Substituted sultam compound derivative and pharmaceutical application thereof

Abstract

The invention provides a novel sultam compound derivative, a composition containing the compound as well as a preparation method and application of the novel sultam compound derivative. The sultam compound derivative is a compound of a chemical formula I, or a tautomer, a stereoisomer, a prodrug, a crystal form, an isotope variant, a pharmaceutically acceptable salt, a hydrate or a solvate thereof. The compounds and compositions of the invention are useful for the treatment of diseases or disorders mediated by pol theta. [Formula I]

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a sultam derivative that inhibits polymerase theta, a pharmaceutical composition containing the derivative, and its preparation method and uses. Background Technology

[0002] DNA double-strand breaks (DSBs) are harmful to cells because they lead to genomic instability and cell death. There are three pathways for DSB repair in cells: non-homologous end-joining (NHEJ), homologous recombination (HR), and theta-mediated end-joining (TMEJ). The NHEJ pathway allows the broken DNA strands to join together without a homologous template. The HR and TMEJ pathways share the characteristic of using homologous sequences. However, HR is a high-fidelity DNA repair pathway, while TMEJ is an error-prone DNA repair pathway that utilizes microhomology.

[0003] The TMEJ pathway includes poly-(ADP-ribose)polymerase PARP1, DNA ligase III, and polymerase theta. Polymerase theta (Polθ, encoded by the POLQ gene) is a 290 kDa A-family polymerase that mediates the TMEJ pathway (Feng et al., 2019, Nature Communication, 10:4286). Polθ possesses an N-terminal helicase-like domain and a C-terminal DNA polymerase domain, separated by a non-structured central amino acid sequence. In the TMEJ pathway, the helicase domain of Polθ replaces the replication protein A (RPA) that binds to the overhangs of single-stranded DNA and promotes the annealing of micro-homologous sequences flanking the DSB. The polymerase domain of Polθ then initiates DNA synthesis to fill the gap (Zatreanu et al., 2021, Nature Communications, 12:3636).

[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 Communication, 12:3636). When the NHEJ or HR pathway is impaired, TMEJ is an essential backup pathway (Higgins, GS et al., 2018. Science, 359(6381), 1217-1218). Therefore, DNA repair-deficient cancers rely on other compensatory repair pathways, while HR or NHEJ-deficient cancers rely on the TMEJ backup pathway. Based on this mechanism, PARP inhibitors (PARPi) have been developed, and PARPi has been successfully used to treat HR-deficient tumors. However, PARPi often faces the problem of drug resistance (Drzewiecka et al., 2022, Genes, 13:1101; and Higgins, GS et al., 2018. Science, 359(6381), 1217-1218).

[0005] Currently, polθ is a promising new target for cancer treatment. Polθ is overexpressed in a variety of cancers, but is almost not expressed (mostly 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 lung cancer, gastric cancer, small bowel cancer, rectal cancer, and colon cancer, especially in lung cancer, breast cancer, ovarian cancer, colon 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 experiments have shown that HR-deficient tumors exhibit high sensitivity to Polθ-mediated DNA repair inhibition, inducing synthetic lethality (Ceccaldi et al., 2015, Nature, 518:258; and Drzewiecka et al., 2022, Genes, 13:1101). The lack of Polθ results in both HR-functional tumor cells and HR-deficient tumor cells being more sensitive to other treatments such as radiotherapy or chemotherapy (Drzewiecka et al., 2022, Genes, 13:1101; and Goullet de Rugy T et al., 2016, Biology open, 5(10), 1485-1492).

[0006] Therefore, there is a need to develop new polθ inhibitors that can effectively inhibit the TMEJ pathway and be used for cancer treatment. Summary of the Invention

[0007] This invention provides novel sulfonamide (cyclic sulfonamide) derivatives, compositions comprising them, methods for their preparation, and uses. The sulfonamide derivatives possess polymerase-θ inhibitory activity and can be effectively used to treat various cancers.

[0008] In one aspect, the present invention relates to compounds of formula I, or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates thereof:

[0009] [Formula I]

[0010]

[0011] In the above formula I,

[0012] R 1 R 2 and R3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups.

[0013] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0014] X is selected from methylene, -NH-, and -NR. z -A group consisting of, wherein the methylene group is optionally substituted with one or more of the following groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl;

[0015] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0016] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0017] R x and R y Each of them is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0018] R Z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0019] R wChoose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0020] On the other hand, the present invention provides a pharmaceutical composition for treating or preventing diseases or disorders such as those mediated by polymerase θ, comprising one or more of the compounds disclosed herein, or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates thereof, and pharmaceutically acceptable carriers or excipients. In a specific embodiment, the composition comprises a therapeutically effective amount of one or more compounds. In a specific embodiment, the composition comprises a preventatively effective amount of one or more compounds.

[0021] In another aspect, the present invention provides the use of the compounds disclosed herein, or their tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutical compositions disclosed herein, in the preparation of a medicament for treating or preventing diseases or disorders mediated by polymerase θ.

[0022] In another aspect, the present invention provides a method for treating or preventing a subject from having a disease or disorder mediated by polymerase θ, comprising administering to the subject one or more compounds disclosed in the present invention, or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions disclosed in the present invention.

[0023] In another aspect, the present invention provides a compound disclosed herein for treating or preventing diseases or disorders such as those mediated by polymerase θ, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition disclosed herein.

[0024] Other objects and advantages of the present invention will be clearly understood by those skilled in the art through the following specific implementations, embodiments and claims.

[0025] definition

[0026] Chemical terminology

[0027] The definitions of specific functional groups and chemical terms will be explained in more detail below.

[0028] When listing a range of values, it is assumed that each value and any subranges within that range are included. For example, "C 1-6Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 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 alkyl.

[0029] The term "C" used in this article 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms (unless otherwise specified). It is also referred to herein as "lower alkyl". In some embodiments, the alkyl group may have 1 to 4 carbon atoms (C1 to C2). 1-4 Alkyl groups or 3 to 6 carbon atoms (C 3-6 Alkyl). C 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, neopentyl, 3-methyl-2-butyl, tert-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc.

[0030] The term "C" used in this article 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group (unless otherwise specified) having 2 to 6 carbon atoms and at least one carbon-carbon double bond (e.g., 1, 2, or 3 carbon-carbon double bonds). At least one carbon-carbon double bond may be present 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, hexenyl, etc.

[0031] The term "C" used in this article 2-6 "Alynyl" refers to a straight-chain or branched hydrocarbon group (unless otherwise specified) having 2 to 6 carbon atoms, at least one carbon-carbon triple bond (e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally at least one carbon-carbon double bond (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, the alkynyl group may have 2 to 4 carbon atoms. In some embodiments, the alkynyl group does not contain any double bonds. At least one carbon-carbon triple bond may be present internally (e.g., 2-butynyl) or terminally (e.g., 1-butynyl). 2-6Examples of alkynyl groups include, but are not limited to: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, etc.

[0032] The term "C" used in this article 1-6 "Alkoxy" refers to the -OR group, where R is a substituted or unsubstituted C. 1-6 Alkyl group (unless otherwise specified). In some embodiments, the alkoxy group may have 1 to 4 carbon atoms. Specific C 1-6 Alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0033] As used herein, the terms "halogenated" or "halogen" refer to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I) (unless otherwise specified). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

[0034] The term "C" used in this article 1-6 "Halogenated alkyl" and "C" 1-6 "Haloalkoxy" refers to the "C" group that has been substituted with at least one halogen group. 1-6 "alkyl" and "C" 1-6 Alkyl groups (unless otherwise specified). Examples of alkyl halides include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Examples of alkoxy halides include, but are not limited to: -OCH2F, -OCHF2, -OCF3, etc.

[0035] The term "C" used in this article 3-10"Cycloalkyl" or "3-10-membered cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms (unless otherwise specified). In some embodiments, the cycloalkyl group may 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 ring carbon atoms. The cycloalkyl group also includes a cyclic system in which the cycloalkyl ring is fused with at least one aryl or heteroaryl group, wherein the fused ring... The dot is on 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, cyclohepttrienyl, 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.

[0036] As used herein, the term "aromatic group" refers to a ring structure (unless otherwise specified) containing a delocalized π-electron ring cloud above and below the molecular plane, wherein the π-cloud contains (4n+2) π electrons. Further discussion of aromaticity can be found in Morrison and Boyd's Organic Chemistry (5th edition, 1987), Chapter 13, "Aromaticity," pp. 477–497, which is incorporated herein by reference. The term "aromatic group" includes aryl and heteroaryl groups.

[0037] The term "C" used in this article 6-14 "Aryl" refers to a free radical of a carbocyclic aromatic group having 6 to 14 ring carbon atoms and zero heteroatoms (unless otherwise specified). In one embodiment, the aryl group may have 6 to 10 ring carbon atoms. The aryl group may be monocyclic or polycyclic (e.g., bicyclic or tricyclic). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, etc. As defined herein, the aryl group also includes a ring system in which the aryl ring is fused with at least one cycloalkyl or heterocyclic group, and the connection point is on the aryl ring.

[0038] As used herein, the term "5- to 12-membered heteroaryl" refers to any monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having a ring carbon atom and at least one heteroatom (e.g., nitrogen, oxygen, and sulfur) (unless otherwise specified). Heteroaryl also includes ring systems fused herein with at least one cycloalkyl, heterocyclic, or aryl ring, with the connection point on the heteroaryl ring. In some embodiments, the heteroaryl may also have 3 to 8, 3 to 7, 4 to 7, 5 to 10, 5 to 7, or 5 to 6 ring carbon atoms or heteroatoms.

[0039] Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and phenylthio. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-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 tetraazinyl. Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl.

[0040] As used herein, the terms “deuterated,” “deuterated,” or “D” mean that at least one hydrogen atom in a compound or group is substituted with deuterium (unless otherwise specified). Deuteration can be monosubstituted, disubstituted, trisubstituted, polysubstituted, or fully substituted. The terms “one or more deuterated” are used interchangeably with “one or more deuterated”.

[0041] As used herein, the term "non-deuterated compound" refers to a compound containing no more than the natural deuterium isotope content (0.015%) (unless otherwise specified).

[0042] The deuterium isotope content at the deuterium substitution site 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%.

[0043] The term "C" used in this article 1-6 "alkylene" refers to a divalent alkyl linking group, which is a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms (unless otherwise specified). Formally, an alkylene refers to an alkane where two CH bonds are replaced by the alkylene group at the junction with the remainder of the compound. In some embodiments, the alkylene may have 1 to 4 carbon atoms (C1 to C2).1-4 Alkylene or 1 to 2 carbon atoms (C 1-2 Alkylenes. Examples of alkylenes 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, 2-methyl-propane-1,3-diyl, etc.

[0044] As used herein, the term "carbamoyl" refers to the -C(=O)-NR'R" group (unless otherwise specified), where R' and R" independently represent hydrogen or C. 1-6 alkyl.

[0045] As used herein, the terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally substituted” means an event or condition in which a chemical group (e.g., a group as defined herein) may be substituted, but also includes events or conditions in which the chemical group is not substituted.

[0046] The term "substituted" refers to a moiety having a substituent that replaces a hydrogen atom on at least one carbon of the main chain. It should be understood that such "substitution" or "substituted" includes implicit limitations, namely that such substitution is consistent with the allowed valence of the substituted atom and substituent, and that the substitution produces a stable compound, for example, one that does not spontaneously transform, for example, through rearrangement, cyclization, elimination, etc. The term "substituted" as used herein is intended to include all allowed substituents in organic compounds. Examples of substituents for the carbon atom include, but are not limited to: 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, hydroxyl, 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, -COR z1 (where R) z1 Selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen) and -CON(R) z2 (R) z3 (where R) z2 and R z3 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl groups, or halogens, wherein the alkyl group is optionally substituted with one or more of the C1-C6 alkyl groups and halogens; or R z2and R z3 Together with the nitrogen atoms to which they are attached, they form nitrogen-containing 3-8 membered heterocyclic groups, wherein the heterocyclic group is optionally substituted with at least one selected from C1-C6 alkyl groups and halogens, wherein each of the alkyl, alkenyl, alkoxy, alkylene, cycloalkyl, heterocyclic, or heteroaryl groups is independently and optionally substituted with one or more selected from C1-C6 alkyl groups and halogens. The number of substituents can be arbitrary, as long as it corresponds to the permissible valence of the substituted atom and the substituent, for example, it can be 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5, 3 to 4, etc.

[0047] General terms

[0048] When the term "about" is used with the corresponding numerical value, it is intended to include variations within ±20% of that value, typically ±10%, more commonly ±5%, and most commonly ±2%. In some implementations, the term "about" may refer to the value itself.

[0049] Unless otherwise expressly stated, any concept expressed in the singular form should be understood to include the concept expressed in the plural form. Therefore, unless otherwise expressly stated, any article expressing a singular concept (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept.

[0050] Unless otherwise expressly stated, the terminology used in this specification has the meaning commonly understood within the art. Therefore, unless otherwise noted, all technical and scientific terms in this specification have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict of meanings, this specification (including definitions) shall prevail.

[0051] Unless otherwise expressly stated, any terminology used in this specification shall be deemed to have its ordinary meaning in the relevant technical field. Therefore, unless otherwise defined, all scientific and other technical terms used in this specification shall have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict of meaning, this specification (including definitions) shall prevail. Detailed Implementation

[0052] compound

[0053] According to one aspect of the invention, a compound of formula I (including subsets of the formulas), or a tautomer, stereoisomer, prodrug, crystal form, isotopic variant, pharmaceutically acceptable salt, hydrate, or solvate thereof is provided.

[0054] As used herein, “compounds of the present invention” refers to compounds of formula I (including subsets thereof), or their tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates.

[0055] In one embodiment, the present invention relates to a compound of formula I, or a tautomer, stereoisomer, prodrug, crystal form, isotopic variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0056] [Formula I]

[0057]

[0058] In the above formula I,

[0059] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups.

[0060] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0061] X is selected from methylene, -NH-, and -NR. z -A group consisting of, wherein the methylene group is optionally substituted with one or more of the following groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl;

[0062] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0063] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R yOne or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0064] R x and R y Each of them is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0065] R Z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0066] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0067] Ring A

[0068] In one embodiment, A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl; preferably, A is a 6-10 membered monocyclic or bicyclic aryl or heteroaryl; more preferably, A is selected from the group consisting of 6 membered monocyclic or heteroaryl and 10 membered bicyclic aryl or heteroaryl, each of the aryl and heteroaryl groups being independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the following: C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; wherein each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently and optionally substituted with one or more of the following: C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; R 1 -R 4 X, Y, and Z are defined as above.

[0069] In one embodiment, A is selected from the group consisting of phenyl, pyridyl, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinazinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cenolinyl, and naphthyl, wherein each of the phenyl, pyridyl, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinazinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cenolinyl, and naphthyl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently and optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; R 1 -R 4 X, Y, and Z are defined as above.

[0070] In one embodiment, A is selected from the group consisting of phenyl, pyridyl, quinolinyl, and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl, and naphthyl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently and optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; R 1 -R 4 X, Y, and Z are defined as above.

[0071] In one embodiment, A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl; preferably, A is a 6-10 membered monocyclic or bicyclic aryl or heteroaryl; more preferably, A is selected from the group consisting of 6 membered monocyclic or heteroaryl and 10 membered bicyclic aryl or heteroaryl, wherein each of the aryl and heteroaryl groups is independently and optionally substituted with an unsubstituted C1-C6 alkyl group, a halogen-substituted C1-C6 alkyl group, a halogen, a cyano group, or a deuterium group; preferably, each of the aryl and heteroaryl groups is independently and optionally substituted with an unsubstituted C1-C6 alkyl group, a halogen-substituted C1-C6 alkyl group, or a halogen; more preferably, each of the aryl and heteroaryl groups is independently and optionally substituted with methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, or iodine; more preferably, each of the aryl and heteroaryl groups is independently and optionally substituted with methyl, trifluoromethyl, fluorine, chlorine, or bromine; R 1 -R 4 X, Y, and Z are defined as above.

[0072] In one embodiment, A is selected from the group consisting of phenyl, pyridyl, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinazinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cenolinyl, and naphthyl, wherein each of the phenyl, pyridyl, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinazinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cenolinyl, and naphthyl groups is independently selected. Selectively substituted with unsubstituted C1-C6 alkyl groups, halogenated C1-C6 alkyl groups, halogens, cyano groups, or deuterium groups; preferably, each of the aryl and heteroaryl groups is independently and optionally substituted with an unsubstituted C1-C6 alkyl group, a halogenated C1-C6 alkyl group, or a halogen; more preferably, each of the aryl and heteroaryl groups is independently and optionally substituted with methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, or iodine; even more preferably, each of the aryl and heteroaryl groups is independently and optionally substituted with methyl, trifluoromethyl, fluorine, chlorine, or bromine; R 1 -R 4 X, Y, and Z are defined as above.

[0073] In one embodiment, A is selected from the group consisting of phenyl, pyridyl, quinolinyl, and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl, and naphthyl groups is independently and optionally substituted with an unsubstituted C1-C6 alkyl group, a halogen-substituted C1-C6 alkyl group, a halogen, a cyano group, or a deuterium group; preferably, each of the aryl and heteroaryl groups is independently and optionally substituted with an unsubstituted C1-C6 alkyl group, a halogen-substituted C1-C6 alkyl group, or a halogen; more preferably, each of the aryl and heteroaryl groups is independently and optionally substituted with methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, or iodine; even more preferably, each of the aryl and heteroaryl groups is independently and optionally substituted with methyl, trifluoromethyl, fluorine, chlorine, or bromine; R 1 -R 4 X, Y, and Z are defined as above.

[0074] In one implementation, A is selected from the following group:

[0075] as well as

[0076] In the above formula,

[0077] R a1 R a2 R a3 R a4 and R a5 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the alkyl groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups, and each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0078] R b1 R b2 R b3 and R b4 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R yEach of the groups is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl;

[0079] R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl;

[0080] R d1 R d2 R d3 R d4 R d5 and R d6 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups, wherein each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently and optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups; and

[0081] R 1 -R 4X, Y, and Z are defined as above.

[0082] In one embodiment, 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, 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 groups, substituted C1-C6 alkyl groups, and halogens; 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, fluorine, chlorine, bromine, and iodine; 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, trifluoromethyl, fluorine, chlorine, and bromine; R 1 -R 4 X, Y, and Z are defined as above.

[0083] In one embodiment, 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 groups, halogen-substituted C1-C6 alkyl groups, halogens, cyano groups, 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 groups, substituted C1-C6 alkyl groups, and halogens; more preferably, R b1 R b2 R b3 and R b4 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, and iodine; more preferably, R b1 R b2 R b3and R b4 Each of these is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluorine, chlorine, and bromine; R 1 -R 4 X, Y, and Z are defined as above.

[0084] In one embodiment, 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 groups, halogen-substituted C1-C6 alkyl groups, halogens, cyano groups, 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 groups, substituted C1-C6 alkyl groups, and halogens; 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, fluorine, chlorine, bromine, and iodine; 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, trifluoromethyl, fluorine, chlorine, and bromine; R 1 -R 4 X, Y, and Z are defined as above.

[0085] In one embodiment, 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 groups, halogen-substituted C1-C6 alkyl groups, halogens, cyano groups, and deuterium; preferably, R d1 R d2 R d3 Rd4 R d5 and R d6 Each of these is independently selected from the group consisting of hydrogen, unsubstituted C1-C6 alkyl groups, substituted C1-C6 alkyl groups, and halogens; 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, fluorine, chlorine, bromine, and iodine; 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, trifluoromethyl, fluorine, chlorine, and bromine; R 1 -R 4 X, Y, and Z are defined as above.

