Substituted acetylene compound derivatives and their pharmaceutical uses

Abstract

This specification provides novel acetylene compound derivatives, compositions containing such compounds, methods for producing the sames, and uses thereof. The acetylene compound derivatives are compounds of the following chemical formula (I), or their tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates. The compounds and compositions of the present invention can be used in the treatment of polθ-mediated diseases or disorders, particularly cancer. JPEG2026522774000373.jpg51149

Description

[Technical Field]

[0001]

[0001] The present invention relates to the field of pharmaceuticals, and more particularly to acetylene derivatives having an inhibitory effect on polymerase theta, pharmaceutical compositions containing the same, and methods for producing the same and its uses. [Background technology]

[0002]

[0002] Double strand breaks (DSBs) in DNA are harmful to cells because they lead to genomic instability and induce cell death. Three pathways are used to repair DSBs in cells: non-homologous end joining (NHEJ), homologous recombination (HR), and theta-mediated end-joining (TMEJ). The NHEJ pathway joins the ends of broken DNA strands together without using a homologous template. Both the HR and TMEJ pathways use homologous sequences. However, while HR is a highly accurate DNA repair pathway, TMEJ is prone to errors due to its reliance on microhomology.

[0003]

[0003] The TMEJ pathway involves poly-(ADP-ribose)polymerase PARP1, DNA ligase III, and polymerase theta. Polymerase theta (Polθ, encoded by POLQ) is a 290kDa polymerase A-system enzyme known to accompany the TMEJ pathway (Feng et al., 2019, Nature Communications, 10:4286). Polθ has an N-terminal helicase-like domain separated by an unstructured central amino acid sequence and a C-terminal DNA polymerase domain. In the TMEJ pathway, the helicase domain of Polθ plays a role in promoting micro-homologous sequence annealing located on both sides of a double-stranded DNA (DSB), instead of replication protein A (RPA) bound to the single-stranded DNA overhang. Subsequently, the polymerase domain of Polθ initiates DNA synthesis to fill the gap (Zatreanu et al., 2021, Nature Communications, 12:3636).

[0004]

[0004] The TMEJ pathway is also known as the alternative NHEJ (alt-NHEJ) pathway or the microhomology-mediated end joining (MMEJ) pathway (Zatreanu et al., 2021, Nature Communications, 12:3636). The TMEJ pathway acts as an essential backup pathway when the NHEJ or HR pathway is damaged (Higgins, GS et al., 2018, Science, 359(6381), 1217-1218). Therefore, DNA-repair-deficient cancers rely on an alternative compensatory repair pathway, while HR- or NHEJ-deficient cancers rely on the TMEJ backup pathway. Based on the above mechanism, PARP inhibitors (PARPi) have been developed, and PARPi have been successfully used to treat HR-deficient tumors. However, PARPi frequently face resistance development problems (Drzewiecka et al., 2022, Genes, 13:1101; and Higgins, GS et al., 2018, Science, 359(6381), 1217-1218).

[0005]

[0005] Currently, polθ has emerged as another promising therapeutic target for cancer. Polθ is overexpressed in various cancers, while it is hardly expressed (almost absent) in normal cells (Higgins, GS et al., 2018. Science, 359(6381), 1217-1218; and Ceccaldi et al., 2015, Nature, 518:258). In fact, Polθ is overexpressed in human tumors, including those of the lung, stomach, small intestine, rectum, and large intestine, with particularly high levels of expression in lung cancer, breast cancer, ovarian cancer, intestinal cancer, and gastric cancer (Drzewiecka et al., 2022, Genes, 13:1101; and Higgins, GS et al., 2018. Science, 359(6381), 1217-1218). Furthermore, in vivo studies have shown that HR-deficient tumors exhibit hypersensitivity to inhibition of Polθ-mediated DNA repair, inducing synthetic lethality (Ceccaldi et al., 2015, Nature, 518:258; and Drzewiecka et al., 2022, Genes, 13:1101). When Polθ is deficient, not only tumor cells with normal HR but also HR-deficient tumor cells become more sensitive to other treatments such as radiation and chemotherapy (Drzewiecka et al., 2022, Genes, 13:1101; and Goullet de Rugy T et al., 2016, Biology open, 5(10), 1485-1492).

[0006]

[0006] Therefore, there is a need to develop novel polθ inhibitors that can effectively suppress the TMEJ pathway and be used in cancer treatment. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007]

[0007] This invention provides novel acetylene derivatives, compositions containing the same, methods for producing the same, and uses thereof. The acetylene derivatives have inhibitory activity against polymerase θ and can be effectively used in the treatment of various types of cancer.

Means for Solving the Problem

[0008]

[0008] In one aspect, the present invention relates to a compound of the following chemical formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, isotope-labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0009]

Chemical Formula

[0010] (I)

[0009]

[0011] In the chemical formula (I),

[0010]

[0012] R 1 、R 2 、R 3 、R 4 and R 5 each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3- to 10-membered cycloalkyl, cyano, hydroxy and -NR x R y and is independently selected from the group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0011]

[0013] X is selected from the group consisting of methylene, ethylene, n-propylene, -NH-, -NR z1 -, and -CR z2 R z3 -, wherein each of the methylene, ethylene and n-propylene may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0012]

[0014] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0013]

[0015] W is selected from the group consisting of carbon and sulfur;

[0014]

[0016] n is either 1 or 2, where n is 1 if W is carbon, and n is 2 if W is sulfur;

[0015]

[0017] A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl groups, where each of the aryl and heteroaryl groups is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y They may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0016]

[0018] L 1 It does not exist, and is selected from the group consisting of -(C1-C6)alkylene- and -(C1-C6)alkylene-NH-;

[0017]

[0019] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0018]

[0020] R 6The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0019]

[0021] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0020]

[0022] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0021]

[0023] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0022]

[0024] R 64 and R 65Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0023]

[0025] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0024]

[0026] R 66 is a 5-10 membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl, and amino;

[0025]

[0027] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0026]

[0028] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups;

[0027]

[0029] R z2 and R z3 These, together with the carbon atoms to which they are bonded, form a 3-6 membered cycloalkane ring, where the cycloalkane ring may be substituted with one or more selected from C1-C6 alkyl and halogen atoms; and

[0028]

[0030] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0029]

[0031]

[0032] In other aspects, the present invention provides pharmaceutical compositions for treating or preventing diseases or disorders such as polymerase θ-mediated diseases or disorders, which comprise one or more of the compounds disclosed herein, or their tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates or solvates, and pharmaceutically acceptable carriers or excipients. In certain embodiments, the composition comprises one or more compounds in therapeutically effective amounts. In certain embodiments, the composition comprises one or more compounds in prophylactically effective amounts.

[0030]

[0033] In other aspects, the present invention provides uses for the compounds disclosed herein, or their tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutical compositions disclosed herein in the manufacture of agents for the treatment or prevention of diseases or disorders mediated by polymerase θ.

[0031]

[0034] In other aspects, the present invention provides a method for treating or preventing a disease or disorder such as a polymerase θ-mediated disease or disorder in a subject, comprising the step of administering to a subject one or more compounds disclosed herein, or their tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutically acceptable compositions disclosed herein, to a subject.

[0032]

[0035] In other aspects, the present invention provides compounds disclosed herein, or tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutically acceptable compositions disclosed herein, for use in the treatment or prevention of diseases or disorders such as those mediated by polymerase θ.

[0033]

[0036] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following specific examples, embodiments and claims.

[0034]

[0037]

[0038] definition

[0035]

[0039] chemical terms

[0036]

[0040] The definitions of specific functional groups and chemical terms are explained in more detail below.

[0037]

[0041] When a range of numbers is listed, it is intended to include each number and any sub-ranges within that range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 It is intended to contain alkyl groups.

[0038]

[0042] Terms used in this specification include "C1-6 "Alkyl" refers to a saturated hydrocarbon group that is (unless otherwise specified) linear or branched and contains 1 to 6 carbon atoms. In this application, this is also referred to as a "lower alkyl" group. In some embodiments, the alkyl group contains 1 to 4 carbon atoms (C 1-4 Alkyl) or 3-6 carbon atoms (C 3-6 It may have an alkyl group. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, 2-pentyl, neo-pentyl, 3-methyl-2-butyl, tert-pentyl, n-hexyl, 2-hexyl, and 3-hexyl.

[0039]

[0043] Terms used in this specification include "C 2-6 "Alkenyl" means a hydrocarbon group that is (unless otherwise specified) linear or branched and has 2 to 6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). One or more carbon-carbon double bonds can be located internally (e.g., 2-butenyl) or terminally (e.g., 1-butenyl). In some embodiments, the alkenyl group may have 2 to 4 carbon atoms. 2-6 Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, and hexenyl.

[0040]

[0044] Terms used in this specification include "C 2-6"Alkynyl" refers to a hydrocarbon group that is (unless otherwise specified) linear or branched, containing 2 to 6 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds), and selectively containing one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, an alkynyl group may have 2 to 4 carbon atoms. In some embodiments, an alkynyl group contains no double bonds. One or more carbon-carbon triple bonds may be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, and hexynyl.

[0041]

[0045] Terms used in this specification include "C 1-6 "Alkoxy" means an -OR group (unless otherwise specified), where R is a substituted or unsubstituted C. 1-6 It is alkyl. In some embodiments, the alkoxy group can have 1 to 4 carbon atoms. Specifically, C 1-6 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0042]

[0046] As used herein, the terms "halo" or "halogen" mean fluoro(F), chloro(Cl), bromo(Br), and iodine(I) (unless otherwise specified). In some embodiments, the halo group is F, Cl, or Br. In some embodiments, the halo group is F or Cl. In some embodiments, the halo group is F.

[0043]

[0047] Terms used in this specification include "C 1-6 "Haloalkyl" and "C 1-6"Haloalkoxy" is the "C" which is substituted with one or more halo groups (unless otherwise specified). 1-6 "Alkyl" and "C 1-6 This means "alkoxy". Examples of haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, and 2,2,2-trifluoro-1,1-dimethylethyl. Examples of haloalkoxy groups include, but are not limited to, -OCH2F, -OCHF2, and -OCF3.

[0044]

[0048] Terms used in this specification include "C 3-10 "Cycloalkyl" or "3-10 membered cycloalkyl" means a cyclic hydrocarbon group that is not aromatic (unless otherwise specified) and has 3-10 cyclic carbon atoms and zero heteroatoms. In some embodiments, a cycloalkyl can have 3-8, 3-7, 3-6, 3-5, 3-4, 4-8, 4-7, 4-6, 5-8, 5-7, or 5-6 cyclic carbon atoms. A cycloalkyl further includes a cyclic system in which the cycloalkyl ring is fused with one or more aryl or heteroaryl groups, where the attachment site is the cycloalkyl ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, cyclononyl, cyclononenyl, cyclodecyl, cyclodecenyl, octahydro-1H-indenyl, decahydronaphthyl, spiro[4.5]decyl, etc.

[0045]

[0049] As used herein, the terms “3- to 10-membered heterocyclic group” or “heterocyclyl” refer to a radical of a 3- to 10-membered cyclic system having a cyclic carbon atom and at least one cyclic heteroatom, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, and phosphorus. Unless otherwise specified, a heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic system, and includes fused, spiro, or bridged cyclic systems. In some embodiments, a heterocyclyl group may have 2-7, 3-8, 3-7, 3-6, 3-5, 3-4, 4-8, 4-7, 4-6, 5-8, 5-7, or 5-6 cyclic carbon atoms and 1-4 heteroatoms. In some embodiments, a heterocyclic group may be a 7- to 11-membered (e.g., 9-membered) bicyclic spiroheterocyclic group. In some embodiments, the heterocyclic group may be a 9-10 membered bicyclic fusion heterocyclic group. In some embodiments, the heterocyclic group may be an 8-10 membered bicyclic bridged heterocyclic group.

[0046]

[0050] Exemplary three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azilidinyl, oxyranil, and thiolanil. Exemplary four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Exemplary five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Exemplary five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. Exemplary six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, pyridinonyl, dithianyl, and dioxanil. Exemplary six-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxekanyl, and thiokanyl. Examples of five-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyls) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.Exemplary oxo-substituted six-membered heterocyclyl groups include, but are not limited to, pyridinonyl groups.

[0047]

[0051] In one embodiment, the heterocyclic group comprises a saturated cyclic radical containing a carbon atom and a heteroatom selected from nitrogen, oxygen, sulfur, and phosphorus. In one embodiment, the saturated heterocyclic group may have a 3- to 10-membered heterocyclic group. In one embodiment, the saturated heterocyclic group may have an 8- to 11-membered (e.g., 9-membered) bicyclic spiroheterocyclic group. In some embodiments, the saturated heterocyclic group may have 2-7, 3-8, 3-7, 3-6, 3-5, 3-4, 4-8, 4-7, 4-6, 5-8, 5-7, or 5-6 cyclic carbon atoms and 1-4 heteroatoms. Examples of such saturated heterocyclic groups include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonil, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxo-thiomorpholinil, and 1,1-dioxo-thiomorpholinil. An example of a saturated spiroheterocric group is 2-oxa-7-azaspiro[3.5]nonan-7-yl.

[0048]

[0052] As used herein, the term “7- to 11-membered polycyclic heterocyclic group” means a monovalent heterocyclic group (unless otherwise specified) which is a polycyclic (or bicyclic) cyclic system having 7 to 11 ring atoms, comprising carbon and one or more heteroatoms (e.g., nitrogen, oxygen, and sulfur). Polycyclic cyclic systems may also be fusion cyclic systems, bridging cyclic systems, and spirocyclic systems. The system type is determined by the bridgehead carbon, which is defined as a carbon atom shared by at least two rings. A fusion cyclic system is a system in which at least two or more rings share a covalent bond and have two bridgehead carbons. A bridging cyclic system is a system in which there are carbons that are part of two or more rings, and the two or more rings are linked by a bridge containing two bridgehead carbons, with one or more carbons between the two bridgehead carbons. A spirocyclic system is a system in which two or more rings are linked by a single bridgehead carbon. Examples of polycyclic heterocyclic groups include:

[0049]

[0053] [ka]

[0050]

[0054] As used herein, the term “aromatic group” means a cyclic structure having a cyclic cloud of delocalized π electrons in the molecular plane, where the π cloud contains (4n+2)π electrons, unless otherwise specified. Further discussion of aromaticity can be found in Morrison and Boyd, *Organic Chemistry*, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477–497, which is incorporated herein by reference. The term “aromatic group” includes both aryl and heteroaryl groups.

[0051]

[0055] Terms used in this specification include "C 6-14 "Aryl" means a radical of a carboxylic aromatic group having 6 to 14 cyclic carbon atoms and zero heteroatoms, regardless of whether it is fused with one or more groups (unless otherwise specified). In one embodiment, an aryl may have 6 to 10 membered cyclic carbon atoms. The aryl group may be monocyclic or polycyclic (e.g., bicyclic or tricyclic). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracyl. The aryl group further includes a cyclic system in which the aryl ring is fused with one or more cycloalkyl or heterocyclyl groups, with the attachment site being the aryl ring, as defined herein.

[0052]

[0056] As used herein, the term “5- to 12-membered heteroaryl” means any monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic cyclic system having a cyclic carbon atom and at least one heteroatom (e.g., nitrogen, oxygen, and sulfur) (unless otherwise specified). A heteroaryl group also includes a cyclic system in which the heteroaryl ring, as defined herein, is fused with one or more cycloalkyl, heterocyclyl, or aryl groups, with the attachment site being the heteroaryl ring. In some embodiments, a heteroaryl group may have 3-8, 3-7, 4-7, 5-10, 5-7, or 5-6 cyclic carbon atoms or heteroatoms.

[0053]

[0057] Exemplary five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl (e.g., 1,2,4-triazinyl, 1,3,5-triazinyl) and tetradinyl. Exemplary seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bisiclyc heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bisiclyc heteroaryl groups include, but are not limited to, naphthilidinyl, pteridinyl, quinolinyl, isoquinolinyl, synnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0054]

[0058] As used herein, the terms “deuterated,” “deuterated,” or “D” mean (unless otherwise specified) that one or more hydrogen atoms in a compound or group are replaced with deuterium. Deuterated can be single substitution, double substitution, triple substitution, multiple substitution, or complete substitution. The term “substituted with one or more deuterium atoms” is used interchangeably with “deuterated one or more times.”

[0055]

[0059] As used herein, the term "non-deuterated compound" means a compound in which the deuterium atom content is not higher than the natural content of deuterium isotopes (0.015%), unless otherwise specified.

[0056]

[0060] The deuterium isotope content at the deuterated position is at least greater than the natural deuterium isotope content (0.015%), or greater than 30%, or greater than 50%, or greater than 75%, or greater than 95%, or greater than 99%.

[0057]

[0061] Terms used in this specification include "C 1-6 "Alkylene" refers to a divalent alkyl group, which is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms (unless otherwise specified). Formulatly, an alkylene group corresponds to an alkane in which two CH bonds are substituted for the rest of the compound at the sites where the alkylene group attaches. In some embodiments, the alkylene group has 1 to 4 carbon atoms (C 1-4 Alkylene) or 1-2 carbon atoms (C 1-2 It may have an alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, and 2-methyl-propane-1,3-diyl.

[0058]

[0062] As used herein, the term "carbamoyl" means (unless otherwise specified) a -C(=O)-NR'R'' group, where R' and R'' are independently hydrogen or C 1-6 This indicates an alkyl group.

[0059]

[0063] As used herein, the terms “selective” or “selectively” mean that the events or situations described herein may or may not occur, and that detailed descriptions include not only cases in which the events or situations occur, but also cases in which they do not occur. For example, “may be substituted” means not only events or situations in which a chemical group (e.g., a group as defined herein) may be substituted, but also events or situations in which a chemical group is not substituted.

[0060]

[0064] The term “substituted” means a moiety having substituents that replace hydrogens on one or more carbon atoms in the skeleton. It should be understood that “substituted” or “substituted” implies the implicit condition that such substitution is carried out by the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound in which no spontaneous deformations such as rearrangement, cyclization, or removal occur. As used herein, the term “substituted” is considered to include all permissible substituents in an organic compound. Exemplary substituents on carbon atoms include C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), 3-10 membered (e.g., 3-8 membered, 5-6 membered, 3-5 membered) cycloalkyl, hydroxy, amino, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), carbamoyl, oxo, 3-8 membered heterocyclic or heteroaryl groups, -COR z1 (Here, R z1(Selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen), and -CON(R z2 )(R z3 )(Here, R z2 and R z3 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, or halogen, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen; or R z2 and R z3 These, together with the nitrogen atom to which they are attached, form a nitrogen-containing 3-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups. (These include, but are not limited to, alkyl, alkenyl, alkoxy, alkylene, cycloalkyl, heterocyclic, or heteroaryl groups, where each of the alkyl, alkenyl, alkoxy, alkylene, cycloalkyl, heterocyclic, or heteroaryl groups may be independently substituted with one or more selected from C1-C6 alkyl and halogen groups.) The number of substituents is any number, as long as the valence of the substituted atom and the substituents allow it, for example, 1-5, 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, etc.

[0061]

[0065]

[0066] Common terminology

[0062]

[0067] When used with a numerical value, the term "approximately" includes a variation of ±20% of the value, generally within ±10%, sometimes within ±5%, and most often within ±2%. In some specific instances, the term "approximately" may refer to the numerical value itself.

[0063]

[0068] Unless otherwise specified, any singular expression should be considered to include the concept of the plural expression. Therefore, unless otherwise specified, any article expressing a singular concept (e.g., "a," "an," "the" in English) should be considered to include the plural concept.

[0064]

[0069] Unless otherwise specified, any terms used in this description should be considered to have their ordinary meaning in the art. Therefore, unless otherwise specified, all scientific and other technical terms used in this description have the meanings generally understood by those skilled in the art to which this invention pertains. In case of any conflict in meaning, this description (including definitions) shall prevail. [Modes for carrying out the invention]

[0065]

[0070] compound

[0066]

[0071] According to one aspect of the present invention, compounds of chemical formula (I) (including subsets of each chemical formula), or tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates thereof are provided.

