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CN-122029146-A - S1PR4 modulator compounds for the treatment of autoimmune diseases and uses thereof

CN122029146ACN 122029146 ACN122029146 ACN 122029146ACN-122029146-A

Abstract

The invention also discloses a compound shown in the formula I and application thereof as an S1PR modulator, in particular an S1PR4 agonist. The compounds of the invention are capable of treating diseases related to the mediation of S1PR4 and mutants thereof, in particular autoimmune diseases. I。

Inventors

  • LI HONGLIN
  • QIAN XUHONG
  • WANG RUI
  • ZHAO ZHENJIANG
  • XU YUFANG
  • HE HUAN
  • GAO WEI
  • XIAO YUNPING
  • YE TIANYU

Assignees

  • 生元泽通(上海)医药有限公司

Dates

Publication Date
20260512
Application Date
20241008
Priority Date
20231008

Claims (13)

  1. A compound of formula I, or an optical isomer or pharmaceutically acceptable salt thereof: A is selected from a substituted or unsubstituted C 5 -C 8 aromatic ring (e.g., phenyl) or a C 8 -C 14 fused aromatic ring (e.g., naphthyl), a substituted or unsubstituted five-or six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N or O; R is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted C 1 -C 10 alkyl (e.g., methyl, trifluoromethyl, trifluoroethyl), substituted or unsubstituted C 3 -C 8 cycloalkyl or cycloalkenyl, substituted or unsubstituted C 1 -C 5 alkoxy, substituted or unsubstituted C 5 -C 8 aryl (e.g., phenyl), substituted or unsubstituted five or six membered heterocyclyl or heteroaryl containing 1-2 heteroatoms selected from N, O or S, substituted or unsubstituted C 1 -C 10 alkylcarbonyl, substituted or unsubstituted C 5 -C 8 arylformyl, and p is an integer from 1 to 3; R 1 is selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted C 1 -C 5 alkoxy, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 3 -C 6 cycloalkenyl, substituted or unsubstituted C 3 -C 8 lactone, substituted or unsubstituted C 1 -C 10 amide, substituted or unsubstituted C 5 -C 8 aryl, substituted or unsubstituted five or six membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, substituted or unsubstituted C 5 -C 8 aromatic heterocyclyl; n is selected from integers from 1 to 3; r 2 is selected from the group consisting of: m is selected from 1-4 integer; q is selected from integers of 1-2.
  2. The compound of claim 1, wherein the compound is of formula II, In the formula, R 1 is selected from the group consisting of hydrogen, halogen (preferably F, cl or Br), cyano, substituted or unsubstituted C 1 -C 5 alkoxy (preferably methoxy), substituted or unsubstituted C 1 -C 10 alkyl (preferably substituted or unsubstituted C 1 -C 6 alkyl, e.g., methyl, ethyl, trifluoromethyl), substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 3 -C 6 cycloalkenyl, substituted or unsubstituted C 5 -C 8 aryl, substituted or unsubstituted five or six membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, substituted or unsubstituted C 5 -C 8 aromatic heterocyclyl; r 2 is selected from the group consisting of: X is selected from C or N; R 3 is absent or is a substituent selected from the group consisting of hydrogen, cyano, halogen, substituted or unsubstituted C 1 -C 10 alkyl (e.g., methyl, trifluoromethyl, trifluoroethyl), substituted or unsubstituted C 3 -C 8 cycloalkyl, cyano, substituted or unsubstituted C 1 -C 5 alkoxy, substituted or unsubstituted C 1 -C 10 alkylcarbonyl, substituted or unsubstituted C 5 -C 8 arylformyl, substituted or unsubstituted C 5 -C 8 aryl, substituted or unsubstituted five-or six-membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S; R 5 is selected from the group consisting of hydrogen, cyano, halogen, substituted or unsubstituted C 1 -C 10 alkyl (e.g., methyl, trifluoromethyl, trifluoroethyl), substituted or unsubstituted C 3 -C 8 cycloalkyl, cyano, substituted or unsubstituted C 1 -C 5 alkoxy, substituted or unsubstituted C 1 -C 10 alkylcarbonyl, substituted or unsubstituted C 5 -C 8 arylformyl, substituted or unsubstituted C 5 -C 8 aryl, substituted or unsubstituted five-or six-membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S; R 4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl or cycloalkenyl, substituted or unsubstituted C 5 -C 8 aryl, substituted or unsubstituted five-or six-membered heterocyclyl or heteroaryl containing 1-2 heteroatoms selected from N, O or S, substituted or unsubstituted C 1 -C 10 alkylcarbonyl, substituted or unsubstituted arylformyl.
