阅读说明：本技术 作为肿瘤免疫类的化合物及其应用 (Compound as tumor immunity class and application thereof ) 是由 郭淑春 刘洋 彭建彪 于 2019-12-27 设计创作，主要内容包括：公开了式(Ⅰ)所示化合物、其光学异构体及其药效上可接受的盐,以及该化合物作为STING激动剂的应用。(I)<Image he="312" wi="700" file="DDA0002592644860000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Disclosed are compounds represented by formula (I), optical isomers thereof, pharmaceutically acceptable salts thereof, and use of the compounds as STING agonists. (I))

A compound represented by the formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

L₁、L₂each independently selected from-O-, -N (R) -and-C (RR) -;

L₃is selected from

R₁、R_1aEach independently selected from H, halogen, OH, NH₂、CN、N₃、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino and C_2-6Alkynyl, wherein said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino or C_2-6Alkynyl is optionally substituted with 1,2 or 3R; .

R₂、R_2aEach independently selected from H, halogen, OH, NH₂、CN、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino and C_2-6Alkynyl, wherein said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino or C_2-6Alkynyl is optionally substituted with 1,2 or 3R;

R₃、R_3aeach independently selected from H, halogen, OH, NH₂、CN、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino and C_2-6Alkynyl, wherein said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino or C_2-6Alkynyl is optionally substituted with 1,2 or 3R;

R₄、R_4aeach independently selected from H, halogen, OH, NH₂、CN、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino and C_2-6Alkynyl radicalWherein said C is_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino or C_2-6Alkynyl is optionally substituted with 1,2 or 3R;

R₅、R_5aeach independently selected from H, halogen, OH, NH₂、CN、N₃、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino and C_3-6Cycloalkyl, wherein said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino or C_3-6Cycloalkyl is optionally substituted with 1,2 or 3R;

X₁selected from BH₃ ^-and-S (R)₆)；

R₆Selected from H, CH₂OC(＝O)R₇、CH₂OC(＝O)OR₇、CH₂CH₂SC(＝O)R₇And CH₂CH₂SSCH₂R₇；

R₇Is selected from C_6-10Aryl, 5-to 10-membered heteroaryl, C_1-6Heterocycloalkyl and C₁-₂₀Alkyl radical, wherein said C₁-₂₀Alkyl is optionally substituted by 1,2,3, 4 or 5C_6-10Aryl radical, C_3-10Cycloalkyl, OH and F;

or, R₁And R₄Are linked together to form a 5-to 6-membered heterocycloalkyl group;

or, R_1aAnd R_4aAre linked together to form a 5-to 6-membered heterocycloalkyl group;

r is respectively and independently selected from H, halogen, OH and NH₂、CN、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino and C_1-6Alkyl- (C ═ O) NH-, in which the C is_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino or C_1-6Alkyl- (C ═ O) NH-optionally substituted with 1,2 or 3R';

r' is selected from F, Cl, Br, I, OH and NH₂And CH₃；

The 5-to 6-membered heterocycloalkyl group, 5-to 10-membered heteroaryl group or C_1-6Heterocycloalkyl comprises 1,2 or 3 substituents independently selected from-O-, -NH-, -S-, -C (═ O) O-, -S (═ O)₂-and N.

The compound according to claim 1, wherein R is independently selected from H, halogen, OH, NH, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof₂、CN、

The compound according to claim 2, optical isomers thereof and pharmaceutically acceptable salts thereof, wherein R is independently selected from H, F, Cl, Br, I, OH, NH, respectively₂、CN、Me、

A compound according to claim 3, optical isomers and pharmaceutically acceptable salts thereof, wherein R is independently selected from H, F, Cl, Br, I, OH, NH₂、CN、Me、

The compound, its optical isomer and pharmaceutically acceptable salt according to any of claims 1 to 4, wherein R₁、R_1aEach independently selected from H, F, Cl, Br, OH, NH₂、CN、N₃、C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio radical, C_1-3Alkylamino and C_2-3Alkynyl, wherein said C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio radical, C_1-3Alkylamino or C_2-3Alkynyl is optionally substituted with 1,2 or 3R.

The compound, its optical isomer and pharmaceutically acceptable salt according to claim 5, wherein R₁、R_1aEach independently selected from H, F, Cl, Br, OH, NH₂、CN、N₃Me and

the compound, its optical isomer and pharmaceutically acceptable salt according to any of claims 1 to 4, wherein R₅、R_5aAre respectively and independentlySelected from H, F, Cl, Br, OH, NH₂、CN、N₃、C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio radical, C_1-3Alkylamino and C_3-6Cycloalkyl, wherein said C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio radical, C_1-3Alkylamino or C_3-6Cycloalkyl is optionally substituted with 1,2 or 3R.

The compound, its optical isomer and pharmaceutically acceptable salt according to claim 7, wherein R₅、R_5aEach independently selected from H, F, Cl, Br, OH, NH₂、CN、N₃、Me、

The compound according to claim 1, optical isomers thereof and pharmaceutically acceptable salts thereof, wherein R is₁And R₄Connected together as a structural unit

The compound according to claim 1, optical isomers thereof and pharmaceutically acceptable salts thereof, wherein R is_1aAnd R_4aConnected together as a structural unit

The compound according to claim 1, optical isomers thereof and pharmaceutically acceptable salts thereof, wherein L₁、L₂Are each independently selected from-O-, -NH-and-CH_2-。

The compound according to claim 1, optical isomers thereof and pharmaceutically acceptable salts thereof, wherein L₃Is selected from

The compound, its optical isomer and pharmaceutically acceptable salt according to claim 11 or 12, wherein the structural unit

The compound according to any one of claims 1 to 3, its optical isomer and its pharmaceutically acceptable salt selected from the group consisting of

Wherein the content of the first and second substances,

X₁as defined in claim 1;

R₁as defined in claim 1, 5, 6 or 9;

R_1aas defined in claim 1, 5, 6 or 10;

R₄as defined in claim 1 or 9;

R_4aas defined in claim 1 or 10;

R₅、R_5aas defined in claim 1, 7 or 8;

L₁、L₂as defined in claim 1, 11 or 13;

L₃as defined in claim 1, 12 or 13.

A compound of the formula, optical isomers thereof, and pharmaceutically acceptable salts thereof, selected from the group consisting of:

a pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 for the manufacture of a medicament for the prevention and/or treatment of STING-related diseases.

The use according to claim 17, wherein the STING-related disease is selected from lymphoma, melanoma, colorectal cancer, breast cancer, acute myeloid leukemia, colon cancer, liver cancer, prostate cancer, pancreatic cancer, renal cancer and glioma, bladder cancer, pleural effusion, malignant pleural effusion, head and neck cancer, fibrosarcoma, renal cell carcinoma, lung cancer, malignant ascites, gastric cancer, ovarian cancer, uterine cancer, neuroblastoma, bone cancer, rhabdomyosarcoma, and esophageal cancer.