CN116870016A - Heteroaromatic compounds and their medicinal uses - Google Patents

Abstract

The present invention relates to a heteroaromatic compound or its enantiomer, diastereomer, racemate, or its pharmaceutically acceptable salt, or isotope or its pharmaceutical composition in the preparation, regulation or treatment of Use in medicines for YAP-related diseases.

Description

Heteroaromatic compounds and their medical uses

This application is a divisional application of the Chinese patent application with the application date of December 1, 2022, application number 2022115316779, and invention name “Heteroaromatic ring compounds and their medical uses”.

Technical Field

The invention belongs to the field of medicines and relates to a heteroaromatic ring compound and its medical use.

Background Art

Focal adhesion kinase (FAK), also known as PTK2 (protein tyrosine kinase 2), is a non-receptor tyrosine kinase located at the intersection of multiple signal transduction pathways and can be activated by integrins, growth factor receptors, G protein-coupled receptors, and cytokines. In addition to participating in signal transduction as a cytoplasmic kinase, related studies have also shown that FAK also plays an important role in the cell nucleus. FAK can promote p53 degradation through ubiquitination, leading to cancer cell growth and proliferation. Tang et al. reported that FAK can also regulate the expression of GATA4 and IL-33, thereby reducing inflammatory responses and immune escape. In the tumor microenvironment, nuclear FAK can regulate the formation of new blood vessels and affect the blood supply of the tumor.

FAK is widely expressed in the body and plays an important role in cell growth, proliferation, migration, and adhesion. It is involved in embryonic development and the occurrence and development of diseases (cancer and cardiovascular disease, etc.). Overexpression of FAK has been found in many types of cancer, 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 indicates a poor prognosis. For example, studies have found that the GTPase RHOAY42C mutation is one of the most common gain-of-function mutations in diffuse gastric cancer, and mice with the RHOAY42C mutation are sensitive to FAK inhibitors, suggesting that inhibiting FAK activity may become a new strategy for the treatment of diffuse gastric cancer.

YAP (Yes-associatied protein) is a Yes-associated protein and a transcriptional coactivator of the Hippo pathway. It is located on human chromosome 11q22 and promotes gene expression by enhancing the activity of transcription factors. External signals activate MST1/2, which binds to the regulatory protein SAV1 and phosphorylates LATS1/2 and MOB, and then directly phosphorylates YAP/TAZ. The phosphorylated YAP/TAZ stagnates in the cytoplasm and inhibits transcription. When this signal pathway is blocked or inactivated, unphosphorylated YAP/TAZ moves from the cytoplasm to the nucleus and binds to transcription factors such as TEADs, Smad, Runx1/2, p63/p73, and ErbB4 to promote gene transcription.

The Hippo-YAP pathway is a signaling pathway discovered in recent years that regulates organ volume and maintains the balance of cell proliferation and apoptosis. It is closely related to the uncontrolled proliferation of tumor cells. The main function of the Hippo-YAP pathway in mammals is to inhibit the activity of transcriptional regulators YAP and TAZ and negatively regulate the progression of tumors. Therefore, the Hippo pathway is also considered to be a tumor suppressor pathway. Specifically, the core members of this pathway include serine/threonine kinases MST1, MST2, LATS1 and LATS2, scaffold proteins SAV1 (binding to MST1 and MST2), MOB1 (binding to LATS1 and LATS2), transcriptional coactivator YAP, and transcription factor TEAD containing the TEA binding domain. In short, when the Hippo pathway is activated, MST1/2 kinase phosphorylates and activates LATS1/2, and the activated LATS1/2 then phosphorylates YAP. The phosphorylated YAP is inactivated and then exported to the nucleus, while the YAP in the cytoplasm is degraded by the proteasome.

Studies have confirmed that the Hippo pathway is involved in the progression of various tumors such as lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer, etc. However, in human tumors, gene mutations in the Hippo pathway rarely occur. Based on this, it is concluded that the dysregulation of the Hippo pathway in human tumors is not only due to mutations in key proteins of the Hippo pathway itself, but more due to cross-talk between other abnormally expressed proteins or signaling pathways in tumor cells and the Hippo pathway. In addition, the role of the Hippo signaling pathway in tumors is closely related to the nuclear translocation of YAP/TAZ. Recently, YAP has been found to be highly expressed in a variety of tumors, which is associated with high pathological grade, advanced TNM stage, lymph node metastasis, etc., and there is a phenomenon of nuclear localization.

Summary of the invention

The purpose of the present invention is to provide a novel heteroaromatic compound and its medical use. The heteroaromatic compound of the present invention has a good inhibitory effect on FAK and unexpectedly also has a good inhibitory effect on YAP.

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

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

_X1 is selected from: CH or N;

X ₂ is selected from: CR ⁶ or N;

X ₃ is selected from: CR ⁷ or N;

^R1 and ^R2 are each independently selected from the following substituted or unsubstituted groups: hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic group; or ^R1 and ^R2 and the P atom to which they are connected together form a 3-6 membered heterocyclic group;

R ³ is independently selected from: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, CF ₃ , CHF ₂ , CH ₂ F, CN, NO ₂ , CONR ^a R ^b ; wherein, R ^a and R ^b are each independently selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl;

R ⁴ is 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, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered 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 by 1-3 R ¹³ ;

R ⁵ is selected from the group consisting of: 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, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered 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 by 1-3 R ¹³ ;

R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently selected from: H, 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, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6 -C10 aryl, 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3 -12-membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10-membered heteroaryl group may be substituted by 1-3 R ¹³ ;

Or R ⁶ , R ⁷ and the atoms to which they are connected form a 5-7 membered cycloalkyl, heterocyclic, aryl or heteroaryl group; wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group may be substituted by 1-3 R ¹³ ;

Or R ⁸ , R ⁹ and the atoms to which they are connected form a 5-7 membered cycloalkyl, heterocyclic, aryl or heteroaryl group; wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group may be substituted by 1-3 R ¹³ groups;

or ^R5 and ^R7 or ^R9 and the atoms to which they are connected form a 5-7 membered cycloalkyl, heterocyclic, aryl or heteroaryl group; wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group may be substituted by 1-3 ^R13 groups;

R ¹⁰ , R ¹¹ and R ¹² are independently selected from the group consisting of 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, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; or in NR ¹¹ R ¹² , R ¹¹ and R ¹² and the N atom to which it is connected together form a 3-6 membered heterocyclic group; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, 3-6 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted by 1-3 R ¹³ ;

R ¹³ is 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, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6- C10 aryl, 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3 -12-membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10-membered heteroaryl group may be substituted by 1-3 groups selected from the following groups: C1-C6 alkyl group, halogen group, 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 substituted;

R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently selected from the group consisting of H, 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; 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 by 1-3 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 heterocyclic group, wherein the 3-6 membered heterocyclic group may be substituted by a group selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C12 cycloalkyl group, a 3-12 membered heterocyclic group, a C3-C12 cycloalkenyl group, a C6-C10 aryl group, and a 5-10 membered heteroaryl group;

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

m is independently selected from 0, 1 or 2;

Limitation: When A is phenyl, R ⁵ is independently OR ¹⁰ , CH ₂ R ¹⁹ or -S(O) _m R ¹¹ ;

Or when A is phenyl, R ⁶ , R ⁷ and the atoms to which they are connected form a 5-7 membered cycloalkyl, heterocyclic, aryl or heteroaryl group; wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group may be substituted by 1-3 R ^{13 groups} .

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

_X1 , ^R1 , ^R2 , ^R3 , ^R4 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 , n and A are as defined above.

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

Or when A is phenyl, R ⁶ , R ⁷ and the atoms to which they are connected form a 5-7 membered cycloalkyl, heterocyclic, aryl or heteroaryl group; wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group may be substituted by 1-3 R ^{13 groups} ,

wherein R ¹⁰ , R ¹⁹ , R ¹¹ , R ¹³ and m are as defined above.

In some embodiments, when A is phenyl, R ⁵ is independently OR ¹⁰ ; wherein R ¹⁰ is as defined above.

In some embodiments, when A is a 5-6 membered heteroaryl, R ⁵ is independently selected from the group consisting of: 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, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered 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 can be replaced by 1-3 R ^13- substituted; wherein m, R ¹¹ and R ¹³ are as defined above.

In some embodiments, X ₁ is N.

In some embodiments, the 5-7 membered cycloalkyl, heterocyclyl, aryl, heteroaryl is selected from: 5-6 membered heterocyclyl or 5-6 membered heteroaryl; preferably pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,

In some embodiments, the heterocyclyl group includes heterocycloalkyl or heterocycloalkenyl.

In some embodiments, the compound has a structure as shown in the following formula (I-1):

wherein X ₁ , R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and n are as defined above;

Preferably, R ¹ and R ² are each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R ¹ and R ² together with the P atom to which they are connected form a 3-6 membered heterocyclic group (e.g., a 5-membered heterocyclic group);

Preferably, R ³ is selected from halogen or CF ₃ ;

Preferably, R ⁴ is selected from H;

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

In some embodiments, the compound has a structure as shown in the following formula (II-1):

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above.

Preferably, R ¹ and R ² are each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R ¹ and R ² together with the P atom to which they are connected form a 3-6 membered heterocyclic group (e.g., a 5-membered heterocyclic group);

Preferably, R ³ is selected from halogen or CF ₃ ;

Preferably, R ⁴ is selected from H;

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

In some embodiments, R ¹⁰ is selected from: H, 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; 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 by 1-3 R ¹³ ; wherein, R ¹³ is as defined above.

In some embodiments, R ¹⁰ is 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 by 1-3 R ¹³ ; wherein R ¹³ is as defined above.

In some embodiments, R ⁶ , R ⁷ , R ⁸ and R ⁹ are 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 ⁶ , R ⁷ and the atoms to which they are connected form a 5-6-membered heterocyclic group or a 5-6-membered heteroaryl group; or R ⁸ , R ⁹ and the atoms to which they are connected form a 5-6-membered heterocyclic group or a 5-6-membered heteroaryl group; wherein the heterocyclic group or heteroaryl group may be substituted by 1-3 R ¹³ ;

wherein R ¹¹ , R ¹² and R ¹³ are as defined above.

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

In some embodiments, the compound has a structure shown in the following formula (I-2)-(I-7):

Wherein, R ²⁰ is 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, _X1 , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R7 , ^R8 , ^R9 and n are as defined above.

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

In some embodiments, ^R1 and ^R2 can form a 4-6 membered heterocyclic group with the atoms to which they are attached. Preferably, the heterocyclic group includes but is not limited to the following groups:

Wherein, * indicates the connection site.

In some embodiments, R ³ is selected from the group consisting of: halogen, CF ₃ , CHF ₂ , CH ₂ F, CN, C1-C6 alkyl.

In some embodiments, R ⁴ is H, C1-C6 alkoxy, 3-6-membered cycloalkyl, 5-6-membered heteroaryl, 5-6-membered 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 ¹¹ and R ¹² are defined as above.

In some embodiments, ^R4 is selected from: H or

In some embodiments, R ⁴ is 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 are the groups corresponding to the specific compounds in the examples.

In some embodiments, the compound is selected from

1)

R ¹ and R ² are each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R ¹ and R ² together with the P atom to which they are attached form a 3-6 membered heterocyclic group, such as a 5 membered heterocyclic group;

R ³ is selected from halogen or CF ₃ ;

^R4 is selected from H;

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

R ¹⁰ is selected from the group consisting of 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, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; or in NR ¹¹ R ¹² , R ¹¹ and R ¹² and the N atom to which it is connected together form a 3-6 membered heterocyclic group; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, 3-6 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted by 1-3 R ¹³ ;

2)

R ¹ and R ² are each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R ¹ and R ² together with the P atom to which they are attached form a 3-6 membered heterocyclic group, such as a 5 membered heterocyclic group;

R ³ is selected from halogen or CF ₃ ;

^R4 is selected from H;

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

R ¹⁰ is selected from the group consisting of 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, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; or in NR ¹¹ R ¹² , R ¹¹ and R ¹² and the N atom to which it is connected together form a 3-6 membered heterocyclic group; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, 3-6 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted by 1-3 R ¹³ ;

3)

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

R ¹ and R ² are each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R ¹ and R ² together with the P atom to which they are attached form a 3-6 membered heterocyclic group, such as a 5 membered heterocyclic group;

R ³ is selected from halogen or CF ₃ ;

^R4 is selected from H;

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

R ¹⁰ is selected from the group consisting of 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, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; or in NR ¹¹ R ¹² , R ¹¹ and R ¹² and the N atom to which it is connected together form a 3-6 membered heterocyclic group; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, 3-6 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted by 1-3 R ¹³ ;

4)

^R1 and ^R2 together with the P atom to which they are attached form a 3-6 membered heterocyclic group, such as a 5 membered heterocyclic group;

R ³ is CF ₃ ;

^R4 is selected from H;

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

R ¹⁰ is selected from the group consisting of 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, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; or in NR ¹¹ R ¹² , R ¹¹ and R ¹² and the N atom to which it is connected together form a 3-6 membered heterocyclic group; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, 3-6 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted by 1-3 R ¹³ ;

or 5)

R ¹ and R ² are each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R ¹ and R ² together with the P atom to which they are attached form a 3-6 membered heterocyclic group, such as a 5 membered heterocyclic group;

^R3 is selected from halogen;

^R4 is selected from H;

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

R ¹⁰ is selected from the group consisting of 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, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; or in NR ¹¹ R ¹² , R ¹¹ and R ^{R 12} and the N atom to which it is connected together form a 3-6 membered heterocyclic group; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, 3-6 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted by 1-3 R ¹³ .

In some embodiments, R ¹⁰ is selected from: H, 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; 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 by 1-3 R ¹³ ; wherein R ¹³ is defined as described above.

In some embodiments, R ¹⁰ is 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, 5-10 membered heteroaryl; or in, together with the N atom to which it is connected, forms 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 can be replaced by 1-3 R ¹³ , wherein R ¹³ is defined as described above.

In some embodiments, R ¹⁰ is selected from the group consisting of: 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, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; or in NR ¹¹ R ¹² , R ¹¹ and R ^{R 12} and the N atom to which it is connected together form a 3-6 membered heterocyclic group; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, 3-6 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted by 1-3 R ¹³ , wherein R ¹³ is as defined 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, the present invention provides a pharmaceutical composition comprising the compound as described in the first aspect or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, hydrate, isotope or prodrug; and a pharmaceutically acceptable carrier or diluent.

In some embodiments, the pharmaceutical composition further comprises one or more selected from the following groups: 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 a combination thereof.

The third aspect of the present invention provides use of the compound as described in the first aspect or the pharmaceutical composition as described in the second aspect in the preparation of a drug for treating a FAK-related disease.

In some embodiments, the FAK-related diseases include various cancers, pulmonary hypertension, and pathological angiogenesis.

In some embodiments, the cancer is selected from the group consisting of skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, uterine cancer, etc. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is diffuse gastric cancer.

In a fourth aspect, the present invention provides use of the compound according to the first aspect or the pharmaceutical composition according to the second aspect in the preparation of a drug for regulating YAP or treating a disease associated with YAP.

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

In some embodiments, the cancer is selected from one or more of skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (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 one or more of lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer, and gastric cancer.

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

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

In a fourth aspect, the present invention provides a method for treating FAK and/or YAP-related diseases, the method comprising administering a therapeutically effective amount of the compound as described in the first aspect or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition as described in the second aspect to a subject identified or diagnosed as having a FAK and/or YAP-related disease.

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

In some embodiments, the cancer is selected from one or more of skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (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 one or more of lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer, and gastric cancer.

