Thiazole compounds, processes for their preparation, uses and pharmaceutical compositions

Abstract

The application belongs to the technical field of pharmacy, and relates to a thiazole compound, a preparation method and application thereof, and a pharmaceutical composition.The thiazole compound is shown in formula (I), is a PRMT5-MTA inhibitor, and can be used for preventing and / or treating PRMT5-mediated diseases, such as ovarian cancer, lung cancer, lymphoma, glioblastoma, colon tumor, melanoma, gastric cancer, pancreatic cancer or bladder cancer.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a thiazole compound, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts. This invention also relates to methods for preparing the thiazole compound, pharmaceutical compositions comprising the thiazole compound, and the use of the thiazole compound in the treatment and / or prevention of PRMT5-related diseases such as tumors. Background Technology

[0002] Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that regulates gene transcription and protein modification processes by symmetrically dimethylating arginine residues on histones and non-histone proteins, thereby affecting various cellular physiological functions. Studies have shown that PRMT5 overexpression plays an important role in the development and progression of various proliferative diseases, metabolic diseases, hematological diseases, and tumors, making it a highly promising therapeutic target.

[0003] The loss of tumor suppressor genes is a key driver of tumorigenesis, often accompanied by the co-loss of adjacent genes. In approximately 15% of human tumors, the tumor suppressor gene CDKN2A at chromosome 9p21 is lost, leading to co-loss of MTAP. MTAP is an intracellular MTA-degrading enzyme that plays a crucial role in the methionine and adenine rescue pathway. MTAP loss leads to intracellular MTA accumulation, and MTA can compete with the methylation donor SAM, a functional substrate of PRMT5, for binding to PRMT5, thereby inhibiting PRMT5 function. Since MTA specifically accumulates in MTAP-deficient tumor cells, enhancing the inhibition of MTA-PRMT5 binding can achieve specific inhibition of PRMT5 activity in tumor cells while reducing the inhibition of PRMT5 activity in normal cells, thus reducing toxicity to normal tissues and improving the therapeutic index and safety.

[0004] Currently, several PRMT5 inhibitors have entered the clinical development stage. Among them, the first-generation PRMT5 inhibitors are mostly substrate-competitive or SAM-competitive inhibitors, which simultaneously inhibit the PRMT5 activity of tumor cells and normal cells, thus leading to a variety of toxic side effects. Among these, hematologic toxicity is the main dose-limiting toxicity of the first-generation PRMT5 inhibitors.

[0005] Therefore, developing selective PRMT5-MTA complex inhibitors that specifically inhibit PRMT5 activity in MTAP-deficient tumor cells while avoiding the toxic side effects caused by inhibiting PRMT5 activity in normal cells will provide a safer and more effective treatment for cancer patients and has broad application prospects. Summary of the Invention

[0006] The purpose of this invention is to provide a novel small molecule compound targeting the PRMT5-MTA complex, its preparation method, pharmaceutical composition, and uses. The compounds of this invention exhibit strong inhibitory activity against the PRMT5-MTA complex, and therefore can be widely used in the preparation of drugs for the treatment and / or prevention of PRMT5-mediated diseases.

[0007] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0008] The first aspect of the present invention is to provide a compound of formula (I), its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts:

[0009]

[0010] in,

[0011] A is selected from

[0012] X is selected from CR a4 、N;R a4 Selected from H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy;

[0013] Y is selected from CH and N;

[0014] W is selected from C or N;

[0015] R a1 Selected from H, halogens, C 1-4 alkyl;

[0016] R a2 R a3 Each is independently selected from H, halogen, cyano, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl; or R a2 and R a3 Together with the attached ring atoms, they form a 4-6 member saturated or unsaturated ring, and the ring may be substituted or unsubstituted;

[0017] B is selected from H, Among them, R b1 Selected from H, halogen, hydroxyl, carboxyl, mercapto, amino, cyano, nitro, azide, sulfonyl (-SO2-OH), C 1-10 Alkyl, C 1-10 Alkyl groups, -C(O)-R6, -C(O)-O-R7, -C(O)-NR8R9, -OC(O)-R 10-N(R) 11 )-C(O)-R 12 -NR 13 -S(O2)-R 14 -NR 15 R 16 -S(O)-R 17 -S(O2)-NR 18 R 19 -S(O)2-R 20 R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl; n is selected from 1, 2, 3, 4, 5 or 6;

[0018] R1 is selected from R4 and -L-R5;

[0019] R4 is selected from substituted or unsubstituted C4. 1-10 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic alkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-12 heteroaryl groups;

[0020] R5 is selected from H, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic alkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-12 heteroaryl groups;

[0021] L is selected from -C(R) c1 (R) c2 )-;

[0022] R c1 R c2 Each is independently selected from H, halogen, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl; or R5 and R c1 Together with the attached carbon atom, they form a 5-12 member saturated or unsaturated ring, and the ring may be substituted or unsubstituted;

[0023] R2 and R3 are independently selected from H and C. 1-4 alkyl.

[0024] In one implementation, A is selected from the following structures:

[0025]

[0026]

[0027] in,

[0028] X is selected from CR a4 、N;R a4 Selected from H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy;

[0029] Y is selected from CH and N;

[0030] R a1 Selected from H, halogens, C 1-4 alkyl;

[0031] R a2 R a3 Each is independently selected from H, halogen, cyano, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl; or R a2 and R a3 Together with the attached ring atoms, they form a 4-6 member saturated or unsaturated ring, and the ring may be substituted or unsubstituted;

[0032] R a5 Selected from H, halogen, hydroxyl, carboxyl, mercapto, amino, cyano, nitro, azide, sulfonic acid (-SO2-OH), C 1-10 Alkyl, C 1-10 Alkyl groups, -C(O)-R6, -C(O)-O-R7, -C(O)-NR8R9, -OC(O)-R 10 -N(R) 11 )-C(O)-R 12 -NR 13 -S(O2)-R 14 -NR 15 R 16 -S(O)-R 17 -S(O2)-NR 18 R 19 -S(O)2-R 20 R6, R7, R8, R9, R 10 R11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl; m is selected from 1, 2, 3 or 4;

[0033] R a6 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl.

[0034] In one implementation, A is selected from the following structures:

[0035]

[0036]

[0037] In one implementation, B is selected from H or the following structure:

[0038]

[0039]

[0040]

[0041] In one implementation, R1 is selected from the following structures:

[0042]

[0043] Specifically, the preferred compounds according to the present invention are as follows:

[0044]

[0045]

[0046]

[0047] The second aspect of the present invention provides a method for preparing the compound, its stereoisomers, geometric isomers, and tautomers, comprising the following steps:

[0048]

[0049] (1) Compound B was prepared by using compound A as the starting material through reductive amination and protecting group introduction reaction;

[0050] (2) Compound C was prepared from compound B through a deprotection reaction;

[0051] (3) The compound shown in formula (II), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts are prepared from compound C by a condensation reaction.

[0052] A second aspect of the present invention also provides another method for preparing the compound, its stereoisomers, geometric isomers, and tautomers, comprising the following steps:

[0053]

[0054] (1) Compound B was prepared by using compound A as the starting material through reductive amination and protecting group introduction reaction;

[0055] (2) Compound D is prepared from compound B via a free radical reaction;

[0056] (3) Compound E was prepared from compound D via a deprotection reaction;

[0057] (4) Compound F was prepared from compound E by a condensation reaction;

[0058] (5) The compound F is obtained by coupling reaction to the compound shown in formula (III), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0059] A second aspect of the present invention also provides a method for preparing the compound, its stereoisomers, geometric isomers, and tautomers, comprising the following steps:

[0060]

[0061] (1) Compound H was prepared by introducing a protecting group using compound G as the starting material;

[0062] (2) Compound I was prepared from compound H via a free radical reaction;

[0063] (3) Compound E was prepared from compound I through deprotection and nucleophilic reactions;

[0064] (4) Compound F was prepared from compound E by a condensation reaction;

[0065] (5) The compound F is obtained by coupling reaction to the compound shown in formula (IV), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0066] A third aspect of the present invention is to provide a pharmaceutical composition comprising the compound, its tautomers or pharmaceutically acceptable salts, and optionally a pharmaceutically acceptable carrier and / or excipients; preferably, the pharmaceutical composition further comprises one or more pharmaceutically active ingredients for the prevention and / or treatment of PRMT5-mediated diseases, other than the compound, its tautomers or pharmaceutically acceptable salts; preferably, the pharmaceutical composition is a pharmaceutically acceptable pharmaceutical preparation for the prevention and / or treatment of PRMT5-mediated tumors.

[0067] In another aspect, the present invention also provides a pharmaceutical formulation comprising at least one of the aforementioned compounds, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, and optionally a pharmaceutically acceptable carrier or / or excipient; preferably, the pharmaceutical formulation is selected from the following dosage forms: parenteral formulations, such as injectable solutions or suspensions; enteral formulations, such as oral formulations, like tablets or capsules; topical formulations, such as lotions, gels, ointments, emulsions, nasal formulations, suppositories, transdermal formulations, or ophthalmic formulations.

[0068] In another aspect, the present invention also provides the use of the said compound, its tautomers, or pharmaceutically acceptable salts, or the said pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of PRMT5-mediated diseases. In other words, the present invention provides a method for the prevention and / or treatment of PRMT5-mediated diseases, comprising administering to a subject in need a preventive and / or therapeutically effective amount of the said compound, its tautomers, or pharmaceutically acceptable salts, or the said pharmaceutical composition.

[0069] The following are definitions of some of the terms used in this invention; other undefined terms have meanings known to those skilled in the art.

[0070] Halogens refer to fluorine, chlorine, bromine, or iodine.

[0071] C 1-10 Alkyl groups are saturated aliphatic hydrocarbon groups containing 1 to 10 carbon atoms and being straight-chain or branched. Examples of such groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0072] C 3-12 Cycloalkyl refers to a monocyclic, fused, spirocyclic, or polycyclic structure having 3 to 12 carbon ring atoms, either saturated or partially unsaturated. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.

[0073] 3-12 membered heterocyclic alkyl groups refer to saturated or unsaturated 3-12 membered cyclic groups containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen. These groups include, but are not limited to: ethylene oxide, butyl oxide, acridineyl, acridineyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, hexahydropiperidinyl, hexahydropyridyl, hexahydropyrimidinyl, hexahydropyrazinyl, etc.

[0074] C 1-10 Alkoxy groups are straight-chain or branched saturated aliphatic hydrocarbon groups having 1 to 10 carbon atoms. Examples of such groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups.

[0075] C 6-10 Aryl refers to an all-carbon aryl group having 6-10 carbon atoms. Examples of such groups include, but are not limited to, phenyl and naphthyl.

[0076] 5-10 membered heteroaryl refers to heteroaromatic systems with 5-10 ring atoms. Examples of such groups include, but are not limited to, furanyl, thiophene, pyrimidinyl, pyrazinyl, imidazolyl, benzothiazolyl, benzofuranyl, pyridinothiazolyl, and pyrazinothiazolyl.

[0077] The compounds described in this invention include their tautomers. Tautomers are structural isomers that interconvert at different energies via low-energy barriers, such as keto-enol and imine-enamine tautomerization.

[0078] The compounds described in this invention also include isotopically labeled compounds thereof, wherein one or more atoms are replaced by naturally found atoms having the same atomic number but different atomic mass or mass number. Examples include, but are not limited to, hydrogen isotopes. 2 H and 3 H; carbon isotopes 11 C 13 C and 14 C; Chloride isotopes 36 Cl; Fluorine isotopes 18 F; Iodine isotopes 123 I and 125 I; nitrogen isotopes 13 N and 15 N; oxygen isotope 15 O、 17 O and 18 O; phosphorus isotopes 32 P and sulfur isotopes 35 S.

[0079] Various hydrates and solvates of the compounds or their salts described in this invention, as well as their polymorphisms, are also included within the scope of this invention.

