Aminothiazole compounds as protein kinase inhibitors

Abstract

The present invention discloses aminothiazole compounds of the following formula (I) and pharmaceutical compositions containing one of these compounds. The present invention also discloses methods for inhibiting tyrosine kinase and treating cancers associated with tyrosine kinase using one of the aminothiazole compounds.

Description

Background Art

[0001] Protein kinases are important in cell signaling pathways that regulate a variety of cellular functions, including differentiation, proliferation, migration, and apoptosis. Dysregulation of protein kinases has been implicated in cancer and many other diseases.

[0002] Tyrosine kinases are a subclass of protein kinases that regulate target protein function by transferring a phosphate from ATP to the hydroxyl group of tyrosine on the target protein. FMS-like tyrosine kinase 3 (FLT3), vascular endothelial growth factor receptor (VEGFR), and tyrosine-protein kinase Kit (c-Kit) are three tyrosine kinases that have been studied as attractive therapeutic targets in cancer treatment.

[0003] FLT3 is a receptor tyrosine kinase, mutations of which can lead to the development of cancers such as acute myeloid leukemia. See Pratz et al., Current Drug Targets, 2010, 11(7), 781-9.

[0004] Vascular endothelial growth factor is a signaling protein that stimulates the growth of new blood vessels by binding to VEGFR and activating vascular endothelial growth factor via transphosphorylation. VEGFR has been identified as a major regulator of tumor angiogenesis. See Hicklin et al., J Clin Oncol., 2005, 23, 1011-1027.

[0005] c-Kit is also a receptor tyrosine kinase that is involved in intracellular signaling. Mutated forms of c-Kit play a key role in the occurrence of some cancers. It has been shown that inhibiting c-Kit can effectively treat gastrointestinal stromal tumors, acute myeloid leukemia and melanoma. See Babaei et al., Drug Des Devel Ther., 2016 10, 2443-2459.

[0006] As effective tyrosine kinase inhibitors, aminothiazole compounds have been extensively explored, but they present several challenges as drug candidates. They have poor kinase selectivity, often cause animal mortality in toxicity studies, and generally lack sufficient in vivo exposure to exert the desired efficacy in preclinical or clinical studies.

[0007] There is a need to develop new aminothiazole compounds that specifically inhibit specific tyrosine kinases, exhibit a desirable safety profile, and exert sufficient in vivo efficacy in treating target cancers. Summary of the invention

[0008] The present invention is based on the unexpected discovery that certain aminothiazole compounds effectively inhibit multiple tyrosine kinases, such as FLT3, VEGFR and c-Kit.

[0009] In one aspect, the present invention relates to aminothiazole compounds of formula (I):

[0010]

[0011] Where R1 is C 1-6 Alkyl or C 1-6 Thioalkyl; X is O or NR a , where R a H or C 1-6 Alkyl; Y is CR b R c or NR d , where R b and R c are independently H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or amino, or R b With R a , key to R b The carbon atom and the bond to R a The nitrogen atoms together form C 3-10 heterocycloalkyl, and R d H or C 1-6 Alkyl, or R d With R a and key to R d and R a The nitrogen atoms together form C 3-10 Heterocycloalkyl; R2 is -CH2CH2R e or NR f R g , where R e H, halogen, C 1-6 Alkyl or OR h , and R f and Rg Each independently is C 1-6 Alkyl or C 3-8 Cycloalkyl, R h H or C 1-6 Alkyl, or R h With R d , key to R h The oxygen atom and the bond to R d The nitrogen atoms together form C 3-10 heterocycloalkyl; and R3 is heteroaryl.

[0012] The term "alkyl" herein refers to a saturated straight or branched hydrocarbon moiety, such as -CH or branched -C3H7. The term "cycloalkyl" refers to a non-aromatic monocyclic, bicyclic, tricyclic or tetracyclic hydrocarbon moiety, such as cyclohexyl, cyclohexene-3-yl or adamantyl. The term "alkoxy" refers to an -O-alkyl group. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. The term "thioalkyl" refers to an -S-alkyl group. Examples of thioalkyl include, but are not limited to, methyl mercaptan, ethyl mercaptan and benzyl mercaptan. The term "heterocycloalkyl" refers to a non-aromatic monocyclic, bicyclic, tricyclic or tetracyclic moiety with one or more ring heteroatoms (e.g., N, O or S). Examples of heterocycloalkyl include, but are not limited to, 4-morpholinyl, 1-piperazinyl, 4-tetrahydropyranyl, and 4-pyranyl. The term "heteroaryl" refers to a moiety having one or more aromatic rings containing at least one heteroatom (e.g., N, O, or S). Examples of heteroaryl moieties include furyl, furylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, and indolyl.

[0013] Unless otherwise specified, alkyl, thioalkyl, alkoxy, cycloalkyl, heterocycloalkyl and heteroaryl mentioned herein include both substituted and unsubstituted moieties. Possible substituents on cycloalkyl, heterocycloalkyl and heteroaryl include C 1-10 Alkyl, C 2-10 Alkenyl, C2-10 Alkynyl, C 3-20 Cycloalkyl, C 3-20 Cycloalkenyl, C 1-20 Heterocycloalkyl, C 1-20 Heterocycloalkenyl, C 1-10 Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1-10 Alkylamino, C 1-20 dialkylamino, arylamino, diarylamino, hydroxy, halogen, thio, C 1-10 Alkylthio, arylthio, C 1-10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, acyl, thioacyl, acyloxy, carboxyl and carboxylic ester. On the other hand, possible substituents on the alkyl group include, except C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 All of the above substituents except the alkynyl group. The cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group may also be condensed with each other.

[0014] If applicable, the above-mentioned aminothiazole compounds include the compounds themselves, as well as their salts, prodrugs and solvates. For example, salts can be formed between anions and positively charged groups (such as amino groups) on aminothiazole compounds. Suitable anions include chlorine, bromine, iodine, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate and maleate. Similarly, salts can also be formed between cations and negatively charged groups (such as carboxylates) on aminothiazole compounds. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions and ammonium cations such as tetramethylammonium ions. Aminothiazole compounds also include those salts containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives that are capable of providing an active aminothiazole compound when administered to a subject. A solvate refers to a complex formed between an active aminothiazole compound and a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.

