Substituted ARYL or heteroaryl compound derivatives and pharmaceutical use thereof

Abstract

Provided herein are novel aryl or heteroaryl compound derivatives, compositions containing the compounds, and preparation methods and uses thereof. The aryl or heteroaryl derivatives are compounds represented by Formula (I), Formula (II) and Formula (III) or tautomers, stereoisomers, prodrugs, crystal forms, isotopically labeled forms, 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 PARG, in particular, cancer. Formula (I); Formula (II); Formula (III).

Description

1 Description Title of Invention: SUBSTITUTED ARYL OR HETEROARYL COMPOUND DERIVATIVES AND PHARMACEUTICAL USE THEREOF Technical Field

[0001] The present disclosure belongs to a technical field of medicine, and particularly relates to aryl or heteroaryl compound derivates with inhibitory effects on PARG, pharmaceutical compositions comprising the same, and preparation methods and uses thereof. Background Art

[0002] DNA repair is essential for the regulation of cell growth and survival. Thus, DNA repair pathways have been targeted for manipulation by medical therapeutics. Single- strand breaks (SSBs) are the most common type of lesion that occurs in cells. Poly(ADP- ribose) glycohydrolase (PARG) and poly(ADP-ribose) polymerase (PARP) play roles in repairing DNA damage caused by SSBs.

[0003] At the early stage of single-strand DNA repair, PARP detects single-strand breaks and begins to synthesize poly ADP-ribose (PAR) itself. Such poly ADP-ribosylation (PARylation) serves as a signal to recruit DNA repair proteins, such as XRCC1(X-ray repair cross-complementing protein 1), and the DNA repair proteins subsequently proceed to repair the SSBs. Then, PARG reverses the action of PARP enzymes by hydrolysing ribose-ribose bonds present in PAR, which is a process referred to as depoly(ADP- ribosyl)ation (dePARylation). When PARP is bound to PAR, its catalytic activity is reduced and therefore PARG activity helps to restore PARP to its catalytically active form (Curtin, N. J., & Szabo, C., 2013, Molecular aspects of medicine, 34(6), 1217-1256). Therefore, a sequential event of PARylation and dePARylation should be well-regulated since imbalance between PARylation and dePARylation can lead to DNA damage.

[0004] Cancer is a result of uncontrolled and unregulated cellular proliferation. A rapid proliferation can cause a high level of oxidative stress within tumor cells, which leads to DNA damage and increased rate of mutation. The mutation can cause deficiencies in2 DNA repair mechanisms, and accordingly, cancer cells with the deficiencies tend to heavily rely on specific DNA repair mechanisms. To date, several therapeutic agents have been developed to target cancer cells that rely on specific DNA repair mechanisms. For example, it has been shown that tumor cells carrying a mutation in BRCA1 and BRCA2 genes often harbor defects in DNA double brand break (DSB) repair and such BRCA1 / BRCA2 deficient tumor cells are more sensitive to PARP inhibitors. In addition, there is some evidence suggesting that defects in DSB repair can also sensitize tumor cells to PARG inhibition, and PARG inhibitors can specifically kill BRCA2-deficient tumors (Fathers, Catherine, et al., 2012, Cell cycle, 11.5: 990-997).

[0005] Furthermore, experimental data has demonstrated the therapeutic efficacy of PARG inhibitors in the treatment of cancer. For example, in vivo tests showed that PARG inhibitors have efficacy against various types of cancers, including breast cancer and cervical cancer (Blenn, C., W`yrsch, P., & Althaus, F. R., 2011, Molecules, 16(2), 1854- 1877). Another PARG inhibitor, adenosine diphosphate (hydroxymethy1)pyrrolidinediol (ADP-HPD), which is an analog of ADP-ribose, showed good selectivity in inhibiting PARG at a low concentration (Slama, J. T., Aboul-Ela, N., & Jacobson, M. K. (1995)., Journal of medicinal chemistry, 38(21), 4332-4336). Nevertheless, existing PARG inhibitors have drawbacks of limited PARG inhibition capabilities or being difficult to obtain, etc.

[0006] Therefore, there is still need to develop novel PARG inhibitors with improved efficacy that can be used for treating cancer. Summary of Invention

[0007] The present disclosure provides novel aryl or heteroaryl compound derivatives, compositions comprising the same, and preparation methods and uses thereof. The aryl or heteroaryl compound derivatives have an inhibitory activity for PARG, and can be effectively used for treating various types of cancers.

[0008]

[0009] Class I

[0010] In one aspect, the present disclosure relates to a compound of the following Formula (I):3 I)

[0013] is a single bond or double bond;

[0014] each of W1, W2and W3is independently selected from carbon and nitrogen, provided that only one of W1, W2and W3is nitrogen;

[0015] X is selected from the following: );

[0018] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0019] Rx2is selected from the group consisting of hydrogen and C1-C6 alkyl;

[0020] Rx3is selected from the group consisting of hydrogen and halogen;

[0021] R1is selected from the group consisting of hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6alkyl), and -C(O)NR11R12, wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, - O(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), a 3-8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally4 substituted with one or more selected from C1-C6alkyl, -O(C1-C6alkyl), oxo, amino, and halogen;

[0022] each of said R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, and 3-8 membered cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0023] R2is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6 alkyl), -OC(=O)-(C1-C6 alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, , wherein each of said alkyl, alkoxy,tionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0024] R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2;

[0025] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0026] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0027] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0028] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and

[0029] each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen,5

[0030] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0031]

[0032] Class II

[0033] In another aspect, the present disclosure relates to a compound of the following Formula (II): I);

[0038] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0039] R1is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6 alkyl), and -C(O)NR11R12, wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, - O(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), a 3-8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally6 substituted with one or more selected from C1-C6alkyl, -O(C1-C6alkyl), oxo, amino, and halogen;

[0040] each of said R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, and 3-8 membered cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0041] R2is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6 alkyl), -OC(=O)-(C1-C6 alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, , wherein each of said alkyl, alkoxy,tionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0042] R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2;

[0043] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0044] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0045] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0046] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and

[0047] each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen,7

[0048] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0049]

[0050] Class III

[0051] In one embodiment, the present disclosure provides a compound of Formula (III): );

[0056] Rx1is selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6alkyl and halogen;

[0057] R2is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6 alkyl), -OC(=O)-(C1-C6 alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, xy,, ore selected from C1-C6alkyl and halogen;8

[0058] R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2;

[0059] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0060] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0061] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0062] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and

[0063] each of R3, R4, R5and R6is independently selected from the group consisting of hydrogen and halogen,

[0064] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0065]

[0066] In another aspect, the present disclosure comprises a compound of Formula (III) which is selected from the group consisting of the following compounds:13 [00, , , , rm, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0069]

[0070] In another aspect, the present disclosure provides a pharmaceutical composition for treating or preventing diseases or disorders, such as diseases or disorders mediated by PARG, which comprises one or more of the compounds disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, 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.

[0071] In another aspect, the present disclosure provides the use of the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, 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 PARG.14

[0072] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by PARG, in a subject, comprising administering to the subject at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.

[0073] In another aspect, the present disclosure provides the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, 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 PARG.

[0074] Other objects and advantages of the present disclosure will be apparent to those skilled in the art from the following descriptions of specific embodiments and examples, and from the following claims. Brief Description of Drawings

[0075] Fig.1 shows the CETSA (Cellular Thermal Shift Assay) results of the compounds according to the present disclosure, indicating their binding stability to PARG enzymes. Description of Embodiments

[0076] Chemical terms

[0077] The definitions of specific functional groups and chemical terms are described in detail below.

[0078] When a range of values is listed, it is intended to encompass each value and any sub- range within the range. For example, “C1-C6alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0079] As used herein (unless otherwise specified), the term “C1-C6alkyl” refers to a saturated hydrocarbon group which is straight-chained or branched, and has 1 to 6 carbon atoms. The term "lower alkyl" also refers to this group. In some embodiments, the alkyl group may have 1 to 4 carbon atoms (C1-4 alkyl) or 3 to 6 carbon atoms (C3-6 alkyl). Examples15 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.

[0080] As used herein (unless otherwise specified), the term “C2-C6alkenyl” 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.

[0081] As used herein (unless otherwise specified), the term “C2-C6 alkynyl” 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-C6alkynyl group include, but are not limited to, ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, etc.

[0082] As used herein (unless otherwise specified), the term “C1-C6 alkoxy” refers to a -OR group, wherein R is substituted or unsubstituted C1--C6alkyl. In some embodiments, the alkoxy group may have 1 to 4 carbon atoms. Specifically, C1-6 alkoxyl 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.

[0083] As used herein (unless otherwise specified), the term “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.

[0084] As used herein (unless otherwise specified), the terms “C3-C14cycloalkyl” or “3- to 14- membered cycloalkyl” or “3- to 14-membered carbocyclic” refers to a saturated or16 unsaturated cyclic hydrocarbon group which is aromatic or non-aromatic and has 3-14 ring carbon atoms and zero heteroatoms. In some embodiments, the cycloalkyl group may have 3 to 14, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 10, 4 to 8, 4 to 7, 4 to 6, 5 to 10, 5 to 8, 5 to 7, or 5 to 6 ring carbon atoms. The cycloalkyl also includes a ring system in which the above mentioned 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, phenyl, naphtyl, anthracyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, cyclononyl, cyclononenyl, cyclodecyl, cyclodecenyl, octahydro-1H-indenyl, decahydronaphthyl, spiro[3.5]nonenyl, spiro[4.5]decyl, and the like.

[0085] As used herein (unless otherwise specified), the term “3-14 membered heterocyclic group”, or the term “heterocyclyl” refers to a radical of a 3- to 14-membered ring system which is aromatic or non-aromatic and has ring carbon atoms and at least one ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur and phosphorus. The point of attachment of the heterocyclic group is on carbon or heteroatom. Unless stated otherwise specifically in the specification, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and includes a fused, spiro, or bridged ring system. In some embodiments, the heterocyclyl group may have 2 to 7, 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, and 1 to 4 heteroatoms. In one embodiment, the heterocyclic group may be an 8- to 14-(e.g., 9) membered bicyclic spiro heterocyclic group. In another embodiment, the heterocyclic group may be an 8- to 14-membered bicyclic fused heterocyclic group. In another embodiment, the heterocyclic group may be an 8-14 membered bicyclic bridged heterocyclic group.

[0086] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl,17 tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, oxazolidin-2-one, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, thiadiazolinyl, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heterocyclyl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl and pyridinyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridinonyl, dithianyl, dioxanyl, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazinanyl, triazinyl (e.g., 1,2,4-triazinyl, 1,3,5-triazinyl). Exemplary 6-membered heterocyclyl groups containing four heteroatoms include, without limitation, tetrazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, thiepanyl, azepinyl, oxepinyl, and thiepinyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups with substituted with oxo include, without limitation, pyridinonyl. Exemplary 5,6-bicyclic heterocyclyl 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 heterocyclyl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.18

[0087] In one embodiment, the heterocyclic group includes a saturated or unsatuated ring radical that comprises carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus. In an embodiment, the heterocyclic group may have a 3-14 membered heterocyclic group. In an embodiment, the heterocyclic group may have an 8-14 (e.g., 9) membered bicyclic spiro heterocyclic group. In some embodiments, the heterocyclic group may have 2 to 10, , 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 4 to 10, 4 to 9, 4 to 8, 5 to 9, 5 to 8, or 5 to 6 ring carbon atoms, and 1 to 4 heteroatoms. Examples of such heterocyclic group include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Examples of spiro heterocyclic group includes 2-oxa-7-azaspiro[3.5]nonan-7-yl and 2- oxa-8-azaspiro[4.5]decan-8-yl.

[0088] As used herein (unless otherwise specified), the term “8-14 membered polycylic heterocyclic group” refers to a monovalent heterocyclic group, which is polycyclic (where there are two or more rings) (e.g, bicyclic) ring system having 7-11 ring atoms, including carbon and one or more heteroatom (e.g., nitrogen, oxygen and sulfur). A polycyclic ring system may be a fused ring ring system, a bridged ring system and a spiro ring system. Which system depends on the bridgehead carbon, which is defined as a carbon atom which is shared by at least two rings. A fused ring ring system is a system in which the two or more rings share a covalent bond and have two bridgehead carbons. A bridged ring system is a system in which there is a carbon that is part of two or more rings and the two or more rings are connected by a bridge containing two bridegehead carbons and there are one or more carbons between the two bridegehead carbons. A spiro ring system is a system in which the two or more rings are joined with a single bridgehead carbon. Examples of the polycyclic heterocyclic group include19 .-membered aryl” 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 membered 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.

[0091] As used herein (unless otherwise specified), the term “5- to 14-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 heteroatom (e.g., nitrogen, oxygen, and sulfur). The point of attachment of the heroaryl is on carbon or heteroatom. 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 10, 3 to 8, 3 to 7, 4 to 7, 5 to 12, 5 to 10, 5 to 7, or 5 to 6 ring carbon atoms or heteroatoms.

[0092] 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 groups20 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.

[0093] As used herein (unless otherwise specified), the term “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”.

[0094] 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.

[0095] 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%.

[0096] As used herein (unless otherwise specified), the term “C1-C6alkylene” 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 (C1-4 alkylene) or 1 to 2 carbon atoms (C1-2 alkylene). 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.21

[0097] As used herein (unless otherwise specified), the term “C2-C6alkenylene” refers to a divalent alkenyl linking group, which is a linear or branched, saturated hydrocarbon group having 2 to 6 carbon atoms. An alkenylene group formally corresponds to an alkene with two C-H bonds replaced by points of attachment of the alkenylene group to the remainder of the compound. In some embodiments, the alkenylene group may have 1 to 4 carbon atoms (C1-C4alkenylene) or 1 to 2 carbon atoms (C1-C2alkenylene).

[0098] As used herein (unless otherwise specified), the term “C2-C6 alkynylene” refers to a divalent alkynyl linking group, which is a linear or branched, saturated hydrocarbon group having 2 to 6 carbon atoms. An alkynylene group formally corresponds to an alkyne with two C-H bonds replaced by points of attachment of the alkynylene group to the remainder of the compound. In some embodiments, the alkynylene group may have 1 to 4 carbon atoms (C1-C4 alkynylene) or 1 to 2 carbon atoms (C1-C2 alkynylene).

[0099] 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 C1-6 alkyl group.

[0100] Regarding the description of bonds in a chemical formula of the present disclosure, a wavy line( )is used to indicate that the stereochemistry at the designated position isnot specified, and may beeither the R- or S-configuration, or a mixture thereof.

[0101] 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.

[0102] 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, it is contemplated that the term “substituted” includes all permissible substituents of organic compounds.22 Exemplary substituents on carbon atoms include, but are not limited to, C1-C6alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), 3-10 membered (e.g., 3-8 membered, 5-6 membered, 3-5 membered) cycloalkyl, hydroxy, amino, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), carbamoyl, oxo, a 3-8 membered heterocyclic or heteroaryl group, -CORz1(wherein Rz1is selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl, and halogen), and -CON(Rz2)(Rz3) (wherein each of Rz2and Rz3is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 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-C6 alkyl 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-C6 alkyl and halogen. The number of substituents may be any number as long as valence of the substituted 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.

[0103]

[0104] General terms

[0105] 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.

[0106] 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 the English language) should be considered to encompass the concept of plural.

[0107] Unless particularly stated otherwise, any term used in the present description should be considered as having the conventional meaning for the relevant technical field.23 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.

[0108] Compounds

[0109] According to an aspect of the present disclosure, provided are a compound of Formula (I) (including subsets of each formula), a compound of Formula (II) (including subsets of each formula) and a compound of Formula (III) (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0110] As used herein, “compound of the present disclosure” refers to the following compounds represented by Formula (I) (including subsets of each formula), Formula (II) (including subsets of each formula) and Formula (III) (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0111]

[0112] Class I

[0113] In one embodiment, the present disclosure comprises a compound of Formula (I): I)[ ] w eren,

[0116] is a single bond or double bond;24

[0117] each of W1, W2and W3is independently selected from carbon and nitrogen, provided that only one of W1, W2and W3is nitrogen;

[0118] X is selected from the following:

[0119] );

[0120]

[0121] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0122] Rx2is selected from the group consisting of hydrogen and C1-C6 alkyl;

[0123] Rx3is selected from the group consisting of hydrogen and halogen;

[0124] R1is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6 alkyl), and -C(O)NR11R12, wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, - O(C1-C6alkyl), -C(O)O(C1-C6alkyl), a 3-8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, -O(C1-C6 alkyl), oxo, amino, and halogen;

[0125] each of said R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and 3-8 membered cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0126] R2is 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6 alkyl), -OC(=O)-(C1-C6 alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group,25 nd h r in h f id lk l lkoxy, oreseecte rom 1- 6 a y an aogen;

[0127] R#is selected from the group consisting of hydroxy, C1-C6 alkoxy and -NR#1R#2;

[0128] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0129] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0130] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0131] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and

[0132] each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen,

[0133] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0134]

[0135] Class II

[0136] In one embodiment, the present disclosure relates to a compound of Formula (II):26 );

[0141] Rx1is selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6alkyl and halogen;

[0142] R1is selected from the group consisting of hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6alkyl), and -C(O)NR11R12, wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, - O(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), a 3-8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, -O(C1-C6 alkyl), oxo, amino, and halogen;

[0143] each of said R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and 3-8 membered cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0144] R2is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen,27 cyano, hydroxy, C1-C6alkoxy, -(C1-C6alkylene)-OH, -(C1-C6alkylene)-O-(C1-C6alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6 alkyl), -OC(=O)-(C1-C6 alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, , wherein each of said alkyl, alkoxy, tionally substituted with one or moreselected from C1-C6alkyl and halogen;

[0145] R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2;

[0146] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0147] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0148] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0149] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and

[0150] each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen,

[0151] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0152]

[0153] Class III

[0154] In one embodiment, the present disclosure relates to a compound of Formula (III):28 I);

[0159] Rx1is selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6alkyl and halogen;

[0160] R2is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6alkoxy, -(C1-C6alkylene)-OH, -(C1-C6alkylene)-O-(C1-C6alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6alkyl), -OC(=O)-(C1-C6alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, , wherein each of said alkyl, alkoxy,tionally substituted with one or more selected from C1-C6alkyl and halogen;

[0161] R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2;

[0162] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0163] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;29

[0164] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0165] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and

[0166] each of R3, R4, R5and R6is independently selected from the group consisting of hydrogen and halogen,

[0167] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0168]

[0169] X in Formulae (I) to (III)

[0170] In one embodiment, X in Formula (I) is selected from the following: );

[0173] Y is absent or oxygen;

[0174] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0175] preferably, Rx1is selected from the group consisting of C1-C6 alkyl, halogen and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl and halogen;

[0176] more preferably, Rx1is selected from the group consisting of C1-C3 alkyl, halogen and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and halogen;30

[0177] still more preferably, Rx1is selected from the group consisting of C1-C2alkyl, halogen and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C2 alkyl and halogen;

[0178] still more preferably, Rx1is selected from the group consisting of methyl, halogen and cyano, wherein each of said methyl is independently optionally substituted with one or more selected from methyl and halogen;

[0179] Rx2is selected from the group consisting of hydrogen and C1-C6alkyl; preferably, Rx2is selected from the group consisting of hydrogen and C1-C3 alkyl; more preferably, Rx2is selected from the group consisting of hydrogen and C1-C2 alkyl; still more preferably, Rx2is selected from the group consisting of hydrogen and methyl;

[0180] Rx3is selected from the group consisting of hydrogen and halogen; and

[0181] W1-W3and R1-R6are as defined herein.

[0182]

[0183] In one embodiment, X in Formula (I) is selected from the following: );

[0186] Y is absent or oxygen;

[0187] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine;

[0188] preferably, Rx1is selected from the group consisting of C1-C6 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine;

[0189] more preferably, Rx1is selected from the group consisting of C1-C3 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and fluorine;31

[0190] still more preferably, Rx1is selected from the group consisting of C1-C2alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C2 alkyl and fluorine;

[0191] still more preferably, Rx1is selected from the group consisting of methyl, fluorine and cyano, wherein each of said methyl is independently optionally substituted with one or more selected from methyl and fluorine;

[0192] Rx2is selected from the group consisting of hydrogen and C1-C6alkyl; preferably, Rx2is selected from the group consisting of hydrogen and C1-C3 alkyl; more preferably, Rx2is selected from the group consisting of hydrogen and C1-C2 alkyl; still more preferably, Rx2is selected from the group consisting of hydrogen and methyl;

[0193] Rx3is selected from the group consisting of hydrogen and fluorine; and

[0194] W1-W3and R1-R6are as defined herein.

[0195]

[0196] In one embodiment, X in Formula (I) is selected from the group consisting of

[0197] and,

[0198] W-W an - are as e ne eren.

[0199]

[0200] In one embodiment, X in Formula (II) and Formula (III) i A),

[0201] wherein:

[0202] Y is absent or oxygen;32

[0203] Rx1is selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0204] preferably, Rx1is selected from the group consisting of C1-C6alkyl, halogen and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0205] more preferably, Rx1is selected from the group consisting of C1-C3alkyl, halogen and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and halogen;

[0206] still more preferably, Rx1is selected from the group consisting of C1-C2alkyl, halogen and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C2alkyl and halogen;

[0207] still more preferably, Rx1is selected from the group consisting of methyl, halogen and cyano, wherein each of said methyl is independently optionally substituted with one or more selected from methyl and halogen; and

[0208] R1-R6are as defined herein.

[0209]

[0210] In one embodiment, X in Formula (II) and Formula (III) i (X-A),

[0211] wherein:

[0212] Y is absent or oxygen;

[0213] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine;

[0214] preferably, Rx1is selected from the group consisting of C1-C6alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine;33

[0215] more preferably, Rx1is selected from the group consisting of C1-C3alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and fluorine;

[0216] still more preferably, Rx1is selected from the group consisting of C1-C2alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C2 alkyl and fluorine;

[0217] still more preferably, Rx1is selected from the group consisting of methyl, fluorine and cyano, wherein each of said methyl is independently optionally substituted with one or more selected from methyl and fluorine; and

[0218] R1-R6are as defined herein.

[0219]

[0220] In one embodiment, X in Formula (II) and Formula (III) is selected from the group consisting of and,.

[0223]

[0224] R1in Formulae (I) and (II)

[0225] In one embodiment, R1is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6 alkyl), and -C(O)NR11R12, wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, -O(C1-C6alkyl), -C(O)O(C1-C6alkyl), a 3-8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic34 group is independently optionally substituted with one or more selected from C1-C6alkyl, -O(C1-C6 alkyl), oxo, amino, and halogen;

[0226] each of said R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, and 3-8 membered cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen; and

[0227] preferably, R1is selected from the group consisting of hydrogen, deuterium, C1-C6alkyl, C2-C6 alkynyl, 3-14 membered carbocyclic or heterocyclic group, cyano, halogen and -O(C1-C6 alkyl), wherein each of said alkyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, -O(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), a 3- 8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, -O(C1-C6 alkyl), oxo, amino, and halogen;

[0228] more preferably, R1is selected from the group consisting of hydrogen, deuterium, C1- C3 alkyl, C2-C3 alkynyl, a 3-10 membered carbocyclic or heterocyclic group, cyano, halogen and -O(C1-C3alkyl), wherein each of said alkyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, -O(C1-C3alkyl), -C(O)O(C1- C3 alkyl), a 3-8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C3 alkyl, -O(C1-C3 alkyl), oxo, amino, and halogen;

[0229] still more preferably, R1is selected from the group consisting of hydrogen, deuterium, C1-C2alkyl, C2-C3alkynyl, a 3-10 membered carbocyclic or heterocyclic group, cyano, halogen and -O(C1-C2 alkyl), wherein each of said alkyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C2 alkyl, 3-6 membered cycloalkyl, halogen, amino, oxo, -O(C1-C2 alkyl), -C(O)O(C1- C2 alkyl), a 3-6 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C2 alkyl, -O(C1-C2 alkyl), oxo, amino, and halogen;35

[0230] still more preferably, R1is selected from the group consisting of hydrogen, deuterium, C1-C2 alkyl, C2-C3 alkynyl, a 3-10 membered carbocyclic or heterocyclic group, cyano, halogen and -O(C1-C2 alkyl), wherein each of said alkyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C2 alkyl, 3-6 membered cycloalkyl, halogen, -O(C1-C2 alkyl) and a 3-6 membered heterocyclic group, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C2 alkyl, -O(C1-C2 alkyl) and halogen; and

[0231] X, W1-W3and R2-R6are as defined herein.

[0232]

[0233] In one embodiment, R1is selected from the group consisting of hydrogen, deuterium, C1-C6alkyl, C2-C6alkynyl, a 3-14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, fluorine, -O(C1-C6alkyl) and a 3-8 membered heterocyclic group, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6alkyl, -O(C1-C6alkyl) and fluorine;

[0234] preferably, R1is selected from the following:

[0235] (R1-A) or (R1-B);

[0237] Ry1is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, a 3-14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, fluorine and -O(C1-C6 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0238] preferably, Ry1is selected from the group consisting of hydrogen, deuterium, C1-C3 alkyl, a 3-10 membered carbocyclic or heterocyclic group, cyano, chlorine, fluorine and - O(C1-C3alkyl), wherein each of said alkyl, carbocyclic and heterocyclic groups is36 independently optionally substituted with one or more selected from C1-C3alkyl, fluorine and -O(C1-C3 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0239] more preferably, Ry1is selected from the group consisting of hydrogen, deuterium, C1- C2 alkyl, a 3-10 membered carbocyclic or heterocyclic group, cyano, chlorine, fluorine and -O(C1-C2 alkyl), wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3 alkyl, fluorine and -O(C1-C2 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0240] still more preferably, Ry1is selected from the group consisting of hydrogen, deuterium, C1-C2 alkyl, a 3-10 membered carbocyclic or heterocyclic group, cyano, chlorine, fluorine and -O(C1-C2 alkyl), wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3 alkyl, fluorine, and -O(C1-C2 alkyl);

[0241] still more preferably, Ry1is selected from the group consisting of hydrogen, deuterium, methyl, a 3-6 membered carbocyclic group, a 3-9 memebered heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from methyl, fluorine, and -OCH3;

[0242] Ry2is selected from the group consisting of 3-8 membered cycloalkyl and a 3-8 membered heterocyclic group, wherein each of said cycloalkyl and heterocyclic group is independently optionally substituted with one or more selected from C1-C6alkyl, -O(C1-C6alkyl) and fluorine;

[0243] preferably, Ry2is selected from the group consisting of 3-6 membered cycloalkyl and - a 3-8 membered heterocyclic group, wherein each of said cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C3 alkyl, -O(C1-C3alkyl) and fluorine;

[0244] more preferably, Ry2is selected from the group consisting of 3-6 membered cycloalkyl and a 3-6 membered heterocyclic group, wherein each of said cycloalkyl, and heterocyclic37 group is independently optionally substituted with one or more selected from C1-C2alkyl, -O(C1-C2 alkyl) and fluorine; and

[0245] still more preferably, Ry2is selected from the group consisting of 3-6 membered cycloalkyl, and a 3-6 membered heterocyclic group, wherein each of said cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C2 alkyl, -O(C1-C2 alkyl), and fluorine;

[0246] still more preferably, Ry2is selected from the group consisting of cyclopropyl, cyclobutyl and pyridynyl, wherein each of said cyclopropyl, cyclobutyl and pyridynyl is independently optionally substituted with one or more selected from -OCH3 and fluorine; and

[0247] X, W1-W3and R2-R6are as defined herein.

[0248]

[0249] In one embodiment, R1is selected from the group consisting of nd, .