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

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

On the other hand, the present 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 with or administering to the subject the compound as described in the first aspect or the pharmaceutical composition as described in the second aspect.

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

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 shows a curve showing the relationship between tumor volume and time in the mouse tumor model of Experimental Example 4 for the compound of the present invention.

FIG. 2 shows part of the western blot results of Experimental Example 2.

FIG3 shows part of the western blot results of Experimental Example 2.

FIG. 4 shows some western blot results of Experimental Example 2.

FIG5 shows part of the western blot results of Experimental Example 2.

DETAILED DESCRIPTION

After extensive and in-depth research, the inventors unexpectedly discovered a class of compounds with good FAK kinase and/or YAP protein inhibitory activity. In addition, the compounds also have better pharmacodynamics/pharmacokinetic properties. On this basis, the present invention was completed.

the term

In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

The term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon radical having the specified number of carbon atoms (i.e., C1-C6 refers to 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, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

The term "alkoxy" refers to a straight or branched or cyclic alkyl group connected by an ether oxygen, and its free valence bond comes 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 and butoxy, etc. Preferably C1-C3 alkoxy.

The term "heteroalkyl" refers to a group in which the carbon atoms in the alkyl group are substituted by 1, 2 or 3 heteroatoms selected from N, O, S, Si or P, and wherein the nitrogen and sulfur atoms are optionally oxidized. In the present invention, "C1-C6 heteroalkyl" refers to a group containing 1-6 (i.e., 1, 2, 3, 4, ₅ or 6) carbon atoms, and 1 _, 2 or ₃ heteroatoms selected from N, O, S or P. Representative examples include (but are not limited to): _CH3OCH2- , _CH3SCH2- , _{CH3CH2OCH2- ,} etc.

The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and having a specified number of carbon atoms. For example, "C2-C6 alkenyl" refers to a group containing 2 to 6 carbon atoms. Alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, heptenyl, octenyl, etc.

The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and having a specified number of carbon atoms. For example, "C2-C6 alkynyl" refers to a group containing 2 to 6 carbon atoms. Alkynyl includes, but is not limited to, ethynyl, propynyl, butynyl, etc.

The term "cycloalkyl" refers to a cyclic alkyl group including a saturated monocyclic ring (e.g., C3-C8), a bicyclic ring (e.g., C5-C12 fused bicyclic ring, C5-C12 membered spiro bicyclic ring) or a polycyclic ring, "C3-C6 cycloalkyl" refers to a ring containing 3 to 6 carbon atoms, and "C3-C12 cycloalkyl" refers to a ring containing 3 to 12 carbon atoms. The cycloalkyl group is preferably a C3-C12 cycloalkyl group, and more preferably a C3-C6 cycloalkyl group. Representative cycloalkyl groups of the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, The term "cycloalkenyl" refers to a cycloalkyl group as defined above and further containing one or more double bonds, including but not limited to cyclopentenyl and 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-membered, i.e., 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered) or polycyclic (e.g., 7-14-membered, i.e., 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered) heterocyclic ring, including fused rings, spirocyclic rings 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 heterocyclic rings with aromatic rings (e.g., benzene rings). The nitrogen and sulfur heteroatoms as ring atoms may be optionally oxidized. The nitrogen in the heterocyclic ring may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. The heterocyclic group can be connected to the residue of any heteroatom or carbon atom of the 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, hexahydroazepine, 4-piperidone, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl and tetrahydro-1,1-dioxythiophene, etc. The spirocyclic, condensed and bridged heterocyclic groups involved may be optionally connected to other groups via single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups via any two or more atoms on the ring.

The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkyloxy" 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" can be substituted or unsubstituted. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes but is not limited to: phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl. The aryl group can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring. The fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring. The connecting line drawn from the ring system indicates that the bond can be attached to any suitable ring atom.

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

Unless otherwise stated, any heteroatom with insufficient valence is assumed to have sufficient hydrogen atoms to complete its valence.

In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above, or a substituent appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of each other. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl ₃ ), cyano, nitro, oxo (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic _, aromatic, _ORa , _SRa , S(=O) _Re , S(=O) _{2Re ,} P(=O) _2Re , S(= _O )2ORe, _P (=O) _2ORe , _{NRbRc , NRbS (} = _{O )} 2Re, _NRbP (=O _{) 2Re} , S(=O _{) 2NRbRc} , P(=O)2NRbRc, C(=O) _ORd , _{C (} =O) _{Ra ,} C(=O) _{NRbRc ,} OC(= _O ) _Ra , 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 _Ra can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic ring or aromatic ring, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic ring or aromatic ring, or R _b and R _c together with the N atom can form a heterocyclic ring; _Re can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic ring or aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring can be optionally substituted. The substituents include, but are not limited to, halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 urea, etc.

Active ingredients

As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably and refer to a compound of Formula I and its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, hydrates, isotopes or prodrugs.

A, _X1 , X2, _X3 , ^R1 , ^R2 , ^R3 _, ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 and n are as defined above.

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

wherein A, X ₁ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and n are as defined above. Preferably, A is phenyl, R ⁵ is independently OR ¹⁰ ; wherein R ¹⁰ is as defined above.

Preferably, the compound has a structure as shown in the following formula (I-1):

Wherein, X ₁ , R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and n are as defined above. Preferably, the compound has a structure as shown in the following formula (II-1):

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above.

Preferably, the compound has a structure as shown in the following formula (I-2)-(I-7):

Wherein, R ²⁰ is 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, _X1 , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R7 , ^R8 , ^R9 and n are as defined above.

Preferably, the compound has a structure shown in 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 ¹⁰ are as defined above.

The salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts. The term "salt" used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included in the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps in the preparation process. The compounds of the present invention may form salts, for example, compound I reacts with a certain amount of acid or base, such as an equivalent amount, and is salted out in a medium, or freeze-dried in an aqueous solution.

The compounds of the present invention contain basic fragments, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salt, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide. [0013] The invention also includes but is not limited to the following: esters, isothioates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonates, dodecanoates, and the like.

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

Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention. The term "prodrug" herein refers to a compound that undergoes chemical transformation by metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when treating a related disease. 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 (such as amides and imino ethers). All these tautomers are part of the present invention.

All stereoisomers of the compounds (e.g., those due to asymmetric carbon atoms that may exist for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist simultaneously with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have two configurations, S or R, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereoisomers derived therefrom, or by separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salt formation with an optically active acid.

The compounds of the present invention are prepared, separated and purified to obtain compounds with a weight content of equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), which are listed in the text description. Such "very pure" compounds of the present invention are also considered part of the present invention.

All configurational isomers of the compounds of the present invention are encompassed, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

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 consistent with those defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures. In addition, asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.

According to the present invention, the ratio of isomers contained in the mixture of isomers can be various. For example, in the mixture of only two isomers, there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by those of ordinary skill in the art, and ratios for more complex mixtures of isomers are also within the scope of the present invention.

The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number from the original atoms. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as ^2H , ^3H , ^13C , ^11C , ^14C , ^15N , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F and ^36Cl , respectively. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as radioactive isotopes of ^3H and ^14C , are also included, which are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. ^3H and carbon-14, i.e. ^14C , are relatively easy to prepare and detect. is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e., ² H, may be preferred in some cases due to their good metabolic stability, which has advantages in certain therapies, such as increasing half-life in vivo or reducing dosage. Isotope-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

If a synthesis of a specific enantiomer of the compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture can be separated, and the chiral auxiliary can be removed to obtain the pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a diastereomeric salt can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography, and then the pure enantiomer can be obtained.

As described herein, the compounds of the present invention can be replaced with any number of substituents or functional groups to expand their scope. Generally, the term "substituted" appears before or after the term "optional", and the general formula including substituents in the formulation of the present invention refers to replacing hydrogen free radicals with designated structural substituents. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents can be the same or different at each position. The term "substituted" used herein includes all allowed organic compound substitutions. In a broad sense, allowed substituents include non-cyclic, cyclic, branched non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, heteroatom nitrogen can have hydrogen substituents or any allowed organic compounds described above to supplement its valence. In addition, the present invention is not intended to limit the allowed substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds. As used herein, the term "stable" refers to compounds that are stable and that maintain the structural integrity of the compound over a period of time sufficient to be detected, and preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application and in vivo, are also included in the claims of the present application.

Pharmaceutical compositions and methods of administration

The pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: cancer, pulmonary hypertension, and pathological angiogenesis.

The compounds of general formula I can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration method and dosage of the original drug can remain unchanged, and the compound of formula I can be taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I. Drug combination also includes taking the compound of formula I and one or more other known drugs in overlapping time periods. When the compound of formula I is used 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 them taken alone.

Drugs or active ingredients that can 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.

The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, film, pill, external ointment, controlled release or sustained release or nano preparation.

The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically 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. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations 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 mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, 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, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

Besides such inert diluents, the composition may 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 such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may include 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 non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of the invention 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 that may be required.

The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula I of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

Preparation method

Methods for preparing compounds of Formula I are described in the following schemes and examples. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order in which the steps of the reaction schemes are carried out may be altered to facilitate the reaction or to avoid unwanted side reaction products.

The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily carried out by a technician in the field to which the present invention belongs.

Usually, in the preparation process, each reaction is usually carried out under the protection of inert gas in a suitable solvent at 0 to 90°C, and the reaction time is usually 2 to 24 hours.

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

i) a pyrimidine analog compound A-1 undergoes a nucleophilic substitution reaction with an amine compound A-2 under alkaline conditions (e.g., N'N-diisopropylethylamine), and a substitution reaction occurs at the 4-position of the pyrimidine chloro analog A-1 to obtain a compound A-3;

ii) Compound A-3 reacts with aromatic amine formic acid A-4 under acidic conditions (such as HCl) to undergo nucleophilic substitution to obtain carboxylic acid compound A-5;

iii) Carboxylic acid compound A-5 and amine compound R-NH ₂ undergo amide condensation reaction in the presence of an amide condensation agent (eg HATU) to obtain compound A-6;

In the formula, A, _X1 , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 and n are as defined above.

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

The present invention has the following main advantages:

(1) The compounds of the present invention have excellent inhibitory ability against FAK kinase and YAP protein;

(2) The compounds of the present invention have lower toxic side effects.

(3) The compounds of the present invention have good pharmacodynamic and pharmacokinetic properties.

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

NMR was measured using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic spectrometers. The measurement solvents included deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated acetone (CD ₃ COCD ₃ ), deuterated chloroform (CDCl ₃ ) and deuterated methanol (CD ₃ OD). Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were measured in parts per million (ppm).

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

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

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

Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures are all degrees Celsius.

The following abbreviations are used throughout this invention:

Defactinib: Defactinib

THF: Tetrahydrofuran

DCM: dichloromethane

PE: Petroleum ether

Na ₂ CO ₃ : Sodium carbonate

MeOH: Methanol

HCl: hydrochloric acid

Pd(PPh ₃ ) ₄ : Tetrakistriphenylphosphine palladium

K ₂ CO ₃ : Potassium carbonate

_H2O : Water

TEA: triethylamine

DIEA: N,N-diisopropylethylamine

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

NaBH ₄ : Sodium borohydride

Sn ₂ (Bu-n) ₆ ：Hexa-n-butyl ditin

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 on carbon

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

EA: Ethyl acetate

Boc ₂ O: di-tert-butyl dicarbonate

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

NaH: Sodium Hydrogen

CH ₃ I: methyl iodide

L-Proline: L-Proline

L-Selectride: Lithium tri-sec-butylborohydride

Example

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: Synthesis of (2-aminophenyl) dimethylphosphine oxide

Compound 2-iodoaniline (10 g, 45.7 mmol) and dimethylphosphine oxide (4.3 g, 54.8 mmol) were dissolved in DMF solution (100 mL), Pd(OAC) ₂ (1.03 g, 4.57 mol), K ₃ PO ₄ (11.63 g, 54.8 mmol) and Xantphos (2.64 g, 4.57 mol) were weighed respectively and added to the reaction system. The nitrogen protection was replaced, and the temperature was slowly raised to 125°C and refluxed with stirring for 6 h. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered through diatomaceous earth and extracted with EA (20 mL*2). The organic phases were combined, washed with saturated brine (30 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography to obtain 7.1 g of (2-aminophenyl)dimethylphosphine oxide, MS m/z (ESI): 170 [M+H] ⁺ .

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

Dissolve 2,4-dichloropyrimidine-5-trifluoromethyl (2.56 g, 11.8 mmol) in DMF (50 mL), add (2-aminophenyl) dimethylphosphine oxide (2.0 g, 11.8 mmol), slowly add DIPEA (2.0 mL, 11.8 mmol) under ice bath conditions, heat to 50°C for 1 h, and monitor the reaction completion. Quench with water, extract with dichloromethane, dry and concentrate, and column chromatography to obtain 920 mg 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) and p-aminobenzoic acid (130 mg, 0.95 mmol) were dissolved in isopropanol (25 mL), 4N hydrochloric acid in 1,4-dioxane solution (1.3 mL, 5.2 mmol) was added, and the mixture was reacted at 65°C for 4 h. The reaction was monitored to be complete. The system was filtered to obtain 276 mg 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)methanamine (22.8 mg, 0.18 mmol), HATU (51.9 mg, 0.14 mmol), DMAP (1.01 mg, 0.009 mmol) and DIPEA (46 μL, 0. 27mmol) was added to DMF (6mL), and then reacted at room temperature for 2h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10mL), extracted with EA (20mL*2), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 15.1mg of (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 ) δ 10.58 (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), 4N hydrochloric acid in 1,4-dioxane solution (0.12 mL, 0.48 mmol) was added, and the mixture was reacted at 70°C for 4 h. The reaction was monitored to be complete. The system was filtered to obtain 135 mg 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)methanamine (38.5 mg, 0.3 mmol mmol), HATU (83.4 mg, 0.23 mmol), DMAP (2.4 mg, 0.02 mmol) and DIPEA (76 μL, 0.45 mmol) were added to DMF (6 mL), and then reacted at room temperature for 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 20 mg 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＝7.1 Hz,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-((4-((2-(dimethylphosphoryl)phenyl)amino)-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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 15 mg 4-((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 2 h. After LCMS monitoring, 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 purified by column chromatography (0-10%, DMC/MeOH) to obtain 13 mg 4-((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-(methyl)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)dimethylphosphine oxide (100 mg, 0.29 mmol) and p-amino-3-methylbenzoic acid (46.3 mg, 0.3 mmol) were dissolved in isopropanol (6 mL), 4N hydrochloric acid in 1,4-dioxane solution (0.1 mL, 0.4 mmol) was added, and the mixture was reacted at 70°C for 4 h. The reaction was monitored to be complete. The system was filtered to obtain 90.0 mg of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(methyl)benzoic acid, MSm/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 2 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL), extracted with EA (20 mL*3), the organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain 40.1 mg 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 p-amino-3-trifluoromethoxybenzoic acid (67.3 mg, 0.3 mmol) were dissolved in isopropanol (6 mL), 4N hydrochloric acid in 1,4-dioxane solution (0.1 mL, 0.4 mmol) was added, and the mixture was reacted at 70°C for 4 h. The reaction was monitored to be complete. The system was filtered to obtain 70.1 mg 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, 0.006 mmol) and DIPEA (43.4 mg, 0.34 mmol) were added to DMF (6 mL), and then reacted at room temperature for 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 15.2 mg 4-((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,1 H),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-(trifluoromethyl)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), 4N hydrochloric acid in 1,4-dioxane solution (0.1 mL, 0.4 mmol) was added, and the mixture was reacted at 70°C for 4 h. The reaction was monitored to be complete. The system was filtered to obtain 102.1 mg 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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 35.0 mg 4-((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), 4N hydrochloric acid in 1,4-dioxane solution (0.1 mL, 0.4 mmol) was added, and the mixture was reacted at 70°C for 4 h. The reaction was monitored to be complete. The system was filtered to obtain 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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 45.2 mg 4-((4-((2-(Dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(ethoxy)benzamide. ¹ HNMR (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: Synthesis of 4-(3-iodo-4-nitrophenyl)morpholine

Dissolve the compound 4-fluoro-2-iodo-1-nitrobenzene (2.5 g, 9.36 mmol) and morpholine (1.6 g, 18.73 mmol) in DMF (50 mL) solution, add K ₂ CO ₃ (2.5 g, 18.73 mmol), slowly heat to 100°C, and stir to react for 8 hours. After the reaction is completed by TLC monitoring, add water to quench, extract with EA (30 mL*2), combine the organic phases, wash with saturated brine (50 mL*2), evaporate under reduced pressure, and purify by ISCO column chromatography (EA/PE 0%-100%) to obtain 4.4 g of 4-(3-iodo-4-nitrophenyl)morpholine, MS m/z (ESI): 335[M+H] ⁺ .

