CN116143773B

CN116143773B - 2-amino-4-thiazolylpyrimidine compound and preparation method and application thereof

Info

Publication number: CN116143773B
Application number: CN202310426024.2A
Authority: CN
Inventors: 杨鹏; 肖易倍; 朱亚胜; 叶秀全; 郝海平; 沈豪; 王晓; 王丽萍
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2023-04-20
Filing date: 2023-04-20
Publication date: 2023-07-21
Anticipated expiration: 2043-04-20
Also published as: CN116143773A

Abstract

The invention discloses a 2-amino-4-thiazolylpyrimidine compound, a preparation method and application thereof, and a compound with a structure shown in a general formula (I) or pharmaceutically acceptable salt thereof, and the compound has obvious inhibition effect on Epidermal Growth Factor (EGFR), and can inhibit proliferation of various tumor cells, including lung cancer, gastric cancer, prostate cancer, ovarian cancer, testicular cancer, colon cancer, leukemia, breast cancer, multiple myeloma, liver cancer, pancreatic cancer, melanoma, glioma, brain glioma, pituitary tumor and other solid tumors and blood tumors. The invention provides an option for tumor treatment.

Description

2-amino-4-thiazolylpyrimidine compound and preparation method and application thereof

Technical Field

The invention relates to a compound and a preparation method and application thereof, in particular to a 2-amino-4-thiazolyl pyrimidine compound and a preparation method and application thereof.

Background

Epidermal growth factor receptor (Epidermal growth factor receptor, EGFR) is a member of the ErbB family of receptor tyrosine kinases, and is a key mediator in regulating many biological processes such as cell proliferation, metabolism and apoptosis. EGFR overexpression or mutation is closely related to tumorigenesis and is an important cause of lung cancer, particularly non-small-cell lung cancer (NSCLC). EGFR has therefore proven to be a therapeutic target for the discovery of anti-cancer drugs, particularly for the treatment of NSCLC.

Successful development of EGFR inhibitors greatly improves survival and quality of life in cancer patients, particularly NSCLC patients. Currently, three generations of EGFR inhibitors have been widely used in the treatment of NSCLC, including a first generation of inhibitors represented by gefitinib, a second generation of covalent inhibitors represented by afatinib, and a third generation of covalent inhibitors represented by octatinib. Although octenib has achieved significant success in the treatment of NSCLC, acquired resistance has become a new challenge in NSCLC treatment.

Ornitinib-induced resistance involves a variety of mechanisms including EGFR-dependent ligand/receptor amplification, third amino acid missense mutation of EGFR kinase domain, activation of bypass signaling pathway (e.g., expression or amplification of c-Met, IGF1R, axl, etc.), and phenotypic transformation of cancer cells. Among them, one important cause of the resistance to octreotide is EGFR ^C797S Mutation. EGFR (epidermal growth factor receptor) ^C797S The mutation is mutation of 797 amino acid residue of EGFR protein from cysteine to serine, EGFR ^C797S The functional and conformational changes of the muteins result in the loss of covalent bond formation and a decrease in cellular potency of third generation EGFR inhibitors with CYS 797. Thus, solving the need for resistance to octenib is an essential and challenging task to develop fourth-generation EGFR potent inhibitors.

Disclosure of Invention

The invention aims to: the invention aims to provide the 2-amino-4-thiazolylpyrimidine compound or the pharmaceutically acceptable salt thereof, which solves the problem of drug resistance caused by target mutation of the octreotide, has a strong inhibition effect on EGFR gene mutation targets and has a strong inhibition effect on EGFR gene mutant cells, and can effectively overcome the problem of drug resistance caused by target mutation.

The technical scheme is as follows: the invention provides a 2-amino-4-thiazolyl pyrimidine compound or a pharmaceutically acceptable salt thereof, and the structure of the compound is shown as a general formula (I):

；

wherein when R is ₁ Is NHR ₃ ，R ₃ Is hydrogen, C ₁ -C ₃ Alkyl, -COR ₁₄ When R is ₂ Selected from the group consisting ofThe method comprises the steps of carrying out a first treatment on the surface of the When R is ₁ Is NHR ₃ ，R ₃ is-SO ₂ R ₁₃ When R is ₂ Selected from->、/>、/>The method comprises the steps of carrying out a first treatment on the surface of the When R is ₁ Is C ₁ -C ₃ In the case of alkyl radicals, R ₂ Selected from->、/>、/>、/>The method comprises the steps of carrying out a first treatment on the surface of the When R is ₁ Is thatWhen R is ₂ Selected from->、/>、/>The method comprises the steps of carrying out a first treatment on the surface of the When R is ₁ Is that，R ₁₇ Is hydrogen, C ₁ -C ₃ In the case of alkyl radicals, R ₂ Selected from->、/>、The method comprises the steps of carrying out a first treatment on the surface of the When R is ₁ Is->，R ₁₇ is-SO ₂ R ₁₈ 、-COR ₁₉ When R is ₂ Selected from the group consisting of、/>、/>、/>；R ₃ Selected from hydrogen, C ₁ -C ₃ Alkyl, -SO ₂ R ₁₃ 、-COR ₁₄ ；R ₄ Selected from hydrogen, -C ₁ -C3-NR ₁₅ R ₁₆ 、C ₁ -C ₃ An alkyl group; r is R ₅ Selected from hydrogen, alkoxy, halogen, C ₁ -C ₃ An alkyl group; r is R ₆ Selected from hydrogen, alkoxy, halogen, C ₁ -C ₃ An alkyl group; r is R ₇ Selected from hydrogen, C ₁ -C ₃ An alkyl group; x is selected from C, N; r is R ₈ Selected from hydrogen, alkoxy, halogen, C ₁ -C ₃ An alkyl group; r is R ₉ Selected from hydrogen, alkoxy, halogen, C ₁ -C ₃ Alkyl,/->；R ₁₀ Selected from hydrogen, alkoxy, halogen, C ₁ -C ₃ An alkyl group; r is R ₁₁ Selected from hydrogen, alkoxy, halogen, C ₁ -C ₃ An alkyl group; r is R ₁₂ Selected from hydrogen, C ₁ -C ₃ An alkyl group; r is R ₁₃ Selected from methyl, ethyl, isopropyl, n-butyl, halogenated C ₁ -C ₄ Alkyl, C ₃ -C ₈ Cycloalkyl, substituted phenyl; r is R ₁₄ Selected from C ₁ -C ₄ Alkyl, halogenated C ₁ -C ₄ Alkyl, C ₃ -C ₈ Cycloalkyl, substituted phenyl; r is R ₁₅ And R is ₁₆ Are independently selected from hydrogen, C ₁ -C ₃ An alkyl group; alternatively, R ₁₅ And R is ₁₆ Forming five-membered nitrogen-containing heterocycle and six-membered nitrogen-containing heterocycle; r is R ₁₈ And R is ₁₉ Are respectively and independently selected from C ₁ -C ₄ Alkyl, halogenated C ₁ -C ₄ Alkyl, C ₃ -C ₈ Cycloalkyl groups.

The 2-amino-4-thiazolyl pyrimidine compound or the pharmaceutically acceptable salt thereof,

R ₅ selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ An alkyl group; r is R ₆ Selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ An alkyl group; r is R ₈ Selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ An alkyl group; r is R ₉ Selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ Alkyl group,；R ₁₀ Selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ An alkyl group; r is R ₁₁ Selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ An alkyl group.

R ₄ selected from-C ₁ -C3-NR ₁₅ R ₁₆ ；R ₅ Selected from hydrogen, -OCH ₃ ；R ₆ Selected from hydrogen, halogen, C ₁ -C ₃ An alkyl group; r is R ₇ Selected from hydrogen, C ₁ -C ₃ An alkyl group; r is R ₈ Selected from hydrogen, -OCH ₃ ；R ₉ Selected from hydrogen, halogen,；R ₁₀ Selected from hydrogen, -OCH ₃ ；R ₁₁ Selected from hydrogen, C ₁ -C ₃ An alkyl group; r is R ₁₂ Selected from C ₁ -C ₃ An alkyl group; r is R ₁₃ Selected from C ₁ -C ₄ Alkyl, C ₃ -C ₈ Cycloalkyl, halophenyl; r is R ₁₄ Selected from C ₁ -C ₄ An alkyl group; r is R ₁₅ And R is ₁₆ Are respectively and independently selected from C ₁ -C ₃ An alkyl group; alternatively, R ₁₅ And R is ₁₆ Forming six-membered nitrogen-containing heterocycle, R ₁₇ Selected from hydrogen, -SO ₂ R ₁₈ ；R ₁₈ Selected from C ₁ -C ₄ An alkyl group.

R ₁ selected from NHR ₃ Methyl, isopropyl,；R ₃ Selected from hydrogen, methyl, isopropyl, -SO ₂ R ₁₃ 、-COR ₁₄ ；R ₄ Selected from->；R ₅ Selected from hydrogen, -OCH ₃ ；R ₆ Selected from hydrogen, methyl; r is R ₇ Selected from hydrogen, methyl, ethyl, isopropyl; r is R ₈ Selected from hydrogen, -OCH ₃ ；R ₉ Selected from hydrogen, fluorine,；R ₁₀ Selected from-OCH ₃ ；R ₁₁ Selected from methyl; r is R ₁₂ Selected from methyl; r is R ₁₃ Selected from methyl, isopropyl, n-butyl, cyclohexyl, and p-fluorophenyl; r is R ₁₄ Selected from methyl groups.

Further, the compound is selected from C-1 to C-38:

;

；/>

。

the preparation method of the 2-amino-4-thiazolylpyrimidine compound or the pharmaceutically acceptable salt thereof comprises the following steps:

，

dissolving A and B in n-butanol, adding trifluoroacetic acid, reacting at 100-150deg.C for 8-15 hr, concentrating the reaction mixture after the reaction, and purifying to obtain the final product.

