WO2021129596A1 - 喹啉类化合物及其应用 - Google Patents

喹啉类化合物及其应用 Download PDF

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WO2021129596A1
WO2021129596A1 PCT/CN2020/138248 CN2020138248W WO2021129596A1 WO 2021129596 A1 WO2021129596 A1 WO 2021129596A1 CN 2020138248 W CN2020138248 W CN 2020138248W WO 2021129596 A1 WO2021129596 A1 WO 2021129596A1
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cancer
alkyl
acid
aryl
het
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PCT/CN2020/138248
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English (en)
French (fr)
Inventor
燕立波
胡诗合
王娅
刘宇
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江苏开元药业有限公司
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Priority to EP20904375.1A priority Critical patent/EP4083031A4/en
Priority to US17/787,599 priority patent/US20230014962A1/en
Publication of WO2021129596A1 publication Critical patent/WO2021129596A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention belongs to the technical field of medicine, and specifically relates to a class of quinoline compounds and their preparations for preventing and/or treating diseases related to fibroblast growth factor receptor 4 (FGFR4) overexpression in organisms and blood vessels.
  • FGFR4 fibroblast growth factor receptor 4
  • RTKs Protein receptor tyrosine kinases
  • RTKs Protein receptor tyrosine kinases
  • Physiological activities such as growth and apoptosis.
  • RTKs are closely related to the occurrence and development of tumors. Therefore, their family members have become the mainstream targets for the development of anti-tumor drugs.
  • tyrosine kinase inhibitors are on the market or in clinical trials, most of which are reversible inhibitors.
  • Such inhibitors have the following shortcomings: 1) poor selectivity; 2) short action time: 3) easy to withstand medicine.
  • Irreversible kinase inhibitors are based on reversible inhibitors, with a Michael acceptor fragment attached to a suitable position. This electrophilic fragment can react electrophilically with cysteine residues near the ATP binding domain to form a covalent bond, thereby To achieve the effect of permanent inactivation, this method makes its effect more intense and lasting. At the same time, there is no competition between irreversible kinase inhibitors and the binding of ATP to kinases, which reduces the possibility of kinase mutations and reduces or avoids the development of drug resistance, with higher selectivity.
  • Fibroblast growth factor receptor is a receptor-type protein tyrosine kinase.
  • FGFR1 FGFR2, FGFR3 and FGFR4
  • FGFR4 is highly expressed in a variety of cancer cells and has the effects of regulating cell proliferation and anti-apoptosis. It can be used as an important target for aggressive cancer.
  • FGFR4 is knocked out, it can effectively reduce the proliferation of cancer cells and promote The apoptosis of cancer cells, at the same time, selectively acting on FGFR4 can avoid the toxic and side effects caused by acting on several other subtypes such as FGFR1 ⁇ 3.
  • the mutation and abnormal activity of FGFR4 in a variety of cancers, especially liver cancer has made it a drug target for the treatment of FGFR4-positive cancers.
  • the purpose of the present invention is to provide a class of quinoline compounds, which have good inhibitory activity on fibroblast growth factor receptor 4 (FGFR4) kinase and can be used as irreversible inhibitors of FGFR4. It provides the possibility for the treatment of diseases mediated by FGFR4.
  • FGFR4 fibroblast growth factor receptor 4
  • X is selected from -CR 4 R 5 -, -NR 4 -, O or S, wherein R 4 and R 5 each independently represent hydrogen, deuterium, halogen, alkyl, aryl or Het;
  • the dashed line indicates that there may be a single bond or a double bond
  • n 0, 1, 2 or 3;
  • R 1 is selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, aryl or Het;
  • R 2 is selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, aryl or Het;
  • R 3 is selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, aryl or Het;
  • P is selected from the following structures:
  • R 11 is a leaving group or an activated ester, and the leaving group is a halogen
  • R 8 , R 9 , R 10 , and R 12 are each independently selected from hydrogen, halogen, hydroxyl, alkoxy, and alkyl , Aryl or Het;
  • Alkyl is a linear or branched saturated hydrocarbon group with 1-6 carbon atoms, a cyclic saturated hydrocarbon group with 3-6 carbon atoms, or a 3-6 linear or branched saturated hydrocarbon group with 1-6 carbon atoms attached.
  • the aryl group is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each of which is optionally substituted by 1, 2 or 3 substituents, and each substituent is independently selected from hydrogen. , Alkyl, cyano, halogen, nitro, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;
  • Het is selected from piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or A monocyclic heterocyclic ring of pyridazinyl; or selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzo Isothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo[1,4]dioxenyl or benzo[1,3]dioxolyl Bicyclic heterocycle; each monocyclic or bicyclic heterocycle is optionally substituted by 1, 2, or 3 substituents, each of which is independently selected from hal
  • Halogen is selected from fluorine, chlorine, bromine or iodine.
  • X is -NR 4 -or O, wherein R 4 is selected from hydrogen, deuterium, halogen, alkyl, aryl or Het;
  • Q is selected from -NR 6 CONR 7 -, -CONR 6 -, -NR 6 CO-, -NR 6 SO 2 NR 7 -, -SO 2 NR 6 -or -NR 6 SO 2 -, where R 6 , R 7 Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
  • the dashed line indicates that there may be a single bond or a double bond
  • n 0, 1, 2 or 3;
  • R 1 is selected from hydrogen, halogen or alkyl
  • R 2 is selected from hydrogen, alkyl or aryl
  • R 3 is selected from alkoxy, alkyl, aryl or Het.
  • X is O
  • Q is selected from -NR 6 CONR 7 -, -CONR 6 -or -NR 6 CO-, wherein R 6 and R 7 each independently represent hydrogen, deuterium, alkyl, aryl or Het;
  • the dashed line indicates that there may be a single bond or a double bond
  • n 0, 1, 2 or 3;
  • R 1 is selected from hydrogen, halogen or alkyl
  • R 2 is an alkyl group or an aryl group
  • R 3 is selected from alkyl, aryl or Het.
  • X is O
  • Q is selected from -NR 6 CONR 7 -, -CONR 6 -or -NR 6 CO-, wherein R 6 and R 7 each independently represent hydrogen, deuterium, alkyl, aryl or Het;
  • the dashed line indicates that there may be a single bond or a double bond
  • n 0 or 1;
  • R 1 is hydrogen or halogen
  • R 2 is an alkyl group or an aryl group
  • R 3 is selected from alkyl, aryl or Het
  • P is selected from the following structures:
  • R 11 is a leaving group or an activated ester, and the leaving group is a halogen;
  • R 8 , R 9 , and R 10 are each independently selected from hydrogen or an alkyl group.
  • the pharmaceutically acceptable salt includes the acid addition salt formed by the compound of general formula I with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Naphthalene sulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenyl acetic acid, mandelic acid; also includes acids formed by compounds of general formula I and inorganic bases Type salt.
  • the pharmaceutically acceptable salts include alkaline metal cation salts, alkaline earth metal cation salts and ammonium cation salts.
  • the compound of general formula I is one of the following compounds:
  • a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient Shape agent.
  • the FGFR4-related disease is selected from but not limited to hyperlipidemia or cancer; the cancer includes lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal cancer , Head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ , Lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharynx cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma , Colorectal villous adenoma, melanoma, cell tumor and sarcoma, and myelodysplastic syndrome.
  • the cancer includes lung
  • the compound of general formula I provided by the present invention and its pharmaceutically acceptable salts, prodrugs, crystal forms, stereoisomers, tautomers, hydrates or solvates are used as receptor tyrosine Kinase inhibitors, especially FGFR4 kinase, have excellent inhibitory activity. Therefore, the above-mentioned compounds can be used to prepare drugs for the treatment of FGFR4-related clinical conditions, such as: preparing drugs for the prevention and/treatment of FGFR4-related cell abnormal proliferation, morphological changes, and hyperkinesis diseases in organisms and blood vessels Use in medicine for diseases related to neonatal or cancer metastasis.
