Heteroaromatic compounds and their medical uses

Abstract

The present invention relates to a heterocyclic aromatic compound and its application. Specifically, the heterocyclic aromatic compound has the structure shown in Formula 0, with the definitions of the various symbols as defined in the specification. The heterocyclic aromatic compound has a good inhibitory effect on YAP. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a heteroaromatic ring compound and its medical use. Background Art

[0002] 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 the degradation of p53 through ubiquitination, thereby 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.

[0003] 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 development and progression of diseases such as cancer and cardiovascular disease. 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 FAK expression often predicts 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. Mice with the RHOAY42C mutation are sensitive to FAK inhibitors, suggesting that inhibiting FAK activity may be a new strategy for treating diffuse gastric cancer.

[0004] YAP (Yes-associated 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 then bind to the regulatory protein SAV1 and phosphorylate LATS1 / 2 and MOB, which then directly phosphorylate YAP / TAZ. Phosphorylated YAP / TAZ remain in the cytoplasm, inhibiting transcription. When this signaling pathway is blocked or inactivated, unphosphorylated YAP / TAZ translocate from the cytoplasm to the nucleus, where they bind to transcription factors such as TEADs, Smads, Runx1 / 2, p63 / p73, and ErbB4 to promote gene transcription.

[0005] The Hippo-YAP pathway is a recently discovered signaling pathway that regulates organ volume and maintains the balance between cell proliferation and apoptosis, and is closely associated with the uncontrolled proliferation of tumor cells. The primary function of the Hippo-YAP pathway in mammals is to inhibit the activity of the transcriptional regulators YAP and TAZ, thereby negatively regulating tumor progression. Therefore, the Hippo pathway is also considered a tumor suppressor pathway. Specifically, the core members of this pathway include the serine / threonine kinases MST1, MST2, LATS1, and LATS2, the scaffold proteins SAV1 (which binds to MST1 and MST2) and MOB1 (which binds to LATS1 and LATS2), the transcriptional coactivator YAP, and the transcription factor TEAD, which contains a TEA-binding domain. In short, when the Hippo pathway is activated, MST1 / 2 kinases phosphorylate and activate LATS1 / 2. Activated LATS1 / 2 then phosphorylate YAP, which then becomes inactive and subsequently exported from the nucleus, while YAP in the cytoplasm is degraded by the proteasome.

[0006] 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, and liver cancer. 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 often 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

[0007] The present invention aims to provide a novel heteroaromatic compound and its medical use. In addition to having a good inhibitory effect on FAK, the heteroaromatic compound of the present invention unexpectedly also has a good inhibitory effect on YAP.

[0008] In the first aspect of the present invention, there is provided a compound of formula 0 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, isotopes or prodrugs,

[0009]

[0010] Wherein, A is selected from: 5-6 membered heteroaryl or phenyl;

[0011] X1 is selected from: CH or N;

[0012] X2 selected from: CR 6or N;

[0013] X3 selected from: CR 7 or N;

[0014] R 1 and R 2 Each is independently selected from the following groups: substituted or unsubstituted: hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl; or R 1 and R 2 The P atom to which it is connected together forms a 3-6 membered heterocyclic group;

[0015] R 3 Independently selected from: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, CF3, CHF2, CH2F, CN, NO2, CONR a R b ; Among them, R a and R b Each is independently selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl;

[0016] R 4 Independently selected from: H, OH, halogen, CF3, CHF2, CH2F, CN, NO2, 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 replaced by 1-3 R 13 replace;

[0017] R 5 Selected from: OR 10 、CH2R 19 、H、OH、halogen、CF3、CHF2、CH2F、CH2CF3、-CN、-NO2、-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 replaced by 1-3 R 13 replace;

[0018] R 6 、R 7 、R 8 and R 9 Each independently selected from: H, OR 11 、Halogen、CF3、-CHF2、CH2F、CN、NO2、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 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 replaced by 1-3 R 13 replace;

[0019] or R 6 、R7 The atoms connected thereto 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 replace;

[0020] or R 8 、R 9 The atoms connected thereto 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 replace;

[0021] or R 5 and R 7 or R 9 The atoms connected thereto 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 replace;

[0022] R 10 、R 11 and R 12 Independently selected from: H, OH, halogen, CF3, CHF2, CH2F, CN, NO2, CH2CF3, 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 In, R 11 and R 12 The nitrogen atom to which it is connected forms 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 replace;

[0023] R 13 Independently selected from: H, OH, halogen, CF3, CHF2, CH2F, CH2CF3, -CN, -NO2, OR 14 、C(O)R 14 、OC(O)R 14 、OC(O)R 14 、-OC(O)OR 14 、-C(O)NR14 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 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 following groups: C1-C6 alkyl, halogen, OH, CN, NO2, CHF2, CH2CF3, CF3, C(O)R 17 、C(O)NR 17 R 18 、S(O) m R 17 、-S(O) m NR 17 R 18 replace;

[0024] R 14 、R 15 、R 16 、R 17 and R 18Each is independently 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 12-membered cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be substituted by 1-3 groups selected from the group consisting of OH, halogen, CN, NO2, NH2, CHF2, CH2CF3, CF3, 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;

[0025] 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;

[0026] n is independently selected from 0, 1, 2, 3 or 4;

[0027] m is independently selected from 0, 1 or 2;

[0028] Limitation: When A is phenyl, R 5 Independently OR 10 、CH2R 19 or -S(O) m R 11 ;

[0029] Or when A is phenyl, R 6 、R 7 The atoms connected thereto 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 replace.

[0030] In some embodiments, the compound has the structure shown in Formula I:

[0031]

[0032] X1, R 1 、R 2 、R 3 、R 4 、R 6 、R7 、R 8 、R 9 、R 10 , n and A are as defined above.

[0033] In some embodiments, when A is phenyl, R 5 Independently OR 10 、CH2R 19 or -S(O) m R 11 ;

[0034] Or when A is phenyl, R 6 、R 7 The atoms connected thereto 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 replace,

[0035] Among them, R 10 、R 19 、R 11 、R 13 and m are defined as above.

[0036] In some embodiments, when A is phenyl, R 5 Independently OR 10 ; Among them, R 10 The definition of is as above.

[0037] In some embodiments, when A is a 5-6 membered heteroaryl, R 5 Independently selected from: H, OH, halogen, CF3, CHF2, CH2F, CH2CF3, -CN, -NO2, -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 replaced by 1-3 R 13 Substitution; wherein m, R 11 and R 13 The definition of is as above.

[0038] In some embodiments, X1 is N.

[0039] 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,

[0040] In some embodiments, the heterocyclyl group includes heterocycloalkyl or heterocycloalkenyl.

[0041] In some embodiments, the compound has the structure shown in the following formula (I-1):

[0042]

[0043] Among them, X1, R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 、R 10 and n are defined as above;

[0044] Preferably, R 1 and R 2 Each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R 1 and R 2 The P atom to which it is connected together forms a 3-6 membered heterocyclic group (e.g., a 5-membered heterocyclic group);

[0045] Preferably, R 3 Selected from halogen or CF3;

[0046] Preferably, R 4 Selected from H;

[0047] Preferably, R 6 、R 7 、R 8 、R 9 Each is independently selected from H, halogen, CF3, C1-C6 alkyl or C1-C6 alkoxy.

[0048] In some embodiments, the compound has the structure shown in the following formula (II-1):

[0049]

[0050] Among them, R 1 、R 2 、R3 、R 4 、R 6 、R 7 、R 8 、R 9 and R 10 The definition of is as above,

[0051] Preferably, R 1 and R 2 Each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R 1 and R 2 The P atom to which it is connected together forms a 3-6 membered heterocyclic group (e.g., a 5-membered heterocyclic group);

[0052] Preferably, R 3 Selected from halogen or CF3;

[0053] Preferably, R 4 Selected from H;

[0054] Preferably, R 6 、R 7 、R 8 、R 9 Each is independently selected from H, halogen, CF3, C1-C6 alkyl or C1-C6 alkoxy.

[0055] In some embodiments, R 10 is 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 R 13 Replacement; wherein, R 13 The definition of is as above.

[0056] 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 replaced by 1-3 R 13 Replacement; wherein, R 13 The definition of is as above.

[0057] In some embodiments, R 6、R 7 、R 8 and R 9 Each independently selected from: H, halogen, CF3, -CHF2, CH2F, CN, NO2, NR 11 R 12 , C1-C6 alkyl, C1-C6 alkoxy; or R 6 、R 7 The atoms to which it is attached form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; or R 8 、R 9 The atoms connected thereto 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 replace;

[0058] Among them, R 11 、R 12 and R 13 The definition of is as above.

[0059] In some embodiments, R 5 and R 6 or R 9 The atoms connected thereto 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 Replacement, R 13 The definition of is as above.

[0060] In some embodiments, the compound has the structure shown in the following formula (I-2)-(I-7):

[0061]

[0062] Among them, R 20 Selected from: H, OH, halogen, CF3, CHF2, CH2F, CH2CF3, -CN, -NO2, C1-C6 alkyl, C1-C6 alkoxy;

[0063] p is 0, 1, or 2;

[0064] A, X1, R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 8 、R 9 and n are defined as above.

[0065] In some embodiments, when A is a 5-6 membered heteroaryl, A is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, and thiadiazolyl.

[0066] In some embodiments, R 1 and R 2 The atoms to which it is connected may form a 4-6 membered heterocyclic group, preferably the heterocyclic group includes but is not limited to the following groups:

[0067]

[0068] Wherein, * indicates the attachment site.

[0069] In some embodiments, R 3 Selected from: halogen, CF3, CHF2, CH2F, CN, C1-C6 alkyl.

[0070] 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, and 5-6 membered heterocyclic group may be substituted by a C1-C6 alkyl group; R 11 and R 12 The definition of is as above.

[0071] In some embodiments, R 4 Select from: H or

[0072]

[0073] In some embodiments, R 4 is H, OH, halogen, CF3, CHF2, CH2F, CN or NO2.

[0074] In some embodiments, A, X1, 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 groups corresponding to specific compounds in the examples.

[0075] In some embodiments, the compound is selected from 1)

[0077]

[0078] R 1 and R 2 Each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R 1 and R 2 The P atom to which it is connected together forms a 3-6 membered heterocyclic group, such as a 5 membered heterocyclic group;

[0079] R 3 Selected from halogen or CF3;

[0080] R 4 Selected from H;

[0081] R 6 、R 8 、R 9 Each is independently selected from H, halogen, CF3, C1-C6 alkyl or C1-C6 alkoxy;

[0082] R 10 Selected from: H, OH, halogen, CF3, CHF2, CH2F, CN, NO2, CH2CF3, 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 In, R 11 and R 12 The nitrogen atom to which it is connected forms 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 replace; 2)

[0084]

[0085] R 1 and R 2 Each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R 1 and R 2 The P atom to which it is connected together forms a 3-6 membered heterocyclic group, such as a 5 membered heterocyclic group;

[0086] R3 Selected from halogen or CF3;

[0087] R 4 Selected from H;

[0088] R 7 、R 8 、R 9 Each is independently selected from H, halogen, CF3, C1-C6 alkyl or C1-C6 alkoxy;

[0089] R 10 Selected from: H, OH, halogen, CF3, CHF2, CH2F, CN, NO2, CH2CF3, 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 In, R 11 and R 12 The nitrogen atom to which it is connected forms 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 replace; 3)

[0091]

[0092] I-10

[0093] A is a six-membered nitrogen-containing heteroaromatic ring;

[0094] R 1 and R 2 Each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R 1 and R 2 The P atom to which it is connected together forms a 3-6 membered heterocyclic group, such as a 5 membered heterocyclic group;

[0095] R 3 Selected from halogen or CF3;

[0096] R 4 Selected from H;

[0097] R 6 、R 7 、R8 、R 9 Each is independently selected from H, halogen, CF3, C1-C6 alkyl or C1-C6 alkoxy.

[0098] R 10 Selected from: H, OH, halogen, CF3, CHF2, CH2F, CN, NO2, CH2CF3, 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 In, R 11 and R 12 The nitrogen atom to which it is connected forms 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 replace; 4)

[0100]

[0101] R 1 and R 2 The P atom to which it is connected together forms a 3-6 membered heterocyclic group, such as a 5 membered heterocyclic group;

[0102] R 3 is CF3;

[0103] R 4 Selected from H;

[0104] R 6 、R 7 、R 8 、R 9 Each is independently selected from H, halogen, CF3, C1-C6 alkyl or C1-C6 alkoxy;

[0105] R 10 Selected from: H, OH, halogen, CF3, CHF2, CH2F, CN, NO2, CH2CF3, 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 In, R 11 and R 12 The nitrogen atom to which it is connected forms 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 replace;

[0106] or 5)

[0107]

[0108] R 1 and R 2 Each independently selected from C1-C6 alkyl or C1-C6 alkoxy, or R 1 and R 2 The P atom to which it is connected together forms a 3-6 membered heterocyclic group, such as a 5 membered heterocyclic group;

[0109] R 3 selected from halogen;

[0110] R 4 Selected from H;

[0111] R 6 、R 7 、R 8 、R 9 Each is independently selected from H, halogen, CF3, C1-C6 alkyl or C1-C6 alkoxy.

[0112] R 10 Selected from: H, OH, halogen, CF3, CHF2, CH2F, CN, NO2, CH2CF3, 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 In, R 11 and R 12The nitrogen atom to which it is connected forms 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 replace.

[0113] In some embodiments, R 10 is 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 R 13 Replacement; wherein, R 13 is defined as above.

[0114] In some embodiments, R 10 Selected from: H, OH, halogen, CF3, CHF2, CH2F, CN, NO2, CH2CF3, 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, and the N atom to which it is connected together form a 3-6 membered heterocyclyl; wherein the C1-C6 alkyl, alkoxy, alkenyl, alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, 3-6 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl may be replaced by 1-3 R 13 Take, where R 13 is defined as above.

[0115] In some embodiments, R 10 Selected from: H, OH, halogen, CF3, CHF2, CH2F, CN, NO2, CH2CF3, 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 NR11 R 12 In, R 11 and R 12 The nitrogen atom to which it is connected forms 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 Substitute, where R 13 is defined as above.

[0116] In some embodiments, the compound is selected from the following compounds:

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123] In some embodiments, the compound is a compound shown in the Examples.

[0124] 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 pharmaceutically acceptable salt, hydrate, isotope or prodrug; and a pharmaceutically acceptable carrier or diluent.

[0125] In some embodiments, the pharmaceutical composition further comprises one or more selected from the group consisting of: a PD-1 inhibitor, a PD-L1 inhibitor, an ALK inhibitor, a PI3K inhibitor, a BTK inhibitor, an EGFR inhibitor, a VEGFR inhibitor, an HDAC inhibitor, a CDK inhibitor, a MEK inhibitor, an Akt inhibitor, an mTOR inhibitor, a SHP2 inhibitor, or a combination thereof.

[0126] The third aspect of 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 medicament for treating FAK-related diseases.

[0127] In some embodiments, the FAK-related diseases include various cancers, pulmonary hypertension, and pathological angiogenesis.

[0128] 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, stomach cancer, uterine cancer, etc. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is diffuse stomach cancer.

[0129] 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 medicament for regulating YAP or treating YAP-related diseases.

[0130] In some embodiments, the YAP-associated disease is selected from cancer.

[0131] 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, urethra 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.

[0132] 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.

[0133] In some embodiments, the FAK-related disease is selected from cancer, pulmonary hypertension, and pathological angiogenesis.

[0134] In some embodiments, the cancer in the FAK-related disease 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, urethra 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.

[0135] In a fourth aspect, the present invention provides a method for treating FAK and / or YAP-related diseases, comprising administering a therapeutically effective amount of the compound according to the first aspect or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to the second aspect to a subject identified or diagnosed as having a FAK and / or YAP-related disease.

[0136] In some embodiments, the YAP-associated disease is selected from cancer.

[0137] 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, urethra 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.

[0138] 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.

[0139] In some embodiments, the FAK-related disease is selected from cancer, pulmonary hypertension, and pathological angiogenesis.

[0140] In some embodiments, the cancer in the FAK-related disease 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, urethra 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.

[0141] In another aspect, the present invention provides a method for inhibiting FAK kinase and / or YAP protein activity in a cell or a subject, comprising the steps of contacting the cell with or administering to the subject the compound of the first aspect or the pharmaceutical composition of the second aspect.

[0142] In some embodiments, the cell is a mammalian cell. In some embodiments, the subject is a mammal, preferably a human.

[0143] 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 described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0144] Figure 1 The graph shows the relationship between tumor volume and time in the mouse tumor model of Experimental Example 4 when the compound of the present invention is used.

[0145] Figure 2 Part of the western blot results of Experimental Example 2 are shown.

[0146] Figure 3 Part of the western blot results of Experimental Example 2 are shown.

[0147] Figure 4 Part of the western blot results of Experimental Example 2 are shown.

[0148] Figure 5 Part of the western blot results of Experimental Example 2 are shown. DETAILED DESCRIPTION

[0149] After extensive and in-depth research, the inventors unexpectedly discovered a class of compounds with excellent FAK kinase and / or YAP protein inhibitory activity. Furthermore, these compounds exhibit improved pharmacodynamics and pharmacokinetic properties. Based on this, the present invention was completed.

[0150] the term

[0151] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0152] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0153] 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 radicals 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.

[0154] The term "alkoxy" refers to a linear, branched, or cyclic alkyl group attached through an ether oxygen, with the free valence bond being derived from the ether oxygen. Alkoxy groups are preferably C1-C6 alkoxy groups, more preferably C1-C3 alkoxy groups. Representative examples include (but are not limited to) methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. C1-C3 alkoxy groups are preferred.

[0155] 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.

[0156] 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 groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0157] 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 groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.

[0158] The term "cycloalkyl" refers to a saturated monocyclic (e.g., C3-C8), bicyclic (e.g., C5-C12 fused bicyclic, C5-C12 membered spiro bicyclic) or polycyclic cyclic alkyl, "C3-C6 cycloalkyl" refers to a cycloalkyl containing 3 to 6 carbon atoms, and "C3-C12 cycloalkyl" refers to a cycloalkyl containing 3 to 12 carbon atoms. Cycloalkyl is preferably C3-C12 cycloalkyl, more preferably C3-C6 cycloalkyl. 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.

[0159] The term "heterocyclyl" generally refers to a stable monocyclic (e.g., 3-8 members, i.e., 3, 4, 5, 6, 7 or 8 members) or bicyclic (e.g., 5-12 members, i.e., 5, 6, 7, 8, 9, 10, 11 or 12 members) or polycyclic (e.g., 7-14 members, i.e., 7, 8, 9, 10, 11, 12, 13 or 14 members) heterocycle, including fused, spiro and / or bridged ring structures, which are saturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. The term also includes polycyclic groups formed by the fusion of a heterocycle with an aromatic ring (e.g., a benzene ring). The nitrogen and sulfur heteroatoms as ring atoms may be optionally oxidized. The nitrogen in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocyclic ring exceeds 1, the heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocyclic ring is not greater than 1. The heterocyclic group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system. Examples of heterocyclic rings include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl, and tetrahydro-1,1-dioxythiophene. The spirocyclic, condensed and bridged heterocyclic groups involved are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0160] 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 including, but 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. Connecting lines drawn from the ring system indicate that the bond can be attached to any suitable ring atom.