[0086] In one implementation, A is

[0087] in,

[0088] R a1 Choose from the group consisting of hydrogen, fluorides, and methyl groups;

[0089] R a2 Choose from the group consisting of hydrogen, fluoride, chloride, bromide, methyl and trifluoromethyl;

[0090] R a3 Choose from the group consisting of hydrogen, fluorides, and methyl groups;

[0091] R a4 Choose from the group consisting of hydrogen, fluorides, and methyl groups;

[0092] R a5 Choose from the group consisting of hydrogen, fluorides, and chlorides; and

[0093] R 1 -R 4 X, Y, and Z are defined as above.

[0094] In one implementation, A is

[0095] in,

[0096] R b1 It is hydrogen;

[0097] Rb2 It is hydrogen;

[0098] R b3 It is a halogen or a fluoride, preferably a fluoride;

[0099] R b4 For hydrogen; and

[0100] R 1 -R 4 X, Y, and Z are defined as above.

[0101] In one implementation, A is

[0102] Among them, R c1 -R c7 It is hydrogen; R 1 -R 4 X, Y, and Z are defined as above.

[0103] In one implementation, A is

[0104] Among them, R d1 -R d6 It is hydrogen; R 1 -R 4 X, Y, and Z are defined as above.

[0105] X

[0106] In one embodiment, X is selected from methylene, -NH-, and -NR. z -A group consisting of, wherein the methylene group is optionally substituted with one or more substituted groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl, R z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; R 1 -R 4 Rings A, Y, and Z are defined as above.

[0107] In one embodiment, X is selected from methylene, -NH-, and -NR. z - A group consisting of R z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; R 1 -R 4 Rings A, Y, and Z are defined as above.

[0108] In one embodiment, X is selected from methylene, -NH-, and -NR.z - A group consisting of R z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted by one or more of the following: C1-C6 alkyl, halogen, cyano, and deuterium; R 1 -R 4 Rings A, Y, and Z are defined as above.

[0109] In one embodiment, X is selected from methylene, -NH-, and -NR. z - A group consisting of R z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more substituted groups selected from C1-C6 alkyl groups and deuterium; R 1 -R 4 Rings A, Y, and Z are defined as above.

[0110] In one embodiment, X is selected from methylene, -NH-, and -NR. z - A group consisting of R z Selected from the group consisting of methylene, ethyl, n-propyl, and butyl, optionally substituted with one or more alkyl groups selected from C1-C6 and deuterium; R 1 -R 4 Rings A, Y, and Z are defined as above.

[0111] In one embodiment, X is selected from methylene, -NH-, and -NR. z - A group consisting of R z The group consisting of methyl and ethyl groups is selected, which may optionally be substituted with one or more alkyl groups selected from C1-C6 and deuterium. In one embodiment, X is selected from methylene, -NH-, and -NR. z - A group consisting of R z Selected from the group consisting of methyl and ethyl, which may optionally be substituted with one or more of methyl, ethyl, and deuterium; R 1 -R 4 Rings A, Y, and Z are as defined above. In one embodiment, X is selected from methylene, -NH-, and -NR. z - A group consisting of R z Selected from the group consisting of methyl and ethyl, which may optionally be substituted with one or more substances selected from methyl and deuterium; R 1 -R 4 Rings A, Y, and Z are as defined above. In one embodiment, X is selected from methylene, -NH-, and -NR. z - A group consisting of R z Select from the group consisting of methyl, isopropyl, and trideuteriomethyl; R 1 -R 4Rings A, Y, and Z are defined as above.

[0112] Y

[0113] In one implementation, Y is selected freely from -N- and -CR. w -A group consisting of. In one implementation, Y is -CR w -, where R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y (R x and R y Each of these is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the following: C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; R 1 -R 4 Rings A, X, and Z are defined as above.

[0114] In one embodiment, Y is -CR w -, where R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium; and R 1 -R 4 Rings A, X, and Z are defined as above. In one embodiment, Y is CR. w -, where R w Choose from the group consisting of hydrogen and cyano groups; and R 1 -R 4 Rings A, X, and Z are defined as above.

[0115] Z

[0116] In one implementation, Z is free to select -N- and -CR. w - A group consisting of R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y (R x and R y Each of these is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the following: C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; R 1 -R 4 Rings A, X, and Y are defined as above.

[0117] In one implementation, Z is free to select -N- and -CR. w - A group consisting of R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium; and R 1 -R 4 Rings A, X, and Y are as defined above. 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 defined as above.

[0118] R 1

[0119] In one embodiment, R 1 Choose from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups, wherein each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups; and R 2 -R 4 Rings A, X, Y, and Z are defined as above.

[0120] In one embodiment, R 1 Selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with a C1-C6 alkyl group, a halogen, a cyano group, a deuterium group, a hydroxyl group, an amino group, a mercapto group, or a carbamoyl group; and R 2 -R 4 Rings A, X, Y, and Z are defined as above.

[0121] In one embodiment, R 1 Selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl groups, halogens, cyano groups, and deuterium; and R 2 -R 4 Rings A, X, Y, and Z are defined as above.

[0122] In one embodiment, R 1 Selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with a halogen; and R2 -R 4 Rings A, X, Y, and Z are defined as above.

[0123] In one embodiment, R 1 Selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl, which may optionally be substituted with a halogen; and R 2 -R 4 Rings A, X, Y, and Z are defined as above.

[0124] In one embodiment, R 1 Selected from the group consisting of methyl and trifluoromethyl groups; and R 2 -R 4 Rings A, X, Y, and Z are defined as above.

[0125] R 2

[0126] In one embodiment, R 2 Choose from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups, wherein each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl groups; and R 1 R 3 R 4 Rings A, X, Y, and Z are defined as above.

[0127] In one embodiment, R 2 Selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and R 1 R 3 R 4 Rings A, X, Y, and Z are defined as above.

[0128] In one embodiment, R 2 Selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl groups, halogens, cyano groups, and deuterium; and R 1 R 3 R4 Rings A, X, Y, and Z are defined as above.

[0129] In one embodiment, R 2 It is a C1-C6 alkyl group, wherein the alkyl group is independently and optionally substituted with one or more of a group selected from C1-C6 alkyl, halogen, cyano, and deuterium; and R 1 R 3 R 4 Rings A, X, Y, and Z are defined as above.

[0130] In one embodiment, R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally and independently substituted with a halogen; and R 1 R 3 R 4 Rings A, X, Y, and Z are defined as above.

[0131] In one embodiment, R 2 Selected from the group consisting of methyl, ethyl, and n-propyl groups, which are independently and optionally substituted with halogens; and R 1 R 3 R 4 Rings A, X, Y, and Z are defined as above.

[0132] In one embodiment, R 2 Selected from the group consisting of methyl and trifluoromethyl; and R 1 R 3 R 4 Rings A, X, Y, and Z are defined as above.

[0133] In one embodiment, R 2 It is trifluoromethyl; and R 1 R 3 R 4 Rings A, X, Y, and Z are defined as above.

[0134] R 3

[0135] In one embodiment, R 3 Choose from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y (where R) x and R yEach of the following is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; wherein each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and R 1 R 2 R 4 Rings A, X, Y, and Z are defined as above.

[0136] In one embodiment, R 3 Selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and R 1 R 2 R 4 Rings A, X, Y, and Z are defined as above.

[0137] In one embodiment, R 3 Selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl groups, halogens, cyano groups, and deuterium; and R 1 R 2 R 4 Rings A, X, Y, and Z are defined as above.

[0138] In one embodiment, R 3 Selected from the group consisting of hydrogen and C1-C6 alkyl groups; and R 1 R 2 R 4 Rings A, X, Y, and Z are defined as above.

[0139] In one embodiment, R 3 For hydrogen; and R 1 R 2 R 4 Rings A, X, Y, and Z are defined as above.

[0140] R 4

[0141] In one embodiment, R 4 It is hydrogen or a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of a group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl and mercapto; and R 1 R 2 R 3 Rings A, X, Y, and Z are defined as above.

[0142] In one embodiment, R 4 It is hydrogen or a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of a group selected from C1-C6 alkyl, halogen, cyano, and deuterium; and R 1 R 2 R 3 Rings A, X, Y, and Z are defined as above.

[0143] In one embodiment, R 4 It is hydrogen or a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of a C1-C6 alkyl group and deuterium; and R 1 R 2 R 3 Rings A, X, Y, and Z are defined as above.

[0144] In one embodiment, R 4 It is hydrogen or a C1-C4 alkyl group, wherein the alkyl group is optionally substituted with one or more substituted groups selected from C1-C6 alkyl groups and deuterium; and R 1 R 2 R 3 Rings A, X, Y, and Z are defined as above.

[0145] In one embodiment, R 4 Selected from the group consisting of hydrogen, methyl, ethyl, and isopropyl, wherein each of the methyl and ethyl groups is optionally substituted with one or more substituted groups selected from C1-C6 alkyl and deuterium; and R 1 R 2 R 3 Rings A, X, Y, and Z are defined as above.

[0146] In one embodiment, R 4 Choose from the group consisting of hydrogen, methyl, ethyl, isopropyl, and trideuteryl; and R 1 R 2 R 3 Rings A, X, Y, and Z are defined as above.

[0147] In one embodiment, R 4 Choose from the group consisting of hydrogen, methyl, isopropyl, and trideuteryl; and R 1 R 2 R 3 Rings A, X, Y, and Z are defined as above.

[0148] In one embodiment, the present invention relates to compounds of the following formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), or their tautomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates.

[0149] [Formula Ia]

[0150]

[0151] [Formula Ib]

[0152]

[0153] [Formula Ic]

[0154]

[0155] [FormulaId]

[0156]

[0157] [Formula Ie]

[0158]

[0159] [Formula If]

[0160]

[0161] [Formula Ig]

[0162]

[0163] [Formula Ih]

[0164]

[0165] In the above formula,

[0166] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups.

[0167] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0168] X is selected from methylene, -NH-, and -NR. z-A group consisting of, wherein the methylene group is optionally substituted with one or more of a group selected from 1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0169] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0170] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0171] R x and R y Each of them is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0172] R Z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0173] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0174] Non-limiting example implementation

[0175] In one embodiment, the present invention relates to compounds of formula II, or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates thereof.

[0176] [Formula II]

[0177]

[0178] In Equation II,

[0179] R1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0180] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0181] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0182] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0183] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0184] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0185] In one embodiment of the compound of formula II, R 1 R 2 and R 3Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl groups;

[0186] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0187] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0188] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of the aryl and heteroaryl groups is optionally substituted independently by one or more of a group selected from C1-C6 alkyl, halogen, cyano and deuterium, wherein the alkyl group is optionally substituted by one or more of a group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl.

[0189] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0190] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0191] In one embodiment of the compound of formula II, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0192] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0193] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0194] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of the aryl and heteroaryl groups is independently and optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano and deuterium, wherein each of the alkyl groups is independently and optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano and deuterium.

[0195] R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium.

[0196] In one embodiment of the compound of formula II, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0197] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0198] R 3 It is hydrogen;

[0199] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0200] Y is -CR w -, where R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0201] Z selects free-N-and-CR w - A group consisting of R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium; and

[0202] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of the aryl and heteroaryl groups is optionally substituted independently with one or more of a C1-C6 alkyl, halogen, cyano and deuterium, wherein the alkyl group is optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano and deuterium.

[0203] In one embodiment of the compound of formula II, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0204] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0205] R3 It is hydrogen;

[0206] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl and deuterium;

[0207] Y is selected from the group consisting of -CH- and -C(CN-);

[0208] Z is selected from the group consisting of -N- and -CH-;

[0209] A is selected from the group consisting of phenyl, pyridyl, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinazinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cenolinyl, and naphthyl, wherein each of the phenyl, pyridyl, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinazinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cenolinyl, and naphthyl groups is independently and optionally substituted with one or more of a C1-C6 alkyl group, halogen, cyano, and deuterium, wherein the alkyl group is optionally substituted with one or more of a C1-C6 alkyl group, halogen, cyano, and deuterium.

[0210] In one embodiment of the compound of formula II, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0211] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0212] R 3 It is hydrogen;

[0213] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl and deuterium;

[0214] Y is either -CH- or -C(CN)-;

[0215] Z is selected from the group consisting of -N- and -CH-;

[0216] A is selected from the group consisting of phenyl, pyridyl, quinolinyl and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl and naphthyl groups is independently and optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium.

[0217] In one embodiment of the compound of formula II, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0218] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0219] R 3 It is hydrogen;

[0220] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl and deuterium;

[0221] Y is either -CH- or -C(CN)-;

[0222] Z is selected from the group consisting of -N- and -CH-;

[0223] A is selected from the group consisting of phenyl, pyridyl, quinolinyl and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl and naphthyl groups is independently and optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium.

[0224] In one embodiment of the compound of formula II, R 1 The methyl group is optionally substituted with a halogen;

[0225] R 2 The methyl group is optionally substituted with a halogen;

[0226] R 3 It is hydrogen;

[0227] R 4 The substituted form is hydrogen, methyl, or ethyl, wherein each of the methyl and ethyl groups is optionally substituted with one or more substituted forms selected from methyl and deuterium;

[0228] Y is either -CH- or -C(CN)-;

[0229] Z selects a group consisting of -N- and -CH-; and

[0230] A is selected from the group consisting of phenyl, pyridyl, quinolinyl and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl and naphthyl groups is independently and optionally substituted by one or more of fluorides, chlorides, bromides, methyl and trifluoromethyl groups.

[0231] In one embodiment of the compound of formula II, R 1 It is methyl or trifluoromethyl;

[0232] R 2 It is trifluoromethyl;

[0233] R 3 It is hydrogen;

[0234] R 4 Choose from the group consisting of hydrogen, methyl, trideuterium methyl, and isopropyl;

[0235] Y is -CH-;

[0236] Z is selected from the group consisting of -N- and -CH-;

[0237] A is selected from the group consisting of phenyl, pyridyl, quinolinyl and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl and naphthyl groups is independently and optionally substituted by one or more of fluorides, chlorides, bromides, methyl and trifluoromethyl groups.

[0238] In one embodiment, the present invention relates to compounds of formula IIa, or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates thereof.

[0239] [Form IIa]

[0240]

[0241] In the above formula IIa,

[0242] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0243] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0244] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0245] R a1 R a2 R a3 R a4 and Ra5 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups, and each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0246] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0247] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0248] In one embodiment of the compound of formula IIa, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl groups;

[0249] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0250] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0251] R a1 R a2 R a3 R a4 and R a5Each of them is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium and hydroxyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl.

[0252] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0253] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0254] In one embodiment of the compound of formula IIa, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0255] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0256] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0257] 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, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, and deuterium; and

[0258] R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium.

[0259] In one embodiment of the compound of formula IIa, R 1It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0260] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0261] R 3 It is hydrogen;

[0262] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0263] Y is -CR w -, where R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0264] Z selects free-N-and-CR w - A group consisting of R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium; and

[0265] R a1 R a2 R a3 R a4 and R a5 Each of them is independently selected from the group consisting of hydrogen, C1-C6 alkyl and halogen, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen and deuterium.

[0266] In one embodiment of the compound of formula IIa, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0267] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0268] R 3 It is hydrogen;

[0269] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl and deuterium;

[0270] Y is selected from the group consisting of -CH- and -C(CN-);

[0271] Z is selected from the group consisting of -N- and -CH-;

[0272] R a1 R a2 R a3 R a4 and R a5 Each of them is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0273] In one embodiment of the compound of formula IIa, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0274] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0275] R 3 It is hydrogen;

[0276] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl and deuterium;

[0277] Y is either -CH- or -C(CN)-;

[0278] Z selects a group consisting of -N- and -CH-; and

[0279] R a1 R a2 R a3 R a4 and R a5 Each of them is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0280] In one embodiment of the compound of formula IIa, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0281] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0282] R 3 It is hydrogen;

[0283] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl and deuterium;

[0284] Y is either -CH- or -C(CN)-;

[0285] Z selects a group consisting of -N- and -CH-; and

[0286] R a1 R a2 R a3 R a4 and R a5 Each of them is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0287] In one embodiment of the compound of formula IIa, R 1 The methyl group is optionally substituted with a halogen;

[0288] R 2 The methyl group is optionally substituted with a halogen;

[0289] R 3 It is hydrogen;

[0290] R 4 It is hydrogen, methyl or ethyl, each of which is optionally substituted with one or more of methyl and deuterium;

[0291] Y is either -CH- or -C(CN)-;

[0292] Z is selected from the group consisting of -N- and -CH-;

[0293] R a1 R a2 R a3 R a4 and R a5 Each of them is independently selected from the group consisting of hydrogen, methyl, fluorine, chlorine, bromine, and trifluoromethyl.

[0294] In one embodiment of the compound of formula IIa, R 1 It is methyl or trifluoromethyl;

[0295] R 2 It is trifluoromethyl;

[0296] R 3 It is hydrogen;

[0297] R 4 It can be hydrogen, methyl, trideuteryl, or isopropyl;

[0298] Y is -CH-;

[0299] Z selects a group consisting of -N- and -CH-; and

[0300] R a1 Choose from the group consisting of hydrogen, fluorides, and methyl groups;

[0301] R a2Choose from the group consisting of hydrogen, fluoride, chloride, bromide, methyl and trifluoromethyl;

[0302] R a3 Choose from the group consisting of hydrogen, fluorides, and methyl groups;

[0303] R a4 Choose from the group consisting of hydrogen, fluorides, and methyl groups; and

[0304] R a5 Choose from the group consisting of hydrogen, fluorides, and chlorides.

[0305] In one embodiment, the present invention relates to compounds of formula IIb, or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates thereof.

[0306] [Formula IIb]

[0307]

[0308] In the above formula IIb,

[0309] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0310] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0311] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0312] R b1 R b2 R b3 and R b4 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R yEach of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups, and each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0313] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0314] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0315] In one embodiment of the compound of formula IIb, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl groups;

[0316] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0317] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0318] R b1 R b2 R b3 and R b4 Each of them is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium and hydroxyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl.

[0319] R x and R yEach of these is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of a group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0320] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0321] In one embodiment of the compound of formula IIb, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0322] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0323] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0324] 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, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, and deuterium; and

[0325] R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium.

[0326] In one embodiment of the compound of formula IIb, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0327] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0328] R 3 It is hydrogen;

[0329] R4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0330] Y is -CR w -, where R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0331] Z selects free-N-and-CR w - A group consisting of R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium; and

[0332] R b1 R b2 R b3 and R b4 Each of them is independently selected from the group consisting of hydrogen, C1-C6 alkyl and halogen, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen and deuterium.

[0333] In one embodiment of the compound of formula IIb, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0334] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0335] R 3 It is hydrogen;

[0336] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl and deuterium;

[0337] Y is selected from the group consisting of -CH- and -C(CN-);

[0338] Z selects a group consisting of -N- and -CH-; and

[0339] R b1 R b2 R b3 and R b4 Each of them is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0340] In one embodiment of the compound of formula IIb, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0341] R2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0342] R 3 It is hydrogen;

[0343] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl and deuterium;

[0344] Y is either -CH- or -C(CN)-;

[0345] Z selects a group consisting of -N- and -CH-; and

[0346] R b1 R b2 R b3 and R b4 Each of them is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0347] In one embodiment of the compound of formula IIb, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0348] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0349] R 3 It is hydrogen;

[0350] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl and deuterium;

[0351] Y is either -CH- or -C(CN)-;

[0352] Z selects a group consisting of -N- and -CH-; and

[0353] R b1 R b2 R b3 and R b4 Each of them is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0354] In one embodiment of the compound of formula IIb, R 1 The methyl group is optionally substituted with a halogen;

[0355] R 2 The methyl group is optionally substituted with a halogen;

[0356] R 3 It is hydrogen;

[0357] R 4 It is hydrogen, methyl or ethyl, each of which is optionally substituted with one or more of methyl and deuterium;

[0358] Y is either -CH- or -C(CN)-;

[0359] Z selects a group consisting of -N- and -CH-; and

[0360] R b1 R b2 R b3 and R b4 Each of them is independently selected from the group consisting of hydrogen, methyl, fluorine, chlorine, bromine, and trifluoromethyl.