[0015] In another aspect, the present invention relates to a method for inhibiting tyrosine kinases (eg, FLT3, VEGFR, and c-Kit). The method comprises contacting the tyrosine kinase with an effective amount of one or more of the above-described aminothiazole compounds.

[0016] Also within the scope of the present invention is a method for treating cancer associated with tyrosine kinases, which comprises administering to a subject in need thereof an effective amount of one or more aminothiazole compounds of formula (I) above.

[0017] The tyrosine kinases associated with cancer may be wild-type or mutant. Examples of tyrosine kinases include, but are not limited to, FLT3, FLT4, VEGFR, platelet-derived growth factor receptor (PDGFR) A, PDGFR B, c-Kit, c-Src (SRC), tyrosine-protein kinase Lyn (LYN) A, LYN B, rearranged during transfection tyrosine kinase (RET), lymphocyte-specific protein tyrosine kinase, Gardner-Rasheed feline sarcoma viral oncogene homolog, discoidin domain receptor 1, kinase insert domain receptor, B lymphocyte kinase, tyrosine-protein kinase Yes (tyrosine-protein kinase Yes), Abelson murineleukemia viral oncogene homolog 1 (ABL1), tyrosine-protein kinase Tek, RET V804L, RET Y791F, FLT3 D835Y, PDGFR A V561D, or ABL1 T315I.

[0018] In one exemplary method, the aminothiazole compound of Formula (I) is used to treat a cancer associated with FLT3, VEGFR or c-Kit.

[0019] Examples of cancer include acute myeloid leukemia, chloroma, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, B-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, myelodysplastic syndrome, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, male genital tract cancer, renal cancer, hepatocellular carcinoma, cancer, lung cancer, ovarian cancer, cervical cancer, uterus cancer, gestational trophoblastic disease, gastric cancer, bile duct cancer, gallbladder cancer, small intestine cancer, esophageal cancer, oropharyngeal cancer, hypopharyngeal cancer, eye cancer, nerve cancer, head and neck cancer, melanoma, plasmacytoma, endocrine gland neoplasms, neuroendocrine cancer, brain cancer,tumor), bone cancer (bonecancer), and sarcoma (such as gastrointestinal stromal tumor (GIST)).

[0020] Pharmaceutical compositions containing one or more aminothiazole compounds of formula (I) above are also within the scope of the present invention. The pharmaceutical compositions can be used to treat cancer.

[0021] The present invention also includes the use of one or more aminothiazole compounds of the above formula (I) for preparing drugs for treating cancer.

[0022] The term "treating" or "treatment" refers to the administration of one or more aminothiazole compounds to a subject who suffers from the above-mentioned disease (i.e., cancer), has symptoms of such a disease, or has a tendency to suffer from such a disease, in order to give a curative effect, such as curing, alleviating, altering, affecting, improving or preventing the above-mentioned disease, its symptoms or a tendency to suffer from it. The term "effective amount" refers to the amount of active compound required to give a therapeutic effect. As recognized by those skilled in the art, the effective dose will vary depending on the type of disease being treated, the route of administration, the excipient usage, and the possibility of co-use with other therapeutic treatments.

[0023] To practice the methods of the present invention, compositions with one or more of the above aminothiazole compounds can be administered parenterally, orally, nasally, rectally, topically or buccally. The term "parenteral" as used herein refers to subcutaneous, intradermal, intravenous, intraperitoneal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection, as well as any suitable infusion technique.

[0024] The sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among them, acceptable carriers and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed oils are generally used as solvents or suspension media (e.g., synthetic mono- or diglycerides). Fatty acids such as oleic acid and its glyceride derivatives can be used for the preparation of injections, and natural medicinal oils such as olive oil and castor oil, especially their polyoxyethylated forms, can also be used for the preparation of injections. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, carboxymethyl cellulose or similar dispersants. For the purpose of formulation, other commonly used surfactants, such as Tweens and Spans or other similar emulsifiers or bioavailability enhancers, which are generally used to prepare pharmaceutical solids, liquids or other dosage forms.

[0025] Compositions for oral administration can be any oral acceptable dosage form, including capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets, conventional carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also usually added. For oral administration in the form of capsules, available diluents include lactose and dry corn starch. When an aqueous suspension or emulsion is administered orally, the active ingredient can be suspended or dissolved in an oil phase combined with an emulsifier or suspending agent. If necessary, certain sweeteners, flavorings or coloring agents can be added.

[0026] Nasal aerosol or inhalation compositions can be prepared according to techniques known in the art of pharmaceutical preparations. For example, such compositions can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0027] Compositions having one or more of the above-described aminothiazole compounds may also be administered in the form of suppositories for rectal administration.

[0028] The carrier in the pharmaceutical composition must be "acceptable" in the sense that it is compatible with the active ingredient of the composition (and preferably capable of stabilizing the active ingredient) and not deleterious to the subject to be treated. One or more solubilizing agents may be used as pharmaceutical excipients to deliver the active 1,5-diphenyl-penta-1,4-dien-3-one compound. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

[0029] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0031] The aminothiazole compounds of formula (I) are disclosed in detail:

[0032]

[0033] wherein the variables R1, R2, R3, X and Y are as defined above in the Summary of the Invention section.

[0034] Typically, the compounds of formula (I) have R3 independently replaced by one or more (CH2) n 5- or 6-membered heteroaryl substituted with Z, wherein n is 0 or 1, and Z is H, halogen, CN, OH, CF3, C 1-6 Alkyl or C 1-6 or a compound of formula (I) having R3 being a 5- or 6-membered heteroaryl fused to a benzene ring substituted with one or more substituents independently selected from the group consisting of H, halogen, CN, OH, CF3, C 1-6 Alkyl and C 1-6 The exemplary compounds have R3 independently replaced by one or more (CH2) n 6-membered heteroaryl substituted with Z, wherein n is 0 or 1, and Z is H, halogen, CN, OH, CF3, C 1-6 Alkyl or C 1-6 Alkoxy. Two examples of R3 are pyridyl or pyrimidinyl.

