Thiadiazole derivative and composition and application thereof

Abstract

The present disclosure relates to a thiadiazole derivative as shown in formula (I), and a pharmaceutical composition thereof. The disclosure also relates to their use for the treatment of PolQ-mediated diseases, e.g., cancers that are deficient in DNA repair. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims the benefit of International Application No. PCT / CN2022 / 131231, filed on November 10, 2022, International Application No. PCT / CN2023 / 079231, filed on March 2, 2023, International Application No. PCT / CN2023 / 082601, filed on March 20, 2023, International Application No. PCT / CN2023 / 088521, filed on April 14, 2023, International Application No. PCT / CN2023 / 096096, filed on May 24, 2023, International Application No. PCT / CN2023 / 097515, filed on May 31, 2023, and International Application No. PCT / CN2023 / 120729, filed on September 22, 2023, the contents of each of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to thiadiazole derivatives as PolQ inhibitors and pharmaceutical compositions thereof, methods for preparing the thiadiazole derivatives, and uses of the thiadiazole derivatives for treating PolQ-mediated diseases, such as cancers with DNA repair defects. Technical Background

[0004] The DNA damage repair process is crucial for genome maintenance and cell viability. Double-strand breaks (DSBs) can be repaired by any of three major pathways: homologous recombination (HR), nonhomologous end joining (NHEJ), and alternative nonhomologous end joining (alt-NHEJ). Alternative nonhomologous end joining (alt-NHEJ), also known as microhomology-stage end joining (MMEJ), is often considered a "backup" DSB repair pathway when NHEJ or HR is impaired. Truong et al., Proc. Natl. Acad. Sci. USA 2013, 110, 7720-5.

[0005] An aberrant DNA damage response (DDR) often sensitizes cancer cells to specific types of DNA damage. Therefore, defective DDRs could be developed as targeted cancer therapies. DNA repair defects have become a proven and effective strategy in cancer treatment, with poly (ADP-ribose) polymerase (PARP) inhibitors demonstrating success in treating BRCA-deficient breast, ovarian, prostate, and pancreatic cancers. Audeh et al., Lancet 2010, 376, 245-51.

[0006] Numerous genetic, cell biological, and biochemical studies have shown that DNA polymerase theta (PolQ) is a key protein involved in MMEJ. Kent et al. Nat. Struct. Mol. Biol. 2015, 22, 230-7; Mateos-Gomez et al. Nature 2015, 518, 254-7. PolQ is unique among human DNA polymerases, containing an N-terminal helicase domain (SF2 HEL308 type) and a C-terminal low-fidelity DNA polymerase domain (A type). Wood and Doublie, DNA Repair (Amst). 2016, 44, 22-32. In homologous recombination-deficient (HRD) cells, PolQ can carry out error-prone DNA synthesis at sites of DNA damage through the alt-NHEJ pathway.

[0007] Studies have shown that the helicase domain of PolQ mediates the removal of replication (RPA) proteins from single-stranded (ssDNA) ends and stimulates annealing. PolQ's anti-recombinase activity promotes the alt-NHEJ pathway. In addition, the helicase domain of PolQ facilitates microhomology-mediated strand annealing. Chan et al., PLoS Genet. 2010, 6, e1001005; Kawamura et al., Int. J. Cancer 2004, 109, 9-16. When the ssDNA overhang contains microhomology greater than 2 base pairs (bp), PolQ can promote end joining in the alt-NHEJ pathway by utilizing this annealing activity. Kent et al., Elife 2016, 5, e13740; Kent, et al., Nat. Struct. Mol. Biol. 2015, 22, 230-7. This reannealing activity is achieved through the coupled interaction of Rad51 with each other, followed by ATPase-mediated displacement of Rad51 from the DSB lesion site. After annealing, the polymerase domain extends the ssDNA ends and fills the remaining gap.

[0008] PolQ expression is low in normal cells but is significantly overexpressed in HRD ovarian, uterine, and breast cancer subpopulations, and PolQ overexpression is associated with poor prognosis in breast cancer (Higgins et al., Oncotarget 2010, 1, 175-84; Lemee et al., Proc. Natl. Acad. Sci. USA 2010, 107, 13390-5; Ceccaldi et al., Nature 2015, 518, 258-62). Recent studies have shown that cancer cells deficient in HR, NHEJ, or ATM are highly dependent on PolQ expression (Ceccaldi et al., 2015, supra; Mateos-Gomez et al., 2015, supra; Wyatt et al., Mol. Cell. 2016, 63, 662-73). Thus, PolQ inhibition may prevent the MMEJ-dependent functional reversion of BRCA1 or BRCA2 mutations, which underlies the emergence of cisplatin and PARPi resistance in tumors (Zatreanu et al., Nat. Commun. 2021, 12, 3636). PolQ is therefore an attractive target for synthetic lethality therapies against cancers harboring DNA repair defects. Summary of the Invention

[0009] The present disclosure provides a compound represented by formula (I):

[0010]

[0011] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; wherein, Ring A, Cy, R 1 , R 2 , R 3 , m, and n are respectively as defined in the present disclosure.

[0012] The present disclosure also provides a pharmaceutical composition comprising: a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; and a pharmaceutically acceptable carrier.

[0013] In addition, the present disclosure provides a method for treating cancer, comprising: administering to a subject a therapeutically effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated product thereof.

[0014] Furthermore, the present disclosure provides a method for inhibiting PolQ, comprising: contacting PolQ with an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated product thereof. Detailed Description of the Invention

[0016] definition

[0017] A number of terms are defined herein as follows to facilitate understanding of what is set forth in this disclosure.

[0018] Generally, the nomenclature used in the present disclosure and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology and pharmacology described in the present disclosure are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs.

[0019] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that claims may be drafted to exclude any optional elements. Thus, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only," and the like in connection with recitation of claim elements or use of a "negative" limitation.

[0020] At various places in this specification, variables defining divalent linking groups are described. Specifically, each linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR(CR'R")- includes -NR(CR'R")- and -(CR'R")NR-, and it is intended that each form be disclosed separately. When a structure requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl", it is understood that "alkyl" or "aryl" refers to a linked alkylene or arylene group, respectively.

[0021] The term "substituted" means that an atom or group of atoms replaces hydrogen as a "substituent" attached to another group. The term "substituted", unless otherwise indicated, refers to any number of substitutions, for example, mono-, di-, tri-, tetra- or penta-substitutions, if such substitutions are permitted. Substituents are independently selected and substitutions can occur at any chemically possible position. It should be understood that substitutions at specific atoms are limited by valence. The term "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms. Exemplary substituents include, but are not limited to, D, halogen, oxo, C1-C -6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkyl-NR c R d , –(CH2CH2O) o C1-C6 alkyl, wherein o is 1-10; C 2-6 Alkenyl-NR c R d , C 2-6 Alkynyl-NR c R d ,–OC 2-6 Alkyl-NR c R d , –CN, –NO2, –N3, –OR a ,–SR a ,–C(O)R b ,–C(O)NR c R d , –CH2C(O)NR c R d ,–C(O)OR a ,–OC(O)R b ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–NR c C(O)NR c R d ,–NR c C(O)OR a , –C(=NR c )NR c R d ,–NR c C(=NR c )NR c R d ,–P(Rf )2,–P(OR e )2,–P(O)R e R f ,–P(O)OR e OR f ,–S(O)R b , –SO(=NR b ),–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ; aryl, heteroaryl, cycloalkyl, or heterocyclic group; wherein the aryl, heteroaryl, cycloalkyl, and heterocyclic group are optionally substituted by the following substituents: D, halogen, oxo, C1-C -6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkyl-NR c R d , C 2-6 Alkenyl-NR c R d , C 2-6 Alkynyl-NR c R d ,–OC 2-6 Alkyl-NR c R d , –CN, –NO2, –N3, –OR a ,–SR a ,–C(O)R b ,–C(O)NR c R d , –CH2C(O)NR c R d ,–C(O)OR a ,–OC(O)R b ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–NR c C(O)NR c R d ,–NR c C(O)OR a , –C(=NR c )NR c R d ,–NR c C(=NRc )NR c R d ,–P(R f )2,–P(OR e )2,–P(O)R e R f ,–P(O)OR e OR f ,–S(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b , or –S(O)2NR c R d ; where each R a , R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0022] The term "Cn-Cm" refers to a range including the stated endpoints, where n and m are integers representing the number of carbon atoms. For example, the term "C1-C6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. "C0 alkyl" refers to a covalent bond.

[0023] The compounds of the present disclosure are stable. As used herein, "stable" refers to compounds that are sufficiently stable to survive isolation to a useful degree of purity from a reaction mixture, and preferably, compounds that can be formulated into an efficacious therapeutic agent.

[0024] It should also be understood that certain features of the disclosure described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the disclosure described in the context of a single embodiment for brevity may also be provided individually or in any suitable subcombination.

[0025] As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon group. The alkyl group may contain from about 1 to about 20, from about 2 to about 20, from about 1 to about 10, from about 1 to about 8, from about 1 to about 6, from about 1 to about 4, or from about 1 to about 3 carbon atoms. For example, the alkyl group may contain any number of carbon atoms, such as C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C 10In some embodiments, the present invention relates to a C-C alkyl group, a C-C alkyl group, a C-C alkyl group, a C-C alkyl group, a C-C alkyl group, a C-C alkyl group, a C-C alkyl group, a C-C alkyl group, a C-C alkyl group, a C-C alkyl group, a C-C alkyl group, a C-C alkyl group, a C-C alkyl group, and a C-C alkyl group. Similarly, C-C in C-C alkyl means that the group has 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched form. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, and t-butyl), pentyl (e.g., n-pentyl, isopentyl, and neopentyl), hexyl, heptyl, and octyl.

[0026] As used herein, the term "alkenyl" refers to a hydrocarbon group having one or more carbon-carbon double bonds. Alkenyl groups can contain any number of carbon atoms, such as C2-C3 alkenyl, C2-C4 alkenyl, C2-C5 alkenyl, C2-C6 alkenyl, C2-C7 alkenyl, C2-C8 alkenyl, C2-C9 alkenyl, C2-C 10 C3-C4 alkenyl, C3-C5 alkenyl, C3-C6 alkenyl, C4-C5 alkenyl, C4-C6 alkenyl and C5-C6 alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0027] As used herein, the term "alkynyl" refers to a hydrocarbon group having one or more carbon-carbon triple bonds. Alkyl groups can contain any number of carbon atoms, such as C2-C3 alkynyl, C2-C4 alkynyl, C2-C5 alkynyl, C2-C6 alkynyl, C2-C7 alkynyl, C2-C8 alkynyl, C2-C9 alkynyl, C2-C 10 Alkynyl, C3-C4 alkynyl, C3-C5 alkynyl, C3-C6 alkynyl, C4-C5 alkynyl, C4-C6 alkynyl, and C5-C6 alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and pentynyl.

[0028] As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents. Exemplary haloalkyl groups include, but are not limited to, -CF3, -C2F5, -CHF2, -CH2F, -CCl3, -CHCl2, and -C2Cl5.

[0029] As used in this article, the term "aryl" refers to unsubstituted or substituted monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbons. In certain embodiments, the aryl has about 6 to about 20 carbon atoms. In certain embodiments, the aryl has about 6 to about 14 carbon atoms. In certain embodiments, the aryl has about 6 to about 10 carbon atoms. Exemplary aryl, includes but is not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl.

[0030] As used herein, the term "cycloalkyl" refers to an unsubstituted or substituted non-aromatic carbocyclic ring. Cycloalkyl can include monocyclic or polycyclic (e.g., having 2, 3, or 4 rings) ring systems, including fused rings, spirocyclic rings, and bridged rings (e.g., bridged bicycloalkyl). In certain embodiments, cycloalkyl has about 3 to about 20 carbon atoms, about 3 to about 14 carbon atoms, about 3 to about 10 carbon atoms, or about 3 to 7 carbon atoms. Cycloalkyl can also have 0, 1, 2, or 3 double bonds and / or 0, 1, or 2 triple bonds. Cycloalkyl can optionally be oxo (=O) or thio (=S). In certain embodiments, cycloalkyl is a C3-C7 monocyclic cycloalkyl. In certain embodiments, cycloalkyl is C 4- C 10 Spirocyclic or bridged ring cycloalkyl. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, cubanyl, adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, and spiro[3.3]heptyl.

[0031] As used herein, the term "heteroaryl" refers to an unsubstituted or substituted aromatic heterocycle having at least one heteroatom ring member, such as boron, sulfur, oxygen, or nitrogen. Heteroaryl includes monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Any N atom of the aryl group can be oxidized to form an N-oxide. Exemplary heteroaryl groups include, but are not limited to, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, and indolinyl. In certain embodiments, the heteroaryl group has from about 1 to about 20 carbon atoms or from about 3 to about 20 carbon atoms. In certain embodiments, the heteroaryl group contains from about 3 to about 14, from about 3 to about 7, about 5, or about 6 ring atoms. In certain embodiments, the heteroaryl group has from about 1 to about 4, from about 1 to about 3, about 1, or about 2 heteroatoms.

[0032] As used herein, the term "heterocyclyl" refers to an unsubstituted or substituted monocyclic (saturated or partially unsaturated ring) or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more ring-forming carbon atoms of the heterocyclyl may be replaced by a heteroatom selected from N, O, S, Si, and B; wherein the ring-forming carbon atoms and heteroatoms of the heterocyclyl may be optionally replaced by one or more oxo (=O) or thio (=S). Heterocyclyl includes monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocyclyl includes monocyclic and polycyclic 3-10-membered, 4-10-membered, 3-7-membered, 4-7-membered, and 5-6-membered heterocyclyls. Heterocyclyl also includes spirocyclic and bridged rings (e.g., 5-10-membered bridged biheterocyclyl). In certain embodiments, the heterocyclyl contains 0 to 3 double bonds. In certain embodiments, the heterocyclyl contains 0 to 2 double bonds.

[0033] The heterocyclic group also includes a group having one or more aromatic rings fused to the non-aromatic heterocyclic ring, for example, benzo or thieno derivatives of piperidine, morpholine, and azepane. In certain embodiments, the heterocyclic group contains 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In certain embodiments, the heterocyclic group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In certain embodiments, the heterocyclic group is a monocyclic 4-6 membered heterocyclic group having 1 or 2 heteroatoms.

[0034] Exemplary heterocyclic groups include, but are not limited to, pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyranyl, oxetanyl, azetidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyrrolyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazepine 1,2,3,4-tetrahydroisoquinolinyl, azabicyclo[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, oxabicyclo[2.1.1]hexyl, azabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[3.1.1]heptyl, diazabicyclo[3.1.1]heptyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2 .1]octyl, oxabicyclo[2.2.2]octyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, azaadamantyl, diazaadamantyl, oxadamantyl, azaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, azaspiro[3.4]octyl, diazaspiro[3.4]octyl, oxazaspiro[3.4]octyl [4.4]nonyl, oxa-azaspiro[3.5]nonyl, azaspiro[2.5]octyl, diazaspiro[2.5]octyl, azaspiro[4.4]nonyl, diazaspiro[4.4]nonyl, oxa-azaspiro[4.4]nonyl, azaspiro[4.5]decyl, diazaspiro[4.5]decyl, diazaspiro[4.4]nonyl, oxa-diazaspiro[4.4]nonyl, and octahydropyrrolo[3,4-c]pyrrolyl.

[0035] In certain embodiments, heterocyclyl refers to any 3 to 10 membered monocyclic or bicyclic saturated ring structure containing at least one heteroatom selected from O, N and S. The heterocyclyl can be attached through any heteroatom or carbon atom thereof, provided that a stable structure is generated. Exemplary heterocyclyls include, but are not limited to, azepanyl, aziridine, azetidinyl, tetrahydropyrrolyl, dioxolane, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and piperazinyl.

[0036] As used herein, the term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0037] As used herein, the term "alkoxy" refers to an -O-alkyl group. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and t-butoxy.

[0038] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with -OH.

[0039] As used herein, the term "cyanoalkyl" refers to an alkyl group substituted with -CN.

[0040] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group.

[0041] As used herein, the term "haloalkoxy" refers to -O-(haloalkyl).

[0042] As used herein, the term "arylalkyl" or "arylalkyl" refers to an alkyl group substituted with an aryl group. An exemplary arylalkyl group is benzyl.

[0043] As used herein, the term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group.

[0044] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group.

[0045] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group.

[0046] In certain embodiments, the compounds of the present disclosure, or salts thereof, are substantially isolated. By "substantially isolated," it is meant that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Substantially isolated can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound of the present disclosure, or a salt thereof.

[0047] The term "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0048] The term "pharmaceutically acceptable excipient" refers to a substance, such as an inert substance, that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a pharmaceutical agent and is compatible therewith, that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. Exemplary excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0049] The term "solvate" refers to a physical association of a compound with one or more solvent molecules.

[0050] The term "subject" refers to a species, including, but not limited to, primates (e.g., humans), cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably in this disclosure to refer to, for example, a mammalian subject, such as a human subject. In certain embodiments, the subject is a human.

[0051] In some embodiments, "treating" or "treatment" of any disease or disorder refers to ameliorating the disease or disorder (i.e., preventing or reducing the development of at least one of the disease or its clinical symptoms). In another embodiment, "treating" refers to improving at least one physical parameter that the subject may not be able to discern. In another embodiment, "treating" refers to regulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet other embodiments, "treating" refers to delaying the onset of a disease or disorder.

[0052] As used herein, the term "isotopic variant" refers to a compound that contains a ratio of isotopes greater than natural abundance at one or more of the atoms comprising the compound. For example, an "isotopic variant" of a compound may be radiolabeled, i.e., contain one or more radioactive isotopes, or may be labeled with a non-radioactive isotope such as, for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15( 15 It will be understood that in compounds subject to such isotopic substitution, the following atoms, if present, may vary so that, for example, any hydrogen may be 2 H / D, any carbon can be 13 C, or any nitrogen can be 15 N, and the presence and position of such atoms can be determined within the capabilities of those skilled in the art.

