WO2022095953A1 - Pyridazine alkyne compounds and use thereof - Google Patents

Pyridazine alkyne compounds and use thereof Download PDF

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WO2022095953A1
WO2022095953A1 PCT/CN2021/128905 CN2021128905W WO2022095953A1 WO 2022095953 A1 WO2022095953 A1 WO 2022095953A1 CN 2021128905 W CN2021128905 W CN 2021128905W WO 2022095953 A1 WO2022095953 A1 WO 2022095953A1
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substituted
alkyl
unsubstituted
cancer
group
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PCT/CN2021/128905
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French (fr)
Chinese (zh)
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张学军
常少华
王洪强
万海星
井真中
李群
陈浩民
田华
杨俊�
李莉娥
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武汉人福创新药物研发中心有限公司
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Publication of WO2022095953A1 publication Critical patent/WO2022095953A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure belongs to the field of medicinal chemistry. Specifically, the present disclosure relates to pyridazine alkyne compounds, and more particularly, the present disclosure relates to a pyridazine alkyne compound, a preparation method thereof, and use thereof in the preparation of medicines.
  • CD73 also known as extracellular 5'-nucleotide hydrolase, is an exonuclease belonging to the metallophosphatase superfamily and is a peripheral glycoprotein whose major form is anchored by glycosylphosphatidylinositol (GPI) It is fixed on the plasma membrane with a molecular weight of 70KD and is encoded by the NT5E gene.
  • GPI glycosylphosphatidylinositol
  • CD73 is widely expressed on the cell surface of different tissues, including brain, lung, heart, spleen, lymph node, kidney, colon, vascular endothelium, and bone marrow; it is also expressed on various immune cells, including macrophages, neutrophils, myeloid suppression cells (MDSCs), dendritic cells (DCs), natural killer cells (NKs), and regulatory T cells (Tregs) (Soleimani A et al., Biochimie, 2020, 176:21-30.); a variety of tumor cells also have Highly expressed CD73, such as: melanoma, breast cancer, pancreatic cancer, ovarian cancer, colon cancer and prostate cancer, etc. (Gao Z et al., Biomed Res Int, 2014, 2014:460654.). CD73 is also present in a soluble form (sCD73) in biological fluids, including serum, and preserves holoenzyme activity.
  • sCD73 soluble form
  • CD73 mainly exerts physiological and pathological effects by hydrolyzing AMP (adenosine monophosphate) to produce extracellular adenosine (ADO).
  • ADO is associated with four G protein-coupled receptors (GPCRs): A1 adenosine A2A adenosine receptor (A2AR), A2B adenosine receptor (A2BR) and A3 adenosine receptor (A3AR) play a role, of which A2AR plays a major role (Linden J et al., Annu.Rev.Immunol., 2019, 37:325-347.).
  • GPCRs G protein-coupled receptors
  • Adenosine receptors are not only expressed in tumor cells, but also expressed on the cell surface of immune cells and vascular endothelial cells infiltrated in the tumor microenvironment. After binding to the receptors, ADO produces a variety of immunosuppressive and tumor-promoting effects. .
  • CD73 is closely related to tumor growth, angiogenesis and metastasis. Under normal physiological conditions, the extracellular ADO level is between 20 and 300 nM, but in the tumor microenvironment, the increase is maintained to the micromolar level (30-100 ⁇ M), and the high extracellular ADO concentration is mainly generated by CD73 hydrolysis of AMP affected. Studies have shown that soluble CD73 (sCD73) levels are increased in the plasma of cancer patients compared to healthy individuals (Klemens MR et al., Biochem. Biophys. Res. Commun., 1990, 172:1371-7..).
  • CD73 is upregulated in pancreatic ductal carcinoma (PDAC) compared to normal pancreatic tissue and is associated with tumor size, metastasis and poor prognosis (Harvey Jerry B et al, Front Immunol, 2020, 11:508.).
  • PDAC pancreatic ductal carcinoma
  • ORIC-533 significantly reduced the ADO concentration in the tumor microenvironment while reducing tumor volume.
  • CD73 inhibitors can block tumor growth by releasing immunosuppression, and can also be used in combination with other targeted therapies and/or immunotherapy and radiotherapy to increase the anti-tumor effect.
  • CD73 inhibitor and radiotherapy may have a synergistic effect (Wennerberg E et al., Cancer Immunol Res., 2013, 19:5626-35.); patients receiving anti-PD-1 antibody immunotherapy CD73 levels were found to be upregulated in melanoma patients, whereas a distinct CD73-overexpressing macrophage population persisted in glioblastoma patients after anti-PD-1 therapy, and CD73 deficiency enhanced anti-PD-1 and anti-CTLA-4 Efficacy in a mouse glioblastoma model (Goswami S et al., Nat.Med., 2020, 26:39-46.); radiotherapy led to the destruction of some tumor cells, resulting in the release of a large amount of intracellular ATP to the extracellular , Under the action of tumor cell surface or free CD73, it is converted into adenosine, which produces an immunosuppressive effect, which is considered to be one of the reasons for the poor prognosis of some patients after radiotherapy. Therefore, the combination of CD
  • CD73 inhibition may be a promising approach for the treatment of tumors.
  • the present disclosure aims to propose a novel CD73 inhibitor, which can be used to prepare a drug for the treatment of tumor-related diseases.
  • the present disclosure proposes a compound, which is a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2 or 3;
  • R 2 is selected from hydrogen, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 3 -C 6 cycloalkyl, unsubstituted or R b substituted 5-8 Member aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, unsubstituted or R b substituted 4-8 membered heterocycloalkyl, or, unsubstituted or R b substituted 4-8 Membered heterocycloalkenyl; said C 1 -C 6 alkyl substituted by R b , said C 3 -C 6 cycloalkyl substituted by R b , said 5-8 substituted by R b Member aryl, said 5-8 membered heteroaryl substituted by R b , said 4-8 membered heterocycloalkyl substituted by R b , or, said 4-8 member substituted by R b In the membered heterocycl
  • the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
  • the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
  • the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
  • the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2 or 3;
  • R 2 is selected from hydrogen, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 3 -C 6 cycloalkyl, unsubstituted or R b substituted 5-8 Member aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, unsubstituted or R b substituted 4-8 membered heterocycloalkyl, or, unsubstituted or R b substituted 4-8 Membered heterocycloalkenyl; said C 1 -C 6 alkyl substituted by R b , said C 3 -C 6 cycloalkyl substituted by R b , said 5-8 substituted by R b Member aryl, said 5-8 membered heteroaryl substituted by R b , said 4-8 membered heterocycloalkyl substituted by R b , or, said 4-8 member substituted by R b In the membered heterocycl
  • the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
  • the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
  • the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, preferably is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
  • R 2 is an unsubstituted or R b substituted C 1 -C 6 alkyl group
  • the number of the substituent R b is 1-3, preferably 1 indivual.
  • the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclo Pentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.
  • R 2 when R 2 is an unsubstituted or substituted 5-8-membered aryl group, the 5-8-membered aryl group is independently phenyl or naphthyl, preferably is phenyl.
  • the 5-8-membered heteroaryl group is independently pyrrole, pyrazole, triazine azole, furan, oxazole, thiophene, thiazole, pyridine, pyrazine or pyrimidine, preferably pyrazole, furan, thiophene and pyridine.
  • R 2 when R 2 is an unsubstituted or substituted 4-8-membered heterocycloalkyl group, the 4-8-membered heterocycloalkyl group is independently azetidine , oxetane, tetrahydropyrrolidinyl, tetrahydrofuranyl, hexahydropyran or tetrahydro-2H-thiopyran 1,1-dioxide, preferably azetidine or oxane Butane.
  • R 2 is a 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b
  • the 4-8-membered heterocycloalkenyl is independently a dihydropyridyl, Tetrahydropyridyl, tetrahydropyrimidinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, dihydroimidazolyl, dihydropyrazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazole base, dihydroisothiazolyl, dihydrothienyl, dihydropyrrolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, dihydropyrazinyl, dihydropyrimidinyl, or fluorobis Hydrofuranyl, preferably 1,2,3,4-tetrahydropyridyl, 1,2-
  • R b is hydroxyl
  • R b is a C 1 -C 6 alkyl group
  • the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, preferably methyl, ethyl, n-propyl or isopropyl.
  • the halogen is F, Cl, Br, I, preferably F or Cl.
  • the halogen is F, Cl, Br or I, preferably F or Cl.
  • m is 0, 1 or 2.
  • the C 1 -C 6 alkyl group is independently a C 1 -C 4 alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
  • R 1 is unsubstituted or R a substituted C 1 -C 6 alkyl, or, unsubstituted or R a substituted C 1 -C 6 alkyl-O-
  • m is 1 or 2, preferably m is 1.
  • R 1 is C 1 -C 6 alkyl substituted by Ra , or C 1 -C 6 alkyl-O- substituted by Ra , the substituted
  • the number is independently 1-3, preferably 2.
  • R 1 is C 1 -C 6 alkyl substituted by Ra , or C 1 -C 6 alkyl-O- substituted by Ra
  • the substitutions are each When independently C 1 -C 6 alkyl, or C 1 -C 6 alkyl-O-, the C 1 -C 6 alkyl described in the substitution is independently C 1 -C 4 alkyl, Preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
  • the halogen is F, Cl, Br or I, preferably F or Cl.
  • R 2 is or
  • the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
  • R 2 is selected from hydrogen, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 3 -C 6 cycloalkyl, unsubstituted or R b substituted 5-8 Member aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, unsubstituted or R b substituted 4-8 membered heterocycloalkyl, or, unsubstituted or R b substituted 4-8 Membered heterocycloalkenyl; said C 1 -C 6 alkyl substituted by R b , said C 3 -C 6 cycloalkyl substituted by R b , said 5-8 substituted by R b Member aryl, said 5-8 membered heteroaryl substituted by R b , said 4-8 membered heterocycloalkyl substituted by R b , or, said 4-8 member substituted by R b In the membered heterocycl
  • the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
  • the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
  • the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
  • the compound represented by formula I, its hydrate, solvate, pharmaceutically acceptable salt or prodrug is wherein R 1 and R 2 have the definitions as previously described.
  • R 1 is selected from difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl or isopropyl;
  • R 2 is selected from methyl, ethyl or cyclopropyl .
  • the compound of formula I is selected from any of the following compounds :
  • the present disclosure proposes a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically Acceptable salts or prodrugs and pharmaceutically acceptable excipients.
  • the pharmaceutical compositions of the present disclosure may include therapeutically effective doses of the above-mentioned compounds, tautomers, stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts thereof
  • prodrugs and pharmaceutically acceptable pharmaceutical carriers, diluents or excipients are mixed to prepare pharmaceutical preparations suitable for oral or parenteral administration.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
  • the formulations may be administered by any route, such as by infusion or bolus injection, by route of absorption through the epithelium or mucocutaneous (eg, oral mucosa or rectum, etc.). Administration can be systemic or local.
  • formulations for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulations can be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulations.
  • the present disclosure proposes that the above-mentioned compounds, or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, interact with PD-1 antibody, PD- Use of L1 antibody, CTLA-4 antibody, or a combination of PD-1 inhibitor, PD-L1 inhibitor, and CTLA-4 inhibitor in the preparation of a medicament for treating CD73-related diseases, and the medicament can be used for treating cancer.
  • cancers include, for example, bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, stomach cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, ovary cancer, pancreatic cancer, prostate cancer, or kidney cancer.
  • the present disclosure proposes that the above-mentioned compounds, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, or the above-mentioned pharmaceutical compositions are prepared for use in Use in medicines for treating diseases related to CD73.
  • the above-mentioned compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above-mentioned pharmaceutical compositions are prepared for the treatment of CD73-related diseases Use in a medicament useful in the treatment of cancer.
  • cancers include, for example, bladder cancer, breast cancer, bile duct cancer, colorectal cancer, colon cancer, stomach cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, Ovarian, pancreatic, prostate or kidney cancer.
  • the present disclosure provides a method for treating a disease related to CD73, the method comprising: administering to a subject the above-mentioned compound, its tautomer, stereoisomer, hydrate, Solvates, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions.
  • the present disclosure provides a method for treating a disease associated with CD73, the method comprising: administering to a subject in combination the aforementioned compound, its tautomer, stereoisomer, Hydrate, solvate, pharmaceutically acceptable salt or prodrug, the pharmaceutical composition with PD-1 antibody, PD-L1 antibody, CTLA-4 antibody or PD-1 inhibitor, PD-L1 inhibitor, CTLA -4 inhibitor.
  • the CD73-related disease is cancer.
  • the cancer is bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, stomach cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, neurological Angioblastoma, melanoma, ovarian, pancreatic, prostate or kidney cancer.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
  • salts are contemplated by the present disclosure. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used in the identification, characterization or purification of the compounds of the present disclosure.
  • composition means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • classes of the term “excipient” include, without limitation, 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 flowability and/or stickiness.
  • prodrug refers to a compound of the present disclosure that can be converted under physiological conditions or by solvolysis to a biologically active compound.
  • the prodrugs of the present disclosure are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds.
  • Prodrugs include compounds formed by connecting a hydroxyl group or amino group in the compounds of the present disclosure to any group. When the prodrugs of the compounds of the present disclosure are administered to mammalian individuals, the prodrugs are cleaved to form a free hydroxyl group, a free hydroxyl group, and a free group, respectively. the amino group.
  • stereoisomer refers to isomers resulting from different arrangements of atoms in a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers and conformers.
  • the compounds of the present disclosure may exist as one of the possible isomers or as a mixture thereof, eg, as pure optical isomers, or as mixtures of isomers, eg, as racemic and non-isomeric isomers.
  • 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 the compound, where (–) or L indicates that the compound is levorotatory.
  • the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl group may be in the cis- or trans- (cis- or trans-) configuration.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques.
  • Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids.
  • Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
  • optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include ⁇ -methyl-benzylamine in stereoisomerically pure form (eg, S and R forms or diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.
  • Resolution of racemic mixtures can also be performed by elution on a chromatographic column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • Compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present disclosure includes all tautomeric forms of compounds.
  • the compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioisotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
  • an "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect.
  • an "effective amount” of one active in a composition refers to the amount required to achieve the desired effect when used in combination with another active in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating the target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
  • Ketone substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • C 1 -C 6 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 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, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbut
  • C 1 -C 6 alkyl-O- is to be understood as an alkyl group attached to the rest of the molecule through an oxygen atom, wherein "C 1 -C 6 alkyl” has the above definition. Such as methyl-O-, ethyl-O-.
  • C3 - C6cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • 4-8 membered heterocyclyl or “4-8 membered heterocycloalkyl” is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S, which may be attached through carbon or nitrogen unless otherwise specified, wherein the -CH2- group is optionally replaced by -C(O)- and wherein, unless otherwise stated to the contrary, a ring nitrogen atom or a ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or a ring nitrogen atom is optionally quaternized; wherein -NH in the ring is optionally substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogens.
  • heterocyclyl group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl group is monocyclic, it must not be aromatic.
  • heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methanesulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indoline, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 -Dioximidazolidinyl.
  • 4-8 membered heterocycloalkenyl is to be understood as a non-aromatic monocyclic or polycyclic group containing 4 to 8 ring atoms, preferably 5 to 6 ring atoms, wherein the 4-8 membered heterocyclic group Cycloalkenyl contains 1 to 3 heteroatoms selected from N, O, S and P and contains at least one carbon-carbon double bond or carbon-nitrogen double bond.
  • Aza, oxa or thia included in the group name means at least one nitrogen, oxygen or sulfur atom, respectively, as a ring atom.
  • the nitrogen or sulfur atom of the 4-8 membered heterocycloalkenyl can optionally be oxidized to the corresponding N-oxide, S-oxide or S-dioxide.
  • Preferred 4-8 membered heterocycloalkenyl groups include, but are not limited to, 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3 ,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl , dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl and their oxides.
  • 5-8 membered aryl is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 5-8 carbon atoms, especially a ring having 6 carbon atoms (" C 6 aryl”), such as phenyl; when the 5-8 membered aryl is substituted, it may be mono- or poly-substituted. Also, the substitution site is not limited, for example, it may be ortho-, para- or meta-substitution.
  • 5-8 membered heteroaryl is to be understood as a monovalent radical having 5-8 ring atoms, especially 5 or 6 carbon atoms, and comprising 1-5 heteroatoms independently selected from N, O and S Monocyclic, bicyclic or tricyclic aromatic ring groups. Monovalent monocyclic, bicyclic or tricyclic aromatic ring groups of 1 to 3 heteroatoms independently selected from N, O and S are preferred and, in addition, may be benzofused in each case.
  • heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl oxadiazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; group, carbazolyl group, acridine group, phenazinyl group, phenothiazinyl group, phenoxazinyl group and the like.
  • halo or halogen is fluorine, chlorine, bromine and iodine.
  • the description method "...independently” used in the present disclosure should be understood in a broad sense, meaning that the described individuals are independent of each other and may be independent of each other. are the same or different specific groups.
  • the description mode "...independently” can either mean that in different groups, the specific options expressed in the same match do not affect each other, or it can mean that in the same group, the same symbols are used together. The specific options expressed between them do not affect each other.
  • the present disclosure provides CD73 inhibitors with novel structures, excellent pharmacokinetic properties, and good efficacy or druggability, which can be used to effectively treat CD73-related diseases and disorders.
  • the compound of the present disclosure has a good inhibitory effect on CD73 enzyme, and has a good in vitro drug effect.
  • the experimental results in mice show that the compounds of the present disclosure exhibit excellent pharmacokinetic properties and good druggability.
  • the compounds of the present disclosure can significantly inhibit the growth of CT-26 colorectal cancer and E.G7-OVA T-cell lymphoma when used alone or in combination with PD-1/L1 antibody.
  • the structures of the compounds of the present disclosure were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10-6 (ppm).
  • the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • M molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
  • IC 50 the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • Comparative compound 2 refers to the compound described in Comparative Example 2.
  • reaction solution was poured into aqueous sodium carbonate solution (500 mL) and aqueous sodium sulfite solution (500 mL), then extracted with dichloromethane (2000 mL ⁇ 2), the organic phases were combined, washed with saturated brine (500 mL), and washed with sodium sulfate. Drying, filtration, and concentration gave (1S,2S)-ethyl 2-formylcyclopropane-1-carboxylate (A-5) (67.0 g, 68% yield) as a yellow oil.
  • Step 4 Synthesis of (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylic acid ethyl ester (A-6)
  • Step 5 Synthesis of (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylic acid (A-7)
  • the sixth step Synthesis of 3,6-dichloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazine (A-9)
  • the fifth step the synthesis of 3,6-dichloro-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (B-8)
  • the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product.
  • the synthetic route of target compound 1 is as follows:
  • the first step 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(propan-1 Synthesis of -alkyn-1-yl)pyridazine (1B)
  • Step 2 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(prop-1-yn-1-yl)pyridazin-3-yl)pyrimidine -2,4(1H,3H)-dione (1)
  • the synthetic route of target compound 2 is as follows:
  • Step 2 5-(6-(But-1-yn-1-yl)-5-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine Synthesis of -2,4(1H,3H)-dione (2)
  • the synthetic route of target compound 3 is as follows:
  • the first step 3-(cyclopropylethynyl)-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidine-5 -Synthesis of pyridazine (3B)
  • Step 2 5-(6-(Cyclopropylethynyl)-5-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4 Synthesis of (1H,3H)-diketone (3)
  • the synthetic route of target compound 4 is as follows:
  • the first step 4-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine-3 Synthesis of -yl)-2-methyl-3-yn-2-ol (4B)
  • Step 2 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl) Synthesis of Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (target product 4)
  • the first step 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(3-methyl) Synthesis of But-1-yn-1-yl)pyridazine (5B)
  • Step 2 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(3-methylbut-1-yn-1-yl)pyridazine-3 Synthesis of -yl)pyrimidine-2,4(1H,3H)-dione (target compound 5)
  • reaction solution was directly lyophilized to obtain a yellow solid 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(3-methylbutan-1- Alkyn-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (5) (40.5 mg, 50.4% yield).
  • the synthetic route of target compound 6 is as follows:
  • the first step 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-((1- Synthesis of Methyl-1H-pyrazol-4-yl)ethynyl)pyridazine (6B)
  • Step 2 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl) Synthesis of Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (target compound 6)
  • the synthetic route of target compound 7 is as follows:
  • the first step Synthesis of tributyl(cyclobutylethynyl)stannane (7A)
  • n-Butyllithium (2.5M, 7.03 mL) was added dropwise to tetrahydrofuran (5 mL) at -5°C, keeping the temperature below 10°C.
  • 6-Chloro-1-hexyne (1 g, 8.58 mmol) was added dropwise to the system at about 5°C, and stirred for 2 hours.
  • tri-n-butyltin chloride (3.07 g, 9.43 mmol) was added dropwise to the system and reacted for 0.5 hour.
  • the reaction system was quenched with potassium fluoride solution (50 mL), then extracted with ethyl acetate (50 mL ⁇ 3), the organic layers were combined, dried over sodium sulfate, and concentrated to obtain tributyl(cyclobutylethynyl)stannane as a yellow oil (7A) (3 g, 94.7% yield).
  • Step 2 3-(Cyclobutylethynyl)-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidine-5 -Synthesis of pyridazine (7B)
  • the synthetic route of target compound 8 is as follows:
  • Step 2 5-(6-(Cyclopropylethynyl)-5-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4( Synthesis of 1H,3H)-dione (target compound 8)
  • the second step 5-[6-(2-cyclopropylethynyl)-5-[(1R,2R)-2-(difluoromethyl)cyclopropyl]pyridazin-3-yl]-1H- Pyrimidine-2,4-dione (target compound 9)
  • the synthetic route of target compound 10 is as follows:
  • reaction system was diluted with water (100 mL), then extracted with ethyl acetate (100 mL ⁇ 2), the organic layers were combined, saturated aqueous sodium carbonate solution (100 mL) was added, and the mixture was stirred for 10 minutes.
  • the fourth step the synthesis of 3,6-dichloro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (10D)
  • 3,6-Dichloropyridazine (450 mg, 3.02 mmol) and (1S,2S)-2-(trifluoromethyl)cyclopropanecarboxylic acid (465 mg, 3.02 mmol) were dissolved in water (15 mL) and concentrated Sulfuric acid (0.5 mL), warmed to 70°C under nitrogen protection. Then an aqueous solution of silver nitrate (257 mg, 1.51 mmol, 1.5 mL) was added rapidly, and then an aqueous solution of ammonium persulfate (2.07 g, 9.06 mmol, 5 mL) was slowly added dropwise, and the reaction was continued at 70° C. for 1 hour.
  • the pH of the reaction solution was adjusted to about 9 with ammonia water, and then extracted with ethyl acetate (40 mL ⁇ 2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product.
  • Step 7 5-[6-(2-Cyclopropylethynyl)-5-[(1S,2S)-2-(trifluoromethyl)cyclopropyl]pyridazin-3-yl]-1H- Pyrimidine-2,4-dione (target compound 10)
  • the synthetic route of target compound 11 is as follows:
  • Triethyl phosphoryl acetate (14.3 g, 63.8 mmol) was dissolved in 1,4-dioxane (20 mL), then n-butyllithium (2.5 M, 30.2 mL) was added dropwise at 0 °C, After completion, the reaction solution was stirred at 25°C for 0.5 hours, then the reaction solution was transferred to a stuffy tank, and then (R)-2-isopropyloxirane (5.00 g, 58.1 mmol) in 1,4 was added.
  • - Dioxane solution (10 mL). Tighten the stuffy jar, heat it up to 145°C and react for 12 hours.
  • the fifth step the synthesis of 3,6-dichloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (11F)
  • an aqueous solution of silver nitrate (3.57 g, 21.0 mmol, 25 mL) was added rapidly, and then an aqueous solution of ammonium persulfate (28.8 g, 126.2 mmol, 50 mL) was slowly added dropwise, and the reaction was continued at 70° C. for 1 hour.
  • the pH of the reaction solution was adjusted to about 9 with aqueous ammonia, then extracted with ethyl acetate (200 mL ⁇ 2), the organic layers were combined, the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product .
  • the sixth step 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (11G) synthesis
  • Step 7 6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-3-(prop-1-yn- Synthesis of 1-yl)pyridazine(11H)
  • the eighth step 5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-(prop-1-yn-1-yl)pyridazin-3-yl)pyrimidine-2, Synthesis of 4(1H,3H)-diketone (11)
  • 6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-3-(prop-1-yn-1-yl ) pyridazine (1.00 g, 2.67 mmol) was dissolved in hydrochloric acid (1 M, 5.00 mL) and reacted at 50° C. for 12 hours.
  • Test Example 1 In vitro inhibitory activity of the compound on recombinant human CD73 enzyme
  • test compound IC50 (nM) Control compound 2 27.03 1 21.61 2 9.118 3 4.638 4 83.94 5 196.2 6 34.80 7 33.74 8 60.03 9 247.6 10 11.19 11 14.71
  • results of the in vitro enzyme test show that the disclosed compounds have a good inhibitory effect on CD73 enzyme. Compared with the control compounds, some of the disclosed compounds show more excellent inhibitory effect on CD73 enzyme.
  • mice Pharmacokinetic test in mice, using male ICR mice, 20-25 g, fasted overnight. Three mice were taken and administered by oral gavage (10 mg/kg). Blood was collected before administration, and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration; another 3 mice were taken and administered intravenously (3 mg/kg) before administration, and Blood was collected at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and plasma was collected and stored at -80°C.
  • Pharmacokinetic test in rats using male SD rats, 250-280 g, fasted overnight. Three rats were taken and administered by oral gavage (10 mg/kg). Blood was collected before administration, and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration; another 3 rats were taken and administered intravenously (3 mg/kg) before administration, and Blood was collected at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and plasma was collected and stored at -80°C.
  • mice pharmacokinetic test show that the compounds of the present disclosure exhibit excellent pharmacokinetic properties. Compared with the control compounds, the compounds of the present disclosure have greater exposure and good druggability.
  • the results of the rat pharmacokinetic test show that the compounds of the present disclosure exhibit excellent pharmacokinetic properties. Compared with the control compounds, the compounds of the present disclosure have greater exposure and good druggability.

Abstract

Provided is a compound for effectively inhibiting the activity of CD73, a preparation method therefor and a use thereof in the preparation of drugs, wherein the compound is a compound represented by formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof.

Description

哒嗪炔烃类化合物及其用途Pyridazine alkyne compounds and their uses
优先权信息priority information
本申请请求2020年11月5日向中国国家知识产权局提交的、专利申请号为202011224592.7的专利申请的优先权和权益，并且通过参照将其全文并入此处。This application claims the priority and rights of patent application No. 202011224592.7 filed with the State Intellectual Property Office of China on November 5, 2020, and is hereby incorporated by reference in its entirety.
技术领域technical field
本公开属于医药化学领域，具体的，本公开涉及哒嗪炔烃类化合物，更具体的，本公开涉及一种哒嗪炔烃类化合物及其制备方法，以及其在制备药物中的用途。The present disclosure belongs to the field of medicinal chemistry. Specifically, the present disclosure relates to pyridazine alkyne compounds, and more particularly, the present disclosure relates to a pyridazine alkyne compound, a preparation method thereof, and use thereof in the preparation of medicines.
