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WO2020156283A1 - 炔基嘧啶或炔基吡啶类化合物、及其组合物与应用 - Google Patents

炔基嘧啶或炔基吡啶类化合物、及其组合物与应用 Download PDF

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WO2020156283A1
WO2020156283A1 PCT/CN2020/073018 CN2020073018W WO2020156283A1 WO 2020156283 A1 WO2020156283 A1 WO 2020156283A1 CN 2020073018 W CN2020073018 W CN 2020073018W WO 2020156283 A1 WO2020156283 A1 WO 2020156283A1
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methyl
ethynyl
pyrazol
alkyl
methylpiperazin
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French (fr)
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张强
于善楠
孙月明
杨磊夫
郑南桥
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北京赛特明强医药科技有限公司
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
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    • C07D401/14—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 three or more hetero rings
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    • C07D403/14—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 three or more hetero rings
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the field of chemical medicine. More specifically, it relates to a class of alkynyl pyrimidine or alkynyl pyridine compounds with ABL, ABL-T315I, KIT, and VEGFR-2 kinase inhibitory activities or their pharmaceutically acceptable salts, isomers, solvates, crystal forms Or prodrugs, and pharmaceutical compositions containing these compounds and the application of these compounds or compositions in the preparation of drugs.
  • Tumors are cells that undergo abnormal signal transduction under the action of various carcinogenic factors, and certain cells in some tissues lose control of their normal growth, leading to disorders of apoptosis and continuous cell proliferation, leading to new biological clones Formed by sexual growth. After tumor cells have lost their normal growth regulation function, they have the ability to grow independently, and the tumor can continue to grow after the growth of carcinogens stops.
  • tumors can be divided into solid tumors and non-solid tumors. Solid tumors are treated by surgical resection, chemotherapy and other methods. Non-solid tumors mainly use chemical drugs to kill cancer cells, but these chemical drugs have more side effects. Large, the cells in the body will be destroyed whether they are malignant tumor cells or not.
  • Leukemia is one of the malignant tumors and is a non-solid tumor, which ranks first in the incidence of pediatric malignancies. According to the natural course of leukemia cells, it can be divided into two categories: acute leukemia and chronic leukemia. Among them, chronic leukemia can be divided into chronic myelogenous leukemia (Chronic Myelogenous Leukemia, CML) and chronic lymphocytic leukemia (Chronic Lymphocytic Leukemia, CLL). Chronic myelogenous leukemia accounts for about 20% of all leukemias and affects people of all ages.
  • CML chronic myelogenous Leukemia
  • CLL chronic lymphocytic Leukemia
  • CML chronic myeloid leukemia
  • the long arm of chromosome 22 is translocated to 9 Chromosome, forming the Philadelphia chromosome, and leading to the fusion of BCR gene and ABL gene to form the BCR-ABL fusion gene, expressing BCR-ABL protein tyrosine kinase, which can cause changes in cell proliferation, adhesion and survival properties, leading to a variety of tumors The production.
  • BCR-ABL is not expressed in normal cells, so it is an ideal drug target for the treatment of chronic myeloid leukemia.
  • the most commonly used small molecule inhibitors for BCR-ABL tyrosine kinase include: the first-generation drug imatinib; the second-generation drugs dasatinib, nilotinib and bosutinib; third Substitute drug Pranatinib.
  • Tyrosine kinase inhibitors play an anti-chronic myeloid leukemia effect mainly by inhibiting the activity of the BCR-ABL fusion protein.
  • Imatinib is a small molecule BCR-ABL tyrosine kinase inhibitor developed by Novartis. It was approved by the FDA in 2001 for the treatment of CML. This is the first tyrosine kinase inhibitor to treat CML, which can treat cancer by targeting specific damaged genes in tumor cells. Compared with other therapeutic drugs, imatinib can effectively alleviate chronic myeloid leukemia, and the 5-year survival rate of patients after treatment can reach 90%. A significant feature of imatinib is that it can specifically inhibit the proliferation of chronic myelogenous leukemia cancer cells, and has almost no harm to normal cells, which greatly reduces the toxic side effects of the drug. Imatinib ushered in a new era of treating diseases with kinases as targets.
  • the main reason for imatinib resistance is that the BCR-ABL gene has mutations including L248V, E255V, Y253H, E355G, E255K, T315I, F359V, M253H, G250E, F317L, H396P, M351T, Q252H, etc., due to ABL kinase
  • the point mutations in the drug reduce the affinity between Imatinib and ABL kinase, resulting in a significant decrease in its therapeutic effect.
  • Nilotinib The second-generation Bcr-Abl tyrosine kinase inhibitor Nilotinib is an aniline pyrimidine derivative, which was approved by the US FDA in October 2007 for the treatment of CML. Its affinity for Bcr-Abl tyrosine kinase is 20 times stronger than Imatinib. Nilotinib can inhibit Imatinib-resistant mutations other than the T315I mutation. However, most patients with CML treated with Nilotinib have common adverse reactions such as elevated lipase and bilirubin, mild to moderate rash, bone marrow suppression, and gastrointestinal reactions.
  • Dasatinib is also a second-generation Bcr-Abl tyrosine kinase inhibitor. It is an oral kinase inhibitor that has inhibitory effects on a variety of kinases. It has an effect on BCR-ABL kinase and SRC family kinases ( SRC kinase is a target of anti-tumor drugs) has a good inhibitory effect. Dasatinib was approved by the FDA in June 2006 for the treatment of CML patients. Dasatinib has less specific structural requirements than imatinib, and it can overcome a variety of resistance to imatinib (except for the T315I mutation). Dasatinib is quickly absorbed after oral administration, reaching the maximum blood concentration within 0.5-3h, and its average half-life is 5-6h. The main adverse reactions of patients after taking dasatinib are bone marrow suppression and neutrophilia.
  • Bosutinib is a new 4-substituted aniline-3-quinolinecarbonitrile drug developed by Wyeth Pharmaceuticals in the United States for the treatment of CML. It was approved for marketing by the FDA in September 2012. It mainly targets imatinib and Rotinib and Dasatinib are kinase inhibitors for CML patients who have failed treatment.
  • the anti-proliferative activities (IC 50 ) of bosutinib on KU812 and K562 cells were 20 nM and 5 nM, respectively, while the anti-proliferative activities of imatinib on KU812 and K562 cells were 210 nM and 88 nM, respectively.
  • Bosutinib also has no inhibitory effect on the T315I mutation.
  • Adverse reactions of patients taking Bosutinib mainly include: nausea, vomiting, abdominal pain, diarrhea, skin rash, elevated liver enzyme levels, thrombocytopenia, anemia and fatigue.
  • the second-generation CML drugs Dasatinib, Nilotinib, and Bosutinib have a wide range of activities in patients who are resistant and intolerant to Imatinib, but they have no inhibitory activity against BCR-ABL and T315I kinase mutations.
  • the third-generation BCR-ABL tyrosine kinase inhibitor Ponatinib is an oral multi-target kinase inhibitor. It is mainly used to overcome BCR-ABL T315I and requires a good inhibitory effect on wild-type BCR-ABL. Ponatinib can inhibit the BCR-ABL kinase activity including the T315I mutation. According to the literature (Rabindran SK, et al.
  • the present invention provides a compound represented by formula (I), its pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug, which can be used to treat or prevent tyrosine kinases (such as ABL, ABL-T315I, KIT and VEGFR-2) caused diseases.
  • tyrosine kinases such as ABL, ABL-T315I, KIT and VEGFR-2
  • Q is CH or N
  • L, Z, and G are each independently selected from N, NR 4 , O, S, or CR 4 , and at least one of them is not CR 4 ;
  • R 1 is hydrogen, halogen, C 1 -C 3 alkyl, halo C 1 -C 3 alkyl;
  • R 2 is -(CH 2 )nR 6
  • R 6 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 alkylthio, -NR a R b , or optionally 1 to 3 selected from halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, hydroxyl, -NR a R b , C 1 -C 3 acyl, hydroxyl C 1 -C 3 alkyl, C 1 -C 3 alkoxy
  • R 3 is hydrogen, C 1 -C 3 alkyl, halogen
  • R 5 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, cyano, C 3 -C 6 cycloalkyl, fluorine, hydroxyl, chlorine;
  • the substituted or unsubstituted 4-8 membered heteroalicyclic group is a 4-8 membered heteroalicyclic group containing 1-2 atoms selected from N, O, and S as ring atoms,
  • R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy C 1 -C 6 alkyl, C 1 -C 3 alkane thio C 1 -C 6 alkyl or mono- or di-C 1 -C 3 alkyl unsubstituted or substituted amino-substituted C 1 -C 6 alkyl.
  • Q is N; L and G are N atoms and Z is CH.
  • R 1 is hydrogen, trifluoromethyl, fluorine, chlorine, methyl.
  • R 2 is -(CH 2 )nR 6
  • R 6 is hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, hydroxyl, halogenated C 1 -C 3 Alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, -NR a R b , or optionally 1 to 3 selected from halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, hydroxyl, -NR a R b , C 1 -C 3 acyl, hydroxyl C 1 -C 3 alkyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl, oxo substituted or unsubstituted 4-6 membered heteroalicyclic group
  • n is an integer from 0 to 3
  • the 4-6 membered heteroalicyclic group is piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, Pyranyl,
  • R a and R b are each independently hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy substituted C 1 -C 3 alkyl.
  • R 6 is hydrogen, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, Hydroxymethylamino, hydroxyethylamino, hydroxypropylamino, methoxyethylamino, methoxypropylamino, dimethylolamino, dihydroxyethylamino, dihydroxypropylamino, dimethoxy Ethylethylamino, dimethoxypropylamino, N-methyl-N-hydroxyethylamino, N-methyl-N-hydroxypropylamino, N-ethyl-N-hydroxyethylamino, N -Ethyl-N-hydroxypropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-methoxyethy
  • R 3 is -H, methyl, fluorine, chlorine.
  • R 4 is hydrogen, C 3 -C 8 cycloalkyl, or 1 to 3 selected from C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, C 1 -C 3 acyl, hydroxyl, fluorine, chlorine, cyano, -CONH 2 , C 3 -C 6 cycloalkyl or -NR a R b substituent substituted or unsubstituted C 1 -C 6 alkyl group, or -(CH 2 )mR 7 , R 7 is optionally 1 to 3 selected from halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, hydroxyl, -NR a R b , C 1 -C 3 acyl, hydroxyl C 1 -C 3 alkyl, C 1 -C 3 alkoxy C 1 -C 3 alkyl,
  • the 4-6 membered heteroalicyclic group is piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, Pyranyl,
  • R a and R b are each independently hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy substituted C 1 -C 3 alkyl.
  • R 4 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl , Isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, hydroxyethyl Group, hydroxypropyl, fluoroethyl, fluoropropyl, cyanomethyl, cyanoethyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, methylsulfide Ethyl, methylthiopropyl, dimethylaminoethyl, dimethylaminopropyl, dimethyl
  • R 5 is hydrogen, methyl, methoxy, cyano, cyclopropyl, fluorine.
  • the pharmaceutically acceptable salt of the compound is selected from the hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, Phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, glucose Acid salt, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclic Hexsulfamate, salicylate, hexonate, trifluoroacetate, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium , One or more of magnesium salt, potassium salt, sodium salt and zinc salt.
  • Another aspect of the present invention relates to the compound of formula (I), its isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs in the preparation and treatment of ABL, ABL-T315I, KIT and VEGFR- 2 and other kinase-related diseases, wherein the diseases related to kinases such as ABL, ABL-T315I, KIT and VEGFR-2 include fundus diseases, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, Rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer , Pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, mela
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) of the present application, its isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and One or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition may also include one or more other therapeutic agents.
  • the present invention also relates to a method for treating diseases or conditions mediated by kinases such as ABL, ABL-T315I, KIT, and VEGFR-2, which includes administering treatment to patients (humans or other mammals, especially humans) in need
  • kinases such as ABL, ABL-T315I, KIT, and VEGFR-2
  • An effective amount of the compound of formula (I) or a salt thereof, the kinase-mediated diseases or conditions such as ABL, ABL-T315I, KIT, and VEGFR-2 include those mentioned above.
  • alkyl refers to a saturated linear and branched hydrocarbon group with the specified number of carbon atoms
  • C 1 -C 10 alkyl refers to an alkyl moiety containing 1 to 10 carbon atoms
  • C 1 -C 3 Alkyl refers to an alkyl moiety containing 1 to 3 carbon atoms.
  • C 1 -C 6 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl Base, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methyl Basepentyl and so on.
  • substituent terms such as “alkyl” are used in combination with other substituent terms, for example, in the terms “C 1 -C 3 alkoxy C 1 -C 6 alkylthio” or “hydroxy substituted C 1 -C 10 alkyl”
  • this linking substituent term e.g., alkyl or alkylthio
  • C 1 -C 3 alkoxy C 1 -C 6 alkylthio include, but are not limited to, methoxymethylthio, methoxyethylthio, ethoxypropylthio and the like.
  • Examples of "hydroxyl substituted C 1 -C 10 alkyl” include but are not limited to hydroxymethyl, hydroxyethyl, hydroxyisopropyl and the like.
  • the alkoxy group is an alkyl-O- group formed by the previously described linear or branched alkyl group and -O-, for example, a methoxy group, an ethoxy group, and the like.
  • the alkylthio group is an alkyl-S- group formed by the previously described linear or branched alkyl group and -S-, for example, methylthio, ethylthio and the like.
  • Alkenyl and alkynyl include straight chain, branched chain alkenyl or alkynyl, and the term C 2 -C 6 alkenyl or C 2 -C 6 alkynyl means a straight or branched chain hydrocarbon group having at least one alkenyl or alkynyl group.
  • haloalkyl such as “halo C 1 -C 10 alkyl” means having one or more halogens, which may be the same or different, on one or more carbon atoms of an alkyl moiety including 1 to 10 carbon atoms A group of atoms.
  • halo C 1 -C 10 alkyl may include, but are not limited to, -CF 3 (trifluoromethyl), -CCl 3 (trichloromethyl), 1,1-difluoroethyl, 2,2 , 2-Trifluoroethyl and hexafluoroisopropyl, etc.
  • halo C 1 -C 10 alkoxy means a haloalkyl-O- group formed by the halogenated C 1 -C 10 alkyl group and -O-, which can be, for example, trifluoromethyl Oxy, trichloromethoxy, etc.
  • C 1 -C 3 acyl includes formyl (-CHO), acetyl (CH 3 CO-), and acetyl (C 2 H 5 CO-).
  • Cycloalkyl means a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms.
  • (C3-C6)cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having 3-6 ring carbon atoms.
  • Exemplary "(C3-C6)cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aryl refers to a group or moiety comprising an aromatic monocyclic or bicyclic hydrocarbon atom group, which contains 6 to 12 carbon ring atoms and has at least one aromatic ring.
  • aryl are phenyl, naphthyl, indenyl and dihydroindenyl (indanyl).
  • the aryl group is phenyl.
  • heteroalicyclic group represents an unsubstituted or substituted stable 4- to 8-membered non-aromatic monocyclic saturated ring system, which consists of carbon atoms and N, It is composed of 1 to 3 heteroatoms selected from O, S, among which N and S heteroatoms can be oxidized at will, and N heteroatoms can also be quaternized at will.
  • heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietane, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazole Alkyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, 1,3-dioxolane, piperidinyl, piperazinyl, tetrahydrofuranyl Hydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3 -Oxathiolanyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxa
  • heteroaryl refers to a group or moiety containing an aromatic monocyclic or bicyclic atom group (which contains 5 to 10 ring atoms), which includes 1 to 3 independently selected from nitrogen, oxygen and sulfur Of heteroatoms.
  • the term also includes bicyclic heterocyclic aryl groups containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, or a heteroaryl ring moiety fused to a cycloalkyl ring moiety. Unless otherwise specified, it represents an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system.
  • heteroaryl groups can be connected to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazole Group, thiadiazolyl, isothiazolyl, pyridyl, oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, iso Benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, dihydrobenzodioxolenyl, benzothienyl, indazinyl , Indolyl, isoindolyl, indoline, benzimidazolyl, di
  • carbonyl refers to a -C(O)- group.
  • halogen and “halo” refer to chlorine, fluorine, bromine or iodine substituents.
  • Hydroxo is intended to mean the -OH radical.
  • cyano as used herein refers to the group -CN.
  • each independently means that when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • the compounds, isomers, crystal forms or prodrugs of formula I and their pharmaceutically acceptable salts can exist in solvated and unsolvated forms.
  • the solvated form may be a water-soluble form.
  • the present invention includes all these solvated and unsolvated forms.
  • the compounds of the present invention may have asymmetric carbon atoms. According to their physical and chemical differences, such diastereomeric mixtures can be separated by known technically mature methods, such as chromatography or fractional crystallization. Into a single diastereomer. The separation of enantiomers can be carried out by first reacting with an appropriate optically active compound, converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereoisomers, and then converting the single diastereoisomers The enantiomers are converted (hydrolyzed) to the corresponding pure enantiomers. All such isomers, including mixtures of diastereomers and pure enantiomers, are considered part of the invention.
  • the compound of the present invention as the active ingredient and the method for preparing the compound are the content of the present invention.
  • the crystalline forms of some compounds may exist as polycrystals, and this form may also be included in the current invention.
  • some compounds can form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also included in the scope of this invention.
  • the compounds of the present invention can be used for therapy in free form, or in the form of pharmaceutically acceptable salts or other derivatives where appropriate.
  • pharmaceutically acceptable salt refers to the organic and inorganic salts of the compounds of the present invention. This salt is suitable for humans and lower animals, without excessive toxicity, irritation, allergic reactions, etc., and has reasonable Benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art.
  • the salt can be formed by reacting the compound of the present invention with a suitable free base or acid.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid, Or by using methods well known in the art, such as ion exchange methods, these salts can be obtained.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconic acid Salt, hemisulfate, caproate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, per-3-phenylpropionate, Phosphate, picrate, propionate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like.
  • Other pharmaceutically acceptable salts include appropriate non-toxic ammonium, quaternary ammonium, and use such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonates and arylsulfonates. Amine cation formed by acid salt.
  • prodrug as used herein means that a compound can be converted into the compound represented by formula (I) of the present invention in vivo. This conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the parent compound in the blood or tissue.
  • the pharmaceutical composition of the present invention comprises the compound of structural formula (I) described herein or a pharmaceutically acceptable salt thereof, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anticancer drugs, antiviral agents, and An additional active agent of an inflammatory agent, an antifungal agent, an antibiotic, or an anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or excipient.
  • the compound of the present invention can be used alone, or in combination with one or more other compounds of the present invention or with one or more other agents.
  • the therapeutic agents can be formulated to be administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition.
  • the so-called "combination therapy" refers to the use of the compound of the present invention together with another agent.
  • the mode of administration is simultaneous co-administration of each agent or sequential administration of each agent. In either case, the purpose is to To achieve the best effect of the drug.
  • Co-administration includes simultaneous delivery of dosage forms and separate separate dosage forms for each compound.
  • the administration of the compound of the present invention can be used simultaneously with other therapies known in the art, for example, the use of radiotherapy or cytostatic agents, cytotoxic agents, other anti-cancer agents and other additional therapies in cancer treatment to improve Cancer symptoms.
  • the present invention is not limited to the order of administration; the compounds of the present invention may be administered previously, concurrently, or after other anticancer agents or cytotoxic agents.
  • one or more compounds or salts of formula (I) as its active ingredient can be closely mixed with the pharmaceutical carrier, which is carried out according to the traditional pharmaceutical ingredient technology.
  • the carrier can take various forms according to the preparation form designed according to different administration methods (for example, oral or parenteral administration).
  • Appropriate pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the "Handbook of Pharmaceutical Excipients", which is jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.
  • the pharmaceutical composition of the present invention may have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear liquids, suspensions, Emulsion; or for topical medication such as ointment, cream; or as suppository for rectal administration.
  • the pharmaceutical ingredients can also be used in unit dosage form suitable for one-time administration of precise dosages.
  • the pharmaceutical ingredient will include a traditional pharmaceutical carrier or excipient and a compound prepared according to the current invention as an active ingredient. In addition, it may also include other medical or pharmaceutical preparations, carriers, adjuvants, and so on.
  • Therapeutic compounds can also be given to mammals instead of humans.
  • the dose of the drug used for a mammal will depend on the species of the animal and its disease or disorder.
  • Therapeutic compounds can be given to animals in the form of capsules, boluses, or tablet potions.
  • the therapeutic compound can also be injected or infused into the animal's body. We prepare these drug forms in a traditional way that meets the standards of veterinary practice.
  • the pharmacological compound can be mixed with animal feed and fed to animals. Therefore, concentrated feed additives or premixes can be prepared to mix with ordinary animal feed.
  • Another object of the present invention is to provide a method for treating cancer in a subject in need, which comprises a method of administering to the subject a therapeutically effective amount of a composition containing the compound of the present invention.
  • the present invention also includes the use of the compound of the present invention or a pharmaceutically acceptable derivative thereof, manufactured for the treatment of cancer (including non-solid tumors, solid tumors, primary or metastatic cancers, as indicated elsewhere herein and including cancer One or more other treatments that are resistant or refractory) and other diseases (including but not limited to fundus disease, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, etc.) .
  • the cancer includes but is not limited to: non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membranous cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain Any of tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary carcinosarcoma, and cholangiocarcinoma.
  • the present invention also provides methods for preparing corresponding compounds.
  • a variety of synthetic methods can be used to prepare the compounds described herein, including the methods involved in the following examples, the compounds of the present invention or their pharmaceutically acceptable salts, isomers
  • the body or hydrate can be synthesized using the following methods and synthetic methods known in the field of organic chemistry synthesis, or by those skilled in the art understanding of variations of these methods. Preferred methods include but are not limited to the following methods.
  • Step 1 A solution of 4-nitropyrazole (1.13g, 10mmol), methyl iodide (2.85g, 20mmol), potassium carbonate (4.14g, 30mmol) in acetone (10mL) is heated to 60°C for 12 hours, then cooled, It was filtered, concentrated, and purified by column chromatography to obtain 1.1 g of white solid product 1-methyl-4-nitro-1H-pyrazole with a yield of 85%.
  • Step 2 Add palladium (carbon load 55% humidity, 10% mass content) to the methanol (20mL) solution of 1-methyl-4-nitro-1H-pyrazole (0.64g, 5mmol), and replace with hydrogen three times. The reaction was stirred at room temperature for 6 hours, filtered through Celite, and the filtrate was concentrated to obtain 0.4 g of the target product 1-methyl-1H-pyrazol-4-amine, with a yield of 82%, MS: 98 [M+H]+.
  • Step 3 Add 2-chloro-5-iodopyrimidine (0.5g, 2.1mmol) and trifluoride to a solution of 1-methyl-1H-pyrazole-4-amine (0.2g, 2mmol) in sec-butanol (2mL) Acetic acid (20 ⁇ l, catalytic) heated at 110 degrees Celsius for 10 hours, cooled, concentrated, and purified by column chromatography to obtain 5-iodo-N-(1-methyl-1H-pyrazol-4-yl)pyrimidine as a white solid product -2-amine 0.45g, yield 75%, MS: 302 [M+H]+.
  • Step 1 Add potassium nitrate (1.22g, 12mmol) to a solution of 3-methylpyrazole (1mL, 12mmol) in sulfuric acid (10mL) in an ice-water bath, stir at room temperature for 15 hours, and transfer to 0 degrees Celsius It was quenched by adding ammonia water and filtered to obtain a white solid product of 5-methyl-4-nitro-1H-pyrazole 1.5g with a yield of 98%; 1 H NMR (400MHz, DMSO-d6) ⁇ 13.44(s, 1H) ,8.39(s,1H),2.51(s,3H).MS:128[M+H] + .
  • Step 2 Add methyl iodide (2.85g, 20mmol) to the acetone solution (15mL) of 5-methyl-4-nitro-1H-pyrazole (1.3g, 10mmol), heat the reaction at 60 degrees Celsius for 20 hours, and cool , Respectively add ethyl acetate and water to quench, the organic phase is dried and concentrated to obtain yellow-brown oil (1,3-dimethyl-4-nitro-1H-pyrazole and 1,5-dimethyl-4- Nitro-1H-pyrazole) 1.5g was used directly in the next step.
  • Step 3 Dissolve the oil obtained in step B1-2 in methanol (30 mL), add wet palladium on carbon (55% humidity, 10% palladium content, 80 mg), replace the reaction system with hydrogen, and stir at room temperature under hydrogen conditions for reaction After 6 hours, filter with celite and concentrate the filtrate to obtain colorless oils (1,3-dimethyl-1H-pyrazol-4-amine and 1,5-dimethyl-1H-pyrazol-4-amine) ) 0.96g was used directly in the next step; MS: 112[M+H] + .
  • Step 4 Add 2-chloro-5-iodopyrimidine (0.5g, 2mmol) and trifluoroacetic acid (20 microliters) to the colorless oil (0.3g) obtained in Step B1-3 in sec-butanol solution (10mL).
  • Step 1 Add potassium nitrate (3.1g, 30mmol) to a solution of 4-nitropyrazole (3.4g, 30mmol) in dry dichloromethane (20mL) in a cold water bath at 15 degrees Celsius, and then add trifluoroacetic anhydride ( 8.4mL, 60mmol) in dry dichloromethane (10mL), stirred at room temperature for 5 hours, poured the reaction solution into ice water, extracted with ethyl acetate to obtain a white solid product 1,4-dinitro-1H-pyrazole 4.7 g;
  • Step 2 Add 1,4-dinitro-1H-pyrazole (1.6g, 10mmol) in ether (15mL) slowly dropwise into potassium hydroxide (1.12g, 20mml) in methanol (60mL) solution, room temperature The reaction was stirred for 1 hour, concentrated, and purified by column chromatography to obtain 1.4 g of a white solid product, 3-methoxy-4-nitro-1H-pyrazole, with a yield of 95%, MS: 144 [M+H] + .
