WO2022007677A1 - Cd73 inhibitor and application in pharmaceutical use - Google Patents

Cd73 inhibitor and application in pharmaceutical use Download PDF

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WO2022007677A1
WO2022007677A1 PCT/CN2021/103508 CN2021103508W WO2022007677A1 WO 2022007677 A1 WO2022007677 A1 WO 2022007677A1 CN 2021103508 W CN2021103508 W CN 2021103508W WO 2022007677 A1 WO2022007677 A1 WO 2022007677A1
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compound
alkyl
synthesis
reaction
mixed
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PCT/CN2021/103508
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French (fr)
Chinese (zh)
Inventor
吴颢
杨晓峰
刘奇声
韩晗
李金花
蒋枫
匡翠文
夏洪峰
张洪波
兰宏
王家炳
丁列明
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贝达药业股份有限公司
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Priority to CN202180043145.8A priority Critical patent/CN115702150A/en
Publication of WO2022007677A1 publication Critical patent/WO2022007677A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • 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

Definitions

  • the present invention relates to a CD73 inhibitor having cancer therapeutic activity.
  • the present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing them.
  • Extracellular 5'-nucleotidase is a cell membrane glycoprotein that exists on the cell membrane surface of a variety of cell types, including endothelial cells, lymphocytes, stromal cells, and tumor cells Wait.
  • CD73 can catalyze the production of adenosine from extracellular 5'-phosphate adenosine (5'-AMP), and adenosine can induce immunosuppressive effects and promote tumor proliferation and/or metastasis.
  • CD73 can also promote tumorigenesis through non-immune-related mechanisms, such as promoting tumor angiogenesis and promoting tumor cell adhesion to extracellular matrix proteins.
  • CD73 has been found to be an independent prognostic factor in prostate cancer and triple-negative breast cancer patients.
  • the present invention will provide a novel structure of small molecule CD73 inhibitor with good antitumor activity.
  • the present invention provides a compound represented by general formula (I), its tautomer or pharmaceutically acceptable salt:
  • R 1 is selected phenyl or 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl unsubstituted or substituted with 1, 2 or 3 substituents substituted by R 3,
  • R 3 is selected from C 1-6 alkyl, -(C 1-4 alkylene) 0-1 -Cyc, -O-(C 1-4 alkylene) 0-1 -Cyc, -S-(C 1-4 alkylene) 0-1 -Cyc, -NH-(C 1-4 alkylene) 0-1 -Cyc, -NH-C 1-6 alkyl, -N(C 1-6 alkyl ) 2 , -OC 1-6 alkyl or -SC 1-6 alkyl, R 3 is optionally unsubstituted or further substituted by one or more R 4 substituents;
  • the Cyc is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclic group, C 6-10 aryl or 5-10-membered heteroaryl, the C 3-10 cycloalkyl, 3-10-membered Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents R 5 ;
  • R 2 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, halogenated C 2-4 alkenyl or C 2-4 alkynyl.
  • R 1 in formula (I) is selected from phenyl or 5-6 membered heteroaryl, and the phenyl or 5-6 membered heteroaryl optionally contains 1 or 2 independently selected A heteroatom from N, O or S, and the heteroaromatic ring group is unsubstituted or substituted with 1, 2 or 3 substituents R 3 ; preferably R 1 is selected from Said R 1 is unsubstituted or substituted with 1, 2 or 3 substituents R 3 .
  • R 3 in formula (I) is meta-substituted.
  • R 2 in formula (I) is selected from halogen, C 1-3 alkyl or C 1-3 alkoxy; preferably chloro, methyl or methoxy.
  • the compound of formula (I) is selected from the compounds of general formula (IA):
  • X 1 is selected from N or CH;
  • X 2 is selected from N or CH;
  • R 3 is selected from C 1-6 alkyl, -(C 1-4 alkylene) 0-1 -Cyc, -O-(C 1-4 alkylene) 0-1 -Cyc, -S-(C 1-4 alkylene) 0-1 -Cyc, -NH-(C 1-4 alkylene) 0-1 -Cyc, -NH-C 1-6 alkyl, -N(C 1-6 alkyl ) 2 , -OC 1-6 alkyl or -SC 1-6 alkyl, R 3 is optionally unsubstituted or further substituted by one or more R 4 substituents;
  • the Cyc is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclic group, C 6-10 aryl or 5-10-membered heteroaryl, the C 3-10 cycloalkyl, 3-10-membered Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents R 5 ;
  • R 2 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, halogenated C 2-4 alkenyl or C 2-4 alkynyl.
  • formula (I) is selected from:
  • the method of synthesizing formula (I) comprises:
  • R 1 and R 2 are defined as described in formula (I).
  • the present invention also provides a pharmaceutical composition, characterized in that, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I) and at least one pharmaceutically acceptable adjuvant.
  • the present invention further provides a pharmaceutical composition, characterized in that the therapeutically effective amount of at least one compound represented by formula (I) and a pharmaceutically acceptable auxiliary material are in a mass percentage of 0.0001:1-10.
  • the present invention provides the application of the compound represented by the structural formula (I) or the pharmaceutical composition in the preparation of medicine.
  • the application is in the preparation of a drug for treating and/or preventing cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • the present invention also provides a method for treating and/or preventing a disease, comprising administering a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
  • the present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any compound represented by the structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cells tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc.
  • a "C1-8 alkyl group” in the "1-8” refers to a straight or branched chain radical form with 7 or 8 carbon atoms arranged group.
  • C 1-3 alkylene refers to a linear or branched divalent saturated hydrocarbon group.
  • methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene For example methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
  • C 2-6 alkenyl or “C 2-6 alkynyl” refers to a straight or branched chain unsaturated hydrocarbon group.
  • Alkoxy refers to the oxyether form of the aforementioned straight or branched chain alkyl groups, ie, -O-alkyl.
  • compositions comprising "a” pharmaceutically acceptable excipient can be interpreted to mean that the composition includes “one or more” pharmaceutically acceptable excipients.
  • aryl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted mono- or fused-ring aromatic group comprising atoms of a carbocyclic ring.
  • the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group.
  • Preferred are phenyl and naphthyl. Most preferred is phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples including, but not limited to, benzocyclopentyl.
  • heterocyclyl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable ring system consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is Saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents comprising 3 to 20 carbon atoms, wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized .
  • the heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure.
  • heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl.
  • heteroaryl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- or 10-membered benzo
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl.
  • the heteroaryl group can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • cycloalkyl refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .
  • substituted refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively.
  • the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , carboxaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.
  • substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxinylmethyl and piperazinylmethyl.
  • substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).
  • Prodrugs of the compounds of the present invention are included within the scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo.
  • any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues.
  • the compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers.
  • the present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.
  • substitution of compounds of formula (I) with heavier isotopes may provide certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can be used.
  • composition refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of this invention.
  • the pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
  • step 1
  • reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a brown solid (136 mg), namely compound 16-1 (M+H + : 298, 454). Used directly in the next step without purification.
  • Example 15 Synthesis of Compound 15 (5-(5-(1-(4-methoxybenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione)
  • Example 18 Synthesis of Compound 18 (5-(5-(1-(3-methoxybenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione)
  • Example 28 Synthesis of Compound 28 (5-(6-methyl-5-(1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrrol-3-yl) Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione)
  • Example 30 Synthesis of Compound 30 (5-(6-methyl-5-(1-((5-methylpyridin-2-yl)methyl)-1H-pyrrol-3-yl)pyridazine-3 -yl)pyrimidine-2,4(1H,3H)-dione)
  • Example 33 Compound 33 (5-(5-(1-(4-hydroxybenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H Synthesis of ,3H)-diketone)
  • Example 37 Synthesis of Compound 37 (5-(5-(3-(4-methoxybenzyl)-1H-pyrrol-1-yl)-6-methylpyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione)
  • Example 40 Synthesis of Compound 40 (5-(5-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione)
  • Example 41 Synthesis of Compound 41 (5-(6-methyl-5-(1-(2-(trifluoromethoxy)benzyl)-1H-pyrrol-3-yl)pyridazin-3-yl )pyrimidine-2,4(1H,3H)-dione)
  • Example 42 Synthesis of Compound 42 (5-(6-methyl-5-(1-(3-(trifluoromethoxy)benzyl)-1H-pyrrol-3-yl)pyridazin-3-yl )pyrimidine-2,4(1H,3H)-dione)
  • Example 44 Synthesis of Compound 44 (3-((3-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrrol-1-yl)methyl)benzoic acid methyl ester)
  • Example 47 Synthesis of Compound 47 (5-(5-(1-(3-(difluoromethyl)benzyl)-1H-pyrrol-3-yl)-6-methylpyridin-3-yl)pyrimidine -2,4(1H,3H)-dione)
  • Example 50 Synthesis of compound 50 (6-((3-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrrol-1-yl)methyl)nicotinonitrile)
  • Example 51 Synthesis of Compound 51 (5-(6-methyl-5-(1-(3-methylbenzyl)-1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidine-2, 4(1H,3H)-dione)
  • Example 54 Synthesis of Compound 54 (5-(6-methyl-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidine -2,4(1H,3H)-dione)
  • Example 1 Detection of enzymatic activity at the cellular level
  • Calu-6 cells were digested, resuspended in TM buffer (25 mM Tris, 5 mM MgCl 2 , pH 7.5), and plated in a 96-well plate at 25,000 cells and 100 ⁇ L/well.
  • TM buffer was used to prepare compound solutions with gradient concentrations, and 50 ⁇ L of DMSO solutions of the compounds to be tested were added to the cells in each well. 0.3, 0 nM (the final concentration of DMSO is 0.625%).
  • Pre-incubate for 30 min on a constant temperature horizontal shaker at 37 °C add 50 ⁇ L of 800 ⁇ M AMP solution to each well, and continue to incubate at 37 °C for 120 min on a constant temperature horizontal shaker, then centrifuge the 96-well plate and transfer 50 ⁇ L of supernatant per well to a new 96-well plate. , add 50 ⁇ L of 130 ⁇ M ATP solution and 100 ⁇ L of Cell-titer Glo working solution to each well, shake and mix, incubate at room temperature for 10 min, read the Luminescence luminescence value with a multi-function microplate reader, and convert the luminescence value reading into inhibition percentage:
  • Max is the DMSO control.
  • R & inter-group substituents of the present invention is 3-substituted compound of the ortho-substituted compound, significantly enhanced activity (Table 2).

Abstract

Provided is a novel compound, having curative activity for cancer. Also provided is a preparation method for the compound and a pharmaceutical composition containing the compound.

Description

CD73抑制剂及其在医药上的应用CD73 inhibitor and its application in medicine 技术领域technical field
本发明涉及一种CD73抑制剂，其具有癌症治疗活性。本发明还涉及这些化合物的制备方法以及包含其的药物组合物。The present invention relates to a CD73 inhibitor having cancer therapeutic activity. The present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing them.
背景技术Background technique
胞外5'-核苷酸酶(ecto-5'-nucleotidase,CD73)是一种细胞膜上的糖蛋白，在多种细胞类型的细胞膜表面存在，包括内皮细胞、淋巴细胞、基质细胞和肿瘤细胞等。CD73能够催化细胞外5'-磷酸腺苷(5'-AMP)生成腺苷，而腺苷可诱导免疫抑制效应，促进肿瘤增殖和/或转移。此外，CD73还能够以非免疫相关机制促进肿瘤生成，如促进肿瘤血管生成、促进肿瘤细胞对细胞外基质蛋白的粘附等。临床上，CD73高水平表达与多种癌症类型的***转移和不良预后相关，已发现CD73是***癌和三阴性乳腺癌患者的独立预后因素。本发明将提供一种新型结构的小分子CD73抑制剂，具有良好的抗肿瘤活性。Extracellular 5'-nucleotidase (ecto-5'-nucleotidase, CD73) is a cell membrane glycoprotein that exists on the cell membrane surface of a variety of cell types, including endothelial cells, lymphocytes, stromal cells, and tumor cells Wait. CD73 can catalyze the production of adenosine from extracellular 5'-phosphate adenosine (5'-AMP), and adenosine can induce immunosuppressive effects and promote tumor proliferation and/or metastasis. In addition, CD73 can also promote tumorigenesis through non-immune-related mechanisms, such as promoting tumor angiogenesis and promoting tumor cell adhesion to extracellular matrix proteins. Clinically, high CD73 expression is associated with lymph node metastasis and poor prognosis in multiple cancer types, and CD73 has been found to be an independent prognostic factor in prostate cancer and triple-negative breast cancer patients. The present invention will provide a novel structure of small molecule CD73 inhibitor with good antitumor activity.
发明内容SUMMARY OF THE INVENTION
本发明提供一种通式(I)所示的化合物、其互变异构体或药用盐：The present invention provides a compound represented by general formula (I), its tautomer or pharmaceutically acceptable salt:
Figure PCTCN2021103508-appb-000001
Figure PCTCN2021103508-appb-000001
其中，in,
R 1选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基未被取代或被1、2或3个取代基R 3所取代， R 1 is selected phenyl or 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl unsubstituted or substituted with 1, 2 or 3 substituents substituted by R 3,
R 3选自C 1-6烷基、-(C 1-4亚烷基) 0-1-Cyc、-O-(C 1-4亚烷基) 0-1-Cyc、-S-(C 1-4亚烷基) 0-1-Cyc、-NH-(C 1-4亚烷基) 0-1-Cyc、-NH-C 1-6烷基、-N(C 1-6烷基) 2、-O-C 1-6烷基或-S-C 1-6烷基，R 3任选未取代或进一步被一个或多个R 4取代基所取代； R 3 is selected from C 1-6 alkyl, -(C 1-4 alkylene) 0-1 -Cyc, -O-(C 1-4 alkylene) 0-1 -Cyc, -S-(C 1-4 alkylene) 0-1 -Cyc, -NH-(C 1-4 alkylene) 0-1 -Cyc, -NH-C 1-6 alkyl, -N(C 1-6 alkyl ) 2 , -OC 1-6 alkyl or -SC 1-6 alkyl, R 3 is optionally unsubstituted or further substituted by one or more R 4 substituents;
所述Cyc选自C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，所述C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基未被取代或被1、2或3个取代基R 5所取代； The Cyc is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclic group, C 6-10 aryl or 5-10-membered heteroaryl, the C 3-10 cycloalkyl, 3-10-membered Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents R 5 ;
R 4或R 5各自独立地选自H、羟基、氨基、卤素、氰基、硝基、-OR a、-SR a、＝O、＝S、-C(O)R a、-C(S)R a、-C(O)OR a、-C(S)OR a、-C(O)N(R a) 2、-N(R a) 2、-S(O) 2R a、-O-S(O 2)OR a、-O-S(O) 2R a或R a，所述R a各自独立地选自H、C 1-6烷基或C 3-6环烷基，R a未被取代或进一步被一个或多个选自卤素、羟基、C 1-3烷基或氰基的取代基取代； R 4 or R 5 is each independently selected from H, hydroxy, amino, halogen, cyano, nitro, -OR a , -SR a , =O, =S, -C(O)R a , -C(S )R a , -C(O)OR a , -C(S)OR a , -C(O)N(R a ) 2 , -N(R a ) 2 , -S(O) 2 R a , - OS (O 2) oR a, -OS (O) 2 R a or R a, said R a is independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, R a is not substituted or further substituted by one or more substituents selected from halogen, hydroxy, C 1-3 alkyl or cyano;
R 2选自氢、卤素、氰基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、卤代C 2-4烯基或C 2-4炔基。 R 2 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, halogenated C 2-4 alkenyl or C 2-4 alkynyl.
一些实施方式中，式(I)中的R 1选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任意地含有1个或2个分别独立地选自N、O或S的杂原子，且所述杂芳环基未被取代或被1、2或3个取代基R 3所取代；优选R 1选自
Figure PCTCN2021103508-appb-000002
Figure PCTCN2021103508-appb-000003
所述R 1未被取代或被1、2或3个取代基R 3所取代。 In some embodiments, R 1 in formula (I) is selected from phenyl or 5-6 membered heteroaryl, and the phenyl or 5-6 membered heteroaryl optionally contains 1 or 2 independently selected A heteroatom from N, O or S, and the heteroaromatic ring group is unsubstituted or substituted with 1, 2 or 3 substituents R 3 ; preferably R 1 is selected from
Figure PCTCN2021103508-appb-000002
Figure PCTCN2021103508-appb-000003
Said R 1 is unsubstituted or substituted with 1, 2 or 3 substituents R 3 .
一些实施方式中，式(I)中的R 3为间位取代。 In some embodiments, R 3 in formula (I) is meta-substituted.
一些实施方式中，式(I)中的R 3选自C 1-6烷基、-C 1-3亚烷基-苯基、-C 1-3亚烷基-C 3-6环烷基或-C 1-3亚烷基-(5-10元杂芳基)，所述R 3任选被选自H、氰基、卤素、羟基、氨基、C 1-3烷基、C 1-3羟基烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、-C(＝O)O-C 1-3烷基或-S(＝O) 2-C 1-3烷基的取代基取代；优选R 3选自C 1-6烷基、
Figure PCTCN2021103508-appb-000004
Figure PCTCN2021103508-appb-000005
所述R 3任选被选自H、氰基、卤素、羟基、氨基、C 1-3烷基、C 1-3羟基烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、-C(＝O)O-C 1-3烷基或-S(＝O) 2-C 1-3烷基的取代基取代。 Some embodiments of formula (I) R 3 is selected from C 1-6 alkyl, -C 1-3 alkylene - phenyl, -C 1-3 cycloalkyl, -C 3-6 alkylene Or -C 1-3 alkylene-(5-10 membered heteroaryl), the R 3 is optionally selected from H, cyano, halogen, hydroxyl, amino, C 1-3 alkyl, C 1- 3 hydroxyalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, -C(=O)OC 1-3 alkyl or -S(=O) 2 -C Substituents of 1-3 alkyl groups are substituted; preferably R 3 is selected from C 1-6 alkyl groups,
Figure PCTCN2021103508-appb-000004
Figure PCTCN2021103508-appb-000005
The R 3 is optionally selected from H, cyano, halogen, hydroxy, amino, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, Substituent substitution of C 1-3 haloalkoxy, -C(=O)OC 1-3 alkyl or -S(=O) 2 -C 1-3 alkyl.
一些实施方式中，式(I)中的R 2选自卤素、C 1-3烷基或C 1-3烷氧基；优选氯、甲基或甲氧基。 In some embodiments, R 2 in formula (I) is selected from halogen, C 1-3 alkyl or C 1-3 alkoxy; preferably chloro, methyl or methoxy.
一些实施方式中，式(I)中的化合物选自通式(IA)所示的化合物：In some embodiments, the compound of formula (I) is selected from the compounds of general formula (IA):
Figure PCTCN2021103508-appb-000006
Figure PCTCN2021103508-appb-000006
其中，in,
X 1选自N或CH； X 1 is selected from N or CH;
X 2选自N或CH； X 2 is selected from N or CH;
R 3选自C 1-6烷基、-(C 1-4亚烷基) 0-1-Cyc、-O-(C 1-4亚烷基) 0-1-Cyc、-S-(C 1-4亚烷基) 0-1-Cyc、-NH-(C 1-4亚烷基) 0-1-Cyc、-NH-C 1-6烷基、-N(C 1-6烷基) 2、-O-C 1-6烷基或-S-C 1-6烷基，R 3任选未取代或进一步被一个或多个R 4取代基所取代； R 3 is selected from C 1-6 alkyl, -(C 1-4 alkylene) 0-1 -Cyc, -O-(C 1-4 alkylene) 0-1 -Cyc, -S-(C 1-4 alkylene) 0-1 -Cyc, -NH-(C 1-4 alkylene) 0-1 -Cyc, -NH-C 1-6 alkyl, -N(C 1-6 alkyl ) 2 , -OC 1-6 alkyl or -SC 1-6 alkyl, R 3 is optionally unsubstituted or further substituted by one or more R 4 substituents;
所述Cyc选自C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，所述C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基未被取代或被1、2或3个取代基R 5所取代； The Cyc is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclic group, C 6-10 aryl or 5-10-membered heteroaryl, the C 3-10 cycloalkyl, 3-10-membered Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents R 5 ;
R 4或R 5各自独立地选自H、羟基、氨基、卤素、氰基、硝基、-OR a、-SR a、＝O、＝S、-C(O)R a、-C(S)R a、-C(O)OR a、-C(S)OR a、-C(O)N(R a) 2、-N(R a) 2、-S(O) 2R a、-O-S(O 2)OR a、-O-S(O) 2R a或R a，所述R a各自独立地选自H、C 1-6烷基或C 3-6环烷基，R a未被取代或进一步被一个或多个选自卤素、羟基、C 1-3烷基或氰基的取代基取代； R 4 or R 5 is each independently selected from H, hydroxy, amino, halogen, cyano, nitro, -OR a , -SR a , =O, =S, -C(O)R a , -C(S )R a , -C(O)OR a , -C(S)OR a , -C(O)N(R a ) 2 , -N(R a ) 2 , -S(O) 2 R a , - OS (O 2) oR a, -OS (O) 2 R a or R a, said R a is independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, R a is not substituted or further substituted by one or more substituents selected from halogen, hydroxy, C 1-3 alkyl or cyano;
R 2选自氢、卤素、氰基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、卤代C 2-4烯基或C 2-4炔基。 R 2 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, halogenated C 2-4 alkenyl or C 2-4 alkynyl.
