Substituted sultam compound derivatives and their pharmaceutical use

Abstract

Provided herein are novel sultam compound derivatives, compositions containing the compounds, and preparation methods and uses thereof. The sultam compound derivatives are compounds represented by Formula (I), or tautomers, stereoisomers, prodrugs, crystal forms, isotope variants, pharmaceutically acceptable salts, hydrates or solvates thereof. The compounds and compositions of the present disclosure can be used to treat diseases or disorders mediated by polθ.

Description

SUBSTITUTED SULTAM COMPOUND DERIVATIVES AND THEIR PHARMACEUTICAL USE

[0001] The present disclosure belongs to a technical field of medicine, and particularly relates to sultam derivates with inhibitory effects on polymerase theta, pharmaceutical compositions containing the same, and preparation methods and uses thereof.

[0002] DNA double strand breaks (DSBs) are detrimental to cells as they contribute to genome instability, which can induce cell death. To repair DSBs, three pathways are performed in cells: non-homologous end joining (NHEJ), homologous recombination (HR), and theta-mediated end-joining (TMEJ). The NHEJ pathway joins the broken ends of DNA strands together without using a homologous template. The HR and TMEJ pathways have commonality in that they both use a homologous sequence. However, HR is a high-fidelity DNA repair pathway, and TMEJ is an error-prone DNA repair pathway that uses microhomologies.

[0003] The TMEJ pathway involves poly-(ADP-ribose) polymerase PARP1, DNA ligase III, and Polymerase theta. Polymerase theta (Polθ, encoded byPOLQ) is a 290kDa polymerase A family enzyme, and is known to mediate the TMEJ pathway (Feng et al., 2019, Nature Communication, 10:4286). Polθ possesses a 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 acts to displace Replication Protein A (RPA) bound to a single strand DNA overhang and facilitate annealing of micro-homologous sequences that flank a DSB. Then, the polymerase domain of Polθ acts to initiate DNA synthesis to fill in gaps (Zatreanu et al., 2021, Nature Communication, 12:3636).

[0004] The TMEJ pathway is also known as alternative NHEJ (alt-NHEJ) pathway or microhomology-mediated end joining (MMEJ) pathway (Zatreanu et al., 2021, Nature Communication, 12:3636). The TMEJ pathway serves as an essential backup pathway in the event that the NHEJ or HR pathway is compromised (Higgins, G. S. et al., 2018. Science, 359(6381), 1217-1218). Accordingly, DNA-repair deficient cancers are dependent on other compensatory repair pathway, and HR- or NHEJ-deficient cancers are dependent on the TMEJ backup pathway. Based on the above mechanism, PARP inhibitors (PARPi) were developed, and HR-deficient tumors have been successfully treated by way of applying PARPi. However, PARPi often face the issue of developing resistance (Drzewiecka et al., 2022, Genes, 13:1101; and Higgins, G. S. et al., 2018. Science, 359(6381), 1217-1218).

[0005] Currently, polθ has been identified as another promising therapeutic target for cancers. While polθ is overexpressed in various cancers, it is little expressed (largely absent) in normal cells (Higgins, G. S. et al., 2018. Science, 359(6381), 1217-1218; and Ceccaldi et al., 2015, Nature, 518:258). Indeed, human neoplasms including those of the lung, stomach, small intestine, rectum, and colon overexpress polθ, and the expression level of polθ is particularly high in lung cancer, breast cancer, ovarian cancer, colorectal cancer and gastric cancer, etc. (Drzewiecka et al., 2022, Genes, 13:1101; and Higgins, G. S. et al., 2018. Science, 359(6381), 1217-1218). Furthermore,in vivotests demonstrated HR-deficient tumors are hypersensitive to inhibition of Polθ-mediated DNA repair, leading to synthetic lethality (Ceccaldi et al., 2015, Nature, 518:258; and Drzewiecka et al., 2022, Genes, 13:1101). Polθ depletion causes both HR-proficient and HR-deficient tumor cells to become more sensitive to other treatments such as radiation 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 effectively inhibit the TMEJ pathway and can be used for treating cancer.

[0007] The present disclosure provides novel sultam (cyclic sulfonamides) derivatives, compositions comprising the same, and preparation methods and uses thereof. The sultam derivatives have an inhibitory activity for polymerase theta, and can be effectively used for treating various types of cancers.

[0008] In one aspect, the present disclosure relates to a compound of the following Formula (I):

[0009] (I)

[0010] wherein:

[0011] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0012] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0013] X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein said methylene is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0014] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0015] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0016] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0017] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0018] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,

[0019] or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0020]

[0021] In another aspect, the present disclosure provides a pharmaceutical composition for treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta, which comprises one or more of the compounds disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier(s) or excipient(s). In a specific embodiment, the composition comprises one or more of the compounds in a therapeutically effective amount. In a specific embodiment, the composition comprises one or more of the compounds in a prophylactically effective amount.

[0022] In another aspect, the present disclosure provides the use of the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by polymerase theta.

[0023] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta, in a subject, comprising administering to the subject at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.

[0024] In another aspect, the present disclosure provides the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta.

[0025] Other objects and advantages of the present disclosure will be apparent to those skilled in the art from the following specific embodiments, examples, and claims.

[0026]

[0027] Definitions

[0028] Chemical terms

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

[0030] When a range of values is listed, it is intended to encompass each value and any sub-range within the range. For example, "C1-6alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0031] As used herein (unless otherwise specified), the term "C1-6alkyl" refers to a saturated hydrocarbon group which is straight-chained or branched, and has 1 to 6 carbon atoms. It is also referred to herein as a "lower alkyl" group. In some embodiments, the alkyl group may have 1 to 4 carbon atoms (C1-4alkyl) or 3 to 6 carbon atoms (C3-6alkyl). Examples of C1-6alkyl group include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, sec-butyl, iso-butyl, n-pentyl, 3-pentyl, 2-pentyl, neo-pentyl, 3-methyl-2-butyl, tert-pentyl, n-hexyl, 2-hexyl, 3-hexyl, and the like.

[0032] As used herein (unless otherwise specified), the term "C2-6alkenyl" refers to a hydrocarbon group which is straight-chained or branched, and has 2-6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). In some embodiments, the alkenyl group may have 2 to 4 carbon atoms. Examples of C2-6alkenyl group include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, etc.

[0033] As used herein (unless otherwise specified), the term "C2-6alkynyl" refers to a hydrocarbon group which is straight-chained or branched, and has 2-6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2 or 3 carbon-carbon triple bonds) and optionally one or more carbon-carbon double bonds (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 bond. One or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-6alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, etc.

[0034] As used herein (unless otherwise specified), the term "C1-6alkoxy" refers to a -OR group, wherein R is substituted or unsubstituted C1-6alkyl. In some embodiments, the alkoxy group may have 1 to 4 carbon atoms. Specifically, C1-6alkoxyl includes, but is not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.

[0035] As used herein (unless otherwise specified), the terms "halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In some embodiments, the halo group is F, Cl or Br. In some embodiments, the halo group is F or Cl. In some embodiments, the halo group is F.

[0036] As used herein (unless otherwise specified), the terms "C1-6haloalkyl" and "C1-6haloalkoxyl" refer to the above "C1-6alkyl" and "C1-6alkoxy" substituted with one or more halo groups. Examples of the haloalkyl group 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 the haloalkoxyl group include, but are not limited to, -OCH2F, -OCHF2, -OCF3, etc.

[0037] As used herein (unless otherwise specified), the terms "C3-10cycloalkyl" or "3-10 membered cycloalkyl" refers to a cyclic hydrocarbon group which is non-aromatic and has 3-10 ring carbon atoms and zero heteroatoms. 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 also includes a ring system in which the above cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring. Examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, cyclononyl, cyclononenyl, cyclodecyl, cyclodecenyl, octahydro-1H-indenyl, decahydronaphthyl, spiro[4.5]decyl, and the like.

[0038] As used herein (unless otherwise specified), the term "aromatic group" as used herein refers to a ring structure having cyclic clouds of delocalized electrons above and below the plane of the molecule, where the clouds contain (4n+2) electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled "Aromaticity," pages 477-497, incorporated herein by reference. The term "aromatic group" is inclusive of both　aryl　and heteroaryl　groups.

[0039] As used herein (unless otherwise specified), the term "C6-14aryl" refers to a radical of a carbocyclic aromatic group, whether or not fused to one or more groups, having 6 to 14 ring carbon atoms and zero heteroatoms. In one embodiment, the aryl may have 6-10 memebered ring carbon atoms. The aryl group may be monocylic or polycylic (e.g., bicyclic or tricyclic). Examples of the aryl group include, but are not limited to, phenyl, naphtyl, anthracyl, and the like. The aryl group also includes ring systems wherein the aryl ring, as defined herein, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment is on the aryl ring.

[0040] As used herein (unless otherwise specified), the term "5- to 12-membered heteroaryl" refers to any monocyclic or polycyclic(e.g., bi-, or tricyclic) aromatic ring system which has ring carbon atoms and at least one heteroatoms (e.g., nitrogen, oxygen, and sulfur). The heteroaryl group also includes ring systems wherein the heteroaryl ring, as defined herein, is fused with one or more cycloalkyl, heterocyclyl or aryl groups wherein the point of attachment is on the heteroaryl ring. In some embodiments, the heteroaryl group may 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.

[0041] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl (e.g., 1,2,4-triazinyl, 1,3,5-triazinyl), and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0042] As used herein (unless otherwise specified), the terms "deuterated", "deuteration", or "D" means that one or more hydrogens in a compound or group are replaced by deuterium. Deuteration can be mono-, di-, tri-, poly-, or fully-substituted. The term "substituted with one or more deuteriums" can be used interchangeably with "deuterated one or more times".

[0043] As used herein (unless otherwise specified), the term "non-deuterated compound" refers to a compound whose content of deuterium atoms is not higher than the natural content (0.015%) of deuterium isotope.

[0044] The content of deuterium isotope at a deuterated position is at least greater than the natural content of deuterium isotope (0.015%), alternatively greater than 30%, yet alternatively greater than 50%, yet alternatively greater than 75%, yet alternatively greater than 95%, or yet alternatively greater than 99%.

[0045] As used herein (unless otherwise specified), the term "C1-6alkylene" refers to a divalent alkyl linking group, which is a linear or branched, saturated hydrocarbon group having 1 to 6 carbon atoms. An　alkylene　group formally corresponds to an alkane with two C-H bonds replaced by points of attachment of the　alkylene　group to the remainder of the　compound. In some embodiments, the alkylene group may have 1 to 4 carbon atoms (C1-4alkylene) or 1 to 2 carbon atoms (C1-2alkylene). Examples of　the alkylene　group include, but are not limited to, methylene, ethylene, propan-1,3-diyl, propan-1,2-diyl, butan-l,4-diyl, butan-1,3-diyl, butan-l,2-diyl, 2-methyl-propan-1,3-diyl and the like.

[0046] As used herein (unless otherwise specified), the term "carbamoyl" refers to the group -C(=O)- NR'R", where R' and R" independently represent a hydrogen or C1-6alkyl group.

[0047] As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, "optionally substituted" refers to the event or circumstance that a chemical group (for example, the groups defined herein) may be substituted as well as the event or circumstance where a chemical group　is not substituted.

[0048] The term "substituted" refers to moieties having　substituents　replacing hydrogen on one or more carbons of the backbone. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable　compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible　substituents　of organic　compounds. Exemplary substituents on carbon atoms include, but are not limited to, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, -(C1-C6alkylene)-OH, -(C1-C6alkylene)-O-(C1-C6alkyl), 3-10 membered (e.g., 3-8 membered, 5-6 membered, 3-5 membered) cycloalkyl, hydroxy, amino, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), mercapto, -S(C1-C6alkyl), -SO2(C1-C6alkyl), carbamoyl, oxo, a 3-8 membered heterocyclic or heteroaryl group, -CORz1(wherein Rz1is selected from the group consisting of hydrogen, C1-C6alkyl, 3-8 membered cycloalkyl, and halogen), and and -CON(Rz2)(Rz3) (wherein each of Rz2and Rz3is independently selected from the group consisting of hydrogen, C1-C6alkyl, or halogen, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and halogen; or Rz2and Rz3, taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 3-8 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl and halogen), wherein each of said alkyl, alkenyl, alkoxy, alkylene, cycloalkyl, heterocyclic or heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl and halogen. The number of substituents may be any number as long as valence of ths substitued atom and the substituent permit, for example 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, and the like.

[0049]

[0050] General terms

[0051] The term "about", when used with a corresponding numeric value, is meant to encompass variations within ± 20% of the numeric value, typically ± 10% of the numeric value, often ± 5% of the numeric value, and most often ± 2% of the numeric value. In some embodiments, the term "about" can mean the numeric value itself.

[0052] Unless particularly stated otherwise, the concept of any expression in singular form should be considered to encompass the concept of the expression in plural form. Therefore, unless particularly stated otherwise, the concept of any article that expresses the concept of singular (for example, "a", "an", "the", and the like in the case of English language) should be considered to encompass the concept of plural.

[0053] Unless particularly stated otherwise, any term used in the present description should be considered as having the conventional meaning for the relevant technical field. Therefore, unless defined otherwise, all the scientific terms and other technical terms used in the present description have the meaning that is generally understood by those skilled in the art to which the present invention pertains. If there is any conflict in meaning, the present description (including the definitions) takes priority.

[0054] Compounds

[0055] According to an aspect of the present disclosure, provided is a compound of Formula (I) (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0056] As used herein, "compound of the present disclosure" refers to the following compound of Formula (I) (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0057] In one embodiment, the present disclosure relates to a compound of Formula (I):

[0058] (I)

[0059] wherein:

[0060] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0061] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0062] X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein said methylene is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0063] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0064] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0065] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0066] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0067] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,

[0068] or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0069]

[0070] Ring A

[0071] In one embodiment, A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl; preferably, A is 6-10 membered monocyclic or bicyclic aryl or heteroaryl; more preferably, A is selected from the group consisting of 6-membered monocyclic aryl or heteroaryl and 10-membered bicyclic aryl or heteroaryl, each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R1-R4, X, Y, and Z are as defined above.

[0072] In one embodiment, A is selected from the group consisting of phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl, wherein wherein each of said phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R1-R4, X, Y, and Z are as defined above.

[0073] In one embodiment, A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, wherein each of said phenyl, pyridinyl, quinolinyl, and naphthyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R1-R4, X, Y, and Z are as defined above.

[0074] In one embodiment, A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl; preferably, A is 6-10 membered monocyclic or bicyclic aryl or heteroaryl, more preferably, A is selected from the group consisting of 6-membered monocyclic aryl or heteroaryl and 10-membered bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted by an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl with halogen, halogen, cyano, deuterium; preferably, each of said aryl and heteroaryl is independently optionally substituted by an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl with halogen, or halogen; more preferably, each of said aryl and heteroaryl is independently optionally substituted by methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, or iodo; more preferably, each of said aryl and heteroaryl is independently optionally substituted by methyl, trifluoromethyl, fluoro, chloro, or bromo; and R1-R4, X, Y, and Z are as defined above.

[0075] In one embodiment, A is selected from the group consisting of phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl, wherein wherein each of said phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl is independently optionally substituted by an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl with halogen, halogen, cyano, deuterium; preferably, each of said aryl and heteroaryl is independently optionally substituted by an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl with halogen, or halogen; more preferably, each of said aryl and heteroaryl is independently optionally substituted by methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, or iodo; more preferably, each of said aryl and heteroaryl is independently optionally substituted by methyl, trifluoromethyl, fluoro, chloro, or bromo; and R1-R4, X, Y, and Z are as defined above.

[0076] In one embodiment, A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, wherein each of said phenyl, pyridinyl, quinolinyl, and naphthyl is independently optionally substituted by an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl with halogen, halogen, cyano, deuterium; preferably, each of said aryl and heteroaryl is independently optionally substituted by an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl with halogen, or halogen; more preferably, each of said aryl and heteroaryl is independently optionally substituted by methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, or iodo; more preferably, each of said aryl and heteroaryl is independently optionally substituted by methyl, trifluoromethyl, fluoro, chloro, or bromo; and R1-R4, X, Y, and Z are as defined above.