Step 2: Synthesis of 2-iodo-4-morpholineaniline

Dissolve 4-(3-iodo-4-nitrophenyl)morpholine (2.0 g, 6.0 mmol) in methanol/water 4:1 (60 mL), then add iron powder (835.7 mg, 14.96 mmol) and ammonium chloride (815.6 mg, 14.96 mmol), slowly heat the reaction system to 80°C and reflux overnight, cool to room temperature after the reaction is complete, filter with celite, quench with saturated NaHCO ₃ (100 mL), extract with EA (100 mL*3), combine the organic phases and concentrate, purify by ISCO column chromatography (PE/EA 0-80%) to obtain 1.6 g 2-iodo-4-morpholineaniline. MS m/z(ESI): 305[M+H]+.

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

The compound 2-iodo-4-morpholinoaniline (2.0 g, 6.48 mmol) and dimethylphosphine oxide (607.1 g, 7.78 mmol) were dissolved in DMF solution (20 mL), Pd(OAC) 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) were weighed and added into the reaction system respectively, nitrogen protection was replaced, the temperature was slowly raised to 125°C, refluxed and stirred for 6 h, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench, diatomaceous earth was filtered, EA (20 mL*2) was extracted, the organic phases were combined, washed with saturated brine (30 mL*2), distilled under reduced pressure, and purified by ISCO column chromatography (PE/EA0-100%) to obtain 1.2 g of (2-amino-5-morpholinophenyl) dimethylphosphine oxide, MS m/z(ESI):255[M+H] ⁺ .

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

Dissolve 2,4-dichloropyrimidine-5-trifluoromethyl (1.2 g, 4.72 mmol) in DMA (20 mL), add (2-amino-5-morpholinophenyl) dimethylphosphine oxide (931.8 mg, 4.29 mmol), slowly add DIPEA (0.8 mL, 4.72 mmol) under ice bath conditions, heat to 50°C and react for 1 h, monitor the reaction completion. Quench with water, extract with dichloromethane (20 mL*2), dry and concentrate, column chromatography to obtain 0.68 g 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), 4N hydrochloric acid in 1,4-dioxane solution (0.1 mL, 0.4 mmol) was added, and the mixture was reacted at 65°C for 8 h. The reaction was complete after TLC monitoring. The system was filtered to obtain 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 react at room temperature for 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 32.0 mg of 4-((4-((2-(dimethylphosphoryl)-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzamide. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.66 (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

Compound 4-fluoro-2-iodo-1-nitrobenzene (2.5 g, 9.36 mmol) and 1,4'-bipiperidine (1.9 g, 11.24 mmol) were dissolved in DMF (50 mL) solution, K ₂ CO ₃ (2.6 g, 18.72 mmol) was added, the temperature was slowly raised to 100°C, and the reaction was stirred for 8 h. After the reaction was completed by TLC monitoring, water was added to quench, EA (30 mL*2) was extracted, the organic phases were combined, washed with saturated brine (50 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography (EA/PE 0%-100%) to obtain 1'-(3-iodo-4-nitrophenyl)-1,4'-bipiperidine 3.2 g, MS m/z (ESI): 416[M+H] ⁺ .

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

1'-(3-iodo-4-nitrophenyl)-1,4'-bipiperidine (3.2 g, 7.71 mmol) was dissolved in methanol/water 4:1 (60 mL), and 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 heated to 80°C and refluxed overnight. After the reaction was complete, it was cooled to room temperature, filtered through celite, quenched with saturated NaHCO ₃ (100 mL), extracted with EA (100 mL*3), the organic phases were combined and concentrated, and purified by ISCO column chromatography (PE/EA 0-100%) to obtain 1.6 g of 4-([1,4'-bipiperidine]-1'-yl)-2-iodoaniline. MS m/z(ESI): 386[M+H]+.

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

Compound 4-([1,4'-dipiperidinyl]-1'-yl)-2-iodoaniline (1.6 g, 4.16 mmol) and dimethylphosphine oxide (393.3 mg, 5.04 mmol) were dissolved in DMF solution (40 mL), and Pd(OAC) ₂ (92.3 mg, 0.42 mol), K ₃ PO ₄ (1.1 g, 5.04 mmol) and Xantphos (243.0 mg, 0.42 mmol) were added to the reaction system, and the nitrogen protection was replaced. The temperature was slowly raised to 125°C and refluxed with stirring for 6 h. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered through diatomaceous earth and extracted with EA (20 mL*2). The organic phases were combined, washed with saturated brine (30 mL*2), and evaporated under reduced pressure. Purification by ISCO column chromatography (0-100% EA/PE) was performed to obtain 760.3 mg of (5-([1,4'-bipiperidinyl]-1'-yl)-2-aminophenyl)dimethylphosphine oxide, MS m/z (ESI): 336[M+H] ⁺ .

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

Dissolve 2,4-dichloropyrimidine-5-trifluoromethyl (600 mg, 1.79 mmol) in DMA (10 mL), add (2-amino-5-morpholinophenyl) dimethylphosphine oxide (353.0 g, 1.62 mmol), slowly add DIPEA (0.3 mL, 1.79 mmol) under ice bath condition, heat to 60°C for 1 h, monitor the reaction completion. Quench with water, extract with dichloromethane (20 mL*2), dry and concentrate, purify by column chromatography (0-100% EA/PE), and obtain 0.32 g (5-([1,4'-bipiperidinyl]-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

(5-([1,4'-bipiperidinyl]-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), and a 4N hydrochloric acid solution in 1,4-dioxane (0.1 mL, 0.4 mmol) was added. The mixture was reacted at 65°C for 8 h. The reaction was complete after TLC monitoring. The system was filtered to obtain 80.3 mg of 4-((4-((4-([1,4'-bipyridyl]-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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 23.5 mg 4-((4-((4-([1,4'-bipyridyl]-1'-yl)-2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzamide. ¹ H NMR (400 MHz, 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] ⁺ .

Embodiment 11

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

Step 1: Synthesis of 3-methoxy-4-nitrobenzamide

At 0°C, 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), and then reacted at room temperature for 0.5 h. After TLC monitoring, ammonia water (2 mL, 20 mmol) was added and reacted for 1 h. After LCMS monitoring, the reaction was quenched with water (20 mL), extracted with DCM (20 mL*3), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 400 mg of 3-methoxy-4-nitrobenzamide, MS m/z (ESI): 197 [M+H] ⁺ .

Step 2: Synthesis of 3-methoxy-N-(methylsulfonyl)-4-nitrobenzamide

At 0°C, 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 0.5 h. Then, methanesulfonyl chloride (0.3 mL, 4 mmol) was added and reacted for 7 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (15 mL), extracted with EA (20 mL*3), the organic phase was washed with water, dried, concentrated, and column chromatography was used to obtain 220 mg 3-methoxy-N-(methylsulfonyl)-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), and then Pd/C (45 mg) was added and 3 drops of concentrated hydrochloric acid were added. The reaction solution was reacted at room temperature overnight under a hydrogen atmosphere. After the reaction was complete, the solution was filtered and the filtrate was dried to obtain 120 mg 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 hydrochloric acid 1,4-dioxane solution (0.18 mL, 0.72 mmol) were added to isopropanol (10 mL), and then reacted at 70°C for 4 h. After the reaction was completed as monitored by LCMS, it was cooled to room temperature, the reaction system was filtered, and the solid obtained by filtration was washed with isopropanol (5 mL*3), and then dried at 50°C for 1 h to obtain 23 mg of 4-((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), ethoxylamine hydrochloride (32.2 mg, 0.33 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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 the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 40 mg 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxybenzamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.47 (s, 1H), 10.53 (s, 1H), 10.07 (s, 1H), 8.49 (d, J=0.9 Hz, 1H), 8.15 (s, 1H), 7.75–7.54 (m, 6H), 7.33 (t, J=7.6 Hz, 1H), 3.91 (q, J=7.0 Hz, 2H), 1.73 (d, J=13.6 Hz, 6H), 1.20 (t, J=7.0 Hz, 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'-tetramethyluronium 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 the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 60 mg 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] ⁺ .

Embodiment 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'-tetramethyluronium 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 the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 40 mg N-(Allyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.52(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] ⁺ .

Embodiment 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-propargylhydroxylamine hydrochloride (35.5 mg, 0.33 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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 the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 40 mg N-(Propargyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.74 (s, 1H), 10.56 (s, 1H), 10.09 (s, 1H), 8.49 (d, J=0.9 Hz, 1H), 8.16 (s, 1H), 7.72–7.57 (m, 6H), 7.33 (t, J=7.4 Hz, 1H), 4.58 (d, J=2.4 Hz, 2H), 3.60 (t, J=2.4 Hz, 1H), 1.73 (d, J=13.6 Hz, 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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 60.5 mg N-(Benzyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.62 (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, 1.5 Hz, 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] ⁺ .

Embodiment 17

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

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

The compound 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-hydroxybenzamide (30.3 mg, 0.054 mmol) was dissolved in MeOH (10 mL), 10% Pd/C (10 mg) was added, and the reaction was allowed to proceed overnight under _H2 atmosphere. After the reaction was completed as monitored by LCMS, the mixture was filtered on celite and distilled under reduced pressure to obtain 15.6 mg of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-hydroxybenzamide. ¹ H NMR (400MHz, 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] ⁺ .

Embodiment 18

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

4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid (50 mg, 0.11 mmol), O-isobutoxyamine hydrochloride (41.4 mg, 0.33 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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 the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 50 mg 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxybenzamide. 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＝13.6 Hz,6H),0.94(d,J＝6.7 Hz,6H).MS m/z(ESI):522[M+H] ⁺ .

Embodiment 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 mmol), 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 2 h. After LCMS monitoring, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 23.1 mg 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] ⁺ .

Embodiment 20

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

Step 1: Synthesis of benzyl 4-nitrobenzoate

Dissolve 4-nitrobenzoic acid (2g, 12mmol) and benzyl bromide (2.05g, 12mmol) in acetonitrile (100mL) solution, add potassium carbonate (2g, 14.4mmol), heat to 60℃, and stir to react for 5h. After the reaction is completed by TLC monitoring, add water to quench, extract with EA (50mL×2), combine the organic phases, wash with saturated brine (50mL×2), evaporate under reduced pressure, and purify by column chromatography (PE＝1) to obtain 3g of 4-nitrobenzoic acid benzyl ester, MS m/z (ESI): 258[M+H] ⁺ .

Step 2: Synthesis of 4-aminobenzoic acid benzyl ester

Dissolve benzyl 4-nitrobenzoate (3g, 12mmol) in methanol/water 4:1 (50mL), then add iron powder (1.68g, 30mmol) and ammonium chloride (1.6g, 30mmol) and slowly heat the reaction system to 80℃ and reflux overnight. After the reaction is complete, cool to room temperature, filter with celite, quench with saturated sodium bicarbonate solution (100mL), extract with EA (100mL×3), combine the organic phases, concentrate, and purify by column chromatography (PE:EA＝4:1) to obtain 2.1g 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-dimethylacetamide (15 mL), 4-aminobenzoic acid benzyl ester (1.7 g, 7.5 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.25 mmol) were added, and the temperature was raised to 60°C for 6 h, and the reaction was monitored to be complete. 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 (2×3 mL). The residue was the target product, and 1.53 g of 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid benzyl ester was obtained, 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: Synthesis of (R)-N,N-dimethylpyrrolidin-3-amine hydrochloride

Dissolve tert-butyl (R)-3-(dimethylamino)pyrrolidine-1-carboxylate (1.3 g, 6.1 mmol) in dichloromethane (20 mL), add 4N hydrochloric acid in 1,4-dioxane (4.5 mL, 18.3 mmol), and stir at room temperature for 3 h. After the reaction is completed by TLC monitoring, evaporate under reduced pressure to obtain 912 mg of (R)-N,N-dimethylpyrrolidine-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) solution, potassium carbonate (2.53 g, 18.3 mmol) was added, the temperature was slowly raised to 100°C, and the reaction was stirred for 6 hours. After the reaction was completed by TLC monitoring, water was added to quench, EA (50 mL × 2) was extracted, the organic phases were combined, washed with saturated brine (30 mL × 2), evaporated under reduced pressure, and purified by column chromatography (EA = 1) to obtain (R)-1-(3-iodo-4-nitrophenyl)-N, N-dimethylpyrrolidin-3-amine 1.4 g, 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-dimethylpyrrolidin-3-amine (1.4 g, 3.88 mmol) was dissolved in methanol/water 4:1 (50 mL), and then iron powder (0.54 g) and ammonium chloride (0.52 g) were added. The reaction system was slowly heated to 80°C and refluxed overnight. After the reaction was completed, it was cooled to room temperature, filtered through celite, quenched with saturated sodium bicarbonate solution (100 mL), extracted with EA (100 mL×3), the organic phases were combined and concentrated, and purified by column chromatography (PE/EA 0-80%) to obtain 1.25 g (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

Dissolve (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) in N,N-dimethylformamide solution (10 mL). Weigh palladium acetate (85 mg, 0.38 mmol), potassium phosphate (0.96 g, 4.54 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.22 g, 0.38mmol) was added into the reaction system, replaced with nitrogen protection, slowly heated to 120℃, refluxed and stirred for 6h, monitored by TLC, after the reaction was completed, quenched with water, filtered through diatomaceous earth, extracted with DCM (30mL×2), combined organic phases, washed with saturated brine (10mL×2), evaporated under reduced pressure, purified by column chromatography to obtain 0.4g of (R)-(2-amino-5-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)dimethylphosphine oxide, MS m/z(ESI):282[M+H] ⁺ .

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

Dissolve benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (147 mg, 0.36 mmol) in N,N-dimethylformamide (5 mL), add (R)-(2-amino-5-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)dimethylphosphine oxide (110 mg, 0.39 mmol), add p-toluenesulfonic acid (13.5 mg, 0.07 mmol), heat to 120 ° C for 2 h, and monitor the reaction to completion. The reaction mixture was quenched with water, extracted with dichloromethane (20 mL×2), dried, concentrated, and subjected to column chromatography to obtain 120 mg of (R)-benzyl 4-((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), palladium hydroxide/carbon (240 mg) was added, and the mixture was reacted for 2 h in a H ₂ atmosphere. The reaction was completed after monitoring by TLC. The system was filtered, and the filtrate was distilled under reduced pressure to obtain 70 mg 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-((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'-tetramethyluronium hexafluorophosphate (71.5 mg, 0.188 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.75 mM) were added. mol) was added to N,N-dimethylformamide (5 mL), and then reacted at room temperature for 15 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 20 mg of (R)-4-((4-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide. MS m/z(ESI): 592.2[M+H] ⁺ .

