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WO2023274280A1 - Forme cristalline d'un inhibiteur de dérivé de biphényle et son procédé de préparation - Google Patents

Forme cristalline d'un inhibiteur de dérivé de biphényle et son procédé de préparation Download PDF

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Publication number
WO2023274280A1
WO2023274280A1 PCT/CN2022/102195 CN2022102195W WO2023274280A1 WO 2023274280 A1 WO2023274280 A1 WO 2023274280A1 CN 2022102195 W CN2022102195 W CN 2022102195W WO 2023274280 A1 WO2023274280 A1 WO 2023274280A1
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Prior art keywords
methyl
biphenyl
imidazo
dichloro
tetrahydro
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Chinese (zh)
Inventor
詹小兰
呙临松
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Priority to CN202280045197.3A priority Critical patent/CN117561256A/zh
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and in particular relates to a crystal form of a biphenyl derivative inhibitor, a preparation method and application thereof.
  • the immune system plays an important role in controlling many diseases, including cancer.
  • tumor cells evade immune attack or suppress the activation of the immune system in various ways.
  • PD-1 programmed cell death protein 1
  • PD-1 a member of the CD28 superfamily, is an immunosuppressive receptor on the surface of immune cells, especially cytotoxic T cells.
  • PD-1 has two ligands PD-L1 and PD-L2, among which PD-L1, programmed cell death receptor-ligand 1, is expressed in a variety of cells, such as macrophages and dendritic cells , and generally highly expressed on tumor cells.
  • PD-L1 plays an immunosuppressive role by combining with PD-1 and makes tumor cells evade the killing of T cells, inhibits the activation of T cells and the production of corresponding cytokines, weakens infectious immunity and tumor immunity, and promotes the development of infectious diseases and tumors. progress.
  • the use of PD-L1 inhibitors such as antibodies or small molecule inhibitors can relieve the immunosuppressive effect of PD-L1 and promote the immune clearance of tumors, thereby achieving the effect of treating tumors.
  • PD-1/PD-L1 is a hot spot in the research of tumor immunotherapy in recent years.
  • the breadth, depth and durability of the monoclonal antibody drug response are very rare.
  • PD-1/PD-L1 monoclonal antibody drugs in clinical practice. marketed and achieved great success.
  • PD-L1 inhibitors can be used to treat almost all major cancers, including non-small cell lung cancer, liver cancer, gastric cancer, intestinal cancer, kidney cancer, etc., and have great clinical application value.
  • PD-L1 inhibitors from macromolecules to small molecules are becoming a new research and development trend and hotspot.
  • Small molecule inhibitors have many natural advantages in terms of administration methods and production costs, and have the potential to replace antibody macromolecules, including BMS at present.
  • Foreign pharmaceutical companies including Incyte and other companies are actively developing PD-L1 small molecule inhibitors.
  • the oral small-molecule inhibitor developed by BMS is currently in the preclinical research stage, and several patents have been published consecutively.
  • the small-molecule inhibitor INCB086550 developed by Incyte is in the first phase of clinical research.
  • the small-molecule inhibitor developed by Aurigene/Curis CA-170 is in Phase II clinical research.
  • Small molecule inhibitors of PD-L1 have good application prospects as drugs in the pharmaceutical industry.
  • small molecule inhibitors of PD-L1 can be administered orally, which has the advantage of stronger compliance than intravenous administration of antibody drugs, and can avoid antibody Serious side effects such as colitis caused by long-term residence in the body.
  • small molecule inhibitors of PD-L1 have a unique mechanism of action that binds to PD-L1 and endocytizes it, which may show different efficacy from antibodies in clinical practice.
  • the production and quality control costs of PD-L1 small molecule inhibitors are lower, and they have a price advantage that is far lower than the cost of macromolecular drugs.
  • PD-L1 antibody inhibitors they can be applied to a variety of major tumors and have a huge market potential.
  • the object of the present invention is to provide a kind of crystal form of the compound shown in general formula (I), its structure is as follows:
  • Ring A is selected from 4-8 membered heterocyclic groups; preferably 4-membered, 7-membered or 8-membered heterocyclic groups;
  • R 1 is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, carboxyl, aldehyde, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, -(CH 2 ) n R a , -(CH 2 ) n OR a , -OC(O)R a , -C( O)R a , -C(O)OR a , -C(O)NR a R b , -(CH 2 ) n NR a C(O)R b or -SO 2 R a , wherein the C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl and C 3-8 cycloalkyl,
  • R a and R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 Haloalkyl or C 3-8 cycloalkyl, wherein said C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl and C 3-8 cycloalkyl, optionally further One or more substituents in deuterium, halogen, hydroxyl, cyano or C 1-6 alkyl;
  • n 0, 1 or 2;
  • x 0, 1 or 2.
  • M is O, -NR 2 or -CR 3 R 4 ;
  • R 2 is selected from hydrogen, deuterium, aldehyde, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, -(CH 2 ) n R a , -(CH 2 ) n OR a , -OC(O)R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -(CH 2 ) n NR a C(O)R b or -SO 2 R a ;
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, carboxyl, aldehyde, oxo, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, -(CH 2 ) n R a , -(CH 2 ) n OR a , -OC(O) R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -(CH 2 ) n NR a C(O)R b or -SO 2 R a , The C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl and C 3-6 cycloalkyl
  • R a and R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 Haloalkyl or C 3-6 cycloalkyl, wherein said C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl and C 3-6 cycloalkyl, optionally further One or more substituents in deuterium, halogen, hydroxyl, cyano or C 1-3 alkyl;
  • n 0, 1 or 2.
  • the crystal form of the compound is the crystal form of the following compound:
  • the crystal form is the compound N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptane-2-yl)methyl )-6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5, Crystalline form of 6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide.
