N2-3-fluoro-5-substituted phenyl-2-aminopyrimidine derivative as well as preparation method and medical application thereof

Abstract

The invention discloses a compound as shown in a formula (I), a preparation method and medical application thereof, including optical isomers and pharmaceutically acceptable salts thereof. The compound has FLT3 and / or IRAK4 inhibitory activity, has proliferation inhibitory activity on various leukemia cell strains and IRAK4 related cell strains, and can be applied to preparation of drugs for resisting blood diseases, inflammation and autoimmune diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a N 2 -3-Fluoro-5-substituted phenyl-2-aminopyrimidine derivatives, optical isomers, salts and preparation methods, as well as their use as Fms-like tyrosine kinase 3 (FLT3), interleukin 1 receptor-associated kinase 4 (IRAK4) or dual-targeted FLT3 / IRAK4 inhibitors in anti-tumor, anti-inflammatory and anti-autoimmune disease drugs. Background Art

[0002] The FLT3 gene is located in the long arm of human chromosome 13, region 1, band 2 (13q12). It is about 100 kb in length and includes 24 exons, 16 of which are highly conserved with the c-KIT gene. It encodes a hematopoietic factor receptor tyrosine kinase, FLT3 kinase. FLT3 is usually expressed in early stem cells and progenitor cells to regulate cell proliferation, survival and differentiation. The FLT3 protein consists of: an extracellular domain composed of 5 immunoglobulin-like structures; a transmembrane domain (TM); a juxtamembrane domain (JM) and two intracellular tyrosine kinase domains (TKDs) connected by a kinase insert domain (KI). Under normal circumstances, the juxtamembrane domain of FLT3 has an autoinhibitory function, so in the absence of a ligand (FL), FLT3 exists as a monomer. When FL binds to the extracellular region of FLT3, FLT3 dimerizes and the tyrosine residues in the activation loop are transphosphorylated. Activated FLT3 can induce multiple intracellular signaling pathways, such as PI3K / Akt / mTOR, RAS / RAF / MEK / ERK, and STAT5, leading to the proliferation and differentiation of hematopoietic cells.

[0003] In 1996, the internal tandem duplication mutation (FLT3-ITD) of the JM coding sequence of the FLT3 gene was first demonstrated in AML cells. In 2001, missense point mutations of the D835 residue in the FLT3 kinase domain (FLT3-TKD) and point mutations, deletions, and insertion mutations of surrounding codons were discovered. FLT3-ITD mutations and FLT3-TKD mutations account for 20% and 10% of AML patients, respectively. Among the FLT3-TKD mutations, the FLT3-D835 mutation is a common target resistance mutation in clinical practice. Both FLT3-ITD and FLT3-TKD mutations can activate FLT3 and downstream signaling pathways in a ligand-independent manner, leading to the occurrence, development, and poor prognosis of AML. Currently, three FLT3 inhibitors have been approved for marketing by the FDA / Japan, and several candidate drugs are in clinical research for AML. Among them, midostaurin, a multi-kinase inhibitor developed by Novartis, was approved by the FDA in April 2017 for the treatment of adult AML patients with FLT3 mutations. Gilteritinib developed by Astellas was approved by the FDA in 2018 for the treatment of relapsed / refractory adult AML patients. Quizartinib developed by Daiichi Sankyo of Japan was also approved for marketing in Japan in 2019 for the treatment of relapsed / refractory (R / R) AML patients. Treatment with FLT3 inhibitors has greatly improved the survival and prognosis of AML patients. At the same time, domestic FLT3 inhibitors have also developed rapidly. Among them, SKLB-1028 jointly developed by Shijiazhuang Pharmaceutical and Sichuan University, crifotinib besylate developed by Guangdong East Sunshine, and HYML-122 developed by Liu Qingsong's research group have successively entered Phase II and Phase III clinical trials.

[0004] IRAK4 (interleukin 1 receptor-associated kinase 4) is a serine / threonine protein kinase associated with immunity and inflammation. It can receive signals from the upstream toll-like receptor family (TLRs) and interleukin-1 receptor family (IL-1R), activate the downstream NF-κB and JNK signaling pathways, and play an important role in human inflammatory response and tumor formation. IRAK4 is a key node in the signaling pathways of IL-1R and TLR family except TLR3, and can mediate the activation of signaling pathways such as NF-κB. When bound to ligands, TLRs and IL-1R can recruit the adapter protein MyD88. MyD88 protein interacts with the N-terminal death domain of IRAK4 and IRAK2 to promote the assembly of the multimeric helical signaling complex myddosome. The complex is composed of 6 MyD88 molecules, 4 IRAK4 molecules and 4 IRAK2 molecules. IRAK4 recruited to the myddosome complex can activate autophosphorylation and recruit IRAK1. At the same time, phosphorylation of IRAK4 promotes the recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6), which subsequently leads to the activation of the NF-κB signaling pathway and the production of proinflammatory cytokines IL-1, IL-8, IL-33 and chemokines through kinases such as TAK1 and IKKα.

[0005] Abnormal activation of IRAK4-related signaling pathways has been elucidated in a variety of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, gout, and so on. Recent studies have shown that IRAK4 also plays an important role in the pathological processes of a variety of tumors, such as macroglobulinemia, non-Hodgkin's lymphoma, large B-cell lymphoma, myelodysplastic syndrome (MDS), and AML. Especially in AML, studies have shown that IRAK4 is overexpressed in MDS / AML patients with mutations in the U2AF1 gene and SF3B1 gene, and the use of IRAK4 inhibitors can significantly inhibit the proliferation of tumor cells. At the same time, in AML cells with FLT3-ITD mutations, IRAK4-related signaling pathways are overactivated, leading to AML disease progression and relapse resistance to FLT3 inhibitors. In this case, the use of FLT3 / IRAK4 dual-target inhibitors has a significant synergistic anti-tumor effect and can overcome the resistance of FLT3i.

[0006] Based on this, targeted inhibition of IRAK4 has become an important disease treatment strategy. Currently, a number of IRAK4 inhibitors have entered the clinical research stage, including PF-06650833 developed by Pfizer, BAY-1834845 and BAY-1830839 developed by Bayer, BMS-978299 developed by Bristol-Myers Squibb, R835 developed by Rigel Pharmaceuticals, and MY004 developed by Shanghai Meiyue Company, which are in Phase I / II clinical studies for rheumatoid arthritis, systemic lupus erythematosus, and psoriasis, respectively. Multiple IRAK4 inhibitors have also entered the preclinical research stage. The candidate drug CA-4948 developed by Curis is the only IRAK4 / FLT3 inhibitor that has entered Phase II clinical studies for anti-tumor (blood tumors such as myelodysplastic syndrome and acute myeloid leukemia).

[0007] Therefore, the development of FLT3, IRAK4 or FLT3 / IRAK4 inhibitors with novel skeletons has potential application value in the treatment of tumors, inflammation and autoimmune diseases. Summary of the invention

[0008] The purpose of the present invention is to provide a class of N having FLT3 and IRAK4 inhibitory activity and anti-tumor effect 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives, which have excellent biological activity and improve the molecular diversity and novelty of the compounds; another object of the present invention is to provide such N-containing 2 -3-Fluoro-5-substituted phenyl-2-aminopyrimidine derivatives and their application.

[0009] The technical solution of the present invention is as follows:

[0010] In the first aspect, the present invention relates to a compound having a structure shown in general formula (I):

[0011]

[0012] or an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0013] in:

[0014] X is selected from (CH2) m , NR4, O, CO, R4 is selected from H, C 1-3 The alkyl group, the C 1-3 The alkyl group can be further substituted by hydroxyl or halogen;

[0015] m is selected from 0, 1, 2, and 3; when m is 0, X does not exist, and R1 is directly connected to the benzene ring;

[0016] Y is selected from NR5, O, chemical bond, R5 is selected from H, C 1-3 When Y is a chemical bond, R2 is directly connected to the pyrimidine ring;

[0017] R1 is selected from -C 1-6 Alkyl-amino, -C 0-3 Alkyl-C 3-10 Cycloalkyl, -C 0-3 Alkyl-C 3-10 Heterocycloalkyl, -C 0-3 Alkyl-C 3-10 Cycloalkyl-amino, -C 0-3 Alkyl-C 3-10 Heterocycloalkyl-amino, -C 0-3 Alkyl-C 3-10 Cycloalkyl-C 1-4 Alkyl-amino, -C 0-3 Alkyl-C 3-10 Heterocycloalkyl-C 1-4 Alkyl-amino, the alkyl, amino, cycloalkyl, heterocycloalkyl part of the above group can be further substituted by 1, 2, 3 or 4 R6 independently; and when there are multiple R6 on the same group, the multiple R6 are independent of each other and can be the same or different; wherein C 0-3 When the subscript C in the alkyl group is 0, it means "C 0-3 "alkyl" does not exist, and the remaining group to which it is attached is directly attached to X or, when X does not exist, directly attached to the benzene ring;

[0018] R6 is selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-5 Alkyl, C 1-5 Alkenyl, C 1-5 Alkynyl, -NHCO-C 1-5 Alkyl, -NHSO 2- C 1-5 Alkyl, -NHSO-C 1-5 Alkyl, -CONH-C 0-5 Alkyl, -SO2NH-C 0-5 Alkyl, -SONH-C 0-5 Alkyl, -amino-C 1-5 Alkyl-C 3-5 Heterocycloalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, -C 1-3 Alkyl-C 3-6 Heterocycloalkyl, -CO-C 1-5 Alkyl, -SO 2- C 1-5 Alkyl, -SO-C1-5 Alkyl, the C 1-5 Alkyl or C 3-5 The heterocycloalkyl moiety may be further substituted by halogen, hydroxyl or cyano; wherein when R6 is selected from -CONH-C 0-5 Alkyl, -SO2NH-C 0-5 Alkyl, -SONH-C 0-5 When C 0-5 When the C subscript of an alkyl group is 0, it means "C 0-5 "Alkyl" does not exist, and the remaining groups connected to it are -CONH2, -SO2NH2, -SONH2;

[0019] R2 is selected from C 1-6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-10 Heterocycloalkyl, the C 1-6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, C 3-10 The heterocycloalkyl group may be further substituted with hydrogen, deuterium, hydroxyl, amino, nitro, cyano, C 1-3 Alkoxy, -NHCO-C 1-3 Alkyl, -NHSO 2- C 1-3 Alkyl, -NHSO-C 1-3 Alkyl, -CO-C 1-3 Alkyl, -SO 2- C 1-3 Alkyl, -SO-C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 The heterocycloalkyl is further substituted, and the heteroatom is selected from any one or more of N, O, and S;

[0020] When R2 is a cyclohexyl group, it can be further substituted by amino, hydroxyl, -NHCO- 1-3 Alkyl, -NHSO 2- C 1-3 Alkyl, C 3-6 Heterocycloalkyl substitution;

[0021] R3 is selected from hydrogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, carboxamide, nitro, 6-10 membered monocyclic or bicyclic aromatic group, 5-10 membered monocyclic or bicyclic heterocyclic group, wherein the heterocyclic group refers to an aliphatic or aromatic monocyclic or bicyclic system, wherein the aromatic group and the heterocyclic group may be further C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3substituted with haloalkyl, halogen, hydroxyl or cyano.

