WO2025031358A1 - N2-3-fluoro-5-substituted phenyl-2-aminopyrimidine derivative, preparation method therefor and pharmaceutical use thereof - Google Patents

Abstract

Disclosed in the present invention are a compound as shown in formula (I), a preparation method therefor and the pharmaceutical use thereof, comprising an optical isomer and a pharmaceutically acceptable salt thereof. The compound of the present invention has FLT3 and/or IRAK4 inhibitory activity, has proliferation inhibitory activity on various leukemia cell strains and IRAK4-related cell strains, and can be used in the preparation of drugs for resisting blood diseases, inflammation and autoimmune diseases.

Description

N2-3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives, preparation method and medical use thereof Technical Field

The present invention relates to the field of medicine, and in particular to an ^N2-3 -fluoro-5-substituted phenyl-2-aminopyrimidine derivative, an optical isomer, a salt and a preparation method thereof, as well as the use of the derivative as an inhibitor of Fms-like tyrosine kinase 3 (FLT3), interleukin 1 receptor-associated kinase 4 (IRAK4) or a dual-targeted FLT3/IRAK4 inhibitor in anti-tumor, anti-inflammatory and anti-autoimmune disease drugs.

Background Art

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.

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.

IRAK4 (interleukin 1 receptor-associated kinase 4) is a serine/threonine protein kinase related to 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 have a significant impact on human It plays an important role in 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 adaptor 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.

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.

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).

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

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

The technical solution of the present invention is as follows:

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

or an optical isomer thereof or a pharmaceutically acceptable salt thereof.

in:

X is selected from (CH ₂ ) _m , NR ₄ , O, CO, R ₄ is selected from H, C _1-3 alkyl, and the C _1-3 alkyl may 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 R ₁ is directly connected to the benzene ring;

Y is selected from NR ₅ , O, a chemical bond, and R ₅ is selected from H, a C _1-3 alkyl group; when Y is a chemical bond, R ₂ is directly connected to the pyrimidine ring;

R ₁ 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, and the alkyl, amino, cycloalkyl, and heterocycloalkyl moieties in the above groups may be further independently substituted by 1, 2, 3, or 4 R _6, respectively; and when there are multiple R ₆ on the same group, the multiple R ₆ are independent of each other and may be the same or different; wherein when the subscript C in the C _0-3 alkyl is 0, it means that "C _0-3 alkyl" does not exist, and the remaining groups connected thereto are directly connected to X or directly connected to the benzene ring when X does not exist;

_R6 is selected from hydrogen, halogen, hydroxyl, amino, cyano, _C1-5 alkyl, _C1-5 alkenyl, _C1-5 alkynyl, -NHCO- _C1-5 alkyl, -NHSO2- _C1-5 alkyl, -NHSO- _C1-5 alkyl, -CONH- _C0-5 alkyl, -SO2NH- _C0-5 alkyl, -SONH- _C0-5 alkyl, -amino- _C1-5 alkyl- _C3-5 heterocycloalkyl, _C3-6 cycloalkyl, _C3-6 heterocycloalkyl, _-C1-3 alkyl- _C3-6 cycloalkyl, _-C1-3 alkyl _{- C3-6} heterocycloalkyl, -CO- _C1-5 alkyl, -SO2 _{- C1-5} alkyl, -SO- _C1-5 alkyl, and the _C1-5 alkyl or _C3-5 heterocycloalkyl portion may be further substituted by halogen, hydroxyl or cyano; _wherein when R When ₆ is selected from -CONH-C _0-5 alkyl, -SO ₂ NH-C _0-5 alkyl, -SONH-C _0-5 alkyl, when the C subscript of the C _0-5 alkyl is 0, it means that "C _0-5 alkyl" does not exist, and the remaining groups connected thereto are -CONH ₂ , -SO ₂ NH ₂ , -SONH ₂ ;

_R2 is selected from _C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, _C3-10 heterocycloalkyl, and the _C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, _C3-10 heterocycloalkyl may be further substituted by hydrogen, deuterium, hydroxyl, amino, nitro, cyano, _C1-3 alkoxy, -NHCO- _C1-3 alkyl, -NHSO2- _C1-3 alkyl, -NHSO- _C1-3 alkyl, -CO- _C1-3 alkyl, _-SO2 - _C1-3 alkyl, -SO- _C1-3 alkyl, _{C3-6 cycloalkyl} , _C3-6 heterocycloalkyl, and the heteroatom is selected from any one or more of N, O, and S;

When R ₂ is cyclohexyl, it may be further substituted by amino, hydroxyl, -NHCO-C _1-3 alkyl, -NHSO _2- C _1-3 alkyl, C _3-6 heterocycloalkyl;

_R3 is selected from hydrogen, cyano, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C2-6 alkenyl, _C2-6 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 substituted by _C1-3 alkyl, C1-3 alkoxy, _C1-3 haloalkyl, halogen, hydroxyl, and cyano.

