Fused tricyclic compounds as kinase inhibitors

Abstract

The invention provides a compound containing a fused tricyclic structure. Specifically, the invention provides a compound with a structure as shown in a formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate and a solvate of the compound. The compound can effectively inhibit protein kinases (including ULK, FAK, ALK, CDK7, HPK1, AXL, FLT3, TNK1 and the like), and is used for treating or preventing diseases or symptoms related to the activity or expression quantity of kinases. # imgabs0 #

Description

Fused tricyclic compounds as kinase inhibitors Technical Field

[0001] The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a novel compound, a synthesis method thereof and its application as a kinase inhibitor in the preparation of drugs for treating various diseases such as tumors. Background Art

[0002] Autophagy, a lysosomal-mediated process for the clearance of protein aggregates and damaged organelles, plays a crucial role in the quality control of intracellular macromolecules and organelles. Kinases are essential components of autophagy. Currently, targeting specific kinases to regulate autophagy has become a therapeutic approach for a variety of human diseases, particularly cancer. This is because autophagy is upregulated in host cells and tissues associated with cancer. Furthermore, cancers associated with mutant RAS are also dependent on autophagy. ULK1 (Unc-51 Like Autophagy Activating Kinase 1) is a serine-threonine kinase and a key autophagy initiator. Under conditions of sufficient nutrients, such as amino acids, mTOC1 is activated, which in turn phosphorylates ULK1 and ATG13, inhibiting autophagy. Under conditions of nutrient deficiency, mTOC1 function on the lysosomal surface is inhibited, leading to rapid dephosphorylation of ULK1 and ATG13. ULK1, along with ATG13, FIP300, and ATG101, form an autophagy complex to induce autophagy. ULK1 also phosphorylates ATG9 at serine 14, promoting the transport of intracellular particles containing ATG9 to the initiation site of autophagy. ULK1 also regulates autophagy by phosphorylating other substrates such as AMBRA1 and Raptor. Inactive mutants of the ULK kinase can block the initiation of autophagy, indicating that inhibiting ULK activity with small molecule inhibitors can regulate autophagy.

[0003] FAK (Focal Adhesion Kinase 1) is a non-receptor tyrosine kinase whose expression is closely associated with the development and progression of various solid tumors, such as ovarian, pancreatic, and breast cancer. Integrin-mediated interactions between FAK and the extracellular matrix lead to conformational changes in FAK, resulting in autophosphorylation at tyrosine 397 and subsequent activation of FAK function. FAK overactivation is also closely associated with tumor cell survival, drug resistance, immunosuppression, and angiogenesis. Recent research has also shown that FAK inhibitors may be effective in treating pulmonary fibrosis.

[0004] ALK was first discovered in anaplastic large cell lymphoma, hence the name ALK (Anaplastic Lymphoma Kinase). Normal ALK is a classic receptor tyrosine kinase, composed of a ligand-binding domain outside the cell membrane, a tyrosine kinase domain inside the cell membrane, and a transmembrane domain. Its activation is regulated by ligands. Alterations in the ALK gene, including point mutations, deletions, and rearrangements, have been found in a variety of tumors. In particular, ALK gene fusion mutations result in the post-translational fusion of the ALK protein kinase domain with other proteins, such as the EML4-ALK fusion mutation commonly seen in non-small cell lung cancer. This mutation often leads to uncontrolled expression and activation of the ALK kinase, which in turn contributes to tumorigenesis. Therefore, ALK is an ideal anti-tumor target.

[0005] CDK7 (Cyclin Dependent Kinase 7) is a unique class of cyclin-dependent proteins. The CDK-activating kinase (CAK) complex, comprised of CDK7, CyclinH, and MAT1, phosphorylates multiple CDK kinases involved in cell cycle regulation, such as CDK2, CDK4, and CDK6. Furthermore, CDK7 promotes transcription initiation by phosphorylating serines 5 and 7 in the C-terminal domain of RNA polymerase II. CDK7 is overexpressed in various tumors, and controlling its expression can reduce tumor cell replication.

[0006] HPK1 (Hematopoietic Protein Kinase 1) is a negative regulator of immune cells such as T cells. It is primarily expressed in hematopoietic cells, including T cells, B cells, macrophages, dendritic cells, and mast cells. Also known as MAP4K1 (Mitogen Activated Protein Kinase Kinase Kinase Kinase 1), it belongs to the Ste20 serine-threonine kinase superfamily. The MAP4K family includes MAP4K1 / HPK1, MAP4K2 / GCK, MAP4K3 / GLK, MAP4K4 / HGK, MAP4K5 / KHS, and MAP4K6 / MINK. HPK1 is a tissue-specific upstream activator of the MEKK / JNK / SAPK signaling pathway.

[0007] HPK1 consists of an N-terminal kinase domain, a central proline-rich domain, and an N-terminal citron homology domain. Upon T cell receptor (TCR) activation, HPK1 is recruited from the cytoplasm to the cell membrane, where it becomes phosphorylated at sites Y381, S171, and T165, leading to full activation of HPK1 function. Activated HPK1 phosphorylates the downstream adaptor protein SLP76 at S376 and Gads at T254, recruiting the negative regulatory factor 14-3-3 to bind to phosphorylated SLP76 and Gads, ultimately disrupting the TCR signaling complex (Lat-Gads-SLP76), affecting the downstream MAPK signaling pathway essential for T cell activation and replication. In addition to TCR signaling, HPK1 can also inhibit T cell signaling by negatively regulating the PKA-dependent prostaglandin E2 (PGE2) receptor. Furthermore, HPK1's kinase activity can be activated by the B cell receptor (BCR) and transforming growth factor receptor, thereby inhibiting the function of various immune cells.

[0008] HPK1 knockout mice show increased T cell activity in response to antigen stimulation, a lowered threshold for T cell activation, and enhanced antigen presentation by dendritic cells. Because HPK1 suppresses immune cells such as T cells, B cells, and dendritic cells, inhibiting HPK1 can enhance the body's immune response, making HPK1 a very important anti-tumor and antiviral target.

[0009] AXL (derived from the Greek word anexelekto) is a receptor tyrosine kinase that belongs to the TAM family. The TAM family includes AXL, Tyro3, ​​and MER. AXL was first discovered as a transforming gene in chronic myeloid leukemia (CML), and its ligand is the vitamin K-dependent growth-promoting factor GAS6. AXL downstream signaling pathways include AXL-PI3K-AKT, RAS-RAF-MEK, and the aforementioned FAK-SRC. Activated AXL signaling pathways play important roles in cell proliferation, survival, migration, and the tumor immunosuppressive microenvironment. Overactivation of the AXL signaling pathway is seen in a variety of solid tumors and hematological tumors, especially acute myeloid leukemia.

[0010] FLT3 (Fms-like Tyrosine Kinase-3) is a member of the type III receptor tyrosine kinase family and is expressed in many hematopoietic progenitor cells. Upon binding to its ligand, FLT3 dimerizes or autophosphorylates, activating the JAK-STAT, PI3K, and MAPK signaling pathways. Activation of these signaling pathways can promote tumor cell proliferation or inhibit apoptosis. FLT3 is expressed in tumor cells from most patients with acute myeloid leukemia and is associated with 30% mutations, including internal tandem duplications (ITDs) and point mutations in the kinase domain. Both of these mutations can aberrantly activate the FLT3 signaling pathway, leading to the development and progression of cancer.

[0011] TNK1 (Thirty-eight-negative kinase-1) is a non-receptor tyrosine kinase that is widely expressed in fetal tissues and restricted to tissues such as the prostate, testis, ovary, colon, and small intestine in adults. MARK can phosphorylate TNK1 at serine 502, promoting interaction between TNK1 and 14-3-3, sequestering TNK1 and inhibiting its kinase function. Conversely, TNK1 released from 14-3-3 aggregates and becomes activated. TNK1 ranked high in genome-wide screens for chemosensitizers in pancreatic cancer and myeloma. In the Hodgkin lymphoma cell line L540, a C-terminal truncation mutant of constitutively activated TNK1 plays an essential role in cell proliferation and survival. In primary patient tumor samples, TNK1 plays a crucial role in the in vitro proliferation and growth of hematologic malignancies.

[0012] In summary, it is of great significance to develop new kinase inhibitors such as ULK, FAK, ALK, CDK7, HPK1, AXL, FLT3, or TNK1.

[0013] Summary of the Invention

[0014] The purpose of the present invention is to provide a new type of kinase inhibitors.

[0015] The first aspect of the present invention provides a compound having a structure shown in the following formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof:

[0016] Wherein, A is selected from Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), or Formula (IIe):

[0017] represents the site at which Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), or Formula (IIe) is linked to the other moieties in Formula (I);

[0018] “*” indicates chiral center;

[0019] X, Y, and T are each independently selected from N or CR 1 ;

[0020] Each R 1 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, OR e , or CN;

[0021] Each R 2 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, OR e SR e NR e R e , CN, or C(O)R h ;

[0022] Each R 3 are independently selected from hydrogen, or C 1-4 Alkyl; or when two R 3 When these two R 3 The carbon atoms to which they are attached may optionally together form a carbonyl group (C=O);

[0023] J and G are each independently selected from NR f , O, S, S(O), S(O)2 or CR g R g ;

[0024] Z is selected from O, NR e , or CH2;

[0025] W is selected from N or CR b ;

[0026] Each R a are each independently selected from hydrogen, halogen, or C 1-4 alkyl;

[0027] Each R b are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR e SRe NR e R e , or CN;

[0028] Each R c are each independently selected from hydrogen, C 1-4 Alkyl, or C 3-6 Cycloalkyl;

[0029] R d Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic group;

[0030] Each R i are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR e SR e , or NR e R e ;

[0031] R f For hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C(O)R h 、C(O)OR e 、C(O)NR e R e 、S(O)2R h , or S(O)2NR e R e The alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more groups selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, OR e SR e NR e R e 、CN、C(O)R h 、C(O)OR e 、C(O)NR e R e NR e C(O)R h 、S(O)2R h 、S(O)2NRe R e , or NR e S(O)2R h ;

[0032] Each R g are independently selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR e SR e NR e R e 、CN、C(O)R h 、C(O)OR e 、C(O)NR e R e NR e C(O)R h , or NR e S(O)2R h ; or two R g The same carbon atom connected to it forms a carbonyl group (C=O); or two R g Together with the carbon atom to which it is attached, they form a 3- to 8-membered ring structure, which optionally contains 0, 1 or 2 heteroatoms selected from N, O, and S;

[0033] Each R e are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, or 3- to 6-membered heterocyclic group; or two R e Together with the nitrogen atom to which they are attached, they form a 3- to 8-membered heterocyclic group containing 1 or 2 nitrogen atoms and 0 or 1 heteroatom selected from O and S;

[0034] Each R h are independently selected from the group consisting of hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl;

[0035] k is selected from 0, 1, 2, or 3;

[0036] n is selected from 0, 1, 2, 3, or 4;

[0037] p and q are each independently selected from 0, 1, 2, 3, 4, or 5;

[0038] f is selected from 2, 3, 4, or 5;

[0039] g is selected from 0, 1, 2, 3, or 4;

[0040] h is selected from 0, 1, 2, or 3;

[0041] i is selected from 0, 1, 2, or 3;

[0042] j is selected from 0, 1, 2, 3, or 4;

[0043] t is selected from 0, 1, 2, 3, or 4;

[0044] The prerequisite is that when X is selected from CH, Y is selected from N, and T is selected from CR 1 , when A is selected from formula (IId), the structural fragment in formula (I) Selected from formula (IIf):

[0045] represents the site where the compound of formula (IIf) is connected to the other parts of formula (I);

[0046] R k Selected from the group consisting of hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group; the remaining groups in formula (IIf) are as defined above;

[0047] wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, cyclic structure, aryl and heteroaryl groups is optionally and independently substituted with 1-3 substituents each independently selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, CN, NO2, OR e SR e NR e R e 、C(O)R h 、C(O)OR e 、C(O)NR e R e NR e C(O)R h 、S(O)2R h , or NR e S(O)2R h , the prerequisite is that the chemical structure formed is stable and meaningful; among them, R e and R h The definition of is as above.

[0048] Unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6 to 12 carbon atoms; the heteroaryl group is a 5- to 15-membered heteroaromatic group; and the cyclic structure is a saturated or unsaturated cyclic group containing or not containing heteroatoms.

[0049] In another preferred embodiment, formula (I) is formula (IIIa) or formula (IIIb):

[0050] The definitions of the groups in formula (IIIa) or (IIIb) are as described above.

[0051] In another preferred embodiment, formula (I) is formula (IVa), formula (IVb), formula (IVc), or formula (IVd):

[0052] The definitions of the groups in Formula (IVa), Formula (IVb), Formula (IVc), or Formula (IVd) are as described above.

[0053] In another preferred embodiment, formula (I) is formula (V):

[0054] The definitions of the groups in formula (V) are as described above.

[0055] In another preferred embodiment, formula (I) is formula (VI):

[0056] R 1 Selected from hydrogen, halogen, C 1-4 Alkyl, or C 1-4 alkyl halide;

[0057] R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, or OR e ;

[0058] G is selected from NR f , O, or CR g R g ;

[0059] Z is selected from O, NR e , or CH2;

[0060] R f For hydrogen, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclyl (preferably 3- to 8-membered heterocyclyl), aryl, heteroaryl, C(O)R h、C(O)OR e 、C(O)NR e R e 、S(O)2R h , or S(O)2NR e R e The alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more groups selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl, OR e SR e NR e R e 、CN、C(O)R h 、C(O)OR e 、C(O)NR e R e NR e C(O)R h 、S(O)2R h 、S(O)2NR e R e , or NR e S(O)2R h ;

[0061] Each R g are independently selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OR e SR e NR e R e 、CN、NR e C(O)R h , or NR e S(O)2R h ;

[0062] Each R e are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic group;

[0063] Each R h are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, aryl, heteroaryl;

[0064] p and q are each independently selected from 0, 1, 2, 3, or 4;

[0065] f is selected from 2, 3, or 4;

[0066] In another preferred embodiment, formula (I) is formula (VII):

[0067] The definitions of the groups in formula (VII) are as described above.

[0068] In another preferred embodiment, formula (I) is formula (VIII):

[0069] h is selected from 0, 1, 2, or 3

[0070] R 1 、R 2 , G is defined as any one of the above.

[0071] In another preferred embodiment, formula (I) is formula (IX):

[0072] The definitions of the groups in formula (IX) are as described above.

[0073] In another preferred embodiment, formula (I) is formula (X):

[0074] R d Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic group;

[0075] R 1 、R 2 , G is defined as any one of the above.

[0076] In another preferred embodiment, formula (I) is formula (XI):

[0077] The definitions of the groups in formula (XI) are as described above.

[0078] In another preferred embodiment, formula (I) is formula (XII):

[0079] j is selected from 0, 1, 2, 3, or 4;

[0080] R 1 、R 2 , G is defined as any one of the above.

[0081] In another preferred embodiment, formula (I) is formula (XIII):

[0082] The definitions of the groups in formula (XIII) are as described above.

[0083] In another preferred embodiment, formula (I) is formula (XIV):

[0084] R k Selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group;

[0085] R 1 , G is defined as any one of the above.

[0086] In another preferred embodiment, the compound is selected from one of the following groups:

[0087] “*” indicates a chiral center.

[0088] The second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.

[0089] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates for preparing a pharmaceutical composition for treating diseases, disorders, or conditions associated with the activity or expression of kinases such as ULK, FAK, ALK, CDK7, HPK1, AXL, FLT3, and TNK1.

[0090] In another preferred embodiment, the disease, disorder or condition is selected from the following group: breast cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, pancreatic cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, mesothelioma, osteosarcoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, eosinophilic syndrome, multiple myeloma and other solid tumors and blood tumors; pulmonary fibrosis; various DNA and RNA virus infections such as AIDS, herpes virus and influenza virus, etc. DETAILED DESCRIPTION

[0091] After extensive and intensive research, the present inventors unexpectedly discovered a class of novel kinase inhibitors, as well as methods for their preparation and use. These compounds can be used to treat various diseases associated with the activity of these kinases. Based on these discoveries, the present invention was completed.

[0092] the term

[0093] Unless otherwise specified, "or" mentioned in this document has the same meaning as "and / or" (referring to "or" and "and").