  • the X-ray powder diffraction pattern of the crystal form A has a diffraction peak at 2 ⁇ of 7.8 ⁇ 0.2°; or has a diffraction peak at 14.1 ⁇ 0.2°; or has a diffraction peak at 15.3 ⁇ 0.2°; or has a diffraction peak at 19.5 ⁇ 0.2°; Diffraction peak at 0.2°; or diffraction peak at 12.0 ⁇ 0.2°; or diffraction peak at 12.4 ⁇ 0.2°; or diffraction peak at 13.2 ⁇ 0.2°; or diffraction peak at 14.6 ⁇ 0.2° or have a diffraction peak at 21.2 ⁇ 0.2°; or have a diffraction peak at 22.0 ⁇ 0.2°; preferably include any 2-5, or 3-5, or 3-6, or 3 of the above-mentioned diffraction peaks -8 places, or 5-8 places, or 6-8 places, more preferably including any 6, 7 or 8 places;
  • the X-ray powder diffraction pattern of the crystal form B has a diffraction peak at 2 ⁇ of 4.2 ⁇ 0.2°; or has a diffraction peak at 12.2 ⁇ 0.2°; or has a diffraction peak at 12.6 ⁇ 0.2°; or has a diffraction peak at 16.5 ⁇ 0.2°; Diffraction peak at 0.2°; or diffraction peak at 16.8 ⁇ 0.2°; or diffraction peak at 18.4 ⁇ 0.2°; or diffraction peak at 18.9 ⁇ 0.2°; or diffraction peak at 21.1 ⁇ 0.2° or have a diffraction peak at 22.2 ⁇ 0.2°; or have a diffraction peak at 22.4 ⁇ 0.2°; preferably include any 2-5, or 3-5, or 3-6, or 3 of the above-mentioned diffraction peaks -8 places, or 5-8 places, or 6-8 places, more preferably including any 6, 7 or 8 places;
  • the X-ray powder diffraction pattern of the crystal form C has a diffraction peak at 2 ⁇ of 11.4 ⁇ 0.2°; or has a diffraction peak at 12.5 ⁇ 0.2°; or has a diffraction peak at 21.1 ⁇ 0.2°; or has a diffraction peak at 23.0 ⁇ 0.2°; Diffraction peak at 0.2°; or diffraction peak at 26.1 ⁇ 0.2°; or diffraction peak at 26.6 ⁇ 0.2°; or diffraction peak at 13.0 ⁇ 0.2°; or diffraction peak at 14.0 ⁇ 0.2° or have a diffraction peak at 14.7 ⁇ 0.2°; or have a diffraction peak at 15.8 ⁇ 0.2°; preferably include any 2-5 of the above-mentioned diffraction peaks, or 3-5, or 3-6, or 3 -8 places, or 5-8 places, or 6-8 places, more preferably including any 6, 7 or 8 places;
  • the X-ray powder diffraction pattern of the crystal form D has a diffraction peak at 2 ⁇ of 9.5 ⁇ 0.2°; or has a diffraction peak at 10.4 ⁇ 0.2°; or has a diffraction peak at 14.5 ⁇ 0.2°; or has a diffraction peak at 19.9 ⁇ 0.2°; Diffraction peak at 0.2°; or diffraction peak at 20.8 ⁇ 0.2°; or diffraction peak at 24.8 ⁇ 0.2°; or diffraction peak at 11.7 ⁇ 0.2°; or diffraction peak at 13.3 ⁇ 0.2° or have a diffraction peak at 17.2 ⁇ 0.2°; or have a diffraction peak at 23.8 ⁇ 0.2°; preferably include any 2-5, or 3-5, or 3-6, or 3 of the above-mentioned diffraction peaks -8 places, or 5-8 places, or 6-8 places, more preferably including any 6, 7 or 8 places.
  • the X-ray powder diffraction pattern of the crystal form A contains at least one or more diffraction peaks at 2 ⁇ of 7.8 ⁇ 0.2°, 14.1 ⁇ 0.2°, and 15.3 ⁇ 0.2°, Preferably two of them are included, more preferably three; optionally, at least one of 19.5 ⁇ 0.2°, 12.0 ⁇ 0.2°, 12.4 ⁇ 0.2°, 13.2 ⁇ 0.2°, 14.6 ⁇ 0.2° can be included, preferably 2, 3, 4 or 5 of them;
  • the X-ray powder diffraction pattern of the crystal form B includes at least one or more diffraction peaks located at 2 ⁇ of 4.2 ⁇ 0.2°, 12.2 ⁇ 0.2°, and 12.6 ⁇ 0.2°, preferably two of them, and more It preferably contains three; optionally, it can further include at least one of 16.5 ⁇ 0.2°, 16.8 ⁇ 0.2°, 18.4 ⁇ 0.2°, 18.9 ⁇ 0.2°, 21.1 ⁇ 0.2°, preferably 2, 3, 4 or 5;
  • the X-ray powder diffraction pattern of the crystal form C contains at least one or more diffraction peaks located at 2 ⁇ of 11.4 ⁇ 0.2°, 12.5 ⁇ 0.2°, and 21.1 ⁇ 0.2°, preferably two of them, and more It preferably contains three; optionally, it can further contain at least one of 23.0 ⁇ 0.2°, 26.1 ⁇ 0.2°, 26.6 ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.0 ⁇ 0.2°, preferably 2, 3, 4 or 5;
  • the X-ray powder diffraction pattern of the crystal form D contains at least one or more diffraction peaks located at 2 ⁇ of 9.5 ⁇ 0.2°, 10.4 ⁇ 0.2°, and 14.5 ⁇ 0.2°, preferably two of them, and more Preferably include three; optionally, it may further include at least one of 19.9 ⁇ 0.2°, 20.8 ⁇ 0.2°, 24.8 ⁇ 0.2°, 11.7 ⁇ 0.2°, 13.3 ⁇ 0.2°, preferably including 2, 3, 4 or 5 bars.