  • Step 3 To 3-methoxy-4-nitro-1H-pyrazole (0.14g, 1mmol) in acetone (5mL) was added methyl iodide (0.3g, 2mmol) and potassium carbonate (0.3g, 2.2 mmol), the reaction was carried out at 60 degrees Celsius for 10 hours, cooled, filtered, and concentrated to obtain 0.15 g of light yellow oily 3-methoxy-1-methyl-4-nitro-1H-pyrazole, which was used directly in the next step .
  • methyl iodide 0.3g, 2mmol
  • potassium carbonate 0.3g, 2.2 mmol
  • Step 4 Add a catalytic amount of palladium on carbon (55% humidity, 10% palladium) to a solution of 3-methoxy-1-methyl-4-nitro-1H-pyrazole (0.15g, 1mmol) in methanol (10mL) Content), after replacing the system with hydrogen for 3 times, the reaction was stirred at room temperature for 5 hours, filtered through Celite, and the filtrate was concentrated to obtain 1.2 g of light purple oily 3-methoxy-1-methyl-1H-pyrazole-4-amine. The yield was 95%, MS: 128[M+H] + .
  • Step 5 3-Methoxy-1-methyl-1H-pyrazole-4-amine (0.26g, 2mmol) in sec-butanol (2mL) was added with 2-chloro-5-iodopyrimidine (0.5g, 2.1mmol) and trifluoroacetic acid (20 ⁇ l, catalytic) heated at 110 degrees Celsius for 10 hours, cooled, concentrated, and purified by column chromatography to obtain a white solid product 5-iodo-N-(3-methoxy-1-methyl (Pyrazol-4-yl)pyrimidin-2-amine 0.55 g, yield 83%, MS: 332[M+H] + .
  • Step 1 Under ice-water bath conditions, slowly add sodium hydride (60% by mass dispersed in oil, 4.827g, 120.7) to 4-nitro-1H-pyrazole (6.598g, 58.35mmol) in tetrahydrofuran (50mL). mmol) was then stirred at room temperature for 20 minutes until homogeneous, then SEMCl (12.0 mL, 67.8 mmol) was added dropwise in an ice-water bath, and the reaction was stirred at room temperature for 3 hours. It was carefully quenched with ice water and extracted with ethyl acetate. The organic phase is dried and concentrated. Purification by column chromatography gave 14.1 g of colorless oily 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole with a yield of 99%.
  • Step 2 Drying to 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.52g, 6.2mmol) at -78°C
  • THF 20 mL
  • a solution of HMDLi (1M THF solution, 7.5 mL, 7.5 mmol) in tetrahydrofuran was slowly added dropwise.
  • iodine 1.8 g, 7 mmol
  • THF 8 mL
  • Step 3 Respectively mix 5-iodo-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (3.7g, 10mmol), cyclopropylboronic acid (1.7mg, 20mmol), anhydrous potassium phosphate (8.5g, 40mmol), Pd(PPh 3 ) 4 (0.86mg, 0.75mmol) were added to the mixed solution of toluene (100mL) and water (1mL), argon After three replacements, it was heated to 100 degrees Celsius and reacted for 24 hours, cooled, concentrated, and purified by column chromatography to obtain the target product 5-cyclopropyl-4-nitro-1-((2-(trimethylsilyl )Ethoxy)methyl)-1H-pyrazole 2.5g, yield 88%.
  • Step 4 Add 5-cyclopropyl-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.5g, 8.8mol) to hydrogen chloride Stir in the 1,4-dioxane (4M) solution (30 mL) for 5 hours at room temperature, and concentrate to obtain 1.7 g of 5-cyclopropyl-4-nitro-1H-pyrazole as a yellow oil and use it directly in the next step; MS: 154[M+H] + .
  • Step 5 Add potassium carbonate (3.5g, 25mmol) and methyl iodide (3.5g, iodomethane) to the acetone solution (15mL) of 5-cyclopropyl-4-nitro-1H-pyrazole (1.7g, 11.1mmol) 25mmol), heated to 60 degrees Celsius and stirred for 20 hours, quenched by adding water, extracted with ethyl acetate, dried and concentrated to obtain a yellow oily 3-cyclopropyl-1-methyl-4-nitro-1H-pyrazole And 5-cyclopropyl-1-methyl-4-nitro-1H-pyrazole 1.8g.
  • Step 6 Dissolve the yellow oil (1.8g) obtained in Step 5 in methanol (30mL), add wet palladium on carbon (55% humidity, 10% mass content), replace with hydrogen, stir and react at room temperature for 5 hours under hydrogen conditions. Filter with celite, and concentrate the filtrate to obtain colorless oils 3-cyclopropyl-1-methyl-1H-pyrazole-4-amine and 5-cyclopropyl-1-methyl-1H-pyrazole-4 -Amine 1.4g, MS: 138 [M+H] + .
  • Step 7 Add 2-chloro-5-iodopyrimidine (0.5g, 2mmol) and trifluoroacetic acid (50 ⁇ l, catalytic) to the oily substance (0.3g, 2mmol) obtained in Step 6 in sec-butanol (4mL) solution It was heated to 110 degrees Celsius and reacted for 10 hours, cooled, concentrated, and purified by column chromatography to obtain 0.61 g of white solid product, and then purified by preparative liquid chromatography to obtain target intermediates D1 (280 mg) and D2 (100 mg).
  • Step 1 Methyl 3-iodo-4-methylbenzoate (2.8g, 10mmol), acetylene trimethylsilane (1.1g, 11mmol), Pd(PPh 3 ) 2 Cl 2 (0.07g, 0.1mmol), CuI (0.02g, 0.1mmol) and triethylamine (3g, 30mmol) were added to acetonitrile (3.5mL), replaced with nitrogen, heated to room temperature and stirred for 15 hours, cooled, filtered through Celite, washed with ethyl acetate, and washed with water , Extraction and purification by column chromatography to obtain 2.3 g of methyl 4-methyl-3-((trimethylsilyl)ethynyl)benzoate as a colorless oil, with a yield of 93%;
  • Step 2 4-Methyl-3-((trimethylsilyl)ethynyl)benzoic acid methyl ester (2.3g) in tetrahydrofuran (10mL), methanol (10mL) and water (2mL) are added to the mixed solution of hydration Lithium hydroxide (0.6g, 15mmol), stirred at room temperature for 10 hours, extracted with ethyl acetate, adjusted the pH of the aqueous phase to 2-3, a large amount of solids precipitated out, filtered to obtain 1.3g of white solid product with a yield of 87%.
  • hydration Lithium hydroxide 0.6g, 15mmol
  • Step 1 1-methyl-4-nitro-2-trifluoromethylbenzene (10.3g, 50mmol) in carbon tetrachloride (80mL) solution was added NBS (9.7g, 55mmol) and benzyl peroxide respectively Acyl (20% humidity, 0.8g, 2.5mmol), heated to 80 degrees Celsius, reacted for 15 hours, cooled, filtered, washed with water, dried and concentrated the organic phase to obtain a pale yellow oily 1-(bromomethyl)-4-nitro-2 -(Trifluoromethyl)benzene 15g is used directly in the next step;
  • Step 2 Add 4-methylpiperazine (4g, 40mmol) and potassium carbonate to the solution of 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (6g) in acetonitrile (300mL) (8.2g, 60mmol), heated to 50 degrees Celsius and reacted for 2 hours, cooled, filtered, concentrated, and purified by column chromatography to obtain the yellow solid product 1-methyl-4-(4-nitro-2-(trifluoromethyl) Benzyl)piperazine 5.5 g, yield 92%, MS: 304 [M+H] + .
  • Step 3 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (3g, 10mmol) in methanol (60mL) was added as a catalyst by adding palladium on carbon, under hydrogen conditions The reaction was stirred for 6 hours, filtered through Celite, and concentrated to obtain 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline as a pale yellow solid product. The yield was 2.6g. 95%, MS: 274[M+H] + .
  • Step 4 4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (270mg, 1mmol), 3-ethynyl-4-methylbenzoic acid (160mg , 1mmol), HATU (400mg, 1.05mmol), triethylamine (200mg, 2mmol) in DMF (5mL) solution was stirred at room temperature for 15 hours, quenched with water, extracted with ethyl acetate, washed with saturated brine, the organic phase was dried and concentrated After purification by column chromatography, 370 mg of a white solid product was obtained, with a yield of 89%, MS: 416 [M+H] + .
  • Step 1 Add NaH (0.48g, 12mmol) to a solution of diethyl diketo acid (1.6g, 10mmol) in tetrahydrofuran (30mL). After stirring for half an hour at room temperature, add 1-(bromomethyl)-2-fluoro -4-nitrobenzene (2.3g, 10mmol) in tetrahydrofuran, stirred overnight at room temperature, quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, dried, purified by column chromatography to obtain a pale yellow oily 2-(2 -Fluoro-4-nitrobenzyl) diethyl diketonate 3.2 g, yield 95%, MS: 314[M+H] + .
  • Step 2 A solution of diethyl 2-(2-fluoro-4-nitrobenzyl)diketonate (3.2g, 10mmol) in hydrochloric acid (33%, 30mL) was heated to 100 degrees Celsius and reacted overnight, cooled and adjusted pH To 2-3, extract with ethyl acetate, dry and concentrate to obtain 1.6 g of light yellow oily 3-(2-fluoro-4-nitrophenyl) propyl acid, yield 76%, MS: 212[MH] - .
  • Step 3 3-(2-Fluoro-4-nitrophenyl)propyl acid (210mg, 1mmol) in thionyl chloride (2mL) was heated at reflux for 2 hours, cooled, concentrated, and dissolved in dry dichloromethane (2mL ), to the above solution was added dropwise a solution of dimethylamine in tetrahydrofuran (1M, 2mL), triethylamine (0.1mL), and stirred at room temperature for 3 hours to prepare a thin plate for purification to obtain a yellow solid product 3-(2-fluoro-4 -Nitrophenyl)-N,N-dimethylpropionamide 215 mg, yield 90%, MS: 241 [M+H] + .
  • Step 4 3-(2-Fluoro-4-nitrophenyl)-N,N-dimethylpropionamide (215mg, 0.9mmol) in methanol (10mL) was added with wet palladium on carbon (10% palladium content, 30mg) catalyzed and replaced the reaction system with hydrogen. The reaction was stirred at room temperature under a hydrogen atmosphere for 5 hours, filtered with Celite, and the filtrate was concentrated to obtain a pale yellow oily 3-(4-amino-2-fluorophenyl)-N,N -155 mg of dimethyl propionamide, 82% yield.
  • Step 5 3-(4-Amino-2-fluorophenyl)-N,N-dimethylpropanamide (155mg) in dry tetrahydrofuran (3mL) was added to a solution of borane in tetrahydrofuran (2M, 3mL) at room temperature Stir overnight, add methanol (5 mL), reflux for 1 hour, and concentrate to obtain 150 mg of product 4-(3-(dimethylamino)propyl)-3-fluoroaniline, which is directly used in the next step, MS: 197[M+H] + .
  • Step 6 3-ethynyl-4-methylbenzoic acid (160mg, 1mmol), HATU (380mg, 1mmol), DIEA (390mg, 3mmol), 4-(3-(dimethylamino)propyl)-3-
  • a solution of fluoroaniline (150mg) in DMF (2mL) was stirred overnight at room temperature, followed by extraction with ethyl acetate, washing with saturated brine, drying the organic phase, concentrating, and purifying by silica gel column chromatography to obtain a pale yellow solid N-(4-(3) -(Dimethylamino)propyl)-3-fluorophenyl)-3-ethynyl-4-methylbenzamide 225 mg, MS: 339 [M+H] + .
  • intermediate F13 was carried out in a similar manner to the synthesis of F12, except that 1-(bromomethyl)-3-fluoro-5-nitrobenzene was used instead of 1-(bromomethyl)-2-fluoro- 4-Nitrobenzene.
  • Step 1 Add NaH (0.48g, 12mmol) to the solution of diethyl diketo acid (1.6g, 10mmol) in tetrahydrofuran (30mL). After stirring for half an hour at room temperature, add 1-(bromomethyl)-3-fluoro -5-nitrobenzene (2.3g, 10mmol) in tetrahydrofuran, stirred overnight at room temperature, quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, dried, purified by column chromatography to obtain a pale yellow oily 2-(3 -Fluoro-5-nitrobenzyl) diethyl diketonate 3.2 g, yield 95%, MS: 314[M+H] + .
  • Step 2 A solution of diethyl 2-(3-fluoro-5-nitrobenzyl)diketonate (3.2g, 10mmol) in hydrochloric acid (33%, 30mL) is heated to 100 degrees Celsius and reacted for 10 hours. TLC detects the raw material After the reaction was completed, methanol (20mL) was added and the reaction was continued for 1 hour, cooled, potassium bicarbonate adjusted to neutral pH, extracted with ethyl acetate, dried, and concentrated to obtain a yellow oily 3-(3-fluoro-5-nitrophenyl) ) Methyl propionate 1.9g, yield 84%.
  • Step 3 Add wet palladium on carbon (55% humidity, 10% content) to a solution of methyl 3-(3-fluoro-5-nitrophenyl)propionate (250mg, 1.1mmol) in methanol (10mL). The reaction was stirred for two hours under the conditions, filtered through Celite, and concentrated to obtain 0.2 g of methyl 3-(3-amino-5-fluorophenyl)propionate as a gray oil, MS: 198 [M+H] + .
  • Step 4 Add 3-(3-amino-5-fluorophenyl)methyl propionate (0.2g) in tetrahydrofuran (1mL) to the solution of aluminum lithium hydrogen (80mg) in dry tetrahydrofuran (2mL) under ice-water bath conditions ) Solution, stirred at room temperature for 2 hours, was quenched by adding saturated sodium hydroxide solution (80 ⁇ l), dried with sodium sulfate, filtered through Celite, washed with tetrahydrofuran, and the filtrate was concentrated to obtain a light purple oily 3-(3-amino) -5-fluorophenyl)propyl-1-ol 0.16g.
  • Step 5 3-ethynyl-4-methylbenzoic acid (160mg, 1mmol), HATU (380mg, 1mmol), DIEA (390mg, 3mmol), 3-(3-amino-5-fluorophenyl)propyl-
  • a solution of 1-alcohol (160mg) in DMF (2mL) was stirred overnight at room temperature, then extracted with ethyl acetate, washed with saturated brine, the organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain a pale yellow solid 235mg, yield 75% , MS: 312[M+H] + .
  • Example 17 4-Methyl-3-((4-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine -5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
  • Example 32 3-((2-((1-(3-Fluoropropyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4- Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
  • Example 40 3-((2-((1-(2-Fluoroethyl)-5-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4- Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
  • Example 42 3-((2-((3-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N -(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
  • N-(3-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)-5-iodopyrimidin-2-amine 34mg, 0.1mmol
  • 3-ethynyl-4-methyl-N -(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide 42mg, 0.1mmol
  • Pd(PPh 3 ) 2 Cl 2 (4mg, 0.005mmol)
  • CuI (2mg, 0.01mmol
  • triethylamine 1.5mL
  • DMF 1.5mL
  • Example 48 3-((2-((1-(2-Fluoroethyl)-3-methoxy-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4 -Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
  • Example 50 4-Methyl-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-N-(4-(( 4-methylpiperazin-1-yl)methyl)phenyl)benzamide
  • Example 54 3-((2-((1-(2-Fluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N- (4-((4-Methylpiperazin-1-yl)methyl)phenyl)benzamide
  • Example 64 N-(3-Fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-((2-((1-(2-methoxyethyl Yl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methylbenzamide
  • Example 65 N-(3-Fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-((2-((1-(3-hydroxypropyl) -1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methylbenzamide
  • Example 72 N-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-((2-((1-(2-fluoroethyl) -1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methylbenzamide
  • Example 84 N-(3-(3-(dimethylamino)propyl)-5-fluorophenyl)-4-methyl-3-((2-((1-methyl-1H-pyrazole -4-yl)amino)pyrimidin-5-yl)ethynyl)benzamide
  • Example 94 4-Methyl-3-((2-((3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine -5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide
  • Example 100 3-((2-((1-(3-Hydroxy-3-methylbutyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)acetylene Yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide
  • Example 104 3-((2-((3-Methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl )Ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide
  • Example 106 3-((2-((1-(2-Methoxyethyl)-3-methoxy-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl) -4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide
  • Example 110 3-((2-((1-(3-hydroxy-3-methylbutyl)-3-methoxy-1H-pyrazol-4-yl)amino)pyrimidin-5-yl) Ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide
  • the synthesis was carried out in a method similar to that in Example 1, except that it was synthesized from 4-(4-((5-iodopyrimidin-2-yl)amino)-3-methoxy-1H-pyrazol-1-yl) -2-methylbutyl-2-ol with 3-ethynyl-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide The reaction yielded a white solid product.
  • Example 111 3-((2-((1,3-Dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3 -Fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide
  • Example 114 4-Methyl-3-((2-((3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine -5-yl)ethynyl)-N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide
  • Example 120 3-((2-((1-(3-hydroxy-3-methylbutyl)-3-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)acetylene Yl)-4-methyl-N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide
  • Example 124 N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-((2-((3-methoxy-1-( Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methylbenzamide
  • Example 126 N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-((2-((1-(2-methoxyethyl Yl)-3-methoxy-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methylbenzamide
  • Example 128 N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-((2-((1-(3-methoxypropane Yl)-3-methoxy-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methylbenzamide
  • Example 129 N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-((2-((1-(2-hydroxy-2- (Methylpropyl)-3-methoxy-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methylbenzamide
  • Example 2 The synthesis was carried out in a similar manner to Example 1, except that it was synthesized from 1-(4-((5-iodopyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropane 2-ol and 3-ethynyl-N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methylbenzamide White solid product.
  • Example 138 (R)-N-(3-Fluoro-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-3-((2-((1- (2-Methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methylbenzamide
  • Example 140 N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-3-((2-((1-methyl -1H-pyrazol-3-yl)amino)pyrimidin-5-yl)ethynyl)benzamide
  • Example 145 4-Methyl-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-N-(3-methyl -4-((4-Methylpiperazin-1-yl)methyl)phenyl)benzamide
  • Example 2 The synthesis was carried out in a similar manner to Example 1, except that it was synthesized from 1-(4-((5-iodopyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropane -2-ol and 3-ethynyl-N-(3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methylbenzamide White solid product.
  • Example 150 3-((2-((1-Butyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3-methyl -4-((4-Methylpiperazin-1-yl)methyl)phenyl)benzamide
  • Example 151 4-Methyl-N-(3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-((2-((1-pentyl) -1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)benzamide
  • test compounds of different concentrations are added to detect the inhibitory effects of the compounds on the enzymatic reactions of ABL, ABL-T315I, and KIT.
  • the specific test methods are as follows:
  • ABL ABL-T315I
  • KIT kinase screening bodies the experimental conditions of ABL, ABL-T315I, and KIT kinase screening bodies are shown in the appendix, and the complete ABL-T315I and KIT kinase can be obtained by fine-tuning according to the ABL experimental protocol. Screening experimental protocol.
  • EDTA (0.5M pH8.0) solution preparation accurately weigh 14.612g EDTA powder, add ultrapure water and dilute to 100mL (if insoluble, heat to 37°C, adjust the pH to 8.0 with NaOH solution)
  • 1 ⁇ Kinase Assay Buffer Add 25mL HEPES solution (1M), 190.175mg EGTA, 5mL MgCl 2 solution (1M), 1mL DTT, 50 ⁇ L Tween-20 into the reagent bottle, and add ultrapure water to make the volume to 500mL (adjust pH To 7.5).
  • 1 ⁇ Detection Buffer Take 1mL 10 ⁇ Detection Buffer and add 9mL water to mix.
  • 4 ⁇ stop solution mix 0.8 mL of the above EDTA (0.5M, pH 8.0) solution, 1 mL 10 ⁇ Detection Buffer and 8.2 mL ultrapure water.
  • 4 ⁇ ABL kinase solution Dilute the kinase stock solution with 1 ⁇ Kinase Assay Buffer to a concentration of 0.62nM, mix well, and store on ice.
  • 4 ⁇ Substrate solution Dilute the substrate ULight TM PolyGT stock solution to 200nM with 1 ⁇ Kinase Assay Buffer, and mix well.
  • 4 ⁇ ATP solution Dilute the ATP stock solution with 1 ⁇ Kinase Assay Buffer to a concentration of 40 ⁇ M, and mix.
  • 4 ⁇ Detection solution Dilute the detection antibody Eu-W1024-labeled Anti-Phosphotyrosine Antibody (PT66) with 1 ⁇ Detection Buffer to a concentration of 8nM, and mix.
  • 2 ⁇ Substrate/ATP mixture Mix the 4 ⁇ substrate solution and 4 ⁇ ATP solution 1:1 in equal amounts (prepared before use).
  • the compound solution diluted with ultrapure water in the above 96-well plate b is transferred to the corresponding well of the 384-well plate according to the standard two-well turntable.
  • Add 2 ⁇ substrate/ATP mixture take 5 ⁇ l of the above 2 ⁇ substrate/ATP mixture into the corresponding reaction wells of 384-well plate with a discharge gun.
  • Negative control set negative control wells in a 384-well plate, add 2.5 ⁇ l 4 ⁇ substrate, 2.5 ⁇ l 4 ⁇ enzyme solution, 2.5 ⁇ l 1 ⁇ Kinase Assay Buffer and 2.5 ⁇ l ultrapure water containing 16% DMSO to each well .
  • Inhibition rate [1-(reading value of experimental well-reading value of negative control well)/(reading value of positive control well-reading value of negative control well)]*100%
  • the corresponding drug concentration and inhibition rate of the input processing GraphPad Prism 5 calculates the corresponding IC 50.
  • the final concentration of ABL kinase in the reaction system is 0.155 nM, the final concentration of ATP is 10 ⁇ M, the final concentration of substrate ULight TM -labeled PolyGT is 50 nM, and the enzymatic reaction time is 2 hours.
  • the highest final concentration of the compound in the reaction system was 2.5 ⁇ M, and a total of 11 concentrations after 3-fold gradient dilution, the lowest final concentration was 0.042 nM.
  • the final concentration of DMSO is 4%.
  • the final concentration of ABL (T315I) kinase in the reaction system is 0.5 nM, the final concentration of ATP is 10 ⁇ M, the final concentration of substrate ULight TM -labeled PolyGT is 50 nM, and the enzymatic reaction time is 2 hours.
  • the highest final concentration of the compound in the reaction system was 2.5 ⁇ M, and a total of 11 concentrations after 3-fold gradient dilution, the lowest final concentration was 0.042 nM.
  • the final concentration of DMSO is 1%.
  • the final concentration of KIT kinase is 0.1 nM
  • the final concentration of ATP is 1 ⁇ M
  • the final concentration of substrate ULight TM -labeled PolyGT is 100 nM
  • the enzymatic reaction time is 2 hours.
  • the highest final concentration of the compound in the reaction system was 2.5 ⁇ M, and a total of 11 concentrations after 3-fold gradient dilution, the lowest final concentration was 0.042 nM.
  • the final concentration of DMSO is 1%.
  • test method is as follows:
  • Negative control add 2.5 ⁇ L/well of 4X substrate/ATP mixture and 7.5 ⁇ L 1X Kinase Assay Buffe to the wells of the 384-well plate.
  • Positive control add 2.5 ⁇ L/well of 4X substrate/ATP mixture to 384-well plate, 2.5 ⁇ L/well of 1X Kinase Assay Buffer containing 16% DMSO, and 5 ⁇ L/well of 2X VEGFR2 kinase solution.
  • the final concentration of DMSO in the reaction system is 4%.
  • Terminate the enzymatic reaction Use a discharge gun to take 5 ⁇ L 4X stop solution into the wells of the 384-well plate, centrifuge to mix, and react at room temperature for 5 minutes.
  • Color reaction Take 5 ⁇ L 4X detection solution with a row gun and add it to the wells of a 384-well plate for color development, centrifuge and mix, and react at room temperature for 60 minutes.
  • Inhibition rate (%) (reading value of positive well-reading value of experimental well)/(reading value of positive control well-reading value of negative control well) ⁇ 100%.
  • IC 50 value the compound concentration at which the enzyme's highest inhibition rate is 50%
  • NT indicates No correlation value.
  • Different concentrations of the test compound are added to the cell culture solution, and the IC50 of the test compound on the proliferation of the target cell is compared to test the in vitro inhibitory effect of the test compound on the target cell.
  • Compound dilution Dissolve all compounds in DMSO to prepare a 10mM stock solution, complete the first serial dilution of the test compound in DMSO, the dilution factor is 3 or 4 times; complete the 80-fold overall dilution of all compounds in the cell culture medium , The resulting compound is a 5 ⁇ compound, which will be added to the wells of a 96-well plate containing cells, so that the final cell culture solution is 1 ⁇ the designed final concentration.
  • the test of the compound is generally designed with 9 concentration gradients, of which the highest final concentration is 25000 nM, the lowest concentration after 4-fold dilution of 9 concentrations is 0.38 nM, and the final concentration of DMSO in all wells is 0.25%.
  • results of the determination of the compounds of the present invention inhibiting the proliferation of K562 and BaF3-BCR-ABL-T315I cells are shown in Table 8, where A means IC 50 is less than or equal to 10 nM, B means IC 50 is greater than 10 nM but less than or equal to 100 nM, and C means IC 50 is greater than but less than or equal to 100nM 1000nM, D represents the IC 50 is greater than 1000nM.
  • the biological data provided by the present invention shows that the compounds of the present invention are beneficial to the treatment or prevention of diseases caused by abnormal kinases such as ABL, ABL-T315I, KIT, and VEGFR-2. Therefore, the compounds of the present invention are beneficial for the treatment of cancers, including primary and metastatic cancers, including solid tumors.
  • Such cancers include but are not limited to: non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membranous cancer, prostate cancer, bladder cancer, leukemia, stomach cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain Tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary carcinosarcoma, cholangiocarcinoma.
