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CN-122010906-A - Aromatic heterocyclic derivative with S1P receptor modulating activity, and preparation method and application thereof

CN122010906ACN 122010906 ACN122010906 ACN 122010906ACN-122010906-A

Abstract

The invention relates to the technical field of pharmaceutical chemistry, in particular to an aromatic heterocyclic derivative with S1P receptor regulating activity, a preparation method and application thereof. In one embodiment, the aromatic heterocyclic derivative is a compound of formula (I) or a geometric isomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof. In another embodiment, the use is as a therapeutic agent, in particular an S1P1 receptor agonist. General formula (I)

Inventors

  • XING GANG
  • CHENG MAOSHENG
  • MA LANYAN
  • WANG XIAO
  • WANG JUNKAI

Assignees

  • 沈阳药科大学

Dates

Publication Date
20260512
Application Date
20260202

Claims (10)

  1. 1. An aromatic heterocyclic derivative with S1P receptor modulating activity is characterized in that the derivative is a compound shown in a general formula (I) or a geometric isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein the compound shown in the general formula (I) is as follows: General formula (I) Wherein X is selected from C or N; R 1 and R 2 are the same or different and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy, phenyl, or substituted or unsubstituted 5-7 membered heteroaryl; r 3 is independently selected from 、 、 、 Or (b) Wherein L is selected from carbonyl, methylene or sulfonyl, n is selected from integers from 0 to 3, and R is selected from carboxyl, hydroxyl, amino or carboxamide; a is selected from benzene ring or 5-9 membered aromatic heterocycle, and hetero atom in the aromatic heterocycle is selected from N, O or S; C is selected from a substituted or unsubstituted saturated five-membered heterocycle or five-membered aromatic heterocycle, and a heteroatom in the five-membered heterocycle or the five-membered aromatic heterocycle is selected from N, O or S; B is selected from a substituted or unsubstituted five-membered aromatic heterocycle, and a heteroatom in the five-membered heteroaromatic ring is selected from N, O or S; or when C is selected from a substituted or unsubstituted saturated five-membered heterocyclic ring, B is selected from Or (b) 。
  2. 2. The aromatic heterocyclic derivative having S1P receptor modulating activity as described in claim 1, wherein the derivative is a compound represented by the general formula (II) or a geometric isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, the compound represented by the general formula (II) being as follows: general formula (II) R 1 and R 2 are the same or different and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy, phenyl, or substituted or unsubstituted 5-7 membered heteroaryl; r 3 is independently selected from 、 、 、 Or (b) Wherein L is selected from carbonyl, methylene or sulfonyl, n is selected from integers from 0 to 3, and R is selected from carboxyl, hydroxyl, amino or carboxamide; a is selected from benzene ring, 5-9 membered aromatic heterocycle, heteroatom in the said aromatic heterocycle is selected from N, O or S; b is selected from a substituted or unsubstituted five-membered aromatic heterocycle, Or (b) The heteroatom in the five-membered aromatic heterocycle is selected from N, O or S; y is independently selected from CH 2 or CO; z is independently selected from CH 2 or CO.