  • the X-ray powder diffraction pattern of the crystal form A optionally further comprises One or more diffraction peaks at 0.2°, 16.7 ⁇ 0.2° or 24.5 ⁇ 0.2°; preferably at least any 2-3, or 4-5, or 6-7 of them; more preferably, including Any 2, 3, 4, 5, 6, 7 places;
  • the X-ray powder diffraction pattern of the crystal form B optionally further includes a position at 2 ⁇ of 22.2 ⁇ 0.2°, 22.4 ⁇ 0.2°, 22.9 ⁇ 0.2°, 23.6 ⁇ 0.2°, 26.6 ⁇ 0.2°, 13.8 ⁇ 0.2° Or one or more diffraction peaks at 14.5 ⁇ 0.2°; preferably at least include any 2-3, or 4-5, or 6-7; more preferably, include any 2, 3, 4, 5, 6, 7;
  • the X-ray powder diffraction pattern of the crystalline form C optionally further includes a position at 2 ⁇ of 14.7 ⁇ 0.2°, 15.8 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.8 ⁇ 0.2°, 23.6 ⁇ 0.2°, 9.1 ⁇ 0.2° Or one or more diffraction peaks at 16.7 ⁇ 0.2°; preferably at least include any 2-3, or 4-5, or 6-7; more preferably, include any 2, 3, 4, 5, 6, 7;
  • the X-ray powder diffraction pattern of the crystal form D optionally further includes a position at 2 ⁇ of 17.2 ⁇ 0.2°, 23.8 ⁇ 0.2°, 25.5 ⁇ 0.2°, 27.1 ⁇ 0.2°, 15.3 ⁇ 0.2°, 15.8 ⁇ 0.2° Or one or more diffraction peaks at 21.4 ⁇ 0.2°; preferably at least include any 2-3, or 4-5, or 6-7; more preferably, include any 2, 3, 4, 5, 6, 7.
  • the X-ray powder diffraction pattern of the crystalline form A optionally includes 2 ⁇ at 7.8 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.3 ⁇ 0.2°, 19.5 ⁇ 0.2°, 12.0 ⁇ 0.2° , 12.4 ⁇ 0.2°, 13.2 ⁇ 0.2°, 14.6 ⁇ 0.2°, 21.2 ⁇ 0.2°, 22.0 ⁇ 0.2°, 22.6 ⁇ 0.2°, 25.0 ⁇ 0.2°, 28.3 ⁇ 0.2°, 16.7 ⁇ 0.2° or 24.5 ⁇ 0.2°
  • the X-ray powder diffraction pattern of the crystal form B optionally includes a position at 2 ⁇ of 4.2 ⁇ 0.2°, 12.2 ⁇ 0.2°, 12.6 ⁇ 0.2°, 16.5 ⁇ 0.2°, 16.8 ⁇ 0.2°, 18.4 ⁇ 0.2°, One of 18.9 ⁇ 0.2°, 21.1 ⁇ 0.2°, 22.2 ⁇ 0.2°, 22.4 ⁇ 0.2°, 22.9 ⁇ 0.2°, 23.6 ⁇ 0.2°, 26.6 ⁇ 0.2°, 13.8 ⁇ 0.2° or 14.5 ⁇ 0.2°, or multiple diffraction peaks,
  • the X-ray powder diffraction pattern of the crystal form B has diffraction peaks at the following positions at 2 ⁇ :
  • the X-ray powder diffraction pattern of the crystal form C optionally includes a position at 2 ⁇ of 11.4 ⁇ 0.2°, 12.5 ⁇ 0.2°, 21.1 ⁇ 0.2°, 23.0 ⁇ 0.2°, 26.1 ⁇ 0.2°, 26.6 ⁇ 0.2°, One of 13.0 ⁇ 0.2°, 14.0 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.8 ⁇ 0.2°, 18.0 ⁇ 0.2°, 19.8 ⁇ 0.2°, 23.6 ⁇ 0.2°, 9.1 ⁇ 0.2° or 16.7 ⁇ 0.2° or multiple diffraction peaks,
  • the X-ray powder diffraction pattern of the crystal form D optionally includes a position at 2 ⁇ of 9.5 ⁇ 0.2°, 10.4 ⁇ 0.2°, 14.5 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.8 ⁇ 0.2°, 24.8 ⁇ 0.2°, One of 11.7 ⁇ 0.2°, 13.3 ⁇ 0.2°, 17.2 ⁇ 0.2°, 23.8 ⁇ 0.2°, 25.5 ⁇ 0.2°, 27.1 ⁇ 0.2°, 15.3 ⁇ 0.2°, 15.8 ⁇ 0.2° or 21.4 ⁇ 0.2° or multiple diffraction peaks,
  • diffraction peaks at optional 4, 5, 6, 8 or 10 positions.
  • the crystal form is N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptane-2-yl)methanol Base)-6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5 , the crystal form B of 6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide;
  • the X-ray powder diffraction pattern of the crystal form B has a diffraction peak at 4.0 ⁇ 0.2°; or has a diffraction peak at 12.0 ⁇ 0.2°; or has a diffraction peak at 12.4 ⁇ 0.2°; or has a diffraction peak at 16.4 ⁇ 0.2° or have a diffraction peak at 16.6 ⁇ 0.2°; or have a diffraction peak at 18.2 ⁇ 0.2°; or have a diffraction peak at 18.7 ⁇ 0.2°; or have a diffraction peak at 20.9 ⁇ 0.2°; or Have a diffraction peak at 22.0 ⁇ 0.2°; or have a diffraction peak at 22.3 ⁇ 0.2°; preferably include any 2-5, or 3-5, or 3-6, or 3-8 of the above-mentioned diffraction peaks , or 5-8, or 6-8, more preferably including any 6, 7 or 8 of them;
  • the X-ray powder diffraction pattern of the crystal form B includes at least one or more diffraction peaks at 2 ⁇ of 4.0 ⁇ 0.2°, 12.0 ⁇ 0.2°, and 12.4 ⁇ 0.2°, preferably two of them, More preferably, it contains three; optionally, it can further include at least one of 16.4 ⁇ 0.2°, 16.6 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.7 ⁇ 0.2°, 20.9 ⁇ 0.2°, preferably 2 or 3 of them , 4 or 5;
  • the X-ray powder diffraction pattern of the crystal form B optionally further comprises One or more diffraction peaks at 0.2° or 14.3 ⁇ 0.2°; preferably at least include any 2-3, or 4-5, or 6-7 of them; more preferably, include any 2 or 3 of them place, 4 places, 5 places, 6 places, 7 places;
  • the X-ray powder diffraction pattern of the crystal form B optionally includes °, 18.7 ⁇ 0.2°, 20.9 ⁇ 0.2°, 22.0 ⁇ 0.2°, 22.3 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.5 ⁇ 0.2°, 26.5 ⁇ 0.2°, 13.6 ⁇ 0.2° or 14.3 ⁇ 0.2°
  • One or more diffraction peaks preferably, including optional 4, 5, 6, 8 or 10 diffraction peaks;
  • the X-ray powder diffraction pattern of the crystal form B is shown in FIG. 10 .
