,158-h。MS m/z：712(M+1) +。
实施例159 化合物159-a,159-b,159-c,159-d,159-e,159-f,159-g,159-h的制备
Figure PCTCN2020107845-appb-000250
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例29中间体29缩合，再经SFC手性拆分制备得到化合物159-a,159-b,159-c,159-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物159-e,159-f,159-g,159-h。MS m/z：726(M+1) +。
实施例160 化合物160-a,160-b,160-c,160-d,160-e,160-f,160-g,160-h的制备
Figure PCTCN2020107845-appb-000251
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例30中间体30缩合，再经SFC手性拆分制备得到化合物160-a,160-b,160-c,160-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物160-e,160-f,160-g,160-h。MS m/z：720(M+1) +。
实施例161 化合物161-a,161-b,161-c,161-d,161-e,161-f,161-g,161-h的制备
Figure PCTCN2020107845-appb-000252
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例31中间体31缩合，再经SFC手性拆分制备得到化合物161-a,161-b,161-c,161-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物161-e,161-f,161-g,161-h。MS m/z：706(M+1) +。
实施例162 化合物162-a,162-b,162-c,162-d,162-e,162-f,162-g,162-h的制备
Figure PCTCN2020107845-appb-000253
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例32中间体32缩合，再经SFC手性拆分制备得到化合物162-a,162-b,162-c,162-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物162-e,162-f,162-g,162-h。MS m/z：720(M+1) +。
实施例163 化合物163-a,163-b,163-c,163-d,163-e,163-f,163-g,163-h的制备
Figure PCTCN2020107845-appb-000254
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例33中间体33缩合，再经SFC手性拆分制备得到化合物163-a,163-b,163-c,163-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物163-e,163-f,163-g,163-h。MS m/z：724(M+1) +。
实施例164 化合物164-a,164-b的制备
Figure PCTCN2020107845-appb-000255
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合得到化合物164-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，缩合得到化合物164-a。MS m/z：702(M+1) +。164b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.66(s,1H),7.61–7.58(m,2H),7.48–7.45(m,2H),7.35–7.31(m,3H),7.24(td,J＝8.0,1.6Hz,1H),6.34(d,J＝2.0Hz,1H),6.02(d,J＝12.0Hz,1H),4.40–4.24(m,3H),4.04(d,J＝9.6Hz,1H),3.78-3.74(m,2H),3.45(s,3H),3.25-3.15(m,2H),2.61–2.56(m,1H),1.99–1.75(m,7H),1.61(s,3H),1.34–1.27(m,2H),1.18(t,J＝7.2Hz,3H),1.13-1.08(m,7H),0.78-0.74(m,1H),-0.01--0.02(m,1H),-0.11--0.16(m,2H).
实施例165 化合物165-a,165-b的制备
Figure PCTCN2020107845-appb-000256
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，最后与实施例7中间体7-2缩合得到化合物165-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，缩合得到化合物165-a。MS m/z：636(M+1) +。165b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ8.01–7.91(m,1H),7.67–7.24(m,8H),5.86(d,J＝12.0Hz,1H),4.38(t,J＝8.3Hz,1H),4.04(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.66(d,J＝12.0Hz,1H),3.46(s,3H),3.26–3.14(m,2H),2.66–2.53(m,1H),2.01–1.72(m,8H),1.61(s,3H),1.47–1.19(m,3H),1.16–1.02(m,6H),0.99–0.84(m,1H),0.78(t,J＝7.6Hz,4H),0.01–-0.04(m,1H),-0.13–-0.20(m,2H).
实施例166 化合物166-a,166-b的制备
Figure PCTCN2020107845-appb-000257
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入异丁酰基，水解，最后与实施例7中间体7-2缩合得到化合物166-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入异丁酰基，水解，缩合得到化合物166-a。MS m/z：650(M+1) +。166-b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.95(s,0H),7.69–7.22(m,8H),5.87(d,J＝12.0Hz,1H),4.43–4.33(m,1H),4.04(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.64(d,J＝12.0Hz,1H),3.46(s,3H),3.26–3.14(m,2H),2.69–2.50(m,1H),2.23–2.13(m,1H),2.00–1.71(m,6H),1.61(s,3H),1.18–1.03(m,6H),0.83(d,J＝6.8Hz,3H),0.79–0.71(m,1H),0.66(d,J＝6.9Hz,3H),0.01–-0.06(m,1H),-0.12–-0.22(m,2H).
实施例167 化合物167-a,167-b的制备
Figure PCTCN2020107845-appb-000258
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，最后与实施例7中间体7-2缩合得到化合物167-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，缩合得到化合物167-a。MS m/z：677(M+1) +。167-b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.99(s,1H),7.71–7.61(m,2H),7.61–7.47(m,3H),7.45–7.26(m,3H),5.68(d,J＝11.6Hz,1H),4.38(t,J＝8.3Hz,1H),4.03(d,J＝9.6Hz,1H),3.77(d,J＝9.6Hz,1H),3.60(d,J＝11.6Hz,1H),3.46(s,3H),3.29–3.15(m,1H),2.96(s,2H),2.65–2.55(m,1H),1.98–1.82(m,3H),1.78(d,J＝6.6Hz,8H),1.61(s,3H),1.31(s,1H),1.16–1.07(m,6H),0.77–0.68(m,1H),0.12(s,2H),-0.06–-0.24(m,2H).
实施例168 化合物168-a,168-b的制备
Figure PCTCN2020107845-appb-000259
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，最后与实施例7中间体7-2缩合得到化合物168-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，缩合得到化合物168-a。MS m/z：651(M+1) +。168-b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.95(s,1H),7.72–7.17(m,8H),5.66(d,J＝11.7Hz,1H),4.38(t,J＝8.3Hz,1H),4.04(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.65–3.54(m,1H),3.52–3.49(m,0H),3.46(s,3H),3.27–3.13(m,2H),2.66(s,6H),2.60(q,J＝7.9Hz,1H),2.01–1.73(m,6H),1.61(s,3H),1.31(s,1H),1.16–1.05(m,6H),0.91(d,J＝7.8Hz,1H),0.70(d,J＝7.0Hz,1H),0.00–-0.05(m,1H),-0.13–-0.22(m,2H).
实施例169 化合物169-a,169-b的制备
Figure PCTCN2020107845-appb-000260
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，最后与实施例7中间体7-2缩合得到化合物169-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，缩合得到化合物169-a。MS m/z：637(M+1) +。169-b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.62(d,J＝1.7Hz,1H),7.59–7.52(m,2H),7.50–7.42(m,2H),7.36(td,J＝7.6,1.4Hz,1H),7.31–7.22(m,2H),5.62(d,J＝11.7Hz,1H),4.37(t,J＝8.3Hz,1H),4.04(d,J＝9.6Hz,1H),3.75(d,J＝9.6Hz,1H),3.55–3.48(m,1H),3.46(s,3H),3.25–3.13(m,2H),2.59(q,J＝7.9Hz,1H),2.51(s,3H),2.00–1.72(m,6H),1.60(s,3H),1.14–1.04(m,7H),0.75(dt,J＝10.0,5.3Hz,1H),-0.01–-0.08(m,1H),-0.16–-0.25(m,2H).
实施例170 化合物170-a,170-b的制备
Figure PCTCN2020107845-appb-000261
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，最后与实施例7中间体7-2缩合得到化合物170-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，缩合得到化合物170-a。MS m/z：665(M+1) +， 1H NMR(400MHz,Methanol-d 4)δ7.63(s,1H),7.56(t,2H),7.47(t,2H),7.39–7.22(m,3H),5.68(d,J＝11.8Hz,1H),4.38(t,J＝8.3Hz,1H),4.05(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.57(d,J＝11.7Hz,1H),3.46(s,3H),3.27–2.98(m,6H),2.63(s,3H),1.99–1.73(m,6H),1.61(s,3H),1.12(t,6H),1.09(s,1H),0.78(t,J＝7.1Hz,3H),0.73–0.65(m,1H),0.01–-0.06(m,1H),-0.14–-0.26(m,2H).
实施例171 化合物171-a,171-b的制备
Figure PCTCN2020107845-appb-000262
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，最后与实施例7中间体7-2缩合得到化合物171-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，缩合得到化合物171-a。MS m/z：651(M+1) +。171-b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.62(s,1H),7.57–7.54(m,2H),7.48-7.43(m,2H),7.36(t,J＝7.2Hz,1H),7.27(t,J＝8.4Hz,2H),5.63(d,J＝11.6Hz,1H),4.38(t,J＝7.6Hz,1H),4.04(d,J＝9.6Hz,1H),3.75(d,J＝9.6Hz,1H),3.52(d,J＝11.6Hz,1H),3.45(s,3H),3.24-3.15(m,2H),2.95(dd,J＝6.8,4.0Hz,2H),2.59(d,J＝7.6Hz,1H),2.95–1.76(m,6H),1.60(s,3H),1.13–1.08(m,6H),0.91(t,J＝7.2Hz,3H),0.73–0.68(m,1H),0.01--0.06(m,1H),-0.17–-0.26(m,2H).
实施例172 化合物172-a,172-b的制备
Figure PCTCN2020107845-appb-000263
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，最后与实施例7中间体7-2缩合得到化合物172-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，缩合得到化合物172-a。MS m/z：679(M+1) +。172-b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.63(s,1H),7.57(t,J＝8.4Hz,2H),7.49-7.45(m,2H),7.37-7.24(m,3H),5.71(d,J＝12.0Hz,1H),4.38(t,J＝8.4Hz,1H),4.05(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.57(d,J＝11.6Hz,1H),3.46(s,3H),3.23–3.13(m,4H),3.02-2.93(m,2H),2.63-2.55(m,1H),1.98–1.75(m,6H),1.61(s,3H),1.39(d,J＝5.2Hz,1H),1.12–1.09(m,6H),0.80(t,J＝7.2Hz,6H),0.73–0.68(m,1H),0.01–-0.06(m,1H),-0.17–-0.26(m,2H).
实施例173 化合物173-a,173-b的制备
Figure PCTCN2020107845-appb-000264
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与实施例7中间体7-2缩合得到化合物173-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，缩合得到化合物173-a。MS m/z：679(M+1) +。173-b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.66–7.49(m,2H),7.46(d,J＝8.0Hz,1H),7.41–7.26(m,3H),7.20–7.05(m,1H),6.06–6.04(m,0.2H),5.73–5.62(m,0.8H),4.43–4.28(m,1H),4.05(d,J＝9.6Hz,0.6H),3.94(d,J＝9.6Hz,0.4H),3.76(d,J＝9.6Hz,0.6H),3.70–3.61(m,0.4H),3.56(d,J＝12.0Hz,1H),3.46(s,2H),3.40(s,1H),3.27–3.10(m,2H),2.89(s,1H),2.69(s,2H),2.37–2.22(m,1H),2.01–1.68(m,6H),1.61(s,2H),1.51(s,1H),1.24(s,1H),1.18–1.05(m,5H),1.03-0.80(m,3H),0.73–0.56(m,2H),0.50-0.45(m,0.5H),-0.06--0.05(m,0.5H),-0.15--0.31(m,2H)。
实施例174 化合物174-a,174-b的制备
Figure PCTCN2020107845-appb-000265
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6b(SFC手性拆分制备得到一单一构型)反应，经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合得到化合物174-b。类似地，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6a(SFC手性拆分制备得到另一单一构型)反应，经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，缩合得到化合物174-a。MS m/z：690(M+1) +。173b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.66(s,1H),7.61–7.58(m,2H),7.48–7.45(m,2H),7.35–7.31(m,3H),7.24(td,J＝8.0,1.6Hz,1H),6.34(d,J＝2.0Hz,1H),6.02(d,J＝12.0Hz,1H),4.40– 4.24(m,3H),4.04(d,J＝9.6Hz,1H),3.78-3.74(m,2H),3.45(s,3H),3.25-3.15(m,2H),2.61–2.56(m,1H),1.99–1.75(m,7H),1.61(s,3H),1.34–1.27(m,2H),1.18(t,J＝7.2Hz,3H),1.13-1.08(m,7H),0.78-0.74(m,1H),-0.01--0.02(m,1H),-0.11--0.16(m,2H).
