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 them, 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) catalyzes the transfer of ADP-ribose residues from NAD+ to target substrates, thereby modifying proteins by ribosylation. This poly(ADP-ribosylation) is a post-translational modification of proteins widely involved in various physiological and pathological processes. PARP can poly(ADP-ribosylate) various nuclear proteins, including histones, RNA polymerases, DNA polymerases, and DNA ligases. PARP is activated by recognizing damaged DNA fragments, leading to glycosylation modifications of nuclear proteins, thereby completing the DNA repair function. In normal cells, other DNA repair mechanisms, such as the BRCA pathway, can also complete DNA repair, enabling 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 in tumor cells relies primarily on the PARP mechanism. In these patients, PARP inhibitors can block DNA repair function and induce 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] 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] Additionally, because 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 injury); 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 infection); and metabolic disorders (metabolic syndrome and type II diabetes and subsequent complications, e.g., diabetic neurological, renal, and ocular complications). Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides PARP inhibitors that can be used to prevent or treat diseases that can be ameliorated by inhibiting PARP. Preferably, the compounds of the present invention have selective inhibitory activity against PARP-1. In addition, the compounds of the present invention possess better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity, e.g., reduced cardiotoxicity and / or fewer side effects), and superior properties, such as 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 pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, During the ceremony,

[0008] [ka] is a single or 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 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 represents, in each occurrence, the halogens -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, form 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 represents, in each occurrence, the 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-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, form 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 is, 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, in each occurrence, are each 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, 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, —NH, —CN, —NO, 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 pharmaceutically 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 pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, and one or more pharmaceutically acceptable carriers, preferably in the form of a solid, liquid, or transdermal formulation.

[0013] Another aspect of the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present 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 pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled 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 pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the effect of Compound 1 in inhibiting tumor growth in the MDA-MB-436 breast cancer mouse tumor model. [Figure 2] FIG. 1 shows the effect of Compound 1 on mouse body weight in the MDA-MB-436 breast cancer mouse tumor model. [Figure 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 INVENTION

[0017] definition Unless otherwise defined within 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 substitutions that would be apparent 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 thereof, 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 a saturated divalent hydrocarbyl 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-chain or branched-chain saturated aliphatic hydrocarbon. In some embodiments, 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 compound 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, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. 1~6 The term "heteroalkyl" may be given to indicate the number of carbon atoms in the chain (in this example, 1 to 6 carbon atoms). For example, the group -CH2OCH2CH3 is referred to as a C3 heteroalkyl group. Attachment to the rest of the molecule can be through a heteroatom or a carbon atom in the heteroalkyl chain. The term "heteroalkylene" can refer to, for example, "C 1~6 heteroalkylene," "C 1~4 "heteroalkylene" refers to the corresponding divalent radical, preferably -CH2OCH2-, including the like.

[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 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., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl, or a bicyclic ring containing a spiro, fused, or bridged ring system (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. A 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 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0025] As used herein, the term "heterocyclyl" or "heterocycle" refers to a heterocyclic ring having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and C(=O), O, S, S(=O), S(=O) and NR ' [where R' is a hydrogen atom, C 1~6 Alkyl or C 1~6 " refers to a saturated or unsaturated, monovalent, monocyclic or bicyclic moiety having one or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups in the ring selected from the group consisting of: a cyclic group, ...

[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 within the fused ring structure. Thus, heterocyclyls of the present invention include heterocyclyl-fused heterocyclyls, heterocyclyl-fused cycloalkyls, monoheterocyclyl-fused monoheterocyclyls, monoheterocyclyl-fused monocycloalkyls, such as 3- to 7-membered (mono)heterocyclyl-fused 3- to 7-membered (mono)heterocyclyls, 3- to 7-membered (mono)heterocyclyl-fused (mono)cycloalkyls, 3- to 7-membered (mono)heterocyclyl-fused C 4~6 Also includes, but is not limited to, (mono)cycloalkyl, examples of which 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" encompasses 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, a 7- to 10-membered bridged heterocycle, an 8- to 10-membered bridged heterocycle, a 7- to 10-membered nitrogen-containing bridged heterocycle, a 7- to 10-membered oxygen-containing bridged heterocycle, a 7- to 10-membered sulfur-containing bridged heterocycle, etc.