[0022] As a preferred embodiment, it has the structure described by general formula (II):

[0023]

[0024] X is selected from (CH2) m , NR4, O, CO, R4 is selected from H, C 1-3 The alkyl group, the C 1-3 The alkyl group can be further substituted by hydroxyl or halogen;

[0025] m is selected from 0, 1, 2, 3;

[0026] R1 is selected from -C 1-6 Alkyl-amino, -C 0-3 Alkyl-C 3-10 Cycloalkyl, -C 0-3 Alkyl-C 3-10 Heterocycloalkyl, -C 0-3 Alkyl-C 3-10 Cycloalkyl-amino, -C 0-3 Alkyl-C 3-10 Heterocycloalkyl-amino, -C 0-3 Alkyl-C 3-10 Cycloalkyl-C 1-4 Alkyl-amino, -C 0-3 Alkyl-C 3-10 Heterocycloalkyl-C 1-4 Alkyl-amino, the alkyl, amino, cycloalkyl, heterocycloalkyl part of the above groups can be further substituted by 1, 2, 3 or 4 R6 independently; and when there are multiple R6 in the same group, the multiple R6 are independent of each other and can be the same or different;

[0027] R6 is selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-5 Alkyl, C 1-5 Alkenyl, C 1-5 Alkynyl, -NHCO-C 1-5 Alkyl, -NHSO 2- C 1-5 Alkyl, -NHSO-C 1-5 Alkyl, -CONH-C 0-5 Alkyl, -SO2NH-C 0-5 Alkyl, -SONH-C 0-5 Alkyl, -amino-C 1-5 Alkyl-C 3-5 Heterocycloalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -C 1-3 Alkyl-C 3-6Cycloalkyl, -C 1-3 Alkyl-C 3-6 Heterocycloalkyl, -CO-C 1-5 Alkyl, -SO 2- C 1-5 Alkyl, -SO-C 1-5 Alkyl, where C 1-5 Alkyl or C 3-5 The heterocycloalkyl moiety may be further substituted with halogen, hydroxy or cyano;

[0028] R3 is selected from hydrogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, carboxamide, nitro, 6-10 membered monocyclic or bicyclic aromatic group, 5-10 membered monocyclic or bicyclic heterocyclic group, wherein the heterocyclic group refers to an aliphatic or aromatic monocyclic or bicyclic system, wherein the aromatic group and the heterocyclic group may be further C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 substituted with haloalkyl, halogen, hydroxyl or cyano.

[0029] As further preferred, X is NH, O, (CH2) m , CO, m is selected from 0, 1, 2; Y is NH. Preferably, R1 is selected from any of the following structures:

[0030]

[0031]

[0032] Preferably, R3 is selected from trifluoromethyl, 6-10 membered monocyclic or bicyclic aromatic group, 5-10 membered monocyclic or bicyclic heterocyclic group, wherein aromatic group and heterocyclic group are selected from any of the following structures:

[0033] Aryl:

[0034] Heterocyclic group:

[0035]

[0036] The aromatic and heterocyclic groups can be further C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 substituted with haloalkyl, halogen, hydroxyl or cyano.

[0037] As a specific preferred embodiment, R3 is trifluoromethyl; X is NH, and Y is NH;

[0038] Right now:

[0039] In the present invention, "alkyl" and the alkyl portion of other groups (such as alkoxy, haloalkyl) can be branched or unbranched.

[0040] In the present invention, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring group, generally a 3-10 membered hydrocarbon ring group, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptatrienyl, bornyl, norpinyl, norcaryl, adamantyl, pinanyl, decahydronaphthyl, norbornyl, spiro[4.5]decyl, etc. The cycloalkyl group may be unsubstituted or substituted by one or more suitable substituents.

[0041] In the present invention, "halogen" refers to fluorine, chlorine, bromine, iodine and the corresponding hydrides.

[0042] In the present invention, "heterocycloalkyl" means that at least one carbon atom in the ring is replaced by at least one heteroatom including nitrogen, oxygen or sulfur. Heterocycloalkyl may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring group, as long as the ring group is not aromatic due to its presence.

[0043] In the present invention, "heterocyclyl" refers to an aliphatic (e.g., a fully or partially saturated heterocycle) or aromatic (e.g., heteroaryl) monocyclic or bicyclic ring system. Examples of monocyclic ring systems are any 5-membered or 6-membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. The 5-membered ring has 0-2 double bonds, and the 6-membered ring has 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazolline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include, but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, 1,4-benzodioxane, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole, indole, indolone, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, pyridopyrimidine, piperonyl, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like.

[0044] In one embodiment of the present invention, the compound of general formula (I) can be selected from the following specific compounds:

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] The numbers below the above 54 compounds are their corresponding codes. For the convenience of description and concise expression, the above codes will be directly used in the following contents of this specification.

[0051] In a second aspect, the present invention provides the above-mentioned N 2 -3-Fluoro-5-substituted phenyl-2-aminopyrimidine derivatives and pharmaceutically acceptable salts.

[0052] In one embodiment of the present invention, the pharmaceutically acceptable salt is an organic acid salt or an inorganic acid salt. The organic acid salt includes formate, acetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, mandelate, citrate, trifluoroacetate, fumarate, oxalate, malate, L-malate, D-malate, lactate, camphorsulfonate, p-toluenesulfonate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, benzoate, tartrate, L-tartrate, D-tartrate, oxalate, succinate, maleate, ascorbate, and amino acid salt. The inorganic acid salt includes hydrochloride, hydrobromide, sulfate, phosphate, nitrate, hydroiodide or perchlorate.

[0053] In a third aspect, the present invention provides the above-mentioned N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives, optical isomers, and salts are prepared by the following route:

[0054]

[0055] The method comprises: reacting compound (I-1) and compound (I-2) in the presence of Pd2(dba)3, Xant-phos and Cs2CO3 at 80°C-120°C in an organic solvent, and after the reaction is completed, treating to obtain compound I or a Boc-protected precursor of compound I, wherein the Boc-protected precursor is further treated with an acid to remove the Boc group to obtain compound I.

[0056] According to the different structures of compound (I-1) and compound (I-2), the synthesis routes can be further divided into the following:

[0057] Route 1:

[0058]

[0059] wherein R1, R2, R3, and Y are as defined in the general formula (I), and R1' is R1 or a Boc-protected precursor of R1; the preparation method comprises the following steps:

[0060] (1) a precursor compound of R1, an amine compound (such as morpholine, 1-N-Boc-cis-2,6-dimethylpiperazine, cis-2,6-dimethylmorpholine, N-Boc-piperazine, 4-Boc-aminopiperidine, 4-Boc-aminomethylpiperidine, R-3-Boc-amino-piperidine, S-3-Boc-aminopiperidine, methylpiperazine, ethylpiperazine, isopropylpiperazine, 1-(3-oxetanyl)piperazine, 4-N-Boc-4-N-methylaminopiperidine, 4-N,N-dimethylaminopiperidine, R -3-Boc-aminopyrrole, S-3-Boc-aminopyrrole, 4-methyl-4-N-Boc-aminopiperidine, hydroxyethylpiperazine, cis-1,2,6-trimethylpiperazine, N-cyclopropylmethylpiperazine, 2-methyl-1-(piperazin-1-yl)propan-2-ol, etc.) are dissolved in a mixed system of DMF / DMSO / CH3CN and water, and a corresponding base (such as potassium carbonate, sodium carbonate, cesium carbonate, triethylamine) and compound 1 are added, and the above reaction solution is reacted at 20-100° C., and after the reaction is completed, the compound 2 is obtained by treatment;

[0061] In step (1), after the reaction is completed by TLC detection, the reaction solution is extracted with ethyl acetate and washed with saturated brine, and the solvent is distilled off under reduced pressure, and silica gel column chromatography is performed to finally obtain the compound 2;

[0062] (2) Compound 2 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas (such as nitrogen), Pd2(dba)3, Xant-phos and Cs2CO3 are added, and the reaction is carried out at 80°C-120°C (such as 110°C). After the reaction is completed, the compound I or the Boc-protected precursor of the compound I is treated, wherein the Boc-protected precursor is further treated with an acid (such as trifluoroacetic acid, hydrochloric acid, sulfuric acid) to remove the Boc group to obtain the compound I.

[0063] In step (2), after the reaction is completed by TLC detection, the solvent is removed by reduced pressure distillation, and the compound I or the Boc-protected precursor of the compound I is purified by silica gel column chromatography. Route 2:

[0064]

[0065] Wherein, X=NH, O; R1, R2, R3, Y are defined as described in the general formula (I); R1' is R1 or a Boc protected precursor of R1; the preparation method comprises the following steps:

[0066] (1) When X=NH: an amine compound (such as N-methyl-4-aminopiperidine, RN-Boc-3-aminopiperidine, SN-Boc-3-aminopiperidine, RN-Boc-3-aminopyrrole, SN-Boc-3-aminopyrrole, N-Boc-4-aminopiperidine, N-Boc-4-aminomethylpiperidine, N-Boc-cis-linked diamine, N-Boc-trans-cyclohexanediamine, N,N-dimethylpropylenediamine, etc.) is dissolved in DMSO or DMF, and compound 4, an inorganic base (such as potassium carbonate, cesium carbonate) and sodium iodide / potassium iodide as a catalyst are added at 0-40°C, and the above reaction solution is reacted in a sealed tube at 80-160°C. After the reaction is completed, the compound 5 is obtained by treatment;

[0067] When X=O: dissolve an alcohol compound (N-methyl-4-piperidinol, etc.) in anhydrous DMF, add sodium hydrogen in batches at 0-10°C under the protection of an inert gas (such as nitrogen, argon), react the resulting mixture at room temperature for 1-5h, add compound 4, react the reaction solution at 70-100°C, and after the reaction is completed, treat to obtain compound 5;

[0068] In step (1), after the reaction is completed by TLC detection, the reaction solution is extracted with ethyl acetate and washed with saturated brine, and the solvent is distilled off under reduced pressure, and silica gel column chromatography is performed to finally obtain the compound 5;

[0069] (2) Compound 5 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas (such as nitrogen), Pd2(dba)3, Xant-phos and Cs2CO3 are added, and the reaction is carried out at 80°C-120°C (such as 110°C). After the reaction is completed, the compound I or the Boc-protected precursor of the compound I is treated, wherein the Boc-protected precursor is further treated with an acid (such as trifluoroacetic acid / hydrochloric acid / sulfuric acid) to remove the Boc group to obtain compound II.

[0070] In step (2), after the reaction is completed by TLC detection, the solvent is distilled off under reduced pressure, and the compound II or the Boc-protected precursor of the compound II is purified by silica gel column chromatography.

[0071] Route 3:

[0072]

[0073] Wherein, X=NH, chemical bond; R1, R2, R3, Y are defined as described in the general formula (I); R1' is R1 or a Boc protected precursor of R1; the preparation method comprises the following steps:

[0074] (2) Under the protection of inert gas, an amine compound (such as N-methyl-piperazine, N-Boc-ethylenediamine, N-Boc-propylenediamine, N-Boc-butylenediamine, N-Boc-pentanediamine, N-methyl-4-aminopiperidine, RN-Boc-3-aminopiperidine, SN-Boc-3-aminopiperidine, RN-Boc-3-aminopyrrole, SN-Boc-3-aminopyrrole, N-Boc-4-aminopiperidine, N-Boc-4-aminomethylpiperidine, N-Boc-cis-linked diamine, N-Boc-trans-cyclohexanediamine, N,N-dimethylpropylenediamine, etc.), compound 6, an inorganic base (such as cesium carbonate, potassium carbonate, sodium carbonate), palladium acetate, and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP) are dissolved in anhydrous dioxane, and the mixture is reacted at 80-120° C. After the reaction is completed, compound 7 is post-treated.

[0075] In step (1), after the reaction is completed by TLC detection, the product is filtered, the filtrate is distilled under reduced pressure to remove the solvent, and the product is subjected to silica gel column chromatography to finally obtain the compound 7;

[0076] (2) Compound 7 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas (such as nitrogen), Pd2(dba)3, Xant-phos and Cs2CO3 are added, and the reaction is carried out at 80°C-120°C (such as 110°C). After the reaction is completed, the compound I or the Boc-protected precursor of the compound I is treated, wherein the Boc-protected precursor is further treated with an acid (such as trifluoroacetic acid / hydrochloric acid / sulfuric acid) to remove the Boc group to obtain compound III.