[0361] In one embodiment of the compound of formula IIb, R 1 It is methyl or trifluoromethyl;

[0362] R 2 It is trifluoromethyl;

[0363] R 3 It is hydrogen;

[0364] R 4 Choose from the group consisting of hydrogen, methyl, trideuterium methyl, and isopropyl;

[0365] Y is -CH-;

[0366] Z is selected from the group consisting of -N- and -CH-;

[0367] R b1 It is hydrogen;

[0368] R b2 It is hydrogen;

[0369] R b3 It is a halogen or a fluoride, preferably a fluoride; and

[0370] R b4 It is hydrogen.

[0371] In one embodiment, the present invention relates to compounds of formula IIc, or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates thereof.

[0372] [Form IIc]

[0373]

[0374] In the above formula IIc,

[0375] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0376] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0377] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0378] R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the alkyl groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups, and each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0379] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0380] R wChoose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0381] In one embodiment of the compound of formula IIc, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl groups;

[0382] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0383] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0384] R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of them is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium and hydroxyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl.

[0385] R x and R y Each of these is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of a group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0386] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0387] In one embodiment of the compound of formula IIc, R 1 R 2 and R 3Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0388] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0389] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0390] R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of them is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, deuterium and hydroxyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen and deuterium;

[0391] R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium.

[0392] In one embodiment of the compound of formula IIc, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0393] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0394] R 3 It is hydrogen;

[0395] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0396] Y is -CR w -, where R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0397] Z selects free-N-and-CR w - A group consisting of R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium; and

[0398] R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of them is independently selected from the group consisting of hydrogen, C1-C6 alkyl and halogen, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen and deuterium.

[0399] In one embodiment of the compound of formula IIc, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0400] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0401] R 3 It is hydrogen;

[0402] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0403] Y is selected from the group consisting of -CH- and -C(CN-);

[0404] Z selects a group consisting of -N- and -CH-; and

[0405] R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of them is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0406] In one embodiment of the compound of formula IIc, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0407] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0408] R 3 It is hydrogen;

[0409] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0410] Y is either -CH- or -C(CN)-;

[0411] Z selects a group consisting of -N- and -CH-; and

[0412] R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of them is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0413] In one embodiment of the compound of formula IIc, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0414] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0415] R 3 It is hydrogen;

[0416] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0417] Y is either -CH- or -C(CN)-;

[0418] Z selects a group consisting of -N- and -CH-; and

[0419] R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of them is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0420] In one embodiment of the compound of formula IIc, R 1 The methyl group is optionally substituted with a halogen;

[0421] R 2 The methyl group is optionally substituted with a halogen;

[0422] R 3 It is hydrogen;

[0423] R 4It is methyl or ethyl, which may optionally be substituted with one or more substances selected from methyl and deuterium;

[0424] Y is either -CH- or -C(CN)-;

[0425] Z selects a group consisting of -N- and -CH-; and

[0426] R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of them is independently selected from the group consisting of hydrogen, methyl, fluorine, chlorine, bromine, and trifluoromethyl.

[0427] In one embodiment of the compound of formula IIc, R 1 It is methyl or trifluoromethyl;

[0428] R 2 It is trifluoromethyl;

[0429] R 3 It is hydrogen;

[0430] R 4 It is methyl, trideuteryl, or isopropyl;

[0431] Y is -CH-;

[0432] Z selects a group consisting of -N- and -CH-; and

[0433] R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of them is hydrogen.

[0434] In one embodiment, the present invention relates to compounds of formula IId, or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates thereof.

[0435] [Formula IId]

[0436]

[0437] In the above formula IId,

[0438] R 1 R 2 and R 3Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0439] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0440] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0441] R d1 R d2 R d3 R d4 R d5 and R d6 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the alkyl groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups, and each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0442] R x and R y Each of these is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of a group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0443] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0444] In one embodiment of the compound of formula IId, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl groups;

[0445] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0446] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0447] 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, C1-C6 alkyl, halogen, cyano, deuterium and hydroxyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl.

[0448] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0449] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0450] In one embodiment of the compound of formula IId, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0451] R 4It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0452] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0453] 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, C1-C6 alkyl, halogen, cyano, deuterium and hydroxyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen and deuterium;

[0454] R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium.

[0455] In one embodiment of the compound of formula IId, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0456] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0457] R 3 It is hydrogen;

[0458] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0459] Y is -CR w -, where R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0460] Z selects free-N-and-CR w - A group consisting of R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium; and

[0461] R d1 R d2 R d3 R d4 R d5 and R d6Each of them is independently selected from the group consisting of hydrogen, C1-C6 alkyl and halogen, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen and deuterium.

[0462] In one embodiment of the compound of formula IId, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0463] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0464] R 3 It is hydrogen;

[0465] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0466] Y is selected from the group consisting of -CH- and -C(CN-);

[0467] Z selects a group consisting of -N- and -CH-; and

[0468] 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, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0469] In one embodiment of the compound of formula IId, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0470] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0471] R 3 It is hydrogen;

[0472] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0473] Y is either -CH- or -C(CN)-;

[0474] Z selects a group consisting of -N- and -CH-; and

[0475] R d1 R d2 Rd3 R d4 R d5 and R d6 Each of them is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0476] In one embodiment of the compound of formula IId, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0477] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0478] R 3 It is hydrogen;

[0479] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0480] Y is either -CH- or -C(CN)-;

[0481] Z selects a group consisting of -N- and -CH-; and

[0482] 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, ethyl, isopropyl, fluorine, chlorine, bromine, iodine and trifluoromethyl.

[0483] In one embodiment of the compound of formula IId, R 1 The methyl group is optionally substituted with a halogen;

[0484] R 2 The methyl group is optionally substituted with a halogen;

[0485] R 3 It is hydrogen;

[0486] R 4 It is methyl or ethyl, which may optionally be substituted with one or more substances selected from methyl and deuterium;

[0487] Y is either -CH- or -C(CN)-;

[0488] Z selects a group consisting of -N- and -CH-; and

[0489] R d1 R d2 R d3 Rd4 R d5 and R d6 Each of them is independently selected from the group consisting of hydrogen, methyl, fluorine, chlorine, bromine, and trifluoromethyl.

[0490] In one embodiment of the compound of formula IId, R 1 It is methyl or trifluoromethyl;

[0491] R 2 It is trifluoromethyl;

[0492] R 3 It is hydrogen;

[0493] R 4 It is methyl, trideuteryl, or isopropyl;

[0494] Y is -CH-;

[0495] Z selects a group consisting of -N- and -CH-; and

[0496] R d1 R d2 R d3 R d4 R d5 and R d6 Each of them is hydrogen.

[0497] In one embodiment, the present invention relates to compounds of formula III, or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates thereof.

[0498] [Formula III]

[0499]

[0500] In Equation III,

[0501] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0502] R 4It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0503] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0504] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0505] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0506] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0507] In one embodiment of the compound of formula III, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl groups;

[0508] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0509] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0510] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of the aryl and heteroaryl groups is optionally substituted independently by one or more of a group selected from C1-C6 alkyl, halogen, cyano and deuterium, wherein the alkyl group is optionally substituted by one or more of a group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl.

[0511] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0512] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0513] In one embodiment of the compound of formula III, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0514] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0515] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0516] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group, wherein each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently and optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group; and

[0517] R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium.

[0518] In one embodiment of the compound of formula III, R 1It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0519] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0520] R 3 It is hydrogen;

[0521] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0522] Y is -CR w -, where R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0523] Z selects free-N-and-CR w - A group consisting of R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium; and

[0524] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of the aryl and heteroaryl groups is optionally substituted independently with one or more of a C1-C6 alkyl, halogen, cyano and deuterium, wherein the alkyl group is optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano and deuterium.

[0525] In one embodiment of the compound of formula III, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0526] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0527] R 3 It is hydrogen;

[0528] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0529] Y is selected from the group consisting of -CH- and -C(CN-);

[0530] Z selects a group consisting of -N- and -CH-; and

[0531] A is selected from the group consisting of phenyl, pyridyl, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinazinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cenolinyl, and naphthyl, wherein each of the phenyl, pyridyl, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinazinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cenolinyl, and naphthyl groups is independently and optionally substituted with one or more of a C1-C6 alkyl group, halogen, cyano, and deuterium, wherein the alkyl group is optionally substituted with one or more of a C1-C6 alkyl group, halogen, cyano, and deuterium.

[0532] In one embodiment of the compound of formula III, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0533] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0534] R 3 It is hydrogen;

[0535] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0536] Y is selected from the group consisting of -CH- and -C(CN-);

[0537] Z selects a group consisting of -N- and -CH-; and

[0538] A is selected from the group consisting of phenyl, pyridyl, quinolinyl and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl and naphthyl groups is independently and optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium.

[0539] In one embodiment of the compound of formula III, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0540] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0541] R 3 It is hydrogen;

[0542] R 4It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0543] Y is selected from the group consisting of -CH- and -C(CN-);

[0544] Z selects a group consisting of -N- and -CH-; and

[0545] A is selected from the group consisting of phenyl, pyridyl, quinolinyl and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl and naphthyl groups is independently and optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl, halogen, cyano and deuterium.

[0546] In one embodiment of the compound of formula III, R 1 The methyl group is optionally substituted with a halogen;

[0547] R 2 The methyl group is optionally substituted with a halogen;

[0548] R 3 It is hydrogen;

[0549] R 4 It is methyl, trideuteryl, or isopropyl;

[0550] Y is selected from the group consisting of -CH- and -C(CN-);

[0551] Z selects a group consisting of -N- and -CH-; and

[0552] A is selected from the group consisting of phenyl, pyridyl, quinolinyl and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl and naphthyl groups is independently and optionally substituted by one or more of fluorides, chlorides, bromides, methyl and trifluoromethyl groups.

[0553] In one embodiment of the compound of formula III, R 1 It is methyl or trifluoromethyl;

[0554] R 2 It is trifluoromethyl;

[0555] R 3 It is hydrogen;

[0556] R 4 It is methyl;

[0557] Y is -CH-;

[0558] Z selects a group consisting of -N- and -CH-; and

[0559] A is a phenyl group, wherein the phenyl group is optionally substituted with one or more of a fluoride, chloride, and methyl group.

[0560] In one embodiment, the present invention relates to compounds of formula IV, or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates thereof.

[0561] [Form IV]

[0562]

[0563] In the above formula IV,

[0564] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0565] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0566] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0567] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[0568] R x and R y Each of them is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0569] R Z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[0570] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[0571] In one embodiment of the compound of formula IV, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl groups;

[0572] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[0573] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0574] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of the aryl and heteroaryl groups is optionally substituted independently by one or more of a group selected from C1-C6 alkyl, halogen, cyano and deuterium, wherein the alkyl group is optionally substituted by one or more of a group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl.

[0575] R x and R y Each of them is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[0576] R z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, and deuterium; and

[0577] R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium.

[0578] In one embodiment of the compound of formula IV, R 1 R 2 and R 3 Each of them is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the alkyl group is independently and optionally substituted by one or more of C1-C6 alkyl, halogen, cyano and deuterium;

[0579] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0580] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[0581] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group, wherein each of the alkyl, alkenyl, alkoxy, and cycloalkyl groups is independently and optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group.

[0582] R z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more substituted groups selected from C1-C6 alkyl groups and deuterium; and

[0583] R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano and deuterium.

[0584] In one embodiment of the compound of formula IV, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0585] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0586] R 3 It is hydrogen;

[0587] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano and deuterium;

[0588] Y is -CR w -, where R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium;

[0589] Z selects free-N-and-CR w - A group consisting of R w Choose from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and deuterium; and

[0590] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group, wherein the alkyl group is optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group; and

[0591] R z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium.

[0592] In one embodiment of the compound of formula IV, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0593] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0594] R 3 It is hydrogen;

[0595] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0596] Y is selected from the group consisting of -CH- and -C(CN-);

[0597] Z is selected from the group consisting of -N- and -CH-;

[0598] A is selected from the group consisting of phenyl, pyridyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cenolinyl, and naphthyl, wherein each of the phenyl, pyridyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cenolinyl, and naphthyl groups is independently and optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group, wherein the alkyl group is optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group; and

[0599] R zIt is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium.

[0600] In one embodiment of the compound of formula IV, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0601] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0602] R 3 It is hydrogen;

[0603] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0604] Y is selected from the group consisting of -CH- and -C(CN-);

[0605] Z is selected from the group consisting of -N- and -CH-;

[0606] A is selected from the group consisting of phenyl, pyridyl, quinolinyl, and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl, and naphthyl groups is independently and optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group, wherein the alkyl group is optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group; and

[0607] R z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium.

[0608] In one embodiment of the compound of formula IV, R 1 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0609] R 2 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen;

[0610] R 3 It is hydrogen;

[0611] R 4 It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium;

[0612] Y is selected from the group consisting of -CH- and -C(CN-);

[0613] Z is selected from the group consisting of -N- and -CH-;

[0614] A is selected from the group consisting of phenyl, pyridyl, quinolinyl, and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl, and naphthyl groups is independently and optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group, wherein the alkyl group is optionally substituted with one or more of a C1-C6 alkyl, halogen, cyano, and deuterium group; and

[0615] R z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl groups and deuterium.

[0616] In one embodiment of the compound of formula IV, R 1 The methyl group is optionally substituted with a halogen;

[0617] R 2 The methyl group is optionally substituted with a halogen;

[0618] R 3 It is hydrogen;

[0619] R 4 It is methyl or ethyl, which may optionally be substituted with one or more substances selected from methyl and deuterium;

[0620] Y is selected from the group consisting of -CH- and -C(CN-);

[0621] Z is selected from the group consisting of -N- and -CH-;

[0622] A is selected from the group consisting of phenyl, pyridyl, quinolinyl, and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl, and naphthyl groups is independently and optionally substituted with one or more of a group selected from fluorides, chlorides, bromides, methyl, and trifluoromethyl; and

[0623] R z It is methyl or ethyl, which may optionally be substituted with one or more of methyl and deuterium.

[0624] In one embodiment of the compound of formula IV, R 1 The methyl group is optionally substituted with a halogen;

[0625] R 2 The methyl group is optionally substituted with a halogen;

[0626] R 3 It is hydrogen;

[0627] R 4 It is methyl, trideuteryl, or isopropyl;

[0628] Y is selected from the group consisting of -CH- and -C(CN-);

[0629] Z is selected from the group consisting of -N- and -CH-;

[0630] A is selected from the group consisting of phenyl, pyridyl, quinolinyl, and naphthyl, wherein each of the phenyl, pyridyl, quinolinyl, and naphthyl groups is independently and optionally substituted with one or more of a group selected from fluorides, chlorides, bromides, methyl, and trifluoromethyl; and

[0631] R z Choose from the group consisting of methyl, trideuteryl, and isopropyl.

[0632] In one embodiment, an example compound of Formula I is shown below:

[0633] Table 1

[0634]

[0635]

[0636]

[0637]

[0638] In another embodiment, an example compound of Formula I is as follows:

[0639] Table 2

[0640]

[0641]

[0642]

[0643]

[0644] As used herein, the terms "tautomer" or "tautomer form" refer to structural isomers with different energies that interconvert via low-barrier transitions. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers include interconversions via rearrangement of some bonding electrons.

[0645] As used in this article, "stereoisomers" refers to compounds with the same chemical composition but different spatial arrangements of atoms or groups. Stereoisomers include diastereomers, enantiomers, and conformational isomers.

[0646] As used herein, the term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated into individual stereoisomers using high-resolution analytical methods, such as electrophoresis and chromatography such as HPLC.

[0647] As used in this article, “enantiomer” refers to two non-overlapping but mirror-image isomers of a compound.

[0648] The stereochemical definitions and rules used in this paper generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, Earn and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more chiral centers. The prefixes d and l or (+) and (-) are used to indicate the direction of rotation of plane-polarized light. Compounds with the prefix (-) or l are levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer is also called an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemate, which occurs 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 enantiomers.

[0649] Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are referred to as “solvates.” When the solvent is water, the complex is referred to as a “hydrate.” This invention covers all solvates of the compounds of this invention. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvates are separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. “Solvate” includes solvates in solution phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0650] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0651] The compounds of this invention can be in amorphous or crystalline forms (crystalline or polymorphic). Furthermore, the compounds of this invention can exist in one or more crystalline forms. Therefore, this invention encompasses all amorphous or crystalline forms of the compounds of this invention within its scope. The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

[0652] As used herein, the term "isotope variant" refers to a compound in which one or more atoms constituting the compound contain a greater proportion of the naturally occurring isotope. For example, an "isotope variant" of a compound may be radiolabeled, i.e., containing one or more radioactive isotopes, or may be made of non-radioactive isotopes such as deuterium (…). 2 H or D), carbon-13 (H or D), carbon-13 13 C), Nitrogen-15 ( 15 The labeling is as follows: N). It should be understood that in compounds that have undergone such isotopic substitution, the following atoms (if present) may vary such that, for example, any hydrogen may be... 2 H / D, any carbon can be 13 C, or any nitrogen, can be 15 N, and the presence and location of such atoms can be determined to the extent that those skilled in the art can do so.

[0653] As used herein, the term "prodrug" refers to a substance that can be converted into the bioactive compound of the present invention under physiological conditions or by solvent degradation. The prodrugs of the present invention are prepared by modifying the functional groups in a compound, the modification of which can be removed by conventional procedures or in vivo to obtain the compound of the present invention. Prodrugs include compounds formed by bonding a hydroxyl or amino group from the compound of the present invention to any group. When a prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug cleaves to form a free hydroxyl or amino group.

[0654] The term "pharmaceutically acceptable salt" refers to a salt that, under reliable medical judgment, is suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and that meets a reasonable benefit / risk ratio.

[0655] The specific compounds disclosed herein may exist in the form of salts, such as salts formed with organic or inorganic bases, including acid addition salts, carboxylates, sulfonates, and phosphates. All such salts are within the scope of this invention, and the compounds mentioned herein also include their salt forms.

[0656] The salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods used for pharmaceutically acceptable salts, such as those described in Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Typically, these salts can be prepared by reacting the free acidic or basic form of the parent compound with a suitable base or acid in water or an organic solvent or a mixture thereof. Non-aqueous media are typically used, such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Acid addition salts (e.g., mono- or di-salts) can be formed using a variety of acids, including inorganic and organic acids.Examples of acid addition salts include mono- or di-salts formed with acids selected from the group consisting of: 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-acetaminobenzoic acid, butyric acid, (+)camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamicacid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, and gentisic acid. acid), glucoheptonicacid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrogen halides (e.g., hydrobromic acid, hydrochloric acid, hydroiodic acid), isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid (acid), nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, papoic 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, p-toluenesulfonic acid, undecenoic acid, valeric acid, and acylated amino acids.

