CN116870016A

CN116870016A - Heteroaromatic compound and medical application thereof

Info

Publication number: CN116870016A
Application number: CN202310532265.5A
Authority: CN
Inventors: 张海生; 代长贵; 卓鉥; 程辉敏; 牛春意; 陈誉; 方磊
Original assignee: Siegershenko Shenzhen Co ltd
Current assignee: Siegershenko Shenzhen Co ltd
Priority date: 2022-12-01
Filing date: 2022-12-01
Publication date: 2023-10-13
Anticipated expiration: 2042-12-01
Also published as: CN116870016B; CN115785154A

Abstract

The application relates to application of a heteroaromatic compound or enantiomer, diastereomer, racemate or pharmaceutically acceptable salt or isotope thereof or pharmaceutical composition thereof in preparing medicines for regulating or treating YAP related diseases.

Description

Heteroaromatic compound and medical application thereof

The application relates to a split application of Chinese patent application with 2022, 12-month and 1-day application number 2022115316779 and the name of 'heteroaromatic compound and medical application'.

Technical Field

The application belongs to the field of medicines, and relates to a heteroaromatic compound and medical application thereof.

Background

Focal Adhesion Kinase (FAK), also known as PTK2 (protein tyrosine kinase 2), is a non-receptor tyrosine kinase located at the junction of multiple signaling pathways and is activated by integrins, growth factor receptors, G-protein coupled receptors, cytokines. In addition to being involved in signaling as a cytoplasmic kinase, related studies have also shown that FAK plays an important role in the nucleus. FAK can promote p53 degradation through ubiquitination, leading to cancer cell growth and proliferation. Tang et al reported that FAK can also modulate the expression of GATA4 and IL-33, thereby reducing inflammatory responses and immune evasion. In the microenvironment of tumors, intracellular FAK can regulate the formation of new blood vessels, affecting the blood supply of tumors.

FAK is widely expressed in vivo, plays an important role in cell growth, proliferation, migration and adhesion, and is involved in embryo development and occurrence and development of diseases (cancer, cardiovascular diseases and the like). Overexpression of FAK is found in many types of cancers, including colon cancer, breast cancer, prostate cancer, thyroid cancer, neuroblastoma, ovarian cancer, cervical cancer, brain cancer, head and neck cancer, liver cancer, esophageal cancer, pancreatic cancer, lung cancer, gastric cancer, and acute leukemia. High expression of FAK often predicts a poor prognosis. For example, it has been found that the GTPase RHOAY42C mutation is one of the most common function-acquired mutations in diffuse gastric cancer, whereas RHOAY42C mutant mice are sensitive to FAK inhibitors, suggesting that inhibition of FAK activity may be a new strategy for treating diffuse gastric cancer.

YAP (Yes-associatied protein) is Yes-related protein, is a transcription coactivator of the Hippo pathway, is located on human chromosome 11q22, and promotes gene expression by enhancing the activity of the transcription factor. The external signal activates MST1/2, and phosphorylates LATS1/2 and MOB after being combined with regulatory protein SAV1, so that YAP/TAZ is directly phosphorylated, and the phosphorylated YAP/TAZ is stagnated in cytoplasm, and transcription is inhibited. When this signaling pathway is blocked or inactivated, the unphosphorylated YAP/TAZ is transferred from the cytoplasm into the nucleus and binds to transcription factors such as TEADs, smad, runx/2, p63/p73, erbB4, etc. to promote gene transcription.

The Hippo-YAP pathway is a recently discovered signaling pathway with the functions of regulating organ volume and maintaining the balance of cell proliferation and apoptosis, and is closely related to uncontrolled proliferation of tumor cells. The major function of the Hippo-YAP pathway in mammals is to inhibit the activity of the transcriptional regulators YAP and TAZ and to down regulate the progression of tumors, thus the Hippo pathway is also considered as a cancer-inhibiting pathway. Specifically, the core members of this pathway include serine/threonine kinases MST1, MST2, LATS1 and LATS2, the scaffold protein SAV1 (binding to MST1 and MST 2), MOB1 (binding to LATS1 and LATS 2), the transcriptional co-activator YAP, and the transcription factor TEAD comprising a TEA binding domain. Briefly, when the Hippo pathway is activated, MST1/2 kinase phosphorylation activates LATS1/2, which in turn phosphorylates YAP, which is inactivated and then out of the nucleus, while cytoplasmic YAP is degraded by the proteasome.

Studies have demonstrated that the Hippo pathway is involved in the progression of a variety of tumors such as lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer, and the like. However, in human tumors, mutations in the gene of the Hippo pathway occur less frequently. Based on this, it was concluded that deregulation of the Hippo pathway in human tumors is due to cross-talk between other aberrantly expressed proteins or signaling pathways within tumor cells and the Hippo pathway in addition to mutations derived from key proteins of the Hippo pathway itself. In addition, the role of the Hippo signaling pathway in tumors is closely related to nuclear translocation of YAP/TAZ. Recently, YAP was found to be highly expressed in various tumors, which is associated with high pathological grading, advanced TNM stage, lymph node metastasis, etc., and the phenomenon of nuclear localization exists.

Disclosure of Invention

The invention aims to provide a novel heteroaromatic compound and medical application thereof. The heteroaromatic compound provided by the invention has a good inhibition effect on FAK, and unexpectedly has a good inhibition effect on YAP.

In a first aspect of the invention there is provided a compound of formula 0 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug thereof,

wherein A is selected from: 5-6 membered heteroaryl or phenyl;

X ₁ selected from: CH or N;

X ₂ selected from: CR (computed radiography) ⁶ Or N;

X ₃ selected from: CR (computed radiography) ⁷ Or N;

R ¹ and R is ² Each independently selected from the group consisting of substituted or unsubstituted: hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl; or R is ¹ And R is ² Together with the P atom to which it is attached, form a 3-6 membered heterocyclic group;

R ³ independently selected from: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, CF ₃ 、CHF ₂ 、CH ₂ F、CN、NO ₂ 、CONR ^a R ^b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^a And R is ^b Each independently selected from: H. C1-C6 alkyl, C3-C6 cycloalkyl;

R ⁴ independently selected from: H. OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F、CN、NO ₂ 、NR ¹¹ R ¹² C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1-3R ¹³ Substitution;

R ⁵ selected from: OR (OR) ¹⁰ 、CH ₂ R ¹⁹ H, OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F、CH ₂ CF ₃ 、-CN、-NO ₂ 、-S(O) _m R ¹¹ C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1-3R ¹³ Substitution;

R ⁶ 、R ⁷ 、R ⁸ and R is ⁹ Each independently selected from: H. OR (OR) ¹¹ Halogen, CF ₃ 、-CHF ₂ 、CH ₂ F、CN、NO ₂ 、NR ¹¹ R ¹² 、-C(O)NR ¹¹ R ¹² 、-C(O)NR ¹¹ OR ¹² 、-C(R ¹¹ )＝NR ¹² 、-NR ¹¹ C(O)R ¹² 、-C(O)R ¹¹ 、-C(O)C(O)R ¹¹ 、-C(O)OR ¹¹ 、-OC(O)R ¹¹ 、-OC(O)OR ¹¹ 、-P(＝O)R ¹¹ R ¹² 、-S(O)(＝NR ¹¹ )R ¹² 、-S(O) _m R ¹¹ 、-NR ¹¹ S(O) _m R ¹² C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1-3R ¹³ Substitution;

or R is ⁶ 、R ⁷ The atoms to which they are attached form 5-7 membered cycloalkyl, heterocyclyl, aryl, heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl groups may be substituted with 1-3R ¹³ Substitution;

or R is ⁸ 、R ⁹ The atoms to which they are attached form 5-7 membered cycloalkyl, heterocyclyl, aryl, heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl groups may be substituted with 1-3R ¹³ Substitution;

or R is ⁵ And R is ⁷ Or R is ⁹ The atoms to which they are attached form 5-7 membered cycloalkyl, heterocyclyl, aryl, heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl groups may be substituted with 1-3R ¹³ Substitution;

R ¹⁰ 、R ¹¹ and R is ¹² Independently selected from: H. OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F、CN、NO ₂ 、CH ₂ CF ₃ 、NR ¹⁴ R ¹⁵ 、S(O) _m R ¹⁴ C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl; or at NR ¹¹ R ¹² Wherein R is ¹¹ And R is ¹² Together with the N atom to which it is attached form a 3-6 membered heterocyclyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, 3-6 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1-3R ¹³ Substitution;

R ¹³ independently selected from: H. OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F、CH ₂ CF ₃ 、-CN、-NO ₂ 、OR ¹⁴ 、C(O)R ¹⁴ 、OC(O)R ¹⁴ 、OC(O)R ¹⁴ 、-OC(O)OR ¹⁴ 、-C(O)NR ¹⁴ R ¹⁵ 、-NR ¹⁴ C(O)NR ¹⁵ R ¹⁶ 、-NR ¹⁴ R ¹⁵ 、-NR ¹⁴ C(O)R ¹⁵ 、-NR ¹⁴ S(O) _m R ¹⁵ 、-S(O) _m R ¹⁴ 、-S(O) _m NR ¹⁴ C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1 to 3 groups selected from the group consisting of: C1-C6 alkyl, halogen, OH, CN, NO ₂ 、CHF ₂ 、CH ₂ CF ₃ 、CF ₃ 、C(O)R ¹⁷ 、C(O)NR ¹⁷ R ¹⁸ 、S(O) _m R ¹⁷ 、-S(O) _m NR ¹⁷ R ¹⁸ Substitution;

R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ and R is ¹⁸ Each independently selected from: H. C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1 to 3 groups selected from the group consisting of: OH, halogen, CN, NO ₂ 、NH ₂ 、CHF ₂ 、CH ₂ CF ₃ 、CF ₃ C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -C (O) - (C1-C6 alkoxy), C3-C12 cycloalkyl, 3-12 membered heterocycloalkyl, C1-C6 alkylamine;

R ¹⁹ is a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl may be substituted with a group selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl;

n is independently selected from 0, 1, 2, 3 or 4;

m is independently selected from 0, 1 or 2;

the limiting conditions are as follows: when A is phenyl, R ⁵ Independently is OR ¹⁰ 、CH ₂ R ¹⁹ or-S (O) _m R ¹¹ ；

Or when A is phenyl, R ⁶ 、R ⁷ The atoms to which they are attached form 5-7 membered cycloalkyl, heterocyclyl, aryl, heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl groups may be substituted with 1-3R ¹³ And (3) substitution.

In some embodiments, the compound has a structure shown in formula I:

X ₁ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ the definitions of n and A are as described above.

In some embodiments, when a is phenyl, R ⁵ Independently is OR ¹⁰ 、CH ₂ R ¹⁹ or-S (O) _m R ¹¹ ；

Or when A is phenyl, R ⁶ 、R ⁷ The atoms to which they are attached form 5-7 membered cycloalkyl, heterocyclyl, aryl, heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl groups may be substituted with 1-3R ¹³ Instead of the above-mentioned,

wherein R is ¹⁰ 、R ¹⁹ 、R ¹¹ 、R ¹³ And m is as defined above.

In some embodiments, when a is phenyl, R ⁵ Independently is OR ¹⁰ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ¹⁰ Is defined as above.

In some embodiments, when A is a 5-6 membered heteroaryl, R ⁵ Independently selected from: H. OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F、CH ₂ CF ₃ 、-CN、-NO ₂ 、-S(O) _m R ¹¹ C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1-3R ¹³ Substitution; wherein m, R ¹¹ And R is ¹³ Is defined as above.

In some embodiments, X ₁ Is N.

In some embodiments, the 5-7 membered cycloalkyl, heterocyclyl, aryl, heteroaryl groups are selected fromSelf-contained: a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; preferably pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxadiazolyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, and,

In some embodiments, the heterocyclyl includes heterocycloalkyl or heterocycloalkenyl.

In some embodiments, the compounds have the structure shown in formula (I-1) below:

wherein X is ₁ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ And n is as defined above;

preferably, R ¹ And R is ² Each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R ¹ And R is ² Together with the P atom to which it is attached, form a 3-6 membered heterocyclyl (e.g., 5 membered heterocyclyl);

preferably, R ³ Selected from halogen or CF ₃ ；

Preferably, R ⁴ Selected from H;

preferably, R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ Each independently selected from H, halogen, CF ₃ C1-C6 alkyl or C1-C6 alkoxy.

In some embodiments, the compounds have a structure represented by the following formula (II-1):

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And R is ¹⁰ The definition of (c) is as described above,

preferably, R ³ Selected from halogen or CF ₃ ；

Preferably, R ⁴ Selected from H;

In some embodiments, R ¹⁰ Selected from: H. C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1-3R ¹³ Substitution; wherein R is ¹³ Is defined as above.

In some embodiments, R ¹⁰ Selected from: H. C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl may be substituted with 1-3R ¹³ Substitution; wherein R is ¹³ Is defined as above.

In some embodiments, R ⁶ 、R ⁷ 、R ⁸ And R is ⁹ Each independently selected from: H. halogen, CF ₃ 、-CHF ₂ 、CH ₂ F、CN、NO ₂ 、NR ¹¹ R ¹² C1-C6 alkyl, C1-C6 alkoxy; or R is ⁶ 、R ⁷ Connected with itThe attached atoms form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; or R is ⁸ 、R ⁹ The atoms to which they are attached form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; wherein the heterocyclic group and heteroaryl group can be substituted by 1-3R ¹³ Substitution;

wherein R is ¹¹ 、R ¹² And R is ¹³ Is defined as above.

In some embodiments, R ⁵ And R is ⁶ Or R is ⁹ The atoms to which they are attached form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; wherein the heterocyclic group and heteroaryl group can be substituted by 1-3R ¹³ Substituted, R ¹³ Is defined as above.

In some embodiments, the compounds have the structures shown in the following formulas (I-2) - (I-7):

wherein R is ²⁰ Selected from: H. OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F、CH ₂ CF ₃ 、-CN、-NO ₂ C1-C6 alkyl, C1-C6 alkoxy;

p is 0, 1 or 2;

A、X ₁ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁷ 、R ⁸ 、R ⁹ and n is as defined above.

In some embodiments, when a is a 5-6 membered heteroaryl, a is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxadiazolyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl.

In some embodiments, R ¹ And R is ² The atoms to which they may be attached form a 4-6 membered heterocyclic group, preferably including, but not limited to, the following groups:

Wherein, represents the site of attachment.

In some embodiments, R ³ Selected from: halogen, CF ₃ 、CHF ₂ 、CH ₂ F. CN, C1-C6 alkyl.

In some embodiments, R ⁴ Is H, C1-C6 alkoxy, 3-6 cycloalkyl, 5-6 heteroaryl, 5-6 heterocyclyl, NR ¹¹ R ¹² Wherein the 3-6 membered cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl may be substituted by C1-C6 alkyl; r is R ¹¹ And R is ¹² Is defined as above.

In some embodiments, R ⁴ Selected from: h or

In some embodiments, R ⁴ H, OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F. CN or NO ₂ 。

In some embodiments, A, X ₁ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ²⁰ And n is a group corresponding to each specific compound in the examples.

In some embodiments, the compound is selected from

1)

R ¹ And R is ² Each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R ¹ And R is ² Together with the P atom to which it is attached, form a 3-6 membered heterocyclyl such as a 5 membered heterocyclyl;

R ³ selected from halogen or CF ₃ ；

R ⁴ Selected from H;

R ⁶ 、R ⁸ 、R ⁹ each independently selected from H, halogen, CF ₃ C1-C6 alkyl or C1-C6 alkoxy;

R ¹⁰ selected from: H. OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F、CN、NO ₂ 、CH ₂ CF ₃ 、NR ¹⁴ R ¹⁵ 、S(O) _m R ¹⁴ C1-C3 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl; or at NR ¹¹ R ¹² Wherein R is ¹¹ And R is ¹² Together with the N atom to which it is attached form a 3-6 membered heterocyclyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, 3-6 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1-3R ¹³ Substitution;

2)

R ³ selected from halogen or CF ₃ ；

R ⁴ Selected from H;

R ⁷ 、R ⁸ 、R ⁹ each independently selected from H, halogen, CF ₃ C1-C6 alkyl or C1-C6 alkoxy;

R ¹⁰ selected from: H. OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F、CN、NO ₂ 、CH ₂ CF ₃ 、NR ¹⁴ R ¹⁵ 、S(O) _m R ¹⁴ C1-C3 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-to 10-membered heterologyAn aryl group; or at NR ¹¹ R ¹² Wherein R is ¹¹ And R is ¹² Together with the N atom to which it is attached form a 3-6 membered heterocyclyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, 3-6 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1-3R ¹³ Substitution;

3)

a is a six-membered nitrogen-containing heteroaromatic ring;

R ³ selected from halogen or CF ₃ ；

R ⁴ Selected from H;

R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ each independently selected from H, halogen, CF ₃ C1-C6 alkyl or C1-C6 alkoxy.

4)

R ¹ and R is ² Together with the P atom to which it is attached, form a 3-6 membered heterocyclyl such as a 5 membered heterocyclyl;

R ³ is CF (CF) ₃ ；

R ⁴ Selected from H;

R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ each independently selected from H, halogen, CF ₃ C1-C6 alkyl or C1-C6 alkoxy;

or 5)

R ³ selected from halogen;

R ⁴ selected from H;

R ¹⁰ Selected from: H. OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F、CN、NO ₂ 、CH ₂ CF ₃ 、NR ¹⁴ R ¹⁵ 、S(O) _m R ¹⁴ C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl; or at NR ¹¹ R ¹² Wherein R is ¹¹ And R is ¹² Together with the N atom to which it is attached form a 3-6 membered heterocyclyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, 3-6 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1-3R ¹³ And (3) substitution.

In some embodiments, R ¹⁰ Selected from: H. OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F、CN、NO ₂ 、CH ₂ CF ₃ 、NR ¹⁴ R ¹⁵ 、S(O) _m R ¹⁴ C1-C3 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, cycloalkenyl, aryl, membered heteroaryl; or in which together with the N atom to which it is attached form a 3-6 membered heterocyclyl; wherein the C1-C6 alkyl, alkoxy, alkenyl, alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, 3-6 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1-3R ¹³ Taking, wherein R ¹³ Is defined as above.

In some embodiments, R ¹⁰ Selected from: H. OH, halogen, CF ₃ 、CHF ₂ 、CH ₂ F、CN、NO ₂ 、CH ₂ CF ₃ 、NR ¹⁴ R ¹⁵ 、S(O) _m R ¹⁴ C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-C12 heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 heteroaryl; or at NR ¹¹ R ¹² Wherein R is ¹¹ And R is ¹² Together with the N atom to which it is attached form a 3-6 membered heterocyclyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, 3-6 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted with 1-3R ¹³ Substitution, wherein R ¹³ Is defined as above.

In some embodiments, the compound is selected from the following compounds:

in some embodiments, the compound is a compound shown in the examples.

In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug thereof; and a pharmaceutically acceptable carrier or diluent.

In some embodiments, the pharmaceutical composition further comprises one or more selected from the group consisting of: PD-1 inhibitors, PD-L1 inhibitors, ALK inhibitors, PI3K inhibitors, BTK inhibitors, EGFR inhibitors, VEGFR inhibitors, HDAC inhibitors, CDK inhibitors, MEK inhibitors, akt inhibitors, mTOR inhibitors, SHP2 inhibitors, or combinations thereof.

In a third aspect of the invention, there is provided the use of a compound according to the first aspect or a pharmaceutical composition according to the second aspect in the manufacture of a medicament for the treatment of a disease associated with FAK.

In some embodiments, the FAK-associated disease comprises various cancers, pulmonary hypertension, pathological angiogenesis, and the like.

In some embodiments, the cancer is selected from: skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, cancer of the head or neck, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urinary tract cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancy, hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumor (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, uterine cancer, and the like. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is diffuse gastric cancer.

In a fourth aspect of the invention there is provided the use of a compound as described in the first aspect or a pharmaceutical composition as described in the second aspect in the manufacture of a medicament for modulating YAP or treating a disease associated with YAP.

In some embodiments, the YAP-related disease is selected from cancer.

In some embodiments, the cancer is selected from: skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, cancer of the head or neck, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urinary tract cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancy, hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumor (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, and uterine cancer.

In some embodiments, the cancer in the YAP-related disease is selected from: lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer, gastric cancer.

In some embodiments, the FAK-associated disease is selected from cancer, pulmonary hypertension, pathological angiogenesis.

In some embodiments, the cancer in the FAK-associated disease is selected from: skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, cancer of the head or neck, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urinary tract cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancy, hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumor (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, uterine cancer, and the like. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is diffuse gastric cancer.

In a fourth aspect of the invention, there is provided a method of treating FAK and/or YAP related diseases, the method comprising administering to a subject identified or diagnosed as having FAK and/or YAP related diseases a therapeutically effective amount of a compound according to the first aspect or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the second aspect.

In some embodiments, the YAP-related disease is selected from cancer.

In another aspect, the invention provides a method for inhibiting FAK kinase and/or YAP protein activity in a cell or a subject, the method comprising the step of contacting the cell or administering to the subject a compound according to the first aspect or a pharmaceutical composition according to the second aspect.

In some embodiments, the cell is a mammalian cell. In some embodiments, the subject is a mammal, preferably a human.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Drawings

FIG. 1 shows tumor volume versus time for compounds of the invention in a mouse tumor model of test example four.

FIG. 2 shows a partial western blot result of test example two.

FIG. 3 shows a partial western blot result of test example two.

FIG. 4 shows a partial western blot result of test example two.

FIG. 5 shows a partial western blot result of test example two.

Detailed Description

The present inventors have conducted extensive and intensive studies and have unexpectedly found a class of compounds having superior FAK kinase and/or YAP protein inhibitory activity. In addition, the compounds have better pharmacodynamic/pharmacokinetic properties. On this basis, the present invention has been completed.

Terminology

In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.

When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH ₂ O-is equivalent to-OCH ₂ -。

The term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon radical having the indicated number of carbon atoms (i.e., C1-C6 refers to containing 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

The term "alkoxy" refers to a straight or branched or cyclic alkyl group attached through an ether oxygen, the free valence of which results from the ether oxygen. Alkoxy is preferably C1-C6 alkoxy, more preferably C1-C3 alkoxy. Representative examples include (but are not limited to): methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. Preferably C1-C3 alkoxy.

The term "heteroalkyl" refers to a group in which a carbon atom in the alkyl group is substituted with 1, 2, 3 heteroatoms selected from N, O, S, si or P, and wherein the nitrogen and sulfur atoms are optionally oxidized, "C1-C6 heteroalkyl" in the present invention refers to a group comprising 1-6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms, and 1, 2, 3 heteroatoms selected from N, O, S or P, representative examples include (but are not limited to): CH (CH) ₃ OCH ₂ -、CH ₃ SCH ₂ -、CH ₃ CH ₂ OCH ₂ -and the like.

The term "alkenyl" means a straight or branched hydrocarbon group containing one or more double bonds and having the indicated number of carbon atoms. For example, "C2-C6 alkenyl" refers to groups containing 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to: ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.

The term "alkynyl" refers to a straight or branched hydrocarbon radical containing one or more triple bonds and having the indicated number of carbon atoms. For example, "C2-C6 alkynyl" refers to groups containing 2 to 6 carbon atoms. Alkynyl groups include, but are not limited to: ethynyl, propynyl, butynyl, and the like.

The term "cycloalkyl" is intended to include saturated monocyclic (e.g., C3-C8), bicyclic (e.g., C5-C12 fused bicyclic, C5-C12 membered spirobicyclic) or polycyclic cyclic alkyl groups, "C3-C6 cycloalkyl" refers to containing 3 to 6 carbon atoms, and "C3-C12 cycloalkyl" refers to containing 3 to 12 carbon atoms. Cycloalkyl is preferably a C3-C12 ring Alkyl, more preferably C3-C6 cycloalkyl. Representative cycloalkyl groups of the present invention include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl,Etc. The term "cycloalkenyl" refers to cycloalkyl groups as defined above and further containing 1 or more double bonds, including but not limited to cyclopentenyl, cyclohexenyl.

The term "heterocyclyl" generally refers to a stable monocyclic (e.g., 3-8 membered, i.e., 3-, 4-, 5-, 6-, 7-, or 8-membered) or bicyclic (e.g., 5-12-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) or polycyclic (e.g., 7-14-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered) heterocycle, including fused-, spiro-, and/or bridged ring structures, which are saturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O and S. The term also includes polycyclic groups formed by the fusion of a heterocyclic ring with an aromatic ring, such as a benzene ring. The nitrogen and sulfur heteroatoms as ring atoms may optionally be oxidized. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is no greater than 1. The heterocyclic group may be attached to any heteroatom or carbon atom residue of a ring or ring system molecule. Examples of heterocycles include, but are not limited to: azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Wherein the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode.

The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system (preferably 6-10 membered aromatic rings) having a total of 5 to 15 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. "aryl" may be substituted or unsubstituted. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to: phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl. The aryl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. The connection lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Heteroaryl is preferably a 5-to 10-membered ring, more preferably 5-or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. The term "halogen" includes fluorine, chlorine, bromine and iodine.

Unless otherwise indicated, it is assumed that any heteroatom in an underfilling state has sufficient hydrogen atoms to complement its valence.

In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position, i.e., each substituent is independent of the other. Technology in the artThe skilled artisan will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a single halogen substituent or a multiple halogen substituent, the latter such as trifluoromethyl or containing Cl) ₃ Alkyl group of (c), cyano group, nitro group, oxo group (e.g., =o), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, alkynyl group, heterocycle, aromatic ring, OR group _a 、SR _a 、S(＝O)R _e 、S(＝O) ₂ R _e 、P(＝O) ₂ R _e 、S(＝O) ₂ OR _e ，P(＝O) ₂ OR _e 、NR _b R _c 、NR _b S(＝O) ₂ R _e 、NR _b P(＝O) ₂ R _e 、S(＝O) ₂ NR _b R _c 、P(＝O) ₂ NR _b R _c 、C(＝O)OR _d 、C(＝O)R _a 、C(＝O)NR _b R _c 、OC(＝O)R _a 、OC(＝O)NR _b R _c 、NR _b C(＝O)OR _e 、NR _d C(＝O)NR _b R _c 、NR _d S(＝O) ₂ NR _b R _c 、NR _d P(＝O) ₂ NR _b R _c 、NR _b C(＝O)R _a Or NR _b P(＝O) ₂ R _e Wherein R is _a Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring, R _b 、R _c And R is _d Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R _b And R is _c Together with the N atom, may form a heterocyclic ring; r is R _e Can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring. Typical substituents described above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring, may be optionally substituted. Such as (but not limited to): halogen, hydroxy, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-C12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxyA group, a C1-C10 sulfonyl group, a C1-C6 ureido group, and the like.

Active ingredient

As used herein, the term "compound of the invention" or "active ingredient of the invention" is used interchangeably to refer to a compound of formula I and its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitroxides, metabolites or pharmaceutically acceptable salts, hydrates, isotopes or prodrugs thereof.

A、X ₁ 、X ₂ 、X ₃ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And n is as defined above.

In the present invention, the compound of formula 0 has the structure shown in formula I:

Therein, A, X ₁ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And n is as defined above. Preferably, A is phenyl, R ⁵ Independently is OR ¹⁰ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ¹⁰ Is defined as above.

Preferably, the compound has a structure represented by the following formula (I-1):

wherein X is ₁ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ And n is defined as above. Preferably, the compound has a structure represented by the following formula (II-1):

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And R is ¹⁰ Is defined as above.

Preferably, the compound has a structure represented by the following formulas (I-2) to (I-7):

p is 0, 1 or 2;

Preferably, the compound has a structure represented by formula (I-8), (I-9) or (I-10):

A、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ and R is ¹⁰ Is defined as above.

Salts which may be formed with the compounds of the present invention are also within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to salts formed with inorganic or organic acids and bases in the acid or base form. Furthermore, when the compound of the present invention contains a basic moiety, it includes, but is not limited to, pyridine or imidazole, and an acidic moiety, including, but not limited to, carboxylic acids, the possible formation of zwitterions ("inner salts") are included within the term "salts". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during the preparation process. The compounds of the invention may form salts, for example, by reacting compound I with an amount of, for example, an equivalent of, an acid or base, salting out in a medium, or lyophilizing in aqueous solution.

The compounds of the present invention contain basic fragments, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that may be salified include acetates (e.g., with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, mesylate, naphthalene sulfonate (e.g., 2-naphthalene sulfonate), nicotinate, nitrate, oxalate, pectate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluene sulfonate such as p-toluenesulfonate, dodecanoate, and the like.

Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, that may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hydrabamine (salts with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and dipentyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl and tetradecyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.

Prodrugs and solvates of the compounds of the invention are also within the scope of coverage. The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to produce a compound, salt, or solvate of the invention when used in the treatment of a related disorder. The compounds of the present invention include solvates, such as hydrates.

The compounds, salts or solvates of the present invention, may exist in tautomeric forms (e.g., amides and imine ethers). All of these tautomers are part of the present invention.

Stereoisomers of all compounds (e.g., those having asymmetric carbon atoms which may be present as a result of various substitutions), including enantiomeric and diastereoisomeric forms thereof, are contemplated as falling within the scope of the present invention. The individual stereoisomers of the compounds of the invention may not be present simultaneously with the other isomers (e.g., having particular activity as one pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures with all or a portion of the other stereoisomers. The chiral center of the present invention has two configurations, S or R, defined by the International Association of theory and application chemistry (IUPAC) 1974. The racemic forms can be resolved by physical methods, such as fractional crystallization, or by separation of crystals by derivatization into diastereomers, or by chiral column chromatography. Individual optical isomers may be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

The compounds of the present invention are prepared, isolated and purified in sequence to give the compounds in an amount of 90% by weight or more, for example 95% or more and 99% or more ("very pure" compounds), as listed in the text description. Such "very pure" compounds of the invention are also included herein as part of the invention.

All configurational isomers of the compounds of the present invention are within the scope of coverage, whether in mixtures, pure or very pure form. The definition of compounds in the present invention includes both the cis (Z) and trans (E) olefin isomers, as well as the cis and trans isomers of carbocycles and heterocycles.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

Specific functional groups and chemical term definitions are described in detail below. For the purposes of the present invention, chemical elements are described in conjunction with Periodic Table of theElements, CAS version, handbook of Chemistry and Physics,75 ^th Ed.. The definition of specific functional groups is also described herein. Furthermore, the basic principles of organic chemistry and specific functional groups and reactivities are described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, which is incorporated by reference in its entirety.

Certain compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures thereof. In addition, an asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers and mixtures thereof are encompassed by the present invention.

According to the invention, the mixture of isomers may contain various isomer ratios. For example, in a mixture of only two isomers, there may be a combination of: all ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomers are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are within the scope of the present invention, as would be readily understood by one of ordinary skill in the art.

The present invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as original compounds. In practice it will often occur that one or more atoms are replaced by an atom of a different atomic weight or mass number than it is. Examples of isotopes that can be listed as compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, respectively, such as ² H、 ³ H、 ¹³ C、 ¹¹ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and F ³⁶ Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, e.g ³ H and ¹⁴ radioisotopes of C are also useful in, among other things, tissue distribution experiments of drugs and substrates. Tritium, i.e. tritium ³ H and carbon-14, i.e ¹⁴ C, their preparation and detection are relatively easy. Is the first choice in isotopes. In addition, heavier isotopic substitutions such as deuterium, i.e ² H may be preferred in some cases because of its good metabolic stability, which may be advantageous in certain therapies, such as increasing half-life or decreasing dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by using readily available isotopically-labeled reagents in place of non-isotopically-labeled reagents using the protocols disclosed in the examples.

If one is to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or by derivatization with chiral auxiliary, separating the resulting diastereomeric mixture and removing the chiral auxiliary to give the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed therewith using an appropriate optically active acid or base, and then the resulting mixture can be separated by conventional means such as fractional crystallization or chromatography to give the pure enantiomer.

As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to extend their inclusion. In general, the term "substituted", whether appearing before or after the term "optional", in the formulas of the present invention includes substituents, means that the specified structural substituent is substituted for the hydrogen radical. When multiple of a particular structure are substituted at a position with multiple particular substituents, the substituents may be the same or different at each position. The term "substitution" as used herein includes all permissible organic compound substitutions. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any of the permissible organic compounds described hereinabove to supplement the valence state thereof. Furthermore, the present invention is not intended to be limited in any way to allow substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds. The term "stable" as used herein refers to a compound that is stable for a period of time sufficient to maintain structural integrity of the compound, preferably for a period of time sufficient to be effective, as used herein for the purposes described above.

