CN111646995B - 4-amino-pyrimidoazenitrogen heterocycle-phenylurea derivative and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the field of chemistry and medicine, and specifically relates to 4-amino-pyrimidoazacyclo-phenylurea derivatives and their preparation methods and applications. The present invention provides a 4-amino-pyrimidoazacyclo-phenylurea derivative, the structural formula of which is shown in Formula I. In addition, the present invention also provides the preparation method and application of the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives. The 4-amino-pyrimidoazacyclo-phenylurea derivatives provided by the invention can be used as FLT3 kinase inhibitors, have good effects, and provide a new option for preparing antitumor drugs.

Description

4-Amino-pyrimidoazheterocyclic-phenylurea derivatives and their preparation methods and uses

technical field

The invention belongs to the field of chemistry and medicine, and specifically relates to 4-amino-pyrimidoazacyclo-phenylurea derivatives and their preparation methods and uses.

Background technique

Leukemia is a clonal disease of abnormal hematopoietic stem cells. Leukemia cells lose the ability to differentiate into mature functional blood cells and stagnate at different stages of cell development. Malignant proliferation, massive proliferation and accumulation of leukemia cells in bone marrow and other hematopoietic tissues and infiltration of other organs and organs The normal hematopoiesis is inhibited, and the clinical manifestations are anemia, hemorrhage, infection and infiltration of various organs. Leukemia is a heterogeneous malignant tumor with various types, complex etiology, and different clinical manifestations. Some leukemias have the characteristics of rapid onset, high mortality, short survival, easy recurrence, poor prognosis, and extremely difficult to cure.

Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins, especially the family of receptor protein tyrosine kinases, which function as growth factor receptors in many cells It plays an important role in the control of signal transduction pathways, such as cell cycle, cell growth, cell differentiation and cell death. Dysregulation of receptor tyrosine kinases is often found in diseases such as proliferative disorders, inflammatory disorders, and immune system disorders.

FLT3 (Fms-like tyrosine kinase 3) is a FMS-like tyrosine kinase 3, which belongs to the type III receptor tyrosine kinase (receptor tyrosine kinase III, RTK III) family member with c-Kit, c-FMS and PDGFR , the structure of FLT3 includes an extracellular domain, a transmembrane domain, and an intramembrane tyrosine kinase domain composed of five immunoglobulin-like components. FLT3 is mainly expressed on the cell surface of normal hematopoietic stem cells and hematopoietic progenitor cells, and its ligand is mainly expressed in bone marrow stromal cells. When the ligand binds to the extramembrane domain of FLT3, it promotes the dimerization of the FLT3 receptor, and at the same time, the tyrosine kinase domain in the cell membrane undergoes autophosphorylation, activating a series of downstream signal transduction pathways, such as Ras/MAPK, PI3K/Akt/ mTOR and STAT5 regulate cell proliferation and differentiation. Mutations in FLT3 usually lead to its abnormal activation. In the absence of ligand binding, autophosphorylation activates downstream signaling pathways, leading to abnormal proliferation of hematopoietic cells and lymphocytes, and various malignant blood diseases.

It has been confirmed that there are two main types of activating mutations in FLT3: internal tandem duplication (internal tandem duplication, ITD) and point mutations in the activation loop of the kinase domain (tyrosine kinase domain, TKD). FLT3-ITD mutation occurs in approximately 25% of acute myeloid leukemia patients and is associated with some poor prognosis, while FLT3-TKD mutation occurs in approximately 5% of acute myeloid leukemia patients.

A large number of studies have shown that FLT3 mutation is one of the most common molecular genetic abnormalities and poor prognosis factors in AML, and its conduction involves multiple signal transduction pathways, making FLT3 an ideal drug target. In previous studies, more than 20 compounds have shown inhibition of FLT3 tyrosine kinase. Many have entered clinical trials. Most of these small-molecule tyrosinase inhibitors are heterocyclic purine analogs, which are ATP analogs, or intermediates whose structure is similar to tyrosine covalently bonded to ATP. FLT3 receptors are still expressed, but the ATP pathway is blocked, so autophosphorylation and continuous phosphorylation of substrates are terminated, thereby blocking the signaling pathway of FLT3-ITD-dependent cell lines and exerting cytotoxic effects.

At present, the research on FLT3-ITD and FLT3-TKD inhibitors is a hotspot in drug development. The single-target FLT3 inhibitor AC220 is currently undergoing phase III clinical trials and is expected to be marketed. However, drug resistance in the later stage of treatment has become an urgent problem to be solved. question. Therefore, the development of inhibitors that are effective against both mutations is the direction of research and development.

Contents of the invention

In order to solve the above problems, the present invention provides a 4-amino-pyrimidoazacyclo-phenylurea derivative, the structural formula of which is shown in Formula I:

Wherein, X is N or C;

C2～C10烯基、C2～C10炔基、C3～C10环烷基、

或取代或未取代的C1～C10烷基；所述取代C1～C10烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C8烷氧基、C3～C8环烷基、C1～C8羰基或取代或未取代的3～6元杂环烷基；所述3～6元杂环烷基的杂原子为N、O或S，杂原子个数为1～3个；所述取代3～6元杂环烷基的取代基为-H、-OH、卤素、C1～C8氧羰基、C1～C8烷基、C1～C8烷氧基或

R₄为-H、-OH、卤素、C1～C8烷基、C1～C8烷氧基或

R₅～R₁₀独立的为-H或C1～C8烷基；R ₁ is -H, -OH, halogen, C1～C10 alkoxy, C1～C10 haloalkoxy,

C2～C10 alkenyl, C2～C10 alkynyl, C3～C10 cycloalkyl,

Or substituted or unsubstituted C1～C10 alkyl; the substituent of the substituted C1～C10 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 carbonyl or substituted or unsubstituted 3-6 membered heterocycloalkyl; said 3-6 membered The heteroatom of the heterocycloalkyl is N, O or S, and the number of heteroatoms is 1 to 3; the substituents of the substituted 3 to 6 membered heterocycloalkyl are -H, -OH, halogen, C1 to C8 Oxycarbonyl, C1～C8 alkyl, C1～C8 alkoxy or

R ₄ is -H, -OH, halogen, C1～C8 alkyl, C1～C8 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C8 alkyl;

_R2 is -H, -OH, halogen, C1~C10 alkyl, C3~C10 cycloalkyl, C1~C10 haloalkyl, amino-substituted C1~C10 alkyl, benzyl, substituted or unsubstituted C5~C10 Aryl or substituted or unsubstituted 5-10 membered heteroaryl; the heteroatom of the 5-10 membered heteroaryl is N, O or S, and the number of heteroatoms is 1-3; the substituted C5～ The substituents of C10 aryl or 5-10 membered heteroaryl are -H, halogen, -NH ₂ , C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1～C8 haloalkoxy, -OH or C1～C8 carbonyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C10 alkyl.

C2～C8烯基、C2～C8炔基、C3～C8环烷基、

或取代或未取代的C1～C8烷基；所述取代C1～C8烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C6烷氧基、C3～C6环烷基、C1～C6羰基或取代或未取代的3～6元杂环烷基；所述3～6元杂环烷基的杂原子为N、O或S，杂原子个数为1～3个；所述取代3～6元杂环烷基的取代基为-H、-OH、卤素、C1～C6氧羰基、C1～C6烷基、C1～C6烷氧基或

R₄为-H、-OH、卤素、C1～C6烷基、C1～C6烷氧基或

R₅～R₁₀独立的为-H或C1～C6烷基；As a preferred solution of the present invention, X is N or C; _R1 is -H, -OH, halogen, C1～C8 alkoxy, C1～C8 haloalkoxy,

C2～C8 alkenyl, C2～C8 alkynyl, C3～C8 cycloalkyl,

Or substituted or unsubstituted C1～C8 alkyl; the substituent of the substituted C1～C8 alkyl is -H,

-CN, -OH, phenyl, halogen, C1~C6 alkoxy, C3~C6 cycloalkyl, C1~C6 carbonyl or substituted or unsubstituted 3~6 membered heterocycloalkyl; said 3~6 membered The heteroatom of the heterocycloalkyl is N, O or S, and the number of heteroatoms is 1 to 3; the substituents of the substituted 3 to 6 membered heterocycloalkyl are -H, -OH, halogen, C1 to C6 Oxycarbonyl, C1~C6 alkyl, C1~C6 alkoxy or

R ₄ is -H, -OH, halogen, C1～C6 alkyl, C1～C6 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C6 alkyl;

_R2 is -H, -OH, halogen, C1~C8 alkyl, C3~C8 cycloalkyl, C1~C8 haloalkyl, amino-substituted C1~C8 alkyl, benzyl, substituted or unsubstituted C5~C8 Aryl or substituted or unsubstituted 5-8 membered heteroaryl; the heteroatom of the 5-8 membered heteroaryl is N, O or S, and the number of heteroatoms is 1-3; the substituted C5～ The substituents of C8 aryl or 5-8 membered heteroaryl are -H, halogen, -NH ₂ , C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1~C6 haloalkoxy, -OH or C1~C6 carbonyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C8 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基、

或取代的C1～C6烷基；所述取代C1～C6烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的3～6元杂环烷基；所述3～6元杂环烷基的杂原子为N、O或S，杂原子个数为1～3个；所述取代3～6元杂环烷基的取代基为-H、-OH、卤素、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；Further, as a preferred solution of the present invention, X is N or C; _R1 is -H, -OH, halogen, C1~C8 alkyl, C1~C6 alkoxy, C1~C6 haloalkoxy,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl,

Or substituted C1～C6 alkyl; the substituent of the substituted C1～C6 alkyl is -H,

-CN, -OH, phenyl, halogen, C1~C4 alkoxy, C3~C6 cycloalkyl, C1~C4 carbonyl or substituted or unsubstituted 3~6 membered heterocycloalkyl; said 3~6 membered The heteroatom of the heterocycloalkyl is N, O or S, and the number of heteroatoms is 1 to 3; the substituents of the substituted 3 to 6 membered heterocycloalkyl are -H, -OH, halogen, C1 to C4 Oxycarbonyl, C1~C4 alkyl, C1~C4 alkoxy or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C4 alkyl;

_R2 is -H, -OH, halogen, C1~C6 alkyl, C3~C6 cycloalkyl, C1~C6 haloalkyl, amino-substituted C1~C6 alkyl, benzyl, substituted or unsubstituted C5~C6 Aryl or substituted or unsubstituted 5-6 membered heteroaryl; the heteroatom of the 5-6 membered heteroaryl is N, O or S, and the number of heteroatoms is 1-3; the substituted C5～ The substituents of C6 aryl or 5-6 membered heteroaryl are -H, halogen, -NH ₂ , C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1～C4 haloalkoxy, -OH or C1～C4 carbonyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C6 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；Preferably, in the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C4 alkyl;

_R2 is -H, -OH, halogen, C1~C6 alkyl, C3~C6 cycloalkyl, C1~C6 haloalkyl, amino-substituted C1~C6 alkyl, benzyl, substituted or unsubstituted C5~C6 Aryl or substituted or unsubstituted 5-6 membered heteroaryl; the heteroatom of the 5-6 membered heteroaryl is N, O or S, and the number of heteroatoms is 1-3; the substituted C5～ The substituents of C6 aryl or 5-6 membered heteroaryl are -H, halogen, -NH ₂ , C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1～C4 haloalkoxy, -OH or C1～C4 carbonyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C6 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基、

或

R₄为-H、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；R₁₁为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

Further, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1~C4 alkoxy, C3~C6 cycloalkyl, C1~C4 carbonyl,

or

R ₄ is -H, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ～R ₁₀ are independently -H or C1～C4 alkyl; R ₁₁ is -H, C1～C4 oxycarbonyl, C1～C4 alkyl, C1～C4 alkoxy or

_R2 is -H, -OH, halogen, C1~C6 alkyl, C3~C6 cycloalkyl, C1~C6 haloalkyl, amino-substituted C1~C6 alkyl, benzyl, substituted or unsubstituted C5~C6 Aryl or substituted or unsubstituted 5-6 membered heteroaryl; the heteroatom of the 5-6 membered heteroaryl is N, O or S, and the number of heteroatoms is 1-3; the substituted C5～ The substituents of C6 aryl or 5-6 membered heteroaryl are -H, halogen, -NH ₂ , C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1～C4 haloalkoxy, -OH or C1～C4 carbonyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C6 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、甲氧基、乙氧基、

甲酰基、乙酰基、

R₄为-H、C1～C4烷基、叔丁基氧基或

R₅～R₁₀独立的为-H、甲基或乙基；Further, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, methoxy, ethoxy,

formyl, acetyl,

R ₄ is -H, C1～C4 alkyl, tert-butyloxy or

R ₅ to R ₁₀ are independently -H, methyl or ethyl;

_R2 is -H, -OH, halogen, C1~C6 alkyl, C3~C6 cycloalkyl, C1~C6 haloalkyl, amino-substituted C1~C6 alkyl, benzyl, substituted or unsubstituted C5~C6 Aryl or substituted or unsubstituted 5-6 membered heteroaryl; the heteroatom of the 5-6 membered heteroaryl is N, O or S, and the number of heteroatoms is 1-3; the substituted C5～ The substituents of C6 aryl or 5-6 membered heteroaryl are -H, halogen, -NH ₂ , C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1～C4 haloalkoxy, -OH or C1～C4 carbonyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C6 alkyl.

叔丁氧羰基、C2～C6烯基、C2～C6炔基、

Most preferably, X is N or C; R ₁ is -H, C1～C8 alkyl,

tert-butoxycarbonyl, C2～C6 alkenyl, C2～C6 alkynyl,

_R2 is -H, -OH, halogen, C1~C6 alkyl, C3~C6 cycloalkyl, C1~C6 haloalkyl, amino-substituted C1~C6 alkyl, benzyl, substituted or unsubstituted C5~C6 Aryl or substituted or unsubstituted 5-6 membered heteroaryl; the heteroatom of the 5-6 membered heteroaryl is N, O or S, and the number of heteroatoms is 1-3; the substituted C5～ The substituents of C6 aryl or 5-6 membered heteroaryl are -H, halogen, -NH ₂ , C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1～C4 haloalkoxy, -OH or C1～C4 carbonyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C6 alkyl.

Preferably, for the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives, X is N or C; _R2 is benzyl, C3-C6 cycloalkyl, substituted or unsubstituted C5-C6 aryl Or a substituted or unsubstituted 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N or O, and the number of heteroatoms is 1-2; the substituted C5-C6 aryl group or The substituents of 5-6 membered heteroaryl groups are -H, halogen, -NH ₂ , C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkane Oxygen, -OH or C1~C4 carbonyl;

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C4 alkyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C6 alkyl.

R₁₂～R₁₉独立的为-H、卤素、-NH₂、C1～C4烷基、C3～C6环烷基、C1～C4卤代烷基、C1～C4烷氧基、C1～C4卤代烷氧基、-OH或C1～C4羰基；Further, X is N or C; R ₂ is benzyl, C3～C6 cycloalkyl,

R ₁₂ to R ₁₉ are independently -H, halogen, -NH ₂ , C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OH or C1～C4 carbonyl;

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C4 alkyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C6 alkyl.

R₁₆～R₁₉独立的为-H、卤素、-NH₂、C1～C4烷基、C1～C4卤代烷基、-OH或C1～C4羰基；Further, X is N or C; R ₂ is benzyl, C3～C6 cycloalkyl,

R ₁₆ to R ₁₉ are independently -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 haloalkyl, -OH or C1-C4 carbonyl;

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C4 alkyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C6 alkyl.

R₁₆～R₁₉独立的为-H、-F、-Cl、-Br、-CF₃、甲基或乙酰基；Still further, X is N or C; R ₂ is benzyl, C3～C6 cycloalkyl,

R ₁₆ to R ₁₉ are independently -H, -F, -Cl, -Br, -CF ₃ , methyl or acetyl;

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C4 alkyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C6 alkyl.

Most preferably, X is N or C; R ₂ is

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C4 alkyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C6 alkyl.