The pharmaceutically acceptable salts are acid addition salts of the compounds of formula (I), wherein the acids used for salt formation include inorganic acids including hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids including acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid, and tartaric acid.

Further, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carrier refers to excipients or diluents that do not cause significant irritation to the organism and do not interfere with the biological activity and properties of the compound being administered. The excipient comprises a flavoring agent, a cosolvent, an emulsifying agent, a solubilizer, an adhesive, a preservative, an antioxidant, an osmotic pressure regulator, a colorant filler, a disintegrating agent, a lubricant and the like, and the diluent comprises starch, physiological saline, sucrose, lactose, dextrin and the like.

The compound or the pharmaceutically acceptable salt thereof disclosed by the invention is applied to the preparation of EGFR gene mutation type inhibitor drugs. The EGFR inhibitor drugs are useful in the treatment of cancer or tumor related diseases.

The application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines for preventing and/or treating cancers or tumor related diseases. Cancers or tumor-related diseases include lung cancer, stomach cancer, prostate cancer, ovarian cancer, testicular cancer, colon cancer, leukemia, breast cancer, multiple myeloma, liver cancer, pancreatic cancer, melanoma, glioma, multiple solid tumors of the pituitary and hematological tumors.

Further, the tumor is a malignant tumor of EGFR gene mutation.

In some of these embodiments, the tumor is EGFR ^{L858R/T790M/C797S} Mutated malignancy.

The compound of the general formula (I) or the pharmaceutically acceptable salt thereof has inhibiting activity on EGFR kinase and has therapeutic effect on related malignant tumors.

The terms used in the present invention generally have the following meanings unless specifically indicated:

the term "alkyl" means a straight or branched chain saturated hydrocarbon group having the stated number of carbon atoms.

The term "C ₁ -C ₄ Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms; c (C) ₁ -C ₄ Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like. Halogenated C ₁ -C ₄ Alkyl means C wherein the alkyl chain is substituted by one or more halogens ₁ -C ₄ An alkyl group.

The term "cycloalkyl" refers to an alkyl group having a cyclic structure including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "alkoxy" refers to an alkyl group having one oxygen atom at the end, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy.

The term "halogen" is fluorine, chlorine, bromine or iodine; fluorine, chlorine and bromine are preferred.

The term "nitrogen-containing heterocycle" includes saturated and unsaturated, multi-membered nitrogen-containing heterocycles including, but not limited to, cyclic ethylamine, cyclopropylamine, morpholine, piperazine, pyrazine, pyrrole, tetrahydropyrrole, imidazole, N-methylpiperazine, N-ethylpiperazine, N-ethylsulfonylpiperazine, and the like.

The invention also discloses a preparation method of the compound shown in the general formula (I).

The beneficial effects are that: compared with the prior art, the 2-amino-4-thiazolyl pyrimidine compound prepared by the invention has inhibition activity on EGFR kinase, so that the compound has antiproliferative activity on various tumor cells, and can effectively solve the problem of drug resistance caused by target mutation of the octenidine.

Description of the embodiments

The invention is further described below. The following examples are only for more clearly illustrating the technical aspects of the present invention, and are not intended to limit the scope of the present invention. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, were purchased from conventional biochemical reagent stores. The present application will be described in detail with reference to specific examples.

Synthesis of the intermediate reactant

(1) Synthesis of 5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-amine (A-1):

step one, synthesis of 2- (2-chloropyrimidin-4-yl) -1- (4-fluorophenyl) ethan-1-one (a-1-1): 2-chloro-4-methylpyrimidine (1 eq, 100 mmol) and ethyl 4-fluorobenzoate (1.1 eq, 110 mmol) were dissolved in 150 mL anhydrous tetrahydrofuran, the solution was cooled to 0℃and lithium bistrimethylsilylamino (2 eq, 200 mmol) was added dropwise. After 3 hours of reaction at 5-10 ℃, the mixture was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by evaporation under vacuum to give a mixture of a-1-keto and enol (16.8 g, 67 mmol) as a pale yellow solid in 67% yield by rapid preparative liquid phase purification. ¹ H NMR (400 MHz, Chloroform-d) δ 13.80 (s, 2H), 8.60 (d,J= 5.0 Hz, 1H), 8.39 (d,J= 5.4 Hz, 2H), 8.12 – 8.02 (m, 2H), 7.85 (dd,J= 5.3, 8.9 Hz, 4H), 7.33 (d,J= 5.1 Hz, 1H), 7.24 – 7.08 (m, 6H), 6.90 (d,J= 5.4 Hz, 2H), 5.99 (s, 2H), 4.45 (s, 2H)。

Step two, synthesis of 2-bromo-2- (2-chloropyrimidin-4-yl) -1- (4-fluorophenyl) ethan-1-one (a-1-2): a-1-1 (1 eq, 10 mmol) was dissolved in 15 mL dry dichloromethane and NBS (1.1 eq, 11 mmol) was added slowly in portions at 0deg.C, after the addition was completed, further stirred at room temperature for 1h, the reaction mixture was concentrated under reduced pressure and the liquid phase was purified to give A-1-2 (3.13 g, 9.5 mmol) as a pale yellow solid in 95% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.73 (d,J= 5.1 Hz, 1H), 8.09 (dd,J= 5.2, 8.9 Hz, 2H), 7.78 (d,J= 5.1 Hz, 1H), 7.26 – 7.16 (m, 2H), 6.20 (s, 1H)。

Step three, synthesis of 5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-amine (a-1): a-1-2 (1 eq, 5 mmol) was dissolved in 20 mL acetonitrile, thiourea (1.1 eq, 5.5 mmol) was added and stirred at room temperature for 8 hours, the precipitated solid was filtered and acetonitrile was washed to give A-1 (0.84 g, 2.75 mmol) as a yellow solid in 55% yield. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.35 (d,J= 5.5 Hz, 1H), 7.76 – 7.49 (m, 2H), 7.35 (t,J= 8.9 Hz, 2H), 6.81 (d,J= 5.5 Hz, 1H)。

(2) Synthesis of 5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) -N-methylthiazol-2-amine (A-2):

referring to the synthetic method of A-1, light yellow solid was obtained in 65% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.71 (d,J= 5.1 Hz, 1H), 8.13 – 8.04 (m, 2H), 7.69 (s, 1H), 7.23 (t,J= 8.8 Hz, 2H), 3.10 – 2.95 (m, 3H)。

(3) Synthesis of 4- (5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) morpholine (A-3):

referring to the synthetic method of A-1, light yellow solid was obtained in 58% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (d,J= 5.6 Hz, 1H), 7.70 – 7.50 (m, 2H), 7.33 (t,J= 8.7 Hz, 2H), 6.82 (d,J= 5.5 Hz, 1H), 3.73 (s, 4H), 3.57 (s, 4H)。

(4) Synthesis of 5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) -2-methylthiazole (A-4):

a-1-2 (1 eq, 5 mmol) was dissolved in 20 mL of N, N-dimethylformamide, thioacetamide (1.5 eq, 7.5 mmol) was added, reacted overnight at 90℃and the reaction mixture was concentrated under reduced pressure to give A-4 (0.8 g, 2.9 mmol) as a pale yellow solid in 58% yield as a rapid prepared liquid phase. ¹ H NMR (400 MHz, Chloroform-d) δ 8.34 (d,J= 5.4 Hz, 1H), 7.60 – 7.46 (m, 2H), 7.16 (t,J= 8.6 Hz, 2H), 6.98 (d,J= 5.3 Hz, 1H), 2.78 (s, 3H)。

(5) Synthesis of 5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) -2-isopropylthiazole (A-5):

referring to the synthetic method of A-4, a pale yellow solid was obtained in 60% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.34 (d,J= 5.4 Hz, 1H), 7.64 – 7.46 (m, 2H), 7.15 (t,J= 8.6 Hz, 2H), 6.98 (d,J= 5.3 Hz, 1H), 3.36 (hept,J= 6.9 Hz, 1H), 1.46 (d,J= 7.0 Hz, 6H)。

(6) Synthesis of N- (5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) methanesulfonamide (A-6):

a-1 (1 eq, 5 mmol) was dissolved in 20 mL tetrahydrofuran at 0deg.C under nitrogen atmosphere, sodium hydride (2 eq, 10 mmol) was added, the reaction was continued at room temperature for 0.5 hours, methanesulfonic anhydride (1.5 eq, 7.5 mmol) was added, the reaction was continued for 3 hours, quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by evaporation under vacuum to give A-6 (1.40 g, 3.65 mmol) as a pale yellow solid in 73% yield by rapid preparative liquid phase purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.31 (s, 1H), 8.47 (d,J= 5.4 Hz, 1H), 7.75 – 7.64 (m, 2H), 7.44 (t,J= 8.9 Hz, 2H), 6.78 (d,J= 5.5 Hz, 1H), 3.03 (s, 3H)。

(7) Synthesis of N- (5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) ethanesulfonamide (A-7):

referring to the synthetic method of A-6, a pale yellow solid was obtained in 68% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.35 (s, 1H), 8.47 (d,J= 5.5 Hz, 1H), 7.80 – 7.61 (m, 2H), 7.44 (t,J= 8.9 Hz, 2H), 6.78 (d,J= 5.4 Hz, 1H), 3.12 (q,J= 7.3 Hz, 2H), 1.25 (t,J= 7.3 Hz, 3H)。

(8) Synthesis of N- (5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) propane-2-sulfonamide (A-8):

referring to the synthetic method of A-6, light yellow solid was obtained in 73% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.29 (d,J= 5.4 Hz, 1H), 7.62 – 7.50 (m, 2H), 7.26 – 7.20 (m, 2H), 6.76 (d,J= 5.4 Hz, 1H), 3.21 (hept,J= 6.8 Hz, 1H), 1.35 (d,J= 6.8 Hz, 6H)。