Metabolites of the compounds and pharmaceutically acceptable salts thereof of the present application, as well as prodrugs that can be converted in vivo to structures of the compounds and pharmaceutically acceptable salts thereof of the present application are also encompassed by the claims of the present application.

Pharmaceutical compositions and methods of administration

The pharmaceutical composition provided by the application is used for preventing and/or treating the following diseases: cancer, pulmonary hypertension, pathological angiogenesis, and the like.

The compounds of formula I may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug may remain unchanged, while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, it may be preferable to use a pharmaceutical composition containing one or more known drugs together with the compound of formula I. Drug combinations also include administration of the compound of formula I with one or more other known drugs over overlapping time periods. When a compound of formula I is administered in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of the compound of formula I alone.

Drugs or active ingredients that may be used in combination with the compounds of formula I include, but are not limited to: PD-1 inhibitors, PD-L1 inhibitors, ALK inhibitors, PI3K inhibitors, BTK inhibitors, EGFR inhibitors, VEGFR inhibitors, HDAC inhibitors, CDK inhibitors, MEK inhibitors, akt inhibitors, mTOR inhibitors, SHP2 inhibitors, or combinations thereof.

Dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, external liniment, controlled release or sustained release preparation, or nanometer preparation.

The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-1000mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate ) Calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), and emulsifying agentWetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.

In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.

When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.

The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: a pharmaceutically acceptable carrier is admixed with a compound of formula I according to the invention or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, thereby forming a pharmaceutical composition.

Preparation method

The following schemes and examples describe methods for preparing compounds of formula I. The starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of the steps of the reaction scheme may be altered to promote the reaction or to avoid unwanted side reaction products.

The process for the preparation of the compounds of formula I according to the invention is described in more detail below, but these particular processes do not constitute any limitation on the invention. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains.

Typically, in the preparation scheme, each reaction is carried out in a suitable solvent, typically under inert gas, at 0 to 90℃for a period of typically 2 to 24 hours.

Preferably, the compounds of the present invention are prepared by the following method

i) Pyrimidine analog compound a-1 and amine compound a-2 under alkaline conditions (e.g.: n' N-diisopropylethylamine) to undergo nucleophilic substitution reaction, and substitution reaction at the 4-position of pyrimidine chloro-analogue A-1 to give compound A-3;

ii) the compound A-3 and the aromatic amine A-4 are acidic (e.g.: HCl) to produce nucleophilic substitution to obtain carboxylic acid compound A-5;

iii) Carboxylic acid compound A-5 and amine compound R-NH ₂ Under the condition of an amide condensing agent (such as HATU), performing an amide condensation reaction to obtain a compound A-6;

in A, X ₁ 、R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ And n is as defined above.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

The invention has the following main advantages:

(1) The compound has excellent inhibition capability on FAK kinase and YAP proteins;

(2) The compound has lower toxic and side effects.

(3) The compound has better pharmacodynamics and pharmacokinetics.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

NMR was performed using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic instruments, and the solvent was determined to contain deuterated dimethyl sulfoxide (DMSO-d ₆ ) Deuterated acetone (CD) ₃ COCD ₃ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), etc., the internal standard being Tetramethylsilane (TMS), the chemical shifts being measured in parts per million (ppm).

Liquid chromatography (LC-MS) was performed using an Agilent 1260 mass spectrometer. HPLC was determined using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100x 3.0mm column).

The thin layer chromatography silica gel plate is Qingdao GF254 silica gel plate, TLC is 0.15-0.20mm, and the preparation thin layer chromatography is 0.4-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to literature reported in the art.

Except for the special descriptions, all reactions of the invention are carried out by continuous magnetic stirring under the protection of dry inert gas (such as nitrogen or argon), and the reaction temperature is in degrees centigrade.

The following abbreviations are used throughout this application

Defactinib: gefamtinib

THF: tetrahydrofuran (THF)

DCM: dichloromethane (dichloromethane)

PE: petroleum ether

Na ₂ CO ₃ : sodium carbonate

MeOH: methanol

HCl: hydrochloric acid

Pd(PPh ₃ ) ₄ : tetratriphenylphosphine palladium

K ₂ CO ₃ : potassium carbonate

H ₂ O: water and its preparation method

TEA: triethylamine

DIEA: n, N-diisopropylethylamine

DMF: n, N-dimethylformamide

DMSO: dimethyl sulfoxide

NaBH ₄ : sodium borohydride

Sn ₂ (Bu-n) ₆ : hexa-n-butylditin

CuI: cuprous iodide

Cs ₂ CO ₃ : cesium carbonate

K ₃ PO ₄ : potassium phosphate

Pd ₂ (dba) ₃ : tris (dibenzylideneacetone) dipalladium

Pd/C: palladium carbon

Xantphos: 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl

EA: acetic acid ethyl ester

Boc ₂ O: di-tert-butyl dicarbonate

Pd(dppf) ₂ Cl ₂ : [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride

NaH: sodium hydrogen

CH ₃ I: methyl iodide

L-Proline: l-proline

L-Selectride: trisec-butyl lithium borohydride

Examples

Example 1

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- (((1-methylpiperidin-4-yl) methyl) benzamide (1)

Step 1, synthesizing (2-aminophenyl) dimethylphosphine oxide

Compound 2-iodoaniline (10 g,45.7 mmol) and dimethylphosphino-oxyhydrogen (4.3 g,54.8 mmol) were dissolved in DMF (100 mL) and Pd (OAC) was weighed out separately ₂ (1.03g,4.57mol)、K ₃ PO ₄ (11.63 g,54.8 mmol) and Xantphos (2.64 g,4.57 mol) were added to the reaction system, replaced with nitrogen protection,slowly heating to 125 deg.C, reflux stirring for 6 hr, TLC monitoring reaction, quenching with water, suction filtering with diatomite, extracting with EA (20 mL. Times.2), mixing organic phases, washing with saturated saline (30 mL. Times.2), vacuum distilling, and purifying by ISCO column chromatography to obtain 7.1g of (2-aminophenyl) dimethylphosphine oxide, and MS m/z (ESI) 170[ M+H ] ] ⁺ 。

Step 2 Synthesis of (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

2, 4-dichloropyrimidine-5-trifluoromethyl (2.56 g,11.8 mmol) was dissolved in DMF (50 mL), and (2-aminophenyl) dimethylphosphine oxide (2.0 g,11.8 mmol) was added thereto, DIPEA (2.0 mL,11.8 mmol) was slowly added under ice bath conditions, and the reaction was allowed to proceed to 50℃for 1 hour, followed by monitoring the completion of the reaction. Quenching with water, extracting with dichloromethane, drying, concentrating, and column chromatography to obtain 920mg of 2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide, MS m/z (ESI): 350[ M+H ]] ⁺ 。

Step 3 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid

2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (300 mg,0.86 mmol), para-aminobenzoic acid (130 mg,0.95 mmol) was dissolved in isopropanol (25 mL), and a 1, 4-dioxane solution of 4N hydrochloric acid (1.3 mL,5.2 mmol) was added and reacted at 65℃for 4h to monitor completion. Suction filtration of the system afforded 276mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 451[ M+H ]] ⁺ 。

Step 4 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- (((1-methylpiperidin-4-yl) methyl) benzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (40.1 mg,0.089 mmol), (1-methylpiperidin-4-yl) methylamine (22.8 mg,0.18 mmol), HATU (51.9 mg,0.14 mmol), DMAP (1.01 mg,0.009 mmol) and DIPEA (46. Mu.L, 0.27 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after completion of the LCMS monitoring reaction, quenched with water (10 mL), extracted with EA (20 mL. Times.2), organic phaseWashing with water, drying, concentrating, and column chromatography gives 15.1mg (4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- (((1-methylpiperidin-4-yl) methyl) benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.58(s,1H),10.08(s,1H),8.55(t,J＝5.7Hz,1H),8.49(s,1H),8.19(s,1H),7.67(ddd,J＝25.0,17.9,8.1Hz,3H),3.31(d,J＝11.5Hz,1H),3.16(s,1H),2.88(t,J＝11.9Hz,1H),2.66(s,1H),1.53(dd,J＝24.3,12.4Hz,1H).MS m/z(ESI)：561[M+H] ⁺ 。

Example 2

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxy-N- (1-methylpiperidin-4-yl) methyl) benzamide (2)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid

2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (120 mg,0.35 mmol) and p-amino-3-methoxybenzoic acid (63.4 mg,0.38 mmol) were dissolved in isopropanol (14 mL), a solution of 4N hydrochloric acid in 1, 4-dioxane (0.12 mL,0.48 mmol) was added, and the reaction was allowed to react at 70℃for 4h, monitoring the completion of the reaction. Suction filtration of the system afforded 135mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid, MS m/z (ESI): 481[ M+H) ] ⁺ 。

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxy-N- (((1-methylpiperidin-4-yl) methyl) benzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid (70.0 mg,0.15 mmol), (1-methylpiperidin-4-yl) methylamine (38.5mg,0.3mmol mmol), HATU (83.4 mg,0.23 mmol), DMAP (2.4 mg,0.02 mmol) and DIPEA (76. Mu.L, 0.45 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after completion of the LCMS monitoring reaction with water (10 mL)The reaction was quenched, extracted with EA (20 ml x 3), the organic phase was washed with water, dried and concentrated, and purified with column chromatography MeOH/DCM (0-10%) to give 20mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxy-N- (1-methylpiperidin-4-yl) methyl) benzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ10.74(s,1H),8.62(s,1H),8.49–8.34(m,1H),8.16(s,1H),7.84(d,J＝8.0Hz,1H),7.60(dd,J＝13.5,6.5Hz,1H),7.51(d,J＝1.5Hz,1H),7.45(t,J＝7.8Hz,1H),7.38(d,J＝8.3Hz,1H),7.21(t,J＝7.1Hz,1H),3.87(s,2H),3.16(t,J＝6.2Hz,1H),2.78(d,J＝10.9Hz,1H),2.16(s,2H),1.85(t,J＝10.8Hz,1H),1.75(s,1H),1.71(s,2H),1.64(d,J＝12.8Hz,1H),1.56–1.44(m,1H).MSm/z(ESI)：591[M+H] ⁺ 。

Example 3

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide (3)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide

Compound 4- ((2- (dimethylphosphoryl) phenyl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (73.0 mg,0.16 mmol), O-methylhydroxylamine hydrochloride (40.6 mg,0.49 mmol), HATU (88.9 mg,0.24 mmol), DMAP (2.0 mg,0.016 mmol) and DIPEA (82 μl,0.48 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h, after completion of lcms monitoring reaction, the reaction was quenched with water (10 mL), EA (20 mL x 3) extracted, the organic phase was washed with water, concentrated, and column chromatographed to purify MeOH/DCM (0-10%) to give 15mg 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.58(s,1H),10.56(s,1H),10.08(s,1H),8.49(s,1H),8.16(s,1H),7.65(ddd,J＝24.1,12.0,5.3Hz,6H),7.33(t,J＝7.2Hz,1H),3.70(s,3H),1.75(s,3H),1.72(s,3H).MSm/z(ESI)：480[M+H] ⁺ 。

Example 4

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzamide (4)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid (30.0 mg,0.063 mmol), O-methylhydroxylamine hydrochloride (15.7 mg,0.19 mmol), HATU (47.53 mg,0.13 mmol), DMAP (1.0 mg,0.063 mmol) and DIPEA (64 μl,0.38 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after lcms monitoring the reaction to completion, quenched with water (10 mL), extracted with EA (20 mL x 3), the organic phase was washed with water, dried and concentrated, and purified by column chromatography (0-10% DMC/MeOH) to give 13mg of 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.69(s,1H),10.71(s,1H),8.58(s,1H),8.44(s,1H),8.15(s,1H),7.90(d,J＝8.4Hz,1H),7.67–7.57(m,1H),7.49(t,J＝7.9Hz,1H),7.41(d,J＝1.6Hz,1H),7.25(t,J＝6.6Hz,2H),3.87(s,3H),3.72(s,3H),1.75(s,3H),1.71(s,3H).MS m/z(ESI)：510[M+H] ⁺ 。

Example 5

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (meth) benzamide (5)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methylbenzoic acid

2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethyloxyPhosphine (100 mg,0.29 mmol), para-amino-3-methylbenzoic acid (46.3 mg,0.3 mmol) was dissolved in isopropyl alcohol (6 mL), and a 1, 4-dioxane solution (0.1 mL,0.4 mmol) of 4N hydrochloric acid was added thereto, and the reaction was allowed to proceed at 70℃for 4 hours, followed by monitoring the completion of the reaction. The system was suction filtered to give 90.0mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (methyl) benzoic acid, MS m/z (ESI): 465[ M+H)] ⁺ 。

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (methyl) benzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (methyl) benzoic acid (50.3 mg,0.11 mmol), O-methylhydroxylamine hydrochloride (26.9 mg,0.32 mmol), HATU (81.4 mg,0.21 mmol), DMAP (1.3 mg,0.01 mmol) and DIPEA (0.11 mL,0.64 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after completion of lcms monitoring the reaction, quenched with water (10 mL), extracted with EA (20 mL x 3), the organic phase was washed with water, dried and concentrated, and purified by column chromatography to give 40.1mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (methyl) benzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.66(s,1H),10.85(s,1H),9.29(s,1H),8.38(s,1H),8.18(s,1H),7.63(s,1H),7.59–7.49(m,3H),7.30(t,J＝7.8Hz,1H),7.13(t,J＝7.0Hz,1H),3.71(s,3H),2.24(s,3H),1.75(s,3H),1.71(s,3H).MS m/z(ESI)：494[M+H] ⁺ 。

Example 6

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (trifluoromethoxy) benzamide (6)

Step 1:4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (trifluoromethoxy) benzoic acid

2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (100 mg,0.29 mmol) and para-ammoniaThe reaction was completed by dissolving 3-trifluoromethoxybenzoic acid (67.3 mg,0.3 mmol) in isopropanol (6 mL), adding a 1, 4-dioxane solution (0.1 mL,0.4 mmol) of 4N hydrochloric acid, and reacting at 70℃for 4 hours. The system was suction filtered to give 70.1mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (trifluoromethoxy) benzoic acid, MS m/z (ESI): 535[ M+H ]] ⁺ 。

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (trifluoromethoxy) benzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (trifluoromethoxy) benzoic acid (30.2 mg,0.056 mmol), O-methylhydroxylamine hydrochloride (14.0 mg,0.17 mmol), HATU (42.6 mg,0.11 mmol), DMAP (1.01 mg, 0.006mmol) and DIPEA (43.4 mg,0.34 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h, lcms monitored the reaction was complete, the reaction quenched with water (10 mL), EA (20 mL x 3) was extracted, the organic phase was washed with water, dried concentrated, and column chromatographed to purify MeOH/DCM (0-10%) to give 15.2mg of 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (trifluoromethoxy) benzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.89(s,1H),10.81(s,1H),9.63(s,1H),8.44(s,1H),8.14(s,1H),7.88(d,J＝8.4Hz,1H),7.74(s,1H),7.69(d,J＝8.4Hz,1H),7.58(dd,J＝12.5,7.6Hz,1H),7.40(t,J＝8.1Hz,1H),7.20(t,J＝7.1Hz,1H),3.73(s,1H),1.74(s,1H),1.71(s,1H).MS m/z(ESI)：564[M+H] ⁺ 。

Example 7

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (isopropoxy) benzamide (7).

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (isopropoxy) benzoic acid

2- ((2-chloro-5- (trifluormethyl)Base) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (100.0 mg,0.29 mmol) and p-amino-3-isopropoxybenzoic acid (59.1 mg,0.3 mmol) were dissolved in isopropanol (6 mL), and a 1, 4-dioxane solution (0.1 mL,0.4 mmol) of 4N hydrochloric acid was added and reacted at 70℃for 4h to monitor the completion of the reaction. The system was suction filtered to give 102.1mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (isopropoxy) benzoic acid, MS m/z (ESI): 509[ M+H ]] ⁺ 。

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (isopropoxy) benzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (isopropoxy) benzoic acid (50.3 mg,0.098 mmol), O-methylhydroxylamine hydrochloride (24.6 mg,0.3 mmol), HATU (74.5 mg,0.2 mmol), DMAP (1.01 mg,0.001 mmol) and DIPEA (0.1 ml,0.6 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after lcms monitoring the reaction to completion, the reaction was quenched with water (10 mL), extracted with EA (20 ml 3), the organic phase was washed with water, dried and concentrated, and column chromatographically purified MeOH/DCM (0-10%) to give 35.0 mg of 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (isopropoxy) benzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.68(s,1H),10.68(s,1H),8.46(s,1H),8.38(s,1H),8.11(dd,J＝7.9,3.9 Hz,1H),7.95(d,J＝8.4 Hz,1H),7.64(dd,J＝13.4,7.7 Hz,1H),7.52(t,J＝7.8 Hz,1H),7.40(d,J＝1.7 Hz,1H),7.29(t,J＝7.4 Hz,1H),7.21(dd,J＝8.4,1.5 Hz,1H),4.69(hept,J＝5.6 Hz,1H),3.71(s,3H),1.75(s,3H),1.71(s,3H),1.30(s,3H),1.29(s,3H).MS m/z(ESI)：538[M+H] ⁺ 。

Example 8

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (ethoxy) benzamide (8)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (ethoxy) benzoic acid

2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (100 mg,0.29 mmol) and p-amino-3-ethoxybenzoic acid (54.6 mg,0.3 mmol) were dissolved in isopropanol (6 mL), a solution of 4N hydrochloric acid in 1, 4-dioxane (0.1 mL,0.4 mmol) was added, and the reaction was monitored for completion at 70℃for 4 h. The system was suction filtered to give 100.2 mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (ethoxy) benzoic acid, MS m/z (ESI): 495[ M+H ]] ⁺ 。

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (ethoxy) benzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- (ethoxy) benzoic acid (50.0 mg,0.1 mmol), O-methylhydroxylamine hydrochloride (25.1 mg,0.3 mmol), HATU (76.1 mg,0.2 mmol), DMAP (1.0 mg,0.01 mmol) and DIPEA (77.5 mg,0.6 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h, lcms monitored the reaction was complete, the reaction quenched with water (10 mL), extracted with EA (20 ml x 3), the organic phase was washed with water, dried and concentrated, and column chromatography purified with MeOH (0-10%) to give 45.2mg 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-3- (ethoxy) benzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.67(s,1H),10.69(s,1H),8.47(d,J＝13.0 Hz,2H),8.13(dd,J＝7.9,3.8 Hz,1H),7.91(d,J＝8.4 Hz,1H),7.63(ddd,J＝13.5,7.7,1.3 Hz,1H),7.50(t,J＝7.8 Hz,1H),7.39(d,J＝1.7 Hz,1H),7.30–7.18(m,2H),4.13(q,J＝6.9 Hz,2H),3.72(s,3H),1.75(s,3H),1.71(s,3H),1.35(t,J＝6.9 Hz,3H).MS m/z(ESI)：524[M+H] ⁺ 。

Example 9

Preparation of 4- ((4- ((2- (dimethylphosphoryl) -4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzamide (9)

Step 1, synthesizing 4- (3-iodo-4-nitrophenyl) morpholine

The compound 4-fluoro-2-iodo-1-nitrobenzene (2.5 g,9.36 mmol) and morpholine (1.6 g,18.73 mmol) were dissolved in DMF (50 mL) and K was added ₂ CO ₃ (2.5 g,18.73 mmol) was slowly warmed to 100deg.C and stirred for 8h. After TLC monitoring the reaction, quenched with water, extracted with EA (30 mL. Times.2), combined with organic phases, washed with saturated brine (50 mL. Times.2), distilled under reduced pressure, purified by ISCO column chromatography (EA/PE 0% -100%) to give 4.4 g of 4- (3-iodo-4-nitrophenyl) morpholine, MS m/z (ESI): 335[ M+H ]] ⁺ 。

Step 2, synthesizing 2-iodine-4-morpholinium aniline

4- (3-iodo-4-nitrophenyl) morpholine (2.0 g,6.0 mmol) was dissolved in methanol/water 4:1 (60 mL), then iron powder (835.7 mg,14.96 mmol) and ammonium chloride (815.6 mg,14.96 mmol) are added, the reaction system is slowly warmed up, reflux is carried out at 80 ℃ overnight, the reaction is cooled to room temperature after completion, diatomite is filtered, and NaHCO is saturated ₃ Quenching (100 mL), extraction with EA (100 mL. Times.3), and spin-concentration of the combined organic phases, purification by ISCO column chromatography (PE/EA 0-80%) afforded 1.6 g of 2-iodo-4-morpholinoaniline. MS m/z (ESI): 305[ M+H ] ]+。

Step 3 Synthesis of (2-amino-5-morpholinophenyl) dimethylphosphine oxide

The compound 2-iodo-4-morpholinium (2.0 g,6.48 mmol) and dimethyl phosphine oxide (607.1 g,7.78 mmol) were dissolved in DMF (20 mL) and Pd (OAC) was weighed out separately ₂ (145.9 mg,0.65 mol)、K ₃ PO ₄ (1.65 g,7.78 mmol) and Xantphos (376.1 mg,0.65 mol) are added into a reaction system, nitrogen protection is replaced, the temperature is slowly raised to 125 ℃ and the reflux stirring reaction is carried out for 6 hours, TLC monitoring reaction is carried out, after the reaction is finished, water quenching is added, the diatomite is used for suction filtration, EA (20 mL. Times.2) is used for extraction, the organic phases are combined, saturated saline solution is used for washing (30 mL. Times.2), reduced pressure distillation and ISCO column chromatography purification (PE/EA 0-100%) are carried out, and 1.2 g of (2-amino-5-morpholinophenyl) dimethylphosphine oxide is obtained, MS m/z (ESI) is 255[ M+H)] ⁺ 。

Step 4 Synthesis of (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) -5-morpholinophenyl) dimethylphosphine oxide

2, 4-dichloropyrimidine-5-trifluoromethyl (1.2 g,4.72 mmol) was dissolved in DMA (20 mL), and (2-amino-5-morpholinophenyl) dimethylphosphine oxide (931.8 mg,4.29 mmol) was added, DIPEA (0.8 mL,4.72 mmol) was slowly added under ice bath conditions, and the reaction was allowed to proceed to 50℃for 1h, followed by monitoring the completion of the reaction. Quenched with water, extracted with dichloromethane (20 mL. Times.2), dried and concentrated, and column chromatographed to give 0.68g of 2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) -5-morpholinophenyl) dimethylphosphine oxide, MS m/z (ESI): 435[ M+H ] ] ⁺ 。

Step 5 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid

2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) -5-morpholinophenyl) dimethylphosphine oxide (150.3 mg,0.35 mmol) and p-amino-3-methoxybenzoic acid (60.7 mg,0.36 mmol) were dissolved in isopropanol (6 mL), a solution of 4N hydrochloric acid in 1, 4-dioxane (0.1 mL,0.4 mmol) was added, the reaction was allowed to proceed at 65℃for 8h, and TLC monitored for completion. The system was suction filtered to give 103.1 mg of 4- ((4- ((2- (dimethylphosphoryl) -4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid, MS m/z (ESI): 566[ M+H ]] ⁺ 。

Step 4 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) -4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid (60.3 mg,0.11 mmol), O-methylhydroxylamine hydrochloride (26.7 mg,0.32 mmol), HATU (83.7 mg,0.22 mmol), DMAP (1.0 mg,0.01 mmol) and DIPEA (0.12 mL,0.65 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after lcms monitored to completion, the reaction was quenched with water (10 mL), extracted with EA (20 mL x 3), the organic phase was washed with water, dried and concentrated, and column chromatographed to purify MeOH/DCM (0-10%) to give 32.0mg 4- ((2- (dimethylphosphoryl) -4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.66(s,1H),10.18(s,1H),8.44(s,1H),8.38(s,1H),7.82(d,J＝8.0Hz,2H),7.39(d,J＝1.6Hz,1H),7.21(d,J＝9.6Hz,1H),7.16–7.02(m,2H),3.87(s,3H),3.81–3.75(m,4H),3.72(s,3H),3.23–3.12(m,4H),1.69(s,3H),1.66(s,3H).MS m/z(ESI)：595[M+H] ⁺ 。

Example 10

Preparation of 4- ((4- ((4- ([ 1,4 '-bipyridyl ] -1' -yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzamide (10)

Step 1 Synthesis of 1'- (3-iodo-4-nitrophenyl) -1,4' -dipiperidine

The compound 4-fluoro-2-iodo-1-nitrobenzene (2.5 g,9.36 mmol) and 1,4' -dipiperidine (1.9 g,11.24 mmol) were dissolved in DMF (50 mL) and K was added ₂ CO ₃ (2.6 g,18.72 mmol) was slowly warmed to 100deg.C and reacted for 8h with stirring. After TLC monitoring the reaction, quench with water, extract with EA (30 mL. Times.2), combine the organic phases, wash with saturated brine (50 mL. Times.2), distill under reduced pressure, purify by ISCO column chromatography (EA/PE 0% -100%) to give 1'- (3-iodo-4-nitrophenyl) -1,4' -dipiperidine 3.2g, MS m/z (ESI): 416[ M+H)] ⁺ 。

Step 2 Synthesis of 4- ([ 1,4 '-dipiperidine ] -1' -yl) -2-iodoaniline

1'- (3-iodo-4-nitrophenyl) -1,4' -dipiperidine (3.2 g,7.71 mmol) was dissolved in methanol/water 4:1 (60 mL), then iron powder (1.1 g,19.28 mmol) and ammonium chloride (1.1 g,19.28 mmol) were added, the reaction system was slowly warmed up and refluxed overnight at 80 ℃, cooled to room temperature after completion of the reaction, filtered through celite, saturated NaHCO ₃ Quenching (100 mL), extracting with EA (100 mL. Times.3), concentrating the combined organic phases, and purifying by ISCO column chromatography (PE/EA 0-100%) to obtain 1.6g of 4- ([ 1,4' -bipiperidine) ]-1' -yl) -2-iodoaniline. MS m/z (ESI): 386[ M+H ]]+。

Step 3 Synthesis of (5- ([ 1,4 '-dipiperidine ] -1' -yl) -2-aminophenyl) dimethylphosphine oxide

Compound 4- ([ 1,4' -dipiperidine)]-1' -yl) -2-iodoaniline (1.6 g,4.16 mmol) and dimethylphosphino-oxyhydrogen (393.3 mg,5.04 mmol) were dissolved in DMF (40 mL) and P was weighed out separatelyd(OAC) ₂ (92.3mg,0.42mol)、K ₃ PO ₄ (1.1 g,5.04 mmol) and Xantphos (243.0 mg,0.42 mmol) were added to the reaction system, nitrogen protection was replaced, the reaction was slowly warmed to 125 ℃ and stirred under reflux for 6h, monitored by tlc, quenched with water after completion of the reaction, suction filtered through celite, extracted with EA (20 ml x 2), combined organic phases, washed with saturated brine (30 ml x 2), distilled under reduced pressure, purified by ISCO column chromatography (0-100% EA/PE) to give (5- ([ 1,4' -dipiperidine)]760.3mg of (1' -yl) -2-aminophenyl) dimethylphosphine oxide, MS m/z (ESI) 336[ M+H ]] ⁺ 。

Step 4 Synthesis of (5- ([ 1,4 '-dipiperidin ] -1' -yl) -2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

2, 4-dichloropyrimidine-5-trifluoromethyl (600 mg,1.79 mmol) was dissolved in DMA (10 mL), (2-amino-5-morpholinophenyl) dimethylphosphine oxide (353.0 g,1.62 mmol) was added, DIPEA (0.3 mL,1.79 mmol) was slowly added under ice bath conditions, and the reaction was allowed to proceed to 60℃for 1h, and completion of the reaction was monitored. Quenched with water, extracted with dichloromethane (20 mL. Times.2), dried and concentrated, and purified by column chromatography (0-100% EA/PE) to give 0.32g (5- ([ 1,4' -bipiperidine) ]-1' -yl) -2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide, MS m/z (ESI): 516[ M+H ]] ⁺ 。

Step 5 Synthesis of 4- ((4- ((4- ([ 1,4 '-bipyridyl ] -1' -yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid

Will (5- ([ 1,4' -dipiperidine)]-1' -yl) -2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (100 mg,0.19 mmol) and p-amino-3-methoxybenzoic acid (34.1 mg,0.20 mmol) were dissolved in isopropanol (6 mL), 4N 1, 4-dioxane solution of hydrochloric acid (0.1 mL,0.4 mmol) was added, the reaction was allowed to proceed for 8h at 65℃and completion of the reaction was monitored by TLC. The system was suction filtered to give 80.3mg of 4- ((4- ((4- ([ 1,4' -bipyridine)]-1' -yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid, MS m/z (ESI): 647[ M+H ]] ⁺ 。

Step 4 Synthesis of 4- ((4- ((4- ([ 1,4 '-bipyridyl ] -1' -yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) -4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid (80.3 mg,0.12 mmol), O-methylhydroxylamine hydrochloride (31.1 mg,0.36 mmol), HATU (91.3 mg,0.24 mmol), DMAP (1.01 mg,0.01 mmol) and DIPEA (0.12 mL,0.72 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after which the LCMS monitors the reaction for completion, quenched with water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with water, dried and concentrated, and column chromatographed purified/MeOH (0-10%) to give 23.5mg of 4- ((4- ([ 1,4' -bipyridine) ]-1' -yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ12.02(s,1H),10.18(s,1H),8.43(s,1H),8.37(s,1H),7.85–7.76(m,2H),7.50(s,1H),7.29(d,J＝7.4Hz,1H),7.10(dd,J＝10.7,7.2Hz,2H),3.97–3.83(m,6H),3.71(s,3H),2.71(dd,J＝23.9,12.1Hz,3H),2.22–2.10(m,3H),1.77(d,J＝10.8Hz,6H),1.69(s,4H),1.66(s,4H),1.29(s,2H),0.90(t,J＝7.4Hz,1H),0.84(d,J＝7.0Hz,2H).MS m/z(ESI)：676[M+H] ⁺ 。

Example 11

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxy-N- (methylsulfonyl) benzamide (11)

Step 1, synthesizing 3-methoxy-4-nitrobenzamide

4-nitro-3-methoxybenzoic acid (1 g,5.1 mmol), oxalyl chloride (0.47 mL,5.6 mmol) and 2 drops of DMF were added to DCM (20 mL) at 0deg.C, then reacted for 0.5h at room temperature, ammonia (2 mL,20 mmol) was added after TLC monitoring reaction was complete, reaction 1h after LCMS monitoring reaction was complete, quenched with water (20 mL), extracted with DCM (20 mL. Times.3), the organic phase was washed with water, dried and concentrated, column chromatography gave 400mg of 3-methoxy-4-nitrobenzamide, MS m/z (ESI): 197[ M+H ]] ⁺ .

Step 2, synthesizing 3-methoxy-N- (methylsulfonyl) -4-nitrobenzamide

3-methoxy-4-nitrobenzamide (200 mg,1 mmol) and sodium hydride (160 mg,4 mmol) were added to THF (15 mL) and reacted at room temperature for 0.5h, after which methanesulfonyl chloride (0.3 mL,4 mmol) was added and reacted for 7h, after completion of lcms monitoring reaction, the reaction was quenched with water (15 mL), extracted with EA (20 mL x 3), the organic phase was washed with water, dried and concentrated, and column chromatographed to give 220mg of 3-methoxy-N- (methanesulfonyl) -4-nitrobenzamide, MS m/z (ESI): 275[ M+H ] ] ⁺ 。

Step 3 Synthesis of 4-amino-3-methoxy-N- (methylsulfonyl) benzamide

3-methoxy-N- (methylsulfonyl) -4-nitrobenzamide (220 mg,0.8 mmol) was dissolved in methanol (25 mL), pd/C (45 mg) was added thereto and 3 drops of concentrated hydrochloric acid were added dropwise thereto, the reaction mixture was reacted overnight at room temperature under a hydrogen atmosphere, and after completion of the reaction, the filtrate was filtered and dried by spin-drying to give 120mg of 4-amino-3-methoxy-N- (methylsulfonyl) benzamide. MS m/z (ESI): 245[ M+H ]] ⁺ 。

Step 4 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxy-N- (methylsulfonyl) benzamide

(2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (43 mg,0.12 mmol), 4-amino-3-methoxy-N- (methylsulfonyl) benzamide (30 mg,0.12 mmol) and 4M 1, 4-dioxane hydrochloride solution (0.18 mL,0.72 mmol) were added to isopropanol (10 mL) and then reacted at 70℃for 4h after LCMS monitoring the reaction completion, cooled to room temperature, the reaction system was suction filtered and the solid obtained by suction filtration was washed with isopropanol (5 mL of 3) and then dried at 50℃for 1h to give 23mg 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxy-N- (methylsulfonyl) benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.65(s,1H),8.44(d,J＝22.8Hz,2H),8.15(s,1H),7.76(s,1H),7.66–7.60(m,1H),7.58(d,J＝1.8Hz,1H),7.44(t,J＝10.0Hz,2H),7.24(s,1H),3.83(s,3H),2.84(s,3H),1.72(d,J＝13.6Hz,6H).MS m/z(ESI)：558[M+H] ⁺ .