Preferably, in the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives, X is N or C; _R3 is -H, halogen, -OH or C1～C4 alkyl; _R2 is benzyl, C3-C6 cycloalkyl, substituted or unsubstituted C5-C6 aryl or substituted or unsubstituted 5-6 membered heteroaryl; the heteroatom of the 5-6 membered heteroaryl is N or O, and the heteroatom The number is 1 to 2; the substituents of the substituted C5-C6 aryl or 5-6 membered heteroaryl are -H, halogen, -NH ₂ , C1-C4 alkyl, C3-C6 cycloalkyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy, -OH or C1~C4 carbonyl;

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基。R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ -R ₁₀ are independently -H or C1-C4 alkyl.

Further, X is N or C; R ₃ is -H, halogen or C1~C4 alkyl; R ₂ is benzyl, C3~C6 cycloalkyl, substituted or unsubstituted C5~C6 aryl or substituted or unsubstituted A substituted 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N or O, and the number of heteroatoms is 1-2; the substituted C5-C6 aryl group or 5-6-membered The substituents of heteroaryl are -H, halogen, -NH ₂ , C1~C4 alkyl, C3~C6 cycloalkyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy, - OH or C1～C4 carbonyl;

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基。R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ -R ₁₀ are independently -H or C1-C4 alkyl.

Furthermore, X is N or C; R ₃ is -H or halogen; R ₂ is benzyl, C3-C6 cycloalkyl, substituted or unsubstituted C5-C6 aryl or substituted or unsubstituted 5-6 Member heteroaryl; the heteroatom of the 5-6 member heteroaryl is N or O, and the number of heteroatoms is 1-2; the substitution of the substituted C5-C6 aryl or 5-6 member heteroaryl The group is -H, halogen, -NH ₂ , C1~C4 alkyl, C3~C6 cycloalkyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy, -OH or C1~C4 carbonyl;

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基。R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ -R ₁₀ are independently -H or C1-C4 alkyl.

Most preferably, X is N or C; R ₃ is -H, -F, -Cl or -Br; R ₂ is benzyl, C3~C6 cycloalkyl, substituted or unsubstituted C5~C6 aryl or substituted Or an unsubstituted 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N or O, and the number of heteroatoms is 1-2; the substituted C5-C6 aryl group or 5- The substituents of 6-membered heteroaryl are -H, halogen, -NH ₂ , C1~C4 alkyl, C3~C6 cycloalkyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy , -OH or C1~C4 carbonyl;

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基。R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ -R ₁₀ are independently -H or C1-C4 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基、

R₄为-H、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；R₁₁为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

As a preferred technical solution of the present invention, in the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives, X is N or C; R is _-H , C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1~C4 alkoxy, C3~C6 cycloalkyl, C1~C4 carbonyl,

R ₄ is -H, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ～R ₁₀ are independently -H or C1～C4 alkyl; R ₁₁ is -H, C1～C4 oxycarbonyl, C1～C4 alkyl, C1～C4 alkoxy or

R₁₂～R₁₉独立的为-H、卤素、-NH₂、C1～C4烷基、C3～C6环烷基、C1～C4卤代烷基、C1～C4烷氧基、C1～C4卤代烷氧基、-OH或C1～C4羰基；R ₂ is benzyl, C3～C6 cycloalkyl,

R ₁₂ to R ₁₉ are independently -H, halogen, -NH ₂ , C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OH or C1～C4 carbonyl;

R ₃ is -H, halogen or C1-C4 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、甲氧基、乙氧基、

甲酰基、乙酰基、

R₄为-H、C1～C4烷基、叔丁基氧基或

R₅～R₁₀独立的为-H、甲基或乙基；Preferably, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, methoxy, ethoxy,

formyl, acetyl,

R ₄ is -H, C1～C4 alkyl, tert-butyloxy or

R ₅ to R ₁₀ are independently -H, methyl or ethyl;

R₁₆～R₁₉独立的为-H、卤素、-NH₂、C1～C4烷基、C1～C4卤代烷基、-OH或C1～C4羰基；R ₂ is benzyl, C3～C6 cycloalkyl,

R ₁₆ to R ₁₉ are independently -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 haloalkyl, -OH or C1-C4 carbonyl;

_R3 is -H or halogen.

叔丁氧羰基、C2～C6烯基、C2～C6炔基、

Most preferably, X is N or C; R ₁ is -H, C1～C8 alkyl,

tert-butoxycarbonyl, C2～C6 alkenyl, C2～C6 alkynyl,

_R2 is

_R3 is -H, -F, -Cl or -Br.

时，结构如式Ⅱ所示：As a preferred technical solution of the present invention, the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives, when R ₂ is

, the structure is shown in Formula II:

C2～C10烯基、C2～C10炔基、C3～C10环烷基、

或取代或未取代的C1～C10烷基；所述取代C1～C10烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C8烷氧基、C3～C8环烷基、C1～C8羰基或取代或未取代的3～6元杂环烷基；所述3～6元杂环烷基的杂原子为N、O或S，杂原子个数为1～3个；所述取代3～6元杂环烷基的取代基为-H、-OH、卤素、C1～C8氧羰基、C1～C8烷基、C1～C8烷氧基或

R₄为-H、-OH、卤素、C1～C8烷基、C1～C8烷氧基或

R₅～R₁₀独立的为-H或C1～C8烷基；Wherein, X is N or C; _R1 is -H, -OH, halogen, C1～C10 alkoxy, C1～C10 haloalkoxy,

C2～C10 alkenyl, C2～C10 alkynyl, C3～C10 cycloalkyl,

Or substituted or unsubstituted C1～C10 alkyl; the substituent of the substituted C1～C10 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 carbonyl or substituted or unsubstituted 3-6 membered heterocycloalkyl; said 3-6 membered The heteroatom of the heterocycloalkyl is N, O or S, and the number of heteroatoms is 1 to 3; the substituents of the substituted 3 to 6 membered heterocycloalkyl are -H, -OH, halogen, C1 to C8 Oxycarbonyl, C1～C8 alkyl, C1～C8 alkoxy or

R ₄ is -H, -OH, halogen, C1～C8 alkyl, C1～C8 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C8 alkyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C10 alkyl.

C2～C8烯基、C2～C8炔基、C3～C8环烷基、

或取代或未取代的C1～C8烷基；所述取代C1～C8烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C6烷氧基、C3～C6环烷基、C1～C6羰基或取代或未取代的3～6元杂环烷基；所述3～6元杂环烷基的杂原子为N、O或S，杂原子个数为1～3个；所述取代3～6元杂环烷基的取代基为-H、-OH、卤素、C1～C6氧羰基、C1～C6烷基、C1～C6烷氧基或

R₄为-H、-OH、卤素、C1～C6烷基、C1～C6烷氧基或

R₅～R₁₀独立的为-H或C1～C6烷基；Preferably, X is N or C; R ₁ is -H, -OH, halogen, C1~C8 alkoxy, C1~C8 haloalkoxy,

C2～C8 alkenyl, C2～C8 alkynyl, C3～C8 cycloalkyl,

Or substituted or unsubstituted C1～C8 alkyl; the substituent of the substituted C1～C8 alkyl is -H,

-CN, -OH, phenyl, halogen, C1~C6 alkoxy, C3~C6 cycloalkyl, C1~C6 carbonyl or substituted or unsubstituted 3~6 membered heterocycloalkyl; said 3~6 membered The heteroatom of the heterocycloalkyl is N, O or S, and the number of heteroatoms is 1 to 3; the substituents of the substituted 3 to 6 membered heterocycloalkyl are -H, -OH, halogen, C1 to C6 Oxycarbonyl, C1~C6 alkyl, C1~C6 alkoxy or

R ₄ is -H, -OH, halogen, C1～C6 alkyl, C1～C6 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C6 alkyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C8 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基、

或取代的C1～C6烷基；所述取代C1～C6烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的3～6元杂环烷基；所述3～6元杂环烷基的杂原子为N、O或S，杂原子个数为1～3个；所述取代3～6元杂环烷基的取代基为-H、-OH、卤素、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；Further preferably, X is N or C; R ₁ is -H, -OH, halogen, C1~C8 alkyl, C1~C6 alkoxy, C1~C6 haloalkoxy,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl,

Or substituted C1～C6 alkyl; the substituent of the substituted C1～C6 alkyl is -H,

-CN, -OH, phenyl, halogen, C1~C4 alkoxy, C3~C6 cycloalkyl, C1~C4 carbonyl or substituted or unsubstituted 3~6 membered heterocycloalkyl; said 3~6 membered The heteroatom of the heterocycloalkyl is N, O or S, and the number of heteroatoms is 1 to 3; the substituents of the substituted 3 to 6 membered heterocycloalkyl are -H, -OH, halogen, C1 to C4 Oxycarbonyl, C1~C4 alkyl, C1~C4 alkoxy or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C4 alkyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C6 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；Further, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C4 alkyl;

R ₃ is -H, -OH, halogen or C1-C4 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基、

R₄为-H、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；R₁₁为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₃为-H、-OH或卤素。Further, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1~C4 alkoxy, C3~C6 cycloalkyl, C1~C4 carbonyl,

R ₄ is -H, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ～R ₁₀ are independently -H or C1～C4 alkyl; R ₁₁ is -H, C1～C4 oxycarbonyl, C1～C4 alkyl, C1～C4 alkoxy or

R ₃ is -H, -OH or halogen.

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、甲氧基、乙氧基、

甲酰基、乙酰基、

R₄为-H、C1～C4烷基、叔丁基氧基或

R₅～R₁₀独立的为-H、甲基或乙基；More preferably, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, methoxy, ethoxy,

formyl, acetyl,

R ₄ is -H, C1～C4 alkyl, tert-butyloxy or

R ₅ to R ₁₀ are independently -H, methyl or ethyl;

_R3 is -H or halogen.

叔丁氧羰基、C2～C6烯基、C2～C6炔基、

Most preferably, X is N or C; R ₁ is -H, C1～C8 alkyl,

tert-butoxycarbonyl, C2～C6 alkenyl, C2～C6 alkynyl,

_R3 is -H, -F, -Cl or -Br.

R₃为-H时，结构如式Ⅲ所示：As a preferred technical solution of the present invention, the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives, when R ₂ is

When R ₃ is -H, the structure is shown in formula III:

C2～C10烯基、C2～C10炔基、C3～C10环烷基、

或取代或未取代的C1～C10烷基；所述取代C1～C10烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C8烷氧基、C3～C8环烷基、C1～C8羰基或取代或未取代的3～6元杂环烷基；所述3～6元杂环烷基的杂原子为N、O或S，杂原子个数为1～3个；所述取代3～6元杂环烷基的取代基为-H、-OH、卤素、C1～C8氧羰基、C1～C8烷基、C1～C8烷氧基或

R₄为-H、-OH、卤素、C1～C8烷基、C1～C8烷氧基或

R₅～R₁₀独立的为-H或C1～C8烷基。Wherein, X is N or C; _R1 is -H, -OH, halogen, C1～C10 alkoxy, C1～C10 haloalkoxy,

C2～C10 alkenyl, C2～C10 alkynyl, C3～C10 cycloalkyl,

Or substituted or unsubstituted C1～C10 alkyl; the substituent of the substituted C1～C10 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 carbonyl or substituted or unsubstituted 3-6 membered heterocycloalkyl; said 3-6 membered The heteroatom of the heterocycloalkyl is N, O or S, and the number of heteroatoms is 1 to 3; the substituents of the substituted 3 to 6 membered heterocycloalkyl are -H, -OH, halogen, C1 to C8 Oxycarbonyl, C1～C8 alkyl, C1～C8 alkoxy or

R ₄ is -H, -OH, halogen, C1～C8 alkyl, C1～C8 alkoxy or

R ₅ -R ₁₀ are independently -H or C1-C8 alkyl.

C2～C8烯基、C2～C8炔基、C3～C8环烷基、

或取代或未取代的C1～C8烷基；所述取代C1～C8烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C6烷氧基、C3～C6环烷基、C1～C6羰基或取代或未取代的3～6元杂环烷基；所述3～6元杂环烷基的杂原子为N、O或S，杂原子个数为1～3个；所述取代3～6元杂环烷基的取代基为-H、-OH、卤素、C1～C6氧羰基、C1～C6烷基、C1～C6烷氧基或

R₄为-H、-OH、卤素、C1～C6烷基、C1～C6烷氧基或

R₅～R₁₀独立的为-H或C1～C6烷基。Preferably, X is N or C; R ₁ is -H, -OH, halogen, C1~C8 alkoxy, C1~C8 haloalkoxy,

C2～C8 alkenyl, C2～C8 alkynyl, C3～C8 cycloalkyl,

Or substituted or unsubstituted C1～C8 alkyl; the substituent of the substituted C1～C8 alkyl is -H,

-CN, -OH, phenyl, halogen, C1~C6 alkoxy, C3~C6 cycloalkyl, C1~C6 carbonyl or substituted or unsubstituted 3~6 membered heterocycloalkyl; said 3~6 membered The heteroatom of the heterocycloalkyl is N, O or S, and the number of heteroatoms is 1 to 3; the substituents of the substituted 3 to 6 membered heterocycloalkyl are -H, -OH, halogen, C1 to C6 Oxycarbonyl, C1~C6 alkyl, C1~C6 alkoxy or

R ₄ is -H, -OH, halogen, C1～C6 alkyl, C1～C6 alkoxy or

R ₅ -R ₁₀ are independently -H or C1-C6 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基、

或取代的C1～C6烷基；所述取代C1～C6烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的3～6元杂环烷基；所述3～6元杂环烷基的杂原子为N、O或S，杂原子个数为1～3个；所述取代3～6元杂环烷基的取代基为-H、-OH、卤素、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基。Further preferably, X is N or C; R ₁ is -H, -OH, halogen, C1~C8 alkyl, C1~C6 alkoxy, C1~C6 haloalkoxy,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl,

Or substituted C1～C6 alkyl; the substituent of the substituted C1～C6 alkyl is -H,

-CN, -OH, phenyl, halogen, C1~C4 alkoxy, C3~C6 cycloalkyl, C1~C4 carbonyl or substituted or unsubstituted 3~6 membered heterocycloalkyl; said 3~6 membered The heteroatom of the heterocycloalkyl is N, O or S, and the number of heteroatoms is 1 to 3; the substituents of the substituted 3 to 6 membered heterocycloalkyl are -H, -OH, halogen, C1 to C4 Oxycarbonyl, C1~C4 alkyl, C1~C4 alkoxy or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ -R ₁₀ are independently -H or C1-C4 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基或取代或未取代的5～6元杂环烷基；所述5～6元杂环烷基的杂原子为N或O，杂原子个数为1～2个；所述取代5～6元杂环烷基的取代基为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

R₄为-H、-OH、卤素、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基。Further, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 carbonyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; said 5-6 membered The heteroatom of the heterocycloalkyl is N or O, and the number of heteroatoms is 1 to 2; the substituents of the substituted 5- to 6-membered heterocycloalkyl are -H, C1-C4 oxycarbonyl, C1-C4 alkane group, C1～C4 alkoxy group or

R ₄ is -H, -OH, halogen, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ -R ₁₀ are independently -H or C1-C4 alkyl.

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C4烷氧基、C3～C6环烷基、C1～C4羰基、

R₄为-H、C1～C4烷基、C1～C4烷氧基或

R₅～R₁₀独立的为-H或C1～C4烷基；R₁₁为-H、C1～C4氧羰基、C1～C4烷基、C1～C4烷氧基或

Further, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, C1~C4 alkoxy, C3~C6 cycloalkyl, C1~C4 carbonyl,

R ₄ is -H, C1～C4 alkyl, C1～C4 alkoxy or

R ₅ ～R ₁₀ are independently -H or C1～C4 alkyl; R ₁₁ is -H, C1～C4 oxycarbonyl, C1～C4 alkyl, C1～C4 alkoxy or

C2～C6烯基、C2～C6炔基、C3～C6环烷基或取代的C1～C4烷基；所述取代C1～C4烷基的取代基为-H、

-CN、-OH、苯基、卤素、甲氧基、乙氧基、

甲酰基、乙酰基、

R₄为-H、C1～C4烷基、叔丁基氧基或

R₅～R₁₀独立的为-H、甲基或乙基。More preferably, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is -H,

-CN, -OH, phenyl, halogen, methoxy, ethoxy,

formyl, acetyl,

R ₄ is -H, C1～C4 alkyl, tert-butyloxy or

R ₅ to R ₁₀ are independently -H, methyl or ethyl.