  • the present invention provides a compound of formula I:
  • the compound of formula I can also exist in the form of its salt, hydrate and solvate, and they are converted into the compound of formula I in vivo.
  • the compounds of the present invention are converted into pharmaceutically acceptable salt forms according to processes known in the art, and they are used in the salt form.
  • the compound of formula I may also exist in polycrystalline or amorphous form.
  • the compounds of formula I may also exist in specific geometric or stereoisomeric forms. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups, and all these isomers and their mixtures are included in the scope of the present invention.
  • prodrug used in the present invention refers to any covalently bound carrier that releases the active parent drug when administered to a mammalian patient.
  • the functional groups present in the compound can be modified by conventional operations or in vivo in a modification manner that can be decomposed into the parent compound to prepare a prodrug.
  • Prodrugs include compounds in which, when administered to a mammalian patient, for example, a hydroxyl group, an amino group, a sulfhydryl group or a carboxyl group is linked to any group after decomposition to form a free hydroxyl group, an amino group, a sulfhydryl group or a carboxyl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols in the compounds of the present invention, or methylamine and ethylamine derivatives of amine functional groups.
  • the pharmaceutical composition involved in the present invention includes a compound of general formula I or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof, and a pharmaceutically acceptable salt, prodrug, crystal form, hydrate or solvate thereof. Accepted carrier or excipient.
  • the pharmaceutical composition of the present invention can be administered in various known ways, such as oral administration, parenteral administration, administration by inhalation spray, or administration via an implanted depot.
  • the pharmaceutical composition of the present invention can be administered alone or in combination with other anti-tumor drugs.
  • the oral composition can be any orally acceptable dosage form, including but not limited to tablets, capsules, emulsions, suspensions, dispersions, and solutions.
  • Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers and the like.
  • Sterile injectable compositions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • Pharmaceutically acceptable carriers and solvents that can be used include water, mannitol, sodium chloride solution and the like.
  • the topical composition can be formulated as an oil, lotion, cream, etc.
  • the carrier used in the composition includes vegetable oil or mineral oil, animal fat, high molecular weight alcohol, and the like.
  • a pharmaceutically acceptable carrier is a carrier in which the active ingredient is soluble.
  • the actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be changed to obtain an amount of the active ingredient that can effectively achieve the desired therapeutic response and is non-toxic to the patient for a specific patient, composition and mode of administration.
  • the selected dosage level depends on many factors, including the activity of the specific compound of the present invention or its salt used, the route of administration, the time of administration, the excretion rate of the specific composition used, the duration of treatment, and the activity used.
  • Other drugs, compounds and/or materials used in combination with the specific composition the age, sex, weight, general health and past medical history of the patient being treated, and similar factors well known in the medical field.
  • the present invention also provides compounds of formula I or pharmaceutically acceptable salts, prodrugs, crystal forms, stereoisomers, tautomers, hydrates or solvates thereof in preparation for prevention and/or treatment
  • FGFR4-related diseases in medicine.
  • the FGFR4-related disease is selected from but not limited to hyperlipidemia or cancer; the cancer includes lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal cancer, head and neck cancer , Endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma , Neurofibromatosis, Bone Cancer, Skin Cancer, Brain Cancer, Colon Cancer, Testicular Cancer, Gastrointestinal Stromal Tumor, Oral Cancer, Pharyngeal Cancer, Multiple Myeloma, Leukemia, Non-Hodgkin's Lymphoma, Colon Villi Adenoma, melanoma, cell tumor and sarcoma, myelodysplastic syndrome.
  • the cancer includes lung
  • the starting materials, reaction reagents, etc. used in the specific embodiments of the present invention are all commercially available.
  • the present invention can be prepared into a salt form by using salt-forming methods commonly used in the art.
  • the synthetic route is as follows:
  • LCMS detects that the raw material is free Remaining, directly concentrate the reaction solution to obtain the crude product, add 10 mL of water to it, extract with ethyl acetate (10 mL ⁇ 3), combine the organic phases, wash twice with saturated aqueous sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate the organic layer by spin-drying , Obtain 0.40 g of crude product for use, MS m/z: 436.9 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 30 mg of a yellow solid, with a yield of 47%, MS m/z: 644.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 20 mg of a yellow solid, with a yield of 36%, MS m/z: 556.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 20 mg of a yellow solid, with a yield of 37%, MS m/z: 542.3 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 50 mg of yellow solid, yield 50%, MS m/z: 504.3 [M+H] + .
  • the preparation method refers to Example 1. Using 4-bromo-3-methoxyaniline as the starting material, 42 mg of yellow solid was obtained, the yield was 39%, MS m/z: 533.1 [M+H] + .
  • the preparation method refers to Example 1. Using 4-bromo-3-methoxyaniline as the starting material, 45 mg of yellow solid is obtained, the yield is 41%, MS m/z: 547.1 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 20 mg of a yellow solid, with a yield of 38%, MS m/z: 522.2 [M+H] + .
  • the preparation method refers to Example 1. Using 4-bromo-3-methoxyaniline as the starting material, 25 mg of yellow solid is obtained, the yield is 46%, MS m/z: 548.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 20 mg of a yellow solid, with a yield of 34%, MS m/z: 596.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 30 mg of a yellow solid, with a yield of 55%, MS m/z: 548.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 15 mg of a yellow solid, with a yield of 26%, MS m/z: 574.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 10 mg of yellow solid, yield 19%, MS m/z: 534.4 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 18 mg of a yellow solid, with a yield of 29%, MS m/z: 619.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 25 mg of yellow solid, yield 44%, MS m/z: 562.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 40 mg of yellow solid, yield 37%, MS m/z: 536.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 57 mg of yellow solid, yield 51%, MS m/z: 556.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 32 mg of a yellow solid, with a yield of 64%, MS m/z: 503.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 35 mg of a yellow solid, with a yield of 70%, MS m/z: 503.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 25 mg of a yellow solid, with a yield of 52%, MS m/z: 485.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 13 mg of a yellow solid, with a yield of 25%, MS m/z: 519.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 10 mg of a yellow solid, with a yield of 20%, MS m/z: 505.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 19 mg of a yellow solid, with a yield of 38%, MS m/z: 507.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 12 mg of a yellow solid, with a yield of 24%, MS m/z: 505.2 [M+H] + .
  • the preparation method refers to Example 1. Using 4-bromo-3-methoxyaniline as the starting material, 9 mg of yellow solid was obtained, the yield was 17%, MS m/z: 536.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 23 mg of yellow solid, yield 44%, MS m/z: 519.2 [M+H] + .
  • the preparation method refers to Example 1, using 4-bromo-3-methoxyaniline as the starting material to obtain 11 mg of yellow solid, yield 20%, MS m/z: 553.2 [M+H] + .
  • Example 28 Biological activity
  • the synthesized compound was tested for its inhibitory activity against FGFR4 by the fluorescence resonance energy transfer (FRET) method (reference for specific implementation methods: Lebakken CS, Kang HC, Vogel KW, A fluorescence lifetime-based binding assay to characterize kinase inhibitors. J Biomol Screen .2007.12(6):828-841.), and compared with the positive control drug, the compound with better activity was screened out.
  • FRET fluorescence resonance energy transfer
  • the pharmacological test results show that the quinoline compounds of the present invention have good FGFR4 kinase and Hep3B cell inhibitory activities, and the IC 50 values of some compounds are equivalent to or better than the positive control drugs Blu9931 and Lenvatinib, and can be used for prevention or treatment with Clinical diseases related to FGFR4 kinase inhibitors.
  • drugs containing the above-mentioned compounds as effective ingredients can be used to prepare drugs for the treatment of clinical conditions related to FGFR4, such as the preparation of prevention and/treatment of FGFR4-related cell abnormal proliferation, morphological changes, and hyperkinesis in organisms.

