阅读说明：本技术 一种免疫调节剂 (Immunomodulator ) 是由 李进 张登友 杨丹梅 黄昊岚 洪新福 罗浩 龚义 林燕萍 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 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);

the B ring is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently 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);

R₄selected from hydrogen, -C_1～10An alkyl group;

R₆is selected from-C_1～10Alkyl, halogen substituted-C_1～10An alkyl group, a 3-to 10-membered cycloalkyl group, a 5-to 10-membered heterocycloalkyl group, a 5-to 10-membered bridged cycloalkyl group, a 3-to 10-membered bridged heterocycloalkyl group; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₆₁Substitution;

each R₆₁Independently selected from halogenElements, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR₆₂、-C_0～4alkylene-OC (O) R₆₂、-C_0～4alkylene-C (O) R₆₂、-C_0～4alkylene-C (O) OR₆₂、-C_0～4alkylene-C (O) NR₆₂R₆₃、-C_0～4alkylene-NR₆₂R₆₃、-C_0～4alkylene-NR₆₂C(O)R₆₃、-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);

R₆₂、R₆₃each independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl);

R₅is selected from-C_0～4alkylene-OR₅₁、-C_0～4alkylene-OC (O) R₅₁、-C_0～4alkylene-C (O) R₅₁、-C_0～4alkylene-C (O) OR₅₁、-C_0～4alkylene-C (O) NR₅₁R₅₂、-C_0～4alkylene-NR₅₁R₅₂、-C_0～4alkylene-NR₅₁C(O)R₅₂、-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 alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further substituted by one, two or three independent R₅₃Substitution;

R₅₁、R₅₂each independently selected from hydrogen and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_1～4alkylene-OR₅₄、-C_1～4alkylene-OC (O) R₅₄、-C_1～4alkylene-C (O) R₅₄、-C_1～4alkylene-C (O) OR₅₄、-C_1～4alkylene-C (O) NR₅₄R₅₅、-C_1～4alkylene-NR₅₄R₅₅、-C_1～4alkylene-NR₅₄C(O)R₅₅、-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 alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further substituted by one, two or three independent R₅₃Substitution;

or, R₅₁、R₅₂Connecting 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₅₃Substitution;

each R₅₃Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-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);

R₅₄、R₅₅each independently selected from hydrogen and-C_1～10An alkyl group;

or, R₅、R₆Connecting to form 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocycle, 5-10 membered spirocycle and 5-10 membered spirocycle; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spirocycle, or heterocyclic spirocycle may be further substituted with one, two, or three independent R₅₆Substitution;

each R₅₆Each independently selected from halogen, cyano, oxo, 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).

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 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);

the B ring is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently 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);

R₄selected from hydrogen, -C_1～6An alkyl group;

R₆is selected from-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-8 membered bridged cycloalkyl, 5-8 membered bridged heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₆₁Substitution;

each R₆₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₆₂、-C_0～2alkylene-OC (O) R₆₂、-C_0～2alkylene-C (O) R₆₂、-C_0～2alkylene-C (O) OR₆₂、-C_0～2alkylene-C (O) NR₆₂R₆₃、-C_0～2alkylene-NR₆₂R₆₃、-C_0～2alkylene-NR₆₂C(O)R₆₃、-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);

R₆₂、R₆₃each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

R₅is selected from-C_0～2alkylene-OR₅₁、-C_0～2alkylene-OC (O) R₅₁、-C_0～2alkylene-C (O) R₅₁、-C_0～2alkylene-C (O) OR₅₁、-C_0～2alkylene-C (O) NR₅₁R₅₂、-C_0～2alkylene-NR₅₁R₅₂、-C_0～2alkylene-NR₅₁C(O)R₅₂、-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 alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further substituted by one, two or three independent R₅₃Substitution;

R₅₁、R₅₂each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_1～2alkylene-OR₅₄、-C_1～2alkylene-OC (O) R₅₄、-C_1～2alkylene-C (O) R₅₄、-C_1～2alkylene-C (O) OR₅₄、-C_1～2alkylene-C (O) NR₅₄R₅₅、-C_1～2alkylene-NR₅₄R₅₅、-C_1～2alkylene-NR₅₄C(O)R₅₅、-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 alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further substituted by one, two or three independent R₅₃Substitution;

or, R₅₁、R₅₂Connecting 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₅₃Substitution;

each R₅₃Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-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);

R₅₄、R₅₅each independently selected from hydrogen and-C_1～6An alkyl group;

or, R₅、R₆Connecting to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle, 6-9 membered spirocycle and 6-9 membered spirocycle; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spirocycle, or heterocyclic spirocycle may be further substituted with one, two, or three independent R₅₆Substitution;

each R₅₆Each independently selected from halogen, cyano, oxo, 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).

