CN117043163A - Pyrrolopyrimidine or pyrrolopyridine derivative and medical application thereof - Google Patents

Abstract

Pyrrolo-pyrimidine or pyrrolo-pyridine derivatives and medical application thereof. Specifically, the compound has a structure shown in a formula I, has a good inhibition effect on Focal Adhesion Kinase (FAK) and simultaneously inhibits related signal paths, and can be used for preparing medicines for treating or preventing cancers, pulmonary hypertension, pathological angiogenesis and other related diseases, and especially for treating diseases caused by excessive or abnormal cell proliferation, such as tumors or cancers.

Description

Pyrrolopyrimidines or pyrrolopyridine derivatives and their medicinal uses Technical field

The present invention belongs to the field of medicine, and specifically relates to a pyrrolopyrimidine or pyrrolopyridine derivative and its medicinal use, especially in the preparation of medicines for treating or preventing cancer, pulmonary hypertension, and pathological angiogenesis-related diseases. uses in.

Background technique

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

FAK is widely expressed in the body, plays an important role in cell growth, proliferation, migration, and adhesion, and is involved in embryonic development and the occurrence and development of diseases (cancer, cardiovascular diseases, etc.). Overexpression of FAK is found in many types of cancer, including colon, breast, prostate, thyroid, neuroblastoma, ovarian, cervical, brain, head and neck, liver, esophageal, and pancreatic cancers cancer, lung cancer, gastric cancer and acute leukemia. High expression of FAK often indicates a poor prognosis. For example, studies have found that GTPase RHOA ^Y42C mutation is one of the most common gain-of-function mutations in diffuse gastric cancer, and mice with RHOA ^Y42C mutation are sensitive to FAK inhibitors, suggesting that inhibiting FAK activity may become a therapeutic option for diffuse gastric cancer. New strategies.

During the function of FAK, the binding of transmembrane integrin receptors to the extracellular matrix (ECM) recruits FAK to the site of integrin accumulation. FAK does not interact directly with integrins but binds to cell membranes and other adhesion proteins through its carboxy-terminal FAT domain. Once recruited, FAK in the inactive state activates its catalytic activity through autophosphorylation of Y397. After phosphorylation, FAK serves as a molecular scaffold to 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. wait. 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 anti-cancer drugs. 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 modulate the FAK signaling pathway.

Contents of the invention

The present invention aims to provide a focal adhesion kinase (FAK) inhibitor compound, including its preparation method, a medicament or composition containing such a compound, and the use of such compound to treat diseases caused by excessive or abnormal cell proliferation, such as cancer. This method has good clinical application prospects. In addition to having a good inhibitory effect on FAK kinase activity, the compound of the present invention also has the effect of reducing activated YAP, and at the same time has better pharmacokinetics, efficacy and toxicological properties.

A first aspect of the present invention provides a compound of formula I, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxidation compounds, etc. substances, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof,

in,

Ring A is independently selected from: C3-C20 heteroaryl and C6-C20 aryl, such as 5-6 membered heteroaryl and phenyl;

Ring B is independently selected from: C3-C20 heteroaryl and C6-C20 aryl, such as 5-6 membered heteroaryl and phenyl; preferably, Ring B is a six-membered aryl or heteroaryl;

L is independently selected from: bond or CH ₂ , preferably, L is CH ₂ ;

X is independently selected from CH or N, preferably, X is N;

R ₁ is independently selected from: halogen, -C(=O)N(CH ₃ ) ₂ , -C(=O)NHCH ₃ , -C(=O)NH ₂ , -CH(=O), -COOH, CN, C1-C6 alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CO ₂ CH ₃ ;

R ₂ is independently selected from: -N(R ₅ )S(O) _m R ₆ , -P(=O)R' ₅ R' ₆ , -S(O) _m NR ₅ R ₆ , -C(=O )NR ₅ R ₆ , -NR ₅ C(=O)R ₆ , -C(=O)R ₅ , -C(=O)OR ₅ , -OC(=O)R ₅ , -S(O) _m R ₅ ;

R ₃ is each independently selected from: -H, -OH, -halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -NO ₂ , -NR ₅ R ₆ , C1-C6 alkyl, C1 -C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered Heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3 -C12 cycloalkenyl, C6-C10 aryl, and 5-10 membered heteroaryl can be substituted by 1-3 R ₉ ;

R ₄ is each independently selected from: H, -OR ₅ , halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -NO ₂ , -NR ₅ R ₆ , -C(=O)NR ₅ R ₆ , -C(=O)NR ₅ OR ₆ , -C(R ₅ )=NR ₆ , -NR ₅ C(=O)R ₆ , -C(=O)R ₅ , -C(=O) C(=O)R ₅ , -C(=O)OR ₅ , -OC(=O)R ₅ , -OC(=O)OR ₅ , -P(=O)R' ₅ R' ₆ , -S (=O)(=NR ₅ )R ₆ , -S(O) _m R ₅ , -NR ₅ S(O) _m R ₆ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl , C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 Alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, The 5-10 membered heteroaryl group can be substituted by 1-3 R ₉ ;

Or any two adjacent R ₄ and the atoms connected to them jointly form a C5-C7 cycloalkyl group, a 5-7 membered heterocyclyl group, a phenyl group, a 5-6 membered heteroaryl group; wherein, the C5- C7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl can be substituted by 1-3 R ₉ ;

R ₅ , R ₆ , R' ₅ and R' ₆ are each independently selected from: H, -OH, halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -NO ₂ , -CH ₂ CF _3. -NR ₇ R ₈ , -S(O) _m R ₇ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3 -12-membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10-membered heteroaryl; or in NR ₇ R ₈ , R ₇ and R ₈ together with the N atom to which they are connected form 3- 10-membered heterocyclic group (including bridged ring and spiro ring); wherein, the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C12 cycloalkyl group, 3-12-membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10-membered heteroaryl can be substituted by 1-3 R ₉ ;

R ₉ is each independently selected from: H, -OH, oxo (=O), halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CN, -NO ₂ , - OR ₁₀ , -C(=O)R ₁₀ , -OC(=O)R ₁₀ , -OC(=O)R ₁₀ , -OC(=O)OR ₁₀ , -C(=O)NR ₁₀ R ₁₁ , -NR ₁₀ C(＝O)NR ₁₁ R ₁₂ , -NR ₁₀ R ₁₁ , -NR ₁₀ C(＝O)R ₁₁ , -NR ₁₀ S(O) _m R ₁₁ , -S(O) _m R ₁₀ , -S(O) _m NR ₁₀ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3 -C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 groups selected from the following group: C1-C6 alkyl, halogen, -OH, -CN, -NO ₂ , -CHF ₂ , -CH ₂ CF ₃ , -CF ₃ , -C(O)R ₁₃ , -C(O)NR ₁₃ R ₁₄ , -S(O) _m R ₁₃ , -S(O) _m NR ₁₃ R ₁₄ substitution;

R ₇ , R ₈ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 Alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 The heteroaryl group can be substituted by 1-3 groups selected from the following group: -OH, halogen, -CN, -NO ₂ , -NH ₂ , -CHF ₂ , -CH ₂ CF ₃ , -CF ₃ , C1 -C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)-(C1-C6 alkoxy), C3-C12 cycloalkyl, 3-12 yuan Heterocycloalkyl, C1-C6 alkylamine;

n and n' are each independently selected from 0, 1, 2, 3 or 4;

m is independently selected from 0, 1 or 2.

In some preferred embodiments, Selected from:

Among them, p is 0, 1 or 2;

R ₄ is defined as above.

In some preferred embodiments, the compound has a structure represented by Formula II or Formula III

in,

p is 0, 1 or 2;

R ₁ , R ₂ , R ₃ , R ₄ , B and n' are defined as above.

In some preferred embodiments, the compound has a structure represented by Formula IV or Formula V

in,

R ₁ , R ₂ , R ₃ , R ₄ , B and n' are as defined above, R ₅ and R ₆ are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3- C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy Base, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl can be substituted with 1-3 substituents selected from the following group: halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CN, -NO ₂ , C1-C6 alkyl, C1-C6 alkoxy.

It should be noted that among the compounds of the present application, the compounds of formulas IV and V have better FAK kinase inhibitory activity than similar molecules; in the compounds of formula III and formula IV, R ₄ in the position meta to the amide bond on the benzene ring is an alkane. Compounds with an oxygen group (C1-C6 alkoxy group, especially methoxy group) or compounds of formula V can improve the selectivity of other kinases (including but not limited to PYK2) relative to similar molecules.

In some preferred embodiments, the compound has one of the following structures:

in,

R ₁ , R ₂ , R ₃ and R ₄ are as defined above. R ₅ and R ₆ are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl, R' is selected from C1-C6 alkyl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, 5-10-membered heteroaryl can be substituted with 1-3 substituents selected from the following group: Halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CN, -NO ₂ , C1-C6 alkyl, C1-C6 alkoxy.

In some preferred embodiments, R ₁ is independently selected from: F, Cl, -C(=O)NH ₂ , -CH(=O), -COOH, -CN, C1-C6 alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F.

In some preferred embodiments, Ring B is selected from: phenyl, pyridyl or pyrazinyl.

In some preferred embodiments, each R ₄ is independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 Aryl, 5-10 membered heteroaryl, -C(O)NR ₅ R ₆ ; wherein, R ₅ and R ₆ are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3 -C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkyl Oxygen, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl can be substituted with 1-3 substituents selected from the following group: halogen, -CF _3. -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CN, -NO ₂ , C1-C6 alkyl group, C1-C6 alkoxy group.

In some preferred embodiments, R ₁ is independently selected from: F, Cl, -C(=O)NH ₂ , -CH(=O), -COOH, -CN, methyl, -CF ₃ , -CHF ₂ , -CH ₂ F; and/or

Each R ₄ is independently selected from: F, Cl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, -C(=O)NH(C1-C6 alkyl), - C(=O)NH(C3-C6 cycloalkyl), -C(=O)NH(3-6 membered heterocyclyl); wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl and 3-6 membered heterocyclyl can be substituted with 1-3 substituents selected from the following group: halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , - CN, -NO ₂ , C1-C6 alkyl, C1-C6 alkoxy; and/or

R ₂ is independently selected from: -N(R ₅ )S(O) _m R ₆ , -P(=O)R' ₅ R' ₆ , -S(O) _m R ₅ ; wherein, R ₅ , R ₆ , R' ₅ and R' ₆ are each independently selected from: H, -OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl , 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, m is 1 or 2; and/or

R ₃ is each independently selected from: -S(O) ₂ CH ₃ , -NCH ₃ S(O) ₂ CH ₃ , -NHS(O) ₂ CH ₃ , -P(=O)(CH ₃ ) ₂ , - P(=O)(OH) ₂ ; and/or

Selected from:

In some preferred embodiments, A, B, L, X, R ₁ , R ₂ , R ₃ , R ₄ , n and n' are the groups corresponding to each specific compound in the embodiments.

In some preferred embodiments, the compound has the structure of one of the following groups or is selected from the following group:

In some preferred embodiments, the compound is a compound shown in the Examples.

A second aspect of the present invention provides a pharmaceutical composition, which contains the compound as described in the first aspect, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, Isomers, geometric isomers, nitrogen oxides, metabolites or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs; and pharmaceutically acceptable carriers, diluents or excipients; Preferably, the pharmaceutical composition further comprises one or more selected from the group consisting of: chemotherapy drugs, PD-1 inhibitors, PD-1 antibodies, PD-L1 inhibitors, PD-L1 antibodies, ALK inhibitors, PI3K inhibitor, BTK inhibitor, EGFR inhibitor, EGFR antibody, VEGFR inhibitor, VEGFR antibody, HDAC inhibitor, CDK inhibitor, MEK inhibitor, Akt inhibitor, mTOR inhibitor, SHP2 inhibitor, KRAS G12C inhibitor , KRAS G12D inhibitor, KRAS G12V inhibitor, c-MET inhibitor, Her2 inhibitor, Her2 antibody, Claudin18.2 antibody.

The third aspect of the present invention provides a compound as described in the first aspect, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, and geometric isomers. Conforms, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, or pharmaceutical compositions as described in the second aspect for use in the prevention or treatment of FAK-related Use in medicines for diseases; preferably, the FAK-related disease is cancer, pulmonary hypertension, or pathological angiogenesis; more preferably, 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 bowel cancer, thyroid cancer, urethra cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis Cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreas Carcinoma, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, uterine cancer.

A fourth aspect of the present invention provides a method for preparing a compound as described in the first aspect, comprising the steps

s4) In an inert solvent and in the presence of a catalyst, compounds I-1 and I-2 react to obtain a compound of formula I;

In the formula, X' is halogen;

Preferably, the method further includes the steps of:

s1) In an inert solvent (such as i-PrOH) and in the presence of a base (such as DIPEA), compounds I-3 and I-4 react to obtain a compound of formula I-5;

s2) In an inert solvent (such as DMF), in the presence of a catalyst (such as Pd(PPh ₃ ) ₂ Cl ₂ and CuI) and under basic conditions (such as DIPEA), compounds I-5 and I-6 react to obtain the formula I-7 compound;

s3) In an inert solvent (such as NMP) and in the presence of alkali (such as tBuOK), compound I-7 reacts to obtain a compound of formula I-1;

In the formula,

X', X" and X"' are each independently halogen (such as Cl, Br, I);

A ring, B ring, X, L, R ₁ , R ₂ , R ₃ , R ₄ , n and n' are as defined above.

A fifth aspect of the present invention provides a method for treating FAK-related diseases, the method comprising administering to a subject identified or diagnosed as having a FAK-related disease a therapeutically effective amount of a compound as described in the first aspect, or its effect on Enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or their pharmaceutically acceptable salts, hydrates, Solvates, isotopes or prodrugs, or pharmaceutical compositions as described in the second aspect.

A sixth aspect of the present invention provides a method for inhibiting FAK kinase activity in a cell or a subject, the method comprising contacting the cell or administering the compound of the first aspect to the subject, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts thereof, Hydrates, solvates, isotopes or prodrugs, or steps of the pharmaceutical composition as described in the second aspect; preferably, the cells are mammalian cells; preferably, the subject is a mammal; more preferably As a person.

The seventh aspect of the present invention provides a compound as described in the first aspect, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, and geometric isomers. Conforms, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, or pharmaceutical compositions as described in the second aspect for use in the prevention or treatment of YAP-related Use in medicines for diseases, especially YAP-positive related diseases; Preferably, the YAP-related disease is cancer; More preferably, 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 bowel cancer, thyroid cancer, urethra cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer, Vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer, Pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, uterine cancer.

The eighth aspect of the present invention provides a compound as described in the first aspect, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, and geometric isomers. Conforms, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, or pharmaceutical compositions as described in the second aspect for use in the prevention or treatment of FAK and Use in medicines for YAP-related diseases, especially diseases related to FAK and YAP positivity; Preferably, the FAK- and YAP-related diseases are cancers; More preferably, the cancers are selected from: skin cancer, bone cancer, nerve Glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small bowel cancer, thyroid cancer, urethra cancer, cervical cancer, endometrial cancer , fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS) , ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, and uterine cancer.

A ninth aspect of the present invention provides a method for treating YAP (especially YAP positive) related diseases, which method includes administering a therapeutically effective amount of a subject identified or diagnosed as having a YAP (especially YAP positive) related disease. Compounds as described in the first aspect, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, and metabolites Or a pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof, or a pharmaceutical composition as described in the second aspect.

A tenth aspect of the present invention provides a method for reducing activated YAP in a cell or a subject, the method comprising contacting the cell or administering to the subject a compound according to the first aspect, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts thereof, Hydrates, solvates, isotopes or prodrugs, or steps of the pharmaceutical composition as described in the second aspect; preferably, the cells are mammalian cells; preferably, the subject is a mammal; more preferably As a person.

On the other hand, a method of treating FAK and YAP-related diseases is provided, the method comprising administering a therapeutically effective amount of a compound as described in the first aspect to a subject identified or diagnosed as having FAK and YAP-related diseases, or Its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates thereof substance, solvate, isotope or prodrug, or a pharmaceutical composition as described in the second aspect.

In another aspect, a method for inhibiting FAK kinase activity in a cell or a subject, and reducing activated YAP in a cell or a subject is provided, the method comprising contacting or exposing the cell to the subject. The subject administers the compound as described in the first aspect, or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide , metabolites or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs, or the steps of the pharmaceutical composition as described in the second aspect; preferably, the cells are mammalian cells; preferably , the subject is a mammal; more preferably, it is a human.

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

Description of the drawings

Figure 1 shows the morphological comparison of normal organoid cells and diffuse gastric cancer organoid cells.

Figure 2 shows the effect of compound 4 (cultured at 2.5 μM for 48 h) on proliferation and morphology of diffuse gastric cancer organoid cells.

Figure 3 shows the effect of compound 6 (cultured at 2.5 μM for 48 h) on proliferation and morphology of diffuse gastric cancer organoid cells.

Figure 4 shows the effect of compound 8 (cultured at 2.5 μM for 48 h) on proliferation and morphology of diffuse gastric cancer organoid cells.

Figure 5 shows the effect of compound 9 (cultured at 2.5 μM for 48 h) on proliferation and morphology of diffuse gastric cancer organoid cells.

Figure 6 shows the effects of Compound 9 and Defactinib on proliferation of diffuse gastric cancer organoid cells.

Figure 7 shows the effect of compound 9 on FAK and YAP protein activities in diffuse gastric cancer organoids.

Figure 8 shows the effect of compound 10 on FAK and YAP protein activities in diffuse gastric cancer organoids.

Figure 9 shows the effects of compounds 8 and 9 on the FAK and YAP protein activities of human diffuse gastric cancer tumor cell lines.

Figure 10 shows the effects of Defactinib, IN10018 and compounds 24, 25, 26, 27, and 28 on the FAK and YAP protein activities of human diffuse gastric cancer tumor cell lines.