[0077]

[0078] In one embodiment, A is selected from the group consisting of:

[0079] , , , and ,

[0080] wherein:

[0081] each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0082] each of Rb1, Rb2, Rb3and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0083] each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6and Rc7is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0084] each of Rd1, Rd2, Rd3, Rd4, Rd5and Rd6is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0085] R1-R4, X, Y, and Z are as defined above.

[0086]

[0087] In one embodiment, each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl with halogen, halogen, cyano, and deuterium; preferably, each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl, and halogen; more preferably, each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodo; more preferably, each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluoro, chloro, and bromo; and R1-R4, X, Y, and Z are as defined above.

[0088]

[0089] In one embodiment, each of Rb1, Rb2, Rb3and Rb4is independently selected from the group consisting of hydrogen, an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl with halogen, halogen, cyano, and deuterium; preferably, each of Rb1, Rb2, Rb3and Rb4is independently selected from the group consisting of hydrogen, an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl, and halogen; more preferably, each of Rb1, Rb2, Rb3and Rb4is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodo; more preferably, each of Rb1, Rb2, Rb3and Rb4is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluoro, chloro, and bromo; and R1-R4, X, Y, and Z are as defined above.

[0090] In one embodiment, each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6and Rc7is independently selected from the group consisting of hydrogen, an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl with halogen, halogen, cyano, and deuterium; preferably, each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6and Rc7is independently selected from the group consisting of hydrogen, an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl, and halogen; more preferably, each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6and Rc7is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl,fluoro, chloro, bromo, and iodo; more preferably, each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6and Rc7is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluoro, chloro, and bromo; and R1-R4, X, Y, and Z are as defined above.

[0091] In one embodiment, each of Rd1, Rd2, Rd3, Rd4, Rd5and Rd6is independently selected from the group consisting of hydrogen, an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl with halogen, halogen, cyano, and deuterium; preferably, each of Rd1, Rd2, Rd3, Rd4, Rd5and Rd6is independently selected from the group consisting of hydrogen, an unsubstituted C1-C6alkyl, a substituted C1-C6alkyl, and halogen; more preferably, each of Rd1, Rd2, Rd3, Rd4, Rd5and Rd6is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, and iodo; more preferably, each of Rd1, Rd2, Rd3, Rd4, Rd5and Rd6is independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluoro, chloro, and bromo; and R1-R4, X, Y, and Z are as defined above.

[0092]

[0093] In one embodiment, A is ,

[0094] wherein:

[0095] Ra1is selected from the group consisting of hydrogen, fluoride, and methyl;

[0096] Ra2is selected from the group consisting of hydrogen, fluoride, chloride, bromide, methyl, and trifluoromethyl;

[0097] Ra3is selected from the group consisting of hydrogen, fluoride, and methyl;

[0098] Ra4is selected from the group consisting of hydrogen, fluoride, and methyl;

[0099] Ra5is selected from the group consisting of hydrogen, fluoride, and chloride; and

[0100] R1-R4, X, Y, and Z are as defined above.

[0101]

[0102] In one embodiment, A is ,

[0103] wherein:

[0104] Rb1is hydrogen;

[0105] Rb2is hydrogen;

[0106] Rb3is halogen or fluoride, preferably, fluoride;

[0107] Rb4is hydrogen; and

[0108] R1-R4, X, Y, and Z are as defined above.

[0109]

[0110] In one embodiment, A is ,

[0111] wherein Rc1-Rc7are hydrogen; and R1-R4, X, Y, and Z are as defined above.

[0112]

[0113] In one embodiment, A is ,

[0114] wherein Rd1-Rd6are hydrogen; and R1-R4, X, Y, and Z are as defined above.

[0115]

[0116] X

[0117] In one embodiment, X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein said methylene is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl, and Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R1-R4, ring A, Y, and Z are as defined above.

[0118] In one embodiment, X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R1-R4, ring A, Y, and Z are as defined above.

[0119] In one embodiment, X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and R1-R4, ring A, Y, and Z are as defined above.

[0120] In one embodiment, X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium; and R1-R4, ring A, Y, and Z are as defined above.

[0121] In one embodiment, X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein Rzis selected from the group consisting of methyl, ethyl, n-propyl, and butyl, which is optionally substituted with one or more selected from C1-C6alkyl and deuterium; and R1-R4, ring A, Y, and Z are as defined above.

[0122] In one embodiment, X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein Rzis selected from the group consisting of methyl, and ethyl, which is optionally substituted with one or more selected from C1-C6alkyl and deuterium. In one embodiment, X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein Rzis selected from the group consisting of methyl, and ethyl, which is optionally substituted with one or more selected from methyl, ethyl, and deuterium; and R1-R4, ring A, Y, and Z are as defined above. In one embodiment, X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein Rzis selected from the group consisting of methyl, and ethyl, which is optionally substituted with one or more selected from methyl and deuterium; and R1-R4, ring A, Y, and Z are as defined above. In one embodiment, X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein Rzis selected from the group consisting of methyl, isopropyl, and trideutriomethyl; and R1-R4, ring A, Y, and Z are as defined above.

[0123]

[0124] Y

[0125] In one embodiment, Y is selected from the group consisting of -N- and -CRw-. In one embodiment, Y is -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy(each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), hydroxy, amino, mercapto, and carbamoyl; and R1-R4, ring A, X, and Z are as defined above.

[0126] In one embodiment, Y is -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium; and R1-R4, ring A, X, and Z are as defined above. In one embodiment, Y is -CRw-, wherein Rwis selected from the group consisting of hydrogen and cyano; and R1-R4, ring A, X, and Z are as defined above.

[0127]

[0128] Z

[0129] In one embodiment, Z is selected from the group consisting of -N- and -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy(each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), hydroxy, amino, mercapto, and carbamoyl; and R1-R4, ring A, X, and Y are as defined above.

[0130] In one embodiment, Z is selected from the group consisting of -N- and -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium; and R1-R4, ring A, X, and Y are as defined above. In one embodiment, Z is selected from the group consisting of -N- and -CH-; and R1-R4, ring A, X, and Y are as defined above.

[0131]

[0132] R1

[0133] In one embodiment, R1is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy(each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R2-R4, ring A, X, Y and Z are as defined above.

[0134] In one embodiment, R1is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R2-R4, ring A, X, Y and Z are as defined above.

[0135] In one embodiment, R1is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and R2-R4, ring A, X, Y and Z are as defined above.

[0136] In one embodiment, R1is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with halogen; and R2-R4, ring A, X, Y and Z are as defined above.

[0137] In one embodiment, R1is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl, which is optionally substituted with halogen; and R2-R4, ring A, X, Y and Z are as defined above.

[0138] In one embodiment, R1is selected from the group consisting of methyl, and trifluoromethyl; and R2-R4, ring A, X, Y and Z are as defined above.

[0139]

[0140] R2

[0141] In one embodiment, R2is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy(each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R1, R3, R4, ring A, X, Y and Z are as defined above.

[0142] In one embodiment, R2is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R1, R3, R4, ring A, X, Y and Z are as defined above.

[0143] In one embodiment, R2is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and R1, R3, R4, ring A, X, Y and Z are as defined above.

[0144] In one embodiment, R2is C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and R1, R3, R4, ring A, X, Y and Z are as defined above.

[0145] In one embodiment, R2is C1-C6alkyl, wherein said alkyl is independently optionally substituted with halogen; and R1, R3, R4, ring A, X, Y and Z are as defined above.

[0146] In one embodiment, R2is selected from the group consisting of methyl, ethyl, and n-propyl, which is independently optionally substituted with halogen; and R1, R3, R4, ring A, X, Y and Z are as defined above.

[0147] In one embodiment, R2is selected from the group consisting of methyl and trifluoromethyl; and R1, R3, R4, ring A, X, Y and Z are as defined above.

[0148] In one embodiment, R2is trifluoromethyl; and R1, R3, R4, ring A, X, Y and Z are as defined above.

[0149]

[0150] R3

[0151] In one embodiment, R3is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy(each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R1, R2, R4, ring A, X, Y and Z are as defined above.

[0152] In one embodiment, R3is selected from the group consisting of hydrogen, and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and R1, R2, R4, ring A, X, Y and Z are as defined above.

[0153] In one embodiment, R3is selected from the group consisting of hydrogen, and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and R1, R2, R4, ring A, X, Y and Z are as defined above.

[0154] In one embodiment, R3is selected from the group consisting of hydrogen, and C1-C6alkyl; and R1, R2, R4, ring A, X, Y and Z are as defined above.

[0155] In one embodiment, R3is hydrogen; and R1, R2, R4, ring A, X, Y and Z are as defined above.

[0156]

[0157] R4

[0158] In one embodiment, R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto; and R1, R2, R3, ring A, X, Y and Z are as defined above.

[0159] In one embodiment, R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and R1, R2, R3, ring A, X, Y and Z are as defined above.

[0160] In one embodiment, R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and deuterium; and R1, R2, R3, ring A, X, Y and Z are as defined above.

[0161] In one embodiment, R4is hydrogen or C1-C4alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and deuterium; and R1, R2, R3, ring A, X, Y and Z are as defined above.

[0162] In one embodiment, R4is selected from the group consisting of hydrogen, methyl, ethyl, and isopropyl, wherein each of said methyl and ethyl is optionally substituted with one or more selected from C1-C6alkyl, and deuterium; and R1, R2, R3, ring A, X, Y and Z are as defined above.

[0163] In one embodiment, R4is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and trideutriomethyl; and R1, R2, R3, ring A, X, Y and Z are as defined above.

[0164] In one embodiment, R4is selected from the group consisting of hydrogen, methyl, isopropyl, and trideutriomethyl; and R1, R2, R3, ring A, X, Y and Z are as defined above.

[0165]

[0166]

[0167] In one embodiment, the present disclosure relates to a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih):

[0168]

[0169] (Ia)

[0170]

[0171] (Ib)

[0172]

[0173]

[0174] (Ic)

[0175]

[0176]

[0177] (Id)

[0178]

[0179]

[0180] (Ie)

[0181]

[0182]

[0183] (If)

[0184]

[0185]

[0186] (Ig)

[0187]

[0188]

[0189] (Ih)

[0190] wherein:

[0191] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0192] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0193] X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein said methylene is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0194] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0195] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0196] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0197] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0198] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,

[0199] or a tautomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0200]

[0201] Non-limiting exemplary embodiments

[0202]

[0203] In one embodiment, the present disclosure relates to a compound of Formula (II)

[0204] (II)

[0205] wherein:

[0206] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0207] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0208] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0209] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0210] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0211] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,

[0212] or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0213]

[0214] In one embodiment of the compound of Formula (II), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0215] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0216] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0217] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0218] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0219] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[0220]

[0221] In one embodiment of the compound of Formula (II), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0222] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0223] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0224] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and

[0225] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium.

[0226]

[0227] In one embodiment of the compound of Formula (II), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0228] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0229] R3is hydrogen;

[0230] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, or deuterium;

[0231] Y is -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium;

[0232] Z is selected from the group consisting of -N- and -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium; and

[0233] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium.

[0234]

[0235] In one embodiment of the compound of Formula (II), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0236] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0237] R3is hydrogen;

[0238] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0241] A is selected from the group consisting of phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl, wherein wherein each of said phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium.

[0242]

[0243] In one embodiment of the compound of Formula (II), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0244] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0245] R3is hydrogen;

[0246] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0249] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, wherein each of said phenyl, pyridinyl, quinolinyl, and naphthyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium.

[0250]

[0251] In one embodiment of the compound of Formula (II), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0252] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0253] R3is hydrogen;

[0254] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0257] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, wherein each of said phenyl, pyridinyl, quinolinyl, and naphthyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium.

[0258]

[0259] In one embodiment of the compound of Formula (II), R1is methyl, which is optionally substituted with halogen;

[0260] R2is methyl, which is optionally substituted with halogen;

[0261] R3is hydrogen;

[0262] R4is hydrogen, methyl or ethyl, wherein each of said methyl and ethyl is optionally substituted with one or more selected from methyl and deuterium;

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

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

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

[0266]

[0267] In one embodiment of the compound of Formula (II), R1is methyl or trifluoromethyl;

[0268] R2is trifluoromethyl;

[0269] R3is hydrogen;

[0270] R4is selected from the group consisting of hydrogen, methyl, trideuteriomethyl, and isopropyl;

[0271] Y is -CH-;

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

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

[0274]

[0275] In one embodiment, the present disclosure relates to a compound of Formula (IIa):

[0276] (IIa)

[0277] wherein:

[0278] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0279] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0280] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0281] each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0282] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0283] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,

[0284] or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0285]

[0286] In one embodiment of the compound of Formula (IIa), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0287] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0288] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0289] each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, and hydroxy, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0290] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0291] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[0292]

[0293] In one embodiment of the compound of Formula (IIa), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0294] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0295] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0296] each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, and hydroxy, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, and deuterium; and

[0297] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium.

[0298]

[0299] In one embodiment of the compound of Formula (IIa), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0300] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0301] R3is hydrogen;

[0302] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0303] Y is -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium;

[0304] Z is selected from the group consisting of -N- and -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium; and

[0305] each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, and halogen, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, and deuterium.

[0306]

[0307] In one embodiment of the compound of Formula (IIa), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0308] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0309] R3is hydrogen;

[0310] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0313] each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0314]

[0315] In one embodiment of the compound of Formula (IIa), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0316] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0317] R3is hydrogen;

[0318] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0321] each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0322]

[0323] In one embodiment of the compound of Formula (IIa), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0324] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0325] R3is hydrogen;

[0326] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0329] each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0330]

[0331] In one embodiment of the compound of Formula (IIa), R1is methyl, which is optionally substituted with halogen;

[0332] R2is methyl, which is optionally substituted with halogen;

[0333] R3is hydrogen;

[0334] R4is hydrogen, methyl or ethyl, wherein each of said methyl and ethyl is optionally substituted with one or more selected from methyl and deuterium;

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

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

[0337] each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, and trifluoromethyl.

[0338]

[0339] In one embodiment of the compound of Formula (IIa), R1is methyl or trifluoromethyl;

[0340] R2is trifluoromethyl;

[0341] R3is hydrogen;

[0342] R4is hydrogen, methyl, trideuteriomethyl, or isopropyl;

[0343] Y is -CH-;

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

[0345] Ra1is selected from the group consisting of hydrogen, fluoride, and methyl;

[0346] Ra2is selected from the group consisting of hydrogen, fluoride, chloride, bromide, methyl, and trifluoromethyl;

[0347] Ra3is selected from the group consisting of hydrogen, fluoride, and methyl;

[0348] Ra4is selected from the group consisting of hydrogen, fluoride, and methyl; and

[0349] Ra5is selected from the group consisting of hydrogen, fluoride, and chloride.

[0350]

[0351] In one embodiment, the present disclosure relates to a compound of Formula (IIb):

[0352] (IIb)

[0353] wherein:

[0354] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0355] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0356] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0357] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0358] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0359] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,

[0360] or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0361]

[0362] In one embodiment of the compound of Formula (IIb), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0363] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0364] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0365] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, and hydroxy, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0366] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0367] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[0368]

[0369] In one embodiment of the compound of Formula (IIb), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0370] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0371] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0372] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, and hydroxy, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, and deuterium; and

[0373] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium.

[0374]

[0375] In one embodiment of the compound of Formula (IIb), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0376] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0377] R3is hydrogen;

[0378] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0379] Y is -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium;

[0380] Z is selected from the group consisting of -N- and -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium; and

[0381] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, and halogen, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, and deuterium.