(9) Synthesis of N- (5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) butane-1-sulfonamide (A-9):

referring to the synthetic method of A-6, pale yellow solid was obtained in 70% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.29 (d,J= 5.4 Hz, 1H), 7.62 – 7.50 (m, 2H), 7.26 – 7.19 (m, 2H), 6.76 (d,J= 5.4 Hz, 1H), 3.15 – 2.96 (m, 2H), 1.77 (tt,J= 6.3, 7.9 Hz, 2H), 1.42 (h,J= 7.4 Hz, 2H), 0.92 (t,J= 7.4 Hz, 3H)。

(10) Synthesis of N- (5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) cyclohexanesulfonamide (A-10):

referring to the synthetic method of A-6, light yellow solid was obtained in 58% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.32 (s, 1H), 8.47 (d,J= 5.5 Hz, 1H), 7.70 (dd,J= 5.5, 8.6 Hz, 2H), 7.43 (t,J= 8.8 Hz, 2H), 6.78 (d,J= 5.5 Hz, 1H), 2.99 (tt,J= 3.4, 11.9 Hz, 1H), 2.08 (dd,J= 3.4, 12.8 Hz, 2H), 1.87 – 1.71 (m, 2H), 1.63 (d,J= 12.8 Hz, 1H), 1.47 – 1.35 (m, 2H), 1.30 – 1.23 (m, 2H), 1.20 – 1.11 (m, 1H)。

(11) Synthesis of N- (5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) -4-fluorobenzenesulfonamide (A-11):

referring to the synthetic method of A-6, pale yellow solid was obtained in 61% yield. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.48 (d,J= 5.4 Hz, 1H), 8.02 – 7.89 (m, 2H), 7.74 – 7.63 (m, 2H), 7.50 – 7.35 (m, 4H), 6.76 (d,J= 5.4 Hz, 1H)。

(12) Synthesis of N- (5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) acetamide (A-12):

referring to the synthetic method of A-6, light yellow solid was obtained in 78% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.60 (s, 1H), 8.49 (d,J= 5.4 Hz, 1H), 7.71 – 7.59 (m, 2H), 7.33 (t,J= 8.9 Hz, 2H), 7.06 (d,J= 5.4 Hz, 1H), 2.22 (s, 3H)。

(13) Synthesis of 5- (2-chloropyrimidin-4-yl) -2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazole (A-13):

step one, synthesis of 5- (2-chloropyrimidin-4-yl) -4- (4-fluorophenyl) -2- (piperidin-4-yl) thiazole: referring to the synthetic method of A-4, pale yellow solid was obtained in 61% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (d,J= 5.3 Hz, 1H), 7.71 – 7.61 (m, 2H), 7.32 (t,J= 8.9 Hz, 2H), 7.16 (d,J= 5.3 Hz, 1H), 3.52 – 3.38 (m, 3H), 3.16 (s, 1H), 3.04 (td,J= 3.1, 12.6 Hz, 2H), 2.31 – 2.21 (m, 2H), 2.06 – 1.96 (m, 2H)。

Step two, synthesis of 5- (2-chloropyrimidin-4-yl) -2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazole (a-13): a-13-1 (1 eq, 5 mmol) was dissolved in 30 mL tetrahydrofuran at 0deg.C, triethylamine (5 eq, 25 mmol) and ethylsulfonyl chloride (1.5 eq, 7.5 mmol) were added, reacted at room temperature for 4 hours, quenched with saturated aqueous ammonium chloride solution and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by evaporation under vacuum to give A-13 (2.10 g, 4.5 mmol) as a pale yellow solid in 90% yield by rapid preparative liquid phase purification. ¹ H NMR (400 MHz, Chloroform-d) δ 8.37 (d,J= 5.4 Hz, 1H), 7.58 – 7.49 (m, 2H), 7.16 (t,J= 8.6 Hz, 2H), 7.00 (d,J= 5.3 Hz, 1H), 4.00 – 3.87 (m, 2H), 3.18 (tt,J= 3.9, 11.5 Hz, 1H), 3.08 – 2.93 (m, 4H), 2.38 – 2.22 (m, 2H), 2.04 – 1.90 (m, 2H), 1.39 (t,J= 7.4 Hz, 3H)。

(14) Synthesis of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (B-1):

step one, 4- (4-nitrophenyl)Synthesis of piperazine-1-carboxylic acid tert-butyl ester (B-1-1): p-fluoronitrobenzene (1 eq, 20 mmol) and 1-t-butoxycarbonyl piperazine (1 eq, 20 mmol) were dissolved in 30 mL N, N-dimethylformamide, and potassium carbonate (2.5 eq, 50 mmol) was added and stirred at 80℃for 12 hours. After the reaction was completed, it was cooled to room temperature, poured into 300, mL, and the solid was precipitated, suction-filtered, washed with water, and dried to give B-1-1 (3.69, g, 12 mmol) as a yellow solid in 60% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (d,J= 9.5 Hz, 2H), 7.01 (d,J= 9.5 Hz, 2H), 3.48 (s, 8H), 1.43 (s, 9H)。

Step two, synthesis of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (B-1): b-1-1 (3.07 g, 10 mmol) was dissolved in methanol, 300 mg palladium on carbon was added thereto and reacted under a hydrogen atmosphere for 12 hours, the palladium on carbon was removed by filtration, and the filtrate was concentrated to give B-1 (2.63 g, 9.5 mmol) as a brown solid in a yield of 95%. ¹ H NMR (400 MHz, Chloroform-d) δ 6.87 – 6.77 (m, 2H), 6.75 – 6.61 (m, 2H), 3.56 (t,J= 5.1 Hz, 4H), 3.46 (s, 2H), 2.96 (t,J= 5.0 Hz, 4H), 1.48 (s, 9H)。

(15) Synthesis of 4- (4-isopropylpiperazin-1-yl) aniline (B-2):

step one, synthesis of 1-isopropyl-4- (4-nitrophenyl) piperazine (B-2-1): referring to the synthesis of B-1-1, a yellow solid was obtained in 65% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.12 (d,J= 9.4 Hz, 2H), 6.82 (d,J= 9.5 Hz, 2H), 3.47 – 3.38 (m, 4H), 2.75 (h,J= 6.5 Hz, 1H), 2.70 – 2.60 (m, 4H), 1.09 (d,J= 6.5 Hz, 6H)。

Step two, synthesis of 4- (4-isopropyl piperazine-1-yl) aniline (B-2): referring to the synthesis method of B-1, brown solid was obtained in 93% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 6.82 (d,J= 8.8 Hz, 2H), 6.65 (d,J= 8.8 Hz, 2H), 3.42 (s, 2H), 3.14 – 2.96 (m, 4H), 2.79 – 2.61 (m, 5H), 1.09 (d,J= 6.5 Hz, 6H)。

(16) Synthesis of 3-methyl-4- (4-methylpiperazin-1-yl) aniline (B-3):

step one, synthesis of 1-methyl-4- (2-methyl-4-nitrophenyl) piperazine (B-3-1): referring to the synthesis of B-1-1, a yellow solid was obtained in 61% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.03 (d,J= 7.6 Hz, 2H), 7.02 – 6.97 (m, 1H), 3.06 (t,J= 4.9 Hz, 4H), 2.71 – 2.51 (m, 4H), 2.38 (s, 3H), 2.36 (s, 3H)。

Step two, synthesis of 3-methyl-4- (4-methylpiperazin-1-yl) aniline (B-3): referring to the synthesis method of B-1, brown solid was obtained in 96% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 6.89 (d,J= 8.3 Hz, 1H), 6.55 (d,J= 2.8 Hz, 1H), 6.50 (dd,J= 2.8, 8.3 Hz, 1H), 3.56 – 3.28 (m, 2H), 2.85 (t,J= 4.8 Hz, 4H), 2.55 (s, 4H), 2.34 (s, 3H), 2.23 (s, 3H)。

(17) Synthesis of 2-methoxy-5-methyl-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (B-4):

step one, synthesis of 1- (1- (5-methoxy-2-methyl-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine (B-4-1): referring to the synthesis of B-1-1, a yellow solid was obtained in 68% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 7.81 (d,J= 0.8 Hz, 1H), 6.54 (s, 1H), 3.93 (s, 3H), 3.37 – 3.30 (m, 2H), 2.78 – 2.34 (m, 11H), 2.32 (s, 3H), 2.25 – 2.22 (m, 3H), 2.02 – 1.96 (m, 2H), 1.71 (qd,J= 3.8, 12.0 Hz, 2H)。

Step two, synthesis of 2-methoxy-5-methyl-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (B-4): referring to the synthesis of B-1, a brown solid was obtained in 93% yield. MS m/z (ES)I) found [M+H] ⁺ 319.2。

(18) Synthesis of 2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinium aniline (B-5):

step one, synthesis of 4- (2-fluoro-4-methoxy-5-nitrophenyl) -1-methyl-1H-pyrazole (B-5-1): 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (1 eq, 10 mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole (1.1 eq, 11 mmol), 1-bis (diphenylphosphine) bis (iron) palladium dichloride (0.05 eq, 0.5 mmol) and potassium carbonate (3 eq, 30 mmol) were dissolved in 30 mL of 1, 4-dioxane and 5 mL water, the air in the system was replaced with nitrogen, reacted at 110℃for 12 hours, after completion of the reaction mixture was concentrated and the liquid phase was rapidly prepared purified to give B-5-1 (1.76 g, 7 mmol) in 70% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.28 (d,J= 7.9 Hz, 1H), 8.18 (d,J= 2.3 Hz, 1H), 7.92 (s, 1H), 7.40 (d,J= 12.8 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H)。

