WO2024251270A1 - Nitrogen-containing aromatic ring compound and medical use thereof - Google Patents

Abstract

The present application relates to a compound as shown in formula I, a composition comprising the compound and a medical use of the compound. The compound of the present application has a relatively good treatment effect on cancer, pulmonary hypertension and pathological angiogenesis.

Description

Nitrogen-containing aromatic ring compounds and their medical uses

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to Chinese patent application No. 2023106779846 filed on June 8, 2023, and the entire text of the above-mentioned Chinese patent application is hereby cited as a part of this application.

Technical Field

The present application relates to a nitrogen-containing aromatic ring compound and its medical use.

Background Art

Focal adhesion kinase (FAK), also known as PTK2 (protein tyrosine kinase 2), is a non-receptor tyrosine kinase located at the intersection of multiple signal transduction pathways and can be activated by integrins, growth factor receptors, G protein-coupled receptors, and cytokines.

FAK can not only participate in signal transduction as a cytoplasmic kinase, but also plays an important role in the cell nucleus. It can promote p53 degradation 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. FAK is widely expressed in the body and plays an important role in cell growth, proliferation, migration, and adhesion. It is involved in embryonic development and the occurrence and development of diseases (cancer and cardiovascular diseases, etc.). Overexpression of FAK has been found in many types of cancer. For example, studies have found that the GTPase RHOAY42C mutation is one of the most common gain-of-function mutations in diffuse gastric cancer, and mice with the RHOAY42C mutation are sensitive to FAK inhibitors, suggesting that inhibiting the activity of FAK may become a new strategy for the treatment of diffuse gastric cancer.

In the process of FAK functioning, the binding of transmembrane integrin receptors to the extracellular matrix (ECM) recruits FAK to the site where integrins are aggregated. FAK does not interact directly with integrins, but binds to the cell membrane and other adhesion proteins through its carboxyl-terminal FAT domain. Once recruited, the inactive FAK activates its catalytic activity through autophosphorylation of Y397. After phosphorylation, FAK, as a molecular scaffold, can recruit Src family kinases. Src can phosphorylate the Y576 and Y577 sites of FAK, further enhancing the activity of FAK and promoting its recruitment of downstream SH2 domain-containing proteins such as Grb2 and PI3K. When Grb2 binds to FAK, it can further recruit SOS to form a complex, thereby further activating the downstream Ras-MAPK signaling pathway.

Based on the above, FAK and its signaling pathway-related targets are considered potential targets for the development of anticancer drugs. However, there are currently no drugs targeting FAK inhibitors on the market, and only some drugs have entered the clinical stage, such as Defactinib, IN10018, GSK-2256098, etc. Therefore, it is crucial to develop new compounds that regulate the FAK signaling pathway.

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

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

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

Based on this, inhibition of active YAP can block related signaling pathways, play a potential role in suppressing tumors, and provide guidance for drug development.

Summary of the invention

In order to solve one of the above-mentioned technical problems existing in the prior art, the present application provides a compound that can be used as a focal adhesion kinase (FAK) inhibitor, as well as a composition containing such a compound and the use of such a compound.

In a first aspect, the present application provides a compound, which is a compound represented by Formula I or a stereoisomer, tautomer, enantiomer, diastereomer, racemate, geometric isomer, nitrogen oxide, solvate, hydrate, crystal form, ester, isotope-labeled compound, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by Formula I:

wherein X is selected from N or -CH-;

Y is selected from -NH-, _-CH2- , O, S or a combination thereof;

Ring A is selected from a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;

Ring B is selected from a 5-15 membered partially unsaturated carbocyclic ring, a 5-15 membered partially unsaturated carboheterocyclic ring, a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;

L represents a single bond or a C _1-10 alkylene group;

M is selected from hydrogen, C _1-10 alkyl, 3-15 membered saturated or partially unsaturated carbocyclic group, 3-15 membered saturated or partially unsaturated heterocyclic group, optionally, the alkyl, saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated heterocyclic group in M is substituted by one or more R ₃ , R ₃ is selected from halogen, cyano, hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, alkoxy, -R ¹ -CN, -R ¹ -NR ² R ³ , -R ¹ -(OH) _q , -R ¹ -COOH, -R ¹ -C(＝O)NR ² R ³ , -C(＝O)R ¹ -OH, -C(＝O)R ¹ , -C(＝O)OR ¹ , -C(＝O)CF ₃ , -S(＝O) ₂ R ¹ , -C(＝O)OR ¹ , -C(＝O)R ¹ CN, -R ¹ -NR ² -R ³ -(OH) _q , -R ¹ -NR ² -R ³ -COOH, -R ¹ -NR ² -R ³ -C(＝O)NR ² R ³ , -R ¹ -NR ² -C(＝O)R ³ -OH, -R ¹ -NR ² -C(＝O)R ³ , -R ¹ -NR ² -S(＝O) ₂ R ³ ;

Optionally, ring A and ring B are fused to form a ring;

Optionally, ring B and M are fused to form a ring;

Ring D is selected from a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;

_R1 is selected from halogen, cyano, nitro, _C1-10 alkyl, _C1-10 haloalkyl, _C1-10 heteroalkyl, C1-10 haloheteroalkyl, _C3-15 saturated or partially unsaturated carbocyclyl, _C3-15 saturated or partially unsaturated heterocyclyl, _6-15 membered aryl, _C7-15 arylalkyl, 5-15 membered heteroaryl or _C4-15 heteroarylalkyl;

R ₂ is selected from -C(=O)NR ⁴ R ⁵ , -C(=O)NR ⁴ -OR ⁵ , -S(=O) ₂ NR ⁴ R ⁵ , -NR ⁴ S(=O) ₂ R ⁵ or -R ⁶ -C(=O)NR ⁴ R ⁵ , optionally, R ⁴ is connected to a carbon atom or a heteroatom on ring D to form a 5-6 membered ring; optionally, R ⁵ is connected to a carbon atom or a heteroatom on ring D to form a 5-6 membered ring;

each substituent ^Ra , ^Rb , ^Rc , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 and ^R6 is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, saturated or partially unsaturated carbocyclyl, saturated or partially unsaturated carbocyclylalkyl, saturated or partially unsaturated heterocyclyl, saturated or partially unsaturated heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;

Optionally, substituents ^Ra , Rb, ^Rc , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 and ^R6 are each independently substituted by one or ^more selected from deuterium, hydroxyl, amino, cyano, halogen, alkyl, cycloalkyl, alkoxy, aryl;

Alternatively, among Ra, ^Rb , ^{Rc , R1} , ^R2 , ^R3 , ^R4 , ^R5 and ^R6 , if there are two adjacent substituents, the two adjacent substituents together with the atoms to which they are attached are linked to form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group or a heteroaryl group;

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

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

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

q is independently selected from 0, 1 or 2.

In some embodiments, X is selected from N.

In some embodiments, Y is selected from -NH-. In some embodiments, Y is selected from -NH-CH ₂ -. In some embodiments, Y is selected from -CH ₂ -CH ₂ -. In some embodiments, Y is selected from O. In some embodiments, Y is selected from S.

In some embodiments, Ring A is selected from a 6-12 membered aromatic ring (e.g., a 6, 7, 8, 9, 10, 11, or 12 membered aromatic ring) or a 5-12 membered heteroaromatic ring (e.g., a 5, 6, 7, 8, 9, 10, 11, or 12 membered heteroaromatic ring).

In some embodiments, Ring A is selected from a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring.

In some embodiments, ring A is selected from a benzene ring, a naphthalene ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a benzene ring and a 5-membered heteroaromatic ring. ring, a fused ring formed by a benzene ring and a 6-membered heteroaromatic ring, and a fused ring formed by a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring.

In some embodiments, ring A is selected from the group represented by formula A-1 to formula A-7:

wherein _X1 to _X8 are each independently selected from C, N, O, S, -NH- or -CH-,

"*" indicates the position where ring A is bonded to -NH-. Indicates the position where ring A and ring B are bonded.

In some embodiments, in Formulae A-1 to A-7, _X1 to _X8 are each independently selected from C and -CH-.

In some embodiments, in Formula A-1 to Formula A-7, _X3 and _X4 are both -CH-, _X1 and _X2 are each independently selected from C, -CH-, N and -NH-, at least one of _X5 , _X6 , _X7 and _X8 is selected from N, O, S or -NH-, and three or four adjacent ones of _X5 , _X6 , _X7 and _X8 are not N at the same time. In some specific embodiments, in Formula A-1 to Formula A-7, _X3 and _X4 are both -CH-, _X1 and _X2 are each independently selected from C, -CH-, N and -NH-, and any one of _X5 , _X6 , _X7 and _X8 is selected from N, O, S or -NH-. In some specific embodiments, in Formula A-1 to Formula A-7, _X3 and _X4 are both -CH-, _X1 and _X2 are each independently selected from C, -CH-, N and -NH-, any two of _X5 , _{X6, X7 and X8} are selected from N, O, S or -NH-, and two adjacent ones of _X5 , _X6 , _X7 and _X8 are not simultaneously O and not simultaneously S. In some specific embodiments, in Formula A-1 to Formula A-7, _X3 and _X4 are both -CH-, _X1 and _X2 are each independently selected from C, -CH-, N and -NH-, any three of _X5 , _X6 , _X7 and _X8 are selected from N, O, S or -NH-, and three adjacent ones of _X5 , _X6 , _X7 and _X8 are not simultaneously N.

In some embodiments, the substituents ^Ra in ring A are each independently selected from deuterium, amino, hydroxyl, cyano, halogen, C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 heteroalkyl, C _1-6 alkoxy, _3-12 -membered saturated or partially unsaturated carbocyclyl, 3-12-membered saturated or partially unsaturated heterocyclyl, 6-15-membered aryl, or 5-15-membered heteroaryl. In some embodiments, the substituents ^Ra in ring A are each independently selected from halogen, C _1-6 alkyl, C _2-6 alkenyl, and C _1-6 alkoxy. In some embodiments, ^Ra is substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _1-10 alkoxy, and 6-15-membered aryl. In some embodiments, ^Ra is connected together with the carbon atoms on ring A to form a 3-6-membered ring. In some embodiments, ^Ra and the carbon atoms on ring A are joined together to form a 5-6 membered ring.

In some embodiments, m is independently selected from 0, 1 or 2.

In some embodiments, Ring A is selected from the group consisting of:

"*" indicates the position where ring A is bonded to -NH-. Indicates the position where ring A and ring B are bonded.

In some specific embodiments, ring A is selected from a benzene ring, a naphthalene ring, a quinoline ring, an isoquinoline ring, a benzopyrrole ring, a benzothiazole ring, and a benzimidazole ring.

In some embodiments, the substituents ^Ra in ring A are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl, vinyl, propenyl, methoxy, ethoxy, propoxy, phenyl and naphthyl. In some embodiments, the substituents ^Ra in ring A are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy and propoxy.

In some embodiments, in Formula I Selected from the group consisting of:

"*" indicates the position where ring A is bonded to -NH-. Indicates the position where ring A and ring B are bonded.

In some embodiments, ring B is selected from a 5-12 membered partially unsaturated carbocyclic ring, a 5-12 membered partially unsaturated carbocyclic ring, a 6-12 membered aromatic ring, or a 5-12 membered heteroaromatic ring. In some embodiments, ring B is selected from a 5-10 membered partially unsaturated carbocyclic ring, a 5-10 membered partially unsaturated carbocyclic ring, a 6-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring. In some embodiments, ring B is selected from a 5-6 membered partially unsaturated carbocyclic ring, a 5-6 membered partially unsaturated carbocyclic ring, a benzene ring, or a 5-6 membered heteroaromatic ring.

In some embodiments, ring B is selected from the group represented by formula B-1 or formula B-2:

Wherein, _Y1 to _Y6 are each independently selected from C, N, O, S, -NH- or -CH-, "*" indicates the position where ring B is bonded to ring A, Indicates the position where ring B and M are bonded.

In some embodiments, ring B is selected from the group represented by formula B-1-1 or formula B-2-1:

Wherein, _Y1 to _Y5 are each independently selected from C, N, O, S, -NH- or -CH-.

In some embodiments, in formula B-1-1 and formula B-2-1, at least one of Y ₁ to Y ₅ is selected from N, O, S and -NH-. In some embodiments, in formula B-1-1 and formula B-2-1, at least two of Y ₁ to Y ₅ are selected from N and -NH-. In some embodiments, in formula B-1-1 and formula B-2-1, any two or any three of Y ₁ to Y ₅ are selected from N and -NH-. In some embodiments, in formula B-1-1, Y ₁ and Y ₄ are selected from -CH-, and Y ₂ and Y ₃ are selected from N.

In some embodiments, the substituents ^R in ring B are each independently selected from deuterium, amino, hydroxyl, cyano, halogen, C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 heteroalkyl, C _1-6 alkoxy, _3-12 -membered saturated or partially unsaturated carbocyclyl, 3-12-membered saturated or partially unsaturated heterocyclyl, 6-15-membered aryl, or 5-15-membered heteroaryl. In some embodiments, the substituents ^R in ring B are each independently selected from deuterium and C _1-6 alkyl. In some embodiments, ^R is substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _1-10 alkoxy, and 6-15-membered aryl.

In some embodiments, n is independently selected from 0, 1 or 2.

In some embodiments, Ring B is selected from the group consisting of:

In some embodiments, Ring B is selected from the group consisting of:

In some embodiments, the substituents ^R in ring B are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl, alkenyl, methoxy, ethoxy, propoxy, phenyl and naphthyl; or, the substituents ^R in ring B are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and pentyl. In some embodiments, the substituents ^R in ring B are each independently selected from hydrogen and methyl.

In some specific embodiments, Ring B is a pyrazole ring.

In some embodiments, in Formula I Selected from the group consisting of:

"*" indicates the position where ring B is bonded to ring A. Indicates the position where ring B and M are bonded.

In some embodiments, ring B is fused with ring A to form a 6-15 membered ring, such as a 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 membered ring. In some embodiments, ring B is fused with ring A to form a 6-10 membered ring. In some embodiments, the ring formed by the fusion of ring B and ring A has a structure shown in the following formula AB:

Wherein, _Y1 to _Y3 are each independently selected from C, N, O, S, -NH- or -CH-.

In some embodiments, the ring formed by the fusion of ring B and ring A is selected from the group consisting of the following structures:

Wherein "*" indicates the position where ring A is bonded to -NH-. Indicates the position where ring B and M are bonded.

In some embodiments, the compound represented by Formula I is selected from the structures represented by Formula I-1 to Formula I-6:

wherein X, Y, _R1 , _R2 , Ra, ^Rb , ^Rc , ^L , M, ring D, m, n and p are as defined in Formula I, and _Y1 to _Y5 are as defined in Formula B-1 and Formula B-2.

In some embodiments, in the above formula I-1 to formula I-6, ^Ra and the carbon atom on the benzene ring to which it is connected are connected to form a 5-6 membered ring.

In some embodiments, in Formulas I-1 to I-3, at least one of _Y1 to _Y5 is selected from O, S or N. In some embodiments, in Formulas I-1 to I-3, _Y2 and _Y3 are both N. In some embodiments, in Formulas I-1 to I-3, _Y2 and _Y1 are both N.

In some embodiments, the carbocyclic ring in the saturated or partially unsaturated carbocyclic group represented by M is selected from the following structures;

In some embodiments, the heterocyclic ring in the saturated or partially unsaturated heterocyclic group represented by M is selected from the following structures;

In M, each x is independently 0, 1, 2 or 3; each y and z is independently 0, 1, 2 or 3.

In some embodiments, the carbocyclic ring in the saturated or partially unsaturated carbocyclic group represented by M is selected from the following structures:

In some embodiments, the heterocyclic ring in the saturated or partially unsaturated heterocyclic group represented by M is selected from the group consisting of the following structures:

In some embodiments, M is selected from the group consisting of hydrogen, C _1-6 alkyl, or the following groups:

wherein R ₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, -R ¹ -C(＝O)NR ² R ³ , -C(＝O)R ¹ -OH, -C(＝O)R ¹ , -R ¹ -COOH, -C(＝O)OR ¹ , -R ¹ -OH, -C(＝O)CF ₃ , -C(＝O)R ¹ CN or -S(＝O) ₂ R ¹ ; and R ¹ , R ² and R ³ are defined the same as in Formula I.

In some embodiments, _R4 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or the following groups:

In some embodiments, M is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and the following groups:

In some embodiments, M is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl. In some embodiments, the alkyl involved in M is substituted by one or more selected from halogen, hydroxyl, cyano, C _3-8 heterocycloalkyl, C _1-6 haloalkyl, C _1-6 alkoxy.

In some embodiments, ring B and M are fused to form a 6-15 membered ring, such as a 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 membered ring. In some embodiments, ring B and M are fused to form a 6-10 membered ring. In some embodiments, the ring formed by the fusion of ring B and M has the structure shown in the following formula BM-1 and formula BM-2:

Wherein, _Y1 to _Y3 are each independently selected from C, N, -NH- or -CH-, and Z is selected from _-CH2- , -NH-, O, and S.

In some embodiments, the ring B and M are fused to form a ring selected from the group consisting of the following structures:

Wherein, _Y1 and _Y2 are each independently selected from C, N, -NH- or -CH-; "*" indicates the position where M and _R4 are bonded, Indicates the position where ring B is bonded to ring A.

In some embodiments, the ring B and M are fused to form a ring selected from the group consisting of the following structures:

"*" indicates the position where M and _R4 are bonded. Indicates the position where ring B is bonded to ring A.

In some embodiments, ring D is selected from a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring. In some embodiments, ring D is selected from a 6-10 membered aromatic ring or a 5-10 membered azaaromatic ring. In some embodiments, ring D is selected from a benzene ring or a 6-membered azaaromatic ring. In some embodiments, ring D is selected from a benzene ring, an imidazole ring, a pyrazole ring, a triazole ring, a tetrazole ring, an oxazole ring, a thiazole ring, a furan ring, a thiophene ring, a pyrrole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring and the group consisting of the following groups:

Indicates the position where ring D and Y are bonded.

In some embodiments, ring D is selected from a benzene ring, a pyridine ring, a pyrimidine ring, and a pyridazine ring.

In some embodiments, the substituents ^Rc in ring D are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 heteroalkyl, _C1-6 alkoxy, 3-12-membered saturated or partially unsaturated carbocyclyl, 3-12-membered saturated or partially unsaturated heterocyclyl, 6-15-membered aryl, or 5-15-membered heteroaryl. In some embodiments, the substituents ^Rc in ring D are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl, alkenyl, methoxy, ethoxy, propoxy, phenyl, and naphthyl. In some embodiments, R ^c is substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _1-10 alkoxy, 6-15 membered aryl. In some embodiments, p is independently selected from 0, 1 or 2. In some specific embodiments, the substituents R ^c in ring D are each independently selected from deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl, alkenyl, methoxy, ethoxy, propoxy, phenyl and naphthyl.

In some embodiments, _R2 is selected from the group consisting of:

Wherein, R ⁴ and R ⁵ are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _1-6 alkoxy, 3-12-membered saturated or partially unsaturated carbocyclic group, 3-12-membered saturated or partially unsaturated heterocyclic group, 6-15-membered aryl or 5-15-membered heteroaryl. In some embodiments, R ⁴ and R ⁵ are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _1-10 alkoxy, 6-15-membered aryl. In some embodiments, R ⁴ and R ⁵ are each independently selected from hydrogen, deuterium, halogen, C _1-6 alkyl, C _1-6 deuterated alkyl and 6-15-membered aryl. In some embodiments, ^R4 and ^R5 are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated tert-butyl, deuterated pentyl, cyclopentyl, pentyl, cyclohexyl, alkenyl, methoxy, ethoxy, propoxy, phenyl and naphthyl.

In some embodiments, the substituent R ⁴ in R ₂ is connected to a carbon atom or a heteroatom on ring D to form a 5-6 membered ring, for example, R ₂ and ring D together are

In some embodiments, the substituent R ⁵ in R ₂ is connected to a carbon atom or a heteroatom on ring D to form a 5-6 membered ring, for example, R ₂ and ring D together are

In some embodiments, in Formula I Selected from the group consisting of:

Wherein, R ⁴ , R ⁵ and R ^c are as defined above.

In some embodiments, R ₁ is selected from halogen, cyano, nitro, C _1-10 alkyl, C _3-10 cycloalkyl and C _1-10 haloalkyl. In some embodiments, R ₁ is selected from halogen, cyano and C _1-6 haloalkyl. In some specific embodiments, R ₁ is selected from fluorine, chlorine, bromine, iodine, cyano, CF ₃ , CHF ₂ and CH ₂ F. In some specific embodiments, R ₁ is selected from fluorine, chlorine, bromine, iodine, cyano and CF ₃ .

In some embodiments, each substituent R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C _1-10 alkyl, C 2-10 alkenyl, C _2-10 alkynyl, C 1-10 heteroalkyl, C _1-10 alkoxy, 3-15 membered saturated or partially unsaturated carbocyclyl, C _4-15 saturated or partially unsaturated carbocyclylalkyl, 3-15 membered saturated or partially unsaturated heterocyclyl, C _3-15 saturated or partially unsaturated heterocyclylalkyl, 6-15 membered aryl, C 7-20 arylalkyl, 5-15 membered heteroaryl or C _4-20 heteroarylalkyl; alternatively, the substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-10 alkyl, C _{2-10 alkenyl, C 2-10} alkynyl, C _1-10 heteroalkyl, C 1-10 alkoxy, 3-15 membered saturated or partially unsaturated carbocyclyl, C ^4-15 saturated or partially unsaturated carbocyclylalkyl, 3-15 membered saturated or partially unsaturated heterocyclyl, C ^3-15 saturated or partially unsaturated heterocyclylalkyl, 6-15 ^membered aryl, C ^7-20 arylalkyl, ^5-15 membered heteroaryl or C _4-20 heteroarylalkyl; ⁶ are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _1-10 alkoxy, and 6-15 membered aryl.

In some embodiments, each substituent R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C 1-6 heteroalkyl, C _1-6 alkoxy, 3-12 membered saturated or partially unsaturated carbocyclyl, C _4-12 saturated or partially unsaturated carbocyclylalkyl, _3-12 membered saturated or partially unsaturated heterocyclyl, C _3-12 saturated or partially unsaturated heterocyclylalkyl, 6-12 membered aryl, C _7-15 arylalkyl, 3-12 membered heteroaryl or C 4-15 heteroarylalkyl; alternatively, the substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C _1-6 alkoxy, 3-12 membered saturated or partially unsaturated carbocyclyl, C ^4-12 saturated or partially unsaturated carbocyclylalkyl, 3-12 membered saturated or partially unsaturated heterocyclyl, C _3-12 saturated or partially unsaturated heterocyclylalkyl, 6-12 ^membered aryl, C ^{7-15 arylalkyl} , ^3-12 membered heteroaryl or C ^4-15 heteroarylalkyl; ⁶ are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, and 6-12 membered aryl.

In some embodiments, each substituent R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, propenyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl and naphthyl. Alternatively, the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from deuterium, hydroxyl, amino, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl and naphthyl. One or more substituted.

In some embodiments, in Formula I, L represents a single bond or a C _1-6 alkylene group. In some embodiments, in Formula I, L represents a single bond or a C _1-4 alkylene group. In some embodiments, in Formula I, L represents a single bond or a C _1-3 alkylene group. In some embodiments, in Formula I, L represents a single bond. In some embodiments, in Formula I, L represents a methylene group. In some embodiments, in Formula I, L represents an ethylene group. In some embodiments, in Formula I, L represents a propylene group.

In some embodiments, the compound represented by Formula I has the structure represented by the following Formula I-1-1 to Formula I-1-6:

wherein L, M, _R1 , _R2 , Ra, ^Rb , ^Rc , ^m , n and p are as defined in Formula I, and _Y1 to _Y4 are as defined in Formula B-1 and Formula B-2.

In some embodiments, in the above formula I-1-1 to formula I-1-6, R ₁ is fluorine, chlorine, bromine, iodine, trifluoromethyl or cyano.

In some embodiments, in the above formula I-1-1 to formula I-1-6, R ₂ is -C(=O)-NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy and deuterated C _1-6 alkyl.

In some embodiments, in the above formula I-1-1 to formula I-1-6, each ^Ra is independently hydrogen or _C1-6 alkoxy.

In some embodiments, in the above formula I-1-1 to formula I-1-6, each R ^b is independently hydrogen or C _1-6 alkyl.

In some embodiments, in Formula I-1-1, Formula I-1-2, Formula I-1-4 and Formula I-1-5, Y ₂ is selected from -NH-, O or S, and any one or any two of Y ₁ , Y ₃ and Y ₄ are N.

In some embodiments, in Formula I-1-3 and Formula I-1-6, any one, any two, or any three of _Y1 to _Y4 are selected from N and -NH-.

In some embodiments, the compound of Formula I has the structure shown in the following Formula Ia to Formula Ib:

Wherein, L, M, ^Ra and ^R4 are defined as above in this application.

In some embodiments, the compound of Formula I has a structure shown in any one of the following Formulas I-1-a to I-1-f:

wherein ^Ra is hydrogen, methoxy, ethoxy or propoxy; ^R4 is selected from _C1-4 alkyl, _C1-4 alkoxy and _C1-4 deuterated alkyl; each _M1 is independently selected from hydrogen and _C1-6 alkyl, L is a single bond or _C1-4 alkylene; each Z is independently selected from O, -S(=O) ₂ , _CR5R6 or _NR7 , and _R5 , _{R6 and R7} are each independently selected from hydrogen, methyl, -C(=O) _CH2 -OH, -C(=O) _CH2CH3 , -CH2 _- COOH, -C(=O) _CH3 , _-CH2- CH2- _OH , _-CH ( _CH3 )-COOH, -C(=O) _CF3 , -COOH, -C(=O) _CH2CN , -S(=O) ₂ - _CH3 or -C(=O) _OCH3 .