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Abstract

本发明公开了一类喹啉类化合物及其应用，该类化合物对FGFR4具有很好的抑制活性，可以作为受体酪氨酸激酶抑制剂，尤其是作为成纤维细胞生长因子受体4(FGFR4)激酶不可逆抑制剂，用于制备预防和/或治疗生物体内与成纤维细胞生长因子受体4(FGFR4)过表达介导相关的疾病的药物以及与血管新生或癌转移相关的疾病的药物。

Description

喹啉类化合物及其应用 技术领域
本发明属于医药技术领域，具体涉及一类喹啉类化合物及其在制备预防和/或治疗生物体内与成纤维细胞生长因子受体4(FGFR4)过表达介导相关的疾病的药物以及与血管新生或癌转移相关的疾病的药物中的用途。
背景技术
蛋白受体酪氨酸激酶(RTKs，receptor tyrosine kinases)在细胞信号转导通路中发挥着重要作用，它将细胞外的信号传递到细胞内，并经过向下游的传导调控肿瘤细胞的增殖、分化、生长及凋亡等生理活动。RTKs与肿瘤的发生发展密切相关，因此，其家族成员已成为抗肿瘤药物研发的主流靶标。目前，将近100多个酪氨酸激酶抑制剂上市或进入临床试验，其中大部分均为可逆抑制剂，该类抑制剂存在以下缺点：1)选择性差；2)作用时间短：3)容易耐药。基于以上原因，不可逆激酶抑制剂的研发已是热门方向。不可逆激酶抑制剂在可逆抑制剂的基础上，在合适的位置连接上迈克尔受体片段，该亲电片段可以与ATP结合域附近的半胱氨酸残基发生亲电反应形成共价键，从而实现以永久性灭活的方式来发挥作用，这种方式使得其作用更为强烈而持久。同时，不可逆激酶抑制剂和ATP与激酶的结合并不存在竞争性，也使得激酶突变的可能性降低而减轻或规避了耐药性的产生，选择性更高。
成纤维细胞生长因子受体是一种受体型蛋白酪氨酸激酶，共有4种FGFR1、FGFR2、FGFR3和FGFR4，对维持细胞的生长、增殖、凋亡、迁移等起关键作用。研究表明，FGFR4在多种癌症细胞中高表达，具有调节细胞增殖和抗细胞凋亡的作用，其可作为侵袭性癌症的重要靶标，当基因敲除FGFR4后，可以有效降低癌症细胞的增殖，促进癌症细胞的凋亡，同时，选择性作用于FGFR4可避免作用到FGFR1～3等其他几个亚型所带来的毒副作用。FGFR4在多种癌症中的突变和异常的活性，尤其是肝癌，已经使其成为一个治疗FGFR4阳性癌症的药物靶点。
目前，已有多个FGFR4激酶抑制剂进入临床试验用于治疗多种癌症，但仍然未有FGFR4激酶不可逆抑制剂上市。因此，开发新的具有高抑制活性和优异药代动力学性质的FGFR4激酶不可逆抑制剂已成为开发新型抗肿瘤药物的关键。
发明内容
针对上述现有技术的不足，本发明的目的是提供一类喹啉类化合物，该化合物对成纤维细胞生长因子受体4(FGFR4)激酶具有很好的抑制活性，可作为FGFR4不可逆抑制剂，为由FGFR4介导的疾病的治疗提供了可能性。
为了实现上述发明目的，本发明采用以下技术手段：
通式I的化合物或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物：
Figure PCTCN2020138248-appb-000001
式I中，
X选自-CR 4R 5-、-NR 4-、O或S，其中R 4、R 5各自独立地表示氢、氘、卤素、烷基、芳基或Het；
Q选自-NR 6CONR 7-、-CONR 6-、-NR 6CO-、-NR 6SO 2NR 7-、-SO 2NR 6-、-NR 6SO 2-、-NR 6-、-NR 6(CH 2) mN-、-NR 6(CH 2) mO-或-CR 6R 7，其中m＝1、2、3、4或5，R 6、R 7各自独立地表示氢、氘、烷基、芳基或Het；
虚线表示可以存在单键或双键；
n＝0、1、2或3；
R 1选自氢、卤素、羟基、烷氧基、烷基、芳基或Het；
R 2选自氢、卤素、羟基、烷氧基、烷基、芳基或Het；
R 3选自氢、卤素、羟基、烷氧基、烷基、芳基或Het；
P选自如下结构：
Figure PCTCN2020138248-appb-000002
其中，R 11为离去基团或活化酯，所述离去基团为卤素；R 8、R 9、R 10、R 12各自独立地选自氢、卤素、羟基、烷氧基、烷基、芳基或Het；
烷基为1-6个碳原子的直链或支链饱和烃基、3-6个碳原子的环状饱和烃基，或连有1-6个碳原子直链或支链饱和烃基的3-6个碳原子的环状饱和烃基；
上述基团中，芳基为选自苯基、萘基、苊基或四氢萘基的碳环，其各自任选被1、2或3个取代基取代，各取代基独立地选自氢、烷基、氰基、卤素、硝基、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het；
Het为选自哌啶基、吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基的单环杂环；或选自喹啉基、喹喔啉基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并呋喃基、苯并噻吩基、2,3-二氢苯并[1,4]二氧杂环己烯基或苯并[1,3]二氧杂环戊烯基的双环杂环；各单环或双环杂环任选被1、2或3个取代基取代，各取代基独立选自卤素、卤代烷基、羟基、烷基或烷氧基；
卤素选自氟、氯、溴或碘。
进一步地，式I中，
X为-NR 4-或O，其中R 4选自氢、氘、卤素、烷基、芳基或Het；
Q选自-NR 6CONR 7-、-CONR 6-、-NR 6CO-、-NR 6SO 2NR 7-、-SO 2NR 6-或-NR 6SO 2-，其中R 6、R 7各自独立地表示氢、氘、烷基、芳基或Het；
虚线表示可以存在单键或双键；
n＝0、1、2或3；
R 1选自氢、卤素或烷基；
R 2选自氢、烷基或芳基；
R 3选自烷氧基、烷基、芳基或Het。
进一步地，式I中，
X为O；
Q选自-NR 6CONR 7-、-CONR 6-或-NR 6CO-，其中R 6、R 7各自独立地表示氢、氘、烷基、芳基或Het；
虚线表示可以存在单键或双键；
n＝0、1、2或3；
R 1选自氢、卤素或烷基；
R 2为烷基或芳基；
R 3选自烷基、芳基或Het。
进一步地，式I中，
X为O；
Q选自-NR 6CONR 7-、-CONR 6-或-NR 6CO-，其中R 6、R 7各自独立地表示氢、氘、烷基、芳基或Het；
虚线表示可以存在单键或双键；
n＝0或1；
R 1为氢或卤素；
R 2为烷基或芳基；
R 3选自烷基、芳基或Het；
P选自如下结构：
Figure PCTCN2020138248-appb-000003
其中，R 11为离去基团或活化酯，所述离去基团为卤素；R 8、R 9、R 10各自独立地选自氢或烷基。
进一步地，所述药学上可接受的盐包括通式I的化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸；还包括通式I化合物与无机碱形成的酸式盐。
进一步地，所述药学上可接受的盐包括碱性金属阳离子盐、碱土金属阳离子盐和铵阳离子盐。
进一步地，通式I的化合物为下述化合物中的一种：
Figure PCTCN2020138248-appb-000004
Figure PCTCN2020138248-appb-000005
Figure PCTCN2020138248-appb-000006
Figure PCTCN2020138248-appb-000007
一种药物组合物，包括上述化合物或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物以及药学上可接受的载体或赋形剂。
上述化合物在制备用于预防和/或治疗FGFR4相关疾病的药物中的用途。
进一步地，所述FGFR4相关疾病选自但不限于高脂血症或癌症；所述的癌症包括肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、***癌、甲状腺癌、女性生殖***癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤，以及骨髓增生异常综合症。
有益效果：本发明提供的通式I的化合物及其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物作为受体酪氨酸激酶抑制剂，尤其对FGFR4激酶具有优良的抑制活性。因此，上述化合物可以用于制备治疗与FGFR4有关的临床病症的药物，如：制备预防和/治疗生物体内与FGFR4相关的细胞异常增殖、形态变化以及运动功能亢进等相关的疾病的药物以及与血管新生或癌转移相关的疾病的药物中的用途。
具体实施方式
本发明提供了式I的化合物：
Figure PCTCN2020138248-appb-000008
药理试验结果表明该化合物对FGFR4具有很好的抑制活性，可作为一类新型的FGFR4不可逆抑制剂，为由FGFR4介导的疾病的治疗提供了可能性。
在本发明中，式I的化合物还可以以其盐、水合物、溶剂合物的形式存在，它们在体内转化为式I的化合物。例如，在本发明的范围内，按照本领域已知的工艺，将本发明化合物转化为药学上可接受的盐的形式，并且以盐形式使用它们。
同时，式I的化合物还可以以多晶或无定形形式存在。
另外，式I的化合物还可以存在特定的几何或立体异构体形式。烷基等取代基中可存在另外的不对称碳原子，所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
本发明中使用的“前药”是指当给予哺乳动物患者时释放活性母体药物的任何共价结合的载体。可通过常规操作或在体内，按可分解为母体化合物的修饰方式，修饰存在于化合物中的官能团，制备前药。前药包括当给予哺乳动物患者时，其中例如：羟基、氨基、巯基或羧基与任何基团连接的分解后分别形成游离羟基、氨基、巯基或羧基的化合物。前药的实例包括但不限于本发明化合物中醇的乙酸酯、甲酸酯和苯甲酸酯衍生物，或者胺官能团甲基胺、乙基胺衍生物。
本发明中涉及的药物组合物包括通式I的化合物或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物以及药学上可接受的载体或赋形剂。