[0077] In step (2), after the reaction is completed by TLC detection, the solvent is distilled off under reduced pressure, and the compound III or the Boc-protected precursor of the compound III is purified by silica gel column chromatography.

[0078] Route 4:

[0079]

[0080] wherein R1, R2, R3, and Y are as defined in the general formula (I), and R1' is R1 or a Boc-protected precursor of R1; the preparation method comprises the following steps:

[0081] (1) Compound 8 is dissolved in DMF, HOBt, EDCI, an amine compound (such as methylpiperazine) and DIPEA are added at 0°C (for example, an ice bath can be used), and the reaction is carried out at 20°C-50°C (for example, the reaction can be directly carried out at room temperature). After the reaction is completed, compound 9 is obtained by post-treatment;

[0082] In step (1), after the reaction is completed by TLC detection, the reaction solution is extracted with ethyl acetate and washed with saturated brine, and then the solvent is distilled off under reduced pressure and subjected to silica gel column chromatography to finally obtain the compound 9;

[0083] (2) Compound 9 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas (such as nitrogen), Pd2(dba)3, Xant-phos and Cs2CO3 are added, and the reaction is carried out at 80°C-120°C (such as 110°C). After the reaction is completed, the compound I or the Boc-protected precursor of the compound I is treated, wherein the Boc-protected precursor is further treated with an acid (such as trifluoroacetic acid / hydrochloric acid / sulfuric acid) to remove the Boc group to obtain compound IV.

[0084] In step (2), after the reaction is completed by TLC detection, the solvent is distilled off under reduced pressure, and the compound IV or the Boc-protected precursor of the compound IV is purified by silica gel column chromatography.

[0085] Specifically, the following methods can be used:

[0086] Method 1: N 2 The synthetic route of 3,-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives is as follows:

[0087]

[0088] The above N 2 The preparation method of 3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives comprises the following steps:

[0089] (1) The raw material 1 is reacted with the corresponding amine under alkaline conditions at 20-100° C. overnight to obtain the intermediate 1, the base used is any one of sodium carbonate, potassium carbonate, and cesium carbonate, and the reaction solvent is any one of CH 3 CN, DMF / H 2 O=10:1, and DMSO;

[0090] (2) Raw material 2 reacts with the corresponding amine or alcohol under alkaline conditions or hydrogen extraction reagent conditions to produce intermediate 2. When raw material 2 is an amine, the base used is any one of cesium carbonate and potassium carbonate, the reaction solvent is any one of DMF and DMSO, the catalyst is any one of sodium iodide and potassium iodide, the reaction temperature is 80-160° C., and the reaction is carried out in a sealed tube for 2-4 days; when raw material 2 is an alcohol, the hydrogen extraction reagent is any one of sodium hydride, bistrimethylaminosilyl lithium, and bistrimethylaminosilyl sodium, the reaction solvent is any one of anhydrous DMF and anhydrous THF, the reaction temperature is 60-120° C., and the reaction is carried out overnight under the protection of inert gas;

[0091] (3) The raw material 3 and the corresponding amine undergo Buchwald-Hartwig coupling reaction under inert gas protection, base, palladium and corresponding ligand catalysis to obtain intermediate 3, the base used in the reaction is any one of cesium carbonate, potassium carbonate and sodium carbonate, the solvent used is dioxane, the palladium catalyst used is palladium acetate, the ligand used is 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP), and the reaction conditions are 80-120°C;

[0092] (4) The raw material 4 reacts with the corresponding amine under the conditions of HOBt, EDCI and DIPEA at 20-60°C to obtain the intermediate 4. The reaction solvent used is any one of dichloromethane and DMF.

[0093] (5) The raw material 5 is reacted at low temperature in aqueous ammonia for 1 h to obtain the intermediate intermediate 5, the reaction solvent is acetonitrile, and the reaction temperature is an ice bath;

[0094] (6) Intermediate 5 is reacted with the corresponding amine under alkaline conditions overnight by heating to obtain intermediate 6. The reaction solvent is any one of dioxane, acetonitrile, and methanol. The base used is any one of triethylamine and DIPEA. The reaction temperature is 70-100°C.

[0095] (7) Intermediate 6 is subjected to Buchwald-Hartwig coupling with any one of intermediates 1, 2, 3, and 4 under inert gas protection and catalytic conditions of base, palladium, and corresponding ligand to directly obtain the compound of formula (1) or obtain the compound of formula (1) by removing the Boc protecting group. The solvent used for the Buchwald-Hartwig coupling is anhydrous dioxane, the base is any one of cesium carbonate, potassium carbonate, and sodium carbonate, the catalyst is any one of Pd2(dba)3 and Pd(OAc)2, the ligand is any one of Xantphos and BINAP, and the reaction temperature is 80-120°C;

[0096] (8) The raw material 6 is reacted with the corresponding amine under alkaline conditions overnight by heating to obtain the intermediate 7. The reaction solvent is any one of dioxane, acetonitrile, and methanol. The base used is any one of triethylamine and DIPEA. The reaction temperature is 70-100°C.

[0097] (9) Under the protection of inert gas, intermediate 7 is subjected to Suzuki coupling reaction with boric acid or boric ester compound under alkaline conditions with palladium catalysis to obtain intermediate 8, the base used in the reaction is any one of cesium carbonate, potassium carbonate and sodium carbonate, the palladium catalyst used is any one of tetrakis(triphenylphosphine)palladium and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, the reaction solvent is any one of dioxane / water, DMF and ethanol / water, and the reaction temperature is 70-140°C;

[0098] (10) Intermediate 8 is subjected to Buchwald-Hartwig coupling with any one of intermediates 1, 2, 3, and 4 under inert gas protection and catalytic conditions of base, palladium, and corresponding ligand to directly obtain the compound of formula (2) or obtain the compound of formula (2) by removing the Boc protecting group. The solvent used for the Buchwald-Hartwig coupling is anhydrous dioxane, the base is any one of cesium carbonate, potassium carbonate, and sodium carbonate, the catalyst is any one of Pd2(dba)3 and Pd(OAc)2, the ligand is any one of Xantphos and BINAP, and the reaction temperature is 80-120°C.

[0099] Method 2:

[0100] The compound of the present invention is dissolved in isopropanol, and an isopropanol, methanol, ethanol or ethyl acetate solution containing 1-1.5 times (1.2 times) equivalents of an organic acid or an inorganic acid is slowly added dropwise at room temperature. After the addition is completed, the reaction solution is stirred at 40-60°C overnight. After the reaction solution is cooled to room temperature, it is filtered, and the solid is washed with ether and dried to obtain the corresponding salt.

[0101] Those skilled in the art can prepare the compounds of the present invention according to actual preparation needs by using various starting compounds conventionally obtained in the art as raw materials.

[0102] In a fourth aspect, the present invention provides a method for preparing the above-mentioned N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives and their optical isomers or pharmaceutically acceptable salts thereof, the structure of which is shown below:

[0103]

[0104] In a fifth aspect, the present invention provides a composition comprising the above-mentioned N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine compounds or pharmaceutically acceptable salts thereof.

[0105] In one embodiment of the present invention, the composition comprises at least one N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, and another targeting molecule (preferably a conventional cytotoxic drug, a compound used after chemotherapy, a compound used in stem cell induction maintenance therapy, and a compound used in acute myeloid leukemia), and an optional pharmaceutically acceptable carrier.

[0106] In a sixth aspect, the present invention provides a pharmaceutical preparation for treating or preventing diseases related to FLT3, IRAK4, or FLT3 / IRAK4, and also contains auxiliary ingredients.

[0107] In one embodiment of the present invention, the pharmaceutical preparation is a tablet, capsule, powder, granule, ointment, solution, suspension, injection, inhalant, gel, microsphere or aerosol, etc. The auxiliary ingredients are cyclodextrin, arginine or meglumine. The cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, (C 1-4 Alkyl)-α-cyclodextrin, (C 1-4 Alkyl)-β-cyclodextrin, (C 1-4 Alkyl)-γ-cyclodextrin, (hydroxy-C 1-4 Alkyl)-α-cyclodextrin, (hydroxy-C 1-4 Alkyl)-β-cyclodextrin, (hydroxy-C 1-4 Alkyl)-γ-cyclodextrin, (carboxyl-C 1-4 Alkyl)-α-cyclodextrin, (carboxyl-C 1-4 Alkyl)-β-cyclodextrin, (carboxyl-C 1-4 The auxiliary components also include medically acceptable carriers, adjuvants or vehicles. Pharmaceutically acceptable pharmaceutical compositions also include ion exchangers, alumina, aluminum stearate, and egg gelatin; buffer substances include phosphates, glycine, arginine, sorbic acid, and the like.

[0108] In a seventh aspect, the present invention provides N 2 - Use of 3-fluoro-5-substituted phenyl-2-aminopyrimidine compounds or pharmaceutically acceptable salts in the preparation of drugs for preventing or treating clinical diseases related to FLT3 and / or IRAK4.

[0109] In one embodiment of the present invention, the FLT3-mediated disease is a blood disease, a solid tumor, an autoimmune disease, and a skin disease, such as psoriasis and atopic dermatitis.

[0110] In a further specific embodiment, the hematological disease is selected from acute myeloid leukemia (AML), acute T-cell leukemia, myelodysplastic syndrome, mixed lineage leukemia (MLL), cellular acute leukemia (T-ALL), B-cell acute leukemia (B-ALL), chronic myelomonocytic leukemia (CMML), chronic lymphocytic leukemia, chronic myeloid leukemia, and chronic neutrophilic leukemia.

[0111] In another embodiment of the present invention, the IRAK4-mediated disease is a hematological disease (such as non-Hodgkin's lymphoma, B-cell lymphoma, mantle cell lymphoma, myelodysplastic syndrome, plasma cell lymphoma, acute myeloid leukemia), a solid tumor, a skin disease (such as melanoma) or an inflammatory or autoimmune disease.

[0112] In a further specific embodiment, the inflammatory or autoimmune disease is selected from ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, allergic rhinitis, autoimmune hematopoietic disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and congenital thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Jones syndrome, idiopathic, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, nephropathy, glomerulopathy, alcoholic liver disease, multiple sclerosis, endocrine eye disease, Graves' disease , sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (including, for example, idiopathic nephrotic syndrome or minimal change disease), chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinal disease, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscular dystrophy, catabolism disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinence pigmenti, Paget's Ted's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, hypereosinophilia, hypersensitivity, allergic reaction, fibrositis, gastritis, gastroenteritis, sinusitis, ocular allergy, silica-induced disease, chronic obstructive pulmonary disease (COPD), cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, white viscera, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, appendicitis, allergic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, cystitis, Dacryoadenitis, dermatitis, juvenile rheumatoid arthritis, dermatomyositis, encephalitis, heart, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, Henlein-Schönlein purpura, hepatitis, suppurative hidradenitis, immunoglobulin A nephropathy, interstitial lung, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, local pneumonia, acute pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, herpetiform dermatitis, scleroderma, vitiligo,Allergic vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, cryopyrin-associated periodic syndrome (CAPS), and osteoarthritis.

[0113] In a seventh aspect, the present invention provides N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine compounds or pharmaceutically acceptable salts thereof are used alone or in combination with one or more other therapeutic agents in clinical diseases related to FLT3 and / or IRAK4. The other therapeutic agents are selected from IDH1 inhibitors, IDH2 inhibitors, BCL-2 inhibitors, hypomethylating agents, and antimetabolites.