实施例175 化合物175-a,175-b的制备
Figure PCTCN2020107845-appb-000266
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6b(SFC手性拆分制备得到一单一构型)反应，经缩合，关环，脱保护，引入丙酰基，水解，最后与实施例7中间体7-2缩合得到化合物175-b。类似地，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6a(SFC手性拆分制备得到另一单一构型)反应，经缩合，关环，脱保护，引入丙酰基，水解，缩合得到化合物175-a。MS m/z：624(M+1) +。
实施例176 化合物176-a,176-b的制备
Figure PCTCN2020107845-appb-000267
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6b(SFC手性拆分制备得到一单一构型)反应，经缩合，关环，脱保护，引入异丙酰基，水解，最后与实施例7中间体7-2缩合得到化合物176-b。类似地，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6a(SFC手性拆分制备得到另一单一构型)反应，经缩合，关环，脱保护，引入异丙酰基，水解，缩合得到化合物176-a。MS m/z：638(M+1) +。
实施例177 化合物177-a,177-b的制备
Figure PCTCN2020107845-appb-000268
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6b(SFC手性拆分制备得到一单一构型)反应，经缩合，关环，脱保护，引入吡咯烷基羰基，水解，最后与实施例7中间体7-2缩合得到化合物177-b。类似地，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6a(SFC手性拆分制备得到另一单一构型)反应，经缩合，关环，脱保护，引入吡咯烷基羰基，水解，缩合得到化合物177-a。MS m/z：665(M+1) +。
实施例178 化合物178-a,178-b的制备
Figure PCTCN2020107845-appb-000269
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6b(SFC手性拆分制备得到一单一构型)反应，经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，最后与实施例7中间体7-2缩合得到化合物178-b。类似地，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6a(SFC手性拆分制备得到另一单一构型)反应，经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，缩合得到化合物178-a。MS m/z：639(M+1) +。
实施例179 化合物179-a,179-b的制备
Figure PCTCN2020107845-appb-000270
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5(SFC 手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6b(SFC手性拆分制备得到一单一构型)反应，经缩合，关环，脱保护，引入甲胺羰基，水解，最后与实施例7中间体7-2缩合得到化合物179-b。类似地，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6a(SFC手性拆分制备得到另一单一构型)反应，经缩合，关环，脱保护，引入甲胺羰基，水解，缩合得到化合物179-a。MS m/z：625(M+1) +。
实施例180 化合物180-a,180-b的制备
Figure PCTCN2020107845-appb-000271
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6b(SFC手性拆分制备得到一单一构型)反应，经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，最后与实施例7中间体7-2缩合得到化合物180-b。类似地，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6a(SFC手性拆分制备得到另一单一构型)反应，经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，缩合得到化合物180-a。MS m/z：653(M+1) +。
实施例181 化合物181-a,181-b的制备
Figure PCTCN2020107845-appb-000272
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6b(SFC手性拆分制备得到一单一构型)反应，经缩合，关环，脱保护，引入乙胺羰基，水解，最后与实施例7中间体7-2缩合得到化合物181-b。类似地，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6a(SFC手性拆分制备得到另一单一构型)反应，经缩合，关环，脱保护，引入乙胺羰基，水解，缩合得到化合物181-a。MS m/z：639(M+1) +。
实施例182 化合物182-a,182-b的制备
Figure PCTCN2020107845-appb-000273
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6b(SFC手性拆分制备得到一单一构型)反应，经缩合，关环，脱保护，引入N’N-二乙基羰基，水解，最后与实施例7中间体7-2缩合得到化合物182-b。类似地，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6a(SFC手性拆分制备得到另一单一构型)反应，经缩合，关环，脱保护，引入N’N-二乙基羰基，水解，缩合得到化合物182-a。MS m/z：667(M+1) +。
实施例183 化合物183-a,183-b的制备
Figure PCTCN2020107845-appb-000274
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6b(SFC手性拆分制备得到一单一构型)反应，经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与实施例7中间体7-2缩合得到化合物183-b。类似地，以实施例1中步骤5的中间体1-5(SFC手性拆分得到的S,S对映体)和实施例6中步骤6的中间体6-6a(SFC手性拆分制备得到另一单一构型)反应，经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，缩合得到化合物183-a。MS m/z：665(M+1) +。
实施例184 化合物184-a,184-b,184-c,184-d,184-e,184-f,184-g,184-h的制备
Figure PCTCN2020107845-appb-000275
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物184-a,184-b,184-c,184-d。类似地，以实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物184-e,184-f,184-g,184-h。MS m/z：708(M+1) +。
实施例185 化合物185-a,185-b,185-c,185-d,185-e,185-f,185-g,185-h的制备
Figure PCTCN2020107845-appb-000276
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物185-a,185-b,185-c,185-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，缩合，再经SFC手性拆分制备得到化合物185-e,185-f,185-g,185-h。MS m/z：642(M+1) +。
实施例186 化合物186-a,186-b,186-c,186-d,186-e,186-f,186-g,186-h的制备
Figure PCTCN2020107845-appb-000277
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环， 脱保护，引入异丙酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物186-a,186-b,186-c,186-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入异丙酰基，水解，缩合，再经SFC手性拆分制备得到化合物186-e,186-f,186-g,186-h。MS m/z：656(M+1) +。
实施例187 化合物187-a,187-b,187-c,187-d,187-e,187-f,187-g,187-h的制备
Figure PCTCN2020107845-appb-000278
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物187-a,187-b,187-c,187-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，缩合，再经SFC手性拆分制备得到化合物187-e,187-f,187-g,187-h。MS m/z：683(M+1) +。
实施例188 化合物188-a,188-b,188-c,188-d,188-e,188-f,188-g,188-h的制备
Figure PCTCN2020107845-appb-000279
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物188-a,188-b,188-c,188-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，缩合，再经SFC手性拆分制备得到化合物188-e,188-f,188-g,188-h。MS m/z：657(M+1) +。
实施例189 化合物189-a,189-b,189-c,189-d,189-e,189-f,189-g,189-h的制备
Figure PCTCN2020107845-appb-000280
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物189-a,189-b,189-c,189-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，缩合，再经SFC手性拆分制备得到化合物189-e,189-f,189-g,189-h。MS m/z：643(M+1) +。
实施例190 化合物190-a,190-b,190-c,190-d,190-e,190-f,190-g,190-h的制备
Figure PCTCN2020107845-appb-000281
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物190-a,190-b,190-c,190-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物190-e,190-f,190-g,190-h。MS m/z：671(M+1) +。
实施例191 化合物191-a,191-b,191-c,191-d,191-e,191-f,191-g,191-h的制备
Figure PCTCN2020107845-appb-000282
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物191-a,191-b,191-c,191-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物191-e,191-f,191-g,191-h。MS m/z：657(M+1) +。
实施例192 化合物192-a,192-b,192-c,192-d,192-e,192-f,192-g,192-h的制备
Figure PCTCN2020107845-appb-000283
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物192-a,192-b,192-c,192-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物192-e,192-f,192-g,192-h。MS m/z：685(M+1) +。
实施例193 化合物193-a,193-b,193-c,193-d,193-e,193-f,193-g,193-h的制备
Figure PCTCN2020107845-appb-000284
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物193-a,193-b,193-c,193-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物193-e,193-f,193-g,193-h。MS m/z：683(M+1) +。
实施例194 化合物194-a,194-b,194-c,194-d,194-e,194-f,194-g,194-h的制备
Figure PCTCN2020107845-appb-000285
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物194-a,194-b,194-c,194-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物194-e,194-f,194-g,194-h。MS m/z：708(M+1) +。
实施例195 化合物195-a,195-b,195-c,195-d,195-e,195-f,195-g,195-h的制备
Figure PCTCN2020107845-appb-000286
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物195-a,195-b,195-c,195-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，缩合，再经SFC手性拆 分制备得到化合物195-e,195-f,195-g,195-h。MS m/z：642(M+1) +。
实施例196 化合物196-a,196-b,196-c,196-d,196-e,196-f,196-g,196-h的制备
Figure PCTCN2020107845-appb-000287
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入异丙酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物196-a,196-b,196-c,196-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入异丙酰基，水解，缩合，再经SFC手性拆分制备得到化合物196-e,196-f,196-g,196-h。MS m/z：656(M+1) +。
实施例197 化合物197-a,197-b,197-c,197-d,197-e,197-f,197-g,197-h的制备
Figure PCTCN2020107845-appb-000288
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物197-a,197-b,197-c,197-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，缩合，再经SFC手性拆分制备得到化合物197-e,197-f,197-g,197-h。MS m/z：683(M+1) +。
实施例198 化合物198-a,198-b,198-c,198-d,198-e,198-f,198-g,198-h的制备
Figure PCTCN2020107845-appb-000289
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物198-a,198-b,198-c,198-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，缩合，再经SFC手性拆分制备得到化合物198-e,198-f,198-g,198-h。MS m/z：657(M+1) +。
实施例199 化合物199-a,199-b,199-c,199-d,199-e,199-f,199-g,199-h的制备
Figure PCTCN2020107845-appb-000290
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物199-a,199-b,199-c,199-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，缩合，再经SFC手性拆分制备得到化合物199-e,199-f,199-g,199-h。MS m/z：643(M+1) +。
实施例200 化合物200-a,200-b,200-c,200-d,200-e,200-f,200-g,200-h的制备
Figure PCTCN2020107845-appb-000291
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和 实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物200-a,200-b,200-c,200-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物200-e,200-f,200-g,200-h。MS m/z：671(M+1) +。
实施例201 化合物201-a,201-b,201-c,201-d,201-e,201-f,201-g,201-h的制备
Figure PCTCN2020107845-appb-000292
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物201-a,201-b,201-c,201-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物201-e,201-f,201-g,201-h。MS m/z：657(M+1) +。
实施例202 化合物202-a,202-b,202-c,202-d,202-e,202-f,202-g,202-h的制备
Figure PCTCN2020107845-appb-000293
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物202-a,202-b,202-c,202-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物202-e,202-f,202-g,202-h。MS m/z：685 (M+1) +。
实施例203 化合物203-a,203-b,203-c,203-d,203-e,203-f,203-g,203-h的制备
Figure PCTCN2020107845-appb-000294
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物203-a,203-b,203-c,203-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物203-e,203-f,203-g,203-h。MS m/z：683(M+1) +。
实施例204 化合物204-a,204-b,204-c,204-d,204-e,204-f,204-g,204-h的制备
Figure PCTCN2020107845-appb-000295
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物204-a,204-b,204-c,204-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，缩合，再经SFC手性拆分制备得到化合物204-e,204-f,204-g,204-h。MS m/z：708(M+1) +。
实施例205 化合物205-a,205-b,205-c,205-d,205-e,205-f,205-g,205-h的制备
Figure PCTCN2020107845-appb-000296
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物205-a,205-b,205-c,205-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，缩合，再经SFC手性拆分制备得到化合物205-e,205-f,205-g,205-h。MS m/z：642(M+1) +。
实施例206 化合物206-a,206-b,206-c,206-d,206-e,206-f,206-g,206-h的制备
Figure PCTCN2020107845-appb-000297
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入异丙酰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物206-a,206-b,206-c,206-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入异丙酰基，水解，缩合，再经SFC手性拆分制备得到化合物206-e,206-f,206-g,206-h。MS m/z：656(M+1) +。
实施例207 化合物207-a,207-b,207-c,207-d,207-e,207-f,207-g,207-h的制备
Figure PCTCN2020107845-appb-000298
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环， 脱保护，引入N-吡咯烷基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物207-a,207-b,207-c,207-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，缩合，再经SFC手性拆分制备得到化合物207-a,207-b,207-c,207-d。MS m/z：683(M+1) +。
实施例208 化合物208-a,208-b,208-c,208-d,208-e,208-f,208-g,208-h的制备
Figure PCTCN2020107845-appb-000299
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物208-a,208-b,208-c,208-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，缩合，再经SFC手性拆分制备得到化合物208-e,208-f,208-g,208-h。MS m/z：657(M+1) +。
实施例209 化合物209-a,209-b,209-c,209-d,209-e,209-f,209-g,209-h的制备
Figure PCTCN2020107845-appb-000300
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物209-a,209-b,209-c,209-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，缩合，再经SFC手性拆分制备得到化合物209-e,209-f,209-g,209-h。MS m/z：643(M+1) +。
实施例210 化合物210-a,210-b,210-c,210-d,210-e,210-f,210-g,210-h 的制备
Figure PCTCN2020107845-appb-000301
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物210-a,210-b,210-c,210-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物210-e,210-f,210-g,210-h。MS m/z：671(M+1) +。
实施例211 化合物211-a,211-b,211-c,211-d,211-e,211-f,211-g,211-h的制备
Figure PCTCN2020107845-appb-000302
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物211-a,211-b,211-c,211-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物211-e,211-f,211-g,211-h。MS m/z：657(M+1) +。
实施例212 化合物212-a,212-b,212-c,212-d,212-e,212-f,212-g,212-h的制备
Figure PCTCN2020107845-appb-000303
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物212-a,212-b,212-c,212-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物212-e,212-f,212-g,212-h。MS m/z：685(M+1) +。
实施例213 化合物213-a,213-b,213-c,213-d,213-e,213-f,213-g,213-h的制备
Figure PCTCN2020107845-appb-000304
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与实施例7中间体7-2缩合，再经SFC手性拆分制备得到化合物213-a,213-b,213-c,213-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，缩合，再经SFC手性拆分制备得到化合物213-e,213-f,213-g,213-h。MS m/z：683(M+1) +。
实施例214 化合物214-a,214-b的制备
Figure PCTCN2020107845-appb-000305
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与L-环丁基-N-乙基甘胺酰胺缩合得到化合物214-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后L-环丁基-N-乙基甘胺酰胺缩合得到化合物214-a。MS m/z：688(M+1) +；214-b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ7.66(s,1H),7.61-7.56(m,2H),7.47(dd,J＝8.0,1.2Hz,1H),7.42(d,J＝8.0Hz,1H),7.38–7.28(m,3H),7.24(td,J＝7.8,1.6Hz,1H),6.91(d,J＝2.0Hz,1H),6.33(d,J＝2.0Hz,1H),6.01(d,J＝12.0Hz,1H),4.40–4.33(m,1H),4.14(s,1H),4.00(d,J＝9.6Hz,1H),3.87(s,3H),3.74(t,J＝11.2Hz,2H),3.42(s,3H),3.28–3.12(m,2H),2.61(dd,J＝15.2,7.6Hz,1H),2.01–1.74(m,7H),1.63(s,3H),1.16–1.07(m,6H),0.81–0.73(m,1H),0.01(dt,J＝10.0,5.2Hz,1H),-0.08–-0.17(m,2H).
实施例215 化合物215-a,215-b的制备
Figure PCTCN2020107845-appb-000306
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物215-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后D-异丙基-N-乙基甘胺酰胺缩合得到化合物215-a。MS m/z：676(M+1) +.215-b的核磁氢谱: 1H NMR(400MHz,Methanol-d 4)δ8.17–7.90(m,1H),7.66(s,1H),7.64–7.54(m,2H),7.52–7.43(m,1H),7.41–7.30(m,4H),7.29–7.16(m,1H),6.33(d,J＝2.2Hz,1H),6.01(d,J＝11.9Hz,1H),4.30–4.19(m,1H),4.04(d,J＝9.6Hz,1H),3.87(s,3H),3.80–3.69(m,2H),3.46(s,3H),3.29–3.13(m,2H),2.11 –1.93(m,1H),1.61(s,3H),1.18–1.06(m,6H),0.92(d,J＝6.8Hz,3H),0.83(d,J＝6.8Hz,3H),0.80–0.73(m,1H),0.06–-0.04(m,1H),-0.07–-0.19(m,2H).
实施例216 化合物216-a,216-b的制备
Figure PCTCN2020107845-appb-000307
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物216-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后D-叔丁基-N-乙基甘胺酰胺缩合得到化合物216-a。MS m/z：690(M+1) +.215-b的核磁氢谱: 1H NMR(400MHz,MeOD)δ8.16(t,J＝5.6Hz,1H),7.68(s,1H),7.82-7.57(m,2H),7.51–7.46(m,2H),7.35–7.32(m,3H),7.26(dd,J＝7.6,1.2Hz,1H),6.34(d,J＝1.6Hz,1H),6.02(d,J＝12.0Hz,1H),4.24(d,J＝8.8Hz,1H),4.02(d,J＝9.6Hz,1H),3.87(s,3H),3.76-3.72(m,2H),3.46(s,3H),3.29–3.15(m,2H),1.60(s,3H),1.15–1.11(m,6H),0.92(s,9H),0.79-0.74(m,1H),0.04–-0.02(m,1H),-0.14(t,J＝7.6Hz,2H).
实施例217 化合物217-a,217-b的制备
Figure PCTCN2020107845-appb-000308
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与D-异丙基-N-乙基甘胺酰胺缩合得到化合物217-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与D-异丙基-N-乙基甘胺酰胺缩合可得到化合物217-a。MS m/z：664(M+1) +。
实施例218 化合物218-a,218-b的制备
Figure PCTCN2020107845-appb-000309
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物218-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与D-叔丁基-N-乙基甘胺酰胺缩合可得到化合物218-a。MS m/z：678(M+1) +。218-b的核磁氢谱: 1H NMR(400MHz,MeOD)δ8.15(t,J＝5.6Hz,1H),7.62(s,1H),7.56-7.49(m,3H),7.39–7.33(m,3H),7.30(dd,J＝8.8,1.6Hz,1H),7.24(td,J＝7.6,1.6Hz,1H),6.51(s,1H),6.00(d,J＝9.2Hz,1H),4.23(d,J＝8.8Hz,1H),4.21-4.16(m,1H),4.00(d,J＝9.6Hz,1H),3.94(s,3H),3.71(d,J＝9.6Hz,1H),3.45(s,3H),3.29–3.13(m,2H),1.96-1.91(m,1H),1.58(s,3H),1.13(t,J＝7.2Hz,3H),1.01(d,J＝5.6Hz,3H),0.93(s,9H),0.86(d,J＝6.8Hz,3H).