Figure 11 shows the effect of Compound 9 and Defactinib on the proliferation of human diffuse gastric cancer tumor cell lines.

Detailed ways

After extensive and in-depth research, the inventor unexpectedly discovered a class of compounds that have good FAK kinase inhibitory activity and simultaneously reduce activated YAP. In addition, the compounds also have better pharmacodynamic/pharmacokinetic properties. On this basis, the present invention was completed.

the term

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

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes substituents that are chemically equivalent when the structural formula is written from right to left. For example, -CH ₂ O- is equivalent to -OCH ₂ -.

The term "alkyl", by itself or as part of another substituent, refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (i.e., C1-C6 means a group containing 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and similar alkyl groups. In this application, alkyl is also intended to include substituted alkyl, that is, one or more positions in the alkyl are substituted, especially 1 to 4 substituents, which may be substituted at any position.

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

The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and having the specified number of carbon atoms. For example, "C2-C6 alkenyl" means containing 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to: vinyl, 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 the specified number of carbon atoms. For example, "C2-C6 alkynyl" means containing 2 to 6 carbon atoms. Alkynyl groups include, but are not limited to: ethynyl, propynyl, butynyl, etc.

The term "cycloalkyl" refers to cyclic alkyl groups including saturated monocyclic (e.g., C3-C8), bicyclic (e.g., C5-C12 fused bicyclic, C5-C12 membered spiro bicyclic) or polycyclic alkyl groups, "C3- "C6 cycloalkyl" means containing 3 to 6 carbon atoms, and "C3-C12 cycloalkyl" means containing 3 to 12 carbon atoms. The cycloalkyl group is preferably a C3-C12 cycloalkyl group, and more preferably a C3-C6 cycloalkyl group. Representative cycloalkyl groups of the present invention include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, wait. It is understood that substituted or unsubstituted cycloalkyl groups, such as branched cycloalkyl groups (such as 1-methylcyclopropyl and 2-methylcyclopropyl), are included in the definition of "cycloalkyl".

The term "cycloalkenyl" refers to a cycloalkyl group as defined above and further containing one or more double bonds, including but not limited to cyclopentenyl and cyclohexenyl.

The term "heterocyclyl" generally refers to a stable monocyclic ring (such as 3-8 membered, that is, 3-, 4-, 5-, 6-, 7- or 8-membered) or bicyclic ring (such as 5-12 membered, that is, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan or 12 yuan) or multiple rings (such as 7-14 yuan, that is, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan, 12-membered, 13-membered or 14-membered) heterocyclic ring, including fused ring, spiro ring and/or bridged ring structure, which is saturated or partially unsaturated, and which contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. The term also includes polycyclic groups formed by the fusion of a heterocyclic ring with an aromatic ring (such as a benzene ring). "Heterocyclyl" may be substituted or unsubstituted. Nitrogen and sulfur heteroatoms as ring atoms may optionally be oxidized. Nitrogen atoms are substituted or unsubstituted (ie, N or NR, where R is H or another substituent, if defined). Heterocycles can be attached to their pendant groups at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclyl groups described herein may be substituted on the carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. A heterocyclic group may be attached to any heteroatom or carbon residue of a ring or ring system molecule. Examples of heterocyclyl include, but are not limited to: azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazole Alkyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroacridine Heptanyl, 4-piperidinonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholine sulfoxide, thiomorpholine sulfone, 1,3-dioxanyl and tetrahydro-1,1-dioxythiophene, etc. Among them, the involved spirocyclic, fused-cyclic and bridged-cyclic heterocyclic groups are optionally connected to other groups through single bonds, or connected to other cycloalkyl, heterocyclic groups through any two or more atoms on the ring. Cyclic groups, aryl groups and heteroaryl groups are further linked to each other.

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

The term "heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, where the heteroatoms are selected from oxygen, nitrogen and sulfur. The heteroaryl group is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazazinyl, triazolyl and tetrazolyl, etc. "Heteroaryl" may be substituted or unsubstituted.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

Unless otherwise stated, any heteroatom that is not satisfied with its valence is assumed to have enough hydrogen atoms to supplement its valence.

In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. Specific substituents are the substituents described accordingly in the foregoing text, or the substituents appearing in each embodiment. Unless otherwise stated, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position, i.e. Each substitution is independent of each other. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as _{trifluoromethyl} or an alkyl group containing Cl), Cyano, nitro, oxo (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, OR _a , SR _a , S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c ,NR _b S(＝O) _{2 Re} ,NR _b P(＝O) _{2 Re} ,S(＝O) ₂ NR _b R _c ,P(＝O) ₂ NR _b R _c ,C(＝O) OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e , NR _d C(=O)NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P(=O) ₂ R _e , where R _a can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, aryl or heteroaryl, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R _b and R _c together with N atoms can form a heterocyclic ring; R _e can independently represent hydrogen, alkyl, cycloalkyl , alkenyl, alkynyl, heterocyclyl, aryl or heteroaryl. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, aryl or heteroaryl may be optionally substituted. The substituents are for example (but not limited to): halogen, hydroxyl, cyano group, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1 -C6 urea group, etc.

Yes-associated protein (YAP) is a proto-oncoprotein that exists in the cytoplasm in an inactive form. When activated, it transfers to the nucleus and activates the transcription of genes related to cell division and apoptosis. YAP is one of the downstream regulatory proteins in the Hippo signaling pathway. It cooperates with the transcriptional coactivator TAZ to guide gene expression by controlling the TEAD transcription factor family. The Hippo signaling pathway is an evolutionarily conserved signaling pathway that plays a key role in organ development, epithelial homeostasis, tissue regeneration, wound healing, and immune regulation. Dysregulation of the Hippo pathway and YAP/TAZ-TEAD activity is associated with a variety of diseases, the most important of which is cancer.

In the present invention, "YAP positive" means that the YAP content in the cell nucleus reaches or exceeds the preset content.

In the present invention, "FAK positive" means that the intracellular phosphorylated FAK content reaches or exceeds a preset content.

active ingredients

As used herein, the terms "compound of the invention" or "active ingredient of the invention" are used interchangeably and refer to a compound of formula I, or an enantiomer, diastereomer, racemate, tautomer thereof Isomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, isotopes or prodrugs thereof.

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

Among them, A, B, L, X, R ₁ , R ₂ , R ₃ , R ₄ , n and n' are defined as above.

Preferably, the compound has a structure represented by Formula II or Formula III

Among them, p, R ₁ , R ₂ , R ₃ , R ₄ , B and n' are defined as above.

Preferably, the compound has a structure represented by Formula IV or Formula V

in,

R ₁ , R ₂ , R ₃ , R ₄ , B and n' are as defined above, R ₅ and R ₆ are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3- C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy Base, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl can be substituted with 1-3 substituents selected from the following group: halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CN, -NO ₂ , C1-C6 alkyl, C1-C6 alkoxy.

Preferably, R ₁ is independently selected from: F, Cl, -C(=O)NH ₂ , -CH(=O), -COOH, CN, methyl, -CF ₃ , -CHF ₂ , -CH ₂ F ;

Ring B is a six-membered aryl or heteroaryl; preferably, ring B is selected from: phenyl, pyridyl or pyrazinyl;

R ₄ is each independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered Heteroaryl, -C(O)NR ₅ R ₆ ; wherein, R ₅ and R ₆ are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3 -12-membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10-membered heteroaryl;

R ₂ is independently selected from: -N(R ₅ )S(O) _m R ₆ , -P(=O)R' ₅ R' ₆ , -S(O) _m R ₅ ;

Among them, R ₅ , R ₆ , R' ₅ and R' ₆ are each independently selected from: H, OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl;

Among them, m is 1 or 2;

Preferably, R ₃ is each independently selected from: -S(O) ₂ CH ₃ , -NCH ₃ S(O) ₂ CH ₃ , -NHS(O) ₂ CH ₃ , -P(=O)(CH ₃ ) ₂ , -P(=O)(OH) ₂ .

The possible salts formed by the compounds in the present invention also belong to the scope of the present invention. Unless otherwise stated, compounds in the present invention are understood to include salts thereof. The term "salt" as used herein refers to an acidic or basic salt formed from an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic moiety, which includes but is not limited to pyridine or imidazole, and when it contains an acidic moiety, including but is not limited to carboxylic acid, the zwitterion ("inner salt") that may be formed is included in Within the scope of the term "salt". Pharmaceutically acceptable (i.e., nontoxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation. The compounds of the present invention may form salts, for example, compound I can be obtained by reacting with a certain amount of, for example, an equivalent amount of acid or base, salting out in a medium, or by freeze-drying in an aqueous solution.

The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (eg, with acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, and benzoates. , benzenesulfonate, hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, enanthate, caproate, hydrochloride, hydrobromide, hydroiodide, glycolate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfates (such as formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoate, etc.

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

Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention. The term "prodrug" here refers to a compound that undergoes chemical transformation through metabolism or chemical processes to produce the compound, salt, or solvate of the present invention when treating related diseases. Compounds of the present invention include solvates, such as hydrates.

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

All stereoisomers of the compounds (eg, those that may exist due to asymmetric carbon atoms for various substitutions), including their enantiomeric and diastereomeric forms, are contemplated by the present invention. The compounds of the invention may be independent stereoisomers that do not exist simultaneously with other isomers (e.g., have a specific activity as a pure or substantially pure optical isomer), or they may be mixtures, e.g. Racemates, or mixtures with all other stereoisomers or portions thereof. The chiral center of the present invention has two configurations: S or R, which are defined as recommended by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as fractional crystallization, or by fractional crystallization by derivatization to diastereoisomers, or by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid followed by recrystallization.

The weight content of the compounds in the present invention obtained by sequential preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), as described in the text List. Such "very pure" compounds of the invention are here also included as part of the invention.

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

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

Definitions of specific functional groups and chemical terms are detailed below. For the purposes of this invention, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivities are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated by reference.

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

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

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

If one wants to design a synthesis of a specific enantiomer of the compound of the present invention, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, and the resulting diastereomeric mixture is separated and then the chiral auxiliary is removed. Pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation, crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.

As described herein, the compounds of the present invention may be provided with any number of substituents or functional groups to broaden their encompassing scope. In general, whether the term "substituted" appears before or after the term "optional", the general formula of the substituent included in the formulation of the present invention means that the substituent of the specified structure is used in place of the hydrogen radical. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents may be the same or different at each position. The term "substitution" as used herein includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, heteroatoms such as nitrogen may have hydrogen substituents or any of the permissible organic compounds described above to supplement their valence. Furthermore, this invention is not intended to be limited in any way to the permitted substituted organic compounds. The present invention considers that combinations of substituents and variable groups are excellent in the treatment of diseases in the form of stable compounds. The term "stable" as used herein refers to a compound that is stable, detectable over a long enough period of time to maintain the structural integrity of the compound, and preferably effective over a long enough period of time, and is used herein for the above purposes.

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

Pharmaceutical compositions and methods of administration

The compound of formula (I) according to the present invention, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, Metabolites or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs, and compounds containing formula (I), or their enantiomers, diastereomers, racemates, interactions Pharmaceutical compositions of isomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof may be used for prophylaxis and/or Treats the following diseases: cancer, pulmonary hypertension, pathological angiogenesis.

The compound described in formula (I), or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or Its pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the original administration method and dosage of the drug can remain unchanged, while the compound of formula (I) is taken at the same time or before or after; or the compound of formula (I), or its enantiomers, non-enantiomers, etc. Enantiomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs , and other drugs are made into a single preparation and administered at the same time. When the compound of formula (I), or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or their Pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs, when taken together with one or several other drugs, can preferably be used simultaneously containing one or several known drugs and a compound of formula (I) , or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts thereof , hydrates, solvates, isotopes or pharmaceutical compositions of prodrugs. Drug combination also includes taking the compound of formula (I), or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, and geometric isomers, during overlapping periods of time. compounds, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, and one or more other known drugs. When the compound of formula (I), or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or their Pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs, when used in combination with one or several other drugs, the compound of formula (I), or its enantiomers, diastereomers isomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs, or have Doses of known drugs may be lower than those taken alone.

It can be used with the compound of formula (I), or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolism Drugs or active ingredients used in combination with the product or its pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs include but are not limited to: chemotherapy drugs, PD-1 inhibitors, PD-1 antibodies, PD -L1 inhibitor, PD-L1 antibody, ALK inhibitor, PI3K inhibitor, BTK inhibitor, EGFR inhibitor, EGFR antibody, VEGFR inhibitor, VEGFR antibody, HDAC inhibitor, CDK inhibitor, MEK inhibitor, Akt inhibitor Agents, mTOR inhibitors, SHP2 inhibitors, KRAS G12C inhibitors, KRAS G12D inhibitors, KRAS G12V inhibitors, c-MET inhibitors, Her2 inhibitors, Her2 antibodies, Claudin18.2 antibodies.

The compound described in formula (I), or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or The pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof may also be used in combination with therapeutic agents for the treatment of pulmonary arterial hypertension (PHA). The PHA therapeutic agent is preferably a vasodilator, such as epoprostenol, tadalafil or ambrisentan.

The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, films, pills, external liniments, controlled-release or sustained-release types, or nano-preparations.

The pharmaceutical composition of the present invention contains a compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount and a pharmaceutically acceptable excipient or carrier. The “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 10-1000 mg of the compound of the present invention/dose. Preferably, the "dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility" here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

"Excipients" refer to the additions other than the main drug in pharmaceutical preparations, and can also be called auxiliary materials.

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

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

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

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

Besides these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

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

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

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

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

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

The invention also provides a method for preparing a pharmaceutical composition, which includes the steps of: combining a pharmaceutically acceptable carrier with the compound of formula (I) of the invention or its crystal form, a pharmaceutically acceptable salt, a hydrate or a solvent. The compounds are mixed to form a pharmaceutical composition.

Preparation

Methods for preparing compounds of formula I are described in the following schemes and examples. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of steps in performing a reaction scheme can be changed to facilitate the reaction or avoid undesired side reaction products.

The preparation methods of the compound of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations can be easily performed by those skilled in the art to which the present invention belongs.

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

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

s1) In an inert solvent (such as i-PrOH) and in the presence of a base (such as DIPEA), compounds I-3 and I-4 react to obtain a compound of formula I-5;

s2) In an inert solvent (such as DMF), in the presence of a catalyst (such as Pd(PPh ₃ ) ₂ Cl ₂ and CuI) and under basic conditions (such as DIPEA), compounds I-5 and I-6 react to obtain the formula I-7 compound;

s3) In an inert solvent (such as NMP) and in the presence of alkali (such as tBuOK), compound I-7 reacts to obtain a compound of formula I-1;

s4) In an inert solvent (such as), in the presence of a catalyst, compounds I-1 and I-2 react to obtain a compound of formula I;

In the formula,

X', X" and X"' are each independently halogen (such as Cl, Br, I);

A ring, B ring, X, L, R ₁ , R ₂ , R ₃ , R ₄ , n and n' are as defined above.

Those skilled in the art will also appreciate that in the methods described herein, intermediate compound functional groups may need to be protected by appropriate protecting groups. Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymer resin.

The reagents or materials used in the present invention are all commercially available or obtained in the manner given in literature reports.

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

The invention has the following main advantages:

(1) The compound of the present invention has excellent inhibitory ability against FAK kinase, and/or can significantly reduce/lower the activated YAP; especially when the two adjacent R _4s on the A ring form a parallel ring structure with the A ring, their The activity is greatly improved; in addition, when R ₄ is an alkoxy group or amide group and R ₂ is N-methylmethanesulfonamide, its activity can also be significantly improved.

(2) The compound of the present invention has low toxic and side effects.

(3) The compound of the present invention has good pharmacodynamics and pharmacokinetic properties.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions such as those described in Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer. Suggested conditions. Unless otherwise stated, percentages and parts are by weight.

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

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid mass spectrometry (LC-MS).

NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic instruments. The measurement solvents included deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated acetone (CD ₃ COCD ₃ ), and deuterated chloroform (CDCl ₃ ). and deuterated methanol (CD ₃ OD), etc., the internal standard is tetramethylsilane (TMS), and the chemical shift is measured in parts per million (ppm).

Liquid mass spectrometry (LC-MS) was detected using an Agilent 1260 mass spectrometer. The HPLC measurement used an Agilent 1100 high-pressure chromatograph (Microsorb 5 micron C18 100 x 3.0mm column).

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

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

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

The following abbreviations are used throughout this invention

THF: Tetrahydrofuran

DCM: dichloromethane

PE: petroleum ether

Na ₂ CO ₃ : sodium carbonate

MeOH: methanol

HCl: hydrochloric acid

Pd(PPh ₃ ) ₄ : Tetrakis triphenylphosphine palladium

K ₂ CO ₃ : potassium carbonate

H ₂ O: water

TEA: triethylamine

DIEA: N,N-diisopropylethylamine

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

NaBH ₄ : sodium borohydride

Sn ₂ (Bu-n) ₆ : Hexahexyl ditin

CuI: cuprous iodide

Cs ₂ CO ₃ : cesium carbonate

K ₃ PO ₄ : potassium phosphate

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

Pd/C: palladium carbon

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

EA: Ethyl acetate

Boc ₂ O: di-tert-butyl dicarbonate

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

NaH: sodium hydrogen

CH ₃ I: methyl iodide

L-Proline: L-Proline

L-Selectride: Lithium tri-sec-butylborohydride

Example

Example 1

2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole Preparation of [2,3-d]pyrimidine-6-carboxylic acid methyl ester

Step 1: Synthesis of N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide

At 0°C, N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide (5.0g, 19.8mmol), 2,4-dichloro-5-iodopyrimidine (5.0 g, 18.2 mmol) and DIPEA (12.0 mL, 72.6 mmol) in i-PrOH (100 mL) were stirred for 3.5 h. After TLC (petroleum ether/ethyl acetate=5/1) showed that the reaction was completed, the reaction mixture was poured into water (150 mL) and extracted twice with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , and then the dried product was filtered and rotary evaporated to obtain crude product. The crude product was purified by FCC (petroleum ether/ethyl acetate = 10/1) to obtain N-(3-(((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazine-2 -N-methylmethanesulfonamide 7.54g. MS m/z (ESI): 455.2[M+H] ⁺ .