[0067]

[0072] As used herein, “compound of the present invention” means the compound of the following chemical formula (I) (including the subsets of each chemical formula), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0068]

[0073] In one embodiment, the present invention relates to a compound of the following chemical formula (I), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0069]

[0074] [ka]

[0070]

[0075] (I)

[0071]

[0076] In the above chemical formula (I),

[0072]

[0077] R 1 、R 2 、R 3 、R 4 and R 5 each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3- to 10-membered cycloalkyl, cyano, hydroxy and -NR x R y and is independently selected from the group consisting of, where each of the alkyl, alkenyl, alkoxy and cycloalkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0073]

[0078] X represents methylene, ethylene, n-propylene, -NH-, -NR z1 -, and -CR[[ID=三十一]] z2 R z3 - and is selected from the group consisting of, where each of the methylene, ethylene and n-propylene may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0074]

[0079] Each of Y and Z is independently selected from the group consisting of -N- and -CR w -;

[0075]

[0080] W is selected from the group consisting of carbon and sulfur;

[0076]

[0081] n is 1 or 2, provided that when W is carbon, n is 1, and when W is sulfur, n is 2;

[0077]

[0082] It should be noted that in the translation, the chemical formula-related content is presented in a literal translation to maintain the integrity of the original patent text, but in actual chemical understanding, more accurate chemical term translations and interpretations may be required according to specific chemical knowledge. Also, the numbering and tags are retained as per the requirements while some of the translated text may seem a bit rigid in terms of grammar for better readability in a chemical context. If there are any further specific chemical-related requirements or adjustments, it can be further optimized.A is selected from the group consisting of monocyclic or bicyclic aryl or heteroaryl having 5 to 12 members, wherein each of said aryl and heteroaryl is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3- to 10-membered cycloalkyl, -NR x R y , amino, mercapto and carbamoyl, and may be substituted with one or more selected from the group consisting of, wherein each of said alkyl, alkenyl, alkoxy and cycloalkyl may be independently substituted with one or more selected from the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0078]

[0083] L 1 is absent, and is selected from the group consisting of -(C1-C6) alkylene- and -(C1-C6) alkylene-NH-;

[0079]

[0084] L 2 is absent, and is selected from the group consisting of -(C1-C6) alkylene-, and wherein said alkylene may be substituted with one or more selected from the group consisting of C1-C6 alkyl and halogen;

[0080]

[0085] R 6 is selected from the group consisting of phenyl and 3- to 10-membered heterocyclyl groups, wherein each of said phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5- to 6-membered heterocyclyl and -CH2-R 66They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0081]

[0086] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0082]

[0087] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0083]

[0088] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0084]

[0089] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0085]

[0090] R 64 and R 65These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0086]

[0091] R 66 is a 5-10 membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl, and amino;

[0087]

[0092] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0088]

[0093] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups;

[0089]

[0094] R z2 and R z3 These, together with the carbon atoms to which they are bonded, form a 3-6 membered cycloalkane ring, where the cycloalkane ring may be substituted with one or more selected from C1-C6 alkyl and halogen atoms; and

[0090]

[0095] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x Ry Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0091]

[0096]

[0097]

[0098] Ring A

[0092]

[0099] In one embodiment, A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl compounds, preferably A is selected from the group consisting of 6-10 member monocyclic or bicyclic aryl or heteroaryl compounds, more preferably A is selected from the group consisting of 6-member monocyclic aryl or heteroaryl compounds and 10-member bicyclic aryl or heteroaryl compounds, and even more preferably A is a 6-member monocyclic aryl or heteroaryl compound, where each of the aryl and heteroaryl compounds is independently a C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y , may be substituted with one or more selected from amino, mercapto and carbamoyl, where each of the alkyl, alkenyl, alkoxy and cycloalkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; and, R 1 ~R 6 , L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0093]

[0100] In one embodiment, A is selected from phenyl, pyridinyl, pyrrolyl, pyrazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolidinyl, quinoxalinyl, phthalazinyl, quinazolinyl, synnolinyl and naphthyl, where the aforementioned phenyl, pyridinyl, pyrrolyl, pyrazolyl, pyridadinyl Each of the following is independently a C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 member cycloalkyl and -NR x R y They may be substituted with one or more selected from, where each of the alkyl, alkenyl, alkoxy and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl groups; R 1 ~R 6 , L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0094]

[0101] In one embodiment, A is phenyl, where phenyl is C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 member cycloalkyl and -NR x R y They may be substituted with one or more selected from, where each of the alkyl, alkenyl, alkoxy and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl groups; and R 1 ~R 6 , L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0095]

[0102] In one embodiment, A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl compounds, preferably A is selected from the group consisting of 6-10 member monocyclic or bicyclic aryl or heteroaryl compounds, more preferably A is selected from the group consisting of 6-member monocyclic aryl or heteroaryl compounds and 10-member bicyclic aryl or heteroaryl compounds, and even more preferably A is a 6-member monocyclic aryl or heteroaryl compound, where each of the aryl and heteroaryl compounds may be independently substituted with one or more selected from unsubstituted C1-C6 alkyl compounds, halogen-substituted C1-C6 alkyl compounds, and halogen compounds; more preferably each of the aryl and heteroaryl compounds may be independently substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine compounds; even more preferably each of the aryl and heteroaryl compounds may be independently substituted with one or more selected from methyl, fluoro, or chloro compounds; and R 1 ~R 6 , L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0096]

[0103] In one embodiment, A is selected from the group consisting of phenyl, pyridinyl, pyrrolyl, pyrazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolidinyl, quinoxalinyl, phthalazinyl, quinazolinyl, sinnolinyl, and naphthyl, where each of the aforementioned phenyl, pyridinyl, pyrrolyl, pyrazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolidinyl, quinoxalinyl, phthalazinyl, quinazolinyl, sinnolinyl, and naphthyl is independently an unsubstituted C1-C6 alkyl or a halogen-substituted C1-C6 alkyl. They may be substituted with one or more selected from alkyl, halogen, cyano, or deuterium; preferably, each of the aryl and heteroaryl may be independently substituted with one or more selected from unsubstituted C1-C6 alkyl and halogen-substituted C1-C6 alkyl or halogen; more preferably, each of the aryl and heteroaryl may be independently substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, or iodine; more preferably, each of the aryl and heteroaryl may be independently substituted with one or more selected from methyl, fluoro, and chloro; and, R 1 ~R 6 , L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0097]

[0104] In one embodiment, A is phenyl, where the phenyl may be substituted with one or more selected from unsubstituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen, cyano and deuterium; preferably, the phenyl may be substituted with one or more selected from unsubstituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl and halogen; more preferably, the phenyl may be substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo and iodine; even more preferably, the phenyl may be substituted with one or more selected from methyl, fluoro and chloro; and R 1 ~R 6 , L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0098]

[0105]

[0106] In one specific example, A is, [ka] And,

[0099]

[0107] Here,

[0100]

[0108] R a1 This is selected from the group consisting of hydrogen and fluorides;

[0101]

[0109] R a2 It is selected from the group consisting of methyl and chloride;

[0102]

[0110] R a3 This is selected from the group consisting of hydrogen and fluorides;

[0103]

[0111] Ra4 is selected from the group consisting of hydrogen and methyl;

[0104]

[0112] R a5 is selected from the group consisting of hydrogen and fluorides; and

[0105]

[0113] R 1 ~R 6 , L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0106]

[0114]

[0115] X

[0107]

[0116] In one specific example,

[0108]

[0117] X is methylene, ethylene, n-propylene, -NH-, -NR z1 - and -CR z2 R z3 -Selected from the group consisting of, where each of methylene, ethylene, and n-propylene may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl,

[0109]

[0118] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups, and

[0110]

[0119] R z2 and R z3These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered cycloalkane ring, where the cycloalkane ring may be substituted with one or more elements selected from C1-C6 alkyl groups and halogens;

[0111]

[0120] Preferably,

[0112]

[0121] X is methylene, ethylene, n-propylene, -NH-, -NR z1 - and -CR z2 R z3 - Selected from the group consisting of,

[0113]

[0122] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups.

[0114]

[0123] R z2 and R z3 These, together with the carbon atoms to which they are bonded, form a 3-5 membered cycloalkane ring, where the cycloalkane ring may be substituted with one or more selected from C1-C6 alkyl and halogen atoms; and

[0115]

[0124] R 1 ~R 6 , rings A, L 1 , L 2 Y, Z, W, and n are synonymous with the definitions above.

[0116]

[0125]

[0126] In one example, X is methylene, ethylene, n-propylene, -NH-, -NR z1 - and -CR z2 R z3 - Selected from the group consisting of,

[0117]

[0127] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano compounds, and deuterium.

[0118]

[0128] R z2 and R z3 These, together with the carbon atoms to which they are bonded, form cyclopropane, cyclobutane, or cyclopentane, which may be substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromo, and iodine.

[0119]

[0129] Preferably,

[0120]

[0130] X is methylene, ethylene, n-propylene, -NH-, -NR z1 - and -CR z2 R z3 - Selected from the group consisting of,

[0121]

[0131] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a C1-C6 alkyl group.

[0122]

[0132] R z2 and R z3 These, together with the carbon atoms to which they are bonded, form cyclopropane, cyclobutane, or cyclopentane, which may be substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromo, and iodine, and

[0123]

[0133] R 1 ~R 6 , rings A, L 1 , L 2 Y, Z, W, and n are synonymous with the definitions above.

[0124]

[0134]

[0135] In one specific example, X is methylene, -NR z1 - and -CR z2 R z3 - Selected from the group consisting of,

[0125]

[0136] R z1 This is selected from the group consisting of methyl, ethyl, n-propyl and n-butyl, which may be substituted with C1-C6 alkyl, and

[0126]

[0137] R z2 and R z3 These, together with the carbon atoms to which they are bonded, form cyclopropane or cyclobutane, which may be substituted with one or more selected from methyl, isopropyl, fluoro, and chloro.

[0127]

[0138] Preferably,

[0128]

[0139] X is methylene, -NR z1 - and -CR z2 R z3 - Selected from the group consisting of,

[0129]

[0140] R z1 is methyl or ethyl, which may be substituted with a C1-C6 alkyl, and

[0130]

[0141] R z2 and R z3 These, together with the carbon atoms to which they are bonded, form cyclopropane, which may be substituted with one or more selected from methyl, isopropyl, fluoro, and chloro.

[0131]

[0142] more,

[0132]

[0143] X is methylene, -NR z1 - and -CR z2 R z3 - Selected from the group consisting of,

[0133]

[0144] R z1 is methyl or ethyl, which may be substituted with methyl or ethyl, and

[0134]

[0145] R z2 and R z3 These, together with the carbon atoms to which they bond, form cyclopropane;

[0135]

[0146] More preferably,

[0136]

[0147] X is methylene, -NR z1 - and -CR z2 R z3 - Selected from the group consisting of,

[0137]

[0148] R z1 This is methyl or ethyl, and may be substituted with methyl.

[0138]

[0149] R z2 and R z3 These, together with the carbon atoms to which they bond, form cyclopropane;

[0139]

[0150] More preferably,

[0140]

[0151] X is methylene, -NR z1 - and -CR z2 R z3 - Selected from the group consisting of,

[0141]

[0152] R z1 It is methyl or isopropyl,

[0142]

[0153] R z2 and R z3 These, together with the carbon atoms to which they bond, form cyclopropane; and

[0143]

[0154] R 1 ~R 6 , rings A, L 1 , L 2 Y, Z, W, and n are synonymous with the definitions above.

[0144]

[0155]

[0156] Y

[0145]

[0157] In one specific example, Y is -N- and -CR w -Selected from the group consisting of -, preferably Y is -CR w -and here, R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl; more preferably, Y is -CR w -and here, R w is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium; more preferably, Y is -CH- and R 1 ~R 6 , rings A, L 1 , L 2 X, Z, W, and n are synonymous with the definitions above.

[0146]

[0158]

[0159] Z

[0147]

[0160] In one specific example, Z is -N- and -CR w - is selected from the group consisting of R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl; preferably, Z is -N- and -CR w - is selected from the group consisting of R w is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium; more preferably, Z is -CH- and R 1 ~R 6 , rings A, L 1 , L 2 X, Y, W, and n are synonymous with the definitions above.

[0148]

[0161]

[0162] W, n

[0149]

[0163] In one embodiment, W is selected from the group consisting of carbon and sulfur; n is 1 or 2; R 1 -R 6 , rings A, L 1 , L 2 X, Y, and Z are the same as the definitions above. If W is carbon, then n is 1 and R 1 -R 6 , rings A, L 1 , L 2 X, Y, and Z are the same as the definitions above. If W is sulfur, then n is 2 and R 1 -R 6 , rings A, L 1 , L 2 X, Y, and Z are synonymous with the definitions above.

[0150]

[0164]

[0165] L 1

[0151]

[0166] In one specific example, L 1 is selected from the group consisting of -(C1-C6)alkylene- and -(C1-C6)alkylene-NH- that does not exist; preferably, L 1 is selected from the group consisting of methylene, ethylene, n-propylene, isopropylene, n-butylene, -methylene-NH-, -ethylene-NH-, -n-propylene-NH-, -iso-propylene-NH- and -n-butylene-NH-; more preferably L 1 is selected from the group consisting of non-existent and methylene; and R 1 -R 6 , rings A, X, L 2 Y, Z, W, and n are synonymous with the definitions above.

[0152]

[0167]

[0168] L 2

[0153]

[0169] In one specific example, L 2 is selected from the group consisting of non-existent and -(C1-C6)alkylene-, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen; preferably, L 2 The following do not exist: methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,1-propylene, 1,1-butylene, 1,2-butylene, 2,2-butylene and [ka] Selected from the group consisting of; more preferably, L 2 Methylene and do not exist. [ka] Selected from the group consisting of; and R 1 -R 6 , rings A, X, L 1 Y, Z, W, and n are synonymous with the definitions above.

[0154]

[0170]

[0171] R 1

[0155]

[0172] In one specific example, R 1 These include hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, and -NR. x R y Selected from the group consisting of, where each of the alkyl, alkenyl, alkoxy and cycloalkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; preferably, R 1 R is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; more preferably, 1 is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano and deuterium; more preferably, R 1 R is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a halogen; and 2 -R 6 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0156]

[0173] In one concrete example, R 1is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl, which may be substituted with a halogen; preferably, R 1 is selected from the group consisting of methyl and trifluoromethyl; more preferably, R 1 is methyl; and, R 2 -R 6 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0157]

[0174]

[0175] R 2

[0158]

[0176] In one concrete example, R 2 These include hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, and -NR. x R y Selected from the group consisting of, where each of the alkyl, alkenyl, alkoxy and cycloalkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; preferably, R 2 R is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; more preferably, 2 is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano and deuterium; more preferably, R 2 is a C1-C6 alkyl group, where the alkyl group may be independently substituted with one or more selected from C1-C6 alkyl groups, halogens, cyanos, and deuterium; and R 1 , R 3 -R 6 , rings A, L1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0159]

[0177] In one concrete example, R 2 is a C1-C6 alkyl group, where the alkyl group may be independently substituted with a halogen; preferably, R 2 is selected from the group consisting of methyl, ethyl, and propyl, which may be independently substituted with halogens; more preferably, R 2 is trifluoromethyl; and, R 1 , R 3 -R 6 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0160]

[0178]

[0179] R 3

[0161]

[0180] In one concrete example, R 3 These include hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, hydroxy, and -NR. x R y Selected from the group consisting of, where each of the alkyl, alkenyl, alkoxy and cycloalkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; preferably, R 3 R is selected from the group consisting of hydrogen, halogen, hydroxyl, and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; more preferably, 3is selected from the group consisting of hydrogen, halogen, hydroxyl and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano and deuterium; more preferably, R 3 is selected from the group consisting of hydrogen, fluoride, chloride, bromide, iodine, hydroxyl, and C1-C6 alkyl; more preferably, R 3 R is selected from the group consisting of hydrogen, fluoride, and hydroxyl; and 1 , R 2 , R 4 -R 6 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0162]

[0181]

[0182] R 4

[0163]

[0183] In one concrete example, R 4 These include hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, and -NR. x R y Selected from the group consisting of, where each of the alkyl, alkenyl, alkoxy and cycloalkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; preferably, R 4 R is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; more preferably, 4 is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano and deuterium; more preferably, R 4is selected from the group consisting of hydrogen and C1-C6 alkyl, and more preferably R 4 is hydrogen; and, R 1 -R 3 , R 5 , R 6 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0164]

[0184]

[0185] R 5

[0165]

[0186] In one concrete example, R 5 These include hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, and -NR. x R y Selected from the group consisting of, where each of the alkyl, alkenyl, alkoxy and cycloalkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; preferably, R 5 R is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; more preferably, 5 is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano and deuterium; more preferably, R 5 is selected from the group consisting of hydrogen and C1-C6 alkyl, and more preferably R 5 is hydrogen; and, R 1 -R 4 , R 6 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0166]

[0187]

[0188] R 6

[0167]

[0189] In one concrete example, R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0168]

[0190] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0169]

[0191] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0170]

[0192] R 63This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0171]

[0193] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0172]

[0194] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0173]

[0195] R 66 R is a 5-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl and amino; R 1 -R 5 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0174]

[0196]

[0197] In one concrete example, R 6 This is a 3-10 membered heterocyclyl group, where the heterocyclyl group is C1-C6 alkyl, halogen, cyano, oxo, carbamoyl, C1-C6 alkoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0175]

[0198] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0176]

[0199] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and halogens;

[0177]

[0200] R 63 This is selected from the group consisting of C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with a halogen;

[0178]

[0201] R 64 and R 65 Each of them is selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0179]

[0202] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group;

[0180]

[0203] R 66 is a 6-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from oxo and carbamoyl groups; and,

[0181]

[0204] R 1 -R 5 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0182]

[0205]

[0206] In one concrete example, R 6 This is a 5-6 member monocyclic heterocyclyl group or a 9-10 member bicyclic heterocyclyl group, where the heterocyclyl group is C1-C6 alkyl, halogen, cyano, oxo, carbamoyl, C1-C6 alkoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0183]

[0207] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0184]

[0208] R 61 and R 62These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and halogens;

[0185]

[0209] R 63 This is selected from the group consisting of C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with a halogen;

[0186]

[0210] R 64 and R 65 Each of them is selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0187]

[0211] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group;

[0188]

[0212] R 66 is a 6-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from oxo and carbamoyl groups; and,

[0189]

[0213] R 1 -R 5 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0190]

[0214]

[0215] In one concrete example, R 6 The group is selected from the following:

[0191]

[0216]

[0217] [ka]

[0192]

[0218] [ka] [ka]

[0193]

[0219] [ka]

[0194]

[0220] [ka]

[0221] [ka]

[0195]

[0222] Here,

[0196]

[0223] R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R6h and R 6i Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, oxo, carbamoyl, C1-C6 alkoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 A group independently selected from the group consisting of the following, where each of the alkyl, alkoxy, and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0197]

[0224] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0198]

[0225] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and halogens;

[0199]

[0226] R 63 This is selected from the group consisting of C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with a halogen;

[0200]

[0227] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0201]

[0228] R64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group;

[0202]

[0229] R 66 is a 6-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from oxo and carbamoyl groups; and

[0203]

[0230] R 1 -R 5 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0204]

[0231]

[0232] In one concrete example, R 6 The group is selected from the following:

[0205]

[0233] [ka] [ka]

[0206]

[0234] Here,

[0207]

[0235] R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R6c , R 6d , R 6e , R 6f , R 6g , R 6h and R 6i Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, oxo, carbamoyl, C1-C6 alkoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 A group independently selected from the group consisting of the following, where each of the alkyl, alkoxy, and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0208]

[0236] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0209]

[0237] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and halogens;

[0210]

[0238] R 63 This is selected from the group consisting of C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with a halogen;

[0211]

[0239] R 64 and R 65Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0212]

[0240] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group;

[0213]

[0241] R 66 is a 6-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from oxo and carbamoyl groups; and

[0214]

[0242] R 1 -R 5 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0215]

[0243]

[0244] In one concrete example, R 6 The group is selected from the following:

[0216]

[0245] [ka] [ka]

[0217]

[0246] Here,

[0218]

[0247] R 611 , R 612 , R 613 , R 614 , R 621 , R 631, R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and R 6i Each of these is hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, fluoro, chloro, bromo, iodine, cyano, oxo, carbamoyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, n-propoxy, isopropoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , pyrazinyl, pyrimidinyl, triazolyl, oxadiazolyl and -CH2-R 66 Independently selected from the group consisting of;

[0219]

[0248] R 61 and R 62 Each of these is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and isopropyl, or

[0220]

[0249] R 61 and R 62 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0221]

[0250] [ka]

[0222]

[0251] R 63This is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, NH2, ethenyl, 1-fluoroethenyl, and 1,2-difluoroethenyl;

[0223]

[0252] R 64 and R 65 Each of these is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and isopropyl, or

[0224]

[0253] R 64 and R 65 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0225]

[0254] [ka]

[0226]

[0255] R 66 This is a 6-10 membered heterocyclyl group, which is as follows:

[0227]

[0256] [ka]

[0228]

[0257] R 1 -R 5 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0229]

[0258]

[0259] In one concrete example, R 6 The group is selected from the following:

[0230]

[0260] [ka] [ka]

[0231]

[0261] Here,

[0232]

[0262] R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and R 6i Each of these is hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 -CH2-R 66 ,

[0233]

[0263]

[0264] [ka]

[0234] Independently selected from the group consisting of;

[0235]

[0265] R 61 and R 62 Each of these is selected from the group consisting of hydrogen, ethyl and isopropyl, or

[0236]

[0266] R 61 and R 62 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0237]

[0267] [ka]

[0238]

[0268] R 63 This is selected from the group consisting of methyl, NH2, ethenyl, and 1-fluoroethenyl;

[0239]

[0269] R 64 and R 65 Each of them is selected from the group consisting of hydrogen and methyl, or

[0240]

[0270] R 64 and R 65 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0241]

[0271] [ka]

[0242]

[0272] R 66 This is a 6-10 membered heterocyclyl group, which is as follows:

[0243]

[0273] [ka]

[0244]

[0274]

[0275] R 1 -R 5 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0245]

[0276] In one concrete example, R 6 is phenyl, where phenyl is defined as C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium; R 1 -R 5 , R 61 -R 66 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0246]

[0277] In one concrete example, R 6 is phenyl, where phenyl is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2 and -C(O)NR 64 R 65They may be substituted with one or more selected from, where each of the alkyl and alkoxy may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0247]

[0278] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl; and,

[0248]

[0279] R 1 -R 5 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0249]

[0280] In one concrete example, R 6 is phenyl, where phenyl is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy and -C(O)NR 64 R 65 The alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, and deuterium;

[0250]

[0281] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl; and R 1 -R 5 , R 64 -R 65 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0251]

[0282] In one concrete example, R 6is phenyl, where the phenyl may be substituted with carbamoyl; and R 1 -R 5 , R 64 -R 65 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0252]

[0283] In one concrete example, R 6 teeth,

[0253]

[0284] [ka] And,

[0254]

[0285] Here,

[0255]

[0286] R 651 , R 652 , R 653 , R 654 and R 655 Each of them is hydrogen or carbamoyl, and R 1 -R 5 , R 64 -R 65 , rings A, L 1 , L 2 X, Y, Z, W, and n are synonymous with the definitions above.