Embodiment 21

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

Step 1: Synthesis of (2-amino-5-bromophenyl) dimethylphosphine oxide

Compound 4-bromo-2-iodoaniline (6.0 g, 20.1 mmol) and dimethylphosphine oxide (1.89 g, 24.2 mmol) were dissolved in DMF solution (40 mL), Pd(OAC) ₂ (425.1 mg, 2.01 mol), K ₃ PO ₄ (5.09 g, 24.2 mmol) and Xantphos (1.16 g, 2.01 mol) were weighed respectively and added into the reaction system. Nitrogen protection was replaced, the temperature was slowly raised to 125°C, refluxed and stirred for 6 h, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench, and the mixture was filtered through diatomaceous earth and extracted with EA (20 mL*2). The organic phases were combined, washed with saturated brine (30 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography to obtain 3.2 g 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

Compound (2-amino-5-bromophenyl) dimethylphosphine oxide (1.0 g, 4.0 mmol)) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (909.1 g, 4.4 mmol) were dissolved in DMA/H ₂ O (5:1) solution (40 mL), and Pd(dppf)Cl ₂ (329.9 mg, 0.4 mol) and Na ₂ (CO ₃ ) ₂ (1.28 g, 12.1 mmol) was added to the reaction system, replaced with nitrogen protection, slowly heated to 80°C, refluxed and stirred for 6 h, monitored by TLC, and after the reaction was completed, quenched with water, extracted with EA (20 mL*2), combined organic phases, washed with saturated brine (30 mL*2), evaporated under reduced pressure, purified by ISCO column chromatography (0-100% EA/PE), and obtained 0.31 g of (2-amino-5-(pyridin-3-yl)phenyl)dimethylphosphine oxide, 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 benzyl 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, and the temperature was slowly raised to 125°C for reaction. The reaction was monitored by TLC for 18 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with EA (20 mL*2). The organic phases were combined, washed with saturated brine (30 mL*2), and evaporated under reduced pressure. The mixture was purified by ISCO column chromatography (0-100% EA/PE) to give 87.0 mg of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminobenzyl benzyl ester, 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 benzyl ester (87.0 mg, 0.14) was dissolved in methanol (6 mL), PdOH/C (200 mg) was added, _H2 was replaced, and the reaction was carried out overnight under _H2 atmosphere. The reaction was monitored by TLC to be complete. The system was filtered to obtain 56.4 mg 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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 12 mg 4-((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-(4,4,5,5-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(diphenylphosphino)-9,9-dimethylxanthene (1.97 g, 3.4 mmol) were weighed and added to the reaction system, nitrogen protection was replaced, the temperature was slowly raised to 120°C, refluxed and stirred for 4 h, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench, and the mixture was filtered through diatomaceous earth and extracted with DCM (200 mL×2). The organic phases were combined, washed with saturated brine (50 mL×2), distilled under reduced pressure, and purified by column chromatography to obtain 6.5 g of (2-amino-5-bromophenyl)dimethylphosphine oxide, MS m/z (ESI): 248[M+H] ⁺ .

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

Dissolve (2-amino-5-bromophenyl)dimethylphosphine oxide (2 g, 8.1 mmol) and diboronic acid pinacol ester (4.1 g, 16.2 mmol) in 1,4-dioxane solution (30 mL). Weigh [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.66 g, 0.81 mmol) and potassium acetate (2.4 g, 24.3 mmol) respectively and add them to the reaction system. Replace nitrogen protection and slowly heat up. The mixture was stirred at reflux at 100°C for 3 h and monitored by TLC. After completion of the reaction, water was added to quench the mixture and the mixture was filtered through diatomaceous earth. The mixture was extracted with DCM (30 mL×2). The organic phases were combined and washed with saturated brine (10 mL×2). The mixture was evaporated under reduced pressure and purified by column chromatography using MeOH/DCM (0-10%) to obtain 1.65 g of (2-amino-5-(4,4,5,5-tetramethyl-1,3-dioxo-2-borolan-2-yl)phenyl)dimethylphosphine oxide. 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

Dissolve (2-amino-5-(4,4,5,5-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 a mixed solution of 1,4-dioxane (50 mL) and water (5 mL). l) and cesium carbonate (1.4 g, 4.25 mmol) were added to the reaction system, and nitrogen protection was replaced. The temperature was slowly raised to 120°C, refluxed and stirred for 6 h, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered through diatomaceous earth and extracted with DCM (50 mL×2). The organic phases were combined, washed with saturated brine (10 mL×2), and evaporated under reduced pressure. Purification by column chromatography gave 0.37 g of (2-amino-5-(pyridin-2-yl)phenyl)dimethylphosphine oxide, 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

Dissolve (2-amino-5-(pyridin-2-yl)phenyl)dimethylphosphine oxide (185 mg, 0.75 mmol) in 1,4-dioxane (10 mL), add benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (306 mg, 0.75 mmol), add p-toluenesulfonic acid (143 mg, 0.75 mmol), heat to 120°C and react for 20 h, monitor the reaction completion. Quench with water, extract with dichloromethane (20 mL×2), dry and concentrate, column chromatography to obtain 200 mg benzyl 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate, MSm/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), palladium hydroxide/carbon (200 mg) was added, and the mixture was reacted for 5 h in a H ₂ atmosphere. The reaction was complete after monitoring by TLC. The system was filtered, and the filtrate was distilled under reduced pressure to obtain 170 mg 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-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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 15 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 70 mg 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide. ¹ H NMR (400 MHz, 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] ⁺ .

Embodiment 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: Synthesis of (2-amino-5-bromophenyl) dimethylphosphine oxide

Compound 4-bromo-2-iodoaniline (6.0 g, 20.1 mmol) and dimethylphosphine oxide (1.89 g, 24.2 mmol) were dissolved in DMF solution (40 mL), Pd(OAC) ₂ (425.1 mg, 2.01 mol), K ₃ PO ₄ (5.09 g, 24.2 mmol) and Xantphos (1.16 g, 2.01 mol) were weighed and added into the reaction system respectively, nitrogen protection was replaced, the temperature was slowly raised to 125°C, refluxed and stirred for 6 h, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench, and the mixture was filtered through diatomaceous earth and extracted with EA (20 mL*2). The organic phases were combined, washed with saturated brine (30 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography (0-100% EA/PE) to obtain 3.2 g of (2-amino-5-bromophenyl)dimethylphosphine oxide, MS m/z (ESI): 249[M+H] ⁺ .

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

Compounds (2-amino-5-bromophenyl) dimethylphosphine oxide (1.0 g, 4.0 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (921.8 g, 4.4 mmol) were dissolved in DMA/H ₂ O (5:1) solution (40 mL), and Pd(dppf)Cl ₂ (329.9 mg, 0.4 mol) and Na ₂ (CO ₃ ) ₂ (1.3 g, 12.1 mmol) was added into the reaction system, replaced with nitrogen protection, slowly heated to 80°C, refluxed and stirred for reaction for 2 h, monitored by TLC, and after the reaction was completed, quenched with water, extracted with EA (20 mL*2), combined organic phases, washed with saturated brine (30 mL*2), evaporated under reduced pressure, purified by ISCO column chromatography (0-100% EA/PE), and obtained 0.3 g 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 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid benzyl ester (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, and the temperature was slowly raised to 125 ° C for reaction. The reaction was monitored by TLC for 18 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with EA (20 mL*2). The organic phases were combined, washed with saturated brine (30 mL*2), and evaporated under reduced pressure. The mixture was purified by ISCO column chromatography (0-100% EA/PE) to give 101.3 mg of benzyl 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminobenzoate, MS m/z (ESI): 408.1 [M+H] ⁺ .

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) was added, H ₂ was replaced, and the reaction was carried out overnight under H ₂ atmosphere. The reaction was completed by TLC monitoring. The system was filtered to obtain 32.1 mg 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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 15.1 mg 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide. ¹ H NMR (400 MHz, 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] ⁺ .

Embodiment 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

Dissolve (2-amino-5-(4,4,5,5-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 a mixed solution of 1,4-dioxane (50 mL) and water (5 mL). ol) and cesium carbonate (1.4 g, 4.25 mmol) were added to the reaction system, and the nitrogen protection was replaced. The temperature was slowly raised to 120°C, refluxed and stirred for reaction for 6 h, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered through diatomaceous earth and extracted with DCM (50 mL×2). The organic phases were combined, washed with saturated brine (10 mL×2), and evaporated under reduced pressure. Purification by column chromatography gave 0.4 g of (2-amino-5-(2-(methylamino)pyrimidin-4-yl)phenyl)dimethylphosphine oxide, 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

Dissolve (2-amino-5-(2-(methylamino)pyrimidin-4-yl)phenyl)dimethylphosphine oxide (110 mg, 0.4 mmol) in 1,4-dioxane (10 mL), add benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (148 mg, 0.36 mmol), add p-toluenesulfonic acid (68 mg, 0.36 mmol), heat to 120 ° C and react for 20 h, and monitor the completion of the reaction. The reaction mixture was quenched with water, extracted with dichloromethane (20 mL×2), dried, concentrated, and purified by column chromatography to obtain 140 mg 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

Benzyl 4-((4-((2-(dimethylphosphoryl)-4-(2-(methylamino)pyrimidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (140 mg, 0.216 mmol) was dissolved in methanol (25 mL), palladium hydroxide/carbon (140 mg) was added, and the mixture was reacted for 5 h in a H ₂ atmosphere. The reaction was complete after monitoring by TLC. The system was filtered, and the filtrate was distilled under reduced pressure to obtain 120 mg 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-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (133 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) were added to N,N-dimethylformamide (3 mL), and then reacted at room temperature for 15 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 60 mg 4-((4-((2-(dimethylphosphoryl)-4-(2-(methylamino)pyrimidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide. 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] ⁺ .

Embodiment 25

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

Step 1: Synthesis of (2-amino-5-fluorophenyl) dimethylphosphine oxide

Compound 4-fluoro-2-iodoaniline (2.0 g, 8.43 mmol) and dimethylphosphine oxide (789.9 mg, 10.1 mmol) were dissolved in DMF solution (40 mL), Pd(OAC) ₂ (188.6 mg, 0.84 mmol), K ₃ PO ₄ (2.15 g, 10.1 mmol) and Xantphos (486.0 mg, 0.84 mol) were weighed and added to the reaction system, nitrogen protection was replaced, the temperature was slowly raised to 125°C, refluxed and stirred for 6 h, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered through diatomaceous earth and extracted with EA (20 mL*2). The organic phases were combined, washed with saturated brine (30 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography to obtain 1.2 g of (2-amino-5-fluorophenyl)dimethylphosphine oxide, 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, nitrogen protection was replaced, the temperature was slowly raised to 125°C, and the reaction was reacted for 18 h. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, and EA (20 mL*2) was used for extraction. The organic phases were combined, washed with saturated brine (30 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography to obtain 150.2 mg of benzyl 4-((4-((2-(2-(dimethylphosphoryl)-4-fluorophenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate, 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), PdOH/C (30 mg) was added, H ₂ was replaced, and the reaction was carried out overnight under H ₂ atmosphere. The reaction was monitored to be complete by TLC. The system was filtered to obtain 98.3 mg 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 (32.2 mg, 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 2 h. After LCMS monitoring, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 42.3 mg 4-((4-((2-(dimethylphosphoryl)-4-fluorophenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide. ¹ H NMR (400 MHz, 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). MSm/z(ESI):498[M+H] ⁺ .

Embodiment 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: Synthesis of 4-bromo-2,3-dihydro-7-benzofuranamine

The compound 2,3-dihydro-7-benzofuranamine (5g, 37mmol) was dissolved in DMF (50mL) solution, and NBS (7.2g, 41mmol) was added in batches. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, water was added to quench the mixture, and EA (30mL*2) was used for extraction. The organic phases were combined, washed with saturated brine (50mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography (EA/PE 0%-100%) to obtain 4.4g of pure 4-bromo-2,3-dihydro-7-benzofuranamine, MSm/z (ESI): 215[M+H] ⁺ .

Step 2: Synthesis of 7-amino-2,3-dihydro-ethyl ester

The compound 4-bromo-2,3-dihydro-7-benzofuranamine (4 g, 18.9 mmol) was dissolved in toluene/ethanol (5:1) solution (40 mL), and DMAP (9.76 g, 80 mmol), Pd(OAC) ₂ (240 mg, 5 mol%), Co ₂ (CO) ₈ (5.45 g, 16 mmol) and Xantphos (1.27 g, 10 mol%) were weighed and added to the reaction system. The nitrogen protection was replaced, and the temperature was slowly raised to 105°C, refluxed and stirred to react overnight. The reaction was monitored by TLC. After the reaction was completed, it was filtered through diatomaceous earth, and the filtrate was quenched with aqueous hydrochloric acid (pH = 4), extracted with EA (20 mL*2), the organic phases were combined, washed with saturated brine (30 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography to obtain 2.00 g 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

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

Step 4: Synthesis of 7-amino-N-methyl-2,3-dihydrobenzofuran-4-carboxamide

Compound 7-amino-2,3-dihydro-4-benzofurancarboxylic acid (1g, 5.58mmol) was added to a 250mL tank reactor, DMF (3mL) was added to dissolve, methylamine hydrochloride (1.5g, 22.32mmol), DIPEA (4mL, 22.32mmol) and HATU (2.54g, 6.7mmol) were weighed and added to a round-bottom flask, the temperature was raised to 115°C, and the reaction was stirred overnight. After the reaction was completed by TLC monitoring, EA and water were extracted, the organic phase was washed twice with saturated brine, and the residue was dried by spin column to obtain 400mg of pure 7-amino-N-methyl-2,3-dihydrobenzofuran-4-carboxamide, 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-methyl-2,3-dihydrobenzofuran-4-carboxamide (63 mg, 0.31 mmol) were dissolved in isopropanol (6 mL), 4N hydrochloric acid in 1,4-dioxane solution (65.2 μL) was added, and the mixture was reacted at 65°C for 4 h. The reaction was monitored by TLC to be complete. The system was filtered to obtain 74 mg of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide, ¹ H NMR (400 MHz, 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] ⁺ .

Embodiment 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, 0.013 mmol) and DIPEA (0.13 mL, 0.75 mmol) were added to DMF (6 mL), and then reacted at room temperature for 2 h. After LCMS monitoring, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 45.3 mg 4-((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). MS m/z (ESI): 552 [M+H] ⁺ .

Embodiment 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-benzylhydroxylamine hydrochloride (59.9 mg, 0.38 mmol), HATU (95.1 mg, 0.26 mmol), DMAP (1.01 mg, 0.013 mmol) and DIPEA (0.13 mL, 0.75 mmol) were added to DMF (6 mL), and then reacted at room temperature for 2 h. After the reaction was completed as monitored by LCMS, 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 chromatography was performed to obtain 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, and the reaction was allowed to proceed overnight under _H2 atmosphere. After the reaction was completed as monitored by LCMS, the mixture was filtered on celite and evaporated under reduced pressure to obtain 25.1 mg, 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-hydroxy-3-methoxybenzamide. 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] ⁺ .

Embodiment 29

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

Step 1: Synthesis of N-(propyloxy)-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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 23 mg N-(Propoxy)-4-((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] ⁺ .

Embodiment 30

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

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

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 2 h. After LCMS monitoring, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 35 mg 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isopropoxybenzamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.27 (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] ⁺ .