[0035] One group of the novel aminothiazole compounds is compounds of formula (II):

[0036]

[0037] Where R1 is C 1-6 alkyl.

[0038] In a subset, the compound of formula (II) has X is O, Y is NR d , and R2 is -CH2CH2R e , where R e OR h , R h With R d , key to R h The oxygen atom and the bond to R d The nitrogen atoms together form C 3-10 The compounds of this subset may have R3, which is independently replaced by one or more (CH2)n 5- or 6-membered heteroaryl substituted with Z, wherein n is 0 or 1, and Z is H, halogen, CN, OH, CF3, C 1-6 Alkyl or C 1-6 or R3 is a 5- or 6-membered heteroaryl fused to a benzene ring substituted with one or more substituents independently selected from H, halogen, CN, OH, CF3, C 1-6 Alkyl and C 1-6 Alkoxy. For example, R3 can be pyridyl or pyrimidinyl. Exemplary compounds include, but are not limited to, the following compounds:

[0039]

[0040] In another subclass, the compound of formula (II) has X is NR a , and Y is CR b R c or NR d , where R a With R b , key to R a The nitrogen atom and the bond to R b The carbon atoms together form C 3-10 Heterocycloalkyl; R c H, halogen, C 1-6 Alkyl, C 1-6 alkoxy or amino; and R d With R a and key to R a and R d The nitrogen atoms together form C 3-10 Heterocycloalkyl.

[0041] It is noteworthy that these compounds can have X as NR a , Y is CR b R c , and R2 is NR f R g , where R a With R b , key to R a The nitrogen atom and the bond to R b The carbon atoms together form C 3-10 Heterocycloalkyl; R c H, halogen, C 1-6 Alkyl, C 1-6 alkoxy or amino; and R f and R g Each is C 1-6 They usually have R3 independently replaced by one or more (CH2) n5- or 6-membered heteroaryl substituted with Z, wherein n is 0 or 1, and Z is H, halogen, CN, OH, CF3, C 1-6 Alkyl or C 1-6 or R3 is a 5- or 6-membered heteroaryl fused to a benzene ring substituted with one or more substituents independently selected from H, halogen, CN, OH, CF3, C 1-6 Alkyl and C 1-6 Alkoxy. R3 can be pyridyl or pyrimidinyl. Exemplary compounds include, but are not limited to, the following compounds:

[0042]

[0043] On the other hand, compounds in this subset may have X as NR a , Y is NR d , and R2 is -CH2CH2R e , where R a With R d and key to R a and R d The nitrogen atoms together form C 3-10 heterocycloalkyl; and R e is H, halogen or OR h , R h H or C 1-6 Typically, these compounds have R3 independently replaced by one or more (CH2) n 5- or 6-membered heteroaryl substituted with Z, wherein n is 0 or 1, and Z is H, halogen, CN, OH, CF3, C 1-6 Alkyl or C 1-6 or R3 is a 5- or 6-membered heteroaryl fused to a benzene ring substituted with one or more substituents independently selected from H, halogen, CN, OH, CF3, C 1-6 Alkyl and C 1-6 Alkoxy. For example, R3 is pyridyl or pyrimidinyl. Exemplary compounds include, but are not limited to, the following compounds:

[0044]

[0045] Another group of the novel aminothiazole compounds described above are compounds of formula (III):

[0046]

[0047] Where R1 is C 1-6 alkyl.

[0048] Exemplary compounds of formula (III) are

[0049] Listed below are exemplary compounds of the invention, each of which is assigned a compound number.

[0050]

[0051] Also within the scope of the present invention are pharmaceutical compositions containing one or more aminothiazole compounds of formula (I) for use in treating cancer.

[0052] The present invention also encompasses a method of treating cancer, comprising administering to a subject in need thereof an effective amount of a compound of formula (I).

[0053] Synthetic chemical transformations and protecting group methods (protection and deprotection) for synthesizing compounds of formula (I) are well known in the art. See, for example, R. Larock, Comprehensive Organic Transformations (2nd edition, VCH Publishers 1999); PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis (4th edition, John Wiley and Sons 2007); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons 1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (2nd edition, John Wiley and Sons 2009); and GJ Yu et al., J. Med. Chem. 2008, 51, 6044-6054.

[0054] The compounds of formula (I) thus prepared can be preliminarily screened for their potential in inhibiting tyrosine kinases or inhibiting the growth of cancer cells expressing specific tyrosine kinases using biochemical assays (e.g., kinase assays described in Examples 2-4 below) or cell assays (e.g., in vitro anticancer activity assays described in Example 5 below). Subsequently, in vivo assays (e.g., xenograft animal model assays) can be used to evaluate their activity in inhibiting tumor growth in mammals. The selected compounds can be further tested to verify their efficacy in treating cancer. For example, the compounds can be administered to animals (e.g., mice) suffering from cancer, and then their therapeutic effects can be evaluated. Based on the results, appropriate dosage ranges and routes of administration can be studied and determined.

[0055] Without further explanation, it is believed that those skilled in the art can make the most of the present invention based on the above description. Therefore, the following specific embodiments should be interpreted as merely illustrative and not limiting the remainder of the present disclosure in any way. All publications cited herein are incorporated herein by reference in their entirety.

[0056] The synthesis and characterization of 13 exemplary compounds of formula (I) are shown in Example 1 below. Analytical data for the compounds thus prepared are also listed in Example 1, and the procedures for testing these compounds are described in Examples 2-5 below.

