CN112142731A

CN112142731A - 2, 4-disubstituted pyrimidine derivative and preparation method and application thereof

Info

Publication number: CN112142731A
Application number: CN202010588937.0A
Authority: CN
Inventors: 陈俐娟
Original assignee: Chengdu Zeiling Biomedical Technology Co ltd
Current assignee: Chengdu Zeiling Biomedical Technology Co ltd
Priority date: 2019-06-28
Filing date: 2020-06-24
Publication date: 2020-12-29
Anticipated expiration: 2040-06-24
Also published as: CN112142731B

Abstract

The invention belongs to the field of chemical medicine, and particularly relates to a 2, 4-disubstituted pyrimidine derivative, and a preparation method and application thereof. The invention providesProvides a 2, 4-disubstituted pyrimidine derivative, the structure of which is shown in formula IV. The invention also provides a preparation method and application of the 2, 4-disubstituted pyrimidine derivative. The 2, 4-disubstituted pyrimidine derivative provided by the invention can be used as a kinase inhibitor with JAK2 and FLT3 dual-functional targets, can also be used as a kinase inhibitor with single JAK2 or FLT3 functional targets, and provides a new choice for preparing a multi-target inhibitor.

Description

2, 4-disubstituted pyrimidine derivative and preparation method and application thereof

Technical Field

The invention belongs to the field of chemical medicine, and particularly relates to a 2, 4-disubstituted pyrimidine derivative, and a preparation method and application thereof. In particular to application of a 2, 4-disubstituted pyrimidine derivative as a Janus tyrosine kinase 2 and FMS-like tyrosine kinase 3(JAK2-FLT3) inhibitor.

Background

Myeloproliferative neoplasms (MPNs) are a group of malignant myeloproliferative diseases derived from pluripotent hematopoietic stem cells, and are manifested by one or more lines of hyperproliferation of myeloid cells, and further one or more lines of peripheral blood, with a tendency to form thrombi, extramedullary hematopoiesis, myelofibrosis and transformation into acute leukemia. Such diseases include Polycythemia Vera (PV), Primary Thrombocythemia (PT) and Primary Myelofibrosis (PMF).

The current clinical treatment methods still cannot cure the diseases of the MPNs. Recent studies have found that JAK2 kinases in the janus kinase (JAK) family play an important role in MPNs. The JAK-signal converter and activator of transcription (JAK-STAT) pathway controls survival, proliferation and differentiation of a variety of cells through cytokine-mediated signaling. Whereas activation of JAK2 phosphorylation, downstream STAT phosphorylation, and gene transcription ultimately leads to increased proliferation, differentiation, and survival of erythrocytes and myeloid cells. A number of JAK2 inhibitors have been clinically tested, among which the JAK2 inhibitor Ruxolitinib has been approved by the FDA for myelofibrosis, and others such as Lestaurtinib (CEP701), CYT-387, LY2784544, BMS-911543, etc. are still under clinical study.

Furthermore, recent studies have shown that FMS-like tyrosine kinase 3(FLT3) mutations are also closely related to MPNs: the ITD (internal tandem repeat) mutation, when knocked into mouse FLT3, can result in the development of myeloproliferative disease in mice. FLT3 is a receptor tyrosine kinase that plays a critical role in the development of hematopoietic progenitor cells. Activated FLT3 tandem repeat (ITD) mutations are found in about 30% of Acute Myeloid Leukemia (AML) patients, and are a high risk factor for disease recurrence. Small molecule FLT3 inhibitors have been in clinical trials as single or combination chemotherapy, however to date these drug candidates either failed to produce a sufficient initial response or failed to maintain therapeutic benefit, primarily due to secondary drug resistance. Clinical data also indicate that peripheral blood leukemia cells decline dramatically after patient treatment, but bone marrow responses are rare, and one of the possible mechanisms of failure is that there may be an independent alternative survival pathway and leukemia cells may adapt through further genetic mutation or metabolism. These pathways may include mTOR-PI3K-Akt, JAK-STAT, or Ras-MAPK. Simultaneous inhibition of these pathways would likely free leukemia cells from the limitations of FLT 3.

On this basis, targeting the JAK2 pathway simultaneously has several advantages: (a) few mutations in JAK2 were found in AML cases, (b) elevated phosphorylation-JAK 2 was found in AML, (c) inhibitors of the negative regulator of JAK signaling, cytokine 1/2/3, were significantly down-regulated in FLT3-TKI resistant strain FLT 3-ITD. Meanwhile, there is evidence that inhibition of two signaling pathways JAK2-FLT3 can enhance the clinical efficacy of AML patients with FLT3-ITD mutations. Based on this, the JAK2/FLT3 double-target inhibitor treatment of MPNs is also becoming a research and development hotspot, so that the JAK2/FLT3 double-target inhibitor Fedratinib is approved by FDA to be preferentially used for myelofibrosis, and the macrocyclic compound Pacritinib is also being clinically researched in the third stage (used for treating myelofibrosis). However, the existing JAK2/FLT3 dual-target inhibitors have poor enzyme activity and low oral bioavailability, and still cannot meet medical requirements, so that the development of inhibitors with better selectivity, higher activity and better in-vivo pharmacokinetics is a hot spot in current research and development.

Disclosure of Invention

The invention provides a 2, 4-disubstituted pyrimidine derivative with JAK2 and FLT3 dual-function targets.

The structure of the 2, 4-disubstituted pyrimidine derivative is shown as a formula IV:

wherein X is N or CH; r₂₂Is C₁～C₆An alkyl group;

R₁、R₂independently is-H, -halogen, -OH, C₁～C₁₀Alkyl or C₁～C₁₀An alkoxy group;

the A ring is a 5-membered or 6-membered N-containing heterocyclic ring, and the number of N atoms is 1; r is linked to N on the ring A, R is C₃～C₁₀Cycloalkyl, substituted or unsubstituted C₁～C₁₀Alkyl radical, C₂～C₁₀Alkynyl, substituted or unsubstituted C₂～C₁₀An alkenyl group,

Said substituted C₁～C₁₀The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₁₀Alkoxy or C₁～C₁₀An oxycarbonyl group; said substituted C₂～C₁₀The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₁₀Alkoxy radical, C₁～C₁₀Oxycarbonyl radical or

m、n＝0～2；

R₅Is C₁～C₁₀Alkoxy, substituted or unsubstituted C₂～C₁₀Alkenyl, substituted or unsubstituted C₁～C₁₀Alkyl, aryl, heteroaryl, and heteroaryl,

Said substituted C₁～C₁₀The substituents of the alkyl groups being-H, -OH, halogenElement, -CN, C₁～C₁₀Alkoxy radical, C₁～C₁₀An oxycarbonyl group,

Said substituted C₂～C₁₀Alkenyl is-H, -OH, halogen, -CN,

Phenyl or

R₆、R₇Independently is-H, C₁～C₁₀Alkyl or halogen substituted phenyl;

R₈、R₉independently is-H, C₁～C₁₀Alkyl, aryl, heteroaryl, and heteroaryl,

R₁₀、R₁₁independently-H or C₁～C₁₀An alkyl group;

R₁₂～R₁₆independently is-H, C₁～C₁₀Alkyl or-CF₃；

R₁₇～R₂₁Independently is-H, C₁～C₁₀Alkyl or-CF₃。

As a preferred embodiment of the present invention, the above-mentioned 2, 4-disubstituted pyrimidine derivative, R₂₂Is C₁～C₄An alkyl group.

In a preferred embodiment of the present invention, the 2, 4-disubstituted pyrimidine derivative has a structure represented by formula i:

wherein X is N or CH;

m、n＝0～2；

Said substituted C₁～C₁₀The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₁₀Alkoxy radical, C₁～C₁₀An oxycarbonyl group,

Said substituted C₂～C₁₀Alkenyl is-H, -OH, halogen, -CN,

Phenyl or

R₁₀、R₁₁independently-H or C₁～C₁₀An alkyl group;

R₁₂～R₁₆independently is-H, C₁～C₁₀Alkyl or-CF₃；

R₁₇～R₂₁Independently is-H, C₁～C₁₀Alkyl or-CF₃。

As a preferred embodiment of the present invention, the above-mentioned 2, 4-disubstituted pyrimidine derivative, R₁、R₂Independently is-H, -halogen, -OH, C₁～C₈Alkyl or C₁～C₈An alkoxy group.

Preferably, R₁、R₂Independently is-H, -halogen, -OH, C₁～C₆Alkyl or C₁～C₆An alkoxy group.

Further preferably, R₁、R₂Independently is-H, -halogen, -OH, C₁～C₄Alkyl or C₁～C₄An alkoxy group.

More preferably, R₁、R₂Independently is-H, halogen or C₁～C₄An alkyl group.

Most preferably, R₁、R₂Independently is-H, -F or methyl.

Preferably, in the 2, 4-disubstituted pyrimidine derivatives, the a ring is a 5-or 6-membered N-containing heterocycle, and the number of N atoms is 1; r is linked to N on the ring A, R is C₃～C₈Cycloalkyl, substituted or unsubstituted C₁～C₈Alkyl radical, C₂～C₈Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₈An alkenyl group,

Said substituted C₁～C₈The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₈Alkoxy or C₁～C₈An oxycarbonyl group; said substituted C₂～C₈The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₈Alkoxy radical, C₁～C₈Oxycarbonyl radical or

m、n＝0～2。

Further preferably, the a ring is a 5-or 6-membered N-containing heterocycle with 1N atom; r is linked to N on the ring A, R is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₆An alkenyl group,

Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₆Alkoxy or C₁～C₆An oxycarbonyl group; said substituted C₂～C₆The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₆Alkoxy radical, C₁～C₆Oxycarbonyl radical or

m、n＝0～2。

Still more preferably, ring a is a 5-or 6-membered N-containing heterocycle with 1N atom; r is linked to N on the ring A, R is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,

Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₄Alkoxy or C₁～C₄An oxycarbonyl group; said substituted C₂～C₄The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₄Alkoxy radical, C₁～C₄Oxycarbonyl radical or

m、n＝0～2。

More preferably, the a ring is a 5-or 6-membered N-containing heterocycle with 1N atom; r is connected with N on the ring A, and R is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,

Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, -CN, C₁～C₄Alkoxy or C₁～C₄An oxycarbonyl group; said substituted C₂～C₄The substituent of the alkenyl is-H, -COOH, phenyl and C₁～C₄Oxycarbonyl radical or

m and n are 0 or 1.

Most preferably, the a ring is a 5-or 6-membered N-containing heterocycle with 1N atom; r is connected with N on the ring A, and R is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,

Said substituted C₁～C₆The substituents for alkyl being-H, -OH, -CN, ethoxy or

Said substituted C₂～C₄The substituent of the alkenyl is-H, -COOH, phenyl,

m and n are 0 or 1.

Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R₅Is C₁～C₈Alkoxy, substituted or unsubstituted C₂～C₈Alkenyl, substituted or unsubstituted C₁～C₈Alkyl, aryl, heteroaryl, and heteroaryl,

Said substituted C₁～C₈The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₈Alkoxy radical, C₁～C₈An oxycarbonyl group,

Said substituted C₂～C₈The substituent of the alkenyl is-H, -OH, halogen, -CN,

Phenyl or

R₁₀、R₁₁independently-H or C₁～C₈An alkyl group; r₁₂～R₁₆Independently is-H、C₁～C₈Alkyl or-CF₃。

Further preferably, R₅Is C₁～C₆Alkoxy, substituted or unsubstituted C₂～C₆Alkenyl, substituted or unsubstituted C₁～C₆Alkyl, aryl, heteroaryl, and heteroaryl,

Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₆Alkoxy radical, C₁～C₆An oxycarbonyl group,

Said substituted C₂～C₆The substituent of the alkenyl is-H, -OH, halogen, -CN,

Phenyl or

R₁₀、R₁₁independently-H or C₁～C₆An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₆Alkyl or-CF₃。

More preferably, R₅Is C₁～C₆Alkoxy radical, C₂～C₆Alkenyl, substituted C₂～C₄Alkenyl radical, C₁～C₆Alkyl, substituted C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,

Said substituted C₁～C₄The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₄Alkoxy radical, C₁～C₄An oxycarbonyl group,

Said substituted C₂～C₄Alkenyl radicalThe substituent is-H, -OH, halogen, -CN,

Phenyl or

R₁₀、R₁₁independently-H or C₁～C₄An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₄Alkyl or-CF₃。

Most preferably, R₅Is C₂～C₆Alkenyl, substituted C₂～C₄Alkenyl radical, C₁～C₆Alkyl, substituted C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,

Said substituted C₁～C₄The substituent of the alkyl is-H, -OH, -CN,

Said substituted C₂～C₄The substituent of the alkenyl is-H,

Phenyl or

R₁₀、R₁₁independently-H or C₁～C₄An alkyl group.

Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R₆、R₇Independently is-H, C₁～C₈Alkyl or halogen substituted phenyl.

Further preferably, R₆、R₇Independently is-H, C₁～C₆Alkyl or halogen substituted phenyl.

More excellentOptionally, R₆、R₇Independently is-H, C₁～C₄Alkyl or chloro substituted phenyl.

Most preferably, R₆、R₇Independently is-H, C₁～C₄Alkyl or

Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R₈、R₉Independently is-H, C₁～C₈Alkyl, aryl, heteroaryl, and heteroaryl,

R₁₇～R₂₁Independently is-H, C₁～C₈Alkyl or-CF₃。

Further preferably, R₈、R₉Independently is-H, C₁～C₆Alkyl, aryl, heteroaryl, and heteroaryl,

R₁₇～R₂₁Independently is-H, C₁～C₆Alkyl or-CF₃。

More preferably, R₈、R₉Independently is-H, C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,

R₁₇～R₂₁Independently is-H, C₁～C₄Alkyl or-CF₃。

Most preferably, R₈、R₉Independently is-H, C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,

As a preferred technical scheme of the invention, the 2, 4-disubstituted pyrimidine derivative has a structure shown in a formula II:

wherein R is₄Is C₃～C₁₀Cycloalkyl, substituted or unsubstituted C₁～C₁₀Alkyl radical, C₂～C₁₀Alkynyl, substituted or unsubstituted C₂～C₁₀An alkenyl group,

m、n＝0～2；

Said substituted C₂～C₁₀Alkenyl is-H, -OH, halogen, -CN,

Phenyl or

R₁₀、R₁₁independently-H or C₁～C₁₀An alkyl group;

R₁₂～R₁₆independently is-H, C₁～C₁₀Alkyl or-CF₃；

R₁₇～R₂₁Independently is-H, C₁～C₁₀Alkyl or-CF₃。

Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R₄Is C₃～C₈Cycloalkyl, substituted or unsubstituted C₁～C₈Alkyl radical, C₂～C₈Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₈An alkenyl group,

m、n＝0～2。

Further preferably, R₄Is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₆An alkenyl group,

m、n＝0～2。

Even more preferably, R₄Is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,

m、n＝0～2。

More preferably, R₄Is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,

m and n are 0 or 1.

Most preferably, R₄Is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,

Said substituted C₂～C₄The substituent of the alkenyl is-H, -COOH, phenyl,

m and n are 0 or 1.

Phenyl or

R₁₀、R₁₁independently-H or C₁～C₈An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₈Alkyl or-CF₃。

Phenyl or

Said substituted C₂～C₄The substituent of the alkenyl is-H, -OH, halogen, -CN,

Phenyl or

Said substituted C₁～C₄The substituent of the alkyl is-H, -OH, -CN,

Said substituted C₂～C₄The substituent of the alkenyl is-H,

Phenyl or

R₁₀、R₁₁independently-H or C₁～C₄An alkyl group.

More preferably, R₆、R₇Independently is-H, C₁～C₄Alkyl or chloro substituted phenyl.

Most preferably, R₆、R₇Independently is-H, C₁～C₄Alkyl or

R₁₇～R₂₁Independently is-H, C₁～C₈Alkyl or-CF₃。

R₁₇～R₂₁Independently is-H, C₁～C₆Alkyl or-CF₃。

R₁₇～R₂₁Independently is-H, C₁～C₄Alkyl or-CF₃。

As a preferred technical scheme of the invention, the 2, 4-disubstituted pyrimidine derivative has a structure shown in a formula III:

wherein R is₁Is methyl or-F; r₃Is C₃～C₁₀Cycloalkyl, substituted or unsubstituted C₁～C₁₀Alkyl radical, C₂～C₁₀Alkynyl, substituted or unsubstituted C₂～C₁₀An alkenyl group,

m、n＝0～2；

Said substituted C₂～C₁₀Alkenyl is-H, -OH, halogen, -CN,

Phenyl or

R₁₀、R₁₁independently-H or C₁～C₁₀An alkyl group;

R₁₂～R₁₆independently is-H, C₁～C₁₀Alkyl or-CF₃；

R₁₇～R₂₁Independently is-H, C₁～C₁₀Alkyl or-CF₃。

Preferably, in the above 2, 4-disubstituted pyrimidine derivatives, R₃Is C₃～C₈Cycloalkyl, substituted or unsubstituted C₁～C₈Alkyl radical, C₂～C₈Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₈An alkenyl group,

Said substituted C₁～C₈The substituent of the alkyl group is-H, -OH, halogen, -CN, C₁～C₈Alkoxy or C₁～C₈An oxycarbonyl group; said substituted C₂～C₈The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₈Alkoxy radical, C₁～C₈Oxycarbonyl radical or

m、n＝0～2。

Further preferably, R₃Is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₆An alkenyl group,

m、n＝0～2。

More preferably, R₃Is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,

Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₄Alkoxy or C₁～C₄An oxycarbonyl group; said substituted C₂～C₄The substituent of the alkenyl is-H. -OH, halogen, -CN, -COOH, phenyl, C₁～C₄Alkoxy radical, C₁～C₄Oxycarbonyl radical or

m、n＝0～2。

More preferably, R₃Is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,

m and n are 0 or 1.