[0382]

[0383] In one embodiment of the compound of Formula (IIb), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0384] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0385] R3is hydrogen;

[0386] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0389] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0390]

[0391] In one embodiment of the compound of Formula (IIb), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0392] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0393] R3is hydrogen;

[0394] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0397] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0398]

[0399] In one embodiment of the compound of Formula (IIb), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0400] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0401] R3is hydrogen;

[0402] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0405] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0406]

[0407] In one embodiment of the compound of Formula (IIb), R1is methyl, which is optionally substituted with halogen;

[0408] R2is methyl, which is optionally substituted with halogen;

[0409] R3is hydrogen;

[0410] R4is hydrogen, methyl or ethyl, wherein each of said methyl and ethyl is optionally substituted with one or more selected from methyl and deuterium;

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

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

[0413] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, and trifluoromethyl.

[0414]

[0415] In one embodiment of the compound of Formula (IIb), R1is methyl or trifluoromethyl;

[0416] R2is trifluoromethyl;

[0417] R3is hydrogen;

[0418] R4is selected from the group consisting of hydrogen, methyl, trideuteriomethyl, and isopropyl;

[0419] Y is -CH-;

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

[0421] Rb1is hydrogen;

[0422] Rb2is hydrogen;

[0423] Rb3is halogen or fluoride, preferably, fluoride; and

[0424] Rb4is hydrogen.

[0425]

[0426] In one embodiment, the present disclosure relates to a compound of Formula (IIc):

[0427] (IIc)

[0428] wherein:

[0429] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0430] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0431] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0432] each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0433] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0434] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,

[0435] or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0436]

[0437] In one embodiment of the compound of Formula (IIc), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0438] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0439] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0440] each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, and hydroxy, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0441] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0442] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[0443]

[0444] In one embodiment of the compound of Formula (IIc), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0445] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0446] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0447] each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, and hydroxy, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, and deuterium; and

[0448] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium.

[0449]

[0450] In one embodiment of the compound of Formula (IIc), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0451] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0452] R3is hydrogen;

[0453] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0454] Y is -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium;

[0455] Z is selected from the group consisting of -N- and -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium; and

[0456] each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7is independently selected from the group consisting of hydrogen, C1-C6alkyl, and halogen, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, and deuterium.

[0457]

[0458] In one embodiment of the compound of Formula (IIc), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0459] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0460] R3is hydrogen;

[0461] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0464] each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0465]

[0466] In one embodiment of the compound of Formula (IIc), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0467] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0468] R3is hydrogen;

[0469] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0472] each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0473]

[0474] In one embodiment of the compound of Formula (IIc), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0475] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0476] R3is hydrogen;

[0477] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0480] each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0481]

[0482] In one embodiment of the compound of Formula (IIc), R1is methyl, which is optionally substituted with halogen;

[0483] R2is methyl, which is optionally substituted with halogen;

[0484] R3is hydrogen;

[0485] R4is methyl or ethyl, which is optionally substituted with one or more selected from methyl and deuterium;

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

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

[0488] each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7is independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, and trifluoromethyl.

[0489]

[0490] In one embodiment of the compound of Formula (IIc), R1is methyl or trifluoromethyl;

[0491] R2is trifluoromethyl;

[0492] R3is hydrogen;

[0493] R4is methyl, trideuteriomethyl, or isopropyl;

[0494] Y is -CH-;

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

[0496] each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7is hydrogen.

[0497]

[0498] In one embodiment, the present disclosure relates to a compound of Formula (IId):

[0499] (IId)

[0500] wherein:

[0501] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0502] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0503] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0504] each of Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0505] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0506] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,

[0507] or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0508]

[0509] In one embodiment of the compound of Formula (IId), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0510] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0511] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0512] each of Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, and hydroxy, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0513] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0514] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[0515]

[0516] In one embodiment of the compound of Formula (IId), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0517] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0518] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0519] each of Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, and hydroxy, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, and deuterium; and

[0520] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium.

[0521]

[0522] In one embodiment of the compound of Formula (IId), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0523] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0524] R3is hydrogen;

[0525] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0526] Y is -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium;

[0527] Z is selected from the group consisting of -N- and -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium; and

[0528] each of Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6is independently selected from the group consisting of hydrogen, C1-C6alkyl, and halogen, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, and deuterium.

[0529]

[0530] In one embodiment of the compound of Formula (IId), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0531] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0532] R3is hydrogen;

[0533] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0536] each of Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0537]

[0538] In one embodiment of the compound of Formula (IId), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0539] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0540] R3is hydrogen;

[0541] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0544] each of Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0545]

[0546] In one embodiment of the compound of Formula (IId), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0547] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0548] R3is hydrogen;

[0549] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0552] each of Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0553]

[0554] In one embodiment of the compound of Formula (IId), R1is methyl, which is optionally substituted with halogen;

[0555] R2is methyl, which is optionally substituted with halogen;

[0556] R3is hydrogen;

[0557] R4is methyl or ethyl, which is optionally substituted with one or more selected from methyl and deuterium;

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

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

[0560] each of Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6is independently selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, and trifluoromethyl.

[0561]

[0562] In one embodiment of the compound of Formula (IId), R1is methyl or trifluoromethyl;

[0563] R2is trifluoromethyl;

[0564] R3is hydrogen;

[0565] R4is methyl, trideuteriomethyl, or isopropyl;

[0566] Y is -CH-;

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

[0568] each of Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6is hydrogen.

[0569]

[0570] In one embodiment, the present disclosure relates to a compound of Formula (III):

[0571] (III)

[0572] wherein:

[0573] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0574] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0575] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0576] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0577] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0578] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,

[0579] or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0580]

[0581] In one embodiment of the compound of Formula (III), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0582] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0583] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0584] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0585] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0586] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[0587]

[0588] In one embodiment of the compound of Formula (III), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0589] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0590] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0591] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and

[0592] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium.

[0593]

[0594] In one embodiment of the compound of Formula (III), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0595] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0596] R3is hydrogen;

[0597] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0598] Y is -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium;

[0599] Z is selected from the group consisting of -N- and -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium; and

[0600] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium.

[0601]

[0602] In one embodiment of the compound of Formula (III), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0603] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0604] R3is hydrogen;

[0605] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0608] A is selected from the group consisting of phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl, wherein wherein each of said phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium.

[0609]

[0610] In one embodiment of the compound of Formula (III), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0611] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0612] R3is hydrogen;

[0613] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0616] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, wherein each of said phenyl, pyridinyl, quinolinyl, and naphthyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium.

[0617]

[0618] In one embodiment of the compound of Formula (III), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0619] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0620] R3is hydrogen;

[0621] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0624] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, wherein each of said phenyl, pyridinyl, quinolinyl, and naphthyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium.

[0625]

[0626] In one embodiment of the compound of Formula (III), R1is methyl, which is optionally substituted with halogen;

[0627] R2is methyl, which is optionally substituted with halogen;

[0628] R3is hydrogen;

[0629] R4is methyl, trideutriomethyl, or isopropyl;

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

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

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

[0633]

[0634] In one embodiment of the compound of Formula (III), R1is methyl or trifluoromethyl;

[0635] R2is trifluoromethyl;

[0636] R3is hydrogen;

[0637] R4is methyl;

[0638] Y is -CH-;

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

[0640] A is phenyl, wherein said phenyl is optionally substituted with one or more selected from fluoride, chloride and methyl.

[0641]

[0642] In one embodiment, the present disclosure relates to a compound of Formula (IV):

[0643] (IV)

[0644] wherein:

[0645] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0646] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0647] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0648] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0649] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0650] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[0651] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,

[0652] Or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0653]

[0654] In one embodiment of the compound of Formula (IV), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0655] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[0656] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0657] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0658] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[0659] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and

[0660] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium.

[0661]

[0662] In one embodiment of the compound of Formula (IV), each of R1, R2and R3is independently selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0663] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0664] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[0665] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0666] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and deuterium; and

[0667] Rwis seleced from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium.

[0668]

[0669] In one embodiment of the compound of Formula (IV), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0670] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0671] R3is hydrogen;

[0672] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium;

[0673] Y is -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium;

[0674] Z is selected from the group consisting of -N- and -CRw-, wherein Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and deuterium;

[0675] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and

[0676] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and deuterium.

[0677]

[0678] In one embodiment of the compound of Formula (IV), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0679] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0680] R3is hydrogen;

[0681] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0684] A is selected from the group consisting of phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl, wherein wherein each of said phenyl, pyridinyl, pyrrolyl, pyrazoly, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, quinolinyl, isoquinolinyl, 4H-quinolizyinyl, quinoxalinyl, pthalazinyl, quinazolinyl, cinnolinyl, and naphthyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, or deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and

[0685] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and deuterium.

[0686]

[0687] In one embodiment of the compound of Formula (IV), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0688] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0689] R3is hydrogen;

[0690] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0693] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, wherein each of said phenyl, pyridinyl, quinolinyl, and naphthyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and

[0694] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and deuterium.

[0695]

[0696] In one embodiment of the compound of Formula (IV), R1is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0697] R2is C1-C6alkyl, wherein said alkyl is optionally substituted with halogen;

[0698] R3is hydrogen;

[0699] R4is C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl and deuterium;

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

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

[0702] A is selected from the group consisting of phenyl, pyridinyl, quinolinyl, and naphthyl, wherein each of said phenyl, pyridinyl, quinolinyl, and naphthyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and deuterium; and

[0703] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and deuterium.

[0704]

[0705] In one embodiment of the compound of Formula (IV), R1is methyl, which is optionally substituted with halogen;

[0706] R2is methyl, which is optionally substituted with halogen;

[0707] R3is hydrogen;

[0708] R4is methyl or ethyl, which is optionally substituted with one or more selected from methyl and deuterium;

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

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

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

[0712] Rzis methyl or ethyl, which is optionally substituted with one or more selected from methyl, and deuterium.

[0713]

[0714] In one embodiment of the compound of Formula (IV), R1is methyl, which is optionally substituted with halogen;

[0715] R2is methyl, which is optionally substituted with halogen;

[0716] R3is hydrogen;

[0717] R4is methyl, trideutriomethyl, or isopropyl;

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

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

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

[0721] Rzis selected from the group consisting of methyl, trideutriomethyl, and isopropyl.

[0722]

[0723] In one embodiment, exemplary compounds of Formula (I) are provided below:

[0724]

[0725] In another embodiment, exemplary compounds of Formula (I) are provided below:

[0726] NO.StructureNO.Structure1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

[0727]

[0728]

[0729] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0730] As used herein, the term "stereoisomers" refers to　compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.

[0731] As used herein, the term "diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may be separated into each stereoisomer under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0732] As used herein, the term "enantiomers" refers to two stereoisomers of a　compound　which are non-superimposable mirror images of one another.

[0733] Stereochemical　definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic　Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic　compounds may exist in optically active forms, i.e., they have the ability to rotate the plane of polarization of plane-polarized light. For describing an optically active　compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) denote the direction in which plane of the polarized light is rotated. A compound prefixed by (-) or 1　is levorotatory. A　compound　prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0734] It will be understood by those skilled in the art that the organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." Where the solvent is water, the complex is known as "hydrate." The present disclosure encompasses all solvates of the compounds disclosed herein. Conventional 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 both stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvates will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" means both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0735] The term "hydrate" refers to a compound that is associated with water. Generally, the number of water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, hydrates of a compound can be represented, for example, by a general formula R·x H2O, wherein R denotes the compound, and x is a number greater than 0. Given compounds 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 smaller than 1, for example, hemihydrates (R·0.5 H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2 H2O) and hexahydrates (R·6 H2O)).

[0736] Compounds disclosed herein may be in an amorphous or crystalline form (crystal form or polymorph). Furthermore, the compounds disclosed herein may exist in one or more crystalline forms. Therefore, the scope of the present disclosure includes all amorphous or crystalline forms of the compounds disclosed herein. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, rate of crystallization, storage temperatures, and other factors may cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0737] As used herein, the term "isotope variant" refers to a　compound　that contains proportions of isotopes at one or more of the atoms that constitute such　compound　that are greater in abundance than is natural. For example, an "isotopic variant" of a　compound　can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a　compound　where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be　2H / D, any carbon may be　13C, or any nitrogen may be　15N, and that the presence and placement of such atoms may be determined by those skilled in the art.

[0738] As used herein, the term "prodrug" refers to substances that can be converted, under physiological conditions or through solvolysis, into the　compound　of the present disclosure having biological activity. The　prodrug　of the present disclosure is prepared by modifying the functional groups in the　compound, and the modification can be removed by conventional operations or removed in vivo, to obtain the compound of the present disclosure. The　prodrug　includes a　compound　which is formed by connecting a hydroxyl group or amino group in the　compound　of the present disclosure to any group. When the　prodrug　of the　compound　of the present disclosure is administered to a mammalian individual, the　prodrug　is dissociated to form a free hydroxyl or amino group.

[0739] The term "pharmaceutically acceptable salt" refers to a salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and is commensurate with a reasonable benefit / risk ratio.

[0740] Certain compounds disclosed herein can exist in the form of salts, for example acid addition salts, or salts with organic or inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds disclosed herein include the salt forms of the compounds.

[0741] The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base form of the parent compound with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Acid addition salts (e.g., mono - or di- salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di- salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1 ,2-disulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L- lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1, 5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L- pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L- tartaric, thiocyanic, p-toluenesulfonic, undecylenic, valeric acids, and acylated amino acids.

[0742] One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is a hydrochloride salt.

[0743] Where the compounds disclosed herein contain an amine function, the compound may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the compounds disclosed herein.

[0744] The compounds of the invention may exist as mono- or di- salts depending upon the pKa　of the acid from which the salt is formed.

[0745] It will be appreciated that for use in medicine the salts of the compounds disclosed herein should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g., hydrochloric, hydrobromic, sulfuric, nitric acid, phosphoric acid sulfuric acid, and perchloric acid and organic acids e.g., succinic, maleic, acetic, oxalic, malonic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g., oxalates or formates may be used, for example in the isolation of compounds disclosed herein and are included within the scope of this invention. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0746] Salts formed using conventional methods in the art such as ion exchange are also included. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0747] The compounds disclosed herein may form acid addition salts with one or more equivalents of the acid. The scope of the present invention includes all possible stoichiometric and non-stoichiometric forms.

[0748]

[0749] Preparation Methods

[0750] According to a further aspect of the present disclosure, provided is a process of preparing a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof. The following schemes are examples of synthetic schemes that may be used to synthesize the compound of Formula (I). In the following schemes, reactive groups can be protected with protecting groups and de-protected by well-established techniques in the art. The compound of Formula (I) described in the present disclosure may be prepared by those skilled in the organic synthesis field by using a standard method, which is discussed below in detail.

[0751]

[0752] According to a further aspect of the present disclosure, a process of preparing the compound of Formula (I) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises any one of Processes A to E:

[0753] - Process A or B produces the compound of Formula (II) (i.e., the compound of Formula (I), wherein X is an optionally substituted methylene);

[0754] - Process C produces the compound of Formula (III) (i.e., the compound of Formula (I), wherein X is -NH-);

[0755] - Process D or E produces the compound of Formula (IV) (i.e., the compound of Formula (I), wherein X is -NRz-, and Rzis as defined above).

[0756]

[0757] Process A

[0758]

[0759] Process A prepares the compound of Formula (II) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0760] (i) preparing a compound of Formula (A-1):

[0761]

[0762] (A-1)

[0763]

[0764] (ii) reacting the compound of Formula (A-1) with a compound of Formula (E) to produce a compound of Formula (A-2):

[0765]

[0766] (E)

[0767] ; and

[0768] (A-2)

[0769]

[0770] (iii) reacting the compound of Formula (A-2) with a compound of Formula (F) to obtain the compound of Formula (II):

[0771] (F)

[0772] wherein R1-R4, Y and Z are as defined above,

[0773] X is an optionally substituted methylene, and

[0774] L1is a halide.

[0775]

[0776] In one embodiment, L1is selected from the group consisting of fluoride, chloride, bromide, and iodide, and preferably is bromide or chloride.