[0053] Compound

[0054] In one aspect, the present disclosure provides a compound represented by formula (I):

[0055]

[0056] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof; wherein:

[0057] Ring A is C5-C 10 Cycloalkyl, 5-10 membered heterocyclic group, C6-C 10 Aryl, or 5-10 membered heteroaryl;

[0058] Cy is C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, or 5-10 membered heteroaryl;

[0059] m is an integer of 1, 2, 3, 4, or 5;

[0060] n is an integer of 1, 2, 3, 4, or 5;

[0061] Every R 1 are independently selected from H, D, –CN, –NO2, –N3, oxo, –SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, –NR C R D ,–OR A ,–SR A ,–NR C OR A ,–C(O)R B ,–C(O)NR C R D ,–C(O)OR A ,–OC(O)R B ,–NR C C(O)R B ,–S(O)R B ,–S(O)2R B ,–S(O)NR C R D ,–NR C S(O)2R D ,–S(O)2NR C R D ,–NR C S(O)2NR C R D ,–NR C S(O)(=NR B )R B ,–SiR G R H R I ,–B(OR E )(OR F ),–P(O)R E R F ,–P(O)OR E OR F , or –OP(O)OR E OR Fwherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 independently selected R 1A or

[0062] Two R's 1 Together with the atoms to which they are attached, they form an oxo, a C3-C7 cycloalkyl, a 4-7 membered heterocyclyl, a phenyl, or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, phenyl, and heteroaryl are optionally substituted by 1, 2, 3, or 4 independently selected R 1A Substituents substituted;

[0063] Every R 1A are independently selected from D, halogen, –CN, –OH, –NH2, –NO2, –SF5, oxo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, –NR c R d ,–OR a ,–SR a ,–C(O)R b ,–C(O)NR c R d ,–C(O)OR a ,–OC(O)R b ,–OC(O)NR c R d ,–NR c C(O)R b ,–NR c C(O)NR c R d ,–NR c C(O)OR a , –S(O)(=NR b )R b ,–S(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R d ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –NR c S(O)(=NR b )R bwherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl groups are optionally substituted with the following substituents: D, halogen, –CN, oxo, –NR c1 R d1 ,–OR a1 ,–SR a1 , C1-C6 alkyl, or C1-C6 haloalkyl;

[0064] Every R 2 are independently selected from H, D, halogen, –CN, –NO2, –N3, –SF5, –OR A ,–SR A ,–C(O)R B ,–C(O)NR C R D ,–C(O)OR A ,–OC(O)R B ,–NR C R D ,–NR C C(O)R B ,–S(O)R B ,–S(O)2R B ,–S(O)NR C R D ,–NR C S(O)2R D ,–S(O)2NR C R D ,–NR C S(O)2NR C R D ,–NR C S(O)(=NR B )R B ,–SiR G R H R I ,–B(OR E )(OR F ),–P(O)R E R F ,–P(O)OR E OR F ,–OP(O)OR E OR F , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl are optionally replaced by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents substituted;

[0065] Every R2A are independently selected from D, halogen, –CN, –OH, –NH2, –NO2, –N3, oxo, C1-C6 alkyl, –OC1-C6 alkyl, C1-C6 haloalkyl, –OC1-C6 haloalkyl, –NHC1-C3 alkyl, –N(C1-C3 alkyl)2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with the following substituents: D, halogen, –CN, –OH, –NH2, C1-C6 alkyl, C1-C6 haloalkyl, –O-C1-C6 alkyl, or –O-C1-C6 haloalkyl; or

[0066] Two adjacent R 2 Together with the atoms to which they are attached, they form a C4-C7 cycloalkyl or a 4-7 membered heterocyclic group, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 2B Substituents substituted;

[0067] Every R 2B are independently selected from D, halogen, oxo, –CN, –OH, –NH2, –NO2, C1-C6 alkyl, C1-C6 haloalkyl, –O-C1-C6 alkyl, or –O-C1-C6 haloalkyl;

[0068] R 3 Selected from:

[0069] i)H, D, –CN, halogen, –NO2, –N3, –SF5, –B(OR 5 )(OR 6 ), –SiR 5 R 6 R 7 ,–SR 8 ,–S(O)R 8 ,–S(O)2R 8 ,–NR 9 R 10 ,–NR 9 C(O)R 8 ,–C(O)R 8 ,–S(O)NR 9 R 10 ,–S(O)2NR 9 R 10 , C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are optionally replaced by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 Substituents substituted;

[0070] Every R4 are independently selected from H, D, halogen, –CN, –NO2, –N3, oxo, –OR A1 ,–OR A2 , C1-C4 alkyl, –C(O)R B ,–C(O)NR C R D ,–C(O)OR A ,–C(O)NR C S(O)R B ,–C(O)NR C S(O)2R B ,–OC(O)R B ,–OC(O)NR C R D ,–NR C R D ,–NR C C(O)R B ,–NR C C(O)NR C R D ,–NR C C(O)OR A ,–SR A ,–S(O)R B ,–S(O)2R B ,–S(O)NR C R D ,–NR C S(O)2R D ,–S(O)2NR C R D ,–NR C S(O)2NR C R D ,–NR C S(O)(=NR B )R B ,–SiR G R H R I , or –B(OR E )(OR F );

[0071] R A1 is selected from H, D, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are optionally replaced by 1, 2, 3, 4, or 5 independently selected from R 11 Substituents substituted;

[0072] Every R 11are independently selected from D, –CN, –N3, halogen, –NO2, oxo, –OR a ,–SR a ,–NR c R d ,–C(O)R b ,–C(O)NR c R d ,–C(O)OR a ,–OC(O)R b ,–OC(O)NR c R d ,–NR c C(O)R b ,–NR c C(O)NR c R d ,–NR c C(O)OR a ,–S(O)R b ,–S(O)2R b ,–S(O)NR c R d ,–NR c S(O)2R d ,–S(O)2NR c R d ,–NR c S(O)2NR c R d ,–NR c S(O)(=NR b )R b ,–SiR g R h R i ,–B(OR e )(OR f ), C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl; wherein the aryl, cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 Substituents substituted;

[0073] R A2 Selected from C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 Aryl, or 5-14 membered heteroaryl; wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 Substituents substituted;

[0074] Every R12 are independently selected from H, D, halogen, –CN, –N3, –NO2, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, –OR a ,–SR a ,–C(O)R b ,–C(O)NR c R d ,–C(O)OR a ,–OC(O)R b ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–NR c C(O)NR c R d ,–NR c C(O)OR a ,–B(OR e )(OR f ), –C(=NR c )NR c R d ,–NR d C(=NR c )NR c R d ,–NR d C(=NR c )R b , –S(O)(=NR b )R b ,–S(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R d ,–S(O)2NR c R d ,–NR c S(O)2NR c R d ,–NR c S(O)(=NR b )R b , or –SiR g R h R iwherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, –NO2, oxo, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, –NH2, –NHC1-C4 alkyl, or –N(C1-C4 alkyl)2;

[0075] ii) C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, each substituent optionally substituted by 1, 2, 3, 4 or 5 independently selected R 13 Substituents substituted;

[0076] Every R 13 are independently selected from H, D, halogen, –SF5, –CN, –NO2, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, –SR A ,–OR A ,–C(O)R B ,–C(O)NR C R D ,–C(O)OR A ,–OC(O)R B ,–OC(O)NR C R D ,–NR C R D ,–NR C C(O)R B ,–NR C C(O)NR C R D ,–NR C C(O)OR A , –C(=NR C )NR C R D ,–NR D C(=NR C )NR C R D ,–NR D C(=NR C )R B ,–SiR G R H R I ,–B(OR E )(OR F ), –S(O)(=NR B )RB ,–S(O)R B ,–S(O)NR C R D ,–S(O)2R B ,–NR C S(O)2R D ,–S(O)2NR C R D ,–NR C S(O)2NR C R D , or –NR C S(O)(=NR B )R B ;

[0077] Every R 5 , R 6 , and R 7 Each of the following substituents is independently selected from H, D, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, or phenyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and phenyl are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following substituents: D, halogen, –CN, –NO2, –N3, oxo, –NR C R D ,–OR A ,–SR A ,–C(O)R B ,–C(O)NR C R D ,–OC(O)NR C R D ,–NR C C(O)R B ,–NR C C(O)NR C R D ,–NR C C(O)OR A ,–S(O)R B ,–S(O)2R B ,–S(O)NR C R D ,–NR C S(O)2R D ,–S(O)2NR C R D ,–NR C S(O)2NR C R D , C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C3-C6 cycloalkyl;

[0078] Every R 8 are independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, or 5-10 membered heteroaryl, each substituent is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 8A Substituents substituted;

[0079] Every R 8A are independently selected from D, halogen, –CN, –NO2, –N3, oxo, –NR C R D ,–OR A ,–SR A ,–SiR G R H R I ,–B(OR E )(OR F ),–C(O)R B ,–C(O)NR C R D ,–OC(O)NR C R D ,–NR C C(O)R B ,–NR C C(O)NR C R D ,–NR C C(O)OR A ,–S(O)R B ,–S(O)2R B ,–S(O)NR C R D ,–NR C S(O)2R D ,–S(O)2NR C R D ,–NR C S(O)2NR C R D ,–NR C S(O)(=NR B )R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, phenyl, and heteroaryl are optionally substituted with the following substituents: D, halogen, –CN, –OH, –NH2, C1-C6 alkyl, C1-C6 haloalkyl, –O-C1-C6 alkyl, or –OC 1-C6 haloalkyl;

[0080] Every R 9 and R 10 are independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following substituents: D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f );

[0081] Every R A are independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10Aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –NO2, oxo, –OR a ,–SR a ,–SF5,–NHOR a ,–C(O)R b ,–C(O)NR c R d ,–C(O)OR a ,–OC(O)R b ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–NR c C(O)NR c R d ,–NR c C(O)OR a ,–B(OR e )(OR f ), –SiR g R h R i , –C(=NR c )NR c R d ,–NR d C(=NR c )NR c R d ,–NR d C(=NR c )R b ,–P(O)R e R f ,–P(O)OR e OR f ,–OP(O)OR e OR f ,–S(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NRc S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –NR c S(O)(=NR b )R b ;

[0082] Every R B are independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocyclylalkyl are optionally replaced by 1, 2, 3, 4, or 5 independently selected R B1 Substituents substituted by:

[0083] Every R B1 are independently selected from D, -CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, C0-C4 alkyl-C3-C 10 Cycloalkyl, C0-C4 alkyl-4-10 membered heterocyclic group, C0-C4 alkyl-C6-C 10 Aryl, C0-C4 alkyl-5-10 membered heteroaryl, –SF5, –C(O)R b ,–OC(O)NR c R d ,–OR a ,–NR c R d ,–NR c C(O)R b ,–NR c C(O)NR c R d ,–NR c C(O)OR a ,–S(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NRc R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ); wherein the alkyl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, and alkyl-heteroaryl are optionally substituted with D, –CN, halogen, oxo, –OH, –NH2, –SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –O-C1-C4 alkyl, –O-C1-C4 haloalkyl, –NH-C1-C4 alkyl, or –NH(C1-C4 alkyl)2;

[0084] Every R C and R D Each independently selected from H, D, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f );or

[0085] R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclyl, optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, oxo, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, or –OC1-C4 haloalkyl;

[0086] Every R a and R a1 are independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: D, halogen, –OH, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl), C1-C4 alkyl, –OC1-C4 alkyl, C1-C4 haloalkyl, or –OC1-C4 haloalkyl;

[0087] Every R b and R b1 Each independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclylalkyl; wherein the alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –OH, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl;

[0088] Every R c and R d are independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10Cycloalkyl, 4-10 membered heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, arylcycloalkyl, arylheterocyclyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocyclyl, heteroarylaryl, or biheteroaryl; wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, arylcycloalkyl, arylheterocyclyl, arylheteroaryl, biaryl, heteroaryl The cycloalkyl, heteroarylheterocyclyl, heteroarylaryl, and biheteroaryl groups are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, –C(O)OR a1 ,–C(O)R b1 ,–S(O)2R b1 , C1-C4 alkyl-O-C1-C4 alkyl, or C1-C4 alkyl-O-C1-C4 alkoxy; or

[0089] R c and R d Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group, optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –OH, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C4 alkoxy-C1-C4 alkyl, or C1-C4 alkoxy-C1-C4 alkoxy;

[0090] Every R E and R e Each independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy)-C1-C4 alkyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C4 alkyl, C3-C 10 Cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocyclyl-C1-C4 alkyl;

[0091] Every R F and R f are independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, or 4-10 membered heterocyclic group;

[0092] Every R G , R H , R I , R g , R h , and R i Each is independently selected from C1-C4 alkyl or phenyl.

[0093] In certain embodiments, the compound of the present disclosure is neither 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide nor 2'-chloro-N-(5-(2-(dimethylamino)-2-oxoethyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0094] In certain embodiments, Ring A is C5-C 10 Cycloalkyl, 5-10 membered heterocyclic group, C6-C 10 aryl, or 5-10 membered heteroaryl.

[0095] In certain embodiments, Ring A is C5-C 10 In certain embodiments, Ring A is a saturated C5-C 10 Cycloalkyl or partially unsaturated C5-C 10 In certain embodiments, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl.

[0096] In certain embodiments, Ring A is a 5-10 membered heterocyclyl. In certain embodiments, Ring A is a saturated 5-10 membered heterocyclyl or a partially unsaturated 5-10 membered heterocyclyl. In certain embodiments, Ring A is an azetidinyl, oxetanyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, dioxanyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, pyridin-2(1H)-onyl, 1,2,4-triazin-5(4H)-onyl, pyrimidin-2(1H)-onyl, or pyrazin-2(1H)-onyl. In certain embodiments, Ring A is a pyridin-2(1H)-onyl.

[0097] In certain embodiments, Ring A is C6-C 10 In certain embodiments, Ring A is phenyl or naphthyl.

[0098] In certain embodiments, Ring A is a 5-10 membered heteroaryl. In certain embodiments, Ring A is a monocyclic 5-10 membered heteroaryl. In certain embodiments, Ring A is a 5-membered heteroaryl. In certain embodiments, Ring A is pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiadiazolyl, or oxadiazolyl. In certain embodiments, Ring A is imidazolyl. In certain embodiments, Ring A is a 6-membered heteroaryl. In certain embodiments, Ring A is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In certain embodiments, Ring A is pyridinyl. In certain embodiments, Ring A is pyridazinyl. In certain embodiments, Ring A is a 7-10 membered heteroaryl. In certain embodiments, Ring A is a 9-membered heteroaryl. In certain embodiments, Ring A is [1,2,4]triazolo[1,5-a]pyridinyl or imidazo[1,2-a]pyridinyl.

[0099] In certain embodiments, Ring A is a 5- or 6-membered heteroaryl. In certain embodiments, Ring A is an imidazolyl, pyridinyl, or pyridazinyl. In certain embodiments, Ring A is an imidazolyl or pyridinyl.

[0100] In certain embodiments, Has the following structure:

[0101] in:

[0102] The symbol “*” represents connection with Cy;

[0103] The symbol "**" represents connection with C=O;

[0104] Every X 1 , X 2 , X 3 , and X 4 are independently selected from N or CR 1 ;

[0105] Every X 5 Independently selected from NR 1 , O, or S; and

[0106] Every R 1 As defined in this disclosure.

[0107] In certain embodiments, has the structure: Among them, X 1 , X 2 , X 3 , and X 4 As defined in this disclosure, respectively. In certain embodiments, X 1 , X 2 , X 3 , and X 4 One of them is N; the other three are independently selected from CR 1 , where R 1 As defined in this disclosure. In certain embodiments, X 1 , X 2 , X 3 , and X 4 Any two of them are N; the other two are independently selected from CR 1 , where R 1 As defined in this disclosure. In certain embodiments, X 1 , X 2 , X 3 , and X 4 Each independently selected from CR 1 , where R 1 As defined in this disclosure.

[0108] In certain embodiments, Has the following structure: Among them, R 1 , X 1 , and X 4 Respectively as defined in this disclosure.

[0109] In certain embodiments, Has the following structure: Among them, X 1 , X 2 , and X 3 As defined in this disclosure, respectively. In certain embodiments, X 1 , X 2 , and X 3 One of them is N; the other two are independently selected from CR 1 , where R 1 As defined in this disclosure. In certain embodiments, X 1 , X 2 , and X 3 Any two N in the 1 , where R 1 As defined in this disclosure. In certain embodiments, X 1 , X 2, and X 3 Each independently selected from CR 1 , where R 1 As defined in this disclosure.

[0110] In certain embodiments, Has the following structure: Among them, each X 1 , X 3 , and X 5 As defined in this disclosure. In certain embodiments, each X 1 and X 3 Each independently selected from CR 1 ;X 5 NR 1 , O or S; where each R 1 As defined in this disclosure. In certain embodiments, X 1 N; X 3 CR 1 ;X 5 NR 1 , O or S; where each R 1 As defined in this disclosure. In certain embodiments, X 1 CR 1 ;X 3 N; X 5 NR 1 , O or S; where each R 1 As defined in this disclosure. In certain embodiments, X 1 N; X 3 is N; and X 5 NR 1 , O or S; among them, R 1 As defined in this disclosure.

[0111] In certain embodiments, Has the following structure: Among them, each R 1 As defined in this disclosure.

[0112] In certain embodiments, Has the following structure: Among them, each R 1 As defined in this disclosure.

[0113] In certain embodiments, Has the following structure: Among them, each R 1 As defined in this disclosure.

[0114] In certain embodiments, Has the following structure: Among them, each R 1 As defined in this disclosure.

[0115] In certain embodiments, Has the following structure: Among them, each R 1 As defined in this disclosure. In certain embodiments, Has the following structure: Among them, each R 1 As defined in this disclosure. In certain embodiments, Has the following structure: Among them, each R 1 As defined in this disclosure. In certain embodiments, Has the following structure: Among them, each R 1 As defined in this disclosure. In certain embodiments, Has the following structure: Among them, each R 1 As defined in this disclosure.

[0116] In certain embodiments, Has the following structure:

[0117] In certain embodiments, Cy is C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, or 5-10 membered heteroaryl.

[0118] In certain embodiments, Cy is C3-C 10 In certain embodiments, Cy is a saturated C3-C 10 Cycloalkyl or partially unsaturated C5-C 10In certain embodiments, Cy is a saturated C5-C7 cycloalkyl. In certain embodiments, Cy is an unsaturated C5-C7 cycloalkyl. In certain embodiments, Cy is a cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0119] In certain embodiments, Cy is a 4-10 membered heterocyclyl. In certain embodiments, Cy is a saturated 4-10 membered heterocyclyl or a partially unsaturated 5-10 membered heterocyclyl. In certain embodiments, Cy is a saturated 5-7 membered heterocyclyl or a partially unsaturated 5-7 membered heterocyclyl. In certain embodiments, each heterocyclyl has one or two heteroatoms, each of which is independently selected from N, O, or S.

[0120] In certain embodiments, Cy is C 6- C 10 In certain embodiments, Cy is phenyl or naphthyl. In certain embodiments, Cy is phenyl.

[0121] In certain embodiments, Cy is a 5-10 membered heteroaryl. In certain embodiments, Cy is a monocyclic 5-10 membered heteroaryl. In certain embodiments, Cy is a 6-membered heteroaryl. In certain embodiments, Cy is pyridyl. In certain embodiments, Cy is a 5-10 membered heteroaryl having one or two heteroatoms, each of which is independently selected from N, O, or S. In certain embodiments, Cy is phenyl or a 6-membered heteroaryl. In certain embodiments, Cy is phenyl or pyridyl. In certain embodiments, Cy is phenyl or pyridin-4-yl.

[0122] In certain embodiments, Has the following structure: Among them, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are independently selected from N or CR 2 ; and each R 2 As defined in this disclosure. In certain embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 One of them is N, and the other four are independently selected from CR 2 , where R 2 As defined in this disclosure. In certain embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y5 Two of them are N; the other three are independently selected from CR 2 , where R 2 As defined in this disclosure. In certain embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 Each independently selected from CR 2 , where R 2 As defined in this disclosure.

[0123] In certain embodiments, Has the following structure: Among them, each R 2 As defined in this disclosure.

[0124] In certain embodiments, Has the following structure: Among them, each R 2 As defined in this disclosure. In certain embodiments, Has the following structure: Among them, each R 2 As defined in this disclosure. In certain embodiments, Has the following structure: Among them, each R 2 As defined in this disclosure. In certain embodiments, Has the following structure: Among them, each R 2 As defined in this disclosure.

[0125] In certain embodiments, Has the following structure:

[0126] In certain embodiments, Has the following structure:

[0127] In certain embodiments, each R 1 are independently selected from H, D, –CN, –NO2, –N3, oxo, –SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10Aryl, 5-10 membered heteroaryl, –NR C R D ,–OR A ,–SR A ,–NR C OR A ,–C(O)R B ,–C(O)NR C R D ,–C(O)OR A ,–OC(O)R B ,–NR C C(O)R B ,–S(O)R B ,–S(O)2R B ,–S(O)NR C R D ,–NR C S(O)2R D ,–S(O)2NR C R D ,–NR C S(O)2NR C R D ,–NR C S(O)(=NR B )R B ,–SiR G R H R I ,–B(OR E )(OR F ),–P(O)R E R F ,–P(O)OR E OR F , or –OP(O)OR E OR F wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 independently selected R 1A Substituents substituted; each R 1A , R A , R B , R C , R D , R E , R F , R G , R H , and R I As defined in this disclosure.

[0128] In certain embodiments, each R 1Each is independently selected from H, D, –CN, –NO2, –N3, oxo, –SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, –OR A ,–SR A ,–OC(O)R B ,–OC(O)NR C R D ,–NR C R D ,–NR C C(O)R B , or –NR C C(O)OR A wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 independently selected R 1A Substituents substituted; each R 1A , R A , R B , R C , and R D As defined in this disclosure.

[0129] In certain embodiments, each R 1 Each is independently selected from H, D, –CN, –NO2, –N3, oxo, –SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, –OR A ,–SR A ,–OC(O)R B ,–OC(O)NR C R D ,–NR C R D ,–NR C C(O)R B , or –NR C C(O)OR A wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 independently selected R 1A Substituents substituted; each R 1A , R A , R B , R C , and R D As defined in this disclosure.

[0130] In certain embodiments, R 1 is H. In certain embodiments, R1 is D. In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 is -F, -Cl, -Br, or -I. In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 is –I.

[0131] In certain embodiments, R 1 for –NR C R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 1 is –NH2, –NHCH3, –N(CH3)2, –NHCH2CH3, –N(CH2CH3)2, –NHCH2CH2CH3, –N(CH2CH2CH3)2, –NHCH(CH3)2, –NHCH2CH2OH, –N(CN)CH3,

[0132] In certain embodiments, R 1 for –OR A , where R A As defined in this disclosure. In certain embodiments, R 1 is –OH, –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)2, –OCH2F, –OCHF2, –OCF3, –OCH2CH2OCHF2,

[0133] In certain embodiments, R 1 For –SR A , where R A As defined in this disclosure. In certain embodiments, R 1 In certain embodiments, R 1 for –NR C ORA , where R A and R C As defined in this disclosure, respectively. In certain embodiments, R 1 –C(O)R B , where R B As defined in this disclosure. In certain embodiments, R 1 is –C(O)CH3, –C(O)CH2CH3, –C(O)CH(CH3)2, or In certain embodiments, R 1 –C(O)NR C R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 1 is -C(O)NH2, -C(O)NHCH3, or -C(O)N(CH3)2. In certain embodiments, R 1 -C(O)OR A , where R A As defined in this disclosure. In certain embodiments, R 1 -OC(O)R B , where R B As defined in this disclosure. In certain embodiments, R 1 for –NR C C(O)R B , where R B and R C As defined in this disclosure, respectively. In certain embodiments, R 1 is –NHC(O)CH3, –NCH3C(O)CH3,

[0134] In certain embodiments, R 1 is C1-C6 alkyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, R 1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, –CD3, –CH2OH, –CH2OMe, –CH2CN, In certain embodiments, R 1 is methyl or -CD3. In certain embodiments, R 1 It is a methyl group.