叔丁氧羰基、C2～C6烯基、C2～C6炔基、

Most preferably, X is N or C; R ₁ is -H, C1～C8 alkyl,

tert-butoxycarbonyl, C2～C6 alkenyl, C2～C6 alkynyl,

R₃为-H、X为C、R₁为

时，结构如式Ⅳ所示：As a preferred technical solution of the present invention, the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives, when R ₂ is

R ₃ is -H, X is C, R ₁ is

, the structure is shown in Formula IV:

Among them, R ₁₆ ~ R ₁₉ are independently -H, halogen, -NH ₂ , C1~C4 alkyl, C3~C6 cycloalkyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy group, -OH or C1~C4 carbonyl.

Preferably, R ₁₆ to R ₁₉ are independently -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 haloalkyl, -OH or C1-C4 carbonyl.

Most preferably, R ₁₆ to R ₁₉ are independently -H, -F, -Cl, -Br, -CF ₃ , methyl or acetyl.

The 4-amino-pyrimidoazheterocyclic-phenylurea derivatives of the present invention have the following structural formula:

The present invention also provides a synthetic method for the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives. The present invention mainly adopts the following synthetic route:

The synthetic method of compound of the present invention is: the structure of the compound of general formula (I) of the present invention is divided into A part and B part as above, wherein A part is amine intermediate (formula V) compound, and B part is active urea intermediate ( Formula VI) compound or isocyanate intermediate.

Scheme one: the synthetic method of A part amine intermediate (formula V) compound is as follows:

Wherein, the synthetic method of pyrimidopyrrole intermediate is shown in the following scheme:

Step a: Ammonification: With 4-chloropyrrolopyrimidine (commercially available) as the starting material SM1, add ammonia water (g/mL≈5 to 7 times) in the autoclave, the pressure is 10 to 15 atmospheres, and the reaction After cooling for 4 hours, intermediate M1 was obtained by filtration and dried without further purification;

Step b: Iodo: Dissolve intermediate M1 in a solvent at room temperature, add N-iodosuccinimide (NIS) (1.5 times equivalent) to react for 1 hour, concentrate the solution, add 30 to 40 times water to carry out Beating, and adding 0.5 equivalent of sodium thiosulfate, after filtration to obtain intermediate M2, no further purification is required after drying; the solvent is tetrahydrofuran, DMF or acetonitrile, etc.;

Step c: Boc protection: Dissolve the intermediate M2 in a solvent, add 2 equivalents of an organic base, add 1 equivalent of Boc anhydride (for example: di-tert-butyl dicarbonate) and react at 50-60°C for 2 hours, and the reaction ends Afterwards, the reaction solution is concentrated, and beaten with 30 to 40 times of water, and the intermediate M3 is obtained after filtration, and no further purification is required after drying; the solvent is acetonitrile, DMF or dioxane, etc.; the organic base is triethylamine , DIEA or pyridine, etc.;

Step d: Suzuki reaction: After mixing the intermediate M3 with boric acid/boric acid pinacol ester, alkali, catalyst, etc., add solvent, and carry out the reaction under the protection of nitrogen. The reaction temperature is 70-90°C, after 2-4 hours of reaction Process, obtain intermediate M4 after simple treatment, need to purify further; Described alkali is the inorganic bases such as salt of wormwood, sodium carbonate, potassium bicarbonate or sodium bicarbonate; Described catalyst is (dppf)PdCl Or _four (three Phenylphosphine) palladium; The solvent is a mixed solvent of dioxane, ethanol and water or a mixed solvent of toluene, ethanol and water;

Step e: Boc removal: Dissolve the intermediate M4 in a solvent at room temperature, add a strong acid, and the pH of the system is about 1. After the reaction is completed, adjust it to alkaline with an inorganic base, and the pH is about 13. After extraction with dichloromethane, the organic After the phase is concentrated, it is beaten with ether, filtered to obtain the intermediate M5, and no further purification is required after drying; the solvent is water or ethanol, etc.; the strong acid is an inorganic strong acid such as sulfuric acid, methanesulfonic acid or hydrochloric acid; Potassium or sodium hydroxide, etc.;

Step f: Substitution: Dissolve intermediate M5 in a solvent, add 1.2 equivalents of halide, react at 70-80°C for 1 hour, filter the reaction solution to remove inorganic salts to obtain a solution of intermediate M6 (compound of formula V), without further purification ; The solvent is acetonitrile, toluene, dioxane or DMF and the like.

The synthetic method of part B amine intermediate (formula VI) compound is as follows:

Dissolve triphosgene in a solvent, add 1 equivalent of amine raw material, and then add an organic base, the reaction temperature is 60-65° C., and react for 4-5 hours. After the reaction is completed, the solid residue is removed by filtration, and the filtrate is concentrated to obtain the intermediate ( Formula VI compound); the solvent is tetrahydrofuran and the like; the organic base is triethylamine or DIEA and the like.

Then, dissolve the intermediate compound (formula V) in a solvent, add 1 equivalent of the intermediate compound (formula VI), react at 70-80°C for 1 hour, a large amount of solids precipitate out, and the filter cake after filtration is the final urea Class compound, namely general formula (I) compound; Described solvent is acetonitrile, dioxane, toluene or DMF etc.;

C2～C10烯基、C2～C10炔基、C3～C10环烷基、

或取代或未取代的C1～C10烷基；所述取代C1～C10烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C8烷氧基、C3～C8环烷基、C1～C8羰基或取代或未取代的3～6元杂环烷基；所述3～6元杂环烷基的杂原子为N、O或S，杂原子个数为1～3个；所述取代3～6元杂环烷基的取代基为-H、-OH、卤素、C1～C8氧羰基、C1～C8烷基、C1～C8烷氧基或

R₄为-H、-OH、卤素、C1～C8烷基、C1～C8烷氧基或

R₅～R₁₀独立的为-H或C1～C8烷基；Wherein, X is N or C; _R1 is -H, -OH, halogen, C1～C10 alkoxy, C1～C10 haloalkoxy,

C2～C10 alkenyl, C2～C10 alkynyl, C3～C10 cycloalkyl,

Or substituted or unsubstituted C1～C10 alkyl; the substituent of the substituted C1～C10 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 carbonyl or substituted or unsubstituted 3-6 membered heterocycloalkyl; said 3-6 membered The heteroatom of the heterocycloalkyl is N, O or S, and the number of heteroatoms is 1 to 3; the substituents of the substituted 3 to 6 membered heterocycloalkyl are -H, -OH, halogen, C1 to C8 Oxycarbonyl, C1～C8 alkyl, C1～C8 alkoxy or

R ₄ is -H, -OH, halogen, C1～C8 alkyl, C1～C8 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C8 alkyl;

_R2 is -H, -OH, halogen, C1~C10 alkyl, C3~C10 cycloalkyl, C1~C10 haloalkyl, amino-substituted C1~C10 alkyl, benzyl, substituted or unsubstituted C5~C10 Aryl or substituted or unsubstituted 5-10 membered heteroaryl; the heteroatom of the 5-10 membered heteroaryl is N, O or S, and the number of heteroatoms is 1-3; the substituted C5～ The substituents of C10 aryl or 5-10 membered heteroaryl are -H, halogen, -NH ₂ , C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1～C8 haloalkoxy, -OH or C1～C8 carbonyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C10 alkyl.

Option II:

The synthesis of the intermediate compound (Formula Ⅴ) is the same as Scheme 1. Dissolve the intermediate compound (Formula Ⅴ) in the solvent, add 1 equivalent of isocyanate intermediate, react at 70-80°C for 1 hour, a large amount of solids precipitate out, and after filtration The filter cake is the final urea compound, i.e. the compound of general formula (I); the solvent is acetonitrile, dioxane, toluene or DMF etc.;

C2～C10烯基、C2～C10炔基、C3～C10环烷基、

或取代或未取代的C1～C10烷基；所述取代C1～C10烷基的取代基为-H、

-CN、-OH、苯基、卤素、C1～C8烷氧基、C3～C8环烷基、C1～C8羰基或取代或未取代的3～6元杂环烷基；所述3～6元杂环烷基的杂原子为N、O或S，杂原子个数为1～3个；所述取代3～6元杂环烷基的取代基为-H、-OH、卤素、C1～C8氧羰基、C1～C8烷基、C1～C8烷氧基或

R₄为-H、-OH、卤素、C1～C8烷基、C1～C8烷氧基或

R₅～R₁₀独立的为-H或C1～C8烷基；Wherein, X is N or C; _R1 is -H, -OH, halogen, C1～C10 alkoxy, C1～C10 haloalkoxy,

C2～C10 alkenyl, C2～C10 alkynyl, C3～C10 cycloalkyl,

Or substituted or unsubstituted C1～C10 alkyl; the substituent of the substituted C1～C10 alkyl is -H,

-CN, -OH, phenyl, halogen, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 carbonyl or substituted or unsubstituted 3-6 membered heterocycloalkyl; said 3-6 membered The heteroatom of the heterocycloalkyl is N, O or S, and the number of heteroatoms is 1 to 3; the substituents of the substituted 3 to 6 membered heterocycloalkyl are -H, -OH, halogen, C1 to C8 Oxycarbonyl, C1～C8 alkyl, C1～C8 alkoxy or

R ₄ is -H, -OH, halogen, C1～C8 alkyl, C1～C8 alkoxy or

R ₅ ~ R ₁₀ are independently -H or C1 ~ C8 alkyl;

_R2 is -H, -OH, halogen, C1~C10 alkyl, C3~C10 cycloalkyl, C1~C10 haloalkyl, amino-substituted C1~C10 alkyl, benzyl, substituted or unsubstituted C5~C10 Aryl or substituted or unsubstituted 5-10 membered heteroaryl; the heteroatom of the 5-10 membered heteroaryl is N, O or S, and the number of heteroatoms is 1-3; the substituted C5～ The substituents of C10 aryl or 5-10 membered heteroaryl are -H, halogen, -NH ₂ , C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1～C8 haloalkoxy, -OH or C1～C8 carbonyl;

R ₃ is -H, -OH, halogen, -NH ₂ or C1-C10 alkyl.

The present invention also provides the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives, including tautomers, stereoisomers and mixtures thereof in all proportions, and compounds substituted by isotopes.

The present invention also provides pharmaceutically acceptable salts of the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives. Wherein, forming a salt with an acid means that it is obtained by reacting the free base of the parent compound with an inorganic acid or an organic acid. Inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like. Organic acids include acetic, propionic, acrylic, oxalic, (D) or (L) malic, fumaric, maleic, hydroxybenzoic, gamma-hydroxybutyric, methoxybenzoic, phthalic , methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid, etc.

The term "pharmaceutically acceptable" used in the present invention means, within the scope of reasonable medical judgment, suitable for use in contact with tissues of humans and other mammals without undue toxicity, irritation, allergic response, etc. Administration to a recipient can directly or indirectly provide a compound or a prodrug of a compound of the present invention.

The present invention also provides pharmaceutically acceptable hydrates of the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives. The term "hydrate" means a compound that further incorporates stoichiometric or non-stoichiometric amounts of water through non-covalent intermolecular forces.

The present invention also provides pharmaceutically acceptable polymorphs of the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives. The term "polymorph" means a solid crystalline form of a compound or complex thereof which can be characterized by physical methods such as X. ray powder diffraction patterns or infrared spectroscopy.

The present invention also provides a pharmaceutically acceptable pharmaceutical composition of the above-mentioned 4-amino-pyrimidoazacyclo-phenylurea derivatives, which is composed of 4-amino-pyrimidines represented by formulas I~IV It is prepared by adding pharmaceutically acceptable auxiliary ingredients to azocyclic-phenylurea derivatives or their salts or hydrates. 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, (carboxy-C _1-4 alkyl)-α-cyclodextrin, (carboxy-C _1-4 alkyl)- β-cyclodextrin, (carboxy-C _1-4 alkyl)-γ-cyclodextrin, sugar ethers of α-cyclodextrin, sugar ethers of β-cyclodextrin, sugars of γ-cyclodextrin ethers, sulfobutyl ether of α-cyclodextrin, sulfobutyl ether of β-cyclodextrin and sulfobutyl ether of γ-cyclodextrin. The auxiliary components also include medically acceptable carriers, adjuvants or vehicles. Also available in pharmaceutically acceptable pharmaceutical compositions are ion exchangers, aluminum oxide, aluminum stearate, lecithin; buffer substances include phosphate, glycine, arginine, sorbic acid and the like.

The above-mentioned pharmaceutical composition may be in liquid form or solid form. Wherein, the liquid form may be in the form of an aqueous solution. The solid form may be in the form of powder, granule, tablet or lyophilized powder. The pharmaceutical composition also contains water for injection, saline solution, glucose aqueous solution, saline for injection/infusion, glucose for injection/infusion, Guernsey's solution or Guernsey's solution containing lactate.

The present invention also provides the use of 4-amino-pyrimidoazacyclo-phenylurea derivatives, salts, hydrates or pharmaceutical compositions shown in the above formulas I to IV in the preparation of FLT3 kinase inhibitors; especially Mutant FLT3 kinases; especially FLT3/ITD mutant kinases.

The present invention also provides the use of 4-amino-pyrimidoazacyclo-phenylurea derivatives, salts, hydrates or pharmaceutical compositions represented by the above formulas I to IV in the preparation of drugs for the treatment of diseases related to cell proliferation disorders use.

The present invention also provides the use of the 4-amino-pyrimidoazacyclo-phenylurea derivatives, salts, hydrates or pharmaceutical compositions represented by the above formulas I to IV in the preparation of drugs for treating tumors.

Further, the tumor is a solid tumor and/or a hematological tumor.

Further, the solid tumor includes lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, ovarian cancer, breast cancer, prostate cancer, bladder cancer , kidney cancer, esophageal cancer, neck cancer, pancreatic cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, thyroid cancer, brain cancer, lymphoma, epidermal hyperplasia, psoriasis, and/or benign prostatic hyperplasia.

Furthermore, the blood tumors include: acute myeloid leukemia, chronic myeloid leukemia, myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophil leukemia, Acute undifferentiated cell leukemia, myelodysplastic syndrome, myelodysplasia, multiple myeloma, and/or myelosarcoma.

The present invention also provides the use of the 4-amino-pyrimidoazacyclo-phenylurea derivatives, salts, hydrates or pharmaceutical compositions represented by the above formulas I to IV in the preparation of oral or intravenous injection preparations. The oral or intravenous injection preparation at least comprises one 4-amino-pyrimidazine-phenylurea derivative, salt, hydrate or pharmaceutical composition represented by formulas I to IV and any excipient and/or adjuvants.

The 4-amino-pyrimidoazacyclo-phenylurea derivatives provided by the invention can be used as FLT3 kinase inhibitors, have good effects, and provide a new option for preparing antitumor drugs.

Description of drawings

Figure 1 MV4-11 verification target pathway;

Figure 2 Molm-13 verification target pathway;

Figure 3Molm-13 pharmacodynamics model in vivo;

Figure 4 MV4-11 in vivo pharmacodynamic model;

Fig. 5 Survival investigation of NCG mice.

Detailed ways

The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples, but the present invention will not be limited.

Unless otherwise specified in the examples, the reaction temperature is room temperature, that is, 20-30°C.

Example 1: 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-( 4-fluorophenyl)urea compound CLJ-1

Step a: Preparation of M1 intermediate

Weigh raw material SM1 (20g, 130mmol) and ammonia water (150mL, 25%-28% industrial ammonia water) into the autoclave, seal the system, insert a thermometer, set the temperature to 130°C, react for 4h and then cool to room temperature. The reaction suspension was directly filtered, and the filter cake was rinsed with ether to obtain intermediate M1. ¹ H NMR (400MHz, DMSO) δ: 11.45(s, 1H), 8.03(s, 1H), 7.06(d, J=3.2Hz, 1H), 6.88(s, 2H), 6.51(d, J=3.3 Hz,1H).