[0161] 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. The heteroaryl group is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl. The term "halogen" includes fluorine, chlorine, bromine and iodine.

[0162] Unless otherwise stated, any heteroatom with insufficient valence is assumed to have sufficient hydrogen atoms to complete the valence.

[0163] 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 the substituent described above, or the substituent appearing in the embodiments. 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 understood by those skilled in the art that the combination of substituents contemplated by the present invention is a combination that is 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., a monohalogen substituent or a polyhalogen substituent, the latter such as a trifluoromethyl group or an alkyl group containing Cl3), cyano, nitro, oxo (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocycle, aromatic ring, OR a SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e , P(=O)2OR eNR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where R a R may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic or aromatic rings. b 、R c and R d may independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, a heterocyclic ring or an aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e and alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle, or aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring, may be optionally substituted. Examples of such 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 heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 urea.

[0164] Active ingredient

[0165] As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably to refer to a compound of Formula I and its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, N-oxides, metabolites, or pharmaceutically acceptable salts, hydrates, isotopes, or prodrugs.

[0166]

[0167] A, X1, X2, X3, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 and n are defined as above.

[0168] In the present invention, the compound of formula 0 has the structure shown in formula I below:

[0169]

[0170] Among them, A, X1, 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 Independently OR 10 ; Among them, R 10 The definition of is as above.

[0171] Preferably, the compound has a structure shown in the following formula (I-1):

[0172]

[0173] Among them, X1, 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):

[0174]

[0175] Among them, R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 and R 10 The definition of is as above.

[0176] Preferably, the compound has a structure as shown in the following formula (I-2)-(I-7):

[0177]

[0178] Among them, R 20 Selected from: H, OH, halogen, CF3, CHF2, CH2F, CH2CF3, -CN, -NO2, C1-C6 alkyl, C1-C6 alkoxy;

[0179] p is 0, 1, or 2;

[0180] A, X1, R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 8 、R 9 and n are defined as above.

[0181] Preferably, the compound has a structure shown in formula (I-8), (I-9) or (I-10):

[0182]

[0183] A.R. 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 and R 10 The definition of is as above.

[0184] The salts that may be formed by the compounds of the present invention also fall within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to acidic or basic salts formed with inorganic or organic acids and bases. 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 within 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 during the preparation process. The compounds of the present invention may form salts, for example, compound I reacts with a certain amount, such as an equivalent amount, of an acid or base, salts out in a medium, or is obtained by freeze-drying in an aqueous solution.

[0185] The compounds of the present invention contain basic moieties, 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 (e.g., acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,

[0014] Examples of the present invention include, for example, hydroxyethylsulfonates, 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., with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, and the like.

[0186] Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (e.g., 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, and the like. Basic nitrogen-containing groups can react with halide quaternary ammonium salts, such as small molecular 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 bromide), etc.

[0187] Prodrugs and solvates of the compounds of the present invention are also encompassed. The term "prodrug" herein refers to a compound that undergoes chemical transformation via metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when used to treat a relevant disease. The compounds of the present invention include solvates, such as hydrates.

[0188] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

[0189] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbon atoms 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 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 either S or R configurations, 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 diastereomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0190] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0191] 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.

[0192] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0193] Specific functional groups and chemical term definitions are detailed below. For the purposes of this invention, chemical elements are referred to in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The definitions of specific functional groups are consistent with those in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito, 1999, which is incorporated by reference in its entirety.

[0194] 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. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and mixtures thereof are encompassed by the present invention.

[0195] According to the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures containing only two isomers can have the following ratios: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are readily understood by those skilled in the art and are also within the scope of the present invention.

[0196] The present invention also includes isotopically labeled compounds that 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. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, 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 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in some cases. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0197] If a synthesis of a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the chiral auxiliary to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomer.

[0198] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted," whether preceded or followed by the term "optionally," in formulas of the present invention including substituents, refers to the replacement of a hydrogen radical with a substituent of the specified structure. When multiple positions in a particular structure are substituted with multiple substituents of the specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible substitutions in organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. For example, heteroatoms of nitrogen may be substituted with hydrogen or any of the permissible organic compounds described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible substitutions in any way to organic compounds. The present invention recognizes that combinations of substituents and variables are advantageous for providing stable compounds for the treatment of diseases. As used herein, the term "stable" refers to compounds that are stable and maintain the structural integrity of the compound over a period of time sufficient to be detected, preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0199] 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.

[0200] Pharmaceutical compositions and methods of administration

[0201] The pharmaceutical composition of the present invention is used to prevent and / or treat the following diseases: cancer, pulmonary hypertension, and pathological angiogenesis.

[0202] The compounds of Formula I may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the original drug's route of administration and dosage can remain unchanged, while the compound of Formula I is administered simultaneously or subsequently. When the compound of Formula I is administered concurrently with one or more other drugs, a pharmaceutical composition containing both the one or more known drugs and the compound of Formula I may be preferably used. Drug combinations also include administering the compound of Formula I and one or more other known drugs during overlapping time periods. When the compound of Formula I is administered in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than when administered alone.

[0203] 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.

[0204] 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.

[0205] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0206] "Pharmaceutically acceptable carriers" refer 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 (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0207] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0208] 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 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 the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0209] Solid dosage forms such as tablets, dragees, 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 opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0210] 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, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0211] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0212] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0213] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0214] Dosage forms for topical administration of the compounds of this 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.

[0215] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0216] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0217] 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.

[0218] Preparation method

[0219] The following schemes and examples describe methods for preparing compounds of Formula I. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or described otherwise. In some cases, the order in which the steps of the reaction schemes are performed may be altered to facilitate the reaction or to avoid unwanted side reaction products.

[0220] 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 combinations can be easily carried out by those skilled in the art.

[0221] Typically, in the preparation process, each reaction is usually carried out under inert gas protection in a suitable solvent at 0 to 90° C., and the reaction time is usually 2 to 24 hours.

[0222] Preferably, the compounds of the present invention are prepared by the following method

[0223]

[0224] 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), causing a substitution reaction at the 4-position of the pyrimidine chloro analog A-1 to obtain compound A-3;

[0225] ii) Compound A-3 reacts with aromatic amine formic acid A-4 under acidic conditions (e.g., HCl) to produce carboxylic acid compound A-5 by nucleophilic substitution;

[0226] iii) Carboxylic acid compound A-5 and amine compound R-NH2 undergo amide condensation reaction in the presence of an amide condensing agent (e.g., HATU) to obtain compound A-6;

[0227] Where A, X1, and R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 and n are defined as above.

[0228] 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 invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0229] The present invention has the following main advantages:

[0230] (1) The compounds of the present invention have excellent inhibitory ability against FAK kinase and YAP protein;

[0231] (2) The compounds of the present invention have relatively low toxic side effects.

[0232] (3) The compounds of the present invention have good pharmacodynamic and pharmacokinetic properties.

[0233] 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 invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0234] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0235] The structures of the compounds of the present invention are confirmed by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0236] NMR was measured using a Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic spectrometer. The measurement solvents included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as the internal standard, and chemical shifts were measured in parts per million (ppm).

[0237] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260 mass spectrometer. HPLC analysis was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100 x 3.0 mm column).

[0238] TLC silica gel plates used were Qingdao GF254 silica gel plates, with a diameter of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative thin layer chromatography. Column chromatography generally used Qingdao 200-300 mesh silica gel as a carrier.

[0239] 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.

[0240] 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.

[0241] The following abbreviations are used throughout this invention:

[0242] Defactinib: Defactinib

[0243] THF: Tetrahydrofuran

[0244] DCM: dichloromethane

[0245] PE: Petroleum ether

[0246] Na2CO3: sodium carbonate

[0247] MeOH: methanol

[0248] HCl: hydrochloric acid

[0249] Pd(PPh3)4: Tetrakistriphenylphosphine palladium

[0250] K2CO3: Potassium carbonate

[0251] H2O: water

[0252] TEA: triethylamine

[0253] DIEA: N,N-diisopropylethylamine

[0254] DMF: N,N-dimethylformamide

[0255] DMSO: dimethyl sulfoxide

[0256] NaBH4: sodium borohydride

[0257] Sn2(Bu-n)6: Hexabutyltin

[0258] CuI: Cuprous iodide

[0259] Cs2CO3: cesium carbonate

[0260] K3PO4: Potassium phosphate

[0261] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium

[0262] Pd / C: Palladium on carbon

[0263] Xantphos: 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

[0264] EA: ethyl acetate

[0265] Boc2O: di-tert-butyl dicarbonate

[0266] Pd(dppf)2Cl2:[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0267] NaH: sodium hydrogen

[0268] CH3I: methyl iodide

[0269] L-Proline: L-proline

[0270] L-Selectride: lithium tri-sec-butylborohydride

[0271] Example

[0272] Example 1

[0273] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(((1-methylpiperidin-4-yl)methyl)benzamide (1)

[0274]

[0275] Step 1: Synthesis of (2-aminophenyl)dimethylphosphine oxide

[0276] 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), K3PO4 (11.63 g, 54.8 mmol) and Xantphos (2.64 g, 4.57 mol) were weighed and added to the reaction system. The atmosphere was replaced with nitrogen for protection. The temperature was slowly raised to 125°C and refluxed with stirring for 6 h. The reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was filtered through celite 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 gave 7.1 g of (2-aminophenyl)dimethylphosphine oxide, MS m / z (ESI): 170 [M+H]. + .

[0277] Step 2: Synthesis of (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0278] 2,4-Dichloropyrimidine-5-trifluoromethyl (2.56 g, 11.8 mmol) was dissolved in DMF (50 mL), and (2-aminophenyl)dimethylphosphine oxide (2.0 g, 11.8 mmol) was added. DIPEA (2.0 mL, 11.8 mmol) was slowly added under ice-cooling conditions. The temperature was raised to 50°C and the reaction was allowed to react for 1 h. The reaction was monitored for completion. Water was added to quench the reaction, and dichloromethane was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 920 mg of 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS m / z (ESI): 350 [M+H] + .

[0279] Step 3: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid

[0280] 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). A 4N hydrochloric acid solution in 1,4-dioxane (1.3 mL, 5.2 mmol) was added. The mixture was reacted at 65°C for 4 h and monitored for completion. The reaction 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] + .

[0281] Step 4: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(((1-methylpiperidin-4-yl)methyl)benzamide

[0282] 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. The mixture was stirred for 2 h at room temperature. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL) and extracted with EA (20 mL*2). The organic phase was washed with water, dried, and concentrated. Column chromatography gave 15.1 mg of (4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(((1-methylpiperidin-4-yl)methyl)benzamide. 1H NMR (400MHz, DMSO-d6) δ10.58(s,1H),10.08(s,1H),8.55(t,J=5.7Hz,1H),8.49(s,1H),8.19(s,1H),7.67(ddd,J=25.0,17 .9,8.1Hz,3H),3.31(d,J=11.5Hz,1H),3.16(s,1H),2.88(t,J=11.9Hz,1H),2.66(s,1H),1.53(dd,J=24.3,12.4Hz,1H).MS m / z(ESI):561[M+H] + .

[0283] Example 2

[0284] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)methyl)benzamide (2)

[0285]

[0286] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxybenzoic acid

[0287] 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (120 mg, 0.35 mmol) and p-amino-3-methoxybenzoic acid (63.4 mg, 0.38 mmol) were dissolved in isopropanol (14 mL). A 4N hydrochloric acid solution in 1,4-dioxane (0.12 mL, 0.48 mmol) was added. The mixture was reacted at 70°C for 4 h and the reaction was monitored for completion. 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] + .

[0288] 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

[0289] 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 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 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 (400MHz, DMSO-d6) δ10.74(s,1H),8.62(s,1H),8.49–8.34(m,1H),8.16(s,1H),7.84(d,J=8.0 Hz,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=8.3H z,1H),7.21(t,J=7.1Hz,1H),3.87(s,2H),3.16(t,J=6.2Hz,1H),2.78(d,J=10.9Hz,1H),2.16(s,2 H),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).MS m / z(ESI):591[M+H] + .

[0290] Example 3

[0291] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide (3)

[0292]

[0293] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0294] 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 the reaction was carried out 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), and the organic phase was washed with water, dried, concentrated, and purified by column chromatography with MeOH / DCM (0-10%) to give 15 mg of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide. 1 H NMR(400MHz,DMSO-d6)δ11.58(s,1H),10.56(s,1H),10.08(s,1H),8.49(s,1H),8.16(s,1H),7.6 5(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).MS m / z(ESI):480[M+H] + .

[0295] Example 4

[0296] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzamide (4)

[0297]

[0298] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzamide

[0299] 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 (400MHz, DMSO-d6) 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] + .

[0300] Example 5

[0301] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(methyl)benzamide (5)

[0302]

[0303] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylbenzoic acid

[0304] 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). A 4N hydrochloric acid solution in 1,4-dioxane (0.1 mL, 0.4 mmol) was added. The mixture was reacted at 70°C for 4 h and the reaction was monitored for completion. 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. MS m / z (ESI): 465 [M+H] + .

[0305] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(methyl)benzamide

[0306] 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 the reaction was carried out 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), and the organic phase was washed with water, dried, concentrated, and purified by column chromatography to obtain 40.1 mg of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(methyl)benzamide. 1 H NMR(400MHz,DMSO-d6)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] + .

[0307] Example 6

[0308] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(trifluoromethoxy)benzamide (6)

[0309]

[0310] Step 1: 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)benzoic acid

[0311] 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). A 4N hydrochloric acid solution in 1,4-dioxane (0.1 mL, 0.4 mmol) was added. The mixture was reacted at 70°C for 4 h and the reaction was monitored for completion. 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] + .

[0312] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(trifluoromethoxy)benzamide

[0313] 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. 1H NMR (400MHz, DMSO-d6) δ11.89(s,1H),10.81(s,1H),9.63(s,1H),8.44(s,1H),8.14(s,1H),7.88(d,J=8.4Hz,1H),7.74(s,1H),7.69( d,J=8.4Hz,1H),7.58(dd,J=12.5,7.6Hz,1H),7.40(t,J=8.1Hz,1H),7.20(t,J=7.1Hz,1H),3.73(s,1H),1.74(s,1H),1.71(s,1H).MS m / z(ESI):564[M+H] + .

[0314] Example 7

[0315] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(isopropoxy)benzamide (7).

[0316]

[0317] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(isopropoxy)benzoic acid

[0318] 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). A 4N hydrochloric acid solution in 1,4-dioxane (0.1 mL, 0.4 mmol) was added. The mixture was reacted at 70°C for 4 h and the reaction was monitored for completion. 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] + .

[0319] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(isopropyloxy)benzamide

[0320] 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 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 35.0 mg. 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(isopropoxy)benzamide. 1 HNMR(400MHz,DMSO-d6)δ11.68(s,1H),10.68(s,1H),8.46(s,1H),8.38(s,1H),8.11(dd,J=7 .9,3.9Hz,1H),7.95(d,J=8.4Hz,1H),7.64(dd,J=13.4,7.7Hz,1H),7.52(t,J=7.8Hz,1H),7. 40(d,J=1.7Hz,1H),7.29(t,J=7.4Hz,1H),7.21(dd,J=8.4,1.5Hz,1H),4.69(hept,J=5.6Hz, 1H),3.71(s,3H),1.75(s,3H),1.71(s,3H),1.30(s,3H),1.29(s,3H).MSm / z(ESI): 538[M+H] + .

[0321] Example 8

[0322] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(ethoxy)benzamide (8)

[0323]

[0324] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(ethoxy)benzoic acid

[0325] 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (100 mg, 0.29 mmol) and p-amino-3-ethoxybenzoic acid (54.6 mg, 0.3 mmol) were dissolved in isopropanol (6 mL). A 4N hydrochloric acid solution in 1,4-dioxane (0.1 mL, 0.4 mmol) was added. The mixture was reacted at 70°C for 4 h and the reaction was monitored for completion. 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] + .

[0326] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(ethoxy)benzamide

[0327] 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 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 45.2 mg 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-3-(ethoxy)benzamide. 1 HNMR(400MHz,DMSO-d6)δ11.67(s,1H),10.69(s,1H),8.47(d,J=13.0Hz,2H),8 .13(dd,J=7.9,3.8Hz,1H),7.91(d,J=8.4Hz,1H),7.63(ddd,J=13.5,7.7,1.3H z,1H),7.50(t,J=7.8Hz,1H),7.39(d,J=1.7Hz,1H),7.30–7.18(m,2H),4.13(q ,J=6.9Hz,2H),3.72(s,3H),1.75(s,3H),1.71(s,3H),1.35(t,J=6.9Hz,3H).MS m / z(ESI):524[M+H] + .

[0328] Example 9

[0329] Preparation of 4-((4-((2-(dimethylphosphoryl)-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzamide (9)

[0330]

[0331] Step 1: Synthesis of 4-(3-iodo-4-nitrophenyl)morpholine

[0332] Dissolve 4-fluoro-2-iodo-1-nitrobenzene (2.5 g, 9.36 mmol) and morpholine (1.6 g, 18.73 mmol) in DMF (50 mL). Add K2CO3 (2.5 g, 18.73 mmol). Slowly raise the temperature to 100°C and stir for 8 h. After completion of the reaction, monitor by TLC. Quench with water and extract with EA (30 mL x 2). Combine the organic phases, wash with saturated brine (50 mL x 2), and evaporate under reduced pressure. 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]. + .

[0333] Step 2: Synthesis of 2-iodo-4-morpholineaniline

[0334] 4-(3-Iodo-4-nitrophenyl)morpholine (2.0 g, 6.0 mmol) was dissolved in methanol / water (4:1) (60 mL). Iron powder (835.7 mg, 14.96 mmol) and ammonium chloride (815.6 mg, 14.96 mmol) were then added. The reaction system was slowly heated to reflux at 80°C overnight. After completion, the reaction was cooled to room temperature, filtered through celite, and quenched with saturated NaHCO₃ (100 mL). The mixture was extracted with EA (100 mL x 3). The combined organic phases were concentrated and purified by ISCO column chromatography (PE / EA 0-80%) to afford 1.6 g of 2-iodo-4-morpholinoaniline. MS m / z (ESI): 305 [M+H]⁺.

[0335] Step 3: Synthesis of (2-amino-5-morpholinophenyl) dimethylphosphine oxide

[0336] 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), K3PO4 (1.65 g, 7.78 mmol) and Xantphos (376.1 mg, 0.65 mol) were weighed and added to the reaction system. The atmosphere was replaced with nitrogen for protection. The temperature was slowly raised to 125°C and the mixture was stirred under reflux for 6 h. The reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was filtered through celite 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 (PE / EA 0-100%) gave 1.2 g of (2-amino-5-morpholinophenyl)dimethylphosphine oxide, MS m / z (ESI): 255 [M+H]. + .

[0337] Step 4: Synthesis of (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-5-morpholinophenyl)dimethylphosphine oxide

[0338] 2,4-Dichloropyrimidine-5-trifluoromethyl (1.2 g, 4.72 mmol) was dissolved in DMA (20 mL), and (2-amino-5-morpholinophenyl)dimethylphosphine oxide (931.8 mg, 4.29 mmol) was added. DIPEA (0.8 mL, 4.72 mmol) was slowly added under ice-cooling conditions. The temperature was raised to 50°C and the reaction was allowed to react for 1 h. The reaction was monitored for completion. The reaction was quenched with water and extracted with dichloromethane (20 mL*2). The mixture was dried, concentrated, and purified by column chromatography to obtain 0.68 g of 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-5-morpholinophenyl)dimethylphosphine oxide. MS m / z (ESI): 435 [M+H]. + .