[0252]

[0253] R2in Formulae (I) to (III)

[0254] In one embodiment, R2is 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C638 alkylene)-O-(C1-C6alkyl), mercapto, -S(C1-C6alkyl), -SO2(C1-C6alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -OC(=O)-(C1-C6 alkyl), oxo, 3-8 membered carbocyclic or heterocyclic group, , , , and , wherein each of said alkyl, alkoxy, alkylene, carbocyclic and heterocyclic groups is optionally substituted with one or more selected from C1-C6 alkyl and halogen;

[0255] R#is selected from the group consisting of hydroxy, C1-C6 alkoxy and -NR#1R#2;

[0256] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6alkyl, or

[0257] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0258] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6alkyl and 3-8 membered cycloalkyl;

[0259] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl;

[0260] preferably, R2is 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, cyano, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, hydroxy, C1-C6alkoxy, -OC(=O)-(C1-C6alkyl), oxo, 3-8 membered carbocyclic or heterocyclic group, , , , and , wherein each of said alkyl, alkylene, carbocyclic and heterocyclic groups is optionally substituted with one or more group selected form C1-C6 alkyl and halogen;

[0261] R#is selected from the group consisting of hydroxy, C1-C6 alkoxy and -NR#1R#2;

[0262] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or39

[0263] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0264] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0265] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl;

[0266] more preferably, R2is 6-10 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C3alkyl, cyano, -(C1-C3 alkylene)-OH, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -SO2(C1-C3 alkyl), -NH2, hydroxy, C1-C3alkoxy, -OC(=O)-(C1-C3alkyl), oxo, 3-5 membered carbocyclic or heterocyclic group, , , , wherein each of said alkyl, alkylene, carbocyclic and heterocyclic groups is optionally substituted with one or more group selected form C1-C3alkyl and fluorine;

[0267] R#is selected from the group consisting of hydroxy, C1-C3alkoxy and -NR#1R#2;

[0268] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl, or

[0269] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0270] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, C1-C3 alkyl and 3-4 membered cycloalkyl;

[0271] still more preferably, R2is 6-10 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from methyl, cyano, --CH2OH, -CH2-O-CH3, -SO2(C1-C3 alkyl), -NH2, hydroxy, C1-C3 alkoxy,40 -OC(=O)-(C1-C3 alkyl), oxo, 3-5 membered carbocyclic or heterocyclic group, ,and , wherein each of said alkyl, alkylene, carbocyclic and ally substituted with one or more group selected form methyland fluorine;

[0272] R#is selected from the group consisting of hydroxy, C1-C3alkoxy and -NR#1R#2;

[0273] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl, or

[0274] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic ring;

[0275] each of R21and R22is independently selected from the group consisting of hydrogen, and methyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium and cyclopropyl; and

[0276] X, W1-W3, R1and R3-R6are as defined herein.

[0277]

[0278] In one embodiment, R2is selected from the following: );

[0281] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6alkyl and -(C1-C3alkylene)-O-(C1-C3alkyl), or Rz11and Rz12, taken together with the carbon atom to which they are attached, form a 3-8 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from C1-C6 alkyl and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;41

[0282] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl), or Rz11and Rz12, taken together with the carbon atom to which they are attached, form a 3-5 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from C1-C3 alkyl and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3alkyl;

[0283] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3, or Rz11and Rz12, taken together with the carbon atom to which they are attached, form a 3-4 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from methyl and -SO2(C1-C3alkyl);

[0284] Z is selected from -NRz14- and -CR'R''-;

[0285] Rz14is selected from hydrogen, C1-C6 alkyl, -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl), C6 alkyl), wherein said alkyl is

[0286] R21is selected from the group consisting of C1-C6alkyl, 3-8 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl and 3-8 membered cycloalkyl;

[0287] R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C6 alkyl;

[0288] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl;

[0289] Rz13is selected from the group consisting of hydrogen, C1-C6 alkyl, -(C1-C3 alkylene)- O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH and cyano, or

[0290] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form 5- to 8-membered42 heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0291] R#is selected from the group consisting of hydroxy, C1-C6 alkoxy and -NR#1R#2; and

[0292] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6alkyl, or

[0293] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0294] preferably, Rz14is selected from hydrogen, C1-C3 alkyl and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substitu-C3 alkyl;

[0295] R21is selected from the group consisting of C1-C3 alkyl, 3-5 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and 3-5 membered cycloalkyl;

[0296] R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C3 alkyl;

[0297] Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1-C2 alkylene)- O-(C1-C2 alkyl), -(C1-C2 alkylene)-OH, and cyano, or

[0298] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5- to 6- membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0299] R#is selected from the group consisting of hydroxy, C1-C3alkoxy and -NR#1R#2; and

[0300] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl, or

[0301] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;43

[0302] more preferably, Rz14is selected from hydrogen, , and - SO2(C1-C2alkyl), wherein said alkyl is optionally substituted with one or more methyl;

[0303] R21is selected from the group consisting of methyl and -ORc, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl;

[0304] R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more selected from deuterium and methyl;

[0305] Rz13is selected from the group consisting of hydrogen, methyl, -CH2-O-CH3, -CH2- OH, and cyano, or

[0306] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0307] R#is selected from the group consisting of hydroxy, C1-C3alkoxy and -NR#1R#2; and

[0308] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl, or

[0309] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic ring;

[0310] R' and R'', taken together with the carbon atom to which they are attached, form 3- to 8-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -OC(=O)-(C1-C6 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more halogen;

[0311] preferably, R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from C1-C3 alkyl, hydroxy, C1-C3 alkoxy, - OC(=O)-(C1-C3 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more fluorine;44

[0312] more preferably, R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from methyl, hydroxy, C1-C3 alkoxy, -OC(=O)-(C1-C3 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more fluorine;

[0313] Rz21is selected from the group consisting of -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0314] preferably, Rz21is selected from the group consisting of -C(=O)-N(C1-C3 alkyl)(C1-C3 alkyl) and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0315] more preferably, Rz21is selected from the group consisting of -C(=O)-N(CH3)2and - SO2(C1-C2 alkyl), wherein said alkyl is optionally substituted with one or more methyl; and

[0316] X, W1-W3, R1and R3-R6are as defined herein.

[0317]

[0318] In one embodiment, R2is selected from the following: -A-[ ] w eren:

[0321] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6 alkyl and -(C1-C3 alkylene)-O-(C1-C3 alkyl);45

[0322] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl);

[0323] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3;

[0324] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3alkylene)- O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and cyano;

[0325] R#is selected from the group consisting of hydroxy, C1-C6 alkoxy and -NR#1R#2; and

[0326] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6alkyl, or

[0327] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0328] preferably, Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1- C2 alkylene)-O-(C1-C2 alkyl), -(C1-C2 alkylene)-OH, and cyano;

[0329] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy and -NR#1R#2; and

[0330] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl, or

[0331] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0332] more preferably, Rz13is selected from the group consisting of hydrogen, methyl, -CH2- d cyano; [03s seece rom e group consisting of hydroxy, C1-C3alkoxy and -NR#1R#2; and

[0334] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl, or

[0335] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic ring;46

[0336] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)(C1-C6alkyl), d SO C C6alkyl), wherein said alkyl is

[0337] R21is selected from the group consisting of C1-C6 alkyl and 3-8 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and 3-8 membered cycloalkyl;

[0338] R22is selected from the group consisting of hydrogen and C1-C6 alkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium and C1-C6 alkyl;

[0339] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl;

[0340] preferably, Rz14is selected from hydrogen, , and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0341] R21is selected from the group consisting of C1-C3 alkyl and 3-5 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and 3-5 membered cycloalkyl;

[0342] R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C3alkyl;

[0343] more preferably, Rz14is selected from hydrogen d - SO2(C1-C2alkyl), wherein said alkyl is optionally subst

[0344] R21is methyl, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl;

[0345] R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more selected from deuterium and methyl;47

[0346] Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C6alkyl)- and -N(- SO2(C1-C6 alkyl))-, wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0347] preferably, Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C3alkyl)- and -N(-SO2(C1-C3 alkyl))-, wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0348] more preferably, Rz15is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(C1-C2 alkyl))-, wherein said alkyl is optionally substituted with one or more methyl;

[0349] each of Rz16and Rz17is independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -OC(=O)-(C1-C6 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more halogen;

[0350] preferably, each of Rz16and Rz17is independently selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, -OC(=O)-(C1-C3 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more fluorine;

[0351] more preferably, each of Rz16and Rz17is independently selected from the group consisting of hydrogen, methyl, hydroxy, C1-C3 alkoxy, -OC(=O)-(C1-C3 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more fluorine;

[0352] Rz18is absent or -CH(C1-C6alkyl)-; preferably, Rz18is absent or -CH(C1-C3alkyl)-; more preferably, Rz18is absent or -CH(CH3)-;

[0353] Rz21is selected from the group consisting of -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0354] preferably, Rz21is selected from the group consisting of -C(=O)-N(C1-C3 alkyl)(C1-C3 alkyl) and -SO2(C1-C3alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0355] more preferably, Rz21is selected from the group consisting of -C(=O)-N(CH3)2 and - SO2(C1-C2alkyl), wherein said alkyl is optionally substituted with one or more methyl; and

[0356] X, W1-W3, R1and R3-R6are as defined herein.48

[0357]

[0358] In one embodiment, R2is selected from the group consisting of49

[0360] X, W1-W3, R1and R3-R6are as defined herein.50

[0361]

[0362] R3, R4, R5and R6

[0363] In one embodiment, each of R3, R4, R5and R6in Formula (I), Formula (II) and / or Formula (III) is independently selected from the group consisting of hydrogen and halogen; preferably, each of R3, R4, R5and R6is independently selected from the group consisting of hydrogen and fluorine; and

[0364] X, W1-W3and R1-R2are as defined herein.

[0365]

[0366] In one embodiment, the present disclosure relates to a compound of Formula (Ia-1), (Ia-2), (Ia-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), (Ic-2) or (Ic-3): -2) -2)51 -2)

[0374] X is selected from the following:

[0375] );

[0376] yg

[0377] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6alkyl and halogen;

[0378] Rx2is selected from the group consisting of hydrogen and C1-C6 alkyl;

[0379] Rx3is selected from the group consisting of hydrogen and halogen;52

[0380] R1is selected from the group consisting of hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6 alkyl), and -C(O)NR11R12, wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, - O(C1-C6alkyl), -C(O)O(C1-C6alkyl), a 3-8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6alkyl, -O(C1-C6alkyl), oxo, amino, and halogen;

[0381] each of said R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, and 3-8 membered cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl and halogen;

[0382] R2is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6alkoxy, -(C1-C6alkylene)-OH, -(C1-C6alkylene)-O-(C1-C6alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6alkyl), -OC(=O)-(C1-C6alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, ,wherein each of said alkyl, alkoxy,ptionally substituted with one or more selected from C1-C6alkyl and halogen;

[0383] R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2;

[0384] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0385] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0386] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and53 cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0387] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and

[0388] each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen,

[0389] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0390]

[0391] In one embodiment, the present disclosure relates to a compound of Formula (II-1), (II-2) or (II-3): -2)

[0395] Y is absent or oxygen;

[0396] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;54

[0397] R1is selected from the group consisting of hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6 alkyl), and -C(O)NR11R12, wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, - O(C1-C6alkyl), -C(O)O(C1-C6alkyl), a 3-8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6alkyl, -O(C1-C6alkyl), oxo, amino, and halogen;

[0398] each of said R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, and 3-8 membered cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl and halogen;

[0399] R2is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6alkoxy, -(C1-C6alkylene)-OH, -(C1-C6alkylene)-O-(C1-C6alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6alkyl), -OC(=O)-(C1-C6alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, ,wherein each of said alkyl, alkoxy,ptionally substituted with one or more selected from C1-C6alkyl and halogen;

[0400] R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2;

[0401] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0402] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0403] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and55 cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0404] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and

[0405] each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen,

[0406] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0407]

[0408] In one embodiment, the present disclosure relates to a compound of Formula (III-1), (III-2) or (III-3): -2)

[0412] Y is absent or oxygen;

[0413] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen;56

[0414] R2is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6 alkyl), -OC(=O)-(C1-C6 alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, ,wherein each of said alkyl, alkoxy,ptionally substituted with one or moreselected from C1-C6 alkyl and halogen;

[0415] R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2;

[0416] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0417] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0418] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0419] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and

[0420] each of R3, R4, R5and R6is independently selected from the group consisting of hydrogen and halogen,

[0421] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0422]

[0423] Non-limiting exemplary embodiments

[0424] 57

[0425] In one embodiment, the present disclosure relates to a compound of Formula (Ia-1), (Ia-2) or (Ia-3): -2)

[0429] X is selected from the following: );

[0432] Y is absent or oxygen;

[0433] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine;

[0434] preferably, Rx1is selected from the group consisting of C1-C6 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine;

[0435] more preferably, Rx1is selected from the group consisting of C1-C3 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and fluorine;58

[0436] still more preferably, Rx1is selected from the group consisting of C1-C2alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C2 alkyl and fluorine;

[0437] still more preferably, Rx1is selected from the group consisting of methyl and cyano, wherein each of said methyl is independently optionally substituted with one or more selected from methyl and fluorine;

[0438] Rx2is selected from the group consisting of hydrogen and C1-C6alkyl; preferably, Rx2is selected from the group consisting of hydrogen and C1-C3 alkyl; more preferably, Rx2is selected from the group consisting of hydrogen and C1-C2 alkyl; still more preferably, Rx2is selected from the group consisting of hydrogen and methyl;

[0439] Rx3is selected from the group consisting of hydrogen and fluorine;

[0440] preferably, X is selected from the group consisting of ;, , C6alkyl, C2-C6alkynyl, 3-14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, fluorine, amino, -O(C1-C6alkyl) and a 3-8 membered heterocyclic group, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, -O(C1-C6 alkyl) and fluorine;

[0443] preferably, R1is selected from the following: B);

[0005] w eren:59

[0446] Ry1is selected from the group consisting of hydrogen, deuterium, C1-C6alkyl, 3-14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, fluorine and -O(C1-C6 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0447] preferably, Ry1is selected from the group consisting of hydrogen, deuterium, C1-C3 alkyl, 3-10 membered carbocyclic or heterocyclic group, cyano, chlorine, fluorine and - O(C1-C3 alkyl), wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3alkyl, fluorine and -O(C1-C3 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0448] more preferably, Ry1is selected from the group consisting of hydrogen, deuterium, C1- C2 alkyl, 3-10 membered carbocyclic or heterocyclic group, cyano, chlorine, fluorine and - O(C1-C2 alkyl), wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3 alkyl, fluorine and -O(C1-C2alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0449] still more preferably, Ry1is selected from the group consisting of hydrogen, deuterium, C1-C2alkyl, a 3-10 membered carbocyclic or heterocyclic group, cyano, chlorine, fluorine and -O(C1-C2 alkyl), wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3alkyl, fluorine, and -O(C1-C2 alkyl);

[0450] still more preferably, Ry1is selected from the group consisting of hydrogen, deuterium, methyl, 3-6 membered carbocyclic group, a 3-9 memebered heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from methyl, fluorine, and -OCH3;

[0451] Ry2is selected from the group consisting of 3-8 membered cycloalkyl and a 3-8 membered heterocyclic group, wherein each of said cycloalkyl and heterocyclic group is60 independently optionally substituted with one or more selected from C1-C6alkyl, -O(C1-C6alkyl) and fluorine;

[0452] preferably, Ry2is selected from the group consisting of 3-6 membered cycloalkyl and - a 3-8 membered heterocyclic group, wherein each of said cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C3 alkyl, -O(C1-C3 alkyl) and fluorine;

[0453] more preferably, Ry2is selected from the group consisting of 3-6 membered cycloalkyl and a 3-6 membered heterocyclic group, wherein each of said cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C2 alkyl, -O(C1-C2 alkyl) and fluorine; and

[0454] still more preferably, Ry2is selected from the group consisting of 3-6 membered cycloalkyl, and a 3-6 membered heterocyclic group, wherein each of said cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C2 alkyl, -O(C1-C2 alkyl), and fluorine;

[0455] still more preferably, Ry2is selected from the group consisting of cyclopropyl, cyclobutyl and pyridynyl, wherein each of said cyclopropyl, cyclobutyl and pyridynyl is independently optionally substituted with one or more selected from -OCH3 and fluorine;

[0456] still more preferably, R1is selected from the group consisting of ;

[0058] R s 3- membered eterocyc c group, w eren sad eterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen,61 cyano, hydroxy, C1-C6alkoxy, -(C1-C6alkylene)-OH, -(C1-C6alkylene)-O-(C1-C6alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6 alkyl), -OC(=O)-(C1-C6 alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, d, wherein each of said alkyl, alkoxy,ptionally substituted with one or moreselected from C1-C6alkyl and halogen;

[0459] R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2;

[0460] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0461] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0462] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0463] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl;

[0464] preferably, R2is selected from the following: );w ee :

[0467] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6 alkyl and -(C1-C3 alkylene)-O-(C1-C3 alkyl), or Rz11and Rz12are taken together with the carbon atom to which they are attached form 3-8 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted62 with one or more group selected from C1-C6alkyl and -SO2(C1-C6alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0468] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3alkyl and -(C1-C2alkylene)-O-(C1-C2alkyl), or Rz11and Rz12, taken together with the carbon atom to which they are attached, form a 3-5 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from C1-C3 alkyl and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0469] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3, or Rz11and Rz12, taken together with the carbon atom to which they are attached, form a 3-4 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from methyl and -SO2(C1-C3 alkyl);

[0470] Z is selected from -NRz14- and -CR'R''-;

[0471] Rz14is selected from hydrogen, C1-C6 alkyl, -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl), C6alkyl), wherein said alkyl is

[0472] R21is selected from the group consisting of C1-C6 alkyl, 3-8 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and 3-8 membered cycloalkyl;

[0473] R22is selected from the group consisting of hydrogen and C1-C6 alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C6alkyl;

[0474] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl;

[0475] Rz13is selected from the group consisting of hydrogen, C1-C6 alkyl, -(C1-C3 alkylene)- O-(C1-C3alkyl), -(C1-C3alkylene)-OH, and cyano, or63

[0476] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5- to 8- membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0477] R#is selected from the group consisting of hydroxy, C1-C6 alkoxy and -NR#1R#2; and

[0478] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6alkyl, or

[0479] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0480] preferably, Rz14is selected from hydrogen, C1-C3 alkyl and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substitu-C3 alkyl;

[0481] R21is selected from the group consisting of C1-C3 alkyl, 3-5 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C3alkyl and 3-5 membered cycloalkyl;

[0482] R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C3 alkyl;

[0483] Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1-C2 alkylene)- O-(C1-C2 alkyl), -(C1-C2 alkylene)-OH, and cyano, or

[0484] when R21is selected from -ORc, Rand Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom which Rcis attached, form 5- to 6-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0485] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy and -NR#1R#2; and

[0486] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl, or64

[0487] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0488] more preferably, Rz14is selected from hydrogen, , and - SO2(C1-C2 alkyl), wherein said alkyl is optionally subs methyl;

[0489] R21is selected from the group consisting of methyl and -ORc, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl;

[0490] R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more selected from deuterium and methyl;

[0491] Rz13is selected from the group consisting of hydrogen, methyl, -CH2-O-CH3, -CH2- OH, and cyano, or

[0492] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0493] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy and -NR#1R#2; and

[0494] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl, or

[0495] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 4-5 membered heterocyclic ring;

[0496] R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 8-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from C1-C6alkyl, hydroxy, C1-C6alkoxy, -OC(=O)-(C1- C6 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more halogen;

[0497] preferably, R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from C1-C3 alkyl, hydroxy, C1-C3 alkoxy, -65 OC(=O)-(C1-C3alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more fluorine;

[0498] more preferably, R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from methyl, hydroxy, C1-C3 alkoxy, -OC(=O)-(C1-C3 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more fluorine;

[0499] Rz21is selected from the group consisting of -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0500] preferably, Rz21is selected from the group consisting of -C(=O)-N(C1-C3 alkyl)(C1-C3 alkyl) and -SO2(C1-C3alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0501] more preferably, Rz21is selected from the group consisting of -C(=O)-N(CH3)2 and - SO2(C1-C2 alkyl), wherein said alkyl is optionally substituted with one or more methyl;

[0502] more preferably, R2is selected from the following: -A-[ ] w eren:

[0505] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6 alkyl and -(C1-C3 alkylene)-O-(C1-C3 alkyl);66

[0506] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl);

[0507] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3;

[0508] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3alkylene)- O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and cyano;

[0509] R#is selected from the group consisting of hydroxy, C1-C6 alkoxy and -NR#1R#2; and

[0510] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6alkyl, or

[0511] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0512] preferably, Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1- C2 alkylene)-O-(C1-C2 alkyl), -(C1-C2 alkylene)-OH, and cyano;

[0513] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy and -NR#1R#2; and

[0514] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl, or

[0515] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring;

[0516] more preferably, Rz13is selected from the group consisting of hydrogen, methyl, -CH2- d cyano; [05s seece rom e group consisting of hydroxy, C1-C3alkoxy and -NR#1R#2; and

[0518] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl, or

[0519] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclic ring;67

[0520] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)(C1-C6alkyl), d d SO C C lk l h i id lk l is

[0521] R21is selected from the group consisting of C1-C6 alkyl and 3-8 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and 3-8 membered cycloalkyl;

[0522] R22is selected from the group consisting of hydrogen and C1-C6 alkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium and C1-C6 alkyl;

[0523] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl;

[0524] preferably, Rz14 is selected from hydrogen , and -SO2(C1-C3alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0525] R21is selected from the group consisting of C1-C3 alkyl and 3-5 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and 3-5 membered cycloalkyl;

[0526] R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C3alkyl;

[0527] more preferably, Rz14is selected from hydrogen, , and - SO2(C1-C2alkyl), wherein said alkyl is optionally substituted with one or more methyl;

[0528] R21is methyl, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl;

[0529] R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more selected from deuterium and methyl;68

[0530] Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C6alkyl)- and -N(- SO2(C1-C6 alkyl))-, wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0531] preferably, Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C3alkyl)- and -N(-SO2(C1-C3 alkyl))-, wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0532] more preferably, Rz15is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(C1-C2 alkyl))-, wherein said alkyl is optionally substituted with one or more methyl;

[0533] each of Rz16and Rz17is independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -OC(=O)-(C1-C6 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more halogen;

[0534] preferably, each of Rz16and Rz17is independently selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, -OC(=O)-(C1-C3 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more fluorine;

[0535] more preferably, each of Rz16and Rz17is independently selected from the group consisting of hydrogen, methyl, hydroxy, C1-C3 alkoxy, -OC(=O)-(C1-C3 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more fluorine;

[0536] Rz18is absent or -CH(C1-C6alkyl)-; preferably, Rz18is absent or -CH(C1-C3alkyl)-; more preferably, Rz18is absent or -CH(CH3)-;

[0537] Rz21is selected from the group consisting of -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0538] preferably, Rz21is selected from the group consisting of -C(=O)-N(C1-C3 alkyl)(C1-C3 alkyl) and -SO2(C1-C3alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0539] more preferably, Rz21is selected from the group consisting of -C(=O)-N(CH3)2 and - SO2(C1-C2alkyl), wherein said alkyl is optionally substituted with one or more methyl;

[0540] still more preferably, R2is selected from the group consisting of70

[0542] each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen; preferably, each of R3, R4and R5is independently selected from the group consisting of hydrogen and fluorine,

[0543] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0544]

[0545] In one embodiment, the present disclosure relates to a compound of Formula (Ib-1), (Ib-2) or (Ib-3): -2)

[0549] X is selected from the following: );[ ] s a sen or oxygen;

[0553] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6alkyl and fluorine;71

[0554] preferably, Rx1is selected from the group consisting of C1-C6alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine;

[0555] more preferably, Rx1is selected from the group consisting of C1-C3alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and fluorine;

[0556] still more preferably, Rx1is selected from the group consisting of C1-C2alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C2 alkyl and fluorine;

[0557] still more preferably, Rx1is selected from the group consisting of methyl, fluorine and cyano, wherein each of said methyl is independently optionally substituted with one or more selected from methyl and fluorine;

[0558] Rx2is selected from the group consisting of hydrogen and C1-C6alkyl; preferably, Rx2is selected from the group consisting of hydrogen and C1-C3 alkyl; more preferably, Rx2is selected from the group consisting of hydrogen and C1-C2 alkyl; still more preferably, Rx2is selected from the group consisting of hydrogen and methyl;

[0559] Rx3is selected from the group consisting of hydrogen and fluorine;

[0560] preferably, X is selected from the group consisting of ;g p g y g , , -C6alkyl, C2-C6alkynyl, 3-14 membered carbocyclic or heterocyclic group, cyano and chlorine, wherein each of said alkyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, fluorine, -O(C1-C6alkyl) and a 3-8 membered heterocyclic group, wherein each of said alkyl,72 cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, -O(C1-C6 alkyl) and fluorine;

[0563] preferably, R1is selected from the following:

[0564] (R1-A) or (R1-B);

[0566] Ry1is selected from the group consisting of hydrogen, deuterium, C1-C6alkyl, 3-14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, fluorine and -O(C1-C6 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0567] preferably, Ry1is selected from the group consisting of hydrogen, C1-C3alkyl, 3-10 membered carbocyclic or heterocyclic group, cyano and chlorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3 alkyl, fluorine and -O(C1-C3 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0568] more preferably, Ry1is selected from the group consisting of hydrogen, C1-C2alkyl, 3-10 membered carbocyclic or heterocyclic group, cyano and chlorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3 alkyl, fluorine and -O(C1-C2 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0569] still more preferably, Ry1is selected from the group consisting of hydrogen, C1-C2alkyl, 3-10 membered carbocyclic or heterocyclic group, cyano and chlorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3 alkyl, fluorine, and -O(C1-C2 alkyl);

[0570] still more preferably, Ry1is selected from the group consisting of hydrogen, methyl, a 3-6 membered carbocyclic group, a 3-9 membered heterocyclic group, cyano and chlorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from methyl, fluorine, and -OCH3;73

[0571] still more preferably, Ry1is selected from the group consisting of hydrogen, methyl, a 3-5 membered carbocyclic group, a 3-6 membered heterocyclic group, cyano and chlorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from fluorine, and -OCH3;

[0572] Ry2is selected from the group consisting of 3-8 membered cycloalkyl and a 3-8 membered heterocyclic group, wherein each of said cycloalkyl and heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, -O(C1-C6 alkyl) and fluorine;

[0573] preferably, Ry2is selected from the group consisting of 3-6 membered cycloalkyl and - a 3-8 membered heterocyclic group, wherein each of said cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C3 alkyl, -O(C1-C3 alkyl) and fluorine;

[0574] more preferably, Ry2is selected from the group consisting of 3-6 membered cycloalkyl and a 3-6 membered heterocyclic group, wherein each of said cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C2alkyl, -O(C1-C2 alkyl) and fluorine; and

[0575] still more preferably, Ry2is selected from the group consisting of 3-6 membered cycloalkyl, and a 3-6 membered heterocyclic group, wherein each of said cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C2alkyl, -O(C1-C2alkyl), and fluorine;

[0576] still more preferably, Ry2is selected from the group consisting of cyclopropyl, cyclobutyl and pyridynyl, wherein each of said cyclopropyl, cyclobutyl and pyridynyl is independently optionally substituted with one or more selected from -OCH3and fluorine;

[0577] still more preferably, Ry2is cyclopropyl;

[0578] still more preferably, R1is selected from the group consisting of74 ;group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6alkyl), -OC(=O)-(C1-C6alkyl), oxo, 3-8 membered carbocyclic or heterocyclic group, xy,ore selected from C1-C6 alkyl and halogen;

[0581] R#is selected from the group consisting of hydroxy, C1-C6 alkoxy and -NR#1R#2;

[0582] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0583] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0584] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6alkyl and 3-8 membered cycloalkyl;

[0585] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl;

[0586] preferably, R2is 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6alkyl, cyano,75 -(C1-C6alkylene)-OH, -(C1-C6alkylene)-O-(C1-C6alkyl), -SO2(C1-C6alkyl), -NH2, - COOH, oxo, 3-8 membered carbocyclic or heterocyclic group, -C(=O)-N(C1-C6 alkyl)(C1- C6 alkyl), , and , wherein each of said alkyl, alkylene, carbocyclic and heterocyclic groups is optionally substituted with one or more C1-C6alkyl;

[0587] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0588] more preferably, R2is selected from the following: );

[0591] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6alkyl and -(C1-C3alkylene)-O-(C1-C3alkyl), or Rz11and Rz12are taken together with the carbon atom to which they are attached form 3-8 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from C1-C6 alkyl and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6alkyl;

[0592] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl), or Rz11and Rz12are taken together with the carbon atom to which they are attached form 3-5 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from C1-C3 alkyl and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0593] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3, or Rz11and Rz12, taken together with the76 carbon atom to which they are attached, form a 3-4 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from methyl and -SO2(C1-C3 alkyl);

[0594] still more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3, or Rz11and Rz12, taken together with the carbon atom to which they are attached, form a 3-4 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more methyl;

[0595] Z is selected from -NRz14- and -CR'R''-;

[0596] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)(C1-C6alkyl), C6alkyl), wherein said alkyl is optionally

[0597] R21is selected from the group consisting of C1-C6 alkyl, 3-8 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and 3-8 membered cycloalkyl;

[0598] R22is selected from the group consisting of hydrogen and C1-C6 alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C6alkyl;

[0599] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3alkylene)- O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, -COOH and cyano, or