[0114] The compound of the present invention has FLT3 and IRAK4 inhibitory activity, has proliferation inhibitory activity on various tumor cell lines, and is effective against various AML mutations such as internal tandem duplication mutations in the juxtamembrane domain and D835 point mutations in the activation loop in the kinase domain. It can overcome the drug resistance caused by clinical point mutations and can be used in the preparation of anti-tumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] Figure 1 The therapeutic effects of compounds 36 and 37 on human acute myeloid leukemia MV-4-11NU / NU mouse transplanted tumors DETAILED DESCRIPTION

[0116] Compound Preparation The present invention will be further illustrated in the following examples, which are intended only to illustrate the present invention but are not intended to limit the present invention in any way.

[0117] Preparation Example 1: N 4 -((1S,4S)-4-aminocyclohexyl)-N 2 -(3-Fluoro-5-(morpholinomethyl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 1)

[0118]

[0119] Step 1: Synthesis of 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 1-2)

[0120] Refer to patent document CN111646978A.

[0121] Step 2: Synthesis of tert-butyl ((1S, 4S)-4-((2-amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexyl)carbamate (Intermediate 1-3)

[0122] At room temperature, intermediate 1-2 (2.14 g, 10.84 mmol) was dissolved in anhydrous methanol (40 mL), and triethylamine (1.65 g, 16.26 mmol) and N-Boc-cis-cyclohexanediamine (1.91 g, 13.55 mol) were added sequentially under stirring. The reaction solution was refluxed overnight to react, and the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with PE:EA=2:1 as the eluent to obtain a white solid 1-3 (3666 mg, 90%). 1 HNMR(500MHz, CDCl3-d6)δ8.03(d,J=1.0Hz,1H),5.30(br,2H),5.01(d,J=7.0Hz,1H),4.16–4.13(m,1H),3. 64(s,1H),1.81–1.75(m,4H),1.67–1.63(m,2H),1.53–1.50(m,2H),1.44(s,9H); ESI-MS: m / z=376.2[M+H]+.

[0123] Step 3: Synthesis of 4-(3-bromo-5-fluorobenzyl)morpholine (Intermediate 1-5)

[0124] Intermediate 1-4 (1 g, 3.73 mmol) was dissolved in DMF / H2O (V DMF =10mL,V H2O =1mL) was added to a mixed system, morpholine (487mg, 5.60mmol) and potassium carbonate (1031mg, 7.46mmol) were added under stirring. The above reaction solution was reacted at 50°C overnight, extracted with ethyl acetate and water 3 times, washed with saturated brine 3 times, the organic layer was dried over anhydrous sodium sulfate, the solvent was recovered under reduced pressure to obtain a residue, and purified by silica gel column chromatography with PE:EA=10:1 as the eluent to obtain a transparent oil (971mg, 95%). 1 HNMR(500MHz, CDCl3-d6)δ7.28(s,1H),7.13(dt,J=8.0,2.0Hz,1H),7.03(d,J=9 .5Hz,1H),3.79–3.66(m,4H),3.45(s,2H),2.44(s,4H); ESI-MS:m / z=274.0[M+H] + .

[0125] Step 4: N 4 -((1S,4S)-4-aminocyclohexyl)-N 2 -(3-Fluoro-5-(morpholinomethyl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 1)

[0126] Under nitrogen protection, anhydrous dioxane (8 mL) was added to a mixture of intermediate 1-3 (200 mg, 0.53 mmol), intermediate 1-5 (175 mg, 0.64 mmol), tris(dibenzylideneacetone)dipalladium (49 mg, 0.053 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (77 mg, 0.13 mmol), and cesium carbonate (345 mg, 1.06 mmol), and the mixture was reacted at 110 ° C overnight, filtered, and the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with PE:EA=1:1 as the eluent to obtain 256 mg of a light yellow solid. It was dissolved in DCM (3 mL), and 0.8 mL of trifluoroacetic acid was added dropwise in an ice bath. The mixture was reacted at room temperature for 5 h, and the solvent was recovered by distillation under reduced pressure to obtain a yellow crude product, which was separated and purified by silica gel column chromatography with DCM: NH3 / EtOH (30:1-20:1) as eluent to obtain a white solid (190 mg, 77%). 1 HNMR(500MHz, CDCl3-d6)δ8.16(s,1H),8.02(s,1H),7.70(dt,J=11.5,2.0Hz, 1H),7.01(s,1H),6.74(d,J=9.0Hz,1H),5.26(d,J=7.0Hz,1H),4.27–4.13(m, 1H),3.70(t,J=4.0Hz,4H),3.40(s,2H),3.03–2.97(m,1H),2.43(s,4H),1.97 –1.83(m,2H),1.82–1.75(m,4H),1.51–1.40(m,2H); ESI-MS: m / z=469.2[M+H] + .

[0127] Preparation Example 2: Synthesis of compounds 8, 14-17, 19-20, 24, 26-28.

[0128] Reference Example 1 Preparation Method:

[0129] Using intermediates 1-2 and 3-fluoro-5-bromobenzyl bromide as starting materials, cyclohexylamine and 1-Boc-(2S,6R)-2,6-dimethylpiperazine were used to replace N-Boc-1,4-cis-cyclohexanediamine and morpholine, respectively. The two intermediates obtained above were subjected to Buchwald-Hartwig reaction in the presence of tri(dibenzylideneacetone)dipalladium and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene for further de-Boc removal to obtain compound 8.

[0130] Cyclopropylamine was used to replace N-Boc-1,4-cis-cyclohexanediamine, and N-Boc-piperazine, 1-Boc-(2S,6R)-2,6-dimethylpiperazine, N-Boc-4-aminopiperidine, N-Boc-4-aminomethylpiperidine, (R)-3-Boc-aminopiperidine, (S)-3-Boc-aminopiperidine, 4-N-Boc-4-N-methylaminopiperidine, (R)-3-Boc-aminopyrrolidine, (S)-3-Boc-aminopyrrolidine, 4-methyl-4-N-Boc-aminopiperidine were used to replace morpholine respectively. The two intermediates obtained above were subjected to Buchwald-Hartwig reaction under the catalysis of tri(dibenzylideneacetone)dipalladium and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, and further de-Boc was performed to obtain compounds 14-17, 19-20, 24, 26-28. The above target molecules are shown in Table 1 below.

[0131] Table 1

[0132]

[0133] Preparation Example 3: N 2 -(3-Fluoro-5-(morpholinomethyl)phenyl)-N 4 - Preparation of isopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 2)

[0134]

[0135] Step 1: N 4 -Synthesis of cyclopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Intermediate 1-6)

[0136] Refer to the preparation method of intermediate 1-3 in Example 1, except that the raw material used is cyclopropylamine, and a white solid (90%) is obtained. 1 HNMR (500MHz, DMSO-d6) δ8.22 (s, 1H), 5.40 (br, 2H), 5.29 (d, = 7.0Hz, 1H), 2.86 (s, 1H), 0.83 (d, J = 5.5Hz, 2H), 0.70 (s, 2H); ESI-MS: m / z = 219.1 [M+H] + .

[0137] Step 2: N 2 -(3-Fluoro-5-(morpholinomethyl)phenyl)-N 4 -Synthesis of cyclopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 2)

[0138] Under nitrogen protection, add intermediate 1-6 (150 mg, 0.69 mmol), intermediate 1-5 (226 mg, 0.83 mmol), tris(dibenzylideneacetone)dipalladium (63 mg, 0.069 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (10 mL), cesium carbonate (449 mg, 1.38 mmol), react at 110 ° C overnight, filter, recover the solvent under reduced pressure to obtain the residue, and purify it by silica gel column chromatography with PE:EA=2:1 as the eluent to obtain a white solid (225 mg, 80%). 1 HNMR(500MHz,DMSO-d6)δ9.89(s,1H),8.22(s,1H),7.91(d,J=12.0Hz,1H),7.62(s,1H),7.28(s,1H),6.70(d,J=9.0Hz ,1H),3.56(s,4H),3.40(s,2H),2.86(s,1H),2.33(s,4H),0.83(d,J=5.5Hz,2H),0.70(s,2H); ESI-MS: m / z=412.2[M+H] + .

[0139] Preparation Example 4: Synthesis of compounds 3-7, 9, 13, 18, 21-23, 25, 29-32.

[0140] The synthesis steps refer to Preparation Example 3, using 4-chloro-5-(trifluoromethyl)pyrimidine-2-amine as the starting material, isopropylamine is replaced by isopropylamine, cyclobutylamine, ethylamine, cyclopentylamine, cyclohexylamine, and methylamine, respectively, to synthesize the corresponding intermediates, and then tri(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene catalyzes the intermediate 1-5 to undergo Buchwald-Hartwig reaction to obtain the target compounds 3-7 and 9.

[0141] Using 3-fluoro-5-bromobenzyl bromide as the starting material, cis-2,6-dimethylmorpholine, N-methyl-piperazine, N-ethyl-piperazine, N-isopropyl-piperazine, 1-(3-oxetanyl)piperazine, 4-N,N-dimethylaminopiperidine, hydroxyethylpiperazine, cis-1,2,6-trimethylpiperazine, N-cyclopropylmethylpiperazine, 2-methyl-1-(piperazin-1-yl)propan-2-ol were used to replace morpholine, and the intermediates obtained above were subjected to Buchwald-Hartwig reaction with intermediates 1-6 under the catalysis of tris(dibenzylideneacetone)dipalladium and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene, and finally compounds 13, 18, 21-23, 25, 29-32 were obtained respectively. The above target molecules are shown in Table 2 below

[0142] Table 2

[0143]

[0144]

[0145]

[0146] Preparation Example 5: N 4 -((1S,4S)-4-aminocyclohexyl)-5-(benzo[d]thiazol-6-yl)-N 2 Preparation of -(3-fluoro-5-(morpholinomethyl)phenyl)pyrimidine-2,4-diamine (Compound 10)

[0147]

[0148] Step 1: Synthesis of tert-butyl (1S,4S)-4-((2-amino-5-bromopyrimidin-4-yl)amino)cyclohexyl)carbamate (Intermediate 1-8).

[0149] Refer to the synthesis of intermediate 1-3 in Preparation Example 1, except that the raw material used is 5-bromo-4-chloro-pyrimidin-2-amine, and a white solid (83.5%) is obtained. 1 HNMR(500MHz, CDCl3-d6)δ7.86(s,1H),.16(d,J=7.5Hz,1H),4.75(s,2H),4.61(s,1H),4.13–3.99 (m,1H),3.66(s,1H),1.85–1.76(m,4H),1.67–1.55(m,4H),1.45(s,9H); ESI-MS: m / z=386.1[M+H] + .

[0150] Step 2: Synthesis of 6-benzothiazole pinacol boronate (Intermediate 1-10).

[0151] Under nitrogen protection, DMF (10 mL) was added to a mixture of raw material 1-9 (300 mg, 1.40 mmol), bipyraclostrobin (538 mg, 2.10 mmol), potassium acetate (481 mg, 4.90 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (102 mg, 0.140 mmol). The mixture was reacted at 100 ° C overnight and cooled to room temperature. Water and ethyl acetate were added to the reaction solution and extracted 3-4 times. The organic layer was washed with saturated brine, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography with PE:EA=2:1 as the eluent to obtain a white solid (183 mg, 50%). 1HNMR(500MHz, CDCl3-d6)δ9.05(s,1H),8.45(s,1H),8.13(d,J=8.0Hz,1H),7.93(dd,J=8.5,1.0Hz,1H),1.37(s,12H); ESI-MS: m / z=262.1[M+H] + .