Example 12

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxybenzamide (12)

Step 1: synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxybenzamide

4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (50 mg,0.11 mmol), ethoxyamine hydrochloride (32.2 mg,0.33 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (65 mg,0.17 mmol), 4-dimethylaminopyridine (2 mg,0.01 mmol) and N, N-diisopropylethylamine (0.12 mL,0.67 mmol) were added to DMF (2 mL) and then reacted at room temperature for 16h, after completion of the LCMS monitoring reaction the reaction was quenched with water (10 mL), EA (20 mL. Times.3) was extracted, the organic phase was washed with water, dried and concentrated, and the column chromatographed to purify MeOH/DCM (0-10%) to 40mg 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxybenzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.47(s,1H),10.53(s,1H),10.07(s,1H),8.49(d,J＝0.9Hz,1H),8.15(s,1H),7.75–7.54(m,6H),7.33(t,J＝7.6Hz,1H),3.91(q,J＝7.0Hz,2H),1.73(d,J＝13.6Hz,6H),1.20(t,J＝7.0Hz,3H).MS m/z(ESI)：494[M+H] ⁺ 。

Example 13

Preparation of N-butoxy-4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (13)

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (50 mg,0.11 mmol), O-butylhydroxylamine hydrochloride (41.4 mg,0.33 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (65 mg,0.17 mmol), 4-dimethylaminopyridine (2 mg,0.01 mmol) and N, N-diisopropylethylamine (0.1) 2mL,0.67 mmol) was added to DMF (2 mL) and then reacted at room temperature for 16h, after LCMS monitoring the reaction completion, the reaction was quenched with water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with water, dried and concentrated, and the MeOH/DCM (0-10%) was purified by column chromatography to give 60mg of N-butoxy-4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.46(s,1H),10.54(s,1H),10.07(s,1H),8.49(s,1H),8.16(s,1H),7.75–7.53(m,6H),7.37–7.26(m,1H),3.87(t,J＝6.5Hz,2H),1.73(d,J＝13.6Hz,6H),1.58(dq,J＝8.1,6.6Hz,2H),1.46–1.36(m,2H),0.92(t,J＝7.3Hz,3H).MS m/z(ESI)：522[M+H] ⁺ .

Example 14

Preparation of N- (allyloxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (14)

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (50 mg,0.11 mmol), O-allylhydroxylamine hydrochloride (36.2 mg,0.33 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (65 mg,0.17 mmol), 4-dimethylaminopyridine (2 mg,0.01 mmol) and N, N-diisopropylethylamine (0.12 mL,0.67 mmol) were added to DMF (2 mL) and then after completion of the reaction by monitoring the LCMS reaction with water (10 mL), the reaction was quenched with EA (20 mL. Times.3) and the organic phase was washed with water, dried and concentrated, and column chromatography purification/MeOH (0-10%) gave 40mg of N- (allyloxy) -4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.52(s,1H),10.57(s,1H),10.08(s,1H),8.49(d,J＝0.9Hz,1H),8.16(s,1H),7.73–7.55(m,6H),7.32(t,J＝7.7Hz,1H),6.00(ddt,J＝17.4,10.4,6.0Hz,1H),5.35(dq,J＝17.3,1.6Hz,1H),5.26(ddt,J＝10.4,2.0,1.2Hz,1H),4.40(dt,J＝6.0,1.3Hz,2H),1.73(d,J＝13.6Hz,6H).MS m/z(ESI)：506[M+H] ⁺ .

Example 15

Preparation of N- (propargyloxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (15)

4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (50 mg,0.11 mmol), O-propargyl hydroxylamine hydrochloride (35.5 mg,0.33 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (65 mg,0.17 mmol), 4-dimethylaminopyridine (2 mg,0.01 mmol) and N, N-diisopropylethylamine (0.12 mL,0.67 mmol) were added to DMF (2 mL) and then after completion of the reaction by monitoring the reaction with water (10 mL), the reaction was quenched with EA (20 mL. Times.3) and the organic phase was washed with water, dried and concentrated to give 40mg of N- (propargyloxy) -4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.74(s,1H),10.56(s,1H),10.09(s,1H),8.49(d,J＝0.9Hz,1H),8.16(s,1H),7.72–7.57(m,6H),7.33(t,J＝7.4Hz,1H),4.58(d,J＝2.4Hz,2H),3.60(t,J＝2.4Hz,1H),1.73(d,J＝13.6Hz,6H).MS m/z(ESI)：504[M+H] ⁺ .

Example 16

Preparation of N- (benzyloxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (16)

Step 1 Synthesis of N- (benzyloxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (120.2 mg,0.27 mmol), O-benzylhydroxylamine hydrochloride (127.7 mg,0.81 mmol), HATU (6201.5 mg,0.53 mmol), DMAP (3.3 mg, 0.027 mmol) and DIPEA (0.28 mL,1.62 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after completion of LCMS monitoring the reaction, quenched with water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with water, dried and concentrated, and the MeOH/DCM (0-10%) was purified by column chromatography to give 60.5mg of N- (benzyloxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.62(s,1H),10.57(s,1H),10.09(s,1H),8.49(s,1H),8.16(s,1H),7.73–7.54(m,6H),7.46(dd,J＝7.9,1.5Hz,2H),7.43–7.29(m,5H),4.91(s,2H),1.75(s,3H),1.72(s,3H).MS m/z(ESI)：556[M+H] ⁺ 。

Example 17

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-hydroxybenzoamide (17)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-hydroxybenzoamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-hydroxybenzoamide (30.3 mg,0.054 mmol) was dissolved in MeOH (10 mL), 10% Pd/C (10 mg) was added at H ₂ After completion of LCMS monitoring reaction, celite filtration and distillation under reduced pressure gave 15.6 mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-hydroxybenzoamide. ¹ H NMR(400 MHz,DMSO-d ₆ ):δ11.07(s,1H),10.56(s,1H),10.05(s,1H),8.91(s,1H),8.48(s,1H),8.15(d,J＝13.0 Hz,1H),7.65(dt,J＝17.3,9.0 Hz,7H),7.32(t,J＝7.2 Hz,1H),1.75(s,3H),1.72(s,3H).MS m/z(ESI)：466[M+H] ⁺ 。

Example 18

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy benzamide (18)

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (50 mg,0.11 mmol), O-isobutoxy amine hydrochloride (41.4 mg,0.33 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (65 mg,0.17 mmol), 4-dimethylaminopyridine (2 mg,0.01 mmol) and N, N-diisopropylethylamine (0.12 mL,0.67 mmol) were added to DMF (2 mL) and then reacted at room temperature for 16 h after completion of LCMS monitoring the reaction, the reaction was quenched with water (10 mL), extracted with EA (20 mL X3), the organic phase was washed with water, dried and concentrated, and the column chromatographed to purify MeOH/DCM (0-10%) to give 50 mg of 4- ((2- (dimethylphosphoryl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy benzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.47(s,1H),10.57(s,1H),10.07(s,1H),8.49(s,1H),8.16(s,1H),7.75–7.53(m,6H),7.32(t,J＝7.4 Hz,1H),3.65(d,J＝6.6 Hz,2H),1.73(d,J＝13.6Hz,6H),0.94(d,J＝6.7 Hz,6H).MS m/z(ESI)：522[M+H] ⁺ .

Example 19

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- (2-hydroxyethoxy) benzamide (19)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- (2-hydroxyethoxy) benzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60.0 mg,0.13 mmol), 2- (aminooxy) ethane-1-ol hydrochloride (30.8 mg,0.40 mmo), HATU (102.7 mg,0.27 mmol), DMAP (1.01 mg,0.013 mmol) and DIPEA (0.14 mL,0.79 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h, lcms monitored the reaction complete, quenched with water (10 mL), extracted with EA (20 ml x 3) with The organic phase was washed with water, dried and concentrated, and the MeOH/DCM (0-10%) was purified by column chromatography to give 23.1 mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- (2-hydroxyethoxy) benzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.62(s,1H),10.57(s,1H),10.10(s,1H),8.49(s,1H),8.16(s,1H),7.68(t,J＝8.9 Hz,1H),7.62(t,J＝7.8 Hz,1H),7.33(t,J＝7.3 Hz,1H),4.80(t,J＝5.8 Hz,1H),3.91(t,J＝4.9 Hz,1H),3.60(dd,J＝10.2,5.4Hz,1H),1.75(s,1H),1.71(s,1H).MS m/z(ESI)：510[M+H] ⁺ 。

Example 20

Preparation of benzyl 4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate

Step 1, synthesizing 4-nitrobenzoic acid benzyl ester

4-Nitrophenyl benzoic acid (2 g,12 mmol) and benzyl bromide (2.05 g,12 mmol) were dissolved in acetonitrile (100 mL), potassium carbonate (2 g,14.4 mmol) was added, the temperature was raised to 60℃and the reaction was stirred for 5h. After TLC monitoring the end of the reaction, water quenching, EA (50 mL. Times.2) extraction, combining the organic phases, washing with saturated brine (50 mL. Times.2), distillation under reduced pressure, column chromatography purification (PE=1) gave 3g of benzyl 4-nitrobenzoate, MS m/z (ESI): 258[ M+H)] ⁺ 。

Step 2, synthesizing 4-benzyl aminobenzoate

Benzyl 4-nitrobenzoate (3 g,12 mmol) was dissolved in methanol/water 4:1 (50 mL), then iron powder (1.68 g,30 mmol) and ammonium chloride (1.6 g,30 mmol) were added and the reaction system was slowly warmed at 80℃under reflux overnight, cooled to room temperature after completion of the reaction, filtered through celite, quenched with saturated sodium bicarbonate solution (100 mL), extracted with EA (100 mL. Times.3), concentrated in vacuo, and purified by column chromatography (PE: EA=4:1) to give 2.1g of benzyl 4-aminobenzoate. MS m/z (ESI): 228[ M+H ] +.

Step 3 Synthesis of benzyl 4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate

2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.63 g,7.5 mmol) was dissolved in N, N-di-To methylacetamide (15 mL) was added benzyl 4-aminobenzoate (1.7 g,7.5 mmol) and N, N-diisopropylethylamine (1.5 mL,8.25 mmol), and the reaction was allowed to proceed to 60℃for 6 hours, followed by monitoring the completion of the reaction. The reaction solution was poured into saturated brine (40 mL), filtered, and the residue was dissolved in methanol (20 mL), filtered, and washed with methanol (2X 3 mL), and the residue was the target product, to give 1.53g of benzyl 4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate, MS m/z (ESI): 408[ M+H)] ⁺ 。

Preparation of (R) -4- ((4- ((4- (3- (dimethylamino) pyrrolidin-1-yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide (20)

Step 1, synthesizing (R) -N, N-dimethyl pyrrolidine-3-amine hydrochloride

Tert-butyl (R) -3- (dimethylamino) pyrrolidine-1-carboxylate (1.3 g,6.1 mmol) was dissolved in dichloromethane (20 mL), and a solution of 4N hydrochloric acid in 1, 4-dioxane (4.5 mL,18.3 mmol) was added and the reaction stirred at ambient temperature for 3h. After the completion of the TLC monitoring reaction, the reaction was distilled under reduced pressure to give 912mg of (R) -N, N-dimethylpyrrolidin-3-amine hydrochloride.

Step 2 Synthesis of (R) -1- (3-iodo-4-nitrophenyl) -N, N-dimethylpyrrolidin-3-amine

(R) -N, N-dimethylpyrrolidin-3-amine hydrochloride (912 mg,6.1 mmol) and 4-fluoro-2-iodo-1-nitrobenzene (1.63 g,6.1 mmol) were dissolved in N, N-dimethylformamide (15 mL), potassium carbonate (2.53 g,18.3 mmol) was added, and the temperature was slowly raised to 100℃and the reaction was stirred for 6h. After TLC monitoring the end of the reaction, quench with water, extract with EA (50 mL. Times.2), combine the organic phases, wash with saturated brine (30 mL. Times.2), distill under reduced pressure, purify by column chromatography (EA=1) to give (R) -1- (3-iodo-4-nitrophenyl) -N, N-dimethylpyrrolidin-3-amine 1.4g, MS m/z (ESI): 362[ M+H)] ⁺ 。

Step 3 Synthesis of (R) -1- (4-amino-3-iodophenyl) -N, N-dimethylpyrrolidin-3-amine

(R) -1- (3-iodo-4-nitrophenyl) -N, N-dimethylpyrroleThe alkyl-3-amine (1.4 g,3.88 mmol) was dissolved in methanol/water 4:1 (50 mL), then iron powder (0.54 g) and ammonium chloride (0.52 g) were added, the reaction system was slowly warmed and refluxed overnight at 80℃and cooled to room temperature after completion of the reaction, celite was filtered, saturated sodium bicarbonate solution (100 mL) quenched, EA (100 mL. Times.3) extracted, the organic phases were combined for rotary concentration, and purified by column chromatography (PE/EA 0-80%) to give 1.25g of (R) -1- (4-amino-3-iodophenyl) -N, N-dimethylpyrrolidin-3-amine. MS m/z (ESI): 332[ M+H ] ] ⁺ 。

Step 4 Synthesis of (R) - (2-amino-5- (3- (dimethylamino) pyrrolidin-1-yl) phenyl) dimethylphosphine oxide

(R) -1- (4-amino-3-iodophenyl) -N, N-dimethylpyrrolidin-3-amine (1.25 g,3.78 mmol) and dimethylphosphine oxide (0.35 g,4.54 mmol) were dissolved in N, N-dimethylformamide solution (10 mL), palladium acetate (85 mg,0.38 mmol), potassium phosphate (0.96 g,4.54 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.22 g,0.38 mmol) were weighed respectively, added to the reaction system, nitrogen protection was replaced, the reaction was slowly warmed to 120℃under reflux stirring for 6h, TLC was monitored, after completion of the reaction, quenched with water, filtered through celite, DCM (30 mL. Times.2) was extracted, the organic phase was combined, saturated brine was washed (10 mL. Times.2), distilled under reduced pressure, and column chromatography was purified to give (R) - (2-amino-5- (3- (dimethylamino) pyrrolidin-1-yl) phenyl) dimethylphosphine oxide 0.4g, m/z (ESM 282H: 282)] ⁺ 。

Step 5 Synthesis of benzyl (R) -4- ((4- ((4- (3- (dimethylamino) pyrrolidin-1-yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate

Benzyl 4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate (147 mg,0.36 mmol) was dissolved in N, N-dimethylformamide (5 mL), and (R) - (2-amino-5- (3- (dimethylamino) pyrrolidin-1-yl) phenyl) dimethylphosphine oxide (110 mg,0.39 mmol) was added, p-toluenesulfonic acid (13.5 mg,0.07 mmol) was added and the reaction was allowed to proceed to 120℃for 2h, followed by monitoring the completion of the reaction. Quenched with water, extracted with dichloromethane (20 mL. Times.2), dried and concentrated, and column chromatographed to give 120mg of benzyl (R) -4- ((4- (3- (dimethylamino) pyrrolidin-1-yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate, MS m/z (ESI): 653.2[M+H] ⁺ 。

Step 6 Synthesis of (R) -4- ((4- ((4- (3- (dimethylamino) pyrrolidin-1-yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid

Benzyl (R) -4- ((4- ((4- (3- (dimethylamino) pyrrolidin-1-yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate (120 mg,0.18 mmol) was dissolved in methanol (25 mL) and palladium hydroxide on carbon (240 mg) was added at H ₂ The reaction was allowed to proceed for 2h in atmosphere and monitored by tlc for completion. The system was suction filtered and the filtrate was distilled under reduced pressure to give 70mg of (R) -4- ((4- ((4- (3- (dimethylamino) pyrrolidin-1-yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 563.2[ M+H ]] ⁺ 。

Step 7 Synthesis of (R) -4- ((4- ((4- (3- (dimethylamino) pyrrolidin-1-yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide

(R) -4- ((4- (3- (dimethylamino) pyrrolidin-1-yl) -2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (70 mg,0.125 mmol), methoxyamine hydrochloride (31.3 mg,0.375 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (71.5 mg,0.188 mmol) and N, N-diisopropylethylamine (0.15 mL,0.75 mmol) were added to N, N-dimethylformamide (5 mL), then after reaction at room temperature for 15h, reaction was quenched with water (10 mL), EA (20 mL. Times.3) was extracted, the organic phase was washed with water, dried and concentrated, and column chromatography purified/DCM (0-10%) to give 20mg (R) -4- ((4- (3- (dimethylamino) pyrrolidin-1-yl) -2- (dimethylphosphoryl) phenyl) amino) -5-methoxy) -benzamide. MS m/z (ESI): 592.2[ M+H ] ] ⁺ .

Example 21

Preparation of 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-3-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide (21)

Step 1, synthesizing (2-amino-5-bromophenyl) dimethylphosphine oxide

The compound 4-bromo-2-iodoaniline (6.0 g,20.1 mmol) and dimethylphosphino-oxyhydrogen (1.89 g,24.2 mmol) were dissolved in DMF (40 mL) and Pd (OAC) was weighed out separately ₂ (425.1mg,2.01mol)、K ₃ PO ₄ (5.09 g,24.2 mmol) and Xantphos (1.16 g,2.01 mol) are added into a reaction system, nitrogen protection is replaced, the temperature is slowly increased to 125 ℃ and reflux stirring is carried out for 6 hours, TLC monitoring reaction is carried out, after the reaction is completed, water quenching is added, diatomite is used for suction filtration, EA (20 mL. Times.2) extraction, organic phases are combined, saturated saline solution is washed (30 mL. Times.2), reduced pressure distillation and ISCO column chromatography purification are carried out, thus obtaining 3.2g of (2-amino-5-bromophenyl) dimethylphosphine oxide, MS m/z (ESI) 249[ M+H)] ⁺ 。

Step 2 Synthesis of (2-amino-5- (pyridin-3-yl) phenyl) dimethylphosphine oxide

The compound (2-amino-5-bromophenyl) dimethylphosphine oxide (1.0 g,4.0 mmol)) and 3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (909.1 g,4.4 mmol) were dissolved in DMA/H ₂ O (5:1) solution (40 mL), pd (dppf) Cl was weighed separately ₂ (329.9 mg,0.4 mol) and Na ₂ (CO ₃ ) ₂ (1.28 g,12.1 mmol) is added into the reaction system, nitrogen protection is replaced, the temperature is slowly increased to 80 ℃ and reflux stirring is carried out for 6h, TLC monitoring reaction is carried out, after the reaction is completed, water quenching is carried out, EA (20 mL. Times.2) is added for extraction, the organic phases are combined, saturated saline water is used for washing (30 mL. Times.2), reduced pressure distillation and ISCO column chromatography purification (0-100% EA/PE) are carried out, thus obtaining (2-amino-5- (pyridin-3-yl) phenyl) dimethylphosphine oxide 0.31g, MS m/z (ESI) 249[ M+H) ] ⁺ 。

Step 3 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-3-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminobenzyl ester

Compound (2-amino-5- (pyridin-3-yl) phenyl) dimethylphosphine oxide (63.7 mg,0.26 mmol) and benzyl 4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate (100.1 mg,0.25 mmol) were dissolved in 1, 4-dioxane (10 mL)), tsOH (23.0 mg,0.05 mmol) was added, nitrogen protection was replaced, reaction was slowly warmed to 125℃for 18h, TLC monitored for anti-reflectionAfter completion of the reaction, quenched with water, extracted with EA (20 ml x 2), combined organic phases washed with saturated brine (30 ml x 2), distilled under reduced pressure, purified by ISCO column chromatography (0-100% EA/PE) to afford 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-3-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminobenzyl ester 87.0mg, ms m/z (ESI): 618[ m+h] ⁺ 。

Step 4 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-3-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid

4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-3-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminobenzyl ester (87.0 mg, 0.14) was dissolved in methanol (6 mL) and PdOH/C (200 mg), H was added ₂ Substitution, at H ₂ The reaction was allowed to react overnight under an atmosphere, and TLC monitored the reaction was complete. The system was suction filtered to give 56.4mg of 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-3-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 528[ M+H ]] ⁺ 。

Step 5 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-3-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-3-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (56.3 mg,0.11 mmol), O-methylhydroxylamine hydrochloride (26.6 mg,0.32 mmol), HATU (83.7 mg,0.22 mmol), DMAP (1.01 mg,0.01 mmol) and DIPEA (0.12 mL,0.66 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h, lcms monitored the reaction was complete, quenched with water (10 mL) and EA (20 mL x 3) was extracted, the organic phase was washed with water, dried and concentrated, and column chromatographically purified MeOH/DCM (0-10%) to give 12mg 4- ((2- (dimethylphosphoryl) -4- (pyridin-3-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide. MS m/z (ESI): 557[ M+H ]] ⁺ 。

Example 22

Preparation of (2-amino-5- (4, 5-tetramethyl-1, 3-dioxo-2-borolan-2-yl) phenyl) dimethylphosphine oxide

Step 1 (2-amino-5-bromophenyl) dimethylphosphine oxide

4-bromo-2-iodoaniline (10 g,33.6 mmol) and dimethylphosphine oxide (3.15 g,40.3 mmol) were dissolved in N, N-dimethylformamide solution (80 mL), palladium acetate (0.76 g,3.4 mmol), potassium phosphate (8.55 g,40.3 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene oxide (1.97 g,3.4 mmol) were weighed respectively, nitrogen protection was replaced, the reaction was stirred under reflux slowly rising to 120℃for 4h with stirring, TLC was monitored, after completion of the reaction, quenched with water, filtered through celite, DCM (200 mL. Times.2) was extracted, the organic phase was combined, saturated brine was washed (50 mL. Times.2), distilled under reduced pressure, column chromatography was purified to give (2-amino-5-bromophenyl) dimethylphosphine oxide 6.5g, MS m/z (ESI): 248[ M+H ]] ⁺ 。

Step 2 (2-amino-5- (4, 5-tetramethyl-1, 3-dioxo-2-borolan-2-yl) phenyl) dimethylphosphine oxide

(2-amino-5-bromophenyl) dimethylphosphine oxide (2 g,8.1 mmol) and pinacol biboronate (4.1 g,16.2 mmol) were dissolved in 1, 4-dioxane solution (30 mL) and [1,1' -bis (diphenylphosphine) ferrocene was weighed out separately]Palladium dichloride dichloromethane complex (0.66 g,0.81 mmol) and potassium acetate (2.4 g,24.3 mmol) are added into a reaction system, nitrogen protection is replaced, the temperature is slowly raised to 100 ℃ and reflux stirring is carried out for 3h, TLC monitoring reaction is carried out, after the reaction is completed, water quenching is added, diatomite is used for suction filtration, DCM (30 mL multiplied by 2) is used for extraction, an organic phase is combined, saturated saline solution is washed (10 mL multiplied by 2), reduced pressure distillation is carried out, and MeOH/DCM (0-10%) is purified by column chromatography, thus obtaining (2-amino-5- (4, 5-tetramethyl-1, 3-dioxo-2-borolan-2-yl) phenyl) dimethylphosphine oxide 1.65g, MS m/z (ESI): 296[ M+H ] ] ⁺ 。

Preparation of 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-2-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide (22)

Step 1 Synthesis of (2-amino-5- (pyridin-2-yl) phenyl) dimethylphosphine oxide

A mixed solution of (2-amino-5- (4, 5-tetramethyl-1, 3-dioxo-2-borolan-2-yl) phenyl) dimethylphosphine oxide (0.5 g,1.7 mmol) and 2-bromopyridine (0.32 g,2.04 mmol) in 1, 4-dioxane (50 mL) and water (5 mL) was dissolved, and [1,1' -bis (diphenylphosphine) ferrocene was weighed out separately]Palladium dichloride dichloromethane complex (0.14 g,0.17 mmol) and cesium carbonate (1.4 g,4.25 mmol) are added into a reaction system, nitrogen protection is replaced, the temperature is slowly raised to 120 ℃ and reflux stirring is carried out for 6h, TLC monitoring reaction is carried out, after the reaction is completed, water quenching is added, diatomite is used for suction filtration, DCM (50 mL multiplied by 2) is used for extraction, organic phases are combined, saturated saline solution is used for washing (10 mL multiplied by 2), reduced pressure distillation and column chromatography purification are carried out, thus obtaining (2-amino-5- (pyridine-2-yl) phenyl) dimethylphosphine oxide 0.37g, MS m/z (ESI) 247[ M+H ]] ⁺ 。

Step 2 Synthesis of benzyl 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-2-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate

(2-amino-5- (pyridin-2-yl) phenyl) dimethylphosphine oxide (185 mg,0.75 mmol) was dissolved in 1, 4-dioxane (10 mL), benzyl 4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate (306 mg,0.75 mmol) was added, p-toluenesulfonic acid (143 mg,0.75 mmol) was added, and the reaction was allowed to proceed to 120℃for 20h, followed by monitoring the end of the reaction. Quenched with water, extracted with dichloromethane (20 mL. Times.2), dried and concentrated, and column chromatographed to give 200mg of benzyl 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-2-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate, MS m/z (ESI): 618[ M+H) ] ⁺ 。

Step 3 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-2-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid

Benzyl 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-2-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate (200 mg,0.324 mmol) was dissolved in methanol (30 mL) and palladium hydroxide on carbon (200 mg) was added to the mixture at H ₂ The reaction was carried out in an atmosphere for 5h, and tlc monitored the reaction was complete. Suction filtration of the system and distillation of the filtrate under reduced pressure gave 170mg of 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-2-yl) phenyl) amino)) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 528[ M+H ]] ⁺ 。

Step 4 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-2-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide

4- ((4- ((2- (dimethylphosphoryl) -4- (pyridin-2-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (170 mg,0.324 mmol), methoxyamine hydrochloride (83 mg,1 mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (190 mg,0.5 mmol) and N, N-diisopropylethylamine (0.4 mL,2 mmol) were added to N, N-dimethylformamide (5 mL) and then reacted at room temperature for 15h, after completion of LCMS monitoring the reaction, the reaction was quenched with water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with water, dried and concentrated, and column chromatography purified with MeOH/DCM (0-10%) to give 70mg of 4- ((2- (dimethylphosphoryl) -4- (pyridin-2-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.56(s,1H),10.89(s,1H),10.11(s,1H),8.71(ddd,J＝4.8,1.8,0.9Hz,1H),8.53(s,1H),8.38(s,1H),8.30(s,1H),8.27(dd,J＝7.6,2.2Hz,1H),8.10(dd,J＝8.0,1.1Hz,1H),7.93(td,J＝7.7,1.9Hz,1H),7.75(d,J＝8.4Hz,2H),7.61(d,J＝8.3Hz,2H),7.39(ddd,J＝7.4,4.8,1.1Hz,1H),3.67(s,3H),1.84(d,J＝13.6Hz,6H).MS m/z(ESI)：557[M+H] ⁺ .

Example 23

Preparation of 4- ((4- ((2- (dimethylphosphoryl) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide (23)

Step 1, synthesizing (2-amino-5-bromophenyl) dimethylphosphine oxide

The compound 4-bromo-2-iodoaniline (6.0 g,20.1 mmol) and dimethylphosphino-oxyhydrogen (1.89 g,24.2 mmol) were dissolved in DMF (40 mL) and Pd (OAC) was weighed out separately ₂ (425.1mg,2.01mol)、K ₃ PO ₄ (5.09 g,24.2 mmol) and Xantphos ]1.16g,2.01 mol) is added into a reaction system, nitrogen protection is replaced, the temperature is slowly increased to 125 ℃ and reflux stirring is carried out for 6h, TLC monitoring reaction is carried out, after the reaction is finished, water quenching is added, diatomite is used for suction filtration, EA (20 mL x 2) is used for extraction, organic phases are combined, saturated saline solution is used for washing (30 mL x 2), reduced pressure distillation and ISCO column chromatography purification (0-100% EA/PE) are carried out, and 3.2g of (2-amino-5-bromophenyl) dimethylphosphine oxide is obtained, MS m/z (ESI) is obtained, wherein 249[ M+H)] ⁺ 。

Step 2 Synthesis of (2-amino-5- (1-methyl-1H-pyrazol-4-yl) phenyl) dimethylphosphine oxide

The compound (2-amino-5-bromophenyl) dimethylphosphine oxide (1.0 g,4.0 mmol) and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (921.8 g,4.4 mmol) were dissolved in DMA/H ₂ O (5:1) solution (40 mL), pd (dppf) Cl was weighed separately ₂ (329.9 mg,0.4 mol) and Na ₂ (CO ₃ ) ₂ (1.3 g,12.1 mmol) was added to the reaction system, nitrogen protection was replaced, the reaction was carried out under reflux and stirring at a slow temperature of 80℃for 2H, TLC was monitored, after the completion of the reaction, water quenching was added, EA (20 mL. Times.2) was extracted, the organic phases were combined, washed with saturated saline (30 mL. Times.2), distilled under reduced pressure, ISCO column chromatography was used to purify (0-100% EA/PE) to give 0.3g of (2-amino-5- (1-methyl-1H-pyrazol-4-yl) phenyl) dimethylphosphine oxide, MS m/z (ESI): 250[ M+H ]] ⁺ 。

Step 3 Synthesis of benzyl 4- ((4- ((2- (dimethylphosphoryl) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminobenzoate

The compound (2-amino-5- (1-methyl-1H-pyrazol-4-yl) phenyl) dimethylphosphine oxide (113.1 mg,0.45 mmol) and benzyl 4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate (167.2 g,0.41 mmol) were dissolved in 1, 4-dioxane solution (10 mL), tsOH (38.9 mg,0.21 mmol) was added, nitrogen protection was replaced, the reaction was slowly warmed to 125℃for 18H, TLC was monitored, after completion of the reaction, quenched with water, EA (20 mL. Times.2) was extracted, the combined organic phases were washed with saturated brine (30 mL. Times.2), distilled under reduced pressure, ISCO column chromatography was performed to give benzyl 4- ((2- (dimethylphosphoryl) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) -5- (trifluoromethyl) pyrimidin-2-yl) aminobenzoate (101 mg, ESm/z (408M): 1.408H: ( ] ⁺ 。

Step 4 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminobenzoic acid

Benzyl 4- ((4- ((2- (dimethylphosphoryl) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminobenzoate (102.1 mg,0.16 mmol) was dissolved in methanol (10 mL), pdOH/C (200 mg), H was added ₂ Substitution, at H ₂ The reaction was allowed to react overnight under an atmosphere, and TLC monitored the reaction was complete. The system was suction filtered to give 32.1mg of 4- ((4- ((2- (dimethylphosphoryl) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminobenzoic acid, MS m/z (ESI): 531[ M+H)] ⁺ 。

Step 5 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminobenzoic acid (25.1 mg,0.047 mmol), O-methylhydroxylamine hydrochloride (11.7 mg,0.14 mmol), HATU (35.8 mg,0.094 mmol), DMAP (1.01 mg,0.005 mmol) and DIPEA (48 μl,0.28 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2H after completion of lcms monitoring the reaction, the reaction was quenched with water (10 mL), EA (20 mL 3) was extracted, the organic phase was washed with water, dried and concentrated, and column chromatography was purifying MeOH/DCM (0-10%) to give 15.1mg of 4- ((2- (dimethylphosphoryl) -4- (1-methyl-1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) methoxybenzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.56(s,1H),10.61(s,1H),10.06(s,1H),8.48(s,1H),8.25(s,1H),8.16(s,1H),7.98(s,1H),7.84–7.66(m,2H),7.59(d,J＝8.6Hz,1H),3.89(s,1H),3.68(s,1H),1.80(s,1H),1.76(s,1H)。MS m/z(ESI)：660[M+H] ⁺ 。

Example 24

Preparation of 4- ((4- ((2- (dimethylphosphoryl) -4- (2- (methylamino) pyrimidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide (24)

Step 1 Synthesis of (2-amino-5- (2- (methylamino) pyrimidin-4-yl) phenyl) dimethylphosphine oxide

A mixed solution of (2-amino-5- (4, 5-tetramethyl-1, 3-dioxo-2-borolan-2-yl) phenyl) dimethylphosphine oxide (0.5 g,1.7 mmol) and 4-bromo-N-methylpyrimidin-2-amine (0.32 g,1.7 mmol) in 1, 4-dioxane (50 mL) and water (5 mL) was dissolved, and [1,1' -bis (diphenylphosphine) ferrocene was weighed out separately]Palladium dichloride dichloromethane complex (0.14 g,0.17 mmol) and cesium carbonate (1.4 g,4.25 mmol) are added into a reaction system, nitrogen protection is replaced, the temperature is slowly raised to 120 ℃ and reflux stirring is carried out for 6h, TLC monitoring reaction is carried out, after the reaction is completed, water quenching is added, diatomite suction filtration is carried out, DCM (50 mL multiplied by 2) is used for extraction, organic phases are combined, saturated saline solution is washed (10 mL multiplied by 2), reduced pressure distillation and column chromatography purification are carried out, thus obtaining (2-amino-5- (2- (methylamino) pyrimidin-4-yl) phenyl) dimethylphosphine oxide 0.4g, MS m/z (ESI) 277[ M+H)] ⁺ 。

Step 2 Synthesis of benzyl 4- ((4- ((2- (dimethylphosphoryl) -4- (2- (methylamino) pyrimidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate

(2-amino-5- (2- (methylamino) pyrimidin-4-yl) phenyl) dimethylphosphine oxide (110 mg,0.4 mmol) was dissolved in 1, 4-dioxane (10 mL), benzyl 4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate (148 mg,0.36 mmol) was added, p-toluenesulfonic acid (68 mg,0.36 mmol) was added, and the reaction was allowed to proceed to 120℃for 20h, followed by monitoring the end of the reaction. Quenched with water, extracted with dichloromethane (20 mL. Times.2), dried and concentrated, and column chromatographed to give 140mg of benzyl 4- ((4- ((2- (dimethylphosphoryl) -4- (2- (methylamino) pyrimidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate, MS m/z (ESI): 648[ M+H ]] ⁺ 。

Step 3 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4- (2- (methylamino) pyrimidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid

4- ((4- ((2- (dimethylphosphoryl) -4- (2- (methylamino) pyrimidin-4-yl) phenyl) amino) -5- (trifluoromethyl) azoxystrobin)Benzyl (140 mg,0.216 mmol) of pyridin-2-yl) amino benzoate (140 mg,0.216 mmol) was dissolved in methanol (25 mL) and palladium hydroxide on carbon (140 mg) was added to hydrogen chloride in H ₂ The reaction was carried out in an atmosphere for 5h, and tlc monitored the reaction was complete. Suction filtration of the system and distillation of the filtrate under reduced pressure gave 120mg of 4- ((4- ((2- (dimethylphosphoryl) -4- (2- (methylamino) pyrimidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 558[ M+H ] ] ⁺ 。

Step 4 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4- (2- (methylamino) pyrimidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide

4- ((4- ((2- (dimethylphosphoryl) -4- (2- (methylamino) pyrimidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (120 mg,0.216 mmol), methoxyamine hydrochloride (58 mg,0.7 mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (133 mg,0.35 mmol) and N, N-diisopropylethylamine (0.25 mL,1.4 mmol) were added to N, N-dimethylformamide (3 mL), then after completion of the reaction at room temperature, the reaction was quenched with water (10 mL), the EA (20 mL. Times.3) was extracted, the organic phase was washed with water, dried and concentrated, and column chromatography was purified/MeOH (0-10%) to give 60mg of 4- ((2- (dimethylphosphoryl) -4- (2- (methylamino) pyrimidin-4-yl) phenyl) -5- (trifluoromethyl) amino) -N-methoxy-benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.57(s,1H),11.01(s,1H),10.13(s,1H),8.54(s,1H),8.39(s,1H),8.35(s,1H),8.25(d,J＝14.0Hz,1H),7.75(d,J＝8.2Hz,2H),7.63(d,J＝8.4Hz,2H),7.28(d,J＝5.2Hz,1H),7.14(d,J＝4.9Hz,1H),3.68(s,3H),2.91(s,3H),1.84(d,J＝13.6Hz,6H).MS m/z(ESI)：587[M+H] ⁺ .