本发明的药物组合物可以采用各种已知的方式施用，例如口服、胃肠外施用、通过吸入喷雾施用或经由植入的贮库施用。本发明的药物组合物可单独给药也可与其他抗肿瘤药物联合用药。口服组合物可以是任何口服可接受的剂型，包含但不限于片剂、胶囊剂、乳剂以及混悬剂、分散物和溶液。常用的药学上可接受的载体或赋形剂包括稳定剂、稀释剂、表面活性剂、润滑剂、抗氧化剂、粘合剂、着色剂、填充剂、乳化剂等。
无菌可注射组合物可按照本领域已知的技术使用适合的分散剂或润湿剂和助悬剂来配制。可以使用的药学上可接受的载体和溶剂包括水、甘露醇、氯化钠溶液等。
局部组合物可被配制成油、洗剂、乳膏剂等。用于组合物的载体包括植物油或矿物油、动物脂肪和高分子量醇等。药学上可接受的载体是活性成分在其中可溶的载体。
可以改变本发明的药物组合物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可以有效实现所需治疗响应、对患者无毒的活性成分的量。所选择的的剂量水平取决于多种因素，包括所用的具体的本发明的化合物或其盐的活性、施用途径、施用时间、所用的具体组合物的***速率、治疗的持续时间、与所用的具体组合物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、一般健康状况和既往病史以及医学领域中公知的类似因素。
本发明还提供了式I的化合物或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物在制备用于预防和/或治疗FGFR4相关疾病的药物中的用途。如：制备预防和/治疗生物体内与FGFR4相关的细胞异常增殖、形态变化以及运动功能亢进等相关的疾病的药物以及与血管新生或癌转移相关的疾病的药物中的用途。
所述FGFR4相关疾病选自但不限于高脂血症或癌症；所述的癌症包括肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、***癌、甲状腺癌、女性生殖***癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤，骨髓增生异常综合症。
下面结合具体实施例描述本发明通式I化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
本发明具体实施例中使用的起始原料、反应试剂等均为市售。本发明可以采用本领域常用的成盐方法制备成盐的形式。
实施例1
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-1)
Figure PCTCN2020138248-appb-000009
合成路线如下：
Figure PCTCN2020138248-appb-000010
化合物I-1-1合成：
于500mL单颈瓶中加入丙二酸亚异丙酯(35.50g，248mmol)，原甲酸三乙酯(36.60g，248mmol)和异丙醇300mL，升温至90℃反应2.5h，分批加入4-溴-3-甲氧基苯胺(25.00g， 124mmol)，继续90℃反应3h，TLC(PE:EA＝1:1)监测反应完毕，反应液降至室温，析出固体，过滤，滤饼用乙醇洗涤3次，滤饼烘干得白色固体40.02g，收率91％，MS m/z:357.1[M+H] +。
化合物I-1-2合成：
于1000mL单颈瓶中加入I-1-1(30.00g，84mmol)和二苯醚600mL，升温至230℃反应0.5h，TLC(PE:EA＝1:1)监测反应完毕，反应液降至室温，析出固体，过滤，滤饼用乙醇洗涤3次，滤饼烘干得浅黄色固体18.03g，收率84％，MS m/z:255.1[M+H] +。
化合物I-1-3合成：
于500mL单颈瓶中加入I-1-2(18.00g，70.8mmol)，氯化亚砜300mL和DMF 1mL，升温至90℃反应2h，TLC(PE:EA＝1:1)监测反应完毕，反应液降至室温，反应液浓缩至干后搅拌下分批加入饱和碳酸氢钠水溶液300mL，EA(150mL×3)萃取，有机相干燥浓缩，经柱层析(PE:EA＝5:1)得浅黄色固体14.60g，收率76％，MS m/z:273.5[M+H] +。
化合物I-1-4合成：
于500mL单颈瓶中加入3-氯-4-硝基苯酚(5.60g，32.1mmol)和DMF 200mL，降温至0℃，分批加入钠氢(1.60g，40.2mmol)，继续0℃反应0.5h，加入I-1-3(7.30g，26.8mmol)，升温至160℃反应16h，TLC(PE:EA＝1:1)监测反应完毕，反应液降至室温，反应液加入冰水300mL，EA(100mL×3)萃取，有机相干燥浓缩，经柱层析(PE:EA＝5:1)得黄色固体3.41g，收率31％，MS m/z:410.2[M+H] +。
化合物I-1-5合成：
于100mL单颈瓶中分别加入I-1-4(3.40g，8.3mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(2.80g，9.1mmol)、碳酸钾(0.46g，33.2mmol)、二氧六环60mL和水20mL，氮气氛围下，加入Pd(dppf)Cl 2(0.60g，0.8mmol)，氮气置换3次，升温至110℃反应3h，TLC(PE:EA＝1:1)监测反应完毕，反应液降至室温，反应液加入冰水100mL，EA(50mL×3)萃取，有机相干燥浓缩，经柱层析(PE:EA＝4:1)得黄色固体1.50g，收率35％，MS m/z:512.1[M+H] +。
化合物I-1-6合成：
于100mL单颈瓶中分别加入I-1-5(0.80g，1.6mmol)、三氟乙酸2mL和二氯甲烷15mL，室温反应1h，LCMS检测原料无剩余，直接将反应液浓缩得到粗品，深黄色固体0.71g，MS m/z:412.1[M+H] +。
化合物I-1-7合成：
于100mL单颈瓶中分别加入I-1-6(0.70g，1.7mmol)、三乙胺(0.50g，5.1mmol)和二氯甲烷10mL，降温至0℃，滴加丙烯酰氯(0.20g，2.0mmol),滴加完毕，室温反应2h,LCMS 检测原料无剩余，加入水10mL，二氯甲烷(50mL×3)萃取，合并有机相，浓缩旋干，经柱层析(PE:EA＝3:1)得黄色固体0.52g，收率66％，MS m/z:466.3[M+H] +。
化合物I-1-8合成：
于100mL单颈瓶中分别加入I-1-7(0.52g，1.1mmol)、还原铁粉(0.60g，11.0mmol)、盐酸10滴和乙醇10mL，升温至80℃反应2h，LCMS检测原料无剩余，直接将反应液浓缩得到粗品，向其中加入水10mL，乙酸乙酯(10mL×3)萃取，合并有机相，饱和氯化钠水溶液洗两次，无水硫酸钠干燥，有机层浓缩旋干，得到粗品0.40g待用，MS m/z:436.9[M+H] +。
化合物I-1-9合成：
于50mL单颈瓶中分别加入I-1-8(0.05g，0.11mmol)、氯甲酸苯酯(0.036g，0.22mmol)、N-甲基吡咯烷酮1mL和乙腈4mL，升温至70℃反应3h，LCMS检测原料无剩余，向其中加入水5mL，乙酸乙酯(5mL×3)萃取，合并有机相，饱和氯化钠水溶液洗两次，无水硫酸钠干燥，有机层浓缩旋干，得到粗品0.06g待用，MS m/z:559.2[M+H] +。
化合物I-1合成：
于50mL单颈瓶中分别加入I-1-9(0.06g，0.11mmol)、环丙胺(0.013g，0.22mmol)、N,N-二异丙基乙胺1mL和四氢呋喃4mL，升温至65℃反应3h，LCMS检测原料无剩余，向其中加入水15mL，乙酸乙酯(15mL×3)萃取，合并有机相，饱和氯化钠水溶液洗两次，无水硫酸钠干燥，有机层浓缩旋干，TLC纯化得黄色固体0.02g，收率36％，MS m/z:519.3[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.56(d,J＝5.4Hz,1H),8.20(d,J＝9.0Hz,1H),8.14(s,1H),7.39(s,2H),7.20(dd,J＝9.1,2.7Hz,1H),6.59(d,J＝5.5Hz,1H),6.31(d,J＝6.7Hz,1H),6.26(d,J＝6.0Hz,1H),6.00(d,J＝12.0Hz,1H),5.80(d,J＝12.0Hz,1H),4.37-4.35(m,1H),4.32-4.30(m,1H),4.02(s,3H),3.92-3.86(m,2H),2.67-2.64(m,3H),0.83-0.77(m,2H),0.60-0.55(m,2H)。
实施例2
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-二乙基磷酸酰基乙酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-2)
Figure PCTCN2020138248-appb-000011
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体30mg，收率47％， MS m/z:644.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.62(d,J＝5.8Hz,1H),8.55(d,J＝9.1Hz,1H),8.21(s,1H),8.07-8.04(m,1H),7.84(s,1H),7.30(s,1H),7.16(d,J＝8.6Hz,1H),6.71(d,J＝5.5Hz,1H),6.03(d,J＝21.6Hz,1H),5.35-5.30(br.s,1H),4.34(d,J＝11.8Hz,2H),4.24-4.19(m,4H),4.11(s,3H),3.88(t,J＝5.2Hz,1H),3.81(t,J＝5.0Hz,1H),3.17(dd,J＝22.0,11.0Hz,2H),2.73-2.68(m,2H),2.62-2.57(m,1H),1.37(t,J＝3.5Hz,6H),0.98-0.94(m,2H),0.82-0.78(m,2H)。
实施例3
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-乙烯磺酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-3)