[0080] Prodrugs of the compounds described in this invention are also included within the scope of this invention. Some derivatives of the compounds described in this invention possess weak or no pharmacological activity, but when these derivatives are administered in vivo or to the body, they can be converted into pharmacologically active compounds of this invention through mechanisms such as hydrolysis and cleavage. These derivatives are called "prodrugs". Further information on the uses of prodrugs can be found in *Pro-drugs as Novel Delivery Systems*, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and *Bioreversible Carriers in Drug Design*, Pergamon Press, 1987 (ed. E.B. Roche, American Pharmaceutical Association).

[0081] The compounds described in this invention include pharmaceutically acceptable salts. A pharmaceutically acceptable salt is a salt that is pharmaceutically acceptable and possesses the pharmacological activity required by the parent compound. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharma. Sci., 1977, 66, 1-19, which is incorporated herein by reference. The compounds described in this invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and accordingly react with some inorganic or organic base, or inorganic and organic acid, to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, hydroiodates, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanates, propynates, oxalates, malonates, succinates, octanoates, sebates, fumarates, maleates, butyn-1,4-dicitates, hexyn-1,6-dicitates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrate, glycolate, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0082] When used as a pharmaceutical, the compounds described herein are typically administered in the form of a pharmaceutical composition. Therefore, pharmaceutical compositions containing the compounds described herein and pharmaceutically acceptable carriers, diluents, or excipients are also included within the scope of this invention. Carriers, excipients, and additives as used herein include any and all solvents, diluents or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the desired particular dosage form. Various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference.

[0083] The compositions of this invention can be administered via any route suitable for the condition to be treated. In particular, administration is possible via: parenteral administration, for example, as an injectable solution or suspension; enteral administration, for example, orally, in tablet or capsule form; or topically, for example, as a lotion, gel, ointment, or emulsion, or in the nose or as a suppository. Topical application is, for example, to the skin. Another form of topical administration is to the eye.

[0084] Pharmaceutical compositions can be administered in solid, semi-solid, liquid, or gaseous form, or may be in the form of dry powders, such as lyophilized forms. Pharmaceutical compositions can be packaged in easily deliverable forms, including, for example, solid dosage forms such as capsules, pouches, sachets, gelatin, paper, tablets, suppositories, granules, pills, lozenges, and tablets. The type of packaging will generally depend on the route of administration. Implantable, sustained-release formulations and transdermal formulations are also covered.

[0085] Examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid or potassium sorbate, mixtures of metaglycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), and starches (e.g., corn starch). The composition may contain: potato starch, cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth gum powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffer, as well as other non-toxic and compatible lubricants, such as sodium lauryl sulfate and magnesium stearate. Colorants, releasing agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition, at the discretion of the formulation personnel.

[0086] The compounds described in this invention can be used alone or in combination with other therapeutic agents for treating the diseases or conditions described in this invention (e.g., cancer). In some embodiments, the compounds described in this invention are combined in a pharmaceutical combination formulation with a second compound having anti-proliferative properties or for treating highly proliferative diseases (e.g., cancer), or in a dosing regimen as a combination therapy. The second compound in the pharmaceutical combination formulation or dosing regimen preferably has an activity complementary to that of the compounds described in this invention so that they do not adversely affect each other. Such compounds are suitably present in the combination in an amount effective for the intended purpose. In one embodiment, the compounds of this invention are combined with other antitumor drugs. The antitumor drugs include: platinum-based drugs, including but not limited to cisplatin, carboplatin, and oxaliplatin; antimicrotubule or antimitotic agents, including but not limited to doxorubicin, paclitaxel, vinorelbine, and docetaxel; topoisomerase inhibitors, including but not limited to camptothecin, topotecan, topotecan, and irinotecan; EGFR inhibitors, including but not limited to erlotinib, mivatinib, ervatumab, and reertinib mesylate; HER2 inhibitors, including but not limited to tucatinib, neratinib, and lapatinib; MAT2A inhibitors, including but not limited to SYH2039, ISM3412, and IDE397; and KRASG12C inhibitors, including but not limited to sotorasib, adagrasib, and gexole.

[0087] The fourth aspect of the present invention is the use of the compound described in the first aspect, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, or the pharmaceutical composition described in the third aspect, in the preparation of a medicament for the prevention and / or treatment of PRMT5-mediated diseases; wherein the PRMT5-mediated diseases include proliferative diseases, metabolic diseases, hematologic diseases, and tumors, and the tumors include MTAP-related tumors, including ovarian cancer, lung cancer, lymphoma, glioblastoma, colonoma, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

[0088] Beneficial technical effects: The compound of the present invention has strong inhibitory activity against PRMT5-MTA. Detailed Implementation

[0089] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention. However, the scope of protection of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0090] In the following embodiments, unless otherwise noted in the structural formula or chemical name, molecules with a single chiral center exist as a racemic mixture. Unless otherwise noted in the structural formula or chemical name, molecules with two or more chiral centers exist as a racemic mixture of diastereomers. The single enantiomer / diastereomer can be obtained by methods known to those skilled in the art.

[0091] Preparation method

[0092] The compounds described in this invention can be synthesized according to the synthetic schemes described herein and / or techniques well known in the art. For example, the compounds provided by this invention can be prepared according to the following general synthetic methods.

[0093] In a general synthetic method, the compound shown in formula (II) is prepared according to scheme-1.

[0094] Option-1

[0095]

[0096] Specifically, in Scheme-1, the PRMT5 inhibitor of the present invention can be prepared by a three-step reaction. For example, starting with compound A, compound B is prepared by a reductive amination reaction; compound C is prepared from compound B by a deprotection reaction; and compound C is prepared from compound C by a condensation reaction to obtain the compound shown in formula (II).

[0097] In a general synthetic method, the compound shown in formula (III) is prepared according to scheme-2.

[0098] Option 2

[0099]

[0100] Specifically, in Scheme-3, the PRMT5 inhibitor of the present invention can be prepared by a 5-step reaction. For example, starting with compound A, compound B is prepared by reductive amination and protecting group introduction reaction; compound D is prepared by free radical reaction of compound B; compound E is prepared by deprotection reaction of compound D; compound F is prepared by condensation reaction of compound E; and compound F is prepared by coupling reaction to obtain the compound shown in formula (III).

[0101] In a general synthetic method, the compound shown in formula (IV) is prepared according to scheme-3.

[0102] Option 3

[0103]

[0104] Specifically, in Scheme-1, the PRMT5 inhibitor of the present invention can be prepared by a 5-step reaction. For example, starting with compound G, compound H is prepared by a protecting group introduction reaction; compound I is prepared from compound H by a free radical reaction; compound E is prepared from compound I by a deprotection reaction and a nucleophilic reaction; compound F is prepared from compound E by a condensation reaction; and compound F is prepared from compound F by a coupling reaction to obtain the compound shown in formula (IV).

[0105] The compounds described in this invention can be synthesized according to one or more synthetic schemes described herein and / or techniques well known in the art. Those skilled in the art will recognize that the synthetic methods of some embodiments described in detail herein can be readily applied to the synthesis of other embodiments. In some embodiments, the compounds described herein can be prepared by appropriate combinations of synthetic methods well known in the art. Many starting materials and other reagents are available from commercial suppliers, such as Alfaisa (China) Chemical Co., Ltd., or can be readily prepared using synthetic methods commonly used in the art.

[0106] 1 H NMR spectra are recorded on instruments operating at 400 MHz or 500 MHz. 1¹H NMR spectra were obtained in solution form (reported in ppm), using CDCl₃ (7.26 ppm), DMSO-d₆ (2.50 ppm), or the internal standard tetramethylsilane (0.00 ppm) as reference standards. When reporting peak multiplicity, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (doublet), dt (doubletuplet). Coupling constants are given in Hertz (Hz).

[0107] When necessary, the (R) and (S) isomers of the non-limiting exemplary compounds, if present, can be separated by methods known to those skilled in the art, such as by forming diastereomeric salts or complexes, which can be separated by, for example, crystallization; by forming diastereomeric derivatives, which can be separated by, for example, crystallization or chromatography; by selectively reacting one enantiomer with an enantiomer-specific reagent, thereby separating the modified and unmodified enantiomers; or by chromatographic separation in a chiral environment, for example, a chiral chromatographic column. Alternatively, specific enantiomers can be prepared by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to another via asymmetric transformation.

[0108] In the following preparation methods and examples, "Me" refers to methyl, "Et" refers to ethyl, "EA" refers to ethyl acetate, "PE" refers to petroleum ether, "MeOH" refers to methanol, "DMSO-d6" refers to deuterated dimethyl sulfoxide, "DCM" refers to dichloromethane, "DMF" refers to N,N-dimethylformamide, "PdCl2(dppf)" refers to 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, "(Boc)2O" refers to ditert-butyl dicarbonate, "HOAc" refers to acetic acid, and "HCl" refers to... Hydrochloric acid, "THF" refers to tetrahydrofuran, "BOP" refers to benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, "TFA" refers to trifluoroacetic acid, "TEA" refers to triethylamine, "TCFH" refers to N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, "DIPEA" refers to N,N-diisopropylethylamine, "rt" refers to room temperature, "mL" refers to milliliters, "mmol" refers to millimoles, "μM" refers to micromoles, "nM" refers to nanomoles, and "℃" refers to degrees Celsius.

[0109] Preparation of intermediate A1:

[0110]

[0111] Step 1: Synthesis of methyl 2,4-dichloro-3-methylquinoline-6-carboxylate

[0112] Methyl 4-aminobenzoate (15 g, 100 mmol) and 2-methylmalonic acid (12.99 g, 11 mmol) were slowly added to POCl3 (100 mL). The reaction mixture was stirred at 90 °C for 5 hours and cooled to room temperature. The reaction mixture was then slowly poured into ice water (500 mL). The pH was adjusted to 10 with 10% sodium hydroxide aqueous solution. The crude product of methyl 2,4-dichloro-3-methylquinoline-6-carboxylate was obtained by filtration. The crude product was then subjected to rapid column chromatography (silica gel, EA / PE = 1 / 4, V / V) to obtain methyl 2,4-dichloro-3-methylquinoline-6-carboxylate as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.72(d,J=1.8Hz,1H),8.27(dd,J=8.7,1.9Hz,1H),8.08(d,J=8.7Hz,1H),3.96(s,3H),2.64(s,3H).

[0113] Step 2: Synthesis of methyl 4-chloro-2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate

[0114] Methyl 2,4-dichloro-3-methylquinoline-6-carboxylate (10.2 g, 37.78 mmol) and (4-methoxyphenyl)methylamine (10.37 g, 75.56 mmol) were degassed in a mixed solution of NMP (100 mL). The reaction mixture was then stirred in an oil bath at 100 °C for 16 hours. After cooling to room temperature, the mixture was slowly poured into 1000 mL of water, filtered, and the filter cake was dried to obtain methyl 4-chloro-2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate as a white solid.

[0115] 1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=1.9Hz,1H),8.01(dd,J=8.7,2.0Hz,1H),7.70(t,J=5.9Hz,1H),7.58(d,J=8 .8Hz,1H),7.38–7.32(m,2H),6.89–6.83(m,2H),4.67(d,J=5.9Hz,2H),3.88(s,3H),3.70(s,3H),2.40(s,3H).

[0116] Step 3: Synthesis of methyl 2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate

[0117] Methyl 4-chloro-2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate (5.476 g, 14.77 mmol), ammonium formate (9.312 g, 147.7 mmol), and Pd / C (550 mg) were degassed in a mixed solution of MeOH (150 mL) and re-purged with hydrogen. The reaction mixture was reacted at 70 °C for 2 hours. After cooling to room temperature, the mixture was filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure to remove volatiles. The residue was subjected to rapid column chromatography (silica gel, EA / PE = 1 / 1, V / V) to give methyl 4-chloro-2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate as a white solid.

[0118] 1 H NMR (400MHz, DMSO-d6) δ8.26(d,J=2.0Hz,1H),7.92(dd,J=8.7,2.1Hz,1H),7.86(s,1H),7.51(d,J=8.7Hz ,1H),7.40–7.32(m,3H),6.89–6.83(m,2H),4.67(d,J=5.9Hz,2H),3.85(s,3H),3.70(s,3H),2.26(s,3H).