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

X is selected from (CH ₂ ) _m , NR ₄ , O, CO, R ₄ is selected from H, C _1-3 alkyl, and the C _1-3 alkyl may be further substituted by hydroxyl or halogen;

m is selected from 0, 1, 2, 3;

R ₁ 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, in which the alkyl, amino, cycloalkyl and heterocycloalkyl moieties in the above groups may be further independently substituted by 1, 2, 3 or 4 R _6, respectively; and when there are multiple R ₆ in the same group, the multiple R ₆ are independent of each other and may be the same or different;

_R6 is selected from hydrogen, halogen, hydroxyl, amino, cyano, _C1-5 alkyl, _C1-5 alkenyl, _C1-5 alkynyl, -NHCO- _C1-5 alkyl, -NHSO2- _C1-5 alkyl, -NHSO- _C1-5 alkyl, -CONH- _C0-5 alkyl, -SO2NH- _C0-5 alkyl, -SONH- _C0-5 alkyl, -amino- _C1-5 alkyl- _C3-5 heterocycloalkyl, _C3-6 cycloalkyl, _C3-6 heterocycloalkyl, _-C1-3 alkyl- _C3-6 cycloalkyl, _-C1-3 alkyl _{- C3-6} heterocycloalkyl, -CO- _C1-5 alkyl, -SO2 _{- C1-5} alkyl, -SO- _C1-5 alkyl, wherein the _C1-5 alkyl or C3-5 _{heterocycloalkyl} portion may be further substituted by halogen, hydroxyl or _cyano ;

_R3 is selected from hydrogen, cyano, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C2-6 alkenyl, _C2-6 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 substituted by _C1-3 alkyl, C1-3 alkoxy, _C1-3 haloalkyl, halogen, hydroxyl, and cyano.

As further preferred, X is NH, O, (CH ₂ ) _m , CO, m is selected from 0, 1, 2; Y is NH. As preferred, R ₁ is selected from any of the following structures:

Preferably, R ₃ 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:

Aryl:

Heterocyclic group:

The aryl and heterocyclic moieties may be further substituted by C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, halogen, hydroxyl, or cyano.

As a specific preferred embodiment, R ₃ is trifluoromethyl; X is NH, and Y is NH;

Right now:

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

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.

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

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.

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.

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

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.

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 thereof.

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.

In a third aspect, the present invention provides a method for preparing the above-mentioned N ² -3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives, optical isomers, and salts, which is achieved by the following route:

The method comprises: reacting compound (I-1) and compound (I-2) in the presence of Pd ₂ (dba) ₃ , Xant-phos and Cs ₂ CO ₃ in an organic solvent at 80° C.-120° C., and treating after the reaction 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.

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

Route 1:

wherein R ₁ , R ₂ , R ₃ and Y are as defined in the general formula (I), and R ₁ ' is R ₁ or a Boc-protected precursor of R ₁ ; the preparation method comprises the following steps:

(1) R The precursor compound of ₁ - amine compounds (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 DMF/DMSO/CH _3. Add the corresponding base (such as potassium carbonate, sodium carbonate, cesium carbonate, triethylamine) and compound 1 to a mixture of CN and water, react the reaction solution at 20-100°C, and after the reaction is completed, treat to obtain compound 2;

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;

(2) Compound 2 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas (such as nitrogen), Pd ₂ (dba) ₃ , Xant-phos and Cs ₂ CO ₃ 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 a Boc-protected precursor of the compound I is obtained, 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.

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:

Wherein, X＝NH, O; R ₁ , R ₂ , R ₃ , and Y are defined as in the general formula (I); R ₁ ' is R ₁ or a Boc-protected precursor of R ₁ ; the preparation method comprises the following steps:

(1) When X=NH: an amine compound (such as N-methyl-4-aminopiperidine, R-N-Boc-3-aminopiperidine, S-N-Boc-3-aminopiperidine, R-N-Boc-3-aminopyrrole, S-N-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;

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;

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;

(2) Compound 5 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas (such as nitrogen), Pd ₂ (dba) ₃ , Xant-phos and Cs ₂ CO ₃ 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 a Boc-protected precursor of the compound I is obtained, 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.

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.