[0094] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may be optionally in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0095] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched hydrocarbon groups. 1-10 ), it means that the alkyl group contains 1 to 10 carbon atoms. For example, C 1-8 The alkyl group refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

[0096] As used herein, the term "alkenyl" when used alone or as part of another substituent refers to a straight or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the number of carbon atoms in the alkenyl group is limited (e.g., C 2-8 ), it means that the alkenyl group contains 2 to 8 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2 to 8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0097] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either alone or as part of another substituent. The alkynyl group may be straight-chain or branched, or a combination thereof. 2-8 When the term "alkynyl" is used, it means that the alkynyl contains 2 to 8 carbon atoms. 2-8 The term "alkynyl" refers to a straight or branched chain alkynyl group having 2 to 8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.

[0098] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated ring, bicyclic or polycyclic (fused, bridged or spiro) ring system group when used alone or as part of another substituent. 3-10 ) refers to a cycloalkyl group containing 3 to 10 carbon atoms. In some preferred embodiments, the term "C 3-8 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but no ring has a completely conjugated π electron system. "Fused cycloalkyl" refers to a full-carbon bicyclic or polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. "Bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. The atoms contained in the cycloalkyl group are all carbon atoms. The following are some examples of cycloalkyl groups, and the present invention is not limited to the following cycloalkyl groups.

[0099] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, such as phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system. Aryl groups can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited to the aryl groups described below.

[0100] "Heteroaryl" refers to a monocyclic or polycyclic group having aromaticity containing one or more heteroatoms (selectively selected from nitrogen, oxygen, and sulfur), or a polycyclic group formed by condensing a heterocyclic group (containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur) with an aryl group, wherein the attachment point is located on the aryl group. The heteroaryl group may be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups.

[0101] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclyls refer to heterocyclyls including spirocyclic, fused, and bridged rings. "Spirocyclic heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with the other rings in the system, in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Fused-ring heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, in which one or more rings may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system, and in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If a heterocyclic group contains both saturated and aromatic rings (for example, a saturated ring and an aromatic ring are fused together), the point of attachment to the parent group must be on the saturated ring. Note: When the point of attachment to the parent group is on the aromatic ring, it is called a heteroaryl group, not a heterocyclic group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.

[0102] As used herein, the term "halogen," by itself or as part of another substituent, refers to F, Cl, Br, and I.

[0103] As used herein, the term "substituted" (with or without the "arbitrarily" modifier) ​​refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described accordingly in the preceding text, or the substituent appearing in the examples. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be connected to another ring, such as a cycloalkyl group, to form a spirobicyclic system, i.e., the two rings have a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents are, for example (but not limited to): C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3- 8-cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde, C 2-10 Acyl, C 2-10 Ester group, amino group.

[0104] For the sake of convenience and in accordance with common understanding, the term "arbitrary substitution" or "optionally substituted" only applies to sites that can be substituted by substituents, and does not include those substitutions that are chemically unfeasible.

[0105] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (e.g., a human) without producing undue side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes a salt of the compound of the present invention having an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or a salt of the compound of the present invention having a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).

[0106] use:

[0107] The present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if any), hydrates, pharmaceutically acceptable carriers or excipients for use in inhibiting kinases.

[0108] The compounds of the present invention are useful as kinase inhibitors.

[0109] The present invention is a single kinase inhibitor that modulates kinase activity to prevent, alleviate, or cure diseases. These diseases include, but are not limited to, breast cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, pancreatic cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, mesothelioma, osteosarcoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, hypereosinophilic syndrome, multiple myeloma, and other solid and hematologic tumors; pulmonary fibrosis; and infections by various DNA and RNA viruses, including AIDS, herpes virus, and influenza virus.

[0110] The compounds of the present invention and their deuterated derivatives, as well as pharmaceutically acceptable salts or isomers thereof (if present), or hydrates thereof, and / or compositions thereof, can be formulated with pharmaceutically acceptable excipients or carriers. The resulting compositions can be administered to mammals, such as men, women, and animals, in vivo for the treatment of conditions, symptoms, and diseases. The compositions can be in the form of tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions, sterile powders, and the like. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (increased), glycine, disintegrants (such as starch, cross-linked sodium carboxymethyl cellulose, complex silicates, and high molecular weight polyethylene glycols), granulation binders (such as polyvinyl pyrrolidone, sucrose, gelatin, and gum arabic), and lubricants (such as magnesium stearate, glycerol, and talc). In a preferred embodiment, the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders. The amount of the compound of the present invention or the pharmaceutical composition administered to the patient is not fixed and is usually administered in a pharmaceutically effective amount. At the same time, the amount of the compound actually administered can be determined by the physician based on actual conditions, including the condition being treated, the selected route of administration, the actual compound administered, the individual condition of the patient, etc. The dosage of the compound of the present invention depends on the specific use of the treatment, the mode of administration, the patient's condition, and the physician's judgment. The ratio or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, route of administration, etc.

[0111] 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.

[0112] Pharmaceutical compositions and methods of administration

[0113] Since the compounds of the present invention have excellent inhibitory activity against kinases, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases related to kinase activity or expression.

[0114] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0115] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0116] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0117] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0118] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0119] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0120] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0121] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0122] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0123] 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.

[0124] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0125] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0126] The main advantages of the present invention include:

[0127] 1. Provided is a compound as shown in formula I.

[0128] 2. Provided is a kinase inhibitor with a novel structure, and its preparation and use. The inhibitor can inhibit the activity of kinase at extremely low concentrations.

[0129] 3. Provides a kinase inhibitor that is well absorbed orally.

[0130] 4. Provided is a pharmaceutical composition for treating diseases related to kinase activity.

[0131] 5. The kinases include ULK, FAK, ALK, CDK7, HPK1, AXL, FLT3, TNK1, etc.

[0132] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0133] Some representative compounds of the present invention can be prepared by the following synthetic methods. In the following reaction formulas, the reagents and conditions of each step can be selected from conventional reagents or conditions for such preparation methods in the art. After the structure of the compound of the present invention is disclosed, the above selection can be made by those skilled in the art based on the knowledge in the art.

[0134] Example

[0135] Abbreviations: Boc = tert-Butoxycarbonyl DCM = Dichloromethane DIPEA or DIEA = N,N-Diisopropylethylamine DMF = N,N-Dimethylformamide DMSO = Dimethyl sulfoxide EtOAc or EA = Ethyl acetate Et = Ethyl HATU = N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) Me = Methyl MeOH = Methanol NMP = N-Methylpyrrolidone Ph = Phenyl Pd2(dba)3 = Trisdibenzylideneacetone dipalladium TEA = Triethylamine TFA = Trifluoroacetic acid THF = Tetrahydrofuran TsCl = p-Toluenesulfonyl chloride TBDPSCl = tert-Butyldiphenylsilyl chloride XantPhos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos = 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0136] Example 1: Preparation of Compounds A1R and A4R

[0137] Compound A1R-a (850 mg, 2.06 mmol) (Compound A1R-a was synthesized according to the D50R method), potassium ethylene trifluoroborate (414 mg, 3.09 mmol), 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (75 mg, 0.103 mmol), and potassium carbonate (854 mg, 6.18 mmol) were dissolved in dimethyl sulfoxide (10 mL). The mixture was heated to 100°C under a nitrogen atmosphere and stirred for 2 hours. After the reaction was complete, it was diluted with water. The mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain Compound A1R-b (600 mg, 81% yield) as a yellow solid. MS m / z 362.1 [M+H] + .

[0138] Compound A1R-b (600 mg, 1.66 mmol) and palladium-carbon catalyst (10%, 200 mg) were dissolved in methanol (10 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 60 minutes. TLC monitored the reaction completion. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound A1R-c (500 mg, 90% yield) as a light yellow solid. MS m / z 334.1 [M+H] + .

[0139] Compound A1R-d was synthesized according to the method in patent (WO2020 / 231808,2020,A1). Compound A1R-c (75 mg, 0.22 mmol) and compound A1R-d (91 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (3 mL), and trifluoroacetic acid (25 mg, 0.22 mmol) was added. The reaction mixture was stirred at 100 ° C overnight. After the reaction was completed, it was diluted with water. The mixed solution was extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20:1) to obtain yellow solid compound A1R-e (90 mg, yield 62%). MS m / z 650.2[M+H] + .

[0140] Compound A1R-e (90 mg, 0.14 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. TLC monitored the reaction completion. The reaction mixture was concentrated under reduced pressure, and methanol (5 mL) and aqueous ammonia (1 mL) were added, followed by stirring at room temperature for 15 minutes. The mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% aqueous ammonia) to obtain Compound A4R (45 mg, 59% yield) as a white solid. 1H NMR (500MHz, DMSO-d6) δ8.53(s,1H),8.03(s,1H),6.94(s,1H),6.65(d,J=10.3Hz,2H),4. 14(dd,J=10.6,2.4Hz,1H),3.89-3.75(m,1H),3.62(dd,J=8.8,5.9Hz,4H),3.38(s,2H),3. 24(s,4H),2.99(d,J=12.2Hz,1H),2.93-2.79(m,2H),2.71(td,J=12.1,3.2Hz,1H),2.67-2 .54(m,2H),2.50-2.40(m,5H),2.27(t,J=11.4Hz,1H),1.58(s,2H),1.03(t,J=7.5Hz,3H). MS m / z 550.2[M+H] + .

[0141] Compound A4R (20 mg, 0.04 mmol) and paraformaldehyde (20 mg) were dissolved in 1,2-dichloroethane (2 mL), followed by the addition of glacial acetic acid (0.1 mL). The reaction mixture was stirred at 60°C for 30 minutes and then cooled to room temperature. Sodium triacetoxyborohydride (25 mg, 0.12 mmol) was added to the reaction mixture at room temperature, followed by stirring for 60 minutes. Upon completion of the reaction, the mixture was diluted with water. The mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% aqueous ammonia) to afford Compound A1R (10 mg, 49% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.03(s,1H),7.00-6.88(m,1H),6.78-6.58(m,2H),4.18(dd,J= 10.6,2.6Hz,1H),3.85(dd,J=10.4,9.2Hz,1H),3.72(d,J=11.1Hz,1H),3.66-3.51(m,3H),3.38(s,2H ),3.30-3.09(m,4H),3.06-2.96(m,1H),2.84(dd,J=39.5,8.7Hz,2H),2.68-2.56(m,2H),2.49-2.41 (m,2H),2.23(s,3H),2.15-1.95(m,2H),1.84-1.62(m,2H),1.62-1.45(m,2H),1.03(t,J=7.5Hz,3H). MS m / z 564.2[M+H] +.

[0142] Example 2: Preparation of Compound A2R

[0143] Compound A4R (20 mg, 0.04 mmol) and N-methyl-4-piperidone (14 mg, 0.12 mmol) were dissolved in dimethylacetamide (2 mL), followed by the addition of glacial acetic acid (0.1 mL). The reaction mixture was stirred at 60°C for 30 minutes, then cooled to room temperature. Sodium triacetoxyborohydride (25 mg, 0.12 mmol) was added to the reaction mixture at room temperature. The reaction mixture was then heated to 75°C and stirred at 75°C for 60 minutes. Upon completion of the reaction, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% aqueous ammonia) to afford Compound A2R (5 mg, 21% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ8.54(s,1H),8.03(s,1H),7.03-6.82(m,1H),6.78-6.54(m,2H),4.19(dd,J=10 .5,2.4Hz,1H),3.84(dd,J=10.3,9.4Hz,1H),3.78-3.68(m,1H),3.67-3.51(m,3H),3.49-3.34(m,2H),3 .30-3.05(m,4H),3.04-2.72(m,5H),2.68-2.51(m,4H),2.49-2.39(m,2H),2.33-2.24(m,1H),2.17(s, 3H), 2.08-1.78 (m, 4H), 1.78-1.66 (m, 2H), 1.66-1.50 (m, 2H), 1.50-1.34 (m, 2H), 1.03 (t, J = 7.5Hz, 3H). MS m / z 647.3[M+H] + .

[0144] Example 3: Preparation of Compound A3R

[0145] Compound A4R (15 mg, 0.04 mmol), tetrahydropyrone (12 mg, 0.12 mmol), glacial acetic acid (0.1 mL), and sodium cyanoborohydride (13 mg, 0.20 mmol) were dissolved in methanol (2 mL) and stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% aqueous ammonia) to afford Compound A3R (3 mg, 17% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.03(s,1H),7.00-6.88(m,1H),6.77-6.56(m,2H),4.20(d ,J=9.5Hz,1H),3.99-3.78(m,3H),3.78-3.70(m,1H),3.69-3.53(m,3H),3.46-3.33(m,2H),3.31 -3.10(m,6H),3.06-2.76(m,3H),2.66-2.53(m,2H),2.49-2.37(m,4H),2.34-2.23(m,1H),2.02 -1.81(m,2H),1.79-1.67(m,2H),1.65-1.51(m,2H),1.50-1.32(m,2H),1.03(t,J=7.5Hz,3H).MS m / z 634.2[M+H] + .

[0146] Example 4: Preparation of Compounds A5R and A8R

[0147] Compound A5R-a was synthesized according to the patent method (WO2020 / 231808, 2020, A1). Compound A1R-c (160 mg, 0.48 mmol) and compound A5R-a (193 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (3 mL), and trifluoroacetic acid (58 mg, 0.48 mmol) was added. The reaction mixture was stirred at 100°C for 4 hours. After the reaction was completed, it was diluted with water. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20:1) to obtain yellow solid compound A5R-b (250 mg, yield 82%). MS m / z 634.5[M+H] + .

[0148] Compound A5R-b (250 mg, 0.39 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. TLC monitored the reaction completion. The reaction mixture was concentrated under reduced pressure, and methanol (5 mL) and aqueous ammonia (1 mL) were added, followed by stirring at room temperature for 15 minutes. The mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% aqueous ammonia) to obtain Compound A5R (125 mg, 59% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.02(s,1H),7.05-6.91(m,1H),6.75-6. 55(m,2H),4.15(dd,J=10.6,2.4Hz,1H),3.87-3.75(m,1H),3.67-3.56(m,1H), 3.31-3.05(m,6H),3.05-2.94(m,1H),2.94-2.80(m,2H),2.76-2.66(m,2H),2 .49-2.40(m,3H),2.33-2.15(m,3H),1.80-1.52(m,6H),1.03(t,J=7.5Hz,3H). MS m / z 534.3[M+H] + .

[0149] Compound A5R (25 mg, 0.05 mmol) and paraformaldehyde (25 mg) were dissolved in 1,2-dichloroethane (2 mL), and glacial acetic acid (0.1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (50 mg, 0.24 mmol) was added to the reaction mixture at room temperature, followed by stirring at room temperature for 60 minutes. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia water) to obtain Compound A8R (17 mg, 66% yield) as a white solid. 1H NMR(500MHz,DMSO-d6)δ8.55(s,1H),8.02(s,1H),6.99(t,J=5.7Hz,1H),6.67(s,2H),4.18 (dd,J=10.6,2.6Hz,1H),3.84(dd,J=10.5,9.1Hz,1H),3.77-3.62(m,1H),3.31-3.06(m,6H ),3.04-2.95(m,1H),2.86(d,J=11.1Hz,1H),2.82-2.74(m,1H),2.66-2.56(m,1H),2.49-2 .39(m,3H),2.34-2.11(m,5H),2.11-2.03(m,1H),1.79-1.51(m,6H),1.03(t,J=7.5Hz,3H). MS m / z 548.3[M+H] + .

[0150] Example 5: Preparation of Compound A6R

[0151] Compound A5R (25 mg, 0.05 mmol) and N-methyl-4-piperidone (23 mg, 0.20 mmol) were dissolved in dimethylacetamide (2 mL), followed by the addition of glacial acetic acid (0.1 mL). The reaction mixture was stirred at 60°C for 30 minutes, cooled to room temperature, and sodium triacetoxyborohydride (42 mg, 0.20 mmol) was added. The reaction mixture was then heated to 75°C and stirred at 75°C for 60 minutes. Upon completion of the reaction, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% aqueous ammonia) to afford Compound A6R (25 mg, 85% yield) as a white solid. 1H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.02(s,1H),6.98(t,J=5.7Hz,1H),6.79-6.54(m,2H),4.19 (dd,J=10.5,2.4Hz,1H),3.84(dd,J=10.4,9.2Hz,1H),3.76-3.63(m,1H),3.30-3.04(m,6H),3.03 -2.86(m,3H),2.79(d,J=11.2Hz,2H),2.60-2.52(m,1H),2.49-2.39(m,3H),2.34-2.24(m,1H),2 .23-2.01(m,6H),1.93-1.78(m,3H),1.77-1.51(m,7H),1.49-1.34(m,2H),1.03(t,J=7.5Hz,3H). MS m / z 631.4[M+H] + .