[0777]

[0778] In one embodiment, step (i) comprises:

[0779] (i-1) preparing a compound of Formula (aa-1):

[0780]

[0781] ;

[0782] (aa-1)

[0783]

[0784] (i-2) dissolving the compound of Formula (aa-1) in methanol to produce a methanol solution and adding SOCl2to the methanol solution to obtain a compound of Formula (aa-2):

[0785] ;

[0786] (aa-2)

[0787]

[0788] (i-3) introducing Cl2gas into the compound of Formula (aa-2) to obtain a compound of Formula (aa-3):

[0789] ; and

[0790] (aa-3)

[0791]

[0792] (i-4) reacting the compound of Formula (aa-3) with triethylamine to obtain the compound of Formula (A-1).

[0793]

[0794] In one embodiment, step (iii) comprises:

[0795] (iii-1) reacting the compound of Formula (A-2) with lithium hydroxide to obtain a compound of Formula (aa-4):

[0796] ; and

[0797] (aa-4)

[0798]

[0799] (iii-2) reacting the compound of Formula (aa-4) with the compound of Formula (F) to obtain the compound of Formula (II).

[0800]

[0801] In one embodiment, an exemplary reaction scheme of Process A may be shown as Scheme I:

[0802] Scheme I

[0803]

[0804]

[0805] Process B

[0806] Process B prepares the compound of Formula (II) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0807] (i) preparing a compound of Formula (B-1):

[0808] ;

[0809] (B-1)

[0810]

[0811] (ii) reacting the compound of Formula (B-1) with a compound of Formula (F) to produce a compound of Formula (B-2):

[0812]

[0813] (F)

[0814] ; and

[0815] (B-2)

[0816]

[0817] (iii) reacting the compound of Formula (B-2) with a compound of Formula (E) to obtain the compound of Formula (II):

[0818]

[0819] (E)

[0820]

[0821] wherein R1-R4, Y and Z are as defined above,

[0822] X is an optionally substituted methylene, and

[0823] L1is a halide.

[0824]

[0825] In one embodiment, L1is selected from the group consisting of fluoride, chloride, bromide, and iodide, and preferably is bromide or chloride.

[0826]

[0827] In one embodiment, step (i) comprises:

[0828] (i-1) preparing a compound of Formula (bb-1):

[0829]

[0830] ;

[0831] (bb-1)

[0832]

[0833] (i-2) dissolving the compound of Formula (bb-1) in methanol to produce a methanol solution and adding SOCl2to the methanol solution to obtain a compound of Formula (bb-2):

[0834] ;

[0835] (bb-2)

[0836]

[0837] (i-3) introducing Cl2gas into the compound of Formula (bb-2) to obtain a compound of Formula (bb-3):

[0838] ; and

[0839] (bb-3)

[0840]

[0841] (i-4) reacting the compound of Formula (bb-3) with triethylamine to obtain the compound of Formula (B-1).

[0842]

[0843] In one embodiment, an exemplary reaction scheme of Process B may be shown as Scheme II:

[0844]

[0845] Scheme II

[0846]

[0847]

[0848] Process C

[0849] Process C prepares the compound of Formula (III) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0850] (i) preparing a compound of Formula (C-1):

[0851] ;

[0852] (C-1)

[0853]

[0854] (ii) reacting the compound of Formula (C-1) with a compound of Formula (F) to obtain a compound of Formula (C-2):

[0855]

[0856] (F)

[0857] ; and

[0858] (C-2)

[0859]

[0860] (iii) reacting the compound of Formula (C-2) with a compound of Formula (E) to obtain the compound of Formula (II):

[0861]

[0862] (E)

[0863]

[0864] wherein R1-R4, Y and Z are as defined above, and

[0865] L1is a halide.

[0866]

[0867] In one embodiment, L1is selected from the group consisting of fluoride, chloride, bromide, and iodide, and preferably is bromide or chloride.

[0868]

[0869] In one embodiment, step (i) comprises:

[0870] (i-1) preparing a compound of Formula (cc-1):

[0871] ;

[0872] (cc-1)

[0873]

[0874] (i-2) reacting the compound of Formula (cc-1) with benzaldehyde, and adding sodium triacetoxyborohydride to obtain a compound of Formula (cc-2):

[0875] ;

[0876] (cc-2)

[0877]

[0878] (i-3) mixing tert-butanol and N-(oxomethylene)sulfamoyl chloride to produce a mixture, and adding the compound of Formula (cc-2) to the mixture to obtain a compound of Formula (cc-3):

[0879] ;

[0880] (cc-3)

[0881]

[0882] (i-4) performing a cyclization reaction of the compound of Formula (cc-3) in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPH3) to obtain the compound of Formula (C-1).

[0883]

[0884] In one embodiment, an exemplary reaction scheme of Process C may be shown as Scheme III:

[0885] Scheme III

[0886]

[0887]

[0888] Process D

[0889] Process D prepares the compound of Formula (IV) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0890] (i) preparing a compound of Formula (D-1):

[0891] (D-1);

[0892]

[0893] (ii) reacting the compound of Formula (D-1) with a compound of Formula (F) to obtain a compound of Formula (D-2):

[0894] (F)

[0895]

[0896] (D-2);

[0897]

[0898] (iii) reacting the compound of Formula (D-2) with a compound of Formula Rz-L2to obtain the compound of Formula (D-3):

[0899] ;

[0900] (D-3)

[0901]

[0902] (iv) introducing H2gas to the compound of Formula (D-3) in the presence of Pd / C to obtain a compound of Formula (D-4):

[0903] ; and

[0904] (D-4)

[0905]

[0906] (v) reacting the compound of Formula (D-4) with a compound of Formula (E) to obtain the compound of Formula (II):

[0907]

[0908]

[0909] (E)

[0910] wherein R1-R4, Rz, ring A, Y and Z are as defined above, and

[0911] each of L1and L2is independently a halide.

[0912]

[0913] In one embodiment, each of L1and L2is selected from the group consisting of fluoride, chloride, bromide, and iodide, and preferably is bromide or chloride.

[0914]

[0915] In one embodiment, step (i) comprises:

[0916] (i-1) preparing a compound of Formula (dd-1):

[0917] ;

[0918] (dd-1)

[0919]

[0920] (i-2) reacting the compound of Formula (dd-1) with benzaldehyde to obtain a compound of Formula (dd-2):

[0921] ;

[0922] (dd-2)

[0923]

[0924] (i-3) mixing tert-butanol and N-(oxomethylene)sulfamoyl chloride to produce a mixture and adding the compound of Formula (dd-2) to the mixture to obtain a compound of Formula (dd-3):

[0925] ;

[0926] (dd-3)

[0927]

[0928] (i-4) performing a cyclization reaction of the compound of Formula (dd-3) in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPH3) to obtain the compound of Formula (D-1).

[0929]

[0930] In one embodiment, an exemplary reaction scheme of Process D may be shown as Scheme IV:

[0931] Scheme IV

[0932] .

[0933]

[0934] Process E

[0935] Process E prepares the compound of Formula (IV) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0936] (i) preparing a compound of Formula (E-1):

[0937] ;

[0938] (E-1)

[0939]

[0940] (ii) reacting the compound of Formula (E-1) with NaH to obtain a compound of Formula (E-2):

[0941] ;

[0942] (E-2)

[0943]

[0944] (iii) reacting the compound of Formula (E-2) with a compound of Formula Rz-L2to obtain a compound of Formula (E-3):

[0945] ;

[0946] (E-3)

[0947]

[0948] (iv) performing an amidation reaction of the compound of Formula (E-3) to obtain a compound of Formula (E-5):

[0949]

[0950] ;

[0951] (E-5)

[0952]

[0953] (v) reacting the compound of Formula (E-5) with H2gas in presence of Pd / C catalyst to obtain a compound of Formula (E-6):

[0954] ; and

[0955] (E-6)

[0956]

[0957] (vi) reacting the compound of Formula (E-6) with a compound of Formula (E) to obtain a compound of Formula (II):

[0958]

[0959] (E)

[0960] wherein R1-R4, Rz, ring A, Y and Z are as defined above, and

[0961] each of L1, and L2is independently a halide.

[0962]

[0963] In one embodiment, step (iv) comprises:

[0964] (iv-1) reacting the compound of Formula (E-3) with a compound of Formula (E-4-1) to obtain a compound of Formula (E-5):

[0965]

[0966] (E-4-1),

[0967] wherein R3, R4, Rz, and ring A are as defined above.

[0968]

[0969] In another embodiment, step (iv) comprises:

[0970] (iv-2) reacting the compound of Formula (E-3) with a compound of Formula (E-4-2) to obtain a compound of Formula (E-4-3):

[0971]

[0972] (E-4-2)

[0973] ; and

[0974] (E-4-3)

[0975]

[0976] (iv-3) reacting the compound of Formula (E-4-3) with a compound of formula R4-L3 to obtain a compound of Formula (E-5),

[0977] wherein R3, R4, Rz, and ring A are as defined above; and

[0978] L3is independently a halide.

[0979]

[0980] In one embodiment, step (i) comprises:

[0981] (i-1) preparing a compound of Formula (ee-1):

[0982] ;

[0983] (ee-1)

[0984]

[0985] (i-2) reacting the compound of Formula (ee-1) with benzaldehyde to obtain a compound of Formula (ee-2):

[0986] ;

[0987] (ee-2)

[0988]

[0989] (i-3) mixing tert-butanol and N-(oxomethylene)sulfamoyl chloride to produce a mixture and adding the compound of Formula (ee-2) to the mixture to obtain a compound of Formula (ee-3):

[0990] ;

[0991] (ee-3)

[0992]

[0993] (i-4) performing a cyclization reaction of the compound of Formula (ee-3) in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPH3) to obtain the compound of Formula (E-1).

[0994]

[0995] In one embodiment, an exemplary reaction scheme of Process E may be shown as Scheme V:

[0996] Scheme V

[0997] .

[0998]

[0999] Therapeutic utilities

[1000] The terms "treat", "treating", "treatment" and the like refer to a course of action (such as administering an inhibitor of Polθ or a pharmaceutical composition comprising same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition afflicting a subject, or at least one of the symptoms associated with a disease, disorder, condition afflicting a subject. Thus, "treatment" may also refer to inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease.

[1001] The terms "prevent", "preventing", "prevention" and the like refer to a course of action (such as administering a Polθ inhibitor or a pharmaceutical composition comprising same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject's risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting the progression of the disease, disorder or condition such that it does not reach a harmful or otherwise undesired state.

[1002] The terms "inhibiting" and "reducing," or any variation of these terms in relation of Polθ, may refer to any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease in Polθ activity of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, compared to a control group. The term "about" as used herein means variations within ± 20%, preferably, within ± 10%, more preferably within ± 5% of a given value.

[1003] "Disease", "disorder" and "condition" are used interchangeably herein.

[1004] The present disclosure provides a compound that prevents or treats a disease or disorder mediated by Polθ or a disease or disorder in which Polθ activity is implicated.

[1005] For some embodiments, the disease or disorder mediated by Polθ is any of proliferative disorders. The term "proliferative disorders" is used interchangeably herein and pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis.

[1006] For some embodiments, the disease or disorder mediated by Polθ is any of HR-deficient cancers, including BRCA1- and BRCA2-deficient cancer, 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.), pancreas cancer (Cancers (Basel) 2022 Aug 23;14(17):4077), and lung cancer (Cancers　2019,　11(5), 722). The present compound, composition and method may further enhance the efficacy of cancer therapies with at least one of the following modes of action (MOAs): (1) therapeutic mode that induces DNA damage, (2) therapeutic mode that modulates cell cycles, and (3) therapeutic mode that inhibits components involved in DNA damage responses (DDRs).

[1007] In a cancer treatment, the therapeutically effective amount of the compound of Formula (I) provided herein is an amount sufficient to provide therapeutic benefits during the course of the treatment, or to delay or minimize one or more symptoms associated with cancer. In a cancer treatment, the therapeutically effective amount of a compound is the amount of the therapeutic agent that, when used alone or in combination with other therapies, provides such therapeutic benefits during the course of the treatment.

[1008] Effective amounts of the compound of the present disclosure vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, whether treatment is prophylactic or therapeutic, as well as the specific activity of the composition itself and its ability to elicit the desired response in the individual. In the context of this disclosure, the patient can be a human or non-human mammal. Typically, dosage regimens are adjusted to provide an optimum therapeutic response, i.e., to optimize safety and efficacy. Accordingly, a therapeutically effective amount is also one of which any undesired collateral effects are outweighed by the beneficial effects of administering the compound as described herein.

[1009]

[1010] Pharmaceutical compositions

[1011] The terms "combination", "combined", and related terms refer to the simultaneous, separate or sequential administration of two or more therapeutic agents or therapies. For example, the compound disclosed herein may be administered with another therapeutic agent or therapy simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. The another therapy may be radiotherapy. The another therapeutic agent may be an anti-cancer agent. The anti-cancer agent may include DNA damage response (DDR) targeting anti-cancer agents. The DNA damage response (DDR) is a collective term for the plethora of different intra- and inter-cellular signaling events and　enzyme　activities that result from the induction and detection of DNA damage. There are at least three　key aspects of DDR that are different in cancers compared with normal cells, which in turn make DDR an attractive source for drug targets that can (and indeed currently are) being exploited to generate new cancer therapies. Loss of one or more DDR pathways, increased replication stress, and higher levels of endogenous DNA damage are all differentiating aspects of cancer DDR that can be targeted therapeutically. A number of anti-cancer agents targeting DDR have been known and developed, e.g., PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (e.g., MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide), etc. (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 compound disclosed herein also belongs to DDR targeting agents.

[1012] In some embodiment, provided is a pharmaceutical composition including the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutical acceptable carrier, wherein the composition may be administered simultaneously, separately or sequentially with additional DDR targeting anti-cancer agent described above.

[1013] In some embodiment, provided is a method of treating or preventing diseases or disorders mediated by polymerase theta, in a subject, comprising administering to the subject the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the method further comprises administering additional DDR targeting anti-cancer agent described above to the subject.

[1014] In some embodiment, provided is a kit comprising:

[1015] - a first pharmaceutical composition or dosage form comprising the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers; and

[1016] - a second pharmaceutical composition or dosage form comprising additional DDR targeting anti-cancer agent described above, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers.

[1017] In some embodiment, the kit is for use in a method of treating and / or preventing diseases or disorders mediated by polymerase theta. In some embodiment, the first pharmaceutical composition or dosage form may be administered simultaneously, separately or sequentially with second pharmaceutical composition or dosage form. In some embodiment, the kit may further comprise a package insert comprising an instruction for simultaneous, sequential or separate use in the treatment and / or prevention of diseases or disorders mediated by polymerase theta.

[1018] The present disclosure further relates to a pharmaceutical composition, comprising a pharmaceutically effective amount of one or more of the compounds disclosed herein, and a pharmaceutically acceptable carrier(s) and / or excipient(s). The composition may further comprise at least one of additional therapeutic agents in amounts effective for achieving the treatment or prevention of diseases or disorders disclosed herein. Pharmaceutically acceptable carriers and excipients are well known in the art, and the choice of carriers and excipients will to a large extent depend on factors such as mode of administration, their effects on solubility and stability, and the nature of dosage form.

[1019]

[1020] Treatment method

[1021] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta, in a subject in need of treatment or prevention, comprising administering to the subject at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.

[1022] The terms "human", "patient" or "subject" are used interchangeably. A "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal 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.

[1023]

[1024] Administration

[1025] The pharmaceutical composition of the present disclosure can be administered via various routes, including, but not limited to, oral, parenteral (injected), (e.g., intravenous, subcutaneous, intramuscular, intravascular administration, or infusion), sublingual, topical, transderamal, ocular, rectal, nasal, and vaginal administration.

[1026] The pharmaceutical composition provided herein is administered in a pharmaceutically effective amount. For example, the pharmaceutically effective amount of the pharmaceutical composition may be in the range of about 0.01 mg to about 500 mg / kg of body weight, or about 10 mg to about 500 mg / kg of body weight. In one embodiment, the amount may be in the range of about 0.1 mg to about 250 mg / kg of body weight, or about 0.1 mg to about 10 mg / kg of body weight, or about 0.1 mg to about 1 mg / kg of body weight. In another embodiment, the amount be in the range of about 1 mg to about 100 mg / kg of body weight, preferably, about 10 mg to about 100 mg / kg of body weight. The amount of the composition to be administered will typically be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[1027]

[1028] Formulation

[1029] The pharmaceutical composition may, for example, be in a form suitable for oral administration such as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection such as a sterile solution, suspension or emulsion, for topical administration such as an ointment or cream, or for rectal administration such as a suppository. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient, and a compound of the present disclosure as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[1030] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. For oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof. Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in the art.