Step two, synthesis of 4- (5-methoxy-2- (1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl) morpholine (B-5-2): referring to the synthesis of B-1-1, the yield was 66%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.16 (s, 1H), 7.91 – 7.79 (m, 2H), 6.79 (s, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.79 – 3.62 (m, 4H), 3.04 – 2.90 (m, 4H)。

Step three, synthesis of 2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinium aniline (B-5): referring to the synthesis method of B-1, the yield was 90%. ¹ H NMR (400 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.83 (s, 1H), 6.77 (s, 1H), 6.65 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.79 – 3.76 (m, 4H), 2.88 – 2.79 (m, 4H)。

(19) Synthesis of 1- (2- (dimethylamino) ethyl) -1H-indol-5-amine (B-6):

step one, synthesis of N, N-dimethyl-2- (5-nitro-1H-indol-1-yl) ethane-1-amine (B-6-1): 5-nitroindole (1 eq, 20 mmol) was dissolved in 50 mL anhydrous tetrahydrofuran at 0 ℃, sodium hydride (4 eq, 80 mmol) was added, after 1 hour of reaction, dimethylaminobromoethane hydrobromide (1.2 eq, 24 mmol) was added, the reaction was continued for 24 hours, quenched with saturated aqueous ammonium chloride solution and the mixture extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by evaporation under vacuum to give B-6-1 (2.72 g, 11.8 mmol) as a pale yellow solid in 59% yield by rapid preparative liquid phase purification. ¹ H NMR (400 MHz, Chloroform-d) δ 8.58 (d,J= 2.2 Hz, 1H), 8.11 (dd,J= 2.3, 9.1 Hz, 1H), 7.36 (d,J= 9.1 Hz, 1H), 7.32 (d,J= 3.2 Hz, 1H), 6.67 (d,J= 3.2 Hz, 1H), 4.26 (t,J= 6.8 Hz, 2H), 2.71 (t,J= 6.8 Hz, 2H), 2.29 (s, 6H)。

Step two, synthesis of 1- (2- (dimethylamino) ethyl) -1H-indol-5-amine (B-6): referring to the synthesis method of B-1, the yield was 99%. ¹ H NMR (400 MHz, Chloroform-d) δ 7.14 (d,J= 8.6 Hz, 1H), 7.04 (d,J= 3.1 Hz, 1H), 6.91 (d,J= 2.2 Hz, 1H), 6.67 (dd,J= 2.2, 8.6 Hz, 1H), 6.29 (dd,J= 0.8, 3.1 Hz, 1H), 4.23 – 4.08 (t,J= 6.8 Hz, 2H), 3.44 (s, 2H), 2.73 – 2.61 (t,J= 6.8 Hz, 2H), 2.28 (s, 6H)。

(20) Synthesis of 1- (2- (diethylamino) ethyl) -1H-indol-5-amine (B-7):

step one, synthesis of N, N-diethyl-2- (5-nitro-1H-indol-1-yl) ethane-1-amine (B-7-1): referring to the synthesis method of B-6-1, the yield was 63%. ¹ H NMR (400 MHz, Chloroform-d) δ 8.57 (d,J= 2.2 Hz, 1H), 8.10 (dd,J= 2.3, 9.1 Hz, 1H), 7.36 (d,J= 9.1 Hz, 1H), 7.31 (d,J= 3.2 Hz, 1H), 6.65 (dd,J= 0.8, 3.2 Hz, 1H), 4.21 (t,J= 6.7 Hz, 2H), 2.80 (t,J= 6.7 Hz, 2H), 2.53 (q,J= 7.1 Hz, 4H), 0.95 (t,J= 7.1 Hz, 6H)。

Step two, synthesis of 1- (2- (diethylamino) ethyl) -1H-indol-5-amine (B-7): referring to the synthesis method of B-6, the yield was 99%. ¹ H NMR (400 MHz, Chloroform-d) δ 7.14 (d,J= 8.6 Hz, 1H), 7.03 (d,J= 3.0 Hz, 1H), 6.91 (d,J= 2.2 Hz, 1H), 6.66 (dd,J= 2.2, 8.6 Hz, 1H), 6.31 – 6.24 (m, 1H), 4.15 – 4.05 (m, 2H), 3.46 (s, 2H), 2.80 – 2.74 (m, 2H), 2.56 (q,J= 7.1 Hz, 4H), 1.00 (t,J= 7.1 Hz, 6H)。

(21) Synthesis of 1- (2-morpholinoethyl) -1H-indol-5-amine (B-8):

step one, synthesis of 4- (2- (5-nitro-1H-indol-1-yl) ethyl) morpholine (B-8-1): referring to the synthesis method of B-6-1, the yield was 57%. ¹ H NMR (400 MHz, Chloroform-d) δ 8.58 (d,J= 2.2 Hz, 1H), 8.12 (dd,J= 2.2, 9.1 Hz, 1H), 7.37 (d,J= 9.0 Hz, 1H), 7.32 (d,J= 3.2 Hz, 1H), 6.68 (dd,J= 0.8, 3.3 Hz, 1H), 4.28 (t,J= 6.6 Hz, 2H), 3.71 – 3.65 (m, 4H), 2.76 (t,J= 6.6 Hz, 2H), 2.50 – 2.45 (m, 4H)。

Step two, synthesis of 1- (2-morpholinoethyl) -1H-indol-5-amine (B-8): referring to the synthesis method of B-6, the yield was 99%. ¹ H NMR (300 MHz, Chloroform-d) δ 7.15 (d,J= 8.6 Hz, 1H), 7.06 (d,J= 3.0 Hz, 1H), 6.92 (dd,J= 0.6, 2.2 Hz, 1H), 6.68 (dd,J= 2.2, 8.6 Hz, 1H), 6.29 (dd,J= 0.8, 3.1 Hz, 1H), 4.18 (t,J= 7.0 Hz, 2H), 3.74 – 3.66 (m, 4H), 2.72 (t,J= 7.0 Hz, 2H), 2.51 – 2.43 (m, 4H)。

2. Synthesis of Compound C-1-C-38

Examples

Synthesis of 5- (2- ((1- (2- (dimethylamino) ethyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-amine (C-1):

a-1 (1 eq, 0.5 mmol) and B-6 (1.1 eq, 0.55 mmol) were dissolved in 10 mL n-butanol, trifluoroacetic acid (1.5 eq, 0.75 mmol) was added and reacted at 120℃for 10 hours, after the reaction was completed, the reaction mixture was concentrated and the liquid phase was rapidly prepared purified to give C-1 (142 mg, 0.30 mmol) in 60% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 8.06 (d,J= 5.4 Hz, 1H), 8.00 (s, 1H), 7.65 – 7.51 (m, 4H), 7.41 – 7.22 (m, 5H), 6.35 (d,J= 3.0 Hz, 1H), 6.20 (d,J= 5.3 Hz, 1H), 4.22 (t,J= 6.7 Hz, 2H), 2.62 (t,J= 6.7 Hz, 2H), 2.20 (s, 6H)。

Example 2:

synthesis of 5- (2- ((1- (2- (dimethylamino) ethyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -4- (4-fluorophenyl) -N-methylthiazol-2-amine (C-2):

referring to the synthesis of C-1, a pale yellow solid was obtained in 63% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.24 (s, 1H), 8.21 – 8.00 (m, 3H), 7.66 – 7.50 (m, 2H), 7.40 – 7.22 (m, 5H), 6.34 (d,J= 3.1 Hz, 1H), 6.18 (d,J= 5.4 Hz, 1H), 4.21 (t,J= 6.6 Hz, 2H), 2.90 (d,J= 4.8 Hz, 3H), 2.60 (t,J= 6.6 Hz, 2H), 2.19 (s, 6H)。

Example 3

Synthesis of 1- (2- (dimethylamino) ethyl) -N- (4- (4-fluorophenyl) -2-morpholinothiazol-5-yl) pyrimidin-2-yl) -1H-indol-5-amine (C-3):

referring to the synthetic method of C-1, a pale yellow solid was obtained in 60% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.11 (d,J= 5.3 Hz, 1H), 8.00 (d,J= 1.4 Hz, 1H), 7.64 – 7.55 (m, 2H), 7.45 – 7.17 (m, 5H), 6.34 (d,J= 3.0 Hz, 1H), 6.21 (d,J= 5.3 Hz, 1H), 4.21 (t,J= 6.7 Hz, 2H), 3.75 (t,J= 4.9 Hz, 4H), 3.51 (t,J= 4.9 Hz, 4H), 2.59 (t,J= 6.6 Hz, 2H), 2.18 (s, 6H)。

Example 4

Synthesis of 1- (2- (dimethylamino) ethyl) -N- (4- (4-fluorophenyl) -2-methylthiazol-5-yl) pyrimidin-2-yl) -1H-indol-5-amine (C-4):

referring to the synthetic method of C-1, pale yellow solid was obtained in 66% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 8.27 (d,J= 5.1 Hz, 1H), 7.92 (s, 1H), 7.67 – 7.57 (m, 2H), 7.42 – 7.23 (m, 5H), 6.40 (d,J= 5.1 Hz, 1H), 6.35 (d,J= 3.0 Hz, 1H), 4.22 (t,J= 6.7 Hz, 2H), 2.73 (s, 3H), 2.61 (t,J= 6.6 Hz, 2H), 2.19 (s, 6H)。

Example 5

Synthesis of 1- (2- (dimethylamino) ethyl) -N- (4- (4-fluorophenyl) -2-isopropylthiazol-5-yl) pyrimidin-2-yl) -1H-indol-5-amine (C-5):

referring to the synthetic procedure for C-1, a pale yellow solid was obtained in 62% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 8.28 (d,J= 5.1 Hz, 1H), 7.95 (s, 1H), 7.69 – 7.58 (m, 2H), 7.41 – 7.25 (m, 5H), 6.43 (d,J= 5.1 Hz, 1H), 6.33 (d,J= 3.0 Hz, 1H), 4.22 (t,J= 6.6 Hz, 2H), 3.33 (h,J= 6.9 Hz, 1H), 2.61 (t,J= 6.6 Hz, 2H), 2.19 (s, 6H), 1.40 (d,J= 6.9 Hz, 6H)。