Step 2: Synthesis of 3-(2-chloro-4-((((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)pyrimidin-5-yl)propionic acid ester

Under nitrogen protection, to 3.0g, 6.6mmol) and methyl propiolate (1.6g, 19.7mmol) were added to the DMF (30mL) solution of Pd(PPh ₃ ) ₂ Cl ₂ (70mg), CuI (126mg, 0.661mmol) and DIPEA ( 3.3 mL, 20.0 mmol). Then, under nitrogen protection, the reaction solution was stirred in a 70°C oil bath for 6 h. After LCMS showed that the reaction was completed, the reaction solution was filtered, and then the filtrate was poured into water (200 mL) and washed with ethyl acetate. The ester (100 mL) was extracted twice. The combined organic phase was washed three times with saturated brine (100 mL), and then the organic phase was dried over anhydrous Na ₂ SO _4. The dried product was then suction filtered and concentrated to obtain a crude product. The crude product was passed through a flash column Purification by chromatography (petroleum ether/ethyl acetate=10/1) gave 3-(2-chloro-4-((((3-(N-methylmethylsulfonamide))pyrazin-2-yl) Methyl)amino)pyrimidin-5-yl)propionate 1.76g. MS m/z (ESI): 411.3 [M+H] ⁺ .

Step 3: Synthesis of 2-chloro-7-(2-(N-methylmethylsulfonamido)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester

To 3-(2-chloro-4-((((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)pyrimidin-5-yl) at 0°C To a solution of propionate (1.23g, 3.04mmol) in NMP (12mL) was added tBuOK (409mg, 3.64mmol). The reaction solution was then warmed to room temperature and stirred overnight. TLC (petroleum ether/ethyl acetate = 5/1 ) shows that after the reaction is completed, the reaction solution is concentrated and dissolved three times with ethyl acetate (200 mL). After combining the organic phases, the organic phase is washed three times with water (100 mL) and then washed once with saturated brine (100 mL). The organic phase Dry over anhydrous Na ₂ SO ₄ , then filter and concentrate the dried product to obtain a crude product. The crude product is purified by flash column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain 2-chloro-7-(2-( N-methylmethylsulfonamido)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester 230mg. MS m/z (ESI): 411.3[M+H] ⁺ .

Step 4: Synthesis of 2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl) -7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester

To 2-chloro-7-(2-(N-methylmethylsulfonamido)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester ( TsOH·H ₂ O (97 mg, 0.510 mmol) was added to a solution of 145 mg, 0.462 mmol) in 2-butanol (14 mL), and then the reaction solution was heated to 115°C and stirred for 8 h. After TLC (DCM/MeOH=15:1) showed that the reaction was completed, the reaction solution was concentrated and dissolved in DCM (10 mL). The organic phase was washed three times with water (10 mL) and then once with saturated brine (10 mL). The organic phase was dried over anhydrous _Na2SO4 , and then the dried product was filtered and _concentrated to obtain crude product. The crude product was purified by flash column chromatography (DCM/MeOH=100/1-20/1) to obtain 2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N- Methylmethylsulfonamide)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester 43.9 mg. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.07 (s, 1H), 8.99 (s, 1H), 8.51 (d, J = 2.4Hz, 1H), 8.43 (d, J = 2.4Hz, 1H) ,8.26-8.19(m,1H),7.84(d,J＝8.8Hz,2H),7.70(d,J＝8.8Hz,2H),7.34(s,1H),6.05(s,2H),3.70( s,3H),3.37(s,3H),3.22(s,3H),2.75(d,J＝4.4Hz,3H).MS m/z(ESI): 525.5[M+H] ⁺ .

Example 2

2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole Preparation of para[2,3-d]pyrimidine-6-carboxylic acid

To 2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methane at room temperature (130 mg, 0.248 mmol) in methanol/water (5 mL/2.5 mL), LiOH·H ₂ O (104 mg, 2.48 mmol). The reaction solution was then heated to 50°C and stirred overnight. After TLC (DCM/MeOH=10:1) showed that the reaction was completed, the reaction solution was concentrated and dissolved in H ₂ O (20 mL). Adjust the pH of the solution to 2 with 1M HCl, filter the precipitated yellow solid to obtain a crude product, and purify the crude product by flash column chromatography (DCM/MeOH=100/1-10/1) to obtain 2-((4-(methylcarbamoyl) )phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-6- Carboxylic acid 125 mg. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.03 (s, 1H), 8.96 (s, 1H), 8.50 (d, J = 2.4Hz, 1H), 8.43 (d, J = 2.8Hz, 1H) ,8.23(dd,J＝8.8,4.0Hz,1H),7.85(d,J＝8.8Hz,2H),7.70(d,J＝8.8Hz,2H),7.27(s,1H),6.02(s, 2H), 3.35 (s, 3H), 3.21 (s, 3H), 2.75 (d, J = 4.4Hz, 3H). MS m/z(ESI): 511.5[M+H] ⁺ .

Example 3

N,N-dimethyl-2-(((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazine-2- Preparation of methyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

2-((4-(Methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H- Pyrro[2,3-d]pyrimidine-6-carboxylic acid (80 mg, 0.157 mmol) and dimethylamine hydrochloride (20 mg, 0.245 mmol) were dissolved in DMF (1.5 mL) solution, and HATU (90 mg, 0.237mmol) and DIPEA (0.1mL, 0.60mmol), and then reacted at room temperature for 2h. After the reaction was monitored by LCMS, the reaction was quenched with water (10mL), and then extracted with EA (20mL) three times, and the organic phase was washed with saturated brine. The organic phase was dried with anhydrous Na ₂ SO ₄ , and then the dried product was suction filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (MeOH/DCM=0-10%) to obtain N, N-dimethyl-2- (((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo [2,3-d]pyrimidine-6-carboxamide 82.0 mg. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.88 (s, 1H), 8.86 (s, 1H), 8.52 (d, J = 2.4 Hz,1H),8.48(d,J＝2.4Hz,1H),8.41-8.19(m,1H),7.84(d,J＝8.8Hz,2H),7.72(d,J＝8.8Hz,2H), 6.82(s,1H),5.81(s,2H),3.31(s,3H),3.17(s,3H),3.11-3.04(m,3H),2.87-2.79(m,3H),2.76(d, J＝4.4Hz,3H).MS m/z(ESI): 538.5[M+H] ⁺ .

Example 4

N-methyl-4-((6-methyl-7-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2, Preparation of 3-d]pyrimidin-2-yl)amino)benzamide

Step 1: Synthesis of 3N-(3-((((2-chloro-5-(propynyl-1))pyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methyl methanesulfonamide

Under nitrogen protection, to 586.3 mg, 1.29 mmol) and tributyl(prop-1-yn-1-yl)stannane (850.0 mg, 2.58 mmol) were added to a solution of toluene (20 mL) respectively. Pd(PPh ₃ ) ₄ (150.0 mg, 0.13 mmol) and CuI (24.75 mg, 0.13 mmol), and then stirred the reaction solution in a 100°C oil bath for 2 h under nitrogen protection. After LCMS showed that the reaction was completed, the reaction solution was filtered, and then poured into water (10 mL). And extracted twice with ethyl acetate (10 mL). The organic phases were combined and then washed with saturated brine (20 mL). The organic phase was dried with anhydrous Na ₂ SO ₄ , and then the dried product was suction filtered and concentrated to obtain a crude product. The crude product was quickly passed through Purify by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain N-(3-(((2-chloro-5-(propynyl-1))pyrimidin-4-yl)amino)methyl (yl)pyrazin-2-yl)-N-methylmethanesulfonamide 230 mg. MS m/z (ESI): 367.1 [M+H] ⁺ .

Step 2: Synthesis of N-(3-((2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide

At 0°C, to N-(3-((((2-chloro-5-(propynyl-1))pyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N - To a solution of methylmethanesulfonamide (230 mg, 0.63 mmol) in DMF (10 mL) was added DBU (0.85 mL, 6.3 mmol). The reaction solution was then heated to 60°C and stirred for 5 h. After TLC (petroleum ether/ethyl acetate=5/1) showed that the reaction was completed, the reaction solution was concentrated and dissolved in ethyl acetate (5 mL). The organic phase was washed three times with water (5 mL) and then once with saturated brine (10 mL). The organic phase was dried over anhydrous _Na2SO4 , and then the dried product was filtered and _concentrated to obtain crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=4/1) to obtain N-(3-((2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 80 mg. MS m/z(ESI): 367.1[M+H] ⁺ .

Step 3: Synthesis of N-methyl-4-((6-methyl-7-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl))-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)benzamide

At room temperature, to N-(3-((2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)- To a solution of N-methylmethanesulfonamide (50 mg, 0.14 mmol) in 2-butanol (5 mL) were added p-aminobenzamide (22.54 mg, 0.15 mmol) and TsOH·H ₂ O (26.6 mg, 0.14 mmol). The reaction solution was then heated to 120°C and stirred for 8 h. After TLC (DCM/MeOH=15:1) showed that the reaction was completed, the reaction solution was concentrated and dissolved in DCM (5 mL). The organic phase was washed three times with water (5 mL) and then once with saturated brine (10 mL). The organic phase was dried over anhydrous _Na2SO4 , and then the dried product was filtered and _concentrated to obtain crude product. The crude product was purified by flash column chromatography (DCM/MeOH=100/1-20/1) to obtain N-methyl-4-((6-methyl-7-(((3-(N-methylmethyl Sulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)benzamide 25 mg. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.66(s,1H),8.64(s,1H),8.56(d,J＝2.4Hz,1H),8.52(d,J＝2.5Hz,1H),8.18(q,J＝4.1Hz,1H ),6.31(d,J＝1.1Hz,1H),5.70(s,2H),3.29(s,3H),3.22(s,3H),2.75(d,J＝4.5Hz,3H),2.24(s ,3H).MS m/z(ESI): 481.2[M+H] ⁺ .

Example 5

2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole Preparation of [2,3-d]pyrimidine-6-carboxamide

2-((4-(Methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H- Pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (30mg, 0.06mmol), HATU (33.5mg, 0.09mmol) and DIPEA (20μL, 0.12mmol) were dissolved in DMF (1mL) and reacted at room temperature for 1h. Add ammonia water (20 μL, 0.12 mmol) and react at room temperature for 2 hours. After monitoring the reaction, add water, add DCM for extraction, dry and concentrate the extract, and purify the concentrate through column chromatography to obtain 2-((4-(methylaminomethyl) Acyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-6 -Carboxamide 10 mg. ¹ H NMR (400MHz, DMSO) δ9.90 (s, 1H), 8.91 (s, 1H), 8.44 (d, J = 2.3Hz, 1H), 8.36 (d, J = 2.5Hz, 1H), 8.18 ( d,J＝4.8Hz,1H),7.92(s,1H),7.81(d,J＝8.8Hz,2H),7.66(d,J＝8.8Hz,2H),7.23(s,1H),7.19( s,1H),6.00(s,2H),3.33(s,4H),3.16(s,3H),2.71(d,J＝4.5Hz,3H).MS m/z(ESI):510.0[M+ H] ⁺ .

Example 6

4-((6-cyano-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 2-yl)amino)-N-methylbenzamide

Step 1: Synthesis of N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide

Dissolve 2,4-dichloro-5-iodopyrimidine (1.2g, 4.37mmol) in DMF (12mL), and add DIPEA (1.3mL, 7.94mmol) and N-(3-(aminomethyl) at 0°C pyrazin-2-yl)-N-methylmethanesulfonamide (0.85g, 3.97mmol), react at 0°C for 2 hours, monitor the reaction to complete, add water, then add ethyl acetate for extraction, dry and concentrate the extract, and pass The concentrate was purified by column chromatography to obtain N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 1.0g, MS m/z(ESI): 454.8[M+H] ⁺ .

Step 2: Synthesis of N-(3-(((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazine -2-yl)-N-methylmethanesulfonamide

N-(3-(((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide (960 mg, 2.11 mmol), 3,3-diethoxyprop-1-yne (0.48mL, 2.75mmol), CuI (81mg, 0.42mmol), Pd(PPh) ₂ Cl ₂ (150mg, 0.21mmol) and DIPEA (10mL) were dissolved in DMF (10 mL), react at 65°C for 14 hours. After monitoring the reaction, add water, then add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain N-(3-(((2-chloro-5- (3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 950 mg, MS m/ z(ESI):455.0[M+H] ⁺ .

Step 3: Synthesis of N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -yl)-N-methylmethanesulfonamide

N-(3-(((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazine-2- (950 mg, 2.09 mmol) was dissolved in THF (9.5 mL), TBAF (12.6 mL, 12.55 mmol) was added, and the reaction was carried out at room temperature overnight. After the reaction was completed, water was added and ethyl acetate was added. Extract, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 400 mg. MS m/z(ESI):454.9[M+H] ⁺ .

Step 4: Synthesis of N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide

N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl) -N-Methylmethanesulfonamide (200mg, 0.44mmol) was dissolved in dioxane (2mL). Under ice bath, add concentrated hydrochloric acid (0.5mL) and react at room temperature for 30 minutes. After monitoring the reaction, add water and then add saturated The pH of the sodium carbonate solution was adjusted to neutral, ethyl acetate was added for extraction, the extract was dried and concentrated, and the concentrate was purified by column chromatography to obtain N-(3-((2-chloro-6-formyl-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 167 mg. MS m/z(ESI):380.9[M+H] ⁺ .

Step 5: Synthesis of N-(3-((2-chloro-6-((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine- 2-yl)-N-methylmethanesulfonamide

N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethyl Sulfonamide (167 mg, 0.44 mmol) and hydroxylamine hydrochloride (80 mg, 1.15 mmol) were dissolved in absolute ethanol (4 mL) and reacted at 50°C for 3 hours. After the reaction was completed, the reaction solution was concentrated, water was added, and then saturated sodium bicarbonate solution was added. Adjust the pH to neutral, filter, and wash the filter cake with water to obtain N-(3-((2-chloro-6-((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidine-7) -(yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 154 mg. MS m/z(ESI):395.9[M+H] ⁺ .

Step 6: Synthesis of N-(3-((2-chloro-6-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide

N-(3-((2-chloro-6-((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-methylmethanesulfonamide (154 mg, 0.39 mmol) was dissolved in DCE (3 mL). Under ice bath, CDI (316 mg, 1.95 mmol) was added, and the reaction was carried out at room temperature for 1.5 h. After the reaction was completed, the reaction solution was concentrated and then Purify by column chromatography to obtain N-(3-((2-chloro-6-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl) -N-methylmethanesulfonamide 132 mg. MS m/z(ESI):377.9[M+H] ⁺ .

Step 7: Synthesis of 4-((6-cyano-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)-N-methylbenzamide

N-(3-((2-chloro-6-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethyl Sulfonamide (100 mg, 0.27 mmol), 4-amino-N-methylbenzamide (47.8 mg, 0.32 mmol) and TsOH (50.5 mg, 0.27 mmol) were dissolved in sec-butanol (5 mL) and refluxed at 115°C. 5h, monitor that the reaction is complete and then cool to room temperature, add water, and then add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 4-((6-cyano-7-((3-(N- Methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide 33 mg. ¹ H NMR (400MHz, DMSO) δ10.10(s,1H),8.98(s,1H),8.61(d,J＝2.5Hz,1H),8.56(d,J＝2.5Hz,1H),8.23( d,J＝4.5Hz,1H),7.77(d,J＝8.9Hz,2H),7.71(d,J＝8.9Hz,2H),7.54(s,1H),5.80(s,2H),3.30– 3.25(m,3H),3.20(s,3H),2.75(d,J＝4.5Hz,3H).MS m/z(ESI):492.1[M+H] ⁺ .

Example 7

4-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 2-yl)amino)-N-methylbenzamide

Step 1: Synthesis of 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide

N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl) -N-methylmethanesulfonamide (70mg, 0.15mmol), 4-amino-N-methylbenzamide (27.8mg, 0.19mmol), BINAP (19mg, 0.03mmol), Pd ₂ (dba) ₃ (14mg ,0.02mmol) and sodium tert-butoxide (30mg, 0.31mmol) were dissolved in dioxane (7mL) under nitrogen protection and reacted at 100°C for 4.5h. After monitoring the reaction, add water, then add ethyl acetate for extraction, dry and concentrate The extract was purified by column chromatography to obtain 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)) Methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide 47 mg, MS m/z (ESI): 569.1 [M+H] ⁺ .

Step 2: Synthesis of 4-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)-N-methylbenzamide

4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2 ,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide (47mg, 0.08mmol) was dissolved in dioxane (0.7mL), and concentrated hydrochloric acid (0.09mL) was added under ice bath. , react at room temperature for 10 minutes. After monitoring the reaction, add water, then add saturated sodium carbonate solution to adjust the pH to neutral, add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 4-((6-methyl Acyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)- N-methylbenzamide 10 mg. ¹ H NMR (400MHz, DMSO) δ10.20 (s, 1H), 9.63 (s, 1H), 9.08 (s, 1H), 8.50 (d, J = 2.5Hz, 1H), 8.40 (d, J = 2.5 Hz,1H),8.23(d,J＝5.0Hz,1H),7.84(d,J＝8.9Hz,2H),7.71(d,J＝8.8Hz,2H),7.56(s,1H),5.98( s,2H),3.40(s,4H),3.20(s,3H),2.75(d,J＝4.5Hz,3H).MS m/z(ESI):495.1[M+H] ⁺ .