Figure PCTCN2020138248-appb-000012
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体20mg，收率36％，MS m/z:556.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.55(d,J＝5.4Hz,1H),8.19(d,J＝9.0Hz,1H),8.10(s,1H),7.38(s,1H),7.37(d,J＝2.7Hz,1H),7.19(dd,J＝9.0,2.7Hz,1H),6.74(dd,J＝16.6,10.0Hz,1H),6.58(d,J＝5.4Hz,1H),6.26(d,J＝16.5Hz,1H),6.14(d,J＝10.1Hz,1H),4.01(s,3H),3.92-3.88(m,2H),3.47(t,J＝5.7Hz,2H),2.71-2.66(m,2H),2.64-2.62(m,1H),2.64(dd,J＝7.0,3.6Hz,1H),0.83-0.76(m,2H),0.61-0.53(m,2H)。
实施例4
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-氯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-4)
Figure PCTCN2020138248-appb-000013
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体20mg，收率37％，MS m/z:542.3[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.64(br.s,1H),8.57(d,J＝8.8Hz,1H),8.24(s,1H),8.14(s,1H),7.85(br.s,1H),7.31(s,1H),7.17(d,J＝7.1Hz,1H),6.76(br.s,1H),6.04(t,J＝17.8Hz,1H),4.31(d,J＝10.7Hz,2H),4.19(s,2H),4.14(s,3H),3.89(m,1H),3.78(m,1H),2.71(m,2H),2.63(m,1H),0.97(m,2H),0.81(m,2H)。
实施例5
4-[3-氯-4-环丙甲酰基氨基苯氧基]-6-[(1-氯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-5)
Figure PCTCN2020138248-appb-000014
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体50mg，收率50％，MS m/z:504.3[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.64(br.s,1H),8.57(d,J＝8.8Hz,1H),8.24(s,1H),8.14(s,1H),7.85(br.s,1H),7.31(s,1H),7.17(d,J＝7.1Hz,1H),6.76(s,1H),6.04(d,J＝17.8Hz,1H),4.35-4.28(m,2H),4.19(s,2H),4.14(s,3H),3.92-3.87(m,1H),3.80-3.75(m,1H),2.78-2.72(m,2H),2.65-2.60(m,1H),0.98-0.94(m,2H),0.87-0.84(m,2H)。
实施例6
4-[3-氯-4-环戊甲酰基氨基苯氧基]-6-[(1-氯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-6)
Figure PCTCN2020138248-appb-000015
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体42mg，收率39％，MS m/z:533.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.68(br.s,2H),8.22(s,1H),8.15(s,1H),7.76(s,1H),7.40-7.30(m,1H),7.21(br.s,1H),6.74(br.s,1H),6.70-6.61(m,1H),6.38(d,J＝16.7Hz,1H),6.08-6.02(m,1H),5.77(d,J＝10.3Hz,1H),4.38-4.32(m,2H),4.13(s,3H),3.92-3.82(m,2H),2.90-2.82(m,1H),2.67-2.60(m,2H),2.08-2.01(m,2H),1.99-1.93(m,2H),1.87-1.81(m,2H),1.73-1.69(m,2H)。
实施例7
4-[3-氯-4-环己甲酰基氨基苯氧基]-6-[(1-氯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-7)
Figure PCTCN2020138248-appb-000016
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体45mg，收率41％，MS m/z:547.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.68(d,J＝8.4Hz,1H),8.22(s,1H),8.15(br.s,1H),7.79(s,1H),7.33(s,1H),7.19(d,J＝8.2Hz,1H),6.75(br.s,1H),6.65(dd,J＝16.9,10.3Hz,1H),6.38(br.s,1H),6.05(br.s,1H),5.78(dd,J＝10.5,1.8Hz,1H),4.37-4.32(m,2H),4.13(s,3H),3.90-3.82(m,2H),2.67-2.62(m,2H),2.43–2.35(m,1H),2.10-2.03(m,2H),1.94-1.86(m,2H),1.79-1.74(m,3H),1.65-1.59(m,3H)。
实施例8
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-哌啶)-4-基]-7-甲氧基喹啉(I-8)
Figure PCTCN2020138248-appb-000017
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体20mg，收率38％，MS m/z:522.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.62(d,J＝5.2Hz,1H),8.42(d,J＝9.0Hz,1H), 8.09(s,1H),7.75(s,1H),7.53(s,1H),7.26(d,J＝2.6Hz,1H),7.14(dd,J＝9.0,2.5Hz,1H),6.50(d,J＝5.0Hz,1H),6.41-6.33(m,1H),5.98-5.89(m,1H),5.76(dd,J＝10.6,1.6Hz,1H),5.59(s,1H),4.32(d,J＝26.5Hz,2H),4.01(s,3H),3.92(d,J＝6.6Hz,1H),2.68(d,J＝3.6Hz,3H),1.41-1.29(m,3H),0.97(t,J＝5.7Hz,2H),0.90(t,J＝6.7Hz,1H),0.79(d,J＝7.9Hz,2H)。
实施例9
4-[3-氯-4-(环戊基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-9)
Figure PCTCN2020138248-appb-000018
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体25mg，收率46％，MS m/z:548.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.57(br.s,1H),8.49(s,1H),8.23(br.s,1H),8.08(br.s,1H),7.60(br.s,1H),7.22(s,1H),7.12(s,1H),6.72(br.s,1H),6.70-6.61(m,1H),6.38(d,J＝16.8Hz,1H),6.04(br.s,1H),5.78(d,J＝10.2Hz,1H),4.40-4.30(m,2H),4.12(s,3H),3.90-3.80(m,2H),3.43(t,J＝7.0Hz,2H),2.67-2.60(m,2H),2.48-2.42(m,2H),1.80-1.70(m,2H),1.68-1.62(m,2H),1.60-1.52(m,2H)。
实施例10
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-苄基喹啉(I-10)
Figure PCTCN2020138248-appb-000019
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体20mg，收率34％，MS m/z:596.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.59(d,J＝5.3Hz,1H),8.27(d,J＝9.1Hz,1H),8.02(s,1H),7.97(s,1H),7.51(d,J＝8.9Hz,2H),7.48-7.40(m,2H),7.35(t,J＝7.2Hz,1H),7.29-7.16(m,1H),6.83(ddd,J＝27.3,16.6,10.3Hz,1H),6.51(d,J＝5.2Hz,1H),6.22-6.08(m,1H),5.98(d,J＝13.7Hz,1H),5.76-5.67(m,1H),5.35(s,2H),4.24(d,J＝36.9Hz,2H),3.76(dd,J＝23.1,17.0Hz,2H),2.71-2.52(m,3H),0.76-0.57(m,2H),0.54-0.35(m,2H)。
实施例11