Route 3:

Wherein, X＝NH, chemical bond; R ₁ , R ₂ , R ₃ , and Y are defined as in the general formula (I); R ₁ ' is R ₁ or a Boc-protected precursor of R ₁ ; the preparation method comprises the following steps:

(2) Under the protection of inert gas, amine compounds (such as N-methyl-piperazine, N-Boc-ethylenediamine, N-Boc-propylenediamine, N-Boc-butylenediamine, N-Boc-pentanediamine, N-methyl-4-aminopiperidine, R-N-Boc-3-aminopiperidine, S-N-Boc-3-aminopiperidine, R-N-Boc-3-aminopyrrole, S-N-Boc-3-aminopyrrole, N-Boc-4-amino Piperidine, 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, 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.

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;

(2) Compound 7 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas (such as nitrogen), Pd ₂ (dba) ₃ , Xant-phos and Cs ₂ CO ₃ 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 a Boc-protected precursor of the compound I is obtained, 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.

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.

Route 4:

wherein R ₁ , R ₂ , R ₃ and Y are as defined in the general formula (I), and R ₁ ' is R ₁ or a Boc-protected precursor of R ₁ ; the preparation method comprises the following steps:

(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;

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;

(2) Compound 9 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas (such as nitrogen), Pd ₂ (dba) ₃ , Xant-phos and Cs ₂ CO ₃ 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 a Boc-protected precursor of the compound I is obtained, 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.

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.

Specifically, the following methods can be used:

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

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

(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. The reaction solvent is any one of CH ₃ CN, DMF/H ₂ O=10:1, and DMSO.

(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;

(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;

(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.

(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;

(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.

(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 ligands 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 Pd ₂ (dba) ₃ and Pd(OAc) ₂ , the ligand is any one of Xantphos and BINAP, and the reaction temperature is 80-120°C;

(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.

(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;

(10) Intermediate 8 and any one of intermediates 1, 2, 3, and 4 undergo Buchwald-Hartwig coupling under inert gas protection and catalytic conditions of base, palladium, and corresponding ligands to directly obtain the compound of formula (2) or to 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.

Method 2:

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.

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.

In a fourth aspect, the present invention provides a key intermediate in the process of 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:

In a fifth aspect, the present invention provides a composition comprising a therapeutically effective amount of the above-mentioned N ² -3-fluoro-5-substituted phenyl-2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the composition comprises at least one therapeutically effective amount of an ^N2-3 -fluoro-5-substituted phenyl-2-aminopyrimidine compound of general formula (I) 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.

In a sixth aspect, the present invention provides a pharmaceutical preparation for treating or preventing diseases related to FLT3, IRAK4, or FLT3/IRAK4, comprising a therapeutically effective amount of the above-mentioned N ² -3 fluoro-5-substituted phenyl-2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, and also comprising auxiliary ingredients. 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, for example, 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, (carboxy-C _1-4 alkyl)-α-cyclodextrin, (carboxy-C _{1-4 alkyl)-β-cyclodextrin, (carboxy-C 1-4 alkyl} )-γ-cyclodextrin, saccharide ethers of α-cyclodextrin, saccharide ethers of β-cyclodextrin, saccharide ethers of γ-cyclodextrin, sulfobutyl ethers of α-cyclodextrin, sulfobutyl ethers of β-cyclodextrin and sulfobutyl ethers of γ-cyclodextrin. The auxiliary components also include medically acceptable carriers, adjuvants or vehicles. Pharmaceutically acceptable pharmaceutical compositions also include ion exchangers, aluminum oxide, aluminum stearate, egg gelatin; buffer substances include phosphates, glycine, arginine, sorbic acid, etc.

In a seventh aspect, the present invention provides the use of N ² -3-fluoro-5-substituted phenyl-2-aminopyrimidine compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for preventing or treating clinical diseases associated with FLT3 and/or IRAK4.

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.

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.

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.

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, periodontal inflammation, hyaline membrane disease, kidney disease, 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 (e.g., including 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 atrophy, metabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinence pigmenti, Paget'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 disease, 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, breast adenitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, localized pneumonia, acute pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquired, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, cryopyrin-associated periodic syndrome (CAPS), and osteoarthritis.

In a seventh aspect, the present invention provides the use of ^N2-3 -fluoro-5-substituted phenyl-2-aminopyrimidine compounds or pharmaceutically acceptable salts thereof 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.

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

Figure 1 shows the therapeutic effects of compounds 36 and 37 on human acute myeloid leukemia MV-4-11NU/NU mouse transplanted tumors

DETAILED DESCRIPTION

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.

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

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

Refer to patent document CN111646978A.

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

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, CDCl ₃ -d ₆ )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]+.