Example 8

4-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 2-yl)amino)-3-methoxy-N-methylbenzamide

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

Dissolve 3-methoxy-4-nitrobenzoic acid (600mg, 3.04mmol), HATU (1.73g, 4.57mmol) and DIPEA (1mL, 6.08mmol) in DMF (6mL), react at room temperature for 1h, add formazan Amine hydrochloride (400 mg, 6.08 mmol), react at room temperature for 3 hours. After monitoring the reaction, add water, then add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 3-methoxy-N-methyl. Base-4-nitrobenzamide 251 mg. MS m/z(ESI):211.0[M+H] ⁺ .

Step 2: Synthesis of 4-amino-3-methoxy-N-methylbenzamide

Dissolve 3-methoxy-N-methyl-4-nitrobenzamide (251mg, 1.20mmol), iron powder (167mg, 2.99mmol) and ammonium chloride (160mg, 2.99mmol) in methanol (12mL) and water (3 mL), react at 70°C for 12 hours, monitor that the reaction is complete, add a small amount of water to the reaction system, filter with suction, concentrate the filtrate, and purify the concentrate by column chromatography to obtain 4-amino-3-methoxy-N- Methylbenzamide 193 mg. MS m/z(ESI):181.1[M+H] ⁺ .

Step 3: Synthesis of 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide

N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl) -N-methylmethanesulfonamide (57mg, 0.13mmol), 4-amino-3-methoxy-N-methylbenzamide (27.2mg, 0.15mmol), BINAP (16mg, 0.03mmol), Pd ₂ (dba) ₃ (12 mg, 0.01 mmol) and sodium tert-butoxide (24 mg, 0.25 mmol) were dissolved in dioxane (3 mL), protected by nitrogen, and reacted at 100°C for 4.5 hours. After monitoring the reaction, add water and then add acetic acid. Extract with ethyl ester, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamide))pyridine)). Azin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide 40 mg, MS m/z ( ESI):599.1[M+H] ⁺ .

Step 4: Synthesis of 4-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide

4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2 ,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (40mg, 0.07mmol) was dissolved in dioxane (0.6mL), and added under ice bath Concentrated hydrochloric acid (0.07mL), react at room temperature for 30 minutes. After monitoring the reaction, add water, then add saturated sodium carbonate solution to adjust the pH to neutral, add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 4 -((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2 -Amino)-3-methoxy-N-methylbenzamide 12 mg. ¹ H NMR (400MHz, DMSO) δ9.64 (s, 1H), 9.06 (s, 1H), 8.50 (d, J = 2.5Hz, 1H), 8.44–8.37 (m, 2H), 8.31 (dd, J ＝11.9,6.5Hz,2H),7.56(s,1H),7.48(d,J＝1.8Hz,1H),7.38(m,1H),5.97(s,2H),3.91(s,3H),3.38 (s,3H),3.19(s,3H),2.77(d,J＝4.5Hz,3H).MS m/z(ESI):525.1[M+H] ⁺ .

Example 9

Synthesis of 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3 Preparation of -d]pyrimidin-2-yl)amino)-N-methylbenzamide

Step 1: Synthesis of N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-methylmethanesulfonamide

N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethyl Dissolve sulfonamide (45 mg, 0.12 mmol) in DCM (1 mL), add BAST (24 μL) under ice bath, and react at room temperature for 5 hours. After monitoring the reaction, add water, then add dichloromethane for extraction, dry and concentrate the extract, and column layer The concentrate was analyzed and purified to obtain N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -N-methylmethanesulfonamide 34 mg, MS m/z (ESI): 403.0 [M+H] ⁺ .

Step 2: Synthesis of 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide

N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N -Methylmethanesulfonamide (28mg, 0.07mmol), 4-amino-N-methylbenzamide (13mg, 0.08mmol) and p-toluenesulfonic acid (13mg, 0.07mmol) were dissolved in sec-butanol (3mL) , react at 115°C for 14 hours. After monitoring the reaction, the system is cooled to room temperature, water is added, and ethyl acetate is added for extraction. The extract is dried and concentrated, and the concentrate is purified by column chromatography to obtain 4-((6-(difluoromethyl)- 7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N- Methylbenzamide 17mg. ¹ H NMR (400MHz, DMSO) δ9.88 (s, 1H), 8.89 (s, 1H), 8.54 (d, J = 2.4Hz, 1H), 8.47 (d, J = 2.5Hz, 1H), 8.19 ( d,J＝4.5Hz,1H),7.75(d,J＝8.9Hz,2H),7.66(d,J＝8.9Hz,2H),7.19(s,1H),6.94(s,1H),5.81( s,2H),3.29(s,3H),3.20(s,3H),2.74(d,J＝4.5Hz,3H).MS m/z(ESI):517.0[M+H] ⁺ .

Example 10

4-((6-chloro-7-((2-(N-methylmethylsulfonamido)pyridin-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2- Preparation of (base)amino)-N-methylbenzamide

Step 1: Synthesis of 2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine

Dissolve 2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (1.0g, 5.8mmol) in POCl ₃ (10mL) solution at 0°C , slowly raise the temperature to 110°C and reflux and stir for 1 hour. After TLC detection, the reaction solution is concentrated and spun dry. Dilute and dissolve with DCM (20mL). Add saturated NaHCO ₃ solution (15mL) for extraction. Separate and combine the organic phases. Add saturated NaCl ( 20 mL) aqueous solution, the organic phase was washed with water, the organic phase was concentrated by rotation, and purified by column chromatography (PE/EA = from 0 to 50%) to obtain 600 mg of 2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine. MS m/z(ESI): 188.0[M+H] ⁺

Step 2: Synthesis of N-(3-((2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyridin-2-yl)-N-methylmethane Sulfonamide

At room temperature, 2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (600 mg, 3.2 mmol) and N-(3-(chloromethyl)pyridin-2-yl)-N- Methylmethanesulfonamide (900 mg, 3.8 mmol) was dissolved in DMF (5 mL) solution, and K ₂ CO ₃ (880 mg, 6.4 mmol) was added. The mixture was then heated to 45°C and stirred for 8 hours. After LCMS showed that the reaction was complete, the reaction mixture was quenched with water (100 mL) and extracted slowly with DCM (80 mL) twice. The combined organic phases were washed with brine (100 mL) and dried over _{anhydrous Na2SO4} . The dry product was filtered and evaporated to give a residue. The residue was purified by ISCO column chromatography (petroleum ether/ethyl acetate=3/1) to obtain N-(3-((2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine-7 -yl)methyl)pyridin-2-yl)-N-methylmethanesulfonamide 200 mg, MS m/z (ESI): 386.0 [M+H] ⁺ .

Step 3: Synthesis of 4-((6-chloro-7-((2-(N-methylmethylsulfonamido)pyridin-3-yl)methyl)-7H-pyrrolo[2,3-d] Pyrimidin-2-yl)amino)-N-methylbenzamide

To N-(3-((2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyridin-2-yl)-N-methyl To a solution of p-aminobenzamide (46.7 mg, 0.31 mmol) and TsOH·H ₂ O (49.3 mg, 0.26 mmol) in 2-butanol (5 mL) was added. The reaction solution was then heated to 120°C and stirred for 8 h. After TLC (DCM/MeOH=15:1) showed that the reaction was completed, the reaction solution was concentrated and dissolved in DCM (5 mL). The organic phase was washed with water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ , and the dried product was filtered and concentrated to obtain crude product. The crude product was purified by flash column chromatography (DCM/MeOH = from 100/1 to 20/1) to obtain 4-((6-chloro-7-((2-(N-methylmethylsulfonamide))pyridine- 3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide 51 mg. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.84 (s, 1H), 8.78 (s, 1H), 8.49 (dd, J = 4.7, 1.7Hz, 1H), 8.19 (d, J = 4.6Hz, 1H),7.79(d,J＝8.8Hz,2H),7.69(d,J＝8.8Hz,2H),7.36(dd,J＝7.8,4.7Hz,1H),7.13(dd,J＝7.8,1.6 Hz,1H),6.74(s,1H),5.58(s,2H),3.27(s,3H),3.17(s,3H),2.75(d,J＝4.5Hz,3H).MS m/z( ESI): 500.3[M+H] ⁺ .

Example 11

4-((6-(difluoromethyl)-7-(2-(dimethylphosphoryl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3 -Preparation of methoxy-N-methylbenzamide

Step 1: Synthesis of 2-(dimethylphosphinylo)benzonitrile

Dissolve 2-iodobenzene cyanide (6.90g, 30.1mmol) and dimethylphosphorus oxide (2.50g, 45.2mmol) in acetonitrile (150mL), and add Pd ₂ (dba) ₃ (900mg, 900mg, respectively) under nitrogen protection. 1.50mmol), Xant-Phos (1.20g, 3.01mmol), Cs ₂ CO ₃ (12.0g, 37.0mmol) and triethylamine (21ml, 150mmol), and then heated to 85°C for 19h. After TLC detects that the reaction is complete, the reaction solution is suction-filtered, the filter cake is washed three times with acetonitrile, and the filtrate is concentrated to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain 4.80 g of 2-(dimethylphosphinylo)benzonitrile as a yellow solid. MS m/z(ESI):180.2[M+H] ⁺ .

Step 2: Synthesis of (2-(aminomethyl)phenyl)dimethylphosphine oxide

Dissolve 2-(dimethylphosphinylo)benzonitrile (4.80g, 28.2mmol) in tetrahydrofuran (60ml), and cool to 0°C. Under nitrogen protection, borane tetrahydrofuran complex (84.6 ml, 1.00 mol/L, 84.6 mmol) was slowly added dropwise to the reaction system, and the temperature was slowly raised to room temperature and stirred for 2 hours. After TLC detected that the reaction was complete, the reaction solution was slowly quenched with methanol (100 mL) and concentrated. The crude product was purified by flash column chromatography (dichloromethane/methanol=10/1) to obtain 1.30 g of (2-(aminomethyl)phenyl)dimethylphosphine oxide as a yellow-brown gum. MS m/z(ESI):184.1[M+H] ⁺

Step 3: Synthesis of (2-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide

Dissolve 2,4-dichloro-5-iodopyrimidine (1.58g, 5.46mmol) and DIPEA (1.80mL, 10.9mmol) in DMF (10mL). After cooling to -5~0℃, add (2- A solution of (aminomethyl)phenyl)dimethylphosphine oxide (1.30 g, 5.46 mmol) in DMF (5 ml). After the dropwise addition is completed, react at 0°C for 2 hours. After monitoring the reaction, add water, then add methylene chloride for extraction, dry and concentrate the extract to obtain a crude product, which is passed through flash column chromatography (petroleum ether/ethyl acetate = 20/1) After purification, 1.35 g of (2-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide was obtained as a white solid. MS m/z (ESI): 422.9[M+H] ⁺ .

Step 4: Synthesis of (2-((((2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl)amino)methyl)phenyl)dimethyl Phosphine oxide

Dissolve (2-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide (1.35g, 3.20mmol) in DMF (50mL). Under nitrogen protection, add Pd(PPh ₃ )Cl ₂ (225 mg, 0.32 mmol), PPh ₃ (42 mg, 0.16 mmol), copper iodide (122 mg, 0.64 mmol), and triethylamine (1.33 mL, 9.61 mmol) respectively. and 3,3-diethoxyprop-1-yne (440 mg, 3.42 mmol). React at 60°C for 4 hours. After TLC monitoring, the reaction system is filtered and the filtrate is poured into 10% NH ₄ Cl aqueous solution (100 mL). , extracted with ethyl acetate, and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (dichloromethane/methanol=10/1) to obtain (2-((((2-chloro-5-(3,3-diethyl) Oxyprop-1-ynyl)pyrimidin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide 665 mg, MS m/z (ESI): 422.1 [M+H] ⁺ .

Step 5: Synthesis of (2-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)dimethyl phosphine oxide

(2-((((2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide ( 665mg, 1.58mmol) was dissolved in tetrahydrofuran (40mL), and TBAF (9.50mL, 9.50mmol, 1mol/L) was added. The temperature was raised to 65°C and the reaction was carried out for 2h. After TLC monitoring, the reaction solution was concentrated to obtain a crude product, which was passed through a flash column. Purification by chromatography (dichloromethane/methanol=20/1) gave (2-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-7 -1.59g of crude product -methyl)phenyl)dimethylphosphine oxide, brown oil. MS m/z (ESI): 422.1 [M+H] ⁺ .

Step 6: Synthesis of 2-chloro-7-(2-(dimethylphosphoryl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde

(2-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)dimethylphosphine oxide ( 1.59g, crude product) was dissolved in 1,4-dioxane (13mL), concentrated hydrochloric acid (8.00mL, 12mol/L) was added in batches, stirred at room temperature for 30min, LCMS monitored that the reaction was complete, and water (30mL) was added to the reaction solution. Dilute and then extract 3 times with ethyl acetate (50 mL). The organic phase was washed with saturated brine, then dried over anhydrous sodium sulfate, the product was filtered and dried, and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (dichloromethane/methanol=15/1) to obtain 2-chloro-7-(2-(dimethylphosphoryl)benzyl)-7H-pyrrolo[2,3-d ] Pyrimidine-6-carbaldehyde crude product 980mg, brown oily substance. MS m/z(ESI):348.1[M+H] ⁺ .

Step 7: Synthesis of (2-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)dimethylphosphine oxide

Dissolve 2-chloro-7-(2-(dimethylphosphoryl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (980 mg, crude product) in dichloromethane (20 mL) , cooled to 0°C, then DAST (750 mL) was added dropwise and the reaction solution was raised to room temperature and stirred for 2 h. After monitoring the reaction with LCMS, the reaction solution was slowly dropped into water to quench, and then extracted three times with ethyl acetate (50 mL). The organic phase was dried with anhydrous sodium sulfate, and the product was dried by suction filtration and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (dichloromethane/methanol=20/1) to obtain 2-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)methyl)phenyl)dimethylphosphine oxide 128 mg, light yellow solid. MS m/z(ESI):370.1[M+H] ⁺ .

Step 8: Synthesis of 4-amino-3-methoxy-N-methylbenzamide

Dissolve 4-amino-3-methoxybenzoic acid (2.00g, 11.9mmol) and methylamine hydrochloride (8.08g, 119.6mmol) in DMF (100mL), and add sodium carbonate (12.7g, 119.6mmol) in batches ), add HATU (9.10g, 23.9mmol) in batches, and react at room temperature overnight. After the reaction was monitored by TLC, the reaction solution was added to water, and then extracted three times with ethyl acetate (50 mL). The organic phase was dried with anhydrous sodium sulfate, and the product was dried by suction filtration and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain 1.42 g of 4-amino-3-methoxy-N-methylbenzamide as a white solid. MS m/z(ESI):181.1[M+H] ⁺ .

Step 9: Synthesis of 4-((6-(difluoromethyl)-7-(2-(dimethylphosphoryl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl) Amino)-3-methoxy-N-methylbenzamide

4-Amino-3-methoxy-N-methylbenzamide (50 mg, 0.28 mmol), 2-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)methyl)phenyl)dimethylphosphine oxide (100 mg, 0.27 mmol) and p-toluenesulfonic acid (55 mg, 0.32 mmol) were dissolved in n-butanol (2.00 mL). The reaction solution was heated to 115°C and allowed to react overnight. After LCMS detected that the reaction was complete, the reaction solution was poured into water (10 mL) and extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by flash column chromatography (dichloromethane/methanol=20/1) and pre-TLC to obtain 4-((6-(difluoromethyl)-7-(2-(dimethylphosphoryl)benzyl) base)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide 3.5 mg, yellow solid. MS m/z(ESI):513.2[M+H] ⁺ .

Example 12

4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazine-2-alkyl)methyl)-7H-pyrrolo[2,3 Preparation of -d]pyrimidine-2-alkyl)amino)-3-methoxy-N-methylbenzamide

Step 1: Synthesis of N-(3-cyanopyrazin-2-yl)-N-methylmethanesulfonamide

3-Chloropyrazine-2-nitrile (8.40g, 60.2mmol), N-methylmethyl-sulfamate (8.00g, 73.3mmol) and K ₂ CO ₃ (9.00g, 65.1mmol) were dissolved in acetonitrile ( 100 mL) mixture was stirred at 85°C for 12 hours. TLC (petroleum ether/ethyl acetate=1/1) showed that after the reaction was completed, the reaction liquid was suction filtered, the filter cake was washed three times with ACN (50 mL), and the filtrate was concentrated to obtain a crude product. The crude product was purified by flash chromatography column (FCC, petroleum ether/ethyl acetate = 3/1) to obtain N-(3-cyanopyrazin-2-yl)-N-methylmethanesulfonamide (13.3g, crude product) . MS m/z(ESI): =213.04[M+H] ⁺ .

Step 2: Synthesis of N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide

To a mixture of N-(3-cyanopyrazin-2-yl)-N-methylmethanesulfonamide (13.3 g) and 1 M HCl (2.4 mL) in MeOH (150 mL) at room temperature was added 10% Pd/C(5.50g). H ₂ was replaced three times, and then the reaction solution was stirred for 12 h in a H ₂ (15 psi) environment. After LCMS showed that the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated to obtain crude product. The crude product was slurried in DCM (100 mL), filtered with suction, and dried to obtain N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide (HCl, 5.26 g, 34.6%) . MS m/z(ESI): 217.04[M+H] ⁺ .

Step 3: Synthesis of N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide

At 0°C, N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide (HCl, 5.26g, 20.83mmol), 2,4-dichloro-5- A solution of iodopyrimidine (5.73 g, 20.84 mmol) and DIPEA (6.88 mL, 41.7 mmol) in DMF (60 mL) was stirred for 2 h. After TLC (petroleum ether/ethyl acetate=5/1) showed that the reaction was completed, the reaction mixture was poured into water (150 mL) and extracted twice with ethyl acetate (100 mL). The combined organic phases were washed three times with saturated brine (100 mL), and then dried over anhydrous Na ₂ SO _4. The dried product was filtered and rotary evaporated to obtain the crude product. The crude product was purified by FCC (petroleum ether/ethyl acetate = 10/1) to obtain N-(3-(((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazine-2 -N-methylmethanesulfonamide (5.88g, 12.9mmol, 62.1%). MS m/z (ESI): 454.9 [M+H] ⁺ .