[0135] In certain embodiments, R 1 is C2-C6 alkenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, R 1 is C2-C6 alkynyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure.

[0136] In certain embodiments, R 1 for

[0137] In certain embodiments, R 1 C3-C 10 The cycloalkyl group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, R 1 is saturated C3-C 10 Cycloalkyl or partially unsaturated C3-C 10 Cycloalkyl, each substituent is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, or cyclohexenyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure.

[0138] In certain embodiments, R 1 is a 4-10 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, R 1is a saturated 4-10 membered heterocyclic group or a partially unsaturated 4-10 membered heterocyclic group, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, R 1 azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, dioxanyl, piperazinyl, morpholinyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 7-oxa-4-azaspiro[2.5]octyl, 3-azabicyclo[4.1.0]heptyl, 3-azabicyclo[4.1.0]heptyl, cyclo[4.1.0]heptan-2-onyl, 4-oxa-7-azaspiro[2.5]octan-8-onyl, morpholin-3-onyl, piperazin-2-onyl, pyrrolidin-2-onyl, pyridin-2(1H)-onyl, or 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-onyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure.

[0139] In certain embodiments, R 1 C6-C 10 The aryl group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, R 1 is phenyl or naphthyl, each substituent optionally replaced by 1, 2, 3, 4, or 5 independently selected R 1A substituted by a substituent, wherein R 1A As defined in this disclosure.

[0140] In certain embodiments, R 1 is a 5-10 membered heteroaryl group optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, R 1 is pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, or isoindolyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure.

[0141] In certain embodiments, each R 1 are independently selected from (i) H, D, -CN, or halogen; or (ii) C1-C6 alkyl or 5-10 membered heteroaryl, each substituent optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, each R 1 are independently selected from (i) H, D, or -CN; or (ii) C1-C6 alkyl or 5-membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, each R 1 are independently selected from H, D, -CN, methyl, or 1-methyl-pyrazolyl. In certain embodiments, each R 1 are independently selected from H or methyl.

[0142] In certain embodiments, one of the R 1 is (i) -CN or halogen; or (ii) C1-C6 alkyl or 5-10 membered heteroaryl, each substituent optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, one of R 1 is -CN, methyl, or 1-methylpyrazolyl. In certain embodiments, one R 1 It is a methyl group.

[0143] In certain embodiments, one of the R 1 is (i) -CN or halogen; or (ii) C1-C6 alkyl or 5-10 membered heteroaryl, each substituent optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure; other R 1 In certain embodiments, one of R 1 is –CN, methyl, or 1-methylpyrazolyl; other R 1 In certain embodiments, one of R 1 is methyl, other R 1 They are H respectively.

[0144] In certain embodiments, both R 1Together with the atoms to which they are attached, they form (i) oxo; or (ii) C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, two R 1 Together with the same atom to which they are attached, they form an oxo group. In certain embodiments, two R 1 Together with the atoms to which they are attached, they form a C3-C7 cycloalkyl group which is optionally substituted by 1, 2, 3, or 4 independently selected R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, two R 1 Together with the atoms to which they are attached, they form a cyclopropyl or cyclobutyl group, each of which is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, two R 1 Together with the atoms to which they are attached, they form a 4-7 membered heterocyclic group optionally substituted by 1, 2, 3, or 4 independently selected R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, two R 1 The phenyl group, taken together with the atoms to which it is attached, is optionally substituted by 1, 2, 3, or 4 independently selected R 1A substituted by a substituent, wherein R 1A As defined in this disclosure. In certain embodiments, two R 1 Together with the atoms to which they are attached, they form a 5-6 membered heteroaryl group optionally substituted by 1, 2, 3, or 4 independently selected R 1A substituted by a substituent, wherein R 1A As defined in this disclosure.

[0145] In certain embodiments, each R 1A independently selected from D, halogen, –CN, –OH, –NH2, –NO2, –SF5, oxo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, –NR c R d ,–OR a ,–SR a ,–C(O)R b ,–C(O)NR c R d ,–C(O)ORa ,–OC(O)R b ,–OC(O)NR c R d ,–NR c C(O)R b ,–NR c C(O)NR c R d ,–NR c C(O)OR a , –S(O)(=NR b )R b ,–S(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R d ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –NR c S(O)(=NR b )R b wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups are optionally replaced by D, halogen, –CN, oxo, –NR c1 R d1 ,–OR a1 ,–SR a1 , C 1- C6 alkyl, or C 1- C6 haloalkyl; wherein each R a , R b , R c , R d , R a1 , R c1 , and R d1 As defined in this disclosure.

[0146] In certain embodiments, R 1A is D, halogen, –CN, –OH, –NH2, –NO2, –SF5, or oxo. In certain embodiments, R 1A is D. In certain embodiments, R 1A In certain embodiments, R 1A is -F, -Cl, -Br, or -I. In certain embodiments, R 1A In certain embodiments, R 1A In certain embodiments, R 1Ais -NH2. In certain embodiments, R 1A In certain embodiments, R 1A In certain embodiments, R 1A For oxygen.

[0147] In certain embodiments, R 1A C1-C4 alkyl is optionally substituted by a substituent selected from the group consisting of: D, halogen, –CN, –OH, –NH2, oxo, –NR c1 R d1 ,–OR a1 ,–SR a1 , C 1- C6 alkyl, or C 1- C6 haloalkyl; wherein each R a1 , R c1 , and R d1 As defined in this disclosure. In certain embodiments, R 1A is –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2CH2CH2CH3, –CH2CH(CH3)2, –C(CH3)3, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, –CF2CH3, –CF2CF3, –CF2CH2CH3, –CH2OH, –CH2CH2OH, –CH(OH)CH3, –CH2CH2CH2OH, –CH(OH)CH2CH2OH, –CH2CN, –CH2CH2CN, or –CH2CH2CH2CN.

[0148] In certain embodiments, each R 2 Independently selected from H, D, halogen, –CN, –NO2, –N3, –SF5, –OR A ,–SR A ,–C(O)R B ,–C(O)NR C R D ,–C(O)OR A ,–OC(O)R B ,–NR C R D ,–NR C C(O)R B ,–S(O)R B ,–S(O)2R B ,–S(O)NR C R D ,–NR C S(O)2R D ,–S(O)2NRC R D ,–NR C S(O)2NR C R D ,–NR C S(O)(=NR B )R B ,–SiR G R H R I ,–B(OR E )(OR F ),–P(O)R E R F ,–P(O)OR E OR F ,–OP(O)OR E OR F , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally replaced by 1, 2, 3, 4, or 5 independently selected from R 2A wherein each R 2A , R A , R B , R C , R D , R E , R F , R G , R H , and R I As defined in this disclosure.

[0149] In certain embodiments, R 2 is H, D, halogen, -CN, -NO2, -N3, or -SF5. In certain embodiments, R 2 is H. In certain embodiments, R 2 is D. In certain embodiments, R 2 In certain embodiments, R 2 is -F, -Cl, -Br, or -I. In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 is –SF5.

[0150] In certain embodiments, R 2 for –OR A , where R A As defined in this disclosure. In certain embodiments, R 2 is –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)2, –OCH2F, –OCHF2, –OCF3, –OCH2CH2F, –OCH2CHF2, –OCF2CH3, –OCH2CF3, –OCH2CN, or –OCH2CONH2. In certain embodiments, R 2 For –SR A , where R A As defined in this disclosure. In certain embodiments, R 2 In certain embodiments, R 2 is –SCH2CH3.

[0151] In certain embodiments, R 2 –C(O)R B , where R B As defined in this disclosure. In certain embodiments, R 2 –C(O)NR C R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 2 -C(O)OR A , where R A As defined in this disclosure. In certain embodiments, R 2 for–OC(O)R B , where R B As defined in this disclosure. In certain embodiments, R 2 for –NR C R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 2 for –NR C C(O)R B , where R B and R C Respectively as defined in this disclosure.

[0152] In certain embodiments, R 2 -S(O)R B , where R BAs defined in this disclosure. In certain embodiments, R 2 is –S(O)2R B , where R B As defined in this disclosure. In certain embodiments, R 2 –S(O)NR C R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 2 for –NR C S(O)2R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 2 –S(O)2NR C R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 2 for –NR C S(O)2NR C R D , where each R C and R D As defined in this disclosure. In certain embodiments, R 2 for –NR C S(O)(=NR B )R B , where each R B and R C As defined in this disclosure.

[0153] In certain embodiments, R 2 For –SiR G R H R I , where R G , R H , and R I As defined in this disclosure, respectively. In certain embodiments, R 2 For –B(OR E )(OR F ), where R E and R F As defined in this disclosure, respectively. In certain embodiments, R 2 –P(O)R E R F , where R E and R F As defined in this disclosure, respectively. In certain embodiments, R2 –P(O)OR E OR F , where R E and R F As defined in this disclosure, respectively. In certain embodiments, R 2 for –OP(O)OR E OR F , where R E and R F Respectively as defined in this disclosure.

[0154] In certain embodiments, R 2 C 1- C6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 2A substituted by a substituent, wherein R 2A As defined in this disclosure. In certain embodiments, R 2 C 1- C6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, halogen, –CN, –OH, –NH2, –NO2, –N3, oxo, –OC 1- C6 alkyl, –OC 1- C6 haloalkyl, –NHC 1- C3 alkyl, or –N(C 1- In certain embodiments, R 2 is –CD3, –CH3, –CH2CH3, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, –CH2OH, –CH(OH)CH3, –CH2CH2OH, –CH2OCH3, –CH2OCHF2, –CH2OCH2F, –CH2OCF3, –CH(OCH3)CH3, –CH2CH2NH2, –CH(NH2)CH3, –CH2N(CH3)2, –CH2CH2N(CH3)2, or –CH2CN.

[0155] In certain embodiments, R 2 C2 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, -CN, -OH, -N3, -OC 1- C6 alkyl, C 1- C6 haloalkyl, –OC 1- C6 haloalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group; wherein the cycloalkyl and heterocyclic groups are optionally replaced by D, halogen, -CN, -OH, C 1-C6 alkyl, C 1- C6 haloalkyl, –O-C1-C6 alkyl, or –OC 1- Substituted with C6 haloalkyl.

[0156] In certain embodiments, R 2 C1 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the following: D, halogen, -CN, -OH, -N3, -OC 1- C6 alkyl, C 1- C6 haloalkyl, –OC 1- C6 haloalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group; wherein the cycloalkyl and heterocyclic groups are optionally replaced by D, halogen, -CN, -OH, C 1- C6 alkyl, C 1- C6 haloalkyl, –O-C1-C6 alkyl, or –OC 1- Substituted with C6 haloalkyl.

[0157] In certain embodiments, R 2 is C2-C6 alkenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2A substituted by a substituent, wherein R 2A As defined in this disclosure. In certain embodiments, R 2 is -CH=CH2 or -CH=CHCH3. In certain embodiments, R 2 is C2-C6 alkynyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2A substituted by a substituent, wherein R 2A As defined in this disclosure. In certain embodiments, R 2 is -C≡CH or -C≡CCH3. In certain embodiments, R 2 is a C3-C6 cycloalkyl group optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2A substituted by a substituent, wherein R 2A As defined in this disclosure. In certain embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 2A substituted by a substituent, wherein R 2A As defined in this disclosure.

[0158] In certain embodiments, R 2is a 4-6 membered heterocyclic group having 1 or 2 heteroatoms, each heteroatom independently selected from N, O, S, Si, and B, wherein one or more heteroatoms are optionally oxo-substituted, wherein the heterocyclic group is optionally substituted by 1, 2, 3, 4, or 5 atoms independently selected from R 2A substituted by a substituent, and wherein R 2A As defined in this disclosure. In certain embodiments, R 2 is azetidinyl, oxetanyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,4-diazacyclooctanyl, 1,4-diazacycloheptyl, or azepanyl, each substituent optionally replaced by 1, 2, 3, 4, or 5 substituents independently selected from R 2A substituted by a substituent, wherein R 2A As defined in this disclosure. In certain embodiments, R 2 is phenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2A substituted by a substituent, wherein R 2A As defined in this disclosure. In certain embodiments, R 2 is a 5-6 membered heteroaryl group optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2A substituted by a substituent, wherein R 2A As defined in this disclosure.

[0159] In certain embodiments, each R 2are independently selected from H, D, –CN, –OH, –NH2, –F, –Cl, –Br, –CH3, –CH2CH3, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, –CH=CH2, –CH=CHCH3, –C≡CH, –C≡CCH3, –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)2, –CH2F, – CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, –CH2OH, –SCH3, –SCH2CH3, –S(O)CH3, –S(O)CH2 CH3, –S(O)2CH3, –S(O)2CH2CH3, –S(O)2NH2, –S(O)2NHCH3, –S(O)2N(CH3)2, –NHS(O)2CH3, –C(O)CH3, –C(O)CH2CH3, –OCH2F, –OCHF2, –OCF3, –OCH2CH2F, –OCH2CHF2, –OCH2CF3, –CH(OH)CH3, –CH2CH2OH, –CH2OCH3, –CH2OCHF2, –CH2OCH2F, –CH2OCF3, –CH(OCH3)CH3, –OCH2CN, –OCH2CONH2, –NHCH3, –N(CH3)2, –CH2CH2NH2, –CH(NH2)CH3, –CH2N(CH3)2, –CH2CH2N(CH3)2, –CH2CN, –COOH, –CONH2, –CONHCH3, –CON(CH3)2, –P(O)(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, –CHO, azetidinyl, oxetanyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,4-diazacyclooctanyl, 1,4-diazepanyl, or azepanyl.

[0160] In certain embodiments, each R 2 are independently selected from (i) H, D, halogen, or -OR A or (ii) C1-C6 alkyl, optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2A substituted by a substituent; wherein, R A and R 2A As defined in this disclosure, respectively. In certain embodiments, each R 2 Each is independently selected from H, -F, -Cl, -CH3, -CF3, or -OCH3.

[0161] In certain embodiments, one of the R2 In certain embodiments, one R 2 is -Cl, -CH3, or -CF3. In certain embodiments, one of R 2 is –OCH3.

[0162] In certain embodiments, wherein three R 2 is not H. In certain embodiments, wherein three R 2 is not H; the first is -F; the second is -Cl, -CH3, or -CF3; the third is -OCH3. In certain embodiments, wherein the three R 2 Not H; the first one is –F; the second one is –Cl; the third one is –OCH3.

[0163] In certain embodiments, each R 2A are independently selected from D, halogen, –CN, –OH, –NH2, –NO2, –N3, oxo, C 1- C6 alkyl, –OC 1- C6 alkyl, C 1- C6 haloalkyl, –OC 1- C6 haloalkyl, –NHC 1- C3 alkyl, –N(C 1- C3 alkyl) 2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally replaced by D, halogen, -CN, -OH, -NH2, C 1- C6 alkyl, C 1- C6 haloalkyl, –O-C1-C6 alkyl, or –OC 1- C6 haloalkyl.

[0164] In certain embodiments, R 2A is D. In certain embodiments, R 2A In certain embodiments, R 2A is -F, -Cl, -Br, or -I. In certain embodiments, R 2A In certain embodiments, R 2A In certain embodiments, R 2A is -NH2. In certain embodiments, R 2A In certain embodiments, R 2A In certain embodiments, R 2A For oxygen.

[0165] In certain embodiments, both R 2, when on adjacent ring atoms, together with the carbon atoms to which they are attached, form a C 4- The C7 cycloalkyl group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 2B substituted by a substituent, wherein R 2B As defined in this disclosure. In certain embodiments, two R 2 , when on adjacent ring atoms, together with the carbon atoms to which they are attached, form a 4-7 membered heterocyclic group optionally substituted by 1, 2, 3, 4 or 5 independently selected R 2B substituted by a substituent, wherein R 2B As defined in this disclosure.

[0166] In certain embodiments, each R 2B are independently selected from D, halogen, oxo, –CN, –OH, –NH2, –NO2, C 1- C6 alkyl, C 1- C6 haloalkyl, –O-C1-C6 alkyl, or –OC 1- C6 haloalkyl. In certain embodiments, R 2B is D. In certain embodiments, R 2B In certain embodiments, R 2B is -F, -Cl, -Br, or -I. In certain embodiments, R 2B In certain embodiments, R 2B In certain embodiments, R 2B In certain embodiments, R 2B is -NH2. In certain embodiments, R 2B In certain embodiments, R 2B C 1- C6 alkyl. In certain embodiments, R 2B C 1- C6 haloalkyl. In certain embodiments, R 2B In certain embodiments, R 2B For –OC 1- C6 haloalkyl.

[0167] In other embodiments, the present disclosure provides a compound represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii):

[0168]

[0169] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof; wherein:

[0170] Every X 1 , X 2 , X 3 , and X 4 are independently selected from N or CR 1 ;

[0171] Every X 5 Independently selected from NR 1 , O or S;

[0172] Each Cy, R 1 , R 2 , R 3 , and m are as defined in this disclosure.

[0173] In some further embodiments, the present disclosure provides a compound represented by formula (IIa), (IIb), (IIc), (IId), or (IIe):

[0174]

[0175] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof; wherein each Cy, R 1 , R 2 , R 3 , and m are as defined in this disclosure.

[0176] In some further embodiments, the present disclosure provides a compound represented by formula (III):

[0177]

[0178] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are independently selected from N or CR 2 ; Ring A, R 1 , R 2 , R 3 , and n are respectively as defined in the present disclosure.

[0179] In some further embodiments, the present disclosure provides a compound represented by formula (IIIa) or (IIIb):

[0180]

[0181] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; wherein, Ring A, R 1 , R 2 , R 3 , and n are as defined in this disclosure.

[0182] In certain embodiments, R 3 H, D, –CN, halogen, –NO2, –N3, –SF5, –B(OR 5 )(OR 6 ), –SiR 5 R 6 R 7 ,–SR 8 ,–S(O)R 8 ,–S(O)2R 8 ,–NR 9 R 10 ,–NR 9 C(O)R 8 ,–C(O)R 8 ,–S(O)NR 9 R 10 ,–S(O)2NR 9 R 10 , C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are optionally replaced by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 wherein each R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 As defined in this disclosure. In certain embodiments, R 3 H, D, –CN, halogen, –NO2, –N3, –SF5, –B(OR 5 )(OR 6 ), –SiR 5 R 6 R 7 ,–SR 8 ,–S(O)R 8 ,–S(O)2R 8 ,–NR 9 R 10 ,–NR 9C(O)R 8 ,–C(O)R 8 ,–S(O)NR 9 R 10 , or –S(O)2NR 9 R 10 , where each R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 As defined in this disclosure. In certain embodiments, R 3 For –B(OR 5 )(OR 6 ), –SiR 5 R 6 R 7 ,–SR 8 ,–S(O)R 8 ,–S(O)2R 8 ,–NR 9 R 10 ,–NR 9 C(O)R 8 ,–C(O)R 8 ,–S(O)NR 9 R 10 , or –S(O)2NR 9 R 10 , where each R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 As defined in this disclosure.

[0183] In certain embodiments, R 3 For –B(OR 5 )(OR 6 ), where R 5 and R 6 Respectively as defined in this disclosure.

[0184] In some further embodiments, the present disclosure provides a compound represented by Formula (IVa), (IVb), (IVc), (IVd), or (IVe):

[0185]

[0186] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; wherein Cy, R 1 , R2 , R 5 , R 6 , and m are as defined in this disclosure.

[0187] In certain embodiments, each R 5 and R 6 Each of the following substituents is independently selected from H, D, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, or phenyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and phenyl are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following substituents: D, halogen, –CN, –NO2, –N3, oxo, –NR C R D ,–OR A ,–SR A ,–SiR G R H R I ,–C(O)R B ,–C(O)NR C R D ,–OC(O)NR C R D ,–NR C C(O)R B ,–NR C C(O)NR C R D ,–NR C C(O)OR A ,–S(O)R B ,–S(O)2R B ,–S(O)NR C R D ,–NR C S(O)2R D ,–S(O)2NR C R D ,–NR C S(O)2NR C R D , C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C3-C6 cycloalkyl; wherein R A , R B , R C , R D , R G , R H , and R I As defined in this disclosure, respectively. In certain embodiments, each R 5 and R 6 are independently selected from H, D, or C1-C8 alkyl.5 and R 6 In certain embodiments, R 5 and R 6 are methyl groups respectively.