[1031]

[1032] Dosage

[1033] The pharmaceutical composition of the present disclosure may be administered in a single dose or in multiple doses. Dosing may occur one time, two times, three times, four times, five times, six times, or more than six times per day. Dosing may occur once a month, once every two weeks, once a week, or once every other day. In some cases, continuous dosing is achieved and maintained as long as necessary. In some embodiments, the pharmaceutical composition of the present disclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the pharmaceutical composition of the present disclosure is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the pharmaceutical composition of the present disclosure is administered chronically on an ongoing basis.

[1034]

[1035] It is noted that the compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention should be understood to applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed herein (including any accompanying claims, and abstract), and / or all of the steps of any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed herein (including any accompanying claims, and abstract), or to any novel one, or any novel combination, of the steps of any method or process disclosed.

[1036] The contents of the articles and documents referred to herein are incorporated herein by reference in its entirety as if all of their contents are described in detail herein.

[1037]

[1038] EXAMPLE

[1039] The present disclosure will be further described below in combination with specific examples. It should be understood that these examples are only used to illustrate the present disclosure and not to limit the scope of the present disclosure. The experimental methods without specific conditions used in the following examples are generally performed under the conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and weight percent.

[1040] Generally, in the preparation process, each reaction is carried out in an inert solvent at a temperature from room temperature to reflux temperature (e.g., 0oC to 100oC, or alternatively 0oC to 80oC). The reaction time is usually 0.1-60 hours, or alternatively 0.5-24 hours.

[1041]

[1042] Abbreviations

[1043] The abbreviations as used herein have the following meanings:

[1044] Et3N: Triethylamine

[1045] MeOH: Methanol

[1046] EtOH: Ethanol

[1047] SOCl2: Thionyl chloride

[1048] CHCl3: Chloroform

[1049] Na2SO4: Sodium sulfate

[1050] LCMS: Liquid chromatography-mass spectrometry

[1051] HPLC: High-performance liquid chromatography

[1052] Boc: tert-Butyloxycarbonyl

[1053] DCM: Dichloromethane

[1054] TFA: Trifluoroacetic acid

[1055] THF: Tetrahydrofuran

[1056] dba: Dibenzylideneacetone

[1057] ACN: Acetonitrile

[1058] EtOAc: Ethyl acetate

[1059] NaOAc: Sodium acetate

[1060] NaBH(OAc)3:Sodium triacetoxyborohydride

[1061] AcOH: Acetic acid

[1062] TLC: Thin Layer Chromatography

[1063] PPh3:Triphenylphosphine

[1064] DIAD: Diisopropyl azodicarboxylate

[1065] HOBT: 1-Hydroxybenzotriazole

[1066] EDCI: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

[1067] DIEA: N, N-Diisopropylethylamine

[1068] DMF: Dimethylformamide

[1069] AlMe3:Trimethylaluminum

[1070] Py: Pyridine

[1071] ODS: Octa-decyl Silica

[1072] TBAF: Tetra-n-butylammonium fluoride

[1073]

[1074]

[1075] Materials and Methods

[1076] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless stated otherwise. All reactions were performed at RT unless stated otherwise. Flash column chromatography was carried out using pre-packed columns filled with Merck flash silica gel 60 (40-63 μm) or C18 flash silica on an ISCO Combiflash Nextgen or a Biotage Selekt.

[1077] Unless state otherwise, all reagents were used without further purification.1H-NMR spectra were obtained in DMSO-d6orCDCl3at room temperature on a Bruker 400 MHz instrument. When more than one conformer was detected, the chemical shifts for the most abundant one was reported. Chemical shifts of1H NMR spectra were recorded in parts per million (ppm) on the δ scale from an internal standard of residual solvent. Splitting patterns are designed as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, coupling constants (Hz), and integrated and often tabulated; LC-MS conditions are described below:

[1078]

[1079] LCMS Method A：

[1080] LCMS Column: SHIMADZU Xtimate C18 2.1*30 mm, 3um

[1081] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

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

[1083] Flow Rate: 0.8 mL / min

[1084] Run time: gradient 10%-80% (solvent B) over 6 minutes and holding at 80% for 0.5 minutes

[1085] Temperature: 50 ℃

[1086]

[1087] LCMS Method B：

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

[1089] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

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

[1091] Flow Rate: 0.8 mL / min

[1092] Run time: gradient 10%-80% (solvent B) over 6 minutes and holding at 80% for 0.5 minutes

[1093] Temperature: 50 ℃

[1094]

[1095] LCMS Method C：

[1096] LCMS Column: SHIMADZU Xtimate C18 2.1*30 mm, 3um

[1097] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

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

[1099] Flow Rate: 0.8 mL / min

[1100] Run time: gradient 30%-90% (solvent B) over 6 minutes and holding at 90% for 0.5 minutes

[1101] Temperature: 50 ℃

[1102]

[1103] LCMS Method D：

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

[1105] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

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

[1107] Flow Rate: 0.8 mL / min

[1108] Run time: gradient 30%-90% (solvent B) over 6 minutes and holding at 90% for 0.5 minutes

[1109] Temperature: 50 ℃

[1110]

[1111]

[1112] Step a.To a solution of (2S)-2-amino-4-[[(3S)-3-amino-3-carboxy-propyl]disulfanyl]-butanoic acid (20 g, 65.61 mmol, HCl) in MeOH (200 mL) was added SOCl2(23.42 g, 196.84 mmol, 14.30 mL) at 0 °C. The mixture was stirred at 25 °C for 12 hr. LCMS showed the desired compound was detected. The reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-amino-4-[[(3S)-3-amino-4-methoxy-4-oxo-butyl]disulfanyl]butanoate (28 g, crude, HCl) as a white solid.1H NMR (DMSO-d6)δ= 8.76 (br s, 6H), 4.14-4.10 (m, 2H), 3.75 (s, 6H), 2.99-2.78 (m, 4H), 2.21 (q,J= 7.2 Hz, 4H).

[1113] Step b.Cl2(61 g, 860.25 mmol) gas was introduced into a mixed solution of methyl (2S)-2-amino-4-[[(3S)-3-amino-4-methoxy-4-oxo-butyl]disulfanyl]butanoate (5.3 g, 15.92 mmol, HCl) in EtOH (20 mL) and CHCl3(40 mL) for 20 min under 0 °C, and the reaction mixture was obtained as white suspension. The white suspension was filtered, and the filter cake was washed with CHCl3(100 mL) and the white solid was collected. Methyl (2S)-2-amino-4-chlorosulfonyl-butanoate (4 g, crude, HCl) was obtained as a white solid, which was directly used for the next step without further purification.

[1114] 1H NMR (DMSO-d6)δ= 10.05 (br, s, 3H), 4.21 (t,J= 7.6 Hz, 1H), 3.67 (s, 3H), 3.21-3.11 (m, 1H), 3.09-2.98 (m, 1H), 2.64-2.55 (m, 1H), 2.40-2.28 (m, 1H).

[1115] Step c.To a solution of methyl (2S)-2-amino-4-chlorosulfonyl-butanoate (4 g, 15.87 mmol, HCl) in CHCl3(50 mL) was added Et3N (4.82 g, 47.60 mmol, 6.62 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hr. LCMS showed the desired compound was detected. The white suspension reaction mixture was washed with water (40 mL Х 3), and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressured to obtain methyl (3S)-1,1-dioxo-1,2-thiazolidine-3-carboxylate (2.38 g, 11.95 mmol, 75.34% yield, 90% purity) as a white solid, which was directly used for the next step without further purification.

[1116] 1H NMR (DMSO-d6)δ= 7.50 (br d,J= 5.6 Hz, 1H), 4.27-4.17 (m, 1H), 3.68 (s, 3H), 3.23-3.11 (m, 1H), 3.09-2.98 (m, 1H), 2.62-2.58 (m, 1H), 2.41-2.25 (m, 1H).

[1117] Step d.To a solution of methyl (3S)-1,1-dioxo-1,2-thiazolidine-3-carboxylate (1 g, 5.58 mmol in dioxane (15 mL) was added 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). The mixture was stirred at 80 °C for 12 hr. LCMS showed the desired compound was detected. The reaction solution was directly blow-dried, then extracted with water (100 mL) and DCM (150 mL Х 3). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by reversed phase column (column: 40 g C18 reversed phase column; mobile phase: [Water (0.05%TFA)-ACN]; B%: 0%-58%, 30 min) to obtain methyl (3S)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidine-3-carboxylate (660 mg, 1.95 mmol, 34.96% yield, 100% purity) as a white solid.

[1118] 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, 5.2 Hz, 1H), 3.82-3.72 (m, 1H), 3.69 (s, 3H), 3.67-3.60 (m, 1H), 2.84-2.70 (m, 1H), 2.51-2.46 (m, 1H), 2.44 (s, 3H).

[1119] Step e.To a solution of methyl (3S)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidine-3-carboxylate (490 mg, 1.45 mmol) in MeOH (2 mL), THF (2 mL) and H2O (1 mL) was added LiOH·H2O (243.12 mg, 5.79 mmol). The mixture was stirred at 25 °C for 12 hr. LCMS showed the desired compound was detected. The residue was purified by reversed phase column (column: 40 g C18 reversed phase column; mobile phase: [Water-ACN]; B%: 0%-48%, 30min) to obtain (S)-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidine-3-carboxylic acid 1,1-dioxide (160 mg, 493.41 μmol, 34.07% yield, 100% purity) as a white solid.

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

[1121]

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

[1123]

[1124] Step a.To a solution of methyl (3S)-1,1-dioxo-1,2-thiazolidine-3-carboxylate (500 mg, 2.79 mmol) in dioxane (15 mL) was added 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). The mixture was stirred at 80 °C for 12 hr. LCMS showed the desired compound was detected. The reaction solution was directly pulled dry, then extracted with water (20 mL) and DCM (30 mL Х 3), the combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reversed phase column (column: 40 g C18 reversed phase column ;mobile phase: [Water (0.05% HCl-ACN]; B%: 0%-50%, 30min) to obtain methyl (3S)-2-[2-methyl-6-(trifluoromethyl) pyrimidin-4-yl]-1,1-dioxo-1,2-thiazolidine-3-carboxylate (430 mg, 1.27 mmol, 22.71% yield, 100% purity) as a colorless oil.

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

[1126]

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

[1128]

[1129] Step a.To a solution of methyl (2S)-2-amino-3-hydroxy-propanoate (5 g, 32.14 mmol, HCl) in THF (50 mL) was added benzaldehyde (2.73 g, 25.71 mmol, 2.60 mL) at 25 °C and the resulting mixture was cooled down to 0 °C. AcOH (500.00 mg, 8.33 mmol, 476.64 μL) and NaOAc (2.11 g, 25.71 mmol) was added, and the reaction mixture was stirred for 1 hr at 0-5 ℃. NaBH(OAc)3(11.58 g, 54.63 mmol) was added portion-wise over 30 min and the reaction mixture was stirred for 16 hr at 15 ℃. LCMS showed desired mass was observed. To the suspension was added a saturated NaHCO3solution (175 mL) over 45 min (gas evolution, pH adjusted to 8-9) at 0-5 °C, then the mixture was extracted with EtOAc (100 mL Х 3), the organic layer was washed with water (100 mL) and dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®;80 g Sepa Flash® Silica Flash Column, Eluent of 0-80% Ethylacetate / Petroleum ether gradient @ 80 mL / min) to obtain methyl (2S)-2-(benzylamino)-3-hydroxy-propanoate (5.6 g, 25.93 mmol, 80.70% yield, 96.9% purity) as a colorless oil.

[1130] MS (ESI) m / z = 210.1 [M+H]+;1H NMR (DMSO-d6):δ =7.32-7.31 (m, 4H), 7.26-7.21 (m, 1H), 4.84 (t,J= 4.8 Hz, 1H), 3.77 (d,J= 13.6 Hz, 1H), 3.63 (s, 3H), 3.61 (d,J= 6.4 Hz, 1H), 3.59-3.56 (m, 2H), 3.26 (t,J= 5.2 Hz, 1H), 2.40 (br s, 1H).

[1131] Step b.A solution of t-BuOH (1.66 g, 22.45 mmol, 2.15 mL) in DCM (10 mL) was added dropwise to a solution of N-(oxomethylene)sulfamoyl chloride (2.89 g, 20.41 mmol, 1.78 mL) in DCM (30 mL) at 0 °C, and then the mixture was stirred at 0 °C for 1 hr under N2atmosphere. Then, a solution of methyl (2S)-2-(benzylamino)-3-hydroxy-propanoate (4.27 g, 20.41 mmol) and Et3N (3.10 g, 30.61 mmol, 4.26 mL) in DCM (30 mL) was added to the above solution at 0 °C. The mixture was stirred at 10-19 °C for 16 hr. LCMS showed desired mass was observed. TLC (Plate 1, SiO2, Petroleum ether: Ethyl acetate = 1: 1) showed a new spot (Rf= 0.8) was observed. The mixture was diluted with water (100 mL) and extracted with dichloromethane (30 mL Х 3), and the combined organic layer was washed with brine (50 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography on silica gel eluting with 0-41% ethyl acetate in petroleum ether to afford methyl (2S)-2-[benzyl(tert-butoxycarbonylsulfamoyl)amino]-3-hydroxy-propanoate (1.5 g, 3.63 mmol, 17.79% yield, 94% purity) as a yellow gum.

[1132] MS (ESI) m / z = 289.0 [M-Boc+H]+;1H NMR (CDCl3)δ= 7.60-7.39 (m, 3H), 7.38-7.29 (m, 3H), 4.71-4.63 (m, 2H), 4.60-4.53 (m, 1H), 4.00 (d,J= 6.8 Hz, 2H), 3.69 (s, 3H), 2.88 (s, 1H), 1.48 (s, 9H).

[1133] Step c.To a solution of methyl (2S)-2-[benzyl(tert-butoxycarbonylsulfamoyl)amino]-3-hydroxy-propanoate (3.26 g, 8.39 mmol) and PPh3(2.64 g, 10.07 mmol) in DCM (60 mL) was added DIAD (2.04 g, 10.07 mmol, 1.95 mL) at 0 °C, and then the mixture was stirred at 16 °C for 2 hr. LCMS showed desired mass was observed. TLC (Plate 1, SiO2, Petroleum ether: Ethyl acetate = 3: 1) showed a new spot (Rf= 0.6) was observed. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography on silica gel eluting with 0-25% ethyl acetate in petroleum ether to afford 2-(tert-butyl) 4-methyl (S)-5-benzyl-1,2,5-thiadiazolidine-2,4-dicarboxylate 1,1-dioxide (2.56 g, 6.91 mmol, 82.37% yield, 100% purity) as a white solid.

[1134] MS (ESI) m / z = 393.0 [M+Na]+;1H 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).

[1135]

[1136] Example 1

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

[1138]

[1139] Step a.To a solution of Intermediate 1 (50 mg, 154.19 μmol) in DMF (2 mL) was added 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). The mixture was stirred at 25 °C for 12 hr. LCMS showed the desired compound was detected. The residue was purified by reversed phase column (column: 40 g C18 reversed phase column; mobile phase: [Water (0.05%TFA)-ACN]; B%: 0%-70%, 30 min) to obtain (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidine-3-carboxamide (31 mg, 57.25 μmol, 37.13% yield, 100% purity, TFA) as a brown solid.

[1140] 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= 7.2 Hz, 1H), 7.19 (s, 1H), 4.84 (dd,J= 7.2, 4.8 Hz, 1H), 3.70-3.56 (m, 2H), 3.17 (s, 3H), 2.59 (s, 3H), 2.45-2.38 (m, 2H), 2.38 (s, 3H).