In some embodiments, ^Ra is connected to the carbon atom on the benzene ring to form a 5-membered ring. In some embodiments, ^Ra is connected to the carbon atom on the benzene ring to form a 6-membered ring.

In some embodiments, R ⁴ is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methyl, deuterated ethyl, deuterated propyl, or deuterated isopropyl.

In some embodiments, L is a single bond, methylene, ethylene, or propylene. In some embodiments, L is a single bond. In some embodiments, L is a methylene. In some embodiments, L is ethylene. In some embodiments, L is propylene.

In some embodiments, each M ₁ is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl. In some embodiments, the alkyl in each M ₁ is independently substituted by one or more selected from hydroxyl, 5-6 membered heterocycloalkyl.

In some embodiments, the compound represented by Formula I is the following compound or its stereoisomers, tautomers, enantiomers, Diastereomers, racemates, geometric isomers, nitrogen oxides, solvates, hydrates, crystal forms, esters, isotopically labeled compounds, metabolites, pharmaceutically acceptable salts or prodrugs:

In a second aspect, the present application provides a pharmaceutical composition comprising the above-mentioned compound or its stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitrogen oxides, solvates, hydrates, crystal forms, esters, isotope-labeled compounds, metabolites, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable excipients thereof.

In a third aspect, the present application provides use of the above-mentioned compound or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing or treating FAK-related diseases.

In some embodiments, the FAK-related disease is selected from cancer, pulmonary hypertension or pathological angiogenesis, and optionally, the cancer includes lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, sheath cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestinal cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis cancer, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is diffuse gastric cancer.

In a fourth aspect, the present application provides a compound as described above or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug or the use of the pharmaceutical composition as described above in the preparation of a drug for regulating or treating a disease associated with YAP.

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

In a fifth aspect, the present application provides a compound as described above or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug or the use of the pharmaceutical composition as described above in the preparation of a drug for regulating or treating diseases related to FAK and YAP.

In some embodiments, the disease associated with FAK and YAP is selected from cancer.

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

In some embodiments, the cancer in the YAP-related disease is selected from one or more of lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer, and gastric cancer.

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

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

In a sixth aspect, the present application provides a method for regulating the Hippo-YAP signaling pathway, comprising administering the above-mentioned compound or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug or the pharmaceutical composition as described above.

In a seventh aspect, the present application provides the use of the above-mentioned compound or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug or the above-mentioned pharmaceutical composition in the preparation of a Hippo-YAP signaling pathway inhibitor.

In an eighth aspect, the present application provides a method for preventing or treating a YAP-related disease, comprising administering a compound as described above or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, hydrate, isotope or prodrug thereof, or a pharmaceutical composition as described above.

In some embodiments, the YAP-associated disease comprises a combination of one or more of skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, and uterine cancer.

In a ninth aspect, the present application provides a method for preventing or treating a FAK-related disease, comprising administering the above-mentioned compound or its enantiomer. isomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug thereof or pharmaceutical composition as described above.

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

In some embodiments, the cancer comprises lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, sheath cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis cancer, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers.

In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is diffuse gastric cancer.

In the tenth aspect, the present application provides a method for inhibiting the activity of FAK kinase and/or YAP protein in a cell or a subject, the method comprising contacting the cell with the above-mentioned compound or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, hydrate, isotope or prodrug or the pharmaceutical composition as described above; or administering the above-mentioned compound or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, hydrate, isotope or prodrug or the pharmaceutical composition as described above to the subject.

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

The compounds provided in the embodiments of the present application have good inhibitory effects on FAK and YAP, and have good therapeutic effects and good clinical application prospects on cancer, pulmonary hypertension, and pathological angiogenesis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 shows the inhibitory effects of Compound 01 and Compound 02 prepared in the examples of the present application on FAK and YAP in the diffuse gastric cancer (DGC) mouse organoid MDO-MCR model.

Figure 2 shows the inhibitory effects of Compound 10, Compound 11, Compound 12 and Compound 13 prepared in the examples of the present application on FAK in the diffuse gastric cancer (DGC) mouse organoid MDO-MCR model.

FIG3 shows the inhibitory effects of Compound 13, Compound 15 and Compound 16 prepared in the examples of the present application on FAK in the diffuse gastric cancer (DGC) mouse organoid MDO-MCR model.

Figure 4 shows the inhibitory effects of Compound 20, Compound 21, Compound 22, Compound 23, Compound 24 and Compound 25 prepared in the examples of the present application on FAK and YAP in the diffuse gastric cancer (DGC) mouse organoid MDO-MCR model.

Figure 5 shows the inhibitory effects of Compound 26, Compound 27, Compound 28, Compound 29, Compound 30 and Compound 14 prepared in the examples of the present application on FAK and YAP in the diffuse gastric cancer (DGC) mouse organoid MDO-MCR model.

FIG6 shows the inhibitory effects of Compound 01 and Compound 02 prepared in the examples of the present application on FAK in the human diffuse gastric cancer cell line SNU668 model.

FIG. 7 shows the inhibitory effects of Compound 03 and Compound 04 prepared in the Examples of the present application on FAK in the human diffuse gastric cancer cell line SNU668 model.

FIG8 shows the inhibitory effects of Compound 26, Compound 27, Compound 28, Compound 29 and Compound 30 prepared in the Examples of the present application on FAK and YAP in the human diffuse gastric cancer tumor cell line SNU668 model.

Figure 9 shows the inhibitory effects of Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, Compound 36 and Compound 37 prepared in the Examples of the present application on FAK and YAP in the human diffuse gastric cancer tumor cell line SNU668 model.

DETAILED DESCRIPTION

In order to make the purpose, technical solution and advantages of the present application more clearly understood, the present application is further described in detail below in conjunction with the embodiments and drawings. The specific embodiments described herein are only used to explain the present application and are not intended to constitute any limitation to the present application.

Definitions and general terms

Unless otherwise specified, all technical terms used in this application have the same meaning as commonly understood by those skilled in the art to which this application belongs. All patents and publications involved in this application are incorporated herein by reference in their entirety.

The term "subject" as used herein refers to an animal. Typically, the animal is a mammal. A subject, for example, also refers to a primate. In some embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" used in this application refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

The term "stereoisomer" as used herein refers to compounds having the same chemical structure but with different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formula described in this application are within the scope of this application.

The term "enantiomer" as used herein refers to stereoisomers that are real objects and mirror images of each other and are not superimposable.

The term "diastereomer" as used herein refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

The term "racemic modification" as used in this application refers to a form of optical movement of molecules, including racemates and mesomers. A raceme is an equimolar mixture of an optically active chiral molecule and its enantiomer, which is composed of equal amounts of molecules with opposite optical rotation directions and equal optical rotation abilities. The optical activities cancel each other out due to the interaction between these molecules, so it is optically inactive and is usually labeled with D, L. A mesomer is a molecule with two or more asymmetric centers but other symmetry factors, such as the existence of a symmetry plane, which makes the entire molecule optically inactive and has no enantiomers. It is usually represented by meso or i.

The term "geometric isomers" used in this application includes: cis-trans isomers, isomeric polymers and syndiotactic polymers, rotational isomers caused by steric hindrance, etc.

As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerizations and imine-enamine isomerizations. Valence tautomers include interconversions that occur via reorganization of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application.

The term "nitrogen oxide" as used in this application refers to when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocyclic rings. The corresponding amines can be treated with oxidants such as hydrogen peroxide or peracids (such as peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514), in which, for example, the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

The term "solvate" used in this application refers to an association formed by one or more solvent molecules and the compound of the present application. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol.

The term "hydrate" as used herein refers to an association formed by water as a solvent molecule.

The term "metabolite" as used herein refers to a product obtained by metabolism of a specific compound or its salt in vivo. A metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described in the present application. Such a product can be obtained by administering a compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present application includes metabolites of a compound, including metabolites produced by contacting a compound of the present application with a mammal for a period of time.

The term "ester" includes compounds or fragments containing carbon atoms or heteroatoms bonded to an oxygen atom bonded to the carbon on the carbonyl group. The term "ester" includes alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, etc.

It should be understood that the compounds of the present application can be described as different tautomers. It should also be understood that when a compound has a tautomeric form, all tautomeric forms are intended to be included within the scope of the present application, and the naming of the compound does not exclude any tautomeric form. It should be understood that some tautomers may have a higher level of activity than other tautomers.

The term "crystalline form" refers to the crystal structures in which a compound (or its salt or solvate) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, etc. The crystal form of a compound can be obtained by crystallization under different conditions.

The term "isotope labeling" refers to the process of replacing the corresponding element in a compound molecule with an isotope. "Isotopes" are the same element with different masses but the same chemical properties. The process of replacing an atom in a molecule with its isotope is called isotope labeling.

The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

The term "pharmaceutically acceptable salt" used in this application refers to organic salts and inorganic salts of the compounds of this application. The term "prodrug" used in this application represents a compound that is converted into a compound shown in formula I, Ia, Ib, I-1 to I-6, I-1-1 to I-1-6, I-1-a to I-1-f in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug to the parent structure by enzymes in the blood or tissues. The prodrug compounds of this application can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in this application contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.

As used herein, the term "treating" any disease or condition refers to improving a disease or condition (i.e., slowing down or preventing or alleviating the development of a disease or at least one clinical symptom thereof) in some embodiments. In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters) or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or deterioration of a disease or condition.

In the present application, the term "C _mn " used alone as a prefix refers to any group having m to n carbon atoms, and C _m refers to any group having m carbon atoms. For example, C _1-20 alkyl refers to an alkyl group containing 1 to 20 carbon atoms; C _1-8 alkoxy refers to an alkoxy group containing 1 to 8 carbon atoms; C _2-6 alkenyl refers to an alkenyl group containing 2 to 6 carbon atoms; C ₆ haloalkyl refers to a haloalkyl group containing 6 carbon atoms. In the present application, "C _mn " and "C _m -C _n " can be used interchangeably, both of which refer to a group having m to n carbon atoms, for example, "C _1-6 " and "C ₁ -C ₆ " both refer to the group having 1, 2, 3, 4, 5 or 6 carbon atoms.

In the present application, the term "m-n membered" used alone as a prefix refers to a ring having m to n ring atoms, such as "3-6 membered saturated or partially unsaturated carbocyclic group" means that the carbocyclic group has 3 to 6 ring atoms, "3-6 membered saturated or partially unsaturated heterocyclic group" means that the heterocyclic group has 3 to 6 ring atoms; "6-10 membered aryl" means that the aryl group has 6 to 10 ring atoms; "5-10 membered heteroaryl" means that the heteroaryl group has 5 to 10 ring atoms.

The term "substituted" or "substituted" as used herein means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. When more than one position in a given structural formula can be replaced by one or more substituents selected from a specific group, the substituent can be replaced identically or differently at each position.

In various parts of this specification, the substituents of the compounds disclosed in the present application are disclosed according to group types or ranges. It is particularly pointed out that the present application includes each independent secondary combination of the individual members of these group types and ranges. For example, the term "C _1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl.

In various parts of this application, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is connected.

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., _C1-6 means containing 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.

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 application, " _C1 - _C6 heteroalkyl" refers to a group containing 1-6 (i.e., 1, 2, 3, 4, ₅ or 6) carbon atoms, and _{1 , 2 or 3 heteroatoms selected from N, O, S or P. Representative examples include (but are not limited to): CH3OCH2-, CH3SCH2- , CH3CH2OCH2- , etc.}

The term "haloalkyl" means that an alkyl group is substituted with one or more halogen atoms, wherein alkyl has the meaning as described in the present application. When a haloalkyl group is a linking group, and "haloalkyl" is listed for the Markush group definition, then "haloalkyl" means a linked haloalkylene group. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.

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, " _C2-6 alkenyl" refers to a group containing 2 to 6 carbon atoms. Alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and having a specified number of carbon atoms. For example, " _C2-6 alkynyl" refers to a hydrocarbon group containing 2 to 6 carbon atoms. Alkynyl includes, but is not limited to, ethynyl, propynyl, butynyl, etc.

The term "cycloalkyl" refers to a saturated monocyclic (e.g., C _3-6 ), bicyclic (e.g., C _5-12 fused bicyclic, C _5-12 membered spiro bicyclic) or polycyclic cyclic alkyl, "C _3-6 cycloalkyl" means that the cycloalkyl contains 3 to 6 carbon atoms, "C _3-12 cycloalkyl" means that the cycloalkyl contains 3 to 12 carbon atoms. Representative cycloalkyl groups of the present application include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, etc.

The term "heterocycloalkyl" and "saturated heterocyclic group" can be used interchangeably, and refers to a group formed by replacing at least one carbon atom of a cycloalkyl ring with a heteroatom, and the heteroatom can be oxygen, nitrogen, sulfur, phosphorus, silicon, etc. Examples of heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, glycidyl, azepanyl, oxetanyl, thiepanyl, glycidyl, azepanyl, oxetanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, and dioxanyl. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and pyrimidinedione groups in which two carbon atoms on the ring are replaced by oxygen atoms.

The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. The alkoxy group may optionally be substituted with one or more substituents described herein. When the alkoxy group is a linking group, and "alkoxy" is listed for the Markush group definition, then "alkoxy" means the attached alkyleneoxy group. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n-propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n-butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, —OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (—OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (—OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (—OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy (—OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butoxy (—OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butoxy (—OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), and the like.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). The term "hydroxyl" refers to "-OH". The term "amino" refers to "-NH ₂ ". The term "cyano" refers to "-CN" or "-C≡N". The term "hydrogen" refers to H, including ¹ H, ² H, ³ H. The term "heteroatom" refers to N, O, S, P, Si and the like.

The term "saturated or partially unsaturated carbocyclyl" and "saturated or partially unsaturated carbocycle" can be used interchangeably to refer to a non-aromatic saturated or partially unsaturated monocyclic or polycyclic system consisting of carbon atoms as ring atoms. In some embodiments, the polycyclic system is a bicyclic or tricyclic ring. Saturated or partially unsaturated carbocyclyl includes saturated or partially unsaturated monocyclic carbocyclyl, saturated or partially unsaturated spirocarbocyclyl, saturated or partially unsaturated fused carbocyclyl, and saturated or partially unsaturated bridged carbocyclyl. In some embodiments, saturated or partially unsaturated carbocyclyl represents a 3-15-membered saturated or partially unsaturated carbocyclyl; in some embodiments, saturated or partially unsaturated carbocyclyl represents a 3-12-membered saturated or partially unsaturated carbocyclyl; in other embodiments, saturated or partially unsaturated carbocyclyl represents a 3-10-membered saturated or partially unsaturated carbocyclyl; in other embodiments, saturated or partially unsaturated carbocyclyl represents a 3-7-membered saturated or partially unsaturated carbocyclyl. The saturated or partially unsaturated carbocyclic group may be independently and optionally substituted by one or more substituents described herein. When the saturated or partially unsaturated carbocyclic group is a linking group, the term "saturated or partially unsaturated carbocyclic group" is represented by "saturated or partially unsaturated carbocyclylene".

The term "saturated or partially unsaturated heterocyclic group" is used interchangeably with "saturated or partially unsaturated heterocyclic ring", "saturated or partially unsaturated carboheterocyclic ring", and "saturated or partially unsaturated carboheterocyclic group" to refer to a non-aromatic saturated or partially unsaturated monocyclic or polycyclic ring system in which the ring atoms contain at least one carbon atom and one or more heteroatoms. The heteroatoms have the meanings as described in the present application. Unless otherwise specified, a saturated or partially unsaturated heterocyclic group may be connected to the rest of the molecule through its carbon atoms or through heteroatoms. In some embodiments, the polycyclic system is bicyclic or tricyclic. Saturated or partially unsaturated heterocyclic groups include saturated or partially unsaturated monoheterocyclic groups, saturated or partially unsaturated spiroheterocyclic groups, saturated or partially unsaturated fused heterocyclic groups, and saturated or partially unsaturated bridged heterocyclic groups. In some embodiments, the saturated or partially unsaturated heterocyclic group represents a 3-15-membered saturated or partially unsaturated heterocyclic group; in some embodiments, the saturated or partially unsaturated heterocyclic group represents a 3-12-membered saturated or partially unsaturated heterocyclic group; in other embodiments, the saturated or partially unsaturated heterocyclic group represents a 3-10-membered saturated or partially unsaturated heterocyclic group; in other embodiments, the saturated or partially unsaturated heterocyclic group represents a 3-7-membered saturated or partially unsaturated heterocyclic group; in other embodiments, the saturated or partially unsaturated heterocyclic group represents a 3-6-membered saturated or partially unsaturated heterocyclic group. The saturated or partially unsaturated heterocyclic group may be independently Optionally substituted with one or more substituents described herein. When a saturated or partially unsaturated heterocyclic group is a linking group, the term "saturated or partially unsaturated heterocyclic group" is represented as "saturated or partially unsaturated heterocyclic group".

The term "aryl" and "aromatic ring" are used interchangeably to refer to aromatic monocyclic and polycyclic ring systems composed of carbon atoms as ring atoms. In some embodiments, the polycyclic ring system is a bicyclic or tricyclic ring. In some embodiments, the aryl group is a 6-15 membered aryl group; in some embodiments, the aryl group is a 6-12 membered aryl group; in other embodiments, the aryl group is a 6-10 membered aryl group; in other embodiments, the aryl group is a phenyl or naphthyl group. When the aryl group is a linking group, the aryl group represents a linked arylene group. The aryl group may be independently and optionally substituted with one or more substituents described herein.

The term "heteroaryl" is used interchangeably with "heteroaromatic ring" and refers to an aromatic monocyclic or polycyclic ring system consisting of at least one carbon atom and one or more heteroatoms as ring atoms. The heteroatoms have the meanings as described herein. Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, pyrazinyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidin ... pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3- [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like. When aryl is a linking group, aryl represents a linked arylene group. The aryl groups may be independently optionally substituted with one or more substituents described herein.

As described in the present application, unless otherwise specified in detail, the combined groups used in the present application, such as hydroxyalkyl, aminoalkyl, hydroxyalkoxy, aminoalkoxy, alkylamino, saturated or partially unsaturated carbocyclylalkyl, saturated or partially unsaturated heterocyclylalkyl, arylalkyl, heteroarylalkyl, and the groups involved, such as amino, hydroxy, alkyl, alkoxy, saturated or partially unsaturated carbocyclyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, have the definitions described in the present application.

As described in the present application, unless otherwise specified, ring substituents, such as saturated or partially unsaturated carbocyclic groups, saturated or partially unsaturated heterocyclic groups, aryls, heteroaryls, can be connected to the rest of the molecule through any connectable position on the ring. For example, piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl. As described in the present application, a ring system formed by a substituent R connected to a central ring by a bond represents that the substituent R can be substituted at any substitutable or any reasonable position on the ring to which it is connected. As described in the present application, a ring system formed by a bond connected to the center of the ring represents that the connecting bond can be connected to the rest of the molecule at any connectable position on the ring system. As described in the present application, if there are two attachment points on a ring connected to the rest of the molecule, the two attachment points can be connected to the rest of the molecule at any connectable position on the ring, and the two ends of the connection can be interchanged.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or solvent associated with the consistency of the dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that greatly reduce the efficacy of the compounds disclosed in the present application when administered to the patient and interactions that will result in a pharmaceutical composition that is not pharmaceutically acceptable. In addition, each excipient must be pharmaceutically acceptable, for example, having a sufficiently high purity. Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. In addition, pharmaceutically acceptable excipients can be selected based on their specific functions in the composition. For example, certain pharmaceutically acceptable excipients that can help produce uniform dosage forms can be selected. Certain pharmaceutically acceptable excipients that can help produce stable dosage forms can be selected. Certain pharmaceutically acceptable excipients that can help carry or transport the compounds of the present application from one organ or part of the body to another organ or part of the body when administered to the patient can be selected. Certain pharmaceutically acceptable excipients that enhance patient compliance can be selected.

Some suitable examples of excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adherents, antioxidants, chelating agents, penetration enhancers, pH adjusters, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents and filter aids. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may serve more than one function, and may provide alternative functions, depending on the formulation. How much of the excipient is present in the formulation and what other excipients are present in the formulation. The compounds of the present invention can be formulated using methods known in the art so as to release the active ingredient quickly, continuously or delayed after administration to the patient.

The skilled artisan has the knowledge and skill in the art to enable them to select appropriate pharmaceutically acceptable excipients in appropriate amounts for use in the present application. In addition, there are a large number of resources available to the skilled artisan that describe pharmaceutically acceptable excipients and are used to select appropriate pharmaceutically acceptable excipients. Examples include Remington"s Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

As used in this application, "pharmaceutically acceptable carrier" includes any and all solvents and solvent mixtures, coatings, complexing agents, solid carriers, dispersion media, surface active excipients, antibacterial and antifungal agents, isotonic and absorption delaying agents for pharmaceutically active substances, and mixtures thereof, which are also known in the art.

Various carriers for formulating pharmaceutically acceptable compositions, and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference. Except for any conventional carriers that are incompatible with the compounds of the present application, such as by producing any undesirable biological effect, or by interacting in a deleterious manner with any other ingredient in the pharmaceutically acceptable composition, it is contemplated that their use is within the scope of the present application.

Suitable pharmaceutically acceptable carriers depend on the form of the drug and are known to those skilled in the art. Non-limiting examples for pharmaceutically acceptable carriers include those having components selected from the group consisting of lactose, gelatin, sugar alcohols (e.g., starch, mannitol, corn starch, etc.), vegetable oils, talc, magnesium stearate, colloidal silicon dioxide, carboxymethyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, Tween buffered aqueous solution, copolyvidone, polysorbate, ethanol, propylene glycol, polyglycol (preferably polyethylene glycol, e.g., PEG400), 80 (i.e., PEG (20), sorbitol monooleate), DMSO, A mixture of water and a cosolvent, for example, an aqueous solution comprising an alcohol such as ethanol and/or a polyglycol such as polyethylene glycol, an ester of a polyol such as glycerol and/or polyethylene glycol with a fatty acid, a surfactant such as an anionic, cationic, nonionic and amphoteric surfactant, a complexing agent such as a cyclodextrin, for example α-cyclodextrin (α-CD) or hydroxypropyl-β-cyclodextrin (HP-β-CD), a salt of a bile acid or a lipid such as an animal or plant phospholipid, a micellizing agent, and an oil such as corn oil, or a mixture of two or more of the aforementioned components.

Unless otherwise indicated, any structural formula given in the present application is also intended to represent the isotopically unenriched forms and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure described by the general formula given in the present application, except that one or more atoms are replaced by atoms with selected atomic weights or mass numbers. Exemplary isotopes that can be introduced into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ¹⁸ F, 31 P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. Radioactive isotopes are present ^therein , such as those compounds of ³ H, ¹⁴ C and ¹⁸ F, or non-radioactive isotopes are present therein, such as ² H and ¹³ C. Such isotopically enriched compounds can be used in metabolic studies (using ¹⁴ C), reaction kinetic studies (using, for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution determinations, or can be used in radiotherapy of patients. ¹⁸ F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of Formula I, Ia, Ib, I-1 to I-6, I-1-1 to I-1-6, I-1-a to I-1-f can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparations herein using an appropriate isotopically labeled reagent in place of the unlabeled reagent originally used.

In addition, the substitution of heavier isotopes, especially deuterium (i.e., ² H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, the half-life in vivo is increased or the dosage requirement is reduced or the therapeutic index is improved. It should be understood that deuterium in the present application is regarded as a substituent of the compound of formula I, Ia, Ib, I-1 to I-6, I-1-1 to I-1-6, I-1-a to I-1-f. The concentration of such heavier isotopes, especially deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" used in the present application refers to the ratio between the isotopic abundance and the natural abundance of the specified isotope. If a substituent of a compound of the present application is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates herein include those wherein the solvent of crystallization may be isotopically substituted, eg _D2O , acetone-d6, DMSO-d6.