Example 25

Preparation of 4- ((4- ((2- (dimethylphosphoryl) -4-fluorophenyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide (25)

Step 1, synthesizing (2-amino-5-fluorophenyl) dimethylphosphine oxide

The compound 4-fluoro-2-iodoaniline (2.0 g,8.43 mmol) and dimethylphosphino-oxyhydrogen (789.9 mg,10.1 mmol) were dissolved in DMF (40 mL) and Pd (OAC) was weighed out separately ₂ (188.6mg,0.84mmol)、K ₃ PO ₄ (2.15 g,10.1 mmol) and Xantphos (486.0 mg,0.84 mol) were added to the reaction system, nitrogen protection was replaced, the reaction was slowly warmed to 125 ℃ and stirred under reflux for 6h, TLC was monitored, after the completion of the reaction, water was added to quench the reaction, the reaction was suction filtered through celite, extracted by EA (20 ml. Times.2), the organic phases were combined, washed with saturated brine (30 ml. Times.2), distilled under reduced pressure, purified by ISCO column chromatography to give (2-amino-5-fluorophenyl) dimethylphosphine oxide 1.2g, ms m/z (ESI): 188[ m+h)] ⁺ 。

Step 2 Synthesis of benzyl 4- ((4- ((2- (dimethylphosphoryl) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminobenzoate

Compound (2-amino-5-fluorophenyl) dimethylphosphine oxide (76.1 mg,0.41 mmol) and benzyl 4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate (150.1 mg,0.37 mmol) were dissolved in DMF solution (10 mL), tsOH (70.3 g,0.37 mmol) was added to replace nitrogen protection, reaction was slowly warmed to 125℃for 18h, TLC monitored, after completion of reaction, water quench was added, EA (20 mL of 2) extraction, the organic phases were combined, washed with saturated saline (30 mL of 2), distilled under reduced pressure, ISCO column chromatography purification was performed to give benzyl 4- ((4- ((2- (2- (dimethylphosphoryl) -4-fluorophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate 150.2mg, MS m/z (ESI): 559 M+H [ ] ⁺ 。

Step 3 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminobenzoic acid

Benzyl 4- ((4- ((2- (2- (dimethylphosphoryl) -4-fluorophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate (150.1 mg,0.27 mmol) was dissolved in methanol (10 mL) and PdOH/C (30 mg), H was added ₂ Substitution, at H ₂ The reaction was allowed to react overnight under an atmosphere, and TLC monitored the reaction was complete. The system was suction filtered to give 98.3mg of 4- ((4- ((2- (2- (dimethylphosphoryl) -4-fluorophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 469[ M+H ]] ⁺ 。

Step 4 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) -4-fluorophenyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide

Compound 4- ((4- ((2- (2- (dimethylphosphoryl) -4-fluorophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60.1 mg,0.13 mmol), O-methylhydroxylamine hydrochloride (32, 2mg,0.39 mmol), HATU (97.3 mg,0.26 mmol), DMAP (1.01 mg,0.013 mmol) and DIPEA (0.13 mL,0.78 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h, lcms monitored the reaction was complete, the reaction was quenched with water (10 mL), EA (20 mL x 3) extracted, the organic phase was washed with water, dried concentrated, and column chromatographed with MeOH/MeOH (0-10%) to give 42.3mg 4- ((2- (dimethylphosphoryl) -4-fluorophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide. ¹ HNMR(400MHz,DMSO-d ₆ )δ11.59(s,1H),10.31(s,1H),10.08(s,1H),8.48(s,1H),8.12(s,1H),7.69–7.51(m,5H),7.48(td,J＝8.6,2.9Hz,1H),3.70(s,3H),1.75(s,3H),1.72(s,3H)。MS m/z(ESI)：498[M+H] ⁺ 。

Example 26

Preparation of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methyl-2, 3-dihydrobenzofuran-4-carboxamide (26)

Step 1, synthesizing 4-bromo-2, 3-dihydro-7-benzofuranamine

The compound 2, 3-dihydro-7-benzofuranamine (5 g,37 mmol) was dissolved in DMF (50 mL) and NBS (7.2 g,41 mmol) was added in portions and the reaction stirred at room temperature overnight. After TLC monitoring the reaction, quench with water, extract with EA (30 mL. Times.2), combine the organic phases, wash with saturated brine (50 mL. Times.2), distill under reduced pressure, purify by ISCO column chromatography (EA/PE 0% -100%) to give 4.4g of pure 4-bromo-2, 3-dihydro-7-benzofuranamine, MSm/z (ESI): 215[ M+H ]] ⁺ 。

Step 2, synthesizing 7-amino-2, 3-dihydro-ethyl ester

The compound 4-bromo-2, 3-dihydro-7-benzofuranamine (4 g,18.9 mmol) in toluene/ethanol (5: 1) Solution (40 mL) was weighed DMAP (9.76 g,80 mmol) and Pd (OAC) separately ₂ (240mg,5mol％)、Co ₂ (CO) ₈ (5.45 g,16 mmol) and Xantphos (1.27 g,10 mol%) are added into the reaction system, nitrogen protection is replaced, the temperature is slowly raised to 105 ℃ and the reflux stirring reaction is carried out overnight, TLC monitoring reaction is carried out, after the reaction is completed, diatomite is used for suction filtration, the filtrate is quenched by adding hydrochloric acid aqueous solution (pH=4), EA (20 mL x 2) is extracted, the organic phases are combined, saturated saline solution is washed (30 mL x 2), reduced pressure distillation and ISCO column chromatography are carried out, thus obtaining 2.00g of pure 7-amino-2, 3-dihydro-ethyl ester, MS m/z (ESI): 208[ M+H) ] ⁺ 。

Step 3 Synthesis of 7-amino-2, 3-dihydro-4-benzofurancarboxylic acid

The compound 7-amino-2, 3-dihydro-ethyl ester (2 g,9.66 mmol) was dissolved in ethanol (20 mL), saturated NaOH solution (30 mL) was added, and the temperature was slowly raised to 60℃and the reaction was stirred for 4h. After TLC monitoring the reaction, water was added to dilute, pH was adjusted to acidity, ethyl acetate (40 mL. 3) was used for extraction, the organic phases were combined, washed with saturated brine (50 mL. 2), distilled under reduced pressure, and purified by ISCO column chromatography to give 7-amino-2, 3-dihydro-4-benzofuran carboxylic acid compound 1.00g, MS m/z (ESI): 178[ M+H)] ⁺ 。

Step 4, synthesizing 7-amino-N-methyl-2, 3-dihydrobenzofuran-4-carboxamide

The compound 7-amino-2, 3-dihydro-4-benzofurancarboxylic acid (1 g,5.58 mmol) was added to a 250mL jar reactor and dissolved in DMF (3 mL) and methylamine hydrochloride (1.5 g,22.32 mmol), DIPEA (4 mL,22.32 mmol) and HATU (2.54 g,6.7 mmol) were weighed respectively into a round bottom flask, warmed to 115℃and stirred overnight. After TLC monitoring the reaction, EA and water are extracted, the organic phase is washed twice with saturated saline solution, the residue after spin-drying is passed through column to obtain 400mg of 7-amino-N-methyl-2, 3-dihydrobenzofuran-4-carboxamide pure product, MS m/z (ESI): 193[ M+H ]] ⁺ 。

Step 5 Synthesis of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methyl-2, 3-dihydrobenzofuran-4-carboxamide

2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (80 mg,0.26 mmol) and 7-amino-N-methyl2, 3-Dihydrobenzofuran-4-carboxamide (63 mg,0.31 mmol) was dissolved in isopropanol (6 mL), a solution of 1, 4-dioxane (65.2. Mu.L) in 4N hydrochloric acid was added, the reaction was continued for 4h at 65℃and completion of the reaction was monitored by TLC. Suction filtration of the system afforded 74mg of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methyl-2, 3-dihydrobenzofuran-4-carboxamide, ¹ H NMR(400MHz,DMSO-d ₆ )δ11.09(s,1H),9.47(s,1H),8.46(s,1H),8.32–8.12(m,2H),7.59(ddd,J＝13.7,7.7,1.4Hz,1H),7.37(t,J＝9.9Hz,2H),7.22(t,J＝7.1Hz,1H),7.13(d,J＝8.4Hz,1H),4.52(t,J＝8.8Hz,3H),3.45(t,J＝8.8Hz,2H),2.77(d,J＝4.3Hz,3H),1.76(s,3H),1.72(s,3H)。MS m/z(ESI):506[M+H] ⁺ 。

example 27

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-3-methoxybenzamide (27)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-3-methoxybenzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid (60.3 mg,0.13 mmol), O-isobutylhydroxylamine hydrochloride (47.1 mg,0.38 mmol), HATU (95.1 mg,0.26 mmol), DMAP (1.01 mg,0.013mmol) and DIPEA (0.13 mL,0.75 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after which the reaction was monitored by lcms to completion, quenched with water (10 mL), extracted with EA (20 ml x 3), the organic phase washed with water, dried and concentrated, and column chromatographed to MeOH/DCM (0-10%) to give 45.3 mg 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-3-methoxybenzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.58(s,1H),10.72(s,1H),8.59(s,1H),8.44(s,1H),8.15(s,1H),7.88(d,J＝8.3 Hz,1H),7.66–7.55(m,1H),7.48(t,J＝7.8 Hz,1H),7.42(d,J＝1.7 Hz,1H),7.30–7.20(m,2H),3.87(s,3H),3.68(d,J＝6.6 Hz,2H),2.00–1.86(m,1H),1.75(s,3H),1.71(s,3H),0.96(d,J＝6.7 Hz,6H)。MSm/z(ESI)：552[M+H] ⁺ 。

Example 28

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-hydroxy-3-methoxybenzamide (28)

Step 1 Synthesis of N- (benzyloxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzoic acid (60.3 mg,0.13 mmol), O-benzyl hydroxylamine hydrochloride (59.9 mg,0.38 mmol), HATU (95.1 mg,0.26 mmol), DMAP (1.01 mg,0.013mmol) and DIPEA (0.13 mL,0.75 mmol) were added to DMF (6 mL) and then reacted for 2h at room temperature after which the reaction was monitored by lcms to completion, quenched with water (10 mL), extracted with EA (20 ml x 3), the organic phase washed with water, dried and concentrated, and column chromatographed to give 60.1 mg of N- (benzyloxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzamide. MS m/z (ESI): 586[ M+H ]] ⁺ 。

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-hydroxy-3-methoxybenzamide

The compound N- (benzyloxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxybenzamide (60.3 mg,0.10 mmol) was dissolved in MeOH (10 mL), 10% pd/C (20 mg) was added to the mixture at H ₂ After completion of LCMS monitoring reaction, 25.1 mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-hydroxy-3-methoxybenzamide was evaporated under reduced pressure. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.17(s,1H),10.72(s,1H),9.00(s,1H),8.60(s,1H),8.44(s,1H),8.16(s,1H),7.85(d,J＝8.3 Hz,1H),7.60(dd,J＝13.5,7.7 Hz,1H),7.48(t,J＝7.8 Hz,1H),7.43(d,J＝1.6 Hz,1H),7.31–7.19(m,2H),3.86(s,3H),1.75(s,3H),1.71(s,3H)。MS m/z(ESI)：496[M+H] ⁺ 。

Example 29

Preparation of N- (propoxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (29).

Step 1 Synthesis of N- (propoxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60.3 mg,0.13 mmol), O-propylhydroxylamine hydrochloride (43.5 mg,0.78 mmol), HATU (98.4 mg,0.26 mmol), DMAP (1.01 mg,0.013 mmol) and DIPEA (0.14 mL,0.78 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after which the reaction was monitored to completion, lcms was quenched with water (10 mL) and extracted with EA (20 ml x 3), the organic phase was washed with water, dried and concentrated, and the column chromatographed to MeOH/DCM (0-10%) to give 23mg N- (propoxy) -4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.45(s,1H),10.57(s,1H),10.07(s,1H),8.49(s,1H),8.17(s,1H),7.77–7.51(m,6H),7.32(t,J＝7.4 Hz,1H),3.82(t,J＝6.6 Hz,2H),1.75(s,3H),1.71(s,3H),1.66–1.56(m,2H),0.95(t,J＝7.4 Hz,3H),0.84(qd,J＝6.6,4.0 Hz,2H)。MS m/z(ESI)：508[M+H] ⁺ 。

Example 30

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isopropoxy benzamide (30)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isopropoxy benzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60.1 mg,0.13 mmol) and O-isopropylhydroxylamine hydrochloride (43.7 mg,0.39 mmol), HATU (98.9 mg,0.26 mmol), DMAP (1.01 mg,0.05 mmol) and DIPEA (0.14 mL,0.78 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after completion of lcms monitoring reaction, quenched with water (10 mL), extracted with EA (20 ml 3), washed with organic phase, dried and concentrated, and column chromatographed to purify MeOH/DCM (0-10%) to give 35 mg 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isopropoxybenzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.27(s,1H),10.58(s,1H),10.06(s,1H),8.49(s,1H),8.17(s,1H),7.65(ddd,J＝14.5,10.8,6.5 Hz,6H),7.32(t,J＝7.4 Hz,1H),4.11(dt,J＝12.4,6.2 Hz,1H),1.75(s,3H),1.72(s,3H),1.20(s,3H),1.19(s,3H)。MS m/z(ESI)：508[M+H] ⁺ 。

Example 31

Preparation of N- (cyclopropylmethoxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (31)

Step 1 Synthesis of N- (cyclopropylmethoxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60.3 mg,0.13 mmol), O- (cyclopropyl) methylhydroxylamine hydrochloride (49.4 mg,0.4 mmol), HATU (98.9 mg,0.26 mmol), DMAP (1.0 mg,0.01 mmol) and DIPEA (0.14 mL,0.78 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after lcms monitoring the reaction completion, quenched with water (10 mL), extracted with EA (20 ml x 3), the organic phase was washed with water, dried and concentrated, column chromatography purified MeOH-DCM (0-10%) gave 42.1mg of N- (cyclopropylmethoxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.49(s,1H),10.57(s,1H),10.07(s,1H),8.49(s,1H),8.16(s,1H),7.75–7.49(m,3H),7.32(t,J＝7.2Hz,1H),3.69(d,J＝7.2Hz,1H),1.75(s,1H),1.71(s,1H),0.59–0.45(m,1H),0.34–0.18(m,1H)。MS m/z(ESI)：520[M+H] ⁺ 。

Example 32

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide (32)

Step 1:4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid

2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (60.3 g,0.17 mmol) and p-amino-3-methoxybenzoic acid (33.4 mg,0.18 mmol) were dissolved in isopropanol (6 mL), a solution of 4N hydrochloric acid in 1, 4-dioxane (0.1 mL,0.4 mmol) was added, and the reaction was allowed to react at 70℃for 4h, and completion was monitored. The system was suction filtered to give 34.2mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid, MS m/z (ESI): 499[ M+H ] ] ⁺ 。

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid (34.2 mg,0.068 mmol), O-isobutylhydroxylamine hydrochloride (25.1 mg,0.2 mmol), HATU (51.7 mg,0.14 mmol), DMAP (1.0 mg, 0.0070 mmol) and DIPEA (53.0 mg,0.41 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h after completion of LCMS monitoring the reaction, quenched with water (10 mL), extracted EA (20 mL. Times.3), washed with water, dried and concentratedColumn chromatography purification of MeOH/DCM (0-10%) gave 23.3mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.30(s,1H),10.71(s,1H),8.54(s,1H),8.50(s,1H),8.15(d,J＝4.0Hz,1H),7.88(d,J＝12.1Hz,1H),7.64(dd,J＝13.4,7.7Hz,1H),7.54(t,J＝7.7Hz,1H),7.27(t,J＝7.3Hz,1H),7.17(d,J＝6.3Hz,1H),3.86(s,3H),3.67(d,J＝6.6Hz,2H),2.00–1.86(m,1H),1.75(s,3H),1.72(s,3H),0.94(d,J＝6.6Hz,6H)。MS m/z(ESI)：570[M+H] ⁺ 。

Example 33

Preparation of 4- ((4- (2- (dimethylphosphoryl) phenoxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide

Step 1, synthesizing (2-hydroxyphenyl) dimethylphosphine oxide

2-iodophenol (0.88 g,4 mmol) and dimethylphosphine oxide (0.375 g,4.8 mmol) were dissolved in N, N-dimethylformamide solution (5 mL), palladium acetate (90 mg,0.4 mmol), potassium phosphate (1.02 g,4.8 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.232 g,0.4 mmol) were weighed respectively, added to the reaction system, nitrogen protection was replaced, the reaction was stirred under reflux at 120℃for 6h with slow warming to 120℃until the reaction was completed, TLC was monitored, after the reaction was completed, water was quenched by celite suction, DCM (20 mL. Times.2) was extracted, the organic phase was combined, saturated brine was washed (5 mL. Times.2), distilled under reduced pressure, column chromatography was purified to give (2-hydroxyphenyl) dimethylphosphine oxide 0.37 g, MS m/z (ESI): 171[ M+H ] ] ⁺ 。

Step 2 Synthesis of benzyl 4- ((4- (2- (dimethylphosphoryl) phenoxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate

(2-hydroxyphenyl) dimethylphosphine oxide (50 mg, 0.254 mmol) was dissolved in N-butanol (3 mL), benzyl 4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate (120 mg,0.294 mmol) was added, N-diisopropylethylamine (0.05 mL,0.294 mmol) was added, and the reaction was allowed to proceed to 14 h at 120℃and monitored for reversionShould end. Quenching with water, extracting with dichloromethane (20 mL ×2), drying, concentrating, and column chromatography to obtain 50 mg4- ((4- (2- (dimethylphosphoryl) phenoxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzyl benzoate, MS m/z (ESI) 542[ M+H ]] ⁺ 。

Step 3 Synthesis of 4- ((4- (2- (dimethylphosphoryl) phenoxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid

Benzyl 4- ((4- (2- (dimethylphosphoryl) phenoxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoate (50 mg,0.092 mmol) was dissolved in methanol (10 mL), palladium hydroxide on carbon (50 mg) was added to the mixture at H ₂ The reaction was carried out in an atmosphere for 15h, and the reaction was complete by TLC. Suction filtration of the system and distillation of the filtrate under reduced pressure gave 42mg of 4- ((4- (2- (dimethylphosphoryl) phenoxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 452[ M+H ] ] ⁺ 。

Step 4 Synthesis of 4- ((4- (2- (dimethylphosphoryl) phenoxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide

4- ((4- (2- (dimethylphosphoryl) phenoxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (42 mg,0.92 mmol), methoxyamine hydrochloride (34 mg,0.4 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (76 mg,0.2 mmol) and N, N-diisopropylethylamine (0.15 mL,0.8 mmol) were added to N, N-dimethylformamide (2.5 mL), then reacted at room temperature for 15h, after completion of LCMS monitoring the reaction, the reaction was quenched with water (10 mL), extracted with EA (20 mL X3), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to purify MeOH/DCM (0-10%) to give 8 mg of 4- ((4- (2- (dimethylphosphoryl) phenoxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide. MS m/z (ESI): 481[ M+H ]] ⁺

Example 34

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-methylbenzamide (34)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-methylbenzoic acid

(2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (60 mg,0.172 mmol), 4-amino-2-methylbenzoic acid (29 mg,0.19 mmol) and 4M 1, 4-dioxane hydrochloride solution (0.25 mL,1 mmol) were added to isopropanol (6 mL), then reacted at 60℃for 4 h, after completion of the LCMS monitoring reaction, cooled to room temperature, the reaction system was suction filtered, the solid obtained by suction filtration was washed with isopropanol (2 mL X3) and then dried at 50℃for 1h to give 37 mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-methylbenzoic acid, MS M/z (ESI): 465[ M+H ] ] ⁺ .

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-methylbenzamide

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-methylbenzoic acid (37 mg,0.08 mmol), O-isobutoxy amine hydrochloride (30 mg,0.24 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (46 mg,0.12 mmol) and N, N-diisopropylethylamine (0.1 mL,0.48 mmol) were added to N, N-dimethylformamide (2.5 mL mmol), then reacted at room temperature for 16h, after completion of LCMS monitoring reaction, the reaction was quenched with water (10 mL), extracted with EA (20 mL X3), dried and concentrated, and purified by column chromatography/DCM (0-10%) to give 30mg of 4- ((2- (dimethylphosphoryl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-methylbenzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.18(s,1H),10.56(s,1H),9.91(s,1H),8.47(s,1H),8.17(s,1H),7.69–7.61(m,1H),7.57(t,J＝7.8 Hz,1H),7.49(s,1H),7.45(s,1H),7.29(t,J＝7.6 Hz,1H),7.14(d,J＝8.3 Hz,1H),3.65(d,J＝6.7 Hz,2H),2.21(s,3H),1.97–1.86(m,1H),1.74(d,J＝13.5 Hz,6H),0.93(d,J＝6.7 Hz,6H).MS m/z(ESI)：536.2[M+H] ⁺ .

Example 35

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxybenzamide

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluorobenzoic acid

(2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (60 mg,0.172 mmol), 4-amino-2-fluorobenzoic acid (30 mg,0.19 mmol) and 4M 1, 4-dioxane hydrochloride solution (0.25 mL,1 mmol) were added to isopropanol (6 mL) and then reacted at 60℃for 4h, after completion of the LCMS monitoring reaction, cooled to room temperature, the reaction system was suction filtered, the solid obtained by suction filtration was washed with isopropanol (2 mL. Times.3) and then dried at 50℃for 1h to give 44mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-fluorobenzoic acid, MS M/z (ESI): 469[ M+H ] ] ⁺ .

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy benzamide

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluorobenzoic acid (44 mg,0.094 mmol), O-isobutoxy amine hydrochloride (35.4 mg,0.282 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (53.6 mg,0.141 mmol) and N, N-diisopropylethylamine (0.1 mL,0.56 mmol) were added to N, N-dimethylformamide (2.5 mL) and then after completion of the reaction at room temperature, LCMS was monitored for completion of the reaction, the reaction was quenched with water (10 mL), the EA (20 mL. Times.3) was extracted, the organic phase was washed with water, dried and concentrated, and column chromatography purification/MeOH (0-10%) gave 30mg of 4- ((2- (dimethylphosphoryl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-isobutoxy benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.23(s,1H),10.57(s,1H),10.22(s,1H),8.52(s,1H),8.13(s,1H),7.73–7.64(m,2H),7.61(t,J＝7.9Hz,1H),7.41(q,J＝7.9,7.3Hz,2H),7.32(t,J＝7.6Hz,1H),3.65(d,J＝6.6Hz,2H),1.91(td,J＝13.2,12.5,5.6Hz,1H),1.73(d,J＝13.6Hz,6H),0.93(d,J＝6.7Hz,6H).MS m/z(ESI)：540[M+H] ⁺ .

Example 36

Preparation of 4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide (36)

Step 1 Synthesis of (2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

2,4, 5-trichloropyrimidine (270 mg,1.47 mmol) was dissolved in ethanol (5 mL), sodium bicarbonate (247 mg,2.94 mmol) and (2-aminophenyl) dimethylphosphine oxide (250 mg,1.47 mmol) were added under ice-bath, and the reaction was allowed to proceed at room temperature for 5 hours, and completion of the reaction was monitored. Adding water, extracting with dichloromethane, drying, concentrating, and column chromatography to obtain 230mg (2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide, MS m/z (ESI): 316.0[ M+H) ] ⁺ 。

Step 2 Synthesis of 4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid

(2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (100 mg,0.32 mmol), para-aminobenzoic acid (53 mg,0.39 mmol) was dissolved in isopropanol (4 mL), a solution of 1, 4-dioxane (63.7. Mu.L) in 4N hydrochloric acid was added, reacted at 70℃for 14h, monitored for reaction completion, the system was suction filtered to give 81mg of 4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 417.1[ M+H)] ⁺ 。

Step 3 Synthesis of 4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide

4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid (81 mg,0.19 mmol) was dissolved in DMF (2 mL), HATU (111 mg,0.29 mmol) DIPEA (64.36 mL,0.39 mmol) was added under ice-bath and reacted at room temperature for 1h, then methoxyamino hydrochloride (32.52 mg,0.39 mmol) and DMAP (0.24 mg, 0.002mmol) were added and the reaction was monitored for completion at room temperature overnight. Water was added, extracted with DCM, dried and concentrated, and MeOH/DCM (0-10%) was purified by column chromatography to give 48mg of 4- ((5-chloro-4- ((2- (dimethylphosphine)Acyl) phenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide. ¹ H NMR(400MHz,DMSO)δ11.55(s,1H),11.16(s,1H),9.75(s,1H),8.53(dd,J＝8.3,3.9Hz,1H),8.25(s,1H),7.75(d,J＝8.8Hz,2H),7.70–7.51(m,4H),7.23(t,J＝6.9Hz,1H),3.69(s,3H),1.78(d,J＝13.6Hz,6H).MS m/z(ESI):446.1[M+H] ⁺ 。

Example 37

(E) Preparation of-4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzoyl chloride (37)

Step 2 Synthesis of (E) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzoyl chloride

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzamide (30.2 mg,58.9 mmol) was dissolved in POCl ₃ (6 mL) heating reflux overnight, LCMS monitoring reaction completion, water quenching, dichloromethane (5 mL. Times.3) extraction, combined organic phases, distillation under reduced pressure, ISCO column chromatography purification of MeOH/DCM (0-10%) to give 15.1 mg (E) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N, 3-dimethoxybenzoyl chloride. ¹ H NMR(400 MHz,DMSO-d ₆ ):δ10.71(s,1H),8.64(s,1H),8.45(s,1H),8.14(s,1H),7.90(d,J＝8.6 Hz,1H),7.67–7.52(m,1H),7.46(t,J＝7.9Hz,1H),7.37(d,J＝1.9 Hz,1H),7.29–7.21(m,2H),4.06(s,3H),3.87(s,3H),1.75(s,3H),1.71(s,3H)。MSm/z(ESI)：528[M+H] ⁺ 。

Example 38

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- (2-methoxyethoxy) benzamide (38)

4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60 mg,0.13 mmol), O- (2-methoxyethyl) hydroxylamine (36.0 mg,0.39 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (98.8 mg,0.26 mmol), 4-dimethylaminopyridine (2 mg,0.01 mmol) and N, N-diisopropylethylamine (0.13 mL,0.68 mmol) were added to DMF (2 mL) and then reacted at room temperature for 16 h after completion of LCMS monitoring the reaction, the reaction was quenched with water (10 mL), extracted with EA (20 mL X3), the organic phase was washed with water, dried and concentrated, and the column chromatographed to purify MeOH/DCM (0-10%) to give 45.0 mg of 4- ((2- (dimethylphosphoryl) phenyl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- (2-methoxyethoxy) benzamide. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.66(s,1H),10.81(s,1H),10.51(s,1H),8.66(d,J＝2.1 Hz,1H),8.54(s,1H),8.48–8.33(m,1H),8.03(d,J＝8.8 Hz,1H),7.91(dd,J＝8.8,2.2 Hz,1H),7.71–7.51(m,2H),7.31(t,J＝7.5 Hz,1H),3.67(d,J＝6.6 Hz,2H),1.93(dq,J＝13.1,6.6 Hz,1H),1.76(s,3H),1.73(s,3H).MS m/z(ESI)：524.2[M+H] ⁺ .

Example 39

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- (2-hydroxy-2-methylpropyloxy) benzamide (39)

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60 mg,0.13 mmol), 1- (aminooxy) -2-methylpropan-2-ol (42.4 mg,0.40 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (98.9 mg,0.26 mmol), 4-dimethylaminopyridine (1.6 mg,0.01 mmol) and N, N-diisopropylethylamine (0.15 mL,0.78 mmol) were added to DMF (2 mL) and then reacted at room temperature for 16h after completion of the LCMS monitoring reaction, quenched with water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was water washed, dried and concentrated to give 63.1mg of 4- ((2- (dimethylphosphoryl) phenyl) ammonia purified by column chromatography MeOH/DCM (0-10%)Phenyl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- (2-hydroxy-2-methylpropyloxy) benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.40(s,1H),10.82(s,1H),9.11(s,1H),8.39(s,1H),8.24(s,1H),7.55(dd,J＝13.7,7.7Hz,1H),7.37(d,J＝7.8Hz,2H),7.16(t,J＝7.4Hz,1H),7.02(d,J＝8.3Hz,1H),4.51(t,J＝8.8Hz,2H),3.66(d,J＝6.7Hz,2H),3.40(t,J＝8.8Hz,2H),2.01–1.88(m,2H),1.75(s,3H),1.72(s,3H),1.18(s,6H).MS m/z(ESI)：538.2[M+H] ⁺ .