背景技术Background technique
CD73又称为胞外5’-核苷酸水解酶，属于金属磷酸酯酶超家族的外切核酸酶，是一种外周糖蛋白，其主要形式是通过糖基磷脂酰肌醇(GPI)锚定在质膜上，分子量为70KD，由NT5E基因编码。CD73广泛表达于不同组织的细胞表面，包括脑、肺、心、脾、***、肾、结肠、血管内皮和骨髓；各种免疫细胞也有表达，包括巨噬细胞、中性粒细胞、髓系抑制细胞(MDSCs)、树突状细胞(DC)、自然杀伤细胞(NK)和调节性T细胞(Treg)(Soleimani A等人，Biochimie,2020,176:21-30.)；多种肿瘤细胞也有高表达的CD73，如：黑色素瘤、乳腺癌、胰腺癌、卵巢癌、结肠癌和***癌等(Gao Z等人，Biomed Res Int,2014,2014:460654.)。CD73也以可溶性形式(sCD73)存在于包括血清在内的生物体液中，并且保存了全酶活性。CD73, also known as extracellular 5'-nucleotide hydrolase, is an exonuclease belonging to the metallophosphatase superfamily and is a peripheral glycoprotein whose major form is anchored by glycosylphosphatidylinositol (GPI) It is fixed on the plasma membrane with a molecular weight of 70KD and is encoded by the NT5E gene. CD73 is widely expressed on the cell surface of different tissues, including brain, lung, heart, spleen, lymph node, kidney, colon, vascular endothelium, and bone marrow; it is also expressed on various immune cells, including macrophages, neutrophils, myeloid suppression cells (MDSCs), dendritic cells (DCs), natural killer cells (NKs), and regulatory T cells (Tregs) (Soleimani A et al., Biochimie, 2020, 176:21-30.); a variety of tumor cells also have Highly expressed CD73, such as: melanoma, breast cancer, pancreatic cancer, ovarian cancer, colon cancer and prostate cancer, etc. (Gao Z et al., Biomed Res Int, 2014, 2014:460654.). CD73 is also present in a soluble form (sCD73) in biological fluids, including serum, and preserves holoenzyme activity.
CD73主要通过水解AMP(单磷酸腺苷)产生胞外腺苷(ADO)来发挥生理、病理作用，ADO通过与4个G蛋白偶联受体(GPCRs)：A1腺苷受体(A1AR)、A2A腺苷受体(A2AR)、A2B腺苷受体(A2BR)和A3腺苷受体(A3AR)来发挥作用，其中起主要作用的是A2AR(Linden J等人，Annu.Rev.Immunol.,2019,37:325-347.)。腺苷受体(ARs)不仅在肿瘤细胞中表达，在肿瘤微环境中浸润的免疫细胞和血管内皮细胞的细胞表面也有表达，ADO通过与受体结合后，产生多种免疫抑制与促肿瘤作用。CD73 mainly exerts physiological and pathological effects by hydrolyzing AMP (adenosine monophosphate) to produce extracellular adenosine (ADO). ADO is associated with four G protein-coupled receptors (GPCRs): A1 adenosine A2A adenosine receptor (A2AR), A2B adenosine receptor (A2BR) and A3 adenosine receptor (A3AR) play a role, of which A2AR plays a major role (Linden J et al., Annu.Rev.Immunol., 2019, 37:325-347.). Adenosine receptors (ARs) are not only expressed in tumor cells, but also expressed on the cell surface of immune cells and vascular endothelial cells infiltrated in the tumor microenvironment. After binding to the receptors, ADO produces a variety of immunosuppressive and tumor-promoting effects. .
CD73与肿瘤的生长、血管生成和转移密切相关。在正常生理条件下，细胞外ADO水平在20至300nM之间，但在肿瘤微环境下，则升高维持至微摩尔水平(30-100μM)，而胞外高ADO浓度主要由CD73水解AMP产生所影响。研究表明癌症患者血浆中可溶性的CD73(sCD73)与健康人相比其水平增加(Klemens M R等人，Biochem.Biophys.Res.Commun.,1990,172:1371-7..)。在胃肠道间质瘤中，肿瘤浸润的NK细胞表达更高水平的CD73，而NK细胞中A2AR信号的缺失可以改善CD73 +肿瘤转移，增强抗肿瘤免疫反应(Young A等人,Cancer Cell.2016；30(3):391-403.)。与正常胰腺组织相比，CD73在胰腺导管癌(PDAC)中表达上调，并且与肿瘤大小、转移和不良预后相关(Harvey Jerry B等人,Front Immunol,2020,11:508.)。ORIC公司的临床前研究中，CD73选择性抑制剂ORIC-533显著降低了肿瘤微环境的ADO浓度，同时减小了肿瘤体积。这些研究结果都表明，CD73在多种肿瘤中表达上调，抑制CD73可能能降低ADO浓度，进而抑制肿瘤的生长、转移。 CD73 is closely related to tumor growth, angiogenesis and metastasis. Under normal physiological conditions, the extracellular ADO level is between 20 and 300 nM, but in the tumor microenvironment, the increase is maintained to the micromolar level (30-100 μM), and the high extracellular ADO concentration is mainly generated by CD73 hydrolysis of AMP affected. Studies have shown that soluble CD73 (sCD73) levels are increased in the plasma of cancer patients compared to healthy individuals (Klemens MR et al., Biochem. Biophys. Res. Commun., 1990, 172:1371-7..). In gastrointestinal stromal tumors, tumor-infiltrating NK cells express higher levels of CD73, and loss of A2AR signaling in NK cells can improve CD73 + tumor metastasis and enhance antitumor immune responses (Young A et al, Cancer Cell. 2016;30(3):391-403.). CD73 is upregulated in pancreatic ductal carcinoma (PDAC) compared to normal pancreatic tissue and is associated with tumor size, metastasis and poor prognosis (Harvey Jerry B et al, Front Immunol, 2020, 11:508.). In ORIC's preclinical studies, the CD73-selective inhibitor ORIC-533 significantly reduced the ADO concentration in the tumor microenvironment while reducing tumor volume. These findings all indicate that CD73 is up-regulated in a variety of tumors, and inhibiting CD73 may reduce the concentration of ADO, thereby inhibiting tumor growth and metastasis.
CD73抑制剂除了单独使用，能通过解除免疫抑制来阻断肿瘤生长，还能与其他靶向疗法和/或免疫疗法、放疗联用，来增加抗肿瘤效果。在几种小鼠的肿瘤模型中，抗CD73与抗PD-1/L1(程序性死亡受体1/配体1)和/或抗CTLA-4(细胞毒性T淋巴细胞相关蛋白4)抗体联合治疗比单独使用抗PD-L1和/或抗CTLA-4抗体治疗更有效(Allard B等人，Clin.Cancer Res.,2013,19:5626-35.)；接受抗PD-1抗体免疫治疗的黑色素瘤患者的CD73水平被发现上调，而在抗PD-1治疗后，胶质母细胞瘤患者中持续存在独特的CD73高表达巨噬细胞群，CD73缺陷增强抗PD-1和抗CTLA-4在小鼠胶质母细胞瘤模型中的疗效(Goswami S等人，Nat.Med.,2020,26:39-46.)；放疗导致部分肿瘤细胞破坏，使胞内的大量ATP释放至胞外，在肿瘤细胞表面或游离的CD73作用下，转变为腺苷，产生免疫抑制作用，这被认为是部分患者放疗后预后不良的原因之一，因此CD73抑制剂与放疗联用可能会产生协同作用(Wennerberg E等人， Cancer Immunol Res,2020,8:465-478.)。In addition to being used alone, CD73 inhibitors can block tumor growth by releasing immunosuppression, and can also be used in combination with other targeted therapies and/or immunotherapy and radiotherapy to increase the anti-tumor effect. Anti-CD73 in combination with anti-PD-1/L1 (programmed death receptor 1/ligand 1) and/or anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) antibodies in several mouse tumor models Treatment is more effective than anti-PD-L1 and/or anti-CTLA-4 antibody treatment alone (Allard B et al., Clin. Cancer Res., 2013, 19:5626-35.); patients receiving anti-PD-1 antibody immunotherapy CD73 levels were found to be upregulated in melanoma patients, whereas a distinct CD73-overexpressing macrophage population persisted in glioblastoma patients after anti-PD-1 therapy, and CD73 deficiency enhanced anti-PD-1 and anti-CTLA-4 Efficacy in a mouse glioblastoma model (Goswami S et al., Nat.Med., 2020, 26:39-46.); radiotherapy led to the destruction of some tumor cells, resulting in the release of a large amount of intracellular ATP to the extracellular , Under the action of tumor cell surface or free CD73, it is converted into adenosine, which produces an immunosuppressive effect, which is considered to be one of the reasons for the poor prognosis of some patients after radiotherapy. Therefore, the combination of CD73 inhibitor and radiotherapy may have a synergistic effect (Wennerberg E et al., Cancer Immunol Res, 2020, 8:465-478.).
目前一些抗CD73单抗(MEDI9447、BMS986179、SRF373/NZV930、CPI-006/CPX-006、TJ004309)和选择性小分子抑制剂(LY3475070、AB680)已进入临床阶段，部分临床试验取得了令人鼓舞的早期结果(NCT02754141)，CD73抑制可能是***的有希望的方法。At present, some anti-CD73 mAbs (MEDI9447, BMS986179, SRF373/NZV930, CPI-006/CPX-006, TJ004309) and selective small molecule inhibitors (LY3475070, AB680) have entered the clinical stage, and some clinical trials have achieved encouraging results of early results (NCT02754141), CD73 inhibition may be a promising approach for the treatment of tumors.
发明内容SUMMARY OF THE INVENTION
本公开旨在提出一种新的CD73抑制剂，可用于制备***相关疾病的药物。The present disclosure aims to propose a novel CD73 inhibitor, which can be used to prepare a drug for the treatment of tumor-related diseases.
本公开的第一方面，本公开提出了一种化合物，为式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：In the first aspect of the present disclosure, the present disclosure proposes a compound, which is a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
Figure PCTCN2021128905-appb-000001
Figure PCTCN2021128905-appb-000001
其中，in,
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
Figure PCTCN2021128905-appb-000002
中R 1独立地选自氢、卤素、羟基、氰基、氨基、未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-；所述的被R a取代的C 1-C 6烷基、或、所述的被R a取代的C 1-C 6烷基-O-中，所述的被R a取代可以是一个或多个取代，所述的R a各自独立地为下列取代基：卤素、羟基、氰基、氨基、C 1-C 6烷基、C 1-C 6烷基-O-、-COOH、-C(＝O)NH 2；当取代基为多个时，所述的取代基相同或不同；当m不为0或1时，R 1独立地为相同或不同；
Figure PCTCN2021128905-appb-000002
wherein R 1 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, unsubstituted or R a substituted C 1 -C 6 alkyl, or, unsubstituted or R a substituted C 1 -C 6 alkyl base-O-; said C 1 -C 6 alkyl substituted by R a , or, said C 1 -C 6 alkyl substituted by R a -O-, said substituted by R a Can be one or more substitutions, and the R a is each independently the following substituents: halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, - COOH, -C(=O)NH 2 ; when there are multiple substituents, the substituents are the same or different; when m is not 0 or 1, R 1 is independently the same or different;
n为0、1、2或3；n is 0, 1, 2 or 3;
R 2选自氢、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 3-C 6环烷基、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、或、未取代或被R b取代的4-8元杂环烯基；所述的被R b取代的C 1-C 6烷基、所述的被R b取代的C 3-C 6环烷基、所述的被R b取代的5-8元芳基、所述的被R b取代的5-8元杂芳基、所述的被R b取代的4-8元杂环烷基、或、所述的被R b取代的4-8元杂环烯基中，所述的被R b取代可以是一个或多个取代，所述的R b各自独立地为下列取代基：卤素、羟基、氰基、氨基、羧基、C 3-C 6环烷基、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、或、C 1-C 6烷基-O-；当取代基为多个时，所述的取代基相同或不同； R 2 is selected from hydrogen, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 3 -C 6 cycloalkyl, unsubstituted or R b substituted 5-8 Member aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, unsubstituted or R b substituted 4-8 membered heterocycloalkyl, or, unsubstituted or R b substituted 4-8 Membered heterocycloalkenyl; said C 1 -C 6 alkyl substituted by R b , said C 3 -C 6 cycloalkyl substituted by R b , said 5-8 substituted by R b Member aryl, said 5-8 membered heteroaryl substituted by R b , said 4-8 membered heterocycloalkyl substituted by R b , or, said 4-8 member substituted by R b In the membered heterocyclic alkenyl, the substitution by R b may be one or more substitutions, and the R b is each independently the following substituents: halogen, hydroxyl, cyano, amino, carboxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, or, C 1 -C 6 alkyl-O-; when the substituent is When multiple, the substituents are the same or different;
所述的未取代或被R b取代的5-8元杂芳基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烷基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烯基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个。 In the described unsubstituted or 5-8-membered heteroaryl group substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
在本公开一优选实施方案中，式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为：In a preferred embodiment of the present disclosure, the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
Figure PCTCN2021128905-appb-000003
Figure PCTCN2021128905-appb-000003
其中，in,
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
Figure PCTCN2021128905-appb-000004
中R 1独立地选自氢、卤素、羟基、氰基、氨基、未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-；所述的被R a取代的C 1-C 6烷基、或、所述的被R a取代的C 1-C 6烷基-O-中，所述的取代各自独立地是指下列取代基中的一个或多个取代：卤素、羟基、氰基、氨基、C 1-C 6烷基、C 1-C 6烷基-O-、-COOH、-C(＝O)NH 2；当取代基为多个时，所述的取代基相同或不同；当m不为0或1时，R 1独立地为相同或不同；
Figure PCTCN2021128905-appb-000004
wherein R 1 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, unsubstituted or R a substituted C 1 -C 6 alkyl, or, unsubstituted or R a substituted C 1 -C 6 alkyl base-O-; in the C 1 -C 6 alkyl substituted by R a , or in the C 1 -C 6 alkyl substituted by R a -O-, the substitutions are each independently Refers to one or more of the following substituents: halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkyl -O-, -COOH, -C(=O) NH 2 ; when there are multiple substituents, the substituents are the same or different; when m is not 0 or 1, R 1 is independently the same or different;
n为0、1、2或3；n is 0, 1, 2 or 3;
R 2选自氢、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 3-C 6环烷基、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、或、未取代或被R b取代的4-8元杂环烯基；所述的被R b取代的C 1-C 6烷基、所述的被R b取代的C 3-C 6环烷基、所述的被R b取代的5-8元芳基、所述的被R b取代的5-8元杂芳基、所述的被R b取代的4-8元杂环烷基、或、所述的被R b取代的4-8元杂环烯基中，所述的取代各自独立地是指下列取代基中的一个或多个取代：卤素、羟基、氰基、氨基、C 3-C 6环烷基、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、或、C 1-C 6烷基-O-；当取代基为多个时，所述的取代基相同或不同； R 2 is selected from hydrogen, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 3 -C 6 cycloalkyl, unsubstituted or R b substituted 5-8 Member aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, unsubstituted or R b substituted 4-8 membered heterocycloalkyl, or, unsubstituted or R b substituted 4-8 Membered heterocycloalkenyl; said C 1 -C 6 alkyl substituted by R b , said C 3 -C 6 cycloalkyl substituted by R b , said 5-8 substituted by R b Member aryl, said 5-8 membered heteroaryl substituted by R b , said 4-8 membered heterocycloalkyl substituted by R b , or, said 4-8 member substituted by R b In the membered heterocycloalkenyl, the substitutions each independently refer to one or more of the following substituents: halogen, hydroxyl, cyano, amino, C 3 -C 6 cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 alkyl substituted by 1-5 same or different halogens, or, C 1 -C 6 alkyl-O-; when there are multiple substituents, the substituents are the same or different;
所述的未取代或被R b取代的5-8元杂芳基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烷基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烯基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个。 In the described unsubstituted or 5-8-membered heteroaryl group substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
在本公开一优选实施方案中，当R 2为未取代或被R b取代的C 1-C 6烷基时，所述C 1-C 6烷基为C 1-C 4烷基，较佳地为甲基、乙基、正丙基、异丙基、正丁基或异丁基。 In a preferred embodiment of the present disclosure, when R 2 is an unsubstituted or R b substituted C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, preferably is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
在本公开一优选实施方案中，当R 2为未取代或被R b取代的C 1-C 6烷基时，所述取代基R b的个数为1-3个，较佳地为1个。 In a preferred embodiment of the present disclosure, when R 2 is an unsubstituted or R b substituted C 1 -C 6 alkyl group, the number of the substituent R b is 1-3, preferably 1 indivual.
在本公开一优选实施方案中，当R 2为未取代或被R b取代的C 3-C 6环烷基，所述C 3-C 6环烷基为环丙基、环丁基、环戊基或环己基，较佳地为环丙基或者环丁基。 In a preferred embodiment of the present disclosure, when R 2 is an unsubstituted or R b substituted C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclo Pentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.
在本公开一优选实施方案中，当R 2为未取代或被R b取代的5-8元芳基时，所述的5-8元芳基独立地为苯基或萘基，较佳地为苯基。 In a preferred embodiment of the present disclosure, when R 2 is an unsubstituted or substituted 5-8-membered aryl group, the 5-8-membered aryl group is independently phenyl or naphthyl, preferably is phenyl.
在本公开一优选实施方案中，当R 2为未取代或被R b取代的5-8元杂芳基时，所述的5-8元杂芳基独立地为吡咯、吡唑、三氮唑、呋喃、噁唑、噻吩、噻唑、吡啶、吡嗪或嘧啶，较佳地为吡唑、呋喃、噻吩、吡啶。 In a preferred embodiment of the present disclosure, when R 2 is an unsubstituted or substituted 5-8-membered heteroaryl group, the 5-8-membered heteroaryl group is independently pyrrole, pyrazole, triazine azole, furan, oxazole, thiophene, thiazole, pyridine, pyrazine or pyrimidine, preferably pyrazole, furan, thiophene and pyridine.
在本公开一优选实施方案中，当R 2为未取代或被R b取代的4-8元杂环烷基时，所述的4-8元杂环烷基独立地为氮杂环丁烷、氧杂环丁烷、四氢吡咯烷基、四氢呋喃基、六氢吡喃或四氢-2H-硫吡喃1,1-二氧化物，较佳地为氮杂环丁烷或氧杂环丁烷。 In a preferred embodiment of the present disclosure, when R 2 is an unsubstituted or substituted 4-8-membered heterocycloalkyl group, the 4-8-membered heterocycloalkyl group is independently azetidine , oxetane, tetrahydropyrrolidinyl, tetrahydrofuranyl, hexahydropyran or tetrahydro-2H-thiopyran 1,1-dioxide, preferably azetidine or oxane Butane.
在本公开一优选实施方案中，当R 2为未取代或被R b取代的4-8元杂环烯 基时，所述的4-8元杂环烯基独立地为二氢吡啶基、四氢吡啶基、四氢嘧啶基、吡咯啉基、咪唑啉基、吡唑啉基、二氢咪唑基、二氢吡唑基、二氢噁唑基、二氢噁二唑基、二氢噻唑基、二氢异噻唑基、二氢噻吩基、二氢吡咯基、3,4-二氢-2H-吡喃基、二氢呋喃基、二氢吡嗪基、二氢嘧啶基或氟代二氢呋喃基，较佳地为1,2,3,4-四氢吡啶基、1,2-二氢吡啶基、1,4-二氢吡啶基、1,2,3,6-四氢吡啶基、3,4-二氢-2H-吡喃基或二氢呋喃基。 In a preferred embodiment of the present disclosure, when R 2 is a 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b , the 4-8-membered heterocycloalkenyl is independently a dihydropyridyl, Tetrahydropyridyl, tetrahydropyrimidinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, dihydroimidazolyl, dihydropyrazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazole base, dihydroisothiazolyl, dihydrothienyl, dihydropyrrolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, dihydropyrazinyl, dihydropyrimidinyl, or fluorobis Hydrofuranyl, preferably 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine group, 3,4-dihydro-2H-pyranyl or dihydrofuranyl.
在本公开一优选实施方案中，R b为羟基。 In a preferred embodiment of the present disclosure, R b is hydroxyl.
在本公开一优选实施方案中，当R b为C 1-C 6烷基时，所述C 1-C 6烷基为C 1-C 4烷基，较佳地为甲基、乙基、正丙基或异丙基。 In a preferred embodiment of the present disclosure, when R b is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, preferably methyl, ethyl, n-propyl or isopropyl.
在本公开一优选实施方案中，当R b为卤素时，所述卤素为F、Cl、Br、I，较佳地为F或者Cl。 In a preferred embodiment of the present disclosure, when R b is halogen, the halogen is F, Cl, Br, I, preferably F or Cl.
在本公开一优选实施方案中，
Figure PCTCN2021128905-appb-000005
为
Figure PCTCN2021128905-appb-000006
或者
Figure PCTCN2021128905-appb-000007
较佳地为
Figure PCTCN2021128905-appb-000008
In a preferred embodiment of the present disclosure,
Figure PCTCN2021128905-appb-000005
for
Figure PCTCN2021128905-appb-000006
or
Figure PCTCN2021128905-appb-000007
preferably
Figure PCTCN2021128905-appb-000008
在本公开一优选实施方案中，当R 1为卤素时，所述卤素为F、Cl、Br或I，较佳地为F或Cl。 In a preferred embodiment of the present disclosure, when R 1 is halogen, the halogen is F, Cl, Br or I, preferably F or Cl.
在本公开一优选实施方案中，当R 1为卤素时，m为0、1或2。 In a preferred embodiment of the present disclosure, when R 1 is halogen, m is 0, 1 or 2.
在本公开一优选实施方案中，当R 1为未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-时，所述的C 1-C 6烷基独立地为C 1-C 4烷基，较佳地为甲基、乙基、正丙基、异丙基、正丁基或异丁基。 In a preferred embodiment of the present disclosure, when R 1 is unsubstituted or R a substituted C 1 -C 6 alkyl, or, unsubstituted or R a substituted C 1 -C 6 alkyl-O- , the C 1 -C 6 alkyl group is independently a C 1 -C 4 alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
在本公开一优选实施方案中，当R 1为未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-时，m为1或2，较佳地m为1。 In a preferred embodiment of the present disclosure, when R 1 is unsubstituted or R a substituted C 1 -C 6 alkyl, or, unsubstituted or R a substituted C 1 -C 6 alkyl-O- , m is 1 or 2, preferably m is 1.
在本公开一优选实施方案中，当R 1为被R a取代的C 1-C 6烷基、或、被R a取代的C 1-C 6烷基-O-时，所述的取代的个数独立地为1-3个，较佳地为2个。 In a preferred embodiment of the present disclosure, when R 1 is C 1 -C 6 alkyl substituted by Ra , or C 1 -C 6 alkyl-O- substituted by Ra , the substituted The number is independently 1-3, preferably 2.
在本公开一优选实施方案中，当R 1为被R a取代的C 1-C 6烷基、或、被R a取代的C 1-C 6烷基-O-时，所述的取代各自独立地为C 1-C 6烷基、或C 1-C 6烷基-O-时，所述的取代中所述的C 1-C 6烷基独立地为C 1-C 4烷基，较佳地为甲基、乙基、正丙基、异丙基、正丁基或异丁基。 In a preferred embodiment of the present disclosure, when R 1 is C 1 -C 6 alkyl substituted by Ra , or C 1 -C 6 alkyl-O- substituted by Ra , the substitutions are each When independently C 1 -C 6 alkyl, or C 1 -C 6 alkyl-O-, the C 1 -C 6 alkyl described in the substitution is independently C 1 -C 4 alkyl, Preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
在本公开一优选实施方案中，当R a为卤素时，所述卤素为F、Cl、Br或I，较佳地为F或Cl。 In a preferred embodiment of the present disclosure, when Ra is halogen, the halogen is F, Cl, Br or I, preferably F or Cl.
在本公开一优选实施方案中，当
Figure PCTCN2021128905-appb-000009
为
Figure PCTCN2021128905-appb-000010
时，所述
Figure PCTCN2021128905-appb-000011
为
Figure PCTCN2021128905-appb-000012
Figure PCTCN2021128905-appb-000013
In a preferred embodiment of the present disclosure, when
Figure PCTCN2021128905-appb-000009
for
Figure PCTCN2021128905-appb-000010
when, the
Figure PCTCN2021128905-appb-000011
for
Figure PCTCN2021128905-appb-000012
Figure PCTCN2021128905-appb-000013
在本公开一优选实施方案中，当
Figure PCTCN2021128905-appb-000014
为
Figure PCTCN2021128905-appb-000015
时，所述
Figure PCTCN2021128905-appb-000016
为
Figure PCTCN2021128905-appb-000017
In a preferred embodiment of the present disclosure, when
Figure PCTCN2021128905-appb-000014
for
Figure PCTCN2021128905-appb-000015
when, the
Figure PCTCN2021128905-appb-000016
for
Figure PCTCN2021128905-appb-000017
在本公开一优选实施方案中，当
Figure PCTCN2021128905-appb-000018
为
Figure PCTCN2021128905-appb-000019
时，所述
Figure PCTCN2021128905-appb-000020
为
Figure PCTCN2021128905-appb-000021
Figure PCTCN2021128905-appb-000022
In a preferred embodiment of the present disclosure, when
Figure PCTCN2021128905-appb-000018
for
Figure PCTCN2021128905-appb-000019
when, the
Figure PCTCN2021128905-appb-000020
for
Figure PCTCN2021128905-appb-000021
Figure PCTCN2021128905-appb-000022
在本公开一优选实施方案中，当
Figure PCTCN2021128905-appb-000023
为
Figure PCTCN2021128905-appb-000024
时，所述
Figure PCTCN2021128905-appb-000025
为
Figure PCTCN2021128905-appb-000026
In a preferred embodiment of the present disclosure, when
Figure PCTCN2021128905-appb-000023
for
Figure PCTCN2021128905-appb-000024
when, the
Figure PCTCN2021128905-appb-000025
for
Figure PCTCN2021128905-appb-000026
在本公开一优选实施方案中，
Figure PCTCN2021128905-appb-000027
为
Figure PCTCN2021128905-appb-000028
或者
Figure PCTCN2021128905-appb-000029
In a preferred embodiment of the present disclosure,
Figure PCTCN2021128905-appb-000027
for
Figure PCTCN2021128905-appb-000028
or
Figure PCTCN2021128905-appb-000029
在本公开一优选实施方案中，R 2为
Figure PCTCN2021128905-appb-000030
或者
Figure PCTCN2021128905-appb-000031
In a preferred embodiment of the present disclosure, R 2 is
Figure PCTCN2021128905-appb-000030
or
Figure PCTCN2021128905-appb-000031
在本公开一优选实施方案中，
Figure PCTCN2021128905-appb-000032
为
Figure PCTCN2021128905-appb-000033
In a preferred embodiment of the present disclosure,
Figure PCTCN2021128905-appb-000032
for
Figure PCTCN2021128905-appb-000033
在本公开一优选实施方案中，如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药为：In a preferred embodiment of the present disclosure, the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
Figure PCTCN2021128905-appb-000034
Figure PCTCN2021128905-appb-000034
其中，in,
R 1独立地选自氢、卤素、羟基、氰基、氨基、未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-；所述的被R a取代的C 1-C 6烷基、或、所述的被R a取代的C 1-C 6烷基-O-中，所述的取代各自独立地是指下列取代基中的一个或多个取代：卤素、羟基、氰基、氨基、C 1-C 6烷基、C 1-C 6烷基-O-、-COOH、-C(＝O)NH 2；当取代基为多个时，所述的取代基相同或不同； R 1 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or R a substituted C 1 -C 6 alkyl, or, unsubstituted or R a substituted C 1 -C 6 alkyl -O-; in the C 1 -C 6 alkyl substituted by R a , or the C 1 -C 6 alkyl substituted by R a -O-, the substitutions are each independently Refers to one or more of the following substituents: halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkyl -O-, -COOH, -C(=O)NH 2 ; When the substituents are multiple, the substituents are the same or different;
R 2选自氢、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 3-C 6环烷基、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、或、未取代或被R b取代的4-8元杂环烯基；所述的被R b取代的C 1-C 6烷基、所述的被R b取代的C 3-C 6环烷基、所述的被R b取代的5-8元芳基、所述的被R b取代的5-8元杂芳基、所述的被R b取代的4-8元杂环烷基、或、所述的被R b取代的4-8元杂环烯基中，所述的取代各自独立地是指下列取代基中的一个或多个取代：卤素、羟基、氰基、氨基、C 3-C 6环烷基、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、或、C 1-C 6烷基-O-；当取代基为多个时，所述的取代基相同或不同； R 2 is selected from hydrogen, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 3 -C 6 cycloalkyl, unsubstituted or R b substituted 5-8 Member aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, unsubstituted or R b substituted 4-8 membered heterocycloalkyl, or, unsubstituted or R b substituted 4-8 Membered heterocycloalkenyl; said C 1 -C 6 alkyl substituted by R b , said C 3 -C 6 cycloalkyl substituted by R b , said 5-8 substituted by R b Member aryl, said 5-8 membered heteroaryl substituted by R b , said 4-8 membered heterocycloalkyl substituted by R b , or, said 4-8 member substituted by R b In the membered heterocycloalkenyl, the substitutions each independently refer to one or more of the following substituents: halogen, hydroxyl, cyano, amino, C 3 -C 6 cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 alkyl substituted by 1-5 same or different halogens, or, C 1 -C 6 alkyl-O-; when there are multiple substituents, the substituents are the same or different;
所述的未取代或被R b取代的5-8元杂芳基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烷基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烯基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个。 In the described unsubstituted or 5-8-membered heteroaryl group substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
在本公开的一优选实施方案中，所述的如式I所示的化合物、其水合物、溶剂化物、药学 上可接受的盐或前药为
Figure PCTCN2021128905-appb-000035
其中，R 1和R 2具有如前面所述的定义。 In a preferred embodiment of the present disclosure, the compound represented by formula I, its hydrate, solvate, pharmaceutically acceptable salt or prodrug is
Figure PCTCN2021128905-appb-000035
wherein R 1 and R 2 have the definitions as previously described.
