Immunomodulator

文档序号：574177 发布日期：2021-05-21 浏览：12次中文

阅读说明：本技术 一种免疫调节剂 (Immunomodulator ) 是由李进张登友白晓光尚巳耘杨丹梅黄昊岚洪新福周贤思刘利李清然陈欣于 2020-11-20 设计创作，主要内容包括：本发明公开了一种免疫调节剂,具体涉及一类抑制IL-17A的化合物及其作为免疫调节剂在制备药物中的用途。本发明公开了式I所示的化合物、或其立体异构体在制备抑制IL-17A类药物中的用途,为临床上筛选和/或制备与IL-17A活性相关的疾病的药物提供了一种新的选择。(The invention discloses an immunomodulator, and particularly relates to a compound for inhibiting IL-17A and application thereof as an immunomodulator in preparation of a medicament. The invention discloses application of a compound shown as a formula I or a stereoisomer thereof in preparing IL-17A inhibiting medicines, and provides a new choice for clinically screening and/or preparing medicines for diseases related to IL-17A activity.)

1. A compound of formula I, or a stereoisomer thereof, or a nitroxide thereof, or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

R₁selected from hydrogen, -C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered)Aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R₁₃Substitution;

R₁₁、R₁₂each independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R₁₃Substitution;

each R₁₃Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -OH, -O (C)_1～10Alkyl), -NH₂、-NH(C_1～10Alkyl), -N (C)_1～10Alkyl) (C_1～10Alkyl groups);

R₂selected from hydrogen, -C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl);

the ring A is selected from 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, 5-10 membered spirocyclic; wherein cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic may be further substituted by one, two or three independent R_A1Substitution;

each R_A1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR_A2、-C_0～4alkylene-OC (O) R_A2、-C_0～4alkylene-C (O) R_A2、-C_0～4alkylene-C (O) OR_A2、-C_0～4alkylene-C (O) NR_A2R_A3、-C_0～4alkylene-NR_A2R_A3、-C_0～4alkylene-NR_A2C(O)R_A3、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring))、-C_0～4Alkylene- (5-to 10-membered aromatic heterocycle);

R_A2、R_A3each independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl);

Y₁、Y₂、Y₃each independently selected from N or CR_Y1；

Each R_Y1Independently selected from hydrogen, halogen, cyano, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -OH, -O (C)_1～10Alkyl), -NH₂、-NH(C_1～10Alkyl), -N (C)_1～10Alkyl) (C_1～10Alkyl groups);

R₃selected from hydrogen, -C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

R_3’is selected from-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), - (C)_0～4Alkylene) O (C)_1～10Alkyl), - (C)_0～4Alkylene) O (C)_0～4Alkylene) (3-to 10-membered cycloalkyl), - (C)_0～4Alkylene) O (C)_0～4Alkylene) (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R₃₁Substitution;

or, R₃、R_3’Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, cyano, carbonyl, nitro, -C_0～4alkylene-OR₃₂、-C_0～4alkylene-OC (O) R₃₂、-C_0～4alkylene-C (O) R₃₂、-C_0～4alkylene-C (O) OR₃₂、-C_0～4alkylene-C (O) NR₃₂R₃₃、-C_0～4alkylene-NR₃₂R₃₃、-C_0～4alkylene-NR₃₂C(O)R₃₃、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl) or-C_0～4alkylene-R₃₄；

R₃₂、R₃₃Are independently selected from hydrogen and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl);

R₃₄is selected from

R₃₅、R₃₆Are independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl);

R₄selected from a 5-to 10-membered aromatic ring, a 5-to 10-membered aromatic heterocycle or-C (O) NR₅R₆(ii) a Wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by one, two or three independent R₄₁Substitution;

each R₄₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR₄₂、-C_0～4alkylene-OC (O) R₄₂、-C_0～4alkylene-C (O) R₄₂、-C_0～4alkylene-C (O) OR₄₂、-C_0～4alkylene-C (O) NR₄₂R₄₃、-C_0～4alkylene-NR₄₂R₄₃、-C_0～4alkylene-NR₄₂C(O)R₄₃、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₄Substitution;

R₄₂、R₄₃are independently selected from hydrogen and-C_1～10Alkyl, -C_1～4alkylene-OC (O) R₄₆、-C_1～4alkylene-C (O) R₄₆、-C_1～4alkylene-C (O) OR₄₆、-C_1～4alkylene-C (O) NR₄₆R₄₇、-C_1～4alkylene-NR₄₆R₄₇、-C_1～4alkylene-NR₄₆C(O)R₄₇、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); or, R₄₂、R₄₃Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₅Substitution;

each R₄₄Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR₄₆、-C_0～4alkylene-OC (O) R₄₆、-C_0～4alkylene-C (O) R₄₆、-C_0～4alkylene-C (O) OR₄₆、-C_0～4alkylene-C (O) NR₄₆R₄₇、-C_0～4alkylene-NR₄₆R₄₇、-C_0～4alkylene-NR₄₆C(O)R₄₇、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle);

each R₄₅Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR₄₆、-C_0～4alkylene-OC (O) R₄₆、-C_0～4alkylene-C (O) R₄₆、-C_0～4alkylene-C (O) OR₄₆、-C_0～4alkylene-C (O) NR₄₆R₄₇、-C_0～4alkylene-NR₄₆R₄₇、-C_0～4alkylene-NR₄₆C(O)R₄₇、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle);

R₄₆、R₄₇are independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl); or, R₄₆、R₄₇Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl;

R₅、R₆each independently selected from hydrogen and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C (O) NR₅₂R₅₃、-C(O)OR₅₂、-S(O)R₅₂、-S(O)₂R₅₂、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 12-membered bridged ring), -C_0～4Alkylene- (5-12 membered bridged heterocycle), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, bridged ring, bridged heterocycle, aromatic ring, aromatic heterocycle may be further substituted with one, two or three R₅₁Substitution;

or, R₅、R₆Are linked to form a 3-to 10-membered heterocycloalkyl group; wherein the heterocycloalkyl group may be further substituted by one,Two or three R₅₁Substitution;

each R₅₁Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR₅₂、-C_0～4alkylene-OC (O) R₅₂、-C_0～4alkylene-C (O) R₅₂、-C_0～4alkylene-C (O) OR₅₂、-C_0～4alkylene-NR₅₂R₅₃、-C_0～4alkylene-NR₅₂C(O)R₅₃、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle) or-C_0～4alkylene-OR₅₅、-C_0～4alkylene-NR₅₅R₅₆(ii) a Wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₅₄Substitution;

each R₅₄Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR₅₂、-C_0～4alkylene-OC (O) R₅₂、-C_0～4alkylene-C (O) R₅₂、-C_0～4alkylene-C (O) OR₅₂、-C_0～4alkylene-NR₅₂R₅₃、-C_0～4alkylene-NR₅₂C(O)R₅₃、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle);

R₅₂、R₅₃are independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl); or, R₅₂、R₅₃Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl;

R₅₅、R₅₆are independently selected from hydrogen and-C_1～10Alkyl, aryl, heteroaryl, and heteroaryl,

R₅₇、R₅₈Are independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl).

2. The compound of claim 1, wherein:

R₁selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R₁₃Substitution;

R₁₁、R₁₂each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R₁₃Substitution;

each R₁₃Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups);

R₂selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl);

the ring A is selected from 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, 6-9 membered spirocyclic; wherein cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic may be further substituted by one, two or three independent R_A1Substitution;

each R_A1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR_A2、-C_0～2alkylene-OC (O) R_A2、-C_0～2alkylene-C (O) R_A2、-C_0～2alkylene-C (O) OR_A2、-C_0～2alkylene-C (O) NR_A2R_A3、-C_0～2alkylene-NR_A2R_A3、-C_0～2alkylene-NR_A2C(O)R_A3、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle);

R_A2、R_A3each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

Y₁、Y₂、Y₃each independently selected from N or CR_Y1；

Each R_Y1Independently selected from hydrogen, halogen, cyano, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups);

R₃selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

R_3’is selected from-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), - (C)_0～2Alkylene) O (C)_1～6Alkyl), - (C)_0～2Alkylene) O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), - (C)_0～2Alkylene) O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R₃₁Substitution;

or, R₃、R₃' are linked to form a 3-to 6-membered cycloalkyl group, a 3-to 6-membered heterocycloalkyl group; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-C (O) R₃₂、-C_0～2alkylene-C (O) OR₃₂；

R₃₂、R₃₃Are independently selected from hydrogen and-C_1～6An alkyl group;

R₄selected from a 5-to 6-membered aromatic ring, a 5-to 6-membered aromatic heterocycle or-C (O) NR₅R₆(ii) a Wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by one, two or three independent R₄₁Substitution;

each R₄₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₄₂、-C_0～2alkylene-OC (O) R₄₂、-C_0～2alkylene-C (O) R₄₂、-C_0～2alkylene-C (O) OR₄₂、-C_0～2alkylene-C (O) NR₄₂R₄₃、-C_0～2alkylene-NR₄₂R₄₃、-C_0～2alkylene-NR₄₂C(O)R₄₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycle)Alkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₄Substitution;

R₄₂、R₄₃are independently selected from hydrogen and-C_1～6Alkyl, -C_1～2alkylene-OC (O) R₄₆、-C_1～2alkylene-C (O) R₄₆、-C_1～2alkylene-C (O) OR₄₆、-C_1～2alkylene-C (O) NR₄₆R₄₇、-C_1～2alkylene-NR₄₆R₄₇、-C_1～2alkylene-NR₄₆C(O)R₄₇、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); or, R₄₂、R₄₃Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₅Substitution;

each R₄₄Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₄₆、-C_0～2alkylene-OC (O) R₄₆、-C_0～2alkylene-C (O) R₄₆、-C_0～2alkylene-C (O) OR₄₆、-C_0～2alkylene-C (O) NR₄₆R₄₇、-C_0～2alkylene-NR₄₆R₄₇、-C_0～2alkylene-NR₄₆C(O)R₄₇、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle);

each R₄₅Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₄₆、-C_0～2alkylene-OC (O) R₄₆、-C_0～2alkylene-C (O) R₄₆、-C_0～2alkylene-C (O) OR₄₆、-C_0～2alkylene-C (O) NR₄₆R₄₇、-C_0～2alkylene-NR₄₆R₄₇、-C_0～2alkylene-NR₄₆C(O)R₄₇、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle);

R₄₆、R₄₇are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or, R₄₆、R₄₇Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl;

R₅、R₆each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C (O) NR₅₂R₅₃、-C(O)OR₅₂、-S(O)R₅₂、-S(O)₂R₅₂、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 10-membered bridged ring), -C_0～2Alkylene- (5-to 10-membered bridged heterocycle), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, bridged ring, bridged heterocycle, aromatic ring, aromatic heterocycle may be further substituted with one, two or three R₅₁Substitution;

or, R₅、R₆Are linked to form a 3-to 6-membered heterocycloalkyl group; wherein the heterocycloalkyl radical may be further substituted by one, two or three R₅₁Substitution;

each R₅₁Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₅₂、-C_0～2alkylene-OC (O) R₅₂、-C_0～2alkylene-C (O) R₅₂、-C_0～2alkylene-C (O) OR₅₂、-C_0～2alkylene-NR₅₂R₅₃、-C_0～2alkylene-NR₅₂C(O)R₅₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle) or-C_0～2alkylene-OR₅₅、-C_0～2alkylene-NR₅₅R₅₆(ii) a Wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₅₄Substitution;

each R₅₄Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₅₂、-C_0～2alkylene-OC (O) R₅₂、-C_0～2alkylene-C (O) R₅₂、-C_0～2alkylene-C (O) OR₅₂、-C_0～2alkylene-NR₅₂R₅₃、-C_0～2alkylene-NR₅₂C(O)R₅₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle);

R₅₂、R₅₃are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or, R₅₂、R₅₃Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl;

R₅₅、R₅₆are independently selected from hydrogen and-C_1～6Alkyl, aryl, heteroaryl, and heteroaryl,

R₅₇、R₅₈Are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl).

3. The compound of claim 1, wherein: the compound of formula I is represented by formula II:

wherein the content of the first and second substances,

R₂selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl);

the ring A is selected from 5-7 membered cycloalkyl and 5-7 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R_A1Substitution;

R_A2、R_A3each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

R_Y1selected from hydrogen, halogen;

r3' is selected from- (C)_0～2Alkylene) O (C)_1～6Alkyl), - (C)_0～2Alkylene) O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), - (C)_0～2Alkylene) O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

the B ring is selected from a 5-6-membered aromatic ring and a 5-6-membered aromatic heterocycle; wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by one, two or three independent R₄₁Substitution;

each R₄₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₄₂、-C_0～2alkylene-OC (O) R₄₂、-C_0～2alkylene-C (O) R₄₂、-C_0～2alkylene-C (O) OR₄₂、-C_0～2alkylene-C (O) NR₄₂R₄₃、-C_0～2alkylene-NR₄₂R₄₃、-C_0～2alkylene-NR₄₂C(O)R₄₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₄Substitution;

R₄₆、R₄₇are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or, R₄₆、R₄₇Are linked to form 3-to 6-membered cycloalkyl and 3-to 6-membered heterocycloalkyl.

4. A compound according to claim 3, characterized in that:

R₁is selected from-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 6-membered aromatic ring, 5-to 6-membered aromatic heterocycle, -NR₁₁R₁₂、-OR₁₁(ii) a Wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R₁₃Substitution;

R₁₁、R₁₂each independently selected from hydrogen and-C_1～6An alkyl group, a 3-to 6-membered cycloalkyl group, a 3-to 6-membered heterocycloalkyl group;

5. The compound of claim 4, wherein: r₁Selected from halogen-substituted alkyl, -O (C)_1～6Alkyl radicals),

6. A compound according to claim 3, characterized in that:

each R_A1Is independently selected from-C_1～6An alkyl group.

7. The compound of claim 6, wherein: a ring is selected from

8. A compound according to claim 3, characterized in that: r₃Selected from hydrogen, -C_1～6An alkyl group; r₃' selected from- (C)_0～2Alkylene) O (C)_1～6Alkyl groups).

9. A compound according to claim 3, characterized in that: r₃、R₃' are linked to form a 3-to 6-membered heterocycloalkyl group.

10. The compound of claim 9, wherein: r₃、R₃The bond of the two units forms a 3-6 membered oxygen-containing heterocycloalkyl group and a 3-6 membered nitrogen-containing heterocycloalkyl group.

11. A compound according to claim 3, characterized in that:

ring B is selected from

R₄₁₁、R₄₁₂Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₄₂、-C_0～2alkylene-OC (O) R₄₂、-C_0～2alkylene-C (O) R₄₂、-C_0～2alkylene-C (O) OR₄₂、-C_0～2alkylene-C (O) NR₄₂R₄₃、-C_0～2alkylene-NR₄₂R₄₃、-C_0～2alkylene-NR₄₂C(O)R₄₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring),-C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₄Substitution;

R₄₂、R₄₃are independently selected from hydrogen and-C_1～6An alkyl group;

each R₄₄Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6An alkyl group.

12. A compound according to claim 3, characterized in that:

ring B is selected from

R₄₁₁Is selected from-C_0～2alkylene-OR₄₂、-C_0～2alkylene-OC (O) R₄₂、-C_0～2alkylene-C (O) R₄₂、-C_0～2alkylene-C (O) OR₄₂、-C_0～2alkylene-C (O) NR₄₂R₄₃、-C_0～2alkylene-NR₄₂R₄₃、-C_0～2alkylene-NR₄₂C(O)R₄₃；

R₄₂、R₄₃Are independently selected from hydrogen and-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₅Substitution;

each R₄₅Are respectively independently selected from-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₄₆、-C_0～2alkylene-OC (O) R₄₆、-C_0～2alkylene-C (O) R₄₆、-C_0～2alkylene-C (O) OR₄₆、-C_0～2alkylene-C (O) NR₄₆R₄₇、-C_0～2alkylene-NR₄₆R₄₇、-C_0～2alkylene-NR₄₆C(O)R₄₇、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle);

R₄₆、R₄₇are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

R₄₁₂selected from hydrogen, -C_1～6An alkyl group.

13. The compound of claim 12, wherein: r₄₂、R₄₃At least one is selected from hydrogen.

14. The compound of claim 2, wherein: the compound of formula I is represented by formula III:

R₁₁、R₁₂each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ringThe rings may further be substituted by one, two or three independent R₁₃Substitution;

R₂selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl);

R_A2、R_A3each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

R_3’Is selected from-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), - (C)_0～2Alkylene) O (C)_1～6Alkyl), - (C)_0～2Alkylene) O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), - (C)_0～2Alkylene) O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～4alkylene-C (O) R₃₂、-C_0～4alkylene-C (O) OR₃₂；

R₃₂、R₃₃Are independently selected from hydrogen and-C_1～10An alkyl group;

R₅、R₆each independently selected from hydrogen and-C_1～6Alkyl, -C (O) NR₅₂R₅₃、-C(O)OR₅₂、-S(O)R₅₂、-S(O)₂R₅₂、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₅₁Substitution;

or, R₅、R₆Are linked to form a 3-to 6-membered heterocycloalkyl group; wherein the heterocycloalkyl radical may be further substituted by one, two or three R₅₁Substitution;

each R₅₁Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl radical、-C_0～2alkylene-OR₅₂、-C_0～2alkylene-OC (O) R₅₂、-C_0～2alkylene-C (O) R₅₂、-C_0～2alkylene-C (O) OR₅₂、-C_0～2alkylene-NR₅₂R₅₃、-C_0～2alkylene-NR₅₂C(O)R₅₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₅₄Substitution;

R₅₂、R₅₃are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or, R₅₂、R₅₃Are linked to form 3-to 6-membered cycloalkyl and 3-to 6-membered heterocycloalkyl.

15. The compound of claim 14, wherein:

R₁is selected from-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 6-membered aromatic ring, 5-to 6-membered aromatic heterocycle, -NR₁₁R₁₂、-OR₁₁(ii) a Wherein alkyl, cycloalkylThe heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted with one, two or three independent R₁₃Substitution;

R₁₁、R₁₂each independently selected from hydrogen and-C_1～6An alkyl group, a 3-to 6-membered cycloalkyl group, a 3-to 6-membered heterocycloalkyl group;

16. The compound of claim 15, wherein: r₁Is selected from-C_1～6Alkyl, trifluoromethyl, -O (C)_1～6Alkyl), -NH (C)_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl), -N (C)_1～6Alkyl) (cyclopropyl),

17. The compound of claim 14, wherein:

each R_A1Is independently selected from-C_1～6An alkyl group.

18. The compound of claim 17, wherein: a ring is selected from

19. The compound of claim 14, wherein: r₃Selected from hydrogen, -C_1～6An alkyl group; r₃' selected from-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, - (C)_0～2Alkylene) O (C)_1～6Alkyl groups).

20. The compound of claim 14, wherein: r₃、R₃The' linked form a 3-to 6-membered cycloalkyl group, a 3-to 6-membered heterocycloalkyl group.

21. The compound of claim 20, wherein: r₃、R₃' are linked to form a 3-to 6-membered oxygen-containing heterocycloalkyl group.

22. The compound of claim 14, wherein:

or, R₅、R₆Are linked to form a 3-to 6-membered heterocycloalkyl group; wherein the heterocycloalkyl radical may be further substituted by one, two or three R₅₁Substitution;

R₅₂、R₅₃are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or, R₅₂、R₅₃Are linked to form 3-to 6-membered cycloalkyl and 3-to 6-membered heterocycloalkyl.

23. The compound of claim 22, wherein:

R₅、R₆are respectively and independently selected from hydrogen,

R₅₁₁、R₅₁₂Are respectively and independently selected from hydrogen, halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₅₂、-C_0～2alkylene-OC (O) R₅₂、-C_0～2alkylene-C (O) R₅₂、-C_0～2alkylene-C (O) OR₅₂、-C_0～2alkylene-NR₅₂R₅₃、-C_0～2alkylene-NR₅₂C(O)R₅₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle);

R₅₂、R₅₃are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl))、-C_0～2Alkylene- (3-to 6-membered heterocycloalkyl).

24. The compound of claim 22, wherein:

R₅、R₆are respectively and independently selected from hydrogen,

R₅₂、R₅₃are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl).

25. The compound of claim 22, wherein: r₅、R₆Each independently selected from hydrogen and-C_1～6Alkyl, -C (O) NH (C)_1～6Alkyl), -C (O) O (C)_1～6Alkyl), -S (O)₂(C_1～6Alkyl groups).

26. The compound of claims 23-25, wherein: r₅、R₆At least one is selected from hydrogen.

27. The compound of claim 22The method is characterized in that: r₅、R₆Linked to form cyclobutylamine and morpholine; wherein the heterocycloalkyl radical may be further substituted by one, two or three R₅₁Substitution; each R₅₁Each independently selected from halogen, carbonyl and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl groups).

28. The compound of claim 2, wherein: the compound of formula I is represented by formula IV:

wherein the content of the first and second substances,

R₁is selected from-C_1～6Alkyl, trifluoromethyl, -O (C)_1～6Alkyl), -NH (C)_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl), -N (C)_1～6Alkyl) (cyclopropyl),

R₂Selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl);

R₁₃independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups);

a ring is selected from

Each R_A1Independently selected from hydrogen, -C_1～6An alkyl group;

R₃selected from hydrogen, -C_1～6An alkyl group;

R₃' selected from-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, - (C)_0～2Alkylene) O (C)_1～6Alkyl groups);

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～4alkylene-C (O) R₃₂、-C_0～4alkylene-C (O) OR₃₂；

R₃₂Are independently selected from hydrogen and-C_1～10An alkyl group;

R_5xis selected from-C_1～6An alkyl group, a 3-to 6-membered cycloalkyl group, a 3-to 6-membered heterocycloalkyl group; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R_5zSubstitution;

each R_5zIndependently selected from hydrogen, halogen, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

R_5yis selected from-OR_5t、-NR_5tR_5t’；

R_5t、R_5t' independently selected from hydrogen and-C_1～6An alkyl group.

29. The compound of claim 28, wherein:

R₁is selected from

A ring is selected from

R₃Selected from hydrogen, methyl;

R₃' is selected from methyl, 5-membered nitrogen-containing heterocycloalkyl, - (methylene) O (methyl);

alternatively, the first and second electrodes may be,R₃、R₃' are linked to form a 5-membered oxygen-containing heterocycloalkyl, a 5-membered nitrogen-containing heterocycloalkyl; wherein the heterocycloalkyl radical may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Is independently selected from-C_1～6Alkyl, -C (O) R₃₂；

R₃₂Are respectively independently selected from-C_1～6An alkyl group;

R_5xis selected from-C_1～6Alkyl, cyclopropane, cyclobutane; wherein cyclopropane and cyclobutane can be further substituted by one, two or three independent R_5zSubstitution;

each R_5zIndependently selected from hydrogen, halogen, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

R_5yselected from-OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups).

30. The compound of claim 1, wherein: the compound shown in the formula I is specifically:

31. use of a compound of any one of claims 1-30, or a stereoisomer thereof, or a nitroxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an IL-17A mediated disease.

32. The use according to claim 31, characterized in that: the IL-17A mediated disease is one or more of diseases related to inflammation, autoimmune diseases, infectious diseases, cancer and precancerous syndrome.

33. A pharmaceutical composition characterized by: the compound of any one of claims 1 to 30, or a stereoisomer thereof, or a nitrogen oxide thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

Technical Field

The invention relates to an immunomodulator and application thereof in preparing a medicament.

Background

IL-17 (interleukin-17) is a proinflammatory cytokine, playing a role in the induction of other inflammatory cytokines, chemokines and adhesion factors. The IL-17 family consists of cytokines involved in acute and chronic inflammatory responses, including IL-17A (CTLA-8), IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F. IL-17A is expressed by TH17 cells, and is involved in the pathogenesis of inflammatory and autoimmune diseases. Human IL-17A is a glycoprotein having a molecular weight of about 17000 daltons. IL-17A signals intracellular through the IL-17 receptor complex (IL-17RA and IL-17RC) (Wright, et al. journal of immunology,2008,181: 2799-2805). The primary functions of IL-17A are to coordinate local tissue inflammation by upregulation of pro-and neutrophil migratory cytokines and chemokines (including IL-6, G-CSF, TNF- α, IL-1, CXCL1, CCL2, CXCL2), and matrix metalloproteases to allow activated T cells to penetrate the extracellular matrix. There are studies that have shown that IL-17A plays a major role in severe asthma and Chronic Obstructive Pulmonary Disease (COPD), and those patients generally do not respond or respond poorly to currently available drugs (Al-Ramli et Al J Allergy Clin Immunol,2009,123: 1185-1187). Upregulation of IL-17A levels has been implicated in a number of diseases including Rheumatoid Arthritis (RA), bone erosion, intraperitoneal abscesses, inflammatory bowel disease, allograft rejection, psoriasis, atherosclerosis, asthma and multiple sclerosis (Gaffen, SL et al.

Targeting the binding of IL-17A to IL-17RA is an effective strategy for the treatment of IL-17A-mediated autoimmune inflammatory diseases. Treatment of animals with IL-17A neutralizing antibodies reduces disease incidence and severity in autoimmune encephalomyelitis (Komiyama Y et al J. Immunol.,2006,177: 566-573). Clinical trials with IL-17A antibodies have shown good results in 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 1 month 2015.

Despite the existence of a variety of IL-17A antibodies, few small molecule specific inhibitors of IL-17 have been studied for oral bioavailability. In view of the cost consideration of antibody production and the limitation of administration route, the development of IL-17A small-molecule inhibitor drugs has good development prospect.

