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CN-122010928-A - PCSK9 inhibitor and application thereof

CN122010928ACN 122010928 ACN122010928 ACN 122010928ACN-122010928-A

Abstract

The invention belongs to the field of medicines, relates to a PCSK9 inhibitor and application thereof, and application of the compound in preparing medicines for treating or preventing PCSK9 mediated diseases, in particular to a compound shown in a formula I, or a stereoisomer or pharmaceutically acceptable salt or prodrug thereof, wherein each substituent in the formula I is as defined in the specification.

Inventors

  • QIN YINLIN
  • SU MEI
  • WANG CHAOLEI
  • ZHANG YA

Assignees

  • 江苏柯菲平医药股份有限公司

Dates

Publication Date
20260512
Application Date
20251110
Priority Date
20241112

Claims (15)

  1. 1. A compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug thereof: Wherein L 1 、L 2 、L 3 and L 4 are each independently selected from CH or N, and no more than two of L 1 、L 2 、L 3 and L 4 are selected from N, the remainder being CH; R 1 is selected from isopropyl, C 1-3 haloalkyl or C 3-5 cycloalkyl, wherein each of said C 3-5 cycloalkyl is optionally substituted with one or more substituents selected from hydrogen, halogen, halo C 1-6 alkyl or C 1-6 alkyl; r 2 is selected from hydrogen or halogen; R 3 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 haloalkyl; x is selected from O or S.
  2. 2. The compound of claim 1, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is represented by formula I-1: Wherein L 1 、L 2 、L 3 and L 4 are each independently selected from CH or N, and no more than two of L 1 、L 2 、L 3 and L 4 are selected from N, the remainder being CH; R 1 is selected from isopropyl, C 1-3 haloalkyl or C 3-5 cycloalkyl, wherein each of said C 3-5 cycloalkyl is optionally substituted with one or more substituents selected from hydrogen, halogen, halo C 1-6 alkyl or C 1-6 alkyl; R 3 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl.
  3. 3. The compound of claim 1 or 2, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein L 1 、L 2 、L 3 and L 4 consist of Selected from:
  4. 4. the compound of claim 1, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is represented by formula I-2: X is selected from O or S; R 1' is selected from halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from hydrogen or halogen; r 2 is selected from hydrogen or halogen; L 1 、L 2 、L 3 and L 4 are each independently selected from CH or N, and no more than two of L 1 、L 2 、L 3 and L 4 are selected from N, the remainder being CH; R 3 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, or C 1-3 alkoxy, wherein the C 1-3 alkyl is optionally substituted with one or more substituents selected from hydrogen or halogen; n is each independently selected from 0, 1 or 2.
  5. 5. The compound of claim 4, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I-2 is represented by formula I-2-1: R 1' is selected from fluorine or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more substituents selected from hydrogen or halogen; n is each independently selected from 0, 1 or 2.
  6. 6. The compound of claim 4, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I-2 is represented by formula I-2-2: R 1' is selected from fluorine or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more substituents selected from hydrogen or halogen; n is each independently selected from 0, 1 or 2.
  7. 7. The compound of claim 5 or 6, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1' is selected from fluoro, methyl, or trifluoromethyl, and n is each independently selected from 0, 1, or 2.
  8. 8. The compound of claim 5 or 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Selected from:
  9. 9. The compound of claim 4, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein L 1 、L 2 、L 3 and L 4 consist of Selected from: R 3 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, or C 1-3 alkoxy, wherein the C 1-3 alkyl is optionally substituted with one or more substituents selected from hydrogen or halogen.
  10. 10. The compound of claim 9, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, halo, cyano, C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 haloalkyl.
  11. 11. The compound of claim 10, or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, fluoro, chloro, cyano, methyl, methoxy, difluoromethyl, or trifluoromethyl.
  12. 12. The compound according to any one of claims 1-11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following:
  13. 13. A pharmaceutical composition comprising a compound, stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  14. 14. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, a solvate, metabolite, co-crystal or prodrug thereof, or a composition of the foregoing, in the manufacture of a medicament for the treatment/prophylaxis of a PCSK 9-mediated disease.
  15. 15. The use according to claim 14, wherein the disease is hyperlipidemia.