Most preferably, R₃Is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,

Said substituted C₂～C₄The substituent of the alkenyl is-H, -COOH, phenyl,

m and n are 0 or 1.

Phenyl or

Phenyl or

Phenyl or

Said substituted C₁～C₄The substituent of the alkyl is-H, -OH, -CN,

Said substituted C₂～C₄The substituent of the alkenyl is-H,

Phenyl or

R₁₀、R₁₁independently-H or C₁～C₄An alkyl group.

Most preferably, R₆、R₇Independently is-H, C₁～C₄Alkyl or

R₁₇～R₂₁Independently is-H, C₁～C₈Alkyl or-CF₃。

R₁₇～R₂₁Independently is-H, C₁～C₆Alkyl or-CF₃。

R₁₇～R₂₁Independently is-H, C₁～C₄Alkyl or-CF₃。

The 2, 4-disubstituted pyrimidine derivative has the following structural formula:

the invention also provides a preparation method of the 2, 4-disubstituted pyrimidine derivative, and the synthetic route is as follows:

the preparation method of the 2, 4-disubstituted pyrimidine derivative comprises the following steps:

1) heating and reacting the raw material 1 with a halide for 4-8 hours under an alkaline condition to obtain an intermediate 1; the alkali is cesium carbonate or potassium carbonate; the solvent for reaction is any one of acetonitrile, N-dimethylformamide or dioxane; the reaction temperature of the raw material 1 and the halide is 60-80 ℃;

2) under the protection of nitrogen and alkaline conditions, the intermediate 1 and a 2, 4-disubstituted pyrimidine compound are subjected to a Suzuki reaction under the conditions of dioxane, water and ethanol to obtain an intermediate 2; the alkali is sodium carbonate or potassium carbonate; the solvent for reaction is any one of a dioxane/water/ethanol mixed system, a toluene/water mixed system and a 1, 2-dichloroethane/water mixed system; the reaction temperature is 80-95 ℃; the reaction time is 2-5 hours; wherein the using amount of the borate is 1.3 equivalent;

3) under the protection of nitrogen and alkaline conditions, carrying out Buchwald-Hartwig coupling reaction on the raw material 2 and the intermediate 2 to obtain a formula intermediate 3; the alkali is cesium carbonate or potassium tert-butoxide; the solvent for reaction is any one of dioxane and toluene; the reaction temperature is 100-110 ℃; the reaction time is 4-6 hours; wherein the dosage of the intermediate 2 is 1.2 equivalent;

4) removing the protection of Boc anhydride from the intermediate 3 under an acidic condition to obtain an intermediate 4; the acid is trifluoroacetic acid or hydrochloric acid; the solvent for reaction is any one of dichloromethane, ethyl acetate and tetrahydrofuran; the reaction temperature is 20-30 ℃; the reaction time is 2-5 hours;

5) the intermediate 4 reacts with a halide under the alkaline condition to obtain a compound shown in a formula I or IV, and the intermediate 4 reacts with an acid under the alkaline condition to obtain a compound shown in a formula I or IV of an amide; the alkali is any one of DIEA, potassium carbonate or cesium carbonate; the solvent for reaction is any one of dichloromethane, N-dimethylformamide or tetrahydrofuran; the reaction temperature is 20-30 ℃; the reaction time is 1-2 hours;

wherein X is N or CH; r₂₂Is C₁～C₆An alkyl group;

m、n＝0～2；

Said substituted C₂～C₁₀Alkenyl is-H, -OH, halogen, -CN,

Phenyl or

R₁₀、R₁₁independently-H or C₁～C₁₀An alkyl group;

R₁₂～R₁₆independently is-H, C₁～C₁₀Alkyl or-CF₃；

R₁₇～R₂₁Independently is-H, C₁～C₁₀Alkyl or-CF₃。

The invention also provides the 2, 4-disubstituted pyrimidine derivatives, including tautomers, stereoisomers, mixtures thereof in all proportions, and isotopically substituted compounds thereof.

The invention also provides pharmaceutically acceptable salts of the 2, 4-disubstituted pyrimidine derivatives. Wherein the salt with an acid is obtained by reacting the free base of the parent compound with an inorganic or organic acid. The inorganic acid includes hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, or the like. The organic acid includes acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, 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, malonic acid, or the like.

The term "pharmaceutically acceptable" as used herein, means that which, within the scope of sound medical judgment, is suitable for use in contact with the tissues of human beings and other mammals without undue toxicity, irritation, allergic response and the like, and which, when administered to a recipient, provides, directly or indirectly, a compound of the invention or a prodrug of the compound.

The invention also provides a pharmaceutically acceptable hydrate of the 2, 4-disubstituted pyrimidine derivative. The term "hydrate" refers to a compound that further binds stoichiometric or non-stoichiometric water by non-covalent intermolecular forces.

The invention also provides a pharmaceutically acceptable polymorphic substance of the 2, 4-disubstituted pyrimidine derivative. The term "polymorph" denotes a solid crystalline form of a compound or a complex thereof, which can be characterized by physical means, such as x-ray powder diffraction patterns or infrared spectroscopy.

The invention also provides a pharmaceutically acceptable pharmaceutical composition of the 2, 4-disubstituted pyrimidine derivative, which is a preparation prepared by adding pharmaceutically acceptable auxiliary components into the 2, 4-disubstituted pyrimidine derivative shown in formulas I-III and IV, salt or hydrate thereof. The auxiliary component is cyclodextrin, arginine or meglumine. The cyclodextrin is selected from alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin and (C)_1-4Alkyl) -alpha-cyclodextrin, (C)_1-4Alkyl) -beta-cyclodextrin, (C)_1-4Alkyl) -gamma-cyclodextrin, (hydroxy-C)_1-4Alkyl) -alpha-cyclodextrin, (hydroxy-C)_1-4Alkyl) -beta-cyclodextrin, (hydroxy-C)_1-4Alkyl) -gamma-cyclodextrin, (carboxy-C)_1-4Alkyl) -alpha-cyclodextrin, (carboxy-C)_1-4Alkyl) -beta-cyclodextrin, (carboxy-C)_1-4Alkyl) -gamma-cyclodextrin, saccharide ethers of alpha-cyclodextrin, saccharide ethers of beta-cyclodextrin, saccharide ethers of gamma-cyclodextrin, sulfobutyl ethers of alpha-cyclodextrin, sulfobutyl ethers of beta-cyclodextrin and sulfobutyl ethers of gamma-cyclodextrin. The auxiliary components also comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. Can be used in pharmaceutically acceptable pharmaceutical composition, such as ion exchanger, aluminum oxide, aluminum stearate, and lecithin; buffer substances include phosphate, glycine, arginine, sorbic acid, and the like.

The pharmaceutical composition may be in liquid form or solid form. Wherein the liquid form may be an aqueous solution. The solid form may be in the form of a powder, granules, tablets or lyophilized powder. The pharmaceutical composition further comprises water for injection, saline solution, aqueous glucose solution, saline for injection/infusion, glucose for injection/infusion, Grignard solution or Grignard solution containing lactate. Further, the preparation is a tablet, a capsule, a powder, a granule, an ointment, a solution, a suspension, an injection, an inhalant, a gel, a microsphere or an aerosol.

The 2, 4-disubstituted pyrimidine derivatives shown in formulas I to III and IV, and the application of the salts, hydrates or pharmaceutical compositions thereof in preparing JAK2 inhibitors.

Use of 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III and IV, salts, hydrates or pharmaceutical compositions thereof in preparation of FLT3 inhibitors.

The 2, 4-disubstituted pyrimidine derivatives shown in formulas I to III and IV, and the salt, hydrate or pharmaceutical composition thereof are used for preparing JAK2-FLT3 inhibitors.

The 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III and IV, and the application of the salts, hydrates or pharmaceutical compositions thereof in preparing medicaments for treating and/or preventing tumors.

In the above uses, the tumor comprises a solid tumor and/or a hematological tumor.

In the above use, the solid tumor comprises: 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, lymphatic cancer, epidermal hyperplasia, psoriasis, prostate cancer, and combinations thereof.

The use as described above, the hematological neoplasm comprising: acute myelogenous leukemia, chronic myelogenous leukemia, myeloma, acute lymphocytic leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated cell leukemia, myelodysplastic syndrome, myelodysplasia, myelofibrosis, multiple myeloma, myelosarcoma, and combinations thereof.

The 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III and IV, and the application of the salts, hydrates or pharmaceutical compositions thereof in preparing medicines for treating and/or preventing immune diseases.

In the above uses, the immune diseases include: psoriasis, rheumatoid arthritis, inflammatory bowel disease (e.g., crohn's disease, ulcerative colitis, etc.), sjogren's syndrome, behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, polymyositis, Dermatomyositis (DM), Periartherococcosis Nodosa (PN), Mixed Connective Tissue Disease (MCTD), scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves ' disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, addison's disease, abnormal immune response, arthritis, dermatitis, radiodermatitis, etc.) (particularly psoriasis, rheumatoid arthritis, inflammatory bowel disease, sjogren's syndrome, dermatitis, etc.) (particularly, psoriasis, rheumatoid arthritis, inflammatory bowel disease, sjogren's syndrome, morbus, behcet's disease, multiple sclerosis, and systemic lupus erythematosus).

Use of 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III and IV, salts, hydrates or pharmaceutical compositions thereof in preparation of drugs for treating and/or preventing inflammatory related diseases.

In the above uses, the inflammatory-related diseases include: inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, Chronic Obstructive Pulmonary Disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, Systemic Inflammatory Response Syndrome (SIRS), post-operative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, and the like.

The 2, 4-disubstituted pyrimidine derivatives shown in formulas I-III and IV, and the application of the salts, hydrates or pharmaceutical compositions thereof in preparing oral or intravenous injection preparations.

For administration purposes, the compounds of the present invention may be administered as the starting chemical, or they may be formulated for administration as a pharmaceutical composition. The pharmaceutical compositions of the present invention comprise a compound of structure I, II, III or iv and a pharmaceutically acceptable carrier, diluent or excipient. The compound of structure I, II, III or IV is present in the composition in an amount effective to treat the particular disease or condition of interest-i.e., an amount sufficient to treat a different cancer and preferably having acceptable toxicity to the patient. JAK2 and/or FLT3 kinase activity of compounds of structure I, II, III or iv can be determined by one of skill in the art, for example, as described in the examples below. Suitable concentrations and dosages can be readily determined by those skilled in the art.

The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered in pure form or in the form of suitable pharmaceutical compositions by an acceptable mode of administration of the active agent for similar uses. The pharmaceutical compositions of the present invention may be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable carriers, diluents or excipients, and they may be formulated in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suspensions, injections, inhalants, gels, microspheres and aerosols. Typical routes of administration for such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical compositions of the present invention may be formulated so as to allow the active ingredients contained therein to be bioavailable when the composition is fitted to a patient. The composition for administration to a subject or patient may take the form of one or more dosage units, for example, wherein a tablet may be a single dosage unit and a container of a compound of the invention in aerosol form may carry a plurality of dosage units. The exact methods of making such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington, The Science and Practice of Pharmacy, 20 th edition (Philadelphia College of Pharmacy and Science, 2000). In any event, the administered composition comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for treating a disease or condition of interest in accordance with the teachings of the present invention.

The pharmaceutical compositions of the present invention may be in solid or liquid form. In one aspect, the carrier is a particle, such that the composition is in the form of a tablet or powder, for example. The carrier may be a liquid, wherein the composition is, for example, an oral syrup, an injectable liquid, or an aerosol, e.g., for administration by inhalation.

When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, including semi-solid, semi-liquid, suspension, and gel forms, among those recognized herein as solid or liquid.

As solid compositions for oral administration, the pharmaceutical compositions may be formulated as powders, granules, compressed tablets, pills, capsules, chewing gums, wafers, and the like. Such solid compositions typically comprise one or more inert diluents or edible carriers. In addition, one or more of the following ingredients may be present: a binder such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch, lactose or dextrin; disintegrating agents, such as alginic acid, sodium alginate, Primogel, corn starch, and the like; lubricants, such as magnesium stearate or hydrogenated vegetable oil; glidants, such as colloidal silicon dioxide; sweetening agents, such as sucrose or saccharin: flavoring agents, such as peppermint, methyl salicylate, or orange flavor; and a colorant.

When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or an oil.

The pharmaceutical composition may be in liquid form, e.g., an acid, syrup, solution, emulsion or suspension. As two examples, the liquid may be for oral administration or delivered by injection. When intended for oral administration, preferred compositions contain, in addition to a compound of the invention, one or more of sweetening agents, preserving agents, dyes/colorants and taste enhancers. In compositions intended for administration by injection, one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffering agents, stabilizing agents and isotonic agents may be included.

The liquid compositions of the invention, whether they be in solution, suspension or other similar form, may include one or more of the following adjuvants: sterile diluents, such as water for injection, saline solutions, preferably physiological saline, ringer's solution and isotonic sodium chloride, fixed oils, such as synthetic monoglycerides or diglycerides, polyethylene glycols, glycerol, propylene glycol or other solvents that may serve as a solvent or suspending medium; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate or phosphate: and agents for adjusting tonicity, such as sodium chloride or glucose. Parenteral formulations may be enclosed in ampoules, disposable syringes or multiple dose glass or rate vials. Physiological saline is a preferred excipient. The injectable pharmaceutical composition is preferably sterile.

Liquid pharmaceutical compositions of the invention intended for parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage can be obtained.

The pharmaceutical composition of the invention is intended for topical administration in advance, in which case the carrier may suitably comprise a solution, emulsion, balm or gel base. For example, the matrix may comprise one or more of the following components: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickeners may be present in the pharmaceutical composition for topical application. If transdermal administration is contemplated, the composition may include a transdermal patch or iontophoretic device.

The pharmaceutical compositions of the invention are intended for rectal administration, for example, in the form of suppositories, which melt in the rectum and release the drug. Compositions for rectal administration may comprise an oily base as a suitable non-irritating excipient. Such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycols.

The pharmaceutical compositions of the present invention may include a variety of materials that alter the physical form of the solid or liquid dosage form. For example, the composition may include a material that forms an envelope around the active ingredient. The material forming the coating is typically inert and may be selected from, for example, sugars, shellac, and other enteric coatings. Alternatively, the active ingredient may be packaged in gelatin capsules.

Pharmaceutical compositions of the invention in solid or liquid form may include agents that bind to the compounds of the invention and thereby facilitate delivery of the compounds. Suitable agents that can function in this capacity include monoclonal or polyclonal antibodies, proteins, or liposomes.

The pharmaceutical compositions of the present invention may be comprised of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to those consisting of pressurized packaging. Delivery may be by liquefied or pressurised gas or by a suitable pump system that dispenses the active ingredient. Aerosols of the compounds of the invention may be delivered in the form of single, biphasic or triphasic systems for delivery of the active ingredient. The aerosol delivered includes the necessary containers, actuators, valves, sub-containers (subcontainers), etc., which together may form a cartridge. One skilled in the art can determine preferred aerosols without undue experimentation.

The invention also provides application of the 2, 4-disubstituted pyrimidine derivatives shown in the formulas I to III and IV, salts, hydrates or pharmaceutical compositions thereof in preparing oral or intravenous injection preparations. The oral or intravenous injection preparation at least comprises one 2, 4-disubstituted pyrimidine derivative shown in formulas I-III and IV, and salt, hydrate or pharmaceutical composition thereof, and any excipient and/or adjuvant.

The 2, 4-disubstituted pyrimidine derivative provided by the invention can be used as a kinase inhibitor with JAK2 and FLT3 dual-functional targets, can also be used as a kinase inhibitor with independent JAK2 or FLT3 functional targets, and provides a new choice for preparing medicines for treating and/or preventing tumors, inflammatory diseases and immune diseases.

Detailed Description

EXAMPLE 16 preparation of hydroxypropyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridin-2-amine (CLJ-100)

Step 1: synthesis of 1-propylpyrazole-4-boronic acid pinacol ester (compound of formula 2)

4-boronic acid pinacol ester (1.9g, 10mmol), 2-iodopropane (3.4g, 20mmol), cesium carbonate (6.5g, 20mmol) were added to acetonitrile (50ml) and reacted in an oil bath at 80 ℃ for 2 hours. After the reaction is finished, filtering while the solution is hot and concentrating the filtrate to obtain the compound of the formula 2.