  • the compounds of the invention also include the treatment of cancers resistant to one or more other treatment methods.
  • the compounds of the present invention can also be used for other diseases related to VEGFR-2, RET and/or c-MET kinases besides cancer, including but not limited to fundus diseases, psoriasis, rheumatoid arthritis, atheroma, Pulmonary fibrosis, liver fibrosis.
  • the compound of the present invention can be used as monotherapy or combination therapy, and can be used in combination with multiple compounds of the present invention or in combination with other drugs other than the present invention.

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Abstract

式(I)的炔基嘧啶或炔基吡啶类化合物或其药学可接受的盐、异构体、溶剂化物、结晶或前药，以及含有这些化合物的药物组合物和这些化合物或组合物在药物制备中的应用，所述药物可以作为ABL、ABL-T315I、KIT及VEGFR-2等激酶抑制剂用于治疗相关的疾病。

Description

炔基嘧啶或炔基吡啶类化合物、及其组合物与应用 技术领域
本发明涉及化学医药领域。更具体涉及一类具有ABL、ABL-T315I、KIT及VEGFR-2等激酶抑制活性的炔基嘧啶或炔基吡啶类化合物或其药学上可接受的盐、异构体、溶剂合物、晶型或前药，以及含有这些化合物的药物组合物和这些化合物或组合物在药物制备中的应用。
背景技术
肿瘤是机体在各类致癌因子的作用下，细胞发生异常信号转导，部分组织的某个细胞失去对其正常生长的调控，导致细胞凋亡的失调和细胞的持续增殖，进而导致新生物克隆性增长而形成。肿瘤细胞在遗失正常的生长调节功能后，拥有自主的生长能力，并且致癌因子停止生长后，肿瘤仍然能够持续生长。临床上可将肿瘤分为实体瘤和非实体瘤，实体瘤即有形瘤通过手术切除、化疗等方法进行治疗，而非实体瘤主要是用化学药物来杀死癌细胞，但是这些化学药物副作用较大，体内的细胞无论是否为恶性肿瘤细胞，都会受到破坏。
白血病是恶性肿瘤之一，属于非实体瘤，其在儿科恶性肿瘤的发病率中排首位。根据白血病细胞的自然病程，可将其分为急性白血病和慢性白血病两大类。其中慢性白血病又可分为慢性粒细胞性白血病(Chronic Myelogenous Leukemia,CML)和慢性淋巴细胞性白血病(Chronic Lymphocytic Leukemia,CLL)。慢性粒细胞白血病占所有白血病的20％左右，发病于全部年龄人群。
目前，选择性作用于特定靶点的低毒和特异性强的新型抗癌药物已经成为抗肿瘤药物研究的新方向，慢性粒细胞白血病(CML)患者中，22号染色体长臂易位至9号染色体，形成费城染色体，并导致BCR基因和ABL基因融合形成BCR-ABL融合基因，表达BCR-ABL蛋白酪氨酸激酶，该激酶能引起细胞增殖、黏附和生存性质的改变，导致多种肿瘤的产生。BCR-ABL在正常细胞中不表达，所以它是治疗慢性粒细胞白血病理想的药物靶标。
目前临床上最常用的针对BCR-ABL酪氨酸激酶小分子抑制剂包括：第一代药物伊马替尼；第二代药物达沙替尼、尼洛替尼和伯舒替尼；第三代药物普纳替尼。酪氨酸激酶抑制剂主要通过抑制BCR-ABL融合蛋白的活性，从而发挥抗慢性粒细胞白血病的作用。
伊马替尼(Imatinib)是由诺华公司研制的小分子BCR-ABL酪氨酸激酶抑制剂，于2001年被FDA批准用来治疗于CML。这是首个治疗CML的酪氨酸激酶抑制剂，它可以通过靶向肿瘤细胞特定的受损基因来治疗癌症。与其它治疗药物相比，伊马替尼可以有效的缓解慢性粒细胞白血病，治疗后患者5年存活率可达90％。它伊马替尼的一个显著特点是它能够特异性的抑制慢性粒细胞白血病癌细胞的增殖，对正常细胞则几乎没有伤害，这大大降低了药物的毒副作用。伊马替尼开创了以激酶为靶标治疗疾 病的新时代。
耐药性的出现在很大程度上降低了伊马替尼的治疗效果。伊马替尼出现耐药性的主要原因是BCR-ABL基因发生了包括L248V、E255V、Y253H、E355G、E255K、T315I、F359V、M253H、G250E、F317L、H396P、M351T、Q252H等突变，由于ABL激酶的点突变，降低了Imatinib和ABL激酶之间的亲和力，导致其治疗效果明显下降。
第二代Bcr-Abl酪氨酸激酶抑制剂尼洛替尼(Nilotinib)是一种苯胺嘧啶类衍生物，于2007年10月获得美国FDA批准上市用来治疗CML。它对Bcr-Abl酪氨酸激酶的亲和力比Imatinib强20倍。Nilotinib可以抑制除T315I突变以外的Imatinib耐药的突变。但使用Nilotinib治疗的CML的患者大多数存在脂肪酶和胆红素升高、轻中度皮疹、骨髓抑制、胃肠道反应等常见的不良反应。
达沙替尼(Dasatinib)也是第二代Bcr-Abl酪氨酸激酶抑制剂，它是一种对多种激酶都有抑制作用的口服激酶抑制剂，其对BCR-ABL激酶和SRC家族激酶(SRC激酶是抗肿瘤药物作用的一个靶点)都有很好的抑制效果。达沙替尼于2006年6月获得FDA批准上市用来治疗CML患者。达沙替尼较伊马替尼特异性结构要求少，它能够克服多种伊马替尼出现的耐药性(除T315I突变)。达沙替尼经口服后迅速被吸收，在0.5-3h内达到最大血药浓度，其平均半衰期为5-6h。患者服用达沙替尼后的主要不良反应表现在骨髓抑制和中性白细胞增多。
伯舒替尼(Bosutinib)是由美国惠氏制药公司研发的4-取代苯胺-3-喹啉甲腈类治疗CML的新药，2012年9月被FDA批准上市，主要是针对伊马替尼、尼罗替尼和达沙替尼治疗失败的CML患者的激酶抑制剂。伯舒替尼对KU812和K562两种细胞的抗增殖活性(IC 50)分别为20nM和5nM，而伊马替尼对KU812和K562细胞的抗增殖活性分别为210nM和88nM。但伯舒替尼同样对T315I突变没有抑制效果。服用伯舒替尼的患者出现的不良反应主要包括:恶心、呕吐、腹痛、腹泻、皮疹、肝酶水平升高、血小板减少及贫血和疲劳。
第二代治疗CML药物Dasatinib、Nilotinib和Bosutinib对Imatinib耐药和不能耐受的患者存在广泛的活性，但是都对BCR-ABL T315I激酶突变没有抑制活性。
尽管以蛋白酪氨酸激酶为靶标的小分子药物用于治疗慢性粒细胞性白血病取得了很大的成功，由于耐药性的出现在很大程度上限制了它使用。目前己鉴定出17种在该激酶区上的突变，其中包括6种己知的伊马替尼耐药性突变(M244V、Y253H、F359C/V/I、G250E、E255K和T315I)和11种新增的突变(K247N、E282K、K285N、V289L、L273F、E292K、N297T、H375P、T406I、W430L和E431G)。由于第二代BCR-ABL酪氨酸激酶抑制剂耐药性的出现，开发出新型BCR-ABL酪氨酸激酶抑制剂是很有必要的。
第三代BCR-ABL酪氨酸激酶抑制剂普纳替尼(Ponatinib)是一种口服型多靶点激酶抑制剂。其主要是用来克服BCR-ABL T315I同时要求对野生型的BCR-ABL也有很好的抑制效果。Ponatinib可抑制含T315I突变在内的BCR-ABL激酶活性，根据文献(Rabindran SK,et al.Cancer Res,2004,64(11),3958-3965)的记载，普纳替尼对野生型BCR-ABL激酶和BCR-ABL T315I激酶的结合模式仅有微小的差别，其对野生型BCR-ABL激酶的抑制活性(IC 50)是BCR-ABL T315I抑制活性(IC 50)的5-7倍。服用Ponatinib的患者会出现严重不良血管事件，包括致命性和危及生命的心肌梗死、卒中、肢体血流中断致组织坏死 等。其严重的副作用限制了该药物的临床应用。
发明内容
本发明所提供式(I)表示的化合物，其药学上可接受的盐，异构体，水合物，溶剂化物，或前药，其可用作治疗或预防由酪氨酸激酶(例如ABL、ABL-T315I、KIT及VEGFR-2)引起的疾病。
Figure PCTCN2020073018-appb-000001
式(I)中，
Q为CH或者N；
L、Z、G各自独立地为选自N、NR 4、O、S或CR 4，且至少有一个不为CR 4；
R 1为氢、卤素、C 1-C 3烷基、卤代C 1-C 3烷基；
R 2为-(CH 2)n-R 6，R 6为氢、C 1-C 6烷基、C 3-C 6环烷基、羟基、卤代C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、-NR aR b、或者任选地被1至3个选自卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、羟基、-NR aR b、C 1-C 3酰基、羟基C 1-C 3烷基、C 1-C 3烷氧基C 1-C 3烷基、氧代中的取代基所取代或者未取代的4-8元杂脂环基，n为0至6的整数；
R 3为氢、C 1-C 3烷基、卤素；
R 4为氢，或由1至3个选自C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的C 3-C 8环烷基，或由1至3个选自C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、氰基、-CONH 2、C 3-C 7环烷基或-NR aR b的取代基所取代或者非取代的C 1-C 9烷基，或者-(CH 2)m-R 7，R 7为任选地被1至3个选自卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、羟基、-NR aR b、C 1-C 3酰基、羟基C 1-C 3烷基、C 1-C 3烷氧基C 1-C 3烷基、氧代中的取代基所取代或者未取代的4-8元杂脂环基，m为0至3的整数；
R 5为氢、C 1-C 3烷基、C 1-C 3烷氧基、氰基、C 3-C 6环烷基、氟、羟基、氯；
所述取代或者未取代的4-8元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-8元杂脂环基，
R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基C 1-C 6烷基、C 1-C 3烷硫基C 1-C 6烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基。
在一些优选的实施方案中，Q为N；L、G为N原子且Z为CH。
在一些优选的实施方案中，R 1为氢、三氟甲基、氟、氯、甲基。
在一些优选的实施方案中，R 2为-(CH 2)n-R 6，R 6为氢、C 1-C 3烷基、C 3-C 6环烷基、羟基、卤代C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、-NR aR b、或者任选地被1至3个选自卤素、C 1-C 3烷基、卤代C 1- C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、羟基、-NR aR b、C 1-C 3酰基、羟基C 1-C 3烷基、C 1-C 3烷氧基C 1-C 3烷基、氧代中的取代基所取代或者未取代的4-6元杂脂环基，n为0至3的整数，
所述4-6元杂脂环基为哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、吡喃基，
R a和R b各自独立地为氢、C 1-C 3烷基、C 3-C 6环烷基、C 1-C 3烷氧基取代的C 1-C 3烷基。
更优选地，R 6为氢、甲氧基、乙氧基、丙氧基、异丙氧基、甲基氨基、乙基氨基、丙基氨基、二甲氨基、二乙氨基、二丙氨基、羟甲基氨基、羟乙基氨基、羟丙基氨基、甲氧基乙基氨基、甲氧基丙基氨基、二羟甲基氨基、二羟乙基氨基、二羟丙基氨基、二甲氧基乙基氨基、二甲氧基丙基氨基、N-甲基-N-羟乙基氨基、N-甲基-N-羟丙基氨基、N-乙基-N-羟乙基氨基、N-乙基-N-羟丙基氨基、N-甲基-N-乙基氨基、N-甲基-N-丙基氨基、N-甲基-N-甲氧基乙基氨基、N-甲基-N-甲氧基丙基氨基、N-乙基-N-甲氧基乙基氨基、N-乙基-N-甲氧基丙基氨基、羟基、甲基、乙基、丙基、异丙基、1-甲基哌嗪-4-基、1-乙基哌嗪-4-基、1-丙基哌嗪-4-基、1-异丙基哌嗪-4-基、1-羟甲基哌嗪-4-基、1-羟乙基哌嗪-4-基、1-羟丙基哌嗪-4-基、(R)-3-(二甲氨基)吡咯烷-1-基、(S)-3-(二甲氨基)吡咯烷-1-基、(R)-3-(二乙氨基)吡咯烷-1-基、(S)-3-(二乙氨基)吡咯烷-1-基、(R)-3-(二丙氨基)吡咯烷-1-基、(S)-3-(二丙氨基)吡咯烷-1-基、(R)-3-(甲基乙基氨基)吡咯烷-1-基、(S)-3-(甲基乙基氨基)吡咯烷-1-基、(R)-3-(甲基丙基氨基)吡咯烷-1-基、(S)-3-(甲基丙基氨基)吡咯烷-1-基、(R)-3-(乙基丙基氨基)吡咯烷-1-基、(S)-3-(乙基丙基氨基)吡咯烷-1-基、(R)-3-(二羟甲氨基)吡咯烷-1-基、(S)-3-(二羟甲氨基)吡咯烷-1-基、(R)-3-(二羟乙氨基)吡咯烷-1-基、(S)-3-(二羟乙氨基)吡咯烷-1-基、(R)-3-(二羟丙氨基)吡咯烷-1-基、(S)-3-(二羟丙氨基)吡咯烷-1-基、(R)-3-(羟甲基乙基氨基)吡咯烷-1-基、(S)-3-(羟甲基乙基氨基)吡咯烷-1-基、(R)-3-(羟甲基丙基氨基)吡咯烷-1-基、(S)-3-(羟甲基丙基氨基)吡咯烷-1-基、(R)-3-(羟乙基丙基氨基)吡咯烷-1-基、(S)-3-(羟乙基丙基氨基)吡咯烷-1-基、(R)-3-(甲基羟乙基氨基)吡咯烷-1-基、(S)-3-(甲基羟乙基氨基)吡咯烷-1-基、(R)-3-(甲基羟丙基氨基)吡咯烷-1-基、(S)-3-(甲基羟丙基氨基)吡咯烷-1-基、(R)-3-(乙基羟丙基氨基)吡咯烷-1-基、(S)-3-(乙基羟丙基氨基)吡咯烷-1-基、吡咯烷-1-基、哌啶-1-基、吗啉基、硫代吗啉基。
在一些优选的实施方案中，R 3为-H、甲基、氟、氯。
在一些优选的实施方案中，R 4为氢，C 3-C 8环烷基，或由1至3个选自C 1-C 3烷氧基、C 1-C 3烷硫基、C 1-C 3酰基、羟基、氟、氯、氰基、-CONH 2、C 3-C 6环烷基或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，或者-(CH 2)m-R 7，R 7为任选地被1至3个选自卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、羟基、-NR aR b、C 1-C 3酰基、羟基C 1-C 3烷基、C 1-C 3烷氧基C 1-C 3烷基、氧代中的取代基所取代或者未取代的4-6元杂脂环基，m为0至3的整数；
所述4-6元杂脂环基为哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、吡喃基，
R a和R b各自独立地为氢、C 1-C 3烷基、C 3-C 6环烷基、C 1-C 3烷氧基取代的C 1-C 3烷基。
更优选地，R 4为选自氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、 甲氧基戊基、甲氧基己基、羟基乙基、羟基丙基、氟代乙基、氟代丙基、氰基甲基、氰基乙基、2-甲基-2-羟基丙基、3-甲基-3-羟基丁基、甲硫基乙基、甲硫基丙基、二甲氨基乙基、二甲氨基丙基、二甲氨基丁基、二甲氨基戊基、二甲氨基己基、二乙氨基乙基、二乙氨基丙基、羟乙基氨基乙基、羟丙基氨基乙基、羟乙基氨基丙基、甲氧基乙基氨基乙基、甲氧基丙基氨基乙基、甲氧基乙基氨基丙基、氨基乙基、氨基丙基、氨基丁基、N-甲基-N-羟乙基氨基乙基、N-甲基-N-羟丙基氨基乙基、N-甲基-N-羟乙基氨基丙基、N-甲基-N-甲氧基乙基氨基乙基、N-甲基-N-甲氧基丙基氨基乙基、N-甲基-N-甲氧基乙基氨基丙基、(3S)-3-氨基丁基、(3R)-3-氨基丁基、(3S)-3-羟基丁基或(3R)-3-羟基丁基、氧杂环丁烷-3-基、四氢呋喃-3-基、四氢-2H-吡喃-4-基、吡咯烷基、哌啶-1-基、哌嗪-1-基、吗啉-4-基、甲基哌嗪-4-基、1-甲基哌啶-4-基。
在一些优选的实施方案中，R 5为氢、甲基、甲氧基、氰基、环丙基、氟。
根据本申请的一些实施方案，所述化合物的药学上可接受的盐为选自所述化合物的盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、羟基乙酸盐、乳酸盐、琥珀酸盐、马来酸盐、酒石酸盐、苹果酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、安息香酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、棕榈酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己氨基磺酸盐、水杨酸盐、己糖酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱盐、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐中的一种或多种。
本发明的另一方面涉及所述式(I)的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药在制备治疗与ABL、ABL-T315I、KIT及VEGFR-2等激酶相关疾病的药物中的应用，其中，所述与ABL、ABL-T315I、KIT及VEGFR-2等激酶相关的疾病包括眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
本发明的又一方面提供了一种药物组合物，该药物组合物包括本申请的式(I)化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，以及一种或多种药学上可接受的载体或赋形剂。
根据本申请的一些实施方案，该药物组合物还可以包括一种或多种其他治疗剂。
本发明还涉及一种治疗ABL、ABL-T315I、KIT及VEGFR-2等激酶介导的疾病或病症的方法，其包括对有需要的患者(人或其他哺乳动物，尤其是人)给药治疗有效量的式(I)化合物或其盐，所述ABL、ABL-T315I、KIT及VEGFR-2等激酶介导的疾病或病症包括前述提及的那些。
具体实施方式
除非另有说明，在本申请(包括说明书和权利要求书)中使用的以下术语具有下面给出的定义。在本申请中，除非另外说明，使用“或”或“和”意味着“和/或”。此外，术语“包括”以及其它形式的使用，例如 “包含”、“含有”和“具有”，不是限制性的。本文使用的章节标题仅仅是为了组织的目的，而不应解释为对所述的主题的限制。
发明详述
除非有特殊说明，烷基表示具有指定数目碳原子的饱和直链、支链烃基，术语C 1-C 10烷基表示含有1至10个碳原子的烷基部分，同理C 1-C 3烷基表示含有1至3个碳原子的烷基部分，比如，C 1-C 6烷基包括甲基、乙基、丙基、异丙基、n-丁基、异丁基、仲-丁基、叔-丁基、n-戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、n-己基、2-己基和2-甲基戊基等。
当取代基术语例如“烷基”与其它取代基术语组合使用时，例如在术语“C 1-C 3烷氧基C 1-C 6烷硫基”或“羟基取代C 1-C 10烷基”中，该连接取代基术语(例如烷基或烷硫基)旨在包含二价的部分，其中连接点通过所述连接取代基。“C 1-C 3烷氧基C 1-C 6烷硫基”的实例包括但不限于甲氧基甲硫基、甲氧基乙硫基和乙氧基丙硫基等。“羟基取代C 1-C 10烷基”的实例包括但不限于羟基甲基、羟基乙基和羟基异丙基等。
烷氧基由先前描述的直链或支链烷基与-O-形成的烷基-O-基团，例如，甲氧基、乙氧基等等。类似的，烷硫基由先前描述的直链或支链烷基与-S-形成的烷基-S-基团，例如，甲硫基，乙硫基等等。
烯基和炔基包括直链、支链烯基或炔基，术语C 2-C 6烯基或者C 2-C 6炔基表示具有至少一个烯基或炔基的直链或支链烃基。
术语“卤代烷基”，例如“卤代C 1-C 10烷基”表示在包括1到10个碳原子的烷基部分的一个或多个碳原子上具有一个或多个可以相同或不同的卤素原子的基团。“卤代C 1-C 10烷基”的实例可以包括但不限于-CF 3(三氟甲基)、-CCl 3(三氯甲基)、1,1-二氟乙基、2,2,2-三氟乙基和六氟异丙基等。类似的，术语“卤代C 1-C 10烷氧基”表示由所述的卤代C 1-C 10烷基与-O-形成的卤代烷基-O-基团，可以为例如三氟甲氧基、三氯甲氧基等等。
术语“C 1-C 3酰基”包括甲酰基(-CHO)、乙酰基(CH 3CO-)、乙酰基(C 2H 5CO-)。
“环烷基”表示含有指定数目碳原子的非芳香的、饱和的、环状的烃基。例如，术语“(C3-C6)环烷基”指的是具有3-6个环碳原子的非芳香的环状烃环。示例性的“(C3-C6)环烷基”包括环丙基、环丁基、环戊基和环己基。
术语“芳基”表示包含芳香的单环或双环烃原子团的基团或部分，其含有6到12个碳环原子且具有至少一个芳香环。“芳基”的实例为苯基、萘基、茚基和二氢茚基(茚满基)。通常，在本发明化合物中，芳基为苯基。
在这里使用的术语“杂脂环基”，除非有特殊说明，代表未被取代的或已被取代的稳定的4至8元非芳香的单环饱和环体系，它们由碳原子以及从N，O，S中选的1至3个杂原子组成，其中N，S杂原子可以被随意氧化，N杂原子还可以被随意季铵化。这类杂环的例子包括但不限于氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、吡咯啉基、吡唑烷基、吡唑啉基、咪唑烷基、咪唑啉基、噁唑啉基、噻唑啉基、四氢呋喃基、二氢呋喃基、四氢噻吩基、1,3-二氧杂环戊烷基、哌啶基、哌嗪基、四氢吡喃基、二氢吡喃基、四氢噻喃基、1,3-二噁烷基、1,4-二噁烷基、1,3-氧硫杂环戊烷基、1,3-氧硫杂环己烷基、1,3-二噻烷基、1,4-氧硫杂环戊烷基、1,4-氧硫杂环己烷基、1,4-二噻烷基、吗啉基、硫吗啉基。
在这里使用的术语“杂芳基”表示包含芳香的单环或双环原子团(其含有5到10个环原子)的基团或部分，其包括1到3个独立地选自氮、氧和硫的杂原子。该术语还包括双环杂环芳基，其中含有与杂环烷基环部分稠合的芳基环部分，或者含有与环烷基环部分稠合的杂芳基环部分。除非有特别说明，代表未被取代或已被取代的稳定的5或6元单环芳香环体系，也可以代表未被取代或已被取代的9或 10个环原子的苯稠杂芳环体系或二环杂芳环体系，它们由碳原子和由1至3个从N，O，S中选择的杂原子组成，其中N、S杂原子可以被氧化，N杂原子还可以被季铵化。杂芳基可以和任何杂原子或碳原子连接组成一个稳定的结构。杂芳基的示例性实例包括但不限于呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、异噻唑基、吡啶基、氧代-吡啶基(吡啶基-N-氧化物)、哒嗪基、吡嗪基、嘧啶基、三嗪基、苯并呋喃基、异苯并呋喃基、2,3-二氢苯并呋喃基、1,3-苯并二氧杂环戊烯基、二氢苯并二氧杂环己烯基、苯并噻吩基、吲嗪基、吲哚基、异吲哚基、二氢吲哚基、苯并咪唑基、二氢苯并咪唑基、苯并噁唑基、二氢苯并噁唑基、苯并噻唑基、苯并异噻唑基、二氢苯并异噻唑基、吲唑基、咪唑并吡啶基、吡唑并吡啶基、苯并三唑基、三唑并吡啶基、嘌呤基、喹啉基、四氢喹啉基、异喹啉基、四氢异喹啉基、喹喔啉基、噌啉基、酞嗪基、喹唑啉基、1,5-二氮杂萘基、1,6-二氮杂萘基、1,7-二氮杂萘基、1,8-二氮杂萘基和蝶啶基。
术语“羰基”指的是-C(O)-基。术语“卤素”和“卤”表示氯、氟、溴或碘取代基。“氧代”表示双键的氧部分；例如，如果直接连接到碳原子上形成一个羰基部分(C＝O)。“羟基”旨在表示-OH原子团。本文所用术语“氰基”是指基团-CN。
术语“各自独立地”是指当一个以上的取代基选自许多可能的取代基时，那些取代基可以相同或不同。
很清楚，式I的化合物、异构体、晶型或前药及其可药用盐可以存在溶剂化形式和非溶剂化形式。例如溶剂化形式可以是水溶形式。本发明包括所有这些溶剂化的和未溶剂化的形式。
本发明的化合物可能有不对称的碳原子，根据它们的理化差异，通过已知技术上已成熟的方法，比如，通过色谱或分步结晶法，这种非对映异构的混合物可以被分离成单一的非对映异构体。对映异构体的分离可通过先用适当有旋光活性的化合物进行反应，把对映异构的混合物转化成非对映异构的混合物，分离非对映异构体，再把单一非对映异构体转化(水解)成相应的纯的对映异构体。所有这样的异构体，包括非对映异构体混合物和纯对映体被认为是该发明的一部分。
作为活性成分的本发明的化合物，以及制备该化合物的方法，都是本发明的内容。而且，一些化合物的晶型形式可以作为多晶体存在，这种形式也可以被包括在目前的发明里。另外，一些化合物可以和水(即水合物)或普通的有机溶剂一起形成溶剂化物，这种溶剂化物也被包括在此项发明的范畴内。
本发明的化合物可以以游离的形式用于治疗，或者在适当情况下以药学上可接受的盐或其它衍生物的形式用于治疗。如本文所用，术语“药学上可接受的盐”是指本发明的化合物的有机盐及无机盐，此盐适用于人类和低等动物，无过度毒性、刺激性、过敏反应等，具有合理的利益/风险比。胺，羧酸，膦酸盐，和其它类型的化合物的药学上可接受的盐在所属领域中是众所周知的。该盐可以由本发明的化合物与合适的游离碱或酸反应而成。包括但不限于，与无机酸如盐酸、氢溴酸、磷酸、硫酸、高氯酸或与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸形成的盐，或通过使用本领域熟知的方法，例如离子交换法，来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、过3-苯基丙酸盐、磷酸盐、苦味酸盐、丙酸盐、硬脂酸盐、硫酸盐、硫氰酸盐、对 甲苯磺酸盐、十一烷酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。其他药学上可接受的盐包括适当的无毒的铵、季铵，和使用诸如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根，低级烷基磺酸盐和芳基磺酸盐形成的胺基阳离子。
另外，本文所用术语“前药”是指一个化合物在体内可以转化为本发明式(I)所示的化合物。此转化受前体药物在血液中水解或在血液或组织中经酶转化为母体化合物的影响。
本发明的药物组合物包含本文所述结构式(I)化合物或其药学上可接受的盐、激酶抑制剂(小分子，多肽，抗体等)、免疫抑制剂、抗癌药、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物的另外的活性剂；以及任何药学上可接受的载体、佐剂或赋形剂。
本发明的化合物可以作为单独使用，也可以与一种或多种其它本发明的化合物或与一种或多种其它药剂联合使用。当联合给药时，治疗剂可以配制成同时给药或顺序地在不同的时间给药，或者所述治疗剂可以作为单一组合物给药。所谓“组合疗法”，指的是使用本发明的化合物与另一种药剂一起使用，给药方式为每种药剂同时共同给药或每种药剂顺序给药，无论哪种情况，目的都是要达到药物的最佳效果。共同给药包括同时递送剂型，以及每种化合物分别的单独剂型。因此，本发明的化合物的给药可以与已知的本领域的其他疗法同时使用，例如，在癌症治疗中使用放射治疗或细胞生长抑制剂、细胞毒性剂、其它抗癌剂等附加疗法来改善癌症状。本发明并不限于给药的顺序；本发明的化合物可以先前施用，同时施用，或在其他抗癌剂或细胞毒性剂之后施用。
为了制备这一发明的药学成分，作为其活性成分的分子式(I)的一种或多种化合物或盐类可紧密的与药学载体混合在一起，这是根据传统的制药配料技术而进行的，其中的载体可根据按不同的给药方式(例如，口服或肠外给药)设计好的制备形式而采用多种多样的形式。适当的药学上可接受的载体在技术上是众所周知的。对一些这类药学可接受的载体的描述可以在《药学赋形剂手册》里找到，该书由美国药学会和英国药学社联合出版。
本发明药物组合物可以有以下形式，比如说，适合口服给药，例如药片，胶囊，药丸，药粉，持续释放的形式，溶液或悬浮液；用于胃肠外注射如透明液，悬浮液，乳状液；或者用于局部用药如膏，霜；亦或作为栓剂用于直肠给药。药学成分也可以单位剂量的形式适合用于精确剂量的一次性给药。该药学成分将包括一种传统的药学载体或赋形剂以及根据目前的发明制成的作为活性成分的化合物，另外，也可以包括其他的医学或药学制剂，载体，辅助剂，等等。
治疗性化合物也可给于哺乳动物而非人类。给一个哺乳动物所用的药物剂量将取决于该动物的种类以及它的疾病状况或其所处的失调状态。治疗性化合物可以以胶囊，大丸药，药片药水的形式喂给动物。也可以通过注射或灌输的方式让治疗性化合物进入动物体内。我们根据符合兽医实践标准的传统的方式制备好这些药物形式。作为一种可选择的方式，药学合成药可以同动物饲料混合在一起喂给动物，因此，浓缩的饲料添加剂或预拌和料可以备以混合普通的动物饲料。
本发明的又一目的是在于提供一种用于治疗有需要的受试者中癌症的方法，其包括给受试者施用含本发明的化合物的组合物的治疗有效量的一种方法。
本发明还包括本发明的化合物或其药学上可接受的衍生物的使用，制造用于治疗癌症(包括非实体瘤、实体瘤、原发性或转移性癌症，如本文别处所指出和包括癌症具有抗性或难治的一种或多种其它治疗)以及其它疾病(包括但不限于眼底疾病、银屑病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化等)的药剂。所述癌症包括但不限于：非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母 细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌中的任一种。
本发明还提供了制备相应化合物的方法，可以使用多种合成方法制备本文所述的化合物，包括下述实施例中所涉及的方法，本发明的化合物或者其药学上可接受的盐，异构体或水合物可以使用下述方法与有机化学合成领域已知的合成方法，或通过本领域技术人员理解对这些方法的变化方法合成，优选方法包括但不限于下述方法。
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。下面提供的实施例可以更好的说明本发明，除非特别说明，所有的温度为℃。
部分中间体的制备
A系列中间体
中间体A1.5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺的合成
Figure PCTCN2020073018-appb-000002
步骤1：4-硝基吡唑(1.13g,10mmol)，碘甲烷(2.85g,20mmol)，碳酸钾(4.14g,30mmol)的丙酮(10mL)溶液加热至60℃摄氏度反应12小时，冷却，过滤，浓缩，柱层析纯化得到白色固体产物1-甲基-4-硝基-1H-吡唑1.1g,收率85％。
步骤2：向1-甲基-4-硝基-1H-吡唑(0.64g,5mmol)的甲醇(20mL)溶液中加入钯(碳负载55％湿度，10％质量含量)，氢气置换三次，室温搅拌反应6小时，硅藻土过滤，滤液浓缩得到目标产物1-甲基-1H-吡唑-4-胺0.4g，收率82％，MS:98[M+H]+。
步骤3：1-甲基-1H-吡唑-4-胺(0.2g,2mmol)的仲丁醇(2mL)溶液中加入2-氯-5-碘嘧啶(0.5g,2.1mmol)和三氟乙酸(20微升，催化)加热110摄氏度反应10个小时，冷却，浓缩，柱层析纯化得到白色固体产物5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺0.45g,收率75％，MS:302[M+H]+。
中间体A2——A29的制备采用与A1的合成类似的方法进行，其具体结构和表征如下表1所示：
Figure PCTCN2020073018-appb-000003
Figure PCTCN2020073018-appb-000004
Figure PCTCN2020073018-appb-000005
Figure PCTCN2020073018-appb-000006
表1：中间体A2至A29的结构和表征
B系列中间体
中间体B1(N-(1,3-二甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺)和B2(N-(1,5-二甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺)的合成
Figure PCTCN2020073018-appb-000007
步骤1：在冰水浴条件下向3-甲基吡唑(1mL,12mmol)的硫酸(10mL)溶液中分批加入硝酸钾(1.22g,12mmol)，室温搅拌15小时，转移至0摄氏度条件下加入氨水淬灭，过滤得到白色固体产物5-甲基-4-硝基-1H-吡唑1.5g，收率98％； 1H NMR(400MHz,DMSO-d6)δ13.44(s,1H),8.39(s,1H),2.51(s,3H).MS:128[M+H] +。
步骤2：5-甲基-4-硝基-1H-吡唑(1.3g,10mmol)的丙酮溶液(15mL)中加入碘甲烷(2.85g,20mmol)，在60摄氏度条件加热反应20小时，冷却，分别加入乙酸乙酯和水淬灭，有机相干燥，浓缩得到黄棕色油状物(1,3-二甲基-4-硝基-1H-吡唑和1,5-二甲基-4-硝基-1H-吡唑)1.5g直接用于下一步。
步骤3：将步骤B1-2所得油状物溶解在甲醇(30mL)中，加入湿钯碳(55％湿度，10％钯含量，80mg)，反应体系用氢气置换后，在氢气条件下室温搅拌反应6小时，用硅藻土过滤，滤液浓缩得无色油状物(1,3-二甲基-1H-吡唑-4-胺和1,5-二甲基-1H-吡唑-4-胺)0.96g直接用于下一步；MS:112[M+H] +。
步骤4：由步骤B1-3得到的无色油状物(0.3g)的仲丁醇溶液(10mL)中分别加入2-氯-5-碘嘧啶(0.5g,2mmol)和三氟乙酸(20微升，催化)加热110摄氏度反应10小时，冷却，浓缩，柱层析纯化得到白色固体产物0.6g，然后由制备液相色谱纯化得到目标中间体B1(N-(1,3-二甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺，250mg)和B2(N-(1,5-二甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺，120mg)。
中间体B3——B18的制备采用与B1和B2的合成类似的方法进行，其具体结构和表征如下表2所示：
Figure PCTCN2020073018-appb-000008
Figure PCTCN2020073018-appb-000009
Figure PCTCN2020073018-appb-000010
表2：中间体B2至B18的结构和表征
C系列中间体
中间体C1：5-碘-N-(3-甲氧基-1-甲基-1H-吡唑-4-基)嘧啶-2-胺的合成
Figure PCTCN2020073018-appb-000011
步骤1：在15摄氏度冷水浴条件下向4-硝基吡唑(3.4g,30mmol)的干燥二氯甲烷(20mL)溶液中加入硝酸钾(3.1g,30mmol)，随后加入三氟乙酸酐(8.4mL,60mmol)的干燥二氯甲烷(10mL)溶液，室温搅拌反应5小时，将反应液倒入冰水中，乙酸乙酯萃取得白色固体产物1,4-二硝基-1H-吡唑4.7g；
步骤2：将1,4-二硝基-1H-吡唑(1.6g,10mmol)的乙醚(15mL)溶液缓慢滴入到氢氧化钾(1.12g,20mml)的甲醇(60mL)溶液中，室温搅拌反应1小时，浓缩，柱层析纯化得到白色固体产物3-甲氧基-4-硝基-1H-吡唑1.4g，收率95％，MS:144[M+H] +。
步骤3：向3-甲氧基-4-硝基-1H-吡唑(0.14g,1mmol)的丙酮(5mL)溶液中分别加入碘甲烷(0.3g,2mmol)和碳酸钾(0.3g,2.2mmol)，在60摄氏度条件下进行反应10小时，冷却，过滤，浓缩得淡黄色油状物3-甲氧基-1-甲基-4-硝基-1H-吡唑0.15g直接用于下一步。
步骤4：将3-甲氧基-1-甲基-4-硝基-1H-吡唑(0.15g，1mmol)的甲醇(10mL)溶液中加入催化量钯碳(55％湿度，10％钯含量)，氢气置换体系3次后，室温搅拌反应5小时，硅藻土过滤，滤液浓缩得到浅紫色油状物3-甲氧基-1-甲基-1H-吡唑-4-胺1.2g,收率95％，MS:128[M+H] +。
步骤5：3-甲氧基-1-甲基-1H-吡唑-4-胺(0.26g,2mmol)的仲丁醇(2mL)溶液中加入2-氯-5-碘嘧啶(0.5g,2.1mmol)和三氟乙酸(20微升，催化)加热110摄氏度反应10个小时，冷却，浓缩，柱层析纯化得到白色固体产物5-碘-N-(3-甲氧基-1-甲基-1H-吡唑-4-基)嘧啶-2-胺0.55g,收率83％，MS:332[M+H] +。
中间体C2——C11的制备采用与C1的合成类似的方法进行，其具体结构和表征如下表3所示：
Figure PCTCN2020073018-appb-000012
Figure PCTCN2020073018-appb-000013
表3：中间体C2至C12的结构和表征
D系列中间体
中间体D1(N-(3-环丙基-1-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺)和D2(N-(5-环丙基-1-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺)
Figure PCTCN2020073018-appb-000014
步骤1：在冰水浴条件下向4-硝基-1H-吡唑(6.598g，58.35mmol)的四氢呋喃(50mL)溶液中缓慢加入氢化钠(质量比60％分散在油中，4.827g，120.7mmol)然后室温搅拌20分钟至均匀，随后在冰水浴条件滴加SEMCl(12.0mL，67.8mmol)，室温搅拌反应3小时。冰水小心淬灭，乙酸乙酯萃取。有机相干燥，浓缩。柱层析纯化得到无色油状物4-硝基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑14.1g,收率99％。