一些实施方式中，式(I)选自：In some embodiments, formula (I) is selected from:
Figure PCTCN2021103508-appb-000007
Figure PCTCN2021103508-appb-000007
Figure PCTCN2021103508-appb-000008
Figure PCTCN2021103508-appb-000008
一些实施方式中，合成式(I)中的方法包括：In some embodiments, the method of synthesizing formula (I) comprises:
Figure PCTCN2021103508-appb-000009
Figure PCTCN2021103508-appb-000009
通式(II)化合物在酸性条件下反应，得到通式(I)化合物，The compound of general formula (II) is reacted under acidic conditions to obtain the compound of general formula (I),
其中R 1和R 2的定义式(I)中所述。 wherein R 1 and R 2 are defined as described in formula (I).
本发明还提供了一种药物组合物，其特征在于，所述药物组合物包含治疗有效量的至少一种式(I)所示的化合物和至少一种药学上可接受的辅料。The present invention also provides a pharmaceutical composition, characterized in that, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I) and at least one pharmaceutically acceptable adjuvant.
本发明进一步提供了一种药物组合物，其特征在于，所述的治疗有效量的至少一种式(I)所示的化合物和药学上可接受的辅料的质量百分比为0.0001:1-10。The present invention further provides a pharmaceutical composition, characterized in that the therapeutically effective amount of at least one compound represented by formula (I) and a pharmaceutically acceptable auxiliary material are in a mass percentage of 0.0001:1-10.
本发明提供了结构式(I)所示化合物或药物组合物在制备药物中的应用。The present invention provides the application of the compound represented by the structural formula (I) or the pharmaceutical composition in the preparation of medicine.
本发明进一步提供了所述应用的优选技术方案：The present invention further provides the preferred technical solution of the application:
作为优选，所述应用为制备治疗和/或预防癌症药物中的应用。Preferably, the application is in the preparation of a drug for treating and/or preventing cancer.
作为优选，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
本发明还提供了一种治疗和/或预防疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或含其的药物组合物。The present invention also provides a method for treating and/or preventing a disease, comprising administering a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
本发明还提供了一种治疗癌症的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或含其的药物组合物。The present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any compound represented by the structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
作为优选，在上述方法中，所述的癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cells tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.
除非另有说明，所述结构通式中使用的一般化学术语具有通常的含义。Unless otherwise indicated, general chemical terms used in the structural formulae have their ordinary meanings.
例如，除非另有说明，本发明所用的术语“卤素”是指氟、氯、溴或碘。For example, unless otherwise specified, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
在本发明中，除非另有说明，“烷基”包括直链或支链的一价饱和烃基。例如，烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基) 丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的，“基 1-8烷基”中的“ 1-8”是指包含有1、2、3、4、5、6、7或8个碳原子的直链或支链形式排列的基团。 In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, a "C1-8 alkyl group" in the "1-8" refers to a straight or branched chain radical form with 7 or 8 carbon atoms arranged group.
“C 1-3亚烷基”是指直链或支链的二价饱和烃基。例如亚甲基、1,2-亚乙基、1,3-亚丙基或1,2-亚异丙基。 "C 1-3 alkylene" refers to a linear or branched divalent saturated hydrocarbon group. For example methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
“C 2-6烯基”或“C 2-6炔基”是指直链或支链的非饱和烃基。 "C 2-6 alkenyl" or "C 2-6 alkynyl" refers to a straight or branched chain unsaturated hydrocarbon group.
“烷氧基”是指前述的直链或支链烷基的氧醚形式，即-O-烷基。"Alkoxy" refers to the oxyether form of the aforementioned straight or branched chain alkyl groups, ie, -O-alkyl.
在本发明中，“一”、“一个”、“该”、“至少一个”和“一个或多个”可互换使用。因此，例如，包含“一种”药学上可接受的赋形剂的组合物可以被解释为表示该组合物包括“一种或多种”药学上可接受的赋形剂。In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
术语“芳基”，在本发明中，除非另有说明，是指未取代或取代的包括碳环的原子的单环或稠环芳香基团。优选芳基为6到10元的单环或双环的芳香环基团。优选为苯基、萘基。最优选为苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基上，其中与母体结构连接在一起的环为芳基环，非限制性实例包括但不限于苯并环戊基。The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted mono- or fused-ring aromatic group comprising atoms of a carbocyclic ring. Preferably, the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group. Preferred are phenyl and naphthyl. Most preferred is phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples including, but not limited to, benzocyclopentyl.
术语“杂环基”，在本发明中，除非另有说明，是指由碳原子和1-3个选自N、O或S的杂原子组成的未取代或取代的稳定环***，其为饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，其中氮或硫杂原子可以选择性地被氧化，并且氮杂原子可以选择性地被季铵化。该杂环基可以被连接到任何的杂原子或碳原子上以形成稳定的结构。这些杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜基和四氢恶二唑基。The term "heterocyclyl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable ring system consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is Saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents comprising 3 to 20 carbon atoms, wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized . The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl.
术语“杂芳基”，在本发明中，除非另有说明，是指未取代或取代的稳定的5元或6元单环芳族环***或未取代或取代的9元或10元苯并稠合杂芳族环***或双环杂芳族环***，其由碳原子和1-4个选自N、O或S的杂原子组成，并且其中所述氮或硫杂原子可以选择性地被氧化，所述氮杂原子可以选择性地被季铵化。杂芳基可以连接在任何杂原子或碳原子上以形成稳定的结构。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、***基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并***基腺嘌呤、喹啉基或异喹啉基。所述杂芳基可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。The term "heteroaryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- or 10-membered benzo A fused heteroaromatic ring system or a bicyclic heteroaromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may be optionally replaced by oxidation, the nitrogen heteroatom can be selectively quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
术语“环烷基”是指具有3-10个碳原子的环状饱和或部分不饱和单环或多环环状烃取代 基，例如，环丙基、环丁基、环戊基或环己基。The term "cycloalkyl" refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .
术语“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于卤素(F、Cl、Br或I)、C 1-8烷基、C 3-12环烷基、-OR 1、-SR 1、＝O、＝S、-C(O)R 1、-C(S)R 1、＝NR 1、-C(O)OR 1、-C(S)OR 1、-NR 1R 2、-C(O)NR 1R 2、氰基、硝基、-S(O) 2R 1、-O-S(O 2)OR 1、-O-S(O) 2R 1、-OP(O)(OR 1)(OR 2)；其中R 1和R 2独立地选自-H、C 1-6烷基、C 1-6卤代烷基。在一些实施例中，取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH 3、-SC 2H 5、甲醛基、-C(OCH 3)、氰基、硝基、-CF 3、-OCF 3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。 The term "substituted" refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively. Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), C 1-8 alkyl, C 3-12 cycloalkyl, -OR 1 , -SR 1 , =O, =S, -C (O)R 1 , -C(S)R 1 , =NR 1 , -C(O)OR 1 , -C(S)OR 1 , -NR 1 R 2 , -C(O)NR 1 R 2 , cyano, nitro, -S(O) 2 R 1 , -OS(O 2 )OR 1 , -OS(O) 2 R 1 , -OP(O)(OR 1 )(OR 2 ); wherein R 1 and R 2 are independently selected from -H, C 1-6 alkyl, C 1-6 haloalkyl. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , carboxaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.
取代烷基的实例包括但不限于2,3-二羟基丙基、2-氨基乙基、2-羟乙基、五氯乙基、三氟甲基、甲氧基甲基、五氟乙基、苯基甲基、二恶茂基甲基和哌嗪基甲基。Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxinylmethyl and piperazinylmethyl.
取代烷氧基的实例包括但不限于2-羟基乙氧基、2-氟乙氧基、2,2-二氟乙氧基、2-甲氧基乙氧基、2-氨基乙氧基、2,3-二羟基丙氧基、环丙基甲氧基、氨基甲氧基、三氟甲氧基、2-二乙基氨基乙氧基、2-乙氧基羰基乙氧基、3-羟基丙氧基。Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
由于式(I)所示化合物将作为药物应用，较优地，使用一定纯度，例如，至少为60％纯度，比较合适的纯度为至少75％，特别合适地纯度为至少98％(％是重量比)。Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).
本发明化合物的药物前体包含在本发明的保护范围内。通常，所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。例如，本申请化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物，其在向受体施用后能够直接或间接地提供本申请的化合物或其具有药学活性的代谢物或残基。Prodrugs of the compounds of the present invention are included within the scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues.
本发明所述化合物可能含有一个或多个不对称中心，并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药学上可接受的盐。The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.
当式(I)所示化合物用较重的同位素(例如氘)替代可能提供某些治疗优势，这是由于更大的代谢稳定性，例如增加体内半衰期或减少剂量要求。Substitution of compounds of formula (I) with heavier isotopes (eg deuterium) may provide certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.
当式(I)所示化合物及其药学上可接受的盐存在溶剂化物或多晶型时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。When the compounds of formula (I) and their pharmaceutically acceptable salts exist as solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.
术语“组合物”，在本发明中，是指包括包含指定量的各指定成分的产品，以及直接或 间接地由指定量的各指定成分的组合生产的任何产品。因此，含有本发明的化合物作为活性成分的药物组合物以及制备本发明化合物的方法也是本发明的一部分。此外，化合物的一些结晶形式可以多晶型存在，并且此多晶型包括在本发明中。另外，一些化合物可以与水(即水合物)或常见的有机溶剂形成溶剂化物，并且此类溶剂化物也落入本发明的范围内。The term "composition", in the present invention, refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of this invention.
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药学上可接受的盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。The pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
具体实施方式detailed description
为使上述内容更清楚、明确，本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。In order to make the above content clearer and clearer, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention, so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific embodiments of the present invention, the technical means or methods that are not specifically described are conventional technical means or methods in the field.
除非另有说明，本发明所有的一部分和百分比均按重量计算，所有温度均指摄氏度。All parts and percentages herein are by weight and all temperatures are in degrees Celsius unless otherwise indicated.
合成方案：Synthesis scheme:
Figure PCTCN2021103508-appb-000010
Figure PCTCN2021103508-appb-000010
通式(II)化合物在酸性条件下反应，得到通式(I)化合物。Compounds of general formula (II) are reacted under acidic conditions to obtain compounds of general formula (I).
中间体化合物M1的制备Preparation of Intermediate Compound M1
Figure PCTCN2021103508-appb-000011
Figure PCTCN2021103508-appb-000011
步骤：step:
将4,6-二氯-3-甲基哒嗪(1.3g)、2,4-二甲氧基-5-嘧啶硼酸(1.6g)、Pd(dppf)Cl 2-CH 2Cl 2(325.64mg)和Cs 2CO 3(3.75g)混合于二氧六环(25mL)与水(5mL)，氮气保护下，升温至70℃反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析纯化(PE:EA＝1:1),得1.1g白色固体，即化合物M1(M+H +:267、269)。 4,6-Dichloro-3-methyl pyridazine (1.3g), 2,4- dimethoxy-5-pyrimidine boronic acid (1.6g), Pd (dppf) Cl 2 -CH 2 Cl 2 (325.64 mg) and Cs 2 CO 3 (3.75 g) were mixed in dioxane (25 mL) and water (5 mL), and the temperature was raised to 70° C. for reaction under nitrogen protection. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. After purification by column chromatography (PE:EA=1:1), 1.1 g of white solid was obtained, namely compound M1 (M+H + : 267, 269).
中间体化合物M2的制备Preparation of intermediate compound M2
Figure PCTCN2021103508-appb-000012
Figure PCTCN2021103508-appb-000012
步骤1：step 1:
将3-氨基-4-溴-6-氯哒嗪(2g)、3-(4,4,5,5-四甲基-1,3,2-二氧杂环己硼烷-2-基)-1-(三异丙基硅烷基)-1H-吡咯(1.6g)、Pd(dppf)Cl 2-CH 2Cl 2(289.45mg)和K 2CO 3(2.20g)混合于二氧六环(25mL)与水(5mL)，氮气保护下，升温至70℃反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析纯化(DCM:MeOH＝30:1),得3.1g白色固体，即化合物M2-1(M+H +:352、354)。 3-Amino-4-bromo-6-chloropyridazine (2g), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl )-1-(triisopropylsilyl)-1H-pyrrole (1.6 g), Pd(dppf)Cl 2 -CH 2 Cl 2 (289.45 mg) and K 2 CO 3 (2.20 g) were mixed in dioxane The ring (25 mL) was reacted with water (5 mL) and warmed to 70°C under nitrogen protection. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography purification (DCM:MeOH=30:1) gave 3.1 g of white solid, namely compound M2-1 (M+H + : 352, 354).
步骤2Step 2
将化合物M2-1(3.1g)、2,4-二甲氧基-5-嘧啶硼酸(3.25g)、Pd(dppf)Cl 2-CH 2Cl 2(341.28mg)和Cs 2CO 3(8.69g)混合于二氧六环(50mL)与水(10mL)，氮气保护下，升温至90℃反应。12h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析纯化(DCM:MeOH＝20:1),得1.1g白色固体，即化合物M2-2(M+H +:299)。 Compound M2-1 (3.1 g), 2,4-dimethoxy-5-pyrimidineboronic acid (3.25 g), Pd(dppf)Cl 2 -CH 2 Cl 2 (341.28 mg) and Cs 2 CO 3 (8.69 g) Mixed with dioxane (50 mL) and water (10 mL), and heated to 90° C. for reaction under nitrogen protection. After 12 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Purification by column chromatography (DCM:MeOH=20:1) gave 1.1 g of white solid, namely compound M2-2 (M+H + : 299).
步骤3Step 3
将化合物M2-2(1.1g)、氯化亚铜(730.83mg)混合于乙腈(50mL)，滴加亚硝酸特丁酯，氮气保护下，升温至70℃反应。2h后，TLC监测显示反应完全。反应液硅藻土过滤，用乙酸乙酯洗滤饼，取滤液柱层析纯化(PE:EA＝1:5),得212mg黄色固体，即化合物M2(M+H +:318,320)。 Compound M2-2 (1.1 g) and cuprous chloride (730.83 mg) were mixed with acetonitrile (50 mL), tert-butyl nitrite was added dropwise, and the temperature was raised to 70° C. for reaction under nitrogen protection. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was filtered through celite, the filter cake was washed with ethyl acetate, and the filtrate was purified by column chromatography (PE:EA=1:5) to obtain 212 mg of yellow solid, namely compound M2 (M+H + : 318,320).
实施例1：化合物1的合成(4-((5-(6-(2,4-二氧基-1,2,3,4-四氢嘧啶-5-基)-3-甲基哒嗪-4-基)-1H-吡唑-1-基)甲基)苯甲腈)Example 1: Synthesis of Compound 1 (4-((5-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrazol-1-yl)methyl)benzonitrile)
Figure PCTCN2021103508-appb-000013
Figure PCTCN2021103508-appb-000013
步骤1：化合物1-1的合成Step 1: Synthesis of Compound 1-1
将化合物1H-吡唑-3-硼酸频哪酯(109mg)、对氰基溴苄(100mg)和K 2CO 3(211mg)混合于乙腈(5mL)，升温至70℃反应过夜。LCMS监测显示反应完全。反应液直接蒸干得白色 粘稠物100mg，即化合物1-1(M+H +:228)。 Compound 1H-pyrazole-3-boronic acid pinacol (109 mg), p-cyanobenzyl bromide (100 mg) and K 2 CO 3 (211 mg) were mixed in acetonitrile (5 mL), and the temperature was raised to 70° C. to react overnight. LCMS monitoring showed the reaction to be complete. The reaction solution was directly evaporated to dryness to obtain 100 mg of white viscous substance, namely compound 1-1 (M+H + : 228).
步骤2：化合物1-2的合成Step 2: Synthesis of Compounds 1-2
将化合物M1(129mg)、1-1(100mg)、K 2CO 3(152mg)、Pd(dppf)Cl 2-CH 2Cl 2(36mg)混合于二氧六环(5mL)与水(1mL)中，氮气保护下，升温至70℃反应。4h后，LCMS监测显示反应完全。反应液直接蒸干。柱层析分离纯化(PE:EA＝1:1)，得70mg白色固体，即化合物1-2(M+H +:413)。 Compound M1 (129 mg), 1-1 (100 mg), K 2 CO 3 (152 mg), Pd(dppf)Cl 2 -CH 2 Cl 2 (36 mg) were mixed in dioxane (5 mL) and water (1 mL) under nitrogen protection, the temperature was raised to 70 °C for the reaction. After 4 h, LCMS monitoring showed that the reaction was complete. The reaction solution was directly evaporated to dryness. Separation and purification by column chromatography (PE:EA=1:1) gave 70 mg of white solid, namely compound 1-2 (M+H + : 413).
步骤3：化合物1的合成Step 3: Synthesis of Compound 1
将化合物1-2(70mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙腈打浆得50mg白色固体，即化合物1(M+H +:386)。 Compound 1-2 (70 mg) was mixed with a 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with acetonitrile to obtain 50 mg of white solid, namely compound 1 (M+H + : 386).
实施例2：化合物2的合成(4-((3-(6-(2,4-二氧基-1,2,3,4-四氢嘧啶-5-基)-3-甲基哒嗪-4-基)-1H-吡唑-1-基)甲基)苯甲腈)Example 2: Synthesis of compound 2 (4-((3-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrazol-1-yl)methyl)benzonitrile)
Figure PCTCN2021103508-appb-000014
Figure PCTCN2021103508-appb-000014
步骤1：化合物2-1的合成Step 1: Synthesis of Compound 2-1
将化合物1H-吡唑-3-硼酸频哪酯(109mg)、对氰基溴苄(100mg)和K 2CO 3(211mg)混合于乙腈(5mL)，升温至70℃反应过夜。LCMS监测显示反应完全。反应液直接蒸干得白色粘稠物100mg，即化合物2-1(M+H +:228)。 Compound 1H-pyrazole-3-boronic acid pinacol (109 mg), p-cyanobenzyl bromide (100 mg) and K 2 CO 3 (211 mg) were mixed in acetonitrile (5 mL), and the temperature was raised to 70° C. to react overnight. LCMS monitoring showed the reaction to be complete. The reaction solution was directly evaporated to dryness to obtain 100 mg of white viscous substance, namely compound 2-1 (M+H + : 228).
步骤2：化合物2-2的合成Step 2: Synthesis of Compound 2-2
将化合物M1(129mg)、2-1(100mg)、K 2CO 3(152mg)、Pd(dppf)Cl 2-CH 2Cl 2(36mg)混合于二氧六环(5mL)与水(1mL)，氮气保护下，升温至70℃反应。4h后，TLC监测显示反应完全。反应液直接蒸干。柱层析分离纯化(PE:EA＝1:1)，得60mg白色固体，即化合物2-2(M+H +:413)。 Compound M1 (129 mg), 2-1 (100 mg), K 2 CO 3 (152 mg), Pd(dppf)Cl 2 -CH 2 Cl 2 (36 mg) were mixed in dioxane (5 mL) and water (1 mL) , under nitrogen protection, the temperature was raised to 70 °C for the reaction. After 4 h, TLC monitoring showed that the reaction was complete. The reaction solution was directly evaporated to dryness. Separation and purification by column chromatography (PE:EA=1:1) gave 60 mg of white solid, namely compound 2-2 (M+H + : 413).
步骤3：化合物2的合成Step 3: Synthesis of Compound 2
将化合物2-2(60mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙腈打浆得40mg白色固体，即化合物2(M+H +:386)。 Compound 2-2 (60 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration, and 40 mg of white solid was obtained by beating with acetonitrile, namely compound 2 (M+H + : 386).
实施例3：化合物3的合成(5-(6-甲基-5-(1-(4-甲基苄基)-1H-吡唑-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 3: Synthesis of Compound 3 (5-(6-methyl-5-(1-(4-methylbenzyl)-1H-pyrazol-3-yl)pyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000015
Figure PCTCN2021103508-appb-000015
步骤1：化合物3-1的合成Step 1: Synthesis of Compound 3-1
将化合物1H-吡唑-3-硼酸频哪酯(109mg)、对甲基溴苄(100mg)和K 2CO 3(211mg)混合于乙腈(5mL)，升温至70℃反应过夜。LCMS监测显示反应完全。反应液直接蒸干得白色粘稠物100mg，即化合物3-1(M+H +:217)。 Compound 1H-pyrazole-3-boronic acid pinacol (109 mg), p-methylbenzyl bromide (100 mg) and K 2 CO 3 (211 mg) were mixed in acetonitrile (5 mL), and the temperature was raised to 70° C. to react overnight. LCMS monitoring showed the reaction to be complete. The reaction solution was directly evaporated to dryness to obtain 100 mg of white viscous substance, namely compound 3-1 (M+H + : 217).
步骤2：化合物3-2的合成Step 2: Synthesis of Compound 3-2
将化合物M1(129mg)、3-1(100mg)、K 2CO 3(152mg)、Pd(dppf)Cl 2-CH 2Cl 2(36mg)混合于二氧六环(5mL)与水(1mL)，氮气保护下，升温至70℃反应过夜。反应液直接蒸干。柱层析分离纯化(PE:EA＝1:1)，得70mg白色固体，即化合物3-2(M+H +:403)。 Compound M1 (129 mg), 3-1 (100 mg), K 2 CO 3 (152 mg), Pd(dppf)Cl 2 -CH 2 Cl 2 (36 mg) were mixed in dioxane (5 mL) and water (1 mL) , under nitrogen protection, the temperature was raised to 70 °C and the reaction was carried out overnight. The reaction solution was directly evaporated to dryness. Separation and purification by column chromatography (PE:EA=1:1) gave 70 mg of white solid, namely compound 3-2 (M+H + : 403).