Step b: Preparation of M2 intermediate

At room temperature, the intermediate M1 (16g, 112mmol) in the previous step was added into 200mL of tetrahydrofuran, and NIS (37.8g, 168mmol) was added in batches, and reacted for 1h. Evaporate the reaction suspension under reduced pressure to obtain a solid mixture, add 300mL of water, add sodium thiosulfate (8.8g, 56mmol) under stirring, the mixture turns from brown to yellow, continue to stir for 0.5h and then filter, the filter cake is used After rinsing with ether, intermediate M2 was obtained. ¹ H NMR (400MHz, DMSO) δ: 11.97(s,1H), 8.07(s,1H), 7.36(s,1H), 6.56(s,2H).

Step c: Preparation of M3 intermediate

The intermediate M2 (28g, 107.7mmol), potassium carbonate (29.7g, 215.4mmol) and Boc anhydride (25.8g, 118.5mmol) from the previous step were added to 500mL of acetonitrile, and the resulting mixture was heated to 60°C and reacted for 2h . After filtering the reaction solution, discard the filter cake, distill the mother liquor under reduced pressure to obtain a solid mixture, add 500mL of water for beating, continue to stir for 0.5h and then filter, drain the filter cake and transfer it to a vacuum drying oven, dry at 60°C for 5 hours to obtain intermediate Body M3. ¹ H NMR (400MHz, DMSO) δ: 8.28(s, 1H), 7.73(s, 1H), 6.87(s, 2H), 1.62(s, 10H).

Step d: Preparation of M4 intermediate

The previous step intermediate M3 (9.56g, 26.6mmol), p-aminophenyl borate hydrochloride (5.5g, 31.8mmol), potassium carbonate (7.3g, 53.1mmol) and dppf (Pd ₂ Cl ₂ ) were added to 250mL In the three-necked flask, add dioxane/ethanol/water=7:3:4 (120 mL in total) as a solvent, replace nitrogen three times, and transfer to an oil bath at 80° C. for 2 h. After the reaction is completed, the reaction solution is concentrated to dryness, and the mixed sample is separated through a column to obtain the intermediate M4. ¹ H NMR (400MHz, DMSO) δ: 9.57(s, 1H), 9.02(s, 1H), 8.28(s, 1H), 7.59(d, J=8.6Hz, 2H), 7.47(s, 1H), 7.44(d, J=8.5Hz, 2H), 6.52(s, 1H), 6.23(s, 2H), 1.61(s, 9H), 1.31(s, 9H).

Step e: Preparation of M5 intermediate

The intermediate M4 (5 g, 15.4 mmol) in the previous step was added to 50 mL of dichloromethane, and concentrated hydrochloric acid (10 mL, 36-38% concentrated hydrochloric acid) was added, and the reaction was completed after 1 h. Add 200mL of dichloromethane and 100mL of water, adjust the pH of the mixture to alkaline (pH about 10), extract and retain the organic phase, and spin dry to obtain intermediate M5. ¹ H NMR (400MHz, DMSO) δ: 11.57(s, 1H), 8.07(s, 1H), 7.12(d, J=8.3Hz, 2H), 7.03(s, 1H), 6.66(d, J=8.3 Hz,2H),5.94(s,2H),5.16(s,2H).

Step f: Preparation of Intermediate M6

The intermediate M5 (225mg, 1mmol) of the previous step, cesium carbonate (650mg, 2mmol), N-(2-chloroethyl) morpholine hydrochloride (223mg, 1.2mmol) were added to 20mL of acetonitrile, heated to 80 ℃ reaction 1h. The reaction solution was spin-dried and extracted with dichloromethane to obtain a relatively pure intermediate M6. ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.68(s, 1H), 7.25(d, J=8.4Hz, 4H), 7.13(s, 1H), 6.80(d, J=8.4Hz, 2H), 4.44 (s,2H), 3.72(s,4H), 2.87(s,2H), 2.59(s,4H). Step g: Preparation of final product CLJ-1

Add the intermediate M6 (338mg, 1mmol) from the previous step into 20mL of dichloromethane, add 4-fluoroisocyanate phenyl (137mg, 1mmol), and react for 0.5h. After 0.5h, a solid precipitates out. After filtering, rinse with ether Filter cake just can obtain high-purity final product CLJ-1. ¹ H NMR (400MHz, DMSO) δ: 9.56(s, 1H), 9.47(s, 1H), 8.54(s, 1H), 7.71(s, 1H), 7.62(d, J=8.6Hz, 2H), 7.52–7.45(m,2H),7.40(d,J=8.6Hz,2H),7.16–7.10(m,2H),4.75(t,J=6.5Hz,2H),3.89(s,4H),3.65 (t,J=6.4Hz,4H).HRMS(ESI),m/z:476.2214[M+H] ⁺ .

Example 2 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(2 -Chlorophenyl)urea compound CLJ-2

The synthesis method was the same as in Example 1, but in step g, 2-chlorophenylisocyanate was used to replace 4-fluorophenylisocyanate to obtain the final product CLJ-2. ¹ H NMR (400MHz,DMSO)δ:11.47(s,1H),10.10(s,1H),8.59(s,1H),8.55(s,1H),8.15(dd,J＝8.3,1.5Hz,1H ),7.72(s,1H),7.66(d,J=8.6Hz,2H),7.46(dd,J=8.0,1.5Hz,1H),7.42(d,J=8.6Hz,2H),7.34–7.28 (m,1H),7.07–7.01(m,1H),4.75(t,J=6.5Hz,2H),3.89(s,4H),3.65(t,J=6.4Hz,3H).HRMS(ESI) ,m/z:492.1922[M+H] ⁺ .

Example 3 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-benzyl Urea compound CLJ-3

The synthesis method was the same as in Example 1, but in step g, benzyl isocyanate was used to replace 4-fluorophenylisocyanate to obtain the final product CLJ-3. ¹ H NMR (400MHz, DMSO) δ: 11.58(s, 1H), 9.31(s, 1H), 8.55(s, 1H), 7.70(s, 1H), 7.59(d, J=8.6Hz, 2H), 7.37–7.30(m,6H),7.27–7.20(m,1H),7.05(s,1H),4.75(t,J＝6.5Hz,2H),4.32(s,2H),3.87(m,9H) ,3.65(t,J＝6.4Hz,3H).HRMS(ESI),m/z:472.2455[M+H] ⁺ .

Example 4 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(4 -Chlorophenyl) urea compound CLJ-4

The synthesis method was the same as in Example 1, but in step g, 4-chlorophenylisocyanate was used to replace 4-fluorophenylisocyanate to obtain the final product CLJ-4. ¹ H NMR (400MHz, DMSO) δ: 8.86(s, 1H), 8.82(s, 1H), 8.14(s, 1H), 7.56(d, J=8.5Hz, 2H), 7.53–7.49(m, 2H ),7.38(d,J=8.5Hz,2H),7.35–7.30(m,3H),6.05(s,2H),4.28(t,J=6.5Hz,2H),3.56–3.50(m,4H) ,2.71(t,J=6.4Hz,2H),2.46(s,4H).HRMS(ESI),m/z:492.1913[M+H] ⁺ .

Example 5 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3 -Chlorophenyl) urea compound CLJ-5

The synthesis method was the same as in Example 1, but in step g, 3-chlorophenylisocyanate was used to replace 4-fluorophenylisocyanate to obtain the final product CLJ-5. ¹ H NMR (400MHz, DMSO) δ: 9.44(s, 1H), 9.33(s, 1H), 8.22(s, 1H), 7.73(s, 1H), 7.59(d, J=8.5Hz, 2H), 7.43–7.35(m,3H),7.32–7.27(m,2H),7.05–6.98(m,1H),6.39(s,2H),4.49(s,2H),3.73(s,4H),2.98( s,4H).HRMS(ESI),m/z:492.1915[M+H] ⁺ .

Example 6 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(2 -Fluorophenyl)urea compound CLJ-6

The synthesis method was the same as in Example 1, but in step g, 2-fluoroisocyanate phenyl was used to replace 4-fluoroisocyanate phenyl to obtain the final product CLJ-6. ¹ H NMR (400MHz, DMSO) δ: 9.23 (s, 1H), 8.62 (s, 1H), 8.16 (dd, J = 15.3, 6.0Hz, 2H), 7.57 (d, J = 8.4Hz, 2H), 7.39(d, J=8.4Hz, 2H), 7.32(s, 1H), 7.29–7.20(m, 1H), 7.15(t, J=7.6Hz, 1H), 7.01(dd, J=12.7, 6.5Hz ,1H),6.04(s,2H),4.28(t,J=6.4Hz,2H),3.54(s,4H),2.70(t,J=6.5Hz,2H),2.45(s,4H).HRMS (ESI),m/z:476.2207[M+H] ⁺ .

Example 7 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(4 -Chloro-3-(trifluoromethyl)phenyl)urea compound CLJ-7

The synthesis method was the same as in Example 1, but in step g, 4-chloro-3-trifluoromethyl-phenylisocyanate was used to replace 4-fluorophenylisocyanate to obtain the final product CLJ-7. ¹ H NMR (400MHz, DMSO) δ: 11.11(s, 1H), 9.99(s, 1H), 9.66(s, 1H), 8.52(s, 1H), 8.14(d, J=1.8Hz, 1H), 7.70(s, 1H), 7.66–7.59(m, 3H), 7.41(d, J＝8.6Hz, 2H), 4.73(t, J＝6.3Hz, 2H), 3.87(s, 4H), 3.64(m ,3H),3.41–3.13(m,4H).HRMS(ESI),m/z:560.1786[M+H] ⁺ .

Example 8 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(p Tolyl) urea compound CLJ-8

The synthesis method was the same as in Example 1, but in step g, p-toluene isocyanate was used to replace 4-fluorophenylisocyanate to obtain the final product CLJ-8. ¹ H NMR (400MHz, DMSO) δ: 9.46(s, 1H), 9.20(s, 1H), 8.52(s, 1H), 7.69(s, 1H), 7.62(d, J=8.6Hz, 2H), 7.39(d, J=8.6Hz, 2H), 7.36(d, J=8.5Hz, 2H), 7.09(d, J=8.3Hz, 2H), 4.73(t, J=6.5Hz, 2H), 3.88( s,4H),3.64(t,J=6.1Hz,3H),3.44–3.11(m,4H),2.25(s,3H).HRMS(ESI),m/z:472.2458[M+H] ⁺ .

Example 9 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3 -Chloro-4-methylphenyl)urea compound CLJ-9

The synthesis method was the same as in Example 1, except that 4-fluoroisocyanate phenyl was replaced with 3-chloro-4-methyl-phenylisocyanate in step g to obtain the final product CLJ-9. ¹ H NMR (400MHz, DMSO) δ: 11.40(s, 1H), 9.66(d, J=4.5Hz, 2H), 8.55(s, 1H), 7.72(s, 1H), 7.71(d, J=1.9 Hz,1H),7.62(d,J=8.6Hz,2H),7.40(d,J=8.6Hz,2H),7.27–7.19(m,2H),4.75(t,J=6.5Hz,2H), 3.89(s,4H),3.66(t,J=6.5Hz,3H),2.26(s,3H).HRMS(ESI),m/z:506.2066[M+H] ⁺ .

Example 10 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3 -Acetophenyl)urea compound CLJ-10

The synthesis method was the same as in Example 1, but in step g, 3-acetylphenylisocyanate was used to replace 4-fluorophenylisocyanate to obtain the final product CLJ-10. ¹ H NMR (400MHz, DMSO) δ: 11.39(s, 1H), 9.70(d, J=8.8Hz, 2H), 8.54(s, 1H), 8.11(t, J=1.8Hz, 1H), 7.73– 7.68(m,2H),7.65(d,J=8.6Hz,2H),7.61–7.57(m,1H),7.48–7.42(m,1H),7.41(d,J=8.6Hz,2H),4.75 (t,J=6.5Hz,2H),3.89(s,4H),3.66(t,J=6.5Hz,2H),2.57(s,3H).HRMS(ESI),m/z:500.2406[M+ H] ⁺ .

Example 11 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-cyclohexyl Urea compound CLJ-11

The synthesis method was the same as in Example 1, but in step g, cyclohexyl isocyanate was used to replace 4-fluorophenylisocyanate to obtain the final product CLJ-11. ¹ H NMR (400MHz, DMSO) δ: 8.38(s, 1H), 8.12(s, 1H), 7.47(d, J=8.6Hz, 2H), 7.30(d, J=8.6Hz, 2H), 7.28( s,1H),6.09(d,J=7.9Hz,1H),4.27(t,J=6.6Hz,2H),3.56–3.51(m,4H),2.69(t,J=6.6Hz,2H), 2.45(d,J=4.1Hz,4H),1.81(dd,J=8.5,3.9Hz,2H),1.67(dd,J=9.0,4.0Hz,2H),1.59–1.49(m,1H),1.38 –1.25(m,2H),1.24–1.12(m,4H).HRMS(ESI),m/z:464.2773[M+H] ⁺ .

Example 12 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(4 -Bromophenyl)urea compound CLJ-12

The synthesis method was the same as in Example 1, but in step g, 4-fluorophenylisocyanate was replaced with 4-bromophenylisocyanate to obtain the final product CLJ-12. ¹ H NMR (400MHz, DMSO) δ: 8.86(s, 1H), 8.82(s, 1H), 8.14(s, 1H), 7.56(d, J=8.5Hz, 2H), 7.53–7.49(m, 2H ),7.38(d,J=8.5Hz,2H),7.35–7.30(m,3H),6.05(s,2H),4.28(t,J=6.5Hz,2H),3.56–3.50(m,4H) ,2.71(t,J＝6.4Hz,2H),2.46(s,4H).HRMS(ESI),m/z:536.1408,538.1390[M+H] ⁺ .

Example 13 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5 -tert-butyl-isoxazol-3-yl)urea compound CLJ-13

Preparation of active urea intermediate 1,3-bis(5-(tert-butyl)isoxazol-3-yl)urea

Triphosgene (47.07g, 156.9mmol) was added to 300mL of tetrahydrofuran, placed in an ice bath, 3-amino-5-tert-butylisoxazole (20g, 142.65mmol) was dissolved in 100mL of tetrahydrofuran, and then added dropwise to In the triphosgene solution, triethylamine (39.8 mL, 285.3 mmol) was finally added dropwise. The reaction was transferred to a 60°C oil bath for 5h. After the reaction is complete, the reaction mixture is filtered, the filtrate is retained, and the filtrate is concentrated under reduced pressure to obtain a solid, that is, an active urea intermediate. ¹ H NMR (400MHz,DMSO)δ:6.71(s,1H),6.35(s,1H),4.90(s,2H),1.36(s,9H),1.35(s,9H).

Combining steps f and h into a "one-pot" reaction process

The intermediate M5 (225mg, 1mmol) of the previous step, cesium carbonate (650mg, 2mmol), N-(2-chloroethyl) morpholine hydrochloride (223mg, 1.2mmol) were added to 20mL of acetonitrile, heated to 80 ℃ reaction 1h. The reaction solution was filtered and the mother liquor was retained. The mother liquor was transferred to 80°C, and the active urea intermediate (306mg, 1mmol) was added. After 0.5h of reaction, a large amount of solid precipitated, filtered and rinsed with ether to obtain the high-purity final product CLJ-13. ¹ H NMR (400MHz, DMSO) δ: 9.53(s, 1H), 8.91(s, 1H), 8.14(s, 1H), 7.56(d, J=8.3Hz, 2H), 7.40(d, J=8.2 Hz,2H),7.33(s,1H),6.52(s,1H),6.06(s,2H),4.29(t,J＝6.3Hz,2H),3.54(s,4H),2.71(t,J =6.4Hz,2H),2.46(s,4H),1.31(s,9H).HRMS(ESI),m/z:505.2672[M+H] ⁺ .