Compounds, pharmaceutical compositions and methods of administration

As used herein, the term "compound of the present application" or "active ingredient of the present application" is used interchangeably to refer to a compound of formula I or Stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitrogen oxides, solvates, hydrates, crystalline forms, esters, isotopically labeled compounds, metabolites, pharmaceutically acceptable salts or prodrugs:

wherein X is selected from N or -CH-;

Y is selected from -NH-, _-CH2- , O, S or a combination thereof;

Ring A is selected from a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;

Ring B is selected from a 5-15 membered partially unsaturated carbocyclic ring, a 5-15 membered partially unsaturated carboheterocyclic ring, a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;

L represents a single bond or a C _1-10 alkylene group;

M is selected from hydrogen, C _1-10 alkyl, 3-15 membered saturated or partially unsaturated carbocyclic group, 3-15 membered saturated or partially unsaturated heterocyclic group, optionally, the alkyl, saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated heterocyclic group involved in M is substituted by one or more R ₃ , R ₃ is selected from halogen, cyano, hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, alkoxy, -R ¹ -CN, -R ¹ -NR ² R ³ , -R ¹ -(OH) _q , -R ¹ -COOH, -R ¹ -C(＝O)NR ² R ³ , -C(＝O)R ¹ -OH, -C(＝O)R ¹ , -C(＝O)OR ¹ , -C(＝O)CF ₃ , -S(＝O) ₂ R ¹ , -C(＝O)OR ¹ , -C(＝O)R ¹ CN, -R 1 - ¹ -NR ² -R ³ -(OH) _q , -R ¹ -NR ² -R ³ -COOH, -R ¹ -NR ² -R ³ -C(＝O)NR ² R ³ , -R ¹ -NR ² -C(＝O)R ³ -OH, -R ¹ -NR ² -C(＝O)R ³ , -R ¹ -NR ² -S(＝O) ₂ R ³ ;

Optionally, ring A and ring B are fused to form a ring;

Optionally, ring B and M are fused to form a ring;

Ring D is selected from a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;

_R1 is selected from halogen, cyano, nitro, _C1-10 alkyl, _C1-10 haloalkyl, _C1-10 heteroalkyl, C1-10 haloheteroalkyl, _C3-15 saturated or partially unsaturated carbocyclyl, _C3-15 saturated or partially unsaturated heterocyclyl, _6-15 membered aryl, _C7-15 arylalkyl, 5-15 membered heteroaryl or _C6-15 heteroarylalkyl;

R ₂ is selected from -C(=O)NR ⁴ R ⁵ , -C(=O)NR ⁴ -OR ⁵ , -S(=O) ₂ NR ⁴ R ⁵ , -NR ⁴ S(=O) ₂ R ⁵ or -R ⁶ -C(=O)NR ⁴ R ⁵ , optionally, R ⁴ is connected to a carbon atom or a heteroatom on ring D to form a 5-6 membered ring; optionally, R ⁵ is connected to a carbon atom or a heteroatom on ring D to form a 5-6 membered ring;

each substituent ^Ra , ^Rb , ^Rc , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 and ^R6 is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, saturated or partially unsaturated carbocyclyl, saturated or partially unsaturated carbocyclylalkyl, saturated or partially unsaturated heterocyclyl, saturated or partially unsaturated heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;

Optionally, substituents ^Ra , Rb, ^Rc , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 and ^R6 are each independently substituted by one or ^more selected from deuterium, hydroxyl, amino, cyano, halogen, alkyl, cycloalkyl, alkoxy, aryl;

Alternatively, among Ra, ^Rb , ^{Rc , R1} , ^R2 , ^R3 , ^R4 , ^R5 and ^R6 , if there are two adjacent substituents, the two adjacent substituents together with the atoms to which they are attached are linked to form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group or a heteroaryl group;

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

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

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

q is independently selected from 0, 1 or 2.

In some embodiments, the compound represented by Formula I is selected from the structures represented by Formula I-1 to Formula I-6:

Wherein, X, Y, R ₁ , R ₂ , Ra, R ^b , R ^c , ^L , M, ring D, m, n, p, and Y ₁ to Y ₅ are as defined above in the present application.

In some embodiments, the compound represented by Formula I has the structure represented by the following Formula I-1-1 to Formula I-1-6:

Wherein, the definitions of L, M, R ₁ , ^R ₂ , Ra, R ^b , R ^c , m, n, p, and Y ₁ to Y ₄ are the same as those described above in the present application.

In some embodiments, R ₁ is selected from halogen, cyano, nitro, C _1-10 alkyl, C _3-10 cycloalkyl and C _1-10 haloalkyl. In some embodiments, R ₁ is selected from halogen, cyano and C _1-6 haloalkyl. In some embodiments, R ₁ is selected from fluorine, chlorine, bromine, iodine, cyano, CF ₃ , CHF ₂ and CH ₂ F. In some embodiments, R ₁ is selected from fluorine, chlorine, bromine, iodine, cyano and CF ₃ .

In some embodiments, each substituent R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C _1-10 alkyl, C _{2-10 alkenyl, C 2-10 alkynyl, C 1-10 heteroalkyl ,} C _1-10 alkoxy, 3-15 membered saturated or partially unsaturated carbocyclyl, C _4-15 saturated or partially unsaturated carbocyclylalkyl, 3-15 membered saturated or partially unsaturated heterocyclyl, C _3-15 saturated or partially unsaturated heterocyclylalkyl, 6-15 membered aryl, C _7-20 arylalkyl, 5-15 membered heteroaryl or C _4-20 heteroarylalkyl. In some embodiments, substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _1-10 alkoxy, 6-15 membered aryl.

In some embodiments, each substituent R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _1-6 alkoxy, 3-10 membered saturated or partially unsaturated carbocyclyl, C _4-12 saturated or partially unsaturated carbocyclylalkyl, 3-10 membered saturated or partially unsaturated heterocyclyl, C _3-12 saturated or partially unsaturated heterocyclylalkyl, 6-10 membered aryl, C _7-15 arylalkyl, 5-10 membered heteroaryl or C _4-15 heteroarylalkyl. In some embodiments, substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, and 6-12 membered aryl.

In some embodiments, each substituent R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, propenyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl and naphthyl. In some embodiments, the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from one or more of deuterium, hydroxyl, amino, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl and naphthyl.

In some embodiments, the compound of Formula I has the structure shown in the following Formula Ia to Formula Ib:

Wherein, L, M, ^Ra and ^R4 are as defined above.

In some embodiments, the compound represented by Formula I has the structure represented by the following Formula I-1-a to Formula I-1-f:

In the above formula I-1-a to formula I-1-f, R ^a is hydrogen, methoxy, ethoxy or propoxy;

^R4 is selected from _C1-4 alkyl, _C1-4 alkoxy and _C1-4 deuterated alkyl; or, ^R4 is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methyl, deuterated ethyl, deuterated propyl or deuterated isopropyl;

Each M ₁ is independently selected from hydrogen and C _1-6 alkyl, or each M ₁ is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl; optionally, the alkyl in each M ₁ is independently substituted by one or more selected from hydroxyl, 5-6 membered heterocycloalkyl;

L is a single bond or a C _1-4 alkylene group;

each Z is independently selected from O, -S(=O) ₂ , _CR5R6 or _{NR7 ,} and _R5 , _R6 and _R7 are each independently selected from hydrogen, methyl, -C(=O) _CH2 -OH, -C(=O) _CH2CH3 , -CH2 _- COOH, -C(=O) _CH3 , -CH2 _{- CH2-} OH, -CH( _CH3 )-COOH, -C(=O) _CF3 , -COOH, _-C (=O) _CH2CN , -S(=O) ₂ - _CH3 or -C(=O) _OCH3 .

In some embodiments, in the above formulas I-1-a to I-1-f, the carbon atoms on the benzene ring to which ^Ra is connected are connected to form a 5-membered ring. In some embodiments, in the above formulas I-1-a to I-1-f, the carbon atoms on the benzene ring to which ^Ra is connected are connected to form a 6-membered ring.

The pharmaceutical composition of the present application comprises the compound described in the present application and a pharmaceutically acceptable excipient thereof. The amount of the compound in the composition of the present application can effectively treat or alleviate the FAK and/or YAP-related diseases of the patient.

In some embodiments, the present application provides a pharmaceutical composition, which further comprises an additional therapeutic agent, wherein the additional therapeutic agent includes other anticancer agents, other drugs for treating pulmonary arterial hypertension, or a combination thereof.

As described in the present application, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient, which, as used in the present application, includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, ^21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, the contents of the documents herein are combined to show that different excipients can be applied to the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except to the extent that any conventional excipients are incompatible with the compounds of the present application, such as by producing any adverse biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is also contemplated by the present application.

The pharmaceutical composition of the present application further comprises i) one or more other FAK inhibitors and/or ii) one or more other types of protein kinase inhibitors and/or one or more other types of therapeutic agents. The one or more other types of protein kinase inhibitors include, for example, PYK2 or src inhibitors, and other types of therapeutic agents include other anticancer agents, other drugs for treating pulmonary hypertension, and the like.

The term "therapeutically effective amount" as used herein refers to the total amount of each active component sufficient to show a significant patient benefit (e.g., viral load reduction). When used for treatment, a therapeutically effective amount of the present application's compound, especially Formula I, Formula I-1 to I-6, Formula I-1-1 to I-1-6, Formula I-1-a to I-1-f compounds and pharmaceutically acceptable salts thereof can be given as unprocessed chemicals, and can also be provided as an active ingredient of a pharmaceutical composition. Therefore, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the present application's compound, especially Formula I, Formula I-1 to I-6, Formula I-1-1 to I-1-6, Formula I-1-a to I-1-f compounds or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

When a separate active ingredient is used for separate administration, the term refers only to the ingredient. When used in combination, the term refers to the combined amount of active ingredients that cause a therapeutic effect regardless of the combination, when administered sequentially or simultaneously. The compounds of the present application, especially compounds of formula I, formula I-1 to I-6, formula I-1-1 to I-1-6, formula I-1-a to I-1-f and pharmaceutically acceptable salts thereof are as described above. In terms of compatibility with other ingredients of the preparation and harmlessness to its recipient, the carrier, diluent or excipient must be acceptable. According to another aspect of the present application, a method for preparing a pharmaceutical preparation is also provided, the method comprising mixing the compounds of the present application, especially compounds of formula I, formula I-1 to I-6, formula I-1-1 to I-1-6, formula I-1-a to I-1-f or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable carriers, diluents or excipients.

The amount of active ingredient combined with one or more excipients to prepare a single dosage form will necessarily vary depending on the host being treated and the specific route of administration. For example, a formulation intended for oral administration to a human will typically contain, for example, 0.5 mg-2 g of active ingredient (suitably 0.5 mg-1 g of active ingredient, such as 0.5 mg-0.5 g of active agent, more suitably 0.5-100 mg, such as 1-30 mg) compounded with a suitable and convenient amount of excipient, which may be about 5% to about 98% by weight of the total composition. The amount of active ingredient that the compound of Formula I, Formula I-1 to I-6, Formula I-1-1 to I-1-6, Formula I-1-a to I-1-f is mixed with a carrier material to prepare a single dosage form will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the excretion rate of the compound used, the duration of treatment, and the age, sex, weight and condition of the patient. A preferred unit dosage form is a unit dosage form containing a daily dose or divided dose of the active ingredient described herein above, or a suitable fraction thereof. Treatment may be initiated with a small dose significantly below the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimum effect is achieved under the circumstances. In general, the concentration level at which the compound is most desirably administered is that which generally provides effective results in terms of anti-tumor effects without causing any harmful or toxic side effects.

In the process of treatment or prevention using the compounds of the present application, if separate doses are required, it is usually administered so that the daily dose obtained is, for example, 0.1 mg/kg-75 mg/kg body weight. In general, a lower dose will be given when a parenteral route is adopted. Thus, for example, for intravenous or intraperitoneal administration, a dose of, for example, 0.1 mg/kg-30 mg/kg body weight is usually used. Similarly, for inhalation administration, a dose of, for example, 0.05 mg/kg–25 mg/kg body weight is used. Oral administration is also suitable, particularly in tablet form. Typically, a unit dosage form will contain about 0.5 mg-0.5 g of the compounds of the present application and the unit dosage form can be administered once, twice, three times or four times a day or, if necessary, with a higher frequency of administration.

The pharmaceutical dosage forms of the compounds and compositions of the present application can be provided in the form of quick release, controlled release, sustained release or targeted drug release systems. For example, conventional dosage forms include solutions and suspensions, (micro) emulsions, ointments, gels and patches, liposomes, tablets, sugar-coated pills, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and lyophilized preparations. Depending on the route of administration used, special devices may be required to apply or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators or special flasks. Pharmaceutical dosage forms are often composed of drugs, excipients and containers/sealing systems. One or more excipients (also known as inactive ingredients) can be added to the compounds of the present application to improve or promote the manufacture, stability, administration and safety of the drug, and can provide a desired drug release curve. The method of line. Therefore, the type of excipient added to the drug can depend on various factors, such as the physical and chemical properties of the drug, the route of administration and the preparation steps. There are pharmaceutical excipients in this field and include those listed in various pharmacopoeias. (See US Pharmacopeia (US Pharmacopeia, USP), Japanese Pharmacopoeia (Japanese Pharmacopoeia, JP), European Pharmacopoeia (European Pharmacopoeia, EP) and British Pharmacopoeia (British pharmacopoeia, BP); US Food and Drug Administration (the US Food and Drug Administration, www.fda.gov) Center for Drug Evaluation and Research (Center for Drug Evaluation and Research, CEDR) publications, such as "Inactive Ingredient Guide" (Inactive Ingredient Guide, 1996); Ash and Ash compiled "Handbook of Pharmaceutical Additives" (Handbook of Pharmaceutical Additives, 2002, Synapse Information Resources, Inc., Endicott NY; etc.)).

The pharmaceutical composition is suitable for administration by any suitable route, for example, by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such preparations can be prepared by any known method in the field of pharmacy, for example, by mixing the active ingredient with a carrier or excipient. Oral administration or injection is preferred.

Pharmaceutical formulations suitable for oral administration are provided as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water emulsions or water-in-oil emulsions.

For example, for oral administration in the form of tablets or capsules, the active drug component can be mixed with a pharmaceutically acceptable oral non-toxic inert carrier (e.g., ethanol, glycerol, water, etc.). Powders are prepared by pulverizing the compound into a suitable fine size and mixing it with a pharmaceutical carrier (e.g., edible sugars such as starch or mannitol) that is also pulverized. Flavoring agents, preservatives, dispersants, and coloring agents may also be present.

Capsules are prepared by preparing a powder mixture as described above and filling it into a formed gelatin shell. Before the filling operation, glidants and lubricants (e.g., colloidal silicon dioxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol) may be added to the powder mixture. Disintegrants or solubilizers (e.g., agar, calcium carbonate or sodium carbonate) may also be added to improve the availability of the drug when the capsule is taken.

In addition, suitable binders, lubricants, disintegrants and colorants may be added to the mixture when necessary or required. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or β-lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth or sodium alginate), carboxymethyl cellulose, polyethylene glycol, etc. Lubricants used in these dosage forms include sodium oleate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc. For example, by making a powdered mixture, granulating or pre-compressing tablets, adding lubricants and disintegrants, and pressing into tablets, tablets are prepared. The appropriately crushed compound is mixed with a diluent or base as described above, optionally with a binder (e.g., carboxymethyl cellulose, alginate, gelatin or polyvinyl pyrrolidone), a dissolution inhibitor (e.g., paraffin), an absorption accelerator (quaternary salt) and/or an absorbent (e.g., bentonite, kaolin or dicalcium phosphate) to prepare a powdered mixture. The powder mixture can be granulated by wetting with a binder (e.g., syrup, starch paste, acadia mucilage, or a solution of a cellulosic or polymeric material) and then forcing it through a screen. An alternative to granulation is to run the powder mixture through a tabletting machine, resulting in poorly formed lumps being broken up to form granules. The granules can be lubricated by adding stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the die of the tabletting machine. The lubricated mixture is then compressed into tablets. The compounds of the present application can also be mixed with a free-flowing inert carrier and compressed into tablets without going through the granulation or pre-compression steps. Protective coatings consisting of a shellac seal coat, a sugar coat or a polymeric material coat and a polish coating of wax can be provided, which may be transparent or opaque. Dyestuffs can be added to these coatings to distinguish different unit doses.

Oral liquid preparations such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given amount contains a predetermined amount of compound. Syrups can be prepared by dissolving the compound in an aqueous solution of appropriate flavoring, while elixirs can be prepared by using a non-toxic solvent. Solubilizers and emulsifiers (e.g., ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavor additives (e.g., peppermint oil or natural sweeteners or saccharin or other artificial sweeteners), etc. can also be added.

If appropriate, dosage unit preparations for oral administration can be microencapsulated. The preparations can also be formulated to delay or sustain release, for example, by coating or embedding in particulate materials such as polymers, wax, etc.

The compounds of the present application, especially the compounds of formula I, formula I-1 to I-6, formula I-1-1 to I-1-6, formula I-1-a to I-1-f and pharmaceutically acceptable salts thereof can also be administered in a liposome delivery system, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be composed of a variety of phospholipids (e.g., cholesterol, octadecylamine or phosphatidylcholine).

The compounds of the present application, especially the compounds of formula I, formula I-1 to I-6, formula I-1-1 to I-1-6, formula I-1-a to I-1-f and pharmaceutically acceptable salts thereof, can also be delivered by using monoclonal antibodies as separate carriers (to which the compound molecules are coupled). The compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl asparagine phenol or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compounds can be coupled with a class of biodegradable polymers for achieving controlled release of the drug, such polymers as cross-linked copolymers or amphiphilic block copolymers of polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

Pharmaceutical formulations suitable for transdermal administration may be presented as discrete patches to maintain close contact with the recipient's epidermis for a prolonged period of time. For example, the active ingredient may be delivered by iontophoresis patches, generally see Pharmaceutical Research 1986, 3(6), 318. Pharmaceutical formulations suitable for topical administration may be prepared as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patches. Pharmaceutical formulations suitable for rectal administration may be presented as suppositories or as enemas. Pharmaceutical formulations suitable for vaginal administration may be presented as vaginal suppositories, vaginal tampons, creams, gels, pastes, foams or sprays. Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions and aqueous and non-aqueous sterile suspensions, aqueous and non-aqueous sterile injection solutions may contain antioxidants, buffers, antibacterial agents and solutes that make the preparation isotonic with the blood of the recipient, and aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents. The preparations can be provided in unit dose or multi-dose containers, such as sealed Ankai and vials, and can be stored under freeze drying (lyophilization) conditions, and only sterile liquid carriers, such as water for injection, need to be added before use. The injection solutions and suspensions prepared at the time of use can be prepared by sterile powder injections, granules and tablets. Pharmaceutical preparations suitable for nasal administration (wherein the carrier is solid) include coarse powders with a particle size of, for example, 20-500 microns, which are administered by nasal inhalation, i.e., rapid inhalation from a coarse powder container close to the nose through the nasal passage. Suitable formulations in which the carrier is a liquid and suitable for administration as a nasal spray or nasal drops include aqueous or oily solutions of the active ingredient. Pharmaceutical formulations suitable for administration by inhalation include dry powders, aerosols, suspensions or solution compositions. Dry powder compositions delivered to the lungs by inhalation typically include a compound of formula (I) of the present application or a pharmaceutically acceptable salt as a finely pulverized powder together with one or more pharmaceutically acceptable excipients as a finely pulverized powder. Pharmaceutically acceptable excipients particularly suitable for dry powders are known to those skilled in the art and include lactose, starch, mannitol and mono-, di- and polysaccharides. Finely pulverized powders can be prepared, for example, by micronization and milling. In general, a size-reduced (e.g., micronized) compound can be defined by a D50 value of about 1 to about 10 microns (e.g., as detected by laser diffraction).

The dry powder can be administered to a patient via a reservoir dry powder inhaler (RDPI), which has a reservoir suitable for storing multiple doses (unmetered doses) of the drug in the form of dry powder. The RDPI typically includes a device for metering each dose of the drug from the reservoir to the delivery position. For example, the metering device may include a metering cup, which can be moved from a first position to a second position, where the cup can be loaded with the drug from the reservoir, and where a metered dose of the drug that can be used for inhalation by the patient is prepared in the second position. Alternatively, the dry powder can be presented as a capsule (such as gelatin or plastic), cartridge or blister package for a multi-dose dry powder inhaler (MDPI). An MDPI is an inhaler in which the drug is contained in a multi-dose package, containing (or otherwise carrying) multiple defined doses (or portions thereof) of the drug. When the dry powder is presented as a blister package, it includes a plurality of blisters for containing the drug in the form of dry powder. The blisters are typically arranged in a regular manner to facilitate the release of the drug therefrom. For example, the blisters may be arranged in a generally circular manner on a disc-type blister pack, or may be elongated, for example, to comprise a strip or ribbon.

Aerosol can be formed by suspending or dissolving the compound of formula I of the application or a pharmaceutically acceptable salt in a liquefied propellant. Suitable propellants include halogenated hydrocarbons, hydrocarbons and other liquefied gases. Representational propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Typically, an aerosol comprising the application's polymorphs or salt is given to the patient via a metered dose inhaler (MDI). Such a device is known to those skilled in the art. Aerosols may contain additional pharmaceutically acceptable excipients commonly used with MDIs, such as surfactants, lubricants, co-solvents and other excipients to improve the physical stability of the formulation, improve valve characteristics, improve solubility or improve taste.

It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The compounds of the present application or compositions containing the compounds of the present application are suitable for the prevention and treatment of FAK-related diseases, wherein FAK-related diseases include cancer, pulmonary hypertension, immune diseases, arthritis, inflammatory bowel disease, pathological angiogenesis, etc. The compounds of the present application and their pharmaceutical compositions are particularly used to prepare drugs for the treatment of cancer, pulmonary hypertension, and pathological angiogenesis. The compounds of the present application or their pharmaceutical compositions can be used therapeutically in combination with: i) one or more other FAK inhibitors and/or, ii) one or more other types of protein kinase inhibitors and/or one or more other types of therapeutic agents, which can be orally administered in the same dosage form, orally administered in separate oral dosage forms (e.g., sequentially or non-sequentially), or injected together or separately (e.g., sequentially or non-sequentially). Among them, other types of therapeutic agents include other anticancer agents and other drugs for the treatment of pulmonary hypertension.

The compounds of the present application or their pharmaceutical compositions are expected to have (among other properties) anti-tumor properties, which are believed to be derived from the inhibition of FAK, for example, the compounds or their pharmaceutical compositions may exhibit anti-proliferative and/or pro-apoptotic and/or anti-invasive and/or anti-cell motility and/or anti-angiogenic activity. Such compounds appear to be useful in the treatment of, for example, FAK-induced tumors, in particular as anti-cancer agents.

Therefore, it is expected that the compounds of the present application or their pharmaceutical compositions can be used to treat diseases or medical conditions mediated solely or in part by FAK, i.e. The compounds can be used to produce FAK inhibitory effects in warm-blooded animals that need such treatment. Therefore, the compounds of the present application provide a method for treating malignant cells, characterized by inhibiting FAK. Specifically, the compounds of the present application or their pharmaceutical compositions can be used to produce anti-proliferation and/or pro-apoptosis and/or anti-invasion and/or anti-cell movement and/or anti-angiogenesis activity effects mediated alone or in part by inhibiting FAK function. Specifically, it is expected that the compounds of the present application can be used to prevent or treat those tumors that are sensitive to inhibition of FAK, which are related to, for example, angiogenesis, proliferation and signal transduction steps, which cause proliferation, invasion, migration and particularly angiogenesis of these tumor cells. Therefore, the compounds of the present application can be used to treat hyperproliferative diseases, including cancer. Benign or malignant tumors may affect any tissue and include non-solid tumors such as leukemia, multiple myeloma or lymphoma, and solid tumors, such as bile duct cancer, bone cancer (including Ewing's tumor), bladder cancer, brain cancer/CNS cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, liver cancer, lung cancer (including non-small cell lung cancer and small cell lung cancer), neural cancer (including neuroblastoma), esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer and Kaposi's sarcoma. It is expected that the compounds of the present application can be used to treat pathogenic angiogenesis (pathological angiogenesis), for example, for the treatment of the cancers mentioned above and other diseases that produce inappropriate or pathogenic angiogenesis, such as age-related macular degeneration (AMD) and cancers associated with solid tumors.

The compounds of the present application or compositions containing the compounds of the present application are suitable for the prevention and treatment of YAP-related diseases. Preferably, the YAP-related disease is selected from cancer; the cancer is selected from: skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer and uterine cancer One or more; more preferably, the cancer is selected from: lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer One or more.

The compounds of the present application or compositions containing the compounds of the present application are suitable for regulating or treating diseases associated with FAK and YAP. Preferably, the diseases associated with FAK and YAP are selected from cancer; the cancer is selected from: skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer and uterine cancer One or more; more preferably, the cancer is selected from: one or more of lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer.

The compounds of the present application or their pharmaceutical compositions can be used alone or, if necessary, in combination with other active compounds. The compounds of Formula I, Formula I-1 to I-6, Formula I-1-1 to I-1-6, Formula I-1-a to I-1-f are considered to be effective when used with the following: alkylating agents, angiogenesis inhibitors, antibodies, metabolic antagonists, antimitotic agents, antiproliferative agents, antiviral agents, Aurora kinase inhibitors, other cell apoptosis promoters (e.g., Bcl-xL, Bcl-w and Bfl-1) inhibitors, activators of death receptor pathways, Bcr-Abl kinase inhibitors, BiTE (Bi-specific T cell engager (Engager)) antibodies, antibody drug conjugates, biological response modifiers, cell cycle protein-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia virus oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDA C) inhibitors, hormone therapy, immunization, inhibitors of programmed cell death proteins (IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, warm-blooded animal target of rapamycin inhibitors, microRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, nonsteroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapy, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, etc., and combinations of one or more of these agents.

In some embodiments, there are two ways of co-administration: 1) the compound or pharmaceutical composition described in the present application and other active drugs that can be used in combination are made into separate preparations, and the two dosage forms can be the same or different, and can be used sequentially or simultaneously; when used sequentially, the first drug has not lost its effective effect in the body when the second drug is administered; 2) the compound or pharmaceutical composition of the present application and other active drugs that can be used in combination are made into a single preparation and administered simultaneously.

The compounds of Formula I, Formula I-1 to I-6, Formula I-1-1 to I-1-6, Formula I-1-a to I-1-f of the present application or their pharmaceutically acceptable salts can be administered in combination with other therapeutic agents, including other therapeutic agents that can be used to treat pulmonary hypertension (PHA). These therapeutic agents include vasodilators, such as epoprostenol (Flolan TM), tadalafil (AdcircaTM) or ambrisentan (VolibrisTM), etc.