[0657] A specific group of salts is formed from the following: acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, ethanesulfonic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (methanesulfonates), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, malonic acid, glucuronic acid, and lactobionic acid. A specific salt is a hydrochloride salt.

[0658] When the compounds disclosed herein contain an amino functional group, they can form quaternary ammonium salts, for example, by reacting with an alkylating agent in accordance with methods known to those skilled in the art. Such quaternary ammonium compounds fall within the scope of the compounds disclosed herein.

[0659] The compounds of this invention can exist as monosalts or disalts, depending on the pK of the acid forming the salt. a .

[0660] It should be understood that, for use in pharmaceuticals, the salts of the compounds disclosed herein must be pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described in Berge, Bigley and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. These pharmaceutically acceptable salts include acid addition salts formed with 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). For example, other salts, such as oxalates or formates, can be used to isolate the compounds disclosed herein and are within the scope of this invention. However, non-pharmaceutically acceptable salts can also be prepared in intermediate form and then converted to pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms can be used, for example, for the purification or isolation of compounds of the present invention, which form part of this invention.

[0661] This invention also includes salts formed using methods conventional in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, D-gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-p-gluconate, glyceryl phosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, and dodecyl sulfate. Sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, dihydroxynaphthalates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-type salts. + (C 1-4 Alkyl salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations that are suitable for counterion formation using halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, etc.

[0662] The compounds disclosed herein can form acid addition salts with one or more equivalents of an acid. The scope of this invention includes all possible stoichiometric and non-stoichiometric forms.

[0663] Preparation method

[0664] According to one aspect of the present invention, a method is provided for preparing compounds of formula I or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates thereof. The following are examples of synthetic schemes for synthesizing compounds of formula I. In the following schemes, the reactive groups may be protected with protecting groups and may be deprotected using techniques well-established in the art. The compounds of formula I described herein can be prepared by those skilled in the art of organic synthesis using standard methods, which will be described in detail below.

[0665] According to another aspect of the invention, the method for preparing a compound of formula I or a tautomer, stereoisomer, prodrug, crystal form, isotopic variant, pharmaceutically acceptable salt, hydrate, or solvate thereof (as defined herein) includes any one of the following methods A through D:

[0666] - Prepare compounds of formula II (i.e., compounds of formula I, where X is an optional substituted methylene group) by method A or B.

[0667] - Method C is used to prepare compounds of formula III (i.e., compounds of formula I, where X is -NH-).

[0668] - Method D or E is used to prepare compound IV (i.e., compound I, where X is -NR). z -, R z (Definition as above).

[0669] Method A

[0670] Method A includes the steps of preparing a compound of formula II as defined herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopic variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Method A includes the following steps:

[0671] Step (i): Preparation of the compound of formula (A-1):

[0672] [Formula A-1]

[0673]

[0674] Step (ii): To prepare compound (A-2) by reacting compound (A-1) with compound (E):

[0675] [Formula E]

[0676] as well as

[0677] [Formula A-2]

[0678]

[0679] Step (iii): Prepare compound (II) by reacting compound (A-2) with compound (F):

[0680] [Formula F]

[0681]

[0682] Among them, R 1 -R 4 Y and Z are defined as above.

[0683] X is an optionally substituted methylene group; and

[0684] L 1 It is a halide.

[0685] In one embodiment, L 1 It is selected from the group consisting of fluoride, chloride, bromide and iodide, preferably bromide or chloride.

[0686] In one embodiment, step (i) includes the following steps:

[0687] Step (i-1): Preparation of compound (aa-1):

[0688] [Formula aa-1]

[0689]

[0690] Step (i-2): Dissolve the compound of formula (aa-1) in methanol to prepare a methanol solution, and add SOCl2 to the methanol solution to obtain the compound of formula (aa-2):

[0691] [Formula aa-2]

[0692]

[0693] Step (i-3): Passing Cl2 gas into compound (aa-2) yields compound (aa-3): and

[0694] [Formula aa-3]

[0695]

[0696] Step (i-4): Compound (A-1) is obtained by reacting compound (aa-3) with triethylamine.

[0697] In one embodiment, step (iii) includes the following steps:

[0698] Step (iii-1): Compound (aa-4) is obtained by reacting compound (A-2) with lithium hydroxide: and

[0699] [Formula aa-4]

[0700]

[0701] Step (iii-2): Compound (II) is prepared by reacting compound (aa-4) with compound (F).

[0702] In one embodiment, an example reaction scheme for method A is shown in scheme I:

[0703] Option I

[0704]

[0705] Method B

[0706] Method B prepares compounds of formula II as defined in this invention, or their tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates, comprising the following steps:

[0707] Step (i): Prepare compound (B-1);

[0708] [Formula B-1]

[0709]

[0710] Step (ii): To prepare compound (B-2) by reacting compound (B-1) with compound (F):

[0711] [Formula F]

[0712] as well as

[0713] [Formula B-2]

[0714]

[0715] Step (iii): Compound (II) is obtained by reacting compound (B-2) with compound (E):

[0716] [Formula E]

[0717]

[0718] Among them, R 1 -R 4 Y and Z are defined as above.

[0719] X is an optionally substituted methylene group; and

[0720] L 1 It is a halide.

[0721] In one embodiment, L 1 It is selected from the group consisting of fluoride, chloride, bromide and iodide, preferably bromide or chloride.

[0722] In one embodiment, step (i) includes the following steps:

[0723] Step (i-1): Prepare compound of formula (bb-1);

[0724] [Formula bb-1]

[0725]

[0726] Step (i-2): Dissolve compound (bb-1) in methanol to prepare a methanol solution, and add SOCl2 to the methanol solution to obtain compound (bb-2): and

[0727] [Formula bb-2]

[0728]

[0729] Step (i-3): Passing Cl2 gas into compound (bb-2) yields compound (bb-3):

[0730] [Formula bb-3]

[0731] as well as

[0732] Step (i-4): Compound (B-1) is obtained by reacting the compound of formula (bb-3) with triethylamine.

[0733] In one embodiment, an example reaction scheme for method B is shown in scheme II:

[0734] plan II

[0735]

[0736] Method C

[0737] Method C prepares compounds of formula III as defined in this invention, or their tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates. Method C includes the following steps:

[0738] Step (i): Preparation of the (C-1) compound;

[0739] [Formula C-1]

[0740]

[0741] Step (ii): To obtain compound (C-2) by reacting compound (C-1) with compound (F):

[0742] [Formula F]

[0743] as well as

[0744] [Formula C-2]

[0745]

[0746] Step (iii): Compound (II) is obtained by reacting compound (C-2) with compound (E):

[0747] [Formula E]

[0748]

[0749] Among them, R 1 -R 4 Y and Z are as defined above; and

[0750] L 1 It is a halide.

[0751] In one embodiment, L 1 It is selected from the group consisting of fluoride, chloride, bromide and iodide, preferably bromide or chloride.

[0752] In one embodiment, step (i) includes the following steps:

[0753] Step (i-1): Prepare compound (cc-1);

[0754] [Formula cc-1]

[0755]

[0756] Step (i-2): React compound (cc-1) with benzaldehyde and add sodium triacetoxyborohydride to obtain compound (cc-2);

[0757] [Formula cc-2]

[0758]

[0759] Step (i-3): A mixture was prepared by mixing tert-butanol with N-(oxomethylene)aminosulfonyl chloride, and compound (cc-2) was added to the mixture to obtain compound (cc-3):

[0760] [Formula cc-3]

[0761]

[0762] Step (i-4): In the presence of diisopropyl azodicarbonate (DIAD) and triphenylphosphine (PPH3), compound (cc-3) is subjected to a cyclization reaction to obtain compound (C-1).

[0763] In one embodiment, an example reaction scheme for method C is shown in scheme III:

[0764] plan III

[0765]

[0766] Method D

[0767] Method D prepares compounds of formula IV as defined in this invention, or their tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates. Method D includes the following steps:

[0768] Step (i): Preparation of compound (D-1):

[0769] [Formula D-1]

[0770]

[0771] Step (ii): Compound (D-2) is obtained by reacting compound (D-1) with compound (F):

[0772] [Formula F]

[0773]

[0774] [Formula D-2]

[0775]

[0776] Step (iii): By reacting compound (D-2) with compound R z -L 2 The compound reacts to give the compound of formula (D-3):

[0777] [Formula D-3]

[0778]

[0779] Step (iv): In the presence of Pd / C, H2 gas is passed into compound (D-3) to obtain compound (D-4):

[0780] [Formula D-4]

[0781]

[0782] Step (v): Compound (II) is obtained by reacting compound (D-4) with compound (E):

[0783] [Formula E]

[0784]

[0785] Among them, R 1 -R 4 Rings A, Y, and Z are defined as above; and

[0786] L 1 and L 2 Each of them is a halide.

[0787] In one embodiment, L 1 and L 2 Each of them is selected from the group consisting of fluoride, chloride, bromide and iodide, preferably bromide or chloride.

[0788] In one embodiment, step (i) includes the following steps:

[0789] Step (i-1): Preparation of compound (dd-1):

[0790] [Formula dd-1]

[0791]

[0792] Step (i-2): React compound (dd-1) with benzaldehyde to obtain compound (dd-2).

[0793] [Formula dd-2]

[0794]

[0795] Step (i-3): A mixture was prepared by mixing tert-butanol with N-(oxomethylene)aminosulfonyl chloride, and compound (dd-2) was added to the mixture to obtain compound (dd-3):

[0796] [Formula dd-3]

[0797]

[0798] Step (i-4): In the presence of diisopropyl azodicarbonate (DIAD) and triphenylphosphine (PPH3), compound (dd-3) is subjected to a cyclization reaction to obtain compound (D-1).

[0799] In one implementation, an example reaction scheme for method D is shown in scheme IV:

[0800] Option IV

[0801]

[0802] Method E

[0803] Method E prepares compounds of formula IV as defined in this invention, or their tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates, or solvates, comprising the following steps:

[0804] Step (i): Preparation of compound (E-1):

[0805] [Equation E-1]

[0806]

[0807] Step (ii): Compound (E-2) is obtained by reacting compound (E-1) with NaH:

[0808] [Equation E-2]

[0809]

[0810] Step (iii): By reacting compound of formula (E-2) with formula R z -L 2 The compound reacts to give the compound of formula (E-3):

[0811] [Equation E-3]

[0812]

[0813] Step (iv): The compound of formula (E-3) is subjected to an amidation reaction to obtain the compound of formula (E-5):

[0814] [Formula E-5]

[0815]

[0816] Step (v): In the presence of a Pd / C catalyst, compound (E-5) is reacted with H2 gas to obtain compound (E-6):

[0817] [Formula E-6]

[0818]

[0819] Step (vi): Compound (II) is obtained by reacting compound (E-6) with compound (E):

[0820] [Formula E]

[0821]

[0822] Among them, R 1 -R 4 R z Rings A, Y, and Z are defined as above; and

[0823] L 1 and L 2 Each of them is a halide.

[0824] In one embodiment, step (iv) includes the following steps:

[0825] Step (iv-1): Compound (E-5) is obtained by reacting compound (E-3) with compound (E-4-1):

[0826] [Equation E-4-1]

[0827]

[0828] Among them, R 3 R 4 R z And ring A is defined as above.

[0829] In another embodiment, step (iv) includes the following steps:

[0830] Step (iv-2): Compound (E-4-3) is obtained by reacting compound (E-3) with compound (E-4-2):

[0831] [Equation E-4-2]

[0832]

[0833] [Equation E-4-3]

[0834]

[0835] Step (iv-3): Compound (E-5) is obtained by reacting compound (E-4-3) with compound (R4-L3):

[0836] Among them, R 3 R 4 R z And ring A as defined above; and

[0837] L 3 It is a halide on its own.

[0838] In one embodiment, step (i) includes the following steps:

[0839] Step (i-1): Preparation of compound (ee-1):

[0840] [Formula ee-1]

[0841]

[0842] Step (i-2): React compound (ee-1) with benzaldehyde to obtain compound (ee-2):

[0843] [Formula ee-2]

[0844]

[0845] Step (i-3): A mixture was prepared by mixing tert-butanol with N-(oxomethylene)aminosulfonyl chloride, and compound (ee-2) was added to the mixture to obtain compound (ee-3):

[0846] [Formula ee-3]

[0847]

[0848] Step (i-4): In the presence of diisopropyl azodicarbonate (DIAD) and triphenylphosphine (PPH3), compound (ee-3) is subjected to a cyclization reaction to obtain compound (E-1).

[0849] In one embodiment, an example reaction scheme for method E is shown in scheme V:

[0850] Option V

[0851]

[0852] Treatment effectiveness

[0853] The terms “treat,” “treating,” and “treatment” refer to a series of actions (such as administering a Polθ inhibitor or a pharmaceutical composition comprising it) initiated after a disease, disorder, or symptom has been diagnosed or observed, in order to temporarily or permanently eliminate, reduce, suppress, alleviate, or improve one or more of the underlying causes of the disease, disorder, or symptom troubling a subject, or one or more of the symptoms associated with the disease, disorder, or symptom troubling the subject. Therefore, treatment includes suppressing (e.g., preventing the development or further development of a disease, disorder, or symptom or its associated clinical symptoms) an active disease.

[0854] The terms “prevent,” “preventing,” and “prevention” refer to a series of actions (such as administering Polθ inhibitors or pharmaceutical compositions containing them) that temporarily or permanently prevent, suppress, inhibit, or reduce (e.g., in the absence of clinical symptoms) a subject’s risk of developing a specific disease, disorder, condition, or similar illness, or delay its onset, in the context of a subject susceptible to such a disease, disorder, or condition (e.g., before the onset of the disease, disorder, condition, or symptom). In some cases, the terms also refer to slowing the progression of a disease, disorder, or condition or inhibiting its progression to a harmful or undesirable state.

[0855] The terms “inhibition” and “reduction”, or variations thereof, related to Polθ, can refer to a measurable reduction or complete inhibition to achieve the 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 more than 99% compared to the control group. The term “approximately” as used herein means a change of a given value within ±20%, preferably within ±10%, and more preferably within ±5%.

[0856] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0857] This invention provides compounds for the prevention or treatment of diseases or disorders mediated by Polθ, or involving Polθ activity.

[0858] In some implementations, the disease or disorder mediated by Polθ is a type of proliferative disorder. The term "proliferative disorder" is used interchangeably herein and refers to unwanted or uncontrolled cell proliferation of excessive or abnormal cells, such as neoplasmic or proliferative growth, whether in vitro or in vivo, in which such cell proliferation is undesirable. Non-limiting examples of proliferative disorders include precancerous cell proliferation and malignant cell proliferation, including but not limited to: malignant growths and tumors, cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders (e.g., fibroproliferative disorders of connective tissue), and atherosclerosis.

[0859] In some embodiments, the disease or disorder mediated by Polθ is any of the HR-deficient cancers, including BRCA1 and BRCA2-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 compounds, compositions, and methods of the present invention can further enhance the therapeutic effect of cancer through one or more of the following modes of action (MOA): (1) a therapeutic mode that induces DNA damage, (2) a therapeutic mode that regulates the cell cycle, and (3) a therapeutic mode that inhibits components involved in the DNA damage response (DDR).

[0860] In cancer treatment, the therapeutically effective amount of a compound of formula I provided herein refers to an amount sufficient to provide therapeutic benefit or delay or minimize one or more cancer-related symptoms during treatment. The therapeutically effective amount of a compound in cancer treatment refers to the amount of a therapeutic agent that provides such therapeutic benefit during treatment, whether used alone or in combination with other treatment methods.

[0861] The effective amount of the compounds of this invention depends on a variety of factors, including the route of administration, target, patient's physiological condition, whether the patient is human or animal, other drugs administered, whether the treatment is preventative or therapeutic, and the specific activity of the composition itself and its ability to elicit the desired response in an individual. In the context of this disclosure, a patient can be human or a non-human mammal. Typically, dosage regimens are adjusted to provide the best therapeutic response, i.e., to optimize safety and efficacy. Therefore, a therapeutically effective amount also refers to a dose in which the beneficial effects of administering the compounds described herein outweigh any adverse side effects.

[0862] Pharmaceutical Composition

[0863] The terms “combination,” “combined,” and related terms refer to the simultaneous, single, or sequential administration of two or more therapeutic agents or therapies. For example, the compounds disclosed herein may be administered simultaneously or sequentially with another therapeutic agent or therapy in separate unit dosage forms, or simultaneously in a single unit dosage form. Another therapeutic approach may be radiotherapy. Another therapeutic agent may be an anticancer drug. Anticancer drugs may include anticancer drugs targeting DNA damage response (DDR). DNA damage response (DDR) refers to the collective term for various intracellular and intercellular signaling events and enzyme activities that occur due to the induction and detection of DNA damage. Cancer cells differ from normal cells in at least three key aspects of DDR, making DDR an attractive drug target (and currently being used) for the development of new cancer therapies. The absence of one or more DDR pathways, increased replication pressure, and elevated levels of endogenous DNA damage are all differentiating aspects of cancer DDR that can serve as therapeutic targets.Currently, several anticancer drugs targeting DDR are known and have been developed, 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, 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., adaserti (adavosertib) (e.g., MK-1775 or AZD1775)), PLK1 inhibitors (e.g., voraseti (Volasertib) (BI) 6727), onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or topoisomerase inhibitors (e.g., belotecone, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide) (see Mark J. O'Connor, Molecular Cell 60, November 19, 2015, p. 547-560, Choi et al., Int J Mol Sci. 2022 Feb; 23(3): 1701). The compounds disclosed in this article also belong to DDR targeted drugs.

[0864] In some embodiments, a pharmaceutical composition is provided comprising the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopic variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier, wherein the composition may be administered simultaneously, alone, or sequentially with the additional DDR-targeted anticancer drug.

[0865] In some embodiments, a method is provided for treating or preventing a polymerase-θ-mediated disease or disorder in a subject, the method comprising administering to the subject a compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopic variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, and the method further comprising administering to the subject the DDR-targeted anticancer drug.

[0866] In some embodiments, a kit is provided comprising:

[0867] - A first pharmaceutical composition or administration method comprising the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopic variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally one or more pharmaceutically acceptable carriers; and

[0868] - A second pharmaceutical composition or administration route comprising the additional DDR-targeted anticancer drug, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally one or more pharmaceutically acceptable carriers.

[0869] In some embodiments, the kit is used for methods of treating and / or preventing diseases or disorders mediated by polymerase θ. In some embodiments, a first pharmaceutical composition or dosage form may be administered simultaneously, alone, or sequentially with a second pharmaceutical composition or dosage form. In some embodiments, the kit may also include instructions for use, containing instructions for simultaneous, sequential, or individual use in the treatment and / or prevention of diseases or disorders mediated by polymerase θ.

[0870] This invention also relates to a pharmaceutical composition comprising a pharmaceutically effective amount of one or more of the compounds disclosed herein and a pharmaceutically acceptable carrier and / or excipient. The composition may also comprise one or more additional therapeutic agents for the purpose of treating or preventing the diseases or disorders disclosed herein. Pharmaceutically acceptable carriers and excipients are well known in the art, and the choice of carriers and excipients will vary considerably depending on factors such as the route of administration, the effect on solubility and stability, and the nature of the dosage form.

[0871] Treatment

[0872] On the other hand, the present invention provides a method for treating or preventing polymerase-θ-mediated diseases or disorders in a subject who requires such treatment or prevention, comprising the step of administering to a subject one or more compounds disclosed herein, or tautomers, stereoisomers, prodrugs, crystal forms, isotopic variants, pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions disclosed herein.