[0119] Step 4: Synthesis of methyl 2-amino-3-methylquinoline-6-carboxylate

[0120] The reaction mixture of methyl 4-chloro-2-((4-methoxybenzyl)amino)-3-methylquinoline-6-carboxylate (6.48 g, 19.29 mmol) and TFA (100 mL) was stirred in an oil bath at 75 °C for 3 hours. After cooling to room temperature, the volatiles were removed by rotary evaporation, and 1,2-dichloroethane (40 × 3) was added for further rotary evaporation to remove the TFA. 20 mL of water was added to the residue, and the pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was filtered, and the filter cake was dried to obtain crude methyl 2-amino-3-methylquinoline-6-carboxylate.

[0121] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,2H),8.48(d,J=1.8Hz,1H),8.36(s,1H),8.20(dd,J=8.7,1.9Hz,1H),7.74(d,J=8.7Hz,1H),3.91(s,3H),2.31(s,3H).

[0122] Step 5: Synthesis of 2-amino-3-methylquinoline-6-carboxylic acid

[0123] Lithium hydroxide monohydrate (1.678 g, 40 mmol) was added to a mixed solution of methyl 2-amino-3-methylquinoline-6-carboxylate (2.16 g, 10 mmol) in H₂O / MeOH / THF (20 mL / 20 mL / 20 mL / ). The reaction mixture was stirred at room temperature for 3 hours. Volatile substances were removed by rotary evaporation, and the pH was adjusted to 6.5 with 1 N HCl. The mixture was filtered, and the filter cake was dried to obtain 2-amino-3-methylquinoline-6-carboxylic acid.

[0124] 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=1.8Hz,1H),7.93(dd,J=8.7,1.9Hz,1H),7.85(s,1H),7.45(d,J=8.7Hz,1H),6.62(s,2H),2.22(s,3H).

[0125] The synthetic route of intermediate A2 is shown below. For specific synthetic methods, please refer to patent US2024376126A1.

[0126]

[0127] Preparation of intermediate A3:

[0128]

[0129] Step 1: Synthesis of (5-(methoxycarbonyl)-2-nitrophenyl)proline

[0130] The reaction mixture of methyl 3-fluoro-4-nitrobenzoate (3.983 g, 20 mmol), proline (2.533 g, 22 mmol), TEA (10.119 g, 100 mmol), and DMSO (20 mL) was placed at 60 °C and stirred for 1 h. The reaction mixture was then slowly poured into 200 mL of ice water, and the pH was adjusted to 4 with 1 N hydrochloric acid. The mixture was filtered to obtain crude product of compound (5-(methoxycarbonyl)-2-nitrophenyl)proline, which could be directly used in the next step after drying.

[0131] Step 2: Synthesis of methyl 3-(2-cyanopyrrolidone-1-yl)-4-nitrobenzene

[0132] Under ice bath conditions, TEA (304 mg, 3 mmol) was added to a reaction mixture of 5-(methoxycarbonyl)-2-nitrophenyl)proline (294 mg, 1 mmol), ammonium chloride (267 mg, 5 mmol), BOP (664 mg, 1.5 mmol), and DCM (10 mL). The resulting reaction mixture was stirred at room temperature for 16 h. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with DCM (20 mL × 3). The organic phases were combined, washed with water (10 mL), washed with saturated sodium chloride (10 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, pyridine (0.5 mL) was added to the obtained non-volatile substance, and trifluoroacetic anhydride (315 mg, 1.5 mmol) was added dropwise under ice bath conditions. The resulting reaction mixture was placed at room temperature and stirred for 2 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL × 3). The organic phases were combined and washed with 1N HCl (20 mL × 2), saturated sodium chloride (20 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to rapid column chromatography (silica gel, EA / PE = 1 / 1, V / V) to give methyl 3-(2-cyanopyrrolidone-1-yl)-4-nitrobenzene as a yellow solid.

[0133] 1 H NMR(400MHz,Chloroform-d)δ7.83–7.79(m,2H),7.62(dd,J=8.4,1.6Hz,1H),4.63(dd,J=7.1,5.5Hz,1H),3.96(s,3H ),3.52–3.43(m,1H),3.35–3.28(m,1H),2.58–2.47(m,1H),2.45–2.34(m,1H),2.28–2.18(m,1H),2.13–2.00(m,1H).

[0134] Step 3: Synthesis of methyl 4-amino-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxaline-8-carboxylate

[0135] The reaction mixture of methyl 3-(2-cyanopyrrolidone-1-yl)-4-nitrobenzoate (275 mg, 1 mmol), iron powder (560 mg, 10 mmol), glacial acetic acid (300 μL, 5 mmol), tetrahydrofuran (5 mL), and water (1 mL) was placed at room temperature and stirred for 16 h. After filtration with diatomaceous earth, most of the solvent was removed by rotary evaporation. The residue was alkalized to pH 7 with saturated sodium bicarbonate solution and then filtered to obtain crude methyl 4-amino-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxaline-8-carboxylic acid.

[0136] 1H NMR(500MHz,Chloroform-d)δ7.82(d,J=2.0Hz,1H),7.72(dd,J=8.3,1.9Hz,1H),6.73(d,J=8.3Hz,1H),4.43(dd,J=8.2,3.5Hz,1H),4.38–4 .28(m,2H),3.86(s,3H),3.55–3.47(m,1H),3.11–3.02(m,1H),2.45– 2.36(m,1H),2.35–2.26(m,1H),2.20–2.10(m,1H),2.09–1.99(m,1H).

[0137] Step 4: Synthesis of 4-amino-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxaloline-8-carboxylic acid

[0138] A reaction mixture of methyl 4-amino-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxaline-8-carboxylic acid (500 mg, 2 mmol), lithium hydroxide monohydrate (168 mg, 4 mmol), methanol (6 mL), tetrahydrofuran (3 mL), and water (3 mL) was stirred at room temperature for 16 h. The volatiles in the reaction mixture were removed by rotary evaporation, the pH was adjusted to 4 with 1 N HCl solution, and the mixture was filtered. The filter cake was dried to obtain 4-amino-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxaline-8-carboxylic acid as a white solid.

[0139] 1 H NMR (400MHz, DMSO-d6) δ12.86(s,1H),9.61(d,J=101.1Hz,2H),7.38(dd,J=8.1,1.7Hz,1H),7.21(d,J=8.2Hz,1H),7 .16(d,J=1.8Hz,1H),4.30–4.22(m,1H),3.48–3.40(m,1H),3.31–3.24(m,1H),2.49–2.44(m,1H),2.14–1.96(m,3H).

[0140] The synthetic routes for intermediates A4 and A5 are shown below. For specific synthetic methods, please refer to the synthetic route and method in patent WO2022132914A1:

[0141]

[0142] Example 1: 2-Amino-N-[(2,6-difluorophenyl)methyl]-3-methyl-N-(1,3-thiazacyclopentan-2-ylmethyl)quinoline-6-carboxamide

[0143]

[0144] Step 1: Synthesis of (2,6-difluorobenzyl)(thiazolyl-2-ylmethyl)carbamate tert-butyl ester (B-1)

[0145]

[0146] HOAc (1.321 g, 22 mmol) was added to a DCM solution of thiazol-2-carboxaldehyde (3.720 g, 20 mmol) and (2,6-difluorophenyl)methylamine (4.294 g, 30 mmol), and the reaction mixture was stirred at room temperature for 16 hours. Triacetoxyborohydride sodium (8.44 g, 40 mmol) was added in portions to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Then, saturated sodium bicarbonate aqueous solution (80 mL) was added to the reaction mixture, and the reaction was quenched by stirring at room temperature for 0.5 hours. (Boc)₂O (8.730 g, 40 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. The resulting mixture was extracted with DCM (100 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, EA / PE = 1:4) to give compound B-1 as a colorless oily liquid.

[0147] 1 H NMR (400MHz, DMSO-d6) δ7.68(d,J=3.3Hz,1H),7.62(d,J=3.2Hz,1H),7.44–7.34(m,1H),7.12–7.02(m,1H),4.72–4.53(m,4H),1.37(s,9H).

[0148] Step 2: Synthesis of 2-({[(2,6-difluorophenyl)methyl]amino}methyl)-1,3-thiazazecyclopentane (C-1)

[0149]

[0150] To a DCM (10 mL) solution of B-1 (944 mg, 2.77 mmol), add TFA (7 mL) and stir at room temperature for 1 hour. Remove volatiles by rotary evaporation, add 1,2-dichloroethane, and remove volatiles again by rotary evaporation; repeat this process three times. Adjust the pH to 8 with saturated sodium bicarbonate, and extract the resulting mixture with DCM (50 mL × 3). Dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by rapid column chromatography (silica gel, EA / PE = 1:3, v / v) to obtain compound C-1 as a colorless oily liquid.

[0151] 1H NMR (400MHz, DMSO-d6) δ7.70(d,J=3.0Hz,1H),7.59(d,J=3.3Hz,1H),7.41–7.33(m,1H),7.04–7.14(m,2H),3.98(s,2H),3.83(s,2H),3.05(s,1H).

[0152] Step 3: Synthesis of 2-amino-N-[(2,6-difluorophenyl)methyl]-3-methyl-N-(1,3-thiazacyclopentan-2-ylmethyl)quinoline-6-carboxamide (Compound 1)

[0153]

[0154] To a solution of compound C-1 (120 mg, 0.5 mmol), 2-amino-3-methylquinoline-6-carboxylic acid (101 mg, 0.5 mmol), and acetonitrile (10 mL), DIPEA (226 mg, 1.75 mmol) and TCFH (168 mg, 0.6 mmol) were added sequentially, and the mixture was stirred overnight at room temperature. Water (20 mL) was added to the reaction mixture, and the pH was adjusted to 7 with 10% citric acid. The mixture was extracted with DCM (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, and the volatiles were removed under reduced pressure. The residue was subjected to rapid column chromatography (silica gel, DCM / MeOH = 96 / 4, V / V) to give the title compound as a white solid.

[0155] 1 H NMR(400MHz,DMSO-d6)δ7.85–7.74(m,2H),7.70(s,1H),7.68–7.65(m,1H),7.55–7.47(m ,2H),7.45–7.33(m,1H),7.11–6.99(m,2H),6.53(s,2H),4.86–4.79(m,4H),2.23(s,3H).

[0156] Example 2: 2-Amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-phenylthiazo-2-yl)methyl)quinoline-6-carboxamide

[0157]

[0158] Step 1: 2,6-Difluorobenzoyl-((5-bromothiazol-2-yl)methyl)tert-butyl carbonate (D-1)

[0159]

[0160] To a DMF solution (6 mL) of compound B-1 (733 mg, 2.15 mmol), NBS (1.533 g, 8.61 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. A saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, EA / PE = 1 / 4) to give compound D-1 as a colorless oily liquid.

[0161] 1 H NMR (400MHz, DMSO-d6) δ7.73(s,1H),7.44–7.34(m,1H),7.14–7.03(m,2H),3.94(s,2H),3.83(s,2H),3.23(s,1H).

[0162] Step 2: Synthesis of 1-(5-bromothiazol-2-yl)-N-(2,6-difluorobenzyl)methylamine (E-1)

[0163]

[0164] To a DCM (20 mL) solution of compound D-1 (1.742 g, 4.16 mmol), TFA (20 mL) was added, and the mixture was stirred at room temperature for 1 hour. Volatile substances were removed by rotary evaporation. 1,2-Dichloroethane (20 mL) was added, and the mixture was then removed by rotary evaporation again. This process was repeated three times. The pH was adjusted to 8 with saturated sodium bicarbonate, and the resulting mixture was extracted with DCM (20 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, silica gel, DCM / EA = 4 / 1) to give compound E-1 as a pale yellow oily liquid.

[0165] 1 H NMR (400MHz, DMSO-d6) δ7.73(s,1H),7.44–7.34(m,1H),7.13–7.04(m,2H),3.93(s,2H),3.82(s,2H),3.23(s,1H).