[0256]

[0287]

[0288] In one embodiment, the present invention relates to compounds of chemical formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) or their tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates:

[0257]

[0289]

[0290] [ka]

[0258]

[0291]

[0292]

[0293] [ka]

[0259]

[0294]

[0295] [ka]

[0260]

[0296] [ka]

[0261]

[0297] [ka]

[0262]

[0298] Here,

[0263]

[0299] R 1 , R 2 , R 3 , R 4 and R 5 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, hydroxy, and -NR. x R y A group consisting of the following is independently selected, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0264]

[0300] X is methylene, ethylene, n-propylene, -NH-, -NR z1 - and -CR z2 R z3 -Selected from the group consisting of, where each of the methylene, ethylene, and n-propylene may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0265]

[0301] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0266]

[0302] W is selected from the group consisting of carbon and sulfur;

[0267]

[0303] n is either 1 or 2, where n is 1 if W is carbon, and n is 2 if W is sulfur;

[0268]

[0304] A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl groups, where each of the aryl and heteroaryl groups is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y They may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0269]

[0305] L 1It does not exist, and is selected from the group consisting of -(C1-C6)alkylene- and -(C1-C6)alkylene-NH-;

[0270]

[0306] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0271]

[0307] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0272]

[0308] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0273]

[0309] R 61 and R 62These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0274]

[0310] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0275]

[0311] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0276]

[0312] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0277]

[0313] R 66 is a 5-10 membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl, and amino;

[0278]

[0314] R x and R yEach of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0279]

[0315] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups;

[0280]

[0316] R z2 and R z3 These, together with the carbon atoms to which they are bonded, form a 3-6 membered cycloalkane ring, where the cycloalkane ring may be substituted with one or more selected from C1-C6 alkyl and halogen atoms; and

[0281]

[0317] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0282]

[0318]

[0319]

[0320] Non-restrictive illustrative examples

[0283]

[0321]

[0284]

[0322]

[0285] In one embodiment, the present invention relates to a compound of chemical formula (II), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0286]

[0323] [ka]

[0287]

[0324] (II)

[0288]

[0325] In the above chemical formula (II),

[0289]

[0326] R 1 , R 2 , R 3 , R 4 and R 5 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, hydroxy, and -NR. x R y A group consisting of the following is independently selected, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0290]

[0327] A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl groups, where each of the aryl and heteroaryl groups is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y They may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0291]

[0328] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0292]

[0329] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0293]

[0330] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0294]

[0331] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0295]

[0332] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; and

[0296]

[0333] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R ySelected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0297]

[0334]

[0335]

[0336] In one embodiment, the present invention relates to a compound of the following chemical formula (IIa-1), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0298]

[0337] [ka]

[0338] (IIa-1)

[0299]

[0339] In the above chemical formula (IIa-1),

[0300]

[0340] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0301]

[0341] L 2The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0302]

[0342] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0303]

[0343] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0304]

[0344] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[0305]

[0345]

[0346]

[0347] In one embodiment of the compound of chemical formula (IIa-1), R a1 , R a2 , R a3 , R a4 and R a5 Each of these is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine;

[0306]

[0348] L 2 The following do not exist: methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,1-propylene, 1,1-butylene, 1,2-butylene, 2,2-butylene and [ka] Selected from the group consisting of; and

[0307]

[0349] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0308]

[0350] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and halogens.

[0309]

[0351]

[0352] In one embodiment of the compound of chemical formula (IIa-1),

[0310]

[0353] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is selected from the group consisting of hydrogen, methyl, fluoro, and chloro;

[0311]

[0354] L 2 Methylene and do not exist. [ka] Selected from the group consisting of; and

[0312]

[0355] R 61 and R 62 Each of these is selected from the group consisting of hydrogen, ethyl and isopropyl, or

[0313]

[0356] R 61 and R 62 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0314]

[0357] [ka]

[0315]

[0358] In one embodiment, the present invention relates to a compound of chemical formula (III), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0316]

[0359] [ka]

[0360] (III)

[0317]

[0361] In the above chemical formula (III),

[0318]

[0362] R 1 , R 2 , R 3 , R 4 and R 5Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, hydroxy, and -NR. x R y A group consisting of the following is independently selected, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0319]

[0363] X is methylene, ethylene, n-propylene, -NH-, -NR z1 - and -CR z2 R z3 -Selected from the group consisting of, where each of the methylene, ethylene, and n-propylene may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0320]

[0364] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0321]

[0365] W is selected from the group consisting of carbon and sulfur;

[0322]

[0366] n is either 1 or 2, where n is 1 if W is carbon, and n is 2 if W is sulfur;

[0323]

[0367] A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl groups, where each of the aryl and heteroaryl groups is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R yThey may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0324]

[0368] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0325]

[0369] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0326]

[0370] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0327]

[0371] R 61 and R 62These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0328]

[0372] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0329]

[0373] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0330]

[0374] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0331]

[0375] R 66 is a 5-10 membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl, and amino;

[0332]

[0376] R x and R yEach of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0333]

[0377] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups;

[0334]

[0378] R z2 and R z3 These, together with the carbon atoms to which they are bonded, form a 3-6 membered cycloalkane ring, where the cycloalkane ring may be substituted with one or more selected from C1-C6 alkyl and halogen atoms; and

[0335]

[0379] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0336]

[0380]

[0381]

[0382] In one embodiment, the present invention relates to a compound of the following chemical formula (IIIa), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0337]

[0383] [ka]

[0384] (IIIa)

[0385]

[0338] In the above chemical formula (IIIa),

[0339]

[0386] R 1 , R 2 , R 3 , R 4 and R 5 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, hydroxy, and -NR. x R y A group consisting of the following is independently selected, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0340]

[0387] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0341]

[0388] A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl groups, where each of the aryl and heteroaryl groups is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y They may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0342]

[0389] L 2The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0343]

[0390] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0344]

[0391] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0345]

[0392] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0346]

[0393] R 63This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0347]

[0394] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0348]

[0395] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0349]

[0396] R 66 is a 5-10 membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl, and amino;

[0350]

[0397] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; and

[0351]

[0398] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x Ry Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0352]

[0399]

[0400]

[0401] In one embodiment, the present invention relates to a compound of the following chemical formula (IIIa-1), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0353]

[0402] [ka]

[0403] (IIIa-1)

[0354]

[0404] In the above chemical formula (IIIa-1),

[0355]

[0405] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0356]

[0406] L 2The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0357]

[0407] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0358]

[0408] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0359]

[0409] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0360]

[0410] R 63This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0361]

[0411] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0362]

[0412] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0363]

[0413] R 66 is a 5-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl and amino; and

[0364]

[0414] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[0365]

[0415]

[0416]

[0417] In one embodiment of the compound of chemical formula (IIIa-1), R a1 , Ra2 , R a3 , R a4 and R a5 Each of these is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine;

[0366]

[0418] L 2 The following do not exist: methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,1-propylene, 1,1-butylene, 1,2-butylene, 2,2-butylene and [ka] Selected from the group consisting of;

[0367]

[0419] R 6 The group is selected from the following:

[0368]

[0420] [ka]

[0421] [ka] [ka]

[0422] [ka]

[0423] [ka]

[0424] [ka]

[0425] [ka]

[0369]

[0426] R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and R 6i Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, oxo, carbamoyl, C1-C6 alkoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 A group independently selected from the group consisting of the following, where each of the alkyl, alkoxy, and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0370]

[0427] R 651 , R 652 , R 653 , R 654 and R 655 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, and -C(O)NR 64 R 65A group consisting of the following is independently selected, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0371]

[0428] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0372]

[0429] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and halogens;

[0373]

[0430] R 63 This is selected from the group consisting of C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with a halogen;

[0374]

[0431] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0375]

[0432] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group; and

[0376]

[0433] R 66This is a 6-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from oxo and carbamoyl groups.

[0377]

[0434]

[0435] In one embodiment of the compound of chemical formula (IIIa-1),

[0378]

[0436] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is selected from the group consisting of hydrogen, methyl, fluoro, and chloro;

[0379]

[0437] L 2 Methylene and do not exist. [ka] Selected from the group consisting of;

[0380]

[0438] R 6 The group is selected from the following:

[0381]

[0439] [ka] [ka]

[0440] [ka]

[0382]

[0441] R 611 , R 612 , R 613 , R 614, R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and R 6i Each of them is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , -CH2-R

Chemical formula

[0387]

[0446] [ka]

[0388]

[0447] R 63 This is selected from the group consisting of methyl, NH2, ethenyl, and 1-fluoroethenyl;

[0389]

[0448] R 64 and R 65 Each of them is selected from the group consisting of hydrogen and methyl, or

[0390]

[0449] R 64 and R 65 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0391]

[0450] [ka]

[0392]

[0451] R 66 This is a 6-10 membered heterocyclyl group, which is as follows:

[0393]

[0452] [ka]

[0394]

[0453] In one embodiment, the present invention relates to a compound of the following chemical formula (IIIb), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0395]

[0454]

[0455] [ka]

[0456] (IIIb)

[0396]

[0457] In the above chemical formula (IIIb),

[0397]

[0458] R 1 , R 2 , R 3 , R 4 and R 5 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, hydroxy, and -NR. x R y A group consisting of the following is independently selected, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0398]

[0459] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0399]

[0460] A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl groups, where each of the aryl and heteroaryl groups is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y They may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0400]

[0461] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0401]

[0462] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0402]

[0463] R 61 and R 62Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0403]

[0464] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0404]

[0465] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0405]

[0466] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0406]

[0467] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0407]

[0468] R 66is a 5-10 membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl, and amino;

[0408]

[0469] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; and

[0409]

[0470] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0410]

[0471]

[0411]

[0472]

[0473] In one embodiment, the present invention relates to a compound of the following chemical formula (IIIb-1), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0412]

[0474] [ka]

[0475] (IIIb-1)

[0413]

[0476] In the above chemical formula (IIIb-1),

[0414]

[0477] R a1 、R a2 、R a3 、R a4 and R a5 each of which is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3- to 10-membered cycloalkyl, -NR x R y , amino, mercapto and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy and cycloalkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0415]

[0478] L 2 is absent and is selected from the group consisting of -(C1-C6) alkylene-, wherein said alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0416]

[0479] R 6 is selected from the group consisting of phenyl and 3- to 10-membered heterocyclyl, wherein each of said phenyl and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 , -NHC(O)R 63 , -C(O)NR 64 R 65 , 5- to 6-membered heterocyclyl and -CH2-R 66 and may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium, wherein each of said alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0417]

[0480] R 61 and R 62Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0418]

[0481] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0419]

[0482] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0420]

[0483] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0421]

[0484] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0422]

[0485] R 66is a 5-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl and amino; and

[0423]

[0486] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[0424]

[0487]

[0488]

[0489] In one embodiment of the compound of chemical formula (IIIb-1), R a1 , R a2 , R a3 , R a4 and R a5 Each of these is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine;

[0425]

[0490] L 2 The following do not exist: methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,1-propylene, 1,1-butylene, 1,2-butylene, 2,2-butylene and [ka] Selected from the group consisting of;

[0426]

[0491] R 6 The group is selected from the following:

[0427]

[0492] [ka]

[0428]

[0493] [ka] [ka]

[0494] [ka]

[0429]

[0495] [ka]

[0496] [ka]

[0497] [ka]

[0430]

[0498] R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and R 6iEach of these is hydrogen, C1-C6 alkyl, halogen, cyano, oxo, carbamoyl, C1-C6 alkoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 A group independently selected from the group consisting of the following, where each of the alkyl, alkoxy, and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0431]

[0499] R 651 , R 652 , R 653 , R 654 and R 655 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, and -C(O)NR 64 R 65 A group consisting of the following is independently selected, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0432]

[0500] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0433]

[0501] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and halogens;

[0434]

[0502] R 63This is selected from the group consisting of C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with a halogen;

[0435]

[0503] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0436]

[0504] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group; and

[0437]

[0505] R 66 This is a 6-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from oxo and carbamoyl groups.

[0438]

[0506]

[0507] In one embodiment of the compound of chemical formula (IIIb-1),

[0439]

[0508] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is selected from the group consisting of hydrogen, methyl, fluoro, and chloro;

[0440]

[0509] L 2 Methylene and do not exist. [ka] Selected from the group consisting of;

[0441]

[0510] R 6 The group is selected from the following:

[0442]

[0511] [ka] [ka]

[0443]

[0512] [ka]

[0444]

[0513] R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i , R 651 , R 652 , R 653 , R 654 and R 655 Each of these is hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 -CH2-R 66 ,

[0445]

[0514]

[0515] [ka] Independently selected from the group consisting of; and

[0446]

[0516] R 651 , R 652 , R 653 , R 654 and R 655 Each of them is independently selected from the group consisting of hydrogen and carbamoyl;

[0447]

[0517] R 61 and R 62 Each of these is selected from the group consisting of hydrogen, ethyl and isopropyl, or

[0448]

[0518] R 61 and R 62 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0449]

[0519] [ka]

[0450]

[0520] R 63 This is selected from the group consisting of methyl, NH2, ethenyl, and 1-fluoroethenyl;

[0451]

[0521] R 64 and R 65 Each of them is selected from the group consisting of hydrogen and methyl, or

[0452]

[0522] R 64 and R 65These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0453]

[0523] [ka]

[0454]

[0524] R 66 This is a 6-10 membered heterocyclyl group, which is as follows:

[0455]

[0525]

[0526] [ka]

[0456]

[0527]

[0528] In one embodiment, the present invention relates to a compound of the following chemical formula (IIIc-1), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0457]

[0529] [ka]

[0530] (IIIc-1)

[0458]

[0531] In the above chemical formula (IIIc-1),

[0459]

[0532] R 1 , R 2 , R 3 , R 4 and R 5Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, hydroxy, and -NR. x R y A group consisting of the following is independently selected, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0460]

[0533] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups;

[0461]

[0534] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0462]

[0535] A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl groups, where each of the aryl and heteroaryl groups is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y They may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0463]

[0536] L 2The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0464]

[0537] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0465]

[0538] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0466]

[0539] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0467]

[0540] R 63This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0468]

[0541] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0469]

[0542] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0470]

[0543] R 66 is a 5-10 membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl, and amino;

[0471]

[0544] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; and

[0472]

[0545] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x Ry Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0473]

[0546] In one embodiment, the present invention relates to a compound of the following chemical formula (IIIc-1), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0474]

[0547]

[0548]

[0549] [ka]

[0550] (IIIc-1)

[0475]

[0551] In the above chemical formula (IIIc-1),

[0476]

[0552] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0477]

[0553] R z1is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups;

[0478]

[0554] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0479]

[0555] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0480]

[0556] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0481]

[0557] R 61 and R 62These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0482]

[0558] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0483]

[0559] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0484]

[0560] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0485]

[0561] R 66 is a 5-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl and amino; and

[0486]

[0562] R x and R yEach of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[0487]

[0563]

[0564]

[0488]

[0565] In one embodiment of the compound of chemical formula (IIIc-1), R a1 , R a2 , R a3 , R a4 and R a5 Each of these is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine;

[0489]

[0566] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a C1-C6 alkyl group;

[0490]

[0567] L 2 The following do not exist: methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,1-propylene, 1,1-butylene, 1,2-butylene, 2,2-butylene and [ka] Selected from the group consisting of;

[0491]

[0568] R 6 The group is selected from the following:

[0492]

[0569]

[0570]

[0571] [ka]

[0572] [ka] [ka]

[0573] [ka]

[0574] [ka]

[0575] [ka]

[0576] [ka]

[0493]

[0577] R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and R 6iEach of these is hydrogen, C1-C6 alkyl, halogen, cyano, oxo, carbamoyl, C1-C6 alkoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 A group independently selected from the group consisting of the following, where each of the alkyl, alkoxy, and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0494]

[0578] R 651 , R 652 , R 653 , R 654 and R 655 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, and -C(O)NR 64 R 65 A group consisting of the following is independently selected, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0495]

[0579] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0496]

[0580] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and halogens;

[0497]

[0581] R 63This is selected from the group consisting of C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with a halogen;

[0498]

[0582] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0499]

[0583] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group; and

[0500]

[0584] R 66 This is a 6-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from oxo and carbamoyl groups.

[0501]

[0585]

[0586] In one embodiment of the compound of chemical formula (IIIc-1),

[0502]

[0587] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is selected from the group consisting of hydrogen, methyl, fluoro, and chloro;

[0503]

[0588] R z1 It is methyl or isopropyl,

[0504]

[0589] L 1 is selected from the group consisting of non-existent and methylene;

[0505]

[0590] L 2 Methylene and do not exist. [ka] Selected from the group consisting of;

[0506]

[0591] R 6 The group is selected from the following:

[0507]

[0592] [ka] [ka]

[0593] [ka]

[0508]

[0594] R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and R 6i Each of these is hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63-C(O)NR 64 R 65 -CH2-R 66 ,

[0509]

[0595] [ka] Independently selected from the group consisting of;

[0510]

[0596] R 651 , R 652 , R 653 , R 654 and R 655 Each of them is independently selected from the group consisting of hydrogen and carbamoyl;

[0511]

[0597] R 61 and R 62 Each of these is selected from the group consisting of hydrogen, ethyl and isopropyl, or

[0512]

[0598] R 61 and R 62 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0513]

[0599] [ka]

[0514]

[0600] R 63 This is selected from the group consisting of methyl, NH2, ethenyl, and 1-fluoroethenyl;

[0515]

[0601] R 64 and R 65 Each of them is selected from the group consisting of hydrogen and methyl, or

[0516]

[0602] R 64 and R 65 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0517]

[0603] [ka]

[0518]

[0604] R 66 This is a 6-10 membered heterocyclyl group, which is as follows:

[0519]

[0605] [ka]

[0520]

[0606]

[0607] In one embodiment, the present invention relates to a compound of the following chemical formula (IIId) or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0521]

[0608] [ka]

[0609] (IIId)

[0522]

[0610] In the above chemical formula (IIId),

[0523]

[0611] R 1 , R 2 , R 3 , R 4 and R 5Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, hydroxy, and -NR. x R y A group consisting of the following is independently selected, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0524]

[0612] m is an integer between 1 and 4;

[0525]

[0613] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0526]

[0614] A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl groups, where each of the aryl and heteroaryl groups is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y They may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0527]

[0615] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0528]

[0616] R 6The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0529]

[0617] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0530]

[0618] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0531]

[0619] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0532]

[0620] R 64 and R 65Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0533]

[0621] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0534]

[0622] R 66 is a 5-10 membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl, and amino;

[0535]

[0623] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; and

[0536]

[0624] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0537]

[0625]

[0626]

[0627] In one embodiment, the present invention relates to a compound of the following chemical formula (IIId-1), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates.

[0538]

[0628] [ka]

[0629] (IIId-1)

[0539]

[0630] In the above chemical formula (IIId-1),

[0540]

[0631] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0541]

[0632] m is an integer between 1 and 4;

[0542]

[0633] L 2 The group consisting of does not exist and -(C1-C6)alkylene-, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0543]

[0634] R6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0544]

[0635] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0545]

[0636] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0546]

[0637] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0547]

[0638] R 64 and R65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0548]

[0639] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0549]

[0640] R 66 is a 5-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl and amino; and

[0550]

[0641] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[0551]

[0642]

[0643]

[0644] In one embodiment of the compound of chemical formula (IIId-1), R a1 , R a2 , R a3 , R a4 and R a5 Each of these is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine;

[0552]

[0645] m is an integer between 1 and 2;

[0553]

[0646] L 2 The following do not exist: methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,1-propylene, 1,1-butylene, 1,2-butylene, 2,2-butylene and [ka] Selected from the group consisting of;

[0554]

[0647] R 6 The group is selected from the following:

[0555]

[0648] [ka] [ka]

[0556]

[0649]

[0557] [ka]

[0558]

[0650] [ka]

[0651] [ka]

[0652]

[0653] [ka]

[0559]

[0654] R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and R 6i Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, oxo, carbamoyl, C1-C6 alkoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 A group independently selected from the group consisting of the following, where each of the alkyl, alkoxy, and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0560]

[0655] R 651 , R 652 , R 653 , R 654 and R 655 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, and -C(O)NR 64 R 65 A group consisting of the following is independently selected, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0561]

[0656] R 61and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl; or

[0562]

[0657] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and halogens;

[0563]

[0658] R 63 This is selected from the group consisting of C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with a halogen;

[0564]

[0659] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0565]

[0660] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group; and

[0566]

[0661] R 66 This is a 6-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from oxo and carbamoyl groups.

[0567]

[0662]

[0663] In one embodiment of the compound of chemical formula (IIId-1),

[0568]

[0664] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is selected from the group consisting of hydrogen, methyl, fluoro, and chloro;

[0569]

[0665] m is 1;

[0570]

[0666] L 2 Methylene and do not exist. [ka] Selected from the group consisting of;

[0571]

[0667] R 6 The group is selected from the following:

[0572]

[0668] [ka] [ka]

[0669] [ka]

[0573]

[0670] R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R6c , R 6d , R 6e , R 6f , R 6g , R 6h and R 6i Each of these is hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 -CH2-R 66 ,

[0574]

[0671]

[0672] [ka] Independently selected from the group consisting of;

[0575]

[0673] R 651 , R 652 , R 653 , R 654 and R 655 Each of them is independently selected from the group consisting of hydrogen and carbamoyl;

[0576]

[0674] R 61 and R 62 Each of these is selected from the group consisting of hydrogen, ethyl and isopropyl, or

[0577]

[0675] R 61 and R 62 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0578]

[0676] [ka]

[0579]

[0677] R 63 This is selected from the group consisting of methyl, NH2, ethenyl, and 1-fluoroethenyl;

[0580]

[0678] R 64 and R 65 Each of them is selected from the group consisting of hydrogen and methyl, or

[0581]

[0679] R 64 and R 65 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0582]

[0680] [ka]

[0583]

[0681] R 66 This is a 6-10 membered heterocyclyl group, which is as follows:

[0584]

[0682]

[0683] [ka]

[0585]

[0684] In one embodiment, an exemplary compound of chemical formula (I) is provided below:

[0586]

[0685] [Table 1]

[0587]

[0686] Table 2 Table 3

[0687] Table 4 Table 5

[0688] Table 6 Table 7

[0689] Table 8 Table 9

[0690] Table 10 Table 11

[0691] Table 12 Table 13

[0692] Table 14 Table 15

[0693] Table 16 Table 17

[0694] Table 18 Table 19

[0695] Table 20 Table 21

[0696] Table 22 Table 23

[0697] Table 24 Table 25

[0698] [Table 26] [Table 27]

[0699] [Table 28] [Table 29]

[0588]

[0700] In another embodiment, an exemplary compound of chemical formula (I) is provided below:

[0589]

[0701] [Table 30] [Table 31]

[0590]

[0702] [Table 32] [Table 33]

[0591]

[0703] [Table 34] [Table 35]

[0592]

[0704] Table 36 Table 37

[0593]

[0705] Table 38 Table 39

[0594]

[0706] Table 40 Table 41

[0595]

[0707] Table 42 Table 43

[0596]

[0708] Table 44 Table 45

[0597]

[0709] Table 46 Table 47

[0598]

[0710] Table 48 Table 49

[0599]

[0711] Table 50 Table 51

[0600]

[0712] Table 52 Table 53

[0601]

[0713] Table 54 Table 55

[0602]

[0714] Table 56 Table 57

[0603]

[0715] [Table 58] [Table 59]

[0604]

[0716] As used herein, the terms “tautomer” or “tautomer type” refer to structural isomers of different energies that are interconvertible across a low energy barrier. For example, proton tautomers (also known as protic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by rearrangement of some bonding electrons.