  • Example 4 compound N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptane-2-yl)methyl )-6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5, Form A of 6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide, X-ray characterization in terms of 2 ⁇ angles and interplanar spacing d values using Cu-K ⁇ radiation The diffraction peaks are shown in Table 1.
  • Example 4 compound N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptane-2-yl)methyl )-6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5, Form B of 6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide, X-ray characterization in terms of 2 ⁇ angles and interplanar spacing d values using Cu-K ⁇ radiation The diffraction peaks are shown in Table 2.
  • Example 4 compound N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptane-2-yl)methyl )-6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5, Form C of 6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide, X-ray characterization in terms of 2 ⁇ angles and interplanar spacing d values using Cu-K ⁇ radiation The diffraction peaks are shown in Table 3.
  • Example 4 compound N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptane-2-yl)methyl )-6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5, Form D of 6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide, X-ray characterization in terms of 2 ⁇ angles and interplanar spacing d values using Cu-K ⁇ radiation The diffraction peaks are shown in Table 4.
  • Example 4 compound N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptane-2-yl)methyl) -6-methoxypyridin-2-yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6 , Relative peak intensities in the X-ray powder diffraction patterns of 7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide in Form A, Form B, Form C and Form D
  • the 2 ⁇ error between the positions of the top ten diffraction peaks and the corresponding positions in Figure 1, Figure 3, Figure 5 and Figure 7 is ⁇ 0.2° ⁇ 0.5°, preferably ⁇ 0.2° ⁇ 0.3°, most preferably ⁇ 0.2° ;
  • the error described in the present invention refers to the X-ray powder diffraction of different batches of samples caused by experimental error factors such as the difference in the level of sample preparation technology, the standardization of operation, the thickness of sample sample preparation, and the use of different sample racks during the experiment.
  • the position of the diffraction peak in the spectrum has a certain degree of overall drift. For those skilled in the art, the overall drift of the diffraction peak position due to experimental errors is predictable.
  • the following tables 5, 6, 7 and 8 are four different The X-ray characteristic diffraction peak data table of the batch crystal form B, and its X-ray powder diffraction patterns are basically shown in Figures 9, 10, 11 and 12:
  • the positions of the corresponding diffraction peaks have drifted to varying degrees.
  • the corresponding 2 ⁇ in 8 are 3.901° (the degree of drift is 0.282°), 4.054° (the degree of drift is 0.129°), 3.973° (the degree of drift is 0.210°), and 4.039° (the degree of drift is 0.144°); or for example
  • the 2 ⁇ is the peak of 16.789°
  • its corresponding 2 ⁇ in Tables 5, 6, 7, and 8 are 16.512° (the degree of drift is 0.277°), 16.634° (the degree of drift is 0.155°), and 16.535° (the degree of drift is 0.155°).
  • the degree is 0.254 °), 16.612 ° (the degree of drift is 0.177 ° ); or for example, the peak of 2 ⁇ in Table 2 is 22.182 °, and its corresponding 2 ⁇ in Table 5, 6, 7, and 8 is respectively 21.915 ° (the degree of drift is 0.267°), 22.020° (the degree of drift is 0.162°), 21.933° (the degree of drift is 0.249°), 22.021° (the degree of drift is 0.161°);
  • the crystal form is an anhydrate.
  • the crystal form is a hydrate, and the number of water is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3 .
  • the preparation method of the crystal form of the above-mentioned compound specifically includes the following steps:
  • Described good solvent is selected from methanol, acetone, ethyl formate, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, One of n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone or Multiple; preferably one or more of ethyl formate, isopropanol or absolute ethanol;
  • the anti-solvent is selected from one or more of heptane, cyclohexane, n-hexane, n-pentane, water, methyl tert-butyl ether, toluene or isopropyl ether; preferably ethyl acetate, methyl One or more of tert-butyl ether or cyclohexane.
  • the preparation method of the crystal form of the above-mentioned compound specifically includes the following steps:
  • Described poor solvent is selected from one or more in heptane, cyclohexane, n-hexane, n-pentane, water, methyl tert-butyl ether, toluene or isopropyl ether; Preferred ethyl acetate, methyl One or more of tert-butyl ether or cyclohexane.
  • the object of the present invention is also to provide a pharmaceutical composition, which contains a therapeutically effective amount of any crystal form of the above compound, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the object of the present invention is also to provide the application of the crystal form of any of the above compounds or the above pharmaceutical composition in the preparation of PD-1/PD-L1 inhibitor drugs.
  • the object of the present invention is also to provide the crystal form of any of the above compounds or the application of the above pharmaceutical composition in the preparation of medicines for treating diseases selected from cancer, infectious diseases, and autoimmune diseases;
  • the cancer is selected from skin cancer , lung cancer, urological tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, head and neck cancer;
  • the infectious disease is selected from bacterial infection, viral infection;
  • the autoimmune disease is selected from organ-specific autoimmune disease, systemic autoimmune disease, wherein, the organ-specific autoimmune disease includes chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent Diabetes, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhage nephritic syndrome, primary biliary cirrhosis, multiple sclerosis, acute idiopathic polyneuritis, the Common systemic autoimmune diseases include r
  • Fig. 1 is an XRPD diagram of free base crystal form A.
  • Fig. 2 is a DSC diagram of free base crystal form A.