[0166] Step 3: Synthesis of 2-amino-N-((5-bromothiazol-2-yl)methyl)-N-(2,6-difluorobenzyl)-3-methylquinoline-6-carboxamide (F-1)

[0167]

[0168] DIPEA (1.476 g, 11.44 mmol) and TCFH (1.099 g, 3.924 mmol) were added sequentially to an acetonitrile solution (25 mL) of compound E-1 (1.044 g, 3.27 mmol) and 2-amino-3-methylquinoline-6-carboxylic acid (661 mg, 3.27 mmol). The mixture was stirred overnight at room temperature. Water (20 mL) was added to the reaction mixture, and the pH was adjusted to 7 with 10% citric acid. The mixture was extracted with DCM (30 mL × 3). The organic phases were combined and washed with saturated sodium chloride (30 mL). The mixture was dried over anhydrous sodium sulfate, and the volatiles were removed under reduced pressure. The residue was subjected to rapid column chromatography (silica gel, DCM / MeOH = 96 / 4, V / V) to give compound (F-1) as a white solid.

[0169] 1 H NMR(400MHz,DMSO-d6)δ7.84–7.75(m,1H),7.67(s,1H),7.55–7.46(m,2H),7.41–7 .30(m,1H),7.06–6.95(m,2H),6.53(s,2H),4.81(s,2H),4.75(s,2H),2.22(s,3H).

[0170] Step 4: Synthesis of 2-amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-phenylthiazo-2-yl)methyl)quinoline-6-carboxamide (Compound 2)

[0171]

[0172] A mixture of compound F-1 (101 mg, 0.2 mmol), phenylboronic acid (29 mg, 0.24 mmol), and 2 M potassium carbonate aqueous solution (300 μL, 0.6 mmol) in dioxane (8 mL) was degassed, and then PdCl2 (dppf) (15 mg, 0.02 mmol) was added. The resulting reaction mixture was degassed and purged with argon (three cycles), and then stirred at 100 °C under an argon atmosphere for 4 hours. The reaction mixture was cooled to room temperature, and volatiles were removed under reduced pressure. The residue was diluted with water (100 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with water (50 mL × 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to give the title compound as a white solid.

[0173] 1H NMR(400MHz, DMSO-d6)δ8.04(s,1H),7.84–7.75(m,2H),7.65–7.59(m,2H),7.56–7.48(m,2H),7.47–7.41(m,2H),7.40–7.32(m,2H),7.04(br s,2H),6.51(s,2H),4.84(s,2H),4.81(s,2H),2.21(s,3H).

[0174] Example 3: 2-Amino-N-[(2,6-difluorophenyl)methyl]-N-{[5-(4-hydroxyphenyl)-1,3-thiazazacyclopentan-2-yl]methyl}-3-methylquinoline-6-carboxamide

[0175]

[0176] According to the method in step 4 of compound 2, compound 3 was prepared from compound F-1 and 4-hydroxyphenylboronic acid as a white solid.

[0177] 1 H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.87–7.79(m,2H),7.77(s,1H),7.55–7.47(m,2H),7.43(d,J=8.7Hz,2H),7 .40–7.32(m,1H),7.11–6.97(m,2H),6.82(d,J=8.9Hz,2H),6.51(s,2H),4.83(s,2H),4.77(s,2H),2.21(s,3H).

[0178] Example 4: 2-Amino-N-{[5-(4-aminophenyl)-1,3-thiazacyclopentanyl-2-yl]methyl}-N-[(2,6-difluorophenyl)methyl]-3-methylquinoline-6-carboxamide

[0179]

[0180] According to the method in step 4 of compound 2, compound 4 was prepared from compound F-1 and 4-aminophenylboronic acid, and was obtained as a white solid.

[0181] 1H NMR (400MHz, DMSO-d6) δ7.81(s,1H),7.79–7.71(m,2H),7.55–7.46(m,2H),7.43–7.31(m,1H),7.27(d,J=8.1Hz, 2H),7.10–6.99(m,2H),6.59(d,J=8.2Hz,2H),6.52(s,2H),5.42(s,2H),4.82(s,2H),4.74(s,2H),2.21(s,3H).

[0182] Example 5: 2-Amino-N-(2,6-difluorobenzyl)-N-((5-(4-methoxyphenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide

[0183]

[0184] Compound 5, a white solid, was prepared from compound F-1 and 4-methoxyphenylboronic acid according to step 4 of compound 2.

[0185] 1 H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.84–7.74(m,2H),7.58–7.47(m,4H),7.42–7.32(m, 1H),7.10–6.96(m,4H),6.51(s,2H),4.83(s,2H),4.78(s,2H),3.79(s,3H),2.21(s,3H).

[0186] Example 6: 2-Amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-(4-(trifluoromethoxy)phenyl)thiazolyl-2-yl)methyl)quinoline-6-carboxamide

[0187]

[0188] According to step 4 of compound 2, compound 6 was prepared from compound F-1 and 4-trifluoromethoxyphenylboronic acid as a white solid.

[0189] 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.83–7.73(m,4H),7.56–7.47(m,2H),7.44(d,J=8.3Hz,2 H),7.41–7.32(m,1H),7.09–6.97(m,2H),6.52(s,2H),4.84(s,2H),4.82(s,2H),2.21(s,3H).

[0190] Example 7: 2-Amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-(4-(trifluoromethyl)phenyl)thiazolyl-2-yl)methyl)quinoline-6-carboxamide

[0191]

[0192] Compound 7, a white solid, was prepared from compound F-1 and 4-trifluoromethylphenylboronic acid according to step 4 of compound 2.

[0193] 1 H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.88–7.83(m,2H),7.83–7.77(m,4H),7.58–7.47(m,2H ),7.41–7.31(m,1H),7.08–6.96(m,2H),6.52(s,2H),4.85(s,2H),4.84(s,2H),2.22(s,3H).

[0194] Example 8: 2-Amino-N-(2,6-difluorobenzyl)-N-((5-(4-fluorophenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide

[0195]

[0196] Compound 8, a white solid, was prepared from compound F-1 and 4-fluorophenylboronic acid according to the method in step 4 of compound 2.

[0197] 1 H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.85–7.75(m,2H),7.72–7.63(m,2H),7.57–7.46(m,2H),7.41 –7.32(m,1H),7.32–7.24(m,2H),7.03(s,2H),6.52(s,2H),4.84(s,2H),4.80(s,2H),2.22(s,3H).

[0198] Example 9: 2-Amino-N-((5-(4-chlorophenyl)thiazolyl-2-yl)methyl)-N-(2,6-difluorobenzyl)-3-methylquinoline-6-carboxamide

[0199]

[0200] Compound 9, a white solid, was prepared from compound F-1 and 4-chlorophenylboronic acid according to step 4 of compound 2.

[0201] 1H NMR(400MHz, DMSO-d6)δ8.07(s,1H),7.84–7.76(m,2H),7.66(d,J=8.5Hz,2H),7.56–7.46(m,4 H),7.41–7.31(m,1H),7.10–6.97(m,2H),6.53(s,2H),4.84(s,2H),4.81(s,2H),2.22(s,3H).

[0202] Example 10: 2-Amino-N-((5-(4-cyanophenyl)thiazolyl-2-yl)methyl)-N-(2,6-difluorobenzyl)-3-methylquinoline-6-carboxamide

[0203]

[0204] According to the method in step 4 of compound 2, compound 10 was prepared from compound F-1 and 4-cyanobenzoboric acid as a white solid.

[0205] 1 H NMR(400MHz,DMSO-d6)δ8.25(s,1H),7.94–7.88(m,2H),7.87–7.76(m,4H),7.59–7.47(m,2H) ),7.42–730(m,1H),7.10–6.96(m,2H),6.57(s,2H),4.85(s,2H),4.84(s,2H),2.22(s,3H).

[0206] Example 11: 2-Amino-N-(2,6-difluorobenzyl)-N-(5-(4-(dimethylamino)phenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide

[0207]

[0208] According to the method in step 4 of compound 2, compound 11 was prepared from compound F-1 and 4-(N,N-dimethyl)phenylboronic acid as a white solid.

[0209] 1 H NMR(400MHz, DMSO-d6)δ7.86–7.75(m,3H),7.54–7.46(m,2H),7.42(d,J=8.7Hz,2H),7.40–7.32(m,1H),7 .12–6.96(m,2H),6.75(d,J=8.5Hz,2H),6.52(s,2H),4.83(s,2H),4.76(s,2H),2.94(s,6H),2.21(s,3H).

[0210] Example 12: N-((5-(4-acetamidophenyl)thiazolyl-2-yl)methyl)-2-amino-N-(2,6-difluorobenzyl)-3-methylquinoline-6-carboxamide

[0211]

[0212] According to the method in step 4 of compound 2, compound 12 was prepared from compound F-1 and 4-acetamidophenylboronic acid as a white solid.

[0213] 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),7.94(s,1H),7.85–7.74(m,2H),7.65(d,J=8.4Hz,2H),7.59–7.46(m, 4H),7.43–7.31(m,1H),7.14–6.94(m,2H),6.52(s,2H),4.83(s,2H),4.79(s,2H),2.22(s,3H),2.06(s,3H).

[0214] Example 13: 2-Amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-(4-(methylsulfonamido)phenyl)thiazo-2-yl)methyl)quinoline-6-carboxamide

[0215]

[0216] According to the method in step 4 of compound 2, compound 13 was prepared from compound F-1 and 4-methanesulfonylaminophenylboronic acid pinacol ester, and was obtained as a white solid.

[0217] 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),7.96(s,1H),7.84–7.74(m,2H),7.59(d,J=8.3Hz,2H),7.54–7.47(m,2H),7.42–7 .32(m,1H),7.26(d,J=8.3Hz,2H),7.04(s,2H),7.10–6.98(m,2H),4.84(s,2H),4.80(s,2H),3.04(s,3H),2.22(s,3H).

[0218] Example 14: Methyl (4-(2-(2-amino-N-(2,6-difluorobenzyl)-3-methylquinoline-6-carbamate)methyl)thiazolyl-5-yl)phenyl)carbamate

[0219]

[0220] Step 1: Synthesis of methyl (4-bromophenyl)carbamate

[0221]

[0222] The reaction mixture of p-bromoaniline (688 mg, 4 mmol), TEA (1.212 g, 12 mmol, 3 equiv.), and THF (10 mL) was degassed and purged with argon (three cycles). Triphosgene (1.187 g, 4 mmol, 1 equiv.) was added at 0 °C and stirred for 1 h. MeOH (8 mL) was then added, and the reaction mixture was stirred at room temperature for 16 h. Water (20 mL) was added to the reaction mixture, and the resulting mixture was extracted with DCM (50 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, EA / DCM = 1:3, v / v) to give methyl (4-bromophenyl)carbamate as a white solid.

[0223] 1 H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 7.70–7.49 (m, 4H), 3.67 (s, 3H).

[0224] Step 2: Synthesis of methyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)carbamate

[0225]

[0226] A mixture of methyl (4-bromophenyl)carbamate (55 mg, 0.24 mmol), bis(pinarate)diboron (73 mg, 0.288 mmol, 1.2 equiv.), potassium acetate (47 mg, 0.48 mmol, 2 equiv.), and PdCl2(dppf) (9 mg, 0.012 mmol, 0.05 equiv.) in 1,4-dioxane was degassed and backfilled with argon (three cycles). The reaction mixture was stirred at 100 °C for 4 hours under an argon atmosphere, cooled to room temperature, and filtered. The filtrate was used directly for the next step.

[0227] Step 3: Synthesis of methyl (4-(2-(2-amino-N-(2,6-difluorobenzyl)-3-methylquinoline-6-carbamate)methyl)thiazolyl-5-yl)phenyl)carbamate (compound 14)

[0228]

[0229] Compound F-1 (101 mg, 0.2 mmol), 2 M K₂CO₃ aqueous solution (150 μL, 0.6 mmol, 3 equiv.), and PdCl₂ (dppf) (15 mg, 0.02 mmol, 0.1 equiv.) were added to the reaction mixture of methyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenyl)carbamate. The resulting mixture was degassed and backfilled with argon (three cycles), and then stirred at 100 °C for 4 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and DCM, and the two layers were separated. The aqueous layer was extracted with DCM (three times). The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography or preparative thin-layer chromatography (silica gel) to give compound 14 as a white solid.