[0030] [ka] etc. The "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 atom, nitrogen atom, sulfur atom) 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, etc.

[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- to 10-membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl group containing a total of 6 to 10 ring atoms, at least one of which is 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. An aryl may have one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO, C 1~6 and optionally substituted with alkyl, etc.

[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, particularly 1, 2, 3, 4, 5, 6, 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 benzofused. 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" is inclusive of fused ring structures, and the point of attachment between the fused ring structure and another group may be from any ring within the fused ring structure. Thus, 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 a 5- to 6-membered (mono)heteroaryl-fused-5- to 6-membered (mono)heteroaryl, a 5- to 6-membered (mono)heteroaryl-fused-phenyl, a 5- to 6-membered (mono)heteroaryl-fused-5- to 6-membered (mono)heterocyclyl, or a 5- to 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, appended 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 optionally further containing 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 the 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 a specified atom have been 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 being "optionally substituted," the substituent may be either (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (if any) may be replaced separately and / or together with independently selected optional substituents. When a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (if any) may each be replaced with independently selected optional substituents.

[0043] When substituents are described as being "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., two, three, four, five, or ten), 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 the ring.

[0047] The present invention also includes all pharmaceutically 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 analogous to those described in the accompanying schemes and / or in the examples and preparations, by substituting an appropriate isotopically labeled reagent for a previously employed non-labeled reagent. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization may be isotopically substituted, e.g., 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 produce racemic mixtures, single mirror image isomers (enantiomers), diastereomeric mixtures, and individual diastereomers. Certain individual molecules may exist as geometric isomers (cis / trans). Similarly, compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (generally referred to as tautomers). Typical 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 intended 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 intended to indicate that the shown stereoisomer exists. When present in a racemic compound, the solid and dotted wedges are used to define relative stereochemistry rather than 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 or 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 pharmaceutically acceptable derivative. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, after administration to a patient in need thereof, can directly or indirectly provide the compound of the present invention or its metabolites or residues. Thus, 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 that form pharmaceutically acceptable salts, and examples 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 pharmaceutically acceptable salts. Specific examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium salts, and the like.

[0058] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically 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 crystalline 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, etc., 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 this 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 that, upon administration to or onto the body, can be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage. Generally, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into compounds with the desired therapeutic activity. Further information on the use of prodrugs can be found in "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. E.B. 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 compounds of the present invention having protecting groups. During any of the processes for preparing 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 protecting groups, such as those described in Protective Groups in Organic Chemistry, edited by J.F.W. McOmie, Plenum Press, 1973; and TW Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. The protecting 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 pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, During the ceremony,

[0067] [ka] is a single or 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 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 represents, in each occurrence, the halogens -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, form 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 represents, in each occurrence, the 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 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, form 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 is, 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, in each occurrence, are each 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, 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, —NH, —CN, —NO, 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 pharmaceutically 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 pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound is 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 pharmaceutically 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, 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 and R are each methyl; or a pharmaceutically 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 and if m>1, then two R 3 The groups may optionally be joined together to form -C 1~4 alkylene-forming, Preferably, R 3 In each occurrence, independently, =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 and if m>1, then two R 3 The groups may optionally be joined together to form -C 1~4 alkylene-forming, 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 pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the groups optionally taken together 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 are each independently selected at each occurrence from the group consisting of H, —F, —OH, —CN, —CHOH, and —CHNH; Provided are the above compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds, or prodrugs 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 are the above compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds, or prodrugs thereof.