在本公开一优选实施方案中，R 1选自二氟甲基、三氟甲基、二氯甲基、三氯甲基或异丙基；R 2选自甲基、乙基或环丙基。 In a preferred embodiment of the present disclosure, R 1 is selected from difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl or isopropyl; R 2 is selected from methyl, ethyl or cyclopropyl .
在本公开一优选实施方案中，如式I所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药选自下列任一化合物：In a preferred embodiment of the present disclosure, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from any of the following compounds :
Figure PCTCN2021128905-appb-000036
Figure PCTCN2021128905-appb-000036
本公开的第二方面，本公开提出了一种药物组合物，所述药物组合物包括治疗有效剂量的上述化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药以及药学上可接受的赋形剂。In a second aspect of the present disclosure, the present disclosure proposes a pharmaceutical composition comprising a therapeutically effective dose of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically Acceptable salts or prodrugs and pharmaceutically acceptable excipients.
根据本公开的具体实施例，可以将本公开的所述药物组合物包括治疗有效剂量的上述化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药以及药学上可接受的药用载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。According to specific embodiments of the present disclosure, the pharmaceutical compositions of the present disclosure may include therapeutically effective doses of the above-mentioned compounds, tautomers, stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts thereof Or prodrugs and pharmaceutically acceptable pharmaceutical carriers, diluents or excipients are mixed to prepare pharmaceutical preparations suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, such as by infusion or bolus injection, by route of absorption through the epithelium or mucocutaneous (eg, oral mucosa or rectum, etc.). Administration can be systemic or local. Examples of formulations for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations can be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulations.
本公开的第三方面，本公开提出了上述化合物、或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药与PD-1抗体、PD-L1抗体、CTLA-4抗体或者PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂联用在制备用于治疗与CD73相关疾病药物中的用途，所述药物可用于治疗癌症。这些癌症包括例如膀胱癌、乳腺癌、胆管癌、直肠癌、结肠癌、胃癌、胆囊癌、神经胶母细胞瘤、头颈癌、肝癌、肺癌、淋巴瘤、神经管母细胞瘤、黑色素瘤、卵巢癌、胰腺癌、***癌或者肾癌。In a third aspect of the present disclosure, the present disclosure proposes that the above-mentioned compounds, or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, interact with PD-1 antibody, PD- Use of L1 antibody, CTLA-4 antibody, or a combination of PD-1 inhibitor, PD-L1 inhibitor, and CTLA-4 inhibitor in the preparation of a medicament for treating CD73-related diseases, and the medicament can be used for treating cancer. These cancers include, for example, bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, stomach cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, ovary cancer, pancreatic cancer, prostate cancer, or kidney cancer.
本公开的第四方面，本公开提出了上述化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备用于治疗与CD73相关疾病药物中的用途。In a fourth aspect of the present disclosure, the present disclosure proposes that the above-mentioned compounds, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, or the above-mentioned pharmaceutical compositions are prepared for use in Use in medicines for treating diseases related to CD73.
根据本公开的具体实施例，上述化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备治疗与CD73相关疾病药物中的用途，所述药物可用于治疗癌症。这些癌症包括例如膀胱癌、乳腺癌、胆管癌、结直肠癌、结肠癌、胃癌、胆囊癌、神经胶母细胞瘤、头颈癌、肝癌、肺癌、淋巴瘤、神经管母细胞瘤、黑色素瘤、卵巢癌、胰腺癌、***癌或者肾癌。According to specific embodiments of the present disclosure, the above-mentioned compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above-mentioned pharmaceutical compositions are prepared for the treatment of CD73-related diseases Use in a medicament useful in the treatment of cancer. These cancers include, for example, bladder cancer, breast cancer, bile duct cancer, colorectal cancer, colon cancer, stomach cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, Ovarian, pancreatic, prostate or kidney cancer.
本公开的第五方面，本公开提出了一种治疗与CD73相关疾病的方法，所述方法包括：向受试者施用上述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药、或药物组合物。In a fifth aspect of the present disclosure, the present disclosure provides a method for treating a disease related to CD73, the method comprising: administering to a subject the above-mentioned compound, its tautomer, stereoisomer, hydrate, Solvates, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions.
本公开的第六方面，本公开提出了一种治疗与CD73相关疾病的方法，所述方法包括：向受试者联合施用前面所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药、所述药物组合物与PD-1抗体、PD-L1抗体、CTLA-4抗体或者PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂。In a sixth aspect of the present disclosure, the present disclosure provides a method for treating a disease associated with CD73, the method comprising: administering to a subject in combination the aforementioned compound, its tautomer, stereoisomer, Hydrate, solvate, pharmaceutically acceptable salt or prodrug, the pharmaceutical composition with PD-1 antibody, PD-L1 antibody, CTLA-4 antibody or PD-1 inhibitor, PD-L1 inhibitor, CTLA -4 inhibitor.
在本公开一优选实施方案中，所述CD73相关疾病为癌症。In a preferred embodiment of the present disclosure, the CD73-related disease is cancer.
在本公开一优选实施方案中，所述癌症为膀胱癌、乳腺癌、胆管癌、直肠癌、结肠癌、胃癌、胆囊癌、神经胶母细胞瘤、头颈癌、肝癌、肺癌、淋巴瘤、神经管母细胞瘤、黑色素瘤、卵巢癌、胰腺癌、***癌或者肾癌。In a preferred embodiment of the present disclosure, the cancer is bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, stomach cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, neurological Angioblastoma, melanoma, ovarian, pancreatic, prostate or kidney cancer.
术语和定义Terms and Definitions
除非另有说明，用于本公开申请，包括本申请说明书和权利要求书中记载的术语和定义如下。Unless otherwise indicated, terms and definitions used in the present disclosure, including the specification and claims of this application, are as follows.
本领域技术人员可以理解，根据本领域中使用的惯例，在本申请的结构式中，
Figure PCTCN2021128905-appb-000037
用于描绘化学键，所述化学键为部分或取代基与核心结构或骨架结构相连的点。 Those skilled in the art can understand that, according to the convention used in the art, in the structural formula of the present application,
Figure PCTCN2021128905-appb-000037
Used to delineate a chemical bond, which is the point at which a moiety or substituent is attached to a core or backbone structure.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
除了药学可接受的盐外，本公开还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本公开化合物的鉴别、表征或纯化。In addition to pharmaceutically acceptable salts, other salts are contemplated by the present disclosure. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used in the identification, characterization or purification of the compounds of the present disclosure.
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。The term "pharmaceutical composition" means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, 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 flowability and/or stickiness.
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本公开化合物。本公开的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本公开化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本公开化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。The term "prodrug" refers to a compound of the present disclosure that can be converted under physiological conditions or by solvolysis to a biologically active compound. The prodrugs of the present disclosure are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds. Prodrugs include compounds formed by connecting a hydroxyl group or amino group in the compounds of the present disclosure to any group. When the prodrugs of the compounds of the present disclosure are administered to mammalian individuals, the prodrugs are cleaved to form a free hydroxyl group, a free hydroxyl group, and a free group, respectively. the amino group.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。The term "stereoisomer" refers to isomers resulting from different arrangements of atoms in a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers and conformers.
依据原料和方法的选择，本公开化合物可以以可能的异构体中的一个或它们的混合物的 形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。就给定的化学结构而言，除了这些立体异构体互为镜像外，这些立体异构体是相同的。具体的立体异构体也可称为对映异构体，并且所述异构体的混合物通常称作对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或方法中没有立体选择性或立体特异性时，可出现所述外消旋混合物或外消旋体。烯烃、C＝N双键等的许多几何异构体也可以存在于本文所述的化合物中，且所有这种稳定的异构体在本公开中均被考虑。当本文所描述化合物含有烯双键时，除非另外说明，否则，这种双键包括E和Z几何异构体。如果化合物中含有二取代的环烷基，环烷基的取代基可能为顺式或反式(cis-或trans-)构型。Depending on the choice of starting materials and methods, the compounds of the present disclosure may exist as one of the possible isomers or as a mixture thereof, eg, as pure optical isomers, or as mixtures of isomers, eg, as racemic and non-isomeric isomers. A mixture of enantiomers, depending on the number of asymmetric carbon atoms. When describing an optically active compound, 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 the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method Spin body. Many geometric isomers of olefins, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are contemplated in this disclosure. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl group may be in the cis- or trans- (cis- or trans-) configuration.
当将本公开式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。When the bond to the chiral carbon in the formula of the present disclosure is depicted in-line, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and Mixtures of both are included within the scope of this formula. A schematic representation of racemate or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise stated, wedge and dashed bonds are used to indicate the absolute configuration of a stereocenter.
旋光性的(R)-或(S)-异构体可使用手性合成子或手性制剂制备，或使用常规技术拆分。含有不对称取代的碳原子的本公开化合物能够以旋光活性形式或外消旋形式分离。化合物的外消旋混合物的拆分可以通过本领域已知的许多方法中的任一种来进行。示例性方法包括使用手性拆分酸的分级重结晶，该手性拆分酸是旋光活性的成盐有机酸。用于分级重结晶方法的适合的拆分剂例如是旋光活性酸，例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或各种旋光活性樟脑磺酸如β-樟脑磺酸的D和L形式。适合于分级结晶方法的其它的拆分剂包括立体异构纯形式的α-甲基-苄胺(例如，S和R形式或者非对映异构纯形式)、2-苯基甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1，2-二氨基环己烷等。外消旋混合物的拆分还可以通过在填充有旋光活性拆分剂(例如，二硝基苯甲酰基苯基甘氨酸)的色谱柱上洗脱来进行。可以采用高效液相色谱(HPLC)法也可以采用超临界流体色谱法(SFC)进行。具体方法的选择以及洗脱条件、色谱柱的选择可以由本领域技术人员根据化合物的结构以及试验结果选择。进一步的，还可以使用已知构型的光学纯的起始原料或试剂，通过立体有机合成，获得本公开所描述化合物的任何对映体或非对映体。Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as β- D and L forms of camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine in stereoisomerically pure form (eg, S and R forms or diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be performed by elution on a chromatographic column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Selection of specific methods, elution conditions, and selection of chromatographic columns can be selected by those skilled in the art according to the structures of compounds and test results. Further, any enantiomer or diastereomer of the compounds described in this disclosure can also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本公开化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本公开包含化合物的所有互变异构形式。The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. Compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form predominates; in phenols, the enol form predominates. The present disclosure includes all tautomeric forms of compounds.
本公开的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)，氚( 3H)，碘-125( 125I)或C-14( 14C)。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。 The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioisotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本公开中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect. For oral dosage forms in the present disclosure, an "effective amount" of one active in a composition refers to the amount required to achieve the desired effect when used in combination with another active in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating the target disorder, disease or condition.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢 的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable . When the substituent is a keto group (ie =0), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
术语“C 1-C 6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C 1-C 3烷基”)，例如甲基、乙基、正丙基或异丙基。 The term "C 1 -C 6 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 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, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, the groups have 1, 2 or 3 carbon atoms (" C1 -C3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl.
术语“C 1-C 6烷基-O-”应理解为烷基基团通过氧原子与分子其余部分相连，其中“C 1-C 6烷基”具有上述定义。如甲基-O-、乙基-O-。 The term "C 1 -C 6 alkyl-O-" is to be understood as an alkyl group attached to the rest of the molecule through an oxygen atom, wherein "C 1 -C 6 alkyl" has the above definition. Such as methyl-O-, ethyl-O-.
术语“C 3-C 6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个碳原子，包括稠合或桥接的多环***。如环丙基、环丁基、环戊基、环己基。 The term "C3 - C6cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
术语“4-8元杂环基”或“4-8元杂环烷基”应理解为表示具有4至8个原子的饱和、不饱和或部分饱和的单环、二环或三环，其中1、2、3、4或5个环原子选自N、O和S，除非另有说明，其可通过碳或氮连接，其中-CH 2-基团任选被-C(O)-代替；及其中除非另有相反说明，环氮原子或环硫原子任选被氧化以形成N-氧化物或S-氧化物或环氮原子任选被季铵化；其中环中的-NH任选被乙酰基、甲酰基、甲基或甲磺酰基取代；及环任选被一个或多个卤素取代。应该理解的是，当杂环基中S原子和O原子的总数超过1时，这些杂原子不彼此相邻。若所述杂环基为二环或三环，则至少一个环可任选为杂芳族环或芳族环，条件是至少一个环是非杂芳族的。若所述杂环基为单环，则其一定不是芳族的。杂环基的实例包括但不限于哌啶基、N-乙酰基哌啶基、N-甲基哌啶基、N-甲酰基哌嗪基、N-甲磺酰基哌嗪基、高哌嗪基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、四氢异喹啉基、四氢喹啉基、二氢吲哚基、四氢吡喃基、二氢-2H-吡喃基、四氢呋喃基、四氢噻喃基、四氢噻喃-1-氧化物、四氢噻喃-1,1-二氧化物、1H-吡啶-2-酮和2,5-二氧代咪唑烷基。 The term "4-8 membered heterocyclyl" or "4-8 membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S, which may be attached through carbon or nitrogen unless otherwise specified, wherein the -CH2- group is optionally replaced by -C(O)- and wherein, unless otherwise stated to the contrary, a ring nitrogen atom or a ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or a ring nitrogen atom is optionally quaternized; wherein -NH in the ring is optionally substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogens. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclyl group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl group is monocyclic, it must not be aromatic. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methanesulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indoline, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 -Dioximidazolidinyl.
术语“4-8元杂环烯基”应理解为含有4至8个环原子，优选5至6个环原子的非芳族单环或多环基团，其中，所述4-8元杂环烯基包含选自N、O、S和P中的1至3个杂原子并且含有至少一个碳-碳双键或碳-氮双键。在基团名称中包含的氮杂、氧杂或硫杂是指至少一个氮、氧或硫原子分别地作为环原子。4-8元杂环烯基的氮或硫原子可以任选被氧化成相应的N-氧化物、S-氧化物或S-二氧化物。优选的4-8元杂环烯基包含但不限于1,2,3,4-四氢吡啶基、1,2-二氢吡啶基、1,4-二氢吡啶基、1,2,3,6-四氢吡啶基、1,4,5,6-四氢嘧啶基、2-吡咯啉基、3-吡咯啉基、2-咪唑啉基、2-吡唑啉基、二氢咪唑基、二氢噁唑基、二氢噁二唑基、二氢噻唑基、3,4-二氢-2H-吡喃基、二氢呋喃基、氟代二氢呋喃基基及其氧化物等。“4-8元杂环烯基”还可包括环上相同碳原子上的两个可用氢原子同时被单一的基团＝O取代(即形成羰基)。The term "4-8 membered heterocycloalkenyl" is to be understood as a non-aromatic monocyclic or polycyclic group containing 4 to 8 ring atoms, preferably 5 to 6 ring atoms, wherein the 4-8 membered heterocyclic group Cycloalkenyl contains 1 to 3 heteroatoms selected from N, O, S and P and contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Aza, oxa or thia included in the group name means at least one nitrogen, oxygen or sulfur atom, respectively, as a ring atom. The nitrogen or sulfur atom of the 4-8 membered heterocycloalkenyl can optionally be oxidized to the corresponding N-oxide, S-oxide or S-dioxide. Preferred 4-8 membered heterocycloalkenyl groups include, but are not limited to, 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3 ,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl , dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl and their oxides. "4-8 membered heterocycloalkenyl" may also include the simultaneous substitution of two available hydrogen atoms on the same carbon atom in the ring with a single group =O (ie, forming a carbonyl group).
术语“5-8元芳基”应理解为具有5-8个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；当所述5-8元芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。 The term "5-8 membered aryl" is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 5-8 carbon atoms, especially a ring having 6 carbon atoms (" C 6 aryl"), such as phenyl; when the 5-8 membered aryl is substituted, it may be mono- or poly-substituted. Also, the substitution site is not limited, for example, it may be ortho-, para- or meta-substitution.
术语“5-8元杂芳基”应理解为具有5-8个环原子，特别是5或6个碳原子，且包含1-5个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团。优选1-3个且独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑 基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。The term "5-8 membered heteroaryl" is to be understood as a monovalent radical having 5-8 ring atoms, especially 5 or 6 carbon atoms, and comprising 1-5 heteroatoms independently selected from N, O and S Monocyclic, bicyclic or tricyclic aromatic ring groups. Monovalent monocyclic, bicyclic or tricyclic aromatic ring groups of 1 to 3 heteroatoms independently selected from N, O and S are preferred and, in addition, may be benzofused in each case. In particular, heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl oxadiazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; group, carbazolyl group, acridine group, phenazinyl group, phenothiazinyl group, phenoxazinyl group and the like.
术语“卤代基”或“卤素”为氟、氯、溴和碘。The term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.
另外，需要说明的是，除非以其他方式明确指出，在本公开中所采用的描述方式“……独立地”应作广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“……独立地”既可以是指在不同基团中，相同符合之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless clearly stated otherwise, the description method "...independently" used in the present disclosure should be understood in a broad sense, meaning that the described individuals are independent of each other and may be independent of each other. are the same or different specific groups. In more detail, the description mode "...independently" can either mean that in different groups, the specific options expressed in the same match do not affect each other, or it can mean that in the same group, the same symbols are used together. The specific options expressed between them do not affect each other.
有益效果beneficial effect
根据本公开的实施例，本公开提供了结构新颖、药代动力学性质优良、药效或成药性好的CD73抑制剂，可以用于有效治疗CD73相关的疾病、病症。According to the embodiments of the present disclosure, the present disclosure provides CD73 inhibitors with novel structures, excellent pharmacokinetic properties, and good efficacy or druggability, which can be used to effectively treat CD73-related diseases and disorders.
本公开的化合物对CD73酶具有良好的抑制作用，体外药效良好。另外小鼠实验结果表明，本公开化合物表现出优良的药代动力学性质，成药性好。The compound of the present disclosure has a good inhibitory effect on CD73 enzyme, and has a good in vitro drug effect. In addition, the experimental results in mice show that the compounds of the present disclosure exhibit excellent pharmacokinetic properties and good druggability.
此外，本公开化合物单用或与PD-1/L1抗体联用都具有显著的抑制CT-26结直肠癌和E.G7-OVA T细胞淋巴瘤生长的作用。In addition, the compounds of the present disclosure can significantly inhibit the growth of CT-26 colorectal cancer and E.G7-OVA T-cell lymphoma when used alone or in combination with PD-1/L1 antibody.
本公开的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本公开的实践了解到。Additional aspects and advantages of the present disclosure will be set forth, in part, from the following description, and in part will become apparent from the following description, or may be learned by practice of the present disclosure.
具体实施方式Detailed ways
下面将结合实施例对本公开的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本公开，而不应视为限定本公开的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The solutions of the present disclosure will be explained below with reference to the embodiments. Those skilled in the art will understand that the following examples are only used to illustrate the present disclosure and should not be construed as limiting the scope of the present disclosure. If no specific technique or condition is indicated in the examples, the technique or condition described in the literature in the field or the product specification is used. The reagents or instruments used without the manufacturer's indication are conventional products that can be obtained from the market.
如无特别说明，本公开的化合物均是通过核磁共振(NMR)和/或质谱(MS)来确定其结构的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)。 Unless otherwise specified, the structures of the compounds of the present disclosure were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The units of NMR shifts are 10-6 (ppm). The solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
本公开的缩写定义如下：Abbreviations of this disclosure are defined as follows:
M：摩尔浓度，如1M盐酸表示1mol/L盐酸溶液M: molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
DCM：二氯甲烷DCM: dichloromethane
DMP：戴斯-马丁氧化剂DMP: Dess-Martin Oxidant
DMF:N,N-二甲基甲酰胺DMF:N,N-Dimethylformamide
DAST：二乙氨基三氟化硫DAST: Diethylaminosulfur trifluoride
DMSO：二甲基亚砜DMSO: Dimethyl Sulfoxide
dioxane：1,4-二氧六环dioxane: 1,4-dioxane
TEA：三乙胺TEA: Triethylamine
THF：四氢呋喃THF: Tetrahydrofuran
TEMPO：2,2,6,6-四甲基哌啶氧化物TEMPO: 2,2,6,6-Tetramethylpiperidine oxide
LC-MS：液质联用色谱LC-MS: Liquid chromatography-mass spectrometry
IC 50：半数抑制浓度，指达到最大抑制效果一半时的浓度。 IC 50 : the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
对照例1：阳性对照化合物1的制备Control Example 1: Preparation of Positive Control Compound 1
5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(对照化合物1)5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione ( Control compound 1)
Figure PCTCN2021128905-appb-000038
Figure PCTCN2021128905-appb-000038
参考专利WO2019168744Al方法制备。Refer to patent WO2019168744Al method for preparation.
1H NMR(400MHz,DMSO-d 6)δ11.51(s,2H)，8.27(s,1H),7.77(s,1H),6.17-5.85(m,1H),2.69(s,3H),2.32-2.29(m,1H),1.77-1.70(m,1H),1.32-1.18(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.51(s, 2H), 8.27(s, 1H), 7.77(s, 1H), 6.17-5.85(m, 1H), 2.69(s, 3H), 2.32-2.29(m,1H),1.77-1.70(m,1H),1.32-1.18(m,2H).
LC-MS,M/Z(ESI):295.0[M+H] +。 LC-MS, M/Z (ESI): 295.0 [M+H] + .
下文所述“对照化合物1”均指对照例1所述化合物。The "Comparative Compound 1" mentioned below refers to the compound described in Comparative Example 1.
对照例2：阳性对照化合物2的制备Control Example 2: Preparation of Positive Control Compound 2
5-(5-((1S,2R)-2-异丙基环丙基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(对照化合物2)5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (control compound 2 )
Figure PCTCN2021128905-appb-000039
Figure PCTCN2021128905-appb-000039
参考专利WO2019168744Al方法制备。Refer to patent WO2019168744Al method for preparation.
1H NMR(400MHz,CD 3OD)δ8.65(s,1H),8.22(s,1H),2.89(s,3H),2.07-2.10(m,1H),1.33-1.45(m,4H),1.10(d,6H). 1 H NMR (400MHz, CD 3 OD) δ 8.65(s, 1H), 8.22(s, 1H), 2.89(s, 3H), 2.07-2.10(m, 1H), 1.33-1.45(m, 4H) ,1.10(d,6H).
LC-MS,M/Z(ESI):287.0[M+H] +。 LC-MS, M/Z (ESI): 287.0 [M+H] + .
下文所述“对照化合物2”均指对照例2所述化合物。"Comparative compound 2" mentioned below refers to the compound described in Comparative Example 2.
制备1：中间体A的制备Preparation 1: Preparation of Intermediate A
3-氯-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(中间体A)3-Chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (Intermediate A)
Figure PCTCN2021128905-appb-000040
Figure PCTCN2021128905-appb-000040
中间体A的合成路线如下所示：The synthetic route of intermediate A is as follows:
Figure PCTCN2021128905-appb-000041
Figure PCTCN2021128905-appb-000041
第一步：(1S,2S)-2-((苄氧基)甲基)环丙烷-1-羧酸乙酯(A-3)的合成The first step: Synthesis of (1S,2S)-2-((benzyloxy)methyl)cyclopropane-1-carboxylic acid ethyl ester (A-3)
Figure PCTCN2021128905-appb-000042
Figure PCTCN2021128905-appb-000042
在氮气保护下把氢化钠(58.5g，1.46mol，含量60％)悬浮在甲苯(3000mL)中，然后在0℃下滴加磷酰基乙酸三乙酯(327.7g，1.46mol)，滴加完毕后在25℃下搅拌1小时，然后把(S)-(+)-缩水甘油苄基醚(200g，1.22mol)加入到反应液中，升温至130℃反应12小时。将反应混合物用水(5000mL)稀释，然后用乙酸乙酯(2000mL×2)萃取，合并有机层相，用饱和食盐水(2000mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-10:1，梯度洗脱)得红色油状物(1S,2S)-2-((苄氧基)甲基)环丙烷-1-羧酸乙酯(A-3)(180g，产率63％)。Under nitrogen protection, sodium hydride (58.5 g, 1.46 mol, content 60%) was suspended in toluene (3000 mL), and then triethyl phosphoryl acetate (327.7 g, 1.46 mol) was added dropwise at 0 °C, and the dropwise addition was completed. After stirring at 25°C for 1 hour, (S)-(+)-glycidyl benzyl ether (200 g, 1.22 mol) was added to the reaction solution, and the temperature was raised to 130°C for 12 hours. The reaction mixture was diluted with water (5000 mL), then extracted with ethyl acetate (2000 mL×2). The organic layers were combined, washed with saturated brine (2000 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-10:1, gradient elution) to obtain (1S,2S)-2-((benzyloxy)methyl as a red oil ) ethyl cyclopropane-1-carboxylate (A-3) (180 g, 63% yield).
1H NMR(400MHz,CDCl 3)δ7.18-7.25(m,5H),4.42(s,2H),4.00-4.04(m,2H),3.33-3.37(m,1H),3.24-3.28(m,1H),1.62-1.66(m,1H),1.46-1.49(m,1H),1.06-1.16(m,4H),0.75-0.78(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ 7.18-7.25(m, 5H), 4.42(s, 2H), 4.00-4.04(m, 2H), 3.33-3.37(m, 1H), 3.24-3.28(m ,1H),1.62-1.66(m,1H),1.46-1.49(m,1H),1.06-1.16(m,4H),0.75-0.78(m,1H).