[0605]

[0717] As used herein, the term "stereoisomer" refers to a compound that has the same chemical structure but differs in the spatial arrangement of its atoms or groups. Stereoiomers include diastereomers, enantiomers, conformers, and others.

[0606]

[0718] As used herein, the term "diastereomer" refers to a stereoisomer having two or more chiral centers, where the molecules are not mirror images of each other. Diastereomers have distinct physical properties, such as melting point, boiling point, spectroscopic properties, or biological activity. Mixtures of diastereomers can be separated into individual stereoisomers by high-resolution analytical methods such as electrophoresis and chromatography, including HPLC.

[0607]

[0719] The term "enantiomer" as used in the specification refers to two stereoisomers of a compound, which are mirror images that cannot be superimposed on each other.

[0608]

[0720] The stereochemical definitions and rules used herein are generally based on SP. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds can exist in an optically active form, that is, they have the ability to rotate the plane of polarization of plane-polarized light. When describing optically active compounds, the prefixes D and L, or R and S, are used to represent the absolute alignment of the molecule with respect to the chiral center. The prefixes d and 1, or (+) and (-), represent the direction in which the plane of polarization rotates. Compounds with prefixes beginning with (-) or 1 are levorotatory. Compounds with prefixes beginning with (+) or d are dextrorotatory. For a given chemical structure, such stereoisomers are identical to each other except that they are mirror images. Certain stereoisomers are also called enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 enantiomer mixture is called a racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemate" and "racemate" refer to an equimolar mixture of two optically inactive enantiomer species.

[0609]

[0721] Those skilled in the art will understand that organic compounds can react with solvents to form complexes, or to precipitate or crystallize them. Such complexes are known as “solvates.” When the solvent is water, the complex is known as a “hydrate.” This invention encompasses all solvates of the compounds of the present invention. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric and non-stoichiometric solvates. In some cases, solvates can be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. “Solvates” include both solution-phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0610]

[0722] The term "hydrate" refers to a compound that has associated with water. Generally, the number of water molecules in a compound hydrate is constant relative to the number of compound molecules in the hydrate. Therefore, a compound hydrate can be represented, for example, by the general formula R·x H2O, where R is the compound and x is a number greater than 0. A given compound can form one or more types of hydrates, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5 H2O)), and polyhydrates (x is a number greater than 1, for example, dihydrate (R·2 H2O) and hexahydrate (R·6 H2O)).

[0611]

[0723] The compounds disclosed herein may be amorphous or crystalline (crystalline form or polymorph). Furthermore, the compounds disclosed herein may exist in one or more crystalline forms. Therefore, the scope of the present invention includes all amorphous or crystalline forms of the compounds disclosed herein. The term “polymorph” means a crystalline form of a compound (or its salt, hydrate, or solvate) in a particular crystalline packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally differ from each other in their X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystalline form, optical and electrical properties, stability, and solubility. One crystalline form may become dominant depending on the recrystallization solvent, rate of crystallization, storage temperature, and other factors. Various polymorphs of a compound can be produced by crystallization under various conditions.

[0612]

[0724] As used herein, the term “isotope-labeled form” of a compound means that the compound contains one or more atoms whose isotopic forms differ from the naturally occurring isotopic distribution of those atoms. Unless a specific isotopic form is specified, all isotopic forms are included as optional. For example, the “isotope-labeled form” of a compound may be radioactively labeled, i.e., it may contain one or more radioactive isotopes, or, for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15( 15 It can be labeled with non-radioactive isotopes such as N). In compounds in which such isotope substitution is performed, if the following atoms are present, for example any hydrogen 2 It may be H / D, and any carbon is 13 It may be C, and any nitrogen is 15 It may also be N, and it will be understood that the presence and position of such an atom can be determined by those skilled in the art.

[0613]

[0725] As used herein, the term “prodrug” means a substance that can be converted into a biologically active compound of the present invention under physiological conditions or by solubilization. Prodrugs of the present invention are produced by modifying a functional group in the compound, and the modification can be removed by normal procedures or in vivo to obtain the chemical of the present invention. Prodrugs include compounds formed by bonding a hydroxyl group or amino group in the compound of the present invention to any group. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug dissociates to form a free hydroxyl group or amino group.

[0614]

[0726]

[0727]

[0728] The term "pharmaceutically acceptable salt" means that, within the bounds of sound medical judgment, it is free from excessive toxicity, irritation, or allergic reactions, and is suitable for use in contact with human and lower animal organisms, commensurate with a reasonable benefit / risk ratio.

[0615]

[0729] Certain compounds disclosed herein may exist in the form of salts, such as acid addition salts, carboxylate salts, sulfonates, and salts with organic or inorganic bases such as phosphates. All such salts are within the scope of the present invention, and references to the compounds disclosed herein also include the salt forms of the compounds.

[0616]

[0730] The salts of the present invention can be synthesized from a parent compound containing a basic or acidic molecule by conventional chemical methods, such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acidic or basic form of the parent compound with a suitable base or acid in water, an organic solvent, or a mixture thereof, and generally, water-insoluble media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Acid addition salts (e.g., mono-salts or di-salts) can be formed using a variety of acids, including inorganic and organic acids. Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+)camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrohalogens (e.g., hydrobromic acid, hydrochloric acid, hydroiodic acid), isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid (+)-L-malic acid, (+)-L-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyruvic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid It includes monosalts or disalts formed with acids selected from the group consisting of p-toluenesulfonic acid, undecylenic acid, valeric acid, and acylated amino acids.

[0617]

[0731] One particular group of salts consists of salts formed from acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (mesylate), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propanoic acid, butanoic acid, malonic acid, glucuronic acid, and lactobionic acid. One particular salt is a hydrochloride salt.

[0618]

[0732] If a compound disclosed herein contains an amine functional group, it can be reacted with an alkylating agent, for example, by methods well known to those skilled in the art, to form a quaternary ammonium salt. Such quaternary ammonium compounds are within the range of compounds disclosed herein.

[0619]

[0733] The compound of the present invention has a pK of the acid in which the salt is formed. a Depending on the circumstances, it may exist as a monosalt or a disalt.

[0620]

[0734] It will be understood that salts of the compounds disclosed herein must be pharmaceutically acceptable for pharmaceutically use. Suitable pharmaceutically acceptable salts will be obvious to those skilled in the art. Pharmaceutically acceptable salts include those described in Berge, Bighley and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. Such pharmaceutically acceptable salts include acid addition salts formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid) and organic acids (e.g., succinic acid, maleic acid, acetic acid, oxalic acid, malonic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid). Other salts, such as oxalates or formates, can be used for the separation of the compounds disclosed herein, and this falls within the scope of the present invention. However, pharmaceutically unacceptable salts can also be produced as intermediate forms and subsequently converted to pharmaceutically acceptable salts. Such pharmaceutically unacceptable salt forms are useful, for example, for the purification or separation of the compound of the invention and also form part of the invention.

[0621]

[0735] This also includes salts formed using conventional methods in the industry, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptate, glycerophosphate, gluconate, hemisulfate, hep This includes tanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and other pharmaceutically acceptable salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl) tetrasalts are included. Typical alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Furthermore, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0622]

[0736] The compounds disclosed herein can form acid addition salts with one or more acid equivalents. The scope of the present invention includes all possible stoichiometric and non-stoichiometric forms.

[0623]

[0737]

[0738] Manufacturing method

[0624]

[0739] Further aspects of the present invention provide methods for producing compounds of chemical formula (I), or their tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates. The following reaction formula is an example of a synthetic reaction formula that may be used for the synthesis of compounds of chemical formula (I). In the following reaction formula, the reactive group is protected by a protecting group and can be deprotected using techniques well established in the art. The compounds of chemical formula (I) described herein can be produced by persons skilled in the field of organic synthesis using standard methods, which are described below in detail.

[0625]

[0740]

[0741] In a further aspect of the present invention, a method for producing a compound of chemical formula (I) as defined herein, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates, includes one of the following methods A and B:

[0626]

[0742]

[0743] -Method A is a compound of chemical formula (II) (i.e., a compound of chemical formula (I), where L 1 is methylene, and R 6 is NR 61 R 62 To manufacture (which is);

[0627]

[0744] -Method B involves a compound of chemical formula (II) (i.e., a compound of chemical formula (I), where L 1 It manufactures (which does not exist).

[0628]

[0745]

[0746] Method A

[0629]

[0747]

[0748] Method A is for producing a compound of chemical formula (II) as defined herein, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates, and Method A comprises the following steps:

[0630]

[0749] (i) Step of preparing the compound of chemical formula (A-1):

[0631]

[0750]

[0751] [ka]

[0632]

[0752]

[0753] (ii) A step to prepare the compound of chemical formula (A-3) by reacting the compound of chemical formula (A-1) with the compound of chemical formula (A-2):

[0633]

[0754]

[0755]

[0756]

[0757] [ka]

[0634]

[0758]

[0759] (iii) The step of reacting the compound of chemical formula (A-3) with tetrabutylammonium fluoride to obtain the compound of chemical formula (A-4):

[0635]

[0760]

[0761] [ka]

[0636]

[0762]

[0763] (iv) The step of reacting the compound of chemical formula (A-4) with Dess-Martin periodinane (DMP) to obtain the compound of chemical formula (A-5):

[0637]

[0764]

[0765] [ka]

[0638]

[0766]

[0767] (v) The step of reacting the compound of chemical formula (A-5) with the compound of chemical formula (A-6) to obtain the compound of chemical formula (II):

[0639]

[0768]

[0769] [ka]

[0640]

[0770] In the above chemical formula,

[0771] R 1 ~R 5 Y, Z, L 2 , ring A, R 61 and R 62 This is synonymous with the definition above.

[0641]

[0772]

[0773] In one specific example, the exemplary reaction equation of method A can be represented by reaction equation I:

[0642]

[0774] Reaction Equation I

[0775] [ka]

[0643]

[0776] Method B

[0644]

[0777] Method B is for producing a compound of chemical formula (III) as defined herein, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates, and Method B comprises the following steps:

[0645]

[0778]

[0779] (i) Step of preparing the compound of chemical formula (B-1):

[0646]

[0780]

[0781] [ka]

[0647]

[0782]

[0783] (ii) A step to prepare the compound of chemical formula (III) by reacting the compound of chemical formula (B-1) with the compound of chemical formula (B-2):

[0648]

[0784]

[0785] [ka]

[0649]

[0786]

[0787] Here, R 1 ~R 5 X, Y, Z, L 2 , ring A, R 6 W and n are synonymous with the above definitions, and

[0788] Hal 1 This is a halide, preferably an iodide.

[0650]

[0789]

[0790] In one specific example, the exemplary reaction equation for method B can be represented by reaction equation II:

[0651]

[0791]

[0792] Reaction Equation II

[0652]

[0793] [ka]

[0653]

[0794] In an embodiment where the compound of chemical formula (III) is the compound of chemical formula (IIIa), step (i) includes the following steps:

[0654]

[0795]

[0796] (i-1) Step of preparing the compound of chemical formula (ba-1):

[0797]

[0798] [ka]

[0655]

[0799]

[0800] (i-2) The step of reacting the compound of chemical formula (ba-1) with the compound of chemical formula (ba-2) to obtain the compound of chemical formula (ba-3):

[0656]

[0801]

[0802]

[0803]

[0804] [ka]

[0657]

[0805]

[0806] (i-3) The step of reacting the compound of chemical formula (ba-3) with trifluoroacetic acid (TFA) to obtain the compound of chemical formula (ba-4):

[0658]

[0807]

[0808]

[0809] [ka]

[0659]

[0810]

[0811] (i-4) The step of reacting the compound of chemical formula (ba-4) with the compound of chemical formula (ba-5) to obtain the compound of chemical formula (ba-6):

[0660]

[0812]

[0813] [ka]

[0661]

[0814]

[0815] [ka]

[0662]

[0816]

[0817] (i-5) The step of reacting the compound of chemical formula (ba-6) with the compound of chemical formula (ba-7) to obtain the compound of chemical formula (IIIa):

[0663]

[0818]

[0819] [ka]

[0664]

[0820] Here, R 1 ~R 5 Y, Z, L 2 And ring A is synonymous with the above definition, and

[0665]

[0821] Hal 2 and Hal 3 Each of these is a halide, preferably a chloride or bromide.

[0666]

[0822]

[0823] In one concrete example, the exemplary reaction equation for step (i) can be represented by reaction equation III:

[0667]

[0824]

[0825] Reaction Equation III

[0668]

[0826] [ka]

[0669]

[0827] In an example where the compound of chemical formula (III) is the compound of chemical formula (IIIb), step (i) includes the following steps:

[0670]

[0828]

[0829] (i-1) Step of preparing the compound of chemical formula (bb-1):

[0671]

[0830]

[0831] [ka]

[0672]

[0832]

[0833] (i-2) Step of reacting the compound of chemical formula (bb-1) with MeOH and SOCl2 to obtain the compound of chemical formula (bb-2):

[0673]

[0834]

[0835] [ka]

[0674]

[0836]

[0837] (i-3) Step of introducing Cl2 gas into the compound of chemical formula (bb-2) to obtain the compound of chemical formula (bb-3):

[0675]

[0838]

[0839] [ka]

[0676]

[0840]

[0841] (i-4) Step of reacting the compound of chemical formula (bb-3) with triethylamine to obtain the compound of chemical formula (bb-4):

[0677]

[0842]

[0843] [ka]

[0678]

[0844]

[0845] (i-5) The step of reacting the compound of chemical formula (bb-4) with the compound of chemical formula (bb-5) to obtain the compound of chemical formula (bb-6):

[0679]

[0846]

[0847]

[0848] [ka]

[0680]

[0849]

[0850] [ka]

[0681]

[0851] (i-6) The step of reacting the compound of chemical formula (bb-6) with the compound of chemical formula (bb-7) to obtain the compound of chemical formula (bb-8):

[0682]

[0852]

[0853] [ka]

[0683]

[0854]

[0855] [ka]

[0684]

[0856] (i-7) The step of reacting the compound of chemical formula (bb-8) with the compound of chemical formula (bb-9) to obtain the compound of chemical formula (IIIb):

[0685]

[0857]

[0858] [ka]

[0686]

[0859] Here, R 1 ~R 5 Y, Z, L 2 And ring A is synonymous with the above definition, and

[0687]

[0860] Hal 4 and Hal 5 Each of these is a halogenated compound, preferably a bromide.

[0688]

[0861]

[0862] In one specific example, the exemplary reaction equation for step (i) can be represented by reaction equation IV:

[0689]

[0863]

[0864] Reaction Equation IV

[0690]

[0865] [ka]

[0691]

[0866]

[0867] In an example where the compound of chemical formula (III) is the compound of chemical formula (IIIc), step (i) includes the following steps:

[0692]

[0868]

[0869] (i-1) Step of preparing the compound of chemical formula (bc-1):

[0693]

[0870]

[0871] [ka]

[0694]

[0872]

[0873] (i-2) Step of reacting the compound of chemical formula (bc-1) with benzaldehyde to obtain the compound of chemical formula (bc-2):

[0695]

[0874]

[0875] [ka]

[0696]

[0876]

[0877] (i-3) A step to obtain the compound of chemical formula (bc-3) by reacting the compound of chemical formula (bc-2) with t-BuOH and N-(oxomethylene)sulfamoyl chloride:

[0697]

[0878]

[0879] [ka]

[0698]

[0880]

[0881] (i-4) Step of reacting the compound of chemical formula (bc-3) with PPh3 to obtain the compound of chemical formula (bc-4):

[0699]

[0882]

[0883] [ka]

[0700]

[0884]

[0885] (i-5) Step of reacting the compound of chemical formula (bc-4) with TFA to obtain the compound of chemical formula (bc-5):

[0701]

[0886]

[0887] [ka]

[0702]

[0888]

[0889] (i-6) The step of reacting the compound of chemical formula (bc-5) with the compound of chemical formula (bc-6) to obtain the compound of chemical formula (bc-7):

[0703]

[0890]

[0891]

[0892]

[0893] [ka]

[0704]

[0894]

[0895] (i-7) The step of reacting the compound of chemical formula (bc-7) with the compound of chemical formula (bc-8) to obtain the compound of chemical formula (bc-9):

[0705]

[0896]

[0897]

[0898]

[0899] [ka]

[0706]

[0900]

[0901] (i-8) The step of reacting the compound of chemical formula (bc-9) with the compound of chemical formula (bc-10) to obtain the compound of chemical formula (bc-11):

[0707]

[0902]

[0903]

[0904]

[0905] [ka]

[0708]

[0906]

[0907] (i-9) Step of reacting the compound of chemical formula (bc-11) with H2 under a Pd / C catalyst to obtain the compound of chemical formula (bc-12):

[0709]

[0908]

[0909] [ka]

[0710]

[0910]

[0911] (i-10) Step of reacting the compound of chemical formula (bc-12) with the compound of chemical formula (bc-13) to obtain the compound of chemical formula (IIIc):

[0711]

[0912]

[0913] [ka]

[0712]

[0914] Here, R 1 ~R5 Y, Z, L 2 , R z1 And ring A is synonymous with the above definition, and

[0713]

[0915] Hal 6 Hal 7 and Hal 8 Each of these is a halogenated compound, preferably an iodide or bromide.

[0714]

[0916]

[0917] In one concrete example, the exemplary reaction equation for step (i) can be represented by reaction equation V:

[0715]

[0918] Reaction equation V

[0716]

[0919] [ka]

[0717]

[0920]

[0921] In an example where the compound of chemical formula (III) is the compound of chemical formula (IIId), step (i) includes the following steps:

[0718]

[0922]

[0923] (i-1) Step of preparing the compound of chemical formula (bd-1):

[0719]

[0924]

[0925] [ka]

[0720]

[0926]

[0927]

[0721] (i-2) Step of reacting the compound of chemical formula (bd-1) with MeOH and SOCl2 to obtain the compound of chemical formula (bd-2):

[0722]

[0928]

[0929] [ka]

[0723]

[0930]

[0931] (i-3) Step of introducing Cl2 gas into the compound of chemical formula (bd-2) to obtain the compound of chemical formula (bd-3):

[0724]

[0932]

[0933] [ka]

[0725]

[0934]

[0935]

[0726] (i-4) Step of reacting the compound of chemical formula (bd-3) with triethylamine to obtain the compound of chemical formula (bd-4):

[0727]

[0936]

[0937] [ka]

[0728]

[0938]

[0939] (i-5) The step of reacting the compound of chemical formula (bd-4) with the compound of chemical formula (bd-5) to obtain the compound of chemical formula (bd-6):

[0729]

[0940]

[0941]

[0942]

[0943]

[0944] [ka]

[0730]

[0945]

[0946] (i-6) The step of reacting the compound of chemical formula (bd-6) with the compound of chemical formula (bd-7) to obtain the compound of chemical formula (bd-8):

[0731]

[0947]

[0948]

[0949]

[0950] [ka]

[0732]

[0951]

[0952] (i-7) The step of reacting the compound of chemical formula (bd-8) with the compound of chemical formula (bd-9) to obtain the compound of chemical formula (bd-10):

[0733]

[0953]

[0954] [ka]

[0734]

[0955]

[0956] [ka]

[0735]

[0957]

[0958] (i-8) The step of reacting the compound of chemical formula (bd-10) with the compound of chemical formula (bd-11) to obtain the compound of chemical formula (IIId):

[0736]

[0959]

[0960] [ka]

[0737]

[0961] Here, R 1 ~R 5 Y, Z, L 2 , m and ring A are synonymous with the above definitions, and

[0738]

[0962] Hal 4 Hal 9 and Hal 10 Each of these is a halogenated compound, preferably a bromide.

[0739]

[0963]

[0964] In one specific example, the exemplary reaction equation for step (i) can be represented by reaction equation VI:

[0740]

[0965] Reaction Equation VI

[0741]

[0966] [ka]

[0742]

[0967]

[0968] Therapeutic usefulness

[0743]

[0969] The terms “to treat,” “to cure,” and “to cure” refer to a series of actions initiated after a disease, disorder, or condition, or its symptoms, have been diagnosed or observed, which are intended to temporarily or permanently eliminate, reduce, suppress, alleviate or improve at least one of the underlying causes of the disease, disorder, or condition affecting the subject, or at least one of the symptoms associated with the disease, disorder, or condition affecting the subject. Therefore, “treatment” may also mean suppressing an active disease (e.g., interrupting the onset or additional onset of a disease, disorder, or condition, or its associated clinical symptoms).

[0744]

[0970] Terms such as “prevent,” “prevent,” and “prevent” refer to a series of actions initiated to prevent, suppress, inhibit, or reduce the risk (e.g., judging the absence of clinical symptoms) or delay the onset of a disease, disorder, condition, or similar illness in an individual (e.g., administering a Polθ inhibitor or a pharmaceutical composition containing the same), and generally refer to individuals susceptible to a particular disease, disorder, or condition. In specific cases, the term means slowing the progression of a disease, disorder, or condition, or inhibiting its progression to prevent it from progressing to a harmful or undesirable condition.

[0745]

[0971] The terms “inhibition” and “reduction,” or variations of such terms related to Polθ, can represent a measurable reduction or complete inhibition to achieve a desired result. For example, Polθ activity can be reduced by approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% or more compared to the control group. As used herein, the term “approximately” means a variation within ±20%, preferably within ±10%, and more preferably within ±5% of a given value.

[0746]

[0972] The terms "disease," "disability," and "condition" are interchangeable in this specification.

[0747]

[0973] The present invention provides compounds for preventing or treating diseases or disorders mediated by Polθ, or diseases or disorders related to Polθ activity.

[0748]

[0974] In some embodiments, Polθ-mediated diseases or disorders are proliferative disorders. The term “proliferative disorder” as used herein is interchangeable and relates to unwanted or uncontrolled cell proliferation of excessive or abnormal cells in vitro or in vivo, such as neoplastic or hyperplastic growth. Examples of proliferative conditions include, but are not limited to, malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone disorders, fibroproliferative disorders (e.g., connective tissue) and atherosclerosis, as well as malignant pre-cell proliferation and malignant cell proliferation.