[0087] In some embodiments, the present application provides 4 each occurrence independently represents a 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 are each independently, in each occurrence, 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] optionally forming More preferably, R 4 are each independently, in each occurrence, 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 form, together with the group to which they are attached, a 5- to 6-membered heteroaromatic ring, preferably an imidazole ring; Provided are the above compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds, or prodrugs thereof.

[0094] In some embodiments, the present application provides compounds wherein ring A is C 4~6The compound 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 pharmaceutically 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 pharmaceutically 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 provides a compound comprising:

[0102] [ka] TIFF0007804371000038.tif249160TIFF0007804371000039.tif241161TIFF0007804371000040.tif244161TIFF0007804371000041.tif254163TIFF0007804371000042.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 pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, and one or more pharmaceutically acceptable carriers, the pharmaceutical composition preferably being in the form of a solid, liquid, or transdermal formulation.

[0104] In some embodiments, the invention provides use of a compound of the invention or a pharmaceutically 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 present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present 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 pharmaceutically 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 human beings 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, nonfat dry milk, glycerol, propylene glycol, water, ethanol, and the like. 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, by injection (intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip infusion), or via transdermal administration, or orally, buccally, nasally, transmucosally, topically, in ophthalmic formulations, or via inhalation.

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

[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 needs and the professional judgment of the person administering or supervising the administration of the composition.

[0115] The amount of the compound of the 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. Generally, an effective dosage is in 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 end 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., those 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, pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents. [Example]

[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 specific sources were not mentioned were commercially available conventional reagents. 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). The solvents used for analysis were deuterated chloroform (CDCl), hexadeuterated dimethyl sulfoxide (DMSO-d), or deuterated methanol (CDOD). Tetramethylsilane (TMS) was used as an internal standard. 1 The multiplicity of H NMR spectral peaks is 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 of 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 specified, reactions in the examples were carried out under a nitrogen atmosphere.

[0129] The progress of the 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] TIFF0007804371000044.tif250160TIFF0007804371000045.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. Upon 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 hour. 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, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 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 a 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 minutes. DIPEA (260 mg) was then added, and the reaction was allowed to proceed at room temperature for 2 hours. Upon 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 hour. 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 LiAlH (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 pale yellow solid (1)-7 (50 mg, 58% yield). MS-ESI m / z: 259.2 [M+H] + .