[0230] 1 H NMR(400MHz,DMSO-d6)δ9.83(s,1H),7.93(s,1H),7.84–7.74(m,2H),7.58–7.46(m,6H),7.42–7 .32(m,1H),7.11–6.98(m,2H),6.52(s,2H),4.83(s,2H),4.78(s,2H),3.68(s,3H),2.21(s,3H).

[0231] Example 15: 2-Amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-(4-(3-methylureido)phenyl)thiazolyl-2-yl)methyl)quinoline-6-carboxamide

[0232]

[0233] Step 1: Synthesis of 1-(4-bromophenyl)-3-methylurea

[0234]

[0235] The reaction mixture of p-bromoaniline (688 mg, 4 mmol), TEA (1.212 g, 12 mmol, 3 equiv.), and THF (10 mL) was degassed and purged with argon (three cycles). Triphosgene (1.187 g, 4 mmol, 1 equiv.) was added at 0 °C and stirred for 1 h. Then, TEA (2.424 g, 24 mmol, 6 equiv.) and methylamine hydrochloride (2.8 g, 20 mmol, 5 equiv.) were added, and the reaction mixture was stirred at room temperature for 16 h. Water (20 mL) was added to the reaction mixture, and the resulting mixture was extracted with DCM (50 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, EA / DCM = 1:3, v / v) to give 1-(4-bromophenyl)-3-methylurea as a white solid.

[0236] 1 H NMR (400MHz, DMSO-d6) δ8.64 (s, 1H), 7.39–7.34 (m, 4H), 2.63 (d, J = 4.6Hz, 3H) 9

[0237] Step 2: Synthesis of 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)urea

[0238]

[0239] A mixture of 1-(4-bromophenyl)-3-methylurea (55 mg, 0.24 mmol), bis(pinarate)diboron (73 mg, 0.288 mmol, 1.2 equiv.), potassium acetate (47 mg, 0.48 mmol, 2 equiv.), and PdCl2(dppf) (9 mg, 0.012 mmol, 0.05 equiv.) in 1,4-dioxane was degassed and backfilled with argon (three cycles). The reaction mixture was stirred at 100 °C for 4 hours under an argon atmosphere, cooled to room temperature, and filtered. The filtrate was used directly for the next step.

[0240] Step 3: Synthesis of 2-amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-(4-(3-methylureido)phenyl)thiazolyl-2-yl)methyl)quinoline-6-carboxamide (compound 15)

[0241]

[0242] Compound F-1 (101 mg, 0.2 mmol), 2 M K₂CO₃ aqueous solution (150 μL, 0.6 mmol, 3 equiv.), and PdCl₂ (dppf) (15 mg, 0.02 mmol, 0.1 equiv.) were added to a reaction mixture of 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)urea. The resulting mixture was degassed and backfilled with argon (three cycles), and then stirred at 100 °C for 4 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and DCM, and the two layers were separated. The aqueous layer was extracted with DCM (three times). The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography or preparative thin-layer chromatography (silica gel) to give compound 15 as a white solid.

[0243] 1 H NMR(400MHz,DMSO-d6)δ8.72(s,1H),7.89(s,1H),7.84–7.75(m,2H),7.56–7.44(m,6H),7.42–7.33(m,1H),7.09 –6.98(m,2H),6.52(s,2H),6.08(q,J=4.5Hz,1H),4.83(s,2H),4.78(s,2H),2.65(d,J=4.6Hz,3H),2.21(s,3H).

[0244] Example 16: 2-Amino-N-((5-(4-carbamoylphenyl)thiazolyl-2-yl)methyl)-N-(2,6-difluorobenzyl)-3-methylquinoline-6-carboxamide

[0245]

[0246] According to the method in step 4 of compound 2, compound 16 was prepared from compound F-1 and (4-carbamoylphenyl)boronic acid as a white solid.

[0247] Example 17: 2-Amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-(4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)quinoline-6-carboxamide

[0248]

[0249] According to step 4 of compound 2, compound 17 was prepared from compound F-1 and (4-(methylcarbamoyl)phenyl)boronic acid as a white solid.

[0250] 1H NMR (400MHz, DMSO-d6) δ8.50(d,J=4.9Hz,1H),8.14(s,1H),7.89(d,J=8.0Hz,2H),7.84–7.77(m,2H),7.72(d,J=8.1Hz,2H),7.5 9–7.46(m,4H),7.42–7.31(m,1H),7.09–6.98(m,2H),6.52(s,2H),4.85(s,2H),4.82(s,2H),2.80(d,J=4.4Hz,3H),2.22(s,3H).

[0251] Example 18: 2-Amino-N-(2,6-difluorobenzyl)-N-(5-(4-(dimethylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide

[0252]

[0253] According to step 4 of compound 2, compound 18 was prepared from compound F-1 and 4-(N,N-dimethylcarbamoyl)phenylboronic acid as a white solid.

[0254] 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),7.85–7.76(m,2H),7.68(d,J=7.9Hz,2H),7.56–7.49(m,2H),7.47(d,J=8.0Hz,2H ),7.42–7.29(m,1H),7.11–6.96(m,2H),6.52(s,2H),4.85(s,2H),4.82(s,2H),2.99(s,3H),2.94(s,3H),2.22(s,3H).

[0255] Example 19: 2-Amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-(4-(methanesulfonyl)phenyl)thiazo-2-yl)methyl)quinoline-6-carboxamide

[0256]

[0257] According to step 4 of compound 2, compound 19 was prepared from compound F-1 and (4-(methylsulfonyl)phenyl)boronic acid as a white solid.

[0258] 1H NMR(400MHz, DMSO-d6)δ8.23(s,1H),7.97(d,J=8.5Hz,2H),7.90(d,J=8.5Hz,2H),7.85–7.77(m,2H),7.58–7.48 (m,2H),7.40–7.31(m,1H),7.09–6.96(m,2H),6.53(s,2H),4.86(s,2H),4.84(s,2H),3.26(s,3H),2.22(s,3H).

[0259] Example 20: 2-Amino-N-(2,6-difluorobenzyl)-3-methyl-N-((5-(4-(N-methylaminosulfonyl)phenyl)thiazolyl-2-yl)methyl)quinoline-6-carboxamide

[0260]

[0261] According to step 4 of compound 2, compound 20 was prepared from compound F-1 and (4-(N-methylaminosulfonyl)phenyl)boronic acid as a white solid.

[0262] 1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.89–7.84(m,2H),7.84–7.77(m,4H),7.57–7.48(m,3H),7.42–7.3 1(m,1H),7.10–6.96(m,2H),6.52(s,2H),4.85(s,2H),4.84(s,2H),2.44(d,J=4.9Hz,3H),2.22(s,3H).

[0263] Example 21: 2-Amino-N-[(2,6-difluorophenyl)methyl]-N-[(5-{3-fluoro-4-[(methylamino)carbonyl]phenyl}-1,3-thiazazacyclopentan-2-yl)methyl]-3-methylquinoline-6-carboxamide

[0264]

[0265] According to step 4 of compound 2, compound 21 was prepared from compound F-1 and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid, and was a white solid.

[0266] 1H NMR(400MHz, DMSO-d6)δ8.93–8.89(m,1H),8.78(q,J=4.9Hz,1H),8.29(s,1H),8.23–8.18(m,1H),8.09–8.04(m,1H),7.85–7.76(m ,2H),7.60–7.45(m,3H),7.42–7.31(m,1H),7.10–6.96(m,2H),6.52(s,2H),4.90–4.80(m,4H),2.84(d,J=4.7Hz,3H),2.22(s,3H).

[0267] Example 22: 2-Amino-N-[(2,6-difluorophenyl)methyl]-N-[(5-{2-fluoro-4-[(methylamino)carbonyl]phenyl}-1,3-thiazazacyclopentan-2-yl)methyl]-3-methylquinoline-6-carboxamide

[0268]

[0269] Step 1: Synthesis of 4-bromo-3-fluoro-N-methylbenzamide

[0270]

[0271] To a DMF solution (4 mL) of 4-bromo-3-fluorobenzoic acid (219 mg, 1 mmol) and methylamine hydrochloride (101 mg, 1.5 mmol, 1.5 equiv.), TEA (606 mg, 6 mmol, 6 equiv.) and HATU (570 mg, 1.5 mmol, 1.5 equiv.) were added sequentially, and the mixture was stirred overnight at room temperature. Water (30 mL) was added to the reaction mixture, and the pH was adjusted to 6 with 1 N hydrochloric acid. The reaction mixture was diluted with EA, and the two layers were separated. The aqueous layer was extracted three times with EA. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography or preparative thin-layer chromatography (silica gel) to give 4-bromo-3-fluoro-N-methylbenzamide as a white solid.

[0272] 1 H NMR (400MHz, DMSO-d6) δ8.66–8.56(m,1H),7.83(dd,J=8.3,7.1Hz,1H),7.77(dd,J=9.9,2.0Hz,1H),7.63(dd,J=8.3,2.0Hz,1H),2.79(d,J=4.5Hz,3H).

[0273] Step 2: Synthesis of 3-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzamide

[0274]

[0275] A mixture of 4-bromo-3-fluoro-N-methylbenzamide (56 mg, 0.24 mmol), bis(pinarate)diboron (73 mg, 0.288 mmol, 1.2 equiv.), potassium acetate (47 mg, 0.48 mmol, 2 equiv.), and PdCl2(dppf) (9 mg, 0.012 mmol, 0.05 equiv.) in 1,4-dioxane was degassed and backfilled with argon (three cycles). The reaction mixture was stirred at 100 °C for 4 hours under an argon atmosphere, cooled to room temperature, and filtered. The filtrate was used directly for the next step.

[0276] Step 3: Synthesis of 2-amino-N-[(2,6-difluorophenyl)methyl]-N-[(5-{2-fluoro-4-[(methylamino)carbonyl]phenyl}-1,3-thiazazacyclopentan-2-yl)methyl]-3-methylquinoline-6-carboxamide

[0277]

[0278] Compound F-1 (101 mg, 0.2 mmol), 2 M K₂CO₃ aqueous solution (150 μL, 0.6 mmol, 3 equiv.), and PdCl₂ (dppf) (15 mg, 0.02 mmol, 0.1 equiv.) were added to a reaction mixture of 3-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborheocyclopent-2-yl)benzamide. The resulting mixture was degassed and backfilled with argon (three cycles), and then stirred at 100 °C for 4 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and DCM, and the two layers were separated. The aqueous layer was extracted with DCM (three times). The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography or preparative thin-layer chromatography (silica gel) to give compound 22 as a white solid.

[0279] 1 H NMR (400MHz, DMSO-d6) δ8.61(q,J=4.6Hz,1H),8.19(s,1H),7.90(t,J=7.9Hz,1H),7.84–7.73(m,4H),7.58–7.47( m,2H),7.41–7.30(m,1H),7.08–6.97(m,2H),6.53(s,2H),4.90–4.81(m,4H),2.81(d,J=4.4Hz,3H),2.22(s,3H).

[0280] Example 23: 2-Amino-N-(2,6-difluorobenzyl)-N-((5-(2-fluorophenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide

[0281]

[0282] According to the method in step 4 of compound 2, compound 23 was prepared from compound F-1 and 2-fluorophenylboronic acid as a white solid.

[0283] 1 H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.87–7.73(m,3H),7.59–7.48(m,2H),7.48 –7.27(m,4H),7.03(s,2H),6.54(s,2H),4.85(s,2H),4.84(s,2H),2.22(s,3H).

[0284] Example 24: 2-Amino-N-(2,6-difluorobenzyl)-N-((5-(3-fluorophenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide

[0285]

[0286] According to step 4 of compound 2, compound 24 was prepared from compound F-1 and 3-fluorophenylboronic acid as a white solid.

[0287] Example 25: 2-Amino-N-(2,6-difluorobenzyl)-N-((5-(3-fluoro-4-hydroxyphenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide

[0288]

[0289] According to step 4 of compound 2, compound 25 was prepared from compound F-1 and (3-fluoro-4-hydroxyphenyl)boronic acid as a white solid.

