WO2022257961A1 - Composé benzohétérocyclique pour traiter des maladies médiées par le récepteur ep2 et ep4 - Google Patents

Composé benzohétérocyclique pour traiter des maladies médiées par le récepteur ep2 et ep4 Download PDF

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WO2022257961A1
WO2022257961A1 PCT/CN2022/097611 CN2022097611W WO2022257961A1 WO 2022257961 A1 WO2022257961 A1 WO 2022257961A1 CN 2022097611 W CN2022097611 W CN 2022097611W WO 2022257961 A1 WO2022257961 A1 WO 2022257961A1
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indazole
propane
carboxylic acid
ethyl
compound
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Chinese (zh)
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张学军
臧杨
李群
丁肖华
王俊南
李禹琼
李莉娥
杨俊�
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武汉人福创新药物研发中心有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the invention belongs to the field of medicine, in particular, the invention relates to a benzoheterocyclic compound for treating diseases mediated by EP2 and EP4 receptors, a preparation method and application.
  • Prostaglandin E2 is an endogenous bioactive lipid. PGE2 induces a wide range of upstream and downstream dependent biological responses by activating prostaglandin receptors, and participates in the regulation of inflammation, pain, renal function, and cardiovascular system. , lung function and cancer and many other physiological and pathological processes. It has been reported that PGE2 is highly expressed in cancerous tissues of various cancers, and it has been confirmed that PGE2 is associated with the occurrence, growth and development of cancer and disease conditions in patients. It is generally believed that PGE2 is associated with the activation of cell proliferation and cell death (apoptosis), and plays an important role in the process of cancer cell proliferation, disease progression and cancer metastasis.
  • apoptosis apoptosis
  • EP1 receptor activates the phospholipase C and inositol triphosphate pathways
  • EP2 and EP4 receptors activate adenylate cyclase and cAMP-protein kinase A
  • the activation of the EP3 receptor both inhibits adenylate cyclase and Activates phospholipase C.
  • EP2 and EP4 are expressed in various immune cells (such as macrophages, dendritic cells, NK cells and CTLs), and inhibiting EP2 and EP4 can enhance immune activity and inhibit tumor growth.
  • immune cells such as macrophages, dendritic cells, NK cells and CTLs
  • PGE2 persistently activates EP receptors in the tumor microenvironment (produced in large quantities by tumor cells), which promotes the accumulation and enhances the activity of a variety of immunosuppressive cells, including type 2 tumor-associated macrophages (TAMS) , Treg cells and myeloid-derived suppressor cells (MDSCs).
  • TAMS type 2 tumor-associated macrophages
  • MDSCs myeloid-derived suppressor cells
  • One of the main features of the immunosuppressive tumor microenvironment is the presence of a large number of MDSCs and TAMs, which in turn are associated with gastric cancer, ovarian cancer, breast cancer, bladder cancer, hepatocellular carcinoma (HCC), head and neck cancer, and other types of cancer patients. It is closely related to poor overall survival.
  • PGE2 has been reported to induce immune tolerance by inhibiting the accumulation of antigen-presenting dendritic cells (DCs) in tumors and inhibiting the activation of tumor-infiltrating DCs), thereby helping tumor cells escape immune surveillance.
  • DCs antigen-presenting dendritic cells
  • PGE2 plays a very important role in promoting the occurrence and development of tumors. It has been found that the expression levels of PGE2 and its related receptors EP2 and EP4 are increased in various malignant tumors including colon cancer, lung cancer, breast cancer, and head and neck cancer. Often closely associated with poor prognosis. Therefore, selectively blocking EP2 and EP4 signaling pathways can inhibit tumor development by changing the tumor microenvironment and regulating tumor immune cells.
  • EP4 antagonists have been shown to be effective in alleviating joint inflammation and pain in rodent models of rheumatoid arthritis and osteoarthritis, and have also been shown to be effective in rodent models of autoimmune disease.
  • EP2 antagonists may be shown to be effective in certain chronic inflammatory diseases (especially inflammatory neurodegenerative diseases such as epilepsy, Alzheimer's disease (AD) , Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and traumatic brain injury (TBI)).
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • ALS amyotrophic lateral sclerosis
  • TBI traumatic brain injury
  • EP2 and EP4 suppresses the expression of progesterone (P4) signaling machinery proteins in epithelial and mesenchymal cell-specific patterns in endometriotic lesions and inhibits the persistence, invasion, biosynthesis and signaling of PGE2 and estrogen (E2) Transduction, thereby inhibiting the production of pro-inflammatory cytokines, reducing the growth, survival and spread of endometriotic lesions, alleviating pelvic pain, and restoring endometrial receptivity.
  • P4 progesterone
  • E2 and estrogen E2 Transduction
  • the object of the present invention is to provide a benzoheterocyclic compound for treating diseases mediated by EP2 and EP4 receptors and its preparation method and application. and heterocyclic compounds, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof.