[0749]

[0975] In some embodiments, the diseases or disorders mediated by Polθ are BRCA1 and BRCA2-deficient cancers, including HR-deficient cancers such as breast cancer, ovarian cancer (J.Med.Chem.2022,65,19,13198-13215), prostate cancer (Biochim Biophys Acta Mol Basis Dis.2020 Dec 1;1866(12):165954), pancreatic cancer (Cancers(Basel) 2022 Aug 23;14(17):4077), and lung cancer (Cancers 2019,11(5),722). The compound, composition, and method can further enhance the efficacy of cancer treatment by at least one of the following modes of action (MOA): (1) a therapeutic mode that induces DNA damage, (2) a therapeutic mode that modulates the cell cycle, and (3) a therapeutic mode that suppresses components related to the DNA damage response (DDR).

[0750]

[0976] In cancer treatment, the therapeutically effective amount of the compound of chemical formula (I) provided herein is sufficient to provide a therapeutic benefit during the course of treatment or to delay or minimize one or more symptoms associated with cancer. The therapeutically effective amount of a compound in cancer treatment means the amount of the therapeutic agent that provides such a therapeutic benefit during the course of treatment, either when used alone or in combination with other therapies.

[0751]

[0977] The effective dose of the compound of the present invention varies depending on a variety of factors, including the means of administration, the target site, the patient's physiological state, whether the patient is human or animal, other drugs administered, whether the treatment is prophylactic or therapeutic, and the specific activity of the composition itself and its ability to elicit a desired response in an individual. In the context of this specification, the patient may be human or a non-human mammal. Generally, dosage regimens are adjusted to provide the optimal therapeutic response, i.e., to optimize safety and efficacy. Thus, the therapeutically effective dose, as described herein, means the amount in which the beneficial effect obtained by administering the compound outweighs any undesirable side effects.

[0752]

[0978]

[0979] Pharmaceutical composition

[0753]

[0980] The terms “combination,” “combined,” and related terms mean the administration of two or more therapeutic agents or therapies simultaneously, separately, or sequentially. For example, the compounds disclosed herein may be administered simultaneously or sequentially with other therapeutic agents or therapies in the form of separate unit doses, or together in the form of a single unit dose. Another therapy may be radiotherapy. Another therapeutic agent may be an anticancer agent. Anticancer agents may include anticancer agents that target the DNA damage response (DDR). The DNA damage response (DDR) is a collective term for the various intracellular and intercellular signaling events and enzymatic activities that occur as a result of the induction and detection of DNA damage. There are at least three major aspects of DDR that differ in cancer compared to normal cells, and for this reason, DDR is an attractive source of drug targets that can be utilized (and are currently utilized) in the creation of new cancer therapies. Loss of one or more DDR pathways, increased replication stress, and higher levels of endogenous DNA damage are all differentiated aspects of cancer DDR that can be therapeutically targeted.Numerous anticancer drugs targeting DDR are known and under development, including PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib)), and BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, Ly2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 inhibitors [e.g., Adavosertib (e.g., MK-1775 or AZD1775)], PLK1 inhibitors [e.g., Volasertib (BI Examples include 6727), onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), and topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide) (Mark J. O'Connor, Molecular Cell 60, November 19, 2015, p.547-560, Choi et al., Int J Mol Sci. 2022). See Feb;23(3):1701). The compounds disclosed herein also belong to the category of DDR targeting agents.

[0754]

[0981] In some embodiments, a pharmaceutical composition is provided comprising a compound disclosed herein, or its tautomers, stereoisomers, prodrugs, crystalline form, isotope-labeled form, pharmaceutically acceptable salt, hydrate or solvate, and a pharmaceutically acceptable carrier, wherein the composition can be administered separately or sequentially with the additional DDR-targeted anticancer agents described above.

[0755]

[0982] In some embodiments, a method is provided for treating or preventing a polymerase θ-mediated disease or disorder in a subject, the method comprising the step of administering to the subject a compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystalline form, isotope-labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, the method further comprising the step of administering to the subject an additional DDR-targeted anticancer agent as described above.

[0756]

[0983] In some implementation examples, a kit including the following is provided:

[0757]

[0984] -A first pharmaceutical composition or dosage form comprising a compound disclosed herein, or its tautomers, stereoisomers, prodrugs, crystalline form, isotope-labeled form, pharmaceutically acceptable salt, hydrate or solvate, and one or more pharmaceutically acceptable carriers; and

[0758]

[0985] - A second pharmaceutical composition or dosage form comprising the aforementioned additional DDR-targeted anticancer agents or their tautomers, stereoisomers, prodrugs, crystalline forms, isotope-labeled forms, pharmaceutically acceptable salts, hydrates or solvates, and one or more pharmaceutically acceptable carriers.

[0759]

[0986] In some embodiments, the kit is intended for use in methods of treating and / or preventing diseases or disorders mediated by polymerase θ. In some embodiments, the first pharmaceutical composition or dosage form may be administered simultaneously, separately, or sequentially with the second pharmaceutical composition or dosage form. In some embodiments, the kit may further include a package insert containing instructions for simultaneous, sequential, or separate use in the treatment and / or prevention of diseases or disorders mediated by polymerase θ.

[0760]

[0987] The present invention also relates to a pharmaceutical composition comprising a pharmaceutically effective amount of one or more compounds disclosed herein, and a pharmaceutically acceptable carrier and / or excipient. The composition may further comprise at least one additional therapeutic agent in an amount effective in achieving the treatment or prevention of a disease or disorder disclosed herein. Pharmaceutically acceptable carriers and excipients are well known in the art, and the choice of carrier and excipient varies greatly depending on factors such as the method of administration, its impact on solubility and stability, and the characteristics of the dosage form.

[0761]

[0988]

[0989] Treatment method

[0762]

[0990] In another aspect, the present invention provides a method for treating or preventing a disease or disorder, such as a polymerase θ-mediated disease or disorder, in a subject subject that requires treatment or prevention of such a disease or disorder, comprising the step of administering to the subject subject at least one compound disclosed herein, or its tautomer, stereoisomer, prodrug, crystalline form, isotope-labeled form, pharmaceutically acceptable salt, hydrate or solvate, or pharmaceutically acceptable composition thereof.

[0763]

[0991] The terms “human,” “patient,” and “subject” are interchangeable. The “subject” under consideration for administration includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is human. In some embodiments, the subject is a non-human animal.

[0764]

[0992]

[0993] Administration

[0765]

[0994] The pharmaceutical compositions of the present invention can be administered via various routes, including, but not limited to, oral, parenteral (injection), (e.g., intravenous, subcutaneous, intramuscular, intravascular, or infusion), sublingual, topical, transdermal, ocular, rectal, nasal, and vaginal administration.

[0766]

[0995] The pharmaceutical compositions provided herein are administered in pharmaceutically effective doses. For example, the pharmaceutically effective dose of a pharmaceutical composition may range from about 0.01 mg to about 500 mg per kg of body weight, or from about 10 mg to about 500 mg per kg of body weight. In some embodiments, the dose may range from about 0.1 mg to about 250 mg per kg of body weight, or from about 0.1 mg to about 10 mg per kg of body weight, or from 0.1 mg to about 1 mg per kg of body weight. In other embodiments, the dose may range from about 1 mg to about 100 mg per kg of body weight, preferably from about 10 mg to about 100 mg per kg of body weight. The amount of composition to be administered is generally determined by a physician taking into consideration relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight, response, and the severity of the patient's symptoms.

[0767]

[0996]

[0997] Dosage form

[0768]

[0998] For example, the pharmaceutical composition may be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release tablets, solutions, or suspensions; in a form for parenteral injection, such as sterile solutions, suspensions, or emulsions; in a form for topical administration, such as ointments or creams; or in a form for rectal administration, such as suppositories. The pharmaceutical composition contains a conventional pharmaceutical carrier or excipient and the compound of the present invention as an active ingredient. It may also include other pharmaceuticals, pharmaceutical preparations, carriers, and adjuvants.

[0769]

[0999] Exemplary parenteral administration forms include solutions or suspensions of the active compound in a sterile aqueous solution, such as aqueous propylene glycol or dextrose solution. Such administration forms can be appropriately buffered as needed. Suitable pharmaceutical carriers include inert diluents or extenders, water, and various organic solvents. Pharmaceutical compositions may optionally contain additional components such as fragrances, binders, and excipients. For oral administration, tablets containing various excipients such as citric acid may be used together with various decomposing agents such as starch, alginic acid, and certain complex silicates, and binders such as sucrose, gelatin, and acacia. Lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting. Similar types of solid compositions may also be used in soft and hard gelatin capsules. Preferred substances include lactose and high molecular weight polyethylene glycol. When an aqueous suspension or elixir is required for oral administration, the active compound therein may be combined with various sweeteners, flavorings, pigments, or dyes, and may, if necessary, be used with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof, along with emulsifiers or suspensions. Methods for preparing various pharmaceutical compositions containing specific amounts of the active compound will be known or obvious to those skilled in the art.

[0770]

[1000]

[1001] Dosage

[0771]

[1002] The pharmaceutical compositions of the present invention can be administered in single or multiple doses. Dosing can be performed once, twice, three times, four times, five times, six times, or six or more times per day. Dosing can be performed once a month, once every two weeks, once a week, or every other day. In some cases, continuous dosing is performed and maintained for as long as necessary. In some embodiments, the pharmaceutical compositions of the present invention are administered for 1, 2, 3, 4, 5, 6, 7, 14, or 28 days or more. In some embodiments, the pharmaceutical compositions of the present invention are administered for 28, 14, 7, 6, 5, 4, 3, 2, or less than 1 day. In some embodiments, the pharmaceutical compositions of the present invention are administered continuously and chronically.

[0772]

[1003]

[1004] It should be noted that compounds, chemical moieties, or groups described in conjunction with specific aspects, embodiments, or examples of the present invention should be understood to be applicable to other aspects, embodiments, or examples described herein, unless incompatible. All features and / or all steps of any disclosed method or process may be combined in any combination, except for mutually exclusive combinations, of such features and / or steps. The present invention is not limited to any aforementioned embodiment. The present invention extends to new features or new combinations of the features disclosed herein (including all appended claims and abstract), or to new features or new combinations of the steps of the disclosed method or process.

[0773]

[1005] The contents of the papers and documents referenced in this application are incorporated into this application in their entirety by reference, as if all of their contents were described in detail therein.

[0774]

[1006]

[1007] Examples

[0775]

[1008] The present invention is described in detail below with specific examples. These examples are provided for illustrative purposes only and should not be understood as limiting the scope of the invention. The experimental methods used in the following examples, without special conditions, are generally carried out under normal conditions or conditions recommended by the manufacturer. Unless otherwise specified, parts and percentages mean parts by weight and percentages by weight.

[0776]

[1009] Generally, in the manufacturing process, each reaction is carried out in an inert solvent at temperatures ranging from room temperature to reflux temperature (e.g., 0°C to 100°C, or 0°C to 80°C). The reaction time is generally 0.1 to 60 hours, or alternatively 0.5 to 24 hours.

[0777]

[1010]

[1011] Abbreviation

[1012] The abbreviations used in this application have the following meanings:

[1013] Et3N: Triethylamine

[1014] MeOH: methanol

[1015] EtOH: Ethanol

[1016] SOCl2: Thionyl Chloride

[1017] CHCl3: Chloroform

[1018] Na2SO4: Sodium sulfate

[1019] LCMS: Liquid Chromatography Mass Spectrometry

[1020] HPLC: High-performance liquid chromatography

[1021] Boc:tert-butyloxycarbonyl

[1022] DCM: Dichloromethane

[1023] TFA: Trifluoroacetic acid

[1024] THF: Tetrahydrofuran

[1025] dba: dibenzylideneacetone

[1026] ACN: Acetonitrile

[1027] æ:ethyl acetate

[1028] NaOAc: Sodium acetate

[1029] NaBH(OAc)3: Sodium triacetoxyborohydride

[1030] Acetic acid (ATOH)

[1031] TLC: Thin-layer chromatography

[1032] PPh3: Triphenylphosphine

[1033] DIAD: Diisopropyl azodicarboxylate

[1034] DIEA: N,N-diisopropylethylamine

[1035] DMF: Dimethylformamide

[1036] AlMe3: Trimethylaluminum

[1037] Py: Pyridine

[1038] DMSO: Dimethyl sulfoxide

[1039] PYBOP: Benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate

[1040] TBAI: Tetra-n-butylammonium iodide

[0778]

[1041]

[1042] Substances and methods

[0779]

[1043] Solvents, reagents, and raw materials were purchased commercially and used as is unless otherwise specified. Unless otherwise specified, all reactions were carried out at room temperature (RT). Flash column chromatography was performed using ISCO Combiflash Nextgen or Biotage Selekt, with pre-packed columns filled with Merck flash silica gel 60 (40-63 μm) or C18 flash silica.

[0780]

[1044] Unless otherwise specified, all reagents were used without further purification. 1 ¹H-NMR spectra were obtained at room temperature using a Bruker 400 MHz instrument with DMSO-d6 or CDCl3. When two or more allomorphs were detected, the chemical transfer of the most numerous allomorph was reported. 1 The chemical transfer of the 1H NMR spectrum was recorded in parts per million (ppm) units on a delta scale as an internal standard for the residual solvent. The resolving patterns were designed as s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, and the coupling constant (Hz), and were often integrated and presented in a table; the LC-MS conditions are described as follows:

[0781]

[1045]

[1046] LCMS method A:

[1047] LCMS column: SHIMADZU Xtimate C18 2.1*30mm, 3μm

[1048] Mobile phase: Solvent A: Water (4L) + TFA (1.5mL)

[1049] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[1050] Flow rate: 0.8mL / min

[1051] Execution time: Maintain a concentration gradient from 10% to 80% (solvent B) for 6 minutes, then maintain a concentration of 80% for 0.5 minutes.

[1052] Temperature: 50℃

[0782]

[1053]

[1054] LCMS method B:

[1055] LCMS column: SHIMADZU Nano Chrom 120 C18 3.0*30mm, 3μm

[1056] Mobile phase: Solvent A: Water (4L) + TFA (1.5mL)

[1057] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[1058] Flow rate: 0.8mL / min

[1059] Execution time: Maintain a concentration gradient from 10% to 80% (solvent B) for 6 minutes, then maintain a concentration of 80% for 0.5 minutes.

[1060] Temperature: 50℃

[0783]

[1061]

[1062] LCMS method C:

[1063] LCMS column: SHIMADZU Xtimate C18 2.1*30mm, 3μm

[1064] Mobile phase: Solvent A: Water (4L) + TFA (1.5mL)

[1065] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[1066] Flow rate: 0.8mL / min

[1067] Execution time: Maintain a concentration gradient of 30% to 90% (solvent B) for 6 minutes, then maintain a concentration of 90% for 0.5 minutes.

[1068] Temperature: 50℃

[0784]

[1069]

[1070] LCMS method D:

[1071] LCMS column: SHIMADZU Nano Chrom 120 C18 3.0*30mm, 3μm

[1072] Mobile phase: Solvent A: Water (4L) + TFA (1.5mL)

[1073] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[1074] Flow rate: 0.8mL / min

[1075] Execution time: Maintain a concentration gradient of 30% to 90% (solvent B) for 6 minutes, then maintain a concentration of 90% for 0.5 minutes.

[1076] Temperature: 50℃

[0785]

[1077]

[1078] Experimental procedure:

[0786]

[1079] Intermediate 1: (S)-1-(6-methyl-4-(trifluoromethyl)pyrrolidine-2-yl)-5-oxo-N-(prop-2-in-1-yl)-N-(m-tolyl)pyrrolidine-2-carboxamide

[1080] [ka]

[0787]

[1081] Step a. To a solution of tert-butyl(2S)-5-oxopyrrolidine-2-carboxylate (1.85 g, 9.97 mmol) and 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (1.5 g, 7.67 mmol) in dioxane (250 mL), xanthophos (443.80 mg, 766.99 μmol), Cs2CO3 (6.25 g, 19.17 mmol), and Pd2(dba)3 (702.35 mg, 766.99 μmol) were added. The mixture was stirred at 80°C for 16 hours under an N2 atmosphere. LCMS confirmed that the desired mass was observed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 80g Sepa Flash® silica flash column, eluate with a 0-34% dichloromethane / petroleum ether gradient @ 70 mL / min) to obtain tert-butyl(2S)-1-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-5-oxo-pyrrolidine-2-carboxylate (1.48 g, 4.25 mmol, yield 27.68%, purity 99%) as a yellow oil.

[1082] MS (ESI) m / z = 345.1 [M+H] + ; 1HNMR (DMSO-d6): δ = 8.37 (s, 1H), 7.40 (s, 1H), 4.85 (dd, J = 9.6,3.2 Hz, 1H), 2.72-2.57 (m, 2H), 2.47 (s, 3H), 2.45-2.37 (m, 1H), 2.07-1.92 (m, 1H), 1.39 (s, 9H).

[0788]

[1083] Step b. To a solution of tert-butyl(2S)-1-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-5-oxo-pyrrolidine-2-carboxylate (1.47 g, 4.27 mmol) in DCM (12 mL), TFA (9.21 g, 80.78 mmol, 6 mL) was added. The mixture was stirred at 25 °C for 12 hours. LC-MS confirmed that the desired mass was observed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was used directly in the next step without further purification to obtain (2S)-1-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-5-oxo-pyrrolidine-2-carboxylic acid (1.31 g, 3.06 mmol, yield 71.71%, purity 94%, TFA) as a yellow solid.

[1084] MS (ESI) m / z = 289.0 [M+H] + ; 1 HNMR (DMSO-d6): δ = 8.40 (s, 1H), 7.41 (s, 1H), 4.96 (dd, J = 9.6,3.2 Hz, 1H), 2.73-2.59 (m, 2H), 2.47 (s, 3H), 2.45-2.36 (m, 1H), 2.07-2.00 (m,1H).

[0789]

[1085] Step c. To a solution of 3-methylaniline (139.41 mg, 1.30 mmol, 140.96 μL) and (2S)-1-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-5-oxo-pyrrolidine-2-carboxylic acid (250 mg, 867.39 μmol) in DMF (6.2 mL), PYBOP (541.66 mg, 1.04 mmol) and DIEA (336.30 mg, 2.60 mmol, 453.24 μL) were added. The mixture was stirred at 25°C for 16 hours. LCMS confirmed that the desired mass was observed. The reaction mixture was diluted with H2O (20 mL) and extracted with AcOEt (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified using a reversed-phase column (column: 80g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; B%: 0%~55%, 30 min) to obtain (2S)-1-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-5-oxo-pyrrolidine-2-carboxamide (537.5 mg, 1.42 mmol, yield 82.11%, purity 100%) as a white solid.

[1086] MS (ESI) m / z = 378.1 [M+H] + .

[0790]

[1087] Step d. To a solution of 3-bromoprop-1-in (378.29 mg, 2.54 mmol, 274.12 μL) and (2S)-1-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-5-oxo-pyrrolidine-2-carboxamide (480 mg, 1.27 mmol) in ACN (3.8 mL), Cs2CO3 (1.24 g, 3.82 mmol) and tetrabutylammonium iodide (28.19 mg, 76.32 μmol) were added. The mixture was stirred at 80°C for 3 hours. LCMS confirmed that the desired mass was observed. The reaction mixture was diluted with H2O (5 mL) and extracted with AcOEt (5 mL × 3). The combined organic layers were washed with brine (5 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g Sepa Flash® Silica Flash Column, eluate with a 0-10% ethyl acetate / petroleum ether gradient @ 40 mL / min) to obtain (S)-1-(6-methyl-4-(trifluoromethyl)pyrrolidine-2-yl)-5-oxo-N-(prop-2-in-1-yl)-N-(m-tolyl)pyrrolidine-2-carboxamide (238.3 mg, 546.69 μmol, yield 42.98%, purity 95.3%) as a yellow solid.

[1088] MS (ESI) m / z = 416.1 [M+H] + ; 1 HNMR (ES23603-144-P1H2, DMSO-d6): δ = 8.40 (s, 1H), 7.52-7.38 (m,4H), 7.30 (d, J = 7.2 Hz, 1H), 4.85 (dd, J = 7.8, 4.4 Hz, 1H), 4.62 (dd, J =17.4, 2.4 Hz, 1H), 4.25 (dd, J = 17.4, 2.4 Hz, 1H), 3.21 (t, J = 2.4 Hz, 1H),2.70-2.59 (m, 4H), 2.56-2.51 (m, 1H), 2.39 (s, 3H), 2.08-2.00 (m, 2H).

[0791]

[1089]

[1090] Intermediate 2: Methyl(3S)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidined-3-carboxylate

[1091] [ka]

[0792]

[1092] Step a. To a solution of (2S)-2-amino-4-[[(3S)-3-amino-3-carboxypropyl]disulfanyl]butanoic acid (20 g, 65.61 mmol, HCl) in MeOH (200 mL), SOCl2 (23.42 g, 196.84 mmol, 14.30 mL) was added at 0 °C. The mixture was stirred at 25 °C for 12 hours. LC-MS confirmed the detection of the desired compound. The reaction mixture was concentrated under reduced pressure to obtain methyl(2S)-2-amino-4-[[(3S)-3-amino-4-methoxy-4-oxobutyl]disulfanyl]butanoate (28 g, crude product, HCl) as a white solid. 1 H NMR(DMSO-d6) δ = 8.76 (br s, 6H), 4.14-4.10 (m, 2H), 3.75 (s, 6H),2.99-2.78 (m, 4H), 2.21 (q, J = 7.2 Hz, 4H).

[0793]

[1093] Step b. Cl2 (61 g, 860.25 mmol) gas was injected at 0°C for 20 minutes into a mixed solution of methyl(2S)-2-amino-4-[[(3S)-3-amino-4-methoxy-4-oxo-butyl]disulfanyl]butanoate (5.3 g, 15.92 mmol, HCl) in EtOH (20 mL) and CHCl3 (40 mL). The reaction mixture was obtained as a white suspension. The white suspension was filtered, and the filter cake was washed with CHCl3 (100 mL) to obtain a white solid. Methyl(2S)-2-amino-4-chlorosulfonyl-butanoate (4 g, crude product, HCl) was obtained as a white solid and was used directly in the next step without further purification.

[1094] 1 H NMR(DMSO-d6) δ = 10.05 (br, s, 3H), 4.21 (t, J = 7.6 Hz, 1H), 3.67 (s,3H), 3.21-3.11 (m, 1H), 3.09-2.98 (m, 1H), 2.64-2.55 (m, 1H), 2.40-2.28 (m, 1H).