Disclosure of Invention

The invention provides a compound shown as a formula I, or a stereoisomer thereof, or a nitrogen oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

R₁selected from hydrogen, -C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle), -NR₁₁R₁₂、-OR₁₁(ii) a Wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may beFurther substituted by one, two or three independent R₁₃Substitution;

R₂selected from hydrogen, -C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl);

each R_A1Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR_A2、-C_0～4alkylene-OC (O) R_A2、-C_0～4alkylene-C (O) R_A2、-C_0～4alkylene-C (O) OR_A2、-C_0～4alkylene-C (O) NR_A2R_A3、-C_0～4alkylene-NR_A2R_A3、-C_0～4alkylene-NR_A2C(O)R_A3、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle);

R_A2、R_A3each independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl);

Y₁、Y₂、Y₃each independently selected from N or CR_Y1；

R₃₄is selected from

R₃₅、R₃₆Are independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl);

R₄₂、R₄₃are independently selected from hydrogen and-C_1～10Alkyl, -C_1～4alkylene-OC (O) R₄₆、-C_1～4alkylene-C (O) R₄₆、 -C_1～4alkylene-C (O) OR₄₆、-C_1～4alkylene-C (O) NR₄₆R₄₇、-C_1～4alkylene-NR₄₆R₄₇、-C_1～4alkylene-NR₄₆C(O)R₄₇、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); or, R₄₂、R₄₃Connecting to form 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₅Substitution;

R₅、R₆each independently selected from hydrogen and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C (O) NR₅₂R₅₃、-C(O)OR₅₂、 -S(O)R₅₂、-S(O)₂R₅₂、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 12-membered bridged ring), -C_0～4Alkylene- (5-12 membered bridged heterocycle), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, bridged ring, bridged heterocycle, aromatic ring, aromatic heterocycle may be further substituted with one, two or three R₅₁Substitution;

or, R₅、R₆Are linked to form a 3-to 10-membered heterocycloalkyl group; wherein the heterocycloalkyl radical may be further substituted by one, two or three R₅₁Substitution;

each R₅₁Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR₅₂、-C_0～4alkylene-OC (O) R₅₂、-C_0～4alkylene-C (O) R₅₂、-C_0～4alkylene-C (O) OR₅₂、-C_0～4alkylene-NR₅₂R₅₃、-C_0～4alkylene-NR₅₂C(O)R₅₃、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle) or-C_0～4alkylene-OR₅₅、 -C_0～4alkylene-NR₅₅R₅₆(ii) a Wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₅₄Substitution;

R₅₅、R₅₆are independently selected from hydrogen and-C_1～10Alkyl, aryl, heteroaryl, and heteroaryl,

R₅₇、R₅₈Are independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl).

Further, the air conditioner is provided with a fan,

R₂selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl);

the ring A is selected from 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, 6-9 membered spirocyclic; wherein the cycloalkyl radicalHeterocycloalkyl, spirocyclic, heterospirocyclic may be further substituted by one, two or three independent R_A1Substitution;

R_A2、R_A3each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

Y₁、Y₂、Y₃each independently selected from N or CR_Y1；

R_3’is selected from-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), - (C)_0～2Alkylene) O(C_1～6Alkyl), - (C)_0～2Alkylene) O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), - (C)_0～2Alkylene) O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-C (O) R₃₂、-C_0～2alkylene-C (O) OR₃₂；

R₃₂、R₃₃Are independently selected from hydrogen and-C_1～6An alkyl group;

each R₄₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₄₂、-C_0～2alkylene-OC (O) R₄₂、-C_0～2alkylene-C (O) R₄₂、-C_0～2alkylene-C (O) OR₄₂、-C_0～2alkylene-C (O) NR₄₂R₄₃、-C_0～2alkylene-NR₄₂R₄₃、-C_0～2alkylene-NR₄₂C(O)R₄₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein alkyl, alkylene, cycloalkyl, heterocycleThe alkyl, aryl or heteroaryl ring may be further substituted by one, two or three R₄₄Substitution;

R₄₂、R₄₃are independently selected from hydrogen and-C_1～6Alkyl, -C_1～2alkylene-OC (O) R₄₆、-C_1～2alkylene-C (O) R₄₆、-C_1～2alkylene-C (O) OR₄₆、-C_1～2alkylene-C (O) NR₄₆R₄₇、-C_1～2alkylene-NR₄₆R₄₇、-C_1～2alkylene-NR₄₆C(O)R₄₇、 -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); or, R₄₂、R₄₃Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₅Substitution;

R₅、R₆each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C (O) NR₅₂R₅₃、-C(O)OR₅₂、 -S(O)R₅₂、-S(O)₂R₅₂、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 10-membered bridged ring), -C_0～2Alkylene- (5-to 10-membered bridged heterocycle), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, bridged ring, bridged heterocycle, aromatic ring, aromatic heterocycle may be further substituted with one, two or three R₅₁Substitution;

or, R₅、R₆Are linked to form a 3-to 6-membered heterocycloalkyl group; wherein the heterocycloalkyl radical may be further substituted by one, two or three R₅₁Substitution;

each R₅₁Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₅₂、-C_0～2alkylene-OC (O) R₅₂、-C_0～2alkylene-C (O) R₅₂、-C_0～2alkylene-C (O) OR₅₂、-C_0～2alkylene-NR₅₂R₅₃、-C_0～2alkylene-NR₅₂C(O)R₅₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle) or-C_0～2alkylene-OR₅₅、 -C_0～2alkylene-NR₅₅R₅₆(ii) a Wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₅₄Substitution;

R₅₅、R₅₆are independently selected from hydrogen and-C_1～6Alkyl, aryl, heteroaryl, and heteroaryl,

R₅₇、R₅₈Are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl).

In some embodiments of the present invention, the first and second substrates are,

R₁is selected from-OCH₃、-CF₃、Methyl, isopropyl, ethyl, isopropyl,cyclopropyl, cyclobutyl,

A ring is selected from

R₃Selected from hydrogen or methyl;

R_3’selected from methyl, - (methylene) O (methyl),

Or R₃、R_3’Are connected to form

Further, the compound of formula I is represented by formula II:

wherein the content of the first and second substances,

R₂selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl);

R_A2、R_A3each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

R_Y1selected from hydrogen, halogen;

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

each R₄₁Independently selected from halogen, cyano, carbonylRadical, nitro radical, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₄₂、-C_0～2alkylene-OC (O) R₄₂、-C_0～2alkylene-C (O) R₄₂、-C_0～2alkylene-C (O) OR₄₂、-C_0～2alkylene-C (O) NR₄₂R₄₃、-C_0～2alkylene-NR₄₂R₄₃、-C_0～2alkylene-NR₄₂C(O)R₄₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₄Substitution;

R₄₂、R₄₃are independently selected from hydrogen and-C_1～6Alkyl, -C_1～2alkylene-OC (O) R₄₆、-C_1～2alkylene-C (O) R₄₆、-C_1～2alkylene-C (O) OR₄₆、-C_1～2alkylene-C (O) NR₄₆R₄₇、-C_1～2alkylene-NR₄₆R₄₇、-C_1～2alkylene-NR₄₆C(O)R₄₇、 -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); or, R₄₂、R₄₃Connecting to form 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₅Substitution;

R₄₆、R₄₇are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or, R₄₆、R₄₇Are linked to form 3-to 6-membered cycloalkyl and 3-to 6-membered heterocycloalkyl.

Further, in the present invention,

R₁is selected from-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 6-membered aromatic ring, 5-to 6-membered aromatic heterocycle, -NR₁₁R₁₂、 -OR₁₁(ii) a Wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R₁₃Substitution;

R₁₁、R₁₂each independently selected from hydrogen and-C_1～6An alkyl group, a 3-to 6-membered cycloalkyl group, a 3-to 6-membered heterocycloalkyl group;

Still more specifically, R₁Selected from halogen-substituted alkyl, -O (C)_1～6Alkyl radicals),

Further, in the present invention,

each R_A1Is independently selected from-C_1～6An alkyl group.

Still more particularly, the A ring is selected from

Further, R₃Selected from hydrogen, -C_1～6An alkyl group; r₃' selected from- (C)_0～2Alkylene) O (C)_1～6Alkyl groups).

Further, R₃、R₃' are linked to form a 3-to 6-membered heterocycloalkyl group.

Still more specifically, R₃、R₃The bond of the two units forms a 3-6 membered oxygen-containing heterocycloalkyl group and a 3-6 membered nitrogen-containing heterocycloalkyl group.

Further, in the present invention,

ring B is selected from

R₄₁₁、R₄₁₂Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₄₂、-C_0～2alkylene-OC (O) R₄₂、-C_0～2alkylene-C (O) R₄₂、-C_0～2alkylene-C (O) OR₄₂、-C_0～2alkylene-C (O) NR₄₂R₄₃、-C_0～2alkylene-NR₄₂R₄₃、-C_0～2alkylene-NR₄₂C(O)R₄₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₄₄Substitution;

R₄₂、R₄₃are independently selected from hydrogen and-C_1～6An alkyl group;

each R₄₄Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6An alkyl group.

Further, in the present invention,

ring B is selected from

R₄₆、R₄₇are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

R₄₁₂selected from hydrogen, -C_1～6An alkyl group.

Still more specifically, R₄₂、R₄₃At least one is selected from hydrogen.

Further, the compound of formula I is represented by formula III:

R₂selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl);

R_A2、R_A3each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

R_3’is selected from-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), - (C)_0～2Alkylene) O (C)_1～6Alkyl), - (C)_0～2Alkylene) O (C)_0～2Alkylene) (3-to 6-membered cycloalkyl), - (C)_0～2Alkylene) O (C)_0～2Alkylene) (3-to 6-membered heterocycloalkyl); wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～4alkylene-C (O) R₃₂、-C_0～4alkylene-C (O) OR₃₂；

R₃₂、R₃₃Are independently selected from hydrogen and-C_1～10An alkyl group;

R₅、R₆each independently selected from hydrogen and-C_1～6Alkyl, -C (O) NR₅₂R₅₃、-C(O)OR₅₂、-S(O)R₅₂、-S(O)₂R₅₂、 -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₅₁Substitution;

or, R₅、R₆Are linked to form a 3-to 6-membered heterocycloalkyl group; wherein the heterocycloalkyl radical may be further substituted by one, two or three R₅₁Substitution;

each R₅₁Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₅₂、-C_0～2alkylene-OC (O) R₅₂、-C_0～2alkylene-C (O) R₅₂、-C_0～2alkylene-C (O) OR₅₂、-C_0～2alkylene-NR₅₂R₅₃、-C_0～2alkylene-NR₅₂C(O)R₅₃、-C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₅₄Substitution;

R₅₂、R₅₃are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or, R₅₂、R₅₃Are linked to form 3-to 6-membered cycloalkyl and 3-to 6-membered heterocycloalkyl.

In some embodiments, R₅、R₆Are respectively and independently selected from hydrogen, methyl, ethyl, -NH (ethyl), -O (tertiary butyl),

Or R₅、R₆Are connected to form

Further, in the present invention,

R₁is selected from-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 6-membered aromatic ring, 5-to 6-membered aromatic heterocycle, -NR₁₁R₁₂、 -OR₁₁(ii) a Wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three independent R₁₃Substitution;

R₁₁、R₁₂each independently selected from hydrogen and-C_1～6An alkyl group, a 3-to 6-membered cycloalkyl group, a 3-to 6-membered heterocycloalkyl group;

Still more specifically, R₁Is selected from-C_1～6Alkyl, trifluoromethyl, -O (C)_1～6Alkyl), -NH (C)_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl), -N (C)_1～6Alkyl radical) (cyclopropyl) to give,

Further, in the present invention,

each R_A1Is independently selected from-C_1～6An alkyl group.

Still more particularly, the A ring is selected from

Further, R₃Selected from hydrogen, -C_1～6An alkyl group; r₃' selected from-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, - (C)_0～2Alkylene) O (C)_1～6Alkyl groups).

Further, R₃、R₃The' linked form a 3-to 6-membered cycloalkyl group, a 3-to 6-membered heterocycloalkyl group.

Still more specifically, R₃、R₃' are linked to form a 3-to 6-membered oxygen-containing heterocycloalkyl group.

Further, in the present invention,

R₅、R₆each independently selected from hydrogen and-C_1～6Alkyl, -C (O) NR₅₂R₅₃、-C(O)OR₅₂、-S(O)R₅₂、-S(O)₂R₅₂、 -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl), -C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two or three R₅₁Substitution;

or, R₅、R₆Are linked to form a 3-to 6-membered heterocycloalkyl group; wherein the heterocycloalkyl radical may be further substituted by one, two or three R₅₁Substitution;

R₅₂、R₅₃are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl); or, R₅₂、R₅₃Are linked to form 3-to 6-membered cycloalkyl and 3-to 6-membered heterocycloalkyl.

Still more particularly, it is contemplated that the first,

R₅、R₆are respectively and independently selected from hydrogen,

R₅₂、R₅₃are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl).

Still more particularly, it is contemplated that the first,

R₅、R₆are respectively and independently selected from hydrogen,

R₅₂、R₅₃are independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl).

Still more specifically, R₅、R₆Each independently selected from hydrogen and-C_1～6Alkyl, -C (O) NH (C)_1～6Alkyl), -C (O) O (C)_1～6Alkyl), -S (O)₂(C_1～6Alkyl groups).

Still more specifically, R₅、R₆At least one is selected from hydrogen.

Still more specifically: r₅、R₆Linked to form cyclobutylamine and morpholine; wherein the heterocycloalkyl radical may be further substituted by one, two or three R₅₁Substitution; each R₅₁Each independently selected from halogen, carbonyl and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -OH, -O (C)_1～6Alkyl groups).

Further, the compound of formula I is represented by formula IV:

wherein the content of the first and second substances,

R₁is selected from-C_1～6Alkyl, trifluoromethyl, -O (C)_1～6Alkyl), -NH (C)_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl), -N (C)_1～6Alkyl) (cyclopropyl),

R₂Selected from hydrogen, -C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl);

a ring is selected from

Each R_A1Independently selected from hydrogen, -C_1～6An alkyl group;

R₃selected from hydrogen, -C_1～6An alkyl group;

R₃' selected from-C_1～6Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, - (C)_0～2Alkylene) O (C)_1～6Alkyl groups);

each R₃₁Independently selected from halogen, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～4alkylene-C (O) R₃₂、-C_0～4alkylene-C (O) OR₃₂；

R₃₂Are independently selected from hydrogen and-C_1～10An alkyl group;

each R_5zIndependently selected from hydrogen, halogen, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

R_5yis selected from-OR_5t、-NR_5tR_5t’；

R_5t、R_5t' independently selected from hydrogen and-C_1～6An alkyl group.

Further, in the present invention,

R₁is selected from

A ring is selected from

R₃Selected from hydrogen, methyl;

R₃' is selected from methyl, 5-membered nitrogen-containing heterocycloalkyl, - (methylene) O (methyl);

or, R₃、R₃' are linked to form a 5-membered oxygen-containing heterocycloalkyl, a 5-membered nitrogen-containing heterocycloalkyl; wherein the heterocycloalkyl radical may be further substituted by one, two or three independent R₃₁Substitution;

each R₃₁Is independently selected from-C_1～6Alkyl, -C (O) R₃₂；

R₃₂Are respectively independently selected from-C_1～6An alkyl group;

R_5xis selected from-C_1～6Alkyl, cyclopropane, cyclobutane; wherein cyclopropane and cyclobutane can be further substituted by one, two or three independent R_5zSubstitution;

each R_5zIndependently selected from hydrogen, halogen, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group;

R_5yselected from-OH, -O (C)_1～6Alkyl), -NH₂、-NH(C_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl groups).

In some embodiments of the invention, the compound of formula I is specifically:

the invention also provides the use of the aforementioned compound, or a stereoisomer thereof, or a nitroxide thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an IL-17A mediated disease.

Further, the IL-17A mediated disease is one or more of diseases related to inflammation, autoimmune diseases, infectious diseases, cancer and precancerous syndrome.

The invention also provides a pharmaceutical composition, which is a preparation prepared from the compound, or a stereoisomer thereof, or a nitric oxide thereof, or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.

The invention also provides the application of the compound or the stereoisomer thereof, or the pharmaceutically acceptable salt thereof, or the solvate thereof, or the prodrug thereof, or the metabolite thereof in preparing the medicines for treating the IL-17A mediated diseases.

IL-17A mediated diseases as defined in the present invention are diseases in which IL-17A plays an important role in the pathogenesis of the disease. The primary function of IL-17A is to coordinate local tissue inflammation and thus play a role in a variety of diseases. IL-17A mediated diseases include one or more of inflammation, autoimmune diseases, infectious diseases, cancer, and diseases related to precancerous syndrome. .

"cancer" or "malignancy" refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the body's ability of affected cells to spread to other sites either locally or through the bloodstream and lymphatic system (i.e., metastasis), and any of a number of characteristic structural and/or molecular features. "cancer cells" refers to cells that undergo multiple stages of early, intermediate or late stage tumor progression. The cancer includes sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer and prostate cancer. In some embodiments, the compound of formula I is used to treat a cancer selected from the group consisting of colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is a metastatic cancer.

Autoimmune diseases are caused by the body's immune response to substances and tissues normally present in the body. Examples of autoimmune diseases include myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type 1 diabetes, graves 'disease, celiac disease, crohn's disease, autoimmune neutropenia, juvenile arthritis, rheumatoid arthritis, fibromyalgia, gillyre 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 pathological inflammation of the tissue. Examples of inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, house dust mite-induced airway inflammation, and interstitial cystitis. There is a significant overlap between inflammatory and autoimmune diseases. Some embodiments of the invention relate to the treatment of the inflammatory disease asthma. The immune system is usually involved in inflammatory diseases, manifested in allergic reactions and in some myopathies, many of which cause abnormal inflammation. IL-17A mediated diseases also include autoimmune inflammatory diseases.

The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.

Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.

"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

"can be further substituted" means that "substitution" can, but need not, occur, and that the description includes instances where it does or does not occur.

The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix C_a～bAlkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C_1～4The alkyl group means an alkyl group having 1 to 4 carbon atoms.

The "alkyl group" as used herein refers to a saturated hydrocarbon chain having the indicated number of member atoms. E.g. C₁～₆Alkyl refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group may be linear 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) and hexyl. Alkyl radicalThe groups may also be part of other groups, such as C₁～C₆An alkoxy group.

"alkylene" as used herein refers to a divalent saturated aliphatic hydrocarbon group having from 1 to 10 carbon atoms and in some embodiments from 1 to 6 carbon atoms. "(C)_a～C_b) Alkylene "refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbyl groups. For example, "(C)₁～C₆) Alkylene "is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Thus, the term "propylene" can be exemplified by the following structure:likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures: furthermore, the term "(C)₁～C₆) Alkylene "is intended to include such branched alkyl groups such as cyclopropylmethylene, which may be exemplified by the following structures:

"cycloalkyl", "cycloalkane" as used herein refers to saturated or partially saturated cyclic groups having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings, including fused, bridged, spiro, and adamantane systems. For polycyclic systems having aromatic and non-aromatic rings that do not contain ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl) applies when the point of attachment is at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentylCyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below:dicyclohexyl anda dicyclohexyl group. Adamantyl includes, but is not limited to, the following structures:

"alkenyl" as used herein refers to a straight or branched chain hydrocarbyl group having from 2 to 10 carbon atoms, and in some embodiments, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms, and having at least 1 site of vinyl unsaturation (> C ═ C <). For example, (Ca-Cb) alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1, 3-butadienyl, and the like.

The "alkenylene group" as used herein refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond and two unsaturated chemical valencies. For example, (C)₃-C₆) Alkenylene radicals include>C＝CH-CH₂-、-CH-CH＝CH-CH₂-and the like.

The "alkynyl group" as used herein refers to a straight-chain monovalent hydrocarbon group or a branched-chain monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C)₂-C₆) Alkynyl is intended to include ethynyl, propynyl and the like.

The "alkynylene group" as used herein refers to a divalent hydrocarbon chain having 2 to 10 carbon atoms and at least one triple bond.

In the invention, "halogen" is fluorine, chlorine, bromine or iodine.

"haloalkyl", "halogen-substituted alkyl" as used herein refers to hydrogen in an alkyl groupThe atoms may be substituted with one or more halogen atoms. E.g. C_1～4The haloalkyl group means an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom is substituted with one or more halogen atoms.

As used herein, "-OR", "-NRR", etc., means that the R group is attached to the oxygen atom OR the nitrogen atom by a single bond.

The "-C (O) R", "-S (O)" mentioned in the present invention₂The oxygen atom in R' or the like is bonded to a carbon atom or a sulfur atom with a double bond.

The "carbonyl group" in the present invention means that an oxygen atom is substituted by a double bond, i.e., "═ O".

As used herein, "heterocycle", "heterocycloalkyl", "heterocycloalkane" refers to a saturated or non-aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. Generally denotes a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of a plurality of ring atoms, preferably a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 9 ring atoms, comprising 1,2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings sharing two ring atoms, i.e. the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, piperidinyl, piperazinyl, piperidinyl, and piperazinyl,Thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azepinyl, diazepanyl, homopiperazinyl or oxazepinyl. An example of a bicyclic saturated heterocycloalkyl is 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]Nonyl radical,Is partially provided withExamples of saturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.

The "aromatic ring", "aryl" as used herein refers to an aromatic hydrocarbon group having a plurality of carbon atoms. The aryl group is typically a monocyclic, bicyclic or tricyclic aryl group having 5 to 20 carbon atoms. Further, the term "aryl" as used herein refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.

The term "aromatic heterocycle", "aromatic heterocyclic group" as used herein means an aromatic unsaturated ring containing at least one hetero atom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. Aromatic monocyclic or bicyclic hydrocarbons which typically contain multiple ring atoms, wherein one or more ring atoms are selected from the group consisting of the heteroatoms of O, N, S. Preferably there are one to three heteroatoms. Heterocyclic aryl represents, for example: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.

"stereoisomers" includes enantiomers and diastereomers;

the term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.

The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Drawings

FIG. 1: the pharmacodynamic profile achieved by example 20 in the EAE model of experimental example 3;

FIG. 2: example 20 protection of histopathological lesions of the tissue cerebrospinal;

FIG. 3: the results of the drug effect achieved by the administration of example 20 and the antibody administered via subcutaneous injection or gavage in the IMQ model;

fig. 4: evaluating the skin thickness change of mice of different administration groups in the IMQ model;

FIG. 5: il6 expression levels in skin tissues of mice of different administration groups in the IMQ model;

FIG. 6: example 20 in the IMQ model was able to inhibit IMQ-induced pathological damage to the skin in mice;

FIG. 7: example 20, administered via the gavage route in the IMQ model, achieved similar efficacy results with antibody administration;

fig. 8: evaluating the skin thickness change of mice of different administration groups in the IMQ model;

FIG. 9: il6 expression levels in skin tissues of mice of different administration groups in the IMQ model;

Detailed Description

The structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shifts (. delta.) are given in units of 10-6 (ppm). NMR was measured using a (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetic instrument using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl)₃) Deuterated methanol (CD3OD) with internal standard Tetramethylsilane (TMS).

LC-MS was measured using Shimadzu LC-MS 2020 (ESI). HPLC was performed using Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (Medium pressure preparative chromatography) Gilson GX-281 reverse phase preparative chromatography was used. The thin layer chromatography silica gel plate is a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier. Supercritical Fluid Chromatography (SFC)

Known starting materials for the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Enduragi chemistry, Chengdulong chemistry, Shaoshi chemistry technology, and Bailingwei technology.

In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention. In the examples, the solution means an aqueous solution unless otherwise specified. In the examples, the reaction temperature is room temperature, unless otherwise specified. In the examples, M is mole per liter, unless otherwise specified. The room temperature is the most suitable reaction temperature and is 20-30 ℃.

Intermediate Z1

Step 1, preparation of intermediate Z-1

Under the protection of nitrogen, 1M tetrahydrofuran solution (170mL) of lithium aluminum hydride in tetrahydrofuran is slowly dropped into trans-4-methylcyclohexanecarboxylic acid (20.0g,140.65mmol) at the temperature of-20 ℃, after dropping, the temperature is slowly raised to room temperature and stirred overnight, the reaction liquid is quenched by water (7mL), 7mL of 15% NaOH aqueous solution is added, 20mL of water is added, suction filtration is carried out after stirring for a moment, the filtrate is decompressed and concentrated to obtain crude product (18.0g,140.39mmol, 99.82% yield) of intermediate Z1-1, LCMS M/Z is 129[ M + 1mmol [ (/ M +/Z) ]]⁺.

Step 2, preparation of intermediate Z-2

To a solution of crude intermediate Z1-1 (18.0g,140.39mmol) in dichloromethane (400mL) under ice-bath and nitrogen protection was added dess-Martin reagent (65.50g,154.43mmol), the reaction was stirred at room temperature for 2 hours, the reaction was concentrated under reduced pressure and purified by silica gel column chromatography to give intermediate Z1-2 as a colorless oily liquid, (15.5g,122.82mmol, 87.49% yield), LCMS M/Z:127[ M +1 ])]⁺.

Step 3, preparation of intermediate Z-3

Ethyl titanate (86.45g,379.17mmol) was added portionwise to a solution of intermediate Z1-2(14.5g,114.90mmol) and S-p-toluenesulfinamide (17.83g,114.90mmol) in dry dichloromethane (500mL) at room temperature, after addition, raised to 50 ℃ and stirred for 2 hours, quenched with 500mL ice water, filtered, the filtrate extracted with dichloromethane (500mL 2), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give intermediate Z1-3(20.6g,84.65mmol, 73.68% yield) as a colorless gummy semi-solid, LCMS M/Z:264[ M +1] M/Z]⁺.

