Substituted sultam compound derivatives and their pharmaceutical uses

Abstract

This specification provides novel sultam compound derivatives, compositions containing such compounds, methods for producing the sames, and uses thereof. The sultam compound derivatives are compounds of the following chemical formula I, or their tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates. The compounds and compositions of the present invention can be used to treat diseases or disorders mediated by polθ. TIFF2026513172000156.tif44149

Description

[Technical Field]

[0001]

[0001] The present invention relates to the field of pharmaceuticals, and more particularly to sultam derivatives having an inhibitory effect on polymerase theta, pharmaceutical compositions containing the same, and methods for producing and using the same. [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 includes poly-(ADP-ribose)polymerase PARP1, DNA ligase III, and polymerase theta. Polymerase theta (Polθ, encoded by POLQ) is a 290 kDa 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 project] [Problems that the invention aims to solve]

[0007]

[0007] This invention provides novel sultam (cyclic sulfonamide) derivatives, compositions containing the same, methods for producing the same, and uses thereof. The sultam 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 its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0009]

[0009] [ka]

[0010] In the aforementioned chemical formula I,

[0011] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[0012] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0013] X is methylene, -NH- and -NR zselected from the group consisting of, wherein the methylene may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0014] Each of Y and Z is independently selected from the group consisting of -N- and -CR w -;

[0015] A is a 5- to 12-member monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3- to 10-member 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;

[0016] R x and R y are each independently selected from hydrogen and C1-C6 alkyl, wherein said alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0017] R Z is C1-C6 alkyl, wherein said alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0018] R w is hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3- to 10-member cycloalkyl, -NR x Ry Selected from the group consisting of hydroxy, amino, mercapto, and carbamoyl.

[0010]

[0019]

[0020]

[0021] 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, isotopic variants, 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.

[0011]

[0022] In other aspects, the present invention provides uses for the compounds disclosed herein, or their tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutically acceptable compositions disclosed herein, in the manufacture of drugs for the treatment or prevention of polymerase θ-mediated diseases or disorders.

[0012]

[0023] 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, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutically acceptable compositions disclosed herein, to a subject.

[0013]

[0024] In other aspects, the present invention provides compounds disclosed herein, or tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, 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.

[0014]

[0025] 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.

[0015]

[0026]

[0027] definition

[0016]

[0028] chemical terms

[0017]

[0029] The definitions of specific functional groups and chemical terms are explained in more detail below.

[0018]

[0030] 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.

[0019]

[0031] The term "C" as used in this specification 1-6"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.

[0020]

[0032] The term "C" as used in this specification 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.

[0021]

[0033] The term "C" as used in this specification 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.

[0022]

[0034] The term "C" as used in this specification 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.

[0023]

[0035] 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.

[0024]

[0036] The term "C" as used in this specification 1-6"Haloalkyl" and "C1-6 haloalkoxy" are (unless otherwise specified) the "C" which is substituted with one or more halo groups. 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.

[0025]

[0037] The term "C" as used in this specification 3-1 "0-cycloalkyl" or "3-10 membered cycloalkyl" means a cyclic hydrocarbon group that is not aromatic (unless otherwise specified) and has 3 to 10 cyclic carbon atoms and zero heteroatoms. In some embodiments, a cycloalkyl can have 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7, or 5 to 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.

[0026]

[0038] 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.

[0027]

[0039] The term "C" as used in this specification 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, aryl may have 6 to 10 membered cyclic carbon atoms. Aryl groups may be monocyclic or polycyclic (e.g., bicyclic or tricyclic). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracyl. Aryl groups further include cyclic systems 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.

[0028]

[0040] 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.

[0029]

[0041] 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, respectively. 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.

[0030]

[0042] 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.”

[0031]

[0043] 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.

[0032]

[0044] 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%.

[0033]

[0045] The term "C" as used in this specification 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.

[0034]

[0046] 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.

[0035]

[0047] 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 both cases in which the events or situations occur and cases in which they do not. For example, “selectively substituted” means not only events or situations in which a chemical group (e.g., a group as defined herein) can be substituted, but also events or situations in which a chemical group is not substituted.

[0036]

[0048] 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 alkyls and halogens. (These include, but are not limited to, alkyl, alkenyl, alkoxy, alkylene, cycloalkyl, heterocyclic, or heteroaryl, each of which may be independently substituted with one or more selected from C1-C6 alkyls and halogens.) 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.

[0037]

[0049]

[0050] Common terminology

[0038]

[0051] 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.

[0039]

[0052] 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.

[0040]

[0053] 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]

[0041]

[0054] compound

[0042]

[0055] 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, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates thereof are provided.

[0043]

[0056] 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, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0044]

[0057] In one embodiment, the present invention relates to a compound of the following chemical formula I, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0045]

[0058] [ka]

[0046]

[0059] In the aforementioned chemical formula I,

[0060] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[0061] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0062] X is methylene, -NH- and -NR z -Selected from the group consisting of, where the methylene may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0063] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0064] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently a 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;

[0065] R x and R y Each of these is independently selected from 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;

[0066] R Z 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, hydroxy, amino, mercapto, and carbamoyl groups; and

[0067] R w The elements 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.

[0047]

[0068]

[0069]

[0070] Ring A

[0048]

[0071] In one embodiment, A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl; preferably, A is a 6-10 member monocyclic or bicyclic aryl or heteroaryl; more preferably, A is selected from the group consisting of 6-member monocyclic aryl or heteroaryl and 10-member bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently a C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y (Here, R x and R y Each of these is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), or 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;R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0049]

[0072] In one embodiment, A is selected from the group consisting of phenyl, pyridinyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl and naphthyl, wherein each of the phenyl, pyridinyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl and naphthyl is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, and -NR x R y (where R x and R y are each independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), and may be substituted with one or more selected therefrom, 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; R 1 ~R 4 , X, Y and Z are as defined above.

[0050]

[0073] In one embodiment, A is selected from the group consisting of phenyl, pyridinyl, quinolinyl and naphthyl, wherein each of the phenyl, pyridinyl, quinolinyl and naphthyl is independently C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, and -NR x R y (where R x and R yEach of these may be independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, 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;R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0051]

[0074] In one embodiment, A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl; preferably, A is a 6-10 member monocyclic or bicyclic aryl or heteroaryl, and more preferably, A is selected from the group consisting of 6-member monocyclic aryl or heteroaryl and 10-member bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl may be independently substituted with an unsubstituted C1-C6 alkyl, a halogen-substituted C1-C6 alkyl, a halogen, a cyano, or a deuterium; preferably, the aryl and heteroaryl Each of the aryls may be independently substituted with an unsubstituted C1-C6 alkyl, a halogen-substituted C1-C6 alkyl, or a halogen; more preferably, each of the aryls and heteroaryls may be independently substituted with methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, or iodine; more preferably, each of the aryls and heteroaryls may be independently substituted with methyl, trifluoromethyl, fluoro, chloro, or bromo; R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0052]

[0075] In one embodiment, A is selected from the group consisting of phenyl, pyridinyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H - quinolidinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl and naphthyl, wherein each of the phenyl, pyridinyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H - quinolidinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl and naphthyl may be independently unsubstituted C1 - C6 alkyl, C1 - C6 alkyl substituted with halogen, halogen, cyano, or substituted with deuterium; preferably, each of the aryl and heteroaryl may be independently unsubstituted C1 - C6 alkyl, C1 - C6 alkyl substituted with halogen or substituted with halogen; more preferably, each of the aryl and heteroaryl may be independently substituted with methyl, ethyl, n - propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo or iodo; even more preferably, each of the aryl and heteroaryl may be independently substituted with methyl, trifluoromethyl, fluoro, chloro or bromo; R 1 ~R 4 , X, Y and Z are as defined above.

[0053]

[0076] In one embodiment, A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of the phenyl, pyridinyl, quinolinyl, and naphthyl may be independently substituted with an unsubstituted C1-C6 alkyl, a halogen-substituted C1-C6 alkyl, a halogen, cyano, or deuterium; preferably, each of the aryl and heteroaryl may be independently substituted with an unsubstituted C1-C6 alkyl, a halogen-substituted C1-C6 alkyl, or a halogen; more preferably, each of the aryl and heteroaryl may be independently substituted with methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, or iodine; even more preferably, each of the aryl and heteroaryl may be independently substituted with methyl, trifluoromethyl, fluoro, chloro, or bromo; R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0054]

[0077]

[0078] In one specific example, A is selected from the following group:

[0055]

[0079] [ka]

[0056]

[0080] In the above chemical formula,

[0081] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and Ry Each of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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;

[0082] R b1 , R b2 , R b3 , and R b4 Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and R y Each of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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;

[0083] R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and R yEach of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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;

[0084] R d1 , R d2 , R d3 , R d4 , R d5 and R d6 Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and R y Each of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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

[0085] R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0057]

[0086]

[0087] In one concrete example, R a1 , R a2 , R a3 , R a4 and R a5Each of these is independently selected from the group consisting of hydrogen, unsubstituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen, cyano, and deuterium; preferably, R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently selected from the group consisting of hydrogen, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, and halogen; more preferably, R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine; more preferably, R a1 , R a2 , R a3 , R a4 and R a5 Each of them is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluoro, chloro, and bromo; R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0058]

[0088]

[0089] In one concrete example, R b1 , R b2 , R b3 and R b4 Each of these is independently selected from the group consisting of hydrogen, unsubstituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen, cyano, and deuterium; preferably, R b1 , R b2 , R b3 and R b4 Each of these is independently selected from the group consisting of hydrogen, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, and halogen; more preferably, R b1 , R b2 , R b3 and R b4Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine; more preferably, R b1 , R b2 , R b3 and R b4 Each of them is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluoro, chloro, and bromo; R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0059]

[0090] In one concrete example, R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of these is independently selected from the group consisting of hydrogen, unsubstituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen, cyano, and deuterium; preferably, R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of these is independently selected from the group consisting of hydrogen, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, and halogen; more preferably, R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine; more preferably, R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7Each of them is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluoro, chloro, and bromo; R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0060]

[0091] In one concrete example, R d1 , R d2 , R d3 , R d4 , R d5 and R d6 Each of these is independently selected from the group consisting of hydrogen, unsubstituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen, cyano, and deuterium; preferably, R d1 , R d2 , R d3 , R d4 , R d5 and R d6 Each of these is independently selected from the group consisting of hydrogen, unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, and halogen; more preferably, R d1 , R d2 , R d3 , R d4 , R d5 and R d6 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodine; more preferably, R d1 , R d2 , R d3 , R d4 , R d5 and R d6 Each of them is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluoro, chloro, and bromo; R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0061]

[0092]

[0093] In one specific example, A is, [ka] And,

[0094] Here,

[0095] R a1 This is selected from the group consisting of hydrogen, fluoride, and methyl;

[0096] R a2 This is selected from the group consisting of hydrogen, fluoride, chloride, bromide, methyl, and trifluoromethyl;

[0097] R a3 This is selected from the group consisting of hydrogen, fluoride, and methyl;

[0098] R a4 This is selected from the group consisting of hydrogen, fluoride, and methyl;

[0099] R a5 is selected from the group consisting of hydrogen, fluorides, and chlorides; and

[0100] R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0062]

[0101]

[0102] In one specific example, A is, [ka] And,

[0103] Here,

[0104] R b1 is hydrogen;

[0105] R b2 is hydrogen;

[0106] R b3is a halogen or a fluoride, preferably a fluoride;

[0107] R b4 is hydrogen; and

[0108] R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0063]

[0109]

[0110] In one specific example, A is, [ka] And,

[0111] Here, R c1 -R c7 is hydrogen; R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0064]

[0112]

[0113] In one specific example, A is, [ka] And,

[0114] Here, R d1 -R d6 is hydrogen; R 1 ~R 4 X, Y, and Z are synonymous with the definitions above.

[0065]

[0115]

[0116] X

[0066]

[0117] In one example, X is methylene, -NH- and -NR z- Selected from the group consisting of, where the methylene may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl, R z 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; R 1 ~R 4 Rings A, Y, and Z are defined as above.

[0067]

[0118] In one example, X is methylene, -NH- and -NR z - is selected from the group consisting of R z 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; R 1 ~R 4 Rings A, Y, and Z are defined as above.

[0068]

[0119] In one example, X is methylene, -NH- and -NR z - is selected from the group consisting of R z R 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; 1 ~R 4 Rings A, Y, and Z are defined as above.

[0069]

[0120] In one example, X is methylene, -NH- and -NR z - is selected from the group consisting of R z is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium; R 1 ~R 4Rings A, Y, and Z are defined as above.

[0070]

[0121] In one example, X is methylene, -NH- and -NR z - is selected from the group consisting of R z R is selected from the group consisting of methyl, ethyl, n-propyl, and butyl, which may be substituted with one or more selected from C1-C6 alkyl and deuterium; 1 ~R 4 Rings A, Y, and Z are defined as above.

[0071]

[0122] In one example, X is methylene, -NH- and -NR z - is selected from the group consisting of R z X is selected from the group consisting of methyl and ethyl, and may be substituted with one or more selected from C1-C6 alkyl and deuterium. In one embodiment, X is methylene, -NH- and -NR z - is selected from the group consisting of R z R is selected from the group consisting of methyl and ethyl, and may be substituted with one or more selected from methyl, ethyl, and deuterium; 1 ~R 4 Rings A, Y, and Z are synonymous with the above definitions. In one embodiment, X is methylene, -NH-, and -NR z - is selected from the group consisting of R z R is selected from the group consisting of methyl and ethyl, and may be substituted with one or more selected from methyl and deuterium; 1 ~R 4 Rings A, Y, and Z are synonymous with the above definitions. In one embodiment, X is methylene, -NH-, and -NR z - is selected from the group consisting of R z R is selected from the group consisting of methyl, isopropyl, and triduteriomethyl; 1 ~R 4 Rings A, Y, and Z are defined as above.

[0072]

[0123]

[0124] Y

[0073]

[0125] In one specific example, Y is -N- and -CR w -Selected from the group consisting of -. In one example, Y is -CR w -and here, R w The elements are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y (R x and R y Each of these is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl), selected from the group consisting of hydroxy, amino, mercapto and carbamoyl; R 1 ~R 4 Rings A, X, and Z are synonymous with the definitions above.

[0074]

[0126] In one specific example, Y is -CR w -and here, R w R is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium; and R 1 ~R 4 Rings A, X, and Z are synonymous with the above definitions. In one specific example, Y is -CR w -and here, R w is selected from the group consisting of hydrogen and cyano; and R 1 ~R 4 Rings A, X, and Z are synonymous with the definitions above.

[0075]

[0127]

[0128] Z

[0076]

[0129] In one specific example, Z is -N- and -CR w - is selected from the group consisting of R w The elements are hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y (R x and R y Each of these is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl), selected from the group consisting of hydroxy, amino, mercapto and carbamoyl; R 1 ~R 4 Rings A, X, and Y are synonymous with the definitions above.

[0077]

[0130] In one specific example, Z is -N- and -CR w - is selected from the group consisting of R w R is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium; and R 1 ~R 4 Rings A, X, and Y are synonymous with the above definitions. In one embodiment, Z is selected from the group consisting of -N- and -CH-, and R 1 ~R 4 Rings A, X, and Y are synonymous with the definitions above.

[0078]

[0131]

[0132] R 1

[0079]

[0133] In one concrete 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 (R x and Ry Each of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl) and R 2 ~R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0080]

[0134] In one concrete example, R 1 R is selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be substituted with C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; and R 2 ~R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0081]

[0135] In one concrete example, 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 and deuterium; and R 2 ~R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0082]

[0136] In one concrete example, 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 R 2 ~R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0083]

[0137] In one concrete example, R 1is selected from the group consisting of methyl, ethyl, n-propyl and isopropyl, which is selectively substituted with a halogen; and R 2 ~R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0084]

[0138] In one concrete example, R 1 is selected from the group consisting of methyl and trifluoromethyl; and R 2 ~R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0085]

[0138]

[0140] R 2

[0086]

[0141] 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 (R x and R y Each of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl) and R 1 , R 3 , R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0087]

[0142] In one concrete example, R 2R 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; and R 1 , R 3 , R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0088]

[0143] In one concrete example, 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 and deuterium; and R 1 , R 3 , R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0089]

[0144] In one concrete example, 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 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0090]

[0145] In one concrete example, R 2 is a C1-C6 alkyl group, where the alkyl group may be independently substituted with a halogen; and R 1 , R 3 , R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0091]

[0146] In one concrete example, R 2 is selected from the group consisting of methyl, ethyl, and n-propyl, which may be independently substituted with halogens; and R 1 , R 3 , R 4Rings A, X, Y, and Z are synonymous with the definitions above.

[0092]

[0147] In one concrete example, R 2 is selected from the group consisting of methyl and trifluoromethyl; and R 1 , R 3 , R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0093]

[0148] In one concrete example, R 2 is trifluoromethyl; and R 1 , R 3 , R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0094]

[0148]

[0150] R 3

[0095]

[0151] In one concrete example, R 3 These include hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, cyano, and -NR. x R y (R x and R y Each of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl) and R 1 , R 2 , R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0096]

[0152] In one concrete example, R 3 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; and R 1 , R 2 , R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0097]

[0153] In one concrete example, R 3 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 and deuterium; and R 1 , R 2 , R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0098]

[0154] In one concrete example, R 3 is selected from the group consisting of hydrogen and C1-C6 alkyl; and R 1 , R 2 , R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0099]

[0155] In one concrete example, R 3 is hydrogen; and R 1 , R 2 , R 4 Rings A, X, Y, and Z are synonymous with the definitions above.

[0100]

[0156]

[0157] R 4

[0101]

[0158] In one concrete example, R 4is hydrogen or C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, and mercapto; and R 1 , R 2 , R 3 Rings A, X, Y, and Z are synonymous with the definitions above.

[0102]

[0159] In one concrete example, R 4 is hydrogen or C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano and deuterium; and R 1 , R 2 , R 3 Rings A, X, Y, and Z are synonymous with the definitions above.

[0103]

[0160] In one concrete example, R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and deuterium; and R 1 , R 2 , R 3 Rings A, X, Y, and Z are synonymous with the definitions above.

[0104]

[0161] In one concrete example, R 4 is hydrogen or a C1-C4 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and deuterium; and R 1 , R 2 , R 3 Rings A, X, Y, and Z are synonymous with the definitions above.

[0105]

[0162] In one concrete example, R 4 R is selected from the group consisting of hydrogen, methyl, ethyl, and isopropyl, where each of methyl and ethyl may be substituted with one or more selected from C1-C6 alkyl and deuterium; and R 1 , R2 , R 3 Rings A, X, Y, and Z are synonymous with the definitions above.

[0106]

[0163] In one concrete example, R 4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and triduteriomethyl; and R 1 , R 2 , R 3 Rings A, X, Y, and Z are synonymous with the definitions above.

[0107]

[0164] In one concrete example, R 4 is selected from the group consisting of hydrogen, methyl, isopropyl and triduteriomethyl; and R 1 , R 2 , R 3 Rings A, X, Y, and Z are synonymous with the definitions above.