[0152] Step 3: Synthesis of tert-butyl ((1S,4S)-4-((2-amino-5-(benzo[d]thiazol-6-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate (Intermediate 1-11)

[0153] Under nitrogen protection, dioxane (6 mL) and water (4 mL) were added to a mixture of intermediate 1-10 (200 mg, 0.52 mmol), intermediate 1-8 (176 mg, 0.68 mmol), cesium carbonate (337 mg, 1.04 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (38 mg, 0.052 mmol), and the mixture was reacted at 100 ° C overnight, cooled to room temperature, filtered, and the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with PE:EA=1:1 as the eluent to obtain a light yellow solid (134 mg, 59%). 1 HNMR (500MHz, CDCl3-d6) δ9.04(s,1H),8.20(d,J=8.0Hz,1H),7.90(d,J=1.5Hz,1H),7.74(s,1H),7.48(dd,J=8.5,1.5Hz,1H),4.93( s,2H),4.87(d,J=7.5Hz,1H),4.11(s,1H),3.62(s,1H),1.85–1.68(m,4H),1.55–1.44(m,4H),1.41(s,9H); ESI-MS: m / z=441.2[M+H] + .

[0154] Step 4: N 4 -((1S,4S)-4-aminocyclohexyl)-5-(benzo[d]thiazol-6-yl)-N 2 Synthesis of -(3-fluoro-5-(morpholinomethyl)phenyl)pyrimidine-2,4-diamine (Compound 10)

[0155] Under nitrogen protection, to a mixture of intermediate 1-11 (120 mg, 0.27 mmol), intermediate 1-5 (90 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (25 mg, 0.027 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (39 mg, 0.068 mmol), cesium carbonate (177 mg, 0.55 mmol) was added anhydrous dioxane (6 mL), and the mixture was reacted at 110 ° C overnight, filtered, and the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with PE:EA=1:1 as the eluent to obtain 112 mg of a light yellow solid. It was dissolved in DCM (2 mL), and 0.5 mL of trifluoroacetic acid was added dropwise in an ice bath. The mixture was reacted at room temperature for 5 h, and the solvent was recovered by distillation under reduced pressure to obtain a yellow crude product, which was separated and purified by silica gel column chromatography with DCM: NH3 / EtOH (30:1-20:1) as eluent to obtain a white solid (70 mg, 48%). 1 HNMR(500MHz,MeOD-d4)δ9.09(s,1H),8.17(d,J=8.5Hz,1H),7.96(t,J=1.5Hz, 1H),7.80(t,J=1.5Hz,1H),7.78(s,1H),7.53(dd,J=7.5,1.5Hz,1H),7.07(s,1 H),6.68(d,J=9.0Hz,1H),3.75–3.60(m,5H),3.44(d,J=6.0Hz,2H),2.92(s,1H ),2.45(s,4H),1.84–1.65(m,6H),1.40–1.27(m,2H); ESI-MS:m / z=534.2[M+H] + .

[0156] Preparation Example 6: 5-(Benzo[d]thiazol-6-yl)-N 4 -cyclohexyl-N 2 Preparation of -(3-fluoro-5-(morpholinomethyl)phenyl)pyrimidine-2,4-diamine (Compound 11)

[0157]

[0158] Step 1: 5-Bromo-N 4 -Synthesis of Cyclohexylpyrimidine-2,4-diamine (Intermediate 1-12)

[0159] At room temperature, intermediate 1-7 (500 mg, 2.40 mmol) was dissolved in anhydrous methanol (5 mL), and triethylamine (364 mg, 3.60 mmol) and cyclohexylamine (286 mg, 2.88 mol) were added sequentially under stirring. The above reaction solution was refluxed overnight to react, and the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with PE:EA=2:1 as the eluent to obtain a white solid 1-12 (520 mg, 80%) 1 HNMR(500MHz, CDCl3-d6)δ7.85(s,1H),5.05(d,J=6.0Hz,1H),4.74(s,2H),3.95–3.88(m,1H),2.03–1.94(m ,2H),1.79–1.70(m,2H),1.69–1.60(m,1H),1.46–1.35(m,2H),1.25–1.17(m,3H); ESI-MS:m / z=271.1[M+H] + .

[0160] Step 2: 5-(Benzo[d]thiazol-6-yl)-N 4 -Synthesis of Cyclohexylpyrimidine-2,4-diamine (Intermediate 1-13)

[0161] Refer to the synthesis of intermediate 1-11 in Example 5, except that the raw material used is intermediate 1-12, and a white solid (85%) is obtained. 1 HNMR (500MHz, CDCl3-d6) δ9.03 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 1. 5Hz,1H),7.72(s,1H),7.48(dd,J=8.5,1.5Hz,1H),4.91(s,2H),4.78(d,J= 8.0Hz,1H),4.04–3.94(m,1H),1.99–1.96(m,2H),1.70–1.66(m,2H),1.63– 1.59(m,1H),1.43–1.33(m,2H),1.19–1.03(m,3H); ESI-MS:m / z=326.1[M+H] + .

[0162] Step 3: 5-(Benzo[d]thiazol-6-yl)-N 4 -cyclohexyl-N 2 Synthesis of -(3-fluoro-5-(morpholinomethyl)phenyl)pyrimidine-2,4-diamine (Compound 11)

[0163] Under nitrogen protection, to a mixture of intermediate 1-13 (150 mg, 0.46 mmol), intermediate 1-5 (152 mg, 0.55 mmol), tris(dibenzylideneacetone)dipalladium (42 mg, 0.046 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (67 mg, 0.012 mmol), cesium carbonate (300 mg, 0.92 mmol) was added anhydrous dioxane (6 mL), and the mixture was reacted at 110 ° C overnight, filtered, and the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with DCM:CH3OH=40:1 as the eluent to obtain a white solid (150 mg, 63%). 1 HNMR(500MHz, CDCl3-d6)δ9.05(s,1H),8.22(d,J=8.5Hz,1H),8.08(dt,J=12.0,2.0Hz,1H),7.91 (d,J=1.0Hz,1H),7.90–7.81(m,2H),7.50(dd,J=8.5,1.5Hz,1H),7.03(s,1H),6.71(d,J=9.0Hz,1 H),4.94(d,J=7.5Hz,1H),4.13–3.95(m,1H),3.71(t,J=4.5Hz,4H),3.46(s,2H),2.46(s,4H),2.0 9–2.06(m,2H),1.80–1.55(m,3H),1.50–1.42(m,2H),1.26–0.96(m,2H); ESI-MS:m / z=519.2[M+H] + .

[0164] Preparation Example 7: Synthesis of Compound 12

[0165] The synthesis steps refer to Preparation Example 6, using 5-bromo-4-chloro-pyrimidine-2-amine as the starting material, and cyclopropylamine instead of cyclohexylamine to synthesize the corresponding intermediate, and then tri(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene catalyzed by Buchwald-Hartwig reaction with intermediate 1-5 to obtain the target compound 12. The above target molecule is shown in Table 3 below.

[0166] Table 3

[0167]

[0168] Preparation Example 8: N 4 -Cyclopropyl-N 2 Preparation of -(3-fluoro-5-((1-methylpiperidin-4-yl)oxy)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 33)

[0169]

[0170] Step 1: Synthesis of 4-(3-bromo-5-fluorophenoxy)-1-methylpiperidine (Intermediate 1-15)

[0171] Under nitrogen protection, 1-methyl-4-piperidinol (810 mg, 6.22 mmol) was dissolved in 25 mL of anhydrous DMF. 60% sodium hydrogen (300 mg, 7.77 mmol) was added to the reaction solution in batches under ice bath conditions. After the reaction solution was reacted at room temperature for 30 minutes, 1-bromo-3,5-difluorobenzene (1 g, 5.18 mmol) was added under ice bath conditions. The reaction solution was reacted at 80°C overnight to obtain a light yellow oil (1151 mg, 77%). 1 HNMR (500MHz, CDCl3-d6) δ6.84(s,1H),6.81(dt,J=8.0,2.0Hz,1H),6.54(dt,J=10.5,2.0Hz,1H),4. 26(s,1H),2.69(br,2H),2.29(s,5H),2.02–1.92(m,2H),1.88–1.74(m,2H); ESI-MS:m / z=288.0[M+H] + .

[0172] Step 2: N 4 -Cyclopropyl-N 2 Synthesis of -(3-fluoro-5-((1-methylpiperidin-4-yl)oxy)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 33)

[0173] Under nitrogen protection, to a mixture of intermediate 1-6 (200 g, 0.92 mmol), intermediate 1-15 (317 mg, 1.10 mmol), tris(dibenzylideneacetone)dipalladium (84 mg, 0.092 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (133 mg, 0.23 mmol), cesium carbonate (596 mg, 1.83 mmol) was added anhydrous dioxane (8 mL), reacted at 110 ° C overnight, filtered, and the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with DCM:CH3OH=20:1 as the eluent to obtain a white solid (220 mg, 56%). 1HNMR(500MHz, CDCl3-d6)δ8.17(d,J=1.0Hz,1H),7.59(s,1H),7.47(d,J=11.5 Hz,1H),6.94(t,J=2.5Hz,1H),6.31(dt,J=10.5,2.5Hz,1H),5.44(s,1H),4.2 7(s,1H),2.91–2.86(m,1H),2.65(s,2H),2.30(s,5H),2.02–1.96(m,2H),1.8 7–1.80(m,2H),1.06–0.90(m,2H),0.74–0.56(m,2H); ESI-MS:m / z=426.2[M+H] + .

[0174] Preparation Example 9: Preparation of 3-((4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-fluorophenyl)(4-methylpiperazin-1-yl)methanone (Compound 34)

[0175]

[0176] Step 1: Synthesis of (3-bromo-5-fluorophenyl)(4-methylpiperazin-1-yl)methanone (Intermediate 1-17)

[0177] 3,5-Difluorobenzoic acid (300 mg, 1.37 mmol) was dissolved in 6 mL DMF, and N-methylpiperazine (169 mg, 1.68 mmol), HOBt (227 mg, 1.68 mmol), EDCI (322 mg, 1.68 mmol) and DIPEA (443 mg, 3.43 mmol) were added under ice bath. After the reaction solution was reacted at room temperature overnight, water and ethyl acetate were added to the reaction solution for extraction 3-4 times, and the organic layer was washed with saturated brine 2-3 times. The solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with PE:EA=2:1 as the eluent to obtain a white solid (200 mg, 48%). 1 HNMR(500MHz, CDCl3-d6)δ7.32(t,J=1.5Hz,1H),7.31–7.28(m,1H),7.06–7.04(m,1H),3 .77(s,2H),3.41(s,2H),2.48(s,2H),2.36(s,2H),2.33(s,3H); ESI-MS: m / z=301.0[M+H] + .

[0178] Step 2: Synthesis of 3-((4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-fluorophenyl)(4-methylpiperazin-1-yl)methanone (Compound 34)

[0179] Refer to Example 8 for the synthesis of compound 33, except that the starting material used was intermediate 1-17, to obtain a white solid (60%). 1 HNMR (500MHz, CDCl3-d6) δ8.17(s,1H),8.05(d,J=11.5Hz,1H),7.54(s,1H),7.31(s,1H),6.74(d,J=8.0Hz,1H),5.47(s,1H),3.80(s, 2H),3.47(s,2H),2.86(d,J=8.0Hz,1H),2.50(s,2H),2.36(s,5H),0.96(d,J=6.5Hz,2H),0.67–0.61(m,2H); ESI-MS: m / z=439.2[M+H] + .

[0180] Preparation Example 10: N 4 -Cyclopropyl-N 2 Preparation of -(3-fluoro-5-(4-methylpiperazin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 35)

[0181]

[0182] Step 1: Preparation of 1-(3-bromo-5-fluorophenyl)-4-methylpiperazine (Intermediate 1-19)

[0183] Under nitrogen protection, anhydrous dioxane (4 mL) was added to a mixture of the intermediate N-methylpiperazine (100 g, 1.0 mmol), 1,3-dibromo-5-fluorobenzene (302 mg, 1.2 mmol), palladium acetate (22 mg, 0.1 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (124 mg, 0.2 mmol) and cesium carbonate (650 mg, 2.0 mmol), and the mixture was reacted at 110°C overnight, filtered, and the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with DCM:CH3OH=20:1 as the eluent to obtain a white solid (200 mg, 74%).