[0600] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5- to 8- membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0601] preferably, Rz14is selected from hydrogen, C1-C3 alkyl and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substitu1-C3 alkyl;77

[0602] R21is selected from the group consisting of C1-C3alkyl, 3-5 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and 3-5 membered cycloalkyl;

[0603] R22is selected from the group consisting of hydrogen and C1-C3alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C3 alkyl;

[0604] Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1-C2 alkylene)- O-(C1-C2alkyl), -(C1-C2alkylene)-OH, -COOH and cyano, or

[0605] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5- to 6- membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0606] more preferably, Rz14is selected from hydrogen d - SO2(C1-C2 alkyl), wherein said alkyl is optionally subst

[0607] R21is selected from the group consisting of methyl and -ORc, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl;

[0608] R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more selected from deuterium and methyl;

[0609] Rz13is selected from the group consisting of hydrogen, methyl, -CH2-O-CH3, -CH2- OH and cyano, or

[0610] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0611] still more preferably, Rz14is selected from hydrogen, , and - SO2(C1-C2alkyl), wherein said alkyl is optionally substituted with one or more methyl;78

[0612] R21is selected from the group consisting of methyl and -ORc, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl;

[0613] R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more methyl;

[0614] Rz13is selected from the group consisting of hydrogen, methyl, -CH2-O-CH3, -CH2- OH, and cyano, or

[0615] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0616] R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 8-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from C1-C6alkyl and amino;

[0617] preferably, R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from C1-C3alkyl and amino;

[0618] more preferably, R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from methyl and amino;

[0619] Rz21is selected from the group consisting of -C(=O)-N(C1-C6alkyl)(C1-C6alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0620] preferably, Rz21is selected from the group consisting of -C(=O)-N(C1-C3alkyl)(C1-C3alkyl) and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3alkyl;

[0621] more preferably, Rz21is selected from the group consisting of -C(=O)-N(CH3)2and - SO2(C1-C2 alkyl), wherein said alkyl is optionally substituted with one or more methyl;

[0622] still more preferably, R2is selected from the following:79 -A-

[0625] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6 alkyl and -(C1-C3 alkylene)-O-(C1-C3 alkyl);

[0626] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl);

[0627] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3;

[0628] Rz13is selected from the group consisting of hydrogen, C1-C6 alkyl, -(C1-C3 alkylene)- O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH and cyano;

[0629] preferably, Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1- C2alkylene)-O-(C1-C2alkyl), -(C1-C2alkylene)-OH and cyano;

[0630] more preferably, Rz13is selected from the group consisting of hydrogen, methyl, -CH2- O-CH3, -CH2-OH and cyano;

[0631] Rz14is selected from hydrogen, C1-C6 alkyl, -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl), C6 alkyl), wherein said alkyl is optionally80

[0632] R21is selected from the group consisting of C1-C6alkyl and 3-8 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and 3-8 membered cycloalkyl;

[0633] R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium and C1-C6 alkyl;

[0634] preferably, Rz14is selected from hydrogen, , and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3alkyl;

[0635] R21is selected from the group consisting of C1-C3alkyl, 3-5 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C3alkyl and 3-5 membered cycloalkyl;

[0636] R22is selected from the group consisting of hydrogen and C1-C3alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C3 alkyl;

[0637] more preferably, Rz14is selected from hydrogen and - SO2(C1-C2 alkyl), wherein said alkyl is optionally substmethyl;

[0638] R21is methyl, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl;

[0639] R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more selected from deuterium and methyl;

[0640] still more preferably, Rz14is selected from hydrogen and - SO2(C1-C2alkyl), wherein said alkyl is optionally substitethyl;

[0641] R21is methyl, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl;

[0642] R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more methyl;81

[0643] Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C6alkyl)- and -N(- SO2(C1-C6 alkyl))-, wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0644] preferably, Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C3alkyl)- and -N(-SO2(C1-C3 alkyl))-, wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0645] more preferably, Rz15is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(C1-C2 alkyl))-, wherein said alkyl is optionally substituted with one or more methyl;

[0646] still more preferably, Rz15is selected from the group consisting of -O-, -NH- and - N(CH3)-;

[0647] each of Rz16and Rz17is independently selected from the group consisting of hydrogen, C1-C6alkyl and amino;

[0648] preferably, each of Rz16and Rz17is independently selected from the group consisting of hydrogen, C1-C3 alkyl and amino;

[0649] more preferably, each of Rz16and Rz17is independently selected from the group consisting of hydrogen, methyl and amino;

[0650] Rz18is absent or -CH(C1-C6alkyl)-; preferably, Rz18is absent or -CH(CH3)-;

[0651] Rz21is selected from the group consisting of -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0652] preferably, Rz21is selected from the group consisting of -C(=O)-N(C1-C3 alkyl)(C1-C3 alkyl) and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3alkyl;

[0653] more preferably, Rz21is selected from the group consisting of -C(=O)-N(CH3)2 and - SO2(C1-C2 alkyl), wherein said alkyl is optionally substituted with one or more methyl;

[0654] still more preferably, R2is selected from the group consisting of82 ;, ng of hydrogen and halogen; preferably, each of R3, R4and R5is independently selected from the group consisting of hydrogen and fluorine,

[0657] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0658]

[0659] In one embodiment, the present disclosure relates to a compound of Formula (Ic-1), (Ic-2) or (Ic-3):83 -2)

[0663] X is selected from the following: );

[0666] Y is absent or oxygen;

[0667] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine;

[0668] preferably, Rx1is selected from the group consisting of C1-C6alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine;

[0669] more preferably, Rx1is selected from the group consisting of C1-C3 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and fluorine;84

[0670] still more preferably, Rx1is selected from the group consisting of C1-C2alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C2 alkyl and fluorine;

[0671] still more preferably, Rx1is selected from the group consisting of methyl, fluorine and cyano, wherein each of said methyl is independently optionally substituted with one or more selected from methyl and fluorine;

[0672] Rx2is selected from the group consisting of hydrogen and C1-C6alkyl; preferably, Rx2is selected from the group consisting of hydrogen and C1-C3 alkyl; more preferably, Rx2is selected from the group consisting of hydrogen and C1-C2 alkyl; still more preferably, Rx2is selected from the group consisting of hydrogen and methyl;

[0673] Rx3is selected from the group consisting of hydrogen and fluorine;

[0674] preferably, X is selected from the group consisting of ;, , C6alkyl, C2-C6alkynyl, 3-14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, fluorine, amino, -O(C1-C6alkyl) and a 3-8 membered heterocyclic group, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, -O(C1-C6 alkyl) and fluorine;

[0677] preferably1(R1-A);

[0678] wherein:

[0679] Ry1is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, 3-14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each85 of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, fluorine and -O(C1-C6 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0680] preferably, Ry1is selected from the group consisting of hydrogen, deuterium, C1-C3alkyl, 3-10 membered carbocyclic or heterocyclic group, cyano, chlorine, fluorine and - O(C1-C3 alkyl), wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3 alkyl, fluorine and -O(C1-C3 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0681] more preferably, Ry1is selected from the group consisting of hydrogen, C1-C2 alkyl, 3-10 membered carbocyclic or heterocyclic group, cyano, chlorine, fluorine and -O(C1-C2 alkyl), wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3 alkyl, fluorine and -O(C1-C2 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0682] still more preferably, Ry1is selected from the group consisting of hydrogen, methyl, a 3-6 membered carbocyclic group, a 3-6 membered heterocyclic group, cyano and chlorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from methyl, fluorine, and -OCH3;

[0683] still more preferably, Ry1is selected from the group consisting of hydrogen, methyl, a 3-6 membered carbocyclic group, a 3-6 membered heterocyclic group, cyano and chlorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from methyl, fluorine, and -OCH3;

[0684] more preferably, R1is selected from the group consisting of ;86

[0686] R2is 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6 alkyl), -OC(=O)-(C1-C6 alkyl), oxo, 3-8 membered carbocyclic or heterocyclic group, ,wherein each of said alkyl, alkoxy,ptionally substituted with one or moreselected from C1-C6 alkyl and halogen;

[0687] R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2;

[0688] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0689] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;

[0690] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0691] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl;

[0692] preferably, R2is 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, cyano, -(C1-C6alkylene)-OH, -(C1-C6alkylene)-O-(C1-C6alkyl), -SO2(C1-C6alkyl), -NH2, - COOH, oxo, 3-8 membered carbocyclic or heterocyclic group, -C(=O)-N(C1-C6 alkyl)(C1- C6 alkyl), , and , wherein each of said alkyl, alkylene, carbocyclic and heterocyclic groups is optionally substituted with one or more C1-C6alkyl;

[0693] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and87 cycloalkyl is independently optionally substituted with one or more selected from deuterium, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0694] more preferably, R2is selected from the following: );

[0697] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6alkyl and -(C1-C3alkylene)-O-(C1-C3alkyl), or Rz11and Rz12taken together with the carbon atom to which they are attached form a 3-8 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from C1-C6 alkyl and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6alkyl;

[0698] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl), or Rz11and Rz12taken together with the carbon atom to which they are attached form a 3-5 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from C1-C3 alkyl and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0699] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3, or Rz11and Rz12taken together with the carbon atom to which they are attached form a 3-4 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from methyl and -SO2(C1-C3 alkyl);

[0700] still more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3, or Rz11and Rz12taken together with the carbon atom to which they are attached form a 3-4 membered carbocyclic ring or88 heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more methyl;

[0701] Z is selected from -NRz14- and -CR'R''-;

[0702] Rz14is selected from hydrogen, C1-C6 alkyl, -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl), and -SO2(C1-C6 alkyl), wherein said alkyl is optionallyore C1-C6alkyl;

[0703] R21is selected from the group consisting of C1-C6 alkyl, 3-8 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl and 3-8 membered cycloalkyl;

[0704] R22is selected from the group consisting of hydrogen and C1-C6 alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C6 alkyl;

[0705] Rz13is selected from the group consisting of hydrogen, C1-C6 alkyl, -(C1-C3 alkylene)- O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, -COOH and cyano, or

[0706] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5- to 8- membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0707] preferably, Rz14is selected from hydrogen, C1-C3 alkyl and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substitu-C3 alkyl;

[0708] R21is selected from the group consisting of C1-C3 alkyl, 3-5 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and 3-5 membered cycloalkyl;

[0709] R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C3alkyl;89

[0710] Rz13is selected from the group consisting of hydrogen, C1-C3alkyl, -(C1-C2alkylene)- O-(C1-C2 alkyl), -(C1-C2 alkylene)-OH, -COOH and cyano, or

[0711] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5- to 6- membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0712] more preferably, Rz14is selected from hydrogen, , and - SO2(C1-C2alkyl), wherein said alkyl is optionally substituted with one or more methyl;

[0713] R21is selected from the group consisting of methyl and -ORc, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl;

[0714] R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more selected from deuterium and methyl;

[0715] Rz13is selected from the group consisting of hydrogen, methyl, -CH2-O-CH3, -CH2- OH, -COOH and cyano, or

[0716] when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo;

[0717] still more preferably, Rz14is selected from hydrogen, , and - SO2(C1-C2 alkyl), wherein said alkyl is optionally substituted with one or more methyl;

[0718] R21is methyl, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl;

[0719] R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more selected from deuterium and methyl;

[0720] Rz13is selected from the group consisting of hydrogen, methyl, -CH2-O-CH3, -CH2- OH, -COOH and cyano, or90

[0721] R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 8-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from C1-C6 alkyl and amino;

[0722] preferably, R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from C1-C3 alkyl and amino;

[0723] more preferably, R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 5-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from methyl and amino;

[0724] Rz21is selected from the group consisting of -C(=O)-N(C1-C6alkyl)(C1-C6alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0725] preferably, Rz21is selected from the group consisting of -C(=O)-N(C1-C3alkyl)(C1-C3alkyl) and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0726] more preferably, Rz21is selected from the group consisting of -C(=O)-N(CH3)2and - SO2(C1-C2 alkyl), wherein said alkyl is optionally substituted with one or more methyl;

[0727] still more preferably, Rz21is -SO2(C1-C2 alkyl), wherein said alkyl is optionally substituted with one or more methyl;

[0728] still more preferably, R2is selected from the following: -A-91

[0730] wherein:

[0731] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6 alkyl and -(C1-C3 alkylene)-O-(C1-C3 alkyl);

[0732] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3alkyl and -(C1-C2alkylene)-O-(C1-C2alkyl);

[0733] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3;

[0734] Rz13is selected from the group consisting of hydrogen, C1-C6 alkyl, -(C1-C3 alkylene)- O-(C1-C3alkyl), -(C1-C3alkylene)-OH, -COOH and cyano;

[0735] preferably, Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1- C2 alkylene)-O-(C1-C2 alkyl), -(C1-C2 alkylene)-OH, -COOH and cyano;

[0736] more preferably, Rz13is selected from the group consisting of hydrogen, methyl, -CH2- O-CH3, -CH2-OH and cyano;

[0737] Rz14is selected from hydrogen, C1-C6 alkyl, -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl), and -SO2(C1-C6 alkyl), wherein said alkyl is optionallyore C1-C6 alkyl;

[0738] R21is selected from the group consisting of C1-C6alkyl and 3-8 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl and 3-8 membered cycloalkyl;

[0739] R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium and C1-C6 alkyl;

[0740] preferably, Rz14is selected from hydrogen -C3 alkyl), wherein said alkyl is optionally substitu92

[0741] R21is selected from the group consisting of C1-C3alkyl and 3-5 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and 3-5 membered cycloalkyl;

[0742] R22is selected from the group consisting of hydrogen and C1-C3alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C3 alkyl;

[0743] more preferably, Rz14is selected from hydrogen and - SO2(C1-C2 alkyl), wherein said alkyl is optionally substl;

[0744] R21is methyl, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl;

[0745] R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more selected from deuterium and methyl;

[0746] Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C6 alkyl)- and -N(- SO2(C1-C6 alkyl))-, wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0747] preferably, Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C3 alkyl)- and -N(-SO2(C1-C3 alkyl))-, wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0748] more preferably, Rz15is -O-;

[0749] each of Rz16and Rz17is independently selected from the group consisting of hydrogen, C1-C6 alkyl and amino;

[0750] preferably, each of Rz16and Rz17is independently selected from the group consisting of hydrogen, C1-C3 alkyl and amino;

[0751] more preferably, each of Rz16and Rz17is independently selected from the group consisting of hydrogen, methyl and amino;

[0752] Rz18is absent or -CH(C1-C6 alkyl)-; preferably, Rz18is absent or -CH(CH3)-;93

[0753] Rz21is selected from the group consisting of -C(=O)-N(C1-C6alkyl)(C1-C6alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0754] preferably, Rz21is selected from the group consisting of -C(=O)-N(C1-C3alkyl)(C1-C3alkyl) and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0755] more preferably, Rz21is -SO2(C1-C2alkyl), wherein said alkyl is optionally substituted with one or more methyl;

[0756] still more preferably, R2is selected from the group consisting of ;[ ] eac o , an s n epen en y seece rom e group conss ng of hydrogen and halogen; preferably, each of R3, R4and R5is independently selected from the group consisting of hydrogen and fluorine,94

[0759] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0760]

[0761] In one embodiment, the present disclosure relates to a compound of Formula (II-1), (II-2) or (II-3): -2)

[0765] Y is absent or oxygen;

[0766] Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6alkyl and fluorine;

[0767] preferably, Rx1is selected from the group consisting of C1-C6 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6alkyl and fluorine;

[0768] more preferably, Rx1is selected from the group consisting of C1-C3 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C3alkyl and fluorine;95

[0769] still more preferably, Rx1is selected from the group consisting of C1-C2alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C2 alkyl and fluorine;

[0770] still more preferably, Rx1is selected from the group consisting of methyl, fluorine and cyano, wherein each of said methyl is independently optionally substituted with one or more selected from methyl and fluorine;

[0771] still more preferably, Rx1is selected from the group consisting of methyl, fluoromethyl, and cyano;

[0772] R1is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6alkyl, 3-8 membered cycloalkyl, fluorine, amino, -O(C1-C6 alkyl) and a 3-8 membered heterocyclic group, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6alkyl, -O(C1-C6alkyl) and fluorine;

[0773] preferably R1is (R1-A);

[0774] wherein:

[0775] Ry1is selected from the group consisting of hydrogen, deuterium, C1-C6alkyl, a 3-14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, fluorine and -O(C1-C6 alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine;

[0776] preferably, Ry1is selected from the group consisting of hydrogen, deuterium, C1-C3alkyl, a 3-10 membered carbocyclic or heterocyclic group, cyano and chlorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3alkyl, fluorine and -O(C1-C3alkyl);

[0777] more preferably, Ry1is selected from the group consisting of hydrogen, deuterium, C1- C2 alkyl, 3-10 membered carbocyclic, cyano and chlorine, wherein each of said alkyl and96 carbocyclic is independently optionally substituted with one or more selected from C1-C3alkyl, fluorine and -O(C1-C2 alkyl);

[0778] still more preferably, Ry1is selected from the group consisting of hydrogen, deuterium, C1-C2alkyl, 3-6 membered carbocyclic, cyano and chlorine, wherein each of said alkyl and carbocyclic is independently optionally substituted with one or more selected from C1-C3 alkyl, fluorine, and -O(C1-C2 alkyl);

[0779] still more preferably, Ry1is selected from the group consisting of hydrogen, deuterium, methyl, a 3-6 membered carbocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl and carbocyclic is independently optionally substituted with one or more selected from methyl, fluorine, and -OCH3;

[0780] more preferably, R1is selected from the group consisting of

[0781] ;

[0782] group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6alkoxy, -(C1-C6alkylene)-OH, -(C1-C6alkylene)-O-(C1-C6alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1- C6alkyl), -OC(=O)-(C1-C6alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, xy,ore selected from C1-C6alkyl and halogen;

[0783] R#is selected from the group consisting of hydroxy, C1-C6 alkoxy and -NR#1R#2;

[0784] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or

[0785] R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring;97

[0786] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0787] Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl;

[0788] preferably, R2is 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, cyano, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, - COOH, oxo, 3-8 membered carbocyclic or heterocyclic group, -C(=O)-N(C1-C6 alkyl)(C1- C6 alkyl), , and , wherein each of said alkyl, alkylene, carbocyclic and heterocyclic groups is optionally substituted with one or more C1-C6 alkyl;

[0789] each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, C1-C6 alkyl and 3-8 membered cycloalkyl;

[0790] more preferably, R2is selected from the following: );

[0793] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6alkyl and -(C1-C3alkylene)-O-(C1-C3alkyl), or Rz11and Rz12taken together with the carbon atom to which they are attached form a 3-8 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from C1-C6 alkyl and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;98

[0794] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl);

[0795] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3;

[0796] still more preferably, each of Rz11and Rz12is methyl;

[0797] Z is -NRz14-;

[0798] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)(C1-C6alkyl), and -SO2(C1-C6 alkyl), wherein said alkyl is optionallyore C1-C6 alkyl;

[0799] R21is selected from the group consisting of C1-C6 alkyl and 3-8 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and 3-8 membered cycloalkyl;

[0800] R22is selected from the group consisting of hydrogen and C1-C6 alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C6 alkyl;

[0801] Rz13is selected from the group consisting of hydrogen, C1-C6 alkyl, -(C1-C3 alkylene)- O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, -COOH and cyano;

[0802] preferably, Rz14is selected from hydrogen, C1-C6 alkyl, and ; [08ected from the group consisting of C1-C6 alkyl and 3-8 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and 3-8 membered cycloalkyl;

[0804] R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0805] Rz13is selected from the group consisting of hydrogen and C1-C3 alkyl;99

[0806] more preferably, Rz14is selected from hydrogen and ;

[0807] R22is selected from the group consisting of hydro3 alkyl, wherein said alkyl is optionally substituted with one or more C1-C3alkyl;

[0808] Rz13is selected from the group consisting of hydrogen and C1-C3alkyl;

[0809] Rz21is selected from the group consisting of -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl;

[0810] preferably, Rz21is -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0811] more preferably, Rz21is -SO2(C1-C2 alkyl), wherein said alkyl is optionally substituted with one or more C1-C2 alkyl;

[0812] still more preferably, R2is selected from the following: );

[0815] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6 alkyl and -(C1-C3 alkylene)-O-(C1-C3 alkyl);

[0816] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3alkyl and -(C1-C2alkylene)-O-(C1-C2alkyl);

[0817] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl;

[0818] Rz13is selected from the group consisting of hydrogen, C1-C6 alkyl, -(C1-C3 alkylene)- O-(C1-C3alkyl), -(C1-C3alkylene)-OH, -COOH and cyano;

[0819] preferably, Rz13is selected from the group consisting of hydrogen and C1-C3alkyl;100

[0820] Rz14is selected from hydrogen, C1-C6 alkyl and ;

[0821] R21is selected from the group consisting ofed cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and 3-8 membered cycloalkyl;

[0822] R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more C1-C3alkyl;

[0823] preferably, Rz14is selected from hydrogen and ;

[0824] R22is selected from the group consisting of hydrogen and C1-C3alkyl, wherein said alkyl is optionally substituted with one or more C1-C3 alkyl;

[0825] Rz21is selected from the group consisting of -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl) and -SO2(C1-C6alkyl), wherein said alkyl is optionally substituted with one or more C1-C6alkyl;

[0826] preferably, Rz21is -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3alkyl;

[0827] more preferably, Rz21is -SO2(C1-C2alkyl), wherein said alkyl is optionally substituted with one or more C1-C2 alkyl;

[0828] still more preferably, R2is selected from the group consisting of ;eac o , a s epe e y seected from the group consisting of hydrogen and halogen; preferably, each of R3, R4and R5is independently selected from the group consisting of hydrogen and fluorine,

[0831] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.101

[0832]

[0833] In one embodiment, the present disclosure relates to a compound of Formula (III), which is selected from the group consisting of the following compounds:103 [08, , , , rm, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0836]

[0837] In one embodiment, exemplary compounds of Formula (I), Formula (II) and Formula (III) are shown below:tzOLSOL90 L80 L60 LELLHL9LL02 LizZ L92 L82 L62 L132 2 2 0 1 9 0 e F F e F F1 5 F NHO S O N N SO NON N N Se F F 133 2 2 1 6 NC NHO S O N N NN N N Se F F F SOO Ne Ftz£LF NH F N ı36 2 3 3 FO S O NH NN N N Se F F 2 3 4 NH NHOO S S F O O N NN N N Se F F N S S FOO NOON N N Se F FNH NHOO S S O O O N N N NN O N N NH S See F 137 2N N F F F 2ĸ£LĶ£LOHZizLŅizLStzLZtzL148ers 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.

[0840] As used herein, the term “stereoisomers” refers to compounds that are identical in chemical constitution, but different in arrangement of atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.

[0841] 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 through high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.149

[0842] As used herein, the term “enantiomers” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0843] 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.

[0844] 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)).

[0845] 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,150 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.

[0846] As used herein, the term “isotopically labeled form” refers to a compound that contains an isotopic form of one or more atoms in the compound that is different from the naturally occurring isotopic distribution of the atom in nature. All isotopic forms are included as options, unless a specific isotopic form is indicated. An “isotopically label form” 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 be2H / D, any carbon may be13C, or any nitrogen may be15N, and that the presence and placement of such atoms may be determined by those skilled in the art.

[0847] 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.

[0848] 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.

[0849] 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.151

[0850] 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, trifluoroacetic, 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.

[0851] One particular group of salts consists of salts formed from acetic, trifluoroacetic, 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. One particular salt is a trifluoroacetic acid salt.

[0852] Where the compounds disclosed herein contain an amine function, the compound may form quaternary ammonium salts, for example by reaction with an alkylating agent152 according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the compounds disclosed herein.

[0853] 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.

[0854] 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.

[0855] 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)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic153 ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0856] 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.

[0857]

[0858] Preparation Methods

[0859] According to a further aspect of the present disclosure, provided are a process of preparing a compound of Formula (I), a process of preparing a compound of Formula (II) and a process of preparing a compound of Formula (III), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof. The following schemes are examples of synthetic schemes that may be used to synthesize the compound of any one of Formula (I), Formula (II) and Formula (III). In the following schemes, reactive groups can be protected with protecting groups and then de-protected by well-established techniques in the art. The compound of any one of Formula (I), Formula (II) and Formula (III) 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.

[0860]

[0861] According to a further aspect of the present disclosure, a process of preparing the compound of Formula (Ia-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises any one of Processes A and A':

[0862]

[0863] - Process A produces the compound of Formula (Ia-1):154 1)

[0866] R2is selected from the following: );ein.

[0869]

[0870] - Process A' produces the compound of Formula (Ia-1'):

[0871] ')

[0872]

[0873] X, R1, Rz11- Rz13and R5are as defined herein.

[0874]

[0875] Processes A and A'

[0876] 155

[0877] Process A prepares the compound of Formula (Ia-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0878] (i) preparing a compound of Formula (A-1):

[0879] );

[0880] Formula (A-1) with oxidative halogenation reagent such as NCS (N-Chlorosuccinimide), NBS (N-Bromosuccinimide), and 1,3-dichloro-5,5- dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (A-2): );ormula (A-2) with X-NH2to obtain a compound of Formula (A-3): );156

[0884] (iv) reacting the compound of Formula (A-3) wit to obtain the compound of Formula (Ia-1);

[0885] wherein,

[0886] X, R1, Rz11-Rz13, Rz21, Z and R5are as described herein;

[0887] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[0888] Halaand Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[0889]

[0890] Process A' prepares the compound of Formula (Ia-1') as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0891] (i) preparing a compound of Formula (A-1): );Formula (A-1) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (A-2): );157

[0895] (iii) reacting the compound of Formula (A-2) with X-NH2to obtain a compound of Formula (A-3): );

[0897] (iv) reacting the compound of Formula (A-3) with (Boc: tert- Butyloxycarbonyl) to obtain the compound of Formula (A);ula (A-4) with Trifluoroacetic acid (TFA) to obtain the compound of Formula (Ia-1'):

[0900] wherein,

[0901] X, R1, Rz11-Rz13and R5are as described herein;

[0902] Halaand Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[0903]

[0904] In one embodiment, an exemplary reaction scheme of Process A may be shown as Scheme I-1 and Scheme I-2:

[0905] Scheme I-1158

[0906]

[0907]

[0908] X, R1, Rz11-Rz13, Z and R5are as described herein;

[0909] Halaand Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[0910]

[0911] Scheme I-2

[0912]

[0913] w eren,

[0914] X, R1, Rz21and R5are as described herein;159

[0915] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[0916] Halaand Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[0917]

[0918] In one embodiment, an exemplary reaction scheme of Process A' may be shown as Scheme II:

[0919] Scheme II

[0922] X, R1, Rz11-Rz13and R5are as described herein;

[0923] Halaand Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[0924]

[0925] In one embodiment, the step (i) of Processes A and A' comprises:

[0926] (i-1) preparing the compound of Formula (a-1) );[ ] (- ) (- a) reactng t e compound of Formula (a-1) with NH2NH2•H2O to obtain a compound of Formula (a-2), then reacting the compound of Formula (a-2) with160 o obtain a compound of Formula (a-3), then reacting the compound of selenadiazole formation reagent such as SeO2, Se, SeCl4, SeOCl, andWoollins Reagent to obtain the compound of Formula (a-4), and then reacting the compound of Formula (a-4) with BnSH (Benzyl mercaptan) to obtain the compound of Formula (A-1): ),g p Formula (a-1) with BnSH to obtain a compound of Formula (a-2'), then reacting the compound of Formula (a-2') with NH2NH2•H2O to obtain a compound of Formula (a-3'), then reacting the compound of Formula (a-3') with to obtain a compound of Formula (a-4'), and then reacting thep mula (a-4') with selenadiazole formation reagent such as SeO2, Se, SeCl4, SeOCl, and Woollins' Reagent to obtain the compound of Formula (A-1):161 ');

[0937] R1and R5are as described herein;

[0938] Halaand Halbare halogens; preferably, fluoro, chloro, bromo or iodo.

[0939]

[0940] In one embodiment, an exemplary reaction scheme of step (i) of Processes A and A' may be shown as Scheme III-1 and Scheme III-2:

[0941] Scheme III-1162

[0942]

[0943]

[0944] R1and R5are as described herein;

[0945] Halaand Halbare halogens; preferably, fluoro, chloro, bromo or iodo.