Example 14 1-(4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-isoxazol-3-yl ) urea compound CLJ-14

Add the intermediate M5 (225mg, 1mmol) from the previous step into 20mL of acetonitrile, heat to 80°C for reaction, add active urea intermediate (306mg, 1mmol), react for 0.5h, a large amount of solids precipitate out, filter, and rinse with ether , the high-purity final product CLJ-14 can be obtained. ¹ H NMR (400MHz, DMSO) δ: 11.74(s, 1H), 9.53(s, 1H), 8.93(s, 1H), 8.11(s, 1H), 7.55(d, J=8.5Hz, 2H), 7.40(d, J=8.5Hz, 2H), 7.19(d, J=2.3Hz, 1H), 6.52(s, 1H), 5.99(s, 2H), 1.31(s, 9H).HRMS(ESI), m/z:392.1831[M+H] ⁺ .

Example 15 1-(4-(4-amino-7-tert-butoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl- Isoxazol-3-yl)urea compound CLJ-15

Add the intermediate M4 (325mg, 1mmol) of the previous step into 20mL of acetonitrile, heat to 80°C for reaction, add the active urea intermediate (306mg, 1mmol), react for 0.5h, a large amount of solid precipitates, filter, and rinse with ether , the high-purity final product CLJ-15 can be obtained. ¹ H NMR (400MHz, DMSO) δ: 9.57(s, 1H), 9.02(s, 1H), 8.28(s, 1H), 7.59(d, J=8.6Hz, 2H), 7.47(s, 1H), 7.44(d,J=8.5Hz,2H),6.52(s,1H),6.23(s,2H),1.61(s,9H),1.31(s,9H).HRMS(ESI),m/z:592.2353 [M+H] ⁺ .

Example 16 4-(2-(4-amino-5-(4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)-7H-pyrrolo[2 ,3-d]tert-butylpyrimidin-7-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester compound CLJ-16

¹ H NMR (400MHz,DMSO)δ:9.53(s,1H),8.91(s,1H),8.14(s,1H),7.56(d,J＝8.5Hz,2H),7.39(d,J＝8.5Hz,2H ),7.33(s,1H),6.52(s,1H),6.06(s,2H),4.29(t,J=6.5Hz,2H),3.28(s,4H),2.73(t,J=6.5Hz ,2H),2.46–2.37(m,4H),1.39(s,9H),1.31(s,9H).HRMS(ESI),m/z:604.3353[M+H] ⁺ .

Example 17 1-(4-(4-amino-7-(2-piperazinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5 -tert-butyl-isoxazol-3-yl)urea compound CLJ-17

Compound CLJ-16 (252mg, 0.5mmol) was added to 20mL of dichloromethane, concentrated hydrochloric acid (10mL, 36-38% concentrated hydrochloric acid) was added, and the reaction was completed after 1h. Add 200mL of dichloromethane and 100mL of water to adjust the pH of the mixture to alkaline (pH about 10), extract and retain the organic phase, and concentrate to obtain the final product CLJ-17. ¹ H NMR (400MHz, DMSO) δ: 9.58(s, 1H), 9.01(s, 1H), 8.14(s, 1H), 7.57(d, J=8.5Hz, 2H), 7.39(d, J=8.5 Hz, 2H), 7.33(s, 1H), 6.52(s, 1H), 6.05(s, 2H), 4.27(t, J=6.6Hz, 2H), 2.75–2.63(m, 6H), 2.41(s ,4H),1.31(s,9H).HRMS(ESI),m/z:504.2829[M+H] ⁺ .

Example 18 1-(4-(4-amino-7-(3-morpholinopropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5 -tert-butyl-isoxazol-3-yl)urea compound CLJ-18

^1H NMR (400MHz, DMSO) δ: 9.53(s, 1H), 8.90(s, 1H), 8.14(s, 1H), 7.56(d, J=8.6Hz, 2H), 7.40(d, J=8.6Hz, 2H),7.31(s,1H),6.52(s,1H),6.05(s,2H),4.20(t,J=7.0Hz,2H),3.59–3.51(m,4H),2.29(dd,J =14.3,7.0Hz,6H),2.02–1.91(m,2H),1.31(s,9H).HRMS(ESI),m/z:519.2825[M+H] ⁺ .

Example 19 1-(4-(4-amino-7-(2-(dimethylamino)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3- (5-tert-butyl-isoxazol-3-yl)urea compound CLJ-19

The synthesis method is the same as in Example 13, replacing N-(2-chloroethyl)morpholine hydrochloride with N,N-dimethyl-2-chloroethyl to obtain the high-purity final product CLJ-19. ¹ H NMR (400MHz, DMSO) δ: 9.54(s, 1H), 8.93(s, 1H), 8.14(s, 1H), 7.56(d, J=8.3Hz, 2H), 7.39(d, J=8.3 Hz,2H),7.33(s,1H),6.52(s,1H),6.05(s,2H),4.26(t,J=6.6Hz,2H),2.67(t,J=6.5Hz,2H), 2.20(s,6H),1.31(s,9H).HRMS(ESI),m/z:463.2563[M+H] ⁺ .

Example 20 1-(4-(4-amino-7-allyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl- Isoxazol-3-yl)urea compound CLJ-20

The synthesis method is the same as in Example 13, replacing N-(2-chloroethyl)morpholine hydrochloride with propylene bromide to obtain the high-purity final product CLJ-20. ¹ H NMR (400MHz, DMSO) δ: 9.53 (s,1H),8.91(s,1H),8.15(s,1H),7.56(d,J=8.5Hz,2H),7.40(d,J=8.4Hz,2H),7.25(s,1H) ,6.52(s,1H),6.06(m,3H),5.18(d,J=10.1Hz,1H),5.09(d,J=17.1Hz,1H),4.81(d,J=5.4Hz,2H) ,1.31(s,9H).HRMS(ESI),m/z:432.2149[M+H] ⁺ .

Example 21 1-(4-(4-amino-7-(cyanomethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl Base-isoxazol-3-yl)urea compound CLJ-21

^1H NMR (400MHz, DMSO) δ: 9.54 (s,1H),8.94(s,1H),8.24(s,1H),7.58(d,J=7.4Hz,2H),7.42(d,J=7.6Hz,2H),7.38(s,1H) ,6.53(s,1H),6.26(s,2H),5.41(s,2H),1.31(s,9H).HRMS(ESI),m/z:431.1937[M+H] ⁺ .

Example 22 1-(4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-iso Oxazol-3-yl)urea compound CLJ-22

^1H NMR(400MHz, DMSO)δ :9.55(s,1H),8.97(s,1H),8.33(s,1H),7.65(s,1H),7.59(d,J＝8.6Hz,2H),7.43(d,J＝8.5Hz, 2H),6.52(s,1H),5.10–4.93(m,1H),1.49(d,J＝6.8Hz,6H),1.31(s,9H).HRMS(ESI),m/z:434.2299[M +H] ⁺ .

Example 23 1-(4-(4-amino-7-(4-hydroxybutyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert Butyl-isoxazol-3-yl)urea compound CLJ-23

^1H NMR(400MHz, DMSO) δ:9.53(s,1H),8.91(s,1H),8.14(s,1H),7.56(d,J=8.4Hz,2H),7.40(d,J=8.4Hz,2H),7.32(s ,1H),6.52(s,1H),6.05(s,2H),4.41(t,J=5.2Hz,1H),4.17(t,J=7.0Hz,2H),4.09(q,J=5.2Hz ,1H),3.41(dd,J＝11.8,6.2Hz,2H),3.18(d,J＝5.2Hz,2H),1.88–1.76(m,2H),1.46–1.36(m,2H),1.31( s,9H).HRMS(ESI),m/z:464.2409[M+H] ⁺ .

Example 24 1-(4-(4-amino-7-(N,N-diethylformyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3- (5-tert-butyl-isoxazol-3-yl)urea compound CLJ-24

¹ H NMR (400MHz,DMSO)δ:9.55(s,1H),8.96(s,1H),8.20(s,1H),7.58(d,J＝8.6Hz,2H),7.44(d,J＝8.5Hz,2H ),7.41(s,1H),6.53(s,1H),6.25(s,2H),3.39(m,4H),1.31(s,9H),1.21–1.06(m,6H).HRMS(ESI) ,m/z:491.2493[M+H] ⁺ .

Example 25 1-(4-(4-amino-7-(2-(methylsulfonyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzene Base)-3-(5-tert-butyl-isoxazol-3-yl)urea compound CLJ-25

Compound CLJ-17 (252mg, 0.5mmol) was dissolved in 20mL of dichloromethane, triethylamine (61mg, 0.6mmol) was added, methanesulfonyl chloride (57mg, 0.5mmol) diluted with dichloromethane was added under ice-cooling , After reacting for 1h, extracting with dichloromethane and water, the organic phase was spin-dried to obtain a relatively pure final product CLJ-25. ¹ H NMR (400MHz, DMSO) δ: 9.53 (s, 1H), 8.92 (s, 1H), 8.15(s, 1H), 7.56(d, J=8.6Hz, 2H), 7.40(d, J=8.5Hz, 2H), 7.34(s, 1H), 6.52(s, 1H), 6.05( s,2H),4.30(t,J＝6.4Hz,2H),3.12–3.03(m,4H),2.85(s,3H),2.79(t,J＝6.5Hz,2H),2.62–2.54(m ,4H),1.31(s,9H).HRMS(ESI),m/z:582.2610[M+H] ⁺ .

Example 26 1-(4-(4-amino-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5 -tert-butyl-isoxazol-3-yl)urea compound CLJ-26

^1H NMR(400MHz, DMSO) δ:9.56(s,1H),8.95(s,1H),8.15(s,1H),7.56(d,J=8.4Hz,2H),7.39(d,J=8.4Hz,2H),7.29(s ,1H),6.53(s,1H),6.09(s,2H),4.33(t,J=5.3Hz,2H),3.71(t,J=5.4Hz,2H),3.26(s,3H),1.31 (s,9H).HRMS(ESI),m/z:450.2249[M+H] ⁺ .

Example 27 1-(4-(4-amino-7-(but-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3- (5-tert-butyl-isoxazol-3-yl)urea compound CLJ-27

^1H NMR(400MHz ,DMSO)δ:9.55(s,1H),8.97(s,1H),8.17(s,1H),7.57(d,J=8.5Hz,2H),7.41(d,J=8.4Hz,2H), 7.32(s,1H),6.53(s,1H),6.12(s,1H),4.97(d,J=2.3Hz,2H),1.81(dd,J=5.3,3.1Hz,3H),1.31(s ,9H).HRMS(ESI),m/z:444.2147[M+H] ⁺ .

Example 28 1-(4-(4-amino-7-(pent-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3- (5-tert-butyl-isoxazol-3-yl)urea compound CLJ-28

^1H NMR(400MHz ,DMSO)δ:9.53(s,1H),8.93(s,1H),8.16(s,1H),7.56(d,J=8.6Hz,2H),7.40(d,J=8.5Hz,2H), 7.31(s,1H),6.52(s,1H),6.12(s,2H),4.98(t,J=2.1Hz,2H),2.25–2.16(m,2H),1.30(s,9H),1.06 (t,J=7.5Hz,3H).HRMS(ESI),m/z:458.2299[M+H] ⁺ .

Example 29 1-(4-(4-amino-7-(but-3-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3- (5-tert-butyl-isoxazol-3-yl)urea compound CLJ-29

^1H NMR(400MHz ,DMSO)δ:9.57(s,1H),8.99(s,1H),8.15(s,1H),7.56(d,J=8.4Hz,2H),7.39(d,J=8.3Hz,2H), 7.32(s,1H),6.52(s,1H),6.05(s,2H),5.82(ddd,J=23.8,10.3,6.7Hz,1H),5.14–4.93(m,2H),4.24(t, J＝7.0Hz, 2H), 2.56(dd, J＝13.3, 6.5Hz, 2H), 1.31(s, 9H).HRMS(ESI), m/z: 446.2302[M+H] ⁺ .

Example 30 1-(4-(4-amino-7-(2-ethoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5 -tert-butyl-isoxazol-3-yl)urea compound CLJ-30

^1H NMR(400MHz, DMSO)δ :9.53(s,1H),8.92(s,1H),8.15(s,1H),7.56(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),7.29(s, 1H), 6.52(s, 1H), 6.06(s, 2H), 4.32(t, J=5.4Hz, 2H), 3.74(t, J=5.5Hz, 2H), 3.46(q, J=6.9Hz, 2H),1.31(s,9H).HRMS(ESI),m/z:464.2406[M+H] ⁺ .

Example 31 1-(4-(4-amino-7-(3-methylbut-2-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl )-3-(5-tert-butyl-isoxazol-3-yl)urea compound CLJ-31

^1H NMR (400MHz, DMSO) δ: 9.53(s, 1H), 8.92(s, 1H), 8.15(s, 1H), 7.56(d, J=8.4Hz, 2H), 7.39(d, J=8.4Hz, 2H), 7.23(s, 1H), 6.52(s, 1H), 6.05(s, 2H), 5.41(t, J=6.8Hz, 1H), 4.76(d, J=7.0Hz, 2H), 1.81( s,3H),1.72(s,3H),1.31(s,9H).HRMS(ESI),m/z:460.2457[M+H] ⁺ .

Example 32 1-(4-(4-Amino-7-(2-methylallyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5 -tert-butyl-isoxazol-3-yl)urea compound CLJ-32

^1H NMR(400MHz ,DMSO)δ:9.53(s,1H),8.92(s,1H),8.15(s,1H),7.56(d,J=8.6Hz,2H),7.40(d,J=8.6Hz,2H), 7.20(s,1H),6.52(s,1H),6.09(s,2H),4.87(s,1H),4.73(s,2H),4.61(s,1H),1.68(s,3H),1.31 (s,9H).HRMS(ESI),m/z:446.2298[M+H] ⁺ .

Example 33 1-(4-(4-amino-7-(pent-4-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3- (5-tert-butyl-isoxazol-3-yl)urea compound CLJ-33

^1H NMR(400MHz ,DMSO)δ:9.77(s,1H),9.58(s,1H),8.48(s,1H),7.68(s,1H),7.61(d,J＝8.6Hz,2H),7.42(d,J ＝8.6Hz, 2H), 6.53(s, 1H), 5.83(ddt, J＝16.8, 10.2, 6.4Hz, 1H), 5.09–4.95(m, 2H), 4.27(t, J＝7.0Hz, 2H) ,2.05(dd,J＝13.7,6.7Hz,2H),1.99–1.87(m,2H),1.31(s,9H).HRMS(ESI),m/z:460.2458[M+H] ⁺ .

Example 34 1-(4-(4-amino-7-(hex-5-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3- (5-tert-butyl-isoxazol-3-yl)urea compound CLJ-34

^1H NMR(400MHz ,DMSO)δ:9.78(s,1H),9.60(s,1H),8.48(s,1H),7.68(s,1H),7.61(d,J＝8.6Hz,2H),7.41(d,J ＝8.6Hz, 2H), 6.53(s, 1H), 5.78(ddt, J＝16.9, 10.2, 6.7Hz, 1H), 5.05–4.90(m, 2H), 4.27(t, J＝7.0Hz, 2H) ,2.06(q,J=7.2Hz,2H),1.83(dt,J=14.9,7.2Hz,2H),1.41–1.31(m,2H),1.31(s,9H).HRMS(ESI),m/ z:474.2618[M+H] ⁺ .

Example 35 1-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-isoxan Azol-3-yl)urea compound CLJ-35

^1H NMR (400MHz, DMSO) δ: 9.53 (s,1H),8.93(s,1H),8.11(s,1H),7.55(d,J=8.5Hz,2H),7.40(d,J=8.5Hz,2H),7.19(d,J= 2.3Hz,1H),6.52(s,1H),5.99(s,2H),3.7(s,3H),1.31(s,9H).HRMS(ESI),m/z:406.1992[M+H] ⁺ .

Example 36 1-(4-(4-Amino-7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-isoxan Azol-3-yl)urea compound CLJ-36

^1H NMR(400MHz, DMSO)δ: 9.78(s,1H),9.61(s,1H),8.48(s,1H),7.69(s,1H),7.61(d,J=8.6Hz,2H),7.42(d,J=8.5Hz,2H ),6.53(s,1H),4.30(q,J=7.2Hz,2H),1.43(t,J=7.2Hz,3H),1.31(s,9H).HRMS(ESI),m/z:420.2142 [M+H] ⁺ .