  • the first aspect of the present invention provides a benzoheterocyclic compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:
  • R 1 and R 2 are respectively hydrogen or -C ⁇ CR 11 , and R 1 and R 2 are different;
  • the R 11 is hydrogen or selected from: C 1 -C 5 alkyl, 3-6 membered cycloalkyl;
  • the R 11 is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, C 1 -C 5 alkyl; when there are multiple substituents, the substituents are the same or different;
  • L 1 is C 1 -C 5 alkylene
  • L 2 does not exist or is unsubstituted or substituted by Rb C 1 -C 3 alkylene;
  • the L 1 is optionally substituted by Ra 1 and/or Ra 2 ;
  • the Ra 1 and Ra 2 are each independently C 1 -C 5 alkyl, halogen, hydroxyl, amino, C 1 -C 5 alkoxy, C 1 -C 5 haloalkyl, C 1 -C 5 haloalkoxy ;
  • Ra 1 and Ra 2 form a 3-6-membered cycloalkyl group or a 4-6-membered heterocycloalkyl group together with the C atoms they are connected to;
  • the Rb is C 1 -C 3 alkyl or halogen
  • Ring A is phenyl or 5-6 membered heteroaryl
  • Ring B does not exist or is 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl;
  • R 3 and R 4 are each independently selected from: hydroxyl, halogen, amino, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, 3-6 membered cycloalkyl, 4-6 membered hetero Cycloalkyl, 3-6 membered cycloalkoxy; said C 1 -C 5 alkyl, C 1 -C 5 alkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3 -6-membered cycloalkoxy is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, amino, cyano, 3-6-membered cycloalkyl;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • R 1 and R 2 are respectively hydrogen or -C ⁇ CR 11 , and R 1 and R 2 are different;
  • the R 11 is hydrogen or selected from: C 1 -C 5 alkyl, 3-6 membered cycloalkyl;
  • the R 11 is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, C 1 -C 5 alkyl; when there are multiple substituents, the substituents are the same or different;
  • L 1 is C 1 -C 5 alkylene
  • L 2 does not exist or is unsubstituted or substituted by Rb C 1 -C 3 alkylene;
  • the L 1 is optionally substituted by Ra 1 and/or Ra 2 ;
  • the Ra 1 and Ra 2 are each independently C 1 -C 5 alkyl, halogen, hydroxyl, amino, C 1 -C 5 alkoxy, C 1 -C 5 haloalkyl, C 1 -C 5 haloalkoxy ;
  • Ra 1 and Ra 2 form a 3-6-membered cycloalkyl group or a 4-6-membered heterocycloalkyl group together with the C atoms they are connected to;
  • the Rb is C 1 -C 3 alkyl or halogen
  • Ring A is phenyl or 5-6 membered heteroaryl
  • Ring B does not exist or is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl;
  • R 3 and R 4 are each independently selected from: hydroxyl, halogen, amino, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, 3-6 membered cycloalkyl, 4-6 membered hetero Cycloalkyl, 3-6 membered cycloalkoxy; said C 1 -C 5 alkyl, C 1 -C 5 alkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3 -6-membered cycloalkoxy is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, amino, cyano, 3-6-membered cycloalkyl;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • the 5-6 membered heteroaryl contains one or more heteroatoms selected from N, O or S; when there are multiple heteroatoms, the The heteroatoms are the same or different; preferably, the 5-6 membered heteroaryl is selected from: thiophene, furan, pyrrole, pyrazole, imidazole, triazole, thiazole, thiadiazole, oxazole, pyridine, pyrimidine , pyridazine, pyrazine.
  • Ra 1 and Ra 2 form oxetane together with their common C atoms.
  • L 1 is -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -; preferably, L 1 is -CH 2 - , -CH(CH 3 )-.
  • R 3 and R 4 are each independently selected from: halogen, cyano, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, 3-6 membered cycloalkyl; C 1 -C 5 alkyl, C 1 -C 5 alkoxy, 3-6 membered cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of hydroxy, fluoro, chloro.
  • ring B does not exist or is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; said heterocycloalkyl or heteroaryl
  • the heteroatom contained in the group is O, N or S; the heterocycloalkyl group includes a monocyclic ring, a parallel ring, a bridged ring or a spiro ring.
  • ring B is oxetane, Or a saturated or partially saturated heterocycle selected from the following heteroaryl groups: thiophene, furan, pyrrole, pyrazole, imidazole, triazole, thiazole, thiadiazole, oxazole, pyridine, pyrimidine, pyridazine, pyrazine .
  • dihydrothiophene tetrahydrothiophene, dihydrofuran, tetrahydrofuran, dihydropyrrole, tetrahydropyrrole, dihydropyrazole, tetrahydropyrazole, dihydroimidazole, tetrahydroimidazole, dihydrotriazole , tetrahydrotriazole, dihydrothiazole, tetrahydrothiazole, dihydrothiadiazole, tetrahydrothiadiazole, dihydrooxazole, tetrahydrooxazole, dihydropyridine, tetrahydropyridine, dihydropyrimidine, four Hydropyrimidine, dihydropyridazine, tetrahydropyridazine, dihydropyrazine, tetrahydropyrazine.
  • ring B is selected from: oxetane, Cyclopropyl, cyclobutyl, phenyl.
  • formula I has the structure Ia, Ib, Ic, Id,
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from CR 3 or N;
  • Ring B, R 1 , R 2 , R 3 , R 4 , Ra (same as R a1 and R a2 in formula I), n and L 2 are as defined in the first aspect;
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 contain at most two Ns;
  • Z 1 , Z 2 , Z 3 , and Z 4 contain at most two Ns.
  • L 2 is absent or selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2 -; preferably, L 2 does not exist or is -CH 2 - or -CH(CH 3 )-.
  • R 1 and R 2 are hydrogen or -C ⁇ CR 11 respectively, and R 1 and R 2 are different;
  • R 11 is hydrogen, C 1 -C 5 alkyl or 3-6 membered cycloalkyl ;
  • the R 11 is methyl.
  • Ra is methyl, ethyl, propyl.
  • ring B does not exist or is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; said heterocycloalkyl or heteroaryl
  • the heteroatom contained in the group is O or N; the heterocycloalkyl group includes a monocyclic ring, a parallel ring, a bridged ring or a spiro ring.
  • Ring B is absent or is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, triazole, thiazole, thiazole Oxadiazole, oxazole, pyridine, pyrimidine, pyridazine, pyrazine.
  • ring B is oxetane, Or a saturated or partially saturated heterocycle selected from the following heteroaryl groups: thiophene, furan, pyrrole, pyrazole, imidazole, triazole, thiazole, thiadiazole, oxazole, pyridine, pyrimidine, pyridazine, pyrazine .
  • dihydrothiophene tetrahydrothiophene, dihydrofuran, tetrahydrofuran, dihydropyrrole, tetrahydropyrrole, dihydropyrazole, tetrahydropyrazole, dihydroimidazole, tetrahydroimidazole, dihydrotriazole , tetrahydrotriazole, dihydrothiazole, tetrahydrothiazole, dihydrothiadiazole, tetrahydrothiadiazole, dihydrooxazole, tetrahydrooxazole, dihydropyridine, tetrahydropyridine, dihydropyrimidine, four Hydropyrimidine, dihydropyridazine, tetrahydropyridazine, dihydropyrazine, tetrahydropyrazine.