[0339] Step 5: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxybenzoic acid

[0340] 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-5-morpholinophenyl)dimethylphosphine oxide (150.3 mg, 0.35 mmol) and p-amino-3-methoxybenzoic acid (60.7 mg, 0.36 mmol) were dissolved in isopropanol (6 mL). A 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 monitored by TLC to determine completion. 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] + .

[0341] Step 6: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzamide

[0342] Compound 4-((4-((2-(dimethylphosphoryl)-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxybenzoic acid (60.3 mg, 0.11 mmol), O-methylhydroxylamine hydrochloride (26.7 mg, 0.32 mmol), HATU (83.7 mg, 0.22 mmol), DMAP (1.0 mg, 0.01 mmol) and DIPEA (0.12 mL, 0.65 mmol) were added to DMF (6 mL), and then reacted at room temperature for 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 32.0 mg. 4-((4-((2-(dimethylphosphoryl)-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzamide. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),10.18(s,1H),8.44(s,1H),8.38(s,1H),7.82(d,J=8.0Hz,2H),7.39(d,J=1.6Hz,1H),7.21 (d,J=9.6Hz,1H),7.16–7.02(m,2H),3.87(s,3H),3.81–3.75(m,4H),3.72(s,3H),3.23–3.12(m,4H),1.69(s,3H),1.66(s,3H).MS m / z(ESI):595[M+H] + .

[0343] Example 10

[0344] Preparation of 4-((4-((4-([1,4'-bipyridyl]-1'-yl)-2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzamide (10)

[0345]

[0346] Step 1: Synthesis of 1'-(3-iodo-4-nitrophenyl)-1,4'-dipiperidine

[0347] Dissolve 4-fluoro-2-iodo-1-nitrobenzene (2.5 g, 9.36 mmol) and 1,4'-dipiperidine (1.9 g, 11.24 mmol) in DMF (50 mL). Add K2CO3 (2.6 g, 18.72 mmol). Slowly raise the temperature to 100°C and stir for 8 h. After the reaction is complete, monitor the reaction by TLC. Quench with water and extract with EA (30 mL x 2). The combined organic phases are washed with saturated brine (50 mL x 2), evaporated under reduced pressure, and purified by ISCO column chromatography (EA / PE 0%-100%) to obtain 3.2 g of 1'-(3-iodo-4-nitrophenyl)-1,4'-dipiperidine. MS m / z (ESI): 416 [M+H]. + .

[0348] Step 2: Synthesis of 4-([1,4'-dipiperidinyl]-1'-yl)-2-iodoaniline

[0349] 1'-(3-Iodo-4-nitrophenyl)-1,4'-dipiperidine (3.2 g, 7.71 mmol) was dissolved in methanol / water (4:1) (60 mL). Iron powder (1.1 g, 19.28 mmol) and ammonium chloride (1.1 g, 19.28 mmol) were then added. The reaction system was slowly heated to reflux at 80°C overnight. After completion, the reaction was cooled to room temperature, filtered through celite, quenched with saturated NaHCO₃ (100 mL), and extracted with EA (100 mL x 3). The combined organic phases were concentrated and purified by ISCO column chromatography (PE / EA 0-100%) to afford 1.6 g of 4-([1,4'-dipiperidinyl]-1'-yl)-2-iodoaniline. MS m / z (ESI): 386 [M+H]+.

[0350] Step 3: Synthesis of (5-([1,4'-dipiperidinyl]-1'-yl)-2-aminophenyl)dimethylphosphine oxide

[0351] 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), K3PO4 (1.1 g, 5.04 mmol) and Xantphos (243.0 mg, 0.42 mmol) were weighed and added to the reaction mixture. The system was replaced with nitrogen protection, and the temperature was slowly raised to 125°C, refluxed and stirred for 6 hours. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, filtered through celite, extracted with EA (20 mL*2), the organic phases were combined, washed with saturated brine (30 mL*2), and distilled under reduced pressure. Purification by ISCO column chromatography (0-100% EA / PE) gave 760.3 mg of (5-([1,4'-dipiperidinyl]-1'-yl)-2-aminophenyl)dimethylphosphine oxide, MS m / z (ESI): 336 [M+H] + .

[0352] Step 4: Synthesis of (5-([1,4'-dipiperidinyl]-1'-yl)-2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0353] 2,4-Dichloropyrimidin-5-trifluoromethyl (600 mg, 1.79 mmol) was dissolved in DMA (10 mL), and (2-amino-5-morpholinophenyl)dimethylphosphine oxide (353.0 g, 1.62 mmol) was added. DIPEA (0.3 mL, 1.79 mmol) was slowly added in an ice bath. The reaction was heated to 60°C for 1 h and monitored for completion. The product was quenched with water and extracted with dichloromethane (20 mL x 2). The product was dried, concentrated, and purified by column chromatography (0-100% EA / PE) to obtain 0.32 g of (5-([1,4'-dipiperidinyl]-1'-yl)-2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS m / z (ESI): 516 [M+H]. + .

[0354] 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

[0355] (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). A 4N hydrochloric acid solution in 1,4-dioxane (0.1 mL, 0.4 mmol) was added and the mixture was reacted at 65°C for 8 h. The reaction was monitored by TLC to determine completion. The system was filtered to yield 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] + .

[0356] Step 6: Synthesis of 4-((4-((4-([1,4'-bipyridyl]-1'-yl)-2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzamide

[0357] 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 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 23.5 mg. 4-((4-((4-([1,4'-bipyridyl]-1'-yl)-2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzamide. 1H NMR(400MHz,DMSO-d6)δ12.02(s,1H),10.18(s,1H),8.43(s,1H),8.37(s,1H),7.85–7.7 6(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] + .

[0358] Example 11

[0359] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxy-N-(methylsulfonyl)benzamide (11)

[0360]

[0361] Step 1: Synthesis of 3-methoxy-4-nitrobenzamide

[0362] 4-Nitro-3-methoxybenzoic acid (1 g, 5.1 mmol), oxalyl chloride (0.47 mL, 5.6 mmol) and 2 drops of DMF were added to DCM (20 mL) at 0°C, and then reacted at room temperature for 0.5 h. After the reaction was completed as monitored by TLC, ammonia (2 mL, 20 mmol) was added and reacted for 1 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (20 mL) and extracted with DCM (20 mL*3). The organic phase was washed with water, dried, concentrated, and column chromatography was performed to obtain 400 mg of 3-methoxy-4-nitrobenzamide, MS m / z (ESI): 197 [M+H]. + .

[0363] Step 2: Synthesis of 3-methoxy-N-(methylsulfonyl)-4-nitrobenzamide

[0364] 3-Methoxy-4-nitrobenzamide (200 mg, 1 mmol) and sodium hydride (160 mg, 4 mmol) were added to THF (15 mL) at 0°C and reacted at room temperature for 0.5 h. Methanesulfonyl chloride (0.3 mL, 4 mmol) was then added and reacted for 7 h. After completion of the reaction as monitored by LCMS, the reaction was quenched with water (15 mL) and extracted with EA (20 mL*3). The organic phase was washed with water, dried, and concentrated. Column chromatography gave 220 mg of 3-methoxy-N-(methylsulfonyl)-4-nitrobenzamide, MS m / z (ESI): 275 [M+H]. + .

[0365] Step 3: Synthesis of 4-amino-3-methoxy-N-(methylsulfonyl)benzamide

[0366] 3-Methoxy-N-(methylsulfonyl)-4-nitrobenzamide (220 mg, 0.8 mmol) was dissolved in methanol (25 mL). Pd / C (45 mg) was then added, followed by 3 drops of concentrated hydrochloric acid. The reaction mixture was allowed to react overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and the filtrate was dried to give 120 mg of 4-amino-3-methoxy-N-(methylsulfonyl)benzamide. MS m / z (ESI): 245 [M+H] + .

[0367] Step 4: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxy-N-(methylsulfonyl)benzamide

[0368] (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 and the reaction system was filtered. 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. 1H NMR (400MHz, DMSO-d6) 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] + .

[0369] Example 12

[0370] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxybenzamide (12)

[0371]

[0372] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxybenzamide

[0373] 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), and the organic phase was washed with water, dried, 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. 1H NMR (400MHz, DMSO-d6) δ11.47(s,1H),10.53(s,1H),10.07(s,1H),8.49(d,J=0.9Hz,1H),8.15(s,1H),7.75 –7.54(m,6H),7.33(t,J=7.6Hz,1H),3.91(q,J=7.0Hz,2H),1.73(d,J=13.6Hz,6H),1.20(t,J=7.0Hz,3H).MS m / z(ESI):494[M+H] + .

[0374] Example 13

[0375] Preparation of N-butoxy-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (13)

[0376]

[0377] 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), and the organic phase was washed with water, dried, concentrated, and purified by column chromatography with MeOH / DCM (0-10%) to obtain 60 mg of the product. N-Butoxy-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0378] Example 14

[0379] Preparation of N-(allyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (14)

[0380]

[0381] 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 reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL) and extracted with EA (20 mL×3). The organic phase was washed with water, dried, concentrated, and purified by column chromatography with MeOH / DCM (0-10%) to give 40 mg of the product. N-(Allyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.57(s,1H),10.08(s,1H),8.49(d, J=0.9Hz,1H),8.16(s,1H),7.73–7.55(m,6H),7.32(t,J=7.7Hz,1H),6.00( ddt,J=17.4,10.4,6.0Hz,1H),5.35(dq,J=17.3,1.6Hz,1H),5.26(ddt,J=1 0.4,2.0,1.2Hz,1H),4.40(dt,J=6.0,1.3Hz,2H),1.73(d,J=13.6Hz,6H).MS m / z(ESI):506[M+H] + .

[0382] Example 15

[0383] Preparation of N-(propargyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (15)

[0384]

[0385] 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 ( The mixture was stirred for 2 h at 4 ℃ for 30 minutes (0.12 mL, 0.67 mmol) and added to DMF (2 mL). The mixture was reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL) and extracted with EA (20 mL×3). The organic phase was washed with water, dried, and concentrated. The mixture was purified by column chromatography using MeOH / DCM (0-10%) to give 40 mg of N-(propargyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. 1 H NMR (400MHz, DMSO-d6) δ11.74(s,1H),10.56(s,1H),10.09(s,1H),8.49(d,J=0.9Hz,1H),8.16(s,1H),7.72 –7.57(m,6H),7.33(t,J=7.4Hz,1H),4.58(d,J=2.4Hz,2H),3.60(t,J=2.4Hz,1H),1.73(d,J=13.6Hz,6H).MS m / z(ESI):504[M+H] + .

[0386] Example 16

[0387] Preparation of N-(benzyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (16)

[0388]

[0389] Step 1: Synthesis of N-(benzyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide

[0390] 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 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 60.5 mg. N-(Benzyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),10.57(s,1H),10.09(s,1H),8.49(s,1H),8.16(s,1H),7.73–7.54(m,6H) ,7.46(dd,J=7.9,1.5Hz,2H),7.43–7.29(m,5H),4.91(s,2H),1.75(s,3H),1.72(s,3H).MSm / z(ESI): 556[M+H] + .

[0391] Example 17

[0392] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-hydroxybenzamide (17)

[0393]

[0394] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-hydroxybenzamide

[0395] 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), and 10% Pd / C (10 mg) was added. The mixture was reacted overnight under a H2 atmosphere. After the reaction was completed as monitored by LCMS, the mixture was filtered through celite and distilled under reduced pressure to give 15.6 mg of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-hydroxybenzamide.1 H NMR (400MHz, DMSO-d6): δ11.07(s,1H),10.56(s,1H),10.05(s,1H),8.91(s,1H),8.48(s,1H),8.15 (d,J=13.0Hz,1H),7.65(dt,J=17.3,9.0Hz,7H),7.32(t,J=7.2Hz,1H),1.75(s,3H),1.72(s,3H).MS m / z(ESI):466[M+H] + .

[0396] Example 18

[0397] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxybenzamide (18)

[0398]

[0399] 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 reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL) and extracted with EA (20 mL×3). The organic phase was washed with water, dried, 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(400MHz,DMSO-d6)δ11.47(s,1H),10.57(s,1H),10.07(s,1H),8.49(s,1H),8.16(s,1H),7.75–7.5 3(m,6H),7.32(t,J=7.4Hz,1H),3.65(d,J=6.6Hz,2H),1.73(d,J=13.6Hz,6H),0.94(d,J=6.7Hz,6H).MS m / z(ESI):522[M+H] + .

[0400] Example 19

[0401] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxyethoxy)benzamide (19)

[0402]

[0403] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxyethoxy)benzamide

[0404] 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 (400MHz, DMSO-d6) δ11.62(s,1H),10.57(s,1H),10.10(s,1H),8.49(s,1H),8.16(s,1H),7.68(t,J=8.9Hz,1H),7.62(t,J=7.8Hz ,1H),7.33(t,J=7.3Hz,1H),4.80(t,J=5.8Hz,1H),3.91(t,J=4.9Hz,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] + .

[0405] Example 20

[0406] Preparation of benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate

[0407]

[0408] Step 1: Synthesis of benzyl 4-nitrobenzoate

[0409] 4-Nitrobenzoic acid (2 g, 12 mmol) and benzyl bromide (2.05 g, 12 mmol) were dissolved in acetonitrile (100 mL). Potassium carbonate (2 g, 14.4 mmol) was added, and the temperature was raised to 60°C. The mixture was stirred for 5 h. After completion of the reaction, the mixture was quenched with water and extracted with EA (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 2), and evaporated under reduced pressure. Purification by column chromatography (PE = 1) yielded 3 g of benzyl 4-nitrobenzoate. MS m / z (ESI): 258 [M+H] + .

[0410] Step 2: Synthesis of benzyl 4-aminobenzoate

[0411] Benzyl 4-nitrobenzoate (3 g, 12 mmol) was dissolved in methanol / water (4:1) (50 mL). Iron powder (1.68 g, 30 mmol) and ammonium chloride (1.6 g, 30 mmol) were then added. The reaction system was slowly heated to 80°C and refluxed overnight. After completion, the reaction was cooled to room temperature, filtered through celite, and quenched with saturated sodium bicarbonate solution (100 mL). The mixture was extracted with EA (100 mL x 3). The combined organic phases were concentrated and purified by column chromatography (PE:EA = 4:1) to yield 2.1 g of benzyl 4-aminobenzoate. MS m / z (ESI): 228 [M+H]+.

[0412] Step 3: Synthesis of benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate

[0413] 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (1.63 g, 7.5 mmol) was dissolved in N,N-dimethylacetamide (15 mL). Benzyl 4-aminobenzoate (1.7 g, 7.5 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.25 mmol) were added. The reaction was heated to 60°C for 6 h, and the reaction was monitored for completion. The reaction solution was poured into saturated brine (40 mL) and filtered. The residue was dissolved in methanol (20 mL), filtered, and washed with methanol (2 × 3 mL). The residue was the target product, yielding 1.53 g of benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate. MS m / z (ESI): 408 [M+H]. + .

[0414] Preparation of (R)-4-((4-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide (20)

[0415]

[0416] Step 1: Synthesis of (R)-N,N-dimethylpyrrolidin-3-amine hydrochloride

[0417] 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). Stir and react at room temperature for 3 hours. After completion of the reaction, monitor by TLC, and evaporate under reduced pressure to obtain 912 mg of (R)-N,N-dimethylpyrrolidin-3-amine hydrochloride.

[0418] Step 2: Synthesis of (R)-1-(3-iodo-4-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine

[0419] (R)-N,N-Dimethylpyrrolidin-3-amine hydrochloride (912 mg, 6.1 mmol) and 4-fluoro-2-iodo-1-nitrobenzene (1.63 g, 6.1 mmol) were dissolved in N,N-dimethylformamide (15 mL). Potassium carbonate (2.53 g, 18.3 mmol) was added, and the temperature was slowly raised to 100°C. The mixture was stirred for 6 h. After completion of the reaction, the mixture was quenched with water and extracted with EA (50 mL × 2). 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 1.4 g of (R)-1-(3-iodo-4-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine. MS m / z (ESI): 362 [M+H]. + .

[0420] Step 3: Synthesis of (R)-1-(4-amino-3-iodophenyl)-N,N-dimethylpyrrolidin-3-amine

[0421] (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). Iron powder (0.54 g) and ammonium chloride (0.52 g) were then added. The reaction system was slowly heated to 80°C and refluxed overnight. After completion, the reaction was cooled to room temperature, filtered through celite, and quenched with saturated sodium bicarbonate solution (100 mL). The mixture was extracted with EA (100 mL × 3). The combined organic phases were concentrated and purified by column chromatography (PE / EA 0-80%) to obtain 1.25 g of (R)-1-(4-amino-3-iodophenyl)-N,N-dimethylpyrrolidin-3-amine. MS m / z (ESI): 332 [M+H] + .

[0422] Step 4: Synthesis of (R)-(2-amino-5-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)dimethylphosphine oxide

[0423] (R)-1-(4-amino-3-iodophenyl)-N,N-dimethylpyrrolidin-3-amine (1.25 g, 3.78 mmol) and dimethylphosphine oxide (0.35 g, 4.54 mmol) were dissolved in N,N-dimethylformamide solution (10 mL), palladium acetate (85 mg, 0.38 mmol), potassium phosphate (0.96 g, 4.54 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.22 g, 0.38 mmol) was added to the reaction system, replaced with nitrogen protection, and the temperature was slowly raised to 120°C, refluxed with stirring, and reacted for 6 h. The reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was filtered through celite and extracted with DCM (30 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 (R)-(2-amino-5-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)dimethylphosphine oxide, MS m / z (ESI): 282 [M+H] + .

[0424] 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

[0425] Benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (147 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (5 mL), and (R)-(2-amino-5-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)dimethylphosphine oxide (110 mg, 0.39 mmol) was added. p-Toluenesulfonic acid (13.5 mg, 0.07 mmol) was added, and the temperature was raised to 120°C for 2 h. The reaction was monitored for completion. The mixture was quenched with water and extracted with dichloromethane (20 mL × 2). The mixture was dried and concentrated, and column chromatography was performed to give 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] + .

[0426] 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

[0427] Benzyl (R)-4-((4-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (120 mg, 0.18 mmol) was dissolved in methanol (25 mL), and palladium hydroxide / carbon (240 mg) was added. The mixture was reacted under a H2 atmosphere for 2 h. The reaction was monitored by TLC to be complete. The system was filtered and the filtrate was evaporated under reduced pressure to give 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]. + .

[0428] 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

[0429] (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), followed by reaction at room temperature for 15 h. After completion of the reaction as monitored by LCMS, the reaction was quenched with water (10 mL) and extracted with EA (20 mL×3). The organic phase was washed with water, dried, and concentrated. The product was purified by column chromatography using 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] + .

[0430] Example 21

[0431] Preparation of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide (21)

[0432]

[0433] Step 1: Synthesis of (2-amino-5-bromophenyl)dimethylphosphine oxide

[0434] 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), K3PO4 (5.09 g, 24.2 mmol) and Xantphos (1.16 g, 2.01 mol) were weighed and added to the reaction system. The atmosphere was replaced with nitrogen for protection. The temperature was slowly raised to 125°C and refluxed with stirring for 6 h. The reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was filtered through celite 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 gave 3.2 g of (2-amino-5-bromophenyl)dimethylphosphine oxide, MS m / z (ESI): 249 [M+H]. + .