[0873] The terms “person,” “patient,” and “subject” are used interchangeably. A “subject” intended for drug administration includes, but is not limited to: humans (i.e., males or females of any age, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0874] Dosage

[0875] The pharmaceutical compositions of the present invention can be administered via a variety of routes, including but not limited to: oral, parenteral (injection) (e.g., intravenous, subcutaneous, intramuscular, intravascular administration or injection), sublingual, topical, transdermal, ocular, rectal, nasal and vaginal administration.

[0876] The pharmaceutical compositions provided herein are administered in pharmaceutically effective amounts. For example, a pharmaceutically effective amount of the pharmaceutical composition may be 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 one embodiment, the amount may be 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 about 0.1 mg to about 1 mg per kg of body weight. In another embodiment, the range of the amount may be 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 dosage of the composition to be administered is typically determined by a physician based on relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound to be administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0877] Dosage form

[0878] For example, the pharmaceutical composition may be in dosage forms suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, suspensions, etc.; dosage forms suitable for parenteral administration, such as sterile solutions, suspensions, or emulsions, etc.; dosage forms suitable for topical administration, such as ointments or creams; or dosage forms suitable for rectal administration, such as suppositories. The pharmaceutical composition may comprise a conventional pharmaceutical carrier or excipient, and the compound of the present invention as the active ingredient. In addition, it may include other pharmaceuticals or pharmaceutical formulations, carriers, excipients, etc.

[0879] Exemplary parenteral dosage forms include solutions or suspensions of the active compound in sterile aqueous solutions, such as propylene glycol or glucose solutions. This route of administration can be appropriately buffered as needed. Suitable drug carriers include inert diluents or fillers, water, and various organic solvents. Pharmaceutical compositions may include other ingredients, such as flavoring agents, binders, excipients, etc., as needed. For oral administration, tablets containing various excipients such as citric acid can be used with various disintegrants such as starch, alginate, and specific complex silicates, and various binders such as sucrose, gelatin, and gum arabic. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are commonly used in tablet compression. Similar types of solid compositions can also be used in soft and hard capsules. Preferred materials 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 or flavorings, colorings or dyes, and, if necessary, with a diluent such as water, ethanol, propylene glycol, glycerin, or combinations thereof, an emulsifier or suspending agent may be added. Methods for preparing various pharmaceutical compositions containing specific amounts of the active compound are known or obvious to those skilled in the art.

[0880] Dosage

[0881] The pharmaceutical compositions of the present invention can be administered in single or multiple doses. The frequency of administration can be once, twice, three times, four times, five times, six times, or more than six times daily. The frequency of administration can be once a month, once every two weeks, once a week, or once every two days. In specific cases, continuous administration and maintenance of the administration period can be performed as needed. In some embodiments, the administration period of the pharmaceutical compositions of the present invention can exceed 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the administration period of the pharmaceutical compositions of the present invention is less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the pharmaceutical compositions of the present invention are administered slowly over a prolonged period.

[0882] Compounds, chemical portions, or groups relating to a specific aspect, embodiment, or example of the invention are applicable to other aspects, embodiments, or examples described herein, unless they are incompatible. All features disclosed in this specification (including all appended claims and abstract) and / or all steps of any method or process disclosed herein may be combined arbitrarily, unless some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to new features or combinations thereof disclosed herein (including all appended claims and abstract), or new features or combinations thereof of the methods or process steps disclosed herein.

[0883] As fully explained in this article, the content of the papers and literature cited in this article is incorporated into this article through citation.

[0884] Example

[0885] The present invention will now be described in more detail with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and do not limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, parts and percentages refer to parts by weight and weight percentages.

[0886] Typically, in the preparation method, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C to 100°C, or 0°C to 80°C). The reaction time is typically 0.1 to 60 hours, or 0.5 to 24 hours.

[0887] abbreviation

[0888] The abbreviations used in this article have the following meanings:

[0889] Et3N: Triethylamine

[0890] MeOH: Methanol

[0891] EtOH: Ethanol

[0892] SOCl2: thionyl chloride

[0893] CHCl3: Chloroform

[0894] Na2SO4: Sodium sulfate

[0895] LCMS: Liquid Chromatography-Mass Spectrometry

[0896] HPLC: High Performance Liquid Chromatography

[0897] Boc: tert-Butoxycarbonyl

[0898] DCM: Dichloromethane

[0899] TFA: Trifluoroacetic acid

[0900] THF: Tetrahydrofuran

[0901] DBA: Dibenzylideneacetone

[0902] ACN: Acetonitrile

[0903] EtOAc: Ethyl acetate

[0904] NaOAc: Sodium acetate

[0905] NaBH(OAc)3: Sodium triacetoxyborohydride

[0906] AcOH: Acetic acid

[0907] TLC: Thin-layer chromatography

[0908] PPh3: Triphenylphosphine

[0909] DIAD: Diisopropyl azodicarbonate

[0910] HOBT: 1-Hydroxybenzotriazole

[0911] EDCI: N-(3-Dimethylaminopropyl)-N′-Ethylcarbodiimide Hydrochloride

[0912] DIEA: N,N-Diisopropylethylamine

[0913] DMF: Dimethylformamide

[0914] AlMe3: Trimethylaluminum

[0915] Py: Pyridine

[0916] ODS: Octadecyl silica

[0917] TBAF: Tetra-n-Butylammonium Fluoride

[0918] Materials and Methods

[0919] Unless otherwise specified, solvents, reagents, and raw materials were purchased from commercial suppliers and used directly. Unless otherwise specified, all reactions were performed at room temperature. Flash column chromatography was performed using ISCO Combiflash Nextgen or Biotage Selek columns pre-packed with Merck Fast Silica 60 (40-63 μm) or C18 Fast Silica.

[0920] Unless otherwise stated, all reagents were used without further purification. 1H-NMR spectra were obtained at room temperature using a Bruker 400MHz instrument in DMSO-d6 or CDCl3. When more than two conformational isomers are detected, the chemical shift of the most enriched conformational isomer is usually reported. 1 Chemical shifts in 1H NMR spectra are reported in parts per million (ppm) using residual solvent as an internal standard, on a delta scale. Partition modes are designed and integrated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, and coupling constants (Hz) are typically listed in tabular form. LC-MS conditions are described below:

[0921] LCMS Method A:

[0922] LCMS column: SHIMADZU Xtimate C18 2.1*30mm, 3µm

[0923] Mobile phase: Solvent A: Water (4 L) + TFA (1.5 mL)

[0924] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[0925] Flow rate: 0.8 mL / min

[0926] Execution time: Maintain a concentration gradient of 10% to 80% (solvent B) for 6 minutes, and maintain an 80% concentration for 0.5 minutes.

[0927] Temperature: 50℃

[0928] LCMS Method B:

[0929] LCMS column: SHIMADZU Nano Chrom 120C18 3.0*30mm, 3um

[0930] Mobile phase: Solvent A: Water (4 L) + TFA (1.5 mL)

[0931] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[0932] Flow rate: 0.8 mL / min

[0933] Execution time: Maintain a concentration gradient of 10% to 80% (solvent B) for 6 minutes, and maintain an 80% concentration for 0.5 minutes.

[0934] Temperature: 50℃

[0935] LCMS Method C:

[0936] LCMS column: SHIMADZU Xtimate C18 2.1*30mm, 3µm

[0937] Mobile phase: Solvent A: Water (4 L) + TFA (1.5 mL)

[0938] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[0939] Flow rate: 0.8 mL / min

[0940] Execution time: Maintain a concentration gradient of 30% to 90% (solvent B) for 6 minutes, and maintain a 90% concentration for 0.5 minutes.

[0941] Temperature: 50℃

[0942] LCMS Method D:

[0943] LCMS column: SHIMADZU Nano Chrom 120C18 3.0*30mm, 3um

[0944] Mobile phase: Solvent A: Water (4 L) + TFA (1.5 mL)

[0945] Solvent B: Acetonitrile (4L) + TFA (0.75mL)

[0946] Flow rate: 0.8 mL / min

[0947] Execution time: Maintain a concentration gradient of 30% to 90% (solvent B) for 6 minutes, and maintain a 90% concentration for 0.5 minutes.

[0948] Temperature: 50℃

[0949] Experimental steps:

[0950] Intermediate 1: (S)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxylic acid 1,1-dioxide

[0951]

[0952] Step a. SOCl2 (23.42 g, 196.84 mmol, 14.30 mL) was added to a solution of (2S)-2-amino-4-[[(3S)-3-amino-3-carboxy-propyl]dithioalkyl]-butyric acid (20 g, 65.61 mmol, HCl) in MeOH (200 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. LCMS results showed the detection of the expected compound. The reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-amino-4-[[(3S)-3-amino-4-methoxy-4-oxo-butyl]dithioalkyl]butyrate (28 g, crude, HCl) as a white solid.

[0953] 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 = 7.2Hz, 4H).

[0954] Step b. Cl2 (61 g, 860.25 mmol) gas was passed into a mixed solution of (2S)-2-amino-4-[[(3S)-3-amino-4-methoxy-4-oxo-butyl]dithioalkyl]butyrate (5.3 g, 15.92 mmol, HCl) in EtOH (20 mL) and CHCl3 (40 mL) at 0 °C for 20 minutes to obtain a white suspension of the reaction mixture. The white suspension was filtered, and the filter cake was washed with CHCl3 (100 mL), collecting the white solid. A white solid of (2S)-2-amino-4-chlorosulfonyl-butyrate (4 g, crude, HCl) was obtained and used directly in the next reaction without further purification.

[0955] 1 H NMR(DMSO-d6)δ=10.05(br,s,3H),4.21(t,J=7.6Hz,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).

[0956] Step c. Et3N (4.82 g, 47.60 mmol, 6.62 mL) was added to a CHCl3 (50 mL) solution of (2S)-2-amino-4-chlorosulfonylbutyrate (4 g, 15.87 mmol, HCl) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. LCMS results showed the detection of the expected compound. The white suspension of the reaction mixture was washed with water (40 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a white solid of (3S)-1,1-dioxo-1,2-thiazolidin-3-carboxylic acid methyl ester (2.38 g, 11.95 mmol, yield 75.34%, purity 90%), which was used directly in the next step without further purification.

[0957] 1 H NMR(DMSO-d6)δ=7.50(br d,J=5.6Hz,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).

[0958] Step d. Add 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) to a solution of (3S)-1,1-dioxo-1,2-thiazolidin-3-carboxylic acid methyl ester (1 g, 5.58 mmol) in dioxane (15 mL). Stir the mixture at 80 °C for 12 hours. LC-MS results showed detection of the expected compound. The reaction solution was directly dried and extracted with water (100 mL) and DCM (150 mL × 3). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reversed-phase column chromatography (column: 40 g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; B%: 0%-58%, 30 min) to give a white solid (3S)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidin-3-carboxylic acid methyl ester (660 mg, 1.95 mmol, yield 34.96%, purity 100%).

[0959] MS(ESI)m / z = 338.9[M+H] + ; 1H NMR(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,1 H),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).

[0960] Step e. LiOH·H2O (243.12 mg, 5.79 mmol) was added to a solution of (3S)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidin-3-carboxylic acid methyl ester (490 mg, 1.45 mmol) in MeOH (2 mL), THF (2 mL), and H2O (1 mL). The mixture was stirred at 25 °C for 12 hours. LCMS results showed the detection of the expected compound. The residue was purified by reversed-phase column chromatography (column: 40 g C18 reversed-phase column; mobile phase: [water-ACN]; B%: 0%-48%, 30 min) to give a white solid (S)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxylic acid 1,1-dioxide (160 mg, 493.41 μmol, yield 34.07%, purity 100%).

[0961] MS(ESI)m / z = 324.8[M+H] + ; 1 H NMR (DMSO-d6)δ

[0962] =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).

[0963] Intermediate 2: (3S)-2-[2-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-1,1-dioxo-1,2-thiazolidin-3-carboxylic acid methyl ester

[0964]

[0965] Step a. Add 4-chloro-2-methyl-6-(trifluoromethyl)pyrimidine (548.45 mg, 2.79 mmol), Cs₂CO₃ (1.82 g, 5.58 mmol), Xantphos (161.45 mg, 279.03 μmol), and Pd₂(dba)₃ (255.51 mg, 279.03 μmol) to a solution of (3S)-1,1-dioxo-1,2-thiazolidin-3-carboxylic acid methyl ester (500 mg, 2.79 mmol) in dioxane (15 mL). Stir the mixture at 80 °C for 12 hours. LCMS results showed detection of the expected compound. After direct drying of the reaction solution, extract with water (20 mL) and DCM (30 mL × 3), combine the organic phases, wash with brine (30 mL), dry to anhydrous Na₂SO₄, filter, and concentrate under reduced pressure to obtain the residue. The residue was purified by reversed-phase column chromatography (column: 40 g C18 reversed-phase column; mobile phase: [water (0.05% HCl-ACN)]; B%: 0%-50%, 30 min) to give a colorless oily (3S)-2-[2-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-1,1-dioxo-1,2-thiazolidin-3-carboxylic acid methyl ester (430 mg, 1.27 mmol, yield 22.71%, purity 100%).

[0966] MS(ESI)m / z = 340.6[M+H] + ; 1 H NMR(DMSO-d6)δ=7.34(s,1H),5.10(dd,J=7.6,5.2Hz,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).

[0967] Intermediate 3: 2-(tert-butyl)4-methyl(S)-5-benzyl-1,2,5-thiadiazolidine-2,4-dicarboxylic acid ester, 1,1-dioxide

[0968]

[0969] Step a. Benzaldehyde (2.73 g, 25.71 mmol, 2.60 mL) was added to a THF (50 mL) solution of (2S)-2-amino-3-hydroxy-propionate (5 g, 32.14 mmol, HCl) at 25 °C, 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 to 5 °C for 1 hour. NaBH(OAc)3 (11.58 g, 54.63 mmol) was added in portions over 30 minutes, and the reaction mixture was stirred at 15 °C for 16 hours. LCMS results showed the expected mass was observed. Saturated NaHCO3 solution (175 mL) was added to the suspension over 45 minutes at 0-5℃ (gas was generated, pH was adjusted to 8-9), the mixture was extracted with EtOAc (100 mL × 3), the organic layer was washed with water (100 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography. 80g Sepa Silica gel rapid column chromatography, eluting with a gradient of 0-80% ethyl acetate / petroleum ether at 80 mL / min, yielded a colorless oily methyl (2S)-2-(benzylamino)-3-hydroxypropionate (5.6 g, 25.93 mmol, yield 80.70%, purity 96.9%).

[0970] MS(ESI)m / z = 210.1[M+H] + ; 1 H NMR (DMSO-d6): δ=7.32-7.31(m,4H),7.26-7.21(m,1H),4.84(t,J=4.8Hz,1H),3.77(d,J=13.6 Hz,1H),3.63(s,3H),3.61(d,J=6.4Hz,1H),3.59-3.56(m,2H),3.26(t,J=5.2Hz,1H),2.40(br s,1H).

[0971] Step b. A DCM solution of t-BuOH (1.66 g, 22.45 mmol, 2.15 mL) in 10 mL was added dropwise to a DCM solution of N-(oxomethylene)aminosulfonyl chloride (2.89 g, 20.41 mmol, 1.78 mL) in 30 mL at 0 °C, and the mixture was stirred for 1 hour at 0 °C under a N2 atmosphere. Then, a DCM solution of (2S)-2-(benzylamino)-3-hydroxypropionate (4.27 g, 20.41 mmol) and Et3N (3.10 g, 30.61 mmol, 4.26 mL) in 30 mL was added to the solution at 0 °C. The mixture was stirred at 10 to 19 °C for 16 hours. LCMS results showed the expected mass. Thin-layer chromatography (TLC) (plate 1, SiO2, petroleum ether: ethyl acetate = 1:1) showed a new spot (R) f =0.8). The mixture was diluted with water (100 mL), extracted with dichloromethane (30 mL × 3), and the combined organic layers were 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 to 41% ethyl acetate in petroleum ether to give a yellow gel-like methyl (2S)-2-[benzyl(tert-butoxycarbonylaminosulfonyl)amino]-3-hydroxypropionate (1.5 g, 3.63 mmol, yield 17.79%, purity 94%).

[0972] MS(ESI)m / z = 289.0[M-Boc+H] + ; 1 H NMR(CDCl3)δ=7.60-7.39(m,3H),7.38-7.29(m,3H),4.71-4.63(m,2H),4.60 -4.53(m,1H),4.00(d,J=6.8Hz,2H),3.69(s,3H),2.88(s,1H),1.48(s,9H).

[0973] Step c. DIAD (2.04 g, 10.07 mmol, 1.95 mL) was added to a DCM (60 mL) solution of (2S)-2-[benzyl(tert-butyloxycarbonylaminosulfonyl)amino]-3-hydroxypropionate (3.26 g, 8.39 mmol) and PPh3 (2.64 g, 10.07 mmol) at 0 °C, and the mixture was stirred at 16 °C for 2 hours. LCMS results showed the expected mass. TLC (plate 1, SiO2, petroleum ether:ethyl acetate = 3:1) results showed new spots (R). f=0.6). The mixture was concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography, eluting with 0 to 25% ethyl acetate in petroleum ether, to give a white solid 1,1-dioxide of 2-(tert-butyl)-4-methyl(S)-5-benzyl-1,2,5-thiadiazolidine-2,4-dicarboxylic acid ester (2.56 g, 6.91 mmol, yield 82.37%, purity 100%).

[0974] MS(ESI)m / z = 393.0 [M+Na] + ; 1 H NMR (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).

[0975] Example 1

[0976] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)isothiazolidin-3-carboxamide 1,1-dioxide

[0977]

[0978] Step a. 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 to a 2 mL solution of intermediate 1 (50 mg, 154.19 μmol). The mixture was stirred at 25 °C for 12 hours. LCMS results showed detection of the expected compound. The residue was purified by reversed-phase column chromatography (column: 40 g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; B%: 0%-70%, 30 min) to give a brown solid (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidin-3-carboxamide (31 mg, 57.25 μmol, yield 37.13%, purity 100%, TFA).

[0979] MS(ESI)m / z = 428.1 [M+H] + ; 1H NMR(DMSO-d6)δ=7.46-7.39(m,2H),7.38-7.32(m,2H),7.26(br d,J=7.2Hz,1H),7.19(s,1H),4.84(dd,J=7.2,4.8Hz,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).

[0980] Example 2

[0981] (3S)-N-(2,4-difluoro-3-methyl-phenyl)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidin-3-carboxamide (compound number 44)

[0982] (S)-N-(2,4-difluoro-3-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide (compound number 2)

[0983]

[0984] Step a. Add 3-[chloro-(2-oxooxazolidine-3-yl)phosphoryl]oxazolidine-2-one (196.26 mg, 770.95 μmol) to a 1 mL solution of intermediate 1 (100 mg, 308.38 μmol) of Py, and add 2,4-difluoro-3-methylaniline (88.28 mg, 616.76 μmol). Stir the mixture at 25 °C for 12 hours. LCMS results showed detection of the expected compound. The residue was purified by reversed-phase column chromatography (column: 40 g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; B%: 0%-56%, 40 min) to give a white solid (3S)-N-(2,4-difluoro-3-methyl-phenyl)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidin-3-carboxamide (compound number 44) (53 mg, 99.07 μmol, yield 32.12%, purity 84%).

[0985] MS(ESI)m / z = 450.1[M+H] + ; 1H NMR(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=7.2Hz,1H),5.16( dd,J=7.6,4.8Hz,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).