第二步：(1S,2S)-2-(羟甲基)环丙烷-1-羧酸乙酯(A-4)的合成The second step: Synthesis of (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylic acid ethyl ester (A-4)
Figure PCTCN2021128905-appb-000043
Figure PCTCN2021128905-appb-000043
把(1S,2S)-2-((苄氧基)甲基)环丙烷-1-羧酸乙酯(A-3)(120g，512.2mmol)溶解在乙醇(1200mL)中，在氮气保护下，加入钯碳(30.0g，含量10％)，然后用氢气置换3次，然后在50Psi压力、50℃下反应24小时。冷却至室温，用硅藻土过滤除去钯碳，滤饼用乙醇洗涤3次，把 滤液浓缩得到黄色油状物(1S,2S)-2-(羟甲基)环丙烷-1-羧酸乙酯(A-4)(65.0g，产率85％)。(1S,2S)-ethyl 2-((benzyloxy)methyl)cyclopropane-1-carboxylate (A-3) (120 g, 512.2 mmol) was dissolved in ethanol (1200 mL) under nitrogen protection , added palladium carbon (30.0 g, content 10%), then replaced with hydrogen 3 times, and then reacted at 50 Psi pressure and 50 °C for 24 hours. Cooled to room temperature, filtered through celite to remove palladium carbon, the filter cake was washed three times with ethanol, and the filtrate was concentrated to obtain (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylic acid ethyl ester as a yellow oil (A-4) (65.0 g, 85% yield).
第三步：(1S,2S)-2-甲酰基环丙烷-1-羧酸乙酯(A-5)的合成The third step: Synthesis of (1S,2S)-2-formylcyclopropane-1-carboxylic acid ethyl ester (A-5)
Figure PCTCN2021128905-appb-000044
Figure PCTCN2021128905-appb-000044
把(1S,2S)-2-(羟甲基)环丙烷-1-羧酸乙酯(A-4)(100g，693.6mmol)溶于二氯甲烷(1500mL)中，在0℃下缓慢加入戴斯-马丁氧化剂(353.0g，832.4mmol)，然后在25℃反应12小时。反应完成后，把反应液倒入碳酸钠水溶液(500mL)和亚硫酸钠水溶液(500mL)中，然后用二氯甲烷(2000mL×2)萃取，合并有机相，用饱和食盐水(500mL)洗涤，硫酸钠干燥，过滤，浓缩得到黄色油状物(1S,2S)-2-甲酰基环丙烷-1-羧酸乙酯(A-5)(67.0g，产率68％)。(1S,2S)-ethyl 2-(hydroxymethyl)cyclopropane-1-carboxylate (A-4) (100 g, 693.6 mmol) was dissolved in dichloromethane (1500 mL) and added slowly at 0 °C Dess-Martin oxidant (353.0 g, 832.4 mmol) was then reacted at 25°C for 12 hours. After the reaction was completed, the reaction solution was poured into aqueous sodium carbonate solution (500 mL) and aqueous sodium sulfite solution (500 mL), then extracted with dichloromethane (2000 mL×2), the organic phases were combined, washed with saturated brine (500 mL), and washed with sodium sulfate. Drying, filtration, and concentration gave (1S,2S)-ethyl 2-formylcyclopropane-1-carboxylate (A-5) (67.0 g, 68% yield) as a yellow oil.
1H NMR(400MHz,CDCl 3)δ9.31(d,1H),4.18(q,2H),2.40-2.46(m,1H),2.24-2.28(m,1H),1.59-1.64(m,1H),1.50-1.54(m,1H),1.35-1.20(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ 9.31(d,1H), 4.18(q,2H), 2.40-2.46(m,1H), 2.24-2.28(m,1H), 1.59-1.64(m,1H) ),1.50-1.54(m,1H),1.35-1.20(m,3H).
第四步：(1S,2S)-2-(二氟甲基)环丙烷-1-羧酸乙酯(A-6)的合成Step 4: Synthesis of (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylic acid ethyl ester (A-6)
Figure PCTCN2021128905-appb-000045
Figure PCTCN2021128905-appb-000045
将(1S,2S)-2-甲酰基环丙烷-1-羧酸乙酯(A-5)(95g，668.3mmol)溶解在二氯甲烷(1200mL)中，在0℃下滴加二乙氨基三氟化硫(237.0g，194mL，1.47mol)，然后在25℃下搅拌反应2小时。将反应混合物用饱和碳酸氢钠水溶液(1000mL)淬灭，然后用二氯甲烷(500mL×2)萃取，合并有机层，用饱和食盐水(1000mL)洗涤有机相，硫酸钠干燥，浓缩得到黄色油状物(1S,2S)-2-(二氟甲基)环丙烷-1-羧酸乙酯(A-6)(95g，粗品)，直接用于下一步。(1S,2S)-ethyl 2-formylcyclopropane-1-carboxylate (A-5) (95 g, 668.3 mmol) was dissolved in dichloromethane (1200 mL), and diethylamino was added dropwise at 0 °C Sulfur trifluoride (237.0 g, 194 mL, 1.47 mol) and the reaction was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (1000 mL), then extracted with dichloromethane (500 mL×2). The organic layers were combined, washed with saturated brine (1000 mL), dried over sodium sulfate, and concentrated to obtain a yellow oil. The compound (1S,2S)-ethyl 2-(difluoromethyl)cyclopropane-1-carboxylate (A-6) (95 g, crude) was used directly in the next step.
1H NMR(400MHz,CDCl 3)δ5.62-5.91(m,1H),4.16(q,2H),1.88-1.96(m,2H),1.26-1.30(m,4H),1.12-1.16(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ 5.62-5.91 (m, 1H), 4.16 (q, 2H), 1.88-1.96 (m, 2H), 1.26-1.30 (m, 4H), 1.12-1.16 (m , 1H).
第五步：(1S,2S)-2-(二氟甲基)环丙烷-1-羧酸(A-7)的合成Step 5: Synthesis of (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylic acid (A-7)
Figure PCTCN2021128905-appb-000046
Figure PCTCN2021128905-appb-000046
把(1S,2S)-2-(二氟甲基)环丙烷-1-羧酸乙酯(A-6)(95.0g，578.7mmol)溶于甲醇(500mL)和水(100mL)中，然后加入氢氧化钠(69.5g，1.74mmol)，在25℃下反应12小时。反应完成后，把反应液浓缩，加入水(500mL)，用甲基叔丁基醚(500mL×2)萃取，收集水相，把水相用1M盐酸调pH＝3，然后用乙酸乙酯(500mL×3)萃取，合并有机相，用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色油状物(1S,2S)-2-(二氟甲基)环丙烷-1-羧酸(A-7)(47.0g，产率60％)。(1S,2S)-ethyl 2-(difluoromethyl)cyclopropane-1-carboxylate (A-6) (95.0 g, 578.7 mmol) was dissolved in methanol (500 mL) and water (100 mL), then Sodium hydroxide (69.5 g, 1.74 mmol) was added, and the reaction was carried out at 25°C for 12 hours. After the reaction was completed, the reaction solution was concentrated, water (500 mL) was added, extracted with methyl tert-butyl ether (500 mL×2), the aqueous phase was collected, the aqueous phase was adjusted to pH=3 with 1M hydrochloric acid, and then ethyl acetate ( 500mL×3) extraction, the organic phases were combined, washed with saturated brine (500mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil (1S,2S)-2-(difluoromethyl)cyclopropane-1 - Carboxylic acid (A-7) (47.0 g, 60% yield).
1H NMR(400MHz,CDCl 3)δ9.52(br.s,1H),5.65-5.94(m,1H),1.89-1.94(m,2H),1.34-1.37(m,1H),1.23-1.27(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ 9.52(br.s, 1H), 5.65-5.94(m, 1H), 1.89-1.94(m, 2H), 1.34-1.37(m, 1H), 1.23-1.27 (m,1H).
第六步：3,6-二氯-4-((1S,2S)-2-(二氟甲基)环丙基)哒嗪(A-9)的合成The sixth step: Synthesis of 3,6-dichloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazine (A-9)
Figure PCTCN2021128905-appb-000047
Figure PCTCN2021128905-appb-000047
将3,6-二氯哒嗪(6.60g，44.3mmol)和(1S,2S)-2-(二氟甲基)环丙烷-1-羧酸(6.03g，44.3mmol)溶解在水(150mL)中，然后加入浓硫酸(6.74mL)，在氮气保护下升温到70℃。然后快 速加入硝酸银的水溶液(4.20g，24.7mmol，7.5mL)，然后再缓慢滴加过硫酸铵的水溶液(30.3g，132.9mmol，75mL)，70℃继续反应2小时。反应液用氨水调pH至9左右，然后用乙酸乙酯(500mL×2)萃取，合并有机层，用饱和食盐水(500mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离(石油醚:乙酸乙酯(V/V)＝20:1-3:1，梯度洗脱)纯化得到黄色油状物3,6-二氯-4-((1S,2S)-2-(二氟甲基)环丙基)哒嗪(A-9)(5.00g，产率46.4％)。3,6-Dichloropyridazine (6.60 g, 44.3 mmol) and (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylic acid (6.03 g, 44.3 mmol) were dissolved in water (150 mL) ), then concentrated sulfuric acid (6.74 mL) was added, and the temperature was raised to 70°C under nitrogen protection. Then an aqueous solution of silver nitrate (4.20 g, 24.7 mmol, 7.5 mL) was added rapidly, and then an aqueous solution of ammonium persulfate (30.3 g, 132.9 mmol, 75 mL) was slowly added dropwise, and the reaction was continued at 70°C for 2 hours. The pH of the reaction solution was adjusted to about 9 with ammonia water, and then extracted with ethyl acetate (500 mL×2). The organic layers were combined, washed with saturated brine (500 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Purified by silica gel column separation (petroleum ether:ethyl acetate (V/V)=20:1-3:1, gradient elution) to obtain 3,6-dichloro-4-((1S,2S)- 2-(Difluoromethyl)cyclopropyl)pyridazine (A-9) (5.00 g, 46.4% yield).
1H NMR(400MHz,CDCl 3)δ7.10(s,1H),5.79-6.08(m,1H),2.39-2.45(m,1H),1.68-1.75(m,1H),1.51-1.54(m,1H),1.22-1.25(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ 7.10(s, 1H), 5.79-6.08(m, 1H), 2.39-2.45(m, 1H), 1.68-1.75(m, 1H), 1.51-1.54(m ,1H),1.22-1.25(m,1H).
LC-MS,M/Z(ESI):239.1[M+H] +。 LC-MS, M/Z (ESI): 239.1 [M+H] + .
第七步：3-氯-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(A)的合成The seventh step: 3-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine ( A) Synthesis
Figure PCTCN2021128905-appb-000048
Figure PCTCN2021128905-appb-000048
将3,6-二氯-4-((1S,2S)-2-(二氟甲基)环丙基)哒嗪(5.00g，20.9mmol)和2,4-二甲氧基嘧啶-5-硼酸(3.85g，20.9mmol)溶解在1,4-二氧六环(50mL)和水(10mL)中，在氮气保护下加入碳酸钠(6.65g，62.7mmol)和[1,1-双(二苯基膦基)二茂铁]二氯化钯(1.53g，2.09mmol)，升温至70℃反应1小时。将反应混合物用水(50mL)稀释，然后用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和食盐水(100mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-2:1，梯度洗脱)得黄色油状物3-氯-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(A)(4.5g，产率48％)。3,6-Dichloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazine (5.00 g, 20.9 mmol) and 2,4-dimethoxypyrimidine-5 - Boric acid (3.85 g, 20.9 mmol) was dissolved in 1,4-dioxane (50 mL) and water (10 mL), and sodium carbonate (6.65 g, 62.7 mmol) and [1,1-bismuth were added under nitrogen (diphenylphosphino)ferrocene]palladium dichloride (1.53 g, 2.09 mmol), the temperature was raised to 70° C. and reacted for 1 hour. The reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-2:1, gradient elution) to obtain 3-chloro-4-((1S,2S)-2-( as a yellow oil Difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (A) (4.5 g, 48% yield).
LC-MS,M/Z(ESI):343.1[M+H] +。 LC-MS, M/Z (ESI): 343.1 [M+H] + .
制备2：中间体B的制备Preparation 2: Preparation of Intermediate B
3-氯-6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2S)-2-(氟甲基)环丙基)哒嗪(中间体B)3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (Intermediate B)
Figure PCTCN2021128905-appb-000049
Figure PCTCN2021128905-appb-000049
中间体B的合成路线如下所示：The synthetic route of intermediate B is shown below:
Figure PCTCN2021128905-appb-000050
Figure PCTCN2021128905-appb-000050
第一步：(1S,2S)-2-((苄氧基)甲基)环丙烷-1-羧酸叔丁酯(B-3)的合成The first step: Synthesis of (1S,2S)-2-((benzyloxy)methyl)cyclopropane-1-carboxylate tert-butyl ester (B-3)
Figure PCTCN2021128905-appb-000051
Figure PCTCN2021128905-appb-000051
在氮气保护下把氢化钠(14.6g，365.4mmol，含量60％)悬浮在甲苯(500mL)中，然后滴加二乙基膦酰基乙酸叔丁酯(92.2g，365.4mmol)，滴加完毕后在25℃下搅拌30分钟，然后把(S)-(+)-缩水甘油苄基醚(50.0g，304.5mmol)加入到反应液中，升温至130℃反应8个小时。将反应混合物用水(100mL)稀释，然后用乙酸乙酯(100mL×2)萃取，合并有机层，用饱和食盐水(50mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-10:1，梯度洗脱)得黄色油状化合物(1S,2S)-2-((苄氧基)甲基)环丙烷-1-羧酸叔丁酯(B-3)(55g，产率68.8％)。Under nitrogen protection, sodium hydride (14.6 g, 365.4 mmol, content 60%) was suspended in toluene (500 mL), and then tert-butyl diethylphosphonoacetate (92.2 g, 365.4 mmol) was added dropwise. After stirring at 25°C for 30 minutes, (S)-(+)-glycidyl benzyl ether (50.0 g, 304.5 mmol) was added to the reaction solution, and the temperature was raised to 130°C for 8 hours. The reaction mixture was diluted with water (100 mL), then extracted with ethyl acetate (100 mL×2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-10:1, gradient elution) to obtain yellow oily compound (1S,2S)-2-((benzyloxy)methyl ) tert-butyl cyclopropane-1-carboxylate (B-3) (55 g, 68.8% yield).
第二步：(1S,2S)-2-(羟甲基)环丙烷-1-羧酸叔丁酯(B-4)的合成The second step: Synthesis of (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate tert-butyl ester (B-4)
Figure PCTCN2021128905-appb-000052
Figure PCTCN2021128905-appb-000052
把(1S,2S)-2-((苄氧基)甲基)环丙烷-1-羧酸叔丁酯(B-3)(55g，209.6mmol)溶解在乙醇(500mL)中，在氮气保护下，加入钯碳(20.0g，含量10％)，然后用氢气置换3次，然后在50Psi压力下50℃反应24小时。冷却至室温，用硅藻土过滤除去钯碳，滤饼用乙醇洗涤3次，把滤液浓缩得到黄色油状物(1S,2S)-2-(羟甲基)环丙烷-1-羧酸叔丁酯(B-4)(36.0g，产率99.7％)。(1S,2S)-2-((benzyloxy)methyl)cyclopropane-1-carboxylate tert-butyl ester (B-3) (55 g, 209.6 mmol) was dissolved in ethanol (500 mL) under nitrogen Then, palladium carbon (20.0 g, content of 10%) was added, and then replaced with hydrogen for 3 times, and then reacted at 50° C. for 24 hours under a pressure of 50 Psi. Cooled to room temperature, filtered through Celite to remove palladium carbon, the filter cake was washed three times with ethanol, and the filtrate was concentrated to obtain a yellow oily product (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylic acid tert-butyl Ester (B-4) (36.0 g, 99.7% yield).
1H NMR(400MHz,CDCl 3)δ3.50–3.63(m,2H),1.67–1.72(m,1H),1.47(s,9H),1.38(t,1H),1.14–1.89(m,1H),0.78-0.84(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ3.50-3.63(m,2H),1.67-1.72(m,1H),1.47(s,9H),1.38(t,1H),1.14-1.89(m,1H) ), 0.78-0.84 (m, 1H).
第三步：(1S,2S)-2-(氟甲基)环丙烷-1-羧酸叔丁酯(B-5)的合成The third step: Synthesis of (1S,2S)-2-(fluoromethyl)cyclopropane-1-carboxylate tert-butyl ester (B-5)
Figure PCTCN2021128905-appb-000053
Figure PCTCN2021128905-appb-000053
将(1S,2S)-2-(羟甲基)环丙烷-1-羧酸叔丁酯(B-4)(2.5g，14.5mmol)溶解在二氯甲烷(25mL) 中，在0℃下滴加二乙氨基三氟化硫(4.68g，3.84mL，29.0mmol)，然后在0℃下搅拌反应1小时。将反应混合物用饱和碳酸氢钠水溶液(100mL)淬灭，然后用二氯甲烷(100mL×2)萃取，合并有机层，用饱和食盐水(50mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-10:1，梯度洗脱)得黄色油状物(1S,2S)-2-(氟甲基)环丙烷-1-羧酸叔丁酯(B-5)(2.0g，产率79％)。(1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate tert-butyl ester (B-4) (2.5 g, 14.5 mmol) was dissolved in dichloromethane (25 mL) at 0 °C Diethylaminosulfur trifluoride (4.68 g, 3.84 mL, 29.0 mmol) was added dropwise and the reaction was stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (100 mL), then extracted with dichloromethane (100 mL×2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-10:1, gradient elution) to obtain yellow oil (1S,2S)-2-(fluoromethyl)cyclopropane- 1-Carboxylic acid tert-butyl ester (B-5) (2.0 g, 79% yield).
1H NMR(400MHz,CDCl 3)δ4.19-4.42(m,2H),1.75–1.82(m,1H),1.55-1.59(m,1H),1.46(s,9H),1.18–1.23(m,1H),0.83-0.88(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.19-4.42(m, 2H), 1.75-1.82(m, 1H), 1.55-1.59(m, 1H), 1.46(s, 9H), 1.18-1.23(m , 1H), 0.83-0.88 (m, 1H).
第四步：(1S,2S)-2-(氟甲基)环丙烷-1-羧酸(B-6)的合成The fourth step: synthesis of (1S,2S)-2-(fluoromethyl)cyclopropane-1-carboxylic acid (B-6)
Figure PCTCN2021128905-appb-000054
Figure PCTCN2021128905-appb-000054
把(1S,2S)-2-(氟甲基)环丙烷-1-羧酸叔丁酯(B-5)(2.0g，11.5mmol)溶解在氯化氢(4M)的1,4-二氧六环(10mL)溶液中，在20℃下搅拌1小时。把反应浓缩得到黄色油状物(1S,2S)-2-(氟甲基)环丙烷-1-羧酸(B-6)(1.3g，产率95％)。Dissolve (1S,2S)-2-(fluoromethyl)cyclopropane-1-carboxylate tert-butyl ester (B-5) (2.0 g, 11.5 mmol) in hydrogen chloride (4M) in 1,4-dioxane The ring (10 mL) solution was stirred at 20°C for 1 hour. The reaction was concentrated to give (1S,2S)-2-(fluoromethyl)cyclopropane-1-carboxylic acid (B-6) (1.3 g, 95% yield) as a yellow oil.
1H NMR(400MHz,CDCl 3)δ4.16-4.52(m,2H),1.88-1.94(m,1H),1.67-1.71(m,1H),1.34–1.37(m,1H),1.01-1.05(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.16-4.52 (m, 2H), 1.88-1.94 (m, 1H), 1.67-1.71 (m, 1H), 1.34-1.37 (m, 1H), 1.01-1.05 (m, 1H).
第五步：3,6-二氯-4-((1S,2S)-2-(氟甲基)环丙基)哒嗪(B-8)的合成The fifth step: the synthesis of 3,6-dichloro-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (B-8)
Figure PCTCN2021128905-appb-000055
Figure PCTCN2021128905-appb-000055
将3,6-二氯哒嗪(630mg，4.23mmol)和(1S,2S)-2-(氟甲基)环丙烷-1-羧酸(B-6)(500mg，4.23mmol)溶解在水中，然后加入浓硫酸(0.5mL)，在氮气保护下升温到70℃。然后快速加入硝酸银的水溶液(359.6mg，2.12mmol，5mL)，然后再缓慢滴加过硫酸铵的水溶液(2.90g，12.7mmol，10mL)，70℃继续反应1小时。反应液用氨水调pH至9左右，然后用乙酸乙酯(100mL×2)萃取，合并有机层，用饱和食盐水(50mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-3:1，梯度洗脱)得到黄色油状物3,6-二氯-4-((1S,2S)-2-(氟甲基)环丙基)哒嗪(B-8)(500mg，产率26％)。3,6-Dichloropyridazine (630 mg, 4.23 mmol) and (1S,2S)-2-(fluoromethyl)cyclopropane-1-carboxylic acid (B-6) (500 mg, 4.23 mmol) were dissolved in water , and then concentrated sulfuric acid (0.5 mL) was added, and the temperature was raised to 70 °C under nitrogen protection. Then an aqueous solution of silver nitrate (359.6 mg, 2.12 mmol, 5 mL) was added rapidly, and then an aqueous solution of ammonium persulfate (2.90 g, 12.7 mmol, 10 mL) was slowly added dropwise, and the reaction was continued at 70° C. for 1 hour. The pH of the reaction solution was adjusted to about 9 with ammonia water, and then extracted with ethyl acetate (100 mL×2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-3:1, gradient elution) gave 3,6-dichloro-4-((1S,2S)- 2-(Fluoromethyl)cyclopropyl)pyridazine (B-8) (500 mg, 26% yield).
第六步：3-氯-6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2S)-2-(氟甲基)环丙基)哒嗪(B)的合成The sixth step: 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (B )Synthesis
Figure PCTCN2021128905-appb-000056
Figure PCTCN2021128905-appb-000056
将3,6-二氯-4-((1S,2S)-2-(氟甲基)环丙基)哒嗪(300mg，1.36mmol)和2,4-二甲氧基嘧啶-5-硼酸溶解在1,4-二氧六环(10mL)和水(2mL)中，在氮气保护下加入碳酸钠(359.6mg，3.39mmol)和[1,1-双(二苯基膦基)二茂铁]二氯化钯(99.3mg，135.7μmol)，升温至70℃反应2小时。将反应混合物用水(50mL)稀释，然后用乙酸乙酯(50mL×2)萃取，合并有机层，用饱和食盐水(50mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。将粗品通过硅胶柱分离(石油醚:乙酸乙酯(V/V)＝5:1-1:1，梯度洗脱)得到黄色固体3-氯-6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2S)-2-(氟甲基)环丙基)哒嗪(B)(150mg，产率34％)。3,6-Dichloro-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (300 mg, 1.36 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid Dissolve in 1,4-dioxane (10 mL) and water (2 mL), add sodium carbonate (359.6 mg, 3.39 mmol) and [1,1-bis(diphenylphosphino)dioxin under nitrogen protection Iron] palladium dichloride (99.3 mg, 135.7 μmol), the temperature was raised to 70° C. to react for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1, gradient elution) to obtain 3-chloro-6-(2,4-dimethoxypyrimidine as a yellow solid) -5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (B) (150 mg, 34% yield).
1H NMR(400MHz,CDCl 3)δ9.06(s,1H),7.55(s,1H),4.45-4.58(m,2H),4.10(s,3H),4.08(s,3H),2.24-2.29(m,1H),1.65-1.69(m,1H),1.31-1.35(m,1H),1.19-1.23(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 9.06(s, 1H), 7.55(s, 1H), 4.45-4.58(m, 2H), 4.10(s, 3H), 4.08(s, 3H), 2.24- 2.29(m,1H), 1.65-1.69(m,1H), 1.31-1.35(m,1H), 1.19-1.23(m,1H).
LC-MS,M/Z(ESI):324.9[M+H] +。 LC-MS, M/Z (ESI): 324.9 [M+H] + .
实施例1：目标化合物1的制备Example 1: Preparation of target compound 1
5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-(丙-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物1)5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(prop-1-yn-1-yl)pyridazin-3-yl)pyrimidine-2,4 (1H,3H)-dione (target compound 1)
Figure PCTCN2021128905-appb-000057
Figure PCTCN2021128905-appb-000057
目标化合物1的合成路线如下所示：The synthetic route of target compound 1 is as follows:
Figure PCTCN2021128905-appb-000058
Figure PCTCN2021128905-appb-000058
第一步：4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)-3-(丙-1-炔-1-基)哒嗪(1B)的合成The first step: 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(propan-1 Synthesis of -alkyn-1-yl)pyridazine (1B)
Figure PCTCN2021128905-appb-000059
Figure PCTCN2021128905-appb-000059
在氮气保护下，把3-氯-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(500mg，1.46mmol)，三丁基(丙-1-炔-1-基)锡烷(960.3mg，2.92mmol)，1,1-双(二苯基磷)二茂铁氯化钯(102.4mg，0.146mmol)，溶于1,4-二氧六环(10mL)中，然后氮气保护下80℃反应3小时。反应完成后，将反应混合物浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1，梯度洗脱)得黄色油状物4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)-3-(丙-1-炔-1-基)哒嗪(1B)(600mg，产率98％)。Under nitrogen protection, 3-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridin oxazine (500 mg, 1.46 mmol), tributyl(prop-1-yn-1-yl)stannane (960.3 mg, 2.92 mmol), 1,1-bis(diphenylphosphonium)ferrocene palladium chloride ( 102.4 mg, 0.146 mmol), dissolved in 1,4-dioxane (10 mL), and then reacted at 80 °C for 3 hours under nitrogen protection. After completion of the reaction, the reaction mixture was concentrated to obtain crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1, gradient elution) to obtain 4-((1S,2S)-2-(difluoromethyl) as a yellow oil )cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(prop-1-yn-1-yl)pyridazine (1B) (600 mg, 98% yield) .
LC-MS,M/Z(ESI):347.0[M+H] +。 LC-MS, M/Z (ESI): 347.0 [M+H] + .
第二步：5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-(丙-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(1)Step 2: 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(prop-1-yn-1-yl)pyridazin-3-yl)pyrimidine -2,4(1H,3H)-dione (1)
Figure PCTCN2021128905-appb-000060
Figure PCTCN2021128905-appb-000060
将4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)-3-(丙-1-炔-1-基)哒嗪(600mg，1.73mmol)溶解在盐酸水溶液(1M，10mL)中，升温至70℃反应10小时。把反应液浓缩，然后通过反相高效液相色谱法进行分离，分离方法为(色谱柱：Waters Xbridge 150×25mm×5μm；流动相：A＝水+碳酸氢铵(10mM)，B＝乙腈；梯度：12％-48％B，10分钟)， 得到黄色固体5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-(丙-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(1)(80mg，产率14.5％)。4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(prop-1-yn- 1-yl)pyridazine (600 mg, 1.73 mmol) was dissolved in an aqueous hydrochloric acid solution (1 M, 10 mL), and the temperature was raised to 70° C. to react for 10 hours. The reaction solution was concentrated, then separated by reversed-phase high performance liquid chromatography, and the separation method was (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: A=water+ammonium bicarbonate (10mM), B=acetonitrile; Gradient: 12%-48% B, 10 min) to give 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(prop-1-yne- 1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (1) (80 mg, 14.5% yield).