  3. A compound according to claim 1, wherein the compound is of formula III, In the formula, R 1 is selected from the group consisting of hydrogen, halogen (preferably F, cl or Br), cyano, substituted or unsubstituted C 1 -C 5 alkoxy (preferably methoxy), substituted or unsubstituted C 1 -C 10 alkyl (preferably substituted or unsubstituted C 1 -C 6 alkyl, e.g., methyl, ethyl, trifluoromethyl), substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 3 -C 6 cycloalkenyl, substituted or unsubstituted C 5 -C 8 aryl, substituted or unsubstituted five or six membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, substituted or unsubstituted C 5 -C 8 aromatic heterocyclyl; r 2 is selected from the group consisting of: R 3 is selected from the group consisting of hydrogen, cyano, halogen, substituted or unsubstituted C 1 -C 10 alkyl (e.g., methyl, trifluoromethyl, trifluoroethyl), substituted or unsubstituted C 3 -C 8 cycloalkyl, cyano, substituted or unsubstituted C 1 -C 5 alkoxy, substituted or unsubstituted C 1 -C 10 alkylcarbonyl, substituted or unsubstituted C 5 -C 8 arylformyl, substituted or unsubstituted C 5 -C 8 aryl, substituted or unsubstituted five-or six-membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S; R 5 is selected from the group consisting of hydrogen, cyano, halogen, substituted or unsubstituted C 1 -C 10 alkyl (e.g., methyl, trifluoromethyl, trifluoroethyl), substituted or unsubstituted C 3 -C 8 cycloalkyl, cyano, substituted or unsubstituted C 1 -C 5 alkoxy, substituted or unsubstituted C 1 -C 10 alkylcarbonyl, substituted or unsubstituted C 5 -C 8 arylformyl, substituted or unsubstituted C 5 -C 8 aryl, substituted or unsubstituted five-or six-membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S; R 4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl or cycloalkenyl, substituted or unsubstituted C 5 -C 8 aryl, substituted or unsubstituted five-or six-membered heterocyclyl or heteroaryl containing 1-2 heteroatoms selected from N, O or S, substituted or unsubstituted C 1 -C 10 alkylcarbonyl, substituted or unsubstituted arylformyl.
  4. A compound selected from the group consisting of the following, or an optical isomer or pharmaceutically acceptable salt thereof:
  5. a compound according to claim 3 wherein, in formula III, R 1 is selected from the group consisting of hydrogen, halogen (preferably F, cl or Br), cyano, substituted or unsubstituted C 1 -C 5 alkoxy (preferably methoxy), substituted or unsubstituted C 1 -C 6 alkyl (preferably methyl, ethyl, propyl); R 2 is: R 3 and R 5 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl (preferably methyl, ethyl or propyl), halogen (preferably F); R 4 is selected from the group consisting of substituted or unsubstituted C 5 -C 8 aryl (preferably phenyl or F substituted phenyl), substituted or unsubstituted five or six membered heterocyclyl or heteroaryl containing 1-2 heteroatoms selected from N, O or S.
  6. A compound selected from the group consisting of the following, or an optical isomer or pharmaceutically acceptable salt thereof:
  7. a compound according to claim 3 wherein, in formula III, R 1 is selected from the group consisting of cyano, substituted or unsubstituted C 1 -C 5 alkoxy (preferably methoxy), substituted or unsubstituted C 1 -C 6 alkyl (preferably methyl, ethyl, propyl); R 2 is: R 3 and R 5 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 3 alkyl (preferably methyl, ethyl or propyl), halogen (preferably F); R 4 is selected from the group consisting of substituted or unsubstituted C 5 -C 8 aryl (preferably phenyl or F substituted phenyl), substituted or unsubstituted five or six membered heteroaryl containing 1 to 2 heteroatoms selected from N, O or S.
  8. A compound selected from the group consisting of the following, or an optical isomer or pharmaceutically acceptable salt thereof:
  9. A pharmaceutical composition comprising a compound of any one of claims 1-8, or an optical isomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  10. Use of a compound of any one of claims 1-8, or an optical isomer or pharmaceutically acceptable salt thereof, in the manufacture of a S1PR modulator, in a preferred embodiment, the S1PR modulator is a S1PR4 selective agonist, a S1PR4 mutant selective agonist.
  11. A method of modulating S1PR in a subject, the method comprising the step of administering to a subject in need thereof an effective amount of a compound of any of claims 1-8, or an optical isomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9.
  12. A compound according to any one of claims 1 to 8, or an optical isomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for use in the treatment or prevention of S1PR4 mediated diseases.
  13. A medicament comprising a compound according to any one of claims 1 to 8, or an optical isomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 for treatment or prevention of S1PR4 mediated diseases.