[0946]

[0947] Scheme III-2,

[0950] R1and R5are as described herein;

[0951] Halaand Halbare halogens; preferably, fluoro, chloro, bromo or iodo.163

[0952]

[0953] In one embodiment, the step (i-1) of Processes A and A' comprises:

[0954] (i-1-a) preparing a compound of Formula (a-5):

[0955] (a-5);pound of Formula (a-5) with halogenation reagent such as NBS, NIS (N-Iodosuccinimide), NCS, Selectfluor (F-TEDA-BF₄), NFSI (N- Fluorobenzenesulfonimide), Cl2, Br2, I2, HF, 2-Chloro-1,3-bis(methoxycarbonyl)guanidine and 1,2-Dibromotetrachloroethane to obtain the compound of Formula (a-6): );

[0958] (i-1-c) reacting the compound of Formula (a-6) wit to obtain a compound of Formula (a-1),

[0959] wherein,

[0960] R1is as described herein; and

[0961] Hala, Halband Haldare halogens; preferably, fluoro, chloro, bromo or iodo.

[0962]

[0963] In the embodiment where R1is hydrogen, the step (i-1) of Processes A and A' comprises:

[0964] (i-1-a') preparing a compound of Formula (a-5'):

[0965] (a-5');

[0966] (i-1-b') reacting the compound of Formula (a-5') with and t-BuOK to obtain a compound of Formula (a-6'):164 );

[0968] (i-1-c') reacting the compound of Formula (a-6') wit to obtain a compound of Formula (a-1),

[0969] wherein,

[0970] Hala, Halband Haldare halogens; preferably, fluoro, chloro, bromo or iodo.

[0971]

[0972] In one embodiment, an exemplary reaction scheme of step (i-1) of Processes A and A' may be shown as Scheme IV-1 and Scheme IV-2:

[0973] Scheme IV-1

[0976] R1is as described herein; and

[0977] Hala, Halband Haldare halogens; preferably, fluoro, chloro, bromo or iodo.

[0978]

[0979] Scheme IV-2

[0980]

[0981] w eren,

[0982] Hala, Halband Haldare halogens; preferably, fluoro, chloro, bromo or iodo.165

[0983]

[0984] In one embodiment, the step (i) of Processes A and A' comprises:

[0985] (i-1') preparing the compound of Formula (a-7) );pound of Formula (a-7) with BnSH to obtain a compound of Formula (a-8): );

[0989] (i-3') reacting the compound of Formula (a-8) with to obtain a compound of Formula (a-9): );

[0991] (i-4') reacting the compound of Formula (a-9) wit to obtain a compound of Formula (A-1);

[0992] wherein,

[0993] R1is as described herein; and

[0994] Hala, Halb, Haldand Haleare halogens; preferably, fluoro, chloro, bromo or iodo.

[0995]

[0996] In one embodiment, an exemplary reaction scheme of step (i) of Processes A and A' may be shown as Scheme V:

[0997] Scheme V166

[0998]

[0999] wherein,

[1000] R1is as described herein; and

[1001] Hala, Halb, Haldand Haleare halogens; preferably, fluoro, chloro, bromo or iodo.

[1002]

[1003] According to a further aspect of the present disclosure, a process of preparing the compound of Formula (Ib-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises one of Process B:

[1004]

[1005] - Process B produces the compound of Formula (Ib-1): 1)[ ] w eren:

[1009] R2is selected from the following:167 );ein.

[1012]

[1013] Process B

[1014]

[1015] Process B prepares the compound of Formula (Ib-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1016] (i) preparing a compound of Formula (B-1): );

[1018] (ii) reacting the compound of Formula (B-1) wit to obtain the compound of Formula (Ib-1);

[1019] wherein,

[1020] X, R1, Rz11-Rz13, Rz21, Z and R5are as described herein;

[1021] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[1022] Halais halogen; preferably, fluoro, chloro, bromo or iodo.

[1023] 168

[1024] In the embodiment where R1is as described herein except hydrogen, the step (i) of Process B comprises:

[1025] (i-1) preparing a compound of Formula (b-1): );f Formula (b-1) with halogenation reagent such as NBS, NIS, NCS, Selectfluor, NFSI, Cl2, Br2, I2, HF, 2-Chloro-1,3- bis(methoxycarbonyl)guanidine and 1,2-Dibromotetrachloroethane to obtain a compound of Formula (b-2): );f Formula (b-2) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (b-3): );[ ] (- ) reactng t e compoun o Formula (b-3) with X-NH2 to obtain a compound of Formula (b-4)169 );ormula (b-4) with R1-B(OH)2 to obtain a compound of Formula (B-1);

[1034] wherein,

[1035] R1is as described herein except hydrogen;

[1036] X and R5are as described herein;

[1037] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1038]

[1039] In the embodiment where R1is hydrogen, the step (i) of Process B comprises:

[1040] (i-1) preparing a compound of Formula (b-1):

[1041] );

[1042] g p of Formula (b-1) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (b-2'): ');170

[1044] (i-3') reacting the compound of Formula (b-2') with X-NH2to obtain a compound of Formula (B-1)

[1045] wherein,

[1046] X and R5are as described herein;

[1047] Halaand Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1048]

[1049] In one embodiment, an exemplary reaction scheme of Process B may be shown as Scheme VI-1 to Scheme VI-4:

[1050] Scheme VI-1,

[1053] R1is as described herein except hydrogen;

[1054] X, Rz11-Rz13, Z and R5are as described herein;

[1055] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1056] 171

[1057] Scheme VI-2

[1058]

[1059] w,

[1060] R1is as described herein except hydrogen;

[1061] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[1062] X, Rz21and R5are as described herein;

[1063] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1064]

[1065]

[1066] Scheme VI-3172

[1067]

[1068]

[1069] X, Rz11-Rz13, Z and R5are as described herein;

[1070] Halaand Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1071]

[1072] Scheme VI-4

[1073]

[1074] wherein,173

[1075] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[1076] X, Rz21and R5are as described herein;

[1077] Halaand Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1078]

[1079] In one embodiment, the step (i-1) of Process B comprises:

[1080] (i-1-a) preparing a compound of Formula (b-5): );

[1082] (i-1-b) reacting the compound of Formula (b-5) wit to obtain a compound of Formula (b-6):);

[1084] (i-1-c) reacting the compound of Formula (b-6) with to obtain a compound of Formula (b-7):);- - reac ng e compound of Formula (b-7) with BnSH to obtain a compound of Formula (b-8):174 );nd of Formula (b-8) with base such as LiOH, NaOH and KOH to obtain a compound of Formula (b-9): );

[1090] (i-1-f) reacting the compound of Formula (b-9) with to obtain a compound of Formula (b-10):);ormula (b-10) with selenadiazole formation reagent such as SeO2, Se, SeCl4, SeOCl, and Woollins' Reagent to obtain a compound of Formula (b-1);

[1093] wherein,

[1094] R5is as described herein;

[1095] Halaand Haldare halogens; preferably, fluoro, chloro, bromo or iodo.

[1096]

[1097] In one embodiment, an exemplary reaction scheme of step (i-1) of Process B may be shown as Scheme VII:175

[1098] Scheme VII

[1101] R5is as described herein;

[1102] Halaand Haldare halogens; preferably, fluoro, chloro, bromo or iodo.

[1103]

[1104] According to a further aspect of the present disclosure, a process of preparing the compound of Formula (Ic-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises one of Process C:

[1105]

[1106] - Process C produces the compound of Formula (Ic-1):X NOSOed froNm N N th Se R Fe f1olF Rlo5176 1)

[1110] R2isH select R2 Nwing: );ein.

[1113]

[1114] Process C

[1115]

[1116] Process C prepares the compound of Formula (Ic-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1117] (i) preparing a compound of Formula (C-1): );177

[1119] (ii) reacting the compound of Formula (C-1) with to obtain the compound of Formula (Ic-1);

[1120] wherein,

[1121] X, R1, Rz11-Rz13, Rz21, Z and R5are as described herein;

[1122] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[1123] Halais halogen; preferably, fluoro, chloro, bromo or iodo.

[1124]

[1125] In the embodiment where R1is hydrogen, the step (i) of Process C comprises:

[1126] (i-1) preparing a compound of Formula (c-1): );pound of Formula (c-1) with HCOOH to obtain a compound of Formula (c-2): );

[1130] (i-3) reacting the compound of Formula to obtain a compound of Formula (c-3):178 );d of Formula (c-3) with BnSH to obtain a compound of Formula (c-4):

[1133] );

[1134] of Formula (c-4) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (c-5):

[1135] );

[1136] g p Formula (c-5) with X-NH2 to obtain a compound of Formula (C-1);

[1137] wherein,

[1138] X and R5are as described herein;

[1139] Hala, Halb, Halcand Haldare halogens; preferably, fluoro, chloro, bromo or iodo.

[1140] 179

[1141] In the embodiment where R1is as described herein except hydrogen, the step (i) of Process C comprises:

[1142] (i-1') preparing a compound of Formula (c-1'): );

[1144] (i-2') reacting the compound of Formula to obtain a compound of Formula (c-2'):

[1145] ');

[1146] d of Formula (c-2') with BnSH to obtain a compound of Formula (c-3'): );- eac g e co pou d of Formula (c-3') with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (c-4'):180

[1149] );

[1150] Formula (c-4') with X-NH2 to obtain a compound of Formula (c-5'); );ormula (c-5') with R1-B(OH)2 to obtain a compound of Formula (C-1);

[1153] wherein,

[1154] R1is as described herein except hydrogen;

[1155] X and R5are as described herein;

[1156] Hala, Halb, Halc, Haldand Haleare halogens; preferably, fluoro, chloro, bromo or iodo.

[1157]

[1158] In one embodiment, an exemplary reaction scheme of Process C may be shown as Scheme VIII-1 to Scheme VIII-4:

[1159] Scheme VIII-1181

[1162] X, Rz11-Rz13, Z and R5are as described herein;

[1163] Hala, Halb, Halcand Haldare halogens; preferably, fluoro, chloro, bromo or iodo.

[1164]

[1165] Scheme VIII-2182

[1166]

[1167] w,

[1168] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[1169] X, Rz21and R5are as described herein;

[1170] Hala, Halb, Halcand Haldare halogens; preferably, fluoro, chloro, bromo or iodo.

[1171]

[1172] Scheme VIII-3183

[1173]

[1174] where

[1175] R1is as described herein except hydrogen;

[1176] X, Rz11-Rz13, Z and R5are as described herein;

[1177] Hala, Halb, Halc, Haldand Haleare halogens; preferably, fluoro, chloro, bromo or iodo.

[1178]

[1179] Scheme VIII-4184

[1180]

[1181] whe,

[1182] R1is as described herein except hydrogen;

[1183] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[1184] X, Rz21and R5are as described herein;

[1185] Hala, Halb, Halc, Haldand Haleare halogens; preferably, fluoro, chloro, bromo or iodo.

[1186]

[1187] According to a further aspect of the present disclosure, a process of preparing the compound of Formula (II-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises one of Process D:

[1188]

[1189] - Process D produces the compound of Formula (II-1):185 1)

[1195] R2is selected from the following: );, , , .

[1198]

[1199] Process D

[1200]

[1201] Process D prepares the compound of Formula (II-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1202] (i) preparing a compound of Formula (D-1):186

[1203] );

[1204] (ii) reacting the compound of Formula (D-1) with to obtain the compound of Formula (II-1);

[1205] wherein, );ed herein;

[1208] R1, Rz11-Rz13, Rz21, Z and R5are as described herein;

[1209] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl; and

[1210] Halais halogen; preferably, fluoro, chloro, bromo or iodo.

[1211]

[1212] In the embodiment where R1is as described herein but is not hydrogen, the step (i) of Process D comprises:

[1213] (i-1) preparing a compound of Formula (d-1):

[1214] );187

[1215] (i-2) reacting the compound of Formula (d-1) with halogenation reagent such as NBS, NIS, NCS, Selectfluor, NFSI, Cl2, Br2, I2, HF, 2-Chloro-1,3- bis(methoxycarbonyl)guanidine and 1,2-Dibromotetrachloroethane to obtain a compound of Formula (d-2):

[1216] );

[1217] f Formula (d-2) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (d-3):

[1218] );

[1219] Formula (d-3) with X-NH2to obtain a compound of Formula (d-4) );[ ] (- ) reactng t e compoun o Formula (d-4) with R1-B(OH)2 to obtain a compound of Formula (D-1);

[1222] wherein,188 1223 X i XA);ed herein;

[1225] R1is as described herein but is not hydrogen;

[1226] R5is as described herein;

[1227] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1228]

[1229] In the embodiment where R1is hydrogen, the step (i) of Process D comprises:

[1230] (i-1) preparing a compound of Formula (d-1): );of Formula (d-1) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (d-2'):

[1233] ');

[1234] - reac ng e compoun o Formula (d-2') with X-NH2 to obtain a compound of Formula (d-1)

[1235] wherein,189 1236 X i XA);ed herein;

[1238] R5is as described herein;

[1239] Halaand Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1240]

[1241] In one embodiment, an exemplary reaction scheme of Process D may be shown as Scheme IX-1 and Scheme IX-4:

[1242] Scheme IX-1,190 124 X i XA);ed herein;

[1247] R1is as described herein but is not hydrogen;

[1248] Rz11-Rz13, Z and R5are as described herein;

[1249] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1250]

[1251] Scheme IX-2, );

[1255] Y and Rxare as defined herein;191

[1256] R1is as described herein but is not hydrogen;

[1257] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[1258] Rz21and R5are as described herein;

[1259] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1260]

[1261] Scheme IX-3

[1266] Rz11-Rz13, Z and R5are as described herein;

[1267] Halaand Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1268]

[1269] Scheme IX-4192

[1274] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[1275] Rz21and R5are as described herein;

[1276] Halaand Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1277]

[1278] In one embodiment, the step (i-1) of Process D comprises:

[1279] (i-1-a) preparing a compound of Formula (d-5):

[1280] );

[1281] (- -b) reactng t e compound of Formula (d-5) with BnSH to obtain a compound of Formula (b-6):193

[1282] );

[1283] nd of Formula (d-6) with base such as LiOH, NaOH and KOH to obtain a compound of Formula (d-7): );

[1285] (i-1-d) reacting the compound of Formula (d-7) with to obtain a compound of Formula (d-8): );Formula (d-9) with selenadiazole formation reagent such as SeO2, Se, SeCl4, SeOCl, and Woollins' Reagent to obtain a compound of Formula (d-1);

[1288] wherein,

[1289] R5is as described herein;

[1290] Halaand Haldare halogens; preferably, fluoro, chloro, bromo or iodo.

[1291]

[1292] In one embodiment, an exemplary reaction scheme of step (i-1) of Process D may be shown as Scheme X:194

[1293] Scheme X

[1296] R5is as described herein;

[1297] Halaand Haldare halogens; preferably, fluoro, chloro, bromo or iodo.

[1298]

[1299] According to a further aspect of the present disclosure, a process of preparing the compound of Formula (III) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises one of Process E:

[1300]

[1301] - Process E produces the compound of Formula (III-1): 1)[ ] w eren:195 130 X i XA);ed herein;

[1307] R2is selected from the following: );.

[1310]

[1311] Process E

[1312]

[1313] Process E prepares the compound of Formula (III-1) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1314] (i) preparing a compound of Formula (E-1): );

[1317] (ii) reacting the compound of Formula (E-1) wit to obtain the compound of Formula (III-1);196

[1318] wherein, 1 1 i A);ed herein;

[1321] Z, Rz11- Rz13, Rz21, R5and R6are as described herein;

[1322] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl; and

[1323] Halais halogen; preferably, fluoro, chloro, bromo or iodo.

[1324]

[1325] In the embodiment where R6is hydrogen, the step (i) of Process E comprises:

[1326] (i-1) preparing a compound of Formula (e-1):

[1327] );

[1328] f Formula (e-1) with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (e-2):

[1329] );

[1330] (- ) reactng t e compoun o Formula (e-2) with X-NH2 to obtain a compound of Formula (e-3):197 );ormula (e-3) with dehalogenation reagent such as Pd / C H2,Grignard reagent, n-BuLi, Zn, and NH4Cl to obtain a compound of Formula (E- 1);

[1333] wherein, );ed herein;

[1336] R5is as described herein; and

[1337] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1338]

[1339] In the embodiment where R6is halogen, the step (i) of Process E comprises:

[1340] (i-1) preparing a compound of Formula (e-1):

[1341] );

[1342] - reac ng e compoun of Formula (e-2') with oxidative halogenation reagent such as NCS, NBS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione to obtain a compound of Formula (e-3'):198

[1343] );

[1344] Formula (e-3') with X-NH2 to obtain a compound of Formula (E-1):

[1345] wherein, );ed herein;

[1348] R5is as described herein; and

[1349] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1350]

[1351] In one embodiment, an exemplary reaction scheme of Process E may be shown as Scheme XI-1 and Scheme XI-4:

[1352] Scheme XI-1

[1353] 199

[1354] wherein, 13 X i XA);ed herein;

[1357] Rz11-Rz13, Z and R5are as described herein;

[1358] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1359]

[1360] Scheme XI-2

[1361]

[1362] w, );ed herein;

[1365] Rz21and R5are as described herein;

[1366] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[1367] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1368] 200

[1369] Scheme XI-3

[1374] Rz11-Rz13, Z and R5are as described herein; and

[1375] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1376]

[1377] Scheme XI-4201

[1382] Rz21and R5are as described herein;

[1383] RBis 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;

[1384] Hala, Halband Halcare halogens; preferably, fluoro, chloro, bromo or iodo.

[1385]

[1386] In one embodiment, the step (i-1) of Process E comprises:

[1387] (i-1-a) preparing a compound of Formula (e-4): );[ ] (- - ) reactng t e compound of Formula (e-4) with i) Phthalimide, DIAD, PPh3 and ii) Hydrazine hydrate to obtain a compound of Formula (e-5):202 );

[1391] (i-1-c) reacting the compound of Formula (e-5) with n a compound of Formula (e-6):);Formula (e-6) with POCl3to obtain a compound of Formula (e-7): );ound of Formula (e-7) with NH2NH2•H2O to obtain a compound of Formula (e-8):

[1396] );

[1397] (i-1-f) reacting the compound of Formula (e-8) with to obtain a compound of Formula (e-9):203

[1398] );

[1399] Formula (e-9) with selenadiazole formation reagent such as SeO2, Se, SeCl4, SeOCl, and Woollins' Reagent to obtain a compound of Formula (e-10): );of Formula (e-10) with BnSH to obtain a compound of Formula (e-11); );g p of Formula (e-11) with halogenation reagent such as NBS, NIS, NCS, Selectfluor, NFSI, Cl2, Br2, I2, HF, 2-Chloro-1,3- bis(methoxycarbonyl)guanidine and 1,2-Dibromotetrachloroethane to obtain a compound of Formula (e-1);

[1404] wherein,

[1405] R5is as described herein;

[1406] Hala, Haldand Haleare halogens; preferably, fluoro, chloro, bromo or iodo.204

[1407]

[1408] In one embodiment, an exemplary reaction scheme of step (i-1) of Process E may be shown as Scheme XII:

[1409] Scheme XII

[1410]

[1411] wherein,

[1412] R5is as described herein;

[1413] Hala, Halb, Haldand Haleare halogens; preferably, fluoro, chloro, bromo or iodo.

[1414] 205

[1415] According to a further aspect of the present disclosure, a process of preparing the compound of Formula (Ia-2), (Ia-3), (Ib-2), (Ib-3), (Ic-2), (Ic-3), (II-2), (II-3), (III-2) and (III-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises any one of Process F, G, H, I and J:

[1416]

[1417] - Process F produces the compound of Formula (Ia-2) and Formula (Ia-3): -3)

[1420] R2is selected from the following: );, , , , ein.

[1423]

[1424] - Process G produces the compound of Formula (Ib-2) and Formula (Ib-3): -3)206

[1426] wherein:

[1427] R2is selected from the following: );ein.

[1430]

[1431] - Process H produces the compound of Formula (Ic-2) and Formula (Ic-3): -3)

[1434] R2is selected from the following: );, , , - , ein.

[1437]

[1438] - Process I produces the compound of Formula (II-2) and Formula (II-3):207 -3)

[1443] R2is selected from the following: );.

[1446]

[1447] - Process J produces the compound of Formula (III-2) and Formula (III-3): -3)208

[1451] Y and Rx1are as defined herein;

[1452] R2is selected from the following: );

[1455]

[1456] Process F

[1457]

[1458] Process F prepares the compound of Formula (Ia-2) and (Ia-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1459] (i) preparing a compound of Formula (Ia-1); and

[1460] (ii) reacting the compound of Formula (Ia-1) with Selectfluor (1-Chloromethyl-4- fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), F-TEDA-BF4) to obtain the compound of Formula (Ia-2) and (Ia-3).

[1461]

[1462] In one embodiment, an exemplary reaction scheme of Process F may be shown as Scheme XIII:

[1463] Scheme XIII,209

[1466] R2is selected from the following: );ein.

[1469]

[1470] Process G

[1471]

[1472] Process G prepares the compound of Formula (Ib-2) and (Ib-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1473] (i) preparing a compound of Formula (Ib-1); and

[1474] (ii) reacting the compound of Formula (Ib-1) with Selectfluor to obtain the compound of Formula (Ib-2) and (Ib-3).

[1475]

[1476] In one embodiment, an exemplary reaction scheme of Process G may be shown as Scheme XIV:

[1477] Scheme XIV,

[1480] R2is selected from the following:210 );ein.

[1483]

[1484] Process H

[1485]

[1486] Process H prepares the compound of Formula (Ic-2) and (Ic-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1487] (i) preparing a compound of Formula (Ic-1); and

[1488] (ii) reacting the compound of Formula (Ic-1) with Selectfluor to obtain the compound of Formula (Ic-2) and (Ic-3).

[1489]

[1490] In one embodiment, an exemplary reaction scheme of Process H may be shown as Scheme XV:

[1491] Scheme XV,

[1494] R2is selected from the following:211 );ein.

[1497]

[1498] Process I

[1499]

[1500] Process I prepares the compound of Formula (II-2) and (II-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1501] (i) preparing a compound of Formula (II-1); and

[1502] (ii) reacting the compound of Formula (II-1) with Selectfluor to obtain the compound of Formula (II-2) and (II-3).

[1503]

[1504] In one embodiment, an exemplary reaction scheme of Process I may be shown as Scheme XVI:

[1505] Scheme XVI,

[1508] Y and Rx1are as defined herein;

[1509] R2is selected from the following:212 );.

[1512]

[1513] Process J

[1514]

[1515] Process J prepares the compound of Formula (III-2) and (III-3) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1516] (i) preparing a compound of Formula (III-1); and

[1517] (ii) reacting the compound of Formula (III-1) with Selectfluor to obtain the compound of Formula (III-2) and (III-3).

[1518]

[1519] In one embodiment, an exemplary reaction scheme of Process J may be shown as Scheme XVII:

[1520] SchRx1 Yem NHOe S X ,

[1523] Y and RxOVII 1 a Rr2e NN as N R N6 d Se FefiFn R5ed se hleecrtfeluionr;

[1524] R2is selected from the followin,g A:CN, 0 oC Rx1 Y NHOS FOR2 NN N R N6 S FeF R5 Rx1 Y NHOSOR F2 NN N R N6 S FeF R5213 );

[1527]

[1528] As used herein (unless otherwise specified), the term “dehalogenation reagent” includes, but is not limited to, Pd / C H2, Grignard reagent, n-BuLi, Zn, NH4Cl. As used herein (unless otherwise specified), the term “selenadiazole formation reagent” includes, but is not limited to, SeO2, Se, SeCl4, SeOCl, and Woollins' Reagent. As used herein (unless otherwise specified), the term “halogenation reagent” includes, but is not limited to, NBS, NIS, NCS, Selectfluor, NFSI, Cl2, Br2, I2, HF, 2-Chloro-1,3- bis(methoxycarbonyl)guanidine and 1,2-Dibromotetrachloroethane. As used herein (unless otherwise specified), the term “oxidative halogenation reagent” includes, but is not limited to, NBS, NCS, and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione.

[1529]

[1530] Therapeutic utilities

[1531] The terms “treat”, “treating”, treatment” and the like refer to a course of action (such as administering an inhibitor of PARG 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.

[1532] The terms “prevent”, “preventing”, “prevention” and the like refer to a course of action (such as administering a PARG inhibitor or a pharmaceutical composition comprising same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom214 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.

[1533] The terms “inhibiting” and “reducing,” or any variation of these terms in relation to PARG, may refer to any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease in PARG 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.

[1534] "Disease", "disorder" and "condition" are used interchangeably herein.

[1535] The present disclosure provides a compound that prevents or treats a disease or disorder mediated by PARG or a disease or disorder in which PARG activity is implicated. The present disclosure also provides a compound that selectively inhibits PARG enzyme activity over PARP1 or ARH3 enzyme activity in vitro or in vivo.

[1536] In some embodiments, the disease or disorder mediated by PARG 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. Any type of cell, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin, may be treated.215

[1537] The anti-proliferative effects of the compounds of Formula (I), Formula (II) or Formula (III), or a pharmaceutically salt thereof have particular application in the treatment of human cancers (by virtue of their ability to inhibit PARG enzyme activity).

[1538] In a particular embodiment of the invention, the proliferative condition to be treated is cancer, such as lung cancer (Dai W et al., Front Pharmacol.2019;10:338), colon cancer (Shirai et al., Cell Death Dis.2013 Jun; 4(6): e656), breast cancer (Chen et al., Sci Adv.2019 Apr; 5(4): eaav4340), ovarian cancer (N. Pillay, R.M. Brady, M. Dey et al., Progress in Biophysics and Molecular Biology 163 (2021) 160-170), prostate cancer (Houl et al., Nat Commun.2019; 10: 5654), liver (Longpo Geng et al., Mol Biomed.2023 Dec; 4: 3), pancreatic cancer (Shirai et al., Cell Death Dis.2013 Jun; 4(6): e656), brain cancer, melanoma (Tentori et al., European Journal of Cancer Volume 41, Issue 18, December 2005, Pages 2948-2957), cervical cancer (Blenn, C., Wyrsch, P., & Althaus, F. R., 2011, Molecules, 16(2), 1854-1877) and skin cancer.

[1539] The therapeutically effective amount of the compound of Formula (I), Formula (II) or Formula (III) 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.

[1540] 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.

[1541] 216

[1542] Pharmaceutical compositions

[1543] 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 a DNA damage response (DDR) targeting anti-cancer agent. The term DNA damage response 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 variety 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 is also one of DDR targeting agents.

[1544] In some embodiments, provided is a pharmaceutical composition including the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a217 pharmaceutical acceptable carrier, wherein the composition may be administered simultaneously, separately or sequentially with additional DDR targeting anti-cancer agent described above.

[1545] In some embodiments, provided is a method of treating or preventing diseases or disorders mediated by PARG, in a subject, comprising administering to the subject the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the method may further comprise administering additional DDR targeting anti-cancer agent described above to the subject.

[1546] In some embodiments, provided is a kit comprising:

[1547] - a first pharmaceutical composition or dosage form comprising the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers; and

[1548] - a second pharmaceutical composition or dosage form comprising additional DDR targeting anti-cancer agent described above, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers.

[1549] In some embodiment, the kit is for use in a method of treating and / or preventing diseases or disorders mediated by PARG. 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 PARG.

[1550] 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. Pharmaceutically218 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.

[1551]

[1552] Treatment method

[1553] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by PARG, 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, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.

[1554] The terms “human”, “patient” or “subject” are used interchangeably herein. 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.

[1555]

[1556] Administration

[1557] 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, transdermal, ocular, rectal, nasal, and vaginal administration.

[1558] 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, or219 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.

[1559]

[1560] Formulation

[1561] 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.

[1562] 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, coloring220 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.

[1563]

[1564] Dosage

[1565] 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, or 2 days, or for less than 1 day. In some embodiments, the pharmaceutical composition of the present disclosure is administered chronically on an ongoing basis.

[1566]

[1567] 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 be 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 herein, 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 by the details of any of the 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 herein.

[1568] The contents of the articles and documents referred to herein are incorporated herein by reference in their entireties as if all of their contents are described in detail herein.221 EXAMPLES

[1569] The present disclosure will be further described below with references to 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.

[1570] 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.

[1571]

[1572] Abbreviations

[1573] The abbreviations as used herein have the following meanings: Et3N Triethylamine MeOH Methanol EtOH Ethanol SOCl2 Thionyl chloride CHCl3 Chloroform Na2SO4 Sodium sulfate LCMS Liquid chromatography–mass spectrometry HPLC High-performance liquid chromatography Boc tert-Butyloxycarbonyl DCM Dichloromethane TFA Trifluoroacetic acid THF Tetrahydrofuran dba Dibenzylideneacetone ACN Acetonitrile EtOAc Ethyl acetate NaOAc Sodium acetate NaBH(OAc)3 Sodium triacetoxyborohydride222 AcOH Acetic acid TLC Thin Layer Chromatography PPh3 Triphenylphosphine DIAD Diisopropyl azodicarboxylate HOBT 1-Hydroxybenzotriazole EDCI N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride DIEA N, N-Diisopropylethylamine DMF Dimethylformamide AlMe3 Trimethylaluminum Py Pyridine ODS Octa-decyl Silica

[1574]

[1575] Materials and Methods

[1576] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at RT unless otherwise stated. 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.