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

At room temperature, the intermediate 1-4 (1 g, 3.73 mmol) was dissolved in a mixed system of DMF/H ₂ O (V _DMF = 10 mL, V _H2O = 1 mL), and morpholine (487 mg, 5.60 mmol) and potassium carbonate (1031 mg, 7.46 mmol) were added under stirring. The reaction solution was reacted at 50°C overnight, extracted with ethyl acetate and water for 3 times, washed with saturated brine for 3 times, the organic layer was dried over anhydrous sodium sulfate, the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with PE:EA = 10:1 as the eluent to obtain a transparent oil (971 mg, 95%). ¹ HNMR (500MHz, CDCl ₃ -d ₆ )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] ⁺ .

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

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: NH ₃ /EtOH (30:1-20:1) as eluent to obtain a white solid (190 mg, 77%). ¹ HNMR (500MHz, CDCl ₃ -d ₆ )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] ⁺ .

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

Reference Example 1 Preparation Method:

Using intermediate 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 underwent a Buchwald-Hartwig reaction in the presence of tri(dibenzylideneacetone)dipalladium and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene as the catalyst, and further de-Boc was performed to obtain compound 8.

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.

Table 1

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

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

Reference Example 1 Preparation of Intermediate 1-3, except that the raw material used was cyclopropylamine, to obtain a white solid (90%). ¹ HNMR (500 MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 5.40 (br, 2H), 5.29 (d, = 7.0 Hz, 1H), 2.86 (s, 1H), 0.83 (d, J = 5.5 Hz, 2H), 0.70 (s, 2H); ESI-MS: m/z = 219.1 [M+H] ⁺ .

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

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-d ₆ )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] ⁺ .

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

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.

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

Table 2

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

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

Reference was made to the synthesis of intermediate 1-3 in Preparation Example 1, except that the raw material used was 5-bromo-4-chloro-pyrimidin-2-amine, and a white solid (83.5%) was obtained. ¹ HNMR (500 MHz, CDCl ₃ -d ₆ ) δ7.86 (s, 1H), .16 (d, J=7.5 Hz, 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] ⁺ .

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

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%). ¹ HNMR (500MHz, CDCl ₃ -d ₆ ) δ9.05 (s, 1H), 8.45 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.93 (dd, J = 8.5, 1.0 Hz, 1H), 1.37 (s, 12H); ESI-MS: m/z = 262.1 [M+H] ⁺ .

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)

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, CDCl ₃ -d ₆ )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] ⁺ .

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

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: NH ₃ /EtOH (30:1-20:1) as eluent to obtain a white solid (70 mg, 48%). ¹ HNMR(500MHz,MeOD-d ₄ )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,1H),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] ⁺ .

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

Step 1: Synthesis of 5-bromo-N ⁴ -cyclohexylpyrimidine-2,4-diamine (Intermediate 1-12)

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 reaction solution was refluxed overnight, 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 (500 MHz, CDCl ₃ -d ₆ )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] ⁺ .

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

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, CDCl ₃ -d ₆ )δ9.03(s,1H),8.19(d,J＝8.5Hz,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] ⁺ .

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

Under nitrogen protection, anhydrous dioxane (6 mL) was added 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), and cesium carbonate (300 mg, 0.92 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:CH ₃ OH=40:1 as the eluent to obtain a white solid (150 mg, 63%). ¹ HNMR (500 MHz, CDCl ₃ -d ₆ )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,1H),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),2.09–2.0 6(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] ⁺ .

Preparation Example 7: Synthesis of Compound 12

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.

Table 3

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

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

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, CDCl ₃ -d ₆ )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] ⁺ .

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

Under nitrogen protection, anhydrous dioxane (8 mL) was added 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(diphenylphosphino)-9,9-dimethylxanthene (133 mg, 0.23 mmol), and cesium carbonate (596 mg, 1.83 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:CH ₃ OH=20:1 as the eluent to obtain a white solid (220 mg, 56%). ¹ HNMR (500MHz, CDCl ₃ -d ₆ )δ8.17(d,J＝1.0Hz,1H),7.59(s,1H),7.47(d,J＝11.5Hz,1H),6.94(t,J＝2.5Hz,1H),6.31(dt,J＝10.5,2.5Hz,1H),5.44(s,1H),4.27(s,1H),2. 91–2.86(m,1H),2.65(s,2H),2.30(s,5H),2.02–1.96(m,2H),1.87–1.8 0(m,2H),1.06–0.90(m,2H),0.74–0.56(m,2H); ESI-MS: m/z＝426.2[M+H] ⁺ .