  3. 3. The aromatic heterocyclic derivative having S1P receptor modulating activity as described in claim 1, wherein the derivative is a compound represented by the general formula (III) or a geometric isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, the compound represented by the general formula (III) being as follows: General formula (III) R 1 and R 2 are the same or different and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy, phenyl, or substituted or unsubstituted 5-7 membered heteroaryl; r 3 is independently selected from Or (b) Wherein L is selected from methylene, n is selected from an integer from 1 to 2, and R is selected from carboxyl, hydroxyl, amino or carboxamide; A is selected from benzene ring or 5-9 membered aromatic heterocycle, and hetero atom in the heteroaryl is selected from N, O or S; b is selected from a substituted or unsubstituted five-membered heteroaryl, and a heteroatom in the five-membered heteroaryl ring is selected from N, O or S; X is selected from C or N; y is selected from C, N, O or S.
  4. 4. The aromatic heterocyclic derivative having S1P receptor modulating activity as described in any one of the claims 1 to 3, characterized in that the derivative is a compound represented by the formula II-1, II-2, II-3, III-1 or III-2 or a geometric isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof: R 1 and R 2 are the same or different and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy, phenyl, or substituted or unsubstituted 5-7 membered heteroaryl; r 3 is independently selected from 、 、 、 Or (b) Wherein L is selected from carbonyl, methylene or sulfonyl, n is selected from integers from 0 to 3, and R is selected from carboxyl, hydroxyl, amino or carboxamide.
  5. 5. The aromatic heterocyclic derivative having S1P receptor-modulating activity as described in claim 1, wherein the derivative is: 4- (5- (1- (4-isobutylphenyl) -1H-1,2, 3-triazol-4-yl) isoindolin-2-yl) propionic acid 4- (5- (1- (4-Isobutylphenyl) -1H-1,2, 3-triazol-4-yl) isoindolin-2-yl) butanoic acid 2- (5- (1- (4-Isobutylphenyl) -1H-1,2, 3-triazol-4-yl) isoindolin-2-yl) ethan-1-ol 3- (5- (1- (4-Isobutylphenyl) -1H-1,2, 3-triazol-4-yl) isoindolin-2-yl) propane-1, 2-diol 3- (5- (1- (4-Isobutylphenyl) -1H-1,2, 3-triazol-4-yl) isoindolin-2-yl) cyclopentane-1-carboxylic acid 4- (5- (1- (4-Isobutylphenyl) -1H-1,2, 3-triazol-4-yl) isoindolin-2-yl) cyclohexane-1-carboxylic acid 4- (5- (1- (4-Isopropylphenyl) -1H-1,2, 3-triazol-4-yl) isoindolin-2-yl) butanoic acid 5- (5- (1- (3- (Pyrrolidin-1-yl) phenyl) -1H-1,2, 3-triazol-4-yl) isoindolin-2-yl) butanoic acid 5- (5- (1- (3- (Pyrrolidin-1-yl) phenyl) -1H-1,2, 3-triazol-4-yl) isoindolin-2-yl) pentanoic acid 4- (5- (1- (4- (Pyrrolidin-1-yl) phenyl) -1H-1,2, 3-triazol-4-yl) isoindolin-2-yl) butanoic acid 5- (5- (1- (4- (Pyrrolidin-1-yl) phenyl) -1H-1,2, 3-triazol-4-yl) isoindolin-2-yl) pentanoic acid 3- (5- (4- (4-Propylphenyl) -1H-1,2, 3-triazol-1-yl) isoindolin-2-yl) propionic acid 3- (5- (4- (4-Propylphenyl) -1H-1,2, 3-triazol-1-yl) isoindolin-2-yl) butanoic acid 3- (5- (4- (4-Isopropylphenyl) -1H-1,2, 3-triazol-1-yl) isoindolin-2-yl) propionic acid 3- (5- (4- (4-Isopropylphenyl) -1H-1,2, 3-triazol-1-yl) isoindolin-2-yl) butanoic acid 3- (5- (4- (4-Tert-butylphenyl) -1H-1,2, 3-triazol-1-yl) isoindolin-2-yl) propionic