[0108]

[0165]

[0166]

[0167] In one embodiment, the present invention relates to compounds of the following chemical formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their tautomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0109]

[0168] [ka]

[0110]

[0169]

[0170] [ka]

[0111]

[0171]

[0172]

[0173]

[0174] [ka]

[0112]

[0175]

[0176]

[0177] [ka]

[0178]

[0113]

[0179]

[0180] [ka]

[0114]

[0181]

[0182]

[0183] [ka]

[0115]

[0184]

[0185]

[0186] [ka]

[0116]

[0187]

[0188]

[0189] [ka]

[0117]

[0190] In the above chemical formula,

[0191] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[0118]

[0192] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0193] X is methylene, -NH- and -NR z -Selected from the group consisting of, where the methylene may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0194] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0195] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently a C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R yThey are selectively 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;

[0196] R x and R y Each of these is independently selected from 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;

[0197] R Z 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, hydroxy, amino, mercapto, and carbamoyl groups; and

[0198] R w The elements 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.

[0119]

[0199]

[0200]

[0201]

[0120] Non-restrictive illustrative examples

[0202]

[0203] In one embodiment, the present invention relates to a compound of the following chemical formula II, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0121]

[0204] [ka]

[0122]

[0205] In the aforementioned chemical formula II,

[0206] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[0207] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0208] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0209] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently a C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R yThey are selectively 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;

[0210] R x and R y Each of these is independently selected from 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

[0211] R w The elements 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.

[0123]

[0213]

[0214] In one embodiment of a compound of chemical formula II, R 1 , R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0215] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0216] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0217] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0218] R x and R y Each of these is independently selected from 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

[0219] R w The elements 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.

[0124]

[0220]

[0221] In one embodiment of a compound of chemical formula II, R 1 , R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium;

[0222] R 4 is hydrogen or 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;

[0223] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0224] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where each of the alkyl may independently be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium;

[0225] R w It is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium.

[0125]

[0226]

[0227] In one embodiment of a compound of chemical formula II, R 1 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;

[0228] R 2 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;

[0229] R 3 is hydrogen;

[0230] R 4 is hydrogen or 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, or deuterium;

[0231] Y is -CR w -and here, R w This is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0232] 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; and

[0233] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium.

[0126]

[0234]

[0235] In one embodiment of a compound of chemical formula II, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0236] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0237] R 3 is hydrogen;

[0238] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and deuterium;

[0239] Y is selected from the group consisting of -CH- and -C(CN)-;

[0240] Z is selected from the group consisting of -N- and -CH-;

[0241] 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 the aforementioned phenyl, pyridinyl, pyrrolyl, pyrazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, 1, Each of 2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolidinyl, quinoxalinyl, phthalazinyl, quinazolinyl, synnolinyl, and naphthyl is independently and selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium.

[0127]

[0242]

[0243] In one embodiment of a compound of chemical formula II, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0244] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0245] R 3 is hydrogen;

[0246] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and deuterium;

[0247] Y is -CH- or -C(CN)-;

[0248] Z is selected from the group consisting of -N- and -CH-;

[0249] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of the phenyl, pyridinyl, quinolinyl, and naphthyl is independently and selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium.

[0128]

[0250]

[0251] In one embodiment of a compound of chemical formula II, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0252] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0253] R 3 is hydrogen;

[0254] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and deuterium;

[0255] Y is -CH- or -C(CN)-;

[0256] Z is selected from the group consisting of -N- and -CH-;

[0257] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of the phenyl, pyridinyl, quinolinyl, and naphthyl is independently and selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium.

[0129]

[0258]

[0259] In one embodiment of a compound of chemical formula II, R 1 is a methyl molecule selectively substituted with a halogen;

[0260] R 2 is a methyl molecule selectively substituted with a halogen;

[0261] R 3 is hydrogen;

[0262] R 4 is hydrogen, methyl, or ethyl, and each of the methyl and ethyl may be substituted with one or more selected from methyl and deuterium;

[0263] Y is -CH- or -C(CN)-;

[0264] Z is selected from the group consisting of -N- and -CH-; and

[0265] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of phenyl, pyridinyl, quinolinyl, and naphthyl may be independently substituted with one or more selected from fluoride, chloride, bromide, methyl, and trifluoromethyl.

[0130]

[0266]

[0267] In one embodiment of a compound of chemical formula II, R 1 This is methyl or trifluoromethyl;

[0268] R 2 It is trifluoromethyl;

[0269] R 3 is hydrogen;

[0270] R 4 This is selected from the group consisting of hydrogen, methyl, triduteriomethyl, and isopropyl;

[0271] Y is -CH-;

[0272] Z is selected from the group consisting of -N- and -CH-;

[0273] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of phenyl, pyridinyl, quinolinyl, and naphthyl may be independently substituted with one or more selected from fluoride, chloride, bromide, methyl, and trifluoromethyl.

[0131]

[0274]

[0275] In one embodiment, the present invention relates to a compound of the following chemical formula IIa, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0132]

[0276] [ka]

[0133]

[0277] In the aforementioned chemical formula IIa,

[0278] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[0279] R 4is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0280] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0281] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and R y Each of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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;

[0282] R x and R y Each of these is independently selected from 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

[0283] R w The elements 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.

[0134]

[0284]

[0285]

[0286] In one embodiment of a compound of chemical formula IIa, R 1 , R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0287] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0288] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0289] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, and hydroxyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl;

[0290] R x and R y Each of these is independently selected from 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

[0291] R w The elements 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.

[0135]

[0292]

[0293] In one embodiment of a compound of chemical formula IIa, R 1 , R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium;

[0294] R 4 is hydrogen or 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;

[0295] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0296] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, and hydroxyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium; and

[0297] R w It is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium.

[0136]

[0298]

[0299] In one embodiment of a compound of chemical formula IIa, R 1 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;

[0300] R 2 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;

[0301] R 3 is hydrogen;

[0302] R 4 is hydrogen or 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;

[0303] Y is -CR w -and here, R w This is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0304] 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; and

[0305]

[0137] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium.

[0138]

[0306]

[0307] In one embodiment of a compound of chemical formula IIa, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0308] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0309] R 3 is hydrogen;

[0310] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and deuterium;

[0311] Y is selected from the group consisting of -CH- and -C(CN)-;

[0312] Z is selected from the group consisting of -N- and -CH-;

[0313] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodine, and trifluoromethyl.

[0139]

[0314]

[0315] In one embodiment of a compound of chemical formula IIa, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0316] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0317] R 3 is hydrogen;

[0318] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and deuterium;

[0319] Y is -CH- or -C(CN)-;

[0320] Z is selected from the group consisting of -N- and -CH-; and

[0321] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodine, and trifluoromethyl.

[0140]

[0322]

[0323] In one embodiment of a compound of chemical formula IIa, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0324] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0325] R 3 is hydrogen;

[0326] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and deuterium;

[0327] Y is -CH- or -C(CN)-;

[0328] Z is selected from the group consisting of -N- and -CH-; and

[0329] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodine, and trifluoromethyl.

[0141]

[0330]

[0331] In one embodiment of a compound of chemical formula IIa, R 1 is a methyl molecule selectively substituted with a halogen;

[0332] R 2 is a methyl molecule selectively substituted with a halogen;

[0333] R 3 is hydrogen;

[0334] R 4 is hydrogen, methyl, or ethyl, and each of the methyl and ethyl may be substituted with one or more selected from methyl and deuterium;

[0335] Y is -CH- or -C(CN)-;

[0336] Z is selected from the group consisting of -N- and -CH-;

[0337] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, and trifluoromethyl.

[0142]

[0338]

[0339] In one embodiment of a compound of chemical formula IIa, R 1 This is methyl or trifluoromethyl;

[0340] R2 It is trifluoromethyl;

[0341] R 3 is hydrogen;

[0342] R 4 These are hydrogen, methyl, triduteriomethyl, or isopropyl;

[0343] Y is -CH-;

[0344] Z is selected from the group consisting of -N- and -CH-; and

[0345] R a1 This is selected from the group consisting of hydrogen, fluoride, and methyl;

[0346] R a2 This is selected from the group consisting of hydrogen, fluoride, chloride, bromide, methyl, and trifluoromethyl;

[0347] R a3 This is selected from the group consisting of hydrogen, fluoride, and methyl;

[0348] R a4 is selected from the group consisting of hydrogen, fluoride, and methyl; and

[0349] R a5 It is selected from the group consisting of hydrogen, fluorides, and chlorides.

[0143]

[0350]

[0351] In one embodiment, the present invention relates to a compound of the following chemical formula IIb, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0144]

[0352] [ka]

[0145]

[0353] In the aforementioned chemical formula IIb,

[0354] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[0355] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0356] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0357] R b1 , R b2 , R b3 , and R b4 Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and R yEach of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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;

[0358] R x and R y Each of these is independently selected from 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

[0359] R w The elements 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.

[0146]

[0360]

[0361]

[0362] In one embodiment of a compound of chemical formula IIb, R 1 , R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0363] R 4is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

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

[0365] R b1 , R b2 , R b3 , and R b4 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, and hydroxyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl;

[0366] R x and R y Each of these is independently selected from 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

[0367] R w The elements 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.

[0147]

[0368]

[0369] In one embodiment of a compound of chemical formula IIb, R 1 , R 2 and R 3Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium;

[0370] R 4 is hydrogen or 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;

[0371] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0372] R b1 , R b2 , R b3 , and R b4 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, and hydroxyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium; and

[0373] R w It is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium.

[0148]

[0374]

[0375] In one embodiment of a compound of chemical formula IIb, R 1 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;

[0376] R 2 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;

[0377] R 3 is hydrogen;

[0378] R 4 is hydrogen or 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;

[0379] Y is -CR w -and here, R w This is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0380] 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; and

[0381] R b1 , R b2 , R b3 , and R b4 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium.

[0149]

[0382]

[0383] In one embodiment of a compound of chemical formula IIb, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0384] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0385] R 3 is hydrogen;

[0386] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and deuterium;

[0387] Y is selected from the group consisting of -CH- and -C(CN)-;

[0388] Z is selected from the group consisting of -N- and -CH-; and

[0389] R b1 , R b2 , R b3 , and R b4 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodine, and trifluoromethyl.

[0150]

[0390]

[0391] In one embodiment of a compound of chemical formula IIb, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0392] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0393] R 3 is hydrogen;

[0394] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and deuterium;

[0395] Y is -CH- or -C(CN)-;

[0396] Z is selected from the group consisting of -N- and -CH-; and

[0397] R b1 , R b2 , R b3 , and R b4Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodine, and trifluoromethyl.

[0151]

[0398]

[0399] In one embodiment of a compound of chemical formula IIb, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0400] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0401] R 3 is hydrogen;

[0402] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups and deuterium;

[0403] Y is -CH- or -C(CN)-;

[0404] Z is selected from the group consisting of -N- and -CH-; and

[0405] R b1 , R b2 , R b3 , and R b4 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodine, and trifluoromethyl.

[0152]

[0406]

[0407] In one embodiment of a compound of chemical formula IIb, R 1 is a methyl molecule selectively substituted with a halogen;

[0408] R 2is a methyl molecule selectively substituted with a halogen;

[0409] R 3 is hydrogen;

[0410] R 4 is hydrogen, methyl, or ethyl, and each of the methyl and ethyl may be substituted with one or more selected from methyl and deuterium;

[0411] Y is -CH- or -C(CN)-;

[0412] Z is selected from the group consisting of -N- and -CH-; and

[0413] R b1 , R b2 , R b3 , and R b4 Each of these is independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, and trifluoromethyl.

[0153]

[0414]

[0415] In one embodiment of a compound of chemical formula IIb, R 1 This is methyl or trifluoromethyl;

[0416] R 2 It is trifluoromethyl;

[0417] R 3 is hydrogen;

[0418] R 4 This is selected from the group consisting of hydrogen, methyl, triduteriomethyl, and isopropyl;

[0419] Y is -CH-;

[0420] Z is selected from the group consisting of -N- and -CH-;

[0421] R b1is hydrogen;

[0422] R b2 is hydrogen;

[0423] R b3 is a halogen or a fluoride, preferably a fluoride; and

[0424] R b4 It is hydrogen.

[0154]

[0425]

[0426] In one embodiment, the present invention relates to a compound of the following chemical formula IIc, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0155]

[0427] [ka]

[0156]

[0428] In the aforementioned chemical formula IIc,

[0429] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[0430] R 4is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0431] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0432] R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and R y Each of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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;

[0433] R x and R y Each of these is independently selected from 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

[0434] R w The elements 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.

[0157]

[0435]

[0436]

[0437] In one embodiment of a compound of chemical formula IIc, R 1 , R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0158]

[0438] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0439] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0440] R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, and hydroxyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl;

[0159]

[0441] R x and R yEach of these is independently selected from 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

[0442] R w The elements 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.

[0443]

[0444] In one embodiment of a compound of chemical formula IIc, R 1 , R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium;

[0445] R 4 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;

[0446] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0447] R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, and hydroxyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0448] R w It is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium.

[0160]

[0449]

[0450] In one embodiment of a compound of chemical formula IIc, R 1 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;

[0451] R 2 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;

[0452] R 3 is hydrogen;

[0453] R 4 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;

[0454] Y is -CR w -and here, R w This is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0455] 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; and

[0456] R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and halogen, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium.

[0161]

[0457]

[0458] In one embodiment of a compound of chemical formula IIc, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0459] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0460] R 3 is hydrogen;

[0461] R 4 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium;

[0462] Y is selected from the group consisting of -CH- and -C(CN)-;

[0463] Z is selected from the group consisting of -N- and -CH-; and

[0464] R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodine, and trifluoromethyl.

[0162]

[0465]

[0466] In one embodiment of a compound of chemical formula IIc, R 1is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0467] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0468] R 3 is hydrogen;

[0469] R 4 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium;

[0470] Y is -CH- or -C(CN)-;

[0471] Z is selected from the group consisting of -N- and -CH-; and

[0472] R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodine, and trifluoromethyl.

[0163]

[0473]

[0474] In one embodiment of a compound of chemical formula IIc, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0475] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0476] R 3 is hydrogen;

[0477] R4 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium;

[0478] Y is -CH- or -C(CN)-;

[0479] Z is selected from the group consisting of -N- and -CH-; and

[0480] R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodine, and trifluoromethyl.

[0164]

[0481]

[0482] In one embodiment of a compound of chemical formula IIc, R 1 is a methyl molecule selectively substituted with a halogen;

[0483] R 2 is a methyl molecule selectively substituted with a halogen;

[0484] R 3 is hydrogen;

[0485] R 4 is methyl or ethyl, which may be substituted with one or more selected from methyl and deuterium;

[0486] Y is -CH- or -C(CN)-;

[0487] Z is selected from the group consisting of -N- and -CH-; and

[0488] R c1 , R c2 , R c3 , Rc4 , R c5 , R c6 and R c7 Each of these is independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, and trifluoromethyl.

[0165]

[0489]

[0490] In one embodiment of a compound of chemical formula IIc, R 1 This is methyl or trifluoromethyl;

[0491] R 2 It is trifluoromethyl;

[0492] R 3 is hydrogen;

[0493] R 4 These are methyl, triduteriomethyl, or isopropyl;

[0494] Y is -CH-;

[0495] Z is selected from the group consisting of -N- and -CH-; and

[0496] R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of them is hydrogen.

[0166]

[0497]

[0498] In one embodiment, the present invention relates to a compound of the following chemical formula IId, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0167]

[0499] [ka]

[0168]

[0500] In the aforementioned chemical formula IId,

[0501] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[0502] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0503] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0504] R d1 , R d2 , R d3 , R d4 , R d5 and R d6 Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and R yEach of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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;

[0505] R x and R y Each of these is independently selected from 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

[0506] R w The elements 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.

[0169]

[0507]

[0508]

[0509] In one embodiment of a compound of chemical formula IId, R 1 , R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0510] R 4is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0511] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0512] R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, and hydroxyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl;

[0513] R x and R y Each of these is independently selected from 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

[0514] R w The elements 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.

[0170]

[0515]

[0516] In one embodiment of a compound of chemical formula IId, R 1 , R 2 and R 3Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium;

[0517] R 4 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;

[0518] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0519] R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, and hydroxyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium;

[0520] R w It is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium.

[0171]

[0521]

[0522] In one embodiment of a compound of chemical formula IId, R 1 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;

[0523] R 2 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;

[0524] R 3is hydrogen;

[0525] R 4 is C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium;

[0526] Y is -CR w -, where R w is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0527] Z is selected from the group consisting of -N- and -CR w -, where R w is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium; and

[0528] R d1 R d2 R d3 R d4 R d5 R d6 each of and is independently selected from the group consisting of hydrogen, C1-C6 alkyl and halogen, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, and deuterium.

[0172]

[0529]

[0530] In one embodiment of the compound of Chemical Formula IId, R 1 is C1-C6 alkyl, where the alkyl may be substituted with halogen;

[0531] R 2 is C1-C6 alkyl, where the alkyl may be substituted with halogen;

[0532] R 3 is hydrogen;

[0533] R 4is C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and deuterium;

[0534] Y is selected from the group consisting of -CH- and -C(CN)-;

[0535] Z is selected from the group consisting of -N- and -CH-; and

[0536] R d1 、R d2 、R d3 、R d4 、R d5 、and R d6 each of which is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0173]

[0537]

[0538] In one embodiment of the compound of Chemical Formula IId, R 1 is C1-C6 alkyl, where the alkyl may be substituted with halogen;

[0539] R 2 is C1-C6 alkyl, where the alkyl may be substituted with halogen;

[0540] R 3 is hydrogen;

[0541] R 4 is C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl and deuterium;

[0542] Y is -CH- or -C(CN)-;

[0543] Z is selected from the group consisting of -N- and -CH-; and

[0544] R d1 、Rd2 , R d3 , R d4 , R d5 , and R d6 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodine, and trifluoromethyl.

[0174]

[0545]

[0546] In one embodiment of a compound of chemical formula IId, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0547] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0548] R 3 is hydrogen;

[0549] R 4 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium;

[0550] Y is -CH- or -C(CN)-;

[0551] Z is selected from the group consisting of -N- and -CH-; and

[0552]

[0553] R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodine, and trifluoromethyl.

[0175]

[0554] In one embodiment of a compound of chemical formula IId, R1 is a methyl molecule selectively substituted with a halogen;

[0555] R 2 is a methyl molecule selectively substituted with a halogen;

[0556] R 3 is hydrogen;

[0557] R 4 is methyl or ethyl, which may be substituted with one or more selected from methyl and deuterium;

[0558] Y is -CH- or -C(CN)-;

[0559] Z is selected from the group consisting of -N- and -CH-; and

[0560] R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 Each of these is independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, and trifluoromethyl.

[0176]

[0561]

[0562] In one embodiment of a compound of chemical formula IId, R 1 This is methyl or trifluoromethyl;

[0563] R 2 It is trifluoromethyl;

[0564] R 3 is hydrogen;

[0565] R 4 These are methyl, triduteriomethyl, or isopropyl;

[0566] Y is -CH-;

[0567] Z is selected from the group consisting of -N- and -CH-; and

[0568] R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 Each of them is hydrogen.

[0569]

[0570]

[0177] In one embodiment, the present invention relates to a compound of the following chemical formula III, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0178]

[0571] [ka]

[0179]

[0572] In the aforementioned chemical formula III,

[0573] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[0574] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0575] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0576] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently a C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y They are selectively 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;

[0577] R x and R y Each of these is independently selected from 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

[0578] R w The elements 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.