The "effective amount" or "effective dose" of the compound or pharmaceutically acceptable composition of the present application refers to an amount that treats or alleviates one or more of the present application. Please refer to the effective amount of the severity of the mentioned disease. According to the method of the present application, the compound and composition can be any dosage and any administration route to effectively treat or alleviate the severity of the disease. The exact amount required will vary according to the patient's condition, which depends on race, age, the patient's general condition, the severity of the infection, special factors, mode of administration, etc. The compound or composition can be co-administered with one or more other therapeutic agents, as discussed in the present application.

Synthesis method

The following schemes and examples describe methods for preparing compounds of formula I. Raw materials and intermediates are purchased from commercial sources, prepared by known steps, or otherwise described. In some cases, the order of the steps of executing the reaction scheme can be changed to promote the reaction or avoid unwanted side reaction products. The preparation method of the compound of formula I of the present application is described in more detail below, but these specific methods do not constitute any limitation to the present application. The present application compound can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily carried out by a technician in the field of the present application.

Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present application, and other methods for preparing the compounds of the present application are considered to be within the scope of the present application. For example, the synthesis of the non-exemplified compounds according to the present application can be successfully completed by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present application, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed in the present application or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the present application.

The structure of the compound of the present application is determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS). NMR is detected using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic spectrometers, and the measurement solvents include deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD ₃ COCD ₃ ), deuterated chloroform (CDCl ₃ ) and deuterated methanol (CD ₃ OD), etc., and tetramethylsilane (TMS) is used as the internal standard. The chemical shift is measured in parts per million (ppm). Liquid chromatography-mass spectrometry (LC-MS) is detected using an Agilent 1260 mass spectrometer. HPLC is determined using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 5 100x3.0mm chromatographic column). The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

The starting materials in the examples of this application are all known and commercially available, or can be synthesized using or according to literature data reported in the field. Unless otherwise specified, all reactions in this application are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperature is degrees Celsius.

The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are usually performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight. Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the recorded content can be applied to the present application method. The preferred implementation methods and materials described in the text are for demonstration purposes only.

Example 1

Synthesis of 2-({2-[(4-{1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-4-yl}-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide (Compound 01)

Step 1: 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide

To a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]-N-methylbenzamide (1000 mg, 3.024 mmol)] and 4-bromo-2-methoxyaniline (610.98 mg, 3.024 mmol) in dioxane (10 mL) was added HCl (0.756 mL) and stirred at 100 ° C for 18 hours after the addition was complete. After the reaction was completed by LCMS monitoring, the mixture was concentrated under reduced pressure to give a crude product. The crude product was slurried with methanol (0.5 mL) and filtered to give 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide (1.3 g, 2.619 mmol, yield: 86.62%) as a yellow solid.

Step 2: 2-methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazol-1-yl]piperidin-1-carboxylate

To a solution of 2-({2-[[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]-5-(trifluoromethyl)pyridin-4-yl}amino)-N-methylbenzamide (450.0 mg, 0.907 mmol) and 2-methylpropan-2-yl 4-[4-(4.4.4,5,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (410.64 mg, 1.088 mmol) in _H2O (1.7 mL) and dioxane (6.8 mL) was added Pd(dppf) _Cl2 (66.37 mg, 0.091 mmol), and _Na2CO3 (240.33 _mg , 2.268 mmol), and the reaction was stirred at 90°C for 18 hours. After TLC (PE:EA=2:1) showed that the reaction was complete, the reaction solution was poured into 20 mL of water and extracted with EtOAc (20 mL). The combined organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the compound 2-methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazol-1-yl]piperidin-1-carboxylate (580.0 mg, 0.87 mmol, yield: 95.94%) as a yellow solid.

Step 3: 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide

HCl (4 mL, 0.58 mmol) was added to a solution of 2-methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]pyrazol-1-yl]hydropyridine-1-carboxylate (387 mg, 0.58 mmol) in dioxane (4 mL), and the reaction solution was stirred at 25°C for 1 hour. After LCMS showed that the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was used directly without further purification. A brown solid compound 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (320.0 mg, 0.57 mmol, yield: 97.30%) was obtained.

Step 4: 2-({2-[(4-{1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-4-yl}-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide

To a solution of 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl}pyrazol-4-yl]-2-methylphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (450.0 mg, 0.79 mmol) and glycolic acid (120.8 mg, 1.59 mmol) in DMA (8 mL) was added HOBt (214.65 mg, 1.588 mmol), EDCI (304.51 mg, 1.588 mmol) and DIEA (0.658 mL, 3.971 mmol). The reaction mixture was stirred at 25° C. for 1 hour. After TLC (PE:EA=0:1) showed that the reaction was completed, the reaction solution was poured into 1 mL of water and extracted with EtOAc (3 mL). The combined organic phase was washed with a saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse preparative chromatography to obtain compound 01 (217.67 mg, 0.348 mmol, yield: 43.88%)

MS m/z(ESI):625.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.45(s,1H),8.7-8.8(m,2H),8.3-8.5(m,3H),7.94(s,1H),7.6 -7.7(m,2H),7.29(d,2H,J＝1.5Hz),7.0-7.2(m,2H),4.59(t,1H,J＝5.0Hz), 4.47(ddd,2H,J＝4.3,7.0,11.1Hz),4.15(t,2H,J＝4.9Hz),3.85(s,4H),3.1 -3.2(m,2H),2.77(d,3H,J＝4.5Hz),2.11(d,2H,J＝10.6Hz),1.8-2.0(m,2H).

Example 2

Synthesis of 2-{[2-({2-methoxy-4-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 02)

Step 1: 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide

To a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]-N-methylbenzamide (1000 mg, 3.024 mmol)] and 4-bromo-2-methoxyaniline (610.98 mg, 3.024 mmol) in dioxane (10 mL) was added HCl (0.756 mL) and stirred at 100 ° C for 18 hours after the addition was complete. After the reaction was completed by LCMS monitoring, the mixture was concentrated under reduced pressure to give a crude product. The crude product was slurried with methanol (0.5 mL) and filtered to give 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide (1.3 g, 2.619 mmol, yield: 86.62%) as a yellow solid.

Step 2: 2-{[2-({2-methoxy-4-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide

To a mixture of 2-(({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]-5-(trifluoromethyl)pyridin-4-yl}amino)-N-methylbenzamide (100.0 mg, 0.20 mmol) and 1-methyl-4-({4.4.4.5.5-tetramethyl-1.3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine (100.0 mg, 0.34 mmol) in dioxane (1 mL) and H ₂ O (0.343 mmol) was added Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (16.5 mg, 0.02 mmol) and Na ₂ CO ₃ (42.7 mg, 0.40 mmol). The reaction mixture was stirred at 100 ° C for 18 hours. After LCMS showed that the reaction was complete. The reaction solution was poured into 5 mL of water and extracted with EtOAc (5 mL). The combined organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse preparative chromatography to obtain compound 02 (10.86 mg, 0.02 mmol, yield: 9.28%).

MS m/z(ESI):581.3[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.45(s,1H),8.7-8.8(m,2H),8.4-8.5(m,1H),8.3-8.4(m,2H),7.93(s,1H),7.67(d, 1H,J＝7.8Hz),7.59(d,1H,J＝7.9Hz),7.28 (d,2H,J＝1.1Hz),7.0-7.2(m,2H),4.17(d,1H,J＝4.1Hz),3.85(s,3H),2.9-3.0(m,3H),2.77( d,3H,J＝4.5Hz),2.29(s,3H),1.9-2.1(m,6H).

Example 3

Synthesis of 2-{[2-({4-[1-(1,1-dioxo-1λ6-thiazin-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 03)

Step 1: 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide

To a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]-N-methylbenzamide (1000 mg, 3.024 mmol)] and 4-bromo-2-methoxyaniline (610.98 mg, 3.024 mmol) in dioxane (10 mL) was added HCl (0.756 mL) and stirred at 100 ° C for 18 hours after the addition was complete. After the reaction was completed by LCMS monitoring, the mixture was concentrated under reduced pressure to give a crude product. The crude product was slurried with methanol (0.5 mL) and filtered to give 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide (1.3 g, 2.619 mmol, yield: 86.62%) as a yellow solid.

Step 2: 2-{[2-({4-[1-(1,1-dioxo-1λ6-thiazin-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide

Pd(dppf)Cl 2 .CH 2 Cl 2 .(11.3 mg, 0.01 mmol) and Na 2 CO 3 (29.2 _mg , 0.28 mmol) were added to a solution of ₂ -({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N- _{methylbenzamide} (75.3 mg, 0.15 mmol) in _{H 2} O (0.25 mL) and _dioxane (1 mL). The reactants were then stirred at 100° C. for 1 hour. After LCMS showed that the reaction was complete, the reaction solution was poured into 5 mL of water and extracted with EtOAc (10 mL). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse preparative chromatography to give compound 03 (27.22 mg, 0.043 mmol, yield: 31.38%)

MS m/z(ESI):616.2[M+H] ⁺ .

^1H NMR(METHANOL-d ₄ ,400MHz)δ8.3-8.4(m,2H),8.11(s,1H),7.97(d,1H,J＝8.3Hz),7.88(s,1H),7.63(d,1H,J＝6.9Hz ),7.43(t,1H,J＝7.7Hz),7.1-7.2(m,2H),7.0 6(d,1H,J＝8.3Hz),4.6-4.7(m,1H),3.95(s,3H),3.3-3.4(m,2H),3.2- 3.3(m,2H),2.90(s,3H),2.6-2.8(m,2H),2.49(dd,2H,J＝3.5,14.3Hz).

Example 4

Synthesis of 2-{[2-({2-methoxy-4-[1-(1-propionylpiperidin-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 04)

Step 1: 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide

To a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]-N-methylbenzamide (1000 mg, 3.024 mmol)] and 4-bromo-2-methoxyaniline (610.98 mg, 3.024 mmol) in dioxane (10 mL) was added HCl (0.756 mL) and stirred at 100 ° C for 18 hours after the addition was complete. After the reaction was completed by LCMS monitoring, the mixture was concentrated under reduced pressure to give a crude product. The crude product was slurried with methanol (0.5 mL) and filtered to give 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide (1.3 g, 2.619 mmol, yield: 86.62%) as a yellow solid.

Step 2: 2-methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazol-1-yl]piperidin-1-carboxylate

To a solution of 2-({2-[[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]-5-(trifluoromethyl)pyridin-4-yl}amino)-N-methylbenzamide (450.0 mg, 0.907 mmol) and 2-methylpropan-2-yl 4-[4-(4.4.4,5,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (410.64 mg, 1.088 mmol) in _H2O (1.7 mL) and dioxane (6.8 mL) was added Pd(dppf) _Cl2 (66.37 mg, 0.091 mmol), and _Na2CO3 (240.33 _mg , 2.268 mmol), and the reaction was then stirred at 100°C for 18 hours. After TLC (PE:EA=2:1) showed that the reaction was complete, the reaction solution was poured into 20 mL of water and extracted with EtOAc (20 mL). The combined organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the compound 2-methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazol-1-yl]piperidin-1-carboxylate (580.0 mg, 0.87 mmol, yield: 95.94%) as a yellow solid.

Step 3: 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide

2-Methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl]phenyl}amino)-5-(trifluoromethyl)pyrimidine To a solution of 1-[(4-[1-(hexahydropyridine-2-yl]amino}phenyl]pyrazol-1-yl]hydropyridine-1-carboxylate (387 mg, 0.58 mmol) in dioxane (4 mL) was added HCl (4 mL, 0.58 mmol), and the reaction solution was stirred at 25 ° C for 1 hour. After LCMS showed that the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product can be used directly without further purification. A brown solid compound 2-{[2-({4-[1-(hexahydropyridine-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (320.0 mg, 0.57 mmol, yield: 97.30%) was obtained.

Step 4: 2-{[2-({2-methoxy-4-[1-(1-propionylpiperidin-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide

TEA (98.13 μL, 0.71 mmol) was added to a solution of 2-{[2-({4-[1-(hexahydropyridine-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (100.0 mg, 0.18 mmol) in DCM (1 mL). After LCMS showed that the reaction was completed, the reaction solution was poured into 3 mL of water and extracted with EtOAc (5 mL). The combined organic phase was washed with a saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse preparative chromatography to give compound 04 (48.42 mg, 0.076 mmol, yield: 43.14%).

MS m/z(ESI):623.3[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.45(s,1H),8.6-8.8(m,2H),8.2-8.5(m,3H),7.94(s,1H), 7.5-7.7(m,2H),7.28(d,2H,J＝1.3Hz),7.0-7.2(m,2H),4.4-4.6(m,2H) ,3.9-4.1(m,1H),3.85(s,3H),3.1-3.2(m,1H),2.77(d,3H,J＝4.5Hz),2 .2-2.5(m,3H),2.0-2.2(m,2H),1.7-2.0(m,2H),1.02(t,3H,J＝7.4Hz).

Example 5

Synthesis of 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 05)

Step 1: 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide

To a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]-N-methylbenzamide (1000 mg, 3.024 mmol)] and 4-bromo-2-methoxyaniline (610.98 mg, 3.024 mmol) in dioxane (10 mL) was added HCl (0.756 mL) and stirred at 100 ° C for 18 hours after the addition was complete. After the reaction was completed by LCMS monitoring, the mixture was concentrated under reduced pressure to give a crude product. The crude product was slurried with methanol (0.5 mL) and filtered to give 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide (1.3 g, 2.619 mmol, yield: 86.62%) as a yellow solid.

Step 2: 2-methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazol-1-yl]piperidin-1-carboxylate

To a solution of 2-({2-[[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]-5-(trifluoromethyl)pyridin-4-yl}amino)-N-methylbenzamide (450.0 mg, 0.907 mmol) and 2-methylpropan-2-yl 4-[4-(4.4.4,5,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (410.64 mg, 1.088 mmol) in _H2O (1.7 mL) and dioxane (6.8 mL) was added Pd(dppf) _Cl2 (66.37 mg, 0.091 mmol), and _Na2CO3 (240.33 _mg , 2.268 mmol), and the reaction was stirred at 105°C for 18 hours. After TLC (PE:EA=2:1) showed that the reaction was complete, the reaction solution was poured into 20 mL of water and extracted with EtOAc (20 mL). The combined organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the compound 2-methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazol-1-yl] Piperidine-1-carboxylate (580.0 mg, 0.87 mmol, yield: 95.94%) as a yellow solid.

Step 3: 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide

HCl (4 mL, 0.58 mmol) was added to a solution of 2-methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]pyrazol-1-yl]hydropyridine-1-carboxylate (387 mg, 0.58 mmol) in dioxane (4 mL), and the reaction solution was stirred at 25°C for 1 hour. After LCMS showed that the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product (320.0 mg, 0.57 mmol, yield: 97.30%). 20 mg of the crude product was purified by reverse preparative chromatography to obtain compound 05 (10.1 mg, purity: 99.08%).

MS m/z(ESI):567.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.2-11.6(m,1H),8.71(d,2H,J＝1.9Hz),8.4-8.5(m,1H),8.36(s ,1H),8.27(s,1H),7.91(s,1H),7.5-7.7(m,2H),7.28(s,2H),7.0-7.2(m,2H ),4.1-4.3(m,1H),3.85(s,3H),3.07(d,2H,J＝12.3Hz),2.77(d,3H,J＝4.4Hz ), 2.62 (t, 2H, J = 11.8Hz), 2.00 (d, 2H, J = 11.0Hz), 1.82 (2H, J = 3.8, 11.9Hz).

Example 6

Synthesis of 2-({2-[(4-{1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-4-yl}-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide (Compound 06)

Step 1: 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide

To a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]-N-methylbenzamide (1000 mg, 3.024 mmol)] and 4-bromo-2-methoxyaniline (610.98 mg, 3.024 mmol) in dioxane (10 mL) was added HCl (0.756 mL) and stirred at 100 ° C for 18 hours after the addition was complete. After the reaction was completed by LCMS monitoring, the mixture was concentrated under reduced pressure to give a crude product. The crude product was slurried with methanol (0.5 mL) and filtered to give 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide (1.3 g, 2.619 mmol, yield: 86.62%) as a yellow solid.

Step 2: 2-methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazol-1-yl]piperidin-1-carboxylate

To a solution of 2-({2-[[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]-5-(trifluoromethyl)pyridin-4-yl}amino)-N-methylbenzamide (450.0 mg, 0.907 mmol) and 2-methylpropan-2-yl 4-[4-(4.4.4,5,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (410.64 mg, 1.088 mmol) in _H2O (1.7 mL) and dioxane (6.8 mL) was added Pd(dppf) _Cl2 (66.37 mg, 0.091 mmol), and _Na2CO3 (240.33 _mg , 2.268 mmol), and the reaction was stirred at 105°C for 18 hours. After TLC (PE:EA=2:1) showed that the reaction was complete, the reaction solution was poured into 20 mL of water and extracted with EtOAc (20 mL). The combined organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the compound 2-methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazol-1-yl]piperidin-1-carboxylate (580.0 mg, 0.87 mmol, yield: 95.94%) as a yellow solid.

Step 3: 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide

HCl (4 mL, 0.58 mmol) was added to a solution of 2-methylpropan-2-yl 4-[4-(3-methoxy-4-{[4-({2-[(methylamino)carbonyl]phenyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]pyrazol-1-yl]hydropyridine-1-carboxylate (387 mg, 0.58 mmol) in dioxane (4 mL), and the reaction solution was stirred at 25°C for 1 hour. After LCMS showed that the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was used directly without further purification. A brown solid compound 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (320.0 mg, 0.57 mmol, yield: 97.30%) was obtained.

Step 4: 2-({2-[(4-{1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-4-yl}-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide

To a solution of 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (50.0 mg, 0.09 mmol) and bromoacetic acid (12.9 mg, 0.09 mmol) in DMF (0.5 mL) was added DIEA (17.1 mg, 0.13 mmol), and the reaction was stirred at 25 ° C for 1 hour. After LCMS showed that the reaction was complete, the reaction solution was poured into 1 mL of water and extracted with EtOAc (5 mL), and the combined organic phases were washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse preparative chromatography to give compound 06 (19.97 mg, 0.032 mmol, yield: 36.33%).

MS m/z(ESI):625.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.45(s,1H),8.7-8.8(m,2H),8.3-8.5(m,3H),7.93(s,1H),7.67(d,2H,J＝8.3Hz),7.29 (d,2H,J＝1.3Hz),7. 0-7.2(m,2H),4.1-4.3(m,1H),3.85(s,3H),3.22(s,2H),3.10(d,4H,J＝11.6Hz),2.77(d,3H, J＝4.5Hz),2.0-2.1(m,4H).

Example 8

(1-acetylpiperidin-4-yl)-1H-pyrazol-4-ylphenyl)amino)-5-trifluoromethylpyrimidin-4-ylamino)N-methylbenzamide (Compound 08)

Dissolve 2-((2-((4-(((4-(hexahydropyridin-3-ylamino)-2,3-dioxocyclobut-4-enyl]amino}methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (30 mg, 0.06 mmol) and N,N-diisopropylethylamine (39 μL, 0.22 mmol) in 2.5 mL DMF, stir under ice bath for 10 min, then add acetyl chloride (5 μL, 0.7 mmol) in DMF (0.5 mL) dropwise. ) solution, after the addition was completed, it was stirred for 1 hour in an ice bath and naturally warmed to room temperature. After the reaction of the raw materials was completed by TLC spot plate monitoring, the reaction solution was poured into 20mL of water for quenching, extracted with ethyl acetate (10mL×3), and the organic phases were combined and washed twice with 10% sodium chloride solution (20mL) and once with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 08 (15mg, 0.03mmol, yield: 45.74%) was obtained by reverse preparative chromatography.

MS m/z(ESI):579.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ:11.37(br s,1H),9.84(br s,1H),8.74(br d,1H,J＝4.4Hz),8.45(s,2H),8.20(s,1H),7.85(s,1H),7.73(d,1H,J＝7.9Hz),7.65(br d,2H,J＝7.8Hz),7.4-7.6(m,3H),7.19(t,1H,J＝7.6Hz),4.4-4.5(m,2H),3.94(br d,1H,J＝13.9Hz),3.2-3.3(m,1H),2.7-2.8(m,4H),2.0-2.1(m,5H),1.7-2.0(m,2H)

Example 9 & Example 11

2-(4-(4-(4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)piperidin- Synthesis of 1-pyridin-1-yl)acetic acid (Compound 09)

Synthesis of N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide (Compound 11)

Step 1: 2-((2-((4-bromophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide

2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (1g, 3.02mmol) and 4-bromoaniline (520.2mg, 3.02mmol) were dissolved in 30mL of n-butanol, and a 4M hydrochloric acid solution in dioxane (227μL, 0.91mmol) was added dropwise, and the mixture was heated to 100°C and stirred overnight. After the reaction was completed by TLC monitoring, the mixture was filtered under reduced pressure, and the filter cake was washed with n-butanol (5mL*3) to obtain a white solid 2-((2-((4-bromophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (1105mg, 2.37mmol, yield: 78.37%)

Step 2: tert-Butyl 4-(4-(4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

2-((2-((4-bromophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (800 mg, 1.72 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (776.8 mg, 2.06 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (125.6 mg, 0.17 mmol) and sodium carbonate (454.6 mg, 4.29 mmol) were dissolved in a mixed solvent of 6 mL 1,4-dioxane and 1.5 mL water. The mixture was evacuated with nitrogen three times and heated to 90 °C under nitrogen protection and stirred overnight. After the reaction was completed by TLC monitoring, the mixture was filtered, concentrated under reduced pressure to remove most of the solvent, 20 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed twice with 10% sodium chloride solution (30 mL) and then washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The organic phases were combined and concentrated under reduced pressure and purified by silica gel column chromatography to obtain tert-butyl 4-(4-(4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (734.6 mg, 1.15 mmol, yield: 67.25%)

Step 3: N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide

15 mL of dichloromethane was added to tert-butyl 4-(4-(4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (734.6 mg, 1.15 mmol), and 10 mL of 4M hydrochloric acid in 1,4-dioxane solution was added dropwise while stirring. After the addition, the reaction was stirred at room temperature for 1.5 h. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure to remove the solvent to obtain compound 11 (650 mg, 1.13 mmol, yield: 98.30%).

MS m/z(ESI):537.2[M+H] ⁺ .

¹ H NMR(DMSO-d6,400MHz)δ11.36(br s,1H),9.84(br s,1H),8.77(br s,1H),8.44(s,2H),8.2-8.3(m,1H ),7.86(s,1H),7.73(br d,1H,J＝7.3Hz),7.64(br s,2H),7.4-7.6(m,3H),7.1-7.3(m,1H),4.39(br s,1H),2.95(br s,1H ),2.79(br d,3H,J＝4.1Hz),2.0-2.2(m,3H),1.48(br s,3H),0.92(br t,2H,J＝6.5Hz).

Step 4: 2-(4-(4-(4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)piperidin-1-yl)acetic acid

Compound 11 (100 mg, 0.18 mmol) and N,N-diisopropylethylamine were dissolved in 10 mL DMF, stirred for 10 minutes under ice bath, and then 2-bromoacetic acid (25.5 mg, 0.18 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 1 hour under ice bath and naturally warmed to room temperature. After TLC plate monitoring, the reaction mixture was poured into 40 mL water for quenching, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and then 10% The mixture was washed twice with sodium chloride solution (30 mL) and once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by reverse preparative chromatography to give compound 09 (18 mg, 0.03 mmol, yield: 17.24%).

MS m/z(ESI):595.2[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.36(br s,1H),9.83(br s,1H),8.74(br d,1H,J＝4.5Hz),8.45(s,2H),8.19(d,1H,J＝2.4Hz),7.84(s,1H),7.73(dd,1H,J＝1.3,7.9Hz), 7.64(br d,2H,J＝7.6Hz),7.4-7.5(m,3H),7.19(t,1H,J＝7.5Hz),4.1-4.2(m,1H),3.22(s,2H),3.09(br d,2H,J＝11.8Hz),2.79(d,3H,J＝4.5Hz),2.5-2.6(m,2H),2.06(br d,4H,J＝3.5Hz)

Example 10

Synthesis of 2-((2-((4-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (Compound 10)

2-((2-((4-(((4-(hexahydropyridin-3-ylamino)-2,3-dioxocyclobut-4-enyl]amino}methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (50 mg, 0.09 mmol), 2-hydroxyacetic acid (8.0 mg, 0.11 mmol), 1-hydroxybenzotriazole (23.6 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33.5 mg, 0.18 mmol) ) was dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (76 μL, 0.44 mmol) was added and stirred at room temperature for 18 h. After TLC monitoring, 20 mL of water was added and extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The organic phases were combined and concentrated under reduced pressure and purified by reverse preparative chromatography to obtain compound 10 (19.5 mg, 0.03 mmol, yield: 37.49%).

MS m/z(ESI):595.3[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.38(br s,1H),9.85(br s,1H),8.75(br d,1H,J＝4.4Hz),8.45(s,2H),8.19(s,1H),7.85(s,1H),7.73(d,1H,J＝7.8Hz),7.64(br d,2H,J＝7.3Hz),7.4-7.5(m,3H),7.19(t,1H,J＝7.6Hz),4.4-4.5(m,2H),4.14(brd,3H,J＝6.4Hz ),3.82(br d,1H,J＝13.0Hz),3.15(br t,1H,J＝12.1Hz),2.8-2.9(m,4H),2.08(br d,2H,J＝10.9Hz),1.8-2.0(m,2H).