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

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

Dissolve 3,5-difluorobenzoic acid (300 mg, 1.37 mmol) in 6 mL DMF, add 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) under ice bath. After the reaction solution is reacted at room temperature overnight, water and ethyl acetate are added to the reaction solution for extraction 3-4 times, the organic layer is washed with saturated brine 2-3 times, and the solvent is recovered under reduced pressure to obtain a residue. Purify by silica gel column chromatography with PE:EA＝2:1 as eluent to obtain a white solid (200 mg, 48%). ¹ HNMR (500 MHz,CDCl ₃ -d ₆ )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] ⁺ .

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

Reference Example 8 Synthesis of Compound 33, except that the starting material used was Intermediate 1-17, to obtain a white solid (60%). ¹ HNMR (500 MHz, CDCl ₃ -d ₆ ) δ8.17 (s, 1H), 8.05 (d, J=11.5 Hz, 1H), 7.54 (s, 1H), 7.31 (s, 1H), 6.74 (d, J=8.0 Hz, 1H), 5.47 (s, 1H), 3.80 (s, 2H), 3.47 (s, 2H), 2.86 (d, J=8.0 Hz, 1H), 2.50 (s, 2H), 2.36 (s, 5H), 0.96 (d, J=6.5 Hz, 2H), 0.67-0.61 (m, 2H); ESI-MS: m/z=439.2 [M+H] ⁺ .

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

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

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. The mixture was filtered off and the solvent was recovered under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with DCM:CH ₃ OH=20:1 as the eluent to obtain a white solid (200 mg, 74%). ¹ HNMR (500MHz, CDCl ₃ -d ₆ )δ6.79(s,1H),6.67(dt,J＝8.0,2.0Hz,1H),6.49(dt,J＝12.0,2.0Hz,1H),3.20 (t, J＝5.0Hz, 4H), 2.53 (t, J＝5.0Hz, 4H), 2.34 (s, 3H); ESI-MS: m/z＝273.0[M+H] ⁺ .

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

Reference Example 8 Synthesis of Compound 33, except that the starting material used was Intermediate 1-19, to obtain a white solid (71%). ¹ HNMR (500 MHz, CDCl ₃ -d ₆ ) δ 8.18 (s, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 6.58 (s, 1H), 6.31 (d, J = 11.5 Hz, 1H), 5.41 (s, 1H), 3.19 (t, J = 5.0 Hz, 4H), 2.89 (dd, J = 6.5, 3.5 Hz, 1H), 2.54 (t, J = 5.0 Hz, 4H), 2.34 (s, 3H), 0.95 (d, J = 6.5 Hz, 2H), 0.76-0.53 (m, 2H); ESI-MS: m/z = 411.2 [M+H] ⁺ .

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

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

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:CH ₃ OH=25:1 as the eluent to obtain a yellow oil (1806mg, 72%). ¹ HNMR (500MHz, CDCl ₃ -d ₆ )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),3.25–3.17(m,1 H),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] ⁺ .

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

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, CDCl ₃ -d ₆ )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),2.30(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] ⁺ .

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

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

Reference Example 11 Synthesis of Intermediate 1-21, except that the starting material is RN-Boc-3-aminopiperidine, to obtain a white solid (50%). ¹ HNMR (500 MHz, CDCl ₃ -d ₆ ) δ 6.55 (dt, J = 8.0, 1.5 Hz, 1H), 6.52 (d, J = 1.5 Hz, 1H), 6.24 (dt, J = 11.5, 2.5 Hz, 1H), 3.89 (dd, J = 13.0, 3.5 Hz, 1H),3.67(s,1H),3.32(s,1H),3.14(s,1H),2.97(t,J＝10.5Hz,1H),1.96(s,1H ),1.78–1.68(m,1H),1.58–1.52(m,2H),1.46(s,9H); ESI-MS: m/z=373.1[M+H] ⁺ .

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

The synthesis of compound 1 in the preparation example was referred to, except that the raw materials used were 1-6 and 1-22, and a white solid (60%) was obtained. ¹ HNMR (500 MHz, CDCl ₃ -d ₆ ) δ8.15 (d, J=1.0 Hz, 1H), 7.35 (s, 1H), 7.24 (br, 1H), 6.38 (s, 1H), 6.03 (dt, J=11.5, 2.0 Hz, 1H), 5.38 (s, 1H), 4.06 (s, 1H), 3.39 (s, 1H), 3.17 (dd, J=11.5, 3.5 Hz, 1H), 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] ⁺ .

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

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.