[0180]

[0579]

[0580]

[0581] In one embodiment of a compound of chemical formula III, R 1 , R 2 and R 3Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0582] R 4 is hydrogen or C1-C6 alkyl, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0583] Each of Y and Z is independently selected from the group consisting of -N- and -CR w -;

[0584] A is a 5- to 12-membered monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0585] R x and R y Each of them is independently selected from 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

[0586] R w is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, -NR x R y , hydroxy, amino, mercapto, and carbamoyl.

[0181]

[0587]

[0588] In one embodiment of a compound of chemical formula III, R 1 , R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium;

[0589] R 4 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;

[0590] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0591] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl may independently be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium; and

[0592] R w It is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium.

[0182]

[0593]

[0594] In one embodiment of a compound of chemical formula III, R 1 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;

[0595] R 2is 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;

[0596] R 3 is hydrogen;

[0597] R 4 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;

[0598] Y is -CR w -and here, R w This is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0599] 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; and

[0600] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium.

[0183]

[0601]

[0602] In one embodiment of a compound of chemical formula III, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0603] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0604] R 3 is hydrogen;

[0605] R 4 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium;

[0606] Y is selected from the group consisting of -CH- and -C(CN)-;

[0607] Z is selected from the group consisting of -N- and -CH-; and

[0608] 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 the aforementioned phenyl, pyridinyl, pyrrolyl, pyrazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, 1, Each of 2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolidinyl, quinoxalinyl, phthalazinyl, quinazolinyl, synnolinyl, and naphthyl is independently and selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium.

[0184]

[0609]

[0610] In one embodiment of a compound of chemical formula III, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0611] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0612] R 3is hydrogen;

[0613] R 4 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium;

[0614] Y is selected from the group consisting of -CH- and -C(CN)-;

[0615] Z is selected from the group consisting of -N- and -CH-; and

[0616] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of the phenyl, pyridinyl, quinolinyl, and naphthyl is independently and selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium.

[0185]

[0617]

[0618] In one embodiment of a compound of chemical formula III, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0619] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0620] R 3 is hydrogen;

[0621] R 4 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium;

[0622] Y is selected from the group consisting of -CH- and -C(CN)-;

[0623] Z is selected from the group consisting of -N- and -CH-; and

[0624] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of the phenyl, pyridinyl, quinolinyl, and naphthyl is independently and selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium.

[0186]

[0625]

[0626] In one embodiment of a compound of chemical formula III, R 1 is a methyl molecule selectively substituted with a halogen;

[0627] R 2 is a methyl molecule selectively substituted with a halogen;

[0628] R 3 is hydrogen;

[0629] R 4 These are methyl, triduteriomethyl, or isopropyl;

[0630] Y is selected from the group consisting of -CH- and -C(CN)-;

[0631] Z is selected from the group consisting of -N- and -CH-; and

[0632] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of phenyl, pyridinyl, quinolinyl, and naphthyl may be independently substituted with one or more selected from fluoride, chloride, bromide, methyl, and trifluoromethyl.

[0187]

[0633]

[0634] In one embodiment of a compound of chemical formula III, R1 This is methyl or trifluoromethyl;

[0635] R 2 It is trifluoromethyl;

[0636] R 3 is hydrogen;

[0637] R 4 It is methyl;

[0638] Y is -CH-;

[0639] Z is selected from the group consisting of -N- and -CH-; and

[0640] A is phenyl, where phenyl may be substituted with one or more selected from fluoride, chloride, and methyl.

[0188]

[0641]

[0642] In one embodiment, the present invention relates to a compound of the following chemical formula IV, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0189]

[0643] [ka]

[0190]

[0644] In the aforementioned chemical formula IV,

[0645] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R yA 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;

[0646] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0647] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0648] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently a C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y They are selectively 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;

[0649] R x and R y Each of these is independently selected from 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;

[0650] R Zis 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, hydroxy, amino, mercapto, and carbamoyl groups; and

[0651] R w The elements 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.

[0191]

[0652]

[0653]

[0654] In one embodiment of a compound of chemical formula IV, R 1 , R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0655] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[0656] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0657] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0658] R x and R y Each of these is independently selected from 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;

[0659] R z 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; and

[0660] R w It is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium.

[0192]

[0661]

[0662] In one embodiment of a compound of chemical formula IV, R 1 , R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl, where the alkyl may be independently substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium;

[0663] R 4 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;

[0664] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[0665] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where each of the alkyl, alkenyl, alkoxy, and cycloalkyl may independently be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium;

[0666] R z is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium; and

[0667] R w It is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium.

[0193]

[0668]

[0669] In one embodiment of a compound of chemical formula IV, R 1 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;

[0670] R 2 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;

[0671] R 3 is hydrogen;

[0672] R 4 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;

[0673] Y is -CR w -and here, R w This is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0674] Z is -N- and -CR w - is selected from the group consisting of R w This is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0675] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium; and

[0676] R z This is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium.

[0194]

[0677]

[0678] In one embodiment of a compound of chemical formula IV, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0679] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0680] R 3 is hydrogen;

[0681] R 4 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium;

[0682] Y is selected from the group consisting of -CH- and -C(CN)-;

[0683] Z is selected from the group consisting of -N- and -CH-;

[0684] 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-quinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, sinnolinyl and naphthyl, where the aforementioned phenyl, pyridinyl, pyrrolyl, pyrazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, 1,2 Each of ,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolidinyl, quinoxalinyl, phthalazinyl, quinazolinyl, synnolinyl, and naphthyl is independently selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium; and

[0685] R z This is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium.

[0195]

[0686]

[0687] In one embodiment of a compound of chemical formula IV, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0688] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0689] R 3 is hydrogen;

[0690] R 4 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium;

[0691] Y is selected from the group consisting of -CH- and -C(CN)-;

[0692] Z is selected from the group consisting of -N- and -CH-;

[0693] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of the phenyl, pyridinyl, quinolinyl, and naphthyl is independently selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium; and

[0694] R z This is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium.

[0196]

[0695]

[0696] In one embodiment of a compound of chemical formula IV, R 1 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0697] R 2 is a C1-C6 alkyl group, where the alkyl group may be substituted with a halogen;

[0698] R 3 is hydrogen;

[0699] R 4 is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium;

[0700] Y is selected from the group consisting of -CH- and -C(CN)-;

[0701] Z is selected from the group consisting of -N- and -CH-;

[0702] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of the phenyl, pyridinyl, quinolinyl, and naphthyl is independently selectively substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium, where the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, and deuterium; and

[0703] R z This is a C1-C6 alkyl group, where the alkyl group may be substituted with one or more elements selected from C1-C6 alkyl groups and deuterium.

[0197]

[0704]

[0705] In one embodiment of a compound of chemical formula IV, R 1 is a methyl molecule selectively substituted with a halogen;

[0706] R 2 is a methyl molecule selectively substituted with a halogen;

[0707] R 3 is hydrogen;

[0708] R 4 is methyl or ethyl, which may be substituted with one or more selected from methyl and deuterium;

[0709] Y is selected from the group consisting of -CH- and -C(CN)-;

[0710] Z is selected from the group consisting of -N- and -CH-;

[0711] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of the phenyl, pyridinyl, quinolinyl, and naphthyl may be independently substituted with one or more selected from fluoride, chloride, bromide, methyl, and trifluoromethyl; and

[0712] R z is methyl or ethyl, which may be substituted with one or more selected from methyl and deuterium.

[0198]

[0713]

[0714] In one embodiment of a compound of chemical formula IV, R 1 is a methyl molecule selectively substituted with a halogen;

[0715] R 2 is a methyl molecule selectively substituted with a halogen;

[0716] R 3 is hydrogen;

[0717] R 4 These are methyl, triduteriomethyl, or isopropyl;

[0718] Y is selected from the group consisting of -CH- and -C(CN)-;

[0719] Z is selected from the group consisting of -N- and -CH-;

[0720] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, where each of the phenyl, pyridinyl, quinolinyl, and naphthyl may be independently substituted with one or more selected from fluoride, chloride, bromide, methyl, and trifluoromethyl; and

[0721] R z It is selected from the group consisting of methyl, triduteriomethyl, and isopropyl.

[0199]

[0722]

[0723] In one embodiment, an exemplary compound of chemical formula I is provided below.

[0200]

[0724] [Table 1] JPEG2026513172000025.jpg211149 JPEG2026513172000026.jpg211149 JPEG2026513172000027.jpg140149

[0201]

[0725] In another embodiment, an exemplary compound of chemical formula I is provided below.

[0202]

[0726] [Table 2] JPEG2026513172000029.jpg141149 JPEG2026513172000030.jpg85149 JPEG2026513172000031.jpg217149 JPEG2026513172000032.jpg124149

[0203]

[0727]

[0728]

[0729] 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.

[0204]

[0730] 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.

[0205]

[0731] 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.

[0206]

[0732] 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.

[0207]

[0733] 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.

[0208]

[0734] 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.

[0209]

[0735] 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)).

[0210]

[0736] 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.

[0211]

[0737] As used herein, the term “isotope variant” means a compound in which one or more atoms constituting such a compound contain a higher proportion of isotopes than naturally occurring. For example, an “isotope variant” of a compound may be radiolabeled, i.e., it may contain one or more radioisotopes, 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.

[0212]

[0738] 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.

[0213]

[0739] 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.

[0214]

[0740] 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.

[0215]

[0741] 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 This includes monosaltes or disaltes formed with acids selected from the group consisting of p-toluenesulfonic acid, undecylenic acid, valeric acid, and acylated amino acids.

[0216]

[0742] 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.

[0217]

[0743] 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.

[0218]

[0744] 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.

[0219]

[0745] 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.

[0220]

[0746] 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.

[0221]

[0747] 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.

[0222]

[0748]

[0749] Manufacturing method

[0223]

[0750] According to one aspect of the present invention, methods for producing compounds of chemical formula I, or their tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates are provided. The following scheme is an example of a synthetic scheme that may be used for the synthesis of compounds of chemical formula I. In the following scheme, reactive groups are protected with protecting groups and can be deprotected using techniques well established in the art. The compounds of chemical formula I described herein can be produced by those skilled in the field of organic synthesis using standard methods, which are described in detail below.

[0224]

[0751]

[0752] 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, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates, includes any one of the following methods A to D:

[0225]

[0753] Method A or B produces a compound of chemical formula II (i.e., a compound of chemical formula I, where X is a selectively substituted methylene group).

[0226]

[0754] -Method C produces a compound of chemical formula III (i.e., a compound of chemical formula I, where X is -NH-).

[0227]

[0755] -Method D or E is a compound of chemical formula IV (i.e., a compound of chemical formula I, where X is -NR) z - and R z This is synonymous with the above definition. ) to manufacture.

[0228]

[0756]

[0757] Method A

[0229]

[0758]

[0759] Method A is for producing a compound of chemical formula II as defined herein, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates, and Method A comprises the following steps:

[0230]

[0760] (i) Step to obtain the compound of chemical formula (A-1):

[0761]

[0762] [ka]

[0231]

[0763]

[0764] (ii) The step of reacting the compound of chemical formula (A-1) with the compound of chemical formula (E) to obtain the compound of chemical formula (A-2):

[0765]

[0766] [ka] and

[0232]

[0767]

[0768] [ka]

[0233]

[0769]

[0770] (iii) The step of reacting the compound of chemical formula (A-2) with the compound of chemical formula (F) to obtain the compound of chemical formula (II):

[0771] [ka]

[0234]

[0772] Here, R 1 ~R 4 Y and Z are synonymous with the above definitions,

[0773] X is a selectively substituted methylene, and

[0774] L 1 It is a halide.

[0235]

[0775]

[0776] In one specific example, L 1 The compound is selected from the group consisting of fluoride, chloride, bromide, and iodide, and is preferably bromide or chloride.

[0236]

[0777]

[0778] In one specific example, step (i) includes the following steps:

[0779] (i-1) Step to obtain the compound of chemical formula (aa-1):

[0780]

[0781]

[0782] [ka]

[0237]

[0783]

[0784] (i-2) The step of dissolving the compound of chemical formula (aa-1) in methanol to prepare a methanol solution, and then adding SOCl2 to the methanol solution to obtain the compound of chemical formula (aa-2):

[0785]

[0786] [ka]

[0238]

[0787]

[0788] (i-3) The step of introducing Cl2 gas into the compound of chemical formula (aa-2) to obtain the compound of chemical formula (aa-3): and

[0789]

[0790] [ka]

[0239]

[0791]

[0792] (i-4) A step in which the compound of chemical formula (aa-3) is reacted with triethylamine to obtain the compound of chemical formula (A-1).

[0240]

[0793]

[0794] In one specific example, step (iii) includes the following steps:

[0795] (iii-1) The step of reacting the compound of chemical formula (A-2) with lithium hydroxide to obtain the compound of chemical formula (aa-4): and

[0796]

[0797] [ka]

[0241]

[0798]

[0799] (iii-2) A step in which a compound of chemical formula (aa-4) and a compound of chemical formula (F) are reacted to obtain a compound of chemical formula (II).

[0242]

[0800]

[0801]

[0243] In one concrete example, the exemplary reaction scheme of Method A can be represented by Scheme I:

[0244]

[0802] Scheme 1

[0803] [ka]

[0245]

[0804]

[0805] Method B

[0246]

[0806] Method B is for producing a compound of chemical formula II as defined herein, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates, and Method B comprises the following steps:

[0247]

[0807] (i) Step to obtain the compound of chemical formula (B-1):

[0808]

[0809] [ka]

[0248]

[0810]

[0811] (ii) The step of reacting the compound of chemical formula (B-1) with the compound of chemical formula (F) to obtain the compound of chemical formula (B-2):

[0249]

[0812]

[0813] [ka] and

[0250]

[0814]

[0815] [ka]

[0251]

[0816]

[0817] (iii) The step of reacting the compound of chemical formula (B-2) with the compound of chemical formula (E) to obtain the compound of chemical formula (II):

[0252]

[0818]

[0819] [ka]

[0253]

[0820]

[0821] Here, R 1 ~R 4 Y and Z are synonymous with the above definitions,

[0822] X is a selectively substituted methylene, and

[0823] L 1 It is a halide.

[0254]

[0824]

[0825] In one specific example, L1 The compound is selected from the group consisting of fluoride, chloride, bromide, and iodide, and is preferably bromide or chloride.

[0255]

[0826]

[0827] In one specific example, step (i) includes the following steps:

[0828] (i-1) Step to obtain the compound of chemical formula (bb-1):

[0828]

[0830]

[0831] [ka]

[0256]

[0832]

[0833] (i-2) The compound of chemical formula (bb-1) is dissolved in methanol to prepare a methanol solution, and SOCl2 is added to the methanol solution to obtain the compound of chemical formula (bb-2):

[0834]

[0835] [ka]

[0257]

[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):

[0258]

[0838]

[0839] [ka] and

[0259]

[0840]

[0841] (i-4) A step in which the compound of chemical formula (bb-3) is reacted with triethylamine to obtain the compound of chemical formula (B-1).

[0260]

[0842]

[0843] In one concrete example, the exemplary reaction scheme of Method B can be represented by Scheme II:

[0261]

[0844]

[0845] Scheme II

[0262]

[0846] [ka]

[0263]

[0847]

[0848] Method C

[0264]

[0849] Method C is for producing a compound of chemical formula III as defined herein, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates, and Method C comprises the following steps:

[0265]

[0850] (i) Step to obtain the compound of chemical formula (C-1):

[0851]

[0852] [ka]

[0266]

[0853]

[0854] (ii) The step of reacting the compound of chemical formula (C-1) with the compound of chemical formula (F) to obtain the compound of chemical formula (C-2):

[0855]

[0856] [ka] and

[0857]

[0858] [ka]

[0267]

[0859]

[0860] (iii) The step of reacting the compound of chemical formula (C-2) with the compound of chemical formula (E) to obtain the compound of chemical formula (II):

[0861]

[0862] [ka]

[0268]

[0863]

[0864] Here, R 1 ~R 4 Y and Z are synonymous with the above definitions, and

[0269]

[0865] L 1 It is a halide.

[0270]

[0866]

[0867] In one specific example, L 1 The compound is selected from the group consisting of fluoride, chloride, bromide, and iodide, and is preferably bromide or chloride.

[0271]

[0868]

[0869] In one specific example, step (i) includes the following steps:

[0272]

[0870] (i-1) Step to obtain the compound of chemical formula (cc-1):

[0871]

[0872] [ka]

[0273]

[0873]

[0874] (i-2) The step of reacting the compound of chemical formula (cc-1) with benzaldehyde and adding sodium triacetoxyborohydride to obtain the compound of chemical formula (cc-2):

[0875]

[0876] [ka]

[0274]

[0877]

[0878] (i-3) A mixture is prepared by mixing tert-butanol and N-(oxomethylene)sulfamoyl chloride, and a compound of chemical formula (cc-2) is added to this mixture to obtain a compound of chemical formula (cc-3):

[0879]

[0880] [ka]

[0275]

[0882] (i-4) A step in which the compound of chemical formula (cc-3) is cyclized in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPH3) to obtain the compound of chemical formula (C-1).

[0276]

[0882]

[0884] In one concrete example, the exemplary reaction scheme of method C can be represented by scheme III:

[0277]

[0885] Scheme III

[0886] [ka]

[0278]

[0887]

[0888] Method D

[0889] Method D is for producing a compound of chemical formula IV as defined herein, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates, and Method D comprises the following steps:

[0279]

[0890] (i) Step to obtain the compound of chemical formula (D-1):

[0891] [ka]

[0280]

[0892]

[0893] (ii) The step of reacting the compound of chemical formula (D-1) with the compound of chemical formula (F) to obtain the compound of chemical formula (D-2):

[0894]

[0895] [ka]

[0896] [ka]

[0281]

[0897]

[0898] (iii) Compound with chemical formula (D-2) z -L 2 The step of reacting with the compound to obtain the compound of chemical formula (D-3):

[0899]

[0900] [ka]

[0282]

[0901]

[0902] (iv) Step of introducing H2 gas into the compound of chemical formula (D-3) in the presence of Pd / C to obtain compound (D-4):

[0903]

[0904] [ka]

[0283]

[0905]

[0906] (v) The step of reacting the compound of chemical formula (D-4) with the compound of chemical formula (E) to obtain the compound of chemical formula (II):

[0284]

[0907]

[0908]

[0909] [ka]

[0285]

[0910] Here, R 1 ~R 4 Rings A, Y, and Z are synonymous with the above definitions, and

[0911] L 1 and L 2 These are all independently halogenated compounds.

[0286]

[0912]

[0913] In one specific example, L 1 and L 2 Each of these is selected from the group consisting of fluoride, chloride, bromide, and iodide, and is preferably bromide or chloride.

[0287]

[0914]

[0915] In one specific example, step (i) includes the following steps:

[0288]

[0916] (i-1) Step to obtain the compound of chemical formula (dd-1):

[0917]

[0918] [ka]

[0289]

[0919]

[0920] (i-2) Step of reacting the compound of chemical formula (dd-1) with benzaldehyde to obtain the compound of chemical formula (dd-2):

[0290]

[0921]

[0922] [ka]

[0291]

[0923]

[0924] (i-3) A mixture is prepared by mixing tert-butanol and N-(oxomethylene)sulfamoyl chloride, and a compound of chemical formula (dd-2) is added to this mixture to obtain a compound of chemical formula (dd-3):

[0925]

[0926] [ka]

[0292]

[0927]

[0928] (i-4) A step in which the compound of chemical formula (dd-3) is cyclized in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPH3) to obtain the compound of chemical formula (D-1).