Step 4: Synthesis of N-(3-(((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazine -2-yl)-N-methylmethanesulfonamide

Under nitrogen protection, to To a solution of 5.88g, 12.9mmol) and 3,3-diethoxyprop-1-yne (2.49g, 19.4mmol) in DMF (80mL), Pd(PPh ₃ ) ₂ Cl ₂ (907mg, 1.29mmol) was added respectively. , CuI (494mg, 2.59mmol), PPh ₃ (170mg, 0.644mmol) and TEA (5.40mL, 38.8mmol). Then under nitrogen protection, the reaction solution was stirred in a 60°C oil bath for 2h. LCMS showed that after the reaction was completed The reaction solution was filtered, poured into water (200 mL), and extracted twice with ethyl acetate (100 mL). The combined organic phases were washed three times with saturated brine (100 mL), and then dried over anhydrous Na ₂ SO ₄ , then the dried product was suction filtered and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain N-(3-(((2-chloro-5-(3, 3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide (8.00 g, crude product). MS m/z(ESI): 455.0[M+H] ⁺ .

Step 5: Synthesis of N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -yl)-N-methylmethanesulfonamide

To N-(3-(((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl) at 25°C To a solution of pyrazin-2-yl)-N-methylmethanesulfonamide (8.00 g, crude product) in THF (40 mL) was added TBAF (1 M, 78 mL, 78.0 mmol). The reaction solution was then stirred in a 60°C oil bath for 1 h. After TLC (petroleum ether/ethyl acetate=5/1) showed that the reaction was completed, the reaction solution was concentrated and dissolved in ethyl acetate (200 mL). The organic phase was washed three times with water (100 mL) and then once with saturated brine (100 mL). The organic phase was dried over anhydrous _Na2SO4 , and then the dried product was filtered and _concentrated to obtain crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=10/1) to obtain N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2, 3-d]pyrimidine-7-acyl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide (2.53 g, 5.56 mmol, 43.0%). MS m/z(ESI): 455.0[M+H] ⁺ .

Step 6: Synthesis of N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide

To N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyridine at 25°C To a solution of oxazin-2-yl)-N-methylmethanesulfonamide (2.53 g, 5.56 mmol) in 1,4-dioxane (40 mL) was added 1 M aqueous HCl (1 M, 16 mL). The reaction solution was then stirred at 25°C for 2 h. After LCMS showed that the reaction was complete, the reaction mixture was poured into water (80 mL) and extracted twice with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous Na ₂ SO ₄ . The dry product was filtered and evaporated to give N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-methylmethanesulfonamide (2.48g, crude product). MS m/z(ESI): 381.0[M+H] ⁺ .

Step 7: Synthesis of N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-methylmethanesulfonamide

To N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)- To a solution of N-methylmethanesulfonamide (2.48 g, crude product) in DCM (40 mL) was slowly added dropwise DAST (2.50 mmol, 19.3 mmol). The reaction solution was then stirred at 25°C for 2 h. After LCMS showed that the reaction was completed, the reaction solution was slowly dropped into water (100 mL) to quench, and then extracted twice with DCM (80 mL). The combined organic phases were washed with brine (100 mL) and dried over _{anhydrous Na2SO4} . The dried product was suction filtered and concentrated to obtain crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=10/1) to obtain N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3- d] Pyrimidine-7-acyl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide (1.38 g, 3.43 mmol, 61.7%, two-step yield). MS m/z(ESI): 403.0[M+H] ⁺ .

Step 8: Synthesis of N-(3-((6-(difluoromethyl)-2-((1-isopropyl-3-methyl-1H-pyrazol-5-yl)amino)-7H-pyrrole) And[2,3-d]pyrimidine-7-acyl)methyl)pyrazine-2-alkyl)-N-methylmethanesulfonamide

Under nitrogen protection, to N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-acyl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (100 mg, 0.248 mmol) and 1,4-1-isopropyl-3-methyl-1H-pyrazole-5-amine (52.0 mg, 0.372 mmol) Pd(OAc) ₂ (12 mg, 0.05 mmol), BINAP (62 mg, 0.099 mmol) and Cs ₂ CO ₃ (242 mg, 0.774 mmol) were added to the dioxane (3 mL) solution. Then, under nitrogen protection, the reaction solution was stirred for 12 h in an environment of 120°C. After LCMS showed that the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), and then dried over anhydrous Na ₂ SO _4. The dried product was suction filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to obtain N-(3-((6-(difluoromethyl)-2-((1-isopropyl-3-methyl) base-1H-pyrazol-5-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-acyl)methyl)pyrazine-2-alkyl)-N-methylmethanesulfonamide 56mg. ¹ HNMR (400MHz, DMSO-d ₆ )9.07(s,1H),8.75(s,1H),8.51(d,J＝4.00Hz,1H),8.45(d,J＝4.00Hz,1H),7.16( m,1H),5.73(m,1H),5.62(s,2H),3.15(d,J＝8Hz,6H),1.17(d,J＝8Hz,6H).MS m/z(ESI): 506.1 [M+H] ⁺ .

Example 13

N-(3-((6-(difluoromethyl)-2-((2-oxoindole-6-alkyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7- Preparation of methyl)pyrazin-2-yl)-N-methylmethanesulfonamide

Under nitrogen protection, to N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-acyl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (80 mg, 0.199 mmol) and 6-aminoindol-2-one (45.0 mg, 0.298 mmol) in 1,4-dioxane (2 mL), respectively Pd(OAc) ₂ (9 mg, 0.04 mmol), BINAP (50 mg, 0.08 mmol) and Cs ₂ CO ₃ (195 mg, 0.579 mmol) were added. Then, under nitrogen protection, the reaction solution was stirred for 12 h in an environment of 120°C. After LCMS showed that the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , and the dried product was suction-filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to obtain N-(3-((6-(difluoromethyl)-2-((2-oxoindole-6- Alkyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 12 mg. MS m/z(ESI): 515.1[M+H] ⁺ .

Example 14

N-(3-((6-(difluoromethyl)-2-((2-methoxy-4-morpholinophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 7-yl)methyl)pyrazine-2alkyl)-N-methylmethanesulfonamide

Under nitrogen protection, to N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-acyl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (80 mg, 0.199 mmol) and 2-methoxy-4-morpholinoaniline (62.2 mg, 0.298 mmol) in 1,4-dioxane (2 mL) Pd(OAc) ₂ (9mg, 0.04mmol), BINAP (50mg, 0.08mmol) and Cs ₂ CO ₃ (195mg, 0.579mmol) were added to the solution respectively. Then, under nitrogen protection, the reaction solution was stirred for 12 h in an environment of 120°C. After LCMS showed that the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phase was washed with saturated brine (50 mL), and the organic phase was dried over anhydrous Na ₂ SO _4. The dried product was then suction-filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to obtain N-(3-((6-(difluoromethyl)-2-((2-oxoindole-6- Alkyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 45 mg. ¹ HNMR (400MHz, DMSO-d ₆ )8.74(s,1H),8.54(d,J＝4.00Hz,1H),8.48(d,J＝4.00Hz,1H),7.84(s,1H),7.69( d,J＝8.00Hz,1H),7.17(t,J＝64.0Hz,1H),6.86(s,1H),6.61(s,1H),6.36–6.33(m,1H),5.70(m,2H ),3.77(s,3H),3.74(t,J＝4.00Hz,4H),3.24(s,3H),3.18(s,3H),3.05(t,J＝4.00Hz,4H).MS m/ z(ESI): 575.1[M+H] ⁺ .

Example 15

N-(3-((6-(difluoromethyl)-2-((2-methoxy-5-methyl-4-(1-methyl-1,2,3,6-tetrahydropyridine) Preparation of -4-alkyl)phenyl]amino))-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide

Under nitrogen protection, to N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-acyl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (80 mg, 0.199 mmol) and 2-methoxy-5-methyl-4-(1-methyl-1,2,3,6-tetrahydropyridine- To a solution of 4-yl)aniline (69.0 mg, 0.298 mmol) in 1,4-dioxane (2 mL), Pd(OAc) ₂ (9 mg, 0.04 mmol), BINAP (50 mg, 0.08 mmol) and Cs ₂ were added respectively. CO ₃ (195 mg, 0.579 mmol). Then, under nitrogen protection, the reaction solution was stirred for 12 h in an environment of 120°C. After LCMS showed that the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), and then dried over anhydrous Na ₂ SO _4. The dried product was then suction-filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to obtain N-(3-((6-(difluoromethyl)-2-((2-methoxy-5-methyl) Base-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-alkyl)phenyl]amino))-7H-pyrrolo[2,3-d]pyrimidin-7-yl )methyl)pyrazin-2-yl)-N-methylmethanesulfonamide. ¹ HNMR (400MHz, DMSO-d ₆ )8.82(s,1H),8.54(d,J＝4Hz,1H),8.48(d,J＝4Hz,1H),7.99(s,1H),7.93(s, 1H),8.22(s,1H),7.14(t,J＝64.0Hz,1H),6.90(s,1H),6.68(s,1H),3.78(s,3H),3.25(s,3H), 3.17(s,5H),2.75(s,2H),2.42(s,3H),2.36(s,2H),2.07(s,3H),1.90(s,1H). MS m/z(ESI): 599.2[M+H] ⁺ .

Example 16

4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazine-2-alkyl)methyl)-7H-pyrrolo[2,3 Preparation of -d]pyrimidine-2-alkyl)amino)-3-methoxy-N-methylbenzamide

Under nitrogen protection, to N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-acyl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (100 mg, 0.248 mmol) and 4-amino-3-methoxy-N-methylbenzamide (67.1 mg, 0.372 mmol) of 1,4-dioxo Pd(OAc) ₂ (12 mg, 0.05 mmol), BINAP (62 mg, 0.099 mmol) and Cs ₂ CO ₃ (242 mg, 0.774 mmol) were added to the six-ring (3 mL) solution. Then, under nitrogen protection, the reaction solution was stirred for 12 h in an environment of 120°C. After LCMS showed that the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), and then dried over anhydrous Na ₂ SO _4. The dried product was then suction-filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to obtain 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamide) )pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2-alkyl)amino)-3-methoxy-N-methylbenzamide 45 mg. ¹ HNMR(400MHz, DMSO-d ₆ )8.90(s,1H),8.55(d,J＝2.56Hz,1H),8.47(d,J＝4.00Hz,1H),8.31-8.26(m,1H), 8.09(s,1H),7.47(d,J＝2.00Hz,1H),7.37-7.34(m,1H),7.21(d,J＝52Hz,1H),5.96(s,1H),3.92(s, 3H), 3.30 (s, 3H), 2.78 (d, J = 4.00Hz, 1H). MS m/z(ESI): 547.1[M+H] ⁺ .

Example 17

(4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazine-2-alkyl)methyl)-7H-pyrrolo[2, Preparation of 3-d]pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

Under nitrogen protection, to N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-acyl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (40 mg, 0.099mmol) and 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)benzamide (35.0 mg , 0.149mmol) in a solution of 1,4-dioxane (1mL), Pd(OAc) ₂ (5mg, 0.02mmol), BINAP (25mg, 0.04mmol) and Cs ₂ CO ₃ (97mg, 0.298mmol) were added respectively. . Then, under nitrogen protection, the reaction solution was stirred for 12 h in an environment of 120°C. After LCMS showed that the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), and then dried over anhydrous Na ₂ SO _4. The dried product was then suction-filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to obtain 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamide) )pyrazine-2-alkyl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidine-4 -base) benzamide 23 mg. ¹ HNMR (400MHz, DMSO-d ₆ ) 8.90 (s, 1H), 8.52 (m, 1H), 8.45 (d, J = 4Hz, 1H), 8.31 (d, J = 12Hz, 1H), 8.22 (m, 1H),8.09(s,1H),7.45(m,1H),7.39-7.37(m,1H),7.18(t,J＝56Hz,1H),5.79(s,2H),3.90(s,3H) ,3.27(s,3H),3.18(s,3H),1.94-1.87(m,2H),1.75-1.72(m,2H),1.27(m,1H),1.24-1.20(m,5H),0.85 -0.70(m,2H).MS m/z(ESI): 630.2[M+H] ⁺ .

Example 18

7-((6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N- Preparation of methyl-2,3-dihydrobenzofuran-4-carboxamide

Step 1: Synthesis of 2-chloro-5-iodo-N-(4-methoxybenzyl)pyrimidin-4-amine

A solution of PMBNH ₂ (5.00 g, 36.4 mmol), 2,4-dichloro-5-iodopyrimidine (10.0 g, 36.4 mmol) and DIPEA (9.00 mL, 54.6 mmol) in DMF (100 mL) was dissolved at 0°C. Stir for 2h. After TLC (petroleum ether/ethyl acetate=5/1) showed that the reaction was completed, the reaction mixture was poured into water (200 mL) and extracted twice with ethyl acetate (100 mL). The combined organic phase was washed three times with saturated brine (100 mL), and then dried over anhydrous Na ₂ SO ₄ . The dried product was then filtered and concentrated to obtain a crude compound. The crude product was passed through flash column chromatography (petroleum ether/ethyl acetate =10/1) purification, obtaining 12.0g of 2-chloro-5-iodo-N-(4-methoxybenzyl)pyrimidin-4-amine. MS m/z (ESI): 375.9[M+H] ⁺ .

Step 2: Synthesis of 2-chloro-5-(3,3-diethoxy-1-propyl-1-alkyl)-N-(4-methoxybenzyl)pyrimidin-4-amine

2-Chloro-5-iodo-N-(4-methoxybenzyl)pyrimidin-4-amine (12.0g, 31.95mmol) and 3,3-diethoxypropyne (6.41g, 50.0mmol) In DMF (120 mL), Pd(PPh ₃ )Cl ₂ (2.34 g, 3.20 mmol), CuI (1.27 g, 6.66 mmol), PPh ₃ (436 mg, 1.66 mmol) and TEA were added to the mixture at 25°C. (10mL, 100mmol). The reaction mixture was then stirred at 60 °C for 2 h under nitrogen atmosphere. After LCMS showed that the reaction was complete, the reaction mixture was poured into water (200 mL) and extracted twice with ethyl acetate (100 mL). The combined organic phases were washed 3 times with brine (100 mL), dried over anhydrous _Na2SO4 , and the dried product was filtered and _evaporated to give a residue. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain 2-chloro-5-(3,3-diethoxy-1-propyl-1-yl)-N- (4-Methoxybenzyl)pyrimidin-4-amine 13.0g. MS m/z(ESI): 376.0[M+H] ⁺ .

Step 3: Synthesis of 2-chloro-6-(diethoxymethyl)-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine

To 2-chloro-5-(3,3-diethoxy-1-propyl-1-yl)-N-(4-methoxybenzyl)pyrimidin-4-amine (13.0 g, crude) in THF (50 mL) was added TBAF (1 M, 105 mL, 105 mmol). The reaction mixture was stirred at 60 °C for 1 h. After TLC (petroleum ether/ethyl acetate=5/1) showed that the reaction was completed, the reaction solution was concentrated and dissolved in EtOAc (250 mL). The above solution was washed three times with water (100 mL) and then washed once with saturated salt brine (150 mL). The organic phase was dried over anhydrous _Na2SO4 , and the dried product was filtered and _evaporated to give the crude compound. The crude compound was purified by flash column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain 2-chloro-6-(diethoxymethyl)-7-(4-methoxybenzyl)-7H -pyrrolo[2,3-d]pyrimidine 7.93g. MS m/z(ESI): 376.0[M+H] ⁺ .

Step 4: Synthesis of 2-chloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde

To 2-chloro-6-(diethoxymethyl)-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine (7.93g, 21.1 6 M hydrochloric acid (36 mL) was added to a solution of 1,4-hexacyclic ring (80 mL). The reaction solution was then stirred at 25°C for 1 h. After LCMS showed that the reaction was completed, the reaction solution was poured into water (100 mL) and extracted twice with EtOAc (150 mL). The combined organic phases were washed with brine (200 mL) and dried over _{anhydrous Na2SO4} . The dry product was filtered and evaporated to give 2-chloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (5.34 g, crude). MS M/Z(ESI): 302.0(M+H) ⁺ .

Step 5: Synthesis of 2-chloro-6-(difluoromethyl)-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2-chloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (5.34 g, crude product) in DCM (50 mL) at 0°C DAST (7.00 mL, 53.1 mmol) was added dropwise. After the dropwise addition is completed, the temperature of the reaction solution is raised to 25°C and stirred for 2 hours. After LCMS showed that the reaction was completed, the reaction mixture was slowly quenched with water (100 mL) and extracted twice with DCM (80 mL). The organic phases were combined, washed with saturated brine (100 mL), and then dried over anhydrous Na ₂ SO ₄ . The dried product was concentrated to obtain crude compound. The crude compound was purified by flash column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain 2-chloro-6-(difluoromethyl)-7-(4-methoxybenzyl)-7H-pyrrole. And [2,3-d]pyrimidine 4.50g. MS m/z(ESI) ⁺ :324.0[M+H] ⁺ . Step 6: Synthesis of 2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine

To 2-chloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (4.50 g, 13.9 mmol) in ACN/H ₂ at 0°C To a mixture of O=5:1 (60 mL), CAN (56 g, 992 mmol) was added. The mixture was then stirred at 0°C for 12 hours. After LCMS showed that the reaction was complete, the reaction mixture was quenched with water (100 mL) and extracted slowly with DCM (80 mL) twice. The combined organic phases were washed with brine (100 mL) and dried over _{anhydrous Na2SO4} . The dry product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate = 10/1) to obtain 2.0 g of 2-chloro-6-difluoromethyl-7H-pyrrolo[2,3-d]pyrimidine, MS m/z ( ESI): 204.02(M+H) ⁺ .