1H NMR(400MHz,CD 3OD)δ8.43(s,1H),8.01(s,1H),5.76-6.05(m,1H),2.54-2.60(m,1H),2.22(s,3H),1.86-1.88(m,1H),1.42-1.46(m,1H),1.31-1.33(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 8.43(s, 1H), 8.01(s, 1H), 5.76-6.05(m, 1H), 2.54-2.60(m, 1H), 2.22(s, 3H) ,1.86-1.88(m,1H),1.42-1.46(m,1H),1.31-1.33(m,1H).
LC-MS,M/Z(ESI):318.9[M+H] +。 LC-MS, M/Z (ESI): 318.9 [M+H] + .
实施例2：目标化合物2的制备Example 2: Preparation of target compound 2
5-(6-(丁-1-炔-1-基)-5-((1S,2S)-2-(二氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物2)5-(6-(But-1-yn-1-yl)-5-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4 (1H,3H)-dione (target compound 2)
Figure PCTCN2021128905-appb-000061
Figure PCTCN2021128905-appb-000061
目标化合物2的合成路线如下所示：The synthetic route of target compound 2 is as follows:
Figure PCTCN2021128905-appb-000062
Figure PCTCN2021128905-appb-000062
第一步：3-(丁-1-炔-1-基)-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(2B)的合成The first step: 3-(but-1-yn-1-yl)-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxy Synthesis of pyrimidin-5-yl)pyridazine (2B)
Figure PCTCN2021128905-appb-000063
Figure PCTCN2021128905-appb-000063
将3-氯-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(200mg，0.583mmol)溶解在N,N-二甲基甲酰胺(5mL)中，在氮气保护下加入碘化亚铜(11.1mg，58.4μmol)，三乙胺(236.2mg，2.33mmol)和双(三苯基膦)二氯化钯(40.9mg，58.4μmol)，然后通入丁-1-炔(15psi)，升温至80℃反应2小时。将反应混合物用水(25mL)稀释，然后用乙酸乙酯(25mL×2)萃取，合并有机层，用饱和食盐水(25mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-1:1，梯度洗脱)得黄色油状物3-(丁-1-炔-1-基)-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(2B)(200mg，95％)。3-Chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (200 mg, 0.583 mmol) was dissolved in N,N-dimethylformamide (5 mL), cuprous iodide (11.1 mg, 58.4 μmol), triethylamine (236.2 mg, 2.33 mmol) and bis(triphenylene) were added under nitrogen protection phosphine) palladium dichloride (40.9 mg, 58.4 μmol), then but-1-yne (15 psi) was passed through, and the temperature was raised to 80° C. to react for 2 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 mL×2). The organic layers were combined, washed with saturated brine (25 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-1:1, gradient elution) to obtain 3-(but-1-yn-1-yl)-4- as a yellow oil ((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (2B) (200 mg, 95%).
LC-MS,M/Z(ESI):361.1[M+H] +。 LC-MS, M/Z (ESI): 361.1 [M+H] + .
第二步：5-(6-(丁-1-炔-1-基)-5-((1S,2S)-2-(二氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(2)的合成Step 2: 5-(6-(But-1-yn-1-yl)-5-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine Synthesis of -2,4(1H,3H)-dione (2)
Figure PCTCN2021128905-appb-000064
Figure PCTCN2021128905-appb-000064
将3-(环丙基乙炔基)-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(200mg，0.555mmol)溶解在盐酸水溶液(1M，5mL)中，升温至50℃反应0.5小时。把反应液浓缩，然后通过反相高效液相色谱法进行分离，分离方法为(色谱柱：3_Phenomenex Luna C18 75×30mm×3μm；流动相：A＝水+0.05体积％HCl(36.5％)，B＝乙腈；梯度：25％-45％B，8分钟)，得到黄色固体5-(6-(丁-1-炔-1-基)-5-((1S,2S)-2-(二氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(2)(70.7mg，产率38％)。3-(Cyclopropylethynyl)-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl) Pyridazine (200 mg, 0.555 mmol) was dissolved in an aqueous hydrochloric acid solution (1 M, 5 mL), and the temperature was raised to 50° C. to react for 0.5 hour. The reaction solution was concentrated, and then separated by reversed-phase high performance liquid chromatography. The separation method was (chromatographic column: 3_Phenomenex Luna C18 75×30mm×3μm; mobile phase: A=water+0.05% by volume HCl (36.5%), B =acetonitrile; gradient: 25%-45% B, 8 min) to give 5-(6-(but-1-yn-1-yl)-5-((1S,2S)-2-(difluoro) as a yellow solid Methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (2) (70.7 mg, 38% yield).
1H NMR(400MHz,CD 3OD)δ8.49(s,1H),8.08(s,1H),5.78-6.08(m,1H),2.59-2.65(m,3H),1.88-1.95(m,1H),1.46-1.52(m,1H),1.37-1.43(m,1H),1.32(t,3H). 1 H NMR (400MHz, CD 3 OD) δ8.49(s, 1H), 8.08(s, 1H), 5.78-6.08(m, 1H), 2.59-2.65(m, 3H), 1.88-1.95(m, 1H), 1.46-1.52(m, 1H), 1.37-1.43(m, 1H), 1.32(t, 3H).
LC-MS,M/Z(ESI):332.9[M+H] +。 LC-MS, M/Z (ESI): 332.9 [M+H] + .
实施例3：目标化合物3的制备Example 3: Preparation of target compound 3
5-(6-(环丙基乙炔基)-5-((1S,2S)-2-(二氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物3)5-(6-(Cyclopropylethynyl)-5-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H )-dione (target compound 3)
Figure PCTCN2021128905-appb-000065
Figure PCTCN2021128905-appb-000065
目标化合物3的合成路线如下所示：The synthetic route of target compound 3 is as follows:
Figure PCTCN2021128905-appb-000066
Figure PCTCN2021128905-appb-000066
第一步：3-(环丙基乙炔基)-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(3B)的合成The first step: 3-(cyclopropylethynyl)-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidine-5 -Synthesis of pyridazine (3B)
Figure PCTCN2021128905-appb-000067
Figure PCTCN2021128905-appb-000067
将3-氯-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(200mg，583.5μmol)和环丙乙炔溶解在N,N-二甲基甲酰胺(5mL)中，在氮气保护下加入碘化亚铜(11.1mg，58.4μmol)，三乙胺(236.2mg，2.33mmol)和双(三苯基膦)二氯化钯(40.9mg，58.4μmol)，反应升温至80℃反应2小时。将反应混合物用水(25mL)稀释，然后用乙酸乙酯(25mL×2)萃取， 合并有机层，用饱和食盐水(25mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-1:1，梯度洗脱)得黄色油状物3-(环丙基乙炔基)-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(3B)(200mg，产率92％)。3-Chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (200 mg, 583.5 μmol) and cyclopropacetylene were dissolved in N,N-dimethylformamide (5 mL), cuprous iodide (11.1 mg, 58.4 μmol), triethylamine (236.2 mg, 2.33 mmol) and Bis(triphenylphosphine)palladium dichloride (40.9 mg, 58.4 μmol), the reaction temperature was raised to 80° C. for 2 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 mL×2). The organic layers were combined, washed with saturated brine (25 mL), dried over sodium sulfate, and concentrated to obtain a crude product. It was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-1:1, gradient elution) to obtain 3-(cyclopropylethynyl)-4-((1S, 2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (3B) (200 mg, 92% yield).
LC-MS,M/Z(ESI):373.2[M+H] +。 LC-MS, M/Z (ESI): 373.2 [M+H] + .
第二步：5-(6-(环丙基乙炔基)-5-((1S,2S)-2-(二氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(3)的合成Step 2: 5-(6-(Cyclopropylethynyl)-5-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4 Synthesis of (1H,3H)-diketone (3)
Figure PCTCN2021128905-appb-000068
Figure PCTCN2021128905-appb-000068
将3-(环丙基乙炔基)-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(200mg，537.1μmol)溶解在盐酸水溶液(1M，10mL)中，升温至75℃反应2小时。把反应液浓缩，然后通过反相高效液相色谱法进行分离，分离方法为(色谱柱:Phenomenex Gemini-NX C18 75×30mm×3μm；流动相：A＝水+碳酸氢铵(10mM)，B＝乙腈；梯度：15％-45％B，8分钟)，得到黄色固体5-(6-(环丙基乙炔基)-5-((1S,2S)-2-(二氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(3)(50mg，产率27％)。3-(Cyclopropylethynyl)-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl) Pyridazine (200 mg, 537.1 μmol) was dissolved in an aqueous hydrochloric acid solution (1 M, 10 mL), and the temperature was raised to 75° C. to react for 2 hours. The reaction solution was concentrated, and then separated by reversed-phase high performance liquid chromatography. The separation method was (chromatographic column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: A = water + ammonium bicarbonate (10 mM), B =acetonitrile; gradient: 15%-45% B, 8 min) to give 5-(6-(cyclopropylethynyl)-5-((1S,2S)-2-(difluoromethyl) ring as a yellow solid Propyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (3) (50 mg, 27% yield).
1H NMR(400MHz,CD 3OD)δ8.43(s,1H),7.99(s,1H),5.78-6.07(m,1H),2.50-2.55(m,1H),1.81-1.87(m,1H),1.62-1.69(m,1H),1.41-1.46(m,1H),1.32-1.36(m,1H),1.15-1.01(m,2H),0.98-0.85(m,2H). 1 H NMR (400MHz, CD 3 OD) δ8.43(s, 1H), 7.99(s, 1H), 5.78-6.07(m, 1H), 2.50-2.55(m, 1H), 1.81-1.87(m, 1H), 1.62-1.69(m, 1H), 1.41-1.46(m, 1H), 1.32-1.36(m, 1H), 1.15-1.01(m, 2H), 0.98-0.85(m, 2H).
LC-MS,M/Z(ESI):345.2[M+H] +。 LC-MS, M/Z (ESI): 345.2 [M+H] + .
实施例4：目标化合物4的制备Example 4: Preparation of target compound 4
5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-(3-羟基-3-甲基丁-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮(目标化合物4)5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridazine-3 -yl)pyrimidine-2,4(1H,3H)-dione (target compound 4)
Figure PCTCN2021128905-appb-000069
Figure PCTCN2021128905-appb-000069
目标化合物4的合成路线如下所示：The synthetic route of target compound 4 is as follows:
Figure PCTCN2021128905-appb-000070
Figure PCTCN2021128905-appb-000070
第一步：4-(4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪-3-基)-2-甲基-3-炔-2-醇(4B)的合成The first step: 4-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine-3 Synthesis of -yl)-2-methyl-3-yn-2-ol (4B)
Figure PCTCN2021128905-appb-000071
Figure PCTCN2021128905-appb-000071
在氮气的保护下将3-氯-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(200.0mg，583.6μmol)和2-甲基丁-3-炔-2-醇(73.6mg，875.3μmol)溶在N,N二甲基甲酰胺(5.00mL)，再向里面加碘化亚铜(11.1mg,58.4μmol)，三乙胺(236.2mg,2.33mmol)和双(三苯基膦)二氯化钯(40.9mg,58.4μmol)，然后80℃反应2小时。反应完毕后，将反应液加入到水(10mL)中，在用乙酸乙酯(20mL×2)萃取，有机相用饱和食盐水(50mL)洗涤两次，之后有机相用无水硫酸钠干燥，有机相浓缩得到黄色油状物4-(4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪-3-基)-2-甲基-3-炔-2-醇(4B)(140.0mg,产率68.6％)。Under nitrogen protection, 3-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridin Zine (200.0 mg, 583.6 μmol) and 2-methylbut-3-yn-2-ol (73.6 mg, 875.3 μmol) were dissolved in N,N dimethylformamide (5.00 mL), and iodide was added to it Cuprous (11.1 mg, 58.4 μmol), triethylamine (236.2 mg, 2.33 mmol) and bis(triphenylphosphine)palladium dichloride (40.9 mg, 58.4 μmol) were then reacted at 80° C. for 2 hours. After the reaction was completed, the reaction solution was added to water (10 mL), extracted with ethyl acetate (20 mL×2), the organic phase was washed twice with saturated brine (50 mL), and then the organic phase was dried with anhydrous sodium sulfate, The organic phase was concentrated to give 4-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridin as a yellow oil Azin-3-yl)-2-methyl-3-yn-2-ol (4B) (140.0 mg, 68.6% yield).
LC-MS,M/Z(ESI):391.2[M+H] +。 LC-MS, M/Z (ESI): 391.2 [M+H] + .
第二步：5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-(3-羟基-3-甲基丁-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标产物4)的合成Step 2: 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl) Synthesis of Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (target product 4)
Figure PCTCN2021128905-appb-000072
Figure PCTCN2021128905-appb-000072
将4-(4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪-3-基)-2-甲基-3-炔-2-醇(140.0mg,358.6μmol)溶在盐酸(1M,3.59mL)里，然后50℃反应12小时。反应完成后，直接将反应冻干，得到粗产品，将粗品通过反相高效液相色谱法进行分离，分离方法为(色谱柱：3_Phenomenex Luna C18 75×30mm×3μm；流动相：A＝水+0.05体积％HCl(36.5％)，B＝乙腈；梯度：16％-36％B，7分钟)，得到黄色固体5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-(3-羟基-3-甲基丁-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(4)(17.5mg,产率13.2％)。4-(4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-yl) -2-Methyl-3-yn-2-ol (140.0 mg, 358.6 μmol) was dissolved in hydrochloric acid (1 M, 3.59 mL), and then reacted at 50° C. for 12 hours. After the reaction is completed, the reaction is directly lyophilized to obtain a crude product, and the crude product is separated by reversed-phase high performance liquid chromatography, and the separation method is (chromatographic column: 3_Phenomenex Luna C18 75 × 30mm × 3 μm; mobile phase: A=water+ 0.05 vol% HCl (36.5%), B = acetonitrile; gradient: 16%-36% B, 7 min) to give 5-(5-((1S,2S)-2-(difluoromethyl) ring as a yellow solid Propyl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (4)(17.5 mg, 13.2% yield).
1H NMR(400MHz,CDCl 3)δ8.46(s,1H),8.04(s,1H),5.82-6.11(m,1H),2.57-2.62(m,1H),1.64-1.92(m,1H),1.64(s,6H),1.47-1.51(m,1H),1.35-1.37(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ 8.46(s,1H), 8.04(s,1H), 5.82-6.11(m,1H), 2.57-2.62(m,1H), 1.64-1.92(m,1H) ),1.64(s,6H),1.47-1.51(m,1H),1.35-1.37(m,1H).
LC-MS,M/Z(ESI):363.2[M+H] +。 LC-MS, M/Z (ESI): 363.2 [M+H] + .
实施例5：目标化合物5的制备Example 5: Preparation of target compound 5
5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-(3-甲基丁-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物5)5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(3-methylbut-1-yn-1-yl)pyridazin-3-yl)pyrimidine -2,4(1H,3H)-dione (target compound 5)
Figure PCTCN2021128905-appb-000073
Figure PCTCN2021128905-appb-000073
目标化合物5的合成路线如下所示：The synthetic route of target compound 5 is shown below:
Figure PCTCN2021128905-appb-000074
Figure PCTCN2021128905-appb-000074
第一步：4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)-3-(3-甲基丁-1-炔-1-基)哒嗪(5B)的合成The first step: 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(3-methyl) Synthesis of But-1-yn-1-yl)pyridazine (5B)
Figure PCTCN2021128905-appb-000075
Figure PCTCN2021128905-appb-000075
在氮气的保护下将3-氯-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(253.2mg,583.6μmol)和3-甲基丁-1-炔(59.6mg,875.3μmol)溶在N,N二甲基甲酰胺(5.00mL)，在向里面加碘化亚铜(11.1mg,58.4μmol)，三乙胺(236.2mg,2.33mmol)和双(三苯基膦)二氯化钯(40.9mg,58.4μmol)，然后80℃反应2小时。反应完毕后，将反应液加入到水(10mL)中，在用乙酸乙酯(30mL×2)萃取，有机相用饱和食盐水(50mL)洗涤两次，之后有机相用无水硫酸钠干燥，有机相浓缩得到黄色油状化合物4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)-3-(3-甲基丁-1-炔-1-基)哒嗪(5B)(180.0mg,产率76.6％)。Under nitrogen protection, 3-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridin Zine (253.2 mg, 583.6 μmol) and 3-methylbut-1-yne (59.6 mg, 875.3 μmol) were dissolved in N,N dimethylformamide (5.00 mL), to which was added cuprous iodide (11.1 mg, 58.4 μmol), triethylamine (236.2 mg, 2.33 mmol) and bis(triphenylphosphine)palladium dichloride (40.9 mg, 58.4 μmol), and then reacted at 80° C. for 2 hours. After the reaction was completed, the reaction solution was added to water (10 mL), extracted with ethyl acetate (30 mL×2), the organic phase was washed twice with saturated brine (50 mL), and then the organic phase was dried with anhydrous sodium sulfate, The organic phase was concentrated to give a yellow oily compound 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-( 3-Methylbut-1-yn-1-yl)pyridazine (5B) (180.0 mg, 76.6% yield).
LC-MS,M/Z(ESI):375.3[M+H] +。 LC-MS, M/Z (ESI): 375.3 [M+H] + .
第二步：5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-(3-甲基丁-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物5)的合成Step 2: 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(3-methylbut-1-yn-1-yl)pyridazine-3 Synthesis of -yl)pyrimidine-2,4(1H,3H)-dione (target compound 5)
Figure PCTCN2021128905-appb-000076
Figure PCTCN2021128905-appb-000076
将4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)-3-(3-甲基丁-1-炔-1-基)哒嗪(80.0mg,213.7μmol)溶在盐酸(1M,2.14mL)里，然后40℃反应12小时。反应完成后，直接将反应液冻干，得到黄色固体5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-(3-甲基丁-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(5)(40.5mg,产率50.4％)。4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-(3-methylbutan- 1-Alyn-1-yl)pyridazine (80.0 mg, 213.7 μmol) was dissolved in hydrochloric acid (1 M, 2.14 mL), and then reacted at 40° C. for 12 hours. After the completion of the reaction, the reaction solution was directly lyophilized to obtain a yellow solid 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(3-methylbutan-1- Alkyn-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (5) (40.5 mg, 50.4% yield).
1H NMR(400MHz,CDCl 3)δ8.67(s,1H),8.23(s,1H),5.84-6.13(m,1H),2.99-3.03(m,1H),2.69-2.71(m,1H),2.03-2.05(m,1H),1.56-1.59(m,2H),1.35-1.37(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ 8.67(s,1H), 8.23(s,1H), 5.84-6.13(m,1H), 2.99-3.03(m,1H), 2.69-2.71(m,1H) ), 2.03-2.05 (m, 1H), 1.56-1.59 (m, 2H), 1.35-1.37 (m, 6H).
LC-MS,M/Z(ESI):347.2[M+H] +。 LC-MS, M/Z (ESI): 347.2 [M+H] + .
实施例6：目标化合物6的制备Example 6: Preparation of target compound 6
5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-((1-甲基-1H-吡唑-4-基)乙炔基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物6)5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridazine-3 -yl)pyrimidine-2,4(1H,3H)-dione (target compound 6)
Figure PCTCN2021128905-appb-000077
Figure PCTCN2021128905-appb-000077
目标化合物6的合成路线如下所示：The synthetic route of target compound 6 is as follows:
Figure PCTCN2021128905-appb-000078
Figure PCTCN2021128905-appb-000078
第一步：4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)-3-((1-甲基-1H-吡唑-4-基)乙炔基)哒嗪(6B)的合成The first step: 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-((1- Synthesis of Methyl-1H-pyrazol-4-yl)ethynyl)pyridazine (6B)
Figure PCTCN2021128905-appb-000079
Figure PCTCN2021128905-appb-000079
在氮气的保护下将3-氯-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(200.0mg,583.6μmol)和4-乙炔基-1-甲基-吡唑(154.8mg,1.46mmol)溶在N,N二甲基甲酰胺(5.00mL)，在向里面加碘化亚铜(22.2mg,116.7μmol)，三乙胺(236.2mg,2.33mmol)和双(三苯基膦)二氯化钯(81.9mg,116.7μmol)，然后80℃反应2小时。反应完毕后，将反应液加入到水(10mL)中，在用乙酸乙酯(30mL×2)萃取，有机相用饱和食盐水(50mL)洗涤两次，之后有机相用无水硫酸钠干燥，有机相浓缩得到黄色油状物4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)-3-((1-甲基-1H-吡唑-4-基)乙炔基)哒嗪(6B)(160.0mg，产率66.5％)。Under nitrogen protection, 3-chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridin oxazine (200.0 mg, 583.6 μmol) and 4-ethynyl-1-methyl-pyrazole (154.8 mg, 1.46 mmol) were dissolved in N,N dimethylformamide (5.00 mL), to which was added iodide Copper (22.2 mg, 116.7 μmol), triethylamine (236.2 mg, 2.33 mmol) and bis(triphenylphosphine)palladium dichloride (81.9 mg, 116.7 μmol) were then reacted at 80° C. for 2 hours. After the reaction was completed, the reaction solution was added to water (10 mL), extracted with ethyl acetate (30 mL×2), the organic phase was washed twice with saturated brine (50 mL), and then the organic phase was dried with anhydrous sodium sulfate, The organic phase was concentrated to give 4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-( (1-Methyl-1H-pyrazol-4-yl)ethynyl)pyridazine (6B) (160.0 mg, 66.5% yield).
LC-MS,M/Z(ESI):413.2[M+H] +。 LC-MS, M/Z (ESI): 413.2 [M+H] + .
第二步：5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-((1-甲基-1H-吡唑-4-基)乙炔基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物6)的合成Step 2: 5-(5-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl) Synthesis of Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (target compound 6)
Figure PCTCN2021128905-appb-000080
Figure PCTCN2021128905-appb-000080
将4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)-3-((1-甲基-1H-吡唑-4-基)乙炔基)哒嗪(160.0mg,450.9μmol)溶在盐酸(1M,3.88mL)里，然后50℃反应12小时。反应完成后，直接将反应冻干，得到粗产品，将粗品通过反相高效液相色谱法进行分离，分离方法为(色谱柱：3_Phenomenex Luna C18 75×30mm×3μm；流动相：A＝水+0.05体积％HCl(36.5％)，B＝乙腈；梯度：18％-38％B，7分钟)纯化得到黄色固体5-(5-((1S,2S)-2-(二氟甲基)环丙基)-6-((1-甲基-1H-吡唑-4-基)乙炔基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(6)(66.8mg,产率43.4％)。4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-((1-methyl- 1H-pyrazol-4-yl)ethynyl)pyridazine (160.0 mg, 450.9 μmol) was dissolved in hydrochloric acid (1 M, 3.88 mL), and then reacted at 50° C. for 12 hours. After the reaction is completed, the reaction is directly lyophilized to obtain a crude product, and the crude product is separated by reversed-phase high performance liquid chromatography, and the separation method is (chromatographic column: 3_Phenomenex Luna C18 75 × 30mm × 3 μm; mobile phase: A=water+ 0.05 vol% HCl (36.5%), B = acetonitrile; gradient: 18%-38% B, 7 min) Purification gave 5-(5-((1S,2S)-2-(difluoromethyl)ring as a yellow solid Propyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (6)(66.8 mg, yield 43.4%).
1H NMR(400MHz,DMSO-d 6)δ11.65(s,1H),11.56(s,1H),8.40(d,1H),8.23(s,1H),7.96 (s,1H),7.82(s,1H),5.91-6.21(m,1H),3.90(s,3H),2.50-2.56(m,1H),1.89-1.93(m,1H),1.43-1.46(m,1H),1.31-1.33(m,1H). 1 H NMR (400MHz, DMSO-d 6 )δ11.65(s,1H), 11.56(s,1H), 8.40(d,1H), 8.23(s,1H), 7.96(s,1H), 7.82( s,1H),5.91-6.21(m,1H),3.90(s,3H),2.50-2.56(m,1H),1.89-1.93(m,1H),1.43-1.46(m,1H),1.31- 1.33(m,1H).
LC-MS,M/Z(ESI):385.2[M+H] +。 LC-MS, M/Z (ESI): 385.2 [M+H] + .
实施例7：目标化合物7的制备Example 7: Preparation of target compound 7
5-(6-(环丁基乙炔基)-5-((1S,2S)-2-(二氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物7)5-(6-(Cyclobutylethynyl)-5-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H )-dione (target compound 7)
Figure PCTCN2021128905-appb-000081
Figure PCTCN2021128905-appb-000081
目标化合物7的合成路线如下所示：The synthetic route of target compound 7 is as follows:
Figure PCTCN2021128905-appb-000082
Figure PCTCN2021128905-appb-000082
第一步：三丁基(环丁基乙炔基)锡烷(7A)的合成The first step: Synthesis of tributyl(cyclobutylethynyl)stannane (7A)
Figure PCTCN2021128905-appb-000083
Figure PCTCN2021128905-appb-000083
在-5℃下，将正丁基锂(2.5M,7.03mL)滴加到四氢呋喃(5mL)中，温度保持在10℃以下。6-氯-1-己炔(1g,8.58mmol)在5℃左右滴加到体系中，并搅拌2小时。接着将三正丁基氯化锡(3.07g,9.43mmol)滴加到体系中，反应0.5小时。反应体系用氟化钾溶液(50mL)淬灭，然后用乙酸乙酯(50mL×3)萃取，合并有机层，硫酸钠干燥，浓缩得到黄色油状物三丁基(环丁基乙炔基)锡烷(7A)(3g，产率94.7％)。n-Butyllithium (2.5M, 7.03 mL) was added dropwise to tetrahydrofuran (5 mL) at -5°C, keeping the temperature below 10°C. 6-Chloro-1-hexyne (1 g, 8.58 mmol) was added dropwise to the system at about 5°C, and stirred for 2 hours. Then, tri-n-butyltin chloride (3.07 g, 9.43 mmol) was added dropwise to the system and reacted for 0.5 hour. The reaction system was quenched with potassium fluoride solution (50 mL), then extracted with ethyl acetate (50 mL×3), the organic layers were combined, dried over sodium sulfate, and concentrated to obtain tributyl(cyclobutylethynyl)stannane as a yellow oil (7A) (3 g, 94.7% yield).
第二步：3-(环丁基乙炔基)-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(7B)的合成Step 2: 3-(Cyclobutylethynyl)-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidine-5 -Synthesis of pyridazine (7B)
Figure PCTCN2021128905-appb-000084
Figure PCTCN2021128905-appb-000084
将3-氯-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(200mg,583.5μmol)和三丁基(环丁基乙炔基)锡烷(7A)(323.1mg,875.3μmol)溶解在1,4-二氧六环(10mL) 中，在氮气保护下加入双(三苯基膦)二氯化钯(40.9mg,58.4μmol)，升温至80℃反应3小时。将反应体系旋干得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1–1:1，梯度洗脱)得到黄色油状物3-(环丁基乙炔基)-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(7B)(200mg，产率88.7％)。3-Chloro-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (200 mg, 583.5 μmol) and tributyl(cyclobutylethynyl)stannane (7A) (323.1 mg, 875.3 μmol) were dissolved in 1,4-dioxane (10 mL), bis(triphenyl) was added under nitrogen protection phosphine) palladium dichloride (40.9 mg, 58.4 μmol), the temperature was raised to 80° C. to react for 3 hours. The reaction system was spin-dried to obtain a crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1, gradient elution) gave 3-(cyclobutylethynyl)-4-((1S, 2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (7B) (200 mg, 88.7% yield).