步骤3：化合物3的合成Step 3: Synthesis of Compound 3
将化合物3-2(70mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙腈打浆得50mg白色固体，即化合物3(M+H +:375)。 Compound 3-2 (70 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with acetonitrile to obtain 50 mg of white solid, namely compound 3 (M+H + : 375).
实施例4：化合物4的合成(5-(5-(1-苄基-1H-吡唑-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 4: Synthesis of Compound 4 (5-(5-(1-benzyl-1H-pyrazol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H )-diketone)
Figure PCTCN2021103508-appb-000016
Figure PCTCN2021103508-appb-000016
步骤1：化合物4-1的合成Step 1: Synthesis of Compound 4-1
将化合物1H-吡唑-3-硼酸频哪酯(109mg)、溴苄(95mg)和K 2CO 3(211mg)混合于乙腈(5mL)，升温至70℃反应过夜。TLC监测显示反应完全。反应液直接蒸干得白色粘稠物100mg，即化合物4-1(M+H +:203)。 Compound 1H-pyrazole-3-boronic acid pinacol (109 mg), benzyl bromide (95 mg) and K 2 CO 3 (211 mg) were mixed in acetonitrile (5 mL), and the temperature was raised to 70° C. to react overnight. TLC monitoring showed the reaction to be complete. The reaction solution was directly evaporated to dryness to obtain 100 mg of white viscous substance, namely compound 4-1 (M+H + : 203).
步骤2：化合物4-2的合成Step 2: Synthesis of Compound 4-2
将化合物M1(129mg)、4-1(100mg)、K 2CO 3(152mg)、Pd(dppf)Cl 2-CH 2Cl 2(36mg)混合于二氧六环(5mL)与水(1mL)，氮气保护下，升温至70℃反应。2h后，TLC监测显示反应完全。反应液直接蒸干。柱层析分离纯化(PE:EA＝1:1)，得70mg白色固体，即化合物4-2(M+H +:389)。 Compound M1 (129 mg), 4-1 (100 mg), K 2 CO 3 (152 mg), Pd(dppf)Cl 2 -CH 2 Cl 2 (36 mg) were mixed in dioxane (5 mL) and water (1 mL) , under nitrogen protection, the temperature was raised to 70 °C for the reaction. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was directly evaporated to dryness. Separation and purification by column chromatography (PE:EA=1:1) gave 70 mg of white solid, namely compound 4-2 (M+H + : 389).
步骤3：化合物4的合成Step 3: Synthesis of Compound 4
将化合物4-2(70mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙腈打浆得50mg白色固体，即化合物4(M+H +:361)。 Compound 4-2 (70 mg) was mixed with a 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with acetonitrile to obtain 50 mg of white solid, namely compound 4 (M+H + : 361).
实施例5：化合物5的合成(5-(5-(1-(4-氯苄基)-1H-吡唑-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 5: Synthesis of Compound 5 (5-(5-(1-(4-chlorobenzyl)-1H-pyrazol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2, 4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000017
Figure PCTCN2021103508-appb-000017
步骤1：化合物5-1的合成Step 1: Synthesis of Compound 5-1
将化合物M1(70mg)、1H-吡唑-3-硼酸频哪酯(76.40mg)、K 2CO 3(72.55mg)、Pd(dppf)Cl 2-CH 2Cl 2(10.72mg)混合于二氧六环(2mL)与水(0.4mL)，氮气保护下，升温至70℃反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。二氯甲烷/石油醚(V:V＝1/1)打浆得70mg白色固体，即化合物5-1(M+H +:299)。 Compound M1 (70 mg), 1H-pyrazole-3-boronic acid pinacol (76.40 mg), K 2 CO 3 (72.55 mg), Pd(dppf)Cl 2 -CH 2 Cl 2 (10.72 mg) were mixed in two Oxane (2 mL) was reacted with water (0.4 mL) under nitrogen protection, and the temperature was raised to 70°C. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Dichloromethane/petroleum ether (V:V=1/1) was slurried to obtain 70 mg of white solid, namely compound 5-1 (M+H + : 299).
步骤2：化合物5-2的合成Step 2: Synthesis of Compound 5-2
将化合物5-1(70mg)、对氯溴化苄(50.60mg)和K 2CO 3(64.86mg)混合于DMF(2mL)，升温至50℃反应。1h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。乙腈打浆得70mg白色固体，即化合物5-2(M+H +:423、425)。 Compound 5-1 (70 mg), p-chlorobenzyl bromide (50.60 mg) and K 2 CO 3 (64.86 mg) were mixed in DMF (2 mL), and the temperature was raised to 50° C. to react. After 1 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Slurry with acetonitrile to obtain 70 mg of white solid, namely compound 5-2 (M+H + : 423, 425).
步骤3：化合物5的合成Step 3: Synthesis of Compound 5
将化合物5-2(90mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙腈打浆得63mg白色固体，即化合物5(M+H +:395、397)。 Compound 5-2 (90 mg) was mixed with a 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with acetonitrile to obtain 63 mg of white solid, namely compound 5 (M+H + : 395, 397).
实施例6：化合物6的合成(5-(6-甲基-5-(1-甲基-1H-吡唑-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 6: Synthesis of Compound 6 (5-(6-methyl-5-(1-methyl-1H-pyrazol-3-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H )-diketone)
Figure PCTCN2021103508-appb-000018
Figure PCTCN2021103508-appb-000018
步骤1：化合物6-1的合成Step 1: Synthesis of Compound 6-1
将化合物M1(70mg)、1-甲基-3-吡唑硼酸频哪醇酯(76.40mg)、K 2CO 3(72.55mg)、Pd(dppf)Cl 2-CH 2Cl 2(10.72mg)混合于二氧六环(2mL)与水(0.4mL)，氮气保护下，升温至70℃反应。2h后，TLC监测显示反应完全。反应液直接蒸干。柱层析分离纯化(PE:EA＝1:1)，得70mg白色固体，即化合物6-1(M+H +:313)。 Compound M1 (70 mg), 1-methyl-3-pyrazoleboronic acid pinacol ester (76.40 mg), K 2 CO 3 (72.55 mg), Pd(dppf)Cl 2 -CH 2 Cl 2 (10.72 mg) It was mixed with dioxane (2 mL) and water (0.4 mL), and under nitrogen protection, the temperature was raised to 70°C for reaction. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was directly evaporated to dryness. After separation and purification by column chromatography (PE:EA=1:1), 70 mg of white solid was obtained, namely compound 6-1 (M+H + : 313).
步骤2：化合物6的合成Step 2: Synthesis of Compound 6
将化合物6-1(70mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙腈打浆得50mg白色固体，即化合物6(M+H +:285)。 Compound 6-1 (70 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with acetonitrile to obtain 50 mg of white solid, namely compound 6 (M+H + : 285).
实施例7：化合物7的合成(5-(5-(1-异丙基-1H-吡唑-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 7: Synthesis of compound 7 (5-(5-(1-isopropyl-1H-pyrazol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H, 3H)-diketone)
Figure PCTCN2021103508-appb-000019
Figure PCTCN2021103508-appb-000019
步骤1：化合物7-1的合成Step 1: Synthesis of Compound 7-1
将化合物M1(70mg)、1-异丙基-3-吡唑硼酸频哪醇酯(77.40mg)、K 2CO 3(72.55mg)、Pd(dppf)Cl 2-CH 2Cl 2(10.72mg)混合于二氧六环(2mL)与水(0.4mL)，氮气保护下，升温至70℃反应。2h后，TLC监测显示反应完全。反应液直接蒸干。柱层析分离纯化(PE:EA＝1:1)，得70mg白色固体，即化合物7-1(M+H +:341)。 Compound M1 (70 mg), 1-isopropyl-3-pyrazoleboronic acid pinacol ester (77.40 mg), K 2 CO 3 (72.55 mg), Pd(dppf)Cl 2 -CH 2 Cl 2 (10.72 mg) ) was mixed with dioxane (2 mL) and water (0.4 mL), and the temperature was raised to 70°C for reaction under nitrogen protection. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was directly evaporated to dryness. Separation and purification by column chromatography (PE:EA=1:1) gave 70 mg of white solid, namely compound 7-1 (M+H + : 341).
步骤2：化合物7的合成Step 2: Synthesis of Compound 7
将化合物7-1(70mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙腈打浆得50mg白色固体，即化合物7(M+H +:313)。 Compound 7-1 (70 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with acetonitrile to obtain 50 mg of white solid, namely compound 7 (M+H + : 313).
实施例8：化合物8的合成(5-(5-(1-(环丙基甲基)-1H-吡唑-4-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 8: Synthesis of Compound 8 (5-(5-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-6-methylpyridazin-3-yl)pyrimidine-2, 4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000020
Figure PCTCN2021103508-appb-000020
步骤1：化合物8-1的合成Step 1: Synthesis of Compound 8-1
将化合物M1(70mg)、4-吡唑硼酸频哪醇酯(76.40mg)、K 2CO 3(72.55mg)、Pd(dppf)Cl 2-CH 2Cl 2(10.72mg)混合于二氧六环(2mL)与水(0.4mL)，氮气保护下，升温至70℃反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。二氯甲烷/石油醚(V:V＝1:1)打浆得70mg白色固体，即化合物8-1(M+H +:299)。 Compound M1 (70 mg), 4-pyrazoleboronic acid pinacol ester (76.40 mg), K 2 CO 3 (72.55 mg), Pd(dppf)Cl 2 -CH 2 Cl 2 (10.72 mg) were mixed in dioxane The ring (2 mL) was reacted with water (0.4 mL) and warmed to 70°C under nitrogen protection. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Dichloromethane/petroleum ether (V:V=1:1) was slurried to obtain 70 mg of white solid, namely compound 8-1 (M+H + : 299).
步骤2：化合物8-2的合成Step 2: Synthesis of Compound 8-2
将化合物8-1(70mg)、溴甲基环丙烷(30.10mg)和K 2CO 3(64.86mg)混合于DMF(2mL)， 升温至50℃反应。1h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。乙腈打浆得60mg白色固体，即化合物8-2(M+H +:353)。 Compound 8-1 (70 mg), bromomethylcyclopropane (30.10 mg) and K 2 CO 3 (64.86 mg) were mixed in DMF (2 mL), and the temperature was raised to 50°C to react. After 1 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Slurry with acetonitrile to obtain 60 mg of white solid, namely compound 8-2 (M+H + : 353).
步骤3：化合物8的合成Step 3: Synthesis of Compound 8
将化合物8-2(60mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙腈打浆得50mg白色固体，即化合物8(M+H +:325)。 Compound 8-2 (60 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C for reaction. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with acetonitrile to obtain 50 mg of white solid, namely compound 8 (M+H + : 325).
实施例9：化合物9的合成(5-(5-(1-(4-氯苄基)-1H-吡唑-4-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 9: Synthesis of Compound 9 (5-(5-(1-(4-chlorobenzyl)-1H-pyrazol-4-yl)-6-methylpyridazin-3-yl)pyrimidine-2, 4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000021
Figure PCTCN2021103508-appb-000021
步骤1：化合物9-1的合成Step 1: Synthesis of Compound 9-1
将化合物8-1(70mg)、对氯溴苄(50.30mg)和K 2CO 3(64.86mg)混合于DMF(2mL)，升温至50℃反应。1h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。乙腈打浆得75mg白色固体，即化合物9-1(M+H +:423)。 Compound 8-1 (70 mg), p-chlorobenzyl bromide (50.30 mg) and K 2 CO 3 (64.86 mg) were mixed in DMF (2 mL), and the temperature was raised to 50° C. to react. After 1 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Slurry with acetonitrile to obtain 75 mg of white solid, namely compound 9-1 (M+H + : 423).
步骤2：化合物9的合成Step 2: Synthesis of Compound 9
将化合物9-1(75mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙腈打浆得50mg白色固体，即化合物9(M+H +:395)。 Compound 9-1 (75 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with acetonitrile to obtain 50 mg of white solid, namely compound 9 (M+H + : 395).
实施例10：化合物10的合成(4-((4-(6-(2,4-二氧基-1,2,3,4-四氢嘧啶-5-基)-3-甲基哒嗪-4-基)-1H-吡唑-1-基)甲基)苯甲腈)Example 10: Synthesis of compound 10 (4-((4-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrazol-1-yl)methyl)benzonitrile)
Figure PCTCN2021103508-appb-000022
Figure PCTCN2021103508-appb-000022
步骤1：化合物10-1的合成Step 1: Synthesis of Compound 10-1
将化合物8-1(70mg)、对氰基溴化苄(50.60mg)和K 2CO 3(64.86mg)混合于DMF(2 mL)，升温至50℃反应。1h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。乙腈打浆得90mg白色固体，即化合物10-1(M+H +:414)。 Compound 8-1 (70 mg), p-cyanobenzyl bromide (50.60 mg) and K 2 CO 3 (64.86 mg) were mixed in DMF (2 mL), and the temperature was raised to 50° C. to react. After 1 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Slurry with acetonitrile to obtain 90 mg of white solid, namely compound 10-1 (M+H + : 414).
步骤3：化合物10的合成Step 3: Synthesis of Compound 10
将化合物10-1(90mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙腈打浆得50mg白色固体，即化合物10(M+H +:386)。 Compound 10-1 (90 mg) was mixed with a 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with acetonitrile to obtain 50 mg of white solid, namely compound 10 (M+H + : 386).
实施例11：化合物11的合成(5-(5-(呋喃-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 11: Synthesis of Compound 11 (5-(5-(furan-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000023
Figure PCTCN2021103508-appb-000023
步骤1：化合物11-1的合成Step 1: Synthesis of Compound 11-1
将化合物M1(100mg)、3-呋喃硼酸(84mg)、K 2CO 3(77.74mg)、Pd(dppf)Cl 2-CH 2Cl 2(21.95mg)混合于二氧六环(4mL)与水(1mL)，氮气保护下，升温至70℃反应。1h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、硅胶拌样，柱色谱分离，洗脱剂比例石油醚/乙酸乙酯(V:V＝5:1-1:3)打浆得80mg黄色固体，即化合物11-1(M+H +:299)。 Compound M1 (100 mg), 3- furanboronic acid (84 mg), K 2 CO 3 (77.74 mg), Pd(dppf)Cl 2 -CH 2 Cl 2 (21.95 mg) were mixed in dioxane (4 mL) and water (1 mL), under nitrogen protection, the temperature was raised to 70°C for reaction. After 1 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried, mixed with silica gel, and separated by column chromatography. The eluent ratio was petroleum ether/ethyl acetate (V:V=5:1-1 : 3) beating to obtain 80 mg of yellow solid, namely compound 11-1 (M+H + : 299).
步骤2：化合物11的合成Step 2: Synthesis of Compound 11
将化合物11-1(80mg)混合于1M稀盐酸溶液(3mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙腈打浆得26mg白色固体，即化合物11(M+H +:271)。 Compound 11-1 (80 mg) was mixed with 1 M diluted hydrochloric acid solution (3 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with acetonitrile to obtain 26 mg of white solid, namely compound 11 (M+H + : 271).
实施例12：化合物12的合成(5-(6-甲基-5-(1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 12: Synthesis of Compound 12 (5-(6-methyl-5-(1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000024
Figure PCTCN2021103508-appb-000024
步骤1：化合物16-1的合成Step 1: Synthesis of Compound 16-1
将化合物M1(70mg)、3-(四甲基-1,3,2-二噁硼戊环-2-基)-1-[三(丙烷-2-基)甲硅烷基]-1H-吡咯(157.22mg)、K 2CO 3(103.65mg)和Pd(dppf)Cl 2-CH 2Cl 2(12.25mg)混合于二氧六环(2.5mL)与水(0.5mL)，氮气保护下，升温至70℃反应。2h后，TLC监测显示 反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得棕色固体(136mg)，即化合物16-1(M+H +:298、454)。无需纯化直接用于下一步。 Compound M1 (70 mg), 3-(tetramethyl-1,3,2-dioxaborolane-2-yl)-1-[tris(propan-2-yl)silyl]-1H-pyrrole (157.22 mg), K 2 CO 3 (103.65 mg) and Pd(dppf)Cl 2 -CH 2 Cl 2 (12.25 mg) were mixed in dioxane (2.5 mL) and water (0.5 mL), under nitrogen protection, The temperature was raised to 70°C for reaction. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a brown solid (136 mg), namely compound 16-1 (M+H + : 298, 454). Used directly in the next step without purification.
步骤2：化合物16-2的合成Step 2: Synthesis of Compound 16-2
将化合物16-1(136mg)和四丁基氟化铵(224.78mg)混合于THF(5mL)，室温搅拌。0.5h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得棕色固体(90mg)，即化合物16-2(M+H +:298)。无需纯化直接用于下一步。 Compound 16-1 (136 mg) and tetrabutylammonium fluoride (224.78 mg) were mixed in THF (5 mL) and stirred at room temperature. After 0.5 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a brown solid (90 mg), namely compound 16-2 (M+H + : 298). Used directly in the next step without purification.
步骤3：化合物12的合成Step 3: Synthesis of Compound 12
将化合物16-2(30mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，DMF/甲醇(V:V＝1/2)打浆得11.8mg浅绿色固体，即化合物12(M+H +:270)。 Compound 16-2 (30 mg) was mixed with a 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration, and slurried with DMF/methanol (V:V=1/2) to obtain 11.8 mg of light green solid, namely compound 12 (M+H + : 270).
实施例13：化合物13的合成(5-(5-(1-(环丙基甲基)-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 13: Synthesis of Compound 13 (5-(5-(1-(cyclopropylmethyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4 (1H,3H)-dione)
Figure PCTCN2021103508-appb-000025
Figure PCTCN2021103508-appb-000025
步骤1：化合物13-1的合成Step 1: Synthesis of Compound 13-1
将化合物16-2(59mg)、溴甲基环丙烷(40.19mg)、Cs 2CO 3(129.31mg)混合于DMF(6mL)，升温至50℃反应。10h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得黄色油状(65mg)，即化合物13-1(M+H +:352)。无需纯化直接用于下一步。 Compound 16-2 (59 mg), bromomethylcyclopropane (40.19 mg), and Cs 2 CO 3 (129.31 mg) were mixed with DMF (6 mL), and the temperature was raised to 50° C. to react. After 10 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a yellow oil (65 mg), namely compound 13-1 (M+H + : 352). Used directly in the next step without purification.
步骤2：化合物13的合成Step 2: Synthesis of Compound 13
将化合物13-1(90mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。反应液旋干得粗品，制备TLC纯化(DCM/MeOH＝10/1)得36.9mg黄色固体，即化合物13(M+H +:324)。 Compound 13-1 (90 mg) was mixed with a 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried to obtain the crude product, which was purified by preparative TLC (DCM/MeOH=10/1) to obtain 36.9 mg of yellow solid, namely compound 13 (M+H + : 324).
实施例14：化合物14的合成(5-(5-(1-(4-氯苄基)-1H-吡咯-3-基)-6-甲基吡啶-3-基)嘧啶-2,4(1H，3H)-二酮)Example 14: Synthesis of compound 14 (5-(5-(1-(4-chlorobenzyl)-1H-pyrrol-3-yl)-6-methylpyridin-3-yl)pyrimidin-2,4( 1H,3H)-dione)
Figure PCTCN2021103508-appb-000026
Figure PCTCN2021103508-appb-000026
步骤1：化合物14-1的合成Step 1: Synthesis of Compound 14-1
将化合物16-2(59mg)、对氯溴化苄(61.16mg)和Cs 2CO 3(129.31mg)混合于DMF(6mL)，升温至50℃反应。1.5h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得黄色固体(80mg)，即化合物14-1(M+H +:421、423)。无需纯化直接用于下一步。 Compound 16-2 (59 mg), p-chlorobenzyl bromide (61.16 mg) and Cs 2 CO 3 (129.31 mg) were mixed in DMF (6 mL), and the temperature was raised to 50°C to react. After 1.5h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted three times with ethyl acetate, washed with saturated brine, dried and concentrated to obtain a yellow solid (80 mg), namely compound 14-1 (M+H + : 421, 423). Used directly in the next step without purification.
步骤2：化合物14的合成Step 2: Synthesis of Compound 14
将化合物14-1(80mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，DCM/MeOH(1/1)打浆得7.6mg淡黄色固体，即化合物14(M+H +:394、396)。 Compound 14-1 (80 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with DCM/MeOH (1/1) to obtain 7.6 mg of pale yellow solid, namely compound 14 (M+H + : 394, 396).
实施例15：化合物15的合成(5-(5-(1-(4-甲氧基苄基)-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 15: Synthesis of Compound 15 (5-(5-(1-(4-methoxybenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000027
Figure PCTCN2021103508-appb-000027
步骤1：化合物15-1的合成Step 1: Synthesis of Compound 15-1
将化合物16-2(59mg)、对甲氧基氯化苄(59.85mg)和Cs 2CO 3(129.31mg)混合于DMF(6mL)，升温至50℃反应。1.5h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得黄色固体(80mg)，即化合物15-1(M+H +:418)。无需纯化直接用于下一步。 Compound 16-2 (59 mg), p-methoxybenzyl chloride (59.85 mg) and Cs 2 CO 3 (129.31 mg) were mixed in DMF (6 mL), and the temperature was raised to 50°C to react. After 1.5h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a yellow solid (80 mg), namely compound 15-1 (M+H + : 418). Used directly in the next step without purification.