[0290] 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),7.92(s,1H),7.84–7.74(m,2H),7.57–7.45(m,3H),7.43–7.32(m, 1H),7.23(dd,J=8.3,2.2Hz,1H),7.11–6.96(m,3H),6.53(s,2H),4.83(s,2H),4.77(s,2H),2.22(s,3H).

[0291] Example 26: 2-Amino-N-((5-(4-amino-3-fluorophenyl)thiazolyl-2-yl)methyl)-N-(2,6-difluorobenzyl)-3-methylquinoline-6-carboxamide

[0292]

[0293] According to step 4 of compound 2, compound 25 was prepared from compound F-1 and (3-fluoro-4-aminophenyl)boronic acid as a white solid.

[0294] 1 H NMR (400MHz, DMSO-d6) δ7.88–7.73(m,3H),7.59–7.54(m,1H),7.54–7.46(m,3H),7.42–7.30(m,2H),7.12(dd,J=8.3 ,2.0Hz,1H),7.09–6.99(m,2H),6.82–6.75(m,1H),6.53(s,2H),5.49(s,2H),4.82(s,2H),4.75(s,2H),2.22(s,3H).

[0295] Example 27: 2-Amino-N-benzyl-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide

[0296]

[0297] Step 1: Synthesis of tert-butylbenzyl (thiazolyl-2-ylmethyl)carbamate (B-2)

[0298]

[0299] According to the method in step 1 of compound 1, compound B-2 was prepared from thiazole-2-carboxaldehyde and benzylamine and was a colorless oily liquid.

[0300] 1 H NMR(400MHz, DMSO-d6)δ7.73(d,J=3.3Hz,1H),7.66(d,J=3.3Hz,1H),7.38–7.3 1(m,2H),7.30–7.21(m,3H),4.61(d,J=26.2Hz,2H),4.46(s,2H),1.40(s,9H).

[0301] Step 2: Synthesis of tert-butylbenzyl ((5-bromothiazol-2-yl)methyl)carbamate (D-2)

[0302]

[0303] According to the method in step 1 of compound 2, compound D-2 was prepared from compound B-2 and is a colorless oily liquid.

[0304] 1 H NMR (400MHz, DMSO-d6) δ7.78 (s, 1H), 7.37–7.30 (m, 2H), 7.30–7.21 (m, 3H), 4.58 (d, J = 15.9Hz, 2H), 4.46 (s, 2H), 1.40 (s, 9H).

[0305] Step 3: Synthesis of N-benzyl-1-(5-bromothiazol-2-yl)methylamine (E-2)

[0306]

[0307] According to the method in step 2 of compound 2, compound E-2 is prepared from compound D-2 and is a colorless oily liquid.

[0308] 1 H NMR (400MHz, DMSO-d6) δ7.76(s,1H),7.39–7.32(m,4H),7.29–7.23(m,1H),3.93(s,2H),3.78(s,2H),3.39(brs,1H).

[0309] Step 4: Synthesis of 2-amino-N-benzyl-N-((5-bromothiazol-2-yl)methyl)-3-methylquinoline-6-carboxamide (F-2)

[0310]

[0311] According to the method in step 3 of compound 2, compound F-2 was prepared from compound E-2 as a white solid.

[0312] 1 H NMR (400MHz, DMSO-d6) δ7.82(s,1H),7.79–7.75(m,2H),7.53–7.44(m,2H),7.40–7.21(m,5H),6.58(s,2H),4.76(s,2H),4.66(s,2H),2.20(s,3H).

[0313] Step 5: Synthesis of 2-amino-N-benzyl-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide (compound 27)

[0314]

[0315] According to the method in step 4 of compound 2, compound 27 was obtained as a white solid from compound F-2 and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid.

[0316] 1 H NMR (400MHz, DMSO-d6) δ8.35–8.27(m,2H),7.81(s,1H),7.78–7.66(m,3H),7.60–7.52(m,2H),7.50–7.4 5(m,1H),7.41–7.24(m,5H),6.55(s,2H),4.83(s,2H),4.71(s,2H),2.80(d,J=4.5Hz,3H),2.20(s,3H).

[0317] Example 28: 2-Amino-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methyl-N-((tetrahydro-2D-pyran-4-yl)methyl ester)quinoline-6-carboxamide

[0318]

[0319] Step 1: Synthesis of (tetrahydro-2D-pyran-4-yl)methyl)(thiazolyl-2-ylmethyl)tert-butyl carbamate (B-3)

[0320]

[0321] According to the method in step 1 of compound 1, compound B-3 was prepared from thiazol-2-carboxaldehyde and (tetrahydro-2H-pyran-4-yl)methylamine and was a colorless oily liquid.

[0322] 1 H NMR(400MHz,DMSO-d6)δ7.73(d,J=3.2Hz,1H),7.69–7.62(m,1H),4.64(s,2H),3.82(dd,J=11 .4,2.5Hz,2H),3.25–3.12(m,4H),1.89–1.75(m,1H),1.49–1.32(m,11H),1.21–1.08(m,2H).

[0323] Step 2: Synthesis of (5-bromothiazolyl-2-yl)methyl)(tetrahydro-2D-pyran-4-yl)methylcarbamate tert-butyl ester (D-3)

[0324]

[0325] According to the method in step 1 of compound 2, compound D-3 was prepared from compound B-3 and is a colorless oily liquid.

[0326] 1 H NMR (400MHz, DMSO-d6) δ7.80 (s, 1H), 4.59 (s, 2H), 3.82 (dd, J = 11.3, 2.5Hz, 2H) ,3.27–3.11(m,4H),1.88–1.75(m,1H),1.46–1.34(m,11H),1.20–1.09(m,2H).

[0327] Step 3: Synthesis of 1-(5-bromothiazol-2-yl)-N-((tetrahydro-2D-pyran-4-yl)methyl)methylamine (E-3)

[0328]

[0329] According to the method in step 2 of compound 2, compound E-3 was prepared from compound D-3 and is a colorless oily liquid.

[0330] 1 H NMR (400MHz, DMSO-d6) δ7.76(s,1H),7.39–7.32(m,4H),7.29–7.23(m,1H),3.93(s,2H),3.78(s,2H),3.39(brs,1H).

[0331] Step 4: Synthesis of 2-amino-N-((5-bromothiazol-2-yl)methyl)-3-methyl-N-((tetrahydro-2D-pyran-4-yl)methyl ester)quinoline-6-carboxamide (F-3)

[0332]

[0333] According to the method in step 3 of compound 2, compound F-3 was prepared from compound E-3 as a white solid.

[0334] Step 5: Synthesis of 2-amino-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methyl-N-((tetrahydro-2D-pyran-4-yl)methyl ester)quinoline-6-carboxamide (compound 28)

[0335]

[0336] According to step 4 of compound 2, compound 28 was obtained as a white solid from compound F-3 and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid.

[0337] 1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.31–8.25(m,1H),7.81(s,1H),7.75–7.65 (m,3H),7.61–7.52(m,1H),7.52–7.43(m,2H),6.51(s,2H),4.96(s,2H),3.95–3. 60(m,2H),3.46–3.36(m,2H),3.31–3.01(m,2H),2.79(d,J=4.6Hz,3H),2.21(s, 3H),2.07–1.87(m,1H),1.74–1.50(m,1H),1.49–1.18(m,2H),0.94–0.71(m,1H).

[0338] Example 29: 2-Amino-N-(cyclohexylmethyl)-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide

[0339]

[0340] Step 1: Synthesis of (cyclohexylmethyl)(thiazol-2-ylmethyl)carbamate tert-butyl ester (B-4)

[0341]

[0342] According to the method in step 1 of compound 1, compound B-4 was prepared from thiazole-2-carboxaldehyde and cyclohexylmethylamine and was a colorless oily liquid.

[0343] 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=3.2Hz,1H),7.65(d,J=5.0Hz,1H),4.62(s,2H),3.09(d,J=6.7Hz,2H ),1.70–1.62(m,2H),1.61–1.52(m,4H),1.39(d,J=22.2Hz,9H),1.17–1.06(m,3H),0.93–0.80(m,2H).

[0344] Step 2: Synthesis of (5-bromothiazol-2-yl)methyl)(cyclohexylmethyl)tert-butyl carbamate (D-4)

[0345]

[0346] According to the method in step 1 of compound 2, compound D-4 was prepared from compound B-4 and is a colorless oily liquid.

[0347] 1H NMR(400MHz,DMSO-d6)δ7.79(s,1H),4.57(s,2H),3.09(d,J=6.9Hz,2H),1.70–1.62(m ,2H),1.61–1.50(m,4H),1.39(d,J=17.9Hz,9H),1.18–1.07(m,3H),0.92–0.79(m,2H).

[0348] Step 3: Synthesis of (5-bromothiazol-2-yl)methyl)(cyclohexylmethyl)tert-butyl carbamate (E-4)

[0349]

[0350] According to the method in step 2 of compound 2, compound E-4 was prepared from compound D-4 and is a colorless oily liquid.

[0351] 1 H NMR(400MHz,DMSO-d6)δ7.72(s,1H),3.90(s,2H),2.87(br s,1H),2.40(d,J=6.6Hz,2H),1.80–1.72(m,2H),1.70–1.59(m,3H),1.45–1.32(m,1H),1.26–1.09(m,3H),0.95–0.81(m,2H).

[0352] Step 4: Synthesis of 2-amino-N-((5-bromothiazol-2-yl)methyl)-N-(cyclohexylmethyl)-3-methylquinoline-6-carboxamide (F-4)

[0353]

[0354] According to the method in step 3 of compound 2, compound F-4 was prepared from compound E-4 as a white solid.

[0355] 1 H NMR(400MHz, DMSO-d6)δ7.88–7.78(m,2H),7.66(d,J=1.9Hz,1H),7.51–7.39(m,2H),6.58(s,2H),4.87(s,2H), 3.30(d,J=7.3Hz,2H),2.22(s,3H),1.75–1.59(m,2H),1.58–1.41(m,4H),1.19–0.86(m,4H),0.60–0.39(m,1H).

[0356] Step 5: Synthesis of 2-amino-N-(cyclohexylmethyl)-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide (compound 29)

[0357]

[0358] According to step 4 of compound 2, compound 34 is obtained as a white solid from compound F-4 and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid.

[0359] Example 30: 2-Amino-N-(cyclopropylmethyl)-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide

[0360]

[0361] Step 1: Synthesis of (cyclopropylmethyl)(thiazol-2-ylmethyl)carbamate tert-butyl ester (B-5)

[0362]

[0363] According to the method in step 1 of compound 1, compound B-5 was prepared from thiazole-2-carboxaldehyde and cyclopropylmethylamine as a colorless oily liquid.

[0364] 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=3.3Hz,1H),7.65(d,J=3.5Hz,1H),4.71(s,2H),3.14(d,J= 6.7Hz,2H),1.40(d,J=21.7Hz,9H),1.02–0.90(m,1H),0.44–0.33(m,2H),0.23–0.15(m,2H).

[0365] Step 2: Synthesis of (5-bromothiazol-2-yl)methyl)(cyclopropylmethyl)tert-butyl carbamate (D-5)

[0366]

[0367] According to the method in step 1 of compound 2, compound D-5 was prepared from compound B-5 and is a colorless oily liquid.

[0368] 1H NMR (400MHz, DMSO-d6) δ7.79 (s, 1H), 4.66 (s, 2H), 3.14 (d, J = 6.9Hz, 2H), 1.4 0(d,J=19.9Hz,9H),1.01–0.89(m,1H),0.42–0.36(m,2H),0.21–0.15(m,2H).

[0369] Step 3: Synthesis of 1-(5-bromothiazol-2-yl)-N-(cyclopropylmethyl)methylamine (E-5)

[0370]

[0371] According to the method in step 2 of compound 2, compound E-5 was prepared from compound D-5 and is a colorless oily liquid.