  • Figure 3 is an XRPD representation of free base Form B.
  • Fig. 4 is a DSC diagram of free base crystal form B.
  • Figure 5 is an XRPD representation of free base Form C.
  • Figure 6 is a DSC diagram of free base Form C.
  • Figure 7 is an XRPD representation of free base Form D.
  • Fig. 8 is a DSC diagram of free base crystal form D.
  • Fig. 9 is an XRPD diagram of batch 1 of free base crystal form B.
  • Fig. 10 is an XRPD diagram of batch 2 of free-base crystal form B.
  • Fig. 11 is an XRPD diagram of batch 3 of the free-base crystal form B.
  • Fig. 12 is an XRPD diagram of batch 4 of the free base crystal form B.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms An alkyl group, most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, “propylene” refers to -(CH 2 ) 3 -, “butylene” refers to -(CH 2 ) 4 -, and the like.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 10 carbon atoms, more preferably containing 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene group, cyclooctyl group, etc.; polycyclic cycloalkyl group includes spiro ring, fused ring and bridged ring cycloalkyl group, preferably cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cycloheptyl group.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 10 ring atoms; further preferably contains 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include oxazinone, pyrazinone, pyridinonyl, pyrrolidinyl, tetrahydropyrrolyl, tetrahydropyrrolidinyl, azetidinyl, oxa Cyclobutanyl, oxanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperyl Pyridonyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, tetrahydropyranyl and pyranyl, etc.; preferably oxazinone, pyrazinone, pyridone, Pyrrolidinyl, tetrahydropyrrolyl, te
  • Polycyclic heterocyclic groups include spiro rings, fused rings and bridged ring heterocyclic groups; the spiro rings, condensed rings and bridged ring heterocyclic groups involved are optionally connected to other groups through single bonds, or through rings Any two or more atoms on the ring are further linked with other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated ⁇ -electron system, preferably 6 to 10 membered, more preferably 6 to 8 membered, such as phenyl and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, more preferably 5 to 8 membered, most preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, Triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyridazinyl or pyrazinyl, etc.; preferably triazolyl, thienyl, thiazolyl, pyridyl, imidazolyl, pyrazolyl, pyridazine Base, pyrazinyl or pyrimidinyl; more preferably pyridyl, imidazolyl,
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as above, preferably alkyl containing 1 to 8 carbon atoms, more preferably An alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • Haloalkyl means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy means an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • Hydroalkyl means an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • Haloalkyl means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy means an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • Hydroalkyl means an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • Haldroxy means an -OH group.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH means methanol
  • DMF N,N-dimethylformamide
  • TFA trifluoroacetic acid
  • MeCN refers to acetonitrile
  • DMA refers to N,N-dimethylacetamide.
  • Et2O means diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone)dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi means methyllithium
  • n-BuLi refers to n-butyllithium
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • t-BuONO refers to t-butyl nitrite.
  • EA means ethyl acetate
  • PE petroleum ether
  • DCM dichloromethane
  • STAB sodium triacetoxyborohydride
  • Pd(dcypf)Cl 2 refers to dichloro[1,1'-bis(dicyclohexylphosphino)ferrocene]palladium.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by a deuterium atom.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the determination of NMR is to use Bruker AVANCE-400 nuclear magnetic apparatus, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard is four Methylsilane (TMS).
  • Agilent 1200 Infinity Series mass spectrometer was used for liquid chromatography-mass chromatography LC-MS determination.
  • the determination of HPLC used Agilent 1200DAD high pressure liquid chromatography (Sunfire C18 150 ⁇ 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150 ⁇ 4.6mm column).
  • Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates.
  • the specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.
  • the first step the preparation of 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde
  • 6-(3-Bromo-2-chlorophenyl)-2-methoxynicotinaldehyde 600mg, 1.83mmol
  • pinacol bis-boronate 607mg, 2.39mol
  • the fourth step N-(2,2'-dichloro-3'-(6-methoxy-5-((oxetan-3-ylamino)methyl)pyridin-2-yl)-[1 ,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide preparation of
  • reaction solution was quenched with saturated aqueous sodium bicarbonate (10 mL), extracted with DCM (20 mL), the organic layer was concentrated under reduced pressure, and the residue was separated and purified by prep-HPLC to obtain the title compound as a white solid (259 mg, 51%).
  • the first step tert-butyl ((1-((6-(2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H- Imidazo[4,5-c]pyridine-2-carbobalylamino ⁇ oxalylamino>)-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3
  • -yl methyl
  • azetidin-3-yl) methyl carbamate
  • the third step N-(3'-(5-((3-(acetylaminomethyl)azetidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2 '-Dichloro-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c ]
  • reaction solution was diluted with DCM (10 mL), washed with saturated aqueous sodium bicarbonate (5 mL), the organic layer was concentrated under reduced pressure, and the residue was separated and purified by prep-HPLC to obtain the title compound as a white solid (18.6 mg, 76%).
  • reaction solution was diluted with DCM (10 mL), washed with saturated aqueous sodium bicarbonate (5 mL), the organic layer was concentrated under reduced pressure, and the residue was separated and purified by prep-HPLC to obtain the title compound as a white solid (28.3 mg, 36%).
  • the first step tert-butyl 6-((6-(2,2'-dichloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-2-carboxalylamino ⁇ oxalylamino>)-[1,1'-biphenyl]-3-yl)-2-methoxypyridin-3-yl ) methyl)-2,6-diazaspiro [3.3] the preparation of heptane-2-carboxylate
  • reaction solution was diluted with DCM (20 mL), washed with saturated aqueous sodium bicarbonate (10 mL), the organic layer was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound as a brown oil (125 mg, 48%).
  • the third step N-(2,2'-dichloro-3'-(5-((6-isobutyryl-2,6-diazaspiro[3.3]heptane-2-yl)methyl) -6-methoxypyridin-2-yl)-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H- Preparation of imidazo[4,5-c]pyridine-2-carboxamide
  • Test Example 1 Determination of the binding inhibitory effect of the compound of the present invention on human PD-1/PD-L1
  • the purpose of this test case is to measure the activity of the compound on human PD-1/PD-L1 binding inhibition.