[0293]

[0929]

[0930] In one concrete example, the exemplary reaction scheme of method D can be represented by scheme IV:

[0294]

[0931] Scheme IV

[0932] [ka]

[0295]

[0933]

[0934] Method E

[0935] Method E is for producing a compound of chemical formula IV as defined herein, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates, and Method E comprises the following steps:

[0296]

[0936] (i) Step to obtain the compound of chemical formula (E-1):

[0297]

[0937]

[0938] [ka]

[0298]

[0939]

[0940] (ii) The step of reacting the compound of chemical formula (E-1) with NaH to obtain the compound of chemical formula (E-2):

[0941]

[0942] [ka]

[0299]

[0943]

[0944] (iii) Compound with chemical formula (E-2) z -L 2 The step of reacting with the compound to obtain the compound of chemical formula (E-3):

[0300]

[0945]

[0946] [ka]

[0301]

[0947]

[0948] (iv) The step of performing an amidation reaction of the compound of chemical formula (E-3) to obtain the compound of chemical formula (E-5):

[0302]

[0949]

[0950]

[0951] [ka]

[0303]

[0952]

[0953] (v) The step of reacting the compound of chemical formula (E-5) with H2 gas in the presence of a Pd / C catalyst to obtain the compound of chemical formula (E-6):

[0304]

[0954]

[0955] [ka]

[0305]

[0956]

[0957] (vi) The step of reacting the compound of chemical formula (E-6) with the compound of chemical formula (E) to obtain the compound of chemical formula (II):

[0306]

[0958]

[0959] [ka]

[0307]

[0960] Here, R 1 ~R 4 , R z Rings A, Y, and Z are synonymous with the above definitions, and

[0961] L 1 and L 2 These are all independently halogenated compounds.

[0308]

[0962]

[0963] In one specific example, step (iv) includes the following steps:

[0309]

[0964] (iv-1) The step of reacting the compound of chemical formula (E-3) with the compound of chemical formula (E-4-1) to obtain the compound of chemical formula (E-5):

[0310]

[0965]

[0966] [ka]

[0967] Here, R 3 , R 4 , R z And ring A is synonymous with the above definition.

[0311]

[0968]

[0969] In another embodiment, step (iv) includes the following steps:

[0312]

[0970] (iv-2) The step of reacting the compound of chemical formula (E-3) with the compound of chemical formula (E-4-2) to obtain the compound of chemical formula (E-4-3):

[0971]

[0972] [ka]

[0973]

[0974] [ka]

[0313]

[0975]

[0976] (iv-3) The step of reacting the compound of chemical formula (E-4-3) with the compound of chemical formula (R4-L3) to obtain the compound of chemical formula (E-5):

[0314]

[0977] Here, R 3 , R 4 , R z , and ring A is synonymous with the above definition; and

[0978] L 3 These are independently halides.

[0315]

[0979]

[0980] In one specific example, step (i) includes the following steps:

[0316]

[0981] (i-1) Step to obtain the compound of chemical formula (ee-1):

[0982]

[0983] [ka]

[0317]

[0984]

[0985] (i-2) The step of reacting the compound of chemical formula (ee-1) with benzaldehyde to obtain the compound of chemical formula (ee-2):

[0986]

[0987] [ka]

[0318]

[0988]

[0989] (i-3) A mixture is prepared by mixing tert-butanol and N-(oxomethylene)sulfamoyl chloride, and the compound of chemical formula (ee-2) is added to this mixture to obtain the compound of chemical formula (ee-3):

[0319]

[0990]

[0991] [ka]

[0320]

[0992]

[0993] (i-4) A step in which the compound of chemical formula (ee-3) is cyclized in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPH3) to obtain the compound of chemical formula (E-1).

[0321]

[0994]

[0995] In one concrete example, the exemplary reaction scheme of method E can be represented by scheme V:

[0322]

[0996] Scheme V

[0997] [ka]

[0323]

[0998]

[0999] Therapeutic usefulness

[1000] 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).

[0324]

[1001] 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.

[0325]

[1002] 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.

[0326]

[1003] The terms "disease," "disability," and "condition" are interchangeable in this specification.

[0327]

[1004] The present invention provides compounds for preventing or treating diseases or disorders mediated by Polθ, or diseases or disorders related to Polθ activity.

[0328]

[1005] In some embodiments, Polθ-mediated diseases or disorders are a type of proliferative disorder. 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 disorders 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.

[0329]

[1006] 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).

[0330]

[1007] 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.

[0331]

[1008] 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.

[0332]

[1009]

[1010] Pharmaceutical composition

[1011] 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, pp. 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.

[0333]

[1012] In some embodiments, a pharmaceutical composition is provided comprising a compound disclosed herein, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates, and pharmaceutically acceptable carriers, wherein the composition can be administered separately or sequentially with the additional DDR-targeted anticancer agents described above.

[0334]

[1013] 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, isotopic variant, 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.

[0335]

[1014] In some implementation examples, a kit including the following is provided:

[0336]

[1015] -A first pharmaceutical composition or dosage form comprising a compound disclosed herein, or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates, and one or more pharmaceutically acceptable carriers; and

[0337]

[1016] - A second pharmaceutical composition or dosage form comprising the aforementioned additional DDR-targeted anticancer agents or their tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates, and one or more pharmaceutically acceptable carriers.

[0338]

[1017] 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.

[0339]

[1018] 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.

[0340]

[1019]

[1020] Treatment method

[1021] 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 that requires treatment or prevention of such a disease or disorder, comprising the step of administering to the subject one or more compounds disclosed herein, or their tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutically acceptable compositions disclosed herein.

[0341]

[1022] 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.

[0342]

[1023]

[1024] Administration

[1025] 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.

[0343]

[1026] 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 amount 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 amount 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.

[0344]

[1027]

[1028] Dosage form

[1029] 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.

[0345]

[1030] 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.

[0346]

[1031]

[1032] Dosage

[1033] 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 a longer period as needed. 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.

[0347]

[1034]

[1035] 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.

[0348]

[1036] 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.

[0349]

[1037]

[1038] [Examples]

[0350] Examples

[1039] 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.

[0351]

[1040] 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.

[0352]

[1041]

[1042] Abbreviation

[1043] The abbreviations used in this application have the following meanings:

[0353]

[1044] Et3N: Triethylamine

[1045] MeOH: methanol

[1046] EtOH: Ethanol

[1047] SOCl2: Thionyl Chloride

[1048] CHCl3: Chloroform

[1049] Na2SO4: Sodium sulfate

[1050] LCMS: Liquid Chromatography Mass Spectrometry

[1051] HPLC: High-performance liquid chromatography

[1052] Boc:tert-butyloxycarbonyl

[1053] DCM: Dichloromethane

[1054] TFA: Trifluoroacetic acid

[1055] THF: Tetrahydrofuran

[1056] dba: dibenzylideneacetone

[1057] ACN: Acetonitrile

[1058] æ:ethyl acetate

[1059] NaOAc: Sodium acetate

[1060] NaBH(OAc)3: Sodium triacetoxyborohydride

[1061] Acetic acid (TOH)

[1062] TLC: Thin-layer chromatography

[1063] PPh3: Triphenylphosphine

[1064] DIAD: Diisopropyl azodicarboxylate

[1065] HOBT: 1-hydroxybenzotriazole

[1066] EDCI: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[1067] DIEA: N,N-diisopropylethylamine

[1068] DMF: Dimethylformamide

[1069] AlMe3: Trimethylaluminum

[1070] Py: Pyridine

[1071] ODS: Octadecyl Silica

[1072] TBAF: Tetra-n-butylammonium fluoride

[1073]

[1074]

[1075]

[0354] Substances and methods

[1076] 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.

[0355]

[1077] 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:

[0356]

[1078]

[1079] LCMS method A:

[1080] LCMS column: SHIMADZU Xtimate C18 2.1*30mm, 3μm

[1081] Mobile phase: Solvent A: Water (4L) + TFA (1.5mL)

[1082] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[1083] Flow rate: 0.8mL / min

[1084] 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.

[1085] Temperature: 50℃

[1086]

[1087]

[0357] LCMS method B:

[1088] LCMS column: SHIMADZU Nano Chrom 120 C18 3.0*30 mm, 3 μm

[1089] Mobile phase: Solvent A: Water (4L) + TFA (1.5mL)

[1090] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[1091] Flow rate: 0.8mL / min

[1092] 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.

[0358]

[1093] Temperature: 50℃

[1094]

[0359]

[1095] LCMS method C:

[1096] LCMS column: SHIMADZU Xtimate C18 2.1*30mm, 3μm

[1097] Mobile phase: Solvent A: Water (4L) + TFA (1.5mL)

[1098] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[1099] Flow rate: 0.8mL / min

[1100] 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.

[1001] Temperature: 50℃

[1002]

[1103]

[0360] LCMS method D:

[1104] LCMS column: SHIMADZU Nano Chrom 120 C18 3.0*30 mm, 3 μm

[1105] Mobile phase: Solvent A: Water (4L) + TFA (1.5mL)

[1106] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[1107] Flow rate: 0.8mL / min

[1108] 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.

[1109] Temperature: 50℃

[1110]

[1111]

[0361] Experimental procedure: Intermediate 1: (S)-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxylic acid 1,1-dioxide [ka]

[0362]

[1112] 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).

[0363]

[1113] 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-chlorosulfanyl-butanoate (4 g, crude product, HCl) was obtained as a white solid and was used directly in the next step without further purification.

[1114] 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).

[0364]

[1115] 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-chlorosulfanylbutanoate (4 g, 15.87 mmol, HCl) in CHCl3 (50 mL). The reaction mixture was stirred at 25°C for 12 hours. LC-MS confirmed the detection of the desired compound. The 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.

[1116] 1 H 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).

[0365]

[1117] 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 drying the reaction solution by direct air, 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-thiazolidinedion-3-carboxylate (660 mg, 1.95 mmol, yield 34.96%, purity 100%) as a white solid.

[1118] MS (ESI) m / z = 338.9 [M+H] + ; 1 HNMR (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).

[0366]

[1119] Step e. A solution of methyl(3S)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidined-3-carboxylate (490 mg, 1.45 mmol) in MeOH (2 mL), THF (2 mL), and H2O (1 mL) was mixed with LiOH·H2O (243.12 mg, 5.79 mmol). The mixture was stirred at 25°C for 12 hours. LCMS 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-ACN]; B%: 0%~48%, 30 min) to obtain (S)-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxylic acid 1,1-dioxide (160 mg, 493.41 μmol, yield 34.07%, purity 100%) as a white solid.

[1120] MS (ESI) m / z = 324.8 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.35 (s, 1H), 7.18 (s, 1H), 4.92 (dd, J = 7.6, 5.2Hz, 1H), 3.76-3.57 (m, 3H), 2.81-2.71 (m, 1H), 2.47-2.43 (m, 6H).

[0367]

[1121]

[1122] Intermediate 2: Methyl(3S)-2-[2-methyl-6-(trifluoromethyl)pyrimidine-4-yl]-1,1-dioxo-1,2-thiazolidined-3-carboxylate

[0368]

[1123] [ka]

[0369]

[1124] Step a. To a solution of methyl(3S)-1,1-dioxo-1,2-thiazolidined-3-carboxylate (500 mg, 2.79 mmol) in dioxane (15 mL), 4-chloro-2-methyl-6-(trifluoromethyl)-pyrimidine (548.45 mg, 2.79 mmol), Cs2CO3 (1.82 g, 5.58 mmol), xanthophos (161.45 mg, 279.03 μmol), and Pd2(dba)3 (255.51 mg, 279.03 μmol) were added. The mixture was stirred at 80°C for 12 hours. LCMS confirmed the detection of the desired compound. After directly drying the reaction solution, it was extracted with water (20 mL) and DCM (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified using a reversed-phase column (column: 40 g C18 reversed-phase column; mobile phase: [water (0.05% HCl-ACN)]; B%: 0%~50%, 30 min) to obtain methyl(3S)-2-[2-methyl-6-(trifluoromethyl)pyrimidine-4-yl]-1,1-dioxo-1,2-thiazolidined-3-carboxylate (430 mg, 1.27 mmol, yield 22.71%, purity 100%) as a colorless oil.

[1125] MS (ESI) m / z = 340.6 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.34 (s, 1H), 5.10 (dd, J = 7.6, 5.2 Hz, 1H),3.89-3.83 (m, 1H), 3.73 (s, 3H), 3.73-3.62 (m, 1H), 2.84-2.70 (m, 1H), 2.57 (s,3H), 2.55-2.51 (m, 1H).

[0370]

[1126]

[1127] Intermediate 3: 2-(tert-butyl)4-methyl (S)-5-benzyl-1,2,5-thiadiazolidine-2,4-dicarboxylate 1,1-dioxide

[1128] [ka]

[0371]

[1129] 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), the mixture was 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(R); 80 g Sepa Flash(R) silica flash column, eluate with a 0-80% ethyl acetate / petroleum ether gradient @ 80 mL / min) to obtain methyl(2S)-2-(benzylamino)-3-hydroxy-propanoate (5.6 g, 25.93 mmol, yield 80.70%, purity 96.9%) as a colorless oil.

[1130] MS (ESI) m / z = 210.1 [M+H] + ; 1HNMR (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).

[0372]

[1131] 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, a solution 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) was 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 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.

[1132] MS (ESI) m / z = 289.0 [M-Boc+H] + ; 1H 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).

[0373]

[1133] 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) revealed a new spot (R f 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.

[1134] 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).

[0374]

[1135]

[1136] Example 1

[1137] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(m-tolyl)isothiazolidine-3-carboxamide 1,1-dioxide

[0375]

[1138] [ka]

[0376]

[1139] Step a. To a solution of intermediate 1 (50 mg, 154.19 μmol) in DMF (2 mL), N,3-dimethylaniline (37.37 mg, 308.38 μmol, 38.52 μL), EDCI (44.34 mg, 231.28 μmol), HOBT (20.83 mg, 154.19 μmol), and DIEA (79.71 mg, 616.76 μmol, 107.43 μL) were added. The mixture was stirred at 25°C for 12 hours. LCMS 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%~70%, 30 min) to obtain (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidinedion-3-carboxamide (31 mg, 57.25 μmol, yield 37.13%, purity 100%, TFA) as a brown solid.

[1140] MS (ESI) m / z = 428.1 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.46-7.39 (m, 2H), 7.38-7.32 (m, 2H), 7.26 (br d, J= 7.2 Hz, 1H), 7.19 (s, 1H), 4.84 (dd, J = 7.2, 4.8 Hz, 1H), 3.70-3.56 (m, 2H),3.17 (s, 3H), 2.59 (s, 3H), 2.45-2.38 (m, 2H), 2.38 (s, 3H).

[0377]

[1141]

[1142] Example 2

[1143] (3S)-N-(2,4-difluoro-3-methylphenyl)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidined-3-carboxamide (compound number 44)

[0378]

[1144] (S)-N-(2,4-difluoro-3-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide (compound number 2)

[1145] [ka]

[0379]

[1146] Step a. To a solution of intermediate 1 (100 mg, 308.38 μmol) in Py (1 mL), 3-[chloro-(2-oxoxazolidine-3-yl)phosphoryl]oxazolidine-2-one (196.26 mg, 770.95 μmol) was added, followed by the addition of 2,4-difluoro-3-methylaniline (88.28 mg, 616.76 μmol). 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%~56%, 40 min) to obtain (3S)-N-(2,4-difluoro-3-methylphenyl)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidinedion-3-carboxamide (compound number 44) (53 mg, 99.07 μmol, yield 32.12%, purity 84%) as a white solid.

[1147] MS (ESI) m / z = 450.1 [M+H] + ; 1 HNMR (DMSO-d6) δ = 10.19 (s, 1H), 7.55-7.51 (m, 1H), 7.32 (s, 1H),7.21 (s, 1H), 7.02 (t, J = 7.2 Hz, 1H), 5.16 (dd, J = 7.6, 4.8 Hz, 1H),3.83-3.59 (m, 2H), 3.50-3.39 (m, 1H), 2.85-2.70 (m, 1H), 2.44 (s, 3H), 2.17 (s,3H).

[0380]

[1148] 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-thiazolidine-3-carboxamide (49 mg, 109.04 μmol) in ACN (1 mL), Cs2CO3 (53.29 mg, 163.55 μmol) and MeI (30.95 mg, 218.07 μmol, 13.58 μL) were added. The mixture was stirred at 80°C for 12 hours. LCMS confirmed the detection of the desired compound. The reaction mixture was purified by Prep-HPLC column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (TFA)-ACN]; gradient: 9 minutes at 50%~-90% B to obtain (3S)-N-(2,4-difluoro-3-methylphenyl)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidined-3-carboxamide (compound number 2) (15.5 mg, 33.45 μmol, yield 30.68%, purity 100%, TFA) as a white solid.

[1149] MS (ESI) m / z = 464.1 [M+H] + ; 1HNMR (DMSO-d6) δ = 7.64-7.55 (m, 1H), 7.38-7.27 (m, 1H), 7.25-7.06(m, 2H), 4.92-4.78 (m, 1H), 3.66-3.56 (m, 2H), 3.50 (s, 1H), 3.13 (d, J = 8.0Hz, 3H), 2.60 (s, 3H), 2.48 (br s, 2H), 2.41-2.20 (m, 3H).

[0381]

[1150]

[1151] Example 3

[1152] (S)-N-(3-chloro-3-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1153] [ka]

[0382]

[1154] Example 3 was carried out using the same method as the synthesis method of Example 2, but in step a, 3-chloro-4-fluoroaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (80.8 mg, 173.45 μmol, 47.78%, 100% purity) as a white solid.

[1155] MS (ESI) m / z = 466.0 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.90 (d, J = 6.0 Hz, 1H), 7.62 (br d, J = 7.2 Hz,2H), 7.34 (s, 1H), 7.20 (s, 1H), 4.87 (dd, J = 7.2, 5.2 Hz, 1H), 3.72-3.59 (m,2H), 3.33 (s, 3H), 2.60 (s, 3H), 2.47-2.35 (m, 2H).

[0383]

[1156]

[1157] Example 4

[1158] (S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1159] [ka]

[0384]

[1160] Example 4 was carried out using the same method as the synthesis method of Example 2, but in step a, 3-chloro-2,4-difluoroaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (10.57 mg, 21.32 μmol, 25.04%, 97.6% purity) as a white solid.

[1161] MS (ESI) m / z = 483.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.83-7.73 (m, 1H), 7.52-7.27 (m, 2H), 7.17 (d, J =16.8 Hz, 1H), 5.64-5.61 (m, 0.2H), 4.92-4.86 (m, 0.8H), 3.81-3.65 (m, 2H), 3.14(d, J = 8.8 Hz, 3H), 2.85-2.65 (m, 0.3H), 2.55-2.50 (m, 3H), 2.48-2.35 (m,1.3H), 2.22-2.17 (m, 0.4H).

[0385]

[1162]

[1163] Example 5

[1164] (S)-N-(3-bromo-2,4-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1165] [ka]

[0386]

[1166] Example 5 was carried out using the same method as the synthesis method of Example 2, but in step a, 3-bromo-2,4-difluoroaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (32.42 mg, 60.14 μmol, yield 55.23%, purity 98%) as a white solid.