[0372] 1 H NMR (400MHz, DMSO-d6) δ7.73(s,1H),3.95(s,2H),2.88(s,1H),2.45(d,J=6.7Hz,2H),0.94–0.83(m,1H),0.43–0.36(m,2H),0.13–0.07(m,2H).

[0373] Step 4: Synthesis of 2-amino-N-((5-bromothiazol-2-yl)methyl)-N-(cyclopropylmethyl)-3-methylquinoline-6-carboxamide (F-5)

[0374]

[0375] According to the method in step 3 of compound 2, compound F-5 was prepared from compound E-5 as a white solid.

[0376] Step 5: Synthesis of 2-amino-N-(cyclopropylmethyl)-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide (compound 35)

[0377]

[0378] According to step 4 of compound 2, compound 30 is obtained as a white solid from compound F-5 and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid.

[0379] 1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),8.30–8.25(m,1H),7.82(s,1H),7.77–7.66(m,3H),7.59–7.54(m,1H),7.54–7.47(m,2H),6.5 4(s,2H),5.04(s,2H),3.30(brs,2H),2.79(d,J=4.6Hz,3H),2.22(s,3H),1.10–0.99(m,1H),0.47–0.38(m,2H),0.18–0.04(m,2H).

[0380] Example 31: 2-Amino-N-cyclohexyl-N-(5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide

[0381]

[0382] Step 1: Synthesis of cyclohexyl(thiazolyl-2-ylmethyl)carbamate tert-butyl ester (B-6)

[0383]

[0384] According to the method in step 1 of compound 1, compound B-6 was prepared from thiazole-2-carboxaldehyde and cyclohexylamine and was a colorless oily liquid.

[0385] 1 H NMR (400MHz, DMSO-d6) δ7.69(d,J=3.2Hz,1H),7.62(d,J=3.3Hz,1H),4.58(s,2H),3.96–3.54(m,1H ),1.76–1.66(m,2H),1.63–1.51(m,3H),1.47–1.30(m,11H),1.28–1.15(m,2H),1.10–0.96(m,1H).

[0386] Step 2: Synthesis of (5-bromothiazol-2-yl)methyl)(cyclohexyl)carbamate tert-butyl ester (D-6)

[0387]

[0388] According to the method in step 1 of compound 2, compound D-6 was prepared from compound B-6 and is a colorless oily liquid.

[0389] 1H NMR(400MHz,DMSO-d6)δ7.77(s,1H),4.54(s,2H),3.91–3.56(m,1H),1.75–1.68(m ,2H),1.61–1.51(m,3H),1.44–1.33(m,11H),1.27–1.20(m,2H),1.12–0.96(m,1H).

[0390] Step 3: Synthesis of N-((5-bromothiazol-2-yl)methyl)cyclohexylamine (E-6)

[0391]

[0392] According to the method in step 2 of compound 2, compound E-2 is prepared from compound D-2 and is a colorless oily liquid.

[0393] 1 H NMR(400MHz,DMSO-d6)δ7.71(s,1H),3.95(s,2H),2.71(br s,1H),2.43–2.33(m,1H),1.87–1.77(m,2H),1.71–1.62(m,2H),1.57–1.49(m,1H),1.24–0.96(m,5H).

[0394] Step 4: Synthesis of 2-amino-N-((5-bromothiazol-2-yl)methyl)-N-cyclohexyl-3-methylquinoline-6-carboxamide (F-6)

[0395]

[0396] According to the method in step 3 of compound 2, compound F-6 was prepared from compound E-6 as a white solid.

[0397] 1 H NMR (400MHz, DMSO-d6) δ7.85(s,1H),7.80(s,1H),7.68(d,J=1.9Hz,1H),7.50(d,J=8.6Hz,1H),7.44(dd,J=8.5,1.9Hz,1H),6. 60(s,2H),4.83(s,2H),3.70–3.56(m,1H),3.34(s,2H),2.23(s,3H),1.69–1.54(m,6H),1.49–1.40(m,1H),0.89–1.09(m,3H).

[0398] Step 5: Synthesis of 2-amino-N-cyclohexyl-N-(5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methylquinoline-6-carboxamide (compound 36)

[0399]

[0400] According to step 4 of compound 2, compound 36 was prepared from compound F-6 and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid, and was a white solid.

[0401] 1 H NMR (400MHz, DMSO-d6) δ8.31–8.24(m,2H),7.84(s,1H),7.73–7.64(m,3H),7.57–7.46(m,3H),6.53(s,2H),4.89(s, 2H),3.80–3.57(m,1H),2.79(d,J=4.6Hz,3H),2.22(s,3H),1.79–1.56(m,6H),1.51–1.40(m,1H),1.12–0.79(m,3H).

[0402] Example 32: 2-Amino-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-N,3-dimethylquinoline-6-carboxamide

[0403]

[0404] Step 1: Synthesis of tert-butyl methyl (thiazol-2-ylmethyl)carbamate (B-7)

[0405]

[0406] NaOAc (902 mg, 11 mmol, 1.1 equiv.) was added to a DCM solution of thiazole-2-carboxaldehyde (1.13 g, 20 mmol) and methylamine hydrochloride (1.013 g, 15 mmol, 1.5 equiv.), and the reaction mixture was stirred at room temperature for 16 hours. Sodium triacetoxyborohydride (4.22 g, 20 mmol, 2 equiv.) was added in portions to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Then, 80 mL of saturated sodium bicarbonate solution was added to the reaction mixture, and the reaction was quenched by stirring at room temperature for 0.5 hours. (Boc)₂O (4.36 g, 20 mmol, 2 equiv.) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. The resulting mixture was extracted with DCM (100 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, EA / PE = 1:2) to obtain compound B-7 as a colorless oily liquid.

[0407] 1 H NMR (400MHz, DMSO-d6) δ7.75(d,J=3.3Hz,1H),7.68(d,J=3.4Hz,1H),4.65(s,2H),2.87(s,3H),1.41(d,J=16.6Hz,9H).

[0408] Step 2: Synthesis of (5-bromothiazol-2-yl)methyl(methyl)carbamate tert-butyl ester (D-7)

[0409]

[0410] According to the method in step 1 of compound 2, compound D-7 was prepared from compound B-7 and is a colorless oily liquid.

[0411] 1 H NMR (400MHz, DMSO-d6) δ7.82 (s, 1H), 4.60 (s, 2H), 2.86 (s, 3H), 1.41 (d, J = 11.4Hz, 9H).

[0412] Step 3: Synthesis of 1-(5-bromothiazol-2-yl)-N-methylmethylamine (E-7)

[0413]

[0414] According to the method in step 2 of compound 2, compound E-7 was prepared from compound D-7 and is a colorless oily liquid.

[0415] Step 4: Synthesis of 2-amino-N-((5-bromothiazol-2-yl)methyl)-N,3-dimethylquinoline-6-carboxamide (F-7)

[0416]

[0417] According to the method in step 3 of compound 2, compound F-7 was prepared from compound E-7 as a white solid.

[0418] Step 5: Synthesis of 2-amino-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-N,3-dimethylquinoline-6-carboxamide (compound 32)

[0419]

[0420] According to step 4 of compound 2, compound 32 was prepared from compound F-7 and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid, and was a white solid.

[0421] 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.31–8.26(m,1H),7.84–7.76(m,2H),7.75–7.66(m,2H), 7.59–7.47(m,3H),6.53(s,2H),4.94(s,2H),3.09(s,3H),2.79(d,J=4.6Hz,3H),2.22(s,3H).

[0422] Example 33: 2-amino-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methyl-N-(1,2,3,4-tetrahydronaphthyl-1-yl)quinoline-6-carboxyl

[0423]

[0424] Step 1: Synthesis of (1,2,3,4-tetrahydronaphthyl-1-yl)(thiazolyl-2-ylmethyl)carbamate tert-butyl ester (B-8)

[0425]

[0426] According to the method in step 1 of compound 1, compound B-8 was prepared from thiazole-2-carboxaldehyde and benzylamine and was a colorless oily liquid.

[0427] Step 2: Synthesis of (5-bromothiazol-2-yl)methyl)(1,2,3,4-tetrahydronaphthyl-1-yl)carbamate tert-butyl ester (D-8)

[0428]

[0429] According to the method in step 1 of compound 2, compound D-8 was prepared from compound B-8 and is a colorless oily liquid.

[0430] Step 3: Synthesis of N-((5-bromothiazol-2-yl)methyl)-1,2,3,4-tetrahydronaphthyl-1-amine (E-8)

[0431]

[0432] According to the method in step 2 of compound 2, compound E-8 was prepared from compound D-8 and is a colorless oily liquid.

[0433] 1 H NMR(400MHz, DMSO-d6)δ7.74(s,1H),7.51(dd,J=7.2,1.9Hz,1H),7.19–7.10(m,2H),7.06(dd,J=7.4,1.7Hz,1H),4. 01(d,J=6.4Hz,2H),3.80–3.72(m,1H),3.19–3.09(m,1H),2.81–2.61(m,2H),1.98–1.83(m,2H),1.79–1.59(m,2H).

[0434] Step 4: Synthesis of 2-amino-N-((5-bromothiazol-2-yl)methyl)-3-methyl-N-(1,2,3,4-tetrahydronaphthyl-1-yl)quinoline-6-carboxamide (F-8)

[0435]

[0436] According to the method in step 3 of compound 2, compound F-8 was prepared from compound E-8 as a white solid.

[0437] 1 H NMR(400MHz,DMSO-d6)δ7.88–7.81(m,2H),7.77(s,1H),7.62–7.56(m,1H),7.54–7 .49(m,1H),7.24–7.14(m,3H),7.14–7.09(m,1H),6.58(s,2H),5.09(dd,J=11.0,5. 8Hz,1H),4.90(d,J=15.6Hz,1H),4.08(d,J=15.7Hz,1H),2.82–2.70(m,1H),2.66– 2.57(m,1H),2.21(s,3H),2.18–2.08(m,1H),2.01–1.82(m,2H),1.55–1.41(m,1H).

[0438] Step 5: Synthesis of 2-amino-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methyl-N-(1,2,3,4-tetrahydronaphthyl-1-yl)quinoline-6-carboxamide (compound 33)

[0439]

[0440] According to the method in step 4 of compound 2, compound 33 was obtained as a white solid from compound F-8 and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid.

[0441] 1 H NMR(400MHz,DMSO-d6)δ8.31–8.324(m,2H),7.90–7.83(m,2H),7.74–7.60(m,3H) ,7.59–7.49(m,2H),7.26–7.16(m,3H),7.15–7.11(m,1H),6.55(s,2H),5.13(dd, J=10.8,5.8Hz,1H),4.99(d,J=15.9Hz,1H),4.11(d,J=15.9Hz,1H),2.85–2.73(m ,4H),2.68–2.58(m,1H),2.27–2.15(m,4H),2.07–1.85(m,2H),1.58–1.44(m,1H).

[0442] Example 34: 2-Amino-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methyl-N-(pyridin-2-ylmethyl)quinoline-6-carboxamide

[0443]

[0444] Example 35: 2-Amino-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methyl-N-(pyrimidin-2-ylmethyl)quinoline-6-carboxamide

[0445]

[0446] Example 36: 2-Amino-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-3-methyl-N-(5,6,7,8-tetrahydroquinoline-8-yl)quinoline-6-carboxamide

[0447]

[0448] Example 37: 4-Amino-N-(2,6-difluorobenzyl)-N-(5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-2,3-dihydro-1H-cyclopentan[c]quinoline-8-carboxamide

[0449]

[0450] Step 1: Synthesis of 4-amino-N-((5-bromothiazol-2-yl)methyl)-N-(2,6-difluorobenzyl)-2,3-dihydro-1H-cyclopentan[c]quinoline-8-carboxamide

[0451]

[0452] According to the method in step 3 of compound 1, 4-amino-N-((5-bromothiazol-2-yl)methyl)-N-(2,6-difluorobenzyl)-2,3-dihydro-1H-cyclopenta[c]quinoline-8-carboxamide was obtained as a pale yellow solid by condensation of compound E-1 and intermediate A2.