Example 12

Synthesis of 2-((2-((4-(1-(1-(2-hydroxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (Compound 12)

2-((2-((4-(((4-(hexahydropyridin-3-ylamino)-2,3-dioxocyclobut-4-enyl]amino}methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (50 mg, 0.09 mmol) was dissolved in 2 mL of 3M ethylene oxide in tetrahydrofuran solution and heated to room temperature. The mixture was stirred for 18 h. After LCMS monitoring showed that the raw material no longer continued to react, the reaction solution was concentrated under reduced pressure and purified by reverse preparative chromatography to obtain compound 12 (9.2 mg, 0.02 mmol, yield: 18.16%).

MS m/z(ESI):581.3[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.42(br s,1H),9.89(br s,1H),8.81(br d,1H,J＝4.4Hz),8.51(s,2H),8.2-8.3(m,2H),7.89(s,1H),7.79(dd,1H,J＝1.3,7.9Hz),7.70(br d,2H,J＝7.8Hz),7.5-7.6(m,3H),7.25(t,1H,J＝7.2Hz),4.1-4.2(m,1H),3.59(t,2H,J＝6.3Hz ),3.06(br d,2H,J＝11.1Hz),2.85(d,3H,J＝4.5Hz),2.5-2.5(m,2H),2.22(br t,2H,J＝11.0Hz).

Example 13

Synthesis of 2-(4-(4-(4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)piperidin-1-yl)propanoic acid (Compound 13)

2-((2-((4-(((4-(hexahydropyridin-3-ylamino)-2,3-dioxocyclobut-4-enyl]amino}methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (100 mg, 0.18 mmol) and N,N-diisopropylethylamine (122 μL, 0.70 mmol) were dissolved in 3 mL DMF, stirred under ice bath for 10 minutes, and then 2-bromopropionic acid (19 μL, 0.21 mmol) was added dropwise. After the addition was completed, the mixture was stirred for 1 h in an ice bath and naturally warmed to room temperature. After the reaction of the raw materials was completed as monitored by TLC spot plate, the reaction solution was poured into 40 mL of water for quenching, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed twice with 10% sodium chloride solution (30 mL) and once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 13 (6.1 mg, 0.01 mmol, yield: 5.73%) was obtained by reverse preparative chromatography.

MS m/z(ESI):609.3[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.38(br s,1H),9.85(br s,1H),8.76(br d,1H,J＝4.3Hz),8.4-8.6(m,2H),8.19(s,1H),7.86(s,1H),7.73(d,1H,J＝7.1Hz),7.65(br d,2H,J＝7.0Hz),7.4-7.5(m,3H),7.18(t,1H,J＝7.6Hz),4.29(br s,1H),3.61(br s,1H),3.20(br d,2H,J＝10.4Hz),2.79(d,5H,J＝4.5Hz),2.15(br s,4H),1.32(br d,3H,J＝7.0Hz).

Embodiment 14

Synthesis of N-methyl-2-{[2-({4-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}benzamide (Compound 14)

Under nitrogen protection, to a solution of 2-({2-[(4-bromophenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide (50 mg, 0.107 mmol) and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyrazol-1-yl]piperidine (37.76 mg, 0.129 mmol) in dioxane (1 mL) and water (0.3 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (7.85 mg, 0.011 mmol) and sodium carbonate (22.73 mg, 0.214 mmol). The mixture was stirred at 100 ° C for 2 hours. LCMS (N230741-028-P1A) detected the formation of products. The reaction solution was poured into 50 mL of water for dilution, extracted with ethyl acetate (30 mL × 2), and the organic phases were combined and washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 1: 99 to 70: 30) to obtain a crude product. The crude product was further purified by reverse preparative chromatography to obtain compound 14 (17.00 mg, 0.028 mmol, yield: 26.55%).

MS m/z(ESI):551.2[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ11.5-11.2(m,1H),9.83(br s,1H),8.75(br d,1H,J＝4.5Hz),8.45(s,1H),8.18(s,1H),7.84(s,1H),7.73(dd,1H,J＝1.1,7.9Hz),7.64(br d,2H,J＝7.6Hz),7.4-7.5(m,3H),7.19(t,1H,J＝7.6Hz),4.1-4.2(m,1H),2.90(br d,2H,J＝11.3Hz),2.79(d,3H,J＝4.5Hz),2.24(s,3H),2.1-2.2(m,2H),1.9-2.0(m,4H).

Embodiment 15

Synthesis of 2-(2-(5-fluoro-4-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-amino)-N-methylbenzamide (Compound 15)

Step 1: 2-(2-(4-bromo-5-fluoro-2-methoxyphenyl)amino)-5-trifluoromethylpyrimidin-4-amino)-N-methylbenzamide

Dissolve 2-(2-chloro-5-trifluoromethylpyrimidin-4-yl)amino)-N-methylbenzamide (1 g, 3.024 mmol) in 30 mL of n-butanol solution, add 4-bromo-5-fluoro-2-methoxyaniline (0.67 g, 3.024 mmol) and hydrochloric acid-dioxane solution (0.227 mL, 0.907 mmol), heat to 100 °C and stir for 15 h. The mixture was cooled to room temperature and 20 mL of water was added. The mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (40 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 = 1/10) to give 2-(2-(4-bromo-5-fluoro-2-methoxyphenyl)amino)-5-trifluoromethylpyrimidine-4-amino)-N-methylbenzamide (1.142 g, 2.221 mmol, yield: 73.43%).

Step 2: tert-Butyl 4-(4-(2-fluoro-5-methoxy-4-(4-(2-methylcarbamoyl)phenyl)amino-5-trifluoromethylpyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Dissolve 2-(2-(4-bromo-5-fluoro-2-methoxyphenyl)amino)-5-trifluoromethylpyrimidine-4-amino)-N-methylbenzamide 8010319_02 (700 mg, 1.36 mmol) in 12 mL 1,4-dioxane solution and 2 mL aqueous solution, add anhydrous sodium carbonate (360.7 mg, 3.4 mmol) and 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (111 mg, 0.13 mmol), add tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (616.2 mg, 1.632 mmol), and heat the temperature to 90°C under nitrogen protection and stir for 15 h. The mixture was cooled to room temperature and 20 mL of water was added. The mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1/1) to give tert-butyl 4-(4-(2-fluoro-5-methoxy-4-(4-(2-methylcarbamoyl)phenyl)amino-5-trifluoromethylpyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (546 mg, 0.797 mmol, 58.59%).

Step 3: 2-(2-(5-fluoro-2-methoxy-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide

Dissolve tert-butyl 4-(4-(2-fluoro-5-methoxy-4-(4-(2-methylcarbamoyl)phenyl)amino-5-trifluoromethylpyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (546 mg, 0.797 mmol) in 5 mL of dichloromethane solution and add dropwise under ice bath. Hydrochloric acid-dioxane solution (4 mL, 8 mmol) was reacted at 0°C for 1 hour. After the reaction, the solvent was removed by vacuum concentration to obtain crude 2-(2-(5-fluoro-2-methoxy-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (460 mg, 0.786 mmol, yield: 98.6%).

Step 4: 2-(2-(5-fluoro-4-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-amino)-N-methylbenzamide

Dissolve 2-(2-(5-fluoro-2-methoxy-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (80 mg, 0.136 mmol) in 8 mL of N,N-dimethylformamide solution, add N,N-diisopropylethylamine (120 μL, 0.683 mmol), 1-hydroxybenzotriazole (37 mg, 0.273 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52.47 mg, 0.273 mmol) and 2-hydroxyacetic acid (11.45 mg, 0.149 mmol), and stir the reaction at room temperature for 15 h. The mixture was cooled to room temperature and 20 mL of water was added. The mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (40 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 = 1/10) to give compound 15 (40 mg, 0.062 mmol, yield: 45.48%).

MS m/z(ESI):643.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.3-11.4(m,1H),8.7-8.8(m,1H),8.6-8.7(m,1H),8.3-8.5(m,2H ),8.2-8.3(m,1H),7.9-8.0(m,1H),7.8-7.9(m,1H),7.7-7.8(m,1H),7.39(br t,1H,J=7.1Hz),7.3-7.3(m,1H),7.1-7.2(m,1H),4.4-4.6(m,3H),4.1-4.2(m,2H),3.8-3.9( m,4H),3.15(br t,1H,J=12.2Hz),2.7-2.9(m,4H),2.0-2.1(m,2H),1.9-2.0(m,1H),1.7-1.9(m,1H).

Example 16

Synthesis of 2-(4-(2-fluoro-5-methoxy-4-(4-(2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)piperidine-1-acetic acid (Compound 16)

2-(2-(5-fluoro-2-methoxy-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (80 mg, 0.136 mmol) was dissolved in 1.2 mL N,N-dimethylformamide solution, and N,N-diisopropylethylamine (120 μL, 0.683 mmol) and 2-bromoacetic acid (20 mg, 0.14 mmol) were added. The mixture was stirred at room temperature for 15 h. After cooling to room temperature, 20 mL of water was added, and the mixture was extracted with dichloromethane (15 mL×3). The organic phases were combined and washed with saturated sodium chloride solution (40 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 = 1/10) to obtain compound 16 (26 mg, 0.04 mmol, yield: 29.56%).

MS m/z(ESI):643.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.3-11.5(m,1H),8.7-8.9(m,1H),8.6-8.7(m,1H),8.3-8.5(m,2H),8.26(s,1H),8.01( s,1H),7.8-7.9(m,1 H),7.71(d,1H,J＝7.3Hz),7.4-7.4(m,1H),7.31(d,1H,J＝7.3Hz),7.1-7.2(m,1H),4.2-4.3(m ,1H),3.89(s,4H),3.09(br d,3H,J＝11.9Hz),2.78(d,4H,J＝4.5Hz),2.5-2.6(m,2H),2.0-2.1(m,4H).

Embodiment 17

Synthesis of N-methyl-2-((2-((4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (Compound 17)

Step 1: Synthesis of 2-((2-((4-bromo-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide

2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (600 mg, 1.81 mmol) and 4-bromo-2,3-dihydrobenzofuran-7-amine (387 mg, 1.81 mmol) were dissolved in n-butanol (25 mL), and then dioxane hydrochloride solution (4M) (0.136 mL) was added, and the mixture was stirred at 100°C for 12 hours. After the reaction was completed, most of the solvent was removed by vortexing, and the mixture was filtered to obtain a gray solid, namely 2-((2-((4-bromo-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (700 mg, 76%).

Step 2: Synthesis of N-methyl-2-((2-((4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino

2-((2-((4-bromo-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (150 mg, 0.29 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine (103 mg, 0.35 mmol), Pd(dppf)Cl2 (25 mg, 0.03 mmol) and sodium carbonate (63 mg, 0.58 mmol) were dissolved in dioxane (2 mL) and water (0.1 mL), nitrogen was replaced three times and nitrogen was protected, and the reaction was stirred at 100°C for 12 hours. After the reaction was completed, water and dichloromethane were added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 17 (70 mg, 41%).

MS m/z(ESI):593.3[M+H] ⁺

¹ H NMR (DMSO-d ₆ ) δ: 11.50 (s, 1H), 9.12 (br s, 1H), 8.71 (br d, J = 2.9Hz, 1H), 8.35 (s, 2H), 8.19-8.11 ( m,1H),7.84(s,1H),7.66(br d,J＝7.3Hz,1H),7.32-7.11(m,2H),7.06(br d,J＝8.4Hz,2H),4.53(br t,J＝7.9Hz,2H),4.22-4.12(m ,1H),3.39(br s,2H),2.89(br d,J＝7.5Hz,2H),2.77(br d,J＝3.9Hz,3H),2.23(s,3H),2.10-1.98(m,6H).

Embodiment 18

Synthesis of 2-((2-((4-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (Compound 18)

Step 1: Synthesis of 2-((2-((4-bromo-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide

2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (600 mg, 1.81 mmol) and 4-bromo-2,3-dihydrobenzofuran-7-amine (387 mg, 1.81 mmol) were dissolved in n-butanol (25 mL), and a dioxane hydrochloride solution (4 M) (0.136 mL), stirred at 100°C for 12 hours. After the reaction was completed, most of the solvent was removed by vortexing, and the mixture was filtered to obtain a gray solid, namely 2-((2-((4-bromo-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (700 mg, yield: 76%).

Step 2: Synthesis of tert-butyl 4-(4-(7-(4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

2-((2-((4-bromo-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (200 mg, 0.39 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (178 mg, 0.47 mmol), Pd(dppf)Cl ₂ (32 mg, 0.04 mmol) and sodium carbonate (83 mg, 0.78 mmol) were dissolved in dioxane (2 mL) and water (0.1 mL), and nitrogen was replaced three times and protected with nitrogen. The reaction was stirred at 100° C. for 12 hours. After the reaction was completed, water and dichloromethane were added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was used to obtain tert-butyl 4-(4-(7-(4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (160 mg, yield: 60%).

Step 3: Synthesis of N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino

4-(4-(7-(4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (160 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid dioxane solution (4M) (0.5 mL) was added in an ice bath, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by spin drying and dried to obtain N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (130 mg, yield: 96%).

Step 4: Synthesis of 2-((2-((4-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino

N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (130 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (1.5 mL), 2-hydroxyacetic acid (20 mg, 0.27 mmol), EDCI (86 mg, 0.44 mmol), HOBt (61 mg, 0.44 mmol) and DIEA (0.11 mL, 0.66 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, water and dichloromethane were added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 18 (55 mg, yield: 38%).

MS m/z(ESI):637.2[M+H] ⁺

¹ H NMR(DMSO-d ₆ )δ:11.49(s,1H),9.08(br s,1H),8.68(br d,J＝4.5Hz,1H),8.60-8.40(m,1H),8.35(s,1H),8.15(s,1H),7.85(s,1H),7.66(d,J＝7.8Hz,1H ),7.21(br s,2H),7.09-7.02(m,2H),4.58-4.41(m,5H),4.19-4.08(m,2H),3.83(br d,J＝12.0Hz,1H),3.41-3.34(m,2H),3.23-3.06(m,1H),2.88-2.75(m,4H),2.09(br d,J＝10.0Hz,2H), 2.02-1.80(m,2H).

Embodiment 19

Synthesis of 2-((2-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (Compound 19)

2-((2-((4-bromophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (80 mg, 0.17 mmol), 2-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaboronan-2-yl)-1H-pyrazol-1-yl)propanol (54.8 mg, 0.21 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (12.6 mg, 0.02 mmol) and sodium carbonate (45.5 mg, 0.43 mmol) were dissolved in a mixed solvent of 2 mL of 1,4-dioxane and 0.5 mL of water. The mixture was evacuated with nitrogen three times and heated to 90 °C under nitrogen protection and stirred overnight. After the reaction was completed by TLC monitoring, the mixture was filtered, concentrated under reduced pressure to remove most of the solvent, 10 mL of water was added, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed twice with 10% sodium chloride solution (20 mL) and once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The organic phases were combined and concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 19 (46.1 mg, 0.09 mmol, Yield: 51.03%)

MS m/z(ESI):526.2[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.36(br s,1H),9.84(br s,1H),8.75(br d,1H,J＝4.4Hz),8.45(s,2H),8.03(s,1H),7.83(s,1H),7.73(d,1H,J＝7.9Hz),7.65(br d,2H,J＝7.1Hz),7.4-7.5(m,3H),7.19(t,1H,J＝7.6Hz),4.74(s,1H),4.03(s,2H),2.79(d,3H ,J＝4.5Hz),1.10(s,6H).

Embodiment 20

Synthesis of 2-((2-((4-(1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (Compound 20)

N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (50 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (1 mL), and acetic acid (20 mg, 0.1 mmol), EDCI (33 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol) and DIEA (33 mg, 0.26 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, water and dichloromethane were added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 20 (30 mg, yield: 56%).

MS m/z(ESI):621.2[M+H] ⁺

¹ H NMR (DMSO-d ₆ ) δ: 11.48 (s, 1H), 9.08 (br s, 1H), 8.69 (br d, J = 4.3Hz, 1H), 8.48 (br s, 1H), 8.35 (s ,1H),8.15(s,1H),7.85(s,1H),7.67(br d,J＝7.9Hz,1H),7.21(br s,2H),7.09-7.01(m,2H),4.58-4.43(m,4H),3.95(br d,J＝14.1Hz,1H),3.32-3.17(m,3H),2.80-2.70(m,4H),2.13-2.03(m,5H),2.01-1.92(m,1H),1.82(br dd ,J＝4.1,12.0Hz,1H).

Embodiment 21

Synthesis of N-methyl-2-((2-((4-(1-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (Compound 21)

N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (50 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (1 mL), and trifluoroacetic acid (11.4 mg, 0.1 mmol), EDCI (33 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol) and DIEA (33 mg, 0.26 mmol) were added, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, water and dichloromethane were added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 21 (10 mg, yield: 18%).

MS m/z(ESI):675.2[M+H] ⁺

¹ H NMR (DMSO-d ₆ ) δ: 11.49 (s, 1H), 9.09 (br s, 1H), 8.69 (br d, J = 4.4Hz, 1H), 8.59-8.32 (m, 2H), 8.19(s,1H),7.86(s,1H),7.66(br d,J＝7.8Hz,1H),7.21(br s,2H),7.09-7.02(m,2H),4.65-4.51(m, 3H),4.41(br d,J＝13.6Hz,1H),3.99(br d,J＝13.8Hz,1H),3.53-3.46(m,1H),3.40-3.37(m,2H),3.14(br t,J＝12.0Hz,1H),2.77(d,J＝4.5Hz, 3H),2.25-2.17(m,2H),2.05-1.95(m,2H).

Embodiment 22

Synthesis of N-methyl-2-((2-((4-(1-(1-propionylpiperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (Compound 22)

N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (50 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (1 mL), and propionic acid (7.4 mg, 0.1 mmol), EDCI (33 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol) and DIEA (33 mg, 0.26 mmol) were added, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, water and dichloromethane were added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 22 (25 mg, yield: 46%).

MS m/z(ESI):635.2[M+H] ⁺

¹ H NMR (DMSO-d ₆ ) δ: 11.50 (s, 1H), 9.11 (br s, 1H), 8.71 (br d, J = 4.4Hz, 1H), 8.60-8.29 (m, 2H), 8.16 ( s,1H),7.85(s,1H),7.66(br d,J＝7.8Hz,1H),7.20(br s,2H),7.08-7.01(m,2H),4.58-4.44(m,4H),3.98(br d,J＝13.9Hz,1H),3.44-3.38(m,2H),3.22-3.15(m,1H),2.81-2.70(m,4H),2.42-2.34(m,2H),2.08(br t,J＝12.4Hz,2H),1.92(br dd,J＝3.5,11.9Hz,1H),1.81(br dd,J＝3.9,11.9Hz,1H),1.02(t,J＝7.4Hz,3H ).

Embodiment 23

Synthesis of 2-((2-((4-(1-(1-(2-cyanoacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (Compound 23)

N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (50 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (1 mL), and cyanoacetic acid (8.5 mg, 0.1 mmol), EDCI (33 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol) and DIEA (33 mg, 0.26 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, water and dichloromethane were added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 23 (15 mg, 27%).

MS m/z(ESI):646.2[M+H] ⁺

¹ H NMR (DMSO-d ₆ ) δ: 11.50 (s, 1H), 9.12 (br s, 1H), 8.71 (br d, J = 4.5Hz, 1H), 8.35 (s, 2H), 8.15 (s, 1H),7.86(s,1H),7.66(br d,J＝7.8Hz,1H),7.36-7.11(m,2H),7.09-7.01(m,2H),4.59-4.39(m,4H), 4.18-4.05(m,2H),3.79(br d,J＝13.9Hz,1H),3.42-3.38(m,2H),3.24(br t,J＝11.7Hz,1H),2.89-2.81(m,1H),2.77(d,J＝4.5Hz, 3H),2.13-1.97(m,3H),1.87(br dd,J＝3.9,12.1Hz,1H).

Embodiment 24

Synthesis of N-methyl-2-((2-((4-(1-(1-propionylpiperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide (Compound 24)

Dissolve 2-((2-((4-(((4-(hexahydropyridin-3-ylamino)-2,3-dioxocyclobut-4-enyl]amino}methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (100 mg, 0.19 mmol) and triethylamine (104 μL, 0.60 mmol) in 4 mL DMF, stir for 10 minutes under ice bath, then add propionic anhydride (24 μL, 0.19 mmol) dropwise. After the addition is complete, place in ice bath. The mixture was stirred for 10 min and naturally warmed to room temperature, and then stirred for 3 h. After the reaction of the raw materials was completed by TLC spot plate monitoring, the reaction solution was poured into 40 mL of water for quenching, extracted with ethyl acetate (20 mL×3), and the organic phases were combined and washed twice with 10% sodium chloride solution (30 mL) and once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 24 (73 mg, 0.12 mmol, yield: 65.78%) was obtained by reverse preparative chromatography.

MS m/z(ESI):593.3[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.30(br s,1H),9.77(br s,1H),8.68(br d,1H,J＝4.3Hz),8.38(s,2H),8.13(s,1H),7.78(s,1H),7.66(d,1H,J＝7.4Hz),7.58(br d,2H,J＝7.8Hz),7.4-7.5(m,3H),7.12(t,1H,J＝7.6Hz),4.3-4.5(m,2H),3.91(br d,1H,J＝13.4Hz),3.0-3.2(m,1H),2.6-2.7(m,4H),2.3-2.4(m,2H),1.9-2.1(m,2H),1.6-1.9( m,2H),0.95(t,3H,J＝7.4Hz).

Embodiment 25

Synthesis of 2-({2-[(4-{5-[1-(2-hydroxyacetyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide (Compound 25)

Step 1: 2-methylpropan-2-yl 4-[3-(4-aminophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-carboxylate

[(E)-amino(4-aminophenyl)methylene]hydroxylamine (164.8 mg, 1.09 mmol), 1-{[(2-methylpropyl-2-yl)oxy]carbonyl}piperidine-4-carboxylic acid (300 mg, 1.31 mmol), N,N-diisopropylethylamine (342 μL, 1.96 mmol) and O-benzotriazole-N,N,N',N'-tetramethyl-urea-M-hexafluorophosphate (413.4 mg, 1.09 mmol) were dissolved in DMF (10 mL) and stirred at 80°C overnight. After the reaction was completed by TLC monitoring, 100 mL of water was added and extracted with ethyl acetate (80 mL×3), the organic phases were combined, and washed once with saturated sodium chloride solution (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The organic phases were combined and concentrated under reduced pressure and then purified by column chromatography to obtain 2-methylpropan-2-yl 4-[3-(4-aminophenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate (347 mg, 1.010 mmol, yield: 92.43%).

Step 2: 2-{[2-({4-[5-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-3-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide

2-Methylpropan-2-yl 4-[3-(4-aminophenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate (320 mg, 0.93 mmol) and 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (307.3 mg, 0.93 mmol) were dissolved in 8 mL of n-butanol, 4 M hydrochloric acid solution in dioxane (70 μL) was added dropwise, and the temperature was raised to 100 °C and stirred overnight. After the reaction was completed as monitored by TLC, the solvent was removed by concentration under reduced pressure, 3 mL of ethyl acetate was added to precipitate the solid, and the solid was filtered. The filter cake was washed with 5 mL × 3 n-butanol to obtain 2-{[2-({4-[5-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-3-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (327 mg, 0.61 mmol, yield: 65.36%)

Step 3: 2-({2-[(4-{5-[1-(2-hydroxyacetyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide

2-{[2-({4-[5-(Hexahydropyridin-4-yl)-1,2,4-oxadiazol-3-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (100 mg, 0.19 mmol), 2-hydroxyacetic acid (17.0 mg, 0.22 mmol), 1-hydroxybenzotriazole (50.2 mg, 0.37 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71.2 mg, 0.37 mmol) were dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (162 μL, 0.93 mmol) was added and stirred at room temperature for 18 h. After the reaction of the raw material was completed as monitored by TLC, 20 mL of water was added and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed once with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The organic phases were combined and concentrated under reduced pressure and then purified by reverse preparative chromatography to obtain compound 25 (73.7 mg, 0.12 mmol, yield: 66.31%).

MS m/z(ESI):597.2[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.27(br s,1H),10.09(br s,1H),8.68(br d,1H,J＝4.0Hz),8.3-8.5(m,2H),7.8-7.8(m,4H),7.68(d,1H,J＝7.1Hz),7 .46(t,1H,J＝7.8Hz),7.16(t,1H,J＝7.6Hz),4.47(t,1H,J＝5.3Hz),4.25(br d,1H,J＝13.1Hz),4.05(br dd,2H,J＝5.1,7.5Hz),3.69(br d,1H,J＝12.6Hz),3.3-3.4(m,1H),3.0-3.2(m,1H),2.8-2.9(m,1H),2.72(d,3H,J＝4.5Hz),2.04 (br dd,2H,J＝3.1,13.2Hz),1.72(br d,1H,J＝11.0Hz),1.60(br d,1H,J＝10.3Hz).