LC-MS,M/Z(ESI):387.2[M+H] +。 LC-MS, M/Z (ESI): 387.2 [M+H] + .
第三步：5-(6-(环丁基乙炔基)-5-((1S,2S)-2-(二氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(7)的合成The third step: 5-(6-(cyclobutylethynyl)-5-((1S,2S)-2-(difluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4 Synthesis of (1H,3H)-diketone (7)
Figure PCTCN2021128905-appb-000085
Figure PCTCN2021128905-appb-000085
将3-(环丁基乙炔基)-4-((1S,2S)-2-(二氟甲基)环丙基)-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(3)(200mg,435.1μmol)溶解在盐酸水溶液(1M，4.35mL)中，升温至50℃反应12小时。将反应体系旋干，粗品通过两次反相高效液相色谱法进行分离，分离方法分别为(色谱柱：3_Phenomenex Luna C18 75×30mm×3μm；流动相：A＝水+0.05体积％HCl(36.5％)，B＝乙腈；梯度：29％-49％B，7.5分钟)和(色谱柱：Phenomenex Gemini-NX C18 75×30mm×3μm；流动相：A＝水+碳酸氢铵(10mmol)，B＝乙腈；梯度：24％-44％B，8分钟)，得到黄色固体化合物5-(6-(环丁基乙炔基)-5-((1S,2S)-2-(二氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(7)(10.3mg，产率6.55％)。3-(Cyclobutylethynyl)-4-((1S,2S)-2-(difluoromethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl) Pyridazine (3) (200 mg, 435.1 μmol) was dissolved in an aqueous hydrochloric acid solution (1 M, 4.35 mL), and the temperature was raised to 50° C. to react for 12 hours. The reaction system was spin-dried, and the crude product was separated by reversed-phase high performance liquid chromatography twice, and the separation methods were respectively (chromatographic column: 3_Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: A = water + 0.05 volume % HCl (36.5 %), B=acetonitrile; gradient: 29%-49% B, 7.5 minutes) and (chromatographic column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: A=water+ammonium bicarbonate (10mmol), B =acetonitrile; gradient: 24%-44% B, 8 min) to give compound 5-(6-(cyclobutylethynyl)-5-((1S,2S)-2-(difluoromethyl) as a yellow solid) Cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (7) (10.3 mg, 6.55% yield).
1H NMR(400MHz,CD 3OD)δ8.47(s,1H),8.02(s,1H),5.94(td,1H),3.39-3.48(m,1H),2.55-2.60(m,1H),2.40-2.48(m,2H),2.27-2.37(m,2H),1.99-2.12(m,2H),1.83-1.89(m,1H),1.42-1.47(m,1H),1.33-1.38(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 8.47(s,1H), 8.02(s,1H), 5.94(td,1H), 3.39-3.48(m,1H), 2.55-2.60(m,1H) ,2.40-2.48(m,2H),2.27-2.37(m,2H),1.99-2.12(m,2H),1.83-1.89(m,1H),1.42-1.47(m,1H),1.33-1.38( m,1H).
LC-MS,M/Z(ESI):359.1[M+H] +。 LC-MS, M/Z (ESI): 359.1 [M+H] + .
实施例8：目标化合物8的制备Example 8: Preparation of target compound 8
5-(6-(环丙基乙炔基)-5-((1S,2S)-2-(氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物8)5-(6-(Cyclopropylethynyl)-5-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H) -diketone (target compound 8)
Figure PCTCN2021128905-appb-000086
Figure PCTCN2021128905-appb-000086
目标化合物8的合成路线如下所示：The synthetic route of target compound 8 is as follows:
Figure PCTCN2021128905-appb-000087
Figure PCTCN2021128905-appb-000087
第一步：3-(环丙基乙炔基)-6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2S)-2-(氟甲基)环丙基)哒嗪(8B)的合成The first step: 3-(cyclopropylethynyl)-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropane Synthesis of pyridazine (8B)
Figure PCTCN2021128905-appb-000088
Figure PCTCN2021128905-appb-000088
在氮气的保护下，将3-氯-6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2S)-2-(氟甲基)环丙基)哒嗪(120.0mg,369.5μmol)和乙炔基环丙烷(24.4mg,369.5μmol)溶在N,N二甲基甲酰胺(5.00mL)，在向里面加碘化亚铜(7.04mg,36.9μmol)，三乙胺(149.6mg,1.48mmol)和双(三苯基膦)二氯化钯(25.9mg,36.9μmol)，然后80℃反应2小时。反应完毕后，将反应液加入到水(10mL)中，在用乙酸乙酯(20mL×2)萃取，有机相用饱和食盐水(50mL)洗涤两次，之后有机相用无水硫酸钠干燥，有机相浓缩得到黄色油状物3-(环丙基乙炔基)-6-(2,4-二甲氧基嘧啶-5-基)-4-((1S，2S)-2-(氟甲基)环丙基)哒嗪(8B)(90.0mg,产率39.2％)。Under the protection of nitrogen, 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridine Zine (120.0 mg, 369.5 μmol) and ethynylcyclopropane (24.4 mg, 369.5 μmol) were dissolved in N,N dimethylformamide (5.00 mL), to which was added cuprous iodide (7.04 mg, 36.9 μmol) , triethylamine (149.6 mg, 1.48 mmol) and bis(triphenylphosphine) palladium dichloride (25.9 mg, 36.9 μmol), and then reacted at 80° C. for 2 hours. After the reaction was completed, the reaction solution was added to water (10 mL), extracted with ethyl acetate (20 mL×2), the organic phase was washed twice with saturated brine (50 mL), and then the organic phase was dried with anhydrous sodium sulfate, The organic phase was concentrated to give 3-(cyclopropylethynyl)-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl) as a yellow oil )cyclopropyl)pyridazine (8B) (90.0 mg, 39.2% yield).
LC-MS,M/Z(ESI):355.2[M+H] +。 LC-MS, M/Z (ESI): 355.2 [M+H] + .
第二步：5-(6-(环丙基乙炔基)-5-((1S,2S)-2-(氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物8)的合成Step 2: 5-(6-(Cyclopropylethynyl)-5-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4( Synthesis of 1H,3H)-dione (target compound 8)
Figure PCTCN2021128905-appb-000089
Figure PCTCN2021128905-appb-000089
将3-(环丙基乙炔基)-6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2S)-2-(氟甲基)环丙基)哒嗪(90.0mg,253.9μmol)溶在盐酸(1M,2.54mL)里，然后50℃反应12小时。反应完成后，直接将反应冻干，得到粗产品，将粗品通过反相高效液相色谱法进行分离，分离方法为(色谱柱：3_Phenomenex Luna C18 75×30mm×3μm；流动相：A＝水+0.05体积％HCl(36.5％)，B＝乙腈；梯度：21％-41％B，7分钟)，得到黄色固体5-(6-(环丙基乙炔基)-5-((1S,2S)-2-(氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(8)(21.4mg,产率23.9％)。3-(Cyclopropylethynyl)-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridin Zine (90.0 mg, 253.9 μmol) was dissolved in hydrochloric acid (1 M, 2.54 mL), and then reacted at 50° C. for 12 hours. After the reaction is completed, the reaction is directly lyophilized to obtain a crude product, and the crude product is separated by reversed-phase high performance liquid chromatography, and the separation method is (chromatographic column: 3_Phenomenex Luna C18 75 × 30mm × 3 μm; mobile phase: A=water+ 0.05 vol% HCl (36.5%), B=acetonitrile; gradient: 21%-41% B, 7 min) to give 5-(6-(cyclopropylethynyl)-5-((1S,2S) as a yellow solid -2-(Fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (8) (21.4 mg, 23.9% yield).
1H NMR(400MHz,CDCl 3)δ8.61(s,1H),8.17(s,1H),4.32-4.86(m,2H),2.43-2.46(m,1H),1.73-1.89(m,1H),1.70-1.72(m,1H),1.09-1.12(m,2H),0.99-1.02(m,2H),0.98-0.99(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 8.61(s,1H), 8.17(s,1H), 4.32-4.86(m,2H), 2.43-2.46(m,1H), 1.73-1.89(m,1H) ),1.70-1.72(m,1H),1.09-1.12(m,2H),0.99-1.02(m,2H),0.98-0.99(m,2H).
LC-MS,M/Z(ESI):327.3[M+H] +。 LC-MS, M/Z (ESI): 327.3 [M+H] + .
实施例9：目标化合物9的制备Example 9: Preparation of target compound 9
5-(6-(环丙基乙炔基)-5-((1R,2R)-2-(二氟甲基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物9)5-(6-(Cyclopropylethynyl)-5-((1R,2R)-2-(difluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H )-dione (target compound 9)
Figure PCTCN2021128905-appb-000090
Figure PCTCN2021128905-appb-000090
目标化合物9的合成路线如下所示：The synthetic route of target compound 9 is shown below:
Figure PCTCN2021128905-appb-000091
Figure PCTCN2021128905-appb-000091
第一步：3-(2-环丙基乙炔基)-4-[(1R,2R)-2-(二氟甲基)环丙基]-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(9A)的合成The first step: 3-(2-cyclopropylethynyl)-4-[(1R,2R)-2-(difluoromethyl)cyclopropyl]-6-(2,4-dimethoxypyrimidine Synthesis of -5-yl)pyridazine (9A)
Figure PCTCN2021128905-appb-000092
Figure PCTCN2021128905-appb-000092
将3-氯-4-[(1R,2R)-2-(二氟甲基)环丙基]-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(250mg,729μmol)和乙炔基环丙烷(120mg,1.82mmol)溶在N,N二甲基乙酰胺(4.00mL)中，然后将二氯双(三苯基膦)钯(II)(102mg,145μmol)，碘化亚铜(27.7mg,145μmol)和三乙胺(295mg,2.92mmol)加入到反应液，在氮气保护下80℃反应2小时。反应完毕后，将反应液倒入水(5mL)中，用乙酸乙酯(20mL×2)萃取，食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩，然后用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-1:1)得到黄色油状化合物3-(2-环丙基乙炔基)-4-[(1R,2R)-2-(二氟甲基)环丙基]-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(9A)(260mg,粗品)。3-Chloro-4-[(1R,2R)-2-(difluoromethyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (250 mg, 729 μmol ) and ethynylcyclopropane (120 mg, 1.82 mmol) were dissolved in N,N dimethylacetamide (4.00 mL), then dichlorobis(triphenylphosphine)palladium(II) (102 mg, 145 μmol), iodine Cuprous compound (27.7 mg, 145 μmol) and triethylamine (295 mg, 2.92 mmol) were added to the reaction solution, and the reaction was carried out at 80° C. for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (5 mL), extracted with ethyl acetate (20 mL×2), washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and then separated with a silica gel column Purification (petroleum ether:ethyl acetate (V/V)=10:1-1:1) gave the compound 3-(2-cyclopropylethynyl)-4-[(1R,2R)-2-( as yellow oil Difluoromethyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)pyridazine (9A) (260 mg, crude).
LC-MS,M/Z(ESI):373.2[M+H] +。 LC-MS, M/Z (ESI): 373.2 [M+H] + .
第二步：5-[6-(2-环丙基乙炔基)-5-[(1R,2R)-2-(二氟甲基)环丙基]哒嗪-3-基]-1H-嘧啶-2,4-二酮(目标化合物9)The second step: 5-[6-(2-cyclopropylethynyl)-5-[(1R,2R)-2-(difluoromethyl)cyclopropyl]pyridazin-3-yl]-1H- Pyrimidine-2,4-dione (target compound 9)
Figure PCTCN2021128905-appb-000093
Figure PCTCN2021128905-appb-000093
将3-(2-环丙基乙炔基)-4-[(1R,2R)-2-(二氟甲基)环丙基]-6-(2,4-二甲氧基嘧啶-5-基)哒嗪(260mg,451μmol)溶在1M盐酸水溶液中(3mL)，在50℃反应12小时。反应完毕后，将反应液浓缩得到产品，通过高效液相色谱法进行分离，分离方法为(色谱柱：Phenomenex luna C18 150×40mm×15μm；流动相：A＝水+0.05％体积盐酸(36.5％)，B＝乙腈；梯度：25％-45％，6.5分钟)，得到黄色固体化合物5-[6-(2-环丙基乙炔基)-5-[(1R,2R)-2-(二氟甲基)环丙基]哒嗪-3-基]-1H-嘧啶-2,4-二酮(9)(41.0mg,产率17.2％)。3-(2-Cyclopropylethynyl)-4-[(1R,2R)-2-(difluoromethyl)cyclopropyl]-6-(2,4-dimethoxypyrimidine-5- base) pyridazine (260 mg, 451 μmol) was dissolved in 1 M aqueous hydrochloric acid (3 mL) and reacted at 50° C. for 12 hours. After the completion of the reaction, the reaction solution was concentrated to obtain the product, which was separated by high performance liquid chromatography, and the separation method was (chromatographic column: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: A=water+0.05% volume hydrochloric acid (36.5% ), B=acetonitrile; gradient: 25%-45%, 6.5 minutes) to give yellow solid compound 5-[6-(2-cyclopropylethynyl)-5-[(1R,2R)-2-(di Fluoromethyl)cyclopropyl]pyridazin-3-yl]-1H-pyrimidine-2,4-dione (9) (41.0 mg, 17.2% yield).
1H NMR(400MHz,DMSO_d 6):δ11.59-11.61(m,1H),11.53(s,1H),8.33-8.35(m,1H),7.88(s,1H),5.89-6.19(m,1H),2.42-2.44(m,1H),1.81-1.85(m,1H),1.69-1.70(m,1H),1.39-1.40(m,1H),1.21-1.26(m,1H),0.99-1.01(m,2H),0.87-0.89(m,2H). 1 H NMR (400MHz, DMSO_d 6 ): δ11.59-11.61(m,1H), 11.53(s,1H), 8.33-8.35(m,1H), 7.88(s,1H), 5.89-6.19(m, 1H), 2.42-2.44(m, 1H), 1.81-1.85(m, 1H), 1.69-1.70(m, 1H), 1.39-1.40(m, 1H), 1.21-1.26(m, 1H), 0.99- 1.01(m,2H),0.87-0.89(m,2H).
LC-MS,M/Z(ESI):345.1[M+H] +。 LC-MS, M/Z (ESI): 345.1 [M+H] + .
实施例10：目标化合物10的制备Example 10: Preparation of target compound 10
5-[6-(2-环丙基乙炔基)-5-[(1S,2S)-2-(三氟甲基)环丙基]哒嗪-3-基]-1H-嘧啶-2,4-二酮(目标化合物10)5-[6-(2-Cyclopropylethynyl)-5-[(1S,2S)-2-(trifluoromethyl)cyclopropyl]pyridazin-3-yl]-1H-pyrimidine-2, 4-diketone (target compound 10)
Figure PCTCN2021128905-appb-000094
Figure PCTCN2021128905-appb-000094
目标化合物10的合成路线如下所示：The synthetic route of target compound 10 is as follows:
Figure PCTCN2021128905-appb-000095
Figure PCTCN2021128905-appb-000095
第一步：(1S,2S)-2-(乙氧羰基)环丙烷甲酸(10A)的合成The first step: Synthesis of (1S,2S)-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (10A)
Figure PCTCN2021128905-appb-000096
Figure PCTCN2021128905-appb-000096
把(1S,2S)-2-(羟甲基)环丙烷甲酸乙酯(5.0g，34.7mmol)溶于乙腈(50mL)中，在25℃下依次加入2,2,6,6-四甲基哌啶氧化物(436.3mg,2.8mmol)，磷酸二氢钠(6.66g,55.5mmol)，磷酸氢二钠(7.88g,55.5mmol)。然后将次氯酸钠溶液(0.5mL)和亚氯酸钠(6.27g,69.4mmol)溶解在25mL水中，0℃下缓慢滴加到反应体系中，接着25℃下搅拌12小时。将反应体系用水(100mL)稀释，然后用乙酸乙酯(100mL×2)萃取，合并有机层相，加入饱和碳酸钠水溶液(100mL)，搅拌10分钟。分离有机相，水相用6M的盐酸溶液调pH至2～3，然后用乙酸乙酯(100mL×2)萃取，合并有机层相，用饱和食盐水(100mL)洗涤有机相，无水硫酸钠干燥，浓缩得到无色油状物(1S,2S)-2-(乙氧羰基)环丙烷甲酸(10A)(4.8g,产率87.5％)。(1S,2S)-ethyl 2-(hydroxymethyl)cyclopropanecarboxylate (5.0 g, 34.7 mmol) was dissolved in acetonitrile (50 mL), followed by adding 2,2,6,6-tetramethyl at 25°C piperidine oxide (436.3 mg, 2.8 mmol), sodium dihydrogen phosphate (6.66 g, 55.5 mmol), disodium hydrogen phosphate (7.88 g, 55.5 mmol). Then sodium hypochlorite solution (0.5 mL) and sodium chlorite (6.27 g, 69.4 mmol) were dissolved in 25 mL of water and slowly added dropwise to the reaction system at 0°C, followed by stirring at 25°C for 12 hours. The reaction system was diluted with water (100 mL), then extracted with ethyl acetate (100 mL×2), the organic layers were combined, saturated aqueous sodium carbonate solution (100 mL) was added, and the mixture was stirred for 10 minutes. The organic phase was separated, the pH of the aqueous phase was adjusted to 2-3 with 6M hydrochloric acid solution, then extracted with ethyl acetate (100 mL×2), the organic layers were combined, the organic phase was washed with saturated brine (100 mL), anhydrous sodium sulfate Drying and concentration gave (1S,2S)-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (10A) (4.8 g, 87.5% yield) as a colorless oil.
1H NMR(400MHz,CDCl 3)δ10.34(br.s,1H),4.14(q,2H),2.11-2.22(m,2H),1.43-1.50(m, 2H),1.25(t,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 10.34(br.s, 1H), 4.14(q, 2H), 2.11-2.22(m, 2H), 1.43-1.50(m, 2H), 1.25(t, 3H) ).
第二步：(1S,2S)-2-(三氟甲基)环丙烷甲酸乙酯(10B)的合成Step 2: Synthesis of (1S,2S)-2-(trifluoromethyl) ethyl cyclopropanecarboxylate (10B)
Figure PCTCN2021128905-appb-000097
Figure PCTCN2021128905-appb-000097
将(1S,2S)-2-(乙氧羰基)环丙烷甲酸(3.0g,19.0mmol)加入到高压釜中，-78℃下加入四氟化硫(9.0g,83.3mmol)，然后反应体系在高压釜中升温到70℃，反应16小时。反应体系加入二氯甲烷(20mL)，用饱和碳酸氢钠水溶液(500mL)洗涤有机相，无水硫酸钠干燥，浓缩得到黄色油状物(1S,2S)-2-(三氟甲基)环丙烷甲酸乙酯(10B)(1.17g,产率33.9％)。(1S,2S)-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (3.0g, 19.0mmol) was added to the autoclave, sulfur tetrafluoride (9.0g, 83.3mmol) was added at -78°C, and then the reaction system The temperature was raised to 70°C in the autoclave, and the reaction was carried out for 16 hours. Dichloromethane (20 mL) was added to the reaction system, the organic phase was washed with saturated aqueous sodium bicarbonate solution (500 mL), dried over anhydrous sodium sulfate, and concentrated to obtain (1S,2S)-2-(trifluoromethyl)cyclopropane as a yellow oil Ethyl formate (10B) (1.17 g, 33.9% yield).
1H NMR(400MHz,CDCl 3)δ4.17-4.19(m,2H),2.10-2.20(m,1H),2.00-2.05(m,1H),1.20-1.40(m,5H). 1 H NMR (400 MHz, CDCl 3 ) δ 4.17-4.19 (m, 2H), 2.10-2.20 (m, 1H), 2.00-2.05 (m, 1H), 1.20-1.40 (m, 5H).
第三步：(1S,2S)-2-(三氟甲基)环丙烷甲酸(10C)的合成The third step: Synthesis of (1S,2S)-2-(trifluoromethyl)cyclopropanecarboxylic acid (10C)
Figure PCTCN2021128905-appb-000098
Figure PCTCN2021128905-appb-000098
把(1S,2S)-2-(三氟甲基)环丙烷甲酸乙酯(1.1g,6.0mmol)溶于四氢呋喃(10mL)和水(5mL)中，然后加入一水合氢氧化锂(634mg,15.1mmol)，在80℃下反应6小时。反应完成后，加入水(20mL)，用二氯甲烷(30mL×2)萃取，收集水相，水相用6M盐酸调pH＝3，然后用二氯甲烷(30mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到棕色油状物(1S,2S)-2-(三氟甲基)环丙烷甲酸(10C)(500mg,产率53.7％)。Ethyl (1S,2S)-2-(trifluoromethyl)cyclopropanecarboxylate (1.1 g, 6.0 mmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL), followed by the addition of lithium hydroxide monohydrate (634 mg, 15.1 mmol), reacted at 80 °C for 6 hours. After the completion of the reaction, add water (20 mL), extract with dichloromethane (30 mL×2), collect the aqueous phase, adjust pH=3 with 6M hydrochloric acid, and then extract with dichloromethane (30 mL×3), and combine the organic phases , washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown oil (1S,2S)-2-(trifluoromethyl)cyclopropanecarboxylic acid (10C) (500 mg, yield 53.7%) ).
1H NMR(400MHz,CDCl 3)δ9.80(br.s,1H),2.20-2.23(m,1H),2.04-2.06(m,1H),1.27-1.44(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.80 (br.s, 1H), 2.20-2.23 (m, 1H), 2.04-2.06 (m, 1H), 1.27-1.44 (m, 2H).
第四步：3,6-二氯-4-((1S,2S)-2-(三氟甲基)环丙基)哒嗪(10D)的合成The fourth step: the synthesis of 3,6-dichloro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (10D)
Figure PCTCN2021128905-appb-000099
Figure PCTCN2021128905-appb-000099
将3,6-二氯哒嗪(450mg,3.02mmol)和(1S,2S)-2-(三氟甲基)环丙烷甲酸(465mg，3.02mmol)溶解在水(15mL)中，然后加入浓硫酸(0.5mL)，在氮气保护下升温到70℃。然后快速加入硝酸银的水溶液(257mg,1.51mmol,1.5mL)，然后再缓慢滴加过硫酸铵的水溶液(2.07g,9.06mmol,5mL)，70℃继续反应1小时。反应液用氨水调pH至9左右，然后用乙酸乙酯(40mL×2)萃取，合并有机层，用饱和食盐水(50mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。然后通过反相高效液相色谱法进行分离，分离方法为(色谱柱：Phenomenex luna C18 150×40mm×15μm；流动相：A＝水+0.1体积％TFA，B＝乙腈；梯度：35％-65％B，10分钟)，得到黄色油状物3,6-二氯-4-((1S,2S)-2-(三氟甲基)环丙基)哒嗪(10D)(350mg,产率43.8％)。3,6-Dichloropyridazine (450 mg, 3.02 mmol) and (1S,2S)-2-(trifluoromethyl)cyclopropanecarboxylic acid (465 mg, 3.02 mmol) were dissolved in water (15 mL) and concentrated Sulfuric acid (0.5 mL), warmed to 70°C under nitrogen protection. Then an aqueous solution of silver nitrate (257 mg, 1.51 mmol, 1.5 mL) was added rapidly, and then an aqueous solution of ammonium persulfate (2.07 g, 9.06 mmol, 5 mL) was slowly added dropwise, and the reaction was continued at 70° C. for 1 hour. The pH of the reaction solution was adjusted to about 9 with ammonia water, and then extracted with ethyl acetate (40 mL×2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Then it was separated by reversed-phase high performance liquid chromatography, and the separation method was (chromatographic column: Phenomenex luna C18 150×40mm×15μm; mobile phase: A=water+0.1 vol% TFA, B=acetonitrile; gradient: 35%-65 %B, 10 min) to give 3,6-dichloro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (10D) (350 mg, 43.8 yield) as a yellow oil %).
LC-MS,M/Z(ESI):256.9[M+H] +。 LC-MS, M/Z (ESI): 256.9 [M+H] + .
第五步：3-氯-6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2S)-2-(三氟甲基)环丙基)哒嗪(10E)的合成The fifth step: 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine ( 10E) Synthesis
Figure PCTCN2021128905-appb-000100
Figure PCTCN2021128905-appb-000100
将3,6-二氯-4-((1S,2S)-2-(三氟甲基)环丙基)哒嗪(350mg,1.32mmol)和2,4-二甲氧基嘧啶 -5-硼酸(343mg,1.32mmol)溶解在二氧六环(5mL)和水(1mL)中，在氮气保护下加入碳酸钠(420mg，3.96mmol)和[1,1-双(二苯基膦基)二茂铁]二氯化钯(97mg,132μmol)，升温至50℃反应12小时。将反应混合物用水(20mL)稀释，然后用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和食盐水(50mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1-3:1，梯度洗脱)得黄色油状物3-氯-6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2S)-2-(三氟甲基)环丙基)哒嗪(10E)(300mg,产率44％)。3,6-Dichloro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (350 mg, 1.32 mmol) and 2,4-dimethoxypyrimidine-5- Boronic acid (343 mg, 1.32 mmol) was dissolved in dioxane (5 mL) and water (1 mL), and sodium carbonate (420 mg, 3.96 mmol) and [1,1-bis(diphenylphosphino) were added under nitrogen protection Ferrocene] palladium dichloride (97 mg, 132 μmol), the temperature was raised to 50° C. to react for 12 hours. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-3:1, gradient elution) to obtain 3-chloro-6-(2,4-dimethoxypyrimidine as a yellow oil) -5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (10E) (300 mg, 44% yield).
LC-MS,M/Z(ESI):361.0[M+H] +。 LC-MS, M/Z (ESI): 361.0 [M+H] + .
第六步：3-(2-环丙基乙炔基)-6-(2,4-二甲氧基嘧啶-5-基)-4-[(1S,2S)-2-(三氟甲基)环丙基]哒嗪(10F)的合成The sixth step: 3-(2-cyclopropylethynyl)-6-(2,4-dimethoxypyrimidin-5-yl)-4-[(1S,2S)-2-(trifluoromethyl) ) Cyclopropyl] Pyridazine (10F) Synthesis
Figure PCTCN2021128905-appb-000101
Figure PCTCN2021128905-appb-000101
将3-氯-6-(2,4-二甲氧基嘧啶-5-基)-4-[(1S,2S)-2-(三氟甲基)环丙基]哒嗪(500mg,1.39mmol)和乙炔基环丙烷(229mg,3.47mmol)溶在N，N二甲基乙酰胺(5.00mL)中，然后将二氯双(三苯基膦)钯(II)(194mg,277umol),碘化亚铜(52.8mg,277μmol)和三乙胺(561mg,5.54mmol)加入到反应液，在氮气保护下80℃反应2小时。反应完毕后，将反应液倒入水(10mL)中，用乙酸乙酯(20mL×2)萃取，食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩，然后用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-1:1)得到黄色油状化合物3-(2-环丙基乙炔基)-6-(2,4-二甲氧基嘧啶-5-基)-4-[(1S,2S)-2-(三氟甲基)环丙基]哒嗪(10F)(503mg,粗品)。3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-[(1S,2S)-2-(trifluoromethyl)cyclopropyl]pyridazine (500 mg, 1.39 mmol) and ethynylcyclopropane (229 mg, 3.47 mmol) were dissolved in N,N dimethylacetamide (5.00 mL), then dichlorobis(triphenylphosphine)palladium(II) (194 mg, 277 umol), Cuprous iodide (52.8 mg, 277 μmol) and triethylamine (561 mg, 5.54 mmol) were added to the reaction solution, and the reaction was carried out at 80° C. for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL×2), washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and then separated with a silica gel column Purification (petroleum ether:ethyl acetate (V/V)=10:1-1:1) gave 3-(2-cyclopropylethynyl)-6-(2,4-dimethoxypyrimidine) as a yellow oily compound -5-yl)-4-[(1S,2S)-2-(trifluoromethyl)cyclopropyl]pyridazine (10F) (503 mg, crude).