[1167] S (ESI) m / z = 527.8 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.85-7.77 (m, 1H), 7.58-7.40 (m, 1H), 7.38-7.29(m, 1H), 7.17 (d, J = 15.2 Hz, 1H), 5.64-5.61 (m, 0.2H), 4.91-4.80 (m, 0.8H),3.80-3.57 (m, 2H), 3.56 (s, 0.6H), 3.14 (d, J = 9.2 Hz, 2.4H), 2.95-2.68 (m,0.3H), 2.65-2.55 (m, 3H), 2.47-2.05 (m, 1.7H).

[0387]

[1168]

[1169] Example 6

[1170] (S)-N-(2,4-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1171] [ka]

[0388]

[1172] Example 6 was carried out using the same method as the synthesis method of Example 2, but in step a, 2,4-difluoroaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (38.28 mg, 79.22 μmol, yield 95.80%, purity 93%) as a white solid.

[1173] MS (ESI) m / z = 449.8 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.88-7.69 (m, 1H), 7.66-7.49 (m, 1H), 7.46-7.09(m, 3H), 5.64-5.60 (m, 0.2H), 4.93-4.73 (m, 0.8H), 3.79-3.57 (m, 2H), 3.52 (s,0.6H), 3.13 (d, J = 8.8 Hz, 2.4H), 2.63-2.52 (m, 3H), 2.46-2.34 (m, 2H).

[0389]

[1174]

[1175] Example 7

[1176] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(2,3,4-trifluorophenyl)isothiazolidine-3-carboxamide 1,1-dioxide

[1177] [ka]

[0390]

[1178] Example 7 was carried out using the same method as the synthesis method of Example 2, but in step a, 2,3,4-trifluoroaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (45.14 mg, 92.62 μmol, yield 99.98%, purity 95.9%) as a white solid.

[1179] MS (ESI) m / z = 467.8 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.65-7.57 (m, 1H), 7.53-7.27 (m, 2H), 7.17 (br d, J= 18.4 Hz, 1H), 5.64-5.60 (m, 0.2H), 4.94-4.84 (m, 0.8H), 3.79-3.58 (m, 2H),3.56 (s, 0.8H), 3.15 (br d, J = 8.4 Hz, 2.4H), 2.95-2.72 (m, 0.4H), 2.70-2.54(m, 3H), 2.43-2.13 (m, 1.6H).

[0391]

[1180]

[1181] Example 8

[1182] (S)-N-(4-fluoro-3-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1183] [ka]

[0392]

[1184] Example 8 was carried out using the same method as the synthesis method of Example 2, but in step a, 4-fluoro-3-methylaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (24.92 mg, 55.95 μmol, yield 26.23%, purity 100%) as a white solid.

[1185] MS (ESI) m / z = 445.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.54-7.49 (m, 1H), 7.44 (td, J = 7.6, 4.0 Hz, 1H),7.34 (s, 1H), 7.32-7.27 (m, 1H), 7.19 (s, 1H), 4.84 (dd, J = 7.6, 5.2 Hz, 1H),3.70-3.52 (m, 2H), 3.15 (s, 3H), 2.59 (s, 3H), 2.47-2.36 (m, 2H), 2.28 (s, 3H).

[0393]

[1186]

[1187] Example 9

[1188] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(2,4,6-trifluorophenyl)isothiazolidine-3-carboxamide 1,1-dioxide

[1189] [ka]

[0394]

[1190] Example 9 was carried out using the same method as the synthesis method of Example 2, but in step a, 2,4-difluoro-3-methylaniline was used instead of 2,4-trifluoroaniline to obtain the target compound (53.16 mg, 110.33 μmol, yield 41.68%, purity 97%) as a white solid.

[1191] MS (ESI) m / z = 467.8 [M+H] + ; 1HNMR (DMSO-d6) δ = 7.59-7.46 (m, 1H), 7.39-7.25 (m, 2H), 7.18 (d, J =10.0 Hz, 1H), 5.67-5.63 (m, 0.4H), 4.99-4.95 (m, 0.6H), 3.81-3.64 (m, 2H), 3.59(s, 1.4H), 3.12 (s, 1.6H), 2.99-2.85 (m, 0.4H), 2.50-2.48 (m, 3H), 2.48-2.47(m, 1H), 2.24-2.20 (m, 0.6H).

[0395]

[1192]

[1193] Example 10

[1194] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(2,4,5-trifluorophenyl)isothiazolidine-3-carboxamide 1,1-dioxide

[1195] [ka]

[0396]

[1196] Example 10 was carried out using the same method as the synthesis method of Example 2, but in step a, 2,4,5-trifluoroaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (39.37 mg, 82.47 μmol, yield 31.16%, purity 97.9%) as a white solid.

[1197] MS (ESI) m / z = 467.8 [M+H] + ; 1HNMR (DMSO-d6) δ = 8.06-7.53 (m, 2H), 7.40-7.27 (m, 1H), 7.24-7.12(m, 1H), 5.62-5.60 (m, 0.2H), 5.03-4.99 (m, 0.4H), 4.88-4.85 (m, 0.4H),3.81-3.56 (m, 2H), 3.52 (s, 0.7H), 3.14 (d, J = 12.4 Hz, 2.3H), 2.88-2.65 (m,0.3H), 2.62-2.53 (m, 3H), 2.44-2.14 (m, 1.7H).

[0397]

[1198]

[1199] Example 11

[1200] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(2,3,4,5-tetrafluorophenyl)isothiazolidine-3-carboxamide 1,1-dioxide

[1201] [ka]

[0398]

[1202] Example 11 was carried out using the same method as the synthesis method of Example 2, but in step a, 2,3,4,5-tetrafluoroaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (36.52 mg, 73.74 μmol, yield 34.76%, purity 98%) as a white solid.

[1203] MS (ESI) m / z = 485.8 [M+H] + ; 1HNMR (DMSO-d6) δ = 8.00-7.50 (m, 1H), 7.39-7.29 (m, 1H), 7.26-7.11(m, 1H), 5.64-5.60 (m, 0.2H), 5.05-4.87 (m, 0.8H), 3.82-3.58 (m, 2H), 3.55 (s,1H), 3.16 (br d, J = 12.0 Hz, 2H), 2.88-2.65 (m, 0.3H), 2.61-2.52 (m, 3H),2.46-2.12 (m, 1.7H)

[0399]

[1204]

[1205] Example 12

[1206] (S)-N-(2,4-difluoro-3-methylphenyl)-N-(methyl-d3)-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1207] [ka]

[0400]

[1208] Example 12 was carried out using the same method as the synthesis method of Example 2, but in step b, triduterio(iodo)methane was used instead of MeI to obtain the target compound (56.71 mg, 119.88 μmol, yield 53.87%, purity 98.6%) as a white solid.

[1209] MS (ESI) m / z = 466.9 [M+H] + ; 1HNMR (DMSO-d6) δ = 7.67-7.52 (m, 1H), 7.37-7.27 (m, 1H), 7.25-7.05(m, 2H), 5.61 (dd, J = 7.6, 4.4 Hz, 0.2H), 4.94-4.79 (m, 0.8H), 3.78-3.54 (m,2H), 2.63-2.52 (m, 3H), 2.49-2.37 (m, 2H), 2.26-2.12 (m, 3H).

[0401]

[1210]

[1211] Example 13

[1212] (S)-N-(2,4-difluoro-3-methylphenyl)-N-isopropyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1213] [ka]

[0402]

[1214] Example 13 was carried out using the same method as the synthesis method of Example 2, but in step b, 2-iodopropane was used instead of MeI to obtain the target compound (58.25 mg, 116.74 μmol, yield 52.46%, purity 98.5%) as a white solid.

[1215] MS (ESI) m / z = 491.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.52-7.40 (m, 1H), 7.37-7.10 (m, 3H), 4.76-4.55(m, 2H), 3.63-3.51 (m, 2H), 2.60 (s, 3H), 2.45-2.28 (m, 2H), 2.24 (br s, 3H),1.18-0.90 (m, 6H).

[0403]

[1216]

[1217] Example 14

[1218] (S)-N-(5-fluoropyridine-3-yl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1219] [ka]

[0404]

[1220] Example 14 was carried out using the same method as the synthesis method of Example 2, but in step a, 5-fluoropyridine-3-amine was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (85.98 mg, 198.85 μmol, yield 56.46%, purity 98%) as a white solid.

[1221] MS (ESI) m / z = 432.8 [M+H] + ; 1 HNMR (DMSO-d6) δ = 8.90-8.72 (m, 1H), 8.69-8.55 (m, 1H), 8.09-7.96(m, 1H), 7.41 (s, 1H), 7.20 (s, 1H), 5.08-4.96 (m, 1H), 3.75-3.62 (m, 1H),3.57-3.47 (m, 1H), 3.34 (br s, 3H), 2.71-2.51 (m, 5H).

[0405]

[1222]

[1223] Example 15

[1224] (S)-N-(isoquinoline-4-yl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1225] [ka]

[0406]

[1226] Example 15 was carried out using the same method as the synthesis method of Example 2, but in step a, isoquinoline-4-amine was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (31.5 mg, 66.33 μmol, yield 24.73%, purity 97.809%) as a white solid.

[1227] MS (ESI) m / z = 464.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 9.55-9.39 (m, 1H), 8.92-8.64 (m, 1H), 8.40-8.29(m, 1H), 8.28-8.06 (m, 1H), 8.06-7.92 (m, 1H), 7.91-7.76 (m, 1H), 7.44-7.27 (m,1H), 7.25-7.07 (m, 1H), 5.89-5.73 (m, 0.3H), 5.03-4.97 (m, 0.4H), 4.71 (dd, J =7.2, 5.6 Hz, 0.3H), 3.88-3.78 (m, 0.2H), 3.74-3.66 (m, 0.7H), 3.62-3.39 (m,1.8H), 3.34-3.25 (m, 2.3H), 2.71 (s, 2H), 2.68-2.57 (m, 0.6H), 2.54 (s, 1H),2.36-2.26 (m, 0.4H), 2.24-2.12 (m, 0.5H), 1.98-1.85 (m, 0.5H).

[0407]

[1228]

[1229] Example 16

[1230] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(naphthalene-1-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1231] [ka]

[0408]

[1232] Example 16 was carried out using the same method as the synthesis method of Example 2, but in step a, naphthalene-1-amine was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (222.51 mg, 477.69 μmol, yield 67.94%, purity 99.5%) as a white solid.

[1233] MS (ESI) m / z = 463.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 8.01 (br s, 3H), 7.79-7.50 (m, 4H), 7.40-7.11 (m,2H), 5.89-5.73 (m, 0.1H), 4.95 (dd, J = 7.6, 6.0 Hz, 0.5H), 4.68-4.64 (m,0.4H), 3.58-3.41 (m, 2H), 3.26 (d, J = 10.4 Hz, 3H), 2.75-2.53 (m, 3H),2.18-1.84 (m, 2H).

[0409]

[1234]

[1235] Example 17

[1236] (S)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1237] [ka]

[0410]

[1238] Example 17 was carried out using the same method as the synthesis method of Example 2, but in step a, 2,4-difluoro-3-(trifluoromethyl)aniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (130.31 mg, 246.22 μmol, yield 44.26%, purity 97.76%) as a white solid.

[1239] MS (ESI) m / z = 517.8 [M+H] + ; 1 HNMR (DMSO-d6) δ = δ = 8.20-8.05 (m, 0.7H), 8.83-7.56 (m, 0.3H), 7.56(d, J = 7.2 Hz, 0.3H), 7.52 (dt, J = 10.8, 7.2 Hz, 0.7H), 7.37-7.30 (m, 1H),7.24-7.12 (m, 1H), 5.63 (dd, J = 7.6, 4.4 Hz, 0.3H), 4.89 (dd, J = 7.6, 4.4 Hz,0.7H), 3.83-3.61 (m, 2H), 3.56 (s, 1H), 3.16 (d, J = 10.0 Hz, 2H), 2.91-2.78(m, 0.3H), 2.62 (s, 3H), 2.46-2.40 (m, 1.4H), 2.39-2.32 (m, 0.3H).

[0411]

[1240]

[1241] Example 18

[1242] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(3,4,5-trifluorophenyl)isothiazolidine-3-carboxamide 1,1-dioxide

[1243] [ka]

[0412]

[1244] Example 18 was carried out using the same method as the synthesis method of Example 2, but in step a, 3,4,5-trifluoroaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (128.17 mg, 272.72 μmol, yield 61.82%, purity 99.45%) as a white solid.

[1245] MS (ESI) m / z = 467.8 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.65 (s, 2H), 7.35 (s, 1H), 7.20 (s, 1H), 4.96 (s,1H), 3.63 (d, J = 5.6 Hz, 2H), 3.17 (s, 3H), 2.57 (s, 3H), 2.48-2.44 (m, 2H).

[0413]

[1246]

[1247] Example 19

[1248] (S)-N-(2,6-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1249] [ka]

[0414]

[1250] Example 19 was carried out using the same method as the synthesis method of Example 2, but in step a, 2,6-difluoroaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (138.80 mg, 306.70 μmol, yield 66.76%, purity 99.30%) as a white solid.

[1251] MS (ESI) m / z = 449.8 [M+H] + ; 1HNMR (DMSO-d6) δ = 7.68-7.56 (m, 0.5H), 7.46-7.31 (m, 2.5H),7.26-7.13 (m, 2H), 5.66 (dd, J = 7.2, 5.2 Hz, 0.4H), 4.94 (dd, J = 7.6, 5.2 Hz,0.6H), 3.85-3.77 (m, 1H), 3.65-3.60 (m, 1H), 3.55 (s, 1.3H), 3.14 (s, 1.7H),2.92 (br dd, J = 14.0, 7.6 Hz, 0.4H), 2.52 (s, 1H), 2.48 (br s, 2H), 2.46-2.19 (m, 1.6H).

[0415]

[1252]

[1253] Example 20

[1254] (S)-N-(2-fluoro-3-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1255] [ka]

[0416]

[1256] Example 20 was carried out using the same method as the synthesis method of Example 2, but in step a, 2-fluoro-3-methylaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (99.8 mg, 208.37 μmol, yield 29.96%, purity 93%) as a white solid.

[1257] MS (ESI) m / z = 445.8 [M+H] + ; 1HNMR (DMSO-d6) δ = 7.57 (br t, J = 7.2 Hz, 0.5H), 7.49-7.37 (m, 1H),7.37-7.26 (m, 1.4H), 7.25-7.18 (m, 1H), 7.16-7.07 (m, 0.6H), 5.64-5.60 (m,0.15H), 4.92-4.80 (m, 0.85H), 3.77-3.58 (m, 2H), 3.61 (s, 0.5H), 3.14 (d, J =6.8 Hz, 2.5H), 2.63-2.50 (m, 3H), 2.49 (s, 0.7H), 2.47-2.36 (m, 1H), 2.32 (s,2.3H), 2.26-2.16 (m, 1H).

[0417]

[1258]

[1259] Example 21

[1260] (S)-N-(2-fluoro-5-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1261] [ka]

[0418]

[1262] Example 21 was carried out using the same method as the synthesis method of Example 2, but in step a, 2-fluoro-5-methylaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (184.73 mg, 396.89 μmol, yield 46.28%, purity 95.7%) as a white solid.

[1263] MS (ESI) m / z = 445.8 [M+H] + ; 1HNMR (DMSO-d6) δ = 7.56 (d, J = 7.2 Hz, 0.5H), 7.43 (d, J = 7.2 Hz,0.3H), 7.39-7.28 (m, 2.7H), 7.23-7.18 (m, 1.5H), 5.63-5.59 (m, 0.15H),4.98-4.77 (m, 0.85H), 3.77-3.57 (m, 2H), 3.52 (s, 0.5H), 3.13 (d, J = 8.0 Hz,2.5H), 2.63-2.50 (m, 3H), 2.49 (s, 0.7H), 2.46-2.38 (m, 1H), 2.36-2.32 (m, 2.3H), 2.29-2.17 (m, 1H).

[0419]

[1264]

[1265] Example 22

[1266] (S)-N-(2-fluoro-4-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1267] [ka]

[0420]

[1268] Example 22 was carried out using the same method as the synthesis method of Example 2, but in step a, 2-fluoro-4-methylaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (138.38 mg, 304.45 μmol, yield 42.37%, purity 98%) as a white solid.

[1269] MS (ESI) m / z = 445.8 [M+H] + ; 1HNMR (DMSO-d6) δ = 7.66-7.48 (m, 1H), 7.38-7.27 (m, 2H), 7.25-7.00(m, 2H), 5.63-5.58 (m, 0.15H), 4.93-4.78 (m, 0.85H), 3.75-3.57 (m, 2H), 2.52(s, 0.5H), 3.13 (d, J = 7.6 Hz, 2.5H), 2.60 (s, 1.4H), 2.59-2.51 (m, 1H),2.50-2.44 (m, 1.6H), 2.43 (s, 3H), 2.32-2.15 (m, 1H).

[0421]

[1270]

[1271] Example 23

[1272] (S)-N-(2-fluoro-3-(trifluoromethyl)phenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1273] [ka]

[0422]

[1274] Example 23 was carried out using the same method as the synthesis method of Example 2, but in step a, 2-fluoro-3-(trifluoromethyl)aniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (155.76 mg, 305.78 μmol, yield 67.46%, purity 98.04%) as a white solid.

[1275] MS (ESI) m / z = 499.9 [M+H] + ; 1HNMR (DMSO-d6) δ = 8.11-7.87 (m, 1H), 7.78-7.41 (m, 2H), 7.37-7.28(m, 1H), 7.22-7.13 (m, 1H), 5.63 (dd, J = 7.6, 4.4 Hz, 0.3H), 4.92-4.77 (m,0.7H), 3.81-3.60 (m, 2H), 3.58 (s, 1H), 3.21-3.15 (m, 2H), 3.08-2.95 (m,0.4H), 2.81 (s, 1H), 2.66-2.60 (m, 0.6H), 2.53 (s, 1H), 2.44 (s, 1H), 2.17-1.92 (m, 1H).

[0423]

[1276]

[1277] Example 24

[1278] (S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1279] [ka]

[0424]

[1280] Example 24 was carried out using the same method as the synthesis method of Example 2, but in step a, 4-fluoro-3-(trifluoromethyl)aniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (156.33 mg, 310.47 μmol, yield 68.50%, purity 99.18%) as a white solid.

[1281] MS (ESI) m / z = 499.8 [M+H] + ; 1HNMR (DMSO-d6) δ = 8.06-7.94 (m, 2H), 7.77-7.53 (m, 1H), 7.34 (s,1H), 7.20 (s, 1H), 5.54-5.63 (m, 0.15H), 4.88-4.81 (m, 0.85H), 3.71-3.52 (m,2H), 3.20 (s, 3H), 2.56 (s, 3H), 2.49-2.31 (m, 2H).

[0425]

[1282]

[1283] Example 25

[1284] (S)-N-(2-chloro-4,6-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1285] [ka]

[0426]

[1286] Example 25 was carried out using the same method as the synthesis method of Example 2, but in step a, 2-chloro-4,6-difluoroaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (172.16 mg, 350.39 μmol, yield 63.32%, purity 98.475%) as a white solid.

[1287] MS (ESI) m / z = 483.8 [M+H] + ; 1HNMR (MeOD-d4) δ = 7.42-7.37 (m, 1H), 7.37-7.32 (m, 0.6H), 7.31-7.22 (m, 1H),7.17 (s, 1H), 7.16-7.10 (m, 0.4H), 5.81-5.68 (m, 0.5H), 5.24-5.06 (m, 0.5H),3.73-3.63 (m, 1H), 3.63-3.60 (m, 2H), 3.59-3.52 (m, 0.5H), 3.47-3.37 (m, 0.5H),3.21-3.17 (m, 1H), 3.05-2.93 (m, 0.5H), 2.67-2.59 (m, 0.5H), 2.57 (s, 2H), 2.51(d, J = 13.2 Hz, 1H), 2.48-2.42 (m, 1H).