Embodiment 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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 42.1 mg N-(Cyclopropylmethoxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.49 (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=7.2 Hz, 1H), 3.69 (d, J=7.2 Hz, 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] ⁺ .

Embodiment 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), 4N hydrochloric acid in 1,4-dioxane solution (0.1 mL, 0.4 mmol) was added, and the mixture was reacted at 70°C for 4 h. The reaction was monitored to be complete. The system was filtered to obtain 34.2 mg 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, 0.007 mmol) and DIPEA (53.0 mg, 0.41 mmol) were added to DMF (6 mL), and then reacted at room temperature for 2 h. After LCMS monitoring, the reaction was completed, and 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 23.3 mg 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N-isobutyloxy-5-methoxybenzamide. ¹ HNMR (400 MHz, 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,1 H),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] ⁺ .

Embodiment 33

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

Step 1: Synthesis of (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(diphenylphosphino)-9,9-dimethylxanthene (0.232 g, 0.4 mmol) were weighed and added to the reaction system. The nitrogen atmosphere was replaced for protection, and the temperature was slowly raised to 120°C and refluxed with stirring for 6 h. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered through diatomaceous earth and extracted with DCM (20 mL×2). The organic phases were combined, washed with saturated brine (5 mL×2), evaporated under reduced pressure, and purified by column chromatography to obtain 0.37 g of (2-hydroxyphenyl)dimethylphosphine oxide, MS m/z (ESI): 171[M+H] ⁺ .

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

Dissolve (2-hydroxyphenyl)dimethylphosphine oxide (50 mg, 0.294 mmol) in n-butanol (3 mL), add benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (120 mg, 0.294 mmol), add N,N-diisopropylethylamine (0.05 mL, 0.294 mmol), heat to 120℃ and react for 14 h, monitor the completion of the reaction. Quench with water, extract with dichloromethane (20 mL×2), dry and concentrate, and obtain 50 mg benzyl 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate by column chromatography, 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/carbon (50 mg) was added, and the mixture was reacted for 15 h in a H ₂ atmosphere. The reaction was completed after monitoring by TLC. The system was filtered, and the filtrate was distilled under reduced pressure to obtain 42 mg 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'-tetramethyluronium 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), and then reacted at room temperature for 15 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 8 mg 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide. MS m/z(ESI):481[M+H] ⁺

Embodiment 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 hydrochloric acid 1,4-dioxane solution (0.25 mL, 1 mmol) were added to isopropanol (6 mL), and then reacted at 60°C for 4 h. After the reaction was completed as monitored by LCMS, the reaction system was cooled to room temperature, and the reaction system was filtered. The solid obtained by filtration was washed with isopropanol (2 mL×3), and then dried at 50°C for 1 h to obtain 37 mg of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-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-isobutoxyamine hydrochloride (30 mg, 0.24 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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), and then reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 30 mg 4-((4-((2-(Dimethylphosphoryl)phenyl)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).MSm/z(ESI): 536.2[M+H] ⁺ .

Embodiment 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 hydrochloric acid 1,4-dioxane solution (0.25 mL, 1 mmol) were added to isopropanol (6 mL), and then reacted at 60°C for 4 h. After the reaction was completed as monitored by LCMS, the mixture was cooled to room temperature, and the reaction system was filtered. The solid obtained by filtration was washed with isopropanol (2 mL×3), and then dried at 50°C for 1 h to obtain 44 mg of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-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-isobutoxybenzamide

4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorobenzoic acid (44 mg, 0.094 mmol), O-isobutoxyamine hydrochloride (35.4 mg, 0.282 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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 reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 30 mg 4-((4-((2-(Dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxybenzamide. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.23(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): 5 40[M+H] ⁺ .

Embodiment 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, reacted at room temperature for 5 h, and the reaction was monitored to be complete. Water was added, dichloromethane was added for extraction, dried and concentrated, and column chromatography was performed to obtain 230 mg (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) and p-aminobenzoic acid (53 mg, 0.39 mmol) were dissolved in isopropanol (4 mL), and a 4N hydrochloric acid solution in 1,4-dioxane (63.7 μL) was added. The mixture was reacted at 70° C. for 14 h and the reaction was monitored to be complete. The system was filtered to obtain 81 mg 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) and DIPEA (64.36 mL, 0.39 mmol) were added under ice bath, and the mixture was reacted at room temperature for 1 h. Then, methoxyamine hydrochloride (32.52 mg, 0.39 mmol) and DMAP (0.24 mg, 0.002 mmol) were added, and the mixture was reacted at room temperature overnight. The reaction was monitored to be complete. Water was added, DCM was added for extraction, dried and concentrated, and purified by column chromatography with MeOH/DCM (0-10%) to obtain 48 mg of 4-((5-chloro-4-((2-(dimethylphosphoryl)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] ⁺ .

Embodiment 37

Preparation of (E)-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

The 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), heated under reflux and reacted overnight. After the reaction was completed as monitored by LCMS, water was added to quench the reaction, and the mixture was extracted with dichloromethane (5 mL*3). The organic phases were combined and evaporated under reduced pressure. The mixture was purified by ISCO column chromatography with MeOH/DCM (0-10%) to obtain 15.1 mg of (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] ⁺ .

Embodiment 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'-tetramethyluronium 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 the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 45.0 mg 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-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] ⁺ .

Embodiment 39

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

4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid (60 mg, 0.13 mmol), 1-(aminooxy)-2-methylpropane-2-ol (42.4 mg, 0.40 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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 16 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 63.1 mg 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxy-2-methylpropoxy)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＝6.7H z,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] ⁺ .

Embodiment 40

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

Step 1: Synthesis of 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 6-aminonicotinic acid methyl ester (55.9 mg, 0.38 mmol) were dissolved in isopropanol (14 mL), 4N hydrochloric acid in 1,4-dioxane solution (0.12 mL, 0.48 mmol) was added, and the mixture was reacted at 70°C for 4 h. The reaction was monitored to be complete. The system was filtered to obtain 100 mg of 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminomethylnicotinic acid methyl ester, 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)aminomethylnicotinic acid methyl ester (90 mg, 0.19 mmol) was dissolved in a mixed solution of THF (10 mL) and methanol (5 mL), and LiOH (14.0 mg, 0.58 mmol) was dissolved in (5 mL) aqueous solution, and the temperature was slowly raised to 65°C and stirred for 4 h. After the reaction was completed, it was monitored by TLC, diluted with water, the pH was adjusted to acidic, extracted with ethyl acetate (40 mL*3), the organic phases were combined, washed with saturated brine (50 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography to obtain 70 mg of 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-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-isobutoxynicotinamide

6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)nicotinic acid (70 mg, 0.16 mmol), O-isobutoxyamine hydrochloride (59.0 mg, 0.47 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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 at room temperature for 16 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL), extracted with EA (20 mL×3), the organic phases were combined, washed with water, dried and concentrated, and purified by column chromatography with MeOH/DCM (0-10%) to obtain 32.1 mg 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxynicotinamide. 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] ⁺ .

Embodiment 41

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

Step 1: Synthesis of 5-amino-N-isobutyloxypicolinamide

5-Aminopicolinic acid (200 mg, 1.45 mmol), O-isobutoxyamine hydrochloride (546.4 mg, 4.4 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.1 g, 2.9 mmol), 4-dimethylaminopyridine (18.3 mg, 0.15 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.7 mmol) were added to DMF (6 mL), and then reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL), extracted with EA (20 mL×3), the organic phases were combined, washed with water, dried, concentrated, and purified by column chromatography with MeOH/DCM (0-10%) to obtain 150 mg 5-amino-N-isobutoxypicolinamide, 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-isobutoxypicolinamide

Compound 6-amino-N-isobutoxypicolinamide (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 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) were added. Nitrogen protection was replaced, and the mixture was heated to 105 ° C under N ₂ atmosphere and stirred overnight. After LCMS monitoring, the reaction was completed, dichloromethane was added to dilute, saturated NaHCO ₃ was quenched, and DCM (20 mL×3) was extracted. The organic phases were combined, washed with water, washed with saturated brine, dried and concentrated, and purified by column chromatography with MeOH/DCM (0-10%) to obtain 25.1 mg 5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxypicolinamide. 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] ⁺ .

Embodiment 42

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

Step 1: Synthesis of dimethyl (2-aminophenyl)phosphonate

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), Pd(dppf)Cl ₂ (1.5 g, 1.83 mol) and K ₃ PO ₄ (9.7 g, 45.7 mmol) were weighed and added to the reaction system, nitrogen protection was replaced, the temperature was slowly raised to 105°C, refluxed and stirred for 13 h, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench, and the mixture was filtered through diatomaceous earth and extracted with EA (20 mL*2). The organic phases were combined, washed with saturated brine (30 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography to obtain 0.71 g 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

Dissolve 2,4-dichloropyrimidine-5-trifluoromethyl (0.71 g, 3.55 mmol) in EtOH (20 mL), add dimethyl (2-aminophenyl)phosphonate (0.7 g, 3.2 mmol), slowly add NaHCO ₃ (542.7 mg, 6.5 mmol) under ice bath conditions, heat to 50°C for 1 h, and monitor the reaction completion. Quench with water, extract with dichloromethane, dry and concentrate, and column chromatography to obtain 95.3 mg 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

Dissolve 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) in isopropanol (10 mL), add 4N hydrochloric acid in 1,4-dioxane solution (0.1 mL), react at 65°C for 4 h, and monitor the reaction until complete. Filter the system to obtain 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), and then reacted at room temperature for 2 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL), extracted with EA (20 mL*2), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 28.6 mg of 2-((2-(((4-(methoxycarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl dimethylphosphonate. 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] ⁺ .

Embodiment 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-isobutoxyamine 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 2 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL), extracted with EA (20 mL*2), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 40 mg (2-((2-(((4-(isobutoxycarbamoyl)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] ⁺ .

Embodiment 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 reacted at room temperature for 2 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL), extracted with EA (20 mL*2), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 53.2 mg 4-((4-((2-(Dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N,5-dimethoxybenzamide. 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] ⁺ .

Embodiment 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 2 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL), extracted with EA (20 mL*2), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 48.2 mg of 4-((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),10.51(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] ⁺ .

Embodiment 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), 4N hydrochloric acid in 1,4-dioxane solution (0.12 mL, 0.48 mmol) was added, and the mixture was reacted at 70°C for 4 h. The reaction was monitored to be complete. The system was filtered to obtain 135 mg 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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 35.1 mg 7-(((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxy-2,3-dihydrobenzofuran-4-carboxamide. ¹ H NMR (400 MHz, 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] ⁺ 。

Embodiment 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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 54.9 mg 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2,3-dihydrobenzofuran-4-carboxamide. ¹ H NMR (400 MHz, 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,1 H),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).MSm/z(ESI): 5 64.2[M+H] ⁺ .

Embodiment 48

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

Step 1: Synthesis of diallylphosphine oxide

At 0°C, allyl magnesium bromide tetrahydrofuran solution (1M, 65.1 mL) was added dropwise to dimethyl phosphate (3.0 g, 21.7 mmol) in Et ₂ O solution (5 mL), slowly heated to room temperature, and reacted for 1 hour. Then K ₂ CO ₃ (4.3 g, 54.8 mmol) in water solution (1.1 mL) was added to the reaction system at 0°C and stirred for 10 minutes. The reaction was filtered, washed with ethanol, and the filtrate was concentrated. The crude product was slurried with ether (2*10 mL), filtered, and the filtrate was concentrated to obtain diallylphosphine oxide, which was directly used in the next step, MS m/z (ESI): 131.0 [M+H] ⁺ .

Step 2: Synthesis of diallyl(2-aminophenyl)phosphine oxide

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) ₂ (345.7 mg, 1.54 mmol), K ₃ PO ₄ (6.5 g, 30.8 mmol) and Xantphos (1.78 g, 3.08 mol) were weighed and added into the reaction system respectively. The nitrogen protection was replaced, and the temperature was slowly raised to 125°C, refluxed and stirred for 6 h, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench, and the mixture was filtered through diatomaceous earth and extracted with EA (20 mL*2). The organic phases were combined, washed with saturated brine (30 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography to obtain 1.8 g of diallyl(2-aminophenyl)phosphine oxide, MS m/z (ESI): 222.1[M+H] ⁺ .

Step 3: Synthesis of benzyl (2-(diallylphosphoryl)phenyl]carbamate

Diallyl (2-aminophenyl) phosphine oxide (1.8 g, 8.1 mmol) was dissolved in DCM (20 mL), and DIPEA (2.8 mL, 16.3 mmol) was added. Cbz-Cl (1.4 mL, 11.8 mmol) was slowly added dropwise under ice bath conditions, and the temperature was raised to room temperature for 1 h. The reaction was monitored to be complete. Water was added to quench the mixture, and dichloromethane was added for extraction. The mixture was dried and concentrated, and 1.6 g of benzyl (2-(diallylphosphoryl)phenyl]carbamate was obtained by ISCO column chromatography. MS m/z (ESI): 356.1 [M+H] ⁺ .

Step 4: Synthesis of benzyl (2-(1-oxido-2,5-dihydrophosphin-1-yl)phenyl]carbamate

Benzyl (2-(diallylphosphoryl)phenyl]carbamate (2.6 g, 7.2 mmol) was dissolved in toluene (25 mL), and the air was replaced by nitrogen. Then Grubbs first-generation catalyst (595.8 mg, 0.72 mmol) was added to the reaction system, and the mixture was refluxed at 110°C for 12 h. The reaction was complete after LCMS monitoring. Water (10 mL) was added to quench the reaction, and DCM (20 mL*2) was used for extraction. The organic phase was washed with water, dried, concentrated, and 2.1 g of benzyl (2-(1-oxidized-2,5-dihydrophosphin-1-yl)phenyl]carbamate was obtained by ISCO column chromatography. MS m/z (ESI): 328.1 [M+H] ⁺ .

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

The compound [2-(1-oxido-2,5-dihydrophosphin-1-yl)phenyl]benzyl carbamate (2.1 g, 6.4 mmol) was dissolved in MeOH (30 mL), 10% Pd/C (400 mg) was added, and the mixture was reacted overnight under H ₂ atmosphere. After the reaction was completed as monitored by LCMS, the mixture was filtered through celite and evaporated under reduced pressure to obtain 1.3 g 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 1-oxide

Dissolve 2,4-dichloropyrimidine-5-trifluoromethyl (552.1 mg, 3.0 mmol) in EtOH (20 mL), add 1-(2-aminophenyl)phosphine epoxide (587.1 mg, 3.0 mmol), slowly add NaHCO ₃ (504.0, 6.0 mmol) under ice bath condition, heat to 85°C for 1 h, monitor the reaction completion. Quench with water, extract with dichloromethane, dry and concentrate, column chromatography to obtain 340 mg 1-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)phosphine 1 oxide, MS m/z (ESI): 342.0 [M+H] ⁺ .

Step 7: Synthesis of 4-((5-chloro-4-((2-(1-phosphinyl-1-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-isobutyloxy-5-methoxybenzamide

Compound 1-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)phosphine 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 ₂ (dba) ₃ (40.3 mg, 0.045 mmol), BINAP (56.0 mg, 0.09 mmol) and tBuOK (86.5 mg, 0.90 mmol) were added. The mixture was replaced with nitrogen for protection. The mixture was heated to 105 °C under N ₂ atmosphere and stirred overnight. After the reaction was completed as monitored by LCMS, dichloromethane was added for dilution, and saturated NaHCO The reaction mixture was quenched at ₃ and extracted with DCM (20 mL×3). The organic phases were combined, washed with water and saturated brine, dried, concentrated, and purified by column chromatography with MeOH/DCM (0-10%) to give 15.1 mg of 4-((5-chloro-4-((2-(1-phosphinyl-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),10.51(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] ⁺ .