[0794]

[1095] Step c. Et3N (4.82 g, 47.60 mmol, 6.62 mL) was added at 0°C to a solution of methyl(2S)-2-amino-4-chlorosulfonyl-butanoate (4 g, 15.87 mmol, HCl) in CHCl3 (50 mL). The reaction mixture was stirred at 25°C for 12 hours. LCMS confirmed the detection of the desired compound. The white suspension reaction mixture was washed with water (40 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl(3S)-1,1-dioxo-1,2-thiazolidined-3-carboxylate (2.38 g, 11.95 mmol, yield 75.34%, purity 90%) as a white solid, which was used directly in the next step without further purification.

[1096] 1H NMR(DMSO-d6) δ = 7.50 (br d, J = 5.6 Hz, 1H), 4.27-4.17 (m, 1H), 3.68(s, 3H), 3.23-3.11 (m, 1H), 3.09-2.98 (m, 1H), 2.62-2.58 (m, 1H), 2.41-2.25 (m,1H).

[0795]

[1097] Step d. To a solution of methyl(3S)-1,1-dioxo-1,2-thiazolidined-3-carboxylate (1 g, 5.58 mmol) in dioxane (15 mL), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (1.07 g, 4.46 mmol), Cs2CO3 (4.55 g, 13.95 mmol), N1,N2-dimethylethane-1,2-diamine (619.83 mg, 7.03 mmol, 756.81 μL) and CuI (1.34 g, 7.03 mmol) were added. The mixture was stirred at 80°C for 12 hours. LCMS confirmed the detection of the desired compound. After direct air drying of the reaction solution, it was extracted with water (100 mL) and DCM (150 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified using a reversed-phase column (column: 40g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; B%: 0%~58%, 30 min) to obtain methyl(3S)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidined-3-carboxylate (660 mg, 1.95 mmol, yield 34.96%, purity 100%) as a white solid.

[1098] MS (ESI) m / z = 338.9 [M+H] + ; 1HNMR (DMSO-d6) δ = 7.36 (s, 1H), 7.21 (s, 1H), 5.00 (dd, J = 7.8, 5.2Hz, 1H), 3.82-3.72 (m, 1H), 3.69 (s, 3H), 3.67-3.60 (m, 1H), 2.84-2.70 (m, 1H),2.51-2.46 (m, 1H), 2.44 (s, 3H).

[0796]

[1099]

[1100] Intermediate 3: (S)-5-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(prop-2-in-1-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1101] [ka]

[0797]

[1102] Step a. Benzaldehyde (2.73 g, 25.71 mmol, 2.60 mL) was added at 25°C to a solution of methyl(2S)-2-amino-3-hydroxy-propanoate (5 g, 32.14 mmol, HCl) in THF (50 mL), and the reaction mixture was cooled to 0°C. AcOH (500.00 mg, 8.33 mmol, 476.64 μL) and NaOAc (2.11 g, 25.71 mmol) were added, and the reaction mixture was stirred at 0-5°C for 1 hour. NaBH(OAc)3 (11.58 g, 54.63 mmol) was added in fractional amounts over 30 minutes, and the reaction mixture was stirred at 15°C for 16 hours. LCMS confirmed that the desired mass was observed. Saturated NaHCO3 solution (175 mL) was added to the suspension over 45 minutes at 0-5°C (gas generation, pH adjusted to 8-9), then extracted with siRNA (100 mL x 3), the organic layer was washed with water (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g Sepa Flash® silica flash column, eluate with a 0-80% ethyl acetate / petroleum ether gradient @ 80 mL / min) to obtain methyl(2S)-2-(benzylamino)-3-hydroxypropanoate (5.6 g, 25.93 mmol, yield 80.70%, purity 96.9%) as a colorless oil.

[1103] MS (ESI) m / z = 210.1 [M+H] + ; 1 HNMR (DMSO-d6): δ = 7.32-7.31 (m, 4H), 7.26-7.21 (m, 1H), 4.84 (t, J= 4.8 Hz, 1H), 3.77 (d, J = 13.6 Hz, 1H), 3.63 (s, 3H), 3.61 (d, J = 6.4 Hz,1H), 3.59-3.56 (m, 2H), 3.26 (t, J = 5.2 Hz, 1H), 2.40 (br s, 1H).

[0798]

[1104] Step b. A solution of t-BuOH (1.66 g, 22.45 mmol, 2.15 mL) in DCM (10 mL) was added dropwise to a solution of N-(oxomethylene)sulfamoyl chloride (2.89 g, 20.41 mmol, 1.78 mL) in DCM (30 mL) at 0°C, and the mixture was stirred at 0°C for 1 hour under an N2 atmosphere. Then, solutions of methyl(2S)-2-(benzylamino)-3-hydroxypropanoate (4.27 g, 20.41 mmol) and Et3N (3.10 g, 30.61 mmol, 4.26 mL) in DCM (30 mL) were added to the solution at 0°C. The mixture was stirred at 10-19°C for 16 hours. LCMS confirmed that the desired mass was observed. TLC (plate 1, SiO2, petroleum ether:ethyl acetate = 1:1) results showed new spots (R f It was confirmed that a concentration of 0.8 was observed. The mixture was diluted with water (100 mL), extracted with dichloromethane (30 mL x 3), washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography eluting with 0-41% ethyl acetate in petroleum ether to obtain methyl(2S)-2-[benzyl(tert-butoxycarbonylsulfamoyl)amino]-3-hydroxypropanoate (1.5 g, 3.63 mmol, yield 17.79%, purity 94%) as a yellow gum.

[1105] MS (ESI) m / z = 289.0 [M-Boc+H] + ; 1 H NMR (CDCl3) δ = 7.60-7.39 (m, 3H), 7.38-7.29 (m, 3H),4.71-4.63 (m, 2H), 4.60-4.53 (m, 1H), 4.00 (d, J = 6.8 Hz, 2H), 3.69 (s, 3H), 2.88 (s, 1H), 1.48 (s, 9H).

[0799]

[1106] Step c. To a solution of methyl(2S)-2-[benzyl(tert-butoxycarbonylsulfamoyl)amino]-3-hydroxypropanoate (3.26 g, 8.39 mmol) and PPh3 (2.64 g, 10.07 mmol) in DCM (60 mL), DIAD (2.04 g, 10.07 mmol, 1.95 mL) was added at 0°C, and the mixture was stirred at 16°C for 2 hours. LCMS confirmed that the desired mass was observed. TLC (Plate 1, SiO2, petroleum ether:ethyl acetate = 3:1) showed new spots (R f It was confirmed that a concentration of 0.6 was observed. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with 0-25% ethyl acetate in petroleum ether to obtain 2-(tert-butyl)4-methyl (S)-5-benzyl-1,2,5-thiadiazolidine-2,4-dicarboxylate 1,1-dioxide (2.56 g, 6.91 mmol, yield 82.37%, purity 100%) as a white solid.

[1107] MS (ESI) m / z = 393.0 [M+Na] + ; 1 HNMR (CDCl3) δ = 7.44-7.31 (m, 5H), 4.58-4.41 (m, 2H), 4.07-4.00 (m,1H), 3.94-3.86 (m, 2H), 3.73 (s, 3H), 1.56 (s, 9H).

[0800]

[1108] Step d. To a solution of 2-(tert-butyl)4-methyl (S)-5-benzyl-1,2,5-thiadiazolidine-2,4-dicarboxylate 1,1-dioxide (1 g, 2.70 mmol) in DCM (10 mL), TFA (7.68 g, 67.31 mmol, 5 mL) was added. The mixture was stirred at 25°C for 12 hours. LC-MS confirmed the detection of the desired compound. The reaction mixture was concentrated under reduced pressure to obtain methyl(3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (650 mg, 1.92 mmol, yield 71.26%, purity 80%, crude product) as a white solid.

[1109] MS (ESI) m / z = 292.8 [M+Na] + .

[0801]

[1110] Step e. To a solution of methyl(3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (650 mg, 2.40 mmol) in DMF (7 mL), MeI (682.64 mg, 4.81 mmol, 184.98 μL) and K2CO3 (997.03 mg, 7.21 mmol) were added. The mixture was stirred at 25°C for 12 hours. LC-MS confirmed the detection of the desired compound. The residue was purified using a reversed-phase column (column: 40g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; B%: 0%~55%, 30 min) to obtain methyl(3S)-2-benzyl-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (660 mg, 2.11 mmol, yield 87.84%, purity 91%) as a white solid.

[1111] MS (ESI) m / z = 325.9 [M+CH3CN+H] + .

[0802]

[1112] Step f. To a solution of 3-methylaniline (422.08 mg, 3.94 mmol, 426.78 μL) in toluene (7 mL), AlMe3 (2 M, 2.95 mL) and methyl(3S)-2-benzyl-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (560 mg, 1.97 mmol) were added. The mixture was stirred at 100°C for 12 hours. LC-MS confirmed the detection of the desired compound. The residue was purified using a reversed-phase column (column: 40g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; B%: 0%~55%, 30 min) to obtain (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (491 mg, 1.27 mmol, yield 64.50%, purity 93%) as a white solid.

[1113] MS (ESI) m / z = 359.9 [M+H] + .

[0803]

[1114] Step g. To a solution of (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (289 mg, 804.02 μmol) in ACN (4 mL), Cs2CO3 (654.92 mg, 2.01 mmol) and 3-bromoprop-1-yin (191.5 mg, 1.61 mmol) were added. The mixture was stirred at 80°C for 12 hours. LC-MS confirmed the detection of the desired compound. The residue was purified by flash silica gel chromatography (ISCO®; 20g Sepa Flash® Silica Flash Column, eluate with 0.46% ethyl acetate / petroleum ether gradient @ 30 mL / min) to obtain (S)-2-benzyl-5-methyl-N-(prop-2-in-1-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide (250 mg, 0.63 mmol, yield 78.2%, purity 96%) as a colorless oil.

[1115] MS (ESI) m / z = 398.9 [M+H] + .

[0804]

[1116] Step h. To a solution of (S)-2-benzyl-5-methyl-N-(prop-2-in-1-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide (600 mg, 1.61 mmol) in THF (12 mL), Pd / C (2 g, 1.88 mmol, purity 10%) was added. The mixture was stirred at 25°C for 12 hours under a 40 Psi H2 atmosphere. LCMS confirmed the detection of the desired compound. The reaction mixture was filtered, the cake was washed with ELISA (30 mL x 3), and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g Sepa Flash® Silica Flash Column, eluate 0-9% MeOH / DCM @ 30 mL / min) to obtain (S)-5-methyl-N-(prop-2-in-1-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide (430 mg, 1.3 mmol, yield 86.8%, purity 91%) as a white solid.

[1117] MS (ESI) m / z = 331.9 [M+Na] + .

[0805]

[1118] Step i. Step i was prepared using a method similar to that described in the synthesis of intermediate 1 (step a).

[1119] MS (ESI) m / z = 467.9 [M+H] + .

[0806]

[1120]

[1121] Example 1

[1122] (S)-N-(3-(6-aminopyridazine-3-yl)prop-2-in-1-yl)-1-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-5-oxo-N-(m-tolyl)pyrrolidine-2-carboxamide

[1123] [ka]

[0807]

[1124] Step a. To a solution of 6-iodopyridazine-3-amine (75.81 mg, 343.04 μmol) and intermediate 1 (95 mg, 228.69 μmol) in THF (2.38 mL), Pd(PPh3)2Cl2 (32.10 mg, 45.74 μmol), Et3N (69.42 mg, 686.07 μmol, 95.49 μL) and CuI (4.36 mg, 22.87 μmol) were added. The mixture was stirred under an N2 atmosphere at 25°C for 12 hours. LCMS confirmed that the desired mass was observed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [water (TFA)-ACN]; gradient: 30%~50% for 10.5 minutes B) to obtain (S)-N-(3-(6-aminopyridazine-3-yl)prop-2-in-1-yl)-1-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-5-oxo-N-(m-tolyl)pyrrolidine-2-carboxamide (8.3 mg, 13.33 μmol, yield 2.92%, purity 100%, TFA) as a yellow solid.

[1125] MS (ESI) m / z = 509.2 [M+H] + ; 1HNMR (MeOD): δ = 8.49 (s, 1H), 7.62 (d, J = 9.6 Hz, 1H), 7.57 (br s, 1H),7.51-7.43 (m, 2H), 7.38-7.33 (m, 2H), 7.24 (s, 1H), 5.06 (dd, J =8.8, 4.0 Hz,1H), 4.99-4.94 (m, 1H), 4.65-4.58 (m, 1H), 2.85-2.74 (m, 1H), 2.65 (s, 3H),2.62-2.53 (m, 1H), 2.45 (s, 3H), 2.18-2.10 (m, 2H).

[0808]

[1126]

[1127] The examples shown in Table 1 were manufactured using the same method as described in the synthesis of Example 1.

[1128] [ka]

[0809]

[1129]

[1130] [Table 60] JPEG2026522774000222.jpg225149 JPEG2026522774000223.jpg225149 JPEG2026522774000224.jpg225149 JPEG2026522774000225.jpg225149

[0810]

[1133] Example 13

[1134] (S)-N-(2,4-difluoro-3-methylphenyl)-N-(4-(4-ethylpiperazine-1-yl)buto-2-in-1-yl)-1-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-5-oxopyrrolidine-2-carboxamide

[1135] [ka]

[0811]

[1136]

[1137] Step a. To a solution of 4-((tert-butyldiphenylsilyl)oxy)buto-2-in-1-ylmethanesulfonate (580 mg, 1.45 mmol) and (S)-N-(2,4-difluoro-3-methylphenyl)-1-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-5-oxopyrrolidine-2-carboxamide (500 mg, 1.20 mmol) in ACN (12 mL), Cs2CO3 (781 mg, 2.4 mmol) was added. The mixture was stirred at 80°C for 3 hours. LCMS confirmed that the desired mass was observed. The reaction mixture was diluted with H2O (30 mL) and extracted with AcOEt (30 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g Sepa Flash® Silica Flash Column, eluate with a 0-50% ethyl acetate / petroleum ether gradient @ 40 mL / min) to obtain (S)-N-(4-((tert-butyldiphenylsilyl)oxy)buto-2-in-1-yl)-N-(2,4-difluoro-3-methylphenyl)-1-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-5-oxopyrrolidine-2-carboxamide (680 mg, yield 78.1%, purity 95.0%) as a yellow oil. MS (ESI) m / z = 720.01 [M+H] + .

[0812]

[1138] Step b. 1,245 mg of the intermediate (S)-N-(4-((tert-butyldiphenylsilyl)oxy)buto-2-in-1-yl)-N-(2,4-difluoro-3-methylphenyl)-1-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-5-oxopyrrolidine-2-carboxamide was dissolved in 10 mL of tetrahydrofuran. The mixture was then stirred under nitrogen protection, and the reaction was carried out at a temperature below 5°C by adding an appropriate amount of 1 M THF to 2.6 mL of tetrabutylammonium fluoride for 3 hours. After the reaction was complete, water was added to the reaction system, and the system was extracted three times with ethyl acetate. The system was then washed with saturated brine and dried over sodium sulfate. The mixture was filtered and concentrated. The residue was then purified by column chromatography to obtain 680 mg of a colorless oil compound in a yield of 81.7%.

[1139] MS (ESI) m / z = 482.01 [M+H] + .

[0813]

[1140] Step c. DMP (753 mg, 1.776 mmol) was added to a solution of (S)-N-(4-((tert-butyldiphenylsilyl)oxy)buto-2-in-1-yl)-N-(2,4-difluoro-3-methylphenyl)-1-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-5-oxopyrrolidine-2-carboxamide (570 mg, 1.183 mmol) in DCM (7 mL). The mixture was stirred at 25°C for 3 hours. LC-MS confirmed the detection of the desired compound. The residue was purified by column chromatography to obtain 416 mg of the colorless oil compound in a yield of 73.4%. MS (ESI) m / z = 480.20 [M+H] + .

[0814]

[1141] Step d. NaBH(OAc)3 (44 mg, 1.776 mmol) was added to a solution of (S)-N-(2,4-difluoro-3-methylphenyl)-1-(6-methyl-4-(trifluoromethyl)pyrrolidine-2-yl)-5-oxo-N-(4-oxobuto-2-in-1-yl)pyrrolidine-2-carboxamide (50 mg, 0.104 mmol) and 1-ethylpiperazine (14.3 mg, 0.125 mmol) in DCM (1 mL). The mixture was stirred at 25°C for 8 hours. LCMS confirmed the detection of the desired compound. The residue was purified by column chromatography to obtain 48 mg of the white solid compound in a yield of 79.7%.

[1142] MS (ESI) m / z = 578.09 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ = 8.54 (d, J = 16.9 Hz, 1H), 7.74 - 6.83 (m,3H), 4.93 (m, 5H), 4.23 - 4.07 (m, 1H), 3.68 (s, 3H), 3.22 (s, 3H), 2.65 - 2.48(m, 5H), 2.40-2.45 (m, 4H), 2.30-2.25 (m, 4H), 2.17 - 1.94 (m, 3H).

[0815]

[1143]

[1144] Example 14

[1145] (S)-N-(2,4-difluoro-3-methylphenyl)-1-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(4-morpholinbut-2-in-1-yl)-5-oxopyrrolidine-2-carboxamide

[1146] [ka]

[0816]

[1147] Example 14 was prepared using the same procedure as described in the synthesis of Example 13.

[1148] MS (ESI) m / z = 551.04 [M+H] + ;

[0817]

[1149]

[1150]

[1151] Example 15

[1152] (S)-N-(2,4-difluoro-3-methylphenyl)-1-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-5-oxo-N-(4-(4-(pyrazine-2-yl)piperazine-1-yl)buto-2-in-1-yl)pyrrolidine-2-carboxamide

[0818]

[1153] [ka]

[0819]

[1154] Example 15 was prepared using the same procedure as described in the synthesis of Example 13.

[1155] MS (ESI) m / z = 628.1 [M+H] + ;

[0820]

[1156]

[1157] Example 16

[1158] (S)-N-(2,4-difluoro-3-methylphenyl)-1-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-5-oxo-N-(4-(4-(pyrimidine-2-yl)piperazine-1-yl)buto-2-in-1-yl)pyrrolidine-2-carboxamide

[1159] [ka]

[0821]

[1160] Example 16 was prepared using the same procedure as described in the synthesis of Example 13.

[1161] MS (ESI) m / z = 628.1 [M+H] + .

[0822]

[1162]

[1163] Example 17

[1164] (S)-N-(3-(5-aminopyrazine-2-yl)prop-2-in-1-yl)-N-(2,4-difluoro-3-methylphenyl)-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1165]

[1166] [ka]

[0823]

[1167] Step a. The mixture of intermediate 2 (1.2 g, 3.55 mmol), 2,4-difluoro-3-methylaniline (761.57 mg, 5.32 mmol), and AlMe3 (5 M, 2.13 mL) in toluene (20 mL) was degassed, purged three times with N2, and then stirred at 100°C for 16 hours under an N2 atmosphere. LCMS confirmed that the desired mass was observed. The reaction mixture was quenched with NH4Cl (10 mL), diluted with water (20 mL), and extracted with RINKAN (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g Sepa Flash® silica flash column, eluate with a 0-40% ethyl acetate / petroleum ether gradient @ 40 mL / min) to obtain (3S)-N-(2,4-difluoro-3-methylphenyl)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidine-3-carboxamide (1.1 g, 2.20 mmol, yield 62.11%, purity 90%) as a white solid.

[1168] MS (ESI) m / z = 450.0 [M+H] + ; 1 HNMR (DMSO-d6) δ = 10.18 (s, 1H), 7.58-7.48 (m, 1H), 7.32 (s, 1H),7.21 (s, 1H), 7.02 (t, J = 9.2 Hz, 1H), 5.16 (dd, J = 7.6, 4.8 Hz, 1H), 3.83-3.63 (m, 2H), 2.85-2.73 (m, 1H), 2.46-2.42 (m, 4H), 2.17 (s, 3H).

[0824]

[1169] Step b. To a solution of (3S)-N-(2,4-difluoro-3-methylphenyl)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidined-3-carboxamide (300 mg, 667.57 μmol) in ACN (3 mL), 3-bromoprop-1-in (248.17 mg, 1.67 mmol, 179.83 μL), TBAI (24.66 mg, 66.76 μmol), and Cs2CO3 (652.52 mg, 2.00 mmol) were added. The mixture was stirred at 80°C for 1 hour. LCMS confirmed the detection of the desired compound. The crude product was further purified by Prep-HPLC (column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (TFA)-ACN]; gradient: 45%~75% for 8 minutes B) to obtain (3S)-N-(2,4-difluoro-3-methyl-phenyl)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-N-prop-2-inyl-1,2-thiazolidined-3-carboxamide (340 mg, purity 99.49%) as a white solid.

[1170] MS (ESI) m / z = 488.1 [M+H] + .

[0825]

[1171] Step c. To a solution of (3S)-N-(2,4-difluoro-3-methylphenyl)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-N-prop-2-inyl-1,2-thiazolidined-3-carboxamide (80 mg, 164.12 μmol) in THF (2 mL), 5-iodopyrazine-2-amine (54.41 mg, 246.18 μmol), Pd(PPh3)2Cl2 (23.04 mg, 32.82 μmol), Et3N (49.82 mg, 492.37 μmol, 68.53 μL) and CuI (3.13 mg, 16.41 μmol) were added. The mixture was stirred at 25°C for 12 hours. LCMS confirmed the detection of the desired compound. The crude product was further purified by Prep-HPLC (column: C18 100×40 mm; mobile phase: [water (TFA)-ACN]; gradient: 38%~68% for 8 minutes B) to obtain (3S)-N-[3-(5-aminopyrazine-2-yl)prop-2-inyl]-N-(2,4-difluoro-3-methylphenyl)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidined-3-carboxamide (25.44 mg, 41.19 μmol, yield 25.10%, purity 94%) as a white solid.

[1172] MS (ESI) m / z = 581.1 [M+H] + ; 1 HNMR (DMSO-d6) δ = 8.00-7.78 (m, 2H), 7.77-7.68 (m, 1H), 7.36-7.27(m, 2H), 7.24-7.07 (m, 1H), 5.01 (d, J = 17.6 Hz, 1H), 4.92-4.79 (m, 1H), 4.70(dd, J = 62.0, 17.6 Hz, 0. 5H), 4.27 (d, J = 17.6 Hz, 0.5H), 3.65-3.58(m, 2H), 2.53 (s, 2H), 2.47 (br s, 1H), 2.46-2.37 (m, 1H), 2.26-2.12 (m, 4H).