Example 6

Synthesis of N- (5- (2- ((1- (2- (dimethylamino) ethyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) methanesulfonamide (C-6):

referring to the synthesis of C-1, a pale yellow solid was obtained in 57% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.25 – 8.05 (m, 2H), 7.68 – 7.58 (m, 2H), 7.41 – 7.29 (m, 5H), 6.41 (d,J= 3.1 Hz, 1H), 6.12 (d,J= 5.3 Hz, 1H), 4.36 (t,J= 6.9 Hz, 2H), 3.02 (t,J= 6.8 Hz, 2H), 2.92 (s, 3H), 2.48 (s, 6H)。

Example 7

Synthesis of N- (5- (2- ((1- (2- (dimethylamino) ethyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) propane-2-sulfonamide (C-7):

referring to the synthetic method of C-1, a pale yellow solid was obtained in 60% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 8.21 – 7.98 (m, 2H), 7.69 – 7.59 (m, 2H), 7.41 – 7.31 (m, 5H), 6.41 (d,J= 3.1 Hz, 1H), 6.12 (d,J= 5.3 Hz, 1H), 4.32 (t,J= 6.8 Hz, 2H), 3.20 (p,J= 6.7 Hz, 1H), 2.90 (t,J= 6.8 Hz, 2H), 2.40 (s, 6H), 1.26 (d,J= 6.8 Hz, 6H)。

Example 8

Synthesis of N- (5- (2- ((1- (2- (dimethylamino) ethyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) butane-1-sulfonamide (C-8):

referring to the synthesis of C-1, a pale yellow solid was obtained in 57% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.20 – 8.05 (m, 2H), 7.68 – 7.55 (m, 2H), 7.44 – 7.28 (m, 5H), 6.41 (d,J= 3.0 Hz, 1H), 6.12 (d,J= 5.3 Hz, 1H), 4.34 (t,J= 6.8 Hz, 2H), 3.10 – 2.87 (m, 4H), 2.43 (s, 6H), 1.75 – 1.61 (m, 2H), 1.45 – 1.34 (m, 2H), 0.88 (t,J= 7.3 Hz, 3H)。

Example 9

Synthesis of N- (5- (2- ((1- (2- (dimethylamino) ethyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) cyclohexanesulfonamide (C-9):

referring to the synthetic method of C-1, light yellow solid was obtained in 59% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (s, 1H), 8.22 – 8.00 (m, 2H), 7.69 – 7.58 (m, 2H), 7.40 – 7.31 (m, 5H), 6.41 (d,J= 3.1 Hz, 1H), 6.12 (d,J= 5.3 Hz, 1H), 4.31 (t,J= 6.8 Hz, 2H), 2.96 – 2.86 (m, 3H), 2.39 (s, 6H), 2.13 – 2.05 (m, 2H), 1.83 – 1.74 (m, 2H), 1.66 – 1.57 (m, 1H), 1.47 – 1.36 (m, 2H), 1.29 – 1.21 (m, 2H), 1.17 – 1.07 (m, 1H)。

Example 10

Synthesis of N- (5- (2- ((1- (2- (dimethylamino) ethyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) -4-fluorobenzenesulfonamide (C-10):

referring to the synthesis of C-1, as a pale yellow solid, 54% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.16 (s, 1H), 8.07 (d,J= 5.3 Hz, 1H), 7.96 – 7.86 (m, 2H), 7.58 – 7.51 (m, 2H), 7.45 – 7.26 (m, 7H), 6.46 (d,J= 3.1 Hz, 1H), 6.13 (d,J= 5.3 Hz, 1H), 4.43 (t,J= 6.8 Hz, 2H), 3.20 (t,J= 6.9 Hz, 2H), 2.60 (s, 6H)。

Example 11

Synthesis of N- (5- (2- ((1- (2- (dimethylamino) ethyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) acetamide (C-11):

referring to the synthetic procedure for C-1, a pale yellow solid was obtained in 58% yield. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 8.22 (d,J= 5.2 Hz, 1H), 8.08 (s, 1H), 7.67 – 7.55 (m, 2H), 7.43 – 7.24 (m, 5H), 6.44 – 6.30 (m, 2H), 4.22 (t,J= 6.7 Hz, 2H), 2.60 (t,J= 6.6 Hz, 2H), 2.20 (d,J= 7.1 Hz, 9H)。

Example 12

Synthesis of N- (5- (2- ((1- (2- (dimethylamino) ethyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) ethanesulfonamide (C-12):

referring to the synthetic method of C-1, a pale yellow solid was obtained in 60% yield. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.22 – 8.07 (m, 2H), 7.68 – 7.58 (m, 2H), 7.43 – 7.31 (m, 5H), 6.42 (d,J= 3.0 Hz, 1H), 6.11 (d,J= 5.3 Hz, 1H), 4.36 (t,J= 6.8 Hz, 2H), 3.10 – 2.92 (m, 4H), 2.47 (s, 6H), 1.22 (d,J= 7.4 Hz, 3H)。

Example 13

Synthesis of N- (5- (2- ((1- (2- (diethylamino) ethyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) ethanesulfonamide (C-13):

referring to the synthesis of C-1, a pale yellow solid was obtained in 63% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.26 – 8.04 (m, 2H), 7.67 – 7.54 (m, 2H), 7.42 – 7.29 (m, 5H), 6.41 (d,J= 3.1 Hz, 1H), 6.12 (d,J= 5.3 Hz, 1H), 4.32 (t,J= 6.8 Hz, 2H), 3.03 (q,J= 6.8, 7.4 Hz, 4H), 2.85 – 2.66 (m, 4H), 1.23 (t,J= 7.3 Hz, 3H), 1.02 (t,J= 7.1 Hz, 6H)。

Example 14

Synthesis of N- (4- (4-fluorophenyl) -5- (2- ((1- (2-morpholinoethyl) -1H-indol-5-yl) amino) pyrimidin-4-yl) thiazol-2-yl) ethanesulfonamide (C-14):

referring to the synthetic method of C-1, light yellow solid was obtained in 59% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 8.24 – 8.05 (m, 2H), 7.74 – 7.63 (m, 2H), 7.44 – 7.30 (m, 5H), 6.39 (d,J= 3.1 Hz, 1H), 6.09 (d,J= 5.3 Hz, 1H), 4.26 (t,J= 6.7 Hz, 2H), 3.56 (t,J= 4.7 Hz, 4H), 3.09 (q,J= 7.4 Hz, 2H), 2.69 (t,J= 6.8 Hz, 2H), 2.46 (s, 4H), 1.26 (t,J= 7.6 Hz, 3H)。

Example 15

Synthesis of N- (4- (4-fluorophenyl) -5- (2- ((4- (-4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) thiazol-2-yl) ethanesulfonamide (C-15):

referring to the synthetic procedure for C-1, a pale yellow solid was obtained in 62% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.08 (d,J= 5.3 Hz, 1H), 7.68 – 7.50 (m, 4H), 7.33 (t,J= 8.9 Hz, 2H), 6.88 (d,J= 9.2 Hz, 2H), 6.13 (d,J= 5.4 Hz, 1H), 3.24 – 3.11 (m, 4H), 3.01 (q,J= 7.3 Hz, 2H), 2.95 – 2.79 (m, 4H), 2.54 (s, 3H), 1.21 (t,J= 7.4 Hz, 3H)。

Example 16

Synthesis of N- (4- (4-fluorophenyl) -5- (2- ((4- (-4-ethylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) thiazol-2-yl) ethanesulfonamide (C-16):

referring to the synthetic method of C-1, light yellow solid was obtained in 59% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.08 (d,J= 5.4 Hz, 1H), 7.62 – 7.54 (m, 4H), 7.33 (t,J= 8.9 Hz, 2H), 6.88 (d,J= 9.1 Hz, 2H), 6.13 (d,J= 5.3 Hz, 1H), 3.19 (s, 4H), 3.06 – 2.84 (m, 6H), 2.84 – 2.72 (m, 2H), 1.21 (t,J= 7.4 Hz, 3H), 1.14 (t,J= 7.2 Hz, 3H)。

Example 17

Synthesis of N- (4- (4-fluorophenyl) -5- (2- ((4- (-4-isopropylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) thiazol-2-yl) ethanesulfonamide (C-17):

referring to the synthetic procedure for C-1, a pale yellow solid was obtained in 64% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.07 (d,J= 5.4 Hz, 1H), 7.66 – 7.54 (m, 4H), 7.38 – 7.21 (m, 2H), 6.88 (d,J= 9.1 Hz, 2H), 6.14 (d,J= 5.3 Hz, 1H), 3.40 – 3.13 (m, 8H), 3.01 – 2.97 (m, 3H), 1.23 – 1.12 (m, 9H)。

Example 18

Synthesis of N- (4- (4-fluorophenyl) -5- (2- ((4- (1-methylpiperidin-4-yl) phenyl) amino) pyrimidin-4-yl) thiazol-2-yl) ethanesulfonamide (C-18):

referring to the synthetic method of C-1, pale yellow solid was obtained in 66% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.06 (d,J= 5.4 Hz, 1H), 7.72 – 7.63 (m, 2H), 7.60 – 7.48 (m, 2H), 7.34 – 7.21 (m, 2H), 7.09 (d,J= 8.7 Hz, 2H), 6.21 (d,J= 5.4 Hz, 1H), 3.39 (s, 2H), 2.99 – 2.82 (m, 4H), 2.70 (s, 4H), 1.97 – 1.74 (m, 4H), 1.18 (t,J= 7.4 Hz, 3H)。