[0427]

[1288]

[1289] Example 26

[1290] (S)-N-(4-fluoro-2-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1291] [ka]

[0428]

[1292] Example 26 was carried out using the same method as the synthesis method of Example 2, but in step a, 4-fluoro-2-methylaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (144.14 mg, 318.90 μmol, yield 59.81%, purity 98.547%) as a white solid.

[1293] MS (ESI) m / z = 445.8 [M+H] + ; 1HNMR (MeOD-d4) δ = 7.80 (dd, J = 8.8, 5.6 Hz, 0.4H), 7.46-7.37 (m, 1.2H),7.29-6.93 (m, 3.4H), 5.09-5.04 (m, 0.4H), 4.93 (dd, J = 8.0, 5.6 Hz, 0.6H),3.62-3.48 (m, 2H), 3.45-3.36 (m, 1H), 3.19 (s, 2H), 2.68-2.62 (m, 2H),2.61-2.55 (m, 2H), 2.50 (s, 1H), 2.45-2.26 (m, 3H).

[0429]

[1294]

[1295] Example 27

[1296] (S)-N-(3-fluoro-2-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1297] [ka]

[0430]

[1298] Example 27 was carried out using the same method as the synthesis method of Example 2, but in step a, 3-fluoro-2-methylaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (51.71 mg, 116.09 μmol, yield 20.03%, purity 100%) as a white solid.

[1299] MS (ESI) m / z = 446.0 [M+H] + ; 1HNMR (MeOD-d4) δ = 7.66 (d, J = 8.1 Hz, 0.5H), 7.45-7.32 (m, 2H), 7.29-7.15 (m,2H), 7.09-6.93 (m, 0.5H), 5.81-5.61 (m, 0.15H), 5.13-4.95 (m, 0.85H), 3.65-3.49(m, 1.5H), 3.44-3.34 (m, 1H), 3.21 (s, 2H), 3.07-3.02 (m, 1.6H), 2.90-2.81 (m,0.8H), 2.67-2.62 (m, 1H), 2.47 (d, J = 2.0 Hz, 1H), 2.43-2.29 (m, 1.4H), 2.28(d, J = 2.4 Hz, 1.2H), 2.15-2.04 (m, 0.5H).

[0431]

[1300]

[1301] Example 28

[1302] (S)-N-(5-fluoro-2-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1303] [ka]

[0432]

[1304] Example 28 was carried out using the same method as the synthesis method of Example 2, but in step a, 5-fluoro-2-methylaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound (123.12 mg, 272.01 μmol, yield 55.88%, purity 98.41%) as a white solid.

[1305] MS (ESI) m / z = 445.8 [M+H] + ; 1HNMR (MeOD-d4) δ = 7.60 (dd, J = 9.2, 2.8 Hz, 0.5H), 7.47-7.38 (m, 2H), 7.28(dd, J = 9.2, 2.8 Hz, 0.5H), 7.21-6.82 (m, 2H), 5.78-5.61 (m, 0.2H), 5.15-4.95(m, 0.8H), 3.64-3.49 (m, 2H), 3.46-3.37 (m, 1H), 3.20 (s, 2H), 3.03-2.91 (m,1H), 2.67-2.54 (m, 3H), 2.50 (s, 1H), 2.47-2.27 (m, 3H), 2.22-2.09 (m, 1H).

[0433]

[1306]

[1307] Example 29

[1308] (R)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1309] [ka]

[0434]

[1310] Example 29 was carried out using the same method as the synthesis of intermediate 1 and Example 1, but (2R)-2-amino-4-[[(3R)-3-amino-3-carboxypropyl]disulfanyl]butanoic acid was used instead of (2S)-2-amino-4-[[(3S)-3-amino-3-carboxypropyl]disulfanyl]butanoic acid, and 3-chloro-4-fluoro-N-methylaniline was used instead of N,3-dimethylaniline to obtain the target compound (7.4 mg, 15.88 μmol, yield 4.38%, purity 100%) as a white solid.

[1311] MS (ESI) m / z = 466.1 [M+H] + ;1 HNMR (MeOD) δ = 7.92-7.87 (m, 1H), 7.69-7.60 (m, 1H), 7.48 (t, J = 8.8 Hz, 1H),7.42 (s, 1H), 7.22 (s, 1H), 5.03 (t, J = 6.0 Hz, 1H), 3.70-3.61 (m, 1H),3.61-3.30 (m, 1H), 3.31 (s, 3H), 2.67 (s, 3H), 2.59-2.52 (m, 2H).

[0435]

[1312]

[1313] Example 30

[1314] (S)-N-methyl-2-(2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)-N-(m-tolyl)isothiazolidine-3-carboxamide 1,1-dioxide

[1315] [ka]

[0436]

[1316] Step a. To a solution of 3-methylaniline (104.22 mg, 972.62 μmol, 105.38 μL) in toluene (4 mL), intermediate 2 (150 mg, 442.10 μmol) and trimethylalumane (2 M, 442.10 μL) 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%~66%, 40 min) to obtain (3S)-2-[2-methyl-6-(trifluoromethyl)pyrimidine-4-yl]-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidined-3-carboxamide (130 mg, 219.59 μmol, yield 49.67%, purity 70%) as a white solid.

[1317] MS (ESI) m / z = 414.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 10.51 (br s, 1H), 7.45 (s, 1H), 7.37-7.30 (m, 2H),7.20 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.12 (dd, J = 7.6, 4.4 Hz,1H), 3.92-3.82 (m, 1H), 3.77-3.66 (m, 1H), 2.84-2.70 (m, 1H), 2.62-2.52 (m,1H), 2.50 (s, 3H), 2.27 (s, 3H).

[0437]

[1318] Step b. To a solution of (3S)-2-[2-methyl-6-(trifluoromethyl)pyrimidine-4-yl]-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidined-3-carboxamide (130 mg, 313.71 μmol) in ACN (1 mL), Cs2CO3 (255.53 mg, 784.26 μmol) and MeI (89.05 mg, 627.41 μmol, 39.06 μL) were added. The mixture was stirred at 80°C for 12 hours. LCMS confirmed the detection of the desired compound. The crude product was further purified by Prep-HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (TFA)-ACN]; gradient: 9 minutes 44%~84%B) to obtain (S)-N-methyl-2-(2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)-N-(m-tolyl)-isothiazolidine-3-carboxamide 1,1-dioxide (26.1 mg, 60.92 μmol, yield 19.42%, purity 100%) as a white solid.

[1319] MS (ESI) m / z = 429.0 [M+H] + ; 1HNMR (DMSO-d6) δ = 7.48-7.34 (m, 3H), 7.32-7.23 (m, 2H), 4.92-4.84(m, 1H), 3.82-3.72 (m, 1H), 3.71-3.65 (m, 1H), 3.19 (s, 3H), 2.69 (s, 3H),2.45-2.40 (m, 2H), 2.38 (s, 3H).

[0438]

[1320]

[1321] Example 31

[1322] (S)-N-(2,4-difluoro-3-methylphenyl)-N-methyl-2-(2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1323] [ka]

[0439]

[1324] Example 31 was carried out using the same method as the synthesis method of Example 30, but in step a, 2,4-difluoro-3-methylaniline was used instead of 3-methylaniline to obtain the target compound (57.1 mg, 122.31 μmol, yield 46.15%, purity 100%) as a white solid.

[1325] MS (ESI) m / z = 465.0 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.69-7.52 (m, 1H), 7.36-7.14 (m, 2H), 5.75-5.68(m, 0.5H), 4.97-4.80 (m, 0.8H), 3.78-3.62 (m, 2H), 3.50 (s, 0.7H), 3.15 (d, J =7.2 Hz, 2.3H), 2.62-2.57 (m, 3H), 2.35-2.28 (m, 2H), 2.26-2.21 (m, 3H).

[0440]

[1326]

[1327] Example 32

[1328] (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-(2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)isothiazolidine-3-carboxamide 1,1-dioxide

[1329] [ka]

[0441]

[1330] Example 32 was carried out using the same method as the synthesis method of Example 30, but in step a, 3-chloro-4-fluoroaniline was used instead of 3-methylaniline to obtain the target compound (57.1 mg, 122.31 μmol, yield 46.15%, purity 100%) as a white solid.

[1331] MS (ESI) m / z = 467.0 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.90 (d, J = 6.0 Hz, 1H), 7.63 (d, J = 6.8 Hz,2H), 7.30 (s, 1H), 4.90 (dd, J = 7.6, 4.4 Hz, 1H), 3.88-3.71 (m, 1H), 3.68-3.61(m, 1H), 3.19 (s, 3H), 2.71 (s, 3H), 2.59-2.54 (m, 1H), 2.44-2.38 (m, 1H).

[0442]

[1332]

[1333] Example 33 (S)-2-(2,6-bis(trifluoromethyl)pyrimidine-4-yl)-N-methyl-N-(m-tolyl)isothiazolidine-3-carboxamide 1,1-dioxide [ka]

[0443]

[1334] Step a. A mixture of methyl(3S)-1,1-dioxo-1,2-thiazolidined-3-carboxylate (500 mg, 2.79 mmol), N,3-dimethylaniline (507.18 mg, 4.19 mmol, 522.87 μL), and AlMe3 (2 M, 4.19 mL) in toluene (2 mL) was degassed, purged three times with N2, and then stirred at 100°C for 12 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 using a reversed-phase column (column: 80g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; B%: 0%~50%, 30 min) to obtain (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidinedion-3-carboxamide (640 mg, 2.27 mmol, yield 81.21%, purity 95%) as a white solid.

[1335] MS (ESI) m / z = 268.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.36 (t, J = 7.6 Hz, 1H), 7.26-7.14 (m, 3H), 6.82(d, J = 4.4 Hz, 1H), 3.90 (br s, 1H), 3.17 (s, 3H), 3.10-2.97 (m, 2H), 2.34 (brs, 4H), 2.19-2.04 (m, 1H).

[0444]

[1336] Step b. The mixture of (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidined-3-carboxamide (100 mg, 372.67 μmol), 4-chloro-2,6-bis(trifluoromethyl)pyrimidine (112.04 mg, 447.21 μmol), Cs2CO3 (364.27 mg, 1.12 mmol), xanthophos (21.56 mg, 37.27 μmol), and Pd2(dba)3 (68.25 mg, 74.53 μmol) in ACN (5 mL) was degassed, purged three times with N2, and then stirred at 80°C for 3 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 reverse-phase HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water (FA)-ACN]; gradient: 9 minutes 49%-89%B) to obtain (S)-2-(2,6-bis(trifluoromethyl)pyrimidine-4-yl)-N-methyl-N-(m-tolyl)isothiazolidine-3-carboxamide 1,1-dioxide (30.09 mg, 60.06 μmol, yield 16.11%, purity 96.28%) as a white solid.

[1337] MS (ESI) m / z = 482.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.67 (s, 1H), 7.49-7.41 (m, 1H), 7.37-7.24 (m,3H), 4.95 (dd, J = 7.6, 5.2 Hz, 1H), 3.90-3.78 (m, 1H), 3.77-3.66 (m, 1H), 3.17(s, 3H), 2.61-2.52 (m, 1H), 2.46-2.40 (m, 1H), 2.37 (s, 3H).

[0445]

[1338]

[1339] Example 34

[1340] (S)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1341] [ka]

[0446]

[1342] Step a. To a solution of intermediate 3 (1 g, 2.70 mmol) and N,3-dimethylaniline (654.28 mg, 5.40 mmol, 674.52 μL) in toluene (10 mL), AlMe3 (2 M, 4.05 mL) was added, and the mixture was stirred at 100 °C for 16 hours under an N2 atmosphere. LC-MS confirmed the presence of the desired product. TLC (Plate 1, SiO2, petroleum ether:ethyl acetate = 10:1) revealed a new spot (R f A concentration of 0.8 was observed. The mixture was poured into saturated NH4Cl (50 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic layer was dried over Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography eluting with 0-55% ethyl acetate in petroleum ether to obtain (3S)-2-benzyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (450 mg, 1.20 mmol, yield 44.52%, purity 96%) as a yellow gum.

[1343] MS (ESI) m / z = 360.0 [M+H] + ; 1HNMR (CDCl3) δ = 7.42-7.34 (m, 3H), 7.33-7.28 (m, 2H), 7.19-7.12 (m,1H), 7.12-7.07 (m, 1H), 6.58-6.13 (m, 2H), 5.05-4.92 (m, 1H), 4.34-4.16 (m,2H), 3.82 (dd, J = 6.8, 2.4 Hz, 1H), 3.48-3.31 (m, 2H), 3.12 (s, 3H), 2.25 (s,3H).

[0447]

[1344] Step b. To a solution of (3S)-2-benzyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (105 mg, 303.98 μmol) in ACN (4 mL), MeI (129.44 mg, 911.95 μmol, 56.77 μL) and Cs2CO3 (247.61 mg, 759.95 μmol) were added. The mixture was stirred at 80°C for 12 hours. LCMS confirmed the detection of the desired compound. The reaction mixture was 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%~55%, 30 min) to obtain (3S)-2-benzyl-N,5-dimethyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (268 mg, crude product) as a white solid.

[1345] MS (ESI) m / z = 373.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.42-7.34 (m, 3H), 7.33-7.26 (m, 3H), 7.25-7.26(m, 3H), 4.40-4.22 (m, 2H), 4.12-4.02 (m, 1H), 3.71-3.63 (m, 1H), 3.25-3.13 (m,2H), 3.06 (s, 2H), 2.66 (s, 1H), 2.57 (s, 2H), 2.23 (d, J = 11.6 Hz, 3H).

[0448]

[1346] Step c. To a solution of (3S)-2-benzyl-N,5-dimethyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (230 mg, 615.85 μmol) in THF (5 mL), Pd / C (6.55 g, 6.16 mmol, purity 10%) was added. The mixture was stirred at 25°C for 12 hours under a 30 Psi H2 atmosphere. LCMS confirmed the detection of the desired compound. The reaction mixture was filtered, the cake was washed with RINKAN (10 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(R); 20g SepaFlash(R) silica flash column, eluate with a 0-5% ethyl acetate / petroleum ether gradient @ 30 mL / min) to obtain (3S)-N,5-dimethyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (109 mg, 357.76 μmol, yield 58.09%, purity 93%) as a white solid. MS (ESI) m / z = 283.9 [M+H] + .

[0449]

[1347] Step d. To a solution of (3S)-N,5-dimethyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (40 mg, 141.17 μmol) in dioxane (2 mL), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (67.77 mg, 282.34 μmol) was added, followed by the addition of Cs2CO3 (114.99 mg, 352.93 μmol), N,N'-dimethylethane-1,2-diamine (15.68 mg, 177.87 μmol, 19.15 μL), and CuI (33.88 mg, 177.87 μmol). The mixture was stirred at 80°C for 12 hours. LC-MS confirmed the detection of the desired compound. The reaction mixture was filtered, and the filtrate was directly purified using a Prep-HPLC column: Boston Prime C18 150*30mm*5μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 8 minutes 45%~75% B to obtain (S)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide (34.69 mg, 78.40 μmol, yield 55.54%, purity 100%) as a white solid.

[1348] MS (ESI) m / z = 443.1 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.52-7.24 (m, 5H), 7.17 (s, 1H), 4.85 (br t, J =6.0 Hz, 1H), 3.64-3.45 (m, 2H), 3.18 (s, 3H), 2.75 (s, 3H), 2.59 (br s, 3H),2.38 (s, 3H).

[0450]

[1349]

[1350] Example 35

[1351] (S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N,5-dimethyl-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1352] [ka]

[0451]

[1353] Example 35 was carried out using the same method as the synthesis method of Example 34, but in step d, 2-bromo-3-cyano-6-methyl-4-(trifluoromethyl)pyridine was used instead of 2-bromo-6-methyl-4-(trifluoromethyl)pyridine to obtain the target compound (28.87 mg, 61.26 μmol, yield 19.29%, purity 99.2%) as a yellow solid.

[1354] MS (ESI) m / z = 467.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.79 (s, 1H), 7.13-7.03 (m, 3H), 6.90 (br s, 1H),5.92 (br t, J = 7.6 Hz, 1H), 3.84 (br dd, J = 10.4, 6.8 Hz, 1H), 3.67 (br t, J= 9.6 Hz, 1H), 3.17 (s, 3H), 2.63 (s, 3H), 2.52 (br s, 3H), 2.17 (s, 3H).

[0452]

[1355]

[1356] Example 36

[1357] (S)-N,5-dimethyl-2-(2-methyl-6-(trifluoromethyl)pyrimidine-4-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1358] [ka]

[0453]

[1359] Example 36 was carried out using the same method as the synthesis method of Example 34, but in step d, 4-bromo-2-methyl-6-(trifluoromethyl)pyrimidine was used instead of 2-bromo-6-methyl-4-(trifluoromethyl)pyridine to obtain the target compound (113.22 mg, 255.32 μmol, yield 60.29%, purity 100%) as a white solid.

[1360] MS (ESI) m / z = 443.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.48-7.40 (m, 1H), 7.38-7.26 (m, 3H), 7.23 (s,1H), 4.91 (dd, J = 7.6, 4.4 Hz, 1H), 3.70 (dd, J = 11.6, 4.4 Hz, 1H), 3.55 (dd,J = 11.6, 4.4 Hz, 1H), 3.20 (s, 3H), 2.83-2.75 (m, 3H), 2.69 (s, 3H), 2.38 (s,3H).

[0454]

[1361]

[1362] Example 37

[1363] (S)-2-(2,6-bis(trifluoromethyl)pyrimidine-4-yl)-N,5-dimethyl-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1364] [ka]

[0455]

[1365] Example 37 was carried out using the same method as the synthesis method of Example 34, but in step d, 4-bromo-2,6-bis-(trifluoromethyl)pyrimidine was used instead of 2-bromo-6-methyl-4-(trifluoromethyl)pyridine to obtain the target compound (4.39 mg, 8.38 μmol, yield 7.92%, purity 95%) as a white solid.

[1366] MS (ESI) m / z = 497.9 [M+H] + ; 1 HNMR (DMSO-d6) δ = 7.60 (s, 1H), 7.50-7.40 (m, 1H), 7.29 (br s, 3H),4.98 (dd, J = 7.6, 4.8 Hz, 1H), 3.79 (dd, J = 12.0, 4.4 Hz, 1H), 3.60-3.55 (m,1H), 3.18 (s, 3H), 2.91 (s, 3H), 2.36 (s, 3H).

[0456]

[1367]

[1368] Example 38

[0457] (3S)-5-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-N-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide [ka]

[0458]

[1369] Step a. To a solution of intermediate 3 (1 g, 2.70 mmol) in DCM (30 mL), TFA (23.03 g, 201.93 mmol, 15.00 mL) was added at 0°C, and the mixture was stirred at 6-16°C for 16 hours. LC-MS (ES22810-438-P1A) confirmed that the desired mass was observed. The mixture was concentrated under reduced pressure to obtain methyl(3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (2.8 g, crude product, TFA) as a brown oil.