实施例219 化合物219-a,219-b,219-c,219-d,219-e,219-f,219-g,219-h的制备
Figure PCTCN2020107845-appb-000310
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物219-a,219-b,219-c,219-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物219-e,219-f,219-g,219-h。MS m/z：682(M+1) +。
实施例220 化合物220-a,220-b,220-c,220-d,220-e,220-f,220-g,220-h的制备
Figure PCTCN2020107845-appb-000311
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物220-a,220-b,220-c,220-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物220-e,220-f,220-g,220-h。MS m/z：696(M+1) +。
实施例221 化合物221-a,221-b,221-c,221-d,221-e,221-f,221-g,221-h的制备
Figure PCTCN2020107845-appb-000312
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物221-a,221-b,221-c,221-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物221-e,221-f,221-g,221-h。MS m/z：682(M+1)+。
实施例222 化合物222-a,222-b,222-c,222-d,222-e,222-f,222-g,222-h的制备
Figure PCTCN2020107845-appb-000313
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物222-a,222-b,222-c,222-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物222-e,222-f,222-g,222-h。MS m/z：696(M+1) +。
实施例223 化合物223-a,223-b,223-c,223-d,223-e,223-f,223-g,223-h的制备
Figure PCTCN2020107845-appb-000314
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物223-a,223-b,223-c,223-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物223-e,223-f,223-g,223-h。MS m/z：682(M+1) +。
实施例224 化合物224-a,224-b,224-c,224-d,224-e,224-f,224-g,224-h的制备
Figure PCTCN2020107845-appb-000315
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物224-a,224-b,224-c,224-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物224-e,224-f,224-g,224-h。MS m/z：696(M+1) +。
实施例225 化合物225-a,225-b的制备
Figure PCTCN2020107845-appb-000316
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物225-b。类似地，以实施例3中步骤3的中间体3-3b和实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物225-a。MS m/z：690(M+1) +。
实施例226 化合物226-a,226-b的制备
Figure PCTCN2020107845-appb-000317
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b 和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物226-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物226-a。MS m/z：624(M+1) +。
实施例227 化合物227-a,227-b的制备
Figure PCTCN2020107845-appb-000318
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入异丁酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物227-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入异丁酰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物227-a。MS m/z：638(M+1) +。
实施例228 化合物228-a,228-b的制备
Figure PCTCN2020107845-appb-000319
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物228-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物228-a。MS m/z：665(M+1) +。
实施例229 化合物229-a,229-b的制备
Figure PCTCN2020107845-appb-000320
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物229-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物229-a。MS m/z：639(M+1) +。
实施例230 化合物230-a,230-b的制备
Figure PCTCN2020107845-appb-000321
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物230-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物230-a。MS m/z：625(M+1) +。
实施例231 化合物231-a,231-b的制备
Figure PCTCN2020107845-appb-000322
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物231-b。类似地，以实施例3中步骤3的中间体3-3b和实 施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物231-a。MS m/z：653(M+1) +。
实施例232 化合物232-a,232-b的制备
Figure PCTCN2020107845-appb-000323
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物232-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物232-a。MS m/z：639(M+1) +。
实施例233 化合物233-a,233-b的制备
Figure PCTCN2020107845-appb-000324
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物233-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物233-a。MS m/z：667(M+1) +。
实施例234 化合物234-a,234-b的制备
Figure PCTCN2020107845-appb-000325
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物234-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物234-a。MS m/z：665(M+1) +。
实施例235 化合物235-a,235-b的制备
Figure PCTCN2020107845-appb-000326
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与实施例7中间体7-2缩合得到化合物235-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与实施例7中间体7-2缩合得到化合物235-a。MS m/z：638(M+1) +。235-b核磁氢谱： 1H NMR(400MHz,Methanol-d 4)δ7.72–7.57(m,1H),7.56–7.49(m,2H),7.48–7.42(m,1H),7.38–7.31(m,1H),7.31–7.21(m,2H),5.53(d,J＝11.8Hz,1H),4.35(d,J＝8.6Hz,1H),4.02(d,J＝9.6Hz,1H),3.73(d,J＝9.6Hz,1H),3.58–3.39(m,7H),3.24–3.10(m,2H),2.57(q,J＝8.0Hz,1H),1.97–1.80(m,4H),1.80–1.69(m,2H),1.59(s,3H),1.08(t,J＝7.3Hz,3H),1.05(s,3H),0.76–0.68(m,1H),-0.04–-0.10(m,1H),-0.17–-0.26(m,2H).
实施例236 化合物236-a,236-b的制备
Figure PCTCN2020107845-appb-000327
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物236-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合得到化合物236-a。MS m/z：626(M+1) +。
实施例237 化合物237-a,237-b的制备
Figure PCTCN2020107845-appb-000328
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物237-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物237-a。MS m/z：640(M+1) +。
实施例238 化合物238-a,238-b的制备
Figure PCTCN2020107845-appb-000329
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物238-b。类似地，以实施例3中步骤3的中间体3-3b和 实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物238-a。MS m/z：704(M+1) +。
实施例239 化合物239-a,239-b的制备
Figure PCTCN2020107845-appb-000330
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物239-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物239-a。MS m/z：638(M+1) +。
实施例240 化合物240-a,240-b的制备
Figure PCTCN2020107845-appb-000331
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入异丁酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物240-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入异丁酰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物240-a。MS m/z：652(M+1) +。
实施例241 化合物241-a,241-b的制备
Figure PCTCN2020107845-appb-000332
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物241-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物241-a。MS m/z：679(M+1) +。
实施例242 化合物242-a,242-b的制备
Figure PCTCN2020107845-appb-000333
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物242-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物242-a。MS m/z：653(M+1) +。
实施例243 化合物243-a,243-b的制备
Figure PCTCN2020107845-appb-000334
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物243-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物243-a。MS m/z：639(M+1) +。
实施例244 化合物244-a,244-b的制备
Figure PCTCN2020107845-appb-000335
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物244-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物244-a。MS m/z：667(M+1) +。
实施例245 化合物245-a,245-b的制备
Figure PCTCN2020107845-appb-000336
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物245-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物245-a。MS m/z：653(M+1) +。
实施例246 化合物246-a,246-b的制备
Figure PCTCN2020107845-appb-000337
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩 合得到化合物246-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物246-a。MS m/z：681(M+1) +。
实施例247 化合物247-a,247-b的制备
Figure PCTCN2020107845-appb-000338
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物247-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物247-a。MS m/z：679(M+1) +。
实施例248 化合物248-a,248-b的制备
Figure PCTCN2020107845-appb-000339
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺得到化合物248-b。类似地，以实施例1中步骤5的中间体1-5b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物248-a。MS m/z：614(M+1) +。
实施例249 化合物249-a,249-b的制备
Figure PCTCN2020107845-appb-000340
参照实施例34的步骤1～6的方法，以实施例1中步骤5的中间体1-5b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环， 脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺得到化合物249-b。类似地，以实施例1中步骤5的中间体1-5b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合得到化合物249-a。MS m/z：628(M+1) +。
实施例250 化合物250-a,250-b,250-c,250-d,250-e,250-f,250-g,250-h的制备
Figure PCTCN2020107845-appb-000341
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物250-a,250-b,250-c,250-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物250-e,250-f,250-g,250-h。MS m/z：632(M+1) +。
实施例251 化合物251-a,251-b,251-c,251-d,251-e,251-f,251-g,251-h的制备
Figure PCTCN2020107845-appb-000342
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物251-a,251-b,251-c,251-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物251-e,251-f,251-g,251-h。MS m/z：646(M+1) +。
实施例252 化合物252-a,252-b,252-c,252-d,252-e,252-f,252-g,252-h的制备
Figure PCTCN2020107845-appb-000343
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物252-a,252-b,252-c,252-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物252-e,252-f,252-g,252-h。MS m/z：632(M+1) +。
实施例253 化合物253-a,253-b,253-c,253-d,253-e,253-f,253-g,253-h的制备
Figure PCTCN2020107845-appb-000344
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物253-a,253-b,253-c,253-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物253-e,253-f,253-g,253-h。MS m/z：646(M+1) +。
实施例254 化合物254-a,254-b,254-c,254-d,254-e,254-f,254-g,254-h的制备
Figure PCTCN2020107845-appb-000345
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和 实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物254-a,254-b,254-c,254-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-异丙基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物254-e,254-f,254-g,254-h。MS m/z：632(M+1) +。
实施例255 化合物255-a,255-b,255-c,255-d,255-e,255-f,255-g,255-h的制备
Figure PCTCN2020107845-appb-000346
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物255-a,255-b,255-c,255-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与D-叔丁基-N-乙基甘胺酰胺缩合，再经SFC手性拆分制备得到化合物255-e,255-f,255-g,255-h。MS m/z：646(M+1) +。
实施例256 化合物256-a,256-b的制备
Figure PCTCN2020107845-appb-000347
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物256-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物256-a。MS m/z：672(M+1) +.256-b的核磁氢谱: 1HNMR(400MHz，MeOD):δ7.82–7.72(m,1H),7.65–7.55(m,2H), 7.51–7.45(m,1H),7.42(dd,J＝8.6,1.8Hz,1H),7.36–7.29(m,2H),7.28–7.21(m,1H),6.33(d,J＝2.2Hz,1H),6.02(d,J＝11.9Hz,1H),4.09(d,J＝9.5Hz,1H),3.87(s,4H),3.74(d,J＝12.0Hz,1H),3.52–3.37(m,5H),2.32(q,J＝9.1Hz,1H),2.03–1.93(m,2H),1.90–1.81(m,1H),1.67(s,5H),1.13(s,3H),0.81–0.71(m,1H),0.02–-0.03(m,1H),-0.09–-0.18(m,2H).
实施例257 化合物257-a,257-b的制备
Figure PCTCN2020107845-appb-000348
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物257-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-乙基-1H-吡唑-5-酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物257-a。MS m/z：686(M+1) +。
实施例258 化合物258-a,258-b的制备
Figure PCTCN2020107845-appb-000349
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物258-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入丙酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物258-a。MS m/z：620(M+1) +。
实施例259 化合物259-a,259-b的制备
Figure PCTCN2020107845-appb-000350
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入异丁酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物259-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入异丁酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物259-a。MS m/z：634(M+1) +。
实施例260 化合物260-a,260-b的制备
Figure PCTCN2020107845-appb-000351
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物260-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-吡咯烷基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物260-a。MS m/z：661(M+1) +。
实施例261 化合物261-a,261-b的制备
Figure PCTCN2020107845-appb-000352
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷 -7-酮缩合得到化合物261-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N,N-二甲基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物261-a。MS m/z：635(M+1) +。
实施例262 化合物262-a,262-b的制备
Figure PCTCN2020107845-appb-000353
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物262-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入甲胺羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物262-a。MS m/z：621(M+1) +。
实施例263 化合物263-a,263-b的制备
Figure PCTCN2020107845-appb-000354
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物263-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-乙基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物263-a。MS m/z：649(M+1) +。
实施例264 化合物264-a,264-b的制备
Figure PCTCN2020107845-appb-000355
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物264-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-乙基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物264-a。MS m/z：635(M+1) +。
实施例265 化合物265-a,265-b的制备
Figure PCTCN2020107845-appb-000356
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物265-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N,N-二乙基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物265-a。MS m/z：663(M+1) +。
实施例266 化合物266-a,266-b的制备
Figure PCTCN2020107845-appb-000357
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4] 辛烷-7-酮得到化合物266-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物266-a。MS m/z：661(M+1) +。
实施例267 化合物267-a,267-b的制备
Figure PCTCN2020107845-appb-000358
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物267-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入N-甲基-N’-环丙基羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物267-a。MS m/z：622(M+1) +。
实施例268 化合物268-a,268-b的制备
Figure PCTCN2020107845-appb-000359
参照实施例34的步骤6制备34-b方法，以中间体34-6为原料，与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合得到化合物268-b。类似地，以制备另一构型34-a的步骤5中间体(34-6的另一构型)为原料，与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合可得到化合物268-a。MS m/z：660(M+1) +。268-b的核磁氢谱: 1HNMR(400MHz,MeOD):δ7.75(d,J＝8.0Hz,1H),7.68(s,1H),7.57-7.50(m,2H),7.42-7.32(m,4H),7.24(t,J＝7.2Hz,1H),6.50(s,1H),6.00(d,J＝8.8Hz,1H),4.47(d,J＝8.0Hz,1H),4.19(s,1H),4.07(d,J＝9.6Hz,1H),3.93(s,3H),3.85(d,J＝9.6Hz,1H),3.49(d,J＝10.0Hz,1H),3.45(s,3H),3.41-3.37(m,1H),2.35–2.28(m,1H),1.99-1.82(m,5H),1.74-1.59(m,5H),0.98(d,J＝4.4Hz,3H),0.86(d,J＝6.4Hz,3H).
实施例269 化合物269-a,269-b,269-c,269-d,269-e,269-f,269-g,269-h的制备
Figure PCTCN2020107845-appb-000360
参照实施例34的步骤1～6的方法，以实施例2中步骤5的中间体2-6和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合，再经SFC手性拆分制备得到化合物269-a,269-b,269-c,269-d。类似地，以实施例2中步骤5的中间体2-6和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合，再经SFC手性拆分制备得到化合物269-e,269-f,269-g,269-h。MS m/z：678(M+1) +。
实施例270 化合物270-a,270-b,270-c,270-d,270-e,270-f,270-g,270-h的制备
Figure PCTCN2020107845-appb-000361
参照实施例34的步骤1～6的方法，以实施例4中步骤5的中间体4-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合，再经SFC手性拆分制备得到化合物270-a,270-b,270-c,270-d。类似地，以实施例4中步骤5的中间体4-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合，再经SFC手性拆分制备得到化合物270-e,270-f,270-g,270-h。MS m/z：678(M+1) +。
实施例271 化合物271-a,271-b,271-c,271-d,271-e,271-f,271-g,271-h的制备
Figure PCTCN2020107845-appb-000362
参照实施例34的步骤1～6的方法，以实施例5中步骤5的中间体5-5和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合，再经SFC手性拆分制备得到化合物271-a,271-b,271-c,271-d。类似地，以实施例5中步骤5的中间体5-5和实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧羰基，水解，最后与(R)-8-氨基-6-氮杂螺[3.4]辛烷-7-酮缩合，再经SFC手性拆分制备得到化合物271-e,271-f,271-g,271-h。MS m/z：628(M+1) +。
实施例272 化合物272-a,272-b的制备
Figure PCTCN2020107845-appb-000363
参照实施例34的步骤1～6的方法，以实施例3中步骤3的中间体3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入甲氧甲酰基，水解，最后与实施例7中间体7-2缩合得到化合物272-b。类似地，以实施例3中步骤3的中间体3-3b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入甲氧甲酰基，水解，缩合得到化合物272-a。MS m/z：638(M+1) +。272-b的核磁氢谱: 1H NMR(400MHz,MeOD)δ7.67–7.51(m,3H),7.49-7.44(m,2H),7.36(t,J＝7.2Hz,1H),7.33–7.24(m,2H),5.56(d,J＝12.0Hz,1H),4.40-4.36(m,1H),4.04(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.59–3.42(m,7H),3.27–3.11(m,2H),2.62-2.54(m,1H),2.03–1.68(m,6H),1.61(s,3H),1.11(t,J＝7.2Hz,3H),1.07(s,3H),0.79–0.70(m,1H),-0.01–-0.08(m,1H),-0.14–-0.24(m,2H).
实施例273 化合物273-a,273-b的制备
步骤1 中间体273-1a、273-1b的制备
Figure PCTCN2020107845-appb-000364
参照实施例1、实施例2和实施例3中类似方法，以间氯苯甲醛为起始原料可制备得到，其中一个非对映体经SFC手性柱拆分分离制备后可分别得到单一手性异构体273-1a(2R,3R)、273-1b(2S,3S)。MS m/z：354(M+1) +。
步骤2 化合物273-a,273-b的制备
Figure PCTCN2020107845-appb-000365
参照实施例34的步骤1～6的方法，以步骤1的中间体273-1b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合得到化合物273-b。类似地，以实施例3中步骤3的中间体273-1b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合得到化合物273-a。MS m/z：688(M+1) +。273-b的核磁氢谱:1HNMR(400MHz，MeOD):δ7.72-7.76(m,2H),7.51-7.56(m,2H),7.29-7.40(m,5H),6.43-6.44(d,J＝2.2,1H),6.03-6.06(d,J＝12.2,1H),4.33-4.37(t,J＝8.3,1H),3.98-4.00(d,J＝9.6,1H),3.93(s,3H),3.75-3.77(d,J＝9.7,1H),3.43(s,3H),3.11-3.24(m,2H),2.94-2.97(d,J＝12.1,1H),2.52-2.60(m,1H),1.75-1.95(m,6H),1.60(s,3H),1.08(s,3H)1.07-1.11(t,J＝7.3,3H),0.51-0.56(m,1H),0.10-0.14(m,1H),-0.06--0.01(m,1H),-0.14--0.09(m,1H).