步骤2：化合物15的合成Step 2: Synthesis of Compound 15
将化合物15-1(80mg,191.64umol)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，制备液相分离得12.3mg白色固体，即化合物15(M+H +:390)。 Compound 15-1 (80 mg, 191.64 umol) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C for reaction. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration, and 12.3 mg of white solid was obtained by preparative liquid phase separation, namely compound 15 (M+H + : 390).
实施例16：化合物16的合成(4-((3-(6-(2,4-二氧基-1,2,3,4-四氢嘧啶-5-基)-3-甲基哒嗪-4-基)-1H-吡咯-1-基)甲基)苯甲腈)Example 16: Synthesis of compound 16 (4-((3-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrrol-1-yl)methyl)benzonitrile)
Figure PCTCN2021103508-appb-000028
Figure PCTCN2021103508-appb-000028
步骤：化合物16-3的合成Step: Synthesis of Compound 16-3
将化合物16-2(60mg)、对氰基溴化苄(47.48mg)和K 2CO 3(55.78mg)混合于DMF(2mL)，升温至50℃反应。10h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。制备TLC纯化(PE/EA＝3/1)得60mg黄色固体，即化合物16-3(M+H +:413)。 Compound 16-2 (60 mg), p-cyanobenzyl bromide (47.48 mg) and K 2 CO 3 (55.78 mg) were mixed in DMF (2 mL), and the temperature was raised to 50°C to react. After 10 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Preparative TLC purification (PE/EA=3/1) yielded 60 mg of yellow solid, compound 16-3 (M+H + : 413).
步骤4：化合物16的合成Step 4: Synthesis of Compound 16
将化合物16-3(60mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。反应液旋干粗品，制备液相分离得3.2mg黄色固体，即化合物16(M+H +:385)。 Compound 16-3 (60 mg) was mixed with a 1M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried to dry the crude product, and 3.2 mg of yellow solid was obtained by preparative liquid phase separation, namely compound 16 (M+H + : 385).
实施例17：化合物17的合成(5-(5-(1-苄基-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 17: Synthesis of Compound 17 (5-(5-(1-benzyl-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H) -diketone)
Figure PCTCN2021103508-appb-000029
Figure PCTCN2021103508-appb-000029
步骤1：化合物17-1的合成Step 1: Synthesis of Compound 17-1
将化合物16-2(60mg)、溴化苄(46.48mg)和Cs 2CO 3(131.72mg)混合于DMF(2mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得60mg黄色固体，即化合物17-1(M+H +:388)。 Compound 16-2 (60 mg), benzyl bromide (46.48 mg) and Cs 2 CO 3 (131.72 mg) were mixed in DMF (2 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 60 mg of yellow solid, namely compound 17-1 (M+H + : 388).
步骤4：化合物17的合成Step 4: Synthesis of Compound 17
将化合物17-2(60mg,145.47umol)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得30mg白色固体，即化合物17(M+H +:360)。 Compound 17-2 (60 mg, 145.47 umol) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C for reaction. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with ethanol to obtain 30 mg of white solid, namely compound 17 (M+H + : 360).
1H-NMR(500MHz,DMSO-d 6)δ11.50-11.37(m,2H),8.28(d,J＝5.9Hz,1H),8.22(s,1H),7.49(s,1H),7.38-7.35(m,2H),7.31-7.28(m,3H),7.03(s,1H),6.52(s,1H),5.21(s,2H),2.76(s,3H). 1 H-NMR (500MHz, DMSO-d 6 )δ11.50-11.37(m, 2H), 8.28(d, J=5.9Hz, 1H), 8.22(s, 1H), 7.49(s, 1H), 7.38 -7.35(m,2H),7.31-7.28(m,3H),7.03(s,1H),6.52(s,1H),5.21(s,2H),2.76(s,3H).
实施例18：化合物18的合成(5-(5-(1-(3-甲氧基苄基)-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 18: Synthesis of Compound 18 (5-(5-(1-(3-methoxybenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000030
Figure PCTCN2021103508-appb-000030
步骤1：化合物18-1的合成Step 1: Synthesis of Compound 18-1
将化合物16-2(20mg)、间甲氧基溴苄(41mg)和Cs 2CO 3(66.2mg)混合于DMF(2mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得11mg黄色固体，即化合物18-1(M+H +:418)。 Compound 16-2 (20 mg), m-methoxybenzyl bromide (41 mg) and Cs 2 CO 3 (66.2 mg) were mixed in DMF (2 mL), and the temperature was raised to 50° C. to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 11 mg of yellow solid, namely compound 18-1 (M+H + : 418).
步骤2：化合物18的合成Step 2: Synthesis of Compound 18
将化合物18-2(11mg)混合于1M稀盐酸溶液(1.5mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得4.2mg黄色固体，即化合物18(M+H +:390)。 Compound 18-2 (11 mg) was mixed with a 1M dilute hydrochloric acid solution (1.5 mL), and the temperature was raised to 70°C for reaction. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration, and 4.2 mg of yellow solid was obtained by beating with ethanol, namely compound 18 (M+H + : 390).
实施例19：化合物19的合成(5-(6-甲基-5-(1-(3-(三氟甲基)苄基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 19: Synthesis of Compound 19 (5-(6-methyl-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrrol-3-yl)pyridazin-3-yl) Pyrimidine-2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000031
Figure PCTCN2021103508-appb-000031
步骤1：化合物19-1的合成Step 1: Synthesis of Compound 19-1
将化合物16-2(50mg)、1-氯甲基-3-三氟甲基苯(118mgl)和Cs 2CO 3(198mg)混合于DMF(4mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM: MeOH＝15:1)得60mg黄色固体，即化合物19-1(M+H +:456)。 Compound 16-2 (50 mg), 1-chloromethyl-3-trifluoromethylbenzene (118 mgl) and Cs 2 CO 3 (198 mg) were mixed in DMF (4 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 60 mg of yellow solid, namely compound 19-1 (M+H + :456).
步骤2：化合物19的合成Step 2: Synthesis of Compound 19
将化合物19-2(60mg)混合于1M稀盐酸溶液(5mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得41.48mg黄色固体，即化合物19(M+H +:428)。 Compound 19-2 (60 mg) was mixed with a 1M dilute hydrochloric acid solution (5 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration, and 41.48 mg of yellow solid was obtained by beating with ethanol, namely compound 19 (M+H + : 428).
实施例20：化合物20的合成(5-(6-甲基-5-(1-(2-(三氟甲基)苄基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 20: Synthesis of Compound 20 (5-(6-methyl-5-(1-(2-(trifluoromethyl)benzyl)-1H-pyrrol-3-yl)pyridazin-3-yl) Pyrimidine-2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000032
Figure PCTCN2021103508-appb-000032
步骤1：化合物20-1的合成Step 1: Synthesis of Compound 20-1
将化合物16-2(50mg)、2-三氟甲基苄基氯(118mg)和Cs 2CO 3(198mg)混合于DMF(4mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得50mg黄色固体，即化合物20-1(M+H +:456)。 Compound 16-2 (50 mg), 2-trifluoromethylbenzyl chloride (118 mg) and Cs 2 CO 3 (198 mg) were mixed in DMF (4 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 50 mg of yellow solid, namely compound 20-1 (M+H + : 456).
步骤2：化合物20的合成Step 2: Synthesis of Compound 20
将化合物20-1(50mg)混合于1M稀盐酸溶液(5mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得32.83mg黄色固体，即化合物20(M+H +:428)。 Compound 20-1 (50 mg) was mixed with a 1 M dilute hydrochloric acid solution (5 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with ethanol to obtain 32.83 mg of yellow solid, namely compound 20 (M+H + : 428).
实施例21：化合物21的合成(5-(6-甲基-5-(1-(喹啉-4-基甲基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 21: Synthesis of Compound 21 (5-(6-methyl-5-(1-(quinolin-4-ylmethyl)-1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000033
Figure PCTCN2021103508-appb-000033
步骤1：化合物21-1的合成Step 1: Synthesis of Compound 21-1
将化合物16-2(40mg)、4-氯甲基喹啉(56.97mg)和Cs 2CO 3(159mg)混合于DMF(3mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得30mg黄色固体，即化合物21-1(M+H +:439)。 Compound 16-2 (40 mg), 4-chloromethylquinoline (56.97 mg) and Cs 2 CO 3 (159 mg) were mixed in DMF (3 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 30 mg of yellow solid, namely compound 21-1 (M+H + : 439).
步骤2：化合物21的合成Step 2: Synthesis of Compound 21
将化合物21-1(30mg)混合于1M稀盐酸溶液(3mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得18.35mg黄色固体，即化合物21(M+H +:411)。 Compound 21-1 (30 mg) was mixed with a 1 M dilute hydrochloric acid solution (3 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with ethanol to obtain 18.35 mg of yellow solid, namely compound 21 (M+H + : 411).
实施例22：化合物22的合成(5-(6-甲基-5-(1-(1-苯乙基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 22: Synthesis of Compound 22 (5-(6-methyl-5-(1-(1-phenethyl)-1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidin-2,4 (1H,3H)-dione)
Figure PCTCN2021103508-appb-000034
Figure PCTCN2021103508-appb-000034
步骤1：化合物22-1的合成Step 1: Synthesis of Compound 22-1
将化合物16-2(30mg)、1-氯-1-苯乙烷(51.1mg)和Cs 2CO 3(119mg)混合于DMF(2mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得20mg黄色固体，即化合物22-1(M+H +:402)。 Compound 16-2 (30 mg), 1-chloro-1-phenylethane (51.1 mg) and Cs 2 CO 3 (119 mg) were mixed in DMF (2 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 20 mg of yellow solid, namely compound 22-1 (M+H + :402).
步骤2：化合物22的合成Step 2: Synthesis of Compound 22
将化合物22-1(20mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得8.3mg黄色固体，即化合物22(M+H +:374)。 Compound 22-1 (20 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration, and 8.3 mg of yellow solid was obtained by beating with ethanol, namely compound 22 (M+H + : 374).
实施例23：化合物23的合成(5-(5-(1-(环戊基甲基)-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 23: Synthesis of Compound 23 (5-(5-(1-(cyclopentylmethyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidin-2,4 (1H,3H)-dione)
Figure PCTCN2021103508-appb-000035
Figure PCTCN2021103508-appb-000035
步骤1：化合物23-1的合成Step 1: Synthesis of Compound 23-1
将化合物16-2(30mg)、氯甲基环戊烷(43.1mg)和Cs 2CO 3(119mg)混合于DMF(2mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得20mg黄色固体，即化合物23-1(M+H +:380)。 Compound 16-2 (30 mg), chloromethylcyclopentane (43.1 mg) and Cs 2 CO 3 (119 mg) were mixed in DMF (2 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 20 mg of yellow solid, namely compound 23-1 (M+H + : 380).
步骤2：化合物23的合成Step 2: Synthesis of Compound 23
将化合物23-1(20mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得16.94mg黄色固体，即化合物23(M+H +:352)。 Compound 23-1 (20 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration, and 16.94 mg of yellow solid was obtained by beating with ethanol, namely compound 23 (M+H + : 352).
实施例24：化合物24的合成(5-(5-(1-(环己基甲基)-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 24: Synthesis of Compound 24 (5-(5-(1-(cyclohexylmethyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidin-2,4( 1H,3H)-dione)
Figure PCTCN2021103508-appb-000036
Figure PCTCN2021103508-appb-000036
步骤1：化合物24-1的合成Step 1: Synthesis of Compound 24-1
将化合物16-2(20mg)、氯甲基环己烷(28mg)和Cs 2CO 3(66.2mg)混合于DMF(2mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得10mg黄色固体，即化合物24-1(M+H +:394)。 Compound 16-2 (20 mg), chloromethylcyclohexane (28 mg) and Cs 2 CO 3 (66.2 mg) were mixed in DMF (2 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 10 mg of yellow solid, namely compound 24-1 (M+H + : 394).
步骤2：化合物24的合成Step 2: Synthesis of Compound 24
将化合物24-1(10mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得5.92mg黄色固体，即化合物24(M+H +:366)。 Compound 24-1 (10 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration, and 5.92 mg of yellow solid was obtained by beating with ethanol, namely compound 24 (M+H + : 366).
实施例25：化合物25的合成(4-((3-(6-(2,4-二氧基-1,2,3,4-四氢嘧啶-5-基)-3-甲基哒嗪-4-基)-1H-吡咯-1-基)甲基)-3-氟苯甲腈)Example 25: Synthesis of compound 25 (4-((3-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrrol-1-yl)methyl)-3-fluorobenzonitrile)
Figure PCTCN2021103508-appb-000037
Figure PCTCN2021103508-appb-000037
步骤1：化合物25-1的合成Step 1: Synthesis of Compound 25-1
将化合物16-2(20mg)、4-(氯甲基)-3-氟苯甲腈(36mg)和Cs 2CO 3(66.2mg)混合于DMF(2mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得20mg黄色固体，即化合物25-1(M+H +:431)。 Compound 16-2 (20 mg), 4-(chloromethyl)-3-fluorobenzonitrile (36 mg) and Cs 2 CO 3 (66.2 mg) were mixed in DMF (2 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 20 mg of yellow solid, namely compound 25-1 (M+H + : 431).
步骤2：化合物25的合成Step 2: Synthesis of Compound 25
将化合物25-1(20mg)混合于1M稀盐酸溶液(3mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得10.54mg黄色固体，即化合物25(M+H +:403)。 Compound 25-1 (20 mg) was mixed with a 1 M dilute hydrochloric acid solution (3 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with ethanol to obtain 10.54 mg of a yellow solid, namely compound 25 (M+H + : 403).
实施例26：化合物26的合成(5-(5-(1-(2,4-二氟苄基)-1H-吡咯-3-基)-6-甲基哒嗪-3- 基)嘧啶-2,4(1H，3H)-二酮)Example 26: Synthesis of Compound 26 (5-(5-(1-(2,4-difluorobenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000038
Figure PCTCN2021103508-appb-000038
步骤1：化合物26-1的合成Step 1: Synthesis of Compound 26-1
将化合物16-2(100mg)、2,4-二氟氯苄(113mg)和Cs 2CO 3(228.7mg)混合于DMF(5mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得80mg黄色固体，即化合物26-1(M+H +:424)。 Compound 16-2 (100 mg), 2,4- difluorobenzyl chloride (113 mg) and Cs 2 CO 3 (228.7 mg) were mixed in DMF (5 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 80 mg of yellow solid, namely compound 26-1 (M+H + : 424).
步骤2：化合物26的合成Step 2: Synthesis of Compound 26
将化合物26-1(80mg)混合于1M稀盐酸溶液(5mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得69.51mg黄色固体，即化合物26(M+H +:396)。 Compound 26-1 (80 mg) was mixed with 1 M dilute hydrochloric acid solution (5 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration, and 69.51 mg of yellow solid was obtained by beating with ethanol, namely compound 26 (M+H + : 396).
实施例27：化合物27的合成(5-(6-甲基-5-(1-(吡啶-2-甲基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 27: Synthesis of Compound 27 (5-(6-methyl-5-(1-(pyridin-2-methyl)-1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidine-2, 4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000039
Figure PCTCN2021103508-appb-000039
步骤1：化合物27-1的合成Step 1: Synthesis of Compound 27-1
将化合物16-2(40mg)、2-氯甲基吡啶(35.58mg)和Cs 2CO 3(91.50mg)混合于DMF(3mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得30mg黄色固体，即化合物27-1(M+H +:389)。 Compound 16-2 (40 mg), 2-chloromethylpyridine (35.58 mg) and Cs 2 CO 3 (91.50 mg) were mixed in DMF (3 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 30 mg of yellow solid, namely compound 27-1 (M+H + : 389).
步骤2：化合物27的合成Step 2: Synthesis of Compound 27
将化合物27-1(30mg)混合于1M稀盐酸溶液(3mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得24.8mg黄色固体，即化合物27(M+H +:361)。 Compound 27-1 (30 mg) was mixed with 1 M dilute hydrochloric acid solution (3 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with ethanol to obtain 24.8 mg of yellow solid, namely compound 27 (M+H + : 361).
实施例28：化合物28的合成(5-(6-甲基-5-(1-((1-甲基-1H-吡唑-3-基)甲基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 28: Synthesis of Compound 28 (5-(6-methyl-5-(1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrrol-3-yl) Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000040
Figure PCTCN2021103508-appb-000040
步骤1：化合物28-1的合成Step 1: Synthesis of Compound 28-1
将化合物16-2(30mg)、3-(氯甲基)-1-甲基-1H-吡唑(47.5mg)和Cs 2CO 3(119mg)混合于DMF(3mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得25mg黄色固体，即化合物28-1(M+H +:392)。 Compound 16-2 (30 mg), 3-(chloromethyl)-1-methyl-1H-pyrazole (47.5 mg) and Cs 2 CO 3 (119 mg) were mixed in DMF (3 mL), and the temperature was raised to 50° C. to react . After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 25 mg of yellow solid, namely compound 28-1 (M+H + : 392).
步骤2：化合物28的合成Step 2: Synthesis of Compound 28
将化合物28-1(25mg)混合于1M稀盐酸溶液(3mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得19.81mg黄色固体，即化合物28(M+H +:364)。 Compound 28-1 (25 mg) was mixed with 1 M dilute hydrochloric acid solution (3 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with ethanol to obtain 19.81 mg of yellow solid, namely compound 28 (M+H + : 364).
实施例29：化合物29的合成(5-(5-(1-(4-乙氧基苄基)-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 29: Synthesis of Compound 29 (5-(5-(1-(4-ethoxybenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000041
Figure PCTCN2021103508-appb-000041
步骤1：化合物29-1的合成Step 1: Synthesis of Compound 29-1
将化合物16-2(20mg)、1-氯甲基-4-乙氧基苯(36mg)和Cs 2CO 3(66.2mg)混合于DMF(2mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得20mg黄色固体，即化合物29-1(M+H +:432)。 Compound 16-2 (20 mg), 1-chloromethyl-4-ethoxybenzene (36 mg) and Cs 2 CO 3 (66.2 mg) were mixed in DMF (2 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 20 mg of yellow solid, namely compound 29-1 (M+H + : 432).
步骤2：化合物29的合成Step 2: Synthesis of Compound 29
将化合物29-1(20mg)混合于1M稀盐酸溶液(3mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得13.00mg黄色固体，即化合物29(M+H +:404)。 Compound 29-1 (20 mg) was mixed with a 1 M dilute hydrochloric acid solution (3 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration and slurried with ethanol to obtain 13.00 mg of a yellow solid, namely compound 29 (M+H + : 404).
实施例30：化合物30的合成(5-(6-甲基-5-(1-((5-甲基吡啶-2-基)甲基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 30: Synthesis of Compound 30 (5-(6-methyl-5-(1-((5-methylpyridin-2-yl)methyl)-1H-pyrrol-3-yl)pyridazine-3 -yl)pyrimidine-2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000042
Figure PCTCN2021103508-appb-000042
步骤1：化合物30-1的合成Step 1: Synthesis of Compound 30-1
将化合物16-2(100mg)、2-(氯甲基)-5-甲基吡啶(98.75mg)和Cs 2CO 3(228.7mg)混合于DMF(5mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝15:1)得80mg黄色固体，即化合物30-1(M+H +:403)。 Compound 16-2 (100 mg), 2-(chloromethyl)-5-methylpyridine (98.75 mg) and Cs 2 CO 3 (228.7 mg) were mixed in DMF (5 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=15:1) gave 80 mg of yellow solid, namely compound 30-1 (M+H + :403).
步骤2：化合物30的合成Step 2: Synthesis of Compound 30
将化合物30-1(80mg)混合于1M稀盐酸溶液(5mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。抽滤得粗品，乙醇打浆得67.23mg黄色固体，即化合物30(M+H +:375)。 Compound 30-1 (80 mg) was mixed with 1 M dilute hydrochloric acid solution (5 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The crude product was obtained by suction filtration, and 67.23 mg of yellow solid was obtained by beating with ethanol, namely compound 30 (M+H + : 375).
实施例31：化合物31的合成(4-((3-(3-氯-6-(2,4-二氧基-1,2,3,4-四氢嘧啶-5-基)哒嗪-4-基)-1H-吡咯-1-基)甲基)苯甲腈)Example 31: Synthesis of Compound 31 (4-((3-(3-Chloro-6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)pyridazine- 4-yl)-1H-pyrrol-1-yl)methyl)benzonitrile)
Figure PCTCN2021103508-appb-000043
Figure PCTCN2021103508-appb-000043
步骤1：化合物31-1的合成Step 1: Synthesis of Compound 31-1
将化合物M2(10mg)、4-(氯甲基)苯甲腈(14.35mg)和Cs 2CO 3(31.05mg)混合于DMF(1mL)，升温至50℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩得粗品。柱层析分离纯化(DCM:MeOH＝40:1)得6mg黄色固体，即化合物31-1(M+H +:418,420)。 Compound M2 (10 mg), 4-(chloromethyl)benzonitrile (14.35 mg) and Cs 2 CO 3 (31.05 mg) were mixed in DMF (1 mL), and the temperature was raised to 50°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a crude product. Column chromatography separation and purification (DCM:MeOH=40:1) gave 6 mg of yellow solid, namely compound 31-1 (M+H + : 418,420).
步骤2：化合物31的合成Step 2: Synthesis of Compound 31
将化合物31-1(8mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。3h后，LCMS监测显示反应完全。直接反相柱制备液相冻干后得0.87mg白色固体，即化合物31(M+H +:405,407)。 Compound 31-1 (8 mg) was mixed with a 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 3 h, LCMS monitoring showed that the reaction was complete. 0.87 mg of white solid, namely compound 31 (M+H + : 405, 407) was obtained after direct reverse phase column preparation and liquid phase lyophilization.