Embodiment 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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 52.1 mg 7-((4-((2-(Dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethyl-2,3-dihydrobenzofuran-4-carboxamide. 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). MS m/z(ESI): 520.1[M+H] ⁺ .

Embodiment 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: Synthesis of N-(4-methoxybenzyl)benzofuran-7-amine

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), Pd 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 weighed and added to the reaction system, nitrogen protection was replaced, the temperature was slowly raised to 105 ° C, refluxed and stirred for 16 h, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench, filtered through diatomaceous earth, extracted with EA (20 mL*2), the organic phases were combined, washed with saturated brine (30 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography to obtain 5.1 g of N-(4-methoxybenzyl)benzofuran-7-amine, 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. The mixture was reacted overnight under H ₂ atmosphere. After the reaction was completed as monitored by LCMS, the mixture was filtered through celite and evaporated under reduced pressure to obtain 2.65 g of benzofuran-7-amine. MS m/z (ESI): 134.0 [M+H] ⁺ .

Step 3: Synthesis of 4-iodobenzofuran-7-amine

Dissolve benzofuran-7-amine (200 mg, 1.5 mmol) and calcium carbonate (195 mg, 1.95 mmol) in a mixed solvent of methanol (5 mL) and dichloromethane (10 mL), cool to 0°C, slowly add benzyltrimethylammonium dichloroiodate (520 mg, 1.5 mmol) in batches, react at 0°C for 1.5 h, and monitor the reaction completion. Quench with water, filter through diatomaceous earth, extract with DCM (20 mL*2), combine the organic phases, wash with saturated brine (30 mL*2), evaporate under reduced pressure, and purify by ISCO column chromatography to obtain 250 mg 4-iodobenzofuran-7-amine, MS m/z (ESI): 260.1 [M+H] ⁺ .

Step 4: Synthesis of ethyl 7-aminobenzofuran-4-carboxylate

The compound 4-iodobenzofuran-7-amine (416.1 mg, 1.6 mmol) was dissolved in ethanol solution (30 mL), and Pd(PPh ₃ ) ₂ Cl ₂ (112.3 mg, 0.16 mol) and Et ₃ N (0.5 mL, 3.2 mmol) were weighed and added to the reaction system to replace the CO gas. Under CO gas atmosphere, the temperature was slowly raised to 70°C and refluxed with stirring for 8 h. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, and EA (20 mL*2) was used for extraction. The organic phases were combined, washed with saturated brine (30 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography to obtain 69.2 mg of ethyl 7-aminobenzofuran-4-carboxylate, MS m/z (ESI): 206.2 [M+H] ⁺ .

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

The compound 7-aminobenzofuran-4-carboxylic acid ethyl ester (2g, 9.66mmol) was dissolved in a mixed solution of THF (10mL) and methanol (5mL), and LiOH (50.8mg, 2.12mmol) was dissolved in a (5mL) aqueous solution, and the temperature was slowly raised to 65°C and stirred for 4h. After the reaction was completed by TLC monitoring, it was diluted with water, the pH was adjusted to acidic, and ethyl acetate (40mL*3) was used for extraction. The organic phases were combined, washed with saturated brine (50mL*2), and distilled under reduced pressure. Purification by ISCO column chromatography gave 96.2mg of 7-amino-4-benzofurancarboxylic 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-benzofurancarboxylic acid compound (50.6 mg, 0.29 mmol) were dissolved in isopropanol (5 mL), 4N hydrochloric acid solution in 1,4-dioxane (0.1 mL, 0.48 mmol) was added, and the mixture was reacted at 70°C for 4 h. The reaction was monitored to be complete. The system was filtered to obtain 96.3 mg 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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 65.9 mg 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzofuran-4-carboxamide. ¹ H NMR (400 MHz, 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] ⁺ .

Embodiment 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) were dissolved in ethanol (6 mL) and reacted at room temperature for 5 h. The reaction was monitored to be complete. Water was added, and dichloromethane was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 0.31 g 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

2-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-5-carboxylic acid methyl ester (300 mg, 0.88 mmol) and p-aminobenzoic acid (146 mg, 1.06 mmol) were dissolved in isopropanol (10 mL), 4N hydrochloric acid in 1,4-dioxane solution (0.22 mL) was added, and the mixture was reacted at 70°C for 6 h. The reaction was monitored to be complete. The system was filtered to obtain 360 mg 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), methoxyamine hydrochloride (137 mg, 1.64 mmol), HATU (467 mg, 1.23 mmol) and DMAP (1 mg, 0.008 mmol) were dissolved in DMF (5 mL), and DIPEA (0.27 mL, 1.64 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated. 375 mg of methyl 4-((2-(dimethylphosphoryl)phenyl)amino)-2-((4-(methoxycarbamoyl)phenyl)amino)pyrimidine-5-carboxylate was obtained by column chromatography. 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 O (10 mL), and NaOH (89 mg, 2.2 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. The organic solvent was removed under reduced pressure, and a 2M HCl solution was added to adjust the pH to neutral or weakly acidic. The mixture was filtered to obtain 210 mg 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, 0.002 mmol) were dissolved in DMF (2 mL), and DIPEA (72.6 μL, 0.44 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 34 mg 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] ⁺ .

Embodiment 52

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

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

(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) were dissolved in ethanol (5 mL) and reacted at room temperature for 5 h. The reaction was monitored to be complete. Water was added, and dichloromethane was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 0.23 g of (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-(dimethylphosphonyl)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid

(2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (114 mg, 0.36 mmol) and p-aminobenzoic acid (49 mg, 0.36 mmol) were dissolved in isopropanol (4 mL), 4N hydrochloric acid in 1,4-dioxane solution (90.2 μL) was added, and the mixture was reacted at 65° C. for 14 h. The reaction was monitored to be complete. The system was filtered to obtain 115 mg of 4-((5-chloro-4-((2-(dimethylphosphonyl)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)pyrimidinylamino-2-yl)amino)-N-isobutyloxybenzamide

4-((5-chloro-4-((2-(dimethylphosphinoyl)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid (115 mg, 0.28 mmol), isobutoxyamine hydrochloride (69 mg, 0.56 mmol), HATU (158 mg, 0.41 mmol) and DMAP (0.33 mg, 0.002 mmol) were dissolved in DMF (2 mL), and DIPEA (91.4 μL, 0.56 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 50 mg of 4-((5-chloro-4-((2-(dimethylphosphinoyl)phenyl)amino)pyrimidinamino-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] ⁺ .

Embodiment 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), reacted at room temperature for 2 h, and the reaction was monitored to be complete. Water was added, and dichloromethane was added for extraction, dried and concentrated, and column chromatography was performed to obtain 180 mg of (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

Dissolve (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) in isopropanol (4 mL), add 4N hydrochloric acid in 1,4-dioxane solution (70 μL, 0.28 mmol), react at 65°C for 4 h, and monitor the reaction until complete. Filter the system to obtain 115 mg 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), methoxyamine hydrochloride (42 mg, 0.50 mmol), HATU (143 mg, 0.38 mmol) and DMAP (0.3 mg, 0.002 mmol) were dissolved in DMF (3 mL), and DIPEA (83 μL, 0.50 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 80 mg 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,1 H),3.68(s,3H),1.76(d,J＝13.5Hz,7H).MS m/z(ESI):490.1[M+H] ⁺ .

Embodiment 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 μL, 1.18 mmol) were dissolved in DMF (5 mL), reacted at 65° C. for 5 h, and the reaction was monitored to be complete. Water was added, and dichloromethane was added for extraction, dried and concentrated, and column chromatography was performed to obtain 87 mg (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-fluoropyridinylamino-2-yl)amino)benzoic acid

Dissolve (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) in isopropanol (4 mL), add 4N hydrochloric acid in 1,4-dioxane solution (73 μL, 0.29 mmol), react at 65°C for 12 h, and monitor the reaction until complete. Filter the system to obtain 80 mg of 4-(((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyridinylamino-2-yl)amino)benzoic acid, MSm/z(ESI):401.1[M+H] ⁺ .

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

4-(((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyridinylamino-2-yl)amino)benzoic acid (80 mg, 0.20 mmol), methoxyamine hydrochloride (34 mg, 0.40 mmol), HATU (114 mg, 0.3 mmol) and DMAP (0.25 mg, 0.002 mmol) were dissolved in DMF (3 mL), and DIPEA (66 μL, 0.40 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 80 mg of ⁴ -((4-((2-(2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyridinylamino-2-yl)amino)-N-methoxybenzamide. 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＝7.1 Hz,1H),3.69(s,3H),1.80(d,J＝13.6Hz,6H).MSm/z(ESI):430.1[M+H] ⁺ .

Embodiment 55

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

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

(2-Aminophenyl)dimethylphosphine oxide (400 mg, 2.35 mmol), 2,4,5-trichloropyrimidine (432 mg, 2.35 mmol) and NaHCO ₃ (395 mg, 4.71 mmol) were dissolved in EtOH (8 mL), reacted at 85° C. for 5 h, and the reaction was monitored to be complete. Water was added, and dichloromethane was added for extraction, dried and concentrated, and column chromatography was performed to obtain 500 mg of (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)pyrimidinyldimethyl-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), and a 4N hydrochloric acid solution in 1,4-dioxane (70 μL, 0.28 mmol) was added. The mixture was reacted at 65° C. for 14 h, and the reaction was monitored to be complete. The system was filtered to obtain 86 mg of 7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidindimethyl-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)pyridinylamino-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide

7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidinyldimethyl-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (86 mg, 0.19 mmol), methoxyamine hydrochloride (32 mg, 0.38 mmol), HATU (107 mg, 0.28 mmol) and DMAP (0.23 mg, 0.002 mmol) were dissolved in DMF (3 mL), and DIPEA (63 μL, 0.38 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. Water was added, DCM was added for extraction, dried and concentrated, and column chromatography was performed to obtain 40 mg of 7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyridinylamino-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,1 H),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] ⁺ .

Embodiment 56

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

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

(2-Aminophenyl)dimethylphosphine oxide (400 mg, 2.35 mmol), 2,4,5-trichloropyrimidine (432 mg, 2.35 mmol) and NaHCO ₃ (395 mg, 4.71 mmol) were dissolved in EtOH (8 mL), reacted at 85° C. for 5 h, and the reaction was monitored to be complete. Water was added, and dichloromethane was added for extraction, dried and concentrated, and column chromatography was performed to obtain 500 mg of (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)pyrimidinylamino-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), and a 4N hydrochloric acid solution in 1,4-dioxane (68 μL, 0.27 mmol) was added. The mixture was reacted at 65° C. for 14 h and the reaction was monitored to be complete. The system was filtered to obtain 70 mg of 7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidindimethyl-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-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (70 mg, 0.15 mmol), isobutoxyamine hydrochloride (38 mg, 0.30 mmol), HATU (86 mg, 0.23 mmol) and DMAP (0.18 mg, 0.002 mmol) were dissolved in DMF (2 mL), and DIPEA (50 μL, 0.30 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 37 mg 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] ⁺ .

Embodiment 57

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

Step 1: Synthesis of 2,5-dichloro-N-(2-iodophenyl)pyrimidin-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), reacted at 85°C for 16 h, and the reaction was monitored to be complete. Water was added, and dichloromethane was added for extraction, dried and concentrated, and column chromatography was performed to obtain 2.0 g, 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), 4N hydrochloric acid in 1,4-dioxane solution (41 μL, 0.16 mmol) was added, and the mixture was reacted at 120°C for 3 h. The reaction was monitored to be complete. The system was filtered to obtain 120 mg 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), isobutoxyamine 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), and DIPEA (0.23 mL, 1.40 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated. 110 mg of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide was obtained by column chromatography. 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 dimethylphosphonate

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 μL, 0.75 mmol), Pd(dppf)Cl ₂ (16 mg, 0.02 mmol) and K ₃ PO ₄ (80 mg, 0.38 mmol) were dissolved in 1,4-dioxane (3 mL), and reacted at 120°C for 16 h under N ₂ protection. The reaction was monitored to be complete. Water was added, DCM was added for extraction, dried and concentrated, and column chromatography was performed to obtain 30 mg 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＝7.7,3.2 Hz,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] ⁺ .

Embodiment 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), 4N hydrochloric acid in 1,4-dioxane solution (82 μL, 0.33 mmol) was added, and the mixture was reacted at 120°C for 3 h. The reaction was monitored to be complete. The system was filtered to obtain 520 mg 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), methoxyamine 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), and DIPEA (0.53 mL, 3.22 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 240 mg 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 μL, 1.05 mmol), Pd(dppf)Cl ₂ (22 mg, 0.02 mmol) and K ₃ PO ₄ (112 mg, 0.53 mmol) were dissolved in 1,4-dioxane (5 mL), reacted at 100° C. for 16 h under N ₂ protection, and the reaction was monitored to be complete. Water was added, DCM was added for extraction, dried and concentrated, and column chromatography was performed to obtain 20 mg 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] ⁺ .

Embodiment 59

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

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), 4N hydrochloric acid in 1,4-dioxane solution (82 μL, 0.33 mmol) was added, and the mixture was reacted at 120°C for 3 h. The reaction was monitored to be complete. The system was filtered to obtain 520 mg 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-isobutyloxybenzamide

4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)benzoic acid (250 mg, 0.54 mmol), isobutoxyamine 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), and DIPEA (0.53 mL, 3.22 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 230 mg 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)phenyldiphosphonate

4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-isobutoxybenzamide (130 mg, 0.24 mmol), dimethyl phosphate (89 μL, 0.97 mmol), Pd(dppf)Cl ₂ (20 mg, 0.02 mmol) and K ₃ PO ₄ (103 mg, 0.48 mmol) were dissolved in 1,4-dioxane (5 mL), reacted at 100° C. for 16 h under N ₂ protection, and the reaction was monitored to be complete. Water was added, DCM was added for extraction, the mixture was dried and concentrated, and column chromatography was performed to obtain 20 mg of dimethyl (2-((5-chloro-2-((4-(isobutoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyldiphosphonate. ¹ H NMR (400 MHz, DMSO) δ 11.43 (s, 1H), 9.86 (s, 1H), 9.77 (s, 1H), 8.51 (t, J = 7.4 Hz, 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 = 6.7 Hz, 2H), 1.20 (m, 1H), 0.91 (d, J = 6.7 Hz, 6H). MS m/z (ESI): 520.1 [M+H] ⁺ .

Embodiment 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), 4N hydrochloric acid in 1,4-dioxane solution (41 μL, 0.16 mmol) was added, and the mixture was reacted at 120°C for 3 h. The reaction was monitored to be complete. The system was filtered to obtain 260 mg 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) were dissolved in 1,4-dioxane (3 mL), reacted at 95° C. for 16 h under N ₂ protection, and the reaction was monitored to be complete. Water was added, DCM was added for extraction, dried and concentrated, and column chromatography was performed to obtain 84 mg 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] ⁺ .

Embodiment 61

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

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

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) were dissolved in 1,4-dioxane (100 mL), reacted at 100°C for 16 h under N ₂ protection, and the reaction was monitored to be complete. Water was added, DCM was added for extraction, dried and concentrated, and column chromatography was performed to obtain 1.7 g (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, MS m/z (ESI): 202.3 [M+H] ⁺ .