  • a centrifuge (5810R) was purchased from Eppendorf, a pipette was purchased from Eppendorf or Rainin, a microplate reader was purchased from BioTek, USA, and the model was H1MFD full-function microplate reader.
  • Binding Domain diluent buffer was purchased from Cisbio Company, the article number was 62DLBDDF; MAb Anti-6HIS Eu cryptate Gold was purchased from Cisbio Company, the article number was 61HI2KLA; PAb Anti Human IgG-XL665 was purchased from Cisbio Company, the article number was 61HFCXLB; PD-L1 -His protein was purchased from Abcam Company, the article number is ab167713; PD-1-Fc protein was purchased from R&D Company, the article number was 1086-PD; Detection buffer was purchased from Cisbio Company, the article number was 62SDBRDD; 384-well plates were purchased from PerkinElmer Company, the article number was 6007290.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • This experiment was carried out in a 384-well plate, the total reaction system was 20 ⁇ L, and the compound was diluted into different concentrations (10 ⁇ M or 1 ⁇ M starting, 3-fold dilution, 11 doses) using the experimental buffer Binding Domain diluent buffer (Cisbio#62DLBDDF) , Dilute PD-L1-His protein (19-238 amino acids) (Abcam#ab167713) to 10nM with experimental buffer, and dilute PD-1-Fc protein (25-167 amino acids) (R&D#1086-PD) with experimental buffer
  • the solution was diluted to 20nM, and the compound, PD-L1 protein, and PD-1 protein were added to a 384-well plate, with a total volume of 10 ⁇ L, placed in a centrifuge at 1000rpm for 1 minute to mix well, incubated at room temperature for 60 minutes, and added to each well.
  • the compound concentration and inhibition rate were used for nonlinear regression fitting using Graphpad Prism software to obtain the IC 50 value, as shown in Table 9 below.
  • Test example 2 Determination of endocytic activity of PD-L1 protein on tumor cell surface induced by compounds of the present invention
  • the purpose of this test case is to test the activity of the compound in inducing endocytosis of PD-L1 on the surface of tumor cells.
  • a centrifuge (5702R) was purchased from Eppendorf, a pipette was purchased from Eppendorf or Rainin, and a flow cytometer was purchased from Beckman Coulter, model DxFlex.
  • PE Mouse Anti-Human CD274 antibody was purchased from BD Pharmingen Company, the article number is 557924; BSA was purchased from Sigma Company, the article number was B2064-100G; PBS was purchased from Gibco Company, the article number was 10010049; 24-well plates were purchased from Corning Company, The item number is 3526.
  • the mouse colon cancer cells MC38-hPDL1 with high expression of hPD-L1 were collected, adjusted to a suitable density, spread on a 24-well plate, and placed in a 37°C, 5% CO 2 incubator to adhere to the wall overnight.
  • the compound was prepared into different concentrations in the medium and added to the 24-well plate, and the solvent control well was set, and incubated in a 37°C, 5% CO2 incubator for 16 hours, then the 24-well plate was taken out, and different treatments in the plate were collected.
  • MC38-hPDL1 cells were washed once with FACS buffer (PBS containing 0.5% BSA), and the cells were prepared to a suitable density with FACS buffer, and PE Mouse Anti-Human CD274 antibody (BD Pharmingen#557924) was added, and shaken at room temperature Incubate in the dark for 30 minutes, wash the cells twice with FACS buffer, resuspend in 100 ⁇ L PBS, use flow cytometry to detect the fluorescent signal on the cell surface, and set the isotype control as a negative control.
  • FACS buffer PBS containing 0.5% BSA
  • PE Mouse Anti-Human CD274 antibody BD Pharmingen#557924
  • the endocytosis rate of the compound was calculated using the fluorescence signals of different treatment groups, and the concentration of the compound and the endocytosis rate were used for nonlinear regression fitting using GraphPad Prism software to obtain the IC 50 value, as shown in Table 10.
  • the compounds shown in the present invention can well induce the endocytosis of PD-L1 on the surface of tumor cells.
  • Test example 3 Inhibitory effect of the compound of the present invention on CHO-PDL1/Jurkat-PD1 cell pathway
  • the purpose of this test case is to test the inhibitory effect of the compound on the CHO-PDL1/Jurkat-PD1 cellular pathway.
  • a centrifuge (5810R) was purchased from Eppendorf, a pipette was purchased from Eppendorf or Rainin, a microplate reader was purchased from BioTek, USA, and the model was H1MFD full-function microplate reader.
  • CHO-PDL1 cells and NFAT-luc2/PD1 Jurkat cells were purchased from Promega Company, product number J1252; RPMI 1640 was purchased from Gibco Company, product number 22400089; FBS was purchased from Gibco Company, product number 10091148; One-Glo reagent was purchased from The 96-well plate was purchased from Promega Company, the product number is E6120; the 96-well plate was purchased from Corning Company, the product number is 3610.
  • Cultivate CHO-PDL1 cells (Promega, #J1252) to a suitable cell density, digest and resuspend the cell suspension with complete medium to a suitable density, spread 100 ⁇ L per well on a 96-well plate (Corning, #3610), put 37°C, 5% CO 2 incubator adherent culture overnight, use analysis medium (RPMI 1640+2% FBS, RPMI 1640 product number is Gibco, #22400089, FBS product number is Gibco, #10091148) to prepare compound solutions with different concentrations, NFAT-luc2/PD1 Jurkat cells (Promega, #J1252) were collected and resuspended to an appropriate cell density using assay medium.
  • RPMI 1640+2% FBS RPMI 1640 product number is Gibco, #22400089, FBS product number is Gibco, #10091148
  • the EC 50 value was fitted according to the compound concentration and the luminescent signal value, and the maximum induction factor of each compound relative to the signal value of the untreated group was calculated, as shown in Table 11.
  • Test Example 4 Determination of the Combination of Invention Compounds to Improve PD-L1 Protein Stability (Melting Temperature)
  • the purpose of the experiment To test the ability of the compound to improve the stability of PD-L1 protein and increase the melting temperature of the protein.