  • ring B is selected from: oxetane, Cyclopropyl, cyclobutyl, phenyl.
  • Formula I has the following structures IIa, IIb, IIc, IId, IIe, If, IIg, IIm, IIn
  • the benzoheterocyclic compound represented by formula I its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, the
  • the benzoheterocyclic compounds shown in the formula I include the following structures:
  • benzoheterocyclic compound shown in formula I includes the following structure:
  • the second aspect of the present invention provides an intermediate B-1:
  • R 6 is -OH, -Cl, -OC 1 -C 5 alkyl, -O-benzyl;
  • Ring A, Ring B, L 1 , R 1 , R 2 , R 3 , R 4 , m, n are as defined in the first aspect.
  • the intermediate B-1 has the structure B-1a or B-1b:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from CR 3 or N;
  • Ring B, R 1 , R 2 , R 3 , R 4 , Ra (same as R a1 and R a2 in formula I), and n are as defined in the first aspect;
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 contain at most two Ns;
  • Z 1 , Z 2 , Z 3 , and Z 4 contain at most two Ns.
  • the intermediate B-1 has the structures B-1c, B-1d, B-1f, B-1g:
  • the third aspect of the present invention provides a method for preparing the benzoheterocyclic compound represented by formula I as described in the first aspect, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable A salt or prodrug method, comprising: 1) reacting intermediate B-1 as described in the second aspect with intermediate B-2 or a salt of intermediate B-2 to obtain the benzo Heterocyclic compounds;
  • the intermediate B-2 has the structure:
  • R 5 is C 1 -C 6 alkyl, benzyl.
  • the salt of intermediate B-2 is hydrochloride.
  • the method also includes:
  • R 6 in the intermediate B-1 is not -OH or -Cl, after converting the group -COR 6 into -COOH or -COCl,
  • the intermediate B-2 has the structure B-2a or B-2b:
  • the fourth aspect of the present invention provides a pharmaceutical composition, which includes: the benzoheterocyclic compound represented by formula I as described in the first aspect, its tautomers, stereoisomers, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises a second drug.
  • the second drug includes antibodies; preferably, the antibodies include anti-PD-L1 antibodies and anti-PD-1 antibodies.
  • the benzoheterocyclic compound represented by formula I as described in the first aspect its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or
  • the mass ratio of the prodrug to the second drug is 1:100 to 100:1, preferably 10:1 to 100:1, more preferably 10:1 to 50:1, for example 10:1, 15:1 1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1.
  • the fifth aspect of the present invention provides a benzoheterocyclic compound represented by formula I as described in the first aspect, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable
  • the purposes of salt or prodrug, or the purposes of pharmaceutical composition as described in the fourth aspect, described purposes comprises:
  • the diseases mediated by the EP2 and/or EP4 receptors include inflammatory diseases (such as arthritis and endometriosis), autoimmune diseases (such as multiple sclerosis), neurodegenerative diseases (such as epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury), cardiovascular disease (such as atherosclerosis), and cancer (such as colon, lung, breast, and head and neck cancers) .
  • inflammatory diseases such as arthritis and endometriosis
  • autoimmune diseases such as multiple sclerosis
  • neurodegenerative diseases such as epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury
  • cardiovascular disease such as atherosclerosis
  • cancer such as colon, lung, breast, and head and neck cancers
  • the sixth aspect of the present invention provides a method for preventing and/or treating diseases mediated by EP2 and/or EP4 receptors, the method comprising administering an effective amount of the formula I to an individual in need thereof Shown are benzoheterocyclic compounds, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof.
  • the method further includes combined use with antibody therapy; preferably, the antibody therapy includes PD-L1 antibody therapy and PD-1 antibody therapy.
  • the mass ratio of prodrug to antibody is 1:100 to 100:1, preferably 10:1 to 100:1, more preferably 10:1 to 50:1, for example 10:1, 15:1, 20 :1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1.
  • the diseases mediated by the EP2 and/or EP4 receptors include inflammatory diseases (such as arthritis and endometriosis), autoimmune diseases (such as multiple sclerosis), neurological Degenerative diseases (e.g. epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and traumatic brain injury), cardiovascular diseases (e.g. atherosclerosis) and cancers (e.g. colon, lung, breast and head and neck cancer).
  • inflammatory diseases such as arthritis and endometriosis
  • autoimmune diseases such as multiple sclerosis
  • neurological Degenerative diseases e.g. epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and traumatic brain injury
  • cardiovascular diseases e.g. atherosclerosis
  • cancers e.g. colon, lung, breast and head and neck cancer.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
  • R 1 ", “R1” and “R 1 " have the same meaning and can be substituted for each other. For other symbols such as R 2 , similar definitions have the same meanings.
  • halogen means fluorine, chlorine, bromine, iodine alone or as part of another substituent.
  • alkyl alone or as part of another substituent, means consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and is bonded to the molecule by a single bond. The rest are connected straight or branched hydrocarbon chain groups.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.
  • An alkyl group can be unsubstituted or substituted with one or more suitable substituents.
  • alkyl groups may also be isotopomers of naturally abundant alkyl groups that are rich in carbon and/or hydrogen isotopes (ie, deuterium or tritium).
  • alkenyl means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds.
  • alkynyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds. "C 2 -C 5 alkynyl" then contains 2-5 carbon atoms.
  • C 1 -C 5 alkyl alone or as part of another substituent, is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4 or 5 carbon atoms.
  • the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, etc. or their isomers.
  • said groups have 1, 2 or 3 carbon atoms (“C 1 -C 3 alkyl”), for example methyl, ethyl, n-propyl or isopropyl.
  • alkylene means a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group.
  • C 1 -C 5 alkylene refers to an alkylene group containing 1, 2, 3, 4, or 5 carbon atoms, examples of which include methylene (-CH 2 -), ethylene (including -CH 2 CH 2 -or -CH(CH 3 )-), isopropylidene (including -CH(CH 3 )CH 2 - or -C(CH 3 ) 2 -), etc.