[0152] Example 6: Preparation of Compound A7R

[0153] Compound A5R (22 mg, 0.04 mmol), tetrahydropyrone (12 mg, 0.12 mmol), glacial acetic acid (0.1 mL), and sodium cyanoborohydride (13 mg, 0.20 mmol) were dissolved in methanol (2 mL) and stirred at room temperature overnight. After completion of the reaction, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia water) to afford Compound A7R (9 mg, 35% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.02(s,1H),6.98(t,J=5.8Hz,1H),6.76-6.54(m,2H ),4.20(dd,J=10.5,2.5Hz,1H),3.94-3.80(m,3H),3.78-3.68(m,1H),3.30-3.05(m,8H), 3.05-2.87(m,3H),2.61-2.52(m,1H),2.49-2.38(m,3H),2.33-2.24(m,1H),2.20(t,J=5. 9Hz, 2H), 1.95-1.80 (m, 2H), 1.77-1.53 ​​(m, 7H), 1.50-1.33 (m, 2H), 1.03 (t, J = 7.5Hz, 3H). MS m / z 618.3[M+H] + .

[0154] Example 7: Preparation of Compound A9R

[0155] Compound A5R (18 mg, 0.03 mmol) and glacial acetic acid (18 mg, 0.30 mmol) were dissolved in pyridine (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19 mg, 0.10 mmol) was added and stirred at room temperature for one hour. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia water) to obtain compound A9R (9 mg, 46% yield) as a white solid. MS m / z 576.3 [M+H] + .

[0156] Example 8: Preparation of Compounds B1R and B3R

[0157] Compound B11R-b2 (420 mg, 0.81 mmol), triphenylphosphine (21 mg, 0.08 mmol), bistriphenylphosphine palladium dichloride (56 mg, 0.08 mmol), and cuprous iodide (15 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (10 mL). Compound B11R-c (170 mg, 0.98 mmol) and triethylamine (327 mg, 3.24 mmol) were added sequentially under nitrogen. The mixture was reacted at 120°C for one hour. LCMS monitored the reaction completion. The reaction solution was evaporated to dryness under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to afford Compound B1R-a (500 mg, 94% yield) as a yellow solid. MS m / z 654.3 [M+H] + .

[0158] Compound B1R-a (500 mg, 0.76 mmol) and palladium on carbon (10%, 100 mg) were added to N,N-dimethylformamide (15 mL) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. After the reaction was completed, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a gray solid compound B1R-b (360 mg, yield 71%). MS m / z 658.3 [M+H] + .

[0159] Compound B1R-b (337 mg, 0.51 mmol) was dissolved in tetrahydrofuran and water (1:1, 15 mL), and lithium hydroxide (61 mg, 2.56 mmol) was added. The mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure and washed with saturated sodium bicarbonate. The organic phase was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to obtain a crude product. The crude product was dissolved in a mixed solution of N,N-dimethylformamide and acetonitrile, and ammonium chloride (54 mg, 1.02 mmol), N,N-diisopropylethylamine (199 mg, 1.53 mmol), and HATU (387 mg, 1.02 mmol) were added in sequence. The reaction was allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain a gray solid compound B1R-c (300 mg, yield 91%). MS m / z 643.3[M+H] + .

[0160] Compound B1R-c (200 mg, 0.31 mmol) was dissolved in methanol (10 mL), and a solution of HCl in dioxane (4.0 M, 2 mL) was added. The reaction mixture was stirred at 40°C for 2 hours. TLC monitored the completion of the reaction. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was dissolved in a small amount of methanol, neutralized with ammonia water, and then concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia water) to obtain compound B3R (150 mg, 89% yield) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.53(s,1H),7.39(s,1H),7.24–7.19(m,1H),7.19–7 .04(m,4H),6.89(s,1H),6.57(s,1H),4.15(dd,J=10.6,2.5Hz,1H),3.84–3.78(m,1H),3. 74(s,3H),3.68(d,J=11.0Hz,1H),3.47(s,2H),3.07–2.85(m,7H),2.72(td,J=12.0,3.0H z, 1H), 2.54 (dd, J = 11.7, 3.3Hz, 1H), 2.28 (t, J = 11.3Hz, 1H), 2.00 (dd, J = 15.9, 8.2Hz, 1H). MS m / z 543.2[M+H] + .

[0161] Compound B3R (45 mg, 0.08 mmol), paraformaldehyde (4 mg, 0.12 mmol), and zinc chloride (22 mg, 0.16 mmol) were dissolved in methanol (1 mL) in sequence, and sodium cyanoborohydride (15 mg, 0.24 mmol) was slowly added. The reaction mixture was stirred at 75°C for 1 hour. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound B1R (20 mg, 43% yield) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.54(s,1H),7.39(s,1H),7.24-7.19(m,1H),7.19-7.05(m,4H),6.8 9(s,1H),6.60(s,1H),4.18(dd,J=10.6,2.6Hz,1H),3.85(dd,J=10.5,8.9Hz,1H),3.79(d,J=11.5Hz,1H) ,3.75(s,3H),3.47(s,2H),3.08-3.00(m,3H),2.95(dd,J=10.2,5.5Hz,2H),2.88(d,J=10.9Hz,1H),2.79 (d,J=10.3Hz,1H),2.68(td,J=11.7,2.9Hz,1H),2.23(s,3H),2.13-2.05(m,1H),1.70(t,J=10.5Hz,1H). MS m / z 557.3[M+H]+.

[0162] Example 9: Preparation of Compound B2R

[0163] Compound B3R (45 mg, 0.08 mmol), N-methyl-4-piperidone (14 mg, 0.12 mmol), and zinc chloride (22 mg, 0.16 mmol) were sequentially dissolved in methanol (1 mL), and sodium cyanoborohydride (15 mg, 0.24 mmol) was added. The reaction mixture was stirred at 75°C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound B2R (26 mg, 49% yield) as a yellow solid. 1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.53(s,1H),7.39(s,1H),7.24-7.19(m,1H),7.19-7.03(m,4 H),6.89(s,1H),6.59(s,1H),4.19(dd,J=10.6,2.6Hz,1H),3.87-3.77(m,2H),3.74(s,3H),3.47( s,2H),3.07-2.88(m,7H),2.80(d,J=11.2Hz,2H),2.66-2.57(m,1H),2.31(td,J=11.2,2.7Hz,1H) ,2.17(d,J=3.6Hz,1H),2.15(s,3H),1.91-1.81(m,3H),1.74(d,J=10.9Hz,2H),1.49-1.37(m,2H). MS m / z 640.3[M+H] + .

[0164] Example 10: Preparation of Compound B4R

[0165] Compound B3R (40 mg, 0.07 mmol), tetrahydropyrone (11 mg, 0.11 mmol), and zinc chloride (19 mg, 0.14 mmol) were sequentially dissolved in methanol (1 mL), followed by the addition of sodium cyanoborohydride (25 mg, 0.21 mmol). The reaction mixture was stirred at 75°C for 1 hour. Upon completion of the reaction, the mixture was concentrated under reduced pressure following TLC monitoring. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to afford compound B4R (26 mg, 57% yield) as a yellow solid. 1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.53(s,1H),7.39(s,1H),7.26-7.20(m,1H),7.19-7.02(m,4H) ,6.89(s,1H),6.59(s,1H),4.20(dd,J=10.5,2.5Hz,1H),3.93-3.87(m,2H),3.86-3.78(m,2H),3.75( s,3H),3.47(s,2H),3.30-3.25(m,2H),3.08-2.98(m,4H),2.98-2.91(m,3H),2.67-2.59(m,1H),2.4 6-2.40(m,1H),2.35-2.27(m,1H),1.88(t,J=10.4Hz,1H),1.73(d,J=12.3Hz,2H),1.48-1.39(m,2H). MS m / z 627.3[M+H] + .

[0166] Example 11: Preparation of Compound B5R

[0167] Compound B3R (30 mg, 0.05 mmol), acetaldehyde (4 mg, 0.08 mmol), and zinc chloride (14 mg, 0.10 mmol) were sequentially dissolved in methanol (1 mL), followed by the addition of sodium cyanoborohydride (9 mg, 0.15 mmol). The reaction mixture was stirred at 75°C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure following TLC monitoring. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to afford Compound B5R (14 mg, 44% yield) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.53(s,1H),7.39(br,1H),7.22(d,J=5.8H z,1H),7.16(s,4H),6.89(s,1H),6.60(s,1H),4.20(dd,J=10.6,2.5Hz,1H),3.88 -3.77(m,2H),3.75(s,3H),3.47(s,2H),3.07-2.86(m,7H),2.70-2.61(m,1H),2. 43-2.31(m,2H),2.1-2.05(m,1H),1.67(t,J=10.6Hz,1H),1.04(t,J=7.2Hz,3H). MS m / z 571.3[M+H] + .

[0168] Example 12: Preparation of Compound B6R

[0169] Compound B3R (30 mg, 0.05 mmol) and 1-ethoxy-1-trimethylsilyloxycyclopropane (96 mg, 0.55 mmol) were dissolved in methanol (1 mL), and acetic acid (1 drop) was added. After stirring at room temperature for one hour, sodium cyanoborohydride (34 mg, 0.55 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC, and the mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound B6R (5 mg, 24% yield) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.53(s,1H),7.39(br,1H),7.23-7.20(m,1H),7.19- 7.08(m,4H),6.89(s,1H),6.60(s,1H),4.21(dd,J=10.7,2.5Hz,1H),3.88-3.78(m,2H),3 .74(s,3H),3.47(s,2H),3.06-2.99(m,3H),2.97-2.91(m,4H),2.62-2.55(m,1H),2.42-2 .35(m,1H),1.99(t,J=11Hz,1H),1.70-1.64(m,1H),0.48-0.42(m,2H),0.40-0.33(m,2H). MS m / z 583.3[M+H] + .

[0170] Example 13: Preparation of Compound B7R

[0171] Compound B3R (25 mg, 0.05 mmol), acetic acid (4 mg, 0.07 mmol), and N,N-diisopropylethylamine (19 mg, 0.15 mmol) were dissolved in acetonitrile (1 mL), and HATU (19 mg, 0.05 mmol) was added. The mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound B7R (15.20 mg, 56% yield) as a gray solid. 1H NMR(500MHz,DMSO-d6)δ8.79(s,1H),8.55(s,1H),7.39(br,1H),7.24-7.20(m,1H),7.19-7.07(m, 4H),6.90(s,1H),6.66(s,1H),4.43(dd,J=22.5,12.4Hz,1H),4.28(dd,J=10.7,2.3Hz,1H),3.94- 3.87(m,2H),3.76(s,3H),3.47(s,2H),3.30-3.22(m,1H),3.08-3.00(m,2H),2.98-2.92(m,2H),2 .91-2.83(m,1H),2.77-2.65(m,1H),2.58-2.51(m,1H),2.42-2.33(m,1H),2.07(d,J=5.6Hz,3H). MS m / z 585.2[M+H] + .

[0172] Example 14: Preparation of Compound B8R

[0173] Compound B3R (25 mg, 0.05 mmol) and N,N-diisopropylethylamine (19 mg, 0.15 mmol) were dissolved in dichloromethane (1 mL). Methanesulfonyl chloride (6 mg, 0.05 mmol) was added under ice-cooling and the mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound B8R (6.34 mg, 22% yield) as a gray solid. 1 H NMR(500MHz,DMSO-d6)δ8.80(s,1H),8.55(s,1H),7.39(br.,1H),7.24-7.21(m,1H),7.20-7.07(m ,4H),6.89(s,1H),6.69(s,1H),4.30(dd,J=10.8,2.6Hz,1H),4.05(d,J=12.3,1H),3.90(dd,J=10 .8,8.1,1H),3.76(s,3H),3.60(d,J=11.5,2H),3.47(s,2H),3.17(br.,1H),3.04(dd,J=9.9,5.3H z, 2H), 2.97-2.89 (m, 5H), 2.78 (dd, J = 12.0, 9.3Hz, 1H) 2.60 (t, J = 11.2Hz, 1H), 2.03-1.96 (m, 1H). MS m / z 621.2[M+H] + .

[0174] Example 15: Preparation of Compound B9R

[0175] Compound B3R (60 mg, 0.11 mmol), 1-Boc-3-azetidinone (28 mg, 0.16 mmol) and zinc chloride (27 mg, 0.22 mmol) were dissolved in methanol (1 mL) in sequence, and sodium cyanoborohydride (14 mg, 0.22 mmol) was added. The reaction mixture was stirred at 75 ° C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure by TLC monitoring. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20:1, 2% ammonia water) to obtain a yellow solid compound B9R-a (41 mg, yield 53%). MS m / z 698.3 [M+H] + .

[0176] Compound B9R-a (41 mg, 0.06 mmol) was dissolved in methanol (1 mL), and a dioxane hydrochloride solution (4.0 M, 0.5 mL) was added. The reaction mixture was stirred at 40°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was dissolved in a small amount of methanol, neutralized with ammonia, and then concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia) to obtain compound B9R-b (35 mg, 99% yield) as a yellow solid.

[0177] Compound B9R-b (35 mg, 0.06 mmol), paraformaldehyde (9 mg, 0.30 mmol), and zinc chloride (16 mg, 0.12 mmol) were sequentially dissolved in methanol (1 mL), followed by the addition of sodium cyanoborohydride (7 mg, 0.12 mmol). The reaction mixture was stirred at 75°C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure following TLC monitoring. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to afford compound B9R (22 mg, 63% yield) as a yellow solid. 1H NMR(500MHz,DMSO-d6)δ8.78(s,1H),8.53(s,1H),7.39(br.,1H),7.25-7.20(m,1H),7.14( dd,J=9.7,5.6Hz,4H),6.89(s,1H),6.59(s,1H),4.19(dd,J=10.6,2.5Hz,1H),3.87-3.77(m ,2H),3.74(s,3H),3.47(s,2H),3.41-3.35(m,2H),3.08-2.99(m,3H),2.98-2.91(m,2H),2. 89-2.71(m,5H),2.69-2.60(m,1H),2.23(s,3H),2.04-1.95(m,1H),1.60(t,J=10.6Hz,1H). MS m / z 612.4[M+H] + .

[0178] Example 16: Preparation of Compound B10R

[0179] Compound B3R (40 mg, 0.07 mmol), N-tert-butyloxycarbonyl-4-piperidone (22 mg, 0.11 mmol), and zinc chloride (49 mg, 0.15 mmol) were sequentially dissolved in methanol (1 mL), followed by the addition of sodium cyanoborohydride (14 mg, 0.22 mmol). The reaction mixture was stirred at 75°C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure following TLC monitoring. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to afford compound B10R-a (25 mg, 47% yield) as a yellow solid. MS m / z 726.5 [M+H] + .

[0180] Compound B10R-a (25 mg, 0.03 mmol) was dissolved in methanol (1 mL), and a dioxane hydrochloride solution (4.0 M, 0.5 mL) was added. The reaction mixture was stirred at 40°C for 2 hours. TLC monitored the completion of the reaction. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in a small amount of methanol, neutralized with aqueous ammonia, and then concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% aqueous ammonia) to obtain Compound B10R (9.84 mg, 47% yield) as a yellow solid. 1H NMR(500MHz,CD3OD)δ8.49(s,1H),7.68(s,1H),7.28-7.13(m,4H),6.57(s,1H),4 .22(dd,J=10.5,2.4Hz,1H),3.94(dd,J=10.4,9.0Hz,1H),3.84(s,3H),3.79(d,J= 11.7Hz,1H),3.68(s,2H),3.17-2.95(m,9H),2.80-2.70(m,1H),2.66-2.56(m,2H) ,2.50-2.41(m,2H),2.05(t,J=10.8Hz,1H),1.96-1.88(m,2H),1.5-1.41(m,2H). MS m / z 626.3[M+H] + .

[0181] Example 17: Preparation of Compound B11R

[0182] 2,4-Dichloro-5-trifluoromethylpyrimidine (1.1 g, 3.28 mmol) was dissolved in dichloromethane (20 mL). Zinc chloride in tetrahydrofuran (6.56 mL, 1.0 M) was added at -10°C under a nitrogen atmosphere. Stirring was continued for one hour after the addition. Compound B11R-a (1.1 g, 3.28 mmol) and N,N-diisopropylethylamine (996 mg, 9.84 mmol) in dichloromethane were then slowly added dropwise under an ice bath. Stirring was continued at room temperature for 3 hours. The reaction was monitored for completion by LCMS, and the reaction solution was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound B11R-b1 (420 mg, 25% yield) as a yellow solid. MS m / z 516.0, 518.0 [M+H] + B11R-b2 (760 mg, yield 45%). MS m / z 516.0, 518.0 [M+H] + .