  • Quantitative PCR instrument (Quantstudio6 Flex) was purchased from Life Company, and the pipette was purchased from Eppendorf or Rainin Company.
  • Protein Thermal Shift TM Dye Kit was purchased from Thermofisher Company, product number 4461146; PD-L1 protein was purchased from Acro Biosystems Company, product number was PD1-H5229; HEPES, 1M Buffer Solution was purchased from Thermofisher Company, product number 15630080; NaCl was purchased from From Sinopharm Chemical Reagent Co., Ltd., the product number is 10019318.
  • the compounds shown in the present invention have the ability to improve the stability of PD-L1 protein in the test of increasing the melting temperature of PD-L1 protein.
  • Test example 5 The in vitro cytotoxic effect of the compound of the present invention on NFAT-luc2/PD1 Jurkat cells and MC38-hPDL1 cells
  • a centrifuge (5810R) was purchased from Eppendorf, a pipette was purchased from Eppendorf or Rainin, a microplate reader was purchased from BioTek, USA, and the model was H1MFD full-function microplate reader.
  • RPMI 1640 was purchased from Gibco Company, the product number is 22400089; FBS was purchased from Gibco Company, the product number was 10091148; PBS was purchased from Gibco Company, the product number was 10010049; Cell Titer-Glo was purchased from Promega Company, the product number was G7573; cell culture plate Purchased from Corning Company, Cat. No. 3610.
  • the cells When the cells are cultured to a suitable degree of confluence, collect the cells, use the complete medium to adjust the cells to a suitable cell concentration, spread the cell suspension on a 96-well plate, 90 ⁇ L per well, and place it in a 37°C, 5% CO 2 incubator Adhere to the wall overnight, use DMSO and medium to prepare compound solutions of different concentrations, set up vehicle control, add the compound solution to a 96-well plate, 10 ⁇ L per well, put it in a 37°C, 5% CO 2 incubator and continue to cultivate for 72 hours , add CellTiter-Glo solution, shake and mix well, incubate in the dark for 10 minutes, and read with BioTek Synergy H1 microplate reader.
  • the compounds shown in the present invention have weak toxic effects on NFAT-luc2/PD1 Jurkat and MC38-hPDL1 cells.
  • Test example 6 Balb/C mouse pharmacokinetics is measured
  • mice Taking Balb/C mice as the experimental animals, the pharmacokinetics of the following compound examples were orally administered at a dose of 5 mg/kg in mice in vivo.
  • Embodiment of the present invention self-made.
  • HPMC 1% Tween 80
  • Balb/C mice male; p.o. after fasting overnight, the dose is 5mg/kg, and the administration volume is 10mL/kg.
  • liquid A is 0.1% formic acid aqueous solution
  • liquid B is acetonitrile
  • Test example 7 Pharmacokinetic determination of tumor-bearing nude mouse plasma and tumor
  • Embodiment of the present invention self-made.
  • HPMC 1% Tween 80
  • Tumor-bearing nude mice female; p.o. after fasting overnight, the dose is 30mg/kg, and the administration volume is 10mL/kg.
  • Tumor tissue was homogenized by adding methanol water at a ratio of 1:3 and centrifuged to obtain the supernatant. Take 40 ⁇ L of the tumor homogenate supernatant and plasma samples and add 160 ⁇ L of acetonitrile for precipitation. After mixing, centrifuge at 3500 ⁇ g for 5-20 minutes.
  • liquid A is 0.1% formic acid aqueous solution
  • liquid B is acetonitrile
  • Test example 8 plasma protein binding rate experiment
  • the purpose of this experimental method is to detect the plasma protein binding of the compounds of the examples in plasma.
  • Ultra-high performance liquid phase tandem mass spectrometry coupled instrument refrigerated centrifuge, vortex instrument, electric heating constant temperature oscillating water tank, pipette, continuous liquid adder, 96-well plate, tissue homogenizer (used for tissue sample analysis), Add internal standard acetonitrile solution, blank matrix (plasma, urine or tissue homogenate, etc.)
  • Compound working solution preparation dilute the stock solution with DMSO to a final concentration of 1 mM.
  • Washing gradient 0.2 ⁇ 1.6min 5%A to 95%A, 3.0 ⁇ 3.1min 95%A to 5%A;
  • Ion source electrospray ionization source (ESI);
  • Drying gas N 2 , temperature 500°C;
  • Electrospray voltage 5000V
  • Detection method positive ion detection
  • Scanning method select the reaction monitoring (MRM) method.
  • the compound of the embodiment of the present invention shows a high plasma protein binding rate.
  • Vernier caliper 500-196, Mitutoyo, Japan
  • Fetal bovine serum (FBS) (10099-141, Gibco);
  • PBS Phosphate buffered saline
  • the compound of the embodiment of the present invention is self-made.
  • MC38-hPDL1 cells Take out MC38-hPDL1 cells from the cell bank, add DMEM medium (DMEM+10% FBS) after recovery, and place them in a CO 2 incubator for culture (incubator temperature is 37°C, CO 2 concentration is 5%). When the number expanded to the required number for inoculation in vivo, MC38-hPDL1 cells were harvested. Count with an automatic cell counter, and resuspend the cells with PBS according to the counting results to make a cell suspension (density 1 ⁇ 10 6 /mL), and place in an ice box until use.
  • DMEM medium DMEM+10% FBS
  • mice Use 6-8 week old female C57 mice weighing approximately 18-22 g. Mice were raised in SPF grade animal room, and raised in single cages, with 4-5 mice per cage. All cages, litter and water were sterilized before use, and all animals had free access to food and water. Before the experiment started, the C57 mice were marked with a disposable ear tag for rats and rats, and the skin of the inoculation site was disinfected with 75% alcohol before inoculation, and each mouse was subcutaneously inoculated with 0.1 mL (containing 1*10 5 cells) of MC38- hPDL1 cells. When the tumor volume reached 40-180mm 3 , group administration began, with 8 rats in each group. Each test compound was orally administered twice a day for 14 days. Tumor volume was measured and mouse body weight was weighed twice a week, and tumor TGI (%) was calculated.