[0453] 1 H NMR (400MHz, DMSO-d6) δ7.77–7.63(m,2H),7.62–7.53(m,2H),7.41–7.30(m,1H),7.07–6.95(m,2H),6.86(s,2H),4.82( s,2H),4.76(s,2H),3.19–3.06(m,2H),2.85(t,J=7.5Hz,2H),2.25–2.12(m,2H),1.30–1.20(m,4H),0.88–0.78(m,1H).

[0454] Step 2: Synthesis of 4-amino-N-(2,6-difluorobenzyl)-N-(5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-2,3-dihydro-1H-cyclopentan[c]quinoline-8-carboxamide

[0455]

[0456] According to step 4 of compound 2, compound 37 was obtained as a white solid by coupling 4-amino-N-((5-bromothiazol-2-yl)methyl)-N-(2,6-difluorobenzyl)-2,3-dihydro-1H-cyclopentanol[c]quinoline-8-carboxamide and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid.

[0457] 1H NMR (400MHz, DMSO-d6) δ8.32–8.25(m,1H),8.21(s,1H),7.74–7.62(m,3H),7.59–7.52(m,2H),7.52–7.46(m,1H),7.42–7.31(m,1H),7. 09–6.95(m,2H),6.55(s,2H),4.86(s,2H),4.83(s,2H),3.16–3.02(m,2H),2.85–2.81(m,2H),2.79(d,J=4.7Hz,3H),2.21–2.11(m,2H).

[0458] Example 38: 4-Amino-N-(2,6-difluorobenzyl)-N-((5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxaline-8-carboxamide

[0459]

[0460] Example 39: 4-Amino-N-(2,6-difluorobenzyl)-N-(5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide

[0461]

[0462] Step 1: Synthesis of 4-amino-N-((5-bromothiazol-2-yl)methyl)-N-(2,6-difluorobenzyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide

[0463]

[0464] According to the method in step 3 of compound 1, 4-amino-N-((5-bromothiazol-2-yl)methyl)-N-(2,6-difluorobenzyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide was obtained as a pale yellow solid by condensation of compound E-1 and intermediate A4.

[0465] 1 H NMR(400MHz,DMSO-d6)δ8.31(s,1H),8.19(s,1H),7.66(s,1H),7.48–7.30(m,3H),7.17(s,2H ),7.09(d,J=3.9Hz,1H),7.06–6.92(m,2H),6.75(t,J=3.3Hz,1H),4.85(s,2H),4.78(s,2H).

[0466] Step 2: Synthesis of 4-amino-N-(2,6-difluorobenzyl)-N-(5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide

[0467]

[0468] According to step 4 of compound 2, compound 39 was obtained as a white solid by coupling 4-amino-N-((5-bromothiazol-2-yl)methyl)-N-(2,6-difluorobenzyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid.

[0469] 1 H NMR(400MHz,DMSO-d6)δ8.36–8.25(m,2H),8.20(s,2H),7.72–7.62(m,2H),7.54–7.40(m,3H),7.39–7.29(m,1H),7.16 (s,2H),7.09(d,J=3.9Hz,1H),7.07–6.92(m,2H),6.79–6.70(m,1H),4.89(s,2H),4.85(s,2H),2.79(d,J=4.5Hz,3H).

[0470] Example 40: 4-Amino-N-(2,6-difluorobenzyl)-N-(5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)imidazo[1,2-a]quinoxaline-8-carboxamide

[0471]

[0472] Step 1: Synthesis of 4-amino-N-((5-bromothiazol-2-yl)methyl)-N-(2,6-difluorobenzyl)imidazo[1,2-a]quinoxaline-8-carboxamide

[0473]

[0474] According to the method in step 3 of compound 1, 4-amino-N-((5-bromothiazol-2-yl)methyl)-N-(2,6-difluorobenzyl)imidazo[1,2-a]quinoxaline-8-carboxamide was obtained as a pale yellow solid by condensation of compound E-1 and intermediate A5.

[0475] 1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.29(s,1H),7.74–7.62(m,2H),7.62–7.50 (m,2H),7.46(s,2H),7.41–7.28(m,1H),7.00(s,2H),4.86(s,2H),4.80(s,2H).

[0476] Step 2: Synthesis of 4-amino-N-(2,6-difluorobenzyl)-N-(5-(3-fluoro-4-(methylcarbamoyl)phenyl)thiazolyl-2-yl)methyl)imidazo[1,2-a]quinoxaline-8-carboxamide

[0477]

[0478] According to step 4 of compound 2, compound 40 is obtained by coupling 4-amino-N-((5-bromothiazol-2-yl)methyl)-N-(2,6-difluorobenzyl)imidazo[1,2-a]quinoxaline-8-carboxamide and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid, which is a white solid.

[0479] 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),8.35–8.25(m,2H),8.25–8.14(m,1H),7.72–7.63(m,3H),7.62–7.54( m,2H),7.53–7.43(m,3H),7.42–7.28(m,1H),7.02(s,2H),4.89(s,2H),4.86(s,2H),2.79(d,J=4.5Hz,3H).

[0480] Biological Test Example 1: PRMT5 In vitro inhibitory activity assay

[0481] Experimental materials

[0482] SAM (S-(5'-adenosine)-L-methionine, Sigma, Cat. No. A7007)

[0483] SAH (S-(5'-adenosine)-L-homocysteine, Sigma, Cat. No. A9384)

[0484] Biotinylated histone peptide (sequence: Ac-SGRGKGGKGLGKGGAKRHRKVGG-K(Biotin)), GL Biochem, Customized)

[0485] 384-hole OptiPlate (Perkin Elmer, Cat. No. 6007299)

[0486] Receptor beads (Perkin Elmer, Cat. No. AL150M)

[0487] Donor Beads (Perkin Elmer, Cat. No. AS106R)

[0488] PRMT5(Active Motif,Cat.No.31921)

[0489] AlphaLISA 5X Epigenetics Buffer 1 (Perkin Elmer, Cat. No. AL008F)

[0490] Experimental methods

[0491] (1) Prepare 1x reaction buffer: 10mM Tris-HCl, pH 8.0, 0.01% Tween-20, 1mM DTT (dithiothreitol).

[0492] (2) Compound dilution: Prepare a 100-fold dilution of the compound to the final detection concentration and transfer 100 nmol to a 384-well plate. Transfer 100 nmol of 100% DMSO to the positive and negative control wells. The final concentration of DMSO is 1%.

[0493] (3) Prepare enzyme solution: Add PRMT5 to 1x reaction buffer to prepare enzyme solution.

[0494] (4) Prepare substrate solution: Add SAM and biotin-labeled histone peptides to 1x reaction buffer to prepare substrate solution.

[0495] (5) Transfer 5 μL of enzyme solution to a 384-well plate, and transfer 5 μL of 1x reaction buffer for the negative control.

[0496] (6) Incubate at room temperature for 15 minutes.

[0497] (7) Add 5 μL of substrate solution to the 384-well plate to start the reaction.

[0498] (8) Incubate at room temperature for 45 minutes.

[0499] (9) Prepare 1x detection buffer using AlphaLISA 5X Epigenetics Buffer 1.

[0500] (10) Add the acceptor beads and donor beads to the 1x detection buffer to prepare the 1x detection solution.

[0501] (11) Add 15 μL of 1x detection solution to a 384-well plate and incubate at room temperature in the dark for 60 minutes.

[0502] (12) Read data in Alpha mode on EnSpire.

[0503] (13) Data processing

[0504] Use equation (1) to fit the data in Excel to obtain the inhibition value.

[0505] Equation (1): inh%=(Max-Signal) / (Max-Min)*100

[0506] The data were fitted in XL Fit using equation (2) to obtain the half-maximal inhibitory concentration (IC50). 50 )value

[0507] Equation (2):

[0508] Y=Bottom+(Top-Bottom) / (1+(IC 50 / X)^HillSlope)

[0509] Y represents the inhibition percentage, and X represents the compound concentration.

[0510] inh% refers to the percentage of inhibition rate, max refers to the maximum reading, min refers to the minimum reading, signal refers to the signal value, bottom refers to the bottom value, top refers to the top value, and HillSlope refers to the curvature.

[0511] The results are shown in Table 1. The experimental results show that all the compounds in the examples exhibited strong inhibitory activity against PRMT5-MTA. In particular, compounds 17, 18, 19, 21, 22, and 37 showed strong inhibitory activity against PRMT5-MTA. 50 The values ​​are all less than 1 nM.

[0512] Table 1

[0513]

Claims

1. A compound of formula (I), its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts: in, A is selected from X is selected from CR a4 、N;R a4 Selected from H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy; Y is selected from CH and N; W is selected from C or N; R a1 Selected from H, halogens, C 1-4 alkyl; R a2 R a3 Each is independently selected from H, halogen, cyano, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl; or R a2 and R a3 Together with the attached ring atoms, they form a 4-6 member saturated or unsaturated ring, and the ring may be substituted or unsubstituted; B is selected from H, in, R b1 Selected from H, halogen, hydroxyl, carboxyl, mercapto, amino, cyano, nitro, azide, sulfonic acid (-SO2-OH), C 1-10 Alkyl, C 1-10 Alkyl groups, -C(O)-R6, -C(O)-O-R7, -C(O)-NR8R9, -OC(O)-R 10 -N(R) 11 )-C(O)-R 12 -NR 13 -S(O2)-R 14 -NR 15 R 16 -S(O)-R 17 -S(O2)-NR 18 R 19 -S(O)2-R 20 R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 3-6 Cycloalkyl; n is selected from 1, 2, 3, 4, 5 or 6; R1 is selected from R4 and -L-R5; R4 is selected from substituted or unsubstituted C4. 1-10 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic alkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-12 heteroaryl groups; R5 is selected from H, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic alkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-12 heteroaryl groups; L is selected from -C(R) c1 (R) c2 )-; R c1 R c2 Each is independently selected from H, halogen, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl; or R5 and R c1 Together with the attached carbon atom, they form a 5-12 member saturated or unsaturated ring, and the ring may be substituted or unsubstituted; R2 and R3 are independently selected from H and C. 1-4 alkyl.

2. The compound according to claim 1, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, characterized in that, A is selected from the following structure: in, X is selected from CR a4 、N;R a4 Selected from H, halogens, C 1-4 Alkyl, C 1-4 Alkoxy; Y is selected from CH and N; R a1 Selected from H, halogens, C 1-4 alkyl; R a2 R a3 Each is independently selected from H, halogen, cyano, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl; or R a2 and R a3 Together with the attached ring atoms, they form a 4-6 member saturated or unsaturated ring, and the ring may be substituted or unsubstituted; R a5 Selected from H, halogen, hydroxyl, carboxyl, mercapto, amino, cyano, nitro, azide, sulfonic acid (-SO2-OH), C 1-10 Alkyl, C 1-10 Alkyl groups, -C(O)-R6, -C(O)-O-R7, -C(O)-NR8R9, -OC(O)-R 10 -N(R) 11 )-C(O)-R 12 -NR 13 -S(O2)-R 14 -NR 15 R 16 -S(O)-R 17 -S(O2)-NR 18 R 19 -S(O)2-R 20 R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl; m is selected from 1, 2, 3 or 4; R a6 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl.

3. The compound according to claims 1-2, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, characterized in that, A is selected from the following structure:

4. The compound according to any one of claims 1-3, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, characterized in that, B is selected from the following structure:

5. The compound according to claim 1, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, characterized in that, R1 is selected from the following structure:

6. The compound according to any one of claims 1-5, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, wherein the compound is selected from:

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises at least one compound according to any one of claims 1 to 6, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, and optionally a pharmaceutically acceptable carrier, excipient, adjuvant, excipient and / or diluent.

8. The pharmaceutical composition according to claim 7, further comprising a pharmaceutically active ingredient other than the compound, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts.

9. Use of the compound of any one of claims 1-6, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, and the pharmaceutical composition of any one of claims 7-8 in the preparation of a medicament for treating and / or preventing PRMT5-mediated diseases.

10. The application according to claim 9, characterized in that, The PRMT5-mediated diseases are selected from tumors, including ovarian cancer, lung cancer, lymphoma, glioblastoma, colonoma, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

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