Example 37 1-(4-(4-Amino-7-propyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-isoxan Azol-3-yl)urea compound CLJ-37

^1H NMR (400MHz, DMSO) δ: 9.80 (s,1H),9.66(s,1H),8.48(s,1H),7.68(s,1H),7.61(d,J=8.5Hz,2H),7.41(d,J=8.5Hz,2H) ,6.53(s,1H),4.23(t,J=7.0Hz,2H),1.90–1.77(m,2H),1.31(s,9H),0.87(t,J=7.4Hz,3H).HRMS( ESI), m/z:434.2303[M+H] ⁺ .

Example 38 1-(4-(4-Amino-7-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-isoxan Azol-3-yl)urea compound CLJ-38

The synthesis method of Example 13 is the same, but bromobutane is replaced by N-(2-chloroethyl)morpholine hydrochloride to obtain the high-purity final product CLJ-38. ¹ H NMR (400MHz, DMSO) δ: 9.78(s,1H),9.61(s,1H),8.48(s,1H),7.68(s,1H),7.61(d,J=8.6Hz,2H),7.41(d,J=8.5Hz,2H ),6.53(s,1H),4.26(t,J=7.1Hz,2H),1.87–1.75(m,2H),1.31(s,9H),1.26(dd,J=14.9,7.5Hz,2H) ,0.91(t,J=7.4Hz,3H).HRMS(ESI),m/z:448.2460[M+H] ⁺ .

Example 39 1-(4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-iso Oxazol-3-yl)urea compound CLJ-39

^1H NMR(400MHz, DMSO) δ:9.78(s,1H),9.62(s,1H),8.47(s,1H),7.73(s,1H),7.61(d,J=8.6Hz,2H),7.44(d,J=8.5Hz ,2H),6.53(s,1H),5.22–5.08(m,1H),2.16(d,J＝7.9Hz,2H),2.02–1.83(m,4H),1.71(d,J＝7.0Hz, 2H),1.31(s,9H).HRMS(ESI),m/z:460.2457[M+H] ⁺ .

Example 40 1-(4-(4-amino-7-hexyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-isoxazole -3-yl)urea compound CLJ-40

^1H NMR(400MHz, DMSO)δ :9.71(s,1H),9.40(s,1H),8.46(s,1H),7.67(s,1H),7.61(d,J＝8.6Hz,2H),7.41(d,J＝8.5Hz, 2H),6.52(s,1H),4.25(t,J＝7.1Hz,2H),1.88–1.77(m,2H),1.31(s,9H),1.28(m,6H),0.86(t,J =6.8Hz,3H).HRMS(ESI),m/z:476.2770[M+H] ⁺ .

Example 41 1-(4-(4-Amino-7-benzyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-isoxan Azol-3-yl)urea compound CLJ-41

^1H NMR(400MHz, DMSO)δ: 9.71(s,1H),8.49(s,1H),7.74(s,1H),7.60(d,J=8.6Hz,2H),7.41(d,J=8.5Hz,2H),7.38–7.27(m ,5H),6.52(s,1H),5.49(s,2H),1.31(s,9H).HRMS(ESI),m/z:482.2303[M+H] ⁺ .

Example 42 1-(4-(4-amino-7-propynyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-iso Oxazol-3-yl)urea compound CLJ-42

In the same synthesis method as in Example 13, propyne bromide was replaced by N-(2-chloroethyl)morpholine hydrochloride to obtain the high-purity final product CLJ-42. ¹ H NMR (400MHz, DMSO) δ: 9.66(s,1H),9.28(s,1H),8.49(s,1H),7.66(s,1H),7.61(d,J=8.5Hz,2H),7.43(d,J=8.5Hz,2H ),6.52(s,1H),5.15(d,J=2.3Hz,2H),3.52(t,J=2.4Hz,2H),1.31(s,9H).HRMS(ESI),m/z:430.1985 [M+H] ⁺ .

Example 43 1-(4-(4-amino-7-(2-cyanoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5- tert-butyl-isoxazol-3-yl)urea compound CLJ-43

^1H NMR(400MHz, DMSO)δ: 9.71(s,1H),9.42(s,1H),8.50(s,1H),7.70(s,1H),7.63(d,J=8.6Hz,2H),7.42(d,J=8.5Hz,2H ),6.53(s,1H),4.56(t,J=6.4Hz,2H),3.19(t,J=6.4Hz,2H),1.31(s,9H).HRMS(ESI),m/z:445.2097 [M+H] ⁺ .

Example 44 1-(4-(4-amino-7H-pyrrolo[2,3-d]pyrimidine-5-)-2-fluorophenyl)-3-(5-tert-butyl-isoxazole- 3-yl)urea compound CLJ-44

Step i: Preparation of M7 intermediate

The previous step intermediate M3 (9g, 25mmol), 3-fluoro-4-aminophenylboronic acid pinacol ester (6.5g, 27.5mmol), potassium carbonate (6.9g, 50mmol) and dppf (PdCl ₂ ) were added to 250mL In the three-necked flask, add dioxane/ethanol/water=7:3:4 (120 mL in total) as a solvent, replace nitrogen three times, and transfer to an oil bath at 80° C. for 2 h. After the reaction is completed, the reaction liquid is concentrated, and the sample is mixed and passed through a column for separation to obtain the intermediate M7.

Step j: Preparation of M8 intermediate

The intermediate M7 (4 g, 11.6 mmol) in the previous step was added to 50 mL of dichloromethane, and concentrated hydrochloric acid (10 mL, 36-38% concentrated hydrochloric acid) was added, and the reaction was completed after 1 h. Add 200mL of dichloromethane and 100mL of water, adjust the pH of the mixture to alkaline (pH about 10), extract and retain the organic phase, and spin dry to obtain the intermediate M8. ¹ H NMR (400MHz, DMSO) δ: 11.66(s, 1H), 8.08(s, 1H), 7.11(d, J=2.1Hz, 1H), 7.07(dd, J=12.5, 1.8Hz, 1H), 6.98(dd,J=8.1,1.8Hz,1H),6.85(dd,J=9.5,8.2Hz,1H),5.99(s,2H),5.21(s,2H).

Step k: Preparation of CLJ-44

The intermediate M8 (243mg, 1mmol) in the previous step was added to 20mL of acetonitrile, and the active urea intermediate (306mg, 1mmol) was added. After reacting for 0.5h, solids were precipitated. After filtration, the filter cake was rinsed with ether to obtain high Purity of the final product CLJ-44. ¹ H NMR (400MHz, DMSO) δ: 13.04(s, 1H), 10.13(s, 1H), 9.20(s, 1H), 8.46(s, 1H), 8.23(t, J=8.5Hz, 1H), 7.61(d, J=2.3Hz, 1H), 7.37(dd, J=12.0, 1.7Hz, 1H), 7.27(d, J=8.4Hz, 1H), 6.51(s, 2H), 1.31(s, 9H ).HRMS(ESI),m/z:410.1734[M+H] ⁺ .

Example 45 1-(4-(4-amino-7-propynyl-7H-pyrrolo[2,3-d]pyrimidine-5-)-2-fluorophenyl)-3-(5-tert-butyl Base-isoxazol-3-yl)urea compound CLJ-45

Combining steps l and m into a "one-pot" reaction process

The intermediate M8 (243mg, 1mmol), cesium carbonate (650mg, 2mmol) and propyne bromide (143mg, 1.2mmol) from the previous step were added to 20mL acetonitrile, heated to 80°C for 1h. The reaction solution was filtered and the mother liquor was retained. The mother liquor was transferred to 80°C, and the active urea intermediate (306 mg, 1 mmol) was added. After 0.5 h of reaction, a large amount of solids precipitated, filtered, and rinsed with ether to obtain the high-purity final product CLJ-45. ¹ H NMR (400MHz, DMSO) δ: 10.01(s, 1H), 9.08(s, 1H), 8.52(s, 1H), 8.26(t, J=8.5Hz, 1H), 7.73(s, 1H), 7.39(dd,J=12.0,1.8Hz,1H),7.30–7.25(m,1H),6.51(s,1H),5.16(d,J=2.4Hz,2H),1.31(s,9H).HRMS (ESI),m/z:448.1891[M+H] ⁺ .

Example 46 1-(4-(4-Amino-7-allyl-7H-pyrrolo[2,3-d]pyrimidine-5)-2-fluorophenyl)-3-(5-tert-butyl -isoxazol-3-yl)urea compound CLJ-46

In the same synthesis method as in Example 45, propene bromide is replaced by propyne bromide to obtain the high-purity final product CLJ-46. ¹ H NMR (400MHz, DMSO) δ: 9.86 (s, 1H), 8.88 (s, 1H ),8.20(t,J=8.5Hz,1H),8.16(s,1H),7.33(s,1H),7.33(dd,J=12.1,1.8Hz,2H),7.26(dd,J=8.5, 1.3Hz,1H),6.51(s,1H),6.19(s,2H),6.05(ddd,J=22.5,10.6,5.5Hz,1H),5.18(dd,J=10.2,1.3Hz,1H), 5.09(dd,J=17.1,1.4Hz,1H),4.80(d,J=5.5Hz,2H),1.31(s,9H).HRMS(ESI),m/z:450.2042[M+H] ⁺ .

Example 47 1-(4-(4-amino-7-(but-3-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5)-2-fluorophenyl)- 3-(5-tert-butyl-isoxazol-3-yl)urea compound CLJ-47

The synthesis method is the same as in Example 45, and 4-bromo-1-butene is replaced by bromopropyne to obtain the high-purity final product CLJ-47. ¹ H NMR (400MHz, DMSO) δ: 10.05 (s, 1H) ,9.12(s,1H),8.49(s,1H),8.25(t,J=8.5Hz,1H),7.73(s,1H),7.36(dd,J=12.0,1.7Hz,1H),7.26( d,J=8.4Hz,1H),6.51(s,1H),5.80(ddt,J=17.0,10.3,6.7Hz,1H),5.10–4.99(m,2H),4.34(t,J=7.0Hz ,2H),2.61(q,J=6.8Hz,2H),1.31(s,9H).HRMS(ESI),m/z:464.2212[M+H] ⁺ .

Example 48 1-(4-(4-Amino-7-methoxyethyl-7H-pyrrolo[2,3-d]pyrimidine-5)-2-fluorophenyl)-3-(5-tert Butyl-isoxazol-3-yl)urea compound CLJ-48

The synthesis method is the same as in Example 45, and the high-purity final product CLJ-48. ¹ H NMR (400MHz, DMSO) δ: 10.10 (s, 1H), 9.16 ( s,1H),8.51(s,1H),8.25(t,J＝8.5Hz,1H),7.70(s,1H),7.43–7.33(m,1H),7.26(m,1H),6.51(s ,1H),4.43(t,J=5.1Hz,2H),3.76(t,J=5.3Hz,2H),1.31(s,9H).HRMS(ESI),m/z:468.2159[M+H] ⁺ .

Example 49 1-(4-(4-Amino-7-ethoxyethyl-7H-pyrrolo[2,3-d]pyrimidine-5)-2-fluorophenyl)-3-(5-tert Butyl-isoxazol-3-yl)urea compound CLJ-49

In the same synthesis method as in Example 45, the high-purity final product CLJ- ^49.1 H NMR (400MHz, DMSO) δ: 10.02 (s, 1H), 9.09 (s) can be obtained by replacing bromopropyne with ethyl bromoethyl ether ,1H),8.48(s,1H),8.26(t,J=8.5Hz,1H),7.68(s,1H),7.37(dd,J=12.0,1.8Hz,1H),7.27(d,J= 8.5Hz, 1H), 6.51(s, 1H), 4.42(t, J=5.3Hz, 2H), 3.78(t, J=5.3Hz, 2H), 3.46(dd, J=14.0, 7.0Hz, 2H) ,1.31(s,9H),1.06(t,J=7.0Hz,3H).HRMS(ESI),m/z:482.2313[M+H] ⁺ .

Example 50 1-(4-(4-amino-7-cyanomethyl-7H-pyrrolo[2,3-d]pyrimidine-5)-2-fluorophenyl)-3-(5-tert-butyl Base-isoxazol-3-yl)urea compound CLJ-50

In the same synthesis method as in Example 45, the high-purity final product CLJ-50. ¹ H NMR (400MHz, DMSO) δ: 10.10 (s, 1H), 9.16 (s, 1H) can be obtained by replacing bromopropyne with chloroacetonitrile ),8.57(s,1H),8.26(t,J=8.5Hz,1H),7.72(s,1H),7.39(dd,J=11.9,1.8Hz,1H),7.28(d,J=8.4Hz ,1H),6.51(s,1H),5.55(s,2H),1.31(s,9H).HRMS(ESI),m/z:449.1848[M+H] ⁺ .

Example 51 1-(4-(4-amino-7-(2-cyanoethyl)-7H-pyrrolo[2,3-d]pyrimidine-5)-2-fluorophenyl)-3-( 5-tert-butyl-isoxazol-3-yl)urea compound CLJ-51

In the same synthesis method as in Example 45, bromopropionitrile was replaced by bromopropyne to obtain the high-purity final product CLJ-5 ^1.1 H NMR (400MHz, DMSO) δ: 10.05 (s, 1H), 9.12 (s, 1H),8.54(s,1H),8.28(t,J=8.5Hz,1H),7.79(s,1H),7.65(s,1H),7.37(dd,J=11.9,1.8Hz,1H), 7.28(d, J=8.5Hz, 1H), 6.51(s, 1H), 4.60–4.51(t, J=6.5Hz, 2H), 3.19(t, J=6.6Hz, 2H), 1.31(s, 9H ).HRMS(ESI),m/z:463.2004[M+H] ⁺ .

Example 52 1-(4-(4-amino-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-isoxazole-3- base) urea compound CLJ-52

The synthetic route is as follows;

The synthetic route is basically the same as in Example 13, except that the starting material is replaced by 4-chloropyrazolo[2,3-d]pyrimidine, and the final product CLJ-52. ¹ H NMR (400MHz, DMSO )δ:13.80(s,1H),9.35(s,1H),9.14(s,1H),8.50(s,1H),7.53(s,2H),7.24–7.18(m,2H),6.73–6.67 (m,2H),6.46(s,1H),1.29(s,9H).HRMS(ESI),m/z:392.1907[M+H] ⁺ .

Example 53 1-(4-(4-Amino-7-allyl-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl- Isoxazol-3-yl)urea compound CLJ-53

^1H NMR(400MHz, DMSO) δ:9.56(s,1H),9.02(s,1H),8.26(s,1H),7.63(t,J=7.0Hz,4H),7.00(dd,J=114.0,63.4Hz,2H),6.53 (s,1H),6.10–6.01(m,1H),5.19(d,J=10.3Hz,1H),5.11(d,J=17.1Hz,1H),4.97(d,J=5.5Hz,2H) ,1.31(s,9H).HRMS(ESI),m/z:433.2099[M+H] ⁺ .

Example 54 1-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5 -tert-butyl-isoxazol-3-yl)urea compound CLJ-54

The synthesis method of this compound is the same as in Example 53, except that N-(2-chloroethylmorpholine) hydrochloride is replaced by bromopropene to obtain the target final product CLJ-54. ¹ H NMR (400MHz, DMSO) δ9.57 ( s,1H),9.04(s,1H),8.25(s,1H),7.66–7.63(m,2H),7.63–7.61(m,2H),6.75(s,2H),6.53(s,1H) ,4.48–4.46(m,2H),3.52–3.48(m,4H),2.83–2.81(m,2H),2.49–2.46(m,4H),1.31(s,9H).HRMS(ESI),m /z:506.2628[M+H] ⁺ .

Example 55 1-(4-(4-amino-7-(2-(piperidin-1-yl)ethyl)-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl )-3-(5-tert-butyl-isoxazol-3-yl)urea compound CLJ-55

The synthesis method of this compound is the same as in Example 53, except that N-(2-chloroethylpiperidine) hydrochloride is replaced by bromopropene to obtain the target final product CLJ-55. ¹ H NMR (400MHz, DMSO) δ: 9.58 ( s,1H),9.05(s,1H),8.25(s,1H),7.66–7.63(m,2H),7.63–7.61(m,2H),6.75(s,2H),6.53(s,1H) ,4.52–4.48(m,2H),4.44–4.40(m,2H),2.78–2.74(m,2H),2.44–2.38(m,4H),1.46–1.40(m 4H),1.31(s,9H ).HRMS(ESI),m/z:504.2829[M+H] ⁺ .