[0184] 1 HNMR(500MHz, CDCl3-d6)δ6.79(s,1H),6.67(dt,J=8.0,2.0Hz,1H),6.49(dt,

[0185] J=12.0,2.0Hz,1H),3.20(t,J=5.0Hz,4H),2.53(t,J=5.0Hz,4H),2.34(s,3H);

[0186] ESI-MS: m / z = 273.0 [M+H] + .

[0187] Step 2: N 4 -Cyclopropyl-N 2 Synthesis of -(3-fluoro-5-(4-methylpiperazin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 35)

[0188] Refer to Example 8 for the synthesis of compound 33, except that the starting material used was intermediate 1-19, to obtain a white solid (71%). 1 HNMR (500MHz, CDCl3-d6) δ8.18(s,1H),7.93(s,1H),7.62(s,1H),6.58(s,1H),6.31(d,J=11.5Hz,1H),5.41(s,1H),3.19(t,J=5.0Hz,4 H),2.89(dd,J=6.5,3.5Hz,1H),2.54(t,J=5.0Hz,4H),2.34(s,3H),0.95(d,J=6.5Hz,2H),0.76–0.53(m,2H); ESI-MS: m / z=411.2[M+H] + .

[0189] Preparation Example 11: N 4 -Cyclopropyl-N 2 Preparation of -(3-fluoro-5-((1-methylpiperidin-4-yl)amino)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 36)

[0190]

[0191] Step 1: Synthesis of N-(3-bromo-5-fluorophenyl)-1-methylpiperidin-4-amine (Intermediate 1-21)

[0192] N-methyl-4-aminopiperidine (1g, 8.8mmol), 1-bromo-3,5-difluorobenzene (2.54g, 13.1mmol), cesium carbonate (5.7g, 17.5mmol) and sodium iodide (0.66g, 4.4mmol) were dissolved in 15mL of DMSO, and the mixture was reacted at 120°C in a sealed tube for 3d. The reaction solution was cooled to room temperature, and water and ethyl acetate were added to the reaction solution for extraction 3-4 times. The organic layer was washed with saturated brine 2-3 times, and the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with DCM:CH3OH=25:1 as the eluent to obtain a yellow oil (1806mg, 72%). 1 HNMR (500MHz, CDCl3-d6) δ6.52(dt,J=8.0,2.0Hz,1H),6.48(s,1H),6.19(dt,J=11.5,2.0Hz,1H),3.74(d,J=7.0Hz,1H),3.2 5–3.17(m,1H),2.81(s,2H),2.31(s,3H),2.19–2.08(m,2H),2.06–1.99(m,2H),1.56–1.44(m,2H); ESI-MS: m / z=287.1[M+H] + .

[0193] Step 2: N 4 -Cyclopropyl-N 2 Synthesis of -(3-fluoro-5-((1-methylpiperidin-4-yl)amino)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 36)

[0194] Refer to Example 8 for the synthesis of compound 33, except that the starting material used was intermediate 1-21, to obtain a white solid (70%). 1 HNMR (500MHz, CDCl3-d6) δ8.15(s,1H),7.61(s,1H),7.38(s,1H),6.33(s,1H),6.01(dt,J=11.0,2.5Hz,1H),5.40(s,1H),3.63(d,J=8.5Hz, 1H),3.21(q,J=9.5Hz,1H),2.90–2.85(m,1H),2.85–2.72(m,2H),2.3 0(s,3H),2.14–1.98(m,4H),1.53–1.41(m,2H),0.95–0.91(m,2H),0.6 9–0.59(m,2H); ESI-MS:m / z=425.2[M+H] + .

[0195] Preparation Example 12: (S)-N 4-Cyclopropyl-N 2 Preparation of -(3-fluoro-5-(piperidin-3-ylamino)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 37)

[0196]

[0197] Step 1: Synthesis of (R)-tert-butyl 3-((3-bromo-5-fluorophenyl)amino)piperidine-1-carboxylate (Intermediate 1-22)

[0198] Refer to Example 11 for the synthesis of intermediate 1-21, except that the starting material is RN-Boc-3-aminopiperidine to obtain a white solid (50%). 1 HNMR (500MHz, CDCl3-d6) δ6.55(dt,J=8.0,1.5Hz,1H),6.52(d,J=1.5Hz,1H),6.24(dt,J=11.5,2.5Hz,1H),3.89(dd,J=13.0,3.5Hz,1H),3.67(s ,1H),3.32(s,1H),3.14(s,1H),2.97(t,J=10.5Hz,1H),1.96(s,1H),1.7 8–1.68(m,1H),1.58–1.52(m,2H),1.46(s,9H); ESI-MS: m / z=373.1[M+H] + .

[0199] Step 2: (R)-N 4 -Cyclopropyl-N 2 Synthesis of -(3-fluoro-5-(piperidin-3-ylamino)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 37)

[0200] The synthesis of compound 1 in the preparation example was referred to, except that the raw materials used were 1-6 and 1-22, to obtain a white solid (60%). 1HNMR(500MHz, CDCl3-d6)δ8.15(d,J=1.0Hz,1H),7.35(s,1H),7.24(br,1H),6.38(s,1H),6. 03(dt,J=11.5,2.0Hz,1H),5.38(s,1H),4.06(s,1H),3.39(s,1H),3.17(dd,J=11.5,3.5Hz,1 H),2.94–2.83(m,2H),2.74–2.70(m,1H),2.58(dd,J=11.5,7.0Hz,1H),1.88(s,1H),1.76–1. 69(m,1H),1.54–1.50(m,2H),1.05–0.90(m,2H),0.70–0.53(m,2H); ESI-MS: m / z=411.2[M+H] + .

[0201] Preparation Example 13: Synthesis of Compounds 38-42, 44-45, 48

[0202] The synthesis steps refer to Preparation Example 12, with 1-bromo-3,5-difluorobenzene as the starting material, (S)-N-Boc-3-aminopiperidine, (S)-N-Boc-3-aminopyrrolidine, (R)-N-Boc-3-aminopyrrolidine, N-Boc-4-aminomethylpiperidine, N-Boc-4-aminopiperidine, N-Boc-cis-cyclohexanediamine, N-Boc-trans-cyclohexanediamine, and N,N-dimethyl-propylenediamine are used to replace (R)-N-Boc-3-aminopiperidine to synthesize the corresponding intermediates, and then tris(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene catalyzes the reaction with the intermediate 1-6 to undergo Buchwald-Hartwig reaction, and the obtained compounds are further de-Boc-grouped by trifluoroacetic acid to obtain target compounds 38-42, 44-45, 48. The above target molecules are shown in Table 4 below.

[0203] Table 4

[0204]

[0205] Preparation Example 14: N 2 -(3-((3-aminopropyl)amino)-5-fluorophenyl)-N 4 - Preparation of cyclopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 43)

[0206]

[0207] Step 1: Synthesis of tert-butyl (3-((3-bromo-5-fluorophenyl)amino)propyl)carbamate (Intermediate 1-23)

[0208] Refer to the synthesis of intermediate 1-19 in Preparation Example 10, except that the raw material used is N-Boc-propylenediamine, and a light yellow oil (41%) is obtained. 1 HNMR(500MHz, CDCl3-d6)δ6.53(dt,J=8.0,1.5Hz,1H),6.51(d,J=1.5Hz,1H),6.22(dt,J=11.5,2.5Hz,1H) ,3.13(t,J=7.0Hz,2H),2.78(t,J=7.0Hz,2H),1.79(t,J=7.0Hz,2H),1.44(s,9H); ESI-MS: m / z=347.1[M+H] + .

[0209] Step 2: N 2 -(3-((3-aminopropyl)amino)-5-fluorophenyl)-N 4 -Synthesis of cyclopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 43)

[0210] Refer to the synthesis of compound 1 in Preparation Example 1, except that the raw materials used are 1-6 and 1-23, to obtain a white solid (63%). 1 HNMR(500MHz,Methanol-d4)δ8.10(s,1H),7.39(d,J=11.5Hz,1H),6.60–6.36(m,1H),6.03(dt,J=11.5,2.0Hz,1H),3.12(t,J=7.0Hz ,2H),2.88–2.83(m,1H),2.75(t,J=7.0Hz,2H),1.77(t,J=7.0Hz,2H),1.01–0.78(m,2H),0.67–0.63(m,2H); ESI-MS: m / z=385.2[M+H] + .

[0211] Preparation Example 15: Synthesis of Compounds 46 and 47

[0212] The synthesis steps refer to Preparation Example 14, using 1,3-dibromo-5-fluorobenzene as the starting material, N-Boc-butylenediamine and N-Boc-pentanediamine are used to replace N-Boc-propylenediamine, respectively, to synthesize the corresponding intermediates, and then tri(dibenzylideneacetone)dipalladium and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene catalyze the intermediates 1-6 to undergo Buchwald-Hartwig reaction, and the resulting compounds are further subjected to trifluoroacetic acid to remove the Boc group to obtain target compounds 46-47. The above target molecules are shown in Table 5 below.

[0213] Table 5

[0214]

[0215]

[0216] Preparation Example 16: (R)-N 2 -(3-Fluoro-5-(piperidin-3-ylamino)phenyl)-N 4 Preparation of -isopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 49)

[0217]

[0218] Step 1: N 4 -Synthesis of isopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Intermediate 1-24)

[0219] Refer to the preparation method of intermediate 1-6 in Example 3, except that the raw material used isopropylamine to obtain a white solid (95%). 1 HNMR(500MHz,DMSO-d6)δ8.22(s,1H),5.40(br,2H),5.29(d,J=7.0Hz,1H),3.25–3.11(m,1H),1.30(d,J=6.5Hz,6H); ESI-MS:m / z=221.1[M+H] + .

[0220] Step 2: (R)-N 2 -(3-Fluoro-5-(piperidin-3-ylamino)phenyl)-N 4 -Synthesis of isopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 49)

[0221] The synthesis of compound 1 in Preparation Example 1 was referred to, except that the starting materials used were 1-24 and 1-22, to obtain a white solid (65%). 1HNMR(500MHz, CDCl3-d6)δ8.13(s,1H),7.46(s,1H),6.96(d,J=11.5Hz,1H),6.45(s,1H),6.03(d t,J=11.0,2.0Hz,1H),4.95(d,J=6.5Hz,1H),4.50–4.32(m,1H),4.07(br,1H),3.38(s,1H),3.23– 3.09(m,1H),2.92–2.79(m,1H),2.74–2.70(m,1H),2.60–2.56(m,1H),1.90–1.81(m,1H),1.75–1 .70(m,1H),1.63–1.58(m,1H),1.53–1.49(m,1H),1.29(d,J=6.5Hz,6H); ESI-MS:m / z=413.2[M+H] + .

[0222] Preparation Example 17: Synthesis of Compound 50

[0223] The synthesis steps refer to Preparation Example 16, using 4-chloro-5-(trifluoromethyl)pyrimidine-2-amine as the starting material, replacing isopropylamine with cyclobutylamine to obtain the corresponding intermediate, and then undergoing Buchwald-Hartwig reaction with intermediate 1-22 in the presence of tri(dibenzylideneacetone)dipalladium and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene as the catalyzer, the obtained compound is further subjected to trifluoroacetic acid to remove the Boc group to obtain the target compound 50, and the above target molecule is shown in Table 6 below.