实施例32：化合物32的合成(4-((3-(6-(2,4-二氧基-1,2,3,4-四氢嘧啶-5-基)-3-甲氧基哒嗪-4-基)-1H-吡咯-1-基)甲基)苯腈)Example 32: Synthesis of compound 32 (4-((3-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methoxypyridin oxazin-4-yl)-1H-pyrrol-1-yl)methyl)benzonitrile)
Figure PCTCN2021103508-appb-000044
Figure PCTCN2021103508-appb-000044
步骤1：化合物32-1的合成Step 1: Synthesis of Compound 32-1
将化合物31-1(10mg)和甲醇钠(12.95mg)混合于甲醇(2mL)，升温至70℃反应。12h后，LCMS监测显示反应完全。旋干甲醇，用乙酸乙酯溶解产物，过滤不溶盐，取滤液旋干即得6mg黄色固体，即化合物32-1(M+H +:429)。 Compound 31-1 (10 mg) and sodium methoxide (12.95 mg) were mixed in methanol (2 mL), and the temperature was raised to 70°C to react. After 12 h, LCMS monitoring showed that the reaction was complete. The methanol was spin-dried, the product was dissolved in ethyl acetate, the insoluble salt was filtered, and the filtrate was taken and spin-dried to obtain 6 mg of yellow solid, namely compound 32-1 (M+H + : 429).
步骤2：化合物35的合成Step 2: Synthesis of Compound 35
将化合物32-1(6mg)混合于1M稀盐酸溶液(2mL)，升温至40℃反应。10h后，LCMS监测显示反应完全。直接反相柱制备液相冻干后得0.86mg白色固体，即化合物32(M+H +:401)。 Compound 32-1 (6 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 40°C to react. After 10 h, LCMS monitoring showed that the reaction was complete. 0.86 mg of white solid, namely compound 32 (M+H + : 401), was obtained after direct reverse phase column preparation liquid phase lyophilization.
实施例33：化合物33(5-(5-(1-(4-羟基苄基)-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮)的合成Example 33: Compound 33 (5-(5-(1-(4-hydroxybenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H Synthesis of ,3H)-diketone)
Figure PCTCN2021103508-appb-000045
Figure PCTCN2021103508-appb-000045
步骤1：化合物33的合成Step 1: Synthesis of Compound 33
25ml三口瓶中加入化合物15(25mg)，溶于DCM(5ml)中，N 2保护，冰浴下冷却，向反应液中滴加BBr 3(0.1ml)，冰浴下反应3小时。向反应液中缓慢滴加饱和碳酸氢钠溶液淬灭反应，反应液蒸干，柱层析分离产物(DCM:MeOH＝10:1),得7mg白色固体，即化合物33。 Compound 15 (25 mg) was added to a 25 ml three-necked flask, dissolved in DCM (5 ml), protected by N 2 , cooled in an ice bath, BBr 3 (0.1 ml) was added dropwise to the reaction solution, and reacted in an ice bath for 3 hours. Saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution to quench the reaction, the reaction solution was evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=10:1) to obtain 7 mg of white solid, namely compound 33.
LCMS：[M+H] +＝376.13 LCMS: [M+H] + = 376.13
实施例34：化合物34的合成(5-(5-(1-(3-羟基苄基)-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮)Example 34: Synthesis of Compound 34 (5-(5-(1-(3-hydroxybenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4 (1H,3H)-dione)
Figure PCTCN2021103508-appb-000046
Figure PCTCN2021103508-appb-000046
步骤1：化合物34的合成Step 1: Synthesis of Compound 34
25ml三口瓶中加入化合物18(30mg)，溶于DCM(5ml)中，N 2保护，冰浴下冷却，向反应液中滴加BBr 3(0.15ml)，冰浴下反应3小时。向反应液中缓慢滴加饱和碳酸氢钠溶液淬灭反应，反应液蒸干，柱层析分离产物(DCM:MeOH＝10:1),得15mg白色固体，即化合物34。 Compound 18 (30 mg) was added to a 25 ml three-necked flask, dissolved in DCM (5 ml), protected by N 2 , cooled in an ice bath, BBr 3 (0.15 ml) was added dropwise to the reaction solution, and reacted in an ice bath for 3 hours. Saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution to quench the reaction, the reaction solution was evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=10:1) to obtain 15 mg of white solid, namely compound 34.
LCMS：[M+H] +＝376.13 LCMS: [M+H] + = 376.13
实施例35：化合物35的合成(5-(5-(3-苄基-1H-吡咯-1-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 35: Synthesis of Compound 35 (5-(5-(3-benzyl-1H-pyrrol-1-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H) -diketone)
Figure PCTCN2021103508-appb-000047
Figure PCTCN2021103508-appb-000047
步骤1：化合物35-1的合成Step 1: Synthesis of Compound 35-1
100ml三口瓶中加入化合物M1(200mg)、苯基(1H-吡咯-3-基)甲酮(154mg)、CuI(15mg)、Cs 2CO 3(500mg)，溶于DMSO(10mL)，N 2保护，油浴70℃下反应4h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝1:1),得150mg淡黄色固体，即化合物35-1。 Compound M1 (200mg), phenyl (1H-pyrrol-3-yl)methanone (154mg), CuI (15mg), Cs 2 CO 3 (500mg) were added to a 100ml three-necked flask, dissolved in DMSO (10mL), N 2 protection, and the reaction was carried out at 70 °C in an oil bath for 4 h. Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:1) to obtain 150 mg of a pale yellow solid, namely compound 35-1 .
步骤2：化合物35-2的合成Step 2: Synthesis of Compound 35-2
50mL单口瓶中加入化合物35-1(150mg)和NaBH 4(200mg)，溶于THF(10mL)，室温反应12h。向反应液中加水淬灭,蒸干反应液，柱层析分离产物(DCM:MeOH＝15:1),得100mg淡黄色固体，即化合物35-2。 Compound 35-1 (150 mg) and NaBH 4 (200 mg) were added to a 50 mL single-neck flask, dissolved in THF (10 mL), and reacted at room temperature for 12 h. Water was added to the reaction solution to quench, the reaction solution was evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=15:1) to obtain 100 mg of a pale yellow solid, namely compound 35-2.
步骤3：化合物35-3的合成Step 3: Synthesis of Compound 35-3
50mL单口瓶中加入化合物35-2(100mg)，溶于DCM(10mL)，冰浴下冷却，向反应液中滴加Et 3SiH(0.2ml)，最后滴加TFA(0.5ml)，冰浴下反应0.5h。向反应液中加入饱和碳酸氢钠溶液淬灭反应。直接蒸干反应液，柱层析分离产物(DCM:MeOH＝20:1)得90mg白色固体，即化合物35-3。 Compound 35-2 (100 mg) was added to a 50 mL single-necked bottle, dissolved in DCM (10 mL), cooled in an ice bath, Et 3 SiH (0.2 ml) was added dropwise to the reaction solution, and finally TFA (0.5 mL) was added dropwise, and the ice bath was added dropwise. The next reaction is 0.5h. Saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction. The reaction solution was directly evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=20:1) to obtain 90 mg of white solid, namely compound 35-3.
步骤4：化合物35的合成Step 4: Synthesis of Compound 35
25mL单口瓶中加入化合物35-3(50mg)，溶于1M盐酸(4mL)，70℃下反应3h。冷却至室温，反应液用饱和碳酸氢钠溶液调节pH为中性，析出白色固体，抽滤，滤饼水洗，烘干。得白色固体15mg，即化合物35(纯度99.16％)。Compound 35-3 (50 mg) was added to a 25 mL single-neck flask, dissolved in 1 M hydrochloric acid (4 mL), and reacted at 70° C. for 3 h. Cooled to room temperature, the pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, a white solid was precipitated, suction filtered, the filter cake was washed with water, and dried. 15 mg of white solid was obtained, namely compound 35 (purity 99.16%).
LCMS：[M+H] +＝360.14 LCMS: [M+H] + = 360.14
实施例36：化合物36的合成(5-(5-(3-(4-氟苄基)-1H-吡咯-1-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 36: Synthesis of Compound 36 (5-(5-(3-(4-fluorobenzyl)-1H-pyrrol-1-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4 (1H,3H)-dione)
Figure PCTCN2021103508-appb-000048
Figure PCTCN2021103508-appb-000048
步骤1：化合物36-1的合成Step 1: Synthesis of Compound 36-1
100ml三口瓶中加入AlCl 3(1.7g)，悬浮于DCM(50mL)中，N 2保护，室温下向反应液中滴加4-氟苯甲酰氯(0.7g)，反应15分钟后，向反应液中滴加1-(苯磺酰基)-1H-吡咯的DCM溶液，室温反应2小时。向反应液中加入50ml冰水，剧烈搅拌30分钟，DCM萃取，有机相无水硫酸钠干燥，有机相蒸干,得1.3g白色固体，即化合物36-1。 After 100ml three-neck flask was added AlCl 3 (1.7g), was suspended in DCM (50mL), under N 2, at room temperature was added dropwise 4-fluorobenzoyl chloride (0.7 g) to the reaction solution, and reacted for 15 minutes, the reaction The DCM solution of 1-(benzenesulfonyl)-1H-pyrrole was added dropwise to the solution, and the reaction was carried out at room temperature for 2 hours. 50 ml of ice water was added to the reaction solution, vigorously stirred for 30 minutes, extracted with DCM, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain 1.3 g of a white solid, namely compound 36-1.
步骤2：化合物36-2的合成Step 2: Synthesis of Compound 36-2
250mL单口瓶中加入化合物36-1(1.3g)，溶于1,4-二氧六环(40mL)和4M NaOH(40ml)中，室温反应12h。向反应液中加水稀释,EA萃取三次，有机相无水硫酸钠干燥，蒸干反应液，得0.6g淡黄色固体，即化合物36-2。Compound 36-1 (1.3 g) was added to a 250 mL single-neck flask, dissolved in 1,4-dioxane (40 mL) and 4M NaOH (40 mL), and reacted at room temperature for 12 h. The reaction solution was diluted with water, extracted three times with EA, the organic phase was dried over anhydrous sodium sulfate, and the reaction solution was evaporated to dryness to obtain 0.6 g of a pale yellow solid, namely compound 36-2.
步骤3：化合物36-3的合成Step 3: Synthesis of Compound 36-3
100ml三口瓶中加入化合物M1(200mg)、4-氟苯基(1H-吡咯-3-基)甲酮(154mg)、CuI(15mg)、Cs 2CO 3(500mg)，溶于DMSO(10mL)，N 2保护，油浴70℃下反应4h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝1:1),得150mg淡黄色固体，即化合物36-3。 Compound M1 (200mg), 4-fluorophenyl (1H-pyrrol-3-yl)methanone (154mg), CuI (15mg), Cs 2 CO 3 (500mg) were added to a 100ml three-necked flask, dissolved in DMSO (10mL) , protected by N 2 , and reacted at 70 °C in an oil bath for 4 h. Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:1) to obtain 150 mg of a pale yellow solid, namely compound 36-3 .
步骤4：化合物36-4的合成Step 4: Synthesis of Compound 36-4
50mL单口瓶中加入化合物36-3(150mg)和NaBH 4(200mg)，溶于THF(10mL)，室温反应12h。向反应液中加水淬灭,蒸干反应液，柱层析分离产物(DCM:MeOH＝15:1),得100mg淡黄色固体，即化合物36-4。 Compound 36-3 (150 mg) and NaBH 4 (200 mg) were added to a 50 mL single-neck flask, dissolved in THF (10 mL), and reacted at room temperature for 12 h. Water was added to the reaction solution to quench, the reaction solution was evaporated to dryness, and the product was isolated by column chromatography (DCM:MeOH=15:1) to obtain 100 mg of pale yellow solid, namely compound 36-4.
步骤5：化合物36-5的合成Step 5: Synthesis of Compound 36-5
50mL单口瓶中加入化合物36-4(100mg)，溶于DCM(10mL)，冰浴下冷却，向反应液中滴加Et 3SiH(0.2ml)，最后滴加TFA(0.5ml)，冰浴下反应0.5h。向反应液中加入饱和碳酸氢钠溶液淬灭反应。直接蒸干反应液，柱层析分离产物(DCM:MeOH＝20:1)得90mg白色固体，即化合物36-5。 Compound 36-4 (100mg) was added to a 50mL single-neck flask, dissolved in DCM (10mL), cooled in an ice bath, Et 3 SiH (0.2ml) was added dropwise to the reaction solution, and finally TFA (0.5ml) was added dropwise, and the ice bath was added dropwise. The next reaction is 0.5h. Saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction. The reaction solution was directly evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=20:1) to obtain 90 mg of white solid, namely compound 36-5.
步骤6：化合物36的合成Step 6: Synthesis of Compound 36
25mL单口瓶中加入化合物36-5(50mg)，溶于1M盐酸(4mL)，70℃下反应3h。冷却至室温，反应液用饱和碳酸氢钠溶液调节pH为中性，析出白色固体，抽滤，滤饼水洗，烘干。得白色固体15mg，即化合物36(纯度99.16％)。Compound 36-5 (50 mg) was added to a 25 mL single-neck flask, dissolved in 1 M hydrochloric acid (4 mL), and reacted at 70° C. for 3 h. Cooled to room temperature, the pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, a white solid was precipitated, suction filtered, the filter cake was washed with water, and dried. 15 mg of white solid was obtained, namely compound 36 (purity 99.16%).
LCMS：[M+H] +＝378.13 LCMS: [M+H] + = 378.13
实施例37：化合物37的合成(5-(5-(3-(4-甲氧基苄基)-1H-吡咯-1-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 37: Synthesis of Compound 37 (5-(5-(3-(4-methoxybenzyl)-1H-pyrrol-1-yl)-6-methylpyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000049
Figure PCTCN2021103508-appb-000049
步骤1：化合物37-1的合成Step 1: Synthesis of Compound 37-1
100ml三口瓶中加入AlCl 3(1.7g)，悬浮于DCM(50mL)中，N 2保护，室温下向反应液中滴加4-甲氧基苯甲酰氯(0.7g)，反应15分钟后，向反应液中滴加1-(苯磺酰基)-1H-吡咯的DCM溶液，室温反应2小时。向反应液中加入50ml冰水，剧烈搅拌30分钟，DCM萃取，有机相无水硫酸钠干燥，有机相蒸干,得1.3g白色固体，即化合物37-1。 100ml three-neck flask was added AlCl 3 (1.7g), was suspended in DCM (50mL) in, under N 2, at room temperature a solution of 4-methoxybenzoyl chloride (0.7 g) to the reaction mixture, the reaction after 15 minutes, A DCM solution of 1-(benzenesulfonyl)-1H-pyrrole was added dropwise to the reaction solution, and the reaction was carried out at room temperature for 2 hours. 50 ml of ice water was added to the reaction solution, vigorously stirred for 30 minutes, extracted with DCM, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain 1.3 g of a white solid, namely compound 37-1.
步骤2：化合物37-2的合成Step 2: Synthesis of Compound 37-2
250mL单口瓶中加入化合物37-1(1.3g)，溶于1,4-二氧六环(40mL)和4M NaOH(40ml)中，室温反应12h。向反应液中加水稀释,EA萃取三次，有机相无水硫酸钠干燥，蒸干反应液，得0.7g淡黄色固体，即化合物37-2。Compound 37-1 (1.3 g) was added to a 250 mL single-neck flask, dissolved in 1,4-dioxane (40 mL) and 4M NaOH (40 mL), and reacted at room temperature for 12 h. The reaction solution was diluted with water, extracted three times with EA, the organic phase was dried over anhydrous sodium sulfate, and the reaction solution was evaporated to dryness to obtain 0.7 g of a pale yellow solid, namely compound 37-2.
步骤3：化合物37-3的合成Step 3: Synthesis of Compound 37-3
100ml三口瓶中加入化合物M1(200mg)、4-甲氧基苯基(1H-吡咯-3-基)甲酮(154mg)、CuI(15mg)、Cs 2CO 3(500mg)，溶于DMSO(10mL)，N 2保护，油浴70℃下反应4h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产 物(PE:EA＝1:1),得150mg淡黄色固体，即化合物37-3。 Compound M1 (200mg), 4-methoxyphenyl (1H-pyrrol-3-yl)methanone (154mg), CuI (15mg), Cs 2 CO 3 (500mg) were added to a 100ml three-necked flask, dissolved in DMSO ( 10 mL), protected by N 2 , and reacted at 70 °C in an oil bath for 4 h. Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:1) to obtain 150 mg of a pale yellow solid, namely compound 37-3 .
步骤4：化合物37-4的合成Step 4: Synthesis of Compound 37-4
50mL单口瓶中加入化合物37-3(150mg)和NaBH 4(200mg)，溶于THF(10mL)，室温反应12h。向反应液中加水淬灭,蒸干反应液，柱层析分离产物(DCM:MeOH＝15:1),得100mg淡黄色固体，即化合物37-4。 Compound 37-3 (150 mg) and NaBH 4 (200 mg) were added to a 50 mL single-neck flask, dissolved in THF (10 mL), and reacted at room temperature for 12 h. Water was added to the reaction solution to quench, the reaction solution was evaporated to dryness, and the product was isolated by column chromatography (DCM:MeOH=15:1) to obtain 100 mg of a pale yellow solid, namely compound 37-4.
步骤5：化合物37-5的合成Step 5: Synthesis of Compound 37-5
50mL单口瓶中加入化合物37-4(100mg)，溶于DCM(10mL)，冰浴下冷却，向反应液中滴加Et 3SiH(0.2ml)，最后滴加TFA(0.5ml)，冰浴下反应0.5h。向反应液中加入饱和碳酸氢钠溶液淬灭反应。直接蒸干反应液，柱层析分离产物(DCM:MeOH＝20:1)得90mg白色固体，即化合物37-5。 Compound 37-4 (100 mg) was added to a 50 mL single-neck bottle, dissolved in DCM (10 mL), cooled in an ice bath, Et 3 SiH (0.2 ml) was added dropwise to the reaction solution, and finally TFA (0.5 mL) was added dropwise, and the ice bath was added dropwise. The next reaction is 0.5h. Saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction. The reaction solution was directly evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=20:1) to obtain 90 mg of white solid, namely compound 37-5.
步骤6：化合物37的合成Step 6: Synthesis of Compound 37
25mL单口瓶中加入化合物37-5(90mg)，溶于1M盐酸(4mL)，70℃下反应3h。冷却至室温，反应液用饱和碳酸氢钠溶液调节pH为中性，析出白色固体，抽滤，滤饼水洗，烘干。得白色固体55mg，即化合物37(纯度99.16％)。Compound 37-5 (90 mg) was added to a 25 mL single-neck flask, dissolved in 1 M hydrochloric acid (4 mL), and reacted at 70° C. for 3 h. Cooled to room temperature, the pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, a white solid was precipitated, suction filtered, the filter cake was washed with water, and dried. 55 mg of white solid was obtained, namely compound 37 (purity 99.16%).
LCMS：[M+H] +＝390.15 LCMS: [M+H] + = 390.15
实施例38：化合物38的合成(5-(5-(3-(4-羟基苄基)-1H-吡咯-1-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 38: Synthesis of Compound 38 (5-(5-(3-(4-hydroxybenzyl)-1H-pyrrol-1-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4 (1H,3H)-dione)
Figure PCTCN2021103508-appb-000050
Figure PCTCN2021103508-appb-000050
步骤1：化合物38的合成Step 1: Synthesis of Compound 38
25ml三口瓶中加入化合物37(25mg)，溶于DCM(5ml)中，N 2保护，冰浴下冷却，向反应液中滴加BBr 3(0.1ml)，冰浴下反应3小时。向反应液中缓慢滴加饱和碳酸氢钠溶液淬灭反应，反应液蒸干，柱层析分离产物(DCM:MeOH＝10:1),得5mg白色固体，即化合物38。 Compound 37 (25 mg) was added to a 25 ml three-necked flask, dissolved in DCM (5 ml), protected by N 2 , cooled in an ice bath, BBr 3 (0.1 ml) was added dropwise to the reaction solution, and the reaction was carried out in an ice bath for 3 hours. Saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution to quench the reaction, the reaction solution was evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=10:1) to obtain 5 mg of white solid, namely compound 38.
LCMS：[M+H] +＝376.13 LCMS: [M+H] + = 376.13
实施例39：化合物39的合成(4-((1-(6-(2,4-二氧基-1,2,3,4-四氢嘧啶-5-基)-3-甲基哒嗪-4-基)-1H-吡咯-3-基)甲基)苯甲腈)Example 39: Synthesis of compound 39 (4-((1-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrrol-3-yl)methyl)benzonitrile)
Figure PCTCN2021103508-appb-000051
Figure PCTCN2021103508-appb-000051
步骤1：化合物39-1的合成Step 1: Synthesis of Compound 39-1
100ml三口瓶中加入AlCl 3(1.7g)，悬浮于DCM(50mL)中，N 2保护，室温下向反应液中滴加4-氰基苯甲酰氯(0.7g)，反应15分钟后，向反应液中滴加1-(苯磺酰基)-1H-吡咯的DCM溶液，室温反应2小时。向反应液中加入50ml冰水，剧烈搅拌30分钟，DCM萃取，有机相无水硫酸钠干燥，有机相蒸干,得1.3g白色固体，即化合物39-1。 After 100ml three-neck flask was added AlCl 3 (1.7g), was suspended in DCM (50mL), under N 2, at room temperature was added dropwise 4-cyanobenzoyl chloride (0.7 g) to the reaction solution, and reacted for 15 minutes, A DCM solution of 1-(benzenesulfonyl)-1H-pyrrole was added dropwise to the reaction solution, and the reaction was carried out at room temperature for 2 hours. 50 ml of ice water was added to the reaction solution, vigorously stirred for 30 minutes, extracted with DCM, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain 1.3 g of a white solid, namely compound 39-1.