Example 56 1-(4-(4-Amino-7-(cyclopropylmethyl)-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5- tert-butyl-isoxazol-3-yl)urea compound CLJ-56

The synthesis method of this compound is the same as in Example 53, except that 2-chlorocyclopropane is replaced by bromopropene to obtain the target final product CLJ-56. ¹ H NMR (400MHz, DMSO) δ: 9.56 (s, 1H), 9.02 (s ,1H),8.25(s,1H),7.66–7.63(m,2H),7.63–7.61(m,2H),6.90(s,2H),6.53(s,1H),5.84–5.76(m,1H ),5.05–4.97(m,2H),4.42–4.39(m,2H),2.66–2.61(m,2H),1.31(s,9H).HRMS(ESI),m/z:447.2257[M+H ] ⁺ .

Example 57 1-(4-(4-Amino-7-propargyl-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl- Isoxazol-3-yl)urea compound CLJ-57

The synthesis method of this compound is the same as in Example 53, except that propyne bromide is replaced by propyne bromide to obtain the target final product CLJ-57. ¹ H NMR (400MHz, DMSO) δ9.63 (s, 1H), 9.10 (s, 1H) ,8.34(s,1H),7.72–7.68(m,4H),6.59(s,1H),5.51(s,2H),5.25(s,2H),3.43(s,1H),1.37(s,9H ).HRMS(ESI),m/z:431.1944[M+H] ⁺ .

Example 58 1-(4-(4-amino-7-methyl-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-iso Oxazol-3-yl)urea compound CLJ-58

The synthesis method of this compound is the same as that of Example 53, except that methyl iodide is replaced by allyl bromide to obtain the target final product CLJ-58. ¹ H NMR (400MHz, DMSO) δ: 9.56 (s, 1H), 9.05 (s, 1H), 8.26(s,1H),7.66–7.61(m,4H),6.53(s,1H),5.41(s,2H),4.03–3.99(m,3H),1.31(s,9H).HRMS(ESI) ,m/z:407.1948[M+H] ⁺ .

Example 59 1-(4-(4-Amino-7-ethyl-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-iso Oxazol-3-yl)urea compound CLJ-59

The synthesis method of this compound is the same as in Example 53, except that iodoethane is replaced by bromopropene to obtain the target final product CLJ-59. ¹ H NMR (400MHz, DMSO) δ: 9.58 (s, 1H), 9.05 (s, 1H) ,8.26(s,1H),7.66–7.61(m,4H),6.53(s,1H),5.41(s,2H),3.97–3.93(m,2H),1.31(s,9H),1.26–1.22 (m,3H).HRMS(ESI),m/z:421.2100[M+H] ⁺ .

Example 60 1-(4-(4-amino-7-(2-cyanoethyl)-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5 -tert-butyl-isoxazol-3-yl)urea compound CLJ-60

The synthesis method of this compound is the same as in Example 53, except that chloropropionitrile is replaced by bromopropene to obtain the target final product CLJ-60. ¹ H NMR (400MHz, DMSO) δ9.62 (s, 1H), 9.10 (s, 1H) ,8.34(s,1H),7.72–7.66(m,4H),6.59(s,1H),5.67(s,2H),4.66(s,2H),3.22–3.18(m,2H),1.36(s ,9H).HRMS(ESI),m/z:446.2056[M+H] ⁺ .

Example 61 1-(4-(4-Amino-7-hexyl-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-isoxan Azol-3-yl)urea compound CLJ-61

The synthesis method of this compound is the same as in Example 53, except that 1-bromohexane is replaced by bromopropene to obtain the target final product CLJ-61. ¹ H NMR (400MHz, DMSO) δ9.56 (s, 1H), 9.03 (s, 1H),8.25(s,1H),7.65–7.59(m,4H),6.54(s,1H),5.42(s,2H),4.34–4.31(m,2H),1.84–1.82(m,4H) ,1.31(s,9H),0.85–0.82(m,7H).HRMS(ESI),m/z:477.2396[M+H] ⁺ .

Example 62 1-(4-(4-Amino-7-propyl-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl-iso Oxazol-3-yl)urea compound CLJ-62

The synthesis method of this compound is the same as in Example 53, except that 1-bromopropyl is replaced by bromopropene to obtain the target final product CLJ-62. ¹ H NMR (400MHz, DMSO) δ: 9.56 (s, 1H), 9.02 (s, 1H),8.25(s,1H),7.64–7.60(m,4H),6.53(s,1H),5.41(s,2H),4.32–4.28(m,2H),1.92–1.84(m,2H) ,1.31(s,9H),0.89–0.85(m,3H).HRMS(ESI),m/z:435.2256[M+H] ⁺ .

Example 63 1-(4-(4-Amino-7-cyclopentyl-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5-tert-butyl- Isoxazol-3-yl)urea compound CLJ-63

The synthesis method of this compound is the same as in Example 53, except that bromocyclopentane is replaced by bromopropene to obtain the target final product CLJ-63. ¹ H NMR (400MHz, DMSO) δ9.55 (s, 1H), 9.03 (s, 1H),8.23(s,1H),7.64–7.60(m,4H),6.72(s,2H),6.53(s,1H),5.28–5.19(m,1H),2.08–2.08(m,4H) ,1.92–1.87(m,2H),1.74–1.67(m,2H),1.31(s,9H).HRMS(ESI),m/z:461.2407[M+H] ⁺ .

Example 64 1-(4-(4-amino-7-(2-ethoxyethyl)-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-( 5-tert-butyl-isoxazol-3-yl)urea compound CLJ-64

The synthesis method of this compound is the same as in Example 53, except that bromoethyl ether is replaced by bromopropene to obtain the target final product CLJ-64. ¹ H NMR (400MHz, DMSO) δ: 9.57 (s, 1H), 9.05 (s, 1H ),8.25(s,1H),7.67–7.61(m,4H),6.88(s,2H),6.54(s,1H),4.49–4.42(m,4H),1.31(s,9H),1.04– 1.00(m,5H).HRMS(ESI),m/z:465.2361[M+H] ⁺ .

Example 65 1-(4-(4-amino-7-(3-methylbut-2-en-1-yl)-7H-pyrazolo[2,3-d]pyrimidin-5-yl)benzene Base)-3-(5-tert-butyl-isoxazol-3-yl)urea compound CLJ-65

The synthesis method of this compound is the same as in Example 53, except that 3,3-dimethylbromopropene is replaced by bromopropene to obtain the target final product CLJ-65. ¹ H NMR (400MHz, DMSO) δ: 9.57 (s, 1H), 9.05(s,1H),8.25(s,1H),7.65–7.59(m,4H),6.53(s,1H),5.42(s,2H),4.94–4.88(m,3H),1.82–1.79( m,5H),1.70(s,3H),1.31(s,9H).HRMS(ESI),m/z:461.2407[M+H] ⁺ .

Example 66 1-(4-(4-amino-7-(2,2-dimethoxyethyl)-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)- 3-(5-tert-butyl-isoxazol-3-yl)urea compound CLJ-66

The synthesis method of this compound is the same as in Example 53, except that 2,2-dimethylbromoethyl is replaced by bromopropene to obtain the target final product CLJ-66. ¹ H NMR (400MHz, DMSO) δ: 9.57 (s, 1H) ,9.04(s,1H),8.27(s,1H),7.66–7.60(m,4H),6.54(s,1H),5.46(s,2H),4.96–4.93(m,1H),4.44–4.42 (m,2H),3.33(s,6H),1.31(s,9H).HRMS(ESI),m/z:481.2307[M+H] ⁺ .

Example 67 1-(4-(4-Amino-7-(4-oxopentyl)-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(5 -tert-butyl-isoxazol-3-yl)urea compound CLJ-67

The synthesis method of this compound is the same as in Example 53, except that 2,2-dimethylbromoethyl is replaced by bromopropene to obtain the target final product CLJ-67. ¹ H NMR (400MHz, DMSO) δ: 9.57 (s, 1H) ,9.05(s,1H),8.21(s,1H),7.66–7.60(m,4H),6.54(s,1H),5.42(s,2H),4.30–4.25(m,2H),2.48–2.42 (m,4H),2.05(s,3H),1.31(s,9H).HRMS(ESI),m/z:477.2396[M+H] ⁺ .

Example 68 1-(4-(4-amino-7H-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3-tert-butyl-1H-pyrazole-5 -yl) urea compound CLJ-68

Preparation of active urea intermediate 1,3-(3-tert-butyl-1H-pyrazol-5-yl)urea

Triphosgene (4.71g, 15.7mmol) was added to 50mL of tetrahydrofuran, placed in an ice bath, 3-amino-5-tert-butylpyrazole (1.99g, 14.3mmol) was dissolved in 5mL of tetrahydrofuran, and then dropped Added to the triphosgene solution, and finally triethylamine (4.0 mL, 28.5 mmol) was added dropwise. The reaction was transferred to a 60°C oil bath for 5h. After the reaction is complete, filter the reaction mixture, retain the filtrate, concentrate the filtrate under reduced pressure to obtain a solid, and separate it through a column to obtain an active urea intermediate. ¹ H NMR (400MHz, DMSO) δ: 12.66(s, 2H), 9.51(s, 2H), 6.30(s, 2H), 1.30(s, 18H).

Add intermediate M5 (225mg, 1mmol) to 20mL acetonitrile, heat to 80°C for reaction, add the active urea intermediate (390mg, 1mmol) from the previous step, react for 0.5h, a large amount of solid precipitates, filter, and rinse with ether , the high-purity final product CLJ-68 can be obtained. ¹ H NMR (400MHz,DMSO)δ:12.64(s,1H),11.54(s,1H),9.52(s,1H),8.86(s,1H),8.11(s,1H),7.80(d,J =8.5Hz, 2H), 7.65(d, J=8.5Hz, 2H), 7.19(d, J=2.3Hz, 1H), 6.54(s, 1H), 6.01(s, 2H), 1.31(s, 9H ).HRMS(ESI),m/z:391.1924[M+H] ⁺ .

Example 69 1-(4-(4-amino-7-(2-morpholinoethyl)-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3-tert Butyl-1H-pyrazol-5-yl)urea compound CLJ-69

The synthesis method of this compound is the same as in Example 54, except that the active intermediate of pyrazole urea is replaced by the active intermediate of isoxazole to obtain the target final product CLJ-69. ¹ H NMR (400MHz, DMSO) δ 12.00 (s, 1H ),9.46(s,1H),9.05(s,1H),8.24(s,1H),7.61(dd,J=21.8,8.6Hz,4H),6.78(s,2H),6.02(s,1H) ,4.46(t,J=6.6Hz,2H),3.54–3.47(m,4H),2.80(t,J=6.7Hz,2H),2.46(d,J=3.8Hz,4H),1.27(s, 9H).HRMS(ESI),m/z:505.2811[M+H] ⁺ .

Example 70 1-(4-(4-Amino-7-ethyl-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3-tert-butyl-1H-pyridine Azol-5-yl)urea compound CLJ-70

The synthesis method of this compound is the same as in Example 59, except that the active intermediate of pyrazole urea is replaced by the active intermediate of isoxazole to obtain the target final product CLJ-70. ¹ H NMR (400MHz, DMSO) δ: 12.01 (s, 1H ),9.42(s,1H),9.00(s,1H),8.25(s,1H),7.61(dd,J=18.2,8.6Hz,4H),6.69(s,2H),6.02(s,1H) ,4.37(dd,J=14.2,7.0Hz,2H),1.42(t,J=7.1Hz,3H),1.19(s,9H).HRMS(ESI),m/z:420.2279[M+H] ⁺ .

Example 71 1-(4-(4-amino-7-(cyclopropylmethyl)-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3-tert-butyl Base-1H-pyrazol-5-yl)urea compound CLJ-71

The synthesis method of this compound is the same as in Example 56, except that the active intermediate of pyrazole urea is replaced by the active intermediate of isoxazole to obtain the target final product CLJ-71. ¹ H NMR (400MHz, DMSO) δ: 12.00 (s, 1H ),9.49(s,1H),9.04(s,1H),8.25(s,1H),7.61(dd,J=21.9,8.5Hz,4H),6.69(s,2H),6.03(s,1H) ,5.03(dd,J=35.8,13.0Hz,2H),4.40(d,J=7.1Hz,2H),2.63(dd,J=13.6,6.8Hz,2H),1.19(s,9H),0.84( dd,J＝10.0,7.0Hz,1H).HRMS(ESI),m/z:446.2456[M+H] ⁺ .

Example 72 1-(4-(4-amino-7-propyl-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3-tert-butyl-1H-pyridine Azol-5-yl)urea compound CLJ-72

The synthesis method of this compound is the same as in Example 62, except that the active intermediate of pyrazolamide is replaced by the active intermediate of isoxazole to obtain the target final product CLJ-72. ¹ H NMR (400MHz, DMSO) δ: 12.00 (s, 1H ), 9.43(s,1H), 8.98(s,1H), 8.25(s,1H), 7.61(dd,J=21.9,8.5Hz,4H),6.02(s,1H),4.29(t,J= 6.2Hz,2H),1.90–1.84(m,2H),1.27(s,9H),0.86(m,3H).HRMS(ESI),m/z:434.2419[M+H] ⁺ .

Example 73 1-(4-(4-amino-7-cyclopentyl-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3-tert-butyl-1H- Pyrazol-5-yl)urea compound CLJ-73

The synthesis method of this compound is the same as in Example 63, except that the active intermediate of pyrazolamide is replaced by the active intermediate of isoxazole to obtain the target final product CLJ-73. ¹ H NMR (400MHz, DMSO) δ12.01 (s, 1H ),9.40(s,1H),8.98(s,1H),8.23(s,1H),7.61(dd,J=19.4,8.4Hz,4H),6.72(s,2H),6.02(s,1H) ,5.23(dt,J=14.8,7.5Hz,1H),2.12–2.03(m,4H),1.90(d,J=8.5Hz,2H),1.73–1.65(m,2H),1.27(s,9H ).HRMS(ESI),m/z:460.2624[M+H] ⁺ .

Example 74 1-(4-(4-amino-7-allyl-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3-tert-butyl-1H- Pyrazol-5-yl)urea compound CLJ-74

The synthesis method of this compound is the same as in Example 53, except that the active intermediate of pyrazole urea is replaced by the active intermediate of isoxazole to obtain the target final product CLJ-74. ¹ H NMR (400MHz, DMSO) δ: 12.04 (s, 1H ),9.41(s,1H),9.00(s,1H),8.25(s,1H),7.61(dd,J＝16.8,7.2Hz,4H),,6.72(s,2H),6.11–6.04(m ,1H),6.02(s,1H),5.19(d,J=10.4Hz,1H),5.11(d,J=17.5Hz,1H),4.97(s,2H),1.27(s,9H).HRMS (ESI),m/z:432.2307[M+H] ⁺ .

Example 75 1-(4-(4-amino-7-(2-cyanoethyl)-pyrazolo[2,3-d]pyrimidin-5-yl)phenyl)-3-(3-tert Butyl-1H-pyrazol-5-yl)urea compound CLJ-75

The synthesis method of this compound is the same as in Example 60, except that the active intermediate of pyrazolamide is replaced by the active intermediate of isoxazole to obtain the target final product CLJ-75. ¹ H NMR (400MHz, DMSO) δ: 12.00 (s, 1H ),9.52(s,1H),9.05(s,1H),8.28(s,1H),7.63(dd,J=19.1,8.1Hz,4H),6.73(s,2H),6.03(s,1H) ,4.61(t,J=6.1Hz,2H),3.17(t,J=6.0Hz,2H),1.27(s,9H).HRMS(ESI),m/z:445.2244[M+H] ⁺ .

Pharmacodynamic test part

The following representative experiments, without limitation, were used to analyze the biological activity of the compounds of the present invention.