[0435] Step 2: Synthesis of (2-amino-5-(pyridin-3-yl)phenyl)dimethylphosphine oxide

[0436] Compounds (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 / H2O (5:1) solution (40 mL), and Pd(dppf)Cl2 (329.9 mg, 0.4 mol) and Na2(CO3)2 (1.28 g) were weighed respectively. , 12.1mmol) was added to the reaction system, replaced with nitrogen protection, and the temperature was slowly raised to 80℃, refluxed and stirred for 6h, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, and EA (20mL*2) was used for extraction. The organic phases were combined, washed with saturated brine (30mL*2), and evaporated under reduced pressure. Purification was carried out by ISCO column chromatography (0-100% EA / PE) to obtain 0.31g of (2-amino-5-(pyridin-3-yl)phenyl)dimethylphosphine oxide, MS m / z (ESI): 249[M+H] + .

[0437] Step 3: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminobenzylbenzyl ester

[0438] 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] + .

[0439] Step 4: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid

[0440] 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminobenzyl benzyl ester (87.0 mg, 0.14 g) was dissolved in methanol (6 mL), PdOH / C (200 mg) was added, H2 was replaced, and the reaction was allowed to proceed overnight under a H2 atmosphere. The reaction was monitored by TLC to be complete. The system was filtered to give 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] + .

[0441] Step 5: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0442] 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 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 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] + .

[0443] Example 22

[0444] Preparation of (2-amino-5-(4,4,5,5-tetramethyl-1,3-dioxo-2-borolan-2-yl)phenyl)dimethylphosphine oxide

[0445]

[0446] Step 1: (2-amino-5-bromophenyl)dimethylphosphine oxide

[0447] 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. The atmosphere was replaced with nitrogen for protection. The temperature was slowly raised to 120°C and refluxed with stirring for 4 h. The reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was filtered through celite and extracted with DCM (200 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 2), evaporated 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] + .

[0448] Step 2: (2-amino-5-(4,4,5,5-tetramethyl-1,3-dioxo-2-borolan-2-yl)phenyl)dimethylphosphine oxide

[0449] 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 celite and 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] + .

[0450] Preparation of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide (22)

[0451]

[0452] Step 1: Synthesis of (2-amino-5-(pyridin-2-yl)phenyl)dimethylphosphine oxide

[0453] (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) were dissolved in a mixed solution of 1,4-dioxane (50 mL) and water (5 mL). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.14 g, 0.17 mmol) was weighed and added. l) and cesium carbonate (1.4 g, 4.25 mmol) were added to the reaction system, and the nitrogen atmosphere was replaced. The temperature was slowly raised to 120°C and refluxed with stirring for 6 h. The reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was filtered through celite 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]. + .

[0454] Step 2: Synthesis of benzyl 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate

[0455] (2-Amino-5-(pyridin-2-yl)phenyl)dimethylphosphine oxide (185 mg, 0.75 mmol) was dissolved in 1,4-dioxane (10 mL), and benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (306 mg, 0.75 mmol) was added. p-Toluenesulfonic acid (143 mg, 0.75 mmol) was added, and the mixture was heated to 120°C for 20 h. The reaction was monitored for completion. The mixture was quenched with water, extracted with dichloromethane (20 mL × 2), dried, concentrated, and purified by column chromatography to obtain 200 mg of benzyl 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate. MS m / z (ESI): 618 [M+H]. + .

[0456] Step 3: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid

[0457] Benzyl 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (200 mg, 0.324 mmol) was dissolved in methanol (30 mL) and palladium hydroxide / carbon (200 mg) was added. The mixture was reacted under a H2 atmosphere for 5 h. The reaction was monitored by TLC to be complete. The system was filtered and the filtrate was distilled under reduced pressure to give 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] + .

[0458] Step 4: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0459] 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(400MHz,DMSO-d6)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),8.1 0(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] + .

[0460] Example 23

[0461] Preparation of 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide (23)

[0462]

[0463] Step 1: Synthesis of (2-amino-5-bromophenyl)dimethylphosphine oxide

[0464] 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), K3PO4 (5.09 g, 24.2 mmol) and Xantphos (1.16 g, 2.01 mol) were weighed and added to the reaction system. The atmosphere was replaced with nitrogen for protection. The temperature was slowly raised to 125°C and the mixture was stirred under reflux for 6 h. The reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was filtered through celite 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) gave 3.2 g of (2-amino-5-bromophenyl)dimethylphosphine oxide, MS m / z (ESI): 249 [M+H]. + .

[0465] Step 2: Synthesis of (2-amino-5-(1-methyl-1H-pyrazol-4-yl)phenyl)dimethylphosphine oxide

[0466] 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 / H2O (5:1) solution (40 mL), and Pd(dppf)Cl2 (329.9 mg, 0.4 mol) and Na2(CO3)2 (1.3 g, The reaction system was added with 1-hydroxy-2-nitro-1-propene-2-nitropropene (12.1 mmol) and nitrogen was replaced. The temperature was slowly raised to 80°C and stirred under reflux for 2 h. The reaction was monitored by TLC. After the reaction was completed, 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 obtain 0.3 g of (2-amino-5-(1-methyl-1H-pyrazol-4-yl)phenyl)dimethylphosphine oxide, MS m / z (ESI): 250 [M+H] + .

[0467] Step 3: Synthesis of benzyl 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminobenzoate

[0468] Compound (2-amino-5-(1-methyl-1H-pyrazol-4-yl)phenyl)dimethylphosphine oxide (113.1 mg, 0.45 mmol) and benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (167.2 g, 0.41 mmol) were dissolved in 1,4-dioxane solution (10 mL), TsOH (38.9 mg, 0.21 mmol) was added, nitrogen protection was replaced, 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 for quenching, 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] + .

[0469] Step 4: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminobenzoic acid

[0470] 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, H2 was replaced, and the reaction was allowed to proceed overnight under a H2 atmosphere. The reaction was monitored by TLC to be complete. 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] + .

[0471] 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

[0472] 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 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 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(400MHz,DMSO-d6)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] + .

[0473] Example 24

[0474] Preparation of 4-((4-((2-(dimethylphosphoryl)-4-(2-(methylamino)pyrimidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide (24)

[0475]

[0476] Step 1: Synthesis of (2-amino-5-(2-(methylamino)pyrimidin-4-yl)phenyl)dimethylphosphine oxide

[0477] (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) were dissolved in a mixed solution of 1,4-dioxane (50 mL) and water (5 mL). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.14 g, 0.17 mmole) was weighed. 1-[(2-amino-5-(2-(methylamino)pyrimidin-4-yl)phenyl)-1-dimethylphosphine oxide] 0.4 g was obtained. MS m / z (ESI): 277 [M+H] + .

[0478] Step 2: Synthesis of benzyl 4-((4-((2-(dimethylphosphoryl)-4-(2-(methylamino)pyrimidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate

[0479] (2-Amino-5-(2-(methylamino)pyrimidin-4-yl)phenyl)dimethylphosphine oxide (110 mg, 0.4 mmol) was dissolved in 1,4-dioxane (10 mL), and benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (148 mg, 0.36 mmol) was added. p-Toluenesulfonic acid (68 mg, 0.36 mmol) was added, and the temperature was raised to 120°C for 20 h. The reaction was monitored for completion. The 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]. + .

[0480] Step 3: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(2-(methylamino)pyrimidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid

[0481] 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 under a H2 atmosphere for 5 h. The reaction was monitored by TLC to be complete. The system was filtered and the filtrate was distilled under reduced pressure to give 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] + .

[0482] Step 4: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(2-(methylamino)pyrimidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0483] 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), and the organic phase was washed with water, dried, 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. 1H NMR (400MHz, DMSO-d6) 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] + .

[0484] Example 25

[0485] Preparation of 4-((4-((2-(dimethylphosphoryl)-4-fluorophenyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide (25)

[0486]

[0487] Step 1: Synthesis of (2-amino-5-fluorophenyl) dimethylphosphine oxide

[0488] 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), K3PO4 (2.15 g, 10.1 mmol) and Xantphos (486.0 mg, 0.84 mol) were weighed and added to the reaction system. The atmosphere was replaced with nitrogen for protection. The temperature was slowly raised to 125°C and refluxed with stirring for 6 h. The reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was filtered through celite 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] + .

[0489] Step 2: Synthesis of benzyl 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminobenzoate

[0490] The 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, and the temperature was slowly raised to 125°C for 18 h. The reaction was monitored by TLC. 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. Purification by ISCO column chromatography gave 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]. + .

[0491] Step 3: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminobenzoic acid

[0492] 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, H2 was replaced, and the reaction was allowed to proceed overnight under a H2 atmosphere. The reaction was monitored by TLC to be complete. 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] + .

[0493] Step 4: Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-fluorophenyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0494] 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(400MHz,DMSO-d6)δ11.59(s,1H),10.31(s,1H),10.08(s,1H),8.48(s,1H),8.12(s,1 H),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] + .

[0495] Example 26

[0496] Preparation of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide (26)

[0497]

[0498] Step 1: Synthesis of 4-bromo-2,3-dihydro-7-benzofuranamine

[0499] Compound 2,3-dihydro-7-benzofuranamine (5 g, 37 mmol) was dissolved in DMF (50 mL) and NBS (7.2 g, 41 mmol) was added portionwise. The mixture was stirred at room temperature overnight. After TLC monitoring, the reaction was quenched with water and extracted with EA (30 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 2), and evaporated under reduced pressure. Purification was performed by ISCO column chromatography (EA / PE 0%-100%) to obtain 4.4 g of pure 4-bromo-2,3-dihydro-7-benzofuranamine. MS m / z (ESI): 215 [M+H] + .

[0500] Step 2: Synthesis of 7-amino-2,3-dihydro-ethyl ester

[0501] Compound 4-bromo-2,3-dihydro-7-benzofuranamine (4 g, 18.9 mmol) was dissolved in toluene / ethanol (5:1) solution (40 mL). DMAP (9.76 g, 80 mmol), Pd(OAC)2 (240 mg, 5 mol%), Co2(CO)8 (5.45 g, 16 mmol) and Xantphos (1.27 g, 10 mol%) were weighed and added to the reaction system. The atmosphere was replaced with nitrogen for protection. The temperature was slowly raised to 105°C and the mixture was stirred under reflux overnight. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered through celite and the filtrate was quenched with aqueous hydrochloric acid (pH = 4). The filtrate was 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 gave 2.00 g of pure 7-amino-2,3-dihydro-ethyl ester, MS m / z (ESI): 208 [M+H]. + .

[0502] Step 3: Synthesis of 7-amino-2,3-dihydro-4-benzofurancarboxylic acid

[0503] Compound 7-amino-2,3-dihydro-ethyl ester (2 g, 9.66 mmol) was dissolved in ethanol (20 mL) and saturated NaOH solution (30 mL) was added. The temperature was slowly raised to 60°C and stirred for 4 h. After the reaction was completed, the mixture was diluted with water and the pH was adjusted to acidic. The mixture was extracted with ethyl acetate (40 mL*3). The organic phases were combined, washed with saturated brine (50 mL*2), and evaporated under reduced pressure. Purification by ISCO column chromatography yielded 1.00 g of 7-amino-2,3-dihydro-4-benzofurancarboxylic acid. MS m / z (ESI): 178 [M+H] + .

[0504] Step 4: Synthesis of 7-amino-N-methyl-2,3-dihydrobenzofuran-4-carboxamide

[0505] 7-Amino-2,3-dihydro-4-benzofurancarboxylic acid (1 g, 5.58 mmol) was added to a 250 mL sealed reactor and dissolved in DMF (3 mL). Methylamine hydrochloride (1.5 g, 22.32 mmol), DIPEA (4 mL, 22.32 mmol), and HATU (2.54 g, 6.7 mmol) were weighed and added to the round-bottom flask. The temperature was raised to 115°C and the reaction was stirred overnight. After completion of the reaction, the mixture was extracted with EA and water. The organic phase was washed twice with saturated brine and dried. The residue was purified by column chromatography to obtain 400 mg of pure 7-amino-N-methyl-2,3-dihydrobenzofuran-4-carboxamide. MS m / z (ESI): 193 [M+H]. + .

[0506] Step 5: Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide

[0507] 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 (400MHz, DMSO-d6) 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] + .

[0508] Example 27

[0509] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-3-methoxybenzamide (27)

[0510]

[0511] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-3-methoxybenzamide

[0512] 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 HNMR(400MHz,DMSO-d6)δ11.58(s,1H),10.72(s,1H),8.59(s,1H),8.44(s, 1H),8.15(s,1H),7.88(d,J=8.3Hz,1H),7.66–7.55(m,1H),7.48(t,J=7.8Hz ,1H),7.42(d,J=1.7Hz,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 = 6.7Hz, 6H). MS m / z(ESI): 552[M+H] + .

[0513] Example 28

[0514] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-hydroxy-3-methoxybenzamide (28)

[0515]

[0516] Step 1: Synthesis of N-(benzyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxybenzamide

[0517] 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 the mixture was 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to give 60.1 mg of N-(benzyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxybenzamide. MS m / z(ESI):586[M+H] + .

[0518] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-hydroxy-3-methoxybenzamide

[0519] 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), and 10% Pd / C (20 mg) was added. The mixture was reacted overnight under a H2 atmosphere. After the reaction was completed as monitored by LCMS, the mixture was filtered through celite and evaporated under reduced pressure to give 25.1 mg of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-hydroxy-3-methoxybenzamide. 1H NMR (400MHz, DMSO-d6) 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=8.3Hz,1H),7. 60(dd,J=13.5,7.7Hz,1H),7.48(t,J=7.8Hz,1H),7.43(d,J=1.6Hz,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] + .

[0520] Example 29

[0521] Preparation of N-(propyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (29).

[0522]

[0523] Step 1: Synthesis of N-(propyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide

[0524] 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 the reaction was carried out 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), and the organic phase was washed with water, dried, concentrated, and purified by column chromatography with MeOH / DCM (0-10%) to give 23 mg of N-(propyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. 1H NMR (400MHz, DMSO-d6) 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=6.6Hz,2H),1.75(s,3H),1.71(s,3H),1.66–1.56(m,2H),0.95(t,J=7.4Hz,3H),0.84(qd,J=6.6,4.0Hz,2H). MS m / z(ESI): 508[M+H] + .

[0525] Example 30

[0526] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isopropoxybenzamide (30)

[0527]

[0528] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isopropoxybenzamide

[0529] 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 the reaction was carried out 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), and the organic phase was washed with water, dried, concentrated, and purified by column chromatography with MeOH / DCM (0-10%) to give 35 mg of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isopropoxybenzamide. 1H NMR (400MHz, DMSO-d6) δ11.27(s,1H),10.58(s,1H),10.06(s,1H),8.49(s,1H),8.17(s,1H),7.65(ddd,J=14.5,10.8 ,6.5Hz,6H),7.32(t,J=7.4Hz,1H),4.11(dt,J=12.4,6.2Hz,1H),1.75(s,3H),1.72(s,3H),1.20(s,3H),1.19(s,3H). MS m / z(ESI): 508[M+H] + .

[0530] Example 31

[0531] Preparation of N-(cyclopropylmethoxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (31)

[0532]

[0533] Step 1: Synthesis of N-(cyclopropylmethoxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide

[0534] 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 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 42.1 mg N-(Cyclopropylmethoxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. 1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.57(s,1H),10.07(s,1H),8.49(s,1H),8.16(s,1H),7.75–7.49(m,3H) ,7.32(t,J=7.2Hz,1H),3.69(d,J=7.2Hz,1H),1.75(s,1H),1.71(s,1H),0.59–0.45(m,1H),0.34–0.18(m,1H). MS m / z(ESI): 520[M+H] + .

[0535] Example 32

[0536] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide (32)

[0537]

[0538] Step 1: 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid

[0539] 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (60.3 g, 0.17 mmol) and p-amino-3-methoxybenzoic acid (33.4 mg, 0.18 mmol) were dissolved in isopropanol (6 mL). A 4N hydrochloric acid solution in 1,4-dioxane (0.1 mL, 0.4 mmol) was added. The mixture was reacted at 70°C for 4 h and the reaction was monitored for completion. 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] + .

[0540] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide

[0541] 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 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-isobutoxy-5-methoxybenzamide. 1 HNMR(400MHz,DMSO-d6)δ11.30(s,1H),10.71(s,1H),8.54(s,1H),8.50(s,1H),8 .15(d,J=4.0Hz,1H),7.88(d,J=12.1Hz,1H),7.64(dd,J=13.4,7.7Hz,1H),7.54(t ,J=7.7Hz,1H),7.27(t,J=7.3Hz,1H),7.17(d,J=6.3Hz,1H),3.86(s,3H),3.67(d, J=6.6Hz,2H),2.00–1.86(m,1H),1.75(s,3H),1.72(s,3H),0.94(d,J=6.6Hz,6H). MS m / z(ESI):570[M+H] + .

[0542] Example 33

[0543] Preparation of 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0544]

[0545] Step 1: Synthesis of (2-hydroxyphenyl)dimethylphosphine oxide

[0546] 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 atmosphere was replaced with nitrogen for protection. The temperature was slowly raised to 120°C and refluxed with stirring for 6 h. The reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was filtered through celite 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] + .

[0547] Step 2: Synthesis of benzyl 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate

[0548] 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), and heat to 120°C for 14 h. Monitor the reaction until complete. Quench with water, extract with dichloromethane (20 mL × 2), dry, concentrate, and column chromatography to obtain 50 mg of benzyl 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate. MS m / z (ESI): 542 [M+H]. + .

[0549] Step 3: Synthesis of 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid

[0550] Benzyl 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate (50 mg, 0.092 mmol) was dissolved in methanol (10 mL) and palladium hydroxide / carbon (50 mg) was added. The mixture was reacted under a H2 atmosphere for 15 h. The reaction was monitored by TLC to be complete. The system was filtered and the filtrate was evaporated under reduced pressure to give 42 mg of 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid. MS m / z (ESI): 452 [M+H] + .

[0551] Step 4: Synthesis of 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0552] 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] +

[0553] Example 34

[0554] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2-methylbenzamide (34)

[0555]

[0556] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylbenzoic acid

[0557] (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 the mixture was reacted at 60°C for 4 h. After completion of the reaction 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 give 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]. + .

[0558] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2-methylbenzamide

[0559] 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(400MHz,DMSO-d6)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=7.8Hz,1H),7.49(s,1H),7.45(s ,1H),7.29(t,J=7.6Hz,1H),7.14(d,J=8.3Hz,1H),3.65(d,J=6.7Hz,2H),2.2 1(s,3H),1.97–1.86(m,1H),1.74(d,J=13.5Hz,6H),0.93(d,J=6.7Hz,6H).MS m / z(ESI):536.2[M+H] + .

[0560] Example 35

[0561] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxybenzamide

[0562]

[0563] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorobenzoic acid

[0564] (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 reaction 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 give 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] + .