Embodiment 26

Synthesis of 2-((2-((4-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (Compound 26)

Step 1: tert-Butyl 4-(4-(4-aminophenyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

Dissolve 4-aminophenylacetylene (300 mg, 2.56 mmol) and 2-methylpropan-2-yl 4-azidohexahydropyridine-1-carboxylate (579.5 mg, 2.56 mmol) in 10 mL THF, slowly add 10 mL of water until the system becomes turbid, add triethylamine (1 mL, 7.17 mmol) and cuprous iodide (48.8 mg, 0.26 mmol), and stir at room temperature overnight. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure to remove most of the solvent, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The organic phases were combined and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain tert-butyl 4-(4-(4-aminophenyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (625 mg, 1.82 mmol, yield: 71.07%).

Step 2: N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide

Dissolve tert-butyl 4-(4-(4-aminophenyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (400 mg, 1.17 mmol) and 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (385.2 mg, 1.17 mmol) in 5 mL of n-butanol, add 4 M hydrochloric acid in dioxane solution (87 μL) dropwise, raise the temperature to 100 °C and stir overnight. After the reaction was completed as monitored by TLC, the solvent was removed by concentration under reduced pressure, 3 mL of ethyl acetate was added to precipitate the solid, and the solid was filtered. The filter cake was washed with 5 mL × 3 n-butanol to obtain N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide (581 mg, 1.08 mmol, yield: 92.78%)

Step 3: 2-((2-((4-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide

N-Methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide (100 mg, 0.19 mmol), 2-hydroxyacetic acid (17.0 mg, 0.22 mmol), 1-hydroxybenzotriazole (50.3 mg, 0.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71.3 mg, 0.37 mmol) were dissolved in 5 mL of N,N-dimethylformamide, N,N-diisopropylethylamine (162 μL, 0.93 mmol) was added and stirred at room temperature for 18 h. After the reaction of the raw material was completed as monitored by TLC, 20 mL of water was added and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed once with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The organic phases were combined and concentrated under reduced pressure and then purified by reverse preparative chromatography to obtain compound 26 (70.9 mg, 0.120 mmol, yield: 62.95%).

MS m/z(ESI):596.2[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.34(br s,1H),9.96(br s,1H),8.75(br d,1H,J＝4.4Hz),8.61(s,1H),8.4-8.6(m,2H),7.7-7.8(m,5H),7.52(t,1H,J＝ 7.9Hz),7.21(t,1H,J＝7.5Hz),4.8-4.9(m,1H),4.60(t,1H,J＝5.4Hz),4.48(br d,1H,J＝12.5Hz),4.1-4.2(m,2H),3.86(br d,1H,J＝12.5Hz),3.2-3.3(m,1H),2.8-3.0(m,1H),2.80(d,3H,J＝4.5Hz),2.17(br d,2H,J＝10.1 Hz),1.8-2.0(m,2H).

Embodiment 27

Synthesis of N-methyl-2-((2-((4-(1-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide (Compound 27)

2-((2-((4-(((4-(hexahydropyridin-3-ylamino)-2,3-dioxocyclobut-4-enyl]amino}methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (80 mg, 0.15 mmol) and triethylamine (83 μL, 0.60 mmol) were dissolved in 5 mL of DMF. After stirring for 10 minutes under ice bath, trifluoroacetic anhydride (41 μL, 0.30 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 10 minutes under ice bath and naturally warmed to room temperature and stirred overnight. After the reaction of the raw materials was completed as monitored by TLC spot plate, the reaction solution was poured into 40 mL of water for quenching and ethyl acetate (20 The organic phases were combined, washed twice with 10% sodium chloride solution (30 mL) and once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The compound 27 (26 mg, 0.04 mmol, yield: 27.10%) was obtained by purification by reverse preparative chromatography.

MS m/z(ESI):633.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ) δ: 11.37 (br s, 1H), 9.83 (br s, 1H), 8.74 (br d, 1H, J=4.5Hz), 8.54 (br s,1H),8.45(s,1H),8.23(s,1H),7.87(s,1H),7.73(d,1H,J＝7.5Hz),7.65(br d,2H,J＝8.0Hz),7.4-7.6(m,3H),7.19(t,1H,J＝7.5Hz),4.5-4.6(m,1H),4.40(br d,1H,J＝13.6 Hz),3.99(br d,1H,J＝13.8Hz),3.4-3.5(m,1H),3.1-3.2(m,1H),2.80(d,3H,J＝4.5Hz),2.1-2.3(m,2H),1.9 -2.0(m,2H).

Embodiment 28

Synthesis of N-methyl-2-((2-((4-(1-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide (Compound 28)

Dissolve N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide (100 mg, 0.19 mmol) and triethylamine (103 μL, 0.74 mmol) in 5 mL DMF. Stir in an ice bath for 10 minutes and then add trifluoroacetic anhydride (52 μL, 0.37 mmol) dropwise. After the addition is complete, stir in an ice bath for 10 minutes, warm to room temperature naturally, and stir overnight. After the reaction of the raw materials was completed as monitored by TLC spot plate, the reaction solution was poured into 40 mL of water for quenching, extracted with ethyl acetate (20 mL×3), and the organic phases were combined and washed twice with 10% sodium chloride solution (30 mL) and once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The compound 28 (25.2 mg, 0.04 mmol, yield: 21.36%) was obtained by purification by reverse preparative chromatography.

MS m/z(ESI):634.2[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.35(br s,1H),9.96(br s,1H),8.75(br d,1H,J＝4.5Hz),8.65(s,1H),8.4-8.6(m,2H),7.7-7.8(m,5H),7.52(t,1H,J＝7.8Hz),7.21(t ,1H,J＝7.5Hz),4.9-5.0(m,1H),4.42(br d,1H,J＝13.6Hz),4.01(br d,1H,J＝13.5Hz),3.5-3.6(m,1H),3.2-3.3(m,1H),2.80(d,3H,J＝4.5Hz),2.2-2.3(m,2H),2.04 (ddq,2H,J＝4.3,7.5,12.0Hz).

Embodiment 29

Synthesis of 2-((2-((4-(1-(1-(2-cyanoacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (Compound 29)

2-((2-((4-(((4-(hexahydropyridin-3-ylamino)-2,3-dioxocyclobut-4-enyl]amino}methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine 2-(4-pyridin-4-yl)amino)-N-methylbenzamide (80 mg, 0.15 mmol), 2-cyanoacetic acid (15.2 mg, 0.18 mmol), 1-hydroxybenzotriazole (40.3 mg, 0.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.2 mg, 0.30 mmol) were dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (130 μL, 0.75 mmol) was added and stirred at room temperature for 18 h. After TLC monitoring, 20 mL of water was added and extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The organic phases were combined and concentrated under reduced pressure and purified by reverse preparative chromatography to obtain compound 29 (30.9 mg, 0.05 mmol, yield: 34.31%).

MS m/z(ESI):604.2[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.37(br s,1H),9.84(br s,1H),8.75(br d,1H,J＝4.4Hz),8.45(s,2H),8.18(s,1H),7.86(s,1H),7.73(d,1H,J＝7.8Hz),7.65(br d,2H,J＝7.4Hz),7.4-7.6(m,3H),7.18(t,1H,J＝7.6Hz),4.4-4.5(m,2H),4.1-4.2(m,2H),3.78 (br d,1H,J＝13.9Hz),3.2-3.3(m,1H),2.8-2.9(m,4H),2.0-2.1(m,2H),1.9-2.0(m,1H),1.83(dq, 1H,J＝4.1,12.1Hz).

Embodiment 30

Synthesis of N-methyl-2-((2-((4-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide (Compound 30)

2-((2-((4-(((4-(hexahydropyridin-3-ylamino)-2,3-dioxocyclobut-4-enyl]amino}methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (80 mg, 0.15 mmol) and N,N-diisopropylethylamine (104 μL, 0.60 mmol) were dissolved in 4 mL DMF, stirred under ice bath for 10 minutes, and then methanesulfonic anhydride (39.0 mg, 0.22 mmol) was slowly added. After the addition was completed, the mixture was stirred for 3 h in an ice bath and naturally warmed to room temperature. After the reaction of the raw materials was completed as monitored by TLC spot plate, the reaction solution was poured into 40 mL of water for quenching, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed twice with 10% sodium chloride solution (30 mL) and once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 30 (36.2 mg, 0.06 mmol, yield: 38.50%) was obtained by reverse preparative chromatography.

MS m/z(ESI):615.2[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ:11.37(br s,1H),9.84(br s,1H),8.74(br d,1H,J＝4.4Hz),8.4-8.6(m,2H),8.23(s,1H),7.87(s,1H),7.73(d,1H,J＝7.6Hz),7.66(br d,2H,J＝7.6Hz),7.4-7.6(m,3H),7.19(t,1H,J＝7.4Hz),4.3-4.4(m,1H),3.69(br d,2H,J＝12.3Hz),2.9-3.0(m,5H),2.80(d,3H,J＝4.5Hz),2.17(br d,2H,J＝10.1Hz),2.0-2.1(m,2H)Hz).

Embodiment 31

Synthesis of 2-({2-[(4-{1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-4-yl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-(trideuteriomethyl)benzamide (Compound 31)

Step 1: 2-{[2-(4-bromophenyl)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide

To a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide (150.0 mg, 0.45 mmol) and 4-bromoaniline (77.33 mg, 0.45 mmol) in n-BuOH (2 mL) was added HCl dioxane solution (0.23 mL), and the reaction was stirred at 100 ° C for 18 hours. After the reaction was completed by LCMS monitoring, the mixture was concentrated under reduced pressure to give a crude product. The crude product was slurried with EtOAc (8.0 mL) and filtered to give 2-{[2-(4-bromophenyl)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide (180.0 mg, 0.396 mmol, yield: 88.15%) as a yellow solid.

Step 2: 2-Methylpropan-2-yl 4-{4-[4-({4-[(2-{[(trideuteriomethyl)amino]carbonyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]pyrazol-1-yl}piperidin-1-carboxylate

Pd(dppf)Cl 2 (24.95 mg, 0.034 mmol) and Na 2 CO 3 (72.27 mg, 0.68 mmol) were added to 2-({2-[[(4-bromophenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]-5-(trifluoromethyl)pyridin-4-yl]amino)-N-(trideuteriomethyl)benzamide (160.0 mg, 0.34 _mmol ) and 2 _- methylpropane-2- _benzamide , and the reaction was stirred at 100° C. for 1 hour. After LCMS showed that the reaction was complete, the reaction solution was poured into 20 mL of water and extracted with EtOAc (5 mL). The combined organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate = 1/1) to give compound 2-methylpropan-2-yl 4-{4-[4-({4-[(2-{[(trideuteriomethyl)amino]carbonyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]pyrazol-1-yl}piperidine-1-carboxylate (180.0 mg, 0.28 mmol, yield: 82.53%) as a yellow solid.

Step 3: 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide

To a solution of 2-methylpropan-2-yl 4-{4-[4-({4-[[(2-[[(trifluoromethyl)amino]carbonyl]phenyl}amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]pyrazol-1-yl}piperidine-1-carboxylate (60.0 mg, 0.09 mmol) in dioxane (0.6 mL) was added HCl (23.45 μL, 0.09 mmol) and then stirred at 25 °C. The reaction was carried out for 1 hour. After LCMS showed that the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was used directly without further purification to obtain a brown solid compound 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide (50.0 mg, 0.093 mmol, yield: 98.79%).

Step 4: 2-({2-[(4-{1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-4-yl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-(trideuteriomethyl)benzamide

To a solution of 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide (50.0 mg, 0.09 mmol) and glycolic acid (14.15 mg, 0.19 mmol) in DMA (1 mL) was added HOBt (25.13 mg, 0.19 mol), EDCI (35.66 mg, 0.19 mmol) and DIEA (60.10 mg, 0.47 mmol), and the reaction was stirred at 25 °C for 1 hour. CMS showed consumption of reactant 1 and production of the desired product. After LCMS showed completion of the reaction, the reaction solution was poured into 5 mL of water, extracted with EtOAc (5 mL), and the combined organic phases were washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse preparative chromatography to give compound 31 (5.69 mg, 0.01 mmol, yield: 10.27%).

MS m/z(ESI):598.3[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.39(d,1H,J＝2.3Hz),9.85(s,1H),8.72(s,1H),8.45(s,1H) ,8.19(s,1H),7.85(s,1H),7.7-7.7(m,1H),7.64(d,2H,J＝7.6Hz),7.4-7. 6(m,4H),7.18(t,1H,J＝7.7Hz),4.4-4.5(m,2H),4.14(d,2H,J＝6.4Hz),3. 83(s,2H),3.1-3.2(m,1H),2.83(s,1H),2.0-2.1(m,2H),1.7-2.0(m,3H).

Embodiment 32

Synthesis of 2-({2-[(4-{1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-3-yl}-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methoxybenzamide (Compound 32)

Step 1: 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methoxybenzamide

HCl (0.72 mL, 2.88 mmol) was added to a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methoxybenzamide (1.0 g, 2.88 mmol) and 4-bromo-2-methoxyaniline (0.64 g, 3.17 mmol) in dioxane (10.0 mL), and the reaction was stirred at 100 ° C for 18 hours. LCMS showed that the reaction was completed. After the reaction was completed by LCMS monitoring, the mixture was concentrated under reduced pressure to give a crude product. The crude product was slurried with EtOAc (20.0 mL) and filtered to give 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methoxybenzamide (607.0 mg, 1.19 mmol, yield: 41.08%) as a yellow solid.

Step 2: 2-methylpropan-2-yl-4-(4-{3-methoxy-4-[(4-{[2-(4-oxo-3-aza-2-oxabutan-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl)amino]phenyl}pyrazol-1-yl)piperidin-1-carboxylate

To a solution of 2-({2-[[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]]-5-(trifluoromethyl)pyrimidin-4-yl]-amino)-N-methoxybenzamide (200.0 mg, 0.39 mmol) and 2-methylpropen-2-yl 4-[4-(4.4.4.5,5-tetramethyl-1,3,3,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (162.03 mg, 0.43 mmol) in _H2O (0.5 mL) and dioxane (2 mL) was added _Na2CO3 ( _82.76 mg, 0.78 mmol), Pd(dppf) _Cl2 (28.57 mg, 0.04 mmol), and the reaction was stirred at 100°C for 18 hours. After LCMS showed that the reaction was complete, the reaction solution was poured into 20 mL of water and extracted with EtOAc (5 mL). The combined organic phase was washed with a saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate = 1/1) to give compound 2-methylpropan-2-yl-4-(4-{3-methoxy-4-[(4-{[2-(4-oxo-3-aza-2-oxabutan-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl)amino]phenyl}pyrazol-1-yl)piperidin-1-carboxylate (225.0 mg, 0.33 mmol, yield: 84.42%) as a yellow solid.

Step 3: 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-3-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methoxybenzamide

HCl (36.62 μL, 0.15 mmol) was added to a solution of 2-methylpropan-2-yl-4-(4-{4-{3-methoxy-4-[[(4-{[2-(4-oxo-3-aza-2-oxo-2-oxabutan-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl)amino]phenyl]phenyl}pyrazol-1-yl)piperidin-1-carboxylate (100 mg, 0.146 mmol) in dioxane (1 mL), and then stirred at 25° C. for 1 hour to react. After LCMS showed that the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was used directly without further purification to give a brown solid compound 2-{[2-({4-[1-(hexahydropyridine-4-yl)pyrazol-3-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methoxybenzamide (80.0 mg, 0.14 mmol, yield: 93.75%).

Step 4: 2-({2-[(4-{1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-3-yl}-2-methoxyphenyl)amino]-5-(trimethoxyphenyl)- (fluoromethyl)pyrimidin-4-yl}amino)-N-methoxybenzamide

To a solution of 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-3-yl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methoxybenzamide (150 mg, 0.25 mmol) and glycolic acid (39.16 mg, 0.52 mmol) in DMA (1 mL) were added HOBt (69.58 mg, 0.52 mmol), EDCI (98.71 mg, 0.52 mmol) and DIEA (166.39 mg, 1.29 mmol), and the reaction was stirred at 25° C. for 1 hour. After LCMS showed that the reaction was complete, the reaction solution was poured into 5 mL of water and extracted with EtOAc (5 mL). The combined organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase preparative chromatography to give compound 32 (39.42 mg, 0.061 mmol, yield: 23.62%).

MS m/z(ESI):641.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.97(d,1H,J＝1.4Hz),10.72(d,1H,J＝1.8Hz),8.76(s,1H),8.3- 8.4(m,3H),7.94(s,1H),7.5-7.6(m,2H),7.28(d,2H,J=1.6Hz),7.0-7.2(m, 2H),4.58(t,1H,J＝5.4Hz),4.46(s,2H),4.15(t,2H,J＝5.5Hz),3.85(s,4H), 3.70(s,3H),3.1-3.2(m,1H),2.84(s,1H),2.1-2.2(m,2H),1.7-2.0(m,2H).

Embodiment 33

Synthesis of N-methoxy-2-{[2-({2-methoxy-4-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}benzamide (Compound 33)

Step 1: 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methoxybenzamide

HCl (0.72 mL, 2.88 mmol) was added to a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methoxybenzamide (1.0 g, 2.88 mmol) and 4-bromo-2-methoxyaniline (0.64 g, 3.17 mmol) in dioxane (10.0 mL), and the reaction was stirred at 100 ° C for 18 hours. LCMS showed that the reaction was completed. After the reaction was completed by LCMS monitoring, the mixture was concentrated under reduced pressure to give a crude product. The crude product was slurried with EtOAc (20.0 mL) and filtered to give 2-({2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methoxybenzamide (607.0 mg, 1.19 mmol, yield: 41.08%) as a yellow solid.

Step 2: N-methoxy-2-{[2-({2-methoxy-4-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}benzamide

To a solution of 2-({2-[[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methoxybenzamide (200.0 mg, 0.39 mmol) and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine (125.1 mg, 0.43 mmol) in H ₂ O (0.4 mL) and dioxane (1.6 mL) was added Na ₂ CO ₃ (82.76 mg, 0.78 mmol), Pd(dppf)Cl ₂ (28.57 mg, 0.04 mmol). The reaction was stirred at 100° C. for 18 hours. After LCMS showed that the reaction was completed, the reaction solution was poured into 5 mL of water and extracted with EtOAc (5 mL). The combined organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse preparative chromatography to obtain compound 33 (37.1 mg, 0.06 mmol, yield: 15.93%).

MS m/z(ESI):597.3[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ10.70(s,1H),8.77(s,1H),8.2-8.5(m,3H),7.92(s,1H),7.5-7.6(m,2H),7.2-7.4(m, 2H),7.0-7.2(m, 2H),4.12(td,1H,J＝5.3,10.3Hz),3.85(s,3H),3.70(s,3H),2.89(d,2H,J＝11.4Hz),2.23(s,3H), 1.9-2.1(m,6H).

Embodiment 34

Synthesis of 2-[(2-{[4-(1H-pyrazol-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)amino]-N-methylbenzamide (Compound 34)

To a mixture of 2-({2-[(4-bromophenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]-5-(trifluoromethyl)pyridin-4-yl}amino)-N-methylbenzamide (750 mg, 1.61 mmol) and 4-(4.4,5,5-tetramethyl-1.3,2-dioxaborolan-2-yl)-1H-pyrazole (468.18 mg, 2.41 mmol) in dioxane (7.5 mL) and H ₂ O (1.9 mL) was added Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (131.68 mg, 0.16 mmol) and Na ₂ CO ₃ (340.98 mg, 3.22 mmol) and the reaction mixture was stirred at 100° C. for 2 hours. LCMS showed that the reaction was complete. The reaction solution was poured into 5 mL of water, extracted with EtOAc (5 mL), the combined organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse preparative chromatography to give compound 34 (241.0 mg, 0.53 mmol, yield: 33.04%) as a white solid.

MS m/z(ESI):454.2[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ12.7-13.1(m,1H),11.36(s,1H),9.82(s,1H),8.74(d,1H,J＝4.5Hz),8.44(s,1H),8.12(d ,1H,J＝1.5Hz),7.88(d,1H,J =2.4Hz),7.72(d,1H,J＝7.8Hz),7.63(d,2H,J＝7.4Hz),7.4-7.5(m,4H),7.18(t,1H,J＝7.6Hz), 2.79(d,3H,J＝4.5Hz),2.54(s,1H).

Embodiment 35

Synthesis of 2-{[2-(4-bromophenyl)-5-trifluoromethylpyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide (Compound 35)

Step 1: 2-amino-N-(trideuteriomethyl)benzamide

To a solution of 2,4-dihydro-1H-benzo[d][1,3]oxazine-2,4-dione (1 g, 6.130 mmol) and 2,3-dihydro-1H-isoindole hydrochloride (138.77 mg, 0.89 mmol) and trideuteromethylamine hydrochloride (1.30 g, 18.390 mmol) in DMF (20 mL) was added DMF (20 mL). The mixture was stirred at 50°C for 12 hours. The product was detected. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL*2). The combined organic phases were washed once with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The combined organic layers were dried and concentrated to obtain a residue. The white solid 2-amino-N-(trideuteromethyl)benzamide (780 mg, crude) was used in the next step without further purification.

Step 2: 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide

N,N-diisopropylethylamine (0.798mL, 4.569mmol) was added to a solution of 2-amino-N-(trideuteriomethyl)benzamide (700mg, 4.57mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (991.38mg, 4.569mmol) in n-butanol (20mL). The mixture was stirred at 25°C for 2 hours. The product was detected. The mixture was diluted with water (100mL) and extracted with ethyl acetate (100mL*2). The organic phases were combined and washed once with saturated sodium chloride solution (60mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The combined organic layer was dried and concentrated to obtain a residue. The residue was purified by preparative high performance liquid chromatography to obtain a white solid 2- {[2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide (400 mg, 1.199 mmol, yield: 26.23%).

Step 3: 2-{[2-(4-bromophenyl)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide

To a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide (100 mg, 0.300 mmol) and 4-bromoaniline (51.55 mg, 0.300 mmol) and trideuteriomethylamine hydrochloride (1.30 g, 18.390 mmol) in n-butanol (2 mL) was added hydrochloric acid-dioxane (4M, 0.150 mL). The mixture was stirred at 100 ° C for 12 hours. LCMS detected product generation. The mixture was concentrated to obtain a residue. The residue was slurried in ethyl acetate (3 mL) to obtain a yellow solid 2-{[2-(4-bromophenyl)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide (100 mg, crude product).

Step 4: 2-{[2-(4-bromophenyl)-5-trifluoromethylpyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide

To a solution of 2-{[2-(4-bromophenyl)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide (100 mg, 0.220 mmol) and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazol-1-yl]piperidine (96.15 mg, 0.330 mmol) in dioxane (1.6 mL) and water (0.4 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16.11 mg, 0.022 mmol) and sodium carbonate (46.66 mg, 0.440 mmol). The mixture was stirred at 100° C. for 2 hours. The mixture was stirred at 25° C. for 2 hours. LCMS detected the formation of product. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL*2). The organic phases were combined and washed once with a saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The combined organic layer was dried and concentrated to obtain a residue. The residue was purified by preparative high performance liquid chromatography to obtain compound 35 (10.32 mg, 0.023 mmol, yield: 10.32%).

MS m/z(ESI):554.3[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ11.37(br d,1H,J=2.4Hz),9.83(br s,1H),8.72(s,1H),8.44(s,1H),8.17(s, 1H),7.83(s,1H),7.73(br d,1H,J＝7.8Hz),7.64(br d,2H,J＝7.1Hz),7.6-7.4(m,4H),7.18(br t,1H,J＝7.5Hz),4.2-4.0(m ,1H),2.87(br d,2H,J＝10.4Hz),2.22(s,3H),2.1-2.0(m,6H).

Example 36 & Example 37

Synthesis of methyl 4-(4-(4-((2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Compound 36)

Synthesis of 4-(4-((4-(2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid (Compound 37)

Step 1: 4-(4-bromo-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid methyl ester

Dissolve 4-bromo-1H-pyrazole (1 g, 6.804 mmol) in 10 mL of tetrahydrofuran solution, add 4-hydroxycyclohexane-1-carboxylic acid methyl ester (1.056 mL, 7.485 mmol), diisopropyl azodicarboxylate (2.679 mL, 13.608 mmol) and triphenylphosphine (3.57 g, 13.608 mmol), stir at room temperature under nitrogen protection for 15 h. Add 20 mL of water to the system, extract with dichloromethane (15 mL × 3), and combine The organic phase was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to give 4-(4-bromo-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid methyl ester (762 mg, 2.654 mmol, 39%).

Step 2: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexane-1-carboxylic acid methyl ester

Dissolve 4-(4-bromo-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid methyl ester (750 mg, 2.542 mmol) in 10 mL 1,4-dioxane solution, add 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1 g, 3.813 mmol), potassium acetate (624 mg, 6.335 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (186.01 mg, 0.254 mmol). Under nitrogen protection, heat to 100 °C and stir for 15 h. The mixture was cooled to room temperature and 20 mL of water was added. The mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to give 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexane-1-carboxylic acid methyl ester (350 mg, 1.047 mmol, 41.19%).

Step 3: 4-(4-((4-(2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid methyl ester (36)

Dissolve 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexane-1-carboxylic acid methyl ester (55.23 mg, 0.165 mmol) in 6 mL 1,4-dioxane solution, add 2-(2-(4-bromo-2,3-dihydrobenzofuran-7-yl)amino)-5-trifluoromethylpyrimidin-4-ylamino)-N-methylbenzamide (70 mg, 0.138 mmol), anhydrous sodium carbonate (36.49 mg, 0.344 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (10.08 mg, 0.014 mmol) and 1.5 mL deionized water. Under nitrogen protection, heat to 90 ° C and stir for 15 h. The mixture was cooled to room temperature and 10 mL of water was added. The mixture was extracted with dichloromethane (6 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 36 (43 mg, 0.068 mmol, 49.12%).