3. The compound of claim 2, 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 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;

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).

4. A compound according to claim 3, characterized in that: r₁Is selected from-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -O (C)_1～6Alkyl), -NH (C)_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl), -N (C)_1～6Alkyl) (3-to 6-membered cycloalkyl),

5. The compound of claim 2, wherein:

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_A1Is independently selected from-C_1～6An alkyl group.

6. The compound of claim 5, wherein: a ring is selected from

7. The compound of claim 2, wherein:

the B ring is selected from 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently selected from halogen, carbonyl, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group.

8. The compound of claim 7, wherein:

ring B is selected from

9. The compound of claim 2, wherein: r₆Is selected from-C_1～6Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-8 membered bridged cycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₆₁Substitution;

each R₆₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₆₂、-C_0～2alkylene-NR₆₂R₆₃；

R₆₂、R₆₃Each independently selected from hydrogen and-C_1～6An alkyl group.

10. The compound of claim 9, wherein: r₆Is selected from-C_1～6Alkyl, cyclobutyl, tetrahydroFuryl, tetrahydropyranyl, t,

11. The compound of claim 2, wherein:

R₅is selected from-C_0～2alkylene-OR₅₁、-C_0～2alkylene-C (O) OR₅₁、-C_0～2alkylene-C (O) NR₅₁R₅₂、-C_0～2alkylene-NR₅₁R₅₂、-C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by one, two or three independent R₅₃Substitution;

R₅₁、R₅₂each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_1～2alkylene-OR₅₄、-C_1～2alkylene-NR₅₄R₅₅、-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 alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further substituted by one, two or three independent R₅₃Substitution;

or, R₅₁、R₅₂Connecting 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₅₃Substitution;

each R₅₃Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-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);

R₅₄、R₅₅each independently selected from hydrogen and-C_1～6An alkyl group.

12. The compound of claim 2, wherein:

R₅、R₆are connected with each other

Each R₅₆Each independently selected from halogen, cyano, oxo, 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).

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

14. use of a compound of any one of claims 1-13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an IL-17A mediated disease.

15. The use according to claim 14, 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.

16. A pharmaceutical composition characterized by: the compound of any one of claims 1 to 13, or a stereoisomer 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 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 and 5-10 membered cycloalkylA heterocyclic alkyl group, a 5-10 membered spirocyclic group; (ii) a 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 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);

the B ring is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently 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);

R₄selected from hydrogen, -C_1～10An alkyl group.

R₆Is selected from-C_1～10Alkyl, halogen substituted-C_1～10An alkyl group, a 3-to 10-membered cycloalkyl group, a 5-to 10-membered heterocycloalkyl group, a 5-to 10-membered bridged cycloalkyl group, a 3-to 10-membered bridged heterocycloalkyl group; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₆₁Substitution;

each R₆₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_0～4alkylene-OR₆₂、-C_0～4alkylene-OC (O) R₆₂、-C_0～4alkylene-C (O) R₆₂、-C_0～4alkylene-C (O) OR₆₂、-C_0～4alkylene-C (O) NR₆₂R₆₃、-C_0～4alkylene-NR₆₂R₆₃、-C_0～4alkylene-NR₆₂C(O)R₆₃、-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);

R₆₂、R₆₃each independently selected from hydrogen and-C_1～10Alkyl, -C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered heterocycloalkyl);

R₅is selected from-C_0～4alkylene-OR₅₁、-C_0～4alkylene-OC (O) R₅₁、-C_0～4alkylene-C (O) R₅₁、-C_0～4alkylene-C (O) OR₅₁、-C_0～4alkylene-C (O) NR₅₁R₅₂、-C_0～4alkylene-NR₅₁R₅₂、-C_0～4alkylene-NR₅₁C(O)R₅₂、-C_0～4Alkylene- (3-to 10-membered cycloalkyl), -C_0～4Alkylene- (3-to 10-membered hetero)Cycloalkyl), -C_0～4Alkylene- (5-to 10-membered aromatic ring), -C_0～4Alkylene- (5-to 10-membered aromatic heterocycle); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further substituted by one, two or three independent R₅₃Substitution;

R₅₁、R₅₂each independently selected from hydrogen and-C_1～10Alkyl, halogen substituted-C_1～10Alkyl, -C_1～4alkylene-OR₅₄、-C_1～4alkylene-OC (O) R₅₄、-C_1～4alkylene-C (O) R₅₄、-C_1～4alkylene-C (O) OR₅₄、-C_1～4alkylene-C (O) NR₅₄R₅₅、-C_1～4alkylene-NR₅₄R₅₅、-C_1～4alkylene-NR₅₄C(O)R₅₅、-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 alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further substituted by one, two or three independent R₅₃Substitution;

or, R₅₁、R₅₂Connecting 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₅₃Substitution;

each R₅₃Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-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);