Step 2: synthesis of 2-chloro-5-methyl-4- (1-isopropyl-1H-pyrazol-4-yl) pyrimidine (compound of formula 3) A compound of formula 2 (1.9g, 10mmol), 2, 4-dichloro-5-fluoropyrimidine (1.7g, 10mmol), potassium carbonate (3.4g, 25mmol) and dppf (Pd2Cl2) (0.75g, 1mmol) were charged into a 250mL three-necked flask, dioxane/ethanol/water (total 70mL) was added as a solvent, and after nitrogen gas was replaced three times, the flask was put into an oil bath at 85 ℃ for reaction for 2 hours. After the reaction is finished, concentrating the reaction solution to be dry, mixing the sample, and separating by a silica gel column to obtain the compound shown in the formula 3 which is a white-like solid. 1H NMR (500MHz, Chloroform-d) 8.43(d, J ═ 8.1Hz,1H),8.14(t, J ═ 1.7Hz,1H),7.46(t, J ═ 1.7Hz,1H),4.78(m,1H),0.99(d, J ═ 8.0Hz,6H).

And step 3: synthesis of 6-Boc-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridin-2-amine (compound of formula 5)

2-amino-N-Boc-5, 6,7, 8-tetrahydronaphthyridine (2.5g, 10mmol), 2-chloro-5-methyl-4- (1-isopropyl-1H-pyrazol-4-yl) pyrimidine (2.7g, 10mmol), cesium carbonate (6.5g, 20mmol), Pd2DBA3(260mg, 1mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (520mg, 2mmol) were put into dioxane (50ml), and after replacement of nitrogen, they were reacted in an oil bath at 103 ℃ for 2 hours. After the reaction is finished, filtering while the reaction is hot, concentrating the filtrate, mixing the crude silica gel with a sample, and separating by a flash column (EA) to obtain the compound shown in the formula 5.

And 4, step 4: synthesis of N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridin-2-amine (compound of formula 6)

6-Boc-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridin-2-amine (2.3g, 5mmol) was added to dichloromethane (50ml), trifluoroacetic acid (1.2g, 10mmol) was added thereto, and the mixture was reacted at room temperature for 1 hour, after the reaction was completed, the solvent was distilled off under reduced pressure to obtain a compound of formula 6.

And 5: synthesis of 6-hydroxypropyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridin-2-amine (CLJ-100)

Adding N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -5,6,7, 8-tetrahydronaphthyridine-2-amine (350mg, 1mmol) into acetonitrile (20ml), adding 3-bromopropanol (180mg, 1.3mmol) and cesium carbonate (650mg, 2mmol), reacting at room temperature for 1H, adding 40ml of water after the reaction is finished, extracting with dichloromethane, distilling the organic phase under reduced pressure, and pulping the crude product with diethyl ether to obtain the final product CLJ-100.¹H NMR(400MHz,DMSO-d₆):9.19(s,1H),8.38–8.30(m,2H),8.11(t,J＝4.2Hz,2H),7.47(d,J＝8.5Hz,1H),4.63(h,J＝6.6Hz,1H),4.44(d,J＝38.4Hz,1H),3.55–3.44(m,4H),2.80(t,J＝5.9Hz,2H),2.73(t,J＝6.1Hz,2H),2.54(d,J＝7.1Hz,2H),2.33(s,3H),1.72–1.64(m,2H),1.48(d,J＝6.7Hz,6H).¹³C NMR(101MHz,DMSO):159.93,158.01,157.82,152.89,151.72,139.55,136.47,129.69,123.47,120.45,117.59,110.21,59.81,55.19,54.71,53.83,50.98,32.20,30.45,23.03,17.19.m/z:408.5230[M+H]⁺.

Example 22 preparation of hydroxyethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine alcohol (CLJ-101)

CLJ-101 Synthesis As in example 1, 6-amino-N-Boc-1, 2,3, 4-tetrahydroisoquinoline was used in place of 2-amino-N-Boc-5, 6,7, 8-tetrahydronaphthyridine and 2-iodoethanol was used in place of 3-bromo-1-propanol to give CL, a final productJ-101。¹H NMR(400MHz,DMSO-d₆):9.20(s,1H),8.29(d,J＝22.7Hz,2H),8.08(s,1H),7.65(d,J＝2.3Hz,1H),7.46(dd,J＝8.3,2.3Hz,1H),6.94(d,J＝8.4Hz,1H),4.62(h,J＝6.6Hz,1H),4.46(s,1H),3.67–3.46(m,4H),2.80(d,J＝5.8Hz,2H),2.71(t,J＝5.8Hz,2H),2.57(t,J＝6.2Hz,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H).¹³C NMR(101MHz,DMSO):159.88,159.00,157.63,139.42,139.31,134.44,129.38,127.92,126.71,120.74,118.31,116.72,116.35,60.74,59.30,56.07,53.83,51.64,29.63,23.03,17.15.m/z:393.5070[M+H]⁺.

Example preparation of 32-hydroxyethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-fluoro-6-amine (CLJ-102)

The pyrimidine moiety synthesis of CLJ-102 was the same as in example 2;

the aromatic amine moiety was synthesized as follows:

step 1: synthesis of 4-fluorophenylethylamine trifluoroacetamide (compound of formula 2)

4-fluorophenylethylamine (7g,50mmol) and triethylamine (13g,125mmol) were dissolved in dichloromethane (100mL), trifluoroacetic anhydride (12.6g,60mmol) was added dropwise, reacted at room temperature for 30min, a large amount of water (about 200mL) was added, vigorously stirred, separated, the organic phase was concentrated by distillation under reduced pressure, and slurried with ether to give a compound of formula 2.

Step 2: synthesis of 7-fluoro-1, 2,3, 4-tetrahydroisoquinoline trifluoroacetamide (compound of formula 3)

Dissolving 4-fluorophenylethylamine trifluoroacetamide (4.7g,20mmol) in concentrated sulfuric acid (20ml), adding glacial acetic acid (5ml) and paraformaldehyde (1.8g,20mmol), reacting at room temperature for 4h, after the reaction is finished, adding concentrated sulfuric acid into a large amount of ice water, extracting with dichloromethane, concentrating, and pulping with n-hexane/diethyl ether (1:1) to obtain the compound of formula 3.

And step 3: synthesis of 7-fluoro-6-nitro-1, 2,3, 4-tetrahydroisoquinoline trifluoroacetamide (compound of formula 4) 4-fluoro-1, 2,3, 4-tetrahydroisoquinoline trifluoroacetamide (4.9g,20mmol) is dissolved in concentrated sulfuric acid (20ml), a solution of potassium nitrate (3g,30mmol) in concentrated sulfuric acid (20ml) is slowly dropped at 0 ℃, reaction is continued for 2h after dropping is completed, the concentrated sulfuric acid is added into a large amount of ice water after the reaction is completed, and after suction filtration and drying, n-hexane/diethyl ether (1:1) is used for pulping to obtain the compound of formula 4.

And 4, step 4: synthesis of 7-fluoro-6-nitro-1, 2,3, 4-tetrahydroisoquinoline (compound of formula 5)

Dissolving 4-fluoro-5-nitro-1, 2,3, 4-tetrahydroisoquinoline trifluoroacetamide (4.4g,15mmol) in methanol (40mL), adding 5mL of concentrated hydrochloric acid, reacting at 60 ℃ for 1h, adjusting to neutrality after the reaction is finished, performing suction filtration, and drying to obtain the compound shown in the formula 5.

And 5: synthesis of N-Boc-7-fluoro-6-nitro-1, 2,3, 4-tetrahydroisoquinoline (Compound of formula 6)

Adding 4-fluoro-5-nitro-1, 2,3, 4-tetrahydroisoquinoline (2g,10mmol) into acetonitrile (50ml), then adding potassium carbonate (2.8g,20mmol) and Boc anhydride (5ml), reacting at 60 ℃ for 1h, after the reaction is finished, adding a large amount of water and extracting with dichloromethane, concentrating the organic phase by vacuum distillation, and pulping with diethyl ether to obtain the compound of formula 6.

Step 6: synthesis of 2-N-Boc-7-fluoro-6-amino-1, 2,3, 4-tetrahydroisoquinoline (Compound of formula 7) Synthesis of Compound of formula 8, CLJ-102 in the same manner as in example 2, 6-amino-N-Boc-1, 2,3, 4-tetrahydroisoquinoline was replaced with 7-fluoro-6-amino-N-Boc-1, 2,3, 4-tetrahydroisoquinoline.¹H NMR(400MHz,DMSO-d₆):8.56(s,1H),8.26(d,J＝25.6Hz,2H),8.01(s,1H),7.67(d,J＝8.0Hz,1H),6.92(d,J＝11.5Hz,1H),4.61(p,J＝6.7Hz,1H),4.54(s,1H),3.82–3.42(m,4H),2.96–2.63(m,4H),2.55(t,J＝6.5Hz,2H),2.30(s,3H),1.46(d,J＝6.6Hz,6H).¹³C NMR(101MHz,DMSO):159.91,159.09,157.81,154.07,151.66,139.34,130.75,129.94,129.42,123.69,120.56,116.87,113.15,60.46,59.27,55.69,53.82,51.37,28.78,23.02,17.08.m/z:411.4974[M+H]⁺.

Example 42 preparation of hydroxypropyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-103)

CLJ-103 Synthesis As in example 2, the final product CLJ-103 was obtained by substituting 3-iodopropanol for 2-iodoethanol.¹H NMR(400MHz,DMSO-d₆):8.56(s,1H),8.27(d,J＝25.6Hz,2H),8.00(s,1H),7.66(d,J＝8.0Hz,1H),6.94(d,J＝11.5Hz,1H),4.62(p,J＝6.7Hz,1H),4.54(s,1H),3.81–3.43(m,4H),2.95–2.64(m,4H),2.53(t,J＝6.5Hz,2H),2.30(s,3H),1.57(m,2H),1.46(d,J＝6.6Hz,6H).¹³C NMR(101MHz,DMSO):159.89,159.00,157.64,139.46,139.31,134.46,129.39,127.83,126.75,120.74,118.30,116.75,116.36,59.96,55.86,55.56,53.83,51.25,30.34,29.66,23.04,17.15。m/z:407.5340[M+H]⁺.

Example 52 preparation of hydroxybutyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-104)

CLJ-104 Synthesis As in example 2, the final product CLJ-104 was obtained by substituting 4-bromo-1-butanol for 2-iodoethanol.¹H NMR(400MHz,DMSO-d₆):9.19(s,1H),8.29(d,J＝23.0Hz,2H),8.08(s,1H),7.64(d,J＝2.3Hz,1H),7.46(dd,J＝8.3,2.3Hz,1H),6.95(d,J＝8.4Hz,1H),4.63(q,J＝6.6Hz,1H),4.56(d,J＝26.0Hz,1H),3.56–3.35(m,4H),2.80(t,J＝5.9Hz,2H),2.63(t,J＝5.8Hz,2H),2.43(t,J＝7.0Hz,2H),2.31(s,3H),1.55(q,J＝7.2Hz,2H),1.48(d,J＝6.7Hz,6H).¹³C NMR(101MHz,DMSO):159.03,158.27,158.19,140.86,139.50,131.80,129.78,127.32,121.05,120.48,118.02,117.76,116.99,60.49,60.22,55.58,53.89,52.27,49.47,29.86,29.68,25.74,23.02,22.91,21.01,17.16.m/z:421.2638[M+H]⁺.

Example 62 preparation of hydroxypentyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-105)

Synthesis of CLJ-105 like example 2, the final product CLJ-105 was obtained by substituting 5-bromo-1-pentanol for 2-iodoethanol.¹H NMR(400MHz,DMSO-d₆)9.19(s,1H),8.32(s,1H),8.27(s,1H),8.08(s,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.3Hz,1H),6.95(d,J＝8.3Hz,1H),4.63(p,J＝6.7Hz,1H),4.34(s,1H),3.40(t,J＝5.7Hz,2H),2.80(t,J＝5.9Hz,2H),2.63(t,J＝5.9Hz,2H),2.43(t,J＝7.3Hz,2H),2.31(s,3H),1.58–1.41(m,10H),1.35(qd,J＝9.8,8.4,4.5Hz,2H).m/z:435.2794[M+H]⁺.

Example 72 preparation of hydroxyethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-fluoropyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-106)

CLJ-106 Synthesis As in example 2, the final product CLJ-106 was obtained by substituting 2, 4-dichloro-5-fluoropyrimidine for 2, 4-dichloro-5-methylpyrimidine.¹H NMR(400MHz,DMSO-d₆)9.49(s,1H),8.49(d,J＝2.9Hz,1H),8.38(s,1H),8.08(s,1H),7.62(s,1H),7.48(d,J＝8.3Hz,1H),6.99(d,J＝8.4Hz,1H),4.66(td,J＝14.4,13.9,7.2Hz,2H),3.83–3.50(m,4H),2.78(d,J＝66.0Hz,6H),1.48(d,J＝6.7Hz,6H).m/z:397.2074[M+H]⁺.

Example 82 preparation of hydroxypropyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-fluoropyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-107)

Synthesis of CLJ-107 As in example 7, the final product CLJ-107 was obtained by substituting 3-iodo-1-propanol for 2-iodoethanol.¹H NMR(400MHz,DMSO-d₆):10.24(s,1H),9.68(s,1H),8.53(d,J＝3.0Hz,1H),8.40(d,J＝2.0Hz,1H),8.10(d,J＝1.1Hz,1H),7.76(d,J＝2.2Hz,1H),7.60(dd,J＝8.4,2.2Hz,1H),7.14(d,J＝8.5Hz,1H),4.67(p,J＝6.6Hz,1H),4.25(d,J＝36.4Hz,2H),3.37(s,4H),3.24(t,J＝8.1Hz,2H),3.12(s,2H),1.94(dq,J＝11.9,6.0Hz,2H),1.48(d,J＝6.6Hz,6H).¹³C NMR(101MHz,DMSO):156.98,149.96,147.48,146.97,146.18,139.09,138.86,134.51,128.24,126.82,118.38,116.85,115.73,59.94,55.80,55.52,54.00,51.18,30.28,29.56,22.94.m/z:411.2230[M+H]⁺.

Example preparation of 92-hydroxybutyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-fluoropyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-108)

Synthesis of CLJ-108 As in example 8, the final product CLJ-108 was obtained by substituting 4-bromo-1-butanol for 3-iodo-1-propanol.¹H NMR(400MHz,DMSO-d₆):9.48(s,1H),8.49(d,J＝3.0Hz,1H),8.38(d,J＝1.9Hz,1H),8.08(d,J＝1.3Hz,1H),7.60(d,J＝2.2Hz,1H),7.46(dd,J＝8.3,2.2Hz,1H),6.98(d,J＝8.4Hz,1H),4.68(h,J＝6.6Hz,1H),4.56(s,1H),3.42(t,J＝6.3Hz,2H),2.81(t,J＝5.9Hz,2H),2.64(t,J＝5.8Hz,2H),2.44(t,J＝7.1Hz,2H),1.60–1.40(m,10H).¹³C NMR(101MHz,DMSO):157.01,149.95,147.47,146.97,145.96,139.05,138.85,134.58,129.78,128.38,126.82,118.39,116.83,115.73,61.22,58.22,55.74,54.00,51.11,31.13,29.61,23.80,22.95.m/z:425.2387[M+H]⁺.

Example 102 preparation of hydroxypentyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-fluoropyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-109)

Synthesis of CLJ-109 As in example 9, the final product CLJ-109 was obtained by substituting 5-bromo-1-pentanol for 4-bromo-1-butanol.¹H NMR(400MHz,DMSO-d₆)9.46(s,1H),8.49(d,J＝3.0Hz,1H),8.38(d,J＝1.6Hz,1H),8.08(s,1H),7.59(s,1H),7.46(dd,J＝8.4,1.9Hz,2H),6.98(d,J＝8.3Hz,1H),4.67(dt,J＝13.3,6.6Hz,2H),4.35(t,J＝4.9Hz,2H),3.50(s,1H),3.44–3.37(m,5H),2.86–2.75(m,4H),2.66(s,0H),2.44(d,J＝5.0Hz,1H),1.58–1.40(m,8H),1.33(dt,J＝15.3,7.1Hz,3H).m/z:439.2543[M+H]⁺.

EXAMPLE 112 preparation of hydroxyacetyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-fluoropyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-110)

CLJ-110 was synthesized as in example 10, substituting 2-hydroxyacetyl chloride for 5-bromo-1-pentanol to give CLJ-120.¹H NMR(400MHz,DMSO-d₆):9.55(d,J＝4.7Hz,1H),8.44(d,J＝45.8Hz,2H),8.09(s,1H),7.68(s,1H),7.55(t,J＝6.6Hz,1H),7.11(dd,J＝13.3,8.1Hz,1H),4.76–4.42(m,4H),4.19(d,J＝5.2Hz,2H),3.64(dt,J＝51.4,5.8Hz,2H),2.83(dt,J＝28.2,5.8Hz,2H),1.48(d,J＝6.6Hz,6H).¹³C NMR(101MHz,DMSO):170.87,156.92,150.02,147.54,146.90,146.25,139.54,138.88,134.92,129.87,126.97,126.44,118.39,117.31,115.71,60.74,54.01,43.89,41.70,29.42,22.96.m/z:411.1867[M+H]⁺.