[1577] All reagents were not further purified, unless otherwise noted.1H-NMR spectra were obtained in DMSO-d6 or CDCl3at room temperature on a Bruker 400 MHz instrument. LC-MS conditions are described below:

[1578]

[1579] LCMS Method A：

[1580] LCMS Column: SHIMADZU Xtimate C182.1*30 mm, 3 um

[1581] Mobile Phase: Solvent A: Water (4 L) + TFA (1.5 mL)

[1582] Solvent B: Acetonitrile (4 L) + TFA (0.75 mL)

[1583] Flow Rate: 0.8 mL / min223

[1584] Run time: Gradient 10% - 80% (solvent B) over 6 minutes and holding at 80% for 0.5 minutes

[1585] Temperature: 50 ℃

[1586]

[1587] LCMS Method B：

[1588] LCMS Column: SHIMADZU Nano Chrom 120 C183.0*30 mm, 3 μm

[1589] Mobile Phase: Solvent A: Water (4 L) + TFA (1.5 mL)

[1590] Solvent B: Acetonitrile (4 L) + TFA (0.75 mL)

[1591] Flow Rate: 0.8 mL / min

[1592] Run time: Gradient 10% - 80% (solvent B) over 6 minutes and holding at 80% for 0.5 minutes

[1593] Temperature: 50 ℃

[1594]

[1595] LCMS Method C：

[1596] LCMS Column: SHIMADZU Xtimate C182.1*30 mm, 3 μm

[1597] Mobile Phase: Solvent A: water (4 L) + TFA (1.5 mL)

[1598] Solvent B: acetonitrile (4 L) + TFA (0.75 mL)

[1599] Flow Rate: 0.8 mL / min

[1600] Run time: Gradient 30%-90% (solvent B) over 6 minutes and holding at 90% for 0.5 minutes

[1601] Temperature: 50 ℃

[1602]

[1603] LCMS Method D：

[1604] LCMS Column: SHIMADZU Nano Chrom 120 C183.0*30 mm, 3μm224

[1605] Mobile Phase: Solvent A: Water (4 L) + TFA (1.5 mL)

[1606] Solvent B: acetonitrile (4 L) + TFA (0.75 mL)

[1607] Flow Rate: 0.8 mL / min

[1608] Run time: Gradient 30%-90% (solvent B) over 6 minutes and holding at 90% for 0.5 minutes

[1609] Temperature: 50 ℃

[1610]

[1611] Preparation Examples

[1612] Preparation of intermediate compounds

[1613] i) Synthesis of tert-butyl N-[(1S)-2,2-difluoro-1-isopropyl-propyl]carbamatepropyl]carbamate

[1617] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (50.00 g, 230.14 mmol) in DCM (1340 mL) were added DIEA (118.97 g, 920.55 mmol, 160.34 mL), EDCI (88.24 g, 460.28 mmol) and HOBt (31.10 g, 230.14 mmol) at 0 °C under N2 atmosphere, then the reaction mixture was stirred at 0 °C for 0.5 h. Then N- methoxymethanamine;hydrochloride (26.94 g, 276.17 mmol) was added to the above mentioned solution, and the resulting mixture was warmed to 20 °C and stirred at 20 °C for 12.5 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in EtOAc (800 mL), then washed with 10% aqueous citric acid225 (500 mL × 3), 10% aqueous NaHCO3(500 mL × 3), saturated aqueous sodium chloride (500 mL × 3), and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl N-[(1S)-1-[methoxy(methyl)carbamoyl]-2-methyl-propyl]carbamate (45 g, 169.75 mmol, 74% yield, 98% purity) as a light yellow oil.

[1618] MS (ESI) m / z = 283.1 [M+Na]+.

[1619] 1H NMR (400 MHz, DMSO-d6) δ = 6.86 (d, J = 8.4 Hz, 1H), 4.29 (br s, 1H), 3.73 (s, 3H), 3.12 (s, 3H), 1.91 (qd, J = 14.0, 6.8 Hz, 1H), 1.38 (s, 9H), 0.85 (dd, J = 12.8, 6.8 Hz, 6H).

[1620]

[1621] Step 2: Synthesis of tert-butyl N-[(1S)-1-acetyl-2-methyl-propyl]carbamate

[1622] This is flow chemistry.

[1623] Solution 1: tert-butyl N-[(1S)-1-[methoxy(methyl)carbamoyl]-2-methyl- propyl]carbamate (45 g, 172.86 mmol) was added to THF (675 mL) under N2;

[1624] Solution 2: MeMgCl (3 M in THF, 230.48 mL) under N2;

[1625] Solution 1 was pumped by Pump 1{S1, P1, 3 mL / min} to flow reactor 1 {FLR1, Others, CSTRs, 12 mL, -10 °C}.

[1626] Solution 2 was pumped by Pump 2{S2, P2, 3 mL / min} to flow reactor 1 {FLR1, Others, CSTRs, 12 mL, -10 °C}.

[1627] The resulting solution was further stirred at flow reactor 2 {FLR2, Others, CSTRs, 60 mL, 15 °C}.

[1628] The residence time of flow reactor 1 was {FLR1, 2 min}.

[1629] The residence time of flow reactor 2 was {FLR2, 10.000 min}.

[1630] The mixture was collected with a bottle (containing sat. NH4Cl) at 0 °C under N2.

[1631] Pump 1 and Pump 2 were started at the same time.

[1632] The pumps were run for 12 minutes and then the reaction mixture was collected.

[1633] After 17 minutes, the collecting of the reaction mixture was stopped.226

[1634] The reaction mixture was quenched with aqueous NH4Cl (200 mL) and diluted with EtOAc (800 mL). The organic phase was washed with saturated aqueous sodium chloride (500 mL × 3), and then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl N-[(1S)-1-acetyl-2-methyl-propyl]carbamate (35.8 g, 142.68 mmol, 83% yield) as a white solid.

[1635] MS (ESI) m / z = 238.1 [M+Na]+.

[1636] 1H NMR (400 MHz, DMSO-d6) δ = 7.15 (d, J = 8.0 Hz, 1H), 3.77 (t, J = 7.2 Hz, 1H), 2.13–2.01 (m, 4H), 0.83 (dd, J = 12.8, 6.8 Hz, 6H).

[1637]

[1638] Step 3: Synthesis of tert-butyl N-[(1S)-2,2-difluoro-1-isopropyl-propyl]carbamate

[1639] To a solution of tert-butyl N-[(1S)-1-acetyl-2-methyl-propyl]carbamate (6.0 g, 27.87 mmol) in DCM (60 mL) was added BAST (30.83 g, 139.35 mmol, 30.52 mL) at 0 °C under nitrogen atmosphere, then the reaction mixture was warmed to 25 °C and stirred at 25 °C for 36 h. TLC (n-hexane: Ethyl acetate = 10:1) showed most of the starting material was consumed, and three new spots were formed. The reaction mixture was poured into saturated NaHCO3 (360 mL) at 0 °C, then extracted with CH2Cl2 (500 mL × 2). The combined organic layers were washed with brine (180 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl N-[(1S)-2,2-difluoro-1-isopropyl- propyl]carbamate (0.54 g, 95% purity) was obtained as a white solid.

[1640] 1H NMR (400 MHz, CDCl3) δ = 4.69 (d, J = 9.6 Hz, 1H), 3.92–3.75 (m, 1H), 2.25– 2.16 (m, 1H), 1.62 (t, J = 18.8 Hz, 3H), 1.47 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H).

[1641]

[1642] Step 4: (S)-2,2-difluoro-4-methylpentan-3-amine

[1643] To a solution of tert-butyl N-[(1S)-2,2-difluoro-1-isopropyl-propyl]carbamate (0.54 g, 2.28 mmol) in DCM (4 mL) was added HCl / dioxane (2 M, 6 mL) under nitrogen atmosphere, then the reaction mixture was stirred at 25 °C for 12 h. TLC (Commercial227 hexanes : Ethyl acetate = 10:1) showed the starting material was consumed, and a new spot was formed. The reaction mixture was concentrated under reduced pressure to obtain (3S)- 2,2-difluoro-4-methyl-pentan-3-amine (355 mg, 1.88 mmol, 83% yield, HCl) as a white solid, which was directly used for the next step without being further purified.

[1644] 1H NMR (400 MHz, CDCl3) δ = 8.97 (br s, 3H), 3.45–3.24 (m, 1H), 2.40–2.21 (m, 1H), 1.84 (t, J = 19.2 Hz, 3H), 1.23 (dd, J = 10.4, 7.2 Hz, 6H).

[1645]

[1646] ii) Synthesis of 6,6-dimethylpiperazin-2-yl)methanol, e

[1649] To a solution of tert-butyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (10 g, 53.41 mmol) in MeOH (100 mL) was added BnNH2 (5.72 g, 53.41 mmol, 5.82 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min under N2 atmosphere. Then228 NaBH(OAc)3 (16.98 g, 80.11 mmol) was added to the above mentioned mixture in batches over 0.5 h. The reaction mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was poured into H2O (150 mL) and extracted with Ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a tert-butyl N-[2-(benzylamino)-1,1-dimethyl-ethyl]carbamate (15 g, 50.65 mmol, 95% yield) as a white solid.

[1650] 1H NMR (400 MHz, CDCl3) δ = 7.53–7.49 (m, 2H), 7.42–7.37 (m, 3H), 4.94 (br s, 1H), 4.17 (s, 2H), 3.08 (s, 2H), 1.42 (s, 6H), 1.40 (s, 9H).

[1651]

[1652] Step 2: Synthesis of tert-butyl N-[2-[benzyl-(2-chloroacetyl)amino]-1,1-dimethyl- ethyl]carbamate

[1653] To a solution of tert-butyl N-[2-(benzylamino)-1,1-dimethyl-ethyl]carbamate (10 g, 35.92 mmol) in THF (100 mL) was added TEA (7.27 g, 71.84 mmol, 10.00 mL) at 0 °C. Then 2-chloroacetyl chloride (4.46 g, 39.51 mmol, 3.15 mL) was added dropwise over 0.5 h to the above mentioned mixture. The reaction mixture was stirred at 0 °C for 2 h under N2 atmosphere. The reaction mixture was poured into H2O (120 mL) and extracted with Ethyl acetate (120 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a tert-butyl N-[2-[benzyl-(2-chloroacetyl)amino]-1,1-dimethyl-ethyl]carbamate (12.75 g, crude) as a brown oil.

[1654] MS (ESI) m / z = 355.2 [M+H]+.

[1655]

[1656] Step 3: Synthesis of tert-butyl 4-benzyl-2,2-dimethyl-5-oxo-piperazine-1-carboxylate

[1657] To a solution of tert-butyl N-[2-[benzyl-(2-chloroacetyl)amino]-1,1-dimethyl- ethyl]carbamate (19.12 g, 53.88 mmol) in MeCN (260 mL) was added Cs2CO3 (35.11 g, 107.76 mmol). The mixture was degassed and purged with N23 times. The reaction mixture was stirred at 60 °C for 4 h under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain the crude product (9 g).229

[1658] The crude product was further purified by flash silica gel chromatography to produce tert-butyl 4-benzyl-2,2-dimethyl-5-oxo-piperazine-1-carboxylate (3.23 g, 7.51 mmol, 14% yield) as a yellow oil.

[1659] MS (ESI) m / z = 263.1 [M-tBu+H]+.

[1660]

[1661] Step 4: Synthesis of tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2-dimethyl-5-oxo- piperazine-1-carboxylate

[1662] To a solution of tert-butyl 4-benzyl-2,2-dimethyl-5-oxo-piperazine-1-carboxylate (2.23 g, 7.00 mmol) in THF (35 mL) was added dropwise LiHMDS (1 M, 10.51 mL, in hexane solution) at -70 °C. The mixture was degassed and purged with N23 times. The reaction mixture was stirred at -70 °C for 30 min under N2 atmosphere. Then chloromethoxymethylbenzene (1.65 g, 10.51 mmol, 1.45 mL) was added dropwise to the above mentioned mixture. The mixture was degassed and purged with N23 times. The reaction mixture was stirred at -70 °C for 1 h under N2 atmosphere. The reaction mixture was quenched with HCl aq. (1 M, 25 mL) and diluted with H2O (100 mL). Then the mixture was extracted with Ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to produce the crude product (3.25 g, 33.5% purity).

[1663] The crude product was dissolved in MeCN (10 mL) and further purified by Prep-HPLC (column: 58-Phenomenex Gemini NX C18150×40mm,5μm;mobile phase: [H2O(0.2% FA)-ACN];gradient:62%-82% B over 11.0 min) to produce tert-butyl 4-benzyl-6- (benzyloxymethyl)-2,2-dimethyl-5-oxo-piperazine-1-carboxylate (1.44 g, 3.25 mmol, 46% yield) as a yellow oil.

[1664] MS (ESI) m / z = 439.3 [M+H]+.

[1665] 1H NMR (400 MHz, CDCl3) δ = 7.35–7.27 (m, 4H), 7.26–7.24 (m, 6H), 4.89 (d, J = 14.8 Hz, 1H), 4.64 (t, J = 3.2 Hz, 1H), 4.58–4.54 (m, 1H), 4.51–4.47 (m, 1H), 4.39 (d, J = 14.8 Hz, 1H), 3.96–3.91 (m, 1H), 3.89–3.83 (m, 2H), 2.57 (d, J = 13.2 Hz, 1H), 1.45 (s, 9H), 1.43 (s, 3H), 1.24 (s, 3H).

[1666] 230

[1667] Step 5: Synthesis of tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2-dimethyl-piperazine- 1-carboxylate

[1668] To a solution of tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2-dimethyl-5-oxo- piperazine-1-carboxylate (1.21 g, 2.76 mmol) in THF (14 mL) was added dropwise BH3- Me2S (10 M, 551.81 μL, in DMS solution) at 0 °C. The mixture was degassed and purged with N23 times. The reaction mixture was stirred at 20 °C for 1 h and 50 °C for 2 h under N2 atmosphere. The reaction mixture was quenched with MeOH (15 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h and 50 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with commercial hexanes (3 mL) at 20 °C for 0.5 h. The suspension was filtered and the filter cake was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography to obtain tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2-dimethyl- piperazine-1-carboxylate (1.13 g, 2.63 mmol, 96% yield) as a yellow oil.

[1669] MS (ESI) m / z = 425.4 [M+H]+.

[1670] 1H NMR (400 MHz, CDCl3) δ = 7.36–7.28 (m, 7H), 7.26–7.21 (m, 3H), 4.47 (q, J = 12.0 Hz, 2H), 4.20–4.13 (m, 1H), 3.92–3.86 (m, 1H), 3.55–3.50 (m, 1H), 3.45–3.38 (m, 1H), 3.35–3.25 (m, 1H), 3.10–3.05 (m, 1H), 2.41 (dd, J = 11.6, 2.4 Hz, 1H), 2.13–2.08 (m, 1H), 1.96–1.80 (m, 1H), 1.44 (s, 9H), 1.38 (s, 3H), 1.25 (s, 3H).

[1671]

[1672] Step 6: Synthesis of 1-benzyl-5-(benzyloxymethyl)-3,3-dimethyl-piperazine

[1673] To a solution of tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2-dimethyl-piperazine-1- carboxylate (1.128 g, 2.66 mmol) in DCM (12 mL) was added TFA (3 mL). The mixture was degassed and purged with N23 times. The reaction mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain 1-benzyl-5-(benzyloxymethyl)-3,3-dimethyl-piperazine (1.16 g, crude, TFA) as a yellow oil.

[1674] MS (ESI) m / z = 325.6 [M+H]+.

[1675] 231

[1676] Step 7: Synthesis of 6,6-dimethylpiperazin-2-yl)methanol

[1677] To a solution of 1-benzyl-5-(benzyloxymethyl)-3,3-dimethyl-piperazine (1.16 g, 2.65 mmol, TFA) in HFIP (11.6 mL) was added Pd / C (1.78 g, 1.67 mmol, 10% purity) under Ar2 atmosphere. The suspension was degassed and purged with Ar 3 times. Then the suspension was degassed and purged with H23 times. The mixture was stirred under H2 (50 Psi) at 50 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was slurried with commercial hexanes (5 mL) at 25 °C for 30 min. The mixture was filtered. The filter cake was washed with commercial hexanes (2 mL × 2) and concentrated under reduced pressure to obtain (6,6-dimethylpiperazin-2-yl)methanol (673 mg, 2.48 mmol, 94% yield, TFA) as a white solid.

[1678] MS (ESI) m / z = 145.1 [M+H]+.

[1679] 1H NMR (400 MHz, CDCl3) δ = 9.46–8.85 (m, 2H), 5.64 (br s, 1H), 3.68–3.56 (m, 3H), 3.50–3.32 (m, 2H), 3.04–2.79 (m, 2H), 1.42 (s, 3H), 1.38 (s, 3H).

[1680]

[1681] iii) Synthesis of (2R,6R)-1,4-dibenzyl-2,6-bis(methoxymethyl)piperazine & (2R,6S)-1,4-dibenzyl-2,6-bis(methoxymethyl)piperazinep y , , y y yp p

[1684] To a solution of phenylmethanamine (8.0 g, 74.66 mmol, 8.14 mL) in MeOH (80 mL) was added (2S)-2-(methoxymethyl)oxirane (19.73 g, 223.98 mmol). The reaction mixture232 was stirred at 80 °C for 16 hr under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain (2S)-1-[benzyl-[(2S)-2-hydroxy-3-methoxy- propyl]amino]-3-methoxy-propan-2-ol (21.5 g, 68.29 mmol, 92% yield) as a yellow oil.

[1685] MS (ESI) m / z = 284.1 [M+H]+.

[1686] 1H NMR (400 MHz, DMSO-d6) δ = 7.37–7.19 (m, 5H), 4.60 (d, J = 4.4 Hz, 2H), 3.75–3.66 (m, 2H), 3.62 (q, J = 14.0 Hz, 2H), 3.31–3.24 (m, 3H), 3.21 (s, 6H), 3.19–3.15 (m, 1H), 2.49–2.43 (m, 2H), 2.40–2.32 (m, 2H).

[1687]

[1688] Step 2: Synthesis of (2S,2'S)-(benzylazanediyl)bis(3-methoxypropane-1,2-diyl) diethanesulfonate

[1689] To a solution of (2S)-1-[benzyl-[(2S)-2-hydroxy-3-methoxy-propyl]amino]-3- methoxy-propan-2-ol (4.0 g, 14.12 mmol) in DCM (40 mL) were added TEA (4.29 g, 42.35 mmol, 5.89 mL) and ethanesulfonyl chloride (5.45 g, 42.35 mmol, 4.01 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 40 min under nitrogen atmosphere to obtain a brown suspension. The reaction mixture was concentrated under reduced pressure at 25 °C to obtain [(1S)-1-[[benzyl-[(2S)-2-ethylsulfonyloxy-3- methoxy-propyl]amino]methyl]-2-methoxy-ethyl] ethanesulfonate (6.60 g, crude) as a brown oil, which was directly used for the next step without further purification.

[1690] MS (ESI) m / z = 468.1 [M+H]+.

[1691]

[1692] Step 3: Synthesis of (2R,6R)-1,4-dibenzyl-2,6-bis(methoxymethyl)piperazine & (2R,6S)-1,4-dibenzyl-2,6-bis(methoxymethyl)piperazine

[1693] To a solution of [(1S)-1-[[benzyl-[(2S)-2-ethylsulfonyloxy-3-methoxy- propyl]amino]methyl]-2-methoxy-ethyl] ethanesulfonate (6.60 g, crude) in EtOH (94 mL) were added TEA (5.71 g, 56.46 mmol, 7.86 mL) and BnNH2(8.10 g, 21.17 mmol, 8.24 mL). The reaction mixture was heated to 80 °C and stirred for 2 hr under nitrogen atmosphere to obtain a brown suspension. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel233 chromatography to obtain a crude product (1.32 g, the mixture of (2R,6R)-1,4-dibenzyl- 2,6-bis(methoxymethyl)piperazine & (2R,6S)-1,4-dibenzyl-2,6- bis(methoxymethyl)piperazine. The mixture was further purified by Prep-SFC (column: DAICEL CHIRALPAK AY-H(250mm﹡30mm,10um);mobile phase: [CO2-EtOH(0.1% NH3·H2O)]; B%:20%, isocratic elution mode) to obtain (2R,6R)-1,4-dibenzyl-2,6- bis(methoxymethyl)piperazine (605 mg, 1.71 mmol, 12% yield) as a yellow oil.

[1694] MS (ESI) m / z = 355.3 [M+H]+.

[1695] 1H NMR (400 MHz, DMSO-d6) δ = 7.47–7.12 (m, 10H), 3.92 (d, J = 14.8 Hz, 1H), 3.67 (d, J = 14.8 Hz, 1H), 3.53–3.47 (m, 3H), 3.46–3.40 (m, 3H), 3.14 (s, 6H), 2.87–2.79 (m, 2H), 2.43–2.38 (m, 2H), 2.35–2.24 (m, 2H).

[1696] And (2S,6R)-1,4-dibenzyl-2,6-bis(methoxymethyl)piperazine (510 mg, 1.36 mmol, 10% yield) as a yellow oil.

[1697] MS (ESI) m / z = 355.3 [M+H]+.

[1698] 1H NMR (400 MHz, DMSO-d6) δ = 7.41–7.13 (m, 10H), 3.87 (d, J = 14.0 Hz, 2H), 3.59 (dd, J = 9.6, 4.4 Hz, 2H), 3.46–3.41 (m, 2H), 3.41–3.37 (m, 4H), 3.16 (s, 6H), 2.65– 2.58 (m, 2H), 2.37 (d, J = 3.2 Hz, 1H), 2.34 (d, J = 3.2 Hz, 1H).

[1699]

[1700] iv) Synthesis of (6S)-6-methyl-2-oxa-5,8-diazaspiro[3.5]nonane234

[1704] 1H-imidazole (5.08 g, 74.58 mmol) and PPh3 (19.56 g, 74.58 mmol) were dissolved in THF (55 mL) under nitrogen atmosphere and cooled to 0 °C. I2 (20.51 g, 80.79 mmol) was added in portions and the mixture was stirred for 30 min. A solution of tert-butyl N-[(1S)- 2-hydroxy-1-methyl-ethyl]carbamate (10.89 g, 62.15 mmol) in THF (218 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 4 h at this temperature, and then was warmed to 25 °C and stirred for further 8 h under N2 atmosphere. The reaction mixture was filtered and the filter cake was washed with EtOAc (30 mL × 3). The combined filtrate was diluted with EtOAc (50 mL) and washed with saturated aqueous Na2S2O3 (160 mL × 2), 10 % aqueous citric acid (160 mL), brine (160 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl N-[(1S)-2-iodo-1-methyl- ethyl]carbamate (8.69 g, 28.95 mmol, 47% yield) as a brown oil.

[1705] MS (ESI) m / z = 230.0 [M-tBu+H]+.

[1706] 1H NMR (400 MHz, CDCl3) δ = 4.60 (br s, 1H), 3.53 (br s, 1H), 3.41 (br s, 1H), 3.32– 3.28 (m, 1H), 1.46 (s, 9H), 1.25 (d, J = 6.4 Hz, 3H).

[1707] 235

[1708] Step 2: Synthesis of tert-butyl N-[(1S)-2-[benzyl(trimethylsilylmethyl)amino]-1- methyl-ethyl]carbamate

[1709] To a solution of 1-phenyl-N-(trimethylsilylmethyl)methanamine (5.89 g, 30.48 mmol) in MeCN (174 mL) were added TEA (6.17 g, 60.96 mmol, 8.48 mL) and tert-butyl N-[(1S)- 2-iodo-1-methyl-ethyl]carbamate (8.69 g, 30.48 mmol) at 0 °C. The mixture was degassed and purged with N2 for times. Then the reaction mixture was stirred at 90 °C for 12 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain a crude product (660 mg), the crude product was further purified by Prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [H2O (0.05% NH3·H2O)-ACN]; gradient:70%-100% B over 9.0 min) to obtain tert-butyl N-[(1S)-2- [benzyl(trimethylsilylmethyl)amino]-1-methyl-ethyl]carbamate (270 mg, 693.16 μmol, 3% yield) as a white solid.

[1710] MS (ESI) m / z = 351.3 [M+H]+.

[1711] 1H NMR (400 MHz, DMSO-d6) δ = 7.30–7.27 (m, 4H), 7.24–7.20 (m, 1H), 6.52 (d, J = 8.0 Hz, 1H), 3.63–3.60 (m, 1H), 3.57 (d, J = 13.6 Hz, 1H), 3.31 (d, J = 13.6 Hz, 1H), 2.18 (d, J = 7.2 Hz, 2H), 1.97 (d, J = 15.2 Hz, 1H), 1.82 (d, J = 14.8 Hz, 1H), 1.37 (m, 9H), 0.98 (d, J = 6.4 Hz, 3H), 0.02 (s, 9H).

[1712]

[1713] Step 3: Synthesis of (2S)-N1-benzyl-N1-(trimethylsilylmethyl)propane-1,2-diamine

[1714] To a solution of tert-butyl N-[(1S)-2-[benzyl(trimethylsilylmethyl)amino]-1-methyl- ethyl]carbamate (260 mg, 741.65 μmol) in DCM (2.6 mL) was added TFA (1.33 g, 11.67 mmol, 866.67 μL). The mixture was degassed and purged with N23 times. The mixture was stirred under N2atmosphere at 25 °C for 2 h. The reaction mixture was quenched with sat. NaHCO3 (aq) (15 mL) and extracted with Ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain (2S)-N1-benzyl-N1- (trimethylsilylmethyl)propane-1,2-diamine (240 mg, crude) as a yellow oil, which was directly used for the next step without further purification.

[1715] MS (ESI) m / z = 251.2 [M+H]+.236

[1716] 1H NMR (400 MHz, DMSO-d6) δ = 7.35–7.29 (m, 4H), 7.27–7.23 (m, 1H), 6.33 (br s, 2H), 3.52 (d, J = 13.6 Hz, 1H), 3.42 (d, J = 13.6 Hz, 1H), 3.18 (q, J = 6.8 Hz, 1H), 2.29– 2.23 (m, 2H), 1.99–1.93 (m, 2H), 1.05 (d, J = 6.4 Hz, 3H), 0.05 (s, 9H).

[1717]

[1718] Step 4: Synthesis of (6S)-8-benzyl-6-methyl-2-oxa-5,8-diazaspiro[3.5]nonane

[1719] Step 1: To a 40 mL vial were added bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridyl]phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (8.96 mg, 7.99 μmol) and 4A MS (100 mg).

[1720] Step 2: (2S)-N1-benzyl-N1-(trimethylsilylmethyl)propane-1,2-diamine (200 mg, 798.55 μmol) + oxetan-3-one (200 mg, 2.78 mmol) was dissolved in MeCN (12 mL) : CF3CH2OH (4 mL);

[1721] Step 3: The reaction vial was capped, and the capped vial was placed in a Penn OC reactor for 16 hr at 25 °C. [450 nm, 1000 rpm stirring, 100% intensity of light, max fan cooling]

[1722] The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain (6S)-8-benzyl-6-methyl- 2-oxa-5,8-diazaspiro[3.5]nonane (52 mg, 185.78 μmol, 23% yield) as a brown oil.

[1723] MS (ESI) m / z = 233.1 [M+H]+.

[1724] 1H NMR (400 MHz, CDCl3) δ = 7.36–7.28 (m, 5H), 4.65–4.51 (m, 2H), 4.35 (q, J = 6.8 Hz, 2H), 3.62–3.46 (m, 2H), 3.17 (d, J = 10.4 Hz, 1H), 2.96–2.92 (m, 1H), 2.72 (d, J = 10.8 Hz, 1H), 2.06 (d, J = 10.8 Hz, 1H), 1.75 (t, J = 10.4 Hz, 1H), 1.29 (br s, 1H), 1.05 (d, J = 6.4 Hz, 3H).