Step 7: Synthesis of (3-(methylsulfonyl)phenyl)methanol

To a mixture of methyl 3-(methylsulfonyl)benzoate (4.0 g, 18.6 mmol) in THF (60 mL) at 25°C was added LAH (780 mg, 20.5 mmol). The mixture was then stirred at 25°C for 12 hours. After LCMS showed that the reaction was complete, the reaction mixture was quenched with water (100 mL) and extracted slowly with DCM (80 mL) twice. The combined organic phases were washed with brine (100 mL) and dried over _{anhydrous Na2SO4} . The dry product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate = 5/1) to obtain 3.0 g of (3-(methylsulfonyl)phenyl)methanol, MS m/z (ESI): 186.0 [M+H] ⁺ .

Step 8: Synthesis of 1-(chloromethyl)-3-(methylsulfonyl)benzene

To a mixture of methyl(3-(methylsulfonyl)phenyl)methanol (3.0 g 16.1 mmol) in CH ₂ Cl ₂ (20 mL) was added SOCl ₂ (2.3 g, 20.5 mmol) at 25°C. The mixture was then stirred at 25°C for 12 hours. After LCMS showed that the reaction was complete, the reaction mixture was quenched with water (100 mL), and then slowly extracted twice with DCM (80 mL2). The combined organic phases were washed with brine (100 mL) and dried over _{anhydrous Na2SO4} . The dry product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate = 5/1) to obtain 2.8 g of 1-(chloromethyl)-3-(methylsulfonyl)benzene, MS m/z (ESI): 186.0 [M +H] ⁺ .

Step 9: Synthesis of 2-chloro-6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine

2-Chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 9.8 mmol) and 1-(chloromethyl)-3-(methylsulfonyl) A mixture of benzene (1.98g) was dissolved in ACN (20mL), K ₂ CO ₃ (2.7g, 19.6mmol) was added, and stirred at 45°C for 8 hours. After LCMS showed that the reaction was complete, the reaction mixture was quenched with water (100 mL), and then slowly extracted with DCM (80 mL) twice. The combined organic phases were washed with brine (100 mL) and dried over _{anhydrous Na2SO4} . The dry product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate=3/1) to obtain 2-chloro-6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrole 2.8g of [2,3-d]pyrimidine, MS m/z (ESI): 371.02[M+H] ⁺ .

Step 10: Synthesis of 7-((6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino )-N-methyl-2,3-dihydrobenzofuran-4-carboxamide

To 2-chloro-6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.27 mmol) and 7-amino-N- was added methyl 2,3,3-dihydrobenzofuran-4-carboxamide (77.8 mg, 0.41) in 1,4-dioxane (3 mL) mmol), Cs ₂ CO ₃ (260 mg, 0.81 mmol), Pd(OAc) ₂ (12 mg, 0.054 mmol) and BINAP (67 mg, 0.11 mmol) were added. The mixture was then stirred at 120°C for 8 hours. After LCMS showed that the reaction was complete, the reaction mixture was cooled and quenched with water (100 mL), and then slowly extracted twice with EA (80 mL). The organic phases were combined, washed with brine (100 mL), and dried over anhydrous Na ₂ SO ₄ . The dry product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate=3/1) to obtain 7-((6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrole) And[2,3-d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide 30 mg. ¹ HNMR (400MHz, DMSO-d ₆ )8.91 (s, 1H), 8.32 (d, J = 8Hz, 1H), 8.26-8.23 (m, 1H), 8.14 (s, 1H), 7.83-7.77 (m, 2H),7.60-7.56(m,1H),7.45-7.38(m,3H),7.31(t,J＝52Hz,1H),7.00(m,1H),5.60(s,2H),3.12(s, 3H), 2.76 (d, J=8Hz, 3H).MS m/z (ESI): 527.02[M+H] ⁺ .

Example 19

4-((6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3- Preparation of methoxy-N-methylbenzamide

Under nitrogen protection conditions, 2-chloro-6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.27mmol) and 4-amino-3-methoxy-N-methylbenzamide (69mg, 0.41mmol) were dissolved in 1,4-dioxane (3mL), and Cs ₂ CO ₃ (260mg, 0.81 mmol), Pd(OAc) ₂ (12m, 0.054mmol) and BINAP (67mg, 0.11mmol), then the reaction system was slowly heated to 120°C and stirred for 8 hours. After LCMS showed that the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (100 mL), and slowly extracted twice with ethyl acetate (80 mL). The organic phases were combined, washed with brine (100 mL), and dried over anhydrous Na ₂ SO ₄ . The dry product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate=1/1) to obtain 4-((6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrole) And[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide 75 mg. ¹ HNMR (400MHz, DMSO-d ₆ )8.85(s,1H),8.33(s,1H),8.05-8.01(m,1H),7.83-7.74(m,3H),7.60(t,J＝8Hz, 1H),7.41-7.38(m,3H),7.28(t,J＝56Hz,1H),7.10(d,J＝8Hz,1H),6.97-6.96(m,1H),4.49(t,J＝8Hz ,1H),3.40(t,J＝8Hz,2H),2.72(d,J＝8Hz,3H).MS m/z(ESI): 515.02[M+H] ⁺ .

Example 20

7-((6-(Difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- Preparation of d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide method

Under nitrogen protection, to N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-acyl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (100 mg, 0.248mmol) and 7-amino-N-methyl-2,3-dihydrobenzofuran-4carboxamide (71.5mg, 0.372mmol) , Pd(OAc) ₂ (12 mg, 0.05 mmol), BINAP (62 mg, 0.099 mmol) and Cs ₂ CO ₃ (242 mg, 0.774 mmol) were added to the 4-dioxane (3 mL) solution. Then, under nitrogen protection, the reaction solution was stirred for 12 h in an environment of 120°C. After LCMS showed that the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phase was washed with saturated brine (50 mL), and the organic phase was dried over anhydrous Na ₂ SO _4. The dried product was then suction-filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to obtain 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamide) )pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxy Amide 76 mg. ¹ HNMR(400MHz, DMSO-d ₆ )8.90(s,1H),8.55(d,J＝2.56Hz,1H),8.84(s,1H),8.55-8.48(m,2H),8.22(s,1H ),8.10(m,1H),7.76(d,J＝8.00Hz,1H),7.32(d,J＝52Hz,1H),7.08(d,J＝8Hz,1H),6.92(s,1H), 5.76(s,2H),4.53(t,J＝12.0Hz,2H),3.42(t,J＝8.00Hz,2H),3.33(s,3H),3.25(s,3H),2.74(d,J =4.00Hz,3H). MS m/z(ESI): 559.1[M+H] ⁺ .

Example 21

4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonylamino)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- Preparation of d]pyrimidin-2-yl)amino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

Under nitrogen protection, to N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-acyl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (100 mg, 0.25 mmol) and 4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide Pd ₂ (dba) ₃ (23.8 mg, 0.025 mmol), BINAP (31.2 mg, 0.05 mmol) and tBuONa (48.0 mg) were added to a solution of 1,4-dioxane (10 mL) (88.6 mg, 0.3 mmol). ,0.5mmol). Then, under nitrogen protection, the reaction solution was stirred for 12 h in an environment of 120°C. After LCMS showed that the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL), and then dried over anhydrous Na ₂ SO _4. The dried product was then suction-filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate = 0/100) to obtain 4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzene Formamide 56mg. ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.95 (s, 1H), 8.55 (d, J = 2.4Hz, 1H), 8.47 (d, J = 2.4Hz, 1H), 8.24 (d, J = 13.1 Hz,1H),8.19(s,1H),7.94(d,J＝5.1Hz,1H),7.33–7.07(m,2H),6.99(s,1H),5.83(s,2H),3.90(s ,3H),3.78(s,1H),3.30(s,5H),3.19(s,4H),2.91(s,2H),2.33(s,5H),1.83(d,J＝10.6Hz,2H) ,1.62(dd,J＝21.2,10.8Hz,2H). MS m/z(ESI): 648.2[M+H] ⁺ .

Example 22

7-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide

Step 1: Synthesis of 4-bromo-2,3-dihydrobenzofuran-7-amine

Dissolve 2,3-dihydrobenzofuran-7-amine (5g, 40.0mmol) in DMF (60mL), add NBS (7.2g, 40.7mmol) in batches, and react at room temperature for 3 hours. After monitoring the reaction, add water. Then add dichloromethane for extraction, dry and concentrate the extract, and then obtain 7.2g of 4-bromo-2,3-dihydrobenzofuran-7-amine through column chromatography, MS m/z (ESI): 214.0 [M+ H] ⁺ .

Step 2: Synthesis of ethyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate

4-Bromo-2,3-dihydrobenzofuran-7-amine (3.5g, 16.28mmol), dicobalt octacarbonyl (5.5g, 16.28mmol), palladium acetate (0.18g, 0.81mmol), XantPhos ( 0.94g, 1.63mmol) and DMAP (7.9g, 65.12mmol) were dissolved in toluene (26mL) and ethanol (9mL), protected by nitrogen, reacted at 105°C for 12h, after monitoring the reaction, add water, then add ethyl acetate for extraction, and dry The extract was concentrated and purified by column chromatography to obtain 1.84 g of 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid ethyl ester, MS m/z (ESI): 208.1 [M+H] ⁺ .

Step 3: Synthesis of 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid

Dissolve 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid ethyl ester (500mg, 2.42mmol) in THF (10mL) and water (10mL), add NaOH (290mg, 7.25mmol), 60 The reaction was carried out overnight at ℃. After monitoring the reaction to complete, the reaction solution was concentrated, 2M hydrochloric acid solution was added to adjust the pH to weak acidity, and then filtered with suction to obtain 340 mg of 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid. MS m/z(ESI):180.0[M+H] ⁺ .

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

Dissolve 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid (340mg, 1.90mmol), HATU (866mg, 2.28mmol) and methylamine hydrochloride (256mg, 3.80mmol) in DMF (5mL ), add DIPEA (1.26mL, 7.60mmol), react at room temperature for 12h, monitor the reaction to complete, add water, then add dichloromethane for extraction, dry and concentrate the extract, and then obtain 3-methoxy-N-methane through column chromatography. Base-4-nitrobenzamide 300 mg, MS m/z (ESI): 193.1[M+H] ⁺ .

Step 5: Synthesis of 7-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide

N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl) -N-Methylmethanesulfonamide (220mg, 0.48mmol), 3-methoxy-N-methyl-4-nitrobenzamide (140mg, 0.73mmol), BINAP (60mg, 0.10mmol), Pd ₂ (dba) ₃ (45 mg, 0.05 mmol) and sodium tert-butoxide (94 mg, 0.97 mmol) were dissolved in dioxane (22 mL), protected by nitrogen, and reacted at 100°C for 4.5 hours. After monitoring the reaction, add water and then add acetic acid. Extract with ethyl ester, dry and concentrate the extract, and then purify by column chromatography to obtain 7-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamide))pyridine Azin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide 210 mg , MS m/z(ESI):611.2[M+H] ⁺ .

Step 6: Synthesis of 7-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide

7-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2 ,3-d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide (210 mg, 0.34 mmol) was dissolved in dioxane (2 mL) and water (2mL), add TFA (1mL) under ice bath, and react at room temperature for 1 hour. After monitoring the reaction, add water, then add dichloromethane for extraction, dry and concentrate the extract, and then purify it by column chromatography to obtain 7-((6 -Formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino )-N-methyl-2,3-dihydrobenzofuran-4-carboxamide 27 mg. ¹ H NMR (500MHz, DMSO) δ9.58 (s, 1H), 8.98 (s, 1H), 8.75 (s, 1H), 8.47 (d, J = 2.2Hz, 1H), 8.39 (d, J = 2.3 Hz,1H),8.12(d,J＝4.6Hz,1H),7.66(d,J＝8.3Hz,1H),7.51(s,1H),7.08(d,J＝8.3Hz,1H),5.87( s,2H),4.48(t,J＝8.7Hz,2H),3.39(t,J＝8.6Hz,2H),3.32(s,3H),3.15(s,3H),2.71(d,J＝4.5 Hz,3H).MS m/z(ESI):537.1[M+H] ⁺ .

Example 23

7-((6-(Difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- Preparation of d]pyrimidin-2-yl)amino)-N-ethyl-2,3-dihydrobenzofuran-4-carboxamide

Step 1: Synthesis of 4methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H- Pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylate

Under nitrogen protection, to N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-acyl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (540 mg, 1.35 mmol) and ethyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate (335.3 mg, 1.62 mmol) - Pd ₂ (dba) ₃ (128.2 mg, 0.14 mmol), BINAP (168.0 mg, 0.27 mmol) and tBuONa (259.5 mg, 2.74 mmol) were added to the dioxane (30 mL) solution. Then, under nitrogen protection, the reaction solution was stirred for 12 h in an environment of 120°C. After LCMS showed that the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), and then dried over anhydrous Na ₂ SO _4. The dried product was then suction-filtered and concentrated to obtain a crude compound. Purification by flash column chromatography (DCM/MeOH=0-10%) gave methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamide))pyridine) Azin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylate 320 mg, MS m/ z(ESI): 560.1[M+H] ⁺ .

Step 2: Synthesis of methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid

To methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H at room temperature - A solution of pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylate (320 mg, 0.56 mmol) in methanol/water (10 mL/20 mL) LiOH·H ₂ O (40.1 mg, 1.68 mmol) was added. The reaction solution was then heated to 50°C and stirred overnight. After TLC (DCM/MeOH=10:1) showed that the reaction was completed, the reaction solution was concentrated and dissolved in H ₂ O (20 mL). Adjust the Ph of the solution to 2 with 1M HCl, and a yellow solid precipitates. The crude product is filtered and purified by flash column chromatography (DCM/MeOH = from 100/1 to 10/1) to obtain methyl 7-((6-(difluoromethyl) base)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino) -2,3-Dihydrobenzofuran-4-carboxylic acid 280 mg, MS m/z (ESI): 546.1 [M+H] ⁺ .

Step 3: Synthesis of 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-N-ethyl-2,3-dihydrobenzofuran-4-carboxamide

Compound methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (60.0 mg, 0.12 mmol) and ethylamine hydrochloride (30.1 mg, 0.37 mmol) were dissolved In DMF (10 mL) solution, HATU (91.3 mg, 0.24 mmol) and DIPEA (0.12 mL, 0.72 mmol) were added to the reaction system, and then reacted at room temperature for 2 h. After LCMS monitored that the reaction was complete, it was quenched with water (10 mL). The reaction was extinguished, and then extracted three times with EA (10 mL). The combined organic phase was washed once with saturated NaCl water, and the organic phase was dried with anhydrous Na ₂ SO _4. The product was then filtered and concentrated to dryness, and then passed through column chromatography of the concentrate ( MeOH/DCM = from 0 to 10%) purification gave 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl) Methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-ethyl-2,3-dihydrobenzofuran-4-carboxamide 32.0 mg. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.84 (s, 1H), 8.55 (d, J = 2.4Hz, 1H), 8.48 (d, J = 2.4Hz, 1H), 8.23 (s, 1H) ,8.13(t,J＝5.6Hz,1H),7.75(d,J＝8.4Hz,1H),7.31–7.05(m,2H),6.92(s,1H),5.75(s,2H),4.52( t,J＝8.8Hz,2H),3.42(t,J＝8.8Hz,2H),3.26–3.21(m,5H),3.19(s,3H),1.10(t,J＝7.2Hz,3H). MS m/z(ESI): 573.2[M+H] ⁺ .

Example 24

7-((6-(Difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- Preparation of d]pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide

Compound methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (50mg, 0.09mmol), O-methylhydroxylamine hydrochloride (23.4mg, 0.28mmol) ), HATU (68.5mg, 0.18mmol), DMAP (1.0mg, 0.01mmol) and DIPEA (0.1mL, 0.54mmol) were added to DMF (6mL), and then reacted at room temperature for 2h. After the reaction was completed, LCMS monitored the reaction with water. (10 mL) to quench the reaction, then extract with EA (20 mL) twice, wash the organic phase once with saturated NaCl aqueous solution, then dry with anhydrous Na ₂ SO ₄ , then filter and concentrate the dry product, and finally pass through the concentrate column layer 7-((6-(Difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2, 3-d]pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide 25 mg. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.39 (s, 1H), 8.84 (s, 1H), 8.55 (d, J = 2.3Hz, 1H), 8.48 (d, J = 2.4Hz, 1H) ,8.27(s,1H),7.77(d,J＝8.4Hz,1H),7.19(t,J＝53.3Hz,1H),6.98(d,J＝8.5Hz,1H),6.93(s,1H) ,5.76(s,2H),4.54(t,J＝8.8Hz,2H),3.68(s,3H),3.41(t,J＝8.6Hz,2H),3.26(s,3H),3.19(s, 3H).MS m/z(ESI): 575.2[M+H] ⁺ .

Example 25

7-((6-(Difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- Preparation of d]pyrimidin-2-yl)amino)-N-isobutyl-2,3-dihydrobenzofuran-4-carboxamide

Compound methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (60.0mg, 0.11mmol), isobutylamine (24.1mg, 0.33mmol), HATU ( 83.7 mg, 0.22 mmol), DMAP (1.5 mg, 0.011 mmol) and DIPEA (0.12 mL, 0.66 mmol) were added to DMF (6 mL), and then reacted at room temperature for 2 h. After the reaction was completed after LCMS monitoring, it was quenched with water (10 mL). The reaction was extinguished, and then extracted three times with EA (10 mL). The organic phase was washed with saturated NaCl aqueous solution, then dried with anhydrous Na ₂ SO ₄ , and then filtered and concentrated to dry the product. Finally, the concentrate was subjected to column chromatography (MeOH/DCM= 0-10%) purification to obtain 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H -pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-isobutyl-2,3-dihydrobenzofuran-4-carboxamide 35.1 mg. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.83 (s, 1H), 8.54 (d, J = 2.3Hz, 1H), 8.48 (d, J = 2.4Hz, 1H), 8.26 (s, 1H) ,8.14(t,J＝5.8Hz,1H),7.74(d,J＝8.4Hz,1H),7.25(t,J＝53.3Hz,53.3Hz,1H),7.08(d,J＝8.4Hz,1H ),6.92(s,1H),5.75(s,2H),4.52(t,J＝8.7Hz,2H),3.41(t,J＝8.7Hz,2H),3.24(s,3H),3.18(s ,3H),3.03(t,J＝6.4Hz,2H),1.81(dp,J＝13.7,6.9Hz,1H),0.88(d,J＝6.7Hz,6H).MS m/z(ESI): 601.2[M+H] ⁺ .