Example 40

Preparation of 6- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy nicotinamide (40)

Step 1 Synthesis of methyl 6- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminomethylnicotinate

2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (120 mg,0.35 mmol) and methyl 6-aminonicotinate (55.9 mg,0.38 mmol) were dissolved in isopropanol (14 mL), a solution of 4N hydrochloric acid in 1, 4-dioxane (0.12 mL,0.48 mmol) was added and reacted at 70℃for 4h, and the reaction was monitored to completion. The system was suction filtered to give 100mg of methyl 6- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminomethylnicotinate, MS m/z (ESI): 466.2[ M+H ]] ⁺ 。

Step 2 Synthesis of 6- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) nicotinic acid

Compound 6- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) aminomethyl nicotinic acid methyl ester (90 mg,0.19 mmol) is dissolved in a mixed solution of THF (10 mL) and methanol (5 mL), liOH (14.0 mg,0.58 mmol) is added to the solution in (5 mL) water, the temperature is slowly raised to 65 ℃ to stir the reaction for 4h after the reaction is monitored by tlc, water is added to dilute, the pH is adjusted to acidity, ethyl acetate (40 mL x 3) is extracted, the organic phase is combined, saturated saline (50 mL x 2) is washed, reduced pressure distillation and ISCO column chromatography purification are carried out to obtain 6- ((4- ((2 ]70mg of (dimethylphosphoryl) phenyl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -nicotinic acid compound, MS m/z (ESI) 452.4[ M+H ] ⁺ 。

Step 3 Synthesis of 6- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy nicotinamide

6- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) nicotinic acid (70 mg,0.16 mmol), O-isobutylamine hydrochloride (59.0 mg,0.47 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (121.7 mg,0.32 mmol), 4-dimethylaminopyridine (2.4 mg,0.02 mmol) and N, N-diisopropylethylamine (0.16 mL,0.96 mmol) were added to DMF (6 mL) and then reacted for 16h at room temperature after completion of the LCMS monitoring reaction, quenched with water (10 mL), EA (20 mL. Times.3) extracted, combined organic phases water, dried and concentrated to give 32.1mg 6- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -isobutylamide after purification by column chromatography MeOH/DCM (0-10%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.66(s,1H),10.81(s,1H),10.51(s,1H),8.66(d,J＝2.1Hz,1H),8.54(s,1H),8.48–8.33(m,1H),8.03(d,J＝8.8Hz,1H),7.91(dd,J＝8.8,2.2Hz,1H),7.71–7.51(m,2H),7.31(t,J＝7.5Hz,1H),3.67(d,J＝6.6Hz,2H),1.93(dq,J＝13.1,6.6Hz,1H),1.76(s,3H),1.73(s,3H),0.95(d,J＝6.7Hz,6H)，MS m/z(ESI)：523.2[M+H] ⁺ 。

Example 41

Preparation of 5- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy pyridine carboxamide (41)

Step 1, synthesizing 5-amino-N-isobutoxy pyridine carboxamide

5-aminopicolinic acid (200 mg,1.45 mmol), O-isobutylamine hydrochloride (546.4 mg,4.4 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.1 g,2.9 mmol), 4-dimethylaminopyridine (18.3 mg,0.15 mmol) and N, N-di- Isopropylethylamine (1.5 mL,8.7 mmol) was added to DMF (6 mL) and then reacted at room temperature for 16h, after completion of LCMS monitoring the reaction, quenched with water (10 mL), extracted with EA (20 mL. Times.3), the combined organic phases were washed with water, concentrated, purified by column chromatography on MeOH/DCM (0-10%) to give 150mg of 5-amino-N-isobutylpyridine carboxamide, MS m/z (ESI): 210.1[ M+H ]] ⁺ 。

Step 2 Synthesis of 5- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy pyridine carboxamide

The compound 6-amino-N-isobutoxy pyridine carboxamide (50.3 mg,0.43 mmol) and 2- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (107.8 mg,0.52 mmol) were dissolved in 1, 4-dioxane (10 mL) and Pd was added ₂ (dba) ₃ (39.4 mg,0.0.043 mmol), BINAP (53.5 mg,0.086 mmol) and tBuOK (82.7 mg,0.86 mmol), under N with nitrogen blanket replaced ₂ Heating to 105deg.C under atmosphere, stirring overnight, adding dichloromethane to dilute, saturated NaHCO after completion of LCMS monitoring reaction ₃ Quench, extract with DCM (20 mL. Times.3), wash the combined organic phases with water, wash with saturated brine, dry concentrate, and purify MeOH/DCM (0-10%) by column chromatography to give 25.1mg of 5- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy pyridine carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.69(s,1H),10.65(s,1H),10.26(s,1H),8.75(s,1H),8.53(s,1H),8.20(d,J＝43.5Hz,1H),7.77(s,1H),7.66(dd,J＝13.4,7.6Hz,1H),7.61(t,J＝7.8Hz,1H),7.31(t,J＝7.4Hz,1H),3.64(d,J＝6.7Hz,2H),1.91(dt,J＝13.4,6.7Hz,1H),1.75(s,3H),1.72(s,3H),0.93(d,J＝6.7Hz,6H).MS m/z(ESI)：523.2[M+H] ⁺ 。

Example 42

Preparation of 2- ((2- (((4- (methoxycarbamoyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphonate (42)

Step 1, synthesizing (2-aminophenyl) phosphonic acid dimethyl ester

The compound 2-iodoaniline (4.0 g,18.26 mmol) and dimethyl phosphate (6.0 g,54.8 mmol) were dissolved in DMF solution (100 mL) and Pd (dppf) Cl was weighed out separately ₂ (1.5 g,1.83 mol) and K ₃ PO ₄ (9.7 g,45.7 mmol) is added into the reaction system, nitrogen protection is replaced, the temperature is slowly increased to 105 ℃ and reflux stirring is carried out for 13h, TLC monitoring reaction is carried out, after the reaction is completed, water quenching is added, diatomite suction filtration is carried out, EA (20 mL x 2) extraction is carried out, organic phases are combined, saturated saline washing (30 mL x 2) is carried out, reduced pressure distillation and ISCO column chromatography purification are carried out, thus obtaining 0.71g of dimethyl (2-aminophenyl) phosphonate, MS m/z (ESI): 202.0[ M+H)] ⁺ 。

Step 2 Synthesis of dimethyl (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) phosphonate

2, 4-dichloropyrimidine-5-trifluoromethyl (0.71 g,3.55 mmol) was dissolved in EtOH (20 mL) and dimethyl (2-aminophenyl) phosphonate (0.7 g,3.2 mmol) was added and NaHCO was slowly added under ice-bath conditions ₃ (542.7 mg,6.5 mmol) and allowed to react at 50℃for 1 hour, the reaction was monitored to be complete. Quenched with water, extracted with dichloromethane, dried and concentrated, and column chromatographed to give 95.3mg of dimethyl (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) phosphonate, MS m/z (ESI) 382.0[ M+H ] ] ⁺ 。

Step 3 Synthesis of 4- ((4- ((2- (dimethoxyphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid

Dimethyl (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) phosphonate (124.8 mg,0.33 mmol) and p-aminobenzoic acid (44.9 mg,0.33 mmol) were dissolved in isopropanol (10 mL), a 1, 4-dioxane solution of 4N hydrochloric acid (0.1 mL) was added, and the reaction was monitored for completion at 65℃for 4 h. The system was suction filtered to give 142.3 mg of 4- ((4- ((2- (dimethoxyphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 483.1[ M+H ]] ⁺ 。

Step 4 2- ((2- (((4- (methoxycarbamoyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphonate

Compound 4- ((4- ((2- (dimethoxyphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60 mg,0.12 mmol), O-methylhydroxylamine hydrochloride (30.1 mg,0.36 mmol), HATU (91.3 mg,0.24 mmol), DMAP (1.5 mg,0.012 mmol) and DIPEA (0.1 mL,0.72 mmol) were added to DMF (10 mL), then the reaction was quenched with water (10 mL) after completion of LCMS monitoring the reaction, EA (20 mL. Times.2) was extracted and the organic phase was washed with water, dried and concentrated to give 28.6 mg of 2- ((2- (((4- (methoxycarbamoyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphonate by column chromatography. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.66(s,1H),10.81(s,1H),10.51(s,1H),8.66(d,J＝2.1 Hz,1H),8.54(s,1H),8.48–8.33(m,1H),8.03(d,J＝8.8 Hz,1H),7.91(dd,J＝8.8,2.2 Hz,1H),7.71–7.51(m,2H),7.31(t,J＝7.5 Hz,1H),3.67(d,J＝6.6 Hz,2H),1.93(dq,J＝13.1,6.6 Hz,1H),1.76(s,3H),1.73(s,3H)。MS m/z(ESI)：512.1[M+H] ⁺ 。

Example 43

Preparation of (2- ((2- (((4- (isobutoxycarbamoyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphonate (43)

Step 1 (2- ((2- (((4- (isobutoxycarbamoyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphonate

Compound 4- ((4- ((2- (dimethoxyphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60 mg,0.12 mmol), O-isobutoxy amine hydrochloride (45.2 mg,0.36 mmol), HATU (91.3 mg,0.24 mmol), DMAP (1.5 mg,0.012 mmol) and DIPEA (0.1 ml,0.72 mmol) were added to DMF (10 mL) and then reacted at room temperature for 2h after lcms monitored reaction complete, quenched with water (10 mL) and EA (20 ml x 2) extracted and the organic phase washed with water, dried and concentrated, column chromatography afforded 40 mg (2- ((2- (((4- (isobutoxycarbonyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphonate). ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.47(s,1H),10.11(s,1H),9.32(s,1H),8.51(s,1H),8.15(s,1H),7.74(dd,J＝14.7,7.3 Hz,2H),7.59(t,J＝14.0Hz,4H),7.41(td,J＝7.7,3.5 Hz,1H),3.68–3.60(m,8H),1.92(td,J＝13.4,6.7 Hz,1H),0.94(d,J＝6.7 Hz,6H).MS m/z(ESI)：554.2[M+H] ⁺ 。

Example 44

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N, 5-dimethoxybenzamide (44)

Step 1:4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N, 5-dimethoxybenzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid (60 mg,0.12 mmol), O-methylhydroxylamine hydrochloride (30.1 mg,0.36 mmol), HATU (91.3 mg,0.24 mmol), DMAP (1.5 mg,0.012 mmol) and DIPEA (0.1 ml,0.72 mmol) were added to DMF (10 mL) and then after completion of the reaction at room temperature lcms monitoring the reaction was quenched with water (10 mL), EA (20 ml x 2) was extracted and the organic phase was washed with water, dried and concentrated to give 53.2 mg 4- ((2- (dimethylphosphoryl) phenyl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N, 5-dimethoxybenzamide by column chromatography. ¹ H NMR(400 MHz,DMSO-d ₆ )δ11.66(s,1H),10.81(s,1H),10.51(s,1H),8.66(d,J＝2.1Hz,1H),8.54(s,1H),8.48–8.33(m,1H),8.03(d,J＝8.8Hz,1H),7.91(dd,J＝8.8,2.2Hz,1H),7.71–7.51(m,2H),7.31(t,J＝7.5Hz,1H),3.67(d,J＝6.6Hz,2H),1.93(dq,J＝13.1,6.6Hz,1H),1.76(s,3H),1.73(s,3H)。MS m/z(ESI)：528.1[M+H] ⁺ 。

Example 45

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxy-2-fluoro-5-methoxybenzamide (45)

Step 1:4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxy-2-fluoro-5-methoxybenzamide

Compound 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60 mg,0.12 mmol), O-ethylhydroxylamine hydrochloride (35.1 mg,0.36 mmol), HATU (91.3 mg,0.24 mmol), DMAP (1.5 mg,0.012 mmol) and DIPEA (0.1 mL,0.72 mmol) were added to DMF (10 mL) and then reacted at room temperature for 2h after completion of lcms monitoring reaction, quenched with water (10 mL), extracted with EA (20 mL x 2), the organic phase was washed with water, concentrated by drying, and column chromatography afforded 48.2mg of 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxy-2-fluoro-5-methoxybenzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.66(s,1H),10.81(s,1H),10.51(s,1H),8.66(d,J＝2.1Hz,1H),8.54(s,1H),8.48–8.33(m,1H),8.03(d,J＝8.8Hz,1H),7.91(dd,J＝8.8,2.2Hz,1H),7.71–7.51(m,2H),7.31(t,J＝7.5Hz,1H),3.67(d,J＝6.6Hz,2H),1.93(dq,J＝13.1,6.6Hz,1H),1.76(s,3H),1.73(s,3H).MS m/z(ESI)：542.2[M+H] ⁺ 。

Example 46

Preparation of 7- (((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxy-2, 3-dihydrobenzofuran-4-carboxamide (46)

Step 1 Synthesis of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid

2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (120 mg,0.35 mmol) and 7-amino-2, 3-dihydrobenzofuran-4-carboxylic acid (63.4 mg,0.38 mmol) were dissolved in isopropanol (14 mL), a solution of 4N hydrochloric acid in 1, 4-dioxane (0.12 mL,0.48 mmol) was added and the reaction was allowed to react at 70℃for 4h, monitoring the reaction completion. The system was suction filtered to give 135mg of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl)) Pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid, MS m/z (ESI): 493.1[ M+H] ⁺ 。

Step 2 Synthesis of 7- (((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxy-2, 3-dihydrobenzofuran-4-carboxamide

Compound 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (60.0 mg,0.12 mmol), O-methylhydroxylamine hydrochloride (35.1 mg,0.36 mmol), HATU (91.3 mg,0.24 mmol), DMAP (1.5 mg,0.012 mmol) and DIPEA (0.1 mL,0.72 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h, after completion of LCMS monitoring the reaction, the reaction was quenched with water (10 mL), extracted with EA (20 mL of 3), the organic phase was washed with water, dried and concentrated, and MeOH/DCM (0-10%) was purified by column chromatography to give 35.1mg of 7- (((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxy-2, 3-dihydrobenzofuran-4-carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.38(s,1H),10.82(s,1H),δ9.10(s,1H),8.39(s,1H),8.24(s,1H),7.55(dd,J＝12.4,7.7Hz,1H),7.37(s,2H),7.16(t,J＝7.4Hz,1H),7.02(d,J＝8.3Hz,1H),4.51(t,J＝8.8Hz,2H),3.93(q,J＝7.0Hz,2H),3.41(t,J＝8.8Hz,2H),1.75(s,3H),1.72(s,3H),1.21(t,J＝7.1Hz,3H).MS m/z(ESI)：536.2[M+H] ⁺ 。

Example 47

Preparation of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2, 3-dihydrobenzofuran-4-carboxamide (47)

Step 1 Synthesis of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2, 3-dihydrobenzofuran-4-carboxamide

Compound 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (60.0 mg,0.12 mmol), O-isobutylhydroxylamine hydrochloride (45.2 mg,0.36 mmol), HATU (91.3 mg,0.24 mmol), DMAP (1.5 mg,0.012 mmol) and DIPEA (0.1 mL,0.72 mmol) were added to DMF (10 mL) and then reacted at room temperature for 2h after completion of the LCMS monitoring reaction, quenched with water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with water, concentrated, and purified by column chromatography to give 54.9mg of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2, 3-dihydrobenzofuran-4-carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.40(s,1H),10.82(s,1H),9.11(s,1H),8.39(s,1H),8.24(s,1H),7.55(dd,J＝13.7,7.7Hz,1H),7.37(d,J＝7.8Hz,2H),7.16(t,J＝7.4Hz,1H),7.02(d,J＝8.3Hz,1H),4.51(t,J＝8.8Hz,2H),3.66(d,J＝6.7Hz,2H),3.40(t,J＝8.8Hz,2H),2.01–1.88(m,2H),1.75(s,3H),1.72(s,3H),0.95(d,J＝6.7Hz,6H).MS m/z(ESI)：564.2[M+H] ⁺ 。

Example 48

Preparation of 4- ((5-chloro-4- ((2- (1-phosphino-1-yl) phenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide (48)

Step 1, synthesizing diallyl phosphine oxide

Allyl magnesium bromide in tetrahydrofuran (1M, 65.1 mL) was added dropwise to Et in dimethyl phosphate (3.0 g,21.7 mmol) at 0deg.C ₂ O solution (5 mL) was slowly warmed to room temperature and reacted for 1 hour. Then K is taken up ₂ CO ₃ An aqueous solution (1.1 mL) of (4.3 g,54.8 mmol) was added to the reaction system at 0deg.C and stirred for 10 minutes. The reaction was filtered, washed with ethanol, and the filtrate was concentrated. Pulping the crude product with diethyl ether (2×10ml), filtering, concentrating the filtrate to obtain diallyl phosphine oxide, and directly using in the next reaction, MS m/z (ESI) 131.0[ M+H ]] ⁺ 。

Step 2, synthesizing diallyl (2-aminophenyl) phosphine oxide

The compound 2-iodoaniline (3.4 g,15.4 mmol) and diallylphosphine oxide (3.0 g,23.0 mmol) were dissolved in DMF solution (60 mL) and Pd (OAc) was weighed out separately ₂ (345.7mg,1.54mmol)、K ₃ PO ₄ (6.5 g,30.8 mmol) and Xantphos (1.78 g,3.08 mol) are added into the reaction system, the nitrogen protection is replaced, the temperature is slowly raised to 125 ℃ and the reflux stirring reaction is carried out for 6 hours, TLC monitoring reaction is carried out, after the reaction is finished, water quenching is added, diatomite is used for suction filtration, EA (20 mL. Times.2) extraction, organic phases are combined, saturated saline solution is used for washing (30 mL. Times.2), reduced pressure distillation and ISCO column chromatography purification are carried out, thus obtaining 1.8g of diallyl (2-aminophenyl) phosphine oxide, MS m/z (ESI) is 222.1[ M+H) ] ⁺ 。

Step 3 Synthesis of benzyl (2- (diallyl phosphoryl) phenyl) carbamate

Diallyl (2-aminophenyl) phosphine oxide (1.8 g,8.1 mmol) was dissolved in DCM (20 mL), DIPEA (2.8 mL,16.3 mmol) was added and Cbz-Cl (1.4 mL,11.8 mmol) was slowly added dropwise under ice-bath conditions, and the reaction was allowed to proceed to room temperature for 1h, monitoring the completion of the reaction. Quenching with water, extracting with dichloromethane, drying, concentrating, and ISCO column chromatography to give 1.6g (2- (diallyl phosphoryl) phenyl)]Benzyl carbamate, MS m/z (ESI): 356.1[ M+H ]] ⁺ 。

Step 4 Synthesis of benzyl (2- (1-oxo-2, 5-dihydro-phosphino-1-yl) phenyl) carbamate

(2- (diallyl phosphoryl) phenyl)]Benzyl carbamate (2.6 g,7.2 mmol) was dissolved in toluene (25 mL) and nitrogen replaced air. Then Grubbs first generation catalyst (595.8 mg,0.72 mmol) was added to the reaction system, reflux reaction at 110deg.C for 12h, LCMS monitored to completion, quench with water (10 mL), extraction with DCM (20 mL. Times.2), washing the organic phase with water, drying and concentrating, ISCO column chromatography gave 2.1g (2- (1-oxo-2, 5-dihydro-phosphino-1-yl) phenyl]Benzyl carbamate, MS m/z (ESI): 328.1[ M+H ]] ⁺ 。

Step 5 Synthesis of 1- (2-aminophenyl) phosphine epoxide

The compound (2- (1-oxo-2, 5-dihydro-phosphin-1-yl) phenyl ]Benzyl carbamate (2.1 g,6.4 mmol) was dissolved in MeOH (30 mL) and 10% Pd/C (400 mg) was added to H ₂ After completion of LCMS monitoring the reaction, the reaction was filtered through celite and evaporated under reduced pressure to give 1.3g of 1- (2-aminophenyl) phosphine epoxide. MS m/z (ESI): 196.1[ M+H ]] ⁺ 。

Step 6 Synthesis of 1- (2- ((2, 5-dichloropyrimidin-4-yl) amino) phenyl) phosphine alkane 1 oxide

2, 4-dichloropyrimidine-5-trifluoromethyl (552.1 mg,3.0 mmol) was dissolved in EtOH (20 mL), 1- (2-aminophenyl) phosphine epoxide (587.1 mg,3.0 mmol) was added and NaHCO was slowly added under ice-bath conditions ₃ (504.0, 6.0 mmol) and allowed to react at 85℃for 1h, the reaction was monitored to be complete. Quenched with water, extracted with dichloromethane, dried and concentrated, and column chromatographed to give 340mg of 1- (2- ((2, 5-dichloropyrimidin-4-yl) amino) phenyl) phosphine alkoxide 1, MS m/z (ESI): 342.0[ M+H ]] ⁺ 。

Step 7 Synthesis of 4- ((5-chloro-4- ((2- (1-phosphino-1-yl) phenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide

The compound 1- (2- ((2, 5-dichloropyrimidin-4-yl) amino) phenyl) phosphine alkane 1 oxide (150.3 mg,0.45 mmol) and 4-amino-2-fluoro-N-isobutoxy-5-methoxybenzamide (134.6 mg,0.53 mmol) were dissolved in 1, 4-dioxane (30 mL) and Pd was added ₂ (dba) ₃ (40.3 mg,0.045 mmol), BINAP (56.0 mg,0.09 mmol) and tBuOK (86.5 mg,0.90 mmol), under N with nitrogen blanket replaced ₂ Heating to 105deg.C under atmosphere, stirring overnight, adding dichloromethane to dilute, saturated NaHCO after completion of LCMS monitoring reaction ₃ Quench, extract with DCM (20 mL. Times.3), wash the combined organic phases with water, wash with saturated brine, dry concentrate, and purify MeOH/DCM (0-10%) by column chromatography to give 15.1mg of 4- ((5-chloro-4- ((2- (1-phosphino-1-yl) phenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.66(s,1H),10.81(s,1H),10.51(s,1H),8.66(d,J＝2.2Hz,1H),8.54(s,1H),8.47–8.35(m,1H),8.03(d,J＝8.8Hz,1H),7.96–7.85(m,1H),7.70–7.53(m,2H),7.31(t,J＝7.4Hz,1H),3.67(d,J＝6.6Hz,3H),2.00–1.89(m,2H),1.76(s,3H),1.72(s,3H),0.94(d,J＝6.7Hz,7H).MS m/z(ESI)：562.2[M+H] ⁺ 。

Example 49

Preparation of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethyl-2, 3-dihydrobenzofuran-4-carboxamide (49)

Step 1 Synthesis of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethyl-2, 3-dihydrobenzofuran-4-carboxamide

Compound 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (60.0 mg,0.12 mmol), ethylamine hydrochloride (30.1 mg,0.37 mmol), HATU (91.3 mg,0.24 mmol), DMAP (1.5 mg,0.01 mmol) and DIPEA (0.12 mL,0.72 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h, lcms monitored the reaction was complete, the reaction was quenched with water (10 mL), EA (20 mL x 3) was extracted, the organic phase was washed with water, dried and concentrated, and column chromatography was purified in DCM (0-10%) to give 52.1mg of 7- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethyl-2, 3-dihydrobenzofuran-4-carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.40(s,1H),10.82(s,1H),9.11(s,1H),8.39(s,1H),8.24(s,1H),7.55(dd,J＝13.7,7.7Hz,1H),7.37(d,J＝7.8Hz,2H),7.16(t,J＝7.4Hz,1H),7.02(d,J＝8.3Hz,1H),4.51(t,J＝8.8Hz,2H),3.66(d,J＝6.7Hz,2H),3.40(t,J＝8.8Hz,2H),2.01–1.88(m,2H),1.75(s,3H),1.72(s,3H)。MS m/z(ESI)：520.1[M+H] ⁺ 。

Example 50

Preparation of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methyl-2, 3-dihydrobenzofuran-4-carboxamide (50)

Step 1, synthesizing N- (4-methoxybenzyl) benzofuran-7-amine

The compound 7-bromobenzofuran (5.0 g,25.4 mmol) and (4-methoxyphenyl) methylamine (4.2 g,25.3 mmol) were dissolved in 1, 4-dioxane solution (200 mL) and Pd was weighed out separately ₂ (dba) ₃ (2.32 g,2.5 mol), tBuONa (4.87 g,50.6 mmol) and BINAP (3.15 g,50.6 mol) were added to the reaction system,replacing nitrogen protection, slowly heating to 105 ℃ for reflux stirring reaction for 16h, TLC monitoring reaction, adding water for quenching after the reaction is completed, carrying out suction filtration by diatomite, extracting by EA (20 mL.2), combining organic phases, washing by saturated saline (30 mL.2), carrying out reduced pressure distillation and ISCO column chromatography purification to obtain 5.1g of N- (4-methoxybenzyl) benzofuran-7-amine, and carrying out MS m/z (ESI) 256.1[ M+H)] ⁺ 。

Step 2 Synthesis of benzofuran-7-amine

The compound N- (4-methoxybenzyl) benzofuran-7-amine (4.5 g,17.8 mmol) was dissolved in MeOH (10 mL) and 10% Pd/C (675 mg) was added at H ₂ After completion of LCMS monitoring the reaction, the reaction was filtered through celite and evaporated under reduced pressure to give 2.65g of benzofuran-7-amine. MS m/z (ESI): 134.0[ M+H ] ] ⁺ 。

Step 3, synthesizing 4-iodobenzofuran-7-amine

Benzofuran-7-amine (200 mg,1.5 mmol) and calcium carbonate (195 mg,1.95 mmol) were dissolved in a mixed solvent of methanol (5 mL) and dichloromethane (10 mL), cooled to 0deg.C, and benzyl trimethyl ammonium dichloroiodate (520 mg,1.5 mmol) was added slowly in portions and reacted at 0deg.C for 1.5h to monitor completion. Quenching with water, suction-filtering with celite, extracting with DCM (20 mL. Times.2), mixing the organic phases, washing with saturated saline (30 mL. Times.2), distilling under reduced pressure, and purifying with ISCO column chromatography to give 250mg of 4-iodobenzofuran-7-amine, MS m/z (ESI): 260.1[ M+H)] ⁺ 。

Step 4, synthesizing 7-aminobenzofuran-4-carboxylic acid ethyl ester

The compound 4-iodobenzofuran-7-amine (416.1 mg,1.6 mmol) was dissolved in ethanol (30 mL) and Pd (PPh) was weighed out separately ₃ ) ₂ Cl ₂ (112.3 mg,0.16 mol) and Et ₃ N (0.5 mL,3.2 mmol) is added into the reaction system to replace CO gas, the temperature is slowly increased to 70 ℃ under the atmosphere condition of CO gas, reflux stirring reaction is carried out for 8h, TLC monitoring reaction is carried out, water quenching is added after the reaction is finished, EA (20 mL x 2) is extracted, organic phases are combined, saturated saline water is used for washing (30 mL x 2), reduced pressure distillation and ISCO column chromatography purification are carried out, and 69.2mg of 7-aminobenzofuran-4-carboxylic acid ethyl ester is obtained, MS m/z (ESI) is 206.2[ M+H ]] ⁺ 。

Step 5 Synthesis of 7-amino-4-benzofurancarboxylic acid

The compound 7-aminobenzofuran-4-carboxylic acid ethyl ester (2 g,9.66 mmol) was dissolved in a mixed solution of THF (10 mL) and methanol (5 mL), liOH (50.8 mg,2.12 mmol) was added to the solution, and the temperature was slowly raised to 65℃and the reaction was stirred for 4h. After TLC monitoring the reaction, adding water to dilute, adjusting pH to acidity, extracting with ethyl acetate (40 mL. Times.3), combining organic phases, washing with saturated brine (50 mL. Times.2), distilling under reduced pressure, purifying by ISCO column chromatography to obtain 96.2mg of 7-amino-4-benzofuran carboxylic acid compound, MS m/z (ESI): 178.0[ M+H)] ⁺ 。

Step 6 Synthesis of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzofuran-4-carboxylic acid

2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (100 mg,0.29 mmol) and 7-amino-4-benzofuran carboxylic acid compound (50.6 mg,0.29 mmol) were dissolved in isopropanol (5 mL), a solution of 4N hydrochloric acid in 1, 4-dioxane (0.1 mL,0.48 mmol) was added, and the reaction was allowed to proceed to completion at 70℃for 4h. The system was suction filtered to give 96.3mg of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzofuran-4-carboxylic acid, MS m/z (ESI): 491.1[ M+H ]] ⁺ 。

Step 7 Synthesis of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzofuran-4-carboxamide

Compound 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzofuran-4-carboxylic acid (60.0 mg,0.12 mmol), O-methylhydroxylamine hydrochloride (30.9 mg,0.37 mmol), HATU (91.3 mg,0.24 mmol), DMAP (1.5 mg,0.012 mmol) and DIPEA (0.12 mL,0.73 mmol) were added to DMF (10 mL) and then reacted at room temperature for 2h, after completion of the LCMS monitoring reaction, the reaction was quenched with water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with water, dried and concentrated, and the MeOH/DCM (0-10%) was purified by column chromatography to give 65.9mg of 7- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzofuran-4-carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.40(s,1H),10.82(s,1H),9.11(s,1H),8.39(s,1H),8.24(s,1H),7.55(dd,J＝13.7,7.7Hz,1H),7.37(d,J＝7.8Hz,2H),7.16(t,J＝7.4Hz,1H),7.02(d,J＝8.3Hz,1H),4.51(t,J＝8.8Hz,2H),3.66(d,J＝6.7Hz,2H),3.40(t,J＝8.8Hz,2H),2.01–1.88(m,2H),1.75(s,3H),1.72(s,3H).MSm/z(ESI)：520.4[M+H] ⁺ 。

Example 51

Preparation of 4- ((2- (dimethylphosphoryl) phenyl) amino) -2- ((4- (methoxycarbamoyl) phenyl) amino) -N-methylpyrimidine-5-carboxamide (51)

Step 1 Synthesis of methyl 2-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidine-5-carboxylate

(2-aminophenyl) dimethylphosphine oxide (300 mg,1.77 mmol), methyl 2, 4-dichloropyrimidine-5-carboxylate (365 mg,1.77 mmol), and NaHCO ₃ (297 mg,3.54 mmol) was dissolved in ethanol (6 mL) and reacted at room temperature for 5h, and the reaction was monitored to be complete. Adding water, extracting with dichloromethane, drying, concentrating, and column chromatography to obtain 0.31g of methyl 2-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidine-5-carboxylate, MS m/z (ESI): 340.0[ M+H ] ] ⁺ 。

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (methoxycarbonyl) pyrimidin-2-yl) amino) benzoic acid

Methyl 2-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidine-5-carboxylate (300 mg,0.88 mmol) and p-aminobenzoic acid (146 mg,1.06 mmol) were dissolved in isopropanol (10 mL), a 1, 4-dioxane solution (0.22 mL) of 4N hydrochloric acid was added, and the reaction was allowed to proceed at 70℃for 6h, and completion was monitored. The system was suction filtered to give 360mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (methoxycarbonyl) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 441.1[ M+H ]] ⁺ 。

Step 3 Synthesis of methyl 4- ((2- (dimethylphosphoryl) phenyl) amino) -2- ((4- (methoxycarbamoyl) phenyl) amino) pyrimidine-5-carboxylate

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (methoxycarbonyl) pyrimidin-2-yl) amino) benzoic acid (360 mg,0.81 mmol), methoxyamino hydrochloride (137 mg,1.64 mmol), HATU (467 mg,1.23 mmol) and DMAP (1 mg,0.008 mmol) was dissolved in DMF (5 mL), DIPEA (0.27 mL,1.64 mmol) was added, and the reaction was allowed to react overnight at room temperature, monitoring the completion of the reaction. Water was added, DCM was added for extraction, and dried and concentrated, and column chromatography gave 375mg of methyl 4- ((2- (dimethylphosphoryl) phenyl) amino) -2- ((4- (methoxycarbamoyl) phenyl) amino) pyrimidine-5-carboxylate, MS m/z (ESI): 470.2[ M+H ] ] ⁺ 。

Step 4 Synthesis of 4- ((2- (dimethylphosphoryl) phenyl) amino) -2- ((4- (methoxycarbamoyl) phenyl) amino) pyrimidine-5-carboxylic acid

