PARP inhibitors, pharmaceutical compositions containing same and uses thereof

Abstract

Compounds of formula (I), pharmaceutical compositions containing same and their use as PARP inhibitors, preferably as selective inhibitors of PARP1. [Case 1] TIFF2024546155000157.tif37166

Description

[Technical field]

[0001] The present invention relates to PARP inhibitors, pharmaceutical compositions containing same, and their use in the prevention or treatment of diseases that can be ameliorated by inhibiting PARP. [Background technology]

[0002] Poly(ADP-ribose) polymerase (PARP) can catalyze the transfer of ADP-ribose residues from NAD+ to target substrates to modify proteins by ribosylation. This poly(ADP-ribosylation) is a post-translational modification of proteins that is widely involved in various physiological and pathological processes. PARP can poly(ADP-ribosylate) various nuclear proteins, including histones, RNA polymerase, DNA polymerase, and DNA ligase. PARP is activated by recognizing damaged DNA fragments, leading to glycosylation modification of nuclear proteins, thereby completing the function of DNA repair. In normal cells, other DNA repair mechanisms, such as the BRCA pathway, can also complete DNA repair that allows cell survival. Therefore, inhibiting PARP does not significantly affect DNA repair in normal cells. In some cancer patients, when the BRCA gene is mutated, gene repair of tumor cells mainly relies on the PARP mechanism. In these patients, PARP inhibitors can block DNA repair function and cause tumor cell apoptosis. In recent years, PARP inhibitors have been used to treat ovarian and breast cancer patients with BRCA mutations, achieving significant therapeutic benefits.

[0003] The currently approved first generation PARP inhibitors have certain inhibitory effects on bone marrow hematopoiesis, limiting their use in combination with chemotherapeutic agents that also inhibit bone marrow hematopoiesis.

[0004] In addition, since PARP is involved in regulating various physiological and pathological processes (promoting oxidative stress response, inflammatory response, exacerbating viral infections, and controlling glucose stability), PARP inhibitors can also be used to treat diseases related to these functions, including diseases characterized by oxidative stress (e.g., ischemia-reperfusion injury, inflammatory diseases, burns, Parkinson's disease, Huntington's disease, Alzheimer's disease, and toxic injuries); inflammatory diseases (asthma, arthritis, colitis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, atherosclerosis, post-myocardial infarction cardiac remodeling, sepsis, endotoxic shock, hemorrhagic shock, graft-versus-host disease, encephalomyelitis, and autoimmune nephritis); viral infections (anti-human immunodeficiency virus-1, Venezuelan equine encephalitis virus, herpes simplex virus, human hepatitis B virus, and human cytomegalovirus infections); and metabolic disorders (metabolic syndrome and type II diabetes and subsequent complications, such as diabetic neurological, renal, and ocular complications). Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides a PARP inhibitor that can be used for the prevention or treatment of diseases that can be ameliorated by inhibiting PARP.Preferably, the compound of the present invention has selective inhibitory activity against PARP-1.In addition, the compound of the present invention possesses better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, favorable half-life and duration of action), improved safety (lower toxicity, e.g., reduced cardiotoxicity and / or fewer side effects), and superior properties, e.g., less resistance. [Means for solving the problem]

[0006] One aspect of the present invention is a compound having the structure of formula (I):

[0007] [ka] or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, During the ceremony,

[0008] [ka] is a single bond or a double bond, X is N or CR 5 and Y is N or CR 5 ' and Z is CR 6 or N,

[0009] [ka] is a single bond, V is CR 7 R A or NR A and

[0010] [ka] is a double bond, V is CR A and R A is H, halogen, -OH, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b, -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR a R b , -OC 1~6 Alkylene-NR a R b and

[0011] [ka] is selected from the group consisting of Ring A is C 3~6 Hydrocarbon ring, 3-10 membered heterocycle, C 6~10 an aromatic ring or a 5- to 14-membered heteroaromatic ring; R and R', in each occurrence, are H, halogen, -OH, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a-C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR a R b and -OC 1~6 Alkylene-NR a R b and preferably, R and R' are each independently selected from the group consisting of H, -CN and C 1~6 alkyl, R 1 and R 2 are halogens, -OH, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b, -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR a R b and -OC 1~6 Alkylene-NR a R b are each independently selected from the group consisting of: R 3 In each occurrence, it represents a halogen, -OH, =O, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR a R b and -OC 1~6 Alkylene-NR a R b are each independently selected from the group consisting of: If m>1, then two R 3 The groups are optionally joined together to form -C 1~6 Alkylene- or -C 2~6 alkenylene-, wherein the alkylene and alkenylene chains are optionally interrupted by one or more groups independently selected from the group consisting of O, C(=O), C(=O)O, NR, S, S=O and S(=O)2; Or, R 3 and R A together with the groups to which they are attached, C 3~6 Hydrocarbon ring, 3-10 membered heterocycle, C 6~10 optionally forming an aromatic ring or a 5- to 14-membered heteroaromatic ring, R 4 In each occurrence, it represents a halogen, -OH, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NRa R b and -OC 1~6 Alkylene-NR a R b and two R 4 When the groups are ortho to each other on ring A, the two R 4 groups, together with the group to which they are attached, optionally form a 3- to 10-membered heterocyclic ring or a 5- to 14-membered heteroaromatic ring; Or, R 3 and R 4 together with the groups to which they are attached, C 3~6 Hydrocarbon ring, 3-10 membered heterocycle, C 6~10 optionally forming an aromatic ring or a 5- to 14-membered heteroaromatic ring, R 5 , R 5 ', R 6 and R 7 In each occurrence, H, halogen, -OH, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR a R b and -OC 1~6 Alkylene-NR a R b are each independently selected from the group consisting of: R a and R b In each occurrence, H, C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Haloalkyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl, The above alkyl, alkylene, haloalkyl, alkenyl, alkenylene, hydrocarbon ring, cyclic hydrocarbyl, heterocycle, heterocyclyl, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl are each independently selected from the group consisting of halogen, -OH, =O, -NH2, -CN, -NO2, -C, -C-O, -C-C-O, -C-O ... 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R c , -OC(=O)R c , -C(=O)OR c , -OR c , -SR c , -S(=O)R c , -S(=O)2R c , -S(=O)2NR c R d , -NR c R d , -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NRc -S(=O)2-R d , -NR c -C(=O)-NR c R d , -C 1~6 Alkylene-OR c , -C 1~6 Alkylene-NR c R d and -OC 1~6 Alkylene-NR c R d and wherein alkyl, alkylene, haloalkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 and optionally further substituted with one or more substituents independently selected from the group consisting of aralkyl; R c and R d In each occurrence, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl, wherein m and n are each independently an integer of 0, 1, 2, 3, or 4; or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0012] Another aspect of the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, and one or more pharma- ceutically acceptable carriers, preferably in the form of a solid, liquid or transdermal formulation.

[0013] Another aspect of the invention provides the use of a compound of the invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labelled compound or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for use as a PARP inhibitor (preferably as a PARP1 selective inhibitor).

[0014] Another aspect of the present invention provides a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labelled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for use as a PARP inhibitor, preferably as a PARP1 selective inhibitor.

[0015] Another aspect of the present invention provides a method for the prevention or treatment of a disease that can be ameliorated by inhibiting PARP (preferably PARP-1), comprising the step of administering to a subject in need thereof an effective amount of a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 shows the efficacy of Compound 1 in inhibiting tumor growth in the MDA-MB-436 breast cancer mouse tumor model. [Diagram 2] FIG. 1 shows the effect of Compound 1 on mouse body weight in the MDA-MB-436 breast cancer mouse tumor model. [Diagram 3]FIG. 1 shows the effect of Compound 1 in inhibiting tumor growth in a breast cancer PDX model. [Figure 4] FIG. 1 shows the effect of Compound 1 on mouse body weight in a breast cancer PDX model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] definition Unless otherwise defined in the context, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of those technologies or equivalent technology substitutes that would be obvious to those skilled in the art. It is believed that the following terms will be readily understood by those skilled in the art, but the following definitions are nevertheless presented to better illustrate the present invention.

[0018] As used herein, the terms "contain," "include," "comprise," "have," or "relate to," and other variations, are inclusive and open-ended and do not exclude additional, unrecited elements or method steps.

[0019] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbyl, preferably having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methylene, ethylene, propylene, or butylene.

[0020] As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "C 1~6"Alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as halogen (in which case the group may be referred to as "haloalkyl") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1~4 "Alkyl" refers to a straight or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0021] As used herein, the term "alkenyl" refers to a hydrocarbyl group containing one or more double bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethenyl, propenyl or allyl. When the compounds of the present invention contain an alkenylene group, the compounds may exist as a pure E (entgegen) form, a pure Z (zusammen) form, or any combination thereof. The term "alkenylene" refers to a divalent hydrocarbyl group containing one or more double bonds.

[0022] As used herein, the term "heteroalkyl" refers to an optionally substituted alkyl group having one or more skeletal atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. 1~6 The term "heteroalkyl" may be given to indicate the number of carbons in the chain (in this example, 1 to 6 carbon atoms). For example, a -CH2OCH2CH3 group would be referred to as a C3 heteroalkyl group. Attachment to the rest of the molecule may be through a heteroatom or a carbon atom in the heteroalkyl chain. The term "heteroalkylene" may be used, for example, as "C 1~6 Heteroalkylene, C 1~4 Heteroalkylene" and the like, preferably -CH2OCH2-.

[0023] As used herein, the terms "cyclic hydrocarbylene", "cyclic hydrocarbyl" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and / or triple bonds in the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3 to 10 ring carbon atoms (preferably having 3 to 8, more preferably 3 to 6), including, but not limited to, cyclopropyl(ene)(ring), cyclobutyl(ene)(ring), cyclopentyl(ene)(ring), cyclohexyl(ene)(ring), cycloheptyl(ene)(ring), cyclooctyl(ene)(ring), cyclononyl(ene)(ring), cyclohexenyl(ene)(ring), and the like.

[0024] As used herein, the term "cycloalkyl" refers to a saturated, non-aromatic, monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl, or bicyclic rings containing spiro, fused, or bridged ring systems (e.g., bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, or decahydronaphthalene, etc.)) optionally substituted with one or more (e.g., 1 to 3) suitable substituents. Cycloalkyl has 3 to 15 carbon atoms. For example, the term "C 3~6 "Cycloalkyl" refers to a saturated or unsaturated, non-aromatic, mono- or polycyclic (e.g., bicyclic) hydrocarbon ring having three to six ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally substituted with one or more (e.g., one to three) suitable substituents, such as methyl-substituted cyclopropyl.

[0025] As used herein, the term "heterocyclyl" or "heterocycle" refers to a heterocycle having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and C(=O), O, S, S(=O), S(=O)2, and NR ' [Where, R' is a hydrogen atom, C 1~6 Alkyl or C 1~6 represents a haloalkyl group]. Heterocyclyl may be attached to the remainder of the molecule via either a carbon atom or a nitrogen atom (if present). In particular, 3-10 membered heterocyclyl refers to groups having 3-10 carbon atoms and heteroatom(s) in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.

[0026] As used herein, the term "heterocyclyl" or "heterocycle" encompasses fused ring structures, and the point of attachment between the fused ring structure and another group may be from any ring in the fused ring structure. Thus, the heterocyclyl of the present invention includes heterocyclyl-fused heterocyclyl, heterocyclyl-fused cycloalkyl, monoheterocyclyl-fused monoheterocyclyl, monoheterocyclyl-fused monocycloalkyl, such as 3- to 7-membered (mono)heterocyclyl-fused 3- to 7-membered (mono)heterocyclyl, 3- to 7-membered (mono)heterocyclyl-fused (mono)cycloalkyl, 3- to 7-membered (mono)heterocyclyl-fused C 4~6 Examples include, but are not limited to, (mono)cycloalkyl, and examples include pyrrolidinyl-fused cyclopropyl, cyclopentyl-fused azacyclopropyl, pyrrolidinyl-fused cyclobutyl, pyrrolidinyl-fused pyrrolidinyl, pyrrolidinyl-fused piperidinyl, pyrrolidinyl-fused piperazinyl, piperidinyl-fused morpholinyl,

[0027] [ka] Including but not limited to:

[0028] As used herein, the term "heterocyclyl" or "heterocycle" includes bridged heterocyclyls and spiroheterocyclyls.

[0029] As used herein, the term "bridged heterocycle" refers to a ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly bonded, including, but not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc.

[0030] [ka] etc. A "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle" and "sulfur-containing bridged heterocycle" optionally further contain one or more additional heteroatoms selected from oxygen, nitrogen and sulfur.

[0031] As used herein, the term "spiroheterocycle" refers to a ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, sulfur atoms) formed by two or more saturated rings sharing one ring atom, including, but not limited to, a 5- to 10-membered spiroheterocycle, a 6- to 10-membered spiroheterocycle, a 6- to 10-membered nitrogen-containing spiroheterocycle, a 6- to 10-membered oxygen-containing spiroheterocycle, and a 6- to 10-membered sulfur-containing heterocycle, such as a 5- to 10-membered spiroheterocycle, a 6- to 10-membered nitrogen-containing spiroheterocycle, a 6- to 10-membered oxygen-containing spiroheterocycle, and a 6- to 10-membered sulfur-containing hetero

[0032] [ka] "Nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle" and "sulfur-containing spiroheterocycle" optionally further contain one or more additional heteroatoms selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl group containing a total of 6 to 10 ring atoms, at least one of the ring atoms being a nitrogen atom.

[0033] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C 6~14 "Aryl" refers to an aromatic group containing 6 to 14 carbon atoms, e.g., phenyl or naphthyl. Aryl may contain one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1~6 and optionally substituted with alkyl.

[0034] The term "aralkyl" preferably refers to aryl-substituted alkyl, where aryl and alkyl are as defined herein. Typically, the aryl group may have 6 to 14 carbon atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0035] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, containing at least one heteroatom (e.g., O, N or S), which may be the same or different. Moreover, in each case, it may be benzo-fused. In particular, heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and their benzo derivatives, or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and their benzo derivatives.

[0036] As used herein, the term "heteroaryl" or "heteroaromatic ring" encompasses fused ring structures, where the point of attachment between the fused ring structure and another group may be from any ring in the fused ring structure. Thus, the heteroaryl groups of the present invention include (mono)heteroaryl-fused (mono)heteroaryl, (mono)heteroaryl-fused (monocyclo)aryl, (mono)heteroaryl-fused (mono)heterocyclyl and (mono)heteroaryl-fused (mono)cycloalkyl, such as 5-6 membered (mono)heteroaryl-fused 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl-fused phenyl, 5-6 membered (mono)heteroaryl-fused 5-6 membered (mono)heterocyclyl or 5-6 membered (mono)heteroaryl-fused C 4~6 (mono)cycloalkyl (e.g., 5-6 membered heteroaryl fused cyclobutyl, 5-6 membered heteroaryl fused cyclopentyl, or 5-6 membered heteroaryl fused cyclohexyl), examples of which include, but are not limited to, indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl,

[0037] [ka] Including, but not limited to, the following:

[0038] As used herein, the term “halo” or “halogen” is defined to include F, Cl, Br, or I.

[0039] The term "alkylthio," as used herein, means an alkyl group, as defined above, attached to the parent molecular moiety through a sulfur atom. 1~6 Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.

[0040] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, and may further optionally contain one or more (e.g., 1, 2, 3 or 4) ring members selected from the group consisting of N, O, C=O, S, S=O and S(=O)2. The nitrogen-containing heterocycle is connected to the rest of the molecule via a nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, the 3- to 14-membered nitrogen-containing heterocycle is a group having 3 to 14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including, but not limited to, a 3-membered nitrogen-containing heterocycle (e.g., aziridinyl), a 4-membered nitrogen-containing heterocycle (e.g., azetidinyl), a 5-membered nitrogen-containing heterocycle (e.g., pyrrolyl, pyrrolidinyl (pyrrolidinyl ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a 6-membered nitrogen-containing heterocycle (e.g., piperidinyl (piperidinyl ring), morpholinyl, thiomorpholinyl, piperazinyl), a 7-membered nitrogen-containing heterocycle, and the like.

[0041] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the specified atom are replaced with an option from the indicated group, provided that the replacement does not exceed the normal valence of the specified atom under the existing circumstances, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0042] When a substituent is described as "optionally substituted," the substituent may be either (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may be replaced separately and / or together with independently selected optional substituents. When a nitrogen of a substituent is described as optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent there are any) may each be replaced with an independently selected optional substituent.

[0043] When substituents are described as "independently selected" from a group, each substituent is selected independently of the other(s). Thus, each substituent can be the same or different from the other substituent(s).

[0044] As used herein, the term "one or more" means one or more than one (e.g., 2, 3, 4, 5 or 10), where reasonable.

[0045] As used herein, unless specified, the point of attachment of a substituent may be from any suitable position on the substituent.

[0046] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any of the substitutable ring-forming atoms in that ring.

[0047] The present invention also includes all pharma- ceutically acceptable isotopically labeled compounds, which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention are hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)), carbon, e.g. 11 C. 13C and 14 C, chlorine, e.g. 36 Cl, fluorine, e.g. 18 F, iodine, e.g. 123 I and 125 I, nitrogen, e.g. 13 N and 15 N, oxygen, e.g. 15 O. 17 O and 18 O, phosphorus, e.g. 32 P, as well as sulfur, e.g. 35 Certain isotopically labeled compounds of the present invention, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. Positron emitting isotopes, e.g. 11 C. 18 F, 15 O and 13 Substitution with N can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by processes similar to those described in the accompanying schemes and / or in the examples and preparations, by substituting a suitable isotopically labeled reagent for a previously used non-labeled reagent. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization may be isotopically substituted, for example, DO, acetone-d6, or DMSO-d6.

[0048] The term "stereoisomer" refers to an isomer with at least one asymmetric center. Compounds with one or more (e.g., one, two, three, or four) asymmetric centers can give rise to racemic mixtures, single mirror image isomers (enantiomers), diastereomeric mixtures, and individual diastereomers. Certain individual molecules can exist as geometric isomers (cis / trans). Similarly, compounds of the present invention can exist as mixtures of two or more structurally distinct forms in rapid equilibrium (generally referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that all such isomers and mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% and 99%) are encompassed within the scope of the present invention.

[0049] Carbon-carbon bonds in the compounds of the present invention are represented herein by solid lines (

[0050] [ka] ), solid wedge (

[0051] [ka] ), or dotted wedge (

[0052] [ka] ). The use of a solid line to depict a bond to an asymmetric carbon atom is meant to indicate that all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.) are included. The use of either a solid or dotted wedge to depict a bond to an asymmetric carbon atom is meant to indicate that the depicted stereoisomer exists. When present in a racemic compound, the solid and dotted wedges are used to define the relative stereochemistry rather than the absolute stereochemistry. Unless otherwise stated, the compounds of the present invention can exist as stereoisomers, which are intended to include cis and trans isomers, optical isomers, e.g., R and S enantiomers, diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemates and diastereomeric pairs).

[0053] The present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as a single polymorph or as a mixture of more than one polymorph in any ratio.

[0054] It should also be understood that certain compounds of the present invention can be used in treatment in free form or, where appropriate, in the form of a pharma- ceutically acceptable derivative.In the present invention, a pharma-ceutically acceptable derivative includes, but is not limited to, a pharma-ceutically acceptable salt, ester, solvate, metabolite or prodrug, which can directly or indirectly provide the compound of the present invention or its metabolite or residue after being administered to a patient in need thereof.Therefore, the "compound of the present invention" referred to herein is also meant to encompass various derivative forms of the compound as referred to above.

[0055] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base salts thereof.

[0056] Suitable acid addition salts are formed from acids which form pharma- ceutically acceptable salts, examples of which include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, and the like.

[0057] Suitable base addition salts are formed from bases which form pharma- ceutically acceptable salts. Specific examples include aluminium salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts and the like.

[0058] For a review of suitable salts, see "Hand book of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharma- ceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0059] As used herein, the term "ester" refers to compounds of various formulas in this application, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the invention in the form of a free acid or alcohol). The compounds of the invention themselves may be esters.

[0060] The compounds of the present invention can exist as solvates (preferably hydrates), in which the compounds of the present invention contain a polar solvent, in particular water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, in particular water, can be present in a stoichiometric or non-stoichiometric ratio.

[0061] Also included within the scope of the invention are metabolic products of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic degradation, and the like, of the administered compound. Accordingly, the invention encompasses metabolic products of compounds of the invention, including compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0062] Prodrugs of the compounds of the present invention are also within the scope of the present invention, which are certain derivatives of the compounds of the present invention that may have little or no pharmacological activity themselves, but can be converted to the compounds of the present invention having the desired activity when administered to or on the body, for example by hydrolytic cleavage. Generally, such prodrugs will be functional derivatives of the compounds that are easily converted in vivo to compounds with the desired therapeutic activity. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association). Prodrugs according to the present invention can be produced, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "promoieties", for example as described in "Design of Prodrugs", by H. Bundgaard (Elsevier, 1985).

[0063] The present invention further encompasses the compounds of the present invention with protective groups.During any of the processes for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules involved, thereby resulting in chemically protected forms of the compounds of the present invention.This can be achieved by utilizing conventional protective groups, such as those described in Protective Groups in Organic Chemistry, edited by JFW McOmie, Plenum Press, 1973; and TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference.Protective groups can be removed at a subsequent convenient stage using methods known in the art.

[0064] As used herein, the term "about" refers to a range within ±10%, preferably within ±5%, and more preferably within ±2% of the specified value.

[0065] compound In some embodiments, the present application provides a compound having the structure of formula (I):

[0066] [ka] or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, During the ceremony,

[0067] [ka] is a single bond or a double bond, X is N or CR 5 and Y is N or CR 5 ' and Z is CR 6 or N,

[0068] [ka] is a single bond, V is CR 7 R A or NR A and

[0069] [ka] is a double bond, V is CR A and R A is H, halogen, -OH, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR a R b , -OC 1~6 Alkylene-NRa R b and

[0070] [ka] is selected from the group consisting of Ring A is C 3~6 Hydrocarbon ring, 3-10 membered heterocycle, C 6~10 an aromatic ring or a 5- to 14-membered heteroaromatic ring; R and R', in each occurrence, are H, halogen, -OH, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR a R b and -OC 1~6 Alkylene-NR a R band preferably, R and R' are each independently selected from the group consisting of H, -CN and C 1~6 alkyl, R 1 and R 2 are halogens, -OH, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR a R b and -OC 1~6 Alkylene-NR a R b are each independently selected from the group consisting of: R 3 In each occurrence, it represents a halogen, -OH, =O, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR a R b and -OC 1~6 Alkylene-NR a R b are each independently selected from the group consisting of: If m>1, then two R 3 The groups are optionally joined together to form -C 1~6 Alkylene- or -C 2~6 alkenylene-, wherein the alkylene and alkenylene chains are optionally interrupted by one or more groups independently selected from the group consisting of O, C(=O), C(=O)O, NR, S, S=O and S(=O)2; Or, R 3 and R A together with the groups to which they are attached, C 3~6 Hydrocarbon ring, 3-10 membered heterocycle, C 6~10 optionally forming an aromatic ring or a 5- to 14-membered heteroaromatic ring, R 4 In each occurrence, it represents a halogen, -OH, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR a R b and -OC 1~6 Alkylene-NR a R b and two R 4 When the groups are ortho to each other on ring A, the two R 4 groups, together with the group to which they are attached, optionally form a 3- to 10-membered heterocyclic ring or a 5- to 14-membered heteroaromatic ring; Or, R 3 and R 4 together with the groups to which they are attached, C 3~6 Hydrocarbon ring, 3-10 membered heterocycle, C 6~10optionally forming an aromatic ring or a 5- to 14-membered heteroaromatic ring, R 5 , R 5 ', R 6 and R 7 In each occurrence, H, halogen, -OH, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR a R b and -OC 1~6 Alkylene-NR a R b are each independently selected from the group consisting of: R a and R b In each occurrence, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 3~10Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl, The above alkyl, alkylene, haloalkyl, alkenyl, alkenylene, hydrocarbon ring, cyclic hydrocarbyl, heterocycle, heterocyclyl, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl are each independently selected from the group consisting of halogen, -OH, =O, -NH2, -CN, -NO2, -C, -C-O, -C-C-O, -C-O ... 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R c , -OC(=O)R c , -C(=O)OR c , -OR c , -SR c , -S(=O)R c , -S(=O)2R c , -S(=O)2NR c R d , -NR c R d , -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NR c -S(=O)2-R d , -NR c -C(=O)-NR c R d , -C 1~6 Alkylene-OR c , -C 1~6 Alkylene-NR c R d and -OC 1~6 Alkylene-NR c R dand wherein alkyl, alkylene, haloalkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH2, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 and optionally further substituted with one or more substituents independently selected from the group consisting of aralkyl; R c and R d In each occurrence, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl, wherein m and n are each independently an integer of 0, 1, 2, 3, or 4; or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0071] In some embodiments, the present application provides A But, C 1~6 Haloalkyl (preferably

[0072] [ka] ), -C(=O)R a (Preferably

[0073] [ka] ) and

[0074] [ka] or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, selected from the group consisting of:

[0075] In some embodiments, the present application provides a compound having the structure of Formula (I)-1.

[0076] [ka] and preferably the compound has the structure of formula (II), (III), (IV) or (V):

[0077] [ka] or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein

[0078] In some embodiments, the present application provides 1 and R 2 are each independently halogen, -CN, C 1~6 Alkyl or C 1~6 haloalkyl, e.g., R 1 and R 2 However, each independently, C 1~6 Alkyl or C 1~6 is haloalkyl, Preferably, R 1 and R 2 are each independently F, -CN, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, or isopropyl, for example, R 1 and R 2 are each independently methyl, trifluoromethyl, ethyl, n-propyl, or isopropyl; Most preferably, R 1 is trifluoromethyl, and R 2 is methyl or R1 and R 2 are both methyl, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0079] In some embodiments, the present application provides 3 each occurrence independently represents a halogen, -OH, =O, -NH2, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a Or -C 1~6 Alkylene-NR a R b If m>1, then two R 3 The groups may be joined together to form -C 1~4 Forming an alkylene- Preferably, R 3 each occurrence independently represents =O, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a Or -C 1~6 Alkylene-NR a R b If m>1, then two R 3 The groups may be joined together to form -C 1~4 Forming an alkylene- More preferably, R 3 is each independently, in each occurrence, =O, -CN, -CH3, -CF3, -CH2CN, -CH2NH2, -CH2CH2NH2, -CH2OH, -CH2CH2OH, or -CH2OCH3; and when m>1, two R 3 The present invention provides a compound as described above, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the groups optionally combine to form -CH2CH2-.

[0080] In some embodiments, R 3 and R A together with the groups to which they are attached, optionally form a 5- to 6-membered heteroaromatic ring, preferably a triazole ring, which is 1~6 Optionally substituted with haloalkyl (preferably trifluoromethyl).

[0081] In some embodiments, the present application provides 6 and R 7 In each occurrence, H, halogen, -OH, -CN, -C 1~6 Alkylene-OR a and -C 1~6 Alkylene-NR a R b are each independently selected from the group consisting of: R 6 and R 7 is independently selected at each occurrence from the group consisting of H, -F, -OH, -CN, -CHOH, and -CHNH; Provided is a compound as described above, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0082] In some embodiments, the present application provides:

[0083] [ka] but,

[0084] [ka] Selected from the group consisting of: Preferably,

[0085] [ka] but,

[0086] [ka] Selected from the group consisting of: Provided is a compound as described above, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0087] In some embodiments, the present application provides 4 each occurrence independently represents halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbyl, 5-14 membered heteroaryl, -S(=O)2NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b -NR a -C(=O)-NR a R b Or -C 1~6 Alkylene-OR a and two R 4 When the groups are ortho to each other on ring A, the two R 4 groups, together with the group to which they are attached, optionally form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaromatic ring; Preferably, R 4 each occurrence independently represents F, -CN, -CH3, -CF3,

[0088] [ka] , -S(=O)2NHCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHCD3, -C(=O)NHCH2CH3, -C(=O)NHCH2CF3, -C(=O)NHCH2CH2OH, -C(=O)NH(cyclopropyl), -NHC(=O)CH3, -NHC(=O)(cyclopropyl), -NHC(=O)NHCH3, -CH2OH,

[0089] [ka] and two R 4 When the groups are ortho to each other on ring A, the two R 4 The groups, together with the groups to which they are attached,

[0090] [ka] and optionally forming More preferably, R 4 each occurrence independently represents F, -CN, -CH3, -CF3,

[0091] [ka] , -S(=O)2NHCH3, -C(=O)NH2, -C(=O)NHCH3, -NHC(=O)CH3, -NHC(=O)(cyclopropyl), -NHC(=O)NHCH3, -CH2OH,

[0092] [ka] and two R 4 When the groups are ortho to each other on ring A, the two R 4 The groups, together with the groups to which they are attached,

[0093] [ka] or Or, R 3 and R 4 optionally forming, together with the group to which they are attached, a 5- to 6-membered heteroaromatic ring, preferably an imidazole ring; Provided is a compound as described above, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0094] In some embodiments, the present application provides a method for the preparation of a compound in which ring A is C 4~6The ring is a hydrocarbon ring, a 5- to 6-membered heterocyclic ring, a C6 aromatic ring, or a 5- to 6-membered heteroaromatic ring, more preferably a bicyclo[1.1.1]pentane ring, a piperidine ring, a benzene ring, an imidazole ring, a thiazole ring, a pyridine ring, a pyrazine ring, a pyridazine ring, or a pyrimidine ring, and most preferably a bicyclo[1.1.1]pentane ring, a piperidine ring, a benzene ring, an imidazole ring, a thiazole ring, a pyridine ring, a pyridazine ring, or a pyrimidine ring, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

[0095] In some embodiments, the present application provides:

[0096] [ka] but,

[0097] [ka] and Preferably,

[0098] [ka] but,

[0099] [ka] or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

[0100] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0101] In a preferred embodiment, the present invention relates to a compound comprising:

[0102] [ka] or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound is selected from the group consisting of: TIFF2024546155000039.tif249160TIFF2024546155000040.tif241161TIFF2024546155000041.tif244161TIFF2024546155000042.tif254163TIFF2024546155000043.tif233161.

[0103] Pharmaceutical compositions and methods of treatment In some embodiments, the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount (prophylactically or therapeutically effective amount) of a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, and one or more pharma- ceutically acceptable carriers, the pharmaceutical compositions being preferably in the form of a solid, liquid, or transdermal formulation.

[0104] In some embodiments, the invention provides the use of a compound of the invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for use as a PARP inhibitor (preferably as a PARP1 selective inhibitor).

[0105] In some embodiments, the invention provides a compound of the invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the invention, for use as a PARP inhibitor (preferably as a PARP1 selective inhibitor).

[0106] In some embodiments, the present invention provides a method for the prevention or treatment of a disease that can be ameliorated by inhibiting PARP (preferably PARP-1), comprising the step of administering to a subject in need thereof an effective amount of a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.

[0107] Diseases that may be ameliorated by inhibiting PARP (preferably PARP-1) include, but are not limited to, cancers, such as ovarian cancer, breast cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, lung cancer, head and neck cancer, thyroid cancer, malignant glioma, leukemia, lymphoma, and multiple myeloma.

[0108] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0109] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The pharmaceutical compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Oral formulations can include standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutical carriers are described, for example, in Remington's Pharmaceutical Sciences (1990).

[0110] The pharmaceutical compositions of the present invention can act systemically and / or locally. To this end, they can be administered via a suitable route, for example, via injection (intravenous, including drip infusion, intraarterial, subcutaneous, intraperitoneal, intramuscular injection), or via transdermal administration, or via oral, buccal, nasal, transmucosal, topical, ophthalmic formulations, or via inhalation.

[0111] For these administration routes, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.

[0112] Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, salves, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0113] As used herein, the term "effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.

[0114] Dosage regimen may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It should be noted that dosage values ​​may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It should further be understood that for any particular subject, specific dosage regimen should be adjusted over time according to individual need and the professional judgment of the person administering or supervising the administration of the composition.

[0115] The amount of the compound of the present invention to be administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the discretion of the prescribing physician. In general, an effective dosage is within the range of about 0.0001 to about 50 mg per kg of body weight per day, e.g., about 0.01 to about 10 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.007 mg to about 3500 mg / day, e.g., about 0.7 mg to about 700 mg / day. In some cases, dosage levels below the lower limit of the range may be more than sufficient, while in other cases, larger doses may be used without causing any adverse side effects, provided that such larger doses are first divided into several smaller doses for administration throughout the day.

[0116] The content or dosage of the compound of the present invention in the pharmaceutical composition is about 0.01 mg to about 1000 mg, suitably 0.1 to 500 mg, preferably 0.5 to 300 mg, more preferably 1 to 150 mg, particularly preferably 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0117] Unless otherwise indicated, the terms "treating" or "treatment," as used herein, mean to reverse, alleviate, inhibit the progression of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0118] As used herein, the term "subject" includes a human or a non-human animal. Exemplary human subjects include a human subject (referred to as a patient) having a disease (e.g., as described herein) or a healthy subject. The term "non-human animal" as used herein includes all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles) and mammals, e.g., non-human primates, farm animals and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0119] In some embodiments, a pharmaceutical composition of the invention may further comprise one or more additional therapeutic or prophylactic agents. EXAMPLES

[0120] [Example] The present invention is further described in conjunction with the following examples, which are not intended to limit the scope of the invention.

[0121] Experimental methods in the present examples were generally carried out under conventional conditions or according to conditions recommended by the manufacturers of raw materials or commercial products, unless otherwise specified. Reagents for which no specific source was mentioned were conventional reagents available commercially. All evaporations were carried out under vacuum using a rotary evaporator. Analytical samples were dried at room temperature under vacuum (1-5 mm Hg). Thin layer chromatography (preparative TLC) or high performance liquid chromatography (HPLC) separations were carried out on preparative silica gel plates. Flash column chromatography purifications were performed using SEPAFLASH prepacked silica gel columns, and mixed solvent systems are reported in volume ratios.

[0122] The structures of the compounds were confirmed by nuclear magnetic resonance spectroscopy (NMR) or mass spectrometry (MS).

[0123] NMR spectra were recorded using a Varian NMR system 400 MHz high resolution NMR instrument. Chemical shifts (δ) are reported in parts per million (ppm). Solvents for analysis were deuterated chloroform (CDCl3), hexadeuterated dimethylsulfoxide (DMSO-d6) or deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as an internal standard. 1 Multiplicities of H NMR spectral peaks are abbreviated as follows: s for singlet, bs for broad singlet, d for doublet, t for triplet, q for quartet, m for multiplet, dd for double doublet, etc.

[0124] The liquid chromatography-mass spectrometry (LC-MS) instrument used was an Agilent 1260 Series 6135 mass spectrometer with electrospray ionization and the analytical method was as follows:

[0125] Agilent LC-MS 1260-6135, column: Agilent ZORBAX SB-C18 (50 mm × 2.1 mm × 5 μm); column temperature: 25 °C; flow rate: 1.5 mL / min; mobile phase gradient from 95% [water + 0.1% trifluoroacetic acid] and 5% [acetonitrile + 0.1% trifluoroacetic acid] to 5% [water + 0.05% trifluoroacetic acid] and 95% [acetonitrile + 0.05% trifluoroacetic acid] over 2.5 min.

[0126] The high-performance liquid chromatography equipment used was a Hanbang 50 ml binary semi-preparative liquid chromatography system, column type: Hedera ODS-2 250 × 10 mm × 10 μm; mobile phase: phase A [water + 0.1% trifluoroacetic acid], phase B [acetonitrile + 0.1% trifluoroacetic acid].

[0127] The thin layer chromatography silica gel plates used were Huanghai GF254 silica gel plates.

[0128] Unless otherwise stated, reactions in the examples were carried out under a nitrogen atmosphere.

[0129] The progress of reactions in the examples was monitored by thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS).

[0130] The abbreviations used in this invention have the following meanings:

[0131] [Table 1] TIFF2024546155000045.tif250160TIFF2024546155000046.tif99162

[0132] [Example 1] Preparation of N-methyl-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (compound (1))

[0133] [ka] Step 1. Preparation of compound (1)-2 6-Chloro-5-nitropyridine-3-carboxylate ((1)-1) (3 g), tributyl(1-ethoxyvinyl)tin (5.8 g) and Pd(PPh3)2Cl2 (91.3 mg) were dissolved in acetonitrile (15 mL). The reaction mixture was purged with nitrogen and heated to 65° C. for 2 h. After completion, the reaction was quenched with 10% aqueous KF solution, filtered and washed with ethyl acetate. The filtrate was concentrated and purified by column chromatography (eluent: petroleum ether-ethyl acetate=20:1). The eluent was collected and the solvent was evaporated under reduced pressure to give a light purple liquid (1)-2 (3.1 g, 89.6% yield). MS-ESI m / z: 267.2 [M+H] + .

[0134] Step 2. Preparation of compound (1)-3 Compound (1)-2 (3.1 g) was dissolved in AcOH (30 mL) and 3M HCl (16 mL) was added. The reaction was carried out at room temperature for 1 h. After completion, the mixture was concentrated and the pH was adjusted to 8-9 using KOH and aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a brown liquid (1)-3 (3.05 g, 100% yield). MS-ESI m / z: 239.2 [M+H] + .

[0135] Step 3. Preparation of compound (1)-4 Compound (1)-3 (750 mg) was dissolved in ethanol (10 mL) and 10% Pd / C (75 mg) was added. The reaction mixture was stirred overnight at room temperature under hydrogen atmosphere. Upon completion, the mixture was filtered through diatomaceous earth, washed with ethanol, and concentrated to give a yellow solid (1)-4 (580 mg, 89% yield). MS-ESI m / z: 209.2 [M+H] + .

[0136] Step 4. Preparation of compound (1)-5 Compound (1)-4 (580 mg) and 3,3,3-trifluoropropionyl chloride (1.1 g) were dissolved in THF (15 mL) and reacted at 0° C. for 5 min. DIPEA (260 mg) was then added and the reaction was allowed to proceed at room temperature for 2 h. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by column chromatography (eluent: petroleum ether-ethyl acetate=9:1). The eluent was collected and the solvent was evaporated under reduced pressure to give a white solid (1)-5 (950 mg, 100% yield). MS-ESI m / z: 319.2 [M+H] + .

[0137] Step 5. Preparation of compound (1)-6 Compound (1)-5 (4.7 g) was dissolved in DMF (305 mL) and potassium carbonate (10.68 g) was added. The reaction mixture was heated to 60° C. for 1 h. After completion, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by column chromatography (eluent: dichloromethane-methanol=20:1). The eluent was collected and the solvent was evaporated under reduced pressure to give a light yellow solid (1)-6 (2.3 g, 52% yield). MS-ESI m / z: 301.2 [M+H] + .

[0138] Step 6. Preparation of compound (1)-7 Compound (1)-6 (100 mg) was dissolved in THF (3 mL) and LiAlH4 (25.3 mg) was added portionwise at 0°C. The reaction was carried out at 0°C for 1 h. Upon completion, the reaction was quenched with sodium sulfate decahydrate, filtered through diatomaceous earth, and the filter cake was washed with dichloromethane-methanol (10:1). The filtrate was concentrated and purified by preparative silica gel plate chromatography (eluent: dichloromethane-methanol = 20:1) to give a light yellow solid (1)-7 (50 mg, 58% yield). MS-ESI m / z: 259.2 [M+H] + .

[0139] Step 7. Preparation of compound (1)-8 Compound (1)-7 (50 mg) and DMF (1.5 mg) were dissolved in DCM (2 mL). Thionyl chloride (138 mg) was added at 0° C. and the reaction was carried out at room temperature for 0.5 h. After completion, the mixture was concentrated to give crude grey solid (1)-8 (70 mg), which was used directly in the next step. MS-ESI m / z: 277.2 [M+H] + .

[0140] Step 8. Preparation of compound (1) The crude product (1)-8, (1)-R (48 mg), KI (6 mg) and DIPEA (0.21 mL) were dissolved in acetonitrile (3 mL) and reacted at 75° C. for 20 min. After completion, the mixture was concentrated and purified by preparative HPLC to give a white solid (1) (2.4 mg, 2.8% yield). MS-ESI m / z: 461.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.39 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 2.9 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.42 - 7.37 (m, 1H), 3.72 (s, 2H), 2.86 - 2.70 (m, 5H), 2.62 - 2.54 (m, 4H), 2.53 - 2.50 (m, 6H).

[0141] [Example 2] Preparation of N-methyl-5-(4-((4-methyl-2-oxo-3-(trifluoromethyl)-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)picolinamide (compound (2))

[0142] [ka] Steps 1 to 7. Preparation of compound (2) Using 4-amino-5-bromopyridine-2-carboxylate ((2)-1) as the starting material, compound (2) was prepared according to a similar method to the synthesis route of compound (1). MS-ESI m / z: 461.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 11.00 (s, 1H), 9.12 (s, 1H), 8.18 (d, J = 2.9 Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 5.5 Hz, 1H), 7.41 (s, 1H), 7.23 (dd, J = 8.8, 2.9 Hz, 1H), 3.84 (s, 2H), 3.40 (t, J = 5.0 Hz, 4H), 3.04 (d, J = 5.1 Hz, 3H), 2.83 - 2.79 (m, 3H), 2.79 - 2.73 (m, 4H).

[0143] [Example 3] Preparation of 5-(3-(cyanomethyl)-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (3))

[0144] [ka] Step 1. Preparation of compound (3)-2 2-(Cyanomethyl)piperazin-1-yl tert-butyl carbonate ((3)-1) (760 mg) was dissolved in 1,4-dioxane (10 mL). Then, 5-bromopyridine-2-carboxylate (728.7 mg), Pd2(dba)3 (617 mg), RuPhos (629 mg) and cesium carbonate (3.3 g) were added. The reaction mixture was heated to 100° C. and reacted for 3 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: dichloromethane-methanol=20:1). The eluent was collected and the solvent was evaporated under reduced pressure to give a yellow oil (3)-2 (1.1 g, 90% yield). MS-ESI m / z: 361.2 [M+H] + .

[0145] Step 2. Preparation of compound (3)-3 Compound (3)-2 (1.1 g) was dissolved in methanol (10 mL) and aqueous methylamine (5 mL, 40% wt) was added. The reaction mixture was sealed and reacted at 90° C. for 1.5 h. After completion, the mixture was concentrated to give a yellow oil (3)-3 (920 mg, yield: 83%). MS-ESI m / z: 360.2 [M+H] + .

[0146] Step 3. Preparation of compound (3)-4 Compound (3)-3 (580 mg) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (4 mL) was added at 0° C. The reaction was carried out at room temperature. After completion, the reaction mixture was concentrated and the residue was diluted with water and dichloromethane. The aqueous phase was adjusted to about pH 10 with ammonia. The mixture was then extracted with dichloromethane and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a pale yellow oil (3)-4 (280 mg, 67% yield). MS-ESI m / z: 260.1 [M+H] + .

[0147] Step 4. Preparation of compound (3) Compound (1)-8 (20 mg) was dissolved in acetonitrile (2 mL). Compound (3)-4 (28.1 mg), DIPEA (28 mg) and potassium iodide (18 mg) were added. The reaction mixture was reacted at 80° C. for 1 h. After completion, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: dichloromethane-methanol=9:1). The eluent was collected and concentrated to obtain a pale yellow solid (3) (2.7 mg, 1% yield). MS-ESI m / z: 500.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 12.31 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.81 (s, 2H), 7.30 - 7.27 (m, 1H), 4.02 (d, J = 14.8 Hz, 1H), 3.82 (d, J = 14.8 Hz, 1H), 3.57 (dd, J = 12.4, 5.0 Hz, 1H), 3.47 (dd, J = 12.4, 3.3 Hz, 1H), 3.40 - 3.28 (m, 2H), 3.24 (m, 1H), 3.02 (d, J = 5.2 Hz, 3H), 2.99 - 2.94 (m, 1H), 2.90 (q, J = 3.2 Hz, 3H), 2.85 (m, 1H), 2.74 - 2.62 (m, 2H).

[0148] [Example 5] Preparation of 5-(3-(2-hydroxyethyl)-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (5))

[0149] [ka] Step 1. Preparation of compound (5)-2 Using methyl 2-(1-BOC-2-piperazinyl)acetate ((5)-1) as the starting material, compound (5)-2 was prepared according to a similar method to the synthesis route of compound (3)-2. MS-ESI m / z: 394.2 [M+H] + .

[0150] Step 2. Preparation of compound (5)-3 Lithium chloride monohydrate (491 mg) and sodium borohydride (615 mg) were dissolved in methanol-tetrahydrofuran (4 mL, v / v 2:1). This solution was slowly added to a solution of (5)-2 (400 mg) in methanol-tetrahydrofuran (8 mL, v / v 2:1) in an ice bath. The reaction was carried out in an ice bath for 1 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate=1:1) to obtain a yellow solid (5)-3 (70 mg, 19% yield). MS-ESI m / z: 366.2 [M+H] + .

[0151] Steps 3-5. Preparation of compound (5) Using (5)-3 as the starting material, compound (5) was prepared according to a similar method to the synthesis route of compound (3). MS-ESI m / z: 505.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 4.9 Hz, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 2.9 Hz, 2H), 5.20 (t, J = 5.8 Hz, 1H), 4.45 (d, J = 5.8 Hz, 2H), 3.81 (dd, J = 142.3, 14.7 Hz, 4H), 3.30 (s, 3H), 3.15 (d, J = 22.0 Hz, 3H), 2.88 - 2.64 (m, 4H), 2.59 (d, J = 4.5 Hz, 2H).

[0152] [Example 6] Preparation of 5-(3-(hydroxymethyl)-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (6))

[0153] [ka] Steps 1 to 5. Preparation of compound (6) Using methyl N-1-Boc-2-piperazine-carboxylate ((6)-1) as the starting material, compound (6) was prepared according to the same synthetic route as compound (5). MS-ESI m / z: 491.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.66 (s, 1H), 8.17 (d, J = 2.8 Hz, 1H), 8.12 - 8.05 (m, 1H), 7.65 (s, 1H), 7.34 (dd, J = 8.7, 2.9 Hz, 1H), 7.31 - 7.25 (m, 1H), 5.22 - 5.17 (m, 1H), 3.90 (d, J = 26.0 Hz, 1H), 3.62 - 3.55 (m, 1H), 3.52 - 3.44 (m, 2H), 3.16 - 3.11 (m, 1H), 3.09 - 3.03 (m, 1H), 2.90 - 2.81 (m, 2H), 2.80 - 2.75 (m, 2H), 2.68 - 2.61 (m, 3H), 2.56 - 2.51 (m, 3H), 2.37 -2.30 (m, 1H).

[0154] [Example 8] Preparation of 5-(3-(methoxymethyl)-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (8))

[0155] [ka] Steps 1-4. Preparation of compound (8) Using tert-butyl 2-(methoxymethyl)piperazine-1-carboxylate ((8)-1) as the starting material, compound (8) was prepared according to a similar method to the synthesis route of compound (3). MS-ESI m / z: 505.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H),8.59 (d, J = 1.8 Hz, 1H), 8.39 (t, J = 4.9 Hz, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.8, 2.9 Hz, 1H), 4.17 (d, J = 14.7 Hz, 1H), 3.69 - 3.58 (m, 2H), 3.50 (dd, J = 9.9, 5.4 Hz, 2H), 3.35 (s, 2H), 3.25 (s, 3H), 3.12 (dt, J = 12.8, 7.0 Hz, 2H), 2.78 (dd, J = 4.2, 2.8 Hz, 5H), 2.51 (s, 3H).

[0156] [Example 9] Preparation of N-methyl-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-(trifluoromethyl)piperazin-1-yl)picolinamide (compound (9))

[0157] [ka] Steps 1-4. Preparation of compound (9) Compound (9) was prepared according to the same synthetic route as compound (3) using tert-butyl 2-trifluoromethylpiperazine-1-carboxylate as the starting material. MS-ESI m / z: 529.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.39 (q, J = 4.8 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.39 - 7.34 (m, 1H), 4.18 (d, J = 15.2 Hz, 1H), 4.08 (d, J = 15.2 Hz, 1H), 3.98 - 3.92 (m, 1H), 3.90 - 3.83 (m, 1H), 3.63 - 3.52 (m, 2H), 3.26 - 3.12 (m, 2H), 3.03 (d, J = 10.0 Hz, 1H), 2.78 (t, J = 4.0 Hz, 6H).

[0158] [Example 10] Preparation of N-methyl-5-(2-methyl-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (compound (10))

[0159] [ka] Steps 1-4. Preparation of compound (10) Using tert-butyl 3-methylpiperazine-1-carboxylate ((10)-1) as the starting material, compound (10) was prepared according to a similar method to the synthesis route of compound (3). MS-ESI m / z: 475.2 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 12.79 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 5.2 Hz, 1H), 7.17 (dd, J = 8.8, 2.8 Hz, 1H), 4.10 (dd, J = 6.8, 3.2 Hz, 1H), 3.80 - 3.59 (m, 2H), 3.50 - 3.40 (m, 1H), 3.27 (td, J = 11.6, 3.2 Hz, 1H), 3.01 (d, J = 5.2 Hz, 3H), 2.98 - 2.93 (m, 1H), 2.91 (q, J = 3.2 Hz, 3H), 2.77 (dt, J = 10.8, 2.4 Hz, 1H), 2.55 (dd, J = 11.2, 3.6 Hz, 1H), 2.38 (td, J = 11.2, 3.6 Hz, 1H), 1.25 (d, J = 6.8 Hz, 3H).

[0160] [Example 11] Preparation of N-methyl-5-(3-methyl-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (compound (11))

[0161] [ka] Steps 1-4. Preparation of compound (11) Using N-1-Boc-2-methylpiperazine ((11)-1) as the starting material, compound (11) was prepared according to a similar method to the synthetic route of compound (3). MS-ESI m / z: 475.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.59 (s, 1H), 8.42 - 8.35 (m, 1H), 8.27 (d, J = 2.9 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.50-7.30 (m, 1H), 4.15 (d, J = 14.6 Hz, 1H), 3.72 (d, J = 11.7 Hz, 1H), 3.61 (d, J = 12.2 Hz, 1H), 3.45 (d, J = 14.6 Hz, 1H), 2.99 (t, J = 10.0 Hz, 1H), 2.80 - 2.75 (m, 7H), 2.62 (d, J = 6.2 Hz, 1H), 2.36 - 2.28 (m, 2H), 1.18 (d, J = 6.1 Hz, 3H).

[0162] [Example 12] Preparation of N-methyl-5-(8-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)picolinamide (compound (12))

[0163] [ka] Steps 1-4. Preparation of compound (12) Compound (12) was prepared according to a similar method to the synthesis route of compound (3) using tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate ((12)-1) as the starting material. MS-ESI m / z: 487.2 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 12.37 (s, 1H), 8.65 (s, 1H), 8.10 - 8.00 (m, 2H), 7.90 (s, 1H), 7.81 - 7.74 (m, 1H), 7.10 (dd, J = 8.8, 2.8 Hz, 1H), 3.78 (s, 2H), 3.50 - 3.43 (m, 2H), 3.42 - 3.33 (m, 2H), 3.20 (d, J = 10.8 Hz, 2H), 3.02 (d, J = 5.2 Hz, 3H), 2.93 - 2.84 (m, 3H), 2.18 - 2.03 (m, 2H), 1.92 - 1.81 (m, 2H).

[0164] [Example 13] Preparation of N-methyl-4-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide (compound (35))

[0165] [ka] Step 1. Preparation of compound (13) Compound (1)-8 (30 mg) and N-methyl-4-(piperazin-1-yl)benzenesulfonamide ((13)-1) (27 mg) were dissolved in anhydrous acetonitrile (3 mL). Then, KI (18 mg) and DIPEA (42 mg) were added sequentially, and the mixture was reacted at 90° C. for 30 min. The reaction was quenched, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified on a preparative silica gel plate to give a white solid (13) (15.5 mg, 28% yield). MS-ESI m / z: 496.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.58 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.11 (q, J = 5.3 Hz, 1H), 7.08 - 7.02 (m, 2H), 3.71 (s, 2H), 3.31-3.25(m, 4H), 2.87-2.67 (m, 3H), 2.55 (t, J = 5.1 Hz, 4H), 2.35 (d, J = 5.0 Hz, 3H).

[0166] [Example 14] Preparation of N-methyl-1'-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (compound (14))

[0167] [ka] Steps 1-3. Preparation of compound (14) Compound (14) was prepared according to the same method as steps 2 to 4 in the synthesis route of compound (3) using 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate ((14)-1) as the starting material. MS-ESI m / z: 458.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.74 - 8.64 (m, 2H), 8.57 (d, J = 1.9 Hz, 1H), 7.98 (s, 2H), 7.70 (s, 1H), 6.68 - 6.31 (m, 1H), 3.78 (s, 2H), 3.21 - 3.17 (m, 2H), 2.81 (d, J = 4.9 Hz, 3H), 2.77 (q, J = 3.5 Hz, 3H), 2.72 (t, J = 5.6 Hz, 2H), 2.59 - 2.53 (s, 2H).

[0168] [Example 15] Preparation of 4-methyl-7-((4-(3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)piperazin-1-yl)methyl)-3-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (compound (15))

[0169] [ka] Step 1. Preparation of compound (15)-1 Compound (1)-8 (450 mg) was dissolved in acetonitrile (6 mL), and 1-tert-butoxycarbonylpiperazine (606 mg), DIEA (630 mg) and KI (27 mg) were added. The reaction was carried out under nitrogen protection at 80° C. for 1 h. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate=2:1) ​​to obtain a white solid (15)-1 (350 mg, yield 50.4%). MS-ESI m / z: 427.2 [M+H] + .

[0170] Step 2. Preparation of compound (15)-2 Compound (15)-1 (350 mg) was dissolved in CHCl (1 mL) and trifluoroacetic acid (1 mL) was slowly added dropwise under ice bath. The mixture was stirred at room temperature for 1 h and then concentrated. The residue was diluted with water and the pH was adjusted to about 10 with ammonia. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude yellow oily product (15)-2 (230 mg), which was used directly in the next step. MS-ESI m / z: 327.1 [M+H] + .

[0171] Step 3. Preparation of compound (15) 6-Bromo-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one ((15)-R) (30 mg) was dissolved in NMP (1 mL) and (15)-2 (92.58 mg) and DIEA (54.95 mg) were added. The mixture was subjected to microwave irradiation at 150° C. for 1 h, then diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by preparative HPLC to give a white solid (15) (1.0 mg, 1.5% yield). MS-ESI m / z: 459.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.21(s, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.39 (s, 1H), 8.17 (s, 1H), 7.70 (d, J = 1.9 Hz, 1H), 6.94 (s, 1H), 4.29 (s, 2H), 3.74 - 3.57 (m, 2H), 3.17 (d, J = 5.2 Hz, 6H), 2.76 (d, J = 6.9, 3.3 Hz, 2H), 2.51 (s, 3H).

[0172] [Example 17] Preparation of 2-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-4-one (compound (17))

[0173] [ka] Step 1. Preparation of compound (17)-1 Methyl 2-bromo-5-methylthiazole-4-carboxylate (900 mg) was dissolved in carbon tetrachloride (10 mL), and N-bromosuccinimide (746 mg) and dibenzoyl peroxide (92.3 mg) were added. The reaction was carried out at 80° C. overnight. After the reaction was completed, the mixture was concentrated and the residue was purified by silica gel column chromatography (eluent: PE-EA=10:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain a light yellow solid (17)-1 (900 mg, yield: 74.9%). MS-ESI m / z: 315.9 [M+H] + .

[0174] Step 2. Preparation of compound (17)-2 Compound (17)-1 (900 mg) was dissolved in anhydrous tetrahydrofuran (10 mL), and benzylamine (520 mg) and potassium carbonate (671 mg) were added. The reaction was carried out at 80° C. for 4 hours. The mixture was then diluted with water, and the pH was adjusted to 10 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: PE-EA=1:1). The eluate was collected, and the solvent was evaporated under reduced pressure to obtain a light yellow solid (17)-2 (720 mg, yield: 74%). MS-ESI m / z: 340.9 [M+H] + .

[0175] Step 3. Preparation of compound (17)-3 Compound (17)-2 (720 mg) was dissolved in tetrahydrofuran (7 mL) and water (3.5 mL), and lithium hydroxide monohydrate (273 mg) was added. The reaction was carried out at room temperature for 4 hours. The mixture was then acidified with dilute hydrochloric acid and concentrated to obtain the crude colorless oily product (17)-3. MS-ESI m / z: 326.9 [M+H] + .

[0176] Step 4. Preparation of compound (17)-4 Compound (17)-3 was dissolved in N,N-dimethylformamide (8 mL), and EDCI (707 mg), HOBT (293 mg), DIPEA (658 mg), and DMAP (53 mg) were added. The reaction was carried out at 65° C. for 4 hours. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH=25:1). The eluate was collected, and the solvent was evaporated under reduced pressure to obtain a light yellow solid (17)-4 (200 mg, yield: 30%). MS-ESI m / z: 308.9 [M+H] + .

[0177] Steps 5-7. Preparation of compound (17)-7 Using (17)-4 as the starting material, compound (17)-7 was prepared according to a similar method to the synthesis route of compound (3). MS-ESI m / z: 555.1 [M+H] + .

[0178] Step 8. Preparation of compound (17) Compound (17)-7 (20 mg) was dissolved in methanesulfonic acid (1 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at 80° C. for 16 hours. After the reaction was completed, the mixture was concentrated. The residue was diluted with water and dichloromethane. The pH of the aqueous phase was adjusted to about 10 with ammonia. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH=10:1). The eluate was collected and concentrated to obtain a light yellow solid (17) (1.8 mg, 11% yield). MS-ESI m / z: 465.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.25 (s, 1H), 7.69 - 7.66 (m, 1H), 4.30 (s, 2H), 3.72 (s, 2H), 3.53 - 3.42 (m, 4H), 2.86 - 2.73 (m, 2H), 2.55 (d, J = 5.2 Hz, 4H).

[0179] [Example 18] Preparation of 4-methyl-7-((4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)piperazin-1-yl)methyl)-3-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (compound (18))

[0180] [ka] Step 1. Preparation of compound (18) Compound (18) was prepared according to a similar method to the synthesis route of compound (3) using 5-(piperazin-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2(3H)-one ((18)-1) as the starting material. MS-ESI m / z: 460.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 10.92 (s, 1H), 10.35 (s, 1H), 8.57 (s, 1H), 7.69 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 8.4 Hz, 1H), 3.69 (s, 2H), 3.52 - 3.38 (m, 4H), 2.84 - 2.70 (m, 3H), 2.55 - 2.52 (m, 4H).

[0181] [Example 19] Preparation of 4-methyl-3-(trifluoromethyl)-7-((4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (compound (19))

[0182] [ka] Step 1. Preparation of compound (19) 2-Chloro-5-trifluoromethylpyrimidine (10 mg) was dissolved in NMP (1 mL), and (15)-2 (19.67 mg) and potassium carbonate (15.14 mg) were added. The mixture was stirred at 80° C. for 2 h. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by preparative HPLC to obtain a white solid (19) (6.3 mg, 24.4% yield). MS-ESI m / z: 473.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.70 (d, J = 1.0 Hz, 2H), 8.58 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 3.86 (t, J = 5.2 Hz, 4H), 3.70 (s, 2H), 3.40-3.20 (m, 4H), 2.77 (q, J = 3.5 Hz, 3H).

[0183] [Example 20] Preparation of 6-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile (compound (20))

[0184] [ka] Step 1. Preparation of compound (20) Using 5-cyano-2-fluoropyridine as the starting material, compound (20) was prepared according to a similar method to the synthesis route of compound (19). MS-ESI m / z: 429.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.57 (d, J = 1.8 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 7.85 (dd, J = 9.1, 2.4 Hz, 1H), 7.68 (d, J = 1.9 Hz, 1H), 6.93 (d, J = 9.1 Hz, 1H), 3.79 - 3.55 (m, 6H), 2.77 (q, J = 3.5 Hz, 4H), 2.48 (s, 3H).

[0185] [Example 21] Preparation of 5-(3-cyano-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (21))

[0186] [ka] Step 1. Preparation of compound (21)-2 tert-Butyl 2-cyanopiperazine-1-carboxylate ((21)-1) (260 mg) was dissolved in 1,4-dioxane (5 mL) and methyl 5-bromopicolinate (169 mg), tris(dibenzylideneacetone)dipalladium (228 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (234 mg) and cesium carbonate (1.22 g) were added. The reaction was carried out at 100° C. for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE-EA=1:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain yellow oily product (21)-2 (300 mg, yield: 69%). MS-ESI m / z: 347.2 [M+H] + .

[0187] Step 2. Preparation of compound (21)-3 Compound (21)-2 (300 mg) was dissolved in methanol (4 mL) and an aqueous solution of methylamine (2 mL, 40% wt) was added. The reaction was carried out in a sealed tube at 50° C. for 1 h. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (eluent: DCM-MeOH=20:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain a yellow solid (21)-3 (150 mg, yield: 50%). MS-ESI m / z: 346.2 [M+H] + .

[0188] Step 3. Preparation of compound (21)-4 Compound (21)-3 (100 mg) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) was added at 0° C. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water and dichloromethane. The pH of the aqueous phase was adjusted to about 10 with ammonia. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude pale yellow oily product (21)-4, which was used directly in the next step. MS-ESI m / z: 246.2 [M+H] + .

[0189] Step 4. Preparation of compound (21) Compound (1)-8 (20 mg) was dissolved in acetonitrile (2 mL), and crude product (21)-4, DIPEA (28 mg) and potassium iodide (2.4 mg) were added. The reaction was carried out at 80° C. for 1 h. After the reaction was completed, the reaction solution was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol=9:1). The eluate was collected and concentrated to obtain a white solid (21) (1.0 mg, yield: 3%). MS-ESI m / z: 486.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.61 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.33 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.48 (dd, J = 8.8, 2.8 Hz, 1H), 4.32 (s, 1H), 4.16 (d, J = 12.8 Hz, 2H), 3.90 (d, J = 14.0 Hz, 1H), 3.82 (d, J = 14.0 Hz, 1H), 3.11 (dd, J = 12.8, 3.2 Hz, 2H), 2.89 - 2.83 (m, 2H), 2.78 (q, J = 4.0 Hz, 6H).

[0190] [Example 23] Preparation of 5-(3-methyl-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (compound (23))

[0191] [ka] Steps 1-4. Preparation of compound (23) Using methyl 5-bromopicolinate as the starting material, compound (23) was prepared according to a similar method to the synthesis route of compound (3). MS-ESI m / z: 461.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.57 (s, 1H), 8.29 - 8.24 (m, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.77 - 7.61 (m, 2H), 7.41 - 7.33 (m, 1H), 7.29 (s, 1H), 3.67 - 3.53 (m, 2H), 3.21 - 3.10 (m, 5H), 2.84 - 2.78 (m, 1H), 2.78 - 2.72 (m, 3H), 2.67 - 2.60 (m, 1H), 1.24 - 1.21 (m, 3H).

[0192] [Example 24] Preparation of N-methyl-5-(4-(1-(8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)piperazin-1-yl)picolinamide (compound (24))

[0193] [ka] Step 1. Preparation of compound (24)-1 Compound (1)-7 (1 g) was dissolved in ethyl acetate (20 mL), followed by the addition of activated manganese dioxide (5.05 g). The reaction was carried out at 50° C. for 3 hours. After the reaction was completed, the solid was filtered off and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol=20:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain a light yellow solid (24)-1 (550 mg, 55% yield). MS-ESI m / z: 257.1 [M+H] + .

[0194] Step 2. Preparation of compound (24)-2 Compound (24)-1 (550 mg) was dissolved in anhydrous tetrahydrofuran (11 mL) and a solution of methylmagnesium bromide (5.4 mL, 1M in THF) was added dropwise at 0° C. The reaction was carried out at 25° C. for 1 h. After the reaction was completed, the reaction was quenched with a saturated aqueous solution of ammonium chloride and the pH was adjusted to approximately 7 with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol=20:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain a yellow solid (24)-2 (558 mg, 95% yield). MS-ESI m / z: 273.1 [M+H] + .

[0195] Step 3. Preparation of compound (24)-3 Compound (24)-2 (558 mg) was dissolved in thionyl chloride (10 mL) and the reaction was carried out at 25° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated to dryness to obtain a yellow solid (24)-3 (590 mg). MS-ESI m / z: 291.0 [M+H] + .

[0196] Step 4: Preparation of compound (24) Compound (24)-3 (568.4 mg) was dissolved in acetonitrile (20 mL), and (1)-R (500.0 mg), DIPEA (1.14 mL) and potassium iodide (57.1 mg) were added. The reaction was carried out at 80° C. for 16 hours. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol=20:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain a light yellow solid (24) (340.0 mg, 42% yield). MS-ESI m / z: 475.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.44 - 8.35 (m, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.8, 2.8 Hz, 1H), 3.80 - 3.67 (m, 1H), 3.34 - 3.27 (m, 4H), 2.82 - 2.68 (m, 5H), 2.69 - 2.56 (m, 2H), 2.48 - 2.43 (m, 3H), 1.38 (d, J = 6.8 Hz, 3H).

[0197] [Examples 90 and 91] Preparation of (R)-N-methyl-5-(4-(1-(8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)piperazin-1-yl)picolinamide (compound (90)) and (S)-N-methyl-5-(4-(1-(8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)piperazin-1-yl)picolinamide (compound (91))

[0198] [ka] Compound (24) (340 mg) was separated by chiral HPLC to give two stereoisomeric compounds, compound (90) and compound (91).

[0199] [Example 25] Preparation of 5-(4-(cyano(8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (25))

[0200] [ka] Step 1. Preparation of compound (25) Compound (24)-1 (25 mg) was dissolved in tetrahydrofuran (1 mL), and trimethylsilyl cyanide (11.6 mg) and zinc iodide (1.6 mg) were added. The mixture was purged with nitrogen three times and then stirred at 0° C. for 5 min. Triethylamine (9.9 mg) and a methanol solution (2 mL) of (1)-R (23.6 mg) were added dropwise, and the reaction was carried out at 50° C. for 16 h. After the reaction was completed, the reaction solution was quenched with a saturated aqueous solution of potassium carbonate and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol=15:1). The eluate was collected and concentrated to obtain a white solid (25) (1.2 mg, 2.5% yield). MS-ESI m / z: 486.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.43 (q, J = 4.8 Hz, 1H), 8.29 (d, J = 3.2 Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 8.8, 3.2 Hz, 1H), 5.82 (s, 1H), 3.58 - 3.47 (m, 4H), 2.81 - 2.70 (m, 5H), 2.61 - 2.54 (m, 2H), 2.52 - 2.51 (m, 3H).

[0201] [Example 26] Preparation of N-methyl-6-(3-methyl-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide (compound (26))

[0202] [ka] Step 1 Preparation of compound (26)-1 Methyl 6-chloropyridazine-3-carboxylate (200 mg) and tert-butyl 2-methylpiperazine-1-carboxylate (243.7 mg) were dissolved in dimethyl sulfoxide (4 mL), followed by the addition of potassium carbonate (480.5 mg). The reaction was carried out at 100° C. for 1 h. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate=5:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain a white solid (26)-1 (200.6 mg, 51% yield). MS-ESI m / z: 337.2 [M+H] + .

[0203] Steps 2-4. Preparation of compound (26) Using (26)-1 as the starting material, compound (26) was prepared according to a similar method to steps 2 to 4 in the synthetic route of compound (3). MS-ESI m / z: 476.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 12.53 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.80 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 9.6 Hz, 1H), 4.23 - 4.12 (m, 2H), 4.02 (d, J = 12.8 Hz, 1H), 3.48 (d, J = 14.8 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.22 (dd, J = 13.2, 8.8 Hz, 1H), 3.03 (d, J = 5.2 Hz, 3H), 2.92 - 2.85 (m, 3H), 2.82 (dt, J = 11.6, 3.6 Hz, 1H), 2.77 - 2.67 (m, 1H), 2.39 (ddd, J = 11.6, 9.6, 3.2 Hz, 1H), 1.24 (d, J = 6.0 Hz, 3H).

[0204] [Example 28] Preparation of N-methyl-5-(3-methyl-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyrimidine-2-carboxamide (compound (28))

[0205] [ka] Steps 1-4. Preparation of compound (28) Compound (28) was prepared according to the same synthetic route as compound (3) using methyl 5-bromopyrimidine-2-carboxylate and tert-butyl 2-methylpiperazine-1-carboxylate as starting materials. MS-ESI m / z: 476.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.52 - 8.47 (m, 3H), 7.67 (d, J = 2.0 Hz, 1H), 4.10 (d, J = 14.8 Hz, 1H), 3.75 (d, J = 12.0 Hz, 1H), 3.64 (d, J = 8.8 Hz, 1H), 3.42 (d, J = 14.8 Hz, 1H), 3.06 - 2.95 (m, 1H), 2.81 (dd, J = 12.4, 8.8 Hz, 1H), 2.81 - 2.68 (m,6H), 2.66 - 2.54 (m, 1H), 2.34 - 2.23 (m, 1H), 1.13 (d, J = 6.0 Hz, 3H).

[0206] [Example 29] Preparation of 5-(4-((7,8-dimethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (29))

[0207] [ka] Steps 1-3. Preparation of compound (29)-3 Using methyl 6-chloro-5-nitropyridine-3-carboxylate as the starting material, compound (29)-3 was prepared according to a similar method to steps 1 to 3 in the synthetic route of compound (1). MS-ESI m / z: 195.1 [M+H] + .

[0208] Step 4. Preparation of compound (29)-4 Compound (29)-3 (400 mg) and 2-(diethylphosphoryl)propanoic acid (432.9 mg) were dissolved in DMF (10 mL), followed by the addition of EDCI (790 mg), DMAP (503.3 mg) and triethylamine (625.3 mg). The reaction was carried out at 60° C. for 16 h. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate=10:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain a light yellow solid (29)-4 (323.3 mg, 41% yield). MS-ESI m / z: 387.1 [M+H] + .

[0209] Step 5. Preparation of compound (29)-5 Compound (29)-4 (323.3 mg) was dissolved in tetrahydrofuran (160 mL) and sodium hydride (341.6 mg, 60% wt) was added. The reaction was carried out at room temperature for 8 hours. After the reaction was completed, the mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol=20:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain a white solid (29)-5 (76 mg, 39% yield). MS-ESI m / z: 233.1 [M+H] + .

[0210] Steps 6-8. Preparation of compound (29) Using (29)-5 as the starting material, compound (29) was prepared according to a similar method to steps 6 to 8 in the synthesis route of compound (1). MS-ESI m / z: 407.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.47 - 8.35 (m, 2H), 8.26 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.8, 2.8 Hz, 1H), 3.64 (s, 2H), 3.33 (t, J = 5.2 Hz, 4H), 2.77 (d, J = 4.8 Hz, 3H), 2.57 - 2.53 (m, 4H), 2.49 (d, J = 1.2 Hz, 3H), 2.13 (d, J = 1.2 Hz, 3H).

[0211] [Example 51] Preparation of (R)-N-methyl-5-(3-methyl-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (compound (51))

[0212] [ka] Steps 1-4. Preparation of compound (51) Using (R)-1-N-Boc-2-methylpiperazine ((51)-1) as the starting material, compound (51) was prepared according to a similar method to the synthesis route of compound (3). MS-ESI m / z: 475.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.56 (s, 1H), 8.47-8.27 (m, 1H), 8.25 (d, J = 2.9 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.69 (s, 1H), 7.43 - 7.34 (m, 1H), 4.12 (d, J = 14.6 Hz, 1H), 3.70 (d, J = 12.0 Hz, 1H), 3.59 (d, J = 12.2 Hz, 2H), 3.06 - 2.88 (m, 2H), 2.84-2.64 (m, 7H), 2.61 (s, 1H), 2.40-2.20 (m, 1H), 1.16 (d, J = 6.1 Hz, 3H).

[0213] [Example 52] Preparation of (S)-N-methyl-5-(3-methyl-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (compound (52))

[0214] [ka] Steps 1-4. Preparation of compound (52) Using (S)-1-N-Boc-2-methylpiperazine ((52)-1) as the starting material, compound (52) was prepared according to a similar method to the synthesis route of compound (3). MS-ESI m / z: 475.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.56 (s, 1H), 8.47-8.27 (m, 1H), 8.25 (d, J = 2.9 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.69 (s, 1H), 7.43 - 7.34 (m, 1H), 4.12 (d, J = 14.6 Hz, 1H), 3.70 (d, J = 12.0 Hz, 1H), 3.59 (d, J = 12.2 Hz, 2H), 3.06 - 2.88 (m, 2H), 2.84-2.64 (m, 7H), 2.61 (s, 1H), 2.40-2.20 (m, 1H), 1.16 (d, J = 6.1 Hz, 3H).

[0215] [Example 53] Preparation of (S)-N-methyl-5-(2-methyl-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (compound (53))

[0216] [ka] Steps 1-4. Preparation of compound (53) Using (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine ((53)-1) as the starting material, compound (53) was prepared according to a similar method to the synthesis route of compound (3). MS-ESI m / z: 475.2 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 12.84 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.17 (dd, J = 8.8, 2.8 Hz, 1H), 4.15 - 4.06 (m, 1H), 3.80 - 3.63 (m, 2H), 3.48 - 3.40 (m, 1H), 3.31 - 3.20 (m, 1H), 3.01 (d, J = 5.2 Hz, 3H), 2.97 - 2.93 (m, 1H), 2.93 - 2.89 (m, 3H), 2.81 - 2.72 (m, 1H), 2.55 (dd, J = 11.2, 3.6 Hz, 1H), 2.44 - 2.32 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H).

[0217] [Example 54] Preparation of (R)-N-methyl-5-(2-methyl-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (compound (54))

[0218] [ka] Steps 1-4. Preparation of compound (54) Using (R)-4-N-tert-butyloxycarbonyl-2-methylpiperazine ((54)-1) as the starting material, compound (54) was prepared according to a similar method to the synthesis route of compound (3). MS-ESI m / z: 475.2 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 12.84 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.17 (dd, J = 8.8, 2.8 Hz, 1H), 4.15 - 4.06 (m, 1H), 3.80 - 3.63 (m, 2H), 3.48 - 3.40 (m, 1H), 3.31 - 3.20 (m, 1H), 3.01 (d, J = 5.2 Hz, 3H), 2.97 - 2.93 (m, 1H), 2.93 - 2.89 (m, 3H), 2.81 - 2.72 (m, 1H), 2.55 (dd, J = 11.2, 3.6 Hz, 1H), 2.44 - 2.32 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H).

[0219] [Examples 55 and 56] Preparation of N-methyl-8-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-6,7,8,9-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-3-carboxamide and N-methyl-7-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-6,7,8,9-tetrahydropyrido[4',3':4,5]imidazo[1,2-a]pyrazine-3-carboxamide [ka] Step 1. Preparation of compound (55)-1 Methyl 4,5-diaminopyridine-carboxylate (900 mg) and benzyloxycarbonyl-glycine (1.24 g) were dissolved in dichloromethane (20 mL) and EDCI (1.67 g), HOBt (1.98 g) and TEA (1.45 g) were added. The reaction was carried out at 40° C. for 3 hours. The reaction solution was poured into water and filtered to give a crude white solid (800 mg). MS-ESI m / z: 359.35 [M+H] + The crude product (500 mg) was dissolved in acetic acid (5 mL) and reacted at 120° C. for 2 h. After cooling, the mixture was concentrated and the residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol=10:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain a light yellow oily product (55)-1 (320 mg, yield: 67%). MS-ESI m / z: 341.34 [M+H] + .

[0220] Step 2. Preparation of compound (55)-2 Compound (55)-1 (300 mg) was dissolved in N,N-dimethylformamide (6 mL), and cesium carbonate (574 mg) and 1,2-dibromoethane (497 mg) were added. The reaction was carried out at 80° C. for 5 hours. After the reaction was completed, water was added to dilute the mixture, which was then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol=20:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain white solid (55)-2 (220 mg, yield: 68%). MS-ESI m / z: 367.38 [M+H] + .

[0221] Step 3. Preparation of compound (55)-3 Compound (55)-2 (220 mg) was dissolved in methanol (5 mL) and an aqueous solution of methylamine (2 mL, 40% wt) was added. The reaction was carried out in a sealed vessel at 90° C. for 1 h. After the reaction was completed, the mixture was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol=10:1). The eluate was collected and the solvent was evaporated under reduced pressure to obtain a light yellow oily product (55)-3 (180 mg, 82% yield). MS-ESI m / z: 366.39 [M+H] + .

[0222] Step 4. Preparation of compound (55)-4 Compound (55)-3 (180 mg) was dissolved in methanol (5 mL) and 10% palladium on carbon (20 mg) was added. The reaction was carried out under hydrogen atmosphere at room temperature overnight. After the reaction was completed, the mixture was filtered through diatomaceous earth and concentrated to give a white solid (55)-4 (90 mg), which was used directly in the next step. MS-ESI m / z: 232.26 [M+H] + .

[0223] Step 5. Preparation of compounds (55) and (56) Compound (55)-4 (90 mg) was dissolved in acetonitrile (5 mL), and (1)-8 (60 mg), DIPEA (130 mg) and potassium iodide (54 mg) were added. The reaction was carried out at 80° C. for 1 h. After the reaction was completed, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol=10:1). The eluate was collected and concentrated to obtain white solid (55) (18 mg) and white solid (56) (16 mg) (yield 33%). (55): MS-ESI m / z: 472.44 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.89 (s, 1H), 8.83-8.63 (m, 1H), 8.63 (d, J = 1.9 Hz, 1H), 8.17 (s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 4.35 (t, J = 5.4 Hz, 2H), 4.01 (d, J = 10.0 Hz, 4H), 3.10 (t, J = 5.4 Hz, 2H), 2.84 (d, J = 4.8 Hz, 3H), 2.87-2.67 (m, 3H). (56): MS-ESI m / z: 472.44 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.87 (d, J = 1.0 Hz, 1H), 8.87-8.67 (m, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 1.0 Hz, 1H), 7.74 (d, J = 1.9 Hz, 1H), 4.31 (t, J = 5.5 Hz, 2H), 4.00 (d, J = 3.3 Hz, 4H), 3.14 - 3.06 (m, 2H), 2.85 (d, J = 4.9 Hz, 3H), 2.88-2.78 (m, 3H).

[0224] [Example 57] Preparation of N-methyl-5-(3-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)picolinamide (compound (57))

[0225] [ka] Steps 1-4. Preparation of compound (57) Using methyl 5-bromopicolinate as the starting material, compound (57) was prepared according to the same synthetic route as compound (3). MS-ESI m / z: 487.2 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.34 (d, J = 4.9 Hz, 1H), 8.16 (d, J = 2.8 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 6.0 Hz, 1H), 3.56 (s, 2H), 2.99 (d, J = 5.2 Hz, 1H), 2.82 - 2.71 (m, 6H), 2.56 - 2.54 (m, 1H), 2.42 - 2.39 (m, 2H), 2.14 - 2.04 (m, 4H), 1.98 - 1.89 (m, 2H).

[0226] [Example 69] Preparation of N,6'-dimethyl-1'-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (compound (69))

[0227] [ka] Steps 1-3: Preparation of compound (69) Compound (69) was prepared according to the same synthetic route as compound (14) using 1'-(tert-butyl) 6-methyl 6'-methyl-3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate ((69)-1) as the starting material. MS-ESI m / z: 472.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.74 - 8.65 (m, 2H), 8.55-8.61 (m, 1H), 8.04 - 7.96 (m, 2H), 7.70-7.76 (m, 1H), 6.40 - 6.35 (m, 1H), 3.95 - 3.90 (m, 2H), 3.19 (s, 1H), 3.01 - 2.91 (m, 2H), 2.84 - 2.80 (m, 3H), 2.73-2.79 (m, 3H), 2.28 (s, 1H), 1.94-2.05 (m, 1H), 1.13 (m, 3H).

[0228] [Example 70] Preparation of N-methyl-5-(2-methyl-1-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)picolinamide (compound (70))

[0229] [ka] Step 1: Preparation of compound (70)-1 Compound (69)-2 (49 mg) was dissolved in anhydrous methanol (3 mL) and 10% wt wet palladium on carbon was added. The reaction was carried out under hydrogen atmosphere at room temperature for 1 h. After the reaction was completed, the mixture was filtered through diatomaceous earth and concentrated to give crude product (70)-1 (50 mg), which was used directly in the next step. MS-ESI m / z: 334.4 [M+H] + .

[0230] Step 2-3: Preparation of compound (70) Using (70)-1) as the starting material, compound (70) was prepared according to a similar method to steps 2-3 in the synthetic route of compound (69). MS-ESI m / z: 474.50 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.69 (d, J = 5.5 Hz, 1H), 8.56-8.62 (m, 1H), 8.49-8.55 (m, 1H), 7.92-7.99 (m, 1H), 7.86 (m, 1H), 7.74 - 7.68 (m, 1H), 4.22 (d, J = 14.5 Hz, 1H), 3.84 (d, J = 14.9 Hz, 1H), 3.72 (d, J = 14.7 Hz, 1H), 3.18 (m, 1H), 2.98-3.1 (m, 1H), 2.85 - 2.73 (m, 6H), 2.62-2.67(m, 1H), 1.99 (m, 1H), 1.79 - 1.59 (m, 3H), 1.17 (m, 3H).

[0231] [Example 71] Preparation of N-methyl-5-(1-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)picolinamide (compound (71))

[0232] [ka] Steps 1-3: Preparation of compound (71) Using ((14)-2) as the starting material, compound (71) was prepared according to a similar method to the synthetic route of compound (70). MS-ESI m / z: 460.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 8.74 - 8.67 (m, 1H), 8.57 (d, J = 1.8 Hz, 1H), 8.52 (d, J = 2.2 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.89 - 7.82 (m, 1H), 7.67 (s, 1H), 3.68 (s, 2H), 3.19 - 3.10 (m, 1H), 2.94 (d, J = 10.6 Hz, 2H), 2.84 - 2.69 (m, 6H), 2.22 - 2.10 (m, 2H), 1.86 - 1.66 (m, 4H).

[0233] [Example 72] Preparation of 5-(2-cyano-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (72))

[0234] [ka] Steps 1-4: Preparation of compound (72) Compound (72) was prepared according to a similar method to the synthesis route of compound (21) using tert-butyl 3-cyanopiperazine-1-carboxylate ((72)-1) as the starting material. MS-ESI m / z: 486.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.55 (d, J = 4.9 Hz, 1H), 8.42 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.60 (d, J = 8.9 Hz, 1H), 5.48 (s, 1H), 3.81 (d, J = 14.3 Hz, 2H), 3.15 (d, J = 11.8 Hz, 1H), 3.05 - 2.95 (m, 2H), 2.83 - 2.74 (m, 6H), 2.69 (s, 1H), 2.58 - 2.53 (m, 1H), 2.38 - 2.30 (m, 1H), 2.21 - 2.12 (m, 1H).

[0235] [Example 73] Preparation of 5-(2-(cyanomethyl)-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (73))

[0236] [ka] Steps 1-4: Preparation of compound (73) Compound (73) was prepared according to a similar method to the synthesis route of compound (72) using tert-butyl 3-(cyanomethyl)piperazine-1-carboxylate ((73)-1) as the starting material. MS-ESI m / z: 500.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.61 (s, 1H), 8.42 (d, J = 4.9 Hz, 1H), 8.31 (d, J = 2.9 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.73 (s, 1H), 7.49 - 7.40 (m, 1H), 4.63 (s, 1H), 3.78 (s, 1H), 3.67 (d, J = 11.0 Hz, 2H), 3.21 - 3.10 (m, 1H), 3.05 - 2.64 (m, 9H), 2.43 - 2.24 (m, 3H).

[0237] [Example 74] Preparation of 5-(2-(methoxymethyl)-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (74))

[0238] [ka] Steps 1-4: Preparation of compound (74) Compound (74) was prepared according to a similar method to the synthesis route of compound (73) using tert-butyl 3-(methoxymethyl)piperazine-1-carboxylate ((74)-1) as the starting material. MS-ESI m / z: 505.3 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 12.98 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 2.9 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.86 (s, 1H), 7.78 (q, J = 5.0 Hz, 1H), 7.18 (dd, J = 8.9, 2.9 Hz, 1H), 4.08 - 4.00 (m, 1H), 3.87 (t, J = 9.0 Hz, 1H), 3.80 - 3.67 (m, 2H), 3.50 (d, J = 12.4 Hz, 1H), 3.35 (dd, J = 8.9, 4.1 Hz, 1H), 3.27 (s, 3H), 3.20 (dd, J = 12.0, 3.5 Hz, 1H), 3.10 (d, J = 11.5 Hz, 1H), 3.00 (d, J = 5.1 Hz, 3H), 2.90 (d, J = 3.3 Hz, 3H), 2.43 (dd, J = 11.3, 3.5 Hz, 1H), 2.39-2.32 (m, J = 11.4, 3.4 Hz, 1H), 2.10-2.02 (m, 1H).

[0239] [Example 75] Preparation of 5-(2-(hydroxymethyl)-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (75))

[0240] [ka] Steps 1-4: Preparation of compound (75) Compound (75) was prepared according to a similar method to the synthesis route of compound (21) using tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate ((75)-1) as the starting material. MS-ESI m / z: 491.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.56 (d, J = 10.2 Hz, 2H), 8.26 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.66 (s, 1H), 7.51 (dd, J = 8.7, 2.9 Hz, 1H), 6.27 - 6.01 (m, 1H), 4.14 - 3.94 (m, 2H), 3.65 (s, 2H), 3.45 (s, 3H), 3.12 (d, J = 7.8 Hz, 1H), 2.96 - 2.61 (m, 7H), 2.18 - 1.93 (m, 2H).

[0241] [Example 76] Preparation of N-methyl-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-(trifluoromethyl)piperazin-1-yl)picolinamide (compound (76))

[0242] [ka] Steps 1-4: Preparation of compound (76) Compound (76) was prepared according to a similar method to the synthesis route of compound (21) using tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate ((76)-1) as the starting material. MS-ESI m / z: 529.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.43 (q, J = 4.8 Hz, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.8, 2.8 Hz, 1H), 5.25 - 5.07 (m, 1H), 3.81 - 3.68 (m, 2H), 3.63 (d, J = 12.4 Hz, 1H), 3.35 - 3.26 (m, 2H), 3.15 (d, J = 12.4 Hz, 1H), 2.96 (d, J = 11.2 Hz, 1H), 2.84 - 2.68 (m, 5H), 2.47 - 2.44 (m, 1H), 2.31 - 2.20 (m, 1H).

[0243] [Example 77] Preparation of 5-(3,3-dimethyl-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (77))

[0244] [ka] Steps 1-4: Preparation of compound (77) Compound (77) was prepared according to a similar method to the synthesis route of compound (21) using tert-butyl 2,2-dimethylpiperazine-1-carboxylate ((77)-1) as the starting material. MS-ESI m / z: 489.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.59 (s, 1H), 8.36 (q, J = 4.8 Hz, 1H), 8.26 (d, J = 2.9 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.39 (d, J = 5.9 Hz, 1H), 3.70 (s, 2H), 3.31 - 3.24 (m, 2H), 3.21 (s, 2H), 2.81 - 2.73 (m, 6H), 2.54 - 2.50 (m, 2H), 1.17 (s, 6H).

[0245] [Example 78] Preparation of N-methyl-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-4,7-diazaspiro[2.5]octan-7-yl)picolinamide (compound (78))

[0246] [ka] Steps 1-4: Preparation of compound (78) Compound (78) was prepared according to a similar method to the synthesis route of compound (21) using tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate ((78)-1) as the starting material. MS-ESI m / z: 487.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.40 (q, J = 4.9 Hz, 1H), 8.27 (d, J = 2.9 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 8.9, 2.9 Hz, 1H), 4.04 (s, 2H), 3.45 (s, 3H), 3.26 (s, 2H), 2.91 (t, J = 5.3 Hz, 2H), 2.78 (dd, J = 8.2, 4.2 Hz, 5H), 0.77 - 0.59 (m, 4H).

[0247] [Example 79] Preparation of N-methyl-5-(1-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazine-2-carboxamide (compound (79))

[0248] [ka] Steps 1-3: Preparation of compound (79) Compound (79) was prepared according to the same synthetic route as compound (14) using methyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazine-2-carboxylate ((79)-1) as the starting material. MS-ESI m / z: 459.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 9.07 (d, J = 1.5 Hz, 1H), 8.89 (d, J = 1.5 Hz, 1H), 8.81 (d, J = 5.0 Hz, 1H), 8.59 (d, J = 1.9 Hz, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.00 (s, 1H), 3.81 (s, 2H), 3.26 (s, 2H), 2.82 (d, J = 4.8 Hz, 3H), 2.78 (q, J = 3.5 Hz, 3H), 2.72 (d, J = 5.4 Hz, 2H), 2.66 (s, 2H).

[0249] [Examples 80 and 81] Preparation of N,3'-dimethyl-1'-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (compound (80)) and N,5'-dimethyl-1'-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (compound (81))

[0250] [ka] Step 1. Preparation of compound (80)-2 Compound ((80)-1) (250 mg) containing two double bond isomers, (6-(methoxycarbonyl)pyridin-3-yl)boronic acid (157.2 mg), Pd(PPh3)4 (83 mg), Na2CO3 (153 mg) and LiCl (61 mg) were added sequentially to a round-bottom flask. Tetrahydrofuran (5 mL) and water (1 mL) were added and the reaction was carried out at 80° C. under nitrogen atmosphere for 2 hours. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried, filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate=1:1). The eluate was collected and concentrated to obtain a light yellow oily product (100 mg, yield: 41%). MS-ESI m / z: 333.40 [M+H] + .

[0251] Steps 2 to 4. Preparation of Compound (80) and Compound (81) Using ((80)-2) containing two double bond isomers as the starting material, compound (80) and compound (81) were prepared according to a similar method to the synthetic route of compound (14). Compound (80):MS-ESI m / z: 472.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.71 (s, 1H), 8.66 (d, J = 9.5 Hz, 1H), 8.60 (s, 1H), 7.97 (s, 2H), 7.74 (s, 1H), 6.21 (s, 1H), 3.83 (d, J = 14.3 Hz, 1H), 3.72 (d, J = 14.2 Hz, 1H), 3.61 (s, 2H), 3.14 (s, 2H), 2.99 (s, 1H), 2.81 (d, J = 4.9 Hz, 3H), 2.78 (d, J = 3.4 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H). Compound (81):MS-ESI m / z: 472.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.46 (s, 2H), 7.98 (s, 1H), 7.77 (d, J = 49.1 Hz, 1H), 3.77 (s, 2H), 3.61 (m, 2H), 3.14 (m, J = 4.6 Hz, 2H), 3.01 (m, 2H), 2.81 (d, J = 4.4 Hz, 3H), 2.78 (m, 3H), 1.23 - 1.16 (s, 3H).

[0252] [Example 82] Preparation of N-methyl-1'-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (compound (82))

[0253] [ka] Steps 1-3: Preparation of compound (82) Compound (82) was prepared according to the same synthetic route as compound (14) using 1'-(tert-butyl) 5-methyl 3',6'-dihydro-[2,4'-bipyridine]-1',5(2'H)-dicarboxylate ((82)-1) as the starting material. MS-ESI m / z: 458.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.66 - 8.51 (m, 2H), 8.13 (dd, J = 8.4, 2.3 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.82 (s, 1H), 3.79 (s, 2H), 3.37 (s, 2H), 3.21 (s, 2H), 2.80 - 2.75 (m, 3H), 2.51 (s, 3H), 2.73 - 2.61 (m, 2H).

[0254] [Example 83] Preparation of 5-methyl-2-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-4-one (compound (83))

[0255] [ka] Steps 1-7: Preparation of compound (83) Using methyl 2-bromo-5-methylthiazole-4-carboxylate ((83)-1) as the starting material, compound (83) was prepared according to a similar method to steps 1-7 in the synthetic route of compound (17). MS-ESI m / z: 479.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.58 (s, 1H), 7.69 (s, 1H), 4.38 (s, 2H), 3.72 (s, 2H), 3.49 - 3.44 (m, 4H), 2.99 (s, 3H), 2.77 (q, J = 3.5 Hz, 3H), 2.56 (t, J = 5.1 Hz, 4H).

[0256] [Example 84] Preparation of 4-methyl-7-((4-(2-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)piperazin-1-yl)methyl)-3-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (compound (84))

[0257] [ka] Step 1. Preparation of compound (84) Compound (84) was prepared according to a similar method to step 3 in the synthesis route of compound (15) using 6-bromo-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one ((84)-1) as the starting material. MS-ESI m / z: 473.4 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 11.5 (s, 1H) 8.66 (d, J = 14.4 Hz, 1H), 7.72 (s, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.63 (s, 1H), 4.31 (s, 2H), 3.73 (d, J = 11.5 Hz, 4H), 3.12 (d, J = 26.9 Hz, 2H), 2.86 (d, J = 50.8 Hz, 2H), 2.64 (s, 2H), 2.33 (d, J = 40.0 Hz, 3H), 2.06 (s, 3H).

[0258] [Example 85] Preparation of 5-(4-((7-cyano-8-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (85))

[0259] [ka] Step 1. Preparation of compound (85)-2 ((85)-1) (50 mg) and 2-cyanacetyl chloride (53 mg) were dissolved in THF (2 mL) and reacted at 0° C. for 5 min. DIPEA (66 mg) was added, the mixture was allowed to warm to room temperature, and the reaction was continued for 2 h. Upon completion, the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The redidue was purified by column chromatography [eluent: petroleum ether-ethyl acetate=9:1], the eluate was collected, and the solvent was evaporated under reduced pressure to give a white solid ((85)-2) (40 mg, yield: 64%). MS-ESI m / z: 244.1 [M+H] + .

[0260] Steps 2-4. Preparation of compound (85) Using methyl 6-acetyl-5-aminonicotinate ((85)-2) as the starting material, compound (85) was prepared according to a similar method to steps 6-8 in the synthetic route of compound (1). MS-ESI m / z: 418.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 12.58 (s, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 5.3 Hz, 1H), 7.21 (dd, J = 8.8, 2.9 Hz, 1H), 3.79 (s, 2H), 3.35 (t, J = 5.1 Hz, 4H), 3.01 (d, J = 5.1 Hz, 3H), 2.93 (s, 3H), 2.69 (t, J = 5.0 Hz, 4H).

[0261] [Example 86] Preparation of (S)-5-(2-cyano-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (compound (86))

[0262] [ka] Steps 1-4. Preparation of compound (86) Compound (86) was prepared according to the same synthetic route as compound (21) using tert-butyl (S)-3-cyanopiperazine-1-carboxylate ((86)-1) as the starting material. MS-ESI m / z: 486.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.63 (d, J = 1.9 Hz, 1H), 8.56 (q, J = 4.8 Hz, 1H), 8.43 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.60 (dd, J = 8.9, 2.9 Hz, 1H), 5.42 (s, 1H), 3.85 - 3.70 (m, 3H), 3.16 (d, J = 11.9 Hz, 1H), 3.01 (d, J = 11.0 Hz, 3H), 2.82 - 2.76 (m, 5H), 2.56 (dd, J = 12.1, 3.3 Hz, 1H), 2.40 - 2.32 (m, 1H).

[0263] [Example 87] Preparation of (R)-N-methyl-5-(3-methyl-4-((4-methyl-2-oxo-3-(trifluoromethyl)-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)picolinamide ((Compound (87))

[0264] [ka] Step 1. Preparation of compound (87) Using ((2)-7) and (51)-4 as starting materials, compound (87) was prepared according to a similar method to step 7 in the synthetic route of compound (2). MS-ESI m / z: 475.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 9.12 (s, 1H), 8.39 (d, J = 4.9 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.44 - 7.36 (m, 2H), 4.09 (d, J = 15.3 Hz, 1H), 3.73 (d, J = 10.4 Hz, 1H), 3.66 (d, J = 12.4 Hz, 1H), 3.58 (d, J = 15.3 Hz, 1H), 3.02 (t, J = 9.6Hz, 1H), 2.86 - 2.84 (m, 2H), 2.82 - 2.75 (m, 4H), 2.74 - 2.70 (m, 3H), 2.70 - 2.65 (m, 1H), 1.16 (d, J = 6.1 Hz, 3H).

[0265] [Example 88] Preparation of (R)-N-methyl-5-(2-methyl-4-((4-methyl-2-oxo-3-(trifluoromethyl)-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)picolinamide ((Compound (88))

[0266] [ka] Step 1. Preparation of compound (88) Using ((2)-7) and (54)-4 as starting materials, compound (88) was prepared according to a similar method to step 7 in the synthetic route of compound (2). MS-ESI m / z: 475.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.87 - 11.74 (m, 1H), 9.12 (s, 1H), 8.38 (d, J = 4.9 Hz, 1H), 8.23 ​​(d, J = 2.7 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.36 (dd, J = 8.9, 2.7 Hz, 1H), 4.25 (s, 1H), 3.79 (d, J = 15.4 Hz, 1H), 3.64 (dd, J = 13.6, 8.0 Hz, 2H), 3.15 - 3.07 (m, 1H), 2.99 (d, J = 11.2 Hz, 1H), 2.79 (d, J = 4.8 Hz, 4H), 2.72 (d, J = 2.6 Hz, 3H), 2.42 (dd, J = 11.2, 3.3 Hz, 1H), 2.37 - 2.26 (m, 1H), 1.20 (d, J = 6.5 Hz, 3H).

[0267] [Example 89] Preparation of N-methyl-1'-((4-methyl-2-oxo-3-(trifluoromethyl)-1,2-dihydro-1,6-naphthyridin-7-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide ((Compound (89))

[0268] [ka] Step 1. Preparation of compound (89) Using ((2)-7) and (14)-3 as starting materials, compound (89) was prepared according to a similar method to step 7 in the synthetic route of compound (2). MS-ESI m / z: 458.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 9.13 (s, 1H), 8.77 - 8.68 (m, 1H), 8.06 - 7.95 (m, 2H), 7.40 (s, 1H), 6.47 (s, 1H), 6.04 (d, J = 6.3 Hz, 1H), 3.82 (s, 2H), 3.57 (s, 1H), 3.25 (d, J = 2.8 Hz, 2H), 2.82 (d, J = 4.9 Hz, 3H), 2.77 - 2.74 (m, 1H), 2.74 - 2.70 (m, 3H), 2.65 - 2.60 (m, 2H).

[0269] [Example 92] Preparation of (S)-5-(3-cyano-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide ((Compound (92))

[0270] [ka] Steps 1-4. Preparation of compound (92) Compound (92) was prepared according to a similar method to the synthesis route of compound (21) using tert-butyl (S)-2-cyanopiperazine-1-carboxylate ((92)-1) as the starting material. MS-ESI m / z: 486.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.33 (d, J = 2.9 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 8.8, 2.9 Hz, 1H), 4.33 (s, 1H), 4.23 - 4.11 (m, 2H), 3.95 - 3.80 (m, 3H), 3.19 - 3.08 (m, 2H), 2.94 - 2.81 (m, 3H), 2.81 - 2.74 (m, 4H).

[0271] [Example 93] Preparation of 6-fluoro-N-methyl-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide ((Compound (93))

[0272] [ka] Steps 1-3. Preparation of compound (93) Compound (93) was prepared according to a similar method to steps 2-4 in the synthesis route of compound (21) using tert-butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate as the starting material. MS-ESI m / z: 479.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.58 (s, 1H), 8.42 (d, J = 4.9 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.69 (s, 1H), 7.64 - 7.52 (m, 1H), 3.73- 7.68 (m, 3H), 3.19 (s, 4H), 2.77 (t, J = 4.0 Hz, 6H), 2.60 (s, 3H).

[0273] [Example 94] Preparation of 5-(4-((4-fluoro-3-methyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide ((compound (94))

[0274] [ka] Step 1. Preparation of compound ((94)-2) Ethyl n-propionate (3.82 g) and ultra-dry tetrahydrofuran (150 mL) were added to a three-neck flask, and the mixture was cooled to −78° C. under nitrogen protection. Lithium diisopropylamide (2M, 28.12 mL) was added dropwise to the reaction, followed by slow addition of a solution of ((94)-1) in tetrahydrofuran (2.24 g, 40 mL). The reaction mixture was then allowed to warm slowly to room temperature and react overnight. The reaction was quenched with a saturated aqueous solution of ammonium chloride, filtered, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography [eluent: petroleum ether-ethyl acetate (20:1 to 10:1)]. A yellow solid ((94)-2) was obtained ((94)-2) (540 mg, yield: 22.5%). MS-ESI m / z: 256.2 [M+H] + .

[0275] Step 2. Preparation of compound ((94)-3) To the autoclave, ((94)-2) (520 mg), Pd(dppf)Cl2 (149 mg), triethylamine (618 mg), N,N-dimethylformamide (10 mL) and methanol (5 mL) were added sequentially. The mixture was heated to 100°C under carbon monoxide atmosphere (2 MPa) and stirred overnight. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [eluent: petroleum ether-ethyl acetate (10:1-3:1)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain a yellow solid ((94)-3) (270 mg, yield: 56.4%). MS-ESI m / z: 236.3 [M+H] + .

[0276] Step 3. Preparation of compound (94)-4 To a reaction flask were added ((94)-3) (270 mg) and tetrahydrofuran (6 mL). Under ice bath, a solution of LiBH4 in tetrahydrofuran (1.73 mL, 2 M in THF) was added dropwise, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution and extracted with dichloromethane. The solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [eluent: dichloromethane-methanol (100:1 to 10:1)]. The eluate was collected, and the solvent was evaporated under reduced pressure to obtain a yellow solid ((94)-4) (150 mg, yield: 63.1%). MS-ESI m / z: 208.4 [M+H] + .

[0277] Step 4. Preparation of compound ((94)-5) To a reaction flask was added ((94)-4) (150 mg) and thionyl chloride (5 mL), and the mixture was heated to 70° C. and stirred for 1 h. After the reaction was completed, the solvent was evaporated under reduced pressure to give a pale yellow solid ((94)-5) (165 mg, yield: 100%). MS-ESI m / z: 226.3 [M+H] + .

[0278] Step 5. Preparation of compound (94) To a reaction flask were added ((94)-5) (165 mg), (1)-R (240 mg), potassium carbonate (250 mg) and acetonitrile (10 mL), and the mixture was heated to 80° C. and stirred overnight. After the reaction was completed, the solvent was evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography [eluent: dichloromethane-methanol (100:1 to 10:1)] and preparative HPLC to give a white solid (94) (60 mg, yield: 20.3%). MS-ESI m / z: 410.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 11.91 (s, 1H), 8.42-8.37 (m, 1H), 8.27 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.41-7.36 (m, 2H), 7.26 (dd, J = 9.6, 6.8 Hz, 1H), 3.62 (s, 2H), 3.38-3.33 (m, 4H), 2.78 (d, J = 4.8 Hz, 3H), 2.56-2.53 (m, 4H), 2.02 (d, J = 2.4 Hz, 3H).

[0279] [Example 95] Preparation of N-(methyl-d3)-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide ((compound (95))

[0280] [ka] Step 1. Preparation of compound (95) Compound (95) was prepared according to a similar method to step 8 in the synthesis route of compound (1) using N-(methyl-d3)-5-(piperazin-1-yl)picolinamide ((95)-1) as the starting material. MS-ESI m / z: 464.2 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.36 (s, 1H), 8.27 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.8, 2.9 Hz, 1H), 3.72 (s, 2H), 3.38 - 3.26 (m, 6H), 2.83 - 2.72 (m, 2H), 2.57- 2.52 (m, 3H).

[0281] [Example 96] Preparation of N-(2-hydroxyethyl)-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide ((Compound (96))

[0282] [ka] Step 1. Preparation of compound (96)-2 Compound ((96)-1) (100 mg) was dissolved in DMF (2 mL), followed by the addition of ethanolamine (38 mg), HATU (237 mg) and diisopropylethylamine (201 mg). The reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, dichloromethane and water were added for phase separation. The aqueous phase was extracted three times with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified on a preparative chromatographic plate [eluent: petroleum ether-ethyl acetate=1:2] to obtain a white solid ((96)-2) (100 mg, yield: 88%). MS-ESI m / z: 351.2 [M+H] + .

[0283] Steps 2-3. Preparation of compound (96) Compound (96) was prepared according to a similar method to steps 3-4 in the synthesis route of compound (21) using 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid ((96)-2) as the starting material. MS-ESI m / z: 491.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.34 (t, J = 6.0 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1H), 4.78 (t, J = 5.2 Hz, 1H), 3.72 (s, 2H), 3.56 - 3.45 (m, 2H), 3.39 - 3.26 (m, 6H), 2.85 - 2.74 (m, 3H), 2.58 - 2.55 (m, 3H).

[0284] [Example 97] Preparation of 5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2,2,2-trifluoroethyl)picolinamide ((compound (97))

[0285] [ka] Step 1. Preparation of compound (97)-1 Compound (96)-1 (400 mg) was dissolved in dichloromethane (4 mL). DMF (20 mg) and oxalyl chloride (330 mg) were added dropwise under ice bath, and the reaction was allowed to proceed at room temperature for 20 min. The mixture was then concentrated to give the crude product (97)-1, which was used directly in the next step.

[0286] Step 2. Preparation of compound (97)-2 The crude product ((97)-1) (200 mg) was dissolved in acetonitrile (4 mL) and DIPEA (238 mg) was added. Trifluoroethylamine (121.6 mg) was slowly added dropwise under ice-water bath, and the mixture was stirred at room temperature for 20 min. The reaction was quenched with water, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography [eluent: dichloromethane-methanol=15:1] to give a white solid ((97)-2) (30 mg). MS-ESI m / z: 389.2 [M+H]+.

[0287] Steps 3-4. Preparation of compound (97) Using (97)-2 as the starting material, compound (97) was prepared according to a similar method to steps 2-3 in the synthetic route of compound (96). MS-ESI m / z: 529.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 8.92 (t, J = 6.8 Hz, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 3.2 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.72 - 7.67 (m, 1H), 7.43 (dd, J = 8.8, 3.2 Hz, 1H), 4.16 - 3.96 (m, 2H), 3.73 (s, 2H), 3.44 - 3.36 (m, 3H), 3.31 (s, 1H), 2.83 - 2.74 (m, 4H), 2.63 - 2.55 (m, 3H).

[0288] [Example 98] Preparation of N-ethyl-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide ((Compound (98))

[0289] [ka] Steps 1-3. Preparation of compound (98) Using ((97)-1) and EtNH2 as starting materials, compound (98) was prepared according to a similar method to steps 2 to 4 in the synthetic route of compound (97). MS-ESI m / z: 475.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.42 (t, J = 6.0 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.70 (s, 1H), 7.40 (dd, J = 9.0, 2.8 Hz, 1H), 3.72 (s, 2H), 3.31 - 3.2 (m, 8H), 2.87 - 2.73 (m, 2H), 2.60- 2.55 (m, 3H), 1.25 - 1.08 (m, 3H).

[0290] [Example 99] Preparation of N-cyclopropyl-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide ((Compound (99))

[0291] [ka] Steps 1-3. Preparation of compound (99) Using ((97)-1) as the starting material, compound (99) was prepared according to a similar method to steps 2-4 in the synthetic route of compound (97). MS-ESI m / z: 487.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.42 (t, J = 6.0 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.70 (s, 1H), 7.40 (dd, J = 9.0, 2.8 Hz, 1H), 3.72 (s, 1H), 3.31 - 3.2 (m, 9H), 2.87 - 2.73 (m, 1H), 2.60- 2.55 (m, 3H), 1.25 - 1.08 (m, 4H).

[0292] [Example 100] Preparation of 5-(4-((7-(difluoromethyl)-8-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide ((Compound (100))

[0293] [ka] Step 1. Preparation of compound ((100)-1) Compound ((29)-3) (1 g) was dissolved in dichloromethane (40 mL) and diethyl (2-chloro-2-oxoethyl)phosphonate (3.3 g) was added at 0° C. Then, triethylamine (2.61 g) was slowly added dropwise and the mixture was allowed to warm to room temperature. After the reaction was completed, it was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography [eluent: EA / PE=(10%-40%)]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain a dark yellow liquid ((100)-1) (860 mg, 44.8% yield). MS-ESI m / z: 373.2 [M+H] + .

[0294] Step 2. Preparation of compound ((100)-2) Compound ((100)-1) (410 mg) and potassium carbonate (760.9 mg) were dissolved in N,N-dimethylacetamide (15 mL) and reacted at 80° C. for 1 hour. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography [eluent: DCM / MeOH=20:1]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain a white solid ((100)-2) (150 mg, yield: 62.5%). MS-ESI m / z: 219.2 [M+H] + .

[0295] Step 3. Preparation of compound ((100)-3) Compound ((100)-2) (50 mg), sodium trifluoromethanesulfinate (63.3 mg) and Mn(OAc)3·2H2O (184.3 mg) were dissolved in acetic acid (2 mL) and reacted at 50°C for 15 min. After the reaction was completed, the reaction solution was concentrated, diluted with water and extracted twice with ethyl acetate. The organic phase was concentrated and purified by silica gel plate chromatography [eluent: PE / EA=1:1] to obtain a brown solid ((100)-3) (16 mg, yield 26.2%). MS-ESI m / z: 269.2 [M+H] + .

[0296] Steps 4-6. Preparation of compound (100) Using ((100)-3) as the starting material, compound (100) was prepared according to a similar method to steps 6-8 in the synthesis route of compound (1). MS-ESI m / z: 443.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.55 (s, 1H), 8.42 - 8.37 (m, 1H), 8.27 (d, J = 2.9 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.69 (s, 1H), 7.47 - 7.33 (m, 1H), 3.75 - 3.65 (m, 3H), 2.81- 2.75 (m, 4H), 2.72- 2.65 (m, 4H), 2.61 - 2.54 (m, 3H), 2.49 - 2.45 (m, 3H).

[0297] [Example 101] Preparation of 5-(4-((4-fluoro-8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide ((Compound (101))

[0298] [ka] Step 1. Preparation of compound ((101)-2) Compound ((101)-1) (200 mg) was suspended in dichloromethane (6 mL). Under ice bath condition, boron trifluoride etherate (990 mg) and xenon difluoride (233.6 mg) were added and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to about 7. The mixture was extracted with dichloromethane, and the organic phases were combined, dried and concentrated. The residue was purified by silica gel column chromatography [eluent: DCM / MeOH=20:1]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain a pale yellow solid ((101)-2) (90 mg, yield: 42%). MS-ESI m / z: 305.2 [M+H] +

[0299] Steps 2-4. Preparation of compound (101) Using ((100)-2) as the starting material, compound (101) was prepared according to a similar method to steps 6-8 in the synthesis route of compound (1). MS-ESI m / z: 479.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.60 - 12.04 (m, 1H), 8.41 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.9, 2.9 Hz, 1H), 3.71 (s, 2H), 3.37 (s, 4H), 2.78 (d, J = 4.9 Hz, 3H), 2.69 - 2.60 (m, 7H).

[0300] [Example 102] Preparation of 5-(4-((4-fluoro-2-oxo-3-(trifluoromethyl)-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide ((Compound (102))

[0301] [ka] Step 1. Preparation of compound ((102)-2) A three-neck flask was charged with ethyl acetate (3.52 g) and ultra-dry tetrahydrofuran (150 mL) and cooled to -78°C under nitrogen protection. Lithium diisopropylamide (2M, 30.0 mL) was added dropwise to the reaction, followed by slow dropwise addition of a solution of ((102)-1) in tetrahydrofuran (2.39 g, 40 mL). The mixture was allowed to warm slowly to room temperature and react overnight. The reaction was quenched with a saturated aqueous solution of ammonium chloride, filtered, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure to give the crude product, which was purified by column chromatography [eluent: petroleum ether-ethyl acetate=20:1] to give a yellow solid ((102)-2) (570 mg, yield: 23.7%). MS-ESI m / z: 242.2 [M+H] + .

[0302] Step 2. Preparation of compound ((102)-3) To a reaction flask were added ((102)-2) (492 mg), sodium trifluoromethanesulfinate (955 mg) and acetic acid (10 mL), followed by slow addition of Mn(OAc)3·2H2O (2.19 g). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the mixture was extracted with ethyl acetate. The organic phases were combined and dried to give the crude product, which was purified by silica gel column chromatography [eluent: petroleum ether-ethyl acetate=20:1]. The eluate was collected and the solvent was evaporated under reduced pressure to give a white solid ((102)-3) (140 mg, yield: 22.2%). MS-ESI m / z: 310.0 [M+H] + .

[0303] Step 3. Preparation of compound ((102)-4) To a reaction flask were added ((102)-3) (119 mg, 0.39 mmol), bis(triphenylphosphine)palladium(II) dichloride (27 mg), tert-butyldimethyl[(tributylstannyl)methoxy]silane (335 mg) and 1,4-dioxane (5 mL). The mixture was heated to 100° C. under nitrogen protection and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature and 10% aqueous KF solution was slowly added dropwise to quench the reaction. The precipitated solid was filtered and the filtrate was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [eluent: petroleum ether-ethyl acetate=30:1]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain a yellow solid ((102)-4) (90 mg, yield: 62.5%). MS-ESI m / z: 376.1 [M+H] + .

[0304] Step 4. Preparation of compound ((102)-5) A reaction flask was charged with ((102)-4) (90 mg), tetrahydrofuran (3 mL), and an aqueous solution of hydrochloric acid (2 M, 1 mL) and stirred at room temperature for 1 h. After the reaction was completed, saturated sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography [eluent: dichloromethane-methanol = 100:1]. The eluate was collected and the solvent was evaporated under reduced pressure to obtain a pale yellow solid ((102)-5) (51 mg, yield: 81.5%). MS-ESI m / z: 262.1 [M+H] + .

[0305] Steps 5-6. Preparation of compound (102) Using ((102)-5) as the starting material, compound (102) was prepared according to a similar method to steps 7-8 in the synthesis route of compound (1). MS-ESI m / z: 464.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ: 12.75 (s, 1H), 8.50-8.45 (m, 1H), 8.34 (d, J = 3.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.50 (dd, J = 11.6, 6.0 Hz, 1H), 4.53 (s, 1H), 4.13-4.02 (m, 2H), 3.43-3.31 (m, 4H), 3.25-3.16 (m, 3H), 2.80 (d, J = 5.2Hz, 3H).

[0306] [Example 103] Preparation of 5-(4-((8-fluoro-7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide ((Compound (103))

[0307] [ka] Steps 1-5. Preparation of compound (103) Compound (103) was prepared according to the same method as steps 1 and 3-6 in the synthesis route of compound (102) using 5-chloro-2-(trifluoromethyl)pyridin-3-amine ((103)-1) as the starting material. MS-ESI m / z: 411.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ: 12.02 (s, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.41 (dd, J = 12.0, 6.4 Hz, 1H), 3.69 (s, 2H), 3.44-3.34 (m, 4H), 2.79 (d, J = 4.8 Hz, 3H), 2.58-2.56 (m, 4H), 2.07 (d, J = 2.8, 3H).

[0308] [Example 104] Preparation of (R)-5-(4-((7-(difluoromethyl)-8-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)-N-methylpicolinamide ((Compound (104))

[0309] [ka] Step 1. Preparation of compound (104) Using ((100)-5) as the starting material, compound (104) was prepared according to a similar method to the synthesis route of compound (1). MS-ESI m / z: 457.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.36 (d, J = 5.0 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.43 - 7.34 (m, 1H), 4.13 (d, J = 14.5 Hz, 1H), 3.70 (d, J = 12.0 Hz, 1H), 3.59 (d, J = 12.3 Hz, 1H), 3.43 (d, J = 14.5 Hz, 2H), 3.06 - 2.87 (m, 2H), 2.78 (d, J = 4.9 Hz, 3H), 2.71 (s, 3H), 2.69 - 2.56 (m, 3H), 1.17 (d, J = 6.1 Hz, 3H).

[0310] [Example 105] Preparation of (R)-5-(4-((7-(difluoromethyl)-8-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)-N-methylpicolinamide ((Compound (105))

[0311] [ka] Step 1. Preparation of compound (105) Using ((100)-5) as the starting material, compound (105) was prepared according to a similar method to step 8 in the synthesis route of compound (1). MS-ESI m / z: 457.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.37 - 8.35 (m, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 8.9, 2.9 Hz, 1H), 4.22 (d, J = 7.6 Hz, 1H), 3.75 (d, J = 14.4 Hz, 1H), 3.66 - 3.54 (m, 2H), 3.20 - 3.04 (m, 2H), 2.94 (d, J = 10.7 Hz, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.72 (d, J = 2.5 Hz, 3H), 2.40- 2.35 (m, 2H), 2.30 - 2.20 (m, 1H), 1.14 (d, J = 6.5 Hz, 3H).

[0312] [Example 106] Preparation of 1'-((7-(difluoromethyl)-8-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide ((Compound (106))

[0313] [ka] Step 1. Preparation of compound (106) Using ((100)-5) as the starting material, compound (106) was prepared according to a similar method to step 8 in the synthesis route of compound (1). MS-ESI m / z: 440.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.70 - 8.67 (m, 2H), 8.56 (d, J = 1.9 Hz, 1H), 7.98 (dd, J = 3.4, 1.5 Hz, 2H), 7.70 (d, J = 1.9 Hz, 1H), 7.23 (m, 1H), 6.42 (s, 1H), 3.77 (s, 2H), 3.32-3.29 (m, 2H), 3.17 (dd, J = 5.8, 3.0 Hz, 2H), 2.81 (d, J = 4.9 Hz, 3H), 2.71 (s, 3H), 2.58-2.54 (m, 2H).

[0314] [Example 107] Preparation of (R)-5-(4-((7,8-dimethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)-N-methylpicolinamide (compound (107))

[0315] [ka] Step 1: Preparation of compound (107) Using (29)-7 and (51)-4 as starting materials, compound (107) was prepared according to a similar method to step 8 in the synthetic route of compound (29). MS-ESI m / z: 421.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.38 (q, J = 4.8 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.8, 2.8 Hz, 1H), 4.10 (d, J = 14.4 Hz, 1H), 3.70 (d, J = 12.0 Hz, 1H), 3.59 (d, J = 12.0 Hz, 1H), 3.41 - 3.38 (m, 2H), 3.02 - 2.91 (m, 1H), 2.84 - 2.69 (m, 4H), 2.64 - 2.55 (m, 1H), 2.52 - 2.51 (m, 3H), 2.34 - 2.24 (m, 1H), 2.13 (s, 3H), 1.19 (d, J = 6.0 Hz, 3H).

[0316] [Example 108] Preparation of (S)-5-(4-((7,8-dimethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)-N-methylpicolinamide (compound (108))

[0317] [ka] Step 1: Preparation of compound (108) Using (29)-7 and (52)-4 as starting materials, compound (108) was prepared according to a similar method to step 8 in the synthetic route of compound (29). MS-ESI m / z: 421.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.38 (q, J = 4.8 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.8, 2.8 Hz, 1H), 4.10 (d, J = 14.4 Hz, 1H), 3.70 (d, J = 12.0 Hz, 1H), 3.59 (d, J = 12.0 Hz, 1H), 3.41 - 3.38 (m, 2H), 3.02 - 2.91 (m, 1H), 2.84 - 2.69 (m, 4H), 2.64 - 2.55 (m, 1H), 2.52 - 2.51 (m, 3H), 2.34 - 2.24 (m, 1H), 2.13 (s, 3H), 1.19 (d, J = 6.0 Hz, 3H).

[0318] Biological assays Experimental example 1: PARP enzyme activity assay and capture assay 1. PARP Enzyme Activity Assay Experimental Materials: PARP1 assay kit, specifically 384-well chemiluminescence assay kit (catalog number: 80551), was purchased from BPS Bioscience, USA.

[0319] Experimental principle: PARP can catalyze the transfer of ADP-ribose residues from NAD+ to target substrates, thereby modifying proteins by ribosylation. This experiment measures PARP1 enzymatic activity by detecting poly(ADP-ribosylation) of histones by PARP1.

[0320] Preparation of reagents and test compounds: The 10x assay buffer included in the kit was diluted 1x with distilled water. Test compounds (10mM stock concentration) were diluted to 10μM in DMSO solution and then serially diluted in a 1:3 ratio. The serially diluted compounds were further diluted 10x with 1x assay buffer.

[0321] Experimental method: The procedure was performed according to the kit instructions: 1. The 5x histone mixture was diluted 1x with PBS and 25μL was added to each well of a 384-well plate and incubated at 4°C overnight. 2. After incubation, 100 μL of PBST (0.05% Tween 20) was added to each well for washing, which was repeated three times. Then, 100 μL of blocking solution was added to each well and incubated at room temperature for 90 minutes. 3. After incubation, the wells were washed 3 times with PBST, then 1.25 μL of 10x assay buffer, 1.25 μL of 10x PARP assay mix, 2.5 μL of activated DNA (5x) and 7.5 μL of distilled water were added to each well. 4. 2.5 μL of diluted test compound was then added to each well. Positive and negative controls received 1× assay buffer containing the same concentration of DMSO. 5. Then, 10 μL of 2.5 ng / μL PARP1 enzyme was added to the test compound and positive control groups, while 10 μL of 1× assay buffer was added to the negative control group, and the mixtures were incubated at room temperature for 60 minutes. 6. Streptavidin-HRP was diluted 1:50 in blocking solution. After incubation, the plate was washed 3 times with PBST and 25 μL of diluted streptavidin-HRP solution was added to each well and incubated at room temperature for 30 minutes. 7. After incubation, the plate was washed 3 times with PBST and 50 μL of equal volumes of Substrate A and Substrate B were added. Luminescence signals were immediately read on a Synergy HTX multimode reader. 8. Data analysis was performed using GraphPad Prism 8.0 software. Inhibition %=100×(mean luminescence signal of positive control group−luminescence signal of compound) / (mean luminescence signal of positive control group−mean luminescence signal of negative control group). IC 50Values ​​were obtained by plotting the log of compound concentration versus percentage inhibition.

[0322] Test results: The enzyme inhibitory effects of the compounds on PARP1 are shown in Table 1.

[0323] [Table 2]

[0324] 2. PARP1 / PARP2 Capture Assay Materials and Reagents:

[0325] [Table 3]

[0326] Buffer preparation: 10 mM potassium phosphate (pH = 7.9), 50 mM sodium chloride, 1 mM ethylenediaminetetraacetic acid, 0.05% polyethylene glycol dodecyl ether, 1 mM dithiothreitol.

[0327] Testing Method: 1. A 4-fold enzyme reaction mixture containing PARP1, PARP2 and GST-Tb antibodies was prepared with buffer, and 4 μL of the enzyme reaction mixture was added to a 384-well plate. 2. 4x PARP1 and PARP2 probe reaction mix was prepared with buffer and 4 μL of probe reaction mix was added to a 384-well plate. 3. A gradient series of diluted compounds was prepared and 4 μL of diluted compounds was added to a 384-well plate and incubated at room temperature for 45 minutes. 4. After incubation, 4 μL of the 4x NAD reaction mixture was added to the 384-well plate and incubated at room temperature for 10 minutes. 5. After incubation, the plate was read using a plate reader. 6. Data analysis: The percentage of inhibition was calculated as follows: Inhibition (%)=(compound group readings-blank group readings) / (vehicle control group readings-blank group readings).

[0328] Test results: The inhibitory effects of the compounds on PARP1 and PARP2 capture are shown in Tables 2-1 and 2-2, respectively.

[0329] [Table 4]

[0330] [Table 5]

[0331] Experimental Conclusion: The example compounds in this application exhibit significant inhibitory effects on PARP1 enzyme activity. In capture assays for PARP1 and PARP2, the example compounds show clear selectivity for inhibiting PARP1 function over PARP2.

[0332] Experimental example 2: Cell proliferation assay Experimental materials: MDA-MB-436 or UWB1.289 cell lines were purchased from Cobioer Biosciences Co. Ltd. (Nanjing, China). STR identification results were complete agreement, and mycoplasma test was negative. MDA-MB-436 cells were cultured in DMEM complete medium containing 10% fetal bovine serum, 1% penicillin-streptomycin, 1% insulin and 16 μg / mL glutathione, and UWB1.289 cells were cultured in RMPI1640 complete medium containing 10% fetal bovine serum and 1% penicillin-streptomycin.

[0333] Testing Method: 1. MDA-MB-436 or UWB1.289 cells were cultured in the aforementioned medium (culture conditions: 37°C, 5.0% CO2 in air) until they reached logarithmic growth phase. The cells were then digested with trypsin containing 0.25% EDTA, centrifuged at 1000 rpm, and the supernatant was discarded. Cell culture medium was added and the cell suspension was diluted to 2 x 10 after counting. 4 135 μL of the cell suspension was taken per well and cultured in a 96-well cell culture plate for 16 hours (culture conditions: 37° C., 5.0% CO2 in air). 2. Test compounds stored at a concentration of 10 mM were diluted 2.5-fold with DMSO, then serially diluted with a 1:3 gradient (9 gradients). The gradient-diluted samples were further diluted 40-fold with serum-free medium, and 15 μL of each was added to a 96-well cell culture plate. The positive control group received serum-free medium containing the same concentration of DMSO, and the negative control group received medium without cells. The cells were then cultured for an additional 7 days. 3. After the incubation period, the cell culture plates were placed at room temperature for 30 minutes. Then, 100 μL of CellCounting-Lite 2.0 reagent (Vazyme, #DD1101) was added to each well, mixed thoroughly, and incubated in the dark at room temperature for 10 minutes. The luminescence signal was read using a Synergy HTX multimode reader. 4. Data analysis was performed using GraphPad Prism 8.0 software. The inhibition rate (%) was calculated as 100 × (mean luminescence signal of the positive control group - luminescence signal of the compound) / (mean luminescence signal of the positive control group - mean luminescence signal of the negative control group). IC 50 Values ​​were obtained by plotting the log of compound concentration versus percentage inhibition.

[0334] Test results: The inhibitory activity of the compounds against the proliferation of UWB1.289 ovarian cancer cells is shown in Table 3.

[0335] [Table 6]

[0336] The inhibitory activity of the compounds against the proliferation of MDA-MB-436 breast cancer cells is shown in Table 4.

[0337] [Table 7]

[0338] Experimental Conclusion: The compounds in the examples of this application exhibit strong inhibitory activity against the proliferation of UWB1.289 ovarian cancer cells and MDA-MB-436 breast cancer cells.

[0339] Experimental Example 3: Liver microsomal metabolism assay Materials: Mixed CD1 mouse liver microsomal enzyme proteins were purchased from Xenotech (#M1000), and NADPH was purchased from Abmole (#M9076).

[0340] Testing Method: 1. 210 μL of phosphate buffer was added to the liver microsomal enzyme reaction system, followed by 12.5 μL of 20 mg / mL liver microsomal enzyme. Then, 25 μL of 10 mM NADPH was added to the system, mixed thoroughly, and incubated in a 37°C water bath for 10 minutes with shaking. 2. Test compounds stored at a concentration of 10 mM were diluted to 100 μM with DMSO. 2.5 μL of diluted test compound was then added to the reaction system, mixed thoroughly, and incubated in a 37° C. water bath with shaking. 3. At 0.5, 5, 10, 20, 30 and 60 minutes, 25 μL of the enzyme reaction mixture was taken and added to 125 μL of cold acetonitrile containing dexamethasone as an internal standard. The mixture was centrifuged at 4000 g for 20 minutes, and the supernatant was mixed with an equal volume of distilled water. The mixed sample was then subjected to quantitative analysis by liquid chromatography-mass spectrometry. 4. Calculation of in vitro drug metabolic half-life and drug clearance rate: t1 / 2 =-0.693 / k. (k: slope of the linear regression of the natural logarithm of the percentage of drug remaining versus incubation time).

[0341] In vitro drug clearance rate = (0.693 / t 1 / 2 ) × (enzyme reaction volume / liver microsomal enzyme content).

[0342] Test results: see Table 5.

[0343] [Table 8]

[0344] The test results show that the example compounds of the present application exhibit good pharmacokinetic properties.

[0345] Experimental Example 4: Pharmacokinetic evaluation in mice Study objective: The pharmacokinetics of the example compounds of the present application was tested in mice.The pharmacokinetic behavior of the compounds of the present invention was studied by measuring the drug concentration in mouse plasma to evaluate their pharmacokinetic characteristics.

[0346] Test animals: 6-8 week old male ICR (CD1) mice

[0347] Testing Method: Oral gavage drug preparation: The appropriate amount of test compound was first weighed and dissolved in DMSO (Macklin cas: 67-68-5) to prepare a 20mg / mL solution. 75μL of this solution was then added to 150μL of Solutol (Sigma cas: 70142-34-6), followed by 1.275mL of 20% Captisol (Selleck cas: 182410-00-0) to obtain a final drug concentration of 1mg / mL.

[0348] Intravenous injection drug preparation: The appropriate amount of test compound was first weighed and dissolved in DMSO (Macklin cas: 67-68-5) to prepare a 30mg / mL solution. Then, 15μL of this solution was added to 150μL of Solutol (Sigma cas: 70142-34-6), followed by 1.335mL of 20% Captisol (Selleck cas: 182410-00-0) to obtain a final drug concentration of 0.3mg / mL.

[0349] Procedure: Mice were fasted overnight and given free access to water before the experiment. Food was restored 2 hours after dosing. Blood samples were collected at different time points after intravenous injection or oral gavage of test compounds in mice to measure compound concentrations in plasma. Approximately 50 μL of blood was collected from each animal using capillary sampling tubes via the orbital venous plexus with sodium heparin as anticoagulant. Blood samples were placed on ice and centrifuged at 3500 r / min for 10 min to separate plasma, and 20 μL of collected plasma was added to 200 μL of acetonitrile (Merck cas: 75-05-8) containing 200 nM dexamethasone (Selleck cas: 50-02-2) as internal standard. The mixture was centrifuged at 8000 r / min for 20 min. After centrifugation, 150 μL of the supernatant was transferred to a new centrifuge tube and 150 μL of 0.1% formic acid (Fisher cas:207868) was added. The mixture was mixed thoroughly and a 5 μL sample was subjected to quantitative analysis by liquid chromatography-mass spectrometry (Q-TOF LC / MS).

[0350] Standard curve determination: 1. Test compounds were serially diluted in DMSO to cover the expected compound concentrations in the plasma samples to be tested, and a blank sample (containing DMSO only) was included. 2. 2 μL of each diluted sample at various concentrations was added to 18 μL of healthy ICR mouse plasma, mixed, and then added to 200 μL of acetonitrile (Merck cas: 75-05-8) containing 200 nM dexamethasone (Selleck cas: 50-02-2) as an internal standard. The mixture was centrifuged (8000 r / min) for 20 min. 150 μL of the supernatant was transferred to a new centrifuge tube, and 150 μL of 0.1% formic acid (Fisher cas: 207868) was added. The mixture was mixed thoroughly, and 5 μL of the sample was subjected to quantitative analysis by liquid chromatography-mass spectrometry (Q-TOF LC / MS). 3. The final standard curve was plotted using the concentration of test compound after dilution on the abscissa and the ratio of the signal between the compound and the internal standard (dexamethasone) on the ordinate. Linear regression using GraphPad Prism 8 software was used to generate the standard curve (R2>0.9900).

[0351] Data Analysis: Calculation of Pharmacokinetic Parameters: The concentrations of the test compounds in plasma at different time points after intravenous injection or oral gavage in ICR mice were determined based on the above standard curve, and the pharmacokinetic parameters (T 1 / 2 , Cmax, AUC, etc.) were calculated.

[0352] Test results: see Table 6.

[0353] [Table 9]

[0354] Experimental Conclusion: The exposure and half-life of the example compounds of the present application in mice was significantly better than that of the reference compound AZD5305.

[0355] Experimental Example 5: Pharmacokinetic evaluation in rats Test Objective: The pharmacokinetics of the example compounds of the present application was tested in rats.The pharmacokinetic behavior of the compounds of the present invention was studied by measuring the drug concentration in rat plasma to evaluate their pharmacokinetic characteristics.

[0356] Test animals: 6-8 week old male SD rats

[0357] Testing Method: Oral gavage drug preparation: The appropriate amount of test compound was first weighed and dissolved in DMSO (Macklin cas: 67-68-5) to prepare a 100mg / mL solution. 100μL of this solution was then added to 200μL of Solutol (Sigma cas: 70142-34-6), followed by 1.7mL of 20% Captisol (Selleck cas: 182410-00-0) to obtain a final drug concentration of 5mg / mL.

[0358] Intravenous injection drug preparation: The appropriate amount of test compound was first weighed and dissolved in DMSO (Macklin cas: 67-68-5) to prepare a 60mg / mL solution. Then, 50μL of this solution was added to 100μL of Solutol (Sigma cas: 70142-34-6), followed by 850μL of 20% Captisol (Selleck cas: 182410-00-0) to obtain a final drug concentration of 3mg / mL.

[0359] Procedure: Rats were fasted overnight and given free access to water before the experiment. Food was restored 2 hours after dosing. Blood samples were collected at different time points after intravenous injection or oral gavage of test compounds in rats to measure compound concentrations in plasma. Approximately 50 μL of blood was collected from each animal using capillary sampling tubes via the orbital venous plexus with sodium heparin as anticoagulant. Blood samples were placed on ice and centrifuged at 3500 r / min for 10 min to separate plasma, and 20 μL of collected plasma was added to 200 μL of acetonitrile (Merck cas: 75-05-8) containing 200 nM dexamethasone (Selleck cas: 50-02-2) as internal standard. The mixture was centrifuged at 8000 r / min for 20 min. After centrifugation, 150 μL of the supernatant was transferred to a new centrifuge tube and 150 μL of 0.1% formic acid (Fisher cas:207868) was added. The mixture was mixed thoroughly and a 5 μL sample was subjected to quantitative analysis by liquid chromatography-mass spectrometry (Q-TOF LC / MS).

[0360] Standard curve determination: 1. Test compounds were serially diluted in DMSO to cover the expected compound concentrations in the plasma samples to be tested, and a blank sample (containing DMSO only) was included. 2. 2 μL of each diluted sample at various concentrations was added to 18 μL of healthy SD rat plasma, mixed, and then added to 200 μL of acetonitrile (Merck cas: 75-05-8) containing 200 nM dexamethasone (Selleck cas: 50-02-2) as an internal standard. The mixture was centrifuged (8000 r / min) for 20 min. 150 μL of the supernatant was transferred to a new centrifuge tube, and 150 μL of 0.1% formic acid (Fisher cas: 207868) was added. The mixture was mixed thoroughly, and 5 μL of the sample was subjected to quantitative analysis by liquid chromatography-mass spectrometry (Q-TOF LC / MS). 3. The final standard curve was plotted using the concentration of test compound after dilution on the abscissa and the ratio of the signal between the compound and the internal standard (dexamethasone) on the ordinate. Linear regression using GraphPad Prism 8 software was used to generate the standard curve (R2>0.9900).

[0361] Data Analysis: Calculation of Pharmacokinetic Parameters: The concentrations of the test compounds in plasma at different time points after intravenous injection or oral gavage in SD rats were determined based on the above standard curve, and the pharmacokinetic parameters (T1 / 2, Cmax, AUC, etc.) were calculated using Phoenix WinNonlin 8.1 non-compartmental analysis model.

[0362] Test results: See Table 7.

[0363] [Table 10]

[0364] The test results indicate that the example compounds of the present application exhibit favorable pharmacokinetic properties.

[0365] Experimental Example 6: In vivo efficacy assay 1. Mouse CDX tumor model Study Objective: The efficacy of the compounds was evaluated in a subcutaneous xenograft model of human breast cancer (MDA-MB-436) cell line in mice.

[0366] Test compound: Olaparib, Compound 1

[0367] Experimental animals: Female NOD SCID mice, aged 4-5 weeks, purchased from Nanjing Jicui.

[0368] Housing and Care: Experimental animals were housed in SPF grade temperature and humidity controlled clean rooms using individually ventilated cages (IVC) with no more than 5 mice per cage. Temperature / humidity was controlled within the range of (23±3)°C / 40-70%. Food and Water: SPF grade mouse chow sterilized by Cobalt-60 irradiation. Drinking water was ultrafiltered and autoclaved. Animals had free access to sterile food and water. Animal Identification: Ear tags.

[0369] Tumor cell lines and tumor models: MDA-MB-436 cells (Nanjing Cobioer Biotechnology Co., Ltd., Catalog number: CBP60385) were cultured in vitro (37°C, 5% CO2) in DMEM complete medium containing 10% fetal bovine serum, 1% penicillin-streptomycin, 1% insulin and 16 μg / mL glutathione. Once the cells met the requirements for in vivo efficacy experiments, they were harvested, counted, prepared and added to a PBS cell suspension. Each mouse (5-6 week old NOD SCID) was subcutaneously injected with 0.9 × 10 7 After inoculation, tumor volumes were measured and calculated three times a week. 3 Once the mice reached the dose, they were grouped for dosing.

[0370] Experimental groups: The experiment was divided into the following groups: vehicle control group, olaparib 100mg / kg group, compound 1 0.1mg / kg group, compound 1 0.3mg / kg group, and compound 1 1.0mg / kg group. All groups were orally administered once a day by gavage. After administration, tumor volume and body weight were measured three times a week, and mice were observed for activity, drinking water, and feeding behavior. After 28 days of administration, tumor volume was used to calculate tumor growth inhibition rate (TGI%), and tumor inhibition effect was statistically analyzed using software such as Excel. TGI = {1 - (tumor volume at the end of administration in the treatment group - tumor volume at the time of grouping in the treatment group) / (tumor volume at the end of administration in the control group - tumor volume at the time of grouping in the control group)} x 100%

[0371] Test results: As shown in Table 8, compound 1 exhibited dose-dependent inhibition of tumor growth. The tumor inhibition effect of 0.1 mg / kg compound 1 was equivalent to that of 100 mg / kg olaparib. Compound 1 at doses of 0.3 mg / kg and 1.0 mg / kg completely inhibited tumor growth after 28 days of treatment. There was no significant difference in body weight between the treatment group and the vehicle control group. Specific results are shown in Figures 1 and 2.

[0372] [Table 11]

[0373] 2. Human Breast Cancer PDX Mouse Model Study Objective: The in vivo efficacy of the test compounds was evaluated in a subcutaneous xenograft tumor model of breast cancer BR-05-0044E in NOD SCID mice.

[0374] Test compound: Compound 1

[0375] Experimental animals: Female NOD SCID mice, 6-8 weeks old and weighing 18-20 grams, were provided by Beijing Charles River Laboratory Animal Technology Co., Ltd. The animals were acclimated to the experimental environment for 3-7 days prior to the experiment. The animals were housed in IVC cages (individually ventilated cages) in SPF grade animal rooms with 4 mice per cage. All cages, bedding and drinking water were sterilized before use. Cages, food and water were changed twice a week. The housing environment and lighting conditions were as follows: temperature: 20-26°C, humidity: 40-70%, light cycle: 12 hours light, 12 hours dark.

[0376] PDX model establishment: The human breast cancer BR-05-0044E model was originally derived from a surgically removed clinical specimen. After the tumor tissue expanded in mice, it grew to 20-30 mm 3A BR-05-0044E tumor tissue block was implanted subcutaneously into the right flank of each mouse. Tumor growth was monitored and the mean tumor volume was approximately 150–200 mm. 3 Once the mice reached 100 mg / kg, they were randomly assigned to groups for dosing. Prior to dosing, animals were weighed and tumor volumes were measured. Randomization was based on tumor volume (randomized block design).

[0377] Experimental groups: The experiment was divided into the following groups: 1. Vehical control group, 2. Compound 1 0.1 mg / kg, 3. Compound 1 0.3 mg / kg, 4. Compound 1 1.0 mg / kg. All groups were orally administered once a day by gavage. Regular checks included observing the effects of drug treatment on tumor growth and animal daily behavior (e.g., activity, food and water intake, body weight change (measured twice a week), appearance, or other abnormalities). The number of animals with death and side effects in each group was recorded.

[0378] Experimental endpoint: The experimental endpoint was to assess whether tumor growth was inhibited, delayed or cured. Tumor diameters were measured twice a week with calipers. Tumor volume was calculated according to the formula: V=0.5a×b 2 where a and b represent the length and width of the tumor, respectively.

[0379] The efficacy of the compound in inhibiting tumor was evaluated by tumor volume and tumor growth inhibition rate (TGI). TGI(%) was calculated as follows: TGI(%)={1-(mean tumor volume at the end of treatment group-mean tumor volume at the start of treatment group) / (mean tumor volume at the end of treatment group-mean tumor volume at the start of treatment group)}×100%.

[0380] Test results: Compound 1 (0.1, 0.3, 1.0 mg / kg) was orally administered by gavage once a day for 21 days in the BR-05-0044E FP5 breast cancer mouse PDX model. All doses tested completely inhibited tumor growth, and tumors in treated mice disappeared completely. After administration was completed, the mice were observed for an additional 2 weeks, and no tumor growth was observed in the treated group. There was no significant difference in body weight between the drug-treated group and the vehicle control group. Specific results are shown in Table 9, Figure 3 and Figure 4.

[0381] [Table 12]

[0382] Experimental Example 7: Effects of compounds on rat reticulocytes Study Objective: Evaluate the effect of the compound on peripheral blood reticulocytes to determine its impact on bone marrow hematopoietic function.

[0383] Test compound: Olaparib, Compound 1

[0384] Experimental animals: Male Sprague-Dawley rats were purchased from Beijing Charles River Laboratory Animal Technology Co., Ltd. Housing and care: Experimental animals were housed in an SPF grade temperature- and humidity-controlled clean room using individually ventilated cages (IVC), with no more than five rats per cage. Temperature / humidity was controlled within the range of (23±3)℃ / 40-70%. Food and water: SPF grade rat feed sterilized by cobalt-60 irradiation. Drinking water was ultrafiltered and autoclaved. Animals had free access to sterile food and water. Animal identification: ear tags.

[0385] Experimental method: The experiment was divided into five groups: vehicle control group, olaparib 100mg / kg, compound 1 0.1mg / kg, compound 1 0.3mg / kg, and compound 1 1.0mg / kg. All treatments were administered orally by gavage once a day for 4 days. Blood samples were collected before and after treatment to measure peripheral blood reticulocyte count.

[0386] Test results: Table 10 shows the changes in peripheral blood reticulocytes in rats after 4 days of administration.After 4 days of administration in rats, 100mg / kg olaparib significantly reduced peripheral blood reticulocytes (p<0.01), indicating its inhibitory effect on bone marrow hematopoietic function.Compound 1 0.1mg / kg, compound 1 0.3mg / kg and compound 1 1.0mg / kg had no significant effect on peripheral blood reticulocytes (p>0.05).Combined with the pharmacodynamic results, compound 1 demonstrated a larger therapeutic window compared to olaparib.

[0387] [Table 13]

[0388] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each reference referenced herein, including all patents, applications, journal articles, books, and any other disclosures, is hereby incorporated by reference in its entirety.

Claims

1. Structure of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, During the ceremony, 【Chemistry 2】 is a single bond or a double bond, X is N or CR 5 and Y is N or CR 5 ' and Z is CR 6 or N, 【Chemistry 3】 is a single bond, V is CR 7 R A or NR A and 【Chemistry 4】 is a double bond, V is CR A and R A is H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6～10 Aryl, 5-14 membered heteroaryl, C 6～12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1～6 Alkylene -CN, -C 1～6 Alkylene-OR a , -C 1～6 Alkylene-NR a R b , -OC 1～6 Alkylene-NR a R b and 【Chemistry 5】 is selected from the group consisting of Ring A is C 3～6 Hydrocarbon ring, 3- to 10-membered heterocycle, C 6～10 an aromatic ring or a 5- to 14-membered heteroaromatic ring; R and R' in each occurrence are H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6～10 Aryl, 5-14 membered heteroaryl, C 6～12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1～6 Alkylene -CN, -C 1～6 Alkylene-OR a , -C 1～6 Alkylene-NR a R b and -OC 1～6 Alkylene-NR a R b and preferably, R and R' are each independently selected from the group consisting of H, -CN and C 1～6 alkyl, R 1 and R 2 are halogens, -OH, -NH 2 , -CN, -NO 2 , C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6～10 Aryl, 5-14 membered heteroaryl, C 6～12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1～6 Alkylene -CN, -C 1～6 Alkylene-OR a , -C 1～6 Alkylene-NR a R b and -OC 1～6 Alkylene-NR a R b are each independently selected from the group consisting of: R 3 represents, in each occurrence, a halogen, -OH, =O, -NH 2 , -CN, -NO 2 , C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6～10 Aryl, 5-14 membered heteroaryl, C 6～12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1～6 Alkylene -CN, -C 1～6 Alkylene-OR a , -C 1～6 Alkylene-NR a R b and -OC 1～6 Alkylene-NR a R b are each independently selected from the group consisting of: If m>1, then two R 3 The groups may be joined together to form -C 1～6 Alkylene- or -C 2～6 Alkenylene- is formed, and the alkylene chain and the alkenylene chain are O, C(=O), C(=O)O, NR, S, S=O and S(=O) 2 or optionally interrupted by one or more groups independently selected from the group consisting of Or, R 3 and R A together with the groups to which they are attached, C 3～6 Hydrocarbon ring, 3- to 10-membered heterocycle, C 6～10 optionally forming an aromatic ring or a 5- to 14-membered heteroaromatic ring, R 4 represents, in each occurrence, a halogen, -OH, -NH 2 , -CN, -NO 2 , C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6～10 Aryl, 5-14 membered heteroaryl, C 6～12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1～6 Alkylene -CN, -C 1～6 Alkylene-OR a , -C 1～6 Alkylene-NR a R b and -OC 1～6 Alkylene-NR a R b and two R 4 When the groups are ortho to each other on ring A, the two R 4 groups, together with the group to which they are attached, optionally form a 3- to 10-membered heterocyclic ring or a 5- to 14-membered heteroaromatic ring; Or, R 3 and R 4 together with the groups to which they are attached, C 3～6 Hydrocarbon ring, 3- to 10-membered heterocycle, C 6～10 optionally forming an aromatic ring or a 5- to 14-membered heteroaromatic ring, R 5 , R 5 ', R 6 and R 7 is, in each occurrence, H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6～10 Aryl, 5-14 membered heteroaryl, C 6～12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1～6 Alkylene -CN, -C 1～6 Alkylene-OR a , -C 1～6 Alkylene-NR a R b and -OC 1～6 Alkylene-NR a R b are each independently selected from the group consisting of: R a and R b In each occurrence, H, C 1～6 Alkyl, C 1～6 Haloalkyl, C 2～6 Alkenyl, C 3～10 Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6～10 Aryl, 5- to 14-membered heteroaryl and C 6～12 aralkyl, The above alkyl, alkylene, haloalkyl, alkenyl, alkenylene, hydrocarbon ring, cyclic hydrocarbyl, heterocycle, heterocyclyl, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl are each independently selected from the group consisting of halogen, -OH, =O, -NH 2 , -CN, -NO 2 , C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6～10 Aryl, 5-14 membered heteroaryl, C 6～12 Aralkyl, -C(=O)R c , -OC(=O)R c , -C(=O)OR c , -OR c , -SR c , -S(=O)R c , -S(=O) 2 R c , -S(=O) 2 NR c R d , -NR c R d , -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NR c -S(=O) 2 -R d , -NR c -C(=O)-NR c R d , -C 1～6 Alkylene-OR c , -C 1～6 Alkylene-NR c R d and -OC 1～6 Alkylene-NR c R d and wherein alkyl, alkylene, haloalkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, ═O, -NH 2 , -CN, -NO 2 , C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6～10 Aryl, 5- to 14-membered heteroaryl and C 6～12 and optionally further substituted with one or more substituents independently selected from the group consisting of aralkyl; R c and R d In each occurrence, H, C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～10 Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6～10 Aryl, 5- to 14-membered heteroaryl and C 6～12 aralkyl, m and n are each independently an integer of 0, 1, 2, 3, or 4; or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

2. R A But, C 1～6 Haloalkyl (preferably 【Chemistry 6】 ), -C(=O)R a (Preferably 【Chemistry 7】 ) and 【Chemistry 8】 2. The compound of claim 1, selected from the group consisting of: or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

3. The compound has the structure of formula (I)-1 【Chemistry 9】 and preferably the compound has the structure of formula (II), (III), (IV) or (V): 【Chemistry 10】 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, having the formula:

4. R 1 and R 2 are each independently halogen, -CN, C 1～6 Alkyl or C 1～6 haloalkyl, e.g., R 1 and R 2 However, each independently, C 1～6 Alkyl or C 1～6 is haloalkyl, Preferably, R 1 and R 2 are each independently F, -CN, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, or isopropyl, for example, R 1 and R 2 are each independently methyl, trifluoromethyl, ethyl, n-propyl, or isopropyl; Most preferably, R 1 is trifluoromethyl, and R 2 is methyl or R 1 and R 2 are all methyl.

4. A compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof.

5. R 3 each occurrence independently represents a halogen, -OH, =O, -NH 2 , -CN,C 1～6 Alkyl, C 1～6 Haloalkyl, -C 1～6 Alkylene -CN, -C 1～6 Alkylene-OR a Or -C 1～6 Alkylene-NR a R b If m>1, then two R 3 The groups may be joined together to form -C 1～4 Forming an alkylene- Preferably, R 3 each occurrence independently represents =O, -CN, C 1～6 Alkyl, C 1～6 Haloalkyl, -C 1～6 Alkylene -CN, -C 1～6 Alkylene-OR a Or -C 1～6 Alkylene-NR a R b If m>1, then two R 3 The groups may be joined together to form -C 1～4 Forming an alkylene- More preferably, R 3 each occurrence independently represents ═O, -CN, -CH 3 , -CF 3 , -CH 2 CN, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 OH, -CH 2 CH 2 OH or -CH 2 OCH 3 If m>1, then two R 3 The groups optionally taken together are -CH 2 CH 2 - Form or Or, R 3 and R A together with the group to which they are attached optionally form a 5- to 6-membered heteroaromatic ring, preferably a triazole ring, which is 1～6 optionally substituted with haloalkyl (preferably trifluoromethyl); 5. A compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof.

6. R 6 and R 7 In each occurrence, H, halogen, -OH, -CN, -C 1～6 Alkylene-OR a and -C 1～6 Alkylene-NR a R b are each independently selected from the group consisting of: R 6 and R 7 In each occurrence, H, -F, -OH, -CN, -CH 2 OH and -CH 2 NH 2 each independently selected from the group consisting of:

6. A compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof.

7. 【Fig. 11】 but, 【Chemistry 12】 Selected from the group consisting of: Preferably, 【Chemistry 13】 but, 【Chemistry 14】 Selected from the group consisting of:

7. A compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof.

8. R 4 each occurrence independently represents halogen, -CN, C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cyclic hydrocarbyl, 5-14 membered heteroaryl, -S(=O) 2 NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)-NR a R b Or -C 1～6 Alkylene-OR a and two R 4 When the groups are ortho to each other on ring A, the two R 4 the groups, together with the group to which they are attached, optionally form a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaromatic ring; Preferably, R 4 is, in each occurrence, independently, F, -CN, -CH 3 , -CF 3 , 【Chemistry 15】 , -S(=O) 2 NHCH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)NHCD 3 , -C(=O)NHCH 2 CH 3 , -C(=O)NHCH 2 CF 3 , -C(=O)NHCH 2 CH 2 OH, -C(=O)NH(cyclopropyl), -NHC(=O)CH 3 , -NHC(=O)(cyclopropyl), -NHC(=O)NHCH 3 , -CH 2 OH, 【Chemistry 16】 and two R 4 When the groups are ortho to each other on ring A, the two R 4 The groups, together with the groups to which they are attached, 【Chemistry 17】 and optionally forming More preferably, R 4 is, in each occurrence, independently, F, -CN, -CH 3 , -CF 3 , 【Chemistry 18】 , -S(=O) 2 NHCH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -NHC(=O)CH 3 , -NHC(=O)(cyclopropyl), -NHC(=O)NHCH 3 , -CH 2 OH, 【Chemistry 19】 and two R 4 When the groups are ortho to each other on ring A, the two R 4 The groups, together with the groups to which they are attached, 【Chemistry 20】 or Or, R 3 and R 4 optionally form, together with the group to which they are attached, a 5- to 6-membered heteroaromatic ring, preferably an imidazole ring; 8. A compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof.

9. Ring A is C 4～6 Hydrocarbon ring, 5-6 membered heterocycle, C 6 an aromatic ring or a 5- to 6-membered heteroaromatic ring, more preferably a bicyclo[1.1.1]pentane ring, a piperidine ring, a benzene ring, an imidazole ring, a thiazole ring, a pyridine ring, a pyrazine ring, a pyridazine ring, or a pyrimidine ring, and most preferably a bicyclo[1.1.1]pentane ring, a piperidine ring, a benzene ring, an imidazole ring, a thiazole ring, a pyridine ring, a pyridazine ring, or a pyrimidine ring; 9. A compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof.

10. 【Fig. 21】 but, 【Chemical 22】 and Preferably, 【Chemistry 23】 but, 【Chemistry 24】 That is, 10. A compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof.

11. The compound is 【Chemistry 25】 【change】 【change】 【change】 【change】 【change】 11. The compound of any one of claims 1 to 10, selected from the group consisting of: or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof.

12. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, and one or more pharma- ceutically acceptable carriers, preferably in the form of a solid, liquid or transdermal formulation.

13. Use of a compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labelled compound or prodrug thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a medicament for use as a PARP inhibitor (preferably as a PARP1 selective inhibitor).

14. 14. The use according to claim 13, wherein the medicament is for the treatment of cancer, preferably the cancer is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, lung cancer, head and neck cancer, thyroid cancer, malignant glioma, leukemia, lymphoma and multiple myeloma.

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