Example 26

7-((6-(Difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- Preparation of d]pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)-2,3-dihydrobenzofuran-4-carboxamide

Compound methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (100 mg, 0.18 mmol), N-methylpiperidin-4-amine (62.8 mg, 0.55mmol), HATU (137.0mg, 0.36mmol), DMAP (2.4mg, 0.018mmol) and DIPEA (0.17mL, 1.08mmol) were added to DMF (10mL), and then reacted at room temperature for 2h. After the reaction was completed, LCMS was monitored. , quench the reaction with water (10 mL), extract 3 times with EA (20 mL), wash the organic phase with saturated brine, and then dry the organic phase with anhydrous Na ₂ SO _4. The dried product is filtered and concentrated, and then passed through the column layer of the concentrate. Purification by analysis (MeOH/DCM = from 0 to 10%) gave 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido))pyrazine-2- methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)-2,3-dihydrobenzofuran -4-carboxamide 64.0 mg. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.83 (s, 1H), 8.54 (d, J = 2.4Hz, 1H), 8.48 (d, J = 2.4Hz, 1H), 8.26 (s, 1H) ,8.01(d,J＝7.6Hz,1H),7.76(d,J＝8.4Hz,1H),7.30–7.05(m,2H),6.92(s,1H),5.75(s,2H),4.52( t,J＝8.8Hz,2H),3.75(s,1H),3.40(t,J＝8.8Hz,3H),3.24(s,3H),3.18(s,3H),2.93–2.83(m,2H ),2.33–2.13(m,5H),1.78(d,J＝10.8Hz,2H),1.61(d,J＝9.9Hz,2H). MS m/z(ESI): 642.2[M+H] ⁺ .

Example 27

N-Methyl-4-((7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-6-(trifluoromethyl)-7H-pyrrolo Preparation of [2,3-d]pyrimidin-2-yl)amino)benzamide

Step 1: Synthesis of 3-(N-methylmethanesulfonamido)pyrazine-2-carboxylic acid

Dissolve compound N-(3-cyanopyrazin-2-yl)-N-methylmethanesulfonamide (3g, 14.15mmol) in EtOH (30ml), then add 10% NaOH (60ml), and the reaction solution is 100°C Condensate and reflux for 16 hours. After the reaction is complete after monitoring by LCMS, spin the reaction solution to dryness. Add concentrated hydrochloric acid to adjust the pH to 5. Extract with DCM (100ml) 6 times. Wash the organic phase with saturated NaCl, dry the organic phase with anhydrous sodium sulfate, and filter. The product was concentrated and dried to obtain 2.5 g of crude product 3-(N-methylmethanesulfonamido)pyrazine-2-carboxylic acid as a light yellow oil solid. MS m/z(ESI):232.0[M+H] ⁺ .

Step 2: Synthesis of 3-(N-methylmethanesulfonamide)pyrazine-2-carboxylic acid methyl ester

Dissolve compound 3-(N-methylmethanesulfonamido)pyrazine-2-carboxylic acid (1g, 4.32mmol) in DMF (20ml), add K ₂ CO ₃ (1.19g, 8.64mmol), MeI ( 2.45g, 7.28mmol), react the reaction solution at 25°C for 1 hour. After LCMS monitors that the reaction is complete, add 20mL of water to dilute the reaction solution, and then extract 4 times with EtOAc (50ml). The combined organic phases are washed once with saturated NaCl, and then washed with The organic phase was dried over sodium sulfate, and the dried product was filtered and concentrated. The concentrate was then purified by column chromatography (PE:EA=1:1) to obtain the light yellow oil solid product 3-(N-methylmethanesulfonamide). )Pyrazine-2-carboxylic acid methyl ester 500mg. MS m/z(ESI):246.1[M+H] ⁺ .

Step 3: Synthesis of N-(3-(hydroxymethyl)pyrazin-2-yl)-N-methylmethanesulfonamide

Dissolve compound 3-(N-methylmethanesulfonamido)pyrazine-2-carboxylic acid methyl ester (1.0g, 4.1mmol) in THF (20ml) at 0°C, and add NaBH ₄ (1.19g, 8.64 mmol), heat the reaction solution to 25°C and react for 1 hour. After the reaction is complete after LCMS monitoring, the reaction solution is diluted with methanol (10 ml), and then extracted with EtOAc (10 ml) three times. The organic phase is washed with saturated NaCl, and then with anhydrous sulfuric acid. The organic phase was dried over sodium, and the dried product was filtered and concentrated, and then the concentrate was purified by column chromatography (PE:EA=4:1) to obtain the light yellow oily solid product N-(3-(hydroxymethyl)pyrazine- 2-yl)-N-methylmethanesulfonamide 270 mg. MS m/z(ESI):218.0[M+H] ⁺ .

Step 4: Synthesis of N-(3-(chloromethyl)pyrazin-2-yl)-N-methylmethanesulfonamide

Dissolve compound N-(3-(hydroxymethyl)pyrazin-2-yl)-N-methylmethanesulfonamide (270 mg, 1.23 mmol) in DCM (5 ml) at 0°C, and slowly add SOCl dropwise ₂ (0.26ml, 3.7mmol), the reaction solution was heated to 25°C and the reaction was stirred overnight. After the reaction was monitored by LCMS, the reaction solution was directly evaporated, diluted with DCM (10ml), and then added with saturated NaHCO ₃ (10mL) solution for extraction and separation. The organic phase was then washed with saturated NaCl (10 mL), and then dried with anhydrous sodium sulfate. The dried product was filtered and concentrated, and then the concentrate was purified by column chromatography (PE:EA=4:1) to obtain Light yellow oil solid product N-(3-(chloromethyl)pyrazin-2-yl)-N-methylmethanesulfonamide 170 mg. MS m/z(ESI):236.0[M+H] ⁺ .

Step 5: Synthesis of 2-chloro-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

Sodium hydride (1.95 g, 48.8 mmol) was added to a solvent of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 32.5 mmol) in THF (50 mL) in an ice-water bath. After stirring at 0° C. for 30 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (6.5 g, 39.0 mmol) was added thereto. Then the reaction device was moved to room temperature and stirred for 2 hours. After TLC monitoring found that the raw materials disappeared, ice water (10 mL) was added to the reaction system and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL) three times. The combined organic phase was first backwashed with water (50 mL), and then dried over anhydrous sodium sulfate. The dried product was filtered and concentrated to dryness under vacuum to obtain 2-chloro-7-(((2-(trimethylmethane) Silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5.9g), MS m/z (ESI): 284.1[M+H] ⁺ . No purification was required, and the compound was used directly react in next step

Step 6: Synthesis of 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-7-((2-(trimethyl Silyl)ethoxy)methyl)-7H-pyrrole[2,3-d]pyrimidine

To a 250 ml three-necked round-bottomed flask, add bis(pinacol) diboron (3.9g, 15.4mmol) and 4,4-di-tert-butyl-2,2-dipyridine (273.8mg, 1.02mmol) in sequence. ), 1,5-cyclooctadienemethoxyiridium dimer (342.6 mg, 0.51 mmol and n-hexane (40 mL). After dissolving, stir at 50°C for 10 min. Then, 2-chloro was added to the mixture. A solution of -7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.9 g, 10.2 mmol) in tetrahydrofuran (12 mL). Subsequently, the reaction system was stirred at 90°C for 1 hour. After LC-MS monitored the disappearance of the raw materials, the heating was stopped. After the reaction solution was cooled to room temperature, ice water (100 mL) was added to the reaction system to dilute. The organic phase was separated. The aqueous phase was extracted three times with ethyl acetate (60 mL). The combined organic phases were first dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained solid residue was separated and purified by silica gel column chromatography (eluent: petroleum Ether/dichloromethane=2/1) to obtain 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-7- ((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2,3-d]pyrimidine 1.8g. MS m/z (ESI): 410.2[M+H] ⁺ .

Step 7: Synthesis of 2-chloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidine

To a 250mL three-necked round-bottomed flask, add copper 2-thiophenecarboxylate (186.9g, 0.98mmol), 1,10-phenanthroline (353.2mg, 1.96mmol), and lithium hydroxide monohydrate (820.7mg, 19.6mmol) in sequence. ), 1-(trifluoromethyl)-1,2-phenyliodonyl-3-(1)-one (4.0g, 9.8mmol) and 2-chloro-6-(4,4,5,5-tetrahydrofuran) Methyl-1,3,2-dioxaboran-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2,3- d]pyrimidine (3.9g, 11.74mmol). Subsequently, the reaction device was evacuated and replaced with nitrogen, repeated three times. Then, dichloromethane (120 mL) was added. After the mixture was stirred to dissolve, the reaction mixture was stirred at 45°C for 10 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a solid residue, which was then separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1). The product was collected and concentrated under reduced pressure to obtain 2-chloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2, 3-d]pyrimidine 802 mg. MS m/z(ESI):352.0[M+H] ⁺ .

Step 8: Synthesis of 2-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine

The compound 2-chloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine ( 0.82g, 2.03mmol) was dissolved in dichloromethane (20mL) solution, and trifluoroacetic acid (20mL) was added. Stir for 2 hours at 60°C. Subsequently, the reaction solution was concentrated under reduced pressure. Methanol (40 mL), water (20 mL) and potassium carbonate (1.38 g, 10.00 mmol) were added to the obtained brown residue. After stirring to dissolve, stir at 60°C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and methanol in the reaction solution was removed. The resulting liquid was extracted with ethyl acetate (20 mL) three times, and the organic phases were combined. The organic phase was first backwashed three times with saturated brine (20 mL), then dried over anhydrous sodium sulfate, and finally concentrated in vacuo to dry the product to obtain 2-chloro-6-(trifluoromethyl)-7H- as a white solid. 0.68g of pyrrolo[2,3-d]pyrimidine, without purification, the compound was directly used in the next reaction. MS m/z(ESI): 222.0[M+H] ⁺ .

Step 9: Synthesis of N-(3-((2-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-methylmethanesulfonamide

At 45°C, the compound 2-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (120 mg, 0.54 mmol) and N-(3-(chloromethyl)pyridine Azin-2-yl)-N-methylmethanesulfonamide (153.0 mg, 0.65 mmol) was dissolved in a solution of ACN (20 mL), and K ₂ CO ₃ (149.0 mg, 1.08 mmol) was added. The mixture was then stirred at 90°C for 8 hours. After LCMS showed that the reaction was complete, the reaction mixture was quenched with water (10 mL) and extracted slowly with DCM (10 mL) twice. The combined organic phases were washed with brine (20 mL) and dried over _{anhydrous Na2SO4} . The dried product was filtered and concentrated, and the concentrate was purified by FCC (petroleum ether/ethyl acetate=3/1) to obtain N-(3-((2-chloro-6-(trifluoromethyl)-7H-pyrrole) And[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 100 mg, MS m/z (ESI): 421.0 [M+H] ⁺ .

Step 10: Synthesis of N-methyl-4-((7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-6-(trifluoromethyl)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)benzamide

Under nitrogen protection, to N-(3-((2-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 Pd ₂ ( dba) ₃ (27.5 mg, 0.03 mmol), BINAP (37.3 mg, 0.06 mmol) and tBuONa (59.6 mg, 0.62 mmol). Then, under nitrogen protection, the reaction solution was stirred for 12 h in an environment of 120°C. After LCMS showed that the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (20 mL), and then dried over anhydrous Na ₂ SO _4. The dried product was then suction-filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to obtain N-methyl-4-((7-((3-(N-methylmethylsulfonamide))pyrazine- 2-yl)methyl)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)benzamide 54 mg. ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.02 (s, 1H), 8.98 (s, 1H), 8.58 (d, J = 2.4Hz, 1H), 8.48 (d, J = 2.4Hz, 1H), 8.22(q,J＝4.3Hz,1H),7.73(d,J＝8.9Hz,2H),7.68(d,J＝8.9Hz,2H),7.24(s,1H),5.83(s,2H), 3.32(s,3H),3.22(s,3H),2.75(d,J＝4.5Hz,3H).MS m/z(ESI): 535.1[M+H] ⁺ .

Example 28

N-methyl-7-((7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-6-(trifluoromethyl)-7H-pyrrolo Preparation of [2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxamide

Under nitrogen protection, to N-(3-((2-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 1, Pd ₂ (dba) ₃ (21.9 mg, 0.024 mmol), BINAP (29.8 mg, 0.048 mmol) and tBuONa (46.1 mg, 0.48 mmol) were added to the 4-dioxane (10 mL) solution. Then, under nitrogen protection, the reaction solution was stirred for 12 h in an environment of 120°C. After LCMS showed that the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted twice with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (20 mL), and then dried over anhydrous Na ₂ SO _4. The dried product was then suction filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to obtain N-methyl-7-((7-((3-(N-methylmethylsulfonamide))pyrazine- 2-yl)methyl)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxy Amide 46 mg. ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.90 (s, 1H), 8.57 (d, J = 2.4Hz, 1H), 8.49 (d, J = 2.4Hz, 1H), 8.45 (s, 1H), 8.11(q,J＝4.3Hz,1H),7.64(d,J＝8.4Hz,1H),7.21(s,1H),7.06(d,J＝8.4Hz,1H),5.74(s,2H), 4.50(t,J＝8.8Hz,2H), 3.41(t,J＝8.8Hz,2H), 3.25(s,3H), 3.19(s,3H), 2.74(d,J＝4.5Hz,3H). MS m/z(ESI): 577.2[M+H] ⁺ .

Example 29

4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- Preparation of d]pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide

Step 1: Synthesis of methyl 4-amino-2-fluoro-5-methoxybenzoate

Dissolve 4-amino-2-fluoro-5-methoxybenzoic acid (500mg, 2.70mmol) in THF (4mL) and methanol (1mL), add 2M (2-diazoethyl) dropwise under ice bath (2mL, 4.05mmol), react at room temperature for 3 hours, monitor the reaction to be complete, add acetic acid to quench the reaction, concentrate the reaction solution, and obtain 4-amino-2-fluoro-5-methoxybenzoic acid by column chromatography. Methyl ester 506 mg, MS m/z (ESI): 200.0 [M+H] ⁺ .

Step 2: Synthesis of methyl 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoate

N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N -Methylmethanesulfonamide (180mg, 0.45mmol), methyl 4-amino-2-fluoro-5-methoxybenzoate (106mg, 0.54mmol), BINAP (56mg, 0.09mmol), Pd ₂ (dba) ₃ (41 mg, 0.04 mmol) and sodium tert-butoxide (86 mg, 0.90 mmol) were dissolved in dioxane (18 mL) under nitrogen protection and reacted at 100°C for 4.5 h. After monitoring the reaction, the reaction mixture was poured into water (30 mL ), and extracted twice with ethyl acetate (15 mL). The organic phases were combined, then washed with saturated brine (30 mL), and then dried over anhydrous Na ₂ SO _4. The dried product was filtered and concentrated, and the concentrate was purified by column chromatography to obtain methyl 4-((6- (Difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2- (Basic) amino)-2-fluoro-5-methoxy benzoate 160 mg, MS m/z (ESI): 566.2 [M+H] ⁺ .

Step 3: Synthesis of 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid

Methyl 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2 ,3-d]pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoate (160mg, 0.28mmol) was dissolved in THF (5mL) and water (5mL), and NaOH (34mg , 0.85mmol), react at room temperature overnight, monitor the reaction to complete and then concentrate the reaction solution, then add 2M hydrochloric acid solution to adjust the pH to weak acidity, concentrate the reaction solution, and then obtain 4-((6-(difluoromethyl)) through column chromatography -7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2 -Fluoro-5-methoxybenzoic acid 80 mg. MS m/z(ESI):552.1[M+H] ⁺ .

Step 4: Synthesis of 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide

4-((6-(Difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3 -d]pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid (80 mg, 0.15 mmol), HATU (67 mg, 0.17 mmol) and O-isobutoxyamine hydrochloride (37 mg ,0.29mmol) was dissolved in DMF (3mL), added DIPEA (0.1mL, 0.58mmol), reacted at room temperature for 12h, after monitoring the reaction was complete, the reaction mixture was poured into water (30mL), and then extracted with ethyl acetate (15mL) 2 times. The organic phases were combined, then washed with saturated brine (30 mL), and then dried over anhydrous Na ₂ SO _4. The dried product was filtered and concentrated, and the concentrate was subjected to column chromatography to obtain 4-((6-(di Fluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl) Amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide 63 mg. ¹ H NMR (400MHz, DMSO) δ11.22(s,1H),8.94(s,1H),8.53(d,J＝2.3Hz,1H),8.45(d,J＝2.4Hz,1H),8.26– 8.15(m,2H),7.20(s,1H),7.15(d,J＝6.2Hz,1H),6.98(s,1H),5.82(s,2H),3.88(s,3H),3.64(d ,J＝6.6Hz,2H),3.28(s,3H),3.18(s,3H),1.90(m,1H),0.92(d,J＝6.6Hz,6H).MS m/z(ESI): 623.2[M+H] ⁺ .

Biological evaluation of compounds

Test Example 1: In vitro enzymatic inhibitory activity of the compound of the present invention

1. Reagents, consumables, instruments

2. Experimental steps

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

2) Serially dilute the compounds in each column 1:3 with DMSO, adding 10 points of each dilution plus a control containing only DMSO.