R₅₄、R₅₅each independently selected from hydrogen and-C_1～10An alkyl group;

or, R₅、R₆Connecting to form 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aromatic ring, 5-10 membered aromatic heterocycle, 5-10 membered spirocycle and 5-10 membered spirocycle; wherein, cycloalkyl, heterocycloalkyl, arylThe ring, heteroaromatic, spirocyclic, heterocyclic ring may be further substituted by one, two or three independent R₅₆Substitution;

each R₅₆Each independently selected from halogen, cyano, oxo, 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).

Further, the air conditioner is provided with a fan,

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 the cycloalkyl, heterocycloalkyl, spiro, heterocyclospiro may be further substituted by one or twoOne 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 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);

the B ring is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently 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);

R₄selected from hydrogen, -C_1～6An alkyl group.

R₆Is selected from-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-8 membered bridged cycloalkyl, 5-8 membered bridged heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₆₁Substitution;

each R₆₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₆₂、-C_0～2alkylene-OC (O) R₆₂、-C_0～2alkylene-C (O) R₆₂、-C_0～2alkylene-C (O) OR₆₂、-C_0～2alkylene-C (O) NR₆₂R₆₃、-C_0～2alkylene-NR₆₂R₆₃、-C_0～2alkylene-NR₆₂C(O)R₆₃、-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);

R₆₂、R₆₃each independently selected from hydrogen and-C_1～6Alkyl, -C_0～2Alkylene- (3-to 6-membered cycloalkyl), -C_0～2Alkylene- (3-to 6-membered heterocycloalkyl);

R₅is selected from-C_0～2alkylene-OR₅₁、-C_0～2alkylene-OC (O) R₅₁、-C_0～2alkylene-C (O) R₅₁、-C_0～2alkylene-C (O) OR₅₁、-C_0～2alkylene-C (O) NR₅₁R₅₂、-C_0～2alkylene-NR₅₁R₅₂、-C_0～2alkylene-NR₅₁C(O)R₅₂、-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 alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may beFurther substituted by one, two or three independent R₅₃Substitution;

R₅₁、R₅₂each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_1～2alkylene-OR₅₄、-C_1～2alkylene-OC (O) R₅₄、-C_1～2alkylene-C (O) R₅₄、-C_1～2alkylene-C (O) OR₅₄、-C_1～2alkylene-C (O) NR₅₄R₅₅、-C_1～2alkylene-NR₅₄R₅₅、-C_1～2alkylene-NR₅₄C(O)R₅₅、-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 alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further substituted by one, two or three independent R₅₃Substitution;

or, R₅₁、R₅₂Connecting 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₅₃Substitution;

each R₅₃Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-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);

R₅₄、R₅₅each independently selected from hydrogen and-C_1～6An alkyl group;

or, R₅、R₆Connecting to form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle, 6-9 membered spirocycle and 6-9 membered spirocycle; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spirocycle, or heterocyclic spirocycle may be further substituted with one, two, or three independent R₅₆Substitution;

each R₅₆Are respectively and independently selected from halogen, cyano,Oxo, 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).

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;

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).

Further specifically, R₁Is selected from-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -O (C)_1～6Alkyl), -NH (C)_1～6Alkyl), -N (C)_1～6Alkyl) (C_1～6Alkyl), -N (C)_1～6Alkyl) (3-to 6-membered cycloalkyl),

Further, in the present invention,

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_A1Is independently selected from-C_1～6An alkyl group.

Further specifically, ring A is selected from

Further, in the present invention,

the B ring is selected from 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aromatic ring, 5-6 membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be further substituted by one, two or three independent R_B1Substitution;

each R_B1Independently selected from halogen, carbonyl, -C_1～6Alkyl, halogen substituted-C_1～6An alkyl group.

Further specifically, ring B is selected from

Further, R₆Is selected from-C_1～6Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-8 membered bridged cycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₆₁Substitution;

each R₆₁Independently selected from halogen, cyano, carbonyl, nitro, -C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_0～2alkylene-OR₆₂、-C_0～2alkylene-NR₆₂R₆₃

R₆₂、R₆₃Each independently selected from hydrogen and-C_1～6An alkyl group.

