Parp1 inhibitors and uses thereof

Abstract

This invention describes PARP1 inhibitors and pharmaceutical compositions comprising such inhibitors. The compounds and compositions of this invention are suitable for the treatment of cancer.

Description

PARP1 inhibitors and their uses Poly(ADP-ribose) polymerase (PARP) or poly(ADP-ribose) synthase (PARS) plays a fundamental role in promoting DNA repair, controlling RNA transcription, mediating cell death, and regulating immune responses. These roles allow PARP inhibitors to target a broad range of conditions. PARP inhibitors have been demonstrated in many disease models, particularly in ischemia-reperfusion injury, inflammatory diseases, degenerative diseases, protection against the adverse effects of cytotoxic compounds, and enhancement of cytotoxic cancer therapies. PARP has also been indicated in retroviral infections, and therefore inhibitors can be used in antiretroviral therapy. PARP inhibitors have been effective in preventing ischemia-reperfusion injury in models of myocardial infarction, stroke, other neurological trauma, organ transplantation, and reperfusion of the eyes, kidneys, intestines, and musculoskeletal system. Inhibitors have been effective in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, CNS inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also shown benefits in several models of degenerative diseases, including diabetes (and its complications) and Parkinson's disease. PARP inhibitors have improved hepatotoxicity following acetaminophen overdose, cardiotoxicity and nephrotoxicity caused by doxorubicin and platinum-based antitumor agents, and skin damage secondary to sulfur mustard. In various cancer models, PARP inhibitors have been shown to enhance radiation and chemotherapy by increasing cell death in cancer cells, limiting tumor growth, reducing metastasis, and prolonging survival in tumor-bearing animals. PARP1 and PARP2 are the PARPs whose roles in DNA damage repair have been most extensively studied. PARP1 is activated by DNA damage interruption and catalyzes the addition of poly(ADP-ribose) (PAR) chains to target proteins. This post-translational modification (called PARation) mediates the recruitment of additional DNA repair factors to DNA lesions. Following this recruitment process, PARP auto-PARation triggers the release of bound PARP from DNA, allowing access to other DNA repair proteins to complete the repair. Therefore, PARP binding to the damaged site, its catalytic activity, and its eventual release from DNA are all crucial steps in the response of cancer cells to DNA damage induced by chemotherapy and radiotherapy. Inhibition of PARP family enzymes has been used as a strategy to selectively kill cancer cells by deactivating complementary DNA repair pathways. Numerous preclinical and clinical studies have demonstrated that tumor cells carrying detrimental alterations to BRCA1 or BRCA2 (key tumor suppressor proteins involved in the repair of double-stranded DNA breaks (DSBs) using homologous recombination (HR)) are selectively sensitive to small-molecule inhibitors of the PARP family of DNA repair enzymes. These tumors exhibit a defective homologous recombination repair (HRR) pathway dependent on PARP enzyme viability. Although PARP inhibitor therapy primarily targets SRCA-mutated cancers, PARP inhibitors have been clinically tested in non-SRCA-mutated tumors (those exhibiting homologous recombination deficiency (HRD)). It is believed that PARP inhibitors with improved selectivity for PARP1 may offer improved efficacy and reduced toxicity compared to other clinically used PARP1 / 2 inhibitors. It is also believed that strong selective inhibition of PARP1 leads to PARP1 truncation on DNA, causing DNA double-strand breaks (DSBs) via replication fork collapse in S phase. Furthermore, it is believed that PARP1-DNA truncation is an effective mechanism for selectively killing tumor cells with HRD. Therefore, there is an unmet medical need for effective and safe PARP inhibitors, especially PARP inhibitors selective for PARP1. This article discloses a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Equation (I), where: R 1 For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 2 For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-haloalkyl or C 1-C 6-Deuteryl; X is N or CR 3 Y is N or CR 4 Z is N or CR 5 R 3 For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 4 For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 5 For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Acynyl, cycloalkyl, or heterocyclic alkyl; wherein the alkyl, alkenyl, acynyl, cycloalkyl, or heterocyclic alkyl is substituted by one or more Rs, depending on the case; each R 6 Independently hydrogen, deuterium, halogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more Rs, depending on the case; or two Rs. 6 Together they form cycloalkyl or heterocycloalkyl groups; each, depending on the case, is oxidized by deuterium, halogen, -CN, -OH, or -OR. a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl or C 1-C 6 heteroalkyl substitutions; each R 7 Independently deuterium, halogen, -CN, -OH, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-olefin or C 2-C 6-Alynyl group; or two R groups on the same carbon atom. 7 Together they form a side oxygen group; or two Rs on the same carbon or different carbons. 7 Together they form cycloalkyl or heterocycloalkyl groups; each of which is substituted with one or more R groups, depending on the case; n is 0 to 4; T is N or CR. 8 U is N or CR 9 R 8 Hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 9 Hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 10 Hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 11 Hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 12 It is either cyano or halogen; each R a Independently for C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6-alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6. Alkyl (heteroaryl); wherein each alkyl, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted by one or more R, depending on the case; each R b Independently hydrogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6-alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6. Alkyl (heteroaryl); wherein each alkyl, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently substituted by one or more R, depending on the case; and each R c and R d Independently hydrogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6-alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6. Alkyl (heteroaryl); wherein each alkyl, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted with one or more R, depending on the case; or R c and R d Together with the atoms to which it is attached, it forms a heterocyclic alkyl group, which may be substituted with one or more Rs, depending on the case; each R is independently deuterium, halogen, -CN, -OH, or -OC. 1-C 6-alkyl, -NH 2. -NHC 1-C 6-alkyl, -N(C) 1-C 6-alkyl) 2. -NHC(=O)OC 1-C 6-alkyl, -C(=O)C 1-C 6-alkyl, -C(=O)OH, -C(=O)OC 1-C 6-alkyl, -C(=O)NH 2. -C(=O)N(C 1-C 6-alkyl) 2. -C(=O)NHC 1-C 6-alkyl, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl or C 1-C 6. Heteroalkyl groups; or two R atoms on the same atom forming a side oxygen group; the restriction condition is that if X is a CR 3 Y is CR 4 And Z is CR 5 When, then R 3 R 4 and R 5One of them is not hydrogen and R 4 Not -OMe; and its constraint is that when X is CH, Y is CH and Z is CH, then R 2 It is not hydrogen. This article also discloses a pharmaceutical composition comprising the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient. This document also discloses a method for treating cancers in individuals of need that include BRCA1 and / or BRCA2 mutations, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. This document also discloses a method for treating cancers in individuals of need that include mutations in genes conferring homology repair deficiency, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, mutations in genes conferring homology repair deficiency include ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof. In some embodiments, the cancer is bladder cancer, brain cancer and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer has metastasized to the brain. This article also discloses a method for treating brain cancer in individuals in need, comprising administering the compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Cross-reference is made to the claims of U.S. Provisional Application No. 63 / 301,907, filed January 21, 2022, and U.S. Provisional Application No. 63 / 376,338, filed September 20, 2022, which are incorporated herein by reference in their entirety. References included All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if specifically and individually indicated that each individual publication, patent or patent application is incorporated by reference. definition In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the invention can be practiced without such details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, the word "comprise" and its variations (such as "comprises" and "comprising") shall be considered to have an open-ended meaning throughout this specification and the claims thereafter. Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention. Throughout this specification, references to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" appearing in different places throughout this specification do not necessarily refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Additionally, unless the context explicitly specifies otherwise, as used in this specification and the appended claims, the singular forms "a / an" and "the" include a plural of indicators. It should also be noted that unless the context explicitly specifies otherwise, the term "or" is generally used to include the meaning of "and / or". Unless otherwise indicated, the following terms have the following meanings as used herein: "Side oxygen group" refers to =O. "Carboxyl group" refers to -COOH. "Cyano" refers to -CN. "alkyl" refers to a straight-chain or branched monovalent hydrocarbon group having one to ten carbon atoms, more preferably one to six carbon atoms. Examples include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, tertiary pentyl and hexyl, as well as longer alkyl groups such as heptyl, octyl and the like. Whenever it appears in this article, such as "C" 1-C "6-alkyl" or "C" 1-6 The numerical range of "alkyl" means that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, although the definition of this invention also covers the presence of the term "alkyl" without specifying a numerical range. In some embodiments, an alkyl group is C14. 1-10 Alkyl group. In some embodiments, the alkyl group is C10. 1-6 Alkyl group. In some embodiments, the alkyl group is C10. 1-5 Alkyl group. In some embodiments, the alkyl group is C10. 1-4 Alkyl group. In some embodiments, the alkyl group is C10. 1-3 Alkyl group. Unless otherwise specifically stated in this specification, alkyl groups may be substituted as appropriate with, for example, oxy-groups, halogens, amino groups, nitriles, hydroxyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and the like. In some embodiments, alkyl groups may be substituted as appropriate with oxy-groups, halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2. Substitution. In some embodiments, the alkyl group is substituted with halogen, -CN, -OH, or -OMe, depending on the situation. In some embodiments, the alkyl group is substituted with halogen, depending on the situation. "Alkenyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to ten carbon atoms, more preferably two to six carbon atoms. The group may be configured in cis or trans configurations around the double bond, and should be understood to include both isomers. Examples include (but are not limited to) vinyl (-CH=CH) 2) 1-Propylene (-CH 2CH=CH 2) Isopropenyl [-C(CH 3)=CH 2], butenyl, 1,3-butadienyl and similar compounds. Whenever they appear in this text, such as "C 2-C "6-olefin" or "C" 2-6The numerical range of "alkenyl" means that an alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkenyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the alkenyl group may be substituted as appropriate with, for example, a syloxy group, halogen, amino group, nitrile group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, the alkenyl group may be substituted as appropriate with a syloxy group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2. Substitution. In some embodiments, the alkenyl group is substituted with a halogen, -CN, -OH, or -OMe, depending on the situation. In some embodiments, the alkenyl group is substituted with a halogen, depending on the situation. "Alynyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include (but are not limited to) ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and similar groups. Whenever it appears in this document, such as "C 2-C "6-acetylenic" or "C" 2-6 The numerical range of "alkynyl" means that the alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkynyl" without specifying a numerical range. Unless otherwise specifically stated in this specification, the alkynyl group may be substituted as appropriate with, for example, a syl group, halogen, amino group, nitrile group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, the alkynyl group may be substituted as appropriate with a syl group, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 or -NO 2. Substitution. In some embodiments, the alkynyl group is substituted with a halogen, -CN, -OH, or -OMe, depending on the situation. In some embodiments, the alkynyl group is substituted with a halogen, depending on the situation. "Phenylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specifically stated in this specification, alkylene may be substituted as appropriate with, for example, a syl group, halogen, amino group, nitrile group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, alkylene may be substituted as appropriate with a syl group, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 or -NO 2. Substitution. In some embodiments, the alkyl group is substituted with halogen, -CN, -OH or -OMe as appropriate. In some embodiments, the alkyl group is substituted with halogen as appropriate. "alkoxy" refers to the formula -OR a The group, wherein R a Alkyl groups are defined as such. Unless otherwise specifically stated in this specification, alkoxy groups may be substituted as appropriate with, for example, alkyl groups, halogens, amino groups, nitriles, hydroxyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and the like. In some embodiments, alkoxy groups may be substituted as appropriate with halogens, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 or -NO 2. Substitution. In some embodiments, the alkoxy group is substituted with a halogen, -CN, -OH, or -OMe, depending on the situation. In some embodiments, the alkoxy group is substituted with a halogen, depending on the situation. "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and can include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded via aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl groups include (but are not limited to) aryl groups derived from the following hydrocarbon ring systems: anthracene, anthracene, anthracene, anthracene, benzene, arsenyl, arsenyl, arsenyl, s-dicyclopentadienylbenzene, s-dicyclopentadienylbenzene, indane, indene, naphthalene, arsenyl, phenanthrene, pleiadene, pyrene, and terphenyl. Unless otherwise specifically stated in this specification, the aryl group may be substituted as appropriate with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl group may be substituted as appropriate with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3. -OH, -OMe, -NH 2 or -NO 2. Substitution. In some embodiments, the aryl group is optionally substituted with halogen, methyl, ethyl, -CN, or -CF. 3. -OH or -OMe substitution. In some embodiments, the aryl group is halogenated as appropriate. "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbon ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded via non-aromatic ring atoms) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyl groups include (but are not limited to) cycloalkyl groups having three to fifteen carbon atoms (C1 to C2). 3-C 15 cycloalkyl or C 3-C 15 Cycloalkenyl), three to ten carbon atoms (C 3-C 10 cycloalkyl or C 3-C 10 Cycloalkenyl), three to eight carbon atoms (C 3-C 8-cycloalkyl or C 3-C 8-cycloalkenyl), three to six carbon atoms (C 3-C 6-cycloalkyl or C 3-C 6-cycloalkenyl), three to five carbon atoms (C 3-C 5-cycloalkyl or C 3-C 5-cycloalkenyl) or three to four carbon atoms (C 3-C 4-cycloalkyl or C 3-C 4. Cycloalkenyl). In some embodiments, the cycloalkyl group is 3 to 10 cycloalkyl or 3 to 10 cycloalkenyl. In some embodiments, the cycloalkyl group is 3 to 6 cycloalkyl or 3 to 6 cycloalkenyl. In some embodiments, the cycloalkyl group is 5 to 6 cycloalkyl or 5 to 6 cycloalkenyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in this specification, cycloalkyl groups may be substituted as appropriate with, for example, oxy, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the cycloalkyl group may be substituted with a side-oxygen group, halogen, methyl group, ethyl group, -CN group, -COOH group, COOMe group, or -CF group, depending on the specific embodiment. 3. -OH, -OMe, -NH 2 or -NO 2. Substitution. In some embodiments, the cycloalkyl group is optionally substituted with a side-oxygen group, halogen, methyl, ethyl, -CN, or -CF. 3. -OH or -OMe substitution. In some embodiments, the cycloalkyl group is halogenated as appropriate. "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine. "Haloalkyl" means an alkyl group as defined above that has been substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like. "Hydroxyalkyl" refers to an alkyl group as defined above that has been substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl. "Aminoalkyl" means an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl. "Deuteryl alkyl" refers to an alkyl group as defined above that is substituted with one or more deuterium groups. In some embodiments, the alkyl group is substituted with one deuterium group. In some embodiments, the alkyl group is substituted with one, two, or three deuterium groups. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuterium groups. Deuteryl alkyl groups include, for example, CD. 3. CH 2D, CHD 2. CH 2CD 3. CD 2CD 3. CHDCD 3. CH 2CH 2D or CH 2CHD 2. In some embodiments, the deuteryl group is CD 3. "Heteroalkyl" refers to an alkyl group in which one or more alkyl skeleton atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. In one state, the heteroalkyl group is C10. 1-C 6. Heteroalkyl groups, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH 2OCH 3. -CH 2CH 2OCH 3. -CH 2CH 2OCH 2CH 2OCH 3. -CH(CH) 3) OCH 3. -CH 2NHCH 3. -CH 2N(CH 3) 2. -CH 2CH 2NHCH 3 or -CH 2CH 2N(CH 3) 2. Unless otherwise specifically stated in this specification, heteroalkyl groups may be substituted as appropriate with, for example, syloxy, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroalkyl groups may be substituted as appropriate with syloxy, halogen, methyl, ethyl, -CN, -CF 3. -OH, -OMe, -NH 2 or -NO 2. Substitution. In some embodiments, the heteroalkyl group may be substituted with a side-oxygen group, halogen, methyl, ethyl, -CN, or -CF, depending on the specific embodiment. 3. -OH or -OMe substitution. In some embodiments, heteroalkyl groups are halogenated as appropriate. "Heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclic alkyl comprises one to three nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one or two nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom and one oxygen atom. Unless otherwise specifically stated in this specification, the heterocyclic alkyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic alkyl is bonded via non-aromatic ring atoms) or bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heterocyclic alkyl may be oxidized as appropriate; the nitrogen atom may be quaternized as appropriate. Representative heterocyclic alkyl groups include (but are not limited to) the following heterocyclic alkyl groups: heterocyclic alkyl groups having two to fifteen carbon atoms (C 2-C 15 Heterocyclic alkyl or C 2-C 15 Heterocyclic alkenyl groups (C16-C16) and heterocyclic alkyl groups having two to ten carbon atoms. 2-C 10 Heterocyclic alkyl or C 2-C 10 Heterocyclic alkenyl groups (C64- ... 2-C 8 heterocyclic alkyl or C 2-C 8 heterocyclic alkenyl groups), heterocyclic alkyl groups having two to seven carbon atoms (C 2-C 7 heterocyclic alkyl or C 2-C 7 heterocyclic alkenyl groups), heterocyclic alkyl groups having two to six carbon atoms (C 2-C 6 heterocyclic alkyl or C 2-C 6 heterocyclic alkenyl groups, heterocyclic alkyl groups having two to five carbon atoms (C 2-C 5 heterocyclic alkyl or C 2-C 5 heterocyclic alkenyl groups), or heterocyclic alkyl groups having two to four carbon atoms (C 2-C 4 heterocyclic alkyl or C 2-C 4. Heterocyclic alkenyl groups. Examples of such heterocyclic alkyl groups include (but are not limited to) aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazodinyl, isothiazolidine, isozolidine, succinyl, octahydroindolyl, octahydroisoindolyl, 2-side-oxypiperidinyl, 2-side-oxypiperidinyl, 2-side-oxypyrrolidinyl, succinyl, piperidinyl, piperidinyl, 4-piperidinoneyl, pyrrolidinyl, pyrazolidine. The terms pyridyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropiperanyl, thiopyrinyl, thiazolinyl, 1-sideoxy-thiopyrinyl, 1,1-disideoxy-thiopyrinyl, 1,3-dihydroisobenzofuran-1-yl, 3-sideoxy-1,3-dihydroisobenzofuran-1-yl, methyl-2-sideoxy-1,3-m-dioxacyclopenten-4-yl, and 2-sideoxy-1,3-m-dioxacyclopenten-4-yl are used. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocyclic alkyl groups have 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is not the same as the total number of atoms constituting the heterocyclic alkyl group (i.e., the skeletal atoms of the heterocyclic alkyl ring), including heteroatoms. In some embodiments, the heterocyclic alkyl group is 3- to 8-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 3- to 7-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 3- to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 4- to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 5- to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 3- to 8-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 3- to 7-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 3- to 6-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 4- to 6-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 5- to 6-membered heterocyclic alkenyl. Unless otherwise specifically stated in this specification, heterocyclic alkyl groups may be substituted as described below with, for example, oxy, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, and the like. In some embodiments, the heterocyclic alkyl group may be substituted as described below with oxy, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF. 3. -OH, -OMe, -NH 2 or -NO 2. Substitution. In some embodiments, the heterocyclic alkyl group is, as appropriate, halogenated, methylated, ethylated, -CN-, -CF-. 3. -OH or -OMe substitution. In some embodiments, the heterocyclic alkyl group is halogenated as appropriate. "Heteroaryl" refers to a 5- to 14-membered ring system group comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl group comprises one to three nitrogen atoms. In some embodiments, a heteroaryl group comprises one or two nitrogen atoms. In some embodiments, a heteroaryl group comprises one nitrogen atom. A heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl group is bonded via aromatic ring atoms) or bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be oxidized as appropriate; the nitrogen atom may be quaternarily ammonized as appropriate. In some embodiments, a heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, a heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include (but are not limited to) aziridine, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzom-dioxacyclopentenyl, benzofuranyl, benzoazirazole, benzothiazolyl, benzo[b][1,4]dioxanyl, 1,4-benzodioxane, benzonaphthofuranyl, benzoazirazole, benzom-dioxacyclohexenyl, benzopiperanyl, benzopiperanone, benzofuranyl, benzofuranone, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, α Linyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, isothiazolyl, imidazolyl, indazole, indoleyl, isoindoleyl, indolinyl, isoindolelinyl, isoquinolinyl, indoleyl, isoazolyl, nitridyl, acetyldiazolyl, 2-side-oxy-nitropyryl, acezolyl, ethylene oxide, 1-oxo-ionylpyridine Pyridyl, 1-oxo-pyrimidinyl, 1-oxo-pyridine, 1-oxo-pyridine, 1-phenyl-1H-pyrroleyl, benzylayl, benzylaylthiayl, benzylayl, pyridyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridyl, pyridyl, pyridine, pyridine, pyrimidinyl, pyridine, quinazolinyl, quinazolinyl, quinolinyl The heteroaryl group may be substituted with, for example, halogen, amino, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Unless otherwise specifically stated in this specification, the heteroaryl group may be substituted with, for example, halogen, amino, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl group may be substituted with, for example, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF. 3. -OH, -OMe, -NH 2 or -NO 2. Substitution. In some embodiments, the heteroaryl group is, as appropriate, halogenated, methylated, ethylated, -CN-, -CF-. 3. -OH or -OMe substitution. In some embodiments, the heteroaryl group is halogenated as appropriate. The terms "as appropriate" or "as appropriate" mean that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "as appropriate, substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, substituted groups may be unsubstituted (e.g., -CH). 2CH 3) Completely replaced (e.g., -CF) 2CF 3) By monosubstitution (e.g., -CH) 2CH 2F) or substitution to any degree between complete substitution and monosubstitution (e.g., -CH) 2CHF 2. -CH 2CF 3. -CF 2CH 3. -CFHCHF 2, etc.). Regarding any group containing one or more substituents, those skilled in the art will understand that such groups are not intended to introduce any substitution or substitution pattern that is spatially impractical and / or synthetically infeasible (e.g., a substituted alkyl group includes, where appropriate, a substituted cycloalkyl group, which is then defined as including, where appropriate, substituted alkyl groups, possibly without end). Therefore, any substituents described should be generally understood to have a maximum molecular weight of about 1,000 Daltons and more typically, at most about 500 Daltons. The term "one or more" when referring to substituents present as they may be means that the subject group is substituted with one, two, three, or four substituents as they may be. In some embodiments, the subject group is substituted with one, two, or three substituents as they may be. In some embodiments, the subject group is substituted with one or two substituents as they may be. In some embodiments, the subject group is substituted with one substituent as they may be. In some embodiments, the subject group is substituted with two substituents as they may be. "Effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to a mammalian individual as a single dose or as part of a series of doses that effectively produces the desired therapeutic effect. As used herein, the terms “treat,” “treated,” “treatment,” or “treating” refer to therapeutic treatment in which the goal is to prevent or alleviate (reduce) unintended physical symptoms, conditions, or diseases, or to achieve beneficial or anticipated clinical outcomes. For the purposes described herein, beneficial or anticipated clinical outcomes include (but are not limited to) symptom relief; reduction in the severity of symptoms, conditions, or diseases; stabilization (i.e., no worsening) of the condition, condition, or disease; delay in the onset or slowing of the progression of symptoms, conditions, or diseases; improvement in the condition, condition, or disease; and remission (whether partial or complete) or improvement (whether detectable or undetectable) of symptoms, conditions, or diseases. Treatment includes eliciting a clinically significant response without excessive side effects. “Treatment” also includes extended survival compared to expected survival without treatment. The terms “treat,” “treated,” “treatment,” or “treating,” and those derived therefrom, do not necessarily imply 100% or complete treatment. Conversely, different levels of treatment exist, and those generally familiar with the technique generally recognize that such levels of treatment have potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any level of treatment for any ailment in mammals. For example, symptoms or signs of the ailment may be reduced by, for instance, approximately 100%, approximately 90%, approximately 80%, approximately 70%, approximately 60%, approximately 50%, approximately 40%, approximately 30%, approximately 20%, or approximately 10%. "Synergy" or "synergistic effect" refers to the combined effect that is greater than the sum of the effects of the individual components at the same dosage. As used in this article, "PARP-related disease or condition" or "PARP-mediated disease or condition" means any disease or other harmful symptom in which PARP or its mutants are known or suspected to be at play. As used in this article, "a disease or condition associated with PARP1" or "a disease or condition mediated by PARP1" means any disease or other harmful condition in which PARP1 or its mutants are known or suspected to be at play. compound This article describes compounds suitable for the treatment of cancer, or their medically acceptable salts, solvates, or stereoisomers. This article discloses a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Equation (I), where: R 1 For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 2 For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-haloalkyl or C 1-C 6-Deuteryl; X is N or CR 3 Y is N or CR 4 Z is N or CR 5 R 3For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 4 For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 5 For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Acynyl, cycloalkyl, or heterocyclic alkyl; wherein the alkyl, alkenyl, acynyl, cycloalkyl, or heterocyclic alkyl is substituted by one or more Rs, depending on the case; each R 6 Independently hydrogen, deuterium, halogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6. Heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more Rs, depending on the case; or two Rs. 6 Together they form cycloalkyl or heterocycloalkyl groups; each, depending on the case, is oxidized by deuterium, halogen, -CN, -OH, or -OR. a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl or C 1-C 6 heteroalkyl substitutions; each R 7 Independently deuterium, halogen, -CN, -OH, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-olefin or C 2-C 6-Alynyl group; or two R groups on the same carbon atom. 7 Together they form a side oxygen group; or two Rs on the same carbon or different carbons. 7 Together they form cycloalkyl or heterocycloalkyl groups; each of which is substituted with one or more R groups, depending on the case; n is 0 to 4; T is N or CR. 8 U is N or CR 9 R 8 Hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 9 Hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 10 Hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 11 Hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case; R 12 It is either cyano or halogen; each R a Independently for C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6-alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6. Alkyl (heteroaryl); wherein each alkyl, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted by one or more R, depending on the case; each R b Independently hydrogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6-alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6. Alkyl (heteroaryl); wherein each alkyl, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is independently substituted by one or more R, depending on the case; and each R c and R dIndependently hydrogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6-alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6. Alkyl (heteroaryl); wherein each alkyl, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted with one or more R, depending on the case; or R c and R d Together with the atoms to which it is attached, it forms a heterocyclic alkyl group, which may be substituted with one or more Rs, depending on the case; each R is independently deuterium, halogen, -CN, -OH, or -OC. 1-C 6-alkyl, -NH 2. -NHC 1-C 6-alkyl, -N(C) 1-C 6-alkyl) 2. -NHC(=O)OC 1-C 6-alkyl, -C(=O)C 1-C 6-alkyl, -C(=O)OH, -C(=O)OC 1-C 6-alkyl, -C(=O)NH 2. -C(=O)N(C 1-C 6-alkyl) 2. -C(=O)NHC 1-C 6-alkyl, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl or C 1-C 6. Heteroalkyl groups; or two R atoms on the same atom forming a side oxygen group; the restriction condition is that if X is a CR 3 Y is CR 4 And Z is CR 5 When, then R 3 R 4 and R 5 One of them is not hydrogen and R 4 Not -OMe; and its constraint is that when X is CH, Y is CH and Z is CH, then R 2 It is not hydrogen. In some embodiments of the compound of formula (I), the compound is not 7-(1-(4-(2,4-difluorophenyl)piperazine-1-yl)ethyl)-3-methylquinoline-2(1H)-one. In some embodiments of the compound of formula (I), the compound is not 7-((4-(3,4-dichlorophenyl)piperazine-1-yl)methyl)-3-ethylquinoline-2(1H)-one. In some embodiments of the compound of formula (I), the compound is not 7-((5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)methyl)-3-ethylquinoline-2(1H)-one. In some embodiments of the compound of formula (I), the compound is not 6-(4-(cyclohexyl(3-methyl-2-sideoxy-1,2-dihydroquinoline-7-yl)methyl)piperazine-1-yl)nicotinonitrile. In some embodiments of the compound of formula (I), the compound is not 6-(4-((3-ethyl-5-methoxy-2-sideoxy-1,2-dihydroquinoline-7-yl)methyl)piperazine-1-yl)nicotinonitrile. In some embodiments of the compound of formula (I), the compound is not 6-(4-(2-methyl-1-(3-methyl-2-sideoxy-1,2-dihydroquinolin-7-yl)propyl)piperazine-1-yl)nicotinonitrile. In some embodiments of the compound of formula (I), the compound is not 6-(4-((3-ethyl-2-sideoxy-1,2-dihydroquinoline-7-yl)methyl)piperazine-1-yl)nicotinonitrile. In some embodiments of the compound of formula (I), the compound is not 6-(4-(1-(3-ethyl-2-sideoxy-1,2-dihydroquinoline-7-yl)-2-methylpropyl)piperazine-1-yl)nicotinonitrile. In some embodiments of the compound of formula (I), X is N. In some embodiments of the compound of formula (I), X is CR. 3 . In some embodiments of the compound of formula (I), Y is N. In some embodiments of the compound of formula (I), Y is CR. 4 . In some embodiments of the compound of formula (I), Z is N. In some embodiments of the compound of formula (I), Z is CR. 5 . In some embodiments of the compounds of formula (I), X is N; Y is N or CR. 4 And Z is N or CR 5 In some embodiments of the compound of formula (I), X is N or CR. 3 Y is N; and Z is N or CR. 5 In some embodiments of the compound of formula (I), X is N or CR. 3 Y is N or CR 4 And Z is N. In some embodiments of the compound of formula (I), one of X, Y, or Z is N. In some embodiments of the compound of formula (I), both of X, Y, or Z are N. In some embodiments of the compound of formula (I), X is CR. 3 Y is CR 4 And Z is CR 5 In some embodiments of compounds of formula (I), X is CH; Y is CH; and Z is CH. In some embodiments of compounds of formula (I), X is CR. 3 Y is N; and Z is CR. 5 In some embodiments of compounds of formula (I), X is CH; Y is N; and Z is CH. In some embodiments of compounds of formula (I), X is N; Y is CR. 4 And Z is CR 5 In some embodiments of compounds of formula (I), X is N; Y is CH; and Z is CH. In some embodiments of the compound of formula (I), the compound has formula (Ia): Formula (Ia). In some embodiments of the compound of formula (I), the compound has formula (Ib): Formula (Ib). In some embodiments of the compound of formula (I), the compound has formula (Ic): Formula (Ic). In some embodiments of the compound of formula (I), the compound has formula (Id): ; Equation (Id); where R 3 R 4 and R 5 One of them is not hydrogen and R 4 Not for -OMe. In some embodiments of the compound of formula (I), the compound has formula (Ie): ; Equation (Ie); where R 2 For deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-alkyl, C 1-C 6-haloalkyl or C 1-C 6-Deuteryl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 6-Hydroalkyl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Acynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, acynyl, cycloalkyl and heterocycloalkyl are substituted with one or more R as appropriate. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 For hydrogen, deuterium, halogens, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 2-C 6. Acynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, acynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R... 1 For hydrogen, deuterium, halogens, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 2-C 6. Acynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, acynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R... 1Halogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 2-C 6. Acynyl or cycloalkyl; wherein the alkyl, acynyl, and cycloalkyl groups are substituted with one or more R groups, depending on the case. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R... 1 Halogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 2-C 6-Alynyl or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 2-C 6-Alynyl or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 C 1-C 6-alkyl or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 C 1-C 6-alkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 It is methyl or ethyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 R is methyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 It is ethyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 It is a cycloalkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1It is cyclopropyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 It is a heterocyclic alkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 C 1-C 6-Hydroalkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 It is a difluoromethyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 Halogen, C 1-C 6. Halogenated or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 It is a halogen or cycloalkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 It is a halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 It is fluorine or chlorine. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 1 It is chlorine. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2 For hydrogen, deuterium, halogen, -OR a C 1-C 6-alkyl or C 1-C 6-Hydroalkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2 For hydrogen, halogen, -OR a Or C 1-C 6-alkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2 It is hydrogen or halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2It is a halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2 It is fluorine. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2 R is methyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2 For -OR a In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2 -OCF 3. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2 For hydrogen, deuterium, halogen, -CN, -OR a -NR c R d C 1-C 2-alkyl, C 1-C 2-haloalkyl or C 1-C 2-Deuteryl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2 For hydrogen, halogen, -OR a Or C 1-C 2 alkyl groups. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2 Halogen, -OR a Or C 1-C 2 alkyl groups. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 2 Halogen or C 1-C 2-alkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 3 For hydrogen, deuterium, halogen, -OR a C 1-C 6-alkyl, C 1-C 6-haloalkyl or C 1-C 6-Deuteryl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 3 For hydrogen, halogen, -OR a Or C 1-C 6-alkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 3 It is hydrogen or halogen or C 1-C 6-alkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 3 It is hydrogen or halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 3 It is a halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 3 It is hydrogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 3 It is not hydrogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 4 Hydrogen, deuterium, halogen, -CN, -NR c R d C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 heteroalkyl, C 2-C 6-alkenyl, C 2-C 6. Acynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, acynyl, cycloalkyl, or heterocycloalkyl group is substituted with one or more R groups, depending on the case. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R... 4 For hydrogen, deuterium, halogen, -OR a C 1-C 6-alkyl, C 1-C 6-haloalkyl or C 1-C 6-Deuteryl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 4 For hydrogen, halogen, -OR a Or C 1-C 6-alkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 4 It is hydrogen or halogen or C 1-C 6-alkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 4 It is hydrogen or halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 4 It is a halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 4 It is hydrogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 4 It is not hydrogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 5 For hydrogen, deuterium, halogen, -OR a C 1-C 6-alkyl, C 1-C 6-haloalkyl or C 1-C 6-Deuteryl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 5 For hydrogen, halogen, -OR a Or C 1-C 6-alkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 5 It is hydrogen or halogen or C 1-C 6-alkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 5 It is hydrogen or halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 5 It is a halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 5 It is hydrogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 5 It is not hydrogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), each R 6 Independently hydrogen, deuterium, halogen, C 1-C 6-alkyl, C 1-C 6-haloalkyl or C 1-C 6-Deuteryl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), each R 6 Independently hydrogen, deuterium, or C 1-C 6-alkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), an R 6 It is hydrogen and another R 6 C 1-C 6-alkyl groups. In some embodiments of compounds of formula (I) or (Ia) to (Ie), each R 6For deuterium. In some embodiments of compounds of formula (I) or (Ia) to (Ie), each R 6 Independently for C 1-C 6-alkyl groups. In some embodiments of compounds of formula (I) or (Ia) to (Ie), each R 6 It is hydrogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), the two R... 6 Together they form a cycloalkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), the two R groups... 6 Together they form a cyclopropyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), each R 7 Independently for C 1-C 6-alkyl, C 1-C 6-haloalkyl or C 1-C 6-Deuteryl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), each R 7 Independently for C 1-C 6-alkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), two R groups on the same or different carbons. 7 Together they form a cycloalkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), the two R groups on the same or different carbons... 7 Together they form a cyclopropyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), n is 0 or 1. In some embodiments of compounds of formula (I) or (Ia) to (Ie), n is 0 to 2. In some embodiments of compounds of formula (I) or (Ia) to (Ie), n is 1 or 2. In some embodiments of compounds of formula (I) or (Ia) to (Ie), n is 1. In some embodiments of compounds of formula (I) or (Ia) to (Ie), n is 2. In some embodiments of compounds of formula (I) or (Ia) to (Ie), n is 3. In some embodiments of compounds of formula (I) or (Ia) to (Ie), n is 4. In some embodiments of compounds of formula (I) or (Ia) to (Ie), T is N. In some embodiments of compounds of formula (I) or (Ia) to (Ie), T is CR. 8 . In some embodiments of compounds of formula (I) or (Ia) to (Ie), U is N. In some embodiments of compounds of formula (I) or (Ia) to (Ie), U is CR. 9 . In some embodiments of compounds of formula (I) or (Ia) to (Ie), for In some embodiments of compounds of formula (I) or (Ia) to (Ie), for . In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 8 Hydrogen, deuterium, halogen, -CN, -OH, -OR a C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 8 For hydrogen, halogen, -CN, -OR a C 1-C 6-alkyl or C 1-C 6-Hydroalkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 8 For hydrogen, halogen, -CN, -OR a Or C 1-C 6-Hydroalkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 8 It is hydrogen, halogen or C 1-C 6-Hydroalkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 8 It is hydrogen or halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 8 It is hydrogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 9 Hydrogen, deuterium, halogen, -CN, -OH, -OR a C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 9 Hydrogen, deuterium, halogen, -CN, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 9 Hydrogen, halogen, -C 1-C 6-alkyl, C 1-C 6. Halogenated or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 9 It is hydrogen, halogen, or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 9 It is hydrogen or halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 9 It is hydrogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 10 Hydrogen, deuterium, halogen, -CN, -OH, -OR a C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 10 For hydrogen, deuterium, halogens, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 10 For hydrogen, halogen, C 1-C 6-alkyl or C 1-C 6-Hydroalkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 10 It is hydrogen or halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 10 It is hydrogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 11 Hydrogen, deuterium, halogen, -CN, -OH, -OR a C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 11 For hydrogen, deuterium, halogens, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl or cycloalkyl. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 11 For hydrogen, halogen, C 1-C 6-alkyl or C 1-C 6-Hydroalkyl group. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 11 It is hydrogen or halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 11 It is hydrogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 12 It is cyano. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 12 It is a halogen. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 12 It is fluorine or chlorine. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 12 It is fluorine. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 12 It is chlorine. In some embodiments of compounds of formula (I) or (Ia) to (Ie), R 12 It is either fluorine or bromine. In some embodiments of the compounds disclosed herein, each R a Independently for C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6. alkyl (heteroaryl); wherein each alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted with one or more Rs, depending on the case. In some embodiments of the compounds disclosed herein, each R... a Independently for C 1-C 6-alkyl, C 1-C 6. Halogenated or cycloalkyl, heterocyclic alkyl; wherein each alkyl, cycloalkyl, and heterocyclic alkyl group is independently substituted with one or more Rs as appropriate. In some embodiments of the compounds disclosed herein, each R... a Independently for C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6-alkyl (heteroaryl). In some embodiments of the compounds disclosed herein, each R a Independently for C 1-C 6-alkyl, C 1-C 6. Halogenated or cycloalkyl, heterocyclic alkyl. In some embodiments of the compounds disclosed herein, each R... a Independently for C 1-C 6-alkyl or C 1-C 6-Hydroalkyl groups. In some embodiments of the compounds disclosed herein, each R... a Independently for C 1-C 6-alkyl. In some embodiments of the compounds disclosed herein, each R a Independently for C 1-C 6-Hydroalkyl groups. In some embodiments of the compounds disclosed herein, each R b Independently hydrogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6. alkyl (heteroaryl); wherein each alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted with one or more Rs, depending on the case. In some embodiments of the compounds disclosed herein, each R... b Independently hydrogen, C 1-C 6-alkyl, C 1-C 6. Halogenated or cycloalkyl, heterocyclic alkyl; wherein each alkyl, cycloalkyl, and heterocyclic alkyl group is independently substituted with one or more Rs as appropriate. In some embodiments of the compounds disclosed herein, each R... b Independently hydrogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6-alkyl (heteroaryl). In some embodiments of the compounds disclosed herein, each R b Independently hydrogen, C 1-C 6-alkyl, C 1-C 6. Halogenated or cycloalkyl, heterocyclic alkyl. In some embodiments of the compounds disclosed herein, each R... b Independently hydrogen, C 1-C 6-alkyl or C 1-C 6-Hydroalkyl groups. In some embodiments of the compounds disclosed herein, each R... b Independently hydrogen or C 1-C 6-alkyl. In some embodiments of the compounds disclosed herein, each R b It is hydrogen. In some embodiments of the compounds disclosed herein, each R... b Independently for C 1-C 6-alkyl. In some embodiments of the compounds disclosed herein, each R b Independently for C 1-C 6-Hydroalkyl groups. In some embodiments of the compounds disclosed herein, each R c and R d Independently hydrogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6. alkyl (heteroaryl); wherein each alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted with one or more Rs, depending on the case. In some embodiments of the compounds disclosed herein, each R... c and R d Independently hydrogen, C 1-C 6-alkyl, C 1-C 6. Halogenated or cycloalkyl, heterocyclic alkyl; wherein each alkyl, cycloalkyl, and heterocyclic alkyl group is independently substituted with one or more Rs as appropriate. In some embodiments of the compounds disclosed herein, each R... c and R d Independently hydrogen, C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl, C 1-C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-C 6-alkyl (cycloalkyl), C 1-C 6-alkyl (heterocyclic alkyl), C 1-C 6-alkyl (aryl) or C 1-C 6-alkyl (heteroaryl). In some embodiments of the compounds disclosed herein, each R c and R d Independently hydrogen, C 1-C 6-alkyl, C 1-C 6. Halogenated or cycloalkyl, heterocyclic alkyl. In some embodiments of the compounds disclosed herein, each R... c and R d Independently hydrogen, C 1-C 6-alkyl or C 1-C 6-Hydroalkyl groups. In some embodiments of the compounds disclosed herein, each R... c and R d Independently hydrogen or C 1-C 6-alkyl. In some embodiments of the compounds disclosed herein, each R c and R d It is hydrogen. In some embodiments of the compounds disclosed herein, each R... c and R d Independently for C 1-C 6-alkyl. In some embodiments of the compounds disclosed herein, each R c and R d Independently for C 1-C 6-Hydroalkyl groups. In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms to which they are attached, they form heterocyclic alkyl groups that are substituted with one or more Rs, depending on the case. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, or -OC. 1-C 6-alkyl, -NH 2. -NHC 1-C 6-alkyl, -N(C) 1-C 6-alkyl) 2. C 1-C 6-alkyl, C 1-C 6-Hydroalkyl, C 1-C 6-Deuteryl, C 1-C 6-hydroxyalkyl, C 1-C 6-aminoalkyl or C 1-C 6 heteroalkyl groups; or two R groups on the same atom together forming a side oxygen group. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC. 1-C 6-alkyl, -NH 2. -NHC 1-C 6-alkyl, -N(C) 1-C 6-alkyl) 2. C 1-C 6-alkyl, C 1-C 6-haloalkyl or C 1-C 6-Deuteryl alkyl; or two Rs on the same atom together forming a side oxygen group. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC. 1-C 6-alkyl, -NH 2. C 1-C 6-alkyl or C 1-C 6-Hydroalkyl group; or two R atoms on the same atom together forming a side oxygen group. Any combination of groups described above for various variables is covered herein. Throughout this specification, those skilled in the art will select groups and their substituents to obtain stable moieties and compounds. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or stereoisomers are selected from the compounds in Table 1. surface 1 Add absolute markers (abs) to the center of the palmarity to indicate that it is a pure sample of the drawn stereoisomer. The OR designation (or) indicates a pure substance, but the absolute configuration of the stereochemical center is unknown. After isomorphic separation using the isolated pure structure, multiple OR designations with the same value (OR indicating purity) will indicate that the sample is one of a pair of pure mirror isomers (but the absolute configuration of the stereochemical center is unknown). The AND sign indicates that two isomers exist at the stereochemical center being described. Assigning different values ​​to the AND sign indicates that these values ​​are independent of each other. Using the AND sign with the same value indicates that the two stereocenters are relative to each other and can only vary uniformly. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts, solvates, or stereoisomers are selected from... . Other forms of the compounds revealed in this article Isomers / Stereomorphisms In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, engegen (E), and zusammen (Z) isomers, and corresponding mixtures thereof. In some cases, the compounds described herein have one or more palmar centers, each center existing in an R or S configuration. The compounds described herein include all non-mirror image isomers, mirror image isomers, and epimers, and corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of mirror image isomers and / or non-mirror image isomers produced by a single preparation step, combination, or interconversion are suitable for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture other than the compound with an optically active resolving agent to form a non-mirror image isomer pair, separating the non-mirror image isomers, and recovering the optically pure mirror image isomers. In some embodiments, a dissociable complex is preferred. In some embodiments, non-mirror image isomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated using these anisotropies. In some embodiments, non-mirror image isomers are separated by piezometric chromatography, or preferably by separation / resolution techniques based on differences in solubility. In some embodiments, optically pure mirror image isomers are subsequently recovered with a resolving agent using any means that do not cause racemization. Labeled compounds In some embodiments, the compounds described herein are present in an isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering a pharmaceutical composition of such isotopically labeled compounds. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those listed herein, but in fact, one or more atoms have undergone atomic substitutions with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively such as 2 H, 3 H, 13 C 14 C l5 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds containing the aforementioned isotopes and / or other isotopes, as well as their pharmaceutically acceptable salts, solvates, or stereoisomers, described herein are within the scope of this invention. Certain isotopically labeled compounds, for example, those containing, etc. 3 H and 14 Compounds containing radioactive isotopes of C are suitable for the distribution analysis of drugs and / or recipient tissues. Tritiumization (i.e....) 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly advantageous due to their ease of preparation and detectability. Furthermore, the use of isotopes such as deuterium (i.e., 2 Heavy isotope substitution (H) produces certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirement. In some embodiments, the compounds described herein are labeled in other ways, including (but not limited to) using chromophores or fluorescent portions, bioluminescent labeling, or chemiluminescent labeling. Medically acceptable salt In some embodiments, the compounds described herein are present in their pharmaceutically acceptable salt form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt in the form of a pharmaceutical composition. In some embodiments, the compounds described herein have acidic or basic groups and thus react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, such salts are prepared in situ during the final separation and purification of the compounds disclosed herein or their solvates or stereoisomers, or are prepared by reacting the purified compound in its free form with a suitable acid or base alone and isolating the salt thereby. Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic acids, organic acids, or inorganic bases. Such salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionate, decanoates, disglucuronates, dihydrophosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, transbutenedioates, glucoheptate, glycerophosphates, glycolic acid salts, hemisulfates, heptanoates, hexyn-1,6-dicitates, hydroxybenzoates, and gamma-hydroxybutyrates. Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, iodide, isobutyrate, lactate, maleate, malonate, methane sulfonate, amygdalinate, metaphosphate, methane sulfonate, methoxybenzoate, methylbenzoate, monohydrophosphate, 1-naphthalene sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, pyrosulfate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propane sulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluene sulfonate, undecanoate, and xylene sulfonate. Furthermore, the compounds described herein can be prepared in a pharmaceutically acceptable salt form by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including (but not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, trans-butenedioic acid, p-toluenesulfonic acid, and tartaric acid. Trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-en-1-carboxylic acid, glucohepanoic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids, such as oxalic acid, although pharmaceutically unacceptable on their own, are used to prepare salts that serve as intermediates for obtaining the compounds, solvates, or stereoisomers thereof disclosed herein and their pharmaceutically acceptable acid addition salts. In some embodiments, the compounds described herein containing free acid groups react with suitable bases (such as hydroxides, carbonates, bicarbonates, and sulfates of pharmaceutically acceptable metal cations), ammonia, or pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amines. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts and similar salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2O. + (C 1-4 alkyl) 4 and similar items. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, and their analogues. It should be understood that the compounds described herein also include quaternary ammoniation of any basic nitrogen-containing group they contain. In some embodiments, such quaternary ammoniation yields water-soluble, oil-soluble, or dispersible products. solvates In some embodiments, the compounds described herein are present in the form of solvates. The present invention provides a method for treating a disease by administering such solvates. The present invention further provides a method for treating a disease by administering such solvates in the form of a pharmaceutical composition. The solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during a crystallization process in a pharmaceutically acceptable solvent (such as water, ethanol, and the like). When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholic compound is formed. The solvates of the compounds described herein are preferably prepared or formed during the processes described herein. By way of example only, the hydrates of the compounds described herein are preferably prepared by recrystallization from an aqueous / organic solvent mixture, the organic solvent used including (but not limited to) dialkyl, tetrahydrofuran, or methanol. Furthermore, the compounds provided herein may exist in both solvated and non-solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form. tautomers In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the chemical formulas described herein. Tautomers are compounds that can interconvert through the migration of hydrogen atoms, which involves the conversion of single bonds with adjacent double bonds. A chemical equilibrium will exist in the bond arrangement in which tautomerization may occur. All tautomer forms of the compounds disclosed herein are covered. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Treatment This article discloses a method for treating diseases in which inhibition of PARP is beneficial, the method comprising administering a compound disclosed herein. This article also discloses a method for treating diseases in which inhibition of PARP1 is beneficial, the method comprising administering a compound disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer (such as stomach cancer and colorectal cancer), or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is leukemia, colorectal cancer, glioblastoma, lymphoma, melanoma, or cervical cancer. In some embodiments, the cancer is bladder cancer, brain cancer and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer. In some embodiments, the cancer is metastatic. In some embodiments, the cancer has metastasized to the brain. In some embodiments, the cancer contains BRCA1 and / or BRCA2 mutations. In some embodiments, cancers containing BRCA1 and / or BRCA2 mutations include bladder cancer, brain cancer and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer. In some embodiments, the cancer is a cancer lacking Flomologous recombination (FIR)-dependent DNA DSB repair activity. The FIR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homology mechanisms to reform continuous DNA helices. The components of the FIR-dependent DNA DSB repair pathway include (but are not limited to) ATM (NM_000051), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE1 1 A (NM_005590) and NBS1 (NM_002485). Other proteins involved in the FIR-dependent DNA DSB repair pathway include regulators such as EMSY. In some embodiments, cancer lacking FIR-dependent DNA DSB repair comprises one or more cancer cells with a reduced or eliminated ability to repair DNA DSBs via this pathway relative to normal cells, i.e., reduced or eliminated activity of the FIR-dependent DNA DSB repair pathway in one or more cancer cells. In some embodiments, the activity of one or more components of the FIR-dependent DNA DSB repair pathway is eliminated in one or more cancer cells in an individual suffering from cancer lacking FIR-dependent DNA DSB repair. In some embodiments, cancer cells exhibit a BRCA1 and / or BRCA2 deficiency phenotype, meaning that BRCA1 and / or BRCA2 activity is reduced or eliminated in the cancer cells. Cancer cells with this phenotype may lack BRCA1 and / or BRCA2, which can be achieved, for example, through mutations or polymorphisms encoding nucleic acids or through amplification, mutations, or polymorphisms of genes encoding regulatory factors (e.g., the EMSY gene encoding a BRCA2 regulatory factor), reducing or eliminating the expression and / or activity of BRCA1 and / or BRCA2 in cancer cells. BRCA1 and BRCA2 are known tumor suppressors, and their wild-type counterparts are frequently lost in tumors containing heterozygous conjugate vectors. Amplification of the EMSY gene, encoding a BRCA2 binding factor, is also known to be associated with breast and ovarian cancer. Carriers of BRCA1 and / or BRCA2 mutations also have a high risk of developing certain cancers, including breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological malignancies, gastrointestinal cancer, and lung cancer. This article also discloses a method for treating cancer in individuals of need that includes mutations in genes conferring homeo repair deficiency, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, mutations in genes conferring homeo repair deficiency include ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof. This article also discloses a method for treating cancer present in the brain, which involves administering the compound disclosed herein or a medically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the cancer in the brain is caused by a primary peripheral tumor that has metastasized to the brain. In some embodiments, the cancer in the brain originates in primary brain tissue. This article also discloses a method for treating brain cancer, which involves administering the compound disclosed herein or its pharmaceutically acceptable salt, solvate or stereoisomer. In some embodiments, brain cancer is a primary brain tumor that begins in the brain and tends to remain stationary there. In some embodiments, brain cancer is a secondary brain tumor. These cancers originate elsewhere in the body and spread to the brain. Lung cancer, breast cancer, kidney cancer, colorectal cancer, and skin cancer are the most common cancers that extend to the brain. In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, are capable of penetrating the blood-brain barrier (BBB). In some embodiments, the ratio of compounds penetrating the BBB is >0.1, where 1 represents complete BBB penetration and 0 represents no penetration. In some embodiments, the ratio of compounds penetrating the BBB is >0.2. In some embodiments, the ratio of compounds penetrating the BBB is >0.3. In some embodiments, the ratio of compounds penetrating the BBB is measured using rat kp,uu analysis. In some embodiments, the compounds have a ratio >0.3 (i.e., 0.3 to 1), which is determined in rat kp,uu analysis. Dosage In some embodiments, a composition containing the compounds described herein is administered for preventative and / or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient with the disease or symptom in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or symptom. The effective amount for this purpose depends on the severity and duration of the disease or symptom, prior therapy, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount may be determined, as appropriate, by methods including (but not limited to) dose escalation and / or dose range clinical trials. In prophylactic applications, a composition containing a compound described herein is administered to a patient who is susceptible to or otherwise at risk of developing a particular disease, condition, or symptom. Such amounts are defined as “preventatively effective amounts or doses.” In this application, the precise amount also depends on the patient’s health condition, weight, and similar factors. When used in a patient, the effective amount for this purpose will depend on the severity and course of the disease, condition, or symptom, prior treatment, the patient’s health condition and response to the drug, and the diagnosis of the treating physician. In one instance, prophylactic treatment comprises administering a pharmaceutical composition to a mammal who has previously experienced at least one symptom or risk factor of a treated disease and is currently in remission, in order to prevent recurrence of symptoms of the disease or symptom, the pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments where the patient’s condition has not improved, the compound is administered long-term, i.e., for a prolonged period of time, including the entire duration of the patient’s life, in order to improve or otherwise control or limit the symptoms of the patient’s disease or condition, based on the physician’s judgment. In some embodiments where the patient's condition improves, the dosage of the medication being administered is temporarily reduced or temporarily suspended for a certain period of time (i.e., a "medication holiday"). In specific embodiments, the length of the medication holiday is between 2 days and 1 year, including, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dosage reduction during the medication holiday is, for example, between 10% and 100%, including, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in certain embodiments, the dose or frequency, or both, is reduced based on symptoms to maintain the degree of improvement in the disease, condition, or symptom. However, in some embodiments, the patient requires long-term intermittent or routine treatment following any recurrence of symptoms. The amount of a given reagent corresponding to this quantity varies depending on factors such as the specific compound, the disease symptoms and their severity, and the identity of the individual or host requiring treatment (e.g., weight, sex), but is still determined based on the specific circumstances surrounding the following: such as the specific reagent administered, the route of administration, the disease being treated, and the individual or host being treated. However, generally, the dosage for adult treatment typically ranges from 0.01 mg to 5000 mg per day. In one embodiment, the dosage for adult treatment is from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is preferably presented as a single dose or as divided doses administered simultaneously or at appropriate time intervals (e.g., as two, three, four or more sub-dose times per day). In one embodiment, the daily dose suitable for the compound described herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is about 0.01 to about 50 mg per kilogram of body weight. In some embodiments, the daily dose or amount of the active ingredient in the dosage form may be lower or higher than the range indicated herein, depending on many variables relating to individual treatment regimens. In various embodiments, the daily and unit doses vary depending on many variables, including (but not limited to) the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual's needs, the severity of the disease or condition being treated, and the physician's judgment. The toxicity and efficacy of such treatments are determined using standard pharmaceutical procedures in cell cultures or laboratory animals, including (but not limited to) LD50. 10 and ED 90The determination of toxicity and therapeutic effect is the dose ratio, known as the therapeutic index, which is expressed as LD50. 50 With ED 50 The ratio between. In some embodiments, data obtained from cell culture analyses and animal studies are used in the formulation of therapeutically effective daily dose ranges and / or therapeutically effective unit doses for mammals (including humans). In some embodiments, the daily dose of the compounds described herein is within the ED range, which has minimal toxicity. 50 Within the range of cyclic concentrations. In some embodiments, depending on the dosage form and route of administration, the daily dose range and / or unit dose may vary within this range. Any of the foregoing embodiments is an additional example of the following, wherein an effective amount of the compound described herein or its pharmaceutically acceptable salt, solvate or stereoisomer is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered to a mammal by injection; and / or (e) administered locally to a mammal; and / or (f) administered non-systemically or locally to a mammal. Any of the aforementioned embodiments are other examples of compounds comprising a single dose of an effective amount, including other examples in which (i) the compound is administered once a day; or (ii) the compound is administered to mammals multiple times during a day. Any of the foregoing embodiments is an additional example of administering an effective amount of the compound multiple times, including the following additional examples, wherein (i) the compound is administered continuously or intermittently in a single dose; (ii) the time interval between multiple administrations is every 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to an individual every 12 hours; and (v) the compound is administered to an individual every 24 hours. In other or alternative embodiments, the method includes a drug holiday, wherein administration of the compound is temporarily suspended or the dose of the compound administered is temporarily reduced; administration of the compound is resumed at the end of the drug holiday. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. Investment channels Suitable routes of administration include (but are not limited to) oral, intravenous, rectal, aerosol, non-enteral, ocular, pulmonary, mucosal, percutaneous, vaginal, ear, nasal, and local administration. Additionally, by way of example only, non-enteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection. In some embodiments, the compounds described herein are administered locally rather than systemically, often by direct injection into an organ, typically in the form of reservoir formulations or sustained-release formulations. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, such as in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target the organ and are selectively absorbed by the organ. In other embodiments, the compounds described herein are provided in the form of rapid-release formulations, extended-release formulations, or intermediate-release formulations. In yet other embodiments, the compounds described herein are administered locally. Pharmaceutical Composition / Mixtures The compounds described herein are administered to individuals in need, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in the form of pharmaceutical compositions, according to standard pharmaceutical practice. In one embodiment, the compounds of the invention may be administered to animals. The compounds may be administered orally or non-enterally, including via intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and local routes of administration. In another embodiment, this document provides a pharmaceutical composition comprising the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable formulation. Suitable formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference. In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, and any combination thereof. The pharmaceutical ingredients described herein are administered to an individual via appropriate routes of administration, including (but not limited to) oral, non-enteric (e.g., intravenous, subcutaneous, intramuscular), intranasal, intrabuccal, topical, rectal, or percutaneous administration. The pharmaceutical formulations described herein include (but are not limited to) aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, rapidly dissolving formulations, tablets, capsules, pills, powders, sugar-coated tablets, foaming formulations, lyophilized formulations, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and mixed immediate-release and controlled-release formulations. Pharmaceutical compositions including the compounds described herein or their pharmaceutically acceptable salts, solvates or stereoisomers are manufactured in a conventional manner, such as by means of conventional mixing, dissolving, granulation, sugar-coating, water milling, emulsification, encapsulation, coating or compression methods only. Pharmaceutical formulations for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, grinding the resulting mixture as appropriate, and, if necessary, adding suitable adjuvants, processing the mixture into granules to obtain a tablet or sugar-coated tablet core. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginate or its salts, such as sodium alginate, are added. In some embodiments, dyes or pigments are added to the tablet or sugar-coated tablet coating to identify or characterize different combinations of active compound dosages. Orally administered pharmaceutical compositions include incorporation inserts made of gelatin and soft-sealable capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Incorporation inserts contain a mixture of the active ingredient and fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and stabilizers as appropriate. In the soft capsules, the active compound is dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Pharmaceutical compositions intended for non-enteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions or dispersions, or sterile powders containing compounds described herein or their pharmaceutically acceptable salts, solvates, or stereoisomers. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, physiological saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and suitable combinations thereof. In some embodiments, the pharmaceutical composition further includes a preservative to prevent microbial growth. combination This article discloses methods for treating cancer using the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, in combination with other therapeutic agents. In some embodiments, the additional therapeutic agent is an anticancer agent. In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered before the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the compound disclosed herein. Example The compounds described herein were synthesized as described in General Procedure 1 and General Procedure 2. General Process 1 General Process 2 Example 1 step 1 :preparation 3- bromine -2- methoxy -6- methyl -5- Nitropyridine: NaOMe (15.76 g, 87.49 mmol, 1.10 equiv, 30% wt) was added dropwise to a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv) in MeOH (50 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was analyzed by TLC (petroleum ether:EtOAc = 1:1, R...). f = 0.4) Monitor the reaction. After completion, concentrate the reactants under reduced pressure and add water (100 mL). Extract the resulting mixture with EtOAc (3 × 100 mL). Wash the combined organic layers with brine (1 × 200 mL) and irradiate with anhydrous Na+. 2SO 4. The sample was dried, filtered, and concentrated to give 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400 MHz, DMSO- d 6) δ 8.66 (s, 1H), 4.04 (s, 3H), 2.70 (s, 3H). step 2 :preparation (E)-2-(5- bromine -6- methoxy -3- Nitropyridine -2- base )-N,N- Dimethyl ethyl -1- amine: A mixture of 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g, 60.72 mmol, 1.00 equiv) in DMF-DMA (100 mL) and DMF (100 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was analyzed by TLC (petroleum ether:EtOAc = 1:1, R...). f = 0.5) Monitor the reaction. Cool the mixture to room temperature and then concentrate it under reduced pressure to give crude (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethyl-1-amine. The crude product was used directly in the next step without further purification. step 3 :preparation 5- bromine -6- methoxy -3- Nitropyridine formaldehyde: Under a nitrogen atmosphere at 0°C, (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)vinyl]dimethylamine (18.01 g, crude material) was subjected to THF (100 mL) and H₂O. Add NaIO to a fraction of the stirred mixture in 2O (100 mL) 4 (28.00 g, 131.07 mmol, 2.20 equiv). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The mixture was analyzed by TLC (petroleum ether:EtOAc = 5:1, R0). f= 0.2) Monitor the reaction. Quench the reactants by adding saturated sodium bisulfite (aqueous solution) (100 mL) at room temperature. Extract the resulting mixture with EtOAc (3×100 mL). Wash the combined organic layers with brine (2×100 mL) and dry over anhydrous Na 2SO 4. After filtration, concentrate the filtrate under reduced pressure. The crude product is used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO- d 6) δ 10.16 (s, 1H), 8.87 (s, 1H), 4.10 (s, 3H). Step 4 : Preparation of 7- ​​​​​​​​​​​​​​​​​​​​​​​​​​​Step 5 : Preparation of 7- Bromo -6- Methoxy -5H-1,5- Pyridine -3- Ethyl formate: At room temperature, TMSI (13.8 mL, 96.42 mmol, 6.00 equiv) was added dropwise to a solution of ethyl 7-bromo-6-methoxy-1,5-pyridine-3-carboxylate (5.00 g, 16.07 mmol, 1.00 equiv) in ACN (400 mL). The final reaction mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-bromo-6-methoxy-5H-1,5-pyridine-3-carboxylate (3.8 g, 80%). LC-MS: (ES+H, m / z): [M+H] + = 296.95. Step 6 : Preparation of 7-[2-( tert-Butyldimethylsilyl ) Ethynyl ]-6- Methoxy -5H-1,5- Pyridine -3- Ethyl formate: Ethyl 7-bromo-6-methoxy-5H-1,5-pyridine-3-carboxylate (1.50 g, 5.05 mmol, 1.00 equiv), tert-butyl(ethynyl)dimethylsilane (850 mg, 6.05 mmol, 1.20 equiv), CuI (0.19 g, 1.01 mmol, 0.20 equiv), Et 3N (1.53 g, 15.15 mmol, 3 equiv) and Pd(PPh 3) 2Cl A mixture of 2 (0.35 g, 0.51 mmol, 0.10 equiv) in DMF (45 mL) was stirred at 50 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (450 mL). The resulting mixture was extracted with EtOAc (3 × 450 mL). The combined organic layers were washed with brine (3 × 450 mL) and dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-[2-(tert-butyldimethylsilyl)ethynyl]-6-acyloxy-5H-1,5-diazepine-3-carboxylate (1.5 g, 83%). LC-MS: (ES+H, m / z): [M+H] + = 357.2. Step 7 : Preparation of 3-[2-( tert-Butyldimethylsilyl ) ethynyl ]-7-( hydroxymethyl )-1H-1,5- diazepine -one-2- : Under a nitrogen atmosphere at 0 °C, LiEt3BH (13.46 mL, 13.46 mmol, 4.00 equiv, 1 M in THF) was added dropwise to a stirred mixture of ethyl 7-[2-(tert-butyldimethylsilyl)ethynyl]-6-acyloxy-5H-1,5-diazepine-3-carboxylate (1.20 g, 3.37 mmol, 1.00 equiv) in THF (30 mL). The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding citric acid (5.05 mL, 5.05 mmol, 1.50 equiv, 1 M) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(hydroxymethyl)-1H-1,5-diazepine-2-one (840 mg, 79%). LC-MS: (ES+H, m / z): [M+H] <00,02312> + = 315.0. Step 8 : Preparation 3-[2-( tert-Butyldimethylsilyl ) ethynyl ]-7-( chloromethyl )-1H-1,5- pyridine -2- one: [[ID=2५]] Under a nitrogen atmosphere at 0 °C, SOCl 2 (0.06 mL, 0.88 mmol, 3.00 equiv, 1.64 g / mL) was added dropwise to a stirred mixture of 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(hydroxymethyl)-1H-1,5-pyridine-2-one (92 mg, 0.29 mmol, 1.00 equiv) and DMF (1 mg, 0.01 mmol, 0.05 equiv) in DCM (5 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(chloromethyl)-1H-1,5-pyridine-2-one (97 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H+MeCN] [[ID=२९]] + = 374.2. Step 9 : Preparation 5-[4-({7-[2-( tert-Butyldimethylsilyl ) ethynyl ]-6- side oxy -5H-1,5- pyridine -3- group } methyl ) piper idine -1- group ] It should be noted that there are some possible typos in the original text (such as "㖠啶" which might be incorrect characters). This translation is done based on the best understanding of the provided text. Pyridine -2- Benzonitrile: Under a nitrogen atmosphere at room temperature, KI (11 mg, 0.07 mmol, 0.20 equiv) was added portionwise to a stirred mixture of 5-(piperidin-1-yl)pyridine-2-carbonitrile hydrochloride (119 mg, 0.53 mmol, 1.48 equiv), DIEA (232 mg, 1.80 mmol, 5.00 equiv), and 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(chloromethyl)-1H-pyrrolo[1,5-a]pyridin-2-one (120 mg, 0.36 mmol, 1.00 equiv) in MeCN (5 mL). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-[4-({7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-pyrrolo[1,5-a]pyridin-3-yl}methyl)piperidin-1-yl]pyridine-2-carbonitrile (120 mg, 69%). Step 10 : Preparation of 5-{4 -[(7- Ethynyl -6- Oxo -5H-1,5- Pyrrolo -3- yl ) Methyl ] Piper idin -1- yl } Pyridine -2- Benzonitrile: TBAF (0.27 mL, 0.27 mmol, 1.10 equiv) was added dropwise to a stirred mixture of 5-[4-({7-[2-(tributyldimethylsilyl)ethynyl]-6-sideoxy-5H-1,5-diphenyl-3-yl}methyl)piperidin-1-yl]pyridin-2-carboxylonitrile (120 mg, 0.24 mmol, 1.00 equiv) in THF (2.5 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 1 h under a nitrogen atmosphere at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (1 × 50 mL) and irradiated with anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by preparative HPLC to give 5-{4-[(7-ethynyl-6-sideoxy-5H-1,5-diphenyl-3-yl)methyl]piperidin-1-yl}pyridin-2-carboxylonitrile (31.3 mg, 34%). LC-MS: (ES-H, m / z): [MH] - =369.1; 1 H NMR (300 MHz, DMSO- d 6) δ 12.17 (s, 1H), 8.48 (d, 1H), 8.42 (d, 1H), 8.15 (s, 1H), 7.75 (d, 1H), 7.64 (d, 1H), 7.36 (dd, 1H), 4.51 (s, 1H), 3.67 (s, 2H), 3.47 - 3.38 (m, 4H), 2.60 - 2.52 (m, 4H). Example 2 step 1 :preparation 5- Nitro -6-( C -1- olefins -2- base ) Pyridine -3- Methyl formate: Methyl 6-chloro-5-nitropyridine-3-carboxylate (10.00 g, 46.17 mmol, 1.00 equiv.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhecyclopentane (15.52 g, 92.34 mmol, 2.00 equiv.), K 2CO 3 (12.76 g, 92.34 mmol, 2.00 equiv.) and Pd(dppf)Cl A mixture of 2 (3.38 g, 4.62 mmol, 0.10 equiv.) in dimethyl methacrylate (150 mL) and water (15 mL) was stirred at 100 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with saturated NaCl (aqueous solution) (3 × 100 mL) and then subjected to anhydrous NaCl. 2SO 4. Dry, filter, and concentrate under reduced pressure. Concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography with PE / EA (1:1) dissolution to give methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 48.74%) as a pale yellow oil. LC-MS: (ES+H, m / z): [M+H] + =222.95; 1 H NMR (300 MHz, DMSO- d 6) δ 9.25 (d, 1H), 8.74 (d, 1H), 5.41 - 5.47 (m, 1H), 5.13 - 5.21 (m, 1H), 3.94 (s, 3H), 2.16 (dd, 3H). step 2 :preparation 5- Nitro -6-( C -1- olefins -2- base ) Pyridine -3- Methyl formate: To a stirred solution of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 22.50 mmol, 1.00 equiv.) in MeOH (100 mL) was added NH 4Cl (25 mL, saturated aqueous solution) and Fe (5.03 g, 90.01 mmol, 4.00 equiv.). The reaction mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature and then concentrated under reduced pressure. The residue was diluted with CH 2Cl 2 / 2-propanol (5:1, 200 mL) and washed with water (250 mL) and brine (250 mL). The organic layer was dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure. This gave methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 90.17%), which was used directly without further purification. LC-MS: (ES+H, m / z): [M+H] + = 193.15; 1 H NMR (300 MHz, DMSO- d 6) δ 8.29 (d, 1H), 7.60 (d, 1H), 5.51 - 5.47 (m, 1H), 5.41 (s, 2H), 5.39 - 5.36 (m, 1H), 3.84 (s, 3H), 2.08 (t, 3H). Step 3 : Preparation of 8- Methyl -6- Side oxy -5H-1,5- Diazine -3- Methyl formate: Under a nitrogen atmosphere at 0 °C, a solution of triphosgene (1.54 g, 5.20 mmol, 0.50 equiv.) in toluene (20 mL) was added to methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 20.29 mmol, 1.00 equiv.) and Et 3N (6.16 g, 60.87 mmol, 3.00 equiv.) in toluene (40 mL). The resulting mixture was stirred overnight at 60 °C under nitrogen. The reaction was monitored by LCMS. The reaction was quenched with MeOH (30 mL) at 0 °C. The resulting mixture was diluted with water (200 mL) and extracted with CH 2Cl 2 / 2-propanol (5:1, 3 × 200 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na 2SO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 8-methyl-6-oxo-5H-1,5-diazepine-3-carboxylate (1.80 g, 40.66%). LC-MS: (ES+H, m / z): [M+H] + = 219.1; 1 H NMR (400 MHz, DMSO- d 6) δ 11.92 (s, 1H), 8.92 (d, 1H), 8.15 (d, 1H), 6.79 (s, 1H), 3.93 (s, 3H), 2.48 (s, 3H). Step 4 : Preparation of 7- chloro -8- methyl -6- oxo -5H-1,5- diazepine -3- methyl carboxylate: Under a nitrogen atmosphere at room temperature, 2,2-dichloroacetic acid (71 mg, 0.55 mmol, 0.20 equiv.) was added dropwise to a solution of methyl 8-methyl-6-oxido-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.75 mmol, 1.00 equiv.) and NCS (587 mg, 4.40 mmol, 1.60 equiv.) in CH 3COOH (7 mL). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 7-chloro-8-methyl-6-oxido-5H-1,5-naphthyridine-3-carboxylate (650 mg, 93.5%). LC-MS: (ES+H, m / z): [M+H] + =253.0; 1 H NMR(300 MHz, DMSO- d 6) δ 8.90 (d, 1H), 8.13 (d, 1H), 3.93 (s, 3H), 2.60 (s, 3H). Step 5 : Preparation of 3- chloro -7-( hydroxymethyl )-4- methyl -1H-1,5- naphthyridine -2- -one: Under a nitrogen atmosphere at 0 °C, LiAlH was added dropwise to a stirred solution of methyl 7-chloro-8-methyl-6-oxido-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.38 mmol, 1.00 equiv.) in THF (5 mL). 4 (2 mL, 2.5 M in THF, 4.75 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding HCl (1 mL, 12 M) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-diazepin-(-)-2-one (230 mg, 43.1%). LC-MS: (ES+H, m / z): [M+H] + = 225.1; 1 H NMR (300 MHz, DMSO- d 6) δ 12.24 (br, 1H), 8.48 (d, 1H), 7.77 (d, 1H), 5.69 (s, 1H), 4.63 (s, 2H), 2.6 (s, 3H). Step 6 : Preparation of 3- chloro -7-( chloromethyl )-4- methyl -1H-1,5- diazepin​​​​​​​​​​​​Step 7 : Preparation of 4-{4-[(7- chloro -8- methyl -6- side oxy group -5H-1,5- pyridine -3- group ) methyl ] piper idin -1- group } benzonitrile: A solution of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-pyridine-2-one (25 mg, 0.10 mmol, 1.00 equiv.), DIEA (66 mg, 0.51 mmol, 5.00 equiv.), KI (4 mg, 0.02 mmol, 0.20 equiv.) and 4-(piperidin-1-yl)benzonitrile (19 mg, 0.10 mmol, 1.00 equiv.) in MeCN (2 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting mixture was concentrated under reduced pressure. The concentrated eluent was then lyophilized to give 4-{4-[(7-chloro-8-methyl-6-side oxy-5H-1,5-pyridine-3-yl)methyl]piperidin-1-yl}benzonitrile (12 mg, 29.6%). LC-MS: (ES-H, m / z): [M-H] - = 392.15; 1 H NMR (400 MHz, DMSO- d 6) δ 12.30 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.02 (d, J= 8.7 Hz, 2H), 3.67 (s, 2H), 3.38 - 3.34 (m, 4H), 2.64 (s, 3H), 2.57-2.54 (m, 4H). Example 3 step 1 :preparation 6- methyl -5- Nitropyridine -3- Methyl formate: Methyl 6-chloro-5-nitropyridine-3-carboxylate (5 g, 273.08 mmol, 1.00 equiv) and methylboronic acid (2.75 g, 46.17 mmol, 2.00 equiv) were reacted with toluene (60 mL) and H2O at room temperature under a nitrogen atmosphere. Pd(dppf)Cl was added to the mixture in 2O (3 mL). 2 (0.83 g, 1.15 mmol, 0.05 equiv) and CsF (7 g, 46.17 mmol, 2.00 equiv). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was added to 500 mL of water and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (200 mL) and precipitated with anhydrous Na+. 2SO 4. Dry, filter, and concentrate. The crude product was purified by silicone column chromatography to give methyl 6-methyl-5-nitropyridine-3-carboxylate (2.9 g, 64%). LC-MS: (ES+H, m / z): [M+H + =197.0; 1H NMR (400 MHz, chloroform-d) δ 9.29 (d, 1H), 8.84 (d, 1H), 4.01 (s, 3H), 2.94 (s, 3H). step 2 :preparation 6- methyl -5- Nitropyridine -3- Methyl formate: methyl 6-methyl-5-nitropyridine-3-carboxylate (35 g, 178.42 mmol, 1.00 equiv) and SeO A mixture of 2 (30 g, 267.64 mmol, 1.50 equiv) in dimethyl ether (200 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. The resulting mixture was then filtered, and the filter cake was washed with EtOAc (5 × 200 mL). The filtrate was concentrated under reduced pressure, and the crude product was then dissolved in THF (200 mL). The resulting mixture was filtered, and the filter cake was washed with THF (3 × 100 mL). The filtrate was concentrated under reduced pressure to give nitropyridine-3-carboxylate (40 g, crude product). LC-MS: (ES + H, m / z): [M+H + =211.1. step 3 :preparation (Z)-6-(2-( ethoxycarbonyl ) Man -1- olefins -1- base )-5- Methyl nitronicotinate: Under a nitrogen atmosphere at 0°C, ethyl 2-(diethoxyphosphatidyl)butyrate (72 g, 285.52 mmol, 1.50 equiv, 60% wt) was added dropwise to a stirred solution of NaH (11.42 g, 285.52 mmol, 1.50 equiv) in 500 mL of THF. The resulting mixture was stirred at 0°C for 10 min, then heated to 40°C and stirred for 10 min under a nitrogen atmosphere. The resulting mixture was cooled to -78°C, and then methyl 6-methoxy-5-nitropyridine-3-carboxylate (40 g, 190.35 mmol, 1.00 equiv) in 50 mL of THF was added dropwise. The resulting mixture was stirred at -78°C for 30 min under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was further controlled by adding saturated NH4+ at 0°C. 4Cl (aqueous solution) (100 mL) was used to quench the reactants. 400 mL of water was added to the resulting mixture and it was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (1 × 500 mL), dried over anhydrous Na 2SO 4, filtered and concentrated. The residue was purified by silica gel column chromatography to give methyl (Z)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nicotinic acid (20 g, 36%, two steps) and methyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nicotinic acid (8.8 g). Data for methyl (Z)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nicotinic acid: LC-MS: (ES+H, m / z): [M+H] + = 309.1; 1H NMR (300 MHz, chloroform-d) δ 9.27 (d, 1H), 8.88 (d, 1H), 7.10 (t, 1H), 4.22 - 4.16 (m, 2H), 4.03 (s, 3H), 2.59 (qd, 2H), 1.25 (t, 3H), 1.19 (t, 3H). Data for methyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nicotinic acid: LC-MS: (ES+H, m / z): [M+H] + = 309.1; 1 1H NMR (300 MHz, chloroform-d) δ 9.45 (d, 1H), 8.88 (d, 1H), 7.87 (s, 1H), 4.34 (q, 2H), 4.05 (s, 3H), 2.67 (q, 2H), 1.39 (t, 3H), 1.15 (t, 3H). Step 0] 4 : Preparation of 7- ethyl -6- side oxy -5H-1,5- pyridine -3- 9 ethyl formate: Under a nitrogen atmosphere at room temperature, CaCl 2 (19.44 g, 175.16 mmol, 6.00 equiv) was added to a stirred mixture of methyl 6-[(1Z)-3-ethoxy-2-ethyl-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (9.00 g, 29.19 mmol, 1.00 equiv) and Fe (16.30 g, 291.93 mmol, 10.00 equiv) in EtOH (200 mL). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with EtOAc (5 × 100 mL), and the combined filtrates were concentrated. The resulting mixture was added to 250 mL of water and extracted with EtOAc (3 × 250 mL). The combined organic layers were washed with brine (1 × 250 mL), dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 7-ethyl-6-oxo-5H-1,5-diazepine-3-carboxylate (5.2 g, 72%). LC-MS: (ES+H, m / z): [M+H] + = 247.1; 1H NMR (400 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.90 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 4.38 (q, 2H), 2.58 (q, 2H), 1.36 (t, 3H), 1.20 (t, 3H). Step 5 : Preparation of 3- ethyl -7-( hydroxymethyl )-1H-1,5- diazepine -2- one: Under a nitrogen atmosphere at 0 °C, LiAlH 4 (13 mL, 32.49 mmol, 2.00 equiv, 2.5 M in THF). The resulting mixture was stirred at 0 °C for 1 h. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M aqueous HCl solution (16 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography to afford 3-ethyl-7-(hydroxymethyl)-1H-1,5-diazepin-2-one (2.00 g, 60%). LC-MS: (ES+H, m / z): [M+H] + = 204.8; 1H NMR (400 MHz, DMSO- d 6) δ 11.91 (s, 1H), 8.38 (d, 1H), 7.74 (s, 1H), 7.62 (d, 1H), 5.49 (t, 1H), 4.62 (d, 2H), 2.55 (dd, 2H), 1.18 (t, 3H). Step 6 : Preparation of 7-( chloromethyl )-3- ethyl -1H-1,5- diazepine -2- one: Under a nitrogen atmosphere at 0 °C, SOCl 2 (1.05 g, 8.81 mmol, 6.00 equiv) was added dropwise to a stirred mixture of 3-ethyl-7-(hydroxymethyl)-1H-1,5-diazepin-2-one (300 mg, 1.47 mmol, 1.00 equiv) and DMF (11 mg, 0.15 mmol, 0.10 equiv) in DCM (10 mL). The resulting mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was purified by silica gel column chromatography to afford 7-(chloromethyl)-3-ethyl-1H-1,5-diazepin-2-one (300 mg, 92%). LC-MS: (ES+H, m / z): [M+H] + = 222.8; 1H NMR (400 MHz, DMSO- d 6) δ 11.99 (s, 1H), 8.50 (d, 1H), 7.76 (s, 1H), 7.70 (d, 1H), 4.93 (s, 2H), 2.56 (td, 2H), 1.19 (t, 3H). Step 7 : Prepare 5-{4-[(7- ethyl -6- side oxy group -5H-1,5- pyrrolo -3- <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​d 6) δ 11.86 (s, 1H), 8.41-8.35 (m, 2H), 7.75 (t, 2H), 7.61 (s, 1H), 7.36 (dd, 1H), 3.64 (s, 2H), 3.52-3.42 (m, 4H), 2.61-2.54 (m, 6H), 1.18 (t, 3H). Example 5 step 1 :preparation 2-[(4- bromine -2- fluorine -6- Nitrophenyl ) amino ] Methyl butyrate: DIEA (27.15 g, 210.10 mmol, 5.00 equiv) was added dropwise to a stirred mixture of 5-bromo-1,2-difluoro-3-nitrobenzene (10.00 g, 42.02 mmol, 1.00 equiv) and methyl 2-aminobutyrate hydrochloride (6.43 g, 42.02 mmol, 1.00 equiv) in NMP (200 mL) at room temperature. The resulting mixture was diluted with water (500 mL). The mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (8 × 300 mL) and then subjected to anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure solvent was concentrated under vacuum to give methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]butyrate (13.00 g, 92%). LC-MS: (ES+H, m / z): [M+H + = 334.9; 1 H NMR (400 MHz, DMSO- d 6) δ 8.09 (t, 1H), 7.88 (dd, 1H), 7.79 (dd, 1H), 4.56 (dtd, 1H), 3.69 (s, 3H), 1.97 - 1.79 (m, 2H), 0.91 (t, 3H). step 2 :preparation 7- bromine -3- Ethyl -5- fluorine -3,4- Dihydrogen -1H- Quinoline -2- ketone: Under a nitrogen atmosphere at 80 °C, methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]butyrate (6.00 g, 17.90 mmol, 1.00 equiv) was added dropwise to a stirred mixture of Fe (5.00 g, 89.52 mmol, 5.00 equiv) in AcOH (100 mL). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was analyzed by TLC (CH4) 2Cl The reaction was monitored using 2 / MeOH = 10 / 1. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by grinding with water (3 × 100 mL). The precipitated solid was collected by filtration and washed with water (3 × 20 mL). This yielded 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinolin-2-one (4.5 g, 92%). 1 H NMR (400 MHz, DMSO- d 6) δ 10.52 (s, 1H), 6.99 (d, 1H), 6.72 (s, 1H), 6.17 (s, 1H), 3.78 (d, 1H), 1.72 - 1.62 (m, 2H), 0.88 (t, 3H). step 3 :preparation 7- bromine -3- Ethyl -5- fluorine -1H- Quinoline -2- ketone: DDQ (4.39 g, 19.33 mmol, 1.20 equiv) was added aliquots of a stirred solution of 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinolin-2-one (4.40 g, 16.11 mmol, 1.00 equiv) in DCM (100 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 2 h under a nitrogen atmosphere at room temperature. The reaction was monitored by LCMS. The reaction was then investigated by adding saturated NaHCO3 at 0 °C. 3. Quench the reactants with an aqueous solution (100 mL). This is achieved by using saturated NaHCO3. The residue was purified by grinding with 3 (aqueous solution) (5 × 100 mL). The precipitated solid was collected by filtration and washed with water (3 × 100 mL) to give 7-bromo-3-ethyl-5-fluoro-1H-quinolin-2-one (3.50 g, 80%). LC-MS: (ES-H, m / z): [MH - = 269.0; 1 H NMR (400 MHz, DMSO- d 6) δ 12.51 (s, 1H), 7.44 (d, 1H), 7.24 (s, 1H), 2.79 (q, 2H), 1.21 (t, 3H). step 4 :preparation 2- Ethyl -8- fluorine -3- lateral oxygen -4H- Quinoline -6- formaldehyde: In a pressure chamber, TMEDA (1.49 g, 12.84 mmol, 1.20 equiv), bis(adamantane-1-yl)(butyl)phosphine (0.77 g, 2.14 mmol, 0.20 equiv), and Pd(OAc) were added to a solution of 7-bromo-3-ethyl-5-fluoro-1H-quinolin-2-one (2.90 g, 10.70 mmol, 1.00 equiv) in toluene (100 mL). 2 (0.24 g, 1.07 mmol, 0.10 equiv). The mixture was purged with nitrogen for 5 min, followed by (CO:H) The mixture was pressurized to 30 atm (2:1). The mixture was stirred overnight at 100°C. The reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under vacuum. The residue was purified by silicone column chromatography, and the pure solvent was concentrated under vacuum to give 2-ethyl-8-fluoro-3-sideoxy-4H-quinoline-6-carboxaldehyde (1.40 g, 59%). LC-MS: (ES-H, m / z): [MH - = 219.0; 1 H NMR (300 MHz, DMSO- d 6) δ 12.74 (s, 1H), 10.01 (d, 1H), 7.65 - 7.47 (m, 2H), 2.86 (q, 2H), 1.24 (t, 3H). step 5 :preparation 6-(4-((2- Ethyl -8- fluorine -3- lateral oxygen -3,4- dihydroquinoline -6- base ) methyl ) Piper 𠯤 -1- base ) Nicotinic nitrile: Ti(OiPr) was added to a stirred solution of 6-(piperazine-1-yl)pyridin-3-carboxynitrile (200 mg, 1.06 mmol, 1.00 equiv) and 2-ethyl-8-fluoro-3-sideoxy-3,4-dihydroquinoline-6-carboxaldehyde (304 mg, 1.38 mmol, 1.30 equiv) in THF (10 mL) under a nitrogen atmosphere at room temperature. 4 (453 mg, 1.60 mmol, 1.50 equiv). Two hours later, NaBH(AcO) was added at 0°C. 3 (901 mg, 4.25 mmol, 4.00 equiv) was added and the reactants were heated to room temperature. After 2 h, the reactants were quenched by adding water (10 mL) at 0 °C. The aqueous layer was extracted with EtOAc (5 × 30 mL). The combined organic phases were concentrated under reduced pressure and the crude product was purified by preparative HPLC to give 6-(4-((2-ethyl-8-fluoro-3-sideoxy-3,4-dihydroquinolin-6-yl)methyl)piperazine-1-yl)nicotinonitrile (56.1 mg, 13%). LC-MS: (ES+H, m / z): [M+H] + =393.2; 1H NMR (300 MHz, DMSO- d 6) δ 12.43 (s, 1H), 8.48 (d, 1H), 7.85 (dd, 1H), 7.16-7.04 (m, 2H), 6.93 (d, 1H), 3.77 - 3.52 (m, 6H), 2.87-2.75 (m, 2H), 2.50-2.43 (m, 4H), 1.22 (t, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -125.38. Example 12 step 1 :preparation 2- fluorine -4-[(1- methoxy -1- Side-oxybutane -2- base ) amino ]-5- Methyl nitrobenzene: DIEA (48.1 mL, 276.34 mmol, 6.00 equiv) was added dropwise to a stirred mixture of methyl 2,4-difluoro-5-nitrobenzene (10.00 g, 46.06 mmol, 1.00 equiv) and methyl 2-aminobutyrate HCl salt (5.40 g, 46.06 mmol, 1.00 equiv) in NMP (100 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The reaction was monitored by LCMS. The reactants were quenched by adding water (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (8 × 200 mL) and irradiated with anhydrous Na+. 2SO 4. Dry, filter, and concentrate. The crude product was purified by silicone column chromatography to give methyl 2-fluoro-4-[(1-methoxy-1-butan-2-yl)amino]-5-nitrobenzene (12 g, 83%). LC-MS: (ES+H, m / z): [M+H + = 315.1; 1 H NMR (400 MHz, DMSO- d 6) δ 8.80-8.56 (m, 2H), 7.21-6.99 (m, 1H), 4.84-4.74 (m, 1H), 3.85-3.81 (s, 3H), 3.77-3.74 (s, 3H), 2.05 - 1.82 (m, 2H), 0.91-0.85 (m, 3H). step 2 :preparation 2- Ethyl -7- fluorine -3- lateral oxygen -2,4- Dihydrogen -1H- Quinoline -6- Methyl formate: Pd(OH) was added fractionally to a stirred mixture of methyl 2-fluoro-4-[(1-methoxy-1-butan-2-yl)amino]-5-nitrobenzoate (12.00 g, 38.18 mmol, 1.00 equiv) in MeOH (180 mL) and EtOAc (30 mL) at room temperature under a nitrogen atmosphere. 2 / C (2.40 g). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by LC-MS. After completion, the resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 300 mL). The filtrate was concentrated and purified by silicone column chromatography (petroleum ether / EtOAc) to give methyl 2-ethyl-7-fluoro-3-sideoxy-2,4-dihydro-1H-quinoline-6-carboxylate (8 g, 83%). LC-MS: (ES+H, m / z): [M+H + = 253.0; 1 H NMR (400 MHz, DMSO- d 6) δ 10.44 (s, 1H), 7.25-7.20 (m, 1H), 7.19-7.14 (s, 1H), 4.00-3.91 (m, 1H), 3.75 (s, 3H), 1.76 - 1.60 (m, 2H), 0.94-0.86 (m, 3H). step 3 :preparation 2- Ethyl -7- fluorine -3- lateral oxygen -4H- Quinoline -6- Methyl formate: At room temperature, 70 mL of DCM containing DDQ (7.56 g, 33.30 mmol, 1.20 equiv) was added to a stirred mixture of methyl 2-ethyl-7-fluoro-3-sideoxy-2,4-dihydro-1H-quinoline-6-carboxylate (7.00 g, 27.75 mmol, 1.00 equiv) in DCM (70 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The residue was then dissolved in saturated NaHCO3. 3. Add to an aqueous solution (200 mL). Collect the precipitated solid by filtration and treat with NaHCO3. Wash with 3 saturated aqueous solution (3 × 200 mL) and water (3 × 200 mL). Purify the solid by grinding with EtOAc (30 mL) / hexane (100 mL). Filter the resulting mixture and wash the filter cake with hexane (3 × 100 mL). Dry the filter cake under reduced pressure to give methyl 2-ethyl-7-fluoro-3-sideoxy-4H-quinoline-6-carboxylate (6 g, 86%). LC-MS: (ES + H, m / z): [M+H + =251.1; 1 H NMR (400 MHz, DMSO- d 6) δ 12.44 (s, 1H), 7.78 (d, 1H), 7.63 (d, 1H), 3.89 (s, 3H), 2.82 (q, 2H), 1.23 (t, 3H). step 4 :preparation 3- Ethyl -6- fluorine -7-( hydroxymethyl )-1H- Quinoline -2- ketone: LiAlH was added dropwise to a stirred mixture of methyl 2-ethyl-7-fluoro-3-sideoxy-4H-quinoline-6-carboxylate (5.00 g, 19.98 mmol, 1.00 equiv) in THF (100 mL) under a nitrogen atmosphere at 0 °C. 4 (40 mL, 39.96 mmol, 2.00 equiv, 1 mol / L in THF). The reaction was monitored by LCMS. The reactants were quenched by adding water (1.5 mL), 15% NaOH (1.5 mL), and water (4.5 mL) at 0 °C. The precipitated solid was collected by filtration and washed with water (3 × 30 mL). The solid was dissolved in water (500 mL) and EtOAc (200 mL). The mixture was extracted with EtOAc (8 × 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by grinding with MeOH (5 mL) and EtOAc (20 mL). The mixture was filtered and the filter cake was washed with EtOAc (3 × 10 mL). The solid was dried under reduced pressure to give 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinolin-2-one (1.2 g, 27%). LC-MS: (ES+H, m / z): [M+H + =223.2; 1 H NMR (400 MHz, DMSO- d 6) δ 12.38 (s, 1H), 7.48 (d, 1H), 7.41 (d, 1H), 5.52 (brs, 1H), 4.64 (s, 2H), 2.80 (q, 2H), 1.18 (t, 3H). step 5 :preparation 7-( bromomethyl )-3- Ethyl -6- fluorine -1H- Quinoline -2- ketone: 3-Ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinolin-2-one (150 mg, 0.68 mmol, 1.00 equiv) was added to a stirred solution of HBr (4 mL, 33% wt in AcOH) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H + =285.0. step 6 :preparation 6-{4-[(2- Ethyl -7- fluorine -3- lateral oxygen -4H- Quinoline -6- base ) methyl ] Piper 𠯤 -1- base } Pyridine -3- Formonitrile: A mixture of 7-(bromomethyl)-3-ethyl-6-fluoro-1H-quinolin-2-one (190 mg, 0.67 mmol, 1.00 equiv), 6-(piperazine-1-yl)pyridin-3-carboxynitrile (150 mg, 0.80 mmol, 1.20 equiv), and DIEA (431 mg, 3.33 mmol, 5.00 equiv) in NMP (5 mL) was stirred at 80 °C for 1 h under a nitrogen atmosphere. The mixture was then cooled to room temperature. The reaction mixture was poured into water (30 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC to give 6-{4-[(2-ethyl-7-fluoro-3-sideoxy-4H-quinolin-6-yl)methyl]piperazine-1-yl}pyridin-3-carboxynitrile (100.2 mg, 38%). LC-MS: (ES+H, m / z): [M+H + =393.1; 1 H NMR (300 MHz, DMSO- d 6) δ 12.31 (s, 1H), 8.48 (d, 1H), 7.85 (dd, 1H), 7.54 (d, 1H), 7.38 (d, 1H), 6.94 (d, 1H), 3.75-3.67 (m, 6H), 2.81 (q, 2H), 2.56-2.51 (m, 4H), 1.21 (t, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -124.28. Example 16 step 1 :preparation 2- bromine -2- Ethyl cyclopropyltriethyl ester: Under a nitrogen atmosphere at -78°C, LDA (42.9 mL, 85.82 mmol, 1.10 equiv, 2.0 M in THF) was added dropwise to a stirred solution of ethyl 2-cyclopropylacetate (10.00 g, 78.02 mmol, 1.00 equiv) in 100 mL of THF. The reaction mixture was stirred for 1 hour, followed by dropwise addition of TMSCl (8.48 g, 78.02 mmol, 1.00 equiv), and the mixture was stirred for 3 hours while being warmed to room temperature. The mixture was then cooled to -78°C and 50 mL of THF containing NBS (15.28 g, 85.82 mmol, 1.10 equiv) was added dropwise. The mixture was then stirred for 2 hours and warmed to room temperature. The reaction was monitored by LCMS. The reaction was further controlled by adding saturated NH4+ at 0°C. The reactants were quenched with 4Cl (aqueous solution) (50 mL). Et was used. The mixture was extracted with 2O (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and then subjected to anhydrous Na+ extraction. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase combi-flash chromatography to give ethyl 2-bromo-2-cyclopropyl acetate (5.00 g, 31%). 1 ¹H NMR (300 MHz, chloroform-d) δ 4.25 (q, 2H), 3.58 (d, 1H), 1.65 - 1.55 (m, 1H), 1.31 (t, 3H), 0.92 - 0.76 (m, 2H), 0.61 - 0.53 (m, 1H), 0.48 - 0.40 (m, 1H). step 2 :preparation 2- Cyclopropyl -2-( Diethoxyphosphoyl ) Ethyl acetate: A solution of ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 24.14 mmol, 1.00 equiv) and triethyl phosphite (5.22 g, 31.39 mmol, 1.30 equiv) was stirred at 130 °C for 24 h under a nitrogen atmosphere. The residue was purified by reverse-phase combi-flash chromatography to give ethyl 2-cyclopropyl-2-(diethoxyphosphatidyl)acetate (2.40 g, 38%). 1 H NMR (300 MHz, chloroform-d) δ 4.26 - 4.07 (m, 6H), 2.19 (dd, 1H), 1.30 (dt, 10H), 0.71 (dddd, 1H), 0.60 (dddd, 1H), 0.47 - 0.37 (m, 1H), 0.24 (ddtd, 1H). step 3 :preparation 6-[(1Z)-2- Cyclopropyl -3- ethoxy -3- Side-oxypropyl -1- olefins -1- base ]-5- Nitropyridine -3- Methyl formate: Under a nitrogen atmosphere at 0°C, ethyl 2-cyclopropyl-2-(diethoxyphosphatidyl)acetate (1.89 g, 7.14 mmol, 1.50 equiv) was added dropwise to a stirred mixture of NaH (0.29 g, 7.14 mmol, 1.50 equiv) in THF (20 mL). The resulting mixture was stirred at 0°C for 10 min, then heated to 40°C and stirred for 10 min under a nitrogen atmosphere. The mixture was cooled to -78°C, and then THF (20 mL) containing methyl 6-methoxy-5-nitropyridine-3-carboxylate (1.00 g, 4.76 mmol, 1.00 equiv) was added dropwise. The resulting mixture was stirred at -78°C for 30 min under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was further controlled by adding saturated NH4+ at 0°C. The reaction was quenched with 4Cl (aqueous solution) (5 mL). 20 mL of water was added to the resulting mixture and it was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxopropyl-1-en-1-yl]-5-nitropyridine-3-carboxylate (700 mg, 46%). LC-MS: (ES+H, m / z): [M+H] + = 320.8. Step 4 : Preparation of 7- cyclopropyl -6- oxo -5H-1,5- pyridine -3- ethyl formate: Under a nitrogen atmosphere at room temperature, CaCl was added to a stirred mixture of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxopropyl-1-en-1-yl]-5-nitropyridine-3-carboxylate (600 mg, 1.87 mmol, 1.00 equiv) and Fe (1.04 g, 18.73 mmol, 10.00 equiv) in EtOH (10 mL). 2 (1.24 g, 11.24 mmol, 6.00 equiv). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (2×50 mL). The filtrate was concentrated under reduced pressure. 50 mL of water was added to the resulting mixture and it was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford ethyl 7-cyclopropyl-6-oxo-5H-1,5-pyridine-3-carboxylate (200 mg, 41%). LC-MS: (ES+H, m / z): [M+H] + =259.0. Step 5 : Prepare 3- cyclopropyl -7-( hydroxymethyl )-1H-1,5- pyridine -2- one: Under a nitrogen atmosphere at 0 °C, LiAlH 4 (0.50 mL, 1.23 mmol, 2.00 equiv, 2.5 M in THF) was added dropwise to a stirred solution of ethyl 7-cyclopropyl-6-oxo-5H-1,5-pyridine-3-carboxylate (1 **mg, 0.62 mmol, 1.00 equiv). The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M aqueous HCl (1 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-pyridine-2-one (100 mg, 75%). LC-MS: (ES+H, m / z): [M+H] + =217.2. Step 6 : Prepare​​​​​​​​​​​​​​​​​​​2 (264 mg, 2.22 mmol, 6.00 equiv). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3-cyclopropyl-1H-1,5-diazepin-2-one. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + = 235.0. Step 7 : Preparation of 3- Cyclopropyl -7-{[4-(5- Fluoropyridine -2- yl ) Piper azin -1- yl ] Methyl }-1H-1,5- Diazepin -2- one: To a stirred solution of 1-(5-fluoropyridin-2-yl)piperazine (100 mg, 0.55 mmol, 1.00 equiv) and 7-(chloromethyl)-3-cyclopropyl-1H-1,5-diazepin-2-one (130 mg, 0.55 mmol, 1.00 equiv) in ACN (3 mL) at room temperature was added DIEA (357 mg, 2.76 mmol, 5.00 equiv) and KI (18 mg, 0.11 mmol, 0.20 equiv). The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature and then poured into H 2O (10 mL), and the resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated and the crude product was purified by preparative HPLC to give 3-cyclopropyl-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-diazepin-2-one (122.8 mg, 58%). LC-MS: (ES+H, m / z): [M+H] + =380.3; 1 H NMR (300 MHz, DMSO- d 6) δ 11.88 (s, 1H), 8.38 (d, 1H), 8.09 (d, 1H), 7.61 (d, 1H), 7.55 - 7.45 (m, 1H), 7.42 (s, 1H), 6.86 (dd, 1H), 3.62 (s, 2H), 3.49 - 2.38 (m, 4H), 2.50 - 2.45 (m, 4H), 2.20 - 2.08 (m, 1H), 1.02 - 0.92 (m, 2H), 0.86 - 0.78 (m, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -143.41. Example 28 and 29 Step 1 : Prepare 7-(1- ethoxyvinyl )-3- methyl -1,5- pyridine -2(1H)- one: At room temperature, add Pd(PPh 3) 2Cl 2(0.44 g, 0.62 mmol, 0.05 equiv) to a stirred mixture of 7-bromo-3-methyl-1H-1,5-pyridine-2-one (3.00 g, 12.54 mmol, 1.00 equiv) and tributyl(1-ethoxyvinyl)stannane (13.60 g, 37.64 mmol, 3.00 equiv) in 1,4-dioxane (20 mL). Stir the resulting mixture under a nitrogen atmosphere at 100 °C for 2 h. After completion, cool the reaction mixture to room temperature and use the resulting solution directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =231.1 Step 2 : Preparation of 7- acetyl -3- methyl -1,5- pyridine -2(1H)- one: Cool the solution of 7-(1-ethoxyvinyl)-3-methyl-1,5-pyridine-2(1H)-one from Step 1 to 0 °C and treat dropwise with concentrated HCl (4 mL). Stir the resulting reaction mixture at room temperature for 1 h and then basify to pH 8 with saturated NaHCO 3 (aqueous solution). Then dilute the resulting mixture with water (100 mL) and extract with CH 2Cl 2 (3 × 200 mL). Wash the combined organic layers with brine (1 × 300 mL), dry over anhydrous Na 2SO 4, filter and concentrate. Purify the crude product by silica gel column chromatography to obtain 7-acetyl-3-methyl-1,5-pyridine-2(1H)-one (1.39 g, 55%, over two steps). LC-MS: (ES+H, m / z): [M+H] + = 203.2 Step 3 : Preparation of 6-[(2R)-2- methyl -4-[1-(7- methyl -6- side oxy -5H-1,5- pyridine -3- group ) ethyl ] piper idine -1- group ] <00031​​-3- Formonitrile: 7-Acetyl-3-methyl-1H-1,5-pyridin-2-one (350 mg, 1.73 mmol, 1.00 equiv) was added to 6-[(2R)-2-methylpiperazine-1-yl]pyridin-3-carboxylonitrile (455 mg, 2.25 mmol, 1.30 equiv) at CH4 2Cl The solution was added to a volume of 2 (8 mL). The resulting mixture was then concentrated under reduced pressure. Ti(OiPr) was added to the mixture at room temperature. 4 (4.6 mL, 15.58 mmol, 9.00 equiv). The resulting mixture was stirred at 80 °C for another 4 h and then cooled to room temperature. EtOH (5 mL) and NaBH were added to the mixture in fractions at room temperature. 3CN (217 mg, 3.46 mmol, 2.00 equiv). The resulting mixture was stirred at 80 °C for 2 h and then cooled to room temperature. The reaction mixture was poured into water (100 mL) and stirred for 1 h, filtered through a diatomaceous earth stopper, and washed with DCM / MeOH (3 / 1; 300 mL). The aqueous layer was extracted with DCM / i-PrOH (5 / 1; 2 × 100 mL), and the combined organic layer was washed with brine (2 × 50 mL) and then subjected to Na+ filtration. 2SO 4. The sample was dried, filtered, and concentrated. The residue was purified by silicone column chromatography to give 6-[(2R)-2-methyl-4-[1-(7-methyl-6-sideoxy-5H-1,5-diphenyl-3-yl)ethyl]piperazine-1-yl]pyridin-3-carboxynitrile (280 mg, 41.6%). LC-MS: (ES-H, m / z): [M+H] + = 389.1. Non-mirror image isomers were separated by palmar HPLC to obtain rel-6-[(2R)-2-methyl-4-[(1R*)-1-(7-methyl-6-sideoxy-5H-1,5-diphenyl-3-yl)ethyl]piperyl-1-yl]pyridin-3-carboxylonitrile (Example 28, 90.6 mg, de = 100%) and rel-6-[(2R)-2-methyl-4-[(1R*)-1-(7-methyl-6-sideoxy-5H-1,5-diphenyl-3-yl)ethyl]piperyl-1-yl]pyridin-3-carboxylonitrile (Example 29, 69.5 mg, de = 100%). Example 28 Information LC-MS: (ES+H, m / z): [M+H] + = 389.2; 1 H NMR (300 MHz, DMSO- d 6) δ 11.90 (s, 1H), 8.48 - 8.43 (dd, 2H), 7.85 - 7.82 (m, 2H), 7.65 - 7.64 (d, 1H), 6.86 - 6.83 (d, 1H), 4.51 (s, 1H), 4.26 - 4.22 (d, 1H), 3.59 - 3.57 (q, 1H), 3.14 - 3.11 (m, 2H), 2.58 - 2.50 (d, 1H), 2.18 - 2.06 (m, 5H), 1.36 - 1.34 (d, 3H), 1.18 - 1.15 (d, 3H). Example 29 Information LC-MS: (ES+H, m / z): [M+H] + = 389.1; 1 H NMR (300 MHz, DMSO- d 6) δ 11.85 (s, 1H), 8.48 - 8.46 (dd, 2H), 7.85 - 7.81 (m, 2H), 7.66 (d, 1H), 6.86 - 6.83 (d, 1H), 4.62 (s, 1H), 4.16 - 4.12 (d, 1H), 3.70 - 3.64 (q, 1H), 3.11 - 3.01 (td, 1H), 2.88 - 2.76 (dd, 2H), 2.26 - 2.03 (m, 5H), 1.34 (d, 3H), 1.22 (d, 3H). The relative stereochemical systems of Examples 28 and 29 are arbitrarily specified. Example 36 step 1 :preparation 5- Nitro -6-( C -1- olefins -2- base ) Pyridine -3- Methyl formate: Methyl 6-chloro-5-nitropyridine-3-carboxylate (10.00 g, 46.17 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhecyclopentane (15.52 g, 92.34 mmol, 2.00 equiv), K 2CO A mixture of 3 (12.76 g, 92.34 mmol, 2.00 equiv) and Pd(dppf)Cl2 (3.38 g, 4.62 mmol, 0.10 equiv) in dimethyl ether (150 mL) and water (15 mL) was stirred at 100 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtoAc (3 × 300 mL). The combined organic layers were washed with saturated NaCl (aqueous solution) (3 × 100 mL) and then subjected to anhydrous NaCl. 2SO 4. Dry, filter, and concentrate under reduced pressure. Concentrate the filtrate under reduced pressure. Purify the residue by silicone column chromatography to give methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 49%) as a pale yellow oil. LC-MS: (ES+H, m / z): [M+H] + =222.95. step 2 :preparation 5- Nitro -6-( C -1- olefins -2- base ) Pyridine -3- Methyl formate: To a stirred solution of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 22.50 mmol, 1.00 equiv) in MeOH (100 mL) was added NH 4Cl (25 mL, saturated aqueous solution) and Fe (5.03 g, 90.01 mmol, 4.00 equiv). The reaction mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature and then concentrated under reduced pressure. The residue was diluted with CH 2Cl 2 / 2-propanol (5:1, 200 mL) and washed with water (250 mL) and brine (250 mL). The organic layer was dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure. This gave methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 90%) which was used directly without further purification. LC-MS: (ES+H, m / z): [M+H] <> + = 193.15. <> 1 H NMR (300 MHz, DMSO- d 6) δ 8.29 (d, 1H), 7.60 (d, 1H), 5.51 - 5.47 (m, 1H), 5.41 (s, 2H), 5.39 - 5.36 (m, 1H), 3.84 (s, 3H), 2.08 (t, 3H). Step 3 : Preparation of 8- methyl -6- side oxy group -5H-1,5- pyridine -3- formate: Under a nitrogen atmosphere at 0 °C, a solution of triphosgene (1.54 g, 5.20 mmol, 0.50 equiv) in toluene (20 mL) was added to methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 20.29 mmol, 1.00 equiv) and Et A solution of 3N (6.16 g, 60.87 mmol, 3.00 equiv) in toluene (40 mL). The resulting mixture was stirred overnight at 60 °C under nitrogen. The reaction was monitored by LCMS. The reactants were quenched with MeOH (30 mL) at 0 °C. The resulting mixture was diluted with water (200 mL) and extracted with CH 2Cl 2 / 2-propanol (5:1, 3 × 200 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 8-methyl-6-oxo-5H-1,5-diazepine-3-carboxylate (1.80 g, 41%). LC-MS: (ES+H, m / z): [M+H] + = 2,191; 1 H NMR (400 MHz, DMSO- d 6) δ 11.9, 2 (s, 1H), 8.92 (d, 1H), 8.15 (d, 1H), 6.79 (s, 1H), 3.93 (s, 3H), 2.48 (s, 3H). Step Four : Preparation of 7- chloro -8- methyl -6- oxo -5H-1,5- diazepine -3- methyl carboxylate: Under a nitrogen atmosphere at room temperature, to methyl 8-methyl-6-oxo-5H-1,5-diazepine-3-carboxylate (600 mg, 2.75 mmol, 1.00 equiv) and NCS (587 mg, 4.40 mmol, 1.60 equiv) in CH 2,2-Dichloroacetic acid (71 mg, 0.55 mmol, 0.20 equiv) was added dropwise to a solution in 3COOH (7 mL). The resulting mixture was stirred overnight at 100 °C and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 94%). LC-MS: (ES+H, m / z): [M+H] + = 253.0; 1 H NMR (300 MHz, DMSO- d 6) δ 8.90 (d, 1H), 8.13 (d, 1H), 3.93 (s, 3H), 2.60 (s, 3H). Step 5 : Preparation of 3- chloro -7-( hydroxymethyl )-4- methyl -1H-1,5- naphthyridine -2- one: Under a nitrogen atmosphere at 0 °C, LiAlH 4 (2 mL, 2.5 M in THF, 4.75 mmol, 2.00 equiv) was added dropwise to a stirred solution of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.38 mmol, 1.00 equiv) in THF (5 mL). The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding HCl (1 mL, 12M) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (230 mg, 43%). LC-MS: (ES+H, m / z): [M+H] + = 225.1; 1 H NMR (300 MHz, DMSO- d6) δ 12.24 (br, 1H), 8.48 (d, 1H), 7.77 (d, 1H), 5.69 (s, 1H), 4.63 (s, 2H), 2.63 (s, 3H). Step 6 : Prepare 3- chloro -7-( chloromethyl )-4- methyl -1H-1,5- pyridine -2- -one: Under a nitrogen atmosphere at 0 °C, SOCl 2 (318 mg, 2.67 mmol, 3.00 equiv) was added dropwise to a stirred solution of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-pyridine-2-one (200 mg, 0.89 mmol, 1.00 equiv) and DMF (7 mg, 0.09 mmol, 0.10 equiv) in DCM (10 mL). The resulting mixture was stirred at room temperature for 10 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-pyridine-2-one (98 mg, 45%). LC-MS: (ES+H, m / z): [M+H] + = 243.0. Step 7 : Prepare 6-{4-[(7- chloro -8- methyl -6- side oxy -5H-1, 5- pyridine ​​​​​​​​​​​ indolyl -1- radical } pyridine -3- carbonitrile: Under a nitrogen atmosphere at room temperature, DIEA (136 mg, 1.05 mmol, 3.00 equiv) and KI (1 mg, 0.01 mmol, 0.10 equiv) were added to a stirred mixture of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (85 mg, 0.35 mmol, 1.00 equiv) and 6-(piperidin-1-yl)pyridine-3-carbonitrile (66 mg, 0.35 mmol, 1.00 equiv) in ACN (1 mL). The resulting mixture was stirred at 80 °C for 1 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product (90 mg), which was further purified by preparative HPLC to give 6-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperidin-1-yl}pyridine-3-carbonitrile (52.5 mg, 28%). LC-MS: (ES+H, m / z): [M+H] + = 395.10; 1 H NMR (300 MHz, DMSO- d 6) δ 12.30 (br, 1H), 8.50 (m, 2H), 7.85 (dd, 1H), 7.69 (d, 1H), 6.94 (d, 1H), 3.67 - 3.62 (m, 6H), 2.65 (s, 3H), 2.50 - 2.49 (m, 4H). Example 42 Step 1 : Preparation of 7-( difluoromethyl )-8- methyl -6- oxo -5H-1,5- naphthyridine -3- Methyl formate: A mixture of methyl 8-methyl-6-oxido-5H-1,5-naphthyridine-3-carboxylate (800 mg, 3.67 mmol, 1.00 equiv), sodium difluoromethanesulfinate (1012 mg, 7.33 mmol, 2.00 equiv), 2-methylpropan-2-peroxol (991 mg, 11.00 mmol, 3.00 equiv) and TFA (418 mg, 3.67 mmol, 1.00 equiv) in CH 2Cl 2 / H 2O (2.5:1, 120 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. Then the resulting mixture was diluted with water (100 mL) and extracted with CH 2Cl 2 / 2-propanol (5:1, 3 × 100 mL). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure to give methyl 7-(difluoromethyl)-8-methyl-6-oxido-5H-1,5-naphthyridine-3-carboxylate (650 mg, 66%). LC-MS: (ES+H, m / z): [M+H] + = 269.1; 1 H NMR (400 MHz, DMSO- d 6) δ 12.39 (s, 1H), 8.99 (d, 1H), 8.19 (m, 1H), 7.26 (t, 1H), 3.94 (s, 3H), 2.72 (s, 3H). Step 2 : Preparation of 3-( Difluoromethyl )-7-( Hydroxymethyl )-4- Methyl -1H-1,5- Naphthyridine -2- One: Under a nitrogen atmosphere, at 0 °C, a solution of lithium aluminum hydride 4 solution (2.5 M in THF, 3.9 mL, 9.75 mmol, 4.00 equiv) was added dropwise to a stirred solution of methyl 7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 2.42 mmol, 1.00 equiv) in THF (65 mL). The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding saturated aqueous NH 4Cl (10 mL) at 0 °C and dried over anhydrous Na 2SO 4. The mixture was filtered and washed with CH 2Cl 2 / MeOH (10:1, 100 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (520 mg, 89%). LC-MS: (ES+H, m / z): [M+H] + = 241.1. 1 1H NMR (400 MHz, methanol-d4) δ 8.58 (d, 1H), 7.73 (d, 1H), 7.20 (t, 1H), 4.79 (s, 2H), 2.81 (t, 3H). Step 3 : Preparation of 7-( chloromethyl )-3-( difluoromethyl )-4- methyl -1H-1,5- naphthyridine [[ID=]] -2- one: Under a nitrogen atmosphere, at 0 °C, to 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl- I H-1,5-naphthyridin-2-one (320 mg, 1.33 mmol, 1.00 equiv) and DMF (5 mg, 0.07 mmol, 0.05 equiv) in CH 2Cl SOCl₂ (475 mg, 4.00 mmol, 3.00 equiv) was added dropwise to the stirred mixture in 2 (32 mL). The resulting mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature and then concentrated under reduced pressure to give 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-diazepin-2-one (crude, 400 mg). LC-MS: (ES+H, m / z): [M+H] = 259.1 + Step 4 : Preparation of 6-(4-{[7-( difluoromethyl )-8- methyl -6- side oxy -5H-1,5- diazepine -3- group ] methyl } piper azin -1- group ) pyridine -3- -acetonitrile: A mixture of 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-diazepin-2-one (380 mg, 1.47 mmol, 1.00 equiv), 6-(piperazin-1-yl)pyridine-3-acetonitrile (415 mg, 2.20 mmol, 1.50 equiv), KI (365 mg, 2.20 mmol, 1.50 equiv) and DIEA (569 mg, 4.40 mmol, 3.00 equiv) in MeCN (4 mL) was stirred at 80 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (3 × 10 mL), dried over anhydrous Na ₂SO 4. Drying. Filter the mixture and wash with EtOAc (50 mL), then concentrate the filtrate under reduced pressure. Purify the residue by preparative HPLC to give 6-(4-{[7-(difluoromethyl)-8-methyl-6-sideoxy-5H-1,5-nitin-3-yl]methyl}piperidin-1-yl)pyridin-3-carboxylonitrile (31 mg, 5%). LC-MS: (ES+H, m / z): [M+H] + =411.2; 1 H NMR (300 MHz, DMSO- d 6) δ 12.17 (br, 1H), 8.57 (d, 1H), 8.41 (d, 1H), 7.85 (dd, 1H), 7.68 (d, 1H), 7.24 (t, 1H), 6.94 (d, 1H),3.80-3.60 (m, 6H), 2.72 (s, 3H), 2.60-2.40 (m, 4H); 19 F NMR (282 MHz, DMSO-d6) δ -115.51. Example 47 step 1 :preparation 3- bromine -2- methoxy -6- methyl -5- Nitropyridine: NaOMe (15.76 g, 87.49 mmol, 1.10 equiv, 30% wt) was added dropwise to a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv) in MeOH (50 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was analyzed by TLC (petroleum ether:EtOAc = 1:1, R...). f= 0.4) Monitor the reaction. After completion, concentrate the reactants under reduced pressure and add water (100 mL). Extract the resulting mixture with EtOAc (3 × 100 mL). Wash the combined organic layers with brine (1 × 200 mL) and irradiate with anhydrous Na+. 2SO 4. The sample was dried, filtered, and concentrated to give 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400 MHz, DMSO- d 6) δ 8.66 (s, 1H), 4.04 (s, 3H), 2.70 (s, 3H). step 2 :preparation (E)-2-(5- bromine -6- methoxy -3- Nitropyridine -2- base )-N,N- Dimethyl ethyl -1- amine: A mixture of 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g, 60.72 mmol, 1.00 equiv) in DMF-DMA (100 mL) and DMF (100 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was analyzed by TLC (petroleum ether:EtOAc = 1:1, R...). f = 0.5) Monitor the reaction. Cool the mixture to room temperature and then concentrate it under reduced pressure to give crude (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethyl-1-amine. The crude product was used directly in the next step without further purification. step 3 :preparation 5- bromine -6- methoxy -3- Nitropyridine formaldehyde: Under a nitrogen atmosphere at 0 °C, sodium periodate (28.00 g, 131.07 mmol, 2.20 equiv) was added portionwise to a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)vinyl]dimethylamine (18.01 g, crude) in THF (100 mL) and H 2O (100 mL). The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by TLC (petroleum ether:EtOAc = 5:1, R f = 0.2). The reaction was quenched by adding saturated sodium bisulfite (aqueous solution) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na f 2SO 4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. 1 1H NMR (400 MHz, DMSO- d 6) δ 10.16 (s, 1H), 8.87 (s, 1H), 4.10 (s, 3H). Step 4 : Preparation of 7- bromo -6- methoxy -1,5- pyridine -3- formic acid ethyl ester: Under a nitrogen atmosphere at room temperature, tin(II) chloride was added portionwise to a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropionate (20.40 g, 107.27 mmol, 4.00 equiv) in EtOH (100 mL). 2 (26.25 g, 134.09 mmol, 5.00 equiv). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the crude product. The crude product was further purified by trituration with hexane (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5%, over three steps). LC-MS: (ES+H, m / z): [M+H] + = 311.0 Step 5 : Preparation of 7- chloro -6- methoxy -1,5- naphthyridine -3- ethyl carboxylate: Under a nitrogen atmosphere at room temperature, CuCl (0.57 g, 5.78 mmol, 1.50 equiv) was added to a stirred mixture of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (1.20 g, 3.85 mmol, 1.00 equiv) in DMF (10 mL). The resulting mixture was stirred overnight at 120 °C. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with 3 × 30 mL of water (10% NH 3·H 2O). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 77.78%). LC-MS: (ES+H, m / z): [M+H] + = 267.0; 1 H NMR (300 MHz, DMSO- d 6) δ 9.27 (d, 1H), 8.63 (d, 1H), 8.57 (s, 1H), 4.41 (q, 2H), 4.12 (s, 3H), 1.37 (t, 3H). Step 6 : Prepare 7- chloro -6- side oxy group -5H-1,5- pyridine -3- ethyl formate: Under a nitrogen atmosphere at room temperature, add TMSI (1.80 g, 9.00 mmol, 3.00 equiv) to the stirred mixture of ethyl 7-chloro-6-methoxy-1,5-pyridine-3-carboxylate (800 mg, 3.00 mmol, 1.00 equiv) in CH 3CN (8 mL). Stir the resulting mixture at 50 °C for 2 h. Monitor the reaction by LCMS. Cool the mixture to room temperature. Dilute the resulting mixture with EtOAc (50 mL). Wash the aqueous layer with 3 × 50 mL of water (10% Et 3N). Wash the combined organic layers with brine (50 mL), dry over anhydrous Na 2SO 4, filter and concentrate. Purify the residue by silica gel column chromatography to obtain ethyl 7-chloro-6-side oxy-5H-1,5-pyridine-3-carboxylate (740 mg, 97.64%). LC-MS: (ES+H, m / z): [M+H] + = 252.9; 1 H NMR (300 MHz, DMSO- d 6) δ12.61 (s, 1H), 8.94 (d, 1H), 8.37 (d, 1H), 8.20 (s, 1H), 4.39 (q, 2H), 1.36 (t, 3H). Step 7 : Prepare 3- chloro -7-( hydroxymethyl )-1H-1,5- pyridine -2- -one: Under a nitrogen atmosphere at 0 °C, LiAlH 4 (2.5 mL, 5.85 mmol, 2.00 equiv) was added dropwise to a stirred mixture of ethyl 7-chloro-6-cyano-5H-1,5-pyridine-3-carboxylate (740 mg, 2.92 mmol, 1.00 equiv) in THF (6 mL). The resulting mixture was stirred at 0 °C for an additional 2 h. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with 1 M HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-chloro-7-(hydroxymethyl)-1H-1,5-pyridine-2-one (250 mg, 40.53%). LC-MS: (ES+H, m / z): [M+H] + = 211.0; 1 H NMR (400 MHz, DMSO- d6) δ12.49 (s, 1H), 8.45 (d, 1H), 8.28 (s, 1H), 7.69 (d, 1H), 5.53 (t, 1H), 4.64 (d, 2H). Step 4 : Preparation of 3- chloro -7-( chloromethyl )-1H-1,5- pyridine -2- -one: Under a nitrogen atmosphere at room temperature, SOCl 2Cl 2 (5 mL) was added dropwise to a stirred mixture of 3-chloro-7-(hydroxymethyl)-1H-1,5-pyridine-2-one (250 mg, 1.18 mmol, 1.00 equiv) in CH 2 (423 mg, 3.56 mmol, 3.00 equiv) and DMF (8 mg, 0.11 mmol, 0.10 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. Thereby, 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (280 mg, crude) was produced. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + = 228.95. Step 9 : Preparation of 3- chloro -7-{[4-(5- fluoropyridin -2- yl ) piper idin -1- yl ] methyl }-1H-1,5- naphthyridin -2- one: At room temperature, DIEA (564 mg, 4.36 mmol, 5 equiv) and KI (14 mg, 0.08 mmol, 0.10 equiv) were added to a stirred mixture of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (200 mg, 0.87 mmol, 1.00 equiv) and 1-(5-fluoropyridin-2-yl)piperidin (126 mg, 0.69 mmol, 0.80 equiv) in CH 3CN (5 mL). The resulting mixture was stirred at 50 °C for 2 h. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature and poured into 20 mL of water. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL), over anhydrous Na 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 3-chloro-7-{[4-(5-fluoropyridin-2-yl)piperidin-1-yl]methyl}-1H-pyrido[1,5-a]pyrimidin-2-one (42.7 mg, 13.08%). LC-MS: (ES+H, m / z): [M+H] + =374.0; 1 1H NMR (300 MHz, DMSO- d 6) δ 12.48 (s, 1H), 8.48 (d, 1H), 8.29 (s, 1H), 8.09 (d, 1H), 7.70 (d, 1H), 7.55 - 7.47 (m, 1H), 6.87 (dd, 1H), 3.66 (s, 2H), 3.46 - 3.42 (m, 4H), 2.53-2.50(m, 4H); 19 F NMR (282 MHz, DMSO- d 6) δ -143.39. Example 48 Step 1 : Preparation of 7-( difluoromethyl )-6- methoxy -1,5- pyrido -3- ethyl formate: Ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (300 mg, 0.96 mmol, 1.00 equiv), [1,3-bis[2,6-bis(isopropyl)phenyl]-2-imidazolidinylidene]difluoromethylsilver(I) (97 mg, 0.17 mmol, 1.10 equiv), [2-[2-(diphenylphosphino)phenoxy]phenyl]diphenylphosphine (181 mg, 0.33 mmol, 0.35 equiv), and Pd(dba)2 (177 mg, 0.30 mmol, 0.32 equiv) in toluene (5 ml) were stirred at 80 °C for 1.5 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc 5:1) to afford ethyl 7-(difluoromethyl)-6-methoxy-1,5-naphthyridine-3-carboxylate (235 mg, 86%). LC-MS: (ES+H, m / z): [M+H] + =283.1; 1 H NMR (300 MHz, DMSO- d 6) δ 9.25 (d, 1H), 8.59 (d, 1H), 8.53 (s, 1H), 7.24 (t, 1H), 4.42 (q, 2H), 4.12 (s, 3H), 1.40 (t, 3H); 19 F NMR (282 MHz, DMSO- d 6) δ -117.83. Step 2 : Preparation of 7-( Difluoromethyl )-6- Methoxy -5H-1,5- Naphthyridine -3- Ethyl carboxylate: At room temperature, TMSI (680 mg, 3.40 mmol, 4.00 equiv) was added dropwise to a solution of ethyl 7-(difluoromethyl)-6-methoxy-1,5-naphthyridine-3-carboxylate (240 mg, 0.85 mmol, 1.00 equiv) in ACN (7 mL). Then the reaction mixture was stirred at 50 °C for 5 h under a nitrogen atmosphere, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc) to give ethyl 7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridine-3-carboxylate (225 mg, 99%). LC-MS: (ES+H, m / z): [M+H] + = 269.1. Step 3 : Preparation of 3-( difluoromethyl )-7-( hydroxymethyl )-1H-1,5- naphthyridine -2- [[ID=2']] one: Under a nitrogen atmosphere at 0 °C, LiAlH 4 (0.69 mL, 2.5 mol / L in THF, 2.00 equiv) was added dropwise to a stirred solution of ethyl 7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridine-3-carboxylate (230 mg, 0.85 mmol, 1.00 equiv) in THF (5 ml). The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was quenched with MeOH (10 mL) and then DCM (50 mL) was added. The solution was filtered and the filter cake was washed with DCM / MeOH (5:1) (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (CH 2Cl 2 / MeOH) to give 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (50 mg, 26%). LC-MS: (ES+H, m / z): [M+H] + = 227.0; 1 H NMR (400 MHz, DMSO- d 6) δ 12.36 (s, 1H), 8.50 (d, 1H), 8.16 (d, 1H), 7.70 (s, 1H), 6.98 (t, 1H), 5.57 (t, 1H), 4.67 (d, 2H). Step 4 : Prepare 7-( chloromethyl )-3-( difluoromethyl )-1H-1,5- pyridine -2- one: Under a nitrogen atmosphere at room temperature, SOCl 2 (126 mg, 1.06 mmol, 3.00 equiv) was added dropwise to a stirred solution of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-pyridine-2-one (80 mg, 0.35 mmol, 1.00 equiv) and DMF (1 mg, 0.02 mmol, 0.05 equiv) in DCM (4 ml). The resulting mixture was stirred at room temperature for 5 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + = 245.0. Step 5 : Prepare 6-(4-{[7-( difluoromethyl )-6- side oxygen group -5H-1,5- pyridine -3- group ] methyl } piper idine -1- group ) pyridine -3- Formonitrile: DIEA (227 mg, 1.76 mmol, 5.00 equiv) was added dropwise to a stirred solution of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-diphenyl-2-one (86 mg, assuming 100% yield, 0.35 mmol, 1.00 equiv), 6-(piperazine-1-yl)pyridin-3-carboxynitrile (66 mg, 0.35 mmol, 1.00 equiv), and KI (11 mg, 0.07 mmol, 0.20 equiv) in ACN (5 mL). The resulting mixture was stirred at 80 °C for 1 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL). The solution was extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silicone column chromatography to give a crude product (80 mg). The crude product was further purified by preparative HPLC to give 6-(4-{[7-(difluoromethyl)-6-sideoxy-5H-1,5-diphenyl-3-yl]methyl}piperidin-1-yl)pyridin-3-carboxylonitrile (42.9 mg, 33%, in two steps). LC-MS: (ES+H, m / z): [M+H] + = 397.1; 1 H NMR (300 MHz, DMSO- d 6) δ 12.33 (s, 1H), 8.54 (d, 1H), 8.48 (d, 1H), 8.16 (s, 1H), 7.85 (dd, 1H), 7.71 (d, 1H), 7.20 - 6.73 (m, 2H), 3.72 - 3.68 (m, 4H), 3.67 (s, 2H), 2.51 - 2.49 (m, 4H); 19 F NMR (282 MHz, DMSO- d 6) δ -119.30. Example 49 step 1 :preparation 2-[(4- bromine -2- fluorine -6- Nitrophenyl ) amino ] Methyl propionate: DIEA (27.15 g, 210.09 mmol, 5.00 equiv) was added dropwise to a stirred mixture of 5-bromo-1,2-difluoro-3-nitrobenzene (10.00 g, 42.01 mmol, 1.00 equiv) and methyl 2-aminopropionate hydrochloride (2.93 g, 21.00 mmol, 1.00 equiv) in NMP (200 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by TLC (petroleum ether / EtOAc = 10 / 1). The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (1 L). The resulting mixture was washed with water (3 × 300 mL) and rinsed with anhydrous Na₂SO₄. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]propionate (7.5 g, 56%) as a red oil. 1 H NMR (400 MHz, DMSO- d 6) δ 8.08 (t, 1H), 7.87 (dd, 1H), 7.77 (dd, 1H), 4.67 - 4.55 (m, 1H), 3.68 (s, 3H), 1.48 (dd, 3H); 19 F NMR (377 MHz, DMSO-d6) δ -122.19. step 2 :preparation 7- bromine -5- fluorine -3- methyl -3,4- Dihydrogen -1H- Quinoline -2- ketone: Fe (5.22 g, 93.43 mmol, 5.00 equiv) was added to a stirred solution of methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]propionate (6.00 g, 18.68 mmol, 1.00 equiv) in HOAc (200 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The mixture was filtered, and the filter cake was washed with DCM:MeOH = 4:1 (3 × 100 mL). The filtrate was concentrated under reduced pressure. The solution was then diluted with saturated NaHCO3. 3. (Aqueous solution) Adjust the pH of the residue to pH 7. Then use CH4. 2Cl 2 (3 × 300 mL) of the extracted mixture. The combined organic layers were washed with brine (1 × 100 mL) and irradiated with anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure to give 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinolin-2-one (4.2 g, 87%). LC-MS: (ES-H, m / z): [MH] - =257.1; 1 H NMR (400 MHz, DMSO- d 6) δ 10.54 (s, 1H), 7.01 (dd, 1H), 6.76 (t, 1H), 6.20 (s, 1H), 3.90 - 3.80 (m, 1H), 1.28 (d, 3H). 19 F NMR (377 MHz, DMSO- d 6) δ -132.99. step 3 :preparation 7- bromine -5- fluorine -3- methyl -1H- Quinoline -2- ketone: DDQ (4.34 g, 19.10 mmol, 1.10 equiv) was added to a stirred mixture of 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinolin-2-one (4.50 g, 17.36 mmol, 1.00 equiv) in DCM (500 mL) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The solution was then diluted with saturated NaHCO3. 3. Dilute the resulting mixture with an aqueous solution (500 mL). Stir the mixture at room temperature for 30 min. Filter the mixture and dilute with saturated NaHCO3. 3. Wash the filter cake with (3 × 100 mL) aqueous solution. Dry the filter cake under reduced pressure. Purify the residue by silicone column chromatography to give 7-bromo-5-fluoro-3-methyl-1H-quinolin-2-one (3 g, 67%). LC-MS: (ES-H, m / z): [MH] - =255.0; 1 H NMR (400 MHz, DMSO- d 6) δ 12.52 (s, 1H), 7.49 - 7.40 (m, 1H), 7.24 (q, 1H), 2.40 (q, 3H). step 4 :preparation 8- fluorine -2- methyl -3- lateral oxygen -4H- Quinoline -6- formaldehyde: In a pressure chamber, bis(adamantane-1-yl)(butyl)phosphine (349 mg, 0.97 mmol, 0.50 equiv), TMEDA (1.13 g, 9.72 mmol, 5.00 equiv), and Pd(OAc)₂ (218 mg, 0.97 mmol, 0.50 equiv) were added to a solution of 7-bromo-5-fluoro-3-methyl-1H-quinolin-2-one (500 mg, 1.94 mmol, 1.00 equiv) in toluene (100 mL). The mixture was purged with nitrogen for 5 min and then subjected to CO₂ at room temperature. 2:H The mixture was pressurized to 30 MPa at a 1:1 ratio. The resulting mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 8-fluoro-2-methyl-3-sideoxy-4H-quinoline-6-carboxaldehyde (300 mg, 74.8%). LC-MS: (ES-H, m / z): [MH] - =205.2; 1 H NMR (400 MHz, DMSO- d 6) δ 12.75 (s, 1H), 10.02 (q, 1H), 7.67 - 7.52 (m, 2H), 2.49 - 2.44 (m, 3H). step 5 :preparation 6-{4-[(8- fluorine -2- methyl -3- lateral oxygen -4H- Quinoline -6- base ) methyl ] Piper 𠯤 -1- base } Pyridine -3- Formonitrile: Tetra(propane-2-yloxy)titanium (551 mg, 1.94 mmol, 2.00 equiv) was added to a stirred mixture of 8-fluoro-2-methyl-3-sideoxy-4H-quinoline-6-carboxaldehyde (200 mg, 0.97 mmol, 1.00 equiv) and 6-(piperazine-1-yl)pyridin-3-carboxynitrile (274 mg, 1.45 mmol, 1.50 equiv) in THF (20 mL) under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 4 h under nitrogen atmosphere at room temperature. NaBH(OAc) was then added to the mixture at room temperature. 3 (822 mg, 3.88 mmol, 4.00 equiv). The resulting mixture was stirred at room temperature for another 4 h. The reaction was monitored by LCMS. The reactants were quenched by adding water (80 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL) and irradiated with anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography, followed by grinding with MeCN (5 mL) to give 6-{4-[(8-fluoro-2-methyl-3-sideoxy-4H-quinoline-6-yl)methyl]piperazine-1-yl}pyridin-3-carboxynitrile (51.1 mg, 14%). LC-MS: (ES+H, m / z): [M+H] + =379.2; 1 H NMR (400 MHz, DMSO- d 6) δ 12.44 (s, 1H), 8.48 (d, 1H), 7.85 (dd, 1H), 7.09 (d, 2H), 6.93 (d, 1H), 3.68 (t, 4H), 3.60 - 3.55 (m,2H), 2.47 (d, 4H), 2.41 (s, 3H); 19 F NMR (377 MHz, DMSO- d 6) δ -125.51. Example 60 step 1 :preparation 3- bromine -2- methoxy -6- methyl -5- Nitropyridine: NaOMe (15.76 g, 87.49 mmol, 1.10 equiv., 30% wt.) was added dropwise to a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv.) in MeOH (50 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was analyzed by TLC (PE:EA = 1:1, R...). f = 0.4) Monitor the reaction. Concentrate the resulting mixture under reduced pressure and add water (100 mL). Extract the resulting mixture with EtOAc (3 × 100 mL). Wash the combined organic layers with brine (1 × 200 mL) and irradiate with anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure to obtain 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400 MHz, DMSO- d 6) δ 8.66 (s, 1H), 4.04 (s, 3H), 2.70 (s, 3H). step 2 :preparation (E)-2-(5- bromine -6- methoxy -3- Nitropyridine -2- base )-N,N- Dimethyl ethyl -1- amine: A mixture of 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g, 60.72 mmol, 1.00 equiv.) in DMF-DMA (100 mL) and DMF (100 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was analyzed by TLC (PE:EA = 1:1, R...). f = 0.5) Monitor the reaction. Cool the mixture to room temperature. Concentrate the resulting mixture under reduced pressure. The crude product is used directly in the next step without further purification. step 3 :preparation 5- bromine -6- methoxy -3- Nitropyridine formaldehyde: Under a nitrogen atmosphere at 0°C, (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)vinyl]dimethylamine (18.01 g, crude material) was subjected to THF (100 mL) and H₂O. Add NaIO to a fraction of the stirred mixture in 2O (100 mL) 4 (28.00 g, 131.07 mmol, 2.20 equiv.). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The mixture was analyzed by TLC (PE:EA = 5:1, R...). f = 0.2) The reaction was monitored. The reactants were quenched by adding saturated sodium hyposulfite (aqueous solution) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and then subjected to anhydrous Na+. 2SO 4. Drying. After filtration, concentrate the filtrate under reduced pressure. The crude product is used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO- d 6) δ 10.16 (s, 1H), 8.87 (s, 1H), 4.10 (s, 3H). step 4 :preparation 7- bromine -6- Methoxy -1,5- Pyridine -3- Formic acid ethyl ester: Under a nitrogen atmosphere at room temperature, SnCl 2 (26.25 g, 134.09 mmol, 5.00 equiv.) was added in portions to a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropionate (20.40 g, 107.27 mmol, 4.00 equiv.) in EtOH (100 mL). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. The crude product was purified by trituration with hexane (50 mL) to give ethyl 7-bromo-6-methoxy-1, ,5-pyridine-3-carboxylate (3.50 g, 18.5% yield, over three steps). LC-MS: (ES+H, m / z): [M+H] + = 311.0 / 313.0; 1 H NMR (400 MHz, DMSO- d 6) δ 9.22 (s, 1H), 8.78 (s, 1H), 8.58 (s, 1H), 4.42 (q, 2H), 4.12 (s, 3H), 1.39 (t 3H). Step 5 : Preparation of 7- bromo -6- methoxy -5H-1,5- pyridine -3- ethyl formate: At room temperature, TMSI (13.8 mL, 96.42 mmol, 6.00 equiv.) was added dropwise to a solution of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (5.00 g, 16.07 mmol, 1.00 equiv.) in ACN (400 mL). The final reaction mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using the following conditions: column, silica gel; mobile phase, EA in DCM, 45% to 60% gradient in 20 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give ethyl 7-bromo-6-methoxy-5H-1,5-naphthyridine-3-carboxylate (3.8 g, 79.5%). LC-MS: (ES+H, m / z): [M+H] + =296.95 / 298.95 Step 6 : Preparation of 3- Bromo -7-( Hydroxymethyl )-1H-1,5- Naphthyridine -2- One: Under a nitrogen atmosphere at 0 °C, LiAlH 4 (1.21 mL, 3.03 mmol, 2.00 equiv, 2.5 M in THF) was added dropwise to a stirred mixture of ethyl 7-bromo-6-methoxy-5H-1,5-naphthyridine-3-carboxylate (450 mg, 1.51 mmol, 1.00 equiv.) in THF (8 mL). The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding HCl (3.03 mL, 3.03 mmol, 2.00 equiv.) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (220 mg, 56.9%). LC-MS: (ES+H, m / z): [M+H] + =255.0 / 257.0. Step 7 : Preparation of 3- bromo -7-( chloromethyl )-1H-1,5- diazepine -2- one: Under a nitrogen atmosphere at 0 °C, SOCl ₂ (321 mg, 2.70 mmol, 3.00 equiv.) was added dropwise to a stirred mixture of 3-bromo-7-(hydroxymethyl)-1H-1,5-diazepin-2-one (230 mg, 0.90 mmol, 1.00 equiv.) and DMF (6 mg, 0.09 mmol, 0.10 equiv.) in DCM (7 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 3-bromo-7-(chloromethyl)-1H-1,5-diazepin-2-one (220 mg, 89.2%). LC-MS: (ES+H, m / z): [M+H] + = 272.9 / 274.9. Step 8 : Preparation of 6-{4-[(7- bromo -6- side oxy -5H-1,5- diazepine -3- group ) methyl ] piper idine -1- group } pyridine -3- nitrile: Under a nitrogen atmosphere at room temperature, KI (18 mg, 0.11 mmol, 0.20 equiv.) was added portionwise to a stirred mixture of 3-bromo-7-(chloromethyl)-1H-1,5-diazepin-2-one (150 mg, 0.54 mmol, 1.00 equiv.), DIEA (354 mg, 2.74 mmol, 5.00 equiv.) and 6-(piperidin-1-yl)pyridine-3-carbonitrile (113 mg, 0.60 mmol, 1.10 equiv.) in MeCN (7 mL). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (120 mg) was purified by preparative HPLC, the pure eluent was concentrated and then lyophilized to give 6-{4-[(7-bromo-6-oxido-5H-1,5-diazepin-3-yl)methyl]piperidin-1-yl}pyridine-3-carbonitrile (25.6 mg, 10.9%). LC-MS: (ES+H, m / z): [M+H] + =425.00 / 427.00; 1 H NMR (400 MHz, DMSO- d 6) δ 12.41 (s, 1H), 8.47 (s, 3H), 7.85 (dd, J = 9.1, 2.4 Hz, 1H), 7.68 (s, 1H), 6.93 (d, J = 9.1 Hz, 1H), 3.78 - 3.59 (m, 6H), 2.48 (d, J = 4.7 Hz, 4H). Example 68 and 69 Step 1 : Preparation of 6- Methoxy -7-( Oxolane -2- yl )-1,5- Diazepine -3- Ethyl formate: In a nitrogen atmosphere at room temperature, ethyl 7-bromo-6-methoxy-1,5-dimethyl-3-carboxylate (5.00 g, 16.07 mmol, 1.00 equiv.) and (4-methoxyphenyl)[4-(trifluoromethyl)phenyl]methyl ketone (1.12 g, 4.01 mmol, 0.25 equiv.) in THF were added to a stirred solution. 5,5'-dimethyl-2,2'-bipyridine (0.74 g, 4.01 mmol, 0.25 equiv.), nickel acetylacetonate (1.03 g, 4.01 mmol, 0.25 equiv.), and Na... 2CO 3 (1.70 g, 16.07 mmol, 1.00 equiv.). The resulting mixture was placed approximately 3 cm away from two 40 W blue LEDs and stirred at room temperature under a nitrogen atmosphere for 7 days. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL) and irradiated with anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give ethyl 6-methoxy-7-(oxacyclopentan-2-yl)-1,5-diphenyl-3-carboxylate (1.6 g, 32.93%). LC-MS: (ES+H, m / z): [M+H] + = 303.15; 1 H NMR (400 MHz, DMSO- d 6) δ 9.20 (d, J = 2.0 Hz, 1H), 8.57 (dd, J = 2.1, 0.8 Hz, 1H), 8.27 - 8.10 (m, 1H), 5.13 - 5.04 (m, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.18 - 4.09 (m, 1H), 4.09 (s, 3H), 3.95 - 3.85 (m, 1H), 2.49 - 2.39 (m, 1H), 2.05 - 1.82 (m, 2H), 1.79 - 1.67 (m, 1H), 1.39 (t, J = 7.1 Hz, 3H). step 2 :preparation 6- Side oxy group -7-( Oxolane -2- yl )-5H-1,5- Pyridine -3- Ethyl formate: Under a nitrogen atmosphere at 0 °C, acetic acid containing HBr (0.25 mL, 33 wt.%, 2.00 equiv.) was added to a stirred solution of ethyl 6-methoxy-7-(oxolan-2-yl)-1,5-pyridine-3-carboxylate (1.30 g, 4.30 mmol, 1.00 equiv.) in MeCN. The resulting mixture was stirred at 0 °C for 0.5 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL) and basified to pH 8 with Et 3N. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 6-side oxy-7-(oxolan-2-yl)-5H-1,5-pyridine-3-carboxylate (730 mg, 58.89%). LC-MS: (ES+H, m / z): [M+H] + = 289.10; 1 H NMR (400 MHz, DMSO- d 6) δ 12.14 (s, 1H), 8.91 (d, J = 1.9 Hz, 1H), 8.18 (d, J = 1.9 Hz, 1H), 7.84 (d, J = 1.1 Hz, 1H), 4.96 - 4.87 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.12 - 4.04 (m, 1H), 3.91 - 3.79 (m, 1H), 2.48 - 2.32 (m, 1H), 1.99 - 1.81 (m, 2H), 1.74 - 1.63 (m, 1H), 1.36 (t, J = 7.1 Hz, 3H). Step 3 : Preparation 7-( Hydroxymethyl )-3-( Oxolane -2- yl )-1H-1,5- diazepine -2- one: Under a nitrogen atmosphere at 0 °C, LiAlH 4 (192 mg, 5.06 mmol, 2.00 equiv.) was added dropwise to a stirred mixture of ethyl 6 - cyano - 7-(oxolan - 2 - yl)-5H-1,5 - diazepine - 3 - carboxylate (730 mg, 2.53 mmol, 1.00 equiv.) in THF (8 mL). The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M HCl (1 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-(hydroxymethyl)-3-(oxolan - 2 - yl)-1H-1,5 - diazepine - 2 - one (280 mg, 44.90%). LC-MS: (ES + H, m / z): [M + H] + = 247.00; 1 H NMR (300 MHz, DMSO - d 6) δ 11.97 (s, 1H), 8.40 (d, J = 1.9 Hz, 1H), 7.80 (s, 1H), 7.64 (d, J = 1.9 Hz, 1H), 5.48 (t, J = 5.6 Hz, 1H), 4.98 - 4.84 (m, 1H), 4.63 (d, J = 5.3 Hz, 2H), 4.18 - 4.01 (m, 1H), 3.91 - 3.75 (m, 1H), 2.45 - 2.31 (m, 1H), 2.02 - 1.78 (m, 2H), 1.74 - 1.58 (m, 1H). Step 4 : Preparation 7-( Chloromethyl )-3-( oxolane -2- yl )-1H-1,5- diazine -2- one: Under a nitrogen atmosphere at 0 °C, SOCl 2 (0.25 mL, 3.41 mmol, 3.00 equiv.) was added dropwise to a stirred solution of 7-(hydroxymethyl)-3-(oxolan-2-yl)-1H-1,5-diazin-2-one (280 mg, 1.13 mmol, 1.00 equiv.) and DMF (8 mg, 0.11 mmol, 0.10 equiv.) in DCM. The resulting mixture was stirred at room temperature for 5 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3-(oxolan-2-yl)-1H-1,5-diazin-2-one (300 mg, crude). LC-MS: (ES+H, m / z): [M+H] + = 265.05. Step 5 : Preparation of 6-(4-{[6- side oxy -7-( oxolane -2- yl )-5H-1,5- diazine -3- yl ] methyl } piper idine -1- yl ) pyridine -3- nitrile: DIEA (292 mg, 2.26 mmol, 4.00 equiv.) and KI (18 mg, 0.11 mmol, 0.20 equiv.) were added to a stirred mixture of 7-(chloromethyl)-3-(oxacyclopentan-2-yl)-1H-1,5-dipyridin-2-one (150 mg, 0.56 mmol, 1.00 equiv.) and 6-(piperazine-1-yl)pyridin-3-carboxynitrile (106 mg, 0.56 mmol, 1.00 equiv.) in MeCN (10 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was then cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and irradiated with anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give 6-(4-{[6-sideoxy-7-(oxacyclopentan-2-yl)-5H-1,5-diphenyl-3-yl]methyl}piperidin-1-yl)pyridin-3-carboxylonitrile (88 mg, 37.29%). LC-MS: (ES+H, m / z): [M+H] + = 417.10. The racemic compound (88 mg) was separated by preparative palmar HPLC under the following conditions: column: CHIRALPAK IH, 2*25 cm, 5 μm; mobile phase A: Hex (10 mM NH4+). 3-MeOH), mobile phase B: EtOH: ACN = 5: 1; flow rate: 20 mL / min; gradient: 50% B to 50% B over 12 min; wavelength: 218 / 282 nm; RT1 (min): 4.62; RT2 (min): 6.76; sample solvent: MeOH: DCM = 1:1 --HPLC; injection volume: 0.75 mL; number of runs: 6. The pure solvent was concentrated under vacuum and then lyophilized to obtain... Example 68 (34.2 mg, 99.7% purity, ee=100%) and Example 69 (34.1 mg, 99.3% purity, ee=99.7%). Example 68 LC-MS: (ES+H, m / z): [M+H] += 417.10; 1 H NMR (300 MHz, DMSO- d 6) δ 11.95 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 1.8 Hz, 1H), 7.84 (dd, J = 9.1, 2.4 Hz, 1H), 7.80 (d, J = 1.3 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 6.93 (d, J = 9.2 Hz, 1H), 4.89 (t, J = 6.8 Hz, 1H), 4.10 - 4.03 (m, 1H), 3.87 - 3.79 (m, 1H), 3.73 - 3.62 (m, 6H), 2.58 - 2.49 (m, 4H), 2.43 - 2.30 (m, 1H), 2.02 - 1.77 (m, 2H), 1.73 - 1.57 (m, 1H). Example 69 : LC-MS: (ES+H, m / z): [M+H] + =417.10; 1 H NMR (300 MHz, DMSO- d 6) δ 11.95 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 1.8 Hz, 1H), 7.85 (dd, J = 9.1, 2.4 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.64 (d, J = 1.9 Hz, 1H), 6.93 (d, J = 9.1 Hz, 1H), 4.90 (t, J = 6.8 Hz, 1H), 4.15 - 4.00 (m, 1H), 3.92 - 3.76 (m, 1H), 3.74 - 3.59 (m, 6H), 2.50 - 2.45 (m, 4H), 2.44 - 2.31 (m, 1H), 2.02 - 1.78 (m, 2H), 1.74 - 1.57 (m, 1H). Example 71 step 1 :preparation (2E)-N-(3- bromine -2- Fluorophenyl )-2- methyl -3- Phenylacetylene -2- Enylamine: A solution of α-methylcinnamic acid (2.56 g, 15.78 mmol, 1.00 equiv.) in DCM (30 mL) was prepared at room temperature under a nitrogen atmosphere using DIEA (8.16 g, 63.15 mmol, 4.00 equiv.) and T... The mixture was treated with 3P (15.07 g, 23.68 mmol, 1.50 equiv., 50 wt% in DCM) for 5 min, followed by the addition of 3-bromo-2-fluoroaniline (3.00 g, 15.78 mmol, 1.00 equiv.) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and irradiated with anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2E)-N-(3-bromo-2-fluorophenyl)-2-methyl-3-phenylprop-2-enylamine (2.00 g, 37.9%). LC-MS: (ES+H, m / z): [M+H + =333.95 / 335.95; 1 H NMR (400 MHz, DMSO- d 6) δ 9.89 (s, 1H), 7.62 -7.41 (m, 7H), 7.21 -7.13 (m, 1H), 6.85 -6.69 (m, 1H), 2.12 (d, J = 1.4 Hz, 3H). step 2 :preparation 7- bromine -8- fluorine -3- methyl -1H- Quinoline -2- ketone: AlCl₂ was added to a stirred solution of (2E)-N-(3-bromo-2-fluorophenyl)-2-methyl-3-phenylprop-2-enylamine (2.00 g, 5.98 mmol, 1.00 equiv.) in chlorobenzene (20 mL) under a nitrogen atmosphere at 0 °C. 3 (2.39 g, 17.95 mmol, 3.00 equiv.). The resulting mixture was stirred at 120 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 7-bromo-8-fluoro-3-methyl-1H-quinolin-2-one (1.00 g, 65.2%). LC-MS: (ES+H, m / z): [M+H] + = 255.80 / 257.80; 1 H NMR (400 MHz, DMSO- d 6) δ 11.94 (s, 1H), 7.82 (s, 1H), 7.44 -7.34 (m, 2H), 2.09 (s, 3H). step 3 :preparation 8- fluorine -7-( hydroxymethyl )-3- methyl -1H- Quinoline -2- ketone: A solution of 7-bromo-8-fluoro-3-methyl-1H-quinoline-2-one (800 mg, 3.12 mmol, 1.00 equiv.), (tributyltinyl)methanol (1.10 g, 3.43 mmol, 1.10 equiv.), and second-generation XPhos precatalyst (123 mg, 0.15 mmol, 0.05 equiv.) in 1,4-dimethylalkanes (10 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinoline-2-one (400 mg, 61.7%). LC-MS: (ES+H, m / z): [M+H] + =208.15 step 4 :preparation 7-( Chloromethyl )-8- fluorine -3- methyl -1H- Quinoline -2- ketone: SOCl₂ was added dropwise to a stirred solution of 8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinolin-2-one (400 mg, 1.93 mmol, 1.00 equiv.) and DMF (14 mg, 0.19 mmol, 0.10 equiv.) in DCM (5 mL) under a nitrogen atmosphere at 0 °C. 2 (2.30 g, 19.30 mmol, 10.00 equiv.). The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was concentrated under reduced pressure to give 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one (400 mg, 91.8%). LC-MS: (ES+H, m / z): [M+H] + =226.3 step 5 :preparation 6-{4-[(8- fluorine -3- methyl -2- lateral oxygen -1H- Quinoline -7- base ) methyl ] Piper 𠯤 -1- base } Pyridine -3- Formonitrile: A solution of 6-(piperazine-1-yl)pyridin-3-carboxynitrile hydrochloride (229 mg, assuming 100% yield, 0.88 mmol, 1.00 equiv.) in MeCN (10 mL) was treated with DIEA (573 mg, 4.43 mmol, 5.00 equiv.) at room temperature under a nitrogen atmosphere for 5 min, followed by the addition of KI (17 mg, 0.10 mmol, 0.10 equiv.) and 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one (200 mg, 0.88 mmol, 1.00 equiv.). The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 6-{4-[(8-fluoro-3-methyl-2-sideoxy-1H-quinolin-7-yl)methyl]piperazine-1-yl}pyridin-3-carboxylonitrile (92.1 mg, 23.8%). LC-MS: (ES+H, m / z): [M+H + =378.10; 1 H NMR (400 MHz, DMSO- d 6) δ 11.77 (s, 1H), 8.47 (d, J= 4.0 Hz, 1H), 7.87 - 7.76 (m, 2H), 7.38 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 8.1, 6.4 Hz, 1H), 6.91 (d, J= 8.0 Hz, 1H), 3.66 - 3.65 (m, 6H), 2.51-2.48 (m, 4H), 2.10 (d, J = 1.3 Hz, 3H). 19 F NMR (377 MHz, DMSO- d 6) δ -135.84. Example 82 step 1 :preparation 2-(5- bromine -3- Nitropyridine -2- base ) malonic acid 1-( Grade III butyl acetate )3- Ethyl acetate: Under a nitrogen atmosphere at room temperature, 3-ethyl 1-tert-butyl propanediol (35.67 g, 189.52 mmol, 1.50 equiv.) was added dropwise to a stirred solution of potassium tributoxide (21.27 g, 189.52 mmol, 1.50 equiv.) in THF (500 ml). Then, at 60 °C for 15 min, 50 ml of THF containing 5-bromo-2-chloro-3-nitropyridine (30.00 g, 126.34 mmol, 1.00 equiv.) was added dropwise. The resulting mixture was stirred at 60 °C for another 3 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The mixture was diluted with HCl (1 M in water) (200 mL). The mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 × 200 mL) and then rinsed with anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure to give 1-(tert-butyl)-3-ethyl 2-(5-bromo-3-nitropyridin-2-yl)malonic acid (45 g, 91.5%). LC-MS: (ES-H, m / z): [MH] - =387.1 step 2 :preparation 2-(5- bromine -3- Nitropyridine -2- base ) Ethyl acetate: 2-(5-bromo-3-nitropyridin-2-yl)malonic acid 1-(tert-butyl) 3-ethyl ester (45.00 g, 115.62 mmol, 1.00 equiv.) was dissolved in CH4 at room temperature under a nitrogen atmosphere. 2Cl TFA (200 mL) was added to the stirred solution in step 2 (300 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The solution was then treated with saturated NaHCO3. Dilute the residue with an aqueous solution (100 mL). Extract the resulting mixture with EtOAc (3 × 500 mL). Wash the combined organic layers with brine (1 × 200 mL) and irradiate with anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (35 g, crude product). LC-MS: (ES+H, m / z): [M+H] + =290.9 step 3 :preparation 2-(3- amino -5- Bromopyridine -2- base ) Ethyl acetate: Saturated NH3 was added to a stirred solution of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (35.00 g, 121.07 mmol, 1.00 equiv.) and Fe (79.72 g, 1219.36 mmol, 7.50 equiv.) in EtOH (250 ml) under a nitrogen atmosphere at room temperature. 250 mL of 4Cl aqueous solution was added. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (300 mL). The resulting mixture was stirred at room temperature for 10 min. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 70 mL). The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 × 200 mL) and then subjected to anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate (9.3 g, 29.7%). LC-MS: (ES+H, m / z): [M+H] + =259.1 step 4 :preparation 2-(5- bromine -3-(2,2- Dimethoxypropylamine ) Pyridine -2- base ) Ethyl acetate: Under a nitrogen atmosphere at room temperature, methyl 2,2-dimethoxypropionate (12.00 g, 80.99 mmol, 1.00 equiv.) in MeOH (120 mL) was added dropwise to a stirred solution containing NaOH (9.72 g, 242.98 mmol, 3.00 equiv.). 2O (120 mL). The resulting mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. The reaction was monitored by TLC. The mixture was acidified to pH 8 with HCl (2 M in water). The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOH (500 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was filtered, and the filter cake was washed with EtOH (3 × 100 mL). The filtrate was concentrated under reduced pressure to give sodium 2,2-dimethoxypropionate (8.5 g, 78.2%). 1 H NMR (300 MHz, D 2O) δ 3.12 (d, J= 1.7 Hz, 6H), 1.33 (s, 3H). DIEA (12.57 g, 97.26 mmol, 3.00 equiv.) and T were added to a stirred solution of sodium 2,2-dimethoxypropionate (7.59 g, 48.63 mmol, 1.50 equiv.) in dimethyl ether (100 ml) at room temperature under a nitrogen atmosphere. 3P (30.95 g, 97.26 mmol, 3.00 equiv, 50 wt% in EtOAc). The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. 2-(3-amino-5-bromopyridin-2-yl)ethyl acetate (8.40 g, 32.42 mmol, 1.00 equiv.) was added to the mixture at room temperature. The resulting mixture was stirred overnight at 100 °C. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (1 × 100 mL) and irradiated with anhydrous Na+. 2SO 4. Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give ethyl 2-(5-bromo-3-(2,2-dimethoxypropionic acid)pyridin-2-yl)acetate (9.3 g, 79.4%). LC-MS: (ES+H, m / z): [M+H] + =375.1 step 5 :preparation 7- bromine -3- methyl -2- Side oxy group -1,2- Dihydro -1,5- Pyridine -4- Ethyl formate: Under a nitrogen atmosphere at room temperature, add H₂O (7 mL) to a stirred solution of ethyl 2-(5-bromo-3-(2,2-dimethoxypropanamido)pyridin-2-yl)acetate (7.00 g, 18.65 mmol, 1.00 equiv.) in TFA (100 mL), and then add 2 drops of a fresh solution of I₂ (30 mg I₂ suspended in TFA (10 mL)). Stir the resulting mixture overnight at 50 °C under a nitrogen atmosphere. Concentrate the resulting mixture in vacuo. Dissolve the residue in toluene (100 mL) and piperidine (6 mL). Reflux the resulting mixture at 120 °C for 2 h, then concentrate under reduced pressure. Purify the residue by silica gel column chromatography to obtain ethyl 7-bromo-3-methyl-2-side oxy-1H-1,5-pyridine-4-carboxylate (3.3 g, 56.9%). LC-MS: (ES+H, m / z): [M+H] + + = 313.0; 1 H NMR (400 MHz, DMSO- d 6) δ 12.20 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.06 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). Step 6 : Preparation of 7- Bromo -4-( Hydroxymethyl )-3- Methyl -1,5- Pyridine -2(1H)- Ketone: Under a nitrogen atmosphere at 0 °C, LiEt 3BH (30 ml, 1 M in THF) was added dropwise to a stirred solution of ethyl 7-bromo-3-methyl-2-oxo-1H-1,5-diazepine-4-carboxylate (3.00 g, 9.64 mmol, 1.00 equiv.) in THF (50 ml). The resulting mixture was stirred at 0 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding water / ice (6 mL) at 0 °C. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with CH 2Cl 2 / MeOH (0 to 10:1 gradient over 30 min) to give 7-bromo-4-(hydroxymethyl)-3-methyl-1,5-diazepin-2(1H)-one (1.8 g, 69.4%). LC-MS: (ES-H, m / z): [M-H] - = 267.0 / 269.0; 1 H NMR (300 MHz, DMSO- d 6) δ 11.95 (s, 1H), 8.57 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 5.04 (t, J = 5.5 Hz, 1H), 4.90 (d, J = 5.2 Hz, 2H), 2.21 (s, 3H). Step 7 : Preparation of 7- Bromo -3- Methyl -2- Oxo -1,2- Dihydro -1,5- Diazepine -4- Formaldehyde: Under a nitrogen atmosphere at room temperature, 1,1-bis(acetyloxy)-3-oxo-3H-1λ⁵,2-benziodoxol-1-yl acetate (3.40 g, 8.02 mmol, 1.20 equiv.) was added to a stirred mixture of 7-bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (1.80 g, 6.68 mmol, 1.00 equiv.) in THF (20 mL). The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The precipitated solid was collected by filtration and washed with water (3 × 5 mL). The residue was purified by reverse-phase combi-flash chromatography to give 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbaldehyde (760 mg, 42.5%). LC-MS: (ES-H, m / z): [M-H] - = 264.9; 1 H NMR (300 MHz, DMSO- d 6) δ 12.28 (s, 1H), 10.88 (s, 1H), 8.62 (d, J= 2.1 Hz, 1H), 7.89 (d, J= 2.1 Hz, 1H), 2.25 (s, 3H). Step 8 : Preparation of 7- Bromo -4-( Difluoromethyl )-3- Methyl -1,5- Naphthyridine -2(1H)- One: Under a nitrogen atmosphere at 0 °C, BAST (2.49 g, 11.23 mmol, 4 equiv.) was added dropwise to a stirred solution of 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbaldehyde (750 mg, 2.80 mmol, 1 equiv.) in THF (5 ml). The resulting mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was quenched with saturated NH 4Cl (aqueous solution) (3 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL) and dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-4-(difluoromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (320 mg, 39.4%). LC-MS: (ES-H, m / z): [M-H] - = 287.0 Step 9 : Preparation of 4-( Difluoromethyl )-7-( Hydroxymethyl )-3- Methyl -1,5- Naphthyridine -2(1H)- One: Under a nitrogen atmosphere at room temperature, (tributylstannyl)methanol (959 mg, 2.98 mmol, 2.40 equiv.) was added to a stirred solution of 7-bromo-4-(difluoromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (360 mg, 1.24 mmol, 1.00 equiv.) and the 2nd generation XPhos precatalyst / (195 mg, 0.24 mmol, 0.20 equiv.) in dioxane (5 ml). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give 4-(difluoromethyl)-7-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (195 mg, 65.2%). LC-MS: (ES+H, m / z): [M+H] + =241.1。 Step 10 : Prepare 7-( chloromethyl )-4-( difluoromethyl )-3- methyl -1,5- pyridine -2(1H)- one: Under a nitrogen atmosphere at 0 °C, add SOCl 2Cl 2 (3 ml) dropwise to a stirred solution of 4-(difluoromethyl)-7-(hydroxymethyl)-3-methyl-1,5-pyridine-2(1H)-one (185 mg, 0.25 mmol, 1.00 equiv.) and DMF (2 mg, 0.02 mmol, 0.10 equiv.) in CH 2 (183 mg, 1.54 mmol, 6.00 equiv.). Stir the resulting mixture under a nitrogen atmosphere at room temperature overnight. Monitor the reaction by LCMS. Concentrate the resulting mixture in vacuo to give 7-(chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-pyridine-2(1H)-one (195 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =259.0 Step 11 : Prepare 6-(4-((8-( difluoromethyl )-7- methyl -6- oxo -5,6- dihydro -1,5- pyridine -3- yl ) methyl ) piper 𠯤 -1- base ) Nicotinamide: DIEA (260 mg, 2.01 mmol, 5.00 equiv.) and KI (13 mg, 0.08 mmol, 0.20 equiv.) were added to a stirred solution of 7-(chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-diphenyl-2(1H)-one (104 mg, 0.40 mmol, 1.00 equiv.) and 6-(piperazine-1-yl)pyridin-3-carboxynitrile (91 mg, 0.48 mmol, 1.20 equiv.) in MeCN (5 ml) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 6-(4-((8-(difluoromethyl)-7-methyl-6-sideoxy-5,6-dihydro-1,5-diphenyl-3-yl)methyl)piperidin-1-yl)nicotinonitrile (crude product). The crude product was further purified by grinding with MeOH (6 mL) to give 6-(4-((8-(difluoromethyl)-7-methyl-6-sideoxy-5,6-dihydro-1,5-diphenyl-3-yl)methyl)piperidin-1-yl)nicotinonitrile (28.3 mg, 16.6%). LC-MS: (ES+H, m / z): [M+H] + =411.10; 1 H NMR (300 MHz, DMSO- d 6) δ 12.25 (s, 1H), 8.48 (t, J= 1.8 Hz, 2H), 8.14 - 7.74 (m, 2H), 7.70 (d, J = 1.9 Hz, 1H), 6.94 (d, J= 9.1 Hz, 1H), 3.39-3.67 (m, 6H), 2.50-2.48 (m, 4H), 2.33 (t, J = 2.8 Hz, 3H). 19 F NMR (282 MHz, DMSO- d 6) δ-117.71. Example 83 step 1 :preparation (2E)-N-(3- bromine -2- Fluorophenyl )-3- ethoxypropyl -2- Enylamine: Pyridine (14.99 g, 189.45 mmol, 1.80 equiv.) was added dropwise to a stirred mixture of 3-bromo-2-fluoroaniline (20.00 g, 105.25 mmol, 1.00 equiv.) in DCM (300 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 5 min under a nitrogen atmosphere at room temperature. (2E)-3-ethoxyprop-2-enyl chloride (21.24 g, 157.88 mmol, 1.50 equiv.) was added dropwise to the mixture after 5 min at room temperature. The resulting mixture was stirred for another 2 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL). The resulting mixture was washed with water (3 × 500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enylamine (24.6 g, 81.1%). LC-MS: (ES+H, m / z): [M+H] + =288.0 / 290.0. step 2 :preparation 7- bromine -8- fluorine -1H- Quinoline -2- ketone: (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxypropyl-2-enylamine (17.00 g, 59.00 mmol, 1.00 equiv.) was subjected to H 2SO The mixture in step 4 (85 mL) was stirred at room temperature for 3 h under a nitrogen atmosphere. The resulting mixture was added dropwise to ice water (1 L) and stirred for 1 h. The precipitated solid was collected by filtration and washed with water (3 × 200 mL). The mixture was concentrated under reduced pressure to give 7-bromo-8-fluoro-1H-quinoline-2-one (14.30 g, crude). LC-MS: (ES+H, m / z): [M+H] + =242.0 / 244.0. step 3 :preparation 7- bromine -3- chlorine -8- fluorine -1H- Quinoline -2- ketone: 7-Bromo-8-fluoro-1H-quinolin-2-one (3.00 g, 12.39 mmol, 1.00 equiv.) and NCS (2.65 g, 19.83 mmol, 1.60 equiv.) were heated at room temperature under a nitrogen atmosphere in CH4. 2,2-Dichloroacetic acid (0.32 g, 2.47 mmol, 0.20 equiv.) was added dropwise to a stirred mixture in 3COOH (50 mL). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, crude). LC-MS: (ES+H, m / z): [M+H] + =275.9 / 277.9; 1 H NMR (400 MHz, DMSO- d 6) δ 12.52 (s, 1H), 8.38 (d, J= 1.6 Hz, 1H), 7.52 - 7.42 (m, 2H). step 4 :preparation 3- chlorine -7- vinyl -8- fluorine -1H- Quinoline -2- ketone: Under a nitrogen atmosphere at room temperature, 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, 8.97 mmol, 1.00 equiv.), CsF (4.09 g, 26.91 mmol, 3.00 equiv.), and Pd(dppf)Cl were added. H was added dropwise to a stirred mixture of 2 (0.33 g, 0.44 mmol, 0.05 equiv.) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (1.38 g, 8.97 mmol, 1.00 equiv.) in dioxane (50 mL). 2O (5 mL). The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 3-chloro-7-vinyl-8-fluoro-1H-quinolin-2-one (750 mg, 37.3%). LC-MS: (ES+H, m / z): [M+H] + =224.0; 1 H NMR (300 MHz, DMSO- d 6) δ 12.38 (s, 1H), 8.34 (d, J= 1.6 Hz, 1H), 7.53-7.46 (m, 2H), 6.95 (dd, J= 17.7, 11.2 Hz, 1H), 6.07 (dd, J= 17.7, 1.0 Hz, 1H), 5.57 (dd, J = 11.2, 1.0 Hz, 1H). step 5 :preparation 3- chlorine -8- fluorine -2- lateral oxygen -1H- Quinoline -7- formaldehyde: Under a nitrogen atmosphere at room temperature, 3-chloro-7-vinyl-8-fluoro-1H-quinoline-2-one (750 mg, 3.35 mmol, 1.00 equiv.), K 2oO 2(OH) 4(123 mg, 0.33 mmol, 0.10 equiv.), NaIO 4 (2.87 g, 13.41 mmol, 4.00 equiv.) and 2,6-dimethylpyridine (718 mg, 6.70 mmol, 2.00 equiv.) were added dropwise to a stirred mixture in THF (15 mL) and H2O was added. 2O (1.5 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silicone column chromatography to give 3-chloro-8-fluoro-2-sideoxy-1H-quinoline-7-carboxaldehyde (630 mg, 83.2%). LC-MS: (ES-H, m / z): [MH] - =224.1. step 6 :preparation 6-{4-[(3- chlorine -8- fluorine -2- lateral oxygen -1H- Quinoline -7- base ) methyl ] Piper 𠯤 -1- base } Pyridine -3- Formonitrile: A mixture of 3-chloro-8-fluoro-2-sidekto-1H-quinoline-7-carboxaldehyde (150 mg, 0.66 mmol, 1.00 equiv.) and 6-(piperazine-1-yl)pyridin-3-carboxynitrile (137 mg, 0.73 mmol, 1.10 equiv.) in DCM (2 ml) was stirred at room temperature for 10 min. The resulting mixture was concentrated under reduced pressure. EtOH (3 mL) containing HOAc (19 mg, 0.33 mmol, 0.50 equiv.) was added to the resulting mixture, and the mixture was stirred at 50 °C for 4 h under a nitrogen atmosphere. The mixture was then cooled to room temperature. NaBH2 was added in fractions to the stirred mixture at 0 °C under a nitrogen atmosphere. 3CN (83 mg, 1.33 mmol, 2.00 equiv.). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The precipitated solid was collected by filtration and washed with EtOH (3 × 2 mL). The residue was purified by silicone column chromatography. The resulting mixture was concentrated under reduced pressure to give 6-{4-[(3-chloro-8-fluoro-2-sideoxy-1H-quinolin-7-yl)methyl]piperazine-1-yl}pyridin-3-carboxylonitrile (69.3 mg, 26.2%). LC-MS: (ES+H, m / z): [M+H] + =398.10; 1 H NMR (400 MHz, DMSO- d 6) δ 12.46 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 1.5 Hz, 1H), 7.85 (dd, J = 9.1, 2.4 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.28 (dd, J= 8.1, 6.3 Hz, 1H), 6.97 - 6.87 (m, 1H), 3.71 - 3.63 (m, 6H), 2.50 - 2.44 (m, 4H); 19 F NMR (282 MHz, DMSO- d6) δ -134.50. The following compounds were synthesized as described above. surface 2. Characteristic data Example A Cell growth inhibition analysis Cell proliferation was measured using DLD-1 BRCA2 (- / -) and parental isogenetic pairs, as well as the MDA-MB-436 (mutant BRCA1) cell line, via cell viability analysis. CellTiter-Glo (CTG)-based cell viability analysis was designed to determine the number of viable cells in the culture induced by the action of compounds by quantitative ATP (which indicates the presence of metabolically active cells). DLD-1 BRCA2 (- / -) and parental isogenetic pairs were cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), while MDA-MB-436 cells were cultured in DMEM supplemented with 10% FBS. Both were incubated at 37°C with 5% CO2. 2. Co-culturing. The compounds of this invention were dispensed into 384-well plates (Corning, 3764) using an Echo acoustic liquid dispenser to achieve final concentrations at 1:3 serial dilutions, with the highest dose being 10 or 30 µM. Cells were seeded into the plates at densities of 50 cells / well (DLD-1 parent), 200 cells / well (DLD-1 BRCA2- / -), or 500 cells / well (MDA-MB-436). After a brief spin cycle, the cells were incubated undisturbed at 37°C and 5% CO2. Cells were cultured in a fully humidified incubator for 7 days. Cell viability was measured using a CellTiter Glo 2.0 analysis kit (Promega, G9243), and growth inhibition rates were calculated and plotted against final compound concentrations. Data were fitted using Xfit to generate IC50 values. 50 value. Example B Biochemistry (FP) analyze Fluorescence polarization (FP)-based analysis is widely used in drug discovery due to its uniformity, stable performance, and lack of interference seen in other analyses. Compounds were characterized using an analysis measuring the substitution of a commercially available fluorescently labeled PARP 1 / 2 inhibitor (PARPi-FL, Tocris Biosciences, #6461), as illustrated in analyses performed in WO2014 / 064149 and WO2021 / 013735A1. The analysis was performed using the following methods: Dissolve the compound in DMSO and prepare serial dilutions within the desired concentration range using an Echo 550 liquid dispensing device in an Optiplate-384F disk. Use 100% DMSO for the high control sample (containing protein) and the low control sample (without protein). Add 20 nL of the compound or DMSO alone to each individual analytical disk well. PARP1 and PARP2 proteins were expressed, purified, and diluted in a solution containing 50 mM Tris at pH 8.0, 0.001% Triton X-100, and 10 mM MgCl2. 2. Add PARPi-FL to an analytical buffer of 150 mM NaCl to achieve a final concentration of 20 nM. Then add PARPi-FL to a final concentration of 3 nM. The analysis plate was centrifuged at 1000 rpm for 1 min and incubated at room temperature for 4 h. Use the Envision disk reader with the following settings to read fluorescence polarization: Excitation Filter - FITC FP 480 - Excitation Slot 3; Emission Filter - FITC FP P-pol 535 - Emission Slot 4; Second Emission Filter - FITC FP S-pol 535 - Emission Slot 3; Mirror Module - FITC FP Dual Enh - Slot 1 The inhibition rate was calculated using the percentage of substitutional Mahalanobis distances greater than the control sample (mP value) according to the following equation: XLFit (Equation 201) is used to calculate the reported IC of each compound. 50 . Data from Examples A and B are provided in Table 3. surface 3 Example C : In vitro human transport protein effluent Madin-Darby canine kidney (MDCKII) cells expressing MDR1 and BCRP were seeded at a density of 545,000 cells / cm² on Corning HTS Transwell® 96-well polycarbonate permeable (0.4 µm pores) supports. Cells were cultured for 4 to 8 days prior to analysis, and monolayer integrity was assessed by measuring transepithelial electrical resistance (TEER). Test and reference compounds were diluted to 10 µM and 1 µM, respectively, with delivery buffer (HBSS HEPES pH 7.4). The final organic solvent concentration was 0.5% (v / v). Cells were incubated at 37°C and 5% CO₂. 2. The bidirectional (top-to-bottom-outer and bottom-outer-to-top) throughput of the test compound and reference compound was determined after 2 hours of incubation at 95% relative humidity. At the end of the incubation, samples from the top and bottom-outer sides were collected and then precipitated with acetonitrile containing the internal standard. After centrifugation at 3200×g, the supernatant was diluted 1:1 (v / v) with water and analyzed by HPLC-MS / MS. Integrity The apparent permeability (Papp, in ×10⁻⁶ cm / s) is calculated using the following equation: Papp = (dQ / dt) / (AxD₀) where dQ / dt is the drug delivery rate (pmol / s), and A is the membrane surface area (0.143 cm²). 2 ), and D0 is the initial donor concentration (nM or pmol / cm). 3 The outflow ratio is calculated as follows: Papp(B→A) / Papp(A→B), where Papp(B→A) is the apparent permeability from the bottom outer side to the top, and Papp(A→B) is the apparent permeability from the top to the bottom outer side. Example D : rats Kp,uu In vivo assay Determination of unbound plasma (Pu) The in vitro binding of test substances and reference compounds to plasma proteins was studied using a balanced dialysis method. Plasma samples containing 5 μM of test substance or blank dialysis buffer (PBS, pH 7.4) were added to individual chambers of the dialysis wells of a high-flux balanced dialysis (HTD) device. The dialysis trays were sealed and placed at 37°C and 5% CO2. Incubate at approximately 100 rpm for 6 hours in a 2-degree incubator. Repeat all experiments twice. Ketoconazole (5 μM) was used as the reference compound. After incubation, remove the seal and pipette 50 μL of dialyzed sample from the buffer and plasma chambers into fresh 96-well plates. Equimatrilyzed samples were performed by adding blank plasma to the buffer sample or blank buffer to the plasma sample. Subsequently, 400 μL (4 volumes) of acetonitrile containing the internal standard was added to all samples to precipitate proteins before UPLC-MS / MS analysis to determine the relative concentration of the test substance. The unbound dissolved fraction in plasma was calculated using the concentration of the test substance in the buffer and plasma samples according to the following equation: Determination of unbound dissolved components (Bu) in brain homogenate. The in vitro binding of test compounds and reference compounds to rodent brain homogenates was investigated using a balanced dialysis method. Brains collected from untreated animals were weighed and homogenized in 4 volumes of PBS (pH 7.4). Brain homogenate samples containing 1 μM of test compound or blank dialysis buffer (PBS, pH 7.4) were added to individual chambers of the dialysis wells of a high-flux balanced dialysis (HTD) apparatus. The dialysis trays were sealed and placed at 37°C and 5% CO2. Incubate at approximately 100 rpm for 6 hours in a 2-degree incubator. Repeat all experiments twice. Telmisartan (5 μM) was used as the reference compound. After incubation, remove the seal and pipette 50 μL of dialyzed sample from the buffer chamber and brain homogenate chamber into fresh 96-well plates. Perform iso-matrix calculations on the samples by adding blank homogenate to the buffer sample or adding blank buffer to the homogenate sample. Subsequently, before performing UPLC-MS / MS analysis to determine the relative concentration of the test substance, add 400 μL (4 volumes) of acetonitrile containing the internal standard to all samples to precipitate the protein. Calculate the unbound dissolved fraction in the diluted brain homogenate using the concentration of the test substance in the buffer sample and homogenate sample according to the following equation: The following equation can be used to correct for the percentage of unbound cells in the undiluted brain: The brain-plasma partition coefficient (Kp) and unbound drug Kp (Kp,uu) were determined in rats. The compound was administered, either alone or in a cartridge (as a mixture), to male Sprague-Dawley rats via oral feeding at a concentration of 0.1 mg / mL / compound in sterile water containing 400 cP of 0.5% (w / v) methylcellulose. One animal was sacrificed at 0.5, 1, 2, 4, 8, and 24 hours post-administration, and brain and blood samples were collected. Plasma was prepared from the blood by refrigerated centrifugation, and the plasma samples were frozen at -80°C until bioanalysis. Brain samples were rinsed with physiological saline to remove residual blood and dried with paper towels. The brain samples were then weighed, homogenized with 3 volumes (v / w) of water, and frozen at -80°C until bioanalysis. Prior to bioanalysis, plasma and brain samples were extracted with 4 volumes of acetonitrile containing an internal standard and centrifuged for 15 minutes. The supernatant was diluted with 2 volumes of water and injected for analysis by HPLC-MS / MS. Drug concentrations in plasma and brain tissue homogenates were determined against calibration curves generated by testing blank rat plasma or brain tissue homogenates across appropriate concentration ranges. Brain homogenate concentrations were corrected against the homogenization buffer dilution factor to obtain the total brain drug concentration. The brain-plasma partition coefficient (Kp) of each compound was determined and calculated as: AUC brain : AUC plasma, with the constraint that the tlast values ​​in each matrix are the same. If the drug concentration versus time curve of one matrix decreases below the lower limit of quantification at an earlier time point than that of another matrix, then the brain Kp is calculated as the average ratio of the total brain drug concentration to the total plasma drug concentration measured at all time points where drug concentrations are quantifiable in both matrices. Kp,uu is then calculated from Kp using the following equation: Kp,uu = Kp * (unbound dissolved fraction in brain homogenate / plasma). Data from Examples C and D are provided in Table 4. surface 4

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof: .

2. A pharmaceutical composition comprising a compound as claimed in claim 1 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof, and a pharmaceutically acceptable excipient.