Example 19

Synthesis of N- (4- (4-fluorophenyl) -5- (2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) thiazol-2-yl) ethanesulfonamide (C-19):

referring to the synthesis of C-1, a pale yellow solid was obtained in 55% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.08 (d,J= 5.4 Hz, 1H), 7.84 – 7.71 (m, 1H), 7.63 – 7.53 (m, 2H), 7.43 – 7.27 (m, 3H), 6.94 (d,J= 8.6 Hz, 1H), 6.14 (d,J= 5.4 Hz, 1H), 3.11 – 2.76 (m, 10H), 2.58 (s, 3H), 2.28 (s, 3H), 1.21 (t,J= 7.4 Hz, 3H)。

Example 20

Synthesis of N- (4- (4-fluorophenyl) -5- (2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) thiazol-2-yl) ethanesulfonamide (C-20):

referring to the synthesis of C-1, as a pale yellow solid, 54% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.16 – 8.04 (m, 2H), 7.70 – 7.58 (m, 3H), 7.38 (t,J= 8.9 Hz, 2H), 6.69 (d,J= 2.6 Hz, 1H), 6.49 (dd,J= 2.5, 8.8 Hz, 1H), 6.08 (d,J= 5.3 Hz, 1H), 3.83 (s, 3H), 3.38 (s, 4H), 3.22 (s, 4H), 3.06 (q,J= 7.3 Hz, 2H), 2.75 (s, 3H), 1.23 (t,J= 7.3 Hz, 3H)。

Example 21

Synthesis of N- (4- (4-fluorophenyl) -5- (2- ((2-methoxy-5-methyl-4- (4- (-4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) thiazol-2-yl) ethanesulfonamide (C-21):

referring to the synthetic method of C-1, light yellow solid was obtained in 59% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (d,J= 6.4 Hz, 1H), 7.87 – 7.53 (m, 3H), 7.49 – 7.40 (m, 2H), 6.94 (s, 1H), 6.26 (d,J= 6.3 Hz, 1H), 4.03 – 3.66 (m, 8H), 3.65 – 3.34 (m, 7H), 3.15 (q,J= 7.3 Hz, 2H), 3.09 – 2.94 (m, 5H), 2.37 (s, 3H), 2.33 – 2.21 (m, 2H), 2.04 (t,J= 12.4 Hz, 2H), 1.28 (t,J= 7.3 Hz, 3H)。

Example 22

Synthesis of N- (4- (4-fluorophenyl) -5- (2- ((4-morpholinophenyl) amino) pyrimidin-4-yl) thiazol-2-yl) ethanesulfonamide (C-22):

referring to the synthesis of C-1, a pale yellow solid was obtained in 55% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 9.47 (s, 1H), 8.16 (d,J= 5.3 Hz, 1H), 7.71 – 7.62 (m, 2H), 7.56 (d,J= 9.1 Hz, 2H), 7.41 (t,J= 8.9 Hz, 2H), 6.86 (d,J= 9.1 Hz, 2H), 6.09 (d,J= 5.3 Hz, 1H), 3.80 – 3.62 (m, 4H), 3.18 – 2.93 (m, 6H), 1.25 (t,J= 7.3 Hz, 3H)。

Example 23

Synthesis of N- (4- (4-fluorophenyl) -5- (2- ((2-methoxy-4-morpholinophenyl) amino) pyrimidin-4-yl) thiazol-2-yl) ethanesulfonamide (C-23):

referring to the synthetic method of C-1, light yellow solid was produced in 56% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.05 (s, 1H), 8.10 (d,J= 5.6 Hz, 2H), 7.69 – 7.56 (m, 3H), 7.40 (t,J= 8.8 Hz, 2H), 6.64 (d,J= 2.6 Hz, 1H), 6.44 (dd,J= 2.6, 8.8 Hz, 1H), 6.07 (d,J= 5.3 Hz, 1H), 3.81 (s, 3H), 3.79 – 3.71 (m, 4H), 3.13 – 3.03 (m, 6H), 1.25 (t,J= 7.4 Hz, 4H)。

Example 24

Synthesis of N- (5- (2- ((3-fluoro-4-morpholinophenyl) amino) pyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2-yl) ethanesulfonamide (C-24):

referring to the synthesis of C-1, a pale yellow solid was obtained in 53% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.10 (s, 1H), 9.73 (s, 1H), 8.22 (d,J= 5.3 Hz, 1H), 7.77 – 7.64 (m, 3H), 7.50 – 7.31 (m, 3H), 7.01 – 6.88 (m, 1H), 6.16 (d,J= 5.3 Hz, 1H), 3.81 – 3.66 (m, 4H), 3.10 (q,J= 7.3 Hz, 2H), 3.01 – 2.86 (m, 4H), 1.25 (t,J= 7.4 Hz, 3H)。

Example 25

Synthesis of N- (4- (4-fluorophenyl) -5- (2- ((2-methoxy-5- (1-methyl-1H-pyrazol-4-yl) -4-morpholinophenyl) amino) pyrimidin-4-yl) thiazol-2-yl) ethanesulfonamide (C-25):

referring to the synthetic method of C-1, light yellow solid was obtained in 59% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.08 (s, 1H), 8.22 (s, 1H), 8.17 – 8.06 (m, 2H), 7.89 (s, 1H), 7.80 (s, 1H), 7.70 – 7.59 (m, 2H), 7.40 (t,J= 8.8 Hz, 2H), 6.80 (s, 1H), 6.08 (d,J= 5.3 Hz, 1H), 3.86 (d,J= 6.2 Hz, 6H), 3.78 – 3.62 (m, 4H), 3.08 (q,J= 7.3 Hz, 2H), 2.96 – 2.74 (m, 4H), 1.24 (t,J= 7.3 Hz, 3H)。

Example 26

Synthesis of 1- (2- (dimethylamino) ethyl) -N- (4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) pyrimidin-2-yl) -1H-indol-5-amine (C-26):

referring to the synthesis of C-1, a pale yellow solid was obtained in 63% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.18 (d,J= 5.2 Hz, 1H), 7.85 (s, 1H), 7.62 – 7.51 (m, 2H), 7.33 (d,J= 1.4 Hz, 2H), 7.20 – 7.05 (m, 4H), 6.52 – 6.37 (m, 2H), 4.25 (t,J= 7.1 Hz, 2H), 3.93 (d,J= 12.7 Hz, 2H), 3.18 (tt,J= 3.8, 11.4 Hz, 1H), 3.07 – 2.93 (m, 4H), 2.72 (t,J= 7.1 Hz, 2H), 2.31 (s, 8H), 2.04 – 1.92 (m, 2H), 1.39 (t,J= 7.4 Hz, 3H)。

Example 27

Synthesis of 1- (2- (diethylamino) ethyl) -N- (4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) pyrimidin-2-yl) -1H-indol-5-amine (C-27):

referring to the synthetic method of C-1, a pale yellow solid was obtained in 60% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.18 (d,J= 5.2 Hz, 1H), 7.86 (t,J= 1.3 Hz, 1H), 7.59 – 7.55 (m, 2H), 7.32 (s, 2H), 7.18 – 7.09 (m, 4H), 6.53 – 6.40 (m, 2H), 4.22 (s, 2H), 3.93 (d,J= 12.7 Hz, 2H), 3.22 – 3.14 (m, 1H), 3.04 – 2.97 (m, 4H), 2.84 (s, 2H), 2.61 (d,J= 8.0 Hz, 4H), 2.30 – 2.23 (m, 2H), 2.02 – 1.94 (m, 2H), 1.39 (t,J= 7.4 Hz, 3H), 1.04 (t,J= 7.1 Hz, 6H)。

Example 28

Synthesis of N- (4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) pyrimidin-2-yl) -1- (2-morpholinoethyl) -1H-indol-5-amine (C-28):

referring to the synthetic procedure for C-1, a pale yellow solid was obtained in 62% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.18 (d,J= 5.2 Hz, 1H), 7.86 (s, 1H), 7.63 – 7.53 (m, 2H), 7.33 (d,J= 1.3 Hz, 2H), 7.19 – 7.07 (m, 4H), 6.50 – 6.43 (m, 2H), 4.25 (t,J= 6.9 Hz, 2H), 3.94 (d,J= 12.7 Hz, 2H), 3.71 (t,J= 4.6 Hz, 4H), 3.18 (tt,J= 3.8, 11.5 Hz, 1H), 3.06 – 2.93 (m, 4H), 2.76 (t,J= 6.9 Hz, 2H), 2.49 (t,J= 4.6 Hz, 4H), 2.31 – 2.24 (m, 2H), 2.03 – 1.95 (m, 2H), 1.39 (t,J= 7.4 Hz, 3H)。

Example 29

Synthesis of 4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) -N- (4- (piperazin-1-yl) phenyl) pyrimidin-2-amine (C-29):

referring to the synthetic method of C-1, a pale yellow solid was obtained in 60% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 8.29 (d,J= 5.2 Hz, 1H), 7.66 – 7.54 (m, 4H), 7.30 (t,J= 8.9 Hz, 2H), 6.90 (d,J= 9.1 Hz, 2H), 6.46 (d,J= 5.2 Hz, 1H), 3.76 – 3.68 (m, 2H), 3.29 – 3.21 (m, 2H), 3.20 – 2.96 (m, 12H), 2.20 (dd,J= 3.6, 13.7 Hz, 2H), 1.84 – 1.70 (m, 2H), 1.24 (t,J= 7.3 Hz, 3H)。

