WO2020156283A1 - Composé alkynylpyrimidine ou alkynylpyridine, et composition et application de celui-ci - Google Patents

Composé alkynylpyrimidine ou alkynylpyridine, et composition et application de celui-ci 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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Chinese (zh)
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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
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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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • 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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    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • 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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    • 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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    • 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

L'invention concerne un composé alkynylpyrimidine ou alkynylpyridine représenté par la formule (I), ou un sel, UN isomère, un solvate, un cristal ou un promédicament pharmaceutiquement acceptable de celui-ci, ainsi que des compositions pharmaceutiques contenant de tels composés et une application de tels composés ou compositions dans la préparation d'un médicament, le médicament pouvant être utilisé en tant qu'inhibiteur de kinases telles que ABL, ABL-T315I, KIT, VEGFR -2, et autres pour le traitement de maladies associées.
PCT/CN2020/073018 2019-01-29 2020-01-19 Composé alkynylpyrimidine ou alkynylpyridine, et composition et application de celui-ci WO2020156283A1 (fr)

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