[1141]

[1142] Example 2

[1143] (3S)-N-(2,4-difluoro-3-methyl-phenyl)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidine-3-carboxamide (Compound No. 44)

[1144] (S)-N-(2,4-difluoro-3-methylphenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)isothiazolidine-3-carboxamide 1,1-dioxide (Compound No. 2)

[1145]

[1146] Step a.To a solution of Intermediate 1 (100 mg, 308.38 μmol) in Py (1 mL) was added 3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (196.26 mg, 770.95 μmol) and was added 2,4-difluoro-3-methyl-aniline (88.28 mg, 616.76 μmol). The mixture was stirred at 25 °C for 12 hr. LCMS showed the desired compound was detected. The residue was purified by reversed phase column (column: 40 g C18 reversed phase column; mobile phase: [Water (0.05%TFA)-ACN]; B%: 0%-56%, 40 min) to obtain (3S)-N-(2,4-difluoro-3-methyl-phenyl)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidine-3-carboxamide (Compound No. 44) (53 mg, 99.07 μmol, 32.12% yield, 84% purity) as a white solid.

[1147] 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= 7.2 Hz, 1H), 5.16 (dd,J= 7.6, 4.8 Hz, 1H), 3.83-3.59 (m, 2H), 3.50-3.39 (m, 1H), 2.85-2.70 (m, 1H), 2.44 (s, 3H), 2.17 (s, 3H).

[1148] Step b.To a solution of (3S)-N-(2,4-difluoro-3-methyl-phenyl)-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidine-3-carboxamide (49 mg, 109.04 μmol) in ACN (1 mL) was added Cs2CO3(53.29 mg, 163.55 μmol) and MeI (30.95 mg, 218.07 μmol, 13.58 μL). The mixture was stirred at 80 °C for 12 hr. LCMS showed the desired compound was detected. The reaction mixture was further purified by Prep-HPLC column: Boston Green ODS 150*30mm*5um;mobile phase: [water(TFA)-ACN];gradient: 50%-90% B over 9 min to obtain (3S)-N-(2,4-difluoro-3-methyl-phenyl)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-1,1-dioxo-1,2-thiazolidine-3-carboxamide (Compound No. 2) (15.5 mg, 33.45 μmol, 30.68% yield, 100% purity, TFA) as a white solid.

[1149] MS (ESI) m / z = 464.1 [M+H]+;1H 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= 8.0 Hz, 3H), 2.60 (s, 3H), 2.48 (br s, 2H), 2.41-2.20 (m, 3H).

[1150]

[1151] Example 3

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

[1153]

[1154] Example 3 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 3-chloro-4-fluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (80.8 mg, 173.45 μmol, 47.78%, 100% purity) as a white solid.

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

[1156]

[1157] Example 4

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

[1159]

[1160] Example 4 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 3-chloro-2,4-difluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (10.57 mg, 21.32 μmol, 25.04%, 97.6% purity) as a white solid.

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

[1162]

[1163] Example 5

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

[1165]

[1166] Example 5 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 3-bromo-2,4-difluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (32.42 mg, 60.14 μmol, 55.23%, 98% purity) as a white solid.

[1167] MS (ESI) m / z = 527.8 [M+H]+;1H 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= 15.2 Hz, 1H), 5.64-5.61 (m, 0.2H), 4.91-4.80 (m, 0.8H), 3.80-3.57 (m, 2H), 3.56 (s, 0.6H), 3.14 (d,J= 9.2 Hz, 2.4H), 2.95-2.68 (m, 0.3H), 2.65-2.55 (m, 3H), 2.47-2.05 (m, 1.7H).

[1168]

[1169] Example 6

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

[1171]

[1172] Example 6 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 2,4-difluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (38.28 mg, 79.22 μmol, 95.80% yield, 93% purity) as a white solid.

[1173] 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= 8.8 Hz, 2.4H), 2.63-2.52 (m, 3H), 2.46-2.34 (m, 2H).

[1174]

[1175] Example 7

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

[1177]

[1178] Example 7 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 2,3,4-trifluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (45.14 mg, 92.62 μmol, 99.98% yield, 95.9% purity) as a white solid.

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

[1180]

[1181] Example 8

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

[1183]

[1184] Example 8 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 4-fluoro-3-methyl-aniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (24.92 mg, 55.95 μmol, 26.23% yield, 100% purity) as a white solid.

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

[1186]

[1187] Example 9

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

[1189]

[1190] Example 9 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 2,4,6-trifluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (53.16 mg, 110.33 μmol, 41.68%, 97% purity) as a white solid.

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

[1192]

[1193] Example 10

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

[1195]

[1196] Example 10 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 2,4,5-trifluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (39.37 mg, 82.47 μmol, 31.16% yield, 97.9% purity) as a white solid.

[1197] MS (ESI) m / z = 467.8 [M+H]+;1H 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= 12.4 Hz, 2.3H), 2.88-2.65 (m, 0.3H), 2.62-2.53 (m, 3H), 2.44-2.14 (m, 1.7H).

[1198]

[1199] Example 11

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

[1201]

[1202] Example 11 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 2,3,4,5-tetrafluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (36.52 mg, 73.74 μmol, 34.76% yield, 98% purity) as a white solid.

[1203] 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= 12.0 Hz, 2H), 2.88-2.65 (m, 0.3H), 2.61-2.52 (m, 3H), 2.46-2.12 (m, 1.7H)

[1204]

[1205] Example 12

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

[1207]

[1208] Example 12 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step b, trideuterio(iodo)methane was used instead of MeI, to obtain the target compound (56.71 mg, 119.88 μmol, 53.87% yield, 98.6% purity) as a white solid.

[1209] MS (ESI) m / z = 466.9 [M+H]+;1H 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, 4.4 Hz, 0.2H), 4.94-4.79 (m, 0.8H), 3.78-3.54 (m, 2H), 2.63-2.52 (m, 3H), 2.49-2.37 (m, 2H), 2.26-2.12 (m, 3H).

[1210]

[1211] Example 13

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

[1213]

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

[1215] MS (ESI) m / z = 491.9 [M+H]+;1H 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).

[1216]

[1217] Example 14

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

[1219]

[1220] Example 14 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 5-fluoropyridin-3-amine was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (85.98 mg, 198.85 μmol, 56.46% yield, 98% purity) as a white solid.

[1221] MS (ESI) m / z = 432.8 [M+H]+;1H 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).

[1222]

[1223] Example 15

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

[1225]

[1226] Example 15 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, isoquinolin-4-amine was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (31.5 mg, 66.33 μmol, 24.73% yield, 97.809% purity) as a white solid.

[1227] MS (ESI) m / z = 464.9 [M+H]+;1H 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, 5.6 Hz, 0.3H), 3.88-3.78 (m, 0.2H), 3.74-3.66 (m, 0.7H), 3.62-3.39 (m, 1.8H), 3.34-3.25 (m, 2.3H), 2.71 (s, 2H), 2.68-2.57 (m, 0.6H), 2.54 (s, 1H), 2.36-2.26 (m, 0.4H), 2.24-2.12 (m, 0.5H), 1.98-1.85 (m, 0.5H).

[1228]

[1229] Example 16

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

[1231]

[1232] Example 16 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, naphthalen-1-amine was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (222.51 mg, 477.69 μmol, 67.94% yield, 99.5% purity) as a white solid.

[1233] 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, 6.0 Hz, 0.5H), 4.68-4.64 (m, 0.4H), 3.58-3.41 (m, 2H), 3.26 (d, J = 10.4 Hz, 3H), 2.75-2.53 (m, 3H), 2.18-1.84 (m, 2H).

[1234]

[1235] Example 17

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

[1237]

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

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

[1240]

[1241] Example 18

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

[1243]

[1244] Example 18 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 3,4,5-trifluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (128.17 mg, 272.72 μmol, 61.82% yield, 99.45% purity) as a white solid.

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

[1246]

[1247] Example 19

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

[1249]

[1250] Example 19 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 2,6-difluoroaniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (138.80 mg, 306.70 μmol, 66.76% yield, 99.30% purity) as a white solid.

[1251] MS (ESI) m / z = 449.8 [M+H]+;1H 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, 5.2 Hz, 0.4H), 4.94 (dd,J= 7.6, 5.2 Hz, 0.6H), 3.85-3.77 (m, 1H), 3.65-3.60 (m, 1H), 3.55 (s, 1.3H), 3.14 (s, 1.7H), 2.92 (br dd,J= 14.0, 7.6 Hz, 0.4H), 2.52 (s, 1H), 2.48 (br s, 2H), 2.46-2.19 (m, 1.6H).

[1252]

[1253] Example 20

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

[1255]

[1256] Example 20 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 2-fluoro-3-methyl-aniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (99.8 mg, 208.37 μmol, 29.96% yield, 93% purity) as a white solid.

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

[1258]

[1259] Example 21

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

[1261]

[1262] Example 21 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 2-fluoro-5-methyl-aniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (184.73 mg, 396.89 μmol, 46.28% yield, 95.7% purity) as a white solid.

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

[1264]

[1265] Example 22

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

[1267]

[1268] Example 22 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 2-fluoro-4-methyl-aniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (138.38 mg, 304.45 μmol, 42.37% yield, 98% purity) as a white solid.

[1269] MS (ESI) m / z = 445.8 [M+H]+;1H 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 = 7.6 Hz, 2.5H), 2.60 (s, 1.4H), 2.59-2.51 (m, 1H), 2.50-2.44 (m, 1.6H), 2.43 (s, 3H), 2.32-2.15 (m, 1H).

[1270]

[1271] Example 23

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

[1273]

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

[1275] MS (ESI) m / z = 499.9 [M+H]+;1H 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, 4.4 Hz, 0.3H), 4.92-4.77 (m, 0.7H), 3.81-3.60 (m, 2H), 3.58 (s, 1H), 3.21-3.15 (m, 2H), 3.08-2.95 (m , 0.4H), 2.81 (s, 1H), 2.66-2.60 (m, 0.6H), 2.53 (s, 1H), 2.44 (s, 1H), 2.17-1.92 (m, 1H).

[1276]

[1277] Example 24

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

[1279]

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

[1281] 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).

[1282]

[1283] Example 25

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

[1285]

[1286] Example 25 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 2-chloro-4,6-difluoro-aniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (172.16 mg, 350.39 μmol, 63.32% yield, 98.475% purity) as a white solid.

[1287] MS (ESI) m / z = 483.8 [M+H]+;1H 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), 3.63-3.60 (m, 2H), 3.59-3.52 (m, 0.5H), 3.47-3.37 (m, 0.5H), 3.21-3.17 (m, 1H), 3.05-2.93 (m, 0.5H), 2.67-2.59 (m, 0.5H), 2.57 (s, 2H), 2.51 (d,J= 13.2 Hz, 1H), 2.48-2.42 (m, 1H).

[1288]

[1289] Example 26

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

[1291]

[1292] Example 26 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 4-fluoro-2-methyl-aniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (144.14 mg, 318.90 μmol, 59.81% yield, 98.547% purity) as a white solid.

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

[1294]

[1295] Example 27

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

[1297]

[1298] Example 27 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 3-fluoro-2-methyl-aniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (51.71 mg, 116.09 μmol, 20.03% yield, 100% purity) as a white solid.

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

[1300]

[1301] Example 28

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

[1303]

[1304] Example 28 was performed using a method that is the same as the one described in the synthesis of Example 2, except that in step a, 5-fluoro-2-methyl-aniline was used instead of 2,4-difluoro-3-methyl-aniline, to obtain the target compound (123.12 mg, 272.01 μmol, 55.88% yield, 98.41% purity) as a white solid.

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

[1306]

[1307] Example 29

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

[1309]

[1310] Example 29 was carried out using methods that are the same as the ones described in the synthesis of Intermediate 1 and Example 1, except that (2R)-2-amino-4-[[(3R)-3-amino-3-carboxy-propyl]disulfanyl]-butanoic acid was used instead of (2S)-2-amino-4-[[(3S)-3-amino-3-carboxy-propyl]disulfanyl]-butanoic acid and 3-chloro-4-fluoro-N-methylaniline was used instead of N,3-dimethylaniline, to obtain the target compound (7.4 mg, 15.88 μmol, 4.38% yield, 100% purity) as a white solid.

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

[1312]

[1313] Example 30

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

[1315]

[1316] Step a.To a solution of 3-methylaniline (104.22 mg, 972.62 μmol, 105.38 μL) in toluene (4 mL) was added Intermediate 2 (150 mg, 442.10 μmol) and trimethylalumane (2 M, 442.10 μL). The mixture was stirred at 100 °C for 12 hrs. LCMS showed the desired compound was detected. The residue was purified by reversed phase column (column: 40 g C18 reversed phase column ;mobile phase: [Water (0.05%TFA)-ACN];B%: 0%-66%, 40 min) to obtain (3S)-2-[2-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidine-3-carboxamide (130 mg, 219.59 μmol, 49.67% yield, 70% purity) as a white solid.

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

[1318] Step b.To a solution of (3S)-2-[2-methyl-6-(trifluoromethyl)pyrimidin-4-yl]-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidine-3-carboxamide (130 mg, 313.71 μmol) in ACN (1 mL) was added Cs2CO3(255.53 mg, 784.26 μmol) and MeI (89.05 mg, 627.41 μmol, 39.06 μL). The mixture was stirred at 80 °C for 12 hrs. LCMS showed the desired compound was detected. 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 over 9 min) to obtain (S)-N-methyl-2-(2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)-N-(m-tolyl)-isothiazolidine-3-carboxamide 1,1-dioxide (26.1 mg, 60.92 μmol, 19.42% yield, 100% purity) as a white solid.

[1319] MS (ESI) m / z = 429.0 [M+H]+;1H 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).

[1320]

[1321] Example 31

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

[1323]

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

[1325] MS (ESI) m / z = 465.0 [M+H]+;1H 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), 3.78-3.62 (m, 2H), 3.50 (s, 0.7H), 3.15 (d,J= 7.2 Hz, 2.3H), 2.62-2.57 (m, 3H), 2.35-2.28 (m, 2H), 2.26-2.21 (m, 3H).

[1326]

[1327] Example 32

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

[1329]

[1330] Example 32 was performed using a method that is the same as the one described in the synthesis of Example 30, except that in step a, 3-chloro-4-fluoroaniline was used instead of 3-methyl-aniline, to obtain the target compound (57.1 mg, 122.31 μmol, 46.15% yield, 100% purity) as a white solid.

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

[1332]

[1333]

[1334] Step a.A mixture of methyl (3S)-1,1-dioxo-1,2-thiazolidine-3-carboxylate (500 mg, 2.79 mmol), N,3-dimethylaniline (507.18 mg, 4.19 mmol, 522.87 μL), AlMe3(2 M, 4.19 mL) in toluene (2 mL) was degassed and purged 3 times with N2, and then the mixture was stirred at 100 °C for 12 hrs under an N2atmosphere. LCMS showed desired mass was observed. The reaction mixture was quenched by addition of NH4Cl (10 mL), and then diluted with water (20 mL) and extracted with EtOAc (20 mL Х 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reversed phase column (column: 80 g C18 reversed phase column; mobile phase: [Water (0.05%TFA)-ACN]; B%: 0%- 50%, 30min) to obtain (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidine-3-carboxamide (640 mg, 2.27 mmol, 81.21% yield, 95% purity) as a white solid.

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

[1336] Step b.A mixture of (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-1,2-thiazolidine-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 and purged 3 times with N2, and then the mixture was stirred at 80 °C for 3 hrs under an N2atmosphere. LCMS showed desired mass was observed. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by reversed-phase HPLC (column: Welch Xtimate C18 150*30mm*5um;mobile phase: [water(FA)-ACN];gradient:49%-89% B over 9 min) to obtain (S)-2-(2,6-bis(trifluoromethyl)pyrimidin-4-yl)-N-methyl-N-(m-tolyl)isothiazolidine-3-carboxamide 1,1-dioxide (30.09 mg, 60.06 μmol, 16.11% yield, 96.28% purity) as a white solid.