acid 5- (5- (4- (4-Tert-butylphenyl) -1H-1,2, 3-triazol-1-yl) isoindolin-2-yl) pentanoic acid 4- (5- (5- (4-Isobutylphenyl) thiazol-2-yl) isoindolin-2-yl) butanoic acid 5- (5- (4-Isobutylphenyl) thiazol-2-yl) isoindolin-2-yl) pentanoic acid 5- (5- (5- (4-Ethylphenyl) thiazol-2-yl) isoindolin-2-yl) butanoic acid 5- (5- (4-Ethylphenyl) thiazol-2-yl) isoindolin-2-yl) pentanoic acid 3- (5- (5- (3, 4-Dimethylphenyl) thiazol-2-yl) isoindolin-2-yl) butanoic acid 4- (6- (1- (4-Propylphenyl) -1H-1,2, 3-triazol-4-yl) -1H-indazol-1-yl) butanoic acid 4- (6- (1- (4-Tert-butylphenyl) -1H-1,2, 3-triazol-4-yl) -1H-indazol-1-yl) butyric acid 4- (6- (1- (4-Isopropoxyphenyl) -1H-1,2, 3-triazol-4-yl) -1H-indazol-1-yl) butanoic acid 4- (6- (1- (4-Isopropylphenyl) -1H-1,2, 3-triazol-4-yl) -1H-indazol-1-yl) butanoic acid 4- (6- (1- (4-Ethoxyphenyl) -1H-1,2, 3-triazol-4-yl) -1H-indazol-1-yl) butanoic acid 4- (6- (1- (3- (Pyrrolidin-1-yl) phenyl) -1H-1,2, 3-triazol-4-yl) -1H-indazol-1-yl) butanoic acid 4- (6- (1- (4-Morpholinylphenyl) -1H-1,2, 3-triazol-4-yl) -1H-indazol-1-yl) butanoic acid 4- (6- (1- (4- (Pyrrolidin-1-yl) phenyl) -1H-1,2, 3-triazol-4-yl) -1H-indazol-1-yl) butanoic acid 4- (6- (1- (4- (4-Propylpiperazin-1-yl) phenyl) -1H-1,2, 3-triazol-4-yl) -1H-indazol-1-yl) butanoic acid 4- (6- (1- (4-Cyclohexylphenyl) -1H-1,2, 3-triazol-4-yl) -1H-indazol-1-yl) butanoic acid 4- (6- (1- (4-Propylphenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butanoic acid 4- (6- (1- (4-Tert-butylphenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butyric acid 4- (6- (1- (4-Isopropoxyphenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butanoic acid 4- (6- (1- (4-Isobutylphenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butanoic acid 4- (6- (1- (4-Isopropylphenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butanoic acid 4- (6- (1- (4-Ethoxyphenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butanoic acid 4- (6- (1- (3- (Pyrrolidin-1-yl) phenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butanoic acid 4- (6- (1- (4-Morpholinophenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butanoic acid 4- (6- (1- (4- (Pyrrolidin-1-yl) phenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butanoic acid 4- (6- (1- (4- (4-Propylpiperazin-1-yl) phenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butanoic acid 4- (6- (1- (4-Cyclohexylphenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butanoic acid 4- (6- (1- (4-Cyclopentylphenyl) -1H-1,2, 3-triazol-4-yl) -2H-indazol-2-yl) butanoic acid.
  6. 6. A pharmaceutical composition having S1P receptor modulating activity, comprising a derivative according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
  7. 7. Use of a derivative according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 for the preparation of a S1P receptor modulator, characterized in that preferably the S1P receptor modulator is a S1P1 receptor agonist.
  8. 8. Use of a derivative according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 for the preparation of a medicament for the prophylaxis or treatment of a disease associated with S1P receptor activity.
  9. 9. The method according to claim 8, wherein the disease is an autoimmune disease.
  10. 10. The method according to claim 9, wherein the autoimmune disease is multiple sclerosis, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis or Crohn's disease.