[0183] Compound B11R-b1 (700 mg, 1.36 mmol), triphenylphosphine (36 mg, 0.14 mmol), bistriphenylphosphine palladium dichloride (48 mg, 0.07 mmol), and cuprous iodide (26 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (20 mL). Compound B11R-c (284 mg, 1.63 mmol) and triethylamine (549 mg, 5.44 mmol) were added sequentially under nitrogen. The mixture was reacted at 120°C for one hour. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain Compound B11R-d (800 mg, 90% yield) as a yellow solid. MS m / z 654.2 [M+H] + .

[0184] Compound B11R-d (800 mg, 1.22 mmol), palladium on carbon (10%, 100 mg), and triethylamine (99 mg, 0.98 mmol) were added to N,N-dimethylformamide (20 mL) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. After the reaction was complete, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain a gray solid compound B11R-e (700 mg, yield 87%). MS m / z 658.2 [M+H] + .

[0185] Compound B11R-e (700 mg, 1.06 mmol) was dissolved in tetrahydrofuran and water (1:1, 50 mL), and lithium hydroxide (601 mg, 5.32 mmol) was added. The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure and washed with saturated sodium bicarbonate. The organic phase was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to obtain the crude product. The crude product was dissolved in a mixture of N,N-dimethylformamide and acetonitrile, and ammonium chloride (84 mg, 1.59 mmol), N,N-diisopropylethylamine (413 mg, 3.18 mmol), and HATU (806 mg, 2.12 mmol) were added in sequence. The mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound B11R-f (700 mg, yield 87%) as a gray solid. MS m / z 643.3[M+H] + .

[0186] Compound B11R-f (300 mg, 0.47 mmol) was dissolved in methanol (10 mL), and a dioxane hydrochloride solution (4.0 M, 2 mL) was added. The reaction mixture was stirred at 40°C for 2 hours. TLC monitored the reaction completion. The system was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was dissolved in a small amount of methanol, neutralized with ammonia, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia) to obtain Compound B11R-g (250 mg, 98% yield) as a yellow solid.

[0187] Compound B11R-g (50 mg, 0.09 mmol), paraformaldehyde (6 mg, 0.18 mmol), and zinc chloride (6 mg, 0.18 mmol) were sequentially dissolved in methanol (1 mL), followed by the addition of sodium cyanoborohydride (12 mg, 0.18 mmol). The reaction mixture was stirred at 75°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to afford Compound B11R (17 mg, 33% yield) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.04(s,1H),7.35(br,1H),7.33(s,1H),7.21-7.18(m ,1H),7.14-7.09(m,3H),6.86(br,1H),6.64(s,1H),4.20(dd,J=10.6,2.7Hz,1H),3.89-3. 77(m,2H),3.75(s,3H),3.45(s,2H),3.09-2.99(m,3H),2.99-2.92(m,2H),2.83(dd,J=40. 6,10.7Hz,2H),2.71-2.63(m,1H),2.22(s,3H),2.12-2.05(m,1H),1.69(t,J=10.6Hz,1H). MS m / z 557.3[M+H] + .

[0188] Example 18: Preparation of Compound B12R

[0189] Compound B11R-g (50 mg, 0.09 mmol), N-methyl-4-piperidone (12 mg, 0.10 mmol), and zinc chloride (25 mg, 0.18 mmol) were sequentially dissolved in methanol (1 mL), and sodium cyanoborohydride (12 mg, 0.18 mmol) was added. The reaction mixture was stirred at 75°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain Compound B12R (22 mg, 37% yield) as a yellow solid.

[0190] 1 H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.03(s,1H),7.34(br,1H),7.33(s,1H),7.21-7.17(m,1H),7.1 1(dd,J=5.6,3.9Hz,3H),6.86(br,1H),6.62(s,1H),4.21(dd,J=10.6,2.6Hz,1H),3.88-3.78(m,2H), 3.75(s,3H),3.45(s,2H),3.06-2.89(m,7H),2.79(d,J=11.1Hz,2H),2.65-2.59(m,1H),2.33-2.26( m,1H),2.19-2.15(m,1H),2.14(s,3H),1.91-1.79(m,3H),1.73(d,J=11.4Hz,2H),1.47-1.37(m,2H). MS m / z 640.3[M+H] + .

[0191] Example 19: Preparation of Compound C1S:

[0192] Compound D1S-e (50 mg, 0.16 mmol, preparation see Example 22) and compound C1S-a (54 mg, 0.16 mmol) were dissolved in 2-methoxyethanol (3 mL), followed by the addition of methanolic hydrochloric acid (2.5 M, 0.16 mL). The reaction mixture was placed in a sealed tube, heated to 120°C, and stirred overnight. TLC monitored the reaction completion. After the reaction mixture cooled to room temperature, an appropriate amount of aqueous ammonia was added to adjust the pH to approximately 7. The mixture was then concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to afford compound C1S (54 mg, 55% yield) as a yellow solid. 1H NMR(500MHz,MeOD-d4)δ8.45(d,J=8.1Hz,1H),7.99(s,1H),7.77(dd,J=8.0,1.6Hz,1H),7.63-7.54(m,1H),7. 26-7.18(m,2H),6.46(s,1H),4.11(dd,J=10.5,2.5Hz,1H),3.92(dd,J=11.2,4.2Hz,2H),3.8-3.80(m,1H),3.7 1-3.69(m,4H),3.38-3.29(m,3H),3.10-3.02(m,1H),3.01-2.91(m,2H),2.71-2.60(m,1H),2.48-2.38(m,1H) ,2.38-2.30(m,1H),1.92(t,J=10.5Hz,1H),1.79(d,J=11.5Hz,2H),1.54-1.43(m,2H),1.16(d,J=11.2Hz,6H). MS m / z 629.6[M+H] + .

[0193] Example 20: Preparation of Compound C2S

[0194] Compound D1S-b (150 mg, 0.57 mmol), N-methyl-4-piperidone (96 mg, 0.85 mmol) and zinc chloride (154 mg, 1.13 mmol) were dissolved in methanol (10 mL) in sequence, and sodium cyanoborohydride (106 mg, 1.70 mmol) was added. The reaction mixture was stirred at 75°C for 1 hour. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain a yellow solid compound C2S-a (150 mg, yield 73%). MS m / z 363.3 [M+H] + .

[0195] Compound C2S-a (150 mg, 0.41 mmol) and palladium on carbon (10%, 15 mg) were added to methanol (10 mL) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound C2S-b (137 mg, 100% yield) as a gray solid. MS m / z 333.3 [M+H] + .

[0196] Compound C2S-b (15 mg, 0.045 mmol), compound C1S-a (17 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (4 mg, 0.004 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (4 mg, 0.009 mmol), and potassium phosphate (29 mg, 0.13 mmol) were dissolved in tert-butanol (1 mL). The reaction mixture was placed in a sealed tube and heated to 110°C under a nitrogen atmosphere with stirring for 3 hours. Completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound C2S (4 mg, 14% yield) as a yellow solid. 1 H NMR(500MHz,CD3OD)δ8.54(d,J=8.4Hz,1H),8.09(s,1H),7.87(dd,J=8.0,1.6Hz,1H),7.70-7.63(m,1H), 7.33(s,1H),7.31-7.29(m,1H),6.55(s,1H),4.20(dd,J=10.5,2.6Hz,1H),3.93(dd,J=10.5,8.9Hz,1H),3 .81-3.78(m,4H),3.21-3.14(m,2H),3.13-3.03(m,2H),3.01(d,J=10.9Hz,1H),2.78-2.70(m,1H),2.51( s,3H),2.49-2.40(m,4H),2.05-1.99(m,2H),1.74-1.65(m,2H),1.31-1.27(m,2H),1.25(d,J=6.8Hz,6H). MS m / z 642.7[M+H] + .

[0197] Example 21: Preparation of Compound C3S

[0198] Compound D6S-d (100 mg, 0.28 mmol), compound C1S-a (114 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (13 mg, 0.01 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (13 mg, 0.03 mmol), and potassium phosphate (175 mg, 0.83 mmol) were dissolved in tert-butanol (2 mL). The reaction mixture was placed in a sealed tube and heated to 110°C under a nitrogen atmosphere and stirred for 3 hours. The reaction was monitored by TLC for completion. After the reaction mixture was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound C3S-a (100 mg, 54% yield) as a yellow solid. MS m / z 673.2, 675.1 [M+H] + .

[0199] Compound C3S-a (50 mg, 0.07 mmol) was dissolved in methanol (1 mL), and a dioxane hydrochloride solution (4.0 M, 1 mL) was added. The reaction solution was stirred at 40°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was dissolved in a small amount of methanol, neutralized with ammonia water, and then concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia water) to give compound C3S-b (30 mg, 70% yield) as a yellow solid.

[0200] Compound C3S-b (30 mg, 0.05 mmol), N-methyl-4-piperidone (9 mg, 0.08 mmol), and zinc chloride (14 mg, 0.10 mmol) were sequentially dissolved in methanol (2 mL) and stirred for 30 min before sodium cyanoborohydride (10 mg, 0.16 mmol) was added. The reaction mixture was stirred at 75°C for 1 hour. The reaction was monitored by TLC, and the mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to afford compound C3S (20 mg, 57% yield) as a yellow solid. 1H NMR(500MHz,MeOD-d4)δ8.53(d,J=8.2Hz,1H),8.10(s,1H),7.87(dd,J=8.0,1.5Hz,1H),7.71-7.65(m,1H),7.37(s,1H) ,7.34-7.29(m,1H),6.55(s,1H),4.48-4.40(m,1H),4.20(dd,J=10.5,2.6Hz,1H),3.92(dd,J=10.4,9.0Hz,1H),3.74-3. 67(m,1H),3.29-3.23(m,1H),3.12-3.03(m,2H),3.02-2.92(m,3H),2.72-2.67(m,1H),2.48-2.40(m,1H),2.36-2.30(m, 1H), 2.29 (s, 3H), 2.12-2.00 (m, 3H), 1.96-1.89 (m, 2H), 1.65-1.55 (m, 2H), 1.27 (d, J = 6.1Hz, 6H), 1.24 (d, J = 6.8Hz, 6H). MS m / z 670.3, 672.2[M+H] + .

[0201] Example 22: Preparation of Compound D1S

[0202] Compound D1S-a (800 mg, 2.19 mmol) was dissolved in methanol (5 mL), and a dioxane hydrochloride solution (4.0 M, 3 mL) was added. The reaction mixture was stirred at 40°C for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was dissolved in a small amount of methanol, neutralized with aqueous ammonia, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% aqueous ammonia) to obtain compound D1S-b (580 mg, 100% yield) as a yellow solid.

[0203] Compound D1S-b (280 mg, 1.06 mmol), tetrahydropyrone D1S-c (126 mg, 1.27 mmol), and zinc chloride (288 mg, 2.11 mmol) were sequentially dissolved in methanol (10 mL), and sodium cyanoborohydride (199 mg, 3.17 mmol) was added. The reaction mixture was stirred at 75°C for 1 hour. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound D1S-d (300 mg, 81% yield) as a yellow solid. MS m / z 350.3 [M+H] + .

[0204] Palladium-carbon catalyst (10%, 80 mg) was added to compound D1S-d (300 mg, 0.86 mmol) dissolved in methanol (10 mL) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. TLC monitored the reaction completion. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain a gray solid compound D1S-e (240 mg, yield 88%). MS m / z 320.3 [M+H] + .

[0205] Compound D1S-f (2.0 g, 13.32 mmol), D1S-g (4.5 g, 14.65 mmol), Pd2(dba)3 (1.22 g, 1.33 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.54 g, 2.66 mmol), and cesium carbonate (8.68 g, 26.63 mmol) were dissolved in 1,4-dioxane (35 mL). The mixture was stirred at 90°C under nitrogen for 2 hours. Completion of the reaction was monitored by TLC. After cooling to room temperature, the reaction mixture was filtered and washed. The filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound D1S-h (4.13 g, 90% yield) as a pale yellow solid. 1 H NMR (500MHz, CDCl3) δ10.13 (s, 1H), 8.41 (s, 1H), 7.56-7.45 (m, 3H), 7.30 (s, 1H), 7.15 (td, J = 7.6, 1.3Hz, 1H), 6.20 (s, 1H). MS m / z 330.4[M+H] + .

[0206] Compound D1S-h (34 mg, 0.10 mmol) and compound D1S-e (30 mg, 0.09 mmol) were dissolved in 2-methoxyethanol (1.5 mL), and methanolic hydrochloric acid (2.5 M, 0.10 mL) was added. The reaction mixture was placed in a sealed tube, heated to 120°C, and stirred overnight. TLC monitored the reaction completion. After the reaction mixture cooled to room temperature, an appropriate amount of aqueous ammonia was added to adjust the pH to approximately 7. The mixture was then concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to afford compound D1S (8 mg, 14% yield) as an off-white solid. 1H NMR (500MHz, DMSO-d6) δ10.16(s,1H),8.67-8.61(m,1H),8.30(s,1H),8.16(s,1H),7.68(dd,J=7.9,1.2Hz,1H),7.48(t,J=9.2H z,1H),7.45(t,J=7.1Hz,1H),7.10(s,1H),7.09-7.04(m,1H),6.63(s,1H),6.54(s,1H),4.18(dd,J=10.5,2.5Hz,1H),3.90(dd, J=10.9,3.6Hz,2H),3.84-3.75(m,2H),3.73(s,3H),3.31-3.24(m,2H),2.99(d,J=11.0Hz,1H),2.96-2.90(m,2H),2.75(d,J=4. 5Hz,3H),2.62-2.55(m,1H),2.46-2.38(m,1H),2.33-2.24(m,1H),1.86(t,J=11.1Hz,1H),1.74-1.71(m,2H)1.47-1.38(m,2H). MS m / z 613.7[M+H] + .

[0207] Example 23: Preparation of Compound D1R

[0208] Compound D1R-a (900 mg, 5.14 mmol), iodomethane (2.19 g, 15.42 mmol), and potassium carbonate (2.13 g, 15.42 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at room temperature for 12 hours. LCMS monitored the completion of the reaction, and the reaction solution was quenched with water. The mixed solution was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound D1R-b (824 mg, 85% yield) as a yellow solid.

[0209] Compound D1R-b (250 mg, 1.32 mmol) and (R)-1-tert-butyloxycarbonyl-3-hydroxymethylpiperazine (286 mg, 1.32 mmol) were dissolved in dimethyl sulfoxide (5 mL). Potassium hydroxide (223 mg, 3.97 mmol) was added and stirred at room temperature for 1 hour. The mixture was then heated to 60°C and reacted for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain compound D1R-c (235 mg, 49% yield) as a yellow solid.

[0210] Compound D1R-c (217 mg, 0.59 mmol) and palladium on carbon (10%, 20 mg) were added to methanol (10 mL) at room temperature, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford a crude gray solid compound D1R-d (199 mg), which was used directly in the next reaction.

[0211] Compound D1R-d (199 mg, 0.59 mmol) and compound D1S-h (215 mg, 0.65 mmol), tris(dibenzylideneacetone)dipalladium (54 mg, 0.06 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (62 mg, 0.12 mmol), and potassium phosphate (377 mg, 1.77 mmol) were dissolved in tert-butanol (10 mL). The reaction mixture was heated to 110°C and stirred for 3 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound D1R-e (206 mg, 55% yield) as a yellow solid.

[0212] Compound D1R-e (199 mg, 0.59 mmol) was dissolved in methanol (5 mL), and a methanolic hydrogen chloride solution (4 M, 2 mL) was added. The reaction mixture was heated and stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% aqueous ammonia) to obtain compound D1R-f (87 mg, 92% yield) as a yellow solid.