实施例274 化合物274-a,274-b的制备
Figure PCTCN2020107845-appb-000366
参照实施例34的步骤1～6的方法，以步骤1的中间体273-1b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护， 引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例11中间体11缩合得到化合物274-b。类似地，以实施例3中步骤3的中间体273-1b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例11中间体11缩合得到化合物274-a。MS m/z：714(M+1) +。化合物274-b的核磁氢谱: 1HNMR(400MHz，MeOD):δ7.78-7.83(m,2H),7.59-7.63(m,2H),7.29-7.41(m,5H),6.470-6.475(d,J＝2.1,1H),6.07-6.10(d,J＝12.4,1H),4.37-4.41(t,J＝8.4,1H),3.97-3.99(d,J＝9.6,1H),3.94(s,3H),3.75-3.78(d,J＝9.6,1H),3.42(s,3H),3.06-3.13(m,1H),2.97-3.00(m,2H),2.56-2.61(m,1H),1.78-1.96(m,6H),1.61(s,3H),1.08(s,3H),0.90-0.96(m,1H),0.53-0.58(m,1H),0.44-0.48(m,2H),0.12-0.19(m,3H),-0.02-0.01(m,1H),-0.14--0.09(m,1H).
实施例275 化合物275-a,275-b的制备
Figure PCTCN2020107845-appb-000367
分别以实施例272中化合物272-b和272-a为原料，在乙醇中经Pd(OH) 2氢化脱氯即可分别得到275-b和275-a。MS m/z：604(M+1) +。化合物275-b的核磁氢谱: 1H NMR(400MHz,MeOD)δ7.62(s,1H),7.57(d,J＝8.4Hz,1H),7.39-7.28(m,6H),5.56(d,J＝11.6Hz,1H),4.61(s,2H),4.37(d,J＝8.8Hz,1H),4.04(d,J＝9.6Hz,1H),3.75(d,J＝9.6Hz,1H),3.47(s,3H),3.45(s,3H),3.25-3.13(m,2H),2.62-2.56(m,2H),2.03–1.70(m,6H),1.61(s,3H),1.11(t,J＝7.6Hz,3H),1.06(s,3H),0.44–0.35(m,1H),-0.01--0.06(m,1H),-0.15–-0.25(m,2H).
实施例276 化合物276-a,276-b的制备
Figure PCTCN2020107845-appb-000368
分别以实施例87中化合物87-b和87-a为原料，在乙醇中经Pd(OH) 2氢化脱氯即可分别得到276-b和276-a。MS m/z：654(M+1) +。 1H NMR(400MHz,Methanol-d 4)δ7.64(s,1H),7.59(d,J＝8.3Hz,1H),7.37(d,J＝4.3Hz,4H),7.33–7.25(m,3H),6.28(d,J＝1.8Hz,1H),6.00(d,J＝12.1Hz,1H),4.37(d,J＝8.6Hz,1H),4.04(d,J＝9.6Hz,1H),3.86(s,3H),3.75(d,J＝9.6Hz,1H),3.45(s,3H),3.26–3.11(m,2H),2.83(d,J＝12.0Hz,1H),2.63–2.54(m,1H),1.99–1.73(m,7H),1.61(s,3H),1.13–1.07(m,6H),0.48–0.40(m,1H),0.02 –-0.03(m,1H),-0.08–-0.17(m,2H).
实施例277 化合物277-a,277-b的制备
Figure PCTCN2020107845-appb-000369
分别以实施例165中化合物165-b和165-a为原料，在乙醇中经Pd(OH) 2氢化脱氯即可分别得到277-b和277-a。MS m/z：602(M+1) +。
实施例278 化合物278-a,278-b的制备
步骤1 中间体278-1a、278-1b的制备
Figure PCTCN2020107845-appb-000370
参照实施例1、实施例2和实施例3中类似方法，以3-氯噻吩-2-甲醛为起始原料可制备得到，其中一个非对映体经SFC手性柱拆分分离制备后可分别得到单一手性异构体278-1a(2R,3S)、278-1b(2S,3R)。MS m/z：260(M+1) +。
步骤2 化合物278-a,278-b的制备
Figure PCTCN2020107845-appb-000371
参照实施例34的步骤1～6的方法，以步骤1的中间体278-1b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例27中间体27缩合得到化合物278-b。类似地，以实施例3中步骤3的中间体278-1b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例27中间体27缩合得到化合物278-a。MS m/z：708(M+1) +。化合物278-b核磁数据： 1HNMR(400M,MeOD),δ7.28-7.51(m,5H),7.17-7.19(d,J＝7.68,1H),6.875-6.880(d,J＝2,1H),6.66-6.67(d,J＝5.36,1H),5.77-5.80(d,J＝11.76,1H),4.58(s,1H),4.35-4.38(m,1H),4.11(s,3H),3.92-3.93(m,2H),3.66-3.68(d,J＝9.68, 1H),3.59-3.62(d,J＝11.72,1H),3.41(s,3H),3.10-3.24(m,2H),2.17-2.21(m,1H),2.01-2.04(m,2H),1.85-1.92(m,1H),1.53-1.57(m,2H),1.49(s,3H),1.07-1.10(t,J＝7.2,3H),1.03(s,3H),0.88-0.92(m,1H),0.55-0.59(m,2H),0.18-0.21(m,1H).
实施例279 化合物279-a,279-b的制备
步骤1 中间体279-1a、279-1b的制备
Figure PCTCN2020107845-appb-000372
参照实施例1、实施例2和实施例3中类似方法，以3-氟-2-氯甲醛为起始原料可制备得到，其中一个非对映体经SFC手性柱拆分分离制备后可分别得到单一手性异构体279-1a(2S,3S)、279-1b(2R,3R)。MS m/z：272(M+1) +。
步骤2 化合物279-a,279-b的制备
Figure PCTCN2020107845-appb-000373
参照实施例34的步骤1～6的方法，以步骤1的中间体279-1b和实施例6中步骤66-6b(SFC手性拆分制备得到一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合得到化合物278-b。类似地，以实施例3中步骤3的中间体279-1b和实施例6中步骤6的6-6a(SFC手性拆分制备得到的另一单一构型)经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例7中间体7-2缩合得到化合物279-a。MS m/z：706(M+1) +。279-b的核磁氢谱: 1H NMR(400MHz,MeOD)δ7.96(t,J＝5.7Hz,1H),7.68–7.57(m,2H),7.47(d,J＝7.9Hz,1H),7.44–7.24(m,4H),7.18-7.14(m,1H),6.36(d,J＝2.1Hz,1H),6.01(d,J＝11.9Hz,1H),4.38(t,J＝8.3Hz,1H),4.03(d,J＝9.6Hz,1H),3.89(s,3H),3.77(dd,J＝13.3,10.7Hz,2H),3.45(s,3H),3.20(dddd,J＝18.9,17.3,9.5,4.3Hz,2H),2.59(h,J＝8.4,8.0Hz,1H),2.00–1.70(m,6H),1.61(s,3H),,1.21–1.04(m,6H),0.74(dt,J＝9.9,5.3Hz,1H),0.03-0.02(m,1H),-0.11(dp,J＝14.0,4.9Hz,2H)。
实施例280 化合物280-a，280-b的制备
Figure PCTCN2020107845-appb-000374
参照实施例34的步骤1-6的方法，以环己基-L-丙氨酸盐酸盐与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，水解，最后与实施例7的中间体7-2缩合，得到化合物280-a，MS m/z：606.0(M+1) +。
类似的，以环己基-L-丙氨酸盐酸盐与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物280-b。， 1H NMR(400MHz,Methanol-d 4)δ7.94(s,1H),7.63–7.48(m,3H),7.41(d,J＝8.1Hz,1H),7.27(d,J＝8.6Hz,1H),6.94(d,J＝2.1Hz,1H),5.48(dd,J＝9.4,6.1Hz,1H),4.36(t,J＝8.3Hz,1H),4.12(s,3H),3.99(d,J＝9.6Hz,1H),3.73(d,J＝9.6Hz,1H),3.43(s,3H),3.24–3.14(m,2H),2.57(q,J＝7.9Hz,1H),2.11–1.98(m,2H),1.98–1.72(m,11H),1.58(s,3H),1.42(s,1H),1.27(dd,J＝20.3,10.1Hz,3H),1.18–0.96(m,5H).
实施例281 化合物281-a，281-b的制备
Figure PCTCN2020107845-appb-000375
参照实施例34的步骤1-6的方法，以环己基-L-丙氨酸盐酸盐与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，酯水解，与实施例7的中间体7-2缩合，脱保护，最后与氯甲酸甲酯反应得到化合物281-a.
类似的，以环己基-L-丙氨酸盐酸盐与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物281-b，MS m/z：556.0(M+1) +， 1H NMR(400MHz,Methanol-d 4)δ7.56(s,1H),7.50(d,J＝8.5Hz,1H),7.28–7.20(m,1H),5.01(t,J＝7.8Hz,1H),4.41–4.31(m,1H),4.00(d,J＝9.5Hz,1H),3.72(d,J＝9.6Hz,1H),3.68(s,3H),3.43(s,3H),3.24–3.12(m,2H),2.63–2.51(m,1H),1.99–1.71(m,12H),1.69(s,1H),1.58(s,3H),1.45–1.18(m,4H),1.10(t,J＝7.3Hz,3H),1.07–0.96(m,2H)。
实施例282 化合物282-a，282-b的制备
Figure PCTCN2020107845-appb-000376
参照实施例34的步骤1-6的方法，以实施例3的中间体3-3b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与环丁基甲胺缩合，得到化合物282-a，MS m/z：617.0(M+1) +.
类似的，以实施例3的中间体3-3b与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物282-b， 1H NMR(400MHz,Methanol-d 4)δ7.62(s,1H),7.58(d,J＝8.3Hz,2H),7.46(d,J＝8.0Hz,1H),7.39(t,J＝5.6Hz,1H),7.36–7.28(m,3H),7.24(t,J＝7.6Hz,1H),6.31(s,1H),6.02(d,J＝12.0Hz,1H),3.96(d,J＝9.4Hz,1H),3.84(s,3H),3.76(d,J＝11.9Hz,1H),3.71(d,J＝9.4Hz,1H),3.38(s,3H),3.33(d,3H),3.27–3.17(m,2H),2.56–2.46(m,1H),2.02–1.91(m,2H),1.91–1.76(m,2H),1.69(q,J＝8.8Hz,2H),1.63(s,3H),1.12(s,3H),0.81–0.74(m,1H),0.06–-0.01(m,1H),-0.13(t,J＝7.6Hz,2H)。
实施例283 化合物283-a，283-b的制备
Figure PCTCN2020107845-appb-000377
分别以实施例86-a和86-b为原料,在乙醇中经Pd/C氢化脱氯即可得到化合物283-a和283-b。MS m/z：640.0(M+1) +，283-b的核磁氢谱： 1H NMR(400MHz,Methanol-d 4)δ7.63(s,1H),7.58(d,J＝8.5Hz,1H),7.45(d,J＝7.9Hz,1H),7.36(d,J＝4.2Hz,4H),7.33–7.24(m,3H),6.27(s,1H),6.01(d,J＝12.0Hz,1H),4.38(t,J＝8.1Hz,1H),4.04(d,J＝9.5Hz,1H),3.86(s,3H),3.76(d,J＝9.5Hz,1H),3.45(s,3H),2.84(d,J＝12.0Hz,1H),2.72(s,3H),2.63–2.54(m,1H),2.00–1.85(m,4H),1.76(d,2H),1.60(s,3H),1.12(s,3H),0.50–0.40(m,2H),0.03–-0.02(m,2H),-0.09–-0.16(m,2H).
实施例284 化合物284-a，284-b的制备
Figure PCTCN2020107845-appb-000378
参照实施例34的步骤1-6的方法，以实施例3的中间体3-3b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与D-环丁基甘氨酰胺缩 合，得到化合物284-a，MS m/z：660.0(M+1) +.
类似的，以实施例3的中间体3-3b与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物284-b， 1H NMR(400MHz,Methanol-d 4)δ7.66(s,1H),7.59(t,J＝9.3Hz,2H),7.46(t,J＝7.1Hz,2H),7.36–7.30(m,3H),7.28–7.21(m,1H),6.33(s,1H),6.02(d,J＝11.9Hz,1H),4.46–4.40(m,1H),4.06(d,J＝9.5Hz,1H),3.86(d,J＝1.1Hz,3H),3.76(dd,J＝10.7,8.1Hz,2H),3.45(d,J＝1.2Hz,3H),2.70–2.58(m,1H),2.05–1.73(m,7H),1.61(s,3H),1.13(s,3H),0.82–0.72(m,2H),0.02–-0.02(m,1H),-0.08–-0.17(m,2H)。
实施例285 化合物285-a，285-b的制备
Figure PCTCN2020107845-appb-000379
参照实施例34的步骤1-6的方法，以实施例3的中间体3-3b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与D-环丁基甘氨酸甲酯缩合，得到化合物285-a，MS m/z：675.0(M+1) +.
类似的，以实施例3的中间体3-3b与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物285-b， 1H NMR(400MHz,Methanol-d 4)δ7.71(d,J＝7.9Hz,1H),7.65(d,J＝1.7Hz,1H),7.61–7.56(m,2H),7.47(dd,J＝7.9,1.4Hz,1H),7.36–7.29(m,3H),7.24(td,J＝7.6,1.6Hz,1H),6.32(d,J＝2.1Hz,1H),6.02(d,J＝11.9Hz,1H),4.45(t,J＝8.2Hz,1H),4.01(d,J＝9.6Hz,1H),3.85(s,3H),3.74(t,J＝11.0Hz,2H),3.69(s,3H),3.42(s,3H),2.74–2.62(m,1H),2.07–1.71(m,7H),1.61(s,3H),1.12(s,3H),0.81–0.73(m,1H),0.02–-0.03(m,1H),-0.09–-0.16(m,2H)。
实施例286 化合物286-a，286-b的制备
中间体286-10的制备
Figure PCTCN2020107845-appb-000380
步骤1，中间体286-1的制备
冰浴下，向丙二酸二叔丁酯(22.72g,105.05mmol)的DMF(250mL)溶液中加入NaH(7.56g,315.14mmol)，混合液冰浴下搅拌30分钟，然后逐滴加入1-溴-4,5-二氟-2-硝基苯(25g,105.05mmol)的DMF(50mL)溶液。反应液在室温下搅拌3小时。
反应液用饱和氯化铵淬灭，乙酸乙酯萃取，合并的有机相用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩后得到286-1(41g，粗品)，未经纯化直接用于下一步反应。
步骤2，中间体286-2的制备
室温下，向286-1(94.0g,216.46mmol)的醋酸(320mL)溶液中缓慢加入HCl(120mL)，反应混合液升温至110度并搅拌2小时。
反应液直接浓缩得到286-2(60g，粗品)，未经纯化直接用于下一步反应。MS m/z：
步骤3，中间体286-3的制备
室温下，向286-2(60g，215.80mmol)的乙醇(300mL)溶液中缓慢滴加浓硫酸(5mL)，反应液升温至85度并搅拌2小时。
反应液浓缩，加水稀释，用乙酸乙酯萃取，合并的有机相依次用饱和碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得到286-3(66g)黄色色油状物。
步骤4，中间体286-4的制备
室温下，向286-3(34.0g,111.08mmol)的DMF(300mL)溶液中加入Cs2CO3(36.19g,111.08mmol)，搅拌30分钟后，冷却至零度，加入MeI(12.61g,88.86mmol)，反应液室温搅拌过夜。反应完成后，加饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并的有机相用水和饱和是食盐水洗涤，无水硫酸钠干燥，浓缩后的粗品用硅胶柱(乙酸乙酯/石油醚＝0％to 60％洗脱)得到中间体286-4(25g，71％)黄色油状物。
步骤5，中间体286-5的制备
冰浴下，向中间体286-4(11.0g,34.36mmol)的DMF(125mL)溶液中分批次加入NaH(907.18mg,37.80mmol)，混合液在冰浴下搅拌30分钟。然后加入MOMBr(5.58g,44.67mmol)的DMF(25mL)溶液，反应液室温搅拌过夜。反应完成后，混合药物浓缩，粗品用硅胶柱分离纯化(乙酸乙酯/石油醚＝0～100％)得到中间体286-5(5g，40％收率)黄色固体。
步骤6，中间体286-6的制备
向中间体286-5(9.4g,25.81mmol)的乙醇溶液中加入醋酸(15mL)和水(50mL)，混合液升温至50度，分批次缓慢加入铁粉(10.81g,193.59mmol)，加完后，反应液升温至85度并搅拌3小时。反应完成后过滤铁粉，并用乙醇洗涤滤饼，滤液浓缩得中间体286-6(8.4g，97％收率，粗品)，MS m/z：334.0(M+1) +
未经纯化直接用于下一步反应。
步骤7，中间体286-7的制备
向中间体286-6(8.4g,25.14mmol)的二氯甲烷(120mL)溶液中加入醋酸酐(2.57g,25.14mmol)，室温下搅拌3小时，反应完成后，浓缩反应液得到中间体286-7(9.4g，99％收率，粗品)。MS(ESI)m/z＝378.0(M+2) +.