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-异丙基喹啉(I-11)
Figure PCTCN2020138248-appb-000020
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体30mg，收率55％，MS m/z:548.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.57(d,J＝4.8Hz,1H),8.44(d,J＝9.0Hz,1H),8.12(d,J＝15.0Hz,1H),7.78(s,1H),7.67-7.49(m,1H),7.24(d,J＝2.3Hz,1H),7.09(t,J＝20.1Hz,1H),6.66(td,J＝17.0,10.7Hz,1H),6.51(d,J＝4.3Hz,1H),6.44-6.28(m,1H),5.96(d,J＝27.4Hz,1H),5.75(d,J＝10.7Hz,1H),5.62(s,1H),4.84(dt,J＝11.7,5.8Hz,1H),4.43-4.16(m,2H),3.84(d,J＝47.8Hz,2H),2.67(dd,J＝6.3,3.2Hz,3H),1.46(d,J＝5.9Hz,5H),0.95-0.88(m,4H),0.78-0.75(m,2H)。
实施例12
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-环戊基喹啉(I-12)
Figure PCTCN2020138248-appb-000021
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体15mg，收率26％， MS m/z:574.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.55(d,J＝4.9Hz,1H),8.35(t,J＝25.3Hz,1H),8.05(s,1H),7.77(s,1H),7.38(s,1H),7.20(s,1H),7.09(d,J＝8.9Hz,1H),6.64(td,J＝17.1,10.7Hz,1H),6.43(d,J＝5.1Hz,1H),6.40-6.25(m,1H),5.93(d,J＝21.7Hz,1H),5.90(s,1H),5.73(d,J＝10.6Hz,1H),5.17(s,1H),4.96(s,1H),4.29(d,J＝24.1Hz,2H),3.76(t,J＝46.6Hz,2H),2.71-2.59(m,3H),2.15-1.80(m,4H),1.85-1.58(m,4H),0.90-0.81(m,3H),0.71-0.62(m,3H)。
实施例13
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-乙基喹啉(I-13)
Figure PCTCN2020138248-appb-000022
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体10mg，收率19％，MS m/z:534.4[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.59(d,J＝5.2Hz,1H),8.42(d,J＝9.0Hz,1H),8.08(s,1H),7.72(s,1H),7.39(d,J＝11.6Hz,1H),7.25(dd,J＝17.1,14.5Hz,2H),7.20(s,1H),6.66(td,J＝17.2,10.6Hz,1H),6.46(d,J＝5.2Hz,1H),6.37(dd,J＝16.1,10.9Hz,1H),5.98(d,J＝31.4Hz,1H),5.75(d,J＝10.5Hz,1H),5.25(s,1H),4.35(s,1H),4.32-4.15(m,3H),3.91(t,J＝5.4Hz,1H),3.79(t,J＝5.4Hz,1H),2.68(dd,J＝6.3,2.8Hz,3H),1.86(s,2H),1.53(q,J＝7.0Hz,3H),0.98-0.91(m,2H),0.91-0.84(m,2H)。
实施例14
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-(2-吗啉基)乙基喹啉(I-14)
Figure PCTCN2020138248-appb-000023
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体18mg，收率29％，MS m/z:619.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.64(d,J＝6.2Hz,1H),8.53(d,J＝9.2Hz,1H),8.21(s,1H),8.03(d,J＝16.3Hz,1H),7.83(s,1H),7.28(s,3H),7.15(d,J＝9.1Hz,1H),6.68(d,J＝16.6Hz,2H),6.39(d,J＝16.4Hz,1H),6.03(d,J＝17.7Hz,1H),5.79(d,J＝11.8Hz,1H),5.35(s,1H),4.70(s,2H),4.33(d,J＝25.8Hz,2H),4.00-3.90(m,3H),3.80-3.87(m,3H),3.38-3.25(m,2H),3.11-3.02(m,4H),1.02-0.92(m,2H),0.85-0.79(m,2H)。
实施例15
4-[3-氯-4-(环己基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-15)
Figure PCTCN2020138248-appb-000024
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体25mg，收率44％，MS m/z:562.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.59(d,J＝5.3Hz,1H),8.31(d,J＝9.0Hz,1H),8.07(s,1H),7.43(s,1H),7.22(d,J＝2.7Hz,1H),7.11(dd,J＝9.0,2.7Hz,1H),6.85(d,J＝9.3Hz,1H),6.73-6.60(m,1H),6.47(d,J＝4.8Hz,1H),6.37(dd,J＝16.8,7.0Hz,1H),5.97(d,J＝28.1Hz,1H),5.76(dd,J＝10.6,1.9Hz,1H),5.01(dd,J＝21.8,7.5Hz,1H),4.32(d,J＝26.4Hz,2H),4.00(s,3H),3.92(t,J＝5.4Hz,1H),3.80(t,J＝5.4Hz,1H),3.73-3.64(m,1H),2.70-2.62(m,2H),2.10-2.01(m,2H),1.83-1.74(m,3H),1.47-1.35(m,2H),1.25-1.15(m,3H)。
实施例16
4-[3-氯-4-(叔丁基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-16)
Figure PCTCN2020138248-appb-000025
Figure PCTCN2020138248-appb-000026
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体40mg，收率37％，MS m/z:536.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.58(d,J＝5.3Hz,1H),8.29(d,J＝9.0Hz,1H),8.07(s,1H),7.43(s,1H),7.21(d,J＝2.7Hz,1H),7.09(dd,J＝9.0,2.6Hz,1H),6.83(d,J＝12.6Hz,1H),6.73-6.60(m,1H),6.46(d,J＝4.7Hz,1H),6.37(dd,J＝16.7,7.1Hz,1H),5.97(d,J＝27.6Hz,1H),5.76(dd,J＝10.6,1.7Hz,1H),5.10(d,J＝25.1Hz,1H),4.37-4.34(m,1H),4.30-4.27(m,1H),3.99(s,3H),3.92(t,J＝5.3Hz,1H),3.80(t,J＝5.3Hz,1H),2.70-2.62(m,2H),1.45(s,9H)。
实施例17
4-[3-氯-4-(苯基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-17)
Figure PCTCN2020138248-appb-000027
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体57mg，收率51％，MS m/z:556.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.60-8.54(m,1H),8.41-8.55(m,1H),8.07(d,J＝8.8Hz,1H),7.75(d,J＝26.2Hz,1H),7.52-7.47(m,2H),7.43(s,1H),7.35(t,J＝7.6Hz,2H),7.28(s,1H),7.21(d,J＝2.6Hz,1H),7.12-7.08(m,2H),6.77-6.62(m,1H),6.48-6.36(m,2H),5.99-5.95(m,1H),5.80(d,J＝10.5Hz,1H),4.42-4.36(m,1H),4.32-4.28(m,1H),3.99-3.92(m,4H),3.84(t,J＝5.5Hz,1H),2.71-2.62(m,2H)。
实施例18
4-[2-氟-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-18)
Figure PCTCN2020138248-appb-000028
Figure PCTCN2020138248-appb-000029