Step 4, preparation of intermediate Z-4

Isopropanol (5.18g,86.30mmol) was added to a 1M solution of diethylaluminum hydride in toluene (130mL) and dried tetrahydrofuran (100mL) at-78 deg.C under nitrogen and stirred for 1 hour at-78 deg.C. The solution obtained above was slowly added dropwise to a dry tetrahydrofuran solution of intermediate Z1-3(21.0g,86.30mmol) at-78 deg.C for 30min, naturally warmed to room temperature and stirred overnight, slowly cooled in ice bathAdding 500mL of saturated ammonium chloride aqueous solution to quench the reaction, stirring for 30min, performing suction filtration through diatomite, adding 500mL of ethyl acetate, separating an organic layer, extracting an aqueous phase by 500mL of 3 ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, recrystallizing a crude product twice by hot petroleum ether and ethyl acetate solutions to obtain an S-shaped intermediate Z1-4(14g,48.3mmol, 56% yield), a white solid, and LCMS M/Z:291[ M +1 ]: M]⁺.

Step 5, preparation of intermediate Z-5

Adding 4M HCl in ethyl acetate (5.16mmol,30mL) into intermediate Z1-4(1.5g,5.16mmol) in methanol under ice bath, slowly raising the temperature to room temperature under the protection of nitrogen, stirring for 2 hours, concentrating under reduced pressure, adding 50mL petroleum ether, pulping, and filtering to obtain intermediate Z1-5(850mg,4.50mmol, 87.22% yield), white solid, LCMS M/Z153 [ M +1] 153]⁺.

Step 6, preparation of intermediate Z-6

Adding concentrated hydrochloric acid (376.22mg,4.50mmol) into 4mL of acetic acid solution of intermediate Z1-5 at room temperature, then raising the temperature to 110 ℃ and stirring for reaction for 3 hours, concentrating the reaction solution under reduced pressure, adding 50mL of petroleum ether, pulping, and filtering to obtain intermediate 1-6(840mg, 4.04mmol, 89.78% yield), white solid, LCMS M/Z172 [ M +1 ]: 172]⁺.

Step 7, preparation of Z1

To a mixture of intermediate Z1-6(840mg,4.91mmol) in 10mL of 1, 4-dioxane and 10mL of water was added Na at room temperature₂CO₃(1.56g,14.72mmol) and di-tert-butyl dicarbonate (1.18g,5.40mmol), reacting overnight at room temperature, concentrating under reduced pressure, adjusting pH to 3 with 6N HCl, extracting the aqueous phase with 50mL of 2 ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating to obtain intermediate Z1(1.0g,3.69mmol, 75.12% yield), white solid, LCMS M/Z272 [ M +1 ]/[]⁺.

Intermediate Z2

Step 1, preparation of intermediate Z2-1

Adding Cs2CO3(290.82g,894.85mmol) into a dried DMF (700mL) solution of ethyl p-nitrophenylacetate (156g,745.71mmol) under the protection of nitrogen at 0 ℃, raising the temperature to room temperature, stirring for 1 hour, then reducing the temperature to 0 ℃, slowly dropwise adding methyl iodide (116.43g,820.28mmol), reacting overnight after dropwise adding, performing suction filtration, diluting the filtrate with 2L ethyl acetate, washing with saturated saline (3X 1.5L), drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain an intermediate Z2-1(165g,739.16 mmol, 99.12% yield), MS M/Z:224[ M + 1[ + ] M + ]]⁺The crude product was used directly in the next step.

Step 2, preparation of intermediate Z2-2

Slowly adding a DMF (300mL) solution of an intermediate Z2-1(11.48g,478.44mmol) into a dry 0.3L mixed solution of DMF and NaH (11.48g,478.44mmol) under the protection of nitrogen at-10 ℃, cooling to-50 ℃ after 30min, adding chloromethyl methyl ether (48.15g,598.05mmol), stirring the reaction solution at-50 ℃ to-10 ℃ for 3h, after the reaction is finished, quenching the cold saturated ammonium chloride, extracting ethyl acetate (2 x 400mL), combining organic phases, washing the organic phases with saturated saline water (400mL x 2), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and separating the crude product by silica gel column chromatography (petroleum ether/ethyl acetate 100: 1-50: 1) to obtain an intermediate Z2-2(45g,168.36mmol, 42.23%) with the yield of MS M/Z: 268[ M + 1: 268)]⁺.

Step 3, preparation of intermediate Z2-3

Dissolving intermediate Z2-2(45g,168.36mmol) in EtOH (100mL), replacing with nitrogen, adding 10% Pd/C (8 g), stirring under normal pressure hydrogen atmosphere for reaction overnight, after the raw material disappears, filtering with diatomaceous earth, washing with ethanol, and concentrating the filtrate under reduced pressure to dryness to obtain intermediate Z2-3(34.6g,145.81mmol, 86.60% yield), MS M/Z:260[ M +1+22 ]]⁺The product was used directly in the next reaction without purification.

Step 4, preparation of intermediate Z2-4

Dissolving intermediate Z2-3(15.9g,67.01mmol) in acetic anhydride (136mL), cooling to 0 deg.C, stirring for 15min, and slowly adding HNO dropwise₃(9.31g,100.51mmol, 68% mass fraction), after dropping, the reaction was stirred for another 30min, the starting material disappeared, and the reaction mixture was poured outAdding into ice water, extracting with ethyl acetate (2X 100mL), combining organic phases, washing with saturated sodium carbonate, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain crude intermediate Z2-4 (17g,52.42mmol, 78.23% yield), MS M/Z: 325[ M +1 ]: 325]⁺。

Step 5, preparation of intermediate Z2-5

Dissolving intermediate Z2-4(21.73g,67.01mmol) in 100mL ethanol, adding NaOH (1.61g,40.20mmol), heating to 50 deg.C, stirring for 0.5 hr, TLC showing disappearance of raw material, concentrating the reaction solution under reduced pressure to dryness, adding H2O (150mL), adjusting pH to 7 with 6N HCl, passing the aqueous phase through CH₂Cl₂(2X 100mL), combined organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give crude intermediate Z2-5 (8g,28.34mmol, 42.29% yield), MS M/Z: 283[ M +1 ])]⁺。

Step 6, preparation of intermediate Z2a, Z2b

Dissolving intermediate Z2-5(21g,74.2mmol) in methanol, adding 10% Pd/C (5g) under nitrogen atmosphere, hydrogenating overnight under normal pressure, after the raw material disappears, filtering with diatomite, concentrating the filtrate under reduced pressure to dryness, purifying with MPLC C18 reversed phase column to obtain racemate, resolving and separating with SFC chiral column to obtain single configuration Z2a (7.5g, 40% yield, chiral column retention time 6.805 min, CHIRALPAK AY-H (AYH0CE-VC001)0.46cm I.D. 25cm L, mobile phase n-hexane/ethanol 80/20(V/V), 35 deg.C, flow rate 1mL/min) and single configuration Z2b (7.5g, 40% yield, chiral column retention time 5.755min, CHIRALPAK AY-H (AYH0CE-VC001)0.46cm I.D. 25cm L, mobile phase n-hexane/ethanol 80/20(V/V), 35 ℃, flow rate: 1mL/min), MS M/z 253[ M +1]]⁺.

Intermediate Z3

Step 1, preparation of intermediate Z3-1

Adding catalytic amount of concentrated H2SO4(1.66 mol,2mL) into ethanol (1L) solution of p-nitroacetoacetic acid (300g,1.66mol) at room temperature, heating to 80 deg.C, stirring for 16 hr, removing raw materials, and concentrating under reduced pressureDried, dissolved in 2L of ethyl acetate, washed with aqueous sodium bicarbonate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate Z3-1(330 g,1.58mol, 95.25% yield), MS M/Z:210[ M +1]]⁺.

Step 2, preparation of intermediate Z3-2

Under the protection of nitrogen, intermediate Z3-1 p-nitrophenylacetic acid ethyl ester (29.4g,140.54mmol) was dissolved in dry 1.2L of N, N-dimethylacetamide, cooling in dry ice-ethanol bath to-40 deg.C, adding cesium carbonate (114.54g,351.34mmol), stirring at 40 deg.C for 15min, slowly adding 2-chloroethyl chloromethyl ether (19.94g,154.59mmol) dropwise into the reaction solution, allowing the reaction to return to room temperature after dropwise addition, and stirred overnight, after the starting material disappeared, 3L of ice water was added to quench the reaction, ethyl acetate (2L × 2) was extracted, the organic phase was washed with saturated brine (2L × 2), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was chromatographed on silica gel column to give intermediate Z3-2(6.5g,24.50mmol, 17.44% yield), MS m/Z:266[ M + 1.]⁺.

Step 3, preparation of intermediate Z3-3

Dissolving intermediate Z3-2(15g,56.55mmol) in EtOH (100mL), replacing with nitrogen, adding 10% Pd/C (3g), stirring under hydrogen atmosphere at normal pressure for reaction overnight, after the raw material disappears, filtering with diatomaceous earth, washing with ethanol, and concentrating the filtrate under reduced pressure to dryness to obtain intermediate Z3-3(12.7g,53.98mmol, 95.46% yield), MS M/Z:236[ M +1]]⁺The product was used directly in the next reaction without purification.

Step 4, preparation of intermediate Z3-4

Dissolving intermediate Z3-3(16g,68.00mmol) in acetic anhydride (136mL), cooling to 0 deg.C, stirring for 15min, and slowly adding HNO dropwise₃(9.45g,102.01mmol, 68% mass fraction), after dropping, the reaction is continued to stir for 30min, the raw material disappears, the reaction solution is poured into ice water, ethyl acetate (2 x 300mL) is used for extraction, the organic phase is washed by saturated sodium carbonate, dried by anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain crude intermediate Z3-4(21g,65.15mmol, 95.81% yield), MS M/Z: 323[ M +1], M/Z]⁺The product was used directly in the next reaction without purification.

Step 5, preparation of intermediate Z3-5

Intermediate Z3-4(21g,65.15mmol) was dissolved in 150ml ethanol and SOCl was added₂(23.25g,195.46mmol, 14.18mL), heating to 50 deg.C and stirring for 1hr, LC-MS shows disappearance of raw material, reaction solution is concentrated to dryness under reduced pressure, CH is added₂Cl₂(150mL) and H₂O (150mL), with saturated NaHCO₃Adjusting the pH value to 8, and passing the water phase through CH₂Cl₂(2X 150mL), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure to give crude intermediate Z3-5 (18g,64.22 mmol, 98.57% yield), MS M/Z281 [ M +1]]⁺The product was used directly in the next reaction without purification.

Step 6, preparation of intermediate Z3a, Z3b

Intermediate Z3-5(19g,67.79mmol) was dissolved in methanol, 10% Pd/C (5.7g) was added under nitrogen atmosphere, the reaction was hydrogenated overnight at normal pressure, after disappearance of the starting material, filtering with diatomaceous earth, concentrating the filtrate under reduced pressure to dryness, purifying with MPLC 18 reverse phase column to obtain racemate, resolving and separating with SFC chiral column to obtain single configuration 3a (7.5g, 44% yield, chiral column retention time 3.814min, CHIRALCEL OD-H (ODH0CD-TC013)0.46cm I.D. 15cm L, mobile phase: 100% methanol, 35 deg.C, flow rate: 1mL/min) and another single configuration 3b (7.5g, 44% yield, chiral column retention time 2.554min, CHIRALCEL OD-H (ODH0CD-TC013)0.46cm I.D. 15cm L, mobile phase: 100% methanol, 35 deg.C, flow rate: 1mL/min), MS m/z:251[ M + 1.]⁺.

Intermediate Z4

Referring to the procedure from step 2 to step 6 of the preparation route for intermediate Z3-5, intermediate Z4.MS M/Z265 [ M + 1: 265 was obtained by replacing 2-chloroethyl chloromethyl ether with 2,2' -dibromodiethyl ether in step 2, with the remainder of the reagents and conditions being unchanged]⁺.

Intermediate Z5

Step 1, preparation of intermediate Z5-1

To a solution of ethyl p-nitrophenylacetate Z3-1(156g,745.71mmol) in dry DMF (700mL) under nitrogen at 0 deg.C was added Cs₂CO₃(290.82g,894.85mmol), warmed to room temperature and stirred for 1 hour, then cooled to 0 ℃ and slowly added with methyl iodide (116.43g,820.28mmol) dropwise, the reaction is carried out overnight, the mixture is filtered, the filtrate is diluted with 2L ethyl acetate, washed with saturated brine (3X 1.5L), dried with anhydrous sodium sulfate of organic phase, filtered and concentrated to obtain intermediate 5-1(165g, 739.16mmol, 99.12% yield), MS M/z:224[ M +1], (M +1)]⁺The crude product was used directly in the next step.

Step 2, preparation of intermediate Z5-2

Dissolving intermediate Z5-1(2.30g,10.30mmol) in EtOH (20mL), replacing with nitrogen, adding 10% Pd/C (0.5g), stirring under hydrogen atmosphere at normal pressure for reaction overnight, filtering with diatomaceous earth after the raw material disappears, washing with ethanol, concentrating the filtrate under reduced pressure to dryness, separating and purifying with silica gel column to obtain intermediate Z5-2(1.30g,6.73mmol, 65.31% yield), MS M/Z: 194[ M +1]]⁺。

Step 3, preparation of intermediate Z5-3

Dissolving intermediate Z5-2(2.70g,13.97mmol) in acetic anhydride (10mL), cooling to 0 deg.C, stirring for 15min, and slowly adding HNO dropwise₃(1.76g,27.94mmol, 68% mass fraction), after dropping, the reaction was stirred for another 30min, the starting material disappeared, the reaction solution was poured into ice water, extracted with ethyl acetate (2 x 30mL), the organic phases were combined, washed with saturated sodium carbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give crude intermediate Z5-3(3.45g,12.32mmol, 88% yield), MS M/Z:281[ M +1 ]: M]⁺。

Step 4, preparation of intermediate Z5-4

Intermediate Z5-3(3.45g,12.32mmol) was dissolved in 20ml ethanol and SOCl was added₂(4.40g,36.96mmol,2.68 mL), heating to 50 deg.C and stirring for 1hr, LC-MS shows disappearance of raw material, concentrating the reaction solution under reduced pressure to dryness, adding CH₂Cl₂(150mL) and H2O (150mL) with saturated NaHCO₃Adjusting the pH value to 8, and passing the water phase through CH₂Cl₂(2X 150mL), combined organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give crude intermediate Z5-4(2.89g,12.07mmol, 98% yield), MS M/Z:239[ M +1]]⁺The product was used directly in the next reaction without purification.

Step 5, preparation of intermediate Z5

Dissolving intermediate Z5-4(2.89g,12.07mmol) in 10ml ethanol, adding Pd/C (0.5g) under nitrogen atmosphere, hydrogenating at normal pressure overnight, filtering with diatomaceous earth after the raw material disappears, concentrating the filtrate under reduced pressure to dryness, purifying with MPLC 18 reversed phase column to obtain intermediate Z5(2.13g,10.26mmol, 85% yield), MS M/Z:209[ M +1]]⁺.

Intermediate Z6

Referring to the procedure of scheme 1 through step 5 of intermediate Z5, the iodomethane in step 1 was replaced with iodoethane and the remaining reagents were run under otherwise unchanged conditions to give intermediate Z6, MS M/Z:223[ M +1]]⁺.

Intermediate Z7

Referring to the procedure of step 1 to step 5 of the preparative route for intermediate Z5, methyl iodide was replaced with 2-bromopropane in step 1, while the reaction was carried out in a DMF-potassium carbonate system instead. The remaining conditions were unchanged to give intermediate Z7, MS M/Z237 [ M +1]]⁺.

Intermediate Z8

Step 1, preparation of intermediate Z8-1

To a solution of ethyl p-nitrophenylacetate Z3-1(350g,1.67 mol) in dry DMF (2L) under nitrogen at 0 deg.C was added Cs₂CO₃(2.73kg,8.37mol), warmed to room temperature and stirred for 1 hour, then iodomethane (1.19kg, 8.37mol) is slowly added dropwise, the reaction is carried out overnight at room temperature after dropwise addition, suction filtration is carried out, the filtrate is diluted with 10L ethyl acetate, washed with saturated brine (3X 10L), dried by organic phase anhydrous sodium sulfate, filtered and concentrated to obtain intermediate Z8-1(320g,1.24mol, 74.17% yield), MS M/Z is 238[ M +1 ]: M/Z]⁺The crude product was used directly in the next step.

Step 2-5, preparation of intermediate Z8

Referring to the method from step 2 to step 5 in the synthetic route of intermediate Z5, intermediate Z8, MS M/Z:223[ M + 1: 223, M +1, was obtained by replacing Z5-1 with intermediate Z8-1 in step 2, and the remaining operating conditions were unchanged]⁺.

Intermediate Z9

Step 1, preparation of intermediate Z9-1

Referring to the preparation method of the intermediate Z8-1 in the step 1 in the synthetic route of the intermediate Z8, the intermediate Z9-1 is obtained by replacing ethyl p-nitrophenylacetate with ethyl 2-fluoro-4-nitrophenylacetate and keeping the rest conditions unchanged, wherein the intermediate MS M/Z is 256[ M +1]]⁺.

Step 2-5, preparation of intermediate Z9

Referring to the method from step 2 to step 5 in the synthetic route of intermediate Z5, intermediate Z9-1 was substituted for intermediate Z5-1 in step 2, and the same conditions were followed to give intermediate Z9, MS M/Z:241[ M +1]]⁺.

Intermediate Z10

Step 1, preparation of intermediate Z10-1

Referring to the preparation method of the intermediate Z8-1 in the step 1 in the synthetic route of the intermediate Z8, the intermediate Z10-1 is obtained by replacing p-nitrophenylacetic ether with 2-fluoro-4-nitro-5-bromo-phenylacetic acid ethyl ester under the same conditions, and the intermediate MS M/Z is 256[ M +1]]⁺.

Step 2-5, preparation of intermediate Z10

Referring to the method from step 2 to step 5 in the synthetic route of intermediate Z5, intermediate Z10-1 was substituted for intermediate Z5-1 in step 2, and the same conditions were followed to give intermediate Z10, MS M/Z:241[ M +1]]⁺.

Intermediate Z11

Step 1, preparation of intermediate Z10-1

Referring to the preparation method of the intermediate Z8-1 in the step 1 in the synthetic route of the intermediate Z8, the intermediate Z11-1 is obtained by replacing p-nitrophenylacetic ether with 3-fluoro-4-nitro-phenylacetic acid ethyl ester and keeping the rest conditions unchanged, wherein the MS M/Z is 256[ M +1]]⁺.

Step 2-5, preparation of intermediate Z11

Referring to the method from step 2 to step 5 in the synthetic route of intermediate Z5, intermediate Z11-1 was substituted for intermediate Z5-1 in step 2, and the same conditions were followed to give intermediate Z11, MS M/Z:241[ M +1]]⁺.

Intermediate Z12

Step 1, preparation of intermediate Z12-1

To a solution of ethyl 4-nitro-phenylacetate (21g,100mmol) in DMF (15mL) was added NaH (60%, 8.40g,210mmol,2.1equiv) in portions under ice-bath, and the mixture was warmed to room temperature and stirred for 1 h. The mixture was cooled to 0 ℃ and dibromoethane (1.72mL,20mmol,2.0equiv) was added, and the reaction was stirred at zero degrees for 30 minutes and then warmed to room temperature and stirred for 1 hour. After completion of the reaction, the mixture was quenched by slow addition of water, extracted with DCM, the combined organic phases were dried over anhydrous magnesium sulphate, filtered and spun dried, and the crude product was purified by silica gel column separation to give Z12-1(6.0g,25.5mmol, 25.5% yield). MS M/z 236[ M +1]]⁺.

Step 2-5, preparation of intermediate Z12

Referring to the method from step 2 to step 5 of the synthetic route of intermediate Z5, intermediate Z12-1 was substituted for intermediate Z5-1 in step 2, and the same conditions were followed to give intermediate Z12, MS M/Z:221[ M +1] (M +1)]⁺.

Intermediate Z13

Step 1, preparation of intermediate Z13-1

Referring to the synthesis method of the intermediate Z12-1, 3-diiodopropane is used for replacing dibromoethane, and the rest conditions are not changed, so that the intermediate Z13-1 can be obtained, and the MS M/Z is 250[ M +1]]⁺.

Step 2-5, preparation of intermediate Z13

Reference intermediate Z5 synthesisThe process of steps 2 to 5 of the route, in step 2, intermediate Z5-1 is replaced by intermediate Z13-1, and the same conditions apply, giving intermediate Z13, MS M/Z:225[ M +1]]⁺.

Intermediate Z14

Step 1, preparation of intermediate Z14-1

Under the protection of nitrogen and ice bath, 4-nitro-ethyl phenylacetate (1g,4.8mmol) in DMF (10mL) is added dropwise to a solution of potassium tert-butoxide (650mg, 5.6mmol) in DMF (10mL), the reaction solution is stirred at zero temperature for reaction for 30min, then bromocyclopentane (860mg, 5.7mmol) is added dropwise, and after the addition is finished, the reaction solution is heated to 70 ℃ and stirred for reaction for 1.5 h. After completion of the reaction, it was cooled to room temperature, poured into water, extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was isolated and purified by silica gel column to give intermediate Z14-1(716mg, 2.58mmol, yield 51%) MS M/Z278 [ M + 1% ]]⁺.

Step 2-5, preparation of intermediate Z14

Referring to the method from step 2 to step 5 of the synthetic route of intermediate Z5, intermediate Z14-1 was substituted for intermediate Z5-1 in step 2, and the same conditions were followed to give intermediate Z14, MS M/Z:263[ M +1]]⁺.

Intermediate Z15

Boc-D-cyclobutylglycine (100mg,0.44mmol) was dissolved in 15mL dry tetrahydrofuran, 1.76mL of 1M borane tetrahydrofuran solution was added under nitrogen, the mixture was allowed to warm to 65 ℃ and stirred overnight, quenched slowly with a little methanol, diluted with water, extracted with ethyl acetate (10 mL. multidot.2), and the organic phases combinedDried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate Z15-1(86mg,0.40mmol, 91% yield), MS M/Z:216[ M +1]]⁺.

To a 25mL eggplant-shaped bottle were added intermediate Z15-1(30mg, 139.35. mu. mol) and DCM (1.5mL) in sequence, and TFA (1mL) was added under ice-bath conditions, followed by reaction for 1hr under ice-bath conditions. Directly spin-drying the system to obtain intermediate Z15 crude product, MS M/Z:116[ M +1]]⁺And used in the next step without purification.

Intermediate Z16

Step 1, preparation of Z16-1

To a solution of cyclobutylformic acid (20g,199.77mmol) in THF (200mL) at zero degrees, LDA (53.50g, 499.42mmol,188mL) was added dropwise over about 30 minutes. The mixture is stirred for 30mins at 0 ℃ and CH is added dropwise₃I (31.19g,219.75mmol), and after the addition was complete, the reaction was stirred overnight at room temperature. After completion of the reaction, the reaction was quenched by addition of water (200mL), pH was adjusted to 4 with 6N HCl, the mixture was extracted with EA (200 mL. multidot.2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried to give Z16-1(21g,183.98mmol, 92.10% yield) as MS M/Z115 [ M +1]]⁺。

Step 2, preparation of Z16-2

To a solution of Z16-1(20g,175.22mmol) in DCM (500mL) at zero degrees under nitrogen protection was added 4,5,6, 7-tetrachloro-2-hydroxy-isoindoline-1, 3-dione (58.58g,175.22mmol), DMAP (2.14g,17.52mmol) and DIC (26.54g,210.26mmol), the mixture was stirred at room temperature for 3 hours, after completion of the reaction, the mixture was distilled under reduced pressure in a water bath below 30 degrees to give Z16-2(69g,173.79mmol, 99.18% yield), which was used directly in the next step without purification. MS M/z 396[ M +1]]⁺。

Step 3, preparation of Z16-3

To a solution of Z16-2(84g,211.57mmol) in NMP (600mL) at zero degrees was added methyl (2Z) -2- [ (R) - (2,4, 6-trimethylphenyl)]Sulfinyl group]Iminoacetic acid ester (69.67g,275.04 mm)ol) and Ni (OAc)₂.4H₂O (13.17g,52.89 mmol), Zn (41.51g,634.70mmol) was added in portions, the temperature of the reaction solution was controlled to be below 20 ℃, after the addition, the reaction solution was stirred at room temperature overnight under nitrogen protection. After the reaction was completed, the mixture was quenched with saturated brine, diluted with EA, filtered to remove solid residue, the filtrate was separated, the lower aqueous phase was extracted with EA 2 more times, EA was combined, spin-dried to obtain a blue-black liquid, which was purified by column chromatography with PE/EA of 2/1, and the product Z16-3(52g,154.09mmol, 72.83% yield) was collected. MS M/z 338[ M +1]]⁺。

Step 4, preparation of Z16-4

To a solution of Z16-3(100g,296.32mmol) in MeOH (1L) at zero degrees was added TFA (67.57g,592.64 mmol,43.88 mL). The reaction mixture is then stirred at room temperature for 1 hour, the reaction mixture is concentrated under reduced pressure, the crude product is diluted with 300mL of water and CH₂Cl₂(300 mL. times.2) and the separated aqueous phase was saturated with K₂CO₃The pH of the solution was adjusted to 8.0 and then adjusted with CH₂Cl₂Extraction, drying of the combined organic phases over anhydrous sodium sulfate, filtration and concentration under reduced pressure gave Z16-4(50.7g, 296.08mmol, 99.92% yield), MS M/Z172 [ M +1]]⁺。

Step 5, preparation of Z16-5

To Z16-4(460mg,2.69mmol) CH at zero degrees₂Cl₂To a solution (30mL) was added slowly TEA (326.20mg, 3.22mmol, 449.62. mu.L) and Boc₂O (703.54mg,3.22mmol), heating the mixture to room temperature, stirring for 2h, quenching the reaction solution with 30mL saturated saline, extracting with DCM, drying the combined organic phases with anhydrous sodium sulfate, filtering, concentrating, separating and purifying the crude product with silica gel column to obtain Z16-5(692mg,2.55mmol, 94.93% yield), MS M/Z:216[ M + 1-56%]⁺。

Step 6, preparation of Z16-6

To a solution of Z16-5(160mg, 589.64. mu. mol) in THF (10mL) was added LiOH₂O (50.15mg,1.19 mmol) in water (10mL), the mixture stirred at room temperature for 2h, adjusted to pH 4.0 with 6N aqueous HCl, then extracted with DCM, the combined organic phases concentrated and the crude product purified by silica gel column separation to give Z16-6(138mg, 567.20. mu. mol, 96.19% yield). MS m/z:244[M+1]⁺。

Step 7, preparation of Z16-7

To a solution of Z16-6(3.0g,13.08mmol) in dry THF (65.5mL) at-5 deg.C were added NMM (1.46g, 14.39mmol) and TEA (2.49g,24.63mmol,3.44mL) and isobutyl chloroformate (1.97g,14.39mmol), the mixture was stirred at-5 deg.C for 30min, and the mixture was filtered. Maintaining the temperature at-5 ℃, dropwise adding a NaBH4(1.49g,39.25mmol) ice water (39.3mL) solution into the filtrate, after dropwise adding, stirring the mixed solution at-5 ℃ for 1 hour, adding water into the reaction solution for quenching, extracting with EA, washing the combined organic phases with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating, and separating and purifying the crude product by using a silica gel column to obtain Z16-7(2.8g,13.01mmol, 99.40% yield), MS M/Z is 230[ M +1] +.