[1725]

[1726] Step 4: Synthesis of (6S)-6-methyl-2-oxa-5,8-diazaspiro[3.5]nonane

[1727] To a solution of (6S)-8-benzyl-6-methyl-2-oxa-5,8-diazaspiro[3.5]nonane (50 mg, 215.22 μmol) in HFIP (3 mL) were added Pd / C (10 mg, 10% purity, wet) and Pd(OH)2 (10 mg) under Ar atmosphere. The suspension was degassed and purged with H23 times. Then the mixture was stirred under H2 (15 Psi) at 25 °C for 12 h. The reaction mixture was filtered through a celite, and washed with MeOH (8 mL × 3). Then the filtrate was concentrated237 under reduced pressure to obtain (6S)-6-methyl-2-oxa-5,8-diazaspiro[3.5]nonane (35 mg, crude) as a light yellow oil, which was directly used for the next step without further purification.

[1728] MS (ESI) m / z = 143.2 [M+H]+.

[1729] 1H NMR (400 MHz, CDCl3) δ = 4.70 (d, J = 6.4 Hz, 1H), 4.54 (br d, J = 6.0 Hz, 1H), 4.42–4.36 (m, 1H), 4.36–4.31 (m, 1H), 3.35 (d, J = 11.6 Hz, 1H), 2.88–2.83 (m, 1H), 2.82– 2.81 (m, 1H), 2.76–2.67 (m, 1H), 2.32 (t, J = 10.8 Hz, 1H), 1.03 (d, J = 6.0 Hz, 3H).

[1730]

[1731] v) Synthesis of tert-butyl (6S)-6-methyl-2,5,8-triazaspiro[3.5]nonane-2- carboxylatep y y y y y (nitromethyl)azetidine-1-carboxylate

[1735] To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (8.76 g, 51.17 mmol) in nitromethane (57.67 g, 944.77 mmol, 51.17 mL) was added TEA (1.04 g, 10.23 mmol, 1.42 mL) at 25 °C under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 1 hr under nitrogen atmosphere. Then the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in DCM (204 mL) and the reaction238 mixture was cooled to -78 °C. TEA (10.36 g, 102.34 mmol, 14.24 mL) was added, then followed by the dropwise addition of a solution of methylsulfonyl methanesulfonate (9.36 g, 53.73 mmol) in DCM (54 mL). The reaction mixture was stirred at -78 °C for 1.5 hr under nitrogen atmosphere. Meanwhile, to a solution of methyl (2S)-2- aminopropanoate;hydrochloride (14.28 g, 102.34 mmol) in DCM (204 mL) was added TEA (10.36 g, 102.34 mmol, 14.24 mL) and the resulting solution was stirred at 25 °C for 10 min. The resulting solution was added to the above reaction mixture via syringe at - 78 °C under nitrogen atmosphere. The reaction mixture was warmed to 25 °C and stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (800 mL) and stirred for 10 min. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (500 mL × 2). The combined organics were washed with saturated NaHCO3 (500 mL × 2) and brine (400 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl 3-[[(1S)-2-methoxy-1-methyl-2-oxo-ethyl]amino]-3- (nitromethyl)azetidine-1-carboxylate (3.32 g, 4.82 mmol, 9% yield,) as a yellow oil.

[1736] MS (ESI) m / z = 261.9 [M-tBu+H]+.

[1737]

[1738] Step 2: Synthesis of tert-butyl (6S)-6-methyl-7-oxo-2,5,8-triazaspiro[3.5]nonane-2- carboxylate

[1739] To a solution of tert-butyl 3-[[(1S)-2-methoxy-1-methyl-2-oxo-ethyl]amino]-3- (nitromethyl)azetidine-1-carboxylate (3.32 g, 10.46 mmol) in MeOH (90 mL) was added Raney-Ni (1.0 g, contain10% water) under Ar atmosphere. The suspension was degassed and purged with H23 times. Then the mixture was stirred under H2 (50 Psi) at 25 °C for 16 h. The reaction mixture was filtered through a plug of Celite eluting with EtOAc (100 mL × 3) and the filtrate was concentrated under reduced pressure to obtain tert-butyl (6S)-6- methyl-7-oxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate (2.67 g, crude) as a yellow solid, which was directly used for the next step without further purification.

[1740] MS (ESI) m / z = 200.2 [M-tBu+H]+.

[1741] 239

[1742] Step 3: Synthesis of 5-benzyl 2-(tert-butyl) (S)-6-methyl-7-oxo-2,5,8- triazaspiro[3.5]nonane-2,5-dicarboxylate

[1743] To a solution of tert-butyl (6S)-6-methyl-7-oxo-2,5,8-triazaspiro[3.5]nonane-2- carboxylate (2.67 g, crude) in THF (30 mL) and H2O (10 mL) were added NaHCO3(2.64 g, 31.37 mmol) and CbzCl (2.68 g, 15.69 mmol, 2.24 mL). The reaction mixture was stirred at 25 °C for 12 hr under nitrogen atmosphere. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (80 mL × 3). The combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain 5-benzyl 2-(tert-butyl) (S)-6-methyl-7-oxo-2,5,8-triazaspiro[3.5]nonane-2,5- dicarboxylate (3.03 g, 7.22 mmol, 69% yield) as a light yellow oil.

[1744] MS (ESI) m / z = 412.0 [M+Na]+.

[1745] 1H NMR (400 MHz, DMSO-d6) δ = 8.27 (d, J = 2.8 Hz, 1H), 7.41–7.31 (m, 5H), 5.15 (d, J = 2.4 Hz, 2H), 4.53–4.40 (m, 1H), 4.25 (q, J = 7.6 Hz, 1H), 4.20–4.18 (m, 1H), 3.80 (d, J = 8.0 Hz, 1H), 3.55 (d, J = 6.4 Hz, 1H), 3.43 (dd, J = 14.4, 6.0 Hz, 1H), 3.17 (d, J = 6.4 Hz, 1H), 1.37 (s, 9H), 1.30 (d, J = 7.2 Hz, 3H).

[1746]

[1747] Step 4: Synthesis of 5-benzyl 2-(tert-butyl) (S)-6-methyl-2,5,8-triazaspiro[3.5]nonane- 2,5-dicarboxylate

[1748] The reaction was a flow chemistry:

[1749] Solution 1: 5-benzyl 2-(tert-butyl) (S)-6-methyl-7-oxo-2,5,8-triazaspiro[3.5]nonane- 2,5-dicarboxylate (3.03 g, 7.78 mmol) in THF (30 mL);

[1750] Solution 2: BH3-Me2S (10 M, 2.33 mL) in THF (2.33 mL).

[1751] Solution 1 was pumped by Pump 1 {S1, P1, 2.952 mL / min} to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1 / 8")mm, 59.84055 mL, 60.0°C}.

[1752] Solution 2 was pumped by Pump 2 {S2, P2, 3.032 mL / min} to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1 / 8")mm, 59.84055 mL, 60.0°C}.

[1753] The residence time of flow reactor 1 {FLR1, 10.0 min}.240

[1754] The mixture was collected with a bottle (Quenched by MeOH (40 mL) at 0 °C).

[1755] The reaction mixture was quenched with MeOH (40 mL) at 0 °C. Then the reaction mixture was stirred at 25 °C for 1 hr and at 50°C for 2 hr under N2 atmosphere. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain 5-benzyl 2-(tert-butyl) (S)-6-methyl-2,5,8- triazaspiro[3.5]nonane-2,5-dicarboxylate (821 mg, 1.79 mmol, 23% yield) as a colorless oil.

[1756] MS (ESI) m / z = 376.2 [M+H]+.

[1757]

[1758] Step 5: Synthesis of tert-butyl (6S)-6-methyl-2,5,8-triazaspiro[3.5]nonane-2- carboxylate

[1759] To a solution of 5-benzyl 2-(tert-butyl) (S)-6-methyl-2,5,8-triazaspiro[3.5]nonane-2,5- dicarboxylate (150 mg, 399.51 μmol) in HFIP (6 mL) was added Pd / C (89 mg, 10% purity, wet) under Ar atmosphere. The suspension was degassed and purged with H23 times. Then the mixture was stirred under H2 (15 Psi) at 25 °C for 12 h. The reaction mixture was filtered through a celite, and washed with MeOH (8 mL × 3), the filtrate was concentrated under reduced pressure to obtain tert-butyl (6S)-6-methyl-2,5,8-triazaspiro[3.5]nonane-2- carboxylate (98 mg, crude) as a light yellow oil, which was directly used for the next step without further purification.

[1760] MS (ESI) m / z = 242.3 [M+H]+.

[1761] 1H NMR (400 MHz, CDCl3) δ = 4.41–4.30 (m, 1H), 3.99–3.90 (m, 1H), 3.76–3.67 (m, 2H), 3.57 (d, J = 9.6 Hz, 1H), 3.05 (d, J = 12.0 Hz, 1H), 2.91–2.82 (m, 1H), 2.71 (br d, J = 12. Hz, 1H), 2.32 (br t, J = 11.2 Hz, 1H), 1.44 (m, 9H), 1.03 (d, J = 6.4 Hz, 3H).

[1762]

[1763] vi) Synthesis of (1-methoxycyclopropyl)-piperazin-1-yl-methanone241azine-1- carboxylate

[1767] To a mixture of tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol) and 1- methoxycyclopropanecarboxylic acid (374.06 mg, 3.22 mmol) in DCM (12 mL) were added DIEA (1.73 g, 13.42 mmol, 2.34 mL) and HATU (1.22 g, 3.22 mmol). The reaction mixture was stirred at 25 °C for 12 h under nitrogen atmosphere. The reaction mixture was poured into water (30 mL) and extracted with DCM (30 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl 4-(1- methoxycyclopropanecarbonyl)piperazine-1-carboxylate (0.82 g, 2.61 mmol, 97% yield) as a colorless oil.

[1768] MS (ESI) m / z = 285.2 [M+H]+.

[1769] 1H NMR (400 MHz, CDCl3) δ = 3.91–3.57 (m, 4H), 3.46 (br d, J = 4.0 Hz, 4H), 3.32 (s, 3H), 1.48 (s, 9H), 1.17–1.07 (m, 2H), 1.00–0.90 (m, 2H).

[1770]

[1771] Step 2: Synthesis of (1-methoxycyclopropyl)-piperazin-1-yl-methanone

[1772] To a solution of tert-butyl 4-(1-methoxycyclopropanecarbonyl)piperazine-1- carboxylate (400 mg, 1.41 mmol) in DCM (3 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 1 hr under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in CH3CN (5 mL) and H2O (4 mL), then freeze-dried to obtain (1- methoxycyclopropyl)-piperazin-1-yl-methanone (334 mg, 895.87 μmol, 64% yield, TFA) as a white solid.242

[1773] 1H NMR (400 MHz, DMSO-d6): 8.82 (br s, 2H), 3.79 (br s, 4H), 3.24 (s, 3H), 3.15 (br s, 4H), 1.99 (s, 1H), 1.26 (d, J = 6.0 Hz, 1H), 1.05–0.99 (m, 2H), 0.94–0.88 (m, 2H).

[1774]

[1775] vii) Synthesis of 6,6-dimethylpiperazine-2-carboxylic acid & methyl 6,6- dimethylpiperazine-2-carboxylate

[1776]

[1777]

[1778] Step 1: Synthesis of 6,6-dimethylpiperazine-2-carbonitrile

[1779] To a solution of 2-methylpropane-1,2-diamine (4.98 g, 56.45 mmol, 5.85 mL) in THF (100 mL) was added 2-chloroprop-2-enenitrile (3.80 g, 43.42 mmol, 3.47 mL) dropwise under N2 atmosphere. The reaction mixture was degassed and purged with N23 times, and the reaction mixture was stirred at 50 °C for 4 h under nitrogen atmosphere to obtain a light yellow suspension. The reaction mixture was not worked up and was directly used for the next step. 6,6-dimethylpiperazine-2-carbonitrile (6.04 g, crude) was obtained as a light-yellow suspension.

[1780] MS (ESI) m / z = 140.2 [M+H]+.

[1781]

[1782] Step 2: Synthesis of 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2- carbonitrile

[1783] To a suspension of 6,6-dimethylpiperazine-2-carbonitrile (6.04 g, crude) in THF (100 mL) were added Et3N (8.78 g, 86.78 mmol, 12.08 mL) and 4-nitrobenzenesulfonyl chloride243 (12.50 g, 56.41 mmol) under N2atmosphere. The suspension was degassed and purged with N23 times. Then the reaction mixture was stirred at 25 °C for 5 h under nitrogen atmosphere. The reaction mixture was poured into H2O (120 mL) and was extracted with EtOAc (150 mL × 3). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2- carbonitrile (1.85 g, 4.15 mmol, 9.57% yield, 72.8% purity) as a yellow solid.

[1784] MS (ESI) m / z = 325.1 [M+H]+.

[1785] 1H NMR (400 MHz, DMSO-d6) δ = 8.46 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 4.27–4.22 (m, 1H), 3.26–3.17 (m, 1H), 3.06–2.98 (m, 2H), 2.69 (q, J = 11.2 Hz, 2H), 1.17 (s, 3H), 1.04 (s, 3H).

[1786]

[1787] Step 3: Synthesis of 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-carboxylic acid

[1788] To a solution of 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-carbonitrile (0.83 g, 2.56 mmol) in AcOH (10 mL) was added HCl (6 M, 16.60 mL) under N2atmosphere to obtain a purple solution. The reaction mixture was stirred at 130 °C for 1 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-carboxylic acid (920 mg, crude, HCl) as a purple solid, which was directly used for the next step without further purification.

[1789] MS (ESI) m / z = 344.1 [M+H]+.

[1790]

[1791] Step 4: Synthesis of benzyl 1-benzyl-6,6-dimethyl-4-(4-nitrophenyl)sulfonyl- piperazine-2-carboxylate

[1792]

[1793] To a solution of 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-carboxylic acid (920 mg, crude, HCl) in CH3CN (20 mL) were added bromomethylbenzene (1.60 g, 9.38 mmol, 1.11 mL), K2CO3(2.96 g, 21.44 mmol) and KI (1.11 g, 6.70 mmol) under N2244 atmosphere. The reaction mixture was stirred at 85 °C for 12 h under N2atmosphere. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (80 mL × 3). The combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain benzyl 1-benzyl-6,6-dimethyl-4-(4- nitrophenyl)sulfonyl-piperazine-2-carboxylate (848 mg, 983.07 μmol, 36.69% yield, 60.7% purity) as a brown oil.

[1794] MS (ESI) m / z = 524.1 [M+H]+.

[1795]

[1796] Step 5: Synthesis of benzyl 1-benzyl-6,6-dimethyl-piperazine-2-carboxylate

[1797] To a solution of benzyl 1-benzyl-6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine- 2-carboxylate (848 mg, 1.62 mmol) in CH3CN (12 mL) and DMF (1.2 mL) were added K2CO3(447.68 mg, 3.24 mmol) and 4-methoxybenzenethiol (681.20 mg, 4.86 mmol) under N2 atmosphere. Then the mixture was stirred at 40 °C for 12 h under N2 atmosphere. [=The reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL × 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 flash silica gel chromatography to obtain benzyl 1-benzyl-6,6-dimethyl- piperazine-2-carboxylate (378 mg, 1.07 mmol, 65.93% yield, 95.6% purity) as a colorless oil.

[1798] MS (ESI) m / z = 339.2 [M+H]+.

[1799]

[1800] Step 6: Synthesis of 6,6-dimethylpiperazine-2-carboxylic acid

[1801] To a solution of benzyl 1-benzyl-6,6-dimethyl-piperazine-2-carboxylate (200 mg, 590.94 μmol) in HFIP (10 mL) was added wet Pd / C (60 mg, 10% purity) under Ar2atmosphere. The suspension was degassed and purged with Ar 3 times. Then the suspension was degassed and purged with H23 times. The reaction mixture was stirred under H2 (50 Psi) at 50 °C for 12 h. Then the reaction mixture was filtered and washed with MeOH (5 mL × 3), the filtrate was concentrated under reduced pressure to obtain 6,6-245 dimethylpiperazine-2-carboxylic acid (100 mg, crude) as a white solid, which was directly used for the next step without further purification.

[1802] MS (ESI) m / z = 159.3 [M+H]+.

[1803] 1H NMR (400 MHz, CD3OD) δ = 3.67 (dd, J = 12.0, 3.6 Hz, 1H), 3.47 (dd, J = 13.6, 3.6 Hz, 1H), 2.87–2.80 (m, 1H), 2.76–2.68 (m, 2H), 1.40 (s, 3H), 1.34 (s, 3H).

[1804]

[1805] Step 7: Synthesis of methyl 6,6-dimethylpiperazine-2-carboxylate

[1806] To a solution of 6,6-dimethylpiperazine-2-carboxylic acid (100 mg, crude) in MeOH (10 mL) was added SOCl2 (300.81 mg, 2.53 mmol) dropwise at 25 °C under N2 atmosphere. Then the reaction mixture was stirred at 50 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain methyl 6,6-dimethylpiperazine- 2-carboxylate (125 mg, crude, 2HCl) as a brown solid, which was directly used for the next step without further purification.

[1807] 1H NMR (400 MHz, CD3OD) δ = 4.84 (dd, J = 12.4, 4.0 Hz, 1H), 3.98 (dd, J = 12.4, 4.0 Hz, 1H), 3.95 (s, 3H), 3.59 (d, J = 14.0 Hz, 1H), 3.44 (t, J = 12.8, 1H), 3.25 (d, J = 14.0 Hz, 1H), 1.60 (s, 6H).

[1808]

[1809] Preparation of Exemplary Compounds

[1810] i) Preparation of Compound 20:

[1811] 3-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- 1-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide246

[1812]

[1813] Sp y p -- -- y-- p p-- --

[1814] A solution of ethyl 2-chloroacetate (10 g, 81.60 mmol) and ethyl formate (6.04 g, 81.60 mmol) in tetrahydrofuran (THF) (150 mL) was stirred at -10°C for 20 min, then t-BuOK (11.90 g, 106.08 mmol) was added in portions so that the temperature of the mixture remained below 0-5 °C. The reaction was warmed to 20 °C for 16 h. The reaction mixture was filtered to obtain a solid which was triturated with EtOAc (100 mL) for 5 h at 25 °C,247 filtered and the solid was dried under vacuum to obtain potassium (Z)-2-chloro-3-ethoxy- 3-oxoprop-1-en-1-olate (14.4 g, 76.3 mmol, 93% yield) as a yellow solid.

[1815] 1H NMR (400 MHz, DMSO-d6): δ = 8.88-8.24 (m, 1H), 4.16 (q, J = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H).

[1816]

[1817] Step 2: Synthesis of Ethyl 6-bromo-8-chloroimidazo[1,2-a]pyridine-3-carboxylate

[1818] To a solution of 5-bromo-3-chloro-pyridin-2-amine (2.14 g, 10.32 mmol) and potassium (Z)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (7.79 g, 41.27 mmol) in EtOH (120 mL) at 25 °C was added H2SO4(3.04 g, 31.95 mmol, 1.66 mL). The reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to 25 °C. EtOH was removed under reduced pressure, water (50 mL) was added and the mixture was extracted with EtOAc (80 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain a residue. The crude residue was purified by column chromatography on silica gel eluting with 0~40% EtOAc in petroleum ether to obtain Ethyl 6-bromo-8-chloroimidazo[1,2-a]pyridine-3-carboxylate (3.17 g, 10.44 mmol, 100% yield) as a white solid.

[1819] MS (ESI) m / z = 304.9 [M+H]+

[1820] 1H NMR (400 MHz, DMSO-d6): δ = 9.24 (s, 1H), 8.301 (s, 1H), 8.05-8.04 (m, 1H), 4.40-4.35 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H).

[1821]

[1822] Step 3: Synthesis of 6-bromo-8-chloro-imidazo[1,2-a]pyridine-3-carbohydrazide

[1823] To a solution of ethyl 6-bromo-8-chloro-imidazo[1,2-a]pyridine-3-carboxylate (1.76 g, 5.81 mmol) in EtOH (35 mL) was added NH2NH2·H2O (3.49 g, 69.73 mmol) at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C under an N2atmosphere for 12 h. The mixture was cooled to 25 °C. The precipitated solid was separated off to obtain the product 6-bromo-8-chloro-imidazo[1,2-a]pyridine-3-carbohydrazide (1.24 g, 4.27 mmol, 73.4% yield) as a white solid.

[1824] MS (ESI) m / z = 291.0 [M+H]+248

[1825] 1H NMR (400 MHz, DMSO-d6): δ = 10.68-9.40 (m, 2H), 8.32 (s, 1H), 7.92 (d, J = 1.6 Hz, 1H), 4.83-4.27 (m, 2H).

[1826]

[1827] Step 4: Synthesis of 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine- 3-carbohydrazide

[1828] To a solution of 6-bromo-8-chloro-imidazo[1,2-a]pyridine-3-carbohydrazide (1.24 g, 4.27 mmol) in THF (30 mL) was added TEA (864 mg, 8.54 mmol) and (2,2-difluoroacetyl) 2,2-difluoroacetate (817.4 mg, 8.54 mmol). The mixture was stirred at 25 °C under an N2atmosphere for 1 h. The mixture was concentrated under reduced pressure to obtain a residue. The crude residue was purified by column chromatography on silica gel eluting with 0~40% EtOAc in petroleum ether to obtain 6-bromo-8-chloro-N'-(2,2- difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide (1.94 g, 5.28 mmol, 99% yield) as a white solid.

[1829] MS (ESI) m / z = 369.0 [M+H]+

[1830] 1H NMR (400 MHz, DMSO-d6): δ = 11.03-10.93 (m, 2H), 9.49 (s, 1H), 8.48 (s, 1H), 8.03 (s, 1H), 6.48 (t, J = 52.8 Hz, 1H).

[1831]

[1832] Step 5: Synthesis of 2-(6-Bromo-8-chloroimidazo[1,2-a]pyridin-3-yl)-5- (difluoromethyl)-1,3,4-selenadiazole

[1833] To a solution 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine-3- carbohydrazide (514 mg, 1.40 mmol) in toluene (14 mL) was added Wollin’s reagent (744 mg, 1.40 mmol) at 25 °C. The mixture was heated to 120 °C and stirred at 120 °C under an N2atmosphere for 16 h. The reaction mixture was diluted with H2O (20 mL), and extracted with DCM (30 mL x 3). The organic phases were dried over anhydrous Na2SO4, filtered and concentrated to obtain a residue. The crude residue was purified by column chromatography on silica gel eluting with 0~40% EtOAc in petroleum ether to obtain 2-(6- Bromo-8-chloroimidazo[1,2-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-selenadiazole (205 mg, 0.50 mmol, 35% yield) as a yellow solid.

[1834] MS (ESI) m / z = 413.9 [M+H]+249

[1835] 1H NMR (400 MHz, CDCl3): δ = 9.91 (d, J = 1.6 Hz, 1H), 8.20 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 6.97 (t, J = 56.0 Hz, 1H).

[1836]

[1837] Step 6: Synthesis of 2-(6-benzylsulfanyl-8-chloro-imidazo[1,2-a]pyridin-3-yl)-5- (difluoromethyl)-1,3,4-selenadiazole

[1838] To a solution of 2-(6-bromo-8-chloro-imidazo[1,2-a]pyridin-3-yl)-5-(difluoromethyl)- 1,3,4-selenadiazole (205 mg, 0.50 mmol) in dioxane (5 mL) were added Pd2(dba)3 (45.5 mg, 0.05 mmol), Xantphos (28.8 mg, 0.05 mmol), BnSH (67.9 mg, 0.55 mmol) and DIPEA (192.7 mg, 1.49 mmol) at 25 °C. The suspension was degassed under vacuum and purged with N2three times. The mixture was heated to 100 °C and stirred at 100 °C under an N2atmosphere for 2 h. The mixture was diluted with H2O (10 mL) and extracted with DCM (30 mL × 3), the combined organic phases were dried over anhydrous Na2SO4and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel eluting with 0~30% EtOAc in petroleum ether to afford 2-(6-benzylsulfanyl-8-chloro-imidazo[1,2-a]pyridin-3-yl)-5-(difluoromethyl)- 1,3,4-selenadiazole (195 mg, 0.43 mmol, 86% yield) as a yellow solid.

[1839] MS (ESI) m / z = 457.0 [M+H]+

[1840] 1H NMR (400 MHz, CDCl3): δ = 9.60 (d, J = 1.3 Hz, 1H), 8.15 (s, 1H), 7.41 (d, J = 1.4 Hz, 1H), 7.28-7.21 (m, 5H), 6.97 (t, J = 56.0 Hz, 1H), 4.14 (s, 2H).

[1841]

[1842] Step 7: Synthesis of 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride

[1843] To a mixture of 2-(6-benzylsulfanyl-8-chloro-imidazo[1,2-a]pyridin-3-yl)-5- (difluoromethyl)-1,3,4-selenadiazole (34.6 mg, 0.08 mmol) in AcOH (0.54 mL) and H2O (0.18 mL) was added NCS (40.5 mg, 0.30 mmol) at 5 °C. The mixture was warmed and stirred at 25 °C under an N2 atmosphere for 4 h. To the reaction mixture was added H2O (10 mL) and the mixture was extracted with DCM (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]imidazo[1,2-a]pyridine-6- sulfonyl chloride (crude) as a yellow solid.250

[1844] MS (ESI) m / z = 432.9 [M+H]+

[1845]

[1846] Step 8: Synthesis of 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-N-(1- methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide

[1847] To a mixture of 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]imidazo[1,2- a]pyridine-6-sulfonyl chloride (0.17 mmol, crude) and 1- methylcyclopropanamine;hydrochloride (27.7 mg, 0.26 mmol) in DCM (1.8 mL) was added TEA (104.3 mg, 1.03 mmol) dropwise at 5 °C. The mixture was warmed to 25 °C and stirred at 25 °C under an N2 atmosphere for 2 h. The reaction 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 afford 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-N-(1- methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (35 mg, 75.63 μmol, 44% yield) as a brown solid.

[1848] MS (ESI) m / z = 467.9 [M+H]+

[1849] 1H NMR (400 MHz, CDCl3): δ = 10.27 (d, J = 1.2 Hz, 1H), 8.30 (s, 1H), 7.88 (d, J= 1.2 Hz, 1H), 6.98 (t, J = 56 Hz, 1H), 5.26 (s, 1H), 1.37 (s, 3H), 0.90-0.83 (2H, m), 0.63- 0.50 (2H, m).

[1850]

[1851] Step 9: Synthesis of tert-butyl (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6-dimethyl- piperazine-1-carboxylate

[1852] To a solution of 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-N-(1- methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (65.5 mg, 0.14 mmol) in dioxane (1.4 mL) was added tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (60.1 mg, 0.28 mmol), Cs2CO3 (137.2 mg, 0.42 mmol) and 1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3- chloropyridine;dichloropalladium (13.7 mg, 0.01 mmol) in one portion at 25 °C. The suspension was degassed under vacuum and purged with N2 three times. The mixture was heated to 100 °C and stirred at 100 °C under an N2 atmosphere for 16 h. The mixture was251 diluted with H2O (10 mL) and extracted with DCM (30 mL × 3), the combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel eluting with 0~50% ethyl acetate in petroleum ether to afford tert-butyl (2S,6S)-4-[3-[5- (difluoromethyl)-1,3,4-selenadiazol-2-yl]-6-[(1- methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6-dimethyl-piperazine-1- carboxylate (17 mg, 26.37 μmol, 19% yield) as a yellow solid.

[1853] MS (ESI) m / z = 646.1 [M+H]+

[1854] 1H NMR (400 MHz, CDCl3): δ = 9.76 (d, J = 1.1 Hz, 1H), 8.09 (s, 1H), 6.96 (t, J = 56.0 Hz, 1H), 6.68 (s, 1H), 5.10 (s, 1H), 4.27 (s, 2H), 4.13–4.02 (m, 4H), 1.51 (s, 9H), 1.37 (s, 3H), 1.31 (d, J = 6.6 Hz, 6H), 0.95-0.93 (m, 2H), 0.60-0.58 (m, 2H).

[1855]

[1856] Step 10: Synthesis of 3-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide

[1857] To a solution of tert-butyl (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]- 6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6-dimethyl-piperazine- 1-carboxylate (17 mg, 26.4 μmol) in DCM (1 mL) was added TFA (121.1 μL). The mixture was stirred at 25 °C under an N2atmosphere for 2 h. To the mixture was added H2O (5 mL) and the mixture was washed with DCM (3 mL x 2). The aqueous phase was adjusted to pH 12 by a saturated NaHCO3 solution, which was extracted with DCM (10 mL x 5). The organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 3-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (13 mg, 23.14 μmol, 88% yield) as a yellow solid.