[0213] Compound D1R-f (30 mg, 0.06 mmol), 4-oxanone (9 mg, 0.09 mmol), and zinc chloride (23 mg, 0.17 mmol) were sequentially dissolved in methanol (2 mL), and sodium cyanoborohydride (11 mg, 0.17 mmol) was added. The reaction mixture was heated and stirred at 65°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound D1R (14 mg, 40% yield) as a yellow solid. 1 H NMR (500MHz, DMSO-d6) δ10.17(s,1H),8.66-8.63(m,1H),8.30(s,1H),8.16(s,1H),7.68(dd,J=7.9,1.3Hz,1H),7.48(t,J =9.2Hz,1H),7.46(t,J=9.0Hz,1H),7.12(s,1H),7.10-7.06(m,1H),6.63(s,1H),6.54(s,1H),4.18(dd,J=10.5,2.5Hz,1H ),3.90(dd,J=10.6,3.6Hz,2H),3.85-3.75(m,2H),3.73(s,3H),3.31-3.25(m,2H),3.02-2.90(m,3H),2.76(d,J=4.5Hz,3 H),2.61-2.55(m,1H),2.46-2.39(m,1H),2.32-2.25(m,1H),1.86(t,J=11.0Hz,1H),1.76-1.69(m,2H),1.47-1.36(m,2H). MS m / z 613.6[M+H] + .

[0214] Example 24: Preparation of Compound D2S

[0215] Compound D2S-a (40 mg, 0.12 mmol), D1S-h (44 mg, 0.13 mmol), Pd2(dba)3 (11 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14 mg, 0.02 mmol), and cesium carbonate (78 mg, 0.24 mmol) were dissolved in 1,4-dioxane (2.5 mL). The mixture was stirred at 95°C for 2 hours under nitrogen. The reaction was monitored for completion by TLC. After cooling to room temperature, the reaction mixture was filtered and washed. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound D2S (3 mg, 4% yield) as an off-white solid. MS m / z 626.7 [M+H] + .

[0216] Example 25: Preparation of Compound D2R

[0217] Compound D1R-f (30 mg, 0.06 mmol), N-methyl-4-piperidone (10 mg, 0.09 mmol), and zinc chloride (23 mg, 0.17 mmol) were sequentially dissolved in methanol (2 mL), and sodium cyanoborohydride (11 mg, 0.17 mmol) was added. The reaction mixture was heated and stirred at 65°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound D2R (18 mg, 51% yield) as a yellow solid. 1 H NMR(500MHz,CD3OD)δ8.09(s,1H),7.59(dd,J=7.8,1.4Hz,1H),7.49(dd,J=8.2,0.8Hz,1H),7.45-7.4 0(m,1H),7.10-7.06(m,1H),6.86(s,1H),6.52(s,1H),6.46(s,1H),4.17(dd,J=10.5,2.6Hz,1H),3.91 -3.86(m,1H),3.79-3.73(m,4H),3.11-2.94(m,5H),2.86(s,3H),2.76-2.69(m,1H),2.46-2.39(m,1H ),2.37-2.29(m,4H),2.19-2.10(m,2H),2.01(t,J=10.8Hz,1H),1.96-1.90(m,2H),1.66-1.56(m,2H). MS m / z 626.7[M+H] + .

[0218] Example 26: Preparation of Compound D3S

[0219] Compound D1S-b (60 mg, 0.23 mmol), 3-oxetanone (25 mg, 0.34 mmol), and zinc chloride (62 mg, 0.45 mmol) were sequentially dissolved in methanol (2 mL), and sodium cyanoborohydride (43 mg, 0.68 mmol) was added. The reaction mixture was stirred at 75°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound D3S-a (50 mg, yield 69%) as a yellow solid. MS m / z 322.3 [M+H] + .

[0220] Compound D3S-a (50 mg, 0.16 mmol) and palladium on carbon (10%, 5 mg) were added to methanol (10 mL) at room temperature, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. TLC monitored the reaction completion. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain a gray solid compound D3S-b (36 mg, yield 79%). MS m / z 292.3 [M+H] + .

[0221] Compound D3S-b (36 mg, 0.12 mmol) and compound D1S-h (41 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.012 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (11 mg, 0.024 mmol), and potassium phosphate (76 mg, 0.36 mmol) were dissolved in tert-butanol (1 mL). The reaction mixture was placed in a sealed tube and heated to 110°C under a nitrogen atmosphere and stirred for 3 hours. The reaction was monitored by TLC. After the reaction mixture was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound D3S (20 mg, 28% yield) as a yellow solid. 1H NMR(500MHz,DMSO-d6)δ10.17(s,1H),8.67-8.61(m,1H),8.31(s,1H),8.17(s,1H),7.68(dd,J=7.9,1.3Hz,1H),7 .51-7.47(m,1H),7.47-7.42(m,1H),7.12(br.,1H),7.10-7.04(m,1H),6.64(br.,1H),6.55(s,1H),4.61-4.53(m, 2H),4.51-4.44(m,2H),4.17(dd,J=10.6,2.6Hz,1H),3.84-3.77(m,2H),3.73(s,3H),3.48-3.41(m,1H),3.06-2. 99(m,1H),2.84-2.77(m,2H),2.76(d,J=4.5Hz,3H),2.69-2.61(m,1H),2.06-1.98(m,1H),1.62(t,J=10.6Hz,1H). MS m / z 585.6[M+H] + .

[0222] Example 27: Preparation of Compound D4S

[0223] Compound D1S-b (50 mg, 0.19 mmol), 1-methyl-3-azetidinone hydrochloride (69 mg, 0.57 mmol), and zinc chloride (77 mg, 0.5 mmol) were sequentially dissolved in methanol (2 mL), and sodium cyanoborohydride (24 mg, 0.38 mmol) was added. The reaction mixture was stirred at 65°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to afford compound D4S-a (45 mg, 71% yield) as a yellow solid.

[0224] Compound D4S-a (45 mg, 0.13 mmol) and palladium on carbon (10%, 5 mg) were added to methanol (5 mL) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude gray solid compound D4S-b (39 mg, 95% yield), which was used directly in the next reaction.

[0225] Compound D4S-b (14 mg, 0.05 mmol), compound D1S-h (17 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (12 mg, 0.02 mmol), and potassium phosphate (29 mg, 0.15 mmol) were dissolved in tert-butanol (3 mL). The reaction mixture was heated to 110°C and stirred for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound D4S (12 mg, 44% yield) as a yellow solid. 1 H NMR(500MHz,CD3OD)δ8.09(s,1H),7.61(dd,J=7.8,1.4Hz,1H),7.50(d,J=8.3Hz,1H),7.45-7.41(m,1 H),7.11-7.06(m,1H),6.91(d,J=2.6Hz,1H),6.54(s,1H),6.49(s,1H),4.20-4.12(m,3H),3.99-3.87( m,3H),3.84-3.78(m,1H),3.76(s,3H),3.29-3.25(m,1H),3.13-3.06(m,1H),2.97-2.92(m,1H),2.88 (s,3H),2.87(s,3H),2.86-2.83(m,1H),2.80-2.73(m,1H),2.19-2.13(m,1H),1.77(t,J=10.6Hz,1H). MS m / z 598.6[M+H] + .

[0226] Example 28: Preparation of Compound D5S

[0227] Compound D5S-a (500 mg, 2.86 mmol) and potassium carbonate (1.18 g, 8.57 mmol) were dissolved in N,N-dimethylformamide (10 mL), and iodoethane (890 mg, 5.71 mmol) was slowly added. The reaction system was stirred at room temperature for 12 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain a yellow solid compound D5S-b (530 mg, yield 91%).

[0228] Compound D5S-b (200 mg, 0.98 mmol) and (S)-1-Boc-3-hydroxymethylpiperazine (213 mg, 0.98 mmol) were dissolved in dimethyl sulfoxide (10 mL). Potassium hydroxide (165 mg, 2.95 mmol) was added, stirred at room temperature for 1 hour, and then heated to 60°C for 12 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain compound D5S-c (160 mg, 43% yield) as a yellow solid.

[0229] Compound D5S-c (160 mg, 0.42 mmol) and palladium on carbon (10%, 20 mg) were added to a methanol solution (10 mL) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After the reaction was complete, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain a gray solid compound D5S-d (50 mg, yield 34%). MS m / z 350.2 [M+H] + .

[0230] Compound D5S-d (50 mg, 0.14 mmol), compound D5S-e (56 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.007 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (7 mg, 0.014 mmol), and potassium phosphate (91 mg, 0.43 mmol) were dissolved in tert-butanol (1 mL). The reaction mixture was placed in a sealed tube and heated to 110°C under a nitrogen atmosphere and stirred for 3 hours. The reaction was monitored by TLC for completion. After the reaction system was cooled to room temperature, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound D5S-f (60 mg, 65% yield) as a yellow solid. MS m / z 643.2 [M+H] + .

[0231] Compound D5S-f (50 mg, 0.08 mmol) was dissolved in methanol (1 mL), and a dioxane hydrochloride solution (4.0 M, 1 mL) was added. The reaction mixture was stirred at 40°C for 2 hours. TLC monitored the completion of the reaction. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was dissolved in a small amount of methanol, neutralized with ammonia, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia) to obtain compound D5S-g (42 mg, 100% yield) as a yellow solid.

[0232] Compound D5S-g (42 mg, 0.08 mmol) was dissolved in methanol (2 mL). N-methyl-4-piperidone (13 mg, 0.12 mmol) and zinc chloride (21 mg, 0.15 mmol) were added to the mixture. After stirring for 30 min, sodium cyanoborohydride (15 mg, 0.23 mmol) was added. The reaction mixture was stirred at 75°C for 1 hour. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound D5S (32 mg, 65% yield) as a yellow solid. 1 H NMR(500MHz,MeOD-d4)δ8.09(s,1H),7.60(dd,J=7.9,1.4Hz,1H),7.50(dd,J=8.2,0.7Hz,1H),7.44-7.39(m,1H),7.11 -7.05(m,1H),6.80(s,1H),6.49(d,J=3.0Hz,2H),4.14(dd,J=10.5,2.6Hz,1H),4.00-3.93(m,2H),3.90-3.83(m,1H),3 .73-3.65(m,1H),3.08-2.99(m,2H),2.98-2.89(m,3H),2.86(s,3H),2.73-2.63(m,1H),2.42-2.34(m,1H),2.32-2.23 (m,4H),2.04(t,J=11.4Hz,2H),1.96(t,J=10.8Hz,1H),1.92-1.84(m,2H),1.63-1.51(m,2H),1.28(t,J=7.0Hz,3H).MS m / z 640.1[M+H] + .

[0233] Example 29: Preparation of Compound D6S

[0234] Compound D6S-a (500 mg, 2.86 mmol), 2-iodopropane (970 mg, 5.71 mmol), and potassium carbonate (1.18 g, 8.57 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction system was stirred at room temperature for 12 hours. After completion, the reaction was quenched with water, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain compound D6S-b (300 mg, 48% yield) as a yellow solid.

[0235] Compound D6S-b (150 mg, 0.69 mmol) and (S)-1-Boc-3-hydroxymethylpiperazine (149 mg, 0.69 mmol) were dissolved in dimethyl sulfoxide (5 mL). Potassium hydroxide (116 mg, 2.07 mmol) was added, stirred at room temperature for 1 hour, and then heated to 60°C for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain compound D6S-c (170 mg, 62% yield) as a yellow solid.

[0236] Compound D6S-c (170 mg, 0.43 mmol) and palladium on carbon (10%, 10 mg) were added to a methanol solution (5 mL) at room temperature. The reaction system was stirred at room temperature under a hydrogen atmosphere for 1 hour. After the reaction was complete, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain a gray solid compound D6S-d (140 mg, yield 89%). MS m / z 364.5 [M+H] + .

[0237] Compound D6S-d (160 mg, 0.44 mmol), compound D1S-h (159 mg, 0.48 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (21 mg, 0.04 mmol), and potassium phosphate (280 mg, 1.32 mmol) were dissolved in tert-butanol (5 mL). The reaction mixture was placed in a sealed tube and heated to 110°C under a nitrogen atmosphere and stirred for 3 hours. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound D6S-e (200 mg, yield 69%) as a yellow solid. MS m / z 657.1 [M+H] + .

[0238] Compound D6S-e (200 mg, 0.30 mmol) was dissolved in methanol (1 mL), and a dioxane hydrochloride solution (4.0 M, 1 mL) was added. The reaction mixture was stirred at 40°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was dissolved in a small amount of methanol, neutralized with ammonia, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia) to obtain compound D6S-f (170 mg, 100% yield) as a yellow solid.

[0239] Compound D6S-f was dissolved in methanol (2 mL) (50 mg, 0.09 mmol), and N-methyl-4-piperidone (15 mg, 0.13 mmol) and zinc chloride (25 mg, 0.18 mmol) were added sequentially. After stirring for 30 min, sodium cyanoborohydride (17 mg, 0.27 mmol) was added. The reaction mixture was stirred at 75 ° C for 1 hour. TLC monitoring of the reaction completion was performed. The mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain a yellow solid compound D6S (23 mg, 39% yield). 1 H NMR(500MHz,MeOD-d4)δ8.11-8.07(m,1H),7.59(dd,J=7.9,1.4Hz,1H),7.55-7.51(m,1H),7.44-7.38(m,1H),7.10-7. 05(m,1H),6.78(s,1H),6.53(s,1H),6.49(s,1H),4.38-4.30(m,1H),4.18(dd,J=10.5,2.6Hz,1H),3.93-3.86(m,1H), 3.73-3.67(m,1H),3.08-3.00(m,4H),2.99-2.94(m,1H),2.86(s,3H),2.73-2.65(m,1H),2.44-2.39(m,1H),2.38-2.3 1(m,4H),2.25-2.15(m,2H),2.00(t,J=10.7Hz,1H),1.96-1.89(m,2H),1.67-1.57(m,2H),1.19(dd,J=6.1,2.1Hz,6H). MS m / z 654.2[M+H] + .

[0240] Example 30: Preparation of Compound E1R

[0241] Compound E1R-a (200 mg, 0.62 mmol) (the synthetic route of intermediate E1R-a is prepared according to the method in patent WO2021 / 003417A1) and compound E1R-b (207 mg, 0.62 mmol) were dissolved in tert-butanol (5 mL), and trifluoroacetic acid (126 mg, 1.23 mmol) was added. The reaction system was stirred at 90 ° C for 14 hours. After the reaction was completed, the reaction solution was quenched with water, and the mixed solution was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to give compound E1R-c (250 mg, yield 65%).

[0242] Compound E1R-c (250 mg, 0.40 mmol) was dissolved in dichloromethane (10 mL), and a dioxane hydrochloride solution (4.0 M, 2 mL) was added. The mixture was stirred at room temperature for 2 hours. TLC monitored the reaction completion. The reaction system was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was dissolved in a small amount of methanol, neutralized with aqueous ammonia, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to obtain Compound E1R (160 mg, 76% yield) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ8.74(s,1H),8.28-8.26(m,1H),8.26(s,1H),8.09(s,1H),7.75(s,1H),7.32(dd,J= 7.2,5.5Hz,1H),7.05(br.,1H),6.50(s,1H),4.15(dd,J=10.5,2.4Hz,1H),4.02(t,J=7.0Hz,2H),3.82-3.7 6(m,1H),3.71(s,3H),3.64(d,J=11.2Hz,1H),2.98(d,J=12.1Hz,1H),2.91-2.81(m,2H),2.71(d,J=3.1Hz, 1H), 2.60 (t, J = 8.0Hz, 2H), 2.49-2.45 (m, 1H), 2.43-2.33 (m, 1H), 2.28 (t, J = 10.9Hz, 1H), 2.16-2.08 (m, 2H). MS m / z 523.2, 525.1[M+H] + .

[0243] Example 31: Preparation of Compound E2R

[0244] Compound E1R (35 mg, 0.07 mmol), paraformaldehyde (3 mg, 0.10 mmol), and zinc chloride (19 mg, 0.14 mmol) were sequentially dissolved in methanol (1 mL), followed by the addition of sodium cyanoborohydride (9 mg, 0.14 mmol). The reaction mixture was stirred at 75°C for 1 hour. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to afford compound E2R (24 mg, 66% yield) as a yellow solid. 1H NMR(500MHz,DMSO-d6)δ8.75(s,1H),8.26(d,J=6.1Hz,2H),8.09(s,1H),7.75(s,1H),7.36 -7.28(m,1H),7.07(s,1H),6.53(s,1H),4.19(d,J=10.4Hz,1H),4.02(t,J=6.9Hz,2H),3.8 6-3.80(m,1H),3.75(d,J=11.6Hz,1H),3.71(s,3H),2.99(t,J=9.0Hz,1H),2.82(dd,J=33. 5,10.4Hz,2H),2.68-2.57(m,3H),2.22(s,3H),2.16-2.03(m,3H),1.69(t,J=10.5Hz,1H). MS m / z 537.3, 539.2[M+H] + .