MS m/z(ESI):635.65[M+H] ⁺ .

¹ HNMR(DMSO-d ₆ ,400MHz)δ11.4-11.6(m,1H),9.0-9.2(m,1H),8.6-8.8(m,1H),8.3-8.4(m,1H),8.1-8 .2(m,1H),7.8-7.9(m,1H),7.6-7.7(m,1H),7.1-7.3(m,2H),6.9-7.1(m,2H),4.53(br t,2H,J＝8.7Hz),4.1-4.3(m,1H),3.4-3.4(m,2H),2.7-2.8(m,3H),2.6-2.7(m,1H),1.8-2.2( m,7H),1.6-1.8(m,2H),1.2-1.3(m,1H).

Step 4: 4-(4-(4-((2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-amino)-2,3-dihydrobenzofuran-4-yl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid (37)

Compound 36 (25 mg, 0.039 mmol) was dissolved in 3 mL of tetrahydrofuran solution, lithium hydroxide (8.25 mg, 0.197 mmol) was dissolved in 3 mL of deionized water, and then added dropwise to the reaction system. The reaction was stirred at room temperature for 15 h. 8 mL of water was added, and the mixture was extracted with dichloromethane (6 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 37 (12.7 mg, 0.020 mmol, 50.14%) was obtained by purification by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1).

MS m/z(ESI):622.23[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.4-11.6(m,1H),9.0-9.2(m,1H),8.6-8.8(m,1H),8.3-8.4(m,1H),8.1-8 .2(m,1H),7.8-7.9(m,1H),7.6-7.7(m,1H),7.1-7.3(m,2H),6.9-7.1(m,2H),4.53(br t,2H,J＝8.7Hz),4.1-4.3(m,1H),3.4-3.4(m,2H),2.7-2.8(m,3H),2.6-2.7(m,1H),1.8-2.2( m,7H),1.6-1.8(m,2H),1.2-1.3(m,1H).

Embodiment 38

Synthesis of methyl 4-(4-(4-((2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Compound 38)

Step 1: 4-(4-(4-((2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid methyl ester

Dissolve 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexane-1-carboxylic acid methyl ester (60.21 mg, 0.180 mmol) in 6 mL 1,4-dioxane solution, add 2-(2-(4-bromophenyl)amino)-5-trifluoromethylpyrimidine-4-amino)-N-methylbenzamide (70 mg, 0.138 mmol), anhydrous sodium carbonate (39.78 mg, 0.375 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (10.99 mg, 0.015 mmol) and 1.5 mL deionized water. Under nitrogen protection, heat to 90 ° C and stir for 15 h. The mixture was cooled to room temperature and 10 mL of water was added. The mixture was extracted with dichloromethane (6 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to give 4-(4-(4-((2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid methyl ester (60 mg, 0.101 mmol, 67.32%).

MS m/z(ESI):594.24[M+H] ⁺ .

Step 2: 4-(4-(4-(2-methylcarbamoyl)phenylamino)-5-trifluoromethylpyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid

Dissolve 4-(4-(4-((2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid methyl ester (40 mg, 0.039 mmol) in 3 mL of tetrahydrofuran solution, dissolve lithium hydroxide (14.14 mg, 0.337 mmol) in 3 mL of deionized water, and then add dropwise to the reaction system. Stir the reaction at room temperature for 15 h. Add 8 mL of water, extract with dichloromethane (6 mL×3), combine the organic phases, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 38 (12.7 mg, 0.019 mmol, 28.19%).

MS m/z(ESI):580.22[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.3-11.5(m,1H),9.7-9.9(m,1H),8.7-8.8(m,1H),8.4-8.5 (m,1H),8.1-8.2(m,1H),7.8-7.8(m,1H),7.7-7.7(m,1H),7.6-7.7(m,2 H),7.4-7.5(m,3H),7.18(t,1H,J＝7.8Hz),4.1-4.2(m,1H),2.8-2.8(m, 3H),2.6-2.6(m,1H),1.9-2.1(m,7H),1.6-1.7(m,2H),1.1-1.4(m,1H).

Embodiment 39

Synthesis of N-methyl-2-[(2-{[4-(1-methylpyrazol-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidine-4-amino]benzamide (Compound 39)

Step 1: 2-({2-[(4-bromophenyl)amino]-5-trifluoromethylpyrimidin-4-ylamino)-N-methylbenzamide

2-{[2-chloro-5-trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (600g, 1.814mmol) was dissolved in 20mL 1-n-butanol solution, 4-bromoaniline (312.1mg, 1.814mmol) and hydrochloric acid-dioxane (200μL, 0.544mmol) were added, and the temperature was raised to 100℃ and stirred for 15h. After cooling to room temperature, the solvent in the reaction system was vacuum concentrated, and 10mL ethyl acetate solution was added. At this time, a large amount of solid precipitated, and the filter cake was filtered and washed with ethyl acetate. The filter cake was dried under vacuum to obtain 2-({2-[(4-bromophenyl)amino]-5-trifluoromethylpyrimidin-4-ylamino)-N-methylbenzamide (520mg, 1.115mmol, 61.47%).

Step 2: N-methyl-2-[(2-{[4-(1-methylpyrazol-4-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-amino]benzamide

Dissolve 2-({2-[(4-bromophenyl)amino]-5-trifluoromethylpyrimidin-4-ylamino)-N-methylbenzamide (60 mg, 0.129 mmol) in 5 mL of 1,4-dioxane solution, add 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (32.13 mg, 0.154 mmol), anhydrous sodium carbonate (34.1 mg, 0.322 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (9.42 mg, 0.013 mmol) and 1.2 mL of deionized water. Under nitrogen protection, heat to 90°C and stir for 15 h. The mixture was cooled to room temperature and 10 mL of water was added. The mixture was extracted with dichloromethane (6 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 39 (30 mg, 0.062 mmol, 48.40%).

MS m/z(ESI):468.17[M+H] ⁺ .

1H NMR(DMSO-d6,400MHz)δ11.2-11.5(m,1H),9.8-9.9(m,1H),8.7-8.8(m,1H),8.4-8.6(m,2H),8.0-8.1 (m,1H),7.8-7.8(m,1H),7.7-7. 7(m,1H),7.63(br d,2H,J＝6.0Hz),7.50(br s,1H),7.45(br d,2H,J＝8.0Hz),7.1-7.2(m,1H), 3.8-3.9(m,3H),2.79(br d,3H,J＝4.1Hz).

Embodiment 40

Synthesis of N-methyl-2-{[2-({4-[1-(3,4,5,6-tetrahydro-2H-pyran-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}benzamide (Compound 40)

Dissolve 2-({2-[(4-bromophenyl)amino]-5-trifluoromethylpyrimidin-4-ylamino)-N-methylbenzamide (60 mg, 0.129 mmol) in 5 mL 1,4-dioxane solution, add 1-(3,4,5,6-tetrahydropyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (32.13 mg, 0.155 mmol), anhydrous sodium carbonate (34.1 mg, 0.322 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (9.42 mg, 0.013 mmol) and 1.2 mL deionized water. Under nitrogen protection, heat to 90 °C and stir for 15 h. The mixture was cooled to room temperature and 10 mL of water was added. The mixture was extracted with dichloromethane (6 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 40 (20.5 mg, 0.037 mmol, 28.83%).

MS m/z(ESI):538.21[M+H] ⁺ .

1H NMR (DMSO-d ₆ ,400MHz)δ11.3-11.4(m,1H),9.8-9.9(m,1H),8.7-8.8(m,1H),8.4-8.6(m,2H),8.2-8 .2(m,1H),7.8-7.9(m,1H),7.7-7.8(m,1H),7.6-7.7(m,2H),7.5-7.5(m,1H),7.48(br d,2H,J＝8.6Hz),7.2-7.2(m,1H),4.40(qd,1H,J＝5.2,10.5Hz),3.9-4.0(m,2H),3.48(dt,2H,J＝ 3.5,11.1Hz),2.79(d,3H,J＝4.5Hz),1.93(br d,4H,J＝4.4Hz).

Embodiment 41

Synthesis of N-methyl-2-({2-[(4-{1-[2-(1,4-oxazin-4-yl)ethyl]pyrazol-3-yl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)benzamide (Compound 41)

Dissolve 2-({2-[(4-bromophenyl)amino]-5-trifluoromethylpyrimidin-4-ylamino)-N-methylbenzamide (50 mg, 0.107 mmol) in 4 mL of 1,4-dioxane solution, add 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl}-1,4-oxazinane (33.60 mg, 0.109 mmol), anhydrous sodium carbonate (28.41 mg, 0.268 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (7.85 mg, 0.011 mmol) and 1 mL of deionized water. Under nitrogen protection, heat to 90°C and stir for 15 h. Cool to room temperature, add 10 mL of water, extract with dichloromethane (6 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify with silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the compound Compound 41 (24.83 mg, 0.043 mmol, 40.20%).

MS m/z(ESI):567.24[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.3-11.4(m,1H),9.8-9.9(m,1H),8.7-8.8(m,1H),8.4-8.6(m,2H),8.1-8.2(m,1H), 7.8-7.8(m,1H),7.7-7.8(m,1H),7.6-7.7 (m,2H),7.5-7.5(m,1H),7.4-7.5(m,2H),7.1-7.2(m,1H),4.2-4.3(m,2H),3.5-3.6(m,4H) ,2.8-2.8(m,3H),2.73(t,2H,J=6.6Hz),2.42(br s,4H).

Embodiment 42

Synthesis of N-methyl-2-((2-((4-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (Compound 42)

N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino (50 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (1 mL), and methylsulfonic anhydride (17.4 mg, 0.1 mmol), EDCI (33 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol) and DIEA (33 mg, 0.26 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, water and dichloromethane were added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 42 (6 mg, yield: 10%).

MS m/z(ESI):657.2[M+H] ⁺

¹ H NMR (DMSO-d ₆ ) δ: 11.50 (s, 1H), 9.12 (br s, 1H), 8.70 (br d, J = 4.5Hz, 1H), 8.35 (s, 2H), 8.19 (s, 1H),7.87(s,1H),7.66(br d,J＝7.4Hz,1H),7.29-7.12(m,2H),7.08-7.02(m,2H),4.54(br t,J＝8.6Hz,2H),4.42-4.34(m,1H), 3.69(br d,J＝12.3Hz,2H),3.01-2.89(m,6H),2.77(d,J＝4.5Hz,3H),2.21-2.14(m,2H),2.12-1.93(m,3H).

Embodiment 43

Synthesis of 2-{[2-({4-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-2,3-dihydro-1-benzofuran-7-yl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide (Compound 43)

Step 1: 2-({2-[(4-bromo-2,3-dihydro-1-benzofuran-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-(trideuteriomethyl)benzamide

To a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide (140 mg, 0.420 mmol) and 4-bromo-2,3-dihydro-1-benzofuran-7-amine (89.80 mg, 0.420 mmol) in dioxane (3 mL) was added hydrochloric acid-dioxane (4M, 0.210 mL). LCMS detected product formation. The mixture was concentrated to obtain a residue. The residue was slurried in ethyl acetate (1 mL) to obtain a yellow solid 2-({2-[(4-bromo-2,3-dihydro-1-benzofuran-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-(trideuteriomethyl)benzamide (160 mg, crude product).

MS m/z(ESI):511.0[M+H] ⁺ .

Step 2: 2-{[2-({4-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-2,3-dihydro-1-benzofuran-7-yl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide

To a solution of 2-({2-[(4-bromo-2,3-dihydro-1-benzofuran-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-(trideuteriomethyl)benzamide (70 mg, 0.137 mmol) and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine (39.87 mg, 0.137 mmol) in dioxane (1 mL) and water (0.3 mL) was added sodium carbonate (29.02 mg, 0.274 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10.02 mg, 0.014 mmol). The mixture was stirred at 100° C. for 2 hours under nitrogen protection. LCMS detected the formation of the product. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (60 mL*2). The organic phases were combined and washed once with a saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The combined organic layer was dried and concentrated to obtain a residue. The residue was purified by preparative high performance liquid chromatography to obtain compound 43 (22.51 mg, 0.038 mmol, yield: 27.48%).

MS m/z(ESI):596.3[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ) δ11.55 (s, 1H), 9.62 (br d, 1H, J = 1.5Hz), 9.16 (br s, 1H), 8.69 (s, 1H), 8.36 (s, 1H),8.16(s,1H),7.91(s,1H),7.68(br d,1H,J＝7.8Hz),7.24(s,1H),7.0-7.1(m,3H),4.5-4.6(m,2H),4.51(br s,1H),3.60(br d,2H,J＝12.1Hz),3.3-3.4(m,2H),3.1-3.2(m,2H),2.85(br d,3H,J＝4.4Hz),2.4-2.3(m,2H),2.3-2.2(m,2H).

Embodiment 44

Synthesis of N-methyl-2-[(2-{[4-(1-methylpyrazol-3-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)amino]benzamide (Compound 44)

Dissolve 2-({2-[(4-bromophenyl)amino]-5-trifluoromethylpyrimidin-4-ylamino)-N-methylbenzamide (50 mg, 0.107 mmol) in 4 mL 1,4-dioxane solution, add 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (26.78 mg, 0.129 mmol), anhydrous sodium carbonate (28.41 mg, 0.268 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (7.85 mg, 0.011 mmol) and 1 mL deionized water. Under nitrogen protection, heat to 90 °C and stir for 15 h. The mixture was cooled to room temperature and 10 mL of water was added. The mixture was extracted with dichloromethane (6 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 44 (23.8 mg, 0.050 mmol, 46.25%).

MS m/z(ESI):468.17[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz)δ11.3-11.4(m,1H),9.8-10.0(m,1H),8.7-8.8(m,1H),8.4-8.6(m,2H),7.6 -7.8(m,6H),7.4-7.6(m,1H),7.2-7.2(m,1H),6.6-6.7(m,1H),3.87(s,3H),2.79(br d,3H,J＝4.1Hz).

Embodiment 45

Synthesis of 2-{[2-(4-[1-(2-hydroxyethyl)pyrazol-3-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 45)

Dissolve 2-({2-[(4-bromophenyl)amino]-5-trifluoromethylpyrimidin-4-ylamino)-N-methylbenzamide (50 mg, 0.107 mmol) in 4 mL 1,4-dioxane solution, add 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-4-pyrazoleboronic acid pinacol ester (30.64 mg, 0.129 mmol), anhydrous sodium carbonate (28.41 mg, 0.268 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (7.85 mg, 0.011 mmol) and 1 mL deionized water. Under nitrogen protection, heat to 90 °C and stir for 15 h. The mixture was cooled to room temperature and 10 mL of water was added. The mixture was extracted with dichloromethane (6 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 45 (20.8 mg, 0.041 mmol, 38.68%).

MS m/z(ESI):498.18[M+H] ⁺ .

¹ H NMR (DMSO-d ₆ ,400MHz) δ11.3-11.4(m,1H),9.8-9.9(m,1H),8.73(br s,1H),8.4-8.6(m,2H),8.1-8.1(m,1H),7.8-7.9(m,1H),7.7-7.8(m,1H),7.6-7.7(m,2H), 7.5-7.6(m,1H) ,7.4-7.5(m,2H),7.2-7.2(m,1H),4.9-5.0(m,1H),4.1-4.2(m,2H),3.7-3.8(m,2H),2.79(d, 3H,J＝4.5Hz).

Embodiment 46

Synthesis of 2-(2-(4-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-pyrazol-3-yl)phenyl)amino)-5-trifluoromethylpyrimidin-4-ylamino)-N-methylbenzamide (Compound 46)

Step 1: 2-({2-[(4-bromophenyl)amino]-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-methylbenzamide

To a solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (1 g, 3.024 mmol) and 4-bromoaniline (1.04 g, 3.024 mmol) in n-butanol (15 mL) was added hydrochloric acid-dioxane (4M, 0.227 mL). The mixture was stirred at 100 ° C for 12 hours. LCMS detected product formation. The mixture was concentrated to obtain a residue. The residue was slurried in ethyl acetate (15 mL) to give a yellow solid 2-({2-[(4-bromophenyl)amino]-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-methylbenzamide (400 mg, crude product).

Step 2: N-methyl-2-[(2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)amino]benzamide

Under nitrogen protection, potassium acetate (210.48 mg, 0.858 mmol) was added to a solution of 2-({2-[(4-bromophenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-N-methylbenzamide (400 mg, 0.858 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (326.78 mg, 1.287 mmol) in dioxane (5 mL). 2.145mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (62.77mg, 0.086mmol) were added. The mixture was stirred at 100°C for 12 hours under nitrogen protection. LCMS detected the formation of products. The mixture was diluted with water (100mL) and extracted with ethyl acetate (100mL*2). The organic phases were combined and washed once with saturated sodium chloride solution (60mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The combined organic layer was dried and concentrated to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether:ethyl acetate=99:1-2:1) to give N-methyl-2-[(2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)amino]benzamide (360 mg, 0.701 mmol, yield: 81.75%) as a white solid.

Step 3: 2-Methylpropan-2-yl 4-[3-(4-{[4-({2-[(methylamino)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazol-1-yl]piperidine-1-carboxylate

To a solution of N-methyl-2-[(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl)amino]benzamide (260 mg, 0.506 mmol) and 2-methylpropan-2-yl 4-(3-bromopyrazol-1-yl)piperidine-1-carboxylate (167.26 mg, 0.506 mmol) in water (1 mL) and dioxane (3 mL) was added sodium carbonate (161.05 mg, 1.519 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (37.06 mg, 0.051 mmol). The mixture was stirred at 100° C. for 2 hours under nitrogen protection. LCMS detected the formation of the product. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL*2). The organic phases were combined and washed once with a saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The combined organic layer was dried and concentrated to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether: ethyl acetate = 99: 1-1: 1) to obtain a yellow solid 2-methylpropan-2-yl 4-[3-(4-{[4-({2-[(methylamino)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazol-1-yl]piperidin-1-carboxylate (150 mg, 0.236 mmol, yield: 46.51%).

Step 4: 2-{[2-(4-bromophenyl)-5-trifluoromethylpyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide

To a solution of 2-methylpropan-2-yl 4-[3-(4-{[4-({2-[(methylamino)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl)pyrazol-1-yl]piperidine-1-carboxylic acid acetonitrile (150 mg, 0.236 mmol) in acetonitrile (2 mL) was added hydrochloric acid/dioxane (2 mL). The mixture was stirred at 25° C. for 12 hours. LCMS detected the formation of the product. The mixture was concentrated to give compound 2-{[2-({4-[1-(piperidin-4-yl)pyrazol-3-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (140 mg, crude product)

Step 5: 2-{[2-(4-bromophenyl)-5-trifluoromethylpyrimidin-4-yl]amino}-N-(trideuteriomethyl)benzamide

To a solution of 2-{[2-({4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (120 mg, 0.224 mmol) and glycolic acid (20.41 mg, 0.268 mmol) in N,N-dimethylacetamide (3 mL) was added 1-hydroxybenzotriazole (60.44 mg, 0.447 mmol), N,N-diisopropylethylamine (0.078, 0.447 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (214.37 mg, 1.118 mmol). The mixture was stirred at 25° C. for 12 hours. LCMS detected the formation of the product. The mixture was purified by reverse preparative chromatography to obtain compound 46 (25.52 mg, 0.043 mmol, yield: 19.15%)

MS m/z(ESI):595.2[M+H] ⁺ .

¹ H NMR(DMSO-d ₆ )δ11.5-11.1(m,1H),9.90(br s,1H),8.75(br d,1H,J＝4.5Hz),8.46(s,1H),7.81(d,1H,J＝2.3Hz),7.7-7.7(m,1H),7.7-7.6(m,4H),7.50(br t,1H,J＝7.5Hz),7.19(t,1H,J＝7.6Hz),6.66(d,1H,J＝2.3Hz),4.56(t,1H,J＝5 .5Hz),4.4-4.5(m,2H),4.14(dd,2H,J＝5.6,8.4Hz),3.9-3.8(m,1H),3.15(br t,1H,J＝12.3Hz),2.79(d,3H,J＝4.5Hz),2.0-2.1(m,2H),1.8-2.0(m,2H).

Biological evaluation of compounds

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

1. Reagents, consumables, and instruments are listed in Table 1.

Table 1

2. Experimental Procedure

1) Transfer compound dilutions to assay plates using Echo550 (784075, Greiner);

2) Seal the test plate and centrifuge at 1000 g for 1 min;

3) Prepare 2X FAK using 1x kinase buffer;

4) Add 5 μL 2X FAK to each well of a 384-well assay plate (784075, Greiner);

5) Centrifuge at 1000 g for 30 seconds and incubate at room temperature for 10 minutes;

6) Prepare a mixture of 2x TK-substrate-biotin and ATP in 1X kinase buffer;

7) Add 5 μL of TK-substrate-biotin and ATP mixture to each well to start the reaction;

8) Centrifuge at 1000 g for 30 seconds, seal the test plate, and incubate at room temperature for 60 minutes;

9) Prepare 4X Sa-XL 665 using HTRF detection buffer;

10) Add 5 μL Sa-XL 665 and 5 μL TK-antibody-Cryptate to each well;

11) Centrifuge the plate at 1000 g for 30 seconds, RT for 1 hour;

12) Read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) on an Envision 2104 plate reader.

3. Data Analysis

1) For each screening plate, calculate the mean data and standard deviation (SD) of the DMSO group (as the blank control group, abbreviated as VC) and the 100 nM Defactinib group (as the Yangshen group, abbreviated as PC);

2) Inhibition percentage of the compound %inhibition=100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)×100;

3) The IC50 was calculated using the nonlinear regression equation of XLfit5.3.1, and the formula is as follows:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)),

X: Log(compound concentration),

Y: inhibition rate (%inh),

Top and Bottom: The units are the same as Y.

logIC50: same as X unit,

HillSlope: Slope coefficient or slope.

4. Experimental Results

The FAK kinase activity _IC50 activity data of specific compounds are shown in Table 2.

Table 2

Experimental Example 2: Pharmacodynamic evaluation of the compound in vitro diffuse gastric cancer (DGC) mouse organoid MDO-MCR model

Experimental steps:

1. Cell Plating

a. When MDO-MCR grows to 70%-80%, remove the culture medium supernatant, rinse twice with PBS and remove the supernatant; add 1mL Tryple to each well, shake evenly from left to right and up and down, and place in the incubator for digestion for 5 minutes; blow the cells into single cells or two or three cell clusters, add PBS containing 2% FBS to stop digestion, transfer to a 15mL centrifuge tube, add cold PBS to 10mL, and place in a centrifuge at 1000rpm for 5 minutes. Remove the supernatant, add 1mL PBS to resuspend, and count;

b. Resuspend the cells in matrix gel to a suspension of 1.6×10 ⁶ cells per ml. Add 6 drops to each well of a 6-well plate, and add 25 μL of cells to each drop. Place the 6-well plate upside down in the incubator for 30 minutes to allow the matrix gel to solidify. Add 2 mL of culture medium to each well and culture in a cell incubator overnight.

2. Cellular Administration

a. Take out the small molecule drug mother solution in advance to thaw, and vortex to mix evenly; b. Take out the culture plate with cells, aspirate 2μL of 1mM mother solution (diluted 1000 times) and gently add it along the wall of the well, and shake it gently to mix it immediately after adding; the dosage concentration of each small molecule in each well is 1μM; c. After all the wells are added, shake it gently to mix, record the time, put it back into the cell culture incubator, and collect the samples after 48 hours.

3. Protein Extraction

a. Remove the supernatant medium, wash twice with PBS, add 1 mL of gel removal solution, shake on ice until the matrix gel is lysed for about 1 hour, collect into a centrifuge tube, centrifuge, and wash once with PBS;

b. Add RIPA lysis buffer containing phosphatase inhibitors and protease inhibitors to the precipitate to lyse the cells. Ultrasonicate on ice for 10 seconds, centrifuge at 12,000 rpm for 10 minutes, take the supernatant, determine and adjust the protein concentration, add 4× loading buffer, and cook the protein.

4.WB detection

SDS-PAGE electrophoresis: 80v, 30min, 120v, 60min; transfer: 80v, 60min; blocking: 5% skim milk for 1H, primary antibody: P-FAKY397 (1:1000, CST), non-p-YAP (1:2000, Abcam), p-YAP (1:1000, CST), actin (1:10000, CST), incubated with 5% BSA·TBST, incubated at 4°C overnight; secondary antibody (Goat-anti-mouse-IgG and Goat-anti-rabbit-IgG, 1:3000, Proteintech): incubated with 5% skim milk·TBST, incubated at room temperature for 1h. Thermo developer was used.

The results are shown in Figures 1, 2, 3, 4 and 5, indicating that the compounds of the present application can inhibit the phosphorylation of FAK (inhibit FAK kinase activity, reduce phosphorylated p-FAK397) and inhibit activated YAP (inhibit YAP activity, reduce non-phosphorylated non-p-YAP, i.e. increase p-YAP S127) in the organoid MDO-MCR model.

Therefore, the compounds of the present application can achieve the purpose of treating diseases (especially cancer) by inhibiting FAK kinase and/or inhibiting activated YAP.