Example 30

Synthesis of 4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine (C-30):

referring to the synthetic method of C-1, pale yellow solid was obtained in 66% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.09 (d,J= 5.2 Hz, 1H), 7.54 – 7.44 (m, 2H), 7.40 (d,J= 8.9 Hz, 2H), 7.11 – 6.96 (m, 3H), 6.88 (d,J= 9.0 Hz, 2H), 6.39 (d,J= 5.2 Hz, 1H), 3.87 (dt,J= 3.6, 12.8 Hz, 2H), 3.22 – 3.04 (m, 5H), 3.01 – 2.87 (m, 4H), 2.59 (t,J= 4.9 Hz, 4H), 2.33 (s, 3H), 2.24 – 2.16 (m, 2H), 1.96 – 1.89 (m, 2H), 1.32 (t,J= 7.4 Hz, 3H)。

Example 31

Synthesis of N- (4- (4-ethylpiperazin-1-yl) phenyl) -4- (2- (1- (ethylsulphonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) pyrimidin-2-amine (C-31):

referring to the synthetic method of C-1, a pale yellow solid was obtained in 60% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.16 (d,J= 5.2 Hz, 1H), 7.58 – 7.54 (m, 2H), 7.47 (d,J= 9.0 Hz, 2H), 7.12 (t,J= 8.7 Hz, 2H), 7.04 – 6.92 (m, 3H), 6.46 (d,J= 5.3 Hz, 1H), 3.95 (d,J= 12.6 Hz, 2H), 3.27 – 3.14 (m, 5H), 3.04 – 2.96 (m, 4H), 2.70 (s, 4H), 2.55 (d,J= 7.5 Hz, 2H), 2.27 (dd,J= 3.5, 13.5 Hz, 2H), 2.03 – 1.95 (m, 2H), 1.40 (t,J= 7.4 Hz, 3H), 1.17 (t,J= 7.2 Hz, 3H)。

Example 32

Synthesis of 4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) -N- (4- (4-isopropylpiperazin-1-yl) phenyl) pyrimidin-2-amine (C-32):

referring to the synthesis of C-1, a pale yellow solid was obtained in 63% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.16 (d,J= 5.2 Hz, 1H), 7.62 – 7.51 (m, 2H), 7.46 (d,J= 9.0 Hz, 2H), 7.12 (t,J= 8.7 Hz, 2H), 7.08 – 6.88 (m, 3H), 6.46 (d,J= 5.3 Hz, 1H), 4.00 – 3.89 (m, 2H), 3.35 – 3.10 (m, 5H), 3.06 – 2.94 (m, 4H), 2.78 (s, 5H), 2.31 – 2.22 (m, 2H), 2.03 – 1.93 (m, 2H), 1.40 (t,J= 7.4 Hz, 3H), 1.15 (d,J= 6.5 Hz, 6H)。

Example 33

Synthesis of 4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) -N- (2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine (C-33):

referring to the synthesis of C-1, a pale yellow solid was obtained in 61% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.32 – 8.13 (m, 2H), 7.62 – 7.52 (m, 3H), 7.12 (t,J= 8.7 Hz, 2H), 6.67 – 6.53 (m, 2H), 6.45 (d,J= 5.2 Hz, 1H), 4.03 – 3.85 (m, 5H), 3.27 – 3.10 (m, 5H), 3.05 – 2.92 (m, 4H), 2.64 (t,J= 4.9 Hz, 4H), 2.39 (s, 3H), 2.28 (dd,J= 3.4, 13.9 Hz, 2H), 2.04 – 1.94 (m, 2H), 1.40 (t,J= 7.4 Hz, 3H)。

Example 34

Synthesis of 4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) -N- (4- (1-methylpiperidin-4-) phenyl) pyrimidin-2-amine (C-34):

referring to the synthetic procedure for C-1, a pale yellow solid was obtained in 58% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 8.33 (d,J= 5.1 Hz, 1H), 7.71 – 7.55 (m, 4H), 7.30 (t,J= 8.9 Hz, 2H), 7.14 (d,J= 8.7 Hz, 2H), 6.52 (d,J= 5.2 Hz, 1H), 3.78 – 3.66 (m, 2H), 3.31 – 3.20 (m, 3H), 3.13 – 2.98 (m, 4H), 2.70 (d,J= 51.8 Hz, 6H), 2.21 (dd,J= 3.6, 13.6 Hz, 2H), 1.93 – 1.71 (m, 6H), 1.22 (t,J= 7.4 Hz, 3H)。

Example 35

Synthesis of 4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) -N- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine (C-35):

/>

referring to the synthetic method of C-1, a pale yellow solid was obtained in 60% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.18 (d,J= 5.2 Hz, 1H), 7.62 – 7.51 (m, 2H), 7.48 – 7.33 (m, 2H), 7.12 (t,J= 8.7 Hz, 2H), 7.09 – 7.00 (m, 2H), 6.49 (d,J= 5.2 Hz, 1H), 3.94 (dt,J= 3.6, 12.8 Hz, 2H), 3.18 (tt,J= 3.8, 11.4 Hz, 1H), 3.05 – 2.96 (m, 8H), 2.78 (s, 4H), 2.50 (s, 3H), 2.33 (s, 3H), 2.30 – 2.24 (m, 2H), 1.98 (td,J= 7.6, 11.6 Hz, 2H), 1.39 (t,J= 7.4 Hz, 3H)。

Example 36

Synthesis of 4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) -N- (4-morpholinophenyl) pyrimidin-2-amine (C-36):

referring to the synthesis of C-1, a pale yellow solid was obtained in 55% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.17 (d,J= 5.2 Hz, 1H), 7.60 – 7.43 (m, 4H), 7.12 (t,J= 8.7 Hz, 2H), 7.02 (s, 1H), 6.94 (d,J= 9.0 Hz, 2H), 6.47 (d,J= 5.2 Hz, 1H), 4.02 – 3.82 (m, 6H), 3.25 – 3.10 (m, 5H), 3.06 – 2.92 (m, 4H), 2.27 (dd,J= 3.5, 13.5 Hz, 2H), 2.05 – 1.93 (m, 2H), 1.40 (t,J= 7.4 Hz, 3H)。

Example 37

Synthesis of 4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) -N- (2-methoxy-4-morpholinophenyl) pyrimidin-2-amine (C-37):

referring to the synthetic procedure for C-1, a pale yellow solid was obtained in 62% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.23 (d,J= 8.7 Hz, 1H), 8.18 (d,J= 5.2 Hz, 1H), 7.61 – 7.50 (m, 3H), 7.12 (t,J= 8.7 Hz, 2H), 6.63 – 6.51 (m, 2H), 6.46 (d,J= 5.2 Hz, 1H), 4.00 – 3.86 (m, 9H), 3.25 – 3.12 (m, 5H), 3.05 – 2.92 (m, 4H), 2.32 – 2.23 (m, 2H), 2.06 – 1.93 (m, 2H), 1.40 (t,J= 7.4 Hz, 3H)。

Example 38

Synthesis of 4- (2- (1- (ethylsulfonyl) piperidin-4-yl) -4- (4-fluorophenyl) thiazol-5-yl) -N- (3-fluoro-4-morpholinophenyl) pyrimidin-2-amine (C-38):

referring to the synthetic procedure for C-1, a pale yellow solid was obtained in 62% yield. ¹ H NMR (400 MHz, Chloroform-d) δ 8.20 (d,J= 5.2 Hz, 1H), 7.64 – 7.52 (m, 3H), 7.17 – 7.09 (m, 4H), 6.93 (t,J= 9.1 Hz, 1H), 6.53 (d,J= 5.2 Hz, 1H), 3.97 – 3.85 (m, 6H), 3.25 – 3.13 (m, 1H), 3.12 – 3.05 (m, 4H), 3.04 – 2.96 (m, 4H), 2.28 (dd,J= 3.6, 13.4 Hz, 2H), 2.04 – 1.94 (m, 2H), 1.40 (t,J= 7.4 Hz, 3H)。

3. Biological evaluation experiment:

(1) In vitro enzyme activity assay for EGFR:

mu.L EGFR or other mutant kinase of EGFR and 1. Mu.L of the compound prepared in examples 1-38 were added to 384 plates and incubated for 5 minutes at room temperature; mu.L of a mixture of polyE4Y1 (0.2. Mu.g/. Mu.L, SIGMA Co., P0275)/ATP (0.5. Mu.M, promega Co., V915B) was added and incubated at room temperature for 60 minutes in the absence of light; mu.L of ADP-Glo ™ Reagent (Promega Co., V912B) was added and incubated at room temperature for 40 minutes; 10. Mu.L of kinase assay reagent (Kinase Detection Reagent) (Promega Corp., V913B) was added, incubated at room temperature for 30 minutes, plates were read on a microplate reader, luminescence was recorded, and IC of each compound on enzyme activity was calculated using analytical software GraphPad Prism ₅₀ Values.

As can be seen from the experimental results, the compound C-1~C-38 prepared in the embodiment of the invention is specific to EGFR ^{L858R/T790M/C797S} Other EGFR mutant kinases have inhibitory activity and the results are shown in tables 1 and 2, wherein the IC of the compounds ₅₀ Classification according to description:

"A" means IC ₅₀ A measured value of 10nM or less; "B" means IC ₅₀ A measured value of 100 or less nM or more than 10nM; "C" means IC ₅₀ The measured value is 1 mu M or less and 100 nM or more.

/>

(2) In vitro cell Activity assay:

determining the inhibition of the proliferation of various cancer cells by the compound according to the CCK-8 method, and obtaining the half inhibition concentration IC of the proliferation inhibition activity of the compound ₅₀ Values. Inoculating logarithmic growth phase cells into 96-well plate at 3000-5000 cells/well, placing at 37deg.C, and 5% CO ₂ Culturing for 24 hours under the condition; to the plates were added 100. Mu.L of a gradient of 10. Mu.M, 5. Mu.M, 2.5. Mu.M, 1.250. Mu.M, 625 nM,312.5 nM,156.25 nM,78.125 nM,39.0625 nM of each concentration of test compound, and the plates were incubated at 37℃with 5% CO ₂ Incubating for 72 hours under incubator conditions; before the end of incubation, 4. 4 h, 10. Mu.L of CCK-8 solution (5. 5 mg/mL) was added to each well. After incubation, OD was measured by using an ELISA reader ₄₅₀ Inhibition = (control OD value-experimental OD value)/control OD value x 100%; after data were obtained, graphPad Prism fit gave IC ₅₀ 。

"+". ++'s representing IC ₅₀ The measured value is not more than 250 nM.