[0565] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxybenzamide

[0566] 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, 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. 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),10.57(s,1H),10.22(s,1H),8.52(s,1H),8.13(s,1H),7.73–7.64(m,2H),7.61(t,J=7.9Hz,1H),7.41(q,J= 7.9,7.3Hz,2H),7.32(t,J=7.6Hz,1H),3.65(d,J=6.6Hz,2H),1.91(td,J =13.2,12.5,5.6Hz,1H),1.73(d,J=13.6Hz,6H),0.93(d,J=6.7Hz,6H).MS m / z(ESI):540[M+H] + .

[0567] Example 36

[0568] Preparation of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-methoxybenzamide (36)

[0569]

[0570] Step 1: Synthesis of (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0571] 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-cooling. The mixture was reacted at room temperature for 5 h and monitored for completion. Water was added and the mixture was extracted with dichloromethane. The mixture was dried and concentrated. Column chromatography was performed to obtain 230 mg of (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS m / z (ESI): 316.0 [M+H] + .

[0572] Step 2: Synthesis of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid

[0573] (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). A 4N hydrochloric acid solution in 1,4-dioxane (63.7 μL) was added and the mixture was reacted at 70°C for 14 h. The reaction was monitored for completion. 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] + .

[0574] Step 3: Synthesis of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0575] 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-cooling. The mixture was allowed to react at room temperature for 1 h. Methoxyamine hydrochloride (32.52 mg, 0.39 mmol) and DMAP (0.24 mg, 0.002 mmol) were then added. The reaction was allowed to react at room temperature overnight and monitored for completion. Water was added, the mixture was extracted with DCM, dried, 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] + .

[0576] Example 37

[0577] Preparation of (E)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzoyl chloride (37)

[0578]

[0579] Step 2: Synthesis of (E)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzoyl chloride

[0580] 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 POCl3 (6 mL) and heated under reflux to react 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 product was purified by ISCO column chromatography using MeOH / DCM (0-10%) to give 15.1 mg of (E)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzoyl chloride. 1 H NMR (400MHz, DMSO-d6): δ10.71(s,1H),8.64(s,1H),8.45(s,1H),8.14(s,1H),7.90(d,J=8.6Hz,1H),7.67–7.52(m,1H ),7.46(t,J=7.9Hz,1H),7.37(d,J=1.9Hz,1H),7.29–7.21(m,2H),4.06(s,3H),3.87(s,3H),1.75(s,3H),1.71(s,3H). MS m / z(ESI): 528[M+H] + .

[0581] Example 38

[0582] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-methoxyethoxy)benzamide (38)

[0583]

[0584] 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 reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL) and extracted with EA (20 mL×3). The organic phase was washed with water, dried, concentrated, and purified by column chromatography with MeOH / DCM (0-10%) to give 45.0 mg of the product. 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-methoxyethoxy)benzamide. 1 H NMR(400MHz,DMSO-d6)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),7.9 1(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):524.2[M+H] + .

[0585] Example 39

[0586] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxy-2-methylpropoxy)benzamide (39)

[0587]

[0588] 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 reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL) and extracted with EA (20 mL×3). The organic phase was washed with water, dried, concentrated, and purified by column chromatography using MeOH / DCM (0-10%) to give 63.1 mg of the product. 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxy-2-methylpropyloxy)benzamide. 1 H NMR(400MHz,DMSO-d6)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=7.4 Hz,1H),7.02(d,J=8.3Hz,1H),4.51(t,J=8.8Hz,2H),3.66(d,J=6.7Hz,2H),3.4 0(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] + .

[0589] Example 40

[0590] Preparation of 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxynicotinamide (40)

[0591]

[0592] Step 1: Synthesis of 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminomethylnicotinate

[0593] 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (120 mg, 0.35 mmol) and methyl 6-aminonicotinate (55.9 mg, 0.38 mmol) were dissolved in isopropanol (14 mL). A 4N hydrochloric acid solution in 1,4-dioxane (0.12 mL, 0.48 mmol) was added. The mixture was reacted at 70°C for 4 h and monitored for completion. The reaction was filtered to obtain 100 mg of methyl 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminomethylnicotinate. MS m / z (ESI): 466.2 [M+H] + .

[0594] Step 2: Synthesis of 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)nicotinic acid

[0595] 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 a (5 mL) aqueous solution. The temperature was slowly raised to 65°C and stirred for 4 hours. After the reaction was completed, the mixture was diluted with water and the pH was adjusted to acidic. The mixture was 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] + .

[0596] Step 3: Synthesis of 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxynicotinamide

[0597] 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 reacted at room temperature for 16 h. After the reaction was completed as monitored by LCMS, the reaction was quenched with water (10 mL) and extracted with EA (20 mL×3). The combined organic phases were washed with water, dried, concentrated, and purified by column chromatography using MeOH / DCM (0-10%) to obtain 32.1 mg of the product. 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxynicotinamide. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0598] Example 41

[0599] Preparation of 5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxypicolinamide (41)

[0600]

[0601] Step 1: Synthesis of 5-amino-N-isobutoxypicolinamide

[0602] 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 reacted at room temperature for 16 h. After completion of the reaction as monitored by LCMS, the reaction was quenched with water (10 mL) and extracted with EA (20 mL×3). The combined organic phases were washed with water, dried, concentrated, and purified by column chromatography with MeOH / DCM (0-10%) to give 150 mg of 5-amino-N-isobutoxypicolinamide. MS m / z (ESI): 210.1 [M+H] + .

[0603] Step 2: Synthesis of 5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxypicolinamide

[0604] 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 Pd2(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. The mixture was replaced with nitrogen for protection. The mixture was heated to 105 ° C. under N2 atmosphere and stirred overnight. After LCMS monitoring, the reaction was completed, and dichloromethane was added to dilute it. The reaction was quenched with saturated NaHCO3 and extracted with DCM (20 mL×3). The organic phases were combined, washed with water, washed with saturated brine, dried, 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. 1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),10.65(s,1H),10.26(s,1H),8.75(s,1 H),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),1.9 1(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] + .

[0605] Example 42

[0606] Preparation of 2-((2-(((4-(methoxycarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl dimethylphosphonate (42)

[0607]

[0608] Step 1: Synthesis of dimethyl (2-aminophenyl)phosphonate

[0609] 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)Cl2 (1.5 g, 1.83 mol) and K3PO4 (9.7 g, 45.7 mmol) were weighed and added to the reaction system. The nitrogen atmosphere was replaced and the temperature was slowly raised to 105°C, and the mixture was refluxed and stirred for 13 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 celite 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 gave 0.71 g of dimethyl (2-aminophenyl)phosphonate, MS m / z (ESI): 202.0 [M+H]. + .

[0610] Step 2: Synthesis of dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate

[0611] 2,4-Dichloropyrimidine-5-trifluoromethyl (0.71 g, 3.55 mmol) was dissolved in EtOH (20 mL), and dimethyl (2-aminophenyl)phosphonate (0.7 g, 3.2 mmol) was added. NaHCO3 (542.7 mg, 6.5 mmol) was slowly added under ice bath conditions. The temperature was raised to 50°C and the reaction was allowed to react for 1 h. The reaction was monitored for completion. Water was added to quench the reaction, and dichloromethane was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 95.3 mg of dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate. MS m / z (ESI): 382.0 [M+H] + .

[0612] Step 3: Synthesis of 4-((4-((2-(dimethoxyphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid

[0613] Dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate (124.8 mg, 0.33 mmol) and p-aminobenzoic acid (44.9 mg, 0.33 mmol) were dissolved in isopropanol (10 mL). A 4N hydrochloric acid solution in 1,4-dioxane (0.1 mL) was added and the mixture was reacted at 65°C for 4 h. The reaction was monitored for completion. The system was filtered 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] + .

[0614] Step 4: 2-((2-(((4-(methoxycarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl dimethylphosphonate

[0615] 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 the mixture was 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to give 28.6 mg of 2-((2-(((4-(methoxycarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl dimethylphosphonate. 1H NMR (400MHz, DMSO-d6) 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): 512.1[M+H] + .

[0616] Example 43

[0617] Preparation of (2-((2-(((4-(isobutoxycarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl dimethylphosphonate (43)

[0618]

[0619] Step 1: (2-((2-(((4-(isobutoxycarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl dimethylphosphonate

[0620] 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 the mixture was 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to give 40 mg of (2-((2-(((4-(isobutoxycarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl dimethylphosphonate. 1H NMR (400MHz, DMSO-d6) δ11.47(s,1H),10.11(s,1H),9.32(s,1H),8.51(s,1H),8.15(s,1H),7.74(dd,J=14.7,7.3Hz,2H),7. 59(t,J=14.0Hz,4H),7.41(td,J=7.7,3.5Hz,1H),3.68–3.60(m,8H),1.92(td,J=13.4,6.7Hz,1H),0.94(d,J=6.7Hz,6H).MS m / z(ESI):554.2[M+H] + .

[0621] Example 44

[0622] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N,5-dimethoxybenzamide (44)

[0623]

[0624] Step 1: 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N,5-dimethoxybenzamide

[0625] 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 the mixture was 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to give 53.2 mg of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N,5-dimethoxybenzamide. 1H NMR (400MHz, DMSO-d6) 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] + .

[0626] Example 45

[0627] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxy-2-fluoro-5-methoxybenzamide (45)

[0628]

[0629] Step 1: 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxy-2-fluoro-5-methoxybenzamide

[0630] 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 the mixture was 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to give 48.2 mg of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxy-2-fluoro-5-methoxybenzamide. 1H NMR(400MHz,DMSO-d6)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),7.9 1(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] + .

[0631] Example 46

[0632] Preparation of 7-(((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxy-2,3-dihydrobenzofuran-4-carboxamide (46)

[0633]

[0634] Step 1: Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid

[0635] 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (120 mg, 0.35 mmol) and 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid (63.4 mg, 0.38 mmol) were dissolved in isopropanol (14 mL). A 4N hydrochloric acid solution in 1,4-dioxane (0.12 mL, 0.48 mmol) was added. The mixture was reacted at 70°C for 4 h and the reaction was monitored for completion. 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] + .

[0636] Step 2: Synthesis of 7-(((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxy-2,3-dihydrobenzofuran-4-carboxamide

[0637] 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(400MHz,DMSO-d6)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=7.4 Hz,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] + .

[0638] Example 47

[0639] Preparation of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2,3-dihydrobenzofuran-4-carboxamide (47)

[0640]

[0641] Step 1: Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2,3-dihydrobenzofuran-4-carboxamide

[0642] 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(400MHz,DMSO-d6)δ11.40(s,1H),10.82(s,1H),9.11(s,1H),8.39(s,1H),8.24(s, 1H),7.55(dd,J=13.7,7.7Hz,1H),7.37(d,J=7.8Hz,2H),7.16(t,J=7.4Hz,1H),7.02(d, J=8.3Hz,1H),4.51(t,J=8.8Hz,2H),3.66(d,J=6.7Hz,2H),3.40(t,J=8.8Hz,2H),2.01 –1.88(m,2H),1.75(s,3H),1.72(s,3H),0.95(d,J=6.7Hz,6H).MSm / z(ESI):564.2[M+H] + .

[0643] Example 48

[0644] Preparation of 4-((5-chloro-4-((2-(1-phosphinyl-1-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide (48)

[0645]

[0646] Step 1: Synthesis of diallylphosphine oxide

[0647] At 0°C, a solution of allylmagnesium bromide in tetrahydrofuran (1M, 65.1 mL) was added dropwise to a solution of dimethyl phosphate (3.0 g, 21.7 mmol) in Et2O (5 mL). The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 1 hour. A solution of K2CO3 (4.3 g, 54.8 mmol) in water (1.1 mL) was then added to the reaction system at 0°C and stirred for 10 minutes. The reaction mixture was filtered, washed with ethanol, and the filtrate was concentrated. The crude product was slurried with diethyl ether (2*10 mL), filtered, and the filtrate was concentrated to obtain diallylphosphine oxide, which was used directly in the next reaction. MS m / z (ESI): 131.0 [M+H] + .

[0648] Step 2: Synthesis of diallyl(2-aminophenyl)phosphine oxide

[0649] 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). Pd(OAc)2 (345.7 mg, 1.54 mmol), K3PO4 (6.5 g, 30.8 mmol) and Xantphos (1.78 g, 3.08 mol) were weighed and added to the reaction system. The atmosphere was replaced with nitrogen for protection. The temperature was slowly raised to 125°C and the mixture was stirred under reflux for 6 h. The reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was filtered through celite 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 gave 1.8 g of diallyl(2-aminophenyl)phosphine oxide, MS m / z (ESI): 222.1 [M+H]. + .

[0650] Step 3: Synthesis of benzyl (2-(diallylphosphoryl)phenyl]carbamate

[0651] 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 in an ice bath. The mixture was allowed to react for 1 h at room temperature and monitored for completion. The reaction was quenched with water, extracted with dichloromethane, dried, concentrated, and purified by ISCO column chromatography to give 1.6 g of benzyl (2-(diallylphosphoryl)phenyl)carbamate. MS m / z (ESI): 356.1 [M+H] + .

[0652] Step 4: Synthesis of benzyl (2-(1-oxido-2,5-dihydrophosphin-1-yl)phenyl]carbamate

[0653] Benzyl (2-(diallylphosphoryl)phenyl]carbamate (2.6 g, 7.2 mmol) was dissolved in toluene (25 mL) and the air was replaced with nitrogen. Grubbs first-generation catalyst (595.8 mg, 0.72 mmol) was then added to the reaction system and refluxed at 110°C for 12 h. The reaction was complete as monitored by LCMS. Water (10 mL) was added to quench the reaction and the mixture was extracted with DCM (20 mL*2). The organic phase was washed with water, dried, and concentrated. ISCO column chromatography gave 2.1 g of benzyl (2-(1-oxido-2,5-dihydrophosphin-1-yl)phenyl]carbamate, MS m / z (ESI): 328.1 [M+H] + .

[0654] Step 5: Synthesis of 1-(2-aminophenyl)phosphine epoxide

[0655] Benzyl (2-(1-oxido-2,5-dihydrophosphin-1-yl)phenyl)carbamate (2.1 g, 6.4 mmol) was dissolved in MeOH (30 mL) and 10% Pd / C (400 mg) was added. The mixture was reacted overnight under a H2 atmosphere. After completion of the reaction 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] + .

[0656] Step 6: Synthesis of 1-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)phosphine 1-oxide

[0657] 2,4-Dichloropyrimidine-5-trifluoromethyl (552.1 mg, 3.0 mmol) was dissolved in EtOH (20 mL), 1-(2-aminophenyl)phosphine epoxide (587.1 mg, 3.0 mmol) was added, and NaHCO3 (504.0, 6.0 mmol) was slowly added under ice-cooling conditions. The temperature was raised to 85°C and the reaction was allowed to react for 1 h. The reaction was monitored for completion. Water was added to quench the reaction, and dichloromethane was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 340 mg of 1-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)phosphine 1-oxide. MS m / z (ESI): 342.0 [M+H] + .

[0658] 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

[0659] 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 Pd2(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 and heated to 105°C under N2 atmosphere and stirred overnight. After the reaction was completed as monitored by LCMS, dichloromethane was added for dilution, saturated NaHCO3 was quenched, and DCM (20 mL×3) was extracted. The combined organic phases were washed with water and saturated brine, dried and concentrated, and purified by column chromatography with MeOH / DCM (0-10%) to obtain 15.1 mg 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-d6)δ11.66(s,1H),10.81(s,1H),10.51(s,1H),8.66(d ,J=2.2Hz,1H),8.54(s,1H),8.47–8.35(m,1H),8.03(d,J=8.8Hz,1H),7.96 –7.85(m,1H),7.70–7.53(m,2H),7.31(t,J=7.4Hz,1H),3.67(d,J=6.6Hz, 3H),2.00–1.89(m,2H),1.76(s,3H),1.72(s,3H),0.94(d,J=6.7Hz,7H).MS m / z(ESI):562.2[M+H] + .

[0660] Example 49

[0661] Preparation of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethyl-2,3-dihydrobenzofuran-4-carboxamide (49)

[0662]

[0663] Step 1: Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethyl-2,3-dihydrobenzofuran-4-carboxamide

[0664] 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-d6)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=6.7 Hz, 2H), 3.40 (t, J = 8.8 Hz, 2H), 2.01–1.88 (m, 2H), 1.75 (s, 3H), 1.72 (s, 3H). MS m / z(ESI):520.1[M+H] + .

[0665] Example 50

[0666] Preparation of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide (50)

[0667]

[0668] Step 1: Synthesis of N-(4-methoxybenzyl)benzofuran-7-amine

[0669] 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). Pd2(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. The atmosphere was replaced with nitrogen for protection. The temperature was slowly raised to 105°C and refluxed with stirring for 16 h. The reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was filtered through celite 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 gave 5.1 g of N-(4-methoxybenzyl)benzofuran-7-amine, MS m / z (ESI): 256.1 [M+H]. + .

[0670] Step 2: Synthesis of benzofuran-7-amine

[0671] Dissolve N-(4-methoxybenzyl)benzofuran-7-amine (4.5 g, 17.8 mmol) in MeOH (10 mL) and add 10% Pd / C (675 mg). Allow to react overnight under a H2 atmosphere. After completion of the reaction as monitored by LCMS, filter through Celite and evaporate under reduced pressure to yield 2.65 g of benzofuran-7-amine. MS m / z (ESI): 134.0 [M+H] + .

[0672] Step 3: Synthesis of 4-iodobenzofuran-7-amine

[0673] Benzofuran-7-amine (200 mg, 1.5 mmol) and calcium carbonate (195 mg, 1.95 mmol) were dissolved in a mixed solvent of methanol (5 mL) and dichloromethane (10 mL). The temperature was lowered to 0°C, and benzyltrimethylammonium dichloroiodate (520 mg, 1.5 mmol) was slowly added in batches. The reaction was allowed to react at 0°C for 1.5 h, and the reaction was monitored for completion. The mixture was quenched with water, filtered through celite, extracted with DCM (20 mL*2), and the organic phases were combined, washed with saturated brine (30 mL*2), evaporated under reduced pressure, and purified by ISCO column chromatography to obtain 250 mg of 4-iodobenzofuran-7-amine. MS m / z (ESI): 260.1 [M+H] + .

[0674] Step 4: Synthesis of ethyl 7-aminobenzofuran-4-carboxylate

[0675] The compound 4-iodobenzofuran-7-amine (416.1 mg, 1.6 mmol) was dissolved in ethanol solution (30 mL), and Pd(PPh3)2Cl2 (112.3 mg, 0.16 mol) and Et3N (0.5 mL, 3.2 mmol) were weighed and added to the reaction system to replace the CO gas. Under a 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 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. Purification by ISCO column chromatography gave 69.2 mg of ethyl 7-aminobenzofuran-4-carboxylate, MS m / z (ESI): 206.2 [M+H] + .

[0676] Step 5: Synthesis of 7-amino-4-benzofurancarboxylic acid

[0677] Compound 7-aminobenzofuran-4-carboxylic acid ethyl ester (2 g, 9.66 mmol) was dissolved in a mixture of THF (10 mL) and methanol (5 mL). LiOH (50.8 mg, 2.12 mmol) was dissolved in a 5 mL aqueous solution. The temperature was slowly raised to 65°C and stirred for 4 h. After completion of the reaction, the mixture was diluted with water and the pH was adjusted to acidic. The mixture was extracted with ethyl acetate (40 mL*3). The organic phases were combined, washed with saturated brine (50 mL*2), and evaporated under reduced pressure. Purification by ISCO column chromatography yielded 96.2 mg of 7-amino-4-benzofurancarboxylic acid. MS m / z (ESI): 178.0 [M+H]. + .