4- ((2- (Dimethylphosphoryl) phenyl) amino) -2- ((4- (methoxycarbamoyl) phenyl) amino) pyrimidine-5-carboxylic acid methyl ester (345 mg,0.74 mmol) was dissolved in THF (10 mL) and H ₂ To O (10 mL), naOH (89 mg,2.2 mmol) was added and the reaction was allowed to proceed overnight at room temperature, monitoring the completion of the reaction. Removing the organic solvent under reduced pressure, adding 2M HCl solution to adjust pH to neutral or weak acidity, and suction filtering to obtain 210mg of 4- ((2- (dimethylphosphoryl) phenyl) amino) -2- ((4- (methoxycarbamoyl) phenyl) amino) pyrimidine-5-carboxylic acid, MS M/z (ESI) 456.2[ M+H ]] ⁺ 。

Step 5 Synthesis of 4- ((2- (dimethylphosphoryl) phenyl) amino) -2- ((4- (methoxycarbamoyl) phenyl) amino) -N-methylpyrimidine-5-carboxamide

4- ((2- (Dimethylphosphoryl) phenyl) amino) -2- ((4- (methoxycarbamoyl) phenyl) amino) pyrimidine-5-carboxylic acid (100 mg,0.22 mmol), methylamine hydrochloride (30 mg,0.44 mmol), HATU (125 mg,0.33 mmol) and DMAP (2.68 mg, 0.002mmol) were dissolved in DMF (2 mL), DIPEA (72.6. Mu.L, 0.44 mmol) was added, reacted overnight at room temperature and the reaction was monitored to completion. Water was added, DCM was added for extraction, and dried and concentrated, and column chromatography gave 34mg of 4- ((2- (dimethylphosphoryl) phenyl) amino) -2- ((4- (methoxycarbamoyl) phenyl) amino) -N-methylpyrimidine-5-carboxamide. ¹ H NMR(400MHz,DMSO)δ11.54(s,1H),10.96(s,1H),9.91(s,1H),8.69(s,1H),8.53(d,J＝3.9Hz,1H),7.91–7.80(m,1H),7.70(m,2H),7.61(d,J＝8.3Hz,2H),7.49(m,3H),3.69(s,3H),2.80(d,J＝4.4Hz,3H),1.66(d,J＝13.3Hz,6H).MS m/z(ESI):469.2[M+H] ⁺ 。

Example 52

Preparation of 4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-isobutoxy benzamide (52)

(2-aminophenyl) dimethylphosphine oxide (250 mg,1.47 mmol), 2,4, 5-trichloropyrimidine (270 mg,1.47 mmol) and NaHCO ₃ (247 mg,2.94 mmol) was dissolved in ethanol (5 mL) and reacted at room temperature for 5h to monitor the completion of the reaction. Adding water, extracting with dichloromethane, drying, concentrating, and column chromatography to obtain 0.23g (2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide, MS m/z (ESI): 316.0[ M+H)] ⁺ 。

Step 2 Synthesis of 4- ((5-chloro-4- ((2- (dimethylphosphono) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid

(2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (114 mg,0.36 mmol) and para-aminobenzoic acid (49 mg,0.36 mmol) were dissolved in isopropanol (4 mL), a solution of 1, 4-dioxane (90.2. Mu.L) in 4N hydrochloric acid was added, reacted at 65℃for 14h, monitored for reaction completion, the system was suction filtered to give 115mg of 4- ((5-chloro-4- ((2- (dimethylphosphinoyl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 417.1[ M+H ]] ⁺ 。

Step 3 Synthesis of 4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-isobutoxy benzamide

4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid (115 mg,0.28 mmol), isobutoxy amine hydrochloride (69 mg,0.56 mmol), HATU (158 mg,0.41 mmol) and DMAP (0.33 mg, 0.002mmol) were dissolved in DMF (2 mL), DIPEA (91.4. Mu.L, 0.56 mmol) was added and the reaction was monitored for completion at room temperature overnight. Water was added, extracted with DCM, dried and concentrated, and column chromatography gave 50mg of 4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-isobutoxybenzamide. ¹ H NMR(400MHz,DMSO)δ11.44(s,1H),11.17(s,1H),9.74(s,1H),8.54(d,J＝4.5Hz,1H),8.25(s,1H),7.74(d,J＝8.8Hz,2H),7.69–7.52(m,4H),7.23(t,J＝7.0Hz,1H),3.65(d,J＝6.7Hz,2H),1.93(m,1H),1.78(d,J＝13.6Hz,6H),0.94(d,J＝6.7Hz,6H).MS m/z(ESI):488.2[M+H] ⁺ 。

Example 53

Preparation of 4- ((5-bromo-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide (53)

Step 1 Synthesis of (2- ((5-bromo-2-chloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

(2-aminophenyl) dimethylphosphine oxide (120 mg,0.71 mmol), 5-bromo-2, 4-dichloropyrimidine (178 mg,0.78 mmol) and DIPEA (0.24 mL,1.42 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 2h, monitoring the completion of the reaction. Adding water, extracting with dichloromethane, drying, concentrating, and column chromatography to obtain 180mg (2- ((5-bromo-2-chloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide, MS m/z (ESI): 359.9[ M+H ]] ⁺ 。

Step 2 Synthesis of 4- ((5-bromo-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid

(2- ((5-bromo-2-chloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (100 mg,0.28 mmol) and p-aminobenzoic acid (38 mg,0.28 mmol) were dissolved in isopropanol (4 mL), and a 1, 4-dioxane solution (70. Mu.L, 0.28 mmol) of 4N hydrochloric acid was added thereto, and the reaction was allowed to proceed at 65℃for 4 hours, followed by monitoring the completion of the reaction. The system was suction filtered to give 115mg of 4- ((5-bromo-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 461.0[ M+H ]] ⁺ 。

Step 3 Synthesis of 4- ((5-bromo-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide

4- ((5-bromo-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid (115 mg,0.25 mmol), methoxyamino hydrochloride (42 mg,0.50 mmol), HATU (143 mg,0.38 mmol) and DMAP (0.3 mg, 0.002mmol) were dissolved in DMF (3 mL), DIPEA (83. Mu.L, 0.50 mmol) was added, and the reaction was monitored for completion at room temperature overnight. Adding waterDCM was added for extraction, dried and concentrated, and column chromatography gave 80mg of 4- ((5-bromo-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide. ¹ H NMR(400MHz,DMSO)δ11.56(s,1H),10.81(s,1H),9.74(s,1H),8.36(m,1H),8.32(s,1H),7.71(d,J＝8.8Hz,2H),7.66–7.52(m,4H),7.24(t,J＝7.0Hz,1H),3.68(s,3H),1.76(d,J＝13.5Hz,7H).MS m/z(ESI):490.1[M+H] ⁺ 。

Example 54

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5-fluoropyrimidin-2-yl) amino) -N-methoxybenzamide (54)

Step 1 Synthesis of (2- ((2-chloro-5-fluoropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide

(2-aminophenyl) dimethylphosphine oxide (100 mg,0.59 mmol), 2, 4-dichloro-5-fluoropyrimidine (109 mg,0.65 mmol) and DIPEA (196. Mu.L, 1.18 mmol) were dissolved in DMF (5 mL) and reacted at 65℃for 5h, monitoring the completion of the reaction. Adding water, extracting with dichloromethane, drying, concentrating, and column chromatography to obtain 87mg (2- ((2-chloro-5-fluoropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide, MS m/z (ESI) 300.0[ M+H ]] ⁺ 。

Step 2 Synthesis of 4- (((4- ((2- (dimethylphosphoryl) phenyl) amino) -5-fluoropyridylamino-2-yl) amino) benzoic acid

(2- ((2-chloro-5-fluoropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (87 mg,0.29 mmol) and p-aminobenzoic acid (40 mg,0.29 mmol) were dissolved in isopropanol (4 mL), and a 1, 4-dioxane solution (73. Mu.L, 0.29 mmol) of 4N hydrochloric acid was added thereto, and the reaction was allowed to proceed at 65℃for 12 hours, followed by monitoring the completion of the reaction. The system was suction filtered to give 80mg of 4- (((4- ((2- (dimethylphosphoryl) phenyl) amino) -5-fluoropyridylamino-2-yl) amino) benzoic acid, MSm/z (ESI): 401.1[ M+H)] ⁺ 。

Step 3 Synthesis of 4- ((4- ((2- (2- (dimethylphosphoryl) phenyl) amino) -5-fluoropyridylamino-2-yl) amino) -N-methoxybenzamide

4- (((4- ((2- (dimethylphosphoryl) phenyl) amino) is reacted with an amine Base) -5-fluoropyridylamino-2-yl) amino benzoic acid (80 mg,0.20 mmol), methoxyamino hydrochloride (34 mg,0.40 mmol), HATU (114 mg,0.3 mmol) and DMAP (0.25 mg, 0.002mmol) were dissolved in DMF (3 mL), DIPEA (66. Mu.L, 0.40 mmol) was added and reacted overnight at room temperature and the reaction was monitored to completion. Water was added, extracted with DCM, dried and concentrated, and column chromatography gave 80mg of 4- ((4- ((2- (2- (dimethylphosphoryl) phenyl) amino) -5-fluoropyridylamino-2-yl) amino) -N-methoxybenzamide. ¹ H NMR(400MHz,DMSO)δ11.59(s,1H),11.55(s,1H),9.66(s,1H),8.76(m,1H),8.20(d,J＝3.3Hz,1H),7.77(d,J＝8.9Hz,2H),7.71–7.52(m,4H),7.19(t,J＝7.1Hz,1H),3.69(s,3H),1.80(d,J＝13.6Hz,6H).MSm/z(ESI):430.1[M+H] ⁺ 。

Example 55

Preparation of 7- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-di-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide (55)

(2-aminophenyl) dimethylphosphine oxide (400 mg,2.35 mmol), 2,4, 5-trichloropyrimidine (433 mg,2.35 mmol) and NaHCO ₃ (399mg, 4.71 mmol) was dissolved in EtOH (8 mL) and reacted at 85℃for 5h, monitoring the reaction was complete. Adding water, extracting with dichloromethane, drying, concentrating, and column chromatography to obtain 500mg (2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide, MS m/z (ESI): 316.0[ M+H)] ⁺ 。

Step 2 Synthesis of 7- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-dimethyl-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid

(2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (89 mg,0.28 mmol) and 7-amino-2, 3-dihydrobenzofuran-4-carboxylic acid (50 mg,0.28 mmol) were dissolved in isopropanol (4 mL), a 1, 4-dioxane solution of 4N hydrochloric acid (70. Mu.L, 0.28 mmol) was added, and the reaction was allowed to proceed for 14h at 65℃and was monitored for completion, and the system was suction filtered to give 86mg of 7- ((5-chloro-4-)(2- (dimethylphosphoryl) phenyl) amino) pyrimidin-dimethyl-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid, MS m/z (ESI): 459.1[ M+H ]] ⁺ 。

Step 3 Synthesis of 7- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyridin-amino-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide

7- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (86 mg,0.19 mmol), methoxyamino hydrochloride (32 mg,0.38 mmol), HATU (107 mg,0.28 mmol) and DMAP (0.23 mg, 0.002mmol) were dissolved in DMF (3 mL), DIPEA (63. Mu.L, 0.38 mmol) was added and the reaction was monitored at room temperature overnight. Water was added, extracted with DCM, dried and concentrated, and column chromatographed to give 40mg of 7- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyridinamino-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide. ¹ H NMR(400MHz,DMSO)δ11.47(s,1H),11.26(s,1H),8.59(s,1H),8.54(m,1H),8.18(s,1H),7.63–7.52(m,2H),7.43(t,J＝7.9Hz,1H),7.15(t,J＝7.0Hz,1H),7.06(d,J＝8.4Hz,1H),4.55(t,J＝8.8Hz,2H),3.72(s,3H),3.44(t,J＝8.9Hz,2H),1.78(d,J＝13.5Hz,6H).MS m/z(ESI):488.2[M+H] ⁺ 。

Example 56

Preparation of 4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide (56)

Step 2 Synthesis of 4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid

(2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (85 mg,0.27 mmol) and 4-amino-2-fluoro-5-methoxybenzoic acid (50 mg,0.27 mmol) were dissolved in isopropanol (4 mL), a solution of 1, 4-dioxane (68. Mu.L, 0.27 mmol) in 4N hydrochloric acid was added, the reaction was monitored at 65℃for 14h, and the system was filtered with suction to give 70mg 7- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-dimethyl-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid, MS m/z (ESI): 465.1[ M+H ] ] ⁺ 。

Step 3 Synthesis of 4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide

7- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-dimethyl-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (70 mg,0.15 mmol), isobutylamine hydrochloride (38 mg,0.30 mmol), HATU (86 mg,0.23 mmol) and DMAP (0.18 mg, 0.002mmol) were dissolved in DMF (2 mL), DIPEA (50. Mu.L, 0.30 mmol) was added and the reaction was monitored at room temperature overnight. Water was added, DCM was added for extraction, and dried and concentrated, and column chromatography gave 37mg of 4- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide. ¹ H NMR(400MHz,DMSO)δ11.29(s,1H),11.22(s,1H),8.44(m,1H),8.30(s,1H),8.22(s,1H),8.09(d,J＝12.7Hz,1H),7.61(m 2H),7.29–7.12(m,2H),3.89(s,3H),3.68(d,J＝6.6Hz,2H),1.79(d,J＝13.6Hz,6H),1.23(s,1H),0.95(d,J＝6.6Hz,6H).MS m/z(ESI):536.2[M+H] ⁺ 。

Example 57

Preparation of (2- ((5-chloro-2- ((5-fluoro-4- (isobutoxycarbamoyl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl dimethyl phosphonate (57)

Step 1, synthesizing 2, 5-dichloro-N- (2-iodophenyl) pyrimidine-4-amine

2-iodoaniline (4.4 g,20.08 mmol), 2,4, 5-trichloropyrimidine (4.4 g,23.98 mmol) and DIPEA (3.5 mL,20.08 mmol) were dissolved in nBuOH (10 mL) and reacted at 85℃for 16h, monitoring the reaction was complete. Adding water, extracting with dichloromethane, drying, concentrating, and column chromatography to obtain 2.0g of 2, 5-dichloro-N- (2-iodophenyl) pyrimidin-4-amine, MS m/z (ESI) 365.9[ M+H ] ] ⁺ 。

Step 2 Synthesis of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid

2, 5-dichloro-N- (2-iodophenyl) pyrimidin-4-amine (200 mg,0.55 mmol) and 4-amino-2-fluoro-5-methoxybenzoic acid (122 mg,0.66 mmol) were dissolved in nBuOH (4 mL), and a 1, 4-dioxane solution (41. Mu.L, 0.16 mmol) of 4N hydrochloric acid was added to react at 120℃for 3 hours, and the reaction was monitored to completion. The system was suction filtered to give 120mg of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid, MS m/z (ESI): 515.0[ M+H ]] ⁺ 。

Step 3 Synthesis of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide

4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid (120 mg,0.23 mmol), isobutylamine hydrochloride (88 mg,0.70 mmol), HATU (178 mg,0.46 mmol) and DMAP (2.9 mg,0.02 mmol) were dissolved in DMF (3 mL), DIPEA (0.23 mL,1.40 mmol) was added and the reaction was allowed to react overnight at room temperature and monitored for completion. Water was added, extracted with DCM, dried and concentrated, and column chromatography gave 110mg of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide. MS m/z (ESI): 586.1[ M+H ] ] ⁺ 。

Step 4 Synthesis of (2- ((5-chloro-2- ((5-fluoro-4- (isobutoxycarbamoyl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl dimethyl phosphonate

4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide (110 mg,0.19 mmol), dimethyl phosphate (69. Mu.L, 0.75 mmol), pd (dppf) Cl ₂ (16 mg,0.02 mmol) and K ₃ PO ₄ (80 mg,0.38 mmol) in 1, 4-dioxane (3 mL), N ₂ Under the protection ofThe reaction was monitored to be complete by reacting at 120℃for 16 h. Water was added, extracted with DCM, dried and concentrated, and column chromatographed to give 30mg of (2- ((5-chloro-2- ((5-fluoro-4- (isobutoxycarbamoyl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl dimethylphosphonate. ¹ H NMR(400MHz,DMSO)δ11.25(s,1H),9.88(s,1H),8.40(t,J＝7.3Hz,1H),8.31(s,1H),8.25(s,1H),7.98(d,J＝12.7Hz,1H),7.65(m,2H),7.29(td,J＝7.7,3.2Hz,1H),7.14(d,J＝6.3Hz,1H),3.85(s,3H),3.67(s,3H),3.65(s,3H),3.63(s,2H),1.20(m,1H),0.91(d,J＝6.6Hz,6H).MS m/z(ESI):568.2[M+H] ⁺ 。

Example 58

Preparation of dimethyl (2- ((5-chloro-2- ((4- (methoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate (58)

Step 1 Synthesis of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) benzoic acid

2, 5-dichloro-N- (2-iodophenyl) pyrimidin-4-amine (400 mg,1.10 mmol) and 4-aminobenzoic acid (180 mg,1.31 mmol) were dissolved in nBuOH (5 mL), and a 1, 4-dioxane solution (82. Mu.L, 0.33 mmol) of 4N hydrochloric acid was added and reacted at 120℃for 3 hours to monitor the completion of the reaction. Suction filtration of the system afforded 520mg of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 466.9[ M+H ] ] ⁺ 。

Step 2 Synthesis of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide

4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) benzoic acid (250 mg,0.54 mmol), methoxyamino hydrochloride (134 mg,1.61 mmol), HATU (408 mg,1.08 mmol) and DMAP (6.6 mg,0.05 mmol) were dissolved in DMF (3 mL), DIPEA (0.53 mL,3.22 mmol) was added, the reaction was allowed to proceed overnight at room temperature and monitored for completion. Water was added, DCM was added for extraction, and the mixture was dried and concentrated, and column chromatography gave 240mg of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide. MS m/z (ESI): 496.0[ M+H ]] ⁺ 。

Step 3 Synthesis of dimethyl (2- ((5-chloro-2- ((4- (methoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate

4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide (130 mg,0.26 mmol), dimethyl phosphate (96. Mu.L, 1.05 mmol), pd (dppf) Cl ₂ (22 mg,0.02 mmol) and K ₃ PO ₄ (112 mg,0.53 mmol) in 1, 4-dioxane (5 mL), N ₂ The reaction was monitored to be complete by reacting for 16h at 100℃under protection. Water was added, DCM was added for extraction, and the mixture was dried and concentrated, and column chromatography gave 20mg of dimethyl (2- ((5-chloro-2- ((4- (methoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate. ¹ H NMR(400MHz,DMSO)δ11.54(s,1H),9.86(s,1H),9.78(s,1H),8.55–8.45(m,1H),8.28(s,1H),7.76–7.55(m,6H),7.30(m,1H),3.73–3.60(m,9H).MS m/z(ESI):568.2[M+H] ⁺ 。

Example 59

Preparation of dimethyl (2- ((5-chloro-2- ((4- (isobutoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) bisphosphonate (51)

2, 5-dichloro-N- (2-iodophenyl) pyrimidin-4-amine (400 mg,1.10 mmol) and 4-aminobenzoic acid (180 mg,1.31 mmol) were dissolved in nBuOH (5 mL), and a 1, 4-dioxane solution (82. Mu.L, 0.33 mmol) of 4N hydrochloric acid was added and reacted at 120℃for 3 hours to monitor the completion of the reaction. Suction filtration of the system afforded 520mg of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 466.9[ M+H ]] ⁺ 。

Step 2 Synthesis of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-isobutoxy benzamide

4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) benzoic acid (250 mg,0.54 mmol), isobutylamine hydrochloride (202 mg,1.61 mmol), HATU (408 mg,1.08 mmol) and DMAP (6.6 mg,0.05 mmol) were dissolved in DMF (3 mL), DIPEA (0.53 mL,3.22 mmol) was added, chamberThe reaction was allowed to warm overnight and monitored for completion. Water was added, DCM was added for extraction, and the mixture was dried and concentrated, and column chromatography gave 230mg of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-isobutoxybenzamide. MS m/z (ESI): 538.1[ M+H ] ] ⁺ 。

Step 3 Synthesis of dimethyl (2- ((5-chloro-2- ((4- (isobutoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) bisphosphonate

4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-isobutoxy benzamide (130 mg,0.24 mmol), dimethyl phosphate (89. Mu.L, 0.97 mmol), pd (dppf) Cl ₂ (20 mg,0.02 mmol) and K ₃ PO ₄ (103 mg,0.48 mmol) in 1, 4-dioxane (5 mL), N ₂ The reaction was monitored to be complete by reacting for 16h at 100℃under protection. Water was added, extracted with DCM, dried and concentrated, and column chromatographed to give 20mg of dimethyl (2- ((5-chloro-2- ((4- (isobutoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) bisphosphonate. ¹ H NMR(400MHz,DMSO)δ11.43(s,1H),9.86(s,1H),9.77(s,1H),8.51(t,J＝7.4Hz,1H),8.28(s,1H),7.74–7.56(m,6H),7.29(m,1H),3.68(s,3H),3.65(s,3H),3.62(d,J＝6.7Hz,2H),1.20(m,1H),0.91(d,J＝6.7Hz,6H).MS m/z(ESI):520.1[M+H] ⁺ 。

Example 60

Preparation of dimethyl (2- ((5-chloro-2- ((4- (methylcarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate (60)

Step 1 Synthesis of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-methylbenzamide

2, 5-dichloro-N- (2-iodophenyl) pyrimidin-4-amine (200 mg,0.55 mmol) and 4-amino-N-methylbenzamide (99 mg,0.66 mmol) were dissolved in nBuOH (4 mL), and a 1, 4-dioxane solution (41. Mu.L, 0.16 mmol) of 4N hydrochloric acid was added thereto and reacted at 120℃for 3 hours to monitor the completion of the reaction. Suction filtration of the system afforded 260mg of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-methylbenzamide, MS m/z (ESI): 480.0[ M+H ] ] ⁺ 。

Step 2 Synthesis of dimethyl (2- ((5-chloro-2- ((4- (methylcarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate

4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-methylbenzamide (150 mg,0.31 mmol), dimethyl phosphate (0.12 mL,1.25 mmol), pd (dppf) Cl ₂ (26 mg,0.03 mmol) and K ₃ PO ₄ (133 mg,0.62 mmol) in 1, 4-dioxane (3 mL), N ₂ The reaction was monitored to be complete by reacting for 16h at 95℃under protection. Water was added, DCM was added for extraction, and the mixture was dried and concentrated, and column chromatography gave 84mg of dimethyl (2- ((5-chloro-2- ((4- (methylcarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate. ¹ H NMR(400MHz,DMSO)δ9.88(s,1H),9.76(s,1H),8.54(s,1H),8.29(s,1H),8.24(d,J＝4.5Hz,1H),7.77–7.60(m,6H),7.30(m,1H),3.68(d,J＝11.3Hz,6H),2.75(d,J＝4.5Hz,3H).MS m/z(ESI):462.1[M+H] ⁺ 。

Example 61

Preparation of dimethyl (2- ((2- ((4- (methoxycarbamoyl) -2, 3-dihydrobenzofuran-7-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) bisphosphonate (61)

2-iodoaniline (4.0 g,18.26 mmol), dimethyl phosphate (5.0 mL,54.78 mmol), pd (dppf) ₂ Cl ₂ (1.5 g,1.83 mmol) and K ₃ PO ₄ (9.7 g,45.65 mmol) in 1, 4-dioxane (100 mL), N ₂ The reaction was monitored to be complete by reacting for 16h at 100℃under protection. Adding water, extracting with DCM, drying, concentrating, and column chromatography to obtain 1.7g (2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide, MS m/z (ESI): 202.3[ M+H) ] ⁺ 。

Oxidation of (2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylPhosphine (1.9 g,9.50 mmol), 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.9 g,8.64 mmol) and NaHCO ₃ (1.4 g,17.28 mmol) was dissolved in EtOH (60 mL) and reacted overnight at 60℃to monitor completion of the reaction. Adding water, extracting with dichloromethane, drying, concentrating, and column chromatography to give 419mg (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) phosphonic acid dimethyl ester, MS m/z (ESI): 382.0[ M+H ]] ⁺ 。

Step 3 Synthesis of 7- ((4- ((2- (2- (dimethoxyphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid

Dimethyl (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) phosphonate (129 mg,0.34 mmol) and 7-amino-2, 3-dihydrobenzofuran-4-carboxylic acid (61 mg,0.34 mmol) were dissolved in isopropanol (8 mL), a solution of 4N hydrochloric acid in 1, 4-dioxane (0.15 mL) was added, and the reaction was allowed to react at 65℃for 3h, monitoring the completion of the reaction. The system was suction filtered to give 120mg of 7- ((4- ((2- (2- (dimethoxyphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid, MS m/z (ESI): 525.1[ M+H) ] ⁺ 。

Step 4 Synthesis of dimethyl (2- ((2- ((4- (methoxycarbamoyl) -2, 3-dihydrobenzofuran-7-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl bisphosphonate

7- ((4- ((2- (2- (dimethoxyphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (60 mg,0.12 mmol), methoxyamino hydrochloride (29 mg,0.35 mmol), HATU (87 mg,0.23 mmol) and DMAP (1.4 mg,0.01 mmol) were dissolved in DMF (10 mL), DIPEA (0.11 mL,0.69 mmol) was added and the reaction was monitored at room temperature for 7h, the reaction was complete. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.50(s,1H),9.50(s,1H),9.18(s,1H),8.43(s,1H),8.26(s,1H),11.50(s,1H),7.60–7.66(m,1H),7.49(t,J＝7.47Hz,1H),7.35(d,J＝7.46Hz,1H)7.26(td,J＝2.83,7.34Hz,1H),7.0(d,J＝8.33Hz,1H),4.5(t,J＝8.77,2H),3.71(s,3H),3.67(s,3H),3.65(s,3H),3.41(t,J＝8.76,2H).MS m/z(ESI)：524.2[M+H] ⁺ .MS m/z(ESI):554.1[M+H] ⁺ 。

Example 62

Preparation of dimethyl (2- ((5-chloro-2- ((4- (methoxycarbamoyl) -2, 3-dihydrobenzofuran-7-yl) amino) pyrimidin-4-yl) amino) phenyl) bisphosphonate (62)

Step 1 Synthesis of 7- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid

2, 5-dichloro-N- (2-iodophenyl) pyrimidin-4-amine (120 mg,0.33 mmol) and 7-amino-2, 3-dihydrobenzofuran-4-carboxylic acid (59 mg,0.33 mmol) were dissolved in isopropanol (8 mL), and a 1, 4-dioxane solution (0.15 mL) of 4N hydrochloric acid was added to react at 120℃for 2h to monitor completion. Suction filtration of the system afforded 71mg 7- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid, MS m/z (ESI): 508.9[ M+H ] ] ⁺ 。

Step 2 Synthesis of 7- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide

7- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (71 mg,0.14 mmol), methoxyamino hydrochloride (35 mg,0.42 mmol), HATU (106 mg,0.28 mmol) and DMAP (1.7 mg,0.01 mmol) were dissolved in DMF (12 mL), DIPEA (0.14 mL,0.83 mmol) was added, and the reaction was allowed to proceed overnight at room temperature and monitored for completion. Adding water, extracting with DCM, drying, concentrating, and column chromatography to obtain 67mg 7- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide, MSm/z (ESI) 538.3[ M+H ]] ⁺ 。

Step 3 Synthesis of dimethyl (2- ((5-chloro-2- ((4- (methoxycarbamoyl) -2, 3-dihydrobenzofuran-7-yl) amino) pyrimidin-4-yl) amino) phenyl bisphosphonate

7- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide (67 mg,0.13 mmol), dimethyl phosphate (34. Mu.L, 0.38 mmo)l)、Pd(dppf) ₂ Cl ₂ (10 mg,0.01 mmol) and K ₃ PO ₄ (66 mg,0.31 mmol) in 1, 4-dioxane (10 mL), N ₂ The reaction was monitored to be complete by reacting for 16h at 100℃under protection. Water was added, extracted with DCM, dried and concentrated, and column chromatographed to give 25mg of dimethyl (2- ((5-chloro-2- ((4- (methoxycarbamoyl) -2, 3-dihydrobenzofuran-7-yl) amino) pyrimidin-4-yl) amino) phenyl bisphosphonate. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.48(s,1H),10.01(s,1H),8.74(s,1H),8.57(t,J＝7.3Hz,1H),8.23(s,1H),7.61(dd,J＝14.4,7.8Hz,1H),7.54(t,J＝7.5Hz,2H),7.22(dd,J＝7.7,4.9Hz,1H),7.05(d,J＝8.4Hz,1H),4.54(t,J＝8.8Hz,2H),3.71(s,6H),3.68(s,3H),3.43(t,J＝8.8Hz,2H).MS m/z(ESI):520.4[M+H] ⁺ 。

Example 63

Preparation of dimethyl (2- ((2- (((4- (isobutoxycarbamoyl) -2, 3-dihydrobenzofuran-7-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) bisphosphonate (63)

2-iodoaniline (4.0 g,18.26 mmol), dimethyl phosphate (5.0 mL,54.78 mmol), pd (dppf) ₂ Cl ₂ (1.5 g,1.83 mmol) and K ₃ PO ₄ (9.7 g,45.65 mmol) in 1, 4-dioxane (100 mL), N ₂ The reaction was monitored to be complete by reacting for 16h at 100℃under protection. Adding water, extracting with DCM, drying and concentrating, and column chromatography to obtain 1.7g (2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide, MS m/z (ESI): 202.1[ M+H)] ⁺ 。

(2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (1.9 g,9.50 mmol), 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.9 g,8.64 mmol) and NaHCO ₃ (1.4 g,17.28 mmol) was dissolved in EtOH (60 mL), reacted overnight at 60 ℃,the reaction was monitored for completion. Adding water, extracting with dichloromethane, drying, concentrating, and column chromatography to give 419mg (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) phosphonic acid dimethyl ester, MS m/z (ESI): 382.0[ M+H ] ] ⁺ 。

Dimethyl (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) phosphonate (129 mg,0.34 mmol) and 7-amino-2, 3-dihydrobenzofuran-4-carboxylic acid (61 mg,0.34 mmol) were dissolved in isopropanol (8 mL), a solution of 4N hydrochloric acid in 1, 4-dioxane (0.15 mL) was added, and the reaction was allowed to react at 65℃for 3h, monitoring the completion of the reaction. The system was suction filtered to give 120mg of 7- ((4- ((2- (2- (dimethoxyphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid, MS m/z (ESI): 525.3[ M+H)] ⁺ 。

Step 4 Synthesis of dimethyl (2- ((2- (((4- (isobutoxycarbamoyl) -2, 3-dihydrobenzofuran-7-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) bisphosphonate

7- ((4- ((2- (2- (dimethoxyphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (60 mg,0.12 mmol), isobutoxy amine hydrochloride (43 mg,0.35 mmol), HATU (87 mg,0.23 mmol) and DMAP (1.4 mg,0.01 mmol) were dissolved in DMF (10 mL), DIPEA (0.11 mL,0.69 mmol) was added and the reaction was monitored for 7h at room temperature. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.14(s,1H),7.46–7.38(m,2H),7.39–7.31(m,2H),7.26(d,J＝8.2Hz,1H),7.02–6.88(m,2H),6.36(dd,J＝17.0,10.1Hz,1H),6.20(dd,J＝17.0,2.1Hz,1H),5.72(dd,J＝10.0,2.1Hz,1H).MS m/z(ESI):596.2[M+H] ⁺ 。

Example 64

Preparation of (2- ((2- ((5-fluoro-4- (isobutoxycarbamoyl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphonate (64)

Step 1 Synthesis of dimethyl (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) phosphonate

(2- (((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (1.0 g,4.98 mmol), 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.0 g,4.53 mmol) and NaHCO ₃ (0.8 g,9.05 mmol) was dissolved in EtOH (40 mL) and reacted overnight at 60℃to monitor completion of the reaction. Adding water, extracting with dichloromethane, drying, concentrating, and column chromatography to obtain 120mg (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) phosphonic acid dimethyl ester, MSm/z (ESI) 382.0[ M+H ]] ⁺ 。

Step 2 Synthesis of 4- ((4- ((2- (Di (methoxyphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid

Dimethyl (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) phosphonate (120 mg,0.32 mmol) and 4-amino-2-fluoro-5-methoxybenzoic acid (58 mg,0.32 mmol) were dissolved in isopropanol (8 mL), a solution of 4N hydrochloric acid in 1, 4-dioxane (0.15 mL) was added, and the reaction was monitored for completion at 65 ℃ for 3 h. The system was suction filtered to give 111mg of 4- ((4- ((2- (di (methoxyphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid, MS m/z (ESI): 531.2[ M+H ] ] ⁺ 。