[0188] In certain embodiments, R 3 For –SiR 5 R 6 R 7 , where R 5 , R 6 , and R 7 Respectively as defined in this disclosure.

[0189] In yet other embodiments, the present disclosure provides a compound represented by formula (Va), (Vb), (Vc), (Vd), or (Ve):

[0190]

[0191]

[0192] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; wherein Cy, R 1 , R 2 , R 5 , R 6 , R 7 , and m are respectively as defined in the present disclosure.

[0193] In certain embodiments, each R 5 , R 6 , and R 7 Each of the following substituents is independently selected from H, D, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, or phenyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and phenyl are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following substituents: D, halogen, –CN, –NO2, –N3, oxo, –NR C R D ,–OR A ,–SR A ,–SiR G R H R I ,–C(O)R B ,–C(O)NR C R D ,–OC(O)NR C R D ,–NR C C(O)RB ,–NR C C(O)NR C R D ,–NR C C(O)OR A ,–S(O)R B ,–S(O)2R B ,–S(O)NR C R D ,–NR C S(O)2R D ,–S(O)2NR C R D ,–NR C S(O)2NR C R D , C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C3-C6 cycloalkyl; wherein R A , R B , R C , R D , R G , R H , and R I Respectively as defined in this disclosure.

[0194] In certain embodiments, R 5 , R 6 , and R 7 are independently selected from C1-C8 alkyl. 5 , R 6 , and R 7 are methyl groups respectively.

[0195] In certain embodiments, R 3 For –SR 8 , where R 8 As defined in this disclosure.

[0196] In some further embodiments, the present disclosure provides a compound represented by formula (VIa), (VIb), (VIc), (VId) or (VIe):

[0197]

[0198] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; wherein Cy, R 1 , R 2 , R 8 , and m are respectively as defined in the present disclosure.

[0199] In certain embodiments, R8 is C1-C8 alkyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 8A substituted by a substituent, wherein R 8A As defined in this disclosure. In certain embodiments, R 8 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally replaced by 1, 2, 3, 4, or 5 substituents independently selected from R 8A substituted by a substituent, wherein R 8A As defined in this disclosure. In certain embodiments, R 8 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, –CH2C(CH3)3, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CN, –C(CH3)2CN, –CH2C(CH3)2CN, –CH2CH2OH, –CH2CH2OCH3, –CH2CH2OCF3, –CH2CH2OCH2CH3, –CH2CH2CH2OH, –CH2CH2C(CH3)2OH, –CH(CH3)CH2OH, –CH2CH(CH3)OH, –CH(CH3)COOH, –CH(CH3)COOCH2CH3, or –CH(CH3)CON(CH3)2.

[0200] In certain embodiments, R 8 is C2-C8 alkenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 8A substituted by a substituent, wherein R 8A As defined in this disclosure. In certain embodiments, R 8 is C2-C8 alkynyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 8A substituted by a substituent, wherein R 8A As defined in this disclosure. In certain embodiments, R 8 C3-C 10 The cycloalkyl group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 8A substituted by a substituent, wherein R 8A As defined in this disclosure. In certain embodiments, R 8 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, or cyclohexenyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 8A substituted by a substituent, wherein R 8AAs defined in this disclosure. In certain embodiments, R 8 for

[0201] In certain embodiments, R 8 is a 4-10 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R 8A substituted by a substituent, wherein R 8A As defined in this disclosure. In certain embodiments, R 8 is azetidinyl, oxetanyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, dioxanyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, or morpholinyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 8A substituted by a substituent, wherein R 8A As defined in this disclosure. In certain embodiments, R 8 C6-C 10 The aryl group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 8A substituted by a substituent, wherein R 8A As defined in this disclosure. In certain embodiments, R 8 is phenyl or naphthyl, each substituent optionally replaced by 1, 2, 3, 4, or 5 independently selected R 8A substituted by a substituent, wherein R 8A As defined in this disclosure.

[0202] In certain embodiments, R 8 is a 5-10 membered heteroaryl group optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R 8A substituted by a substituent, wherein R 8A As defined in this disclosure. In certain embodiments, R 8is pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzo[b]thienyl, benzo[c]thienyl, indazolyl, benzo[d]imidazolyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, Pyrrolol[3,2-b]pyridinyl, pyrrolol[3,2-c]pyridinyl, pyrrolol[2,3-c]pyridinyl, pyrrolol[2,3-b]pyridinyl, pyrrolol[3,4-b]pyridinyl, pyrrolol[3,4-c]pyridinyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, furo[3,2-b]pyridinyl, furo[3,2- c]pyridinyl, furo[2,3-c]pyridinyl, furo[2,3-b]-pyridinyl, benzo[c]isoxazolyl, furo[3,4-b]pyridinyl, furo[3,4-c]pyridinyl, benzo[d]isothiazolyl, benzo[d]thiazolyl, thieno[3,2-b]pyridinyl, thieno[3,4-c]pyridinyl, benzo[ d][1,2,3]-triazolyl, pyrazolo[4,3-b]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, imidazo[4,5-c]pyridinyl, imidazo[4,5-b] Pyridinyl, pyrrolo[3,2-c]pyridazinyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3-b]-pyrazinyl, pyrrolo[2,3-d]pyridazinyl, pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-c]pyridazinyl, pyrrolo[3,4-c]pyridazinyl, pyrrolo[3,4-d]pyrimidinyl, pyrrolo[3, 4-b]pyrazinyl, pyrrolo[3,4-d]pyridazinyl, pyrrolo[3,4-d]-pyrimidinyl, 6H-pyrrolo[3,4-c]pyridazinyl, thiazolo[4,5-b]pyrazinyl, thiazolo[5,4-d]-pyrimidinyl, thiazolo[4,5-d]pyrimidinyl, imidazo[2,1-b][1,3,4]thiadiazolyl, imidazo[5 ,1-b][1,3,4]-thiadiazolyl, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazolyl, [1,2,4]-triazolo[5,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-b][1,2,4]thiadiazolyl, imidazo[1,2-b][1,2,4]-thiadiazolyl, thiazolo[5,4-d]thiazolyl, thiazolo[4,5-d]thiazolyl, thiazolo[3,2-b][1,2,4]-triazolyl, isothiazolo[2,3-b][1,2,4]triazolyl, 2H-pyrazolo[4,3-d]-thiazolyl, 4H-imidazo[4,5-d]thiazolyl, 2H-pyrazolo[3,4-d] thiazolyl, imidazo[5,1-b]-[1,3,4]-thiadiazol-5(6H)-onyl, or 5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-4-onyl; each substituent is optionally replaced by 1, 2, 3, 4, or 5 independently selected from R, 8A substituted by a substituent, wherein R 8A As defined in this disclosure.

[0203] In certain embodiments, R 8 is C1-C8 alkyl or C3-C 10 Cycloalkyl, each substituent is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 8A substituted by a substituent, wherein R 8A As defined in this disclosure. In certain embodiments, R 8 is –CH2CH3, –CH2CF3, –CH2CH2OH, –CH2CH(CH3)OH, –CH(CH3)CH2OH, –CH2CH2OCH3, –CH2CH2CH2CN, –CH2CH2CH2OH, –CH2CH2C(CH3)2OH, –CH(CH3)CO2H, –CH(CH3)CO2CH2CH3, –CH2CH2OSi(CH3)2C(CH3)3, or 2-hydroxycyclopentyl.

[0204] In certain embodiments, R 3 -S(O)R 8 , where R 8 As defined in this disclosure.

[0205] In yet other embodiments, the present disclosure provides a compound represented by Formula (VIIa), (VIIb), (VIIc), (VIId), or (VIIe):

[0206]

[0207] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; wherein Cy, R 1 , R 2 , R 8 , and m are respectively as defined in the present disclosure.

[0208] In certain embodiments, R 3 is –S(O)2R 8 , where R 8 As defined in this disclosure.

[0209] In yet other embodiments, the present disclosure provides a compound represented by Formula (VIIIa), (VIIIb), (VIIIc), (VIIId), or (VIIIe):

[0210]

[0211] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; wherein Cy, R 1 , R 2 , R 8 , and m are respectively as defined in the present disclosure.

[0212] In certain embodiments, R 3 for –NR 9 R 10 , where R 9 and R 10 Respectively as defined in this disclosure.

[0213] In yet other embodiments, the present disclosure provides a compound represented by Formula (IXa), (IXb), (IXc), (IXd), or (IXe):

[0214]

[0215] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; wherein Cy, R 1 , R 2 , R 9 , R 10 , and m are respectively as defined in the present disclosure.

[0216] In certain embodiments, R 9 is H. In certain embodiments, R 9 is D. In certain embodiments, R 9 C1-C6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f As defined in this disclosure, respectively. In certain embodiments, R 9 is –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2CH2CH2CH3, –CH2CH(CH3)2, or –C(CH3)3.

[0217] In certain embodiments, R 9 C3-C7 cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R fAs defined in this disclosure, respectively. In certain embodiments, R 9 It is cyclopropyl.

[0218] In certain embodiments, R 10 is H. In certain embodiments, R 10 is D. In certain embodiments, R 10 C1-C6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f As defined in this disclosure, respectively. In certain embodiments, R 10 is –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2CH2CH2CH3, –CH2CH(CH3)2, –C(CH3)3, –CH2CF3, –CH2CH2OH, –CH2CH2OCH 3. –CH2CH2OCH2CH2OH, –CH2CH2CN, –CH2CH2N(CH3)C(O)CH3, –CH2CH2N(CH3)S(O)2CH3, or –CH2CH2N(CH3)S(O)2N(CH3)2.

[0219] In certain embodiments, R 10C2-C6 alkenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f As defined in this disclosure, respectively. In certain embodiments, R 10 C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d, or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0220] In certain embodiments, R 10 is C3-C7 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f As defined in this disclosure, respectively. In certain embodiments, R 10 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)Rb ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0221] In certain embodiments, R 10 is a 4-7 membered heterocyclyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f As defined in this disclosure, respectively. In certain embodiments, R 10is azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, dioxanyl, tetrahydropyranyl, piperazinyl, or morpholinyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0222] In certain embodiments, R 10 is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR cR d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0223] In certain embodiments, R 10 is a 5-6 membered heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f As defined in this disclosure, respectively. In certain embodiments, R 10is pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,3-triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0224] In certain embodiments, R 10 is arylalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0225] In certain embodiments, R 10 is heteroarylalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0226] In certain embodiments, R 10is cycloalkylalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0227] In certain embodiments, R 10 is heterocyclylalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR cR d , or –B(OR e )(OR f ), where R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0228] In certain embodiments, R 3 for –NR 9 C(O)R 8 , where R 8 and R 9 As defined in this disclosure, respectively. In certain embodiments, R 3 –C(O)R 8 , where R 8 As defined in this disclosure. In certain embodiments, R 3 –S(O)NR 9 R 10 , where R 9 and R 10 As defined in this disclosure, respectively. In certain embodiments, R 3 –S(O)2NR 9 R 10 , where R 9 and R 10 Respectively as defined in this disclosure.

[0229] In certain embodiments, R 3 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each substituent optionally replaced by 1, 2, 3, 4, 5, 6, 7, or 8 substituents independently selected from R 4 substituted by a substituent, wherein R 4 As defined in this disclosure.

[0230] In yet other embodiments, the present disclosure provides a compound represented by Formula (Xa), (Xb), (Xc), (Xd), or (Xe):

[0231]

[0232] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof; wherein:

[0233] Each Y 3 , R 1 , R 2 , R 3 , and R4 Respectively as defined in this disclosure.

[0234] In certain embodiments, Y 3 CR 2 or N, where R 2 As defined in this disclosure. In certain embodiments, Y 3 CR 2 , where R 2 As defined in this disclosure. In certain embodiments, Y 3 In certain embodiments, Y 3 is N.

[0235] In certain embodiments, Has the following structure:

[0236] In certain embodiments, Has the following structure:

[0237] In certain embodiments, R 3 is C1-C8 alkyl optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent, wherein R 4 As defined in this disclosure. In certain embodiments, R 3 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, –CH2C(CH3)3, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, –CH(CH3)F, –C(CH3)2F, –CH2CH(CH3)F, –CH2C(CH3)2F, –CF2CH3, –CF2CH2CH3, –CF2CH2CH2CH3, –CF2CH(CH3)2, –CF2C(CH3)3, –CF2CH2OH, –CF2CH2CH2OH, –CF2CH2OCH3, –CH2CN, –CH(CH3)CN, –C(CH3)2CN, or –CH2C(CH3)2CN.

[0238] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl group, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; wherein one of R4 for –OR A1 ; Among them, R 4 and R A1 As defined in this disclosure, respectively. In certain embodiments, R 3 is a linear or branched C1-C3 alkyl group, optionally substituted by 1, 2, 3, 4, 5, or 6 independently selected from R 4 substituted by a substituent; wherein one of R 4 for –OR A1 ; Among them, R 4 and R A1 Respectively as defined in this disclosure.

[0239] In certain embodiments, R 3 for Among them, each R 4 and R A1 As defined in this disclosure.

[0240] In yet other embodiments, the present disclosure provides a compound represented by Formula (XIa), (XIb), (XIc), (XId), or (XIe):

[0241]

[0242] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof; wherein each Y 3 , R 1 , R 2 , R 4 , R A1 , and m are respectively as defined in the present disclosure.

[0243] In certain embodiments, Y 3 CR 2 or N, where R 2 As defined in this disclosure. In certain embodiments, Y 3 CR 2 , where R 2 As defined in this disclosure. In certain embodiments, Y 3 In certain embodiments, Y 3 is N.

[0244] In certain embodiments, each R 4 are independently selected from H, D, halogen, -NO2, -N3, oxo, or C1-C4 alkyl. In certain embodiments, one of R 4 is D. In certain embodiments, one R 4In certain embodiments, one of R 4 is -F, -Cl, -Br, or -I. In certain embodiments, one of R 4 In certain embodiments, wherein the two R 4 In certain embodiments, one R 4 In certain embodiments, one R 4 In certain embodiments, one of the R 4 In certain embodiments, the two R 4 Together with the carbon atom to which it is attached, it forms an oxo group. In certain embodiments, one R 4 is C1-C4 alkyl. In certain embodiments, one of R 4 It is a methyl group.

[0245] In certain embodiments, R A1 is H. In certain embodiments, R A1 is D. In certain embodiments, R A1 is C1-C8 alkyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 11 substituted by a substituent, wherein R 11 As defined in this disclosure. In certain embodiments, R A1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each of which is optionally replaced by 1, 2, 3, 4, or 5 substituents independently selected from R 11 substituted by a substituent, wherein R 11 As defined in this disclosure. In certain embodiments, R A1 is H, D, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, –CH2C(CH3)3, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, –CH2CH2OH, –CH2CH(CH3)OH, –CH2CH2OCH3, –CH2CH2OCH2CH3, –CH2CH2OCH2CH2OH, –CH2CH2OCH2CH2OCH3, – CH2CH2OCH2CH2OCH2CH3, –CH2CH2SCH3, –CH2CH2SCH2CH3, –CH2CH2OCH2CH2SCH3, –CH2CH2OCH2CH2SCH3, –CH2CH2OCH2CH2SCH2CH3, –CH2CH(CH3)OCH3, –CH2C(CH3)2CN, –CH2C(CH3)2F, –CH2C(CH3)2OH, CH2C(CH3)2OCH3, or –CH2C(CH3)2CH2OH.

[0246] In certain embodiments, R A1 is C2-C8 alkenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 11 substituted by a substituent, wherein R 11 As defined in this disclosure. In certain embodiments, R A1 is C2-C8 alkynyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 11 substituted by a substituent, wherein R 11 As defined in this disclosure. In certain embodiments, R 3 is a linear or branched C1-C8 alkyl group, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 OR A2 ; Among them, R 4 and R A2 As defined in this disclosure, respectively. In certain embodiments, R 3 is a linear or branched C1-C3 alkyl group optionally substituted by 1, 2, 3, 4, 5 or 6 groups independently selected from R 4 substituted by a substituent; one of the R 4 OR A2 ; Among them, R 4 and R A2 Respectively as defined in this disclosure.

[0247] In certain embodiments, R 3 for Among them, each R 4 and R A2 As defined in this disclosure.

[0248] In yet other embodiments, the present disclosure provides a compound represented by Formula (XIIa), (XIIb), (XIIc), (XIId), or (XIIe):

[0249]

[0250] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof; wherein each Cy, R 1 , R 2 , R 4 , R A2 , and m are as defined in this disclosure, when R A2 C6-C 14 aryl or 5-14 membered heteroaryl, at least one R 4For not for H.

[0251] In certain embodiments, each R 4 are independently selected from H, D, halogen, –CN, –NO2, –N3, oxo, or C1-C4 alkyl, when R A2 C6-C 14 aryl or 5-14 membered heteroaryl, at least one R 4 Not for H.

[0252] In certain embodiments, one of the R 4 is D. In certain embodiments, one R 4 In certain embodiments, one of R 4 is -F, -Cl, -Br, or -I. In certain embodiments, one of R 4 In certain embodiments, wherein the two R 4 In certain embodiments, one R 4 In certain embodiments, one R 4 In certain embodiments, one of the R 4 In certain embodiments, the two R 4 Together with the carbon atom to which it is attached, it forms an oxo group. In certain embodiments, one R 4 is C1-C4 alkyl. In certain embodiments, one of R 4 It is a methyl group.

[0253] In certain embodiments, R A2 C3-C 14 The cycloalkyl group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent; wherein, R 12 As defined in this disclosure. In certain embodiments, R A2 is saturated C3-C 14 Cycloalkyl or partially unsaturated C3-C 14 Cycloalkyl, each substituent is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 12 substituted by a substituent; wherein, R 12 As defined in this disclosure.

[0254] In certain embodiments, R A2is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl, spiro[5.6]dodecyl, spiro[6.6]tridecyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[5.2.0]nonyl, octahydropentadienyl, octahydro-1H-indenyl, decahydroazulenyl, decahydroindenyl, hydronaphthyl, decahydro-1H-benzo[7]annulyl, dodecahydroheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, adamantyl, cyclopentenyl, or cyclohexenyl, each ring optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent; wherein, R 12 As defined in this disclosure. In certain embodiments, R A2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each ring optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted by a substituent; wherein, R 12 As defined in this disclosure.

[0255] In certain embodiments, R 3 for Among them, each R 4 and R 12 As defined in this disclosure.

[0256] In certain embodiments, R A2 is a saturated 4-14 membered heterocyclic group or a partially unsaturated 4-14 membered heterocyclic group, each substituent being optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 12 substituted by a substituent; wherein, R 12 As defined in this disclosure. In certain embodiments, R A2are azetidinyl, oxetanyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,4-diazacyclooctanyl, 1,4-diazacycloheptyl, azepanyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 3,9-diazaspiro[5.5]undecyl, 2 -oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, 7-oxa-2-azaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.4]octyl, octahydropyrrolo[3,4-c]pyrrolyl, hexahydrofuro[3,4-c]pyrrolyl, hexahydrothieno[3,4-c]pyrrolyl, octahydrocyclopentyl[b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, hexahydrofuro[3,2-b]pyrrolyl, octahydropyrano[3,2-b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, pyridinyl, hexahydropyrrolo[1,2-a]imidazolyl, octahydropyrrolo[2,3-c]pyridinyl, octahydropyrrolo[3,2-c]pyridinyl, octahydroimidazo[1,2-a]pyridinyl, octahydropyrrolo[3,4-c]pyridinyl, decahydroquinolinyl, octahydrochromenyl, decahydroquinoxalinyl, octahydropyrido[1,2-a]pyrazinyl, octahydropyrazino[2,1-c][1,4]oxazinyl, octahydropyrido[2,1-c][1,4]oxazinyl, octahydropyrano[3,2-c]pyridinyl, decahydro-2,6-naphthyridinyl, 2- azabicyclo[1.1.1]pentyl, 5-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.3.1]nonyl, 3-azabicyclo[3.3.2]decyl, 3-azabicyclo[3.3.3]undecyl, or 3,6-diazabicyclo[3.1.1]heptyl, each ring optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent; wherein, R 12 As defined in this disclosure.

[0257] In certain embodiments, R A2 is azetidinyl, oxetanyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,4-diazacyclooctanyl, 1,4-diazacycloheptyl, azepanyl, or 2,6-diazaspiro[3.3]heptyl, each of which is optionally replaced by 1, 2, 3, 4, or 5 substituents independently selected from R12 substituted by a substituent; wherein, R 12 As defined in this disclosure.