Further specifically, R₆Is selected from-C_1～6Alkyl, cyclobutyl, tetrahydrofuryl, tetrahydropyranyl, t,

Further, in the present invention,

R₅is selected from-C_0～2alkylene-OR₅₁、-C_0～2alkylene-C (O) OR₅₁、-C_0～2alkylene-C (O) NR₅₁R₅₂、-C_0～2alkylene-NR₅₁R₅₂、-C_0～2Alkylene- (5-to 6-membered aromatic ring), -C_0～2Alkylene- (5-to 6-membered aromatic heterocycle); wherein the aromatic ring or the aromatic heterocyclic ring can be further substituted by one, two or three independent R₅₃Substitution;

R₅₁、R₅₂each independently selected from hydrogen and-C_1～6Alkyl, halogen substituted-C_1～6Alkyl, -C_1～2alkylene-OR₅₄、-C_1～2alkylene-NR₅₄R₅₅、-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 alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further substituted by one, two or three independent R₅₃Substitution;

or, R₅₁、R₅₂Connecting 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl; wherein cycloalkyl, heterocycloalkyl may be further substituted by one, two or three independent R₅₃Substitution;

each R₅₃Are respectively and independently selected from halogen, cyano, carbonyl, nitro and-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);

R₅₄、R₅₅each independently selected from hydrogen and-C_1～6An alkyl group.

Further, said R₅Is selected from

Further, in the present invention,

R₅、R₆are connected with each other

Each R₅₆Each independently selected from halogen, cyano, oxo, 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).

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

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

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 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.

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.

"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. E.g. C₁～C₆Alkyl 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 alkanesThe radical group has 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. The alkyl group may also be part of another group, such as C₁～C₆An alkoxy group.

"cycloalkyl" refers to a saturated or partially saturated cyclic group having from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, and spiro ring 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, cyclopentyl, cyclooctyl, 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.

"alkenyl" refers to a straight or branched chain hydrocarbyl group having 2 to 10 carbon atoms and in some embodiments 2 to 6 carbon atoms or 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.

"alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical 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, (C2-C6) alkynyl is intended to include ethynyl, propynyl, and the like.

"halogen" is fluorine, chlorine, bromine or iodine.

"haloalkyl" means an alkyl group in which the hydrogen atom may be replaced by 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.

"heterocycle", "heterocycloalkyl" 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;

"heteroaromatic ring" refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom;

"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.

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.

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 mol per liter and% is mass%, unless otherwise specified.

Dichloromethane is used as DCM. HBTU is O-benzotriazole-tetramethyluronium hexafluorophosphate. DIEA is N, N-diisopropylethylamine. TFA is trifluoroacetic acid; THF: tetrahydrofuran. EDCI 1-ethyl- (3-dimethylaminopropyl) carbodiimide. DIPEA is N, N-diisopropylethylamine. DMP is dimethyl phthalate. HOAt is N-hydroxy-7-azabenzotriazole.

Intermediate 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 1-1, LCMS M/z is 129[ M +1] M/z]⁺.

To a solution of crude intermediate 1-1 (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 1-2 as a colorless oily liquid, (15.5g,122.82mmol, 87.49% yield), LCMS M/z:127[ M +1]]⁺。

Adding ethyl titanate (86.45g,379.17mmol) to a solution of intermediate 1-2(14.5g,114.90mmol) and S-p-toluenesulfinamide (17.83g,114.90mmol) in dry dichloromethane (500mL) at room temperature in portions, after the addition, raising the temperature to 50 ℃ and stirring for 2 hours, adding 500mL of ice water to quench the reaction, filtering, extracting the filtrate with dichloromethane (500mL x 2), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain a filtrateTo intermediate 1-3(20.6g,84.65mmol, 73.68% yield), a colorless gummy semi-solid, LCMS M/z:264[ M +1]]⁺。

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. Slowly dripping the obtained solution into a dry tetrahydrofuran solution of an intermediate 1-3(21.0g,86.30mmol) at-78 ℃, after 30min dripping, naturally raising the temperature to room temperature and stirring overnight, slowly adding 500mL of saturated ammonium chloride aqueous solution under ice bath to quench reaction, stirring for 30min, filtering through diatomite, adding 500mL of ethyl acetate, separating an organic layer, extracting an aqueous phase through 500mL of 3 ethyl acetate, combining organic phases, drying through anhydrous sodium sulfate, filtering, concentrating, recrystallizing the crude product twice through hot petroleum ether and ethyl acetate solution to obtain an intermediate 1-4(14g,48.3mmol, 56% yield) with S configuration, a white solid, and LCMS M/z:291[ M +1] of LCMS M/z]⁺.