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

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

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

6) Incubate at 25°C for 60 minutes.

7) Add 5 μL of Sa-XL665 solution and 5 μL of TK Antibody-Eu3 ⁺ to the assay plate. Centrifuge at 1000rpm for 1 minute.

8) Incubate at 25°C for 60 minutes.

9) Read the fluorescent signal on the Envision 2104 plate reader.

3.Data analysis

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

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

3) Use the nonlinear regression equation of XLfit 5.3.1 to calculate IC50. The formula is as follows:

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

X:Log(compound concentration)

Y: Inhibition rate (%inh)

Top and Bottom: Same unit as Y

logIC50: the same unit as X

HillSlope: slope coefficient or slope

4.Experimental results

The FAK kinase activity IC50 activity data of specific compounds are shown in Table 1.

Table 1

The above results show that the compound of the present invention has a good inhibitory effect on FAK, and its IC ₅₀ is between 0.001 μM and 10 μM, that is, it has good in vitro FAK enzymatic inhibitory activity.

Test Example 2: Pharmacodynamic evaluation of compounds in in vitro diffuse gastric cancer (DGC) organoid model

Experimental Procedure: Organoids were expanded in 6-well plates (7 Matrigel aliquots per well) for 2-3 days before assessment. After passaging, 1000 cells were plated in 5 μL Matrigel aliquots into each well of a 96-well plate containing 100 μL 50% L-WRN medium. After 24 hours of organoid culture, compounds were added. Dissolve the compound with DMSO and prepare a stock solution with a final concentration of 10 μM. Then use DMSO to dilute the stock solution to 1000 times the usage concentration. Then add culture medium to dilute it to the usage concentration. Add the dilution to the culture well plate. After a compound is added once, the culture medium will not be replaced and the compound will not be re-added. The organoids were then cultured for the specified number of days, and then the effects of the compounds were evaluated in the following three ways. In all three ways, DMSO was used as a negative control, and Defactinib or IN10018 was used as a positive control.

1. Observe cell morphology through a microscope. There are differences in cell morphology between normal cells and diffuse gastric cancer organoid models. As shown in Figure 1, normal organoids are spherical and vacuum-shaped, while diffuse gastric cancer organoids are solid grapes. has an irregular shape, so observing the effect of drugs on cell morphology has become one of the important indicators for evaluating drug effects; experimental results show that the compounds of the present invention can restore cell morphology in the in vitro DGC organoid model, as shown in Figures 1-5 shows (the results of some compounds of the present invention are not shown), compounds 4, 6, 8, and 9 of the present invention can restore cell morphology when treated with the DGC organoid model at a concentration of 2.5 μM, and the effects of compounds 8 and 9 are significantly better than Defactinib. At the same time, it was also clearly observed that it had a better inhibitory effect on cell proliferation than Defactinib.

2. Cell viability assessment using reagents and protocols from CellTiter-Glo (Promega G7570). Mix 50 μL of CellTiter-Glo reagent and 50 μL of culture medium and add to each well, shake the plate gently for 30 minutes at room temperature to dissolve the Matrigel, and read the plate on a Tecan plate reader.

Experimental results show that the compounds of the present invention can inhibit the cell growth of human diffuse organoid cell model. As shown in Figure 6, at 2.5 μM, compound 9 can inhibit cell proliferation more significantly than Defactinib.

3. After 48 hours of cell culture and drug administration, the cells were lysed, proteins were extracted, and Western Blot technology was used for protein detection. After gel imaging, the gray value of the protein bands was analyzed to examine the presence of compounds in DGC. Effects on phosphorylated FAK (P-FAK(Y397)) and activated YAP in organoid models. (For detailed methods, see Haisheng Zhang, Cancer Discovery, 2020). The results are shown in Figure 7-8.

Experimental results show that the compound of the present invention can inhibit the phosphorylation of FAK (inhibit FAK kinase activity and reduce phosphorylated FAK) and reduce activated YAP in a dose-dependent manner in the DGC organoid model. Defactinib cannot inhibit YAP activity.

Test Example 3: In vitro pharmacodynamic evaluation of compounds in human diffuse gastric cancer tumor cell line SNU668 model

1. Cell plating

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

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

c. Take out the petri dish, add 2-3ml of complete culture medium to stop digestion, transfer to a 15ml centrifuge tube, put it into a centrifuge and centrifuge at 1000rpm for 5 minutes;

d. Aspirate the supernatant, add 1 ml of complete culture medium, resuspend, and count;

e. Take out the 12-well plate, place 150,000 cells and 900 μL culture medium in each well, and place it in a cell culture incubator for overnight culture.

2. Cell drug delivery

a. Dissolve the small molecule drug mother solution Defactinib, IN10018, Compound 24, Compound 25, Compound 26, Compound 27, Compound 28, and DMSO in advance, and mix by pipetting several times;

b. The dosage concentration of each small molecule in each well is 1μM or 2.5μM. First use 1mM or 2.5mM stock, and use culture medium to dilute each small molecule to 10μM or 25μM respectively;

c. Take out the culture plate on which the cells are seeded, mark the number of each well, and add the corresponding small molecules and concentrations into the wells using a 200 μL pipette to suck 100 μL and gently drop by drop in a circle;

d. After all the wells have been added, shake slightly twice to allow the drug to spread evenly, record the time, and put it back into the cell culture incubator.

3. Extract protein

a. After 24 hours or 48 hours of administration, discard the culture medium, wash with PBS, and discard the PBS;

b. Add RIPA lysis buffer containing phosphatase inhibitors and PMSF to the well plate to lyse the cells, centrifuge at 12,000 rpm for 5 minutes, take the supernatant, measure and adjust the protein concentration, add 4× loading buffer, and cook the protein.

4.WB detection

Perform SDS-PAGE electrophoresis: 80v, 30mm, 120v, 60min; transfer: 80v, 60min; blocking: 5% skim milk for 1h, primary antibody (non-p-YAP (1:1500, Abcam), p-FAK Y397 ( 1:1000, CST), actin (1:10000, CST): prepared with 5% BSA·TBST, incubated at 4°C overnight; secondary antibodies (Goat-anti-mouse-IgG and Goat-anti-rabbit-IgG, 1: 3000, Proteintech): Prepared with 5% skim milk, incubate at room temperature for 1-2 hours.

The results are shown in Figures 9-10. The results show that the compound of the present invention can inhibit the phosphorylation of FAK (inhibit FAK kinase activity and reduce phosphorylated FAK) and reduce activated YAP in the human diffuse gastric cancer tumor cell line SNU668 model. . However, Defactinib and IN10018 have no effect on inhibiting YAP activity.

According to the aforementioned culture and administration methods of SNU668, 1000 cells/well were plated in a 96-well cell plate. Defactinib and compound 9 at 0.5uM and 2.5μM were added the next day, and cell viability was assessed on days 2, 4 and 6 using reagents and protocols from CellTiter-Glo (Promega G7570). Mix 50 μL of CellTiter-Glo reagent and 50 μL of culture medium and add to each well, and gently shake the plate for 30 minutes at room temperature. Read the plate on a Tecan plate reader.

Experimental results show that compound 9 of the present invention can inhibit the cell growth of human diffuse gastric cancer tumor cell line model. As shown in Figure 11, at 0.5 μM and 2.5 μM, compound 9 can inhibit cell proliferation more significantly than Defactinib.

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

All documents mentioned in this application are incorporated by reference in this application to the same extent as if each individual document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims (13)

A compound of formula I, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceuticals thereof an acceptable salt, hydrate, solvate, isotope or prodrug, in, Ring A is independently selected from: C3-C20 heteroaryl and C6-C20 aryl, such as 5-6 membered heteroaryl and phenyl; Ring B is independently selected from: C3-C20 heteroaryl and C6-C20 aryl, such as 5-6 membered heteroaryl and phenyl; preferably, Ring B is a six-membered aryl or heteroaryl; L is independently selected from: bond or CH ₂ , preferably, L is CH ₂ ; X is independently selected from CH or N, preferably, X is N; R ₁ is independently selected from: halogen, -C(=O)N(CH ₃ ) ₂ , -C(=O)NHCH ₃ , -C(=O)NH ₂ , -CH(=O), -COOH, CN, C1-C6 alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CO ₂ CH ₃ ; R ₂ is independently selected from: -N(R ₅ )S(O) _m R ₆ , -P(=O)R' ₅ R' ₆ , -S(O) _m NR ₅ R ₆ , -C(=O )NR ₅ R ₆ , -NR ₅ C(=O)R ₆ , -C(=O)R ₅ , -C(=O)OR ₅ , -OC(=O)R ₅ , -S(O) _m R ₅ ; R ₃ is each independently selected from: -H, -OH, halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -NO ₂ , -NR ₅ R ₆ , C1-C6 alkyl, C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heterocyclic group Aryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3- C12 cycloalkenyl, C6-C10 aryl, and 5-10 membered heteroaryl can be substituted by 1-3 R ₉ ; R ₄ is each independently selected from: -H, -OR ₅ , halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -NO ₂ , -NR ₅ R ₆ , -C(=O)NR ₅ R ₆ , -C(=O)NR ₅ OR ₆ , -C(R ₅ )=NR ₆ , -NR ₅ C(=O)R ₆ , -C(=O)R ₅ , -C(=O )C(=O)R ₅ , -C(=O)OR ₅ , -OC(=O)R ₅ , -OC(=O)OR ₅ , -P(=O)R' ₅ R' ₆ , - S(=O)(=NR ₅ )R ₆ , -S(O) _m R ₅ , -NR ₅ S(O) _m R ₆ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkene base, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1- C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl , 5-10 membered heteroaryl can be substituted by 1-3 R ₉ ; Or any two adjacent R ₄ and the atoms connected to them jointly form a C5-C7 cycloalkyl group, a 5-7 membered heterocyclyl group, a phenyl group, a 5-6 membered heteroaryl group; wherein, the C5- C7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl can be substituted by 1-3 R ₉ ; R ₅ , R ₆ , R' ₅ and R' ₆ are each independently selected from: H, -OH, halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -NO ₂ , -CH ₂ CF _3. -NR ₇ R ₈ , -S(O) _m R ₇ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3 -12-membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10-membered heteroaryl; or in NR ₇ R ₈ , R ₇ and R ₈ together with the N atom to which they are connected form 3- 10-membered heterocyclic group (including bridged ring and spiro ring); wherein, the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C12 cycloalkyl group, 3-12-membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10-membered heteroaryl can be substituted by 1-3 R ₉ ; R ₉ is each independently selected from: H, -OH, oxo (=O), halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CN, -NO ₂ , - OR ₁₀ , -C(=O)R ₁₀ , -OC(=O)R ₁₀ , -OC(=O)R ₁₀ , -OC(=O)OR ₁₀ , -C(=O)NR ₁₀ R ₁₁ , -NR ₁₀ C(＝O)NR ₁₁ R ₁₂ , -NR ₁₀ R ₁₁ , -NR ₁₀ C(＝O)R ₁₁ , -NR ₁₀ S(O) _m R ₁₁ , -S(O) _m R ₁₀ , -S(O) _m NR ₁₀ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3 -C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 groups selected from the following group: C1-C6 alkyl, halogen, -OH, -CN, -NO ₂ , -CHF ₂ , -CH ₂ CF ₃ , -CF ₃ , -C(O)R ₁₃ , -C(O)NR ₁₃ R ₁₄ , -S(O) _m R ₁₃ , -S(O) _m NR ₁₃ R ₁₄ substitution; R ₇ , R ₈ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 Alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 The heteroaryl group can be substituted by 1-3 groups selected from the following group: -OH, halogen, -CN, -NO ₂ , -NH ₂ , -CHF ₂ , -CH ₂ CF ₃ , -CF ₃ , C1 -C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)-(C1-C6 alkoxy), C3-C12 cycloalkyl, 3-12 yuan Heterocycloalkyl, C1-C6 alkylamine; n and n' are each independently selected from 0, 1, 2, 3 or 4; m is independently selected from 0, 1 or 2. The compound of claim 1, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, and metabolites Or its pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs, characterized in that, Selected from: Among them, p is 0, 1 or 2; R ₄ is as defined in claim 1. The compound of claim 1, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, and metabolites or a pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof, characterized in that the compound has a structure represented by formula II, formula III, formula IV or formula V in, p is 0, 1 or 2; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , B and n' are as defined in claim 1 . The compound of claim 1, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, and metabolites Or its pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug, characterized in that R ₁ is independently selected from: F, Cl, -C(=O)NH ₂ , -CH(=O) , -COOH, -CN, C1-C6 alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F. The compound according to any one of claims 1 to 4, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen Oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, characterized in that ring B is selected from: phenyl, pyridyl or pyrazinyl. The compound according to any one of claims 1 to 5, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, and geometric isomers, Nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, characterized in that R ₄ is independently selected from: H, halogen, C1-C6 alkyl, C1-C6 Alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)NR ₅ R ₆ ; wherein, R ₅ and R ₆ Each is independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5 -10-membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, 5-10-membered The heteroaryl group may be substituted with 1-3 substituents selected from the group consisting of: halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CN, -NO ₂ , C1-C6 alkane base, C1-C6 alkoxy group. The compound according to any one of claims 1 to 6, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, and geometric isomers, Nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, characterized in that R ₁ is independently selected from: F, Cl, -C(=O)NH ₂ , -CH(=O), -COOH, -CN, methyl, -CF ₃ , -CHF ₂ , -CH ₂ F; and/or R ₄ is each independently selected from: F, Cl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, -C(=O)NH(C1-C6 alkyl), - C(=O)NH(C3-C6 cycloalkyl), -C(=O)NH(3-6 membered heterocyclyl); wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl and 3-6 membered heterocyclyl can be substituted with 1-3 substituents selected from the following group: halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , - CN, -NO ₂ , C1-C6 alkyl, C1-C6 alkoxy; and/or R ₂ is independently selected from: -N(R ₅ )S(O) _m R ₆ , -P(=O)R' ₅ R' ₆ , -S(O) _m R ₅ ; wherein, R ₅ , R ₆ , R' ₅ and R' ₆ are each independently selected from: H, -OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl , 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, m is 1 or 2; and/or R ₃ is each independently selected from: -S(O) ₂ CH ₃ , -NCH ₃ S(O) ₂ CH ₃ , -NHS(O) ₂ CH ₃ , -P(=O)(CH ₃ ) ₂ , - P(=O)(OH) ₂ ; and/or Selected from: The compound according to any one of claims 1 to 7, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen Oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, characterized in that the compound has the structure of one of the following groups: in, The definitions of R ₁ , R ₂ , R ₃ and R ₄ are the same as those of formula I, formula II, formula III, formula IV or formula V. R ₅ and R ₆ are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl, R' is selected from C1-C6 Alkyl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, 5-10-membered heteroaryl can Substituted with 1-3 substituents selected from the group consisting of: halogen, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CN, -NO ₂ , C1-C6 alkyl, C1- C6 alkoxy; Preferably, the compound has one of the following structures: A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 8, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, Conforms, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof; and pharmaceutically acceptable carriers, diluents or excipients; preferably Preferably, the pharmaceutical composition further comprises one or more selected from the group consisting of: chemotherapy drugs, PD-1 inhibitors, PD-1 antibodies, PD-L1 inhibitors, PD-L1 antibodies, ALK inhibitors, PI3K Inhibitors, BTK inhibitors, EGFR inhibitors, EGFR antibodies, VEGFR inhibitors, VEGFR antibodies, HDAC inhibitors, CDK inhibitors, MEK inhibitors, Akt inhibitors, mTOR inhibitors, SHP2 inhibitors, KRAS G12C inhibitors, KRAS G12D inhibitor, KRAS G12V inhibitor, c-MET inhibitor, Her2 inhibitor, Her2 antibody, Claudin18.2 antibody. A compound as claimed in any one of claims 1 to 8, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, and geometric isomers body, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof, or a pharmaceutical composition as claimed in claim 9 for use in the prevention or treatment of diseases related to FAK Use in medicine; Preferably, the FAK-related disease is cancer, pulmonary hypertension, or pathological angiogenesis; More preferably, 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 bowel cancer, thyroid cancer, urethra cancer, cervical cancer, endometrial cancer, fallopian tube cancer, renal pelvis cancer , vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer , pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, and uterine cancer. A method for preparing a compound as claimed in claim 1, characterized in that it includes the steps s4) In an inert solvent and in the presence of a catalyst, compounds I-1 and I-2 react to obtain a compound of formula I; In the formula, X' is halogen; Preferably, the method further includes the steps of: s1) In an inert solvent (such as i-PrOH) and in the presence of a base (such as DIPEA), compounds I-3 and I-4 react to obtain a compound of formula I-5; s2) In an inert solvent (such as DMF), in the presence of a catalyst (such as Pd(PPh ₃ ) ₂ Cl ₂ and CuI) and under basic conditions (such as DIPEA), compounds I-5 and I-6 react to obtain the formula I-7 compound; s3) In an inert solvent (such as NMP) and in the presence of alkali (such as tBuOK), compound I-7 reacts to obtain a compound of formula I-1; In the formula, X', X" and X"' are each independently halogen (such as Cl, Br, I); A ring, B ring, X, L, R ₁ , R ₂ , R ₃ , R ₄ , n and n' are as defined in claim 1. A method for treating FAK-related diseases, characterized in that the method includes administering a therapeutically effective amount of a compound according to any one of claims 1-8 to a subject identified or diagnosed as having a FAK-related disease, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts thereof, Hydrates, solvates, isotopes or prodrugs, or a pharmaceutical composition according to claim 9. A method for inhibiting FAK kinase activity in a cell or subject, characterized in that the method comprises contacting the cell or administering to the subject any one of claims 1-8 Compounds, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable compounds thereof salt, hydrate, solvate, isotope or prodrug, or the steps of the pharmaceutical composition of claim 9; preferably, the cell is a mammalian cell; preferably, the subject is a mammal ; More preferably, it is human.