[0258] In certain embodiments, R 3 for Among them, each R 4 and R 12 As defined in this disclosure. In certain embodiments, at least one R 4 Not for H; R A2 C6-C 14 The aryl group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 12 substituted by a substituent; wherein, R 12 As defined in this disclosure. In certain embodiments, at least one R 4 Not for H; R A2 is phenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 substituted by a substituent; wherein, R 12 As defined in this disclosure.

[0259] In certain embodiments, R 3 for Among them, each R 4 and R 12 As defined in this disclosure, at least one R 4 Not for H.

[0260] In certain embodiments, R A2 is a 5-14 membered heteroaryl group optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R 12 ; Among them, R 12 As defined in this disclosure; at least one R 4 Not for H.

[0261] In certain embodiments, R A2is pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzo[b]thienyl, benzo[c]thienyl, indazolyl, benzo[d]imidazolyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, Pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,4-c]pyridinyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, furo[2,3-b]pyridinyl, benzo[c]isoxazolyl, furo[3,4-b]pyridinyl, furo[3,4-c]pyridinyl, benzo[ d]isothiazolyl, benzo[d]thiazolyl, thieno[3,2-b]pyridinyl, thieno[3,4-c]pyridinyl, benzo[d][1,2,3]triazolyl, pyrazolo[4,3-b]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, imidazo[4,5-c]pyridinyl, imidazo[4,5-b]pyridinyl , pyrrolo[3,2-c]pyridazinyl, pyrrolo[3,2-d]-pyrimidinyl, pyrrolo[2,3-b]pyrazinyl, pyrrolo[2,3-d]pyridazinyl, pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-c]pyridazinyl, pyrrolo[3,4-c]pyridazinyl, pyrrolo[3,4-d]pyrimidinyl, pyrrolo[3,4-b]pyrazinyl, pyrrolo[3,4-d]pyridazinyl, pyrrolo[3,4-d]pyrimidinyl, 6H-pyrrolo[3,4-c]pyridazinyl;Thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyrazinyl, thiazolo[5,4-d]pyrimidinyl, thiazolo[4,5-d]pyrimidinyl, imidazo[2,1-b][1,3,4]thiadiazolyl, imidazo[5,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[3,4-b][1,3,4]-thiadiazolyl, [1,2,4]triazolo[5,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-b][1,2,4]thiadiazolyl, imidazo[1,2-b][1,2,4]thiadiazolyl, thiazole imidazo[5,1-b][1,3,4]thiadiazol-5(6H)-onyl, or 5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-4-onyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 independently selected R; 12 substituted by a substituent; wherein, R 12 As defined in this disclosure; at least one R 4 Not for H.

[0262] In certain embodiments, R A2 is pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 12 substituted by a substituent; wherein, R 12 As defined in this disclosure; at least one R 4 Not for H.

[0263] In certain embodiments, R 3 for Among them, each R 4 and R 12 As defined in this disclosure; at least one R 4 Not for H.

[0264] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl group, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4substituted by a substituent; one of the R 4 –C(O)R B ; Among them, R 4 and R B As defined in this disclosure, respectively. In certain embodiments, R 3 is a linear or branched C1-C3 alkyl group, optionally substituted by 1, 2, 3, 4, 5, or 6 independently selected from R 4 substituted by a substituent; one of the R 4 –C(O)R B ; Among them, R 4 and R B Respectively as defined in this disclosure.

[0265] In certain embodiments, R 3 for Among them, each R 4 and R B As defined in this disclosure; wherein one R 4 –C(O)R B .

[0266] In some further embodiments, the present disclosure provides a compound represented by formula (XIIIa), (XIIIb), (XIIIc), (XIIId), or (XIIIe):

[0267]

[0268] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof; wherein each R 4 are independently selected from H, D, halogen, –CN, NO2, –N3, oxo, or C1-C4 alkyl, wherein one R 4 Not H; and every Cy, R 1 , R 2 , R B , and m are respectively as defined in the present disclosure.

[0269] In certain embodiments, one of the R 4 is D. In certain embodiments, one R 4 In certain embodiments, one of R 4 is -F, -Cl, -Br, or -I. In certain embodiments, one of R 4 In certain embodiments, wherein the two R 4 In certain embodiments, one R 4 In certain embodiments, one R4 In certain embodiments, one of the R 4 In certain embodiments, the two R 4 Together with the carbon atom to which it is attached, it forms an oxo group. In certain embodiments, one R 4 is C1-C4 alkyl. In certain embodiments, one of R 4 It is a methyl group.

[0270] In certain embodiments, R B C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl, each substituent optionally replaced by 1, 2, 3, 4, or 5 substituents independently selected from R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure. In certain embodiments, R B is C1-C6 alkyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure. In certain embodiments, R B is methyl, ethyl, or propyl, each substituent optionally replaced by 1, 2, 3, 4 or 5 independently selected R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure. In certain embodiments, R B is C2-C6 alkenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure. In certain embodiments, R B is C2-C6 alkynyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure. In certain embodiments, R B C3-C 10 The cycloalkyl group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure. In certain embodiments, R B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or spiro[3.3]heptyl, each ring optionally substituted by 1, 2, 3, 4, or 5 independently selected RB1 substituted by a substituent; wherein, R B1 As defined in this disclosure.

[0271] In certain embodiments, R B is a 4-10 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure. In certain embodiments, R B is a saturated 4-10 membered heterocyclic group or a partially unsaturated 4-10 membered heterocyclic group, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure.

[0272] In certain embodiments, R B are azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, dioxanyl, piperazinyl, morpholinyl, azepanyl, diazacyclooctanyl, 1,4-diazacycloheptyl, 4-oxa-7-azaspiro[2.5]octyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 1,8-diazaspiro[4.5]decyl, octadecyl, 1,4-diazaspiro[2.5]decyl, 1,4-diazaspiro[3.3]heptyl, 1,4-diazaspiro[3.4]octyl, 1,4-diazaspiro[3.5]nonyl, 1,4-diazaspiro[4 ...5]decyl, 1,4-diazaspiro[3.3 pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydropyrazino[2,1-c][1,4]oxazinyl, or 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazinyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure.

[0273] In certain embodiments, R B is tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazacycloheptyl, 4-oxa-7-azaspiro[2.5]octyl, 1,8-diazaspiro[4.5]decyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, octahydropyrrolo[1,2-a]pyrazinyl, hexahydropyrrolo[1,2-a]-pyrazinyl, 5,6,7,8-tetrahydro[1,2,4]-triazolo[4,3-a]pyrazinyl, or octahydropyrazino[2,1-c][1,4]oxazinyl, each ring optionally substituted by 1, 2, or 3 groups independently selected from (i) cyano, –OR a , or –NR c R d; or (ii) C1-C4 alkyl, optionally substituted with –OH; wherein R a , R c , and R d Respectively as defined in this disclosure.

[0274] In certain embodiments, R B is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,4-diazahept-1-yl, 4-oxa-7-azaspiro[2.5]octan-7-yl, 1,8-diazaspiro[4.5]dec-8-yl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, octahydropyrrolo[1,2-a]pyrazin-2-yl, hexahydropyrrolo[1,2-a]pyrazin-2-yl, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, or octahydropyrazino[2,1-c][1,4]oxazin-8-yl, each of which is optionally replaced by 1, 2, or 3 substituents independently selected from cyano, methyl, ethyl, 2-hydroxyethyl, hydroxy, methoxy, or dimethylamino.

[0275] In certain embodiments, R B 3-hydroxypyrrolidin-1-yl, 3-methoxy-pyrrolidin-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 4-cyanopiperidin-1-yl, 3-hydroxypiperidin-1-yl, 4-hydroxy-piperidin-1-yl, 4-methoxypiperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-methyl-1,4-diazepept-1-yl, 4-oxa-7-azaspiro [2.5]octan-7-yl, 1-ethyl-1,8-diazaspiro[4.5]dec-8-yl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, octahydropyrrolo[1,2-a]pyrazin-2-yl, 7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2-yl, 3-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, or octahydro-pyrazino[2,1-c][1,4]oxazin-8-yl.

[0276] In certain embodiments, R 3 is –CF2CH2COCH3, Among them, each R B1 As defined in this disclosure.

[0277] In certain embodiments, R B C6-C 10The aryl group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure. In certain embodiments, R B is phenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure. In certain embodiments, R B is a 5-10 membered heteroaryl group optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure. In certain embodiments, R B is pyrrolyl, furyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,3-triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure.

[0278] In certain embodiments, R B is arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl, each substituent optionally replaced by 1, 2, 3, 4, or 5 substituents independently selected from R B1 substituted by a substituent; wherein, R B1 As defined in this disclosure.

[0279] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl group, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 Substituents, one of which R 4 –C(O)NR C R D ; Among them, R 4 , R C , and R D As defined in this disclosure, respectively. In certain embodiments, R 3 is a linear or branched C1-C3 alkyl group, each substituent is optionally substituted by 1, 2, 3, 4, 5, or 6 substituents independently selected from R 4 Substituents, one of which R 4 –C(O)NR C R D ; Among them, R 4 , R C , and R DRespectively as defined in this disclosure.

[0280] In certain embodiments, R 3 for Among them, each R 4 , R C , and R D Respectively as defined in this disclosure.

[0281] In some further embodiments, the present disclosure provides a compound represented by Formula (XIVa), (XIVb), (XIVc), (XIVd), or (XIVe):

[0282]

[0283] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof; wherein each R 4 are independently selected from H, D, halogen, –CN, –NO2, –N3, oxo, or C1-C4 alkyl; one of R 4 Not H; every Cy, R 1 , R 2 , R C , R D , and m are as defined in this disclosure.

[0284] In certain embodiments, one of the R 4 is D. In certain embodiments, one R 4 In certain embodiments, one of R 4 is -F, -Cl, -Br, or -I. In certain embodiments, one of R 4 In certain embodiments, wherein the two R 4 In certain embodiments, one R 4 In certain embodiments, one R 4 In certain embodiments, one of the R 4 In certain embodiments, the two R 4 Together with the carbon atom to which it is attached, it forms an oxo group. In certain embodiments, one R 4 is C1-C4 alkyl. In certain embodiments, one of R 4 It is a methyl group.

[0285] In certain embodiments, R C is (i) H, D, or –CN; or (ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl, each substituent optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R C is H, D, C1-C6 alkyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NRc S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R C is H, D, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2CH2CH2CH3, –CH2CH(CH3)2, or –C(CH3)3.

[0286] In certain embodiments, R C is (i) H; or (ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ); where each R a , R b , Rc , R d , R e , and R f As defined in this disclosure, respectively. In certain embodiments, R C is (i) H; or (ii) C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, cycloalkylalkyl, or heteroarylalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cyano, halogen, C1-C4 alkyl, –OR a , or –NR c R d ; where each R a , R c , and R d As defined in this disclosure. In certain embodiments, R C is (i) H; or (ii) methyl, ethyl, propyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, pyrazolyl, cyclopropylmethyl, or pyridyl-methyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of cyano, fluoro, methyl, hydroxy, methoxy, or dimethylamino. In certain embodiments, R C R is H, methyl, ethyl, 2-cyanoethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-dimethylaminoethyl, isopropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-methoxy-2-methylpropyl, cyclopropyl, 4-hydroxy-cyclohexyl, tetrahydropyran-4-yl, 1-methylpyrazol-4-yl, (1-hydroxycyclopropyl)methyl, (1-methoxycyclopropyl)methyl, or pyridin-2-ylmethyl. In certain embodiments, R C is H, methyl, or ethyl.

[0287] In certain embodiments, R D are independently selected from (i) H, D, or -CN; or (ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl, each substituent optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d Respectively as defined in this disclosure.

[0288] In certain embodiments, R D is H. In certain embodiments, R D is D. In certain embodiments, R D C1-C6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R D is –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2CH2CH2CH3, –CH2CH(CH3)2, –C(CH3)3, –CH2CF3 , –CH2CH2OH, –CH2CH2OCH3, –CH(CH3)CH2OH, –CH(CH3)CH2OCH3, –CH2CH(CH3)OH, –CH2CH(CH3) OCH3, –CH2C(CH3)2OH, –CH2C(CH3)2OCH3, –CH2CH2NH2, –CH2CH2NH(CH3), –CH2CH2N(CH3)2, –C H2CH2CN, –CH2CH2N(CH3)C(O)CH3, –CH2CH2N(CH3)S(O)2CH3, or –CH2CH2N(CH3)S(O)2N(CH3)2.

[0289] In certain embodiments, R D C2-C6 alkenyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c Rd , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R D C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d Respectively as defined in this disclosure.

[0290] In certain embodiments, R D C3-C 10 The cycloalkyl group is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NRc R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R D is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d Respectively as defined in this disclosure.

[0291] In certain embodiments, R Dis a 4-10 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R D is azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, dioxanyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, diazaoctanyl, 1,4-diazacycloheptyl, 2,6-diazaspiro[3.3]heptyl, 6-diazaspiro[3.4]octyl, or 2,7-diazaspiro[3.5]nonyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2Rb ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d Respectively as defined in this disclosure.

[0292] In certain embodiments, R D C6-C 10 The aryl group is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R D is phenyl or naphthyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c Rd ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d Respectively as defined in this disclosure.

[0293] In certain embodiments, R D is a 5-10 membered heteroaryl group optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R Dis pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, or isobenzofuranyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d Respectively as defined in this disclosure.

[0294] In certain embodiments, R D C6-C 10 Aryl-C1-C6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2Rb ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R D is benzyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d Respectively as defined in this disclosure.

[0295] In certain embodiments, R D is a 5-10 membered heteroaryl-C1-C6 alkyl group optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R D is –CH2-pyrrolyl, –CH2-imidazolyl, –CH2-oxazolyl, –CH2-isoxazolyl, –CH2-thiazolyl, –CH2-tetrazolyl, –CH2-pyrazolyl, –CH2-1,2,4-triazolyl, –CH2-1,2,3-triazolyl, –CH2-thiadiazolyl, –CH2-oxadiazolyl, –CH2-pyridinyl, –CH2-pyrimidinyl, –CH2-pyrazinyl, –CH 2-pyridazinyl, –CH2-indolyl, or –CH2-isoindolyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c Rd , or –B(OR c )(OR d ); where each R a , R b , R c , and R d Respectively as defined in this disclosure.

[0296] In certain embodiments, R D C3-C 10 Cycloalkyl-C1-C6alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, oxo, C1-C4alkyl, C1-C4haloalkyl, C1-C4cyanoalkyl, C1-C4alkyl-O-C1-C4alkyl, C1-C4alkyl-O-C1-C4haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R D is –CH2-cyclopropyl, –CH2-cyclobutyl, –CH2-cyclopentyl, or –CH2-cyclohexyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following substituents: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NRc C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d Respectively as defined in this disclosure.

[0297] In certain embodiments, R D is a 4-10 membered heterocyclyl-C1-C6 alkyl group optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R Dis –CH2-azetidinyl, –CH2-oxetanyl, –CH2-tetrahydropyrrolyl, –CH2-tetrahydrofuranyl, –CH2-piperidinyl, –CH2-dioxanyl, –CH2-tetrahydropyranyl, –CH2-piperazinyl, –CH2-morpholinyl, –CH2-azepanyl, –CH2-diazacyclooctanyl, –CH2-1,4-diazacycloheptyl, or –CH2-azepanyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR c )(OR d ); where each R a , R b , R c , and R d Respectively as defined in this disclosure.

[0298] In certain embodiments, R D is (i) H; or (ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a ,–OC(O)NR cR d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c R d , or –B(OR e )(OR f ); where each R a , R b , R c , R d , R e , and R f As defined in this disclosure, respectively. In certain embodiments, R D is (i) H; or (ii) C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, cycloalkylalkyl, or heteroarylalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of cyano, halogen, C1-C4 alkyl, –OR a , or –NR c R d ; where each R a , R c , and R d As defined in this disclosure, respectively. In certain embodiments, R D is (i) H; or (ii) methyl, ethyl, propyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, pyrazolyl, cyclopropylmethyl, or pyridyl-methyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of cyano, fluoro, methyl, hydroxy, methoxy, or dimethylamino. In certain embodiments, R D is H, methyl, ethyl, 2-cyanoethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-dimethylaminoethyl, isopropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-methoxy-2-methylpropyl, cyclopropyl, 4-hydroxy-cyclohexyl, tetrahydropyran-4-yl, 1-methylpyrazol-4-yl, (1-hydroxycyclopropyl)methyl, (1-methoxycyclopropyl)methyl, or pyridin-2-ylmethyl.

[0299] In certain embodiments, R 3 For –CF2CH2CONHCH3, –CF2CH2CON(CH3)2,

[0300] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl group, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 -C(O)OR A ; Among them, R 4 and R A As defined in this disclosure, respectively. In certain embodiments, R 3 is a linear or branched C1-C3 alkyl group, optionally substituted by 1, 2, 3, 4, 5, or 6 independently selected from R 4 substituted by a substituent; one of the R 4 -C(O)OR A ; Among them, R 4 and R A As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 and R A As defined in this disclosure. In certain embodiments, R 3 for

[0301] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 –C(O)NR C S(O)R B ; Among them, R 4 , R B , and R C As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 , R B , and R C Respectively as defined in this disclosure.

[0302] In certain embodiments, R 3is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; wherein one R 4 –C(O)NR C S(O2)R B ; Among them, R 4 , R B , and R C As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 , R B , and R C As defined in this disclosure, respectively. In certain embodiments, R 3 for

[0303] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; wherein one R 4 for–OC(O)R B ; Among them, R 4 and R B As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 and R B Respectively as defined in this disclosure.

[0304] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; wherein one R 4 -OC(O)NR C R D ; Among them, R 4 , R C , and R D As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 , R C , and R D Respectively as defined in this disclosure.

[0305] In certain embodiments, R 3is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 ; One of the R 4 for –NR C R D ; Among them, R 4 , R C , and R D As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 , R C , and R D As defined in this disclosure, respectively. In certain embodiments, R 3 is –CF2CH2NH2, –CF2CH2NHCH3, –CF2CH2N(CH3)2, –CF2CH2NHCH2CH3, –CF2CH2N(CH2CH3)2, –CF2CH2CH2NH2, –CF2CH2CH2NHCH3, –CF2CH2CH2N(CH3)2, –CF2CH2CH2NHCH2CH3, or –CF2CH2CH2N(CH2CH3)2.

[0306] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 for –NR C C(O)R B ; Among them, R 4 , R B , and R C As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 , R B , and R C Respectively as defined in this disclosure.

[0307] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 for –NR C C(O)NR C R D ; where each R4 , R C , and R D As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 , R C , and R D Respectively as defined in this disclosure.

[0308] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 for –NR C C(O)OR A ; Among them, R 4 , R A , and R C As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 , R A , and R C Respectively as defined in this disclosure.

[0309] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 For –SR A ; Among them, R 4 and R A As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 and R A Respectively as defined in this disclosure.

[0310] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 -S(O)R B ; Among them, R 4 and R B As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 and R B As defined in this disclosure.

[0311] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 is –S(O)2R B ; Among them, R 4 and R B As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 and R B As defined in this disclosure.

[0312] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 –S(O)NR C R D ; Among them, R 4 , R C , and R D As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 , R C , and R D As defined in this disclosure.

[0313] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 for –NR C S(O)2R D ; Among them, R 4 , R C , and R D As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 , R C , and R DAs defined in this disclosure.

[0314] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, each substituent is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 –S(O)2NR C R D ; Among them, R 4 , R C , and R D As defined in this disclosure, respectively. In certain embodiments, R 3 for Among them, each R 4 , R C , and R D As defined in this disclosure.

[0315] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 for –NR C S(O)2NR C R D ; where each R 4 , R C , and R D As defined in this disclosure. In certain embodiments, R 3 for Among them, each R 4 , R C , and R D As defined in this disclosure.

[0316] In certain embodiments, R 3 is a linear or branched C1-C8 alkyl or C1-C3 alkyl, each substituent is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; one of the R 4 for –NR C S(O)(=NR B )R B ; where each R 4 , R B , and R C As defined in this disclosure. In certain embodiments, R 3 for Among them, each R4 , R B , and R C As defined in this disclosure.

[0317] In certain embodiments, R 3 is C2-C8 alkenyl optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; wherein, R 4 As defined in this disclosure. In certain embodiments, R 3 In certain embodiments, R 3 is C2-C8 alkynyl optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent; wherein, R 4 As defined in this disclosure.

[0318] In certain embodiments, R 3 C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, each substituent optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 13 substituted by a substituent; wherein, R 13 As defined in this disclosure.

[0319] In certain embodiments, R 3 C6-C 10 The aryl group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 13 substituted by a substituent; wherein, R 13 As defined in this disclosure. In certain embodiments, R 3 is phenyl or naphthyl, each ring is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 13 ; Among them, R 13 As defined in this disclosure. In certain embodiments, R 3 is phenyl optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 13 substituted by a substituent; wherein, R 13 As defined in this disclosure.