Step 8, preparation of intermediate Z16

To a solution of Z16-7(2.8g,13.01mmol) in DCM (20mL) was added TFA (5mL) at zero degrees, the reaction mixture was stirred at zero degrees for 1 hour, after completion of the reaction, the mixture was concentrated and dried to give Z16(1.25g,7.34mmol, 79.24% yield). MS M/z 130[ M +1]]⁺。

Intermediate Z17

Step 1, preparation of Z17-1

To a solution of Z15-1(300mg,1.39mmol) in DMF (4mL) was added Ag2O (968.77mg,4.18mmol, 135.68. mu.L) and iodomethane (1.98g,13.93mmol) under nitrogen. Stirring at room temperature for 18hr, after reaction, spin-drying the reaction solution, separating and purifying the crude product with silica gel column (eluent: petroleum ether/ethyl acetate ratio of 5: 1 to 1: 1) to obtain intermediate Z17-1(200mg,872.16 μmol, 62.59% yield), MS M/Z:230[ M + 1%]⁺。

Step 2, preparation of Z17

At zero deg.C, TFA (0.2mL) was added to a solution of Z17-1(20mg, 87.22. mu. mol) in DCM (1mL), stirred at room temperature for 2 hours, and after completion of the reaction, the reaction solution was spin-dried to give intermediate Z17(10mg, 77.40. mu. mol, 88.74% yield), MS M/Z:130[ M + ]1]⁺。

Intermediate Z18

Step 1, preparation of Z18-1

To a solution of 1-methylcyclobutanecarboxamide (100mg,774.25 μmol) in dry THF (5mL) was added BH3.THF (3.87mmol,3.8mL) at room temperature, and the mixture was warmed to 65 ℃ and stirred overnight. After completion of the reaction, it was cooled to 0 ℃ and quenched by the addition of 4mL MeOH, and the mixture was concentrated under reduced pressure to give crude intermediate Z18-1(85mg, 738.02. mu. mol, 95.32% yield) which was used in the next reaction without purification. MS M/z 116[ M +1]]⁺。

Step 2, preparation of Z18-2

To a mixture of Z18-1(85mg, 738.02. mu. mol) in THF (3mL)/H2O (3mL) was added NaHCO3 (185.98mg,2.21mmol) and CbzOSU (248.95mg, 738.02. mu. mol) under ice-bath, and the mixture was stirred at room temperature for 2H. After the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give crude product, which was separated and purified by silica gel column to give intermediate Z18-2(30mg, 88.91. mu. mol, 12.05% yield), MS M/Z338 [ M + 1%]⁺。

Step 3, preparation of Z18

LiOH (1.06mg, 44.46. mu. mol) was added to a solution of Z18-2(15mg, 44.46. mu. mol) in THF (4.29mL)/H2O (1.71mL) at room temperature, and the reaction mixture was stirred under protection of N2 for 2hr, after completion of the reaction. Spin-drying the reaction mixture, adding DCM (50 mL. times.2) and water (50 mL. times.2), adding HCl to adjust pH to 4, separating to obtain an aqueous phase, adjusting pH of the aqueous phase to 8 with NaOH, adding 15mL of DCM for extraction, separating the organic phase, drying over anhydrous sodium sulfate, and spin-drying to obtain intermediate Z18(3mg, 26.05. mu. mol, 58.59% yield), MS M/Z:116[ M + 1%]⁺。

Intermediate Z19

Step 1 to step 2, preparation of Z19-2

Boc-D-cyclobutylglycine (500mg,2.18mmol) was dissolved in DCM (5mL) and NH was added sequentially under nitrogen₄Cl (233.30mg,4.36mmol), HBTU (1.07g,2.84mmol), DIPEA (1.13g,8.72mmol,1.52 mL), stirring at room temperature for 2 hours, adding a little water for quenching, DCM (25X 2) extracting, combining organic phases, washing with water, drying over anhydrous sodium sulfate, concentrating under reduced pressure to dryness, TLC (PE: EA ═ 1:1, Rf ═ 0.25), chromatographing to obtain intermediate Z19-1(430mg,1.88mmol, 86.37% yield), MS M/Z:229[ M + 1: 0.25%]⁺，¹H NMR(400MHz,Methanol-d4)δ 3.98(d,J＝8.8Hz,1H),2.71–2.53(m,1H),2.09–1.80(m,6H),1.47(s,9H).

A25 mL eggplant-shaped bottle was charged with intermediate Z19-1(430mg,1.88mmol), and THF (12mL) and BH were added under nitrogen at room temperature₃THF (4.7mL, 1M in THF), was stirred under nitrogen at 65 ℃ for 2 hours. Slowly adding a little methanol dropwise to quench, and then adding NaHCO₃The pH value of the system is adjusted to 8-9 by the aqueous solution, and the Z19-2 system is used for the next reaction. MS M/z 215[ M +1]]⁺.

Step 3 to step 4, preparation of Z19

Referring to the method of step 2 to step 3 of intermediate Z18, Z18-2 was replaced with Z19-2 in step 2, and the rest of the methods were the same to give Z19, MS M/Z:337[ M +1]]⁺.

Intermediate Z20

Boc-D-cyclobutylglycine (500mg,2.18mmol) was dissolved in DMF (5mL), 1-aminoacetone hydrochloride (359mg,3.28mmol), HATU (1.24g,3.28mmol), TEA (0.69g,6.84mmol) were added sequentially under nitrogen protection, the reaction was stirred at room temperature for 1 hour, quenched with a little water, extracted with ethyl acetate (25 x 2), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude intermediate Z20-1, which was used directly in the next step without purification, MS M/Z:266[ M +1 ]/[ MS M/Z]⁺.

Dissolving the crude intermediate Z20-1 obtained in the previous stepHeating to 140 deg.C in 4mL DMF under microwave for 2hr, diluting with water, extracting with ethyl acetate (25X 2), combining organic phases, washing with water, drying over anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude intermediate Z20-2, and directly using in next step without purification, MS M/Z:285[ M +1]⁺The intermediate Z20-2 is subjected to Boc removal by TFA, and the crude product is separated and purified by MPLC 18 reverse phase column to obtain intermediate Z20, MS M/Z is 166[ M +1]]⁺.

Intermediate Z21

Referring to the preparation method of the intermediate Z20, the initial raw material 1-amino acetone hydrochloride is replaced by acethydrazide, and other reagents and operation methods are not changed, so that the intermediate Z21, MS M/Z:167[ M +1]]⁺.

Intermediate Z22

Step 1, preparation of intermediate Z22-1

To a solution of Fmoc-D- (1-methylcyclobutyl) glycine (10g,27.37mmol) in dichloromethane (137mL) under ice-bath was added HBTU (8.34g,32.84mmol) and triethylamine (8.31g,82.10mmol), followed by ammonium chloride (2.96, 54.73 mmol). The reaction was gradually warmed to room temperature and stirred for 1 hour, the reaction was diluted with water, extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, and the crude product obtained was dried and purified by silica gel column separation to give intermediate Z22-1 (9g, 24.7mmol, 90% yield), MS m/Z: 365.0(M +1)⁺。

Step 2, preparation of intermediate Z22-2

Z22-1(500mg, 1.38mmol) was added to a 50mL three-necked flask in ice bath, followed by THF (6mL) and BH under nitrogen₃THF (2.76mL) was heated to 65 ℃ under nitrogen and the reaction was stirred for 5 hours. The reaction was cooled to room temperature and methanol (1mL), Boc was added₂O (451mg, 2.1mmol) and water (1mL), and the reaction was continuedStirred at room temperature for 1 hour. After the system was spun dry, diluted with water, extracted with ethyl acetate, the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, and the crude product after spinning was purified with a normal phase silica gel column to give intermediate Z22-2(161mg,0.36mmol, 26% yield), MS m/Z: 451.0(M +1)⁺。

Step 3, preparation of intermediate Z22

To Z22-2(161mg,0.36mmol) in THF (6mL), H₂LiOHH was added to a mixed solution of O (2mL) and MeOH (1mL)₂O (20mg, 0.5mmol), stirred at rt overnight, after reaction was complete, the reaction was directly spin dried and the crude product was washed with petroleum ether to afford intermediate Z22(66mg, 0.31mmol, 85% yield). MS m/z: 229.0(M +1)⁺。

Preparation of intermediate Z23

Step 1, Synthesis of Z23-1

To a solution of 2- (4-bromophenyl) acetate (20g,0.83mmol) in acetonitrile (220mL) at zero degrees was added DBU (15g, 98.73mmol) and p-ABSA (19.76g, 82.27 mmol). The reaction solution was warmed to 25 ℃ and stirred for 48 h. After the reaction was complete, saturated aq₄The reaction was quenched with Cl, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and then separated and purified by normal phase silica gel column to give Z23-1(8g,29.63mmol, yield 36%).

Step 2, Synthesis of Z23-2

To Z23-1(1g,3.72mmol) in toluene (16mL) was added Rh₂(esp)₂(14mg,0.018mmol), N-Cbz 3-chloropropylamine (846mg,3.72mmol), mixed solution was replaced with nitrogen, and then heated to 60 ℃ under nitrogen protection and stirred for 5 hours. After cooling to room temperature tetrabutylammonium bromide (1.2g,3.72mmol) and CsOH.H were added₂O (1.25g,7.43mmol), stirring the mixture overnight at room temperature, filtering the reaction solution, washing with ethyl acetate, concentrating the filtrate, and separating and purifying the crude product with normal phase silica gel column to obtain Z23-2(1.29g,2.97 mmol). MS M/z 432[ M +1]]⁺.

Step 3, Synthesis of Z23-3

To Z23-2(4.8g,11.14mmol) in dioxane (70mL) was added AcNH₂(986mmol,55.68mmol), Pd₂(dba)₃(510mg,0.55mmol), Xantphos (645mg,1.12mmol) and CS₂CO₃(10.9g,33.43mmol), the reaction mixture was replaced with nitrogen several times, and stirred at 80 ℃ overnight under nitrogen. After the reaction was completed, the reaction solution was concentrated, water and ethyl acetate were added for extraction, the combined organic phases were dried over anhydrous sodium sulfate, and the concentrated crude product was separated and purified by a normal phase silica gel column to obtain Z23-3(2.7g,6.5mmol, 59% yield). MS M/z 411[ M +1]]⁺。

Step 4, Synthesis of Z23-4

Ac to Z23-3(3.8g,9.3mmol) at zero degrees₂Adding 65% nitric acid (1.5mL, 18.6 mmol) into O (40mL), gradually heating the mixture to room temperature, stirring overnight, concentrating the reaction solution after the reaction is finished, diluting the crude product with water, extracting with ethyl acetate, drying the combined organic phase, separating and purifying with normal phase silica gel column to obtain Z23-4(3.2g, 7.0mmol, yield 75%), and MS M/Z:456[ M + 1% ]]⁺。

Step 5, Synthesis of Z23-5

To a solution of Z23-4(3.2g, 7.0mmol) in ethanol (35mL) at zero degrees was added SOCl₂(1mL), after the addition was complete, the temperature was slowly raised to 70 ℃ and stirred at this temperature for 5 hours. After the reaction was completed, the solution was spin-dried, and the crude product was purified by normal phase silica gel column to give Z23-5(1.36g, 3.29mmol, yield 47%) MS M/Z414 [ M +1]]⁺。

Step 6, Synthesis of Z23-6

Adding ammonia water (1.5mL) into a methanol (15mL) solution of Z23-5(1.36g, 3.29mmol) at zero temperature, adding an aqueous solution of sodium hydrosulfite (2.6g, 15mmol), filtering to remove solids in the mixed solution after the reaction is finished, adding water and ethyl acetate into the concentrated filtrate for extraction, washing the combined organic phase with water and saturated saline solution, concentrating, and separating and purifying the crude product by a silica gel column to obtain Z23-6 (819mg, 2.1mmol, 65% yield), MS M/Z is 384[ M +1 ]/[ 384]⁺. Used in the next reaction without purification.

Preparation of intermediate Z24

Step 1, preparation of intermediate Z24-1

A reaction flask was charged with a solution of 4-bromo-3-fluoro-2-nitroaniline (10g,42.55mmol) in dioxane (200mL) and water (20mL), followed by the addition of 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (8.94g,42.55mmol), Pd (dppf) Cl₂(1.55g,2.12mmol) and K₂CO₃(17.60g,127.54mmol), mixing uniformly, vacuumizing and protecting with nitrogen, heating to 100 ℃ for reaction for 3 hours, cooling to room temperature after reaction, filtering, adding ethyl acetate and brine into the filtrate for layering, concentrating and drying to obtain crude Z24-1(9.69g,40.68mmol, 95.60% yield), MS m/Z: 239.0(M +1)⁺。

Step 2, preparation of intermediate Z24-2

Ac2O (484mg,4.74mmol) was added to a solution of Z24-1(700mg,2.94mmol) in acetic acid (7mL), the mixture was heated to 90 ℃ for reaction for 2 hours, after the reaction was completed, the mixture was added dropwise to 35mL of water, and after filtration and concentration, Z24-2(618mg,2.21 mmol, 75.04% yield) was obtained. MS m/z: 281.0(M +1)⁺

Step 3, preparation of intermediate Z24-3

m-CPBA (246.31mg,1.43mmol) is added into a dichloromethane solution of Z24-2(200mg, 713.65. mu. mol), the mixed solution is stirred at room temperature overnight, the raw material 1/3 remains, the reaction solution is heated to 40 ℃ to continue reacting for 4 hours, then sodium carbonate aqueous solution and ethyl acetate are added for extraction, an organic layer is washed by sodium sulfite aqueous solution, and a separated organic layer is concentrated to obtain an intermediate Z24-3 (205mg, 691.98. mu. mol, 96.96% yield), MS m/Z: 297.0(M +1)⁺

Step 4, preparation of intermediate Z24-4

To a solution of Z24-3(1.9g,6.41mmol) in dichloromethane (50mL) under ice-bath was added BF₃OEt (2.74g,19.28 mmol), gradually warmed to room temperature and stirred for 2 hours, quenched with sodium carbonate after the reaction, extracted with ethyl acetate, and dried the organic phase to obtain a crude product, which is separated and purified with a forward silica gel column (eluent, dichloromethane/ethyl acetate 10: 1-5: 1) to obtain Z24-4(1.37g,4.62mmol, 72.11% yield)Rate) product. MS m/z: 297.0(M +1)⁺

Step 5, preparation of intermediate Z24-5

Adding NaClO into a reaction bottle₂(1.31g,12.95mmol) and NaH₂PO₄(1.59g,10.17mmol), cooling to 0 ℃ after mixing, dropping a mixed solution of Z24-4(1.37g,4.62mmol) in t-butanol (12mL) and water (9mL), stirring at constant temperature for 1 hour, adjusting the pH to 5-6 after the reaction, extracting with ethyl acetate, and concentrating the organic phase to obtain Z24-5(1.38g,4.42 mmol, 95.57% yield). MS m/z: 297.0(M +1)⁺

Step 6, preparation of intermediate Z24-6

To a solution of Z24-5(600mg,1.92mmol) in EtOH (12mL) was added SOCl dropwise₂(685.82mg,5.76mmol, 418.18. mu.L), and after completion of the dropwise addition, the reaction was warmed to 60 ℃ for 12 hours. Cooled to room temperature, the reaction was poured into sodium bicarbonate solution, then extracted with ethyl acetate and concentrated to give crude Z24-6(434mg,1.46mmol, 75.72% yield), MS m/Z: 299.0(M +1)⁺

Step 7, preparation of intermediate Z24

Palladium on carbon was added to a solution of Z24-6(434mg,1.61mmol) in ethanol (8mL), replaced with hydrogen balloon, stirred at room temperature for 12 hours, after completion of the reaction, palladium on carbon was filtered off, the filtrate was concentrated and purified with a forward silica gel column (dichloromethane/methanol 50/1, v/v) to give Z24(187mg,697.02 μmol, 43.40% yield), MS m/Z: 269.0(M +1)⁺。

Preparation of intermediate Z25

Referring to the synthesis method of the intermediate Z22, Boc-D- (cyclobutyl) glycine is used as a raw material, condensation is carried out on the raw material and methylamine, carbonyl is reduced by borane, Fmoc is added, and finally, hydrochloric acid is used for removing Boc to obtain an intermediate Z25, MS m/Z: 351.0(M +1)⁺。

Preparation of intermediate Z26

Referring to the procedure from step 1 to step 2 of the synthetic route for intermediate Z22, the same procedure was followed except for the substitution of Fmoc-D- (1-methylcyclobutyl) glycine for Boc-D- (cyclobutyl) glycine and ammonium chloride for dimethylamine in step 1 to give intermediate Z26-2, MS m/Z: 243.0(M +1)⁺。

While in the bath, HCl/EA was added to a solution of Z26-2(15mg, 61.89. mu. mol) in DCM (0.5mL) and the reaction was stirred under nitrogen for 2h, after completion of the reaction, the solvent was spun dry to give intermediate Z26, MS m/Z: 143.0(M +1)⁺. To be provided with

Preparation of intermediate Z27

Step 1, preparation of intermediate Z27-1

A reaction flask was charged with a solution of 4-bromo-3-fluoro-2-nitroaniline (10g,42.55mmol) in dioxane (200mL) and water (20mL), followed by the addition of 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (8.94g,42.55mmol), Pd (dppf) Cl₂(1.55g,2.12mmol) and K₂CO₃(17.60g,127.54mmol), mixing uniformly, vacuumizing and protecting with nitrogen, heating to 100 ℃ for reaction for 3 hours, cooling to room temperature after reaction, filtering, adding ethyl acetate and brine into the filtrate for layering, concentrating and drying to obtain crude Z27-1(9.69g,40.68mmol, 95.60% yield), MS m/Z: 239.0(M +1)⁺

Step 2, preparation of intermediate Z27-2

To a solution of Z27-1(700mg,2.94mmol) in acetic acid (7mL) was added Ac₂O (484mg,4.74mmol), the mixture was heated to 90 ℃ and reacted for 2 hours, after the reaction was completed, it was added dropwise to 35ml of water, and after filtration and concentration, Z27-2(618mg,2.21 mmol, 75.04% yield) was obtained. MS m/z: 281.0(M +1)⁺

Step 3, preparation of intermediate Z27-3

m-CPBA (246.31mg,1.43mmol) was added to a dichloromethane solution of Z27-2(200mg, 713.65. mu. mol), the mixture was stirred at room temperature overnight with 1/3 of the starting material remaining, the reaction solution was warmed to 40 ℃ and thenAfter 4h of further reaction, aqueous sodium carbonate and ethyl acetate were added for extraction, the organic layer was washed with aqueous sodium sulfite, and the separated organic layer was concentrated to give intermediate Z27-3 (205mg,691.98 μmol, 96.96% yield), MS m/Z: 297.0(M +1)⁺

Step 4, preparation of intermediate Z27-4

To a solution of Z27-3(1.9g,6.41mmol) in dichloromethane (50mL) under ice-bath was added BF₃OEt (2.74g,19.28 mmol), gradually warmed to room temperature and stirred for 2 hours, quenched with sodium carbonate after the reaction, extracted with ethyl acetate, and dried to obtain a crude product, which is separated and purified by a forward silica gel column (eluent, dichloromethane/ethyl acetate ═ 10: 1-5: 1) to obtain a Z27-4(1.37g,4.62mmol, 72.11% yield) product. MS m/z: 297.0(M +1)⁺

Step 5, preparation of intermediate Z27-5

Adding NaClO into a reaction bottle₂(1.31g,12.95mmol) and NaH₂PO₄(1.59g,10.17mmol), cooling to 0 ℃ after mixing, dropping a mixed solution of Z27-4(1.37g,4.62mmol) in t-butanol (12mL) and water (9mL), stirring at constant temperature for 1 hour, adjusting the pH to 5-6 after the reaction, extracting with ethyl acetate, and concentrating the organic phase to obtain Z27-5(1.38g,4.42 mmol, 95.57% yield). MS m/z: 297.0(M +1)⁺

Step 6, preparation of intermediate Z27-6

To a solution of Z27-5(600mg,1.92mmol) in EtOH (12mL) was added SOCl dropwise₂(685.82mg,5.76mmol, 418.18. mu.L), and after completion of the dropwise addition, the reaction was warmed to 60 ℃ for 12 hours. Cooled to room temperature, the reaction was poured into sodium bicarbonate solution, then extracted with ethyl acetate and concentrated to give crude Z27-6(434mg,1.46mmol, 75.72% yield), MS m/Z: 299.0(M +1)⁺

Step 7, preparation of intermediate Z27

Palladium on carbon was added to a solution of Z27-6(434mg,1.61mmol) in ethanol (8mL), replaced with hydrogen balloon, stirred at room temperature for 12 hours, after completion of the reaction, palladium on carbon was filtered off, the filtrate was concentrated and purified with a forward silica gel column (dichloromethane/methanol 50/1, v/v) to give Z27(187mg,697.02 μmol, 43.40% yield), MS m/Z: 269.0(M +1)⁺。

Preparation of intermediate Z28

Referring to the procedure from step 1 to step 7 of the synthetic route for intermediate Z27, starting from 4-chloro-5-bromo-2-nitrobenzene, the same procedure was followed to give intermediate Z28. MS m/z: 285.0(M +1)⁺。

Preparation of intermediate Z29

Referring to the procedure of step 1 to step 7 of the synthetic scheme for intermediate Z27, starting from 4-methyl-5 bromo-2 nitrobenzene, the same procedure was followed to give intermediate Z29, MS m/Z: 265.0(M +1)⁺。

Preparation of intermediate Z30

Referring to the procedure of step 1 to step 7 of the synthetic scheme for intermediate Z27, starting from 2-amino-5-bromo-3-nitropyridine, the same procedure was followed to give intermediate Z29, MS m/Z: 252.0(M +1)⁺。

Preparation of intermediate Z31

Referring to the procedure of step 1 to step 7 of the synthetic scheme for intermediate Z27, starting from 4-bromo-5-fluoro-2-nitroaniline, the same procedure was followed to give intermediate Z31, MS m/Z: 269.0(M +1)⁺。

Preparation of intermediate Z32

Referring to the procedure of step 1 to step 7 of the synthetic scheme for intermediate Z27, starting from 4-bromo-2-fluoro-6-nitroaniline, the same procedure was followed to give intermediate Z32, MS m/Z: 269.0(M +1)⁺。

Preparation of intermediate Z33

Step 1, preparation of intermediate Z33-1

To a solution of di-tert-butyl malonate (22.72g,105.05mmol) in DMF (250mL) under ice-bath was added NaH (7.56g,315.14mmol), the mixture was stirred at zero degrees for 30 minutes, and then a solution of 1-bromo-4, 5-difluoro-2-nitrobenzene (25g, 105.05mmol) in DMF (50mL) was added dropwise. The reaction solution was stirred at room temperature for 3 hours.

The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give Z33-1(41g, crude) which was used in the next reaction without purification.

Step 2, preparation of intermediate Z33-2

HCl (120mL) was added slowly to a solution of Z33-1(94.0g,216.46mmol) in acetic acid (320mL) at room temperature, and the reaction mixture was warmed to 110 ℃ and stirred for 2 h.

The reaction was directly concentrated to give Z33-2(60g, crude) which was used in the next reaction without purification.

Step 3, preparation of intermediate Z33-3

Concentrated sulfuric acid (5mL) was slowly added dropwise to a solution of Z33-2(60g, 215.80mmol) in ethanol (300mL) at room temperature, and the reaction was heated to 85 ℃ and stirred for 2 hours.

The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate, and the combined organic phases were washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Z33-3(66g) as a yellow oil.

Step 4, preparation of intermediate Z33-4

Cs2CO3(36.19g, 111.08mmol) was added to a solution of Z33-3(34.0g,111.08mmol) in DMF (300mL) at room temperature, stirred for 30 minutes, cooled to zero, MeI (12.61g,88.86mmol) was added, and the reaction was stirred overnight at room temperature. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column (0% to 60% ethyl acetate/petroleum ether) to give intermediate Z33-4(25g, 71%) as a yellow oil.