步骤2：化合物39-2的合成Step 2: Synthesis of Compound 39-2
250mL单口瓶中加入化合物39-1(1.3g)，溶于1,4-二氧六环(40mL)和4M NaOH(40ml)中，室温反应12h。向反应液中加水稀释,EA萃取三次，有机相无水硫酸钠干燥，蒸干反应液，得0.7g淡黄色固体，即化合物39-2。Compound 39-1 (1.3 g) was added to a 250 mL single-neck flask, dissolved in 1,4-dioxane (40 mL) and 4M NaOH (40 mL), and reacted at room temperature for 12 h. The reaction solution was diluted with water, extracted three times with EA, the organic phase was dried over anhydrous sodium sulfate, and the reaction solution was evaporated to dryness to obtain 0.7 g of a pale yellow solid, namely compound 39-2.
步骤3：化合物39-3的合成Step 3: Synthesis of Compound 39-3
100ml三口瓶中加入化合物M1(200mg)、4-氰基苯基(1H-吡咯-3-基)甲酮(154mg)、CuI(15mg)、Cs 2CO 3(500mg)，溶于DMSO(10mL)，N 2保护，油浴70℃下反应4h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝1:1),得150mg淡黄色固体，即化合物39-3。 In a 100ml three-necked flask, compound M1 (200mg), 4-cyanophenyl (1H-pyrrol-3-yl)methanone (154mg), CuI (15mg), Cs 2 CO 3 (500mg) were added, dissolved in DMSO (10 mL) ), under N 2, the reaction deg.] C oil bath at 70 4h. Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:1) to obtain 150 mg of a pale yellow solid, namely compound 39-3 .
步骤4：化合物39-4的合成Step 4: Synthesis of Compound 39-4
50mL单口瓶中加入化合物7-3(150mg)和NaBH 4(200mg)，溶于THF(10mL)，室温反应12h。向反应液中加水淬灭,蒸干反应液，柱层析分离产物(DCM:MeOH＝15:1),得100mg淡黄色固体，即化合物39-4。 Compound 7-3 (150 mg) and NaBH 4 (200 mg) were added to a 50 mL single-neck flask, dissolved in THF (10 mL), and reacted at room temperature for 12 h. Water was added to the reaction solution to quench, the reaction solution was evaporated to dryness, and the product was isolated by column chromatography (DCM:MeOH=15:1) to obtain 100 mg of a pale yellow solid, namely compound 39-4.
步骤5：化合物39-5的合成Step 5: Synthesis of Compound 39-5
50mL单口瓶中加入化合物39-4(100mg)，溶于DCM(10mL)，冰浴下冷却，向反应液中滴加Et 3SiH(0.2ml)，最后滴加TFA(0.5ml)，冰浴下反应0.5h。向反应液中加入饱和碳酸氢钠溶液淬灭反应。直接蒸干反应液，柱层析分离产物(DCM:MeOH＝20:1)得90mg白色固体，即化合物39-5。 Compound 39-4 (100 mg) was added to a 50 mL single-neck bottle, dissolved in DCM (10 mL), cooled in an ice bath, Et 3 SiH (0.2 ml) was added dropwise to the reaction solution, and finally TFA (0.5 mL) was added dropwise, and the ice bath was added dropwise. The next reaction is 0.5h. Saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction. The reaction solution was directly evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=20:1) to obtain 90 mg of white solid, namely compound 39-5.
步骤7：化合物39的合成Step 7: Synthesis of Compound 39
25mL单口瓶中加入化合物39-5(50mg)，溶于1M盐酸(4mL)，70℃下反应3h。冷 却至室温，反应液用饱和碳酸氢钠溶液调节pH为中性，析出白色固体，抽滤，滤饼水洗，烘干。得白色固体15mg，即化合物39(纯度99.16％)。Compound 39-5 (50 mg) was added to a 25 mL single-neck flask, dissolved in 1 M hydrochloric acid (4 mL), and reacted at 70° C. for 3 h. Cooled to room temperature, the pH of the reaction solution was adjusted to be neutral with saturated sodium bicarbonate solution, a white solid was precipitated, suction filtered, the filter cake was washed with water, and dried. 15 mg of white solid was obtained, namely compound 39 (purity 99.16%).
LCMS：[M+H] +＝385.13 LCMS: [M+H] + = 385.13
实施例40：化合物40的合成(5-(5-(1-(4-甲氧基苄基)-1H-吡唑-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 40: Synthesis of Compound 40 (5-(5-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000052
Figure PCTCN2021103508-appb-000052
步骤1：化合物40-1的合成Step 1: Synthesis of Compound 40-1
50ml三口瓶中加入化合物M1(100mg)、3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑(110mg)、Pd(dppf)Cl 2(30mg)、K 2CO 3(100mg)，溶于1,4-二氧六环(10mL)，水(2ml)中，N 2保护，油浴70℃下反应4h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝1:2),得100mg黄色固体，即化合物40-1。 Compound M1 (100mg), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (110mg) were added to a 50ml three-necked flask , Pd(dppf)Cl 2 (30mg), K 2 CO 3 (100mg), dissolved in 1,4-dioxane (10mL), water (2ml), protected by N 2 , and reacted at 70°C in oil bath for 4h . Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:2) to obtain 100 mg of a yellow solid, namely compound 40-1.
步骤2：化合物40-2的合成Step 2: Synthesis of Compound 40-2
50ml单口瓶中加入化合物40-2(100mg)、对甲氧基苄氯(110mg)、K 2CO 3(100mg)，溶于DMF(10ml)中，油浴60℃下反应2h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝1:1),得70mg黄色固体，即化合物40-2。 Compound 40-2 (100 mg), p-methoxybenzyl chloride (110 mg) and K 2 CO 3 (100 mg) were added to a 50 ml single-neck bottle, dissolved in DMF (10 ml), and reacted in an oil bath at 60° C. for 2 h. Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:1) to obtain 70 mg of yellow solid, namely compound 40-2.
步骤3：化合物40的合成Step 3: Synthesis of Compound 40
25mL单口瓶中加入化合物40-2(70mg)，溶于1M盐酸(4mL)，70℃下反应3h。冷却至室温，反应液用饱和碳酸氢钠溶液调节pH为中性，析出白色固体，抽滤，滤饼水洗，烘干。得白色固体45mg，即化合物40(纯度99.16％)。Compound 40-2 (70 mg) was added to a 25 mL single-neck flask, dissolved in 1 M hydrochloric acid (4 mL), and reacted at 70° C. for 3 h. Cooled to room temperature, the pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, a white solid was precipitated, suction filtered, the filter cake was washed with water, and dried. 45 mg of white solid was obtained, namely compound 40 (purity 99.16%).
LCMS：[M+H] +＝391.14 LCMS: [M+H] + = 391.14
实施例41：化合物41的合成(5-(6-甲基-5-(1-(2-(三氟甲氧基)苄基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 41: Synthesis of Compound 41 (5-(6-methyl-5-(1-(2-(trifluoromethoxy)benzyl)-1H-pyrrol-3-yl)pyridazin-3-yl )pyrimidine-2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000053
Figure PCTCN2021103508-appb-000053
步骤1：化合物41-1的合成Step 1: Synthesis of Compound 41-1
50ml单口瓶中加入中间体M2(50mg)、1-(溴甲基)-2-(三氟甲氧基)苯(74mg)、K 2CO 3(100mg)，溶于DMF(5ml)中，油浴50℃下反应2h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝1:1),得30mg黄色固体，即化合物41-1。 Add intermediate M2 (50mg), 1-(bromomethyl)-2-(trifluoromethoxy)benzene (74mg), K 2 CO 3 (100mg) in a 50ml single-neck bottle, dissolve in DMF (5ml), The reaction was carried out at 50°C for 2h in an oil bath. Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:1) to obtain 30 mg of yellow solid, namely compound 41-1.
步骤2：化合物41的合成Step 2: Synthesis of Compound 41
25mL单口瓶中加入化合物41-1(30mg)，溶于1M盐酸(3mL)，70℃下反应3h。冷却至室温，反应液用饱和碳酸氢钠溶液调节pH为中性，析出白色固体，抽滤，滤饼水洗，烘干。得白色固体15mg，即化合物41(纯度99.16％)。Compound 41-1 (30 mg) was added to a 25 mL single-neck flask, dissolved in 1 M hydrochloric acid (3 mL), and reacted at 70° C. for 3 h. Cooled to room temperature, the pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, a white solid was precipitated, suction filtered, the filter cake was washed with water, and dried. 15 mg of white solid was obtained, namely compound 41 (purity 99.16%).
LCMS：[M+H] +＝444.12 LCMS: [M+H] + = 444.12
实施例42：化合物42的合成(5-(6-甲基-5-(1-(3-(三氟甲氧基)苄基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 42: Synthesis of Compound 42 (5-(6-methyl-5-(1-(3-(trifluoromethoxy)benzyl)-1H-pyrrol-3-yl)pyridazin-3-yl )pyrimidine-2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000054
Figure PCTCN2021103508-appb-000054
步骤1：化合物42-1的合成Step 1: Synthesis of Compound 42-1
50ml单口瓶中加入中间体M2(50mg)、1-(溴甲基)-3-(三氟甲氧基)苯(74mg)、K 2CO 3(100mg)，溶于DMF(5ml)中，油浴50℃下反应2h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝1:1),得30mg黄色固体，即化合物42-1。 In a 50ml single-necked bottle, add intermediate M2 (50mg), 1-(bromomethyl)-3-(trifluoromethoxy)benzene (74mg), K 2 CO 3 (100mg), dissolve in DMF (5ml), The reaction was carried out at 50°C for 2h in an oil bath. Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:1) to obtain 30 mg of yellow solid, namely compound 42-1.
步骤2：化合物42的合成Step 2: Synthesis of Compound 42
25mL单口瓶中加入化合物42-1(30mg)，溶于1M盐酸(3mL)，70℃下反应3h。冷却至室温，反应液用饱和碳酸氢钠溶液调节pH为中性，析出白色固体，抽滤，滤饼水洗，烘干。得白色固体15mg，即化合物42(纯度99.16％)。Compound 42-1 (30 mg) was added to a 25 mL single-neck flask, dissolved in 1 M hydrochloric acid (3 mL), and reacted at 70° C. for 3 h. Cooled to room temperature, the pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, a white solid was precipitated, suction filtered, the filter cake was washed with water, and dried. 15 mg of white solid was obtained, namely compound 42 (purity 99.16%).
LCMS：[M+H] +＝444.12 LCMS: [M+H] + = 444.12
实施例43：化合物43的合成(4-((3-(6-(2,4-二氧基-1,2,3,4-四氢嘧啶-5-基)-3-甲基哒嗪-4-基)-1H-吡咯-1-基)甲基)苯甲酸甲酯)Example 43: Synthesis of compound 43 (4-((3-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrrol-1-yl)methyl)benzoic acid methyl ester)
Figure PCTCN2021103508-appb-000055
Figure PCTCN2021103508-appb-000055
步骤1：化合物43-1的合成Step 1: Synthesis of Compound 43-1
50ml单口瓶中加入中间体M2(50mg)、4-(溴甲基)苯甲酸甲酯(57mg)、Cs 2CO 3(120mg)，溶于DMF(5ml)中，油浴50℃下反应2h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝1:1),得35mg黄色固体，即化合物43-1。 Add intermediate M2 (50mg), methyl 4-(bromomethyl)benzoate (57mg), Cs 2 CO 3 (120mg) to a 50ml single-neck bottle, dissolve in DMF (5ml), and react in an oil bath at 50°C for 2h . Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:1) to obtain 35 mg of yellow solid, namely compound 43-1.
步骤2：化合物43的合成Step 2: Synthesis of Compound 43
25mL单口瓶中加入化合物43-1(35mg)，溶于1M盐酸(3mL)，70℃下反应3h。冷却至室温，反应液用饱和碳酸氢钠溶液调节pH为中性，析出白色固体，抽滤，滤饼水洗，烘干。得白色固体20mg，即化合物43(纯度99.16％)。Compound 43-1 (35 mg) was added to a 25 mL single-neck flask, dissolved in 1 M hydrochloric acid (3 mL), and reacted at 70° C. for 3 h. Cooled to room temperature, the pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, a white solid was precipitated, suction filtered, the filter cake was washed with water, and dried. 20 mg of white solid was obtained, namely compound 43 (purity 99.16%).
LCMS：[M+H] +＝418.14 LCMS: [M+H] + = 418.14
实施例44：化合物44的合成(3-((3-(6-(2,4-二氧基-1,2,3,4-四氢嘧啶-5-基)-3-甲基哒嗪-4-基)-1H-吡咯-1-基)甲基)苯甲酸甲酯)Example 44: Synthesis of Compound 44 (3-((3-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrrol-1-yl)methyl)benzoic acid methyl ester)
Figure PCTCN2021103508-appb-000056
Figure PCTCN2021103508-appb-000056
步骤1：化合物44-1的合成Step 1: Synthesis of Compound 44-1
50ml单口瓶中加入中间体M2(50mg)、3-(溴甲基)苯甲酸甲酯(57mg)、Cs 2CO 3(120mg)，溶于DMF(5ml)中，油浴50℃下反应2h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝1:1),得35mg黄色固体，即化合物44-1。 Add intermediate M2 (50mg), methyl 3-(bromomethyl)benzoate (57mg), Cs 2 CO 3 (120mg) to a 50ml single-neck bottle, dissolve in DMF (5ml), and react in an oil bath at 50°C for 2h . Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:1) to obtain 35 mg of yellow solid, namely compound 44-1.
步骤2：化合物44的合成Step 2: Synthesis of Compound 44
25mL单口瓶中加入化合物44-1(35mg)，溶于1M盐酸(3mL)，70℃下反应3h。冷却至室温，反应液用饱和碳酸氢钠溶液调节pH为中性，析出白色固体，抽滤，滤饼水洗，烘干。得白色固体20mg，即化合物44(纯度99.16％)。Compound 44-1 (35 mg) was added to a 25 mL single-neck flask, dissolved in 1 M hydrochloric acid (3 mL), and reacted at 70° C. for 3 h. Cooled to room temperature, the pH of the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution, a white solid was precipitated, suction filtered, the filter cake was washed with water, and dried. 20 mg of white solid was obtained, namely compound 44 (purity 99.16%).
LCMS：[M+H] +＝418.14 LCMS: [M+H] + = 418.14
实施例45：化合物45的合成(5-(5-(1-(3-(羟甲基)苄基)-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 45: Synthesis of Compound 45 (5-(5-(1-(3-(hydroxymethyl)benzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine -2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000057
Figure PCTCN2021103508-appb-000057
步骤1：化合物45的合成Step 1: Synthesis of Compound 45
25mL三口瓶中加入化合物44(20mg)、NaBH 4(10mg)，溶于THF(3mL)中，N 2保护，油浴50℃下，向反应液中滴加MeOH(0.3ml)。50℃下反应3h。冷却至室温，向反应液中滴加水淬灭反应。直接蒸干反应液，柱层析分离产物(DCM:MeOH＝10:1),得5mg白色固体，即化合物45(纯度99.16％)。 Compound 44 (20 mg) and NaBH 4 (10 mg) were added to a 25 mL three-neck flask, dissolved in THF (3 mL), protected by N 2 , and MeOH (0.3 ml) was added dropwise to the reaction solution in an oil bath at 50°C. The reaction was carried out at 50°C for 3h. After cooling to room temperature, water was added dropwise to the reaction solution to quench the reaction. The reaction solution was directly evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=10:1) to obtain 5 mg of white solid, namely compound 45 (purity 99.16%).
LCMS：[M+H] +＝390.15 LCMS: [M+H] + = 390.15
实施例46：化合物46的合成(5-(5-(1-(4-(二氟甲基)苄基)-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 46: Synthesis of Compound 46 (5-(5-(1-(4-(difluoromethyl)benzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl) Pyrimidine-2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000058
步骤1：化合物46-1的合成
Figure PCTCN2021103508-appb-000058
Step 1: Synthesis of Compound 46-1
50ml单口瓶中加入中间体M2(100mg)、4-(溴甲基)苯甲酸甲酯(120mg)、Cs 2CO 3(300mg)，溶于DMF(10ml)中，油浴50℃下反应2h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝1:1),得80mg黄色固体，即化合物46-1。 Add intermediate M2 (100mg), methyl 4-(bromomethyl)benzoate (120mg), Cs 2 CO 3 (300mg) to a 50ml single-neck bottle, dissolve in DMF (10ml), and react in an oil bath at 50°C for 2h . Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:1) to obtain 80 mg of yellow solid, namely compound 46-1.
步骤2：化合物46-2的合成Step 2: Synthesis of Compound 46-2
50mL三口瓶中加入化合物46-1(80mg)、NaBH 4(50mg)，溶于THF(10mL)中，N 2保护，油浴50℃下，向反应液中滴加MeOH(1ml)。50℃下反应3h。冷却至室温，向反 应液中滴加水淬灭反应。直接蒸干反应液，柱层析分离产物(DCM:MeOH＝10:1),得45mg白色固体，即化合物46-2。 Compound 46-1 (80 mg) and NaBH 4 (50 mg) were added to a 50 mL three-necked flask, dissolved in THF (10 mL), protected by N 2 , and MeOH (1 ml) was added dropwise to the reaction solution in an oil bath at 50°C. The reaction was carried out at 50°C for 3h. After cooling to room temperature, water was added dropwise to the reaction solution to quench the reaction. The reaction solution was directly evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=10:1) to obtain 45 mg of white solid, namely compound 46-2.
步骤3：化合物46-3的合成Step 3: Synthesis of Compound 46-3
50mL单口瓶中加入化合物46-2(45mg)、PCC(50mg)，溶于DCM(10mL)中，室温反应3h。直接蒸干反应液，柱层析分离产物(DCM:MeOH＝15:1),得30mg黄色固体，即化合物46-3。Compound 46-2 (45 mg) and PCC (50 mg) were added to a 50 mL single-neck flask, dissolved in DCM (10 mL), and reacted at room temperature for 3 h. The reaction solution was directly evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=15:1) to obtain 30 mg of yellow solid, namely compound 46-3.
步骤4：化合物46-4的合成Step 4: Synthesis of Compound 46-4
25mL单口瓶中加入化合物46-3(30mg)，溶于DCM(5mL)中，冰浴下冷却，向反应液中滴加DSAT(0.5ml)，滴加完毕，反应液缓慢升至室温，反应3h。向反应液中滴加饱和碳酸氢钠溶液淬灭反应，直接蒸干反应液，柱层析分离产物(DCM:MeOH＝15:1),得20mg黄色固体，即化合物46-4。Compound 46-3 (30mg) was added to a 25mL single-neck bottle, dissolved in DCM (5mL), cooled in an ice bath, DSAT (0.5ml) was added dropwise to the reaction solution, the addition was completed, the reaction solution was slowly raised to room temperature, and the reaction 3h. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to quench the reaction, the reaction solution was directly evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=15:1) to obtain 20 mg of yellow solid, namely compound 46-4.
步骤5：化合物46的合成Step 5: Synthesis of Compound 46
25mL单口瓶中加入化合物46-4(20mg)，溶于MeOH(2ml)和1M盐酸(2mL)中，40℃下反应5h。冷却至室温，反应液用碳酸氢钠调节pH为中性，蒸干反应液，柱层析分离产物(DCM:MeOH＝10:1)，得白色固体10mg，即化合物46(纯度99.16％)。Compound 46-4 (20 mg) was added to a 25 mL single-neck flask, dissolved in MeOH (2 mL) and 1 M hydrochloric acid (2 mL), and reacted at 40° C. for 5 h. Cooled to room temperature, the pH of the reaction solution was adjusted to neutral with sodium bicarbonate, the reaction solution was evaporated to dryness, and the product was isolated by column chromatography (DCM:MeOH=10:1) to obtain 10 mg of white solid, namely compound 46 (purity 99.16%).
LCMS：[M+H] +＝410.14 LCMS: [M+H] + = 410.14
实施例47：化合物47的合成(5-(5-(1-(3-(二氟甲基)苄基)-1H-吡咯-3-基)-6-甲基吡啶-3-基)嘧啶-2,4(1H，3H)-二酮)Example 47: Synthesis of Compound 47 (5-(5-(1-(3-(difluoromethyl)benzyl)-1H-pyrrol-3-yl)-6-methylpyridin-3-yl)pyrimidine -2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000059
Figure PCTCN2021103508-appb-000059
步骤1：化合物47-1的合成Step 1: Synthesis of Compound 47-1
50ml单口瓶中加入中间体M2(100mg)、3-(溴甲基)苯甲酸甲酯(120mg)、Cs 2CO 3(300mg)，溶于DMF(10ml)中，油浴50℃下反应2h。冷却至室温，向反应液中加水稀释，乙酸乙酯萃取，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝1:1),得80mg黄色固体，即化合物47-1。 Add intermediate M2 (100mg), methyl 3-(bromomethyl)benzoate (120mg), Cs 2 CO 3 (300mg) to a 50ml single-neck bottle, dissolve in DMF (10ml), and react in an oil bath at 50°C for 2h . Cool to room temperature, add water to the reaction solution to dilute, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=1:1) to obtain 80 mg of yellow solid, namely compound 47-1.