[0057] All chemicals and solvents were purchased from commercial suppliers and used as received. All reactions were performed under a dry nitrogen atmosphere. Reactions were monitored by TLC using Merck 60F254 silica gel glass backing (5 x 10 cm); and zones were visually detected under UV irradiation (254 nm) or by spraying with phosphomolybdic acid reagent (Aldrich) followed by heating at 80°C. All flash column chromatography was performed using Merck Kieselgel 60, No. 9385, 230-400 mesh ASTM silica gel as the stationary phase. Proton ( 1 H) NMR spectra were measured on a Varian Mercury-300 or Varian Mercury-400 spectrometer. Chemical shifts are reported in parts per million (ppm) on the delta scale relative to the resonance of the solvent peak. The following abbreviations are used to describe couplings: s = singlet; d = doublet; t = triplet; q = quartet; quin = quintet; br = broad; and m = multiplet. LCMS data were measured on an Agilent MSD-1100 ESI-MS / MS, Agilent 1200 Series LC / MSD VL, and Waters Acquity UPLC-ESI-MS / MS systems.

[0058] Example 1 :Synthesis of Compound 1-13

[0059] Compounds 1-13 were prepared according to the synthetic route shown in the following Scheme 1. Among the reagents listed, TEA is triethylamine, KOAc is potassium acetate, Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium(0), DMAc is N,N-dimethylacetamide, CsF is cesium fluoride, HCl is hydrochloric acid, NaHCO3 is sodium bicarbonate, NaH is sodium hydride, NMP is 1-methyl-2-pyrrolidone, KOH is potassium hydroxide, and DMSO is dimethyl sulfoxide.

[0060]

[0061] Scheme 1. Reagents and conditions: (a) TEA, CH2Cl2, 0°C to rt; (b) KOAc, Pd(PPh3)4, DMAc, 150°C (for Py = pyridin-2-yl, CsF is used instead of KOAc); (c) 12N HCl, H2O, reflux; (d) NaHCO3, H2O, rt; (e) NaH, NMP, 0°C; (f) DMSO, RH, 100°C, or diethylene glycol dimethyl ether, KOH, 160°C (for RH = 4-(2-hydroxyethyl)-morpholine; and (g) 6N HCl, 0°C.

[0062] Step I. Synthesis of 2,2-dimethyl-N-thiazol-2-yl-propionamide B

[0063] To 2-aminothiazole A (300mmol) and triethylamine (330mmol) in anhydrous CH at 0 ℃ Cl Add trimethylacetyl chloride (310mmol) in the mixture in (250mL), and the mixture is stirred at room temperature for 1 hour under argon atmosphere. The mixture is washed with 6N HCl (60mL), and the organic layer is separated, and magnesium sulfate (MgSO ) is dried, and concentrated under reduced pressure. Residue is purified by chromatography (20% EtOAc / hexane) on silica gel, to obtain title product B, and it is off-white solid (72%). 1 H NMR (300MHz, DMSO-d6): δ11.75 (s, 1H), 7.46 (d, J = 6.0Hz, 1H), 7.17 (d, J = 6.0Hz, 1H), 1.22 (s, 9H); MS (ES + )m / z C8H 12 N2OS calculated value: 184.07; found value: 185.1 (M+H + ).

[0064] Step II. Synthesis of Compound C (Py = pyridin-3-yl, pyridin-4-yl and pyrimidin-5-yl)

[0065] A mixture of 2,2-dimethyl-N-thiazole-2-yl-propionamide B (30mmol), chloropyridine (30mmol), potassium acetate (120mmol) and tetrakis (triphenylphosphine) palladium (0) (1.5mmol) in N,N-dimethylacetamide (60mL) was heated at 150°C for 24 hours under an argon atmosphere. Most of the solvent was removed by distillation (120°C / 160mm Hg), and the residue was washed with water (250mL). The precipitate was collected by filtration, redissolved in CH3OH / CH2Cl2 (200mL), and filtered through a diatomaceous earth (Celite) pad. The filtrate was concentrated under reduced pressure, and purified by chromatography on silica gel (1% MeOH / CH2Cl2), to obtain the desired product, which was an off-white solid (40-85%).

[0066] Step II. Synthesis of Compound C (Py = pyridin-2-yl)

[0067] A mixture of 2,2-dimethyl-N-thiazole-2-yl-propionamide B (10mmol), chloropyridine (10mmol), cesium fluoride (20mmol) and tetrakis (triphenylphosphine) palladium (0) (0.5mmol) in dimethyl sulfoxide (20mL) was heated at 160°C for 16 hours under an argon atmosphere. The resulting mixture was partitioned with 0.5N HCl (150mL) and CH2Cl2 (150mL). The organic layer was separated, dried over MgSO4, concentrated under reduced pressure, and purified by chromatography on silica gel (3% acetone / CH2Cl2) to obtain the desired product as a light brown solid (20%).

[0068] Only one of C was selected to show its NMR spectrum and mass spectrum.

[0069]

[0070] 2,2-Dimethyl-N-(5-pyridin-4-yl-thiazol-2-yl)-propionamide. 1 H NMR (400MHz, CDCl3): δ9.28 (bs, 1H), 8.61 (dd, J=4.8, 1.6Hz, 2H), 7.84 (s, 1H), 7.42 (dd, J=4.8, 1.6Hz, 2H), 1.38 (s, 9H); MS (ES + )m / z C 13 H 15 N3OS calculated value: 261.09; found value: 262.1 (M+H + ).

[0071] Step III. Synthesis of Compound D

[0072] The mixture of C (5mmol) and 12N HCl (5mL) in water (5mL) is heated to reflux and reaches 2 hours.Under reduced pressure, most of solvent is removed, and CH is used OH (15mL) dilution residue.Most of solvent is removed by distillation, and residue is dried under vacuum, to obtain D hydrochloride, it is light brown solid.

[0073] A stirred suspension of the above solid in water (30 mL) was adjusted to pH = 7 with sodium bicarbonate at room temperature and the mixture was stirred at 50°C for 2 hours. The precipitate was collected by filtration and dried under vacuum to give the desired product D as a light brown solid (85-90%).

[0074] Only one of D was selected to show its NMR spectrum and mass spectrum.