Description

PCSK9 inhibitor and application thereof The invention claims priority of a PCSK9 inhibitor and application thereof, which are submitted to the China national intellectual property office on the 11 th and 12 th of 2024, the patent application number is 202411606429.5, and the invention claims priority of a prior application, which is submitted to the China national intellectual property office on the 24 th of 2025, the patent application number is 202510121938.7, and the invention name is a PCSK9 inhibitor and application thereof. The entire contents of the above-mentioned prior application are incorporated by reference into the present invention. Technical Field The invention belongs to the field of medicines, and particularly relates to a PCSK9 inhibitor and application thereof, and application of the compound in preparing medicines for treating or preventing PCSK9 mediated diseases. Background Epidemiological, genetic and clinical intervention studies have demonstrated that LDL-C is a causative risk factor for ASCVD and that reducing LDL-C levels significantly reduces the incidence of ASCVD and the risk of mortality. Intervention with different intensities according to ASCVD risk stratification is a core strategy of blood lipid management, and ASCVD overall risk assessment is a basis of blood lipid management decisions. LDL-C is the primary target for lipid-lowering therapy, with greater amplitude of LDL-C lowering and longer duration, more risk of ASCVD lowering. Although statins can reduce serum LDL-C levels, they are currently the major lipid lowering agents in the clinic. However, statins have limited lipid lowering capacity (LDL-C decrease < 50%), and have a dose-response bottleneck (dose multiplication, lipid lowering amplitude increases by only 6%). Meanwhile, the PCSK9 can be up-regulated by statin treatment, and the effectiveness of statin is further reduced. Thus, about 50% of individuals using statins are unable to reduce their LDL-C levels to the desired level. In addition, hepatotoxic and myotoxic side effects also exist. The incidence of sustained increases in aminotransferase levels in the first three months of administration is 0.5% -3.0%, and myotoxicities including myalgia, myositis and rhabdomyolysis, myositis and severe rhabdomyolysis are rare. Patients taking statin drugs often have statin intolerance. The existing treatment gold standard has great disadvantages in curative effect, tolerance and compliance, a new target mechanism is needed to optimize a medication scheme, and the advent of PCSK9 targets provides a solution idea for the development of new lipid-lowering drugs. Proprotein convertase subtilisin/kexin type 9 (PCSK 9) is a serine protease secreted primarily by liver synthesis. Under normal physiological functions, most of the low-density lipoprotein cholesterol (LDL-C) is combined with LDL receptors (LDL-R) existing on the surface of liver cells to form a complex, the complex is engulfed into the liver cells, the complex is dissociated in the acidic environment, then the LDL-C is gradually degraded in lysosomes of the liver cells, and the LDL-R and the LDL-C are dissociated and then return to the surface of the liver cells again to capture the rest of the LDL-C and enter the next degradation cycle. PCSK9 can combine with LDL-R and then combine with LDL-C to form a new complex, and enters the lysosome to be degraded together, so that free LDL-R in blood is reduced, and the degradation of LDL-C is reduced, so that the level of LDL-C is increased. Under pathological action, related research evidence shows that the mutation in the PCSK9 gene can cause the expression of PCSK9 protein to be increased, promote the rise of LDL-C level to cause the occurrence of familial hypercholesterolemia, and can also effectively regulate the lipid metabolism level in vivo to influence the occurrence and development of coronary heart disease. In human and animal models, there have been studies showing that treatment with statins increases plasma PCSK9 levels, resulting in a partial attenuation of the statin effect on LDL-R expression, further reducing statin effectiveness. The PCSK9 monoclonal antibody or siRNA medicine can further reduce LDL-C by at least 50% on statin treatment, but the price of the PCSK9 monoclonal antibody or siRNA medicine on the market at present is generally set higher, the production cost is high, and injection administration is needed. Thus, there is an urgent need for the development of small molecule PCSK9 inhibitors that are highly safe, have fewer adverse effects, and can be orally administered and more economically produced. Related patent researches on the global micromolecular PCSK9 inhibitor are carried out, and the clinical progress actively comprises an AZD0780 (clinical 3 phase) WO2020150473A2 as an aslicon micromolecular drug. Disclosure of Invention In one aspect, the invention provides a compound of formula I, or a stereoisomer thereof, or a pharmaceutica