[0826]

[1173]

[1174] The examples shown in Table 2 were manufactured using a method similar to the one described in the synthesis of Example 17.

[1175] [ka]

[0827]

[1176]

[1177] [Table 61] JPEG2026522774000233.jpg225149 JPEG2026522774000234.jpg225149 JPEG2026522774000235.jpg225149 JPEG2026522774000236.jpg225149 JPEG2026522774000237.jpg225149 JPEG2026522774000238.jpg225149 JPEG2026522774000239.jpg225149 JPEG2026522774000240.jpg225149 JPEG2026522774000241.jpg225149 JPEG2026522774000242.jpg225149 JPEG2026522774000243.jpg225149 JPEG2026522774000244.jpg225149 JPEG2026522774000245.jpg225149 JPEG2026522774000246.jpg225149 JPEG2026522774000247.jpg225149 JPEG2026522774000248.jpg225149 JPEG2026522774000249.jpg225149 JPEG2026522774000250.jpg225149 JPEG2026522774000251.jpg225149 JPEG2026522774000252.jpg225149 JPEG2026522774000253.jpg225149 JPEG2026522774000254.jpg225149 JPEG2026522774000255.jpg225149 JPEG2026522774000256.jpg225149 JPEG2026522774000257.jpg225149 JPEG2026522774000258.jpg225149 JPEG2026522774000259.jpg225149 JPEG2026522774000260.jpg225149 JPEG2026522774000261.jpg225149 JPEG2026522774000262.jpg225149 JPEG2026522774000263.jpg225149 JPEG2026522774000264.jpg225149 JPEG2026522774000265.jpg225149 JPEG2026522774000266.jpg225149 JPEG2026522774000267.jpg225149 JPEG2026522774000268.jpg225149 JPEG2026522774000269.jpg225149 JPEG2026522774000270.jpg225149 JPEG2026522774000271.jpg225149 JPEG2026522774000272.jpg225149 JPEG2026522774000273.jpg225149

[0828]

[1206] The examples shown in Table 3 were manufactured using a method similar to the one described in the synthesis of Example 17.

[1207] [ka]

[1208]

[1209] [Table 62] JPEG2026522774000276.jpg225149

[1210] The examples shown in Table 4 were manufactured using a method similar to the one described in the synthesis of Example 17.

[1211] [ka]

[0829]

[1212] [Table 63]

[0830]

[1213] The examples shown in Table 5 were prepared using the same method as described in the synthesis of intermediate 3 and Example 17.

[0831]

[1214] [ka]

[0832]

[1215] [Table 64] JPEG2026522774000281.jpg225149

[0833]

[1216] The examples shown in Table 2 were manufactured using a method similar to the one described in the synthesis of Example 17.

[1217] [ka]

[0834]

[1218]

[1219] [Table 65] JPEG2026522774000284.jpg225149

[0835]

[1220] Example 145

[1221] (S)-N-(3-(6-carbamoylpyridine-3-yl)prop-2-in-1-yl)-N-(4-fluoro-3-methylphenyl)-5-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-4-thia-5-azaspiro[2,4]heptan-6-carboxamide 4,4-dioxide

[1222] [ka]

[0836]

[1223] Step a. To a solution of intermediate 2 (500 mg, 1.47 mmol) in DMF (7 mL), K2CO3 (2.03 g, 14.7 mmol) and 1,2-dibromoethane (828 mg, 4.41 mmol) were added. The mixture was then stirred at 80°C for 2 hours. LCMS confirmed the detection of the desired mass. The reaction mixture was dissolved in HCl (5 mL), washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g Sepa Flash® silica flash column, eluate with a 0-50% ethyl acetate / petroleum ether gradient @ 40 mL / min) to obtain methyl(S)-5-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-4-thia-5-azaspiro[2,4]heptan-6-carboxylate 4,4-dioxide (210 mg, yield 39.1%, purity 95.0%) as a yellow oil. MS(ESI)m / z=365.01[M+H] + .

[0837]

[1224] Step b. A mixture of methyl(S)-5-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-4-thia-5-azaspiro[2.4]heptan-6-carboxylate 4,4-dioxide (200 mg, 0.547 mmol), 4-fluoro-3-methylaniline (102.6 mg, 0.82 mmol), and AlMe3 (5M, 0.65 mL) in toluene (5.4 mL) was degassed, purged three times with N2, and then stirred at 100°C for 16 hours under an N2 atmosphere. LCMS confirmed that the desired mass was observed. The reaction mixture was quenched with NH4Cl (10 mL), diluted with water (20 mL), and extracted with RINKAN (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g Sepa Flash® silica flash column, eluate with a 0-40% ethyl acetate:petroleum ether gradient @ 40 mL / min) to obtain (S)-N-(4-fluoro-3-methylphenyl)-5-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-4-thia-5-azaspiro[2,4]heptan-6-carboxamide 4,4-dioxide (120 mg, 0.26 mmol, yield 47.9%, purity 90%) as a white solid. MS (ESI) m / z = 458.01 [M+H] + .

[0838]

[1225] Step c. To a solution of (S)-N-(4-fluoro-3-methylphenyl)-5-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-4-thia-5-azaspiro[2.4]heptan-6-carboxamide 4,4-dioxide (100 mg, 0.218 mmol) in ACN (2 mL), 3-bromoprop-1-yin (64.8 mg, 0.545 mmol), TBAI (8.1 mg, 21.8 μmol), and Cs2CO3 (213 mg, 0.65 mmol) were added. The mixture was stirred at 80°C for 1 hour. LCMS confirmed the detection of the desired compound. The crude product was further purified by Prep-HPLC (column: Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (TFA)-ACN]; gradient: 45%~75% for 8 minutes B) to obtain (S)-N-(4-fluoro-3-methylphenyl)-5-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(prop-2-in-1-yl)-4-thia-5-azaspiro[2,4]heptan-6-carboxamide 4,4-dioxide (85 mg, yield 78.6%, purity 95.0%) as a white solid. MS (ESI) m / z = 496.01 [M+H] + .

[0839]

[1226] Step d. To a solution of (S)-N-(4-fluoro-3-methylphenyl)-5-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(prop-2-in-1-yl)-4-thia-5-azaspiro[2.4]heptan-6-carboxamide 4,4-dioxide (50 mg, 0.10 mmol) in THF (2 mL), 5-iodopicolinamide (37.2 mg, 0.15 mmol), Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Et3N (30.3 mg, 0.3 mmol, 41.8 μL) and CuI (3.8 mg, 0.02 mmol) were added. The mixture was stirred at 25°C for 12 hours. LCMS confirmed the detection of the desired compound. The crude product was further purified by Prep-HPLC (column: C18 100×40 mm; mobile phase: [water (TFA)-ACN]; gradient: 38%~68% for 8 minutes B) to obtain (S)-N-(3-(6-carbamoylpyridine-3-yl)prop-2-in-1-yl)-N-(4-fluoro-3-methylphenyl)-5-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-4-thia-5-azaspiro[2.4]heptan-6-carboxamide 4,4-dioxide (15 mg, 0.024 mmol, yield 24.3%, purity 95%) as a white solid.

[1227] MS (ESI) m / z = 616.01 [M+H] + .

[0840]

[1228]

[1229] biological analysis

[1230] pol θ Expression and purification of polymerase domains

[0841]

[1231] The DNA sequence of the polQ gene (Genebank ID# NM 199420.4) was chemically synthesized. The DNA sequence encoding the polymerase domain (amino acids 1792-2590) was subclone into an E. coli expression plasmid, and a 10X histidine SUMO tag was fused to the N-terminus of the polymerase domain.

[0842]

[1232] The protein was expressed in E. coli and purified using a two-step IMAC (immobilized metal chelate affinity chromatography) process. Briefly, the overexpressed E. coli lysate was purified using Ni-NTA, and the N-terminal tag was degraded by SUMO protease. Subsequently, the 10X histidine-SUMO tag fragments were removed using Ni-NTA beads. The resulting protein was used for Picogreen analysis as described below.

[0843]

[1233]

[1234] Polθ polymerase activity analysis

[0844]

[1235] 1) Manufacturing of DNA complexes

[1236] The method for producing the DNA complex was slightly modified from a previously reported protocol (Zatreanu et al., 2021, Nature Communications, 12:3636). Briefly, the polθ substrate was prepared by mixing Oligo1 (5'-GCG GCT GTC ATA AG-3') and Oligo2 (5'-GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACA GCC GCG-3') in annealing buffer (20mM Tris-Cl, pH 7.5, 50mM NaCl) to final concentrations of 22 μM and 20 μM, respectively. Polθ products were prepared by mixing Oligo3 (5'-CGC GGC TGT CAT AAG ACG CAA TCT GAG ATT TGA TGC CAT TGT CAA TGT AGC-3') and Oligo2 (5'-GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACA GCC GCG-3') to a final concentration of 20 μM. Polθ products were used for top-level signal control in Picogreen analysis. Both substrates and products were heated to 95°C for 5 minutes and then slowly cooled to room temperature.

[0845]

[1237]

[1238] 2) Picogreen analysis

[1239] To evaluate the in vitro polθ activity inhibitory ability of the test compound, Picogreen analysis was performed to determine polθ IC2. 50 (nM) was measured.

[0846]

[1240] The reaction was carried out at room temperature in analytical buffer (25 mM Tris-HCl, pH 7.5, 12.5 mM NaCl, 0.5 mM MgCl2, 5% (v / v) glycerol, 0.01% (v / v) Triton X-100, 0.01% (w / v) bovine serum albumin, 1 mM DTT). 30 μL of the double polymerase mixture (8 nM Polθ enzyme in analytical buffer) was dispensed into a 96-well plate, and the test compound was diluted with 100% DMSO to obtain an appropriate dose range for the 12-point concentration reaction. 1 μL of this mixture was dispensed into each well, and then 30 μL of the double substrate mixture (100 nM DNA and 40 μM dNTPs in analytical buffer) was added. After 90 minutes of incubation, the reaction was interrupted and 40 μL of Picogreen solution (Picogreen diluted 1:80, Invitrogen, Cat# P7581, 25 mM Tris-HCl, pH 7.5, 10 mM EDTA, pH 7.5) was added to stain the DNA.

[0847]

[1241] Fluorescence intensity was measured using an Ensight plate reader (Perkin Elmer) at excitation / emission = 485 nm / 520 nm. Data was analyzed using GraphPad Prism software (version 8.4.3) for IC. 50 I calculated it.

[0848]

[1242] The compounds from Examples 1 to 145 were tested using the analytical method described above, and the results are shown in the table below.

[0849]

[1243]

[1244] [Table 66] JPEG2026522774000287.jpg185149 JPEG2026522774000288.jpg59149

[0850]

[1251] Reference: 1nM < *** < 50nM; 51nM < ** < 100nM; and * > 101nM

[0851]

[1252]

[1253] As shown in the table above, the tested compounds demonstrated good activity in inhibiting Polθ polymerase.

[0852]

[1254]

[1255] 3) Cell viability analysis

[1256] DLD1-BRCA2 KO (Horizon Discovery, Cat# HD 105-007) cells and DLD1-mother cells were maintained in a humid atmosphere of 5% CO2 at 37°C in culture medium (RPMI-1640 containing 2 mM L-glutamine and 25 mM sodium bicarbonate, supplemented with 10% FBS). Cells were seeded in 96-well plates at final concentrations of 1,500 cells per well (DLD1-BRCA2 KO) and 600 cells per well (DLD1-mother cells). After 4 hours, the test compound was added to the cells (final DMSO concentration was 1%), and the medium was changed every 3-4 days for 14 days. To measure viability, cells were cultured for 4 hours in culture medium supplemented with 0.1 mg / ml Resazurin (Merck, Cat# R7017). Fluorescence was measured at Ex / Em = 560nm / 590nm using an EnSight multimode plate reader (Perkin Elmer). Data analysis and IC were performed using GraphPad Prism (version 10.0.2). 50 The calculation was performed. Result: The IC250 was determined for the selected compound of the present invention. 50 The prices are shown in the table below.

[0853]

[1257]

[1258] [Table 67] JPEG2026522774000290.jpg208149 JPEG2026522774000291.jpg73149

[0854]

[1266] Reference: ***<1μM; 1.1μM<**<5μM; and *>5.1μM

[0855]

[1267]

[1268] Although the compounds, compositions, dosage forms, and methods of the present invention have been described in terms of specific embodiments, those skilled in the art will see that modifications or alterations can be applied to the compounds, compositions, dosage forms, and methods described in the present invention without departing from the spirit and scope of the invention. All such modifications or alterations will be obvious to those skilled in the art and will be deemed to be within the spirit and scope of the invention as defined in the appended claims.

[0856]

[1269]

[1270] The present invention provides the following examples:

[0857]

[1271] Example 1. Compounds of the following chemical formula (I), or their tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates:

[1272] [ka]

[1273] (I)

[0858]

[1274] In the above chemical formula (I),

[1275] R 1 , R 2 , R 3 , R 4 and R 5Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, hydroxy, and -NR. x R y A group consisting of the following is independently selected, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0859]

[1276] X is methylene, ethylene, n-propylene, -NH-, -NR z1 - and -CR z2 R z3 -Selected from the group consisting of, where each of the methylene, ethylene, and n-propylene may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0860]

[1277] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0861]

[1278] W is selected from the group consisting of carbon and sulfur;

[0862]

[1279] n is either 1 or 2, where n is 1 if W is carbon, and n is 2 if W is sulfur;

[0863]

[1280] A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl groups, where each of the aryl and heteroaryl groups is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R yThey may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0864]

[1281] L 1 This is selected from the group consisting of non-existent -(C1-C6)alkylene- and -(C1-C6)alkylene-NH-;

[0865]

[1282] L 2 is selected from the group consisting of non-existent and -(C1-C6)alkylene-, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0866]

[1283] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0867]

[1284] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0868]

[1285] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0869]

[1286] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0870]

[1287] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0871]

[1288] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0872]

[1289] R 66 is a 5-10 membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl, and amino;

[0873]

[1290] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0874]

[1291] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups;

[0875]

[1292] R z2 and R z3 These, together with the carbon atoms to which they are bonded, form a 3-6 membered cycloalkane ring, where the cycloalkane ring may be substituted with one or more selected from C1-C6 alkyl and halogen atoms; and

[0876]

[1293] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0877]

[1294]

[1295]

[1296] Example 2. In Example 1, the compound is a compound of the following chemical formula (II).

[1297] [ka]

[1298] (II)

[0878]

[1299] In the above chemical formula (II),

[1300] R 1 , R 2 , R 3 , R 4 and R 5 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, hydroxy, and -NR. x R y A group consisting of the following is independently selected, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0879]

[1301] A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl groups, where each of the aryl and heteroaryl groups is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y They may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0880]

[1302] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0881]

[1303] L 2The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0882]

[1304] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0883]

[1305] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0884]

[1306] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; and

[0885]

[1307] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0886]

[1308]

[1309] Example 3. In Example 1 or 2, the compound is a compound of the following chemical formula (IIa-1).

[1310] [ka]

[1311] (IIa-1)

[0887]

[1312] In the above chemical formula (IIa-1),

[1313] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0888]

[1314] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0889]

[1315] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0890]

[1316] R 61and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0891]

[1317] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[0892]

[1318]

[1319] Example 4. In Example 2 or 3, R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0893]

[1320] R 61 and R 62 These compounds, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 membered heterocyclic group, wherein the heterocyclic group may be substituted with a C1-C6 alkyl group, and the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and halogens.

[0894]

[1321]

[1322] Example 5. In Example 1, the compound is a compound of the following chemical formula (III).

[0895]

[1323] [ka]

[1324] (III)

[0896]

[1325] In the above chemical formula (III),

[0897]

[1326] R 1 , R 2 , R 3 , R 4 and R 5 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, hydroxy, and -NR. x R y A group consisting of the following is independently selected, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0898]

[1327] X is methylene, ethylene, n-propylene, -NH-, -NR z1 - and -CR z2 R z3 -Selected from the group consisting of, where each of the methylene, ethylene, and n-propylene may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0899]

[1328] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0900]

[1329] W is selected from the group consisting of carbon and sulfur;

[0901]

[1330] n is either 1 or 2, where n is 1 if W is carbon, and n is 2 if W is sulfur;

[0902]

[1331] A is selected from the group consisting of 5-12 member monocyclic or bicyclic aryl or heteroaryl groups, where each of the aryl and heteroaryl groups is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y They may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0903]

[1332] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0904]

[1333] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0905]

[1334] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0906]

[1335] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0907]

[1336] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0908]

[1337] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0909]

[1338] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0910]

[1339] R66 is a 5-10 membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl, and amino;

[0911]

[1340] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0912]

[1341] R z1 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups;

[0913]

[1342] R z2 and R z3 These, together with the carbon atoms to which they are bonded, form a 3-6 membered cycloalkane ring, where the cycloalkane ring may be substituted with one or more selected from C1-C6 alkyl and halogen atoms; and

[0914]

[1343] R w These are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0915]

[1344]

[1345] Example 6. In Example 1 or 5, the compound is a compound of the following chemical formula (IIIa-1).

[0916]

[1346] [ka]

[1347] (IIIa-1)

[0917]

[1348] In the above chemical formula (IIIa-1),

[1349] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0918]

[1350] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0919]

[1351] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0920]

[1352] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0921]

[1353] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0922]

[1354] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0923]

[1355] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0924]

[1356] R 64 and R 65These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0925]

[1357] R 66 is a 5-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl and amino; and

[0926]

[1358] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[0927]

[1359]

[1360] Example 7. In Example 1 or 5, the compound is a compound of the following chemical formula (IIIb-1).

[1361] [ka]

[1362] (IIIb-1)

[0928]

[1363] In the above chemical formula (IIIb-1),

[1364] R a1 , R a2 , R a3 , R a4 and R a5Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0929]

[1365] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0930]

[1366] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0931]

[1367] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0932]

[1368] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0933]

[1369] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0934]

[1370] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0935]

[1371] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0936]

[1372] R 66 is a 5-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl and amino; and

[0937]

[1373] R x and Ry Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[0938]

[1374]

[1375] Example 8. In Example 1 or 5, the compound is a compound of the following chemical formula (IIIc-1).

[1376] [ka]

[1377] (IIIc-1)

[0939]

[1378] In the above chemical formula (IIIc-1),

[0940]

[1379] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0941]

[1380] R z1is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups;

[0942]

[1381] L 2 The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0943]

[1382] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0944]

[1383] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0945]

[1384] R 61 and R 62These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0946]

[1385] R 63 This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0947]

[1386] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0948]

[1387] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0949]

[1388] R 66 is a 5-10 membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl, and amino;

[0950]

[1389] R x and R yEach of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[0951]

[1390]

[1391] Example 9. In Example 1 or 5, the compound is a compound having the following chemical formula (IIId-1).

[1392] [ka]

[1393] (IIId-1)

[0952]

[1394] In the above chemical formula (IIId-1),

[1395] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl groups;

[0953]

[1396] m is an integer between 1 and 4;

[0954]

[1397] L 2The group consisting of -(C1-C6)alkylene- is selected, where the alkylene may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0955]

[1398] R 6 The group is selected from the group consisting of phenyl and 3-10 membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C1-C6 alkoxy, mercapto, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen and deuterium;

[0956]

[1399] R 61 and R 62 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0957]

[1400] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0958]

[1401] R 63This is selected from the group consisting of hydrogen, C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with one or more selected from C1-C6 alkyl and halogen;

[0959]

[1402] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0960]

[1403] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with one or more selected from C1-C6 alkyl and halogen groups, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and halogen groups;

[0961]

[1404] R 66 is a 5-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from C1-C6 alkyl, halogen, oxo, carbamoyl and amino; and

[0962]

[1405] R x and R y Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[0963]

[1406]

[1407] Example 10. In any one of Examples 3 and 6-9, R a1 , R a2 , R a3, R a4 and R a5 Each of these is a compound selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine.

[0964]

[1408]

[1409] Example 11. In any one of Example 1 and Examples 5-10, R 6 The compound is selected from the following group:

[0965]

[1410]

[1411] [ka] [ka]

[0966]

[1412] [ka]

[0967]

[1413] [ka]

[0968]

[1414]

[1415]

[1416] [ka] [ka]

[0969]

[1417] R 611 , R 612 , R 613 , R 614 , R 621 , R 631 , R 632 , R 633 , R 634 , R 641 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and R 6i Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, oxo, carbamoyl, C1-C6 alkoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 ,-NHC(O)R 63 -C(O)NR 64 R 65 , 5-6 member heterocyclyl and -CH2-R 66 A group independently selected from the group consisting of the following, where each of the alkyl, alkoxy, and heterocyclyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0970]

[1418] R 651 , R 652 , R 653 , R 654 and R 655 Each of these is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, and -C(O)NR 64 R 65 A group consisting of the following is independently selected, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0971]

[1419] R 61 and R 62Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with a C1-C6 alkyl, or

[0972]

[1420] R 61 and R 62 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and halogens;

[0973]

[1421] R 63 This is selected from the group consisting of C1-C6 alkyl, NH2, and C2-C6 alkenyl, where each of the alkyl and alkenyl may be substituted with a halogen;

[0974]

[1422] R 64 and R 65 Each of these is selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0975]

[1423] R 64 and R 65 These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 membered heterocyclic group, where the heterocyclic group may be substituted with a C1-C6 alkyl group; and

[0976]

[1424] R 66 This is a 6-10 member heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from oxo and carbamoyl groups.

[0977]

[1425]

[1426] Example 12. In any one of Example 1 and Examples 5-11, R 6A compound selected from the group consisting of the following.

[1427]

Chem.

Chem.

[0978]

[1428]

Chem.

[0979]

[1429] R 611 、R 612 、R 613 、R 614 。、R 621 、R 631 、R 632 、R 633 、R 634 、R 641 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R[[ID=6I]] 6f 、R 6g 、R 6h and R 6i each independently is hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O)2NH2, -NR 61 R 62 、-NHC(O)R 63 、-C(O)NR 64 R 65 、-CH2-R 66 、

[1430]

Chem.