[0075] PA194090C

[0076]

[0077] 5-Pyridin-4-yl-thiazol-2-ylamine. 1 H NMR (300MHz, DMSO-d6): δ8.41(dd,J=4.8,1.5Hz,2H),7.73(s,1H),7.48(s,2H),7.35(dd,J=4.8,1.5Hz,2H); MS(ES + )m / z C8H7N3S calculated value: 177.04; found value: 178.1 (M+H + ).

[0078] Step IV. Synthesis of Compound E

[0079] To D or commercially available 4-pyridin-3-yl-thiazole-2-ylamine (4mmol) and 4,6-dichloro-2-methylpyrimidine (8mmol) in 1-methyl-2-pyrrolidone (20mL) was added sodium hydride (60% in oil, 10mmol) at 0°C, and the mixture was stirred at 0°C for 1 hour under an argon atmosphere. The reaction was quenched with water (100mL) at 0°C, and the reaction was adjusted to pH=2 with 6N HCl. The slurry was adjusted to pH=7 with sodium bicarbonate, and the precipitate was collected by filtration, washed with water (50mL), and dried under vacuum. The residue was purified by chromatography on silica gel (20% EtOAc / CH2Cl2, then 5% to 10% MeOH / CH2Cl2 gradient) to obtain the desired product E as a brown solid (45-60%).

[0080] Only one of E was selected to show its NMR spectrum and mass spectrum.

[0081]

[0082] (6-Chloro-2-methyl-pyrimidin-4-yl)-(5-pyridin-4-yl-thiazol-2-yl)-amine. 1 H NMR (300MHz, DMSO-d6): δ12.15(s,1H),8.53(dd,J=4.5,1.5Hz,2H),8.18(s,1H),7.59(dd,J=4.5,1.5Hz,2H),6.90(s,1H),2.59(s,3H); MS(ES + )m / zC 13 H 10 Calculated value of ClN5S: 303.03; Found: 304.1 (M+H + ).

[0083] Step V. Synthesis of Compounds 1-4 and 7-13

[0084] A mixture of compound E (2mmol) and 1-ethylpiperazine (8mmol) in dimethyl sulfoxide (2mL) was heated at 100°C for 1 hour. After cooling to room temperature, the mixture was diluted with water (50mL). The precipitate was collected by filtration, washed with water (10mL) and dried under vacuum. The residue was purified by chromatography on alumina (0.5% to 1.5% MeOH / CH2Cl2 gradient), to obtain the free alkali of each compound 1-4 and 7-13, which was a pale solid.

[0085] The above solid was added to stirred 6N HCl (10 mL) at 0°C, and the solution was filtered through a 0.45 μm PVDF membrane. Acetone (40 mL) was added dropwise to the stirred filtrate over the course of 1 hour, and stirred at 0°C for another 1 hour. The precipitate was collected by filtration, washed with acetone (15 mL), and dried under vacuum to obtain the hydrochloride salt of each compound 1-4 and 7-13 as a yellow solid (90-95%).

[0086] [6-(4-Ethyl-piperazin-1-yl)-2-methyl-pyrimidin-4-yl]-(5-pyridin-4-yl-thiazol-2-yl)-amine hydrochloride. 1H NMR (400MHz, DMSO-d6): δ11.55(bs,1H),8.72(d,J=5.6Hz,2H),8.61(s,1H),8.14(d,J=5.2Hz,2H),6.27(s,1H),4.35(d,J=13.2Hz,2H), 3.55(d,J=12.0Hz,2H),3.45(t,J=13.0Hz,2H),3.13(t,J=5.8Hz,2H),3.02(q,J=10.0Hz,2H),2.50(s,3H),1.28(t,J=6.8Hz,3H); MS(ES + )m / z C 19 H 23 N7S calculated value: 381.17; found value: 382.2 (M+H + ).

[0087] {6-[4-(2-Fluoro-ethyl)-piperazin-1-yl]-2-methyl-pyrimidin-4-yl}-(5-pyridin-4-yl-thiazol-2-yl)-amine hydrochloride (Compound 2). 1 H NMR (300 MHz, DMSO-d6): δ11.89 (bs, 1H), 8.73 (d, J = 6.3 Hz, 2H), 8.62 (s, 1H), 8.15 (d, J = 5.7 Hz, 2H), 6.26 (s, 1H), 4.95 (d, J = 47.4 Hz, 2H), 4.38 (s, 2H, overlapped with water peak), 3.70-3.35 (m, 6H), 3.18 (bs, 2H), 2.50 (s, 3H); MS (ES + )m / z C 19 H 22 FN7S calculated value: 399.16; found value: 400.1 (M+H + ).

[0088] 2-{4-[2-Methyl-6-(5-pyridin-4-yl-thiazol-2-ylamino)-pyrimidin-4-yl]-piperazin-1-yl}-ethanol hydrochloride (Compound 3). 1 H NMR (400MHz, DMSO-d6): δ11.03(s,1H),8.73(d,J=7.2Hz,2H),8.63(s,1H),8.15(d,J=7.2Hz,2H),6.26(s,1H),4.34(d,J= 12.4Hz, 2H), 3.82 (t, J = 5.2Hz, 2H), 3.62 (d, J = 12.0Hz, 2H), 3.43 (t, J = 12.4Hz, 2H), 3.30-3.09 (m, 4H), 2.49 (s, 3H); MS (ES+ )m / z C 19 H 23 N7OS calculated value: 397.17; found value: 398.1 (M+H + ).

[0089] [6-(4-Dimethylamino-piperidin-1-yl)-2-methyl-pyrimidin-4-yl]-(5-pyridin-4-yl-thiazol-2-yl)-amine hydrochloride (Compound 4). 1 H NMR (300MHz, DMSO-d6): δ11.07(s,1H),8.73(d,J=6.9Hz,2H),8.62(s,1H),8.15(d,J=6.9Hz,2H),6.25(s,1H),4.43(d,J=12.9Hz,2H),3. 44(quin,J=5.2Hz,1H),2.94(t,J=12.5Hz,2H),2.69(d,J=4.5Hz,6H),2.49(s,3H),2.15(d,J=10.5Hz,2H),1.60(q,J=11.0Hz,2H); MS(ES + )m / z C 20 H 25 N7S calculated value: 395.19; found value: 396.1 (M+H + ).