步骤8，中间体286-8的制备
冰浴下，向286-7(1g,2.66mmol)的HNO3(68％)(3.0mL)溶液中逐滴加入H2SO4(98％)(3.0mL)，反应液冰浴下搅拌1小时。反应完成后，用饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯萃取，有机相浓缩后得到粗品中间体286-8(0.9g，80％收率)。MS(ESI)m/z＝422.0(M+1) +.
步骤9，中间体286-9的制备
冰浴下，向286-8(3.13g,7.43mmol)的乙醇溶液中加入SOCl 2(5.30g,44.59mmol,3.23mL)，反应液升温至60℃并搅拌过夜。反应完成后，浓缩反应液，粗品用硅胶柱分离纯化，得到中间体286-9(575mg，20％收率)。MS(ESI)m/z＝379.0(M+1) +.
步骤10，中间体286-10的制备
向中间体286-9(0.570g,1.50mmol)的乙醇(50mL)溶液中加入Pd/C(0.057g)，H2置换后，H2保护下室温搅拌过夜。反应完成后，过滤除掉Pd/C，滤液浓缩，MPLC C18反相柱纯化得到消旋体286-10(420mg,90％纯度，93％收率)。MS m/z：271.0(M+1) +
化合物286-a，286-b的制备
Figure PCTCN2020107845-appb-000381
参照实施例34的步骤1-6的方法，以实施例3的中间体3-3b与上述中间体286-10为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与中间体7-2缩合，得到化合物286，MS m/z：706.0(M+1) +，将化合物286送SFC手性拆分制备，可得到手性碳位置两个异构体，分别标记为286-a和286-b。 1H NMR(400MHz,Methanol-d 4)δ7.56(d,J＝7.5Hz,1H),7.47(dd,J＝8.0,1.3Hz,1H),7.40(s,1H),7.37–7.29(m,3H),7.27–7.21(m,1H),6.36(s,1H),6.01(d,J＝11.8Hz,1H),4.37(d,J＝8.4Hz,1H),4.07(d,J＝9.5Hz,1H),3.87(s,3H),3.71(dd,J＝17.9,10.7Hz,2H),3.46(s,3H),3.24–3.11(m,3H),2.66–2.52(m,1H),2.02–1.79(m,6H),1.63(s,3H),1.14–1.09(m,6H),0.02–-0.03(m,2H),-0.13(t,J＝7.4Hz,2H).
实施例287 化合物287-a，287-b的制备
Figure PCTCN2020107845-appb-000382
分别以实施例105-a和105-b为原料，在乙醇中经Pd/C氢化脱氯，即可分别得到化合物287-a和287-b，MS m/z：668.0(M+1) +，287-b的核磁氢谱： 1H NMR(400MHz,MeOD)δ8.01(s,1H),7.67(d,J＝1.2Hz,1H),7.60(d,J＝8.6Hz,1H),7.49(d,J＝8.5Hz,1H),7.37-7.35(m,5H),7.32–7.26(m,2H),6.28(d,J＝2.1Hz,1H),6.01(d,J＝12.1Hz,1H),4.41(d,J＝8.5Hz,1H),4.03(d,J＝9.7Hz,1H),3.87(s,3H),3.76(d,J＝9.7Hz,1H),3.47(s,3H),3.29–3.12(m,2H),2.83(d,J＝12.1Hz,1H),2.23(dd,J＝19.6,9.5Hz,1H),2.09(dd,J＝19.7,9.3Hz,1H),1.97–1.84(m,1H),1.80–1.67(m,1H),1.59-1.57(m,5H),1.15–1.06(m,9H),0.45(dd,J＝11.8,7.8Hz,1H),0.01–-0.01(m,1H),-0.13(d,J＝7.5Hz,2H).
实施例288 化合物288-a，288-b的制备
Figure PCTCN2020107845-appb-000383
参照上述实施例287的方法，由相应的化合物氢化脱氯得到化合物288-a和288-b。MS m/z：654.0(M+1) +，288-b的核磁氢谱： 1H NMR(400MHz,MeOD)δ7.94(d,J＝4.4Hz,1H),7.67(d,J＝1.2Hz,1H),7.61(d,J＝8.6Hz,1H),7.50(d,J＝8.4Hz,1H),7.41–7.33(m,5H),7.31–7.25(m,2H),6.29(d,J＝2.1Hz,1H),6.01(d,J＝12.1Hz,1H),4.42(d,J＝8.4Hz,1H),4.04(d,J＝9.7Hz,1H),3.87(s,3H),3.77(d,J＝9.7Hz,1H),3.48(s,3H),2.83(d,J＝12.1Hz,1H),2.73(d,J＝3.8Hz,3H),2.22(dd,J＝19.8,9.1Hz,1H),2.07(dd,J＝19.8,9.2Hz,1H),1.91(ddd,J＝19.8,13.0,5.6Hz,1H),1.73(tdd,J＝13.5,9.4,4.1Hz,1H),1.65–1.49(m,5H),1.11(s,3H),1.07(s,3H),0.45(dd,J＝12.6,7.0Hz,1H),0.02–-0.01(m,1H),-0.10–-0.19(m,2H).
实施例289 化合物289-a，289-b的制备
中间体289-3的制备
Figure PCTCN2020107845-appb-000384
参照专利相关合成方法，以Fmoc-D-(环丁基)甘氨酸为原料经缩合硼烷还原上Boc、脱Fmoc步骤得到中间体289-3。MS m/z：215.0(M+1) +
化合物289-a，289-b的制备
Figure PCTCN2020107845-appb-000385
参照实施例34的步骤1-6的方法，以实施例3的中间体3-3b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，与中间体289-3缩合，最后脱Boc得到化合物289-a，MS m/z：646.0(M+1) +.
类似的，以实施例3的中间体3-3b与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物289-b，核磁谱图 1H NMR(400MHz,Methanol-d 4)δ7.83(d,J＝1.3Hz,1H),7.80(d,1H),7.58(dd,J＝8.7,1.7Hz,1H),7.52(ddd,J＝7.9,3.8,1.5Hz,2H),7.39–7.36(m,1H),7.34(d,J＝2.2Hz,1H),7.29(td,J＝7.7,1.6Hz,1H),6.46(d,J＝2.2Hz,1H),6.16(d,J＝12.2Hz,1H),4.08(d,J＝9.5Hz,1H),3.93(s,3H),3.89(q,2H),3.48(s,3H),3.02(dd,J＝13.1,3.4Hz,1H),2.81(dd,J＝13.0,9.8Hz,1H),2.49–2.38(m,1H),2.11–2.01(m,1H),1.94–1.69(m,6H),1.65(s,3H),1.11(s,3H),0.93–0.86(m,1H),0.14–0.08(m,1H),-0.02–-0.14(m,2H)。
实施例290 化合物290-a，290-b的制备
Figure PCTCN2020107845-appb-000386
参照实施例34的步骤1-6的方法，以实施例3的中间体3-3b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与(1-氟环丁基)甲胺盐酸盐缩合，得到化合物290-a，MS m/z：635.0(M+1) +。
类似的，以实施例3的中间体3-3b与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物290-b核磁谱图 1H NMR(400MHz,Methanol-d 4)δ7.68–7.63(m,1H),7.62–7.56(m,2H),7.53(t,J＝6.0Hz,1H),7.50–7.45(m,1H),7.38–7.30(m,3H),7.29– 7.21(m,1H),6.33(d,J＝2.1Hz,1H),6.01(d,J＝12.0Hz,1H),4.13(s,0H),4.00(d,J＝9.5Hz,1H),3.86(s,3H),3.74(t,J＝11.0Hz,2H),3.64–3.52(m,2H),3.40(s,3H),2.27–2.11(m,4H),1.86–1.75(m,1H),1.65(s,3H),1.60–1.50(m,1H),1.31(s,2H),1.13(s,3H),0.96–0.85(m,1H),0.77(dt,J＝10.4,5.8Hz,1H),-0.08–-0.17(m,2H)。
实施例291 化合物291-a，291-b的制备
Figure PCTCN2020107845-appb-000387
参照实施例34的步骤1-6的方法，以实施例3的中间体3-3b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与1-(氨基甲基)环丁醇缩合，得到化合物291-a，MS m/z：633.0(M+1) +
类似的，以实施例3的中间体3-3b与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物291-b， 1H NMR(400MHz,Methanol-d4)δ7.70–7.63(m,1H),7.62–7.54(m,2H),7.46(dd,J＝8.0,1.3Hz,1H),7.39(t,J＝5.7Hz,1H),7.36–7.29(m,3H),7.30–7.19(m,2H),6.32(d,J＝2.2Hz,1H),6.00(d,J＝11.9Hz,1H),3.98(d,J＝9.5Hz,1H),3.85(s,3H),3.73(dd,J＝13.7,10.7Hz,2H),3.45–3.37(m,5H),2.08–1.91(m,4H),1.78–1.66(m,2H),1.63(s,3H),1.60–1.48(m,1H),1.12(s,3H),0.00(m,2H),-0.13(td,J＝6.9,6.4,3.4Hz,2H).。
实施例292 化合物292-a，292-b的制备
Figure PCTCN2020107845-appb-000388
参照实施例34的步骤1-6的方法，以实施例3的中间体3-3b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与(R)-1-环丁基-2甲氧基乙胺缩合，得到化合物292-a，MS m/z：661.0(M+1) +。
类似的，以实施例3的中间体3-3b与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物292-b， 1H NMR(400MHz,Methanol-d 4)δ7.67–7.63(m,1H),7.62–7.50(m,3H),7.48(dd,J＝7.9,1.4Hz,1H),7.37–7.30(m,3H),7.29–7.21(m,1H),6.33(d,J＝2.1Hz,1H),6.01(d,J＝12.0Hz,1H),4.00(d,J＝9.5Hz,1H),3.86(s,3H),3.74(t,J＝11.0Hz,2H),3.65–3.52(m,2H),3.40(s,3H),2.17(m,4H),1.80(m,1H),1.65(s,3H),1.56(m,1H),1.13(s,3H),0.95–0.86(m,1H),0.81–0.72(m,1H),-0.08–-0.17(m,2H)。
实施例293 化合物293-a，293-b的制备
Figure PCTCN2020107845-appb-000389
参照实施例34的步骤1-6的方法，以实施例3的中间体3-3b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与(R)-2-氨基-2环丁基乙醇缩合，得到化合物293-a，MS m/z：647.0(M+1) +.
类似的，以实施例3的中间体3-3b与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物293-b。， 1H NMR(400MHz,Methanol-d 4)δ7.65(s,1H),7.58(td,J＝5.8,3.1Hz,2H),7.47(dd,J＝8.0,1.4Hz,1H),7.37–7.29(m,3H),7.25(td,J＝7.7,1.6Hz,1H),7.16(d,J＝8.9Hz,1H),6.33(d,J＝2.2Hz,1H),6.01(d,J＝12.0Hz,1H),4.02–3.92(m,2H),3.86(s,3H),3.80–3.72(m,2H),3.47(d,2H),3.42(s,3H),2.57–2.44(m,1H),2.08–1.75(m,6H),1.62(s,3H),1.13(s,3H),0.82–0.72(m,1H),0.03–-0.03(m,1H),-0.08–-0.18(m,2H)
实施例294 化合物294-a，294-b的制备
Figure PCTCN2020107845-appb-000390
向实施例288中化合物288-a(40mg，0.05mmol)的二氯甲烷(1mL)溶液中加入HBTU(25.92mg,68.40umol)，DIPEA(20.40mg,157.84umol,27.49uL)和醋酸(3.48mg,57.88umol)，氮气条件下，室温搅拌反应1小时。反应结束后，减压浓缩得粗品，用反相柱(ACN/0.05％FA)分离纯化得化合物294-a(20mg，,26.08umol)收率50％。MS m/z：688.0(M+1) +.
类似的，以实施例288中化合物288-b为原料，与醋酸缩合得化合物294-b。， 1H NMR(400MHz,Methanol-d 4)δ7.64(d,J＝1.7Hz,1H),7.58(t,J＝7.7Hz,2H),7.47(dd,J＝7.9,1.3Hz,1H),7.36–7.30(m,3H),7.25(td,J＝7.7,1.6Hz,1H),7.11(d,J＝9.0Hz,1H),6.33(d,J＝2.1Hz,1H),6.02(d,J＝12.0Hz,1H),4.09–4.01(m,1H),3.99(d,J＝9.3Hz,1H),3.86(s,3H),3.77(d,J＝3.0Hz,1H),3.74(s,1H),3.42(s,3H),3.21–3.10(m,2H),2.44–2.32(m,1H),2.06–1.94(m,1H),1.93–1.86(m,2H),1.85–1.74(m,4H),1.63(s,3H),1.12(s,3H),0.82–0.72(m,1H),0.02–-0.01(m,1H),-0.08–-0.19(m,2H)
实施例295 化合物295-a，295-b的制备
Figure PCTCN2020107845-appb-000391
以化合物288-a为原料，参照实施例293的合成方法，与环丙基甲酸缩合，得到化合物295-a，MS m/z：714.0(M+1) +
类似的以288-b为原料，同样的方法缩合，得到化合物295-b。， 1H NMR(400MHz,Methanol-d 4)δ7.63(d,J＝1.7Hz,1H),7.62–7.54(m,2H),7.47(dq,J＝7.9,1.3Hz,1H),7.32(m,3H),7.29–7.20(m,1H),7.15(d,J＝8.9Hz,1H),6.33(q,J＝1.8Hz,1H),6.01(dd,J＝11.9,1.8Hz,1H),4.06(td,J＝8.6,4.8Hz,1H),3.97(d,J＝9.3Hz,1H),3.89–3.83(m,3H),3.77(s,1H),3.78–3.72(m,1H),3.41(d,J＝1.2Hz,3H),3.26–3.10(m,2H),2.45–2.32(m,1H),2.07–1.95(m,1H),1.85(m,6H),1.63(s,3H),1.48(tt,J＝7.9,4.7Hz,1H),1.12(s,3H),0.84–0.70(m,3H),0.73–0.62(m,2H),0.02(s,1H),-0.07–-0.18(m,2H).
实施例296 化合物296-a，296-b的制备
Figure PCTCN2020107845-appb-000392
参照实施例34的步骤1-6的方法，以实施例1的中间体1-5b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，酯水解，与实施例7的中间体7-2缩合，脱保护，最后与氯甲酸甲酯反应得到化合物296-a，MS m/z：626.0(M+1) +
类似的，以实施例1的中间体1-5b与实施例6中步骤66-6b(SFC手性 拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物296-b。， 1H NMR(400MHz,Methanol-d 4)δ7.55(s,1H),7.52–7.46(m,2H),7.43(d,J＝7.7Hz,1H),7.39–7.19(m,5H),5.58(d,J＝7.9Hz,1H),4.36(t,J＝8.3Hz,1H),4.01(d,J＝9.6Hz,1H),3.96–3.89(m,1H),3.73(d,J＝9.6Hz,1H),3.58(s,3H),3.43(s,3H),3.24–3.12(m,2H),2.63–2.52(m,1H),2.01–1.82(m,6H),1.79–1.72(m,2H),1.58(s,3H),1.10(t,J＝7.3Hz,3H),1.04(d,J＝5.3Hz,3H),0.80(d,J＝6.7Hz,3H).