步骤2：在-78℃的条件下向4-硝基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑(1.52g,6.2mmol)的干燥THF(20mL)溶液中缓慢滴加HMDSLi(1M的THF溶液，7.5mL，7.5mmol)的四氢呋喃溶液。在-78℃搅拌1小时后,继续缓慢滴加入碘(1.8g，7mmol)的THF(8mL)溶液。在-78℃条件下继续反应1.5小时，然后使用饱和氯化铵溶液淬灭。使用乙酸乙酯萃取，并用饱和Na 2S 2O 3洗涤，有机相干燥，浓缩，并由柱层析纯化(硅胶柱，10％的乙酸乙酯的石油醚溶液流动相)得到2.2g产物5-碘-4-硝基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑，收率95％。
步骤3：分别将5-碘-4-硝基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑(3.7g,10mmol),环丙基硼酸(1.7mg,20mmol)，无水磷酸钾(8.5g,40mmol)，Pd(PPh 3) 4(0.86mg,0.75mmol)分别加入到甲苯(100mL)和水(1mL)的混合溶液中，氩气置换3次后加热到100摄氏度反应24小时，冷却，浓缩，柱层析纯化得到目标产物无色油状物5-环丙基-4-硝基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑2.5g，收率88％。
步骤4：将5-环丙基-4-硝基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑(2.5g，8.8mol)加入到氯化氢的1,4-二氧六环(4M)溶液(30mL)中室温搅拌5小时，浓缩得到黄色油状物5-环丙基-4-硝基-1H-吡唑1.7g直接用于下一步；MS:154[M+H] +。
步骤5：将5-环丙基-4-硝基-1H-吡唑(1.7g,11.1mmol)的丙酮溶液(15mL)中分别加入碳酸钾(3.5g,25mmol)和碘甲烷(3.5g,25mmol)，加热至60摄氏度搅拌反应20小时，加水淬灭，乙酸乙酯萃取，有机相干燥，浓缩得黄色油状物3-环丙基-1-甲基-4-硝基-1H-吡唑和5-环丙基-1-甲基-4-硝基-1H-吡唑1.8g。
步骤6：将步骤5所得黄色油状物(1.8g)溶于甲醇(30mL)中，加入湿钯碳(55％湿度，10％质量含量)，氢气置换，在氢气条件下室温搅拌反应5小时，用硅藻土过滤，滤液浓缩得无色油状物3-环丙基-1-甲基-1H-吡唑-4-胺和5-环丙基-1-甲基-1H-吡唑-4-胺1.4g，MS:138[M+H] +。
步骤7：将步骤6所得油状物(0.3g，2mmol)的仲丁醇(4mL)溶液中加入2-氯-5-碘嘧啶(0.5g,2mmol)和三氟乙酸(50微升，催化)加热至110摄氏度反应10个小时，冷却，浓缩，柱层析纯化得到白色固体产物0.61g，然后由制备液相色谱纯化得到目标中间体D1(280mg)和D2(100mg)。
E系列中间体
中间体E1：3-乙炔基-4-甲基苯甲酸的合成
Figure PCTCN2020073018-appb-000015
步骤1：3-碘-4-甲基苯甲酸甲酯(2.8g,10mmol)，乙炔三甲基硅烷(1.1g,11mmol)，Pd(PPh 3) 2Cl 2(0.07g,0.1mmol)，CuI(0.02g,0.1mmol),三乙基胺(3g,30mmol)分别加入乙腈(3.5mL)中，氮气置换后加热至室温搅拌反应15小时，冷却，硅藻土过滤乙酸乙酯洗涤，水洗，萃取，柱层析纯化得无色油状物4-甲基-3-((三甲基硅基)乙炔基)苯甲酸甲酯2.3g,收率93％；
步骤2：4-甲基-3-((三甲基硅基)乙炔基)苯甲酸甲酯(2.3g)的四氢呋喃(10mL)，甲醇(10mL)和水(2mL)的混合溶液中加入水合氢氧化锂(0.6g,15mmol)，室温搅拌反应10小时，乙酸乙酯萃取，水相调节pH至2-3，大量固体析出，过滤得白色固体产物1.3g,收率87％。
F系列中间体
中间体F1.3-炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯基甲酰胺
Figure PCTCN2020073018-appb-000016
步骤1：1-甲基-4-硝基-2-三氟甲基苯(10.3g,50mmol)的四氯化碳(80mL)溶液中分别加入NBS(9.7g,55mmol)和过氧化苯甲酰(20％湿度,0.8g,2.5mmol)，加热至80摄氏度反应15小时，冷却，过滤，水洗，有机相干燥浓缩得浅黄色油状物1-(溴甲基)-4-硝基-2-(三氟甲基)苯15g直接用于下一步；
步骤2：1-(溴甲基)-4-硝基-2-(三氟甲基)苯(6g)的乙腈(300mL)溶液中加入4-甲基哌嗪(4g,40mmol)和碳酸钾(8.2g,60mmol)，加热到50摄氏度反应2小时，冷却，过滤，浓缩，柱层析纯化得黄色固体产物1-甲基-4-(4-硝基-2-(三氟甲基)苯甲基)哌嗪5.5g,收率92％，MS:304[M+H] +。
步骤3：1-甲基-4-(4-硝基-2-(三氟甲基)苯甲基)哌嗪(3g，10mmol)的甲醇(60mL)溶液中加入钯碳催化，在氢气条件下搅拌反应6小时，硅藻土过滤，浓缩得淡黄色固体产物4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯胺2.6g,收率95％，MS:274[M+H] +。
步骤4：4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯胺(270mg,1mmol)，3-乙炔基-4-甲基苯甲酸(160mg,1mmol)，HATU(400mg,1.05mmol)，三乙胺(200mg,2mmol)的DMF(5mL)溶液室温搅拌15小时，加水淬灭，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，柱层析纯化得到类白色固体产物370mg，收率89％，MS:416[M+H] +。
中间体F2——F11的制备采用与F1的合成类似的方法进行，其具体结构和表征如下表4所示：
Figure PCTCN2020073018-appb-000017
Figure PCTCN2020073018-appb-000018
表4：中间体F2至F11的结构和表征
中间体F12.N-(4-(3-(二甲基氨基)丙基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺
Figure PCTCN2020073018-appb-000019
步骤1：二酮酸二乙酯(1.6g,10mmol)的四氢呋喃(30mL)溶液中加入NaH(0.48g,12mmol)，室温搅拌半小时后，滴加1-(溴甲基)-2-氟-4-硝基苯(2.3g,10mmol)的四氢呋喃溶液，室温搅拌过夜，加入饱和氯化铵溶液淬灭，乙酸乙酯萃取，干燥，由柱层析纯化得浅黄色油状物2-(2-氟-4-硝基苯甲基)二酮酸二乙酯3.2g,收率95％，MS:314[M+H] +。
步骤2：2-(2-氟-4-硝基苯甲基)二酮酸二乙酯(3.2g,10mmol)的盐酸(33％,30mL)溶液加热至100摄氏度反应过夜，冷却，调节pH至2-3，乙酸乙酯萃取，干燥，浓缩得浅黄色油状物3-(2-氟-4-硝基苯基)丙基酸1.6g,收率76％，MS:212[M-H] -。
步骤3：3-(2-氟-4-硝基苯基)丙基酸(210mg,1mmol)的二氯亚砜(2mL)回流加热2小时，冷却，浓缩，溶于干燥二氯甲烷(2mL)中,向上述溶液中依次滴加二甲胺的四氢呋喃(1M,2mL)溶液，三乙胺(0.1mL)，室温搅拌3小时，制备薄板纯化得到黄色固体产物3-(2-氟-4-硝基苯基)-N,N-二甲基丙酰胺215mg,收率90％，MS:241[M+H] +。
步骤4：3-(2-氟-4-硝基苯基)-N,N-二甲基丙酰胺(215mg,0.9mmol)的甲醇(10mL)溶液中加入湿钯碳(10％钯含量，30mg)催化，氢气置换反应体系后，在氢气氛下室温搅拌反应5小时，用硅藻土过滤，滤 液浓缩得到淡黄色油状物3-(4-氨基-2-氟苯基)-N,N-二甲基丙酰胺155mg，收率82％。
步骤5：3-(4-氨基-2-氟苯基)-N,N-二甲基丙酰胺(155mg)的干燥四氢呋喃(3mL)溶液中加入硼烷的四氢呋喃(2M,3mL)溶液，室温搅拌过夜，加入甲醇(5mL)，回流1小时，浓缩，得150mg产物4-(3-(二甲氨基)丙基)-3-氟苯胺直接用于下一步，MS:197[M+H] +。
步骤6：3-乙炔基-4-甲基苯甲酸(160mg,1mmol)，HATU(380mg,1mmol)，DIEA(390mg,3mmol)，4-(3-(二甲氨基)丙基)-3-氟苯胺(150mg)的DMF(2mL)溶液室温搅拌过夜，依次用乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，由硅胶柱层析纯化得浅黄色固体N-(4-(3-(二甲基氨基)丙基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺225mg，MS:339[M+H] +。
中间体F13.N-(3-(3-(二甲氨基)丙基)-5-氟苯基)-3-乙炔基-4-甲基苯甲酰胺的合成
Figure PCTCN2020073018-appb-000020
中间体F13的制备采用与F12的合成类似的方法进行，不同之处在于用1-(溴甲基)-3-氟-5-硝基苯替代1-(溴甲基)-2-氟-4-硝基苯。
中间体F14. 3-乙炔基-N-(3-氟-5-(3-羟基丙基)苯基)-4-甲基苯甲酰胺
Figure PCTCN2020073018-appb-000021
步骤1：二酮酸二乙酯(1.6g,10mmol)的四氢呋喃(30mL)溶液中加入NaH(0.48g,12mmol)，室温搅拌半小时后，滴加1-(溴甲基)-3-氟-5-硝基苯(2.3g,10mmol)的四氢呋喃溶液，室温搅拌过夜，加入饱和氯化铵溶液淬灭，乙酸乙酯萃取，干燥，由柱层析纯化得浅黄色油状物2-(3-氟-5-硝基苯甲基)二酮酸二乙酯3.2g,收率95％，MS:314[M+H] +。
步骤2：2-(3-氟-5-硝基苯甲基)二酮酸二乙酯(3.2g,10mmol)的盐酸(33％,30mL)溶液加热至100摄氏度反应10小时，TLC检测原料反应完毕，加入甲醇(20mL)继续加热反应1小时，冷却，碳酸氢钾调节pH至中性，乙酸乙酯萃取，干燥，浓缩得黄色油状物3-(3-氟-5-硝基苯基)丙酸甲酯1.9g，收率84％。
步骤3：3-(3-氟-5-硝基苯基)丙酸甲酯(250mg,1.1mmol)的甲醇(10mL)溶液中加入湿钯碳(55％湿度，10％含量)，在氢气条件下搅拌反应两小时，用硅藻土过滤，浓缩得灰色油状物3-(3-氨基-5-氟苯基)丙酸甲酯0.2g，MS:198[M+H] +。
步骤4：在冰水浴条件下向铝锂氢(80mg)的干燥四氢呋喃(2mL)溶液中滴加3-(3-氨基-5-氟苯基)丙 酸甲酯(0.2g)的四氢呋喃(1mL)溶液，室温搅拌反应2小时，加入饱和氢氧化钠溶液(80微升)淬灭，分别用硫酸钠干燥，硅藻土过滤，四氢呋喃洗涤，滤液浓缩得浅紫色油状物3-(3-氨基-5-氟苯基)丙基-1-醇0.16g。
步骤5：3-乙炔基-4-甲基苯甲酸(160mg,1mmol),HATU(380mg,1mmol),DIEA(390mg,3mmol),3-(3-氨基-5-氟苯基)丙基-1-醇(160mg)的DMF(2mL)溶液室温搅拌过夜，依次用乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，由硅胶柱层析纯化得浅黄色固体235mg，收率75％，MS:312[M+H] +。
实施例
实施例1. 4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(30mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物35mg,收率60％， 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),9.91(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(dd,J＝8.5,2.1Hz,1H),7.92-7.89(m,2H),7.71(d,J＝8.5Hz,1H),7.52-7.50(m,2H),3.82(s,3H),3.57(s,2H),2.54(s,3H),2.40(s,8H),2.19(s,3H).MS:589[M+H] +。
Figure PCTCN2020073018-appb-000022
实施例2. 3-((2-((1-(2-羟基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
2-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)乙基-1-醇(33mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物31mg,收率50％； 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),9.92(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(d,J＝8.2Hz,1H),7.98–7.87(m,2H),7.71(d,J＝8.5Hz,1H),7.58–7.47(m,2H),4.87(t,J＝5.3Hz,1H),4.11(t,J＝5.6Hz,2H),3.72(q,J＝5.5Hz,2H),3.57(s,2H),2.54(s,3H),2.44-2.23(m,8H),2.16(s,3H).MS:619[M+H] +。
实施例3. 4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
5-碘-N-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)嘧啶-2-胺(37mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物35mg,收率53％； 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),9.91(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.10–8.03(m,1H),7.98(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.58(s,1H),7.51(d,J＝8.1Hz,1H),4.38(dd,J＝10.3,5.0Hz,1H),3.97(dd,J＝11.6,3.5Hz,2H),3.57(s,2H),3.49-3.43(m,2H),2.54(s,3H),2.39(br,8H),2.19(s,3H),1.97-1.90(m,4H).MS:659[M+H] +。
Figure PCTCN2020073018-appb-000023
实施例4. 3-((2-((1-环丙基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-环丙基-1H-吡唑-4-基)-5-碘嘧啶-2-胺(33mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物36mg，收率58％； 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),9.90(s,1H),8.66(s,2H),8.21(d,J＝2.1Hz,1H),8.13(s,1H),8.06(d,J＝8.5Hz,1H),7.98(s,1H),7.94–7.86(m,1H),7.71(d,J＝8.6Hz,1H),7.52-7.50(m,2H),3.70(br,1H),3.57(s,2H),2.54(s,3H),2.49-2.34(m,8H),2.17(s,3H),1.02(s,2H),0.98–0.90(m,2H).MS:615[M+H] +。
实施例5. 3-((2-((1-环丁基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-环丁基-1H-吡唑-4-基)-5-碘嘧啶-2-胺(33mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物33mg,收率52％； 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),9.90(s,1H),8.66(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.09–8.04(m,1H),7.98(s,1H),7.94–7.87(m,1H),7.71(d,J＝8.5Hz,1H),7.58(s,1H),7.51(d,J＝8.1Hz,1H),4.86–4.75(m,1H),3.57(br,2H),2.55(s,3H),2.45– 2.32(m,10H),2.17(s,3H),1.78(d,J＝6.6Hz,2H),1.24(br,2H).MS:629[M+H] +。
Figure PCTCN2020073018-appb-000024
实施例6. 3-((2-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
5-碘-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)嘧啶-2-胺(35mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物33mg，收率52％； 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),9.91(s,1H),8.66(s,2H),8.21(s,1H),8.13(s,1H),8.07(d,J＝8.5Hz,1H),7.92(d,J＝17.4Hz,2H),7.71(d,J＝8.5Hz,1H),7.56(s,1H),7.51(d,J＝8.1Hz,1H),4.23(t,J＝5.3Hz,2H),3.67(t,J＝5.4Hz,2H),3.57(s,2H),3.24(s,3H),2.55(s,3H),2.39(br,8H),2.18(s,3H).MS:633[M+H] +。
实施例7. 4-甲基-3-((2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-乙基-1H-吡唑-4-基)-5-碘嘧啶-2-胺(32mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物36mg,收率60％； 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),9.90(s,1H),8.65(s,2H),8.21(d,J＝2.1Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(d,J＝8.6Hz,1H),7.94(s,1H),7.90(d,J＝7.8Hz,1H),7.71(d,J＝8.5Hz,1H),7.54(s,1H),7.51(d,J＝8.1Hz,1H),4.11(q,J＝7.3Hz,2H),3.57(s,2H),2.55(s,3H),2.37(d,J＝21.0Hz,8H),2.17(s,3H),1.36(t,J＝7.2Hz,3H).MS:603[M+H] +。
Figure PCTCN2020073018-appb-000025
实施例8. 3-((2-((1-(叔丁基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-(叔丁基)-1H-吡唑-4-基)-5-碘嘧啶-2-胺(34mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基) 甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物34mg,收率54％； 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),9.85(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝1.9Hz,1H),8.06(d,J＝8.6Hz,1H),7.97(s,1H),7.95–7.86(m,1H),7.71(d,J＝8.6Hz,1H),7.58(s,1H),7.51(d,J＝8.1Hz,1H),3.57(s,2H),2.54(s,3H),2.37(d,J＝24.0Hz,8H),2.16(s,3H),1.52(s,9H).MS:631[M+H] +。
实施例9. 3-((2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-(异丙基)-1H-吡唑-4-基)-5-碘嘧啶-2-胺(33mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物35mg,收率57％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.89(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(d,J＝8.6Hz,1H),7.94(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.55(s,1H),7.51(d,J＝8.1Hz,1H),4.48(q,J＝6.6Hz,1H)3.59(s,2H),2.54(s,3H),2.45(br,8H),2.26(s,3H),1.41(d,J＝6.6Hz,6H).MS:617[M+H] +。
Figure PCTCN2020073018-appb-000026
实施例10. 4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
N-(1-(1-甲基哌啶)-1H-吡唑-4-基)-5-碘嘧啶-2-胺基(39mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物36mg，收率53％； 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),9.89(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(d,J＝8.5Hz,1H),7.96(s,1H),7.94–7.83(m,1H),7.71(d,J＝8.5Hz,1H),7.56(s,1H),7.51(d,J＝8.1Hz,1H),4.08(t,J＝5.3Hz,1H),3.57(s,2H),2.85(d,J＝11.1Hz,2H),2.54(s,3H),2.37(d,J＝24.5Hz,8H),2.20(s,3H),2.16(s,3H),2.07-2.01(m,2H),1.98–1.91(m,4H).MS:672[M+H] +。
实施例11. 3-((2-((1-(2-(二甲氨基)乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-(2-(二甲氨基)乙基)-1H-吡唑-4-基)-5-碘嘧啶-2-胺(36mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，碘化亚铜(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物33mg,收率51％； 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.94(s,1H),8.65(s,2H),8.22(d,J＝2.2Hz,1H),8.16–8.05(m,2H),7.99–7.87(m,2H),7.71(d,J＝8.5Hz,1H),7.59–7.47(m,2H),4.22(t,J＝6.5Hz,2H),3.60(s,2H),2.76(t,J＝6.6Hz,2H),2.61(br,8H),2.54(s,3H),2.35(s,3H),2.26(s,6H).MS:646[M+H] +。
Figure PCTCN2020073018-appb-000027
实施例12. 3-((2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
3-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)丙基-1-醇(35mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物33mg,收率52％； 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),9.92(s,1H),8.65(s,2H),8.21(d,J＝2.1Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(d,J＝8.1Hz,1H),7.97–7.87(m,2H),7.71(d,J＝8.6Hz,1H),7.58–7.47(m,2H),4.56(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.57(s,2H),3.39(q,J＝5.9Hz,2H),2.54(s,3H),2.39(br,8H),2.17(s,3H),1.90(t,J＝6.6Hz,2H).MS:633[M+H] +。
实施例13. 3-((2-((1-(3-甲氧基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
5-碘-N-(1-(3-甲氧基丙基)-1H-吡唑-4-基)嘧啶-2-胺(36mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物35mg,收率54％； 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),9.92(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(d,J＝8.5Hz,1H),7.93-7.89(m,2H),7.71(d, J＝8.6Hz,1H),7.58–7.47(m,2H),4.12(t,J＝7.0Hz,2H),3.57(s,2H),3.28(d,J＝6.2Hz,2H),3.24(s,3H),2.55(s,3H),2.39(s,8H),2.18(s,3H),1.98(t,J＝6.6Hz,2H).MS:647[M+H] +。
Figure PCTCN2020073018-appb-000028
实施例14. 4-甲基-3-((4-甲基-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
5-溴-4-甲基-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(27mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物18mg，收率30％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.82(s,1H),8.54(s,1H),8.21(d,J＝2.1Hz,1H),8.12(d,J＝1.9Hz,1H),8.07(d,J＝8.6Hz,1H),7.96–7.87(m,2H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝7.3Hz,2H),3.82(s,3H),3.58(s,2H),2.57(d,J＝11.2Hz,6H),2.44–2.39(m,8H),2.21(s,3H).MS:603[M+H] +。
实施例15. 3-((2-((1-(叔丁基)-1H-吡唑-4-基)氨基)4-甲基嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
5-溴-N-(1-(叔丁基)-1H-吡唑-4-基)-4-甲基嘧啶-2-胺(31mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物16mg,收率25％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.77(s,1H),8.54(s,1H),8.21(d,J＝2.1Hz,1H),8.12(d,J＝2.0Hz,1H),8.06(d,J＝8.5Hz,1H),7.98(s,1H),7.94–7.86(m,1H),7.71(d,J＝8.6Hz,1H),7.59(s,1H),7.51(d,J＝8.1Hz,1H),3.57(s,2H),2.58(s,3H),2.55(s,3H),2.40-2.34(s,8H),2.16(s,3H),1.52(s,9H).MS:645[M+H] +。
Figure PCTCN2020073018-appb-000029
实施例16. 3-((2-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)4-甲基嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
5-溴-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)-4-甲基嘧啶-2-胺(31mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物20mg，收率31％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.81(s,1H),8.54(s,1H),8.21(d,J＝2.2Hz,1H),8.15–8.03(m,2H),7.98–7.86(m,2H),7.71(d,J＝8.5Hz,1H),7.59–7.48(m,2H),4.23(t,J＝5.3Hz,2H),3.68(t,J＝5.4Hz,2H),3.57(s,2H),3.24(s,3H),2.58(s,3H),2.56(s,3H),2.40-2.34(m,8H),2.16(s,3H).MS:647[M+H] +。
实施例17. 4-甲基-3-((4-甲基-2-((1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
5-溴-4-甲基-N-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)嘧啶-2-胺(34mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物22mg,收率33％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.82(s,1H),8.54(s,1H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝1.9Hz,1H),8.09–8.04(m,1H),8.02–7.96(m,1H),7.90(dd,J＝7.9,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.58(s,1H),7.51(d,J＝8.0Hz,1H),4.39(q,J＝8.6,8.2Hz,1H),3.96(dd,J＝9.0,5.8Hz,2H),3.57(s,2H),3.46(td,J＝11.0,4.1Hz,2H),2.58(s,3H),2.56(s,3H),2.39(br,8H),2.19(s,3H),1.99–1.88(m,4H).MS:673[M+H] +。
Figure PCTCN2020073018-appb-000030
实施例18. 3-((2-((1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
1-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)-2-甲基丙基-2-醇(36mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物33mg，收率51％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.95(s,1H),8.66(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.1Hz,1H),7.94(s,1H),7.90(dd,J＝7.9,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.55(s,1H),7.51(d,J＝8.1Hz,1H),4.69(s,1H),3.98 (s,2H),3.57(s,2H),2.54(s,3H),2.45-2.35(m,8H),2.17(s,3H),1.06(s,6H).MS:647[M+H] +。
实施例19. 3-((2-((1-(3-羟基-3-甲基丁基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
4-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)-2-甲基丁基-2-醇(37mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物38mg,收率57％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.94(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.94(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.51(d,J＝8.7Hz,2H),4.44(s,1H),4.19–4.09(m,2H),3.56(s,2H),3.41–3.36(m,2H),2.54(s,3H),2.39-2.33(m,6H),2.16(s,3H),1.92–1.83(m,2H),1.12(s,6H).MS:661[M+H] +。
Figure PCTCN2020073018-appb-000031
实施例20. 3-((2-((1-(氰甲基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
2-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)乙腈(33mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物31mg，收率50％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),10.08(s,1H),8.69(s,2H),8.21(d,J＝2.2Hz,1H),8.16–8.10(m,2H),8.06(dd,J＝8.5,2.2Hz,1H),7.91(dd,J＝8.0,2.0Hz,1H),7.70(d,J＝13.7Hz,2H),7.51(d,J＝8.1Hz,1H),5.49(s,2H),3.57(s,2H),2.55(s,3H),2.45-2.35(s,8H),2.17(s,3H).MS:614[M+H] +。
实施例21. 3-((2-((1-(氰乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
2-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)丙腈(34mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白 色固体产物34mg，收率54％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),10.01(s,1H),8.67(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.1Hz,1H),8.08-8.05(m,2H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.63(s,1H),7.51(d,J＝8.1Hz,1H),4.38(t,J＝6.4Hz,2H),3.57(s,2H),3.05(t,J＝6.4Hz,2H),2.54(s,3H),2.45-2.35(s,8H),2.18(s,3H).MS:628[M+H] +。
Figure PCTCN2020073018-appb-000032
实施例22. 3-((2-((1-(2-氟乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-(2-氟乙基)-1H-吡唑-4-基)-5-碘嘧啶-2-胺(33mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物31mg,收率50％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.97(s,1H),8.66(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),8.00(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.60(s,1H),7.51(d,J＝8.2Hz,1H),4.80(t,J＝4.7Hz,1H),4.69(t,J＝4.7Hz,1H),4.41(dt,J＝27.9,4.8Hz,2H),3.57(s,2H),2.54(s,3H),2.39(s,8H),2.17(s,3H).MS:621[M+H] +。
实施例23. 3-((2-((1-(3-氟丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-(3-氟丙基)-1H-吡唑-4-基)-5-碘嘧啶-2-胺(35mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物32mg,收率50％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.96(s,1H),8.66(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.97(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.57(s,1H),7.51(d,J＝8.1Hz,1H),4.49(t,J＝5.8Hz,1H),4.38(t,J＝5.8Hz,1H),4.19(t,J＝6.9Hz,2H),3.56(s,2H),3.42–3.37(m,2H),2.54(s,3H),2.39-2.33(m,8H),2.18–2.10(m,3H).MS:635[M+H] +。