[1337] MS (ESI) m / z = 482.9 [M+H]+;1H 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, 5.2 Hz, 1H), 3.90-3.78 (m, 1H), 3.77-3.66 (m, 1H), 3.17 (s, 3H), 2.61-2.52 (m, 1H), 2.46-2.40 (m, 1H), 2.37 (s, 3H).

[1338]

[1339] Example 34

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

[1341]

[1342] Step a.To a solution of Intermediate 3 (1 g, 2.70 mmol) and N,3-dimethylaniline (654.28 mg, 5.40 mmol, 674.52 μL) in toluene (10 mL) was added AlMe3(2 M, 4.05 mL), then the mixture was stirred at 100 °C for 16 hrs under an N2atmosphere. LCMS showed desired product was observed. TLC (Plate 1, SiO2, Petroleum ether: Ethyl acetate = 10: 1) showed a new spot (Rf= 0.8) was observed. The mixture was poured into sat. NH4Cl (50 mL) and extracted with ethyl acetate (10 mL Х 3), the combined organic layer was dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel eluting with 0-55% ethyl acetate in petroleum ether to afford (3S)-2-benzyl- N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (450 mg, 1.20 mmol, 44.52% yield, 96% purity) as a yellow gum.

[1343] MS (ESI) m / z = 360.0 [M+H]+;1H 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, 2.4 Hz, 1H), 3.48-3.31 (m, 2H), 3.12 (s, 3H), 2.25 (s, 3H).

[1344] Step b.To a solution of (3S)-2-benzyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (105 mg, 303.98 μmol) in ACN (4 mL) was added MeI (129.44 mg, 911.95 μmol, 56.77 μL) and Cs2CO3(247.61 mg, 759.95 μmol). The mixture was stirred at 80 °C for 12 hrs. LCMS showed the desired compound was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by reversed phase column (column: 40 g C18 reversed phase column; mobile phase: [Water (0.05%TFA)-ACN]; B%: 0%-55%, 30min) to obtain (3S)-2-benzyl-N,5-dimethyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (268 mg, crude) as a white solid.

[1345] MS (ESI) m / z = 373.9 [M+H]+;1H 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= 11.6 Hz, 3H).

[1346] Step c.To a solution of (3S)-2-benzyl-N,5-dimethyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (230 mg, 615.85 μmol) in THF (5 mL) was added Pd / C (6.55 g, 6.16 mmol, 10% purity). The mixture was stirred at 25 °C for 12 hr under an H2atmosphere at 30 Psi. LCMS showed the desired compound was detected. The reaction mixture was filtered, the cake was washed with EtOAc (10 mL Х 3), then the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-5% Ethyl acetate / Petroleum ethergradient @30 mL / min) to obtain (3S)-N,5-dimethyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (109 mg, 357.76 μmol, 58.09% yield, 93% purity) as a white solid. MS (ESI) m / z = 283.9 [M+H]+.

[1347] Step d.To a solution of (3S)-N,5-dimethyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (40 mg, 141.17 μmol) in dioxane (2 mL) was added 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (67.77 mg, 282.34 μmol), and was then 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 hrs. LCMS showed the desired compound was detected. The reaction mixture was filtered and the filtrate was directly purified by Prep-HPLC column: Boston Prime C18 150*30mm*5um;mobile phase: [water (ammonia hydroxide v / v)-ACN];gradient:45%-75% B over 8 min to obtain (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, 55.54% yield, 100% purity) as a white solid.

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

[1349]

[1350] Example 35

[1351] (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

[1352]

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

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

[1355]

[1356] Example 36

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

[1358]

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

[1360] MS (ESI) m / z = 443.9 [M+H]+;1H 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, 4.4 Hz, 1H), 3.70 (dd,J= 11.6, 4.4 Hz, 1H), 3.55 (dd,J= 11.6, 4.4 Hz, 1H), 3.20 (s, 3H), 2.83-2.75 (m, 3H), 2.69 (s, 3H), 2.38 (s, 3H).

[1361]

[1362] Example 37

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

[1364]

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

[1366] MS (ESI) m / z = 497.9 [M+H]+;1H 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, 4.8 Hz, 1H), 3.79 (dd,J= 12.0, 4.4 Hz, 1H), 3.60-3.55 (m, 1H), 3.18 (s, 3H), 2.91 (s, 3H), 2.36 (s, 3H).

[1367]

[1368]

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

[1370] 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= 14.8 Hz, 2H), 4.09 (dd,J= 8.0, 4.4 Hz, 1H), 3.65-3.51 (m, 4H), 3.46-3.32 (m, 1H).

[1371] Step b.To a solution of methyl (3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (1.4 g, 3.64 mmol, TFA) in DMF (15 mL) was added K2CO3(2.52 g, 18.21 mmol) followed by MeI (1.03 g, 7.29 mmol, 453.55 μL), then the mixture was stirred at 4-12 °C for 16 hrs. LCMS showed desired mass was observed. TLC (Plate 1, SiO2, Petroleum ether: Ethyl acetate = 1: 1) showed a new spot (Rf= 0.5) was observed. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (10 mL Х 3), the combined organic layer was dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel eluting with 0~28% ethyl acetate in petroleum ether to afford methyl (3S)-2-benzyl-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (723 mg, 2.54 mmol, 69.81% yield, 100% purity) as a colorless oil.

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

[1373] Step c.To a solution of methyl (3S)-2-benzyl-5-methyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (723 mg, 2.54 mmol) and 3-methylaniline (544.94 mg, 5.09 mmol, 551.00 μL) in toluene (10 mL) was added AlMe3(549.90 mg, 7.63 mmol, 2 M, 3.81 mL), then the mixture was stirred at 100 °C for 16 hrs under an N2atmosphere. LCMS showed desired mass was observed. TLC (Plate 1, SiO2, Petroleum ether: Ethyl acetate = 3: 1) showed a new spot (Rf= 0.2) was observed. The mixture was poured into a 1M NaOH (70 mL) and extracted with DCM (10 mL Х 3), the combined organic layer was washed with brine (50 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel eluting with 0~30% ethyl acetate in petroleum ether to afford (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (750 mg, 1.54 mmol, 60.72% yield, 74% purity) as a brown oil.

[1374] MS (ESI) m / z = 360.0 [M+H]+;1H 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= 7.2 Hz, 1H), 4.73 (d,J= 14.4 Hz, 1H), 4.11 (d,J= 14.4 Hz, 1H), 3.94 (dd,J= 8.8, 5.2 Hz, 1H), 3.76 (dd,J= 10.0, 8.8 Hz, 1H), 3.33 (dd,J= 10.0, 10.0 Hz, 1H), 2.80 (s, 3H), 2.31 (s, 3H).

[1375] Step d.To a solution of (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (310 mg, 862.45 μmol) and Cs2CO3(843.01 mg, 2.59 mmol) in DMF (6 mL) was added trideuterio(iodo)methane (375.05 mg, 2.59 mmol, 161.04 μL) followed by TBAI (31.86 mg, 86.24 μmol), then the mixture was stirred at 80 °C for 3 hrs. LCMS showed desired mass was observed. TLC (Plate 1, SiO2, Petroleum ether: Ethyl acetate = 3: 1) showed a new spot (Rf= 0.15) was observed. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (10 mL Х 3), the combined organic layer was washed with brine (50 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel eluting with 0~35% ethyl acetate in petroleum ether to afford (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (320 mg, 832.96 μmol, 96.58% yield, 98% purity) as a yellow gum.

[1376] MS (ESI) m / z = 377.0 [M+H]+;1H 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= 7.2 Hz, 1H), 3.13 (d,J= 7.6 Hz, 2H), 2.73 (s, 3H), 2.24 (s, 3H).

[1377] Step e.To a solution of (3S)-2-benzyl-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (320 mg, 849.96 μmol) in THF (10 mL) was added Pd / C (1 g, 10% purity), then the mixture was charged three times with Ar and three times H2. The mixture was stirred at 25 °C for 16 hrs under an H2environment at 30 Psi. LCMS showed desired mass was observed. The mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate (10 mL Х 3) and the filtrate was concentrated under reduced pressure to afford (3S)-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (179 mg, 577.57 μmol, 67.95% yield, 92.4% purity) as a white gum.

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

[1379] Step f.To a solution of (3S)-5-methyl-N-(m-tolyl)-1,1-dioxo-N-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (150 mg, 523.81 μmol) and Cs2CO3(512.00 mg, 1.57 mmol) in dioxane (10 mL) was added 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (188.59 mg, 785.71 μmol) 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), then the mixture was stirred at 80 °C for 16 hrs under an N2atmosphere. LCMS showed desired mass was observed. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by reversed phase flash (0~60% MeCN in water (0.1% TFA)) and dried by lyophilization to obtain (3S)-5-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-N-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (169.54 mg, 303.02 μmol, 57.85% yield, 100% purity, TFA) as a white solid.

[1380] MS (ESI) m / z = 445.9 [M+H]+;1H 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, 5.2 Hz, 1H), 3.63-3.49 (m, 2H), 2.75 (s, 3H), 2.59 (s, 3H), 2.38 (s, 3H).

[1381]

[1382] Example 39

[1383] (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

[1384]

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

[1386] MS (ESI) m / z = 471.2 [M+H]+;1H 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= 4.8 Hz, 3H), 2.65 (d,J= 12.8 Hz, 3H), 2.45 (s, 3H), 1.15 (d,J= 6.4 Hz, 3H), 1.08 (dd,J= 6.8, 2.4 Hz, 3H).

[1387]

[1388]

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

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

[1391] Step b.To a solution of methyl (3S)-2-benzyl-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxylate (700 mg, 1.82 mmol, TFA) in DMF (5 mL) was added K2CO3(755.19 mg, 5.46 mmol) followed by trideuterio(iodo)methane (528.04 mg, 3.64 mmol, 226.72 μL), then the mixture was stirred at 10-17 °C for 16 hrs. LCMS showed desired mass was observed. TLC (Plate 1, SiO2, Petroleum ether: Ethyl acetate = 3: 1) showed a new spot (Rf = 0.1) was observed. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (10 mL Х 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 column chromatography on silica gel eluting with 0~10% ethyl acetate in petroleum ether to afford methyl (3S)-2-benzyl-1,1-dioxo-5-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxylate (306 mg, 1.06 mmol, 58.47% yield, 100% purity) as a white gum.

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

[1393] Step c.To a solution of methyl (3S)-2-benzyl-1,1-dioxo-5-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxylate (90 mg, 313.21 μmol) and N,3-dimethylaniline (75.91 mg, 626.42 μmol, 78.26 μL) in toluene (4.5 mL) was added AlMe3(2 M, 469.81 μL), then the mixture was stirred at 100 °C for 16 hrs. LCMS showed desired mass was observed. The mixture was poured into a 1M NaOH (50 mL) and extracted with ethyl acetate (10 mL Х 3), the combined organic layer was washed with brine (50 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel eluting with 0~46% ethyl acetate in petroleum ether to afford (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (80 mg, 169.99 μmol, 27.14% yield, 80% purity) as a yellow gum.

[1394] MS (ESI) m / z = 377.0 [M+H]+;1H 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= 7.2 Hz, 1H), 3.19-3.08 (m, 5H), 2.24 (s, 3H).

[1395] Step d.To a solution of (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (120 mg, 318.74 μmol) in THF (2 mL) was added Pd / C (360 mg, 10% purity), then the mixture was charged with three times Ar and three times H2. The mixture was stirred at 25 °C for 16 hrs under an H2environment at 30 Psi. LCMS showed desired mass was observed. The mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate (10 mL Х 3) and the filtrate was concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography on silica gel eluting with 0~30% ethyl acetate in petroleum ether to afford (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (30 mg, 104.76 μmol, 32.87% yield, 100% purity) as a colorless gum.

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

[1397] Step e.To a solution of (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (30 mg, 104.76 μmol) and Cs2CO3(102.40 mg, 314.28 μmol) in dioxane (1 mL) was added 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (37.72 mg, 157.14 μmol) followed by N1,N2-dimethylethane-1,2-diamine (11.64 mg, 132.00 μmol, 14.21 μL) and CuI (25.14 mg, 132.00 μmol), then the mixture was stirred at 80 °C for 16 hrs under an N2atmosphere. LCMS showed desired mass was observed. The mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate (10 mL Х 3) and the filtrate was concentrated under reduced pressure to afford the residue. The residue was purified by reversed phase flash (0~48% MeCN in water (neutral)) and dried by lyophilization to obtain (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-5-(trideuteriomethyl)-1,2,5-thiadiazolidine-3-carboxamide (26.97 mg, 60.54 μmol, 57.79% yield, 100% purity) as a purple solid.

[1398] MS (ESI) m / z = 446.3 [M+H]+;1H 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, 5.2 Hz, 1H), 3.63-3.49 (m, 2H), 2.75 (s, 3H), 2.59 (s, 3H), 2.38 (s, 3H).

[1399]

[1400] Example 41

[1401] (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

[1402]

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

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

[1405]

[1406]

[1407] Step a.To a solution of Intermediate 3 (1 g, 2.70 mmol) in toluene (10 mL) was added AlMe3(2 M, 2.02 mL), then the mixture was stirred at 100 °C for 16 hrs under an N2atmosphere. LCMS showed desired mass was observed. TLC (Plate 1, SiO2, Petroleum ether: Ethyl acetate = 3: 1) showed a new spot (Rf= 0.1) was observed. The mixture was poured into a 1M NaOH (50 mL) and extracted with ethyl acetate (10 mL Х 3), the combined organic layers were washed with brine (50 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel eluting with 0~60% ethyl acetate in petroleum ether to afford (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (300 mg, 784.55 μmol, 58.12% yield, 94% purity) as a yellow solid.

[1408] MS (ESI) m / z = 359.9 [M+H]+;1H 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, 7.2 Hz, 0.4H), 5.20 (dd,J=10.4, 7.6 Hz, 0.6H), 4.35-4.15 (m, 2H), 3.86-3.75 (m, 1H), 3.53-3.42 (m, 1H), 3.41-3.31 (m, 1H), 3.12 (s, 3H), 2.25 (s, 3H).

[1409] Step b.To a solution of (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (270 mg, 751.16 μmol) in THF (10 mL) was added NaH (60.09 mg, 1.50 mmol, 60% purity) at 0 °C, then the mixture was stirred at 0 °C for 0.5 hrs. Then SEM-Cl (250.47 mg, 1.50 mmol, 265.89 μL) was added and the mixture was stirred at 7-11 °C for 2 hrs. LCMS showed desired mass was observed. TLC (Plate 1, SiO2, Petroleum ether: Ethyl acetate = 1: 1) showed a new spot (Rf= 0.8) was observed. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (10 mL Х 3), the combined organic layers were washed with brine (50 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel eluting with 0~35% ethyl acetate in petroleum ether to afford (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, 65.92% yield, 97% purity) as a yellow gum.

[1410] MS (ESI) m / z = 512.1 [M+Na]+;1H 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= 7.2 Hz, 1H), 3.70-3.52 (m, 2H), 3.43 (dd,J= 10.4, 6.4 Hz, 1H), 3.31 (dd,J= 10.0, 8.0 Hz, 1H), 3.11 (s, 3H), 2.26 (s, 3H), 0.86 (t,J= 8.4 Hz, 2H), 0.01 (s, 9H).

[1411] Step c.To a solution of (3S)-2-benzyl-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(2-trimethylsilylethoxymethyl)-1,2,5-thiadiazolidine-3-carboxamide (250 mg, 510.52 μmol) in THF (7 mL) was added wet Pd / C (750 mg, 10% purity), then the mixture was charged with three times Ar and three times H2, the mixture was stirred at 25 °C for 16 hrs under an H2environment at 15 Psi. LCMS showed desired mass was observed. The mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate (10 mL Х 3) and the filtrate was concentrated under reduced pressure to afford (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(2-trimethylsilylethoxymethyl)-1,2,5-thiadiazolidine-3-carboxamide (199 mg, 468.14 μmol, 91.70% yield, 94% purity) as a colorless gum.