[0245] Example 32: Preparation of Compound E3R

[0246] Compound E1R (35 mg, 0.07 mmol), N-methyl-4-piperidone (12 mg, 0.10 mmol), and zinc chloride (19 mg, 0.14 mmol) were sequentially dissolved in methanol (1 mL), followed by the addition of sodium cyanoborohydride (9 mg, 0.14 mmol). The reaction mixture was stirred at 75°C for 1 hour. Upon completion of the reaction, the reaction system was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to afford compound E3R (25 mg, 61% yield) as a yellow solid. 1H NMR (500MHz, DMSO-d6) δ8.75(s,1H),8.28-8.26(m,1H),8.26(s,1H),8.09(s,1H),7.75(s,1H),7.32(dd,J=7. 4,5.2Hz,1H),7.06(s,1H),6.52(s,1H),4.20(dd,J=10.6,2.4Hz,1H),4.02(t,J=7.0Hz,2H),3.83(dd,J=10.5, 8.9Hz,1H),3.76(d,J=11.6Hz,1H),3.71(s,3H),2.99-2.89(m,3H),2.80(d,J=11.1Hz,2H),2.63-2.53(m,3H), 2.30(dd,J=11.0,8.0Hz,1H),2.20-2.08(m,6H),1.91-1.81(m,3H),1.74(d,J=10.4Hz,2H),1.48-1.37(m,2H). MS m / z 620.3, 622.2[M+H] + .

[0247] Example 33: Preparation of Compound E4R

[0248] Compound E1R (35 mg, 0.07 mmol), tetrahydropyrone (10 mg, 0.10 mmol), and zinc chloride (19 mg, 0.14 mmol) were sequentially dissolved in methanol (1 mL), followed by the addition of sodium cyanoborohydride (9 mg, 0.14 mmol). The reaction mixture was stirred at 75°C for 1 hour. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to afford compound E4R (23 mg, 57% yield) as a yellow solid. 1H NMR(500MHz,DMSO-d6)δ8.75(s,1H),8.27(br.,1H),8.26(br.,1H),8.09(s,1H),7.75(s,1H),7.36-7.28( m,1H),7.06(s,1H),6.53(s,1H),4.23-4.18(m,1H),4.02(t,J=6.9Hz,2H),3.93-3.87(m,2H),3.87-3.81(m ,1H),3.80-3.75(m,1H),3.71(s,3H),3.29-3.25(m,2H),3.01-2.90(m,2H),2.63-2.55(m,3H),2.47-2.35( m,2H),2.33-2.26(m,1H),2.15-2.08(m,2H),1.88(t,J=11.1Hz,1H),1.76-1.70(m,2H),1.48-1.38(m,2H). MS m / z 607.3, 609.2[M+H] + .

[0249] Example 34: Preparation of Compound E5R

[0250] Compound E1R (20 mg, 0.04 mmol) was dissolved in acetonitrile (1 mL), and acetic acid (5 mg, 0.08 mmol), N,N-diisopropylethylamine (15 mg, 0.12 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (30 mg, 0.08 mmol) were added sequentially. The mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound E5R (16 mg, 73% yield) as a yellow solid. MS m / z 565.2, 567.1 [M+H] + .

[0251] 1H NMR(500MHz,DMSO-d6)δ8.78-8.72(m,1H),8.27(s,1H),8.26(t,J=2.1Hz,1H),8.10(s,1H),7.76(br.,1H) ),7.33(dd,J=7.3,4.6Hz,1H),7.11(d,J=5.0Hz,1H),6.59(s,1H),4.43(t,J=14.7Hz,1H),4.28(dd,J=10 .7,2.6Hz,1H),4.02(t,J=7.0Hz,2H),3.94-3.82(m,3H),3.72(s,3H),3.29-3.19(m,1H),2.90-2.82(m,1 H), 2.77-2.63 (m, 1H), 2.60 (t, J = 8.0Hz, 2H), 2.47-2.33 (m, 1H), 2.17-2.08 (m, 2H), 2.07 (d, J = 1.8Hz, 3H). MS m / z 565.2, 567.1[M+H] + .

[0252] Example 35: Preparation of Compound E6R

[0253] Compound E1R (20 mg, 0.04 mmol) was dissolved in acetonitrile (1 mL), followed by the addition of propionic acid (4 mg, 0.06 mmol), N,N-diisopropylethylamine (15 mg, 0.12 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30 mg, 0.08 mmol). The mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain solid compound E6R (10 mg, 45% yield). 1H NMR (500MHz, CD3OD) δ8.32-8.29(m,1H),8.27-8.23(m,1H),8.00(s,1H),7.40(dd,J=8.1,4. 7Hz,1H),7.28(s,1H),6.54(d,J=5.5Hz,1H),4.62-4.51(m,1H),4.29-4.21(m,1H),4.09(t, J=7.0Hz,2H),4.06-3.96(m,1H),3.95-3.90(m,1H),3.83(br.,1H),3.80(s,3H),3.04-2.82 (m,3H),2.66(t,J=8.0Hz,2H),2.55-2.42(m,3H),2.24-2.17(m,2H),1.14(t,J=7.5Hz,3H). MS m / z 579.3, 581.1[M+H] + .

[0254] Example 36: Preparation of Compound E7R

[0255] Compound E1R (20 mg, 0.04 mmol) was dissolved in acetonitrile (1 mL), and cyclopropanecarboxylic acid (7 mg, 0.08 mmol), N,N-diisopropylethylamine (15 mg, 0.12 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30 mg, 0.08 mmol) were added sequentially. The mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain solid compound E7R (10.36 mg, 46% yield). 1H NMR(500MHz,CD3OD)δ8.30(dd,J=4.7,1.6Hz,1H),8.25(d,J=8.0Hz,1H),7.99(s,1H),7.40(dd,J=8 .1,4.7Hz,1H),7.28(s,1H),6.54(s,1H),4.63-4.19(m,4H),4.09(t,J=7.0Hz,2H),3.98-3.90(m,1 H),3.84(dd,J=11.6,3.1Hz,1H),3.80(s,3H),3.11-3.00(m,1H),2.97-2.87(m,1H),2.66(t,J=8.0 Hz,2H),2.60-2.51(m,1H),2.25-2.16(m,2H),2.03(br.,1H),0.96-0.89(m,2H),0.88-0.80(m,2H). MS m / z 591.2, 593.2[M+H] + .

[0256] Example 37: Preparation of Compound E8R

[0257] Compound E1R (50 mg, 0.09 mmol), 1-Boc-3-azetidinone (25 mg, 0.14 mmol), and zinc chloride (25 mg, 0.18 mmol) were dissolved in methanol (2 mL), and sodium cyanoborohydride (11 mg, 0.18 mmol) was added. The reaction mixture was stirred at 75°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure following TLC monitoring. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to afford compound E8R-a (48 mg, 74% yield) as a yellow solid.

[0258] Compound E8R-a (48 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL), and a dioxane hydrochloride solution (4.0 M, 1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. TLC monitored the reaction completion, and the reaction solution was concentrated under reduced pressure. The resulting crude product was dissolved in a small amount of methanol, neutralized with ammonia, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia) to obtain compound E8R-b (40 mg, 98% yield) as a yellow solid.

[0259] Compound E8R-b (40 mg, 0.07 mmol), paraformaldehyde (3 mg, 0.10 mmol), and zinc chloride (19 mg, 0.14 mmol) were dissolved in methanol (2 mL), followed by the addition of sodium cyanoborohydride (9 mg, 0.14 mmol). The reaction mixture was stirred at 75°C for 1 hour. Completion of the reaction was monitored by TLC. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to afford compound E8R (18 mg, 44% yield) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ8.75(s,1H),8.27(br.,1H),8.26(s,1H),8.09(s,1H),7.76(br., 1H),7.35-7.29(m,1H),7.07(br.,1H),6.53(s,1H),4.19(dd,J=10.5,2.6Hz,1H),4.02(t ,J=7.0Hz,2H),3.87-3.74(m,3H),3.71(s,3H),3.00-2.94(m,1H),2.90-2.70(m,6H),2.6 3-2.57(m,3H),2.23(s,3H),2.15-2.08(m,2H),2.02-1.95(m,1H),1.61(t,J=10.6Hz,1H). MS m / z 592.2, 594.1[M+H] + .

[0260] Example 38: Preparation of Compound E9R

[0261] Compound E1R (100 mg, 0.19 mmol), N-Boc-4-piperidone (57 mg, 0.29 mmol), and zinc chloride (52 mg, 0.38 mmol) were dissolved in methanol (5 mL), and sodium cyanoborohydride (24 mg, 0.38 mmol) was added. The reaction mixture was stirred at 75°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to afford compound E9R-a (100 mg, 74% yield) as a yellow solid.

[0262] Compound E9R-a (100 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL), and a dioxane hydrochloride solution (4.0 M, 1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. TLC monitored the reaction completion. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was dissolved in a small amount of methanol, neutralized with aqueous ammonia, and then concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to obtain compound E9R-b (70 mg, 82% yield) as a yellow solid.

[0263] Compound E9R-b (20 mg, 0.03 mmol), acetaldehyde (2 mg, 0.05 mmol), and zinc chloride (8 mg, 0.06 mmol) were dissolved in methanol (2 mL), followed by the addition of sodium cyanoborohydride (4 mg, 0.06 mmol). The reaction mixture was stirred at 75°C for 1 hour. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% aqueous ammonia) to afford compound E9R (11 mg, 53% yield) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ8.75(s,1H),8.29-8.26(m,1H),8.26(s,1H),8.09(s,1H),7.75(br.,1H),7.35-7.30( m,1H),7.06(br.,1H),6.52(s,1H),4.20(dd,J=10.5,2.3Hz,1H),4.02(t,J=7.0Hz,2H),3.83(dd,J=10.5,8.9 Hz,1H),3.79-3.74(m,1H),3.71(s,3H),2.99-2.87(m,5H),2.60(t,J=7.9Hz,2H),2.57-2.54(m,1H),2.34-2. 26(m,3H),2.23-2.17(m,1H),2.15-2.08(m,2H),1.92-1.73(m,5H),1.46-1.37(m,2H),0.98(t,J=7.2Hz,3H). MS m / z 634.2, 636.2[M+H] + .

[0264] Example 39: Preparation of Compound E10R

[0265] Compound E9R-b (20 mg, 0.03 mmol) and 1-ethoxy-1-trimethylsilyloxycyclopropane (11 mg, 0.06 mmol) were dissolved in methanol (1 mL). One drop of acetic acid was added dropwise. The mixture was stirred at room temperature for one hour, and then sodium cyanoborohydride (19 mg, 0.3 mmol) was added. The reaction system was stirred at room temperature for another 12 hours. The reaction was monitored for completion by TLC, and the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to afford compound E10R (7.68 mg, 36% yield) as a yellow solid. 1 H NMR (500MHz, CD3OD) δ8.29(dd,J=4.6,1.5Hz,1H),8.26(dd,J=8.1,1.5Hz,1H),7.99(s,1H),7.39(dd,J=8.1,4.7Hz,1H),7.24( s,1H),6.49(s,1H),4.18(dd,J=10.5,2.5Hz,1H),4.09(t,J=7.0Hz,2H),3.89(dd,J=10.3,9.0Hz,1H),3.79(s,3H),3.73(d,J=1 1.8Hz,1H),3.14-2.96(m,5H),2.74-2.69(m,1H),2.66(t,J=8.0Hz,2H),2.46-2.39(m,1H),2.38-2.31(m,1H),2.29-2.17(m,4 H), 2.02 (t, J = 10.7Hz, 1H), 1.91 (d, J = 12.4Hz, 2H), 1.68-1.62 (m, 1H), 1.58-1.48 (m, 2H), 0.51-0.47 (m, 2H), 0.44-0.39 (m, 2H). MS m / z646.3, 648.2[M+H] + .

[0266] Example 40: Preparation of Compound E11R

[0267] Compound E9R-b (20 mg, 0.03 mmol) was dissolved in acetonitrile (1 mL), and acetic acid (4 mg, 0.06 mmol), N,N-diisopropylethylamine (12 mg, 0.09 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were added sequentially. The mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain solid compound E11R (14.35 mg, yield 67%). 1H NMR(500MHz,DMSO-d6)δ8.75(s,1H),8.29-8.26(m,1H),8.26(s,1H),8.09(s,1H),7.75(br.,1H),7.34-7.30( m,1H),7.06(br.,1H),6.52(s,1H),4.39(d,J=12.2Hz,1H),4.20(d,J=10.8Hz,1H),4.02(t,J=7.0Hz,2H),3.86 -3.80(m,2H),3.79-3.74(m,1H),3.71(s,3H),3.01(t,J=12.7Hz,1H),2.96-2.87(m,3H),2.65-2.53(m,5H),2. 39-2.32(m,1H),2.15-2.08(m,2H),1.99(s,3H),1.94(t,J=10.5Hz,1H),1.83-1.73(m,2H),1.45-1.30(m,2H). MS m / z648.2, 650.2[M+H] + .

[0268] Example 41: Preparation of Compound A10R

[0269] The trifluoroacetate salt of compound A4R (80 mg, 0.12 mmol) and N-tert-butyloxycarbonyl-4-piperidone (48 mg, 0.24 mmol) were dissolved in tetrahydrofuran (3 mL) and stirred at room temperature for 15 minutes. Then, sodium triacetoxyborohydride (102 mg, 0.48 mmol) was added and stirring continued at room temperature for 6 hours. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound A10R-a (47 mg, 52% yield) as a yellow solid. MS m / z 733.3 [M+H] + .

[0270] Compound A10R-a (47 mg, 0.06 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 60 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrated crude product was dissolved in methanol (4 mL). Ammonia water (2 mL) was added, and the mixture was stirred for 15 minutes and concentrated under reduced pressure again. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia water) to obtain Compound A10R (22.5 mg, 55% yield) as a white solid. 1H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.06-7.99(m,1H),6.94(s,1H),6.73-6.59(m,2H),4.19(dd ,J=10.5,2.3Hz,1H),3.90-3.80(m,1H),3.76-3.68(m,1H),3.66-3.52(m,4H),3.43-3.35(m,2H) ,3.29-3.16 (m, 4H),3.02-2.84 (m, 5H),2.65-2.51 (m, 3H),2.47-2.25 (m, 6H),1.90 (t, J = 10.3 Hz, 1H),1.75-1.65 (m, 2H),1.64-1.50 (m, 2H),1.32-1.20 (m, 2H),1.03 (t, J = 7.5 Hz, 3H), one of the H is in the solvent peak. MS m / z 633.1 [M+H] + .

[0271] Example 42: Preparation of Compound A11R

[0272] Compound A4R (40 mg, 0.06 mmol) and N-tert-butyloxycarbonyl-4-cyclobutanone (21 mg, 0.12 mmol) were dissolved in tetrahydrofuran (3 mL) and stirred at room temperature for 15 minutes. Then, sodium triacetoxyborohydride (26 mg, 0.12 mmol) was added and stirring continued at room temperature for 6 hours. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia water) to obtain compound A11R-a (14 mg, 32% yield) as a yellow solid. MS m / z 705.5 [M+H] + .

[0273] Compound A4R-a (14 mg, 0.02 mmol) was dissolved in dichloromethane (2 mL) and a 4 M solution of hydrogen chloride in dioxane (0.2 mL) was slowly added dropwise under an ice bath. The reaction mixture was stirred at room temperature for 1 hour. Ammonia was added to adjust the pH to 8-10 and the mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer plate separation to afford compound A11R-b (10 mg, 83% yield) as a white solid. MS m / z 605.3 [M+H] + .

[0274] Compound A11R-b (10 mg, 0.016 mmol) was dissolved in methanol (1 mL), and paraformaldehyde (1.5 mg, 0.048 mmol) was added, followed by acetic acid (1 drop). The mixture was stirred at room temperature for 30 minutes, and then sodium cyanoborohydride (3 mg, 0.05 mmol) was added. The reaction mixture was stirred at room temperature overnight, quenched with water, and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation to obtain compound A11R (0.43 mg, yield 0.42%) as a white solid. MS m / z 619.0 [M+H] + .