[0224] Table 6

[0225]

[0226]

[0227] Preparation Example 18: (R)-N 4 -Cyclopropyl-N 2 Preparation of -(3-fluoro-5-(piperidin-3-ylamino)phenyl)-5-(furan-3-yl)pyrimidine-2,4-diamine (Compound 51)

[0228]

[0229] Step 1: 5-Bromo-N 4 -Synthesis of cyclopropylpyrimidine-2,4-diamine (Intermediate 1-25)

[0230] The synthesis procedure refers to the synthesis of intermediate 1-12 in Preparation Example 6, except that the raw material used is cyclopropylamine, and a white solid (90%) is obtained. 1HNMR(500MHz,DMSO-d6)δ7.77(s,1H),6.54(d,J=3.5Hz,1H),6.24(s,2H),2.79(td ,J=7.5,3.5Hz,1H),0.70–0.62(m,2H),0.60–0.58(m,2H); ESI-MS:m / z=229.0[M+H] + .

[0231] Step 2: N 4 -Cyclopropyl-5-(furan-3-yl)pyrimidine-2,4-diamine (Intermediate 1-26) Synthesis Under nitrogen protection, dioxane (6 mL) and water (1.5 mL) were added to a mixture of intermediate 1-25 (200 mg, 0.87 mmol), 3-furanboric acid (127 mg, 1.13 mmol), cesium carbonate (567 mg, 1.75 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (64 mg, 0.087 mmol), and the mixture was reacted at 100 ° C overnight, cooled to room temperature, filtered, and the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with PE:EA=2:1 as the eluent to obtain a light yellow solid (113 mg, 60%). 1 HNMR(500MHz,DMSO-d6)δ7.78–7.75(m,1H),7.72(d,J=2.0Hz,1H),7.69(s,1H),6.63(d,J=2.0Hz,1H),6.10(s,2H) ,5.95(d,J=3.5Hz,1H),2.80(td,J=7.5,3.5Hz,1H),0.65–0.62(m,2H),0.55–0.52(m,2H); ESI-MS:m / z=217.1[M+H] + .

[0232] Step 3: (R)-N 4 -Cyclopropyl-N 2 Synthesis of -(3-fluoro-5-(piperidin-3-ylamino)phenyl)-5-(furan-3-yl)pyrimidine-2,4-diamine (Compound 51)

[0233] Refer to the synthesis of compound 1 in Preparation Example 1, except that the starting materials used are 1-26 and 1-22, to obtain a white solid (45%). 1HNMR (500MHz, CDCl3-d6) δ7.85(s,1H),7.53(t,J=1.5Hz,1H),7.49(s,1H),7.38(d,J=11.5Hz,1H),7.11(s ,1H),6.48–6.46(m,1H),6.45(s,1H),5.99(dt,J=11.5,2.0Hz,1H),5.24(s,1H),4.01(s,1H),3.39(s,1H) ,3.19(d,J=11.5Hz,1H),2.89–2.82(m,2H),2.76–2.64(m,1H),2.57(dd,J=11.0,7.5Hz,1H),1.95–1.88(m ,1H),1.76–1.71(m,1H),1.52–1.43(m,1H),0.95–0.84(m,2H),0.61–0.53(m,2H); ESI-MS:m / z=409.2[M+H] + .

[0234] Preparation Example 19: Synthesis of Compounds 52-54

[0235] Synthesis steps: Refer to Preparation Example 18, using 5-bromo-N 4 -cyclopropylpyrimidine-2,4-diamine was used as the starting material, 1-methyl-1H-pyrazole-4-boric acid, phenylboric acid and pyridine-4-boric acid were used to replace 3-furanboric acid to obtain the corresponding intermediates, and then tri(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene catalyzed the Buchwald-Hartwig reaction with the intermediate 1-22, and the obtained compounds were further subjected to trifluoroacetic acid to remove the Boc group to obtain the target compounds 52-54. The above target molecules are shown in Table 7 below.

[0236] Table 7

[0237]

[0238] Preparation Example 20: N 4 -Cyclopropyl-N 2 -(3-Fluoro-5-((1-methylpiperidin-4-yl)amino)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine salt compound (55-68)

[0239]

[0240] Compound 36 was dissolved in isopropanol, and an isopropanol / methanol / ethanol / ethyl acetate solution containing 1.2 times the equivalent of an organic acid or an inorganic acid was slowly added dropwise at room temperature. After the addition was completed, the reaction solution was stirred at 40°C overnight. After the above reaction solution was cooled to room temperature, it was filtered, the solid was washed with ether, and dried to obtain the corresponding salts (55, citrate of compound 36; 56, hemifumarate of compound 36; 57, malate of compound 36; 58, L-malate of compound 36; 59, D-malate of compound 36; 60, methanesulfonate of compound 36; 61, L-tartrate of compound 36; 62, D-tartrate of compound 36; 63, succinate of compound 36; 64, maleate of compound 36; 65, formate of compound 36; 66, acetate of compound 36; 67, hydrochloride of compound 36; 68, phosphate of compound 36), and the above target molecules are described in the following table.

[0241] Table 8

[0242]

[0243] Preparation Example 21: Preparation of Compounds 69-82

[0244] The synthesis steps refer to Preparation Example 20, using compound 37 as the starting material and reacting with different acids in corresponding solvents to obtain compounds 69-82. The target molecules are described in the following table.

[0245] Table 9

[0246]

[0247] Biological Activity Assay Part Example 22. Kinase Activity Test The inhibitory activity of the compounds provided by the present invention on FLT3, FLT3-D835Y and IRAK4 kinases was tested.

[0248] Instrument: Envision ELISA reader TM (PerkinElmer, USA).

[0249] Materials: Human recombinant FLT3, purchased from CarnaBiosciences, GST-fused FLT3 protein (aa564-993), FLT3 activity detection kit KinEASE TM TK, purchased from Cisbio; human recombinant FLT3-D835Y, purchased from Eurofins, GST-fused FLT3 protein fragment (containing D835Y mutation) (aa564-end), FLT3-D835Y activity detection kit KinEASE TMTK was purchased from Cisbio; human recombinant IRAK4 was purchased from Yiqiao Shenzhou, and the IRAK4 protein fragment fused with GST (Met1-Ser460) was obtained.

[0250] Sample processing: Dissolve in DMSO and store at low temperature. The concentration of DMSO in the final system is controlled within the range that does not affect the detection activity.

[0251] Experimental steps: FLT3, FLT3-D835Y and substrate (specific biotin-labeled polypeptide TKSubstrate) were diluted with HTRF kinase buffer solution (1.25XKinasebuffer, 6.25mM MgCl2, 1.25mM MnCl2, 1.25mM DTT), and IRAK4 and substrate were diluted with HTRF kinase buffer solution (1XKinasebuffer, 5mM MgCl2, 1mM MnCl2, 1mM DTT). 4 μL enzyme, 4 μL substrate and 2 μL of different concentrations of the test compound were added to the 384 reaction plate (ProxiPlateTM-384Plus, PerkinElmer). The specific reaction system was FLT3: 2% DMSO, 0.5 ng / μL FLT3, 1 μM TK-S, 2 μM ATP; FLT3-D835Y: 2% DMSO, 0.4 ng / μL FLT3-D835Y, 1 μM TK-S, 1 μM ATP; IRAK4: 2% DMSO, 2 ng / μL IRAK4, 1 μM TK-S, 100 μM ATP. After incubation at room temperature for 1 hour, the antibody was added for detection. At the same time, a solvent control group and a blank control group were set up in which DMSO was used to replace the test compound, and 3 replicate wells were set up for each sample and each concentration. The activity of the sample was tested under a single concentration condition, such as 10 μM, for the initial screening. For samples that show activity under certain conditions, such as an inhibition rate greater than 50, the activity dose dependence, i.e. IC 50 The values ​​were obtained by nonlinear fitting of the sample activity to the sample concentration. The software used for the calculation was GraphpadPrism8, and the model used for fitting was sigmoidaldose-response (varibleslope). For most inhibitor screening models, the bottom and top of the fitting curve were set to 0 and 100.

[0252] Table 10 Inhibitory activity of the present invention on FLT3, FLT3-D835Y, and IRAK4 kinases

[0253]

[0254]

[0255]

[0256]

[0257] IC 50 50% inhibitory concentration

[0258] The results in Table 10 show that most of the compounds exhibited good FLT3 and IRAK4 kinase inhibitory activity, indicating that this class of compounds has the potential to treat FLT3, IRAK4, and FLT3 / IRAK4 related diseases.

[0259] Example 23. Cell proliferation inhibitory activity test

[0260] Cell lines: MV-4-11 (human acute myelomonocytic leukemia, expressing FLT3-ITD homozygous mutation), Molm-13 (human acute myelomonocytic leukemia, FLT3-ITD heterozygous mutation), BaF3-FLT3-ITD (human acute myelomonocytic engineered cell line, expressing FLT3-ITD homozygous mutation), THP-1 (human monocytic leukemia, high expression of IRAK4), TF-1 (human erythroid leukemia, high expression of IRAK4), OCY-LY10 (diffuse large B-cell lymphoma, MyD88 mutation), HL-60 (human promyelocytic leukemia cells), Kasumi-1 (human acute myeloblastic leukemia, FLT3 wild type), Jurkat (acute T-cell leukemia).

[0261] Experimental steps: MTS method was used to determine the antiproliferative activity (IC 50 ): The cells in the logarithmic growth phase were digested with trypsin and counted. 4 The cells / well were inoculated in a 96-well plate at a density of 100 cells / well and placed in a 37°C incubator containing 5% CO2 for overnight culture. Six concentration gradients were set for each test compound, and three sets of replicate wells were set for each concentration. After addition, the cells were cultured for 72 hours and 20μ0 MTS was added. After incubation at 37°C for 2 hours, the light absorption value at 490nm (L1) was measured using a SpectraMAX340 microplate reader, and the reference wavelength was 690nm (L2). The (L1-L2) value was plotted against different concentrations of the inhibitor, and the IC value of the compound was calculated using GraphPadPrism5 software. 50 (Inhibition rate = (OD value of control group - OD value of drug administration group) / OD value of control group * 100%).

[0262] Table 11 Inhibitory activity of the compounds of the present invention on human acute myelomonocytic leukemia cells MV-4-11

[0263]

[0264]

[0265] IC 50 : Half inhibitory concentration

[0266] CA-4948 structure:

[0267]

[0268] Table 12 Inhibitory activity of the compounds of the present invention on human acute myeloid monocytic leukemia cells Molm-13

[0269] Compound No. <![CDATA[Molm-13 IC 50 (nM)]]> Compound No. <![CDATA[Molm-13 IC 50 (nM)]]> 1 7.18±0.28 36 7.00±0.46 14 15.45±0.84 37 9.64±0.35 15 14.68±4.11 40 10.72±0.33 16 62.57±19.74 41 15.82±1.24 17 58.61±9.59 42 6.92±0.73 18 23.19±2.02 44 29.44±4.57 19 48.88±4.16 45 8.76±1.00 20 47.01±5.77 CA-4948 101.84±13.95

[0270] IC 50 50% inhibitory concentration

[0271] Table 13 Inhibitory activity of the compounds of the present invention on human acute myeloid monocytic leukemia cells BaF3-FLT3-ITD

[0272]

[0273] IC 50 : Half inhibitory concentration

[0274] The above Tables 11, 12 and 13 show that the compounds of the present invention have excellent anti-proliferation activity against FLT3-ITD mutated MV-4-11, Molm-13 and BaF3-FLT3-ITD cells.

[0275] Table 14 Inhibitory activity of the compounds of the present invention on human monocytic leukemia cells THP-1

[0276] Compound No. <![CDATA[THP-1IC 50 (nM)]]> Compound No. <![CDATA[THP-1IC 50 (nM)]]> 36 208.57 42 520.57 37 454.40 44 823.47 40 543.50 45 155.33 41 515.00 CA-4948 >20000

[0277] Table 15 Inhibitory activity of the compounds of the present invention on human erythroid leukemia cells TF-1

[0278] Compound No. <![CDATA[TF-1IC 50 (nM)]]> Compound No. <![CDATA[TF-1IC 50 (nM)]]> 36 29.28 42 37.92 37 29.68 44 141.33 40 39.09 45 25.81 41 63.06 CA-4948 >20000

[0279] The above Tables 14 and 15 show that the compounds of the present invention have excellent anti-proliferation activity against THP-1 and TF-1 cells with high expression of IRAK4.