[1412] 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= 8.8 Hz, 1H), 4.50 (s, 2H), 4.25 (q,J= 8.0 Hz, 1H), 3.56 (dd,J= 8.8, 7.2 Hz, 2H), 3.44 (dd,J= 9.6, 7.2 Hz, 1H), 3.32 (s, 3H), 3.16 (dd,J= 10.0, 8.4 Hz, 1H), 2.41 (s, 3H), 0.91-0.82 (m, 2H), 0.01 (s, 9H).

[1413] Step d.To a solution of (3S)-N-methyl-N-(m-tolyl)-1,1-dioxo-5-(2-trimethylsilylethoxymethyl)-1,2,5-thiadiazolidine-3-carboxamide (180 mg, 450.47 μmol) and Cs2CO3(440.32 mg, 1.35 mmol) in dioxane (5 mL) was added 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (162.18 mg, 675.71 μmol) 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), then the mixture was stirred at 80 °C for 16 hrs under an N2atmosphere. LCMS showed desired mass was observed. The mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel eluting with 0~30% ethyl acetate in petroleum ether to (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, 48.95% yield, 97% purity) as a yellow gum.

[1414] MS (ESI) m / z = 581.1 [M+Na]+;1H 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, 5.6 Hz, 1H), 4.86-4.60 (m, 2H), 3.70-3.51 (m, 4H), 3.30 (s, 3H), 2.59 (s, 3H), 2.43 (s, 3H), 0.94-0.75 (m, 2H), -0.01 (s, 9H).

[1415] Step e.To a solution of (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-5-(2-trimethylsilylethoxymethyl)-1,2,5-thiadiazolidine-3-carboxamide (100 mg, 178.99 μmol) and TMEDA (208.00 mg, 1.79 mmol, 270.13 μL) in THF (2 mL) was added TBAF (1 M, 357.98 μL), then the mixture was stirred at 70 °C for 3 h. LCMS showed starting material remained. Then TBAF (0.4 mL) was added and the mixture was stirred for another 3 h. LCMS showed starting material remained. Then TBAF (0.4 mL) was added and the mixture was stirred for another 3 h. LCMS showed desired mass was observed. TLC (Plate 1, SiO2, Petroleum ether: Ethyl acetate = 1: 1) showed a new spot (Rf= 0.55) was observed. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (10 mL Х 3), the combined organic layer was dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel eluting with 0~45% ethyl acetate in petroleum ether to afford the crude product (57.2% purity). The mixture was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) to obtain the crude product (87.1% purity). The reaction mixture was purified by reversed phase flash (0~58% MeCN in water (0.1% TFA)) and dried by lyophilization to obtain (3S)-N-methyl-2-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-1,1-dioxo-1,2,5-thiadiazolidine-3-carboxamide (9.85 mg, 22.80 μmol, 12.74% yield, 99.156% purity, TFA) as a yellow solid.

[1416] MS (ESI) m / z = 429.2 [M+H]+;1H 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, 4.8 Hz, 1H), 3.64-3.54 (m, 1H), 3.54-3.45 (m, 1H), 3.29 (s, 3H), 2.61 (s, 3H), 2.43 (s, 3H).

[1417]

[1418] Example 43

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

[1420]

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

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

[1423]

[1424] Biological assays

[1425] Expression and purification of polθ polymerase domain

[1426] The DNA sequence of a 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, resulting in the fusion of 10XHistidine-SUMO tag at the N terminus of the polymerase domain.

[1427] The protein was expressed in E. coli. and purified using a 2-step IMAC (immobilized metal chelate affinity chromatography) procedure. Briefly stated, the overexpressed E. coli lysate was subjected to Ni-NTA purification, and an N-terminal tag was digested by a SUMO protease. Then, the excised fragment of 10XHistidine-SUMO tag was removed using Ni-NTA beads. The resulting protein was used for the Picogreen assay, as described below.

[1428]

[1429]

[1430] Polθ polymerase activity assay

[1431] 1) DNA complex preparation

[1432] The methods of DNA complex preparation used, are slightly modified versions of the methods of the protocol previously reported (Zatreanu et al., 2021, Nature Communications, 12:3636). Briefly stated, a polθ substrate was prepared by mixing Oligo1 (5'- GCG GCT GTC ATA AG - 3') and Oligo2 (5' - GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACA GCC GCG - 3') in an annealing buffer (20mM Tris-Cl, pH 7.5, 50mM NaCl) to achieve the final concentration of 22uM and 20uM, respectively. The Polθ product was prepared by mixing Oligo3 (5' - CGC GGC TGT CAT AAG ACG CAA TCT GAG ATT TGA TGC CAT TGT CAA TGT AGC - 3') and Oligo2 (5' - GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACA GCC GCG - 3') to achieve the final concentration of 20uM. The polθ product was used for the top signal control in the Picogreen assay. Both substrate and product were heated to 95℃ for 5 minutes and cooled slowly to room temperature.

[1433]

[1434] 2) Picogreen assay

[1435] To evaluate the ability of test compounds to inhibit the activity of polθ in vitro, a Picogreen assay was performed to measure polθ IC50(nM).

[1436] The reactions were performed at room temperature in an assay buffer (25mM Tris-HCl, pH 7.5, 12.5mM NaCl, 0.5mM MgCl2, 5% (v / v) glycerol, 0.01% (v / v) Triton X-100, 0.01% (w / v) Bovine serum albumin, 1mM DTT). Thirty microliters of 2Xpolymerase mixture (8 nM Pol θ enzyme in an assay buffer) were distributed to 96 well plates, test compounds were prepared by dilution in 100% DMSO to obtain the correct dose range for a 12-point concentration response and 1μl was dispensed into each well, and then 30 microliters of 2Xsubstrate mix (100nM DNA and 40uM dNTPs in an assay buffer) was added. After 90 minutes of incubation, the reaction was stopped and DNA was stained by adding 40 microliters of Picogreen solution (1:80 dilution of Picogreen, Invitrogen, Cat# P7581, 25mM Tris-HCl, pH 7.5, 10mM EDTA, pH 7.5).

[1437] The fluorescence intensity was measured at excitation / emission=485nm / 520nm using an Ensight plate reader (Perkin Elmer). The data was analyzed by GraphPad Prism software (Version 8.4.3) to calculate IC50.

[1438] The compounds of Examples 1 to 43 were tested in the above-mentioned assay, and the results are shown in the following table:

[1439]

[1440]

[1441] As the above Table demonstrates, it is demonstrated that the tested compounds exhibit good activity in inhibiting the Polθ polymerase.

[1442]

[1443] 3) Cell viability assay

[1444] DLD1-BRCA2 KO (Horizon Discovery, Cat# HD 105-007) cells and DLD1-parental cells were maintained in culture media (RPMI-1640 including 2mM L-glutamin and 25mM sodium bicarbonate, supplemented with 10% FBS), at 37°C in a humidified atmosphere with 5% CO2. Cells were seeded at the final concentration of 1,500 cells / well (DLD1-BRCA2 KO) and 600 cells / well (DLD1-parental) in a 96-well plate. Four hours later, test compounds were added (the final concentration of DMSO was 1%) to the cells. Media were replaced every 3-4 days for 14 days. To measure viability, cells were incubated in culture media supplemented with 0.1mg / ml of Resazurin (Merck, Cat# R7017) for 4 hours. The fluorescence was measured at Ex / Em=560nm / 590nm using an EnSight multimode plate reader (Perkin Elmer). Data analysis and IC50calculation were done using GraphPad Prism (Version 10.0.2).　Results: IC50values determined for select compounds of the invention are presented in the Table below.

[1445]

[1446]

[1447] While the compounds, compositions, formulations, and methods of this disclosure have been described in terms of specific embodiments, it will be apparent to those skilled in the art that variations or modifications may be applied to the compounds, compositions, formulations, and methods described herein without departing from the spirit and scope of this disclosure. All such variations or modifications apparent to those skilled in the art are deemed to be within the spirit and scope of this disclosure as defined by the appended claims.

[1448]

[1449] The present disclosure provides the following embodiments:

[1450] Embodiment 1. A compound of the following Formula (I):

[1451] (I)

[1452] wherein:

[1453] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1454] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[1455] X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein said methylene is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1456] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[1457] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1458] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1459] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[1460] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,

[1461] or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1462]

[1463] Embodiment 2. The compound according to Embodiment 1, wherein the compound is a compound represented by Formula (II):

[1464] (II)

[1465] wherein:

[1466] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1467] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[1468] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[1469] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1470] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[1471] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[1472]

[1473] Embodiment 3. The compound according to any one of preceding embodiments, wherein the compound is a compound represented by Formula (III):

[1474] (III)

[1475] wherein:

[1476] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1477] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[1478] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[1479] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1480] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[1481] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[1482]

[1483] Embodiment 4. The compound according to any one of preceding embodiments, wherein the compound is a compound represented by Formula (IV):

[1484] (IV)

[1485] wherein:

[1486] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1487] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[1488] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[1489] A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1490] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1491] Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[1492] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[1493]

[1494] Embodiment 5. The compound according to any one of preceding embodiments, wherein the compound is a compound represented by Formula (IIa):

[1495] (Iia)

[1496] wherein:

[1497] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1498] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[1499] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[1500] each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1501] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[1502] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[1503]

[1504] Embodiment 6. The compound according to any one of preceding embodiments, wherein the compound is a compound represented by Formula (Iib):

[1505] (Iib)

[1506] wherein:

[1507] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1508] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[1509] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[1510] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1511] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[1512] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[1513]

[1514] Embodiment 7. The compound according to any one of preceding embodiments, wherein the compound is a compound represented by Formula (Iic):

[1515] (Iic)

[1516] wherein:

[1517] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1518] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[1519] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[1520] each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1521] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[1522] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[1523]

[1524] Embodiment 8. The compound according to any one of preceding embodiments, wherein the compound is a compound represented by Formula (Iid):

[1525] (Iid)

[1526] wherein:

[1527] each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1528] R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;

[1529] each of Y and Z is independently selected from the group consisting of -N- and -CRw-;

[1530] each of Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;

[1531] each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; and

[1532] Rwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.

[1533]

[1534] Embodiment 9. The compound according to any one of preceding embodiments, wherein R3is hydrogen.

[1535]

[1536] Embodiment 10. The compound according to any one of preceding embodiments, wherein R4is hydrogen or C1-C4alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and deuterium.

[1537]

[1538] Embodiment 11. The compound according to any one of preceding embodiments, wherein Y is selected from the group consisting of CH and C(CN); and Z is selected from the group consisting of N and CH.

[1539]

[1540] Embodiment 12. The compound according to any one of preceding embodiments, wherein each of R1and R2is independently C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.

[1541]

[1542]

[1543]

[1544]

[1545]

[1546] Embodiment 14. A pharmaceutical composition for treating or preventing diseases or disorders mediated by polymerase theta, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreas cancer, or lung cancer, comprising the compound according to any one of preceding embodiments, or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof; and a pharmaceutically acceptable carrier(s) or excipient(s).

[1547]

[1548] Embodiment 15. The pharmaceutical composition according to claim 14, wherein the composition is administered separately, sequentially or simultaneously with DNA damage response (DDR) targeting anti-cancer agent, preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (e.g., nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (e.g., MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[1549]

[1550] Embodiment 16. 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 for use in the prevention or treatment of diseases or disorders mediated by polymerase theta, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreas cancer, or lung cancer.

[1551]

[1552] Embodiment 17. The compound according to embodiment 16, wherein the compound is administered separately, sequentially or simultaneously with DNA damage response (DDR) targeting anti-cancer agent, preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[1553]

[1554] Embodiment 18. A method of treating or preventing diseases or disorders mediated by polymerase theta in a subject, comprising administering to the subject at least one 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.

[1555]

[1556] Embodiment 19. The method of embodiment 18, wherein the diseases or disorders mediated by polymerase theta are cancer, preferably breast cancer, ovarian cancer, prostate cancer, pancreas cancer, or lung cancer.

[1557]

[1558] Embodiment 20. The method of any one of embodiments 18 to 19, further comprising administering to the subject additional DDR targeting anti-cancer agent, preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

Claims

1.A compound of the following Formula (I):(I)wherein:each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;X is selected from the group consisting of methylene, -NH-, and -NRz-, wherein said methylene is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;each of Y and Z is independently selected from the group consisting of -N- and -CRw-;A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; andRwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl,or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.2.The compound according to claim 1, wherein the compound is a compound represented by Formula (II):(II)wherein:each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;each of Y and Z is independently selected from the group consisting of -N- and -CRw-;A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; andRwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.3.The compound according to claim 1, wherein the compound is a compound represented by Formula (III):(III)wherein:each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;each of Y and Z is independently selected from the group consisting of -N- and -CRw-;A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; andRwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.4.The compound according to claim 1, wherein the compound is a compound represented by Formula (IV):(IV)wherein:each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;each of Y and Z is independently selected from the group consisting of -N- and -CRw-;A is 5-12 membered monocyclic or bicyclic aryl or heteroaryl, wherein each of said aryl and heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, amino, mercapto, and carbamoyl, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;Rzis C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; andRwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.5.The compound according to any one of claims 1-2, wherein the compound is a compound represented by Formula (IIa):(IIa)wherein:each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;each of Y and Z is independently selected from the group consisting of -N- and -CRw-;each of Ra1, Ra2, Ra3, Ra4and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; andRwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.6.The compound according to any one of claims 1-2, wherein the compound is a compound represented by Formula (IIb):(IIb)wherein:each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;each of Y and Z is independently selected from the group consisting of -N- and -CRw-;each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; andRwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.7.The compound according to any one of claims 1-2, wherein the compound is a compound represented by Formula (IIc):(IIc)wherein:each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;each of Y and Z is independently selected from the group consisting of -N- and -CRw-;each of Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, and Rc7is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; andRwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.8.The compound according to any one of claims 1-2, wherein the compound is a compound represented by Formula (IId):(IId)wherein:each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, halogen, 3-10 membered cycloalkyl, cyano, and -NRxRy, wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;R4is hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, and mercapto;each of Y and Z is independently selected from the group consisting of -N- and -CRw-;each of Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, hydroxy, C1-C6alkoxy, 3-10 membered cycloalkyl, and -NRxRy(wherein each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl), wherein each of said alkyl, alkenyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl;each of Rxand Ryis independently selected from hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl; andRwis selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, deuterium, C2-C6alkenyl, C1-C6alkoxy, 3-10 membered cycloalkyl, -NRxRy, hydroxy, amino, mercapto, and carbamoyl.9.The compound according to any one of preceding claims, wherein R3is hydrogen.10.The compound according to any one of preceding claims, wherein R4is hydrogen or C1-C4alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and deuterium.11.The compound according to any one of preceding claims, wherein Y is selected from the group consisting of CH and C(CN); and Z is selected from the group consisting of N and CH.12.The compound according to any one of preceding claims, wherein each of R1and R2is independently C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, deuterium, hydroxy, amino, mercapto, and carbamoyl.13.The compound according to any one of preceding claims, wherein the compound is selected from the group consisting of:14.A pharmaceutical composition for preventing or treating diseases or disorders mediated by polymerase theta, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreas cancer, or lung cancer, comprising the 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(s) or excipient(s).15.The pharmaceutical composition according to claim 14, wherein the composition is administered separately, sequentially or simultaneously with DNA damage response (DDR) targeting anti-cancer agent, preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).16.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 for use in the prevention or treatment of diseases or disorders mediated by polymerase theta, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreas cancer, or lung cancer.17.The compound according to claim 16, wherein the compound is administered separately, sequentially or simultaneously with DNA damage response (DDR) targeting anti-cancer agent, preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).18.A method of treating or preventing diseases or disorders mediated by polymerase theta 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, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof.19.The method of claim 18, wherein the diseases or disorders mediated by polymerase theta are cancer, preferably breast cancer, ovarian cancer, prostate cancer, pancreas cancer, or lung cancer.20.The method of any one of claims 18 to 19, further comprising administering to the subject additional DDR targeting anti-cancer agent, preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

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