[0275] Example 43: Preparation of Compound A12R

[0276] The trifluoroacetic acid salt of compound A4R (35 mg, 0.05 mmol) and 3-oxetanone (7 mg, 0.10 mmol) were dissolved in tetrahydrofuran (2 mL) and stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (42 mg, 0.20 mmol) was added and stirring continued for 1 hour. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% ammonia water) to obtain compound A12R (7 mg, 21% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ8.56(s,1H),8.03(s,1H),7.03-6.88(m,1H),6.78-6.56(m,2H),4.63 -4.40(m,4H),4.19(dd,J=10.6,2.5Hz,1H),3.89-3.81(m,1H),3.76(d,J=11.2Hz,1H),3.68-3 .55(m,4H),3.48-3.38(m,3H),3.29-3.19(m,4H),3.08-2.97(m,1H),2.88-2.72(m,2H),2.70 -2.56(m,3H),2.48-2.40(m,2H),2.07-1.95(m,1H),1.68-1.49(m,3H),1.03(t,J=7.5Hz,3H). MS m / z 606.1[M+H] + .

[0277] Example 44: Preparation of Compound A13R

[0278] Compound A13R-a (1.19 g, 3.78 mmol), potassium ethylene trifluoroborate (607 mg, 4.53 mmol), 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (138 mg, 0.189 mmol), and potassium carbonate (1.57 g, 11.33 mmol) were dissolved in dimethyl sulfoxide (15 mL). The mixture was heated to 100°C under a nitrogen atmosphere and stirred for 2 hours. After the reaction was completed, it was diluted with water. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound A13R-b (360 mg, yield 36%) as a yellow solid. MS m / z 262.9 [M+H] + .

[0279] Compound A13R-b (600 mg, 1.37 mmol) and palladium on carbon (10%, 60 mg) were dissolved in methanol (10 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 60 minutes. TLC monitored the reaction completion. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the crude product A13R-c (321 mg, 100% yield). MS m / z 235.1 [M+H] + .

[0280] Compound 5 (40 mg, 0.17 mmol) and compound 1d (71 mg, 0.19 mmol) were dissolved in N,N-dimethylacetamide (3 mL), and p-toluenesulfonic acid (44 mg, 0.26 mmol) was added, heated to 100°C and reacted for 6 hours. After the reaction was completed, the reaction solution was adjusted to pH 7-9 by adding ammonia water, and then extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to obtain compound A13R (25 mg, yield 26%). 1H NMR(500MHz,DMSO-d6)δ8.57(s,1H),8.03(s,1H),6.95(br,1H),6.70(br,1H),6.67( s,1H),4.17(dd,J=10.6,2.6Hz,1H),3.95(d,J=10.2Hz,1H),3.87-3.78(m,2H),3.68 -3.57(m,6H),3.42-3.37(m,3H),3.28-3.19(m,3H),3.15(t,J=10.7Hz,1H),3.08-3. 02(m,1H),2.69-2.59(m,3H),2.48-2.42(m,2H),1.58(br,2H),1.03(t,J=7.5Hz,3H). MS m / z 647.0[M+H] + .

[0281] Example 45: Preparation of Compound A14R

[0282] Compound A4R (30 mg, 0.05 mmol) and compound 1-ethoxy-1-trimethylsilyloxycyclopropane (95 mg, 0.5 mmol) were dissolved in methanol, and one drop of acetic acid was added. The mixture was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (34 mg, 0.50 mmol) was added. The mixture was stirred at room temperature for 14 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 14R (2.56 mg, yield 8%). 1 H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.03(s,1H),6.95(br,1H),6.71-6.60(m,2H),4.20(dd,J=10 .5,2.4Hz,1H),3.88-3.81(m,1H),3.75-3.67(m,1H),3.66-3.55(m,4H),3.38(br,2H),3.24(br,4H ),3.03-2.96(m,1H),2.97-2.87(m,2H),2.65-2.57(m,2H),2.47-2.33(m,4H),1.97(t,J=10.5Hz, 1H),1.70-1.63(m,1H),1.58(br,2H),1.03(t,J=7.5Hz,3H),0.49-0.40(m,2H),0.40-0.32(m,2H). MS m / z 590.4[M+H] + .

[0283] Example 46: Preparation of Compound A2S

[0284] Compound A2S-a (1000 mg, 4.20 mmol) and compound 2S-b (908 mg, 4.20 mmol) were dissolved in dimethyl sulfoxide (30 mL), and potassium hydroxide (1178 mg, 21.00 mmol) was added. The mixture was stirred at room temperature for 5 hours, and then the temperature was raised to 60°C overnight. After the reaction was completed, it was diluted with water. The mixed solution was extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a yellow solid compound A2S-c (800 mg, yield 46%). MS m / z 413.1 [M+H] + .

[0285] Compound A2S-c (800 mg, 1.94 mmol), potassium ethylene trifluoroborate (414 mg, 3.09 mmol), 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (75 mg, 0.103 mmol), and potassium carbonate (854 mg, 6.18 mmol) were dissolved in dimethyl sulfoxide (10 mL). The mixture was heated to 100°C under a nitrogen atmosphere and stirred for 2 hours. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound A2S-d (670 mg, 96% yield) as a yellow solid. MS m / z 362.1 [M+H] + .

[0286] Compound A2S-d (600 mg, 1.66 mmol) and palladium-carbon catalyst (10%, 200 mg) were dissolved in methanol (10 mL). The reaction mixture was stirred at room temperature under 1 atmosphere of hydrogen for 60 minutes. TLC monitored the reaction completion. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound A2S-e (500 mg, 90% yield) as a light yellow solid. MS m / z 334.1 [M+H] + .

[0287] Compound A2S-e (120 mg, 0.36 mmol) and compound A1R-d (152 mg, 0.40 mmol) were dissolved in N,N-dimethylformamide (3 mL), and trifluoroacetic acid (82 mg, 0.72 mmol) was added. The reaction mixture was stirred at 100°C overnight. After completion of the reaction, the mixture was diluted with water and triethylamine (1 mL) was added. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol:aqueous ammonia = 10:1:0.2) to obtain compound A2S-f (80 mg, 40% yield) as a yellow solid. MS m / z 550.2 [M+H] + .

[0288] Compound A2S-f (20 mg, 0.04 mmol) and N-methyl-4-piperidone (14 mg, 0.12 mmol) were dissolved in dimethylacetamide (2 mL), followed by the addition of glacial acetic acid (0.1 mL). The reaction mixture was stirred at 60°C for 30 minutes, then cooled to room temperature. Sodium triacetoxyborohydride (25 mg, 0.12 mmol) was added to the reaction mixture at room temperature. The reaction mixture was then heated to 75°C and stirred at 75°C for 60 minutes. Upon completion of the reaction, the mixture was diluted with water. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1, 2% aqueous ammonia) to afford Compound A2S (4 mg, 17% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ8.58-8.49(m,1H),8.03(s,1H),6.98-6.90(m,1H),6.72-6.60(m,2H),4.1 9(dd,J=10.5,2.3Hz,1H),3.89-3.79(m,1H),3.76-3.69(m,1H),3.67-3.52(m,4H),3.42-3.36(m,2 H),3.26-3.18(m,4H),3.01-2.82(m,5H),2.65-2.54(m,3H),2.48-2.44(m,2H),2.33-2.16(m,5H), 2.03-1.83(m,3H),1.82-1.72(m,2H),1.62-1.53(m,2H),1.50-1.40(m,2H),1.03(t,J=7.5Hz,3H). MS m / z 647.0[M+H] + .

[0289] Example 47: Kinase activity inhibition test

[0290] 1. ULK kinase activity inhibition experiment

[0291] Compounds were tested for ULK1 and ULK2 kinase inhibitory activity using the ADP-Glo ​​assay. Prepare 1x kinase reaction buffer (working concentrations: HEPES: 50 mM, MgCl2: 10 mM, Brij35: 0.01%, EGTA: 1 mM, DTT: 2 mM). Prepare 2x kinase and 4x substrate buffers: ULK1 kinase solution at a working concentration of 0.5 nM; substrate mixture solution at a working concentration of 100 μM ATP and a final concentration of 0.1 mg / mL substrate MBP; ULK2 kinase solution at a working concentration of 0.15 nM; substrate mixture solution at a working concentration of 6 μM ATP and a final concentration of 0.1 mg / mL substrate MBP. Serially dilute the compound with DMSO and shake on a shaker for 20 minutes. Prepare 2x kinase using 1x enzyme reaction buffer. Transfer 20 nL of compound to a 384-well plate. Add 2 μL of kinase to each well of the plate. Seal the plate with sealing film and centrifuge at 1000 rpm for 60 seconds. Incubate at 25°C for 10 minutes. Prepare a 2X ATP & MBP mixture using 1X enzyme reaction buffer and add 2 μL of the 2X ATP & substrate mixture to the reaction plate. Seal the plate with sealing film and centrifuge at 1000 rpm for 60 seconds. Incubate at 25°C for 60 minutes. Transfer 4 μL of ADP-Glo ​​to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Transfer 8 μL of detection solution to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Read the RLU (Relative Luminescence Unit) signal using a BMG microplate reader. Signal intensity is used to indicate kinase activity. Inhibition rate is calculated as follows: Compound inhibition rate (% inh) = 100% - (Compound - Positive Control) / (Negative Control - Positive Control) * 100%. The IC50 (half maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula: Data analysis was performed using Graphpad 7.0 software. Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*Hill Slope)). X: log value of compound concentration, Y: inhibition rate (%inhibition). Compound IC 50 See Table 1 for the values.

[0292] 2. FAK kinase activity inhibition experiment

[0293] Method A:

[0294] Compounds were tested for FAK kinase inhibitory activity using the HTRF method. 1X kinase reaction buffer (working concentrations: MgCl2: 5mM, SEB: 25nM, DTT: 1mM) was prepared. Kinase reaction conditions were: FAK kinase: 0.1ng / μL; substrate mixture: ATP: 10μM; final substrate concentration: 1μM. Compounds were serially diluted with DMSO and shaken on a shaker for 20 minutes. 2X kinase was prepared using 1X enzyme reaction buffer. Using an Echo 655, 25nL of compound was transferred to a 384-well plate. 2.5μL of kinase was added to each well of the plate. The plate was sealed with film and centrifuged at 1000rpm for 60 seconds. Incubated at 25°C for 12 hours. 2X ATP / substrate mix was prepared using 1X enzyme reaction buffer and 2.5μL of 2X ATP & substrate mix was added to the plate. Seal the plate with a sealing film, centrifuge at 1000rpm for 60 seconds, and incubate at 25°C for 50 minutes. Prepare 2X XL665 & antibody solution with HTRF detection buffer. Add 5μL of the prepared detection solution to each well and incubate at 25°C for 60min. Use a plate reader to read the fluorescence signals at 620nm (Cryptate) and 665nm (XL665). Calculate the ratio of each well (Ratio_665 / 620nm). The inhibition rate is calculated as follows: Compound inhibition rate (%inh) = 100% - (Compound ratio - Positive control ratio) / (Negative control ratio - Positive control ratio) * 100%. Use the following nonlinear fitting formula to obtain the IC of the compound. 50 (50% inhibitory concentration): Data analysis was performed using Graphpad 7.0 software. Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*Hill Slope)). X: log value of compound concentration, Y: inhibition rate (%inhibition). Compound IC 50 The values ​​are shown in Tables 2, 3 and 4.

[0295] Method B:

[0296] Compounds were tested for FAK kinase inhibitory activity using the Lantha screen assay. Compounds were dissolved in 100% DMSO to a 10 mM stock solution. 1× Kinase buffer (25 mM HEPES, pH 7.5, 0.01 mM Triton, 0.5 mM EGTA, 0.01% Brij-35) was prepared. Test compounds were serially diluted and 5 μL of each compound was transferred to the reaction plate. A kinase solution was prepared at 2x the final concentration using 1× Kinase buffer. 5 μL of kinase solution was added to the compound wells and positive control wells; 5 μL of 1× Kinase buffer was added to the negative control wells. The reaction plate was shaken to mix thoroughly. A mixture of ATP and Fluorescein-polyGT was prepared at 4x the final concentration using 1× Kinase buffer. The reaction was initiated by adding 2.5 μL of the substrate mixture. After shaking, the mixture was incubated at room temperature for 30 minutes. Prepare the assay solution at 2x the final concentration (final concentration: 2 nM antibody, 10 mM EDTA). Add 10 μL of assay solution to stop the kinase reaction, centrifuge briefly, vortex to mix, and incubate for 60 minutes. Fluorescence values ​​were read using Envision at an excitation wavelength of 340 nm and emission wavelengths of 520 nm and 495 nm. Data were collected and the fluorescence value at 520 nm / 495 nm was calculated. Inhibition was calculated using the formula: Percent inhibition = (max-sample ratio) / (max-min) * 100. Where min is the mean of the negative control wells, representing the conversion reading of the wells without enzyme activity; max is the mean of the positive control wells, representing the conversion reading of the wells with DMSO inhibition. Curve fitting was performed using XLFit Excel add-in version 5.4.0.8 to determine the IC50 value for each compound's effect on enzyme activity. The formula is as follows: Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)^HillSlope). Compound IC 50 The values ​​are shown in Tables 3 and 4.

[0297] 3. AXL and FLT3 kinase activity inhibition experiment

[0298] Mobility shift assays were used to test the FLT3 and AXL kinase inhibitory activity of the compounds. Compounds were dissolved in 100% DMSO to a 10 mM stock solution, and 1× Kinase buffer was prepared. Test compounds were serially diluted 5-fold and 250 nL of the compound at a 100x final concentration was transferred to the destination plate 3573 using an Echo 550 dispenser. A kinase solution was prepared at a 2.5x final concentration using 1× Kinase buffer. 10 μL of the 2.5x final concentration of the kinase solution was added to the compound wells and positive control wells; 10 μL of 1× Kinase buffer was added to the negative control wells. Centrifuge at 1000 rpm for 30 seconds, shake the plate to mix, and incubate at room temperature for 10 minutes. A mixture of ATP and Kinase substrate 25 was prepared at a 5 / 3x final concentration using 1× Kinase buffer. The reaction was initiated by adding 15 μL of the 5 / 3x final concentration of the ATP and substrate solution. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 120 minutes. Add 30 μL of Stop Detection Solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and vortex to mix. Read the conversion rate using a Caliper EZ Reader.

[0299] %Inhibition=Conversion%_max.Conversion%_sampleConversion%_max.Conversion%_min×100, where: Conversion%_sample is the conversion rate reading of the sample; Conversion%_min: the mean value of the negative control wells, representing the conversion rate reading of the wells with no enzyme activity; Conversion%_max: the mean value of the positive control wells, representing the conversion rate reading of the wells with no compound inhibition. With the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, the log(inhibitor) vs. response-Variable slope analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC50 value of each compound on the enzyme activity. The formula is as follows: Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)). Compound IC 50 The values ​​are shown in Tables 3 and 4.

[0300] 4. ALK kinase activity inhibition experiment

[0301] Compounds were tested for ALK kinase inhibitory activity using the HTRF assay. 1X kinase reaction buffer was prepared. Kinase reaction conditions were: kinase: 0.04 ng / μL; substrate mixture solution: ATP working concentration: 2 μM; substrate final concentration: 1 μM. Compounds were serially diluted with DMSO and shaken on a shaker for 20 minutes. 2X kinase was prepared using 1X enzyme reaction buffer. 1 μL of compound was transferred to a 384-well plate. 2 μL of kinase was added to each well of the plate. The plate was sealed with film and centrifuged at 1000 rpm for 60 seconds. Incubated at 25°C for 10 minutes. 2.5X ATP / substrate mixture was prepared using 1X enzyme reaction buffer. 2 μL of 2.5X ATP & substrate mixture was added to the plate. The plate was sealed with film and centrifuged at 1000 rpm for 60 seconds. Incubated at 25°C for 50 minutes. 4X Sa-XL 665 was prepared using HTRF assay buffer. 5 μL of Sa-XL 665 and 5 μL of TK-antibody-Cryptate were added to each well, centrifuged at 1000 rpm for 60 seconds, and incubated at 25°C for 60 minutes. The fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665) were read using a BMG. The ratio of each well (Ratio_665 / 615 nm) was calculated as follows: Compound inhibition rate (%inh) = 100% - (Compound ratio - Positive control ratio) / (Negative control ratio - Positive control ratio) * 100%. The IC value of the compound was obtained using the following nonlinear fitting formula: 50 (50% inhibitory concentration): Data analysis was performed using Graphpad 7.0 software. Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*Hill Slope)). X: log value of compound concentration, Y: inhibition rate (%inhibition). Compound IC 50 The values ​​are shown in Tables 3 and 4.