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

Adding concentrated hydrochloric acid (376.22mg,4.50mmol) into 4mL of acetic acid solution of intermediates 1-5 at room temperature, heating to 110 deg.C, stirring for reaction for 3 hr, concentrating the reaction solution under reduced pressure, adding 50mL of petroleum ether, pulping, and vacuum filtering to obtain intermediates 1-6(840mg,4.04mmol, 89.78% yield), white solid, LCMS M/z 172[ M +1 ]: M/z]⁺。

To a mixture of intermediate 1-6(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 1(1.0g,3.69mmol, 75.12% yield), white solid, LCMS M/z 272[ M +1] M]⁺。

Intermediate 2

4- (Trifluoromethanesulfonyloxy) -2, 5-dihydrofuran-3-carboxylic acid methyl ester (1.02g,3.68mmol), 4-pinacolboronic acid ester-3-fluorophenyl-1, 2-diamine (2.78g,11.03mmol) and potassium carbonate (1.53g,11.03mmol) were added in this order to a mixed solution of 1, 4-dioxane (100mL) and water (0.50mL), and after 10 minutes of ultrasonic degassing with nitrogen, Pd (PPh) was added₃)₄(213mg,0.184mmol), heating to 80 deg.C under nitrogen protection, stirring for 8 hr, cooling to room temperature, concentrating under reduced pressure, separating and purifying the residue with silica gel column to obtain intermediate 2-1(390mg, 42%), LCMS M/z:253[ M +1]]⁺。

Dissolving intermediate 2-1(300mg,1.19mmol) in methanol (10mL), adding 10% Pd/C (30mg) under nitrogen protection, replacing with hydrogen for 3-5 times, hydrogenating at room temperature under normal pressure for 12 hr, filtering the reaction solution with diatomaceous earth, concentrating the filtrate to obtain intermediate 2(302mg, 100%), and LCMS M/z:255[ M +1]]⁺。

Intermediate 3

Adding 1M LiHMDS tetrahydrofuran solution (27mL) into 100mL dry tetrahydrofuran solution of 3-oxomorpholine-4-tert-butoxycarbonyl ester (5g,24.85mmol) under nitrogen protection at-60 ℃, stirring for 1 hour, adding diphenyl chlorophosphate (7.01g,26.09mmol) at-60 ℃, stirring the reaction solution for 4 hours at room temperature after the addition is finished, slowly adding water to quench the reaction, extracting with ethyl acetate 50mL 2, combining organic phases, concentrating under reduced pressure, and separating and purifying with silica gel column (PE/EA is 2:1) to obtain intermediate 3-1(7.3g,16.84mmol, 67.79% yield), colorless liquid, LCMS M/z:434[ M +1 ]/[ M +/z]⁺。

Adding intermediate 3-1(1.1g,2.54mmol), triphenylphosphine (133.15mg,507.63umol) and pinacol diboron (1.29g,5.08mmol) in sequence to 1, 4-dioxane (50mL), ultrasonically degassing under nitrogen for 10min, addingPd(PPh₃)₂Cl₂(178.18mg,253.81umol), heating to 90 ℃ under nitrogen protection, stirring for 5 hours, cooling the reaction solution to room temperature, concentrating under reduced pressure, and separating and purifying the residue with a silica gel column (PE/EA ═ 7:1) to obtain intermediate 3-2(400mg,642.71umol, 25.32% yield) as a pale yellow liquid.

To a mixed solution of 4-bromo-3-fluoro-2-nitroaniline (1.8g,7.66mmol) in 20mL of ethanol and 2mL of water were added iron powder (2.99g,53.61mmol) and glacial acetic acid (7.66mmol,1mL) in this order, followed by heating to 80 ℃ and stirring for 3 hours, cooling to room temperature, then sodium carbonate (2 g) was added and stirring was carried out for half an hour, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column separation and purification (PE/EA ═ 3:1) to give intermediate 3-3(1.2g,5.85mmol, 76.42% yield) as a pale yellow solid, LCMS M/z:205[ M +1 mmol/1 ] 205]⁺。

Mixing intermediates 3-2(400.00mg,642.71umol), 3-3(131.77mg,642.71umol) and Na₂CO₃(136.26mg,1.29mmol)、Pd(dppf)Cl₂(47.05mg,64.27umol) of a mixed solution of 8mL of 1, 4-dioxane and 2mL of water was reacted at 100 ℃ for 1 hour under microwave conditions, and after concentration under reduced pressure, the residue was isolated and purified by silica gel column (PE/EA. RTM.4: 1) to give intermediate 3-4(30mg,96.98umol, 15.09% yield) as a pale yellow liquid, LCMS M/z:310[ M + 1: (M): 310: (M): 1: (M): 1]⁺。

Dissolving intermediate 3-4(309mg,1.0mmol) in methanol (5mL), adding 10% Pd/C (100mg) under nitrogen protection, replacing with hydrogen for 3-5 times, hydrogenating at 70 deg.C and 50psi for 12 hr, cooling to room temperature, filtering the reaction solution with diatomaceous earth, concentrating the filtrate, and separating and purifying by silica gel column chromatography (PE/EA is 4:1) to obtain intermediate 3(150mg, 50%), LCMS M/z is 212[ M + 1-Boc: (M + 1-Boc)]⁺。