实施例297 化合物297-a，297-b的制备
Figure PCTCN2020107845-appb-000393
参照实施例34的步骤1-6的方法，以实施例1的中间体1-5b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，酯水解，与实施例9的中间体9缩合，脱保护，最后与氯甲酸甲酯反应得到化合物297-a，MS m/z：612.0(M+1) +
类似的，以实施例1的中间体1-5b与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物297-b。， 1H NMR(400MHz,Methanol-d 4)δ7.79(d,J＝1.6Hz,1H),7.76(d,J＝8.7Hz,1H),7.60–7.51(m,3H),7.44–7.27(m,4H),6.37(d,J＝2.2Hz,1H),6.06(d,J＝12.1Hz,1H),3.98(d,J＝9.7Hz,1H),3.92(s,3H),3.88(d,J＝12.1Hz,1H),3.75(d,J＝9.7Hz,1H),3.55–3.52(m,2H),3.42(s,3H),3.17(s,3H),2.18–2.07(m,2H),1.92–1.83(m,2H),1.82–1.67(m,2H),1.64(s,3H),1.31(s,6H),1.12(s,3H).
实施例298 化合物298-a，298-b的制备
中间体298-7的制备
Figure PCTCN2020107845-appb-000394
步骤1，中间体298-1的制备
冰浴下，向NaH(251.65mg,10.49mmol)的THF(25mL)分散液中滴加三乙基2-膦酰基丙酯(2.04g,10.49mmol)，冰浴下搅拌20min分钟，然后滴加环丁基甲醛(840mg,9.99mmol)，滴加完毕后，逐渐升至室温并搅拌过夜。反应完后用饱和氯化铵淬灭，乙酸乙酯萃取，合并的有机相旋干，粗品用硅 胶柱分离纯化得到中间体298-1(1.6g,9.51mmol,95.24％收率)。
步骤2，中间体298-2的制备
-78℃条件下。向中间体298-1(9.0g,53.50mmol)的DCM(60mL)溶液中滴加DIBAL(15.11g,107.00mmol,18.93mL)，滴加完毕后，保温反应2小时，TLC检测反应完全，滴加水淬灭，过滤反应液，滤液分层，有机相旋干得到的粗品，用硅胶柱分离纯化得到中间体298-2(5.6g,44.38mmol,82.95％收率)。
步骤3，中间体298-3的制备
冰浴下，向中间体298-2(1.5g,12.12mmol)的DCM(60mL)溶液中加入CBr 4(4.57g,13.94mmol)，然后滴加PPh 3(3.33g,127.30mmol)的DCM(5mL)溶液。反应液在0℃下搅拌1小时，然后过滤反应混合液，滤液浓缩后得到的粗品，用硅胶柱纯化(洗脱剂石油醚)得到中间体298-3(2.2g,11.6mmol,95.96％收率)。
步骤4，中间体298-4的制备
室温下，向298-3(1.4g,7.40mmol)和(2Z)-2-[((S)-叔丁基亚磺酰基]亚氨基乙酸乙酯)(507mg，2.47mmol)的THF(15mL)溶液中加入Sat.NaBr.H 2O(679.68mg,2.59mmol,30mL)，随后加入Indium(1.13g,9.87mmol)。反应混合液在氮气保护下室温搅拌过夜。混合液过滤，滤液加水稀释，乙酸乙酯萃取，合并的有机相用食盐水洗涤，无水硫酸钠干燥，过滤，然后浓缩得到中间298-4(770mg,2.44mmol)粗品，未经纯化直接用于下一步反应。MS m/z：316.0(M+1) +
步骤5，中间体298-5的制备
冰浴下。向298-4(150mg,475.48umol)的甲醇溶液(1.6mL)中滴加HCl/EA(4M，0.5mL)，反应液室温下搅拌1小时，后浓缩，粗品溶解在THF(2mL)和水(2mL)的混合液，在冰浴下，NaHCO 3(79.88mg,950.96umol)和CbzOSU(118.50mg,475.48umol)依次加入反应液中，反应液室温下搅拌30分钟，混合液用水稀释，乙酸乙酯萃取，无水硫酸钠干燥，过滤浓缩后得粗品，用硅胶柱分离纯化得到中间体298-5(20mg,57.90umol,12.18％收率)。MS m/z：346.0(M+1) +
步骤6，中间体298-6的制备
室温氮气保护下，向298-5(500mg,1.45mmol)的干燥二氯甲烷(10mL)加入CH 2ICl(1.1mL),冷却至零下20度到零下25度，缓慢滴加ZnEt 2(8.7mL)，滴加完毕后，反应液室温搅拌过夜。
反应液用饱和氯化铵淬灭，乙酸乙酯萃取，合并的有机相浓缩得到粗品，粗品中还有约10％的298-5未反应完，将粗品溶于MeOH/THF/H 2O(1/1/1,共150mL)溶液中，加入K 2OsO 4(70mg，0.19mmol)，混合液室温搅拌过夜，反应完成后，反应液浓缩，加水稀释，乙酸乙酯萃取，合并的有机相用水和饱和食盐水洗涤，浓缩后得粗品，用硅胶柱分离纯化得到中间体298-6(313 mg，收率59％)。MS m/z：360.0(M+1) +
步骤7,中间体298-7的制备
向298-6(420mg,1.17mmol)的THF(2mL)/MeOH(2mL)/H 2O(2mL)的混合溶液中加入LiOH.H2O(147.22mg,3.51mmol)，反应液室温搅拌过夜，反应完成后，反应液减压浓缩，粗品用水稀释，用6N稀盐酸调pH到至4～6，用二氯甲烷萃取，合并的有机相用无水硫酸钠干燥，过滤、浓缩后得到中间体298-7(340mg,1.03mmol,87.80％收率)，MS m/z：332.0(M+1) +
化合物298的制备
Figure PCTCN2020107845-appb-000395
参照实施例34的步骤1-6的方法，以上述中间体298-7与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，酯水解，与实施例9的中间体9缩合，脱保护，最后与氯甲酸甲酯反应得到化合物298-a，MS m/z：582.0(M+1) +
类似的，以298-7与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物298-b， 1H NMR(400MHz,Methanol-d 4)δ7.68–7.40(m,2H),7.26(dd,J＝8.6,1.8Hz,1H),4.96(d,J＝9.4Hz,1H),4.35(d,J＝8.6Hz,1H),4.02(d,J＝9.5Hz,1H),3.73(d,J＝9.6Hz,1H),3.66(s,3H),3.44(s,3H),3.26–3.11(m,2H),2.63–2.45(m,2H),2.09–1.81(m,6H),1.79–1.70(m,2H),1.58(s,3H),1.53–1.15(m,4H),1.10(t,J＝7.3Hz,3H),1.01(s,3H),0.51–0.35(m,2H),0.30–0.18(m,2H).。
实施例299 化合物299-a，299-b的制备
中间体299-1的制备
Figure PCTCN2020107845-appb-000396
室温下，向1-甲氧基环丁基酰胺(100mg,774.25umol)的干燥THF(5mL)溶液中滴加BH 3.THF(3.87mmol,3.8mL)，然后反应液在65℃下搅拌过夜。混合液缓慢降至0℃，用4mL甲醇淬灭反应。混合液减压蒸馏得到299-1(85mg,738.02umol,95.32％收率)的粗品，未经纯化直接用于下一步，MS m/z：116.0(M+1) +
化合物299-a，299-b的制备
Figure PCTCN2020107845-appb-000397
参照实施例34的步骤1-6的方法，以实施例3的中间体3-3b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与中间体299-1缩合，得到化合物298-a，MS m/z：647.0(M+1) +
类似的，以实施例3中的3-3b和实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物299-b， 1H NMR(400MHz,Methanol-d 4)δ7.56–7.46(m,3H),7.42(d,J＝8.0Hz,1H),7.38–7.29(m,2H),7.28–7.20(m,2H),5.57(d,J＝8.2Hz,1H),4.41–4.33(m,1H),4.02(d,J＝9.5Hz,1H),3.94(s,1H),3.74(d,J＝9.6Hz,1H),3.58(s,3H),3.44(s,3H),2.72(s,3H),2.59(q,J＝7.6Hz,1H),2.02–1.82(m,6H),1.82–1.70(m,3H),1.57(s,3H),1.31(s,7H),1.07–1.00(m,3H),0.94–0.87(m,3H).。
实施例300 化合物300-a，300-b的制备
中间体300-7的制备
Figure PCTCN2020107845-appb-000398
步骤1，300-1的制备
氮气保护下，将叔丁醇钾(16.91g,150.72mmol)溶解在THF(300mL)中，搅拌下滴加三乙基膦酰乙酸酯(33.6g,149.87mmol)，滴加完毕后常温反应30分钟，滴入对溴苯乙酮(10g,50.24mmol)的THF(100mL)溶液，20分钟滴完。然后回流反应3小时。反应液浓缩后硅胶柱分离纯化(乙酸乙酯/石油醚做洗脱剂)得到中间体300-1(13.5g,50.16mmol,99.84％收率)，淡黄色油状液体。MS m/z：269.0(M+1) +
步骤2，300-2的制备
干冰乙醇浴下，向300-1(13.5g,50.16mmol)的DCM(300mL)溶液中， 氮气保护下，滴加DIBAL-H(14.17g,100.32mmol,100mL)，滴完保温反应1小时。然后逐渐升至室温，加水淬灭，反应液过滤，滤饼用DCM洗涤，滤液中合并的有机相旋干，粗品经硅胶柱纯化分离得到300-2(8.4g,36.99mmol,73.74％收率)，MS m/z：211.0(M+1) +
步骤3，300-3的制备
常温下，向300-2(7.6g,33.47mmol)的DCM(30mL)和PE(60mL)混合溶液中，滴加HBr(5.42g,66.93mmol,13.6mL)，滴完后常温搅拌2小时，静置后，反应液分层，下层水相用石油醚萃取，合并有机相旋干，得粗品用硅胶柱分离纯化，得到300-3(9.3g,32.07mmol,95.83％收率)。
步骤4，300-4的制备
常温下，向Zn(2.44g,37.24mmol)的DMF(100mL)悬浊液中依次加入E-乙基-2-((叔丁基亚磺酰胺)已亚胺)酯，300-3(9g,31.04mmol)，和碘单质(100mg，0.4mmol)反应混合液室温搅拌过夜，加水稀释，乙酸乙酯萃取，合并的有机相浓缩得到300-4粗品(12.92g,31.03mmol,100.00％收率)，未经纯化直接用于下一步。MS m/z：416.0,418.0(M+1) +
步骤5,300-5的制备
向300-4(12.5g,30.02mmol)的甲醇(50mL)溶液中滴加HCl/EA(2.19g,60.04mmol)，滴完后室温搅拌1小时，反应液加水稀释，乙酸乙酯萃取，用Na 2CO 3调pH＝8～9，再次用乙酸乙酯萃取，有机相浓缩干，油状物溶液在THF(70mL)中，依次加入H 2O(70mL)，K 2CO 3(8.30g,60.04mmol)和(Boc) 2O(13.10g,60.04mmol)，搅拌反应2小时，精致分层，水层用乙酸乙酯萃取，合并的有机相旋干，粗品用硅胶柱分离纯化，得到300-5(1g,2.43mmol,8.08％收率)。MS m/z：412.0,414.0(M+1) +
步骤6，300-6的制备
向300-5(1g,2.43mmol)的甲醇溶液中加入Pd/C(147.28mg,1.21mmol)和三乙胺(490.88mg,4.85mmol)，混合液置换H 2后，在H 2保护下室温搅拌过夜。反应结束后，过滤，滤液旋干，加乙酸乙酯萃取，有机相旋干得300-6(813.54mg,2.43mmol,100.00％收率)，淡黄色油状物。未经纯化直接用于下一步。MS m/z：336.0(M+1) +
步骤7，300-7的制备
向300-6(815mg,2.43mmol)的乙醇(10mL)溶液中加入NaOH(291.56mg,7.29mmol)和水(1mL)，加热至60℃反应3小时，反应液浓缩后加水，加乙酸乙酯萃取，水相加稀盐酸调pH＝4～5，分层，取有机层旋干，得到300-7(558mg,1.82mmol,74.71％收率)，淡黄色油状物。MS m/z：308.0(M+1)+
化合物300-a，300-b的制备
Figure PCTCN2020107845-appb-000399
参照实施例34的步骤1-6的方法，以上述中间体300-7与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与中间体7-2缩合，得到化合物300-a，MS m/z：642.0(M+1) +
类似的，以300-7和实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物300-b， 1H NMR(400MHz,MeOD)δ8.02(s,0.3H),7.79–7.45(m,4H),7.38-7.26(m,3H),6.71(d,J＝8.8Hz,0.3H),5.57(d,J＝12.0Hz,1H),4.75(d,J＝8.4Hz,1H),4.37-4.34(m,1H),4.10–3.96(m,3H),3.60–3.41(m,4H),3.25–3.05(m,2H),2.90–2.79(m,1H),2.67-2.60(m,1H),2.07-2.00(m,1H),1.93-1.88(m,1H),1.87–1.73(m,1H),1.59-1.51(m,1H),1.49–1.31(m,2H),1.09-1.06(m,6H),0.97(s,3H),0.77-0.72(m,1H),-0.01–-0.08(m,1H),-0.22(t,J＝7.6Hz,2H).。
实施例301 化合物301-a，301-b的制备
Figure PCTCN2020107845-appb-000400
参照实施例34的步骤1-6的方法，以实施例298的中间体298-7与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，酯水解，引入三氟已酰基，脱保护，最后与中间体7-2缩合，得化合物301-a，MS m/z：620.0(M+1) +。
类似的，以298-7和实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物301-b。
实施例302 化合物302-a，302-b的制备
Figure PCTCN2020107845-appb-000401
参照实施例34的步骤1-6的方法，以2-Boc-氨-3-(2-氯苯基)-3-甲氧基丙酸与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与中间体7-2缩合，得到化合物302-a，MS m/z：664.0(M+1) +
类似的，以2-Boc-氨-3-(2-氯苯基)-3-甲氧基丙酸和实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物302-b。， 1HNMR(400MHz,CD3OD)δ7.61-7.24(m,8H),6.94(d,J＝2.1Hz,1H),5.91(d,J＝3.4Hz,1H),5.52(d,J＝3.4Hz,1H),4.37(d,J＝8.7Hz,1H),4.02(d,J＝9.6Hz,1H),3.91(s,3H),3.74(d,J＝9.6Hz,1H),3.44(s,3H),3.31(s,3H),3.19(m,2H),2.58(m,1H),2.00-1.73(m,6H),1.59(s,3H),1.32-1.06(m,2H),0.93(s,3H),0.94-0.85(m,1H).