  • Tumor volume (mm 3 )
  • TGI (%) [(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group))/(average tumor volume at the end of treatment of the solvent control group - Average tumor volume at the beginning of treatment in solvent control group)] ⁇ 100%;
  • TGI (%) [1-(average tumor volume at the end of administration of a treatment group-average tumor volume at the beginning of administration of this treatment group)/average tumor volume at the beginning of administration of this treatment group] ⁇ 100%.
  • Example 4 Compound SD rats repeated gavage toxicity test for 14 days
  • the purpose of this study is to investigate the possible toxic reaction of the compound of Example 4 given to SD rats after repeated gavage for 14 days.
  • Test article N-(3'-(5-((6-acetyl-2,6-diazaspiro[3.3]heptane-2-yl)methyl)-6-methoxypyridine-2 -yl)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole A[4,5-c]pyridine-2-carboxamide (compound of Example 4)
  • the average exposure amount (AUC last ) of the compound of Example 4 in the animal body all increases with dosage; There was no significant gender difference in the exposure of the compound of Example 4 in animals. After 14 days of repeated administration, compared with the first administration, there was no significant accumulation of the compound of Example 4 in the animals of each dose group.
  • FIB Neut and FIB increased in 100mg/kg dose group; FIB increased in female animals in 15 and 50mg/kg dose groups.
  • the compound of Example 4 was administered to SD rats repeatedly by intragastric administration at doses of 15, 50, and 100 mg/kg, once a day, for 14 consecutive days, and the maximum tolerated dose (MTD) was 100 mg/kg.
  • the obtained solid detection XRPD is Form A. After detection and analysis, it has an XRPD pattern as shown in FIG. 1 and a DSC pattern as shown in FIG. 2 .
  • the obtained solid detection XRPD is crystal form B. After detection and analysis, it has an XRPD pattern as shown in FIG. 3 and a DSC pattern as shown in FIG. 4 .
  • a relatively stable crystal form of the compound of Example 4 was found through the crystal form beating experiment stability investigation experiment.
  • the free base crystal form B has good stability under high temperature and high humidity conditions, and the maximum single-heterogeneity increase is less than 0.1%.
  • the hygroscopicity of the free base crystal form B of the compound of Example 4 was investigated under different relative humidity conditions to provide a basis for the screening and storage of the compound crystal form.
  • the free base crystal form B of the compound is placed in saturated water vapor with different relative humidity, so that the compound and the water vapor reach a dynamic equilibrium, and the percentage of the weight gain of the compound after the equilibrium is calculated.
  • the free base crystal form B has a hygroscopic weight gain of about 0.815%, which is slightly hygroscopic. After one cycle of moisture absorption and desorption under the condition of 0-95% relative humidity, the XRPD spectrum of the free base crystal form B does not change, that is, the crystal form B is not transformed.
  • thermodynamic solubility of the compound at 37°C was determined by HPLC and external standard method.
  • Free base crystal form B has good solubility in the pH range and environment of the entire gastrointestinal tract.

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Abstract

L'invention concerne une forme cristalline d'un composé de formule générale (I), son procédé de préparation, une composition pharmaceutique contenant la quantité thérapeutiquement efficace de la forme cristalline, et son utilisation en tant qu'inhibiteur de PD-1/PD-L1 dans le traitement de cancers, de maladies infectieuses et de maladies auto-immunes.
PCT/CN2022/102195 2021-06-29 2022-06-29 Forme cristalline d'un inhibiteur de dérivé de biphényle et son procédé de préparation Ceased WO2023274280A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024155717A1 (fr) * 2023-01-20 2024-07-25 Aligos Therapeutics, Inc. Procédés et compositions pour le ciblage de pd-l1
CN118994208A (zh) * 2024-10-25 2024-11-22 江苏豪森药业集团有限公司 一种联苯类衍生物的制备方法
WO2025174835A1 (fr) * 2024-02-15 2025-08-21 Aligos Therapeutics, Inc. Procédés et compositions pour cibler pd-l1
US12428427B2 (en) 2021-12-16 2025-09-30 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1

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CN110267953A (zh) * 2016-12-22 2019-09-20 因赛特公司 四氢咪唑并[4,5-c]吡啶衍生物作为pd-l1内在化诱导剂
WO2020024997A1 (fr) * 2018-08-01 2020-02-06 上海轶诺药业有限公司 Préparation et application de classe de composés hétérocycliques à teneur en n ayant une fonction immunorégulatrice
WO2021136354A1 (fr) * 2020-01-03 2021-07-08 上海翰森生物医药科技有限公司 Inhibiteur de dérivé biphényle, son procédé de préparation et son utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110267953A (zh) * 2016-12-22 2019-09-20 因赛特公司 四氢咪唑并[4,5-c]吡啶衍生物作为pd-l1内在化诱导剂
WO2020024997A1 (fr) * 2018-08-01 2020-02-06 上海轶诺药业有限公司 Préparation et application de classe de composés hétérocycliques à teneur en n ayant une fonction immunorégulatrice
WO2021136354A1 (fr) * 2020-01-03 2021-07-08 上海翰森生物医药科技有限公司 Inhibiteur de dérivé biphényle, son procédé de préparation et son utilisation

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12428427B2 (en) 2021-12-16 2025-09-30 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
WO2024155717A1 (fr) * 2023-01-20 2024-07-25 Aligos Therapeutics, Inc. Procédés et compositions pour le ciblage de pd-l1
WO2025174835A1 (fr) * 2024-02-15 2025-08-21 Aligos Therapeutics, Inc. Procédés et compositions pour cibler pd-l1
CN118994208A (zh) * 2024-10-25 2024-11-22 江苏豪森药业集团有限公司 一种联苯类衍生物的制备方法
CN118994208B (zh) * 2024-10-25 2025-02-11 江苏豪森药业集团有限公司 一种联苯类衍生物的制备方法

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