Step 3 Synthesis of (2- ((2- ((5-fluoro-4- (isobutoxycarbamoyl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl dimethyl phosphonate

4- ((4- ((2- (Di (methoxy phosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid (60 mg,0.11 mmol), isobutoxy amine hydrochloride (43 mg,0.34 mmol), HATU (86 mg,0.23 mmol) and DMAP (1.4 mg,0.01 mmol) were dissolved in DMF (3 mL), DIPEA (0.11 mL,0.68 mmol) was added, the reaction was monitored overnight at room temperature, the reaction was complete, water was added, DCM was added for extraction, dried and concentrated, column chromatography gave 53mg (2- ((5-fluoro-4- (isobutoxycarbonyl) -2-methoxy)Phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino phenyl dimethyl phosphonate. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.31(s,1H),9.42(s,1H),8.59(s,1H),8.52(s,1H),8.12(s,1H),7.83–7.61(m,3H),7.37(td,J＝7.4,2.9Hz,1H),7.16(d,J＝6.3Hz,1H),3.85(s,3H),3.68(s,2H),3.65(s,4H),3.63(s,3H),2.00–1.85(m,1H),0.94(d,J＝6.7Hz,6H).MS m/z(ESI):602.3[M+H] ⁺ 。

Example 65

Preparation of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide (65)

Step 1, synthesizing (2-aminophenyl) diethyl phosphine oxide

2-iodoaniline (4.6 g,21.2 mmol), diethylphosphine oxide (0.89 mL,25.45 mmol), pd (OAc) ₂ (0.5 g,2.12 mmol), xantPhos (1.2 g,2.1 mmol) and K ₃ PO ₄ (5.4 g,25.45 mmol) in DMF (120 mL), N ₂ The reaction was monitored to be complete by reacting for 16h at 120℃under protection. Adding water, extracting with DCM, drying, concentrating, and column chromatography to obtain 1.8g (2-aminophenyl) diethylphosphine oxide, MS m/z (ESI) 198.3[ M+H ] ] ⁺ 。

Step 2 Synthesis of (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) diethylphosphine oxide

(2-aminophenyl) diethylphosphine oxide (1.0 g,5.08 mmol), 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.0 g,4.62 mmol) and DIPEA (0.60 g,4.62 mmol) were dissolved in DMF (15 mL), reacted overnight at 60℃and monitored for completion. Adding water, extracting with dichloromethane, drying, concentrating, and column chromatography to obtain 83mg (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) diethylphosphine oxide, MS m/z (ESI): 378.1[ M+H ]] ⁺ 。

Step 3 Synthesis of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid

(2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) diethyloxyPhosphine (83 mg,0.22 mmol) and 4-aminobenzoic acid (30 mg,0.22 mmol) were dissolved in isopropanol (6 mL), and a 1, 4-dioxane solution (0.1 mL) of 4N hydrochloric acid was added thereto, and the reaction was allowed to proceed at 65℃for 3 hours, followed by monitoring the completion of the reaction. The system was suction filtered to give 80mg of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid, MS m/z (ESI): 479.0[ M+H ]] ⁺ 。

Step 4 Synthesis of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide

4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (80 mg,0.17 mmol), methoxyamino hydrochloride (43 mg,0.51 mmol), HATU (128 mg,0.34 mmol) and DMAP (2.1 mg,0.02 mmol) were dissolved in DMF (15 mL), DIPEA (0.17 mL,1.01 mmol) was added and reacted at room temperature for 7h to monitor completion. Water was added, DCM was added for extraction, and the mixture was dried and concentrated, and column chromatography gave 63mg of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxybenzamide. ¹ HNMR(400MHz,DMSO-d ₆ )δ11.40(s,1H),10.82(s,1H),9.11(s,1H),8.39(s,1H),8.24(s,1H),7.55(dd,J＝13.7,7.7Hz,1H),7.37(d,J＝7.8Hz,2H),7.16(t,J＝7.4Hz,1H),7.02(d,J＝8.3Hz,1H),4.51(t,J＝8.8Hz,2H),3.66(d,J＝6.7Hz,2H),3.40(t,J＝8.8Hz,2H),2.01–1.88(m,2H),1.75(s,3H),1.72(s,3H),0.95(d,J＝6.7Hz,7H).MS m/z(ESI):508.2[M+H] ⁺ 。

Example 66

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-chlorobenzamide (66)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-chlorobenzoic acid

(2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (60 mg,0.172 mmol), 4-amino-2-chlorobenzoic acid (33 mg,0.19 mmol) and 4M hydrochloric acid 1A solution of 4-dioxane (0.25 mL,1 mmol) was added to isopropanol (6 mL), then reacted at 60℃for 4h, after completion of LCMS monitoring, the reaction system was cooled to room temperature, the solid obtained by suction filtration was washed with isopropanol (2 mL. Times.3), and then dried at 50℃for 1h to give 50mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-chlorobenzoic acid, MS m/z (ESI): 485.1[ M+H ] ] ⁺ .

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-chlorobenzoamide

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-chlorobenzoic acid (50 mg,0.1 mmol), O-isobutylamine hydrochloride (38 mg,0.3 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (57 mg,0.15 mmol) and N, N-diisopropylethylamine (0.1 mL,0.6 mmol) were added to N, N-dimethylformamide (2.5 mL) and then reacted at room temperature for 16h, after LCMS monitoring the reaction was completed, the reaction was quenched with water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with water, dried and concentrated, and column chromatography gave 40mg of 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-chlorobenzamide. ¹ HNMR(400MHz,DMSO-d ₆ )δ11.36(s,1H),10.60(s,1H),10.11(s,1H),8.51(s,1H),8.15(s,1H),7.85(s,1H),7.61(ddt,J＝24.5,16.6,8.2Hz,3H),7.34–7.15(m,2H),3.66(d,J＝6.7Hz,2H),1.74(d,J＝13.6Hz,6H),1.23(s,1H),0.93(d,J＝6.7Hz,6H).MS m/z(ESI)：556.1[M+H] ⁺ .

Example 67

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-methoxybenzamide (67)

Step 1 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-methoxybenzoic acid

Will (2- ((2-chloro)-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl dimethylphosphine oxide (60 mg,0.172 mmol), 4-amino-2-methoxybenzoic acid (32 mg,0.19 mmol) and 4M 1, 4-dioxane hydrochloride solution (0.25 mL,1 mmol) were added to isopropanol (6 mL) and then reacted at 60℃for 4h, after completion of the LCMS monitoring reaction, the reaction system was cooled to room temperature, the solid obtained by suction filtration was washed with isopropanol (2 mL. Times.3) and then dried at 50℃for 1h to give 32mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-methoxybenzoic acid, MS M/z (ESI): 481.1[ M+H ] ] ⁺ .

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-methoxybenzamide

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-methoxybenzoic acid (32 mg,0.07 mmol), O-isobutoxy amine hydrochloride (25 mg,0.2 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (38 mg,0.1 mmol) and N, N-diisopropylethylamine (0.07 mL,0.4 mmol) were added to N, N-dimethylformamide (2.5 mL) and then reacted at room temperature for 16h, after completion of LCMS monitoring the reaction, the reaction was quenched with water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with water, dried and concentrated, and column chromatographed to give 15mg of 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-methoxybenzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.79(s,1H),10.61(s,1H),10.00(s,1H),8.50(s,1H),8.16(s,1H),7.64(dd,J＝13.5,7.6Hz,1H),7.54(t,J＝7.8Hz,1H),7.48(d,J＝8.5Hz,1H),7.43–7.32(m,2H),7.28(t,J＝7.5Hz,1H),3.64(d,J＝6.7Hz,2H),3.61(s,3H),1.74(d,J＝13.6Hz,6H),1.23(s,1H),0.93(d,J＝6.7Hz,6H).MS m/z(ESI)：552.2[M+H] ⁺ .

Example 68

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-cyanobenzamide (68)

Step 1 Synthesis of methyl 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-cyanobenzoate

A solution of (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (100 mg,0.29 mmol), methyl 4-amino-2-cyanobenzoate (55.5 mg,0.32 mmol) and 4N hydrochloric acid in 1, 4-dioxane (0.43 mL,1.74 mmol) was added to isopropanol (10 mL) and then reacted at 60℃for 4h, after LCMS monitoring the reaction completion, cooled to room temperature, the reaction system was suction filtered and the resulting solid was washed with isopropanol (2 mL. Times.3) and then dried at 50℃for 1h to give 108mg methyl 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-cyanobenzoate, MS m/z (ESI): 490.1[ M+H ] ] ⁺ .

Step 2 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-cyanobenzoic acid

Methyl 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-cyanobenzoate (108 mg,0.23 mmol) and lithium hydroxide (17 mg,0.71 mmol) were added to a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL) and then reacted overnight at 50 ℃, after completion of the LCMS monitoring reaction, cooled to room temperature, saturated citric acid solution was added to adjust the reaction system to neutral, EA (10 mL. Times.3) was extracted, dried and concentrated to give 45mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-cyanobenzoic acid, MS m/z (ESI): 476.1[ M+H ]] ⁺ .

Step 3 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-cyanobenzamide

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-cyanobenzoic acid (45 mg,0.1 mmol), O-isobutylamine hydrochloride (38 mg,0.3 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (57 mg,0.15 mmol) and N, N-diisopropylethylamine (0.1 mL,0.6 mmol) were added to N, N-dimethylformamide (2.5 mL) and then reacted at room temperature for 16h, LCMS monitored reaction completion After all, the reaction was quenched with water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with water, dried and concentrated, and column chromatography gave 8mg of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2-cyanobenzamide. ¹ HNMR(400MHz,DMSO-d ₆ )δ10.79(s,1H),10.61(s,1H),10.00(s,1H),8.50(s,1H),8.16(s,1H),7.64(dd,J＝13.5,7.6Hz,1H),7.54(t,J＝7.8Hz,1H),7.48(d,J＝8.5Hz,1H),7.43–7.32(m,2H),7.28(t,J＝7.5Hz,1H),3.64(d,J＝6.7Hz,2H),3.61(s,3H),1.74(d,J＝13.6Hz,6H),1.23(s,1H),0.93(d,J＝6.7Hz,6H).MS m/z(ESI)：547.2[M+H] ⁺ .

Example 69

Preparation of N- (cyclopentyloxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (69)

Step 1 Synthesis of 2- (cyclopentyloxy) isoindoline-1, 3-dione

Bromocyclopentane (1 mL,9 mmol), N-hydroxyphthalimide (1 g,6 mmol) and potassium carbonate (2.16 g,16 mmol) were added to dimethylsulfoxide (10 mL) at room temperature and reacted for 5min, followed by reaction at 80℃for 3h. After completion of the LCMS monitoring reaction, the reaction mixture was cooled to room temperature, water (10 mL) was added to precipitate the product, the reaction system was suction filtered, and the solid obtained by suction filtration was washed with petroleum ether (3 mL. Times.3), and then dried in vacuo for 1h to give 400mg of 2- (cyclopentyloxy) isoindoline-1, 3-dione, MS m/z (ESI): 232.1[ M+H ]] ⁺ .

Step 2, synthesizing O-cyclopentyl hydroxylamine

2- (cyclopentyloxy) isoindoline-1, 3-dione (400 mg,1.7 mmol), hydrazine hydrate (0.1 mL,2.1 mmol) and methanol (1 mL) were added to dichloromethane (9 mL), then reacted at room temperature for 4h, after completion of TLC monitoring the reaction, quenched with water (10 mL), extracted with dichloromethane (10 mL. Times.3), the organic phase was washed with water, dried and concentrated to give 60mg of O-cyclopentylhydroxylamine.

Step 3 Synthesis of N- (cyclopentyloxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (30 mg,0.07 mmol), O-cyclopentylhydroxylamine (27 mg,0.27 mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (51 mg,0.13 mmol) and N, N-diisopropylethylamine (0.1 mL,0.54 mmol) were added to N, N-dimethylformamide (3 mL), then reacted at room temperature for 16h, after completion of LCMS monitoring the reaction, the reaction was quenched with water (10 mL), extracted with EA (10 mL. Times.3), the organic phase was washed with water, dried and concentrated, and column chromatography afforded 16mg of N- (cyclopentyloxy) -4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.31(s,1H),10.58(s,1H),10.08(s,1H),8.49(s,1H),8.17(s,1H),7.64(dt,J＝26.9,8.0Hz,6H),7.32(t,J＝7.5Hz,1H),4.49(s,1H),1.85–1.77(m,2H),1.73(d,J＝13.6Hz,6H),1.69–1.60(m,3H),1.57–1.49(m,2H),1.25–1.21(m,1H).MS m/z(ESI)：534.2[M+H] ⁺ .

Example 70

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- ((tetrahydro-2H-pyran-4-yl) methoxy) benzamide (70)

Step 1 Synthesis of 2- ((tetrahydro-2H-pyran-4-yl) methoxy) isoindoline-1, 3-dione

4-Bromomethyltetrahydropyran (400 mg,2.2 mmol), N-hydroxyphthalimide (304 mg,1.8 mmol) and potassium carbonate (672 mg,4.86 mmol) were added to dimethyl sulfoxide (4 mL) at room temperature and reacted for 5min, followed by reaction at 80℃for 3h. After completion of the LCMS reaction, the reaction mixture was cooled to room temperature, water (10 mL) was added to precipitate the product, the reaction system was suction filtered, and the solid obtained by suction filtration was washed with petroleum ether (3 mL. Times.3), and then dried in vacuo for 1H to give 180mg of 2- ((tetrahydro-2H-pyran-4-yl) methoxy) isoindoline-1, 3-dione. MS m/z (ESI): 262.2[ M+H ] ] ⁺ .

Step 2 Synthesis of O- ((tetrahydro-2H-pyran-4-yl) methyl) hydroxylamine

2- ((tetrahydro-2H-pyran-4-yl) methoxy) isoindoline-1, 3-dione (180 mg,0.69 mmol), hydrazine hydrate (0.07 mL,0.83 mmol) and methanol (0.7 mL) were added to dichloromethane (6 mL) and then reacted at room temperature for 4H, after TLC monitoring the reaction was complete, the reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL. Times.3), the organic phase was washed with water, dried and concentrated to give 47mg of O- ((tetrahydro-2H-pyran-4-yl) methyl) hydroxylamine.

Step 3 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- ((tetrahydro-2H-pyran-4-yl) methoxy) benzamide

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (40 mg,0.09 mmol), O- ((tetrahydro-2H-pyran-4-yl) methyl) hydroxylamine (47 mg,0.36 mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (68 mg,0.18 mmol), N, N-diisopropylethylamine (0.13 mL,0.72 mmol) and 4-dimethylaminopyridine (4 mg,0.03 mmol) were added to N, N-dimethylformamide (3 mL), then after completion of the reaction at room temperature for 16H, LCMS monitoring the reaction, the reaction was quenched with water (10 mL), EA (10 mL. Times.3) was extracted, the organic phase was washed, dried and concentrated, column chromatography afforded 40mg of 4- ((2- (dimethylphosphoryl) phenyl) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-tetrahydro-pyran-2H-methoxy-4- ((methoxy) amino), ¹ H NMR(400MHz,DMSO-d ₆ )δ11.49(s,1H),10.56(s,1H),10.07(s,1H),8.49(s,1H),8.16(s,1H),7.77–7.54(m,6H),7.32(t,J＝7.7Hz,1H),3.85(dd,J＝11.4,4.3Hz,2H),3.73(d,J＝6.6Hz,2H),3.28(s,2H),1.73(d,J＝13.5Hz,6H),1.67(d,J＝13.7Hz,2H),1.26(dp,J＝17.5,6.7,5.9Hz,3H).MS m/z(ESI)：564.2[M+H] ⁺ .

Example 71

Preparation of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- ((tetrahydro-2H-pyran-4-yl) oxy) benzamide (71)

Step 1 Synthesis of 2- ((tetrahydro-2H-pyran-4-yl) oxy) isoindoline-1, 3-dione

4-Bromotetrahydropyran (1 g,6 mmol), N-hydroxyphthalimide (890mg, 5.5 mmol) and 1, 8-diazabicyclo [5.4.0 ] at room temperature]Undec-7-ene (0.8 mL,5.5 mmol) was added to N, N-dimethylformamide (10 mL) and then reacted at 80℃for 4h. After completion of the LCMS reaction, quench the reaction with water (20 mL), extract EA (20 mL. Times.3), wash the organic phase with water, dry and concentrate, and column chromatography gives 400mg of 2- ((tetrahydro-2H-pyran-4-yl) oxy) isoindoline-1, 3-dione, MS m/z (ESI): 248.1[ M+H ]] ⁺ .

Step 2 Synthesis of O- (tetrahydro-2H-pyran-4-yl) hydroxylamine

2- ((tetrahydro-2H-pyran-4-yl) oxy) isoindoline-1, 3-dione (400 mg,3.24 mmol), hydrazine hydrate (0.25 mL,4.23 mmol) and methanol (2 mL) were added to dichloromethane (20 mL) and then reacted at room temperature for 4H, after TLC monitoring the reaction was complete, the reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL. Times.3), the organic phase was washed with water, dried and concentrated to give 170mg of O- (tetrahydro-2H-pyran-4-yl) hydroxylamine.

Step 3 Synthesis of 4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N- ((tetrahydro-2H-pyran-4-yl) oxy) benzamide

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (50 mg,0.11 mmol), O- (tetrahydro-2H-pyran-4-yl) hydroxylamine (52 mg,0.44 mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (84 mg,0.22 mmol), N, N-diisopropylethylamine (0.16 mL,0.89 mmol) and 4-dimethylaminopyridine (4 mg,0.03 mmol) were added to N, N-dimethylformamide (3 mL), then after completion of the reaction at room temperature, the reaction was quenched with water (10 mL), EA (10 mL. Times.3) was extracted, the organic phase was washed with water, dried and concentrated, and column chromatography afforded 50mg of 4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-tetrahydro-pyran-4-yl benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.40(s,1H),10.57(s,1H),10.08(s,1H),8.49(s,1H),8.16(s,1H),7.71–7.48(m,6H),7.32(t,J＝8.0Hz,1H),4.05(ddd,J＝14.1,10.4,5.9Hz,1H),3.85(dd,J＝10.9,5.4Hz,2H),3.39(d,J＝13.6Hz,2H),1.95–1.84(m,2H),1.73(d,J＝13.6Hz,6H),1.56(dp,J＝13.3,4.5Hz,2H).MS m/z(ESI)：550.2[M+H] ⁺ .

Example 72

Preparation of N- (cyclopentylmethoxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (72)

Step 1, synthesizing 2- (cyclopentylmethoxy) isoindoline-1, 3-dione

Bromomethylcyclopentane (1 g,6 mmol), N-hydroxyphthalimide (284 mg,5.12 mmol), potassium carbonate (1.77 g,12.8 mmol) were added to dimethylsulfoxide (10 mL) and reacted at room temperature for 5min, followed by reaction at 80℃for 3h. After completion of the LCMS monitoring reaction, the reaction mixture was cooled to room temperature, water (10 mL) was added to precipitate the product, the reaction system was suction filtered, and the solid obtained by suction filtration was washed with petroleum ether (3 mL. Times.3), and then vacuum-dried for 1h to give 630mg of 2- (cyclopentylmethoxy) isoindoline-1, 3-dione, MS m/z (ESI): 246.1[ M+H ] ] ⁺ .

Step 2, synthesizing O- (cyclopentylmethyl) hydroxylamine

2- (cyclopentylmethoxy) isoindoline-1, 3-dione (630 mg,2.57 mmol), hydrazine hydrate (0.4 mL,5.14 mmol) and methanol (2 mL) were added to dichloromethane (20 mL) and then reacted at room temperature for 4h, after completion of TLC monitoring the reaction, quenched with water (10 mL), extracted with dichloromethane (10 mL. Times.3), the organic phase was washed with water, dried and concentrated to give 51mg of O- (cyclopentylmethyl) hydroxylamine.

Step 3 Synthesis of N- (cyclopentylmethoxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide

4- ((4- ((2- (Dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (50 mg,0.11 mmol), O- (cyclopentylmethyl) hydroxylamine (51 mg,0.44 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (84 mg,0.22 mmol), N, N-diiso-Propylethylamine (0.16 mL,0.89 mmol) and 4-dimethylaminopyridine (4 mg,0.03 mmol) were added to N, N-dimethylformamide (3 mL), then reacted at room temperature for 16h, after completion of LCMS monitoring the reaction, quenched with water (10 mL), extracted with EA (10 mL. Times.3), the organic phase was washed with water, dried and concentrated, and column chromatographed to give 12mg of N- (cyclopentylmethoxy) -4- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.50(s,1H),10.56(s,1H),10.08(s,1H),8.49(s,1H),8.16(s,1H),7.83–7.48(m,6H),7.32(t,J＝7.5Hz,1H),3.75(d,J＝7.1Hz,2H),2.19(p,J＝7.5Hz,1H),1.73(d,J＝13.5Hz,7H),1.63–1.44(m,4H),1.28(dd,J＝30.9,10.9Hz,3H).MS m/z(ESI)：548.2[M+H] ⁺ .

Example 73

Preparation of 7- (((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide (73)

Step 1 Synthesis of 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide

Compound 7- ((4- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (60.0 mg,0.12 mmol), O-methylhydroxylamine hydrochloride (30.9 mg,0.37 mmol), HATU (91.3 mg,0.24 mmol), DMAP (1.5 mg,0.01 mmol) and DIPEA (0.12 mL,0.72 mmol) were added to DMF (6 mL) and then reacted at room temperature for 2h, after completion of LCMS monitoring the reaction, the reaction was quenched with water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with water, dried and concentrated, and MeOH/DCM (0-10%) was purified by column chromatography to give 34.1mg of 7- ((2- (dimethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.40(s,1H),10.82(s,1H),9.11(s,1H),8.39(s,1H),8.24(s,1H),7.55(dd,J＝13.7,7.7Hz,1H),7.37(d,J＝7.8Hz,2H),7.16(t,J＝7.4Hz,1H),7.02(d,J＝8.3Hz,1H),4.51(t,J＝8.8Hz,2H),3.71(d,J＝6.7Hz,3H),3.40(t,J＝8.8Hz,2H),2.01–1.88(m,2H),1.75(s,3H),1.72(s,3H).MS m/z(ESI)：522.1[M+H] ⁺ 。

Example 74

Preparation of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxybenzamide (74)

Step 1: synthesis of (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) diethylphosphine oxide

(2-aminophenyl) diethylphosphine oxide (2.0 g,10.14 mmol) was dissolved in DMF (20 mL), and 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.37 mL,10.14 mmol) and DIPEA (1.68 mL,10.14 mmol) were added at 0deg.C under nitrogen and stirred overnight at 60deg.C to monitor completion of the reaction. Saturated ammonium chloride solution (3 mL) was added, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give intermediate (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) diethylphosphine oxide (606 mg, yield: 15.82%) as a beige solid. MS m/z (ESI): 378.10[ M+H ]] ⁺ .

Step 2: synthesis of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid

(2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) diethylphosphine oxide (400 mg,1.06 mmol) was dissolved in isopropanol (20 mL), 4-aminobenzoic acid (145.23 mg,1.06 mmol), hydrochloric acid/1, 4-dioxane (0.5 mL,2.00 mmol) was added sequentially at 0deg.C, nitrogen protection, and stirred at 65deg.C for 3 hours to monitor completion of the reaction. Filtration gave intermediate 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (349 mg, yield: 68.89%) as an off-white solid. MS m/z (ESI): 479.10[ M+H ] ] ⁺ .

Step 3: synthesis of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxybenzamide

4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60 mg,0.13 mmol) was dissolved in DMF (2 mL) and ethylcarbamate hydrochloride (37 mg,0.38 mmol), HATU (95.46 mg,0.25 mmol), DIPEA (0.12 mL,0.75 mmol) and DMAP (1.53 mg,0.01 mmol) were added sequentially at 0deg.C, and the reaction was monitored for completion at room temperature under nitrogen blanket for 5 hours. Saturated ammonium chloride solution was added, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified with (petroleum ether: ethyl acetate=0:1) to give 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-ethoxybenzamide (52 mg, yield: 78.86%) as a white solid. MS m/z (ESI): 522.20[ M+H ]] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.46(br s,1H),10.85(br s,1H),10.07(br s,1H),8.47(s,1H),8.19(br s,1H),7.69(br d,J＝8.2Hz,2H),7.52-7.63(m,4H),7.28(br t,J＝6.9Hz,1H),3.89(q,J＝7.0Hz,2H),1.86-2.10(m,4H),1.18(t,J＝7.1Hz,3H),0.87-1.02(m,6H)

Example 75

Preparation of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy benzamide (75)

Step 1: synthesis of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxybenzamide

4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzoic acid (60 mg,0.13 mmol) was dissolved in DMF (2 mL) and isobutylhydroxylamine hydrochloride (47.30 mg,0.38 mmol), HATU (95.46 mg,0.25 mmol), DIPEA (0.12 mL,0.75 mmol) and DMAP (1.53 mg,0.01 mmol) were added sequentially at 0deg.C and the reaction was monitored for completion under nitrogen blanket at room temperature for 5 hours. Adding saturated ammonium chloride solution, acetic acid ethylThe ester was extracted, the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified with (petroleum ether: ethyl acetate=0:1) to give 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy benzamide (XTC 003-190) (52 mg, yield: 75.39%) as a white solid. MS m/z (ESI) 550.2[ M+H ]] ⁺ .

¹ H NMR(DMSO-d6)δ:11.47(br s,1H),10.84(br s,1H),10.06(br s,1H),8.47(s,1H),8.19(br s,1H),7.69(br d,J＝8.1Hz,2H),7.53-7.63(m,4H),7.28(br t,J＝7.0Hz,1H),3.64(s,1H),3.62(s,1H),1.93-2.03(m,4H),0.89-1.00(m,12H).

Example 76

Preparation of 4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide (76)

Step 1: synthesis of (2-aminophenyl) diethylphosphine oxide

2-iodoaniline (10 g,45.66 mmol) was dissolved in DMF (240 mL) and diethylphosphine oxide (5.81 g,54.79 mmol), K was added ₃ PO ₄ (11.63 g,54.79 mmol), xantphos (2.64 g,4.57 mmol) and Pd (OAc) ₂ (1.03 g,4.57 mmol), nitrogen, and stirring overnight at 120℃monitored for reaction completion. Cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic layer was washed 3 times with saturated brine, dried and concentrated to give a residue. The residue was purified by column chromatography to give (2-aminophenyl) diethylphosphine oxide (8.5 g, yield: 94.39%) as a yellow solid. MS m/z (ESI): 178.10[ M+H ] ] ⁺ .

Step 2: synthesis of (2- ((2, 5-dichloropyrimidin-4-yl) amino) phenyl) diethylphosphine oxide

(2-aminophenyl) diethylphosphine oxide (1.0 g,5.07 mmol) was dissolved in EtOH (12 mL) and 2,4, 5-trichloropyrimidine (930 mg,5.07 mmol) and NaHCO were added ₃ (426 mg,5.07 mmol) was stirred at 85℃for 90 minutes and monitored for completion of the reaction. Cooling to room temperature, diluting with water, extracting with EA, drying the organic layer, and concentratingThe residue was obtained. The residue was purified by column chromatography to give (2- ((2, 5-dichloropyrimidin-4-yl) amino) phenyl) diethylphosphine oxide (982 mg, yield: 56.27%) as a yellow solid. MS m/z (ESI): 344.04[ M+H ]] ⁺ .

Step 3: synthesis of 4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid

(2- ((2, 5-dichloropyrimidin-4-yl) amino) phenyl) diethylphosphine oxide (500 mg,1.45 mmol) was dissolved in isopropanol (16 mL), 4-aminobenzoic acid (160 mg,1.17 mmol) and HCl/1, 4-dioxane (4M, 0.73mL,2.92 mmol) were added, stirred overnight at 80℃and monitored for completion. Cooled to room temperature, filtered, and the filter cake was washed with isopropanol, PE to give 4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid (381 mg, yield: 58.95%) as a white solid. MS m/z (ESI): 445.11[ M+H ] ] ⁺ .

Step 4: synthesis of 4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide

4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid (100 mg,0.22 mmol) was dissolved in DMF (4 mL), methoxyamine hydrochloride (56 mg,0.67 mmol), HTAU (171 mg,0.45 mmol), DIPEA (203 mg,1.57 mmol) and DMAP (2.75 mg,0.02 mmol) were added and stirred overnight at room temperature to monitor completion of the reaction. Water was added to the mixture to dilute the mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a residue. Column chromatography purification gave 4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-methoxybenzamide (65 mg, yield: 61.02%) as a white solid. MS m/z (ESI) 474.1[ M+H ]] ⁺ .

¹ H NMR(DMSO-d6)δ:11.56(br s,1H),11.34(s,1H),9.76(s,1H),8.56(br d,J＝4.5Hz,1H),8.26(s,1H),7.75(d,J＝8.7Hz,2H),7.64(d,J＝8.7Hz,2H),7.51-7.62(m,2H),7.23(br t,J＝7.3Hz,1H),1.94-2.12(m,4H),1.01(br t,J＝7.7Hz,3H),0.97(t,J＝7.7Hz,3H).

Example 77

Preparation of 4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-ethoxybenzamide (77)

Step 1: synthesis of 4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-ethoxybenzamide

4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid (100 mg,0.22 mmol) was dissolved in DMF (4 mL), ethoxyamine hydrochloride (88 mg,0.91 mmol), HTAU (257 mg,0.68 mmol), DIPEA (287 mg,2.25 mmol) and DMAP (6 mg,0.04 mmol) were added and stirred overnight at room temperature to monitor completion of the reaction. Water was added to the mixture to dilute the mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a residue. Column chromatography purification of the residue afforded 4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-ethoxybenzamide (60 mg, yield: 54.70%) as a white solid. MSm/z (ESI): 488.1[ M+H ] ] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.43(s,1H),11.32(s,1H),9.73(s,1H),8.53-8.58(m,1H),8.25(s,1H),7.74(dd,J＝8.9,1.8Hz,2H),7.64(d,J＝8.5Hz,2H),7.48-7.61(m,2H),7.22(t,J＝7.2Hz,1H),3.90(q,J＝7.0Hz,2H),1.96-2.10(m,4H),1.16-1.22(m,3H),1.00(br t,J＝7.6Hz,3H),0.97(br t,J＝7.6Hz,3H)

Example 78

Preparation of 4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-isobutoxy benzamide (78)

Step 1: synthesis of 4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -N-isobutoxybenzamide

4- ((5-chloro-4- ((2- (diethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) benzoic acid (150 mg,0.34 mmol) was dissolved in DMF (1 mL) and isobutylamine hydrochloride (127 mg, 1) was added.02 mmol), HTAU (257 mg,0.68 mmol), DIPEA (306 mg,2.37 mmol) and DMAP (4 mg,0.03 mmol), stirred overnight at room temperature, monitored for reaction completion. Water was added to the mixture to dilute the mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography to give the title compound (75 mg, 43.11%) as a white solid. MS m/z (ESI): 516.1[ M+H ]] ⁺ .

¹ H NMR(DMSO-d6)δ:11.43(s,1H),11.31(s,1H),9.72(s,1H),8.52-8.59(m,1H),8.24(s,1H),7.70-7.76(m,2H),7.63(d,J＝8.7Hz,2H),7.50-7.61(m,2H),7.21(br t,J＝7.3Hz,1H),3.61-3.66(m,2H),1.97-2.08(m,4H),1.91(dt,J＝13.4,6.7Hz,1H),0.88-1.05(m,12H).

Example 79

Preparation of 4- (5-chloro-4- (2- (diethylphosphate) phenylamino) pyrimidin-2-ylamino) -2-fluoro-N-isobutoxy-5-methoxybenzamide (79)

Step 1: synthesis of 4- (5-chloro-4- (2- (diethylphosphoric acid) phenylamino) pyrimidin-2-ylamino) -2-fluoro-5-methoxybenzoic acid

2- (2, 5-dichloropyrimidin-4-yl) aminophenyl) diethylphosphine oxide (200 mg,0.58 mmol) and 4-amino-2-fluoro-5-methoxybenzoic acid (107.6 mg,058 mmol) were dissolved in isopropanol (6 mL), cooled to 0℃and 4M hydrochloric acid/1, 4-dioxane solution (0.29 mL,1.16 mmol) was added dropwise with stirring, and after the addition was completed, the mixture was heated to 70℃and reacted overnight. The reaction solution was cooled to room temperature and then filtered to give 4- (5-chloro-4- (2- (diethylphosphoric acid) phenylamino) pyrimidin-2-ylamino) -2-fluoro-5-methoxybenzoic acid (139 mg, yield: 48.28%) as a white solid. MS m/z (ESI): 493.1[ M+H ] ] ⁺ .