  • cycloalkyl or “carbocyclyl” by themselves or as part of another substituent refer to a cyclic alkyl group.
  • mn-membered cycloalkyl or " Cm - Cncycloalkyl” is understood to mean a saturated, unsaturated or partially saturated carbocycle having m to n atoms.
  • 3-15 membered cycloalkyl or “C 3 -C 15 cycloalkyl” refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which May contain 1 to 4 rings.
  • "3-6 membered cycloalkyl” then contains 3-6 carbon atoms.
  • cycloalkyl groups may be substituted with one or more substituents.
  • a cycloalkyl group can be a cycloalkyl group fused to an aryl or heteroaryl ring group.
  • Halo is used interchangeably with the term “halogen substitution”, alone or as part of another substituent.
  • Haloalkyl or halogen-substituted alkyl refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens.
  • heterocycloalkyl or “heterocyclyl”, by themselves or as part of another substituent, refer to rings in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms Alkyl, said heteroatoms such as but not limited to N, O, S and P.
  • mn-membered heterocycloalkyl or " Cm - Cnheterocycloalkyl” is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms.
  • 4-6 membered heterocycloalkyl is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 6 atoms.
  • the number of carbons is also meant to include heteroatoms.
  • heteroaryl is used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic”, by itself or as part of another substituent, and refers to a monocyclic or polycyclic aromatic ring system, in certain implementations In the scheme, 1 to 3 atoms in the ring system are heteroatoms, that is, elements other than carbon, including but not limited to N, O, S or P.
  • 5-6 membered heteroaryl alone or as part of another substituent, is understood to mean an aromatic ring group having 5 to 6 ring atoms, including heteroatoms. Including but not limited to thiophene, furan, pyrrole, pyrazole, imidazole, triazole, thiazole, thiadiazole, oxazole, pyridine, pyrimidine, pyridazine, pyrazine.
  • the compounds provided herein, including intermediates useful in the preparation of the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof.
  • "Protected derivatives” are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also known as protecting groups).
  • Suitable protecting groups for the carboxyl moiety include benzyl, tert-butyl, etc., and isotopes, etc.
  • Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable hydroxy protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.
  • “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or circumstance.
  • “optionally substituted aryl” means that the aryl is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl.
  • “optional” or “optionally” substitution covers the situation that the compound structure/group is not substituted, and the compound structure/group is substituted by one or more defined substituents.
  • “optionally substituted aryl” means unsubstituted aryl and aryl substituted with one or more substituents selected from the defined substituents.
  • “Multiple” means more than two, including two or more.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
  • the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms.
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
  • the prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or D are dextrorotatory.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
  • solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
  • Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • examples of categories of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably humans.
  • terapéuticaally effective amount refers to the amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician is seeking to elicit a biological or medical response in a tissue, system, animal, individual, or human, and includes any of the following or more: (1) Preventing a disease: eg, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed disease pathology or symptoms. (2) Inhibiting a disease: For example, inhibiting a disease, disorder or condition (ie preventing further development of the pathology and/or symptoms) in an individual experiencing or developing pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: For example, alleviating a disease, disorder or condition (ie reversing the pathology and/or symptoms) in an individual experiencing or developing the pathology or symptoms of the disease, disorder or condition.
  • treatment and other similar synonyms include the following meanings:
  • antibody includes all classes of immunoglobulins. Antibodies may be monoclonal or polyclonal and may be of any species of origin including, for example, mouse, rat, rabbit, horse or human. Antibodies may be chimeric or humanized, especially when they are used for therapeutic purposes. Antibodies can be obtained or prepared by methods known in the art.
  • P-L1 antibody or "anti-PD-L1” refers to an antibody directed against programmed death ligand 1 (PD-L1).
  • PD-1 antibody or "anti-PD-1” refers to an antibody directed against programmed death protein 1 (PD-1).
  • antibody therapy refers to the medical use of antibodies that bind to target cells or proteins of target cells to treat cancer and/or stimulate an immune response in a subject that results in the recognition, attack and and/or destroy, and in some embodiments of the invention, to activate or stimulate a subject's memory immune response that results in subsequent recognition, attack and/or destruction of cancer cells in the subject.
  • PD-L1 antibody therapy refers to the use of antibodies against programmed death-ligand 1 (anti-PD-L1 ) to modulate the immune response of a subject.
  • the PD-L1 antibody inhibits or blocks the interaction of PD-L1 with programmed cell death protein 1 (PD-1), wherein blockade of the interaction between PD-L1 and PD-1 inhibits PD-1 negatively regulates T cell activation to attack and destroy cancer cells.
  • PD-1 programmed cell death protein 1
  • PD-1 antibody therapy refers to the use of antibodies against the programmed cell death protein 1 PD-1 (anti-PD-1) to modulate the immune response of a subject.
  • the PD1 antibody inhibits or blocks the interaction of PD-1 and PD-L1, wherein the inhibition or blockage of the interaction between PD-L1 and PD-1 inhibits the effect of PD-1 on T cell activation Negative regulation, thereby attacking and destroying cancer cells.
  • the reaction temperature can be appropriately selected according to the solvent, starting material, reagent, etc.
  • the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting material, reagent, etc.
  • the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Without affecting the next step reaction, the target compound can also directly enter the next step reaction without separation and purification.
  • the benzo heterocyclic compound is represented by formula I described in the present invention Show benzoheterocyclic compounds.
  • the benzoheterocyclic compound used for the treatment of diseases mediated by EP2 and EP4 receptors described in the present invention can be used for the treatment of inflammatory diseases (such as arthritis and endometriosis), autoimmune diseases (such as multiple sclerosis), neurodegenerative diseases (such as epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury), cardiovascular diseases (such as atherosclerosis) and cancers (such as colon cancer , lung, breast and head and neck cancers).
  • inflammatory diseases such as arthritis and endometriosis
  • autoimmune diseases such as multiple sclerosis
  • neurodegenerative diseases such as epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury
  • cardiovascular diseases such as atherosclerosis
  • cancers such as colon cancer , lung, breast and head and neck cancers.