MTT method to measure MV4-11, Molm-13 and RS4; 11 cell proliferation inhibition experiment

The effect of test compounds of the invention on the viability of cancer cells was tested on MV4-11 and Molm-13 cells, which are human leukemia cell lines expressing constitutive FLT3 receptors and containing the FLT3-ITD mutation. If the compound has a strong growth inhibitory activity on cells expressing FLT3-ITD, it means that the compound has a significant effect on the FLT3-ITD mutant strain. If the growth inhibitory activity on cells expressing FLT3-WT is poor, it means that the compound has poor effect on FLT3-WT wild type, which means that the selectivity is better. In the present invention, the FLT3-ITD highly specific compound AC220 (CAS: 950769-58-1) was selected as a positive control, which was synthesized in our laboratory according to the preparation method in the literature (J.Med.Chem.2009, 52, 7808-7816).

MV4-11 cells (from the American Type Culture Center, cultivated and preserved by the Cell Bank of the State Key Laboratory of Biotherapy, Sichuan University) were installed in 96-well culture dishes, and the medium was 100 μL IMDM, Molm-13 cells (from the American Type Culture Center, cultured and preserved by the cell bank of the State Key Laboratory of Biotherapy, Sichuan University) was installed in a 96-well culture dish, the medium was 100 μL RPMI1640, containing 10% fetal bovine serum, and there were 10000-15000 cells per well, and the test compound was in Prepared in 100% DMSO, added to the cells to obtain a concentration of 100nM to 0.032nM (6 concentration points according to the 5-fold dilution concentration) and cultured in a culture dish at 37° C. in 5% CO ₂ for 72 hours. RS4; 11 cells (from the American Type Culture Center, cultured and preserved by the State Key Laboratory of Biotherapy, Sichuan University) were installed in 96-well culture dishes, and the medium was 100 μL RPMI1640, containing 10% fetal bovine serum. 10000-15000 cells, the test compound was prepared in 100% DMSO, added to the cells to obtain a concentration of 1000nM, and the culture dish was incubated at 37°C in 5% CO ₂ for 72h. At endpoint, 20 μL of MTT (5 mg/mL) was added to each well and cells were incubated for an additional 1-4 hours. After overnight treatment with 20% SDS, the absorbance value at a wavelength of 570 nM was obtained on a spectrophotometer (Molecular Devices, Sunnyvale, USA). _IC50 values were calculated using percent growth compared to untreated controls, and the results of the assay are shown in Table 1.

Table 1. _IC50 values of test compounds for inhibition of leukemia cell proliferation

*****:0.01-0.1nM; *****:0.1-1nM; ****:1-10nM; ***:10-100nM; **:100-1000nM; *:>1000nM

The results show that the test compounds of the present invention have better inhibitory activity on MV4-11 and Molm-13 cell proliferation, wherein some compounds exhibit better antiproliferative activity than AC220, while RS4; 11 inhibitory activity is poor, It is a novel, potential and potential inhibitor for the treatment of FLT3-ITD related diseases.

In vitro kinase inhibition assay

In a reaction tube, add buffer (8mM) MOPS, pH 7.0, 0.2mM EDTA, 10mM MnCl ₂ ), the kinase to be tested, the substrate of the kinase to be tested, 10mM magnesium acetate and γ ^33P -ATP solution, and different concentration of the compound, then MgATP was added to the reaction to initiate the enzymatic reaction process and incubated at room temperature for 40 minutes. Finally, 5 microliters of 3% phosphate buffer was used to stop the reaction, and 10 microliters of the reaction solution was titrated onto the Filtermat A membrane, washed three times with 75 mM phosphate solution for 5 minutes each time, and then washed once with methanol. Finally, the Filtermat A membrane was dried and scintillation counted. The scintillation count value reflected the degree of phosphorylation of the substrate, which could characterize the inhibition of kinase activity.

Table 2 FLT3 kinase inhibitor activity of some compounds of the present invention

test compound FLT3 (IC₅₀,nM) CLJ-13 20 CLJ-14 6 CLJ-20 7 CLJ-21 9 CLJ-22 20 CLJ-42 13 CLJ-44 4

The results show that the compound of the present invention has better enzymatic inhibitory activity on FLT3 in vitro.

Table 3 The dissociation constant of compound CLJ-20 of the present invention to FLT3 mutant kinase

mutation type Kd, nM FLT3 WT 4.37 FLT3 (D835V) 7.04 FLT3(ITD) 20.52 FLT3(ITD,D835V) 41.26 FLT3(ITD,F691L) 48.47 FLT3 (N841I) 2.37 FLT3(R834Q) 10.15 FLT3(D835H) 5.14 FLT3(D835Y) 7.78 FLT3(K663Q) 2.48

The results showed that CLJ-20 also binds well to multiple mutations of the FLT3 kinase.

Some of the tested compounds verified the target effect on Western Blot

Test method: MV4-11 cells and Molm-13 cells were treated with compounds of specified concentrations. Cells were then collected and total protein was extracted with RIPA lysis buffer (beyotime Co. P0013B, components: 50 mM Tris, pH 7.4, 150 mM NaCl, 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 1). 1 mM sodium orthovanadate, sodium fluoride, EDTA and leupeptin). Protein concentration was measured by BCA protein assay (ThermoScientific, USA). An equivalent sample (30 μg protein) was subjected to SDS-PAGE, and then the protein was transferred to a PVDF membrane (Millipore, USA). After blocking with 5% skim milk at room temperature for 1 hour, the membrane was incubated with the designated primary antibody (FLT3 (Cell signaling technology, 3462S), p-FLT3 (Cell signaling technology, 3464S), STAT5 (Cell signaling technology, 9363S), p-STAT5 (Abcam, ab32364), ERK (Zen Bioscience, 220003), p-ERK (Zen Bioscience, 340767), β-Actin (Abways, AB0035)) were incubated overnight at 4°C, and then treated with horseradish peroxide Enzyme-conjugated appropriate secondary antibodies (Abways, F300409) were probed for 1 hour. Immunoreactive bands were visualized using enhanced chemiluminescence (Millipore, USA). The molecular size of detected proteins was determined by comparison with relevant protein markers (ThermoScientific, USA).

The experimental results are shown in Figures 1 and 2. The results show that the test compound CLJ-20 can significantly down-regulate p-FLT3, p-STAT5, and p-ERK in a dose-dependent manner, and AC220 also showed the same effect, indicating that the test compound is indeed It inhibits the activity of FLT3, thereby affecting the phosphorylation of downstream signaling pathways.

In vivo pharmacodynamics experiment of compound CLJ-20 on NOD/SCID nude mice

The purpose of this experiment is to detect the anti-tumor effect of the compound of the present invention in vivo, using a mouse subcutaneous tumor model, the cell lines used are MV4-11 and Molm-13 cells, and the clinical drug AC220 being developed is used as a positive control.

Test method: Use 6-8 week old NOD/SCID mice (purchased from Beijing Huafukang Biotechnology Co., Ltd.), inoculate the mice at the concentration of 10 ⁷ /0.1mL/molm-13 and MV4-11 cells After the subcutaneous rib area, with the tumor growing to ^200-500mm3 , the mice were divided into groups (6 in each group) and administered. The drug dissolution method was 2% DMSO + 2% PEG-400 + 96% saline, and the experimental group As the drug solvent control group, 200 microliters of oral gavage per day, compound CLJ-20 was orally gavaged at a dose of 3 mg/kg per day, compound CLJ-20 was orally gavaged at a dose of 10 mg/kg per day, and the positive drug AC220 was orally gavaged at a dose of 3 mg/kg per day. Perform oral gavage. The observation index is to measure the body weight of the mice and the long and short diameters of the tumor every two days, calculate the tumor volume, and observe the physiological state of the mice in each group.

Experimental results: The experimental results of the Molm-13 model are shown in Figure 3, and the results of the MV4-11 model are shown in Figure 4. The experimental results show that the compound CLJ-20 has obvious anti-tumor effect on the Molm-13 model in vivo. At an oral dose of 3 mg/kg, it can significantly inhibit tumor growth, and the tumor inhibition rate is as high as 94%. The tumor inhibition rate at 10 mg/kg As high as 96%, and AC220 also showed a good anti-tumor effect, the tumor inhibition rate reached 98%, indicating that CLJ-20 and AC220 have comparable in vivo effects. In the MV4-11 model, the tumor inhibition rate of the test drug CLJ-20 was as high as 98% at 3 mg/kg, and two mice achieved tumor regression, and all tumors disappeared on the eighth day after administration of 10 mg/kg , and the AC220 3mg/kg group also achieved tumor regression in all mice on the eighth day. No adverse reactions such as weight loss, skin rash, and diarrhea were found in the mice during the administration. However, the AC220 group showed a slight decrease in body weight, indicating that at the tested dose, CLJ-20 has low toxicity within the administered dose range.

Investigation of the Survival Period of Compound CLJ-20 in NCG Mouse Model

Test method: Use 7-8 week old NCG mice (purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.), inoculate in the tail vein of mice at a concentration of ¹⁰⁶ Molm-13 cells/mouse, the cells can be in the blood of mice A large number of proliferations in the circulatory system lead to paralysis of hind limbs and even death in mice. The mice were divided into groups (8 in each group) and administered. The drug dissolution method was 2% DMSO+2% PEG-400+96% normal saline. CLJ-20 was administered orally orally at a dose of 10 mg/kg per day for 30 consecutive days. The therapeutic effect of CLJ-20 was investigated by observing and recording the survival time of the mice after the establishment of the model.

The experimental results showed that, as shown in FIG. 5 , the median survival period (MST) of mice in the solvent control group was 20 days. The median survival time of the 10mg/kg dose group reached 46.5 days, which was 26.5 days longer than that of the control group, fully prolonging the survival time by more than double. This shows that CLJ-20 has the effect of significantly inhibiting tumor growth and prolonging the survival period in AML xenograft orthotopic transplantation model.

Although, the present invention has been described in detail with general descriptions, specific examples and experiments above, but on the basis of the present invention, some modifications or improvements can be made to it, which is important for those skilled in the art. Obvious. Therefore, modifications or improvements made on the basis of not departing from the spirit of the present invention all belong to the protection scope of the present invention.

Claims (20)

1.4-Amino-pyrimidoazacyclo-phenylurea derivatives, the structural formula of which is shown in formula I:

Wherein, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is

-CN, -OH, phenyl, C1~C4 alkoxy, C3~C6 cycloalkyl, C1~C4 carbonyl,

R ₄ is C1～C4 alkoxy or

R ₅ ~ R ₆ , R ₉ ~ R ₁₀ are independently C1 ~ C4 alkyl; R ₁₁ is -H, C1 ~ C4 oxycarbonyl or

_R2 is

_R3 is -H or halogen. 2. 4-amino-pyrimidoazheterocyclic-phenylurea derivatives according to claim 1, characterized in that: X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is

-CN, -OH, phenyl, methoxy, ethoxy,

formyl, acetyl,

R ₄ is tert-butyloxy or

R ₅ ~ R ₆ , R ₉ ~ R ₁₀ are independently methyl or ethyl; _R2 is

_R3 is -H or halogen. 3. 4-amino-pyrimidoazheterocyclic-phenylurea derivatives according to claim 2, characterized in that: X is N or C; R is _-H , C1～C8 alkyl,

tert-butoxycarbonyl, C2～C6 alkenyl, C2～C6 alkynyl,

_R2 is

_R3 is -H, -F, -Cl or -Br. 4. 4-amino-pyrimidoazheterocyclic-phenylurea derivatives according to claim 1, characterized in that: when R ₂ is

, the structure is shown in Formula II:

Wherein, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is

-CN, -OH, phenyl, C1~C4 alkoxy, C3~C6 cycloalkyl, C1~C4 carbonyl,

R ₄ is C1～C4 alkoxy or

R ₅ ~ R ₆ , R ₉ ~ R ₁₀ are independently C1 ~ C4 alkyl; R ₁₁ is -H, C1 ~ C4 oxycarbonyl or

_R3 is -H or halogen. 5. 4-amino-pyrimidoazheterocyclic-phenylurea derivatives according to claim 4, characterized in that: X is N or C; R is _-H , C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is

-CN, -OH, phenyl, methoxy, ethoxy,

formyl, acetyl,

R ₄ is tert-butyloxy or

R ₅ ~ R ₆ , R ₉ ~ R ₁₀ are independently methyl or ethyl; _R3 is -H or halogen. 6. 4-amino-pyrimidoazheterocyclic-phenylurea derivatives according to claim 5, characterized in that: X is N or C; R ₁ is -H, C1～C8 alkyl,

tert-butoxycarbonyl, C2～C6 alkenyl, C2～C6 alkynyl,

_R3 is -H, -F, -Cl or -Br. 7. 4-amino-pyrimidoazheterocyclic-phenylurea derivatives according to claim 1, characterized in that: when R ₂ is

When R ₃ is -H, the structure is shown in formula III:

Wherein, X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is

-CN, -OH, phenyl, C1~C4 alkoxy, C3~C6 cycloalkyl, C1~C4 carbonyl,

R ₄ is C1～C4 alkoxy or

R ₅ ~ R ₆ , R ₉ ~ R ₁₀ are independently C1 ~ C4 alkyl; R ₁₁ is -H, C1 ~ C4 oxycarbonyl or

8. 4-amino-pyrimidoazheterocyclic-phenylurea derivatives according to claim 7, characterized in that: X is N or C; R ₁ is -H, C1～C8 alkyl,

C2～C6 alkenyl, C2～C6 alkynyl, C3～C6 cycloalkyl or substituted C1～C4 alkyl; the substituent of the substituted C1～C4 alkyl is

-CN, -OH, phenyl, methoxy, ethoxy,

formyl, acetyl,

R ₄ is tert-butyloxy or

R ₅ -R ₆ , R ₉ -R ₁₀ are independently methyl or ethyl. 9. 4-amino-pyrimidoazheterocyclic-phenylurea derivatives according to claim 8, characterized in that: X is N or C; R ₁ is -H, C1～C8 alkyl,

tert-butoxycarbonyl, C2～C6 alkenyl, C2～C6 alkynyl,

10.4-Amino-pyrimidoazacyclo-phenylurea derivatives, the structural formula is as follows:

11. A pharmaceutically acceptable salt of the 4-amino-pyrimidoazacyclo-phenylurea derivative according to any one of claims 1-10. 12. The pharmaceutically acceptable hydrate of the 4-amino-pyrimidoazacyclo-phenylurea derivative according to any one of claims 1-10. 13. A pharmaceutical composition, comprising the 4-amino-pyrimidoazacyclo-phenylurea derivative according to any one of claims 1 to 10, the salt according to claim 11 or the hydrated compound according to claim 12 The substance is an active ingredient, and a pharmaceutically acceptable carrier is added. 14. The 4-amino-pyrimidoazacyclo-phenylurea derivative according to any one of claims 1 to 10, the salt according to claim 11, the hydrate according to claim 12 or the hydrate according to claim 13 Use of the pharmaceutical composition in the preparation of FLT3 kinase inhibitors. 15. The use according to claim 14, characterized in that: the FLT3 kinase is a mutant FLT3 kinase. 16. The use according to claim 15, characterized in that: the mutant FLT3 kinase is a FLT3/ITD mutant kinase. 17. The 4-amino-pyrimidoazacyclo-phenylurea derivative according to any one of claims 1 to 10, the salt according to claim 11, the hydrate according to claim 12 or the hydrate according to claim 13 Use of the pharmaceutical composition in the preparation of drugs for treating tumors. 18. The use according to claim 17, said tumors comprise solid tumors and/or hematological tumors. 19. The use according to claim 18, said solid tumor comprising: lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, ovarian cancer, Breast cancer, prostate cancer, bladder cancer, kidney cancer, esophageal cancer, neck cancer, pancreatic cancer, colorectal cancer, stomach cancer, non-small cell lung cancer, thyroid cancer, brain cancer, lymphoma, epidermal hyperplasia, psoriasis and/or or enlarged prostate. 20. The use according to claim 18, said blood tumors comprising: acute myelogenous leukemia, chronic myeloid leukemia, myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia , chronic neutrophil leukemia, acute undifferentiated cell leukemia, myelodysplastic syndrome, myelodysplasia, multiple myeloma, and/or myelosarcoma.

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