[0678] Step 6: Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzofuran-4-carboxylic acid

[0679] 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (100 mg, 0.29 mmol) and 7-amino-4-benzofurancarboxylic acid (50.6 mg, 0.29 mmol) were dissolved in isopropanol (5 mL). A 4N hydrochloric acid solution in 1,4-dioxane (0.1 mL, 0.48 mmol) was added. The mixture was reacted at 70°C for 4 h and the reaction was monitored for completion. 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] + .

[0680] Step 7: Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzofuran-4-carboxamide

[0681] 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(400MHz,DMSO-d6)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):520.4[M+H] + .

[0682] Example 51

[0683] Preparation of 4-((2-(dimethylphosphoryl)phenyl)amino)-2-((4-(methoxycarbamoyl)phenyl)amino)-N-methylpyrimidine-5-carboxamide (51)

[0684]

[0685] Step 1: Synthesis of methyl 2-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-5-carboxylate

[0686] (2-Aminophenyl)dimethylphosphine oxide (300 mg, 1.77 mmol), methyl 2,4-dichloropyrimidine-5-carboxylate (365 mg, 1.77 mmol) and NaHCO3 (297 mg, 3.54 mmol) were dissolved in ethanol (6 mL) and reacted at room temperature for 5 h. The reaction was monitored for completion. 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] + .

[0687] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(methoxycarbonyl)pyrimidin-2-yl)amino)benzoic acid

[0688] Methyl 2-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-5-carboxylate (300 mg, 0.88 mmol) and p-aminobenzoic acid (146 mg, 1.06 mmol) were dissolved in isopropanol (10 mL). A 4N hydrochloric acid solution in 1,4-dioxane (0.22 mL) was added and the mixture was reacted at 70°C for 6 h. The reaction was monitored for completion. 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] + .

[0689] Step 3: Synthesis of methyl 4-((2-(dimethylphosphoryl)phenyl)amino)-2-((4-(methoxycarbamoyl)phenyl)amino)pyrimidine-5-carboxylate

[0690] 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 at room temperature overnight and monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried and concentrated, and column chromatography was performed to give 375 mg of methyl 4-((2-(dimethylphosphoryl)phenyl)amino)-2-((4-(methoxycarbamoyl)phenyl)amino)pyrimidine-5-carboxylate. MS m / z (ESI): 470.2 [M+H] + .

[0691] Step 4: Synthesis of 4-((2-(dimethylphosphoryl)phenyl)amino)-2-((4-(methoxycarbamoyl)phenyl)amino)pyrimidine-5-carboxylic acid

[0692] Methyl 4-((2-(dimethylphosphoryl)phenyl)amino)-2-((4-(methoxycarbamoyl)phenyl)amino)pyrimidine-5-carboxylate (345 mg, 0.74 mmol) was dissolved in THF (10 mL) and H₂O (10 mL). NaOH (89 mg, 2.2 mmol) was added and the mixture was allowed to react overnight at room temperature. The reaction was monitored for completion. The organic solvent was removed under reduced pressure, and 2M HCl solution was added to adjust the pH to neutral or weakly acidic. The mixture was filtered to give 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] + .

[0693] Step 5: Synthesis of 4-((2-(dimethylphosphoryl)phenyl)amino)-2-((4-(methoxycarbamoyl)phenyl)amino)-N-methylpyrimidine-5-carboxamide

[0694] 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). DIPEA (72.6 μL, 0.44 mmol) was added and the mixture was allowed to react overnight at room temperature. The reaction was monitored for completion. Water was added, the mixture was extracted with DCM, dried, concentrated, and purified by column chromatography to afford 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,1 H),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] + .

[0695] Example 52

[0696] Preparation of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-isobutoxybenzamide (52)

[0697]

[0698] Step 1: Synthesis of (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0699] (2-Aminophenyl)dimethylphosphine oxide (250 mg, 1.47 mmol), 2,4,5-trichloropyrimidine (270 mg, 1.47 mmol) and NaHCO3 (247 mg, 2.94 mmol) were dissolved in ethanol (5 mL) and reacted at room temperature for 5 h. The reaction was monitored for completion. 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] + .

[0700] Step 2: Synthesis of 4-((5-chloro-4-((2-(dimethylphosphonyl)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid

[0701] (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). A 4N hydrochloric acid solution in 1,4-dioxane (90.2 μL) was added and the mixture was reacted at 65°C for 14 h. The reaction was monitored for completion. 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] + .

[0702] Step 3: Synthesis of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidinylamino-2-yl)amino)-N-isobutoxybenzamide

[0703] 4-((5-chloro-4-((2-(dimethylphosphino)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). DIPEA (91.4 μL, 0.56 mmol) was added and allowed to react at room temperature overnight. The reaction was monitored for completion. Water was added, the mixture was extracted with DCM, dried, concentrated, and purified by column chromatography to afford 50 mg of 4-((5-chloro-4-((2-(dimethylphosphino)phenyl)amino)pyrimidin-2-yl)amino)-N-isobutoxybenzamide. 1 H NMR (400MHz, DMSO) δ11.44(s,1H),11.17(s,1H),9.74(s,1H),8.54(d,J=4.5Hz,1H),8.25(s,1H),7.74(d,J=8.8Hz,2H),7. 69–7.52(m,4H),7.23(t,J=7.0Hz,1H),3.65(d,J=6.7Hz,2H),1.93(m,1H),1.78(d,J=13.6Hz,6H),0.94(d,J=6.7Hz,6H).MS m / z(ESI):488.2[M+H] + .

[0704] Example 53

[0705] Preparation of 4-((5-bromo-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-methoxybenzamide (53)

[0706]

[0707] Step 1: Synthesis of (2-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0708] (2-Aminophenyl)dimethylphosphine oxide (120 mg, 0.71 mmol), 5-bromo-2,4-dichloropyrimidine (178 mg, 0.78 mmol) and DIPEA (0.24 mL, 1.42 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 2 h. The reaction was monitored for completion. Water was added, and dichloromethane was added for extraction. The mixture was 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] + .

[0709] Step 2: Synthesis of 4-((5-bromo-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid

[0710] (2-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (100 mg, 0.28 mmol) and p-aminobenzoic acid (38 mg, 0.28 mmol) were dissolved in isopropanol (4 mL). A 4N hydrochloric acid solution in 1,4-dioxane (70 μL, 0.28 mmol) was added. The mixture was reacted at 65°C for 4 h and monitored for completion. The reaction was filtered 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] + .

[0711] Step 3: Synthesis of 4-((5-bromo-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0712] 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). DIPEA (83 μL, 0.50 mmol) was added and the mixture was allowed to react overnight at room temperature. The reaction was monitored for completion. Water was added, the mixture was extracted with DCM, dried, concentrated, and purified by column chromatography to afford 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,1H),3.68(s,3H),1.76(d,J=13.5Hz,7H).MS m / z(ESI):490.1[M+H] + .

[0713] Example 54

[0714] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-N-methoxybenzamide (54)

[0715]

[0716] Step 1: Synthesis of (2-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0717] (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) and reacted at 65°C for 5 h. The reaction was monitored for completion. Water was added, and the mixture was extracted with dichloromethane. The mixture was dried and concentrated, and column chromatography was performed to obtain 87 mg of (2-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS m / z (ESI): 300.0 [M+H] + .

[0718] Step 2: Synthesis of 4-(((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyridinylamino-2-yl)amino)benzoic acid

[0719] (2-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (87 mg, 0.29 mmol) and p-aminobenzoic acid (40 mg, 0.29 mmol) were dissolved in isopropanol (4 mL). A 4N hydrochloric acid solution in 1,4-dioxane (73 μL, 0.29 mmol) was added. The mixture was reacted at 65°C for 12 h and monitored for completion. The reaction was filtered to obtain 80 mg of 4-(((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyridinylamino-2-yl)amino)benzoic acid. MS m / z (ESI): 401.1 [M+H] + .

[0720] Step 3: Synthesis of 4-((4-((2-(2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyridinylamino-2-yl)amino)-N-methoxybenzamide

[0721] 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 at room temperature overnight and monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried and concentrated, and then purified by column chromatography to give 80 mg of 4-((4-((2-(2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyridinylamino-2-yl)amino)-N-methoxybenzamide.1 H NMR (400MHz, DMSO) δ11.59(s,1H),11.55(s,1H),9.66(s,1H),8.76(m,1H),8.20(d,J=3.3Hz,1H),7. 77(d,J=8.9Hz,2H),7.71–7.52(m,4H),7.19(t,J=7.1Hz,1H),3.69(s,3H),1.80(d,J=13.6Hz,6H).MS m / z(ESI):430.1[M+H] + .

[0722] Example 55

[0723] Preparation of 7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidindi-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide (55)

[0724]

[0725] Step 1: Synthesis of (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0726] (2-Aminophenyl)dimethylphosphine oxide (400 mg, 2.35 mmol), 2,4,5-trichloropyrimidine (432 mg, 2.35 mmol) and NaHCO3 (395 mg, 4.71 mmol) were dissolved in EtOH (8 mL) and reacted at 85°C for 5 h. The reaction was monitored for completion. Water was added, and dichloromethane was added for extraction. The mixture was 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] + .

[0727] Step 2: Synthesis of 7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidindimethyl-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid

[0728] (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (89 mg, 0.28 mmol) and 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid (50 mg, 0.28 mmol) were dissolved in isopropanol (4 mL). A 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 for completion. 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] + .

[0729] Step 3: Synthesis of 7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyridinylamino-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide

[0730] 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). DIPEA (63 μL, 0.38 mmol) was added and the mixture was allowed to react overnight at room temperature. The reaction was monitored for completion. Water was added, the mixture was extracted with DCM, dried, concentrated, and purified by column chromatography to afford 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,1H),7.06(d,J=8.4Hz,1H),4.55(t,J=8.8Hz,2H),3.72(s,3H),3.44(t,J=8.9Hz,2H),1.78(d,J=13.5Hz,6H).MS m / z(ESI):488.2[M+H] + .

[0731] Example 56

[0732] Preparation of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide (56)

[0733]

[0734] Step 1: Synthesis of (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0735] (2-Aminophenyl)dimethylphosphine oxide (400 mg, 2.35 mmol), 2,4,5-trichloropyrimidine (432 mg, 2.35 mmol) and NaHCO3 (395 mg, 4.71 mmol) were dissolved in EtOH (8 mL) and reacted at 85°C for 5 h. The reaction was monitored for completion. Water was added, and dichloromethane was added for extraction. The mixture was 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] + .

[0736] Step 2: Synthesis of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidinylamino-2-yl)amino)-2-fluoro-5-methoxybenzoic acid

[0737] (2-(((2,5-Dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (85 mg, 0.27 mmol) and 4-amino-2-fluoro-5-methoxybenzoic acid (50 mg, 0.27 mmol) were dissolved in isopropanol (4 mL). A 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 for completion. 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] + .

[0738] Step 3: Synthesis of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide

[0739] 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). DIPEA (50 μL, 0.30 mmol) was added and the mixture was allowed to react overnight at room temperature. The reaction was monitored for completion. Water was added, the mixture was extracted with DCM, dried, concentrated, and purified by column chromatography to afford 37 mg of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide. 1 HNMR (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] + .

[0740] Example 57

[0741] Preparation of (2-((5-chloro-2-((5-fluoro-4-(isobutoxycarbamoyl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl dimethylphosphonate (57)

[0742]

[0743] Step 1: Synthesis of 2,5-dichloro-N-(2-iodophenyl)pyrimidin-4-amine

[0744] 2-Iodoaniline (4.4 g, 20.08 mmol), 2,4,5-trichloropyrimidine (4.4 g, 23.98 mmol), and DIPEA (3.5 mL, 20.08 mmol) were dissolved in nBuOH (10 mL) and reacted at 85°C for 16 h. The reaction was monitored for completion. Water was added, and the mixture was extracted with dichloromethane. The mixture was dried and concentrated, and column chromatography was performed to obtain 2.0 g of 2,5-dichloro-N-(2-iodophenyl)pyrimidin-4-amine. MS m / z (ESI): 365.9 [M+H] + .

[0745] Step 2: Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid

[0746] 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). A 4N hydrochloric acid solution in 1,4-dioxane (41 μL, 0.16 mmol) was added. The mixture was reacted at 120°C for 3 h and monitored for completion. The reaction 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] + .

[0747] Step 3: Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide

[0748] 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). DIPEA (0.23 mL, 1.40 mmol) was added and the mixture was allowed to react overnight at room temperature. The reaction was monitored for completion. Water was added, the mixture was extracted with DCM, dried, concentrated, and column chromatography was performed to obtain 110 mg of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide. MS m / z (ESI): 586.1 [M+H] + .

[0749] Step 4: Synthesis of (2-((5-chloro-2-((5-fluoro-4-(isobutoxycarbamoyl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl dimethylphosphonate

[0750] 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)Cl2 (16 mg, 0.02 mmol), and K3PO4 (80 mg, 0.38 mmol) were dissolved in 1,4-dioxane (3 mL). The mixture was reacted at 120°C under nitrogen for 16 h, and the reaction was monitored for completion. Water was added, the mixture was extracted with dichloromethane, dried, concentrated, and purified by column chromatography to afford 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),7.2 9(td,J=7.7,3.2Hz,1H),7.14(d,J=6.3Hz,1H),3.85(s,3H),3.67(s,3H),3.65(s,3H),3.63(s,2H),1.20(m,1H),0.91(d,J=6.6Hz,6H).MS m / z(ESI):568.2[M+H] + .

[0751] Example 58

[0752] Preparation of dimethyl (2-((5-chloro-2-((4-(methoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate (58)

[0753]

[0754] Step 1: Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)benzoic acid

[0755] 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). A 4N hydrochloric acid solution in 1,4-dioxane (82 μL, 0.33 mmol) was added. The mixture was reacted at 120°C for 3 h. The reaction was monitored for completion. 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] + .

[0756] Step 2: Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0757] 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). DIPEA (0.53 mL, 3.22 mmol) was added and the mixture was allowed to react overnight at room temperature. The reaction was monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried, concentrated, and purified by column chromatography to yield 240 mg of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-methoxybenzamide. MS m / z (ESI): 496.0 [M+H] + .

[0758] Step 3: Synthesis of dimethyl (2-((5-chloro-2-((4-(methoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate

[0759] 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)Cl2 (22 mg, 0.02 mmol), and K3PO4 (112 mg, 0.53 mmol) were dissolved in 1,4-dioxane (5 mL). The mixture was reacted at 100°C under N2 protection for 16 h, and the reaction was monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried, concentrated, and purified by column chromatography 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] + .

[0760] Example 59

[0761] Preparation of dimethyl (2-((5-chloro-2-((4-(isobutoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyldiphosphonate (51)

[0762]

[0763] Step 1: Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)benzoic acid

[0764] 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). A 4N hydrochloric acid solution in 1,4-dioxane (82 μL, 0.33 mmol) was added. The mixture was reacted at 120°C for 3 h. The reaction was monitored for completion. 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] + .

[0765] Step 2: Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-isobutyloxybenzamide

[0766] 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). DIPEA (0.53 mL, 3.22 mmol) was added and the mixture was allowed to react overnight at room temperature. The reaction was monitored for completion. Water was added, and the mixture was extracted with DCM. 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] + .

[0767] Step 3: Synthesis of dimethyl (2-((5-chloro-2-((4-(isobutoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyldiphosphonate

[0768] 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)Cl2 (20 mg, 0.02 mmol), and K3PO4 (103 mg, 0.48 mmol) were dissolved in 1,4-dioxane (5 mL). The mixture was reacted at 100°C under N2 protection for 16 h, and the reaction was monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried, concentrated, and purified by column chromatography to obtain 20 mg of dimethyl (2-((5-chloro-2-((4-(isobutoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyldiphosphonate. 1 H NMR (400MHz, DMSO) δ11.43(s,1H),9.86(s,1H),9.77(s,1H),8.51(t,J=7.4Hz,1H),8.28(s,1H),7.74–7.56(m,6H),7.2 9(m,1H),3.68(s,3H),3.65(s,3H),3.62(d,J=6.7Hz,2H),1.20(m,1H),0.91(d,J=6.7Hz,6H).MSm / z(ESI):520.1[M+H] + .

[0769] Example 60

[0770] Preparation of dimethyl (2-((5-chloro-2-((4-(methylcarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate (60)

[0771]

[0772] Step 1: Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-methylbenzamide

[0773] 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). A 4N hydrochloric acid solution in 1,4-dioxane (41 μL, 0.16 mmol) was added. The mixture was reacted at 120°C for 3 h and monitored for completion. The reaction 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] + .

[0774] Step 2: Synthesis of dimethyl (2-((5-chloro-2-((4-(methylcarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate

[0775] 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)Cl2 (26 mg, 0.03 mmol), and K3PO4 (133 mg, 0.62 mmol) were dissolved in 1,4-dioxane (3 mL) and reacted at 95°C under N2 protection for 16 h. The reaction was monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried, concentrated, and purified by column chromatography to give 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=4.5H z,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] + .

[0776] Example 61

[0777] Preparation of dimethyl (2-((2-((4-(methoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyldiphosphonate (61)

[0778]

[0779] Step 1: Synthesis of (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0780] 2-Iodoaniline (4.0 g, 18.26 mmol), dimethyl phosphate (5.0 mL, 54.78 mmol), Pd(dppf)2Cl2 (1.5 g, 1.83 mmol), and K3PO4 (9.7 g, 45.65 mmol) were dissolved in 1,4-dioxane (100 mL) and reacted at 100°C under N2 protection for 16 h. The reaction was monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried and concentrated, and column chromatography was performed to obtain 1.7 g of (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS m / z (ESI): 202.3 [M+H]+ .

[0781] Step 2: Synthesis of dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate

[0782] (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 NaHCO3 (1.4 g, 17.28 mmol) were dissolved in EtOH (60 mL) and reacted at 60°C overnight. The reaction was monitored for completion. Water was added, and dichloromethane was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 419 mg of dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate. MS m / z (ESI): 382.0 [M+H] + .

[0783] Step 3: Synthesis of 7-((4-((2-(2-(dimethoxyphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid

[0784] 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 for completion. 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] + .

[0785] Step 4: Synthesis of dimethyl (2-((2-((4-(methoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyldiphosphonate

[0786] 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 reaction was allowed to react at room temperature for 7 h, and the reaction was monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried and concentrated, and column chromatography was performed to give 43 mg of dimethyl (2-((2-((4-(methoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyldiphosphonate. 1 H NMR(400MHz,DMSO-d6)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] + .

[0787] Example 62

[0788] Preparation of dimethyl (2-((5-chloro-2-((4-(methoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)pyrimidin-4-yl)amino)phenyldiphosphonate (62)

[0789]

[0790] Step 1: Synthesis of 7-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid

[0791] 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). A 4N hydrochloric acid solution in 1,4-dioxane (0.15 mL) was added. The mixture was reacted at 120°C for 2 h. The reaction was monitored for completion. 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] + .