  • the benzoheterocyclic compound of the present invention has a good antagonism to EP2, a good inhibitory effect on EP4 calcium flow, and a good affinity with EP2 receptors and/or EP4 receptors.
  • the benzoheterocyclic compound of the present invention has low clearance rate of intravenous administration, high oral administration exposure, exhibits excellent pharmacokinetic properties, has a relatively high free fraction in human plasma, and has good thermodynamics Good solubility and druggability.
  • the combination with antibody drugs (such as anti-PD-L1 antibody, anti-PD-1 antibody) showed a significant tumor inhibitory effect.
  • Fig. 1 is the evaluation result of the compound in the present invention to the antigen presenting cell of human PBMC cell differentiation experiment;
  • Fig. 2 is the evaluation result of the compound in the present invention to human PBMC cell differentiation experiment M2 type macrophage;
  • Fig. 3 is the evaluation result of the compound in the present invention to human PBMC cell differentiation experiment M1 type macrophage;
  • Figure 4 is the results of the anti-tumor effect of the compound of the present invention combined with anti-mouse PD-1 antibody in the CT-26 mouse colon cancer tumor model.
  • IC 50 half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved
  • n-butyllithium 14.56mL, 29.1mmol, 2.5M n-hexane solution
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • PE petroleum ether
  • Acidic preparation method A Welch, Ultimate C 18 column, 10 ⁇ m, 21.2 mm ⁇ 250 mm.
  • Mobile phase A was 1 ⁇ pure trifluoroacetic acid aqueous solution
  • mobile phase B was acetonitrile solution.
  • Gradient conditions 0 to 3 minutes, maintain 90% of mobile phase A, gradient elution in 3 to 18 minutes, change from 90% to 5%, and maintain 5% in 18 to 22 minutes.
  • the synthetic route is as follows:
  • the first step the preparation of 4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 3 Preparation of 1-((1,1’-diphenyl)-4-ylmethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the starting material 1-((1,1'-diphenyl)-4-ylmethyl)-4-(propan-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester ( 80mg, 0.21mmol) was added to tetrahydrofuran (3mL), methanol (1mL) and water (1mL), lithium hydroxide (15mg, 0.63mmol) was added, and stirred at room temperature for 16h.
  • the synthetic route is as follows:
  • the first step the preparation of 5-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 3 Preparation of 1-((1,1’-diphenyl)-4-ylmethyl)-5-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the starting material 1-((1,1'-diphenyl)-4-ylmethyl)-5-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester 50mg, 0.13mmol was added to tetrahydrofuran (3mL), methanol (1mL) and water (1mL), lithium hydroxide (10mg, 0.40mmol) was added, and stirred at room temperature for 4h.
  • the synthetic route is as follows:
  • the first step the preparation of 4-(butane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 3 Preparation of 1-((1,1’-diphenyl)-4-ylmethyl)-4-(butane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the fifth step 6-(1-((1,1'-diphenyl)-4-ylmethyl)-4-(butane-1-yn-1-yl)-1H-indazole-7- Formamide) spiro[3.3]heptane-2-carboxylic acid (I-3) preparation
  • the synthetic route is as follows:
  • Step 1 Preparation of 1-((1,1’-diphenyl)-4-ylmethyl)-4-bromo-1H-indazole-7-carboxylic acid methyl ester
  • the second step the preparation of 1-((1,1'-diphenyl)-4-ylmethyl)-4-(cyclopropaneethynyl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 3 Preparation of 1-((1,1’-diphenyl)-4-ylmethyl)-4-(cyclopropaneethynyl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • Step 1 Preparation of 1-((1,1’-diphenyl)-4-ylmethyl)-4-bromo-1H-indazole-7-carboxylic acid methyl ester
  • the third step 1-((1,1'-diphenyl)-4-ylmethyl)-4-(3-hydroxy-3-methylbutane-1-yn-1-yl)-1H- Preparation of indazole-7-carboxylic acid
  • the starting material 1-((1,1'-diphenyl)-4-ylmethyl)-4-(3-hydroxy-3-methylbutane-1-yn-1-yl)-1H- Add methyl indazole-7-carboxylate (70mg, 0.16mmol) into tetrahydrofuran (3mL) and water (1mL), add lithium hydroxide (12mg, 0.50mmol), and stir at room temperature for 16h.
  • the fifth step 6-(1-((1,1'-diphenyl)-4-ylmethyl)-4-(3-hydroxy-3-methylbutane-1-yn-1-yl) Preparation of -1H-indazole-7-carboxamide) spiro[3.3]heptane-2-carboxylic acid (I-5)
  • the synthetic route is as follows:
  • the first step the preparation of 4-(propane-1-yn-1-yl)-1H-indazole-7-acetic acid methyl ester
  • Step 3 Preparation of 1-((1,1’-diphenyl)-4-ylmethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-acetic acid
  • the starting material 1-((1,1'-diphenyl)-4-ylmethyl)-4-(propan-1-yn-1-yl)-1H-indazole-7-acetic acid methyl ester ( 80mg, 0.21mmol) was added to tetrahydrofuran (3mL), methanol (1mL) and water (1mL), lithium hydroxide (15mg, 0.63mmol) was added, and stirred at room temperature for 16h.
  • the synthetic route is as follows:
  • the first step the preparation of 5-(propane-1-yn-1-yl)-1H-indazole-7-acetic acid methyl ester
  • Step 3 Preparation of 1-((1,1’-diphenyl)-4-ylmethyl)-5-(propane-1-yn-1-yl)-1H-indazole-7-acetic acid
  • the synthetic route is as follows:
  • the first step the preparation of 4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • the second step the preparation of 4-(propane-1-yn-1-yl)-1-(4-(trifluoromethoxy)benzyl)-1H-indazole-7-carboxylic acid methyl ester
  • the third step the preparation of 4-(propane-1-yn-1-yl)-1-(4-(trifluoromethoxy)benzyl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • the first step the preparation of (4-((7-(methoxycarbonyl)-4-(propane-1-yn-1-yl)-1H-indazol-1-yl)methyl)benzyl)boronic acid
  • the starting material (4-((7-(methoxycarbonyl)-4-(propane-1-yn-1-yl)-1H-indazol-1-yl)methyl)benzyl)boronic acid (80 mg, 0.23mmol) was added to 1,4-dioxane (5mL) and water (1mL), and chloro(2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl )(2-amino-1,1-biphenyl-2-yl)palladium(II) (17mg, 0.02mmol) and potassium phosphate (196mg, 0.92mmol), 1,1'-bisdiphenylphosphinoferrocene Palladium dichloride (19mg, 0.02mmol), 4-bromo-2-methoxypyrimidine (53mg, 0.28mmol), stirred at 90°C for 1h.
  • Step 3 Preparation of 1-(4-(2-methoxypyrimidin-4-yl)benzyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the starting material 1-(4-(2-methoxypyrimidin-4-yl)benzyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester ( 70mg, 0.17mmol) was added to tetrahydrofuran (3mL), methanol (1mL) and water (1mL), lithium hydroxide (13mg, 0.51mmol) was added, and stirred at room temperature for 16h.
  • the synthetic route is as follows:
  • the first step the preparation of (4-((7-(methoxycarbonyl)-4-(propane-1-yn-1-yl)-1H-indazol-1-yl)methyl)benzyl)boronic acid
  • the second step the preparation of 4-(propane-1-yn-1-yl)-1-(4-(thiazol-2-yl)benzyl)-1H-indazole-7-carboxylic acid methyl ester
  • the third step the preparation of 4-(propane-1-yn-1-yl)-1-(4-(thiazol-2-yl)benzyl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • Step 1 Preparation of 1-(4-iodophenyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • the second step the preparation of 1-(4-(1H-pyrazol-1-yl)benzyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 4 Preparation of 1-(4-(1H-pyrazol-1-yl)benzyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • the first step the preparation of 2-amino-4-bromo-3-methylbenzoic acid methyl ester
  • the second step the preparation of (3-bromo-6-(methoxycarbonyl)-2-methylphenyl)-1-tetrafluoroborate diazonium salt
  • the compound 2-amino-4-bromo-3-methylbenzoate (5.0 g, 20.5 mmol) was added to 50% HBF 4 aqueous solution (5 mL) at room temperature, cooled to 0 ° C, and sodium nitrite ( 1.42g, 20.6mmol) in 5mL aqueous solution, stirred at 0°C for 1h. After filtration and drying, the crude compound (3-bromo-6-(methoxycarbonyl)-2-methylphenyl)-1-tetrafluoroborate diazonium salt (6.6 g, yield 94%) was obtained.
  • the third step the preparation of 4-bromo-1H-indazole-7-carboxylic acid methyl ester
  • Step 4 Preparation of 4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 5 Preparation of 1-(4-cyclopropylbenzyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 6 Preparation of 1-(4-cyclopropylbenzyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the seventh step 6-(1-(4-cyclopropylbenzyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxamide)spiro[3.3]heptane - Preparation of methyl 2-formate
  • the synthetic route is as follows:
  • Step 1 Preparation of 1-(4-iodophenyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • the third step the preparation of 1-(4-(2-methoxypyridin-4-yl)phenyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • Methyl 1-(4-(2-methoxypyridin-4-yl)phenyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylate (100mg , 0.24mmol) was added to tetrahydrofuran (3mL) and water (1mL), lithium hydroxide (18mg, 0.73mmol) was added, and stirred at room temperature for 16h.
  • the synthetic route is as follows:
  • the first step the preparation of 2-(4-(bromomethyl)benzyl)propan-2-ol
  • the second step the preparation of 1-(4-(2-hydroxypropan-2-yl)benzyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 3 Preparation of 1-(4-(2-hydroxypropan-2-yl)benzyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • the first step the preparation of 4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • the second step the preparation of 4-(propane-1-yn-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxylic acid methyl ester
  • the third step the preparation of 4-(propane-1-yn-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxylic acid
  • the first step the preparation of 1-(bromomethyl)-3-cyclopropylbenzene
  • the second step the preparation of 1-(3-cyclopropylbenzyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 3 Preparation of 1-(3-cyclopropylbenzyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • the first step the preparation of 4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • the second step the preparation of 4-(propane-1-yn-1-yl)-1-(3-(trifluoromethoxy)benzyl)-1H-indazole-7-carboxylic acid methyl ester
  • the third step the preparation of 4-(propane-1-yn-1-yl)-1-(3-(trifluoromethoxy)benzyl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • the first step the preparation of 4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • the second step the preparation of 1-(1-(4-cyclopropylphenyl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 3 Preparation of 1-(1-(4-cyclopropylphenyl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • the first step the preparation of 4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • the second step the preparation of (R)-1-(1-(4-bromophenyl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 3 Preparation of (R)-1-(1-(4-cyclopropylphenyl)ethyl)-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Step 4 Preparation of (R)-1-(1-(4-cyclopropylphenyl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the first step the preparation of 4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • the second step the preparation of 4-(propane-1-yn-1-yl)-1-(4-(trifluoromethoxy)phenyl)ethyl)-1H-indazole-7-carboxylic acid methyl ester
  • the third step the preparation of 4-(propane-1-yn-1-yl)-1-(4-(trifluoromethoxy)phenyl)ethyl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • Step 1 Preparation of (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol
  • the second step the preparation of (R)-1-(4-(2-methoxypyrimidin-4-yl)phenyl)ethanol
  • the synthetic route is as follows:
  • the synthetic method of compound I-20b refers to the synthetic method of its isomer I-20a, changing (R)-1-(4-bromophenyl)ethanol into (s)-1-(4-bromophenyl)ethanol , through the same six-step reaction to obtain the compound (Sa, R)-6-(1-(1-(4-(2-methoxypyrimidin-4-yl)phenyl)ethyl)-4-(propane- 1-yn-1-yl)-1H-indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic acid (34.5 mg, 59% yield).