Example 122 preparation of Hydroxyacetyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-111)

CLJ-111 was synthesized as in example 11, substituting 2, 4-dichloro-5-methylpyrimidine for 2, 4-dichloro-5-fluoropyrimidine to give the final product CLJ-111.¹H NMR(400MHz,DMSO-d₆):9.30(d,J＝4.8Hz,1H),8.30(d,J＝20.6Hz,2H),8.09(s,1H),7.74(s,1H),7.55(d,J＝7.4Hz,1H),7.09(dd,J＝13.7,8.2Hz,1H),4.72–4.44(m,4H),4.18(d,J＝5.5Hz,2H),3.64(dt,J＝50.9,5.8Hz,2H),2.92–2.73(m,2H),2.31(s,3H),1.48(d,J＝6.6Hz,6H).¹³C NMR(101MHz,DMSO):170.86,159.90,158.92,157.69,139.95,139.33,134.83,129.45,126.90,125.90,120.67,118.22,117.22,116.59,60.74,53.84,43.89,41.72,29.48,23.04,17.16.m/z:407.2117[M+H]⁺.

EXAMPLE 132 preparation of propionamidoformyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-112)

CLJ-112 was synthesized as in example 12, substituting propyl isocyanate for 2-hydroxyacetyl chloride to provide the final product CLJ-112.¹H NMR(400MHz,DMSO-d₆):9.26(s,1H),8.30(d,J＝22.9Hz,2H),8.09(s,1H),7.71(d,J＝2.2Hz,1H),7.54(dd,J＝8.4,2.2Hz,1H),7.03(d,J＝8.3Hz,1H),6.50(t,J＝5.5Hz,1H),4.63(hept,J＝6.7Hz,1H),4.43(s,2H),3.55(t,J＝5.8Hz,2H),3.02(q,J＝7.8,7.0Hz,2H),2.76(t,J＝5.8Hz,2H),2.32(s,3H),1.46(dd,J＝18.8,6.9Hz,8H),0.84(t,J＝7.4Hz,3H).¹³C NMR(101MHz,DMSO):159.90,158.95,157.88,157.67,139.70,139.32,135.21,129.43,126.99,126.60,120.70,118.43,117.08,116.51,53.83,45.50,42.47,41.44,29.22,23.56,23.04,17.15,11.87.m/z:434.2590[M+H]⁺.

Example 142 preparation of 3- (3-Chloroanilinoformyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-113)

CLJ-113 Synthesis example 13 was repeated using 3-chlorophenyl isocyanate instead of propyl isocyanate to give CLJ-113 as the final product.¹H NMR(400MHz,DMSO-d₆):9.30(s,1H),8.73(s,1H),8.31(d,J＝21.9Hz,2H),8.09(s,1H),7.72(d,J＝26.0Hz,2H),7.57(d,J＝8.3Hz,1H),7.45(d,J＝8.3Hz,1H),7.26(t,J＝8.1Hz,1H),7.09(d,J＝8.4Hz,1H),6.98(d,J＝7.9Hz,1H),4.61(d,J＝16.3Hz,3H),3.71(t,J＝5.8Hz,2H),2.85(t,J＝5.9Hz,2H),2.32(s,3H),1.49(d,J＝6.7Hz,6H).¹³C NMR(101MHz,DMSO):159.90,158.95,157.69,155.14,142.73,139.93,139.34,135.07,133.20,130.35,129.44,126.68,126.38,121.69,120.70,119.38,118.38,118.27,117.16,116.57,53.84,45.80,41.95,29.27,23.04,17.16.m/z:502.2044[M+H]⁺.

Example 152-preparation of acetamidoformyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-114)

Synthesis of CLJ-114 As in example 14, the 3-chlorophenyl isocyanate was replaced with ethyl isocyanate to give the final product CLJ-114.¹H NMR(400MHz,DMSO-d₆):9.26(s,1H),8.30(d,J＝22.7Hz,2H),8.08(s,1H),7.70(d,J＝2.2Hz,1H),7.53(dd,J＝8.3,2.3Hz,1H),7.03(d,J＝8.3Hz,1H),6.49(t,J＝5.4Hz,1H),4.62(h,J＝6.5Hz,1H),4.41(s,2H),3.54(t,J＝5.8Hz,2H),3.08(dt,J＝12.5,6.3Hz,2H),2.75(t,J＝5.9Hz,2H),2.31(s,3H),1.48(d,J＝6.6Hz,6H),1.03(t,J＝7.1Hz,3H).¹³C NMR(101MHz,DMSO):159.90,158.95,157.80,157.67,139.71,139.32,135.21,129.43,126.95,126.59,120.70,118.43,117.08,116.51,53.83,45.46,41.38,35.38,29.23,23.04,17.15,16.15.m/z:420.2434[M+H]⁺.

Example 162 preparation of Acetylmethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-115)

Synthesis of CLJ-115 As in example 15, the ethyl isocyanate was replaced by 1-chloropropone to give the final product CLJ-115.¹H NMR(400MHz,DMSO-d₆):9.24(s,1H),8.30(d,J＝24.3Hz,2H),8.09(s,1H),7.67(d,J＝2.2Hz,1H),7.47(dd,J＝8.4,2.3Hz,1H),6.94(d,J＝8.4Hz,1H),4.63(hept,J＝6.6Hz,1H),3.53(s,2H),2.82(t,J＝5.8Hz,2H),2.68(t,J＝5.8Hz,2H),2.31(s,3H),2.13(s,3H),1.48(d,J＝6.6Hz,6H).¹³C NMR(101MHz,DMSO):207.56,159.90,158.99,157.64,139.55,139.32,134.09,129.40,127.42,126.69,120.72,118.38,116.80,116.40,67.91,55.46,53.83,51.13,29.50,28.01,23.04,17.15.m/z:405.2325[M+H]⁺.

Example 172 preparation of carbamoylmethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-116)

CLJ-116 Synthesis As in example 16, 1-chloropropionamide was used in place of 1-chloropropionone ester to give CLJ-116 as the final product.¹H NMR(400MHz,DMSO-d₆):9.24(s,1H),8.30(d,J＝23.8Hz,2H),8.09(s,1H),7.68(d,J＝2.2Hz,1H),7.48(dd,J＝8.4,2.2Hz,1H),7.20(dd,J＝38.0,3.0Hz,2H),6.96(d,J＝8.4Hz,1H),4.63(hept,J＝6.7Hz,1H),3.61(s,2H),3.03(s,2H),2.86(t,J＝5.8Hz,2H),2.71(t,J＝5.8Hz,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H).¹³C NMR(101MHz,DMSO):172.30,159.91,158.98,157.64,139.56,139.32,134.19,129.41,127.44,126.71,120.71,118.37,116.78,116.41,61.74,55.65,53.83,51.34,29.54,23.05,17.15.m/z:406.2277[M+H]⁺.

Example 182- (2-ethoxyethyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-117)

CLJ-117 was synthesized as in example 17, substituting 2-ethoxychloroethane for 1-chloropropylamide to give CLJ-117 as the final product.¹H NMR(400MHz,DMSO-d₆):9.20(s,1H),8.30(d,J＝22.7Hz,2H),8.08(s,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.94(d,J＝8.3Hz,1H),4.63(hept,J＝6.7Hz,1H),3.61–3.51(m,4H),3.46(q,J＝7.0Hz,2H),2.79(d,J＝5.8Hz,2H),2.70(t,J＝5.8Hz,2H),2.64(t,J＝6.0Hz,2H),2.31(s,3H),1.49(d,J＝6.7Hz,6H),1.12(t,J＝7.0Hz,3H).¹³C NMR(101MHz,DMSO):159.87,159.01,157.63,139.46,139.32,134.35,129.35,127.83,126.68,120.76,118.31,116.74,116.34,68.48,65.94,57.73,56.03,53.83,51.59,29.65,23.02,17.15,15.62.m/z:421.2638[M+H]⁺.

Example 192 preparation of cyanomethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-118)

CLJ-118 Synthesis As in example 18, the 2-ethoxychloroethane was replaced by chloroacetonitrile to give CLJ-118 as a final product.¹H NMR(400MHz,DMSO-d₆):9.24(s,1H),8.30(d,J＝21.8Hz,2H),8.09(s,1H),7.69(d,J＝2.3Hz,1H),7.51(dd,J＝8.3,2.2Hz,1H),7.00(d,J＝8.4Hz,1H),4.63(hept,J＝6.7Hz,1H),3.91(s,2H),3.62(s,2H),2.86(d,J＝6.0Hz,2H),2.77(d,J＝5.7Hz,2H),2.32(s,3H),1.49(d,J＝6.7Hz,6H).¹³C NMR(101MHz,DMSO):159.87,158.97,157.66,139.77,139.34,133.54,129.35,126.77,126.45,120.74,118.35,116.96,116.47,116.34,53.85,53.79,49.74,45.59,29.43,23.01,17.16.m/z:388.2171[M+H]⁺.

Example 202 preparation of propargyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-119)

Synthesis of CLJ-119 As in example 19, the chloroacetonitrile was replaced by 3-chloropropyne to give CLJ-119 as the final product.¹H NMR(400MHz,DMSO-d₆):9.22(s,1H),8.30(d,J＝22.4Hz,2H),8.09(s,1H),7.75–7.61(m,1H),7.56–7.42(m,1H),6.98(d,J＝8.4Hz,1H),4.63(p,J＝6.7Hz,1H),3.59(s,2H),3.51–3.40(m,2H),3.23–3.13(m,1H),2.84(s,2H),2.72(s,2H),2.32(s,3H),1.49(d,J＝6.7Hz,6H).m/z:387.2219[M+H]⁺.

Example 212 preparation of allyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-120)

Synthesis of CLJ-120 As in example 20, the final product CLJ-120 was obtained by substituting allyl chloride for 3-chloropropyne.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.33(s,1H),8.27(d,J＝0.8Hz,1H),8.08(s,1H),7.66(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝8.3Hz,1H),5.91(ddt,J＝16.6,10.2,6.3Hz,1H),5.26(dq,J＝17.2,1.7Hz,1H),5.18(ddt,J＝10.1,2.2,1.2Hz,1H),4.62(h,J＝6.7Hz,1H),3.48(s,2H),3.12(dt,J＝6.4,1.4Hz,2H),2.81(t,J＝5.9Hz,2H),2.65(t,J＝5.8Hz,2H),2.31(s,3H),1.49(d,J＝6.6Hz,6H).m/z:389.2375[M+H]⁺.

Example 222 preparation of- (3-methyl-2-butenyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-121)

Synthesis of CLJ-121 As in example 21, 1-chloro-3-methyl-2-butene was used instead of allyl chloride to give the final product CLJ-121.¹H NMR(400MHz,DMSO-d₆):9.20(s,1H),8.32(s,1H),8.27(s,1H),8.08(s,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝8.4Hz,1H),5.28(td,J＝7.4,6.9,3.9Hz,1H),4.63(hept,J＝6.6Hz,1H),3.47(s,2H),3.06(d,J＝6.8Hz,2H),2.80(t,J＝5.9Hz,2H),2.64(t,J＝5.8Hz,2H),2.31(s,3H),1.74(d,J＝1.5Hz,3H),1.66(d,J＝1.4Hz,3H),1.49(d,J＝6.6Hz,6H).m/z:417.2688[M+H]⁺.

Example 232 preparation of- (2-pentynyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-122)

CLJ-122 was synthesized as in example 22, substituting 1-chloro-2-pentyne for 1-chloro-3-methyl-2-butene to give the final product CLJ-122.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.30(d,J＝22.4Hz,2H),8.09(s,1H),7.66(s,1H),7.48(d,J＝8.4Hz,1H),6.98(d,J＝8.3Hz,1H),4.63(dt,J＝13.5,6.8Hz,1H),3.57(s,2H),3.38(d,J＝22.7Hz,2H),2.83(t,J＝5.7Hz,2H),2.70(t,J＝5.9Hz,2H),2.32(s,3H),2.22(d,J＝7.6Hz,2H),1.49(d,J＝6.7Hz,6H),1.10(q,J＝7.4,6.9Hz,3H).m/z:415.2332[M+H]⁺.

Example 242 preparation of- (2-butynyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-123)

Synthesis of CLJ-123 As in example 23, 1-chloro-2-pentene was replaced with 1-chloro-2-butyne to give the final product CLJ-123.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.33(s,1H),8.27(s,1H),8.08(s,1H),7.66(d,J＝2.3Hz,1H),7.48(dd,J＝8.4,2.2Hz,1H),6.97(d,J＝8.4Hz,1H),4.63(hept,J＝6.7Hz,1H),3.38(q,J＝2.4Hz,2H),2.82(t,J＝5.8Hz,2H),2.70(t,J＝5.9Hz,2H),2.32(s,3H),1.83(t,J＝2.3Hz,3H),1.49(d,J＝6.6Hz,6H).m/z:401.2375[M+H]⁺.

Example 252 preparation of- (Phenylpropenyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-124)

CLJ-124 was synthesized as in example 24, substituting cinnamyl chloride for 1-chloro-2-butyne to provide the final product CLJ-124.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.30(d,J＝22.2Hz,2H),8.09(s,1H),7.68(d,J＝2.2Hz,1H),7.54–7.42(m,3H),7.34(t,J＝7.6Hz,2H),7.28–7.22(m,1H),6.96(d,J＝8.4Hz,1H),6.61(d,J＝15.9Hz,1H),6.39(dt,J＝15.9,6.4Hz,1H),4.63(hept,J＝6.7Hz,1H),3.54(s,2H),3.31–3.21(m,2H),2.84(t,J＝5.8Hz,2H),2.71(t,J＝5.8Hz,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H).m/z:467.2688[M+H]⁺.

Example 262- (4-Alkenylpentanoyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-125) preparation

Step 1: preparation of 2- (4-alkenylpentanoyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-125)

N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (348mg,1mmoL), HATU (380mg,1mmoL), N, N-diisopropylethylamine (320mg,2.5mmoL), 4-pentenoic acid (100mg,1mmoL) were added to dichloromethane (20mL), stirred at room temperature for 30 minutes, concentrated under reduced pressure to remove the solvent, stirred with crude silica gel, and separated by silica gel column using a dichloromethane/methanol system to obtain CLJ-125 as a final product.¹H NMR(400MHz,DMSO-d₆):9.28(d,J＝4.7Hz,1H),8.30(d,J＝20.9Hz,2H),8.08(s,1H),7.76–7.69(m,1H),7.54(t,J＝8.6Hz,1H),7.09(dd,J＝8.4,4.7Hz,1H),5.93–5.80(m,1H),5.11–5.01(m,1H),4.99–4.91(m,1H),4.69–4.50(m,3H),3.67(t,J＝5.9Hz,2H),2.89–2.81(m,1H),2.75(t,J＝5.9Hz,1H),2.29(d,J＝14.7Hz,5H),1.48(d,J＝6.7Hz,6H).m/z:431.2481[M+H]⁺.

Example 272 preparation of- (3-cyanopropionyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-126)

Synthesis of CLJ-126 As in example 26, the final product CLJ-126 was obtained by substituting 3-cyanopropionic acid for 4-pentenoic acid.¹H NMR(400MHz,DMSO-d₆):9.30(d,J＝5.3Hz,1H),8.34(s,1H),8.28(s,1H),8.09(s,1H),7.74(dd,J＝5.7,2.3Hz,1H),7.62–7.50(m,1H),7.29(s,1H),7.10(dd,J＝11.5,8.4Hz,1H),6.72(s,1H),4.71–4.46(m,3H),3.68(q,J＝6.5Hz,2H),2.88(q,J＝6.0,5.3Hz,1H),2.75(t,J＝6.0Hz,1H),2.61(t,J＝7.0Hz,2H),2.34(d,J＝11.9Hz,5H),1.49(d,J＝6.7Hz,6H).m/z:430.2277[M+H]⁺.

Example 28 preparation of (E) -2- (3, 7-dimethyl-2, 6-pentadienyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-127)

CLJ-127 Synthesis As in example 24, geranyl bromide was used in place of 1-chloro-2-butyne to provide the final product CLJ-127.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.30(d,J＝22.1Hz,2H),8.08(s,1H),7.66(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.94(d,J＝8.3Hz,1H),5.31–5.24(m,1H),5.15–5.03(m,1H),4.63(p,J＝6.6Hz,1H),3.51(s,2H),3.11(s,2H),2.81(d,J＝5.9Hz,2H),2.68(s,2H),2.31(s,3H),2.17–1.98(m,4H),1.66(d,J＝1.4Hz,6H),1.59(d,J＝1.3Hz,3H),1.49(d,J＝6.7Hz,6H).m/z:485.3314[M+H]⁺.