[1858] MS (ESI) m / z = 546.1 [M+H]+

[1859] 1H NMR (400 MHz, CDCl3): δ = 9.84 (d, J = 0.9 Hz, 1H), 8.16 (s, 1H), 7.09 (t, J = 52.0 Hz, 1H), 6.94 (s, 1H), 5.40 (s, 1H), 3.65 (dd, J = 11.4, 2.6 Hz, 2H), 3.54-3.47 (m, 2H), 3.39 (dd, J = 11.4, 6.2 Hz, 2H), 1.35 (s, 3H), 1.31 (d, J = 6.4 Hz, 6H), 0.93-0.90 (m, 2H), 0.59-0.56 (m, 2H).

[1860] 252

[1861] The compounds listed in the table below were prepared by the corresponding general procedures starting from the corresponding intermediates or examples referring to the procedure described above. No. Structure 1H NMR / MS (ESI) m / z (s, s, 3 m, s, s, ), 2 s, s, ), q, .4

[1863] ii) Preparation of Compound 13

[1864] 3-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin- 1-yl)-2-(4-fluorophenyl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6- sulfonamide253

[1865]

[1866]

[1867] Step 1: Synthesis of 5-benzylsulfanyl-3-chloro-pyridin-2-amine

[1868] To a mixture of 5-bromo-3-chloro-pyridin-2-amine (5 g, 24.10 mmol) and phenylmethanethiol (3.29 g, 26.51 mmol) in dioxane (80 mL) were added Pd2(dba)3 (1.10 g, 1.21 mmol), Xantphos (697.28 mg, 1.21 mmol) and DIEA (9.34 g, 72.30 mmol) at 25 °C. The suspension was degassed under vacuum and purged with an N2 atmosphere three times. The mixture was heated to 100 °C and stirred at 100 °C under an N2atmosphere for 2 h. The mixture was cooled to 25 °C and diluted with H2O (50 mL) and extracted with EtOAc (30 mL × 3). The organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The crude residue was purified by flash silica gel chromatography (Eluent of 0~20% ethyl acetate / petroleum ether) to afford 5-benzylsulfanyl-3-chloro-pyridin-2-amine (5.3 g, 20.93 mmol, 87% yield) as a brown solid.

[1869] MS (ESI) m / z = 292.1 [M+CH3CN]+.254

[1870] 1H NMR (400 MHz, DMSO-d6): δ = 7.74 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.29–7.24 (m, 2H), 7.23–7.20 (m, 1H), 7.19–7.15 (m, 2H), 6.48 (s, 2H), 3.97 (s, 2H) .

[1871]

[1872] Step 2: Synthesis of 6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl) imidazo [1, 2-a] pyridine

[1873] To a mixture of 5-benzylsulfanyl-3-chloro-pyridin-2-amine (5.0 g, 19.94 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (4.76 g, 21.93 mmol) in EtOH (100 mL) was added NaHCO3(2.01 g, 23.93 mmol) at 25 °C. The mixture was heated to 85°C and stirred at 85°C under an N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The crude residue was purified by column chromatography on silica gel eluting with 0~10% ethyl acetate in petroleum ether to obtain 6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl) imidazo [1, 2-a] pyridine (2.5 g, 6.37 mmol, 32% yield) as a yellow solid.

[1874] MS (ESI) m / z = 370.7[M+H+2]+.

[1875] 1H NMR (400 MHz, DMSO-d6): δ = 7.96–7.92 (m, 2H), 7.87 (d, J = 1.2 Hz, 1H), 7.72 (s, 1H), 7.29–7.27 (m, 3H), 7.25 (d, J = 1.2 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.16–7.11 (m, 3H), 4.02 (s, 2H).

[1876]

[1877] Step 3: Synthesis of 2-[6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl)imidazo[1,2- a]pyridin-3-yl]-5-(difluoromethyl)-1,3,4-selenadiazole

[1878] 1) Solution 1: 6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (2.2 g, 5.96 mmol) , 2-bromo-5-(difluoromethyl)-1,3,4-selenadiazole (3.12 g, 11.93 mmol), bis[2-(2-pyridyl)phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (272.56 mg, 298.22 μmol), N-cyclohexyl-N- methyl-cyclohexanamine (2.33 g, 11.93 mmol) in CH3CN (110 mL)

[1879] 2) Solution 1(S1) was pumped by Pump 1 (P1, 30 mL / min) to flow reactor 1 (FLR1, Coils reactor, 3.175(1 / 8’’)mm, 50 mL, 40 °C) with a 455 nm LED light (400 W).

[1880] 3) The reaction mixture was continuously circulated for (FLR1, 120 min).

[1881] 4) The tubing was washed with a solvent.255

[1882] 5) The 455 nm LED light (400 W) was turned on.

[1883] 6) All the reaction mixture was collected, a sample was taken for analysis, a sample was taken for LC-MS analysis

[1884] 7) The LED light and peristaltic pump were turned off.

[1885] 8) The tubing was washed with a solvent.

[1886] 9) The reaction mixture was given to the client for workup.

[1887] The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain a crude product. The crude product was triturated with CH3CN (2 mL) at 25 °C for 10 min. The mixture was filtered and the cake was dried to obtain 2-[6-benzylsulfanyl-8-chloro-2-(4- fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-5-(difluoromethyl)-1,3,4-selenadiazole (320 mg, 582.30 µmol, 10% yield) as a white solid.

[1888] MS (ESI) m / z = 502.7 [M+H]+.

[1889] 1H NMR (400 MHz, CDCl3) δ = 9.69 (d, J = 1.2 Hz, 1H), 7.63–7.58 (m, 2H), 7.44 (d, J = 1.2 Hz, 1H), 7.32–7.28 (m, 4H), 7.26–7.19 (m, 3H), 7.01 (t, J = 53.6 Hz, 1H), 4.16 (s, 2H).

[1890]

[1891] Step 4: Synthesis of 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-2-(4- fluorophenyl)imidazo[1,2-a]pyridine-6-sulfonyl chloride

[1892] To a solution of 2-[6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl)imidazo[1,2- a]pyridin-3-yl]-5-(difluoromethyl)-1,3,4-selenadiazole (163.99 mg, 298.23 μmol) in CH3CN (5 mL), H2O (200 μL) and AcOH (100 μL) was added 1,3-dichloro-5,5-dimethyl- imidazolidine-2,4-dione (88.14 mg, 447.35 μmol) at 0-5 °C in an ice-bath. The resulting mixture was stirred at 0-5 °C (ice-bath) for 1 h. The mixture was concentrated under reduced pressure using a water pump at 30 °C, then concentrated under reduced pressure using an oil pump at 30 °C to obtain 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-6-sulfonyl chloride (150 mg, crude) as a yellow solid.

[1893] MS (ESI) m / z = 527.8 [M+H]+.256

[1894]

[1895] Step 5: Synthesis of 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-2-(4- fluorophenyl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide

[1896] To a solution of 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-2-(4- fluorophenyl)imidazo[1,2-a]pyridine-6-sulfonyl chloride (164.68 mg, 312.97 μmol) in CH3CN (4 mL) were added 4Å MS (1.5 g) and another solution of 1- methylcyclopropanamine;hydrochloride (67.34 mg, 625.93 μmol) in THF (2 mL) and Pyridine (2 mL) at 0-5 °C (ice-bath). The reaction mixture was stirred at 0-5 °C (ice-bath) for 0.75 h. The mixture was filtered, and the cake was washed with EtOAc (15 mL × 2). The combined filtrates were concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain 8-chloro-3-[5- (difluoromethyl)-1,3,4-selenadiazol-2-yl]-2-(4-fluorophenyl)-N-(1- methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (65.11 mg, 116.10 μmol, 37% yield) as a light yellow solid.

[1897] MS (ESI) m / z = 561.5 [M+H]+.

[1898]

[1899] Step 6: Synthesis of tert-butyl (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]-2-(4-fluorophenyl)-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]- 2,6-dimethyl-piperazine-1-carboxylate

[1900] To a mixture of 8-chloro-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-2-(4- fluorophenyl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (76.36 mg, 136.20 μmol) and tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (58.38 mg, 272.40 μmol) in dioxane (5 mL) were added [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5- dichloro-imidazol-2-ylidene]-dichloro-(2-methylpyridin-1-ium-1-yl)palladium (11.44 mg, 13.62 μmol) and Cs2CO3 (133.13 mg, 408.61 μmol). The resulting mixture was degassed and purged with N23 times, and then the mixture was stirred at 100 °C for 1 h under an N2atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-2-(4-fluorophenyl)-6-[(1-257 methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6-dimethyl-piperazine-1- carboxylate (52 mg, 70.39 μmol, 51% yield) as a yellow solid.

[1901] MS (ESI) m / z = 692.2 [M+H]+.

[1902] 1H NMR (400 MHz, CDCl3) δ = 9.76 (d, J = 1.2 Hz, 1H), 7.66–7.59 (m, 2H), 7.26– 7.22 (m, 2H), 7.02 (t, J = 53.6 Hz, 1H), 6.69 (d, J = 1.2 Hz, 1H), 5.04 (s, 1H), 4.31–4.23 (m, 2H), 4.16–4.05 (m, 4H), 1.51 (s, 9H), 1.39 (s, 3H), 1.33 (d, J = 6.4 Hz, 6H), 0.99–0.94 (s, 2H), 0.64–0.57 (m, 2H).

[1903] Step 7: Synthesis of 3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-8-[(3S,5S)-3,5- dimethylpiperazin-1-yl]-2-(4-fluorophenyl)-N-(1-methylcyclopropyl)imidazo[1,2- a]pyridine-6-sulfonamide TFA salt

[1904] To a solution of tert-butyl (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-tselenadiazol-2-yl]- 2-(4-fluorophenyl)-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6- dimethyl-piperazine-1-carboxylate (48.1 mg, 65.05 μmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by reversed-phase column ([water(0.05%TFA)-ACN];B%: 0%-55%, 20 min) and dried by lyophilization to obtain 3- [5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-8-[(3S,5S)-3,5-dimethylpiperazin-1-yl]-2-(4- fluorophenyl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (28.42 mg, 37.76 μmol, 58% yield, TFA) as a light yellow solid.

[1905] MS (ESI) m / z = 639.8 [M+H]+.

[1906] 1H NMR (400 MHz, CD3CN) δ = 9.76 (d, J = 1.2 Hz, 1H), 8.80 (br s, 2H), 7.77–7.65 (m, 2H), 7.34–7.28 (m, 2H), 7.18 (t, J = 53.6 Hz, 1H), 7.03 (d, J = 1.2 Hz, 1H), 6.48 (s, 1H), 3.91–3.82 (m, 4H), 3.80–3.73 (m, 2H), 1.49 (d, J = 6.4 Hz, 6H), 1.23 (s, 3H), 0.85– 0.76 (m, 2H), 0.53–0.45 (m, 2H).

[1907]

[1908] The compounds listed in the table below were prepared by the corresponding general procedures starting from the corresponding intermediates or examples referring to the procedure described above. No. Structure 1H NMR / MS (ESI) m / z258 1H NMR (400 MHz, DMSO) δ 8.44 (d, J = 1.4 Hz, 1H), 7.29 (d, J = 1.4 Hz, 1H), 6.74 (t, J = 57.3 Hz, 1H), 5.18 (s, 1H), 3.55 ), m, 3 3 ), 8 z, 3 ), ), 0, .7 m, 1 .4 ), 1 .0 ).259 1H NMR (400 MHz, DMSO) δ 8.41 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 1.5 Hz, 1H), 7.52 (dd, J = 7.5, 1.5 Hz, 1H), 7.32 (d, J = z, m, ), ), 0 8 z, .9 z, ), 5 0 d, z, 59 ), ), ), 8260 1H NMR (400 MHz, Chloroform) δ 9.30 (d, J = 1.5 Hz, 1H), 7.82 (s, 1H), 7.67 (d, J = 1.4 Hz, 1H), 6.66 (t, J = 57.3 Hz, 1H), – 7 3 ), 6 1 m,

[1910] iii) Preparation of Compound 14:

[1911] 2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-8-[(3S,5S)-3,5- dimethylpiperazin-1-yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6- sulfonamide261

[1912]

[1913] p y y y p py p p

[1914] To a solution of ethyl 3-cyclopropyl-3-oxo-propanoate (25 g, 160.07 mmol) in DCM (800 mL) were added TsOH·H2O (6.09 g, 32.01 mmol) and NBS (29.91 g, 168.08 mmol). Then the reaction mixture was stirred at 20 °C for 16 hr under nitrogen atmosphere. The reaction mixture was quenched with sat. aq NaHCO3, (1000 mL), then extracted with DCM (800 mL × 3), the combined organic phases were washed with brine (800 mL), and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain ethyl 2-262 bromo-3-cyclopropyl-3-oxo-propanoate (72.4 g, 247.62 mmol, 77% yield) as a light yellow oil.

[1915] MS (ESI) m / z = 237.0 [M+H+2]+.

[1916] 1H NMR (400 MHz, DMSO-d6) δ = 5.77 (s, 1H), 4.22 (q, J = 7.2 Hz, 2H), 2.32–2.21 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H), 1.12–1.06 (m, 2H), 0.99–0.93 (m, 2H).

[1917]

[1918]

[1919] Step 2: Synthesis of ethyl 6-bromo-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridine-3- carboxylate

[1920] A solution of ethyl 2-bromo-3-cyclopropyl-3-oxo-propanoate (71.2 g, 302.88 mmol) and 5-bromo-3-chloro-pyridin-2-amine (69.12 g, 333.17 mmol) in EtOH (1440 mL) was stirred at 200 °C for 20 min under 3 MPa. The reaction mixture was concentrated under reduced pressure to obtain a residue, the residue was dissolved in EtOAc (1000 mL), then washed with HCl (1 M, 600 mL × 3) and saturated aqueous sodium chloride (800 mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain a crude product (10.5 g), the crude product was slurred with EtOAc (8 mL) at 25 °C for 0.5 hr, then filtered, the filter cake was washed with EtOAc (2 mL) and collected the white solid. ethyl 6-bromo-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridine-3-carboxylate (7.05 g, 20.46 mmol, 7% yield) was obtained as a white solid.

[1921] MS (ESI) m / z = 344.9 [M+H+2]+.

[1922] 1H NMR (400 MHz, DMSO-d6) δ = 9.27 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 2.90–2.67 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 1.15–1.04 (m, 4H).

[1923]

[1924] Step 3: Synthesis of ethyl 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2- a]pyridine-3-carboxylate

[1925] To a solution of ethyl 6-bromo-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridine-3- carboxylate (2.3 g, 6.69 mmol) in dioxane (68 mL) were added phenylmethanethiol (997.1 mg, 8.03 mmol, 940.6 μL), Xantphos (774.20 mg, 1.34 mmol), DIEA (4.33 g, 33.47 mmol,263 5.83 mL) and Pd2(dba)3(1.23 g,1.34 mmol). The mixture was degassed and purged with N2 3 times, and then the mixture was stirred at 80 °C under N2 atmosphere for 6 h. The mixture was filtered, and the filtrate was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain ethyl 6- benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridine-3-carboxylate (2 g, 4.60 mmol, 69% yield) as a light yellow solid.

[1926] MS (ESI) m / z = 388.8 [M+H+2]+.

[1927] 1H NMR (400 MHz, CDCl3) δ = 9.20 (s, 1H), 7.35–7.28 (m, 2H), 7.26–7.17 (m, 4H), 4.45 (q, J = 6.8 Hz, 2H), 4.05 (s, 2H), 2.83–2.74 (m, 1H), 1.44 (t, J = 7.2 Hz, 3H), 1.29– 1.25 (m, 2H), 1.12–1.06 (m, 2H).

[1928]

[1929] Step 4: Synthesis of 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridine- 3-carbohydrazide

[1930] To a solution of ethyl 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2- a]pyridine-3-carboxylate (2 g, 5.17 mmol) in EtOH (35 mL) was added NH2NH2·H2O (16.74 g, 284.31 mmol, 16.23 mL, 85% purity) dropwise at 25 °C. The mixture was heated and stirred at 80 °C under N2 atmosphere for 12 h. The mixture was cooled to 25 °C. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by re-crystallization with EtOH (15 mL). The mixture was filtered and the filter cake was concentrated under reduced pressure to obtain 6-benzylsulfanyl-8-chloro-2- cyclopropyl-imidazo[1,2-a]pyridine-3-carbohydrazide (1.88 g, 4.64 mmol, 90% yield as a white solid.

[1931] MS (ESI) m / z = 373.2 [M+H]+.

[1932]

[1933] Step 5: Synthesis of 6-benzylsulfanyl-8-chloro-2-cyclopropyl-N'-(2,2- difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide264

[1934] To a solution of 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridine-3- carbohydrazide (1.87 g, 5.02 mmol) in THF (33 mL) were added TEA (1.27 g, 12.54 mmol, 1.75 mL) and (2,2-difluoroacetyl) 2,2-difluoroacetate (1.05 g, 6.02 mmol). The mixture was degassed and purged with N23 times. The mixture was stirred at 25 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated reduced pressure to obtain a residue. The residue was slurried with (EtOAc / MeOH=1 / 1) (15 mL) at 25 °C for 30 min. The mixture was filtered and the filter cake was concentrated under reduced pressure to obtain 6-benzylsulfanyl-8-chloro-2-cyclopropyl-N'-(2,2-difluoroacetyl)imidazo[1,2- a]pyridine-3-carbohydrazide (1.45 g, 3.09 mmol, 62% yield) as a white solid.

[1935] MS (ESI) m / z = 451.1 [M+H]+.

[1936]

[1937] Step 6: Synthesis of 2-(6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2- a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-selenadiazole

[1938] To a solution of 6-benzylsulfanyl-8-chloro-2-cyclopropyl-N'-(2,2- difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide (1.45 g, 3.22 mmol) in toluene (25 mL) was added 2,4-diphenyl-2,4-diselenoxo-1,3,2,4diselenadiphosphetane (1.71 g, 3.22 mmol). The mixture was degassed and purged with N23 times. The mixture was stirred at 110 °C under N2 atmosphere for 3 h. The reaction mixture was concentrated reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain 2-(6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridin-3-yl)-5- (difluoromethyl)-1,3,4-selenadiazole (714 mg, 1.35 mmol, 42% yield) as a brown solid.

[1939] MS (ESI) m / z = 497.0 [M+H]+.

[1940]

[1941] Step 7: Synthesis of 8-chloro-2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol- 2-yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride

[1942] To a solution of 2-(6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[1,2-a]pyridin-3- yl)-5-(difluoromethyl)-1,3,4-selenadiazole (243 mg, 490.08 μmol) in AcOH (3.517 mL) and H2O (1.1506 mL) was added NCS (261.77 mg, 1.96 mmol) at 5 °C. The mixture was stirred at 25 °C under N2 atmosphere for 12 h. To the mixture was added ice water (~7 mL) and more solid appeared. The solid was filtered and concentrated under reduced265 pressure to obtain a 8-chloro-2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride (312 mg, crude) as a light brown solid.

[1943] MS (ESI) m / z = 473.0 [M+H]+.

[1944]

[1945] Step 8: Synthesis of tert-butyl (2S,6S)-4-[2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4- selenadiazol-2-yl]-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6- dimethyl-piperazine-1-carboxylate

[1946] To a solution of 8-chloro-2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride (53 mg, 112.25 μmol) in DCM (0.6 mL) were added 4A MS (0.05 g, 112.25 μmol), TEA (34.08 mg, 336.75 μmol, 46.87 μL) and 1- methylcyclopropanamine;hydrochloride (18.11 mg, 168.38 μmol) at 5 °C. The mixture was stirred at 25 °C under N2 atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain 8-chloro-2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4- selenadiazol-2-yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (39 mg, 63.87 μmol, 57% yield) as a brown solid.

[1947] MS (ESI) m / z = 508.0 [M+H]+.

[1948]

[1949] Step 9: Synthesis of tert-butyl (2S,6S)-4-[2-cyclopropyl-6-[[(1S)-2,2-difluoro-1- isopropyl-propyl]sulfamoyl]-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]imidazo[1,2- a]pyridin-8-yl]-2,6-dimethyl-piperazine-1-carboxylate

[1950] To a solution of 8-chloro-2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (20 mg, 39.46 μmol) in dioxane (1.5 mL) were added tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (16.91 mg, 78.92 μmol), Cs2CO3(38.57 mg, 118.39 μmol) and [1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(2-methylpyridin-1-ium- 1-yl)palladium (3.32 mg, 3.95 μmol). The mixture was degassed and purged with N23 times, and then the mixture was stirred at 100 °C under N2 atmosphere for 2 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl (2S,6S)-4-[2-cyclopropyl-3-[5-266 (difluoromethyl)-1,3,4-selenadiazol-2-yl]-6-[(1- methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6-dimethyl-piperazine-1- carboxylate (15 mg, 15.99 μmol, 41% yield as a yellow solid.

[1951] MS (ESI) m / z = 686.2 [M+H]+.

[1952]

[1953] Step 10: Synthesis of 2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-8- [(3S,5S)-3,5-dimethylpiperazin-1-yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6- sulfonamide

[1954] To a solution of tert-butyl (2S,6S)-4-[2-cyclopropyl-3-[5-(difluoromethyl)-1,3,4- selenadiazol-2-yl]-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6- dimethyl-piperazine-1-carboxylate (15 mg, 21.91 μmol) in DCM (0.3 mL) was added TFA (149.89 mg, 1.31 mmol, 97.65 μL). The mixture was stirred at 25 °C under N2 atmosphere for 2 h. The mixture was concentrated under N2to obtain a residue. The residue was dissolved in MeCN (1 mL) and purified by reversed-phase HPLC (20 g C18 Column, Eluent of 0-40% MeCN / H2O (0.05% TFA condition) gradient @ 30 mL / min) to obtain the crude product (5 mg, 64.75% purity). The crude product was purified by Prep-HPLC (column: 56-Boston Green ODS 150×30mm,5μm;mobile phase: [H2O(0.01% TFA)- ACN];gradient:18%-58% B over 10.0 min) to obtain Compound 2-cyclopropyl-3-[5- (difluoromethyl)-1,3,4-selenadiazol-2-yl]-8-[(3S,5S)-3,5-dimethylpiperazin-1-yl]-N-(1- methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (1.74 mg, 2.49 μmol, 11% yield, TFA) as a light yellow solid.

[1955] MS (ESI) m / z = 586.2 [M+H]+.

[1956] 1H NMR (400 MHz, CD3OD) δ = 10.14 (s, 1H), 7.27 (t, J = 54.4 Hz, 1H), 7.11 (d, J = 1.2 Hz, 1H), 3.99–3.76 (m, 4H), 3.75–3.67 (m, 2H), 2.23–1.96 (m, 1H), 1.58 (d, J = 6.4 Hz, 6H), 1.34–1.29 (m, 2H), 1.26 (s, 3H), 1.25–1.15 (m, 2H), 0.86–0.76 (m, 2H), 0.55– 0.49 (m, 2H).

[1957]

[1958] The compounds listed in the table below were prepared by the corresponding general procedures starting from the corresponding intermediates or examples referring to the procedure described above.267 No. Structure 1H NMR / MS (ESI) m / z 1H NMR 400 MH CD3OD δ = 1010 d J = 16 H 1H), d, ), z, m, J 78 ), – ), d, m, m, m, ), J 9 5, m,268 1H NMR (400 MHz, Chloroform) δ 8.69 (d, J = 1.5 Hz, 1H), 7.24 (d, J = 1.4 Hz, 1H), 6.67 (t, J = 57.4 Hz, 1H), 5.41 (d, J 9, – z, ). ), z, .7 .7 29 8 ), m, 4 9 ), ), s, –269 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 7.16 – 6.82 (m, 3H), 3.76 (t, J = 9.2 Hz, 5H), 3.68 – 3.54 (m, 3H), 2.69 (s, m, 9 ), z, z, 8 ), 1 e ), m, 22 m, 4 ), – s,270 1H NMR (400 MHz, DMSO) δ 8.39 (d, J = 1.6 Hz, 1H), 7.28 (d, J = 1.4 Hz, 1H), 6.73 (t, J = 57.4 Hz, 1H), 5.06 (s, 1H), 5 m, 67 4 ), – 5 94 2 = 3 d, J 4 ), – z, ), .271 1H NMR (400 MHz, CD3OD) δ = 10.16 (d, J = 1.6 Hz, 1H), 7.27 (t, J = 54.0 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 5.64– ), – ), d, z, m, s, m, ), d, z, m, s, m, ), s, J 17272 1H NMR (400 MHz, CD3OD) δ = 10.09 (d, J = 1.2 Hz, 1H), 7.25 (t, J = 54.0 Hz, 1H), 7.06 (d, J = 1.2 Hz, 1H), 4.36– 9 ), z, ), J 22 0 m, .6 ), – ), ), .6 15 = m, J 09 ), ), z,273 3H), 1.36–1.29 (m, 2H), 1.26 (s, 3H), 1.24–1.17 (m, 2H), 0.87–0.80 (m, 2H), 0.56–0.48 (m, 2H). (t, z, 8 = z, .4 ), z, = .0 19 19 ), ), – – 8 z, ), .274 1H NMR (400 MHz, CD3OD) δ = 10.15–10.06 (m, 1H), 7.27 (t, J = 54.4 Hz, 1H), 7.13–7.07 (m, 1H), 4.70–4.66 (m, .4 3 ), . 4 ), z, 6 ), . 3 ), – z, – 0 ), 4 s, 4 ),275 1H NMR (400 MHz, DMSO) δ 8.46 (d, J = 1.4 Hz, 1H), 7.30 (d, J = 1.4 Hz, 1H), 6.76 (t, J = 57.3 Hz, 1H), 4.99 (s, 1H), – ), m, 08 ), – m, m, m, ), s, .8 ), 5 ), = ), 2276 1H NMR (400 MHz, DMSO) δ 9.08 (d, J = 1.4 Hz, 1H), 7.71 (d, J = 1.4 Hz, 1H), 6.72 (t, J = 57.3 Hz, 1H), 5.49 (s, 1H), .3 99 7 ), 5 d, m, ). .4 62 24 8 ), d, m, p, –277 1H NMR (400 MHz, DMSO) δ = 9.96–9.70 (m, 1H), 8.73 (s, 1H), 7.60 (t, J = 53.6 Hz, 1H), 7.07–7.00 (m, 1H), 4.23 ), – ), s, z, – .3 d, – z, 5 ), d, ), s, 01 3 ), 4 = = ),278 1.10 – 0.91 (m, 2H), 0.91 – 0.69 (m, 2H), 0.54 – 0.32 (m, 2H), 0.27 – 0.02 (m, 2H). 2 ), = = z, ), m,

[1960] iv) Preparation of Compound 24:

[1961] 2-cyclobutyl-3-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6- sulfonamide279

[1962]

[1963] ep : yn ess o e y - romo- -cyco uy- -oxo-propanoae

[1964] To a solution of ethyl 3-cyclobutyl-3-oxo-propanoate (14.53 g, 85.37 mmol) in DCM (465 mL) were added NBS (15.95 g, 89.64 mmol) and TsOH·H2O (3.25 g, 17.07 mmol) slowly. The mixture was degassed and purged with N23 times. The mixture was stirred at 25 °C under N2 for 2 h. The reaction mixture was quenched by addition saturated aqueous NaHCO3(~400 mL) at 0 °C and extracted with DCM (400 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by280 flash silica gel chromatography to obtain ethyl 2-bromo-3-cyclobutyl-3-oxo-propanoate (15.67 g, 27.68 mmol, 32.42% yield, 44% purity) as a pink oil.

[1965] MS (ESI) m / z = 251.1 [M+H+2]+.

[1966]

[1967] Step 2: Synthesis of ethyl 6-bromo-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridine-3- carboxylate

[1968] To a solution of ethyl 2-bromo-3-cyclobutyl-3-oxo-propanoate (15.67 g, 62.91 mmol) in EtOH (314 mL) was added 5-bromo-3-chloro-pyridin-2-amine (14.36 g, 69.20 mmol), the mixture was stirred at 200 °C for 20 min under 4 MPa. The reaction mixture was concentrated reduced pressure to obtain a residue. The reaction mixture was concentrated under reduced pressure to obtain a residue, the residue was dissolved in EtOAc (600 mL), then washed with HCl aq. (1 M, 400 mL × 3) and saturated aqueous sodium chloride (400 mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain ethyl 6-bromo-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridine-3-carboxylate (656 mg, 1.52 mmol, 2.42% yield, 83% purity) as a yellow solid.

[1969] MS (ESI) m / z = 358.9 [M+H+2]+.