LC-MS,M/Z(ESI):391.1[M+H] +。 LC-MS, M/Z (ESI): 391.1 [M+H] + .
第七步：5-[6-(2-环丙基乙炔基)-5-[(1S,2S)-2-(三氟甲基)环丙基]哒嗪-3-基]-1H-嘧啶-2,4-二酮(目标化合物10)Step 7: 5-[6-(2-Cyclopropylethynyl)-5-[(1S,2S)-2-(trifluoromethyl)cyclopropyl]pyridazin-3-yl]-1H- Pyrimidine-2,4-dione (target compound 10)
Figure PCTCN2021128905-appb-000102
Figure PCTCN2021128905-appb-000102
将3-(2-环丙基乙炔基)-6-(2,4-二甲氧基嘧啶-5-基)-4-[(1S,2S)-2-(三氟甲基)环丙基]哒嗪(503mg,503μmol)溶在1M的硫酸水溶液中(5mL)，在50℃反应12小时。反应完毕后，将反应液浓缩得到产品，然后通过高效液相色谱法进行分离，分离方法为(色谱柱：Phenomenex luna C18 150×40mm×15μm；流动相：A＝水+0.05％体积盐酸(36.5％)，B＝乙腈；梯度：30％-50％，12分钟)，得到黄色固体化合物5-[6-(2-环丙基乙炔基)-5-[(1S,2S)-2-(三氟甲基)环丙基]哒嗪-3-基]-1H-嘧啶-2,4-二酮(10)(29.0mg,产率15.2％)。3-(2-Cyclopropylethynyl)-6-(2,4-dimethoxypyrimidin-5-yl)-4-[(1S,2S)-2-(trifluoromethyl)cyclopropane yl]pyridazine (503 mg, 503 μmol) was dissolved in a 1 M aqueous sulfuric acid solution (5 mL) and reacted at 50° C. for 12 hours. After completion of the reaction, the reaction solution was concentrated to obtain the product, which was then separated by high performance liquid chromatography, and the separation method was (chromatographic column: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: A=water+0.05% volume hydrochloric acid (36.5 %), B=acetonitrile; gradient: 30%-50%, 12 min) to give yellow solid compound 5-[6-(2-cyclopropylethynyl)-5-[(1S,2S)-2-( Trifluoromethyl)cyclopropyl]pyridazin-3-yl]-1H-pyrimidine-2,4-dione (10) (29.0 mg, 15.2% yield).
1H NMR(400MHz,DMSO_d 6):δ8.38(s,1H),7.96(s,1H),2.70-2.72(m,1H),2.32-2.34(m,1H),1.66-1.70(m,1H),1.49-1.51(m,2H),1.00-1.03(m,2H),0.82-0.84(m,2H). 1 H NMR (400MHz, DMSO_d 6 ): δ8.38(s, 1H), 7.96(s, 1H), 2.70-2.72(m, 1H), 2.32-2.34(m, 1H), 1.66-1.70(m, 1H), 1.49-1.51(m, 2H), 1.00-1.03(m, 2H), 0.82-0.84(m, 2H).
LC-MS,M/Z(ESI):363.1[M+H] +。 LC-MS, M/Z (ESI): 363.1 [M+H] + .
实施例11：目标化合物11的制备Example 11: Preparation of target compound 11
5-(5-((1S,2R)-2-异丙基环丙基)-6-(丙-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(目标化合物11)5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-(prop-1-yn-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H, 3H)-dione (target compound 11)
Figure PCTCN2021128905-appb-000103
Figure PCTCN2021128905-appb-000103
目标化合物11的合成路线如下所示：The synthetic route of target compound 11 is as follows:
Figure PCTCN2021128905-appb-000104
Figure PCTCN2021128905-appb-000104
第一步：(S)-2-氯-3-甲基丁烷-1-醇(11B)的合成The first step: Synthesis of (S)-2-chloro-3-methylbutan-1-ol (11B)
Figure PCTCN2021128905-appb-000105
Figure PCTCN2021128905-appb-000105
把(S)-2-氯-3-甲基丁酸(30.0g,0.22mmol)溶于四氢呋喃(300mL)中，在0-10℃下把四氢铝锂(9.17g,0.24mmol)缓慢加入，加完后在25℃下搅拌1小时，然后升温至50℃反应1小时。反应完成后，把反应液降温到0-10℃，依次加入水(9mL)，15％氢氧化钠水溶液(9mL)和水(27mL)。然后用硅藻土过滤，滤饼用四氢呋喃洗涤(100mL×3)，滤液浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-2:1)得黄色油状物(S)-2-氯-3-甲基丁烷-1-醇(11B)(8.4g,产率31％)。(S)-2-Chloro-3-methylbutanoic acid (30.0 g, 0.22 mmol) was dissolved in tetrahydrofuran (300 mL), and lithium tetrahydroaluminum (9.17 g, 0.24 mmol) was slowly added at 0-10 °C After the addition, the mixture was stirred at 25°C for 1 hour, and then heated to 50°C for 1 hour. After the reaction was completed, the reaction solution was cooled to 0-10° C., and water (9 mL), 15% aqueous sodium hydroxide solution (9 mL) and water (27 mL) were added successively. Then it was filtered through celite, the filter cake was washed with tetrahydrofuran (100 mL×3), and the filtrate was concentrated to obtain the crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-2:1) to obtain (S)-2-chloro-3-methylbutan-1-ol (11B) as a yellow oil ) (8.4 g, 31% yield).
1H NMR(400MHz,CDCl 3)δ3.91-3.94(m,1H),3.74-3.82(m,2H),2.06-2.09(m,1H),1.99-2.05(m,1H),1.04(dd,6H). 1 H NMR (400MHz, CDCl 3 ) δ 3.91-3.94 (m, 1H), 3.74-3.82 (m, 2H), 2.06-2.09 (m, 1H), 1.99-2.05 (m, 1H), 1.04 (dd ,6H).
第二步：(R)-2-异丙基环氧乙烷(11C)的合成The second step: the synthesis of (R)-2-isopropyl oxirane (11C)
Figure PCTCN2021128905-appb-000106
Figure PCTCN2021128905-appb-000106
把氢氧化钾(52.1g,0.93mol)溶于水(50mL)中，降温到0-5℃，然后将(S)-2-氯-3-甲基丁烷-1-醇(25.0g,0.20mol)滴加进去，然后在25℃反应1小时。反应完成后，把反应液在25℃下进行蒸馏，馏分用干冰乙醇浴冷却收集，得到黄色油状物(R)-2-异丙基环氧乙烷(11C)(16.0 g,产率91.1％)。Potassium hydroxide (52.1g, 0.93mol) was dissolved in water (50mL), cooled to 0-5°C, then (S)-2-chloro-3-methylbutan-1-ol (25.0g, 0.20 mol) was added dropwise, and then reacted at 25°C for 1 hour. After the reaction was completed, the reaction solution was distilled at 25°C, and the fractions were collected by cooling with a dry ice ethanol bath to obtain a yellow oil (R)-2-isopropyloxirane (11C) (16.0 g, yield 91.1%) ).
1H NMR(400MHz,CDCl 3)δ2.71-2.74(m,2H),2.52-2.54(m,1H),1.47-1.53(m,1H),1.04(d,3H),0.97(d,3H). 1 H NMR (400MHz, CDCl 3 ) δ 2.71-2.74(m, 2H), 2.52-2.54(m, 1H), 1.47-1.53(m, 1H), 1.04(d, 3H), 0.97(d, 3H) ).
第三步：(1S,2R)-2-异丙基环丙烷-1-羧酸乙酯(11D)的合成The third step: Synthesis of (1S,2R)-2-isopropylcyclopropane-1-carboxylic acid ethyl ester (11D)
Figure PCTCN2021128905-appb-000107
Figure PCTCN2021128905-appb-000107
把磷酰基乙酸三乙酯(14.3g,63.8mmol)溶于1,4-二氧六环(20mL)中，然后在0℃下滴加正丁基锂(2.5M,30.2mL)，滴加完成后，反应液在25℃下搅拌0.5小时，然后把反应液转移到闷罐中，然后再加入(R)-2-异丙基环氧乙烷(5.00g，58.1mmol)的1,4-二氧六环溶液(10mL)。把闷罐拧紧，升温至145℃反应12小时。反应完成后，把反应体系降温，然后加水(100mL)，用甲基叔丁基醚(100mL×2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩得黄色油状物(1S,2R)-2-异丙基环丙烷-1-羧酸乙酯(11D)(7.0g,产率80.8％)。Triethyl phosphoryl acetate (14.3 g, 63.8 mmol) was dissolved in 1,4-dioxane (20 mL), then n-butyllithium (2.5 M, 30.2 mL) was added dropwise at 0 °C, After completion, the reaction solution was stirred at 25°C for 0.5 hours, then the reaction solution was transferred to a stuffy tank, and then (R)-2-isopropyloxirane (5.00 g, 58.1 mmol) in 1,4 was added. - Dioxane solution (10 mL). Tighten the stuffy jar, heat it up to 145°C and react for 12 hours. After the completion of the reaction, the reaction system was cooled, then water (100 mL) was added, extracted with methyl tert-butyl ether (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oil (1S, 2R) -2-Isopropylcyclopropane-1-carboxylic acid ethyl ester (11D) (7.0 g, 80.8% yield).
1H NMR(400MHz,CDCl 3)δ4.09-4.13(m,2H),1.36-1.39(m,1H),1.19-1.27(m,5H),1.09-1.13(m,1H),0.96-0.99(m,6H),0.69-0.75(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ 4.09-4.13 (m, 2H), 1.36-1.39 (m, 1H), 1.19-1.27 (m, 5H), 1.09-1.13 (m, 1H), 0.96-0.99 (m,6H),0.69-0.75(m,1H).
第四步：(1S,2R)-2-异丙基环丙烷-1-羧酸(11E)的合成Step 4: Synthesis of (1S,2R)-2-isopropylcyclopropane-1-carboxylic acid (11E)
Figure PCTCN2021128905-appb-000108
Figure PCTCN2021128905-appb-000108
把(1S,2R)-2-异丙基环丙烷-1-羧酸乙酯(7.00g,44.8mmol)溶于1，4-二氧六环(60mL)和水(60mL)中，然后加入氢氧化钠(17.9g,448.1mmol)，在100℃下反应7小时。反应完成后，用甲基叔丁基醚(100mL×2)萃取，收集水相，把水相用浓盐酸调pH＝1-2，然后用甲基叔丁基醚(100mL×2)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色油状物(1S,2R)-2-异丙基环丙烷-1-羧酸(11E)(6.40g，粗品)，直接用于下一步。(1S,2R)-ethyl 2-isopropylcyclopropane-1-carboxylate (7.00 g, 44.8 mmol) was dissolved in 1,4-dioxane (60 mL) and water (60 mL), then added Sodium hydroxide (17.9 g, 448.1 mmol) was reacted at 100° C. for 7 hours. After the reaction was completed, extract with methyl tert-butyl ether (100 mL×2), collect the aqueous phase, adjust the pH of the aqueous phase to 1-2 with concentrated hydrochloric acid, and then extract with methyl tert-butyl ether (100 mL×2), The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (1S,2R)-2-isopropylcyclopropane-1-carboxylic acid (11E) (6.40 g) as a yellow oil. , crude product), used directly in the next step.
1H NMR(400MHz,CDCl 3)δ1.56-1.60(m,1H),1.45-1.50(m,1H),1.37-1.40(m,1H),1.21-1.27(m,1H),1.60-1.85(m,6H),0.97-1.02(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ 1.56-1.60 (m, 1H), 1.45-1.50 (m, 1H), 1.37-1.40 (m, 1H), 1.21-1.27 (m, 1H), 1.60-1.85 (m,6H),0.97-1.02(m,1H).
第五步：3,6-二氯-4-((1S,2R)-2-异丙基环丙基)哒嗪(11F)的合成The fifth step: the synthesis of 3,6-dichloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (11F)
Figure PCTCN2021128905-appb-000109
Figure PCTCN2021128905-appb-000109
将3,6-二氯哒嗪(6.27g,42.1mmol)和(1S,2S)-2-(二氟甲基)环丙烷-1-羧酸(5.39g,42.1mmol)溶解在水(100mL)中，然后加入浓硫酸(5.39mL)，在氮气保护下升温到70℃。然后快速加入硝酸银的水溶液(3.57g,21.0mmol,25mL)，然后再缓慢滴加过硫酸铵的水溶液(28.8g,126.2mmol,50mL)，70℃继续反应1小时。反应完成后，反应液用氨水调pH至9左右，然后用乙酸乙酯(200mL×2)萃取，合并有机层，用饱和食盐水(100mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-3:1)得黄色油状物3,6-二氯-4-((1S,2R)-2-异丙基环丙基)哒嗪(11F)(3.20g,产率32.9％)。3,6-Dichloropyridazine (6.27 g, 42.1 mmol) and (1S,2S)-2-(difluoromethyl)cyclopropane-1-carboxylic acid (5.39 g, 42.1 mmol) were dissolved in water (100 mL) ), then concentrated sulfuric acid (5.39 mL) was added, and the temperature was raised to 70°C under nitrogen protection. Then an aqueous solution of silver nitrate (3.57 g, 21.0 mmol, 25 mL) was added rapidly, and then an aqueous solution of ammonium persulfate (28.8 g, 126.2 mmol, 50 mL) was slowly added dropwise, and the reaction was continued at 70° C. for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to about 9 with aqueous ammonia, then extracted with ethyl acetate (200 mL×2), the organic layers were combined, the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product . Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-3:1) to obtain 3,6-dichloro-4-((1S,2R)-2-isopropyl as a yellow oil cyclopropyl)pyridazine (11F) (3.20 g, 32.9% yield).
LC-MS,M/Z(ESI):231.0[M+H] +。 LC-MS, M/Z (ESI): 231.0 [M+H] + .
第六步：3-氯-6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2R)-2-异丙基环丙基)哒嗪(11G)的合成The sixth step: 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (11G) synthesis
Figure PCTCN2021128905-appb-000110
Figure PCTCN2021128905-appb-000110
将3,6-二氯-4-((1S,2R)-2-异丙基环丙基)哒嗪(2.10g,9.09mmol)和2,4-二甲氧基嘧啶-5-硼酸(1.67g,9.09mmol)溶解在1,4-二氧六环(10mL)和水(3mL)中，在氮气保护下加入碳酸钠(2.89g,27.3mmol)和[1,1-双(二苯基膦基)二茂铁]二氯化钯(664.8mg,0.91mmol)，升温至100℃反应2小时。将反应混合物用水(100mL)稀释，然后用乙酸乙酯(150mL×2)萃取，合并有机相，用饱和食盐水(100mL)洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-2:1)得黄色油状物3-氯-6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2R)-2-异丙基环丙基)哒嗪(11G)(2.00g,产率65.7％)。3,6-Dichloro-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (2.10 g, 9.09 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid ( 1.67g, 9.09mmol) was dissolved in 1,4-dioxane (10mL) and water (3mL), sodium carbonate (2.89g, 27.3mmol) and [1,1-bis(diphenylene) were added under nitrogen protection phosphino) ferrocene] palladium dichloride (664.8 mg, 0.91 mmol), the temperature was raised to 100° C. to react for 2 hours. The reaction mixture was diluted with water (100 mL), then extracted with ethyl acetate (150 mL×2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Separation and purification with silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-2:1) to obtain 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl) as a yellow oil )-4-((1S,2R)-2-isopropylcyclopropyl)pyridazine (11G) (2.00 g, 65.7% yield).
LC-MS,M/Z(ESI):335.1[M+H] +。 LC-MS, M/Z (ESI): 335.1 [M+H] + .
第七步：6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2R)-2-异丙基环丙基)-3-(丙-1-炔-1-基)哒嗪(11H)的合成Step 7: 6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-3-(prop-1-yn- Synthesis of 1-yl)pyridazine(11H)
Figure PCTCN2021128905-appb-000111
Figure PCTCN2021128905-appb-000111
将3-氯-6-(2,4-二甲氧基嘧啶-5-基)-4-[(1S,2R)-2-异丙基环丙基]哒嗪(1.10g,3.29mmol)，二氯双(三苯基膦)钯(II)(230mg,328μmol)和三丁基(丙-1-炔基)锡烷(1.30g,3.94mmol)溶在N,N二甲基甲酰胺(10mL)中，然后在氮气保护下110℃反应2小时。反应完毕后，将反应液倒入水(20mL)中，再用乙酸乙酯(50mL×2)萃取，有机相用食盐水(50mL)洗涤，硫酸钠干燥，将反应液浓缩通过硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-5:1)黄色油状化合物6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2R)-2-异丙基环丙基)-3-(丙-1-炔-1-基)哒嗪(11H)(1.00g,产率89.1％)。3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-[(1S,2R)-2-isopropylcyclopropyl]pyridazine (1.10 g, 3.29 mmol) , dichlorobis(triphenylphosphine)palladium(II) (230 mg, 328 μmol) and tributyl(prop-1-ynyl)stannane (1.30 g, 3.94 mmol) in N,N dimethylformamide (10 mL), and then reacted at 110 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (50 mL×2), the organic phase was washed with brine (50 mL), dried over sodium sulfate, and the reaction solution was concentrated and purified by silica gel column separation (Petroleum ether:ethyl acetate (V/V)=10:1-5:1) Yellow oily compound 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2R) -2-Isopropylcyclopropyl)-3-(prop-1-yn-1-yl)pyridazine (11H) (1.00 g, 89.1% yield).
LC-MS,M/Z(ESI):339.1[M+H] +。 LC-MS, M/Z (ESI): 339.1 [M+H] + .
第八步：5-(5-((1S,2R)-2-异丙基环丙基)-6-(丙-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(11)的合成The eighth step: 5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-(prop-1-yn-1-yl)pyridazin-3-yl)pyrimidine-2, Synthesis of 4(1H,3H)-diketone (11)
Figure PCTCN2021128905-appb-000112
Figure PCTCN2021128905-appb-000112
将6-(2,4-二甲氧基嘧啶-5-基)-4-((1S,2R)-2-异丙基环丙基)-3-(丙-1-炔-1-基)哒嗪(1.00g,2.67mmol)溶在盐酸(1M,5.00mL)里面，在50℃下反应12小时。反应完毕后，将反应液浓缩，然后通过反相高效液相色谱法进行分离，分离方法为(色谱柱：Phenomenex luna C18 150×40mm×15μm；流动相：A＝水+0.225％体积甲酸(99％)，B＝乙腈；梯度：28％-58％，10分钟)，得到黄色固体化合物5-(5-((1S,2R)-2-异丙基环丙基)-6-(丙-1-炔-1-基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮(11)(295mg,产率36.7％)。6-(2,4-Dimethoxypyrimidin-5-yl)-4-((1S,2R)-2-isopropylcyclopropyl)-3-(prop-1-yn-1-yl ) pyridazine (1.00 g, 2.67 mmol) was dissolved in hydrochloric acid (1 M, 5.00 mL) and reacted at 50° C. for 12 hours. After the completion of the reaction, the reaction solution was concentrated, and then separated by reversed-phase high performance liquid chromatography, and the separation method was (chromatographic column: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: A=water+0.225% volume formic acid (99 %), B=acetonitrile; gradient: 28%-58%, 10 min) to give yellow solid compound 5-(5-((1S,2R)-2-isopropylcyclopropyl)-6-(propane- 1-yn-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (11) (295 mg, 36.7% yield).
1H NMR(400MHz,CD 3OD):δ8.40(s,1H),7.84(s,1H),2.22(s,3H),2.14-2.17(m,1H),1.19-1.21(m,1H),1.13-1.17(m,1H),1.09-1.11(m,1H),1.08(s,3H),1.06(s,3H),1.04-1.05(m,1H). 1 H NMR (400MHz, CD 3 OD): δ8.40(s,1H), 7.84(s,1H), 2.22(s,3H), 2.14-2.17(m,1H), 1.19-1.21(m,1H) ),1.13-1.17(m,1H),1.09-1.11(m,1H),1.08(s,3H),1.06(s,3H),1.04-1.05(m,1H).
LC-MS,M/Z(ESI):311.1[M+H] +。 LC-MS, M/Z (ESI): 311.1 [M+H] + .
测试例1：化合物对重组人CD73酶体外抑制活性Test Example 1: In vitro inhibitory activity of the compound on recombinant human CD73 enzyme
试验在含25mM Tris(Biosharp；77-86-1)、25mM MgCl 2(南京化学试剂有限公司；7791-18-6)的Tris-MgCl 2buffer中进行。用Tris-MgCl 2buffer将Human-CD73(Novoprotein；C446)配制为3×母液，按20μL/孔加入到96孔白板中，使终浓度为0.1μg/mL；用Tris-MgCl 2buffer将化合物终浓度稀释为合适的浓度梯度的3×母液，将化合物按照20μL/孔加入到上述的96孔测试白板中，混匀后，常温孵育30min，同时设定阳性对照组(不加化合物)和阴性对照组(不加CD73)；用Tris-MgCl 2buffer将AMP(Sigma；A1752-5G)配制为3×母液，按照20μL/孔加入到上述的96孔白板中，使终浓度为100μM，混匀，继续37℃孵育60min；ATP用Tris-MgCl 2buffer将ATP(Sigma；A7699-1G)配制为7×母液，按照10μL/孔加入到上述的96孔白板中，终浓度为100μM，混匀，继续孵育5min，用ATP-GLO试剂盒(Promega；G7573)检测。 Experiments were performed in Tris-MgCl 2 buffer containing 25 mM Tris (Biosharp; 77-86-1), 25 mM MgCl 2 (Nanjing Chemical Reagent Co., Ltd.; 7791-18-6). Human-CD73 (Novoprotein; C446) was prepared as 3× stock solution with Tris-MgCl 2 buffer, and added to 96-well white plate at 20 μL/well to make the final concentration 0.1 μg/mL; the compound was finalized with Tris-MgCl 2 buffer. The concentration was diluted to a 3× stock solution of an appropriate concentration gradient, and the compound was added to the above-mentioned 96-well test white plate according to 20 μL/well. After mixing, incubate at room temperature for 30 min. At the same time, set a positive control group (no compound) and a negative control. Group (without the addition of CD73); AMP (Sigma; A1752-5G) was prepared as a 3× stock solution with Tris-MgCl 2 buffer, and 20 μL/well was added to the above-mentioned 96-well white plate to make the final concentration 100 μM, mixed well, Continue to incubate at 37°C for 60 min; ATP (Sigma; A7699-1G) was prepared into 7× stock solution with Tris-MgCl 2 buffer, and added to the above 96-well white plate according to 10 μL/well, the final concentration was 100 μM, mix well, and continue Incubate for 5 min and detect with ATP-GLO kit (Promega; G7573).
按以下公式计算不同浓度化合物对Human-CD73抑制率，然后以化合物浓度为X轴，抑制率为Y轴，通过Prism软件计算化合物对Human-CD73抑制的IC 50值： Calculate the inhibition rate of different concentrations of compounds on Human-CD73 according to the following formula, and then take the compound concentration as the X-axis and the inhibition rate as the Y-axis, and calculate the IC50 value of the compound's inhibition of Human-CD73 by Prism software:
Figure PCTCN2021128905-appb-000113
Figure PCTCN2021128905-appb-000113
表1 测试化合物对Human-CD73酶体外抑制活性Table 1 In vitro inhibitory activity of test compounds on Human-CD73 enzyme
测试化合物test compound IC 50(nM) IC50 (nM)
对照化合物2Control compound 2 27.0327.03
11 21.6121.61
22 9.1189.118
33 4.6384.638
44 83.9483.94
55 196.2196.2
66 34.8034.80
77 33.7433.74
88 60.0360.03
99 247.6247.6
1010 11.1911.19
1111 14.7114.71
体外酶试验结果表明，本公开化合物对CD73酶具有良好的抑制作用，与对照化合物相比，部分公开化合物显示出更优异的CD73酶的抑制作用。The results of the in vitro enzyme test show that the disclosed compounds have a good inhibitory effect on CD73 enzyme. Compared with the control compounds, some of the disclosed compounds show more excellent inhibitory effect on CD73 enzyme.
测试例2：药代动力学试验Test Example 2: Pharmacokinetic Test
小鼠药代动力学试验，使用雄性ICR小鼠，20-25g，禁食过夜。取3只小鼠，口服灌胃给药(10mg/kg)。在给药前、和在给药后15、30分钟以及1、2、4、8、24小时采血；另外取3只小鼠，静脉注射给药(3mg/kg)，在给药前、和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g，2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Pharmacokinetic test in mice, using male ICR mice, 20-25 g, fasted overnight. Three mice were taken and administered by oral gavage (10 mg/kg). Blood was collected before administration, and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration; another 3 mice were taken and administered intravenously (3 mg/kg) before administration, and Blood was collected at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the volume of acetonitrile solution containing the internal standard to mix, vortex for 1 minute, centrifuge at 13,000 rpm for 10 minutes at 4°C, take the supernatant and add 3 times the volume of water to mix, take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
大鼠药代动力学试验，使用雄性SD大鼠，250-280g，禁食过夜。取3只大鼠，口服灌胃给药(10mg/kg)。在给药前、和在给药后15、30分钟以及1、2、4、8、24小时采血；另外取3只大鼠，静脉注射给药(3mg/kg)，在给药前、和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g，2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取 上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Pharmacokinetic test in rats, using male SD rats, 250-280 g, fasted overnight. Three rats were taken and administered by oral gavage (10 mg/kg). Blood was collected before administration, and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration; another 3 rats were taken and administered intravenously (3 mg/kg) before administration, and Blood was collected at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the volume of acetonitrile solution containing the internal standard to mix, vortex for 1 minute, centrifuge at 13,000 rpm for 10 minutes at 4°C, take the supernatant and add 3 times the volume of water to mix, take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
表2 小鼠药代动力学试验结果Table 2 Pharmacokinetic test results in mice
Figure PCTCN2021128905-appb-000114
Figure PCTCN2021128905-appb-000114
注：—表示未测试Note: - means not tested
小鼠药代动力学试验结果表明，本公开化合物表现出优良的药代动力学性质，与对照化合物相比，本公开化合物具有更大的暴露量，成药性好。The results of the mouse pharmacokinetic test show that the compounds of the present disclosure exhibit excellent pharmacokinetic properties. Compared with the control compounds, the compounds of the present disclosure have greater exposure and good druggability.
表3 大鼠药代动力学试验结果Table 3 Pharmacokinetic test results in rats
Figure PCTCN2021128905-appb-000115
Figure PCTCN2021128905-appb-000115
注：—表示未测试Note: - means not tested
大鼠药代动力学试验结果表明，本公开化合物表现出优良的药代动力学性质，与对照化合物相比，本公开化合物具有更大的暴露量，成药性好。The results of the rat pharmacokinetic test show that the compounds of the present disclosure exhibit excellent pharmacokinetic properties. Compared with the control compounds, the compounds of the present disclosure have greater exposure and good druggability.