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体32mg，收率64％，MS m/z:503.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.80(s,1H),8.58(d,J＝5.2Hz,1H),8.05(s,1H),7.77(s,2H),7.45(s,1H),6.85(ddd,J＝36.4,16.8,10.5Hz,1H),6.73(s,1H),6.35(d,J＝5.2Hz,1H),6.16(d,J＝16.6Hz,1H),5.98(d,J＝19.5Hz,1H),5.73(t,J＝8.3Hz,1H),4.25(d,J＝37.8Hz,2H),3.96(s,3H),3.77(d,J＝8.3Hz,2H),2.60-2.56(m,3H),2.03-1.97(m,1H),0.72-0.58(m,2H),0.52-0.36(m,2H)。
实施例19
4-[3-氟-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-19)
Figure PCTCN2020138248-appb-000030
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体35mg，收率70％，MS m/z:503.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.59(d,J＝5.2Hz,1H),8.29-8.13(m,2H),7.99(s,1H),7.42(s,1H),7.29(dd,J＝11.8,2.5Hz,1H),7.06(d,J＝9.0Hz,1H),6.95-6.73(m,2H),6.50(d,J＝5.2Hz,1H),6.16(d,J＝16.6Hz,1H),5.96(d,J＝15.6Hz,1H),5.79-5.66(m,1H),4.23(d,J＝38.7Hz,2H),3.95(s,3H),3.82-3.66(m,2H),2.58-2.51(m,2H),2.01-1.99(m,1H),0.66-0.60(m,2H),0.45-0.34(m,2H)。
实施例20 4-[4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-20)
Figure PCTCN2020138248-appb-000031
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体25mg，收率52％， MS m/z:485.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.62-8.39(m,2H),8.01(s,1H),7.53(t,J＝8.5Hz,2H),7.41(s,1H),7.19-7.08(m,2H),6.85(ddd,J＝36.0,16.6,10.5Hz,1H),6.42(dd,J＝10.9,3.7Hz,2H),6.16(d,J＝16.3Hz,1H),5.97(d,J＝15.9Hz,1H),5.77-5.67(m,1H),4.23(d,J＝38.2Hz,2H),3.95(s,3H),3.82-3.70(m,2H),2.63-2.54(m,2H),2.03-1.97(m,1H),0.65-0.55(m,2H),0.47-0.36(m,2H)。
实施例21
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-1,2,5,6-四氢吡啶)-3-基]-7-甲氧基喹啉(I-21)
Figure PCTCN2020138248-appb-000032
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体13mg，收率25％，MS m/z:519.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.61(s,1H),8.22(s,2H),7.89(s,1H),7.35(s,1H),7.18(s,1H),6.89(d,J＝19.0Hz,2H),6.50(s,2H),5.82(d,J＝5.1Hz,1H),4.90(s,2H),4.67-4.60(m,2H),4.22(s,3H),2.71(s,1H),2.50-2.43(m,2H),1.10-0.96(m,2H),0.90-0.81(m,2H)。
实施例22
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-2,5-二氢吡咯)-3-基]-7-甲氧基喹啉(I-22)
Figure PCTCN2020138248-appb-000033
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体10mg，收率20％，MS m/z:505.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.59(s,1H),8.23(s,2H),7.88(s,1H),7.32(s,1H),7.19(s,1H),6.88(d,J＝20.0Hz,2H),6.52(s,2H),5.82(d,J＝4.9Hz,1H),4.90(s,2H),4.67(d,J＝25.6Hz,2H),4.22(s,3H),2.71(s,1H),0.96(d,J＝4.7Hz,3H),0.81(s,2H)。
实施例23
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-6-[(1-丙烯酰基-四氢吡咯)-3-基]-7-甲氧基喹啉(I-23)
Figure PCTCN2020138248-appb-000034
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体19mg，收率38％，MS m/z:507.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.64(d,J＝5.1Hz,1H),8.41(d,J＝9.0Hz,1H),8.10(s,1H),7.77(s,1H),7.54(s,1H),7.26(d,J＝3.6Hz,1H),7.16(dd,J＝9.0,2.5Hz,1H),6.50(d,J＝5.1Hz,1H),6.41-6.37(m,1H),5.98-5.90(m,1H),5.76(dd,J＝10.6,1.8Hz,1H),5.58(s,1H),4.32(d,J＝20.5Hz,2H),4.00(s,3H),3.92(d,J＝6.6Hz,1H),2.68(d,J＝3.6Hz,3H),1.41-1.30(m,1H),1.05-0.97(m,2H),0.90(t,J＝6.7Hz,1H),0.79(d,J＝7.9Hz,2H)。
实施例24
4-[3-氯-4-(环丙基氨基)羰基苯氧基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-24)
Figure PCTCN2020138248-appb-000035
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体12mg，收率24％，MS m/z:505.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.66(br.s,1H),8.57(d,J＝9.0Hz,1H),8.26(s,1H),8.15(s,1H),7.85(br.s,1H),7.33(s,1H),7.17(d,J＝7.2Hz,1H),6.76(s,1H),6.06(d,J＝18.0 Hz,1H),4.35-4.29(m,2H),4.17(s,2H),4.16(s,3H),3.95-3.87(m,1H),3.82-3.75(m,1H),2.79-2.72(m,2H),2.65-2.61(m,1H),0.98-0.90(m,2H),0.89-0.83(m,2H)。
实施例25
4-[3-氯-4-(环丙基氨基羰基)氨基苯巯基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-25)
Figure PCTCN2020138248-appb-000036
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体9mg，收率17％，MS m/z:536.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.55(d,J＝5.5Hz,1H),8.21(d,J＝9.0Hz,1H),8.13(s,1H),7.37(s,2H),7.19(dd,J＝9.0,2.8Hz,1H),6.58(d,J＝5.6Hz,1H),6.30(d,J＝6.7Hz,1H),6.24(d,J＝6.0Hz,1H),6.01(d,J＝12.0Hz,1H),5.82(d,J＝12.0Hz,1H),4.37-4.34(m,1H),4.33-4.30(m,1H),4.01(s,3H),3.93-3.86(m,2H),2.67-2.62(m,3H),0.83-0.78(m,2H),0.60-0.53(m,2H)。
实施例26
4-[3-氯-4-(环丙基氨基羰基)氨基苯氨基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-26)
Figure PCTCN2020138248-appb-000037
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体23mg，收率44％，MS m/z:519.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.62(d,J＝5.6Hz,1H),8.25(d,J＝9.0Hz,1H),8.17(s,1H),7.42(s,2H),7.21(dd,J＝9.2,2.7Hz,1H),6.60(d,J＝5.6Hz,1H),6.35(d,J＝6.8Hz,1H),6.28(d,J＝6.0Hz,1H),6.02(d,J＝12.0Hz,1H),5.85(d,J＝12.0Hz,1H),4.38-4.35(m, 1H),4.33-4.30(m,1H),4.05(s,3H),3.92-3.84(m,2H),2.67-2.65(m,1H),2.65-2.62(m,2H),0.83-0.77(m,2H),0.65-0.58(m,2H)。