Step 5, preparation of intermediate Z33-5

To a solution of intermediate Z33-4(11.0g,34.36mmol) in DMF (125mL) under ice-bath was added NaH (907.18mg,37.80mmol) in portions and the mixture was stirred at zero degrees for 30 min. Then, a solution of MOMBr (5.58g,44.67mmol) in DMF (25mL) was added and the reaction was stirred at room temperature overnight. After the reaction was completed, the mixed drug was concentrated, and the crude product was separated and purified by silica gel column (ethyl acetate/petroleum ether ═ 0 to 100%) to obtain intermediate Z33-5(5g, 40% yield) as a yellow solid.

Step 6, preparation of intermediate Z33-6

Acetic acid (15mL) and water (50mL) were added to an ethanol solution of intermediate Z33-5(9.4g,25.81mmol), the mixture was warmed to 50 degrees, iron powder (10.81g,193.59mmol) was added in portions, and after the addition, the reaction mixture was warmed to 85 degrees and stirred for 3 hours. After the reaction was complete, the iron powder was filtered and the filter cake was washed with ethanol and the filtrate was concentrated to give intermediate Z33-6(8.4g, 97% yield, crude), MS m/Z: 334.0(M +1)⁺

Used in the next reaction without purification.

Step 7, preparation of intermediate Z33-7

To a solution of intermediate Z33-6(8.4g,25.14mmol) in dichloromethane (120mL) was added acetic anhydride (2.57g,25.14 mmol), the mixture was stirred at room temperature for 3 hours, and after completion of the reaction, the reaction was concentrated to give intermediate Z33-7(9.4g, 99% yield, crude). MS (ESI) 378.0(M +2) M/z⁺.

Step 8, preparation of intermediate Z33-8

In ice bath to Z33-7(1g,2.66mmol) of HNO3 (68%) (3.0mL) was added dropwise H2SO4 (98%) (3.0mL) and the reaction was stirred at zero degrees for 1 hour. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate and the organic phase was concentrated to give crude intermediate Z33-8(0.9g, 80% yield). MS (ESI) 422.0 (M +1)⁺.

Step 9, preparation of intermediate Z33-9

To a solution of Z33-8(3.13g,7.43mmol) in ethanol was added SOCl under ice-cooling₂(5.30g,44.59mmol,3.23 mL), the reaction was warmed to 60 ℃ and stirred overnight. After completion of the reaction, the reaction solution was concentrated, and the crude product was isolated and purified by silica gel column to obtain intermediate Z33-9(575mg, 20% yield). MS (ESI) 379.0(M +1) M/z⁺.

Step 10, preparation of intermediate Z33

Pd/C (0.057g) was added to a solution of intermediate Z33-9(0.570g,1.50mmol) in ethanol (50mL), and after replacement with H2, the mixture was stirred overnight at room temperature under protection of H2. After completion of the reaction, Pd/C was removed by filtration, the filtrate was concentrated and purified by MPLC 18 reverse phase column to give racemate Z33(420mg, 90% purity, 93% yield). MS m/z: 271.0(M +1)⁺。

Preparation of intermediate Z34

Referring to the operations from step 1 to step 6 in the synthetic route of intermediate Z2, intermediate Z34 was obtained by the same operations with ethyl 2- (3-fluoro-4-nitrophenyl) acetate as the starting material. MS m/z: 271.0(M +1)⁺。

Preparation of intermediate Z35

Step 1, Synthesis of Z35-1

To a solution of 2- (4-bromophenyl) acetate (20g,0.83mmol) in acetonitrile (220mL) at zero degrees was added DBU (15g, 98.73mmol) and p-ABSA (19.76g, 82.27mmol)l). The reaction solution was warmed to 25 ℃ and stirred for 48 h. After the reaction was complete, saturated aq₄The reaction was quenched with Cl, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and then separated and purified by normal phase silica gel column to give Z35-1(8g,29.63mmol, yield 36%).

Step 2, Synthesis of Z35-2

Rh2(esp)2(14mg,0.018mmol) and N-Cbz 3-chloropropylamine (846mg,3.72mmol) were added to Z35-1(1g,3.72mmol) in toluene (16mL), and the mixture was heated to 60 ℃ under nitrogen and stirred for 5 hours. After cooling to room temperature, tetrabutylammonium bromide (1.2g,3.72mmol) and CsOH.H2O (1.25g,7.43mmol) were added, the mixture was stirred at room temperature overnight, the reaction solution was filtered, washed with ethyl acetate, the filtrate was concentrated, and the crude product was isolated and purified by normal phase silica gel column to give Z35-2(1.29g,2.97 mmol). MS M/z 432[ M +1]]⁺.

Step 3, Synthesis of Z35-3

To Z35-2(4.8g,11.14mmol) in dioxane (70mL) was added AcNH₂(986mmol,55.68mmol), Pd₂(dba)₃(510mg,0.55mmol), Xantphos (645mg,1.12mmol) and CS₂CO₃(10.9g,33.43mmol), the reaction mixture was purged with nitrogen several times and stirred at 80 ℃ overnight under nitrogen. After the reaction was completed, the reaction solution was concentrated, water and ethyl acetate were added for extraction, the combined organic phases were dried over anhydrous sodium sulfate, and the concentrated crude product was separated and purified by a normal phase silica gel column to obtain Z35-3(2.7g,6.5mmol, 59% yield). MS M/z 411[ M +1]]⁺.

Step 4, Synthesis of Z35-4

Adding 65% nitric acid (1.5mL, 18.6 mmol) into Ac2O (40mL) of Z35-3(3.8g,9.3mmol) at zero degree, gradually heating the mixed solution to room temperature, stirring overnight, concentrating the reaction solution after the reaction is finished, adding water to dilute the crude product, extracting with ethyl acetate, drying the combined organic phase, separating and purifying with normal phase silica gel column to obtain Z35-4(3.2g, 7.0mmol, yield 75%), MS M/Z:456[ M + 1% ] (M +1) ]]⁺.

Step 5, Synthesis of Z35-5

To a solution of Z35-4(3.2g, 7.0mmol) in ethanol (35mL) at zero degrees was added SOCl₂(1mL), was added dropwiseAfter completion, the temperature was slowly raised to 70 ℃ and stirred at this temperature for 5 hours. After the reaction was completed, the solution was spin-dried, and the crude product was purified by normal phase silica gel column to give Z35-5(1.36g, 3.29mmol, yield 47%) MS M/Z414 [ M +1]]⁺.

Step 6, Synthesis of Z35

Adding ammonia water (1.5mL) into a methanol (15mL) solution of Z35-5(1.36g, 3.29mmol) at zero temperature, adding an aqueous solution of sodium hydrosulfite (2.6g, 15mmol), filtering to remove solids in the mixed solution after the reaction is finished, adding water and ethyl acetate into the concentrated filtrate for extraction, washing the combined organic phase with water and saturated saline solution, concentrating, and separating and purifying the crude product by a silica gel column to obtain Z35(819 mg,2.1 mmol, 65% yield), MS M/Z is 384[ M +1 ]/[ 384]⁺. Used in the next reaction without purification.

Preparation of intermediate Z36

Referring to the method from step 1 to step 6 in the synthetic route of intermediate Z2, benzyl p-nitrophenylacetate was used as the starting material in step 1, 3-iodotetrahydrofuran was used in step 2 instead of MOMCl to react with Z36-1, and the rest of the steps were the same to give intermediate Z36, MS M/Z:341[ M +1 ]: 341]⁺。

Preparation of intermediate Z37

Referring to the method from step 1 to step 6 of the synthetic route of intermediate Z2, benzyl p-nitrophenylacetate was used as the starting material in step 1, 3-iodotetrahydro-2H-pyran was used in step 2 instead of MOMCl to react with Z37-1, and the rest of the steps were the same, to give intermediate Z37, MS M/Z:355[ M +1]⁺。

Preparation of intermediate Z38

Referring to the method from step 2 to step 6 in the synthetic route of the intermediate Z2, the intermediate Z2-1 is used as a raw material, 3-iodopyrrolidine-1-carboxylic acid tert-butyl ester is used for replacing MOMCl to react with Z2-1, after the nitro group is reduced, acetyl protection is carried out, after Boc is removed, Cbz protection is carried out, then nitration reaction is carried out, deacetylation protection is carried out, and finally the nitro group is reduced, so that the intermediate Z38 can be obtained, MS M/Z:412[ M +1] M]⁺。

Preparation of intermediate Z39

Referring to the method from step 2 to step 6 in the synthetic route of intermediate Z2, intermediate Z2-is used as a raw material, MOMCl is replaced by 4- ((methylsulfonyl) oxy) piperidine-1-carboxylic acid tert-butyl ester to react with Z2-1, after the nitro group is reduced, acetyl protection is carried out, then nitration reaction is carried out, Cbz protection is carried out, deacetylation protection is carried out, and finally the nitro group is reduced, so that intermediate Z39 can be obtained, and MS M/Z is 426 [ M +1 ]: 426]⁺。

Preparation of intermediate Z40

Referring to the above diamine intermediate synthesis route, ethyl 2- (1-methyl-1H-pyrazol-4-yl) acetate is used as a raw material to react with 4 fluoronitrobenzene to obtain an intermediate compound Z40-1, methyl is added with methyl iodide, then nitro is reduced, nitration reaction and deacetylation reaction are carried out, and finally nitro is reduced. Obtaining an intermediate Z40, MS M/Z:289[ M +1]]⁺。

EXAMPLE 1 preparation of Compounds 1a and 1b

Step 1, 1-1a preparation

Intermediate Z1(138mg, 508.57. mu. mol), EDCI (117.17mg, 610.28. mu. mol), DIPEA (328.63mg, 2.54mmol, 442.90. mu.L), HOAt (83.00mg, 610.28. mu. mol) and intermediate o-benzeneDiamine Z2a (128.16mg, 508.57. mu. mol) was added to DCM (3mL) in sequence, the reaction was carried out at room temperature for 1 hour, water was added for quenching, most of the organic solvent was removed under reduced pressure, ethyl acetate (20 mL. times.3) was extracted, the organic phases were combined, washed with saturated ammonium chloride and saturated common salt, respectively, dried over anhydrous sodium sulfate, dried under reduced pressure, and the crude product was purified and separated by silica gel column chromatography to give a mixture of structural isomers of intermediate 1-1a (142mg, 281. mu. mol, 55% yield), MS M/Z:506(M +1)⁺And the two were not separated and used for the next step.

Step 2, 1-2a preparation

The mixture of structural isomers of intermediate 1-1a (142mg, 281. mu. mol) was added to AcOH (2mL), reacted at 55 ℃ for 12h, concentrated under reduced pressure, spun dry, and taken up with saturated NaHCO₃Adjusting pH of the solution to be alkalescent, extracting with DCM (10X 2), and extracting with anhydrous Na₂SO₄Drying and spin-drying gave crude 1-2a (141mg, 279. mu. mol, 99.35% yield) which was used in the next step without purification, MS m/z:506(M +1)⁺。

Step 3, 1-3a preparation

Dissolving the intermediate 1-2a (141mg,279 mu mol) in DCM (3mL), dropwise adding TFA (1.5mL) under ice bath, continuously stirring and reacting for 1h under ice bath, and concentrating under reduced pressure to obtain a crude product of the intermediate 1-3a, wherein the MS m/z: 406(M +1)⁺And directly used for the next reaction without purification.

Step 4, 1-4a preparation

Adding HBTU (87.00mg,342.70 mu mol) and DIPEA (102.21mg,790.84 mu mol,137.75 mu L) into DCM (3mL) solution of 1-methyl-1H-pyrazole-5-carboxylic acid (36.57mg,289.97 mu mol) in sequence, adding crude intermediate 1-3a in the previous step after 15min, reacting for 2H at room temperature, adding water for quenching, extracting with ethyl acetate (20mL) 3, combining organic phases, washing with saturated ammonium chloride and saturated common salt water respectively, drying with anhydrous sodium sulfate, performing reduced pressure spin drying, purifying and separating the crude product by MPLC reversed-phase 18 column chromatography (acetonitrile/0.05% water 0-40%) to obtain 1-4a (97mg,195 mu mol, 70% yield), MS m/z: 496(M +1)⁺。

Step 5, 1-5a preparation

To a mixture of 1-4a (97mg, 195. mu. mol) in MeOH (1mL) and water (0.1mL) was added NaOH (62mg, 1.56mmol) and the mixture was reacted at 80 deg.CAfter 10 h, LC-MS showed the starting material had reacted, adjusted pH to 4 with 1N HCl, extracted with DCM (10 ml. times.2), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude intermediate 1-5a (82mg, 176. mu. mol, 90% yield), MS M/z:468[ M +1]]⁺And directly used for the next reaction without purification.

Step 6, preparation of Compound 1a

HBTU (24.36mg,64.29 μmol), DIPEA (19.17mg,148.36 μmol,25.84 μ L) are sequentially added into a DCM (1mL) solution of an intermediate 1-5a (23.4mg,50 μmol), an intermediate Z15(64.29 μmol) is added after 15min, the reaction is carried out at room temperature for 1h, the concentration is carried out under reduced pressure, and the crude product is purified and separated by MPLC reversed-phase C18 column chromatography (acetonitrile/0.05% water is 0-40%) to obtain a compound 1a (20mg,35 μmol, 70% yield), MS m/Z: 565(M +1)⁺. The nuclear magnetic data is¹H NMR (400MHz,Methanol-d₄)δ7.58(s,1H),7.52(d,J＝8.5Hz,1H),7.49(d,J＝2.1Hz,1H),7.27(dd, J＝8.6,1.7Hz,1H),7.09(d,J＝8.9Hz,1H),6.95(d,J＝2.1Hz,1H),5.09(d,J＝8.6Hz,1H), 4.08(s,3H),4.01–3.88(m,J＝4.7Hz,2H),3.73(d,J＝9.5Hz,1H),3.46(d,J＝5.0Hz,2H), 3.39(s,3H),2.56–2.42(m,1H),2.11–1.97(m,3H),1.94–1.87(m,1H),1.87–1.80(m,2H), 1.80–1.76(m,2H),1.74–1.67(m,1H),1.59(s,3H),1.48–1.42(m,1H),1.38–1.34(m,1H), 1.26–1.05(m,3H),1.05–0.98(m,1H),0.98–0.93(m,1H),0.90(d,J＝6.5Hz,4H).

Similarly, compound 1b can be obtained by the same route as above using intermediates Z1 and Z2b as starting materials.

Examples 2 to 18, preparation of Compounds 2a/2b to 18a/18b

The compounds in the following table can be obtained by reacting intermediates 1 to 5a and 1 to 5b with the corresponding condensation starting materials in the table, respectively, according to the procedure of example 1.

EXAMPLE 19 preparation of Compounds 19a, 19b

Referring to example 1, a method for preparing compound 1a, using intermediate Z1 and intermediate Z3a as raw materials, via a similar synthetic route, comprises condensation, imidazole ring closing, Boc removal protection, introduction of 1-methyl-1H-pyrazole-5-acyl, ester hydrolysis, condensation with amine Z25, and finally Fmoc removal with lithium hydroxide, to obtain compound 19 a. Similarly, compound 19b can be obtained by the same procedure starting from intermediate Z1 and intermediate Z3b, MS m/Z: 563(M +1)⁺. Nuclear magnetic hydrogen spectrum of compound 19 a:¹H NMR(400MHz,Methanol-d₄)δ8.54(s,1H),7.58(s,1H),7.53(d,J＝8.5Hz,1H),7.47(d,J＝ 2.1Hz,1H),7.24(dd,J＝8.5,1.8Hz,1H),6.93(d,J＝2.2Hz,1H),5.05(d,J＝8.6Hz,1H),4.67 (d,J＝8.6Hz,1H),4.05(s,3H),4.02–3.94(m,4H),2.95–2.85(m,1H),2.84–2.74(m,1H), 2.68(dd,J＝12.9,9.6Hz,1H),2.57–2.50(m,1H),2.49(s,3H),2.34–2.21(m,1H),2.09–1.90 (m,3H),1.82–1.55(m,6H),1.49–1.25(m,4H),1.24–0.91(m,4H),0.88(d,J＝6.5Hz,3H).

example 20 preparation of Compound 20

Reference example 1 preparation of Compound 1a starting from Boc-D-cyclohexylglycine and intermediate Z8 by a similar synthetic route via condensation, imidazole ring closure, Boc protection removal,Introducing 1-methyl-1H-pyrazole-5-acyl, hydrolyzing ester, condensing with an intermediate Z19 protected by Fmoc, and removing Fmoc to obtain a compound 20, wherein MS m/Z: 520(M +1)⁺。¹H NMR(400MHz,Methanol-d₄)δ7.80(s,1H),7.72(d,J＝8.7Hz,1H),7.57(dd,J＝8.6,1.7Hz, 1H),7.49(d,J＝2.1Hz,1H),7.04(d,J＝2.1Hz,1H),5.17(dd,J＝8.7,2.8Hz,1H),4.10–4.04 (m,1H),4.03(s,3H),2.94(dd,J＝13.2,3.3Hz,1H),2.79(dd,J＝13.1,9.6Hz,1H),2.44–2.18 (m,2H),2.11–1.95(m,2H),1.89–1.70(m,7H),1.69(s,3H),1.62(s,3H),1.57–0.99(m,7H).

Examples 21 to 83, preparation of Compounds 21 to 83

Method A the corresponding compounds in the following table were obtained by condensation of the corresponding amines in the following table with 20-5a acid according to the method of step 6 and step 7 in the preparation of example 20.

Method B first step, the condensation of the corresponding amine in the following Table with 20-5a acid, according to the methods of steps 6 and 7 of the preparation of example 20; in the second step, referring to the Fmoc removal operation in step 3 of the synthetic route of intermediate Z18, the condensation product replaces intermediate Z18-2, and the rest of the procedures are the same, so that the corresponding compounds in the table can be obtained.

The method C comprises the following steps: the first step, referred to the method of steps 6 and 7 in the preparation of example 20, was condensation of the corresponding amine in the following table with 20-5a acid; in the second step, referring to the procedure of removing Boc in step 8 of intermediate Z16, the above condensation product was used in place of intermediate Z16-8, and the same procedure was followed to obtain the final product.

The compounds in the table are prepared by the method A without specific indication.

Example 84 preparation of Compound 84

To a solution of compound 21(50mg, 86.84. mu. mol) in DMF (1mL) under ice bath was added TEA (17.58mg, 173.69. mu. mol,24 in sequence.23 μ L) and 1- [ [ (4-nitrophenoxy) carbonyl]Oxy radical]And (3) ethyl 2-methylpropionate, and stirring the mixed solution at zero degree to react for 2 hours after the reaction is finished. The mixture was subjected to PreHPLC (ACN/H)₂O,0.05％NH₄HCO₃) Isolation and purification gave compound 84(20mg,26.84 μmol, 30.91% yield, 98.5% purity), MS m/z: 734(M +1) +. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ7.66–7.53(m,1H),7.47(d,J＝2.1Hz,2H),7.26–7.16(m, 1H),6.93(dd,J＝2.1,0.7Hz,1H),6.74–6.54(m,1H),5.12–5.03(m,1H),4.69–4.57(m,1H), 4.13–4.08(m,1H),4.06(d,J＝1.1Hz,3H),4.00–3.86(m,3H),3.16–3.10(m,1H),2.92–2.80 (m,1H),2.74(d,J＝32.3Hz,3H),2.58–2.44(m,2H),2.33–2.22(m,1H),2.09–1.91(m,3H), 1.81–1.73(m,2H),1.72–1.62(m,4H),1.51–1.34(m,5H),1.23–1.16(m,2H),1.15–1.08(m, 8H),1.07–0.92(m,2H),0.88(d,J＝6.5Hz,3H).

example 85 preparation of Compound 85

To a solution of compound 20(60mg, 115.46. mu. mol) and carboxymethylcellulose (20.80mg, 115.46. mu. mol) in MeOH (0.3mL) at room temperature was added NaOAc.3H₂O (15.70mg, 115.46. mu. mol), and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated, and the crude product was subjected to mHPLC (ACN/H)₂O,0.05％NH₄HCO₃) Isolation and purification gave compound 85(13mg,18.01 μmol, 15.60% yield, 94.465% pure), MS m/z: 682(M +1) +. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ7.57(d,J＝30.1Hz,2H),7.47(d,J＝2.2Hz,1H),7.26 (dd,J＝8.6,1.7Hz,1H),6.98–6.90(m,1H),5.14–5.05(m,1H),4.06(s,3H),4.04–3.56(m, 6H),2.84–2.50(m,3H),2.48–2.37(m,1H),2.34–2.19(m,1H),2.18–2.05(m,1H),2.03– 1.88(m,2H),1.87–1.64(m,9H),1.60(dd,J＝6.6,4.2Hz,6H),1.49–0.98(m,7H).

example 86 preparation of Compound 86

Preparation of step 1, 86-1

To 20-2(1g,2.25mmol) of H at room temperature₂NaOH (450 mg, 11.27mmol) was added to the O (3mL)/EtOH (15mL) mixture and the mixture was warmed to 80 ℃ and stirred for 18 h. After the reaction, water was added to dilute the reaction solution, and ethyl acetate was added for extraction. The separated aqueous phase was adjusted to pH 4-5 with 3N HCl, then extracted with ethyl acetate and the separated organic phase was concentrated to give crude compound 86-1(0.9g,2.17mmol, 96.08% yield) which was used in the next reaction without further purification. MS m/z: 416(M +1) +.

Preparation of step 2, 86-2

HBTU (450.58mg,1.19mmol) and DIPEA (354.57mg,2.74mmol, 477.86. mu.L) were added to a solution of 86-1(380mg, 914.51. mu. mol) in DCM (6mL), stirred at room temperature for 30min, added intermediate Z-15(136.92 mg,1.19mmol), and the reaction was stirred for an additional 2 h. After completion of the reaction, the reaction was spun down and the crude product was isolated and purified by mHPLC (TFA (0.005%)/H₂O, ACN) to give compound 86-2(136.92mg,1.19mmol), MS m/z: 513(M +1)⁺。

Preparation of step 3, 86-3

To a solution of 86-2(62.50mg, 109.72. mu. mol) in DCM (1.5mL) was added (1.54g,13.51mmol, 1mL) at zero degrees, and the reaction mixture was stirred at zero degrees for 1 hour. The mixture was concentrated to give crude 86-3(56mg, 106.34. mu. mol, 96.93% yield, TF), MS m/z: 413(M +1)⁺。

Step 4, 86 preparation

HBTU (17.91mg, 47.27. mu. mol) and DIPEA (14.10mg, 109.07. mu. mol, 19.00. mu.L) were added to a solution of 86-3(15mg, 36.36. mu. mol) and 5-methylisoxazolecarboxylic acid (5.08mg, 39.99. mu. mol) in DCM (0.5mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was spun down and the crude product was isolated and purified by mHPLC (FA (0.005%)/H2O, ACN) to give compound 86(4mg, 7.67. mu. mol, 21.09% yield), MS m/z: 522(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ8.82(s,1H),7.59(d,J＝1.8 Hz,1H),7.51(d,J＝8.5Hz,1H),7.30–7.22(m,1H),6.50(d,J＝9.0Hz,1H),5.08(d,J＝8.4Hz, 1H),3.95–3.85(m,1H),3.41–3.37(m,2H),2.63(s,3H),2.38(s,1H),2.18(s,1H),2.14–2.04 (m,1H),1.93(s,2H),1.84–1.65(m,11H),1.60(d,J＝12.1Hz,7H),1.45(d,J＝12.6Hz,1H), 1.41–1.01(m,8H).

examples 87 to 102, preparation of Compounds 86 to 102

Referring to the procedure for Synthesis step 4 of example 86, a carboxylic acid in the following table was used in place of 5-methylisoxazole carboxylic acid to condense with intermediate compound 86-3 to give the corresponding compound in the table.