  • the synthetic route is as follows:
  • the first step the preparation of 4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • the third step 1-(3-(4-cyclopropylphenyl)oxetan-3-yl)-4-(propane-1-yn-1-yl)-1H-indazole-7-formic acid Preparation of esters
  • Methyl 1-(3-(4-bromophenyl)oxetan-3-yl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester 300mg , 0.71mmol
  • cyclopropylboronic acid 300mg, 3.53mmol
  • tetrakis (triphenylphosphine) palladium 80mg, 0.071mmol
  • potassium fluoride 123mg, 2.12mmol was added to toluene (3ml) and water (0.5 ml), heated to 100°C and stirred for 12h.
  • the synthetic route is as follows:
  • Methyltriphenylphosphine bromide (9.86g, 27.6mmol) was dissolved in tetrahydrofuran (100mL), potassium tert-butoxide (1mol/L solution in tetrahydrofuran, 27.6mL) was slowly added dropwise under ice cooling, and stirred for 1 hour.
  • 1-(4-Bromophenyl)-3-oxetanyl-1-carbonitrile (6.9g, 27.6mmol) was dissolved in tetrahydrofuran (10mL) and slowly added to the above solution, gradually raised to room temperature and stirred overnight for 16 Hour.
  • Step 8 Preparation of 1-(4-(1-methyl-2-oxabicyclo[2.2.1]hexane-4-yl)phenyl)ethan-1-one
  • Step 9 Preparation of 1-(4-(1-methyl-2-oxabicyclo[2.2.1]hexane-4-yl)phenyl)ethan-1-ol
  • reaction solution was concentrated and purified by column chromatography to obtain 1-(4-(1-methyl-2-oxabicyclo[2.2.1]hexane-4-yl)phenyl)ethyl)-4-(propane-1 -Alkyn-1-yl)-1H-indazole-7-carboxylic acid methyl ester (500 mg, 86% yield).
  • the synthetic route is as follows:
  • reaction solution was poured into water (30 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • the reaction solution was concentrated to obtain a crude product.
  • the synthetic route is as follows:
  • the first step the preparation of N-methoxy-N-methyl-6-(trifluoromethoxy)pyridinamide
  • the second step the preparation of 1-(6-(trifluoromethoxy)pyridin-3-yl)ethan-1-one
  • the third step the preparation of 1-(6-(trifluoromethoxy)pyridin-3-yl)ethan-1-ol
  • the fifth step 4-(propane-1-yn-1-yl)-1-(1-(6-(trifluoromethoxy)pyridin-3-yl)ethane)-1H-indazole-7- Preparation of formic acid
  • the synthetic route is as follows:
  • Step 1 Preparation of 1-(1-(5-bromopyridin-2-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • Methyl 1-(1-(5-bromopyridin-2-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylate 400 mg, 1.00 mmol
  • tetrakistriphenylphosphopalladium 116mg, 0.1mmol
  • cyclopropylboronic acid 431mg, 5.02mmol
  • potassium fluoride 321mg, 5.52mmol
  • reaction solution was concentrated and purified by column chromatography to obtain 1-(1-(5-cyclopropylpyridin-2-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7 - Methyl formate (250 mg, 69% yield).
  • Step 3 Preparation of 1-(1-(5-cyclopropylpyridin-2-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • the first step the preparation of 1-(5-chloropyrazin-2-yl)-ethan-1-ol
  • the second step the preparation of 1-(5-cyclopropylpyrazin-2-yl)-ethan-1-ol
  • 1-(5-cyclopropylpyrazin-2-yl)-ethan-1-ol (613 mg, 3.73 mmol), methyl 4-(propan-1-yn-1-yl)-1H-indazole- 7-Carboxylate (400mg, 1.87mmol) and triphenylphosphine (1.47g, 5.60mmol) were dissolved in tetrahydrofuran (10mL), and azobisisopropyl ester (1.13g, 5.60mmol) was slowly added dropwise under ice-cooling , followed by warming to room temperature and stirring for 16 hours.
  • reaction solution was concentrated and purified by column chromatography to obtain 1-(1-(5-cyclopropylpyrazin-2-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole- 7-Methyl carboxylate (400 mg, 30% yield).
  • Step 4 Preparation of 1-(1-(5-cyclopropylpyrazin-2-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • Step 1 Preparation of 1-(1-(6-bromopyridin-3-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • reaction solution was poured into water (50 mL), extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a brown crude product.
  • Step 3 Preparation of 1-(1-(6-cyclopropylpyridin-3-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • reaction solution was added to water (50 mL), and extracted with ethyl acetate (10 mL*3). The combined organic phases were washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • Resolution method Use Column: Chiralpak AD-3 type chiral resolution column (specification: 50 ⁇ 4.6mm, 3um) for chiral resolution, mobile phase A is supercritical fluid CO 2 , mobile phase B is isopropyl Alcohol (containing 0.05% diethanolamine); gradient conditions: mobile phase B is 40%, flow rate is 3mL/min; column temperature is maintained at 35°C, and column pressure is maintained at 100bar.
  • (R)-6-(1-(1-(6-cyclopropylpyridin-3-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7 -Carboxamido)spiro[3.3]heptane-2-carboxylic acid methyl ester retention time is 0.754min.
  • the retention time of amido)spiro[3.3]heptane-2-carboxylic acid methyl ester was 1.448min.
  • Step 7 (Sa,S)-6-(1-(1-(6-cyclopropylpyridin-3-yl)ethyl)-4-(propane-1-yn-1-yl)-1H- Preparation of indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic acid (I-30b)
  • the synthetic route is as follows:
  • reaction solution was concentrated and purified by column chromatography to obtain 1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7 - Methyl formate (200 mg, 43% yield).