[0320] In certain embodiments, R 3 C3-C 10 The cycloalkyl group is optionally substituted by 1, 2, 3, 4, or 5 independently selected R 13 substituted by a substituent; wherein, R 13 As defined in this disclosure. In certain embodiments, R3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each ring optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 13 ; Among them, R 13 As defined in this disclosure.

[0321] In certain embodiments, R 3 is a 5-10 membered heteroaryl group optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R 13 substituted by a substituent; wherein, R 13 As defined in this disclosure. In certain embodiments, R 3 is pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each ring optionally substituted by 1, 2, 3, 4, or 5 independently selected R 13 substituted by a substituent; wherein, R 13 As defined in this disclosure.

[0322] In certain embodiments, R 3 is a 4-10 membered heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 members independently selected from R 13 substituted by a substituent; wherein, R 13 As defined in this disclosure. In certain embodiments, R 3 is azetidinyl, oxetanyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,4-diazacyclooctanyl, 1,4-diazacycloheptyl, azepanyl, or 2,6-diazaspiro[3.3]heptyl, each ring optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 13 substituted by a substituent; wherein, R 13 As defined in this disclosure.

[0323] In certain embodiments, R 13 is H. In certain embodiments, R 13 is D. In certain embodiments, R 13 In certain embodiments, R 13 is -F, -Cl, -Br, or -I. In certain embodiments, R 13 In certain embodiments, R 13 In certain embodiments, R 13 In certain embodiments, R 13 For oxygen.

[0324] In certain embodiments, R 13 In certain embodiments, R 13 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, or -C(CH3)3. In certain embodiments, R 13 In certain embodiments, R 13 In certain embodiments, R 13 is C1-C6 haloalkyl. In certain embodiments, R 13 is -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CH3, or -CF2CH2CH3. In certain embodiments, R 13 In certain embodiments, R 13 is –CH2CN, –CH2CH2CN, or –CH2CH2CH2CN.

[0325] In certain embodiments, R 13 For –SR A , where R A As defined in this disclosure. In certain embodiments, R 13 for –OR A , where R A As defined in this disclosure. In certain embodiments, R 13 is –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)2, –OCH2F, –OCHF2, –OCF3, –OCH2CH2F, –OCH2CHF2, or –OCH2CF3.

[0326] In certain embodiments, R 13 –C(O)R B , where R B As defined in this disclosure. In certain embodiments, R 13 –C(O)NR C R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 13 -C(O)OR A , where R A As defined in this disclosure. In certain embodiments, R 13 for–OC(O)R B , where RB As defined in this disclosure. In certain embodiments, R 13 -OC(O)NR C R D , where R C and R D Respectively as defined in this disclosure.

[0327] In certain embodiments, R 13 for –NR C R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 13 for –NR C C(O)R B , where R B and R C As defined in this disclosure, respectively. In certain embodiments, R 13 for –NR C C(O)NR C R D , where each R C and R D As defined in this disclosure. In certain embodiments, R 13 for –NR C C(O)OR A , where R A and R C As defined in this disclosure, respectively. In certain embodiments, R 13 =NR C )NR C R D , where each R C and R D As defined in this disclosure. In certain embodiments, R 13 for –NR D C(=NR C )NR C R D , where each R C and R D As defined in this disclosure. In certain embodiments, R 13 for –NR D C(=NR C )R B , where R B , R C , and R D Respectively as defined in this disclosure.

[0328] In certain embodiments, R 13For –SiR G R H R I , where R G , R H , and R I As defined in this disclosure, respectively. In certain embodiments, R 13 For –B(OR E )(OR F ), where R E and R F As defined in this disclosure, respectively. In certain embodiments, R 13 =S(O)(=NR B )R B , where each R B As defined in this disclosure. In certain embodiments, R 13 -S(O)R B , where R B As defined in this disclosure. In certain embodiments, R 13 –S(O)NR C R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 13 is –S(O)2R B , where R B As defined in this disclosure. In certain embodiments, R 13 for –NR C S(O)2R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 13 –S(O)2NR C R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 13 for –NR C S(O)2NR C R D , where R C and R D As defined in this disclosure, respectively. In certain embodiments, R 13 for –NR C S(O)(=NR B )R B , where R B and R C Respectively as defined in this disclosure.

[0329] In yet other embodiments, the present disclosure provides a compound represented by Formula (XVa), (XVb), (XVc), (XVd), or (XVe):

[0330]

[0331] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; wherein, Y 3 , R 1 , R 2 , and R 3 Respectively as defined in this disclosure.

[0332] In yet other embodiments, the present disclosure provides a compound represented by Formula (XVIa), (XVIb), (XVIc), (XVId), or (XVIe):

[0333]

[0334] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; wherein, Y 3 , R 1 , R 2 , and R 3 Respectively as defined in this disclosure.

[0335] In other embodiments, the present disclosure provides a compound represented by Formula (XVIIa), (XVIIb), (XVIIc), (XVIId), or (XVIIe):

[0336]

[0337] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; Y 3 , R 1 , R 2 , and R 3 Respectively as defined in this disclosure.

[0338] In certain embodiments, R A is H or D. In certain embodiments, R A C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10Aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –NO2, oxo, –OR a ,–SR a ,–SF5,–NHOR a ,–C(O)R b ,–C(O)NR c R d ,–C(O)OR a ,–OC(O)R b ,–OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–NR c C(O)NR c R d ,–NR c C(O)OR a ,–B(OR e )(OR f ), –C(=NR c )NR c R d ,–NR d C(=NR c )NR c R d ,–NR d C(=NR c )R b ,–P(O)R e R f ,–P(O)OR e OR f ,–OP(O)OR e OR f ,–S(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NRc R d , or –NR c S(O)(=NR b )R b , where R a , R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0339] In certain embodiments, R B is H or D. In certain embodiments, R B C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl, each substituent optionally replaced by 1, 2, 3, 4, or 5 substituents independently selected from R B1 wherein each R B1 independently selected from D, -CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, C0-C4 alkyl-C3-C 10 Cycloalkyl, C0-C4 alkyl-4-10 membered heterocyclic group, C0-C4 alkyl-C6-C 10 Aryl, C0-C4 alkyl-5-10 membered heteroaryl, –SF5, –C(O)R b ,–OC(O)NR c R d ,–OR a ,–NR c R d ,–NR c C(O)R b ,–NR c C(O)NR c R d ,–NR c C(O)OR a ,–S(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NRc S(O)2NR c R d , or –B(OR e )(OR f ); wherein the alkyl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, and alkyl-heteroaryl are optionally substituted with a substituent selected from the group consisting of D, –CN, halogen, oxo, –OH, –NH2, –SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –O-C1-C4 alkyl, –O-C1-C4 haloalkyl, –NH-C1-C4 alkyl, or –NH(C1-C4 alkyl)2; wherein R a , R b , R c , R d , R e , and R f Respectively as defined in this disclosure.

[0340] In certain embodiments, R C and R D are independently selected from H, D, or -CN. In certain embodiments, R C and R D are independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following substituents: D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OC(O)NR c R d ,–NR c R d ,–NR c C(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R b ,–S(O)2NR c R d ,–NR c S(O)2NR c Rd , or –B(OR e )(OR f ); where R a , R b , R c , R d , R e , and R f As defined in this disclosure, respectively. In certain embodiments, R C and R D The 4-7 membered heterocyclyl formed together with the nitrogen atom to which it is attached is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, oxo, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, or –OC1-C4 haloalkyl.

[0341] In certain embodiments, R a is H or D. In certain embodiments, R a is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following substituents: D, halogen, –OH, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, C1-C4 alkyl, –OC1-C4 alkyl, C1-C4 haloalkyl, or –OC1-C4 haloalkyl.

[0342] In certain embodiments, R a1 is H or D. In certain embodiments, R a1 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following substituents: D, halogen, –OH, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, C1-C4 alkyl, –OC1-C4 alkyl, C1-C4 haloalkyl, or –OC1-C4 haloalkyl.

[0343] In certain embodiments, R b is H or D. In certain embodiments, R b C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following substituents: D, -OH, -CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C 6- C 10 Aryl, C 3- C 10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl.

[0344] In certain embodiments, R b1 is H or D. In certain embodiments, R b1 C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following substituents: D, -OH, -CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C 6- C 10 Aryl, C 3- C 10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl.

[0345] In certain embodiments, R c and R d are independently selected from H or D. In certain embodiments, R c and R d are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C 6- C 10 Aryl, 5-10 membered heteroaryl, C 3- C 10cycloalkyl, 4-10 membered heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, arylcycloalkyl, arylheterocyclyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocyclyl, heteroarylaryl, or biheteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of D, –OH, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, –C(O)OR a1 ,–C(O)R b1 ,–S(O)2R b1 , C1-C4 alkyl-O-C1-C4 alkyl, or C1-C4 alkyl-O-C1-C4 alkoxy; wherein each R a1 and R b1 As defined in this disclosure. In certain embodiments, R c and R d The 4-7 membered heterocyclic group formed together with the nitrogen atom to which it is attached is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, -OH, -CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C4 alkoxy-C1-C4 alkyl, or C1-C4 alkoxy-C1-C4 alkoxy.

[0346] In certain embodiments, R E is H or D. In certain embodiments, R E C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy)-C1-C4 alkyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C4 alkyl, C3-C 10 Cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocyclyl-C1-C4 alkyl.

[0347] In certain embodiments, R F is H or D. In certain embodiments, RF C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, or 4-10 membered heterocyclic group.

[0348] In certain embodiments, R e C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy)-C1-C4 alkyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C4 alkyl, C3-C 10 Cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocyclyl-C1-C4 alkyl.

[0349] In certain embodiments, R f is H or D. In certain embodiments, R f C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, or 4-10 membered heterocyclic group.

[0350] In certain embodiments, R G , R H and R I are independently selected from C1-C4 alkyl or phenyl. G is C1-C4 alkyl or phenyl. G is C1 alkyl, C2 alkyl, C3 alkyl, or C4 alkyl. In certain embodiments, R G is methyl, ethyl, propyl, butyl, or phenyl. In certain embodiments, R G is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl. H is C1-C4 alkyl or phenyl. H is C1 alkyl, C2 alkyl, C3 alkyl, or C4 alkyl. In certain embodiments, R H is methyl, ethyl, propyl, butyl, or phenyl. In certain embodiments, R H is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl. Iis C1-C4 alkyl or phenyl. I is C1 alkyl, C2 alkyl, C3 alkyl, or C4 alkyl. In certain embodiments, R I is methyl, ethyl, propyl, butyl, or phenyl. In certain embodiments, R I is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl.

[0351] In certain embodiments, R g , R h and R i are independently selected from C1-C4 alkyl or phenyl. g is C1-C4 alkyl or phenyl. g is C1 alkyl, C2 alkyl, C3 alkyl, or C4 alkyl. In certain embodiments, R g is methyl, ethyl, propyl, butyl, or phenyl. In certain embodiments, R g is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl. h is C1-C4 alkyl or phenyl. h is C1 alkyl, C2 alkyl, C3 alkyl, or C4 alkyl. In certain embodiments, R h is methyl, ethyl, propyl, butyl, or phenyl. In certain embodiments, R h is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl. i is C1-C4 alkyl or phenyl. i is C1 alkyl, C2 alkyl, C3 alkyl, or C4 alkyl. In certain embodiments, R i is methyl, ethyl, propyl, butyl, or phenyl. In certain embodiments, R i is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or phenyl.

[0352] In some embodiments, the present disclosure provides a compound as follows:

[0353]

[0354]

[0355]

[0356]

[0357]

[0358] or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof.

[0359] The compounds described in the present disclosure may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of the present disclosure. The compounds described in the present disclosure containing asymmetrically substituted carbon atoms may be separated as optical isomers or racemates. Many geometric isomers of olefins, C=N double bonds, etc. may also be present in the compounds described in the present disclosure, and all stable isomers are also within the scope of the present disclosure. The cis and trans geometric isomers of the compounds described in the present disclosure are also within the scope of the present disclosure and can be separated into mixtures of isomers or separated isomeric forms. In addition, atropisomers and mixtures thereof, such as restricted rotation resulting from the binding of two aromatic or heteroaromatic rings to each other, are also included within the scope of the present disclosure.

[0360] The compounds of the present invention also include tautomers. Tautomers are produced by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomers include proton transfer tautomers, which have the same chemical formula and total charge. Exemplary proton transfer tautomers include keto-enol tautomerism, amide-imidic acid tautomerism, lactam-lactide tautomerism, amide-imidic acid tautomerism, and enamine-imine tautomerism. Protons in the ring structure can be interconverted at two or more positions in the heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole; certain hydroxyl-substituted compounds can exist as tautomers, as shown below: Tautomers may be in equilibrium or may be formed by appropriate substitution to stabilize the steric structure.

[0361] In certain embodiments, the compounds of the present invention may exist as rotational isomers. Descriptions of the compounds of the present invention are intended to encompass any individual rotational isomer, as well as mixtures of rotational isomers in any proportion, and are not intended to represent a specific rotational isomer. Descriptions of a specific rotational isomer are intended to encompass the described rotational isomer, substantially free of other rotational isomers.

[0362] The present invention further includes isotope-labeled compounds or intermediates of the present invention. "Isotope" refers to atoms with the same atomic number but different molecular weights. For example, isotopes of hydrogen include protium and deuterium.

[0363] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. Exemplary pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues (such as amines); alkali or organic salts of acidic residues (such as carboxylic acids). Pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418, and Pharm. Sci. 1977, 66, 2, each of which is incorporated herein by reference in its entirety.

[0364] Pharmaceutical composition

[0365] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: a compound as shown in formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; and a pharmaceutically acceptable excipient.

[0366] The pharmaceutical composition can be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), can be used as an injectable (e.g., aqueous or oily suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, glucose or sterile aqueous solutions, and similar pharmaceutical carriers), can be used topically (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), can be used by inhalation (e.g., fine powders or liquid aerosols), can be administered by insufflation (e.g., fine powders), or can be administered parenterally (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as suppositories for rectal administration).

[0367] Pharmaceutically acceptable excipients can be excipients such as carriers (e.g., solid, liquid, or semisolid carriers), adjuvants, diluents, fillers or extenders, granulating agents, coating agents, release controlling agents, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavoring agents, sweeteners, taste masking agents, or stabilizers.

[0368] Pharmaceutically acceptable carriers can be, for example, solid, liquid, or gaseous. Exemplary solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Exemplary liquid carriers include syrup, peanut oil, olive oil, and water. Exemplary gaseous carriers include carbon dioxide and nitrogen. When preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, glycols, oils, alcohols, flavorings, preservatives, and colorants can be used to form oral liquid preparations, such as suspensions, elixirs, and solutions; for example, starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrant carriers can be used to form oral solid preparations, such as powders, capsules, and tablets.

[0369] Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs, suspensions, sublingual tablets, wafers, or patches, such as buccal patches.

[0370] Thus, tablet compositions may contain a unit dose of active compound and an inert diluent or carrier, such as a sugar or sugar alcohol, for example, lactose, sucrose, sorbitol, or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, and hydroxypropylmethylcellulose, and starch, such as corn starch. Tablets may also contain standard ingredients such as binders and granulating agents, such as polyvinylpyrrolidone, disintegrants (e.g., swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents, such as citrate / bicarbonate mixtures.

[0371] The pharmaceutical compositions suitable for parenteral administration of the present invention can be prepared as solutions or suspensions of the active compound in water. Suitable surfactants can include, for example, hydroxypropyl cellulose. Dispersions can also be prepared in oil using glycerol, liquid polyethylene glycol, and mixtures thereof. In addition, preservatives can be included to prevent the harmful growth of microorganisms.

[0372] The present disclosure is suitable for the pharmaceutical composition of injection including sterile aqueous solution or dispersion. In addition, the composition can be in the form of sterile powder for the temporary preparation of such sterile injection solution or dispersion. In all cases, the final injection form must be sterile and must be an effective fluid for injection. The pharmaceutical composition must be stable under manufacturing and storage conditions; therefore, the contamination effect of microorganisms (such as bacteria and fungi) should be prevented. The carrier can be a solvent or dispersion medium (such as glycerol, ethylene glycol and liquid polyethylene glycol) containing, for example, water, ethanol, polyol, vegetable oil, and a suitable mixture thereof.

[0373] The pharmaceutical compositions of the present disclosure may be in a form suitable for topical use, for example, an aerosol, cream, ointment, lotion, or dusting powder. Additionally, the compositions may be in a form suitable for use in a transdermal device.

[0374] In addition to the above-mentioned carrier components, the pharmaceutical preparations described in the present disclosure may optionally include one or more additional carrier components such as diluents, buffers, flavorings, adhesives, surfactants, thickeners, lubricants, and preservatives (including antioxidants). In addition, other adjuvants may be included to make the preparation isotonic with the blood of the intended recipient.

[0375] How to use

[0376] In some embodiments, the present disclosure provides a method for treating or inhibiting cancer, comprising administering to a subject a therapeutically effective amount of a compound as shown in Formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; or a pharmaceutical composition described herein.

[0377] In certain embodiments, the cancer is characterized by overexpression of PolQ. In certain embodiments, the cancer is characterized by increased reliance on MMEJ-DSB repair. In certain embodiments, the cancer is characterized by HR-deficiency. In certain embodiments, the cancer is characterized by reduced or absent expression of HR-related genes. In certain embodiments, the cancer lacks the 53BP1 / Shieldin complex. In certain embodiments, the cancer is resistant to PARPi treatment. In certain embodiments, the cancer is characterized by NHEJ deficiency. In certain embodiments, the cancer is characterized by reduced or absent expression of NHEJ-related genes.

[0378] In other embodiments, the present disclosure provides a method for treating or preventing a disease in a subject characterized by PolQ overexpression, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; or a pharmaceutical composition described herein.

[0379] The term "PolQ overexpression" refers to increased expression or activity of the PolQ enzyme in a diseased cell, e.g., a cancer cell, relative to the expression or activity of the PolQ enzyme in a control cell (e.g., a non-diseased cell of the same type). In certain embodiments, PolQ overexpression is at least 2-fold, at least 3-fold, at least 4-fold, at least 6-fold, at least 10-fold, at least 20-fold, or at least 50-fold relative to the PolQ expression in the control cell. Exemplary PolQ overexpressing cancers include, but are not limited to, ovarian cancer, breast cancer, cervical cancer, uterine cancer, pancreatic cancer, lung cancer, colorectal cancer, gastric cancer, bladder cancer, and prostate cancer.

[0380] In yet other embodiments, the present disclosure provides a method for treating or preventing a disease in a subject characterized by increased reliance on MMEJ-DSB repair, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof; or a pharmaceutical composition described herein.

[0381] In yet other embodiments, the present disclosure provides a method for treating or preventing a disease in a subject characterized by HR-deficiency, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof; or a pharmaceutical composition described herein.

[0382] In certain embodiments, the HR-related gene is ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, CtIP (BCL11A), ERCC4 (FANCQ), FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (PALB2), FANCP (SLX4), LIG1, MRE11, NBS1, NBN, PTEN, RAD50, RAD51B, RAD51C, RAD54, RECQL4, RPA1, RPA2, SMARCA2, SMARCA4, WRN, or XRCC2.

[0383] In yet other embodiments, the present disclosure provides a method for treating or preventing a disease in a subject in which the 53BP1 / Shieldin complex is deficient, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof; or a pharmaceutical composition described herein.

[0384] In yet other embodiments, the present disclosure provides a method for treating or preventing a disease in a subject that is resistant to PARPi treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; or a pharmaceutical composition described herein.

[0385] In other embodiments, the present disclosure provides a method for treating or preventing a disease in a subject, wherein the disease is characterized by NHEJ deficiency, or reduced or absent expression of an NHEJ-related gene, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; or a pharmaceutical composition described herein.

[0386] In certain embodiments, the NHEJ-related gene is 53BP1, DCLRE1C, LIG4, NHEJ1, POLL, POLM, PRKDC, RIF1, SHLD1, SHLD2, SHLD3, XRCC4, XRCC5, or XRCC6.

[0387] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0388] In certain embodiments, the therapeutically effective amount of the compounds of the present disclosure is about 0.1 to about 100 mg / kg / day, about 0.1 to about 50 mg / kg / day, about 0.1 to about 25 mg / kg / day, about 0.1 to about 20 mg / kg / day, about 0.1 to about 15 mg / kg / day, about 0.1 to about 10 mg / kg / day, or about 0.1 to about 5 mg / kg / day. In some embodiments, the therapeutically effective amount of the compounds of the present disclosure is about 0.1 to about 100 mg / kg / day. In other embodiments, the therapeutically effective amount of the compounds of the present disclosure is about 0.1 to about 50 mg / kg / day. In yet other embodiments, the therapeutically effective amount of the compounds of the present disclosure is about 0.1 to about 25 mg / kg / day. In yet other embodiments, the therapeutically effective amount of the compounds of the present disclosure is about 0.1 to about 20 mg / kg / day. In yet other embodiments, the therapeutically effective amount of the compounds of the present disclosure is about 0.1 to about 15 mg / kg / day. In yet other embodiments, the therapeutically effective amount of a compound of the present disclosure is about 0.1 to about 10 mg / kg / day. In other embodiments, the therapeutically effective amount of a compound of the present disclosure is about 0.1 to about 5 mg / kg / day.

[0389] It should be understood that the dosage may be expressed in units other than mg / kg / day. For example, a parenteral dosage may be expressed as mg / kg / day. 2 / day. A person of ordinary skill in the art can easily convert the dosage from mg / kg / day to mg / m based on the height or weight or both of a given subject. 2 / day. For example, for a person weighing 65 kg, 1 mg / m 2 The dose per day is approximately equivalent to 58 mg / kg / day.

[0390] Depending on the condition, disease or condition to be treated and the condition of the subject, the compounds provided herein can be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, CIV, intracisternal injection or infusion, subcutaneous injection or implantation), inhaled, nasal, vaginal, rectal, sublingual or topical (e.g., transdermal or topical) routes of administration. The compounds provided herein can be formulated into appropriate dosage units together with pharmaceutically acceptable excipients, carriers, adjuvants or vehicles suitable for each route of administration.

[0391] In some embodiments, the compounds provided herein are administered orally. In other embodiments, the compounds provided herein are administered parenterally. In yet other embodiments, the compounds provided herein are administered intravenously. In yet other embodiments, the compounds provided herein are administered intramuscularly. In yet other embodiments, the compounds provided herein are administered subcutaneously. In yet other embodiments, the compounds provided herein are administered topically.

[0392] The compounds provided herein can be delivered as a single dose, such as a single bolus, or as an oral tablet or pill; or delivered over time, such as by continuous infusion over time or by divided bolus doses over time. Where necessary, the compounds provided herein can be administered repeatedly, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.

[0393] The compounds provided herein can be administered once a day (QD) or divided into multiple daily doses, such as twice a day (BID) and three times a day (TID). In addition, it can be continuous administration, i.e., daily administration, or intermittent administration. The terms "intermittent" or "intermittently" used in the present disclosure mean stopping and starting administration at regular or irregular intervals. For example, the compounds of the present disclosure are administered intermittently, referring to administration for one to six days per week, cyclical administration (e.g., daily administration for two to eight consecutive weeks, followed by a rest period of time, up to one week without administration), or administration every other day.

[0394] The compounds provided herein can also be used in combination or in combination with other therapeutic agents to treat and / or prevent the diseases described herein.

[0395] synthesis

[0396] The compounds of the present invention, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, such as those described below.

[0397] The described reaction of preparing the compound of the present invention can be carried out in a suitable solvent, and the described solvent can be easily selected by the technical staff of the described organic synthesis field. Suitable solvent can not react substantially with starting material (reactant), intermediate or product at the temperature of carrying out the described reaction, for example, and temperature range can be from the freezing temperature of solvent to the boiling temperature of solvent. Given reaction can be carried out in a kind of solvent or the mixture of more than a kind of solvent. According to above-mentioned specific reaction step, those skilled in the art can select the solvent that is applicable to specific reaction step.

[0398] The preparation of the compounds of the present invention may involve the above-mentioned protection and deprotection of various chemical groups. The need for the above-mentioned protection and deprotection, as well as the selection of the suitable protecting group, can be easily determined by those skilled in the art. Disclosed chemical protecting groups are as follows, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith el ah, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th Ed. (Wiley, 2019); Peturssion et al,"Protecting Groups in Carbohydrate Chemistry" J Chem. Educ., 1997, 74 (11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 5th Ed., (Wiley, 2014).

[0399] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0400] As used herein, the terms "ambient temperature," "room temperature," and "rt" generally refer to temperatures in the art, such as reaction temperature, which refers to the temperature of the space in which the reaction is performed, for example, a temperature of about 20°C to about 30°C.

[0401] The compounds of the present invention can be prepared according to various preparation routes known in the literature. The following schemes provide general guidance for preparing the compounds of the present invention. It will be appreciated by those skilled in the art that the preparation methods described in the following schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention. Exemplary synthetic methods for preparing the compounds of the present invention are shown in the following schemes.

[0402] The following examples are provided to illustrate some of the above concepts described in this summary. While the examples are considered to provide embodiments, they should not be considered to limit the more general embodiments described herein.

[0403] Abbreviations

[0404]

[0405]

[0406] Synthesis scheme

[0407] A series of heterocyclic amide derivatives represented by formula (I) can be prepared by the method shown in Scheme 1. Heterocyclic amide derivatives (I) can be prepared by reacting carboxylic acid 1-1 with a suitable 1,3,4-thiadiazole-2-amine derivative 1-2 under standard amide coupling conditions (for example, in the presence of an activating reagent such as BOP, PyBOP, HATU, HBTU, EDCI, or T3P, and a base such as Hunig's base, Et3N, pyridine or MAP). Alternatively, carboxylic acid 1-1 can be reacted with a chlorinating agent such as oxalyl chloride, thionyl chloride, POCl3 or TCFH to obtain the corresponding acid chloride 1-3, which is then reacted with a suitable amine 1-2 to obtain the corresponding heterocyclic amide derivative (I).

[0408] Solution 1

[0409]

[0410] In addition, a series of heterocyclic amide derivatives represented by formula (I) can be prepared by the method shown in Scheme 2. Amide derivatives 2-3 can be prepared by reacting carboxylic acid 2-1 with a suitable 1,3,4-thiadiazole-2-amine derivative 2-2 in a similar manner to Scheme 1. Amide derivatives 2-3 wherein W is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) are coupled with compounds 2-5 wherein V is boronic acid, boronic ester, trimethyltin or tributyltin under standard Suzuki coupling conditions or Stille coupling conditions (e.g., in the presence of a palladium catalyst such as Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, Pd(PPh3)4, and a base such as t-BuOK, t-BuONa, Cs2CO3, K2CO3, or Na2CO3) to afford heterocyclic amide derivatives (I).

[0411] Or amide derivative 2-3 wherein W is boronic acid, boronic ester, trimethyltin or tributyltin, is coupled with compound 2-5 wherein V is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) under standard Suzuki coupling conditions or Stille coupling conditions (e.g., in the presence of a palladium catalyst such as Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, Pd(PPh3)4, and a base such as t-BuOK, t-BuONa, Cs2CO3, K2CO3, or Na2CO3) to give a heterocyclic amide derivative (I).

[0412] Option 2

[0413]

[0414] A series of heterocyclic carboxylic acid intermediates of formula 3-5 can be prepared by the method shown in Scheme 3. Compound 3-1 and compound 3-3 are subjected to CC coupling according to the Suzuki coupling or Stille coupling conditions described in Scheme 2 to provide ester compound 3-4. Compound 3-4 is subjected to saponification in the presence of a base such as LiOH, NaOH, KOH, or Me3SnOH to provide the corresponding acid 3-5. Alternatively, as shown in Scheme 3, carboxylic acid 3-2 and compound 3-3 are subjected to Suzuki coupling under standard Suzuki coupling conditions or Stille coupling conditions to directly provide the corresponding acid 3-5.

[0415] Option 3

[0416]

[0417] A series of 1,3,4-thiadiazole-2-amine derivatives of formula 4-3 can be prepared by the method shown in Scheme 4. Carboxylic acid 4-1 or cyanide 4-2 is reacted with thiosemicarbazide in the presence of a dehydrating agent such as POCl3, TFA, PCl5, P2O5 or PPA to give 1,3,4-thiadiazole-2-amine derivative 4-3.

[0418] Option 4

[0419]

[0420] A series of 1,3,4-thiadiazole-2-amine derivatives represented by formula 5-4 can be prepared by the method shown in Scheme 5. Difluoromalonate monoethyl ester 5-2 and semicarbazide in the presence of a dehydrating agent such as POCl3, TFA, PCl5, P2O5 or PPA can give 1,3,4-thiadiazole-2-amine derivative 5-4. Alternatively, compound 5-5 or malonyl chloride monoethyl ester 5-6 can be condensed with semicarbazide to give 1,3,4-thiadiazole-2-amine derivative 5-7, which can be reacted with a fluorinating agent such as N-fluorobenzenesulfonimide (NFSI). It can be further converted into 1,3,4-thiadiazole-2-amine derivative 5-4 by reaction with N-fluoropyridinium salt (NFPY).

[0421] Alternatively, aminothiadiazole 5-8 can be directly prepared from 1,3,4-thiadiazole-2-amine derivative 5-4 by reacting 2-bromo-2,2-difluoroacetate compound 5-9 and H2O2 in the presence of a catalyst such as Cp2Fe.

[0422] Option 5

[0423]

[0424] A series of 5-(difluoromethyl)-1,3,4-thiadiazole-2-amine derivatives shown in formula 6-6 can be prepared by the method shown in Scheme 6. 2,2-difluoro-2-(trimethylsilyl)acetic acid ethyl ester 6-1 and XR AA wherein X is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs), R AA is C0-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl or R 4 (wherein, C0-C7 alkyl, C2-C7 alkenyl, or C2-C7 alkynyl is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 4 Substituents are substituted with (substituted with) a C-C coupling reaction in the presence of a suitable reagent such as KF or TBAF can produce compound 6-2. Saponification of compound 6-2 in the presence of a base such as LiOH, NaOH, KOH, or Me3SnOH can yield the corresponding acid 6-3. Cyclization of acid 6-3 with thiosemicarbazide according to the conditions described in Scheme 4 can yield the corresponding 5-(difluoromethyl)-1,3,4-thiadiazol-2-amine derivative 6-6.

[0425] Alternatively, 5-amino-1,3,4-thiadiazol-2-one derivative 6-5 can be prepared in the presence of an electrophilic fluorination reagent such as DAST, BAST or XeF2 to give 5-(difluoromethyl)-1,3,4-thiadiazol-2-amine derivative 6-6. 5-amino-1,3,4-thiadiazol-2-one derivative 6-5 can be prepared by reacting amide compound 6-4 with an organometallic reagent such as R AA MgBr was prepared under standard Weinreb ketone synthesis conditions.

[0426] Option 6

[0427]

[0428] A series of 5-(difluoromethyl)-1,3,4-thiadiazole-2-amine derivatives of formula 7-4 can be prepared by the method shown in Scheme 7. 2-Bromo-2,2-difluoroacetic acid ethyl ester 7-1 and HO-R A2 A CO coupling reaction in the presence of a base such as Na2CO3, K2CO3, NaH, or t-BuOK can provide compound 7-2. Saponification of compound 7-2 in the presence of a base such as LiOH, NaOH, KOH, or Me3SnOH can provide the corresponding acid 7-3. Cyclization of acid 7-3 with thiosemicarbazide according to the conditions described in Scheme 4 can provide the corresponding 5-(difluoromethyl)-1,3,4-thiadiazol-2-amine derivative 7-4.

[0429] Option 7

[0430] Example

[0431] Example 1: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((((S)-tetrahydrofuran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0432]

[0433] Step 1: (S)-2-((tetrahydrofuran-3-yl)oxy)acetic acid

[0434]

[0435] To a solution of (S)-3-hydroxytetrahydrofuran (0.88 g, 10 mmol) and Na2CO3 (1.60 g, 15 mmol) in DMF (10 mL) was added ICH2COONa (3.16 g, 15 mmol) and stirred at rt overnight. The reaction mixture was diluted with water (20 mL), the pH was adjusted to 1 with HCl solution (2 M), and extracted with EtOAc (20 mL). The aqueous phase was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (0-15%) to give the title compound (156 mg) as a yellow solid. LCMS calculated for C6H9O4 [MH] - : m / z = 145.1; found: 145.0.

[0436] Step 2: (S)-5-(((tetrahydrofuran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine

[0437]

[0438] To a cooled mixture (ice-water bath) of thiosemicarbazide (109 mg, 1.2 mmol) and (S)-2-((tetrahydrofuran-3-yl)oxy)acetic acid (146 mg, 1.0 mmol) was added POCl3 (4 mL) dropwise. The mixture was stirred at 75°C for 3 h., cooled and poured into ice water (10 mL). The aqueous phase was adjusted to pH 12 with solid Na2CO3 and then purified by prep-HPLC on a C18 column eluting with MeCN / H2O (0-10%) to afford the title compound (60 mg) as a yellow solid. LCMS calculated for C7H 12 N3O2S[M+H] + : m / z = 202.1; found: 202.0.

[0439] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((((S)-tetrahydrofuran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0440] To a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (59 mg, 0.2 mmol, Int-1), TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL) was added (S)-5-(((tetrahydrofuran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine (30 mg, 0.15 mmol). The mixture was stirred at rt for 5 h. and then concentrated under reduced pressure. The residue was purified by prep-HPLC eluting with MeCN / H2O (10-50%) to give the title compound (28 mg, 29% yield) as a white solid. LCMS calculated for C 21 H 21 ClFN4O4S[M+H] + : m / z = 479.1; found: 479.0.

[0441] Example 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((((R)-tetrahydrofuran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0442]

[0443] This compound was prepared in a similar manner to steps 1 to 3 of Example 1, except that (S)-3-hydroxytetrahydrofuran was substituted with (R)-3-hydroxytetrahydrofuran in step 1. LCMS calculated value: C 21 H 21 ClFN4O4S[M+H] + : m / z = 479.1; found: 479.0.

[0444] Example 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0445]

[0446] Step 1: 5-(((Tetrahydro-2H-pyran-4-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine

[0447]

[0448] This compound was prepared in a similar manner to steps 1-2 of Example 1, except that tetrahydro-4-pyranol was used in place of (S)-3-hydroxytetrahydrofuran in step 1. LCMS calculated value: C8H 14 N3O2S[M+H] +: m / z = 216.1; found: 216.1.

[0449] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0450] This compound was prepared in a similar manner to step 3 of Example 1 using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value: C 22 H 23 ClFN4O4S[M+H] + : m / z = 493.1; found: 493.0.

[0451] Example 4: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(((-4-oxoadamantan-1-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0452]

[0453] Step 1: 5-((5-amino-1,3,4-thiadiazol-2-yl)methoxy)adamantan-2-one

[0454]

[0455] This compound was prepared in a similar manner to steps 1-2 of Example 1, except that 5-hydroxyadamantan-2-one was used instead of (S)-3-hydroxytetrahydrofuran in step 1. LCMS calculated value: C 13 H 18 N3O2S[M+H] + : m / z = 280.1; found: 280.1.

[0456] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(((-4-oxoadamantan-1-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0457] This compound was prepared in a similar manner to step 3 of Example 1 using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-((5-amino-1,3,4-thiadiazol-2-yl)methoxy)adamantan-2-one as starting materials. LCMS calculated value: C 27 H 27ClFN4O4S[M+H] + : m / z = 557.1; found: 557.1.

[0458] Example 5: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(((-4-hydroxyadamantan-1-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0459]

[0460] To a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(((-4-oxoadamantan-1-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide (15 mg, 0.027 mmol, Example 4) in MeOH (2 mL) was added NaBH4 (2 mg, 0.057 mmol). The mixture was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC using MeCN / H2O (10-50%) as the eluent to afford the title compound (8 mg, 50% yield) as a white solid. LCMS calculated value: C 27 H 29 ClFN4O4S[M+H] + : m / z = 559.1; found: 559.0.

[0461] Example 6: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0462]

[0463] Step 1: 5-(((Tetrahydro-2H-pyran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine

[0464]

[0465] This compound was prepared in a similar manner to steps 1-2 of Example 1, except that (S)-3-hydroxytetrahydrofuran was replaced with tetrahydropyran-3-ol in step 1. LCMS calculated value: C8H 14 N3O2S[M+H] + : m / z = 216.1; found: 216.1.

[0466] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0467] This compound was prepared in a similar manner to that in Step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine (Step 1 of Example 6) as starting materials. LCMS calculated value: C 22 H 23 ClFN4O4S[M+H] + : m / z = 493.1; found: 493.0.

[0468] Example 7: 4-(2-Fluoro-6-methoxyphenyl)-6-methyl-N-(5-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0469]

[0470] This compound was prepared in a similar manner to that in Step 3 of Example 1 using 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-2) and 5-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine (Step 1 of Example 6) as starting materials. LCMS calculated value: C 22 H 24 FN4O4S[M+H] + : m / z = 459.1; found: 459.1.

[0471] Example 8: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((cyclohex-3-en-1-yloxy)methyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0472]

[0473] Step 1: 2-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)acetic acid

[0474]

[0475] To a solution of 4-((tert-butyldimethylsilyl)oxy)cyclohexanol (1.44 g, 5 mmol) and Na2CO3 (1.6 g, 15.0 mmol) in DMF (10 mL) was added ICH2COONa (2.1 g, 10 mmol). The reaction mixture was stirred at rt overnight and then quenched with water (20 mL). The mixture was adjusted to pH 1-2 with HCl solution (2 M) and then extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (20-50%) to give the title compound (0.63 g) as a yellow oil. LCMS calculated value: C 14 H 27 O4Si[MH] - : m / z = 287.2; found: 287.2.

[0476] Step 2: 5-((cyclohex-3-en-1-yloxy)methyl)-1,3,4-thiadiazol-2-amine

[0477]

[0478] To a cooled mixture of thiosemicarbazide (109 mg, 1.2 mmol) and 2-((4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)acetic acid (300 mg, 1.1 mmol) (ice-water bath) was added POCl3 (4 mL) dropwise. The mixture was stirred at 75°C for 3 h, cooled to rt, and then poured into ice water (10 mL). The aqueous phase was adjusted to pH 12. The product was then purified by prep-HPLC on a C18 column eluting with MeCN / H2O (0-10%) to afford the title compound (43 mg) as a yellow oil. LCMS calculated for C9H 14 N3OS[M+H] + : m / z = 212.1; found: 212.0.

[0479] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((cyclohex-3-en-1-yloxy)methyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0480] This compound was prepared in a similar manner to step 3 of Example 1 using 2-fluoro-6-methoxyphenylboronic acid (Int-1) and 5-((cyclohex-3-en-1-yloxy)methyl)-1,3,4-thiadiazole-2-amine as starting materials. LCMS calculated value: C 23 H 23 ClFN4O3S[M+H] +: m / z = 489.1; found: 489.1.

[0481] Example 9: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((((S)-1-methylphenylsulfonylpyrrolidin-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0482]

[0483] Step 1: (S)-5-(((1-methylphenylsulfonylpyrrolidin-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine

[0484]

[0485] This compound was prepared in a similar manner to steps 1-2 of Example 1, except that (S)-1-methylbenzenesulfonylpyrrolidin-3-ol was used instead of (S)-3-hydroxytetrahydrofuran in step 1. LCMS calculated value: C 14 H 19 N4O3S[M+H] + : m / z = 355.1; found: 355.0.

[0486] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((((S)-1-methylphenylsulfonylpyrrolidin-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0487] This compound was prepared in a similar manner to step 3 of Example 1 using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and (S)-5-(((1-methylbenzenesulfonylpyrrolidin-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value: C 28 H 28 ClFN5O5S2[M+H] + : m / z = 632.1; found: 632.1.

[0488] Example 10: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-(fluoromethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0489]

[0490] Step 1: 2-(5-(Hydroxymethyl)-1,3,4-thiadiazol-2-yl)isoindoline-1,3-dione

[0491]

[0492] A mixture of (5-amino-1,3,4-thiadiazol-2-yl)methanol (2.62 g, 20 mmol) and phthalic anhydride (3.0 g, 20.2 mol) in anhydrous 1,4-dioxane (80 mL) was heated to 100°C and stirred for 24 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using EtOAc / PE (50-100%) as the eluent to give the title compound (2.3 g) as a white solid. LCMS calculated value: C 11 H8N3O3S[M+H] + : m / z = 262.0; found: 262.0.

[0493] Step 2: 2-(5-(Fluoromethyl)-1,3,4-thiadiazol-2-yl)isoindoline-1,3-dione

[0494]

[0495] To a solution of 2-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)isoindoline-1,3-dione (524 mg, 2.0 mmol) in anhydrous DCM (5 mL) was added DAST (480 mg, 3.0 mmol) at -20°C under N2 atmosphere. The mixture was stirred at 0°C for 5 h. The mixture was diluted with EtOAc (50 mL), washed with saturated Na2CO3 solution and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc / PE (30-50%) to give the title compound (230 mg) as a yellow oil. LCMS calculated value: C 11 H7FN3O2S[M+H] + : m / z = 264.0; found: 264.0.