[0090] [6-(4-Ethyl-piperazin-1-yl)-2-methyl-pyrimidin-4-yl]-(5-pyridin-3-yl-thiazol-2-yl)-amine hydrochloride (Compound 7). 1 H NMR (400MHz, DMSO-d6): δ11.23(bs,1H),9.15(s,1H),8.68(d,J=5.2Hz,1H), 8.60(d,J=8.0Hz,1H),8.19(s,1H),7.93(t,J=6.2Hz,1H),6.21(s,1H),4.35 (d,J=14.4Hz,2H),3.55(d,J=11.6Hz,2H),3.40(t,J=13.2Hz,2H),3.13(t,J =5.8Hz, 2H), 3.01 (q, J = 6.9Hz, 2H), 2.50 (s, 3H), 1.28 (t, J = 6.6Hz, 3H); MS (ES + )m / z C 19 H 23 N7S calculated value: 381.17; found value: 382.2 (M+H + ).

[0091] {6-[4-(2-Fluoro-ethyl)-piperazin-1-yl]-2-methyl-pyrimidin-4-yl}-(5-pyridin-3-yl-thiazol-2-yl)-amine hydrochloride (Compound 8). 1 H NMR (400MHz, DMSO-d6): δ11.80(bs,1H),9.16(s,1H),8.68(d,J=5.6Hz,1H),8.62(d,J=8.0Hz,1H),8.20(s,1H),7.95(t ,J=6.8Hz,1H),6.22(s,1H),4.98(d,J=46.8Hz,2H),4.34(bs,2H),3.70-3.35(m,6H),3.16(bs,2H),2.49(s,3H); MS(ES + )m / z C 19 H 22 FN7S calculated value: 399.16; found value: 400.1 (M+H + ).

[0092] 2-{4-[2-Methyl-6-(5-pyridin-3-yl-thiazol-2-ylamino)-pyrimidin-4-yl]-piperazin-1-yl}-ethanol hydrochloride (Compound 9). 1 H NMR (400MHz, DMSO-d6): δ11.02(bs,1H),9.18(s,1H),8.69(s,1H),8.64(d,J=7.6Hz,1H),8.22(s,1H),7.96(d,J=5.2Hz,1 H),6.25(s,1H),4.33(d,J=11.2Hz,2H),3.80(s,1H),3.60(d,J=11.6Hz,2H),3.19(s,2H),3.13(s,2H),2.48(s,3H); MS(ES) + )m / z C 19 H 23 N7OS calculated value: 397.17; found value: 398.1 (M+H + ).

[0093] [6-(4-Dimethylamino-piperidin-1-yl)-2-methyl-pyrimidin-4-yl]-(5-pyridin-3-yl-thiazol-2-yl)-amine hydrochloride (Compound 10). 1H NMR (400MHz, DMSO-d6): δ11.27(bs,1H),9.18(s,1H),8.69(d,J=5.2Hz,1H) ,8.64(d,J=8.0Hz,1H),8.23(s,1H),7.97(t,J=6.8Hz,1H),6.36(bs,1H),4 .42(d,J=8.8Hz,2H),3.43(bs,1H),2.99(t,J=12.4Hz,2H),2.68(s,3H),2. 67(s,3H),2.55(s,3H),2.17(d,J=10.8Hz,2H),1.64(q,J=9.2Hz,2H); MS(ES + )m / z C 20 H 25 N7S calculated value: 395.19; found value: 396.2 (M+H + ).

[0094] [6-(4-Ethyl-piperazin-1-yl)-2-methyl-pyrimidin-4-yl]-(5-pyridin-2-yl-thiazol-2-yl)-amine hydrochloride (Compound 11). 1 H NMR (300MHz, DMSO-d6): δ11.34(s,1H),8.54(d,J=4.8Hz,1H),8.32(s,1H),8.01-7.96(m,2H),7.40-7.34(m,1H),6 .31(s,1H),4.37(d,J=13.2Hz,2H),3.62-3.38(m,4H),3.20-2.90(m,4H),2.47(s,3H),1.26(t,J=7.4Hz,3H); MS(ES + )m / z C 19 H 23 N7S calculated value: 381.17; found value: 382.2 (M+H + ).

[0095] [6-(4-Ethyl-piperazin-1-yl)-2-methyl-pyrimidin-4-yl]-(5-pyrimidin-5-yl-thiazol-2-yl)-amine hydrochloride (Compound 12). 1 H NMR (400MHz, DMSO-d6): δ11.35(bs,1H),9.20-9.03(m,3H),8.09(s,1H),6.28(s,1H),4.40(s,2H),3. 56(d,J=12.4Hz,2H),3.44(d,J=7.4Hz,2H),3.13(bs,2H),3.02(d,J=8.0Hz,2H),1.28(bs,3H); MS(ES+ )m / z C 18 H 22 N8S calculated value: 382.17; found value: 383.3 (M+H + ).

[0096] [6-(4-Ethyl-piperazin-1-yl)-2-methyl-pyrimidin-4-yl]-(4-pyridin-3-yl-thiazol-2-yl)-amine hydrochloride (Compound 13). 1 H NMR (400MHz, DMSO-d6): δ11.80(bs,1H),11.54(bs,1H),9.28(s,1H),8.94( d,J=8.4Hz,1H),8.84(d,J=5.2Hz,1H),8.15-8.07(m,2H),6.31(bs,2H),4.3 5(d,J=14.0Hz,2H),3.55(d,J=12.0Hz,2H),3.45(t,J=13.0Hz,2H),3.15-3. 07(m,2H),3.00(q,J=10.0Hz,2H),2.49(s,3H),1.27(t,J=7.4Hz,3H); MS(ES + )m / z C 19 H 23 N7S calculated value: 381.17; found value: 382.1 (M+H+).