Intermediate 4

5-bromo-2-methylpyrimidine-4-carboxylic acid methyl ester (3.88g,11.90mmol), 4-pinacolboronic acid ester-3-fluorophenyl-1, 2-diamine (4.5g,17.85mmol) and potassium carbonate (3.29g,23.80mmol) were added to a mixed solution of 1, 4-dioxane (50mL) and water (10mL) in this order, nitrogen was ultrasonically degassed for 10min, and P was addedd(PPh₃)₂Cl₂(835.29mg,1.19mmol), heating to 80 deg.C under nitrogen protection, stirring for 5 hr, cooling to room temperature, concentrating under reduced pressure, separating and purifying the residue with silica gel column to obtain intermediate 4(1.15g, 35%), LCMS M/z:277[ M +1]]⁺。

Intermediate 5

Boc-D-cyclobutylglycine (800mg,3.49mmol) was dissolved in DCM (8mL), cooled to 0 deg.C, HBTU (1.06g,4.19mmol), DIEA (2.25g,17.45mmol) and ethylamine hydrochloride (284mg,3.49mmol) were added sequentially, after 15min turned to room temperature for 1.5 h, LC-MS showed disappearance of starting material, washed with saturated ammonium chloride (10 mL. times.3), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 3:1) to give intermediate 5-1, white solid (822mg,3.21mmol, 92% yield), MS M/z:257[ M +1 ]/[ M ]/[ 1]]⁺。

5-1(822mg,3.21mmol) was dissolved in DCM (3mL), TFA (1.5mL) was added slowly under ice-bath, stirring was carried out for 1.5 h under ice-bath, the starting material disappeared, and concentrated to dryness under reduced pressure to give a TFA salt of 5 (820mg, 100%) as a colorless semi-viscous solid, MS M/z:157[ M +1] +, and the crude product was used in the next step without purification.

Example 1

Sequentially adding intermediate 1(138mg,508.57umol), EDCI (117.17mg,610.28umol), DIPEA (328.63mg,2.54mmol,442.90uL), HOAt (83.00mg,610.28umol) and intermediate o-phenylenediamine 4(140.50mg,508.57umol) into DCM (3mL), reacting at room temperature for 1 hour, adding water for quenching, removing most of organic solvent under reduced pressure, extracting with ethyl acetate (20 mL. about.3), combining organic phases, washing with saturated ammonium chloride and saturated common salt water, drying with anhydrous sodium sulfate, spin-drying under reduced pressure, purifying and separating the crude product by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to obtain intermediateMixture of structural isomers of form C1-1 (149mg,281.34umol, 55.32% yield), MS M/z:512(M +1)⁺And the two were not separated and used for the next step.

The mixture of structural isomers of intermediate C1-1 (149mg,281.34umol) was added to AcOH (2mL), reacted at 55 ℃ for 12h, concentrated under reduced pressure and spin-dried 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 C1-2(143mg,279.52umol, 99.35% yield) which was used in the next step without purification, MS m/z:512(M +1)⁺。

Intermediate C1-2(143mg,279.52umol) was dissolved in DCM (3mL), TFA (1.5mL) was added dropwise in ice bath, the reaction was stirred for 1h in ice bath, and the reaction mixture was concentrated under reduced pressure to give crude intermediate C1-3 (113mg,274.62umol, 98.25% yield), MS m/z: 412(M +1)⁺And directly used for the next reaction without purification.

HBTU (87.00mg,342.70umol), DIPEA (102.21mg,790.84umol,137.75uL) are sequentially added into a DCM (3mL) solution of 1-methyl-1H-pyrazole-5-carboxylic acid (36.57mg,289.97umol), after 15min, an intermediate C1-3(108.47mg,263.61umol) is added, the reaction is carried out at room temperature for 2H, water is added for quenching, ethyl acetate (20mL of 3) is extracted, organic phases are combined, saturated ammonium chloride and saturated common salt are respectively washed, anhydrous sodium sulfate is dried and decompressed and dried, and the crude product is purified and separated by MPLC 18 column chromatography (acetonitrile/0.05% of water is 0-40%) to obtain an intermediate C1-4(136mg,261.76umol, 99.30% yield), MS m/z: 520(M +1)⁺。

Adding NaOH (31.41mg,785.28umol) into a mixture of intermediate C1-4(136mg,261.76umol) with MeOH (5mL) and water (0.5mL), reacting at 50 ℃ for 10 hours, adjusting pH to 4 with 1N HCl by LC-MS (LC-MS) after the raw materials are reacted, extracting with DCM (10 mL. x.2), combining organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude product (117mg,231.43umol, 88.41% yield) of intermediate C1-5, wherein MS M/z is 506[ M +1] M/z]⁺And directly used for the next reaction without purification.