Example 29 preparation of (E) -methyl 4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoate (CLJ-128)

CLJ-128 Synthesis As in example 28, geranyl bromide was replaced with methyl (E) -4-bromo-2-butenoate to give CLJ-128 as the final product.¹H NMR(400MHz,DMSO-d₆):9.22(s,1H),8.33(s,1H),8.29(s,1H),8.08(s,1H),7.67(d,J＝2.2Hz,1H),7.52–7.44(m,1H),6.96(d,J＝8.8Hz,2H),6.10(d,J＝15.7Hz,1H),4.63(hept,J＝6.7Hz,1H),3.68(s,3H),3.52(s,2H),2.83(t,J＝5.8Hz,2H),2.68(t,J＝5.8Hz,2H),2.32(s,3H),1.49(d,J＝6.6Hz,6H).m/z:447.2430[M+H]⁺.

Example 302 preparation of- (5-alkenylhexyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-129)

Synthesis of CLJ-129 As in example 29, methyl (E) -4-bromo-2-butenoate was replaced with 6-bromo-1-hexene to give the final product CLJ-129.¹H NMR(400MHz,DMSO-d₆):9.19(s,1H),8.33(d,J＝0.7Hz,1H),8.27(d,J＝0.7Hz,1H),8.08(d,J＝0.7Hz,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝8.4Hz,1H),5.82(ddt,J＝16.9,10.2,6.6Hz,1H),5.03(dq,J＝17.2,1.7Hz,1H),4.96(ddt,J＝10.2,2.3,1.2Hz,1H),4.63(p,J＝6.6Hz,1H),3.47(s,2H),2.80(t,J＝5.8Hz,2H),2.63(t,J＝5.8Hz,2H),2.44(t,J＝7.2Hz,2H),2.35–2.28(m,3H),2.07(q,J＝7.1Hz,2H),1.58–1.37(m,10H).m/z:431.2845[M+H]⁺.

Example 312- (3-Enylbutyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-130)

Synthesis of CLJ-130 As in example 30, the end product CLJ-130 was obtained by substituting 4-bromo-1-butene for 6-bromo-1-hexene.¹H NMR(400MHz,DMSO-d₆):9.20(s,1H),8.33(s,1H),8.27(s,1H),8.08(s,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.96(d,J＝8.3Hz,1H),5.86(ddt,J＝17.0,10.2,6.7Hz,1H),5.10(dq,J＝17.2,1.7Hz,1H),5.00(ddt,J＝10.3,2.4,1.3Hz,1H),4.63(hept,J＝6.6Hz,1H),3.51(s,2H),2.80(t,J＝5.9Hz,2H),2.67(t,J＝5.8Hz,2H),2.34–2.25(m,5H),1.49(d,J＝6.7Hz,6H).m/z:403.2532[M+H]⁺.

Example 322 preparation of- (4-Enopentyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-131)

CLJ-131 was synthesized as in example 31 using 5-bromoThe 4-bromo-1-butene is replaced by the-1-pentene to obtain the final product CLJ-131.¹H NMR(400MHz,DMSO-d₆):9.20(s,1H),8.33(d,J＝0.7Hz,1H),8.27(d,J＝0.7Hz,1H),8.11–8.06(m,1H),7.65(d,J＝2.2Hz,1H),7.47(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝8.4Hz,1H),5.86(ddt,J＝16.9,10.1,6.6Hz,1H),5.08–4.94(m,2H),4.63(p,J＝6.7Hz,1H),3.48(s,2H),2.80(t,J＝5.8Hz,2H),2.64(t,J＝5.8Hz,2H),2.44(t,J＝7.3Hz,2H),2.31(s,3H),2.09(tdd,J＝6.6,5.3,1.4Hz,2H),1.62(p,J＝7.4Hz,2H),1.49(d,J＝6.7Hz,6H).m/z:417.2688[M+H]

Example 332 preparation of- (2-methyl-2-pentenoyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-132)

CLJ-132 Synthesis As in example 26, the end product CLJ-132 was obtained by substituting 2-methyl-2-pentenoic acid for 4-pentenoic acid.¹H NMR(400MHz,DMSO-d₆):9.29(s,1H),8.30(d,J＝23.2Hz,2H),8.09(s,1H),7.75(s,1H),7.56(d,J＝8.4Hz,1H),7.07(d,J＝8.3Hz,1H),5.51(t,J＝7.4Hz,1H),4.59(d,J＝28.3Hz,3H),3.68(t,J＝6.0Hz,2H),2.69(s,5H),2.31(s,3H),2.10(p,J＝7.4Hz,2H),1.76(s,3H),1.48(d,J＝6.8Hz,6H).m/z:445.2638[M+H]

Example 342- (3-Benzoylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-133) preparation

CLJ-133 was synthesized as in example 33, replacing 2-methyl-2-pentenoic acid with 3-benzoylacrylic acid to give the final product CLJ-133.¹H NMR(400MHz,DMSO-d₆):9.31(d,J＝2.2Hz,1H),8.33(s,1H),8.28(s,1H),8.13–8.02(m,3H),7.85–7.79(m,1H),7.76(d,J＝2.2Hz,1H),7.74–7.68(m,1H),7.64–7.50(m,4H),7.15(dd,J＝8.5,4.3Hz,1H),4.73(d,J＝36.9Hz,2H),4.63(p,J＝6.7Hz,1H),3.83(dt,J＝11.2,5.9Hz,2H),2.88(dt,J＝23.7,6.0Hz,2H),2.32(s,3H),1.49(dd,J＝6.7,1.9Hz,6H).m/z:507.2430[M+H].

Example 352- (5-Enohexanoyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-134) preparation

Synthesis of CLJ-134 As in example 34, the final product CLJ-134 was obtained by substituting 5-hexenoic acid for 3-benzoylacrylic acid.¹H NMR(400MHz,DMSO-d₆):9.29(d,J＝5.0Hz,1H),8.34(s,1H),8.28(s,1H),8.09(s,1H),7.74(dd,J＝8.0,2.2Hz,1H),7.59–7.52(m,1H),7.10(dd,J＝8.5,4.8Hz,1H),5.83(ddtd,J＝16.6,9.8,6.5,3.1Hz,1H),5.06–4.95(m,2H),4.68–4.60(m,1H),4.56(d,J＝14.9Hz,2H),3.67(q,J＝5.8Hz,2H),2.80(dt,J＝39.4,6.0Hz,2H),2.41(t,J＝7.4Hz,2H),2.32(s,3H),2.07(q,J＝7.8Hz,2H),1.63(td,J＝7.7,5.1Hz,2H),1.49(d,J＝6.7Hz,6H).m/z:445.2638[M+H]⁺.

Example 362- (2-Methylallyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-135)

CLJ-135 Synthesis the final product CLJ-135 was obtained in the same manner as in example 31, except that 3-bromo-2-methylpropene was used instead of 4-bromo-1-butene.¹H NMR(400MHz,DMSO-d₆):9.20(s,1H),8.32(s,1H),8.26(s,1H),8.09(s,1H),7.67(d,J＝2.2Hz,1H),7.48(dd,J＝8.3,2.3Hz,1H),6.94(d,J＝8.4Hz,1H),4.97–4.85(m,2H),4.62(p,J＝6.7Hz,1H),3.42(s,2H),2.98(s,2H),2.81(t,J＝5.9Hz,2H),2.58(t,J＝5.8Hz,2H),2.31(s,3H),1.73(s,3H),1.48(d,J＝6.7Hz,6H).m/z:403.2532[M+H]⁺.

Example 37 preparation of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid (CLJ-136)

Step 1: (E) synthesis of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid (CLJ-136)

Adding (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) methyl crotonate (446.6mg,1mmol) into methanol (5mL), adding an aqueous solution of sodium hydroxide (2mmol/L,2.5mL), heating at 50 ℃ for reaction for 2H, adjusting to neutrality by using diluted hydrochloric acid, and performing suction filtration and drying to obtain the final product CLJ-136.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.30(d,J＝22.4Hz,2H),8.08(s,1H),7.67(d,J＝2.3Hz,1H),7.48(dd,J＝8.3,2.2Hz,1H),6.96(d,J＝8.4Hz,1H),6.79(dt,J＝15.6,5.9Hz,1H),6.02–5.94(m,1H),4.62(h,J＝6.6Hz,1H),3.51(s,2H),3.27(d,J＝5.5Hz,2H),3.18(s,1H),2.83(t,J＝5.8Hz,2H),2.67(t,J＝5.8Hz,2H),2.31(s,3H),1.49(d,J＝6.6Hz,6H).m/z:433.2274[M+H]⁺.

Example 38 preparation of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid propionamide (CLJ-137)

Step 1: (E) synthesis of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid propionamide (CLJ-137)

(E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) crotonic acid (432mg,1mmol), propylamine (120mg,2mmol), N, N-diisopropylethylamine (320mg,2.5mmol) and HATU (380mg,1mmol) were added to dichloromethane (10mL), reacted at room temperature for 1H, suction filtered and dried to obtain the final product CLJ-137.¹H NMR(400MHz,DMSO-d₆):9.23(s,1H),8.30(d,J＝21.5Hz,2H),8.08(s,1H),8.01(s,1H),7.68(s,1H),7.48(d,J＝8.3Hz,1H),6.97(d,J＝8.4Hz,1H),6.63(dt,J＝15.3,5.9Hz,1H),6.13(d,J＝15.4Hz,1H),4.63(p,J＝6.6Hz,1H),3.57(d,J＝39.5Hz,3H),3.08(d,J＝6.3Hz,2H),2.85(s,2H),2.71(d,J＝22.4Hz,2H),2.32(s,3H),1.43(s,8H),1.27(s,2H),0.86(s,4H).m/z:474.2903[M+H]⁺.

Example 39 preparation of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid (piperidin-1-ylethylamine) amide (CLJ-138)

CLJ-138 Synthesis example 38 was performed using 1- (2-aminoethyl) piperidine instead of propylamine to give CLJ-138 as the final product.¹H NMR(400MHz,DMSO-d₆):9.22(s,1H),8.33(s,1H),8.27(s,1H),8.09(s,2H),7.68(d,J＝2.2Hz,1H),7.48(dd,J＝8.3,2.2Hz,1H),6.96(d,J＝8.3Hz,1H),6.67(dt,J＝15.4,5.9Hz,1H),6.14(d,J＝15.5Hz,1H),4.62(h,J＝6.6Hz,1H),3.53(s,2H),3.29–3.21(m,3H),2.87–2.81(m,2H),2.69(d,J＝8.0Hz,2H),2.32(s,3H),1.49(d,J＝6.6Hz,12H).m/z:543.3482[M+H]⁺.

Example 40 preparation of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid tert-butylamide (CLJ-139)

CLJ-139 Synthesis the same as in example 39, substituting tert-butylamine for 1- (2-aminoethyl) piperidine gave the final product CLJ-139.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.30(d,J＝22.0Hz,2H),8.09(s,1H),7.71–7.56(m,2H),7.48(dd,J＝8.3,2.2Hz,1H),6.96(d,J＝8.4Hz,1H),6.58(dt,J＝15.4,5.9Hz,1H),6.15(dd,J＝15.4,1.6Hz,1H),4.63(p,J＝6.6Hz,1H),3.50(s,2H),3.26–3.15(m,2H),2.84(t,J＝5.8Hz,2H),2.66(t,J＝5.8Hz,2H),2.32(s,3H),1.49(d,J＝6.6Hz,6H),1.29(s,9H).m/z:488.3060[M+H]⁺.

Example 41 preparation of (E) -4- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid diethylamide (CLJ-140)

CLJ-140 Synthesis As in example 40, the final product, CLJ-140, was obtained by replacing tert-butylamine with diethylamine.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.30(d,J＝22.5Hz,2H),8.08(s,1H),7.67(d,J＝2.2Hz,1H),7.48(dd,J＝8.4,2.2Hz,1H),6.96(d,J＝8.4Hz,1H),6.71(dt,J＝15.1,6.0Hz,1H),6.61–6.52(m,1H),4.63(hept,J＝6.7Hz,1H),3.52(s,2H),3.38(s,3H),3.30–3.25(m,2H),2.83(t,J＝5.9Hz,2H),2.68(t,J＝5.8Hz,2H),2.32(s,3H),1.49(d,J＝6.7Hz,6H),1.17–0.99(m,7H).m/z:488.3062[M+H]⁺.

Example 422 preparation of cyanomethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-141)

Synthesis of the pyrimidine moiety of CLJ-141 example 19; synthesis of aromatic amine moiety As in step 3 of example 3, 1,2,3, 4-tetrahydroisoquinoline was used in place of 7-fluoro-1, 2,3, 4-tetrahydroisoquinoline trifluoroacetamide, and the resulting product was subjected to silica gel column chromatography using petroleum ether/ethyl acetate (5: 1).¹H NMR(400MHz,DMSO-d₆):9.25(s,1H),8.30(d,J＝21.5Hz,2H),8.09(s,1H),7.65(d,J＝2.3Hz,1H),7.50(dd,J＝8.3,2.2Hz,1H),7.04(d,J＝8.4Hz,1H),4.63(hept,J＝6.7Hz,1H),3.93(s,2H),3.68(s,2H),2.84–2.71(m,4H),2.32(s,3H),1.49(d,J＝6.6Hz,6H).m/z:388.2171[M+H]⁺.

Example 432- (2-methyl-2-pentenoyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-142)

CLJ-142 was synthesized in the same manner as in example 33 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used instead of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-142 as a final product.¹H NMR(400MHz,DMSO-d₆):9.29(s,1H),8.31(d,J＝21.1Hz,2H),8.09(s,1H),7.74(s,1H),7.55–7.49(m,1H),7.08(d,J＝8.3Hz,1H),5.53(t,J＝7.3Hz,1H),4.62(d,J＝6.3Hz,3H),3.68(t,J＝5.9Hz,2H),2.76(t,J＝6.0Hz,2H),2.11(p,J＝7.5Hz,2H),1.78(s,3H),1.49(d,J＝6.7Hz,6H),0.99(t,J＝7.5Hz,3H).m/z:445.2638[M+H]⁺.

EXAMPLE 442 preparation of hydroxybutyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-143)

CLJ-143 was synthesized in the same manner as in example 5 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used in place of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-143 as a final product.¹H NMR(400MHz,DMSO-d₆):9.20(s,1H),8.30(d,J＝24.4Hz,2H),8.08(s,1H),7.62(d,J＝2.3Hz,1H),7.46(dd,J＝8.2,2.3Hz,1H),7.00(d,J＝8.3Hz,1H),4.62(dq,J＝13.4,6.7Hz,2H),3.43(t,J＝6.3Hz,2H),2.73(d,J＝5.7Hz,2H),2.64(t,J＝5.8Hz,2H),2.46(t,J＝7.0Hz,2H),2.32(s,3H),1.62–1.43(m,11H).m/z:421.2638[M+H]⁺.

Example 452 preparation of butyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-144)

Synthesis of CLJ-144 As in example 19, 1-bromobutane was used instead of chloroacetonitrile to give the final product CLJ-144.¹H NMR(400MHz,DMSO-d₆):9.19(s,1H),8.29(d,J＝23.5Hz,2H),8.09(s,1H),7.65(s,1H),7.47(d,J＝7.7Hz,1H),6.94(d,J＝8.2Hz,1H),4.70–4.56(m,J＝6.8Hz,1H),3.46(s,2H),2.79(s,2H),2.61(s,2H),2.41(s,2H),2.31(s,3H),1.48(d,J＝6.8Hz,8H),1.31(p,J＝7.3Hz,2H),0.90(t,J＝7.2Hz,3H).m/z:405.2688[M+H]⁺.

Example 462-preparation of hydroxyethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinoline-7-fluoro 6-amine (CLJ-145)

CLJ-145 Synthesis As in example 3, the final product CLJ-145 was obtained by substituting 4-bromon-butanol for 2-iodoethanol.¹H NMR(400MHz,DMSO-d₆):8.56(s,1H),8.30(s,1H),8.23(s,1H),8.02(s,1H),7.68(d,J＝8.1Hz,1H),6.93(d,J＝11.5Hz,1H),4.61(p,J＝6.7Hz,1H),4.54(s,1H),3.50(s,2H),3.42(d,J＝6.3Hz,2H),2.78(t,J＝5.9Hz,2H),2.64(t,J＝5.9Hz,2H),2.44(t,J＝7.0Hz,2H),2.30(s,3H),1.58–1.41(m,10H).m/z:439.2543[M+H]⁺.

Example 47 preparation of (E) -4- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid (CLJ-146)

CLJ-146 was synthesized in the same manner as in example 37 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used instead of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-146 as a final product.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.29(d,J＝20.0Hz,2H),8.07(s,1H),7.60(d,J＝2.2Hz,1H),7.48(dd,J＝8.3,2.2Hz,1H),7.02(d,J＝8.3Hz,1H),6.82(dt,J＝15.6,5.9Hz,1H),5.99(d,J＝15.6Hz,1H),4.61(h,J＝6.7Hz,1H),3.57(s,2H),3.29(s,2H),2.72(dt,J＝36.8,5.9Hz,4H),2.31(s,3H),1.49(d,J＝6.7Hz,6H).m/z:433.2274[M+H]⁺.