Description

S1PR4 modulator compounds for the treatment of autoimmune diseases and uses thereof Technical Field The present invention relates to the field of pharmacy. In particular, the present invention relates to novel compounds of S1PR4 modulators useful in the prevention and treatment of autoimmune diseases and uses thereof. Background Sphingosine-1-phosphate (S1P) can mediate the transfer of biological signals to G protein-coupled receptors on biological membranes or act directly on intracellular receptors, thus playing a special role in mediating inflammatory reactions, allergic reactions, and participating in migration, proliferation and differentiation of immune cells, etc. Abnormal regulation of S1P signals is associated with autoimmune diseases, cardiovascular diseases, neurological diseases, cancers, and the like. As one of the G protein coupled receptor family members, 5 different S1P receptor subtypes are currently found in mammals, S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 (older names EDG1, EDG5, EDG3, EDG6 and EDG 8), respectively. Wherein S1PR1, S1PR2 and S1PR3 are widely expressed in various body tissues, and S1PR4 is mainly and intensively expressed in the lymphatic system and the blood system, and S1PR5 is mainly expressed in the central nervous system. At present, the research proves that the S1P can be combined with the S1PR1 on the cell surface to activate the beta-arestin signaling pathway to enable a receptor to sink, so that lymphocyte homing is induced, and the metastasis of the lymphocyte from peripheral lymph nodes and secondary lymphoid organs to the outside is inhibited, so that the effect of preventing the lymphocyte from migrating to an inflammation part is achieved, and the effect of inhibiting and regulating the immunity is very good. The targeted regulation of the S1PR1 signal path can realize the regulation of various autoimmune diseases, such as systemic lupus erythematosus, ulcerative colitis, crohn' S disease, multiple sclerosis, rheumatoid arthritis, psoriasis, ankylosing spondylitis and the like. However, the current marketed drugs targeting S1PR1 have better agonistic activity on other subtypes of S1PR, lack of selectivity, and especially the activation of S1PR3 can cause off-target side effects such as bradycardia, so that the development of selective S1PRs agonists has important significance. However, few reports of S1PR4 selective drugs are currently available, and almost all of the disclosed S1PR4 agonists/antagonists were developed by Edward Roberts of the united states Scripps institute, but these S1PR4 modulators were only discussed as in vitro tool molecules and no systematic mechanism studies and patent evaluations were performed. Therefore, the development of orally effective selective S1PR4 agonists/antagonists for use in the treatment of autoimmune diseases is of great scientific value. Disclosure of Invention It is an object of the present invention to provide related compounds as S1PR modulators, in particular S1PR4 agonists. It is another object of the present invention to provide a pharmaceutical composition comprising the above compound. It is a further object of the present invention to provide the use of the above compound or pharmaceutical composition for the preparation of a medicament for treating S1PR 4-related diseases or modulating S1P receptors. In a first aspect, the present invention provides a compound of formula I, or an optical isomer or pharmaceutically acceptable salt thereof: A is selected from a substituted or unsubstituted C 5-C8 aromatic ring (e.g., phenyl) or a C 8-C14 fused aromatic ring (e.g., naphthyl), a substituted or unsubstituted five-or six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N or O; R is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted C 1-C10 alkyl (e.g., methyl, trifluoromethyl, trifluoroethyl), substituted or unsubstituted C 3-C8 cycloalkyl or cycloalkenyl, substituted or unsubstituted C 1-C5 alkoxy, substituted or unsubstituted C 5-C8 aryl (e.g., phenyl), substituted or unsubstituted five or six membered heterocyclyl or heteroaryl containing 1-2 heteroatoms selected from N, O or S, substituted or unsubstituted C 1-C10 alkylcarbonyl, substituted or unsubstituted C 5-C8 arylformyl, and p is an integer from 1 to 3; R 1 is selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted C 1-C5 alkoxy, substituted or unsubstituted C 1-C10 alkyl, substituted or unsubstituted C 3-C8 cycloalkyl, substituted or unsubstituted C 2-C6 alkenyl, substituted or unsubstituted C 3-C6 cycloalkenyl, substituted or unsubstituted C 3-C8 lactone, substituted or unsubstituted C 1-C10 amide, substituted or unsubstituted C 5-C8 aryl, substituted or unsubstituted five or six membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, substituted or unsubstituted C 5-C8 aromatic heterocyclyl; n is selected from integers fro