[0792] Step 2: Synthesis of 7-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide

[0793] 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 at room temperature overnight and monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried and concentrated, and column chromatography was performed to give 67 mg of 7-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide. MS m / z (ESI): 538.3 [M+H] + .

[0794] Step 3: Synthesis of dimethyl (2-((5-chloro-2-((4-(methoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)pyrimidin-4-yl)amino)phenyldiphosphonate

[0795] 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)2Cl2 (10 mg, 0.01 mmol), and K3PO4 (66 mg, 0.31 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was reacted at 100°C under N2 protection for 16 h, and the reaction was monitored for completion. Water was added, the mixture was extracted with DCM, dried, concentrated, and purified by column chromatography 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 (400MHz, DMSO-d6) δ11.48(s,1H),10.01(s,1H),8.74(s,1H),8.57(t,J=7.3Hz,1H),8.23(s,1H),7.61(dd,J=14.4,7.8Hz,1H),7.54(t, J=7.5Hz,2H),7.22(dd,J=7.7,4.9Hz,1H),7.05(d,J=8.4Hz,1H),4.54(t,J=8.8Hz,2H),3.71(s,6H),3.68(s,3H),3.43(t,J=8.8Hz,2H).MS m / z(ESI):520.4[M+H] + .

[0796] Example 63

[0797] Preparation of dimethyl (2-((2-(((4-(isobutoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyldiphosphonate (63)

[0798]

[0799] Step 1: Synthesis of (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0800] 2-Iodoaniline (4.0 g, 18.26 mmol), dimethyl phosphate (5.0 mL, 54.78 mmol), Pd(dppf)2Cl2 (1.5 g, 1.83 mmol), and K3PO4 (9.7 g, 45.65 mmol) were dissolved in 1,4-dioxane (100 mL). The mixture was reacted at 100°C under N2 protection for 16 h. The reaction was monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried and concentrated, and column chromatography was performed to obtain 1.7 g of (2-(((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS m / z (ESI): 202.1 [M+H] + .

[0801] Step 2: Synthesis of dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate

[0802] (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 NaHCO3 (1.4 g, 17.28 mmol) were dissolved in EtOH (60 mL) and reacted at 60°C overnight. The reaction was monitored for completion. Water was added, and dichloromethane was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 419 mg of dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate. MS m / z (ESI): 382.0 [M+H] + .

[0803] Step 3: Synthesis of 7-((4-((2-(2-(dimethoxyphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid

[0804] 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 for completion. 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] + .

[0805] Step 4: Synthesis of dimethyl (2-((2-(((4-(isobutoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyldiphosphonate

[0806] 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 reaction was allowed to react at room temperature for 7 h, and the reaction was monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried and concentrated, and column chromatography was performed to give 83 mg of dimethyl (2-((2-(((4-(isobutoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyldiphosphonate. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0807] Example 64

[0808] Preparation of (2-((2-((5-fluoro-4-(isobutoxycarbamoyl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl dimethylphosphonate (64)

[0809]

[0810] Step 1: Synthesis of dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate

[0811] (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 NaHCO3 (0.8 g, 9.05 mmol) were dissolved in EtOH (40 mL) and reacted at 60°C overnight. The reaction was monitored for completion. Water was added, and dichloromethane was added for extraction. The mixture was dried and concentrated, and column chromatography was performed to obtain 120 mg of dimethyl (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphonate. MS m / z (ESI): 382.0 [M+H] + .

[0812] Step 2: Synthesis of 4-((4-((2-(di(methoxyphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid

[0813] 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 for completion. 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] + .

[0814] Step 3: Synthesis of (2-((2-((5-fluoro-4-(isobutoxycarbamoyl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl dimethylphosphonate

[0815] 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 monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried and concentrated, and column chromatography was performed to give 53 mg of (2-((2-((5-fluoro-4-(isobutoxycarbamoyl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl dimethylphosphonate.1 H NMR (400MHz, DMSO-d6) 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] + .

[0816] Example 65

[0817] Preparation of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide (65)

[0818]

[0819] Step 1: Synthesis of (2-aminophenyl)diethylphosphine oxide

[0820] 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 K3PO4 (5.4 g, 25.45 mmol) were dissolved in DMF (120 mL) and reacted at 120°C under N2 protection for 16 h. The reaction was monitored for completion. Water was added, and the mixture was extracted with DCM. The mixture was dried and concentrated, and column chromatography was performed to obtain 1.8 g of (2-aminophenyl)diethylphosphine oxide. MS m / z (ESI): 198.3 [M+H] + .

[0821] Step 2: Synthesis of (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide

[0822] (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 for completion. 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] + .

[0823] Step 3: Synthesis of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid

[0824] (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) were dissolved in isopropanol (6 mL). A 4N hydrochloric acid solution in 1,4-dioxane (0.1 mL) was added and the mixture was reacted at 65°C for 3 h. The reaction was monitored for completion. The system was filtered 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] + .

[0825] Step 4: Synthesis of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0826] 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). DIPEA (0.17 mL, 1.01 mmol) was added and the mixture was reacted at room temperature for 7 h. The reaction was monitored for completion. Water was added, the mixture was extracted with DCM, dried, concentrated, and purified by column chromatography to afford 63 mg of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide. 1H NMR (400MHz, DMSO-d6) 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,1 H),7.02(d,J=8.3Hz,1H),4.51(t,J=8.8Hz,2H),3.66(d,J=6.7Hz,2H),3.40(t,J= 8.8Hz,2H),2.01–1.88(m,2H),1.75(s,3H),1.72(s,3H),0.95(d,J=6.7Hz,7H).MS m / z(ESI):508.2[M+H] + .

[0827] Example 66

[0828] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2-chlorobenzamide (66)

[0829]

[0830] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-chlorobenzoic acid

[0831] (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 the mixture was 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 give 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]. + .

[0832] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2-chlorobenzamide

[0833] 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to obtain 40 mg 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2-chlorobenzamide. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0834] Example 67

[0835] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2-methoxybenzamide (67)

[0836]

[0837] Step 1: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methoxybenzoic acid

[0838] (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 the mixture was reacted at 60° C. for 4 h. After completion of the reaction 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 give 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]. + .

[0839] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2-methoxybenzamide

[0840] 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to obtain 15 mg. 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2-methoxybenzamide. 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),10.61(s,1H),10.00(s,1H),8.50(s,1 H),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] + .

[0841] Example 68

[0842] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2-cyanobenzamide (68)

[0843]

[0844] Step 1: Synthesis of methyl 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanobenzoate

[0845] (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 a 4N hydrochloric acid solution in 1,4-dioxane (0.43 mL, 1.74 mmol) were added to isopropanol (10 mL), and the mixture was reacted at 60°C for 4 h. After completion of the reaction 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 give 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]. + .

[0846] Step 2: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanobenzoic acid

[0847] 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 and the reaction system was adjusted to neutral by adding saturated citric acid solution. The mixture was extracted with EA (10 mL×3) and dried and concentrated to give 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]. + .

[0848] Step 3: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2-cyanobenzamide

[0849] 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to obtain 8 mg. 4-((4-((2-(Dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2-cyanobenzamide. 1 HNMR(400MHz,DMSO-d6)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]+ .

[0850] Example 69

[0851] Preparation of N-(cyclopentyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (69)

[0852]

[0853] Step 1: Synthesis of 2-(cyclopentyloxy)isoindoline-1,3-dione

[0854] 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) and reacted for 5 minutes at room temperature, followed by 3 hours at 80°C. After completion of the reaction 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 resulting solid was washed with petroleum ether (3 mL x 3) and then dried under vacuum for 1 hour to yield 400 mg of 2-(cyclopentyloxy)isoindoline-1,3-dione. MS m / z (ESI): 232.1 [M+H]. + .

[0855] Step 2: Synthesis of O-cyclopentylhydroxylamine

[0856] 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) and extracted with dichloromethane (10 mL × 3). The organic phase was washed with water, dried and concentrated to obtain 60 mg of O-cyclopentylhydroxylamine.

[0857] Step 3: Synthesis of N-(cyclopentyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide

[0858] 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, 0.54 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to obtain 16 mg N-(Cyclopentyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. 1 H NMR (400MHz, DMSO-d6) 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] + .

[0859] Example 70

[0860] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-((tetrahydro-2H-pyran-4-yl)methoxy)benzamide (70)

[0861]

[0862] Step 1: Synthesis of 2-((tetrahydro-2H-pyran-4-yl)methoxy)isoindoline-1,3-dione

[0863] 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) and reacted for 5 minutes at room temperature, followed by 3 hours at 80°C. After completion of the reaction 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 resulting solid was washed with petroleum ether (3 mL x 3) and then dried under vacuum for 1 hour to yield 180 mg of 2-((tetrahydro-2H-pyran-4-yl)methoxy)isoindoline-1,3-dione. MS m / z (ESI): 262.2 [M+H] + .

[0864] Step 2: Synthesis of O-((tetrahydro-2H-pyran-4-yl)methyl)hydroxylamine

[0865] 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) and extracted with dichloromethane (10 mL×3). The organic phase was washed with water, dried and concentrated to give 47 mg of O-((tetrahydro-2H-pyran-4-yl)methyl)hydroxylamine.

[0866] Step 3: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-((tetrahydro-2H-pyran-4-yl)methoxy)benzamide

[0867] 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to obtain 40 mg of the product. 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-((tetrahydro-2H-pyran-4-yl)methoxy)benzamide, 1 H NMR (400MHz, DMSO-d6) 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(d d,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] + .

[0868] Example 71

[0869] Preparation of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-((tetrahydro-2H-pyran-4-yl)oxy)benzamide (71)

[0870]

[0871] Step 1: Synthesis of 2-((tetrahydro-2H-pyran-4-yl)oxy)isoindoline-1,3-dione

[0872] 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 reacted at 80°C for 4 h. After completion of the reaction as monitored by LCMS, the reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The organic phase was washed with water, dried, concentrated, and purified by column chromatography to afford 400 mg of 2-((tetrahydro-2H-pyran-4-yl)oxy)isoindoline-1,3-dione. MS m / z (ESI): 248.1 [M+H]. + .

[0873] Step 2: Synthesis of O-(tetrahydro-2H-pyran-4-yl)hydroxylamine

[0874] 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) and extracted with dichloromethane (10 mL×3). The organic phase was washed with water, dried and concentrated to obtain 170 mg of O-(tetrahydro-2H-pyran-4-yl)hydroxylamine.

[0875] Step 3: Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-((tetrahydro-2H-pyran-4-yl)oxy)benzamide

[0876] 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to obtain 50 mg of the product. 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-((tetrahydro-2H-pyran-4-yl)oxy)benzamide. 1H NMR(400MHz,DMSO-d6)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] + .

[0877] Example 72

[0878] Preparation of N-(cyclopentylmethoxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (72)

[0879]

[0880] Step 1: Synthesis of 2-(cyclopentylmethoxy)isoindoline-1,3-dione

[0881] Bromomethylcyclopentane (1 g, 6 mmol), N-hydroxyphthalimide (834 mg, 5.12 mmol), and potassium carbonate (1.77 g, 12.8 mmol) were added to dimethyl sulfoxide (10 mL) and reacted at room temperature for 5 minutes, followed by reaction at 80°C for 3 hours. After completion of the reaction 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 resulting solid was washed with petroleum ether (3 mL x 3) and then dried under vacuum for 1 hour to yield 630 mg of 2-(cyclopentylmethoxy)isoindoline-1,3-dione. MS m / z (ESI): 246.1 [M+H]. + .

[0882] Step 2: Synthesis of O-(cyclopentylmethyl)hydroxylamine

[0883] 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.

[0884] Step 3: Synthesis of N-(cyclopentylmethoxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide

[0885] 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), and the organic phase was washed with water, dried, concentrated, and column chromatography to obtain 12 mg N-(Cyclopentylmethoxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide. 1 H NMR (400MHz, DMSO-d6) 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=7.5H z,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] + .

[0886] Example 73

[0887] Preparation of 7-(((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide (73)

[0888]

[0889] Step 1: Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide

[0890] 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-d6)δ11.40(s,1H),10.82(s,1H),9.11(s,1H),8.39(s,1H ),8.24(s,1H),7.55(dd,J=13.7,7.7Hz,1H),7.37(d,J=7.8Hz,2H),7.16(t, J=7.4Hz,1H),7.02(d,J=8.3Hz,1H),4.51(t,J=8.8Hz,2H),3.71(d,J=6.7Hz ,3H),3.40(t,J=8.8Hz,2H),2.01–1.88(m,2H),1.75(s,3H),1.72(s,3H).MS m / z(ESI):522.1[M+H] + .

[0891] Example 74

[0892] Preparation of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxybenzamide (74)

[0893]

[0894] Step 1: Synthesis of (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide

[0895] (2-Aminophenyl)diethylphosphine oxide (2.0 g, 10.14 mmol) was dissolved in DMF (20 mL) under nitrogen. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (1.37 mL, 10.14 mmol) and DIPEA (1.68 mL, 10.14 mmol) were added at 0°C and stirred at 60°C overnight, monitoring the reaction for completion. Saturated ammonium chloride solution (3 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified 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, 15.82% yield) as a beige solid. MS m / z (ESI): 378.10 [M+H] + .

[0896] Step 2: Synthesis of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid

[0897] (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (400 mg, 1.06 mmol) was dissolved in isopropanol (20 mL). 4-Aminobenzoic acid (145.23 mg, 1.06 mmol) and hydrochloric acid / 1,4-dioxane (0.5 mL, 2.00 mmol) were added sequentially at 0°C under nitrogen protection. Stir at 65°C for 3 hours and monitor the reaction for completion. Filtration afforded the intermediate 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid (349 mg, 68.89% yield) as an off-white solid. MS m / z (ESI): 479.10 [M+H] + .

[0898] Step 3: Synthesis of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxybenzamide

[0899] 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 sequentially at 0°C under nitrogen protection. The reaction was allowed to proceed at room temperature for 5 hours and the reaction was monitored for completion. Saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with (petroleum ether:ethyl acetate = 0:1) to give 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxybenzamide (52 mg, yield: 78.86%) as a white solid. MS m / z (ESI): 522.20 [M+H] + .

[0900] 1 H NMR(DMSO-d6)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)

[0901] Example 75

[0902] Preparation of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxybenzamide (75)

[0903]

[0904] Step 1: Synthesis of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxybenzamide

[0905] 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid (60 mg, 0.13 mmol) was dissolved in DMF (2 mL), and isobutylhydroxylamine hydrochloride (47.30 mg, 0.38 mmol), HATU (95.46 mg, 0.25 mmol), DIPEA (0.12 mL, 0.75 mmol) and DMAP (1.53 mg, 0.01 mmol) were added sequentially at 0°C under nitrogen protection at room temperature for 5 hours. The reaction was monitored for completion. Saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. 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-isobutoxybenzamide (XTC003-190) (52 mg, yield: 75.39%) as a white solid. MS m / z (ESI): 550.2 [M+H] + .

[0906] 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).

[0907] Example 76

[0908] Preparation of 4-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-methoxybenzamide (76)

[0909]

[0910] Step 1: Synthesis of (2-aminophenyl)diethylphosphine oxide

[0911] 2-Iodoaniline (10 g, 45.66 mmol) was dissolved in DMF (240 mL). Diethylphosphine oxide (5.81 g, 54.79 mmol), K₃PO₄ (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 at 120°C overnight under nitrogen atmosphere and monitored for reaction completion. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed three times with saturated brine, dried, and concentrated to obtain a residue. The residue was purified by column chromatography to obtain (2-aminophenyl)diethylphosphine oxide (8.5 g, 94.39% yield) as a yellow solid. MS m / z (ESI): 178.10 [M+H] + .

[0912] Step 2: Synthesis of (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)diethylphosphine oxide

[0913] (2-Aminophenyl)diethylphosphine oxide (1.0 g, 5.07 mmol) was dissolved in EtOH (12 mL), and 2,4,5-trichloropyrimidine (930 mg, 5.07 mmol) and NaHCO₃ (426 mg, 5.07 mmol) were added. The mixture was stirred at 85°C for 90 minutes and the reaction was monitored for completion. The mixture was cooled to room temperature, diluted with water, extracted with EA, and the organic layer was dried and concentrated to obtain a residue. The residue was purified by column chromatography to obtain (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (982 mg, yield: 56.27%) as a yellow solid. MS m / z (ESI): 344.04 [M+H] + .

[0914] Step 3: Synthesis of 4-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid

[0915] (2-((2,5-Dichloropyrimidin-4-yl)amino)phenyl)diethylphosphine oxide (500 mg, 1.45 mmol) was dissolved in isopropanol (16 mL), and 4-aminobenzoic acid (160 mg, 1.17 mmol) and HCl / 1,4-dioxane (4M, 0.73 mL, 2.92 mmol) were added. The mixture was stirred at 80°C overnight and monitored for completion. The reaction was cooled to room temperature, filtered, and the filter cake was washed 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] + .

[0916] Step 4: Synthesis of 4-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-methoxybenzamide

[0917] 4-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid (100 mg, 0.22 mmol) was dissolved in DMF (4 mL). Methoxyamine hydrochloride (56 mg, 0.67 mmol), HTAU (171 mg, 0.45 mmol), DIPEA (203 mg, 1.57 mmol), and DMAP (2.75 mg, 0.02 mmol) were added and stirred at room temperature overnight. The reaction was monitored for completion. 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. Column chromatography was used 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] + .

[0918] 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).

[0919] Example 77

[0920] Preparation of 4-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-ethoxybenzamide (77)

[0921]

[0922] Step 1: Synthesis of 4-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-ethoxybenzamide

[0923] 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). 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 and stirred at room temperature overnight. The reaction was monitored for completion. 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. MS m / z (ESI): 488.1 [M+H] + .

[0924] 1 H NMR(DMSO-d6)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,2 H),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(br t,J=7.6Hz,3H)

[0925] Example 78

[0926] Preparation of 4-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-isobutoxybenzamide (78)

[0927]

[0928] Step 1: Synthesis of 4-((5-chloro-4-((2-(diethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-isobutoxybenzamide

[0929] 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). 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 and stirred at room temperature overnight. The reaction was monitored for completion. 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 title compound (75 mg, 43.11%) as a white solid. MS m / z (ESI): 516.1 [M+H] + .

[0930] 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).

[0931] Example 79

[0932] Preparation of 4-(5-chloro-4-(2-(diethylphospho)phenylamino)pyrimidin-2-ylamino)-2-fluoro-N-isobutoxy-5-methoxybenzamide (79)

[0933]

[0934] Step 1: Synthesis of 4-(5-chloro-4-(2-(diethylphospho)phenylamino)pyrimidin-2-ylamino)-2-fluoro-5-methoxybenzoic acid

[0935] 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). The temperature was cooled to 0°C, and a 4M hydrochloric acid / 1,4-dioxane solution (0.29 mL, 1.16 mmol) was added dropwise with stirring. After the addition was complete, the mixture was heated to 70°C and allowed to react overnight. The reaction mixture was cooled to room temperature and filtered to yield 4-(5-chloro-4-(2-(diethylphospho)phenylamino)pyrimidin-2-ylamino)-2-fluoro-5-methoxybenzoic acid (139 mg, 48.28% yield) as a white solid. MS m / z (ESI): 493.1 [M+H] + .