实施例27
4-[2,6-二氯-4-(环丙基氨基羰基)氨基苯氨基]-6-[(1-丙烯酰基-1,2,3,6-四氢吡啶)-4-基]-7-甲氧基喹啉(I-27)
Figure PCTCN2020138248-appb-000038
制备方法参考实施例1，以4-溴-3-甲氧基苯胺为起始原料，得黄色固体11mg，收率20％，MS m/z:553.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.70(s,1H),8.59(d,J＝5.2Hz,1H),8.03(s,1H),7.73(d,J＝13.6Hz,1H),7.43(s,1H),7.33(t,J＝9.0Hz,1H),7.21(d,J＝8.4Hz,1H),6.94-6.75(m,2H),6.56(s,1H),6.43(d,J＝5.1Hz,1H),6.16(d,J＝17.0Hz,1H),5.98(d,J＝15.5Hz,1H),5.73(d,J＝10.7Hz,1H),4.28(s,1H),4.19(s,1H),3.95(s,3H),3.76(s,2H),2.57-2.51(m,1H),1.98-1.90(m,1H),0.67-0.62(m,2H),0.54-0.42(m,2H)。
实施例28：生物学活性
1.目标化合物的FGFR4抑制活性测定
所合成的化合物用荧光共振能量转移(FRET)法测定对FGFR4的抑制活性(具体实施办法参考文献：Lebakken CS,Kang HC,Vogel KW,A fluorescence lifetime-based binding assay to characterize kinase inhibitors.J Biomol Screen.2007.12(6):828–841.)，并与阳性对照药比较，筛选出活性较好的化合物。FGFR4通过直接购买试剂盒获得。
2.目标化合物的Hep3B细胞抑制活性测定
a.细胞复苏，培养细胞至对数生长期；b.配制化合物：供试品溶解在DMSO中，浓度为30mM，以1∶3比例梯度稀释，共10个梯度；c.将4～6*10 4/ml密度的细胞，接种到384孔板中，每个孔中接种25μL，加入化合物，化合物的终浓度为30，10，3.33，1.11，0.37，0.123，0.041，0.014，0.005，0.002mM；c.化合物与细胞孵育72h，通过CTG方法检测细胞活性。
下表是部分化合物的体外FGFR4激酶活性及体外癌细胞活性测试结果：
Figure PCTCN2020138248-appb-000039
Figure PCTCN2020138248-appb-000040
(表中化合物代号对应于前面的化合物代号)
从上表可知：本发明的上述化合物及其医学上可接受的盐具有FGFR4抑制作用，可为制备治疗/预防与FGFR4相关疾病的药物提供依据。
药理测试结果表明，本发明中喹啉类化合物化合物具有较好的FGFR4激酶和Hep3B细胞抑制活性，部分化合物IC 50值与阳性对照药Blu9931和Lenvatinib相当或优于阳性对照，可用于预防或治疗与FGFR4激酶抑制剂有关的临床疾病。
本发明的上述化合物及其医学上可接受的盐具有FGFR4抑制作用，可用作医药品中的有效成分。因此，含有上述化合物作为有效成分的药物，可以用于制备治疗与FGFR4有关的临床病症的药物，如：制备预防和/治疗生物体内与FGFR4相关的细胞异常增殖、形态变化以及运动功能亢进等相关的疾病的药物以及与血管新生或癌转移相关的疾病的药物中的用途。
如上所述，尽管参照特定的优选实施例已经表示和表述了本发明，但其不得解释为对本发明自身的限制。在不脱离所附权利要求定义的本发明的精神和范围前提下，可对其在形式上和细节上作出各种变化。

Claims (10)

  1. 通式I的化合物或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物：
    Figure PCTCN2020138248-appb-100001
    式I中，
    X选自-CR 4R 5-、-NR 4-、O或S，其中R 4、R 5各自独立地表示氢、氘、卤素、烷基、芳基或Het；
    Q选自-NR 6CONR 7-、-CONR 6-、-NR 6CO-、-NR 6SO 2NR 7-、-SO 2NR 6-、-NR 6SO 2-、-NR 6-、-NR 6(CH 2) mN-、-NR 6(CH 2) mO-或-CR 6R 7，其中m＝1、2、3、4或5，R 6、R 7各自独立地表示氢、氘、烷基、芳基或Het；
    虚线表示可以存在单键或双键；
    n＝0、1、2或3；
    R 1选自氢、卤素、羟基、烷氧基、烷基、芳基或Het；
    R 2选自氢、卤素、羟基、烷氧基、烷基、芳基或Het；
    R 3选自氢、卤素、羟基、烷氧基、烷基、芳基或Het；
    P选自如下结构：
    Figure PCTCN2020138248-appb-100002
    其中，R 11为离去基团或活化酯；R 8、R 9、R 10、R 12各自独立地选自氢、卤素、羟基、烷氧基、烷基、芳基或Het；
    烷基为1-6个碳原子的直链或支链饱和烃基、3-6个碳原子的环状饱和烃基，或连有1-6个碳原子直链或支链饱和烃基的3-6个碳原子的环状饱和烃基；
    上述基团中，芳基为选自苯基、萘基、苊基或四氢萘基的碳环，其各自任选被1、2或3个取代基取代，各取代基独立地选自氢、烷基、氰基、卤素、硝基、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het；
    Het为选自哌啶基、吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、 噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基的单环杂环；或选自喹啉基、喹喔啉基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并呋喃基、苯并噻吩基、2,3-二氢苯并[1,4]二氧杂环己烯基或苯并[1,3]二氧杂环戊烯基的双环杂环；各单环或双环杂环任选被1、2或3个取代基取代，各取代基独立选自卤素、卤代烷基、羟基、烷基或烷氧基；
    卤素选自氟、氯、溴或碘。
  2. 根据权利要求1所述的化合物，其特征在于：式I中，
    X为-NR 4-或O，其中R 4选自氢、氘、卤素、烷基、芳基或Het；
    Q选自-NR 6CONR 7-、-CONR 6-、-NR 6CO-、-NR 6SO 2NR 7-、-SO 2NR 6-或-NR 6SO 2-，其中R 6、R 7各自独立地表示氢、氘、烷基、芳基或Het；
    虚线表示可以存在单键或双键；
    n＝0、1、2或3；
    R 1选自氢、卤素或烷基；
    R 2选自氢、烷基或芳基；
    R 3选自烷氧基、烷基、芳基或Het。
  3. 根据权利要求1所述的化合物，其特征在于：式I中，
    X为O；
    Q选自-NR 6CONR 7-、-CONR 6-或-NR 6CO-，其中R 6、R 7各自独立地表示氢、氘、烷基、芳基或Het；
    虚线表示可以存在单键或双键；
    n＝0、1、2或3；
    R 1选自氢、卤素或烷基；
    R 2为烷基或芳基；
    R 3选自烷基、芳基或Het。
  4. 根据权利要求1所述的化合物，其特征在于：式I中，
    X为O；
    Q选自-NR 6CONR 7-、-CONR 6-或-NR 6CO-，其中R 6、R 7各自独立地表示氢、氘、烷基、芳基或Het；
    虚线表示可以存在单键或双键；
    n＝0或1；
    R 1为氢或卤素；
    R 2为烷基或芳基；
    R 3选自烷基、芳基或Het；
    P选自如下结构：
    Figure PCTCN2020138248-appb-100003
    其中，R 11为离去基团或活化酯；R 8、R 9、R 10各自独立地选自氢或烷基。
  5. 根据权利要求1所述的化合物，其特征在于：所述药学上可接受的盐包括通式I的化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸；还包括通式I化合物与无机碱形成的酸式盐。
  6. 根据权利要求5所述的化合物，其特征在于：所述药学上可接受的盐包括碱性金属阳离子盐、碱土金属阳离子盐和铵阳离子盐。
  7. 根据权利要求1所述的化合物，其特征在于：式I的化合物为下述化合物中的一种：
    Figure PCTCN2020138248-appb-100004
    Figure PCTCN2020138248-appb-100005
    Figure PCTCN2020138248-appb-100006
    Figure PCTCN2020138248-appb-100007
  8. 一种药物组合物，其特征在于：包括权利要求1所述的化合物或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物，以及药学上可接受的载体或赋形剂。
  9. 权利要求1所述的化合物在制备用于预防和/或治疗FGFR4相关疾病的药物中的用途。
  10. 根据权利要求9所述的应用，其特征在于：所述FGFR4相关疾病选自但不限于高脂血症或癌症；所述的癌症包括肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、***癌、甲状腺癌、女性生殖***癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤，及骨髓增生异常综合症。
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