Example 103 preparation of Compound 103

To a solution of 86-3(30mg, 72.72. mu. mol) in DMA (1mL) was added CDI (31.40mg, 218.15. mu. mol) and Et₃N (36.72mg, 363.58. mu. mol), the mixture was warmed to 80 ℃ under nitrogen and stirred overnight, then (cyclopropylmethyl) methylamine (30.96mg, 363.58. mu. mol) was added and the reaction was stirred for an additional 3 hours. Reaction solution throughHplc (ACN/0.05% FA) to give crude product, and pre.hplc to give compound 103(11mg,20.47 μmol, 28.15% yield, 97.46% purity), MS m/z: 524(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz, Methanol-d4)δ7.73(d,J＝1.7Hz,1H),7.68(d,J＝8.7Hz,1H),7.55(dd,J＝8.7,1.7Hz,1H), 6.82(d,J＝9.0Hz,1H),3.93(tt,J＝9.7,5.7Hz,1H),3.46(dd,J＝11.3,4.1Hz,1H),3.38(dd,J＝11.3,6.0Hz,2H),3.17(dd,J＝6.7,1.6Hz,2H),3.04(s,3H),2.45–2.33(m,1H),2.17–2.07(m, 1H),2.05–1.95(m,2H),1.86–1.79(m,3H),1.79–1.70(m,5H),1.64(s,3H),1.62(s,3H),1.41 –0.92(m,9H),0.49(d,J＝8.0Hz,2H),0.21(t,J＝5.3Hz,2H).

example 104 preparation of Compound 104

Referring to the procedures of steps 4 to 7 of the synthetic route of example 20, the same procedures were repeated except for using 1-methyl-1H-1, 2, 4-triazole-5-carboxylic acid in place of 1-methyl-1H-pyrazole-5-acyl group in step 4 to give compound 104, MS m/z: 521(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,MeOD)δ7.99(s,1H),7.82–7.62(m,2H),7.63–7.44(m,1H), 7.18(d,J＝8.2Hz,1H),5.24(d,J＝7.9Hz,1H),4.15(s,3H),4.05(dd,J＝17.3,7.4Hz,1H),3.00 –2.86(m,2H),2.78(dd,J＝13.1,9.6Hz,1H),2.45–2.18(m,3H),2.07–1.08(m,27H).

example 105 preparation of Compound 105

Referring to the procedure from step 2 to step 4 of the synthetic route of example 86, substituting intermediate Z19 for form Z15 in step 2 and 3, 5-dimethylisoxazole-4-carboxylic acid for 5-methylisoxazole-4-carboxylic acid in step 4, the same procedure was followed to give compound 105-3, hydrolyzing Fmoc with LiOH to give compound 105, MS m/Z: 535(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ8.53(s,1H),7.60(s,1H),7.51(d,J＝8.6Hz,1H),7.36–7.18 (m,1H),5.08(d,J＝8.7Hz,1H),4.00–3.85(m,1H),2.84–2.71(m,1H),2.62–2.54(m,1H), 2.52(d,J＝1.0Hz,3H),2.32(d,J＝1.0Hz,3H),2.28(d,J＝8.2Hz,1H),2.07(d,J＝10.2Hz,1H), 1.97(d,J＝11.4Hz,2H),1.87–1.78(m,2H),1.73(d,J＝16.1Hz,5H),1.65(s,3H),1.60(s,3H), 1.41(d,J＝13.2Hz,1H),1.37–1.14(m,5H),1.14–1.02(m,1H).

example 106 preparation of Compound 106

Referring to the procedures of steps 1 to 4 of the synthetic scheme of example 86, acid condensation of Z19 with 106-1 was replaced by intermediate Z22 in step 2, Cbz protecting group was removed with Pd/C in step 3, condensation of 3-methylisoxazole-4-carboxylic acid in place of 5-methylisoxazole-4-carboxylic acid 106-3 in step 4 gave intermediate 106-4, and finally Boc protecting group removal with TFA gave compound 106, MS m/Z: 535(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ8.56(d,J＝ 1.2Hz,1H),7.80(d,J＝1.6Hz,1H),7.73(d,J＝8.7Hz,1H),7.58(dd,J＝8.7,1.7Hz,1H),5.25 (d,J＝8.1Hz,2H),4.34–4.20(m,1H),3.00–2.80(m,3H),2.14(d,J＝1.1Hz,3H),2.11–1.81 (m,7H),1.74(d,J＝4.5Hz,7H),1.63(s,4H),1.56–1.05(m,9H),0.93(s,3H).

example 107 preparation of Compound 107

Referring to the procedures of step 4 and step 5 of the synthetic route of example 106, compound 107, MS m/z: 535(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ9.25(s,1H),7.83(d,J＝1.7Hz,1H),7.73(d,J ＝8.7Hz,1H),7.58(dd,J＝8.7,1.7Hz,1H),5.15(d,J＝8.0Hz,1H),4.27(ddt,J＝9.5,5.7,2.8Hz, 1H),2.90(qd,J＝13.3,6.8Hz,2H),2.36(s,3H),2.18(ddt,J＝13.1,9.1,4.9Hz,1H),2.05(d,J＝ 12.1Hz,2H),2.00–1.81(m,5H),1.81–1.68(m,7H),1.63(s,4H),1.54–1.16(m,8H),1.09(qd, J＝12.2,3.4Hz,1H),0.93(s,3H).

EXAMPLE 108 preparation of Compound 108

Referring to the procedures of step 4 and step 5 of the synthetic route of example 106, compound 108 was obtained by removing the Boc protecting group under TFA conditions in step 4 using 1-methyl-1H-1, 2, 4-triazole-5-carboxylic acid instead of 3-methylisoxazole-4-carboxylic acid: 535(M +1) +. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ7.99(s,1H),7.75(d,J＝1.6Hz,1H), 7.68(d,J＝8.7Hz,1H),7.52(dd,J＝8.6,1.7Hz,1H),5.23(d,J＝7.9Hz,1H),4.28–4.20(m, 1H),4.16(s,3H),2.97–2.80(m,2H),1.89(dddd,J＝24.8,16.7,11.1,7.2Hz,6H),1.77(d,J＝ 12.7Hz,2H),1.73(s,4H),1.63(s,4H),1.53(d,J＝12.6Hz,1H),1.49–1.06(m,7H),0.91(s, 3H).

example 109 preparation of Compound 109

Referring to the procedure of synthetic route example 1, steps 1 to 6, the starting material in step 1 was changed to 2- (((benzyloxy) carbonyl) amino) -2- (tetrahydro-2H-pyran-2-yl) acetic acid and intermediate Z8, and example compound 109.MS m/Z: 523(M +1) +. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.60(d,J＝ 4.1Hz,2H),7.54–7.46(m,4H),7.27(d,J＝1.4Hz,1H),7.25(d,J＝1.7Hz,1H),6.97(dd,J＝ 2.1,0.8Hz,1H),6.92(dd,J＝2.1,0.7Hz,1H),6.48(d,J＝8.9Hz,2H),5.35(d,J＝4.9Hz,1H), 5.32(d,J＝6.2Hz,1H),4.09(s,3H),4.07(s,3H),4.05–3.83(m,9H),3.59–3.37(m,11H),2.58 –2.46(m,2H),2.43–2.31(m,2H),2.09–1.65(m,30H),1.62(s,6H),1.59(s,6H),1.57–1.43 (m,8H).

example 110 preparation of Compound 110

Referring to the synthetic route for example 109, example compound 110 can be prepared by condensing 2- ((tert-butoxycarbonyl) amino) -2- (4, 4-difluorocyclohexyl) acetic acid with intermediate Z8 in step 1 and proceeding analogously to the remaining steps: 523(M +1) +. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.48(d,J＝2.1Hz,1H),7.27(dd,J＝8.5,1.8Hz, 1H),6.93(d,J＝2.2Hz,1H),6.50(d,J＝9.0Hz,1H),5.20(d,J＝8.6Hz,1H),4.08(s,3H),3.89 (tt,J＝9.4,4.8Hz,1H),3.39(t,J＝5.1Hz,2H),2.45–1.66(m,7H),1.62(s,3H),1.59(s,3H), 1.53–1.05(m,6H),1.03–0.76(m,4H).

example 111 preparation of Compound 111

Referring to the procedure of synthetic schemes step 1 through step 6 of example 1, starting from 2- (adamantan-1-yl) -2- ((tert-butoxycarbonyl) amino) acetic acid and intermediate Z8 in step 1, through similar steps, intermediate Z22 was condensed in step 5 to afford compound 111-6, which was then deprotected with TFA in DCM to afford compound 111 of example, MS m/Z: 700(M +1) +. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ7.84(s,1H),7.75 (d,J＝8.7Hz,1H),7.59(d,J＝8.8Hz,1H),7.54–7.45(m,1H),7.13(s,1H),6.88(d,J＝8.8Hz, 1H),5.16(s,1H),4.01(s,3H),2.97–2.81(m,2H),2.06(s,3H),2.01–1.86(m,4H),1.82(d,J＝ 13.3Hz,5H),1.74(t,J＝8.9Hz,12H),1.64(s,5H),1.52–1.37(m,1H),0.93(s,3H).

example 112 to example 119, preparation of compound 112 to compound 119

Referring to the synthetic route of example 111, the corresponding example compounds in the table can be prepared by condensing Z8 with only the Boc-protected amino acid in the table in step 1 instead of 2- (adamantan-1-yl) -2- ((tert-butoxycarbonyl) amino) acetic acid, with the remaining steps being identical.

Example 119 preparation of Compound 119

DMAP (493.99ug, 4.04. mu. mol) and EDCI (5.79mg, 30.33. mu. mol) were added to a solution of (S) -2- (tert-butoxycarbonylamino) -3-methylbutyric acid (4.39mg, 20.22. mu. mol) in DCM (1mL) at room temperature, and the mixture was stirred at room temperature for 15min and then 22(10mg, 20.22. mu. mol) was added. The reaction solution is stirred and reacted for 2 hours at room temperature. After completion of the reaction, aqueous NaHCO3 was added for dilution, extracted with DCM, and the combined organic phases were dried to give the crude product which was isolated and purified by mhhplc (ACN/H2O/TFA (TFA ═ 0.05%) to give compound 119(6mg,8.65 μmol, 42.77% yield), MS m/z: 694(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ7.78–7.64(m,2H),7.55– 7.46(m,2H),7.08–6.93(m,2H),5.15(d,J＝8.1Hz,1H),4.27–4.14(m,1H),4.04(s,4H),4.02 –3.93(m,1H),3.85(d,J＝5.9Hz,1H),2.27–2.13(m,1H),2.09–1.93(m,2H),1.85(d,J＝13.3 Hz,1H),1.81–1.68(m,2H),1.63(d,J＝5.1Hz,6H),1.59–1.47(m,3H),1.37(s,12H),1.33– 1.15(m,4H),1.15–1.01(m,1H),0.93–0.77(m,10H).

example 120 preparation of Compound 120

Referring to the synthetic route of example 109,(s) -2-amino-2- (spiro [2.5 ] was used in step 1]Octyl-6-yl) acetic acid was condensed with intermediate Z8, and the remaining procedure was analogous to that described for example compound 120, MS m/Z: 547(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ7.70(d,J＝1.6Hz,1H),7.64(d,J＝8.7Hz,1H),7.49 (d,J＝2.2Hz,1H),7.47(dd,J＝8.6,1.7Hz,1H),7.00(d,J＝2.2Hz,1H),6.72(d,J＝8.9Hz,1H), 5.20(d,J＝8.3Hz,1H),4.05(s,3H),3.97–3.87(m,1H)3.49–3.34(m,2H),2.45–2.31(m,1H), 2.31–2.17(m,1H),2.07–1.90(m,2H),1.90–1.66(m,7H),1.62(d,J＝8.7Hz,6H),1.48(d,J＝ 12.4Hz,1H),1.31(dqd,J＝48.5,12.4,3.8Hz,2H),1.01(d,J＝13.4Hz,1H),0.93(d,J＝13.4Hz, 1H),0.29(m,2H),0.21(m,2H).

example 121 preparation of Compound 121

Referring to the synthetic route of example 1, in step 1, starting from(s) -2- ((tert-butoxycarbonyl) amino) -2-cyclohexylacetic acid and intermediate Z11, the analogous synthetic procedure, ring closure, de-Boc, condensation of N-methylpyrazole acid, hydrolysis of ethyl ester and final condensation of (R) -2-aminobutan-1-ol gave example compound 121, MS m/Z: 513(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.50–7.44(m,1H),7.37(s,1H),7.03–6.91(m,2H), 6.77(d,J＝8.7Hz,1H),5.09(d,J＝8.7Hz,1H),4.29(s,1H),4.06(s,3H),3.81(tq,J＝10.5,5.6 Hz,1H),3.44(qd,J＝10.9,5.4Hz,2H),3.31(s,3H),2.16–2.03(m,1H),1.97(d,J＝12.8Hz, 1H),1.76(dd,J＝29.2,9.7Hz,2H),1.69(d,J＝5.8Hz,2H),1.59(d,J＝6.1Hz,7H),1.38 (dtd,J＝44.4,14.6,13.8,7.3Hz,3H),1.25(s,4H),1.12(ddd,J＝36.2,16.8,10.3Hz,1H),0.98 (t,J＝7.4Hz,1H),0.82(t,J＝7.4Hz,3H).

example 122 preparation of Compound 122

Example compound 122 was prepared by condensation of intermediate 121-5 with Z15 according to the procedure for the preparation of example 121, step 6. MS m/z: 539(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.71-7.61(m,1H),7.47 (d,J＝2.2Hz,1H),7.37(s,1H),7.03–6.91(m,2H),6.65(d,J＝9.0Hz,1H),5.09(d,J＝8.8 Hz,1H),4.29(t,J＝6.6Hz,1H),4.06(s,3H),3.98–3.85(m,1H),3.40(qd,J＝11.2,4.9Hz,2H), 2.39(tq,J＝15.4,8.8,8.1Hz,1H),2.14(s,1H),2.02–1.92(m,3H),1.87–1.76(m,4H),1.79– 1.63(m,4H),1.59(d,J＝12.7Hz,5H),1.52–1.20(m,2H),1.24–1.19(m,1H),1.23–1.05(m, 1H),0.98(t,J＝7.4Hz,1H).

examples 123 and 124, preparation of Compounds 123 and 124

Step 1, preparation of example 123

By condensing intermediate 121-5 with (R) methyl 2-amino-2-cyclobutyl acetate according to the synthesis procedure of step 6 of example 121, example 123, MS m/z: 539(M +1)⁺。

Step 2, preparation of example 124

Compound 123(15mg,26.47 μmol) was dissolved in MeOH (5mL), NaOH (21.17mg,529.41 μmol) was added, the reaction was stirred at room temperature overnight, after completion of the reaction, the solvent was removed under reduced pressure, the crude product was dispersed in 1M HCl and EA solution, the separated EA layer was concentrated, and the crude product was isolated and purified by Pre-HPLC to give example compound 124(6mg,0.01mmol, yield 36.8%) as a white solid MS M/z: 553(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ 7.49(dd,J＝6.6,1.8Hz,2H),7.28–7.16(m,1H),7.00(d,J＝2.2Hz,1H),5.12(d,J＝8.3Hz, 1H),4.33(dd,J＝8.9,3.2Hz,1H),4.04(s,3H),2.65(dt,J＝16.7,8.1Hz,1H),2.24–2.11(m,1H), 2.03(ddt,J＝12.2,8.1,3.7Hz,2H),2.02–1.78(m,2H),1.80–1.65(m,3H),1.62(s,6H),1.47 (d,J＝12.7Hz,1H),1.44–0.93(m,6H).

example 125 preparation of Compound 125

Referring to the synthetic route to example 121, in step 1, intermediate Z9 was substituted for intermediate Z11, and the remaining reagent methods were unchanged to give compound 125, MS m/Z: 513(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄) δ7.69–7.55(m,1H),7.47(d,J＝2.1Hz,1H),7.24(s,1H),6.93(d,J＝2.1Hz,1H),6.61(d,J＝ 8.7Hz,1H),5.07(d,J＝8.8Hz,1H),4.06(s,3H),3.83–3.74(m,1H),3.53–3.45(m,1H), 3.41–3.35(m,1H),2.87(s,1H),2.19–2.06(m,1H),2.03–1.92(m,1H),1.86–1.78(m,1H), 1.75–1.66(m,2H),1.65–1.52(m,7H),1.49–1.41(m,1H),1.38–1.28(m,3H),1.27–1.16(m, 2H),1.16–1.05(m,1H),0.86(t,J＝7.4Hz,4H).

example 126 preparation of Compound 126

Referring to the synthetic route for example 121, substituting intermediate Z10 for intermediate Z11 in step 1, the same reagents are followed to give example compound 126, MS m/Z: 513(M +1)⁺。

Examples 127 and 128, preparation of Compounds 127 and 128

Step 1, preparation of intermediate 127-1

HBTU (1.63g,4.30 mmol) and DIPEA (1.28g,9.92mmol,1.73mL) were added to a solution of 20-5a (1.4g,3.31mmol) in DMF (15mL) under ice-bath, the mixture was stirred at 0 ℃ for 10min, then tert-butyl carbazate (655.33mg,4.96mmol) was added, the reaction was warmed to room temperature and stirred for 3 h. After the reaction is finished, the solvent is removed by rotation, and the crude product is separated and purified by mHPLC to obtain an intermediate127-1(1.1g,2.05mmol, 61.89% yield), MS m/z: 538(M +1)⁺。

Step 2, preparation of intermediate 127-2

127-1(580mg,1.08mmol) was dissolved in HCl/EA (4M,7mL) solution at room temperature, the mixture was stirred at room temperature for 30min, after completion of the reaction, the solvent was removed by rotation to give intermediate 127-2(485mg,1.02mmol, 94.85% yield), MS M/z: 438(M +1)⁺。

Preparation of step 3, examples 127 and 128

To a solution of 127-2(80mg, 168.78. mu. mol) in EtOH (8mL) was added methyl cyclobutanecarbamate hydrochloride (30.30mg, 202.53. mu. mol) and TEA (85.39mg, 843.89. mu. mol, 117.70. mu.L) at room temperature, and the reaction mixture was warmed to 90 ℃ and stirred overnight. After completion of the reaction, the reaction solution was spun off, and the crude product was isolated and purified by PreHPLC to give example compound 127(8.7mg, 16.20. mu. mol, 9.60% yield, 93.2% purity), MS m/z: 501(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ7.71–7.63(m,2H),7.50(d,J＝2.1Hz,1H),7.46(dd,J＝8.7, 1.8Hz,1H),7.03(d,J＝2.2Hz,1H),5.16(d,J＝8.0Hz,1H),4.03(s,3H),3.75–3.62(m,1H), 2.43–2.29(m,4H),2.27–2.16(m,1H),2.18–2.06(m,1H),2.07–1.99(m,1H),2.00–1.88(m, 1H),1.85(m,7H),1.81–1.63(m,2H),1.52(d,J＝12.7Hz,1H),1.45–1.28(m,2H),1.29–1.12 (m,2H),1.15–1.00(m,1H).

and example compound 128(9mg,17.10 μmol, 10.13% yield 95.3% purity). MS m/z: 502(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ7.77–7.60(m,2H),7.57–7.39(m,2H),7.00(d, J＝2.2Hz,1H),5.15(d,J＝8.1Hz,1H),4.04(s,3H),3.76–3.64(m,1H),2.45–2.28(m,4H), 2.27–2.16(m,1H),2.11(m,1H),2.06–1.92(m,2H),1.88(m,7H),1.74(m,2H),1.53(m,1H), 1.43–1.25(m,3H),1.25–1.02(m,3H).

example 129 preparation of Compound 129

Intermediate 127-2(74mg, 156) was added under ice-bath12. mu. mol) was added to a solution of TEA (47.39mg, 468.36. mu. mol, 65.32. mu.L) in DCM (5mL), p-nitrophenyl chloroformate (34.61mg, 171.73. mu. mol) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed by evaporation and the crude product was isolated and purified by mHPLC to give compound 129(11.7 mg,24.31 μmol, 15.57% yield, 96.3% purity). MS m/z: 502(M +1)⁺. Nuclear magnetic data:¹H NMR(400 MHz,Methanol-d4)δ7.74–7.66(m,2H),7.54–7.48(m,2H),7.01(d,J＝2.2Hz,1H),5.16(d,J ＝8.0Hz,1H),4.04(s,3H),2.29–2.15(m,1H),2.02(m,1H),1.84(m,1H),1.76(m,8H),1.54(m, 1H),1.43–1.28(m,2H),1.28–1.14(m,2H),1.08(m,1H).

example 130 preparation of Compound 130

Referring to the procedure of step 6 of the synthetic route to example 19, substituting Z16 for Z25 and the same procedure was followed to give example compound 130, MS m/Z: 577(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.63(d,J＝ 1.7Hz,1H),7.56(d,J＝8.4Hz,1H),7.50(d,J＝2.1Hz,1H),7.29(dd,J＝8.5,1.8Hz,1H),6.95 (d,J＝2.1Hz,1H),6.83(d,J＝9.4Hz,1H),5.10(d,J＝8.6Hz,1H),4.69(d,J＝8.5Hz,1H),4.08 (s,3H),4.05–3.97(m,4H),3.53(dd,J＝11.4,4.0Hz,1H),3.40(dd,J＝11.4,7.8Hz,1H),2.89 (dt,J＝12.5,6.1Hz,1H),2.57(dt,J＝12.6,7.9Hz,1H),2.13–1.96(m,2H),1.92–1.67(m,5H), 1.63–1.25(m,6H),1.23–0.96(m,4H),0.94(s,3H),0.91(d,J＝6.5Hz,3H).

example 131 preparation of Compound 131

Referring to the synthesis of example 19, intermediate Z19 was substituted for intermediate Z25 in step 6, the same procedure was followed, and Fmoc was finally removed to give example compound 131, MS m/Z: 562(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz, Methanol-d₄)δ8.54(s,1H),7.58(s,1H),7.53(d,J＝8.4Hz,1H),7.47(s,1H),7.25(d,J＝10.2 Hz,1H),6.93(d,J＝2.2Hz,1H),5.06(d,J＝8.6Hz,1H),4.66(d,J＝8.5Hz,1H),4.05(s,3H), 4.03–3.93(m,3H),3.93–3.85(m,1H),2.94–2.84(m,1H),2.78(dd,J＝13.2,3.6Hz,1H), 2.67–2.56(m,1H),2.56–2.46(m,1H),2.35–2.24(m,1H),2.10–1.89(m,3H),1.82–1.56(m, 6H),1.52–1.43(m,1H),1.42–1.36(m,1H),1.35–1.29(m,1H),1.25–0.90(m,4H),0.88(d,J＝ 6.5Hz,3H).

example 132 preparation of Compound 132

Referring to the synthesis of example 19, the same procedure was followed, substituting intermediate Z15 for intermediate Z25 in step 6, to give example compound 132, MS m/Z: 563(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄) δ7.61(s,1H),7.55(d,J＝8.5Hz,1H),7.49(d,J＝2.1Hz,1H),7.27(dd,J＝8.5,1.8Hz,1H), 7.00(d,J＝9.0Hz,1H),6.95(d,J＝2.2Hz,1H),5.10(d,J＝8.6Hz,1H),4.63(d,J＝8.5Hz,1H), 4.08(s,3H),4.02–3.97(m,3H),3.93–3.85(m,1H),3.46–3.35(m,2H),2.93–2.83(m,1H), 2.54–2.45(m,1H),2.42–2.33(m,1H),2.10–2.04(m,1H),2.04–1.98(m,1H),1.95–1.90(m, 1H),1.83–1.55(m,8H),1.25–1.08(m,3H),1.07–0.92(m,3H),0.90(d,J＝6.5Hz,3H).

example 133 preparation of Compound 133

To a solution of compound 19a (50mg, 86.84. mu. mol) in DMF (1mL) under ice-cooling was added TEA (17.58mg, 173.69. mu. mol, 24.23. mu.L), and the mixture was stirred at zero temperature for 2 hours. The reaction solution was separated and purified by Pre.HPLC (ACN/H)₂O, 0.05％NH₄HCO₃) Example compound 133(20mg,26.84 μmol, 30.91% yield, 98.5% purity), ms (esi) M/z 734(M +1) was obtained⁺Nuclear magnetic data：¹H NMR(400MHz,Methanol-d₄)δ7.66–7.53(m,1H),7.47 (d,J＝2.1Hz,2H),7.26–7.16(m,1H),6.93(dd,J＝2.1,0.7Hz,1H),6.74–6.54(m,1H),5.12– 5.03(m,1H),4.69–4.57(m,1H),4.13–4.08(m,1H),4.06(d,J＝1.1Hz,3H),4.00–3.86(m, 3H),3.16–3.10(m,1H),2.92–2.80(m,1H),2.74(d,J＝32.3Hz,3H),2.58–2.44(m,2H),2.33 –2.22(m,1H),2.09–1.91(m,3H),1.81–1.73(m,2H),1.72–1.62(m,4H),1.51–1.34(m,5H), 1.23–1.16(m,2H),1.15–1.08(m,8H),1.07–0.92(m,2H),0.88(d,J＝6.5Hz,3H).

Example 134 preparation of Compound 134

Referring to the method of steps 1 to 4 of the synthetic route of example 86, step 1 starting from intermediate 19-2a was hydrolyzed, condensed to intermediate Z16, deprotected to Boc, and finally reacted with methyl chloroformate to give compound 134, ms (esi) M/Z527 (M +1)⁺Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.61(d,J＝2.0Hz,1H),7.54(d,J＝ 8.4Hz,1H),7.28(dd,J＝8.4,1.8Hz,1H),6.81(d,J＝9.4Hz,1H),4.70(d,J＝8.6Hz,2H),4.07– 3.92(m,4H),3.66(s,3H),3.53(dd,J＝11.4,4.1Hz,1H),3.41(dd,J＝11.4,7.8Hz,1H),2.89 (dt,J＝12.4,6.1Hz,1H),2.57(dt,J＝12.7,7.9Hz,1H),1.96–1.64(m,7H),1.64–1.46(m,2H), 1.45–1.26(m,3H),1.23–1.08(m,2H),1.03–0.96(m,1H),0.94(s,3H),0.89(d,J＝6.5Hz, 3H).

example 135 preparation of Compound 135

By using 2- (adamantan-1-yl) -2- ((t-butoxycarbonyl) amino) acetic acid and intermediate Z8 as starting materials and by carrying out condensation and ring closure procedures according to the procedures of steps 1 and 2 of the synthetic route of example 1 to obtain intermediate 135-2, and then by hydrolyzing the ester and condensing the ester according to the syntheses of steps 1 to 6 of the synthetic route of example 86Intermediate Z16, followed by Boc removal and final condensation of N-methylpyrazole carboxylic acid, gave compound 135, MS (ESI) M/Z ═ 615(M +1)⁺Nuclear magnetic data:¹H NMR(400 MHz,Methanol-d₄)δ7.80–7.70(m,2H),7.61–7.51(m,2H),7.14–7.05(m,2H),5.12(s,1H), 4.64(d,J＝8.9Hz,1H),4.12–3.99(m,7H),3.57(dd,J＝11.4,3.9Hz,1H),2.94(dt,J＝12.6,6.4 Hz,1H),2.59–2.47(m,1H),2.07(s,3H),1.94-1.50(m,15H),1.36-1.30(m,2H),1.00(s,3H).

example 136 preparation of Compound 136

Step 1, preparation of intermediate 136-1

To a solution of intermediate 135-3(150mg, 302.66. mu. mol) in DCM (3mL) was added TFA (34.51mg, 302.66. mu. mol,2mL) under ice-bath, and the mixture was stirred at zero degrees for 1 h. The mixture was concentrated to give crude 136-1(140mg, 274.77. mu. mol, 90.79% yield, TF) which was used in the next reaction without purification. MS (ESI) M/z 396(M +1)⁺，

Step 2, preparation of intermediate 136-2

To a 136-1(140mg, 274.77. mu. mol, TF) mixture of THF (3mL)/H2O (3mL) was added NaHCO3(46.16mg, 549.54. mu. mol) and CbzOSU (68.48mg, 274.77. mu. mol) at zero degrees. The mixture was stirred at room temperature for 30 min. After completion of the reaction, water was added for dilution, pH was adjusted to 4-6 with 6N HCl, the mixture was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by evaporation to give intermediate 136-2(140mg,264.34 μmol, 96.20% yield), ms (esi) M/z ═ 530(M +1)⁺.