[0980] <00W7905>

[1431] R 651 , R 652 , R 653 , R 654 and R 655 Each of them is independently selected from the group consisting of hydrogen and carbamoyl;

[0981]

[1432] R 61 and R 62 Each of these is selected from the group consisting of hydrogen, ethyl and isopropyl, or

[0982]

[1433] R 61 and R 62 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0983]

[1434] [ka]

[0984]

[1435] R 63 This is selected from the group consisting of methyl, NH2, ethenyl, and 1-fluoroethenyl;

[0985]

[1436] R 64 and R 65 Each of them is selected from the group consisting of hydrogen and methyl, or

[0986]

[1437] R 64 and R 65 These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows:

[0987]

[1438] [ka]

[0988]

[1439] R 66 This is a 6-10 membered heterocyclyl group, which is as follows:

[0989]

[1440] [ka]

[0990]

[1441]

[1442] Implemented Example 13. In any one of Implemented Examples 1 to 12, the compound is selected from the group consisting of the following:

[0991]

[1443] [Table 68]

[1444] [Table 69]

[1445] [Table 70]

[1446] [Table 71]

[1447] [Table 72]

[1448] [Table 73]

[1449] Table 74

[1450] Table 75

[1451] Table 76

[1452] Table 77

[1453] Table 78

[1454] Table 79

[1455] Table 80

[1456] Table 81

[0992]

[1457]

[1458]

[1459] Example 14. A pharmaceutical composition for treating or preventing a polymerase θ-mediated disease or disorder, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, or lung cancer, comprising a compound described in any one of Examples 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotope-labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier or excipient.

[0993]

[1460]

[1461] Example 15. In Example 14, the composition is an anticancer agent that targets an additional DNA damage response (DDR), preferably a PARP inhibitor (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), an ATR inhibitor (e.g., VE-821, VE-822, VX-970 (also known as M6620 or belzocertib), AZD6738 (e.g., ceraracertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nexasertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., plexasertib)), WEE1 inhibitors (e.g., adavocertib (e.g., MK-1775 or AZD1775)), PLK1 inhibitors (e.g., volasertib (BI)) A pharmaceutical composition administered separately, sequentially, or simultaneously with 6727), onvancertib (e.g., PCM-075, NMS-1286937), APE1 inhibitor (e.g., methoxyamine), or topoisomerase inhibitor (e.g., berotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[0994]

[1462]

[1463] Example 16. A compound described in any one of Examples 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotope-labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the prevention or treatment of a polymerase θ-mediated disease or disorder, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreatic cancer or lung cancer.

[0995]

[1464]

[1465] Example 17. In Example 16, the compound is an anticancer agent that targets additional DNA damage response (DDR), preferably a PARP inhibitor (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), an ATR inhibitor (e.g., VE-821, VE-822, VX-970 (also known as M6620 or belzocertib), AZD6738 (e.g., ceraracertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nexasertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., plexasertib)), WEE1 inhibitors (e.g., adavocertib (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., volasertib (BI)) Compounds administered separately, sequentially, or simultaneously with 6727), onvancertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or topoisomerase inhibitors (e.g., berotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[0996]

[1466]

[1467] 18. A method for treating or preventing a polymerase θ-mediated disease or disorder in a subject, comprising the step of administering to the subject at least one compound described in any one of 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotope-labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0997]

[1468]

[1469] Example 19. A method relating to Example 18 in which the disease or disorder mediated by polymerase θ is cancer, preferably breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, or lung cancer.

[0998]

[1470]

[1471] Example 20. In Example 18 or 19, the target body is further enhanced with an additional DDR-targeting anticancer agent, preferably a PARP inhibitor (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), an ATR inhibitor (e.g., VE-821, VE-822, VX-970 (also known as M6620 or belzocertib), AZD6738 (e.g., ceraracertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nexasertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., plexasertib)), WEE1 inhibitors (e.g., adavocertib (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., volasertib (BI)) A method further comprising the step of administering an onban sertive (e.g., PCM-075, NMS-1286937), an APE1 inhibitor (e.g., methoxyamine), or a topoisomerase inhibitor (e.g., berotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

Claims

1. Compounds of the following chemical formula (I), or their tautomers, stereoisomers, prodrugs, crystalline forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates, or solvates: 【Chemistry 1】 In the aforementioned chemical formula (I), R １ 、 R ２ 、 R ３ 、 R ４ and R ５ each of which is independently selected from the group consisting of hydrogen, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C １ -C ６ alkoxy, halogen, 3- to 10-membered cycloalkyl, cyano, hydroxy and -NR ｘ R ｙ wherein each of said alkyl, alkenyl, alkoxy and cycloalkyl may be independently substituted with one or more selected from C １ -C ６ alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; X is methylene, ethylene, n-propylene, -NH-, -NR ｚ１ - and -CR ｚ２ R ｚ３ - Selected from the group consisting of, where each of the methylene, ethylene and n-propylene is C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; Y and Z are -N- and -CR respectively ｗ - Independently selected from the group consisting of; W is selected from the group consisting of carbon and sulfur; n is either 1 or 2, where n is 1 if W is carbon, and n is 2 if W is sulfur; A is selected from the group consisting of 5- to 12-membered monocyclic or bicyclic aryl or heteroaryl compounds, where each of the aryl and heteroaryl compounds is independently C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, halogen, 3-10 membered cycloalkyl, -NR ｘ R ｙ It may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; L １ It does not exist, -(C １ -C ６ ) Alkylene- and -(C １ -C ６ ) Selected from the group consisting of alkylene-NH-; L ２ It does not exist, and -(C １ -C ６ ) Selected from the group consisting of alkylene, where the alkylene is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６ This is selected from the group consisting of phenyl and 3- to 10-membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C １ -C ６ Alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C １ -C ６ Alkoxy, mercapto, amino, -COOH, -S(O) ２ NH ２ , -NR ６１ R ６２ ,-NHC(O)R ６３ , -C(O)NR ６４ R ６５ , 5-6 member heterocyclyl and -CH ２ -R ６６ They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, and deuterium; R ６１ and R ６２ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６１ and R ６２ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６３ is hydrogen, C １ -C ６ Alkyl, NH ２ and C ２ -C ６ Selected from the group consisting of alkenyls, where each of the alkyl and alkenyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６４ and R ６５ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６４ and R ６５ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６６ is a 5- to 10-membered heterocyclyl group, wherein the heterocyclyl group may be substituted with one or more selected from C １ -C ６ alkyl, halogen, oxo, carbamoyl and amino; R ｘ and R ｙ each of which is independently selected from the group consisting of hydrogen and C １ -C ６ -alkyl, and wherein said alkyl may be substituted with one or more selected from the group consisting of C １ -C ６ -alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; R ｚ１ C １ -C ６ It is an alkyl group, where the alkyl group is C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｚ２ and R ｚ３ These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered cycloalkane ring, where the cycloalkane ring is C １ -C ６ It may be substituted with one or more selected from alkyl and halogens; and R ｗ is hydrogen, C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenil, C １ -C ６ Alkoxy, 3-10 membered cycloalkyl, -NR ｘ R ｙ Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

2. The compound according to claim 1, wherein the compound is a compound of the following chemical formula (II). 【Chemistry 2】 In the above chemical formula (II), R １ , R ２ , R ３ , R ４ and R ５ Each of them is hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C １ -C ６ Alkoxy, halogen, 3-10 membered cycloalkyl, cyano, hydroxy and -NR ｘ R ｙ A group consisting of is independently selected, where each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; A is selected from the group consisting of 5- to 12-membered monocyclic or bicyclic aryl or heteroaryl compounds, where each of the aryl and heteroaryl compounds is independently C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, halogen, 3-10 membered cycloalkyl, -NR ｘ R ｙ It may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; Y and Z are -N- and -CR respectively ｗ - Independently selected from the group consisting of; L ２ It does not exist, and -(C １ -C ６ ) Selected from the group consisting of alkylene, where the alkylene is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６１ and R ６２ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６１ and R ６２ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ Independently selected from the group consisting of alkyls, where the alkyl is C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; and R ｗ is hydrogen, C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenil, C １ -C ６ Alkoxy, 3-10 membered cycloalkyl, -NR ｘ R ｙ Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

3. The compound according to claim 1 or 2, wherein the compound is a compound of the following chemical formula (IIa-1). 【Transformation 3】 In the above chemical formula (IIa-1), R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ Each of them is hydrogen, C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, halogen, 3-10 membered cycloalkyl, -NR ｘ R ｙ A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; L ２ It does not exist, and -(C １ -C ６ ) Selected from the group consisting of alkylene, where the alkylene is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６１ and R ６２ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６１ and R ６２ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ Independently selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

4. R ６１ and R ６２ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６１ and R ６２ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with alkyl, where the alkyl is C １ -C ６ The compound according to claim 2 or 3, which may be substituted with one or more selected from alkyl and halogen elements.

5. The compound according to claim 1, wherein the compound is a compound of the following chemical formula (III). 【Chemistry 4】 In the aforementioned chemical formula (III), R １ , R ２ , R ３ , R ４ and R ５ Each of them is hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C １ -C ６ Alkoxy, halogen, 3-10 membered cycloalkyl, cyano, hydroxy and -NR ｘ R ｙ A group consisting of is independently selected, where each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; X is methylene, ethylene, n-propylene, -NH-, -NR ｚ１ - and -CR ｚ２ R ｚ３ - Selected from the group consisting of, where each of the methylene, ethylene and n-propylene is C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; Y and Z are -N- and -CR respectively ｗ - Independently selected from the group consisting of; W is selected from the group consisting of carbon and sulfur; n is either 1 or 2, where n is 1 if W is carbon, and n is 2 if W is sulfur; A is selected from the group consisting of 5- to 12-membered monocyclic or bicyclic aryl or heteroaryl compounds, where each of the aryl and heteroaryl compounds is independently C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, halogen, 3-10 membered cycloalkyl, -NR ｘ R ｙ It may be substituted with one or more selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; L ２ It does not exist, and -(C １ -C ６ ) Selected from the group consisting of alkylene, where the alkylene is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６ This is selected from the group consisting of phenyl and 3- to 10-membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C １ -C ６ Alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C １ -C ６ Alkoxy, mercapto, amino, -COOH, -S(O) ２ NH ２ , -NR ６１ R ６２ ,-NHC(O)R ６３ , -C(O)NR ６４ R ６５ , 5-6 member heterocyclyl and -CH ２ -R ６６ They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, and deuterium; R ６１ and R ６２ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６１ and R ６２ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６３ is hydrogen, C １ -C ６ Alkyl, NH ２ and C ２ -C ６ Selected from the group consisting of alkenyls, where each of the alkyl and alkenyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６４ and R ６５ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６４ and R ６５ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６６ is a 5-10 member heterocyclyl group, where the heterocyclyl group is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, oxo, carbamoyl, and amino; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ Independently selected from the group consisting of alkyls, where the alkyl is C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｚ１ C １ -C ６ It is an alkyl group, where the alkyl group is C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｚ２ and R ｚ３ These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered cycloalkane ring, where the cycloalkane ring is C １ -C ６ It may be substituted with one or more selected from alkyl and halogens; and R ｗ is hydrogen, C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenil, C １ -C ６ Alkoxy, 3-10 membered cycloalkyl, -NR ｘ R ｙ Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

6. The compound according to claim 1 or 5, wherein the compound is a compound of the following chemical formula (IIIa-1). 【Transformation 5】 In the above chemical formula (IIIa-1), R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ Each of them is hydrogen, C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, halogen, 3-10 membered cycloalkyl, -NR ｘ R ｙ A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; L ２ It does not exist, and -(C １ -C ６ ) Selected from the group consisting of alkylene, where the alkylene is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６ This is selected from the group consisting of phenyl and 3- to 10-membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C １ -C ６ Alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C １ -C ６ Alkoxy, mercapto, amino, -COOH, -S(O) ２ NH ２ , -NR ６１ R ６２ ,-NHC(O)R ６３ , -C(O)NR ６４ R ６５ , 5-6 member heterocyclyl and -CH ２ -R ６６ They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, and deuterium; R ６１ and R ６２ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６１ and R ６２ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６３ is hydrogen, C １ -C ６ Alkyl, NH ２ and C ２ -C ６ Selected from the group consisting of alkenyls, where each of the alkyl and alkenyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６４ and R ６５ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６４ and R ６５ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６６ is a 5-10 member heterocyclyl group, where the heterocyclyl group is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, oxo, carbamoyl and amino; and R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ Independently selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

7. The compound according to claim 1 or 5, wherein the compound is a compound of the following chemical formula (IIIb-1). 【Transformation 6】 In the above chemical formula (IIIb-1), R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ Each of them is hydrogen, C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, halogen, 3-10 membered cycloalkyl, -NR ｘ R ｙ A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; L ２ It does not exist, and -(C １ -C ６ ) Selected from the group consisting of alkylene, where the alkylene is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６ This is selected from the group consisting of phenyl and 3- to 10-membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C １ -C ６ Alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C １ -C ６ Alkoxy, mercapto, amino, -COOH, -S(O) ２ NH ２ , -NR ６１ R ６２ ,-NHC(O)R ６３ , -C(O)NR ６４ R ６５ , 5-6 member heterocyclyl and -CH ２ -R ６６ They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, and deuterium; R ６１ and R ６２ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６１ and R ６２ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６３ is hydrogen, C １ -C ６ Alkyl, NH ２ and C ２ -C ６ Selected from the group consisting of alkenyls, where each of the alkyl and alkenyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６４ and R ６５ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６４ and R ６５ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６６ is a 5-10 member heterocyclyl group, where the heterocyclyl group is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, oxo, carbamoyl and amino; and R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ Independently selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

8. The compound according to claim 1 or 5, wherein the compound is a compound of the following chemical formula (IIIc-1). 【Transformation 7】 In the above chemical formula (IIIc-1), R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ Each of them is hydrogen, C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, halogen, 3-10 membered cycloalkyl, -NR ｘ R ｙ A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｚ１ C １ -C ６ It is an alkyl group, where the alkyl group is C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; L ２ It does not exist, and -(C １ -C ６ ) Selected from the group consisting of alkylene, where the alkylene is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６ This is selected from the group consisting of phenyl and 3- to 10-membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C １ -C ６ Alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C １ -C ６ Alkoxy, mercapto, amino, -COOH, -S(O) ２ NH ２ , -NR ６１ R ６２ ,-NHC(O)R ６３ , -C(O)NR ６４ R ６５ , 5-6 member heterocyclyl and -CH ２ -R ６６ They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, and deuterium; R ６１ and R ６２ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６１ and R ６２ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６３ is hydrogen, C １ -C ６ Alkyl, NH ２ and C ２ -C ６ Selected from the group consisting of alkenyls, where each of the alkyl and alkenyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６４ and R ６５ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６４ and R ６５ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６６ is a 5-10 member heterocyclyl group, where the heterocyclyl group is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, oxo, carbamoyl, and amino; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ Independently selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

9. The compound according to claim 1 or 5, wherein the compound is a compound of the following chemical formula (IIId-1). 【Transformation 8】 In the above chemical formula (IIId-1), R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ Each of them is hydrogen, C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, halogen, 3-10 membered cycloalkyl, -NR ｘ R ｙ A group selected from amino, mercapto, and carbamoyl, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently C １ -C ６ They may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; m is an integer between 1 and 4; L ２ It does not exist, and -(C １ -C ６ ) Selected from the group consisting of alkylene, where the alkylene is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６ This is selected from the group consisting of phenyl and 3- to 10-membered heterocyclyl groups, where each of the phenyl and heterocyclyl groups is C １ -C ６ Alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy, C １ -C ６ Alkoxy, mercapto, amino, -COOH, -S(O) ２ NH ２ , -NR ６１ R ６２ ,-NHC(O)R ６３ , -C(O)NR ６４ R ６５ , 5-6 member heterocyclyl and -CH ２ -R ６６ They may be substituted with one or more selected from, where each of the alkyl, alkoxy and heterocyclyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, and deuterium; R ６１ and R ６２ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６１ and R ６２ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６３ is hydrogen, C １ -C ６ Alkyl, NH ２ and C ２ -C ６ Selected from the group consisting of alkenyls, where each of the alkyl and alkenyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６４ and R ６５ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with an alkyl group, or R ６４ and R ６５ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with one or more selected from alkyl and halogen, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６６ is a 5-10 member heterocyclyl group, where the heterocyclyl group is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, oxo, carbamoyl and amino; and R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ Independently selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

10. R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ The compound according to any one of claims 3 and 6 to 9, wherein each of is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine.

11. R ６ The compound according to any one of claims 1 and 5 to 10, wherein the compound is selected from the group consisting of the following. 【Chemistry 9】 【change】 【change】 【change】 【change】 【change】 R ６１１ , R ６１２ , R ６１３ , R ６１４ , R ６２１ , R ６３１ , R ６３２ , R ６３３ , R ６３４ , R ６４１ , R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ , R ６ｅ , R ６ｆ , R ６ｇ , R ６ｈ and R ６ｉ Each of them is hydrogen, C １ -C ６ Alkyl, halogen, cyano, oxo, carbamoyl, C １ -C ６ Alkoxy, amino, -COOH, -S(O) ２ NH ２ , -NR ６１ R ６２ ,-NHC(O)R ６３ , -C(O)NR ６４ R ６５ , 5-6 member heterocyclyl and -CH ２ -R ６６ Independently selected from the group consisting of, where each of the alkyl, alkoxy and heterocyclyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, and deuterium; R ６５１ , R ６５２ , R ６５３ , R ６５４ and R ６５５ Each of them is hydrogen, C １ -C ６ Alkyl, halogen, cyano, deuterium, oxo, carbamoyl, hydroxy and -C(O)NR ６４ R ６５ Independently selected from the group consisting of, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, and deuterium; R ６１ and R ６２ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyls, where the alkyl is C １ -C ６ It may be substituted with alkyl; or R ６１ and R ６２ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 6-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with alkyl, where the alkyl is C １ -C ６ It may be substituted with one or more elements selected from alkyl and halogens; R ６３ C １ -C ６ Alkyl, NH ２ and C ２ -C ６ A selection from the group consisting of alkenyls, where each of the alkyl and alkenyl may be substituted with a halogen; R ６４ and R ６５ Each of them is hydrogen and C １ -C ６ Selected from the group consisting of alkyl groups, or R ６４ and R ６５ These, together with the nitrogen atom to which they are bonded, form a nitrogen-containing 5-8 member heterocyclic group, where the heterocyclic group is C １ -C ６ It may be substituted with alkyl; and R ６６ This is a 6- to 10-membered heterocyclyl group, where the heterocyclyl group may be substituted with one or more selected from oxo and carbamoyl groups.

12. R ６ The compound according to any one of claims 1 and 5 to 11, which is selected from the group consisting of the following. 【Chemistry 10】 【change】 R ６１１ , R ６１２ , R ６１３ , R ６１４ , R ６２１ , R ６３１ , R ６３２ , R ６３３ , R ６３４ , R ６４１ , R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ , R ６ｅ , R ６ｆ , R ６ｇ , R ６ｈ and R ６ｉ Each of these is hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, fluoro, cyano, oxo, carbamoyl, methoxy, difluoromethoxy, isopropoxy, amino, -COOH, -S(O) ２ NH ２ , -NR ６１ R ６２ ,-NHC(O)R ６３ , -C(O)NR ６４ R ６５ ien-CH ２ -R ６６ , 【Chemistry 11】 Independently selected from the group consisting of; R ６５１ , R ６５２ , R ６５３ , R ６５４ and R ６５５ Each of them is independently selected from the group consisting of hydrogen and carbamoyl; R ６１ and R ６２ Each of these is selected from the group consisting of hydrogen, ethyl and isopropyl, or R ６１ and R ６２ These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows: 【Chemistry 12】 R ６３ is methyl, NH ２ Selected from the group consisting of ethenyl and 1-fluoroethenyl; R ６４ and R ６５ Each of them is selected from the group consisting of hydrogen and methyl, or R ６４ and R ６５ These, together with the nitrogen atom to which they bond, form a nitrogen-containing 6-8 membered heterocyclic group, which is as follows: 【Chemistry 13】 R ６６ This is a 6- to 10-membered heterocyclyl group, which is as follows: 【Chemistry 14】

13. The compound according to any one of claims 1 to 12, wherein the compound is selected from the group consisting of the following. Table 1

14. A pharmaceutical composition for preventing or treating a polymerase θ-mediated disease or disorder, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, or lung cancer, comprising a compound according to any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotope-labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier or excipient.

15. The composition is an anticancer agent that targets an additional DNA damage response (DDR), preferably a PARP inhibitor (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), an ATR inhibitor (e.g., VE-821, VE-822, VX-970 (also known as M6620 or belzocertib), AZD6738 (e.g., ceraracertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nexasertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., plexasertib)), WEE1 inhibitors (e.g., adavocertib (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., volasertib (BI The pharmaceutical composition according to claim 14, administered separately, sequentially, or simultaneously with 6727), onbancertib (e.g., PCM-075, NMS-1286937), APE1 inhibitor (e.g., methoxyamine), or topoisomerase inhibitor (e.g., berotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

16. A compound according to any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotope-labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the prevention or treatment of a polymerase θ-mediated disease or disorder, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreatic cancer or lung cancer.

17. The aforementioned compounds are anticancer agents that target additional DNA damage responses (DDR), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or belzocertib), AZD6738 (e.g., ceraracertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nexasertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., plexasertib)), WEE1 inhibitors (e.g., adavocertib (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., volasertib (BI The compound according to claim 16, administered separately, sequentially, or simultaneously with 6727), onbancertib (e.g., PCM-075, NMS-1286937), APE1 inhibitor (e.g., methoxyamine), or topoisomerase inhibitor (e.g., berotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

18. A method for preventing or treating a polymerase θ-mediated disease or disorder in a subject, comprising the step of administering to the subject at least one compound described in any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotope-labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

19. The method according to claim 18, wherein the disease or disorder mediated by polymerase θ is cancer, preferably breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, or lung cancer.

20. The target organism may be an anticancer agent that targets an additional DDR, preferably a PARP inhibitor (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), an ATR inhibitor (e.g., VE-821, VE-822, VX-970 (also known as M6620 or belzocertib), AZD6738 (e.g., ceraracertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (nexasertib or peposertib), AZD7648), CHK1 / 2 inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., plexasertib)), WEE1 inhibitors (e.g., adavocertib (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., volasertib (BI The method according to claim 18 or 19, further comprising the step of administering 6727), onbancertib (e.g., PCM-075, NMS-1286937), an APE1 inhibitor (e.g., methoxyamine), or a topoisomerase inhibitor (e.g., berotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

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