Figure PCTCN2020073018-appb-000033
实施例24. 3-((2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1,3-二甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺(32mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物31mg,收率51％； 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),9.30(s,1H),8.61(s,2H),8.21(d,J＝2.1Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(dd,J＝8.6,2.1Hz,1H),7.90(dd,J＝7.9,1.9Hz,1H),7.82(s,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.0Hz,1H),3.74(s,3H),3.57(s,2H),2.54(s,3H),2.40(br,8H),2.20(s,3H),2.10(s,3H).MS:603[M+H] +。
实施例25. 3-((2-((1-(2-羟基乙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
2-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)乙基-1-醇(35mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物33mg，收率52％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.29(s,1H),8.62(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.1Hz,1H),7.90(dd,J＝8.0,1.9Hz,1H),7.85(s,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),4.87(t,J＝5.3Hz,1H),4.03(t,J＝5.7Hz,2H),3.71(q,J＝5.5Hz,2H),3.57(s,2H),2.54(s,3H),2.46–2.28(m,8H),2.17(s,3H),2.12(s,3H).MS:633[M+H] +。
Figure PCTCN2020073018-appb-000034
实施例26. 3-((2-((1-(2-甲氧基乙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
5-碘-N-(1-(2-甲氧基乙基)-3-甲基-1H-吡唑-4-基)嘧啶-2-胺(36mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4- 甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物35mg，收率54％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.27(s,1H),8.61(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.84(s,1H),7.70(d,J＝8.5Hz,1H),7.50(d,J＝8.1Hz,1H),4.14(t,J＝5.3Hz,2H),3.65(t,J＝5.3Hz,2H),3.57(s,2H),3.23(s,3H),2.54(s,3H),2.39(br,8H),2.18(s,3H),2.11(s,3H).MS:647[M+H] +。
实施例27. 3-((2-((1-(3-羟基丙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
3-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)丙基-1-醇(36mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物35mg，收率54％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.28(s,1H),8.62(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.4,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.84(s,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),4.58(t,J＝5.1Hz,1H),4.05(t,J＝7.0Hz,2H),3.57(s,2H),3.40(q,J＝6.0Hz,2H),2.54(s,3H),2.40(s,8H),2.19(s,3H),2.11(s,3H),1.89(q,J＝6.6Hz,2H).MS:647[M+H] +。
Figure PCTCN2020073018-appb-000035
实施例28. 3-((2-((1-(3-甲氧基丙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
5-碘-N-(1-(3-甲氧基丙基)-3-甲基-1H-吡唑-4-基)嘧啶-2-胺(37mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物31mg，收率47％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.29(s,1H),8.62(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(dd,J＝8.4,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.84(s,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.2Hz,1H),4.04(t,J＝7.0Hz,2H),3.57 (s,2H),3.30(t,J＝6.2Hz,2H),3.24(s,3H),2.54(s,3H),2.39(br,8H),2.15(d,J＝24.8Hz,6H),1.96(q,J＝6.5Hz,2H).MS:661[M+H] +。
实施例29. 3-((2-((1-(氰甲基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
2-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)乙腈(34mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物31mg,收率49％； 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),9.46(s,1H),8.66(s,2H),8.24–8.17(m,2H),8.14(d,J＝1.9Hz,1H),8.11–8.02(m,1H),7.91(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.51(d,J＝8.1Hz,1H),5.40(s,2H),3.57(s,2H),2.55(s,3H),2.45-2.35(m,8H),2.21(s,3H),2.18(s,3H).MS:628[M+H] +。
Figure PCTCN2020073018-appb-000036
实施例30. 3-((2-((1-(氰乙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
2-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)丙腈(36mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物33mg,收率51％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.37(s,1H),8.63(s,2H),8.21(d,J＝2.2Hz,1H),8.16–8.03(m,2H),7.98(s,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),4.30(t,J＝6.4Hz,2H),3.57(s,2H),3.04(t,J＝6.4Hz,2H),2.54(s,3H),2.45-2.35(m,8H),2.21(s,3H),2.15(s,3H).MS:642[M+H] +。
实施例31. 3-((2-((1-(2-氟乙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-(2-氟乙基)-3-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺(35mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却， 乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物29mg,收率46％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.32(s,1H),8.63(s,2H),8.21(d,J＝2.2Hz,1H),8.16–8.03(m,2H),7.90(d,J＝7.9Hz,2H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),4.80(t,J＝4.7Hz,1H),4.68(t,J＝4.7Hz,1H),4.33(dt,J＝27.8,4.8Hz,2H),3.57(s,2H),2.54(s,3H),2.45-2.35(m,8H),2.18(s,3H),2.16(s,3H).MS:635[M+H] +。
Figure PCTCN2020073018-appb-000037
实施例32. 3-((2-((1-(3-氟丙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-(3-氟丙基)-3-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺(36mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物33mg，收率51％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.31(s,1H),8.62(s,2H),8.21(d,J＝2.3Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(d,J＝8.4Hz,2H),7.71(d,J＝8.6Hz,1H),7.51(d,J＝8.1Hz,1H),4.51(t,J＝5.8Hz,1H),4.39(t,J＝5.8Hz,1H),4.11(t,J＝7.0Hz,2H),3.57(s,2H),2.54(s,3H),2.39(s,8H),2.18(s,3H),2.15-2.09(m,5H).MS:649[M+H] +。
实施例33. 3-((2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1,5-二甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺(32mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物29mg，收率48％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.20(s,1H),8.58(s,2H),8.21(d,J＝2.3Hz,1H),8.15–8.03(m,2H),7.90(dd,J＝7.9,2.1Hz,1H),7.71(d,J＝8.4Hz,1H),7.54–7.44(m,2H),3.72(d,J＝2.7Hz,3H),3.57(s,2H),2.53(s,3H),2.45-2.35(m,8H),2.19(s,3H),2.15(d,J＝2.8Hz,3H).MS:603[M+H] +。
Figure PCTCN2020073018-appb-000038
实施例34. 3-((2-((1-(2-羟基乙基)-5-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
2-(4-((5-碘嘧啶-2-基)氨基)-5-甲基-1H-吡唑-1-基)乙基-1-醇(35mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物25mg，收率39％； 1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),9.20(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝2.0Hz,1H),8.09–8.03(m,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.55–7.47(m,2H),4.88(t,J＝5.3Hz,1H),4.05(t,J＝5.8Hz,2H),3.70(q,J＝5.7Hz,2H),3.57(s,2H),2.53(s,3H),2.40-2.34(m,8H),2.18(s,3H),2.16(s,3H).MS:633[M+H] +。
实施例35. 3-((2-((1-(2-甲氧基乙基)-5-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
5-碘-N-(1-(2-甲氧基乙基)-5-甲基-1H-吡唑-4-基)嘧啶-2-胺(36mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物33mg,收率51％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.19(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.56–7.47(m,2H),4.17(t,J＝5.4Hz,2H),3.65(t,J＝5.4Hz,2H),3.58(s,2H),3.23(s,3H),2.54(s,3H),2.41(s,8H),2.21(s,3H),2.17(s,3H).MS:647[M+H] +。
Figure PCTCN2020073018-appb-000039
实施例36. 3-((2-((1-(3-羟基丙基)-5-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
3-(4-((5-碘嘧啶-2-基)氨基)-5-甲基-1H-吡唑-1-基)丙基-1-醇(36mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物35mg，收率54％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.19(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.15–8.03(m,2H),7.90(dd,J＝7.9,1.9Hz,1H),7.71(d,J＝8.5 Hz,1H),7.51(d,J＝7.4Hz,2H),4.59(t,J＝5.0Hz,1H),4.06(t,J＝7.1Hz,2H),3.57(s,2H),3.40(q,J＝6.0Hz,2H),2.54(s,3H),2.45-2.35(s,8H),2.17(s,6H),1.86(t,J＝6.7Hz,2H).MS:647[M+H] +。
实施例37. 3-((2-((1-(3-甲氧基丙基)-5-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
5-碘-N-(1-(3-甲氧基丙基)-5-甲基-1H-吡唑-4-基)嘧啶-2-胺(37mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物38mg，收率57％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.20(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.55–7.47(m,2H),4.05(t,J＝7.0Hz,2H),3.57(s,2H),3.29(t,J＝6.1Hz,2H),3.24(s,3H),2.53(s,3H),2.37(br,8H),2.18(s,3H),2.16(s,3H),1.95(q,J＝6.5Hz,2H).MS:661[M+H] +。
Figure PCTCN2020073018-appb-000040
实施例38. 3-((2-((1-(氰甲基)-5-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
2-(4-((5-碘嘧啶-2-基)氨基)-5-甲基-1H-吡唑-1-基)乙腈(34mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物32mg，收率51％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.33(s,1H),8.61(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.70(d,J＝14.4Hz,2H),7.51(d,J＝8.2Hz,1H),5.45(s,2H),3.57(s,2H),2.54(s,3H),2.39(br,8H),2.25(s,3H),2.18(s,3H).MS:628[M+H] +。
实施例39. 3-((2-((1-(氰乙基)-5-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
2-(4-((5-碘嘧啶-2-基)氨基)-5-甲基-1H-吡唑-1-基)丙腈(36mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg, 0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物35mg,收率55％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.27(s,1H),8.59(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.4,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.62(s,1H),7.51(d,J＝8.1Hz,1H),4.31(t,J＝6.4Hz,2H),3.57(s,2H),3.03(t,J＝6.4Hz,2H),2.54(s,3H),2.39(br,8H),2.23(s,3H),2.18(s,3H).MS:642[M+H] +。
Figure PCTCN2020073018-appb-000041
实施例40. 3-((2-((1-(2-氟乙基)-5-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-(2-氟乙基)-5-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺(35mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物31mg,收率49％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.22(s,1H),8.59(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝7.9,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.58(s,1H),7.50(d,J＝8.2Hz,1H),4.80(t,J＝4.8Hz,1H),4.68(t,J＝4.8Hz,1H),4.35(dt,J＝27.4,4.8Hz,2H),3.57(s,2H),2.54(s,3H),2.39(br,8H),2.19(br,6H).MS:635[M+H] +。
实施例41. 3-((2-((1-(3-氟丙基)-5-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(1-(3-氟丙基)-5-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺(36mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物31mg,收率48％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.22(s,1H),8.59(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝1.9Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.56(s,1H),7.50(d,J＝8.2Hz,1H),4.52(t,J＝5.8Hz,1H),4.40(t,J＝5.8Hz,1H),4.12(t,J＝7.0Hz,2H),3.57(s,2H),2.54(s,3H),2.39(s,8H),2.18(s,6H),2.23–2.04(m,2H).MS:649[M+H] +。
Figure PCTCN2020073018-appb-000042
实施例42. 3-((2-((3-环丙基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(3-环丙基-1-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺(34mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物28mg,收率45％； 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),9.34(s,1H),8.62(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.80(s,1H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),3.71(s,3H),3.57(s,2H),2.54(s,3H),2.39(br,8H),2.17(s,3H),1.95(tt,J＝8.3,5.1Hz,1H),0.77(dt,J＝8.2,2.7Hz,2H),0.70(dt,J＝5.1,2.7Hz,2H).MS:629[M+H] +。
实施例43. 3-((2-((5-环丙基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
N-(5-环丙基-1-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺(34mg,0.1mmol)，3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(42mg,0.1mmol)，Pd(PPh 3) 2Cl 2(4mg,0.005mmol)，CuI(2mg,0.01mmol),三乙胺(1.5mL)的DMF(1.5mL)溶液由氩气置换后，加热到65摄氏度反应15小时，冷却，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩，制备薄层板(硅胶负载，二氯甲烷：甲醇＝10：1)纯化得到白色固体产物24mg，收率38％； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),8.95(s,1H),8.56(s,2H),8.21(d,J＝2.2Hz,1H),8.12(d,J＝2.0Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.50(d,J＝8.1Hz,1H),7.32(s,1H),3.81(s,3H),3.57(s,2H),2.53(s,3H),2.39(s,8H),2.18(s,3H),1.68(ddd,J＝8.4,5.4,3.1Hz,1H),0.85–0.76(m,2H),0.63(dd,J＝5.3,2.1Hz,2H).MS:629[M+H] +。
Figure PCTCN2020073018-appb-000043
实施例44. 3-((2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲氧基-1-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺进行偶联反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),8.97(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(dd,J＝8.6,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.70(d,J＝13.6Hz,2H),7.51(d,J＝8.3Hz,1H),3.79(s,3H),3.68(s,3H),3.61–3.52(m,2H),2.54(s,3H),2.39-2.33(m,8H),2.16(s,3H).MS:619[M+H] +。
实施例45. 3-((2-((1-(3-羟基-3-甲基丁基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由4-(4-((5-碘嘧啶-2-基)氨基)-3-甲氧基-1H-吡唑-1-基)-2-甲基丁基-2-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),8.96(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.07(dd,J＝8.4,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.75–7.67(m,2H),7.51(d,J＝8.1Hz,1H),4.44(s,1H),4.04–3.95(m,2H),3.79(s,3H),3.57(s,2H),2.53(s,3H),2.40(br,8H),2.19(s,3H),1.90–1.81(m,2H),1.14(s,6H).MS:691[M+H] +。
Figure PCTCN2020073018-appb-000044
实施例46. 3-((2-((1-(腈基甲基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-3-甲氧基-1H-吡唑-1-基)乙腈与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),9.18(s,1H),8.62(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.06(dd,J＝8.4,2.2Hz,1H),7.90(d,J＝7.0Hz,2H),7.71(d,J＝8.5Hz,1H),7.51(d,J＝8.1Hz,1H),5.31(s,2H),3.85(s,3H),3.57(s,2H),2.54(s,3H),2.39(s,8H),2.18(s,3H).MS:644[M+H] +。
实施例47. 3-((2-((1-(2-羟基乙基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-3-甲氧基-1H-吡唑-1-基)乙基-1-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),8.98(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz, 1H),8.13(d,J＝1.9Hz,1H),8.07(d,J＝8.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.74–7.67(m,2H),7.51(d,J＝8.2Hz,1H),4.87(t,J＝5.3Hz,1H),3.96(t,J＝5.6Hz,2H),3.79(s,3H),3.70(q,J＝5.5Hz,2H),3.60–3.55(m,2H),2.53(s,3H),2.40(s,8H),2.19(s,3H).MS:649[M+H] +。
Figure PCTCN2020073018-appb-000045
实施例48. 3-((2-((1-(2-氟乙基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-(2-氟乙基)-3-甲氧基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),9.01(s,1H),8.59(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(d,J＝8.5Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.78(s,1H),7.71(d,J＝8.6Hz,1H),7.51(d,J＝8.1Hz,1H),4.78(t,J＝4.7Hz,1H),4.66(t,J＝4.6Hz,1H),4.25(dt,J＝27.7,4.7Hz,2H),3.81(s,3H),3.57(s,2H),2.53(s,3H),2.39(s,8H),2.16(s,3H).MS:651[M+H] +。
实施例49. 3-((2-((1-(2-甲氧基乙基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲氧基-1-(2-甲氧基乙基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),8.97(s,1H),8.58(s,2H),8.21(d,J＝2.2Hz,1H),8.13(d,J＝1.9Hz,1H),8.06(dd,J＝8.5,2.2Hz,1H),7.90(dd,J＝8.0,2.0Hz,1H),7.74–7.67(m,2H),7.51(d,J＝8.1Hz,1H),4.08(t,J＝5.3Hz,2H),3.79(s,3H),3.64(t,J＝5.3Hz,2H),3.57(s,2H),3.25(s,3H),2.53(s,3H),2.38(s,8H),2.16(s,3H).MS:663[M+H] +。
Figure PCTCN2020073018-appb-000046
实施例50. 4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),9.94(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.95–7.85(m,2H),7.72(d,J＝ 8.4Hz,2H),7.54–7.45(m,2H),7.26(d,J＝8.3Hz,2H),3.82(s,3H),3.41(s,2H),2.54(s,3H),2.34(br,8H),2.15(s,3H).MS:521[M+H] +。
实施例51. 3-((2-((1-(3-羟基-3-甲基丁基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由4-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)-2-甲基丁基-2-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.72(d,J＝8.4Hz,2H),7.54–7.45(m,2H),7.26(d,J＝8.5Hz,2H),4.46(s,1H),4.19–4.10(m,2H),3.41(s,2H),2.54(s,3H),2.34(br,8H),2.14(s,3H),1.92–1.83(m,2H),1.12(s,6H).MS:593[M+H] +。
Figure PCTCN2020073018-appb-000047
实施例52. 3-((2-((1-(氰甲基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)乙腈与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),10.09(s,1H),8.69(s,2H),8.16–8.08(m,2H),7.89(dd,J＝8.0,2.0Hz,1H),7.76–7.70(m,2H),7.68(s,1H),7.50(d,J＝8.1Hz,1H),7.26(d,J＝8.5Hz,2H),5.49(s,2H),3.41(s,2H),2.54(s,3H),2.36(br,8H),2.15(s,3H).MS:546[M+H] +。
实施例53. 3-((2-((1-(2-羟基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)乙基-1-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96(s,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.73(d,J＝8.4Hz,2H),7.55(s,1H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.90(t,J＝5.3Hz,1H),4.11(t,J＝5.6Hz,2H),3.72(q,J＝5.4Hz,2H),3.41(s,2H),2.54(s,3H),2.34(br,8H),2.14(s,3H).MS:551[M+H] +。
Figure PCTCN2020073018-appb-000048
实施例54. 3-((2-((1-(2-氟乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-(2-氟乙基)-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),9.98(s,1H),8.67(s,2H),8.11(d,J＝1.9Hz,1H),8.01(s,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.76–7.69(m,2H),7.60(s,1H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.81(t,J＝4.7Hz,1H),4.69(t,J＝4.7Hz,1H),4.45(t,J＝4.7Hz,1H),4.38(t,J＝4.7Hz,1H),3.41(s,2H),2.54(s,3H),2.32(br,8H),2.14(s,3H).MS:553[M+H] +。
实施例55. 3-((2-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),9.94(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝8.5Hz,2H),7.56(s,1H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.5Hz,2H),4.23(t,J＝5.3Hz,2H),3.67(t,J＝5.3Hz,2H),3.42(s,2H),3.23(s,3H),2.54(s,3H),2.34(br,8H),2.16(s,3H).MS:565[M+H] +。
Figure PCTCN2020073018-appb-000049
实施例56. 3-((2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)丙基-1-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),9.94(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96–7.85(m,2H),7.73(d,J＝8.5Hz,2H),7.57–7.46(m,2H),7.26(d,J＝8.5Hz,2H),4.59(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.44–3.34(m,4H),2.54(s,3H),2.34(s,8H),2.15(s,3H),1.94–1.86(m,2H).MS:565[M+H] +。
实施例57. 3-((2-((1-(2-氰乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)丙腈与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),10.02(s,1H),8.67(s,2H),8.11(d,J＝1.9Hz,1H),8.06(s,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝8.5Hz,2H),7.63(s,1H),7.49(d,J＝8.2Hz,1H),7.26(d,J＝8.5Hz,2H),4.38(t,J＝6.4Hz,2H),3.42(s,2H),3.05(t,J＝6.4Hz,2H),2.54(s,3H),2.36(s,8H),2.17(s,3H).MS:560[M+H] +。
Figure PCTCN2020073018-appb-000050
