阅读说明：本技术 作为免疫调节的芳环衍生物及其制备方法和应用 (Aromatic ring derivatives as immunomodulating agents, process for their preparation and their use ) 是由 陆洪福 彭建彪 邢唯强 郭海兵 于 2019-12-06 设计创作，主要内容包括：涉及一种式(Ⅰ)所示化合物及其药效上可接受的盐,以及该化合物作为S1P1激动剂的应用。<Image he="261" wi="700" file="DDA0002615887940000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Relates to a compound shown in formula (I), pharmaceutically acceptable salts thereof and application of the compound as an S1P1 agonist.)

A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

n is selected from 1,2 and 3;

R₁each independently selected from H, F, Cl, Br, OH, NH₂、CN、CH₃、CH₂CH₃And CF₃；

R₄Each independently selected from H, F, Cl, Br, OH, NH₂、CN、CH₃、CH₂CH₃And CF₃；

Or, R₁And R₄Are connected together to form a C_3-6A cycloalkyl group;

R₂selected from H, halogen, OH, NH₂CN and C_1-3Alkyl radical, said C_1-3Alkyl is optionally substituted with 1,2 or 3R;

R₃is selected from C_3-7Cycloalkyl radical, C_3-7Cycloalkenyl radical, C_2-6Alkenyl and 3-to 6-membered heterocycloalkyl, C_3-7Cycloalkyl radical, C_3-7Cycloalkenyl radical C_2-6Alkenyl or 3-6 membered heterocycloalkyl optionally substituted with 1,2 or 3R;

ring A is selected from phenyl and 6-membered heteroaryl, optionally substituted with 1,2 or 3R_aSubstitution;

ring B is selected from 5-membered heteroaryl, said 5-membered heteroaryl being optionally substituted with R_bSubstitution;

R_aeach independently selected from H, halogen, OH, NH₂CN and C_1-3Alkyl radical, said C_1-3Alkyl is optionally substituted with 1,2 or 3R; r_bSelected from H, halogen、OH、NH₂CN and C_1-3Alkyl radical, said C_1-3Alkyl is optionally substituted with 1,2 or 3R;

r is respectively and independently selected from H, F, Cl, Br, OH and NH₂、CN、C_1-3Alkyl and CF₃；

T₁Selected from N and CH;

T₂selected from N and CH;

L₁is selected fromAnd

L₂selected from the group consisting of single bonds, O and S;

the 5-membered heteroaryl, 6-membered heteroaryl and 3-6-membered heterocycloalkyl contain 1,2 or 3 heteroatoms or groups of heteroatoms independently selected from O, NH, S and N.

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₂Selected from H, F, Cl, Br, OH, NH₂、CN、CH₃And CH₂CH₃Said CH₃Or CH₂CH₃Optionally substituted with 1,2 or 3R.

A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R₂Selected from H, F, Cl, Br, OH, NH₂、CN、CH₃、CH₂CH₃And CF₃。

A compound according to any one of claims 1to 3, or a pharmaceutically acceptable salt thereof, wherein R₃Is selected from C_3-6Cycloalkyl radical, C_3-6Cycloalkenyl radical, C_2-3Alkenyl and 3-to 6-membered heterocycloalkyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkenyl radical, C_2-3Alkenyl or 3 ^ eThe 6-membered heterocycloalkyl is optionally substituted with 1,2 or 3R.

A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R₃Is selected from The above-mentioned

A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R₃Is selected from

A compound according to claim 1 or 6, or a pharmaceutically acceptable salt thereof, wherein the building block

A compound according to any one of claims 1to 3, or a pharmaceutically acceptable salt thereof, wherein R_aSelected from H, F, Cl, Br, OH, NH₂、CN、CH₃And CH₂CH₃Said CH₃Or CH₂CH₃Optionally substituted with 1,2 or 3R.

A compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R_aSelected from H, F, Cl, Br, OH, NH₂、CN、CH₃、CH₂CH₃And CF₃。

A compound according to any one of claims 1to 3, or a pharmaceutically acceptable salt thereof, wherein R_bSelected from H, F, Cl, Br, OH, NH₂、CN、CH₃And CH₂CH₃Said CH₃Or CH₂CH₃Optionally substituted with 1,2 or 3R.

A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R_bSelected from H, F, Cl, Br, OH, NH₂、CN、CH₃、CH₂CH₃And CF₃。

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl and pyridyl, optionally substituted with 1,2 or 3R_aAnd (4) substitution.

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from pyrrolyl, imidazolyl, pyrazolyl, thiazolyl and oxazolyl, optionally substituted with R_bAnd (4) substitution.

A compound according to any one of claims 1, 12 or 13 or a pharmaceutically acceptable salt thereofAcceptable salts, wherein the structural units

A compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein the building blockIs selected from

A compound according to any one of claims 1to 3, or a pharmaceutically acceptable salt thereof, wherein the structural unitIs selected from

A compound according to any one of claims 1to 11, or a pharmaceutically acceptable salt thereof, selected from,

wherein the content of the first and second substances,

T₁、T₂as claimed in claim 1;

T₃selected from N and C (R)_a)；

L₁、L₂As claimed in claim 1;

R₁、R₄as claimed in claim 1;

R₂the method according to claim 1to 3;

R_aas claimed in claims 1, 8 and 9;

R_bas claimed in claims 1, 10 and 11;

ring C is selected from C_3-6Cycloalkyl radical, C_3-6Cycloalkenyl and 3-to 6-membered heterocycloalkyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkenyl or 3-6 membered heterocycloalkyl optionally substituted with 1,2 or 3R;

optionally, ring C is selected fromThe above-mentioned

optionally, ring C is selected from

The compound according to claim 17, or a pharmaceutically acceptable salt thereof, selected from

Wherein the content of the first and second substances,

T₃selected from N and C (R)_a)；

R_aAs claimed in claims 1, 8 and 9;

R_bas claimed in claims 1, 10 and 11;

R₁、R₄as claimed in claim 1;

R₂the method according to claim 1to 3.

A compound of the formula or a pharmaceutically acceptable salt thereof,

a pharmaceutical composition comprising a compound according to any one of claims 1to 19, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

Use of a compound according to any one of claims 1to 19 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 20 for the manufacture of a medicament for the prophylaxis and/or treatment of diseases which are associated with the S1P1 receptor.

The use according to claim 21, wherein the S1P1 receptor-related disease is selected from ulcerative colitis, crohn' S disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, primary biliary cholangitis, allergic dermatitis, cerebral hemorrhage, graft-versus-host disease, psoriasis, type I diabetes, acne, microbial or microbial and viral infections or viral diseases.