[0097] Step V. Synthesis of Compounds 5 and 6

[0098] Potassium hydroxide (10mmol) was added to a mixture of compound E (1mmol) and 4-(2-hydroxyethyl)-morpholine (4mmol) in diglyme (1mL) at 100°C, and the mixture was stirred at 160°C for 10 minutes under an argon atmosphere. The reaction was quenched with water (20mL) at 0°C, and adjusted to pH=2 with 6NHCl. The slurry was adjusted to pH=7 with sodium bicarbonate, and the precipitate was collected by filtration, washed with water (10mL) and dried under vacuum. The residue was purified by chromatography on alumina (0.5% to 1.5% MeOH / CH2Cl2 gradient), to obtain the free base of compound 6, which was an off-white solid.

[0099] 6N HCl (1 mL) was added to a suspension of the above solid in MeOH (10 mL) at 0°C under stirring. Most of the solvent was removed under reduced pressure, and the residue was treated with EtOH (10 mL). The precipitate was collected by filtration, washed with acetone (10 mL) and dried under vacuum to obtain the hydrochloride of each compound 5-6 as a yellow solid (45-50%).

[0100] [2-Methyl-6-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-(5-pyridin-4-yl-thiazol-2-yl)-amine hydrochloride (Compound 5). 1 H NMR (400MHz, DMSO-d6): δ11.61(s,1H),8.74(d,J=5.2Hz,2H),8.64(s,1H),8.17(d,J=5.2Hz,2H), 6.37(s,1H),4.72(s,2H),4.00-3.80(m,4H),3.64-3.42(m,4H),3.16(bs,2H),2.59(s,3H); MS(ES + )m / z C 19 H 22 N6O2S calculated value: 398.15; found value: 399.2 (M+H + ).

[0101] [2-Methyl-6-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-(5-pyridin-3-yl-thiazol-2-yl)-amine hydrochloride (Compound 6). 1 H NMR (400MHz, DMSO-d6): δ11.51(bs,1H),9.20(s,1H),8.71(d,J=5.6Hz,1H),8.66(d,J=8.4Hz,1H),8.24(s,1H),7.98(dd,J=8.0,5.6Hz,1H),6.35(s ,1H),4.72(t,J=4.8Hz,2H),3.96(d,J=10.8Hz,2H),3.85(t,J=12.0Hz,2H ),3.55(bs,2H),3.47(d,J=12.4Hz,2H),3.19(bs,2H),2.59(s,3H); MS(ES + )m / z C 19 H 22 N6O2S calculated value: 398.15; found value: 399.1 (M+H + ).

[0102] Example 2 :Inhibits FLT3 activity

[0103] The following studies were performed to test specific compounds prepared according to Example 1 in inhibiting FLT3 activity.

[0104] GST-FLT3-KD containing the FLT3 kinase catalytic domain (residues Y567-S993) WTFLT3 was expressed in Sf9 insect cells transfected with baculovirus containing pBac-PAK8-GST-FLT3-KD plasmid. WT The Kinase-Glo assay was performed in a 96-well plate at 30 °C for 4 h to test compounds in a final volume of 50 μl containing the following components: 75 ng GST-FLT3-KD WT Protein, 25mM HEPES, pH 7.4, 4mM MnCl2, 10mM MgCl2, 2mM DTT, 0.02% Triton X-100, 0.1mg / ml bovine serum albumin, 25μM Her2 peptide substrate, 0.5mM Na3VO4 and 1μM ATP. After incubation, 50μl Kinase-Glo Plus reagent (Promega, Madison, WI, USA) was added to each well, and the mixture was incubated at 25°C for 20 minutes. A 70-μL aliquot of each reaction mixture was transferred to a black microtiter plate and fluorescence was measured on a Wallac Vector 1420 multi-label counter (PerkinElmer, Shelton, CT, USA).

[0105] A variety of compounds were tested. Unexpectedly, compounds 1-11 showed IC values ​​below 100 nM. 50 (the concentration of inhibitor at which the response is reduced by half) value.

[0106] Example 3 :Inhibits VEGFR2 activity

[0107] The following studies were performed to test specific compounds prepared according to Example 1 at inhibiting VEGFR2 activity. Note that VEGFR2 is one of the three major isoforms of VEGFR.

[0108] Recombinant GST-VEGFR2 (residues V789-V1356) containing the kinase domain was expressed in Sf9 insect cells. Kinase assays were performed in 96-well plates with test compounds at 30°C for 120 minutes in a final volume of 50 μl reactions with the following components: 25 mM HEPES pH 7.4, 10 mM MgCl2, 4 mM MnCl2, 0.5 mM Na3VO4, 2 mM DTT, 0.02% TritonX100, 0.01% BSA, 1 μM ATP, 2 μM poly-Glu4:Tyr peptide, 50-100 ng recombinant VEGFR2. After incubation, 50 μl Kinase-Glo Plus reagent (Promega, Madison, WI, USA) was added to each well, and the mixture was incubated at 25°C for 20 minutes. A 70-μL aliquot of each reaction mixture was transferred to a black microtiter plate, and fluorescence was measured on a Wallac Vector 1420 multilabel counter (PerkinElmer, Shelton, CT, USA).

[0109] A variety of compounds were tested in the VEGFR2 assay. Compounds 1, 9, and 10 unexpectedly showed IC values ​​below 30 nM. 50 value.

[0110] Example 4 :Inhibits c-Kit activity

[0111] The following studies were performed to test specific compounds prepared according to Example 1 in inhibiting c-Kit activity.

[0112] N-terminally His-tagged human c-KIT (residues T544-V976) recombinant protein expressed in the Sf9 baculovirus-insect cell expression system was purified for use in the c-KIT ADP Kinase-Glo assay. The c-Kit-ADP Kinase-Glo assay was performed in a 96-well plate at 30°C for 150 minutes in a final volume of 10 μl containing 40 mM Tris pH 7.4, 20 mM MgCl2, 2 mM MnCl2, 2 mM DTT, 0.01% BSA, 20 μM ATP, 20 μM poly (Glu, Tyr) 4:1 peptide, 0.1 mM Na3VO4, 250 ng of recombinant c-Kit protein and the indicated concentrations of test compounds. At 25°C, under a 40-minute incubation, the cells were quenched by the addition of 5 μl of ADP-Glo TMThe reaction was terminated with 10 μl of kinase detection reagent (Promega, Madison, WI, USA), followed by incubation for another 30 min. Finally, a 30 μl aliquot of each reaction mixture was transferred to a black microtiter plate and fluorescence was measured on a Wallac Vector 1420 multilabel counter (Perkin-Elmer, Shelton, CT, USA).