实施例58. 3-((2-((1-(3-甲氧基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(3-甲氧基丙基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝8.5Hz,2H),7.55(s,1H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.12(t,J＝6.9Hz,2H),3.41(s,2H),3.28(t,J＝6.2Hz,2H),3.24(s,3H),2.54(s,3H),2.34(br,8H),2.15(s,3H),1.98(q,J＝6.6Hz,2H).MS:579[M+H] +。
实施例59. N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-氨与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝2.0Hz,1H),7.92(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.6,2.0Hz,1H),7.58–7.47(m,3H),7.34(t,J＝8.5Hz,1H),3.82(s,3H),3.47(s,2H),2.54(s,3H),2.37(br,8H),2.14(s,3H).MS:539[M+H] +。
Figure PCTCN2020073018-appb-000051
实施例60. N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(3-羟基-3-甲基丁基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由4-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)-2-甲基丁基-2-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,3H),7.35(d,J＝8.4Hz,1H),4.46(s,1H),4.19–4.10(m,2H),3.47(s,2H),2.54(s,3H),2.38(br,8H),2.14(s,3H),1.92–1.83(m,2H),1.12(s,6H).MS:611[M+H] +。
实施例61. 3-((2-((1-(腈甲基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)乙腈与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),10.09(s,1H),8.70(s,2H),8.16–8.08(m,2H),7.89(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.6,2.0Hz,1H),7.68(s,1H),7.58–7.47(m,2H),7.35(t,J＝8.5Hz,1H),5.49(s,2H),3.47(s,2H),2.55(s,3H),2.38(br,8H),2.15(s,3H).MS:564[M+H] +。
Figure PCTCN2020073018-appb-000052
实施例62. N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-羟基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)乙基-1-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.46(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96(s,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.75(dd,J＝12.6,2.1Hz,1H),7.59–7.47(m,3H),7.35(t,J＝8.5Hz,1H),4.90(t,J＝5.3Hz,1H),4.11(t,J＝5.6Hz,2H),3.72(q,J＝5.5Hz,2H),3.51(s,2H),2.54(s,3H),2.38(br,8H),2.34(s,3H).MS:569[M+H] +。
实施例63. N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-氟乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-(2-氟乙基)-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.46(s,1H),9.99(s,1H),8.67(s,2H),8.11(d,J＝1.9Hz,1H),8.01(s,1H),7.89(dd,J＝8.0,1.9Hz,1H),7.74(dd,J＝12.6,2.0Hz,1H),7.62–7.47(m,3H),7.35(t,J＝8.4Hz,1H),4.81(t,J＝ 4.8Hz,1H),4.69(t,J＝4.7Hz,1H),4.42(dt,J＝28.0,4.8Hz,2H),3.48(s,2H),2.54(s,3H),2.40(br,8H),2.20(s,3H).MS:571[M+H] +。
Figure PCTCN2020073018-appb-000053
实施例64. N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.74(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,3H),7.34(t,J＝8.4Hz,1H),4.23(t,J＝5.3Hz,2H),3.67(t,J＝5.3Hz,2H),3.47(s,2H),3.23(s,3H),2.54(s,3H),2.37(br,8H),2.15(s,3H).MS:583[M+H] +。
实施例65. N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)丙基-1-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96–7.84(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,3H),7.34(t,J＝8.5Hz,1H),4.59(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.47(s,2H),3.39(q,J＝6.0Hz,2H),2.54(s,3H),2.33(br,8H),2.15(s,3H),1.90(t,J＝6.6Hz,2H).MS:583[M+H] +。
Figure PCTCN2020073018-appb-000054
实施例66. N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-氰基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)丙腈与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),10.02(s,1H),8.67(s,2H),8.09(dd,J＝16.5,1.3Hz,2H),7.89(dd,J＝8.0,2.0Hz,1H),7.85–7.69(m,2H),7.58–7.47(m,2H),7.34(t,J＝8.4Hz,1H),4.38(t,J＝6.4Hz,2H),3.47(s,2H),3.05(t,J＝6.4Hz,2H),2.55(s,3H),2.31(br,8H),2.14(s,3H).MS:578[M+H] +。
实施例67. N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(3-甲氧基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(3-甲氧基丙基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),9.96(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,3H),7.34(t,J＝8.5Hz,1H),4.12(t,J＝7.0Hz,2H),3.47(s,2H),3.28(t,J＝6.2Hz,2H),3.23(s,3H),2.54(s,3H),2.37(br,8H),2.15(s,3H),1.98(q,J＝6.6Hz,2H).MS:597[M+H] +。
Figure PCTCN2020073018-appb-000055
实施例68. N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.98(d,J＝2.1Hz,1H),7.92(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.50(d,J＝8.3Hz,2H),7.43(d,J＝8.4Hz,1H),3.82(s,3H),3.52(s,2H),2.54(s,3H),2.42(br,8H),2.15(s,3H).MS:555[M+H] +。
实施例69. N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基-3-((2-((1-(3-羟基-3-甲基丁基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由4-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)-2-甲基丁基-2-醇与N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝2.0Hz,1H),7.98(d,J＝2.1Hz,1H),7.95(s,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.51(d,J＝10.1Hz,2H),7.43(d,J＝8.5Hz,1H),4.46(s,1H),4.20–4.10(m,2H),3.52(s,2H),2.54(s,3H),2.42(s,8H),2.15(s,3H),1.92–1.83(m,2H),1.13(s,6H).MS:627[M+H] +。
Figure PCTCN2020073018-appb-000056
实施例70. N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基-3-((2-((1-(氰基甲基)-1H-吡唑-4-基)氨基)嘧啶 -5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)乙腈与N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),10.09(s,1H),8.69(s,2H),8.16–8.09(m,2H),7.97(d,J＝2.1Hz,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.75–7.66(m,2H),7.51(d,J＝8.1Hz,1H),7.43(d,J＝8.4Hz,1H),5.49(s,2H),3.52(s,2H),2.55(s,3H),2.42(br,8H),2.15(s,3H).MS:580[M+H] +。
实施例71. N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-羟基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)乙基-1-醇与N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝2.0Hz,1H),8.00–7.93(m,2H),7.88(dd,J＝8.0,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.58–7.47(m,2H),7.43(d,J＝8.5Hz,1H),4.90(d,J＝5.3Hz,1H),4.11(t,J＝5.6Hz,2H),3.72(t,J＝5.5Hz,2H),3.52(s,2H),2.54(s,3H),2.45-2.33(m,8H),2.15(s,3H).MS:585[M+H] +。
Figure PCTCN2020073018-appb-000057
实施例72. N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-氟乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-(2-氟乙基)-1H-吡唑-4-基)-5-碘嘧啶-2-胺与N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),9.99(s,1H),8.67(s,2H),8.11(d,J＝1.9Hz,1H),8.04–7.95(m,2H),7.89(dd,J＝8.0,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.60(s,1H),7.51(d,J＝8.1Hz,1H),7.43(d,J＝8.4Hz,1H),4.75(dt,J＝47.4,4.7Hz,2H),4.42(dt,J＝27.9,4.7Hz,2H),3.52(s,2H),2.54(s,3H),2.43(s,8H),2.18(s,3H).MS:587[M+H] +。
实施例73. N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)嘧啶-2-胺与N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝2.0Hz,1H),7.98(d,J＝2.1 Hz,1H),7.94(s,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.56(s,1H),7.50(d,J＝8.2Hz,1H),7.43(d,J＝8.5Hz,1H),4.23(t,J＝5.3Hz,2H),3.67(t,J＝5.3Hz,2H),3.52(s,2H),3.23(s,3H),2.54(s,3H),2.43(br,8H),2.18(s,3H).MS:599[M+H] +。
Figure PCTCN2020073018-appb-000058
实施例74. N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)丙基-1-醇与N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.98(d,J＝2.1Hz,1H),7.94(s,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.71(dd,J＝8.5,2.1Hz,1H),7.54(s,1H),7.50(d,J＝8.1Hz,1H),7.43(d,J＝8.4Hz,1H),4.59(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.52(s,2H),3.39(q,J＝6.0Hz,2H),2.54(s,3H),2.43(br,8H),2.16(s,3H),1.90(t,J＝6.6Hz,2H).MS:599[M+H] +。
实施例75. N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-氰基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)丙腈与N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),10.02(s,1H),8.67(s,2H),8.14–8.04(m,2H),7.98(d,J＝2.1Hz,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.63(s,1H),7.51(d,J＝8.1Hz,1H),7.43(d,J＝8.5Hz,1H),4.38(t,J＝6.4Hz,2H),3.52(s,2H),3.05(t,J＝6.4Hz,2H),2.54(s,3H),2.43(br,8H),2.18(s,3H).MS:594[M+H] +。
Figure PCTCN2020073018-appb-000059
实施例76. N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(3-甲氧基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(3-甲氧基丙基)-1H-吡唑-4-基)嘧啶-2-胺与N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.98(d,J＝2.2 Hz,1H),7.94(s,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.71(dd,J＝8.4,2.2Hz,1H),7.55(s,1H),7.50(d,J＝8.1Hz,1H),7.43(d,J＝8.4Hz,1H),4.12(t,J＝6.9Hz,2H),3.52(s,2H),3.28(t,J＝6.2Hz,2H),3.24(s,3H),2.54(s,3H),2.43(br,8H),2.17(s,3H),1.98(q,J＝6.5Hz,2H).MS:613[M+H] +。
实施例77. N-(3-氟-4-((4-(2-羟基乙基)哌嗪-1-基)甲基)苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-(2-羟基乙基)哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.93(s,1H),8.65(s,2H),8.10(s,1H),7.94-7.84(m,2H),7.73(d,J＝12.4Hz,1H),7.66-7.45(m,3H),7.34(t,J＝8.4Hz,1H),4.39-4.31(m,1H),3.82(s,3H),3.47(s,4H),2.54(s,3H),2.39(br,10H).MS:569[M+H] +。
Figure PCTCN2020073018-appb-000060
实施例78.(R)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与(R)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.94(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.95-7.85(m,2H),7.73(dd,J＝12.6,2.1Hz,1H),7.58-7.49(m,3H),7.35(t,J＝8.5Hz,1H),3.82(s,3H),3.56(s,2H),2.70-2.66(m,1H),2.61-2.55(m,5H),2.48-2.41(m,1H),2.29(t,J＝7.4Hz,1H),2.10(s,6H),1.93-1.77(m,1H),1.61(br,1H).MS:553[M+H] +。
实施例79.(S)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与(S)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),9.93(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.94-7.85(m,2H),7.74(dd,J＝12.5,2.0Hz,1H),7.60-7.47(m,3H),7.37(t,J＝8.5Hz,1H),3.82(s,3H),3.62(s,2H),2.70(t,J＝8.6Hz,1H),2.60-2.45(m,4H),2.54(s,3H),2.45(s,6H),2.00(dt,J＝9.8,5.9Hz,1H),1.79(dd,J＝13.6,6.9Hz,1H).MS:553[M+H] +。
Figure PCTCN2020073018-appb-000061
实施例80. 4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-苯基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-苯基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.28(s,1H),9.93(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.92(s,1H),7.96–7.86(m,1H),7.79(d,J＝8.0Hz,2H),7.54–7.46(m,2H),7.36(t,J＝7.8Hz,2H),7.11(t,J＝7.4Hz,1H),3.82(s,3H),2.54(s,3H).MS:409[M+H] +。
实施例81.N-(3-氟-5-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-5-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),9.94(s,1H),8.66(s,2H),8.12(d,J＝1.9Hz,1H),7.95–7.85(m,2H),7.69(dt,J＝11.4,2.2Hz,1H),7.57–7.47(m,3H),6.87(d,J＝9.0Hz,1H),3.82(s,3H),3.48(s,2H),2.54(s,3H),2.43(br,8H),2.25(s,3H).MS:539[M+H] +。
Figure PCTCN2020073018-appb-000062
实施例82.N-(4-((二甲氨基)甲基)-3-氟苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与N-(4-((二甲氨基)甲基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),9.94(s,1H),8.65(s,2H),8.11(d,J＝1.9Hz,1H),7.95–7.85(m,2H),7.75(dd,J＝12.6,2.0Hz,1H),7.60–7.47(m,3H),7.36(t,J＝8.4Hz,1H),3.82(s,3H),3.47(s,2H),2.54(s,3H),2.19(s,6H).MS:484[M+H] +。
实施例83.N-(3-((二甲氨基)甲基)-5-氟苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与N-(3-((二甲氨基)甲基)-5-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz, DMSO-d 6)δ10.43(s,1H),9.94(s,1H),8.66(s,2H),8.13(d,J＝1.9Hz,1H),7.95–7.86(m,2H),7.69(dt,J＝11.5,2.2Hz,1H),7.58–7.46(m,3H),6.85(dd,J＝9.6,1.7Hz,1H),3.82(s,3H),3.39(s,2H),2.54(s,3H),2.18(s,6H).MS:484[M+H] +。
Figure PCTCN2020073018-appb-000063
实施例84.N-(3-(3-(二甲氨基)丙基)-5-氟苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与N-(3-(3-(二甲氨基)丙基)-5-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.92(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.60(dt,J＝11.5,2.2Hz,1H),7.50(d,J＝8.7Hz,2H),7.44(d,J＝1.6Hz,1H),6.81(dt,J＝9.6,1.9Hz,1H),3.82(s,3H),2.59(t,J＝7.7Hz,2H),2.54(s,3H),2.23(t,J＝7.1Hz,2H),2.14(s,6H),1.72(q,J＝7.4Hz,2H).MS:512[M+H] +。
实施例85.N-(3-氟-5-(3-羟基丙基)苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-5-(3-羟基丙基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。
1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),7.92(s,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.60(dt,J＝11.5,2.1Hz,1H),7.50(d,J＝8.7Hz,2H),7.44(s,1H),6.80(d,J＝9.6Hz,1H),4.53(t,J＝5.1Hz,1H),3.82(s,3H),3.47–3.34(m,2H),2.62(t,J＝7.8Hz,2H),2.54(s,3H),1.74(q,J＝7.0Hz,2H).MS:485[M+H] +。
Figure PCTCN2020073018-appb-000064
实施例86.N-(4-(3-(二甲氨基)丙基)-3-氟苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与N-(4-(3-(二甲基氨基)丙基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),9.95(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.95–7.84(m,2H),7.70(dd,J ＝12.6,2.0Hz,1H),7.54–7.45(m,3H),7.26(t,J＝8.6Hz,1H),3.82(s,3H),2.58(t,J＝7.7Hz,2H),2.54(s,3H),2.23(t,J＝7.2Hz,2H),2.14(s,6H),1.68(q,J＝7.5Hz,2H).MS:512[M+H] +。
实施例87.(R)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-((2-((1-(2-羟基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)乙基-1-醇与(R)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.94(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96(s,1H),7.88(dd,J＝7.9,1.9Hz,1H),7.72(dd,J＝12.5,2.0Hz,1H),7.58-7.47(m,3H),7.35(t,J＝8.4Hz,1H),4.89(t,J＝5.3Hz,1H),4.11(t,J＝5.6Hz,2H),3.72(q,J＝5.5Hz,2H),3.56(q,J＝12.9Hz,2H),2.70-2.65(m,3H),2.52(s,3H),2.43(q,J＝8.4Hz,1H),2.33-2.21(m,1H),2.07(s,6H),1.88-1.78(m,1H),1.61-1.58(m,1H).MS:583[M+H] +。
Figure PCTCN2020073018-appb-000065
实施例88.(S)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-((2-((1-(2-羟基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)乙基-1-醇与(S)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),9.86(s,1H),8.59(s,2H),8.03(d,J＝2.0Hz,1H),7.88(s,1H),7.81(dd,J＝8.0,2.0Hz,1H),7.65(dd,J＝12.5,2.1Hz,1H),7.51–7.40(m,3H),7.28(t,J＝8.4Hz,1H),4.81(t,J＝5.2Hz,1H),4.04(t,J＝5.5Hz,2H),3.65(q,J＝5.3Hz,2H),3.49(q,J＝13.1Hz,2H),2.65–2.47(m,3H),2.47(s,3H),2.36(td,J＝8.7,5.9Hz,1H),2.25–2.14(m,1H),2.00(s,6H),1.76(dd,J＝12.9,6.5Hz,1H),1.57–1.46(m,1H).MS:583[M+H] +。
实施例89.(R)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-((2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)丙基-1-醇与(R)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.94(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.72(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,3H),7.35(t,J＝8.4Hz,1H),4.58(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.56(q,J＝13.1Hz,2H),3.40-3.34(m,2H),2.71–2.56(m,3H),2.54(s,3H),2.49–2.38(m,1H),2.27(s,1H),2.07(s,6H),1.96–1.78(m,3H),1.59(s,1H). MS:597[M+H] +。
Figure PCTCN2020073018-appb-000066
实施例90.(S)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-((2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)丙基-1-醇与(S)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.93(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96-7.85(m,2H),7.73(dd,J＝12.4,2.0Hz,1H),7.53(dt,J＝14.3,5.4Hz,3H),7.36(t,J＝8.4Hz,1H),4.58(t,J＝5.1Hz,1H),4.13(t,J＝7.0Hz,2H),3.56(q,J＝13.1Hz,2H),3.39(q,J＝5.9Hz,2H),2.68(d,J＝5.2Hz,2H),2.60(t,J＝7.4Hz,1H),2.55(s,3H),2.44(d,J＝6.7Hz,1H),2.31-2.25(m,1H),2.08(s,6H),2.02-1.80(m,3H),1.59(br,1H).MS:597[M+H] +。
实施例91. 3-((2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1,3-二甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),9.28(s,1H),8.61(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.82(s,1H),7.73(d,J＝8.5Hz,2H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),3.74(s,3H),3.42(s,2H),2.53(s,3H),2.36(br,8H),2.17(s,3H),2.11(s,3H).MS:535[M+H] +。
Figure PCTCN2020073018-appb-000067
实施例92. 3-((2-((1-乙基-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-乙基-3-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),9.26(s,1H),8.61(s,2H),8.10(s,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.85(s,1H),7.73(d,J＝8.4Hz,2H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.03(d,J＝7.2Hz,2H),3.44(s,2H),2.53(s,3H),2.38(br,8H),2.22(s,3H),2.11(s,3H),1.34(t,J＝7.2Hz,3H).MS:549[M+H] +。
实施例93. 3-((2-((1-(叔丁基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-叔丁基-3-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),9.21(s,1H),8.61(s,2H),8.09(d,J＝1.9Hz,1H),7.88(s,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.73(d,J＝8.5Hz,2H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),3.42(s,2H),2.53(s,3H),2.35(br,8H),2.17(s,3H),2.11(s,3H),1.49(s,9H).MS:577[M+H] +。
Figure PCTCN2020073018-appb-000068
实施例94. 4-甲基-3-((2-((3-甲基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲基-1-(四氢吡喃-4-基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.28(s,1H),9.27(s,1H),8.61(s,2H),8.10(d,J＝2.0Hz,1H),7.92–7.85(m,2H),7.74(d,J＝8.2Hz,2H),7.49(d,J＝8.1Hz,1H),7.28(d,J＝8.2Hz,2H),4.29(td,J＝9.9,4.9Hz,1H),3.95(dt,J＝11.6,3.3Hz,2H),3.51–3.42(m,4H),2.64(br,8H),2.54(s,3H),2.38(s,3H),2.11(s,3H),1.92(td,J＝10.9,9.7,3.8Hz,4H).MS:605[M+H] +。
实施例95. 3-((2-((1-(2-羟基乙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)乙基-1-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.31(d,J＝4.2Hz,1H),9.28(s,1H),8.62(s,2H),8.11(d,J＝1.9Hz,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.85(s,1H),7.76(d,J＝8.2Hz,2H),7.49(d,J＝8.1Hz,1H),7.29(d,J＝8.1Hz,2H),4.88(t,J＝5.4Hz,1H),4.03(t,J＝5.6Hz,2H),3.71(q,J＝5.3Hz,2H),3.52(s,3H),3.42(s,2H),2.85(br,8H),2.54(s,3H),2.12(s,3H).MS:565[M+H] +。
Figure PCTCN2020073018-appb-000069
实施例96. 3-((2-((1-(2-甲氧基基乙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(2-甲氧基乙基)-3-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),9.27(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.84(s,1H),7.76–7.69(m,2H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),4.15(t,J＝5.3Hz,2H),3.66(t,J＝5.4Hz,2H),3.42(s,2H),3.24(s,3H),2.54(s,3H),2.35(br,8H),2.16(s,3H),2.11(s,3H).MS:579[M+H] +。
实施例97. 3-((2-((1-(3-羟基丙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)丙基-1-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),9.28(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.84(s,1H),7.72(d,J＝8.3Hz,2H),7.49(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.58(t,J＝5.1Hz,1H),4.05(t,J＝7.0Hz,2H),3.44–3.37(m,4H),2.53(s,3H),2.34(s,8H),2.15(s,3H),2.11(s,3H)1.88(t,J＝6.6Hz,2H).MS:579[M+H] +。
Figure PCTCN2020073018-appb-000070
实施例98. 3-((2-((1-(3-甲氧基丙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(3-甲氧基丙基)-3-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H),9.29(s,1H),8.62(s,2H),8.10(d,J＝1.8Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.84(s,1H),7.75(d,J＝8.2Hz,2H),7.49(d,J＝8.1Hz,1H),7.29(d,J＝8.1Hz,2H),4.04(t,J＝7.0Hz,2H),3.52(s,2H),3.24(s,3H),2.87(br,8H),2.53(br,6H),2.12(s,3H),1.97(q,J＝6.6Hz,2H),1.18(t,J＝7.3Hz,2H).MS:593[M+H] +。