Table 4

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

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

Reference was made to the synthesis of intermediate 1-19 in Preparation Example 10, except that the raw material used was N-Boc-propylenediamine, and a light yellow oil (41%) was obtained. ¹ HNMR (500 MHz, CDCl ₃ -d ₆ )δ6.53 (dt, J＝8.0, 1.5 Hz, 1H), 6.51 (d, J＝1.5 Hz, 1H), 6.22 (dt, J＝11.5, 2.5 Hz, 1H), 3.13 (t, J＝7.0 Hz, 2H), 2.78 (t, J＝7.0 Hz, 2H), 1.79 (t, J＝7.0 Hz, 2H), 1.44 (s, 9H); ESI-MS: m/z＝347.1[M+H] ⁺ .

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

The synthesis of compound 1 in Preparation Example 1 was carried out with reference to the method except that the raw materials used were 1-6 and 1-23, and a white solid (63%) was obtained. ¹ HNMR (500 MHz, Methanol-d ₄ ) δ8.10 (s, 1H), 7.39 (d, J=11.5 Hz, 1H), 6.60-6.36 (m, 1H), 6.03 (dt, J=11.5, 2.0 Hz, 1H), 3.12 (t, J=7.0 Hz, 2H), 2.88-2.83 (m, 1H), 2.75 (t, J=7.0 Hz, 2H), 1.77 (t, J=7.0 Hz, 2H), 1.01-0.78 (m, 2H), 0.67-0.63 (m, 2H); ESI-MS: m/z=385.2 [M+H] ⁺ .

Preparation Example 15: Synthesis of Compounds 46 and 47

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.

Table 5

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

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

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

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

The synthesis of compound 1 in Preparation Example 1 was carried out with reference to the method except that the raw materials used were 1-24 and 1-22, and a white solid (65%) was obtained. ¹ HNMR (500 MHz, CDCl ₃ -d ₆ ) δ8.13 (s, 1H), 7.46 (s, 1H), 6.96 (d, J = 11.5 Hz, 1H), 6.45 (s, 1H), 6.03 (dt, J = 11.0, 2.0 Hz, 1H), 4.95 (d, J = 6.5 Hz, 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] ⁺ .

Preparation Example 17: Synthesis of Compound 50

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.

Table 6

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

Step 1: Synthesis of 5-bromo-N ⁴ -cyclopropylpyrimidine-2,4-diamine (Intermediate 1-25)

The synthesis steps refer 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. ¹ HNMR (500 MHz, DMSO-d ₆ ) δ7.77 (s, 1H), 6.54 (d, J＝3.5 Hz, 1H), 6.24 (s, 2H), 2.79 (td, J＝7.5, 3.5 Hz, 1H), 0.70–0.62 (m, 2H), 0.60–0.58 (m, 2H); ESI-MS: m/z＝229.0 [M+H] ⁺ .

Step 2: Synthesis of N ⁴ -cyclopropyl-5-(furan-3-yl)pyrimidine-2,4-diamine (Intermediate 1-26)

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-furanboronic acid (127 mg, 1.13 mmol), cesium carbonate (567 mg, 1.75 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (64 mg, 0.087 mmol). After reacting at 100 ° C overnight, the mixture was 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-d ₆ )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] ⁺ .

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

The synthesis of compound 1 in Preparation Example 1 was carried out with reference to the method except that the raw materials used were 1-26 and 1-22, and a white solid (45%) was obtained. ¹ HNMR (500 MHz, CDCl ₃ -d ₆ ) δ7.85 (s, 1H), 7.53 (t, J = 1.5 Hz, 1H), 7.49 (s, 1H), 7.38 (d, J = 11.5 Hz, 1H), 7.11 (s, 1H), 6.48-6.46 (m, 1H), 6.45 (s, 1H), 5.99 (dt, J = 11.5, 2.0 Hz, 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] ⁺ .

Preparation Example 19: Synthesis of Compounds 52-54

The synthesis steps refer to Preparation Example 18, with 5-bromo-N ⁴ -cyclopropylpyrimidine-2,4-diamine as the starting material, 1-methyl-1H-pyrazole-4-boric acid, phenylboric acid and pyridine-4-boric acid respectively replacing 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.

Table 7

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)

Dissolve compound 36 in isopropanol, and slowly dropwise add isopropanol/methanol/ethanol/ethyl acetate solution containing 1.2 times the equivalent of organic acid or inorganic acid at room temperature. After the dropwise addition is completed, the reaction solution is stirred at 40°C overnight. After the above reaction solution is cooled to room temperature, it is filtered, the solid is 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, The succinate of compound 36; 64, the maleate of compound 36; 65, the formate of compound 36; 66, the acetate of compound 36; 67, the hydrochloride of compound 36; 68, the phosphate of compound 36), the above target molecules are as shown in the following table

Table 8

Preparation Example 21: Preparation of Compounds 69-82

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.