HBTU (24.36mg,64.29umol), DIPEA (19.17mg,148.36umol,25.84uL) were added sequentially to a solution of intermediate C1-5(25mg,49.45umol) in DCM (1mL) for 15min before additionAdding the intermediate 5(10.04mg,64.29umol), reacting at room temperature for 1h, concentrating under reduced pressure, and purifying and separating the crude product by MPLC reversed-phase C18 column chromatography (acetonitrile/0.05% water 0-40%) to obtain the compound 1(20mg,31umol, 63% yield), MS m/z: 644(M +1)⁺。¹HNMR(400MHz,MeOD):δ8.83(s,1H),7.50(d,J＝2.1Hz,1H),7.40(d,J＝8.1Hz,1H),7.28–7.20(m,1H),6.97(d,J＝2.1Hz,1H),5.10(d,J＝8.7Hz,1H),4.34–4.30(m,1H),4.09(s,3H),3.25–3.08(m,2H),2.83(s,3H),2.72–2.58(m,1H),2.13–2.00(m,2H),1.95–1.68(m,9H),1.50–1.42(m,2H),1.40–1.30(m,3H),1.25–1.14(m,2H),1.08(t,J＝7.3Hz,3H),0.91(d,J＝6.5Hz,3H).

Example 2

Referring to the synthesis method of compound 1, intermediate C1-5 and (R) -2-amino-2-cyclobutyl-1-ethanol are condensed to obtain compound 2.MS m/z: 603(M +1)⁺。¹HNMR(400MHz,MeOD):δ8.82(s,1H),7.51–7.48(m,1H),7.43(d,J＝6.3Hz,1H),7.24(dd,J＝8.2,6.6Hz,1H),6.97(d,J＝2.1Hz,1H),5.11(d,J＝8.7Hz,1H),4.09(s,3H),3.93–3.83(m,1H),3.58–3.46(m,2H),2.83(s,3H),2.61–2.47(m,1H),2.10–1.93(m,3H),1.88–1.77(m,3H),1.76–1.64(m,4H),1.49–1.42(m,1H),1.40–1.28(m,3H),1.25–1.14(m,2H),1.09–0.96(m,2H),0.91(d,J＝6.5Hz,3H).

Example 3

According to the synthesis method of the compound 1, the intermediate 1 and the intermediate 2 are subjected to condensation, imidazole ring closing, Boc removal, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid, ester hydrolysis and recondensation to obtain a compound 3.MS m/z: 622(M +1)⁺。

Example 4

According to the synthesis method of the compound 1, the intermediate 1 and the intermediate 3 are subjected to condensation, imidazole ring closing, Boc removal, condensation with 1-methyl-1H-pyrazole-5-carboxylic acid and condensation with the intermediate 5 to obtain a compound 4.MS m/z: 637(M +1)⁺。

Example 5

According to the synthesis method of the reference compound 1, the intermediate 1 and the intermediate 2 are subjected to condensation, imidazole ring closing, Boc removal, condensation with methyl chloroformate, ester hydrolysis and condensation with the intermediate 5 to obtain a compound 5.MS m/z: 594(M +1)⁺。

Example 6

According to the synthesis method of the compound 1, the intermediate 1 and the intermediate 2 are subjected to condensation, imidazole ring closing, Boc removal, condensation with propionic acid, ester hydrolysis and condensation with the intermediate 5 to obtain a compound 6.MS m/z: 592(M +1)⁺。

Example 7

According to the synthesis method of the compound 1, the intermediate 1 and the intermediate 2 are subjected to condensation, imidazole ring closing, Boc removal, condensation with methyl isocyanate, ester hydrolysis and condensation with the intermediate 5 to obtain a compound 7.MS m/z: 593(M +1)⁺。

Example 8

Reference compound 1 synthesis method, intermediate 1 and intermediate 2 are condensedClosing imidazole ring, removing Boc, condensing with 1-pyrrolidine carbonyl chloride, hydrolyzing ester, and condensing with an intermediate 5 to obtain a compound 8.MS m/z: 633(M +1)⁺。

Examples 9 to 35

The compounds in the following table can be obtained by condensation of intermediates C1-5 with different amino acids, respectively, according to the method of example 1.