[0986] Step b. Cs₂CO₃ (53.29 mg, 163.55 μmol) and MeI (30.95 mg, 218.07 μmol, 13.58 μL) were added to a solution of (3S)-N-(2,4-difluoro-3-methyl-phenyl)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidin-3-carboxamide (49 mg, 109.04 μmol) in ACN (1 mL). The mixture was stirred at 80 °C for 12 hours. LCMS results showed the detection of the expected compound. The reaction mixture was further purified by Prep-HPLC (column: BostonGreen ODS150*30mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 50%-90% B over 9 minutes) to give a white solid (3S)-N-(2,4-difluoro-3-methyl-phenyl)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidin-3-carboxamide (compound number 2) (15.5 mg, 33.45 μmol, yield 30.68%, purity 100%, TFA).

[0987] MS(ESI)m / z = 464.1 [M+H] + ; 1 H NMR(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).

[0988] Example 3

[0989] (S)-N-(3-chloro-3-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[0990]

[0991] Example 3 used the same synthesis method as Example 2, but in step a, 3-chloro-4-fluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (80.8 mg, 173.45 μmol, 47.78%, purity 100%).

[0992] MS(ESI)m / z = 466.0 [M+H] + ; 1 H NMR(DMSO-d6)δ=7.90(d,J=6.0Hz,1H),7.62(brd,J=7.2Hz,2H),7.34(s,1H),7.20(s,1H),4 .87(dd,J=7.2,5.2Hz,1H),3.72-3.59(m,2H),3.33(s,3H),2.60(s,3H),2.47-2.35(m,2H).

[0993] Example 4

[0994] (S)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[0995]

[0996] Example 4 used the same synthesis method as Example 2, but in step a, 3-chloro-2,4-difluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (10.57 mg, 21.32 μmol, 25.04%, 97.6% purity).

[0997] MS(ESI)m / z = 483.9[M+H] + ; 1 H NMR(DMSO-d6)δ=7.83-7.73(m,1H),7.52-7.27(m,2H),7.17(d,J=16.8Hz,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=8.8Hz,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).

[0998] Example 5

[0999] (S)-N-(3-bromo-2,4-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1000]

[1001] Example 5 used the same synthesis method as Example 2, but in step a, 3-bromo-2,4-difluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the desired compound as a white solid (32.42 mg, 60.14 μmol, yield 55.23%, purity 98%).

[1002] MS(ESI)m / z = 527.8 [M+H] + ; 1 H NMR(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=15.2Hz,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=9.2Hz,2.4H),2.95-2.68(m,0.3H),2.65-2.55(m,3H),2.47-2.05(m,1.7H).

[1003] Example 6

[1004] (S)-N-(2,4-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1005]

[1006] Example 6 used the same synthesis method as Example 2, but in step a, 2,4-difluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (38.28 mg, 79.22 μmol, yield 95.80%, purity 93%).

[1007] MS(ESI)m / z = 449.8 [M+H] + ; 1H NMR(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=8.8Hz,2.4H),2.63-2.52(m,3H),2.46-2.34(m,2H).

[1008] Example 7

[1009] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,3,4-trifluorophenyl)isothiazolidin-3-carboxamide 1,1-dioxide

[1010]

[1011] Example 7 used the same synthesis method as Example 2, but in step a, 2,3,4-trifluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (45.14 mg, 92.62 μmol, yield 99.98%, purity 95.9%).

[1012] MS(ESI)m / z = 467.8 [M+H] + ; 1 H NMR(DMSO-d6)δ=7.65-7.57(m,1H),7.53-7.27(m,2H),7.17(br d,J=18.4Hz,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=8.4Hz,2.4H),2.95-2.72(m,0.4H),2.70-2.54(m,3H),2.43-2.13(m,1.6H).

[1013] Example 8

[1014] (S)-N-(4-fluoro-3-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1015]

[1016] Example 8 used the same synthesis method as Example 2, but in step a, 4-fluoro-3-methyl-aniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (24.92 mg, 55.95 μmol, yield 26.23%, purity 100%).

[1017] MS(ESI)m / z = 445.9 [M+H] + ; 1 H NMR(DMSO-d6)δ=7.54-7.49(m,1H),7.44(td,J=7.6,4.0Hz,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).

[1018] Example 9

[1019] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,6-trifluorophenyl)isothiazolidin-3-carboxamide 1,1-dioxide

[1020]

[1021] Example 9 used the same synthesis method as Example 2, but in step a, 2,4,6-trifluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (53.16 mg, 110.33 μmol, yield 41.68%, purity 97%).

[1022] MS(ESI)m / z = 467.8 [M+H] + ; 1 H NMR(DMSO-d6)δ=7.59-7.46(m,1H),7.39-7.25(m,2H),7.18(d,J=10.0Hz,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).

[1023] Example 10

[1024] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,4,5-trifluorophenyl)isothiazolidin-3-carboxamide 1,1-dioxide

[1025]

[1026] Example 10 used the same synthesis method as Example 2, but in step a, 2,4,5-trifluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (39.37 mg, 82.47 μmol, yield 31.16%, purity 97.9%).

[1027] MS(ESI)m / z = 467.8 [M+H] + ; 1 H NMR(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=12.4Hz,2.3H),2.88-2.65(m,0.3H),2.62-2.53(m,3H),2.44-2.14(m,1.7H).

[1028] Example 11

[1029] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(2,3,4,5-tetrafluorophenyl)isothiazolidin-3-carboxamide 1,1-dioxide

[1030]

[1031] Example 11 used the same synthesis method as Example 2, but in step a, 2,3,4,5-tetrafluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (36.52 mg, 73.74 μmol, yield 34.76%, purity 98%).

[1032] MS(ESI)m / z = 485.8 [M+H] + ; 1H NMR(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=12.0Hz,2H),2.88-2.65(m,0.3H),2.61-2.52(m,3H),2.46-2.12(m,1.7H).

[1033] Example 12

[1034] (S)-N-(2,4-difluoro-3-methylphenyl)-N-(methyl-d3)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1035]

[1036] Example 12 used the same synthesis method as Example 2, but in step b, trideuterium (iodine)methane was used instead of MeI to obtain the target compound as a white solid (56.71 mg, 119.88 μmol, yield 53.87%, purity 98.6%).

[1037] MS(ESI)m / z = 466.9 [M+H] + ; 1 H NMR(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=7.6,4.4Hz,0.2 H),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).

[1038] Example 13

[1039] (S)-N-(2,4-difluoro-3-methylphenyl)-N-isopropyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1040]

[1041] Example 13 used the same synthesis method as Example 2, but 2-iodopropane was used instead of MeI in step b, to obtain the target compound as a white solid (58.25 mg, 116.74 μmol, yield 52.46%, purity 98.5%).

[1042] MS(ESI)m / z = 491.9[M+H] + ; 1 H NMR(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).

[1043] Example 14

[1044] (S)-N-(5-fluoropyridin-3-yl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1045]

[1046] Example 14 used the same synthesis method as Example 2, but in step a, 5-fluoropyridine-3-amine was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (85.98 mg, 198.85 μmol, yield 56.46%, purity 98%).

[1047] MS(ESI)m / z = 432.8[M+H] + ; 1 H NMR(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).

[1048] Example 15

[1049] (S)-N-(isoquinolin-4-yl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1050]

[1051] Example 15 used the same synthesis method as Example 2, but in step a, isoquinoline-4-amine was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (31.5 mg, 66.33 μmol, yield 24.73%, purity 97.809%).

[1052] MS(ESI)m / z = 464.9[M+H] + ; 1 H NMR(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=7.2,5.6Hz,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).

[1053] Example 16

[1054] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(naphthyl-1-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1055]

[1056] Example 16 used the same synthesis method as Example 2, but in step a, naphthalene-1-amine was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (222.51 mg, 477.69 μmol, yield 67.94%, purity 99.5%).

[1057] MS(ESI)m / z = 463.9 [M+H] + ; 1H NMR(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=7.6,6.0Hz,0.5H),4. 68-4.64(m,0.4H),3.58-3.41(m,2H),3.26(d,J=10.4Hz,3H),2.75-2.53(m,3H),2.18-1.84(m,2H).

[1058] Example 17

[1059] (S)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1060]

[1061] Example 17 used the same synthesis method as Example 2, but in step a, 2,4-difluoro-3-(trifluoromethyl)aniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (130.31 mg, 246.22 μmol, yield 44.26%, purity 97.76%).

[1062] MS(ESI)m / z = 517.8 [M+H] + ; 1 H NMR(DMSO-d6)δ=δ=8.20-8.05(m,0.7H),8.83-7.56(m,0.3H),7.56(d,J=7.2Hz,0.3H),7 .52(dt,J=10.8,7.2Hz,0.7H),7.37-7.30(m,1H),7.24-7.12(m,1H),5.63(dd,J=7.6,4. 4Hz,0.3H),4.89(dd,J=7.6,4.4Hz,0.7H),3.83-3.61(m,2H),3.56(s,1H),3.16(d,J=10 .0Hz,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).

[1063] Example 18

[1064] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(3,4,5-trifluorophenyl)isothiazolidin-3-carboxamide 1,1-dioxide

[1065]

[1066] Example 18 used the same synthesis method as Example 2, but in step a, 3,4,5-trifluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (128.17 mg, 272.72 μmol, yield 61.82%, purity 99.45%).

[1067] MS(ESI)m / z = 467.8 [M+H] + ; 1 H NMR (DMSO-d6) δ = 7.65 (s, 2H), 7.35 (s, 1H), 7.20 (s, 1H), 4.96 (s, 1H), 3.63 (d, J = 5.6Hz, 2H), 3.17 (s, 3H), 2.57 (s, 3H), 2.48-2.44 (m, 2H).

[1068] Example 19

[1069] (S)-N-(2,6-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1070]

[1071] Example 19 used the same synthesis method as Example 2, but in step a, 2,6-difluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (138.80 mg, 306.70 μmol, yield 66.76%, purity 99.30%).

[1072] MS(ESI)m / z = 449.8 [M+H] + ; 1 H NMR(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=7.2,5.2Hz,0.4H) ,4.94(dd,J=7.6,5.2Hz,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=14.0,7.6Hz,0.4H),2.52(s,1H),2.48(br s,2H),2.46-2.19(m,1.6H).

[1073] Example 20

[1074] (S)-N-(2-fluoro-3-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1075]

[1076] Example 20 used the same synthesis method as Example 2, but in step a, 2-fluoro-3-methyl-aniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (99.8 mg, 208.37 μmol, yield 29.96%, purity 93%).

[1077] MS(ESI)m / z = 445.8 [M+H] + ; 1 H NMR (DMSO-d6) δ=7.57 (br t,J=7.2Hz,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=6.8Hz,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).

[1078] Example 21

[1079] (S)-N-(2-fluoro-5-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1080]

[1081] Example 21 used the same synthesis method as Example 2, but in step a, 2-fluoro-5-methyl-aniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (184.73 mg, 396.89 μmol, yield 46.28%, purity 95.7%).

[1082] MS(ESI)m / z = 445.8 [M+H] + ; 1H NMR (DMSO-d6) δ =7.56(d,J=7.2Hz,0.5H),7.43(d,J=7.2Hz,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=8.0Hz,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).

[1083] Example 22

[1084] (S)-N-(2-fluoro-4-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1085]

[1086] Example 22 used the same synthesis method as Example 2, but in step a, 2-fluoro-4-methyl-aniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (138.38 mg, 304.45 μmol, yield 42.37%, purity 98%).

[1087] MS(ESI)m / z = 445.8 [M+H] + ; 1 H NMR(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 = 7.6Hz, 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).

[1088] Example 23

[1089] (S)-N-(2-fluoro-3-(trifluoromethyl)phenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1090]

[1091] Example 23 used the same synthesis method as Example 2, but in step a, 2-fluoro-3-(trifluoromethyl)aniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (155.76 mg, 305.78 μmol, yield 67.46%, purity 98.04%).

[1092] MS(ESI)m / z = 499.9 [M+H] + ; 1 H NMR(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=7.6,4.4Hz,0.3H),4.92-4.77(m,0.7H),3.8 1-3.60(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).

[1093] Example 24

[1094] (S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1095]

[1096] Example 24 used the same synthesis method as Example 2, but in step a, 4-fluoro-3-(trifluoromethyl)aniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (156.33 mg, 310.47 μmol, yield 68.50%, purity 99.18%).

[1097] MS(ESI)m / z = 499.8 [M+H] + ; 1H NMR(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).

[1098] Example 25

[1099] (S)-N-(2-chloro-4,6-difluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1100]

[1101] Example 25 used the same synthesis method as Example 2, but in step a, 2-chloro-4,6-difluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline to obtain the target compound as a white solid (172.16 mg, 350.39 μmol, yield 63.32%, purity 98.475%).

[1102] MS(ESI)m / z = 483.8[M+H] + ; 1 H NMR(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),3.6 3-3.60(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=13.2Hz,1H),2.48-2.42(m,1H).

[1103] Example 26

[1104] (S)-N-(4-fluoro-2-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1105]

[1106] Example 26 used the same synthesis method as Example 2, but in step a, 4-fluoro-2-methylaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound as a white solid (144.14 mg, 318.90 μmol, yield 59.81%, purity 98.547%).

[1107] MS(ESI)m / z = 445.8 [M+H] + ; 1 H NMR(MeOD-d4)δ=7.80(dd,J=8.8,5.6Hz,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).

[1108] Example 27

[1109] (S)-N-(3-fluoro-2-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1110]

[1111] Example 27 used the same synthesis method as Example 2, but in step a, 3-fluoro-2-methylaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound as a white solid (51.71 mg, 116.09 μmol, yield 20.03%, purity 100%).

[1112] MS(ESI)m / z = 446.0 [M+H] + ; 1H NMR(MeOD-d4)δ=7.66(d,J=8.1Hz,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=2.0Hz,1H),2.43-2.29(m,1.4H),2.28(d,J=2.4Hz,1.2H),2.15-2.04(m,0.5H).

[1113] Example 28

[1114] (S)-N-(5-fluoro-2-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1115]

[1116] Example 28 used the same synthesis method as Example 2, but in step a, 5-fluoro-2-methylaniline was used instead of 2,4-difluoro-3-methylaniline to obtain the target compound as a white solid (123.12 mg, 272.01 μmol, yield 55.88%, purity 98.41%).

[1117] MS(ESI)m / z = 445.8 [M+H] + ; 1 H NMR(MeOD-d4)δ=7.60(dd,J=9.2,2.8Hz,0.5H),7.47-7.38(m,2H),7.28(dd ,J=9.2,2.8Hz,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).

[1118] Example 29

[1119] (R)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1120]

[1121] Example 29 employed the same synthetic method as Intermediate 1 and Example 1, but used (2R)-2-amino-4-[[(3R)-3-amino-3-carboxy-propyl]dithioalkyl]-butyric acid instead of (2S)-2-amino-4-[[(3S)-3-amino-3-carboxy-propyl]dithioalkyl]-butyric acid, and used 3-chloro-4-fluoro-N-methylaniline instead of N,3-dimethylaniline, to obtain the target compound as a white solid (7.4 mg, 15.88 μmol, yield 4.38%, purity 100%).

[1122] MS(ESI)m / z = 466.1 [M+H] + ; 1 H NMR(MeOD)δ=7.92-7.87(m,1H),7.69-7.60(m,1H),7.48(t,J=8.8Hz,1H),7.42(s,1H),7.22(s,1H),5. 03(t,J=6.0Hz,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).

[1123] Example 30

[1124] (S)-N-methyl-2-(2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)-N-(m-tolyl)isothiazolidin-3-carboxamide 1,1-dioxide

[1125]

[1126] Step a. Intermediate 2 (150 mg, 442.10 μmol) and trimethylalumane (2 M, 442.10 μL) were added to a 4 mL solution of 3-methylaniline (104.22 mg, 972.62 μmol, 105.38 μL) in toluene. The mixture was stirred at 100 °C for 12 hours. LCMS results showed detection of the expected compound. The residue was purified by reversed-phase column chromatography (column: 40 g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; B%: 0%-66%, 40 min) to give a white solid (3S)-2-[2-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidin-3-carboxamide (130 mg, 219.59 μmol, yield 49.67%, purity 70%).

[1127] MS(ESI)m / z = 414.9[M+H] + ; 1 H NMR(DMSO-d6)δ=10.51(br s,1H),7.45(s,1H),7.37-7.30(m,2H),7.20(t,J=7.6Hz,1H),6.90(d,J=7.6Hz,1H),5.12(dd,J=7.6,4.4Hz ,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).

[1128] Step b. Cs₂CO₃ (255.53 mg, 784.26 μmol) and MeI (89.05 mg, 627.41 μmol, 39.06 μL) were added to a solution of (3S)-2-[2-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidin-3-carboxamide (130 mg, 313.71 μmol) in ACN (1 mL). The mixture was stirred at 80 °C for 12 hours. LCMS results showed detection of the expected compound. The crude product was further purified by Prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 44%-84% B, 9 min) to give a white solid (S)-N-methyl-2-(2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)-N-(m-tolyl)-isothiazolidin-3-carboxamide 1,1-dioxide (26.1 mg, 60.92 μmol, yield 19.42%, purity 100%).

[1129] MS(ESI)m / z = 429.0 [M+H] + ; 1 H NMR(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).

[1130] Example 31

[1131] (S)-N-(2,4-difluoro-3-methylphenyl)-N-methyl-2-(2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1132]

[1133] Example 31 used the same synthesis method as Example 30, but 2,4-difluoro-3-methylaniline was used instead of 3-methylaniline in step a, to obtain the target compound as a white solid (57.1 mg, 122.31 μmol, yield 46.15%, purity 100%).

[1134] MS(ESI)m / z = 465.0 [M+H] + ; 1 H NMR(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),3.78-3.6 2(m,2H),3.50(s,0.7H),3.15(d,J=7.2Hz,2.3H),2.62-2.57(m,3H),2.35-2.28(m,2H),2.26-2.21(m,3H).

[1135] Example 32

[1136] (S)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-(2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)isothiazolidin-3-carboxamide 1,1-dioxide

[1137]

[1138] Example 32 used the same synthesis method as Example 30, but in step a, 3-chloro-4-fluoroaniline was used instead of 3-methylaniline to obtain the target compound as a white solid (57.1 mg, 122.31 μmol, yield 46.15%, purity 100%).

[1139] MS(ESI)m / z = 467.0 [M+H] + ; 1 H NMR(DMSO-d6)δ=7.90(d,J=6.0Hz,1H),7.63(d,J=6.8Hz,2H),7.30(s,1H),4.90(dd,J=7.6,4.4Hz,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).

[1140] Example 33

[1141] (S)-2-(2,6-bis(trifluoromethyl)pyrimidin-4-yl)-N-methyl-N-(m-tolyl)isothiazolidin-3-carboxamide 1,1-dioxide

[1142]

[1143] Step a. The mixture of (3S)-1,1-dioxo-1,2-thiazolidin-3-carboxylic acid methyl ester (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 and purged three times with N2. The mixture was then stirred at 100 °C for 12 hours under N2 atmosphere. LCMS results showed the expected mass. The reaction mixture was quenched with NH4Cl (10 mL), diluted with water (20 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reversed-phase column chromatography (column: 80 g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; B%: 0%-50%, 30 min) to give a white solid (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidin-3-carboxamide (640 mg, 2.27 mmol, yield 81.21%, purity 95%).

[1144] MS(ESI)m / z = 268.9[M+H]+ ; 1 H NMR(DMSO-d6)δ=7.36(t,J=7.6Hz,1H),7.26-7.14(m,3H),6.82(d,J=4.4Hz,1H),3.90(br s,1H),3.17(s,3H),3.10-2.97(m,2H),2.34(br s,4H),2.19-2.04(m,1H).