Example 48 preparation of (E) -4- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid isobutyramide (CLJ-147)

CLJ-147 was synthesized in the same manner as in example 41, using 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline in place of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline and isobutylamine in place of diethylamine to obtain CLJ-147.¹H NMR(400MHz,DMSO-d₆):9.22(s,1H),8.30(d,J＝19.8Hz,1H),8.07(s,1H),7.99(t,J＝5.8Hz,1H),7.61(d,J＝1.6Hz,1H),7.48(dt,J＝13.7,6.8Hz,1H),7.02(d,J＝8.4Hz,1H),6.64(dt,J＝15.5,5.8Hz,1H),6.17(d,J＝15.5Hz,1H),4.75–4.49(m,1H),3.59(s,1H),3.28(d,J＝5.5Hz,1H),2.96(t,J＝6.3Hz,1H),2.78(d,J＝5.1Hz,1H),2.70(s,1H),2.31(s,1H),1.77–1.65(m,1H),1.48(d,J＝6.7Hz,3H),0.86(d,J＝6.7Hz,3H).m/z:488.3060[M+H]⁺.

Example 49 preparation of (E) -4- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid diethylamide (CLJ-148)

Synthesis of CLJ-148 As in example 48, the final product, CLJ-148, was obtained by substituting diethylamine for isobutylamine.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.29(d,J＝20.9Hz,2H),8.07(s,1H),7.60(d,J＝1.7Hz,1H),7.49(dd,J＝8.3,2.1Hz,1H),7.02(d,J＝8.4Hz,1H),6.71(dt,J＝15.0,6.0Hz,1H),6.59(s,1H),4.62(s,1H),3.58(s,2H),3.42–3.27(m,8H),2.76(d,J＝5.2Hz,2H),2.69(d,J＝5.1Hz,2H),1.09(dt,J＝28.2,6.9Hz,6H).m/z:488.3062[M+H]⁺.

Example 50 preparation of (E) -4- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoic acid (3-trifluoromethylphenethylamine) amide (CLJ-149)

CLJ-149 Synthesis example 49 was repeated, using 3-trifluoromethylphenethylamine instead of diethylamine to give the final product CLJ-149.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.64(t,J＝6.0Hz,1H),8.29(d,J＝20.6Hz,2H),8.07(s,1H),7.69–7.52(m,5H),7.49(dd,J＝8.3,2.0Hz,1H),7.02(d,J＝8.4Hz,1H),6.72(dt,J＝15.5,5.7Hz,1H),6.21(d,J＝15.5Hz,1H),4.61(dt,J＝13.3,6.6Hz,1H),4.44(d,J＝5.9Hz,2H),3.58(s,2H),3.28(d,J＝5.4Hz,2H),2.77(d,J＝5.4Hz,2H),2.69(d,J＝5.3Hz,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H).

m/z:590.2777[M+H]⁺.

Example 51 preparation of (E) -4-dimethylamino-1- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) -2-butenoic acid (CLJ-150)

CLJ-150 Synthesis As in example 26, 4-dimethylamino-2-butenoic acid was used in place of 4-pentenoic acid to give the final product CLJ-150.¹H NMR(400MHz,DMSO-d₆):9.30(d,J＝5.2Hz,1H),8.30(d,J＝20.8Hz,2H),8.09(s,1H),7.75(d,J＝6.4Hz,1H),7.56(t,J＝9.0Hz,1H),7.10(t,J＝8.8Hz,1H),6.85(d,J＝15.1Hz,1H),6.70–6.56(m,1H),4.71(s,1H),4.65–4.57(m,2H),3.77(dt,J＝18.4,5.8Hz,2H),3.51(d,J＝6.6Hz,2H),2.84(dt,J＝28.8,6.0Hz,2H),2.32(s,3H),1.49(d,J＝6.6Hz,6H).m/z:460.2747[M+H]⁺.

Example 522 preparation of cyanoethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-151)

CLJ-151 Synthesis example 19 was repeated using 3-chloropropionitrile instead of 2-chloroacetonitrile to give CLJ-151 as the final product.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.29(d,J＝22.7Hz,2H),8.08(s,1H),7.67(d,J＝2.2Hz,1H),7.48(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝8.3Hz,1H),4.63(hept,J＝6.7Hz,1H),2.76(ddt,J＝20.6,9.8,5.7Hz,8H),2.31(s,3H),1.48(d,J＝6.6Hz,6H).m/z:402.2328[M+H]⁺.

Example 532- (3-benzoylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-152) preparation

CLJ-152 was synthesized in the same manner as in example 34, using 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline instead of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-152 as a final product.¹H NMR(400MHz,DMSO-d₆):9.31(d,J＝3.6Hz,1H),8.34(s,1H),8.28(d,J＝7.3Hz,1H),8.12–8.01(m,3H),7.85–7.75(m,2H),7.73–7.67(m,1H),7.62–7.50(m,4H),7.10(d,J＝8.3Hz,1H),4.79(d,J＝40.6Hz,2H),4.61(dq,J＝13.3,6.7Hz,1H),3.82(dt,J＝10.9,5.9Hz,2H),2.82(dt,J＝24.6,5.9Hz,2H),2.32(d,J＝4.6Hz,3H),1.48(dd,J＝16.7,6.6Hz,6H).m/z:507.2430[M+H]⁺.

Example 542-preparation of cyanoethyl-N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-153)

CLJ-153 was synthesized in the same manner as in example 52 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used instead of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-153 as a final product.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.29(d,J＝24.5Hz,2H),8.07(s,1H),7.60(d,J＝2.2Hz,1H),7.48(dd,J＝8.3,2.3Hz,1H),7.01(d,J＝8.3Hz,1H),4.63(p,J＝6.7Hz,1H),3.63(s,2H),2.76(dq,J＝15.2,4.9Hz,8H),2.31(s,3H),1.49(d,J＝6.6Hz,6H).m/z:402.2328[M+H]⁺.

Example 552- (3-Phenylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-154)

CLJ-154 was synthesized as in example 53, substituting 3-benzoylacrylic acid for 3-phenylacrylic acid to obtain the final product CLJ-154.¹H NMR(400MHz,DMSO-d₆):9.32(d,J＝6.4Hz,1H),8.37(d,J＝17.1Hz,1H),8.29(s,1H),8.10(s,1H),7.91–7.69(m,3H),7.55(d,J＝15.1Hz,2H),7.41(q,J＝6.6Hz,4H),7.10(d,J＝8.0Hz,1H),4.95(s,1H),4.74(s,1H),4.64(dt,J＝13.9,7.7Hz,1H),3.88(dt,J＝55.8,5.8Hz,2H),2.81(dt,J＝33.6,5.8Hz,2H),2.28(s,3H),1.55–1.42(m,6H).m/z:479.2481[M+H]⁺.

Example 562- (3-Phenylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-155)

CLJ-155 was synthesized in the same manner as in example 53, 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was substituted for 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-155 as a final product.¹H NMR(400MHz,DMSO-d₆):9.31(d,J＝3.6Hz,1H),8.31(d,J＝21.8Hz,2H),8.10(s,1H),7.82–7.70(m,3H),7.63–7.50(m,2H),7.48–7.31(m,4H),7.14(d,J＝8.4Hz,1H),4.95–4.57(m,3H),3.88(dt,J＝55.9,5.8Hz,2H),2.87(dt,J＝32.1,5.9Hz,2H),2.32(s,3H),1.49(d,J＝6.6Hz,6H).m/z:479.2483[M+H]⁺.

Example 572- (3- (4-Methylbenzoyl) propionyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-156)

CLJ-156 was synthesized as in example 56, substituting 3- (4-methylbenzoyl) propionic acid for 3-phenylacrylic acid to give the final product CLJ-156.¹H NMR(400MHz,DMSO-d₆):9.30(d,J＝5.9Hz,1H),8.31(d,J＝20.9Hz,2H),8.09(d,J＝1.7Hz,1H),7.88(d,J＝8.0Hz,2H),7.75(dd,J＝11.7,1.8Hz,1H),7.61–7.51(m,1H),7.33(d,J＝7.8Hz,2H),7.11(dd,J＝25.0,8.4Hz,1H),4.71–4.49(m,3H),3.71(dt,J＝35.7,5.9Hz,2H),3.24(t,J＝6.2Hz,2H),2.95–2.71(m,4H),2.35(d,J＝24.3Hz,6H),1.49(d,J＝6.6Hz,6H).m/z:523.2743[M+H]⁺.

Example preparation of 582- (2-Methylphenylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-157)

CLJ-157 Synthesis As in example 57, the final product CLJ-157 was obtained by substituting 2-methyl-phenylacrylic acid for 3- (4-methylbenzoyl) propionic acid.¹H NMR(400MHz,DMSO-d₆):9.30(s,1H),8.31(d,J＝21.5Hz,2H),8.09(s,1H),7.76(s,1H),7.56(d,J＝8.4Hz,1H),7.42(d,J＝4.5Hz,4H),7.32(pd,J＝5.7,3.9,3.3Hz,1H),7.11(d,J＝8.5Hz,1H),6.58(s,1H),4.63(d,J＝6.0Hz,3H),3.77(t,J＝5.8Hz,2H),2.88(t,J＝5.9Hz,2H),2.32(s,3H),2.06(s,3H),1.48(d,J＝6.6Hz,6H).m/z:493.2638[M+H]⁺.

Example 592- (3- (4-Methylbenzoyl) propionyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-158) preparation

CLJ-158 was synthesized in the same manner as in example 57 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used instead of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-158 as a final product.¹H NMR(400MHz,DMSO-d₆):9.30(d,J＝15.6Hz,1H),8.42–8.22(m,2H),8.08(d,J＝5.5Hz,1H),7.88(d,J＝7.8Hz,2H),7.77(dd,J＝35.8,2.1Hz,1H),7.53(td,J＝8.3,2.2Hz,1H),7.33(d,J＝7.9Hz,2H),7.09(t,J＝8.1Hz,1H),4.77–4.53(m,3H),3.71(dt,J＝33.7,5.9Hz,2H),3.24(s,2H),2.88–2.64(m,4H),2.44–2.23(m,6H),1.48(dd,J＝6.6,5.0Hz,6H).m/z:523.2743[M+H]⁺.

Example 602- (2-Methylphenylacryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-159)

CLJ-159 was synthesized in the same manner as in example 58 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used instead of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-159 as a final product.¹H NMR(400MHz,DMSO-d₆):9.30(s,1H),8.30(d,J＝20.3Hz,2H),8.08(s,1H),7.77(s,1H),7.53(dd,J＝8.4,2.2Hz,1H),7.45–7.37(m,4H),7.31(tq,J＝5.4,3.5,2.4Hz,1H),7.10(d,J＝8.4Hz,1H),6.58(d,J＝1.9Hz,1H),4.65(d,J＝36.4Hz,3H),3.76(t,J＝5.9Hz,2H),2.81(t,J＝6.0Hz,2H),2.31(s,3H),2.11–1.99(m,3H),1.47(dd,J＝7.1,3.6Hz,6H).m/z:493.2638[M+H]⁺.

Example 612- (3- (4-Methylbenzoyl) acryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine (CLJ-160) preparation

CLJ-160 Synthesis As in example 57, 3- (4-methylbenzoyl) acrylic acid was used in place of 3- (4-methylbenzoyl) propionic acid to give CLJ-160 as a final product.¹H NMR(400MHz,DMSO-d₆):9.31(d,J＝2.1Hz,1H),8.33(s,1H),8.28(s,1H),8.09(s,1H),7.96(dd,J＝8.3,2.8Hz,2H),7.84–7.72(m,2H),7.59–7.48(m,2H),7.39(d,J＝8.0Hz,2H),7.14(dd,J＝8.5,3.8Hz,1H),4.79–4.58(m,3H),3.82(dt,J＝10.1,5.9Hz,2H),2.88(dt,J＝23.6,6.0Hz,2H),2.40(s,3H),2.32(s,3H),1.48(dd,J＝6.7,1.7Hz,6H).m/z:521.2587[M+H]⁺.

Example 622- (3- (4-Methylbenzoyl) acryloyl) -N- (4- (1-isopropyl-1H-pyrazol-4-yl) 5-methylpyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-7-amine (CLJ-161) preparation

CLJ-161 was synthesized in the same manner as in example 61 except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline was used instead of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-161 as a final product.¹H NMR(400MHz,DMSO-d₆):9.31(d,J＝3.4Hz,1H),8.39–8.21(m,2H),8.08(d,J＝10.4Hz,1H),7.96(dd,J＝8.0,4.3Hz,2H),7.88–7.68(m,2H),7.61–7.47(m,2H),7.38(dd,J＝8.1,4.2Hz,2H),7.10(d,J＝8.3Hz,1H),4.94–4.49(m,3H),3.82(dt,J＝9.7,5.9Hz,2H),2.81(dt,J＝24.2,5.9Hz,2H),2.40(d,J＝3.7Hz,3H),2.32(d,J＝4.5Hz,3H),1.48(dd,J＝16.3,6.7Hz,6H).m/z:521.2587[M+H]⁺.

Example 634- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butyric acid methyl ester (CLJ-162) preparation

Synthesis of CLJ-162 As in example 29, the final product, CLJ-162, was obtained by substituting methyl 4-bromobutyrate for methyl (E) -4-bromo-2-butenoate.¹H NMR(400MHz,DMSO-d₆):9.18(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.64(s,1H),7.46(d,J＝8.4Hz,1H),6.95(d,J＝8.3Hz,1H),4.62(dt,J＝13.2,6.6Hz,1H),3.57(d,J＝9.1Hz,3H),3.46(s,2H),2.78(d,J＝5.3Hz,2H),2.62(t,J＝5.6Hz,2H),2.44(t,J＝6.9Hz,2H),2.36(t,J＝7.2Hz,2H),2.31(s,3H),1.83–1.74(m,2H),1.48(d,J＝6.6Hz,6H).m/z:449.2587[M+H]⁺.

Example 64 preparation of (E) -methyl 4- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butenoate (CLJ-163)

CLJ-163 Synthesis example 29 was repeated using 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline in place of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline to give CLJ-163 as a final product.¹H NMR(400MHz,DMSO-d₆):9.21(s,1H),8.32(s,1H),8.26(d,J＝5.5Hz,1H),8.07(d,J＝6.0Hz,1H),7.61(s,1H),7.50–7.45(m,1H),7.00(t,J＝9.9Hz,1H),6.93(dt,J＝15.7,5.8Hz,1H),6.10(d,J＝15.7Hz,1H),4.62(dt,J＝13.3,6.6Hz,1H),3.68(s,3H),3.58(s,2H),3.32–3.29(m,2H),2.75(d,J＝5.1Hz,2H),2.67(t,J＝5.4Hz,2H),2.30(d,J＝9.3Hz,3H),1.48(d,J＝6.7Hz,6H).m/z:447.2430[M+H]⁺.

Example preparation of methyl 654- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) butyrate (CLJ-164)

Synthesis of CLJ-164 As in example 64, the final product CLJ-164 was obtained by substituting methyl 4-bromobutyrate for methyl (E) -4-bromo-2-butenoate.¹H NMR(400MHz,DMSO-d₆):9.19(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.61(s,1H),7.45(dd,J＝8.3,1.8Hz,1H),6.99(d,J＝8.3Hz,1H),4.62(dp,J＝12.9,6.4Hz,1H),3.56(s,3H),3.52(s,2H),2.71(d,J＝5.3Hz,2H),2.62(t,J＝5.6Hz,2H),2.46(t,J＝6.9Hz,2H),2.36(t,J＝7.2Hz,2H),2.30(d,J＝11.3Hz,3H),1.79(p,J＝7.1Hz,2H),1.47(dd,J＝11.7,5.9Hz,6H).m/z:449.2587[M+H]⁺.

Example 664-dimethylamino-1- (6- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) -2-butanamide (CLJ-165) preparation

CLJ-165 Synthesis As in example 51, the end product was obtained by substituting 4-dimethylaminobutyric acid for (E) -4-dimethylamino-2-butenoic acid

CLJ-165。¹H NMR(400MHz,DMSO-d₆):9.30(d,J＝6.4Hz,1H),8.33(s,1H),8.28(s,1H),8.09(s,1H),7.75(dd,J＝10.1,2.2Hz,1H),7.56(ddd,J＝14.8,8.4,2.2Hz,1H),7.10(d,J＝8.4Hz,1H),4.68–4.54(m,3H),3.68(dt,J＝12.1,5.9Hz,2H),3.09–2.99(m,2H),2.88(s,8H),2.56–2.51(m,2H),2.32(s,3H),1.87(p,J＝7.0Hz,2H),1.48(d,J＝6.6Hz,6H).m/z:462.2903[M+H]⁺.