Example 36

Referring to the method of synthetic route 1, steps 1 through 6, substituting Boc-D-cyclohexylglycine for intermediate 1 in step 1 and (R) -2-amino-cyclobutylmethanol for intermediate 5 in step 6, the remaining operating steps are the same and give compound 36, MS m/z: 561(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ7.87(s,1H),7.48(s,2H),7.16(dd,J＝8.2,6.4Hz,1H),6.95(s,1H),5.11(d,J＝8.7Hz,1H),4.46–4.38(m,1H),4.07(s,3H),3.53-3.48(m,2H),2.53(s,1H),2.50(s,3H),2.14–1.71(m,11H),1.38–1.03(m,6H).

example 37

Referring to the synthesis of compound 1, (2S) -2- ((tert-butoxycarbonyl) amino) -2- (2,2, 4-trimethylcyclohexyl) acetic acid was condensed with intermediate 4, ring-closed, then ester was hydrolyzed first, and (R) -2-amino-N-ethyl-2- (1-methylcyclobutyl) acetamide was condensed, and the Cbz protecting group was removed, and finally reacted with methyl chloroformate to give compound 37, MS m/z: 622(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ8.81(s,1H),7.36(s,1H),7.19(dd,J＝8.3,6.5Hz,1H),5.40(d,J＝2.8Hz,1H),4.38(s,1H),3.70(s,3H),3.27–3.00(m,3H),2.82(s,3H),2.18(q,J＝9.4Hz,1H),2.04(q,J＝9.5Hz,1H),1.97–1.79(m,2H),1.77–1.66(m,2H),1.63–1.47(m,4H),1.41–1.25(m,3H),1.14(s,3H),1.12–1.06(m,6H),0.99(s,3H),0.84(d,J＝6.4Hz,3H).

example 38

Taking an intermediate compound C37-4 as a raw material, condensing with acetic acid to obtain a compound 38, MS m/z: 622(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ8.81(s,1H),7.36(s,1H),7.19(dd,J＝8.3,6.5Hz,1H),5.69(d,J＝2.9Hz,1H),4.38(s,1H),3.26–3.08(m,2H),2.82(s,3H),2.18(q,J＝9.3Hz,1H),2.07(s,3H),2.06–1.95(m,2H),1.94–1.79(m,1H),1.79–1.66(m,3H),1.66–1.47(m,4H),1.46–1.33(m,2H),1.31–1.26(m,1H),1.14(s,3H),1.11–1.06(m,6H),0.97(s,3H),0.85(d,J＝6.5Hz,3H).

example 39

Referring to the synthesis of compound 1,2- ((tert-butoxycarbonyl) amino) -2- (2,2, 4-trimethylcyclohexyl) acetic acid as a starting material was condensed with intermediate 4, ring-closed, then Cbz protecting group was removed, 1-methyl-1H-pyrazole-5-carboxylic acid was condensed, ester was hydrolyzed, and then R) -2-amino-N-ethyl-2- (1-methylcyclobutyl) acetamide was condensed to give compound 39.MS m/z: 686(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d₄)δ8.81(s,1H),7.51(d,J＝2.2Hz,1H),7.46(d,J＝8.3Hz,1H),7.33–7.25(m,1H),6.93(d,J＝2.2Hz,1H),5.92(d,J＝3.4Hz,1H),4.45–4.32(m,1H),4.12(s,3H),3.25–3.07(m,2H),2.83(s,3H),2.19(q,J＝9.4Hz,1H),2.05(td,J＝9.2,4.5Hz,2H),1.96–1.75(m,2H),1.75–1.47(m,6H),1.47–1.35(m,1H),1.16(s,3H),1.13–1.05(m,6H),1.00(s,3H),0.96–0.90(m,1H),0.87(d,J＝6.4Hz,3H).

example 40

The intermediate C39-4 is used as a raw material to be condensed with (R) -2-amino-2- (1-methylcyclobutyl) ethanol to obtain a compound 40, MS m/z: 645(M +1)⁺. Nuclear magnetic data:¹H NMR(400MHz,Methanol-d4)δ8.80(s,1H),7.50(d,J＝2.2Hz,1H),7.35(d,J＝8.2Hz,1H),7.22(dd,J＝8.3,6.5Hz,1H),6.92(d,J＝2.1Hz,1H),5.86(d,J＝3.4Hz,1H),4.11(d,J＝4.7Hz,3H),4.06–4.00(m,1H),3.63–3.45(m,2H),2.81(s,3H),2.09–1.99(m,1H),1.99–1.73(m,4H),1.60(s,5H),1.45–1.21(m,3H),1.08(s,3H),1.03(s,3H),1.00(s,3H),0.86(d,J＝6.5Hz,3H).

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

Examples	IC50
		Compound 1	+++
Compound 2	+++
		Compound 3	+++
Compound 4	+++
		Compound 36	+
Compound 37	++
		Compound 38	+
Compound 39	++
		Compound 40	++

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.