[1145] Step b. The mixture of (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidin-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), Xantphos (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 under N₂ atmosphere for 3 hours. LCMS results showed the expected mass. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by reversed-phase HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water(FA)-acetonitrile]; gradient: 49%-89% B, 9 min) to give a white solid (S)-2-(2,6-bis(trifluoromethyl)pyrimidin-4-yl)-N-methyl-N-(m-tolyl)isothiazolidin-3-carboxamide 1,1-dioxide (30.09 mg, 60.06 μmol, yield 16.11%, purity 96.28%).

[1146] MS(ESI)m / z = 482.9[M+H] + ; 1 H NMR(DMSO-d6)δ=7.67(s,1H),7.49-7.41(m,1H),7.37-7.24(m,3H),4.95(dd,J=7.6,5.2Hz,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).

[1147] Example 34

[1148] (S)-N,5-Dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1149]

[1150] Step a. AlMe3 (2M, 4.05mL) was added to a toluene (10mL) solution of intermediate 3 (1g, 2.70mmol) and N,3-dimethylaniline (654.28mg, 5.40mmol, 674.52μL), and the mixture was stirred at 100°C for 16 hours under a N2 atmosphere. LCMS results showed the expected product. TLC (plate 1, SiO2, petroleum ether:ethyl acetate = 10:1) showed new spots (R). f =0.8). The mixture was poured into saturated NH4Cl (50 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were 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 to 55% ethyl acetate in petroleum ether to give a yellow gel-like (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%).

[1151] MS(ESI)m / z = 360.0 [M+H] + ; 1 H NMR(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=6.8,2.4Hz,1H),3.48-3.31(m,2H),3.12(s,3H),2.25(s,3H).

[1152] Step b. MeI (129.44 mg, 911.95 μmol, 56.77 μL) and Cs₂CO₃ (247.61 mg, 759.95 μmol) were added 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). The mixture was stirred at 80 °C for 12 hours. LCMS results showed the detection of the expected compound. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase column chromatography (column: 40 g C18 reversed-phase column; mobile phase: [water (0.05% TFA)-ACN]; B%: 0%-55%, 30 min) to give a white solid (3S)-2-benzyl-N,5-dimethyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (268 mg, crude).

[1153] MS(ESI)m / z = 373.9 [M+H] + ; 1 H NMR(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=11.6Hz,3H).

[1154] Step c. Add Pd / C (6.55 g, 6.16 mmol, 10% purity) 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). Stir the mixture at 30 Psi H2 atmosphere and 25 °C for 12 hours. LCMS results showed detection of the expected compound. Filter the reaction mixture, wash the filter cake with EtOAc (10 mL × 3), and concentrate the filtrate under reduced pressure to obtain the residue. Purify the residue by rapid silica gel column chromatography (…). 20g Silica gel rapid column chromatography; elution with 0-5% ethyl acetate / petroleum ether gradient, 30 mL / min) yielded a white solid (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%). MS (ESI) m / z = 283.9 [M+H] + .

[1155] Step d. 2-Bromo-6-methyl-4-(trifluoromethyl)pyridine (67.77 mg, 282.34 μmol) was added 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), 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. LCMS results showed the detection of the expected compound. The reaction mixture was filtered, and the filtrate was directly purified by Prep-HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonium hydroxide v / v)-ACN]; gradient: 45%-75% B, 8 min) to give a white solid (S)-N,5-dimethyl-2-(6-methyl-4-(trifluoromethyl)pyridin-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%).

[1156] MS(ESI)m / z = 443.1 [M+H] + ; 1 H NMR(DMSO-d6)δ=7.52-7.24(m,5H),7.17(s,1H),4.85(br t,J=6.0Hz,1H),3.64-3.45(m,2H),3.18(s,3H),2.75(s,3H),2.59(br s,3H),2.38(s,3H).

[1157] Example 35

[1158] (S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N,5-dimethyl-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide-1,1-dioxide

[1159]

[1160] Example 35 used the same synthesis method as 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 as a yellow solid (28.87 mg, 61.26 μmol, yield 19.29%, purity 99.2%).

[1161] MS(ESI)m / z = 467.9 [M+H] + ; 1 H NMR(DMSO-d6)δ=7.79(s,1H),7.13-7.03(m,3H),6.90(br s,1H),5.92(br t,J=7.6Hz,1H),3.84(br dd,J=10.4,6.8Hz,1H),3.67(br t,J=9.6Hz,1H),3.17(s,3H),2.63(s,3H),2.52(br s,3H),2.17(s,3H).

[1162] Example 36

[1163] (S)-N,5-Dimethyl-2-(2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1164]

[1165] Example 36 used the same synthesis method as 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 give the target compound as a white solid (113.22 mg, 255.32 μmol, yield 60.29%, purity 100%).

[1166] MS(ESI)m / z = 443.9[M+H] + ; 1 H NMR(DMSO-d6)δ=7.48-7.40(m,1H),7.38-7.26(m,3H),7.23(s,1H),4.91(dd,J=7.6,4.4Hz,1H),3.70(dd,J =11.6,4.4Hz,1H),3.55(dd,J=11.6,4.4Hz,1H),3.20(s,3H),2.83-2.75(m,3H),2.69(s,3H),2.38(s,3H).

[1167] Example 37

[1168] (S)-2-(2,6-bis(trifluoromethyl)pyrimidin-4-yl)-N,5-dimethyl-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide-1,1-dioxide

[1169]

[1170] Example 37 used the same synthetic method as 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 give the desired compound as a white solid (4.39 mg, 8.38 μmol, yield 7.92%, purity 95%).

[1171] MS(ESI)m / z = 497.9 [M+H] + ; 1 H NMR(DMSO-d6)δ=7.60(s,1H),7.50-7.40(m,1H),7.29(br s,3H),4.98(dd,J=7.6,4.8Hz,1H),3.79(dd,J=12.0,4.4Hz,1H),3.60-3.55(m,1H),3.18(s,3H),2.91(s,3H),2.36(s,3H).

[1172] Example 38

[1173] (3S)-5-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-N-(trideuteryl)-1,2,5-thiadiazolidine-3-carboxamide

[1174]

[1175] Step a. Add TFA (23.03 g, 201.93 mmol, 15.00 mL) to a DCM (30 mL) solution of intermediate 3 (1 g, 2.70 mmol) at 0 °C, and stir the mixture at 6 to 16 °C for 16 hours. The desired mass was observed by LCMS (ES22810-438-P1A). The mixture was concentrated under reduced pressure to give a brown oily methyl (3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid (2.8 g, crude, TFA).

[1176] MS(ESI)m / z=292.9[M+Na]+; 1H NMR (DMSO-d6) δ = 7.48 (br s, 1H), 7.41-7.21 (m, 5H), 4.27 (q, J = 14.8Hz, 2H), 4.09 (dd, J = 8.0, 4.4Hz, 1H), 3.65-3.51 (m, 4H), 3.46-3.32 (m, 1H).

[1177] Step b. K₂CO₃ (2.52 g, 18.21 mmol) was added to a DMF (15 mL) solution of (3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester (1.4 g, 3.64 mmol, TFA) followed by the addition of MeI (1.03 g, 7.29 mmol, 453.55 μL). The mixture was stirred at 4–12 °C for 16 hours. The desired mass was observed by LCMS analysis. New spots (R) were observed by TLC (plate 1, SiO₂, petroleum ether:ethyl acetate = 1:1). f =0.5). The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic layers were 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 to 28% ethyl acetate in petroleum ether to give a colorless oily methyl (3S)-2-benzyl-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid (723 mg, 2.54 mmol, yield 69.81%, purity 100%).

[1178] MS(ESI)m / z=306.9[M+Na]+; 1 H NMR(CDCl3)δ=7.44-7.28(m,5H),4.48(s,2H),3.87(dd,J=8.0,5.6Hz,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).

[1179] Step c. AlMe3 (549.90 mg, 7.63 mmol, 2 M, 3.81 mL) was added to a toluene (10 mL) solution of (3S)-2-benzyl-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester (723 mg, 2.54 mmol) and 3-methylaniline (544.94 mg, 5.09 mmol, 551.00 μL), and the mixture was stirred for 16 hours under N2 atmosphere and at 100 °C. LCMS results showed the expected mass. New spots (R) were observed by TLC (plate 1, SiO2, petroleum ether:ethyl acetate = 3:1). f=0.2). The mixture was poured into 1M NaOH (70 mL) and extracted with DCM (10 mL × 3). The organic layers were then combined, 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 to 30% ethyl acetate in petroleum ether to give a brown oily (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%).

[1180] MS(ESI)m / z=360.0[M+H]+; 1 H NMR(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=7.2Hz,1H),4.73(d,J=14.4Hz,1H),4.11(d,J=14. 4Hz, 1H), 3.94 (dd, J = 8.8, 5.2Hz, 1H), 3.76 (dd, J = 10.0, 8.8Hz, 1H), 3.33 (dd, J = 10.0, 10.0Hz, 1H), 2.80 (s, 3H), 2.31 (s, 3H).

[1181] Step d. Trideuterium (iodide)methane (375.05 mg, 2.59 mmol, 161.04 μL) was added to a DMF (6 mL) 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), followed by the addition of TBAI (31.86 mg, 86.24 μmol). The mixture was stirred at 80 °C for 3 hours. LCMS results showed the expected mass. TLC (plate 1, SiO₂, petroleum ether:ethyl acetate = 3:1) showed new spots (R). f=0.15). The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), washed with brine (50 mL), and the combined organic layers were 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 to 35% ethyl acetate in petroleum ether to give a yellow gel-like (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(trideuterylmethyl)-1,2,5-thiadiazolidine-3-carboxamide (320 mg, 832.96 μmol, yield 96.58%, purity 98%).

[1182] MS(ESI)m / z=377.0[M+H]+; 1 H NMR(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=7.2Hz,1H),3.13(d,J=7.6Hz,2H),2.73(s,3H),2.24(s,3H).

[1183] Step e. Add Pd / C (1 g, 10% purity) to a THF (10 mL) solution of (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(trideutermethyl)-1,2,5-thiadiazolidine-3-carboxamide (320 mg, 849.96 μmol), followed by bubbling with Ar three times and H2 three times. Stir the mixture at 30 Psi, H2 atmosphere, and 25 °C for 16 hours. LCMS results show the expected mass. Filter the mixture through a celite pad. The filter cake was washed with ethyl acetate (10 mL × 3), and the filtrate was concentrated under reduced pressure to give a white, gelatinous (3S)-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(trideuterylmethyl)-1,2,5-thiadiazolidine-3-carboxamide (179 mg, 577.57 μmol, yield 67.95%, purity 92.4%).

[1184] MS(ESI)m / z=286.9[M+H]+; 1 H NMR(CDCl3)δ=7.37(br t,J=7.6Hz,1H),7.27(s,1H),7.07-6.95(m,2H),5.45(br d,J=7.2Hz,1H),4.32-4.17(m,1H),3.30(br dd,J=9.2,5.6Hz,1H),2.98-2.84(m,1H),2.65(s,3H),2.41(s,3H).

[1185] Step f. To a solution of (3S)-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(trideuterylmethyl)-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 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 a N₂ atmosphere. The desired mass was observed by LCMS. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by reversed-phase rapid chromatography (0 to 60% MeCN in water (0.1% TFA) solution) and lyophilized to give a white solid (3S)-5-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-N-(trideuterylmethyl)-1,2,5-thiadiazolidine-3-carboxamide (169.54 mg, 303.02 μmol, yield 57.85%, purity 100%, TFA).

[1186] MS(ESI)m / z=445.9[M+H]+; 1 H NMR(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=7.6,5.2Hz,1H),3.63-3.49(m,2H),2.75(s,3H),2.59(s,3H),2.38(s,3H).

[1187] Example 39

[1188] (S)-N-Isopropyl-5-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1189]

[1190] Example 39 used the same synthesis method as Example 38, but in step d, 2-iodopropane was used instead of trideuterium (iodine)methane to obtain the target compound as a white solid (1.93 mg, 4.09 μmol, yield 1.75%, purity 99.63%).

[1191] MS(ESI)m / z = 471.2[M+H]+ ; 1 H NMR(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=4.8Hz,3H),2.65(d,J=12.8Hz,3H),2.45(s,3H),1.15(d,J=6.4Hz,3H),1.08(dd,J=6.8,2.4Hz,3H).

[1192] Example 40

[1193] (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-5-(trideutermethyl)-1,2,5-thiadiazolidine-3-carboxamide

[1194]

[1195] Step a. Add TFA (7.68 g, 67.31 mmol, 5 mL) to a solution of intermediate 3 (1 g, 2.70 mmol) in DCM (15 mL) at 0 °C, and then stir the mixture at 5 to 11 °C for 16 hours. LCMS results showed the expected mass. The mixture was concentrated under reduced pressure to give a pale yellow oily methyl (3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (1.04 g, crude, TFA).

[1196] MS(ESI)m / z = 292.9[M+Na] + ; 1 H NMR(DMSO-d6)δ=8.87(s,1H),7.38-7.28(m,5H),4.27(q,J=14.8Hz,2H),4.0 9(dd,J=8.0,4.0Hz,1H),3.62-3.55(m,1H),3.54(s,3H),3.42-3.35(m,1H).

[1197] Step b. K₂CO₃ (755.19 mg, 5.46 mmol) was added to a DMF (5 mL) solution of (3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester (700 mg, 1.82 mmol, TFA) followed by the addition of trideuterium (iodine)methane (528.04 mg, 3.64 mmol, 226.72 μL). The mixture was stirred at 10–17 °C for 16 hours. The expected mass was observed by LCMS. New spots (R) were observed by TLC (plate 1, SiO₂, petroleum ether:ethyl acetate = 3:1). f =0.1). The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic layers were 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 to 10% ethyl acetate in petroleum ether to give a white, gelatinous (3S)-2-benzyl-1,1-dioxo-5-(trideutermethyl)-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester (306 mg, 1.06 mmol, yield 58.47%, purity 100%).

[1198] MS(ESI)m / z = 309.9[M+Na] + ; 1 H NMR (CDCl3) δ = 7.42-7.30 (m, 5H), 4.50-4.46 (m, 2H), 3.87 (dd, J = 7.6, 5.6Hz, 1H), 3.67 (s, 3H), 3.55 (dd, J = 10.0, 8.0Hz, 1H), 3.39-3.31 (m, 1H).

[1199] Step c. AlMe3 (2M, 469.81μL) was added to a solution of (3S)-2-benzyl-1,1-dioxo-5-(trideutermethyl)-1,2,5-thiadiazolidine-3-carboxylic acid methyl ester (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. The desired mass was observed by LCMS. The mixture was poured into 1M NaOH (50 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic layers were 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 and eluted with 0 to 46% ethyl acetate in petroleum ether to give a yellow gel-like (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(trideutermethyl)-1,2,5-thiadiazolidine-3-carboxamide (80 mg, 169.99 μmol, yield 27.14%, purity 80%).

[1200] MS(ESI)m / z = 377.0 [M+H] + ; 1 H NMR(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=7.2Hz,1H),3.19-3.08(m,5H),2.24(s,3H).

[1201] Step d. Pd / C (360 mg, 10% purity) was added to a THF (2 mL) solution of (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(trideutermethyl)-1,2,5-thiadiazolidine-3-carboxamide (120 mg, 318.74 μmol), and then Ar and H2 were bubbled through the mixture three times and three times, respectively. The mixture was stirred at 30 Psi, H2 atmosphere, and 25 °C for 16 hours. LCMS results showed the expected mass. The mixture was filtered through a diatomaceous earth mat. The filter cake was washed with ethyl acetate (10 mL × 3), and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography and eluted with 0 to 30% ethyl acetate in petroleum ether to give a colorless, colloidal (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(trideutermethyl)-1,2,5-thiadiazolidine-3-carboxamide (30 mg, 104.76 μmol, yield 32.87%, purity 100%).

[1202] MS(ESI)m / z = 286.9[M+H] + ; 1 H NMR(CDCl3)δ=7.36(t,J=8.0Hz,1H),7.28-7.25(s,1H),7.02-6.95(m,2H),5.43(br d,J=8.0Hz,1H),4.25-4.18(m,1H),3.33(s,3H),3.30(dd,J=9.6,6.0Hz,1H),2.90(dd,J=9.2,8.4Hz,1H),2.41(s,3H).

[1203] Step e. To a solution of (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(trideuterylmethyl)-1,2,5-thiadiazolidine-3-carboxamide (30 mg, 104.76 μmol) and Cs₂CO₃ (102.40 mg, 314.28 μmol) in dioxane (1 mL), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (37.72 mg, 157.14 μmol) was added, followed by the addition of N₁,N₂-dimethylethane-1,2-diamine (11.64 mg, 132.00 μmol, 14.21 μL) and CuI (25.14 mg, 132.00 μmol). The mixture was stirred at 80 °C for 16 hours under a N₂ atmosphere. The expected mass was observed by LCMS. The mixture was filtered through a diatomaceous earth mat. The filter cake was washed with ethyl acetate (10 mL × 3), and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by reversed-phase rapid chromatography (0% to 48% MeCN in water (neutral) solution), lyophilized, and given a purple solid (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-5-(trideutermethyl)-1,2,5-thiadiazolidine-3-carboxamide (26.97 mg, 60.54 μmol, yield 57.79%, purity 100%).

[1204] MS(ESI)m / z = 446.3[M+H] + ; 1 H NMR(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=7.6,5.2Hz,1H),3.63-3.49(m,2H),2.75(s,3H),2.59(s,3H),2.38(s,3H).

[1205] Example 41

[1206] (S)-5-Isopropyl-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1207]

[1208] Example 41 used the same synthesis method as Example 38, but 2-iodopropane was used instead of MeI in step b, and iodomethane was used instead of trideuterium (iodo)methane in step d, to obtain the target compound as a white solid (27.04 mg, 53.96 μmol, yield 17.88%, purity 93.9%).

[1209] MS(ESI)m / z = 470.9[M+H] + ; 1 H NMR(MeOD-d4)δ=7.49-7.40(m,2H),7.37(br d,J=7.6Hz,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 .8,2.0Hz,2H),3.28(s,3H),2.63(s,3H),2.44(s,3H),1.29(d,J=6.8Hz,3H),1.20(d,J=6.4Hz,3H).

[1210] Example 42

[1211] (S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide

[1212]

[1213] Step a. After adding AlMe3 (2M, 2.02mL) to a toluene (10mL) solution of intermediate 3 (1g, 2.70mmol), the mixture was stirred at 100°C for 16 hours under a N2 atmosphere. LCMS results showed the expected mass. TLC (plate 1, SiO2, petroleum ether:ethyl acetate = 3:1) showed new spots (R). f=0.1). The mixture was poured into 1M NaOH (50 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic layers were 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 to 60% ethyl acetate in petroleum ether to give a yellow solid (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%).

[1214] MS(ESI)m / z = 359.9 [M+H] + ; 1 H NMR(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=10.8,7.2Hz,0.4 H), 5.20 (dd, J = 10.4, 7.6Hz, 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).

[1215] Step b. Add NaH (60.09 mg, 1.50 mmol, 60% purity) to a THF (10 mL) solution of (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (270 mg, 751.16 μmol) at 0 °C and stir the mixture at 0 °C for 0.5 h. Then, add SEM-Cl (250.47 mg, 1.50 mmol, 265.89 μL) and stir the mixture at 7–11 °C for 2 h. LCMS results showed the expected mass. TLC (plate 1, SiO2, petroleum ether:ethyl acetate = 1:1) showed new spots (R). f=0.8). The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), the combined organic layers were 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, eluted with 0 to 35% ethyl acetate in petroleum ether, to give a yellow gel-like (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%).