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

(2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.9 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) were dissolved in EtOH (60 mL) and reacted at 60° C. overnight. The reaction was monitored to be complete. Water was added, and dichloromethane was added for extraction. The mixture was dried and concentrated. 419 mg of dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate was obtained by column chromatography. 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), and a 4N hydrochloric acid solution in 1,4-dioxane (0.15 mL) was added. The mixture was reacted at 65° C. for 3 h and the reaction was monitored to be complete. The system was filtered to obtain 120 mg 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 diphosphonate

7-((4-((2-(2-(dimethoxyphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (60 mg, 0.12 mmol), methoxyamine 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), and DIPEA (0.11 mL, 0.69 mmol) was added. The mixture was reacted at room temperature for 7 h and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated. 43 mg of dimethyl (2-((2-((4-(methoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl diphosphonate was obtained by column chromatography. ¹ H NMR (400 MHz, 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] ⁺ .

Embodiment 62

Preparation of dimethyl (2-((5-chloro-2-((4-(methoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)pyrimidin-4-yl)amino)phenyldiphosphonate (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), 4N hydrochloric acid in 1,4-dioxane solution (0.15 mL) was added, and the mixture was reacted at 120°C for 2 h. The reaction was monitored to be complete. The system was filtered to obtain 71 mg of 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), methoxyamine 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), and DIPEA (0.14 mL, 0.83 mmol) was added. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated. 67 mg of 7-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide was obtained by column chromatography. MS m/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 diphosphonate

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 μL, 0.38 mmol), Pd(dppf) ₂ Cl ₂ (10 mg, 0.01 mmol) and K ₃ PO ₄ (66 mg, 0.31 mmol) were dissolved in 1,4-dioxane (10 mL), reacted at 100° C. for 16 h under N ₂ protection, and the reaction was monitored to be complete. Water was added, DCM was added for extraction, the mixture was dried and concentrated, and column chromatography was performed to obtain 25 mg of dimethyl (2-((5-chloro-2-((4-(methoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)pyrimidin-4-yl)amino)phenyldiphosphonate. ¹ H NMR (400 MHz, 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＝7.7,4.9 Hz,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] ⁺ .

Embodiment 63

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

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

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) were dissolved in 1,4-dioxane (100 mL), reacted at 100°C for 16 h under N ₂ protection, and the reaction was monitored to be complete. Water was added, DCM was added for extraction, dried and concentrated, and column chromatography was performed to obtain 1.7 g (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, MS m/z (ESI): 202.1 [M+H] ⁺ .

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

(2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.9 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) were dissolved in EtOH (60 mL) and reacted at 60° C. overnight. The reaction was monitored to be complete. Water was added, and dichloromethane was added for extraction. The mixture was dried and concentrated. 419 mg of dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate was obtained by column chromatography. 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), and a 4N hydrochloric acid solution in 1,4-dioxane (0.15 mL) was added. The mixture was reacted at 65°C for 3 h and the reaction was monitored to be complete. The system was filtered to obtain 120 mg 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 diphosphonate

7-((4-((2-(2-(dimethoxyphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (60 mg, 0.12 mmol), isobutoxyamine 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), and DIPEA (0.11 mL, 0.69 mmol) was added. The mixture was reacted at room temperature for 7 h and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated. 83 mg of dimethyl (2-((2-(((4-(isobutoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl diphosphonate was obtained by ^column chromatography. 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] ⁺ .

Embodiment 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) were dissolved in EtOH (40 mL) and reacted at 60° C. overnight. The reaction was monitored to be complete. Water was added, and dichloromethane was added for extraction. The mixture was dried and concentrated. 120 mg of dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate was obtained by column chromatography. MS m/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), and a 4N hydrochloric acid solution in 1,4-dioxane (0.15 mL) was added. The mixture was reacted at 65°C for 3 h and the reaction was monitored to be complete. The system was filtered to obtain 111 mg 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 dimethylphosphonate

4-((4-((2-(di(methoxyphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid (60 mg, 0.11 mmol), isobutoxyamine 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), and DIPEA (0.11 mL, 0.68 mmol) was added. The mixture was reacted at room temperature overnight and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated. 53 mg of (2-((2-((5-fluoro-4-(isobutoxycarbamoyl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl dimethylphosphonate was obtained by column chromatography. ¹ H NMR (400 MHz, 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] ⁺ .

Embodiment 65

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

Step 1: Synthesis of (2-aminophenyl)diethylphosphine 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) were dissolved in DMF (120 mL), reacted at 120°C for 16 h under N ₂ protection, and the reaction was monitored to be complete. Water was added, DCM was added for extraction, dried and concentrated, and column chromatography was performed to obtain 1.8 g (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) and reacted at 60°C overnight. The reaction was monitored to be complete. Water was added, and dichloromethane was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 83 mg of (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

Dissolve (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (83 mg, 0.22 mmol) and 4-aminobenzoic acid (30 mg, 0.22 mmol) in isopropanol (6 mL), add 4N hydrochloric acid in 1,4-dioxane solution (0.1 mL), react at 65°C for 3 h, and monitor the reaction until complete. Filter the system to obtain 80 mg 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), methoxyamine 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), and DIPEA (0.17 mL, 1.01 mmol) was added. The mixture was reacted at room temperature for 7 h and the reaction was monitored to be complete. Water was added, and DCM was added for extraction. The mixture was dried and concentrated. 63 mg of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide was obtained by column chromatography. ¹ HNMR (400 MHz, 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,7 H).MS m/z(ESI):508.2[M+H] ⁺ .

Embodiment 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 1,4-dioxane solution (0.25 mL, 1 mmol) were added to isopropanol (6 mL), and then reacted at 60°C for 4 h. After the reaction was completed as monitored by LCMS, the mixture was cooled to room temperature, and the reaction system was filtered. The solid obtained by filtration was washed with isopropanol (2 mL×3), and then dried at 50°C for 1 h to obtain 50 mg 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-chlorobenzamide

4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-chlorobenzoic acid (50 mg, 0.1 mmol), O-isobutoxyamine hydrochloride (38 mg, 0.3 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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 16 h. After the reaction was completed as monitored by LCMS, 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 chromatography was performed to obtain 40 mg 4-((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] ⁺ .

Embodiment 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

(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 hydrochloric acid 1,4-dioxane solution (0.25 mL, 1 mmol) were added to isopropanol (6 mL), and then reacted at 60°C for 4 h. After the reaction was completed as monitored by LCMS, the mixture was cooled to room temperature, and the reaction system was filtered. The solid obtained by filtration was washed with isopropanol (2 mL×3), and then dried at 50°C for 1 h to obtain 32 mg 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-isobutyloxy-2-methoxybenzamide

4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methoxybenzoic acid (32 mg, 0.07 mmol), O-isobutoxyamine hydrochloride (25 mg, 0.2 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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 16 h. After the reaction was completed as monitored by LCMS, 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 chromatography was performed to obtain 15 mg 4-((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] ⁺ .

Embodiment 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

(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) were added to isopropanol (10 mL), and then reacted at 60°C for 4 h. After the reaction was completed as monitored by LCMS, the reaction system was cooled to room temperature, and the reaction system was filtered. The solid obtained by filtration was washed with isopropanol (2 mL×3), and then dried at 50°C for 1 h to obtain 108 mg of 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 at 50°C overnight. After the reaction was completed as monitored by LCMS, the mixture was cooled to room temperature, saturated citric acid solution was added to adjust the reaction system to neutrality, and EA (10 mL×3) was used for extraction, and the mixture was dried and concentrated to obtain 45 mg 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-isobutyloxy-2-cyanobenzamide

4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanobenzoic acid (45 mg, 0.1 mmol), O-isobutoxyamine hydrochloride (38 mg, 0.3 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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 16 h. After the reaction was completed as monitored by LCMS, 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 chromatography was performed to obtain 8 mg 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] ⁺ .

Embodiment 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 dimethyl sulfoxide (10 mL) at room temperature and reacted for 5 min, and then reacted at 80°C for 3 h. After the reaction was complete as monitored by LCMS, the mixture was cooled to room temperature, and water (10 mL) was added to precipitate the product. The reaction system was filtered, and the solid obtained by filtration was washed with petroleum ether (3 mL×3), and then vacuum dried for 1 h to obtain 400 mg of 2-(cyclopentyloxy)isoindoline-1,3-dione, MSm/z (ESI): 232.1 [M+H] ⁺ .

Step 2: Synthesis of O-cyclopentylhydroxylamine

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), and then reacted at room temperature for 4 h. After the reaction was completed as monitored by TLC, the reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL×3), and the organic phase was washed with water, dried and concentrated to obtain 60 mg 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-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (51 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.1 mL, 0. 54mmol) was added to N,N-dimethylformamide (3mL), and then reacted at room temperature for 16h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10mL), extracted with EA (10mL×3), and the organic phase was washed with water, dried and concentrated. Column chromatography gave 16mg of N-(cyclopentyloxy)-4-((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] ⁺ .

Embodiment 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 5 min, and then reacted at 80 ° C for 3 h. After the reaction was completed by LCMS monitoring, it was cooled to room temperature, and water (10 mL) was added to precipitate the product. The reaction system was filtered, and the solid obtained by filtration was washed with petroleum ether (3 mL×3), and then vacuum dried for 1 h to obtain 180 mg 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 4 h. After the reaction was completed as monitored by TLC, the reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL×3), and the organic phase was washed with water, dried and concentrated to obtain 47 mg 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-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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), and then reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL), extracted with EA (10 mL×3), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 40 mg 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-((tetrahydro-2H-pyran-4-yl)methoxy)benzamide, ¹ H NMR (400 MHz, 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] ⁺ .

Embodiment 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 (890 mg, 5.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 mL, 5.5 mmol) were added to N,N-dimethylformamide (10 mL) at room temperature, and then reacted at 80°C for 4 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (20 mL), extracted with EA (20 mL×3), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 400 mg 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 4 h. After the reaction was completed as monitored by TLC, the reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL×3), and the organic phase was washed with water, dried and concentrated to obtain 170 mg 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-azobenzotriazole)-N,N,N',N'-tetramethyluronium 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), and then reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL), extracted with EA (10 mL×3), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 50 mg 4-((4-((2-(Dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-((tetrahydro-2H-pyran-4-yl)oxy)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] ⁺ .

Embodiment 72

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

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

Bromomethylcyclopentane (1g, 6mmol), N-hydroxyphthalimide (834mg, 5.12mmol), potassium carbonate (1.77g, 12.8mmol) were added to dimethyl sulfoxide (10mL) at room temperature and reacted for 5min, and then reacted at 80℃ for 3h. After the reaction was complete as monitored by LCMS, the mixture was cooled to room temperature, and water (10mL) was added to precipitate the product. The reaction system was filtered, and the solid obtained by filtration was washed with petroleum ether (3mL×3), and then vacuum dried for 1h to obtain 630mg 2-(cyclopentylmethoxy)isoindoline-1,3-dione, MS m/z (ESI): 246.1[M+H] ⁺ .

Step 2: Synthesis of 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 4 h. After the reaction was completed as monitored by TLC, the reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL×3), and the organic phase was washed with water, dried and concentrated to obtain 51 mg 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'-tetramethyluronium 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), and then reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL), extracted with EA (10 mL×3), the organic phase was washed with water, dried and concentrated, and column chromatography was performed to obtain 12 mg 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] ⁺ .

Embodiment 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 2 h. After the reaction was completed as monitored by LCMS, 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 purified by column chromatography with MeOH/DCM (0-10%) to obtain 34.1 mg 7-((4-((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 . m/z(ESI): 522.1[M+H] ⁺ .

Embodiment 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

Dissolve (2-aminophenyl)diethylphosphine oxide (2.0 g, 10.14 mmol) in DMF (20 mL), protect with nitrogen, add 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.37 mL, 10.14 mmol) and DIPEA (1.68 mL, 10.14 mmol) at 0°C, stir at 60°C overnight, and monitor the reaction completion. Add saturated ammonium chloride solution (3 mL), extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain the intermediate (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (606 mg, yield: 15.82%), 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

Dissolve (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (400 mg, 1.06 mmol) in isopropanol (20 mL), add 4-aminobenzoic acid (145.23 mg, 1.06 mmol), hydrochloric acid/1,4-dioxane (0.5 mL, 2.00 mmol) at 0°C, protect with nitrogen, stir at 65°C for 3 hours, monitor the reaction completion. Filter to obtain the intermediate 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid (349 mg, yield: 68.89%), 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 ethylhydroxylamine 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 in sequence at 0°C. The mixture was protected by nitrogen and reacted at room temperature for 5 hours. The reaction was monitored to be complete. 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 obtain 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxybenzamide (52 mg, yield: 78.86%), 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)

Embodiment 75

Preparation of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxybenzamide (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 in sequence at 0°C. The mixture was protected by nitrogen and reacted at room temperature for 5 hours. The reaction was monitored to be complete. 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 obtain 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutyloxybenzamide (XTC003-190) (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).

Embodiment 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 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) were added. The mixture was stirred overnight at 120°C under nitrogen protection and the reaction was monitored to be complete. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic layer was washed with saturated brine three times, dried and concentrated to obtain a residue. The residue was purified by column chromatography to obtain (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

Dissolve (2-aminophenyl)diethylphosphine oxide (1.0 g, 5.07 mmol) in EtOH (12 mL), add 2,4,5-trichloropyrimidine (930 mg, 5.07 mmol) and NaHCO ₃ (426 mg, 5.07 mmol), stir at 85°C for 90 minutes, and monitor the reaction completion. Cool to room temperature, dilute with water, extract with EA, dry and concentrate the organic layer to obtain a residue. Purify the residue by column chromatography to obtain (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (982 mg, yield: 56.27%), 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

Dissolve (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (500 mg, 1.45 mmol) in isopropanol (16 mL), add 4-aminobenzoic acid (160 mg, 1.17 mmol) and HCl/1,4-dioxane (4M, 0.73 mL, 2.92 mmol), stir overnight at 80°C, and monitor the reaction to be complete. Cool to room temperature, filter, and wash the filter cake with isopropanol and PE to obtain 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), and 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 at room temperature overnight to monitor the reaction completion. Dilute with water, extract with ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. Purify by column chromatography to obtain 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).

Embodiment 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), and ethoxylamine 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. The mixture was stirred overnight at room temperature and the reaction was monitored to be complete. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by column chromatography to obtain 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(brt,J＝7.6Hz,3H),0.97(brt,J＝7.6Hz,3H)

Embodiment 78

Preparation of 4-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-isobutoxybenzamide (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 isobutoxyamine hydrochloride (127 mg, 1.02 mmol), HTAU (257 mg, 0.68 mmol), DIPEA (306 mg, 2.37 mmol) and DMAP (4 mg, 0.03 mmol) were added. The mixture was stirred overnight at room temperature and the reaction was monitored to be complete. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by column chromatography to obtain the target 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).

Embodiment 79

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

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

Dissolve 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, 0.58 mmol) in isopropanol (6 mL), cool to 0°C, add 4M hydrochloric acid/1,4-dioxane solution (0.29 mL, 1.16 mmol) dropwise with stirring, and heat to 70°C to react overnight. After the reaction solution is cooled to room temperature, filter to obtain 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-(diethylphospho)phenylamino)pyrimidin-2-ylamino)-2-fluoro-N-isobutoxy-5-methoxybenzamide

Dissolve 4-(5-chloro-4-(2-(diethylphosphoric acid)phenylamino)pyrimidin-2-ylamino)-2-fluoro-5-methoxybenzoic acid (65 mg, 0.13 mmol) and isobutoxyamine hydrochloride (66.4 mg, 0.52 mmol) in DMF (2 mL), add HATU (100.4 mg, 0.26 mmol) and DMAP (1.6 mg, 0.01 mmol), cool to 0°C, add DIPEA (0.15 mL, 0.91 mmol) dropwise with stirring, and after completion of the addition, warm to room temperature and react overnight. 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (methanol: dichloromethane = 1: 20) to obtain 4-(5-chloro-4-(2-(diethylphosphoryl)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).