Example preparation of 674-dimethylamino-1- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) -2-butanamide (CLJ-166)

CLJ-166 can be synthesized in the same manner as in example 66, except that 7-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline is used instead of 6-amino-2-N-BOC-1, 2,3, 4-tetrahydroisoquinoline, whereby CLJ-166 is a final product.¹H NMR(400MHz,DMSO-d₆):9.31(d,J＝12.8Hz,1H),8.34(d,J＝8.0Hz,1H),8.28(s,1H),8.09(d,J＝1.9Hz,1H),7.76(d,J＝2.7Hz,1H),7.52(dd,J＝8.4,2.4Hz,1H),7.09(dd,J＝8.4,4.3Hz,1H),4.63(dd,J＝7.7,5.3Hz,3H),3.68(dt,J＝14.1,5.9Hz,2H),3.09–2.99(m,2H),2.82(t,J＝5.9Hz,1H),2.76(s,6H),2.74–2.67(m,1H),2.55(dd,J＝13.4,6.8Hz,2H),2.32(d,J＝2.5Hz,3H),1.88(p,J＝7.0Hz,2H),1.49(d,J＝6.6Hz,6H).m/z:462.2903[M+H]⁺.

Example 68 preparation of (E) -4-dimethylamino-1- (7- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -1,2,3, 4-tetrahydroisoquinolin-2-yl) -2-butenamide (CLJ-167)

CLJ-167 Synthesis as in example 67, using (E) -4-dimethylaminoThe final product CLJ-167 can be obtained by replacing 4-dimethylamino butyric acid with 2-butenoic acid.¹H NMR(400MHz,DMSO-d₆):9.32(d,J＝10.3Hz,1H),8.34(d,J＝5.4Hz,1H),8.28(s,1H),8.10(s,1H),7.76(d,J＝13.3Hz,1H),7.54(dd,J＝8.3,2.3Hz,1H),7.10(d,J＝8.4Hz,1H),6.95(dd,J＝23.4,15.0Hz,1H),6.65(dt,J＝14.7,6.8Hz,1H),4.79(s,1H),4.69(s,1H),4.63(q,J＝6.7Hz,1H),3.79(dt,J＝15.3,5.9Hz,2H),3.68(d,J＝6.9Hz,2H),2.79(dt,J＝30.7,5.8Hz,2H),2.63(s,6H),2.32(s,3H),1.50(d,J＝6.7Hz,6H).m/z:460.2747[M+H]⁺.

Example 69 preparation of (R) -5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) -isoindoline-2-pyrroline-carboxamide (CLJ-168)

CLJ-168 was synthesized in the same manner as in example 26 except that 5-aminoisoindoline was used in place of 1,2,3, 4-tetrahydroisoquinoline, and (R) -2-pyrrolinemcarboxylic acid was used in place of 4-pentenoic acid.¹H NMR(400MHz,DMSO-d₆):9.42(d,J＝4.7Hz,1H),8.34(s,1H),8.29(s,1H),8.10(d,J＝2.6Hz,1H),7.93(t,J＝3.0Hz,1H),7.64(dd,J＝8.4,2.0Hz,1H),7.25(t,J＝8.5Hz,1H),4.87(ddd,J＝74.2,28.4,14.4Hz,3H),4.64(dt,J＝20.2,6.0Hz,2H),3.80(q,J＝7.5Hz,1H),3.01(dt,J＝10.9,6.0Hz,1H),2.74–2.60(m,1H),2.32(s,3H),2.15–2.01(m,1H),1.76–1.59(m,3H),1.49(d,J＝1.1Hz,3H),1.48(d,J＝1.2Hz,3H).m/z:432.2512[M+H]⁺.

Example 70 preparation of (R) -5- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indoline-2-pyrroline carboxamide (CLJ-169)

CLJ-169 was synthesized as in example 69, replacing 5-aminoisoindoline with 5-aminoindoline.¹H NMR(400MHz,DMSO-d₆):9.28(s,1H),8.32(s,1H),8.26(s,1H),8.08(s,1H),7.99(d,J＝8.7Hz,1H),7.79(s,1H),7.51(d,J＝8.8Hz,1H),4.63(p,J＝6.8Hz,1H),4.23(q,J＝9.1Hz,1H),4.06(q,J＝9.1Hz,1H),3.86(t,J＝6.9Hz,1H),3.38(q,J＝7.0Hz,1H),3.17(t,J＝8.3Hz,2H),3.10–2.97(m,1H),2.79–2.64(m,1H),2.31(s,3H),2.17–2.00(m,1H),1.84–1.60(m,3H),1.48(d,J＝6.5Hz,6H).m/z:432.2512[M+H]⁺.

Example 715- ((4- (1-isopropyl-1H-pyrazol-4-yl) -5-methylpyrimidin-2-yl) amino) indoline-3-morpholinopropionamide (CLJ-170) preparation

CLJ-170 was synthesized as in example 70, replacing (R) -2-pyrroline carboxylic acid with 3-morpholinopropionic acid.¹H NMR(400MHz,DMSO-d₆):9.26(s,1H),8.32(s,1H),8.26(s,1H),8.07(s,1H),7.98(d,J＝8.8Hz,1H),7.77(s,1H),7.50(d,J＝8.9Hz,1H),4.62(h,J＝6.6Hz,1H),4.10(t,J＝8.5Hz,2H),3.61(s,4H),3.44(s,2H),3.16(t,J＝8.3Hz,2H),2.66(s,4H),2.48(s,2H),2.31(s,3H),1.48(d,J＝6.7Hz,6H).m/z:476.2774[M+H]⁺.

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

MTT method for detecting MV4-11, MOLM-13 and SET-2 cell proliferation inhibition experiment

To test the effect of the test compounds of the invention on cancer cell viability, MV4-11, MOLM-13 and SET-2 were purchased from ATCC (American model culture Collection), MV4-11 and MOLM-13 are human leukemia cell lines, express the FLT3 receptor, and contain the FLT3-ITD mutation; SET-2 is a primary thrombocythemia cell, persistently expresses the JAK2 receptor, and comprises the V617F mutation.

MV4-11, MOLM-13 and SET-2 cells were plated in 96-well dishes in 100. mu.L IMDM containing 10% fetal bovine serum (100 mL/vial, from grassland Green-wildlife, cryopreserved in a closed environment at-20 ℃ C.) with 10000-15000 cells per well, test compounds were prepared in 100% DMSO (dimethylsulfoxide) and added to the cells to obtain concentrations of 100nM to 0.032nM (6 concentration points at 5-fold dilution), and the blank control group was plated with 10 nM cells per well0 μ L of fresh medium, an equal volume of fresh medium containing DMSO in an amount equal to the highest experimental concentration of the drug was added to each well of the solvent control group, 3-5 parallel wells were placed in each group, and 5% CO was added at 37 deg.C₂And culturing for 72 h. At the end point, 20. mu.L of MTT (5mg/mL) was added to each well and the cells were incubated for an additional 1-3 hours. After treatment with 20% SDS overnight, the absorbance OD at a wavelength of 570nM was obtained on a spectrophotometer (Molecular Devices, Sunnyvale, USA).

The inhibition ratio of each experimental group was calculated as [ (mean OD value of solvent control group-mean OD value of experimental group)/(mean OD value of solvent control group-mean OD value of blank control group) ] × 100%.

After calculating the inhibition rate of each concentration of compound on cell proliferation activity, the treatment concentration of compound and the corresponding inhibition rate were fitted to a dose-response curve using graphpad prism software, and IC was fitted₅₀The value is obtained. The results are shown in Table 1.

In vitro kinase Activity assay

In one reaction tube, buffer (8mM MOPS, pH 7.0,0.2mM EDTA,10mM MnCl) was added in sequence₂) The kinase to be tested, the substrate for the kinase to be tested, a 10mM magnesium acetate and gamma 33P-ATP solution, and compounds at different concentrations, MgATP was then added to the reaction to start the enzymatic reaction process, and incubated at room temperature for 40 minutes. Finally, stopping the reaction by using 5 microliter of 3% phosphate buffer solution, titrating 10 microliter of reaction solution onto a Filtermat A membrane, washing three times by using 75mM phosphate solution, washing for 5 minutes each time by using methanol, finally drying the Filtermat A membrane and carrying out scintillation counting on the Filtermat A membrane, wherein the scintillation counting value reflects the phosphorylation degree of a substrate, so that the kinase activity inhibition condition can be represented. The kinase activity @500nM indicates the inhibition (%) of the enzyme at 500nM level, as determined by Eurofins. The results are shown in Table 1.

TABLE 1 IC inhibition of cell proliferation by test Compounds₅₀Value and kinase Activity

The result shows that most of tested compounds have good inhibitory activity on cell proliferation of MV4-11, MOLM-13 and SET-2, and good activity on JAK2 and FLT3, and are novel and potential inhibitors with the potential of treating JAK2-FLT3-ITD related diseases.

The test compound with good activity is preferably selected to carry out FLT3 and JAK family kinase half inhibition activity IC₅₀Value determination, buffer (8mM MOPS, pH 7.0,0.2mM EDTA,10mM MnCl) was added to one reaction tube in sequence₂) The kinase to be tested, the substrate for the kinase to be tested, a 10mM magnesium acetate and gamma 33P-ATP solution, and compounds at different concentrations, MgATP was then added to the reaction to start the enzymatic reaction process, and incubated at room temperature for 40 minutes. Finally, stopping the reaction by using 5 microliter of 3% phosphate buffer solution, titrating 10 microliter of reaction solution onto a Filtermat A membrane, washing three times by using 75mM phosphate solution, washing for 5 minutes each time by using methanol, finally drying the Filtermat A membrane and carrying out scintillation counting on the Filtermat A membrane, wherein the scintillation counting value reflects the phosphorylation degree of a substrate, so that the kinase activity inhibition condition can be represented. The results are shown in Table 2.

TABLE 2 Activity of preferred compounds of the invention against JAK1/2/3 and FLT3 kinase inhibitors

The results show that the preferable compounds CLJ-118, CLJ-128 and CLJ-144 of the invention have better in vitro enzymology inhibitory activity and good selectivity.

Claims

The structure of the 2, 4-disubstituted pyrimidine derivative is shown as a formula IV:

wherein X is N or CH; r₂₂Is C₁～C₆An alkyl group;

R₁、R₂independently is-H, -halogen, -OH, C₁～C₁₀Alkyl or C₁～C₁₀An alkoxy group;

the A ring is a 5-membered or 6-membered N-containing heterocyclic ring, and the number of N atoms is 1; r is linked to N on the ring A, R is C₃～C₁₀Cycloalkyl, substituted or unsubstituted C₁～C₁₀Alkyl radical, C₂～C₁₀Alkynyl, substituted or unsubstituted C₂～C₁₀An alkenyl group,

Said substituted C₁～C₁₀The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₁₀Alkoxy or C₁～C₁₀An oxycarbonyl group; said substituted C₂～C₁₀The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₁₀Alkoxy radical, C₁～C₁₀Oxycarbonyl radical or
m、n＝0～2；

R₅Is C₁～C₁₀Alkoxy, substituted or unsubstituted C₂～C₁₀Alkenyl, substituted or unsubstituted C₁～C₁₀Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₁₀The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₁₀Alkoxy radical, C₁～C₁₀An oxycarbonyl group,
Said substituted C₂～C₁₀The substituent of the alkenyl is-H, -OH, halogen, -CN,
Phenyl or

R₆、R₇Independently is-H, C₁～C₁₀Alkyl or halogen substituted phenyl;

R₈、R₉independently is-H, C₁～C₁₀Alkyl, aryl, heteroaryl, and heteroaryl,

R₁₀、R₁₁independently-H or C₁～C₁₀An alkyl group;

R₁₂～R₁₆independently is-H, C₁～C₁₀Alkyl or-CF₃；

R₁₇～R₂₁Independently is-H, C₁～C₁₀Alkyl or-CF₃。
2. The 2, 4-disubstituted pyrimidine derivative according to claim 1, which has the structure shown in formula i:

wherein X is N or CH;

R₁、R₂independently is-H, -halogen, -OH, C₁～C₁₀Alkyl or C₁～C₁₀An alkoxy group;

the A ring is a 5-membered or 6-membered N-containing heterocyclic ring, and the number of N atoms is 1; r is linked to N on the ring A, R is C₃～C₁₀Cycloalkyl, substituted or unsubstituted C₁～C₁₀Alkyl radical, C₂～C₁₀Alkynyl, substituted or unsubstituted C₂～C₁₀An alkenyl group,

Said substituted C₁～C₁₀The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₁₀Alkoxy or C₁～C₁₀An oxycarbonyl group; said substituted C₂～C₁₀The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₁₀Alkoxy radical, C₁～C₁₀Oxycarbonyl radical or
m、n＝0～2；

R₅Is C₁～C₁₀Alkoxy, substituted or unsubstituted C₂～C₁₀Alkenyl, substituted or unsubstituted C₁～C₁₀Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₁₀The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₁₀Alkoxy radical, C₁～C₁₀An oxycarbonyl group,
Said substituted C₂～C₁₀The substituent of the alkenyl is-H, -OH, halogen, -CN,
Phenyl or

R₆、R₇Independently is-H, C₁～C₁₀Alkyl or halogen substituted phenyl;

R₈、R₉independently is-H, C₁～C₁₀Alkyl, aryl, heteroaryl, and heteroaryl,

R₁₀、R₁₁independently-H or C₁～C₁₀An alkyl group;

R₁₂～R₁₆independently is-H, C₁～C₁₀Alkyl or-CF₃；

R₁₇～R₂₁Independently is-H, C₁～C₁₀Alkyl or-CF₃。
3. A 2, 4-disubstituted pyrimidine derivative according to claim 1 or 2, characterized in that:

R₁、R₂independently is-H, -halogen, -OH, C₁～C₈Alkyl or C₁～C₈An alkoxy group;

preferably, R₁、R₂Independently is-H, -halogen, -OH, C₁～C₆Alkyl or C₁～C₆An alkoxy group;

further preferably, R₁、R₂Independently is-H, -halogen, -OH, C₁～C₄Alkyl or C₁～C₄An alkoxy group;

more preferably, R₁、R₂Independently is-H, halogen or C₁～C₄An alkyl group;

most preferably, R₁、R₂Independently is-H, -F or methyl.
4. A 2, 4-disubstituted pyrimidine derivative according to any one of claims 1 to 3, wherein:

the A ring is a 5-membered or 6-membered N-containing heterocyclic ring, and the number of N atoms is 1; r is linked to N on the ring A, R is C₃～C₈Cycloalkyl, substituted or unsubstituted C₁～C₈Alkyl radical, C₂～C₈Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₈An alkenyl group,

Said substituted C₁～C₈The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₈Alkoxy or C₁～C₈An oxycarbonyl group; said substituted C₂～C₈The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₈Alkoxy radical, C₁～C₈Oxycarbonyl radical or
m、n＝0～2；

Preferably, the a ring is a 5-or 6-membered N-containing heterocycle with 1N atom; r is linked to N on the ring A, R is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₆An alkenyl group,
Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₆Alkoxy or C₁～C₆An oxycarbonyl group; said substituted C₂～C₆The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₆Alkoxy radical, C₁～C₆Oxycarbonyl radical or
m、n＝0～2；

Further preferably, the a ring is a 5-or 6-membered N-containing heterocycle with 1N atom; r is linked to N on the ring A, R is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,
Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₄Alkoxy or C₁～C₄An oxycarbonyl group; said substituted C₂～C₄The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₄Alkoxy radical, C₁～C₄Oxycarbonyl radical or
m、n＝0～2；

More preferably, the a ring is a 5-or 6-membered N-containing heterocycle with 1N atom; r is connected with N on the ring A, and R is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,

Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, -CN, C₁～C₄Alkoxy or C₁～C₄An oxycarbonyl group; said substituted C₂～C₄The substituent of the alkenyl is-H, -COOH, phenyl and C₁～C₄Oxycarbonyl radical or
m, n is 0 or 1;

most preferably, the a ring is a 5-or 6-membered N-containing heterocycle with 1N atom; r is connected with N on the ring A, and R is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,

Said substituted C₁～C₆The substituents for alkyl being-H, -OH, -CN, ethoxy or
Said substituted C₂～C₄The substituent of the alkenyl is-H, -COOH, phenyl,
m and n are 0 or 1.
5. A2, 4-disubstituted pyrimidine derivative according to any one of claims 1 to 4, wherein:

R₅is C₁～C₈Alkoxy, substituted or unsubstituted C₂～C₈Alkenyl, substituted or unsubstituted C₁～C₈Alkyl, aryl, heteroaryl, and heteroaryl,

Said substituted C₁～C₈The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₈Alkoxy radical, C₁～C₈An oxycarbonyl group,
Said substituted C₂～C₈The substituent of the alkenyl is-H, -OH, halogen, -CN,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₈An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₈Alkyl or-CF₃；

Preferably, R₅Is C₁～C₆Alkoxy, substituted or unsubstituted C₂～C₆Alkenyl, substituted or unsubstituted C₁～C₆Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₆Alkoxy radical, C₁～C₆An oxycarbonyl group,
Said substituted C₂～C₆The substituent of the alkenyl is-H, -OH, halogen, -CN,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₆An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₆Alkyl or-CF₃；

More preferably, R₅Is C₁～C₆Alkoxy radical, C₂～C₆Alkenyl, substituted C₂～C₄Alkenyl radical, C₁～C₆Alkyl, substituted C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₄The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₄Alkoxy radical, C₁～C₄An oxycarbonyl group,
Said substituted C₂～C₄The substituent of the alkenyl is-H, -OH, halogen, -CN,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₄An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₄Alkyl or-CF₃；