实施例99. 3-((2-((1-(2-羟基-2-甲基丙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由1-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)- 2-甲基丙基-2-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.28(s,1H),9.30(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.86(s,1H),7.75(d,J＝8.2Hz,2H),7.49(d,J＝8.1Hz,1H),7.28(d,J＝8.1Hz,2H),4.67(s,1H),3.91(s,2H),3.50(s,2H),2.74(br,8H),2.56–2.43(m,6H),2.13(s,3H),1.07(s,6H).MS:593[M+H] +。
Figure PCTCN2020073018-appb-000071
实施例100. 3-((2-((1-(3-羟基-3-甲基丁基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由4-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)-2-甲基丁基-2-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H),9.28(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.92–7.82(m,2H),7.75(d,J＝8.2Hz,2H),7.49(d,J＝8.2Hz,1H),7.29(d,J＝8.2Hz,2H),4.44(s,1H),4.11–4.02(m,2H),3.50(s,2H),2.54(s,3H),2.48-2.32(m,11H),2.11(s,3H),1.91–1.82(m,2H),1.13(s,6H).MS:607[M+H] +。
实施例101. 3-((2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲氧基-1-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),8.95(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.73(d,J＝8.4Hz,2H),7.69(s,1H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),3.79(s,3H),3.68(s,3H),3.42(s,2H),2.53(s,3H),2.36(br,8H),2.17(s,3H).MS:551[M+H] +。
Figure PCTCN2020073018-appb-000072
实施例102. 3-((2-((1-乙基-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-乙基-3-甲氧基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR (400MHz,DMSO-d 6)δ10.26(s,1H),8.94(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.76–7.69(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),3.96(q,J＝7.2Hz,2H),3.79(s,3H),3.42(s,2H),2.53(s,3H),2.39(br,8H),2.18(s,3H),1.33(t,J＝7.2Hz,3H).MS:565[M+H] +。
实施例103. 3-((2-((1-叔丁基-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-叔丁基-3-甲氧基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),8.89(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝7.9,2.0Hz,1H),7.78–7.69(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.2Hz,2H),3.80(s,3H),3.42(s,2H),2.53(s,3H),2.37(br,8H),2.18(s,3H),1.47(s,9H).MS:593[M+H] +。
Figure PCTCN2020073018-appb-000073
实施例104. 3-((2-((3-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.28(s,1H),8.94(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.8Hz,1H),7.80–7.71(m,3H),7.49(d,J＝8.1Hz,1H),7.28(d,J＝8.2Hz,2H),4.19(tt,J＝10.3,4.8Hz,1H),3.95(dt,J＝11.8,3.2Hz,2H),3.80(s,3H),3.52–3.39(m,4H),2.75–2.67(m,8H),2.53(s,3H),2.43(s,3H),1.96-1.85(m,4H).MS:621[M+H] +。
实施例105. 3-((2-((1-(2-羟基乙基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-3-甲氧基-1H-吡唑-1-基)乙基-1-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),8.96(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.76–7.69(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.3Hz,2H),4.87(t,J＝5.3Hz,1H),3.96(t,J＝5.6Hz,2H),3.80(s,3H),3.70(q,J＝5.3Hz,2H),3.42(s,2H),2.53(s,3H),2.37(br,8H),2.18(s,3H).MS:581[M+H] +。
Figure PCTCN2020073018-appb-000074
实施例106. 3-((2-((1-(2-甲氧基乙基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲氧基-1-(2-甲氧基乙基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),8.96(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.77–7.68(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),4.08(t,J＝5.3Hz,2H),3.79(s,3H),3.64(t,J＝5.3Hz,2H),3.43(s,2H),3.25(s,3H),2.53(s,3H),2.39(s,8H),2.21(s,3H).MS:595[M+H] +。
实施例107. 3-((2-((1-(3-羟基丙基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-3-甲氧基-1H-吡唑-1-基)丙基-1-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),8.95(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.92–7.85(m,1H),7.72(d,J＝7.7Hz,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),4.58(t,J＝5.1Hz,1H),3.98(t,J＝7.0Hz,2H),3.79(s,3H),3.46–3.37(m,4H),2.53(s,3H),2.34(s,8H),2.15(s,3H),1.92–1.83(m,2H).MS:595[M+H] +。
Figure PCTCN2020073018-appb-000075
实施例108. 3-((2-((1-(3-甲氧基丙基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲氧基-1-(3-甲氧基丙基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),8.96(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝8.7Hz,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.4Hz,2H),3.97(t,J＝7.0Hz,2H),3.79(s,3H),3.43(s,2H),3.30(d,J＝6.1Hz,2H),3.25(s,3H),2.53(s,3H),2.40(s,8H),2.22(s,3H),1.96(q,J＝6.6Hz,2H).MS:609[M+H] +。
实施例109. 3-((2-((1-(2-羟基-2-甲基丙基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由1-(4-((5-碘嘧啶-2-基)氨基)-3-甲氧基-1H-吡唑-1-基)-2-甲基丙基-2-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),8.99(s,1H),8.59(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.76–7.68(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.5Hz,2H),4.64(s,1H),3.83(s,2H),3.79(s,3H),3.43(s,2H),2.53(s,3H),2.40(brs,8H),2.22(s,3H),1.09(s,6H).MS:609[M+H] +。
Figure PCTCN2020073018-appb-000076
实施例110. 3-((2-((1-(3-羟基-3-甲基丁基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由4-(4-((5-碘嘧啶-2-基)氨基)-3-甲氧基-1H-吡唑-1-基)-2-甲基丁基-2-醇与3-乙炔基-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),8.95(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.76–7.69(m,3H),7.48(d,J＝8.1Hz,1H),7.26(d,J＝8.2Hz,2H),4.44(s,1H),4.04–3.95(m,2H),3.79(s,3H),3.43(s,2H),2.53(s,3H),2.40(s,8H),2.22(s,3H),1.90–1.81(m,2H),1.14(s,6H).MS:623[M+H] +。
实施例111. 3-((2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1,3-二甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.28(s,1H),8.61(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝7.9,1.9Hz,1H),7.82(s,1H),7.73(dd,J＝12.4,2.0Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.4Hz,1H),3.74(s,3H),3.47(s,2H),2.54(s,3H),2.38(br,8H),2.14(s,3H),2.10(s,3H).MS:553[M+H] +。
Figure PCTCN2020073018-appb-000077
实施例112. 3-((2-((1-乙基-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-乙基-3-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.27(s,1H),8.61(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.85(s,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.03(q,J＝7.2Hz,2H),3.47(s,2H),2.54(s,3H),2.37(br,8H),2.16(s,3H),2.11(s,3H),1.34(t,J＝7.2Hz,3H).MS:567[M+H] +。
实施例113. 3-((2-((1-(叔丁基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-叔丁基-3-甲基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),9.21(s,1H),8.61(s,2H),8.09(d,J＝1.9Hz,1H),7.88(s,1H),7.92-7.78(m,1H),7.73(dd,J＝12.4,2.0Hz,1H),7.58-7.46(m,2H),7.34(t,J＝8.4Hz,1H),3.47(s,2H),2.53(s,3H),2.39(br,8H),2.16(s,3H),2.11(s,3H),1.49(s,9H).MS:595[M+H] +。
Figure PCTCN2020073018-appb-000078
实施例114. 4-甲基-3-((2-((3-甲基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲基-1-(四氢吡喃-4-基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.27(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.89(d,J＝11.1Hz,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.29(td,J＝9.9,5.0Hz,1H),3.95(dt,J＝11.7,3.3Hz,2H),3.49–3.39(m,4H),2.54(s,3H),2.35(br,8H),2.14(s,3H),2.11(s,3H),1.97–1.90(m,4H).MS:623[M+H] +。
实施例115. 3-((2-((1-(2-羟基乙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)乙基-1-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体 产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.28(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.92–7.83(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.87(t,J＝5.3Hz,1H),4.03(t,J＝5.6Hz,2H),3.71(q,J＝5.5Hz,2H),3.47(s,2H),2.54(s,3H),2.38(br,8H),2.14(s,3H),2.12(s,3H).MS:583[M+H] +。
Figure PCTCN2020073018-appb-000079
实施例116. 3-((2-((1-(2-甲氧基乙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(2-甲氧基乙基)-3-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.28(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.84(s,1H),7.73(dd,J＝12.5,1.9Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.15(t,J＝5.3Hz,2H),3.65(t,J＝5.4Hz,2H),3.47(s,2H),3.24(s,3H),2.54(s,3H),2.32(br,8H),2.14(s,3H).,2.11(s,3H).MS:597[M+H] +。
实施例117. 3-((2-((1-(3-羟基丙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)丙基-1-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),9.29(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.92–7.82(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,2H),7.34(t,J＝8.5Hz,1H),4.58(t,J＝5.1Hz,1H),4.05(t,J＝7.0Hz,2H),3.47(s,2H),3.40(t,J＝5.8Hz,2H),2.54(s,3H),2.38(brs,8H),2.14(s,3H),2.11(s,3H),1.89(q,J＝6.6Hz,2H).MS:597[M+H] +。
Figure PCTCN2020073018-appb-000080
实施例118. 3-((2-((1-(3-甲氧基丙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(3-甲氧基丙基)-3-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产 物； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),9.30(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.92-7.82(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58-7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.04(t,J＝7.0Hz,2H),3.47(s,2H),3.29(t,J＝6.2Hz,2H),3.24(s,3H),2.54(s,3H),2.40(br,8H),2.14(s,3H),2.12(s,3H),1.97(q,J＝6.6Hz,2H).MS:611[M+H] +。
实施例119. 3-((2-((1-(2-羟基-2-甲基丙基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由1-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)-2-甲基丙基-2-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),9.31(s,1H),8.62(s,2H),8.09(d,J＝1.9Hz,1H),7.92–7.83(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.47(m,2H),7.34(t,J＝8.5Hz,1H),4.67(s,1H),3.91(s,2H),3.47(s,2H),2.54(s,3H),2.31(br,8H),2.14(s,3H),2.13(s,3H),1.07(s,6H).MS:611[M+H] +。
Figure PCTCN2020073018-appb-000081
实施例120. 3-((2-((1-(3-羟基-3-甲基丁基)-3-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由4-(4-((5-碘嘧啶-2-基)氨基)-3-甲基-1H-吡唑-1-基)-2-甲基丁基-2-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),9.28(s,1H),8.62(s,2H),8.10(d,J＝1.9Hz,1H),7.92–7.83(m,2H),7.73(dd,J＝12.5,2.0Hz,1H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.44(s,1H),4.11–4.02(m,2H),3.47(s,2H),2.54(s,3H),2.35(br,8H),2.14(s,3H),2.11(s,3H),1.91–1.82(m,2H),1.13(s,6H).MS:625[M+H] +。
实施例121.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲氧基-1-甲基-1H-吡唑-4-基)嘧啶-2-氨与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),8.96(s,1H),8.58(s,2H),8.10(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.69(s,1H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),3.79(s,3H),3.68(s,3H),3.47(s,2H),2.53(s,3H),2.38(br,8H),2.14(s,3H).MS:569[M+H] +。
Figure PCTCN2020073018-appb-000082
实施例122. 3-((2-((1-乙基-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-乙基-3-甲氧基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),8.95(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.90–7.85(m,1H),7.73(d,J＝8.6Hz,2H),7.57–7.46(m,2H),7.34(t,J＝8.4Hz,1H),3.96(q,J＝7.2Hz,2H),3.79(s,3H),3.47(s,2H),2.53(s,4H),2.40–2.30(m,14H),2.14(s,3H),1.33(t,J＝7.2Hz,3H).MS:583[M+H] +。
实施例123. 3-((2-((1-叔丁基-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-叔丁基-3-甲氧基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),8.90(s,1H),8.58(s,2H),8.09(d,J＝2.0Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝13.2Hz,2H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),3.80(s,3H),3.47(s,2H),2.53(s,3H),2.38(br,8H),2.17(s,3H),1.47(s,9H).MS:611[M+H] +。
Figure PCTCN2020073018-appb-000083
实施例124.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((3-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲氧基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),8.95(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.80–7.68(m,2H),7.57–7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.19(dt,J＝10.8,5.6Hz,1H),3.99–3.89(m,2H),3.80(s,3H),3.47-3.39(m,4H),2.53(s,3H),2.38(br,8H),2.15(s,3H),1.99-1.86(m,4H).MS:639[M+H] +。
实施例125.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-羟基乙基)-3-甲氧基-1H-吡唑-4-基)氨基) 嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由2-(4-((5-碘嘧啶-2-基)氨基)-3-甲氧基-1H-吡唑-1-基)乙基-1-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),8.96(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.76-7.69(m,2H),7.58-7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.86(t,J＝5.3Hz,1H),3.96(t,J＝5.6Hz,2H),3.80(s,3H),3.70(q,J＝5.5Hz,2H),3.47(s,2H),2.53(s,3H),2.39-2.33(m,8H),2.15(s,3H).MS:599[M+H] +。
Figure PCTCN2020073018-appb-000084
实施例126.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-甲氧基乙基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲氧基-1-(2-甲氧基乙基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),8.95(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.77–7.68(m,2H),7.57–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.08(t,J＝5.3Hz,2H),3.79(s,3H),3.65(t,J＝5.3Hz,2H),3.47(s,2H),3.25(s,3H),2.53(s,3H),2.38-2.32(m,8H),2.14(s,3H).MS:613[M+H] +。
实施例127.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(3-羟基丙基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由3-(4-((5-碘嘧啶-2-基)氨基)-3-甲氧基-1H-吡唑-1-基)丙基-1-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),8.96(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.71(s,2H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.59(t,J＝5.1Hz,1H),3.98(t,J＝7.0Hz,2H),3.79(s,3H),3.49–3.37(m,4H),2.53(s,3H),2.36(br,8H),2.15(s,3H),1.88(t,J＝6.7Hz,2H).MS:613[M+H] +。
Figure PCTCN2020073018-appb-000085
实施例128.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(3-甲氧基丙基)-3-甲氧基-1H-吡唑-4-基)氨 基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(3-甲氧基-1-(3-甲氧基丙基)-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),8.97(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(d,J＝10.6Hz,2H),7.58–7.46(m,2H),7.34(t,J＝8.5Hz,1H),3.97(t,J＝7.0Hz,2H),3.79(s,3H),3.47(s,2H),3.31(t,J＝6.1Hz,2H),3.25(s,3H),2.53(s,3H),2.40–2.31(m,8H),2.15(s,3H),1.96(q,J＝6.6Hz,2H).MS:627[M+H] +。
实施例129.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-羟基-2-甲基丙基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由1-(4-((5-碘嘧啶-2-基)氨基)-3-甲氧基-1H-吡唑-1-基)-2-甲基丙基-2-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.44(s,1H),8.99(s,1H),8.59(s,2H),8.09(d,J＝1.9Hz,1H),7.88(dd,J＝7.9,1.9Hz,1H),7.77–7.68(m,2H),7.57–7.46(m,2H),7.34(t,J＝8.5Hz,1H),4.64(s,1H),3.83(s,2H),3.79(s,3H),3.47(s,2H),2.53(s,3H),2.36(br,8H),2.15(s,3H),1.09(s,6H).MS:627[M+H] +。
Figure PCTCN2020073018-appb-000086
实施例130.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(3-羟基-3-甲基丁基)-3-甲氧基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由4-(4-((5-碘嘧啶-2-基)氨基)-3-甲氧基-1H-吡唑-1-基)-2-甲基丁基-2-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),8.96(s,1H),8.58(s,2H),8.09(d,J＝1.9Hz,1H),7.87(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.73(s,1H),7.57–7.46(m,2H),7.34(t,J＝8.4Hz,1H),4.44(s,1H),4.04–3.95(m,2H),3.79(s,3H),3.47(s,2H),2.53(s,3H),2.36(br,8H),2.14(s,3H),1.90–1.81(m,2H),1.14(s,6H).MS:641[M+H] +。
实施例131. 3-((2-((1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz, DMSO-d 6)δ12.60(br,1H),10.47(s,1H),9.93(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.95(br,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.75(dd,J＝12.5,2.0Hz,1H),7.64–7.47(m,3H),7.36(t,J＝8.5Hz,1H),3.53(s,2H),3.11–3.02(m,3H),2.54(s,3H),2.51(br,8H).MS:525[M+H] +。
Figure PCTCN2020073018-appb-000087
实施例132.(R)-3-((2-((1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1H-吡唑-4-基)嘧啶-2-胺与(R)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ12.83–12.29(m,1H),10.47(s,1H),9.93(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.89(dd,J＝8.0,1.9Hz,1H),7.76-7.70(m,3H),7.60–7.47(m,2H),7.37(t,J＝8.4Hz,1H),3.76–3.62(m,2H),3.60(d,J＝6.4Hz,2H),3.40(s,2H),2.69(t,J＝8.4Hz,1H),2.54(s,3H),2.35(s,6H),1.98(br,1H),1.76(br,1H).MS:539[M+H] +。
实施例133.(S)-3-((2-((1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1H-吡唑-4-基)嘧啶-2-胺与(S)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ12.57(br,1H),10.49(s,1H),9.93(s,1H),9.55(s,1H),8.66(s,2H),8.10(d,J＝2.0Hz,1H),7.89(dd,J＝8.0,1.9Hz,1H),7.77(br,2H),7.58(s,2H),7.38(s,1H),3.76(s,2H),3.64(s,2H),3.40(br,2H),2.81(br,1H),2.70(s,6H),2.54(s,3H),2.20-2.11(m,1H),1.94–1.87(m,1H).MS:539[M+H] +。
Figure PCTCN2020073018-appb-000088
实施例134.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由1-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)-2-甲基丙基-2-醇与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),9.96(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.95(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.76(dd,J＝12.5,2.0Hz,1H),7.60–7.47(m,3H),7.37(t,J＝8.4Hz, 1H),4.69(s,1H),3.98(s,2H),3.56(s,2H),2.54-2.50(m,14H),1.06(s,6H).MS:597[M+H] +。
实施例135.N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由1-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)-2-甲基丙基-2-醇与N-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-乙炔基-4-甲基苯甲酰胺胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.96(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),8.01–7.92(m,2H),7.88(dd,J＝8.0,1.9Hz,1H),7.73(dd,J＝8.4,2.1Hz,1H),7.58–7.40(m,3H),4.70(s,1H),3.98(s,2H),3.56(s,2H),2.54(s,3H),2.49(br,8H),2.41(s,3H),1.06(s,6H).MS:613[M+H] +。
Figure PCTCN2020073018-appb-000089
实施例136.(R)-N-(3-氯-4-((3-(二甲氨基)吡咯烷-1-基)甲基)苯基)-3-((2-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)嘧啶-2-胺与(R)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氯苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),9.95(s,1H),8.66(s,2H),8.11(d,J＝1.9Hz,1H),8.01–7.92(m,2H),7.88(dd,J＝7.9,1.9Hz,1H),7.71(dd,J＝8.4,2.1Hz,1H),7.56(s,1H),7.50(d,J＝8.1Hz,1H),7.43(d,J＝8.4Hz,1H),4.23(t,J＝5.3Hz,2H),3.70–3.58(m,4H),3.23(s,3H),2.69(q,J＝6.7,4.9Hz,2H),2.60(dd,J＝8.1,5.9Hz,1H),2.54(s,3H),2.49–2.43(m,1H),2.38–2.30(m,1H),2.08(s,6H),1.90–1.80(m,1H),1.62(d,J＝8.6Hz,1H).MS:613[M+H] +。