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

1. Experimental Procedure

1) Cell plating

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

b. SNU-668 cells: Add 1 mL of 0.25% trypsin to a 10 cm dish, shake it evenly, and place it in an incubator for digestion for 2-3 minutes; take out the dish, add 2-3 mL of complete culture medium to terminate digestion, transfer to a 15 mL centrifuge tube, and centrifuge it at 1000 rpm for 5 minutes; remove the supernatant, add 1 mL of complete culture medium to resuspend, and count; take out a 96-well plate, plate 1000 cells per well, and place it in a cell culture incubator for overnight culture;

c. MDO-MCR: Add 1 mL of typle to each well of a 6-well plate, shake evenly from side to side and up and down, and place in an incubator for digestion for 5 minutes; observe under a microscope, blow off into single or two or three cell clusters, add PBS containing 2% FBS to stop digestion, transfer to a 15 mL centrifuge tube, add cold PBS to 10 mL, place in a centrifuge and centrifuge at 1000 rpm for 5 minutes; remove the supernatant, add 1 mL of PBS to resuspend, and count; resuspend the cells with matrix gel to a concentration of 2×10 ⁵ cells per milliliter, and place 5 μL of cell suspension in the center of each well of a 96-well plate, place in a cell culture incubator upside down for 15 minutes to allow the matrix gel to solidify, add 100 μL of culture medium, and culture in an incubator overnight.

2) Cellular drug delivery

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

b. Each small molecule was diluted 1:3 into 9 concentration gradients using culture medium based on the 10 mM stock solution;

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

d. After all wells have been added, gently shake the culture plate to ensure even diffusion of the drug, record the time, and return it to the cell culture incubator.

3) CELL TITER-GLO test

Four days after administration, discard the culture medium, mix the culture medium and cell titer-glo detection solution in a 1:1 ratio, add 100 μL to each well, incubate at room temperature with shaking for 10 min, and detect with an ELISA reader.

2. Experimental conclusion

The experimental results (see Table 3 for details) show that some compounds of the present application can inhibit the cell growth of human diffuse gastric cancer tumor cell line model, and the inhibitory activity is better than that of clinical FAK inhibitors Defactinib and IN10018.

Table 3

Experimental Example 4: Evaluation of the pharmacokinetics of compounds in vivo

1. Experimental Design

Three male SD rats were intragastrically administered with 5 mg/kg or 10 mg/kg of the compound once, and blood was collected before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration.

2. Preparation

Preparation of 5mg/kg dosing solution: accurately weigh 5.5mg of compound (according to purity), add 0.55mL DMSO, stir and sonicate to obtain a clear solution. Take 0.5mL of the above solution, add 1mL Solutol, stir for 1min; add 8.5mL of physiological saline, stir for 1min, and obtain a clear solution with a solution concentration of 0.5mg/mL.

Preparation of 10mg/kg dosing solution: accurately weigh 12mg of compound (according to purity), add 0.6mL DMSO, stir and ultrasonicate to obtain a clear solution. Take 0.5mL of the above solution, add 1mL Solutol, stir for 1min; add 8.5mL of physiological saline, stir for 1min, and obtain a clear solution with a solution concentration of 1.0mg/mL.

3. Animal Operation

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

4. Analytical methods

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

5. Experimental Results

The experimental results show that the compounds of the present application have good pharmacokinetic parameters in rats, and the specific results are shown in Table 4.

Table 4

Test Example 5: Pharmacodynamic evaluation of the present compound in vitro in the human diffuse gastric cancer cell line SNU-668 model (western blot detection of FAK and YAP activity)

1. Experimental Procedure

1) Cell plating

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

b. Add 1 mL of trypsin to a 10 cm dish and place it in an incubator for 3-5 minutes;

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

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

e. Dilute the cells to 1.5×10 ⁵ cells per ml, add 1 mL of cell suspension to each well of a 12-well plate, and culture in a cell culture incubator for 24 hours.

2) Cellular drug delivery

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

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

c. After adding to all the wells, shake gently, record the time, put back into the cell culture incubator, and collect the samples after 48 hours.

3) Protein extraction

a. 48 hours after administration, discard the culture medium, wash with PBS, and discard the PBS;

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

4) Western blot detection

SDS-PAGE electrophoresis: 80v, 30min, 120v, 60min; transfer: 80v, 60min; blocking: 5% skim milk for 1H, primary antibody: P-FAKY397 (1:1000, CST), non-p-YAP (1:2000, Abcam), p-YAP (1:1000, CST), actin (1:10000, CST), incubated with 5% BSA·TBST, incubated at 4°C overnight; secondary antibody (Goat-anti-mouse-IgG and Goat-anti-rabbit-IgG, 1:3000, Proteintech): incubated with 5% skim milk·TBST, incubated at room temperature for 1h. Thermo developer was used.

2. Experimental conclusion

The results are shown in Figures 6, 7, 8 and 9, indicating that the compounds of the present application can inhibit the phosphorylation of FAK (inhibit FAK kinase activity, reduce phosphorylated p-FAK397) and inhibit activated YAP (inhibit YAP activity, reduce non-phosphorylated non-p-YAP, i.e. increase p-YAP S127) in the human diffuse gastric cancer cell line SNU668 model.

Although the embodiments of the present application have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations on the present application. Ordinary technicians in this field can change, modify, replace and modify the above embodiments within the scope of the present application.

Claims (28)

A compound, which is a compound represented by formula I or its stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitrogen oxides, solvates, hydrates, crystal forms, esters, isotope-labeled compounds, metabolites, pharmaceutically acceptable salts or prodrugs:
wherein X is selected from N or -CH-; Y is selected from -NH-, _-CH2- , O, S or a combination thereof; Ring A is selected from a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring; Ring B is selected from a 5-15 membered partially unsaturated carbocyclic ring, a 5-15 membered partially unsaturated carboheterocyclic ring, a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring; L represents a single bond or a C _1-10 alkylene group; M is selected from hydrogen, C _1-10 alkyl, 3-15 membered saturated or partially unsaturated carbocyclic group, 3-15 membered saturated or partially unsaturated heterocyclic group, optionally, the alkyl, saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated heterocyclic group involved in M is substituted by one or more R ₃ , R ₃ is selected from halogen, cyano, hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, alkoxy, -R ¹ -CN, -R ¹ -NR ² R ³ , -R ¹ -(OH) _q , -R ¹ -COOH, -R ¹ -C(＝O)NR ² R ³ , -C(＝O)R ¹ -OH, -C(＝O)R ¹ , -C(＝O)OR ¹ , -C(＝O)CF ₃ , -S(＝O) ₂ R ¹ , -C(＝O)OR ¹ , -C(＝O)R ¹ CN, -R 1 - ¹ -NR ² -R ³ -(OH) _q , -R ¹ -NR ² -R ³ -COOH, -R ¹ -NR ² -R ³ -C(＝O)NR ² R ³ , -R ¹ -NR ² -C(＝O)R ³ -OH, -R ¹ -NR ² -C(＝O)R ³ , -R ¹ -NR ² -S(＝O) ₂ R ³ ; Optionally, ring A and ring B are fused to form a ring; Optionally, ring B and M are fused to form a ring; Ring D is selected from a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring; _R1 is selected from halogen, cyano, nitro, _C1-10 alkyl, _C1-10 haloalkyl, _C1-10 heteroalkyl, C1-10 haloheteroalkyl, _C3-15 saturated or partially unsaturated carbocyclyl, _C3-15 saturated or partially unsaturated heterocyclyl, _6-15 membered aryl, _C7-15 arylalkyl, 5-15 membered heteroaryl or _C6-15 heteroarylalkyl; R ₂ is selected from -C(=O)NR ⁴ R ⁵ , -C(=O)NR ⁴ -OR ⁵ , -S(=O) ₂ NR ⁴ R ⁵ , -NR ⁴ S(=O) ₂ R ⁵ or -R ⁶ -C(=O)NR ⁴ R ⁵ , optionally, R ⁴ is connected to a carbon atom or a heteroatom on ring D to form a 5-6 membered ring; optionally, R ⁵ is connected to a carbon atom or a heteroatom on ring D to form a 5-6 membered ring; each substituent ^Ra , ^Rb , ^Rc , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 and ^R6 is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, saturated or partially unsaturated carbocyclyl, saturated or partially unsaturated carbocyclylalkyl, saturated or partially unsaturated heterocyclyl, saturated or partially unsaturated heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; Optionally, substituents ^Ra , Rb, ^Rc , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 and ^R6 are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, alkyl, cycloalkyl ^, alkoxy, aryl; Alternatively, among Ra, ^Rb , ^{Rc , R1} , ^R2 , ^R3 , ^R4 , ^R5 and ^R6 , if there are two adjacent substituents, the two adjacent substituents together with the atoms to which they are attached are linked to form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group or a heteroaryl group; m is independently selected from 0, 1, 2, 3 or 4; n is independently selected from 0, 1, 2 or 3; p is independently selected from 0, 1, 2, 3 or 4; q is independently selected from 0, 1 or 2. The compound according to claim 1, characterized in that ring A is selected from a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring; optionally, ring A is selected from the group represented by formula A-1 to formula A-7:
wherein _X1 to _X8 are each independently selected from C, N, O, S, -NH- or -CH-, "*" indicates the position where ring A is bonded to -NH-. Indicates the position where ring A and ring B are bonded; Alternatively, in Formula A-1 to Formula A-7, _X1 to _X8 are each independently selected from C and -CH-; or, _X1 and _X2 are each independently selected from C, -CH-, N and -NH-, _X3 and _X4 are both -CH-, and at least one of _X5 , _X6 , _X7 and _X8 is selected from N, O, S or -NH-; Optionally, the substituents ^Ra in ring A are each independently selected from deuterium, amino, hydroxyl, cyano, halogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 heteroalkyl, _C1-6 alkoxy, 3-12-membered saturated or partially unsaturated carbocyclyl, 3-12-membered saturated or partially unsaturated heterocyclyl, 6-15-membered aryl or 5-15-membered heteroaryl; or, the substituents ^Ra in ring A are each independently selected from halogen, _C1-6 alkyl, _C2-6 alkenyl and _C1-6 alkoxy; Optionally, ^Ra is substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, _C1-10 alkyl, _C3-10 cycloalkyl, _C1-10 alkoxy, 6-15-membered aryl; Optionally, ^Ra and the carbon atoms on ring A are joined together to form a 3-6 membered ring; Optionally, m is independently selected from 0, 1 or 2. The compound according to claim 1 or 2, characterized in that ring A is selected from the group consisting of the following groups:

"*" indicates the position where ring A is bonded to -NH-. Indicates the position where ring A and ring B are bonded; Optionally, ring A is a benzene ring; Optionally, the substituents ^Ra in ring A are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, phenyl and naphthyl; or, the substituents ^Ra in ring A are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy and propoxy. The compound according to any one of claims 1 to 3, characterized in that Selected from the group consisting of:
"*" indicates the position where ring A is bonded to -NH-. Indicates the position where ring A and ring B are bonded. The compound according to any one of claims 1 to 4, characterized in that ring B is selected from a 5-10 membered partially unsaturated carbocyclic ring, a 5-10 membered partially unsaturated carbon heterocyclic ring, a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring; or, ring B is selected from a 5-6 membered partially unsaturated carbocyclic ring, a 5-6 membered partially unsaturated carbon heterocyclic ring, a benzene ring or a 5-6 membered heteroaromatic ring; optionally, ring B is selected from a group represented by formula B-1 or formula B-2:
wherein _Y1 to _Y6 are each independently selected from C, N, O, S, -NH- or -CH-, "*" indicates the position where ring B is bonded to ring A. Indicates the position where ring B is bonded to M; Optionally, ring B is selected from the group represented by formula B-1-1 or formula B-2-1:
wherein _Y1 to _Y5 are each independently selected from C, N, O, S, -NH- or -CH-; Alternatively, in formula B-1-1 and _formula B-2-1, at least one of Y ₁ to Y ₅ is selected from N, O _, S and -NH-, or Any one, any two, or any three are selected from N and -NH-; Optionally, the substituents R ^b in ring B are each independently selected from deuterium, amino, hydroxyl, cyano, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _1-6 alkoxy, 3-12-membered saturated or partially unsaturated carbocyclyl, 3-12-membered saturated or partially unsaturated heterocyclyl, 6-15-membered aryl or 5-15-membered heteroaryl, or, the substituents R ^b in ring B are each independently selected from deuterium and C _1-6 alkyl; Optionally, R ^b is substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _1-10 alkoxy, 6-15 membered aryl; Optionally, n is independently selected from 0, 1 or 2. The compound according to any one of claims 1 to 5, characterized in that ring B is selected from the group consisting of the following groups:
Optionally, Ring B is selected from the group consisting of:
"*" indicates the position where ring B is bonded to ring A. Indicates the position where ring B is bonded to M; Optionally, ring B is a pyrazole ring; Alternatively, the substituents R ^b in ring B are each independently selected from deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl, alkenyl, methoxy, ethoxy, propoxy, phenyl and naphthyl; or, the substituents R ^b in ring B are each independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and pentyl; Alternatively, ring B is fused with ring A to form a 6-15 membered ring, or ring B is fused with M to form a 6-15 membered ring. The compound according to any one of claims 1 to 6, characterized in that Selected from the group consisting of:
"*" indicates the position where ring B is bonded to ring A. Indicates the position where ring B and M are bonded. The compound according to any one of claims 1 to 7, characterized in that the compound represented by formula I is selected from the structures represented by formula I-1 to formula I-6:

wherein X, Y, _R1 , _R2 , Ra, ^Rb , ^Rc , ^L , M, ring D, m, n and p are defined the same as in Formula I; _Y1 to _Y5 are defined the same as in Formula B-1 and Formula B-2; optionally, ^Ra is connected to the carbon atom on the benzene ring to which it is connected to form a 5-membered ring or a 6-membered ring. The compound according to any one of claims 1 to 8, characterized in that the carbocyclic ring in the saturated or partially unsaturated carbocyclic group represented by M is selected from the following structures;
The heterocyclic ring in the saturated or partially unsaturated heterocyclic group represented by M is selected from the following structures;
In ring M, each x is independently 0, 1, 2 or 3; each y and z is independently 0, 1, 2 or 3; Optionally, the carbocyclic ring in the saturated or partially unsaturated carbocyclic group represented by M is selected from the following structures:
Optionally, the heterocycle in the saturated or partially unsaturated heterocyclic group represented by M is selected from the following structures:

The compound according to any one of claims 1 to 9, characterized in that M is selected from the group consisting of hydrogen, C _1-6 alkyl or the following groups:
wherein R ₄ is selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, -R ¹ -C(=O)NR ² R ³ , -C(=O)R ¹ -OH, -C(=O)R ¹ , -R ¹ -COOH, -C(=O)OR ¹ , -R ¹ -OH, -C(=O)CF ₃ , -C(=O)R ¹ CN or -S(=O) ₂ R ¹ ; R ¹ , R ² and R ³ are the same as defined in Formula I; Optionally, _R4 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or the following groups:
Optionally, the alkyl group represented by M is substituted by one or more selected from halogen, hydroxyl, cyano, C _3-8 heterocycloalkyl, C _1-6 haloalkyl, and C _1-6 alkoxy. The compound according to any one of claims 1 to 10, characterized in that M is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl and the following groups:
The compound according to any one of claims 1 to 11, characterized in that ring D is selected from a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring; or, ring D is selected from a 6-10 membered aromatic ring or a 5-10 membered nitrogen heteroaromatic ring; or, ring D is selected from a benzene ring or a 6-membered nitrogen heteroaromatic ring; or, ring D is selected from a benzene ring, an imidazole ring, a pyrazole ring, a triazole ring, a tetrazole ring, an oxazole ring, a thiazole ring, a furan ring, a thiophene ring, a pyrrole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring and the group consisting of the following groups:
Indicates the position where ring D is bonded to Y; Optionally, ring D is selected from a benzene ring, a pyridine ring, a pyrimidine ring and a pyridazine ring. The compound according to any one of claims 1 to 12, characterized in that Selected from the group consisting of:
wherein R ⁴ , R ⁵ and R ^c are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _1-6 alkoxy, 3-12-membered saturated or partially unsaturated carbocyclic group, 3-12-membered saturated or partially unsaturated heterocyclic group, 6-15-membered aryl or 5-15-membered heteroaryl; optionally, R ⁴ , R ⁵ and R ^c are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _1-10 alkoxy, 6-15-membered aryl; Alternatively, ^R4 and ^R5 are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated tert-butyl, deuterated pentyl, cyclopentyl, cyclohexyl, alkenyl, methoxy, ethoxy, propoxy, phenyl and naphthyl; Alternatively, the substituents R ^c in ring D are each independently selected from deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl, alkenyl, methoxy, ethoxy, propoxy, phenyl and naphthyl; Optionally, p is independently selected from 0, 1 or 2. The compound according to any one of claims 1 to 13, characterized in that R ₁ is selected from halogen, cyano, nitro, C _1-10 alkyl, C _3-10 cycloalkyl and C _1-10 haloalkyl; or, R ₁ is selected from halogen, cyano and C _1-6 haloalkyl; or, R ₁ is selected from fluorine, chlorine, bromine, iodine, cyano, CF ₃ , CHF ₂ and CH ₂ F; or, R ₁ is selected from fluorine, chlorine, bromine, iodine, cyano and CF ₃ ; Alternatively, each substituent R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C _1-10 alkyl, C 2-10 alkenyl, C _2-10 alkynyl, C _1-10 heteroalkyl, C 1-10 alkoxy, 3-15 membered saturated or partially unsaturated carbocyclyl, C _4-15 saturated or partially unsaturated carbocyclylalkyl, 3-15 membered saturated or partially unsaturated heterocyclyl, C 3-15 saturated or partially unsaturated heterocyclylalkyl, 6-15 membered aryl, C 7-20 arylalkyl, 5-15 membered heteroaryl or C _4-20 heteroarylalkyl; Alternatively, the substituents _{R 1} , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C _1-10 alkyl, C _2-10 alkenyl, C 2-10 alkynyl, C 1-10 heteroalkyl, C 1-10 alkoxy, 3-15 membered saturated or partially unsaturated carbocyclyl, C ^4-15 saturated or partially unsaturated carbocyclylalkyl, 3-15 membered saturated or partially unsaturated heterocyclyl, C ^3-15 saturated or partially unsaturated heterocyclylalkyl, 6-15 membered aryl, C 7-20 ^arylalkyl , ^{5-15 membered} heteroaryl or C _4-20 heteroarylalkyl; ⁶ are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _1-10 alkoxy, and 6-15 membered aryl; Alternatively, each substituent R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C 1-6 alkoxy, 3-10 membered saturated or partially unsaturated carbocyclyl, C _4-12 saturated or partially unsaturated carbocyclylalkyl, 3-10 membered saturated or partially unsaturated heterocyclyl, C 3-12 saturated or partially unsaturated heterocyclylalkyl, 6-10 membered aryl, C 7-15 arylalkyl, 5-10 membered heteroaryl or C _4-15 heteroarylalkyl; Alternatively, the substituents _{R 1} , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 alkyl, C _2-6 alkenyl, C ^2-6 alkynyl, C 1-6 heteroalkyl, C ^1-6 alkoxy, 3-10 membered saturated or partially unsaturated carbocyclyl, C _4-12 saturated or partially unsaturated carbocyclylalkyl, 3-10 membered saturated or partially unsaturated heterocyclyl, C _3-12 saturated or partially unsaturated heterocyclylalkyl, 6-10 membered aryl, C 7-15 ^arylalkyl , ^{5-10 membered} heteroaryl or C ^4-15 heteroarylalkyl; ⁶ are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, and 6-12 membered aryl; Optionally, each substituent R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, propenyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl and naphthyl; optionally, the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl and naphthyl. The compound according to any one of claims 1 to 14, characterized in that the compound represented by formula I has a structure represented by the following formula I-1-1 to formula I-1-6:
wherein L, M, R ₁ , R ₂ , ^Ra , R ^b , R ^c , m, n and p are as defined in Formula I, and Y ₁ to Y ₄ are as defined in Formula B-1 and Formula B-2; Optionally, in Formula I-1-1 to Formula I-1-6, R ₁ is selected from fluorine, chlorine, bromine, iodine, trifluoromethyl or cyano; Alternatively, in Formula I-1-1 to Formula I-1-6, R ₂ is selected from -C(=O)-NR ⁴ R ⁵ , and R ⁴ and R ⁵ are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 deuterated alkyl; Alternatively, in Formula I-1-1 to Formula I-1-6, each R ^a is independently selected from hydrogen or C _1-6 alkoxy; Alternatively, in Formula I-1-1 to Formula I-1-6, each R ^b is independently selected from hydrogen or C _1-6 alkyl; Optionally, in Formula I-1-1, Formula I-1-2, Formula I-1-4 and Formula I-1-5, Y ₂ is selected from -NH-, O or S, and any one or any two of Y ₁ , Y ₃ and Y ₄ are N; Optionally, in Formula I-1-3 and Formula I-1-6, any one, any two, or any three of _Y1 to _Y4 are selected from N and -NH-. The compound according to any one of claims 1 to 15, characterized in that the compound represented by formula I has a structure represented by the following formula Ia to formula Ib:
Wherein, the definitions of L, M, ^Ra and ^R4 are the same as those described in any one of claims 1-15. The compound according to any one of claims 1 to 16, characterized in that the compound represented by formula I has a structure represented by the following formula I-1-a to formula I-1-f:
wherein ^Ra is hydrogen, methoxy, ethoxy or propoxy; optionally, ^Ra is connected to the carbon atom on the benzene ring to which it is connected to form a 5-membered ring; ^R4 is selected from _C1-4 alkyl, _C1-4 alkoxy and _C1-4 deuterated alkyl; or, ^R4 is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methyl, deuterated ethyl, deuterated propyl or deuterated isopropyl; Each M ₁ is independently selected from hydrogen and C _1-6 alkyl, or each M ₁ is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl; optionally, the alkyl in each M ₁ is independently substituted by one or more selected from hydroxyl, 5-6 membered heterocycloalkyl; L is a single bond or a C _1-4 alkylene group; or L is a single bond, a methylene group, an ethylene group or a propylene group; each Z is independently selected from O, -S(=O) ₂ , _CR5R6 or _{NR7 ,} and _R5 , _R6 and _R7 are each independently selected from hydrogen, methyl, -COOH, -C(=O) _CH2- OH, -C(=O) _CH2CH3 , -CH2 _- COOH, -C(=O) _CH3 , -CH2 _- CH2- _OH , -CH( _{CH3 )} -COOH, -C(=O) _CF3 , -C(=O) _CH2CN , -S(=O) ₂ - _CH3 or -C(=O) _OCH3 . The compound according to any one of claims 1 to 17, characterized in that the compound is the compound shown below or its stereoisomer, tautomer, enantiomer, diastereomer, racemate, geometric isomer, nitrogen oxide, solvate, hydrate, crystal form, ester, isotope-labeled compound, metabolite, pharmaceutically acceptable salt or prodrug:








A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or its stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitrogen oxides, solvates, hydrates, crystal forms, esters, isotope-labeled compounds, metabolites, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable excipients thereof. Use of the compound according to any one of claims 1 to 18 or the pharmaceutical composition according to claim 19 in the preparation of a medicament for preventing or treating a FAK-related disease. The use according to claim 20, wherein the FAK-related disease is selected from cancer, pulmonary hypertension or pathological angiogenesis; Optionally, the cancer comprises lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, sheath cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis cancer, brain stem glioma, pituitary adenoma or a combination of one or more of the foregoing cancers; Optionally, the cancer is gastric cancer; optionally, the cancer is diffuse gastric cancer. A use of a compound according to any one of claims 1 to 18 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug, or the pharmaceutical composition according to claim 19 in the preparation of a drug for regulating or treating a disease associated with YAP; Optionally, the YAP-related disease is selected from cancer; the cancer is selected from: skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer and uterine cancer. One or more; Alternatively, the cancer is selected from one or more of gastric cancer, lung cancer, colon cancer, ovarian cancer, prostate cancer, and liver cancer. A use of a compound according to any one of claims 1 to 18 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug or the pharmaceutical composition according to claim 19 in the preparation of a drug for regulating or treating a disease related to FAK and YAP; Optionally, the disease associated with FAK and YAP is selected from cancer; Optionally, 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's 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; Alternatively, the cancer is selected from one or more of: gastric cancer, lung cancer, colon cancer, ovarian cancer, prostate cancer, and liver cancer; Optionally, the cancer is gastric cancer. A method for regulating the Hippo-YAP signaling pathway, comprising administering a compound according to any one of claims 1 to 18 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug or the pharmaceutical composition according to claim 19. Use of a compound according to any one of claims 1 to 18 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug or the pharmaceutical composition according to claim 19 in the preparation of a Hippo-YAP signaling pathway inhibitor. A method for preventing or treating a YAP-related disease, comprising administering a compound according to any one of claims 1 to 18 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug thereof or a pharmaceutical composition according to claim 19; Optionally, the YAP-related disease comprises one or more combinations 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's 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. A method for preventing or treating a FAK-related disease, comprising administering a compound according to any one of claims 1 to 18 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug thereof or a pharmaceutical composition according to claim 19; Optionally, the FAK-related disease is selected from cancer, pulmonary hypertension or pathological angiogenesis; Optionally, the cancer comprises lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, sheath cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis cancer, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. A method for inhibiting FAK kinase and/or YAP protein activity in a cell or a subject, the method comprising contacting the cell with a compound as described in any one of claims 1 to 18, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, hydrate, isotope or prodrug thereof, or a pharmaceutical composition as described in claim 19; or administering to a subject a compound as described in any one of claims 1 to 18, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, hydrate, isotope or prodrug thereof, or a pharmaceutical composition as described in claim 19.