Claims (22)

  1. 式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
    Figure PCTCN2021128905-appb-100001
    Figure PCTCN2021128905-appb-100001
    其中，in,
    m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    Figure PCTCN2021128905-appb-100002
    中R 1独立地选自氢、卤素、羟基、氰基、氨基、未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-；所述的被R a取代的C 1-C 6烷基、或、所述的被R a取代的C 1-C 6烷基-O-中，所述的被R a取代可以是一个或多个取代，所述的R a各自独立地为下列取代基：卤素、羟基、氰基、氨基、C 1-C 6烷基、C 1-C 6烷基-O-、-COOH、-C(＝O)NH 2；当取代基为多个时，所述的取代基相同或不同；当m不为0或1时，R 1独立地为相同或不同；
    Figure PCTCN2021128905-appb-100002
    wherein R 1 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, unsubstituted or R a substituted C 1 -C 6 alkyl, or, unsubstituted or R a substituted C 1 -C 6 alkyl base-O-; said C 1 -C 6 alkyl substituted by R a , or, said C 1 -C 6 alkyl substituted by R a -O-, said substituted by R a Can be one or more substitutions, and the R a is each independently the following substituents: halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, - COOH, -C(=O)NH 2 ; when there are multiple substituents, the substituents are the same or different; when m is not 0 or 1, R 1 is independently the same or different;
    n为0、1、2或3；n is 0, 1, 2 or 3;
    R 2选自氢、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 3-C 6环烷基、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、或、未取代或被R b取代的4-8元杂环烯基；所述的被R b取代的C 1-C 6烷基、所述的被R b取代的C 3-C 6环烷基、所述的被R b取代的5-8元芳基、所述的被R b取代的5-8元杂芳基、所述的被R b取代的4-8元杂环烷基、或、所述的被R b取代的4-8元杂环烯基中，所述的被R b取代可以是一个或多个取代，所述的R b各自独立地为下列取代基：卤素、羟基、氰基、氨基、羧基、C 3-C 6环烷基、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、或、C 1-C 6烷基-O-；当取代基为多个时，所述的取代基相同或不同； R 2 is selected from hydrogen, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 3 -C 6 cycloalkyl, unsubstituted or R b substituted 5-8 Member aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, unsubstituted or R b substituted 4-8 membered heterocycloalkyl, or, unsubstituted or R b substituted 4-8 Membered heterocycloalkenyl; said C 1 -C 6 alkyl substituted by R b , said C 3 -C 6 cycloalkyl substituted by R b , said 5-8 substituted by R b Member aryl, said 5-8 membered heteroaryl substituted by R b , said 4-8 membered heterocycloalkyl substituted by R b , or, said 4-8 member substituted by R b In the membered heterocyclic alkenyl, the substitution by R b may be one or more substitutions, and the R b is each independently the following substituents: halogen, hydroxyl, cyano, amino, carboxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens, or, C 1 -C 6 alkyl-O-; when the substituent is When multiple, the substituents are the same or different;
    所述的未取代或被R b取代的5-8元杂芳基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烷基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烯基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个。 In the described unsubstituted or 5-8-membered heteroaryl group substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
  2. 式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
    Figure PCTCN2021128905-appb-100003
    Figure PCTCN2021128905-appb-100003
    其中，in,
    m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    Figure PCTCN2021128905-appb-100004
    中R 1独立地选自氢、卤素、羟基、氰基、氨基、未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-；所述的被R a取代的C 1-C 6烷基、或、所述的被R a取代的C 1-C 6烷基-O-中，所述的取代各自独立地是指下列取代基中的一个或多个取代：卤素、羟基、氰基、氨基、C 1-C 6烷基、C 1-C 6烷基-O-、-COOH、-C(＝O)NH 2；当取代基为多个时，所述的取代基相同或不同；当m不为0或1时，R 1独立地为相同或不同；
    Figure PCTCN2021128905-appb-100004
    wherein R 1 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, unsubstituted or R a substituted C 1 -C 6 alkyl, or, unsubstituted or R a substituted C 1 -C 6 alkyl base-O-; in the C 1 -C 6 alkyl substituted by R a , or in the C 1 -C 6 alkyl substituted by R a -O-, the substitutions are each independently Refers to one or more of the following substituents: halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkyl -O-, -COOH, -C(=O) NH 2 ; when there are multiple substituents, the substituents are the same or different; when m is not 0 or 1, R 1 is independently the same or different;
    n为0、1、2或3；n is 0, 1, 2 or 3;
    R 2选自氢、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 3-C 6环烷基、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、或、未取代或被R b取代的4-8元杂环烯基；所述的被R b取代的C 1-C 6烷基、所述的被R b取代的C 3-C 6环烷基、所述的被R b取代的5-8元芳基、所述的被R b取代的5-8元杂芳基、所述的被R b取代的4-8元杂环烷基、或、所述的被R b取代的4-8元杂环烯基中，所述的取代各自独立地是指下列取代基中的一个或多个取代：卤素、羟基、氰基、氨基、C 3-C 6环烷基、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、或、C 1-C 6烷基-O-；当取代基为多个时，所述的取代基相同或不同； R 2 is selected from hydrogen, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 3 -C 6 cycloalkyl, unsubstituted or R b substituted 5-8 Member aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, unsubstituted or R b substituted 4-8 membered heterocycloalkyl, or, unsubstituted or R b substituted 4-8 Membered heterocycloalkenyl; said C 1 -C 6 alkyl substituted by R b , said C 3 -C 6 cycloalkyl substituted by R b , said 5-8 substituted by R b Member aryl, said 5-8 membered heteroaryl substituted by R b , said 4-8 membered heterocycloalkyl substituted by R b , or, said 4-8 member substituted by R b In the membered heterocycloalkenyl, the substitutions each independently refer to one or more of the following substituents: halogen, hydroxyl, cyano, amino, C 3 -C 6 cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 alkyl substituted by 1-5 same or different halogens, or, C 1 -C 6 alkyl-O-; when there are multiple substituents, the substituents are the same or different;
    所述的未取代或被R b取代的5-8元杂芳基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烷基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烯基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个。 In the described unsubstituted or 5-8-membered heteroaryl group substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
  3. 根据权利要求1或2所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula I according to claim 1 or 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that,
    当R 2为未取代或被R b取代的C 1-C 6烷基时，所述C 1-C 6烷基为C 1-C 4烷基； When R 2 is an unsubstituted or C 1 -C 6 alkyl group substituted by R b , the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group;
    和/或，当R 2为未取代或被R b取代的C 1-C 6烷基时，所述取代基R b的个数为1-3个； And/or, when R 2 is an unsubstituted or R b substituted C 1 -C 6 alkyl group, the number of the substituent R b is 1-3;
    和/或，当R 2为未取代或被R b取代的C 3-C 6环烷基，所述C 3-C 6环烷基为环丙基、环丁基、环戊基或环己基； And/or, when R 2 is an unsubstituted or R b substituted C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ;
    和/或，当R 2为未取代或被R b取代的5-8元芳基时，所述的5-8元芳基独立地为苯基或萘基； And/or, when R 2 is an unsubstituted or 5-8-membered aryl group substituted by R b , the 5-8-membered aryl group is independently phenyl or naphthyl;
    和/或，当R 2为未取代或被R b取代的5-8元杂芳基时，所述的5-8元杂芳基独立地为吡咯、吡唑、三氮唑、呋喃、噁唑、噻吩、噻唑、吡啶、吡嗪或嘧啶； And/or, when R 2 is an unsubstituted or substituted 5-8-membered heteroaryl group, the 5-8-membered heteroaryl group is independently pyrrole, pyrazole, triazole, furan, oxa azole, thiophene, thiazole, pyridine, pyrazine or pyrimidine;
    和/或，当R 2为未取代或被R b取代的4-8元杂环烷基时，所述的4-8元杂环烷基独立地为氮杂环丁烷、氧杂环丁烷、四氢吡咯烷基、四氢呋喃基、六氢吡喃或四氢-2H-硫吡喃1,1-二氧化物； And/or, when R 2 is an unsubstituted or substituted 4-8-membered heterocycloalkyl group, the 4-8-membered heterocycloalkyl group is independently azetidine, oxetane Alkane, tetrahydropyrrolidinyl, tetrahydrofuranyl, hexahydropyran or tetrahydro-2H-thiopyran 1,1-dioxide;
    和/或，当R 2为未取代或被R b取代的4-8元杂环烯基时，所述的4-8元杂环烯基独立地为二氢吡啶基、四氢吡啶基、四氢嘧啶基、吡咯啉基、咪唑啉基、吡唑啉基、二氢咪唑基、二氢吡唑基、二氢噁唑基、二氢噁二唑基、二氢噻唑基、二氢异噻唑基、二氢噻吩基、二氢吡咯基、3,4-二氢-2H-吡喃基、二氢呋喃基、二氢吡嗪基、二氢嘧啶基或氟代二氢呋喃基； And/or, when R 2 is an unsubstituted or substituted 4-8-membered heterocyclic alkenyl group, the 4-8-membered heterocyclic alkenyl group is independently dihydropyridyl, tetrahydropyridyl, tetrahydropyrimidinyl, pyrroline, imidazolinyl, pyrazolinyl, dihydroimidazolyl, dihydropyrazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, dihydroiso thiazolyl, dihydrothienyl, dihydropyrrolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, dihydropyrazinyl, dihydropyrimidinyl or fluorodihydrofuranyl;
    和/或，R b为羟基； and/or, R b is hydroxyl;
    和/或，当R b为C 1-C 6烷基时，所述C 1-C 6烷基为C 1-C 4烷基； and/or, when R b is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group;
    和/或，当R b为卤素时，所述卤素为F、Cl、Br、I。 And/or when R b is halogen, the halogen is F, Cl, Br, I.
  4. 根据权利要求1或2所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula I according to claim 1 or 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that,
    当R 2为未取代或被R b取代的C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基或异丁基； When R 2 is unsubstituted or C 1 -C 6 alkyl substituted by R b , the C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl or isopropyl Butyl;
    和/或，当R 2为未取代或被R b取代的C 1-C 6烷基时，所述取代基R b的个数为1个； And/or, when R 2 is an unsubstituted or R b substituted C 1 -C 6 alkyl group, the number of the substituent R b is 1;
    和/或，当R 2为未取代或被R b取代的C 3-C 6环烷基，所述C 3-C 6环烷基为环丙基或者环丁基； And/or, when R 2 is an unsubstituted or R b substituted C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is cyclopropyl or cyclobutyl;
    和/或，当R 2为未取代或被R b取代的5-8元芳基时，所述的5-8元芳基独立地为苯基； And/or, when R 2 is an unsubstituted or 5-8-membered aryl group substituted by R b , the 5-8-membered aryl group is independently phenyl;
    和/或，当R 2为未取代或被R b取代的5-8元杂芳基时，所述的5-8元杂芳基独立地为吡唑、呋喃、噻吩、吡啶； And/or, when R 2 is an unsubstituted or substituted 5-8-membered heteroaryl group, the 5-8-membered heteroaryl group is independently pyrazole, furan, thiophene, or pyridine;
    和/或，当R 2为未取代或被R b取代的4-8元杂环烷基时，所述的4-8元杂环烷基独立地为氮杂环丁烷或氧杂环丁烷； And/or, when R 2 is an unsubstituted or 4-8 membered heterocycloalkyl substituted by R b , the 4-8 membered heterocycloalkyl is independently azetidine or oxetane alkyl;
    和/或，当R 2为未取代或被R b取代的4-8元杂环烯基时，所述的4-8元杂环烯基独立地为1,2,3,4-四氢吡啶基、1,2-二氢吡啶基、1,4-二氢吡啶基、1,2,3,6-四氢吡啶基、3,4-二氢-2H-吡喃基或二氢呋喃基； And/or, when R 2 is an unsubstituted or substituted 4-8-membered heterocycloalkenyl group, the 4-8-membered heterocycloalkenyl group is independently 1,2,3,4-tetrahydro Pyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridyl, 3,4-dihydro-2H-pyranyl or dihydrofuran base;
    和/或，R b为羟基； and/or, R b is hydroxyl;
    和/或，当R b为C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基或异丙基； And/or, when R b is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl or isopropyl;
    和/或，当R b为卤素时，所述卤素为F或者Cl。 And/or, when R b is halogen, the halogen is F or Cl.
  5. 根据权利要求1或2所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula I according to claim 1 or 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that,
    所述
    Figure PCTCN2021128905-appb-100005
    为
    Figure PCTCN2021128905-appb-100006
    或者
    Figure PCTCN2021128905-appb-100007
    said
    Figure PCTCN2021128905-appb-100005
    for
    Figure PCTCN2021128905-appb-100006
    or
    Figure PCTCN2021128905-appb-100007
    和/或，当R 1为卤素时，所述卤素为F、Cl、Br或I； and/or, when R 1 is halogen, the halogen is F, Cl, Br or I;
    和/或，当R 1为卤素时，m为0、1或2； and/or, when R 1 is halogen, m is 0, 1 or 2;
    和/或，当R 1为未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-时，所述的C 1-C 6烷基独立地为C 1-C 4烷基； And/or, when R 1 is an unsubstituted or R a substituted C 1 -C 6 alkyl group, or, an unsubstituted or R a substituted C 1 -C 6 alkyl group-O-, the C 1 - C6 alkyl is independently C1 - C4 alkyl;
    和/或，当R 1为未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-时，m为1或2； And/or, when R 1 is unsubstituted or R a substituted C 1 -C 6 alkyl, or, unsubstituted or R a substituted C 1 -C 6 alkyl-O-, m is 1 or 2;
    和/或，当R 1为被R a取代的C 1-C 6烷基、或、被R a取代的C 1-C 6烷基-O-时，所述的取代的个数独立地为1-3个； And/or, when R 1 is a C 1 -C 6 alkyl substituted by Ra , or a C 1 -C 6 alkyl-O- substituted by Ra, the number of said substitutions is independently 1-3;
    和/或，当R 1为被R a取代的C 1-C 6烷基、或、被R a取代的C 1-C 6烷基-O-时，所述的取代各自独立地为C 1-C 6烷基、或C 1-C 6烷基-O-时，所述的取代中所述的C 1-C 6烷基独立地为C 1-C 4烷基； And/or, when R 1 is C 1 -C 6 alkyl substituted by Ra , or C 1 -C 6 alkyl-O- substituted by R a , the substitutions are each independently C 1 -C 6 alkyl, or C 1 -C 6 alkyl-O-, the C 1 -C 6 alkyl described in the substitution is independently C 1 -C 4 alkyl;
    和/或，当R a为卤素时，所述卤素为F、Cl、Br或I。 And/or when Ra is halogen, the halogen is F, Cl, Br or I.
  6. 根据权利要求1或2所述的式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula I according to claim 1 or 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that,
    所述
    Figure PCTCN2021128905-appb-100008
    为
    Figure PCTCN2021128905-appb-100009
    said
    Figure PCTCN2021128905-appb-100008
    for
    Figure PCTCN2021128905-appb-100009
    和/或，当R 1为卤素时，所述卤素为F或Cl； and/or, when R 1 is halogen, the halogen is F or Cl;
    和/或，当R 1为卤素时，m为0、1或2； and/or, when R 1 is halogen, m is 0, 1 or 2;
    和/或，当R 1为未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-时，所述的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基或异丁基； And/or, when R 1 is an unsubstituted or R a substituted C 1 -C 6 alkyl group, or, an unsubstituted or R a substituted C 1 -C 6 alkyl group-O-, the C 1 - C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
    和/或，当R 1为未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-时，m为1； And/or, when R 1 is an unsubstituted or R a substituted C 1 -C 6 alkyl group, or, an unsubstituted or R a substituted C 1 -C 6 alkyl group-O-, m is 1;
    和/或，当R 1为被R a取代的C 1-C 6烷基、或、被R a取代的C 1-C 6烷基-O-时，所述的取代的个数独立地为2个； And/or, when R 1 is a C 1 -C 6 alkyl substituted by Ra , or a C 1 -C 6 alkyl-O- substituted by Ra, the number of said substitutions is independently 2;
    和/或，当R 1为被R a取代的C 1-C 6烷基、或、被R a取代的C 1-C 6烷基-O-时，所述的取代各自独立地为C 1-C 6烷基、或C 1-C 6烷基-O-时，所述的取代中所述的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基或异丁基； And/or, when R 1 is C 1 -C 6 alkyl substituted by Ra , or C 1 -C 6 alkyl-O- substituted by R a , the substitutions are each independently C 1 -C 6 alkyl, or C 1 -C 6 alkyl -O-, the C 1 -C 6 alkyl described in the substitution is independently methyl, ethyl, n-propyl, isopropyl , n-butyl or isobutyl;
    和/或，当R a为卤素时，所述卤素为F或Cl。 And/or, when Ra is halogen, the halogen is F or Cl.
  7. 根据权利要求1或2所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 1 or 2, characterized in that,
    当
    Figure PCTCN2021128905-appb-100010
    为
    Figure PCTCN2021128905-appb-100011
    时，所述
    Figure PCTCN2021128905-appb-100012
    为
    Figure PCTCN2021128905-appb-100013
    Figure PCTCN2021128905-appb-100014
    when
    Figure PCTCN2021128905-appb-100010
    for
    Figure PCTCN2021128905-appb-100011
    when, the
    Figure PCTCN2021128905-appb-100012
    for
    Figure PCTCN2021128905-appb-100013
    Figure PCTCN2021128905-appb-100014
    和/或，当
    Figure PCTCN2021128905-appb-100015
    为
    Figure PCTCN2021128905-appb-100016
    时，所述
    Figure PCTCN2021128905-appb-100017
    为
    Figure PCTCN2021128905-appb-100018
    and/or, when
    Figure PCTCN2021128905-appb-100015
    for
    Figure PCTCN2021128905-appb-100016
    when, the
    Figure PCTCN2021128905-appb-100017
    for
    Figure PCTCN2021128905-appb-100018
    和/或，当
    Figure PCTCN2021128905-appb-100019
    为
    Figure PCTCN2021128905-appb-100020
    时，所述
    Figure PCTCN2021128905-appb-100021
    为
    Figure PCTCN2021128905-appb-100022
    and/or, when
    Figure PCTCN2021128905-appb-100019
    for
    Figure PCTCN2021128905-appb-100020
    when, the
    Figure PCTCN2021128905-appb-100021
    for
    Figure PCTCN2021128905-appb-100022
    和/或，当
    Figure PCTCN2021128905-appb-100023
    为
    Figure PCTCN2021128905-appb-100024
    时，所述
    Figure PCTCN2021128905-appb-100025
    为
    Figure PCTCN2021128905-appb-100026
    and/or, when
    Figure PCTCN2021128905-appb-100023
    for
    Figure PCTCN2021128905-appb-100024
    when, the
    Figure PCTCN2021128905-appb-100025
    for
    Figure PCTCN2021128905-appb-100026
  8. 根据权利要求1或2所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 1 or 2, characterized in that,
    Figure PCTCN2021128905-appb-100027
    为
    Figure PCTCN2021128905-appb-100028
    或者
    Figure PCTCN2021128905-appb-100029
    Figure PCTCN2021128905-appb-100027
    for
    Figure PCTCN2021128905-appb-100028
    or
    Figure PCTCN2021128905-appb-100029
    和/或，R 2为
    Figure PCTCN2021128905-appb-100030
    或者
    Figure PCTCN2021128905-appb-100031
    and/or, R2 is
    Figure PCTCN2021128905-appb-100030
    or
    Figure PCTCN2021128905-appb-100031
  9. 根据权利要求1或2所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 1 or 2, characterized in that,
    Figure PCTCN2021128905-appb-100032
    为
    Figure PCTCN2021128905-appb-100033
    Figure PCTCN2021128905-appb-100032
    for
    Figure PCTCN2021128905-appb-100033
    和/或，R 2为
    Figure PCTCN2021128905-appb-100034
    或者
    Figure PCTCN2021128905-appb-100035
    and/or, R2 is
    Figure PCTCN2021128905-appb-100034
    or
    Figure PCTCN2021128905-appb-100035
  10. 根据权利要求1或2所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，其为The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 1 or 2, characterized in that its for
    Figure PCTCN2021128905-appb-100036
    Figure PCTCN2021128905-appb-100036
    其中，in,
    R 1独立地选自氢、卤素、羟基、氰基、氨基、未取代或被R a取代的C 1-C 6烷基、或、未取代或被R a取代的C 1-C 6烷基-O-；所述的被R a取代的C 1-C 6烷基、或、所述的被R a取代的C 1-C 6烷基-O-中，所述的取代各自独立地是指下列取代基中的一个或多个取代：卤素、羟基、氰基、氨基、C 1-C 6烷基、C 1-C 6烷基-O-、-COOH、-C(＝O)NH 2；当取代基为多个时，所述的取代基相同或不同； R 1 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or R a substituted C 1 -C 6 alkyl, or, unsubstituted or R a substituted C 1 -C 6 alkyl -O-; in the C 1 -C 6 alkyl substituted by R a , or the C 1 -C 6 alkyl substituted by R a -O-, the substitutions are each independently Refers to one or more of the following substituents: halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkyl -O-, -COOH, -C(=O)NH 2 ; When the substituents are multiple, the substituents are the same or different;
    R 2选自氢、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 3-C 6环烷基、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、或、未取代或被R b取代的4-8元杂环烯基；所述的被R b取代的C 1-C 6烷基、所述的被R b取代的C 3-C 6环烷基、所述的被R b取代的5-8元芳基、所述的被R b取代的5-8元杂芳基、所述的被R b取代的4-8元杂环烷基、或、所述的被R b取代的4-8元杂环烯基中，所述的取代各自独立地是指下列取代基中的一个或多个取代：卤素、羟基、氰基、氨基、C 3-C 6环烷基、C 1-C 6烷基、被1-5个相同或不同的卤素取代的C 1-C 6烷基、或、C 1-C 6烷基-O-；当取代基为多个时，所述的取代基相同或不同； R 2 is selected from hydrogen, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 3 -C 6 cycloalkyl, unsubstituted or R b substituted 5-8 Member aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, unsubstituted or R b substituted 4-8 membered heterocycloalkyl, or, unsubstituted or R b substituted 4-8 Membered heterocycloalkenyl; said C 1 -C 6 alkyl substituted by R b , said C 3 -C 6 cycloalkyl substituted by R b , said 5-8 substituted by R b Member aryl, said 5-8 membered heteroaryl substituted by R b , said 4-8 membered heterocycloalkyl substituted by R b , or, said 4-8 member substituted by R b In the membered heterocycloalkenyl, the substitutions each independently refer to one or more of the following substituents: halogen, hydroxyl, cyano, amino, C 3 -C 6 cycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 alkyl substituted by 1-5 same or different halogens, or, C 1 -C 6 alkyl-O-; when there are multiple substituents, the substituents are the same or different;
    所述的未取代或被R b取代的5-8元杂芳基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烷基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个；所述的未取代或被R b取代的4-8元杂环烯基中，杂原子选自N、S、O和P中的一种或多种，杂原子数为1-3个。 In the described unsubstituted or 5-8-membered heteroaryl group substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3; the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b , the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
  11. 根据权利要求1或2所述的如式I所示的化合物、其水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，其为
    Figure PCTCN2021128905-appb-100037
    The compound of formula I, its hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 1 or 2, wherein it is
    Figure PCTCN2021128905-appb-100037
    其中，R 1和R 2具有如权利要求1所述的定义。 wherein R 1 and R 2 are as defined in claim 1 .
  12. 根据权利要求11所述的如式I所示的化合物、其水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 1选自二氟甲基、三氟甲基、二氯甲基、三氯甲基或异丙基； The compound of formula I, its hydrate, solvate, pharmaceutically acceptable salt or prodrug according to claim 11, wherein R 1 is selected from difluoromethyl, trifluoromethyl, Dichloromethyl, trichloromethyl or isopropyl;
    R 2选自甲基、乙基或环丙基。 R 2 is selected from methyl, ethyl or cyclopropyl.
  13. 根据权利要求1或2所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述的如式I所示的化合物选自下列任一化合物：The compound according to claim 1 or 2, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that, said compound as described in formula I The compound shown is selected from any of the following compounds:
    Figure PCTCN2021128905-appb-100038
    Figure PCTCN2021128905-appb-100038
  14. 一种药物组合物，其特征在于，其包含如权利要求1-13中任一项所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，和药学上可接受的赋形剂。A pharmaceutical composition is characterized in that, it comprises the compound shown in formula I as described in any one of claim 1-13, its tautomer, stereoisomer, hydrate, solvate , a pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable excipient.
  15. 根据权利要求1-13中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药、权利要求14所述药物组合物与PD-1抗体、PD-L1抗体、CTLA-4抗体或者PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂联用在制备用于治疗与CD73相关疾病药物中的用途。The compound of any one of claims 1-13, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, the pharmaceutical combination of claim 14 Use of the compound with PD-1 antibody, PD-L1 antibody, CTLA-4 antibody or PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor in the preparation of a drug for the treatment of CD73-related diseases.
  16. 根据权利要求1-13中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药、或如权利要求14所述的药物组合物在制备用于治疗与CD73相关疾病药物中的用途。The compound of any one of claims 1-13, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or as claimed in claim 14 Use of the pharmaceutical composition in the preparation of a medicament for treating diseases related to CD73.
  17. 根据权利要求15或16所述的用途，其特征在于，所述CD73相关疾病为癌症。The use according to claim 15 or 16, wherein the CD73-related disease is cancer.
  18. 根据权利要求17所述的用途，其特征在于，所述癌症为膀胱癌、乳腺癌、胆管癌、直肠癌、结肠癌、胃癌、胆囊癌、神经胶母细胞瘤、头颈癌、肝癌、肺癌、淋巴瘤、神经管母细胞瘤、黑色素瘤、卵巢癌、胰腺癌、***癌或者肾癌。The use according to claim 17, wherein the cancer is bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, stomach cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, Lymphoma, medulloblastoma, melanoma, ovarian, pancreatic, prostate or kidney cancer.
  19. 一种治疗与CD73相关疾病的方法，其特征在于，包括：向受试者施用权利要求1-13中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药、或如权利要求14所述的药物组合物。A method for treating a disease related to CD73, comprising: administering to a subject the compound according to any one of claims 1-13, its tautomer, stereoisomer, hydrate, A solvate, a pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of claim 14.
  20. 一种治疗与CD73相关疾病的方法，其特征在于，包括：向受试者联合施用权利要求1-13中任一项所述的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药、权利要求14所述药物组合物与PD-1抗体、PD-L1抗体、CTLA-4抗体或者PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂。A method for treating a disease related to CD73, comprising: administering the compound, tautomer, stereoisomer and hydrate thereof according to any one of claims 1-13 in combination to a subject , solvate, pharmaceutically acceptable salt or prodrug, the pharmaceutical composition of claim 14 with PD-1 antibody, PD-L1 antibody, CTLA-4 antibody or PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitors.
  21. 根据权利要求19或20所述的方法，其特征在于，所述CD73相关疾病为癌症。The method of claim 19 or 20, wherein the CD73-related disease is cancer.
  22. 根据权利要求21所述的方法，其特征在于，所述癌症为膀胱癌、乳腺癌、胆管癌、直肠癌、结肠癌、胃癌、胆囊癌、神经胶母细胞瘤、头颈癌、肝癌、肺癌、淋巴瘤、神经管 母细胞瘤、黑色素瘤、卵巢癌、胰腺癌、***癌或者肾癌。The method according to claim 21, wherein the cancer is bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, gastric cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, Lymphoma, medulloblastoma, melanoma, ovarian, pancreatic, prostate or kidney cancer.
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WO2023201267A1 (en) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers

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