[0139] Step 7. Preparation of Compounds (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 gray 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 minutes. 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 1-7. Preparation of compound (2) Using 4-amino-5-bromopyridine-2-carboxylate ((2)-1) as the starting material, compound (2) was prepared according to the same method as the synthetic 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). 5-Bromopyridine-2-carboxylate (728.7 mg), Pd2(dba)3 (617 mg), RuPhos (629 mg), and cesium carbonate (3.3 g) were then 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 solution (5 mL, 40% wt) was added. The reaction mixture was sealed and reacted at 90° C. for 1.5 hours. 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 approximately 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 give 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 hour. 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 the same method as the synthetic 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 hour. 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 the same method as the synthetic 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 1-5. 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 method as the synthetic route of 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 the same method as the synthetic 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) Using tert-butyl 2-trifluoromethylpiperazine-1-carboxylate as the starting material, compound (9) was prepared according to the same method as the synthetic route of compound (3). 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 the same method as the synthetic 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) Using tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate ((12)-1) as the starting material, compound (12) was prepared according to the same synthetic route as compound (3). 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). KI (18 mg) and DIPEA (42 mg) were then added sequentially, and the mixture was reacted at 90° C. for 30 minutes. 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 using 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate ((14)-1) as the starting material, following a similar method to steps 2 to 4 in the synthesis of compound (3). 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 hour. 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, 50.4% yield). 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 hour 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 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 pale 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 pale 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 give 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 pale 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 synthetic 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 the same synthetic route as 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 hours. 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 the same synthetic route as 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 h. 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 give 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 hour. After completion of the reaction, 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 hour. 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 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 the same method as the synthetic 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 pale 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, 1 M in THF) was added dropwise at 0° C. The reaction was carried out at 25° C. for 1 hour. After completion of the reaction, 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 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 pale 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 minutes. 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 hours. 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 hour. 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 give 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 method similar to steps 2 to 4 in the synthesis 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) Using methyl 5-bromopyrimidine-2-carboxylate and tert-butyl 2-methylpiperazine-1-carboxylate as starting materials, compound (28) was prepared according to the same method as the synthetic route of compound (3). 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 steps 1 to 3 in the synthesis 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 hours. 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 give a pale 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 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 the same method as 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 synthetic 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 synthetic 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 synthetic 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 synthetic 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 obtain 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 hours. 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 pale 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 hour. 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 pale 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 overnight at room temperature under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered through diatomaceous earth and concentrated to give 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 hour. 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 give 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 method as the synthetic route of 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 a hydrogen atmosphere at room temperature for 1 hour. 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] Steps 2-3: Preparation of compound (70) Using (70)-1 as the starting material, compound (70) was prepared according to steps 2-3 in the synthesis 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 the same method as the synthetic 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 the same synthetic route as 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 the same synthetic route as 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 the same synthetic route as 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 the same method as the synthetic 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 the same method as the synthetic 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 the same method as the synthetic 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) Using methyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazine-2-carboxylate ((79)-1) as the starting material, compound (79) was prepared according to the same method as the synthetic route of compound (14). 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 a 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 pale yellow oily product (100 mg, yield: 41%). MS-ESI m / z: 333.40 [M+H] + .

[0251] Steps 2-4. Preparation of Compound (80) and Compound (81) Using (80)-2) containing two double bond isomers as the starting material, compounds (80) and (81) were prepared according to the same method as 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 steps 1 to 7 in the synthesis 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 using 6-bromo-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one ((84)-1) as the starting material according to a method similar to step 3 in the synthesis of compound (15). 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 minutes. DIPEA (66 mg) was added, and the mixture was allowed to warm to room temperature and continued for 2 hours. 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 steps 6-8 in the synthesis 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 method as the synthetic route of 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 method similar to step 7 in the synthesis 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 method similar to step 7 in the synthesis 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 method similar to step 7 in the synthesis 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 the same method as the synthetic 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 using tert-butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate as the starting material, following a similar method to steps 2 to 4 in the synthesis of compound (21). 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-necked flask, and the mixture was cooled to −78° C. under nitrogen protection. Lithium diisopropylamide (2 M, 28.12 mL) was added dropwise to the reaction mixture, followed by the slow addition of a tetrahydrofuran solution of (94)-1 (2.24 g, 40 mL). The reaction mixture was then allowed to warm slowly to room temperature and react overnight. The reaction mixture 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 (540 mg, yield: 22.5%). MS-ESI m / z: 256.2 [M+H] + .