[0280] Table 16 Proliferation inhibitory activity of preferred compounds 36 and 37 of the present invention on the MyD88 mutated large B cell lymphoma cell line OCY-LY10

[0281] <![CDATA[36IC 50 (nM)]]> <![CDATA[37IC 50 (nM)]]> 0.06312 7.975

[0282] The above Table 16 shows that the preferred compounds 36 and 37 have excellent anti-proliferative activity against the MyD88 mutated large B-cell lymphoma cell line OCY-LY10.

[0283] Table 17 Proliferation inhibition activity of preferred compounds 36 and 37 of the present invention on other cell lines

[0284] Cell lines <![CDATA[36IC 50 (nM)]]> <![CDATA[37IC 50 (nM)]]> HL-60 66.67 ND Kasumi-1 5.718 ND Jurkat 1192 2773

[0285] Table 17 above shows that the preferred compound 36 has excellent antiproliferative activity against HL-60 and Kasumi-1 cell lines

[0286] In vivo antitumor activity test

[0287] Example 24. MV-4-11 transplanted tumor model

[0288] Experimental method: NU / NU mice were subcutaneously injected with human MV-4-11 cells, with a cell inoculation volume of 5×10 6 / mouse, wait until the tumor grows to 100-300mm 3 Afterwards, the animals were randomly divided into a 0.5% CMC-Na solvent control group, a cytarabine (AraC) control group and a drug-treated group according to their weight and tumor size, with 5 mice in each group. They were treated with 10 mg / kg of compound 36 and 37 daily for one week and then stopped. The tumor growth of the mice was observed. The control group was subcutaneously injected with cytarabine (20 mg / kg) 5 times a week for 3 consecutive weeks, and the negative control group (0.5% CMC-Na group) was given an equal amount of solvent for 21 days. During the experiment, the tumor volume was measured twice a week and the mouse weight was weighed. The experimental results are shown in the figure. Figure 1 Shown

[0289] sc: subcutaneous injection

[0290] po: oral administration

[0291] from Figure 1 It can be seen that compounds 36 and 37 provided by the invention can induce almost complete tumor disappearance in the human acute myeloid leukemia MV-4-11 transplanted tumor model.

Claims

1. A N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives, characterized in that It has the structure shown in the general formula (Ⅰ): or an optical isomer thereof or a pharmaceutically acceptable salt thereof; in: X is selected from (CH2) m , NR4, O, CO, R4 is selected from H, C 1-3 The alkyl group, the C 1-3 The alkyl group can be further substituted by hydroxyl or halogen; m is selected from 0, 1, 2, and 3; when m is 0, X does not exist, and R1 is directly connected to the benzene ring; Y is selected from NR5, O, chemical bond, R5 is selected from H, C 1-3 The alkyl group; R1 is selected from -C 1-6 Alkyl-amino, -C 0-3 Alkyl-C 3-10 Cycloalkyl, -C 0-3 Alkyl-C 3-10 Heterocycloalkyl, -C 0-3 Alkyl-C 3-10 Cycloalkyl-amino, -C 0-3 Alkyl-C 3-10 Heterocycloalkyl-amino, -C 0-3 Alkyl-C 3-10 Cycloalkyl-C 1-4 Alkyl-amino, -C 0-3 Alkyl-C 3-10 Heterocycloalkyl-C 1-4 Alkyl-amino, wherein the alkyl, amino, cycloalkyl, and heterocycloalkyl moieties may be further independently substituted by 1, 2, 3, or 4 R6; and when multiple R6 exist on the same group, the multiple R6 are independent of each other and may be the same or different; R6 is selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-5 Alkyl, C 1-5 Alkenyl, C 1-5 Alkynyl, -NHCO-C 1-5 Alkyl, -NHSO 2- C 1-5 Alkyl, -NHSO-C 1-5 Alkyl, -CONH-C 0-5 Alkyl, -SO2NH-C 0-5 Alkyl, -SONH-C 0-5 Alkyl, -amino-C 1-5 Alkyl-C 3-5 Heterocycloalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl, -C 1-3 Alkyl-C 3-6 Heterocycloalkyl, -CO-C 1-5 Alkyl, -SO 2- C 1-5 Alkyl, -SO-C 1-5 Alkyl, where C 1-5 Alkyl or C 3-5 The heterocycloalkyl moiety may be further substituted with halogen, hydroxy or cyano; R2 is selected from C 1-6 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-10 Heterocycloalkyl, the alkyl, cyclopropyl, cyclobutyl, cyclopentyl, heterocycloalkyl may be further substituted with hydrogen, deuterium, hydroxyl, amino, nitro, cyano, C 1-3 Alkoxy, -NHCO-C 1-3 Alkyl, -NHSO 2- C 1-3 Alkyl, -NHSO-C 1-3 Alkyl, -CO-C 1-3 Alkyl, -SO 2- C 1-3 Alkyl, -SO-C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Substituted with heterocycloalkyl, wherein the heteroatom in the heterocycloalkyl is selected from any one or more of N, O and S; When R2 is a cyclohexyl group, it can be further substituted by amino, hydroxyl, -NHCO- 1-3 Alkyl, -NHSO 2- C 1-3 Alkyl, C 3-6 Heterocycloalkyl substitution; R3 is selected from H, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, carboxamide, nitro, 6-10 membered monocyclic or bicyclic aromatic group, 5-10 membered monocyclic or bicyclic heterocyclic group, wherein the heterocyclic group refers to an aliphatic or aromatic monocyclic or bicyclic system, wherein the aromatic group and the heterocyclic group may be further C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 substituted with haloalkyl, halogen, hydroxyl or cyano.

2. The compound according to claim 1, characterized in that It has the structure shown in the general formula (II):

3. The compound according to claim 1 or 2, characterized in that The X is NH, O, (CH2) m , CO, m is selected from 0, 1, 2; said R1 is selected from any of the following structures: The R3 is selected from hydrogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, carboxamide, nitro, 6-10 membered monocyclic or bicyclic aromatic group, 5-10 membered monocyclic or bicyclic heterocyclic group, wherein the heterocyclic group refers to an aliphatic or aromatic monocyclic or bicyclic system, wherein the aromatic group and the heterocyclic group may be further C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 substituted with haloalkyl, halogen, hydroxyl or cyano.

4. The compound according to claim 1, characterized in that The aryl and heterocyclic groups are: Aryl: Heterocyclic group: The aryl or heterocyclic moiety may be further C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 substituted with haloalkyl, halogen, hydroxyl or cyano.

5. The compound according to claim 1 or 2, characterized in that R3 is trifluoromethyl; X is NH, and Y is NH.

6. The compound according to claim 1, characterized in that Selected from the following compounds: and optical isomers or pharmaceutically acceptable salts.

7. The compound according to any one of claims 1 to 6, characterized in that The pharmaceutically acceptable salts include acid addition salts formed with the compound and the following acids: formic acid, acetic acid, propionic acid, pyruvic acid, glycolic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, mandelic acid, citric acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, L-malic acid, D-malic acid, lactic acid, camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, salicylic acid, benzoic acid, tartaric acid, L-tartaric acid, D-tartaric acid, oxalic acid, succinic acid, maleic acid, ascorbic acid, amino acids, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, hydroiodic acid or perchloric acid.

8. A method for preparing the compound according to any one of claims 1 to 6, characterized in that: include: Compound (I-1) and compound (I-2) are reacted in an organic solvent at 80°C-120°C in the presence of Pd2(dba)3, Xant-phos and Cs2CO3. After completion of the reaction, compound I or a Boc-protected precursor of compound I is obtained by treatment, wherein the Boc-protected precursor is further treated with an acid to remove the Boc group to obtain compound I.

9. The preparation method according to claim 8, characterized in that: include: Route 1: wherein R1, R2, R3, and Y are defined as in claim 1, and R1' is R1 or a Boc-protected precursor of R1; and the preparation method comprises the following steps: (1) dissolving an amine compound in a mixture of DMF / DMSO / CH3CN and water, adding a corresponding base and compound 1, reacting the reaction solution at 20-100° C., and treating after the reaction to obtain compound 2; (2) Compound 2 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas, Pd2(dba)3, Xant-phos and Cs2CO3 are added to react at 80°C-120°C. After the reaction is completed, the compound I or a Boc-protected precursor of the compound I is treated, wherein the Boc-protected precursor is further treated with an acid to remove the Boc group to obtain the compound I; Route 2: Wherein, X=NH, O; R1, R2, R3, Y are defined as in claim 1, R1' is R1 or a Boc protected precursor of R1; the preparation method comprises the following steps: (1) When X=NH: dissolve the amine compound in DMSO or DMF, add compound 4, an inorganic base, and sodium iodide / potassium iodide as a catalyst at 0-40°C, and react the reaction solution in a sealed tube at 80-160°C. After the reaction is completed, the compound 5 is obtained by treatment; When X=O: the alcohol compound is dissolved in anhydrous DMF, and sodium hydrogen is added thereto in batches at 0-10°C under the protection of an inert gas. After the obtained mixed solution is reacted at room temperature for 1-5h, compound 4 is added thereto, and the reaction solution is reacted at 70-100°C. After the reaction is completed, compound 5 is obtained by treatment; (2) Compound 5 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas, Pd2(dba)3, Xant-phos and Cs2CO3 are added to react at 80°C-120°C. After the reaction is completed, the compound II or a Boc-protected precursor of the compound II is treated, wherein the Boc-protected precursor is further treated with an acid to remove the Boc group to obtain the compound II; Route 3: Wherein, X=NH, chemical bond; R1, R2, R3, Y are defined as in claim 1, R1' is R1 or a Boc protected precursor of R1; the preparation method comprises the following steps: (1) Under the protection of inert gas, an amine compound, compound 6, an inorganic base, palladium acetate, and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) are dissolved in anhydrous dioxane, and the mixture is reacted at 80-120° C. After the reaction is completed, compound 7 is post-treated; (2) Compound 7 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas, Pd2(dba)3, Xant-phos and Cs2CO3 are added to react at 80°C-120°C. After the reaction is completed, the compound III or a Boc-protected precursor of the compound III is treated, wherein the Boc-protected precursor is further treated with an acid to remove the Boc group to obtain the compound III; Route 4: wherein R1, R2, R3, and Y are defined as in claim 1, and R1' is R1 or a Boc-protected precursor of R1; and the preparation method comprises the following steps: (1) Compound 8 was dissolved in DMF, HOBt, EDCI, an amine compound and DIPEA were added at 0°C, and the reaction was carried out at 20°C-50°C. After the reaction was completed, compound 9 was obtained after post-treatment; (2) Compound 9 and Compound 3 are dissolved in a reaction solvent, and Pd2(dba)3, Xant-phos and Cs2CO3 are added under inert gas protection, and the reaction is carried out at 80°C-120°C. After the reaction is completed, compound IV or a Boc-protected precursor of compound IV is obtained by post-treatment, wherein the Boc-protected precursor is further treated with trifluoroacetic acid to remove the Boc group to obtain compound IV.

10. A key intermediate for preparing any of the compounds of claims 1-7, characterized in that: The intermediate is selected from any of the following structures:

11. A pharmaceutical composition, characterized in that The method comprises one or more compounds according to any one of claims 1 to 7.

12. A pharmaceutical preparation, characterized in that The method comprises one or more compounds according to any one of claims 1 to 7.

13. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a clinical disease associated with FLT3 and / or IRAK4.

14. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating blood diseases, solid tumors, skin diseases, inflammation or autoimmune diseases.

15. The use according to claim 13 or 14, characterized in that: The compounds are used alone or in combination with one or more other therapeutic agents.

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