"+". ++'s representing IC ₅₀ The measured value is 500nM or less and more than 250 nM.

"++" means IC ₅₀ The measured value is 1 mu M or less and 500nM or more.

"+" indicates IC ₅₀ The measured value is greater than 1. Mu.M.

"-" means IC ₅₀ Not measured.

(3) In vivo antitumor (H1975 TM (EGFR) ^{L858R/T790M/C797S} ) Activity assay):

the drug was the compound (C-26) produced in example 26; the cell strain is a human lung adenocarcinoma H1975TM cell; the test animals were SPF-grade BALB/c nude mice (Kwangsi laboratory animal Co., ltd.); a female; 6 in each group, 18 in total; the drug dosage settings are as in table 4.

The experimental method comprises the following steps: taking tumor in vigorous growth phase, inoculating H1975TM cells of human lung adenocarcinoma into 25 BALB/c nude mice under right armpit skin under aseptic condition, and inoculating cell amount of 5×10 ⁶ . The diameter of the transplanted tumor is measured by a vernier caliper for the transplanted tumor of the nude mice, and the tumor grows to 85 mm ³ When the number of the tumor-bearing nude mice is about 18, the nude mice with good growth state and good tumor size uniformity are selected and divided into 3 groups, and 6 nude mice in each group are respectively administered according to a dose setting table, namely (1) a model group, (2) a low-dose group of test drugs and (3) a high-dose group of test drugs. The antitumor effect of the test substance was dynamically observed by using a method for measuring tumor diameter. Tumor diameter was measured once every other day, and the weight of nude mice was weighed while measuring tumor diameter. The nude mice were euthanized 25 days after administration, the tumor mass was removed by surgery and weighed, and the tumor inhibition rate (%) was calculated from the tumor mass weight. Tumor inhibition rate (%) = (model tumor weight-dosing tumor weight)/model tumor weight x 100%.

The experimental results are shown in table 5: the test agent example 26 has obvious inhibition effect on tumor growth, and the inhibition effect of the high-dose group (100 mg/kg) is superior to that of the low-dose group (25 mg/kg), and the tumor inhibition rates of the high-dose group and the low-dose group are 62.9% and 47.5%, respectively. The dosing group had no obvious effect on the body weight of the animals compared to the control group.

TABLE 5 influence of test samples on tumor growth in human prostate cancer cells Du-145 nude mice transplantable tumors

In comparison with the control group of the model, ^* P＜0.05， ^** P＜0.01， ^*** P＜0.001， ^**** P＜0.0001。

Claims

1. a2-amino-4-thiazolyl pyrimidine compound or a pharmaceutically acceptable salt thereof is characterized in that the structure of the compound is shown as a general formula (I):

；

wherein when R is ₁ Is NHR ₃ ，R ₃ Is hydrogen, C ₁ -C ₃ Alkyl, -COR ₁₄ When R is ₂ Selected from the group consisting of；

When R is ₁ Is NHR ₃ ，R ₃ is-SO ₂ R ₁₃ When R is ₂ Selected from the group consisting of、/>、/>；

When R is ₁ Is C ₁ -C ₃ In the case of alkyl radicals, R ₂ Selected from the group consisting of、/>、/>、；

When R is ₁ Is thatWhen R is ₂ Selected from->、/>、/>；

When R is ₁ Is that，R ₁₇ is-SO ₂ R ₁₈ When R is ₂ Selected from->、/>、、/>；

R ₄ Selected from hydrogen, -C ₁ -C ₃ -NR ₁₅ R ₁₆ 、C ₁ -C ₃ An alkyl group;

R ₅ selected from hydrogen, methoxy, ethoxy, n-propoxy, isopropoxy, halogen, C ₁ -C ₃ An alkyl group;

R ₆ selected from hydrogen, methoxy, ethoxy, n-propoxy, isopropoxy, halogen, C ₁ -C ₃ An alkyl group;

R ₇ selected from hydrogen, C ₁ -C ₃ An alkyl group;

x is selected from C, N;

R ₈ selected from hydrogen, methoxy, ethoxy, n-propoxy, isopropoxy, halogen, C ₁ -C ₃ An alkyl group;

R ₉ selected from hydrogen, methoxy, ethoxy, n-propoxy, isopropoxy, halogen, C ₁ -C ₃ Alkyl group,；

R ₁₀ Selected from hydrogen, methoxy, ethoxy, n-propoxy, isopropoxy, halogen, C ₁ -C ₃ An alkyl group;

R ₁₁ selected from hydrogen, methoxy, ethoxy, n-propoxy, isopropoxy, halogen, C ₁ -C ₃ An alkyl group;

R ₁₂ selected from hydrogen, C ₁ -C ₃ An alkyl group;

R ₁₃ selected from methyl, ethyl, isopropyl, n-butyl, halogenated C ₁ -C ₄ Alkyl, C ₃ -C ₈ Cycloalkyl, p-fluorophenyl;

R ₁₄ selected from C ₁ -C ₄ Alkyl, halogenated C ₁ -C ₄ Alkyl, C ₃ -C ₈ Cycloalkyl;

R ₁₅ and R is ₁₆ Are independently selected from hydrogen, C ₁ -C ₃ An alkyl group; alternatively, R _15、 R ₁₆ Together with the nitrogen atom to which it is attached；

R ₁₈ Selected from C ₁ -C ₄ Alkyl, halogenated C ₁ -C ₄ Alkyl, C ₃ -C ₈ Cycloalkyl groups.

2. The 2-amino-4-thiazolylpyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 1,

R ₅ selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ An alkyl group;

R ₆ selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ An alkyl group;

R ₈ selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ An alkyl group;

R ₉ selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ Alkyl group,；

R ₁₀ Selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ An alkyl group;

R ₁₁ selected from hydrogen, -OCH ₃ Halogen, C ₁ -C ₃ An alkyl group.

3. The 2-amino-4-thiazolylpyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 2,

R ₄ selected from-C ₁ -C ₃ -NR ₁₅ R ₁₆ ；

R ₅ Selected from hydrogen, -OCH ₃ ；

R ₆ Selected from hydrogen, halogen, C ₁ -C ₃ An alkyl group;

R ₇ selected from hydrogen, C ₁ -C ₃ An alkyl group;

R ₈ selected from hydrogen, -OCH ₃ ；

R ₉ Selected from hydrogen, halogen,；

R ₁₀ Selected from hydrogen, -OCH ₃ ；

R ₁₁ Selected from hydrogen, C ₁ -C ₃ An alkyl group;

R ₁₂ selected from C ₁ -C ₃ An alkyl group;

R ₁₃ selected from methyl, ethyl, isopropyl, n-butyl, C ₃ -C ₈ Cycloalkyl, p-fluorophenyl;

R ₁₄ selected from C ₁ -C ₄ An alkyl group;

R ₁₅ and R is ₁₆ Are respectively and independently selected from C ₁ -C ₃ An alkyl group; alternatively, R _15、 R ₁₆ Together with the nitrogen atom to which it is attachedFormation of;

R ₁₈ Selected from C ₁ -C ₄ An alkyl group.

4. The 2-amino-4-thiazolylpyrimidine compound or a pharmaceutically acceptable salt thereof according to claim 1,

R ₁ selected from NHR ₃ Methyl, isopropyl,、/>；

R ₃ Selected from hydrogen, methyl, isopropyl, -SO ₂ R ₁₃ 、-COR ₁₄ ；

R ₄ Selecting、/>、/>；

R ₅ Selected from hydrogen, -OCH ₃ ；

R ₆ Selected from hydrogen, methyl;

R ₇ selected from hydrogen, methyl, ethyl, isopropyl;

R ₈ selected from hydrogen, -OCH ₃ ；

R ₉ Selected from hydrogen, fluorine,；

R ₁₀ Selected from-OCH ₃ ；

R ₁₁ Selected from methyl;

R ₁₂ selected from methyl;

R ₁₃ selected from methyl, isopropyl, n-butyl, cyclohexyl, and p-fluorophenyl;

R ₁₄ selected from methyl groups.

5. 2-amino-4-thiazolylpyrimidine compounds or pharmaceutically acceptable salts thereof, wherein the compounds are selected from the group consisting of compounds represented by structural formulas (C-1) to (C-38):

；

。

6. a process for the preparation of a 2-amino-4-thiazolylpyrimidine compound of claim 1 or a pharmaceutically acceptable salt thereof, comprising the steps of:

；

7. The 2-amino-4-thiazolylpyrimidine compound of claim 1 to 5, wherein the pharmaceutically acceptable salt is an acid addition salt of the compound of formula (I), wherein the acid used for salifying is selected from the group consisting of inorganic acids selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids selected from the group consisting of acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid, and tartaric acid.

8. A pharmaceutical composition characterized by: a compound comprising the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof or a compound according to claim 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. Use of a 2-amino-4-thiazolylpyrimidine compound or a pharmaceutically acceptable salt thereof according to claims 1 to 5 in the manufacture of a medicament for the prevention and/or treatment of a tumor-related disease selected from lung cancer, stomach cancer, prostate cancer, ovarian cancer, testicular cancer, colon cancer, leukemia, breast cancer, multiple myeloma, liver cancer, pancreatic cancer, melanoma, glioma, brain glioma, pituitary solid tumor and hematological tumor.

10. The use according to claim 9, wherein the tumor is a malignancy of EGFR gene mutation.