[0275] Step 2. Preparation of compound (94)-3 To an 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 a 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 to 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 an 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 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 were 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 complete, 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 using N-(methyl-d3)-5-(piperazin-1-yl)picolinamide ((95)-1) as the starting material according to a method similar to step 8 in the synthesis of compound (1). 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 hours. After the reaction was complete, dichloromethane and water were added for phase separation. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were 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 using 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid ((96)-2) as the starting material, following a similar method to steps 3-4 in the synthesis of compound 21. 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 minutes. The mixture was then concentrated to give 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 in an ice-water bath, and the mixture was stirred at room temperature for 20 minutes. 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 obtain 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 method similar to steps 2-3 in the synthesis 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 2-4 in the synthesis 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 steps 2 to 4 of the synthesis 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, the reaction 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 minutes. 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, 26.2% yield). 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 method similar to steps 6 to 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 conditions, boron trifluoride etherate (990 mg) and xenon difluoride (233.6 mg) were added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, 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 steps 6 to 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) Ethyl acetate (3.52 g) and ultra-dry tetrahydrofuran (150 mL) were added to a three-necked flask and cooled to -78 °C under nitrogen protection. Lithium diisopropylamide (2 M, 30.0 mL) was added dropwise to the reaction mixture, followed by the slow addition of a tetrahydrofuran solution of (102)-1 (2.39 g, 40 mL). The mixture was slowly warmed to room temperature and reacted 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 the slow addition of Mn(OAc)3·2H2O (2.19 g). The mixture was stirred overnight at room temperature. 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) A reaction flask was charged with ((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 quenched by slowly adding 10% aqueous KF solution dropwise. 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) To a reaction flask were added ((102)-4) (90 mg), tetrahydrofuran (3 mL), and an aqueous solution of hydrochloric acid (2 M, 1 mL), and the mixture was stirred at room temperature for 1 hour. 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 method similar 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 = 5.2 Hz, 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 using 5-chloro-2-(trifluoromethyl)pyridin-3-amine ((103)-1) as the starting material, following a similar method to steps 1 and 3-6 in the synthesis route of compound (102). 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 synthetic 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 method similar 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 method similar 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 method similar to step 8 in the synthesis 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 method similar to that in step 8 of 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: A PARP1 assay kit, specifically a 384-well chemiluminescence assay kit (catalog number: 80551), was purchased from BPS Bioscience, USA.

[0319] Experimental principle: PARP catalyzes 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 to 1x with distilled water. Test compounds (10mM stock concentration) were diluted to 10µM in DMSO solution and then serially diluted at a 1:3 ratio. The serially diluted compounds were further diluted 10x with 1x assay buffer.

[0321] Experimental method: The procedure was carried out according to the kit instructions: 1. The 5x histone mixture was diluted to 1x with PBS, and 25 μL 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 three times with PBST, and then 1.25 μL of 10x assay buffer, 1.25 μL of 10x PARP assay mixture, 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. Next, 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 three 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 three times with PBST and 50 μL of equal volumes of Substrate A and Substrate B mixed was added. The luminescence signal was immediately read on a Synergy HTX multimode reader. 8. Data analysis was performed using GraphPad Prism 8.0 software. Inhibition % = 100 x (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 50Values ​​were obtained by plotting the logarithm of compound concentration against 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 Experimental 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] Experimental Method: 1. A 4-fold enzyme reaction mixture containing PARP1, PARP2 and GST-Tb antibody was prepared using a buffer solution, and 4 μL of the enzyme reaction mixture was added to a 384-well plate. 2. 4x PARP1 and PARP2 probe reaction mixtures were prepared using buffer and 4 μL of the probe reaction mixture was added to a 384-well plate. 3. A series of gradient 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 completely consistent, and mycoplasma testing 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. UWB1.289 cells were cultured in RMPI1640 complete medium containing 10% fetal bovine serum and 1% penicillin-streptomycin.

[0333] Experimental 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 the 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 collected per well and cultured in a 96-well cell culture plate for 16 hours (culture conditions: 37° C., 5.0% CO 2 in air). 2. Test compounds stored at a concentration of 10 mM were diluted 2.5 times with DMSO, and then serially diluted with a 1:3 gradient (9 gradients). The gradient-diluted samples were further diluted 40 times 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. Then, the cells were cultured for an additional 7 days. 3. After the incubation period, the cell culture plate was 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 logarithm of compound concentration against 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 protein was purchased from Xenotech (No. M1000), and NADPH was purchased from Abmole (No. M9076).

[0340] Experimental Method: 1. 210 μL of phosphate buffer solution 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 with shaking in a 37°C water bath for 10 minutes. 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 collected 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: Evaluation of pharmacokinetics in mice Study Objective: The pharmacokinetics of the example compounds of the present application was tested in mice. By measuring the drug concentration in mouse plasma, the pharmacokinetic behavior of the compounds of the present invention was studied to evaluate their pharmacokinetic characteristics.