实施例304 化合物304-a，304-b的制备
中间体304-5的制备
Figure PCTCN2020107845-appb-000402
步骤1，中间体304-1的制备
冰浴下，向环己基乙醛(100g,891.50mmol)的THF(1.5L)溶液加入硝基乙酸乙酯(118.66g,891.50mmol)，反应体系用氮气置换，然后缓慢加入TiCl 4(169.10g,891.50mmol)，反应液搅拌30分钟。冰浴下，4-甲基吗啡啉(90.18g,891.50mmol)缓慢小心加入然后搅拌4小时。反应液缓慢倒入冰水中，用乙酸乙酯萃取，有机相浓缩得到中间体304-1(60g,264.02mmol,98.72％收率)的粗品，黄色油状物，直接用于下一步反应。
步骤2，中间体304-2的制备
冰浴下，向304-1(60g,264.02mmol)的CH 3OH(500mL)中缓慢加入CH 3ONa(57.03g,1.06mol)，反应液缓慢升至室温并搅拌3小时，混合液用水稀释，乙酸乙酯萃取，有机相旋干得到中间体304-2(68g,262.25mmol,99.33％收率)，黄色油状物。
步骤3，中间体304-3的制备
冰浴下，向304-2(13g,50.14mmol)的醋酸(180mL)中缓慢分批次加入Zn(3.2g，50.14mmol)。反应液室温搅拌4小时，后过滤，滤液旋干，粗 品用饱和碳酸钠稀释，乙酸乙酯萃取，浓缩有机相得粗品用反相HPLC分离纯化得到中间体304-3(10g,43.6mmol,87％收率)黄色油状物。
步骤4，中间体304-4的制备
向304-3(7g,30.53mmol)的DCM(100mL)中加入Cbz-Osu(8.36g,33.58mmol)和TEA(6.18g,61.05mmol,8.52mL)。反应液室温搅拌过夜。然后混合液浓缩，硅胶柱分离纯化(PE/EA＝4:1)得中间体304-4(5g,13.76mmol,45.07％收率)黄色油状物。
步骤5，中间体304-5的制备
向304-4(2g,5.50mmol)的甲醇(8mL)和水(6mL)的混合液中加入NaOH(330.17mg,8.25mmol)，反应液室温下搅拌反应1小时，有机相旋干，粗品用二氯甲烷萃取，水相用1M的HCl调pH至酸性<3,再次用乙酸乙酯萃取，有机相旋干得304-5(1.5g，4.5mmol，81％收率)。MS m/z：336.0(M+1) +
化合物304-a，304-b的制备
Figure PCTCN2020107845-appb-000403
参照实施例34的步骤1-6的方法，以中间体304-5与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与中间体7-2缩合，得到化合物304-a，MS m/z：664.0(M+1) +.
类似的，以304-5和实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物304-b。， 1H NMR(400MHz,Methanol-d 4)δ7.55(d,J＝2.1Hz,1H),7.33–7.21(m,1H),6.99(d,J＝2.2Hz,1H),5.65(d,J＝2.6Hz,1H),4.40–4.28(m,1H),4.12(s,3H),4.01(d,J＝9.5Hz,1H),3.73(d,J＝9.5Hz,1H),3.63–3.56(m,1H),3.43(s,3H),3.27–3.09(m,5H),2.64–2.51(m,1H),2.05–1.67(m,12H),1.58(s,3H),1.36–1.15(m,8H),1.14–1.06(m,3H)
实施例305 化合物305-a，305-b的制备
Figure PCTCN2020107845-appb-000404
参照实施例34的步骤1-6的方法，以2-Boc-氨-3-(2-氯苯基)-3-甲氧基丙酸与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，酯水解，与实施例7的中间体7-2缩合，脱保护，最后与氯甲酸甲酯反应得到化合物305-a，MS m/z：614.0(M+1) +
类似的，以2-Boc-氨-3-(2-氯苯基)-3-甲氧基丙酸与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物305-b。， 1H NMR(400MHz,Methanol-d 4)δ7.61-7.53(m,3H),743–7.33(m,3H),7.26(dd,J＝8.5,1.8Hz,1H),5.41-4.37(m,2H),4.42–4.32(m,1H),4.02(d,J＝9.6Hz,1H),3.74(d,J＝9.6Hz,1H),3.54(s,2H),3.44(s,3H),3.24(s,3H),3.28–3.11(m,1H),2.60-2.56(m,1H),1.95-1.77(m,3H),1.59(s,3H),1.31(s,3H),1.11(t,J＝7.3Hz,3H),0.96–0.85(m,2H).
实施例306 化合物306-a，306-b的制备
中间体306-7的制备
Figure PCTCN2020107845-appb-000405
参照实施例298中中间体298-7的制备方法，以环己烷基甲醛为原料，依次经Horner-Wittig反应，DIBAL氧化，CBr 4上溴，(2Z)-2-[((S)-叔丁基亚磺酰基]亚氨基乙酸乙酯)加成反应后得化合物306-4，脱叔丁基亚磺酰基上Cbz保护氨基，氯碘甲烷和二乙基锌关环丙烷，分离纯化得目的，用锇酸钾氧化未反应的烯键为双羟基，进而除掉未反应的原料。最后水解酯得中间体306-7。
化合物306-a，306-b的制备
Figure PCTCN2020107845-appb-000406
参照实施例34的步骤1-6的方法，以上述中间体306-7与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，脱保护，引入1-甲基-1H-吡唑-5-酰基，酯水解，最后与中间体7-2缩合，得到化合物306-a，MS m/z：660.0(M+1) +。
类似的，以306-7与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物306-b， 1H NMR(400MHz, Methanol-d 4)δ7.93(t,J＝4.9Hz,1H),7.58(t,J＝2.4Hz,1H),7.55–7.49(m,2H),7.43(t,J＝7.6Hz,1H),7.27(ddd,J＝8.6,5.7,1.8Hz,1H),6.89(dd,J＝21.8,2.1Hz,1H),5.72(dd,J＝11.2,8.6Hz,1H),4.40–4.27(m,1H),4.10(s,3H),4.01(d,J＝9.6Hz,1H),3.73(d,J＝9.5Hz,1H),3.44(s,3H),3.26–3.10(m,2H),2.58(q,J＝7.8Hz,1H),2.04–1.66(m,12H),1.59(s,3H),1.49(dd,J＝8.7,6.2Hz,1H),1.15(s,2H),1.13–1.06(m,6H),0.53–0.44(m,1H),0.39–0.30(m,1H),0.30–0.22(m,1H),0.19–0.12(m,1H)。
实施例307 化合物307-a，307-b的制备
Figure PCTCN2020107845-appb-000407
参照实施例34的步骤1-6的方法，以305-7与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，酯水解，与实施例7的中间体7-2缩合，脱保护，最后与氯甲酸甲酯反应得到化合物307-a，MS m/z：624.0(M+1) +。
类似的，以305-7与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物307-b。
实施例308 化合物308-a，308-b的制备
Figure PCTCN2020107845-appb-000408
参照实施例34的步骤1-6的方法，以实施例3的中间体3-3b与实施例6中步骤6的6-6a(SFC手性拆分制备得到一单一构型)为原料经缩合，关环，酯水解，与实施例7的中间体7-2缩合，脱保护，最后引入三氟乙酰基，得到化合物308-a，MS m/z：676.0(M+1) +。
类似的，以3-3b与实施例6中步骤66-6b(SFC手性拆分制备得到的另一单一构型)为原料，经相同的步骤，得到化合物308-b，1H NMR(400MHz,Methanol-d4)δ7.73–7.55(m,2H),7.55–7.42(m,3H),7.38–7.25(m,3H),5.91(d,J＝12.1Hz,1H),4.42–4.34(m,1H),4.04(d,J＝9.5Hz,1H),3.82–3.73(m,2H),3.46(s,3H),3.26–3.13(m,2H),2.64–2.55(m,1H),2.00–1.72(m,6H),1.61(s,3H),1.14–1.08(m,3H),1.07(s,3H),0.84–0.75(m,1H),0.03–-0.03(m,1H),-0.07–-0.19(m,2H).
为了说明本发明的有益效果，本发明提供了以下试验例。
试验例1：IL-17酶联免疫吸附测定(ELISA)实验
1、实验方法
通过竞争性ELISA实验定量检测待测化合物对受体-配体结合的抑制效果。具体才做如下：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200μL5％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(实施例制得的化合物)，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。
2、实验结果
按照上述方法测得实施例制备的化合物对IL-17A的抑制活性，结果见表1，其中各化合物的IC 50按照以下说明分类，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、化合物对IL-17A的抑制活性
化合物 IC 50 化合物 IC 50 化合物 IC 50 化合物 IC 50 化合物 IC 50
34-a +++ 107-a +++ 194-a +++ 228-a +++ 264-a +++
34-b +++ 107-b +++ 194-b +++ 228-b +++ 264-b +++
35-a +++ 108-a +++ 194-c + 229-a +++ 265-a +++
35-b +++ 108-b +++ 194-d + 229-b +++ 265-b +++
36-a +++ 109-a +++ 194-e +++ 230-a +++ 266-a +++
36-b +++ 109-b +++ 194-f +++ 230-b +++ 266-b +++
37-a +++ 110-a +++ 195-a +++ 231-a +++ 267-a +++
37-b +++ 110-b +++ 195-b +++ 231-b +++ 267-b +++
38-a +++ 111-a +++ 195-e +++ 232-a +++ 268-a +++
38-b +++ 111-b +++ 195-f +++ 232-b +++ 268-b +++
39-a +++ 112-a +++ 195-g + 233-a +++ 269-a +++
39-b +++ 112-b +++ 195-h + 234-b +++ 269-b +++
40-a +++ 112-c + 201-a +++ 235-a +++ 269-c +
40-b +++ 112-d + 201-b +++ 235-b +++ 269-d +
41-a +++ 112-e +++ 201-e +++ 236-a +++ 269-e +++
41-b +++ 112-f +++ 201-f +++ 236-b +++ 269-f +++
42-a +++ 112-g + 201-g + 237-a +++ 269-g +
42-b +++ 112-h + 201-h + 237-b +++ 269-h +
43-a +++ 113-a +++ 204-a +++ 238-a +++ 270-a +++
43-b +++ 113-b +++ 204-b +++ 238-b +++ 270-b +++
44-a +++ 113-c + 204-c + 239-a +++ 270-c +
44-b +++ 113-d + 204-d + 239-b +++ 270-d +
45-a +++ 113-e +++ 204-e +++ 240-a +++ 270-e +++
45-b +++ 113-f +++ 204-f +++ 240-b +++ 270-f +++
46-a +++ 113-g + 204-g + 241-a +++ 270-g +
46-b +++ 113-h + 204-h + 241-b +++ 270-h +
47-a +++ 137-a +++ 205-a +++ 242-a +++ 271-a +++
47-b +++ 137-b +++ 205-b +++ 242-b +++ 271-b +++
48-a +++ 137-c + 205-c + 243-a +++ 271-c +
48-b +++ 137-d + 205-d + 243-b +++ 271-d +
49-a +++ 137-e +++ 205-e +++ 244-a +++ 271-e +++
49-b +++ 137-f +++ 205-f +++ 244-b +++ 271-f +++
50-a +++ 137-g + 205-g + 245-a +++ 271-g +
50-b +++ 137-h + 205-h + 245-b +++ 271-h +
51-a +++ 138-a +++ 211-a +++ 246-a +++ 272-a +++
51-b +++ 138-b +++ 211-b +++ 246-b +++ 272-b +++
52-a +++ 138-c + 211-c + 247-a +++ 273-a +++
52-b +++ 138-d + 211-d + 247-b +++ 273-b +++
53-a +++ 138-e +++ 211-e +++ 248-a +++ 274-a +++
53-b +++ 138-f +++ 211-f +++ 248-b +++ 274-b +++
54-a +++ 138-g + 211-g + 249-a +++ 275-a +++
54-b +++ 138-h + 211-h + 249-b +++ 275-b +++
55-a +++ 139-a +++ 214-a +++ 250-a +++ 276-a +++
55-b +++ 139-b +++ 214-b +++ 250-b +++ 276-b +++
56-a +++ 139-c + 215-a +++ 250-c + 277-a +++
56-b +++ 139-d + 215-b +++ 250-d + 277-b +++
57-a +++ 139-e +++ 216-a +++ 250-e +++ 278-a +++
57-b +++ 139-f +++ 216-b +++ 250-f +++ 278-b +++
58-a +++ 139-g + 217-a +++ 250-g + 279-a +++
58-b +++ 139-h + 217-b +++ 250-h + 279-b +++
59-a +++ 164-a +++ 218-a +++ 251-a +++ 280-a +++
59-b +++ 164-b +++ 218-b +++ 251-b +++ 280-b +++
60-a +++ 165-a +++ 219-a +++ 251-c + 281-b +++
60-b +++ 165-b +++ 219-b +++ 251-d + 282-b +++
60-c + 166-a +++ 219-c + 251-e +++ 283-b +++
60-d + 166-b +++ 219-d + 251-f +++ 284-b +++
60-e +++ 167-a +++ 219-e +++ 251-g + 285-b +++
60-f +++ 167-b +++ 219-f +++ 251-h + 286-b +++
60-g + 168-a +++ 219-g + 252-a +++ 287-b +++
60-h + 168-b +++ 219-h + 252-b +++ 288-b +++
86-a +++ 169-a +++ 220-a +++ 252-c + 289-b +++
86-b +++ 169-b +++ 220-b +++ 252-d + 290-b ++
87-a +++ 170-a +++ 220-c + 252-e +++ 291-b +++
87-b +++ 170-b +++ 220-d + 252-f +++ 292-b +++
88-a +++ 171-a +++ 220-e +++ 252-g + 293-b +++
88-b +++ 171-b +++ 220-f +++ 252-h + 294-b +++
89-a +++ 172-a +++ 220-g + 253-a +++ 295-b +++
89-b +++ 172-b +++ 220-h + 253-b +++ 296-b +++
90-a +++ 173-a +++ 221-a +++ 253-c + 297-b +++
90-b +++ 173-b +++ 221-b +++ 253-d + 298-b +++
91-a +++ 174-a +++ 221-c + 253-e +++ 299-b ++
91-b +++ 174-b +++ 221-d + 253-f +++ 300-b ++
92-a +++ 175-a +++ 221-e +++ 253-g + 301-b +++
92-b +++ 175-b +++ 221-f +++ 253-h + 302-b +++
93-a +++ 176-a +++ 221-g + 254-a +++ 303-b +
93-b +++ 176-b +++ 221-h + 254-b +++ 304-b +++
94-a +++ 177-a +++ 222-a +++ 254-c + 305-b +
94-b +++ 177-b +++ 222-b +++ 254-d + 306-b +++
95-a +++ 178-a +++ 222-c + 254-e +++ 307-b +++
95-b +++ 178-b +++ 222-d + 254-f +++ 308-b +++
96-a +++ 179-a +++ 222-e +++ 254-g +    
96-b1 +++ 179-b +++ 222-f +++ 254-h +    
96-b2 +++ 180-a +++ 222-g + 255-a +++    
97-a +++ 180-b +++ 222-h + 255-b +++    
97-b +++ 181-a +++ 223-a +++ 255-c +    
98-a +++ 181-b +++ 223-b +++ 255-d +    
98-b +++ 182-a +++ 223-c + 255-e +++    
99-a +++ 182-b +++ 223-d + 255-f +++    
99-b +++ 183-a +++ 223-e +++ 255-g +    
100-a +++ 183-b +++ 223-f +++ 255-h +    
100-b1 +++ 184-a +++ 223-g + 256-a +++    
100-b2 +++ 184-b +++ 223-h + 256-b +++    
101-a +++ 184-c + 224-a +++ 257-a +++    
101-b +++ 184-d + 224-b +++ 257-b +++    
102-a +++ 184-e +++ 224-c + 258-a +++    
102-b +++ 184-f +++ 224-d + 258-b +++    
103-a +++ 184-g + 224-e +++ 259-a +++    
103-b1 +++ 184-h + 224-f +++ 259-b +++    
103-b2 +++ 193-a +++ 224-g + 260-a +++    
104-a +++ 193-b +++ 224-h + 260-b +++    
104-b1 +++ 193-c + 225-a +++ 261-a +++    
104-b2 +++ 193-d + 225-b +++ 261-b +++    
105-a +++ 193-e +++ 226-a +++ 262-a +++    
105-b +++ 193-f +++ 226-b +++ 262-b +++    
106-a +++ 193-g + 227-a +++ 263-a +++    
106-b +++ 193-h + 227-b +++ 263-b +++    
试验结果表明，本发明提供的化合物具有良好的IL-17A抑制活性，可以作为IL-17A抑制剂，用于制备治疗与IL-17A活性异常相关疾病的药物。
综上所述，本发明公开的式I所示的化合物，表现出了良好的IL-17A抑制活性，可以用来制备IL-17A抑制剂以及预防和/或治疗IL-17A介导的疾病(比如炎症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征等)的药物，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 (22)

  1. 式I所示的化合物、或其立体异构体、或其药学上可接受的盐：
    Figure PCTCN2020107845-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、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)；
    R 3、R 4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)、-O(C 1～10烷基)、-O(C 0～4亚烷基)(3～10元环烷基)、-O(C 0～4亚烷基)(3～10元杂环烷基)；或者，其中烷基、环烷基、杂环烷基进一步被一个、两个或三个R 31取代；
    或者R 3、R 4相连形成3～10元环烷基、3～10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R 31取代；
    每个R 31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)、-O(C 0～4亚烷基)(3～10元环烷基)、-O(C 0～4亚烷基)(3～10元杂环烷基)；
    A环选自3～10元环烷基、3～10元杂环烷基、5～10元芳环、5～10元芳杂环；或者，其中环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R A1取代；
    每个R A1分别独立选自卤素、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)；或者，其中环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R A4取代；
    每个R A4分别独立选自卤素、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；
    R A2、R A3分别独立选自氢、-C 1～10烷基；
    X 1选自CR x1或N；
    X 2选自NR x2、O、S或-(CR x3＝CR x4)-；
    R x1、R x3、R x4分别独立选自氢、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)；
    R x2选自氢、-C 1～10烷基、-C(O)(C 1～10烷基)；
    L 1选自-C 1～10亚烷基-；
    R 5选自-C 1～10烷基、卤素取代的-C 1～10烷基；
    R 6选自氢、-C 1～10烷基、卤素取代的-C 1～10烷基；
    L 2选自-C 0～4亚烷基-C(O)NR L21-、-C 0～4亚烷基-NR L21C(O)-、-C 0～4亚烷基-S(O)NR L21-、-C 0～4亚烷基-S(O) 2NR L21-、-C 0～4亚烷基-NR L21S(O)-、-C 0～4亚烷基-NR L21S(O) 2-、-C 0～4亚烷基-P(O)(OH)NR L21-、-C 0～4亚烷基-NR L21P(O)(OH)-、-C 0～4亚烷基-C(O)-、-C 0～4亚烷基-NR L21-；