Step 2: synthesis of 4- (5-chloro-4- (2- (diethylphosphate) phenylamino) pyrimidin-2-ylamino) -2-fluoro-N-isobutoxy-5-methoxybenzamide

4- (5-chloro-4- (2- (diethylphosphoric acid) phenylamino) pyrimidin-2-ylamino) -2-fluoro-5-methoxybenzoic acid (65 mg,0.13 mmol) and iso Ding YanganThe hydrochloride salt (66.4 mg,0.52 mmol) was dissolved in DMF (2 mL), HATU (100.4 mg,0.26 mmol) and DMAP (1.6 mg,0.01 mmol) were added, the temperature was lowered to 0deg.C, DIPEA (0.15 mL,0.91 mmol) was added dropwise with stirring, and after the dropwise addition was completed, the reaction was allowed to proceed to room temperature overnight. 15mL of water was added, extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and purified by silica gel column chromatography (methanol: dichloromethane=1:20) to give 4- (5-chloro-4- (2- (diethylphosphate) phenylamino) pyrimidin-2-ylamino) -2-fluoro-N-isobutoxy-5-methoxybenzamide (51.8 mg, yield: 69.23%). MS m/z (ESI): 564.2[ M+H ]] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.40(s,1H),11.29(s,1H),8.47(dd,J＝8.6,3.8Hz,1H),8.30(s,1H),8.23(s,1H),8.06-8.15(m,1H),7.53-7.61(m,2H),7.23(t,J＝7.2Hz,1H),7.19(d,J＝6.5Hz,1H),3.90(s,3H),3.68(br d,J＝6.6Hz,2H),2.00-2.12(m,4H),1.90-2.00(m,1H),0.93-1.05(m,12H).

Example 80

Preparation of 4- (5-chloro-4- (2- (diethylphosphoric acid) phenylamino) pyrimidine-2-amino) -2-fluoro-N, 5-dimethoxybenzamide (80)

The steps are as follows: synthesis of 4- (5-chloro-4- (2- (diethylphosphoric acid) phenylamino) pyrimidine-2-amino) -2-fluoro-N, 5-dimethoxybenzamide

4- (5-chloro-4- (2- (diethylphosphoric acid) phenylamino) pyrimidin-2-ylamino) -2-fluoro-5-methoxybenzoic acid (60 mg,0.12 mmol) and methoxyamine hydrochloride (40.7 mg,0.48 mmol) were dissolved in DMF (2 mL), HATU (90.7 mg,0.24 mmol) and DMAP (1.5 mg,0.01 mmol) were added, the temperature was lowered to 0℃and DIPEA (0.14 mL,0.84 mmol) was added dropwise with stirring, and after the addition was completed, the reaction was allowed to proceed to room temperature overnight. Water (15 mL) was added, extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (methanol: dichloromethane=1:20) to give 4- (5-chloro-4- (2- (diethylphosphorus)Acid) phenylamino) pyrimidine-2-amino) -2-fluoro-N, 5-dimethoxy benzamide (10.0 mg, yield: 16.7%). MS m/z (ESI): 522.2[ M+H ]] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.32-11.40(m,2H),8.44(dd,J＝8.4,3.8Hz,1H),8.28(s,1H),8.20(s,1H),8.09(d,J＝12.8Hz,1H),7.50-7.58(m,2H),7.16-7.24(m,2H),3.88(s,3H),3.69(s,3H),1.98-2.07(m,4H),1.00(t,J＝7.7Hz,3H),0.96(br t,J＝7.6Hz,3H).

Example 81

Preparation of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N, 5-dimethoxybenzamide (81)

(2-aminophenyl) diethylphosphine oxide (2 g,10.14 mmol) was dissolved in DMF (20 mL), nitrogen blanket, 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.38 mL,10.14 mmol), DIPEA (1.68 mL,10.14 mmol) was added at 0deg.C, and reacted overnight at 60deg.C. At the end of the reaction, water and ethyl acetate were added to extract, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation to give the target compound (2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) diethylphosphine oxide (677 mg, yield: 17.67%) by silica gel column chromatography (petroleum ether: ethyl acetate=1:1). MS m/z (ESI): 378.0[ M+H ] ] ⁺ .

Step 2 Synthesis of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid

(2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) diethylphosphine oxide (200 mg,0.53 mmol), 4-amino-2-fluoro-5-methoxybenzoic acid (98.2 mg,0.53 mmol) was dissolved in isopropanol (10 mL), nitrogen was added to the ice bath, and the reaction was monitored to be complete by adding 4M hydrochloric acid/1, 4-dioxane solution (0.25 mL) at 65 ℃. Filtration gives 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (tri)Fluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid (100 mg, yield: 36%). MS m/z (ESI): 527.2[ M+H ]] ⁺ .

Step 3 Synthesis of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N, 5-dimethoxybenzamide

4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid (50 mg,0.095 mmol), methoxyamine hydrochloride (23.4 mg,0.28 mmol), HATU (72.3 mg,0.19 mmol), DMAP (1.2 mg,0.01 mmol) were dissolved in DMF (1 mL), DIPEA (73.7 mg,0.57 mmol) was added to an ice bath and the reaction was stirred at room temperature for 5 hours and was detected to be complete. Water was added thereto, extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated, and column chromatography gave 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N, 5-dimethoxybenzamide (36 mg, yield: 68%). MS m/z (ESI): 556.2[ M+H ] ] ⁺ .

¹ H NMR(DMSO-d6)δ:11.40(s,1H),10.98(br s,1H),8.49-8.58(m,2H),8.19(br s,1H),7.92(brd,J＝12.0Hz,1H),7.51-7.59(m,2H),7.26(br t,J＝7.1Hz,1H),7.19(br d,J＝6.3Hz,1H),3.87(s,3H),3.71(s,3H),1.97-2.05(m,4H),0.96(dt,J＝17.3,7.6Hz,6H).

Example 82

Preparation of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide (82)

Step 1 Synthesis of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid

(2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) diethylphosphine oxide (200 mg,0.53 mmol), 4-amino-2-fluoro-5-methoxybenzoic acid (98.2 mg,0.53 mmol) were dissolved in isopropanol (10 mL), nitrogen protected, 4M hydrochloric acid/1, 4-dioxane solution (0.25 mL) was added to an ice bath and stirred at 65deg.CThe reaction was monitored for completion after 3 hours. Filtration gave 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid (100 mg, yield: 36%). MS m/z (ESI): 527.2[ M+H ]] ⁺ .

Step 2 Synthesis of 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzamide

4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-5-methoxybenzoic acid (50 mg,0.095 mmol), isobutylamine hydrochloride (35.8 mg,0.28 mmol), HATU (72.3 mg,0.19 mmol), DMAP (1.2 mg,0.01 mmol) were dissolved in DMF (1 mL), DIPEA (73.7 mg,0.57 mmol) was added to an ice bath and the reaction was monitored for completion at room temperature for 5 hours. Water was added thereto, extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated, and column chromatography gave 4- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2-fluoro-N-isobutoxy-5-methoxybenzoyl (22 mg, yield: 39%). MS m/z (ESI): 598.3[ M+H ] ] ⁺ .

¹ H NMR(DMSO-d6)δ:11.32(s,1H),10.98(br s,1H),8.56(d,J＝5.0Hz,1H),8.50(s,1H),8.19(brs,1H),7.83-7.97(m,1H),7.51-7.59(m,2H),7.26(br t,J＝7.3Hz,1H),7.17(br d,J＝6.0Hz,1H),3.86(d,J＝1.3Hz,3H),3.67(br d,J＝6.6Hz,2H),1.92-2.06(m,5H),0.92-1.00(m,12H).

Example 83

Preparation of 7- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide (83)

Step 1: synthesis of 7- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid

(2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) diethylphosphine oxide (669 mg,1.77 mmol), 7-amino-2, 3-di-Hydrobenzofuran-4-carboxylic acid (324 mg,1.81 mmol) was dissolved in isopropanol (20 mL), 4M HCl/1, 4-dioxane (0.44 mL,1.77 mmol) was added, and the reaction was allowed to proceed overnight at 65℃under nitrogen, monitoring the completion of the reaction. Filtration gave 7- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (687 mg, yield: 74.53%). MS m/z (ESI) 521.1[ M+H ]] ⁺ .

Step 2: synthesis of 7- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide

7- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (150 mg,0.29 mmol), HATU (219 mg,0.58 mmol), DMAP (3.5 mg,0.03 mmol) and methoxyamine hydrochloride (73 mg,0.86 mmol) were dissolved in DMF (2 mL) and DIPEA (0.29 mL,1.73 mmol) was added at 0deg.C and the reaction was monitored for completion at room temperature for 3 h. Water, dichloromethane were added, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation to give the title compound 7- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide (83 mg, yield: 50.9%) by silica gel column chromatography (dichloromethane: methanol=10:1). MS m/z (ESI) 550.2[ M+H ] ] ⁺ .

¹ HNMR(500MHz,DMSO-d6)δ11.50(s,1H),11.07(s,1H),9.09(s,1H),8.38(s,1H),8.28(s,1H),7.54–7.43(m,1H),7.43–7.27(m,2H),7.15(t,J＝7.5Hz,1H),7.02(d,J＝8.3Hz,1H),4.47(t,J＝8.8Hz,2H),3.70(s,3H),3.40(t,J＝8.8Hz,2H),2.09–1.89(m,4H),0.96(dt,J＝17.1,7.6Hz,6H).

Example 84

Preparation of 7- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2, 3-dihydrobenzofuran-4-carboxamide (84)

(2- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) diethylphosphine oxide (669 mg,1.77 mmol), 7-amino-2, 3-dihydrobenzofuran-4-carboxylic acid (324 mg,1.81 mmol) was dissolved in isopropanol (20 mL), 4M HCl/1, 4-dioxane (0.44 mL,1.77 mmol) was added, and the reaction was stirred overnight at 65deg.C under nitrogen to monitor the completion of the reaction. Filtration gave the target product 7- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (687 mg, yield: 74.53%). MS m/z (ESI) 521.1[ M+H ]] ⁺ .

Step 2: synthesis of 7- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-isobutoxy-2, 3-dihydrobenzofuran-4-carboxamide)

7- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -2, 3-dihydrobenzofuran-4-carboxylic acid (150 mg,0.29 mmol), HATU (219 mg,0.58 mmol), DMAP (3.5 mg,0.03 mmol) and isobutylamine hydrochloride (109 mg,0.86 mmol) were dissolved in DMF (2 mL) and DIPEA (0.29 mL,1.73 mmol) was added at 0deg.C and the reaction was monitored for completion at room temperature. Water, dichloromethane extraction, combining the organic phases, drying over anhydrous sodium sulfate, filtration, concentration, and silica gel column chromatography (dichloromethane: methanol=10:1) afforded the target compound 7- ((4- ((2- (diethylphosphoryl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide (XTC 003-199) (70 mg, yield: 40.39%). MS m/z (ESI): 592.3[ M+H ] ] ⁺ .

¹ HNMR(400 MHz,DMSO-d6)δ11.41(s,1H),11.09(s,1H),9.

12(s,1H),8.39(s,1H),8.30(s,1H),7.58–7.43(m,1H),7.43–7.27(m,2H),7.16(t,J＝7.0 Hz,1H),7.04(d,J＝8.3 Hz,1H),4.49(t,J＝8.8 Hz,2H),3.68(d,J＝6.7 Hz,2H),3.42(t,J＝8.9 Hz,2H),2.15–1.83(m,5H),0.98(m,12H).

Example 85

Preparation of 7- (5-chloro-4- ((2- (diethylphosphoric acid) phenylamino) pyrimidin-2-ylamino) -N-isobutoxy-2, 3-dihydrobenzofuran-4-carboxamide (85)

Step 1: synthesis of 7- (5-chloro-4- ((2- (diethylphosphoric acid) phenylamino) pyrimidin-2-ylamino) -N-isobutoxy-2, 3-dihydrobenzofuran-4-carboxamide

To a solution of compound 7- (5-chloro-4- ((2- (diethylphosphoric acid) phenyl) amino) pyrimidin-2-ylamino) -2, 3-dihydrobenzofuran-4-carboxylic acid (80 mg,0.1643 mmol) in DMF (25 mL) was added the compounds isobutyloxyamine hydrochloride (83 mg,0.6571 mmol), HATU (125mg,0.3286 mmol), DMAP (2 mg,0.0329 mmol) and DIPEA (149 mg,1.1501 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL), and the organic layer was concentrated and dried to give a residue. The residue was purified by Prep-HPLC. To give the target compound 7- (5-chloro-4- ((2- (diethylphosphoric acid) phenylamino) pyrimidin-2-ylamino) -N-isobutoxy-2, 3-dihydrobenzofuran-4-carboxamide (59 mg,0.11 mmol) as a white solid MS m/z (ESI): 558.2[ M+H ]] ⁺ .

¹ H NMR(400 MHz,DMSO-d ₆ )δ11.42(s,1H),11.36(s,1H),8.62(s,1H),8.56(dd,J＝8.8,3.9 Hz,1H),8.16(s,1H),7.54(d,J＝8.3 Hz,1H),7.49(ddd,J＝12.7,7.7,1.6 Hz,1H),7.40(t,J＝7.9 Hz,1H),7.18–7.10(m,1H),7.06(d,J＝8.4 Hz,1H),4.52(t,J＝8.8 Hz,2H),3.67(d,J＝6.7 Hz,2H),3.42(t,J＝8.8 Hz,2H),2.03(dtd,J＝15.3,7.6,7.0,4.3 Hz,4H),1.94(p,J＝6.4 Hz,1H),1.01(t,J＝7.6 Hz,3H),0.99–0.92(m,9H).

Example 86

Preparation of 7- (5-chloro-4- ((2- (diethylphosphoric acid) phenyl) amino) pyrimidin-2-ylamino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide (86)

Step 1: synthesis of 7- (5-chloro-4- ((2- (diethylphosphate) phenyl) amino) pyrimidin-2-ylamino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide

To a solution of compound 7- (5-chloro-4- ((2- (diethylphosphoric acid) phenyl) amino) pyrimidin-2-ylamino) -2, 3-dihydrobenzofuran-4-carboxylic acid (80 mg,0.1643 mmol) in DMF (25 mL) was added the compound methoxyamine hydrochloride (55 mg,0.6571 mmol), HATU (125 mg,0.3286 mmol), DMAP (2 mg,0.0329 mmol) and DIPEA (149 mg,1.1501 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL), and the organic layer was concentrated and dried to give a residue. The residue was purified by Prep-HPLC. The synthesis of the target compound 7- (5-chloro-4- ((2- (diethylphosphoric acid) phenyl) amino) pyrimidin-2-ylamino) -N-methoxy-2, 3-dihydrobenzofuran-4-carboxamide (52 mg,0.93 mmol) was obtained as a white solid. MS m/z (ESI): 516.2[ M+H ]] ⁺ .

¹ H NMR(400 MHz,DMSO-d6)δ11.47(s,1H),11.45(s,1H),8.66(s,1H),8.56(dd,J＝8.3,3.9 Hz,1H),8.17(s,1H),7.56(d,J＝8.3 Hz,1H),7.49(ddd,J＝12.7,7.8,1.6 Hz,1H),7.41(t,J＝7.9 Hz,1H),7.19–7.11(m,1H),7.06(d,J＝8.4 Hz,1H),4.53(t,J＝8.8 Hz,2H),3.71(s,3H),3.44(d,J＝8.7 Hz,2H),2.03(dqd,J＝10.5,7.6,3.9Hz,4H),0.99(dt,J＝17.2,7.6Hz,6H).

Example 87

Preparation of 7- (5-chloro-4- (2- (dimethylphosphoryl) phenylamino) pyrimidin-2-ylamino) -N-isobutoxy-2, 3-dihydrobenzofuran-4-carboxamide (87)

Step 1 Synthesis of 7- (5-chloro-4- (2- (dimethylphosphoryl) phenylamino) pyrimidin-2-ylamino) -N-isobutoxy-2, 3-dihydrobenzofuran-4-carboxamide

7- (5-chloro-4- (2- (dimethylphosphoryl) phenylamino) pyrimidin-2-ylamino) -2, 3-dihydrobenzofuran-4-carboxylic acid 202_01 (30 mg,0.07 mmol) and isobutylamine hydrochloride 202_02 (33.3 mg,0.28 mmol) were dissolved in DMF (4.5 mL), HATU (50.1 mg,0.14 mmol) and DMAP (0.1 mg,0.001 mmol) were added, DIPEA (76. Mu.L, 0.49 mmol) was added at 0deg.C,the reaction was carried out at room temperature overnight. Water (20 mL), ethyl acetate (20 mL) and ethyl acetate (20 mL. Times.3) were added, the organic phases were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (methanol: dichloromethane=1:20) to give 7- (5-chloro-4- (2- (dimethylphosphoryl) phenylamino) pyrimidin-2-ylamino) -N-isobutoxy-2, 3-dihydrobenzofuran-4-carboxamide (21.4 mg, yield: 57.14%). MS m/z (ESI) 530.2[ M+H ]] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.37(s,1H),11.26(s,1H),8.58-8.65(m,1H),8.50-8.58(m,1H),8.17(s,1H),7.49-7.64(m,2H),7.41(br t,J＝7.7Hz,1H),7.15(br t,J＝7.5Hz,1H),7.06(d,J＝8.4Hz,1H),4.55(t,J＝8.7Hz,2H),3.67(d,J＝6.7Hz,2H),3.40-3.46(m,2H),1.87-2.04(m,1H),1.78(d,J＝13.4Hz,6H),0.95(d,J＝6.7Hz,6H).

Example 88

Preparation of (88) methyl Hydrogen (2- ((5-chloro-2- ((4- (isobutoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate

Step 1 Synthesis of 2, 5-dichloro-N- (2-iodophenyl) pyrimidin-4-amine

2-iodoaniline (5.0 g,22.8 mmol), 2,4, 5-trichloropyrimidine (6.3 g,34.2 mmol), DIPEA (3.8 mL,22.8 mmol) was dissolved in nBuOH (15 mL) and reacted at 85℃for 16h, monitoring the reaction was complete. Cooled to room temperature, left to stand until no more precipitate was generated, and filtered to give 2, 5-dichloro-N- (2-iodophenyl) pyrimidin-4-amine (2.6 g, yield: 31%). MS m/z (ESI): 365.9[ M+H ] ] ⁺ .

Step 2 Synthesis of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) benzoic acid

2, 5-dichloro-N- (2-iodophenyl) pyrimidin-4-amine (4.3 g,11.6 mmol), 4-aminobenzoic acid (1.7 g,12.2 mmol) was dissolved in nBuOH (50 mL), and a 1, 4-dioxane solution (0.9 mL,3.5 mmol) of 4N hydrochloric acid was added thereto, and the reaction was allowed to proceed at 120℃for 3 hours, followed by monitoring the completion of the reaction. The system was suction filtered to give 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) benzoic acid (5.0 g, yield:92％)。MS m/z(ESI):467.0[M+H] ⁺ .

step 3 Synthesis of 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-isobutoxybenzamide

4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) benzoic acid (2.0 g,4.3 mmol), isobutylamine hydrochloride (1.6 g,12.9 mmol) were dissolved in THF (50 mL), EDCI (1.2 g,6.4 mmol), HOBt (869 mg,6.4 mmol) and DIPEA (4.3 mL,25.8 mmol) were added to an ice-water bath and the reaction was monitored for completion at room temperature overnight. The solvent was removed by spinning, water (20 mL) was added, and the solid was filtered, dried and purified by column chromatography (dichloromethane: ethyl acetate=4:1) to give 4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-isobutoxybenzamide (1.1 g, yield: 48%). MS m/z (ESI): 538.01[ M+H ]] ⁺ .

Step 4 Synthesis of dimethyl (2- ((5-chloro-2- ((4- (isobutoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate

4- ((5-chloro-4- ((2-iodophenyl) amino) pyrimidin-2-yl) amino) -N-isobutoxy benzamide (600 mg,1.1 mmol), dimethyl phosphate (0.2 mL,2.24 mmol), pd (dppf) ₂ Cl ₂ (106mg,0.13mmol),K ₃ PO ₄ (318 mg,1.7 mmol) in 1, 4-dioxane (35 mL), N ₂ The reaction was monitored to be complete by reacting for 16h at 100℃under protection. Water (10 mL) was added, ethyl acetate (3X 20 mL) was extracted, dried over anhydrous sodium sulfate, and concentrated, and column chromatography (dichloromethane: ethyl acetate=5:1 to 3:2) gave dimethyl (2- ((5-chloro-2- ((4- (isobutoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate (348 mg, yield: 61%). MS m/z (ESI): 520.1[ M+H ]] ⁺ .

Step 5: synthesis of methyl hydrogen (2- ((5-chloro-2- ((4- (isobutoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate

Dimethyl (2- ((5-chloro-2- ((4- (isobutoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate (50 mg,0.1 mmol) was dissolved in a mixed solvent of THF (2 mL), water (1 mL) and MeOH (0.5 mL), N ₂ The reaction was monitored to be complete by reacting for 2h at 60℃under protection. Spin-removing solvent, and separating with preparative HPLC to obtain methyl hydrogen (2- (. About.)5-chloro-2- ((4- (isobutoxycarbamoyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) phosphonate (34 mg, yield: 70%). MS m/z (ESI): 506.1[ M+H ] ] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.46(br s,1H),10.43(s,1H),9.79(s,1H),8.56(br t,J＝7.0Hz,1H),8.30(s,1H),7.77(d,J＝8.1Hz,2H),7.62-7.71(m,4H),7.21-7.29(m,1H),3.66(d,J＝6.6Hz,3H),3.54-3.57(m,2H),1.87-2.03(m,1H),0.95(d,J＝6.6Hz,6H).

Other specific compounds of the present application can be prepared by a method similar to the method described in the above examples (with appropriate adjustments of reagents and conditions, if necessary).

Biological evaluation of Compounds

Test example one: in vitro enzymatic inhibitory Activity of the Compounds of the application

1. Reagent, consumable and instrument

2. Experimental procedure

1) Add 50. Mu.L of compound to 384 well dilution plates.

2) Compounds of each column were treated with DMSO at 1:3 serial dilutions, 10+0 points per dilution.

3) Diluted compound solutions in each row were transferred to 0.1 μl to 384 assay plates using Echo, containing 2 replicates per column.

4) mu.L of 2 Xenzyme solution was added to the assay plate and centrifuged at 1000rpm for 1 min. Incubate at 25℃for 15 min.

5) mu.L of 2 Xsubstrate solution was added to 384-well assay plates.

6) Incubate at 25℃for 60 min.

7) mu.L of Sa-XL665 solution and 5. Mu.L of TK antibody-Eu ³⁺ Added to the assay plate. Centrifuge at 1000rpm for 1 minute.

2) Incubate at 25℃for 60 min.

8) The fluorescent signal was read on an Envision 2104 plate reader.

3. Data analysis

1) For each screening plate, mean data and Standard Deviation (SD) of DMSO and 100nM Defactinib (as control) were calculated

2) Percent inhibition of compound (% inh) =100 (max-sample value)/(max-min)

3) The IC50 was calculated using the nonlinear regression equation of XLfit 5.3.1, as follows:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

log (concentration of Compound)

Inhibition ratio (% inh)

Top and Bottom unit consistent with Y unit

logIC ₅₀ Consistent with units of X

Hillslope, gradient coefficient or gradient

Specific IC ₅₀ The activity data are shown in Table 1.

4. Conclusion of experiment:

the compound has better in-vitro FAK enzymatic inhibition activity, and partial compound is superior to the FAK inhibitor Defectinib in clinical stage.

TABLE 1

Test example two: pharmacodynamics evaluation (western blot detection of YAP activity) of the compound in vitro human diffuse gastric cancer tumor cell line SNU-668 model

1. Experimental procedure

1) Cell plating

SNU-668 cells (product number 00668, KCLB) grown to 80% -90% density, the culture supernatant was aspirated, and the supernatant was rinsed once with PBS;

adding 2mL pancreatin into 10cm dish, and placing into incubator for digestion for 3-5min;

c. taking out the culture plate, adding 5mL1640 culture medium (containing 10% FBS) to stop digestion, transferring to a 15mL centrifuge tube, and centrifuging at 1000rpm for 5min;

d. the supernatant was removed, 5mL of 1640 medium (containing 10% FBS) was added, and after sufficient resuspension, the mixture was counted;

e. the 12-well plate was removed and 1.5X10 each well was plated ⁵ Individual cells and 900. Mu.mL culture medium is put into a cell culture box for culturing for 24 hours.

2) Cell administration

a. Taking out the mother solution (1 mM) of the compound to be tested in advance, dissolving the mother solution with DMSO, blowing for several times, and uniformly mixing;

b. taking out the culture plate with the well-planted cells, sucking 1ul of 1mM mother solution (diluted 1000 times), gently adding along the hole wall, and immediately shaking and uniformly mixing after adding;

c. after all the holes are added, the medicine is slightly shaken for two times to be uniformly diffused, the time is recorded, and the medicine is put back into a cell incubator for 24 hours and then collected.

3) Protein extraction

a. After 24h of administration, the medium was discarded, washed with PBS, and the PBS was discarded;

b. cells were lysed with RIPA lysate containing phosphatase inhibitor and PMSF, centrifuged at 12000rpm at 4℃for 10min, the supernatant was taken, the protein concentration was determined and adjusted, and 4 Xloading buffer was added to cook the protein.

4) Western blot detection

SDS-PAGE electrophoresis was performed: 80v,30min,120v,60min; transferring: 80v,60min; closing: 5% skim milk 1H, primary antibody: P-FAKY397 (1:1000, CST), non-P-YAP (1:2000, abcam), P-YAP (1:1000, CST), actin (1:10000, CST), with 5% BSA TBST, overnight incubation at 4 ℃; secondary antibodies (coat-anti-mouse-IgG and coat-anti-rabit-IgG, 1:3000, proteintech): prepared with 5% skim milk and incubated for 1h at room temperature. Thermo developer is used.

2. Conclusion of the experiment

The results are shown IN fig. 2, 3, 4 and 5, and show that the compound of the invention can inhibit the phosphorylation of FAK (inhibit FAK kinase activity, reduce phosphorylated FAK) and simultaneously reduce activated YAP (inhibit YAP activity, reduce non-phosphorylated non-p-YAP) IN the SNU668 model of human diffuse gastric cancer tumor cell line, while Defactinib and IN10018 have no effect of inhibiting YAP activity.

Test example three: pharmacodynamic evaluation (cell proliferation inhibition detection) of compound in vitro human diffuse gastric cancer tumor cell line SNU-668 model

1. Experimental procedure

1) Cell plating

SNU-668 cells (product number 00668, KCLB) grow to 70% -80%, the culture supernatant is aspirated, and the supernatant is rinsed once with PBS for aspiration;

b.10cm dish is added with 1mL of 0.25% pancreatin, evenly shaken left and right and up and down, and put into an incubator for digestion for 2-3min;

c. taking out the culture dish, adding 2-3mL of complete culture medium to stop digestion, transferring to a 15mL centrifuge tube, and centrifuging at 1000rpm in a centrifuge for 5min;

d. the supernatant was aspirated, 1mL of complete medium was added for resuspension and counted;

e. taking out the 96-well plate, paving 1000 cells in each well, and placing the cells in a cell culture box for overnight culture;

2) Cell administration

a. Taking out the medicine to be tested in advance to dissolve, and swirling uniformly;

b. Each small molecule was diluted 1:3 with medium to 9 concentration gradients, based on 1mM stock solution;

c. taking out the culture plate with the well-planted cells, sucking out the culture medium, slowly adding 100 mu L of fresh culture medium along the hole wall by using a row gun, marking the serial number of each hole, respectively adding corresponding small molecules and concentration into the holes along the hole wall by using the row gun to suck 100 mu L of culture medium containing the medicine;

d. after all the holes are added, the culture plate is gently shaken to uniformly diffuse the medicine, the time is recorded, and the medicine is put back into the cell culture box;

3) CELL TITER-GLO detection

After 4 days of administration, the medium was discarded, the medium and the cell titer-glo assay solution were mixed 1:1, 100. Mu.L was added to each well, incubated for 10min with shaking at room temperature, and detected by an ELISA.

2. Conclusion of the experiment

The experimental results (see Table 2 IN detail) show that partial compounds of the invention can inhibit the cell growth of a human diffuse gastric cancer tumor cell line model, and the inhibition activity is superior to that of the clinical FAK inhibitors of Defactinib and IN10018, and other similar structural kinase inhibitors, such as a compound D3a.

TABLE 2

Test example four: in vivo pharmacodynamic evaluation of Compounds

1. Experimental procedure

Cells were prepared from diffuse gastric carcinoma organoids and primed with Matrigel base: the ratio of medium (1:1) was resuspended. Each time will contain 1X 10 ⁶ 200 μl of the mixture was subcutaneously injected into the ventral side of NSG mice (6-8 weeks old). Tumor volumes were measured every two days, starting two weeks after injection. Tumor volume was calculated by equation 0.5×a ² X b, where a is the width in millimeters and b is the length in millimeters. When the tumor reaches about 100mm ³ At this time, the administration treatment was started, and DMSO, deferiprone (Defectinib) (12.5 mg/kg), compound 3 (12.5 mg/kg), and Compound 3 (5 mg/kg) were injected intraperitoneally every other day.

2. Experimental results

The experimental results are shown in fig. 1, and it can be seen from the figure that 5mg/kg of the compound 3 of the present invention can significantly inhibit the growth of tumor in the mouse model of diffuse gastric cancer, and the inhibition effect is better than 12.5mg/kg of the positive control compound Defactinib (difatinib).

Test example five: in vivo pharmacokinetic evaluation of Compounds

1. Test design

3 male SD rats were given 5mg/kg of the compound 1 time by single gastric lavage, and blood was collected before and after administration for 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours.

2. Formulation configuration

5.5mg of the compound (converted to purity) was precisely weighed, 0.55mL of DMSO was added, and the mixture was stirred and sonicated to give a solution of the solvent. Taking 0.5mL of the above solution, adding 1mL of Solutol into the solution, and stirring for 1min; 8.5mL of physiological saline is added, and the mixture is stirred for 1min to obtain clear solution with the concentration of 0.5mg/mL.

3. Animal handling

The preparation prepared in the step 2 was administered to rats by intragastric administration at a dose of 10 mL/kg. Rats were fasted overnight prior to dosing and fed was restored 4 hours after dosing; animals were normally drinking water throughout the test period.

4. Analysis method

Plasma concentrations were determined using LC-MS/MS methods.

5. Experimental results

The experimental results show that the compound of the application has good pharmacokinetic parameters in rats, and the specific results are shown in table 3.

TABLE 3 Table 3

Numbering of compounds	32	55	73	Defactinib
					Route of administration	Stomach lavage	Stomach lavage	Stomach lavage	Stomach lavage
Dosage (mg/kg)	5	5	5	5
					Pharmacokinetic parameters	-	-	-	-
T _1/2 (h)	1.01	2.91	2.32	1.20
					T _max (h)	0.25	0.25	2.00	4.00
C _max (nM)	215.72	186.83	70.91	99.51
					AUC _0-last (nM·h)	399.20	498.14	383.43	424.2
AUC _0-inf (nM·h)	404.13	599.75	411.72	440.54

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

1. Use of a compound having the structure or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof, or isotope thereof, or pharmaceutical composition thereof, in the manufacture of a medicament for modulating or treating a disease associated with YAP:

2. The use according to claim 1, wherein the YAP related disease is selected from cancer.

3. The use according to claim 2, wherein the cancer is selected from the group consisting of: skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, cancer of the head or neck, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urinary tract cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancy, hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumor (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, and uterine cancer.

4. The use according to claim 2, wherein the cancer is selected from the group consisting of: lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer.

5. Use of a compound having the structure or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof, or isotope thereof, or pharmaceutical composition thereof, in the manufacture of a medicament for modulating or treating a disease associated with FAK and YAP:

6. The use according to claim 5, wherein the FAK and YAP related disease comprises cancer.

7. The use according to claim 6, wherein the cancer is selected from: skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, cancer of the head or neck, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urinary tract cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancy, hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumor (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, uterine cancer.

8. The use according to claim 6, wherein the cancer is selected from: lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer.