Substituted imidazopyridine compound derivatives and their pharmaceutical use

Abstract

Provided herein are novel imidazopyridine compound derivatives, compositions containing the compounds, and preparation methods and uses thereof. The imidazopyridine compound derivatives are compounds represented by Formula (I) or (II), 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.

Description

DescriptionTitle of Invention: SUBSTITUTED IMIDAZOPYRIDINE COMPOUND DERIVATIVES AND THEIR PHARMACEUTICAL USETechnical Field

[0001] The present disclosure relates to imidazopyridine compound derivates with inhibitory effect on PARG, pharmaceutical compositions containing 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. Singlestrand 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 inDNA 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 (hydroxymethyl)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 a 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 imidazopyridine compounds derivatives, compositions comprising the same, and preparation methods and uses thereof. The imidazopyridine compound derivatives have an inhibitory activity for PARG, and can be effectively used for treating various types of cancers.

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

[0009] R2(I)

[0010] wherein:

[0011] === is a single bond or double bond;

[0012] each of X1, X2, and X3is independently C or N;

[0013] one of Y1and Y2is N and the other one of Y1and Y2is CRY1or NRY2;

[0014] provided that where one of Y1and Y2is CRY1, only one of X1, X2, and X3is N, and where one of Y1and Y2is NRY2, all of X1, X2, and X3are C;

[0015] each of RY1and RY2is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3-10 membered carbocyclic group, a 3-12 membered heterocyclic group, 6- to 14-membered aryl, 5- to 12-membered.' Nheteroaryl, andH, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0016] Rxis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0017] Ryis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl, alkenyl, alkynyl,alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl;

[0018] R1is -CH2-(Hal), -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen;

[0019] R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, halogen, cyano, -C(=O)-NH2, -C(=O)-N(C1-C6alkyl)2, -C(=O)-OH, -C(=O)-Ci-C6alkyl, -C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O- (Ci-C6alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)-CH(phenyl)-O-(Ci-C6alkyl), -S(=O)2- (Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-Ce alkyl);

[0020] R3is Ci-Ce alkyl which is optionally substituted with one or more halogens; and

[0021] each of R4and R5is independently hydrogen or halogen,

[0022] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0023] In another aspect, the present disclosure relates to a compound of the following Formula (II):

[0025] wherein:

[0026] W is absent, oxygen, or CH2;

[0027] RY3is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3-10 membered carbocyclic group, a 3-12 membered heterocyclic group, 6- to 14-. Rz. Rw~Nmembered aryl, 5- to 12-membered heteroaryl, and [structural formula], wherein each of said alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0028] Rzis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0029] Rwis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl;

[0030] R1is -CH2-(Hal), -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen;

[0031] R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, halogen, cyano, -C(=O)-NH2, -C(=O)-N(C1-C6alkyl)2, -C(=O)-OH, -C(=O)-Ci-C6alkyl, -C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O- (Ci-C6alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)-CH(phenyl)-O-(Ci-C6alkyl), -S(=O)2- (Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-Ce alkyl);

[0032] R3is cyano or Ci-Ce alkyl optionally substituted with one or more halogens; and

[0033] each of R4and R5is independently hydrogen or halogen,

[0034] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0035] In another aspect, the present disclosure provides a pharmaceutical composition comprising the compounds disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier(s) or excipient(s).

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] Other objects and advantages of the present disclosure will be apparent to those skilled in the art from the following specific embodiments, examples, and claims.

[0041] Description of Embodiments

[0042] Definitions

[0043] Chemical terms

[0044] The definitions of specific functional groups and chemical terms are described in more detail below.

[0045] When a range of values is listed, it is intended to encompass each value and any subrange within the range. For example, “Ci-Ce alkyl” is intended to encompass Ci, 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.

[0046] As used herein (unless otherwise specified), the term “Ci-Ce alkyl” refers to a saturated hydrocarbon group which is straight-chained or branched, and has 1 to 6 carbon atoms. It is also referred to herein as a "lower alkyl" group. In one embodiment, the alkyl group may have 1 to 4 carbon atoms (C1-C4 alkyl) or 3 to 6 carbon atoms (C3-C6 alkyl). Examples of Ci-Ce alkyl 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.

[0047] As used herein (unless otherwise specified), the term “Ci-Ce alkylene” 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 bond replaced by points of attachment of the alkylene group to the remainder of the compound. Examples of alkylene groups 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-l,3-diyl and the like.

[0048] As used herein (unless otherwise specified), the term “C2-C6 alkenyl” 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 one embodiment, the alkenyl group may have 2 to 4 carbon atoms. Examples of C2-6 alkenyl group include, but are not limited to, vinyl, 1 -propenyl, 2- propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, etc.

[0049] As used herein (unless otherwise specified), the term “C2-C6 alkenylene” 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 one embodiment, the alkenylene group may have 1 to 4 carbon atoms (C1-C4 alkenylene) or 1 to 2 carbon atoms (C1-C2 alkenylene).

[0050] 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 one embodiment, the alkynyl group may have 2 to 4 carbon atoms. In one embodiment, the alkynyl group does not contain any double bond. One or more carboncarbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-6 alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, etc.

[0051] As used herein (unless otherwise specified), the term “C2-C6 alkynylene” refers to a divalent alkynyl linking group, which is a linear or branched hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon triple bonds. 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. Examples of alkynylene groups include, but are not limited to, acetylene, l-propyn-l,3-diyl, 2- propyn-l,3-diyl, 1 -butyne- 1,4-diyl, 2-butyne-l,4-diyl, 3 -butyne- 1,4-diyl, l-butyne-1,3- diyl, 2 -butyne- 1,4-diyl, 3 -butyne- 1,4-diyl, 3-butyne-2,4-diyl and the like.

[0052] As used herein (unless otherwise specified), the term “Ci-Ce alkoxy” refers to a -OR group, wherein R is substituted or unsubstituted Ci-Ce alkyl. In one embodiment, the alkoxy group may have 1 to 4 carbon atoms. Specifically, Ci-ealkoxyl 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.

[0053] As used herein (unless otherwise specified), the terms “halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In one embodiment, the halo group is F, Cl or Br. In one embodiment, the halo group is F or Cl. In one embodiment, the halo group is F.

[0054] As used herein (unless otherwise specified), the terms “carbocyclic group” refers to a non-aromatic cyclic hydrocarbon group having from 3 to 15 ring carbon and zero heteroatoms in the non-aromatic ring system. In one embodiment, the carbocyclic group may have 3 to 14, 3 to 12, 5 to 14, 5 to 10, 5 to 8, or 6 to 7 ring carbon atoms. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[0055] As used herein (unless otherwise specified), the terms “heterocarbocyclic group” refers a group or radical of a 3- to 15-membered non-aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, silicon, and sulfur. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclic group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. In one embodiment, the heterocarbocyclic group may have 4 to 14, 5 to 10, 5 to 8, 5 to 7, or 6 to 7 ring atoms.

[0056] As used herein (unless otherwise specified), the terms “C3-C15 cyclic group”, “3-15 membered cyclic group” or “3- to 15- membered cyclic group” refers to a cyclic hydrocarbon group which is non-aromatic and has 3-15 ring carbon atoms and zero heteroatoms. In one embodiment, 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 8, 5 to 7, or 5 to 6 ring carbon atoms. The cyclic group also includes a ring system in which the above cyclic group is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the ring of the cyclic group. Examples of the cyclic group include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, and the like.

[0057] As used herein (unless otherwise specified), the terms “C3-10 cycloalkyl” or “3-10 membered cycloalkyl” refers to a cyclic hydrocarbon group which is non-aromatic and has 3-10 ring carbon atoms and zero heteroatoms. In some embodiments, the cycloalkyl group may have 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7, or 5 to 6 ring carbon atoms. The cycloalkyl also includes a ring system in which the above cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring. Examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, bicyclo[l.l.l]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, cyclononyl, cyclononenyl, cyclodecyl, cyclodecenyl, octahydro- IH-indenyl, decahydronaphthyl, spiro[4.5]decyl, and the like.

[0058] As used herein (unless otherwise specified), the term “3-10 membered cycloalkylene” refers to a divalent cycloalkyl linking group, which is a hydrocarbon ring system having 3-10 ring carbon. A polycyclic ring system may be a fused ring ring system, a bridged ring system and a spiro ring system. Examples of cycloalkylene are cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and the like.

[0059] As used herein (unless otherwise specified), the term “3- to 15-membered heterocyclic group” “3-15 membered heterocyclic group”, “3-15 membered heterocyclyf’or the term “3- to 15-membered heterocyclyl” refers to a radical of a 3- to 15 membered saturated or partially unsaturated ring system which is non-aromatic and has ring carbon atoms and at least one ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, and phosphorus. The point of attachment of the heroaryl 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 one embodiment, the heterocyclyl group may have 2 to 10, 2 to 7, 3 to 10, 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 12, 5 to 8, 5 to 7, 5 to 6, 9 to 11, 9 to 10 ringcarbon atoms, and 1 to 4 heteroatoms. In one embodiment, the heterocyclic group may be a 7- to 14-membered bicyclic spiro heterocyclic group.

[0060] 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, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5- dione. Exemplary 5 -membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadi azolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyri dinonyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, pyridazinonyl triazinanyl. Exemplary 7- membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 10-membered heterocyclyl groups include, without limitation, phthalazinonyl.

[0061] In one embodiment, the heterocyclic group includes a saturated ring radical that comprises carbon atoms and from heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus. In an embodiment, the saturated heterocyclic group may have a 3- to 14- membered heterocyclic group. In an embodiment, the saturated heterocyclic group may have 14-membered bicyclic spiro heterocyclic group. In one embodiment, the saturated heterocyclic group may have 2 to 13, 2 to 12, 2 to 12, 2 to 10, 3 to 13, 3 to 12, 3 to 12, 3 to 11, 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. Examples of such saturated heterocyclic group include, but are not limited to, dioxolanyl, thienyl [1,3] di thianyl, 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 saturated spiro heterocyclic group includes 2-oxa-7-azaspiro[3.5]nonan-7-yl.

[0062] As used herein (unless otherwise specified), the term “C6-C14aryl”, “6-14 membered aryl” or “6- to 14-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- to 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.

[0063] As used herein (unless otherwise specified), the term “5- to 14-membered heteroaryl” or “5-14 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 heteroatoms (e.g., nitrogen, oxygen, silicon, 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 one embodiment, the heteroaryl group may have 3 to 13, 3 to 12, 3 to 10, 3 to 8, 3 to 7, 4 to 7, 5 to 10, 5 to 7, or 5 to 6 ring carbon atoms or heteroatoms.

[0064] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5 -membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5 -membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6- membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groupscontaining 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, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0065] 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”.

[0066] 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 Ci-6 alkyl group.

[0067] As used herein (unless otherwise specified), the term “polycyclic ring” 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 polycyclic ring includes, but not limited to following groups:

[0069] 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.

[0070] The term “substituted” refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. Exemplary substituents on carbon atoms include, but are not limited to, Ci-Ce alkyl, halogen, cyano, deuterium, C2-C6 alkenyl, Ci-Ce alkoxy, -(Ci-Ce alkylene)-OH, -(Ci-Ce alkylene)-O-(Ci-Ce alkyl), 3- to 14-membered (e.g., 3- to 10 membered, 5- to 6-membered, 3- to 5-membered) cycloalkyl, hydroxy, amino, -NH2, - NH(CI-C6alkyl), -N(CI-C6alkyl)(Ci-C6alkyl), -(Ci-C6alkylene)-N(Ci-C6alkyl)2, mercapto, -S(Ci-Ce alkyl), -SO2(Ci-Ce alkyl), carbamoyl, oxo, a 3-8 (e.g, 3-6) membered heterocyclic or heteroaryl group, -CORzl(wherein Rzlis selected from the group consisting of hydrogen, Ci-Ce alkyl, 3- to 8-membered cycloalkyl, and halogen), and and -CON(Rz2)(Rz3) (wherein each of Rz2and Rz3is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, or halogen, wherein said alkyl is optionally substituted with one or more selected from Ci-Ce alkyl and halogen; or Rz2and Rz3, taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 3- to 8-membered heterocyclic group, wherein said heterocyclic group is optionallysubstituted with one or more selected from Ci-Ce 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 Ci-Ce alkyl and halogen. The number of substituents may be any number as long as valence of ths substitued atom and the substituent permit, for example 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5, 3 to 4, and the like.

[0071]

[0072] General terms

[0073] 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.

[0074] Unless particularly stated otherwise, the concept of any expression in singular form should be considered to encompass the concept of the expression in plural form. Therefore, unless particularly stated otherwise, the concept of any article that expresses the concept of singular (for example, “a”, “an”, “the”, and the like in the case of English language) should be considered to encompass the concept of plural.

[0075] Unless particularly stated otherwise, any term used in the present description should be considered as having the conventional meaning for the relevant technical field. Therefore, unless defined otherwise, all the scientific terms and other technical terms used in the present description have the meaning that is generally understood by those skilled in the art to which the present invention pertains. If there is any conflict in meaning, the present description (including the definitions) takes priority.

[0076]

[0077] Compounds of Formula (I) or Formula (II)

[0078] According to an aspect of the present disclosure, provided is a compound of Formula (I) or Formula (II), (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0079]

[0080] In one embodiment, the present disclosure relates to a compound of Formula (I):

[0081] R2(I)

[0082] wherein:

[0083] === is a single bond or double bond;

[0084] each of X1, X2, and X3is independently C or N;

[0085] one of Y1and Y2is N and the other one of Y1and Y2is CRY1or NRY2;

[0086] provided that where one of Y1and Y2is CRY1, only one of X1, X2, and X3is N, and where one of Y1and Y2is NRY2, all of X1, X2, and X3are C;

[0087] each of RY1and RY2is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3-10 membered carbocyclic group, a 3-12 membered heterocyclic group, 6- to 14-membered aryl, 5- to 12-memberedY Nheteroaryl, and' R, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0088] Rxis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0089] Ryis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl, alkenyl, alkynyl,alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl;

[0090] R1is -CH2-(Hal), -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen;

[0091] R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, halogen, cyano, -C(=O)-NH2, -C(=O)-N(C1-C6alkyl)2, -C(=O)-OH, -C(=O)-Ci-C6alkyl, -C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O- (Ci-C6alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)-CH(phenyl)-O-(Ci-C6alkyl), -S(=O)2- (Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-Ce alkyl);

[0092] R3is Ci-Ce alkyl which is optionally substituted with one or more halogens; and

[0093] each of R4and R5is independently hydrogen or halogen,

[0094] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0095]

[0096] In one embodiment of the compound of Formula (I),

[0097] X1, X2, X3, Y1, and Y2meet one of the following cases: (i) X1is N, X2and X3are C, Y1is N, and Y2is CRY1; (ii) X1is N, X2and X3are C, Y1is CRY1, and Y2is N; (iii) X1and X3are C, X2is N, Y1is N, and Y2is CRY1; (iv) X1and X3are C, X2is N, Y1is CRY1, and Y2is N; (v) X1and X2are C, X3is N, Y1is N, and Y2is CRY1; (vi) X1and X2are C, X3is N, Y1is CRY1, and Y2is N; (vii) X1, X2, and X3are C, Y1is N, and Y2is NRY2; and (viii) X1, X2, and X3are C, Y1is NRY2, and Y2is N,

[0098] each of RY1and RY2is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3-10 membered carbocyclic group, a 3-12 membered heterocyclic group, 6- to 14-membered aryl, 5- to 12-membered., RY' Nheteroaryl, and 'Hwherein each of said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0099] Rxis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0100] Ryis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl;

[0101] preferably,

[0102] each of RY1and RY2is selected from the group consisting of hydrogen, cyano, halogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, a 3-10 membered carbocyclic group, a \,-R"'<N3-12 membered heterocyclic group, 6- to 14-membered aryl, and', wherein each of said alkyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, and aryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0103] Rxis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more Ci-Ce alkyl,

[0104] Ryis Ci-Ce alkyl optionally substituted with deuterium,

[0105] more preferably,

[0106] RY1is selected from the group consisting of hydrogen, cyano, halogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, a 3-10 membered carbocyclic group, a 3-12 membered. „. RX...„RYX Nheterocyclic group, 6- to 14-membered aryl, andH, wherein each of said alkyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, and aryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and halogen,

[0107] RY2is C1-C6alkyl,

[0108] Rxis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more Ci-Ce alkyl, and

[0109] Ryis Ci-Ce alkyl optionally substituted with deuterium.

[0110] In one embodiment of the compound of Formula (I),

[0111] X1, X2, X3, Y1, and Y2meet one of the following cases: (i) X1is N, X2and X3are C, Y1is N, and Y2is CRY1; (ii) X1is N, X2and X3are C, Y1is CRY1, and Y2is N; (iii) X1and X3are C, X2is N, Y1is N, and Y2is CRY1; (iv) X1and X3are C, X2is N, Y1is CRY1, and Y2is N; (v) X1and X2are C, X3is N, Y1is N, and Y2is CRY1; (vi) X1and X2are C, X3is N, Y1is CRY1, and Y2is N; (vii) X1, X2, and X3are C, Y1is N, and Y2is NRY2; and (viii) X1, X2, and X3are C, Y1is NRY2, and Y2is N,

[0112] each of RY1and RY2is independently selected from the group consisting of FHH H FCIFCNFCH3 |— CF3| — / 1—|_ / I / CF*Hi,CF3r° r° F°

[0114]

[0115] In one embodiment of the compound of Formula (I),

[0116] X1, X2, X3, Y1, and Y2meet one of the following cases: (i) X1is N, X2and X3are C, Y1is N, and Y2is CRY1; (ii) X1is N, X2and X3are C, Y1is CRY1, and Y2is N; (iii) X1and X3are C, X2is N, Y1is N, and Y2is CRY1; (iv) X1and X3are C, X2is N, Y1is CRY1, and Y2is N; (v) X1and X2are C, X3is N, Y1is N, and Y2is CRY1; (vi) X1and X2are C, X3is N, Y1is CRY1, and Y2is N; (vii) X1, X2, and X3are C, Y1is N, and Y2is NRY2; and (viii) X1, X2, and X3are C, Y1is NRY2, and Y2is N,

[0117] RY1is selected from the group consisting of

[0120] RY2is is Ci-Ce alkyl.

[0121]

[0122] In one embodiment of the compound of Formula (I),

[0123] R1is -CH2-(Hal), -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen,

[0124] preferably,

[0125] R1is -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen, and

[0126] more preferably,

[0127] R1is -CHF2or -CF3.

[0128]

[0129] In one embodiment of the compound of Formula (I),

[0130] R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, halogen, cyano, -C(=O)-NH2, -C(=O)-N(C1-C6alkyl)2, -C(=O)-OH, -C(=O)-Ci-C6alkyl, -C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O- (Ci-C6alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)-CH(phenyl)-O-(Ci-C6alkyl), -S(=O)2- (Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-C6 alkyl), and

[0131] preferably, R2is 6-10 membered heterocyclyl which contains one or more nitrogen atoms or one nitrogen atom and one oxygen atom as the ring hetero atoms and is optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, halogen, cyano, C2-Ce alkenyl, C2-Ce alkynyl, hydroxy, Ci-Ce alkoxy, NH2, carbamoyl, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, Ci-Ce alkoxy, and carbamoyl.

[0132] In one embodiment of the compound of Formula (I), R2is selected from the following:

[0134] wherein:

[0135] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-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 group selected from Ci-Ce alkyl and -SO2(C1-C6alkyl);

[0136] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and';

[0137] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2;

[0138] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl

[0139] Z is selected from -NRz14and -CR'R";

[0140] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2, 'O.R22GXAK, Ar and -SO2-(Ci-C6alkyl);

[0141] 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;

[0142] R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium;

[0143] Ar is 6-14 membered aryl;

[0144] R' and R" are hydrogen, or 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 Ci-Ce alkyl, hydroxy, Ci-Ce alkoxy, oxo, and amino, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more halogen; and

[0145] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2 and -SO2-(C1-C6alkyl).

[0146] In one embodiment of the compound of Formula (I), R2is selected from the following:

[0150] (R2-B);

[0151] wherein:

[0152] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-C3 alkyl),

[0153] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(Ci-C2 alkyl),

[0154] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3;

[0155] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and';

[0156] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2;

[0157] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl;

[0158] preferably, in formula (R2-A-1), Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1-C3 alkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, and O\ and R is selected from the group consisting of hydroxy, methoxy, ethoxy, -NH2, and -N(CH3)2,

[0159] more preferably, in formula (R2-A-l), Rzl3is selected from the group consisting of hydrogen, methyl, -CH2-O-CH3, -CH2-OH, -COOH, -C(=O)-OCH3, -C(=O)-NH2, and - C(=O)-N(CH3)2;

[0160] preferably, in formulae (R2-A-2) and (R2-A-3), Rzl3is C1-C3 alkyl,

[0161] more preferably, in formulae (R2-A-2) and (R2-A-3), Rzl3is methyl;O\R21

[0162] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2, 'o0X O.R22XAK, Ar and -SO2-(Ci-C6alkyl),

[0163] preferably, Rz14is selected from hydrogen,xZA,Arand -SO2- (C1-C4 alkyl),

[0164] more preferably, Rz14is selected from hydrogen,xZA,Ar, - SO2-(methyl), and -SO2-(isopropyl);

[0165] 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;

[0166] R22is selected from the group consisting of hydrogen and Ci-Ce alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium,

[0167] R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more halogens,

[0168] more preferably, R22is selected from the group consisting of hydrogen, methyl, and CHF2;

[0169] Ar is 6-14 membered aryl,

[0170] preferably, Ar is phenyl;

[0171] Rzl5is selected from the group consisting of -O-, -NH-, -N(Ci-Ce alkyl)- and -N(- SO2(Ci-C6alkyl))-,

[0172] preferably, Rzl5is selected from the group consisting of -O-, -NH-, -N(C1-C3alkyl)- and -N(-SO2(C1-C3alkyl))-,

[0173] more preferably, Rzl5is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(C1-C2alkyl))-,

[0174] still more preferably, in formula (R2-A-2), Rzl5is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(CH3))-,

[0175] still more preferably, in formula (R2-A-3), Rzl5is selected from the group consisting of -O-, -NH-, and -N(CH3)-;

[0176] Rzl6is selected from the group consisting of hydroxy, Ci-Ce alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens,

[0177] preferably, Rzl6is selected from hydroxy, C1-C3 alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens,

[0178] more preferably, Rzl6is selected from hydroxy, methoxy, -O-CHF2, and -NH2;

[0179] Rzl7is Ci-C6alkyl,

[0180] preferably, Rzl7is C1-C3 alkyl,

[0181] more preferably, Rzl7is methyl;

[0182] Rzl8is Ci-C6alkyl,

[0183] preferably, Rzl8is C1-C3 alkyl,

[0184] more preferably, Rzl8is methyl; and

[0185] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2 and -SO2-(C1-C6alkyl),

[0186] preferably, Rz21is selected from the group consisting of -C(=O)-N(C1-C4alkyl)2and -SO2-(C1-C4alkyl),

[0187] more preferably, Rz21is selected from the group consisting of -C(=O)-N(CH3)2, - SO2-(methyl), and -SO2-(isopropyl).

[0188]

[0189] In one embodiment of the compound of Formula (I),

[0190] R3is Ci-Ce alkyl which is optionally substituted with one or more halogens,

[0191] preferably, R3is C1-C3 alkyl which is optionally substituted with one or more halogens,

[0192] more preferably, R3is methyl or ethyl, wherein said methyl and ethyl is independently optionally substituted with one or more halogens, and

[0193] still more preferably, R3is selected from the group consisting of methyl, ethyl, - CH2F, -CHF2, and -CF2-CH3.

[0194]

[0195] In one embodiment of the compound of Formula (I),

[0196] each of R4and R5is independently hydrogen or halogen,

[0197] preferably, each of R4and R5is independently hydrogen, -F, or -Cl, and

[0198] more preferably, each of R4and R5is independently hydrogen or -F,

[0199]

[0200] In one embodiment, the present disclosure relates to a compound of Formula (II):

[0201]

[0202]

[0203] W is absent, oxygen, or CH2;

[0204] RY3is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3- 10 membered carbocyclic group, a 3-12 membered heterocyclic group, 6- to 14-membered aryl, 5- to 12-membered heteroaryl, and', wherein each of said alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0205] Rzis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0206] Rwis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl, alkenyl, alkynyl,alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl;

[0207] R1is -CH2-(Hal), -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen;

[0208] R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, halogen, cyano, -C(=O)-NH2, -C(=O)-N(C1-C6alkyl)2, -C(=O)-OH, -C(=O)-Ci-C6alkyl, -C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O- (Ci-C6alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)-CH(phenyl)-O-(Ci-C6alkyl), -S(=O)2- (Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-Ce alkyl);

[0209] R3is cyano or Ci-Ce alkyl optionally substituted with one or more halogens; and

[0210] each of R4and R5is independently hydrogen or halogen,

[0211] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0212]

[0213] In one embodiment of the compound of Formula (II),

[0214] RY3is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3- 10 membered carbocyclic group, a 3-12 membered heterocyclic group, 6- to 14-membered aryl, 5- to 12-membered heteroaryl, andR, wherein each of said alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0215] Rzis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0216] Rwis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl,

[0217] preferably,

[0218] RY3is selected from the group consisting of cyano, C2-C6 alkynyl, Ci-Ce alkoxy, a 3- 10 membered carbocyclic group, 6- to 14-membered aryl, 5- to 12-membered heteroaryl, and [structural formula], wherein each of said alkynyl, alkoxy, carbocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0219] Rzis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more Ci-Ce alkyl,

[0220] Rwis Ci-Ce alkyl optionally substituted with deuterium,

[0221] more preferably,

[0222] RY3is selected from the group consisting of cyano, C2-C3 alkynyl, C1-C3 alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl, thiadiazolyl,Nand ’H, wherein each of alkynyl, alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl, and thiadiazolyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, and NH2,

[0223] Rzis C1-C3 alkylene or cyclopropylene, wherein each of said alkylene and cyclopropylene is independently optionally substituted with one or more C1-C3 alkyl, and

[0224] Rwis C1-C3 alkyl optionally substituted with deuterium.

[0225]

[0226] In one embodiment of the compound of Formula (II),

[0227] RY3is selected from the group consisting ofCN[structural formula images as shown in PDF] HEIGHT="68" WIDTH="224" SRC="imgf000030_0001.tif" / > [structural formula labels within image]

[0228] [CF₃ label associated with structural formula image] HEIGHT="76" WIDTH="305" SRC="imgf000030_0003.tif" / >

[0229]

[0230] [CH₃ and NH₂ labels associated with structural formula image] HEIGHT="249" WIDTH="345" SRC="imgf000030_0005.tif" / >

[0231] [CH₃ NH₂ labels within structural image]CF3

[0236] In one embodiment of the compound of Formula (II),

[0237] RY3is selected from the group consisting of

[0239]

[0240] CH3

[0241]

[0242] CF3

[0243] s CF2H HN— HN— HN— HN-CD3

[0244]

[0245]

[0246] In one embodiment of the compound of Formula (II),

[0247] R1is -CH2-(Hal), -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen,

[0248] preferably,

[0249] R1is -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen, and

[0250] more preferably,

[0251] R1is -CHF2or -CF3.

[0252]

[0253] In one embodiment of the compound of Formula (II),

[0254] R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, halogen, cyano, -C(=O)-NH2, -C(=O)-N(C1-C6alkyl)2, -C(=O)-OH, -C(=O)-Ci-C6alkyl,-C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O- (Ci-C6alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)-CH(phenyl)-O-(Ci-C6alkyl), -S(=0)2- (Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-Ce alkyl),

[0255] preferably, R2is 6-10 membered heterocyclyl which contains one or more nitrogen atoms or one nitrogen atom and one oxygen atom as the ring hetero atoms and is optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, halogen, cyano, C2-Ce alkenyl, C2-Ce alkynyl, hydroxy, Ci-Ce alkoxy, NH2, carbamoyl, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, Ci-Ce alkoxy, and carbamoyl.

[0256] In one embodiment of the compound of Formula (II), R2is selected from the following:

[0258] wherein:

[0259] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-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 group selected from Ci-Ce alkyl and -SO2(Ci-Ce alkyl);

[0260] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and V ' 'R*;

[0261] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2;

[0262] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl

[0263] Z is selected from -NRz14and -CR'R";0

[0264] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2,' o0XXA°.KR22, Ar and -SO2-(Ci-C6alkyl);

[0265] 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;

[0266] R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium;

[0267] Ar is 6-14 membered aryl;

[0268] R' and R" are hydrogen, or 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 Ci-Ce alkyl, hydroxy, Ci-Ce alkoxy, oxo, and amino, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more halogen; and

[0269] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2and -SO2-(Ci- G> alkyl).

[0270] In one embodiment of the compound of Formula (II), R2is selected from the following:

[0274] Rz21(R2-B);

[0275] wherein:

[0276] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-C3 alkyl),

[0277] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(Ci-C2 alkyl),

[0278] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3;

[0279] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and';

[0280] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2;

[0281] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl;

[0282] preferably, in formula (R2-A-1), Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1-C3 alkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, ando' and R is selected from the group consisting of hydroxy, methoxy, ethoxy, -NH2, and -N(CH3)2,

[0283] more preferably, in formula (R2-A-l), Rzl3is selected from the group consisting of hydrogen, methyl, -CH2-O-CH3, -CH2-OH, -COOH, -C(=O)-OCH3, -C(=O)-NH2, and - C(=O)-N(CH3)2;

[0284] preferably, in formulae (R2-A-2) and (R2-A-3), Rzl3is Ci-C3alkyl,

[0285] more preferably, in formulae (R2-A-2) and (R2-A-3), Rzl3is methyl;0 \R21

[0286] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2, 'o OXAK, Ar and -SO2-(Ci-C6alkyl),n0

[0287] preferably, Rz14is selected from hydrogen,xA,Arand -SO2- (C1-C4 alkyl),o0

[0288] more preferably, Rz14is selected from hydrogen,' A, Ar, -SO2-(methyl), and -SO2-(isopropyl);

[0289] 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;

[0290] R22is selected from the group consisting of hydrogen and Ci-Ce alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium,

[0291] R22is selected from the group consisting of hydrogen and Ci-C3alkyl, wherein said alkyl is optionally substituted with one or more halogens,

[0292] more preferably, R22is selected from the group consisting of hydrogen, methyl, and CHF2;

[0293] Ar is 6-14 membered aryl,

[0294] preferably, Ar is phenyl;

[0295] Rzl5is selected from the group consisting of -O-, -NH-, -N(Ci-Ce alkyl)- and -N(- SO2(Ci-C6alkyl))-,

[0296] preferably, Rzl5is selected from the group consisting of -O-, -NH-, -N(C1-C3alkyl)- and -N(-SO2(C1-C3alkyl))-,

[0297] more preferably, Rzl5is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(C1-C2alkyl))-,

[0298] still more preferably, in formula (R2-A-2), Rzl5is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(CH3))-,

[0299] still more preferably, in formula (R2-A-3), Rzl5is selected from the group consisting of -O-, -NH-, and -N(CH3)-;

[0300] Rzl6is selected from the group consisting of hydroxy, Ci-Ce alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens,

[0301] preferably, Rzl6is selected from hydroxy, Ci-C3alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens,

[0302] more preferably, Rzl6is selected from hydroxy, methoxy, -O-CHF2, and -NH2;

[0303] Rzl7is Ci-C6alkyl,

[0304] preferably, Rzl7is Ci-C3alkyl,

[0305] more preferably, Rzl7is methyl;

[0306] Rzl8is Ci-C6alkyl,

[0307] preferably, Rzl8is Ci-C3alkyl,

[0308] more preferably, Rzl8is methyl; and

[0309] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2and -SO2-(Ci- G> alkyl),

[0310] preferably, Rz21is selected from the group consisting of -C(=O)-N(CI-C4alkyl)2and -SO2-(C1-C4alkyl),

[0311] more preferably, Rz21is selected from the group consisting of -C(=O)-N(CH3)2, - SO2-(methyl), and -SO2-(isopropyl).

[0312]

[0313] In one embodiment of the compound of Formula (II),

[0314] R3is cyano or Ci-Ce alkyl optionally substituted with one or more halogens,

[0315] preferably, R3is cyano or C1-C3 alkyl optionally substituted with one or more halogens, and

[0316] more preferably, R3is cyano, methyl, ethyl, -CH2F, or -CF2-CH3.

[0317]

[0318] In one embodiment of the compound of Formula (II),

[0319] each of R4and R5is independently hydrogen or halogen,

[0320] preferably, each of R4and R5is independently hydrogen, -F, or -Cl,

[0321] more preferably, each of R4and R5is independently hydrogen or -F, and

[0322] still more preferably, R4is hydrogen and R5is hydrogen or -F.

[0323]

[0324] Non-limiting exemplary embodiments of the compounds of Formula (I)

[0325] In one embodiment, the present disclosure relates to a compound of Formula (la), Formula (lb), Formula (Ic), Formula (Id), or Formula (le):

[0329] wherein:

[0330] Hal is halogen;

[0331] each of R11and R12is independently hydrogen or halogen;

[0332] each of RY1and RY2is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3-10 membered carbocyclic group, a 3-12 membered heterocyclic group, 6- to 14-membered aryl, 5- to 12-membered ' / R’k,. RYX Nheteroaryl, and H, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0333] Rxis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0334] Ryis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl;

[0335] R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl,halogen, cyano, -C(=O)-NH2, -C(=O)-N(C1-C6alkyl)2, -C(=O)-OH, -C(=O)-Ci-C6alkyl, -C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O- (Ci-C6alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)-CH(phenyl)-O-(Ci-C6alkyl), -S(=O)2- (Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-Ce alkyl);

[0336] R3is Ci-Ce alkyl which is optionally substituted with one or more halogens; and

[0337] each of R4and R5is independently hydrogen or halogen,

[0338] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0339]

[0340] In one embodiment of a compound of Formula (la), Formula (lb), Formula (Ic), Formula (Id), or Formula (le),

[0341] Hal is halogen, preferably -F or -Cl, more preferably -F;

[0342] each of R11and R12is independently hydrogen or halogen,

[0343] preferably, each of R11and R12is independently hydrogen, -F, or -Cl,

[0344] more preferably, both R11and R12are -F, or one of R11and R12is -F and the other one is hydrogen;

[0345] preferably, each of RY1and RY2is selected from the group consisting of hydrogen, cyano, halogen, Ci-Ce alkyl, C2-Ce alkynyl, Ci-Ce alkoxy, a 3-10 membered carbocyclic, RC RY\ N group, a 3-12 membered heterocyclic group, 6- to 14-membered aryl, and ’Hwherein each of said alkyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, and aryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl, Rxis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more Ci-Ce alkyl, and Ryis Ci-Ce alkyl optionally substituted with deuterium,

[0346] more preferably, RY1is selected from the group consisting of hydrogen, cyano, halogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, a 3-10 membered carbocyclic group, a.. RX. RYX N'3-12 membered heterocyclic group, 6- to 14-membered aryl, and [structural formula], wherein each of said alkyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, and aryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and halogen,

[0347] RY2is C1-C6alkyl,

[0348] Rxis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more Ci-Ce alkyl, and

[0349] Ryis Ci-Ce alkyl optionally substituted with deuterium,

[0350] still more preferably, RY1is selected from the group consisting ofHHHDHFFCIHCNHCH3 |— CF3PH|_ / |_ / CF2H,, CF3|-° |-° |-o

[0353] RY2is C1-C6alkyl,

[0354] still more preferably, RY1is selected from the group consisting ofFHH FCI|-CN |-CH3|-^=

[0355]

[0357] RY2is C1-C3 alkyl;

[0358] preferably, R1is -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen,

[0359] more preferably, R1is -CHF2 or -CF3;

[0360] preferably, R2is 6-10 membered heterocyclyl which contains one or more nitrogen atoms or one nitrogen atom and one oxygen atom as the ring hetero atoms and is optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, carbamoyl, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with oneor more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, Ci-Ce alkoxy, and carbamoyl,

[0361] more preferably, R2is selected from the following:

[0362]

[0363] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-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 group selected from Ci-Ce alkyl and -SO2(C1-C6alkyl),

[0364] Rzl3is selected from the group consisting of hydrogen, Ci-Ce alkyl, -(C1-C3Ovalkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, and '

[0365] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2,

[0366] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl,

[0367] Z is selected from -NRz14and -CR'R",

[0368] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2,and -SO2-(Ci-C6alkyl),

[0369] R21is selected from the group consisting of Ci-Ce alkyl and 3-8 membered cycloalkyl, wherein each of said alkyl and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl and 3-8 membered cycloalkyl,

[0370] R22is selected from the group consisting of hydrogen and Ci-Ce alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium,

[0371] Ar is 6-14 membered aryl,

[0372] R' and R" are hydrogen, or 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 Ci-Ce alkyl, hydroxy, Ci-Ce alkoxy, oxo, and amino, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more halogen,

[0373] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2 and -SO2-(C1-C6alkyl),

[0374] still more preferably, R2is selected from the following:— — 7O d

[0378] R (R2-B),

[0379] still more preferably, R2is selected from Formula (R2-A-l), Formula (R2-A-2), Formula (R2-A-4), and Formula (R2-B),

[0380] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-C3 alkyl),

[0381] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(Ci-C2 alkyl),

[0382] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3,

[0383] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and'

[0384] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2,

[0385] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl,

[0386] preferably, in formula (R2-A-1), Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1-C3 alkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, andand R#is selected from the group consisting of hydroxy, methoxy, ethoxy, -NH2, and -N(CH3)2,

[0387] more preferably, in formula (R2-A-l), Rzl3is selected from the group consisting of hydrogen, methyl, -CH2-O-CH3, -CH2-OH, -COOH, -C(=O)-OCH3, -C(=O)-NH2, and - C(=O)-N(CH3)2,

[0388] preferably, in formulae (R2-A-2) and (R2-A-3), Rzl3is C1-C3 alkyl,

[0389] more preferably, in formulae (R2-A-2) and (R2-A-3), Rzl3is methyl,Ov

[0390] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2, 'o o^R22XAK, Ar and -SO2-(C1-C6alkyl),o o vU,

[0391] preferably, Rz14is selected from hydrogen,' ZA,Arand -SO2- (C1-C4 alkyl),n0X O.R22

[0392] more preferably, Rz14is selected from hydrogen,' ZA,Ar, - SO2-(methyl), and -SO2-(isopropyl),

[0393] 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;

[0394] R22is selected from the group consisting of hydrogen and Ci-Ce alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium,

[0395] preferably, R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more halogens,

[0396] more preferably, R22is selected from the group consisting of hydrogen, methyl, and CHF2,

[0397] Ar is 6-14 membered aryl, preferably, Ar is phenyl,

[0398] Rzl5is selected from the group consisting of -O-, -NH-, -N(Ci-Ce alkyl)- and -N(- SO2(Ci-C6alkyl))-,

[0399] preferably, Rzl5is selected from the group consisting of -O-, -NH-, -N(C1-C3alkyl)- and -N(-SO2(C1-C3alkyl))-,

[0400] more preferably, Rzl5is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(C1-C2alkyl))-,

[0401] still more preferably, in formula (R2-A-2), Rzl5is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(CH3))-,

[0402] still more preferably, in formula (R2-A-3), Rzl5is selected from the group consisting of -O-, -NH-, and -N(CH3)-,

[0403] Rzl6is selected from the group consisting of hydroxy, Ci-Ce alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens,

[0404] preferably, Rzl6is selected from hydroxy, C1-C3 alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens,

[0405] more preferably, Rzl6is selected from hydroxy, methoxy, -O-CHF2, and -NH2,

[0406] Rzl7is Ci-Ce alkyl, preferably, Rzl7is C1-C3 alkyl, more preferably, Rzl7is methyl,

[0407] Rzl8is Ci-Ce alkyl, preferably, Rzl8is C1-C3 alkyl, more preferably, Rzl8is methyl,

[0408] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2 and -SO2-(C1-C6alkyl),

[0409] preferably, Rz21is selected from the group consisting of -C(=O)-N(C1-C4alkyl)2and -SO2-(C1-C4alkyl),

[0410] more preferably, Rz21is selected from the group consisting of -C(=O)-N(CH3)2, - SO2-(methyl), and -SO2-(isopropyl),

[0411] still more preferably, R2is selected from the following:N N N

[0416] bb -U ^NHA6 6 6 6 d u'NH2QOHQ0'- Q80

[0419] still more preferably, R2is selected from the following:

[0424] preferably, R3is C1-C3 alkyl which is optionally substituted with one or more halogens,

[0425] more preferably, R3is methyl or ethyl, wherein said methyl and ethyl is independently optionally substituted with one or more halogens,

[0426] still more preferably, R3is selected from the group consisting of methyl, ethyl, - CH2F, -CHF2, and -CF2-CH3;

[0427] preferably, each of R4and R5is independently hydrogen, -F, or -Cl, and

[0428] more preferably, each of R4and R5is independently hydrogen or -F,

[0429] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0430]

[0431] In one embodiment of a compound of Formula (la), Formula (lb), Formula (Ic), Formula (Id), or Formula (le),

[0432] Hal is halogen;

[0433] each of R11and R12is independently hydrogen or halogen;

[0434] RY1is selected from the group consisting of hydrogen, cyano, halogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, a 3-7 membered carbocyclic group, a 4-6 membered heterocyclic group containing an oxygen atom and / or nitrogen atom as a ring heteroatom,, Rt ^RYNphenyl, andH, wherein each of said alkyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, and phenyl is independently optionally substituted with one or more selected from C1-C3 alkyl, C1-C3 haloalkyl, and halogen;

[0435] RY2is Ci-C6alkyl;

[0436] Rxis Ci-Ce alkylene or 3-7 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more Ci-Ce alkyl;

[0437] Ryis Ci-Ce alkyl optionally substituted with deuterium;

[0438] R2is selected from the following:

[0440] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-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 group selected from Ci-Ce alkyl and -SO2(Ci-Ce alkyl);

[0441] Rzl3is selected from the group consisting of hydrogen, Ci-Ce alkyl, -(C1-C3Ovalkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, and ';

[0442] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2;

[0443] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl;

[0444] Z is selected from -NRz14and -CR'R";0 \R21

[0445] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2, ' o oXAK, Ar and -SO2-(Ci-C6alkyl);

[0446] 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;

[0447] R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium;

[0448] Ar is 6-14 membered aryl;

[0449] R' and R" are hydrogen, or 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 Ci-Ce alkyl, hydroxy, Ci-Ce alkoxy, oxo, and amino, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more halogen;

[0450] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2and -SO2-(Ci- G> alkyl);

[0451] R3is C1-C3 alkyl which is optionally substituted with one or more halogens; and

[0452] each of R4and R5is independently hydrogen or halogen,

[0453] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0454]

[0455] In one embodiment of a compound of Formula Formula (la), Formula (lb), Formula (Ic), Formula (Id), or Formula (le),

[0456] Hal is halogen;

[0457] each of R11and R12is independently hydrogen or halogen;

[0458] RY1is selected from the group consisting of hydrogen, cyano, halogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, a 3-7 membered carbocyclic group, a 4-6 membered heterocyclic group containing an oxygen atom and / or nitrogen atom as a ring heteroatom, x,. RYphenyl, and’ H, wherein each of said alkyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, and phenyl is independently optionally substituted with one or more selected from C1-C3 alkyl, C1-C3 haloalkyl, and halogen;

[0459] RY2is Ci-C6alkyl;

[0460] Rxis Ci-Ce alkylene or 3-7 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more Ci-Ce alkyl;

[0461] Ryis Ci-Ce alkyl optionally substituted with deuterium;

[0462] R1is -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen;

[0463] R2is selected from the following:I

[0467] Rz21(R2-B);

[0468] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-C3 alkyl);

[0469] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and'

[0470] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2,

[0471] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl;0 \R21

[0472] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2, k o0JXOR22XAK, Ar and -SO2-(Ci-C6alkyl);

[0473] 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;

[0474] R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium;

[0475] Ar is 6-14 membered aryl;

[0476] Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C6alkyl)- and -N(-SO2(C1-C6alkyl))-;

[0477] Rz16is selected from the group consisting of hydroxy, C1-C6alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens;

[0478] Rz17is C1-C6alkyl;

[0479] Rz18is C1-C6alkyl;

[0480] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2and -SO2-(Ci- G> alkyl);

[0481] R3is C1-C3 alkyl which is optionally substituted with one or more halogens;; and

[0482] each of R4and R5is independently hydrogen or halogen,

[0483] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0484]

[0485] In one embodiment of a compound of Formula Formula (la), Formula (lb), Formula (Ic), Formula (Id), or Formula (le),

[0486] Hal is -F;

[0487] both R11and R12are -F, or one of R11and R12is -F and the other one is hydrogen;

[0488] RY1is selected from the group consisting ofH H H FCI|— CN |— CH3CF3P HI / | / CF*H,,CF3r° r°

[0489] HN—

[0490]

[0491] RY2is C1-C3 alkyl;

[0492] R1is -CHF2or -CF3;

[0493] R2is selected from the following:

[0496] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(Ci-C2 alkyl);

[0497] in formula (R2-A-1), Rz13is selected from the group consisting of hydrogen, C1-C3alkyl, -(C1-C3 alkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, andand R#is selected from the group consisting of hydroxy, methoxy, ethoxy, -NH2, and -N(CH3)2;

[0498] in formula (R2-A-2), Rzl3is C1-C3 alkyl;oR22

[0499] Rz14is selected from hydrogen, Z,Arand -SO2-(Ci-C4 alkyl);

[0500] R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more halogens;

[0501] Ar is phenyl;

[0502] Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C3 alkyl)- and -N(-SO2(C1-C3 alkyl))-;

[0503] Rz16is selected from hydroxy, C1-C3 alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens;

[0504] Rz17is C1-C3 alkyl;

[0505] Rz21is selected from the group consisting of -C(=O)-N(CI-C4 alkyl )2and -SO2-(Ci- C4 alkyl);

[0506] R3is selected from the group consisting of methyl, ethyl, -CH2F, -CHF2, and -CF2- CH3; and

[0507] each of R4and R5is independently hydrogen or -F,

[0508] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0509]

[0510] In one embodiment of a compound of Formula Formula (la), Formula (lb), Formula (Ic), Formula (Id), or Formula (le),

[0511] Hal is -F;

[0512] both R11and R12are -F, or one of R11and R12is -F and the other one is hydrogen;

[0513] RY1is selected from the group consisting ofFHH FCI|-CN |~CH3|— ^ |-^=

[0514]

[0516] RY2is C1-C3 alkyl;

[0517] R1is -CHF2or -CF3;

[0518] R2is selected from the following:

[0523] R3is selected from the group consisting of methyl, ethyl, -CH2F, -CHF2, and -CF2- CH3; and

[0524] each of R4and R5is independently hydrogen or -F,

[0525] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0526]

[0527] In one embodiment, the exemplary compounds of Formula (I) are provided below:

[0528] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0529]

[0530] In another embodiment, the exemplary compounds of Formula (I) are provided below:99N\2\^N>^ ":t:r^isr601 801 Z.01 A V s\ ^0* °a / \ - 7A ^'d^Z^N =l^z^NdySld ddJHN \-0° AZzHN’^ r\Z°zHN*'\Z0 00901 SOI frOl A AN0-A0AdpN0 0^ KN0° / ^ d^Z^N d^ Z^Nd^Z^N'd ddVo r° / “ °3HN" \Z'2HN*'\Z0 00£01 JOI 101s\ ° °^f< °-° KN0 0A x dy^N d^Z^NJySj' d ddH fl,;t y < AV001 66 86> AAS-«J4 pNod^ Z^N d^Z^Nd^Z^N'ddXdH?rt:r,:t:rZNvL6 ^SA 96 S6S\0JZ,A X Ad^Z^Nd^ Z^N d dLCx 'H CY H < r- ' O / \ ex \ > LL _ _ \ / <£C C / « <n - \ / ox) Yr > >to U- x Nr X zzYA.-- N WO^Tr \O " r ^k'" 8£Z Z. EI CM. 9EI 0 ^=z\wsX °NlF " Nr ° dy^'JXNd ddHX x NNCrS£Z H l H frEI EEIsA ywd\ / i / d0“k ° / r^ -Hxr Hr Nr Z Z E x NI I! r / 'NAHd d OEI / 'A H frY T Y r r rSs? M pNdJySl' pNJo / / "o / X dyY'd JXNd dH HHxr xr'»X^ xx611 8ZZ LZZNXrc<rrf'bA r x X rdX NJ^YN XdHx Nr911 CfV H x szz vzz pN0°7xJXNdF F F, NAF y o o \ V\sI T o o VsNU x,'sX^ AX _ _'st z5x X VAAiX H YAAI383NVAAF F H 384 385HNCl. M.c|NClZA'AH HH0531] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0532]

[0533] Non-limiting exemplary embodiments of the compounds of Formula (II)

[0534] In one embodiment, the present disclosure relates to a compound of Formula (Ila), Formula (lib), or Formula (lie):

[0538] wherein:

[0539] Hal is halogen;

[0540] each of R13and R14is independently hydrogen or halogen;

[0541] RY3is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3- 10 membered carbocyclic group, a 3-12 membered heterocyclic group, 6- to 14- H ^RwNmembered aryl, 5- to 12-membered heteroaryl, and, wherein each of said alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0542] Rzis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;

[0543] Rwis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2- Ce alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl;

[0544] R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, halogen, cyano, -C(=O)-NH2, -C(=O)-N(C1-C6alkyl)2, -C(=O)-OH, -C(=O)-Ci-C6alkyl, -C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O-(C1-C6 alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)-CH(phenyl)-O-(Ci-C6alkyl), -S(=0)2- (Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-Ce alkyl);

[0545] R3is cyano or Ci-Ce alkyl optionally substituted with one or more halogens; and

[0546] each of R4and R5is independently hydrogen or halogen,

[0547] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0548]

[0549] In one embodiment of a compound of Formula (Ila), Formula (lib), or Formula (lie),

[0550] Hal is halogen, preferably -F or -Cl, more preferably -F;

[0551] each of R13and R14is independently hydrogen or halogen,

[0552] preferably, each of R13and R14is independently hydrogen, -F, or -Cl,

[0553] more preferably, both R13and R14are -F, or one of R13and R14is -F and the other one is hydrogen;

[0554] preferably, RY3is selected from the group consisting of cyano, C2-Ce alkynyl, Ci-Ce alkoxy, a 3-10 membered carbocyclic group, 6- to 14-membered aryl, 5- to 12-membered,, R'Aheteroaryl, and [structural formula], wherein each of said alkynyl, alkoxy, carbocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl,

[0555] Rzis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more Ci-Ce alkyl,

[0556] Rwis Ci-Ce alkyl optionally substituted with deuterium,

[0557] more preferably, RY3is selected from the group consisting of cyano, C2-C3alkynyl, C1-C3 alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl,.,, R „. RWNthiadiazolyl, and, wherein each of alkynyl, alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl, and thiadiazolyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, and NH2,

[0558] Rzis C1-C3 alkylene or cyclopropylene, wherein each of said alkylene and cyclopropylene is independently optionally substituted with one or more C1-C3 alkyl,

[0559] Rwis C1-C3 alkyl optionally substituted with deuterium

[0560] still more preferably, RY3is selected from the group consisting of|— CN | — = | ——

[0563] FN-^ HO hr HZNK3 HO l\r H I J.HN-CD3

[0568]

[0569] still more preferably, RY3is selected from the group consisting of

[0571]

[0574] HN- HN- HN-, HN-CD3H>

[0577] preferably, R2is 6-10 membered heterocyclyl which contains one or more nitrogen atoms or one nitrogen atom and one oxygen atom as the ring hetero atoms and is optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, halogen, cyano, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, Ci-Ce alkoxy, NH2, carbamoyl, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, Ci-Ce alkoxy, and carbamoyl,

[0578] more preferably, R2is selected from the following:DZ13 ^7^ ' I

[0579] Rz12(R2-A), or Rz21(R2-B);

[0580] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-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 group selected from Ci-Ce alkyl and -SO2(Ci-Ce alkyl);

[0581] Rzl3is selected from the group consisting of hydrogen, Ci-Ce alkyl, -(C1-C3alkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, and

[0582] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2;

[0583] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl

[0584] Z is selected from -NRz14and -CR'R";

[0585] Rz14is selected from hydrogen, Ci-Ce alkyl, -C(=O)-N(Ci-Ce alkyl)2,and -SO2-(Ci-C6alkyl);

[0586] 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;

[0587] R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium;

[0588] Ar is 6-14 membered aryl;

[0589] R' and R" are hydrogen, or 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 Ci-Ce alkyl, hydroxy, Ci-Ce alkoxy, oxo, and amino, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more halogen; and

[0590] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2 and -SO2-(Ci- G> alkyl)

[0591] still more preferably, R2is selected from the following:

[0595] Rz21(R2-B);

[0596] wherein:

[0597] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-C3 alkyl),

[0598] preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(Ci-C2 alkyl),

[0599] more preferably, each of Rz11and Rz12is independently selected from the group consisting of hydrogen, methyl and -CH2-O-CH3;

[0600] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and';

[0601] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2;

[0602] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl;

[0603] preferably, in formula (R2-A-1), Rz13is selected from the group consisting of hydrogen, C1-C3 alkyl, -(C1-C3 alkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, and O' ' R' and R#is selected from the group consisting of hydroxy, methoxy, ethoxy, -NH2, and -N(CH3)2,

[0604] more preferably, in formula (R2-A-l), Rzl3is selected from the group consisting of hydrogen, methyl, -CH2-O-CH3, -CH2-OH, -COOH, -C(=O)-OCH3, -C(=O)-NH2, and - C(=O)-N(CH3)2;

[0605] preferably, in formulae (R2-A-2) and (R2-A-3), Rzl3is C1-C3 alkyl,

[0606] more preferably, in formulae (R2-A-2) and (R2-A-3), Rzl3is methyl;O

[0607] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2,'O VX°' R22VV' R-xAK,Arand -SO2-(Ci-C6alkyl),

[0608] preferably, Rz14is selected from hydrogen,and -SO2- (C1-C4 alkyl),

[0609] more preferably, Rz14is selected from hydrogen,', Ar, -SO2-(methyl), and -SO2-(isopropyl);

[0610] 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;

[0611] R22is selected from the group consisting of hydrogen and Ci-Ce alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium,

[0612] R22is selected from the group consisting of hydrogen and Ci-C3alkyl, wherein said alkyl is optionally substituted with one or more halogens,

[0613] more preferably, R22is selected from the group consisting of hydrogen, methyl, and CHF2;

[0614] Ar is 6-14 membered aryl,

[0615] preferably, Ar is phenyl;

[0616] Rzl5is selected from the group consisting of -O-, -NH-, -N(Ci-Ce alkyl)- and -N(- SO2(Ci-C6alkyl))-,

[0617] preferably, Rzl5is selected from the group consisting of -O-, -NH-, -N(C1-C3alkyl)- and -N(-SO2(C1-C3alkyl))-,

[0618] more preferably, Rzl5is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(C1-C2alkyl))-,

[0619] still more preferably, in formula (R2-A-2), Rzl5is selected from the group consisting of -O-, -NH-, -N(CH3)- and -N(-SO2(CH3))-,

[0620] still more preferably, in formula (R2-A-3), Rzl5is selected from the group consisting of -O-, -NH-, and -N(CH3)-;

[0621] Rzl6is selected from the group consisting of hydroxy, Ci-Ce alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens,

[0622] preferably, Rzl6is selected from hydroxy, Ci-C3alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens,

[0623] more preferably, Rzl6is selected from hydroxy, methoxy, -O-CHF2, and -NH2;

[0624] Rzl7is Ci-C6alkyl,

[0625] preferably, Rzl7is C1-C3 alkyl,

[0626] more preferably, Rzl7is methyl;

[0627] Rzl8is Ci-C6alkyl,

[0628] preferably, Rzl8is C1-C3 alkyl,

[0629] more preferably, Rzl8is methyl; and

[0630] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2 and -SO2-(C1-C6alkyl),

[0631] preferably, Rz21is selected from the group consisting of -C(=O)-N(C1-C4alkyl)2and -SO2-(C1-C4alkyl),

[0632] more preferably, Rz21is selected from the group consisting of -C(=O)-N(CH3)2, - SO2-(methyl), and -SO2-(isopropyl),

[0633] still more preferably, R2is selected from the following:

[0636] O

[0637]

[0641] still more preferably, R2is selected from the following:

[0649] preferably, R3is cyano or C1-C3 alkyl optionally substituted with one or more halogens,

[0650] more preferably, R3is cyano, methyl, ethyl, -CH2F, or -CF2-CH3;

[0651] preferably, each of R4and R5is independently hydrogen, -F, or -Cl,

[0652] more preferably, each of R4and R5is independently hydrogen or -F, and

[0653] still more preferably, R4is hydrogen and R5is hydrogen or -F,

[0654] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0655]

[0656] In one embodiment of a compound of Formula (Ila), Formula (lib), or Formula (lie),

[0657] Hal is halogen;

[0658] each of R13and R14is independently hydrogen or halogen;

[0659] RY3is selected from the group consisting of cyano, C2-C3 alkynyl, C1-C3 alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl, thiadiazolyl, ■, _, R7„, RWNand ’’H, wherein each of alkynyl, alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl, and thiadiazolyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, and NH2;

[0660] Rzis C1-C3 alkylene or cyclopropylene, wherein each of said alkylene and cyclopropylene is independently optionally substituted with one or more C1-C3 alkyl;

[0661] Rwis C1-C3 alkyl optionally substituted with deuterium;

[0662] R2is selected from the following:

[0664] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-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 group selected from Ci-Ce alkyl and -SO2(C1-C6alkyl);

[0665] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and G ' R‘;

[0666] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2;

[0667] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl;

[0668] Z is selected from -NRz14and -CR'R";O

[0669] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2,'

[0670] 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;

[0671] R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium;

[0672] Ar is 6-14 membered aryl;

[0673] R' and R" are hydrogen, or 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 Ci-Ce alkyl, hydroxy, Ci-Ce alkoxy, oxo, and amino, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more halogen;

[0674] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2 and -SO2-(Ci- G> alkyl);

[0675] R3is cyano or C1-C3 alkyl optionally substituted with one or more halogens; and

[0676] each of R4and R5is independently hydrogen or halogen,

[0677] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0678]

[0679] In one embodiment of a compound of Formula (Ila), Formula (lib), or Formula (lie),

[0680] Hal is halogen;

[0681] each of R13and R14is independently hydrogen or halogen;

[0682] RY3is selected from the group consisting of cyano, C2-C3 alkynyl, C1-C3 alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl, thiadiazolyl,,, RWY Nand1 H, wherein each of alkynyl, alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl, and thiadiazolyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, and NH2;

[0683] Rzis C1-C3 alkylene or cyclopropylene, wherein each of said alkylene and cyclopropylene is independently optionally substituted with one or more C1-C3 alkyl;

[0684] Rwis C1-C3 alkyl optionally substituted with deuterium;

[0685] R2is selected from the following:

[0689] Rz21(R2-B);

[0690] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-C3 alkyl);

[0691] Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and';

[0692] R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2;

[0693] each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl;O

[0694] Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2,oOArand -SO2-(Ci-C6alkyl);

[0695] 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;

[0696] R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium;

[0697] Ar is 6-14 membered aryl;

[0698] Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C6alkyl)- and -N(-SO2(C1-C6alkyl))-;

[0699] Rz16is selected from the group consisting of hydroxy, C1-C6alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens;

[0700] Rz17is C1-C6alkyl;

[0701] Rz18is C1-C6alkyl;

[0702] Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2and -SO2-(Ci- G> alkyl);

[0703] R3is cyano or C1-C3 alkyl optionally substituted with one or more halogens; and

[0704] each of R4and R5is independently hydrogen or halogen,

[0705] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0706]

[0707] In one embodiment of a compound of Formula (Ila), Formula (lib), or Formula (lie),

[0708] Hal is -F;

[0709] both R13and R14are -F, or one of R13and R14is -F and the other one is hydrogen;

[0710] RY3is selected from the group consisting of

[0712]

[0716]

[0717]

[0718]

[0719] R1is -CHF2or -CF3;

[0720] R2is selected from the following:

[0721]

[0722] Rz16Rz18

[0723] (R2-A-4),K(R2-A-5), or

[0724] Rz21(R2-B);

[0725] each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(Ci-C2 alkyl);

[0726] in formula (R2-A-1), Rz13is selected from the group consisting of hydrogen, C1-C3alkyl, -(C1-C3 alkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, andand R#is selected from the group consisting of hydroxy, methoxy, ethoxy, -NH2, and -N(CH3)2;

[0727] in formulae (R2-A-2) and (R2-A-3), Rz13is C1-C3 alkyl;.0.

[0728] Rz14is selected from hydrogen,and -SO2-(Ci-C4alkyl);

[0729] R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more halogens;

[0730] Ar is phenyl;

[0731] Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C3 alkyl)- and -N(-SO2(C1-C3 alkyl))-;

[0732] Rz16is selected from hydroxy, C1-C3 alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens;

[0733] Rz17is C1-C3 alkyl;

[0734] Rz18is C1-C3 alkyl;

[0735] Rz21is selected from the group consisting of -C(=O)-N(CI-C4 alkyl)2 and -SO2-(Ci- C4 alkyl);

[0736] R3is cyano, methyl, ethyl, -CH2F, or -CF2-CH3;

[0737] each of R4and R5is independently hydrogen or -F,

[0738] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0739]

[0740] In one embodiment of a compound of Formula (Ila), Formula (lib), or Formula (lie),

[0741] Hal is -F;

[0742] both R13and R14are -F, or one of R13and R14is -F and the other one is hydrogen;

[0743] RY3is selected from the group consisting of[chemical structure labels as shown in image]

[0748]

[0751] R1is -CHF2or -CF3;

[0752] R2is selected from the following:

[0760] R3is cyano, methyl, ethyl, -CH2F, or –CF2-CH3; and

[0761] each of R4and R5is independently hydrogen or -F,

[0762] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0763]

[0764] In one embodiment, the exemplary compounds of Formula (II) are provided below:SOLSOL90 LZO LH H H^o-^yN'y / x'ox' Xr ~a ^isr^ 5*>sHN°0v pN0 0%7sX., 0 0 ^ d^ / ^N 1 Nd^y^Nd d dH H H^o'yxNyxxo-x x'oxxyNyx^o / ^rsr ^rr“ pXN3\ oMo-a? Qo:1A &- X A &JyX^N d^ / ^NddX d4° kX, OxIZx W X X_ / O "OD>k r^ X x dA jx=1^ / 4 d^ / XN' d-yXN'A M!4 d\- ° \- °ZHN^X / 0 KMAs\0K0S<o?=lyZ^N d-y^Nd d\-0ZyXo- H HN^X / 0 Xr 0pN0 0s?a< H pNA0:0V %7pN0 0%7d- / ^N'd-^ / ^N =ly / ^N4d d80160 LOIL

[0765] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0766]

[0767] In another embodiment, the exemplary compounds of Formula (II) are provided below:No. No. No. Structure Structure StructureF F F N^Z^F N. Q \\ i V V V V J Z<'N"S'> Z'N" A / =\ 61 62HL Z|Z x~~N H? 63HL x / A / / I °Z / ^NI '' / Z I °H ^N '"H HF FF,N^Z^F N< Z^F \\ Q \\ i N. i V V X ¥ P n ^N'SV^NA J1N- Z^N'S>^NX\ / =\ H I I / - Ss64HL L- Z V / / 69 ZZN Z 70Hl 1 / — bs XZ^N Z N-\ / IA Z > ° Z A^N " H ^N "H HF FF,N^Z " F,NZ^F N^Z "F\\ i \\ i \\ qv V YAV N<jr81 Z Z Zhi L. / — \ 82 83ZZ^N vZ^N '' Z^N H H Z^NH F F F XN^Z^F,N^fZ " F / W^F\x i y Z^N'SV^NA / =\ / V V L v y Z^M'S\X^MZ HN-CD3HL z / \\ 2-0Z" N'SV?''NA / =\ / ^Z^N N—J84 111 112HL / / 0 HL L. z — K N—JZ-Z'-'N 1oHH’NY^NV Xi N ''H SHH H H Q ZA % i » XX '"<y"\4 ^? = in Oil zOXIZA6£l O^ w1 / O \xxC / 3 X >4N> A5 O- OOo A 4 4 4 \ / _ / \ _ Olly" IzH^ °^ ° 4ZI"d ^ o d dH 4A '" X NT HZ^xZ%A^t ( 9 — < x N £l / r w yx N 1.x 1 N HV££l Z£l $<4 < O C0 xO \KIZd^ / ^N d^ / ^N4H F- °^0- X I zr0A°"0in OZl 0 611<>fXv 0dd X^lz-4' 0d^Z^Nd<d d' '.r 811 Lil 911 PPA^d^ / 44oV _ dN1V%ASil Z^NN^Z-L 0til N £11 V e / XWy\ AN^ ] H NV°r 4 °"b* fA &J-y^NdLS L LĹ L LJ r ' °y ■ yroz £0Z zoz1 Ndy^Nd d dH. y H. yNHzdO N-a. N10Z OOZ 661 1 N \dy / ^N4C co 7, Os°IZd ( _ _ \O "x / ZO^^ dK= <- H. y An_- “ H H\7. yx-ox"'' <N-y*^ox' N NN— AN~x N-^xU.— ( / V-< % J H 861 ^HOMJQS, H Z.61 961sX (To A1 NJy^N'dd Jy^Nd°^VH / HO'^Y'N'V—H / y^i\r "’~ CrN NS61 fr6l £61d A cx d^ J^NJdo ° X 1°^ 1 °-yN\NyNNZ61 161 061 < ) — << J 1 Hv yN^A N. < > — < d 1 H V yN^A Ny d A -Cx j4dy / ^NJy^N dy / *N'dd d6 L Lr rIwrvz'vzV r# V 'O II / \ _° / \ ex J »ne° 'Z!H HH / "xY Y Nr8SZ LSZ • V 9SZ Y / 0^ A^*y $r* d^ / ^N 1 Nd JSYNdd H t rH<- °^o > On<- ' ° ' VZILLN\1ZN'ZCrd y d YSSI YN 9VZ stz e 1 HjZd d- z^N A dy r / Zfd d V " I?H oH>r5w< ^o / / ,' <N'Zso'o > ow'x■ ' ^isr ' ° ' \zx Vtt! £VZ 801>Lr< S « Y? Y ^ yN^<?, N ON dy / ^N rC °% xd d^r^NdHV'" / N' / VLOZ 90Z SOI d-yY'NdOZ LSSLťsiFX NVF FHo Vs,NY~" F o rxNV. ZYHo V ^6' Z vvs364 365 366 YZS0TX NO=S=ONHF F NX T VF,NZv N^ / ^F HHo VsH N 1 r\,Hh oNs1 k 7 V / X s. J X J ^ o' j >-<] ^ o' YZ rV 367 368 3690 N / I.O=S=O H1 1F F F,N==r 'FH,NH Nxs1 Zx o V HN1Ho Vsx^siV Z ^6' YZ370 L' o' >— <] 371 374l>SM rU Y^NNHN dXZ N HH H0768] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0769]

[0770] As used herein, the term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0771] As used herein, the term “stereoisomers” refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.

[0772] As used herein, the term “diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may be separated into each stereoisomer under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0773] As used herein, the term “enantiomers” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0774] The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0775] 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.

[0776] 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)).

[0777] Compounds disclosed herein may be in an amorphous or crystalline form (crystal form or polymorph). Furthermore, the compounds disclosed herein may exist in one or more crystalline forms. Therefore, the scope of the present disclosure includes all amorphous or crystalline forms of the compounds disclosed herein. The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, rate of crystallization, storage temperatures, and other factors may cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0778] As used herein, the term “isotopically labeled form” of 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.

[0779] 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 produce 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.

[0780] 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.

[0781] 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.

[0782] The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base form of the parent compound with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Acid addition salts (e.g., mono - or di- salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di- salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L- aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(lS)-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.

[0783] One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is a hydrochloride salt.

[0784] Where the compounds disclosed herein contain an amine function, the compound may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the compounds disclosed herein.

[0785] The compounds of the invention may exist as mono- or di- salts depending upon the pKaof the acid from which the salt is formed.

[0786] It will be appreciated that for use in medicine the salts of the compounds disclosed herein should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g., hydrochloric, hydrobromic, sulfuric, nitric acid, phosphoric acid sulfuric acid, and perchloric acid and organic acids e.g., succinic, maleic, acetic, oxalic, malonic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g., oxalates or formates may be used, for example in the isolation of compounds disclosed herein and are included within the scope of this invention. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non- pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0787] 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, dodecyl sulfate, 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+(Ci-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, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0788] 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.

[0789]

[0790] Preparation Methods

[0791] According to a further aspect of the present disclosure, provided are a process of preparing a compound of Formula (I), and a process of preparing a compound of Formula (II), or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof. The following schemes are examples of synthetic schemes that may be used to synthesize any of the compound of Formula (I) and the compound of Formula (II). In the following schemes, reactive groups can be protected with protecting groups and de-protected by well-established techniques in the art. The compound of any one of Formula (I) and Formula (II) 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.

[0792]

[0793] According to a further aspect of the present disclosure, a process of preparing a compound of Formula (I) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises any one of the following General Procedures 1 to 13:

[0794]

[0795] General Procedure 1:

[0796] General Procedure 1 prepares the compound of Formula (I), particularly Formula (la) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0797] (a) reacting Intermediate A with oxidative halogenation reagent such as a compound of Formula (aa) or NCS to produce a compound of Formula (la):

[0798] Intermediate A

[0801] (b) reacting the compound of Formula (la) with a compound of Formula (ab) to produce a compound of Formula (lb):(ab)

[0804] (c) reacting the compound of Formula (lb) with H2 gas in the presence of a catalyst (e.g., Pd / C) to produce a compound of Formula (1c):

[0806] (d) reacting the compound of Formula (1c) with R2-Boc in the presence of Pd- PEPPSI-IHept-Cl to produce a compound of Formula (Id):

[0808] (e) deprotecting the compound of Formula (Id) to produce a compound of Formula

[0810] wherein R2and R3are as defined herein and each of R11and R12is independently fluoro(-F) or hydrogen.

[0811] Exemplary reaction conditions for each step of General Procedure 1 are described in the description below of Example 33.

[0812] In one embodiment, an exemplary reaction scheme may be Scheme A shown below:

[0813] Scheme AR3NH2TEA MC, 0-5 °C, 2 h

[0814] R2— Boc Pd-PEPPSI-IHept Cl, Cs2CO31,4-dioxane, 100 °C, 3 h

[0816]

[0817] General Procedure 2:

[0818] General Procedure 2 prepares the compound of Formula (I), particularly Formula (la) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0819] (a) reacting Intermediate A with CuCN to produce a compound of Formula (2a):

[0820]

[0821]

[0822] (b) reacting the compound of Formula (2a) with oxidative halogenation reagent such as NCS to produce a compound of Formula (2b):

[0824] (c) reacting the compound of Formula (2b) with a compound of Formula (ab) to produce a compound of Formula (2c):(ab)

[0827] (d) reacting the compound of Formula (2c) with R2-Boc in the presence of Pd- PEPPSI to produce a compound of Formula (2d):

[0828]

[0829] (e) deprotecting the compound of Formula (2d) to produce a compound of Formula (2e):

[0831] wherein R2and R3are as defined herein and each of R11and R12is independently fluoro(-F) or hydrogen.

[0832] Exemplary reaction conditions for each step of General Procedure 1 are described in the description below of Example 2.

[0833] In one embodiment, an exemplary reaction scheme may be Scheme B shown below:

[0834] Scheme BNCS AcOH, H2O, 25 °C, 12 hR2BOC R3NH2, TEA Cs2CO3, Pd-PEPPSI DCM, rt, 2 h 1,4-Dioxane,110 °C, 3hrs

[0835]

[0836]

[0837] General Procedure 3:

[0838] General Procedure 3 prepares the compound of Formula (lb) or Formula (II) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0839] (a) reacting a compound of Formula (3a) with a compound of Formula (ca) to produce a compound of Formula (3b):VH

[0840] O

[0841] (ca)

[0842] O O (3b)

[0843] (b) reacting the compound of Formula (3b) with NBS to produce a compound of Formula (3 c):

[0844] O O

[0845] (c) reacting the compound of Formula (3c) with a compound of Formula (cb) to produce a compound of Formula (3d):N NH2

[0846] C|(cb)>- RYN

[0847]

[0848] (d) reacting the compound of Formula (3d) with BnSH (benzyl mercaptan) to produce a compound of Formula (3e):RYN

[0849]

[0850] (e) reacting the compound of Formula (3e) with NFbNFb’FfcO to produce a compound of Formula (3f):'2RYN

[0851] (3f)

[0852] (f) reacting the compound of Formula (3f) with a compound of Formula (cc) to produce a compound of Formula (3g):

[0853] F F (cc)

[0854]

[0855] (g) reacting the compound of Formula (3g) with a thiation agent such as Lawesson’s Reagent to produce a compound of Formula (3f):

[0856]

[0857] (h) reacting the compound of Formula (3f) with oxidative halogenation reagent such as NCS or a compound of Formula (cd) to produce a compound of Formula (3g):

[0858] (cd)

[0859] (3g)

[0860] (i) reacting the compound of Formula (3g) with a compound of Formula (ce) to produce a compound of Formula (3h):

[0861] Raa'NH2 (ce)

[0862] (3h)

[0863] (j) reacting the compound of Formula (3h) with a compound of Formula (cf) in the presence of Pd-PEPPSI-iheps to produce a compound of Formula (3i):

[0864] R2-Boc (cf)

[0865]

[0866] (k) deprotecting the compound of Formula (3i) to produce a compound of Formula (3j):

[0867]

[0868] wherein

[0869] RYis RY1or RY3defined herein;

[0870] R11is as defined herein;

[0872] R3is as defined herein.

[0873]

[0874] In one embodiment, an exemplary reaction scheme may be Scheme C shown below:

[0875] Scheme CFit, OH > NBS CDI, THF, MgCl2, DCM, rt, 1 h reflux, 60 'C, 16 hBnSH EtOH, 150 'C, 12 h Pd2(dba)3, Xantphos, DIPEA, 1,4-Dloxane, 80 'C, 3 hNH2NH2·H2O EtOH, 80 °C, 12 hrs THF, rt, 2 hrs

[0876]

[0878]

[0879] General Procedure 4:

[0880] General Procedure 4 prepares the compound of Formula (II), particularly Formula (Ila) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopicallylabeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0881] (a) preparing a compound of Formula (4a):

[0882] (4a)

[0883] (b) reacting the compound of Formula (4a) with a compound of Formula (da) to produce a compound of Formula (4b):

[0884] r3 NH2(da)

[0885] (4b)

[0886] (c) reacting the compound of Formula (4b) with a compound of Formula (db) to produce a compound of Formula (4c):

[0887] R2’NH(db)

[0889] wherein R2and R3are as defined herein.

[0890] In one embodiment, an exemplary reaction scheme may be Scheme D shown below:

[0891] Scheme DNH2NH2·H2O, DIPEA DCM, 0 °C, 1 h Acetic acid, reflux, 1 hLawesson's Reagent BnSH Toluene, 120 °C Pd2(dba)3, Xantphos, DIPEA,1,4-Dloxane, 80 'C, 3 hR3^NH2HCIAcOH, H2O, ACN, rt, 1 hr TEA,DCM, r.t., 2 h

[0894]

[0895] General Procedure 5:

[0896] General Procedure 5 prepares the compound of Formula (II), particularly Formula (Ila) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0897] (a) reacting a compound of Formula (5a) with a compound of Formula (5b) to produce a compound of Formula (5c):

[0898]

[0901] (b) reacting the compound of Formula (5c) with a compound of Formula (5d) to produce a compound of Formula (5d):

[0902]

[0903]

[0904] (c) reacting the compound of Formula (5e) with a compound of Formula (da) to produce a compound of Formula (5f):oCI'NA / - N.

[0905] 0 Cl(da)

[0906]

[0907] (d) reacting the compound of Formula (5f) with a compound of Formula (db) to produce a compound of Formula (5g):z-\-NHo

[0908] \2(db)

[0910] (e) reacting the compound of Formula (5g) with a compound of Formula (5h) in the presence of Pd-PEPPSI-IHept Cl to produce a compound of Formula (5i):

[0911] R2-Boc (5h)

[0913] (f) deprotecting the compound of Formula (5i) to produce a compound of Formula (5j):

[0914] r2(5j)

[0915] wherein

[0916] Ra is a substituent;

[0917] each of R11and R12is independently fluoro(-F) or hydrogen; and

[0918] R2is as defined herein.

[0919] Exemplary reaction conditions for each step of General Procedure 5 are described in the description below of Example 61.

[0920] In one embodiment, an exemplary reaction scheme may be Scheme E shown below:

[0921] Scheme EPd2(dba)3, Xantphos, DIEA NaHCO3, EtOH dioxane, 25-100 °C, 2 h 25-85 °C, 12 hlr(ppy)2(dtbbpy)PF6, Cy2NMe, MeCN AcOH, CH3CN, H2O, 0-5 °C,1 h 40 °C, 2 h, 400W Blue LEDs (455 nm)

[0922]

[0924]

[0925] General Procedure 6:

[0926] General Procedure 6 prepares the compound of Formula (I) or (II) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0927] (a) preparing a compound of Formula (6a):

[0928]

[0929] (b) reacting the compound of Formula (6a) with oxidative halogenation reagent such as NCS to produce a compound of Formula (6b):

[0930] Cl (6b)

[0931] (c) reacting the compound of Formula (6b) with a compound of Formula (6c) to produce a compound of Formula (6d):

[0932] Raa~NH2(6c)

[0933]

[0934] (d) reacting the compound of Formula (6d) with a compound of Formula (6e) to produce a compound of Formula (6f):

[0935] R2’Boc(6e)

[0936]

[0937] (e) deprotecting the compound of Formula (6f) to produce a compound of Formula

[0938]

[0939] wherein

[0940] R2is as defined herein;

[0941] R11is fluoro(-F) or hydrogen;

[0942] Raa isor; and

[0943] R3is as defined herein.

[0944] Exemplary reaction conditions for each step of General Procedure 6 are described in the description below of Example 23.

[0945] In one embodiment, an exemplary reaction scheme may be Scheme F shown below:

[0946] Scheme FNH2NH2. H2O EtOH, 80°C, 12 hBnSH, Pd2(dba)3, Lawesson's reagent Xantphos, DIPEA Toluene, 120°C, 16 h 1,4-Dloxane, 80°C, 3 h

[0947] NCSAcOH, H2O, r.t., 4 hR2BOC Pd-PEPPSI-iheps, Cs2CO31,4-Dioxane, 100°C, 16 h

[0948]

[0949]

[0950] General Procedure 7:

[0951] General Procedure 7 prepares the compound of Formula (I) or (II) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0952] (a) preparing a compound of Formula (7a):

[0953]

[0954] (b) reacting the compound of Formula (7a) with oxidative halogenation reagent such as NCS to produce a compound of Formula (7b):

[0955]

[0956] (c) reacting the compound of Formula (7b) with a compound of Formula (7c) to produce a compound of Formula (7d):

[0957] Raa~NH2(7c)

[0958]

[0959] (d) reacting the compound of Formula (7d) with a compound of Formula (7e) to produce a compound of Formula (7f):R2-Boc

[0960] (7e)

[0961]

[0962] (e) deprotecting the compound of Formula (7f) to produce a compound of Formula (7g):

[0963]

[0964] wherein

[0965] R2is as defined herein;

[0966] R11is fluoro(-F) or hydrogen;

[0968] R3is as defined herein.

[0969] In one embodiment, an exemplary reaction scheme may be Scheme G shown below:

[0970] Scheme G

[0971] NCS AcOH, H2O, 0 'C to r.t., 3 hR2BOC Pd-PEPPSI-iheps, Cs2CO31,4-Dioxane, 100°C, 7 h

[0972] Boc

[0973]

[0974] General Procedure 8:

[0975] General Procedure 8 prepares the compound of Formula (I), particularly Formula (Ic) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[0976] (a) reacting a compound of Formula (ha) with a compound of Formula (hb) to produce a compound of Formula (8a):

[0977]

[0978] (hb)

[0979] (8a)

[0980] (b) reacting the compound of Formula (8a) with a compound of Formula (8b) to produce a compound of Formula (8c):

[0981] (8b)FR11

[0982]

[0983] (c) reacting the compound of Formula (8c) with a compound of Formula (he) to produce a compound of Formula (8d):

[0984] (he)

[0985]

[0986] (d) reacting the compound of Formula (8d) with a compound of Formula (8e) to produce a compound of Formula (8f):

[0987] RaaNH2(8e)

[0989] (e) reacting the compound of Formula (8f) with a compound of Formula (8g) to produce a compound of Formula (8h):

[0990] R2-Boc(8g)

[0992] (f) deprotecting the compound of Formula (8h) to produce a compound of Formula (8i):

[0993]

[0994] wherein

[0995] R2is as defined herein;

[0996] R11is fluoro(-F) or hydrogen;

[0997] Raa isK'; and

[0998] R3is as defined herein.

[0999]

[1000] Exemplary reaction conditions for each step of General Procedure 8 are described in the description below of Example 319.

[1001] In one embodiment, an exemplary reaction scheme may be Scheme H shown below:

[1002] Scheme HPd2(dba)3, Xantphos DIPEAj1,4-dioxane, 100 °C, 3 h

[1003] AcOH, CH3CN, H2O 5 °C, 2 hR2BOC Pd-PEPPSI-iheps, Cs2CO31,4-dioxane, 100 °C, 3 h

[1004]

[1005]

[1006] General Procedure 9:

[1007] General Procedure 9 prepares the compound of Formula (I) or (II) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1008] (a) preparing the compound of Formula (3h) according to General Procedure 3:

[1009]

[1010] (b) reacting the compound of Formula (3h) with R2-Boronic ester or R2-Boronic acid in the presence of a catalyst such as Pd-PEPPSI-iheps to produce a compound of Formula (9a):

[1011]

[1012] wherein

[1013] RYis RY1or RY3defined herein;

[1014] R11is as defined herein;

[1015] Raaisor; and

[1016] R3is as defined herein.

[1017] Exemplary reaction conditions for each step of General Procedure 9 are described in the description below of Example 362.

[1018] In one embodiment, an exemplary reaction scheme may be Scheme I shown below:

[1019] Scheme IR2-Boronic ester or R2-Boronic acid Pd-PEPPSI-iheps, Cs2CO31,4-Dioxane, 100 'C, 2 h

[1020] General Procedure 3 - Formula (3h)

[1021]

[1022] General Procedure 10:

[1023] General Procedure 10 prepares the compound of Formula (I), particularly Formula (la) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1024] (a) preparing the compound of Formula (1c) according to General Procedure 1:

[1026] (b) reacting the compound of Formula (1c) with R2-NH to produce a compound of Formula (10a):

[1028]

[1029] In one embodiment, an exemplary reaction scheme may be Scheme J shown below:

[1030] Scheme JR2-NH Pd-PEPPSI-IHept Cl, Cs2CO31,4-dioxane, 100 °C, 3 h

[1031]

[1032]

[1033] General Procedure 11:

[1034] General Procedure 11 prepares the compound of Formula (I) or (II) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1035] (a) preparing the compound of Formula (3h) according to General Procedure 3:

[1036]

[1037] (b) reacting the compound of Formula (3h) with R2-NH to produce a compound of Formula (Ila):

[1038]

[1039]

[1040] Exemplary reaction conditions for each step of General Procedure 11 are described in the description below of Example 39.

[1041] In one embodiment, an exemplary reaction scheme may be Scheme K shown below:

[1042] Scheme KR2-NH Pd-PEPPSI-IHept Cl, Cs2CO31,4-dioxane, 100 °C, 3 hGeneral Procedure 3

[1043] - Formula (3h)

[1044]

[1045] General Procedure 12:

[1046] General Procedure 12 prepares the compound of Formula (I), particularly Formula (le) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1047] (a) reacting a compound of Formula (12a) with RY2-I to produce a compound of Formula (12b):O. IV-oN

[1048] (12a)ON \

[1049] (12b)

[1050] (b) reacting the compound of Formula (12b) with NFbNFb’FfcO to produce a compound of Formula (12c):O.,NH*V-NHN

[1051]

[1052] (c) reacting the compound of Formula (12c) with a compound of Formula (la) to produce a compound of Formula (12d):

[1054] (12d)

[1055] (d) reacting the compound of Formula (12d) with a thiation agent such as Lawesson’s Reagent to produce a compound of Formula (12e):

[1057] (e) reacting the compound of Formula (12e) with CISO3H to produce a compound of Formula (12f):

[1058]

[1059] (f) reacting the compound of Formula (12f) with a compound of Formula (lb) to produce a compound of Formula (12g):

[1060] Br(lb)

[1061]

[1062] (g) reacting the compound of Formula (12g) with Raa-NH2to produce a compound of Formula (12h):

[1063] (12h)

[1064] (h) reacting the compound of Formula (12h) with R2-Boc to produce a compound of Formula ( 12i):

[1065]

[1066] (i) deprotecting the compound of Formula (12i) to produce a compound of Formula

[1067]

[1068] wherein

[1069] R2and RY2are as defined herein;

[1070] R11is fluoro(-F) or hydrogen; and

[1071] RaaisK.

[1072]

[1073] In one embodiment, an exemplary reaction scheme may be Scheme L shown below:

[1074] Scheme Lo o

[1077]

[1078] General Procedure 13:

[1079] General Procedure 13 prepares the compound of Formula (II), particularly Formula (Ila) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, which comprises:

[1080] (a) preparing the compound of Formula (5g) according to General Procedure 5:

[1082] (b) reacting the compound of Formula (5g) with R2-NH to produce a compound of Formula (13a):

[1083] (13a)

[1084] wherein

[1085] Ra is a substituent;

[1086] each of R11and R12is independently fluoro(-F) or hydrogen; and

[1087] R2is as defined herein.

[1088]

[1089] In one embodiment, an exemplary reaction scheme may be Scheme M shown below:

[1090] Scheme MR2-NH Pd-PEPPSI-IHept Cl, Cs2CO31,4-dioxane, 100 °C, 1 hGeneral Procedure 5

[1091] - Formula (5g)

[1092]

[1093] Therapeutic utilities

[1094] 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” mayalso 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.

[1095] 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 symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting the progression of the disease, disorder or condition such that it does not reach a harmful or otherwise undesired state.

[1096] The terms “inhibiting” and “reducing,” or any variation of these terms in relation of 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.

[1097] " Disease", "disorder" and "condition" are used interchangeably herein.

[1098]

[1099] 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.

[1100] 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 invitro 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.

[1101] The anti-proliferative effects of the compounds of Formula (I) or Formula (II), or a pharmaceutically salt thereof have particular application in the treatment of human cancers (by virtue of their ability to inhibit PARG enzyme activity).

[1102] 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), pancreas 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.

[1103]

[1104] Pharmaceutical compositions / formulation

[1105] The present disclosure further relates to a pharmaceutical composition, comprising a pharmaceutically effective amount of one or more of the compounds disclosed herein, and a pharmaceutically acceptable carrier(s) and / or excipient(s). The composition may further comprise at least one of additional therapeutic agents in amounts effective for achieving the treatment or prevention of diseases or disorders disclosed herein. Pharmaceutically acceptable carriers and excipients are well known in the art, and the choice of carriers and excipients will to a large extent depend on factors such as mode of administration, their effects on solubility and stability, and the nature of dosage form.

[1106] The present disclosure further relates to a pharmaceutical composition, comprising a pharmaceutically effective amount of one or more of PARG inhibitors disclosed herein,and a pharmaceutically acceptable carrier(s) and / or excipient(s). The composition may further comprise at least one of additional therapeutic agents in amounts effective for achieving the treatment or prevention of diseases or disorders disclosed herein. Pharmaceutically acceptable carriers and excipients are well known in the art, and the choice of carriers and excipients will to a large extent depend on factors such as mode of administration, their effects on solubility and stability, and the nature of dosage form.

[1107] 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 and / 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.

[1108] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. For oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof. Methods of preparing various pharmaceuticalcompositions with a specific amount of active compound are known, or will be apparent, to those skilled in the art.

[1109]

[1110] T reatment method

[1111] 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 the 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.

[1112] The terms “human”, “patient” or “subject” are used interchangeably. A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[1113]

[1114] Administration

[1115] 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.

[1116] The composition provided herein is administered in a pharmaceutically effective amount. For example, the pharmaceutically effective amount of the composition disclosed herein may be in the range of about 0.01 mg to about 500 mg / kg of body weight, or about 10 mg to about 500 mg / kg of body weight. In one embodiment, the amount may be in the range of about 0.1 mg to about 250 mg / kg of body weight, or about 0.1 mg to about 10 mg / kg of body weight, or about 0.1 mg to about 1 mg / kg of body weight. In another embodiment, the amount be in the range of about 1 mg to about 100 mg / kg of body weight, preferably, about 10 mg to about 100 mg / kg of body weight. The amountof the compound or 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.

[1117]

[1118] Dosage

[1119] In a cancer treatment, the therapeutically effective amount of the compound disclosed herein or each inhibitor disclosed 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 each inhibitor disclosed herein 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.

[1120] Effective amounts of the compound or each inhibitor disclosed herein 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 or each inhibitor disclosed herein as described herein.

[1121] 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 ofthe present disclosure is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the pharmaceutical composition of the present disclosure is administered chronically on an ongoing basis.

[1122]

[1123] Combined therapy

[1124] 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.

[1125] The anti-cancer agent may include DNA damage response (DDR) targeting anticancer agents. The DNA damage response (DDR) is a collective term for the plethora of different intra- and inter-cellular signaling events and enzyme activities that result from the induction and detection of DNA damage. There are at least three key aspects of DDR that are different in cancers compared with normal cells, which in turn make DDR an attractive source for drug targets that can (and indeed currently are) being exploited to generate new cancer therapies. Loss of one or more DDR pathways, increased replication stress, and higher levels of endogenous DNA damage are all differentiating aspects of cancer DDR that can be targeted therapeutically. A number of anti-cancer agents targeting DDR have been known and developed, e.g., PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE- 821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC- 0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (e.g., MK- 1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide), etc. (see Mark J. O’Connor, Molecular Cell 60, November 19, 2015, p. 547-560, Choi et al., Int JMol Sci. 2022 Feb; 23(3): 1701). The compound disclosed herein also belongs to DDR targeting agents.

[1126]

[1127] In some embodiment, 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 one or more pharmaceutical acceptable carriers and / or excipients, wherein the composition may be administered simultaneously, separately or sequentially with additional DDR targeting anti-cancer agent described above.

[1128] In some embodiment, 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 further comprises administering additional DDR targeting anti -cancer agent described above to the subject.

[1129] In some embodiment, provided is a kit or product comprising:

[1130] - 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 / or excipients; and

[1131] - 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 and / or excipients.

[1132] In some embodiment, the kit or product 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 or product may further comprise a package insert comprisingan instruction for simultaneous, sequential or separate use in the treatment and / or prevention of diseases or disorders mediated by PARG.

[1133]

[1134] It is noted that the compounds, chemical moi eties or groups described in conjunction with a particular aspect, embodiment or example of the invention should be understood to applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed herein (including any accompanying claims, and abstract), and / or all of the steps of any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed herein (including any accompanying claims, and abstract), or to any novel one, or any novel combination, of the steps of any method or process disclosed.

[1135] The contents of the articles and documents referred to herein are incorporated herein by reference in its entirety as if all of their contents are described in detail herein.

[1136] Examples

[1137] The present disclosure will be further described below by descriptions of specific examples. It should be understood that the descriptions of these examples are only used to illustrate the present disclosure and not to limit the scope of the present disclosure. The experimental methods describing no specific conditions used in the examples presented below 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.

[1138] 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., 0 °C to 100 °C, or alternatively 0 °C to 80 °C). The reaction time is usually 0.1-60 hours, or alternatively 0.5-24 hours.

[1139]

[1140] Abbreviations

[1141] The abbreviations as used herein have the following meanings:Et₃N: TriethylamineHC1: Hydrochloric acidMeOH: MethanolEtOH: EthanolSOCl₂: Thionyl chloridePOCl₃: Phosphorus(V) oxychlorideDCE: Di chloroethaneTEA: TriethylamineDIEA: N, N-DiisopropylethylamineNaClO: Sodium hypochloriteBnSH: Benzyl Mercaptan, BenzenemethanethiolXantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxantheneCuCN: Copper(I) cyanideNCS: N-ChlorosuccinimideNIS: N-IodosuccinimideCs₂CO₃: Cesium carbonateNaHCO₃: Sodium bicarbonateNH₂NH₂·H₂O: Hydrazine hydrateMeCN: AcetonitrilePd-PEPPSI-IHept-Cl: Dichloro[1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)CHCl₃: ChloroformNa₂SO₄: Sodium sulfateLCMS: Liquid chromatography-mass spectrometryHPLC: High-performance liquid chromatographyBoc: tert-ButyloxycarbonylDCM: DichloromethaneTFA: Trifluoroacetic acidTHF: Tetrahydrofurandba: DibenzylideneacetoneACN: AcetonitrileEtOAc: Ethyl acetateNaOAc: Sodium acetateAcOH: Acetic acidTLC: Thin Layer ChromatographyDMF: DimethylformamideODS: Octa-decyl SilicaNBS: N-BromosuccinimidePE: Petroleum etherBAST: bis(2-methyoxyethyl)aminosulfur Trifluoride

[1142]

[1143] Materials and Methods

[1144] 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 prepacked columns filled with Merck flash silica gel 60 (40-63 pm) or C18 flash silica on an ISCO Combiflash Nextgen or a Biotage Selekt.

[1145] Unless otherwise noted, all reagents were without being further purified. 'H-NMR spectra were obtained in MeOH-d4 or CD₃CN or DMSO-d6 or CDCl₃ at room temperature on a Bruker 400 MHz instrument. When more than one conformer was detected, the chemical shifts for the most abundant one was reported. Chemical shifts of1H NMR spectra were recorded in parts per million (ppm) on the 5 scale from an internal standard of residual solvent. Splitting patterns are designed as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constants (Hz), and integrated and often tabulated; LC-MS conditions are described below:

[1146]

[1147]

[1148] LCMS Method A:

[1149] LCMS Column: SHIMADZU Xtimate C182.1*30 mm, 3um

[1150] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

[1151] Solvent B: acetonitrile (4L)+TFA(0.75mL)

[1152] Flow Rate: 0.8 mL / min

[1153] Run time: gradient 10%-80% (solvent B) over 6 minutes and holding at 80% for 0.5 minutes

[1154] Temperature: 50 °C

[1155]

[1156] LCMS Method B:

[1157] LCMS Column: SHIMADZU Nano Chrom 120 C18 3.0*30 mm, 3um

[1158] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

[1159] Solvent B: acetonitrile (4L)+TFA(0.75mL)

[1160] Flow Rate: 0.8 mL / min

[1161] Run time: gradient 10%-80% (solvent B) over 6 minutes and holding at 80% for 0.5 minutes

[1162] Temperature: 50 °C

[1163]

[1164] LCMS Method C:

[1165] LCMS Column: SHIMADZU Xtimate C182.1*30 mm, 3um

[1166] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

[1167] Solvent B: acetonitrile (4L)+TFA(0.75mL)

[1168] Flow Rate: 0.8 mL / min

[1169] Run time: gradient 30%-90% (solvent B) over 6 minutes and holding at 90% for 0.5 minutes

[1170] Temperature: 50 °C

[1171]

[1172] LCMS Method D:

[1173] LCMS Column: SHIMADZU Nano Chrom 120 C18 3.0*30 mm, 3um

[1174] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

[1175] Solvent B: acetonitrile (4L)+TFA(0.75mL)

[1176] Flow Rate: 0.8 mL / min

[1177] Run time: gradient 30%-90% (solvent B) over 6 minutes and holding at 90% for 0.5 minutes

[1178] Temperature: 50 °C

[1179]

[1180] Experimental Procedure:

[1181] Intermediate A

[1182] 2-(6-benzylsulfanyl-8-chloro-l-iodo-imidazo[l,5-a]pyridin-3-yl)-5- (difluoromethyl)-l,3,4-thiadiazoleNN

[1183]

[1184] Step 1: 6-bromo-8-chloro-imidazo[l,5-a]pyridine-3-carbohydrazide

[1185] To a solution of ethyl 6-bromo-8-chloro-imidazo[l,5-a]pyridine-3-carboxylate (5.1 g, 16.8 mmol) in EtOH (55 mL) was added NH₂NH₂·H₂O (2.97 g, 50.4 mmol, 85% purity) at 25 °C. The mixture was heated and stirred at 80 °C under a nitrogen atmosphere for 12 h. The mixture was concentrated under reduced pressure to produce a residue. The residue as a crude product was purified by flash column chromatography to afford 6- bromo-8-chloro-imidazo[l,5-a]pyridine-3-carbohydrazide (4.44 g, 91.3% yield) as a violet solid.

[1186] 1H NMR (400 MHz, DMSO-d6): d = 10.02 (br s, 1H), 9.49 (s, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 4.57 (br s, 2H).

[1187]

[1188] Step 2: 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[l,5-a]pyridine-3- carbohydrazide

[1189] To a solution of 6-bromo-8-chloro-imidazo[l,5-a]pyridine-3-carbohydrazide (4.40 g, 15.2 mmol) in THF (70 mL) were added TEA (3.08 g, 30.4 mmol) and (2,2- difluoroacetyl) 2,2-difluoroacetate (3.97 g, 22.8 mmol). The mixture was stirred at 25 °C under a nitrogen atmosphere for 15 h. The mixture was concentrated under reduced pressure to produce a residue. The residue as a crude product was purified by flash column chromatography to afford 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[l,5- a]pyridine-3 -carbohydrazide (4.69 g, 83.9% yield) as a light-yellow solid

[1190] 1H NMR (400 MHz, DMSO-d6): 3 = 10.93 (br s, 2H), 9.42 (s, 1H), 7.84 (s, 1H), 7.63 (s, 1H), 6.44 (t, J= 52.8 Hz, 1H).

[1191]

[1192] Step 3: 2-(6-bromo-8-chloro-imidazo[l,5-a]pyridin-3-yl)-5-(difluoromethyl)-l,3,4- thiadi azole

[1193] To a solution of 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[l,5-a]pyridine-3- carbohydrazide (4.69 g, 12.7 mmol) in Toluene (70 mL) was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (7.74 g, 19.1 mmol) at 25 °C. The mixture was heated and stirred at 110 °C under a nitrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue as a crude product was purified by column chromatography to afford 2-(6-bromo- 8-chloro-imidazo[l,5-a]pyridin-3-yl)-5-(difluoromethyl)-l,3,4-thiadiazole (736 mg, 15.7% yield) as a yellow solid.

[1194] 1H NMR (400 MHz, DMSO-d6): 3 = 9.49 (s, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.69 (d, J= 1.2 Hz, 1H), 7.67 (t, J = 53.2 Hz, 1H).

[1195]

[1196] Step 4: 6- 2-(6-benzylsulfanyl-8-chloro-imidazo[l,5-a]pyridin-3-yl)-5- (difluorom ethyl)- 1,3,4-thiadiazole

[1197] To a solution of 2-(6-bromo-8-chloro-imidazo[l,5-a]pyridin-3-yl)-5- (difluoromethyl)-l,3,4-thiadiazole (490 mg, 1.34 mmol) in dioxane (9 mL) were added Pd2(dba)3 (122 mg, 0.13 mmol), Xantphos (77.5 mg, 0.13 mmol), BnSH (199 mg, 1.61mmol) and DIEA (519 mg, 4.02 mmol) at 25 °C to produce a suspension. The suspension was degassed under vacuum and purged with N2 three times. The mixture was heated and stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was quenched with NaClO (5 mL), then diluted with H2O (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography to afford 6- 2-(6-benzylsulfanyl-8-chloro-imidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (470 mg, 1.15 mmol, 85.7% yield) as a yellow solid.

[1198] 1H NMR (400 MHz, DMSO-d6): 3 = 9.44 (s, 1H), 7.77 (s, 1H), 7.37-7.34 (m, 2H), 7.33-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.09 (t, J= 53.6 Hz, 1H), 6.98 (d, J= 1.6 Hz, 1H), 4.18 (s, 2H).

[1199]

[1200] Step 5: 2-(6-benzylsulfanyl-8-chloro-l-iodo-imidazo[l,5-a]pyridin-3-yl)-5- (difluorom ethyl)- 1,3,4-thiadiazole

[1201] To a solution of 2-(6-benzylsulfanyl-8-chloro-imidazo[l,5-a]pyridin-3-yl)-5- (difluoromethyl)-1,3,4-thiadiazole (598 mg, 1.46 mmol) in DCM (10 mL) was added NIS (658 mg, 2.93 mmol) at 5 °C. The mixture was warmed and stirred at 25 °C under a nitrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography to afford 2-(6-benzylsulfanyl-8-chloro-l-iodo-imidazo[l,5-a]pyridin-3-yl)-5- (difluoromethyl)-1,3,4-thiadiazole (348 mg, 44.4% yield) as a yellow solid.

[1202] MS (ESI) m / z = 534.7 [M+H]+

[1203]

[1204] The following compounds were prepared by a procedure similar to the procedure for preparing compound Intermediate A described above.MS (ESI) m / z Compound Structure Name[M+H]+

[1207] F F

[1208] (3R)-2,2-difluoro-4-methyl-pentan-3-amine hydrochloride

[1209]

[1210] Step 1: tert-butyl N-[(lR)-2,2-difluoro-l-isopropyl-propyl]carbamate

[1211] To a solution of tert-butyl N-[(lR)-l-acetyl-2-methyl-propyl]carbamate (6.85 g, 31.82 mmol) in DCM (70 mL) was added BAST (35.20 g, 159.09 mmol, 34.85 mL) at 0 °C under a nitrogen atmosphere. Then the reaction mixture was warmed to 25 °C and stirred at 25 °C for 36 hr. The reaction mixture was quenched with saturated NaHCO₃ (80 mL) slowly, and extracted with CH2CI2 (120 mL x 2). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl N-[(1R)-2,2-difluoro-1-isopropyl-propyl]carbamate (3.16 g, 10.65 mmol, 33.48% yield, 80% purity) as a white solid.

[1212] MS (ESI) m / z = 182.1 [M-tBu+H]+.

[1213]

[1214] Step 2: (3R)-2,2-difluoro-4-methyl-pentan-3 -amine hydrochloride

[1215] To a solution of tert-butyl N-[(1R)-2,2-difluoro-1-isopropyl-propyl]carbamate (1.0 g, 4.21 mmol) in DCM (10 mL) was added HCl / dioxane (2 M, 10.00 mL) at 25 °C under a nitrogen atmosphere. Then, the reaction mixture was stirred at 25 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to produce (3R)-2,2-difluoro-4-methyl-pentan-3 -amine (725 mg, crude, HC1) as a white solid, which was directly used for next step without being further purified.

[1216] ¹H NMR (400MHz, CDCl₃): δ = 8.88 (br s, 3H), 3.36–3.18 (m, 1H), 2.30–2.15 (m, 1H), 1.76 (t, J = 19.2 Hz, 3H), 1.15 (dd, J = 10.0, 7.2 Hz, 6H).

[1217]

[1218] The following compounds were prepared by a procedure similar to the procedure used to prepare the compound Intermediate C described above.MS (ESI) m / z Compound Structure Name[M+H]+(3 S)-2,2-difhioro-4-methyl- C-l \ HCI 138.1NH2pentan-3 -amine hydrochlorideF F

[1219]

[1220] Intermediate D

[1222] (2R)-l-fluoro-3-methyl-butan-2-amine hydrochloride

[1223] Step 1: tert-butyl N-[(lR)-l-(fluoromethyl)-2-methyl-propyl]carbamate

[1224] A mixture of 18-CROWN-6 (796.95 mg, 3.02 mmol) and KF (350.34 mg, 6.03 mmol) was dissolved in MeCN (10 mL). The mixture was stirred at 25 °C for 15 min. Tert-butyl(4R)-4-isopropyl-2,2-dioxo-oxathiazolidine-3-carboxylate (800 mg, 3.02 mmol,) was added to the above mentioned mixture at 25 °C. Then, the mixture was stirred at 25 °C under a nitrogen atmosphere for 24 h. TLC (petroleum ether / ethyl acetate=1 / 2, I₂) showed the starting material was consumed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was dissolved in DCM (8 mL) and 20% H2SO4 (2 mL). The mixture was stirred for 3 h. The mixture was diluted with NaHCCL (15 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄ and concentrated under reduced pressure to produce tert-butyl N-[(lR)-l-(fluoromethyl)-2- methyl-propyl]carbamate (520 mg, crude) as a colorless oil.

[1225] ¹H NMR (400MHz, DMSO-d₆): δ = 4.74–4.65 (m, 1H), 4.61–4.34 (m, 2H), 3.62–3.48 (m, 1H), 1.93–1.83 (m, 1H), 1.46 (s, 9H), 0.98 (t, J = 7.2 Hz, 6H).

[1226]

[1227] Step 2: (2R)-l-fluoro-3-methyl-butan-2-amine hydrochloride

[1228] To a solution of tert-butyl N-[(lR)-l-(fluoromethyl)-2-methyl-propyl]carbamate (520 mg, 2.53 mmol) in DCM (5 mL) was added HCl / dioxane (4 mL) at 15 °C. The mixture was stirred at 15 °C for 3 h. 'H NMR (ES24327-671-P1A) showed the isolated compound was the desired compound. The mixture was concentrated under reduced pressure to produce (2R)-l-fluoro-3-methyl-butan-2-amine (320 mg, crude, HC1) as a white solid.

[1229] ¹H NMR (400MHz, DMSO-d₆): δ = 8.40 (br s, 3H), 4.79–4.54 (m, 2H), 3.17 (d, J = 24.8 Hz, 1H), 2.02–1.92 (m, 1H), 0.97 (dd, J =10.2, 6.8 Hz, 6H).

[1230]

[1231] The following compounds were prepared by a procedure similar to the procedure used to prepare the compound Intermediate D described above.MS (ESI) m / z Compound Structure Name[M+H]+(2 S)- 1 -fluoro-3 -methyl-butan-2- D-l HCI 106.1'X^'NH2amine hydrochloride

[1232]

[1233] Intermediate EY HCIH2NX\X

[1234] I

[1235] (2R)-l,l-difluoro-3-methyl-butan-2-amine hydrochloride

[1236] Step 1: (NE, S)-2-methyl-N-(2-methylpropylidene)propane-2-sulfinamide

[1237] To a solution of (S)-2-methylpropane-2-sulfinamide (15 g, 123.76 mmol) and 2- methylpropanal (17.85 g, 247.52 mmol, 22.59 mL) in DCE (500 mL) was added CuSCL (59.26 g, 371.28 mmol). Then, the reaction mixture was stirred at 60 °C for 12 hr under anitrogen atmosphere. The reaction mixture was cooled to 20 °C, and then filtered. The filtrate was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain (NE, S)-2-methyl-N-(2- methylpropylidene)propane-2-sulfinamide (21.2 g, 120.94 mmol, 97.72% yield) as a colorless oil.

[1238] 'H NMR (400MHz, CDCh): d = 7.99 (t, J= 4.4 Hz, 1H), 2.76-2.70 (m, 1H), 1.22 (s, 9H), 1.19 (d, J = 4.0 Hz, 3H), 1.17 (d, J = 4.0 Hz, 3H).

[1239]

[1240] Step 2: (S)-N-[(lR)-l-[benzenesulfonyl(difluoro)methyl]-2-methyl-propyl]-2- methyl-propane-2-sulfmamide

[1241] To a solution of (NE, S)-2-methyl-N-(2-methylpropylidene)propane-2-sulfinamide (1.92 g, 10.93 mmol, 1.05 eq) and difluoromethylsulfonylbenzene (2 g, 10.41 mmol) in THF (53 mL) was added LiHMDS (1 M in THF, 12.49 mL) dropwise at -78 °C under a nitrogen atmosphere. Then, the reaction mixture was stirred at -78 °C for 1 hr under a nitrogen atmosphere. The reaction mixture was quenched with saturated NaCl aqueous solution (200 mL) at -78 °C. The solution mixture was extracted with EtOAc (250 mL x 3), and the combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to produce a residue. The residue was slurried with EtOAc (10 mL) and Petroleum ether (15 mL) at 20 °C for 1 hr. Then, the mixture was filtered and the filter cake was washed with Petroleum ether (5 mL x 2), dried under reduced pressure to obtain (S)-N-[(lR)-l-[benzenesulfonyl(difluoro)methyl]-2-methyl-propyl]-2-methyl- propane-2-sulfmamide (3.15 g, 8.49 mmol, 81.62% yield, 99.09% purity) as a white solid.

[1242] MS (ESI) m / z = 368.2 [M+H]+.

[1243]

[1244] Step 3: (S)-N-[(lR)-l-(difluoromethyl)-2-methyl-propyl]-2-methyl-propane-2- sulfinamide

[1245] To a solution of (S)-N-[(lR)-l-[benzenesulfonyl(difluoro)methyl]-2-methyl-propyl]- 2-methyl-propane-2-sulfinamide (2.34 g, 6.37 mmol) in MeOH (70 mL) were added Mg (1.55 g, 63.68 mmol) and I₂ (16.16 mg, 63.68 μmol) at 20 °C under a nitrogen atmosphere. Then the reaction mixture was stirred at 20 °C for 12 hr under a nitrogen atmosphere. The reaction mixture was quenched with water (50 mL) and HC1 (0.5 M, 50 mL). The solutionmixture was extracted with EtOAc (200 mL x 3), and the combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain (S)-N-[(1R)-1- (difluoromethyl)-2-methyl-propyl]-2-methyl-propane-2-sulfinamide (1.42 g, 5.88 mmol, 92.31% yield, 94.1% purity) as a white solid.

[1246] MS (ESI) m / z = 228.3 [M+H]+.

[1247]

[1248] Step 4: (2R)-l,l-difluoro-3-methyl-butan-2-amine hydrochloride

[1249] To a solution of (S)-N-[(lR)-l-(difluoromethyl)-2-methyl-propyl]-2-methyl-propane- 2-sulfinamide (1.42 g, 6.25 mmol) in DCM (10 mL) was added HCl / dioxane (2 M, 20 mL). The reaction mixture was stirred at 20 °C for 12 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to produce a (2R)-1,1- difluoro-3-methyl-butan-2-amine (897 mg, 5.34 mmol, 85.47% yield, 95% purity, HC1) as a white solid.

[1250] 'H NMR (400MHz, DMSO-t / 6): d = 8.62 (s, 3H), 6.41 (td, J = 53.2, 2.8 Hz, 1H), 3.52-3.39 (m, 1H), 2.05 (qd, J= 13.6, 6.8 Hz, 1H), 1.02 (d, J= 6.8 Hz, 6H).

[1251]

[1252] The following compounds were prepared by a procedure similar to the procedure used to prepare the compound Intermediate E described above.MS (ESI) m / z Compound Structure Name[M+H]+F\ / F= HCI (2S)- 1, 1 -difluoro-3 -methyl-butan-2- E-l 124.1amine hydrochloride

[1253]

[1254] Intermediate F1^ HCI

[1255] NH2

[1256] tert-butyl N-[(lS)-l-ethyl-2-methyl-propyl]carbamate hydrochloride

[1257] Step 1: tert-butyl N-[(lR)-l-formyl-2-methyl-propyl]carbamate

[1258] To a solution of DMSO (9.61 g, 122.98 mmol, 9.61 mL) in DCM (140 mL) was slowly added a solution of oxalyl dichloride (7.80 g, 61.49 mmol) in DCM (40 mL). The mixture was degassed and purged with N2 three times. Then, the mixture was stirred at -78 °C under a nitrogen atmosphere for 15 min. A solution of tert-butyl N-[(1R)-1- (hydroxymethyl)-2-methyl-propyl]carbamate (10 g, 49.19 mmol) in DCM (40 mL) was added slowly to the above mentioned mixture, and then the mixture was stirred at -78 °C under a nitrogen atmosphere for 0.5 h. TEA (24.89 g, 245.97 mmol) was added and the reaction mixture was warmed to 25 °C. The mixture was stirred at 25 °C under a nitrogen atmosphere for 12 h. The mixture was diluted with H2O (300 mL) and extracted with DCM (100 mL x 3). The organic layers were washed with 2 M HC1 (200 mL x 2) and brine (200 mL x 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to produce tert-butyl N-[(lR)-l-formyl-2-methyl-propyl]carbamate (9.37 g, crude) as a yellow solid.

[1259] 'H NMR (400MHz, CDCh) d = 9.64 (s, 1H), 5.10 (br s, 1H), 4.25-4.22 (m, 1H), 2.33-2.22 (m, 1H), 1.44 (s, 9H), 1.02 (d, J= 6.8 Hz, 3H), 0.94 (d, J= 6.8 Hz, 3H).

[1260]

[1261] Step 2: tert-butyl N-[(lR)-l-isopropylallyl]carbamate

[1262] To a mixture of methyl(triphenyl)phosphonium;iodide (9.64 g, 23.85 mmol) in THF (100 mL) was dropwise added t-BuOK (1 M, 29.81 mL) in THF at 0 °C. The mixture was stirred at 0 °C under a nitrogen atmosphere for 30 min. Then, to the resulting mixture was dropwise added a solution of tert-butyl N-[(lR)-l-formyl-2-methyl- propyl]carbamate (3 g, 14.91 mmol) in THF (10 mL) at 0 °C. The resulting mixture was warmed to 25 °C and stirred for 3 hr at 25 °C. The mixture was quenched with saturated aq. NH₄Cl (30 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (30 mLx 3), dried over Na₂SO₄, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography and the combined desired fractions was concentrated under reduced pressure to produce tert-butyl N-[(lR)-l-isopropylallyl]carbamate (1.5 g, 5.27 mmol, 35.35% yield, 70% purity) as a colorless liquid.

[1263] 'H NMR (400MHz, CDCh) d = 5.82-5.68 (m, 1H), 5.23-5.07 (m, 2H), 4.51 (br s, 1H), 3.99 (br s, 1H), 1.84-1.70 (m, 1H), 1.45 (s, 9H), 0.90 (dd, J= 6.8, 8.4 Hz, 6H).

[1264]

[1265] Step 3: tert-butyl N-[(lS)-l-ethyl-2-methyl-propyl]carbamate

[1266] To a solution of tert-butyl N-[(lR)-l-isopropylallyl]carbamate (1.8 g, 6.32 mmol) in EtOAc (20 mL) was added wet Pd / C (480.60 mg, 451.61 pmol, 10% purity) under an Ar atmosphere. The resulting mixture was degassed and purged with Ar three times and then purged with H2 three times. Then, the mixture was stirred at 25 °C for 16 hr under H2 (30 Psi) atmosphere. Through TLC, it was confirmed that the reaction was clean. The mixture was filtered and concentrated under reduced pressure to produce tert-butyl N- [(lS)-l-ethyl-2-methyl-propyl]carbamate (1.1 g, 5.46 mmol, 86.43% yield) as a white solid.

[1267] 'H NMR (400MHz, CDCh) d = 4.34-4.00 (m, 1H), 3.42-3.18 (m, 1H), 1.78-1.65 (m, 1H), 1.58-1.50 (m, 1H), 1.45 (s, 9H), 1.32-1.23 (m, 1H), 0.98-0.80 (m, 9H)

[1268]

[1269] Step 4: (3S)-2-methylpentan-3-amine hydrochloride

[1270] To a solution of tert-butyl N-[(lS)-l-ethyl-2-methyl-propyl]carbamate (1.1 g, 5.46 mmol) in DCM (6 mL) was added HCl / dioxane (2 M, 6 mL). The resulting mixture was stirred at 25 °C for 16 hr. The mixture was concentrated to produce (3 S)-2-methylpentan- 3-amine (720 mg, 5.23 mmol, 95.72% yield, HC1) as a white solid.

[1271] 'H NMR (400MHz, CDCh) d = 8.36 (br s, 3H), 3.08-2.83 (m, 1H), 2.16-2.04 (m, 1H), 1.85-1.69 (m, 2H), 1.15-1.01 (m, 9H).

[1272]

[1273] The following compounds were prepared by a procedure similar to the procedure used to prepare the compound Intermediate F described above.MS (ESI) m / z Compound Structure Name[M+H]+(3R)-2-methylpentan-3 -amineF-l HCI 102.1hydrochloride1274]

[1275] Intermediate G

[1277] Step 1: (2S)-l-[benzyl-[(2S)-2-hydroxy-3-methoxy-propyl]amino]-3-methoxy- propan-2-ol

[1278] To a mixture of phenylmethanamine (2.00 g, 18.7 mmol) in methanol (20 mL) was added (S)-2-(methoxymethyl)oxirane (4.9 g, 56.0 mmol). The reaction mixture was stirred at 80 °C for 16 h and then concentrated under vacuum. The residue was purified by column chromatography to afford (2S)-l-[benzyl-[(2S)-2-hydroxy-3-methoxy- propyl]amino]-3-methoxy-propan-2-ol (4.08g, 14.4 mmol, 77.18% yield) as a yellow oil.

[1279] MS (ESI) m / z = 284.1 [M+H]+.

[1280]

[1281] Step 2: [(lS)-l-[[benzyl-[(2S)-2-ethylsulfonyloxy-3-methoxy-propyl]amino]methyl]- 2-methoxy-ethyl] ethanesulfonate

[1282] To a solution of (2S)-l-[benzyl-[(2S)-2-hydroxy-3-methoxy-propyl]amino]-3- methoxy-propan-2-ol (2.00 g, 7.07 mmol) in DCM (20 mL) were added TEA (2.96 mL, 21.2 mmol) and ethanesulfonyl chloride (2.73 g, 21.2 mmol) under a nitrogen atmosphere at 0°C. The mixture was stirred at 0°C for 40 mins and then concentrated under vacuum at 25 °C to afford [(lS)-l-[[benzyl-[(2S)-2-ethylsulfonyloxy-3-methoxy- propyl]amino]methyl]-2-methoxy-ethyl] ethanesulfonate (1.76 g, 3.77 mmol, 53.3% yield) as yellow oil.

[1283] MS (ESI) m / z = 468.1 [M+H]+.

[1284]

[1285] Step 3: (2R,6R)-l,4-dibenzyl-2,6-bis(methoxymethyl)piperazine

[1286] To a solution of [(lS)-l-[[benzyl-[(2S)-2-ethylsulfonyloxy-3-methoxy- propyl]amino]methyl]-2-methoxy-ethyl] ethanesulfonate (175.72 mg, 0.38 mmol) in ethanol (2.5 mL) were added TEA (0.21 mL, 1.50 mmol) and Phenylmethanamine (1.20 g, 11.2 mmol). The mixture was heated to 80°C for 2 h and, then was concentrated under vacuum. The resulting residue was purified by column chromatography to afford (2R,6R)-l,4-dibenzyl-2,6-bis(methoxymethyl)piperazine (36.3 mg, 0.10 mmol, 27.25 % yield) as yellow oil.

[1287] MS (ESI) m / z = 355.1 [M+H]+.

[1288]

[1289] Step 4: (2R,6R)-2,6-bis(methoxymethyl)piperazine

[1290] To a solution of (2R,6R)-l,4-dibenzyl-2,6-bis(methoxymethyl)piperazine (300 mg, 846.30 pmol) in HFIP (8 mL) were added wet Pd / C (30 mg, 28.19 pmol, 10% purity) and Pd(OH)2 (30 mg, 213.62 pmol) under an Ar atmosphere to produce a suspension. The suspension was degassed and purged with EE three times. The mixture was stirred under EE (15 Psi) at 25 °C for 36 hr. The reaction mixture was filtered through a celite and washed with MeOH (8 mL x 3). The filtrate was concentrated under reduced pressure to produce (2R,6R)-2,6-bis(methoxymethyl)piperazine (225 mg, crude) as a colorless oil.

[1291] MS (ESI) m / z = 175.1 [M+H]+.

[1292]

[1293] The following compounds were prepared by a procedure similar to the procedure used to prepare compound Intermediate G described above.MS (ESI) m / z Compound Structure Name[M+H]+HN. (2R,6S)-2,6- G-l 175.1bis(methoxymethyl)piperazineHH(2S,6S)-2,6- G-2 A 175.1bis(methoxymethyl)piperazineHH(2S,6R)-2,6- G-3 A 175.1bis(methoxymethyl)piperazineH

[1294]

[1295] Intermediate H

[1296]

[1297] (6,6-dimethylpiperazin-2-yl)methanol

[1298] Step 1: tert-butyl N-[2-(benzylamino)-l,l-dimethyl-ethyl]carbamate

[1299] To a solution of tert-butyl N-(l,l-dimethyl-2-oxo-ethyl)carbamate (10 g, 53.41 mmol) in MeOH (100 mL) was added BnNEE (5.72 g, 53.41 mmol, 5.82 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min under a nitrogen atmosphere. Then NaBH(OAc)3 (16.98 g, 80.11 mmol) was added to the above mixture in batches over 0.5 h. The reaction mixture was stirred at 25 °C for 1 h under a nitrogen atmosphere. The reaction mixture was poured into H2O (150 mL) and extracted with Ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce tert-butyl N-[2-(benzylamino)-l,l-dimethyl-ethyl]carbamate (15 g, 50.65 mmol, 94.83% yield, 94% purity) as a white solid.

[1300] MS (ESI) m / z = 279.2 [M+H]+.

[1301]

[1302] Step 2: tert-butyl N-[2-[benzyl-(2-chloroacetyl)amino]-l,l-dimethyl-ethyl]carbamate

[1303] To a solution of tert-butyl N-[2-(benzylamino)-l,l-dimethyl-ethyl]carbamate (10 g, 35.92 mmol) in THF (100 mL) was addded 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 mixture. The reaction mixture was stirred at 0 °C for 2 h under a nitrogen atmosphere. LCMS (ES24325-2036-P1A) showed the desired mass was detected. The reaction mixture was poured into H2O (120 mL) and extracted with Ethyl acetate (120 mL x 3). The combined organic layers were washed with brine (100 mL),dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce tert-butyl N-[2-[benzyl-(2-chloroacetyl)amino]-l, l-dimethyl-ethyl]carbamate (12.75 g, crude) as a brown oil.

[1304] MS (ESI) m / z = 355.2 [M+H]+.

[1305]

[1306] Step 3: tert-butyl 4-benzyl-2,2-dimethyl-5-oxo-piperazine-l-carboxylate

[1307] To a solution of tert-butyl N-[2-[benzyl-(2-chloroacetyl)amino]-l,l-dimethyl- ethyl]carbamate (19.12 g, 53.88 mmol) in MeCN (260 mL) was addded CS2CO3 (35.11 g, 107.76 mmol). The mixture was degassed and purged with N2 three times. The reaction mixture was stirred at 60 °C for 4 h under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce tert-butyl 4-benzyl-2,2-dimethyl-5-oxo-piperazine-l-carboxylate (3.23 g, 7.51 mmol, 13.93% yield) as a yellow oil.

[1308] MS (ESI) m / z = 263.1 [M-tBu+H]+.

[1309]

[1310] Step 4: tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2-dimethyl-5-oxo-piperazine-l- carb oxy late

[1311] To a solution of tert-butyl 4-benzyl-2,2-dimethyl-5-oxo-piperazine-l -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 N2 three times. The reaction mixture was stirred at -70 °C for 30 min under a nitrogen 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 N2 three times. The reaction mixture was stirred at -70 °C for 1 h under a nitrogen atmosphere. The reaction mixture was quenched with HC1 aq. (1 M, 25 mL) and diluted with H2O (100 mL). Then the mixture was extracted with Ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2-dimethyl-5-oxo-piperazine-l-carboxylate (1.44 g, 3.25 mmol, 46.41% yield, 99% purity) as a yellow oil.

[1312] MS (ESI) m / z = 439.3 [M+H]+.

[1313]

[1314] Step 5: tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2-dimethyl-piperazine-l- carb oxy late

[1315] 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 pL, in DMS solution) at 0 °C. The mixture was degassed and purged with N2 three times. The reaction mixture was stirred at 20 °C for 1 h and 50 °C for 2 h under a nitrogen 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 a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to produce 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 produce a crude product. The crude product was purified by flash silica gel chromatography to produce tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2- dimethyl-piperazine-1 -carboxylate (1.13 g, 2.63 mmol, 95.50% yield) as a yellow oil.

[1316] MS (ESI) m / z = 425.4 [M+H]+.

[1317]

[1318] Step 6: l-benzyl-5-(benzyloxymethyl)-3,3-dimethyl-piperazine

[1319] To a solution of tert-butyl 4-benzyl-6-(benzyloxymethyl)-2,2-dimethyl-piperazine-l- carboxylate (1.128 g, 2.66 mmol) in DCM (12 mL) was added TFA (3 mL). The mixture was degassed and purged with N2 three times. The reaction mixture was stirred at 25 °C for 1 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to produce l-benzyl-5-(benzyloxymethyl)-3,3-dimethyl- piperazine (1.16 g, crude, TFA) as a yellow oil.

[1320] MS (ESI) m / z = 325.6 [M+H]+.

[1321]

[1322] Step 7: (6,6-dimethylpiperazin-2-yl)methanol

[1323] To a solution of l-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 an Ar atmosphere. The suspension was degassed and purged with Ar₂ three times. Then the suspension was degassed and purged with H2 three 3 times. The mixture was stirred under H2 (50 Psi) at 50 °C for 12 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to produce 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 x 2) and concentrated under reduced pressure to produce (6,6-dimethylpiperazin-2-yl)methanol (673 mg, 2.48 mmol, 93.59% yield) as a white solid.

[1324] MS (ESI) m / z = 145.1 [M+H]+.

[1325]

[1326] Intermediate I

[1328] (6S)-6-methyl-2-oxa-5,8-diazaspiro [3.5] nonane

[1329] Step 1: tert-butyl N-[(lS)-2-iodo-l-methyl-ethyl]carbamate

[1330] 777-imidazole (5.08 g, 74.58 mmol) and PPI13 (19.56 g, 74.58 mmol) were dissolved in THF (55 mL) under a 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 tertbutyl N-[(lS)-2-hydroxy-l-methyl-ethyl]carbamate (10.89 g, 62.15 mmol) in THF (218 mL) was added dropwise at 0 °C. After stirring for 4 h at this temperature, the reaction mixture was warmed to 25 °C and stirred for a further 8 h under a nitrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with EtOAc (30 mL x 3). The combined filtrate was diluted with EtOAc (50 mL) and washed with saturated aqueous Na2S20s (160 mL x 2), 10 % aqueous citric acid (160 mL), and brine (160 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl N-[(lS)-2-iodo-l-methyl-ethyl]carbamate (8.69 g, 28.95 mmol, 46.59% yield) as a brown oil.

[1331] MS (ESI) m / z = 230.0 [M-tBu+H]+.

[1332]

[1333] Step 2: tert-butyl N-[(lS)-2-[benzyl(trimethylsilylmethyl)amino]-l-methyl- ethyl]carbamate

[1334] To a solution of l-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-[(lS)-2-iodo-l-methyl-ethyl]carbamate (8.69 g, 30.48 mmol) at 0 °C. The mixture was degassed and purged with N2 three times. Then, the reaction mixture was stirred at 90 °C for 12 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl N-[(lS)-2-[benzyl(trimethylsilylmethyl)amino]-l- methyl-ethyl]carbamate (270 mg, 693.16 pmol, 2.27% yield) as a white solid.

[1335] MS (ESI) m / z = 351.3 [M+H]+.

[1336]

[1337] Step 3: (2S)-N1 -benzyl -Nl-(trimethylsilylmethyl)propane-l,2-diamine

[1338] To a solution of tert-butyl N-[(lS)-2-[benzyl(trimethylsilylmethyl)amino]-l-methyl- ethyl]carbamate (260 mg, 741.65 pmol) in DCM (2.6 mL) was added TFA (1.33 g, 11.67 mmol, 866.67 pL). The mixture was degassed and purged with N2 three times. The mixture was stirred under a nitrogen atmosphere at 25 °C for 2 h. The reaction mixture was quenched with sat. NaHCO₃ (aq) (15 mL) and extracted with Ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce (2S)-N1 -benzyl -Nl- (trimethylsilylmethyl)propane-l,2-diamine (240 mg, crude) as a yellow oil.

[1339] MS (ESI) m / z = 251.2 [M+H]+.

[1340]

[1341] Step 4: (6S)-8-benzyl-6-methyl-2-oxa-5,8-diazaspiro[3.5]nonane

[1342] To a 40 mL vial were added bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridyl]phenyl]iridium(l+), 4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine;hexafluorophosphate (8.96 mg, 7.99 pmol) and 4A MS (100 mg). (2S)- Nl-benzyl-Nl-(trimethylsilylmethyl)propane-l,2-diamine (200 mg, 798.55 pmol) andoxetan-3-one (200 mg, 2.78 mmol) were dissolved in MeCN (12 mL) : CF₃CH₂OH (4 mL). The reaction vial was capped and placed in a Penn OC reactor for 16 h at 25 °C. The reaction mixture was concentrated under reduced pressure to produce 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 pmol, 23.26% yield) as a brown oil.

[1343] MS (ESI) m / z = 233.1 [M+H]+.

[1344]

[1345] Step 5: (6S)-6-methyl-2-oxa-5,8-diazaspiro[3.5]nonane

[1346] To a solution of (6S)-8-benzyl-6-methyl-2-oxa-5,8-diazaspiro[3.5]nonane (50.00 mg, 215.22 pmol) in HFIP (3 mL) were added Pd / C (10 mg, 10% purity, wet) and Pd(OH)2 (10 mg) under an Ar atmosphere to produce a suspension. The suspension was degassed and purged with H2 three times. Then, the mixture was stirred under H2 (15 Psi) at 25 °C for 12 hr. The reaction mixture was filtered through a celite, and washed with MeOH (8 mL x 3). The filtrate was concentrated under reduced pressure to produce (6S)-6-methyl- 2-oxa-5,8-diazaspiro[3.5]nonane (35 mg, crude) as a light yellow oil.

[1347] MS (ESI) m / z = 143.2 [M+H]+.

[1348]

[1349] Intermediate J

[1350]

[1351] 5-benzyl 2-(tert-butyl) (S)-6-methyl-2,5,8-triazaspiro [3.5] nonane-2,5- dicarboxylate

[1352] Step 1: tert-butyl 3-[[(lS)-2-methoxy-l-methyl-2-oxo-ethyl]amino]-3- (nitromethyl)azetidine- 1 -carboxylate

[1353] 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 a nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 1 hr under a nitrogen atmosphere, and then, concentrated under reduced pressure toproduce a residue. The residue was dissolved in DCM (204 mL) and the reaction mixture was cooled to -78 °C. TEA (10.36 g, 102.34 mmol, 14.24 mL) was added then a solution of methyl sulfonyl methanesulfonate (9.36 g, 53.73 mmol) in DCM (54 mL) was added dropwise. The reaction mixture was left to stir at -78 °C for 1.5 hr under a 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 mixture was stirred at 25 °C for 10 min. The resulting solution was added to the above mentioned mixture via syringe at -78 °C under a 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 layer was extracted with CH₂Cl₂ (500 mL × 2). The combined organic layers were washed with saturated NaHCO₃ (500 mL × 2) and brine (400 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to produce 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, 9.43% yield) as a yellow oil.

[1354] MS (ESI) m / z = 261.9 [M-tBu+H]+.

[1355]

[1356] Step 2: tert-butyl (6S)-6-methyl-7-oxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate

[1357] To a solution of tert-butyl 3-[[(lS)-2-methoxy-l-methyl-2-oxo-ethyl]amino]-3- (nitromethyl)azetidine-l -carboxylate (3.32 g, 10.46 mmol) in MeOH (90 mL) was added Raney-Ni (1.0 g, containl0% water) under an Ar atmosphere to produce a suspension. The suspension was degassed and purged with H2 three times. Then the mixture was stirred under H₂ (50 Psi) at 25 °C for 16 hr. The reaction mixture was filtered through a plug of Celite eluting with EtOAc (100 mL x 3). The filtrate was concentrated under reduced pressure to produce tert-butyl (6S)-6-methyl-7-oxo-2,5,8-triazaspiro[3.5]nonane- 2-carboxylate (2.67 g, crude) as a yellow solid.

[1358] MS (ESI) m / z = 200.2 [M-tBu+H]+.

[1359]

[1360] Step 3: 5-benzyl 2-(tert-butyl) (S)-6-methyl-7-oxo-2,5,8-triazaspiro[3.5]nonane-2,5- di carb oxy late

[1361] 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 a nitrogen atmosphere. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce 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, 69.04% yield, 92.8% purity) as a light yellow oil.

[1362] MS (ESI) m / z = 412.0 [M+Na]+.

[1363]

[1364] Step 4: 5-benzyl 2-(tert-butyl) (S)-6-methyl-2,5,8-triazaspiro[3.5]nonane-2,5- di carb oxy late

[1365] The reaction was performed by flow chemistry:

[1366] 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);

[1367] Solution 2: BH₃-Me₂S (10 M, 2.33 mL) in THF (2.33 mL).

[1368] Solution 1 was pumped by Pump 1 {SI, Pl, 2.952 mL / min} to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175(l / 8")mm, 59.84055 mL, 60.0°C{. Solution 2 was pumped by Pump 2 {S2, P2, 3.032 mL / min} to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175(l / 8")mm, 59.84055 mL, 60.0°C}. The residence time of flow reactor 1 {FLR1, 10.0 min} was 10 min. The mixture was collected with a bottle. The reaction mixture was quenched with MeOH (40 mL) at 0 °C. Then, the reaction mixture was stirred at 25 °C for 1 h and stirred at 50°C for 2 h under a nitrogen 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, 23.05% yield) as a colorless oil.

[1369] MS (ESI) m / z = 376.2 [M+H]+.

[1370]

[1371] Intermediate KB0

[1372] I

[1373] N, N-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-l-carboxamide

[1374] To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6- tetrahydropyridine;hydrochloride (1.0 g, 4.07 mmol) in DCM (20 mL) were added TEA (1.24 g, 12.22 mmol, 1.70 mL) and N, N-dimethylcarbamoyl chloride (656.92 mg, 6.11 mmol) dropwise at 0 °C under a nitrogen atmosphere. Then the mixture was stirred at 25 °C for 12 h under a nitrogen atmosphere. The mixture was quenched by an addition of H2O (30 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce N, N-dimethyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxamide (0.98 g, 3.32 mmol, 81.60% yield) as a white solid.

[1375] MS (ESI) m / z = 281.2 [M+H]+.

[1376]

[1377] The following compounds were prepared by a procedure similar to the procedure used to prepare the compound Intermediate K described above.MS (ESI) m / z Compound Structure Name[M+H]+O. „OB 1 -(isopropyl sulfonyl)-4-(4, 4,5,5- K-l tetramethyl-l,3,2-dioxaborolan-2- 316.0yl)-l,2,3,6-tetrahydropyridineo=H0x1378]

[1379] Intermediate LH

[1381] (6S)-2,6-dimethyl-2,5,8-triazaspiro [3.5] nonane

[1382] Step 1: 5,8-dibenzyl 2-(tert-butyl) (S)-6-methyl-2,5,8-triazaspiro[3.5]nonane-2,5,8- tri carb oxy late

[1383] To a solution of 5-benzyl 2-(tert-butyl) (S)-6-methyl-2,5,8-triazaspiro[3.5]nonane- 2,5-dicarboxylate (0.57 g, 1.52 mmol, Intermediate J) in THF (6 mL) and H2O (2 mL) were added Na2COs (241.36 mg, 2.28 mmol) and CbzCl (388.47 mg, 2.28 mmol, 325.08 pL). The reaction mixture was stirred at 25 °C for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain 5,8-dibenzyl 2- (tert-butyl) (S)-6-methyl-2, 5, 8-triazaspiro[3.5]nonane-2, 5, 8-tri carboxylate (500 mg, 689.77 pmol, 45.44% yield) as a colorless oil.

[1384] MS (ESI) m / z = 510.2 [M+H]+.

[1385]

[1386] Step 2: dibenzyl (6S)-6-methyl-2,5,8-triazaspiro[3.5]nonane-5,8-dicarboxylate

[1387] To a solution of 5,8-dibenzyl 2-(tert-butyl) (S)-6-methyl-2,5,8- triazaspiro[3.5]nonane-2,5,8-tricarboxylate (500 mg, 981.18 pmol) in DCM (5 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 2hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure at 25 °C to produce dibenzyl (6S)-6-methyl-2,5,8-triazaspiro[3.5]nonane-5,8- dicarboxylate (450 mg, crude, TFA) as a colorless oil.

[1388] MS (ESI) m / z = 410.1 [M+H]+.

[1389]

[1390] Step 3: dibenzyl (6S)-2,6-dimethyl-2,5,8-triazaspiro[3.5]nonane-5,8-dicarboxylate

[1391] To a solution of dibenzyl (6S)-6-methyl-2,5,8-triazaspiro[3.5]nonane-5,8- dicarboxylate (400 mg, 764.09 pmol, TFA) in DCM (12 mL) were added AcOH (68.83 mg, 1.15 mmol, 65.61 pL, 1.5 eq) and formaldehyde (124.01 mg, 1.53 mmol, 37% aqueous solution). The reaction mixture was stirred at 25 °C for 1 h under a nitrogen atmosphere, and then NaBH(OAc)3 (323.88 mg, 1.53 mmol) was added to the above mentioned solution. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated NaHCO₃ (15 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain dibenzyl (6S)-2,6-dimethyl-2,5,8- triazaspiro[3.5]nonane-5,8-dicarboxylate (240 mg, 367.79 pmol, 48.13% yield) as a colorless oil.

[1392] MS (ESI) m / z = 424.2 [M+H]+.

[1393]

[1394] Step 4: (6S)-2,6-dimethyl-2,5,8-triazaspiro[3.5]nonane

[1395] To a solution of dibenzyl (6S)-2,6-dimethyl-2,5,8-triazaspiro[3.5]nonane-5,8- dicarboxylate (240 mg, 566.70 pmol) in HFIP (6 mL) was added wet Pd / C (127 mg, 118.96 pmol, 10% purity) under an Ar atmosphere. The suspension was degassed and purged with H₂ three times. Then the mixture was stirred under H₂ (15 Psi) at 25 °C for 12 hr. The reaction mixture was filtered through a celite, and washed with MeOH (8 mL x 3). The filtrate was concentrated under reduced pressure to produce (6S)-2,6-dimethyl- 2,5,8-triazaspiro[3.5]nonane (200 mg, crude) as a light yellow oil, which was directly used for next step without being further purified.

[1396] MS (ESI) m / z = 178.4 [M+Na]+.

[1397]

[1398] Intermediate MTFAN[ M1399] AA o

[1400] (l-methoxycyclopropyl)-piperazin-l-yl-methanone

[1401] Step 1: tert-butyl 4-(l-m ethoxy cy cl opropanecarbonyl)piperazine-l -carboxylate

[1402] 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 a nitrogen atmosphere. The reaction mixture was poured into water (30 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain tert-butyl 4-(l- methoxycyclopropanecarbonyl)piperazine-l -carboxylate (0.82 g, 2.61 mmol, 97.11% yield, 90.4% purity) as a colorless oil.

[1403] MS (ESI) m / z = 285.2 [M+H]+.

[1404]

[1405] Step 2: (1-m ethoxy cy cl opropyl)-piperazin-l-yl-methanone

[1406] To a solution of tert-butyl 4-( 1-m ethoxy cy cl opropanecarbonyl)piperazine-l- 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 a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was dissolved in CH₃CN (5 mL) and H₂O (4 mL), then freeze-dried to obtain (1-m ethoxy cy cl opropyl)-piperazin-l-yl-m ethanone (334 mg, 895.87 pmol, 63.69% yield) as a white solid.

[1407] 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).

[1408]

[1409] The following compounds were prepared by a procedure similar to the procedure used to prepare the compound Intermediate M described above.MS (ESI) m / z Compound Structure Name[M+H]+TFANLsj J (S)-(l-m ethoxy cy cl opropyl)(2- M-l 199.1methylpiperazin-l-yl)methanone

[1410]

[1411] Intermediate NH2HCI N

[1412] 0 H

[1413] methyl 6,6-dimethylpiperazine-2-carboxylate dihydrochloride

[1414]

[1415] Step 1: 6,6-dimethylpiperazine-2-carbonitrile

[1416] To a solution of 2-methylpropane-l,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 a nitrogen atmosphere. The reaction mixture was degassed and purged with N2 three times, and the reaction mixture was stirred at 50 °C for 4 h under a nitrogen atmosphere to obtain 6,6-dimethylpiperazine-2-carbonitrile (6.04 g, crude) as a lightyellow.

[1417] MS (ESI) m / z = 140.2 [M+H]+.

[1418]

[1419] Step 2: 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-carbonitrile

[1420] To a suspension of 6,6-dimethylpiperazine-2-carbonitrile (6.04 g, crude) in THF (100 mL) were added EtsN (8.78 g, 86.78 mmol, 12.08 mL) and 4-nitrobenzenesulfonyl chloride (12.50 g, 56.41 mmol) under a nitrogen atmosphere. The suspension wasdegassed and purged with N2 three times. Then the reaction mixture was stirred at 25 °C for 5 h under a nitrogen atmosphere. The reaction mixture was poured into H2O (120 mL) and was extracted with EtOAc (150 mL x 3). The combined organic phases were dried over Na₂SO₄, filtered and concentrated under reduced pressure to produce 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) as a yellow solid.

[1421] MS (ESI) m / z = 325.1 [M+H]+.

[1422]

[1423] Step 3: 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-carboxylic acid

[1424] 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 HC1 (6 M, 16.60 mL) under a nitrogen atmosphere to obtain a purple solution. The reaction mixture was stirred at 130 °C for 1 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to produce 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-carboxylic acid (920 mg, crude, HC1) as a purple solid.

[1425] MS (ESI) m / z = 344.1 [M+H]+.

[1426]

[1427] Step 4: benzyl l-benzyl-6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2- carb oxy late

[1428] To a solution of 6,6-dimethyl-4-(4-nitrophenyl)sulfonyl-piperazine-2-carboxylic acid (920 mg, crude, HC1) 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 a nitrogen atmosphere. The reaction mixture was stirred at 85 °C for 12 h under a nitrogen atmosphere. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (80 mL x 3). The combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce 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 pmol, 36.69% yield) as a brown oil.

[1429] MS (ESI) m / z = 524.1 [M+H]+.

[1430]

[1431] Step 5: benzyl l-benzyl-6,6-dimethyl-piperazine-2-carboxylate

[1432] To a solution of benzyl l-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 a nitrogen atmosphere. Then the mixture was stirred at 40 °C for 12 h under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain benzyl l-benzyl-6,6-dimethyl-piperazine-2-carboxylate (378 mg, 1.07 mmol, 65.93% yield) as a colorless oil.

[1433] MS (ESI) m / z = 339.2 [M+H]+.

[1434]

[1435] Step 6: 6,6-dimethylpiperazine-2-carboxylic acid

[1436] To a solution of benzyl l-benzyl-6,6-dimethyl-piperazine-2-carboxylate (200 mg, 590.94 pmol) in HFIP (10 mL) was added wet Pd / C (60 mg, 10% purity) under an Ar atmosphere. The suspension was degassed and purged with Ar₂ three times. Then the suspension was degassed and purged with H2 three times. The reaction mixture was stirred under H₂ (50 Psi) at 50 °C for 12 h. The reaction mixture was filtered and washed with MeOH (5 mL x 3). The filtrate was concentrated under reduced pressure to obtain 6,6-dimethylpiperazine-2-carboxylic acid (100 mg, crude) as a white solid.

[1437] MS (ESI) m / z = 159.3 [M+H]+.

[1438]

[1439] Step 7: methyl 6,6-dimethylpiperazine-2-carboxylate dihydrochloride

[1440] To a solution of 6,6-dimethylpiperazine-2-carboxylic acid (100 mg, crude) in MeOH (10 mL) was added SOCI2 (300.81 mg, 2.53 mmol) dropwise at 25 °C under a nitrogen atmosphere. Then the reaction mixture was stirred at 50 °C for 12 h under a nitrogenatmosphere. The reaction mixture was concentrated under reduced pressure to obtain methyl 6,6-dimethylpiperazine-2-carboxylate (125 mg, crude, 2HC1) as a brown solid.

[1441] 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).

[1442]

[1443] Intermediate OHO^ / UTFAA0

[1444] AA

[1445] (l-hydroxycyclopropyl)-piperazin-l-yl-methanone

[1446]

[1447] To a solution of tert-butyl 4-(l -hydroxy cy cl opropanecarbonyl)piperazine-l- carboxylate (150 mg, 554.89 pmol) in DCM (3 mL) was added TFA (1 mL). The mixture was degassed and purged with N2 three times. The reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The mixture was concentrated via N2 bubbling to produce a residue. The residue was dissolved in CH3CN (5 mL) and H2O (4 mL), then freeze-dried to obtain (l-hydroxycyclopropyl)-piperazin-l-yl-methanone (160 mg, crude, TFA) as a white solid.

[1448] 'H NMR (400 MHz, CDCh) 3 = 9.11 (br s, 1H), 7.18 (br s, 2H), 4.48-3.60 (m, 4H), 3.56-2.89 (m, 3H), 1.29-0.75 (m, 4H).

[1449]

[1450] Intermediate PH

[1451]

[1452] (3S,4R)-4-methoxy-3-methyl-2-oxa-8-azaspiro [4.5] decane

[1453]

[1454] Step 1: tert-butyl (3S,4R)-4-methoxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8- carb oxy late

[1455] A solution of tert-butyl (3S,4R)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8- carboxylate (120 mg, 442.23 pmol) in THF (5 mL) was degassed and purged with N2 three times. Then NaH (53.06 mg, 1.33 mmol, 60% purity) was added to the above mentioned solution slowly at 0 °C under a nitrogen atmosphere. The suspension was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 0.5 h under a nitrogen atmosphere. Then Mel (627.70 mg, 4.42 mmol, 275.30 pL) was added dropwise to the above mentioned mixture at 0 °C and the mixture was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The mixture was stirred at 50 °C for 12 h under a nitrogen atmosphere. The reaction mixture was quenched by an addition of sat. aq. NH₄Cl (~20 mL) at 0 °C and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce tert-butyl (3S,4R)-4-methoxy-3-methyl-2-oxa-8- azaspiro[4.5]decane-8-carboxylate (140 mg, 431.71 pmol, 97.62% yield) as a colorless oil.

[1456] MS (ESI) m / z = 230.1 [M+H-56]+.

[1457]

[1458] Step 2: (3S,4R)-4-methoxy-3-methyl-2-oxa-8-azaspiro[4.5]decane

[1459] To a solution of tert-butyl (3S,4R)-4-methoxy-3-methyl-2-oxa-8- azaspiro[4.5]decane-8-carboxylate (70 mg, 215.85 pmol) in DCM (2.1 mL) was added TFA (0.7 mL). The mixture was degassed and purged with N2 three times. The reaction mixture was stirred at 25 °C for 1.5 h under a nitrogen atmosphere. The mixture was concentrated via N2 bubbling to produce a residue. The residue was dissolved in CH3CN (5 mL) and H2O (4 mL), and then freeze-dried to obtain (3 S,4R)-4-m ethoxy-3 - methyl-2-oxa-8-azaspiro[4.5]decane (60 mg, crude, TFA) as a brown oil.

[1460] 'H NMR (400 MHz, CD3CN) 3 = 8.32-7.82 (m, 2H), 3.80-3.73 (m, 1H), 3.68 (d, J = 9.2 Hz, 1H), 3.49 (d, J= 9.2 Hz, 1H), 3.35 (s, 3H), 3.20-3.01 (m, 5H), 1.89-1.71 (m, 3H), 1.64-1.55 (m, 1H), 1.30 (d, J= 6.4 Hz, 3H).

[1461]

[1462] Intermediate Q

[1463] (3S,4R)-4-(difluoromethoxy)-3-methyl-2-oxa-8-azaspiro [4.5] decane

[1465]

[1466] Step 1: tert-butyl (3S,4R)-4-(difluoromethoxy)-3-methyl-2-oxa-8- azaspiro [4.5 ] decane- 8 -carb oxy late

[1467] To a solution of tert-butyl (3S,4R)-4-hydroxy-3-methyl-2-oxa-8- azaspiro[4.5]decane-8-carboxylate (100 mg, 368.53 pmol) in DCM (1 mL) and H2O (1 mL) was added KOAc (289.34 mg, 2.95 mmol). The solution was stirred for a while to dissolve the solids. After the stirring, to the solution was added [bromo(difluoro)methyl]- trimethyl-silane (299.39 mg, 1.47 mmol). The mixture was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 12 h under a nitrogen atmosphere. The residue was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce tert-butyl (3S,4R)-4- (difluoromethoxy)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (22 mg, 58.19 pmol, 15.79% yield) as a colorless oil.

[1468] MS (ESI) m / z = 322.1 [M+H]+.

[1469]

[1470] Step 2: (3S,4R)-4-(difluoromethoxy)-3-methyl-2-oxa-8-azaspiro[4.5]decane

[1471] To a solution of tert-butyl (3S,4R)-4-(difluoromethoxy)-3-methyl-2-oxa-8- azaspiro[4.5]decane-8-carboxylate (22 mg, 68.46 pmol) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was degassed and purged with N2 three times. The reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The mixture was concentrated via N2 bubbling to produce a residue. The residue was dissolved inCH₃CN (5 mL) and H2O (4 mL), and then freeze-dried to obtain (3S,4R)-4- (difluoromethoxy)-3-methyl-2-oxa-8-azaspiro[4.5]decane (21 mg, crude, TFA) as a brown oil.

[1472] 'H NMR (400 MHz, CD3CN) 3 = 8.57-8.19 (m, 2H), 6.46 (t, J= 74.4 Hz, 1H), 3.94 (d, J = 5.4 Hz, 1H), 3.87-3.79 (m, 2H), 3.59 (d, J = 8.8 Hz, 1H), 3.27-3.17 (m, 2H), 3.12-2.94 (m, 2H), 1.88-1.69 (m, 4H), 1.29 (d, J= 6.4 Hz, 3H).

[1473]

[1474] Intermediate RHA

[1475] H Boc

[1476] (6S)-6-methyl-2,5,8-triazaspiro [3.5] nonane-2-carboxylate

[1477] 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 pmol) in HFIP (6 mL) was added Pd / C (89 mg, 10% purity, wet) under an Ar atmosphere. The suspension was degassed and purged with H2 three times. Then the mixture was stirred under H2 (15 Psi) at 25 °C for 12 hr. The reaction mixture was filtered through a celite, and washed with MeOH (8 mL x 3). The filtrate was concentrated under reduced pressure to produce tert-butyl (6S)-6-methyl- 2,5,8-triazaspiro[3.5]nonane-2-carboxylate (98 mg, crude) as a light yellow oil.

[1478] MS (ESI) m / z = 242.3 [M+H]+.

[1479]

[1480] Example 2

[1481] 1-cyano-N-((S)-2,2-difluoro-4-methylpentan-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (General Procedure 2)

[1483]

[1484] Step 1: 6-benzylsulfanyl-8-chloro-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2- yl]imidazo[l,5-a]pyridine-l-carbonitrile

[1485] To 2-(6-benzylsulfanyl-8-chl oro-1 -iodo-imidazo[l,5-a]pyridin-3-yl)-5- (difluoromethyl)-l,3,4-thiadiazole (400 mg, 0.748 mmol) was added CuCN (201 mg, 2.24 mmol) in DMSO (3.74 mL). The mixture was warmed and stirred at 180°C for 15 min in a microwave. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography to afford 6-benzylsulfanyl-8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]imidazo[1,5-a]pyridine-1-carbonitrile (246 mg, 0.567 mmol, 75.80 % yield) as a yellow solid.

[1486] MS (ESI) m / z = 434.0 [M+H]+

[1487]

[1488] Step 2: 8-chloro-1-cyano-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]imidazo[1,5-a]pyridine-6-sulfonyl chloride

[1489] To a mixture of 6-benzylsulfanyl-8-chloro-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2- yl]imidazo[l,5-a]pyridine-l-carbonitrile (234 mg, 0.539 mmol) in Acetic acid (2.72 mL) and Water (0.89 mL) was added NCS (288 mg, 2.16 mmol) at 5 °C. The mixture was warmed and stirred at 25 °C under a nitrogen atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to afford 8-chloro-l-cyano-3-[5- (difluorom ethyl)- 1,3,4-thiadiazol-2-yl]imidazo[ 1, 5-a]pyridine-6-sulfonyl chloride (221 mg, 100 % yield) as a yellow solid.

[1490] MS (ESI) m / z = 410.0 [M+H]+

[1491]

[1492] Step 3: (R)-8-chloro-l-cyano-N-(2,2-difluoro-4-methylpentan-3-yl)-3-(5- (difluorom ethyl)- 1,3,4-thiadiazol-2-yl)imidazo[ 1, 5-a]pyridine-6-sulfonamide

[1493] To a mixture of 8-chloro-l-cyano-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2- yl)imidazo[l,5-a]pyridine-6-sulfonyl chloride (62 mg, 0.150 mmol) and (R)-2,2-difluoro- 4-methylpentan-3 -amine (36 mg, 0.210 mmol) in DCM (1.44 mL, 0.13M) was added TEA (0.13 mL, 0.900 mmol) dropwise at 5 °C. The mixture was warmed and stirred at 25 °C under a nitrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography to afford (R)-8-chloro-l-cyano-N-(2,2-difluoro-4-methylpentan-3-yl)-3- (5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)imidazo[l,5-a]pyridine-6-sulfonamide (28 mg, 0.0548 mmol, 36.54 % yield) as a yellow solid.

[1494] MS (ESI) m / z = 511.9 [M+H]+

[1495]

[1496] Step 4: tert-butyl (2S,6S)-4-(1-cyano-6-(N-((R)-2,2-difluoro-4-methylpentan-3-yl)sulfamoyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

[1497] To a mixture of (R)-8-chloro-l-cyano-N-(2,2-difluoro-4-methylpentan-3-yl)-3-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)imidazo[l,5-a]pyridine-6-sulfonamide (28 mg, 0.0548 mmol) in 1,4-Dioxane (1.3701mL, 0.04M, 50V) were added tert-butyl (2S,6S)- 2,6-dimethylpiperazine-1-carboxylate (15 mg, 0.0712 mmol), Pd-PEPPSI-IHept-Cl (5.3 mg, 0.00548 mmol), and cesium carbonate (3.00 eq, 17 mg, 0.164 mmol) at 25 °C. The mixture was warmed and stirred at 100 °C under a nitrogen atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography to afford tert-butyl (2S,6S)-4-(l-cyano- 6-(N-((R)-2,2-difluoro-4-methylpentan-3-yl)sulfamoyl)-3-(5-(difluoromethyl)-l,3,4- thiadiazol-2-yl)imidazo[l,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-l-carboxylate (30 mg, 0.0436 mmol, 79.48 % yield) as a yellow solid.

[1498] MS (ESI) m / z = 588.1 [M+H]+

[1499]

[1500] Step 5: l-cyano-N-((R)-2,2-difluoro-4-methylpentan-3-yl)-3-(5-(difluoromethyl)- l,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-l-yl)imidazo[l,5-a]pyridine-6- sulfonamide

[1501] To a mixture of tert-butyl (2S,6S)-4-(l-cyano-6-(N-((R)-2,2-difluoro-4- methylpentan-3-yl)sulfamoyl)-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)imidazo[l,5- a]pyridin-8-yl)-2,6-dimethylpiperazine-l -carboxylate (31 mg, 0.0450 mmol) in DCM (0.13mL, 0.1 IM) was added TFA (0.20 mL, 2.70 mmol) at 25 °C. The mixture was warmed and stirred at 25 °C under a nitrogen atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography to afford l-cyano-N-((R)-2,2-difluoro-4-methylpentan-3-yl)- 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (17 mg, 0.0242 mmol, 53.75 % yield) as a yellow solid.

[1502] MS (ESI) m / z = 588.1 [M+H]+

[1503] 1H NMR (400 MHz, DMSO) 5 9.75 (s, 1H), 9.06 (s, 2H), 8.54 (d, J = 9.8 Hz, 1H), 7.73 (t, J = 53.0 Hz, 1H), 7.42 (s, 1H), 4.00 (s, 2H), 3.76 - 3.55 (m, 3H), 2.91 (s, 2H), 2.09 - 1.96 (m, 1H), 1.56 (t, J = 19.4 Hz, 3H), 1.39 (d, J = 6.3 Hz, 6H), 0.91 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H).

[1504]

[1505] Example 33

[1506] N-[(lR)-l-(difluoromethyl)-2-methyl-propyl]-3-[5-(difluoromethyl)-l,3,4- thiadiazol-2-yl]-8-[(3S,5S)-3,5-dimethylpiperazin-l-yl]imidazo[l,5-a]pyridine-6- sulfonamide (General Procedure 1)

[1507]

[1508]

[1509] Step 1: 8-chloro-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-l-iodoimidazo[l,5- a]pyridine-6-sulfonyl chloride

[1510] To a solution of 2-(6-(benzylthio)-8-chloro-l-iodoimidazo[l,5-a]pyridin-3-yl)-5- (difluoromethyl)-l,3,4-thiadiazole (300 mg, 560.99 pmol) in acetonitrile (6 mL), acetic acid (75 pL) and H2O (150 pL) was added l,3-dichloro-5,5-dimethyl-imidazolidine-2,4- dione (221.05 mg, 1.12 mmol) at 5 °C. The mixture was stirred at 5 °C under a nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure to produce 8- chloro-3-(5-(difhioromethyl)-l,3,4-thiadiazol-2-yl)-l-iodoimidazo[l,5-a]pyridine-6- sulfonyl chloride (301 mg, crude) as a yellow solid.

[1511] MS (ESI) m / z = 510.1 [M+H]+

[1512]

[1513] Step 2: (R)-8-chloro-N-(1,1-difluoro-3-methylbutan-2-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine-6-sulfonamide

[1514] (2R)-1,1-difluoro-3-methyl-butan-2-amine (187.99 mg, 1.18 mmol, HC1) was dissolved in pyridine (1 mL) and THF (1 mL)(a mixture of A). To a solution of 8- chloro-3-[5-(difhioromethyl)-l,3,4-thiadiazol-2-yl]-l-iodo-imidazo[l,5-a]pyridine-6- sulfonyl chloride (301 mg, 588.93 pmol) in MeCN (3 mL) was added 4A MS (50 mg, 588.93 pmol) and the mixture of A at 5 °C. The mixture was stirred at 15 °C under a nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure to produce a residue. The crude residue was purified by column chromatography on silica gel eluting with 0-20% ethyl acetate in petroleum ether to obtain (R)-8-chloro-N-(1,1-difluoro-3-methylbutan-2-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine-6-sulfonamide (199 mg, 322.91 pmol, 54.83% yield) as a light-yellow solid.

[1515] 1H NMR (400MHz, DMSO-d6): 5 = 10.18-10.08 (m, 1H), 7.38 (d, J = 13.2 Hz, 1H), 7.08 (t, J = 53.6 Hz, 1H), 5.82 (t, J = 55.2 Hz, 1H), 5.08 (dd, J = 10.0, 2.0, Hz, 1H), 3.66- 3.54 (m, 1H), 2.04-1.96 (m, 1H), 1.07 (t, J = 6.0 Hz, 6H).

[1516]

[1517] Step 3: (R)-8-chloro-N-(l,l-difluoro-3-methylbutan-2-yl)-3-(5-(difluoromethyl)- l,3,4-thiadiazol-2-yl)imidazo[l,5-a]pyridine-6-sulfonamide

[1518] To a solution of (R)-8-chloro-N-(l,l-difluoro-3-methylbutan-2-yl)-3-(5- (difluorom ethyl)- 1,3,4-thiadiazol-2-yl)- 1 -iodoimidazo[ 1,5-a]pyridine-6-sulfonamide (199 mg, 332.90 pmol) in MeOH (5 mL) was added Pd / C (354.27 mg, 332.90 pmol, 10% purity) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (40 psi) at 25°C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to produce (R)-8-chloro-N-(l,l-difluoro-3-methylbutan-2-yl)-3-(5-(difluoromethyl)-l,3,4- thiadiazol-2-yl)imidazo[l,5-a]pyridine-6-sulfonamide (170 mg, crude) as a brown solid.

[1519] 1H NMR (400MHz, DMSO-d6): 5 = 9.81 (s, 1H), 8.06 (s, 1H), 7.70 (t, J = 52.8 Hz, 1H), 7.59 (s, 1H), 6.02 (t, J = 54.4 Hz, 1H), 3.61-3.50 (m, 1H), 1.91-1.81 (m, 1H), 0.93- 0.89 (m, 3H), 0.89-0.84 (m, 3H).

[1520]

[1521] Step 4: tert-butyl (2S,6S)-4-(6-(N-((R)-1,1-difluoro-3-methylbutan-2-yl)sulfamoyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

[1522] To a solution of (R)-8-chloro-N-(l,l-difluoro-3-methylbutan-2-yl)-3-(5- (difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-sulfonamide (150 mg, 317.88 pmol) in 1,4-Dioxane (3 mL) were added CS2CO3 (207.14 mg, 635.75 pmol), tertbutyl (2S,6S)-2,6-dimethylpiperazine-l -carboxylate (102.18 mg, 476.82 pmol), and Pd- PEPPSI-IHept-Cl (30.92 mg, 31.79 pmol) at 15 °C. The mixture was heated to 100 °C and stirred at this temperature under a nitrogen atmosphere for 3 h. The mixture was concentrated under reduced pressure to produce a residue. The crude residue was purified by column chromatography to obtain tert-butyl (2S,6S)-4-(6-(N-((R)-1,1-difluoro-3-methylbutan-2-yl)sulfamoyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (120 mg, 169.92 pmol, 53.45% yield) as a brown solid.

[1523] 1H NMR (400MHz, DMSO-d6): 5 = 9.76 (s, 1H), 7.82 (s, 1H), 7.07 (t, J = 53.6 Hz, 1H), 6.33 (s, 1H), 5.79 (t, J = 55.2 Hz, 1H), 4.91 (d, J = 10.0 Hz, 1H), 4.34-4.27 (m, 2H),4.10 (dd, J = 8.4, 3.2, Hz, 2H), 3.67-3.60 (m, 1H), 3.57 (dd, J = 12.0, 1.8, Hz, 2H), 2.04- 1.99 (m, 1H), 1.52 (s, 9H), 1.33 (d, J = 6.8 Hz, 6H), 1.05 (t, J = 6.4 Hz, 6H).

[1524]

[1525] Step 5: N-((R)-l,l-difluoro-3-methylbutan-2-yl)-3-(5-(difluoromethyl)-l,3,4- thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-l-yl)imidazo[l,5-a]pyridine-6- sulfonamide

[1526] To a solution of tert-butyl (2S,6S)-4-(6-(N-((R)-l,l-difluoro-3-methylbutan-2- yl)sulfamoyl)-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)imidazo[l,5-a]pyridin-8-yl)- 2,6-dimethylpiperazine-l -carboxylate (120 mg, 184.69 pmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 15°C for 2 h. The mixture was concentrated under reduced pressure to produce a residue. The residue was purified by prep-HPLC to obtain N-((R)-1,1-difluoro-3-methylbutan-2-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)imidazo[1,5-a]pyridine-6-sulfonamide (60.01 mg, 89.95 pmol, 48.70% yield) as a yellow solid.

[1527] MS (ESI) m / z = 550.3 [M+H]+

[1528] 1H NMR (400 MHz, DMSO-d6) 5 9.61 (s, 1H), 9.09-8.94 (m, 2H), 8.44 (d, J = 9.2 Hz, 1H), 7.99 (s, 1H), 7.68 (t, J = 53.2 Hz, 1H), 6.86 (s, 1H), 6.00 (t, J = 54.8 Hz, 1H), 3.93-3.84 (m, 2H), 3.59-3.51 (m, 1H), 3.46 (d, J = 10.0 Hz, 2H), 3.25 (dd, J = 12.8, 6.8 Hz, 2H), 1.91-1.81 (m, 1H), 1.43 (d, J = 6.8 Hz, 6H), 0.90 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H).

[1529]

[1530] The following compounds were prepared by a procedure similar to the procedure of Example 33.MS (ESI) m / zExample Structure 1H NMR (400MHz)[M+H]+LF(CD3OD) S = 9.84 (s, 1H), 7.87 (s, 1H), 6.94 (s, 1H), 3.99-3.95 (m, 2H), 3.72-3.6 5 582.1 4 (m, 1H), 3.56 (dd, J = 13.6, 3.2 Hz, 2H), 3.39-3.34 (m, 2H), 2.11 (m, 1H), 1.6 2-1.49 (m, 9H), 1.03-0.92 (m, 6H).A(CD30D) S = 9.84 (s, 1H), 7.87 (s, 1H),6.94 (s, 1H), 3.99-3.95 (m, 2H), 3.72-3.6 X 582.1 4 (m, 1H), 3.56 (dd, J = 13.6, 3.2 Hz, 2H), 3.39-3.34 (m, 2H), 2.11 (m, 1H), 1.6 2-1.49 (m, 9H), 1.03-0.92 (m, 6H). AF (CD3OD) S = 9.84 (s, 1H), 7.87 (s, 1H), i o o \ V\ 1s7.34 (t, J = 53.6 Hz, 1H), 6.94 (s, 1H), \ 1?s' X>x. J*7\ N A N A 3.99-3.95 (m, 2H), 3.72-3.64 (m, 1H), 3. F FHLX / N528.3 56 (dd, J = 13.6, 3.2 Hz, 2H), 3.39-3.34(m, 2H), 2.11 (m, 1H), 1.62-1.49 (m, 9 A.H H), 1.03-0.92 (m, 6H).F(CD3OD) S = 9.84 (s, 1H), 7.87 (s, 1H), = o o \ V\sI 7.34 (t, J = 53.6 Hz, 1H), 6.94 (s, 1H), x yXr N X y^rx N J-V 3.99-3.95 (m, 2H), 3.72-3.64 (m, 1H), F FHI V 528.33.56 (dd, J = 13.6, 3.2 Hz, 2H), 3.39-3.3 4 (m, 2H), 2.11 (m, 1H), 1.62-1.49 (m, A 9H), 1.03-0.92 (m, 6H).HF (DMSO-d6) S = 9.61 (s, 1H), 9.09-8.94 (m,,N=A" F 2H), 8.44 (d, J = 9.2 Hz, 1H), 7.99 (s, 1H), T 0 O Vs7.68 (t, J = 53.2 Hz, 1H), 6.86 (s, 1H), 6.00 F^ >xX N yr NA T, (t, J = 54.8 Hz, 1H), 3.93-3.84 (m, 2H), FHL AyN550.33.59-3.51 (m, 1H), 3.46 (d, J = 10.0 Hz, 2H), 3.25 (dd, J = 12.8, 6.8 Hz, 2H), 1.91-1.81 A. (m, 1H), 1.43 (d, J = 6.8 Hz, 6H), 0.90 (d, J = H 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H).F (CD3OD) S = 9.85 (s, 1H), 7.88 (s, 1H), N^A^F 7.34 (t, J = 53.2 Hz, 1H), 6.89 (s, 1H), AA N 1y o o Vs4.41 (d, J = 4.8 Hz, 1H), 4.29 (d, J = ANAU 4.8 Hz, 1H), 4.00-3.95 (m, 2H), 3.57 (dHL J<a / N532.2d, J = 13.2, 3.2 Hz, 2H), 3.44-3.38 (m, 1H), 3.37-3.34 (m, 2H), 1.91-1.82 (m, 1 A... H), 1.57 (d, J = 6.4 Hz, 6H), 0.97-0.91 H (m, 6H).F (CD3OD) S = 9.85 (s, 1H), 7.88 (s, 1H),, NAF 7.34 (t, J = 53.2 Hz, 1H), 6.89 (s, 1H), x T / o oN* VsA 4.41 (d, J = 4.8 Hz, 1H), 4.29 (d, J = -X^xN X N-A I. 4.8 Hz, 1H), 4.00-3.95 (m, 2H), 3.57 (dHX JAN532.2d, J = 13.2, 3.2 Hz, 2H), 3.44-3.38 (m, 1H), 3.37-3.34 (m, 2H), 1.91-1.82 (m, 1 A.. H), 1.57 (d, J = 6.4 Hz, 6H), 0.97-0.91 H (m, 6H).F (CD3CN) S = 9.70 (s, 1H), 8.80 (br s, 2,NAF H), 7.80 (s, 1H), 7.25 (t, J = 53.6 Hz, 1 y H), 6.77 (s, 1H), 5.82 (br d, J = 8.8 Hz, X^ o o \ Vx AsJx A 1H), 3.91 (br s, 2H), 3.54 (dd, J = 2.8, N x XhI JAN528.3 13.2 Hz, 2H), 3.40-3.30 (m, 2H), 3.16- 3.02 (m, 1H), 1.79-1.73 (m, 1H), 1.52 (d, J = 6.4 Hz, 6H), 1.48-1.38 (m, 1H), XX.. 1.35-1.25 (m, 1H), 0.86-0.77 (m, 6H), 0. H 72 (dt, J = 3.2, 7.2 Hz, 3H).F (CD3CN) S = 9.70 (s, 1H), 8.80 (br s, 2, IV^F H), 7.80 (s, 1H), 7.25 (t, J = 53.6 Hz, 1 X T / o o \ V\s1 H), 6.77 (s, 1H), 5.82 (br d, J = 8.8 Hz,1H), 3.91 (br s, 2H), 3.54 (dd, J = 2.8, N NA,HI IYN 528.3 13.2 Hz, 2H), 3.40-3.30 (m, 2H), 3.16- 3.02 (m, 1H), 1.79-1.73 (m, 1H), 1.52 (d, J = 6.4 Hz, 6H), 1.48-1.38 (m, 1H), A 1.35-1.25 (m, 1H), 0.86-0.77 (m, 6H), 0. H 72 (dt, J = 3.2, 7.2 Hz, 3H).F (CD3OD) S = 9.85 (d, J = 0.8 Hz, 1H),,N^r ^F7.34 (t, J = 53.6 Hz, 1H), 6.97 (s, 1H), Y owo \ V\ 1sK / k -^sC ^x 7^ 4.39 (d, J = 4.8 Hz, 1H), 4.27 (d, J = N |HH ks X- / N566.2 4.8 Hz, 1H), 4.07-4.02 (m, 2H), 3.70-3.5 N C! 3 (m, 2H), 3.34-3.31 (m, 2H), 3.07-2.90 XX (m, 1H), 1.90-1.82 (m, 1H), 1.50 (br s, H. 6H), 0.96-0.93 (m, 6H).F (CD3OD) S = 9.85 (d, J = 0.8 Hz, 1H), N^A\x 1 7.34 (t, J = 53.6 Hz, 1H), 6.97 (s, 1H), = °x / ° rsA Jst 4.39 (d, J = 4.8 Hz, 1H), 4.27 (d, J = N V NA J,H L JAN 566.2 4.8 Hz, 1H), 4.07-4.02 (m, 2H), 3.70-3.5 N 'CL3 (m, 2H), 3.34-3.31 (m, 2H), 3.07-2.90 XX (m, 1H), 1.90-1.82 (m, 1H), 1.50 (br s, H. 6H), 0.96-0.93 (m, 6H).F NS^AF (DMSO-d6) S = 9.63 (s, 1H), 9.13-9.00(m, 2H), 8.55 (d, J = 9.2 Hz, 1H), 7.69 Y°.°NV (t, J = 53.2 Hz, 1H), 6.98 (s, 1H), 6.02 W WN F H L>=( 584.2 (t, J = 54.8 Hz, 1H), 3.95 (s, 2H), 3.61- N 'Cl3.43 (m, 4H), 3.27-3.2 (m, 1H), 1.90-1.8 XX. 1 (m, 1H), 1.37 (br s, 6H), 0.91 (d, J = H 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H).F (DMSO-d6) S = 9.63 (s, 1H), 9.13-9.00 N^AF\x" \\ 1 (m, 2H), 8.55 (d, J = 9.2 Hz, 1H), 7.69 = °w° rs(t, J = 53.2 Hz, 1H), 6.98 (s, 1H), 6.02 T > J YA 584.2 (t, J = 54.8 Hz, 1H), 3.95 (s, 2H), 3.61-HW N C! 3.43 (m, 4H), 3.27-3.2 (m, 1H), 1.90-1.8 XX H. 1 (m, 1H), 1.37 (br s, 6H), 0.91 (d, J =6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). F (CDC13) S = 9.83 (s, 1H), 7.07 (t, J = 5 N^AR 3.6 Hz, 1H), 6.65 (s, 1H), 4.89 (d, J = Y o„pNvs10.0 Hz, 1H), 4.30-4.22 (m, 2H), 3.85 (d d, J = 12.0, 3.2 Hz, 2H), 3.74-3.61 (m, > F A FNH'sy L^7jY" C,N698.2 1H), 3.01 (dd, J = 11.6, 4.0 Hz, 2H), 2.2N a 0-2.09 (m, 1H), 1.51 (s, 9H), 1.37 (d, J = 6.4 Hz, 6H), 1.31-1.24 (m, 3H), 1.07 XX (d, J = 6.8 Hz, 3H), 0.93 (br d, J = 6.8 H. Hz, 3H).F (CDC13) S = 9.83 (s, 1H), 7.07 (t, J = 5. V^F 3.6 Hz, 1H), 6.65 (s, 1H), 4.89 (d, J = X T / O O V As10.0 Hz, 1H), 4.30-4.22 (m, 2H), 3.85 (d x A.,'st ^ d, J = 12.0, 3.2 Hz, 2H), 3.74-3.61 (m, 383 F F H 698.2 1H), 3.01 (dd, J = 11.6, 4.0 Hz, 2H), 2.20-2.09 (m, 1H), 1.51 (s, 9H), 1.37 (d, J N.Cl= 6.4 Hz, 6H), 1.31-1.24 (m, 3H), 1.07 (d, J = 6.8 Hz, 3H), 0.93 (br d, J = 6.8 H Hz, 3H).F (CD3CN) S = 9.70 (s, 1H), 9.14-8.25 (m, 2H), 7.47-7.02 (t, J = 53.6 Hz, 1H), \ Tz o o VsA 6.86 (s, 1H), 6.06-5.89 (m, 1H), 4.01 (b r s, 2H), 3.61 (br d, J = 11.6 Hz, 2H), 384H562.33.13-3.05 (m, 1H), 3.05-2.84 (m, 2H), 1.N Cl 82-1.69 (m, 1H), 1.54-1.37 (m, 7H), 1.36-1.25 (m, 1H), 0.88-0.78 (m, 6H), 0.77 H -0.69 (m, 3H).F (CD3CN) S = 9.70 (s, 1H), 9.14-8.25 F (m, 2H), 7.47-7.02 (t, J = 53.6 Hz, 1H), z oKp \ V\ As6.86 (s, 1H), 6.06-5.89 (m, 1H), 4.01 (b r s, 2H), 3.61 (br d, J = 11.6 Hz, 2H), 385HY> AIvW 562.3 3.13-3.05 (m, 1H), 3.05-2.84 (m, 2H), 1.N Cl 82-1.69 (m, 1H), 1.54-1.37 (m, 7H), 1.3 '''' 6-1.25 (m, 1H), 0.88-0.78 (m, 6H), 0.77 H -0.69 (m, 3H).

[1531]

[1532] Example 49

[1534]

[1535] Step 1: ethyl 3-cyclopropyl-3-oxo-propanoate

[1536] To a solution of cyclobutylcarboxylic acid (1.00 eq, 30.00 g, 300 mmol) in THF (100 mL) was added dropwise a solution of CDI (1.05 eq, 51016 mg, 315 mmol) in dry THF (50 mL) at RT and stirred for 0.5 h. Then MgC12 (1.20 eq, 34235 mg, 360 mmol), and (3- ethoxy-3-oxo-propanoyl)oxypotassium (1.10 eq, 56102 mg, 330 mmol) in THF (300 mL) were added. The reaction mixture was stirred for 0.5 h at 60 °C. The resulting solutionwas taken up in EtOAc (500 ml) and the organics were washed with 4 x 300 ml sat. NH₄Cl. The organics were then separated and dried with MgSO₄. The crude product was concentrated under reduced pressure to afford ethyl 3-cyclopropyl-3-oxo-propanoate (49.94 g, 293 mmol, 97.92 % yield) as a brown oil.

[1537] MS (ESI) m / z = 157.2 [M+H]+.

[1538]

[1539] Step 2: ethyl 2-bromo-3-cyclopropyl-3-oxo-propanoate

[1540] 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 a nitrogen atmosphere. The reaction mixture was quenched with sat. aq NaHCO₃ (1000 mL), then extracted with DCM (800 mL x 3). The combined organic phases were washed with brine (800 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain ethyl 2-bromo-3-cyclopropyl-3-oxo-propanoate (72.4 g, 247.62 mmol, 77.35% yield, 80.4% purity) as a light yellow oil.

[1541] MS (ESI) m / z = 237.0 [M+H+2]+.

[1542]

[1543] Step 3: ethyl 6-bromo-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridine-3-carboxylate

[1544] 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 HC1 (1 M, 600 mL x 3) and saturated aqueous sodium chloride (800 mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain a crude product (10.5 g). The crude product was slurried with EtOAc (8 mL) at 25°C for 0.5 hr, then filtered. The filter cake was washed with EtOAc (2 mL), and a white solid was collected. Ethyl 6-bromo-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridine-3- carboxylate (7.05 g, 20.46 mmol, 6.75% yield, 99.7% purity) was obtained as a white solid.

[1545] MS (ESI) m / z = 344.9 [M+H+2]+.

[1546]

[1547] Step 4: ethyl 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridine-3- carb oxy late

[1548] To a solution of ethyl 6-bromo-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridine-3- carboxylate (2.3 g, 6.69 mmol) in dioxane (68 mL) were added phenylmethanethiol (748.25 mg, 6.02 mmol, 707.23 pL), Xantphos (387.31 mg, 669.38 pmol), DIEA (2.60 g, 20.08 mmol, 3.50 mL) and Pd2(dba)3(612.96 mg, 669.38 pmol). The mixture was degassed and purged with N2 three times, and then stirred at 80°C under a nitrogen atmosphere for 3 h. To the above mentioned mixture were added Xantphos (387.31 mg, 669.38 pmol), DIEA (1.73 g, 13.39 mmol, 2.33 mL) and Pd2(dba)3(612.96 mg, 669.38 pmol). The mixture was degassed and purged with N2 three times, and then stirred at 80°C under a nitrogen atmosphere for another 3 h. The mixture was filtered, and the filtrate was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce ethyl 6-benzylsulfanyl-8-chloro-2- cy cl opropyl-imidazo[l,2-a]pyridine-3 -carboxylate (2 g, 4.60 mmol, 68.73% yield, 89% purity) as a light yellow solid.

[1549] MS (ESI) m / z = 388.8 [M+H+2]+.

[1550]

[1551] Step 5: 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridine-3- carbohydrazide

[1552] To a solution of ethyl 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,2- a]pyridine-3 -carboxylate (2 g, 5.17 mmol) in EtOH (35 mL) was added NH2NH2·H2O (9.13 g, 155.08 mmol, 8.85 mL, 85% purity) dropwise at 25°C. The mixture was heated and stirred at 80 °C under a nitrogen atmosphere for 12 h. To the above mentioned mixture was added NH2NH2·H2O (7.61 g, 129.23 mmol, 7.38 mL, 85% purity) dropwise at 25°C. The mixture was heated and stirred at 80°C under a nitrogen atmosphere for 4 h. The mixture was cooled to 25°C. The mixture was concentrated under reducedpressure to produce 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridine-3- carbohydrazide (1.88 g, 4.64 mmol, 89.73% yield) as a white solid.

[1553] MS (ESI) m / z = 373.2 [M+H]+.

[1554]

[1555] Step 6: 6-benzylsulfanyl-8-chloro-2-cyclopropyl-N'-(2,2-difluoroacetyl)imidazo[l,2- a]pyridine-3 -carbohydrazide

[1556] To a solution of 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,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 N2 three times. The mixture was stirred at 25 °C under a nitrogen atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to produce 6-benzylsulfanyl-8-chloro-2-cyclopropyl-N'-(2,2- difluoroacetyl)imidazo[l,2-a]pyridine-3 -carbohydrazide (1.45 g, 3.09 mmol, 61.56% yield) as a white solid.

[1557] MS (ESI) m / z = 451.1 [M+H]+.

[1558]

[1559] Step 7: 2-(6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridin-3-yl)-5- (difluorom ethyl)- 1,3,4-thiadiazole

[1560] To a solution of 6-benzylsulfanyl-8-chloro-2-cyclopropyl-N'-(2,2- difluoroacetyl)imidazo[l,2-a]pyridine-3 -carbohydrazide (347.7 mg, 0.77 mmol) in toluene (4.5 mL) was added Lawesson’s reagents (343.09 mg, 0.85 mmol). The mixture was degassed and purged with N2 three times. The mixture was stirred at 120°C under a nitrogen atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce 2-(6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,2- a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (342 mg, 0.76 mmol, 98.79% yield) as a brown solid.

[1561] MS (ESI) m / z = 449.1 [M+H]+.

[1562]

[1563] Step 8: 8-chloro-2-cyclopropyl-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2- yl]imidazo[l,2-a]pyridine-6-sulfonyl chloride

[1564] To a solution of 2-(6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridin- 3-yl)-5-(difluoromethyl)-l,3,4-thiadiazole (243 mg, 490.08 pmol) 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 a nitrogen atmosphere for 12 h. The solid was filtered and concentrated under reduced pressure to produce 8-chloro-2-cyclopropyl-3-[5- (difluoromethyl)-l,3,4-thiadiazol-2-yl]imidazo[l,2-a]pyridine-6-sulfonyl chloride (312 mg, crude) as a light brown solid.

[1565] MS (ESI) m / z = 425.0 [M+H]+.

[1566]

[1567] Step 9: 8-chloro-2-cyclopropyl-N-[(lR)-2,2-difhioro-l-isopropyl-propyl]-3-[5- (difluorom ethyl)- 1,3,4-thiadiazol-2-yl]imidazo[ 1,2-a]pyridine-6-sulfonamide

[1568] To a solution of 8-chloro-2-cyclopropyl-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2- yl]imidazo[l,2-a]pyridine-6-sulfonyl chloride (28.8 mg, 0.067 mmol) in MeCN (1 mL) were added 4A MS (0.0025 g) and a solution of (3R)-2,2-difluoro-4-methyl-pentan-3- amine (23.52 mg, 0.135 mmol, HC1) in Py (0.5 mL) and THF (0.5 mL) at 0 °C. The mixture was stirred at 25 °C under a nitrogen atmosphere for 12 h. The mixture was filtered and the cake was washed with DCM (8 mL x 2). The combined filtrates were concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel to produce 8-chloro-2-cyclopropyl-N-[(lR)-2,2-difluoro-l-isopropyl- propyl]-3-[5-(difhioromethyl)-l,3,4-thiadiazol-2-yl]imidazo[l,2-a]pyridine-6- sulfonamide (18.3 mg, 0.035 mmol, 51.37% yield) as a white solid.

[1569] MS (ESI) m / z = 526.1 [M+H]+.

[1570]

[1571] Step 10: tert-butyl (2S,6S)-4-[2-cyclopropyl-6-[[(lR)-2,2-difluoro-l-isopropyl- propyl]sulfamoyl]-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]imidazo[l,2-a]pyridin-8- yl]-2,6-dimethyl-piperazine-l -carboxylate

[1572] To a solution of 8-chloro-2-cyclopropyl-N-[(lR)-2,2-difluoro-l-isopropyl-propyl]-3- [5-(difluoromethyl)- 1,3,4-thiadiazol-2-yl]imidazo[ 1,2-a]pyridine-6-sulfonamide (45 mg,78.55 pmol) in dioxane (2 mL) were added tert-butyl (2S,6S)-2,6-dimethylpiperazine-l- carboxylate (33.67 mg, 157.11 pmol), CS2CO3 (76.78 mg, 235.66 pmol) and [l,3-bis[2,6- bis(l-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(2-methylpyridin-l- ium-l-yl)palladium (6.60 mg, 7.86 pmol). The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce tert-butyl (2S,6S)-4- [2-cyclopropyl-6-[[(lR)-2,2-difhioro-l-isopropyl-propyl]sulfamoyl]-3-[5- (difluorom ethyl)- 1,3,4-thiadiazol-2-yl]imidazo[ 1,2-a]pyridin-8-yl]-2,6-dimethyl- piperazine-1 -carboxylate (50 mg, 64.61 pmol, 82.25% yield) as a brown oil.

[1573] MS (ESI) m / z = 604.2 [M+H]+.

[1574]

[1575] Step 11: 2-cyclopropyl-N-[(lR)-2,2-difhioro-l-isopropyl-propyl]-3-[5- (difhioromethyl)-l,3,4-thiadiazol-2-yl]-8-[(3S,5S)-3,5-dimethylpiperazin-l- yl]imidazo[l,2-a]pyridine-6-sulfonamide

[1576] To a solution of tert-butyl (2S,6S)-4-[2-cyclopropyl-6-[[(lS)-2,2-difluoro-l- isopropyl-propyl]sulfamoyl]-3-[5-(difhioromethyl)-l,3,4-thiadiazol-2-yl]imidazo[l,2- a]pyridin-8-yl]-2,6-dimethyl-piperazine-l-carboxylate (50 mg, 66.60 pmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at 25 °C under a nitrogen atmosphere for 0.5 h. The mixture was concentrated under a nitrogen atmosphere to produce a residue. The residue was purified by column chromatography to produce 2- cyclopropyl-N-[(lR)-2,2-difhioro-l-isopropyl-propyl]-3-[5-(difhioromethyl)-l,3,4- thiadiazol-2-yl]-8-[(3S,5S)-3,5-dimethylpiperazin-l-yl]imidazo[l,2-a]pyridine-6- sulfonamide (31.13 mg, 40.59 pmol, 60.94% yield) as a yellow solid.

[1577] MS (ESI) m / z = 604.1 [M+H]+.

[1578] 1H NMR (400 MHz, CDC13) 5 9.96 (s, 1H), 7.12 (d, J = 53.7 Hz, 1H), 6.91 (s, 1H), 3.68 (td, J = 13.6, 2.6 Hz, 1H), 3.59 – 3.45 (m, 4H), 3.44-3.39 (m, 2H), 2.23 – 2.08 (m, 2H), 1.59 (t, J = 19.0 Hz, 4H), 1.36 (d, J = 6.2 Hz, 6H), 1.30 – 1.20 (m, 4H), 1.00 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H).

[1579] The following compounds were prepared by a procedure similar to the procedure of Example 49.MS (ESI) m / zExample Structure 1H NMR[M+H]+^F1H NMR (400 MHz, DMSO) S 8.66 (s, 1H), 7.24 (s, 1H), 5.29 (s, 1H), 5.01 (s, 1H), 3.97 11 608.1 (s, 1H), 3.46 - 3.33 (m, 2H), 3.29 - 3.10 (m,4H), 1.89 (s, 1H), 1.77 (s, 1H), 1.50 (s, 1H), A 1.24 - 1.12 (m, 6H), 1.08 - 0.74 (m, 10H).1H NMR (400 MHz, DMSO) S 8.66 (s, 1H), 7.24 (s, 1H), 5.29 (s, 1H), 5.01 (s, 1H), 3.97 12 608.1 (s, 1H), 3.46 - 3.33 (m, 2H), 3.29 - 3.10 (m,4H), 1.89 (s, 1H), 1.77 (s, 1H), 1.50 (s, 1H), 1.24 - 1.12 (m, 6H), 1.08 - 0.74 (m, 10H).1H NMR (400 MHz, DMSO) S 8.59 (s, 1H), 7.27 (s, 1H), 5.02 (s, 1H), 4.42 (s, 1H), 4.17 (s, 1H), 3.49 - 3.37 (m, 2H), 3.29 - 3.13 (m, 21Jxi« 590.14H), 2.78 (s, 1H), 1.77 (s, 1H), 1.49 (d, J = Xj 9.2 Hz, 2H), 1.22 - 1.13 (m, 6H), 1.08 - 0.77(m, 10H).1H NMR (400 MHz, DMSO) S 8.59 (s, 1H), / 7.27 (s, 1H), 5.02 (s, 1H), 4.42 (s, 1H), 4.17(s, 1H), 3.49 - 3.37 (m, 2H), 3.29 - 3.13 (m, 22 590.14H), 2.78 (s, 1H), 1.77 (s, 1H), 1.49 (d, J = 9.2 Hz, 2H), 1.22 - 1.13 (m, 6H), 1.08 - 0.77 A (m, 10H).1H NMR (400 MHz, DMSO) S 7.99 (s, 1H), 7.27 (s, 1H), 7.03 (t, 1H), 5.16 (s, 1H), 3.73 (s, 1H), 3.59 - 3.51 (m, 2H), 3.28 - 3.16 (m, 25 618.1 3H), 3.04 - 2.88 (m, 2H), 2.47 - 2.33 (m,7 A 2H), 2.24 - 2.13 (m, 2H), 1.97 (d, J = 32.8 A Hz, 2H), 1.81 - 1.69 (m, 4H), 1.65 (s, 1H),1.22 - 1.13 (m, 6H), 1.06 - 0.92 (m, 6H).1H NMR (400 MHz, DMSO) S 7.99 (s, 1H), 7.27 (s, 1H), 7.03 (t, 1H), 5.16 (s, 1H), 3.73 (s, 1H), 3.59 - 3.51 (m, 2H), 3.28 - 3.16 (m, 26 618.1 3H), 3.04 - 2.88 (m, 2H), 2.47 - 2.33 (m,2H), 2.24 - 2.13 (m, 2H), 1.97 (d, J = 32.8 Hz, 2H), 1.81 - 1.69 (m, 4H), 1.65 (s, 1H), Xx 1.22 - 1.13 (m, 6H), 1.06 - 0.92 (m, 6H).1H NMR (400 MHz, DMSO) S 8.41 (s, 1H), 7.27 (s, 1H), 6.77 (s, 1H), 5.32 (s, 1H), 5.01 (s, 1H), 3.97 (s, 1H), 3.51 - 3.37 (m, 2H), 27 604.0 3.32 - 3.15 (m, 5H), 2.54 - 2.37 (m, 2H),A $ 2.26 - 2.13 (m, 2H), 2.07 - 1.83 (m, 3H),1.78 (s, 1H), 1.24 - 1.13 (m, 6H), 1.10 - 0.99 X:>. (m, 6H).1H NMR (400 MHz, DMSO) S 8.41 (s, 1H),NAS 7.27 (s, 1H), 6.77 (s, 1H), 5.32 (s, 1H), 5.01(s, 1H), 3.97 (s, 1H), 3.51 - 3.37 (m, 2H), 604.0 3.32 - 3.15 (m, 5H), 2.54 - 2.37 (m, 2H),2.26 - 2.13 (m, 2H), 2.07 - 1.83 (m, 3H), A 1.78 (s, 1H), 1.24 - 1.13 (m, 6H), 1.10 - 0.99(m, 6H).1H NMR (400 MHz, DMSO) S 8.59 (s, 1H), 7.27 (s, 1H), 6.68 (s, 1H), 5.08 (s, 1H), 4.42 (s, 1H), 4.17 (s, 1H), 3.62 - 3.49 (m, 2H), 586.1 3.34 - 3.13 (m, 4H), 3.10 - 3.00 (m, 2H),2.50 - 2.35 (m, 2H), 2.24 - 2.11 (m, 2H), 1.93 (t, J = 34.7 Hz, 3H), 1.69 (s, 1H), 1.22 - A1.15 (m, 6H), 1.10 - 1.04 (m, 6H). 1H NMR (400 MHz, DMSO) S 8.59 (s, 1H), 7.27 (s, 1H), 6.68 (s, 1H), 5.08 (s, 1H), 4.42 V (s, 1H), 4.17 (s, 1H), 3.62 - 3.49 (m, 2H),586.1 3.34 - 3.13 (m, 4H), 3.10 - 3.00 (m, 2H),2.50 - 2.35 (m, 2H), 2.24 - 2.11 (m, 2H), 1.93 (t, J = 34.7 Hz, 3H), 1.69 (s, 1H), 1.22 - A1.15 (m, 6H), 1.10 - 1.04 (m, 6H). 1H NMR (400 MHz, DMSO) S 8.41 (s, 1H), 7.27 (s, 1H), 5.07 (s, 1H), 4.42 (s, 1H), 4.17 (s, 1H), 3.50 - 3.39 (m, 2H), 3.30 - 3.16 (m, 604.0 5H), 2.91 (s, 1H), 2.52 - 2.37 (m, 2H), 2.10(dd, J = 64.5, 16.4 Hz, 4H), 1.78 (s, 1H), XX 1.38 (s, 1H), 1.25 - 1.11 (m, 6H), 1.03 - 0.89(m, 6H).1H NMR (400 MHz, DMSO) S 8.41 (s, 1H), 7.27 (s, 1H), 5.07 (s, 1H), 4.42 (s, 1H), 4.17 V (s, 1H), 3.50 - 3.39 (m, 2H), 3.30 - 3.16 (m,604.0 5H), 2.91 (s, 1H), 2.52 - 2.37 (m, 2H), 2.10(dd, J = 64.5, 16.4 Hz, 4H), 1.78 (s, 1H), 1.38 (s, 1H), 1.25 - 1.11 (m, 6H), 1.03 - 0.89 A (m, 6H).1H NMR (400 MHz, CDC13) S 9.96 (s, 1H),,NA " F 7.12 (t, J = 53.9 Hz, 1H), 6.91 (s, 1H), 3.68 V M (td, J = 13.6, 2.6 Hz, 1H), 3.57 - 3.47 (m, pA 604.1 4H), 3.43-3.39 (m, 2H), 2.22 - 2.08 (m, 2H),1.60 (t, J = 19.0 Hz, 3H), 1.35 (d, J = 6.1 Hz, 6H), 1.29-1.20 (m, 4H), 0.98 (d, J = 6.8 Hz, A 3H), 0.90 (d, J = 6.7 Hz, 3H).1H NMR (400 MHz, DMSO) S 8.47 (s, 1H), 7.27 (s, 1H), 6.73 (s, 1H), 5.47 (s, 1H), 3.73 (s, 1H), 3.58 (s, 1H), 3.56 - 3.44 (m, 2H), 588.13.27 - 3.19 (m, 2H), 3.14 - 3.01 (m, 2H), 1.93 (s, 1H), 1.78 - 1.58 (m, 4H), 1.22 - 1.13 A (m, 6H), 1.10 - 1.01 (m, 6H).1H NMR (400 MHz, DMSO) S 8.47 (s, 1H),7.27 (s, 1H), 6.73 (s, 1H), 5.47 (s, 1H), 3.73 (s, 1H), 3.58 (s, 1H), 3.56 - 3.44 (m, 2H), ApA 588.13.27 - 3.19 (m, 2H), 3.14 - 3.01 (m, 2H), 1.93 (s, 1H), 1.78 - 1.58 (m, 4H), 1.22 - 1.13 A (m, 6H), 1.10 - 1.01 (m, 6H).1H NMR (400 MHz, CDCl3) S 10.01 (s, 1H), 7.12 (t, 1H), 7.02 (s, 1H), 5.78 (t, J = 55.2 Hz, 1H), 3.88 - 3.76 (m, 4H), 3.72 - 590.1 3.64 (m, 2H), 3.61 - 3.49 (m, 1H), 2.23 - A C 2.14 (m, 1H), 2.04 - 1.95 (m, 1H), 1.58 (d, J A = 6.0 Hz, 6H), 1.30 - 1.14 (m, 4H), 1.01 (t, J = 7.6 Hz, 6H).1H NMR (400 MHz, CDCl3) S 10.01 (s, 1H), 7.12 (t, 1H), 7.02 (s, 1H), 5.78 (t, J = 55.2 Hz, 1H), 3.88 - 3.76 (m, 4H), 3.72 - 590.1 3.64 (m, 2H), 3.61 - 3.49 (m, 1H), 2.23 - 2.14 (m, 1H), 2.04 - 1.95 (m, 1H), 1.58 (d, J A = 6.0 Hz, 6H), 1.30 - 1.14 (m, 4H), 1.01 (t, J = 7.6 Hz, 6H).1H NMR (400 MHz, CD3OD) S = 10.13 (d, N J = 1.2 Hz, 1H), 7.25 (t, J = 53.6 Hz, 1H),7.10 (d, J = 1.2 Hz, 1H), 3.95-3.89 (m, 2H), v^ 538.1 3.84-3.75 (m, 2H), 3.73-3.65 (m, 2H), 2.23- 2.16 (m, 1H), 1.56 (d, J = 6.4 Hz, 6H), 1.32- 1.28 (m, 2H), 1.25 (s, 3H), 1.24-1.14 (m, A 2H), 0.86-0.76 (m, 2H), 0.53-0.47 (m, 2H).1H NMR (400 MHz, CD3OD) S = 10.20 (s, NAS 1H), 7.26 (t, J = 54.4 Hz, 1H), 7.14 (s, 1H),3.97-3.88 (m, 2H), 3.88-3.78 (m, 2H), 3.78- 549.1 3.69 (m, 2H), 2.22-2.14 (m, 1H), 1.57 (s, V - 3H), 1.55 (s, 3H), 1.54-1.48 (m, 2H), 1.48- 1.41 (m, 2H), 1.32-1.26 (m, 2H), 1.25-1.15 Xx (m, 2H).1H NMR (400 MHz, DMSO) S 8.22 (s,,NA"^F1H),, 7.27 (s, 1H), 6.73 (s, 1H), 5.55 (s, 1H),3.57 - 3.48 (m, 2H), 3.29 - 3.16 (m, 2H), 588.1 3.12 - 2.99 (m, 2H), 1.77 - 1.60 (m, 4H),1.50 (s, 1H), 1.27 - 1.14 (m, 6H), 1.11 -0.93 (m, 2H), 0.91 - 0.73 (m, 2H), 0.47 - 0.33 (m, A 2H), 0.23 - 0.08 (m, 2H).1H NMR (400 MHz, CD3OD) S = 10.15- 10.08 (m, 1H), 7.18-7.10 (m, 1H), 3.96-3.90 (m, 2H), 3.85-3.80 (m, 2H), 3.76-3.69 (m, 556.1 2H), 2.18-2.13 (m, 1H), 1.58 (d, J = 6.4 Hz,6H), 1.36-1.30 (m, 2H), 1.26 (s, 3H), 1.24- Jj. 1.15 (m, 2H), 0.87-0.78 (m, 2H), 0.55-0.50(m, 2H).1H NMR (400 MHz, CD3OD) S = 10.10 (d,J = 1.6 Hz, 1H), 7.26 (t, J = 54.4 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 4.05-3.89 (m, 5H), 552.0 3.82-3.71 (m, 2H), 2.69-2.56 (m, 4H), 2.30- 2.19 (m, 10.9 Hz, 1H), 2.19-2.07 (m, 1H), A 1.63 (d, J = 6.4 Hz, 6H), 1.26 (s, 3H), 0.88- 0.78 (m, 2H), 0.56-0.46 (m, 2H). 1H NMR (400 MHz, DMSO) S 9.06 (s, 1H), N VK7.27 (s, 1H), 6.76 (s, 1H), 5.33 (s, 1H), 3.55- 3.42 (m, 2H), 3.30 - 3.15 (m, 5H), 2.53 - 563.1 2.40 (m, 2H), 2.25 - 2.12 (m, 2H), 1.98 (d, J = 32.8 Hz, 2H), 1.23 - 1.06 (m, 8H), 0.99 - A 0.81 (m, 2H).1H NMR (400 MHz, DMSO) S 9.06 (s, 1H), 7.27 (s, 1H), 6.76 (s, 1H), 5.33 (s, 1H), 3.55 ^Vt-yo - 3.42 (m, 2H), 3.30 - 3.15 (m, 5H), 2.53 - 563.12.40 (m, 2H), 2.25 - 2.12 (m, 2H), 1.98 (d, J = 32.8 Hz, 2H), 1.23 - 1.06 (m, 8H), 0.99 - A. 0.81 (m, 2H).1H NMR (400 MHz, DMSO) S 8.41 (s, 1H), 7.36 (s, 1H), 5.20 (s, 1H), 3.52 - 3.37 (m, 2H), 3.32 - 3.14 (m, 5H), 2.52 - 2.37 (m, 570.12H), 2.10 (dd, J = 64.7, 16.4 Hz, 4H), 1.78 (s, 1H), 1.29 - 1.11 (m, 9H), 0.50 - 0.30 (m, x 2H), 0.27 - 0.05 (m, 2H).1H NMR (400 MHz, DMSO) S 8.57 (s, 1H), 7.30 (s, 1H), 6.77 (s, 1H), 5.21 (s, 1H), 3.54 - 3.34 (m, 2H), 3.30 - 3.14 (m, 7H), 2.79 - 582.0 2.60 (m, 2H), 2.54 - 2.38 (m, 2H), 2.14 (d, J = 32.8 Hz, 2H), 1.77 (s, 1H), 1.41 - 1.27 (m, / x. 3H), 1.23 - 1.08 (m, 6H), 0.50 - 0.27 (m,2H), 0.24 - 0.07 (m, 2H).1H NMR (400 MHz, DMSO) S 8.36 (s, 1H), N^Y^F 7.14 (s, 1H), 6.77 (s, 1H), 4.80 (s, 1H), 3.60- 3.46 (m, 2H), 3.31 - 3.17 (m, 3H), 3.13 - 588.0 3.02 (m, 2H), 2.85 - 2.64 (m, 2H), 2.60 - 2.40 (m, 2H), 1.68 (s, 1H), 1.24 - 1.12 (m, Xi. 6H), 0.95 - 0.87 (m, 3H), 0.50 - 0.32 (m,2H), 0.26 - 0.06 (m, 2H).1H NMR (400 MHz, DMSO) S 8.38 (s, 1H), 7.07 (s, 1H), 6.76 (s, 1H), 4.89 (s, 1H), 3.73 A V (s, 1H), 3.60 - 3.45 (m, 2H), 3.32 - 3.17 (m,654.0 3H), 3.13 - 3.06 (m, 2H), 2.86 - 2.65 (m, ApiA C 2H), 2.62 - 2.37 (m, 2H), 1.77 - 1.57 (m,4H), 1.43 (s, 1H), 1.26 - 1.12 (m, 6H), 1.08 A -0.95 (m, 6H).F 1H NMR (400 MHz, DMSO) S 8.38 (s, 1H), \ / N I 7.07 (s, 1H), 6.76 (s, 1H), 4.89 (s, 1H), 3.73(s, 1H), 3.60 - 3.45 (m, 2H), 3.32 - 3.17 (m, 330 654.0 3H), 3.13 - 3.06 (m, 2H), 2.86 - 2.65 (m,2H), 2.62 - 2.37 (m, 2H), 1.77 - 1.57 (m, 4H), 1.43 (s, 1H), 1.26 - 1.12 (m, 6H), 1.08 AH -0.95 (m, 6H).F 1H NMR (400 MHz, DMSO) S 8.41 (s, 1H),ni 7.35 (s, 1H), 6.77 (s, 1H), 5.19 (s, 1H), 3.52- 3.38 (m, 2H), 3.32 - 3.10 (m, 5H), 2.37 - 334 580.1 2.21 (m, 2H), 2.11 - 1.99 (m, 2H), 1.77 (s,1H), 1.27 - 1.14 (m, 9H), 1.11 -0.96 (m, 6H), 0.48 - 0.31 (m, 2H), 0.24 - 0.08 (m, H 2H).F1H NMR (400 MHz, CD3OD) S = 10.15- 1Ho Vs 10.05 (m, 1H), 7.25 (t, J = 54.4 Hz, 1H),7.12-7.06 (m, 1H), 5.74 (t, J = 56.8 Hz, 1H), 356 574.03.95-3.65 (m, 6H), 2.28-2.12 (m, 1H), 1.56 (br d, J = 6.8 Hz, 6H), 1.32-1.14 (m, 4H), A 1.09-0.97 (m, 4H).H VFi_i N 1 1H NMR (400 MHz, CD3OD) S = 10.19 (d,J = 1.2 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 3.97-3.88 (m, 2H), 3.88-3.79 (m, 2H), 3.79- 361 567.13.72 (m, 2H), 2.20-2.10 (m, 1H), 1.57 (s, 3H), 1.55 (s, 3H), 1.55-1.42 (m, 4H), 1.34- / I 1.28 (m, 2H), 1.26-1.15 (m, 2H).H

[1580]

[1581] Example 23

[1582] N-((R)-2,2-difluoro-4-methylpentan-3-yl)-3-(5-(difluoromethyl)-l,3,4-thiadiazol- 2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-l-yl)imidazo[l,2-a]pyridine-6-sulfonamide (General Procedure 6)

[1584] Step 1: 6-bromo-8-chloroimidazo[l,2-a]pyridine-3 -carbohydrazide

[1585] To a solution of ethyl 6-Bromo-8-chloro-imidazo[l,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 and stirred at 80°C under a nitrogen atmosphere for 12 h. The mixture was cooled to 25°C. The precipitated solid was separated off to produce the product, 6-Bromo-8-chloro-imidazo[l,2-a]pyridine-3 -carbohydrazide (1.24 g, 4.27 mmol, 73.4% yield) as a white solid.

[1586] MS (ESI) m / z = 291.0 [M+H]+

[1587]

[1588] Step 2: 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[l,2-a]pyridine-3- carbohydrazide

[1589] To a solution of 6-bromo-8-chloro-imidazo[l,2-a]pyridine-3 -carbohydrazide (1.24 g, 4.27 mmol) in THF (30 mL) were 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 a nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure to produce a residue. The crude residue was purified by column chromatography to obtain 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[l,2-a]pyridine-3- carbohydrazide (1.94 g, 5.28 mmol, 99% yield) as a white solid

[1590] MS (ESI) m / z = 369.0 [M+H]+

[1591]

[1592] Step 3: 2-(6-bromo-8-chloroimidazo[l,2-a]pyridin-3-yl)-5-(difluoromethyl)-l,3,4- thiadi azole

[1593] To a solution 6-Bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[l,2-a]pyridine-3- carbohydrazide (627 mg, 1.71 mmol) in Toluene (11 mL) was added Lawesson’s reagent (759 mg, 1.86 mmol) at 25°C. The mixture was heated and stirred at 110°C under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to 25°C and concentrated to produce a residue, which was triturated with MeOH. Filtration was performed and cake was collected. 2-(6-Bromo-8-chloroimidazo[l,2-a]pyridin-3-yl)-5- (difluoromethyl)-l,3,4-thiadiazole (220 mg, 0.60 mmol, 35% yield) was produced as a white solid.

[1594] MS (ESI) m / z = 365.9 [M+H]+

[1595]

[1596] Step 4: 2-(6-(benzylthio)-8-chloroimidazo[l,2-a]pyridin-3-yl)-5-(difluoromethyl)- 1.3.4-thiadiazole

[1597] To a solution of 2-(6-Bromo-8-chloroimidazo[l,2-a]pyridin-3-yl)-5- (difluoromethyl)-l,3,4-thiadiazole (193 mg, 0.53 mmol) in Dioxane (5 mL) was added Pd2(dba)3 (48 mg, 0.05 mmol), Xantphos (61 mg, 0.11 mmol), BnSH (66 mg, 0.53 mmol) and DIPEA (137 mg, 1.06 mmol) at 25°C. The suspension was degassed under vacuum and purged with N2 three times. The mixture was heated and stirred at 80°C under a nitrogen atmosphere for 3 h. The mixture was diluted with H2O (10 mL) and extracted with DCM (30 mL x 3), and the combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography to afford 2-(6-(Benzylthio)-8-chloroimidazo[l,2- a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (95.5 mg, 0.23 mmol, 43% yield) as a yellow solid.

[1598] MS (ESI) m / z = 408.0 [M+H]+

[1599]

[1600] Step 5: 8-chloro-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)imidazo[l,2-a]pyridine- 6-sulfonyl chloride

[1601] To a mixture of 2-(6-(Benzylthio)-8-chloroimidazo[l,2-a]pyridin-3-yl)-5- (difhioromethyl)-l,3,4-thiadiazole (105 mg, 0.26 mmol) in AcOH (1.83 mL) and H2O (0.61 mL) was added NCS (137 mg, 1.02 mmol) at 5 °C. The mixture was warmed and stirred at 25°C under a nitrogen atmosphere for 4 h. To the reaction mixture was added H2O (10 mL). 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)-l,3,4-thiadiazol-2-yl)imidazo[l,2-a]pyridine-6- sulfonyl chloride (crude) as a yellow solid.

[1602] MS (ESI) m / z = 383.9 [M+H]+

[1603]

[1604] Step 6: (R)-8-chloro-N-(2,2-difluoro-4-methylpentan-3-yl)-3-(5-(difluoromethyl)- 1.3.4-thiadiazol-2-yl)imidazo[l,2-a]pyridine-6-sulfonamide

[1605] To a mixture of 8-chloro-3-(5-(difhioromethyl)-l,3,4-thiadiazol-2-yl)imidazo[l,2- a]pyridine-6-sulfonyl chloride (0.26 mmol, crude) and (R)-2,2-difluoro-4-methylpentan- 3-amine;hydrochloride (58 mg, 0.38 mmol) in DCM (2.5 mL) was added TEA (155 mg, 1.54 mmol) dropwise at 5 °C. The mixture was warmed and stirred at 25 °C under a nitrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography to afford (R)-8-chloro-N-(2,2-difluoro-4-methylpentan-3-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridine-6-sulfonamide (63.8 mg, 0.13 mmol, 51% yield) as a brown solid.

[1606] MS (ESI) m / z = 486.3 [M+H]+

[1607]

[1608] Step 7: tert-butyl (2S,6S)-4-(6-(N-((R)-2,2-difluoro-4-methylpentan-3-yl)sulfamoyl)- 3-(5-(difhioromethyl)-l,3,4-thiadiazol-2-yl)imidazo[l,2-a]pyridin-8-yl)-2,6- dimethylpiperazine-1 -carboxylate

[1609] To a solution of (R)-8-chloro-N-(2,2-difluoro-4-methylpentan-3-yl)-3-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)imidazo[l,2-a]pyridine-6-sulfonamide (124 mg, 238.30 pmol) in dioxane (3 mL) were added tert-butyl (2S,6S)-2,6-dimethylpiperazine-l- carboxylate (76.60 mg, 357.45 pmol), Cs2CO3 (232.93 mg, 714.90 pmol) and [1,3- bis[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(2- methylpyridin-l-ium-l-yl)palladium (20.02 mg, 23.83 pmol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to afford tert-butyl (2S,6S)-4-(6-(N-((R)-2,2-difluoro-4-methylpentan-3- yl)sulfamoyl)-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)imidazo[l,2-a]pyridin-8-yl)- 2,6-dimethylpiperazine-l -carboxylate (37 mg, 39.02 pmol, 16.37% yield, 70% purity) as a brown oil.

[1610] MS (ESI) m / z = 664.3 [M+H]+

[1611]

[1612] Step 8: N-[(lR)-2,2-difluoro-l-isopropyl-propyl]-3-[5-(difluoromethyl)-l,3,4- thiadiazol-2-yl]-8-[(3S,5S)-3,5-dimethylpiperazin-l-yl]imidazo[l,5-a]pyridine-6- sulfonamide

[1613] To a mixture of tert-butyl (2S,6S)-4-(6-(N-((R)-2,2-difluoro-4-methylpentan-3- yl)sulfamoyl)-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)imidazo[l,2-a]pyridin-8-yl)- 2,6-dimethylpiperazine-l -carboxylate (37 mg, 55.74 pmol) in DCM (1 mL) was added TFA (0.3 mL). The mixture was stirred at 25 °C under a nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to afford N-[(lR)-2,2-difluoro-l- isopropyl-propyl]-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-8-[(3S,5S)-3,5-dimethylpiperazin-1-yl]imidazo[1,5-a]pyridine-6-sulfonamide (7.31 mg, 10.49 pmol, 18.81% yield) as a yellow solid.

[1614] MS (ESI) m / z = 564.1 [M+H]+

[1615] 1H NMR (400MHz, CD3OD) 5 = 9.84 (s, 1H), 7.87 (s, 1H), 7.34 (t, 1H), 6.94 (s, 1H), 3.99-3.95 (m, 2H), 3.72-3.64 (m, 1H), 3.56 (dd, J = 13.6, 3.2 Hz, 2H), 3.39-3.34 (m, 2H), 2.11 (m, 1H), 1.62-1.49 (m, 9H), 1.03-0.92 (m, 6H).

[1616]

[1617] The following compounds were prepared by a procedure similar to the procedure of Example 23.MS (ESI) m / zExample Structure 1H NMR[M+H]+1H NMR (400MHz, CD3OD) S = 9.84 (s, Y v A 1H), 7.87 (s, 1H), 7.34 (t, 1H), 6.94 (s, 1H),3.99-3.95 (m, 2H), 3.72-3.64 (m, 1H), 3.56 24 564.1(dd, J = 13.6, 3.2 Hz, 2H), 3.39-3.34 (m, 2H), 2.11 (m, 1H), 1.62-1.49 (m, 9H), 1.03-0.92 A (m, 6H).1H NMR (400 MHz, DMSO) S 9.55 (s, 1H), 7.82 - 7.69 (m, 3H), 6.75 (t, 1H), 4.99 (d, J = 14.8 Hz, 2H), 3.97 (s, 1H), 3.45 - 3.33 (m, 85 550.1A A 2H), 3.30 - 3.16 (m, 2H), 2.75 - 2.64 (m,2H), 2.22 (s, 1H), 1.26 - 1.15 (m, 6H), 1.09 - A 0.96 (m, 6H).N^ / ^F 1H NMR (400 MHz, DMSO) S 9.55 (s, 1H),7.82 - 7.69 (m, 3H), 6.75 (t, 1H), 4.99 (d, J = 14.8 Hz, 2H), 3.97 (s, 1H), 3.45 - 3.33 (m, 86 550.12H), 3.30 - 3.16 (m, 2H), 2.75 - 2.64 (m, 2H), 2.22 (s, 1H), 1.26 - 1.15 (m, 6H), 1.09 - A 0.96 (m, 6H).

[1619] Example 39

[1620]

[1621] (R)-2-cyclopropyl-N-(l,l-difluoro-3-methylbutan-2-yl)-3-(5-(difluoromethyl)- l,3,4-thiadiazol-2-yl)-8-(4-(l-methoxycyclopropane-l-carbonyl)piperazin-l- yl)imidazo[l,2-a]pyridine-6-sulfonamide (General Procedure 11)

[1622] To a solution of (R)-8-chloro-2-cyclopropyl-N-(l,l-difluoro-3-methylbutan-2-yl)-3- (5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)imidazo[l,2-a]pyridine-6-sulfonamide (33 mg, 0.064 mmol) in 1,4-Dioxane (1 mL) were added (1 -methoxy cy cl opropyl)-piperazin-l-yl- methanone (13.06 mg, 0.071 mmol), CS2CO3 (63.01 mg, 0.193 mmol) and [l,3-bis[2,6- bis(l-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(2-methylpyridin-l- ium-l-yl)palladium (6.27 mg, 0.006 mmol). The mixture was degassed and purged with N2 three times. The mixture was stirred at 100°C under a nitrogen atmosphere for 3 h and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce (R)-2-cyclopropyl-N-(l,l-difluoro-3- methylbutan-2-yl)-3-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-8-(4-(l- methoxy cyclopropane- 1 -carbonyl)piperazin- 1 -yl)imidazo[ 1,2-a]pyridine-6-sulfonamide (5.5 mg, 0.008 mmol, 12.7% Yield) as a yellow solid.

[1623] MS (ESI) m / z 660.2 [M+H]+

[1624] 1H NMR (400 MHz, DMSO) 5 8.43 (d, J = 1.4 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 6.76 (t, J = 57.3 Hz, 1H), 5.74 (s, 1H), 5.01 (td, J = 57.3, 0.5 Hz, 1H), 4.06 - 3.85 (m, 3H), 3.65 (ddd, J = 5.1, 3.6, 1.4 Hz, 2H), 3.40 - 3.32 (m, 4H), 3.24 (s, 3H), 1.59 - 1.40 (m, 2H), 1.21 - 1.10 (m, 2H), 1.02 (d, J = 6.4 Hz, 6H), 0.99 - 0.78 (m, 6H).

[1625]

[1626] The following compounds were prepared by a procedure similar to the procedure of Example 39.MS (ESI) m / zExample Structure 1H NMR[M+H]+F 1H NMR (400 MHz, DMSO) S 8.43 (d, J = \ / N. 1 1.4 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 6.76 (t, J = 57.3 Hz, 1H), 5.74 (s, 1H), 5.01 (td, J = 57.3, 0.5 Hz, 1H), 4.06 - 3.85 (m, 3H), 40 660.23.65 (ddd, J = 5.1, 3.6, 1.4 Hz, 2H), 3.40 - s 3.32 (m, 4H), 3.24 (s, 3H), 1.59 - 1.40 (m, N 2H), 1.21 - 1.10 (m, 2H), 1.02 (d, J = 6.4 Hz, 6H), 0.99 - 0.78 (m, 6H).F 1H NMR (400 MHz, DMSO) S 8.41 (d, J =,N^Z^F 1.4 Hz, 1H), 7.33 (d, J = 1.4 Hz, 1H), 6.76 owo Vs(t, J = 57.3 Hz, 1H), 5.31 (s, 1H), 3.84 - 3.65 (m, 3H), 3.58 (d, J = 12.5 Hz, 1H), 3.43 41 660.2 (dt, J = 12.3, 5.4 Hz, 2H), 3.26 (dt, J = 12.4,5.4 Hz, 2H), 2.68 (d, J = 2.8 Hz, 1H), 2.38 (s, 1H), 1.80 (s, 1H), 1.77 - 1.70 (m, 4H), / \..< NH21.68 - 1.44 (m, 3H), 1.43 - 1.33 (m, 5H), °A 1.05 - 0.92 (m, 8H), 0.89 - 0.78 (m, 2H).F 1H NMR (400 MHz, DMSO) S 8.41 (d, J =1.4 Hz, 1H), 7.33 (d, J = 1.4 Hz, 1H), 6.76 V o p VS (t, J = 57.3 Hz, 1H), 5.31 (s, 1H), 3.84 - - A) >ow= 3.65 (m, 3H), 3.58 (d, J = 12.5 Hz, 1H), 3.43 42 \ O ZT° 660.2 (dt, J = 12.3, 5.4 Hz, 2H), 3.26 (dt, J = 12.4,5.4 Hz, 2H), 2.68 (d, J = 2.8 Hz, 1H), 2.38 k >" ' 0ZyNHz (s, 1H), 1.80 (s, 1H), 1.77 - 1.70 (m, 4H),1.68 - 1.44 (m, 3H), 1.43 - 1.33 (m, 5H), °A 1.05 - 0.92 (m, 8H), 0.89 - 0.78 (m, 2H).F1H NMR (400 MHz, DMSO) S 8.69 (d, J = 1.6 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H), 6.76 (t, J = 57.3 Hz, 1H), 5.29 (s, 1H), 3.80 (s, 3H), 3.77 - 3.66 (m, 2H), 3.47 (ddd, J = 89 A v 662.2 16.8, 13.2, 6.2 Hz, 3H), 3.15 (d, J = 12.3 Hz,N 1H), 1.94 (s, 1H), 1.70 (dd, J = 27.8, 13.9 VKXX Hz, 3H), 1.64 - 1.45 (m, 2H), 1.23 (s, 6H), SH1.06 - 0.94 (m, 8H), 0.89 - 0.77 (m, 2H).1H NMR (400 MHz, DMSO) S 8.69 (d, J = 1.6 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H), 6.76 (t, J = 57.3 Hz, 1H), 5.29 (s, 1H), 3.80 (s, 3H), 3.77 - 3.66 (m, 2H), 3.47 (ddd, J = 90 662.216.8, 13.2, 6.2 Hz, 3H), 3.15 (d, J = 12.3 Hz, 1H), 1.94 (s, 1H), 1.70 (dd, J = 27.8, 13.9 Hz, 3H), 1.64 - 1.45 (m, 2H), 1.23 (s, 6H), 1.06 - 0.94 (m, 8H), 0.89 - 0.77 (m, 2H).1H NMR (400 MHz, DMSO) S 8.18 (d, J =F 1.4 Hz, 1H), 6.95 (d, J = 1.6 Hz, 1H), 6.62, N^ / ^F (t, J = 57.3 Hz, 1H), 5.47 (s, 1H), 5.23 - 4.82 (m, 3H), 4.63 (d, J = 12.5 Hz, 2H), 3.97 (tdd, J = 21.0, 7.6, 0.8 Hz, 1H), 3.32 - 3.18 9^ 632.2(m, 3H), 3.15 - 3.01 (m, 3H), 2.47 (ddt, J = 12.1, 9.8, 7.7 Hz, 2H), 2.17 (ddt, J = 12.4, 9.7, 7.8 Hz, 2H), 2.07 - 1.86 (m, 2H), 1.80 Xb (s, 1H), 1.67 (dp, J = 19.2, 6.4 Hz, 1H), 1.20(d, J = 6.0 Hz, 3H), 1.00 (d, J = 6.4 Hz, 6H).1H NMR (400 MHz, DMSO) S 8.18 (d, J = F 1.4 Hz, 1H), 6.95 (d, J = 1.6 Hz, 1H), 6.62 N^ / ^F (t, J = 57.3 Hz, 1H), 5.47 (s, 1H), 5.23 - 4.82 (m, 3H), 4.63 (d, J = 12.5 Hz, 2H), 3.97 (tdd, J = 21.0, 7.6, 0.8 Hz, 1H), 3.32 - 3.18 632.2(m, 3H), 3.15 - 3.01 (m, 3H), 2.47 (ddt, J = 12.1, 9.8, 7.7 Hz, 2H), 2.17 (ddt, J = 12.4, 9.7, 7.8 Hz, 2H), 2.07 - 1.86 (m, 2H), 1.80 Xb (s, 1H), 1.67 (dp, J = 19.2, 6.4 Hz, 1H), 1.20(d, J = 6.0 Hz, 3H), 1.00 (d, J = 6.4 Hz, 6H).F,N^Z^F 1H NMR (400 MHz, DMSO) S 8.41 (d, J =1.4 Hz, 1H), 7.34 (d, J = 1.4 Hz, 1H), 6.76 (t, J = 57.3 Hz, 1H), 5.31 (s, 1H), 3.84 - 3.65 (m, 3H), 3.58 (d, J = 12.5 Hz, 1H), 3.46 9?gt< 660.2- 3.28 (m, 4H), 2.76 - 2.58 (m, 2H), 1.93 (s, 1H), 1.79 - 1.44 (m, 7H), 1.39 - 1.30 (m, Q / XMNH24H), 1.07 - 0.89 (m, 8H), 0.88 - 0.76 (m, Q— ( 2H).F TW^F 1H NMR (400 MHz, DMSO) S 8.41 (d, J = X V / o p \ Vx S i 1.4 Hz, 1H), 7.34 (d, J = 1.4 Hz, 1H), 6.76(t, J = 57.3 Hz, 1H), 5.31 (s, 1H), 3.84 - 3.65 (m, 3H), 3.58 (d, J = 12.5 Hz, 1H), 3.46 660.2- 3.28 (m, 4H), 2.76 - 2.58 (m, 2H), 1.93 (s, 1H), 1.79 - 1.44 (m, 7H), 1.39 - 1.30 (m, $ / X^NH24H), 1.07 - 0.89 (m, 8H), 0.88 - 0.76 (m, o— ( 2H).F,N=< ^N 1F1H NMR (400 MHz, CD3OD) S = 10.14 (d,J = 1.2 Hz, 1H), 7.27 (t, J = 54.2 Hz, 1H), 7.10 (d, J= 1.2 Hz, 1H), 4.29-3.83 (m, 4H),x=V X> 608.2 3.66 (br s, 4H), 3.38 (s, 3H), 2.22-2.07 (m,1H), 1.34-1.29 (m, 2H), 1.26-1.20 (m, 5H), 0 1.15-1.08 (m, 2H), 1.07-1.01 (m, 2H),0.88-0.79 (m, 2H), 0.55-0.47 (m, 2H). / °2^°1H NMR (400 MHz, DMSO) S 8.03 (d, J = VF / N^r *Fn1.6 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 5.14 i(s, 1H), 3.86 (t, J = 4.7 Hz, 2H), 3.66 (t, J = 4.7 Hz, 2H), 3.39 (dt, J = 11.5, 4.8 Hz, 4H), VpZ626.2 3.25 (s, 3H), 1.50 (p, J = 10.4 Hz, 1H), 1.28(s, 3H), 1.19 - 1.07 (m, 2H), 1.04 - 0.94 (m, 0 2H), 0.93 - 0.81 (m, 2H), 0.69 - 0.54 (m,2H), 0.46 - 0.32 (m, 2H), 0.25 - 0.08 (m, '°25 2H).F 1H NMR (400 MHz, CD3OD) S = 10.06 (d,,N^r 'FJ = 1.2 Hz, 1H), 7.24 (t, J = 54.0 Hz, 1H),7.02 (d, J = 1.2 Hz, 1H), 4.35 (d, J = 11.6 Hz, 1H), 4.21–4.14 (m, 1H), 3.62 (d, J= 5.6 568.1 Hz, 2H), 3.45-3.37 (m, 1H), 2.65-2.54 (m,2H), 2.22-2.13 (m, 1H), 1.45 (s, 3H), 1.32- N 1.26 (m, 2H), 1.24 (s, 3H), 1.23 (s, 3H),H°^A 1.22-1.14 (m, 2H), 0.84-0.77 (m, 2H), H 0.53-0.44 (m, 2H).F 1H NMR (400 MHz, CD3OD) S = 10.07 (d,J = 1.2 Hz, 1H), 7.25 (t, J = 54.0 Hz, 1H), N. A 7.02 (d, J = 1.2 Hz, 1H), 4.36 (d, J = 11.6Hz, 1H), 4.21–4.16 (m, 1H), 3.64 (d, J= 5.6 568.1 Hz, 2H), 3.48-3.39 (m, 1H), 2.67-2.55 (m,2H), 2.23-2.14 (m, 1H), 1.46 (s, 3H), 1.34- 1.26 (m, 2H), 1.26 (s, 3H), 1.23 (s, 3H), -- ftH 1.23-1.13 (m, 2H), 0.86-0.78 (m, 2H),0.54-0.45 (m, 2H)F 1H NMR (400 MHz, CD3OD) S = 10.07 (d,, N^ / ^F J = 1.2 Hz, 1H), 7.24 (t, J = 54.0 Hz, 1H),7.03 (d, J = 1.2 Hz, 1H), 4.57-4.50 (m, 1H), 4.17-4.08 (m, 2H), 3.81 (s, 3H), 2.77 (t, J = 596.1 11.2 Hz, 1H), 2.65 (d, J = 11.2 Hz, 1H), N 2.23-2.14 (m, 1H), 1.39 (s, 3H), 1.31-1.27(m, 3H), 1.26 (s, 3H), 1.22 (s, 3H), 1.20- 1.15 (m, 1H), 0.84-0.72 (m, 2H), 0.52-0.44 Sh(m, 2H).F 1H NMR (400 MHz, CD3OD) S = 10.10- 10.05 (m, 1H), 7.24 (t, J = 54.0 Hz, 1H), 7.03-7.00 (m, 1H), 4.57-4.50 (m, 1H), 4.17–4.10 (m, 2H), 3.81 (s, 3H), 2.77 (t, J = 596.1 11.2 Hz, 1H), 2.65 (d, J = 11.2 Hz, 1H),2.22-2.12 (m, 1H), 1.39 (s, 3H), 1.31-1.27 (m, 3H), 1.26 (s, 3H), 1.22 (s, 3H), 1.20- 1.14 (m, 1H), 0.84-0.76 (m, 2H), 0.52-0.43 -# (m, 2H).F 1H NMR (400 MHz, CD3OD) S = 10.11 (d,,N^ft 'F J = 0.8 Hz, 1H), 7.26 (t, J = 54.0 Hz, 1H), \\ i 7.09 (s, 1H), 4.40- 4.31 (m, 1H), 4.21-4.11(m, 2H), 3.93 (t, J = 6.4 Hz, 1H), 3.84 (d, J = 9.6 Hz, 1H), 3.12-3.02 (m, 2H), 3.01-2.91 594.1(m, 1H), 2.27-2.15 (m, 1H), 2.13-1.99 (m, 2H), 1.93-1.79 (m, 2H), 1.45 (d, J = 6.4 Hz, Q., 3H), 1.36-1.29 (m, 2H), 1.26 (s, 3H), 1.23- 1.18 (m, 2H), 0.87-0.80 (m, 2H), 0.55-0.47 °A (m, 2H).F1H NMR (400 MHz, CD3OD) S = 10.09 (d,, N%AF\\ A J = 1.2 Hz, 1H), 7.25 (t, J = 54.0 Hz, 1H),7.06 (d, J = 1.2 Hz, 1H), 4.36-4.29 (m, 1H), 4.28-4.01 (m, 2H), 4.01-3.87 (m, 2H), 3.49 Vpft 594.1 (d, J = 4.0 Hz, 1H), 3.10-2.96 (m, 2H),2.21-2.14 (m, 1H), 2.13-2.03 (m, 2H), 6 / \.aNH22.01-1.77 (m, 2H), 1.34 (d, J = 6.4 Hz, 3H), o —!.,r1.29-1.26 (m, 2H), 1.24 (s, 3H), 1.20-1.16(m, 2H), 0.84-0.76 (m, 2H), 0.53-0.44 (m,2H).F 1H NMR (400 MHz, CD3OD) S = 10.11 (s,1H), 7.26 (t, J = 54.4 Hz, 1H), 7.09 (s, 1H), 4.41-4.29 (m, 1H), 4.21-4.09 (m, 2H), 3.93 (t, J = 6.4 Hz, 1H), 3.84 (d, J = 9.2 Hz, 1H), 3.12-3.05 (m, 2H), 3.03-2.89 (m, 1H), 594.1 2.26-2.16 (m, 1H), 2.14-1.98 (m, 2H),1.94-1.78 (m, 2H), 1.45 (d, J = 6.0 Hz, 3H), Q / X^NH21.36-1.29 (m, 2H), 1.26 (s, 3H), 1.24-1.17(m, 2H), 0.87-0.80 (m, 2H), 0.56-0.48 (m,2H).F 1H NMR (400 MHz, CD3OD) S = 10.11 (s,1H), 7.26 (t, J = 54.4 Hz, 1H), 7.08 (s, 1H), N^ / ^F 4.36-4.33 (m, 1H), 4.30-4.22 (m, 1H),4.12-4.08 (m, 1H), 4.01 (d, J = 9.2 Hz, 1H), 3.90 (d, J = 9.2 Hz, 1H), 3.50 (d, J = 4.0 Hz, 594.1 2H), 3.19-2.97 (m, 2H), 2.24-2.17 (m, 1H),2.16-2.06 (m, 2H), 1.99 (d, J = 13.6 Hz, 0 1H), 1.82 (d, J = 13.6 Hz, 1H), 1.35 (d, J = / \-NH26.4 Hz, 3H), 1.33-1.28 (m, 2H), 1.25 (s, °A 3H), 1.23-1.17 (m, 2H), 0.87-0.78 (m, 2H),0.55-0.47 (m, 2H).1H NMR (400 MHz, DMSO) S 9.00 (d, J = F 1.4 Hz, 1H), 7.50 (d, J = 1.4 Hz, 1H), 7.00 N^ / ^-F (t, J = 35.5 Hz, 1H), 6.75 (t, J = 35.5 Hz,1H), 5.22 (s, 1H), 4.05 (qd, J = 5.8, 2.4 Hz, 1H), 3.68 (d, J = 12.5 Hz, 1H), 3.58 (d, J = 12.5 Hz, 1H), 3.44 (dt, J = 12.4, 5.4 Hz, 659.22H), 3.35 (d, J = 2.3 Hz, 1H), 3.28 - 3.18 (m, 3H), 2.46 (did, J = 13.0, 7.4, 5.8 Hz, 2H), 2.19 (ddd, J= 13.0, 10.3, 6.6 Hz, 2H), 8-v 2.08 - 1.89 (m, 2H), 1.71 (dt, J = 12.4, 5.40\ I Hz, 2H), 1.49 - 1.33 (m, 5H), 1.19 (s, 3H),0.48 - 0.30 (m, 2H), 0.25 - 0.06 (m, 2H). F 1H NMR (400 MHz, CD3CN) S = 9.99 (d, J, N^-Z^F = 1.6 Hz, 1H), 7.21 (t, J = 54.4 Hz, 1H),6.95 (d, J = 1.6 Hz, 1H), 6.49 (t, J = 75.2 Hz, 1H), 6.31 (s, 1H), 4.07-3.92 (m, 4H), 3.92-x=\lt 3.85 (m, 1H), 3.71 (d, J = 9.2 Hz, 1H), 3.36- 645.13.25 (m, 1H), 3.21-3.10 (m, 1H), 2.13-2.12 (m, 1H), 1.85-1.70 (m, 4H), 1.35 (d, J = 6.0 Hz, 3H), 1.28-1.25 (m, 2H), 1.22 (s, 3H), gv1.19-1.15 (m, 2H), 0.83-0.78 (m, 2H), ° \ F 0.52-0.45 (m, 2H).F 1H NMR (400 MHz, DMSO) S 8.41 (d, J =ZN«AF 1.4 Hz, 1H), 7.38 (d, J = 1.4 Hz, 1H), 6.76 \\ I (t, J = 57.3 Hz, 1H), 5.17 (s, 1H), 4.05 (qd, J = 5.8, 2.4 Hz, 1H), 3.68 (d, J = 12.5 Hz, 1H), 3.58 (d, J = 12.5 Hz, 1H), 3.44 (dt, J = 623.2 12.4, 5.5 Hz, 2H), 3.35 (d, J = 2.7 Hz, 4H),3.30 - 3.17 (m, 3H), 2.44 (ddt, J = 12.2, 9.6, 7.6 Hz, 2H), 2.19 (ddt, J = 12.4, 9.6, 7.7 Hz, 2H), 2.09 - 1.89 (m, 2H), 1.70 (dt, J = 12.4, 0— ( 5.5 Hz, 2H), 1.47 - 1.33 (m, 5H), 1.26 (s,3H), 0.48 - 0.32 (m, 2H), 0.25 - 0.06 (m,2H).F 1H NMR (400 MHz, CD3CN) S = 9.95 (d, J,N^r 'p = 1.2 Hz, 1H), 7.18 (t, J = 54.4 Hz, 1H), \\ i 6.94 (d, J = 1.2 Hz, 1H), 6.29 (s, 1H), 3.88- 3.76 (m, 4H), 3.60 (d, J = 8.8 Hz, 1H), 3.47- 3.39 (m, 1H), 3.37 (s, 3H), 3.31-3.24 (m, 609.1N 1H), 3.15 (d, J = 4.8 Hz, 1H), 2.14-2.07 (m,1H), 1.89-1.71 (m, 3H), 1.66-1.59 (m, 1H), 1.32 (d, J = 6.4 Hz, 3H), 1.27-1.22 (m, 2H), f r*°\o — ( 1.19 (s, 3H), 1.16-1.12 (m, 2H), 0.80-0.75(m, 2H), 0.48-0.42 (m, 2H).F 1H NMR (400 MHz, DMSO) S 8.41 (d, J = N^A 1.4 Hz, 1H), 7.39 (d, J = 1.4 Hz, 1H), 6.77 N 1F(t, J = 57.4 Hz, 1H), 5.23 (s, 1H), 3.84 - 3.74 (m, 2H), 3.64 (dt, J = 5.6, 4.0 Hz, 2H), 3.49 - 3.42 (m, 4H), 3.29 - 3.18 (m, 4H), 622.02.45 (ddt, J = 12.2, 9.7, 7.4 Hz, 2H), 2.19 (ddt, J = 12.3, 9.6, 7.5 Hz, 2H), 2.07 - 1.86 0 (m, 2H), 1.23 (s, 3H), 1.18 - 1.05 (m, 2H),0.94 - 0.82 (m, 2H), 0.47 - 0.32 (m, 2H), 0.24 - 0.06 (m, 2H).1H NMR (400 MHz, DMSO) S 8.41 (d, J = VF1.4 Hz, 1H), 7.39 (d, J = 1.4 Hz, 1H), 5.29(s, 1H), 3.88 - 3.76 (m, 2H), 3.71 - 3.62 (m, 2H), 3.54 - 3.37 (m, 4H), 3.33 - 3.19 (m, ° 640.1 4H), 2.47 (did, J = 13.1, 7.4, 5.8 Hz, 2H),2.19 (ddd, J = 13.0, 10.2, 6.6 Hz, 2H), 2.10 0 N - 1.88 (m, 2H), 1.17 (s, 3H), 1.16 - 1.05 (m,;z x° -^5 2H), 0.96 - 0.83 (m, 2H), 0.47 - 0.32 (m,2H), 0.24 - -0.02 (m, 2H).F 1H NMR (400 MHz, CD3OD) S = 10.09 (d, N^ / ^FN 1 J = 1.2 Hz, 1H), 7.26 (t, J = 54.4 Hz, 1H),7.04 (d, J = 1.2 Hz, 1H), 3.73-3.65 (m, 2H), 598.1 3.64-3.54 (m, 6H), 3.44 (s, 6H), 3.40-3.37(m, 2H), 2.27-2.14 (m, 1H), 1.37-1.26 (m, 3H), 1.26-1.23 (m, 4H), 0.90-0.77 (m, 2H), H 0.55-0.46 (m, 2H).1H NMR (400 MHz, CD3CN) S = 9.97 (d, J = 1.6 Hz, 1H), 7.18 (t, J = 54.0 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.25 (s, 1H), 4.32 (d, J = 9.2 Hz, 1H), 4.17-4.07 (m, 2H), 3.99-3.91 (m, 2H), 3.33-3.26 (m, 1H), 593.1 3.17-3.09 (m, 1H), 2.13-2.08 (m, 1H),2.02-1.97 (m, 1H), 1.82-1.76 (m, 2H), 1.74-1.68 (m, 1H), 1.27 (d, J = 7.2 Hz, 3H), 1.26-1.21 (m, 2H), 1.20 (s, 3H), 1.17-1.12 (m, 2H), 0.81-0.76 (m, 2H), 0.49-0.44 (m,2H).FwS 1H NMR (400 MHz, CD3CN) S 10.00-9.95 u N 1 (m, 1H), 7.46-7.33 (m, 5H), 7.17 (t, J = 54.4Hz, 1H), 6.87-6.83 (m, 1H), 6.24 (s, 1H), 5.16 (s, 1H), 3.81-3.66 (m, 4H), 3.60-3.46 658.0(m, 2H), 3.42 (s, 3H), 3.40-3.25 (m, 2H), 2.13-2.06 (m, 1H), 1.26-1.20 (m, 2H), 1.18 (s, 3H), 1.16-1.11 (m, 2H), 0.81-0.73 (m, c5 2H), 0.50-0.40 (m, 2H).^6F NXF 1H NMR (400 MHz, CDC13) S 10.09 (d, J =1.4 Hz, 1H), 7.01 (d, J = 1.4 Hz, 1H), 5.09 (s, 1H), 4.07-4.01 (m, 1H), 3.95-3.88 (m, 2H), 3.81-3.75 (m, 2H), 3.55 (d, J = 5.9 Hz, 595.1 1H), 3.29-3.22 (m, 1H), 3.18-3.11 (m, 1H),2.12-1.91 (m, 4H), 1.79-1.72 (m, 2H), 1.38 (d, J = 6.3 Hz, 3H), 1.33 (s, 3H), 1.27-1.25 (m, 4H), 0.90 (t, J = 5.9 Hz, 2H), 0.58-0.55 9- (m, 2H).0•-,F 1H NMR (400 MHz, CD3CN) S = 9.97 (d, J N^Xu N. I = 1.6 Hz, 1H), 7.18 (t, J = 54.4 Hz, 1H),6.92 (d, J = 1.6 Hz, 1H), 6.34 (s, 1H), 5.05- 4.65 (m, 1H), 4.48-4.43 (m, 2H), 4.04-3.94 (m, 1H), 3.60-3.31 (m, 1H), 3.30 (s, 3H), 622.23.07-2.80 (m, 2H), 2.16-2.09 (m, 1H), 1.55-1.35 (m, 3H), 1.28-1.20 (m, 3H), 1.19 x> (s, 3H), 1.18-1.12 (m, 1H), 1.08-0.96 (m, xS 2H), 0.96-0.89 (m, 2H), 0.84-0.73 (m, 2H), 1 0.51-0.41 (m, 2H).FN^AF 1H NMR (400 MHz, DMSO) S = 9.88 (d, J u N 1 = 1.2 Hz, 1H), 8.35 (s, 1H), 7.60 (t, J = 54.0Hz, 1H), 7.04 (d, J = 1.2 Hz, 1H), 4.08-3.69 Z Z. (m, 4H), 3.65-3.55 (m, 5H), 2.23-2.13 (m,594.11H), 1.27-1.22 (m, 2H), 1.15-1.12 (m, 2H), 1.11 (s, 3H), 0.99-0.94 (m, 2H), 0.83-0.78 N (m, 2H), 0.72-0.67 (m, 2H), 0.47 -0.40 (m,2H).F,NXFH N 1 1H NMR (400 MHz, DMSO) S = 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 (d, J = 48.8 626.1 Hz, 2H), 4.10-3.67 (m, 4H), 3.68-3.50 (m,4H), 3.26 (s, 3H), 2.23-2.14 (m, 1H), 1.27- 0 1.22 (m, 2H), 1.16-1.12 (m, 2H), 1.05-0.89 N(m, 4H), 0.86-0.72 (m, 4H). xS1FH N 1 1H NMR (400 MHz, CDC13) S 9.98 (d, J =1.5 Hz, 1H), 7.01 (t, J = 54.4 Hz, 1H), 6.71 (d, J = 1.4 Hz, 1H), 5.51 (s, 1H), 4.31 (d, J = 654.2 2.4 Hz, 1H), 4.19 (d, J = 2.3 Hz, 1H), 4.01(s, 3H), 3.38 (s, 3H), 2.07-2.02 (m, 1H), x> 1.43 (s, 3H), 1.41 (s, 3H), 1.25-0.82 (m,14H).>< S1F,N^< " FHN1 1H NMR (400 MHz, CD3OD) S = 10.14 (d,J = 1.6 Hz, 1H), 7.26 (t, J = 54.0 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 3.64 (s, 8H), 3.47- 616.2 3.37 (m, 1H), 2.20-2.15 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H), 1.34-1.28 (m, 2H), 1.24 (s, 0 3H), 1.24-1.18 (m, 2H), 0.86-0.80 (m, 2H), N 0.54-0.47 (m, 2H).O=S=OF 1H NMR (ES21275-1044-P1H, 400 MHz,CD3OD) S = 10.16 (d, J = 1.2 Hz, 1H), 7.28 N^XFu N. 1 (t, J = 54.4 Hz, 1H), 7.16 (d, J = 1.2 Hz,1H), 4.94-4.92 (m, 1H), 4.81-4.70 (m, 2H), 4.55-4.37 (m, 1H), 4.35-4.27 (m, 1H), 579.24.26-4.12 (m, 1H), 3.92-3.79 (m, 1H), 3.18 (s, 3H), 2.95 (br d, J = 11.6 Hz, 1H), 2.72 (t, J = 11.6 Hz, 1H), 2.30-2.16 (m, 1H), 1.40-, N d~JON,. '. 1.29 (m, 6H), 1.25 (s, 3H), 1.17-1.11 (m, ' H1H), 0.85-0.80 (m, 2H), 0.56-0.46 (m, 2H).F1H NMR (400 MHz, CDC13) S 10.15 (s, H N 1 1H), 7.01 (t, 1H), 7.00 (s, 1H), 3.76 - 3.66 (m, 4H), 3.57 - 3.49 (m, 4H), 2.87 (s, 588.1 3H), 2.07 - 2.01 (m, 1H), 1.35 (s, 3H),1.29 - 1.22 (m, 4H), 0.92 - 0.88 (m, 2H), 0N 0.88 - 0.82 (m, 1H), 0.58 (q, J = 5.2 Hz, o=s=o1 2H).1H NMR (400 MHz, CD3OD) S = 10.12 (br F s, 1H), 7.28 (t, J = 54.0 Hz, 1H), 7.15 (br s,,N^T< 'F 1H), 5.37 (br d, J = 12.8 Hz, 1H), 5.27 (d, J H N 1 = 7.6 Hz, 1H), 4.95 (d, J = 7.6 Hz, 1H), 4.78(d, J = 8.0 Hz, 1H), 4.71 (d, J = 8.0 Hz, 1H), 566.1 4.01 (br d, J = 11.6 Hz, 1H), 3.70-3.64 (m,1H), 3.19 (brd, J = 12.8 Hz, 1H), 3.11-3.00 (m, 1H), 2.26-2.14 (m, 1H), 1.51 (d, J = 6.4 Hz, 3H), 1.35-1.26 (m, 3H), 1.25 (s, 3H),. AH 1.21-1.17 (m, 1H), 0.87-0.76 (m, 2H),0.56-0.46 (m, 2H).F1H NMR (400 MHz, DMSO) S 8.60 (d, 1H), 7.38 (d, 1H), 6.75 (t, 1H), 5.21 (s, 1H), 3.72 Yv Vs(m, 5H), 3.40 - 3.33 (m, 2H), 3.33 (s, 6H), 376 664.22.84 - 2.72 (m, 2H), 2.08 (m, 1H), 1.71 (dd, 4H), 1.50 (m, 1H), 1.10 - 0.96 (m, 8H), 0.90- 0.76 (m, 2H).HF, IV^F1H NMR (400 MHz, DMSO) S 8.60 (d, 1H), V o p VS 7.38 (d, 1H), 6.75 (t, 1H), 5.21 (s, 1H), 3.72 (m, 5H), 3.40 - 3.33 (m, 2H), 3.33 (s, 6H), 377 664.22.84 - 2.72 (m, 2H), 2.08 (m, 1H), 1.71 (dd, 4H), 1.50 (m, 1H), 1.10 - 0.96 (m, 8H), 0.90 A - 0.76 (m, 2H).H

[1627]

[1628] Example 61

[1630] 3-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]-8-[(3S,5S)-3,5-dimethylpiperazin-l- yl]-2-(4-fluorophenyl)-N-(l-methylcyclopropyl)imidazo[l,2-a]pyridine-6- sulfonamide (General Procedure 5)

[1631] Step 1: 5-benzylsulfanyl-3-chloro-pyridin-2-amine

[1632] 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 N2 atmosphere three times. The mixture was heated to 100 °C and stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to 25 °C and diluted with H₂O (50 mL) and extracted with EtOAc (30 mL x 3). The organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to produce a residue.The crude residue was purified by flash silica gel chromatography to afford 5- benzylsulfanyl-3-chloro-pyridin-2-amine (5.3 g, 20.93 mmol, 86.82% yield) as a brown solid.

[1633] MS (ESI) m / z = 251.0 [M+H]+.

[1634]

[1635] Step 2: 6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl) imidazo [1, 2-a] pyridine

[1636] To a mixture of 5-benzylsulfanyl-3-chloro-pyridin-2-amine (5.0 g, 19.94 mmol) and 2-bromo-l-(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 a nitrogen atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to produce 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, 31.95% yield) as a yellow solid.

[1637] MS (ESI) m / z = 370.7 [M+H+2]+.

[1638]

[1639] Step 3: 2-[6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl)imidazo[l,2-a]pyridin-3-yl]- 5-(difluoromethyl)-l,3,4-thiadiazole

[1640] 1) Solution 1: 6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl)imidazo[l,2-a]pyridine (2.2 g, 5.96 mmol), 2-bromo-5-(difluoromethyl)-l,3,4-thiadiazole (2.56 g, 11.93 mmol), bis[2-(2-pyridyl)phenyl]iridium(l+);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)

[1641] 2) Solution 1 was pumped by Pump 1 {SI, Pl, 30 mL / min} to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175(l / 8”)mm, 50 mL, 40 °C} with 455 nm LED light (400 W).

[1642] 3) The reaction mixture was continuously circulated for 120 min {FLR1, 120 min}.

[1643] 4) The tubing was washed with solvent

[1644] 5) The 455 nm LED light (400 W) was turned on.

[1645] 6) All the reaction mixture was collected. A sample was taken for analysis.

[1646] 7) The LED light and peristaltic pump were turned off.

[1647] 8) The tubing was washed with solvent.

[1648] The mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce 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 produce 2-[6-benzylsulfanyl-8-chloro-2-(4- fluorophenyl)imidazo[l,2-a]pyridin-3-yl]-5-(difluoromethyl)-l,3,4-thiadiazole (300 mg, 583.00 μmol, 9.77% yield,) as a white solid.

[1649] MS (ESI) m / z = 502.9 [M+H]+.

[1650]

[1651] Step 4: 8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-2-(4- fluorophenyl)imidazo[l,2-a]pyridine-6-sulfonyl chloride

[1652] To a solution of 2-[6-benzylsulfanyl-8-chloro-2-(4-fluorophenyl)imidazo[l,2- a]pyridin-3-yl]-5-(difluoromethyl)-1,3,4-thiadiazole (150 mg, 298.23 pmol) in CH₃CN (5 mL), H₂O (200 μL) and AcOH (100 μL) was added 1,3 -di chi oro-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 hr. 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 produce 8-chloro-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2- yl]-2-(4-fluorophenyl)imidazo[l,2-a]pyridine-6-sulfonyl chloride (150 mg, crude) as a yellow solid.

[1653] MS (ESI) m / z = 479.0 [M+H]+.

[1654]

[1655] Step 5: 8-chloro-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]-2-(4-fluorophenyl)-N- ( 1 -methylcyclopropyl)imidazo[ 1,2-a]pyridine-6-sulfonamide

[1656] To a solution of 8-chloro-3-[5-(difhroromethyl)-l,3,4-thiadiazol-2-yl]-2-(4- fluorophenyl)imidazo[l,2-a]pyridine-6-sulfonyl chloride (150 mg, 312.97 μmol) in CH₃CN (4 mL) were added 4A 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 hr. The mixture was filtered and the cake was washed with EtOAc (15 mL x 2). The combined filtrates were concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce 8- chloro-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]-2-(4-fluorophenyl)-N-(l- methylcyclopropyl)imidazo[l,2-a]pyridine-6-sulfonamide (70 mg, 116.10 μmol, 37.10% yield) as a light yellow solid.

[1657] MS (ESI) m / z = 514.0 [M+H]+.

[1658]

[1659] Step 6: tert-butyl (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-2-(4- fluorophenyl)-6-[(l-methylcyclopropyl)sulfamoyl]imidazo[l,2-a]pyridin-8-yl]-2,6- dimethyl-piperazine-1 -carboxylate

[1660] To a mixture of 8-chloro-3-[5-(difhioromethyl)-l,3,4-thiadiazol-2-yl]-2-(4- fluorophenyl)-N-(l-methylcyclopropyl)imidazo[l,2-a]pyridine-6-sulfonamide (70 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 [l,3-bis[2,6-bis(l-ethylpropyl)phenyl]-4,5- dichloro-imidazol-2-ylidene]-dichloro-(2-methylpyridin-l-ium-l-yl)palladium (11.44 mg, 13.62 μmol) and Cs₂CO₃ (133.13 mg, 408.61 μmol). The resulting mixture was degassed and purged with N2 atmosphere three times. Then the mixture was stirred at 100 °C for 1 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce tert-butyl (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-2-(4-fluorophenyl)-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6-dimethyl-piperazine-1-carboxylate (50 mg, 70.39 μmol, 51.68% yield) as a yellow solid.

[1661] MS (ESI) m / z = 592.2 [M+H]+.

[1662]

[1663] Step 7: 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-8-[(3S,5S)-3,5- dimethylpiperazin-l-yl]-2-(4-fluorophenyl)-N-(l-methylcyclopropyl)imidazo[l,2- a]pyridine-6-sulfonamide

[1664] To a solution of tert-butyl (2S,6S)-4-[3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-2-(4-fluorophenyl)-6-[(1-methylcyclopropyl)sulfamoyl]imidazo[1,2-a]pyridin-8-yl]-2,6-dimethyl-piperazine-1 -carboxylate (45 mg, 65.05 μmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 0.5 hr. The mixture was concentrated under reduced pressure to produce a residue. The residue was purified by column chromatograph \ " O / y _ _ to produce 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-8-[(3S,5S)-3,5- dimethylpiperazin-1-yl]-2-(4-fluorophenyl)-N-(l-methylcyclopropyl)imidazo[l,2- a]pyridine-6-sulfonamide (26.65 mg, 37.76 μmol, 58.06% yield, TFA) as a light yellow XX “solid.^XX"'O-

[1665] MS (ESI) m / z = 592.2 [M+H]+.

[1666] 'H NMR (400MHz, CD3CN) 3 = 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).

[1667]

[1668] The following compounds were prepared by a procedure similar to the procedure of Example 61.MS (ESI) m / zExample Structure 1H NMR[M+H]+1H NMR (400 MHz, DMSO) S 8.52 (s, 1H), 7.41 (s, 1H), 7.33 - 7.23 (m, 3H), 6.96 (s, 1H), 6.69 (s, 1H), 5.16 (s, 1H), 3.84 - 3.74 62 604.1 (m, 3H), 3.48 - 3.37 (m, 2H), 3.30 - 3.21 (m,2H), 3.20 - 3.10 (m, 2H), 1.74 (s, 1H), 1.32 - 1.22 (m, 3H), 1.21 - 1.07 (m, 6H), 0.47 - 0.32 (m, 2H), 0.23 - 0.08 (m, 2H).F 1H NMR (400 MHz, DMSO) S 8.37 (s, 1H), A 7.64 (s, 1H), 7.37 (s, 1H), 7.27 - 7.09 (m, y%? X 3H), 6.69 (s, 1H), 5.19 (s, 1H), 3.87 - 3.72 63HLx / A? 604.1 (m, 3H), 3.50 - 3.37 (m, 2H), 3.30 - 3.20 (m,2H), 3.20 - 3.09 (m, 2H), 1.75 (s, 1H), 1.40 - 1.28 (m, 3H), 1.25 - 1.11 (m, 6H), 0.48 - H 0.31 (m, 2H), 0.25 - 0.06 (m, 2H).LF1H NMR (400 MHz, DMSO) S 8.52 (s, 1H), y v Xs7.67 - 7.55 (m, 2H), 7.26 (s, 1H), 7.22 -7.13 (m, 2H), 5.17 (s, 1H), 3.49 - 3.38 (m, 2H), 131 610.1'J 3.30 - 3.06 (m, 4H), 1.74 (s, 1H), 1.28 - 1.23 (m, 3H), 1.22 - 1.15 (m, 6H), 0.47 - 0.28 (m, / I 2H), 0.27 - 0.03 (m, 2H).HFNAA 1H NMR (400 MHz, DMSO) S 8.52 (s, 1H),7.48 - 7.32 (m, 3H), 7.26 (s, 1H), 7.09 (s, y V J' 1H), 6.70 (s, 1H), 5.16 (s, 1H), 3.51 - 3.37 243HL xM / / 592.2(m, 2H), 3.33 - 3.10 (m, 4H), 1.74 (s, 1H), 1.30 - 1.23 (m, 3H), 1.23 - 1.11 (m, 6H), A ' 0.50 - 0.33 (m, 2H), 0.25 - 0.03 (m, 2H). HF 1H NMR (400 MHz, DMSO) S 8.52 (s, 1H),7.39 (d, J = 16.7 Hz, 2H), 7.26 (s, 1H), 7.16 (s, 1H), 6.71 (s, 1H), 5.16 (s, 1H), 3.49 - 3.38 y v A (m, 2H), 3.30 - 3.20 (m, 2H), 3.18 (dd, J = 255 610.14.9, 2.1 Hz, 1H), 3.16 - 3.12 (m, 1H), 1.74 (s, 1H), 1.31 - 1.23 (m, 3H), 1.22 - 1.13 (m, A. ' 6H), 0.47 - 0.33 (m, 2H), 0.23 - 0.07 (m, H 2H).F, NAF 1H NMR (400 MHz, DMSO) S 8.38 (s, 1H), N.sA 7.57 (s, 1H), 7.05 (s, 1H), 6.95 (d, J = 7.7 Hz,2H), 6.75 (s, 1H), 4.81 (s, 1H), 3.63 - 3.47 256 H' Y^LAAAF 610.VA 'J 1 (m, 2H), 3.34 - 3.17 (m, 2H), 3.14 - 3.03 (m, X H\F2H), 1.74 (s, 1H), 1.24 - 1.12 (m, 6H), 0.51 - 0.31 (m, 2H), 0.24 - 0.02 (m, 2H).

[1669]

[1670] Example 161

[1672] (2R)-4-[2-cyclopropyl-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]-6-[(l- methylcyclopropyl)sulfamoyl]imidazo[l,2-a]pyridin-8-yl]-6,6-dimethyl-piperazine-2- carboxylic acid

[1673] To a solution of methyl (2R.)-4-[2-cyclopropyl-3-[5-(difluoromethyl)-l,3,4- thiadiazol-2-yl]-6-[(l-methylcyclopropyl)sulfamoyl]imidazo[l,2-a]pyridin-8-yl]-6,6- dimethyl-piperazine-2-carboxylate (18.10 mg, 28.17 pmol) in MeOH (0.9 mL) was added a solution of LiOH·H₂O (4.73 mg, 112.67 pmol) in H2O (0.45 mL). The mixture was degassed and purged with N2 three times. The mixture was stirred at 25 °C under anitrogen atmosphere for 2 h. The mixture was purified by column chromatography to produce (2R)-4-[2-cyclopropyl-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]-6-[(l- methylcyclopropyl)sulfamoyl]imidazo[l,2-a]pyridin-8-yl]-6,6-dimethyl-piperazine-2- carboxylic acid (9.42 mg, 14.99 pmol, 53.21% yield, 100% purity) as a yellow solid.

[1674] MS (ESI) m / z = 582.1 [M+H]+.

[1675] ¹H NMR (400 MHz, CD₃OD) δ = 10.09-10.05 (m, 1H), 7.24 (t, J= 54.4 Hz, 1H), 7.09-7.03 (m, 1H), 4.68-4.64 (m, 1H), 4.38-4.30 (m, 1H), 4.05-3.98 (m, 1H), 3.00 (t, J= 11.6 Hz, 1H), 2.76 (br d, J= 12.8 Hz, 1H), 2.21-2.13 (m, 1H), 1.56 (s, 3H), 1.41 (s, 3H), 1.30-1.24 (m, 3H), 1.22-1.20 (m, 3H), 1.19-1.13 (m, 1H), 0.88-0.73 (m, 2H), 0.52-0.43 (m, 2H).

[1676]

[1677] The following compounds were prepared by a procedure similar to the procedure of Example 161.MS (ESI) m / zExample Structure 1H NMR[M+H]+F 1H NMR (400 MHz, CD3OD) S = 10.09- 10.05 (m, 1H), 7.24 (t, J = 54.4 Hz, 1H), 7.09-7.03 (m, 1H), 4.68-4.64 (m, 1H), 4.38- 4.30 (m, 1H), 4.05-3.98 (m, 1H), 3.00 (t, J = 162 582.1 11.6 Hz, 1H), 2.76 (br d, J = 12.8 Hz, 1H),2.21-2.13 (m, 1H), 1.56 (s, 3H), 1.41 (s, 3H), 1.30-1.24 (m, 3H), 1.22-1.20 (m, 3H), 1.19- -Ta 1.13 (m, 1H), 0.88-0.73 (m, 2H), 0.52-0.43 SH(m, 2H).

[1678]

[1679] Example 319

[1680] N-((R)-2,2-difluoro-4-methylpentan-3-yl)-l-(5-(difluoromethyl)-l,3,4-thiadiazol- 2-yl)-4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide (General Procedure 8)

[1681] H

[1682]

[1683] Step 1: 6-benzylsulfanyl-4-chloro-lH-indazole

[1684] To a mixture of 6-bromo-4-chloro-lH-indazole (2.0 g, 8.64 mmol) in 1,4-Dioxane (25 mL, 10 w / v) was added BnSH (3.22 g, 25.9 mmol), Pd2(dba)3 (791 mg, 0.86 mmol), Xantphos (499 mg, 0.86 mmol), and DIPEA (3.35 g, 25.9 mmol). The mixture was stirred at 100°C under a nitrogen atmosphere for 3 h. The mixture was quenched with H2O (10 mL) and extracted with EtOAc (30 mL x 3). The organic phase was washed with brine (20 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to produce the residue. The residue was purified by column chromatography on silica gel eluting with EtOAc in PE to afford 6- benzylsulfanyl-4-chloro-lH-indazole (2.3 g, 96.88% yield) as a yellow solid.

[1685] 1H NMR (400 MHz, DMSO-d6): 5 = 13.33 (s, 1H), 8.05 (s, 1H), 7.40-7.36 (m, 3H), 7.33-7.28 (m, 2H), 7.26-7.21 (m, 1H), 7.18 (d, J = 1.2 Hz, 1H), 4.35 (s, 2H).

[1686]

[1687] Step 2: 2-(6-benzylsulfanyl-4-chloro-indazol-l-yl)-5-(difhioromethyl)-l,3,4- thiadi azole

[1688] To a mixture of 6-benzylsulfanyl-4-chloro-lH-indazole (1.22 g, 4.44 mmol) in DMF (12 mL, 10 w / v) were added CS2CO3 (2.17 g, 6.66 mmol) and 2-bromo-5- (difluoromethyl)-l,3,4-thiadiazole (1.43 g, 6.66 mmol). The mixture was stirred at 60°C under a nitrogen atmosphere for 1 h. The mixture was filtered. The residue was diluted with H2O (15 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (10 mL x 2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography on silica gel eluting with MeOH in DCM to afford 2-(6-benzylsulfanyl-4-chloro-indazol- 1 -yl)-5-(difluorom ethyl)- 1,3,4-thiadiazole (1.54 g, 84.83% yield) as a light-yellow solid.

[1689] 1H NMR (400 MHz, DMSO-d6): 5 = 8.67 (s, 1H), 8.29 (s, 1H), 7.73-7.54 (m, 2H), 7.48-7.45 (m, 2H), 7.34-7.32 (m, 2H), 7.30-7.26 (m, 1H), 4.46 (s, 2H).

[1690]

[1691] Step 3: 4-chloro-l-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]indazole-6-sulfonyl chloride

[1692] To a mixture of 2-(6-benzylsulfanyl-4-chloro-indazol-l-yl)-5-(difluoromethyl)-l,3,4- thiadiazole (1.54 g, 3.77 mmol) in MeCN (20 mL), AcOH (250 pL), and H2O (500 pL) was added l,3-dichloro-5,5-dimethyl-imidazolidine-2, 4-dione (1.11 g, 5.65 mmol). The mixture was stirred at 5°C under a nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure to afford 4-chloro-l-[5-(difluoromethyl)-l,3,4- thiadiazol-2-yl]indazole-6-sulfonyl chloride (2.46 g, crude, 100 %) as a light yellow solid.

[1693] MS (ESI) m / z = 384.8 [M+H]+

[1694]

[1695] Step 4: 4-chloro-N-[(lR)-2,2-difhroro-l-isopropyl-propyl]-l-[5-(difhroromethyl)- l,3,4-thiadiazol-2-yl]indazole-6-sulfonamide

[1696] To a mixture of 4-chloro-l-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]indazole-6- sulfonyl chloride (95 mg, 0.247 mmol) in DCM (3mL) were added TEA (1248 mg, 1.23 mmol) and (3R)-2,2-difluoro-4-methyl-pentan-3-amine (51 mg, 0.370 mmol). The mixture was stirred at 25 °C under a nitrogen atmosphere for 15 h. The mixture was filtered. The residue was diluted with H2O (15 mL) and extracted with DCM (20 mL x 3). The organic layer was washed with brine (10 mL x 2). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography on silica gel eluting with 10% MeOH in DCM to afford 4-chloro-N-[(lR)-2,2-difhioro-l-isopropyl-propyl]-l-[5- (difluoromethyl)-l,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (30 mg, 25.03 % yield) as a white solid.

[1697] MS (ESI) m / z = 486.2 [M+H]+

[1698]

[1699] Step 5: tert-butyl (2S,6S)-4-[6-[[(lR)-2,2-difluoro-l-isopropyl-propyl]sulfamoyl]-l- [5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]indazol-4-yl]-2,6-dimethyl-piperazine-l- carb oxy late

[1700] To a mixture of 4-chloro-N-[(lR)-2,2-difluoro-l-isopropyl-propyl]-l-[5- (difluoromethyl)-l,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (30 mg, 0.0617 mmol) in 1,4-Dioxane (3mL) were added tert-butyl (2S,6S)-2,6-dimethylpiperazine-l -carboxylate (26 mg, 0.123 mmol), CS2CO3 (60 mg, 0.185 mmol) and Pd-PEPPSI-IHeptCl (6.0 mg, 0.00617 mmol). The mixture was stirred at 100°C under a nitrogen atmosphere for 3 h. The mixture was filtered. The residue was diluted with H2O (15 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (10 mL x 2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography to afford tert-butyl (2S,6S)-4-[6-[[(lR)-2,2-difluoro-l-isopropyl- propyl]sulfamoyl]-l-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]indazol-4-yl]-2,6- dimethyl-piperazine-1 -carboxylate (31 mg, 75.65 % yield) as a brown oil.

[1701] MS (ESI) m / z = 563.1 [M+H]+

[1702]

[1703] Step 6: N-((R)-2,2-difhioro-4-methylpentan-3-yl)-l-(5-(difhioromethyl)-l,3,4- thiadiazol-2-yl)-4-((3S,5S)-3,5-dimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide

[1704] To tert-butyl (2S,6S)-4-[6-[[(lR)-2,2-difhioro-l-isopropyl-propyl]sulfamoyl]-l-[5- (difluoromethyl)-l,3,4-thiadiazol-2-yl]indazol-4-yl]-2,6-dimethyl-piperazine-l- carboxylate (30 mg, 45.2 pmol) was added HClZEtOAc (0.5 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to afford N-((R)- 2,2-difluoro-4-methylpentan-3-yl)-l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4- ((3S,5S)-3,5-dimethylpiperazin-l-yl)-lH-indazole-6-sulfonamide (13 mg, 51% yield) as a light yellow solid.

[1705] MS (ESI) m / z = 563.1 [M+H]+

[1706] 1H-NMR (400 MHz, DMSO-d6) 5 = 9.84 (s, 1H), 7.87 (s, 1H), 7.34 (t, J = 53.6 Hz, 1H), 6.94 (s, 1H) 5.21 (m, 2H), 4.31 (m, 2H), 4.15 (dd, 2H), 3.61 (dd, 2H), 1.86 (t, 3H), 1.41 (d, 6H), 1.10 (d, 3H), 0.89 (d, 3H)

[1707]

[1708] Example 352

[1710] 2-cyclopropyl-3-[5-(difluoromethyl)-l,3,4-thiadiazol-2-yl]-8-[4-[(2S)-2-methoxy- 2-phenyl-acetyl]piperazin-l-yl]-N-(l-methylcyclopropyl)imidazo[l,2-a]pyridine-6- sulfonamide[17H]

[1712] Step 1: ethyl 2-bromo-3-cyclopropyl-3-oxo-propanoate

[1713] 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 a nitrogen atmosphere. The reaction mixture was quenched with sat. aq NaHCO₃, (1000 mL), then extracted with DCM (800 mL x 3). The combined organic phases were washed with brine (800 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain ethyl 2-bromo-3-cyclopropyl-3-oxo-propanoate (72.4 g, 247.62 mmol, 77.35% yield) as a light yellow oil.

[1714] MS (ESI) m / z = 237.0 [M+H+2]+.

[1715]

[1716] Step 2: ethyl 6-bromo-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridine-3-carboxylate

[1717] 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) wasstirred 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 HC1 (1 M, 600 mL x 3) and saturated aqueous sodium chloride (800 mL), then dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to obtain a crude product (10.5 g). The crude product was slurried with EtOAc (8 mL) at 25 °C for 0.5 hr, then filtered. The filter cake was washed with EtOAc (2 mL), and a white solid was collected. Ethyl 6-bromo-8-chloro-2-cyclopropyl-imidazo[l,2- a]pyridine-3 -carboxylate (7.05 g, 20.46 mmol, 6.75% yield, 99.7% purity) was produced as a white solid.

[1718] MS (ESI) m / z = 344.9 [M+H+2]+.

[1719]

[1720] Step 3: ethyl 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridine-3- carb oxy late

[1721] To a solution of ethyl 6-bromo-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridine-3- carboxylate (2.3 g, 6.69 mmol) in dioxane (68 mL) were added phenylmethanethiol (748.25 mg, 6.02 mmol, 707.23 pL), Xantphos (387.31 mg, 669.38 pmol), DIEA (2.60 g, 20.08 mmol, 3.50 mL) and Pd2(dba)3(612.96 mg, 669.38 pmol). The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 80°C under a nitrogen atmosphere for 3 h. To the above mentioned mixture were added Xantphos (387.31 mg, 669.38 pmol), DIEA (1.73 g, 13.39 mmol, 2.33 mL) and Pd2(dba)3(612.96 mg, 669.38 pmol). The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 80°C under a nitrogen atmosphere for another 3 h. The mixture was filtered, and the filtrate was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography to produce ethyl 6- benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridine-3-carboxylate (2 g, 4.60 mmol, 68.73% yield, 89% purity) as a light yellow solid.

[1722] MS (ESI) m / z = 388.8 [M+H+2]+.

[1723]

[1724] Step 4: 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,2-a]pyridine-3- carbohydrazide

[1725] To a solution of ethyl 6-benzylsulfanyl-8-chloro-2-cyclopropyl-imidazo[l,2- a]pyridine-3 -carboxylate (2 g, 5.17 mmol) in EtOH (35 mL) was added NH2NH2·H2O (9.13 g, 155.08 mmol, 8.85 mL, 85% purity) dropwise at 25°C. The mixture was heated and stirred at 80 °C under a nitrogen atmosphere for 12 h. To the above mentioned mixture was added NH2NH2·H2O (7.61 g, 129.23 mmol, 7.38 mL, 85% purity) dropwise at 25°...

Claims

CLAIMS

1. A compound of the following Formula (I):R2(I)wherein:=== is a single bond or double bond;each of X1, X2, and X3is independently C or N;one of Y1and Y2is N and the other one of Y1and Y2is CRY1or NRY2; provided that where one of Y1and Y2is CRY1, only one of X1, X2, and X3is N, and where one of Y1and Y2is NRY2, all of X1, X2, and X3are C;each of RY1and RY2is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3-10 membered carbocyclic group, a 3-12 membered heterocyclic group, 6- to 14-membered aryl, 5- to 12-membered heteroaryl, and H, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O- (Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;Rxis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;Ryis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl,alkenyl, alkynyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl;R1is -CH2-(Hal), -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen;R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, halogen, cyano, -C(=O)-NH2, -C(=O)-N(Ci-Ce alkyl)2, -C(=O)-OH, -C(=O)-Ci-Ce alkyl, -C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O-(Ci-Ce alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)- CH(phenyl)-O-(Ci-Ce alkyl), -S(=O)2-(Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-Ce alkyl);R3is Ci-Ce alkyl which is optionally substituted with one or more halogens; and each of R4and R5is independently hydrogen or halogen,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

2. The compound of claim 1, wherein the compound is selected from the group consisting of compounds of Formula (la), Formula (lb), Formula (Ic), Formula (Id), and Formula (le):wherein:Hal is halogen;each of R11and R12is independently hydrogen or halogen;each of RY1and RY2is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3-10 membered carbocyclic group, a 3-12 membered heterocyclic group, 6- to 14-., RYY Nmembered aryl, 5- to 12-membered heteroaryl, and ' l, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;Rxis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;Ryis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl;R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, halogen, cyano, -C(=O)-NH2, -C(=O)-N(Ci-Ce alkyl)2, -C(=O)-OH, -C(=O)-Ci-Ce alkyl, -C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O-(Ci-Ce alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)-CH(phenyl)-O-(Ci-Ce alkyl), -S(=O)2-(Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-Ce alkyl);R3is Ci-Ce alkyl which is optionally substituted with one or more halogens; and each of R4and R5is independently hydrogen or halogen,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

3. The compound of claim 2, whereinHal is halogen;each of R11and R12is independently hydrogen or halogen;RY1is selected from the group consisting of hydrogen, cyano, halogen, Ci-Ce alkyl, C2-C6 alkynyl, Ci-Ce alkoxy, a 3-7 membered carbocyclic group, a 4-6 membered heterocyclic group containing an oxygen atom and / or nitrogen atom asXNa ring heteroatom, phenyl, andH, wherein each of said alkyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, and phenyl is independently optionally substituted with one or more selected from C1-C3 alkyl, C1-C3 haloalkyl, and halogen;RY2is Ci-C6alkyl;Rxis Ci-Ce alkylene or 3-7 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more Ci-Ce alkyl;Ryis Ci-Ce alkyl optionally substituted with deuterium;R2is selected from the following:N N X JrRZ11RZRz12(R2-A), or Rz21(R2-B);each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-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 group selected from Ci-C6alkyl and -SO2(Ci-C6alkyl);Rzl3is selected from the group consisting of hydrogen, Ci-Ce alkyl, -(C1-C30vAo.alkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, and ';R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2; each of R#1and R#2is independently selected from the group consisting ofhydrogen and C1-C3 alkyl;Z is selected from -NRz14and -CR'R";ORz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2,0O'°^R22Arand -SO2-(Ci-C6alkyl);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;R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium;Ar is 6-14 membered aryl;R' and R" are hydrogen, or 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 Ci-Ce alkyl, hydroxy, Ci-Ce alkoxy, oxo, and amino, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more halogen;Rz21is selected from the group consisting of -C(=O)-N(C1-C6alkyl)2and -SO2- (C1-C6alkyl);R3is C1-C3 alkyl which is optionally substituted with one or more halogens; and each of R4and R5is independently hydrogen or halogen,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

4. The compound of claim 2, whereinHal is halogen;each of R11and R12is independently hydrogen or halogen;RY1is selected from the group consisting of hydrogen, cyano, halogen, Ci-Ce alkyl, C2-Ce alkynyl, Ci-Ce alkoxy, a 3-7 membered carbocyclic group, a 4-6 membered heterocyclic group containing an oxygen atom and / or nitrogen atom as. ^. R.... RvYNa ring heteroatom, phenyl, and4 H, wherein each of said alkyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, and phenyl is independently optionally substituted with one or more selected from C1-C3 alkyl, C1-C3 haloalkyl, and halogen;RY2is Ci-C6alkyl;Rxis Ci-Ce alkylene or 3-7 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more Ci-Ce alkyl;Ryis Ci-Ce alkyl optionally substituted with deuterium;R1is -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen;R2is selected from the following:Rz21(R2-B);each of Rz11and Rz12is independently selected from the group consisting ofhydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-C3 alkyl);Rzl3is selected from the group consisting of hydrogen, Ci-Ce alkyl, -(C1-C3 0alkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, and'R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2, each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl;O^021 Rz14is selected from hydrogen, Ci-Ce alkyl, -C(=O)-N(Ci-Ce alkyl)2,O O Y RR22 22Arand -SO2-(Ci-C6alkyl);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;R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium;Ar is 6-14 membered aryl;Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C6alkyl)- and -N(-SO2(C1-C6alkyl))-;Rz16is selected from the group consisting of hydroxy, C1-C6alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens;Rz17is C1-C6alkyl;Rz18is C1-C6alkyl;Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2and -SO2-(Ci-C6alkyl);R3is C1-C3 alkyl which is optionally substituted with one or more halogens;; and each of R4and R5is independently hydrogen or halogen,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

5. The compound of claim 2, whereinHal is -F;both R11and R12are -F, or one of R11and R12is -F and the other one is hydrogen; RY1is selected from the group consisting ofH FDFFFCIFCNFCH3 |— CF3| — / 1—CF2H / CF 3oRY2is C1-C3 alkyl;R1is -CHF2or -CF3;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-(Ci-C2alkyl);in formula (R2-A-l), Rzl3is selected from the group consisting of hydrogen, Ci- 0 V^R# C3 alkyl, -(C1-C3 alkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, and and R#is selected from the group consisting of hydroxy, methoxy, ethoxy, -NH2, and -N(CH3)2;in formula (R2-A-2), Rzl3is C1-C3 alkyl;ORz14is selected from hydrogen,',Arand -SO2-(Ci-C4 alkyl);R22is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more halogens;Ar is phenyl;Rz15is selected from the group consisting of -O-, -NH-, -N(C1-C3 alkyl)- and -N(-SO2(C1-C3 alkyl))-;Rzl6is selected from hydroxy, C1-C3 alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens;Rz17is C1-C3 alkyl;Rz21is selected from the group consisting of -C(=O)-N(CI-C4 alkyl)2and -SO2-(C1-C4 alkyl);R3is selected from the group consisting of methyl, ethyl, -CH2F, -CHF2, and - CF2-CH3; andeach of R4and R5is independently hydrogen or -F,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form,pharmaceutically acceptable salt, hydrate or solvate thereof.

6. The compound of claim 1, wherein the compound is selected from the group consisting of the following:No. Structure No. Structure No. StructureF F F ZN^=< ^F ZNAF NYFvpoNrYovoNU1 F FHL LF F ” UA 2N3N N XCN CNX. AX X.xH H HF VFVF,Nv S zN^A^F YovoNU X'' ox / pNvsY V v4 5 F F H L X / N 6FFHI VAx A. AxH H H F FF,N%AF zV< v,NA" F \ zz / o o \ V\s1 X YZ o o \ V\sI YovoNU \ >x.,'sVx fyr AL,'si ^N NV, yr N yX N JV7 YAW 8 F FHL LN9FFHL > A / NF FHUY N F N X HX. xx H..FAxHXFFzVX^F ZN;Y^F x\,?V zN^s< 'F\\ i10 F FHL X / N11 12 T=V Z xX.0.H -0H HF F F,N^X^F Y Y owo \ V\sI Xv Xs0 O VsA pA > X^K Y NA14 X«- pA 15FFHA / A - A...1H ' H HF FF, N^ / " AN^ / A ZN*Y ^FX F ^ FH SA AN<N17 18x\x ■X\ XN4X. ' HOHA.. X -~ H ' HF F XFN^AFZNA^Fv°.° V z / o o \ V\siylW AX 20 FH^ X^ / N21HA x F ^J^ / NNFN XXFXX H A.H H F F XF, NAF ZNA^F,N^r > v T / o p \ M\ < L Yv XsF ’ A23 24 x«' AZX x?. A...H H H F FFzN;5?f 'FNZ~NY^, A FFXv v °^> XsXs26 xr py 27Ay.A x>H H HszsLLZ8Z26Z2İ82L82£82, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

7. A compound of the following Formula (II):wherein:W is absent, oxygen, or CH2;RY3is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3-10 membered carbocyclic group, a 3-12 membered heterocyclic, FC „. RW\ N group, 6- to 14-membered aryl, 5- to 12-membered heteroaryl, andwherein each of said alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci- Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;Rzis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;Rwis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl;R1is -CH2-(Hal), -CH-(Hal)2, or -C(Hal)3, wherein Hal is halogen;R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with oneor more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, halogen, cyano, -C(=O)-NH2, -C(=O)-N(Ci-Ce alkyl)2, -C(=O)-OH, -C(=O)-Ci-Ce alkyl, -C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O-(Ci-Ce alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)- CH(phenyl)-O-(Ci-Ce alkyl), -S(=O)2-(Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-Ce alkyl);R3is cyano or Ci-Ce alkyl optionally substituted with one or more halogens; and each of R4and R5is independently hydrogen or halogen,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

8. The compound of claim 7, wherein the compound is selected from the group consisting of compounds of Formula (Ila), Formula (lib), and Formula (lie):Hal is halogen;each of R13and R14is independently hydrogen or halogen;RY3is selected from the group consisting of C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, deuterium, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, a 3-10 membered carbocyclic group, a 3-12 membered heterocyclic V " N" group, 6- to 14-membered aryl, 5- to 12-membered heteroaryl, and’Hwherein each of said alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group, aryl, and heteroaryl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;Rzis Ci-Ce alkylene or 3-10 membered cycloalkylene, wherein each of said alkylene and cycloalkylene is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, and carbamoyl;Rwis selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, halogen, cyano, carbamoyl, acetamido, NH2, mercapto, hydroxy, and 3-10 membered cycloalkyl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, and cycloalkyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, halogen, cyano, hydroxy, NH2, mercapto, deuterium, and carbamoyl;R2is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, halogen, cyano, -C(=O)-NH2, -C(=O)-N(Ci-Ce alkyl)2, -C(=O)-OH,-C(=O)-Ci-Ce alkyl, -C(=O)-(3-10 membered cycloalkylene)-OH, -C(=O)-(3-10 membered cycloalkylene)-O-(Ci-C6 alkyl), -C(=O)-CH(phenyl)-OH, -C(=O)- CH(phenyl)-O-(Ci-Ce alkyl), -S(=O)2-(Ci-Ce alkyl), hydroxy, Ci-Ce alkoxy, NH2, acetamido, mercapto, oxo, and deuterium, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl, and alkoxy is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce alkoxy, halogen, cyano, hydroxy, NH2, mercapto, and -S(=O)2-(Ci-Ce alkyl);R3is cyano or Ci-Ce alkyl optionally substituted with one or more halogens; and each of R4and R5is independently hydrogen or halogen,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

9. The compound of claim 8, whereinHal is halogen;each of R13and R14is independently hydrogen or halogen;RY3is selected from the group consisting of cyano, C2-C3 alkynyl, C1-C3 alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl,, ^Rw\Nthiadiazolyl, and'H, wherein each of alkynyl, alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl, and thiadiazolyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, and NH2;Rzis C1-C3 alkylene or cyclopropylene, wherein each of said alkylene and cyclopropylene is independently optionally substituted with one or more C1-C3 alkyl;Rwis C1-C3 alkyl optionally substituted with deuterium;R2is selected from the following:Rz11Rz13Rz12each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-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 group selected from Ci-C6alkyl and -SO2(Ci-C6alkyl);Rzl3is selected from the group consisting of hydrogen, Ci-Ce alkyl, -(C1-C3OV^Ralkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, and#;R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2; each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl;Z is selected from -NRz14and -CR'R";Rz14is selected from hydrogen, Ci-Ce alkyl, -C(=O)-N(Ci-Ce alkyl)2,and -SO2-(Ci-C6alkyl);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;R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium;Ar is 6-14 membered aryl;R' and R" are hydrogen, or 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 Ci-Ce alkyl, hydroxy, Ci-Ce alkoxy, oxo, and amino, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more halogen;Rz21is selected from the group consisting of -C(=O)-N(Ci-Ce alkyl)2and -SO2-(Ci-C6alkyl);R3is cyano or C1-C3 alkyl optionally substituted with one or more halogens; and each of R4and R5is independently hydrogen or halogen,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

10. The compound of claim 8, whereinHal is halogen;each of R13and R14is independently hydrogen or halogen;RY3is selected from the group consisting of cyano, C2-C3 alkynyl, C1-C3 alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl,< Nthiadiazolyl, and, wherein each of alkynyl, alkoxy, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, phenyl, pyridyl, imidazolyl, and thiadiazolyl is independently optionally substituted with one or more selected from Ci-Ce alkyl, Ci-Ce haloalkyl, 3-10 membered cycloalkyl, Ci-Ce alkoxy, -O-(Ci-Ce haloalkyl), halogen, cyano, hydroxy, and NH2;Rzis C1-C3 alkylene or cyclopropylene, wherein each of said alkylene and cyclopropylene is independently optionally substituted with one or more C1-C3 alkyl;Rwis C1-C3 alkyl optionally substituted with deuterium;R2is selected from the following:N--Rz11RZ13 N Rz12Rz13N V-RZ15Rz14(R2-A-l), H (R2-A-2),NRZ-13Rz15(R2-A-3),Rz21(R2-B);each of Rz11and Rz12is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and -(C1-C3 alkylene)-O-(Ci-C3 alkyl);Rz13is selected from the group consisting of hydrogen, C1-C6alkyl, -(C1-C3 alkylene)-O-(C1-C3 alkyl), -(C1-C3 alkylene)-OH, and';R#is selected from the group consisting of hydroxy, C1-C3 alkoxy, and -NR#1R#2; each of R#1and R#2is independently selected from the group consisting of hydrogen and C1-C3 alkyl;0 Rz14is selected from hydrogen, C1-C6alkyl, -C(=O)-N(C1-C6alkyl)2,' o oXO.R22XAK, Ar and -SO2-(Ci-C6alkyl);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;R22is selected from the group consisting of hydrogen and C1-C6alkyl, wherein said alkyl is optionally substituted with one or more selected from halogen and deuterium;Ar is 6-14 membered aryl;Rzl5is selected from the group consisting of -O-, -NH-, -N(C1-C6alkyl)- and -N(-SO2(C1-C6alkyl))-;Rz16is selected from the group consisting of hydroxy, C1-C6alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens; Rz17is C1-C6alkyl;Rz18is C1-C6alkyl;Rz21is selected from the group consisting of -C(=O)-N(C1-C6alkyl)2and -SO2- (C1-C6alkyl);R3is cyano or C1-C3 alkyl optionally substituted with one or more halogens; and each of R4and R5is independently hydrogen or halogen,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

11. The compound of claim 8, whereinHal is -F;both R13and R14are -F, or one of R13and R14is -F and the other one is hydrogen; RY3is selected from the group consisting ofFCN1-=- I = <1R1is -CHF2or -CF3;R2is selected from the following:N— -Rz11Rz13N Rz12Rz1315Rz14(R2-A-l), (R2-A-2),Rz13RZ15Rz21(R2-B);each of Rz11and Rz12is independently selected from the group consisting of hydrogen, C1-C3 alkyl and -(C1-C2 alkylene)-O-(Ci-C2 alkyl);in formula (R2-A-l), Rzl3is selected from the group consisting of hydrogen, Ci- OC3 alkyl, -(C1-C3 alkylene)-O-(Ci-C3 alkyl), -(C1-C3 alkylene)-OH, and' and R#is selected from the group consisting of hydroxy, methoxy, ethoxy, -NH2, and -N(CH3)2;in formulae (R2-A-2) and (R2-A-3), Rz13is C1-C3 alkyl;o oR 2222Y R22Rz14is selected from hydrogen,Arand -SO2-(C1-C4alkyl);R22is selected from the group consisting of hydrogen and C1-C3 alkyl, whereinsaid alkyl is optionally substituted with one or more halogens;Ar is phenyl;Rzl5is selected from the group consisting of -O-, -NH-, -N(C1-C3alkyl)- and -N(- SO2(C1-C3alkyl))-;Rz16is selected from hydroxy, C1-C3 alkoxy, and -NH2, wherein said alkoxy is optionally substituted with one or more halogens;Rz17is C1-C3 alkyl;Rz18is C1-C3 alkyl;Rz21is selected from the group consisting of -C(=O)-N(C1-C4alkyl)2and -SO2- (C1-C4alkyl);R3is cyano, methyl, ethyl, -CH2F, or -CF2-CH3;each of R4and R5is independently hydrogen or -F,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

12. The compound of claim 7, wherein the compound is selected from the group consisting of the following:Z62HHHxrN xx xrN OSl 6frl 8frl ^X^S, N O dA Or* O x N dy / ^N AA Ad J-yT^N'4dH HHx Nr yyXrLVl 9frl Sfrl A<4S^dA * Arf~b xJSAN f A0 0d J-y^NdLL dH H0 V Hxx Xr ^ "o J / r°?''yNy^o / 4 "> yfrfrl £frl ZVl 4zZIr^v / 0 \^* 4N ° ° 4N0 0X! JyZ^N J-y^N? AN0z0 JyZ^Nd d AdH HH'xox"'yN'yz^ox''Vxrd Im Ofrl 6£l AJAHp< XpANA 0^ H0 A A A adyAl' Jy / A'd A °"d y Nb^J~ ^dH Hxr xN NrAA / NVS \ N^ZAfr£l C V / —X <f\ ££l Z£l tH r N 1 ^ 1 HU a N^J n'0PN° AA 2rd^r ^N4 4862H H H JAA> A)HHH^A¥jVNZ9l 191 091 dA * dA *=1^ / 4'd ddH LI H H ANArN>Nr°" ^oH N^hr6SI XS1 LSI dA * A AJ^ / AN' "iA ^d ddAA H0 N 0 N9SI Y N SSI r frSlj- AA A dA * °^A &- y / d^A'N4 d 4H HYr H'"-., / N-x>*"-a NA^A< A SSI oyxiXgJLzjN ZSl ISl AA Xd^ / ^N'd d A 1NA &-d662f r° f r°. y H...yy "8£L\ ZL\jx? A0 0Jy / ^Ndd d„ dyUd a,.0 N 0 N 0 N0Z. I 691-X X x- " -8< A CX JyZ^Nd d^y*Nd A / 0zHN*y> / ZHN*\ r / °H^hr 0 XrL9\ 991X -<x ' X •*f A °0J^Y^Ndd dH. yzHN" y r°^^..bN0fr9l £91 “ = -X * ■'Jy^Ndd J-y^NdooeLOEZOEIwrvk, OxIZz"vV r _ / o ^ / 'O / II / \ _o / \ ex J »w OC^>z°^H ° 'zxOA" O 0zzHx\\__'a>^ O~N\1VN>^* Q / . "■dk|ssz. A 9VZ SfrZ d^ O? Ox dz^N A d^ d / ^ON ^ d^ d / ^NHHx-o / / ,' <N'y*s'o-x• V ^hTm tZ 80Z, N ON d^z^N AA Ad d-y^NdHX°>r^0-' ' O / ''YN'VXXO / d“ Ao-' ^isr0 N 0LOZ 90Z N SOZ N-?v N^ZLd— ( / — < T I Hj^lA ^ \= / yN^A N^ d^Z^N 1 Nd?<d d^ / ^Ndl-°'<ivoz £0Z zoz d deoeweH Hxr. y \- QZHN" \PNL0£ 90£. o S0£dy^Nd d0\- QSHN" \P H.yy, 0 0roc £0£ 86Z z Z -- Jy^t' =lyZN'J-y^Nd dd°^X0- HH"■ ■aLf> Z 96Z S6Z Z -A d 0 o 4? z ^ rT0? -.d o o 4O? - =I^Z^N pNd 0 0%7J^Z^N J^yZ^Ndd d.. y.. y Hx'o-x"yN'y*^o'xN N^rrV6Z £6Z Z6Z ^zyi^ydpN0 0V0 0%7J^Z^N t A ° ° ^ d d JySl'dHx xHo' '''y'N'yXxo'xH 'xo / ,'yN'yx^o / ^0 / / '' <N'Z*^0x'kZ16Z 06Z 68Z d A 'x-N°> A °^0s?□A &-dZ^NdJ> Z 1d N'Nsoe^VN>--"^OH \H? \H?Y'NV^'OHr> >-. ^isr -o ’ )<- ^OA UAZOX c / IZ° / CX ZZt IZ£ A o _° 0Z£ ° 00^z__ o A A ZTdy^N rX A dy^NAY dy'Xl'd d X X dYYrN ^rr^rr6l£ 8l£ LIE AA ‘ -v,) ZKC / / —\\- / / r \o i / > _ A A X A A X^ o r ex J^AN' >w dyYN'° dy^N dddH^isr" V9l£ Sl£ frl£ A A Y d^ / ^Ndy^N ddX£o ' 1N£l£ Zl£ ll£ \ jf / V o< y— << d 1 Hr?dy / ^NdH H H■■ y xr N N Yr0l£ 60£ 80£1NX Y x- d-Y^N d-y^Ndd d~yXN' dd90SZOEFF NVFHo Vs H N 1 H N. 1 [XN'sL T^6' VjVv362 363^i\rZ1. o=s=oH AHFF,NVF F HNx 1. NV 'F HN\ 1 H N 1 ^d' S—<]365 366cdN^hr O=S=Oo=s=o. N-JN'1 HF F NYF V FuNv 1, NYFHN1HoNU rxVL- I368 369 V^N0N AO=S=O H11F F F NV HNx 1 NY^F H N 1 HN\ 1371 374hk / O^CNJ^o^ HN V^ / N' HH H, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

13. 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 polymerase theta, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreas cancer, or lung cancer.

14. A method of treating or preventing diseases or disorders, such as diseases or disorders mediated by polymerase theta in a subject in need of treatment or prevention, comprising administering to the subject at least one compound 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.

15. A pharmaceutical composition 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).

16. A pharmaceutical composition for treating or preventing diseases or disorders mediated by polymerase theta, preferably cancer, more preferably breast cancer, ovarian cancer, prostate cancer, pancreas cancer, or lung cancer, comprising the compound according to any one of 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).

17. The pharmaceutical composition according to claim 16, wherein the composition is administered separately, sequentially or simultaneously with additional DNA damage response (DDR) targeting anti -cancer agent(s), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATMinhibitors (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), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

Images