[0302] 5. HPK1 kinase activity inhibition experiment

[0303] HPK1 kinase inhibitory activity of the compounds was assessed using a mobility shift assay. Compounds were dissolved in 100% DMSO to a 10 mM stock solution, and 1× Kinase buffer was prepared. Test compounds were serially diluted 5-fold and 250 nL of the compound at a 100x final concentration was transferred to the destination plate 3573 using an Echo 550 dispenser. A kinase solution was prepared at a 2.5x final concentration using 1× Kinase buffer. 10 μL of the 2.5x final concentration kinase solution was added to the compound wells and positive control wells; 10 μL of 1× Kinase buffer was added to the negative control wells. Centrifuge at 1000 rpm for 30 seconds, shake the plate to mix, and incubate at room temperature for 10 minutes. A mixture of ATP and Kinase substrate 25 was prepared at a 5 / 3x final concentration using 1× Kinase buffer. The reaction was initiated by adding 15 μL of the 5 / 3x final concentration ATP and substrate solution. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for 120 minutes. Add 30 μL of Stop Detection Solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and vortex to mix. Read the conversion rate using a Caliper EZ Reader.

[0304] %Inhibition = Conversion%_max.Conversion%_sampleConversion%_max.Conversion%_min × 100, where: Conversion%_sample is the sample conversion reading; Conversion%_min is the mean of the negative control wells, representing the conversion reading of the wells without enzyme activity; Conversion%_max is the mean of the positive control wells, representing the conversion reading of the wells without compound inhibition. Using the logarithm of concentration as the X-axis and the percentage inhibition as the Y-axis, we fitted the dose-effect curve using the log(inhibitor) vs. response-variable slope function in GraphPad Prism 5 to determine the IC value of each compound for enzyme activity. 50 The formula is as follows: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)). Compound IC 50 The values ​​are shown in Table 4.

[0305] 6.CDK7 kinase activity inhibition experiment

[0306] Compounds were tested for CDK7 / CycH / MAT1 kinase inhibitory activity using the ADP-Glo ​​assay. Prepare 1X kinase reaction buffer (working concentrations: HEPES: 50 mM, MgCl2: 10 mM, Brij35: 0.01%, DTT: 2 mM). Kinase reaction conditions were: kinase: 3.5 ng / μL; substrate mixture: ATP: 30 μM; final CDK substrate concentration: 0.1 mg / mL. Compounds were serially diluted with DMSO and shaken on a shaker for 20 minutes. Prepare 2X kinase using 1X enzyme reaction buffer. Transfer 1 μL of compound to a 384-well plate. Add 2 μL of kinase to each well of the plate. Seal the plate with film, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 10 minutes. Prepare 4X ATP & substrate mix using 1X enzyme reaction buffer and add 1 μL of 4X ATP & substrate mix to the plate. Seal the plate with a sealing film and centrifuge at 1000rpm for 60 seconds, and incubate at 25℃ for 60 minutes. Transfer 4μL ADP-Glo ​​to a 384 reaction plate at 1000rpm, centrifuge for 1min, and incubate at 25℃ for 40min. Transfer 8μL Detection solution to a 384 reaction plate at 1000rpm, centrifuge for 1min, and incubate at 25℃ for 40min. Use a BMG microplate reader to read the RLU (Relative luminescence unit) signal, and the signal intensity is used to characterize the activity of the kinase. The inhibition rate is calculated as follows: Compound inhibition rate (%inh) = 100% - (compound - positive control) / (negative control - positive control) * 100%. The following nonlinear fitting formula is used to obtain the IC of the compound. 50 (50% inhibitory concentration): Data analysis was performed using Graphpad 7.0 software. Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*Hill Slope)). X: log value of compound concentration, Y: inhibition rate (%inhibition). Compound IC 50 The values ​​are shown in Table 4.

[0307] 7. TNK1 kinase activity inhibition experiment

[0308] Compounds were tested for TNK1 kinase inhibitory activity using the ADP-Glo ​​method. Prepare 1x kinase reaction buffer (working concentrations: HEPES: 50 mM, MgCl2: 10 mM, Brij35: 0.01%, EGTA: 1 mM, DTT: 2 mM). Prepare 2x kinase and 4x substrate buffers: TNK1 kinase solution at a working concentration of 5 nM; substrate mixture solution at a working concentration of ATP of 45 μM and a final concentration of substrate MBP of 0.1 mg / mL; ULK2 kinase solution at a working concentration of 0.15 nM; substrate mixture solution at a working concentration of ATP of 6 μM and a final concentration of substrate MBP of 0.1 mg / mL. Serially dilute the compound with DMSO and shake on a shaker for 20 minutes. Prepare 2x kinase using 1x enzyme reaction buffer. Transfer 20 nL of compound to a 384-well plate. Add 2 μL of kinase to each well of the plate. Seal the plate with a sealing film, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 10 minutes. Prepare a 2x ATPATP&MBP mixture with 1X enzyme reaction buffer, and add 2μL of 2x ATP&substrate mixture to the reaction plate. Seal the plate with a sealing film, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 60 minutes. Transfer 4μL of ADP-Glo ​​to a 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Transfer 8μL of detection solution to a 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Use a BMG microplate reader to read the RLU (Relative luminescence unit) signal, and the signal intensity is used to characterize the activity of the kinase. The inhibition rate is calculated as follows: Compound inhibition rate (%inh) = 100% - (compound - positive control) / (negative control - positive control) * 100%. The following nonlinear fitting formula is used to obtain the IC of the compound. 50 (50% inhibitory concentration): Data analysis was performed using Graphpad 7.0 software. Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*Hill Slope)). X: log value of compound concentration, Y: inhibition rate (%inhibition). Compound IC 50 The values ​​are shown in Tables 4 and 5.

[0309] Table 1: Inhibitory activity of compounds against ULK (IC 50 ,nM)

[0310] Table 2: Inhibitory activity of compounds against FAK (IC 50 ,nM)

[0311] Table 3: Inhibitory activity of compounds against FAK, AXL, FLT3 and ALK (IC 50 ,nM)

[0312] Table 4: Inhibitory activity of compounds against FAK, ALK, FLT3, HPK1, CDK7, and TNK1 (IC 50 ,nM)

[0313] Table 5: Inhibitory activity of compounds against TNK1 (IC 50 ,nM)

[0314] Example 48: Pharmacokinetic study in rats

[0315] Instrument: Waters XEVO TQ-S LC-MS / MS. All measurement data were collected and processed by Masslynx V4.1 software, and calculated and processed using Microsoft Excel. Pharmacokinetic parameters were calculated using WinNonLin 8.0 software using the statistical moment method. These parameters mainly include the kinetic parameter T max 、T 1 / 2 、C max , AUC 0-24h Chromatographic column: ACQUITY UPLC BEH C18 (2.1 mm × 50 mm, 1.7 μm); column temperature: 40°C; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 0.350 mL / min; gradient elution: 0.50 min: 10% B; 1.50 min: 90% B; 2.50 min: 90% B; 2.51 min: 10% B; 3.50 min: stop. Injection volume: 1 μL.

[0316] Animals: Three male Sprague-Dawley rats, weighing 200-220 g, were housed in the laboratory of the Experimental Animal Center for two days before use. They were fasted for 12 hours before and 4 hours after dosing, with free access to water during the experiment. Blood samples were collected at designated intervals after gavage.

[0317] Solvent: 0.4% ethanol + 0.4% Tween 80 + 99.2% (0.5% methylcellulose M450) Preparation of oral administration solution: Accurately weigh the compound, add it to the solvent, and sonicate at room temperature for 5 minutes to completely dissolve the drug to prepare a 0.3 mg / ml solution.

[0318] Drug samples: Typically, multiple structurally similar samples (molecular weights differing by at least 2 units) are collected, accurately weighed, and administered together (cassette PK). This allows for simultaneous screening of multiple compounds and comparison of their oral absorption rates. Single administration is also used to study the pharmacokinetics of drug samples in rats.

[0319] Blood was collected from the orbital cavity at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after oral administration. Fifty microliters of plasma was added to 200 microliters of acetonitrile (containing the internal standard verapamil, 2 ng / mL). The mixture was vortexed for 3 minutes and centrifuged at 20,000 rcf at 4°C for 10 minutes. The supernatant was then analyzed by LC-MS / MS.

[0320] The compound is accurately weighed and prepared into different concentrations, and quantitative analysis is performed on the mass spectrometer to establish a standard curve. Then the concentration of the compound in the plasma is tested to obtain the concentration of the compound at different time points. All the measurement data are collected and processed by relevant software, and the pharmacokinetic parameters are calculated using the statistical moment method (mainly including the kinetic parameter T max 、T 1 / 2 、C max , AUC 0-24h The kinetic parameters of some representative compounds are shown in Table 6.

[0321] Table 6 Pharmacokinetic parameters in rats

[0322] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound having the structure shown by the following formula (I), or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate: Among them, A is selected from formula (IIa), formula (IIb), formula (IIc), formula (IId), or formula (IIe): The site where Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), or Formula (IIe) is linked to other parts in Formula (I); "*” represents a chiral center; X, Y, and T are each independently selected from N or CR 1 ; Each R 1 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, OR e , or CN; Each R 2 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, OR e , SR e , NR e R e , CN, or C(O)R h ; Each R 3 is independently selected from hydrogen, or C 1-4 alkyl; or when two Rs 3 are simultaneously attached to the same carbon atom, these two Rs 3 and the carbon atom to which they are attached may optionally together form a carbonyl group (C=O); J and G are each independently selected from NR f , O, S, S(O), S(O)2 or CR g R g ; Z is selected from O, NR e , or CH2; W is selected from N or CR b ; Each R a is independently selected from hydrogen, halogen, or C 1-4 alkyl; Each R b is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, OR e , SR e , NR e R e , or CN; Each R c is independently selected from hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl; R d selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclic group; Each R i is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, OR e , SR e , or NR e R e ; R f is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, C(O)R h , C(O)OR e , C(O)NR e R e , S(O)2R h , or S(O)2NR e R e ; the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted with one or more groups selected from the group consisting of: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, aryl, heteroaryl, OR e , SR e , NR e R e , CN, C(O)R h , C(O)OR e , C(O)NR e R e , NR e C(O)R h , S(O)2R h , S(O)2NR e R e , or NR e S(O)2R h ; Each R g is independently selected from the group consisting of: hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, OR e , SR e , NR e R e , CN, C(O)R h , C(O)OR e , C(O)NR e R e , NR e C(O)R h , or NR e S(O)2R h ; or two Rs g together with the same carbon atom to which they are attached form a carbonyl (C═O); or two Rs g together with the same carbon atom to which they are attached form a 3- to 8-membered ring structure, which ring structure optionally contains 0, 1 or 2 heteroatoms selected from N, O, S; Each R e is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or a 3- to 6-membered heterocyclic group; or two Rs e together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclic group containing 1 or 2 N atoms and 0 or 1 heteroatom selected from O, S; Each R h is independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, aryl, heteroaryl; k is selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, 3, or 4; p and q are each independently selected from 0, 1, 2, 3, 4, or 5; f is selected from 2, 3, 4, or 5; g is selected from 0, 1, 2, 3, or 4; h is selected from 0, 1, 2, or 3; i is selected from 0, 1, 2, or 3; j is selected from 0, 1, 2, 3, or 4; t is selected from 0, 1, 2, 3, or 4; Provided that when X is selected from CH, Y is selected from N, and T is selected from CR 1 , and A is selected from formula (IId), the structural fragment in formula (I) Selected from formula (IIf): "---” represents the site where Formula (IIf) is linked to other parts in Formula (I); R k selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group; the definitions of the remaining groups in formula (IIf) are as described above; Among them, each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, cyclic structure, aryl and heteroaryl is optionally and independently substituted with 1-3 substituents independently selected from the following group: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, CN, NO2, OR e , SR e , NR e R e , C(O)R h , C(O)OR e , C(O)NR e R e , NR e C(O)R h , S(O)2R h , or NR e S(O)2R h , provided that the chemical structure formed is stable and meaningful; wherein, R e and R h are as defined above. Unless otherwise specified, the above-mentioned aryl is an aromatic group containing 6-12 carbon atoms; heteroaryl is a 5- to 15-membered heteroaromatic group; the cyclic structure is a saturated or unsaturated cyclic group containing or not containing heteroatoms.

2. The compound according to claim 1, wherein Formula (I) is Formula (IIIa) or Formula (IIIb): The definitions of the groups in Formula (IIIa) or Formula (IIIb) are as described in claim 1.

3. The compound according to any one of claims 1-2, characterized in that, Formula (I) is Formula (IVa), Formula (IVb), Formula (IVc), or Formula (IVd): The definitions of the groups in Formula (IVa), Formula (IVb), Formula (IVc), or Formula (IVd) are as described in claim 1.

4. The compound according to any one of claims 1-3, characterized in that, Formula (I) is Formula (V): The definitions of the groups in Formula (V) are as described in claim 1.

5. [Corrected according to Rule 26 on 26.03.2024] The compound according to any one of claims 1-4, characterized in that, Formula (I) is Formula (VI): R 1 selected from hydrogen, a halogen, C 1-4 alkyl, or C 1-4 haloalkyl; R 2 selected from hydrogen, a halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or OR e ; G is selected from NR f , O, or CR g R g ; Z is selected from O, NR e , or CH2; R f is hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group (preferably 3- to 8-membered heterocyclic group), aryl, heteroaryl, C(O)R h , C(O)OR e , C(O)NR e R e , S(O)2R h , or S(O)2NR e R e ; the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more groups selected from the group consisting of: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, aryl, heteroaryl, OR e , SR e , NR e R e , CN, C(O)R h , C(O)OR e , C(O)NR e R e , NR e C(O)R h , S(O)2R h , S(O)2NR e R e , or NR e S(O)2R h ; Each R g is independently selected from the group consisting of: hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, OR e , SR e , NR e R e , CN, NR e C(O)R h , or NR e S(O)2R h ; Each R e is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or a 3- to 6-membered heterocyclic group; Each R h is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, aryl, heteroaryl; p and q are each independently selected from 0, 1, 2, 3, or 4; f is selected from 2, 3, or 4.

6. The compound according to any one of claims 1-3, characterized in that, Formula (I) is Formula (VII): The definitions of the groups in Formula (VII) are as described in claim 1.

7. The compound according to any one of claims 1-3 and 6, characterized in that, Formula (I) is Formula (VIII): h is selected from 0, 1, 2, or 3; R 1 and R 2 and G are defined as described in claim 5.

8. The compound according to any one of claims 1-3, characterized in that, Formula (I) is Formula (IX): The definitions of the groups in Formula (IX) are as described in claim 1.

9. The compound according to any one of claims 1-3 and 8, characterized in that, Formula (I) is Formula (X): R d selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or a 3- to 6-membered heterocyclic group; R 1 and R 2 and G are defined as described in claim 5.

10. The compound according to any one of claims 1-3, characterized in that, Formula (I) is Formula (XI): The definitions of the groups in Formula (XI) are as described in claim 1.

11. The compound according to any one of claims 1-3 and 10, characterized in that, Formula (I) is Formula (XII): j is selected from 0, 1, 2, 3, or 4; R 1 and R 2 and G are defined as described in claim 5.

12. The compound according to claim 1, wherein Formula (I) is Formula (XIII): The definitions of the groups in Formula (XIII) are as described in claim 1.

13. The compound according to any one of claims 1 and 12, characterized in that, Formula (I) is Formula (XIV): R k selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group; R 1 The definitions of R and G are as described in claim 5.

14. The compound according to claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, selected from one of the following groups: "*” represents a chiral center.

15. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1 to 14, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate, and a pharmaceutically acceptable carrier.

16. Use of a compound according to any one of claims 1 to 14, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, characterized in that, A pharmaceutical composition for the preparation of a drug for treating diseases, disorders or conditions related to the kinase activity or expression level of ULK, FAK, ALK, CDK7, HPK1, AXL, FLT3, TNK1, etc.

17. The use according to claim 16, characterized in that, The diseases, disorders or conditions are selected from the following groups: breast cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, throat cancer, pancreatic cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, mesothelioma, osteosarcoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegalic polycythemia, eosinophilic leukocytosis syndrome, multiple myeloma, and other various solid tumors and hematological tumors; pulmonary fibrosis; various DNA and RNA virus infections such as AIDS, herpes virus, and influenza virus, etc.

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