  • Step 3 Preparation of 1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • the synthetic route is as follows:
  • the first step 1-(1-(5-bromopyrimidin-2-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-7-indazole-7-carboxylic acid methyl ester preparation
  • reaction solution was poured into water (50 mL), extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • Step 3 Preparation of 1-(1-(5-cyclopropylpyrimidin-2-yl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • reaction solution was added to water (50 mL), and extracted with ethyl acetate (10 mL*3). The combined organic phases were washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • SFC resolution method use Kromasil (S, S) Whelk-O1 type chiral resolution column (specification: 50 ⁇ 4.6mm, 3.5um) for chiral resolution, mobile phase A is supercritical fluid CO 2 , flow Phase B is ethanol (containing 0.05% diethanolamine); Gradient conditions: mobile phase B is from 5% to 80%, flow rate is 10mL/min; 40% gradient keeps 10min, 50% gradient keeps 10min, column temperature keeps at At 35°C, the column pressure was maintained at 100 bar.
  • the seventh step (Sa,S)-6-(1-(1-(5-cyclopropylpyrimidin-2-yl)ethyl)-4-(propane-1-yn-1-yl)-1H- Preparation of indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic acid (I-32b)
  • the synthetic route is as follows:
  • the first step the preparation of 1-(4-(difluoromethyl)phenyl)ethan-1-one
  • the second step the preparation of 1-(4-(difluoromethyl)phenyl)ethan-1-ol
  • reaction solution was concentrated and purified by column chromatography to obtain 1-(1-(4-(difluoromethyl)phenyl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7 - Methyl formate (450 mg, 60% yield).
  • Step 4 Preparation of 1-(1-(4-(difluoromethyl)phenyl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxylic acid
  • SFC resolution method use Chiralpak AD-3 chiral resolution column (specification: 50 ⁇ 4.6mm, 3um) for chiral resolution, mobile phase A is supercritical fluid CO 2 , mobile phase B is isopropanol (containing 0.05% diethanolamine); Gradient conditions: the mobile phase B is 40% of the gradient to maintain 10min, the column temperature is maintained at 35 ° C, the column pressure is maintained at 100bar, the peak time: 0.581min.
  • the synthetic route is as follows:
  • SFC resolution method use Chiralpak AD-3 chiral resolution column (specification: 50 ⁇ 4.6mm, 3um) for chiral resolution, mobile phase A is supercritical fluid CO 2 , mobile phase B is isopropanol (Containing 0.05% diethanolamine); Gradient conditions: mobile phase B is 40% gradient and kept for 10min, column temperature was kept at 35°C, column pressure was kept at 100bar, peak eluting time: 2.245min.
  • reaction solution was concentrated, water (3mL) was added, and then dilute hydrochloric acid (1mol/L aqueous solution) was added to adjust the pH value of the solution to about 2.
  • (Sa,S)-6-(1-(1-(4-(difluoro Methyl)phenyl)ethyl)-4-(propane-1-yn-1-yl)-1H-indazole-7-carboxamide)spiro[3.3]heptane-2-carboxylic acid (I-34b) (62.5 mg, yield 80%).
  • the synthetic route is as follows:
  • the first step 1-((1R)-1-(4-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl)ethyl)-4-(propane-1-yne- Preparation of 1-yl)-1H-indazole-7-carboxylic acid methyl ester
  • the synthetic route is as follows:
  • the first step 1-((1S)-1-(4-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl)ethyl)-4-(propane-1-yne- Preparation of 1-yl)-1H-indazole-7-carboxylic acid methyl ester

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Abstract

L'invention concerne un composé benzohétérocyclique représenté par la formule (I), un tautomère, un stéréoisomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci pour traiter des maladies médiées par le récepteur EP2 et EP4, qui peut être utilisé pour traiter des maladies médiées par le récepteur EP2 et EP4.
PCT/CN2022/097611 2021-06-08 2022-06-08 Composé benzohétérocyclique pour traiter des maladies médiées par le récepteur ep2 et ep4 WO2022257961A1 (fr)

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Citations (6)

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WO2019204523A1 (fr) * 2018-04-17 2019-10-24 Tempest Therapeutics, Inc. Carboxamides bicycliques et leurs procédés d'utilisation
CN110386941A (zh) * 2019-08-15 2019-10-29 上海邦耀生物科技有限公司 Ep4受体拮抗剂和pd-1抑制剂联合用于癌症的治疗
CN110891935A (zh) * 2017-04-18 2020-03-17 泰普斯特医疗公司 双环化合物及其在癌症治疗中的用途
WO2020151566A1 (fr) * 2019-01-22 2020-07-30 凯复制药有限公司 Composé inhibant la transduction du signal pge2/ep4, son procédé de préparation et ses applications thérapeutiques
US20200283438A1 (en) * 2017-04-18 2020-09-10 Tempest Therapeutics, Inc. Bicyclic compounds and their use in the treatment of cancer
WO2020208088A1 (fr) * 2019-04-09 2020-10-15 Rottapharm Biotech S.R.L. Combinaison pharmaceutique d'un antagoniste d'ep4 et d'inhibiteurs de points de contrôle immunitaires pour le traitement de tumeurs

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110891935A (zh) * 2017-04-18 2020-03-17 泰普斯特医疗公司 双环化合物及其在癌症治疗中的用途
US20200283438A1 (en) * 2017-04-18 2020-09-10 Tempest Therapeutics, Inc. Bicyclic compounds and their use in the treatment of cancer
WO2019204523A1 (fr) * 2018-04-17 2019-10-24 Tempest Therapeutics, Inc. Carboxamides bicycliques et leurs procédés d'utilisation
WO2020151566A1 (fr) * 2019-01-22 2020-07-30 凯复制药有限公司 Composé inhibant la transduction du signal pge2/ep4, son procédé de préparation et ses applications thérapeutiques
WO2020208088A1 (fr) * 2019-04-09 2020-10-15 Rottapharm Biotech S.R.L. Combinaison pharmaceutique d'un antagoniste d'ep4 et d'inhibiteurs de points de contrôle immunitaires pour le traitement de tumeurs
CN110386941A (zh) * 2019-08-15 2019-10-29 上海邦耀生物科技有限公司 Ep4受体拮抗剂和pd-1抑制剂联合用于癌症的治疗
WO2021027567A1 (fr) * 2019-08-15 2021-02-18 上海宇耀生物科技有限公司 Combinaison d'un antagoniste du récepteur ep4 et d'un inhibiteur de pd-1 pour le traitement du cancer

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