步骤2：化合物47-2的合成Step 2: Synthesis of Compound 47-2
50mL三口瓶中加入化合物47-1(80mg)、NaBH 4(50mg)，溶于THF(10mL)中，N 2保护，油浴50℃下，向反应液中滴加MeOH(1ml)。50℃下反应3h。冷却至室温，向反应液中滴加水淬灭反应。直接蒸干反应液，柱层析分离产物(DCM:MeOH＝10:1),得45mg淡黄色固体，即化合物47-2。 Compound 47-1 (80 mg) and NaBH 4 (50 mg) were added to a 50 mL three-neck flask, dissolved in THF (10 mL), protected by N 2 , and MeOH (1 ml) was added dropwise to the reaction solution in an oil bath at 50°C. The reaction was carried out at 50°C for 3h. After cooling to room temperature, water was added dropwise to the reaction solution to quench the reaction. The reaction solution was directly evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=10:1) to obtain 45 mg of pale yellow solid, namely compound 47-2.
步骤3：化合物47-3的合成Step 3: Synthesis of Compound 47-3
50mL单口瓶中加入化合物47-2(45mg)、PCC(50mg)，溶于DCM(10mL)中，室温反应3h。直接蒸干反应液，柱层析分离产物(DCM:MeOH＝15:1),得30mg黄色固体，即化合物47-3。Compound 47-2 (45 mg) and PCC (50 mg) were added to a 50 mL single-neck flask, dissolved in DCM (10 mL), and reacted at room temperature for 3 h. The reaction solution was directly evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=15:1) to obtain 30 mg of yellow solid, namely compound 47-3.
步骤4：化合物47-4的合成Step 4: Synthesis of Compound 47-4
25mL单口瓶中加入化合物47-3(30mg)，溶于DCM(5mL)中，冰浴下冷却，向反应液中滴加DSAT(0.5ml)，滴加完毕，反应液缓慢升至室温，反应3h。向反应液中滴加饱和碳酸氢钠溶液淬灭反应，直接蒸干反应液，柱层析分离产物(DCM:MeOH＝15:1),得20mg黄色固体，即化合物47-4。Compound 47-3 (30mg) was added to a 25mL single-neck bottle, dissolved in DCM (5mL), cooled in an ice bath, DSAT (0.5ml) was added dropwise to the reaction solution, the addition was completed, the reaction solution was slowly raised to room temperature, and the reaction 3h. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to quench the reaction, the reaction solution was directly evaporated to dryness, and the product was separated by column chromatography (DCM:MeOH=15:1) to obtain 20 mg of yellow solid, namely compound 47-4.
步骤5：化合物47的合成Step 5: Synthesis of Compound 47
25mL单口瓶中加入化合物47-4(20mg)，溶于MeOH(2ml)和1M盐酸(2mL)中，40℃下反应5h。冷却至室温，反应液用碳酸氢钠调节pH为中性，蒸干反应液，柱层析分离产物(DCM:MeOH＝10:1)，得白色固体10mg，即化合物47(纯度99.16％)。Compound 47-4 (20 mg) was added to a 25 mL single-neck flask, dissolved in MeOH (2 mL) and 1 M hydrochloric acid (2 mL), and reacted at 40° C. for 5 h. Cooled to room temperature, the pH of the reaction solution was adjusted to neutrality with sodium bicarbonate, the reaction solution was evaporated to dryness, and the product was isolated by column chromatography (DCM:MeOH=10:1) to obtain 10 mg of white solid, namely compound 47 (purity 99.16%).
LCMS：[M+H] +＝410.14 LCMS: [M+H] + = 410.14
实施例48：化合物48的合成(5-(6-甲基-5-(1-(吡啶-4-甲基)-1H-吡咯-3-基)吡啶-3-基)嘧啶-2,4(1H，3H)-二酮)Example 48: Synthesis of Compound 48 (5-(6-methyl-5-(1-(pyridin-4-methyl)-1H-pyrrol-3-yl)pyridin-3-yl)pyrimidin-2,4 (1H,3H)-dione)
Figure PCTCN2021103508-appb-000060
Figure PCTCN2021103508-appb-000060
步骤1：化合物48-1的合成Step 1: Synthesis of Compound 48-1
将化合物16-2(59mg)、4-(溴甲基)吡啶(40.96mg)、Cs 2CO 3(129.31mg)混合于DMF(6mL)，室温反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩，制备TLC纯化(DCM/MeOH＝20/1)得30mg 黄色固体，即化合物48-1(M+H +:389)。 Compound 16-2 (59 mg), 4-(bromomethyl)pyridine (40.96 mg), and Cs 2 CO 3 (129.31 mg) were mixed with DMF (6 mL) and reacted at room temperature. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried, concentrated, and purified by preparative TLC (DCM/MeOH=20/1) to obtain 30 mg of yellow solid, namely compound 48-1 (M+H + :389).
步骤2：化合物48的合成Step 2: Synthesis of Compound 48
将化合物48-1(30mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。反应液旋干，二氯甲烷打浆得4.4mg黄色固体，即化合物48(M+H +:361)。 Compound 48-1 (30 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried and slurried with dichloromethane to obtain 4.4 mg of a yellow solid, namely compound 48 (M+H + : 361).
1H NMR(600MHz,DMSO-d6)δ11.89(s,1H),11.72(s,1H),8.77(d,J＝5.7Hz,2H),8.55(s,1H),8.44(d,J＝5.8Hz,1H),7.82(s,1H),7.55(d,J＝5.6Hz,2H),7.19(t,J＝2.5Hz,1H),6.83(s,1H),5.53(s,2H),2.84(s,3H). 1 H NMR(600MHz,DMSO-d6)δ11.89(s,1H),11.72(s,1H),8.77(d,J=5.7Hz,2H),8.55(s,1H),8.44(d,J ＝5.8Hz, 1H), 7.82(s, 1H), 7.55(d, J＝5.6Hz, 2H), 7.19(t, J＝2.5Hz, 1H), 6.83(s, 1H), 5.53(s, 2H) ),2.84(s,3H).
实施例49：化合物49的合成(5-(6-甲基-5-(1-(4-甲基苄基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 49: Synthesis of Compound 49 (5-(6-methyl-5-(1-(4-methylbenzyl)-1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidine-2, 4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000061
Figure PCTCN2021103508-appb-000061
步骤1：化合物49-1的合成Step 1: Synthesis of Compound 49-1
将化合物16-2(59mg)、4-甲基氯苄(41.85mg)、Cs 2CO 3(129.31mg)混合于DMF(6mL)，升温至50℃反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩，制备TLC纯化(PE/EA＝1/1)得70mg黄色固体，即化合物49-1(M+H +:402)。 Compound 16-2 (59 mg), 4-methylbenzyl chloride (41.85 mg), and Cs 2 CO 3 (129.31 mg) were mixed with DMF (6 mL), and the temperature was raised to 50° C. to react. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated, and purified by preparative TLC (PE/EA=1/1) to obtain 70 mg of yellow solid, namely compound 49-1 (M+H + :402).
步骤2：化合物49的合成Step 2: Synthesis of Compound 49
将化合物49-1(70mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。反应液旋干，二氯甲烷打浆得15.2mg白色固体，即化合物49(M+H +:374)。 Compound 49-1 (70 mg) was mixed with a 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried and slurried with dichloromethane to obtain 15.2 mg of white solid, namely compound 49 (M+H + : 374).
1H NMR(600MHz,Methanol-d4)δ8.73(s,1H),8.66(s,1H),7.76(d,J＝2.1Hz,1H),7.18(s,4H),7.02(t,J＝2.6Hz,1H),6.87(t,J＝2.5Hz,1H),5.20(s,2H),2.90(s,3H),2.32(s,3H). 1 H NMR(600MHz,Methanol-d4)δ8.73(s,1H),8.66(s,1H),7.76(d,J=2.1Hz,1H),7.18(s,4H),7.02(t,J =2.6Hz,1H),6.87(t,J=2.5Hz,1H),5.20(s,2H),2.90(s,3H),2.32(s,3H).
实施例50：化合物50的合成(6-((3-(6-(2,4-二氧基-1,2,3,4-四氢嘧啶-5-基)-3-甲基哒嗪-4-基)-1H-吡咯-1-基)甲基)烟腈)Example 50: Synthesis of compound 50 (6-((3-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrrol-1-yl)methyl)nicotinonitrile)
Figure PCTCN2021103508-appb-000062
Figure PCTCN2021103508-appb-000062
步骤1：化合物50-1的合成Step 1: Synthesis of Compound 50-1
将化合物16-2(59mg)、6-(溴甲基)烟腈(58.64mg)、Cs 2CO 3(129.31mg)混合于DMF(6mL)，室温反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩，制备TLC纯化(DCM/MeOH＝20/1)得75mg黄色固体，即化合物50-1(M+H +:414)。 Compound 16-2 (59 mg), 6-(bromomethyl)nicotinonitrile (58.64 mg), and Cs 2 CO 3 (129.31 mg) were mixed with DMF (6 mL) and reacted at room temperature. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried, concentrated, and purified by preparative TLC (DCM/MeOH=20/1) to obtain 75 mg of yellow solid, namely compound 50-1 (M+H + :414).
步骤2：化合物50的合成Step 2: Synthesis of Compound 50
将化合物50-1(75mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。反应液旋干，二氯甲烷打浆得62.6mg黄色固体，即化合物50(M+H +:386)。 Compound 50-1 (75 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried and slurried with dichloromethane to obtain 62.6 mg of yellow solid, namely compound 50 (M+H + : 386).
1H NMR(600MHz,DMSO-d6)δ11.46(s,1H),11.43(s,1H),9.02(d,J＝2.1Hz,1H),8.31(dd,J＝8.2,2.2Hz,1H),8.28(d,J＝3.6Hz,1H),8.24(s,1H),7.52(d,J＝2.1Hz,1H),7.23(d,J＝8.2Hz,1H),7.07(t,J＝2.5Hz,1H),6.58(dd,J＝2.9,1.9Hz,1H),5.44(s,2H),2.76(s,3H). 1 H NMR (600MHz, DMSO-d6) δ 11.46 (s, 1H), 11.43 (s, 1H), 9.02 (d, J=2.1Hz, 1H), 8.31 (dd, J=8.2, 2.2Hz, 1H) ),8.28(d,J＝3.6Hz,1H),8.24(s,1H),7.52(d,J＝2.1Hz,1H),7.23(d,J＝8.2Hz,1H),7.07(t,J =2.5Hz,1H),6.58(dd,J=2.9,1.9Hz,1H),5.44(s,2H),2.76(s,3H).
实施例51：化合物51的合成(5-(6-甲基-5-(1-(3-甲基苄基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 51: Synthesis of Compound 51 (5-(6-methyl-5-(1-(3-methylbenzyl)-1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidine-2, 4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000063
Figure PCTCN2021103508-appb-000063
步骤1：化合物51-1的合成Step 1: Synthesis of Compound 51-1
将化合物16-2(59mg)、3-甲基氯苄(41.67mg)、Cs 2CO 3(129.31mg)混合于DMF(6mL)，升温至50℃反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩，制备TLC纯化(PE/EA＝1/1)得72mg黄色固体，即化合物51-1(M+H +:402)。 Compound 16-2 (59 mg), 3-methylbenzyl chloride (41.67 mg), and Cs 2 CO 3 (129.31 mg) were mixed with DMF (6 mL), and the temperature was raised to 50° C. to react. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated, and purified by preparative TLC (PE/EA=1/1) to obtain 72 mg of yellow solid, namely compound 51-1 (M+H + :402).
步骤2：化合物51的合成Step 2: Synthesis of Compound 51
将化合物51-1(72mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS 监测显示反应完全。反应液旋干，二氯甲烷打浆得58.3mg白色固体，即化合物51(M+H +:374)。 Compound 51-1 (72 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried and slurried with dichloromethane to obtain 58.3 mg of white solid, namely compound 51 (M+H + : 374).
1H NMR(600MHz,DMSO-d6)δ12.04(s,1H),11.80(s,1H),8.61(s,1H),8.48(d,J＝5.6Hz,1H),7.87(d,J＝2.1Hz,1H),7.25(t,J＝7.5Hz,1H),7.17–7.08(m,4H),6.80(t,J＝2.4Hz,1H),5.21(s,2H),2.86(s,3H),2.29(s,3H). 1 H NMR(600MHz,DMSO-d6)δ12.04(s,1H),11.80(s,1H),8.61(s,1H),8.48(d,J=5.6Hz,1H),7.87(d,1H) =2.1Hz,1H),7.25(t,J=7.5Hz,1H),7.17-7.08(m,4H),6.80(t,J=2.4Hz,1H),5.21(s,2H),2.86(s ,3H),2.29(s,3H).
实施例52：化合物52的合成(5-(6-甲基-5-(1-(2-甲基苄基)-1H-吡咯-3-基)吡啶-3-基)嘧啶-2,4(1H，3H)-二酮)Example 52: Synthesis of Compound 52 (5-(6-methyl-5-(1-(2-methylbenzyl)-1H-pyrrol-3-yl)pyridin-3-yl)pyrimidine-2,4 (1H,3H)-dione)
Figure PCTCN2021103508-appb-000064
Figure PCTCN2021103508-appb-000064
步骤1：化合物52-1的合成Step 1: Synthesis of Compound 52-1
将化合物16-2(59mg)、2-甲基氯苄(41.67mg)、Cs 2CO 3(129.31mg)混合于DMF(6mL)，升温至50℃反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩，制备TLC纯化(PE/EA＝1/1)得68mg黄色固体，即化合物52-1(M+H +:402)。 Compound 16-2 (59 mg), 2-methylbenzyl chloride (41.67 mg), and Cs 2 CO 3 (129.31 mg) were mixed with DMF (6 mL), and the temperature was raised to 50° C. to react. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated, and purified by preparative TLC (PE/EA=1/1) to obtain 68 mg of yellow solid, namely compound 52-1 (M+H + :402).
步骤2：化合物52的合成Step 2: Synthesis of Compound 52
将化合物52-1(72mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。反应液旋干，二氯甲烷打浆得63.1mg白色固体，即化合物52(M+H +:374)。 Compound 52-1 (72 mg) was mixed with 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried and slurried with dichloromethane to obtain 63.1 mg of white solid, namely compound 52 (M+H + : 374).
1H NMR(600MHz,DMSO-d6)δ11.99(s,1H),11.78(s,1H),8.59(s,1H),8.47(d,J＝5.9Hz,1H),7.76(s,1H),7.25–7.21(m,2H),7.18(dq,J＝8.7,3.9Hz,1H),7.05(t,J＝2.5Hz,1H),6.93(d,J＝7.4Hz,1H),6.81(t,J＝2.4Hz,1H),5.29(s,2H),2.84(s,3H),2.31(s,3H). 1 H NMR(600MHz,DMSO-d6)δ11.99(s,1H),11.78(s,1H),8.59(s,1H),8.47(d,J=5.9Hz,1H),7.76(s,1H) ),7.25–7.21(m,2H),7.18(dq,J=8.7,3.9Hz,1H),7.05(t,J=2.5Hz,1H),6.93(d,J=7.4Hz,1H),6.81 (t, J=2.4Hz, 1H), 5.29(s, 2H), 2.84(s, 3H), 2.31(s, 3H).
实施例53：化合物53的合成(5-(5-(1-(4-氨基苄基)-1H-吡咯-3-基)-6-甲基哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 53: Synthesis of Compound 53 (5-(5-(1-(4-aminobenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidin-2,4 (1H,3H)-dione)
Figure PCTCN2021103508-appb-000065
Figure PCTCN2021103508-appb-000065
步骤1：化合物53-1的合成Step 1: Synthesis of Compound 53-1
将化合物16-2(59mg)、4-硝基氯苄(50.90mg)、Cs 2CO 3(129.31mg)混合于DMF(6mL)，室温反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯 萃取三次，饱和食盐水洗涤，干燥、浓缩，制备TLC纯化(PE/EA＝1/1)得77mg黄色固体，即化合物53-1(M+H +:433)。 Compound 16-2 (59 mg), 4-nitrobenzyl chloride (50.90 mg), and Cs 2 CO 3 (129.31 mg) were mixed with DMF (6 mL) and reacted at room temperature. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated, and purified by preparative TLC (PE/EA=1/1) to obtain 77 mg of yellow solid, namely compound 53-1 (M+H + :433).
步骤2：化合物53-2的合成Step 2: Synthesis of Compound 53-2
将化合物53-1(72mg)，钯碳(10mg)混合于无水乙醇(5mL)中，升温至80℃反应。2h后，LCMS监测显示反应完全。反应液旋干，过滤除去钯碳，旋干得到63.5mg白色固体，即化合物53-2(M+H +:403)。 Compound 53-1 (72 mg) and palladium on carbon (10 mg) were mixed in absolute ethanol (5 mL), and the temperature was raised to 80°C to react. After 2 h, LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried, filtered to remove palladium-carbon, and spin-dried to obtain 63.5 mg of white solid, namely compound 53-2 (M+H + : 403).
步骤3：化合物53的合成Step 3: Synthesis of Compound 53
将化合物53-2(63.5mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。反应液旋干，二氯甲烷打浆得6.9mg白色固体，即化合物53(M+H +:375)。 Compound 53-2 (63.5 mg) was mixed with a 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried and slurried with dichloromethane to obtain 6.9 mg of white solid, namely compound 53 (M+H + : 375).
1H NMR(600MHz,DMSO-d6)δ11.77(s,1H),11.66(s,1H),8.41(d,J＝16.2Hz,2H),7.68(s,1H),7.27–7.20(m,2H),7.06(t,J＝2.5Hz,1H),6.95(s,2H),6.68(s,1H),5.14(s,2H),2.80(s,2H),1.24(s,3H). 1 H NMR (600MHz, DMSO-d6)δ11.77(s,1H),11.66(s,1H),8.41(d,J=16.2Hz,2H),7.68(s,1H),7.27-7.20(m ,2H),7.06(t,J＝2.5Hz,1H),6.95(s,2H),6.68(s,1H),5.14(s,2H),2.80(s,2H),1.24(s,3H) .
实施例54：化合物54的合成(5-(6-甲基-5-(1-(4-(甲磺酰基)苄基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 54: Synthesis of Compound 54 (5-(6-methyl-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidine -2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000066
Figure PCTCN2021103508-appb-000066
步骤1：化合物54-1的合成Step 1: Synthesis of Compound 54-1
将化合物16-2(59mg)、4-甲磺酰基氯苄(60.58mg)、Cs 2CO 3(129.31mg)混合于DMF(6mL)，室温反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩，制备TLC纯化(PE/EA＝1/1)得62mg白色固体，即化合物54-1(M+H +:466)。 Compound 16-2 (59 mg), 4-methanesulfonyl benzyl chloride (60.58 mg), and Cs 2 CO 3 (129.31 mg) were mixed with DMF (6 mL), and reacted at room temperature. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated, and purified by preparative TLC (PE/EA=1/1) to obtain 62 mg of white solid, namely compound 54-1 (M+H + :466).
步骤2：化合物54的合成Step 2: Synthesis of Compound 54
将化合物54-1(62mg)混合于1M稀盐酸溶液(2mL)，升温至70℃反应。5h后，LCMS监测显示反应完全。反应液旋干，二氯甲烷打浆得21.8mg白色固体，即化合物54(M+H +:438)。 Compound 54-1 (62 mg) was mixed with a 1 M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 70°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried and slurried with dichloromethane to obtain 21.8 mg of white solid, namely compound 54 (M+H + : 438).
1H NMR(600MHz,DMSO-d6)δ11.95(s,1H),11.76(s,1H),8.57(s,1H),8.46(d,J＝6.0Hz,1H),7.96–7.91(m,2H),7.87(s,1H),7.56–7.52(m,2H),7.18(dd,J＝3.0,2.0Hz,1H),6.81(t,J＝2.4Hz,1H),5.40(s,2H),3.20(s,3H),2.85(s,3H). 1 H NMR (600MHz, DMSO-d6)δ11.95(s,1H),11.76(s,1H),8.57(s,1H),8.46(d,J=6.0Hz,1H),7.96-7.91(m ,2H),7.87(s,1H),7.56–7.52(m,2H),7.18(dd,J=3.0,2.0Hz,1H),6.81(t,J=2.4Hz,1H),5.40(s, 2H), 3.20(s, 3H), 2.85(s, 3H).
实施例55：化合物55的合成(5-(6-甲氧基-5-(1-(4-甲氧基苄基)-1H-吡咯-3-基)哒嗪-3-基)嘧啶-2,4(1H，3H)-二酮)Example 55: Synthesis of Compound 55 (5-(6-Methoxy-5-(1-(4-methoxybenzyl)-1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione)
Figure PCTCN2021103508-appb-000067
Figure PCTCN2021103508-appb-000067
步骤1：化合物55-1的合成Step 1: Synthesis of Compound 55-1
将4-溴-1,2-二氢哒嗪-3,6-二酮(2.00g)、3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-(三异丙基甲硅烷基)-1H-吡咯(7.30g)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.42g)、Cs 2CO 3(17.06g)混合于二氧六环(100mL)和水(30mL)的混合溶剂中，氮气保护下，加热至70℃反应。3h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩，柱层析纯化(DCM/MeOH＝20/1)得0.83g黄色液体，即化合物55-1(M+H +:334)。 4-Bromo-1,2-dihydropyridazine-3,6-dione (2.00g), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro Alk-2-yl)-1-(triisopropylsilyl)-1H-pyrrole (7.30 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloride Methane complex (0.42 g) and Cs 2 CO 3 (17.06 g) were mixed in a mixed solvent of dioxane (100 mL) and water (30 mL), heated to 70° C. for reaction under nitrogen protection. After 3 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried, concentrated, and purified by column chromatography (DCM/MeOH=20/1) to obtain 0.83 g of a yellow liquid, namely compound 55-1 (M +H + :334).