Step 3, preparation of intermediate 136-3

To 136-2(140mg, 264.34. mu. mol), Z22(72.43mg, 317.21. mu. mol) and HBTU (80.53mg, 317.21. mu. mol) in CH at room temperature₂Cl₂DIPEA (102.49mg, 793.01. mu. mol, 138.13. mu.L) was added to the solution (5 mL). The mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was concentrated, and the crude product was subjected to mHPLC (CH)₃CN/H₂O,0.05 percent TF) to obtainTo intermediate 136-3(170mg,229.75 μmol, 86.91% yield), ms (esi) M/z 740(M +1)⁺。

Step 4, preparation of intermediate 136-4

Pd/C (80mg, 658.71. mu. mol) was added to a solution of 136-3(170mg, 229.75. mu. mol) in MeOH (4mL), and after hydrogen substitution, the mixture was stirred at room temperature under hydrogen for 2 hours. After completion of the reaction, Pd/C was filtered off and the filtrate was concentrated to give intermediate 136-4(135mg,222.84 μmol, 96.99% yield), ms (esi) M/z 606(M +1)⁺。

Step 5, preparation of Compound 136

To a mixture of 136-4(135mg, 222.84. mu. mol) and 2-methylpyrazole-3-carboxylic acid (30.91mg, 245.13. mu. mol) in DCM (7 mL)/DMF (3mL) was added HBTU (73.54mg, 289.70. mu. mol) and DIPEA (86.40mg, 668.53. mu. mol). The mixture was stirred at room temperature for 1 hour under nitrogen protection. The mixture was quenched with 0.2ml meoh, concentrated under reduced pressure, and the crude product was isolated and purified by hplc (CH3CN/H2O, 0.05% TF) to give compound 136-6(80mg,112.06 μmol, 50.29% yield), ms (esi) M/z 714(M +1)⁺。

Step 6, preparation of Compound 136

To a solution of 136-6(80mg, 112.06. mu. mol) in CH2Cl2(2.3mL) under ice-cooling was added TFA (2.31g,20.26 mmol,1.5mL), and the mixture was stirred at zero degrees for 1 hour. After completion of the reaction, the mixture was concentrated and the crude product was purified by hplc (ACN/H2O, 0.05% FA) to give compound 136(45mg,73.31 μmol, 65.42% yield), ms (esi) M/z 614(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ8.49(s,1H),7.60(t,2H), 7.53(d,J＝2.2Hz,1H),7.30(dd,J＝8.4,1.9Hz,1H),7.02(d,J＝2.2Hz,1H),5.15(s,1H),4.79 (d,J＝8.7Hz,1H),4.14(dd,J＝10.6,2.6Hz,1H),4.09(s,3H),4.08–3.99(m,2H),3.95(d,J＝ 8.7Hz,1H),2.98–2.76(m,3H),2.75–2.64(m,1H),2.02(s,3H),1.88–1.71(m,10H),1.63(t, 8H),0.88(s,3H).

example 137 preparation of Compound 137

Referring to the procedure from step 1 to step 5 of the synthetic route for example 136, compound 137, ms (esi) M/Z714 (M +1) was obtained by substituting intermediate Z16 for intermediate Z22 in step 3 and trifluoroacetic acid for 2-methylpyrazole-3-carboxylic acid in step 5, which were the same as the above-mentioned procedure⁺。

Example 138 preparation of Compound 138

Referring to the procedure from step 1 to step 6 of the synthetic scheme of example 1, 2- ((tert-butoxycarbonyl) amino) -2- (7-methylspiro [2.5 ] was used in step 1]Oct-4-yl) acetic acid instead of Z1 and intermediate Z3 instead of intermediate Z2a, the remaining steps being the same, intermediate 138-6 is obtained. Removal of the Boc protecting group via TFA/DCM system gave compound 138, ms (esi) M/z 602 (M +1)⁺。

Example 139 preparation of Compound 139

By following the condensation procedure of step 6 of example 1, using intermediate 138-5 as a starting material, compound 139, ms (esi) M/Z ═ 589(M +1), was obtained by condensation under the same conditions as those of Z15⁺。

Example 140 preparation of Compound 140

By following the condensation procedure of step 6 of example 1, using intermediate 138-5 as a starting material and condensing under the same conditions as those for Z16, Compound 140 was obtained, MS (ESI) M/Z603 (M +1)⁺。

Example 141 preparation of Compound 141

Referring to the procedures from step 1 to step 6 of the synthetic route of example 1, intermediate 141-6 was obtained by substituting 2- ((tert-butoxycarbonyl) amino) -2- (2,2, 4-trimethylcyclohexyl) acetic acid for Z1 and intermediate Z3 for intermediate Z2a in step 1, and the remaining steps were the same. Removal of the Boc protecting group via TFA/DCM system gave compound 141, ms (esi) M/z 604 (M +1)⁺. Nuclear magnetic data¹H NMR(400MHz,Methanol-d₄)δ8.53(s,1H),7.66(d,J＝1.7Hz,1H),7.62 (d,J＝8.4Hz,1H),7.57–7.52(m,1H),7.45(dd,J＝8.0,1.4Hz,1H),7.34–7.31(m,1H), 7.26–7.21(m,1H),6.32(d,J＝2.2Hz,1H),6.01(d,J＝12.0Hz,1H),4.82(d,J＝8.5Hz,2H), 4.17–4.11(m,1H),4.08–4.00(m,2H),3.92(d,J＝8.5Hz,1H),3.85(s,3H),3.73(d,J＝11.9Hz, 1H),2.94–2.87(m,2H),2.87–2.77(m,2H),2.75–2.65(m,1H),1.86–1.71(m,3H), 1.66–1.48(m,2H),1.22–1.13(m,1H),1.10(s,3H),0.84(s,3H),0.75(dt,J＝9.6,4.9Hz,1H), -0.15–-0.24(m,2H).

Examples 142 and 143, preparation of Compounds 142 and 143

Referring to the preparation method of example 141, starting from intermediate 141-5, the corresponding compounds 142, 143 were obtained by condensation with amines as shown in the following table.

Example 144 preparation of Compound 144

Referring to the procedure of example 141, step 3 through step 5, step 1, starting from 141-3, was reacted with acetic anhydride to form an acetyl group on a quaternary amine, followed by hydrolysis of the ester group and condensation of intermediate Z15 to give compound 144, MS (ESI) M/Z604 (M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.58(s,1H),7.53(d,J＝8.5Hz,1H),7.26 (dd,J＝8.5,1.6Hz,1H),5.68(d,J＝2.9Hz,1H),4.64(d,J＝8.5Hz,1H),4.04–3.96(m,3H), 3.94–3.84(m,1H),3.48–3.38(m,2H),2.95–2.81(m,1H),2.55–2.45(m,1H),2.44–2.32(m, 1H),2.10(s,3H),2.07–2.00(m,1H),1.96–1.89(m,1H),1.89–1.79(m,1H),1.79–1.71(m, 2H),1.70–1.60(m,4H),1.60–1.56(m,1H),1.43–1.35(m,2H),1.08(s,3H),1.06–1.01(m, 1H),0.98(s,3H),0.96–0.89(m,1H),0.87(d,J＝6.4Hz,3H).

example 145 preparation of Compound 145

By following the procedure of example 144, starting from 144-2 and condensing intermediate Z16, compound 145, ms (esi) M/Z539 (M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.63(s,1H),7.58(d,J＝8.5Hz,1H), 7.35(d,J＝8.2Hz,1H),5.68(s,1H),4.68–4.63(m,1H),4.07–3.92(m,5H),3.53(dd,J＝11.4, 4.1Hz,1H),3.46–3.35(m,1H),2.95–2.79(m,1H),2.60–2.46(m,1H),2.08(s,3H), 2.00–1.94(m,1H),1.93–1.84(m,2H),1.83–1.71(m,2H),1.69–1.55(m,3H),1.55–1.48(m, 1H),1.45–1.35(m,2H),1.34–1.27(m,2H),1.04(s,3H),0.98(s,3H),0.95(s,3H),0.92–0.87 (m,1H),0.85(d,J＝6.3Hz,3H).

example 146 preparation of Compound 146

Referring to the procedure of example 141, step 3 through step 5, starting from 141-3, step 1 was reacted with methyl chloroformate, followed by hydrolysis of the ester group and condensation of intermediate Z16 to give compound 146, ms (esi) M/Z555 (M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.59(s,1H),7.52(d,J＝8.4Hz,1H),7.26(dd,J＝8.5,1.8Hz, 1H),6.79(d,J＝9.3Hz,1H),4.68(d,J＝8.5Hz,1H),4.04–3.92(m,4H),3.61(s,1H),3.62– 3.47(m,4H),3.45–3.32(m,1H),2.92–2.80(m,2H),2.60-2.54(m,1H),2.38–2.23(m,2H), 2.03-2.01(m,2H),1.89–1.70(m,9H),1.59–1.09(m,12H).

example 147 preparation of Compound 147

Referring to the procedure from step 1 to step 6 of the synthetic route of example 1, in step 1, condensation was carried out starting from 2- (((benzyloxy) carbonyl) amino) -2- (4, 4-difluorocyclohexyl) acetic acid and intermediate Z3 instead of Z1 and Z2a, and in step 3, Cbz was removed using PdCl2 plus Et3SiH in DCM and TEA system, and the remaining conditions were unchanged to give example compound 147, ms (esi) M/Z ═ 585(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.58(d, J＝8.6Hz,1H),7.48(d,J＝2.1Hz,1H),7.33(dd,J＝8.6,1.8Hz,1H),7.04(d,J＝8.9Hz,1H), 6.94(d,J＝2.2Hz,1H),5.22(d,J＝8.5Hz,1H),4.60(d,J＝8.6Hz,1H),4.07(s,3H),4.02–3.95 (m,3H),3.88(ddd,J＝9.2,4.9,2.6Hz,1H),3.47–3.40(m,1H),3.37(dd,J＝11.3,5.9Hz,1H), 2.87(dt,J＝12.7,6.3Hz,1H),2.52–2.23(m,3H),2.19–1.98(m,3H),1.87–1.53(m,4H),1.41 –1.31(m,3H),0.95–0.84(m,4H).

examples 148 and 149 preparation of Compounds 148 and 149

Referring to the procedures of synthetic schemes step 1 to step 6 of example 147, substituting the amino acid starting material in the table for 2- (((benzyloxy) carbonyl) amino) -2- (4, 4-difluorocyclohexyl) acetic acid in step 1, the same procedure was followed to give the corresponding compounds 148, 149.

Example 150 preparation of Compound 150

Referring to the synthesis procedure of example 1, starting from Boc-D-cyclohexylglycine and intermediate Z3 in step 1, the same steps of condensation, ring closure, Boc removal, condensation of 2-methylpyrazole 4-carboxylic acid, ester hydrolysis, and final condensation of cyclobutylmethylamine are performed to give compound 150, ms (esi) M/Z ═ 585(M +1)⁺. Nuclear magnetic data¹H NMR(400MHz,Methanol-d₄)δ7.54(d,J＝6.5Hz,1H),7.50(d,J＝5.6Hz,1H),7.47(d,J＝2.1Hz,1H),7.22(dd,J＝8.5,1.8Hz, 1H),6.93(d,J＝2.1Hz,1H),5.09(d,J＝8.7Hz,1H),4.54(d,J＝8.6Hz,1H),4.06(s,3H),4.02 (d,J＝8.6Hz,1H),3.99–3.90(m,2H),3.19–3.07(m,2H),2.89(dt,J＝12.6,6.3Hz,1H),2.47– 2.31(m,2H),2.19–2.05(m,1H),1.89–1.63(m,7H),1.60–1.48(m,2H),1.37–1.02(m,5H).

Example 151 preparation of Compound 151

Referring to the synthesis of example 150, condensation of intermediate 151-5 with methylamine in step 6 gave compound 151, ms (esi) M/z 465(M +1)⁺. Nuclear magnetic data¹H NMR(400MHz,DMSO-d₆)δ12.30(d,J＝8.7Hz,1H), 8.76(s,1H),7.61(s,1H),7.53–7.43(m,2H),7.41–7.32(m,1H),7.15–6.98(m,2H),5.01 (t,J＝8.6Hz,1H),4.53(t,J＝7.2Hz,1H),4.01(s,3H),3.87–3.72(m,3H),3.35(s, 3H),2.93–2.83(m,1H),2.24–2.15(m,1H),2.14–2.04(m,1H),1.94–1.82(m,1H), 1.77–1.68(m,1H),1.68–1.55(m,2H),1.44–1.32(m,1H),1.25–1.20(m,1H),1.19–1.05(m, 3H),1.04–0.92(m,1H).

Example 152 preparation of Compound 152

With reference to the synthetic route of example 1, using Boc-D-cyclohexylglycine andintermediate Z30 is the starting material and undergoes the same steps of condensation, ring closure, Boc removal, condensation of 2-methylpyrazole 4-carboxylic acid, ester hydrolysis, final condensation of intermediate Z15 and the like to yield compound 152, ms (esi) M/Z550 (M +1)⁺. Nuclear magnetic data¹HNMR(400MHz,MeOD):δ ppm 8.39-8.43(m,1H),8.01(t,J＝2.0Hz,1H),7.88(s,1H),7.48(d,J＝3.6Hz,1H), 7.25-7.31(m,1H),6.94(d,J＝2.0Hz,1H),5.10-5.13(m,2H),4.58(d,J＝8.8Hz,1H),4.51(d,J ＝8.8Hz,1H),4.13(d,J＝7.2Hz,1H),4.06(s,3H),3.88-4.05(m,5H),2.86-3.07(m, 3H),2.27-2.49(m,5H),1.70-2.02(m,8H),1.22-1.40(m,7H),.

Examples 153 to 157 preparation of Compounds 152-

Referring to the synthetic route of example 152, compound 152-157 was obtained by carrying out the same procedure in step 1, substituting starting material Z27 for the corresponding intermediate diamine in the table below.

Example 158 preparation of Compound 158

Referring to the synthetic route to example 152, step 1 was performed using (2S) -2- (((((benzyloxy) carbonyl) amino) -2- (spiro [2.5 ] carbonyl)]The same procedures used octan-4-yl) acetic acid instead of Boc-D-cyclohexylglycine and intermediate Z32 instead of intermediate Z27 gave compound 158, ms (esi) M/Z593 (M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4) δ7.46(d,J＝2.1Hz,1H),7.43–7.38(m,1H),7.20–7.03(m,2H),6.90(m,1H),5.72(d,J＝11.6 Hz,1H),4.53(m,1H),4.14(m,1H),4.02–3.93(m,2H),3.93–3.83(m,1H),3.49–3.33(m,2H), 3.03–2.80(m,1H),2.53–2.17(m,2H),2.02(d,J＝12.9Hz,1H),1.97–1.86(m,2H),1.84– 1.41(m,12H),0.60(d,J＝13.6Hz,1H),0.14(m,2H),-0.33(m,1H),-0.60(m,1H).

example 159 preparation of Compound 159

Referring to the synthetic route for example 152, substituting (2S) -2- ((((benzyloxy) carbonyl) amino) -2- (tetrahydro-2H-pyran-2-yl) acetic acid for Boc-D-cyclohexylglycine in step 1, and intermediate Z27 for intermediate Z32 gave compound 159, ms (esi) M/Z ═ 569(M +1)⁺。

Example 160 preparation of Compound 160

Referring to the synthetic route of example 136, Boc-D-cyclohexylglycine condensed with intermediate Z32 to form a ring, followed by hydrolysis of ethyl ester, condensation of intermediate Z15, removal of Boc, and transesterification with ethyl trifluoroacetate gave compound 160, ms (esi) M/Z555 (M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.44(t,J＝1.5Hz,1H), 7.20–7.09(m,1H),4.98(d,J＝9.1Hz,1H),4.16–3.85(m,4H),3.50–3.33(m,2H),3.01–2.81 (m,1H),2.52–2.27(m,2H),2.25–2.09(m,1H),2.05–1.88(m,2H),1.90–1.56(m,8H),1.45– 0.93(m,6H).

example 161 preparation of Compound 161

Condensing intermediate 160-3 with 3-methylisoxazole-4-carboxylic acid to obtain compound 161, MS: (ESI)m/z＝568(M+1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ9.22(s,1H),7.49(s,1H),7.21(ddd,J＝11.9,4.6, 1.4Hz,2H),5.09(d,J＝8.1Hz,1H),4.50(dd,J＝26.4,8.8Hz,1H),4.14–3.83(m,4H),3.49– 3.33(m,2H),2.90(ddt,J＝22.4,12.9,6.2Hz,1H),2.46-2.30(m,5H),2.12(qd,J＝9.3,8.2,5.5 Hz,1H),2.05–1.89(m,2H),1.88–1.55(m,8H),1.54–0.99(m,6H).

example 162 preparation of Compound 162

Referring to the synthesis of example 150, Boc-D-cyclohexylglycine condensed with intermediate Z32 to form a ring, followed by removal of Boc protecting group, condensation of 2-methylpyrazole 4-carboxylic acid, hydrolysis of ethyl ester, condensation of intermediate Z22, and finally removal of Boc protecting group, provided compound 162, ms (esi) M/Z ═ 580(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.47 (d,J＝2.2Hz,1H),7.39(d,J＝1.5Hz,1H),7.04(dd,J＝12.0,1.5Hz,1H),6.94(d,J＝2.2Hz, 1H),5.31(s,2H),5.09(d,J＝8.7Hz,1H),5.03(s,4H),4.62(d,J＝8.7Hz,1H),4.06(s,3H),4.05 –3.91(m,4H),3.34(s,1H),2.90(dt,J＝12.9,6.4Hz,1H),2.62(dd,J＝13.3,3.3Hz,1H),2.53– 2.39(m,2H),2.16–2.03(m,1H),2.01–1.74(m,3H),1.70(s,1H),1.51(dtd,J＝13.8,10.1,9.0, 4.7Hz,1H),1.43–1.33(m,1H),1.34–1.25(m,3H),1.22(s,2H),1.22–1.04(m,1H),1.07– 0.85(m,1H),0.93(s,2H).

example 163 preparation of Compound 163

By condensation of intermediate Z22 with 162-3, substituting intermediate Z17, according to step 4 of the synthetic route for example 162, compound 163 is obtained, ms (esi) M/Z581 (M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.48(d,J＝2.2 Hz,1H),7.39(s,1H),7.20(d,J＝9.1Hz,1H),7.09(d,J＝12.1Hz,1H),6.96(s,1H),5.09(d,J＝8.5Hz,1H), 4.46(d,J＝8.9Hz,1H),4.05(d,J＝0.9Hz,4H),3.96(dd,J＝7.9,6.3Hz,2H),3.60(q,J＝7.1Hz,1H),3.22(t, J＝4.9Hz,1H),3.17(s,3H),2.87(dt,J＝13.0,6.6Hz,1H),2.43–2.30(m,2H),2.23–2.07(m,1H),2.06– 1.88(m,2H),1.86–1.64(m,6H),1.29(s,4H),1.17(t,J＝7.1Hz,1H),0.94–0.84(m,1H).

example 164 preparation of Compound 164

Following the procedure of steps 1 to 6 of the synthetic scheme of example 1, substituting Boc-D-cyclohexylglycine for intermediate Z1 in step 1, the remaining reagents and procedures were the same, giving compound 164, ms (esi) M/Z551 (M +1)⁺. Nuclear magnetic data:

¹H NMR(400MHz,Methanol-d₄)δ7.59(d,J＝1.7Hz,1H),7.56–7.45(m,2H),7.28(dd,J ＝8.6,1.8Hz,1H),7.10(d,J＝8.9Hz,1H),6.95(d,J＝2.1Hz,1H),5.11(d,J＝8.7Hz,1H),4.08 (s,3H),3.95(dd,J＝9.2,4.5Hz,2H),3.73(d,J＝9.5Hz,1H),3.48–3.44(m,2H),3.40(s,3H), 2.49(h,J＝8.3,7.7Hz,1H),2.12(s,1H),2.05–1.98(m,1H),1.94–1.67(m,8H),1.59(s,3H), 1.46(d,J＝12.9Hz,1H),1.41–1.13(m,5H).

examples 165 and 166, preparation of Compounds 164 and 165

The procedure was as in step 1 to step 6 of the synthetic route of example 1, intermediate Z1 was replaced with Boc-D-cyclohexylglycine in step 1 and intermediate structure Z15 was replaced with the intermediate structure of Table in step 6, and the remaining procedures were the same, and finally the Fmoc protecting group was removed with LiOH under the THF/H2O system to give compounds of the corresponding structures of the tables, according to the procedure of step 3 of the synthetic route of intermediate Z18.

Example 167 preparation of Compound 167

Referring to the operation steps of step 1 and step 2 of example 1, Boc-D-cyclohexylglycine and intermediate Z2a were used as starting materials, and compound 167-2 was obtained by condensation and ring closure. Referring to the operation of example 86, 167-2 was used as a starting material, ester was hydrolyzed to condense intermediate Z15, boc protecting group was removed, and isopropyl acid was condensed to obtain compound 167, MS (ESI) M/Z: 551(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.57(d,J＝1.7Hz,1H),7.48(d,J＝8.5 Hz,1H),7.25(dd,J＝8.5,1.8Hz,1H),7.01(d,J＝8.9Hz,1H),4.91(d,J＝8.5Hz,1H),3.99– 3.89(m,2H),3.67(d,J＝9.5Hz,1H),3.52–3.38(m,3H),3.36(s,3H),2.63–2.40(m,2H),2.03 –1.94(m,2H),1.92–1.70(m,3H),1.68(s,1H),1.60(s,3H),1.43–0.95(m,11H).

examples 168 to 174 preparation of Compounds 168-174

Referring to the synthetic route of example 167, the substitution of the carboxylic acid in step 6 with the carboxylic acid of Table was condensed with intermediate 167-5 to give compound 168-174, which corresponds to the structure of Table.

Example 175 preparation of Compound 175

Referring to the procedure from step 1 to step 6 of the synthetic scheme of example 1, substituting 2- ((tert-butoxycarbonyl) amino) -2- (2,2, 4-trimethylcyclohexyl) acetic acid for intermediate Z1 in step 1 and intermediate Z16 for intermediate Z15 in step 6, the same procedure was followed to give compound 175, ms (esi) M/Z ═ 607(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz, Methanol-d₄)δ7.59(d,J＝1.7Hz,1H),7.52(d,J＝2.1Hz,2H),7.28(dd,J＝8.5,1.8Hz,1H), 7.15(d,J＝9.2Hz,1H),6.92(d,J＝2.1Hz,1H),5.85(d,J＝3.4Hz,1H),4.14(s,3H),4.09–4.02 (m,1H),3.97(d,J＝9.6Hz,1H),3.76(d,J＝9.6Hz,1H),3.57(dd,J＝11.4,4.2Hz,1H),3.49– 3.44(m,1H),3.42(s,3H),2.15–1.99(m,3H),1.98–1.84(m,2H),1.84–1.70(m,3H),1.69– 1.60(m,4H),1.59(s,3H),1.56–1.48(m,1H),1.44–1.36(m,1H),1.08(s,3H),1.05(s,3H),1.01 (s,3H),0.97–0.91(m,1H),0.88(d,J＝6.4Hz,3H).

example 176 preparation of Compound 176

Referring to the procedure of synthetic routes step 1 to step 6 of example 1, starting from Boc-D-cyclohexylglycine and intermediate Z34 replacing Z1 and Z2a, the same procedure was followed to give compound 176, ms (esi) M/Z ═ 569(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.47(d,J＝2.2Hz,2H),7.35(s,2H),7.17(d,J＝8.9Hz,1H),7.10(d,J＝8.9Hz,1H),7.05–6.98(m,2H),6.94(d,J＝2.1Hz,2H),5.08(d,J＝8.7 Hz,2H),4.06(s,6H),3.99–3.84(m,5H),3.76–3.63(m,2H),3.51–3.40(m,4H),3.37(d,J＝ 6.3Hz,6H),2.47(d,J＝6.1Hz,2H),2.23–1.62(m,25H),1.57(d,J＝13.2Hz,7H),1.48–0.95 (m,15H).

example 177 preparation of Compound 177

Similar to the synthesis of compound 176, following the same procedure as outlined in step 1 to step 6 of the synthetic route of example 1, substituting Boc-D-cyclohexylglycine and intermediate Z33 for Z1 and Z2a, compound 177, ms (esi) M/Z ═ 569(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.37(d,J＝2.2Hz, 1H),7.23–7.13(m,2H),6.95(d,J＝8.8Hz,1H),6.84(d,J＝2.2Hz,1H),4.99(d,J＝8.7Hz,1H), 3.96(s,3H),3.92–3.76(m,2H),3.59–3.47(m,1H),3.37(t,J＝4.6Hz,2H),3.26(s,3H),2.40 (q,J＝7.9Hz,1H),2.06–1.75(m,3H),1.71(ddd,J＝15.8,7.5,4.4Hz,4H),1.59(s,1H),1.54(s, 3H),1.37–0.87(m,8H),0.85–0.73(m,1H).

example 178 preparation of Compound 178

Referring to the procedure of synthetic routes 1 through 6 of example 1, starting with Boc-D-cyclohexylglycine and intermediate Z35 instead of Z1 and Z2a, and (S) -ALPHA-methyl-cyclobutanemethylamine instead of Z15 in step 6, the same procedure was followed to give compound 178-1, ms (esi) M/Z ═ 666(M +1)⁺。

Pd/C (20mg,164.68 μmol) was added to a solution of 178-1(50.00mg,75.10 μmol) in 2-isopropanol (8mL), the mixture was stirred at room temperature for 2 hours under hydrogen gas for hydrogen substitution, after completion of the reaction, the mixture was filtered, and the crude product obtained by concentrating the filtrate was subjected to separation and purification by mHPLC to obtain compound 178(6.7mg,12.16 μmol, 16.19% yield, 96.5% purity), ms (esi) M/z 569(M +1)⁺。¹H NMR(400MHz,DMSO-d6)δ8.94(d,J＝7.6Hz,1H),7.66– 7.56(m,1H),7.50(d,J＝2.1Hz,1H),7.39(dd,J＝26.8,8.6Hz,1H),7.25(m,1H),7.07(t,J＝1.5 Hz,1H),5.12–5.02(m,1H),4.23(t,J＝11.3Hz,1H),3.98(d,J＝1.2Hz,3H),3.85–3.70(m, 1H),3.43(m,1H),3.18(dd,J＝15.1,11.5Hz,1H),3.09(m,1H),2.86–2.76(m,1H),2.25–1.99 (m,2H),1.97–1.69(m,4H),1.69–1.48(m,4H),1.47–1.27(m,3H),1.29–1.04(m,4H),1.03– 0.92(m,1H),0.83(dd,J＝42.6,6.6Hz,3H).