[1970]

[1971] Step 3: Synthesis of ethyl 6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2- a]pyridine-3-carboxylate

[1972] To a solution of ethyl 6-bromo-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridine-3- carboxylate (538.8 mg, 1.51 mmol) in dioxane (16 mL) were added phenylmethanethiol (224.55 mg, 1.81 mmol, 212.24 μL), DIEA (584.13 mg, 4.52 mmol, 787.24 μL), Xantphos (87.17 mg, 150.66 μmol) and Pd2(dba)3 (137.96 mg, 150.66 μmol). The mixture was degassed and purged with N23 times, and then the mixture was stirred at 80 °C under N2atmosphere for 3 h. LCMS (ES24325-2167-P1A) showed desired mass was detected. The mixture was filtered, and the filtrate was diluted with H2O (50 mL) and extracted with Ethyl acetate (50 mL × 3). The organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel to obtain ethyl 6-benzylsulfanyl-8-281 chloro-2-cyclobutyl-imidazo[1,2-a]pyridine-3-carboxylate (536 mg, 1.17 mmol, 77.82% yield, 87.7% purity) as a yellow oil.

[1973] MS (ESI) m / z = 401.1 [M+H]+.

[1974]

[1975] Step 4: Synthesis of 6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridine-3- carbohydrazide

[1976] To a solution of ethyl 6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2- a]pyridine-3-carboxylate (822 mg, 2.05 mmol) in EtOH (12 mL) was added dropwise NH2NH2.H2O (2.57 g, 51.26 mmol, 2.49 mL, 100% purity) at 25 °C. The mixture was degassed and purged with N23 times. The mixture was heated and stirred at 80 °C under N2atmosphere for 12 h. LCMS (ES24325-2176-P1A) showed desired mass was detected and 10.4% of ethyl 6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridine-3- carboxylate remained. The mixture was stirred at 90 °C under N2atmosphere for 3 h. The mixture was cooled to 25 °C. The mixture was concentrated under reduced pressure to obtain a residue. The mixture was slurried with ethyl acetate (4 mL) at 25 °C for 30 min. The mixture was filtered and the filter cake was concentrated under reduced pressure to obtain 6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridine-3-carbohydrazide (948 mg, 1.90 mmol, 92.86% yield, 77.7% purity) as a brown solid.

[1977] MS (ESI) m / z = 387.1 [M+H]+.

[1978]

[1979] Step 5: Synthesis of 6-benzylsulfanyl-8-chloro-2-cyclobutyl-N'-(2,2- difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide

[1980] To a solution of 6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridine-3- carbohydrazide (928 mg, 2.40 mmol) in THF (20 mL) were added (2,2-difluoroacetyl) 2,2- difluoroacetate (500.97 mg, 2.88 mmol) and TEA (606.77 mg, 6.00 mmol, 834.62 μL). The mixture was degassed and purged with N23 times, and then the mixture was stirred at 25 °C under N2atmosphere for 3 h. LCMS (ES24325-2181-P1A) showed desired mass was detected and 29.2% of 6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2- a]pyridine-3-carbohydrazide remained. (2,2-difluoroacetyl) 2,2-difluoroacetate (250.48 mg, 1.44 mmol) and TEA (291.25 mg, 2.88 mmol, 400.62 μL) were added to the above282 mentioned mixture. The mixture was degassed and purged with N23 times, and then the mixture was stirred at 25 °C under N2 atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in MeCN (4 mL) and purified by reversed-phase HPLC (80 g C18 column, Eluent of 0~43% MeCN / H2O gradient @ 30 mL / min) to obtain 6-benzylsulfanyl-8-chloro-2-cyclobutyl-N'- (2,2-difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide (365 mg, 651.62 μmol, 27.17% yield, 83% purity) as a yellow solid.

[1981] MS (ESI) m / z = 465.1 [M+H]+.

[1982]

[1983] Step 6: Synthesis of 2-(6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridin- 3-yl)-5-(difluoromethyl)-1,3,4-selenadiazole

[1984] To a solution of 6-benzylsulfanyl-8-chloro-2-cyclobutyl-N'-(2,2- difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide (320 mg, 688.30 μmol) in toluene (8 mL) was added 2,4-diphenyl-2,4-diselenoxo-1,3,2,4diselenadiphosphetane (439.41 mg, 825.96 μmol). The mixture was degassed and purged with N23 times. The mixture was stirred at 120 °C under N2 atmosphere for 12 hrs. LCMS (ES24325-2192-P1A) showed the desired mass was observed. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain 2-(6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridin-3-yl)-5- (difluoromethyl)-1,3,4-selenadiazole (177 mg, 315.91 μmol, 45.90% yield, 91% purity) as a brown solid.

[1985] MS (ESI) m / z = 510.9 [M+H]+.

[1986] 1H NMR (400 MHz, CDCl3) δ = 9.80 (d, J = 1.6 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.32–7.27 (m, 4H), 7.26–7.19 (m, 1H), 7.00 (t, J = 54.4 Hz, 1H), 4.13 (s, 2H), 3.90–3.81 (m, 1H), 2.79–2.65 (m, 2H), 2.59–2.46 (m, 2H), 2.25–2.07 (m, 2H).

[1987]

[1988] Step 7: Synthesis of 8-chloro-2-cyclobutyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol- 2-yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride283

[1989] To a solution of 2-(6-benzylsulfanyl-8-chloro-2-cyclobutyl-imidazo[1,2-a]pyridin-3- yl)-5-(difluoromethyl)-1,3,4-selenadiazole (163 mg, 319.70 μmol) in AcOH (2.38 mL) and H2O (0.7813 mL) was added NCS (170.76 mg, 1.28 mmol) at 5 °C. The mixture was degassed and purged with N23 times. The mixture was stirred at 25 °C under N2 atmosphere for 12 h. To the mixture was added ice water (~5 mL) and more solid appeared. The solid was filtered and concentrated under reduced pressure to obtain 8-chloro-2- cyclobutyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]imidazo[1,2-a]pyridine-6- sulfonyl chloride (93 mg, crude) as a brown solid.

[1990] MS (ESI) m / z = 486.9 [M+H]+.

[1991]

[1992] Step 8: Synthesis of 8-chloro-2-cyclobutyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol- 2-yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide

[1993] To a solution of 8-chloro-2-cyclobutyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride (93 mg, 191.29 μmol) in DCM (3 mL) were added 4A MS (0.1 g, 191.29 μmol), 1-methylcyclopropanamine;hydrochloride (30.87 mg, 286.93 μmol) and TEA (58.07 mg, 573.86 μmol, 79.87 μL) at 5 °C. The mixture was degassed and purged with N23 times. The mixture was stirred at 25 °C under N2 atmosphere for 2 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to obtain 8-chloro- 2-cyclobutyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2-yl]-N-(1- methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (96 mg, 164.04 μmol, 85.76% yield, 89% purity) as a light brown solid.

[1994] MS (ESI) m / z = 522.0 [M+H]+.

[1995]

[1996] Step 9: Synthesis of tert-butyl (2S,6S)-4-[2-cyclobutyl-3-[5-(difluoromethyl)-1,3,4- selenadiazol-2-yl]-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6- dimethyl-piperazine-1-carboxylate

[1997] To a solution of 8-chloro-2-cyclobutyl-3-[5-(difluoromethyl)-1,3,4-selenadiazol-2- yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (50 mg, 96.00 μmol) in dioxane (2.5 mL) were added tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate284 (41.15 mg, 192.00 μmol), Cs2CO3(156.39 mg, 479.99 μmol) and [1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(2-methylpyridin-1-ium- 1-yl)palladium (8.07 mg, 9.60 μmol). The mixture was degassed ...

Claims

380 CLAIMS

1. A compound of the following Formula (I): (I)is a single bond or double bond; each of W1, W2and W3is independently selected from carbon and nitrogen, provided that only one of W1, W2and W3is nitrogen; X is selected from the following: );Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, and C2-C6alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen; Rx2is selected from the group consisting of hydrogen and C1-C6 alkyl; Rx3is selected from the group consisting of hydrogen and halogen; R1is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6 alkyl), and -C(O)NR11R12, wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, -O(C1-C6alkyl), -C(O)O(C1-C6alkyl), a 3-8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one381 or more selected from C1-C6alkyl, -O(C1-C6alkyl), oxo, amino, and halogen; each of said R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and 3-8 membered cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen; R2is 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6alkoxy, -(C1-C6alkylene)-OH, -(C1-C6alkylene)- O-(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6alkyl)(C1-C6alkyl), -OC(=O)-(C1-C6alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, , and, wherein each of said alkyl, alkoxy, alkylene, carbocyclic andgroups is optionally substituted with one or more selected from C1-C6 alkyl and halogen; R#is selected from the group consisting of hydroxy, C1-C6 alkoxy and -NR#1R#2; each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring; each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl; Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.382

2. A compound of the following Formula (II): I);Rx1is selected from the group consisting of hydrogen, C1-C6alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6alkyl and halogen; R1is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6alkyl), and -C(O)NR11R12, wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, -O(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), a 3-8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6alkyl, -O(C1-C6alkyl), oxo, amino, and halogen; each of said R11and R12is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and 3-8 membered cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen; R2is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl, halogen, cyano, hydroxy, C1-C6 alkoxy, -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-383 O-(C1-C6alkyl), mercapto, -S(C1-C6alkyl), -SO2(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -OC(=O)-(C1-C6 alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, , and, wherein each of said alkyl, alkoxy, alkylene, carbocyclic and heterocyclic groups is optionally substituted with one or more selected from C1-C6alkyl and halogen; R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2; each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6alkyl, or R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring; each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6 alkyl and 3-8 membered cycloalkyl; Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

3. The compound of claim 1, wherein the compound is selected from the group consisting of compounds of Formula (Ia-1), Formula (Ia-2), Formula (Ia-3), Formula (Ib-1), Formula (Ib-2), Formula (Ib-3), Formula (Ic-1), Formula (Ic-2) and Formula (Ic-3):384 -2) -2) -2)Xio NOna SllOte y suFd fro bstiNtu Nm N th ted Se F we g1ro F Ru5385 3)R1iHs selec R2 N R);x p consisting of hydrogen, C1-C6alkyl, halogen, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently opt ith one or more selected from C1-C6alkyl and halogen; Rx2is selected from the group consisting of hydrogen and C1-C6 alkyl; Rx3is selected from the group consisting of hydrogen and halogen; R1is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, a 3-14 membered carbocyclic or heterocyclic group, oxo, cyano, hydroxy, halogen, -O(C1-C6 alkyl), and -C(O)NR11R12, wherein each of said alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6alkyl, 3-8 membered cycloalkyl, halogen, amino, oxo, -O(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), a 3-8 membered heterocyclic group, and -C(O)NH2, wherein each of said alkyl, cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1-C6alkyl, -O(C1-C6alkyl), oxo, amino, and halogen; each of said R11and R12is independently selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, and 3-8 membered cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and halogen; R2is a 3-14 membered heterocyclic group, wherein said heterocyclic group is independently optionally substituted with one or more selected from C1-C6 alkyl,386 halogen, cyano, hydroxy, C1-C6alkoxy, -(C1-C6alkylene)-OH, -(C1-C6alkylene)- O-(C1-C6 alkyl), mercapto, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -OC(=O)-(C1-C6 alkyl), oxo, a 3-8 membered carbocyclic or heterocyclic group, , and, wherein each of said alkyl, alkoxy, alkylene, carbocyclic and heterocyclic groups is optionally substituted with one or more selected from C1-C6 alkyl and halogen; R#is selected from the group consisting of hydroxy, C1-C6 alkoxy and -NR#1R#2; each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring; each of R21and R22is independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3-8 membered cycloalkyl and halogen, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from deuterium, halogen, C1-C6alkyl and 3-8 membered cycloalkyl; Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered heteroaryl; and each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

4. The compound of claim 3, wherein the compound is selected from the group consisting of compounds of Formula (Ia-1), Formula (Ia-2) and Formula (Ia-3):387 -2)X is selected from the following: );Y is absent or oxygen; Rx1is selected from the group consisting of C1-C6 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine; Rx2is selected from the group consisting of hydrogen and C1-C6alkyl; Rx3is selected from the group consisting of hydrogen and fluorine; R1is selected from the following: 1A1B);Ry1is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, a 3- 14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6alkyl, fluorine and - O(C1-C6 alkyl), wherein each of said alkyl is independently optionally substituted388 with one or more fluorine; Ry2is selected from the group consisting of 3-8 membered cycloalkyl and a 3-8 membered heterocyclic group, wherein each of said cycloalkyl and heterocyclic group is independently optionally substituted with one or more selected from C1- C6 alkyl, -O(C1-C6 alkyl) and fluorine; R2is selected from the following: B);each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6 alkyl and -(C1-C3 alkylene)-O-(C1-C3 alkyl), or Rz11and Rz12, taken together with the carbon atom to which they are attached, form a 3-8 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6alkyl; Z is selected from -NRz14- and -CR'R''-; Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)(C1-C6alkyl), C6 alkyl), wherein saidyl; R21is selected from the group consisting of C1-C6 alkyl, 3-8 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6alkyl and 3-8 membered cycloalkyl; R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C6 alkyl; Ar is selected from the group consisting of 6-14 membered aryl and 5-14 membered389 heteroaryl; Rz13is selected from the group consisting of hydrogen, C1-C6 alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and cyano, or when R21is selected from -ORc, Rz13and Rc, tak ther with the carbon atomto which Rz13is attached and the oxygen atom to which Rcis attached, form a 5- to 8-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo; R#is selected from the group consisting of hydroxy, C1-C6alkoxy and -NR#1R#2; and each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring; R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 8-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -OC(=O)-(C1-C6 alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more halogen; Rz21is selected from the group consisting of -C(=O)-N(C1-C6alkyl)(C1-C6alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6alkyl; and each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

5. The compound of claim 4, wherein the compound is selected from the group consisting of compounds of Formula (Ia-1), Formula (Ia-2) and Formula (Ia-3), wherein: X is selected from the following:390 B);s a sent or oxygen; Rx1is selected from the group consisting of C1-C3alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C3alkyl and fluorine; Rx2is selected from the group consisting of hydrogen and C1-C3 alkyl; Rx3is selected from the group consisting of hydrogen and fluorine; R1is selected from the following: (R1-A) or (R1-B);Ry1is selected from the group consisting of hydrogen, deuterium, C1-C2alkyl, 3- 10 membered carbocyclic or heterocyclic group, cyano, chlorine, fluorine and - O(C1-C2alkyl), wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C3 alkyl, fluorine, and -O(C1-C2 alkyl); Ry2is selected from the group consisting of 3-6 membered cycloalkyl, and a 3-6 membered heterocyclic group, wherein each of said cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1- C2 alkyl, -O(C1-C2 alkyl), and fluorine; R2is selected from the following:391 B);each of Rzand Rzis independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl); Rz13is selected from the group consisting of hydrogen, C1-C3alkyl, -(C1-C2alkylene)-O-(C1-C2 alkyl), -(C1-C2 alkylene)-OH, and cyano; R#is selected from the group consisting of hydroxy, C1-C3alkoxy and -NR#1R#2; and each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl, or R#1and R#2, taken together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring; Rz14is selected from hydrogen, , and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3alkyl; R21is selected from the group consisting of C1-C3 alkyl and 3-5 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C3 alkyl and 3-5 membered cycloalkyl; R22is selected from the group consisting of hydrogen and C1-C3alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C3 alkyl; Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C3 alkyl)- and -N(- SO2(C1-C3alkyl))-, wherein said alkyl is optionally substituted with one or more C1-C3 alkyl; each of Rz16and Rz17is independently selected from the group consisting of392 hydrogen, C1-C3alkyl, hydroxy, C1-C3alkoxy, -OC(=O)-(C1-C3alkyl), oxo and amino, wherein said alkyl is optionally substituted with one or more fluorine; Rz18is absent or -CH(C1-C3 alkyl)-; Rz21is selected from the group consisting of -C(=O)-N(C1-C3 alkyl)(C1-C3 alkyl) and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3alkyl; and each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen; or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

6. The compound of claim 3, wherein the compound is selected from the group consisting of compounds of Formula (Ib-1), Formula (Ib-2) and Formula (Ib-3): -2)X is selected from the following: );Y is absent or oxygen; Rx1is selected from the group consisting of hydrogen, C1-C6alkyl, fluorine, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently393 optionally substituted with one or more selected from C1-C6alkyl and fluorine; Rx2is selected from the group consisting of hydrogen and C1-C6 alkyl; Rx3is selected from the group consisting of hydrogen and fluorine; R1is selected from the following: (R1-A) or (R1-B);Ryis selected from the group consisting of hydrogen, deuterium, C1-C6alkyl, 3- 14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, fluorine and - O(C1-C6alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine; Ry2is selected from the group consisting of 3-8 membered cycloalkyl and a 3-8 membered heterocyclic group, wherein each of said cycloalkyl and heterocyclic group is independently optionally substituted with one or more selected from C1- C6alkyl, -O(C1-C6alkyl) and fluorine; R2is selected from the following: B);each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C6 alkyl and -(C1-C3 alkylene)-O-(C1-C3 alkyl), or Rz11and Rz12taken together with the carbon atom to which they are attached form a 3-8 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more selected from C1-C6 alkyl and -SO2(C1-C6alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl; Z is selected from -NRz14- and -CR'R''-;394 Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)(C1-C6alkyl), and -SO2(C1-C6alkyl), wherein said alkyl is optionally ;s seecte rom t e group consstng of C1-C6alkyl, 3-8 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and 3-8 membered cycloalkyl; R22is selected from the group consisting of hydrogen and C1-C6 alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C6 alkyl; Rz13is selected from the group consisting of hydrogen, C1-C6 alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, -COOH and cyano, or when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5- to 8-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more oxo; R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 8-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from C1-C6 alkyl and amino; Rz21is selected from the group consisting of -C(=O)-N(C1-C6alkyl)(C1-C6alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6alkyl; and each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

7. The compound of claim 6, wherein the compound is selected from the group consisting of compounds of Formula (Ib-1), Formula (Ib-2) and Formula (Ib-3), wherein: X is selected from the following:395 B);s a sent or oxygen; Rx1is selected from the group consisting of C1-C2alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C2alkyl and fluorine; Rx2is selected from the group consisting of hydrogen and C1-C3 alkyl; Rx3is selected from the group consisting of hydrogen and fluorine; R1is selected from the following: (R1-A) or (R1-B);Ry1is selected from the group consisting of hydrogen, methyl, a 3-6 membered carbocyclic group, a 3-9 memebered heterocyclic group, cyano and chlorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from methyl, fluorine, and -OCH3; Ry2is selected from the group consisting of 3-6 membered cycloalkyl, and a 3-6 membered heterocyclic group, wherein each of said cycloalkyl, and heterocyclic group is independently optionally substituted with one or more selected from C1- C2alkyl, -O(C1-C2alkyl), and fluorine; R2is selected from the following:396 B);each of Rzand Rzis independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl); Rz13is selected from the group consisting of hydrogen, C1-C3alkyl, -(C1-C2alkylene)-O-(C1-C2 alkyl), -(C1-C2 alkylene)-OH and cyano; Rz14is selected from hydrogen and -SO2(C1-C2 alkyl), wherein said alkyl is optionallmore methyl; R21is methyl, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl; R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more selected from deuterium and methyl; Rz15is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(C1- C2 alkyl))-, wherein said alkyl is optionally substituted with one or more methyl; each of Rz16and Rz17is independently selected from the group consisting of hydrogen, C1-C3 alkyl and amino; Rz18is absent or -CH(CH3)-; Rz21is selected from the group consisting of -C(=O)-N(C1-C3alkyl)(C1-C3alkyl) and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3alkyl; and each of R3, R4and R5is independently selected from the group consisting of hydrogen and fluorine, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.397

8. The compound of claim 3, wherein the compound is selected from the group consisting of compounds of Formula (Ic-1), Formula (Ic-2) and Formula (Ic-3): -2));Y is absent or oxygen; Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine; Rx2is selected from the group consisting of hydrogen and C1-C6alkyl; Rx3is selected from the group consisting of hydrogen and fluorine; 1 i1A);he group consisting of hydrogen, deuterium, C1-C6 alkyl, 3- 14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6 alkyl, fluorine and - O(C1-C6 alkyl), wherein each of said alkyl is independently optionally substituted398 with one or more fluorine; R2is selected from the following: B);each of Rzand Rzis independently selected from the group consisting of hydrogen, C1-C6alkyl and -(C1-C3alkylene)-O-(C1-C3alkyl), or Rz11and Rz12, taken together with the carbon atom to which they are attached, form a 3-8 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from C1-C6 alkyl and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl; Z is selected from -NRz14- and -CR'R''-; Rz14is selected from hydrogen, C1-C6 alkyl, -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl), and -SO2(C1-C6 alkyl), wherein said alkyl is optionallymore C1-C6 alkyl; R21is selected from the group consisting of C1-C6 alkyl, 3-8 membered cycloalkyl and -ORc, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and 3-8 membered cycloalkyl; R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C6 alkyl; Rz13is selected from the group consisting of hydrogen, C1-C6 alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, -COOH and cyano, or when R21is selected from -ORc, Rz13and Rc, taken together with the carbon atom to which Rz13is attached and the oxygen atom to which Rcis attached, form a 5- to 8-membered heterocyclic ring, wherein said heterocyclic ring is optionally399 substituted with one or more oxo; R' and R'', taken together with the carbon atom to which they are attached, form a 3- to 8-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more group selected from C1-C6 alkyl and amino; Rz21is selected from the group consisting of -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl) and -SO2(C1-C6alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl; each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen; or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

9. The compound of claim 8, wherein the compound is selected from the group consisting of compounds of Formula (Ic-1), Formula (Ic-2) and Formula (Ic-3), wherein: X is selected from the following: );Y is absent or oxygen; Rx1is selected from the group consisting of C1-C2 alkyl, fluorine and cyano, wherein each of said alkyl is independently optionally substituted with one or more selected from C1-C2 alkyl and fluorine; Rx2is selected from the group consisting of hydrogen and C1-C3 alkyl; Rx3is selected from the group consisting of hydrogen and fluorine; 11A);Ry1is selected from the group consisting of hydrogen, methyl, a 3-6 membered carbocyclic group, a 3-6 membered heterocyclic group, cyano and chlorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from methyl, fluorine, and -OCH3;400 R2is selected from the following:each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl); Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1-C2 alkylene)-O-(C1-C2 alkyl), -(C1-C2 alkylene)-OH, -COOH and cyano; Rz14is selected from hydrogen, , and -SO2(C1-C2 alkyl), wherein said alkyl is optionally substituted with one or more methyl; R21is methyl, wherein said methyl is optionally substituted with one or more selected from methyl and cyclopropyl; R22is selected from the group consisting of hydrogen and methyl, wherein each of said methyl is optionally substituted with one or more selected from deuterium and methyl; Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C3 alkyl)- and -N(- SO2(C1-C3alkyl))-, wherein said alkyl is optionally substituted with one or more C1-C3 alkyl; each of Rz16and Rz17is independently selected from the group consisting of hydrogen, methyl and amino; Rz18is absent or -CH(CH3)-; Rz21is selected from the group consisting of -C(=O)-N(C1-C3 alkyl)(C1-C3 alkyl) and -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or401 more C1-C3alkyl; and each of R3, R4and R5is independently selected from the group consisting of hydrogen and fluorine, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

10. The compound of claim 2, wherein the compound is selected from the group consisting of compounds of Formula (II-1), Formula (II-2) and Formula (II-3): -2)Rx1is selected from the group consisting of hydrogen, C1-C6 alkyl, fluorine, cyano, and C2-C6 alkenyl, wherein each of said alkyl and alkenyl is independently optionally substituted with one or more selected from C1-C6 alkyl and fluorine; R1is (R1-A), wherein Ry1is selected from the group consisting of hydrog, uterium, C1-C6 alkyl, 3-14 membered carbocyclic or heterocyclic group, cyano, chlorine and fluorine, wherein each of said alkyl, carbocyclic and heterocyclic groups is independently optionally substituted with one or more selected from C1-C6alkyl, fluorine and -O(C1-C6alkyl), wherein each of said alkyl is independently optionally substituted with one or more fluorine; R2is selected from the following:402 B);each of Rzand Rzis independently selected from the group consisting of hydrogen, C1-C6alkyl and -(C1-C3alkylene)-O-(C1-C3alkyl), or Rz11and Rz12taken together with the carbon atom to which they are attached form a 3-8 membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more group selected from C1-C6alkyl and -SO2(C1-C6alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl; Z is -NRz14-; Rz14is selected from hydrogen, C1-C6 alkyl, -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl), and -SO2(C1-C6 alkyl), wherein said alkyl is optionallymore C1-C6 alkyl; R21is selected from the group consisting of C1-C6 alkyl and 3-8 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from C1-C6 alkyl and 3-8 membered cycloalkyl; R22is selected from the group consisting of hydrogen and C1-C6 alkyl, wherein said alkyl is optionally substituted with one or more selected from deuterium and C1-C6 alkyl; Rz13is selected from the group consisting of hydrogen, C1-C6 alkyl, -(C1-C3 alkylene)-O-(C1-C3alkyl), -(C1-C3alkylene)-OH, -COOH and cyano; Rz21is selected from the group consisting of -C(=O)-N(C1-C6 alkyl)(C1-C6 alkyl) and -SO2(C1-C6 alkyl), wherein said alkyl is optionally substituted with one or more C1-C6 alkyl; each of R3, R4and R5is independently selected from the group consisting of hydrogen and halogen;403 or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

11. The compound of claim 10, wherein the compound is selected from the group consisting of compounds of Formula (II-1), Formula (II-2) and Formula (II-3), wherein: Y is absent or oxygen; Rx1is selected from the group consisting of methyl, fluorine and cyano, wherein each of said methyl is independently optionally substituted with one or more selected from methyl and fluorine; R1is (R1-A); wherein: Ry1is selected from the group consisting of hydrogen, deuterium, C1-C2alkyl, 3-6 membered carbocyclic, cyano and chlorine, wherein each of said alkyl and carbocyclic is independently optionally substituted with one or more selected from C1-C3 alkyl, fluorine, and -O(C1-C2 alkyl); R2is selected from the following: );each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(C1-C2 alkyl); Rz13is selected from the group consisting of hydrogen and C1-C3 alkyl; Rz14is selected from hydrogen and ; R22is selected from the group consisting of hydrogen and C1-C3alkyl, wherein said alkyl is optionally substituted with one or more C1-C3 alkyl; Rz21is -SO2(C1-C3 alkyl), wherein said alkyl is optionally substituted with one or more C1-C3 alkyl; and404 each of R3, R4and R5is independently selected from the group consisting of hydrogen and fluorine, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

12. A compound, which is selected from the group consisting of the following compounds:90keo-tz60k0 LizZ L-tz9 Liz8 Liz6 Liz£ZtzZZizez-tzOEizLEizZEtz433e e1 5 F NHO S O N N SO NON N N Se F F 434 2 2 1 6 NC NHO S O N N SO NON N N Se F FF F NHO S F O N NH NN N N Se F F 437 NH NOO S S F O O N S FO N NONN N N N S See F F F FNHO S O N NN N N Se F F 438 NHO S O O NN O N NH Se F FŏtztztztztzœtztzLVvťtztz449 rm,p armaceutca y acceptabe sat, ydrate, or sovate t ereo.

13. A pharmaceutical composition for treating or preventing diseases or disorders mediated by PARG, preferably cancer, more preferably lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, or skin cancer, comprising the compound according to any one of claims 1 to 12, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier(s) or excipient(s).

14. The pharmaceutical composition according to claim 13, wherein the composition is administered separately, sequentially or simultaneously with DNA damage response targeting anti-cancer agents, 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 (ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib),450 AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK- 1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (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).

15. A compound according to any one of claims 1 to 12, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treating or preventing diseases or disorders mediated by PARG, preferably cancer, more preferably lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, or skin cancer.

16. The compound according to claim 15, wherein the compound is administered separately, sequentially or simultaneously with DNA damage response targeting anti-cancer agents, 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 (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 (prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (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).

17. A method of treating or preventing diseases or disorders, such as diseases or disorders mediated by PARG in a subject in need of treatment or prevention, comprising administering to the subject at least one compound according to any one of claims 1 to 12, or a tautomer, stereoisomer, prodrug, crystal form,451 isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

18. The method of claim 17, wherein the diseases or disorders mediated by PARG are cancer, preferably lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, or skin cancer.

19. The method of any one of claims 17 and 18, further comprising administering to the subject additional DNA damage response targeting anti-cancer agents, 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 (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 (prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (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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