实施例137.(R)-N-(3-氯-4-((3-(二甲氨基)吡咯烷-1-基)甲基)苯基)-3-((2-((1-(3-甲氧基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(3-甲氧基丙基)-1H-吡唑-4-基)嘧啶-2-胺与(R)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氯苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),9.96(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.99–7.84(m,3H),7.71(dd,J＝8.4,2.2Hz,1H),7.55(s,1H),7.50(d,J＝8.1Hz,1H),7.42(d,J＝8.4Hz,1H),4.12(t,J＝7.0Hz,2H),3.69–3.52(m,2H),3.35(s,3H),3.28(t,J＝6.2Hz,2H),2.75–2.57(m,3H),2.54(s,3H),2.50–2.42(m,1H),2.35-2.31(m,1H),2.08(s,6H),1.98(q,J＝6.6Hz,2H),1.87-1.82(m,1H),1.65-1.58(m,1H).MS:627[M+H] +。
Figure PCTCN2020073018-appb-000090
实施例138.(R)-N-(3-氟-4-((3-(二甲氨基)吡咯烷-1-基)甲基)苯基)-3-((2-((1-(2-甲氧基乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(2-甲氧基乙基)-1H-吡唑-4-基)嘧啶-2-胺与(R)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.94(s,1H),7.89(dd,J＝7.9,2.0Hz,1H),7.74(dd,J＝12.5,2.0Hz,1H),7.58–7.54(m,2H),7.50(d,J＝8.1Hz,1H),7.36(t,J＝8.5Hz,1H),4.23(t,J＝5.3Hz,2H),3.66(t,J＝5.3Hz,2H),3.61(t,J＝9.7Hz,2H),3.40(s,2H),3.23(s,3H),3.02(br,2H),2.69(dd,J＝9.6,7.0Hz,1H),2.54(s,3H),2.33(s,6H),1.98–1.91(m,1H),1.79-1.70(s,1H).MS:597[M+H] +。
实施例139.(R)-N-(3-氟-4-((3-(二甲氨基)吡咯烷-1-基)甲基)苯基)-3-((2-((1-(3-甲氧基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-(3-甲氧基丙基)-1H-吡唑-4-基)嘧啶-2-胺与(R)-N-(4-((3-(二甲氨基)吡咯烷-1-基)甲基)-3-氟苯基)-3-乙炔基-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),9.96(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.96–7.84(m,2H),7.75(dd,J＝12.5,2.0Hz,1H),7.61–7.48(m,3H),7.38(t,J＝8.5Hz,1H),4.12(t,J＝6.9Hz,2H),3.65(br,4H),3.28(t,J＝6.2Hz,2H),3.23(s,3H),3.10(q,J＝7.3Hz,2H),2.72-2.54(m,7H),2.54(s,3H),2.16–2.01(m,1H),1.98(q,J＝6.6Hz,2H),1.97–1.83(m,1H).MS:611[M+H] +。
Figure PCTCN2020073018-appb-000091
实施例140.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基-3-((2-((1-甲基-1H-吡唑-3-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),10.24(s,1H),8.67(s,2H),8.11(d,J＝1.9Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.6,1.9Hz,1H),7.61–7.47(m,3H),7.34(t,J＝8.5Hz,1H),6.57(d,J＝2.2Hz,1H),3.76(s,3H),3.47(s,2H),2.54(s,3H),2.37(s,8H),2.14(s,3H).MS:539[M+H] +。
实施例141.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基-3-((2-(噻唑-4-基氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(5-碘嘧啶-2-基)噻唑-4-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.46(s,1H),8.85–8.80(m,3H),8.14(d,J＝1.9Hz,1H),7.92(dd,J＝8.1,1.9Hz,1H),7.84(s,1H),7.72(dd,J＝12.5,2.0Hz,1H),7.60(s,1H),7.53(dd,J＝8.3,2.4Hz,2H),7.34(t,J＝8.5Hz,1H),3.47(s,2H),2.54(s,3H),2.37(br,8H),2.15(s,3H).MS:542[M+H] +。
Figure PCTCN2020073018-appb-000092
实施例142.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-(异恶唑-4-基氨基)嘧啶-5-基)乙炔基)-4-甲基苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(5-碘嘧啶-2-基)异恶唑-4-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),9.92(s,1H),9.10(d,J＝2.3Hz,1H),8.55(d,J＝2.3Hz,1H),8.15(d,J＝1.9Hz,1H),7.94(dd,J＝7.9,1.9Hz,1H),7.74(dd,J＝12.5,2.0Hz,1H),7.61–7.50(m,3H),7.35(t,J＝8.5Hz,1H),7.29(s,1H),3.48(s,2H),2.58(d,J＝2.7Hz,3H),2.48–2.31(m,8H),2.17(s,3H).MS:526[M+H] +。
实施例143.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基-3-((2-((1-甲基-1H-吡咯烷-3-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡咯烷-3-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),9.77(s,1H),8.61(s,2H),8.09(d,J＝1.9Hz,1H),7.87(dd,J＝8.0,2.0Hz,1H),7.74(dd,J＝12.5,2.1Hz,1H),7.58–7.46(m,2H),7.35(t,J＝8.4Hz,1H),7.09(t,J＝2.1Hz,1H),6.56(t,J＝2.5Hz,1H),6.06(dd,J＝2.7,1.8Hz,1H),3.59(s,3H),3.49(s,2H),2.54(s,3H),2.42(br,8H),2.23(s,3H).MS:538[M+H] +。
Figure PCTCN2020073018-appb-000093
实施例144.N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基-3-((2-(噻吩-3-基氨基)嘧啶-5-基)乙炔基)苯 甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(噻吩-3-基)嘧啶-2-胺与3-乙炔基-N-(3-氟-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),10.42(s,1H),8.73(s,2H),8.11(d,J＝1.9Hz,1H),7.89(dd,J＝8.0,2.0Hz,1H),7.73(dd,J＝12.5,2.0Hz,1H),7.64(dd,J＝3.2,1.3Hz,1H),7.58–7.44(m,3H),7.34(t,J＝8.5Hz,1H),7.23(dd,J＝5.2,1.4Hz,1H),3.47(s,2H),2.55(s,3H),2.38(s,8H),2.14(s,3H).MS:541[M+H] +。
实施例145. 4-甲基-3-((2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.94(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.92(s,1H),7.88(dd,J＝8.0,1.9Hz,1H),7.60–7.45(m,4H),7.16(d,J＝8.1Hz,1H),3.82(s,3H),3.38(s,2H),2.54(s,3H),2.37(s,8H),2.32(s,3H),2.14(s,3H).MS:535[M+H] +。
Figure PCTCN2020073018-appb-000094
实施例146. 3-((2-((1-(2-氟乙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-(2-氟乙基)-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.97(s,1H),8.67(s,2H),8.10(d,J＝1.9Hz,1H),8.01(s,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.63–7.52(m,3H),7.49(d,J＝8.1Hz,1H),7.17(d,J＝8.1Hz,1H),4.81(t,J＝4.7Hz,1H),4.69(t,J＝4.7Hz,1H),4.42(dt,J＝27.9,4.7Hz,2H),3.39(s,2H),2.54(s,3H),2.37(s,8H),2.32(s,3H),2.18(s,3H).MS:567[M+H] +。
实施例147. 3-((2-((1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由1-(4-((5-碘嘧啶-2-基)氨基)-1H-吡唑-1-基)-2-甲基丙-2-醇与3-乙炔基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.95(s,1H),8.66(s,2H),8.10(d,J＝1.9Hz,1H),7.98–7.92(m,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.61–7.52(m,3H),7.48(d,J＝8.1Hz,1H),7.17(d,J＝ 8.1Hz,1H),3.98(s,2H),3.39(s,2H),2.54(s,3H),2.38(s,8H),2.32(s,3H),2.21(s,3H),1.06(s,6H).MS:593[M+H] +。
Figure PCTCN2020073018-appb-000095
实施例148. 3-((2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-乙基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.93(s,1H),8.65(s,2H),8.11(d,J＝1.9Hz,1H),7.95(d,J＝0.7Hz,1H),7.88(dd,J＝8.0,2.0Hz,1H),7.61–7.52(m,3H),7.48(d,J＝8.1Hz,1H),7.16(d,J＝8.0Hz,1H),4.11(q,J＝7.2Hz,2H),3.38(s,2H),2.54(s,3H),2.35(s,8H),2.32(s,3H),2.14(s,3H),1.36(t,J＝7.3Hz,3H).MS:549[M+H] +。
实施例149. 4-甲基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-丙基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.93(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.96–7.84(m,2H),7.61–7.45(m,4H),7.17(d,J＝8.1Hz,1H),4.04(t,J＝7.0Hz,2H),3.39(s,2H),2.54(s,3H),2.37-2.32(m,11H),2.18(s,3H),1.77(q,J＝7.2Hz,2H),0.84(t,J＝7.4Hz,3H).MS:563[M+H] +。
Figure PCTCN2020073018-appb-000096
实施例150. 3-((2-((1-丁基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)-4-甲基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)苯甲酰胺
以与实施例1相似的方法进行合成，不同之处在于由N-(1-丁基-1H-吡唑-4-基)-5-碘嘧啶-2-胺与3-乙炔基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.92(s,1H),8.65(s,2H),8.10(d,J＝1.9Hz,1H),7.96–7.84(m,2H),7.61–7.53(m,2H),7.57–7.45(m,2H),7.17(d,J＝8.1Hz,1H),4.07(t,J＝7.0Hz,2H),3.39(s,2H),2.54(s,3H),2.34(d,J＝17.5Hz,11H),2.17(s,3H),1.78–1.68(m,2H),1.30–1.20(m,2H),0.89(t,J＝7.4 Hz,3H).MS:577[M+H] +。
实施例151. 4-甲基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-((2-((1-戊基-1H-吡唑-4-基)氨基)嘧啶-5-基)乙炔基)苯甲酰胺
Figure PCTCN2020073018-appb-000097
以与实施例1相似的方法进行合成，不同之处在于由5-碘-N-(1-戊基-1H-吡唑-4-基)嘧啶-2-胺与3-乙炔基-N-(3-甲基-4-((4-甲基哌嗪-1-基)甲基)苯基)-4-甲基苯甲酰胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ10.18(s,1H),9.92(s,1H),8.65(s,2H),8.10(d,J＝2.0Hz,1H),7.96–7.84(m,2H),7.61–7.53(m,2H),7.57–7.45(m,2H),7.17(d,J＝8.1Hz,1H),4.07(t,J＝7.0Hz,2H),3.39(s,2H),2.54(s,3H),2.38(s,8H),2.32(s,3H),2.20(s,3H),1.75(q,J＝7.2Hz,2H),1.36–1.24(m,2H),1.27–1.16(m,2H),0.86(t,J＝7.2Hz,3H).MS:591[M+H] +。
生物试验所用仪器、材料和试剂
Figure PCTCN2020073018-appb-000098
Figure PCTCN2020073018-appb-000099
表5.示出了本申请生物试验所用部分仪器、材料和试剂
实验例1.化合物抑制ABL、ABL-T315I、KIT激酶活性的测试
在体外组装的酶促反应中，加入不同浓度的待测化合物，以检测化合物对ABL、ABL-T315I、KIT酶促反应的抑制作用，具体测试方法如下：
下述将以ABL为例，阐述试剂配制方案和完整的实验步骤；ABL、ABL-T315I、KIT激酶筛选体的实验条件见附录，根据ABL的实验方案微调即可得到完整ABL-T315I和KIT激酶筛选的实验方案。
1.试剂配制：
EDTA(0.5M pH8.0)溶液配制:准确称量14.612g EDTA粉末，加入超纯水后定容到100mL(若有不溶加热到37℃，用NaOH溶液调pH至8.0)
1×Kinase Assay Buffer：于试剂瓶中分别加入25mL HEPES溶液(1M)、190.175mg EGTA、5mL MgCl 2溶液(1M)、1mL DTT、50μL Tween-20，加超纯水定容到500mL(调pH到7.5)。
1×Detection Buffer:取1mL 10×Detection Buffer加入9mL水混匀。
4×终止液：将0.8mL上述EDTA(0.5M、pH 8.0)溶液、1mL 10×Detection Buffer及8.2mL超纯水混匀。
4×ABL激酶溶液:用1×Kinase Assay Buffer稀释激酶原液到浓度为0.62nM，混匀，冰上保存。
4×底物溶液：用1×Kinase Assay Buffer稀释底物ULight TM PolyGT原液到200nM，混匀。
4×ATP溶液：用1×Kinase Assay Buffer稀释ATP原液到浓度为40μM，混匀。
4×检测液：用1×Detection Buffer稀释检测抗体Eu-W1024-labeled Anti-Phosphotyrosine Antibody(PT66)到浓度为8nM，混匀。
2×底物/ATP混合液：将4×底物溶液和4×ATP溶液1:1等量混匀(使用前配制)。
2、实验步骤
1)化合物的稀释，
在96孔板a中，将化合物用DMSO溶液按3倍比例稀释，形成11个梯度，第12个梯度为纯DMSO溶液(作为阳性对照)；取一块新的96孔板b，将上述溶液用超纯水稀释6.25倍(DMSO浓度为16％)
2)将化合物转盘到384孔板
将上述96孔板b中用超纯水稀释过的化合物溶液按照2复孔的标准转盘到384孔板相应孔中。
3)加4×激酶溶液：用排枪取2.5μl上述4×激酶溶液加入到384孔板相应的反应孔中，混匀室温预反应5分钟。
4)加2×底物/ATP混合液:用排枪取5μl上述2×底物/ATP混合液到384孔板相应的反应孔中。
5)阴性对照：在384孔板中设置阴性对照孔，每孔加入2.5μl 4×底物、2.5μl 4×酶溶液、2.5μl 1×Kinase Assay Buffer和2.5μl含16％DMSO的超纯水。
6)离心混匀，避光室温反应2小时。
7)终止酶促反应：
吸取5μl上述4×终止液到384孔板相应孔，离心混匀，室温反应5分钟。
8)显色反应：
吸取5μl上述4×检测液加入到384孔板相应孔，离心混匀，室温反应1小时。
9)将384孔板放入读板仪，调取相应的程序检测信号。
10)IC 50分析：
孔读值＝10000*EU665值/EU615值
抑制率＝[1-(实验孔读值-阴性对照孔读值)/(阳性对照孔读值-阴性对照孔读值)]*100％
将药物浓度和相应抑制率输入GraphPad Prism 5处理计算出相应的IC 50。
附录：
ABL激酶活性抑制分子筛选实验条件：
反应体系中ABL激酶终浓度为0.155nM，ATP的终浓度10μM，底物ULight TM-labeled PolyGT终浓度为50nM，酶促反应时间为2小时。
反应体系中化合物最高终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。
DMSO终浓度为4％。
ABL-T315I激酶活性抑制分子筛选实验条件：
反应体系中ABL(T315I)激酶终浓度为0.5nM，ATP的终浓度10μM，底物ULight TM-labeled PolyGT终浓 度为50nM，酶促反应时间为2小时。
反应体系中化合物最高终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。
DMSO终浓度为1％。
KIT激酶活性抑制分子筛选实验条件：
反应体系中KIT激酶终浓度为0.1nM，ATP的终浓度1μM，底物ULight TM-labeled PolyGT终浓度为100nM，酶促反应时间为2小时。
反应体系中化合物最高终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。
DMSO终浓度为1％。
本发明中化合物对酪氨酸激酶ABL、ABL-T315I、KIT抑制活性的测定结果见表6，其中A表示IC 50小于或等于10nM，B表示IC 50大于10nM但小于或等于100nM，C表示IC 50大于100nM但小于或等于1000nM，D表示IC 50大于1000nM。
实验例2.化合物抑制VEGFR-2激酶活性的测试
基于Perkin Elmer公司的LANCE TR-FRET技术，测试方法如下：
1.化合物稀释：从最高浓度2500nM开始进行3倍梯度稀释后共11个浓度(本实验使用的药物的最大终浓度为2500nM，最低终浓度为0.042nM)。
2.用排枪取2.5μL经梯度稀释的化合物，加入384孔板中。
3.加酶：用排枪取5μL 2X VEGFR2激酶溶液(浓度为0.5nM)加入到384孔板相应的反应孔中，混匀后室温预反应30分钟。
4.排枪取2.5μL 4X Ultra ULight TM-JAK-1(Tyr1023)Peptide(浓度为200nM)/ATP(浓度为40μM)混合液加入到384孔板相应的反应孔中。
5.阴性对照：在384孔板孔加入2.5μL/孔4X底物/ATP混合液和7.5μL 1X Kinase Assay Buffe。
6.阳性对照：在384孔板中加入2.5μL/孔4X底物/ATP混合液，2.5μL/孔含16％DMSO的1X Kinase Assay Buffer，5μL/孔2X VEGFR2激酶溶液。反应体系中DMSO的终浓度为4％。
7.离心混匀，避光室温反应60分钟。
8.终止酶促反应：用排枪取5μL 4X终止液加入到384孔板中孔中，离心混匀，室温反应5分钟。
9.显色反应：用排枪取5μL 4X检测液加入到384孔板中孔中进行显色，离心混匀，室温反应60分钟。
10.将384孔板放入Envision读板仪读板，调取相应的程序检测信号。
11.原始数据的分析和处理：
将药物浓度和相应抑制率输入GraphPad Prism5计算处理，化合物的抑制率的计算方法如下：
抑制率(％)＝(阳性孔读值-实验孔读值)/(阳性对照孔读值-阴性对照孔读值)x100％。用GraphPad Prism5软件处理得出相应的IC 50值(酶最高抑制率50％时的化合物浓度)。
本发明中化合物对酪氨酸激酶VEGFR2抑制活性的测定结果见表6，其中A表示IC 50小于或等于10nM，B表示IC 50大于10nM但小于或等于100nM，C表示IC 50大于100nM但小于或等于1000nM，D表示IC 50大于1000nM，NT表示未有相关值。
表6.化合物对ABL、ABL-T315I、KIT、VEGFR-2酪氨酸激酶抑制活性测定结果
Figure PCTCN2020073018-appb-000100
Figure PCTCN2020073018-appb-000101
Figure PCTCN2020073018-appb-000102
Figure PCTCN2020073018-appb-000103
实验例3.化合物抑制K562及BaF3-BCR-ABL-T315I细胞增殖的测试，具体方法如下:
在细胞培养液中加入不同浓度的待测化合物，比较待测化合物对目标细胞的增殖的IC50来测试待测化合物对目标细胞的体外抑制效果。
相关溶液配置和稀释：
化合物稀释：所有化合物溶于DMSO配成10mM贮备液，在DMSO中完成待测化合物的第一次梯度稀释，稀释倍数为3倍或4倍；在细胞培养液中完成所有化合物的80倍整体稀释，得到的化合物为5×化合物，该化合物将加入到含细胞的96孔板的孔中，使得最终细胞培养液中为1×设计终浓度。
对化合物的测试一般设计为9个浓度梯度，其中最高终浓度为25000nM，经4倍稀释9个浓度后最低浓度为0.38nM，所有孔中DMSO终浓度为0.25％。
实验步骤
1)将细胞转移至15mL离心管中，以1000rpm离心4分钟。
2)弃去上清液，加入完全培养液，吹打均匀，取10μL细胞悬浮液和10μL 0.4％胎盼蓝混匀，用细胞计数仪进行计数，记录细胞数及存活率。
3)每孔接种80μL的细胞悬液到96孔板中(不同细胞接种细胞密度见表7)
表7.细胞密度
细胞名称 培养基 接种密度
K562 RPMI 1640+10％FBS 10000/well
BaF3-BCR-ABL-T315I RPMI 1640+10％FBS 5000/well
4)在每孔中加入20μL上述用培养液稀释过的5×化合物，混合摇匀。
5)在含5％CO2的37℃培养箱中培养72小时后每孔加入10μL CCK-8试剂，培养2小时(可以根据颜色深浅来调节反应时间)；
6)在多功能读板机于450nm处读其OD值。
7)数据处理：细胞存活率(％)＝[(As-Ab)/(Ac-Ab)]*100％
As：实验孔(含有细胞的培养基、CCK-8、化合物)的OD值；
Ac：对照孔(含有细胞的培养基、CCK-8)的OD值；
Ab：空白孔(不含细胞和化合物的培养基、CCK-8)的OD值。
然后将数值导入Graphpad Prism5软件进行曲线拟合，计算IC50。
本发明中化合物抑制K562、BaF3-BCR-ABL-T315I细胞增殖的测定结果见表8，其中A表示IC 50小于或等于10nM，B表示IC 50大于10nM但小于或等于100nM，C表示IC 50大于100nM但小于或等于1000nM，D表示IC 50大于1000nM。
表8.化合物抑制K562、BaF3-BCR-ABL-T315I细胞增殖的测定结果
Figure PCTCN2020073018-appb-000104
Figure PCTCN2020073018-appb-000105
Figure PCTCN2020073018-appb-000106
本发明所提供的生物学数据表明，本发明的化合物有利于治疗或预防由于ABL、ABL-T315I、KIT及VEGFR-2等激酶异常而引起的疾病。因此，本发明的化合物有利于治疗癌症，包括原发性和转移性癌症，包括实体瘤。此类癌症包括但不限于:非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。本发明的化合物也包括治疗耐一种或多种其它治疗方法的癌症。本发明的化合物还可用于与VEGFR-2、 RET和/或c-MET激酶有关的除了癌症以外的其他疾病，包括但不限于眼底疾病，银屑病、风湿性关节炎、动脉粥样化、肺纤维化、肝纤维化。本发明的化合物可以作为单一疗法或联合疗法，可以与多个本发明的化合物联合用药或与本发明以外的其他药物联合用药。
以上所述仅为本发明的较佳实施方式而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (12)

  1. 式(I)表示的化合物、其药学上可接受的盐、异构体、溶剂化物或前药，
    Figure PCTCN2020073018-appb-100001
    式(I)中，
    Q为CH或者N；
    L、Z、G各自独立地为选自N、NR 4、O、S或CR 4，且至少有一个不为CR 4；
    R 1为氢、卤素、C 1-C 3烷基、卤代C 1-C 3烷基；
    R 2为-(CH 2)n-R 6，R 6为氢、C 1-C 6烷基、C 3-C 6环烷基、羟基、卤代C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷硫基、-NR aR b、或者任选地被1至3个选自卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、羟基、-NR aR b、C 1-C 3酰基、羟基C 1-C 3烷基、C 1-C 3烷氧基C 1-C 3烷基、氧代中的取代基所取代或者未取代的4-8元杂脂环基，n为0至6的整数；
    R 3为氢、C 1-C 3烷基、卤素；
    R 4为氢，或由1至3个选自C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、卤代C 1-C 3烷基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的C 3-C 8环烷基，或由1至3个选自C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 3酰基、羟基、卤素、氰基、-CONH 2、C 3-C 7环烷基或-NR aR b的取代基所取代或者非取代的C 1-C 9烷基，或者-(CH 2)m-R 7，R 7为任选地被1至3个选自卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、羟基、-NR aR b、C 1-C 3酰基、羟基C 1-C 3烷基、C 1-C 3烷氧基C 1-C 3烷基、氧代中的取代基所取代或者未取代的4-8元杂脂环基，m为0至3的整数；
    R 5为氢、C 1-C 3烷基、C 1-C 3烷氧基、氰基、C 3-C 6环烷基、氟、羟基、氯；
    所述取代或者未取代的4-8元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-8元杂脂环基，
    R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基C 1-C 6烷基、C 1-C 3烷硫基C 1-C 6烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基。
  2. 根据权利要求1所述化合物、其药学上可接受的盐、异构体、溶剂化物或前药，其中，Q为N；L、G为N原子且Z为CH。
  3. 根据权利要求1或2所述化合物、其药学上可接受的盐、异构体、溶剂化物、或前药，其中，R 1为氢、三氟甲基、氟、氯、甲基。
  4. 根据权利要求1所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药，其中，R 2为-(CH 2)n-R 6，R 6为氢、C 1-C 3烷基、C 3-C 6环烷基、羟基、卤代C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫 基、-NR aR b、或者任选地被1至3个选自卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、羟基、-NR aR b、C 1-C 3酰基、羟基C 1-C 3烷基、C 1-C 3烷氧基C 1-C 3烷基、氧代中的取代基所取代或者未取代的4-6元杂脂环基，n为0至3的整数，
    所述4-6元杂脂环基为哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、吡喃基，
    R a和R b各自独立地为氢、C 1-C 3烷基、C 3-C 6环烷基、C 1-C 3烷氧基取代的C 1-C 3烷基。
  5. 根据权利要求4所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药，其中，R 6为氢、甲氧基、乙氧基、丙氧基、异丙氧基、甲基氨基、乙基氨基、丙基氨基、二甲氨基、二乙氨基、二丙氨基、羟甲基氨基、羟乙基氨基、羟丙基氨基、甲氧基乙基氨基、甲氧基丙基氨基、二羟甲基氨基、二羟乙基氨基、二羟丙基氨基、二甲氧基乙基氨基、二甲氧基丙基氨基、N-甲基-N-羟乙基氨基、N-甲基-N-羟丙基氨基、N-乙基-N-羟乙基氨基、N-乙基-N-羟丙基氨基、N-甲基-N-乙基氨基、N-甲基-N-丙基氨基、N-甲基-N-甲氧基乙基氨基、N-甲基-N-甲氧基丙基氨基、N-乙基-N-甲氧基乙基氨基、N-乙基-N-甲氧基丙基氨基、羟基、甲基、乙基、丙基、异丙基、1-甲基哌嗪-4-基、1-乙基哌嗪-4-基、1-丙基哌嗪-4-基、1-异丙基哌嗪-4-基、1-羟甲基哌嗪-4-基、1-羟乙基哌嗪-4-基、1-羟丙基哌嗪-4-基、(R)-3-(二甲氨基)吡咯烷-1-基、(S)-3-(二甲氨基)吡咯烷-1-基、(R)-3-(二乙氨基)吡咯烷-1-基、(S)-3-(二乙氨基)吡咯烷-1-基、(R)-3-(二丙氨基)吡咯烷-1-基、(S)-3-(二丙氨基)吡咯烷-1-基、(R)-3-(甲基乙基氨基)吡咯烷-1-基、(S)-3-(甲基乙基氨基)吡咯烷-1-基、(R)-3-(甲基丙基氨基)吡咯烷-1-基、(S)-3-(甲基丙基氨基)吡咯烷-1-基、(R)-3-(乙基丙基氨基)吡咯烷-1-基、(S)-3-(乙基丙基氨基)吡咯烷-1-基、(R)-3-(二羟甲氨基)吡咯烷-1-基、(S)-3-(二羟甲氨基)吡咯烷-1-基、(R)-3-(二羟乙氨基)吡咯烷-1-基、(S)-3-(二羟乙氨基)吡咯烷-1-基、(R)-3-(二羟丙氨基)吡咯烷-1-基、(S)-3-(二羟丙氨基)吡咯烷-1-基、(R)-3-(羟甲基乙基氨基)吡咯烷-1-基、(S)-3-(羟甲基乙基氨基)吡咯烷-1-基、(R)-3-(羟甲基丙基氨基)吡咯烷-1-基、(S)-3-(羟甲基丙基氨基)吡咯烷-1-基、(R)-3-(羟乙基丙基氨基)吡咯烷-1-基、(S)-3-(羟乙基丙基氨基)吡咯烷-1-基、(R)-3-(甲基羟乙基氨基)吡咯烷-1-基、(S)-3-(甲基羟乙基氨基)吡咯烷-1-基、(R)-3-(甲基羟丙基氨基)吡咯烷-1-基、(S)-3-(甲基羟丙基氨基)吡咯烷-1-基、(R)-3-(乙基羟丙基氨基)吡咯烷-1-基、(S)-3-(乙基羟丙基氨基)吡咯烷-1-基、吡咯烷-1-基、哌啶-1-基、吗啉基、硫代吗啉基。
  6. 根据权利要求1所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药，其中，R 3为-H、甲基、氟、氯。
  7. 根据权利要求1所述化合物、其药学上可接受的盐、异构体、溶剂化物、或前药，其中，R 4为氢，C 3-C 8环烷基，或由1至3个选自C 1-C 3烷氧基、C 1-C 3烷硫基、C 1-C 3酰基、羟基、氟、氯、氰基、-CONH 2、C 3-C 6环烷基或-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，或者-(CH 2)m-R 7，R 7为任选地被1至3个选自卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、羟基、-NR aR b、C 1-C 3酰基、羟基C 1-C 3烷基、C 1-C 3烷氧基C 1-C 3烷基、氧代中的取代基所取代或者未取代的4-6元杂脂环基，m为0至3的整数；
    所述4-6元杂脂环基为哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、吡喃基，
    R a和R b各自独立地为氢、C 1-C 3烷基、C 3-C 6环烷基、C 1-C 3烷氧基取代的C 1-C 3烷基。
  8. 根据权利要求7所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药，其中，R 4为选自氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、异己基、环丙基、环丁基、环戊基、环己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、羟基乙基、羟基丙基、氟代乙基、氟代丙基、氰基甲基、氰基乙基、2-甲基-2-羟基丙基、3-甲基-3-羟基丁基、甲硫基乙基、甲硫基丙基、二甲氨基乙基、二甲氨基丙基、二甲氨基丁基、二甲氨基戊基、二甲氨基己基、二乙氨基乙基、二乙氨基丙基、羟乙基氨基乙基、羟丙基氨基乙基、羟乙基氨基丙基、甲氧基乙基氨基乙基、甲氧基丙基氨基乙基、甲氧基乙基氨基丙基、氨基乙基、氨基丙基、氨基丁基、N-甲基-N-羟乙基氨基乙基、N-甲基-N-羟丙基氨基乙基、N-甲基-N-羟乙基氨基丙基、N-甲基-N-甲氧基乙基氨基乙基、N-甲基-N-甲氧基丙基氨基乙基、N-甲基-N-甲氧基乙基氨基丙基、(3S)-3-氨基丁基、(3R)-3-氨基丁基、(3S)-3-羟基丁基或(3R)-3-羟基丁基、氧杂环丁烷-3-基、四氢呋喃-3-基、四氢-2H-吡喃-4-基、吡咯烷基、哌啶-1-基、哌嗪-1-基、吗啉-4-基、甲基哌嗪-4-基、1-甲基哌啶-4-基。
  9. 根据权利要求1所述化合物、其药学上可接受的盐、异构体、溶剂化物、或前药，其中，R 5为氢、甲基、甲氧基、氰基、环丙基、氟。
  10. 根据权利要求1至9中任一项所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药，其中，所述化合物选自如下结构：
    Figure PCTCN2020073018-appb-100002
    Figure PCTCN2020073018-appb-100003
    Figure PCTCN2020073018-appb-100004
    Figure PCTCN2020073018-appb-100005
    Figure PCTCN2020073018-appb-100006
    Figure PCTCN2020073018-appb-100007
    Figure PCTCN2020073018-appb-100008
    Figure PCTCN2020073018-appb-100009
    Figure PCTCN2020073018-appb-100010
  11. 权利要求1至9中任一项所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药在制备治疗与ABL、ABL-T315I、KIT及VEGFR-2激酶相关疾病的药物中的应用，其中，所述与ABL、ABL-T315I、KIT及VEGFR-2激酶相关的疾病包括眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
  12. 一种药物组合物，包括权利要求1至9中任一项所述的化合物、其药学上可接受的盐、异构体、溶剂化物、或前药，以及一种或多种药学上可接受的载体或赋形剂。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114656470A (zh) * 2022-04-19 2022-06-24 辽宁大学 新型取代喹唑啉类化合物及其制备方法和应用
CN114656470B (zh) * 2022-04-19 2023-11-10 辽宁大学 取代喹唑啉类化合物及其制备方法和应用

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