Embodiment 80

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

Step: Synthesis of 4-(5-chloro-4-(2-(diethylphospho)phenylamino)pyrimidine-2-amino)-2-fluoro-N,5-dimethoxybenzamide

Dissolve 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) in DMF (2 mL), add HATU (90.7 mg, 0.24 mmol) and DMAP (1.5 mg, 0.01 mmol), cool to 0°C, add DIPEA (0.14 mL, 0.84 mmol) dropwise with stirring, and after completion of the addition, warm to room temperature and react overnight. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (methanol: dichloromethane = 1:20) to obtain 4-(5-chloro-4-(2-(diethylphosphoric acid)phenylamino)pyrimidine-2-amino)-2-fluoro-N,5-dimethoxybenzamide (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).

Embodiment 81

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

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

Dissolve (2-aminophenyl)diethylphosphine oxide (2g, 10.14mmol) in DMF (20mL), protect with nitrogen, add 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.38mL, 10.14mmol) and DIPEA (1.68mL, 10.14mmol) at 0℃, and react at 60℃ overnight. After the reaction, add water and ethyl acetate to extract, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate by rotary evaporation. Silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target compound (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (677mg, yield: 17.67%). 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

Dissolve (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (200 mg, 0.53 mmol) and 4-amino-2-fluoro-5-methoxybenzoic acid (98.2 mg, 0.53 mmol) in isopropanol (10 mL), protect with nitrogen, add 4M hydrochloric acid/1,4-dioxane solution (0.25 mL) in an ice bath, react at 65°C for 3 hours, and monitor the reaction completion. Filter to obtain 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 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 in an ice bath, stirred at room temperature for 5 hours, and the reaction was detected to be complete. Water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain 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(brs,1H),7.92(brd,J＝12.0Hz, 1H),7.51-7.59(m,2H),7.26(br t,J＝7.1Hz,1H),7.19(brd,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).

Embodiment 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

Dissolve (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (200 mg, 0.53 mmol) and 4-amino-2-fluoro-5-methoxybenzoic acid (98.2 mg, 0.53 mmol) in isopropanol (10 mL), protect with nitrogen, add 4M hydrochloric acid/1,4-dioxane solution (0.25 mL) in an ice bath, stir at 65°C for 3 hours, and monitor the reaction completion. Filter to obtain 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), isobutoxyamine 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 in an ice bath, and the mixture was reacted at room temperature for 5 hours. The reaction was monitored to be complete. Water was added, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain 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).

Embodiment 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

Dissolve (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (669 mg, 1.77 mmol) and 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid (324 mg, 1.81 mmol) in isopropanol (20 mL), add 4M HCl/1,4-dioxane (0.44 mL, 1.77 mmol), protect with nitrogen, react at 65°C overnight, and monitor the reaction completion. Filter to obtain 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), DIPEA (0.29 mL, 1.73 mmol) was added at 0°C, and the reaction was allowed to react at room temperature for 3 hours. The reaction was monitored to be complete. Add water, extract with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate by rotary evaporation, and chromatograph on a silica gel column (dichloromethane: methanol = 10: 1) to obtain the target 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%). 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).

Embodiment 84

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

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

Dissolve (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (669 mg, 1.77 mmol) and 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid (324 mg, 1.81 mmol) in isopropanol (20 mL), add 4M HCl/1,4-dioxane (0.44 mL, 1.77 mmol), protect with nitrogen, stir at 65°C for overnight, and monitor the reaction completion. Filter to obtain 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 isobutoxyamine hydrochloride (109 mg, 0.86 mmol) were dissolved in DMF (2 mL), DIPEA (0.29 mL, 1.73 mmol) was added at 0°C, and the reaction was allowed to react at room temperature for 3 hours. The reaction was monitored to be complete. Water was added, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on a silica gel column (dichloromethane: methanol = 10: 1) to obtain the target compound 7-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide (XTC003-199) (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).

Embodiment 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-(diethylphospho)phenylamino)pyrimidin-2-ylamino)-N-isobutoxy-2,3-dihydrobenzofuran-4-carboxamide

Compound isobutylamine hydrochloride (83 mg, 0.6571 mmol), HATU (125 mg, 0.3286 mmol), DMAP (2 mg, 0.0329 mmol) and DIPEA (149 mg, 1.1501 mmol) were added 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), and the mixture was stirred overnight at room temperature. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL), and the organic layer was concentrated and dried to obtain a residue. The residue was purified by Prep-HPLC. 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) was obtained 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＝8.8Hz,2H),3.67(d,J＝6.7 Hz,2H),3.42(t,J＝8.8 Hz,2H),2.03(dtd,J＝15.3,7.6,7.0,4.3Hz,4H),1.94(p,J＝6.4 Hz,1H),1.01(t,J＝7.6 Hz,3H),0.99–0.92 (m,9H).

Embodiment 86

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

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

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) were added 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), and the mixture was stirred overnight at room temperature. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL), and the organic layer was concentrated and dried to obtain a residue. The residue was purified by Prep-HPLC. The target compound 7-(5-chloro-4-((2-(diethylphospho)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＝8.8Hz,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).

Embodiment 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 isobutoxyamine 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 μL, 0.49 mmol) was added at 0°C, and the reaction was carried out at room temperature overnight. Water (20 mL) was added, and ethyl acetate (20 mL×3) was used for extraction. 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 obtain 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).

Embodiment 88

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

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) were dissolved in nBuOH (15 mL), reacted at 85 ° C for 16 h, and the reaction was monitored to be complete. Cooled to room temperature, allowed to stand until no more precipitation was produced, and filtered to obtain 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

Dissolve 2,5-dichloro-N-(2-iodophenyl)pyrimidin-4-amine (4.3g, 11.6mmol) and 4-aminobenzoic acid (1.7g, 12.2mmol) in nBuOH (50mL), add 4N hydrochloric acid in 1,4-dioxane solution (0.9mL, 3.5mmol), react at 120℃ for 3h, and monitor the reaction completion. Filter the system to obtain 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)benzoic acid (5.0g, 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-isobutyloxybenzamide

4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)benzoic acid (2.0 g, 4.3 mmol) and isobutoxyamine 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 in an ice-water bath. The mixture was reacted overnight at room temperature and the reaction was monitored to be complete. The solvent was removed by vortexing, water (20 mL) was added, and the mixture was filtered. The solid was dried and then purified by column chromatography (dichloromethane: ethyl acetate = 4:1) to obtain 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-isobutoxybenzamide (600 mg, 1.1 mmol), dimethyl phosphate (0.2 mL, 2.24 mmol), Pd(dppf) ₂ Cl ₂ (106 mg, 0.13 mmol), and K ₃ PO ₄ (318 mg, 1.7 mmol) were dissolved in 1,4-dioxane (35 mL), and the mixture was reacted at 100° C. for 16 h under N ₂ protection, and the reaction was monitored to be complete. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, concentrated, and column chromatography (dichloromethane:ethyl acetate=5:1 to 3:2) was performed to obtain 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), and reacted at 60 ° C for 2 h under N ₂ protection. The reaction was monitored to be complete. The solvent was removed by rotation, and methyl hydrogen (2-((5-chloro-2-((4-(isobutoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate (34 mg, yield: 70%) was obtained by separation using preparative HPLC. MSm/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 in the present application can be prepared by methods similar to those described in the above examples (when necessary, the reagents and conditions are appropriately adjusted).

Biological evaluation of compounds

Test Example 1: In vitro enzyme inhibition activity of the compounds of the present invention

1. Reagents, consumables, and instruments

2. Experimental Procedure

1) Add 50 μL of compound to a 384-well dilution plate.

2) Serially dilute the compounds in each column at 1:3 with DMSO, with each dilution reaching 10+0 points.

3) Use Echo to transfer 0.1 μL of the diluted compound solution in each row to a 384 assay plate, with each column containing 2 replicates.

4) Add 5 μL of 2X enzyme solution to the assay plate and centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 15 minutes.

5) Add 5 μL of 2X substrate solution to the 384-well assay plate.

6) Incubate at 25°C for 60 minutes.

7) Add 5 μL of Sa-XL665 solution and 5 μL of TK antibody-Eu ³⁺ to the assay plate and centrifuge at 1000 rpm for 1 minute.

2) Incubate at 25°C for 60 minutes.

8) Read the fluorescence signal on an Envision 2104 plate reader.

3. Data Analysis

1) For each screening plate, calculate the mean data and standard deviation (SD) for DMSO and 100 nM Defactinib (as control)

2) Inhibition percentage of compound (%inh) = 100*(maximum value - sample value)/(maximum value - minimum value)

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

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

X:Log(compound concentration)

Y: Inhibition rate (%inh)

Top and Bottom: Same as Y unit

logIC ₅₀ : same as X

HillSlope: Slope coefficient or slope

Specific _IC50 activity data are shown in Table 1.

4. Experimental conclusion:

The compounds of the present invention have good in vitro FAK enzymatic inhibitory activity, and some of the compounds are superior to the clinical FAK inhibitor Defactinib.

Table 1

Experimental Example 2: Pharmacodynamic evaluation of the compound of the present invention in vitro in the human diffuse gastric cancer cell line SNU-668 model (western blot detection of YAP activity)

1. Experimental Procedure

1) Cell plating

a. Grow SNU-668 cells (Cat. No. 00668, KCLB) to 80%-90% density, remove the culture supernatant, rinse once with PBS and remove the supernatant;

b. Add 2 mL of trypsin to a 10 cm dish and place it in an incubator for 3-5 minutes;

c. Take out the culture plate, add 5 mL 1640 medium (containing 10% FBS) to terminate digestion, transfer to a 15 mL centrifuge tube, and centrifuge at 1000 rpm for 5 minutes;

d. Remove the supernatant, add 5 mL 1640 medium (containing 10% FBS), resuspend and mix thoroughly, and then count;

e. Take out a 12-well plate, place 1.5×10 ⁵ cells and 900 μL culture medium in each well, and culture in a cell culture incubator for 24 hours.

2) Cellular drug delivery

a. Take out the mother solution (1 mM) of the compound to be tested in advance, dissolve it with DMSO, and pipette several times to mix evenly;

b. Take out the culture plate with cells, aspirate 1ul of 1mM stock solution (diluted 1000 times) and gently add it along the wall of the well. Shake gently to mix evenly after adding;

c. After adding the drug to all the wells, shake it slightly to ensure even diffusion of the drug. Record the time and place it back into the cell culture incubator. Collect the samples after 24 hours.

3) Protein extraction

a. 24 hours after administration, discard the culture medium, wash with PBS, and discard the PBS;

b. Lyse the cells with RIPA lysis buffer containing phosphatase inhibitors and PMSF, centrifuge at 12000 rpm for 10 min at 4°C, take the supernatant, determine the protein concentration and adjust the protein concentration, add 4× loading buffer, and cook the protein.

4) Western blot detection

SDS-PAGE electrophoresis: 80v, 30min, 120v, 60min; transfer: 80v, 60min; blocking: 5% skim milk for 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, incubated at 4°C overnight; secondary antibody (Goat-anti-mouse-IgG and Goat-anti-rabbit-IgG, 1:3000, Proteintech): with 5% skim milk, incubated at room temperature for 1h. Use Thermo developer.

2. Experimental conclusion

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

Experimental Example 3: In vitro pharmacodynamic evaluation of the compound in the human diffuse gastric cancer cell line SNU-668 model (cell proliferation inhibition assay)

1. Experimental Procedure

1) Cell plating

a. When SNU-668 cells (Cat. No. 00668, KCLB) grow to 70%-80%, remove the culture medium supernatant, rinse once with PBS and remove the supernatant;

b. Add 1 mL of 0.25% trypsin to a 10 cm dish, shake it evenly, and place it in an incubator for 2-3 minutes;

c. Take out the culture dish, add 2-3 mL of complete medium to terminate digestion, transfer to a 15 mL centrifuge tube, and centrifuge at 1000 rpm for 5 min;

d. Remove the supernatant, add 1 mL of complete medium to resuspend, and count;

e. Take out the 96-well plate, plate 1000 cells per well, and place it in a cell culture incubator for overnight culture;

2) Cellular administration

a. Take out the drug to be tested in advance, dissolve it, and vortex it evenly;

b. Each small molecule was diluted 1:3 into 9 concentration gradients using culture medium based on the 1 mM stock solution;

c. Take out the culture plate with cells, aspirate the culture medium, slowly add 100 μL of fresh culture medium along the wall of the well with a dispenser, mark the number of each well, and add the corresponding small molecules and concentrations respectively, and aspirate 100 μL of drug-containing culture medium along the wall of the well with a dispenser;

d. After all wells have been added, gently shake the culture plate to ensure that the drug is evenly diffused, record the time, and return it to the cell culture incubator;

3) CELL TITER-GLO test

Four days after administration, the culture medium was discarded, the culture medium and cell titer-glo detection solution were mixed in a 1:1 ratio, 100 μL was added to each well, and the cells were incubated at room temperature with shaking for 10 min, and then detected by an ELISA reader.

2. Experimental conclusion

The experimental results (see Table 2 for details) show that some compounds of the present invention can inhibit the cell growth of human diffuse gastric cancer tumor cell line model, and the inhibitory activity is better than that of clinical FAK inhibitors Defactinib and IN10018, and other similar structural kinase inhibitors, such as compound D3a.

Table 2

Experimental Example 4: In vivo pharmacodynamic evaluation of compounds

1. Experimental Procedure

Cells were prepared from diffuse gastric cancer organoid cultures and resuspended in a ratio of Matrigel: medium (1:1). Each time, 200 μl of the mixture containing 1×10 ⁶ cells was subcutaneously injected into the ventral flank of NSG mice (6-8 weeks old). Starting two weeks after injection, tumor volume was measured every two days. Tumor volume was calculated by the formula 0.5×a ² ×b, where a is the width in millimeters and b is the length in millimeters. Treatment was started when the tumor reached approximately 100 mm ³ , and DMSO, Defactinib (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 FIG1 , from which it can be seen that in the diffuse gastric cancer mouse model, 5 mg/kg of the compound 3 of the present invention can significantly inhibit tumor growth, and its inhibitory effect is better than that of the positive control compound Defactinib (defactinib) at 12.5 mg/kg.

Experimental Example 5: Evaluation of the pharmacokinetics of compounds in vivo

1. Experimental Design

Three male SD rats were intragastrically administered with 5 mg/kg of the compound once, and blood was collected before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration.

2. Preparation configuration

Accurately weigh 5.5 mg of the compound (according to the purity), add 0.55 mL of DMSO, stir and sonicate to obtain a clear solution. Take 0.5 mL of the above solution, add 1 mL of Solutol, stir for 1 min; add 8.5 mL of physiological saline, stir for 1 min, and obtain a clear solution with a solution concentration of 0.5 mg/mL.

3. Animal Operation

The preparation prepared in step 2 was administered to rats by gavage at a dose of 10 mL/kg. The rats were fasted overnight before administration and resumed feeding 4 hours after administration; the animals drank water normally during the entire experimental period.

4. Analytical methods

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

5. Experimental results

The experimental results show that the compounds of the present application have good pharmacokinetic parameters in rats, and the specific results are shown in Table 3.

Table 3

Compound No. 32 55 73 Defactinib Route of administration Oral gavage Oral gavage Oral gavage Oral gavage Dosage (mg/kg) 5 5 5 5 Pharmacokinetic parameters - - - - T _1/2 (h) 1.01 2.91 2.32 1.20 _Tmax (h) 0.25 0.25 2.00 4.00 _Cmax (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 the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (8)

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.