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

[0347] Experimental 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 20 mg / mL solution. 75 μL of this solution was then added to 150 μL of Solutol (Sigma cas: 70142-34-6), followed by 1.275 mL of 20% Captisol (Selleck cas: 182410-00-0) to obtain a final drug concentration of 1 mg / 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 30 mg / mL solution. Then, 15 μL of this solution was added to 150 μL of Solutol (Sigma cas: 70142-34-6), followed by 1.335 mL of 20% Captisol (Selleck cas: 182410-00-0) to obtain a final drug concentration of 0.3 mg / 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 the test compound in mice, and the plasma concentration of the compound was measured. Approximately 50 μL of blood was collected from each animal using capillary sampling tubes via the orbital venous plexus using heparin sodium as an anticoagulant. The blood samples were placed on ice and centrifuged at 3500 r / min for 10 minutes to separate the plasma. 20 μL of the collected plasma was 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 at 8000 r / min for 20 minutes. 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 minutes. 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 thoroughly mixed, 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 standard curves described above, 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 Study Objective: The pharmacokinetics of the example compounds of the present application was tested in rats. By measuring the drug concentration in rat plasma, the pharmacokinetic behavior of the compounds of the present invention was studied to evaluate their pharmacokinetic characteristics.

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

[0357] Experimental 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 100 mg / mL solution. 100 μL of this solution was then added to 200 μL of Solutol (Sigma cas: 70142-34-6), followed by 1.7 mL of 20% Captisol (Selleck cas: 182410-00-0) to obtain a final drug concentration of 5 mg / 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 60 mg / mL solution. Then, 50 μL of this solution was added to 100 μL of Solutol (Sigma cas: 70142-34-6), followed by 850 μL of 20% Captisol (Selleck cas: 182410-00-0) to obtain a final drug concentration of 3 mg / 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 the test compound in rats, and plasma compound concentrations were measured. Approximately 50 μL of blood was collected from each animal using capillary sampling tubes via the orbital venous plexus with sodium heparin as an anticoagulant. The blood samples were placed on ice and centrifuged at 3500 r / min for 10 minutes to separate the plasma. 20 μL of the collected plasma was 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 at 8000 r / min for 20 minutes. 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 minutes. 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 thoroughly mixed, 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] Example 6: In vivo efficacy assay 1. Murine CDX tumor model Study Objective: The efficacy of the compound 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, 4-5 weeks old, 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 five 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 line and tumor model: MDA-MB-436 cells (Nanjing Cobioer Biotechnology Co., Ltd., Catalog No. CBP60385) were cultured in vitro in DMEM complete medium containing 10% fetal bovine serum, 1% penicillin-streptomycin, 1% insulin, and 16 μg / mL glutathione at 37°C and 5% CO2. Once the cells met the requirements for in vivo efficacy experiments, they were harvested, counted, and prepared into a PBS cell suspension. Each mouse (5-6 week-old NOD SCID) was subcutaneously injected with 0.9 × 10 cells into the right flank. 7 After inoculation, tumor volumes were measured and calculated three times a week. 3 Once this was reached, the mice were grouped for dosing.

[0370] Experimental groups: The experiment was divided into the following groups: vehicle control group, olaparib 100 mg / kg group, compound 1 0.1 mg / kg group, compound 1 0.3 mg / kg group, and compound 1 1.0 mg / kg group. All groups were orally administered once daily by gavage. After administration, tumor volume and body weight were measured three times a week, and the mice were observed for activity, water intake, and feeding behavior. After 28 days of administration, tumor volume was used to calculate the tumor growth inhibition rate (TGI%), and the 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)} × 100%

[0371] Test results: As shown in Table 8, Compound 1 exhibited dose-dependent inhibition of tumor growth. The tumor inhibitory effect of 0.1 mg / kg of Compound 1 was equivalent to that of 100 mg / kg of 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 four mice per cage. All cages, bedding, and drinking water were sterilized before use. Cages, food, and water were changed twice a week. The housing 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 tumor tissue expanded in mice, it reached a size of 20–30 mm. 3A BR-05-0044E tumor tissue block was implanted subcutaneously into the right flank of each mouse. Tumor growth was monitored until the mean tumor volume reached approximately 150–200 mm. 3 Once the mice reached 100 mg / kg, they were randomly assigned to groups for treatment. Before treatment, 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. Vehicle 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 daily by gavage. Periodic monitoring included observing the effects of drug treatment on tumor growth and the animals' daily behavior (e.g., activity, food and water intake, weight change (measured twice a week), appearance, or other abnormalities). The number of animals dying and experiencing 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 using the formula: V = 0.5a x b 2 The calculation was performed using the formula: where a and b represent the length and width of the tumor, respectively.

[0379] The efficacy of the compound in inhibiting tumor growth 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 in the treatment group - mean tumor volume at the start of treatment in the treatment group) / (mean tumor volume at the end of treatment in the vehicle control group - mean tumor volume at the start of treatment in the vehicle control group)} × 100%.

[0380] Test Results: In a BR-05-0044E FP5 breast cancer mouse PDX model, Compound 1 (0.1, 0.3, 1.0 mg / kg) was orally administered by gavage once daily for 21 days. All tested doses completely inhibited tumor growth, and tumors in the treated mice completely disappeared. After administration, the mice were observed for an additional two 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, Figures 3 and 4.

[0381] [Table 12]

[0382] Experimental Example 7: Effect of compounds on rat reticulocytes Study Objective: Evaluate the effect of the compound on peripheral blood reticulocytes to determine its influence 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 and humidity were controlled within the range of (23±3)°C / 40-70%. Food and water: SPF-grade rat food 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 100 mg / kg, compound 1 0.1 mg / kg, compound 1 0.3 mg / kg, and compound 1 1.0 mg / kg. All treatments were administered orally by gavage once daily for 4 days. Blood samples were collected before and after treatment to measure peripheral blood reticulocyte counts.

[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 of 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).In combination with the pharmacodynamic results, compound 1 demonstrated a larger therapeutic range than olaparib.

[0387] [Table 13]

[0388]

[0013] Various modifications of the present invention, in addition to those described herein, will be 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 cited herein, including all patents, applications, journal articles, books, and any other disclosures, is hereby incorporated by reference in its entirety. Several embodiments are shown. Item 1 Structure of Formula (I): [ka] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, During the ceremony, [ka] is a single or double bond, X is N or CR 5 and Y is N or CR 5 ' and Z is CR 6 or N,

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Claims

1. Structure of Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, During the ceremony, 【Chemistry 2】 is a single or double bond, X is N or CR 5 and Y is N or CR 5 ' and Z is CR 6 or N, 【Transformation 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- to 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 【Transformation 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- to 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 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- to 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- to 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 optionally 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, form 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- to 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 taken 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, form 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- to 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, in each occurrence, are each independently selected from 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, 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 pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, wherein R and R' are each independently selected from the group consisting of H, -CN, and C1-6 alkyl.

3. R A But C 1～6 haloalkyl, -C(=O)R a and 【Transformation 6】 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, selected from the group consisting of:

4. RA, 【Transformation 7】 or 【Transformation 8】 4. The compound of claim 3, wherein:

5. The compound has the structure of formula (I)-1 【Chemistry 9】 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, having the formula:

6. The compound of claim 1, wherein the compound has the structure of formula (II), (III), (IV) or (V): 【Chemistry 10】 6. The compound of claim 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, having the formula:

7. R 1 and R 2 are each independently halogen, -CN, C 1～6 Alkyl or C 1～6 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, which is haloalkyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, wherein R 1 and R 2 are each independently C 1-6 alkyl or C 1-6 haloalkyl.

9. The compound of claim 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, wherein R 1 and R 2 are each independently F, -CN, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, or isopropyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, wherein R 1 and R 2 are each independently methyl, trifluoromethyl, ethyl, n-propyl, or isopropyl.

11. A compound according to claim 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, wherein R 1 is trifluoromethyl and R 2 is methyl, or R 1 and R 2 are both methyl.

12. 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 and if m>1, then two R 3 The groups may optionally be joined together to form -C 1～4 to form alkylene- Or, R 3 and R A together with the groups to which they are attached optionally form a 5- to 6-membered heteroaromatic ring, which is C 1～6 optionally substituted with haloalkyl; 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof.

13. R 3 in each occurrence is independently =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 , and when m>1, two R 3 groups optionally join together to form -C 1-4 alkylene-, or or R 3 and RA together with the group to which they are attached optionally form a triazole ring, which is optionally substituted with trifluoromethyl; 13. The compound of claim 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof.

14. A compound as described in claim 13, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, wherein R 3 , in each occurrence, is independently =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 , and when m>1, two R 3 groups optionally join together to form -CH 2 CH 2 -.

15. 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 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, each independently selected from the group consisting of:

16. The compound of claim 15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, wherein R 6 and R 7 are each independently selected from the group consisting of H, -F, -OH, -CN, -CH 2 OH, and -CH 2 NH 2 in each occurrence. 【Request Item 17】 【Chemistry 11】 but, 【Chemistry 12】 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, selected from the group consisting of: 【Request Item 18】 【Chemistry 13】 but, 【Chemistry 14】 18. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, selected from the group consisting of:

19. R 4 each occurrence independently represents a 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 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; Or, R 3 and R 4 optionally form, together with the group to which they are attached, a 5- to 6-membered heteroaromatic ring; 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof.

20. R 4 , in each occurrence, is independently selected from 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 when two R 4 groups are ortho to each other on ring A, the two R 4 groups together with the group to which they are attached form 【Chemistry 17】 optionally forming 20. The compound of claim 19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof.

21. R 4 , in each occurrence, is independently selected from F, —CN, —CH 3 , —CF 3 , [Chemistry 18] , -S(=O)2NHCH3, -C(=O)NH2, -C(=O)NHCH3, -NHC(=O)CH3, -NHC(=O)(cyclopropyl), -NHC(=O)NHCH3, -CH2OH, 【Chemistry 19】 and when two R 4 groups are ortho to each other on ring A, the two R 4 groups together with the group to which they are attached form 【Chemistry 20】 or or R 3 and R 4 together with the group to which they are attached optionally form an imidazole ring; 20. The compound of claim 19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof.

22. Ring A is C 4～6 Hydrocarbon ring, 5- to 6-membered heterocycle, C 6 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, wherein the ring is an aromatic ring or a 5- to 6-membered heteroaromatic ring.

23. The compound of claim 22, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, wherein ring A is 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.

24. The compound of claim 23, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, wherein ring A is 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. 【Request Item 25】 【Chemistry 21】 but, 【Chemistry 22】 2. The compound of claim 1, wherein: 【Request Item 26】 【Chemistry 23】 but, 【Chemistry 24】 26. The compound of claim 25, wherein:

27. The compound is 【Chemistry 25】 【change】 【change】 【change】 【change】 【change】 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, selected from the group consisting of:

28. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, and one or more pharmaceutically acceptable carriers.

29. A compound described in any one of claims 1 to 27, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or isotopically labeled compound thereof, or a pharmaceutical composition described in claim 28, for use as a PARP1 selective inhibitor.

30. 30. The compound or pharmaceutical composition for use according to claim 29, wherein the medicament is for the treatment of cancer.

31. A compound or pharmaceutical composition for use according to claim 30, wherein 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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