Table 9

Biological activity assay part

Example 22. Kinase activity test The compounds provided by the present invention are tested for their inhibitory activity against FLT3, FLT3-D835Y and IRAK4 kinases.

Instrument: Envision ^™ microplate reader (PerkinElmer, USA).

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 ^TM TK was purchased from Cisbio; human recombinant IRAK4 was purchased from Yiqiao Shenzhou, and the IRAK4 protein fragment fused with GST (Met1-Ser460) was obtained.

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.

Experimental steps: FLT3, FLT3-D835Y and substrate (specific biotin-labeled peptide TKSubstrate) were diluted with HTRF kinase buffer (1.25XKinasebuffer, 6.25mM MgCl ₂ , 1.25mM MnCl ₂ , 1.25mM DTT), and IRAK4 and substrate were diluted with HTRF kinase buffer (1XKinasebuffer, 5mM MgCl ₂ , 1mM MnCl ₂ , 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 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 showing activity under certain conditions, such as inhibition rate %Inhibition greater than 50, the activity dose dependence, i.e., _IC50 value, was tested. The sample concentration was obtained by nonlinear fitting of the sample activity. The software used for 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.

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

IC ₅₀ : Half maximal inhibitory concentration

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.

Example 23. Cell proliferation inhibitory activity test

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).

Experimental steps: MTS method was used to determine the antiproliferative activity (IC ₅₀ ) of the test compound against MV-4-11 and other cell lines: cells in the logarithmic growth phase were digested with trypsin, counted, and seeded in a 96-well plate at a density of 1×10 ⁴ cells/well, 100 cells per well, and placed in a 37°C incubator containing 5% CO ₂ 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 20 μ0 MTS was added. After incubation at 37°C for 2 hours, the light absorption value at 490 nm (L1) was measured using a SpectraMAX340 microplate reader, and the reference wavelength was 690 nm (L2). The (L1-L2) value was plotted against different concentrations of the inhibitor, and the IC ₅₀ of the compound was calculated using GraphPad Prism 5 software (inhibition rate = (OD value of the control group - OD value of the drug group) / OD value of the control group * 100%).

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

IC ₅₀ : Half maximal inhibitory concentration

CA-4948 structure:

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

IC ₅₀ : Half maximal inhibitory concentration

Table 13 Inhibitory activity of the compounds of the present invention on human acute myelomonocytic leukemia cells BaF3-FLT3-ITD

IC ₅₀ : Half maximal inhibitory concentration

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.

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

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

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.

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

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.

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

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

In vivo antitumor activity test

Example 24. MV-4-11 transplanted tumor model

Experimental method: NU/NU mice were subcutaneously injected with human MV-4-11 cells, with a cell inoculation amount of 5×10 ⁶ /mouse. After the tumor grew to 100-300 mm ³ , 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 the animal 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 to observe the tumor growth of the mice. 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 Figure 1

s.c: subcutaneous injection

p.o: oral administration

As can be seen from FIG1 , 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 (15)

A N ² -3-fluoro-5-substituted phenyl-2-aminopyrimidine derivative, characterized in that it has a structure represented by the general formula (I):
or an optical isomer thereof or a pharmaceutically acceptable salt thereof; in: X is selected from (CH ₂ ) _m , NR ₄ , O, CO, R ₄ is selected from H, C _1-3 alkyl, and the C _1-3 alkyl may be further substituted by hydroxyl or halogen; m is selected from 0, 1, 2, and 3; when m is 0, X is absent, and R ₁ is directly connected to the benzene ring; Y is selected from NR ₅ , O, a chemical bond, and R ₅ is selected from H, a C _1-3 alkyl group; R ₁ 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, and the alkyl, amino, cycloalkyl, and heterocycloalkyl moieties may be further independently substituted by 1, 2, 3 or 4 R _6, respectively; and when there are multiple R ₆ on the same group, the multiple R ₆ are independent of each other and may be the same or different; R ₆ is selected from hydrogen, halogen, hydroxyl, 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, -SO ₂ NH-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, wherein the C _1-5 alkyl or C _3-5 heterocycloalkyl portion may be further substituted by halogen, hydroxyl or cyano; R ₂ is selected from C _1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-10 heterocycloalkyl, and the alkyl, cyclopropyl, cyclobutyl, cyclopentyl, heterocycloalkyl may be further substituted by 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 heterocycloalkyl, and the heteroatom in the heterocycloalkyl is selected from any one or more of N, O, and S; When R ₂ is cyclohexyl, it may be further substituted by amino, hydroxyl, -NHCO-C _1-3 alkyl, -NHSO ₂ -C _1-3 alkyl, C _3-6 heterocycloalkyl; _R3 is selected from H, cyano, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C2-6 alkenyl, _C2-6 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 substituted by _C1-3 alkyl, C1-3 alkoxy, _C1-3 haloalkyl, halogen, hydroxyl, and cyano. The compound according to claim 1, characterized in that it has a structure represented by general formula (II):
The compound according to claim 1 or 2, characterized in that X is NH, O, (CH ₂ ) _m , CO, m is selected from 0, 1, 2; and R ₁ is selected from any of the following structures:
The _R3 is selected from hydrogen, cyano, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C2-6 alkenyl, _C2-6 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 substituted by _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, halogen, hydroxyl, and cyano. The compound according to claim 1, characterized in that the aryl group and the heterocyclic group are: Aryl: Heterocyclic group:
The aryl or heterocyclic moiety may be further substituted by C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, halogen, hydroxyl, or cyano. The compound according to claim 1 or 2, characterized in that _R3 is trifluoromethyl; X is NH, and Y is NH. The compound according to claim 1, characterized in that it is selected from the following compounds:




and optical isomers or pharmaceutically acceptable salts. The compound according to any one of claims 1 to 6, characterized in that the pharmaceutically acceptable salt comprises an acid addition salt of the compound with 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. A method for preparing the compound according to any one of claims 1 to 6, characterized in that it comprises:
Compound (I-1) and compound (I-2) react in the presence of Pd ₂ (dba) ₃ , Xant-phos and Cs ₂ CO ₃ at 80° C.-120° C. in an organic solvent. After the reaction is completed, compound I or a Boc-protected precursor of compound I is obtained by treatment. The Boc-protected precursor is further treated with an acid to remove the Boc group to obtain compound I. The preparation method according to claim 8, characterized in that it comprises: Route 1:
wherein R ₁ , R ₂ , R ₃ and Y are as defined in claim 1, and R ₁ ' is R ₁ or a Boc-protected precursor of R ₁ ; the preparation method comprises the following steps: (1) dissolving an amine compound in a mixture of DMF/DMSO/CH ₃ CN and water, adding a corresponding base and compound 1, reacting the reaction solution at 20-100° C., and treating the reaction solution to obtain compound 2 after the reaction is completed; (2) Compound 2 and Compound 3 are dissolved in a reaction solvent, and under the protection of an inert gas, Pd ₂ (dba) ₃ , Xant-phos and Cs ₂ CO ₃ are added for reaction at 80° C.-120° C. After the reaction is completed, the compound is treated to obtain a compound I or a Boc-protected precursor of the compound I, 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; R ₁ , R ₂ , R ₃ , and Y are defined as in claim 1, and R ₁ ' is R ₁ or a Boc protected precursor of R ₁ ; 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, Pd ₂ (dba) ₃ , Xant-phos and Cs ₂ CO ₃ are added for reaction at 80° C.-120° C. After the reaction is completed, the compound II or a Boc-protected precursor of the compound II is obtained by treatment, 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; R ₁ , R ₂ , R ₃ , and Y are defined as described in claim 1, and R ₁ ' is R ₁ or a Boc protected precursor of R ₁ ; 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, Pd ₂ (dba) ₃ , Xant-phos and Cs ₂ CO ₃ are added for reaction at 80° C.-120° C. After the reaction is completed, the compound III or a Boc-protected precursor of the compound III is obtained by treatment, wherein the Boc-protected precursor is further treated with an acid to remove the Boc group to obtain the compound III; Route 4:
wherein R ₁ , R ₂ , R ₃ and Y are as defined in claim 1, and R ₁ ' is R ₁ or a Boc-protected precursor of R ₁ ; 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 Pd ₂ (dba) ₃ , Xant-phos and Cs ₂ CO ₃ are added under inert gas protection, and the reaction is carried out at 80° C.-120° C. After the reaction is completed, the compound IV or a Boc-protected precursor of the compound IV is obtained by treatment, wherein the Boc-protected precursor is further treated with trifluoroacetic acid to remove the Boc group to obtain the compound IV. A key intermediate for preparing any of the compounds described in claims 1-7, characterized in that the intermediate is selected from any of the following structures:

A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of one or more compounds according to any one of claims 1 to 7. A pharmaceutical preparation, characterized in that it comprises one or more compounds according to any one of claims 1 to 7. Use of a 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. The use according to claim 13 is characterized in that the compound or a pharmaceutically acceptable salt thereof is used in the preparation of drugs for treating blood diseases, solid tumors, skin diseases, inflammation or autoimmune diseases. The use according to claim 13 or 14, characterized in that the compound is used alone or in combination with one or more other therapeutic agents.