[1216] MS(ESI)m / z = 512.1[M+Na] + ; 1 H NMR(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=10.4,6.4Hz,1H),3.31(dd,J=10.0, 8.0Hz, 1H), 3.11 (s, 3H), 2.26 (s, 3H), 0.86 (t, J = 8.4Hz, 2H), 0.01 (s, 9H).

[1217] Step c. Add wet Pd / C (750 mg, 10% purity) to a THF (7 mL) 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), then purge the mixture three times with Ar and three times with H2. Stir the mixture at 15 Psi, H2 atmosphere, and 25 °C for 16 hours. LCMS results show the expected mass. Filter the mixture through a diatomaceous earth mat. The filter cake was washed with ethyl acetate (10 mL × 3), and the filtrate was concentrated under reduced pressure to give a colorless, colloidal (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%).

[1218] MS(ESI)m / z = 422.0[M+Na] + ; 1H NMR(CDCl3)δ=7.40-7.34(m,1H),7.27-7.23(m,1H),7.04-6.96(m,2H),5.34(d,J=8.8Hz,1H),4.50(s,2H),4.25(q,J=8.0Hz,1H),3.56(d d,J=8.8,7.2Hz,2H),3.44(dd,J=9.6,7.2Hz,1H),3.32(s,3H),3.16(dd,J=10.0,8.4Hz,1H),2.41(s,3H),0.91-0.82(m,2H),0.01(s,9H).

[1219] Step d. 2-Bromo-6-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 a dioxane (5 mL) solution was added, followed by N₁,N₂-dimethylethane-1,2-diamine (50.03 mg, 567.60 μmol, 61.09 μL) and CuI (108.10 mg, 567.60 μmol). The mixture was stirred at 80 °C for 16 hours under a N₂ atmosphere. LCMS results showed the expected mass. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography and eluted with 0 to 30% ethyl acetate in petroleum ether to give a yellow gel-like (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%).

[1220] MS(ESI)m / z = 581.1 [M+Na] + ; 1 H NMR(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=7.6,5.6Hz,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).

[1221] Step e. TBAF (1M, 357.98 μL) was added to a THF (2 mL) 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), and the mixture was stirred at 70 °C for 3 hours. LCMS results showed residual starting material. Then TBAF (0.4 mL) was added and the mixture was stirred for another 3 hours. LCMS results showed residual starting material. Then TBAF (0.4 mL) was added and the mixture was stirred for another 3 hours. LCMS results showed the desired mass. TLC (plate 1, SiO2, petroleum ether:ethyl acetate = 1:1) observed new spots (R) f =0.55). The mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic layers were 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 to 45% ethyl acetate in petroleum ether to give the crude product (purity 57.2%). The mixture was purified by Prep-TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to give the crude product (purity 87.1%). The reaction mixture was purified by reversed-phase rapid chromatography (0 to 58% MeCN aqueous solution (0.1% TFA)) and lyophilized to give (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.

[1222] MS(ESI)m / z = 429.2[M+H] + ; 1 H NMR(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=7.2,4.8Hz,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).

[1223] Example 43

[1224] (S)-2-(2,6-bis(trifluoromethyl)pyrimidin-4-yl)-N-methyl-N-(m-tolyl)-1,2,5-thiadiazolidine-3-carboxamide-1,1-dioxide

[1225]

[1226] Example 43 used the same synthetic method as 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 give the desired compound as a white solid (78.21 mg, 179.44 μmol, yield 40.17%, purity 98.52%).

[1227] MS(ESI)m / z = 430.1[M+H] + ; 1 H NMR(DMSO-d6)δ=7.48-7.40(m,1H),7.37(s,1H),7.33(br d,J=8.0Hz,1H),7.27(br d,J=7.6Hz,1H),7.19(s,1H),4.83(t,J=6.0Hz,1H),3.57-3.52(m,2H),3.20(s,3H),2.66(s,3H),2.38(s,3H).

[1228] Biological analysis

[1229] Expression and purification of the polθ polymerase domain

[1230] 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 subcloned into an E. coli expression plasmid, thereby fusing a 10X histidine-SUMO tag to the N-terminus of the polymerase domain.

[1231] 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 using SUMO protease. The cleaved fragment of the 10X histidine-SUMO tag was then removed using Ni-NTA beads. The resulting protein was used for Picogreen analysis as described below.

[1232] Analysis of Polθ polymerase activity

[1233] 1) Preparation of DNA complex

[1234] The DNA complex preparation method used was a slightly modified version of a previously reported protocol (Zatreanu et al., 2021, Nature Communications, 12:3636). In short, Oligo1 (5'-GCG GCTGTCATA AG-3') and Oligo2 (5'-GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTTATG ACA GCC GCG-3') were mixed in annealing buffer (20 mM Tris-Cl, pH 7.5, 50 mM NaCl) to achieve final concentrations of 22 μM and 20 μM, respectively, thereby preparing the polθ substrate. Oligo3 (5'-CGC GGC TGT CATAAG ACG CAA TCT GAG ATT TGA TGC CAT TGT CAA TGT AGC-3') and Oligo2 (5'-GCT ACATTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACA GCC GCG-3') were mixed to achieve a final concentration of 20 μM to prepare the Polθ product. The Polθ product was used as the top layer signal control in Picogreen analysis. Both the substrate and product were heated to 95 °C and held for 5 minutes, then slowly cooled to room temperature.

[1235] 2) Picogreen analysis

[1236] To evaluate the ability of the tested compounds to inhibit polθ activity in vitro, Picogreen analysis was performed to measure polθ IC50. 50 (nM).

[1237] The reaction was performed at room temperature in analysis 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 MDT). 30 μL of the 2X polymerase mixture (8 nM Polθ enzyme in analysis buffer) was dispensed into 96-well plates. The experimental compounds were prepared by dilution in 100% DMSO to obtain the correct dosage range for the 12-point reaction, and 1 μL was added to each well. Then, 30 μL of the 2X substrate mixture (100 nM DNA and 40 μM dNTPs in analysis buffer) was added to each well. After incubation for 90 minutes, the reaction was stopped, and 40 μL of Picogreen solution (Picogreen 1:80 dilution, Invitrogen, Cat#P7581, 25 mM Tris-HCl, pH 7.5, 10 mM EDTA, pH 7.5) was added to stain the DNA.

[1238] Fluorescence intensity was measured using an Ensight plate reader (Perkin Elmer) at excitation / emission wavelengths of 485 nm / 520 nm. The data were analyzed using GraphPad Prism software (version 8.4.3) to calculate the IC50. 50 .

[1239] The compounds in Examples 1 to 43 were analyzed according to the above-described analytical method, and the results are shown in the table below.

[1240]

[1241]

[1242] Note: 1 nM < *** < 100 nM; 101 nM < ** < 500 nM; and * > 501 nM

[1243] As shown in the table above, the tested compounds exhibit good activity in inhibiting Polθ polymerase.

[1244] 3) Analyze cell viability

[1245] DLD1-BRCA2 KO (Horizon Discovery, Cat#HD 105-007) cells and DLD1-parental cells were maintained at 37°C under a humid atmosphere of 5% CO2 in medium (RPMI-1640 containing 2 mM L-glutamine and 25 mM sodium bicarbonate, supplemented with 10% FBS). Cells were seeded into 96-well plates at a final concentration of 1500 cells per well (DLD1-BRCA2 KO) and 600 cells per well (DLD1-parental cells). After 4 hours, the test compound (DMSO final concentration 1%) was added to the cells. The medium was changed every 3 to 4 days for 14 days. To measure viability, cells were incubated for 4 hours in medium supplemented with 0.1 mg / ml Resazurin (Merck, Cat#R7017). Fluorescence was measured at Ex / Em = 560nm / 590nm using an EnSight multi-mode reader (Perkin Elmer). Data analysis and IC analysis were performed using GraphPad Prism (version 10.0.2). 50 Calculation. Results: The following table shows the IC50 values ​​of the compounds selected in this invention. 50 value.

[1246] Compound serial number <![CDATA[IC in DLD-1 BRCA2(- / -) cells 50 (uM)]]> 2 *** 3 *** 4 *** 5 *** 8 *** 12 *** 13 *** 14 * 18 *** 20 *** 21 *** 23 *** 27 *** 34 *** 38 *** 40 *** 41 *** 42 * 43 *

[1247] Note: *** < 10uM; 11uM < ** < 50uM; and * > 51uM

[1248] While the compounds, compositions, dosage forms, and methods of the present invention have been described through specific examples, those skilled in the art will understand that modifications or alterations can be made to the compounds, compositions, dosage forms, and methods described herein without departing from the spirit and scope of the invention. All such modifications or alterations will be readily apparent to those skilled in the art and are considered to be within the spirit and scope of the invention as defined in the appended claims.

[1249] The present invention provides the following embodiments:

[1250] Implementation Method 1. A compound of Formula I, or a tautomer, stereoisomer, prodrug, crystal form, isotopic variant, pharmaceutically acceptable salt, hydrate, or solvate thereof:

[1251] [Formula I]

[1252]

[1253] in:

[1254] R 1 R 2 and R 3Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups.

[1255] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[1256] X is selected from methylene, -NH-, and -NR. z -A group consisting of, wherein the methylene group is optionally substituted with one or more of the following groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl;

[1257] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[1258] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[1259] R x and R y Each of them is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[1260] R Z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[1261] R wChoose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[1262] Embodiment 2. The compound according to Embodiment 1, wherein the compound is a compound represented by Formula II:

[1263] [Formula II]

[1264]

[1265] in:

[1266] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups.

[1267] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[1268] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[1269] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[1270] R x and R yEach of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[1271] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[1272] Embodiment 3. The compound according to Embodiment 1 or 2, wherein the compound is a compound represented by Formula III:

[1273] [Formula III]

[1274]

[1275] in:

[1276] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups.

[1277] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[1278] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[1279] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R yOne or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[1280] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[1281] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[1282] Embodiment 4. The compound according to any one of Embodiments 1 to 3, wherein the compound is a compound represented by Formula IV:

[1283] [Form IV]

[1284]

[1285] in:

[1286] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups.

[1287] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[1288] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[1289] A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups;

[1290] R x and R y Each of them is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl;

[1291] R Z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[1292] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[1293] Embodiment 5. The compound according to any one of Embodiments 1 to 4, wherein the compound is a compound represented by Formula IIa:

[1294] [Form IIa]

[1295]

[1296] in:

[1297] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups.

[1298] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[1299] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[1300] R a1 R a2 R a3 R a4 and R a5 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl;

[1301] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[1302] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[1303] Embodiment 6. The compound according to any one of Embodiments 1 to 5, wherein the compound is a compound represented by Formula IIb:

[1304] [Formula IIb]

[1305]

[1306] in:

[1307] R1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups.

[1308] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[1309] Each of Y and Z is independently selected from -N- and -CR. w -A group;

[1310] R b1 R b2 R b3 and R b4 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl;

[1311] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[1312] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R yIt is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[1313] Embodiment 7. The compound according to any one of Embodiments 1 to 6, wherein the compound is a compound represented by Formula IIc:

[1314] [Form IIc]

[1315]

[1316] in:

[1317] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups.

[1318] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[1319] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[1320] R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R yEach of the groups is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl;

[1321] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[1322] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[1323] Embodiment 8. The compound according to any one of Embodiments 1 to 7, wherein the compound is a compound represented by Formula IId:

[1324] [Formula IId]

[1325]

[1326] in:

[1327] R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups.

[1328] R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto;

[1329] Each of Y and Z is independently chosen from -N- and -CR. w -A group;

[1330] R d1 R d2 R d3 R d4 R d5 and R d6 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl;

[1331] R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and

[1332] R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

[1333] Embodiment 9. The compound according to any one of Embodiments 1 to 8, R 3 It is hydrogen.

[1334] Embodiment 10. The compound according to any one of Embodiments 1 to 9, R 4 It is hydrogen or C1-C4 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 alkyl and deuterium.

[1335] Implementation Method 11. In the compound according to any one of Implementation Methods 1 to 10, Y is selected from the group consisting of CH and C (CN); Z is selected from the group consisting of N and CH.

[1336] Embodiment 12. The compound according to any one of Embodiments 1 to 11, R 1 and R 2Each of them is independently a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the following: C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[1337] Embodiment 13. The compound according to any one of Embodiments 1 to 12, wherein the compound is selected from the group consisting of:

[1338]

[1339]

[1340]

[1341] as well as

[1342] Embodiment 14. A pharmaceutical composition for treating or preventing diseases or disorders mediated by polymerase θ, preferably for treating or preventing cancer, more preferably for treating or preventing breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, or lung cancer, comprising a compound according to any one of Embodiments 1 to 13, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof; and a pharmaceutically acceptable carrier or excipient.

[1343] Implementation Method 15. The pharmaceutical composition according to Implementation Method 14, wherein the composition is administered separately, sequentially, or simultaneously with an anticancer drug targeting the DNA damage response (DDR), wherein the anticancer drug is 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, 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., adaserte (Adavosertib) (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., vorasetib) (BI) 6727), onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or topoisomerase inhibitors (e.g., belotecone, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[1344] Implementation 16. A compound, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, for the prevention or treatment of diseases or disorders mediated by polymerase θ, preferably for the treatment or prevention of cancer, more preferably for the treatment or prevention of breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, or lung cancer, according to any one of Implementation 1 to 13.

[1345] Implementation Method 17. The compound according to Implementation Method 16, wherein the compound is administered separately, sequentially, or simultaneously with an anticancer drug targeting DNA damage response (DDR), wherein the anticancer drug is 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, 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., adaserte (Adavosertib) (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., vorasetib) (BI) 6727), onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or topoisomerase inhibitors (e.g., belotecone, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[1346] Implementation Method 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 according to any one of Implementation Methods 1 to 13, or a tautomer, stereoisomer, prodrug, crystal form, isotopic variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1347] Implementation 19. According to the method of implementation 18, the disease or disorder mediated by the polymerase θ is cancer, preferably breast cancer, ovarian cancer, prostate cancer, pancreatic cancer or lung cancer.

[1348] Implementation Method 20. The method according to Implementation Method 18 or 19 further comprises administering to the subject an additional anticancer drug targeting DDR, said anticancer drug 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, 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., adaserte (Adavosertib) (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., vorasetib) (BI) 6727), onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or topoisomerase inhibitors (e.g., belotecone, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

Claims

1. A compound of formula I, or a tautomer, stereoisomer, prodrug, crystal form, isotopic variant, pharmaceutically acceptable salt, hydrate, or solvate thereof: [Formula I] in: R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto; X is selected from methylene, -NH-, and -NR. z -A group consisting of, wherein the methylene group is optionally substituted with one or more of the following groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl; Each of Y and Z is independently chosen from -N- and -CR. w -A group; A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R x and R y Each of them is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; R Z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

2. The compound according to claim 1, wherein, The compound is represented by formula II: [Formula II] in: R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto; Each of Y and Z is independently chosen from -N- and -CR. w -A group; A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

3. The compound according to claim 1, wherein, The compound is represented by formula III: [Formula III] in: R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto; Each of Y and Z is independently chosen from -N- and -CR. w -A group; A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

4. The compound according to claim 1, wherein, The compound is a compound represented by formula IV: [Form IV] in: R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto; Each of Y and Z is independently chosen from -N- and -CR. w -A group; A is a 5-12 membered monocyclic or bicyclic aryl or heteroaryl group, wherein each of the aryl and heteroaryl groups is independently and optionally selected from C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y One or more substitutions of alkyl, alkenyl, alkoxy and cycloalkyl groups, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted by one or more substitutions selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R x and R y Each of them is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted by one or more of C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto and carbamoyl; R Z It is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

5. The compound according to claim 1 or 2, wherein, The compound is a compound represented by formula IIa: [Form IIa] in: R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto; Each of Y and Z is independently chosen from -N- and -CR. w -A group; R a1 R a2 R a3 R a4 and R a5 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl; R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

6. The compound according to claim 1 or 2, wherein, The compound is represented by formula IIb: [Formula IIb] in: R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto; Each of Y and Z is independently chosen from -N- and -CR. w -A group; R b1 R b2 R b3 and R b4 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl; R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

7. The compound according to claim 1 or 2, wherein, The compound is a compound represented by formula IIc: [Form IIc] in: R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto; Each of Y and Z is independently chosen from -N- and -CR. w -A group; R c1 R c2 R c3 R c4 R c5 R c6 and R c7 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl; R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

8. The compound according to claim 1 or 2, wherein, The compound is represented by formula IId: [Formula IId] in: R 1 R 2 and R 3 Each of these is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NR. x R y The group consisting of, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently and optionally substituted with one or more of the C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl groups; R 4 It is hydrogen or C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxy and mercapto; Each of Y and Z is independently chosen from -N- and -CR. w -A group; R d1 R d2 R d3 R d4 R d5 and R d6 Each of these radicals is independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, hydroxyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and -NR. x R y (where R) x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl, wherein the alkyl group is optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl, wherein each of the alkyl, alkenyl, alkoxy and cycloalkyl groups is independently optionally substituted with one or more of the group consisting of C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto and carbamoyl; R x and R y Each of the groups is independently selected from hydrogen and C1-C6 alkyl groups, wherein the alkyl group is optionally substituted with one or more of the groups selected from C1-C6 alkyl, halogen, cyano, deuterium, hydroxyl, amino, mercapto, and carbamoyl; and R w Choose from hydrogen, C1-C6 alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, -NR x R y It is a group consisting of hydroxyl, amino, mercapto, and carbamoyl groups.

9. The compound according to any one of claims 1 to 8, wherein, R 3 It is hydrogen.

10. The compound according to any one of claims 1 to 9, wherein, R 4 It is hydrogen or C1-C4 alkyl, wherein the alkyl group is optionally substituted with one or more of C1-C6 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); Z is chosen from the group consisting of N and CH.

12. The compound according to any one of claims 1 to 11, wherein, R 1 and R 2 Each of them is independently a C1-C6 alkyl group, wherein the alkyl group is optionally substituted with one or more of the following: C1-C6 alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

13. The compound according to any one of claims 1 to 12, wherein, The compounds are selected from the group consisting of: as well as 14. A pharmaceutical composition for treating or preventing diseases or disorders mediated by polymerase θ, preferably for treating or preventing cancer, more preferably for treating or preventing 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, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof; and a pharmaceutically acceptable carrier or excipient.

15. The pharmaceutical composition according to claim 14, wherein, The composition is administered separately, sequentially, or simultaneously with an anticancer drug targeting DNA damage response (DDR), wherein the anticancer drug is 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, 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., adaserte (Adavosertib) (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., vorasetib) (BI) 6727), onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or topoisomerase inhibitors (e.g., belotecone, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

16. A compound of any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, for the prevention or treatment of a disease or disorder mediated by polymerase θ, preferably for the treatment or prevention of cancer, more preferably for the treatment or prevention of breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, or lung cancer.

17. The compound according to claim 16, wherein, The compound is administered separately, sequentially, or simultaneously with an anticancer drug targeting DNA damage response (DDR), wherein the anticancer drug is 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, 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., adaserte (Adavosertib) (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., vorasetib) (BI) 6727), onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or topoisomerase inhibitors (e.g., belotecone, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

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 according to any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystal 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 method according to claim 18 or 19, wherein, This also includes administering additional anticancer drugs targeting DDR to the subjects, 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, 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., adaserte (Adavosertib) (MK-1775 or AZD1775)), PLK1 inhibitors (e.g., vorasetib) (BI) 6727), onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or topoisomerase inhibitors (e.g., belotecone, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

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