[1370] MS (ESI) m / z = 292.9 [M+Na]+; 1 HNMR (DMSO-d6) δ = 7.48 (br s, 1H), 7.41-7.21 (m, 5H), 4.27 (q, J =14.8 Hz, 2H), 4.09 (dd, J = 8.0, 4.4 Hz, 1H), 3.65-3.51 (m, 4H), 3.46-3.32 (m,1H).

[0459]

[1371] Step b. Add K2CO3 (2.52 g, 18.21 mmol) to a solution of methyl(3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (1.4 g, 3.64 mmol, TFA) in DMF (15 mL), then add MeI (1.03 g, 7.29 mmol, 453.55 μL), and stir the mixture at 4-12°C for 16 hours. LC-MS results confirmed that the desired mass was observed. TLC (Plate 1, SiO2, petroleum ether:ethyl acetate = 1:1) results showed a new spot (R fA concentration of 0.5 was observed. The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic layer was dried over Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography eluting with 0-28% ethyl acetate in petroleum ether to obtain methyl(3S)-2-benzyl-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (723 mg, 2.54 mmol, yield 69.81%, purity 100%) as a colorless oil.

[1372] MS (ESI) m / z = 306.9 [M+Na]+; 1 HNMR (CDCl3) δ = 7.44-7.28 (m, 5H), 4.48 (s,2H), 3.87 (dd, J = 8.0,5.6 Hz, 1H), 3.67 (s, 3H), 3.55 (dd, J = 10.0, 8.0 Hz, 1H), 3.36 (dd, J = 10.0,5.6 Hz, 1H), 2.78 (s, 3H).

[0460]

[1373] Step c. To a solution of methyl(3S)-2-benzyl-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (723 mg, 2.54 mmol) and 3-methylaniline (544.94 mg, 5.09 mmol, 551.00 μL) in toluene (10 mL), AlMe3 (549.90 mg, 7.63 mmol, 2 M, 3.81 mL) was added, and the mixture was stirred at 100 °C for 16 hours under an N2 atmosphere. LCMS results confirmed that the desired mass was observed. TLC (Plate 1, SiO2, petroleum ether:ethyl acetate = 3:1) results showed a new spot (R fA concentration of 0.2 was observed. The mixture was poured into 1M NaOH (70 mL) and extracted with DCM (10 mL x 3). The combined organic layer was 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 0-30% ethyl acetate in petroleum ether to obtain (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (750 mg, 1.54 mmol, yield 60.72%, purity 74%) as a brown oil.

[1374] MS (ESI) m / z = 360.0 [M+H]+; 1 HNMR (CDCl3) δ = 8.11 (br s, 1H), 7.46-7.29 (m, 5H), 7.19-7.13 (m,1H), 7.11-7.05 (m, 2H), 6.93 (d, J = 7.2 Hz, 1H), 4.73 (d, J = 14.4 Hz, 1H),4.11 (d, J = 14.4 Hz, 1H), 3.94 (dd, J = 8.8, 5.2 Hz, 1H), 3.76 (dd, J = 10.0,8.8 Hz, 1H), 3.33 (dd, J = 10.0, 10.0 Hz, 1H), 2.80 (s, 3H), 2.31 (s, 3H).

[0461]

[1375] Step d. To a solution of (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (310 mg, 862.45 μmol) and Cs2CO3 (843.01 mg, 2.59 mmol) in DMF (6 mL), triduterio(iodo)methane (375.05 mg, 2.59 mmol, 161.04 μL) was added, followed by the addition of TBAI (31.86 mg, 86.24 μmol), and the mixture was stirred at 80°C for 3 hours. LC-MS results confirmed that the desired mass was observed. TLC (Plate 1, SiO2, petroleum ether:ethyl acetate = 3:1) results showed a new spot (R fA value of 0.15 was observed. The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 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 0-35% ethyl acetate in petroleum ether to obtain (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (320 mg, 832.96 μmol, yield 96.58%, purity 98%) as a yellow gum.

[1376] MS (ESI) m / z = 377.0 [M+H]+; 1 HNMR (CDCl3) δ = 7.42-7.33 (m, 5H), 7.18-7.12 (m, 1H), 7.11-7.06 (m,1H), 6.61-6.14 (m, 2H), 4.52-4.26 (m, 2H), 3.84 (t, J = 7.2 Hz, 1H), 3.13 (d, J= 7.6 Hz, 2H), 2.73 (s, 3H), 2.24 (s, 3H).

[0462]

[1377] Step e. To a solution of (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (320 mg, 849.96 μmol) in THF (10 mL), Pd / C (1 g, 10% purity) was added, and the mixture was then packed with Ar three times and H2 three times. The mixture was stirred at 30 Psi under an H2 atmosphere at 25°C for 16 hours. LCMS confirmed that the desired mass was observed. The mixture was filtered through a Celite pad. The filter cake was washed with ethyl acetate (10 mL x 3), and the filtrate was concentrated under reduced pressure to obtain (3S)-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (179 mg, 577.57 μmol, yield 67.95%, purity 92.4%) as a white gum.

[1378] MS (ESI) m / z = 286.9 [M+H]+; 1 HNMR (CDCl3) δ = 7.37 (br t, J = 7.6 Hz, 1H), 7.27 (s, 1H), 7.07-6.95(m, 2H), 5.45 (br d, J = 7.2 Hz, 1H), 4.32-4.17 (m, 1H), 3.30 (br dd, J = 9.2,5.6 Hz, 1H), 2.98-2.84 (m, 1H), 2.65 (s, 3H), 2.41 (s, 3H).

[0463]

[1379] Step f. To a solution of (3S)-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (150 mg, 523.81 μmol) and Cs2CO3 (512.00 mg, 1.57 mmol) in dioxane (10 mL), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (188.59 mg, 785.71 μmol) was added, followed by the addition of CuI (125.70 mg, 660.00 μmol) and N1,N2-dimethylethane-1,2-diamine (58.18 mg, 660.00 μmol, 71.04 μL). The mixture was then stirred at 80°C for 16 hours under an N2 atmosphere. LCMS confirmed that the desired mass was observed. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by reverse-phase flushing (0-60% MeCN in water (0.1% TFA)) and dried by freeze-drying to obtain (3S)-5-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-N-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (169.54 mg, 303.02 μmol, yield 57.85%, purity 100%, TFA) as a white solid.

[1380] MS (ESI) m / z = 445.9 [M+H]+; 1HNMR (MeOD-d4) δ = 7.47-7.41 (m, 1H), 7.39 (s, 1H), 7.37-7.28 (m,3H), 7.16 (s, 1H), 4.85 (dd, J = 7.6, 5.2 Hz, 1H), 3.63-3.49 (m, 2H), 2.75 (s,3H), 2.59 (s, 3H), 2.38 (s, 3H).

[0464]

[1381]

[1382] Example 39

[1383] (S)-N-isopropyl-5-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1384] [ka]

[0465]

[1385] Example 39 was carried out using the same method as the synthesis method of Example 38, but in step d, 2-iodopropane was used instead of triduterio(iodo)methane to obtain the target compound (1.93 mg, 4.09 μmol, yield 1.75%, purity 99.63%) as a white solid.

[1386] MS (ESI) m / z = 471.2 [M+H] + ; 1HNMR (MeOD-d4) δ = 7.50-7.40 (m, 2H), 7.40-7.32 (m, 2H), 7.24-7.13(m, 2H), 4.86-4.78 (m, 1H), 4.75-4.69 (m, 1H), 3.54-3.44 (m, 1H), 3.43-3.37 (m,1H), 2.80 (d, J = 4.8 Hz, 3H), 2.65 (d, J = 12.8 Hz, 3H), 2.45 (s, 3H), 1.15(d, J = 6.4 Hz, 3H), 1.08 (dd, J = 6.8, 2.4Hz, 3H).

[0466]

[1387]

[1388] Example 40 (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-5-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide [ka]

[0467]

[1389] Step a. To a solution of intermediate 3 (1 g, 2.70 mmol) in DCM (15 mL), TFA (7.68 g, 67.31 mmol, 5 mL) was added at 0°C, and the mixture was stirred at 5-11°C for 16 hours. LCMS confirmed that the desired mass was observed. The mixture was concentrated under reduced pressure to obtain methyl(3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (1.04 g, crude product, TFA) as a pale yellow oil.

[1390] MS (ESI) m / z = 292.9 [M+Na] + ; 1HNMR (DMSO-d6) δ = 8.87 (s, 1H), 7.38-7.28 (m, 5H), 4.27 (q, J = 14.8Hz, 2H), 4.09 (dd, J = 8.0, 4.0 Hz, 1H), 3.62-3.55 (m, 1H), 3.54 (s, 3H),3.42-3.35 (m, 1H).

[0468]

[1391] Step b. To a solution of methyl(3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (700 mg, 1.82 mmol, TFA) in DMF (5 mL), K2CO3 (755.19 mg, 5.46 mmol) was added, followed by the addition of triduterio(iodo)methane (528.04 mg, 3.64 mmol, 226.72 μL). The mixture was then stirred at 10-17°C for 16 hours. LC-MS confirmed that the desired mass was observed. TLC (Plate 1, SiO2, petroleum ether:ethyl acetate = 3:1) revealed a new spot (R f A concentration of 0.1 was observed. The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 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 0-10% ethyl acetate in petroleum ether to obtain methyl(3S)-2-benzyl-1,1-dioxo-5-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxylate (306 mg, 1.06 mmol, yield 58.47%, purity 100%) as a white gum.

[1392] MS (ESI) m / z = 309.9 [M+Na] + ; 1 HNMR (CDCl3) δ = 7.42-7.30 (m, 5H), 4.50-4.46 (m, 2H), 3.87 (dd, J =7.6, 5.6 Hz, 1H), 3.67 (s, 3H), 3.55 (dd, J = 10.0, 8.0 Hz, 1H), 3.39-3.31 (m,1H).

[0469]

[1393] Step c. AlMe3 (2M, 469.81μL) was added to a solution of methyl(3S)-2-benzyl-1,1-dioxo-5-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxylate (90 mg, 313.21 μmol) and N,3-dimethylaniline (75.91 mg, 626.42 μmol, 78.26 μL) in toluene (4.5 mL), and the mixture was stirred at 100°C for 16 hours. LCMS confirmed that the desired mass was observed. The mixture was poured into 1 M NaOH (50 mL), extracted with ethyl acetate (10 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 0-46% ethyl acetate in petroleum ether to obtain (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (80 mg, 169.99 μmol, yield 27.14%, purity 80%) as a yellow gum.

[1394] MS (ESI) m / z = 377.0 [M+H] + ; 1 HNMR (CDCl3) δ = 7.45-7.33 (m, 5H), 7.18-7.11 (m, 1H), 7.11-7.07 (m,1H), 6.59-6.09 (m, 2H), 4.49-4.29 (m, 2H), 3.84 (t, J = 7.2 Hz, 1H), 3.19-3.08(m, 5H), 2.24 (s, 3H).

[0470]

[1395] Step d. Pd / C (360 mg, 10% purity) was added to a solution of (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (120 mg, 318.74 μmol) in THF (2 mL), and the mixture was then packed with Ar three times and H2 three times. The mixture was stirred at 30 Psi under an H2 atmosphere at 25°C for 16 hours. LCMS confirmed that the desired mass was observed. The mixture was filtered through a Celite pad. The filter cake was washed with ethyl acetate (10 mL x 3), and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to obtain (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (30 mg, 104.76 μmol, yield 32.87%, purity 100%) as a colorless gum.

[1396] MS (ESI) m / z = 286.9 [M+H] + ; 1 HNMR (CDCl3) δ = 7.36 (t, J = 8.0 Hz, 1H), 7.28-7.25 (s, 1H),7.02-6.95 (m, 2H), 5.43 (br d, J = 8.0 Hz, 1H), 4.25-4.18 (m, 1H), 3.33 (s,3H), 3.30 (dd, J = 9.6, 6.0 Hz, 1H), 2.90 (dd, J = 9.2, 8.4 Hz, 1H), 2.41 (s,3H).

[0471]

[1397] Step e. A solution of (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (30 mg, 104.76 μmol) and Cs2CO3 (102.40 mg, 314.28 μmol) in dioxane (1 mL) was mixed with 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (37.72 mg, 157.14 μmol). Then, N1,N2-dimethylethane-1,2-diamine (11.64 mg, 132.00 μmol, 14.21 μL) and CuI (25.14 mg, 132.00 μmol) were added, and the mixture was stirred at 80°C for 16 hours under an N2 atmosphere. LCMS confirmed that the desired mass was observed. The mixture was filtered through a Celite pad. The filter cake was washed with ethyl acetate (10 mL x 3), and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase flush (0-48% MeCN in water (neutral)) and dried by freeze-drying to obtain (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-5-(triduteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (26.97 mg, 60.54 μmol, yield 57.79%, purity 100%) as a purple solid.

[1398] MS (ESI) m / z = 446.3 [M+H] + ; 1 HNMR (MeOD-d4) δ = 7.47-7.41 (m, 1H), 7.39 (s, 1H), 7.37-7.28 (m,3H), 7.16 (s, 1H), 4.85 (dd, J = 7.6, 5.2 Hz, 1H), 3.63-3.49 (m, 2H), 2.75 (s,3H), 2.59 (s, 3H), 2.38 (s, 3H).

[0472]

[1399]

[1400] Example 41

[1401] (S)-5-isopropyl-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1402] [ka]

[0473]

[1403] Example 41 was carried out using the same method as the synthesis method of Example 38, but in step b, 2-iodopropane was used instead of MeI, and in step d, iodomethane was used instead of triduterio(iodo)methane to obtain the target compound (27.04 mg, 53.96 μmol, yield 17.88%, purity 93.9%) as a white solid.

[1404] MS (ESI) m / z = 470.9 [M+H] + ; 1 HNMR (MeOD-d4) δ = 7.49-7.40 (m, 2H), 7.37 (br d, J = 7.6 Hz, 1H),7.34-7.29 (m, 2H), 7.21 (s, 1H), 4.98-4.92 (m, 1H), 3.81-3.72 (m, 1H), 3.48(dd, J = 6.8, 2.0 Hz, 2H), 3.28 (s, 3H), 2.63 (s, 3H), 2.44 (s, 3H), 1.29 (d, J= 6.8 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H).

[0474]

[1405]

[1406] Example 42 (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide [ka]

[0475]

[1407] Step a. After adding AlMe3 (2M, 2.02mL) to a solution of intermediate 3 (1g, 2.70 mmol) in toluene (10mL), the mixture was stirred at 100°C for 16 hours under an N2 atmosphere. LCMS confirmed that the desired mass was observed. TLC (Plate 1, SiO2, petroleum ether:ethyl acetate = 3:1) revealed a new spot (R f A concentration of 0.1 was observed. The mixture was poured into 1 M NaOH (50 mL), extracted with ethyl acetate (10 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 0-60% ethyl acetate in petroleum ether to obtain (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (300 mg, 784.55 μmol, yield 58.12%, purity 94%) as a yellow solid.

[1408] MS (ESI) m / z = 359.9 [M+H] + ; 1 HNMR (CDCl3) δ = 7.40-7.34 (m, 3H), 7.33-7.29 (m, 2H), 7.18-7.12 (m,1H), 7.12-7.07 (m, 1H), 6.61-6.09 (m, 2H), 5.37 (dd, J = 10.8, 7.2 Hz, 0.4H),5.20 (dd, J =10.4, 7.6 Hz, 0.6H), 4.35-4.15 (m, 2H), 3.86-3.75 (m, 1H),3.53-3.42 (m, 1H), 3.41-3.31 (m, 1H), 3.12 (s, 3H), 2.25 (s, 3H).

[0476]

[1409] Step b. To a solution of (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (270 mg, 751.16 μmol) in THF (10 mL), NaH (60.09 mg, 1.50 mmol, 60% purity) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Subsequently, SEM-Cl (250.47 mg, 1.50 mmol, 265.89 μL) was added, and the mixture was stirred at 7-11°C for 2 hours. LCMS results confirmed that the desired mass was observed. TLC (Plate 1, SiO2, petroleum ether:ethyl acetate = 1:1) results showed a new spot (R f A value of 0.8 was observed. The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 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 0-35% ethyl acetate in petroleum ether to obtain (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(2-trimethylsilylethoxymethyl)-1,2,5-thiadiazolidine-3-carboxamide (250 mg, 495.20 μmol, yield 65.92%, purity 97%) as a yellow gum.

[1410] MS (ESI) m / z = 512.1 [M+Na] + ; 1 HNMR (CDCl3) δ = 7.45-7.31 (m, 5H), 7.20-7.13 (m, 1H), 7.12-7.07 (m,1H), 6.63-6.14 (m, 2H), 4.74-4.50 (m, 2H), 4.41-4.26 (m, 2H), 3.83 (t, J = 7.2Hz, 1H), 3.70-3.52 (m, 2H), 3.43 (dd, J = 10.4, 6.4 Hz, 1H), 3.31 (dd, J =10.0, 8.0 Hz, 1H), 3.11 (s, 3H), 2.26 (s, 3H), 0.86 (t, J = 8.4 Hz, 2H), 0.01 (s, 9H).

[0477]

[1411] Step c. To a solution of (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(2-trimethylsilylethoxymethyl)-1,2,5-thiadiazolidine-3-carboxamide (250 mg, 510.52 μmol) in THF (7 mL), wet Pd / C (750 mg, 10% purity) was added. The mixture was then packed with Ar three times and H2 three times, and the mixture was stirred at 15 Psi under an H2 atmosphere at 25°C for 16 hours. LCMS confirmed that the desired mass was observed. The mixture was filtered through a Celite pad. The filter cake was washed with ethyl acetate (10 mL x 3), and the filtrate was concentrated under reduced pressure to obtain (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(2-trimethylsilylethoxymethyl)-1,2,5-thiadiazolidine-3-carboxamide (199 mg, 468.14 μmol, yield 91.70%, purity 94%) as a colorless gum.

[1412] MS (ESI) m / z = 422.0 [M+Na] + ; 1 HNMR (CDCl3) δ = 7.40-7.34 (m, 1H), 7.27-7.23 (m, 1H), 7.04-6.96 (m,2H), 5.34 (d, J = 8.8 Hz, 1H), 4.50 (s, 2H), 4.25 (q, J = 8.0 Hz, 1H), 3.56(dd, J = 8.8, 7.2 Hz, 2H), 3.44 (dd, J = 9.6, 7.2 Hz, 1H), 3.32 (s, 3H), 3.16(dd, J = 10.0, 8.4 Hz, 1H), 2.41 (s, 3H), 0.91-0.82 (m, 2H), 0.01 (s, 9H).

[0478]

[1413] Step d. To a solution of (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(2-trimethylsilylethoxymethyl)-1,2,5-thiadiazolidine-3-carboxamide (180 mg, 450.47 μmol) and Cs2CO3 (440.32 mg, 1.35 mmol) in dioxane (5 mL), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (162.18 mg, 675.71 μmol) was added. Then, N1,N2-dimethylethane-1,2-diamine (50.03 mg, 567.60 μmol, 61.09 μL) and CuI (108.10 mg, 567.60 μmol) were added, and the mixture was stirred at 80°C for 16 hours under an N2 atmosphere. LCMS confirmed that the desired mass was observed. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting 0-30% ethyl acetate in petroleum ether to obtain (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-5-(2-trimethylsilylethoxymethyl)-1,2,5-thiadiazolidine-3-carboxamide (127 mg, 220.50 μmol, yield 48.95%, purity 97%) as a yellow gum.