    R L21选自氢、-C 1～10烷基；
    R选自-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)、-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)、
    Figure PCTCN2020107845-appb-100002
    其中C环选自3～10元环烷基、3～10元杂环烷基、5～10元芳环、5～10元芳杂环；或者，其中亚烷基、环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环进一步被被一个、两个或三个R d取代；
    R a、R a’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)、-O(C 1～10烷基)、-O(C 0～4亚烷基)(3～10元环烷基)、-O(C 0～4亚烷基)(3～10元杂环烷基)；或者，其中烷基、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 a1取代；
    或者R a、R a’相连形成3～10元环烷基、3～10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、-OH、-O(C 1～10烷基)；
    R b、R c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-(5～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；或者，其中烷基、环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R b1取代；
    或者R a、R b相连形成3～10元杂环烷基、5～10元芳杂环、5～12元螺杂环、5～12元桥杂环；或者，其中杂环烷基、芳杂环、螺杂环、桥杂环进一步被一个、两个或三个R d取代；
    每个R b1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)；
    每个R d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 d1、-C 0～4亚烷基-OC(O)R d1、-C 0～4亚烷基-C(O)R d1、-C 0～4亚烷基-C(O)OR d1、-C 0～4亚烷基-C(O)NR d1R d2、-C 0～4亚烷基-NR d1R d2、-C 0～4亚烷基-NR d1C(O)R d2；
    R d1、R d2分别独立选自氢、-C 1～10烷基、3～10元环烷基、3～10元杂环烷基。
  2. 根据权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐，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、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)；
    R 3、R 4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)、-O(C 1～6烷基)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；或者，其中烷基、环烷基、杂环烷基进一步被一个、两个或三个R 31取代；
    或者R 3、R 4相连形成3～6元环烷基、3～6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R 31取代；
    每个R 31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)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；
    A环选自5～6元芳环、5～6元芳杂环、3～6元环烷基、3～6元杂环烷基；或者，其中芳环、芳杂环、3～6元环烷基、3～6元杂环烷基进一步被一个、 两个或三个R A1取代；
    每个R A1分别独立选自卤素、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)；或者，其中环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R A4取代；
    每个R A4分别独立选自卤素、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；
    R A2、R A3分别独立选自氢、-C 1～6烷基；
    X 1选自CR x1或N；
    X 2选自NR x2、O、S或-(CR x3＝CR x4)-；
    R x1、R x3、R x4分别独立选自氢、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)；
    R x2选自氢、-C 1～6烷基、-C(O)(C 1～6烷基)；
    L 1选自-C 1～6亚烷基-；
    R 5选自-C 1～6烷基、卤素取代的-C 1～6烷基；
    R 6选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
    L 2选自-C 0～2亚烷基-C(O)NR L21-、-C 0～2亚烷基-NR L21C(O)-、-C 0～2亚烷基-C(O)-、-C 0～2亚烷基-NR L21-；
    R L21选自氢、-C 1～6烷基；
    R选自-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)、-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)、
    Figure PCTCN2020107845-appb-100003
    其中C环选自3～6元环烷基、3～6元杂环烷基、5～6元芳环、5～6元芳杂环；或者，其中亚烷基、环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环进一步被被一个、两个或三个R d取代；
    R a、R a’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)、-O(C 1～6烷基)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；或者，其中烷基、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 a1取代；
    或者R a、R a’相连形成3～6元环烷基、3～6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、-OH、-O(C 1～6烷基)；
    R b、R c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-(5～6元芳环)、-C 0～2亚烷基-(5～6元芳杂环)；或者，其中烷基、环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R b1取代；
    或者R a、R b相连形成3～10元杂环烷基、5～10元芳杂环、5～12元螺杂环、5～12元桥杂环；或者，其中杂环烷基、芳杂环、螺杂环、桥杂环进一步被一个、两个或三个R d取代；
    每个R b1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)；
    每个R d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 d1、-C 0～2亚烷基-OC(O)R d1、-C 0～2亚烷基-C(O)R d1、-C 0～2亚烷基-C(O)OR d1、-C 0～2亚烷基-C(O)NR d1R d2、-C 0～2亚烷基-NR d1R d2、-C 0～2亚烷基-NR d1C(O)R d2；
    R d1、R d2分别独立选自氢、-C 1～6烷基、3～6元环烷基、3～6元杂环烷基。
  3. 根据权利要求1或2所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：所述式I的化合物如式II所示：
    Figure PCTCN2020107845-appb-100004
    其中，
    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、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)；
    R 3、R 4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)、-O(C 1～6烷基)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；或者，其中烷基、环烷基、杂环烷基进一步被一个、两个或三个R 31取代；
    或者R 3、R 4相连形成3～6元环烷基、3～6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R 31取代；
    每个R 31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)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；
    A环选自5～6元芳环、5～6元芳杂环、3～6元环烷基、3～6元杂环烷基；或者，其中芳环、芳杂环、3～6元环烷基、3～6元杂环烷基进一步被一个、两个或三个R A1取代；
    每个R A1分别独立选自卤素、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)；或者，其中环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R A4取代；
    每个R A4分别独立选自卤素、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；
    R A2、R A3分别独立选自氢、-C 1～6烷基；
    L 1选自-C 1～6亚烷基-；
    R 5选自-C 1～6烷基、卤素取代的-C 1～6烷基；
    R 6选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
    R a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)、-O(C 1～6烷基)、-O(C 0～2亚烷基)(3～6元环烷基)、-O(C 0～2亚烷基)(3～6元杂环烷基)；或者，其中烷基、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 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、-OH、-O(C 1～6烷基)；
    R b、R c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-(5～6元芳环)、-C 0～2亚烷基-(5～6元芳杂环)；或者，其中烷基、环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R b1取代；
    或者R a、R b相连形成3～10元杂环烷基、5～10元芳杂环、5～12元螺杂环、5～12元桥杂环；或者，其中杂环烷基、芳杂环、螺杂环、桥杂环进一步被一个、两个或三个R d取代；
    每个R b1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)。
  4. 根据权利要求3所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：
    R 1选自-C 1～6烷基、3～6元环烷基、3～6元杂环烷基、5～6元芳环、5～6元芳杂环、-NR 11R 12、-OR 11；或者，其中环烷基、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、3～6元环烷基、3～6元杂环烷基；
    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)。
  5. 根据权利要求4所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：R 1选自
    Figure PCTCN2020107845-appb-100005
    卤代或未卤代的C 1～3烷基、卤代或未卤代的C 1～3烷氧基、
    Figure PCTCN2020107845-appb-100006
    R 13选自甲基、乙基，R 1a、R 1b分别独立选自氢、C 1～2烷基、C 1～2烷氧基、
    Figure PCTCN2020107845-appb-100007
    优选的，所述C 1～3烷基选自甲基、乙基、
    Figure PCTCN2020107845-appb-100008
    所述卤素选自氟、氯、溴。
  6. 根据权利要求3所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：
    R 3、R 4分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、3～6元环烷基、3～6元杂环烷基、-O(C 1～6烷基)、-O(3～6元环烷基)；或者，其中烷基、环烷基、杂环烷基进一步被一个、两个或三个R 31取代；
    每个R 31独立选自卤素、-C 1～6烷基、卤素取代的-C 1～6烷基、-OH、-O(C 1～6烷基)、-O(3～6元环烷基)。
  7. 根据权利要求6所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：R 3、R 4至少有一个为氢；优选的，R 3、R 4一个为氢，另一个选自卤素或甲基取代的以下基团：C 1～3烷基、C 1～3烷氧基、
    Figure PCTCN2020107845-appb-100009
    更优选的，所述C 1～3烷基选自甲基、乙基、
    Figure PCTCN2020107845-appb-100010
    所述卤素选自氟、氯、溴。
  8. 根据权利要求3所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：
    A环选自5～6元芳环、5～6元芳杂环、4～6元饱和环烷基；或者，其中芳环、芳杂环、4～6元饱和环烷基进一步被一个、两个或三个R A1取代；
    每个R A1分别独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR A2、-OC(O)R A2、-C(O)R A2、-C(O)OR A2、-C(O)NR A2R A3、-NR A2R A3、-NR A2C(O)R A3、3～6元环烷基、3～6元杂环烷基、5～6元芳环、5～6元芳杂环；或者，其中环烷基、杂环烷基、芳环、芳杂环进一步被一个、两个或三个R A4取代；
    每个R A4分别独立选自卤素、氰基、羰基、硝基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR A2、-OC(O)R A2、-C(O)R A2、-C(O)OR A2、-C(O)NR A2R A3、-NR A2R A3、-NR A2C(O)R A3；
    R A2、R A3分别独立选自氢、-C 1～6烷基；
    优选的，A环选自苯环、4～6元饱和环烷基，或者，其中苯环、4～6元饱和环烷基进一步被一个、两个或三个R A1取代，每个R A1分别独立选自卤素，所述卤素优选为氟、氯、溴。
  9. 根据权利要求3所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：L 1选自-C 1～4亚烷基-；R 5选自-C 1～4烷基；R 6选自氢、-C 1～4烷基。
  10. 根据权利要求9所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：L 1选自亚甲基、亚乙基、亚正丙基、亚异丙基；R 5选自甲基、乙基、正丙基、异丙基；R 6选自氢、甲基、乙基、正丙基、异丙基。
  11. 根据权利要求3所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：
    R a选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、3～6元环烷基、3～6元杂环烷基、6～11元螺环、6～11元螺杂环、5～10元桥环、5～10元桥杂环、-O(C 1～6烷基)、-O(3～6元环烷基)、-O(3～6元杂环烷基)；或者，其中烷基、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 a1取代；优选的，所述螺环为
    Figure PCTCN2020107845-appb-100011
    所述桥环为
    Figure PCTCN2020107845-appb-100012
    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、-OH、-O(C 1～6烷基)。
  12. 根据权利要求11所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：R a选自
    Figure PCTCN2020107845-appb-100013
    Figure PCTCN2020107845-appb-100014
    或者，其中
    Figure PCTCN2020107845-appb-100015
    Figure PCTCN2020107845-appb-100016
    进一步被一个、两个或三个甲基、卤素、甲氧基取代，所述卤 素优选为氟、氯、溴。
  13. 根据权利要求3所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：
    R b、R c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，其中烷基、环烷基、杂环烷基进一步被一个、两个或三个R b1取代；
    每个R b1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)。
  14. 根据权利要求13所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：R b、R c至少有一个为氢；优选的，R b、R c一个为氢，另一个为L cR c1；L c选自C 0～2亚烷基，优选为无、亚甲基、亚乙基；R c1选自C 1～2烷基、
    Figure PCTCN2020107845-appb-100017
    或者，其中C 1～2烷基、
    Figure PCTCN2020107845-appb-100018
    进一步被一个、两个或三个
    R b1取代，每个R b1独立选自卤素、羟基、C 1～2烷基、C 1～2烷氧基；所述卤素选自氟、氯、溴。
  15. 根据权利要求3所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：R a、R b相连形成5～12元螺杂环，进一步地，所述螺杂环为
    Figure PCTCN2020107845-appb-100019
  16. 根据权利要求3～15任一项所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：
    R 2为氢。
  17. 根据权利要求1或2所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：所述化合物的结构如式III所示：
    Figure PCTCN2020107845-appb-100020
    其中，R 1如权利要求4或5所述；
    R 2为氢；
    R 3、R 4如权利要求6或7所述；
    A环如权利要求8所述；
    R 5、R 6、L 1如权利要求9或10所述；
    n为0～3的整数，优选为0～1的整数；
    R f选自氢、L 0R f1；其中，L 0为C 0～3亚烷基，优选为无或亚甲基；R f1选自氨基、羟基、C 1～3烷基、C 1～3烷氧基、COOCH 3；
    R e选自取代或未取代的4～6元饱和环烷基，优选为取代或未取代的
    Figure PCTCN2020107845-appb-100021
    所述取代基选自卤素、羟基、C 1～3烷基、C 1～3烷氧基，所述卤素优选为氟。
  18. 根据权利要求1～17任一项所述的化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：所述化合物选自：
    Figure PCTCN2020107845-appb-100022
    Figure PCTCN2020107845-appb-100023
    Figure PCTCN2020107845-appb-100024
    Figure PCTCN2020107845-appb-100025
    Figure PCTCN2020107845-appb-100026
    Figure PCTCN2020107845-appb-100027
    Figure PCTCN2020107845-appb-100028
    Figure PCTCN2020107845-appb-100029
    Figure PCTCN2020107845-appb-100030
    Figure PCTCN2020107845-appb-100031
    Figure PCTCN2020107845-appb-100032
    Figure PCTCN2020107845-appb-100033
    Figure PCTCN2020107845-appb-100034
    Figure PCTCN2020107845-appb-100035
    Figure PCTCN2020107845-appb-100036
    Figure PCTCN2020107845-appb-100037
    Figure PCTCN2020107845-appb-100038
    Figure PCTCN2020107845-appb-100039
    Figure PCTCN2020107845-appb-100040
    Figure PCTCN2020107845-appb-100041
    Figure PCTCN2020107845-appb-100042
    Figure PCTCN2020107845-appb-100043
    Figure PCTCN2020107845-appb-100044
    Figure PCTCN2020107845-appb-100045
  19. 权利要求1-18任一项所述的化合物、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。
  20. 权利要求19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，优选为类风湿性关节炎、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、哮喘或多发性硬化症。
  21. 权利要求1-18任一项所述的化合物、或其立体异构体、或其药学上可接受的盐在制备IL-17A抑制剂中的用途。
  22. 一种药物组合物，其特征在于：它是以权利要求1～18任一项所述的化合物、或其立体异构体、或其药学上可接受的盐为活性成分，加上药学上可接受的辅料制备而成的制剂。
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WO2024017880A1 (en) 2022-07-22 2024-01-25 UCB Biopharma SRL Imidazotriazine derivatives as il-17 modulators

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