步骤2：化合物55-2的合成Step 2: Synthesis of Compound 55-2
将化合物55-1(0.83g)溶于三氯氧磷(10mL)中，升温至100℃反应。1h后，LCMS监测显示反应完全。反应液缓慢加入水中，淬灭三氯氧磷，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩，柱层析纯化(PE/EA＝1/1)得到0.23g白色固体，即化合物55-2(M+H +:215)。 Compound 55-1 (0.83 g) was dissolved in phosphorus oxychloride (10 mL), and the temperature was raised to 100°C to react. After 1 h, LCMS monitoring showed that the reaction was complete. The reaction solution was slowly added to water, quenched with phosphorus oxychloride, extracted three times with ethyl acetate, washed with saturated brine, dried, concentrated, and purified by column chromatography (PE/EA=1/1) to obtain 0.23 g of a white solid, namely compound 55 -2 (M+H + : 215).
步骤3：化合物55-3的合成Step 3: Synthesis of Compound 55-3
将化合物55-2(0.25g)、(2,4-二甲氧基嘧啶-5-基)硼酸(0.25g)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.05g)、K 2CO 3(0.32g)混合于二氧六环(10mL)和水(2mL)的混合溶剂中，氮气保护下，加热至60℃反应。1h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯萃取三次，饱和食盐水洗涤，干燥、浓缩，制备TLC纯化(DCM/MeOH＝20/1)得0.14g白色固体，即化合物55-3(M+H +:319)。 Compound 55-2 (0.25g), (2,4-dimethoxypyrimidin-5-yl)boronic acid (0.25g), [1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium dichloromethane complex (0.05 g), K 2 CO 3 (0.32 g) were mixed in a mixed solvent of dioxane (10 mL) and water (2 mL), heated to 60° C. for reaction under nitrogen protection. After 1 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried, concentrated, and purified by preparative TLC (DCM/MeOH=20/1) to obtain 0.14 g of a white solid, namely compound 55-3 (M+ H + :319).
步骤4：化合物55-4的合成Step 4: Synthesis of Compound 55-4
将化合物55-3(0.14g)、4-甲氧基氯苄(0.13g)、Cs 2CO 3(0.27g)混合于DMF(10mL)，升温至50℃反应。2h后，TLC监测显示反应完全。反应液倒入适量水中混匀，乙酸乙酯 萃取三次，饱和食盐水洗涤，干燥、浓缩，制备TLC纯化(DCM/MeOH＝20/1)得143mg白色固体，即化合物55-4(M+H +:439)。 Compound 55-3 (0.14 g), 4-methoxybenzyl chloride (0.13 g), and Cs 2 CO 3 (0.27 g) were mixed with DMF (10 mL), and the temperature was raised to 50° C. to react. After 2 h, TLC monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried, concentrated, and purified by preparative TLC (DCM/MeOH=20/1) to obtain 143 mg of white solid, namely compound 55-4 (M+H + :439).
步骤5：化合物55-5的合成Step 5: Synthesis of Compound 55-5
将化合物55-4(0.14g)、甲醇钠(0.18g)混合于甲醇(20mL)，升温至60℃封管反应。12h后，LCMS监测显示反应完全。反应液倒入适量水中混匀，二氯甲烷萃取三次，饱和食盐水洗涤，干燥、浓缩，制备TLC纯化(DCM/MeOH＝20/1)得48mg白色固体，即化合物55-5(M+H +:434)。 Compound 55-4 (0.14 g) and sodium methoxide (0.18 g) were mixed with methanol (20 mL), and the temperature was raised to 60° C. to seal the reaction. After 12 h, LCMS monitoring showed that the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed, extracted with dichloromethane three times, washed with saturated brine, dried, concentrated, and purified by preparative TLC (DCM/MeOH=20/1) to obtain 48 mg of white solid, namely compound 55-5 (M+H + :434).
步骤6：化合物55的合成Step 6: Synthesis of Compound 55
将化合物55-5(48mg)混合于1M稀盐酸溶液(2mL)，升温至50℃反应。5h后，LCMS监测显示反应完全。反应液旋干，制备液相纯化得30mg灰色固体，即化合物55(M+H +:406)。 Compound 55-5 (48 mg) was mixed with a 1M dilute hydrochloric acid solution (2 mL), and the temperature was raised to 50°C to react. After 5 h, LCMS monitoring showed that the reaction was complete. The reaction solution was spin-dried and purified by preparative liquid phase to obtain 30 mg of gray solid, namely compound 55 (M+H + : 406).
1H NMR(600MHz,DMSO-d6)δ11.43(s,1H),8.24(s,1H),8.12(s,1H),7.66(s,1H),7.23(d,J＝8.2Hz,2H),6.97(s,1H),6.92(d,J＝8.2Hz,2H),6.63(s,1H),5.11(s,2H),4.13(s,3H),3.73(s,3H). 1 H NMR (600MHz, DMSO-d6) δ 11.43(s, 1H), 8.24(s, 1H), 8.12(s, 1H), 7.66(s, 1H), 7.23(d, J=8.2Hz, 2H ), 6.97(s, 1H), 6.92(d, J=8.2Hz, 2H), 6.63(s, 1H), 5.11(s, 2H), 4.13(s, 3H), 3.73(s, 3H).
下述的实施例采用上述方法合成，或使用相应中间体的类似方法合成。The following examples were synthesized using the methods described above, or analogously using the corresponding intermediates.
Figure PCTCN2021103508-appb-000068
Figure PCTCN2021103508-appb-000068
Figure PCTCN2021103508-appb-000069
Figure PCTCN2021103508-appb-000069
对比实施例1Comparative Example 1
按照WO2019168744A1实施例2的方法合成对比化合物1，Synthesize comparative compound 1 according to the method of Example 2 of WO2019168744A1,
Figure PCTCN2021103508-appb-000070
Figure PCTCN2021103508-appb-000070
药理实验Pharmacological experiments
实施例1：细胞水平的酶学活性检测Example 1: Detection of enzymatic activity at the cellular level
将Calu-6细胞消化，使用TM buffer(25mM Tris,5mM MgCl 2,pH 7.5)重悬细胞，按 25000细胞、100μL/孔铺96孔板。TM buffer配制梯度浓度的化合物溶液，分别向各孔细胞中加入50μL各浓度的待测化合物DMSO溶液，化合物终浓度为20000、6666.7、2222.2、740.7、246.9、82.3、27.4、9.1、3.0、1.0、0.3、0nM(DMSO终浓度均为0.625％)。37℃恒温水平摇床预孵育30min，各孔中加入50μL 800μM AMP溶液，37℃恒温水平摇床继续孵育120min后，将96孔板离心，每孔转移50μL上清液至新的96孔板中，每孔中加入50μL 130μM ATP溶液和100μL Cell-titer Glo工作液，震荡混匀后室温孵育10min，多功能酶标仪读取Luminescence发光值，将发光值读数转换为抑制百分数： Calu-6 cells were digested, resuspended in TM buffer (25 mM Tris, 5 mM MgCl 2 , pH 7.5), and plated in a 96-well plate at 25,000 cells and 100 μL/well. TM buffer was used to prepare compound solutions with gradient concentrations, and 50 μL of DMSO solutions of the compounds to be tested were added to the cells in each well. 0.3, 0 nM (the final concentration of DMSO is 0.625%). Pre-incubate for 30 min on a constant temperature horizontal shaker at 37 °C, add 50 μL of 800 μM AMP solution to each well, and continue to incubate at 37 °C for 120 min on a constant temperature horizontal shaker, then centrifuge the 96-well plate and transfer 50 μL of supernatant per well to a new 96-well plate. , add 50 μL of 130 μM ATP solution and 100 μL of Cell-titer Glo working solution to each well, shake and mix, incubate at room temperature for 10 min, read the Luminescence luminescence value with a multi-function microplate reader, and convert the luminescence value reading into inhibition percentage:
抑制百分数＝(1-读数/最大值)*100。Percent inhibition = (1-reading/max)*100.
“最大值”为DMSO对照。"Max" is the DMSO control.
用GraphPad Prism软件进行曲线拟合并得到IC50值。Curve fitting was performed with GraphPad Prism software and IC50 values were obtained.
实施例化合物在Calu-6细胞水平的酶学IC50数据参见表1。See Table 1 for the enzymatic IC50 data of the example compounds at the level of Calu-6 cells.
表1Table 1
化合物名称Compound name IC50(nM)IC50(nM) 化合物名称Compound name IC50(nM)IC50(nM)
11 20842084 2929 114114
22 54.454.4 3030 12.412.4
33 4949 3131 4.84.8
44 37.437.4 3232 4.64.6
55 25.125.1 3333 5.75.7
66 455455 3434 8.28.2
77 462462 3535 9595
88 617617 3636 7373
99 2828 3737 9696
1010 9.49.4 3838 7171
1111 173173 3939 7979
1212 308308 4040 5050
1313 239239 4141 6363
1414 3.13.1 4242 3030
1515 2.12.1 4343 10.310.3
1616 9.59.5 4444 7.37.3
1717 22.222.2 4545 31.631.6
1818 10.210.2 4646 24.224.2
1919 5959 4747 34.734.7
2020 8383 4848 39.839.8
21twenty one 23twenty three 4949 1414
22twenty two 4949 5050 21.821.8
23twenty three 376376 5151 1616
24twenty four 121121 5252 19.519.5
2525 26.626.6 5353 1818
2626 14.714.7 5454 21.421.4
2727 13.513.5 5555 96.396.3
2828 32.632.6 D1D1 49.149.1
本发明的化合物具有良好活性，且预料不到地是，本发明R 3取代基间位取代化合物比邻位取代化合物，活性显著增强(表2)。 The compounds of this invention have good activity, and unexpectedly, R & inter-group substituents of the present invention is 3-substituted compound of the ortho-substituted compound, significantly enhanced activity (Table 2).
表2Table 2
Figure PCTCN2021103508-appb-000071
Figure PCTCN2021103508-appb-000071
虽然本发明已通过其实施方式进行了全面的描述，但是值得注意的是，各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。Although the present invention has been fully described in terms of its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to be included within the scope of the appended claims of the present invention.

Claims (11)

  1. 一种通式(I)所示的化合物、其互变异构体、氘代物或药用盐：A compound shown in general formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt:
    Figure PCTCN2021103508-appb-100001
    Figure PCTCN2021103508-appb-100001
    其中，in,
    R 1选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基未被取代或被1、2或3个取代基R 3所取代， R 1 is selected phenyl or 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl unsubstituted or substituted with 1, 2 or 3 substituents substituted by R 3,
    R 3选自C 1-6烷基、-(C 1-4亚烷基) 0-1-Cyc、-O-(C 1-4亚烷基) 0-1-Cyc、-S-(C 1-4亚烷基) 0-1-Cyc、-NH-(C 1-4亚烷基) 0-1-Cyc、-NH-C 1-6烷基、-N(C 1-6烷基) 2、-O-C 1-6烷基或-S-C 1-6烷基，R 3任选未取代或进一步被一个或多个R 4取代基所取代； R 3 is selected from C 1-6 alkyl, -(C 1-4 alkylene) 0-1 -Cyc, -O-(C 1-4 alkylene) 0-1 -Cyc, -S-(C 1-4 alkylene) 0-1 -Cyc, -NH-(C 1-4 alkylene) 0-1 -Cyc, -NH-C 1-6 alkyl, -N(C 1-6 alkyl ) 2 , -OC 1-6 alkyl or -SC 1-6 alkyl, R 3 is optionally unsubstituted or further substituted by one or more R 4 substituents;
    所述Cyc选自C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，所述C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基未被取代或被1、2或3个取代基R 5所取代； The Cyc is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclic group, C 6-10 aryl or 5-10-membered heteroaryl, the C 3-10 cycloalkyl, 3-10-membered Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents R 5 ;
    R 4或R 5各自独立地选自H、羟基、氨基、卤素、氰基、硝基、-OR a、-SR a、＝O、＝S、-C(O)R a、-C(S)R a、-C(O)OR a、-C(S)OR a、-C(O)N(R a) 2、-N(R a) 2、-S(O) 2R a、-O-S(O 2)OR a、-O-S(O) 2R a或R a，所述R a各自独立地选自H、C 1-6烷基或C 3-6环烷基，R a未被取代或进一步被一个或多个选自卤素、羟基、C 1-3烷基或氰基的取代基取代； R 4 or R 5 is each independently selected from H, hydroxy, amino, halogen, cyano, nitro, -OR a , -SR a , =O, =S, -C(O)R a , -C(S )R a , -C(O)OR a , -C(S)OR a , -C(O)N(R a ) 2 , -N(R a ) 2 , -S(O) 2 R a , - OS (O 2) oR a, -OS (O) 2 R a or R a, said R a is independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, R a is not substituted or further substituted by one or more substituents selected from halogen, hydroxy, C 1-3 alkyl or cyano;
    R 2选自氢、卤素、氰基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、卤代C 2-4烯基或C 2-4炔基。 R 2 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, halogenated C 2-4 alkenyl or C 2-4 alkynyl.
  2. 根据权利要求1所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 1选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任意地含有1个或2个分别独立地选自N、O或S的杂原子，且所述杂芳环基未被取代或被1、2或3个取代基R 3所取代；优选R 1选自
    Figure PCTCN2021103508-appb-100002
    Figure PCTCN2021103508-appb-100003
    所述R 1未被取代或被1、2或3个取代基R 3所取代。     The compound according to claim 1, its tautomer, deuterated product or pharmaceutically acceptable salt, wherein R 1 is selected from phenyl or 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl group optionally containing 1 or 2 substituents each independently selected from N, O or S heteroatom, and the heteroaryl ring is unsubstituted or substituted 1, 2 or 3 substituents R 3 substituted with ; preferably R 1 is selected from
    Figure PCTCN2021103508-appb-100002
    Figure PCTCN2021103508-appb-100003
    Said R 1 is unsubstituted or substituted with 1, 2 or 3 substituents R 3 .
  3. 根据权利要求1或2中所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 3为间位取代。 The compound according to claim 1 or 2, its tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 3 is meta-substituted.
  4. 根据权利要求1-3中任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 3选自C 1-6烷基、-C 1-3亚烷基-苯基、-C 1-3亚烷基-C 3-6环烷基或-C 1-3亚烷基-(5-10元杂芳基)，所述R 3任选被选自H、氰基、卤素、羟基、氨基、C 1-3烷基、C 1-3羟基烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、-C(＝O)O-C 1-3烷基或-S(＝O) 2-C 1-3烷基的取代基取代；优选R 3选自C 1-6烷基、
    Figure PCTCN2021103508-appb-100004
    Figure PCTCN2021103508-appb-100005
    所述R 3任选被选自H、氰基、卤素、羟基、氨基、C 1-3烷基、C 1-3羟基烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、-C(＝O)O-C 1-3烷基或-S(＝O) 2-C 1-3烷基的取代基取代。     The compound according to any one of claims 1-3, its tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 3 is selected from C 1-6 alkyl, -C 1-3 subgroup Alkyl-phenyl, -C 1-3 alkylene-C 3-6 cycloalkyl or -C 1-3 alkylene-(5-10 membered heteroaryl), the R 3 is optionally selected from H, cyano, halogen, hydroxyl, amino, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, -C(=O)OC 1-3 alkyl or -S(=O) 2 -C 1-3 alkyl substituent; preferably R 3 is selected from C 1-6 alkyl,
    Figure PCTCN2021103508-appb-100004
    Figure PCTCN2021103508-appb-100005
    The R 3 is optionally selected from H, cyano, halogen, hydroxy, amino, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, Substituent substitution of C 1-3 haloalkoxy, -C(=O)OC 1-3 alkyl or -S(=O) 2 -C 1-3 alkyl.
  5. 根据权利要求1-5中任一项所述的化合物、其互变异构体、氘代物或药用盐，其特征在于，R 2选自卤素、C 1-3烷基或C 1-3烷氧基；优选氯、甲基或甲氧基。 The compound, tautomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein R 2 is selected from halogen, C 1-3 alkyl or C 1-3 Alkoxy; preferably chlorine, methyl or methoxy.
  6. 根据权利要求1-6中任一项所述的化合物、其互变异构体、氘代物或药用盐，其选自通式(IA)所示的化合物：The compound according to any one of claims 1-6, its tautomer, deuterated substance or pharmaceutically acceptable salt, which is selected from the compound represented by general formula (IA):
    Figure PCTCN2021103508-appb-100006
    Figure PCTCN2021103508-appb-100006
    其中，in,
    X 1选自N或CH； X 1 is selected from N or CH;
    X 2选自N或CH； X 2 is selected from N or CH;
    R 3选自C 1-6烷基、-(C 1-4亚烷基) 0-1-Cyc、-O-(C 1-4亚烷基) 0-1-Cyc、-S-(C 1-4亚烷基) 0-1-Cyc、-NH-(C 1-4亚烷基) 0-1-Cyc、-NH-C 1-6烷基、-N(C 1-6烷基) 2、-O-C 1-6烷基或-S-C 1-6烷基，R 3任选未取代或进一步被一个或多个R 4取代基所取代； R 3 is selected from C 1-6 alkyl, -(C 1-4 alkylene) 0-1 -Cyc, -O-(C 1-4 alkylene) 0-1 -Cyc, -S-(C 1-4 alkylene) 0-1 -Cyc, -NH-(C 1-4 alkylene) 0-1 -Cyc, -NH-C 1-6 alkyl, -N(C 1-6 alkyl ) 2 , -OC 1-6 alkyl or -SC 1-6 alkyl, R 3 is optionally unsubstituted or further substituted by one or more R 4 substituents;
    所述Cyc选自C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，所述C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基未被取代或被1、2或3个取代基R 5所取代； The Cyc is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclic group, C 6-10 aryl or 5-10-membered heteroaryl, the C 3-10 cycloalkyl, 3-10-membered Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents R 5 ;
    R 4或R 5各自独立地选自H、羟基、氨基、卤素、氰基、硝基、-OR a、-SR a、＝O、＝S、-C(O)R a、-C(S)R a、-C(O)OR a、-C(S)OR a、-C(O)N(R a) 2、-N(R a) 2、-S(O) 2R a、-O-S(O 2)OR a、-O-S(O) 2R a或R a，所述R a各自独立地选自H、C 1-6烷基或C 3-6环烷基，R a未被取代或进一步被一个或多个选自卤素、羟基、C 1-3烷基或氰基的取代基取代； R 4 or R 5 is each independently selected from H, hydroxy, amino, halogen, cyano, nitro, -OR a , -SR a , =O, =S, -C(O)R a , -C(S )R a , -C(O)OR a , -C(S)OR a , -C(O)N(R a ) 2 , -N(R a ) 2 , -S(O) 2 R a , - OS (O 2) oR a, -OS (O) 2 R a or R a, said R a is independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, R a is not substituted or further substituted by one or more substituents selected from halogen, hydroxy, C 1-3 alkyl or cyano;
    R 2选自氢、卤素、氰基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、卤代C 2-4烯基或C 2-4炔基。 R 2 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, halogenated C 2-4 alkenyl or C 2-4 alkynyl.
  7. 一种化合物、其互变异构体、氘代物或药用盐，其选自：A compound, its tautomer, deuterated substance or pharmaceutically acceptable salt selected from:
    Figure PCTCN2021103508-appb-100007
    Figure PCTCN2021103508-appb-100007
    Figure PCTCN2021103508-appb-100008
    Figure PCTCN2021103508-appb-100008
  8. 一种制备根据权利要求1中所述的通式(I)化合物、其互变异构体、氘代物或药用盐的方法，该方法包括：A method for preparing a compound of general formula (I), its tautomer, deuterated substance or a pharmaceutically acceptable salt thereof according to claim 1, the method comprising:
    Figure PCTCN2021103508-appb-100009
    Figure PCTCN2021103508-appb-100009
    通式(II)化合物在酸性条件下反应，得到通式(I)化合物，The compound of general formula (II) is reacted under acidic conditions to obtain the compound of general formula (I),
    其中R 1和R 2的定义如权利要求1中所述。 wherein R 1 and R 2 are as defined in claim 1 .
  9. 一种药物组合物，其特征在于，所述药物组合物含有治疗有效量的权利要求1-8任一项所述的化合物和至少一种药学上可接受的辅料。A pharmaceutical composition, characterized in that, the pharmaceutical composition contains a therapeutically effective amount of the compound according to any one of claims 1-8 and at least one pharmaceutically acceptable adjuvant.
  10. 权利要求1-8任一项所述的化合物或权利要求9所述的药物组合物在制备药物中的应用。Use of the compound according to any one of claims 1-8 or the pharmaceutical composition according to claim 9 in the preparation of medicine.
  11. 一种治疗和/或预防疾病的方法，包括向治疗对象施用治疗有效量的权利要求1-8任一项所述的化合物或权利要求9所述的药物组合物。A method of treating and/or preventing a disease, comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-8 or the pharmaceutical composition of claim 9.
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