[1414] MS (ESI) m / z = 581.1 [M+Na] + ; 1 HNMR (CDCl3) δ = 7.46 (s, 1H), 7.41-7.34 (m, 1H), 7.26-7.22 (m, 2H),7.20 (br s, 1H), 7.03 (s, 1H), 5.09 (dd, J = 7.6, 5.6 Hz, 1H), 4.86-4.60 (m,2H), 3.70-3.51 (m, 4H), 3.30 (s, 3H), 2.59 (s, 3H), 2.43 (s, 3H), 0.94-0.75 (m,2H), -0.01 (s, 9H).

[0479]

[1415] Step e. To a solution of (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-5-(2-trimethylsilylethoxymethyl)-1,2,5-thiadiazolidine-3-carboxamide (100 mg, 178.99 μmol) and TMEDA (208.00 mg, 1.79 mmol, 270.13 μL) in THF (2 mL), TBAF (1 M, 357.98 μL) was added, and the mixture was stirred at 70°C for 3 hours. LC-MS confirmed that the starting material remained. Next, TBAF (0.4 mL) was added, and the mixture was stirred for a further 3 hours. LC-MS confirmed that the starting material remained. Next, TBAF (0.4 mL) was added, and the mixture was stirred for a further 3 hours. LC-MS confirmed that the desired mass was observed. TLC (Plate 1, SiO2, petroleum ether:ethyl acetate = 1:1) results showed a new spot (R f A concentration of 0.55 was observed. The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic layer was dried over Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography eluting 0-45% ethyl acetate in petroleum ether to obtain the crude product (purity 57.2%). The mixture was purified by Prep-TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain the crude product (purity 87.1%). The reaction mixture was purified by reverse-phase flushing (0-58% MeCN in water (0.1% TFA)) and dried by lyophilization to obtain (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (9.85 mg, 22.80 μmol, yield 12.74%, purity 99.156%, TFA) as a yellow solid.

[1416] MS (ESI) m / z = 429.2 [M+H] + ; 1HNMR (MeOD-d4) δ = 7.47-7.41 (m, 1H), 7.39 (br s, 1H), 7.37-7.26 (m,3H), 7.15 (s, 1H), 5.02 (dd, J = 7.2, 4.8 Hz, 1H), 3.64-3.54 (m, 1H), 3.54-3.45(m, 1H), 3.29 (s, 3H), 2.61 (s, 3H), 2.43 (s, 3H).

[0480]

[1417]

[1418] Example 43

[1419] (S)-2-(2,6-bis(trifluoromethyl)pyrimidine-4-yl)-N-methyl-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1420] [ka]

[0481]

[1421] Example 43 was carried out using the same method as the synthesis method of Example 42, but in step d, 4-chloro-2,6-bis-(trifluoromethyl)pyrimidine was used instead of 2-bromo-6-methyl-4-(trifluoromethyl)pyridine to obtain the target compound (78.21 mg, 179.44 μmol, yield 40.17%, purity 98.52%) as a white solid.

[1422] MS (ESI) m / z = 430.1 [M+H] + ; 1HNMR (DMSO-d6) δ = 7.48-7.40 (m, 1H), 7.37 (s, 1H), 7.33 (br d, J =8.0 Hz, 1H), 7.27 (br d, J = 7.6 Hz, 1H), 7.19 (s, 1H), 4.83 (t, J = 6.0 Hz,1H), 3.57-3.52 (m, 2H), 3.20 (s, 3H), 2.66 (s, 3H), 2.38 (s, 3H).

[0482]

[1423]

[1424] biological analysis

[1425] Expression and purification of the polθ polymerase domain

[1426] 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.

[0483]

[1427] 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.

[0484]

[1428]

[1429]

[1430] Polθ polymerase activity analysis

[1431] 1) Manufacturing of DNA complexes

[1432] The DNA complex was prepared using a slightly modified version of a previously reported protocol (Zatreanu et al., 2021, Nature Communications, 12:3636). Briefly, 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') were mixed in annealing buffer (20mM Tris-Cl, pH 7.5, 50mM NaCl) to prepare polθ substrates with final concentrations of 22μM and 20μM, 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 as 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.

[0485]

[1433]

[1434] 2) Picogreen analysis

[1435] 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.

[0486]

[1436] 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.

[0487]

[1437] 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.

[0488]

[1438] The compounds from Examples 1 to 43 were tested using the analytical method described above, and the results are shown in the table below.

[0489]

[1439] [Table 3] TIFF2026513172000128.tif81149 Reference: 1nM < *** < 100nM; 101nM < ** < 500nM; and * > 501nM

[0490]

[1441] As can be seen in the table above, the tested compounds showed good activity in inhibiting Polθ polymerase.

[0491]

[1442]

[1443] 3) Cell viability analysis

[1444] 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%). 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 IC25 was determined for the selected compound of the present invention. 50 The prices are shown in the table below.

[0492]

[1445] [Table 4] Reference: ***<10μM; 11μM<**<50μM; and *>51μM

[0493]

[1446]

[1447] 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.

[0494]

[1448]

[1449] The present invention provides the following examples:

[0495]

[1450] Example 1: A compound of chemical formula I or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[1451] [ka]

[1452] In the aforementioned chemical formula I,

[1453] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[1454] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[1455] X is methylene, -NH- and -NR z -Selected from the group consisting of, where the methylene may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[1456] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[1457] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently a C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, halogen, 3-10 member cycloalkyl, -NR x R y They are selectively 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;

[1458] R x and R y Each of these is independently selected from 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;

[1459] R Z 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, hydroxy, amino, mercapto, and carbamoyl groups; and

[1460] R wThe elements 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.

[0496]

[1461]

[1462]

[1463] Example 2. The compound is the compound of chemical formula II, as described in Example 1.

[1464] [ka]

[1465] In the aforementioned chemical formula II,

[1466] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[1467] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[1468] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[1469] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently a C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y They are selectively 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;

[1470] R x and R y Each of these is independently selected from 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

[1471] R w The elements 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.

[0497]

[1472]

[1473] Example 3. The compound is a compound of chemical formula III, as described in Example 1 or 2.

[1474] [ka]

[1475] In the aforementioned chemical formula III,

[1476] R 1 , R2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[1477] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[1478] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[1479] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently a C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y They are selectively 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;

[1480] R x and R y Each of these is independently selected from 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

[1481] R w The elements 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.

[0498]

[1482]

[1483] Example 4. The compound is a compound of chemical formula IV, as described in any one of Examples 1 to 3.

[1484] [ka]

[1485] In the aforementioned chemical formula IV,

[1486] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[1487] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[1488] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[1489] A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently a C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 member cycloalkyl, -NR x R y They are selectively 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;

[1490] R x and R y Each of these is independently selected from 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;

[1491] R Z 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, hydroxy, amino, mercapto, and carbamoyl groups; and

[1492] R w The elements 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.

[0499]

[1493]

[1494] Example 5. The compound is a compound of chemical formula IIa, as described in any one of Examples 1 to 4.

[1495] [ka]

[1496] In the aforementioned chemical formula IIa,

[1497] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[1498] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[1499] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[1500] R a1 , R a2 , R a3 , R a4 and R a5 Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and R yEach of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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;

[1501] R x and R y Each of these is independently selected from 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

[1502] R w The elements 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.

[0500]

[1503]

[1504] Example 6. The compound is a compound of chemical formula IIb, as described in any one of Examples 1 to 5.

[1505] [ka]

[1506] In the aforementioned chemical formula IIb,

[1507] R 1 , R 2 and R 3Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[1508] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[1509] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[1510] R b1 , R b2 , R b3 and R b4 Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and R y Each of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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;

[1511] R x and R yEach of these is independently selected from 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

[1512] R w The elements 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.

[0501]

[1513]

[1514] Example 7. The compound is a compound of chemical formula IIc, as described in any one of Examples 1 to 6.

[1515] [ka]

[1516] In the aforementioned chemical formula IIc,

[1517] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[1518] R 4is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[1519] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[1520] R c1 , R c2 , R c3 , R c4 , R c5 , R c6 and R c7 Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and R y Each of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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;

[1521] R x and R y Each of these is independently selected from 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

[1522] R w The elements 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.

[0502]

[1523]

[1524] Example 8. The compound is a compound of chemical formula IId, as described in any one of Examples 1 to 7.

[1525] [ka]

[1526] In the aforementioned chemical formula IId,

[1527] R 1 , R 2 and R 3 Each of these is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, 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;

[1528] R 4 is hydrogen or a C1-C6 alkyl group, where the alkyl group may be substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano groups, deuterium groups, hydroxyl groups, and mercapto groups;

[1529] Y and Z are -N- and -CR respectively. w -Independently selected from the group consisting of;

[1530] R d1 , R d2 , R d3 , R d4 , R d5 and R d6Each of these is independently hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxy, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR x R y (Here, R x and R y Each of the following is independently selected from hydrogen and C1-C6 alkyl, and the alkyl may be substituted with one or more selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl); and 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;

[1531] R x and R y Each of these is independently selected from 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

[1532] R w The elements 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.

[0503]

[1533]

[1534] Example 9.R 3 The compound is hydrogen, as described in one of the examples 1 to 8.

[0504]

[1535]

[1536] Example 10.R 4The compound according to any one of Examples 1 to 9, wherein is hydrogen or a C1-C4 alkyl group, where the alkyl group is selectively substituted with one or more selected from C1-C6 alkyl groups and deuterium.

[0505]

[1537]

[1538] Example 11: A compound described in any one of Examples 1 to 10, wherein Y is selected from the group consisting of CH and C(CN); and Z is selected from the group consisting of N and CH.

[0506]

[1539]

[1540] Example 12.R 1 and R 2 Each of the compounds described in any one of Examples 1 to 11 is independently a C1-C6 alkyl group, where the alkyl group is selectively substituted with one or more selected from C1-C6 alkyl groups, halogens, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups.

[0507]

[1541]

[1542] Implemented Example 13. The compound is selected from the group consisting of the following, and is the compound described in any one of Implemented Examples 1 to 12. [ka]

[1543] [ka] [ka]

[0508]

[1544] [ka] [ka] [ka]

[0509]

[1545]

[1546] 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 its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates; and a pharmaceutically acceptable carrier or excipient.

[0510]

[1547]

[1548] Example 15. The composition is an anticancer agent that targets the 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 berzosertib), AZD6738 (e.g., ceralasertib)), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (e.g., 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)) The pharmaceutical composition described in Example 14, administered separately, sequentially, or simultaneously with 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[0511]

[1549]

[1550] Example 16. A compound described in any one of Examples 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotopic variant, 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.

[0512]

[1551]

[1552] Example 17. The compound is an anticancer agent that targets the 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 berzosertib), AZD6738 (e.g., ceralasertib)), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (e.g., 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)) The compound described in Example 16, administered separately, sequentially, or simultaneously with 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[0513]

[1553]

[1554] Example 18. A method for treating or preventing a polymerase θ-mediated disease or disorder in a subject, comprising administering to the subject at least one compound described in any one of Examples 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotopic variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0514]

[1555]

[1556] 19. The method according to 18, wherein the disease or disorder mediated by polymerase θ is cancer, preferably breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, or lung cancer.

[0515]

[1557]

[1558] Example 20. The target organism may be further subjected to additional anticancer agents targeting 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 berzosertib), AZD6738 (e.g., ceralasertib)), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK inhibitors (e.g., CC-115, M3814 (e.g., 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)) The method according to Implement Example 18 or 19, further comprising administering 6727), Onvansertib (e.g., PCM-075, NMS-1286937), an APE1 inhibitor (e.g., methoxyamine), or a topoisomerase inhibitor (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

Claims

1. The compound of the following chemical formula (I), or its tautomers, stereoisomers, prodrugs, crystalline forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates. 【Chemistry 1】 In the aforementioned chemical formula (I), R １ 、 R ２ and R ３ each 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 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; R ４ is hydrogen or 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 elements selected from alkyl, halogen, cyano, deuterium, hydroxy, and mercapto; X is methylene, -NH- and -NR ｚ - Selected from the group consisting of, where the methylene is C １ -C ６ It may be substituted with one or more elements 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; A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl 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 It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ A alkyl group is independently selected, where the alkyl group is C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R Ｚ 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; 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 and R ３ 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 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 It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ４ is hydrogen or 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 elements selected from alkyl, halogen, cyano, deuterium, hydroxy, and mercapto; Y and Z are -N- and -CR respectively ｗ - Independently selected from the group consisting of; A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, 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 It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ A alkyl group is independently selected, where the alkyl group is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; and R ｗ is selected from the group consisting of hydrogen, C １ -C ６ -alkyl, halogen, cyano, deuterium, C ２ -C ６ -alkenyl, C １ -C ６ -alkoxy, 3- to 10-membered cycloalkyl, -NR ｘ R ｙ , hydroxy, amino, mercapto and carbamoyl.

3. The compound according to claim 1, wherein the compound is a compound of the following chemical formula (III). 【Transformation 3】 In the aforementioned chemical formula (III), R １ 、 R ２ and R ３ each 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 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; R ４ is hydrogen or 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 elements selected from alkyl, halogen, cyano, deuterium, hydroxy, and mercapto; Y and Z are -N- and -CR respectively ｗ - Independently selected from the group consisting of; A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, 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 It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ A alkyl group is independently selected, where the alkyl group is C １ -C ６ It 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.

4. The compound according to claim 1, wherein the compound is a compound of the following chemical formula (IV). 【Chemistry 4】 In the aforementioned chemical formula (IV), R １ , R ２ and R ３ 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 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 It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ４ is hydrogen or 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 elements selected from alkyl, halogen, cyano, deuterium, hydroxy, and mercapto; Y and Z are -N- and -CR respectively ｗ - Independently selected from the group consisting of; A is a 5-12 member monocyclic or bicyclic aryl or heteroaryl, where each of the aryl and heteroaryl is independently C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, 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 It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ A alkyl group is independently selected, where the alkyl group is C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R Ｚ 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; 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.

5. The compound according to claim 1 or 2, wherein the compound is a compound of the following chemical formula (IIa). 【Transformation 5】 In the above chemical formula (IIa), R １ , R ２ and R ３ 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 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 It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ４ is hydrogen or 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 elements selected from alkyl, halogen, cyano, deuterium, hydroxy, and mercapto; Y and Z are -N- and -CR respectively ｗ - Independently selected from the group consisting of; R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ Each of them independently contains hydrogen and C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, 3-10 membered cycloalkyl and -NR ｘ R ｙ (Here, R ｘ and R ｙ Each of them independently contains hydrogen and C １ -C ６ Selected from alkyl groups, the alkyl group is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.) Selected from the group consisting of alkyl, alkenyl, alkoxy, and cycloalkyl, each of the alkyl, alkenyl, alkoxy, and cycloalkyl is independently C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ A alkyl group is independently selected, where the alkyl group is C １ -C ６ It 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.

6. The compound according to claim 1 or 2, wherein the compound is a compound of the following chemical formula (IIb). 【Transformation 6】 In the above chemical formula (IIb), R １ , R ２ and R ３ 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 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 It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ４ is hydrogen or 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 elements selected from alkyl, halogen, cyano, deuterium, hydroxy, and mercapto; Y and Z are -N- and -CR respectively ｗ - Independently selected from the group consisting of; R ｂ１ , R ｂ２ , R ｂ３ and R ｂ４ Each of them independently contains hydrogen and C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, 3-10 membered cycloalkyl and -NR ｘ R ｙ (Here, R ｘ and R ｙ Each of them independently contains hydrogen and C １ -C ６ Selected from alkyl groups, the alkyl group is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.) Selected from the group consisting of alkyl, alkenyl, alkoxy, and cycloalkyl, each of the alkyl, alkenyl, alkoxy, and cycloalkyl is independently C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ A alkyl group is independently selected, where the alkyl group is C １ -C ６ It 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.

7. The compound according to claim 1 or 2, wherein the compound is a compound of the following chemical formula (IIc). 【Transformation 7】 In the above chemical formula (IIc), R １ , R ２ and R ３ 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 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 It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ４ is hydrogen or 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 elements selected from alkyl, halogen, cyano, deuterium, hydroxy, and mercapto; Y and Z are -N- and -CR respectively ｗ - Independently selected from the group consisting of; R ｃ１ , R ｃ２ , R ｃ３ , R ｃ４ , R ｃ５ , R ｃ６ and R ｃ７ Each of them independently contains hydrogen and C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, 3-10 membered cycloalkyl and -NR ｘ R ｙ (Here, R ｘ and R ｙ Each of them independently contains hydrogen and C １ -C ６ Selected from alkyl groups, the alkyl group is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.) Selected from the group consisting of alkyl, alkenyl, alkoxy, and cycloalkyl, each of the alkyl, alkenyl, alkoxy, and cycloalkyl is independently C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ A alkyl group is independently selected, where the alkyl group is C １ -C ６ It 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.

8. The compound according to claim 1 or 2, wherein the compound is a compound of the following chemical formula (IId). 【Transformation 8】 In the above chemical formula (IId), R １ , R ２ and R ３ 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 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 It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ４ is hydrogen or 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 elements selected from alkyl, halogen, cyano, deuterium, hydroxy, and mercapto; Y and Z are -N- and -CR respectively ｗ - Independently selected from the group consisting of; R ｄ１ , R ｄ２ , R ｄ３ , R ｄ４ , R ｄ５ and R ｄ６ These are hydrogen and C １ -C ６ Alkyl, halogen, cyano, deuterium, C ２ -C ６ Alkenyl, hydroxy, C １ -C ６ Alkoxy, 3-10 membered cycloalkyl and -NR ｘ R ｙ (Here, R ｘ and R ｙ Each of them independently contains hydrogen and C １ -C ６ Selected from alkyl groups, the alkyl group is C １ -C ６ It may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.) Selected from the group consisting of alkyl, alkenyl, alkoxy, and cycloalkyl, each of the alkyl, alkenyl, alkoxy, and cycloalkyl is independently C １ -C ６ It may be substituted with one or more elements selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; R ｘ and R ｙ Each of them is hydrogen and C １ -C ６ A alkyl group is independently selected, where the alkyl group is C １ -C ６ It 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.

9. R ３ The compound according to any one of claims 1 to 8, wherein is hydrogen.

10. R ４ is hydrogen or C １ -C ４ It is an alkyl group, where the alkyl group is C １ -C ６ The compound according to any one of claims 1 to 9, which may be substituted with one or more elements selected from alkyl and deuterium.

11. The compound according to any one of claims 1 to 10, wherein Y is selected from the group consisting of CH and C(CN); and Z is selected from the group consisting of N and CH.

12. R １ and R ２ Each of them independently C １ -C ６ It is an alkyl group, where the alkyl group is C １ -C ６ The compound according to any one of claims 1 to 11, which may be substituted with one or more selected from alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

13. The compound according to any one of claims 1 to 12, wherein the compound is selected from the group consisting of the following. 【Chemistry 9】 【change】 【change】 【change】

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, isotopic variant, pharmaceutically acceptable salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier or excipient.

15. The composition is an anticancer agent that targets the 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 (e.g., Nesocertib or Pepocertib), 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, isotopic variant, 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 targeting the DNA damage response (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 administering to the subject at least one compound described in any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystalline form, isotopic variant, pharmaceutically acceptable salt, hydrate or solvate thereof.

19. The method according to claim 18, wherein the disease or disorder mediated by the 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 (e.g., MK-1775 or AZD1775)), PLK1 inhibitors (e.g., volasertib (BI The method according to claim 18 or 19, further comprising 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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