Example 179 preparation of Compound 179

To a solution of compound 178(10.00mg, 18.81. mu. mol) in DCM (5mL) was added Ac2O (5.76mg, 56.42. mu. mol) and TEA (9.52mg, 94.04. mu. mol, 13.12. mu.L), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed by evaporation and the crude product was isolated and purified by mhhplc to give 179(2.9mg,5.05 μmol, 26.88% yield)⁺. Nuclear magnetic data¹H NMR(400MHz,DMSO-d6)δ7.64–7.52(m,2H),7.50(d,J＝2.1Hz, 1H),7.46–7.25(m,2H),7.07(d,J＝2.0Hz,1H),5.08(d,J＝8.4Hz,1H),4.56–4.19(m,1H), 3.99(s,3H),3.74(q,J＝8.2Hz,1H),3.50–3.32(m,2H),3.28–3.12(m,1H),2.93–2.77(m,1H), 2.39–2.05(m,3H),2.05–1.84(m,4H),1.84–1.56(m,6H),1.56–1.32(m,4H),1.12(m,6H), 0.90–0.71(m,3H).

Example 180 preparation of Compound 180

To 178(11.00mg, 20.69. mu. mol) in DCM (4mL) was added methyl chloroformate (2.93mg, 31.03. mu. mol) and TEA (2.09mg, 20.69. mu. mol, 2.89. mu.L) at zero degrees, and the reaction mixture was stirred at zero degrees for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product was isolated and purified by mhhplc to give compound 180(1.1mg,1.87 μmol, 9.02% yield), ms (esi) M/z 590(M +1)⁺. Nuclear magnetic data¹H NMR(400MHz,DMSO-d6)δ7.60–7.50 (m,2H),7.50(m,1H),7.37(d,J＝8.7Hz,1H),7.24(d,J＝7.3Hz,1H),7.05(d,J＝2.1Hz,1H), 5.06(d,J＝8.6Hz,1H),4.39–4.21(m,1H),3.99(s,3H),3.60(d,J＝13.4Hz,3H),3.55–3.43(m, 1H),3.43–3.20(m,2H),2.81(s,1H),2.32–2.02(m,3H),1.95–1.68(m,3H),1.68-1.63(s,3H), 1.56–1.40(m,3H),1.35(m,1H),1.11(m,6H),0.81(m,3H).

Example 181 preparation of Compound 181

To a solution of compound 178(15.00mg, 28.21. mu. mol) in MeOH (5mL) at room temperature was added a formaldehyde alcohol solution (5 mg), the mixture was stirred at room temperature for 30min, then NaCNBH3(5.32mg, 84.64. mu. mol) was added and the reaction solution was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product was isolated and purified 181 by mHPLC (8.4mg,15.39 μmol, 54.56% yield)⁺. Nuclear magnetic data¹H NMR(400MHz,DMSO-d6)δ 7.60–7.50(m,2H),7.48(d,J＝2.1Hz,1H),7.36(m,1H),7.13(d,J＝8.5Hz,1H),7.05(dd,J＝ 2.1,1.0Hz,1H),5.05(d,J＝8.8Hz,1H),4.67–4.03(m,1H),4.00(s,3H),3.75(m,2H),3.43(m, 2H),3.17–2.95(m,1H),2.95–2.80(m,4H),2.77(s,1H),2.28–2.00(m,2H),1.96–1.66(m, 4H),1.66–1.48(m,4H),1.48–1.19(m,4H),1.19–0.92(m,4H),0.92–0.70(m,3H).

Example 182 preparation of Compound 182

In analogy to the synthesis of compound 178, compound 182-1, ms (esi) M/Z ═ 656(M +1), obtained in the same manner as in step 6 by substituting Boc-D-cyclohexylglycine and intermediate Z35 for Z1 and Z2a as starting materials and (R) -2-aminobutanol for Z15 in step 6, with reference to the procedures of synthetic routes step 1 to step 6 of example 1⁺。

Removal of the Cbz protecting group using 182-1 as starting material, according to the procedure for compound 180, gave compound 182, ms (esi) M/z-522 (M +1)⁺. Nuclear magnetic data¹H-NMR(MeOD)0.79(3.0H,t,J＝7.44Hz),1.03-1.42(6.0H,m), 1.43-1.57(2.0H,m),1.73(2.0H,t,J＝13.78Hz),1.84(1.0H,d,J＝13.08Hz),2.05(1.0H,t,J＝7.66 Hz),2.16-2.26(1.0H,m),2.61-2.72(1.0H,m),2.87-2.97(1.0H,m),3.33-3.46(4.0H,m),3.54-3.63 (1.0H,m),3.74-3.84(1.0H,m),4.03(3.0H,s),4.37(1.0H,d,J＝11.68Hz),5.15(1.0H,d,J＝8.44 Hz),7.02(1.0H,d,J＝2.20Hz),7.46-7.55(2.0H,m),7.77(1.0H,d,J＝8.60Hz),7.82(1.0H,d, J＝1.32Hz).

Example 183 preparation of Compound 183

Starting from compound 182, compound 183 was obtained by acetylating in accordance with the synthesis method of example 179, ms (esi) M/z 564(M +1)⁺. Nuclear magnetic data¹H-NMR(MeOD)0.71-0.82(3.0H,m),1.05-1.43(7.0H,m), 1.48-1.60(2.0H,m),1.74(2.0H,t,J＝16.59Hz),1.85(1.0H,d,J＝13.24Hz),2.00-2.09(2.0H,m), 2.18-2.30(1.0H,m),2.42-2.53(1.0H,m),2.84-3.01(1.0H,m),3.37(2.0H,t,J＝5.96Hz),3.45-3.67 (2.0H,m),3.74-3.91(2.0H,m),4.03(3.0H,s),4.45(1.0H,q,J＝28.54Hz),5.18(1.0H,q,J＝3.36 Hz),7.04(1.0H,d,J＝2.08Hz),7.50(1.0H,d,J＝2.04Hz),7.60-7.65(1.0H,m),7.75-7.83(2H,m).

Example 184 preparation of Compound 184

Using compound 182 as a starting material, according to the synthesis method of example 180, and methyl chloroformate were reacted to obtain compound 184, ms (esi) M/z ═ 580(M +1)⁺. Nuclear magnetic data¹H-NMR(MeOD)0.76(3.0H,q,J＝7.16Hz),1.05-1.44 (7.0H,m),1.48-1.62(2.0H,m),1.74(2.0H,t,J＝17.17Hz),1.85(1.0H,d,J＝12.76Hz),2.05(1.0H, d,J＝12.64Hz),2.19-2.31(1.0H,m),2.37-2.47(1.0H,m),2.83-2.94(1.0H,m),3.37(2.0H,d, J＝5.48Hz),3.42-3.55(2.0H,m),3.66-3.84(4.0H,m),4.03(3.0H,s),4.34(1.0H,q,J＝8.74Hz), 5.18(1.0H,d,J＝8.04Hz),7.04(1.0H,d,J＝2.16Hz),7.50(1.0H,d,J＝2.12Hz),7.62(1.0H,d, J＝7.68Hz),7.73-7.82(2.0H,m).

Example 185 preparation of Compound 185

In analogy to the synthesis of compound 178, compound 185-1, ms (esi) M/Z ═ 652(M +1) can be obtained by following the procedure of synthetic route step 1 to step 6 of example 1, substituting Boc-D-cyclohexylglycine and intermediate Z35 for Z1 and Z2a as starting materials, substituting cyclobutylmethylamine for Z15 in step 6, and following the same remaining procedure⁺。

Removal of the Cbz protecting group using 185-1 as starting material, according to the procedure for compound 180, gave compound 185, ms (esi) M/z 518(M +1)⁺. Nuclear magnetic data¹H NMR(400MHz,DMSO-d6)δ9.00(d,J＝7.1Hz,1H),7.75(t,J＝5.9 Hz,1H),7.71–7.58(m,2H),7.51(d,J＝2.1Hz,1H),7.32(d,J＝8.8Hz,1H),7.07(dd,J＝2.2, 1.1Hz,1H),5.14–5.04(m,1H),4.26(d,J＝11.6Hz,1H),3.97(s,3H),3.43(m,1H),3.22(d,J＝ 11.6Hz,1H),3.19–2.93(m,3H),2.87–2.76(m,1H),2.39–2.24(m,1H),2.19–2.04(m,1H), 1.91(d,J＝12.4Hz,1H),1.82–1.52(m,7H),1.51–1.32(m,3H),1.31–0.92(m,5H).

Example 186 preparation of Compound 186

In analogy to the synthesis of example 178, referring to the procedure of synthetic route step 1 to step 6 of example 1, substituting Boc-D-cyclohexylglycine and intermediate Z35 for Z1 and Z2a as starting materials, substituting (R) -2-amino-2-cyclopropyl-1-ethanol for Z15 in step 6, and the same procedure for the remaining steps, compound 186-1, ms (esi) M/Z ═ 668(M +1)⁺。

Removal of the Cbz protecting group, followed by reaction with acetic anhydride, affords compound 186, ms (esi) M/z 576(M +1)⁺. Nuclear magnetic data¹H-NMR(MeOD)0.11-0.24(2.0H,m),0.26-0.53(2.0H,m),0.78-0.91(1.0H,m),1.02-1.43 (7.0H,m),1.54(1.0H,d,J＝11.32Hz),1.67-1.89(3.0H,m),2.05(2.0H,s),2.17-2.30(1.0H,m), 2.42-2.53(1.0H,m),2.85-3.00(1.0H,m),3.18-3.27(1.0H,m),3.44-3.67(4.0H,m),3.83(1.0H,q, J＝15.55Hz),4.03(3.0H,s),4.43(1.0H,q,J＝28.06Hz),5.17(1.0H,d,J＝7.96Hz),7.04(1.0H,d, J＝2.16Hz),7.50(1.0H,d,J＝2.04Hz),7.59-7.65(1.0H,m),7.76(1.0H,d,J＝6.40Hz),7.79(1.0H, s).

Example 187 preparation of Compound 187

Using compound 186-2 as a starting material, according to the synthesis method of example 180, and methyl chloroformate were reacted to give compound 187, ms (esi) M/z 592(M +1)⁺. Nuclear magnetic data¹H-NMR(MeOD)0.11-0.24(2.0H,m),0.27-0.52 (2.0H,m),0.77-0.90(1.0H,m),1.02-1.45(7.0H,m),1.55(1.0H,d,J＝11.40Hz),1.75(2.0H,q, J＝11.67Hz),1.85(1.0H,d,J＝13.28Hz),2.04(1.0H,d,J＝12.08Hz),2.17-2.28(1.0H,m), 2.35-2.46(1.0H,m),2.81-2.93(1.0H,m),3.18-3.26(1.0H,m),3.42-3.59(4.0H,m),3.71(3.0H,d, J＝12.28Hz),4.03(3.0H,s),4.32(1.0H,q,J＝8.82Hz),5.16(1.0H,d,J＝7.92Hz),7.03(1.0H,d, J＝2.16Hz),7.50(1.0H,d,J＝2.12Hz),7.56-7.62(1.0H,m),7.74(1.4H,d,J＝1.20Hz),7.76(1H,s).

Example 188 preparation of Compound 188

In analogy to the synthesis of example 178, referring to the procedure of synthetic route step 1 to step 6 of example 1, substituting Boc-D-cyclohexylglycine and intermediate Z35 for Z1 and Z2a as starting materials and substituting Z22 for Z15 in step 6, the same applies to the remaining operating steps to give compound 188-1, ms (esi) M/Z ═ 795(M +1)⁺。

Removal of the Cbz protecting group, followed by reaction with acetic anhydride and finally removal of the Boc in the TFA system, gives compound 188, ms (esi) M/z 603(M +1)⁺. Nuclear magnetic data:¹H-NMR(MeOD)0.87(3.0H,d,J＝33.77Hz),1.08-1.63 (9.0H,m),1.65-1.96(7.0H,m),2.14-2.31(2.0H,m),2.32-2.48(1.0H,m),2.77-3.11(3.0H,m), 3.44-3.62(2.0H,m),3.63-3.94(2.0H,m),3.98-4.15(4.0H,m),4.16-4.32(2.0H,m),5.17(1.0H,d, J＝5.80Hz),7.04(1.0H,s),7.50(1.0H,s),7.60(1.0H,q,J＝8.70Hz),7.73-7.89(2.0H,m).

example 189, preparation of Compound 189

Using compound 188-2 as a starting material, according to the synthesis method of example 180, reaction with methyl chloroformate followed by removal of Boc protecting group gave compound 189, ms (esi) M/z 619(M +1)⁺. Nuclear magnetic data:¹H-NMR(MeOD)0.82(3.0H, s),1.00-1.64(10.0H,m),1.65-1.91(6.0H,m),2.03(1.0H,d,J＝11.76Hz),2.20(1.0H,d,J＝8.52 Hz),2.54-2.61(1.0H,m),2.77-2.97(3.0H,m),3.54(2.0H,s),3.69(3.0H,d,J＝12.68Hz),4.03 (3.0H,s),4.17(1.0H,d,J＝8.44Hz),4.50(1.0H,t,J＝13.44Hz),5.14(1.0H,d,J＝7.88Hz),7.01 (1.0H,s),7.51(2.0H,d,J＝12.00Hz),7.73(1.0H,d,J＝8.24Hz),7.77(1.0H,s).

examples 190 to 199, preparation of compound 189 to 199

The method A comprises the following steps: referring to the procedure of synthetic route 1, step 1 to step 6 of example 1, starting from Boc-D-cyclohexylglycine in step 1 and the diamine intermediate of Table II, intermediate Z15 was replaced by the corresponding amine of Table II in step 6, and the remaining steps were the same, giving the corresponding structural compounds of the tables.

The method B comprises the following steps: referring to the procedure of synthetic route 1, steps 1 to 6 of example 1, starting with Boc-D-cyclohexylglycine in step 1 and the diamine intermediate of Table II, intermediate Z15 was replaced with the corresponding amine of Table II in step 6, and the remaining steps were the same, giving the corresponding intermediate; referring to the Fmoc removal procedure in step 3 of the synthetic route for intermediate Z18, the condensation product was substituted for intermediate Z18-2 and the remaining procedures were the same to give the corresponding compounds in the Table.

The method C comprises the following steps: referring to the procedure of synthetic route 1, steps 1 to 6 of example 1, starting with Boc-D-cyclohexylglycine in step 1 and the diamine intermediate of Table II, intermediate Z15 was replaced with the corresponding amine of Table II in step 6, and the remaining steps were the same, giving the corresponding intermediate; referring to the intermediate Z16 step 8 for the de-Boc procedure, the above intermediate was used instead of intermediate Z16-8 and the remaining procedure was the same and the corresponding compounds in the table were obtained.

The method D comprises the following steps: referring to the procedure of synthetic route 1, steps 1 to 6 of example 1, starting with Boc-D-cyclohexylglycine in step 1 and the diamine intermediate of Table II, intermediate Z15 was replaced with the corresponding amine of Table II in step 6, and the remaining steps were the same, giving the corresponding intermediate; the Cbz protecting group was cleaved with Pd/C according to the procedure described in step 3 of example 106 to give the corresponding compounds in the table.

The compounds of the examples in the table were prepared by method A, without specific mention.

Examples 200 and 201, preparation of Compounds 200 and 201

Referring to the procedures from step 2 to step 4 in the synthetic route of example 86, compounds of the corresponding structures in the tables can be obtained by condensing intermediate Z15 with amine in the following table in step 2 instead of intermediate 86-1 and by substituting 5-methylisoxazolecarboxylic acid with acid in the tables in step 4.

In order to illustrate the advantageous effects of the present invention, the present invention provides the following test examples.

Test example 1 IL-17 enzyme-linked immunosorbent assay (ELISA) test

The inhibition of receptor-ligand binding by IL-17A inhibitors was quantitatively determined by competitive ELISA. IL-17a (Nano Biological incc. Cat #12047-H07B) at 0.2. mu.g/ml was incubated in 96-well plates at 37 degrees for 30 minutes at 100. mu.l per well. The plate was washed 4 times with PBST (PBS, 0.05% Tween-20), 200. mu.l each well, and 200. mu.l of 5% skim milk was added and incubated for 30 minutes on a 25-degree shaker. 100X concentrations of test compound were prepared, ranging from 0.003. mu.M to 30. mu.M. The plates were washed 4 times with PBST (PBS, 0.05% Tween-20), mixed with 89. mu.l PBST and 1. mu.l of 100 Xconcentration test compound and preincubated for 10min at 25 ℃. Add 10. mu.l of 16nM IL-17R and incubate for 30min on a 25 degree shaker. After washing the plate 4 times, 100. mu.l of anti-Fc-tag HRP-conjugated antibody was added and incubated for 30 minutes on a 25 ℃ shaker. After washing the plate 4 times, 100. mu.l of TMB substrate solution was added and incubated at 25 ℃ in the dark. After addition of 20% HCl, the light absorption was measured at a wavelength of 450nm using a microplate reader.

The compounds prepared in the examples were tested for IL-17A inhibitory activity according to the methods described above, and the results are shown in Table 1, in which the IC of each compound was determined₅₀Sorted by description, in table 1:

"+" denotes IC₅₀Measuring less than 100. mu.M and greater than 1. mu.M;

"+ +" denotes IC₅₀Measured at less than 1 μ M and greater than 100 nM;

"+ + + +" denotes IC₅₀The assay value is less than 100 nM;

"-" indicates not yet tested.

TABLE 1 inhibitory Activity of Compounds on IL-17A

Test example 2 inhibition of IL17A protein by Compounds of the invention induces HT-29 cells to produce the chemokines GRO α/CXCL1

Mix 5x10⁴Individual/well human colorectal epithelial cells HT-29 (Chengdu Zhongyuan Co., Ltd.) were added to a 96-well plate and cultured overnight in an incubator at 37 ℃.30 ng/mL of IL17A protein (R)&D, #317-ILB) with a gradient concentration of IL17A small molecule inhibitor or with 0.3. mu.g/mL positive control IL17A antibody (R)&D, # AF-317-NA) was added to the above 96-well plate after 1 hour of incubation at 37 ℃ and co-incubated with HT-29 cells for 48 hours at 37 ℃ before the level of GRO α in the cell culture supernatant was measured using a GRO α ELISA kit (Cisbio, #62HCXC1 PEG).

The compounds prepared in the examples were subjected to neutralization of human IL 17A-mediated signaling in HT-29 cells according to the methods described above, and the results are shown in Table 2.

TABLE 2 inhibitory Activity of Compounds on IL-17A

Examples	HT-29 IC₅₀(μM)
		Compound 19a	0.073
Compound 20	0.089
		Compound 21	0.148
Compound 22	0.143
		Compound 23	0.302
Compound 164	0.044
		Compound 183	0.142
Compound 197	0.53

Test example 3 drug Effect model of encephalomyelitis in mice

The MOG protein was used to elicit a encephalomyelitis model in 10-week female C57BL/6 mice. The solution of example 20 was administered by gavage (30mg/kg) or intraperitoneal injection (3,10,30mg/kg) twice daily, or the IL17A antibody solution (first, second 10mg/kg, then 5mg/kg) once every three days, from the day before the model was created; blank solvent was given to control and model groups. Scoring was performed daily according to the scoring system of the mouse encephalomyelitis model, and a scoring curve was drawn. The results of disease scoring (fig. 1) show that the intraperitoneal injection of the compound of example 20 can inhibit the pathogenesis of encephalomyelitis of mice in a dose-dependent manner, within the end-of-day score, the inhibition of the severity of encephalomyelitis by 10mg/kg and 30mg/kg of the compound is remarkably different from that of a model group, and meanwhile, the gastric lavage of the compound of example 20 also has an inhibition effect on the severity of diseases.

At day 21 of the model, mouse brain and spinal cord samples were collected, fixed in 4% paraformaldehyde, HE-stained, and the protective effect of example 20 on histopathological lesions of the tissue cerebrospinal was examined. The results of HE staining (fig. 2) show that example 20 inhibits inflammatory lesions in the brain and spinal cord region caused by the disease by each route and each dose.

Test example 4 efficacy model of psoriasis induced by mouse imiquimod cream

Female C57BL/6N mice, 10 weeks old, were shaved about 2.5 x 4cm of hair and sequentially applied with Imiquimod (IMQ, Imiquimod) cream from day one to day five to create a psoriasis model. Each group was administered twice daily by subcutaneous injection of examples 20-3,10,30mg/kg, by gavage of examples 20-30mg/kg, by intraperitoneal injection of IL17A antibody solution (2mg/kg) every other day, or by intraperitoneal injection of dexamethasone solution (10mg/kg) once daily, respectively. Example 20, administered at different doses according to PASI scores, photographs of dorsal lesions, intraperitoneal injections or gavage routes, reduced the level of IMQ-induced skin inflammation (figure 3).

The skin thickness of the mice was measured on the first and fifth days of the experiment, and the skin thickness changes were examined, which showed that the various groups of example 20 and IL17A antibody administration reversed the skin thickening caused by IMQ to different extents (fig. 4).

The skin of each group of mice is collected on the fifth day of the experiment, and the transcription levels of the IL6 and IL1 beta genes are detected by an RT-qPCR method, and the result shows that (figure 5) each group of example 20 and IL17A antibody administration can reverse the up-regulation of the IL6 expression level in skin tissues to a certain extent and can remarkably reverse the up-regulation of the IL1 beta gene expression level.

On the fifth day of the experiment, mouse skin samples were collected and fixed in 4% paraformaldehyde for HE staining to examine the effect of example 20 on IMQ-induced pathological damage to the skin. Example 20, given concurrently with gavage, also had an inhibitory effect on disease severity. The results of HE staining (fig. 6) show that both example 20 and IL17A antibody administration are able to inhibit inflammatory lesions of the skin.

Test example 5 mouse imiquimod cream-induced psoriasis efficacy model

Female C57BL/6N mice, 10 weeks old, were shaved about 2.5 x 4cm of hair and sequentially applied with Imiquimod (IMQ, Imiquimod) cream from day one to day five to create a psoriasis model. Each group was administered twice daily by gavage with the antibody solution IL17A (2mg/kg) intraperitoneally every other day or dexamethasone (10mg/kg) once daily, each of examples 20-1,3,10,30 mg/kg. Photographs of dorsal lesions were taken according to PASI scores (fig. 7), and administration of different doses of example 20 reduced the level of IMQ-induced skin inflammation, with the remaining dose effects similar to IL17A antibody except for the 1mg/kg dose.

The skin thickness of mice was measured on the first and fifth days of the experiment, and the skin thickness change was examined, and the results showed (fig. 8) that the IL17A antibody and example 20 had inhibition of IMQ-induced skin thickening, and the skin thickness change of the high dose example 20(30mg/kg) was significantly different from that of the model group.

The skin of each group of mice is collected on the fifth day of the experiment, the transcription levels of IL6 and IL1 beta genes are detected by an RT-qPCR method, and the result shows that (figure 9) the up-regulation of the expression level of IL6 in skin tissues is reversed to a certain extent by each group of example 20 and IL17A antibody administration; in addition to example 20(3mg/kg), the up-regulation of the expression level of il1 β gene was significantly reversed by each group administration.

Experiments show that the compounds of the embodiment of the invention have good IL-17A inhibitory activity and can be effectively used for treating diseases with abnormal IL-17A activity.

In conclusion, the novel compound shown in the formula I shows good IL-17A inhibitory activity, and provides a new medicinal possibility for clinically treating diseases related to IL-17A activity abnormity.

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