Most preferably, R₅Is C₂～C₆Alkenyl, substituted C₂～C₄Alkenyl radical, C₁～C₆Alkyl, substituted C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₄The substituent of the alkyl is-H, -OH, -CN,

Said substituted C₂～C₄The substituent of the alkenyl is-H,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₄An alkyl group.
6. A2, 4-disubstituted pyrimidine derivative according to any one of claims 1 to 5, wherein:

R₆、R₇independently is-H, C₁～C₈Alkyl or halogen substituted phenyl;

preferably, R₆、R₇Independently is-H, C₁～C₆Alkyl or halogen substituted phenyl;

more preferably, R₆、R₇Independently is-H, C₁～C₄Alkyl or chloro substituted phenyl;

most preferably, R₆、R₇Independently is-H, C₁～C₄Alkyl or
7. A2, 4-disubstituted pyrimidine derivative according to any one of claims 1 to 6, wherein:

R₈、R₉independently is-H, C₁～C₈Alkyl, aryl, heteroaryl, and heteroaryl,
R₁₇～R₂₁Independently is-H, C₁～C₈Alkyl or-CF₃；

It is preferable that，R₈、R₉Independently is-H, C₁～C₆Alkyl, aryl, heteroaryl, and heteroaryl,
R₁₇～R₂₁Independently is-H, C₁～C₆Alkyl or-CF₃；

More preferably, R₈、R₉Independently is-H, C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
R₁₇～R₂₁Independently is-H, C₁～C₄Alkyl or-CF₃；

Most preferably, R₈、R₉Independently is-H, C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
8. The 2, 4-disubstituted pyrimidine derivative according to claim 2, which has the structure shown in formula ii:

wherein R is₄Is C₃～C₁₀Cycloalkyl, substituted or unsubstituted C₁～C₁₀Alkyl radical, C₂～C₁₀Alkynyl, substituted or unsubstituted C₂～C₁₀An alkenyl group,
Said substituted C₁～C₁₀The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₁₀Alkoxy or C₁～C₁₀An oxycarbonyl group; said substituted C₂～C₁₀The substituent of the alkenyl is-H, -OH, halogen-CN, -COOH, phenyl, C₁～C₁₀Alkoxy radical, C₁～C₁₀Oxycarbonyl radical or
m、n＝0～2；

R₅Is C₁～C₁₀Alkoxy, substituted or unsubstituted C₂～C₁₀Alkenyl, substituted or unsubstituted C₁～C₁₀Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₁₀The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₁₀Alkoxy radical, C₁～C₁₀An oxycarbonyl group,
Said substituted C₂～C₁₀Alkenyl is-H, -OH, halogen, -CN,
Phenyl or

R₆、R₇Independently is-H, C₁～C₁₀Alkyl or halogen substituted phenyl;

R₈、R₉independently is-H, C₁～C₁₀Alkyl, aryl, heteroaryl, and heteroaryl,

R₁₀、R₁₁independently-H or C₁～C₁₀An alkyl group;

R₁₂～R₁₆independently is-H, C₁～C₁₀Alkyl or-CF₃；

R₁₇～R₂₁Independently is-H, C₁～C₁₀Alkyl or-CF₃。
9. A 2, 4-disubstituted pyrimidine derivative according to claim 8, wherein:

R₄is C₃～C₈Cycloalkyl, substituted or unsubstituted C₁～C₈Alkyl radical, C₂～C₈Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₈An alkenyl group,
Said substituted C₁～C₈The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₈Alkoxy or C₁～C₈An oxycarbonyl group; said substituted C₂～C₈The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₈Alkoxy radical, C₁～C₈Oxycarbonyl radical or
m、n＝0～2；

Preferably, R₄Is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₆An alkenyl group,
Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₆Alkoxy or C₁～C₆An oxycarbonyl group; said substituted C₂～C₆The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₆Alkoxy radical, C₁～C₆Oxycarbonyl radical or
m、n＝0～2；

Further preferably, R₄Is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,
Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₄Alkoxy or C₁～C₄An oxycarbonyl group; said substituted C₂～C₄The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₄Alkoxy radical, C₁～C₄Oxycarbonyl radical or
m and n are integers of 0-2; m and n are 0-2;

more preferably, R₄Is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,
Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, -CN, C₁～C₄Alkoxy or C₁～C₄An oxycarbonyl group; said substituted C₂～C₄The substituent of the alkenyl is-H, -COOH, phenyl and C₁～C₄Oxycarbonyl radical or
m, n is 0 or 1;

most preferably, R₄Is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,
Said substituted C₁～C₆The substituents for alkyl being-H, -OH, -CN, ethoxy or
Said substituted C₂～C₄The substituent of the alkenyl is-H, -COOH, phenyl,
m and n are 0 or 1.
10. A 2, 4-disubstituted pyrimidine derivative according to claim 8 or 9, characterized in that:

R₅is C₁～C₈Alkoxy, substituted or unsubstituted C₂～C₈Alkenyl, substituted or unsubstituted C₁～C₈Alkyl, aryl, heteroaryl, and heteroaryl,

Said substituted C₁～C₈The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₈Alkoxy radical, C₁～C₈An oxycarbonyl group,
Said substituted C₂～C₈The substituent of the alkenyl is-H, -OH, halogen, -CN,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₈An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₈Alkyl or-CF₃；

Preferably, R₅Is C₁～C₆Alkoxy, substituted or unsubstituted C₂～C₆Alkenyl, substituted or unsubstituted C₁～C₆Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₆Alkoxy radical, C₁～C₆An oxycarbonyl group,
Said substituted C₂～C₆The substituent of the alkenyl is-H, -OH, halogen, -CN,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₆An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₆Alkyl or-CF₃；

More preferably, R₅Is C₁～C₆Alkoxy radical, C₂～C₆Alkenyl, substituted C₂～C₄Alkenyl radical, C₁～C₆Alkyl, substituted C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₄The substituent of the alkyl is-H, -OH, halogen、-CN、C₁～C₄Alkoxy radical, C₁～C₄An oxycarbonyl group,
Said substituted C₂～C₄The substituent of the alkenyl is-H, -OH, halogen, -CN,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₄An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₄Alkyl or-CF₃；

Most preferably, R₅Is C₂～C₆Alkenyl, substituted C₂～C₄Alkenyl radical, C₁～C₆Alkyl, substituted C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₄The substituent of the alkyl is-H, -OH, -CN,

Said substituted C₂～C₄The substituent of the alkenyl is-H,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₄An alkyl group.
11. A 2, 4-disubstituted pyrimidine derivative according to any one of claims 8 to 10, wherein:

R₆、R₇independently is-H, C₁～C₈Alkyl or halogen substituted phenyl;

preferably, R₆、R₇Independently is-H, C₁～C₆Alkyl or halogen substituted phenyl;

more preferably, R₆、R₇Independently is-H, C₁～C₄Alkyl or chloro substituted phenyl;

most preferably, R₆、R₇Independently is-H, C₁～C₄Alkyl or
12. A 2, 4-disubstituted pyrimidine derivative according to any one of claims 8 to 11, wherein:

R₈、R₉independently is-H, C₁～C₈Alkyl, aryl, heteroaryl, and heteroaryl,
R₁₇～R₂₁Independently is-H, C₁～C₈Alkyl or-CF₃；

Preferably, R₈、R₉Independently is-H, C₁～C₆Alkyl, aryl, heteroaryl, and heteroaryl,
R₁₇～R₂₁Independently is-H, C₁～C₆Alkyl or-CF₃；

More preferably, R₈、R₉Independently is-H, C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
R₁₇～R₂₁Independently is-H, C₁～C₄Alkyl or-CF₃；

Most preferably, R₈、R₉Independently is-H, C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
13. The 2, 4-disubstituted pyrimidine derivative according to claim 2, which has the structure shown in formula iii:

wherein R is₁Is methyl or-F; r₃Is C₃～C₁₀Cycloalkyl, substituted or unsubstituted C₁～C₁₀Alkyl radical, C₂～C₁₀Alkynyl, substituted or unsubstituted C₂～C₁₀An alkenyl group,
Said substituted C₁～C₁₀The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₁₀Alkoxy or C₁～C₁₀An oxycarbonyl group; said substituted C₂～C₁₀The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₁₀Alkoxy radical, C₁～C₁₀Oxycarbonyl radical or
m、n＝0～2；

R₅Is C₁～C₁₀Alkoxy, substituted or unsubstituted C₂～C₁₀Alkenyl, substituted or unsubstituted C₁～C₁₀Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₁₀The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₁₀Alkoxy radical, C₁～C₁₀An oxycarbonyl group,
Said substituted C₂～C₁₀Alkenyl is-H, -OH, halogen, -CN,
Phenyl or

R₆、R₇Independently is-H, C₁～C₁₀Alkyl or halogen substituted phenyl;

R₈、R₉independently is-H, C₁～C₁₀Alkyl, aryl, heteroaryl, and heteroaryl,

R₁₀、R₁₁independently-H or C₁～C₁₀An alkyl group;

R₁₂～R₁₆independently is-H, C₁～C₁₀Alkyl or-CF₃；

R₁₇～R₂₁Independently is-H, C₁～C₁₀Alkyl or-CF₃。
14. A 2, 4-disubstituted pyrimidine derivative according to claim 13, wherein:

R₃is C₃～C₈Cycloalkyl, substituted or unsubstituted C₁～C₈Alkyl radical, C₂～C₈Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₈An alkenyl group,
Said substituted C₁～C₈The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₈Alkoxy or C₁～C₈An oxycarbonyl group; said substituted C₂～C₈The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₈Alkoxy radical, C₁～C₈Oxycarbonyl radical or
m and n are integers of 0-2; m and n are 0-2;

preferably, R₃Is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₆An alkenyl group,
Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₆Alkoxy or C₁～C₆An oxycarbonyl group; said substituted C₂～C₆The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₆Alkoxy radical, C₁～C₆Oxycarbonyl radical or
m、n＝0～2；

Further preferably, R₃Is C₃～C₆Cycloalkyl, substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,
Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₄Alkoxy or C₁～C₄An oxycarbonyl group; said substituted C₂～C₄The substituent of the alkenyl is-H, -OH, halogen, -CN, -COOH, phenyl, C₁～C₄Alkoxy radical, C₁～C₄Oxycarbonyl radical or
m、n＝0～2；

More preferably, R₃Is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,
Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, -CN, C₁～C₄Alkoxy or C₁～C₄An oxycarbonyl group; said substituted C₂～C₄The substituent of the alkenyl is-H, -COOH, phenyl and C₁～C₄Oxycarbonyl radical or
m, n is 0 or 1;

most preferably, R₃Is substituted or unsubstituted C₁～C₆Alkyl radical, C₂～C₆Alkynyl, C₂～C₁₀Alkenyl, substituted C₂～C₄An alkenyl group,
Said substituted C₁～C₆The substituents for alkyl being-H, -OH, -CN, ethoxy or
Said substituted C₂～C₄The substituent of the alkenyl is-H, -COOH, phenyl,
m and n are 0 or 1.
15. A 2, 4-disubstituted pyrimidine derivative according to claim 13 or 14, wherein:

R₅is C₁～C₈Alkoxy, substituted or unsubstituted C₂～C₈Alkenyl, substituted or unsubstituted C₁～C₈Alkyl, aryl, heteroaryl, and heteroaryl,

Said substituted C₁～C₈The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₈Alkoxy radical, C₁～C₈An oxycarbonyl group,
Said substituted C₂～C₈The substituent of the alkenyl is-H, -OH, halogen, -CN,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₈An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₈Alkyl or-CF₃；

Preferably, R₅Is C₁～C₆Alkoxy, substituted or unsubstituted C₂～C₆Alkenyl, substituted or unsubstituted C₁～C₆Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₆The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₆Alkoxy radical, C₁～C₆An oxycarbonyl group,
Said substituted C₂～C₆The substituent of the alkenyl is-H, -OH, halogen, -CN,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₆An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₆Alkyl or-CF₃；

More preferably, R₅Is C₁～C₆Alkoxy radical, C₂～C₆Alkenyl, substituted C₂～C₄Alkenyl radical, C₁～C₆Alkyl, substituted C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₄The substituent of the alkyl is-H, -OH, halogen, -CN, C₁～C₄Alkoxy radical, C₁～C₄An oxycarbonyl group,
Said substituted C₂～C₄The substituent of the alkenyl is-H, -OH, halogen, -CN,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₄An alkyl group; r₁₂～R₁₆Independently is-H, C₁～C₄Alkyl or-CF₃；

Most preferably, R₅Is C₂～C₆Alkenyl, substituted C₂～C₄Alkenyl radical, C₁～C₆Alkyl, substituted C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
Said substituted C₁～C₄The substituent of the alkyl is-H, -OH, -CN,

Said substituted C₂～C₄The substituent of the alkenyl is-H,
Phenyl or
R₁₀、R₁₁independently-H or C₁～C₄An alkyl group.
16. A 2, 4-disubstituted pyrimidine derivative according to any one of claims 13 to 15, wherein:

R₆、R₇independently is-H, C₁～C₈Alkyl or halogen substituted phenyl;

preferably, R₆、R₇Independently is-H, C₁～C₆Alkyl or halogen substituted phenyl;

more preferably, R₆、R₇Independently is-H, C₁～C₄Alkyl or chloro substituted phenyl;

most preferably, R₆、R₇Independently is-H, C₁～C₄Alkyl or
17. A 2, 4-disubstituted pyrimidine derivative according to any one of claims 13 to 16, wherein:

R₈、R₉independently is-H, C₁～C₈Alkyl, aryl, heteroaryl, and heteroaryl,
R₁₇～R₂₁Independently is-H, C₁～C₈Alkyl or-CF₃；

Preferably, R₈、R₉Independently is-H, C₁～C₆Alkyl, aryl, heteroaryl, and heteroaryl,
R₁₇～R₂₁Independently is-H, C₁～C₆Alkyl or-CF₃；

More preferably, R₈、R₉Independently is-H, C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
R₁₇～R₂₁Independently is-H, C₁～C₄Alkyl or-CF₃；

Most preferably, R₈、R₉Independently is-H, C₁～C₄Alkyl, aryl, heteroaryl, and heteroaryl,
A 2, 4-disubstituted pyrimidine derivative of the formula:
19. a pharmaceutically acceptable salt or hydrate of the 2, 4-disubstituted pyrimidine derivative of any one of claims 1 to 18.
20. A pharmaceutical composition which is a preparation prepared by adding pharmaceutically acceptable auxiliary components to the 2, 4-disubstituted pyrimidine derivative according to any one of claims 1 to 18 or the salt or hydrate according to claim 19; preferably, the formulation is a tablet, capsule, powder, granule, ointment, solution, suspension, injection, inhalant, gel, microsphere or aerosol; preferably, the formulation is an oral or intravenous formulation.
21. Use of a 2, 4-disubstituted pyrimidine derivative according to any one of claims 1 to 18, a salt or hydrate according to claim 19 or a pharmaceutical composition according to claim 20 for the preparation of a JAK2 inhibitor.
22. Use of a 2, 4-disubstituted pyrimidine derivative according to any one of claims 1 to 18, a salt or hydrate according to claim 19 or a pharmaceutical composition according to claim 20 in the preparation of an FLT3 inhibitor.
23. Use of the 2, 4-disubstituted pyrimidine derivative according to any one of claims 1 to 18, the salt or hydrate according to claim 19 or the pharmaceutical composition according to claim 20 for the preparation of a medicament for the treatment or/and prevention of a tumor.
24. The use of claim 23, the tumor comprising a solid tumor and/or a hematological tumor; the solid tumor comprises: 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, lymphatic cancer, epidermal hyperplasia, psoriasis and/or prostate cancer; the hematological neoplasm comprises: acute myeloid leukemia, chronic myeloid leukemia, myeloma, acute lymphocytic leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated cell leukemia, myelodysplastic syndrome, myelodysplasia, myelofibrosis, multiple myeloma, and/or myelosarcoma.
25. Use of the 2, 4-disubstituted pyrimidine derivative according to any one of claims 1 to 18, the salt or hydrate according to claim 19 or the pharmaceutical composition according to claim 20 for the preparation of a medicament for the treatment or/and prevention of an immunological disease.
26. The use of claim 25, the immune disease comprising: psoriasis, rheumatoid arthritis, inflammatory bowel disease, sjogren's syndrome, behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, polymyositis, dermatomyositis, periarteritis nodosa, mixed connective tissue disease, scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves 'disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, addison's disease, abnormal immune responses, arthritis, dermatitis, and/or radiodermatitis, and the like; preferably, the immune disease comprises: psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, and/or systemic lupus erythematosus.
27. Use of the 2, 4-disubstituted pyrimidine derivative according to any one of claims 1 to 18, the salt or hydrate according to claim 19 or the pharmaceutical composition according to claim 20 for the preparation of a medicament for the treatment or/and prevention of inflammatory-related diseases.
28. The use of claim 27, the inflammatory-related disease comprising: inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome, post-operative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis and/or pulmonary sarcoidosis, and the like.