Description

Aromatic heterocyclic derivative with S1P receptor modulating activity, and preparation method and application thereof Technical Field The present invention belongs to the field of pharmaceutical chemistry. The present invention relates to aromatic heterocyclic derivatives as modulators of the S1P receptor, to a process for their preparation and to their use as therapeutic agents, in particular as S1P1 receptor agonists. Background Sphingosine-1-phosphate (S1P) is a key bioactive lipid mediator that is widely involved in and regulates a variety of important physiological and pathological processes such as cell proliferation, migration, survival and immune inflammatory responses by activating the S1P receptor (S1 PR1-S1PR 5) in the G protein-coupled receptor (GPCR) family. Among them, the S1P1 receptor subtype plays a central role in immunomodulation, which mediates the process of lymphocyte migration from secondary lymphoid organs to the circulatory system (blood and lymph). Based on this clear mechanism, S1P receptor modulators (particularly functional modulators) have become an important class of drugs for the treatment of autoimmune diseases. The medicine can induce receptor internalization and functional down regulation by combining with S1P1 receptor on lymphocyte surface, so that lymphocyte is effectively retained in lymphoid tissue, recruitment path to inflammation site is blocked, and effect of inhibiting autoimmune reaction is finally achieved. At present, several S1P receptor agonists are marketed in batches, and the indications are autoimmune diseases such as multiple sclerosis. In addition to the already established immunomodulatory functions, more and more preclinical and clinical studies have revealed that the S1P1 receptor signaling pathway also plays an important role in the progression of diseases such as tumorigenesis, angiogenesis, atherosclerosis and thrombosis. Therefore, the targeting of the S1P receptor not only provides a mature treatment strategy for autoimmune diseases, but also has great treatment potential in the fields of oncology, cardiovascular diseases and the like. In view of the clear mechanism and wide treatment prospect of the S1P receptor signaling pathway, the research and development of novel, efficient and safe targeted S1P receptor drugs has great scientific significance and market value for meeting clinical demands. Disclosure of Invention The object of the present invention is to provide aromatic heterocyclic derivatives as S1P receptor modulators, methods of preparation thereof and use as therapeutic agents, in particular S1P1 receptor agonists. In a first aspect, the present invention provides an aromatic heterocyclic derivative having S1P receptor modulating activity, which is a compound of formula (I) or a geometric isomer, enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein the compound of formula (I) is as follows: General formula (I) Wherein X is selected from C or N; R 1 and R 2 are the same or different and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C 1-C10 alkyl, substituted or unsubstituted C 3-C8 cycloalkyl, substituted or unsubstituted C 1-C6 alkoxy, phenyl, or substituted or unsubstituted 5-7 membered heteroaryl; r 3 is independently selected from 、、、Or (b)Wherein L is selected from carbonyl, methylene or sulfonyl, n is selected from integers from 0 to 3, and R is selected from carboxyl, hydroxyl, amino or carboxamide; a is selected from benzene ring or 5-9 membered aromatic heterocycle, and hetero atom in the aromatic heterocycle is selected from N, O or S; C is selected from a substituted or unsubstituted saturated five-membered heterocycle or five-membered aromatic heterocycle, and a heteroatom in the five-membered heterocycle or the five-membered aromatic heterocycle is selected from N, O or S; B is selected from a substituted or unsubstituted five-membered aromatic heterocycle, and a heteroatom in the five-membered heteroaromatic ring is selected from N, O or S; or when C is selected from a substituted or unsubstituted saturated five-membered heterocyclic ring, B is selected from Or (b); Preferably, the structural unitSelected from: ; B is selected from: ; R 1 and R 2 are the same or different and are independently selected from hydrogen, halogen, cyano, amino, substituted or unsubstituted C 1-C10 alkyl, substituted or unsubstituted C 3-C8 cycloalkyl, substituted or unsubstituted C 1-C6 alkoxy, phenyl, or substituted or unsubstituted 5-7 membered heteroaryl; r 3 is independently selected from 、、、Or (b)Wherein L is selected from carbonyl, methylene or sulfonyl, n is selected from integers from 0 to 3, and R is selected from carboxyl, hydroxyl, amino or carboxamide; Further preferably, A is phenyl, a structural unit And B is selected from: ; R 1 and R 2 are the same or different and are independently selected from hydrogen, halogen, cyano, amino,