[0936] Step 2: Synthesis of 4-(5-chloro-4-(2-(diethylphospho)phenylamino)pyrimidin-2-ylamino)-2-fluoro-N-isobutoxy-5-methoxybenzamide

[0937] 4-(5-chloro-4-(2-(diethylphospho)phenylamino)pyrimidin-2-ylamino)-2-fluoro-5-methoxybenzoic acid (65 mg, 0.13 mmol) and isobutoxyamine hydrochloride (66.4 mg, 0.52 mmol) were dissolved in DMF (2 mL), HATU (100.4 mg, 0.26 mmol) and DMAP (1.6 mg, 0.01 mmol) were added, and the temperature was lowered to 0°C. DIPEA (0.15 mL, 0.91 mmol) was added dropwise with stirring. After the addition was complete, the temperature was raised to room temperature and the reaction was allowed to proceed overnight. 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (methanol:dichloromethane = 1:20) gave 4-(5-chloro-4-(2-(diethylphospho)phenylamino)pyrimidin-2-ylamino)-2-fluoro-N-isobutoxy-5-methoxybenzamide (51.8 mg, yield: 69.23%). MS m / z (ESI): 564.2 [M+H] + .

[0938] 1H NMR(DMSO-d6)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).

[0939] Example 80

[0940] Preparation of 4-(5-chloro-4-(2-(diethylphospho)phenylamino)pyrimidin-2-amino)-2-fluoro-N,5-dimethoxybenzamide (80)

[0941]

[0942] Step: Synthesis of 4-(5-chloro-4-(2-(diethylphospho)phenylamino)pyrimidin-2-amino)-2-fluoro-N,5-dimethoxybenzamide

[0943] 4-(5-chloro-4-(2-(diethylphospho)phenylamino)pyrimidin-2-ylamino)-2-fluoro-5-methoxybenzoic acid (60 mg, 0.12 mmol) and methoxyamine hydrochloride (40.7 mg, 0.48 mmol) were dissolved in DMF (2 mL), HATU (90.7 mg, 0.24 mmol) and DMAP (1.5 mg, 0.01 mmol) were added, and the temperature was lowered to 0°C. DIPEA (0.14 mL, 0.84 mmol) was added dropwise with stirring. After the addition was complete, the mixture was warmed to room temperature and reacted overnight. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were 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 give 4-(5-chloro-4-(2-(diethylphospho)phenylamino)pyrimidin-2-amino)-2-fluoro-N,5-dimethoxybenzamide (10.0 mg, yield: 16.7%). MS m / z (ESI): 522.2 [M+H] + .

[0944] 1H NMR(DMSO-d6)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).

[0945] Example 81

[0946] Preparation of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N,5-dimethoxybenzamide (81)

[0947]

[0948] Step 1: Synthesis of (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide

[0949] (2-Aminophenyl)diethylphosphine oxide (2 g, 10.14 mmol) was dissolved in DMF (20 mL) under nitrogen atmosphere. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (1.38 mL, 10.14 mmol) and DIPEA (1.68 mL, 10.14 mmol) were added at 0°C and allowed to react overnight at 60°C. After completion of the reaction, water and ethyl acetate were added for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. The filtrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford the target compound (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide) (677 mg, yield: 17.67%). MS m / z (ESI): 378.0 [M+H] + .

[0950] Step 2: Synthesis of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid

[0951] (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) were dissolved in isopropanol (10 mL) under nitrogen protection. 4M hydrochloric acid / 1,4-dioxane solution (0.25 mL) was added in an ice bath. The mixture was reacted at 65°C for 3 hours and monitored for completion. Filtration afforded 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] + .

[0952] Step 3: Synthesis of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N,5-dimethoxybenzamide

[0953] 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), and 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 stirred at room temperature for 5 hours. The reaction was determined to be complete. Water was added, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N,5-dimethoxybenzamide (36 mg, 68% yield). MS m / z(ESI):556.2[M+H] + .

[0954] 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(br d,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).

[0955] Example 82

[0956] Preparation of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide (82)

[0957]

[0958] Step 1: Synthesis of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid

[0959] (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) were dissolved in isopropanol (10 mL) under nitrogen protection. 4M hydrochloric acid / 1,4-dioxane solution (0.25 mL) was added in an ice bath. The mixture was stirred at 65°C for 3 hours and the reaction was monitored for completion. Filtration afforded 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] + .

[0960] Step 2: Synthesis of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide

[0961] 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), and 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 allowed to react at room temperature for 5 hours. The reaction was monitored for completion. Water was added, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzoyl (22 mg, 39% yield). MS m / z(ESI):598.3[M+H] + .

[0962] 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(br s,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).

[0963] Example 83

[0964] Preparation of 7-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide (83)

[0965]

[0966] Step 1: Synthesis of 7-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid

[0967] 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). Under nitrogen protection, react at 65°C overnight and monitor the reaction for 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] + .

[0968] Step 2: Synthesis of 7-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide

[0969] 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 for completion. Water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. The mixture was then purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford 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] + .

[0970] 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).

[0971] Example 84

[0972] Preparation of 7-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2,3-dihydrobenzofuran-4-carboxamide (84)

[0973]

[0974] Step 1: Synthesis of 7-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid

[0975] 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). Stir under nitrogen at 65°C overnight and monitor for reaction completion. Filter to obtain the desired 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] + .

[0976] Step 2: Synthesis of 7-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy-2,3-dihydrobenzofuran-4-carboxamide)

[0977] 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 for completion. Water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (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] + .

[0978] 1 HNMR(400MHz,DMSO-d6)δ11.41(s,1H),11.09(s,1H),9.

[0979] 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=7.0Hz,1H),7.04(d,J=8. 3Hz,1H),4.49(t,J=8.8Hz,2H),3.68(d,J=6.7Hz,2H),3.42(t,J=8.9Hz,2H),2.15–1.83(m,5H),0.98(m,12H).

[0980] Example 85

[0981] Preparation of 7-(5-chloro-4-((2-(diethylphospho)phenylamino)pyrimidin-2-ylamino)-N-isobutoxy-2,3-dihydrobenzofuran-4-carboxamide (85)

[0982]

[0983] Step 1: Synthesis of 7-(5-chloro-4-((2-(diethylphospho)phenylamino)pyrimidin-2-ylamino)-N-isobutoxy-2,3-dihydrobenzofuran-4-carboxamide

[0984] To a solution of 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) were added 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), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL), and the organic layer was concentrated and dried to obtain a residue. The residue was purified by Prep-HPLC. The target compound, 7-(5-chloro-4-((2-(diethylphospho)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] + .

[0985] 1H NMR (400MHz, DMSO-d6) δ11.42(s,1H),11.36(s,1H),8.62(s,1H),8.56(dd,J=8.8,3.9Hz,1H),8.16( s,1H),7.54(d,J=8.3Hz,1H),7.49(ddd,J=12.7,7.7,1.6Hz,1H),7.40(t,J=7.9Hz,1H),7.18–7.10(m ,1H),7.06(d,J=8.4Hz,1H),4.52(t,J=8.8Hz,2H),3.67(d,J=6.7Hz,2H),3.42(t,J=8.8Hz,2H),2.0 3(dtd,J=15.3,7.6,7.0,4.3Hz,4H),1.94(p,J=6.4Hz,1H),1.01(t,J=7.6Hz,3H),0.99–0.92(m,9H).

[0986] Example 86

[0987] Preparation of 7-(5-chloro-4-((2-(diethylphospho)phenyl)amino)pyrimidin-2-ylamino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide (86)

[0988]

[0989] Step 1: Synthesis of 7-(5-chloro-4-((2-(diethylphospho)phenyl)amino)pyrimidin-2-ylamino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide

[0990] To a solution of 7-(5-chloro-4-((2-(diethylphospho)phenyl)amino)pyrimidin-2-ylamino)-2,3-dihydrobenzofuran-4-carboxylic acid (80 mg, 0.1643 mmol) in DMF (25 mL) were added methoxyamine hydrochloride (55 mg, 0.6571 mmol), HATU (125 mg, 0.3286 mmol), DMAP (2 mg, 0.0329 mmol), and DIPEA (149 mg, 1.1501 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL), and the organic layer was concentrated and dried to 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, was obtained as a white solid (52 mg, 0.93 mmol). MS m / z (ESI): 516.2 [M+H] + .

[0991] 1 H NMR (400MHz, DMSO-d6) δ11.47(s,1H),11.45(s,1H),8.66(s,1H),8.56(dd,J=8.3,3.9Hz ,1H),8.17(s,1H),7.56(d,J=8.3Hz,1H),7.49(ddd,J=12.7,7.8,1.6Hz,1H),7.41(t,J= 7.9Hz,1H),7.19–7.11(m,1H),7.06(d,J=8.4Hz,1H),4.53(t,J=8.8Hz,2H),3.71(s,3H) ,3.44(d,J=8.7Hz,2H), 2.03(dqd,J=10.5,7.6,3.9Hz,4H), 0.99(dt,J=17.2,7.6Hz,6H).

[0992] Example 87

[0993] Preparation of 7-(5-chloro-4-(2-(dimethylphosphoryl)phenylamino)pyrimidin-2-ylamino)-N-isobutoxy-2,3-dihydrobenzofuran-4-carboxamide (87)

[0994]

[0995] Step 1: Synthesis of 7-(5-chloro-4-(2-(dimethylphosphoryl)phenylamino)pyrimidin-2-ylamino)-N-isobutoxy-2,3-dihydrobenzofuran-4-carboxamide

[0996] 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), and 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 mixture was reacted at room temperature overnight. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (methanol:dichloromethane = 1:20) to give 7-(5-chloro-4-(2-(dimethylphosphoryl)phenylamino)pyrimidin-2-ylamino)-N-isobutoxy-2,3-dihydrobenzofuran-4-carboxamide (21.4 mg, yield: 57.14%). MS m / z (ESI): 530.2 [M+H]+ .

[0997] 1 H NMR(DMSO-d6)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).

[0998] Example 88

[0999] Preparation of methyl hydrogen (2-((5-chloro-2-((4-(isobutoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate (88)

[1000]

[1001] Step 1: Synthesis of 2,5-dichloro-N-(2-iodophenyl)pyrimidin-4-amine

[1002] 2-Iodoaniline (5.0 g, 22.8 mmol), 2,4,5-trichloropyrimidine (6.3 g, 34.2 mmol), and DIPEA (3.8 mL, 22.8 mmol) were dissolved in nBuOH (15 mL) and reacted at 85°C for 16 h. The reaction was monitored for completion. The mixture was cooled to room temperature and allowed to stand until no more precipitation occurred. Filtration afforded 2,5-dichloro-N-(2-iodophenyl)pyrimidin-4-amine (2.6 g, 31% yield). MS m / z (ESI): 365.9 [M+H] + .

[1003] Step 2: Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)benzoic acid

[1004] Dissolve 2,5-dichloro-N-(2-iodophenyl)pyrimidin-4-amine (4.3 g, 11.6 mmol) and 4-aminobenzoic acid (1.7 g, 12.2 mmol) in nBuOH (50 mL). Add 4N hydrochloric acid in 1,4-dioxane (0.9 mL, 3.5 mmol). React at 120°C for 3 h. Monitor the reaction until complete. Filter the mixture to obtain 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)benzoic acid (5.0 g, 92% yield). MS m / z (ESI): 467.0 [M+H] + .

[1005] Step 3: Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-isobutoxybenzamide

[1006] 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 allowed to react overnight at room temperature and monitored for completion. The solvent was removed by vortexing, and water (20 mL) was added. The product was filtered, dried, and purified by column chromatography (dichloromethane:ethyl acetate = 4:1) to afford 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-isobutoxybenzamide (1.1 g, 48% yield). MS m / z (ESI): 538.01 [M+H] + .

[1007] Step 4: Synthesis of dimethyl (2-((5-chloro-2-((4-(isobutoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate

[1008] 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)2Cl2 (106 mg, 0.13 mmol), and K3PO4 (318 mg, 1.7 mmol) were dissolved in 1,4-dioxane (35 mL) and reacted at 100°C under N2 protection for 16 h. The reaction was monitored for completion. Water (10 mL) was added, and the product was extracted with ethyl acetate (3 × 20 mL). The product was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:ethyl acetate = 5:1 to 3:2) to afford dimethyl (2-((5-chloro-2-((4-(isobutoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate (348 mg, 61% yield). MS m / z(ESI):520.1[M+H] + .

[1009] Step 5: Synthesis of methyl hydrogen (2-((5-chloro-2-((4-(isobutoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate

[1010] 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). The reaction was stirred at 60°C under N2 protection for 2 h, and the reaction was monitored for completion. The solvent was removed by swirl, and preparative HPLC was used to separate the residue to give methyl hydrogen (2-((5-chloro-2-((4-(isobutoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate (34 mg, yield: 70%). MS m / z (ESI): 506.1 [M+H] + .

[1011] 1 H NMR(DMSO-d6)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,1 H),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).

[1012] Other specific compounds in the present application can be prepared by methods similar to those described in the above examples (when necessary, appropriate adjustments are made to the reagents and conditions).

[1013] Biological evaluation of compounds

[1014] Test Example 1: In vitro enzyme inhibitory activity of the compounds of the present invention

[1015] 1. Reagents, consumables, and instruments

[1016]

[1017] 2. Experimental Procedure

[1018] 1) Add 50 μL of compound to a 384-well dilution plate.

[1019] 2) Serially dilute the compounds in each column with DMSO at a ratio of 1:3, with each dilution reaching 10+0 points.

[1020] 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.

[1021] 4) Add 5 μL of 2X enzyme solution to the assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 15 minutes.

[1022] 5) Add 5 μL of 2X substrate solution to a 384-well assay plate.

[1023] 6) Incubate at 25°C for 60 minutes.

[1024] 7) Mix 5 μL Sa-XL665 solution and 5 μL TK antibody-Eu 3+ Add to the assay plate and centrifuge at 1000 rpm for 1 minute.

[1025] 2) Incubate at 25°C for 60 minutes.

[1026] 8) Read the fluorescence signal on an Envision 2104 plate reader.

[1027] 3. Data Analysis

[1028] 1) For each screening plate, calculate the mean data and standard deviation (SD) of DMSO and 100 nM Defactinib (as a control)

[1029] 2) Inhibition percentage of compound (%inh) = 100*(maximum value - sample value) / (maximum value - minimum value)

[1030] 3) Calculate IC50 using the nonlinear regression equation of XLfit 5.3.1, as follows:

[1031] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[1032] X:Log(compound concentration)

[1033] Y: inhibition rate (%inh)

[1034] Top and Bottom: Same as Y unit

[1035] logIC 50 : The same unit as X

[1036] HillSlope: Slope coefficient or slope

[1037] Specific IC 50 Activity data are shown in Table 1.

[1038] 4. Experimental conclusions:

[1039] 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.

[1040] Table 1

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052] 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 (YAP activity detected by western blot)

[1053] 1. Experimental Procedure

[1054] 1) Cell plating

[1055] a. Grow SNU-668 cells (Cat. No. 00668, KCLB) to 80%-90% confluence, remove the culture supernatant, and rinse once with PBS;

[1056] b. Add 2 mL of trypsin to a 10 cm dish and place in an incubator for 3-5 minutes.

[1057] c. Remove the culture plate and add 5 mL of 1640 medium (containing 10% FBS) to terminate the digestion. Transfer the plate to a 15 mL centrifuge tube and centrifuge at 1000 rpm for 5 minutes.

[1058] d. Remove the supernatant and add 5 mL of 1640 medium (containing 10% FBS), resuspend and mix thoroughly, and count;

[1059] e. Take out a 12-well plate and place 1.5×10 5 cells and 900 μL culture medium, and culture in a cell culture incubator for 24 h.

[1060] 2) Cellular drug delivery

[1061] a. Prepare the test compound stock solution (1 mM) in advance, dissolve it in DMSO, and pipette several times to mix well.

[1062] b. Remove the culture plate seeded with cells and pipette 1 μl of 1 mM stock solution (diluted 1000-fold) gently along the well wall. Immediately shake gently to mix thoroughly.

[1063] c. After adding the drug to all wells, shake the tubes slightly to ensure even drug diffusion. Record the time and place the tubes back into the cell culture incubator. Collect the samples after 24 hours.

[1064] 3) Protein extraction

[1065] a. 24 hours after administration, discard the culture medium, wash with PBS, and discard the PBS;

[1066] b. Lyse cells with RIPA lysis buffer containing phosphatase inhibitors and PMSF, centrifuge at 12,000 rpm for 10 min at 4°C, collect the supernatant, determine the protein concentration and adjust the protein concentration, add 4× loading buffer, and cook the protein.

[1067] 4) Western blot detection

[1068] SDS-PAGE electrophoresis was performed at 80 v for 30 min and 120 v for 60 min. Transfer was performed at 80 v for 60 min. Blocking was performed with 5% skim milk for 1 h. Primary antibodies included p-FAKY397 (1:1000, CST), non-p-YAP (1:2000, Abcam), p-YAP (1:1000, CST), and actin (1:10,000, CST) diluted in 5% BSA / TBST, and incubation was performed overnight at 4°C. Secondary antibodies (Goat anti-mouse IgG and Goat anti-rabbit IgG, 1:3000, Proteintech) were diluted in 5% skim milk and incubated for 1 h at room temperature. Thermo Fisher Scientific developer was used.

[1069] 2. Experimental Conclusion

[1070] The results are as follows Figure 2 、 3 As shown in Figures 4 and 5, the results show that the compound 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.

[1071] 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)

[1072] 1. Experimental Procedure

[1073] 1) Cell plating ...

Claims

1. Use of a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating or treating YAP-related diseases, in, R 1 and R 2 Each independently selected from: hydroxyl, C1-C6 alkyl, C1-C6 alkoxy; R 3 Independently selected from: halogen, C1-C6 alkyl, CF3, CHF2, CH2F, CN; R 4 Independently selected from: H, OH, halogen, CF3, CHF2, CH2F, CN, C1-C6 alkyl, C1-C6 alkoxy; R 6 、R 7 、R 8 and R 9 Each is independently selected from: H, halogen, CF3, -CHF2, CH2F, CN, C1-C6 alkyl, C1-C6 alkoxy; R 10 Selected from: H, CF3, CHF2, CH2F, CN, CH2CF3, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally replaced by 1-3 R 13 replace; R 13 Independently selected from: OH, halogen, CF3, CHF2, CH2F, CH2CF3, -CN, C1-C6 alkyl, C1-C6 alkoxy.

2. The use according to claim 1, characterized in that: R 1 and R 2 Each is independently selected from C1-C6 alkyl or C1-C6 alkoxy; R 3 Selected from halogen or CF3; R 4 Selected from H; R 6 、R 7 、R 8 、R 9 Each is independently selected from H, halogen, CF3, C1-C6 alkyl or C1-C6 alkoxy.

3. The use according to claim 1, characterized in that R 10 Selected from: H, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally replaced by 1-3 R 13 replace.

4. The use according to claim 1, wherein The compound is selected from:

5. Compounds Or use of a pharmaceutically acceptable salt thereof in preparing a drug for regulating or treating a YAP-related disease.

6. The use according to any one of claims 1 to 5, characterized in that The YAP-related disease is selected from cancer.

7. The use according to claim 6, characterized in that 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.

8. The use according to claim 7, characterized in that The cancer is selected from one or more of lung cancer, colon cancer, ovarian cancer, prostate cancer, and liver cancer.

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