[0113] A variety of compounds were tested. Unexpectedly, compounds 1-7 and 11-12 showed IC values ​​below 100 nM. 50 value.

[0114] Example 5 :In vitro anticancer activity

[0115] Studies were performed as follows to evaluate the in vitro anticancer activity of specific compounds prepared according to Example 1 using cell lines and the MTS cell survival assay (MTS stands for 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium).

[0116] Leukemia cell lines MOLM-13, MV4:11 and Kasumin-1 were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA). Human gastrointestinal stromal tumor GIST-T1 cell line was purchased from Cosmo Bio Co., LTD (Tokyo, Japan). At 37°C and 5% CO2, all leukemia cell lines were maintained in RPMI1640 culture medium supplemented with 10% fetal bovine serum (FBS), 10U / ml penicillin and 10g / ml streptomycin. Cell line GIST-T1 was cultured in DMEM culture medium supplemented with 10% FBS, 0.01% non-essential amino acids, 10U / ml penicillin and 10g / ml streptomycin.

[0117] GIST882, GIST48 and GIST430 cells are all cultured in an incubator maintained at 37°C and 5% CO2. GIST882 is cultured in RPMI-1640 supplemented with 20% fetal bovine serum (FBS). GIST48 is cultured in F10 supplemented with 20% fetal bovine serum (FBS), 0.5% Mito, serum extender (serum extender) (BD Bioscience, 355006) and 1% bovine pituitary extract (BD Bioscience 354123). GIST430 is cultured in IMDM supplemented with 20% FBS. GIST882, GIST430 and GIST48 cells are provided by Jonathan A. Fletcher, PhD (Harvard Medical School, US).

[0118] MOLM-13, MV4:11 and Kasumin-1 MTS assays

[0119] The cells were cultured at 1×10 4 Cells were plated in triplicate at a density of 10 cells / 100 μl / well in 96-well culture plates and treated with the indicated concentrations of test compounds ranging from 1 nM to 10 μM for 72 hours. Aqueous One Solution cell proliferation assay (MTS assay; Promega, Madison, WI, USA) was used to determine cytotoxicity. The optical density at 492 nm was measured using a microplate photometer (Victor2; Perkin-Elmer, Waltham, MA, USA). When cells were treated with test compounds for 72 h, the IC was determined by MTS assay. 50 The values ​​were calculated using GraphPad Prism 6. Each experiment was repeated three times.

[0120] GIST-T1 MTS assay

[0121] GIST-T1 cells were seeded in triplicate in 96-well culture plates at a density of 8000 cells / 100 μl / well and treated with the indicated concentrations of test compounds ranging from 1 nM to 10 μM for 72 hours. Aqueous One Solution cell proliferation assay (MTS assay; Promega, Madison, WI, USA) was used to determine cytotoxicity. The optical density at 492 nm was measured using a microplate photometer (Victor2; Perkin-Elmer, Waltham, MA, USA). When cells were treated with test compounds for 72 h, the IC was determined by MTS assay. 50 The values ​​were calculated using GraphPad Prism 6. Each experiment was repeated three times.

[0122] GIST882, GIST48, and GIST430 MTS assay

[0123] GIST cells (4×10 4 ) were treated with different doses of compounds. Treated GIST882 cells were cultured for 144 hours at 37°C in 5% CO2, and GIST48 and GIST430 cells were cultured for 120 hours. Cell proliferation was determined by incubating cells with methylene blue (Clontech, CA, US) for 1 hour. Absorbance was measured at 450nm using a SpectraMax M5 microplate reader (Molecular Devices, US).

[0124] GI of specific compounds of formula (I) 50 The values ​​of (concentration at 50% of maximum inhibition of cell proliferation) are shown in the table below:

[0125]

[0126] ND: Not measured

[0127] Other Implementations

[0128] All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature having the same, equivalent or similar purpose. Therefore, unless otherwise clearly indicated, each feature disclosed is only an example of a series of equivalent or similar features.

[0129] In addition, based on the foregoing description, those skilled in the art can easily determine the basic characteristics of the present invention, and without departing from the spirit and scope of the present invention, those skilled in the art can make various changes and modifications to the present invention to adapt it to various uses and situations. Therefore, other embodiments are also within the scope of the following claims.

Claims

1. A compound of the following formula (II) or a pharmaceutically acceptable salt thereof: in, R1 is C 1-6 alkyl; X is O, Y is NR d , and R2 is -CH2CH2R e , where R e OR h , R h With R d , key to R h The oxygen atom and the bond to R d The nitrogen atoms of X is NR a , Y is CR b R c , and R2 is NR f R g , where R a With R b , key to R a The nitrogen atom and the bond to R b The carbon atoms of c is H; and R f and R g Each is C 1-6 Alkyl, or X is NR a , Y is NR d , and R2 is -CH2CH2R e , where R a With R d and key to R a and R d The nitrogen atoms of e is H, halogen or OR h , R h H or C 1-6 Alkyl, and R3 is pyridyl or pyrimidinyl.

2. The compound or salt according to claim 1, wherein the compound is 3. The compound or salt according to claim 1, wherein the compound is 4. The compound or salt according to claim 1, wherein the compound is one of the following compounds:

5. The compound or salt according to claim 1, wherein the compound is one of the following compounds:

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or salt according to claim 1.

7. Use of the compound or salt according to any one of claims 1 to 5 in the preparation of a medicament as a tyrosine kinase inhibitor for treating cancer, wherein the cancer is leukemia.

8. Use of the compound or salt according to any one of claims 1 to 5 in the preparation of a medicament as a tyrosine kinase inhibitor for treating cancer, wherein the cancer is gastrointestinal stromal tumor.

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