[0496] Step 3: 5-(Fluoromethyl)-1,3,4-thiadiazol-2-amine

[0497]

[0498] A mixture of 2-(5-(fluoromethyl)-1,3,4-thiadiazol-2-yl)isoindoline-1,3-dione (230 mg, 0.8 mmol) and hydrazine hydrate solution (0.2 mL, 80% purity) in ethanol (5 mL) was heated to 80°C and stirred for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC using MeCN / H2O (5-15%) as the eluent to give the title compound (45 mg) as a colorless oil. LCMS calculated for C3H5FN3S [M+H] +: m / z = 134.0; found: 134.0.

[0499] Step 4: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-(fluoromethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0500] To a solution of 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-2) (53 mg, 0.2 mmol), TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL) was added 5-(fluoromethyl)-1,3,4-thiadiazol-2-amine (27 mg, 0.2 mmol). The mixture was stirred at rt for 5 h. and then concentrated under reduced pressure. The residue was purified by prep-HPLC eluting with MeCN / H2O (15-45%) to give the title compound (10 mg) as a white solid. LCMS calculated value C 17 H 15 F2N4O2S[M+H] + : m / z = 377.1; found: 377.0.

[0501] Example 11: 4-(2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0502]

[0503] This compound was prepared in a similar manner to step 4 of Example 10 using 5-(difluoromethyl)-1,3,4-thiadiazol-2-amine and 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-2) as starting materials. LCMS calculated value: C 17 H 14 F3N4O2S[M+H] + : m / z = 395.1; found: 395.0.

[0504] Example 12: 4-(2-Fluoro-6-methoxyphenyl)-6-methyl-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0505]

[0506] This compound was prepared in a similar manner to step 4 of Example 10 using 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine and 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-2) as starting materials. LCMS calculated value: C 17 H 13F4N4O2S[M+H] + : m / z = 413.1; found: 413.0.

[0507] Example 13: 4-(2-Fluoro-6-methoxyphenyl)-6-methyl-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0508]

[0509] Step 1: 5-(Pyridin-4-yl)-1,3,4-thiadiazol-2-amine

[0510]

[0511] To a cooled mixture of thiosemicarbazide (1.09 g, 12 mmol) and 4-cyanopyridine (1.04 g, 10 mmol) (ice-water bath) was added TFA (20 mL) dropwise. The mixture was stirred at 90°C for 6 h, then concentrated under reduced pressure and poured into ice-water (50 mL). The aqueous phase was adjusted to pH 12 with solid KOH and diluted with EtOAc (100 mL). The organic phase was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (50-80%) to give the title compound (0.4 g) as a yellow oil. LCMS calculated for C7H7N4S [M+H] + : m / z = 179.0; found: 179.0.

[0512] Step 2: 4-(2-Fluoro-6-methoxyphenyl)-6-methyl-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0513] This compound was prepared in a similar manner to step 4 of Example 10 using 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine and 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-2) as starting materials. LCMS calculated value: C 21 H 17 FN5O2S[M+H] + : m / z = 422.1; found: 422.1.

[0514] Example 14: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0515]

[0516] Step 1: 5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazol-2-amine

[0517]

[0518] To a cooled mixture of thiosemicarbazide (1.09 g, 12 mmol) and 4-methoxy-3-methylbenzoic acid (1.66 g, 10 mmol) (ice-water bath), POCl3 (10 mL) was added dropwise. The mixture was stirred at 75°C for 3 h., cooled and poured into ice water (50 mL). The aqueous phase was adjusted to pH 12 with solid KOH and diluted with EtOAc (100 mL). The organic phase was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc / PE (30-40%) to give the title compound (0.68 g) as a yellow oil. LCMS calculated value: C 10 H 12 N3OS[M+H] + : m / z = 222.1; found: 222.1.

[0519] Step 2: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0520] This compound was prepared in a similar manner to step 4 of Example 10 using 5-(4-methoxy-3-methylphenyl)-1,3,4-thiadiazol-2-amine and 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-2) as starting materials. LCMS calculated value: C 24 H 22 FN4O3S[M+H] + : m / z = 465.1; found: 465.1.

[0521] Example 15: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)nicotinamide

[0522]

[0523] This compound was prepared in a similar manner to step 3 of Example 1 using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-methyl-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value: C 17 H 15 ClFN4O2S[M+H] +: m / z = 393.1; found: 393.1.

[0524] Example 16: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0525]

[0526] This compound was prepared in a similar manner to step 3 of Example 1 using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-cyclopropyl-1,3,4-thiadiazole-2-amine as starting materials. LCMS calculated value: C 19 H 17 ClFN4O2S[M+H] + : m / z = 419.1; found: 419.1.

[0527] Example 17: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0528]

[0529] This compound was prepared in a similar manner to step 3 of Example 1 using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(difluoromethyl)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value: C 17 H 13 ClF3N4O2S[M+H] + : m / z = 429.0; found: 429.1.

[0530] Example 18: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-isopropyl-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0531]

[0532] This compound was prepared in a similar manner to step 3 of Example 1 using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-isopropyl-1,3,4-thiadiazole-2-amine as starting materials. LCMS calculated value: C 19 H 19 ClFN4O2S[M+H] + : m / z = 421.1; found: 421.1.

[0533] Example 19: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0534]

[0535] This compound was prepared in a similar manner to step 3 of Example 1 using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-ethyl-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value: C 18 H 17 ClFN4O2S[M+H] + : m / z = 407.1; found: 407.1.

[0536] Example 20: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1-fluorocyclopropyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0537]

[0538] Step 1: 5-(1-fluorocyclopropyl)-1,3,4-thiadiazol-2-amine

[0539]

[0540] To a cooled mixture of thiosemicarbazide (1.09 g, 12 mmol) and 1-fluorocyclopropane-1-carboxylic acid (1.04 g, 10 mmol) (ice-water bath) was added POCl3 (10 mL) dropwise. The mixture was stirred at 75°C for 3 h, cooled and poured into ice water (50 mL). The aqueous phase was adjusted to pH 12 with solid KOH and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (0-10%) to give the title compound (0.6 g) as a yellow oil. LCMS calculated for C5H7FN3S [M+H] + : m / z = 160.0; found: 160.0.

[0541] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1-fluorocyclopropyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0542] This compound was prepared in a similar manner to step 3 of Example 1 using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(1-fluorocyclopropyl)-1,3,4-thiadiazole-2-amine as starting materials. LCMS calculated value: C 19 H16 ClF2N4O2S[M+H] + : m / z = 437.1; found: 437.1.

[0543] Example 21: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0544]

[0545] Step 1: 5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-amine

[0546]

[0547] To a mixture of 2,2-difluoropropionic acid (1.1 g, 10 mmol) and thiosemicarbazide (910 mg, 10 mmol) was slowly added POCl3 (8 mL). The mixture was stirred at 75°C for 3 h., then poured into ice water (30 mL) and stirred at 0°C for 2 h. The resulting mixture was adjusted to pH 8-10 with solid NaOH. The aqueous phase was extracted with EtOAc (30 mL x 4). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluted with MeCN / H2O (10-30%) to give the title compound (170 mg) as a yellow solid. LCMS calculated value: C4H6F2N3S[M+H] + : m / z = 166.0; found: 166.1.

[0548] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0549] This compound was prepared in a similar manner to step 3 of Example 1 using intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-amine as starting materials. 1 H NMR (600MHz, DMSO-d6) δ13.59 (s, 1H), 8.92 (s, 1H), 7.60 (t, J=8.4Hz, 1H), 7.43 (s, 1H), 6.94 (d, J=8.4Hz, 1H), 3.55 (s, 3H), 2.60 (s, 3H), 2.19 (t, J F-H =19.2 Hz). LCMS calculated value C 18 H15 ClF3N4O2S[M+H] + : m / z = 443.1; found: 443.1.

[0550] Example 22: 2'-Chloro-N-(5-(ethylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0551]

[0552] Step 1: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carboxylic acid methyl ester

[0553]

[0554] A mixture of methyl 4-chloro-6-methylnicotinate (31.5 g, 8 mmol), (2-chloro-5-methoxypyridin-4-yl)boronic acid (0.94 g, 5.0 mmol), K2CO3 (4.4 g, 16 mmol), and Pd(dppf)Cl2 (0.34 g, 0.5 mmol) in 1,4-dioxane (24 mL) and H2O (3 mL) was degassed and replaced with nitrogen three times, then stirred at 80°C for 16 h. The mixture was diluted with EtOAc, washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (50-70%) to give the title compound (0.3 g) as a yellow solid. LCMS calculated value: C 14 H 14 ClN2O3[M+H] + : m / z = 293.1; found: 293.1.

[0555] Step 2: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0556]

[0557] To a solution of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (0.3 g, 1.0 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH. .H2O (0.13 g, 3.0 mmol). After stirring at rt overnight, the reaction mixture was diluted with water, then adjusted to pH 2–3 with HCl solution (2 M), and concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN / H2O (10–15%) to afford the title compound as a yellow oil. LCMS calculated value: C 13 H 12 ClN2O3[M+H] + : m / z = 279.1; found: 279.1.

[0558] Step 3: 2'-Chloro-N-(5-(ethylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0559] To a solution of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (112 mg, 0.4 mmol), TCFH (168 mg, 0.6 mmol) and NMI (66 mg, 0.8 mmol) in DMF (2 mL) was added 5-(ethylthio)-1,3,4-thiadiazole-2-amine (65 mg, 0.4 mmol, Example 30, Step 1). The mixture was stirred at rt overnight and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (20-30%) to give the title compound (48 mg) as a white solid. LCMS calculated value C 17 H 17 ClN5O2S[M+H] + : m / z = 422.0; found: 422.1.

[0560] Example 23: 4-(2,3-difluoro-6-methoxyphenyl)-6-methyl-N-(5-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0561]

[0562] To a mixture of 4-(2,3-difluoro-6-methoxyphenyl)-6-methylnicotinic acid (70 mg, 0.25 mmol, Int-3), TCFH (112 mg, 0.4 mmol) and NMI (66 mg, 0.5 mmol) in DMF (3 mL) was added 5-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine (64 mg, 0.3 mmol, Example 6, Step 1). The reaction mixture was stirred at rt for 4 h. and then concentrated under reduced pressure. The residue was purified by prep-HPLC eluting with MeCN / H2O (15-45%) to give the title compound (41 mg) as a white solid. LCMS calculated value C 22 H 23 F2N4O4S[M+H] + : m / z = 477.1; found: 477.2.

[0563] Example 24: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(methoxymethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0564]

[0565] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value: C 18 H 17 ClFN4O3S[M+H] + : m / z = 423.1; found: 423.1.

[0566] Example 25: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(ethoxymethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0567]

[0568] Step 1: 5-(Ethoxymethyl)-1,3,4-thiadiazol-2-amine

[0569]

[0570] This compound was prepared in a similar manner to that in step 2 of Example 1, except that ethoxyacetic acid was used instead of (S)-2-((tetrahydrofuran-3-yl)oxy)acetic acid. LCMS calculated value: C5H 10 N3OS[M+H] +: m / z = 160.1; found: 160.1.

[0571] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(ethoxymethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0572] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(ethoxymethyl)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value: C 19 H 19 ClFN4O3S[M+H] + : m / z = 437.1; found: 437.1.

[0573] Example 26: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((2,2,2-trifluoroethoxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0574]

[0575] Step 1: 5-((2,2,2-trifluoroethoxy)methyl)-1,3,4-thiadiazol-2-amine

[0576]

[0577] This compound was prepared in a similar manner to that in step 2 of Example 1, using 2-(2,2,2-trifluoroethoxy)acetic acid instead of (S)-2-((tetrahydrofuran-3-yl)oxy)acetic acid. LCMS calculated value: C5H7F3N3OS[M+H] + : m / z = 214.0; found: 214.0.

[0578] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((2,2,2-trifluoroethoxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0579] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-((2,2,2-trifluoroethoxy)methyl)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value: C 19 H 16 ClF4N4O3S[M+H] + : m / z = 491.1; found: 491.1.

[0580] Example 27: 4-(2-Fluoro-6-methoxy-3-methylphenyl)-6-methyl-N-(5-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0581]

[0582] To a mixture of 4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinic acid (68 mg, 0.25 mmol, Int-4), TCFH (112 mg, 0.4 mmol) and NMI (66 mg, 0.5 mmol) in DMF (3 mL) was added 5-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine (64 mg, 0.3 mmol, Example 6, Step 1). The reaction mixture was stirred at rt for 4 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC eluting with MeCN / H2O (15-50%) to give the title compound (30 mg) as a white solid. LCMS calculated for C 23 H 26 FN4O4S[M+H] + : m / z = 473.2; found: 473.2.

[0583] Example 28: 4-(2-Fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methyl-N-(5-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0584]

[0585] To a mixture of 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid (83 mg, 0.25 mmol, Int-5), TCFH (112 mg, 0.4 mmol) and NMI (66 mg, 0.5 mmol) in DMF (3 mL) was added 5-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)-1,3,4-thiadiazol-2-amine (64 mg, 0.3 mmol, Example 6, Step 1). The reaction mixture was stirred at rt for 4 h. and then concentrated under reduced pressure. The residue was purified by prep-HPLC eluting with MeCN / H2O (25-50%) to give the title compound (56 mg) as a white solid. LCMS calculated for C 23 H 23 F4N4O4S[M+H] + : m / z = 527.1; found: 527.1.

[0586] Example 29: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-methoxyethyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0587]

[0588] Step 1: 5-((2-methoxyethyl)thio)-1,3,4-thiadiazol-2-amine

[0589]

[0590] To a mixture of 5-amino-1,3,4-thiadiazole-2-thiol (265 mg, 2.0 mmol) and KOH (1.12 g, 20.0 mmol) in water (10 mL) was slowly added 1-iodo-2-methoxyethane (370 mg, 2.0 mmol) under ice-water bath conditions. The mixture was stirred at 0°C for 1 h. and diluted with water (30 mL). The aqueous phase was extracted with DCM (30 mL x 3). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (300 mg) as a white solid. LCMS calculated value: C5H 10 N3OS2[M+H] + : m / z = 192.0; found: 192.0.

[0591] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-methoxyethyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0592] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-((2-methoxyethyl)thio)-1,3,4-thiadiazole-2-amine as starting materials. LCMS calculated value: C 19 H 19 ClFN4O3S2[M+H] + : m / z = 469.1; found: 469.1.

[0593] Example 30: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(ethylthio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0594]

[0595] Step 1: 5-(Ethylthio)-1,3,4-thiadiazol-2-amine

[0596]

[0597] To a mixture of 5-amino-1,3,4-thiadiazole-2-thiol (265 mg, 2.0 mmol) and KOH (1.12 g, 20.0 mmol) in water (10 mL) was slowly added iodoethane (312 mg, 2.0 mmol) under ice-water bath conditions. The mixture was stirred at 0°C for 1 h. The reaction mixture was diluted with water (30 mL). The aqueous phase was extracted with DCM (30 mL x 3). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the target compound (300 mg) as a white solid. LCMS calculated value: C5H 10 N3OS2[M+H] + : m / z = 162.0; found: 162.0.

[0598] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(ethylthio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0599] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(ethylthio)-1,3,4-thiadiazole-2-amine as starting materials. LCMS calculated value: C 18 H 17 ClFN4O2S2[M+H] + : m / z = 439.0; found: 439.0.

[0600] Example 31: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((2,2,2-trifluoroethyl)thio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0601]

[0602] Step 1: 5-((2,2,2-trifluoroethyl)thio)-1,3,4-thiadiazol-2-amine

[0603]

[0604] Under ice-water bath conditions, to a mixture of 5-amino-1,3,4-thiadiazole-2-thiol (265 mg, 2.0 mmol) and KOH (0.56 g, 10 mmol) in water (10 mL) was slowly added 2,2,2-trifluoroethyl trifluoromethanesulfonate (465 mg, 2.0 mmol). The mixture was stirred at 0°C for 1 h. and diluted with water (30 mL). The aqueous phase was extracted with DCM (30 mL x 3). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the target compound (200 mg) as a white solid. LCMS calculated value: C4H5F3N3S2[M+H] + : m / z = 216.0; found: 216.0.

[0605] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((2,2,2-trifluoroethyl)thio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0606] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-((2,2,2-trifluoroethyl)thio)-1,3,4-thiadiazole-2-amine as starting materials. LCMS calculated value: C 18 H 14 ClF4N4O2S2[M+H] + : m / z = 493.0; found: 493.0.

[0607] Example 32: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-hydroxyethyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0608]

[0609] Step 1: 5-((2-((tert-Butyldimethylsilyl)oxy)ethyl)thio)-1,3,4-thiadiazol-2-amine

[0610]

[0611] To a mixture of 5-amino-1,3,4-thiadiazole-2-thiol (530 mg, 4.0 mmol) and Cs2CO3 (3.91 g, 12 mmol) in DMF (10 mL) was slowly added 2-bromoethoxy) (tert-butyl) dimethylsilane (1.44 g, 6.0 mmol) in an ice-water bath. The mixture was stirred at rt for 4 h., diluted with water (40 mL), and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.1 g) as a white solid. LCMS calculated value: C 10 H 22 N3OS2Si[M+H] + : m / z = 292.1; found: 292.1.

[0612] Step 2: N-(5-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0613]

[0614] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value: C 24 H 31 ClFN4O3S2Si[M+H] + : m / z = 569.1; found: 569.1.

[0615] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-hydroxyethyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0616] A solution of N-(5-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide (200 mg, 0.35 mmol) in water (4 mL) and TFA (4 mL) was stirred at 50°C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN / H2O (30-50%) to give the title compound (59.8 mg) as a white solid. 1H NMR (600 MHz, DMSO-d6) δ 13.2 (s, 1H), 8.88 (s, 1H), 7.60 (t, J = 9.0 Hz, 1H), 7.41 (s, 1H), 6.93 (d, J = 9.0 Hz, 1H), 5.10 (t, J = 5.4 Hz, 1H), 3.68 (q, J = 6.0 Hz 2H), 3.56 (s, 3H), 3.32-3.25 (m, 2H), 2.59 (s, 3H). LCMS calculated value C 18 H 17 ClFN4O3S2[M+H] + : m / z = 455.0; found: 455.1.

[0617] Example 33: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((3-hydroxypropyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0618]

[0619] This compound was prepared in a similar manner to Steps 1-3 of Example 32, except that (3-bromopropoxy)(tert-butyl)dimethylsilane was used in place of 2-bromoethoxy)(tert-butyl)dimethylsilane in Step 1. LCMS calculated value: C 19 H 19 ClFN4O3S2[M+H] + : m / z = 469.0; found: 469.1.

[0620] Example 34: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((3-hydroxy-3-methylbutyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0621]

[0622] Step 1: 4-((5-amino-1,3,4-thiadiazol-2-yl)thio)-2-methylbutan-2-ol

[0623]

[0624] To a mixture of 5-amino-1,3,4-thiadiazole-2-thiol (265 mg, 2 mmol) and Cs2CO3 (1.95 g, 6 mmol) in DMF (5 mL) was slowly added 4-bromo-2-methylbutan-2-ol (0.5 g, 3 mmol) under ice-water bath conditions. The mixture was stirred at rt overnight, diluted with water (40 mL), and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluted with MeCN / H2O (30-50%) to give the title compound (100 mg) as a yellow solid. LCMS calculated for C7H 14 N3OS2[M+H] + : m / z = 220.1; found: 220.1.

[0625] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((3-hydroxy-3-methylbutyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0626] To a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (59 mg, 0.2 mmol, Int-1), TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL) was added 4-((5-amino-1,3,4-thiadiazol-2-yl)thio)-2-methylbutan-2-ol (66 mg, 0.3 mmol). The mixture was stirred at rt for 2 h. and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC using MeCN / H2O (25-50%) as the eluent to give the title compound (28 mg) as a white solid. LCMS calculated for C 21 H 23 ClFN4O3S2[M+H] + : m / z = 497.1; found: 497.1.

[0627] Example 35: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-hydroxypropyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0628]

[0629] This compound was prepared in a similar manner to Steps 1-2 of Example 34, except that 1-bromopropan-2-ol was used instead of 4-bromo-2-methylbutan-2-ol in Step 1. LCMS calculated value: C 19 H 19ClFN4O3S2[M+H] + : m / z = 469.0; found: 469.1.

[0630] Example 36: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((3-cyanopropyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0631]

[0632] Step 1: 4-((5-amino-1,3,4-thiadiazol-2-yl)thio)butanenitrile

[0633]

[0634] To a mixture of 5-amino-1,3,4-thiadiazole-2-thiol (265 mg, 2 mmol) and Cs2CO3 (1.95 g, 6 mmol) in DMF (5 mL) was slowly added 4-bromobutyronitrile (0.45 g, 3 mmol) under ice-water bath conditions. The mixture was stirred at rt overnight, diluted with water (40 mL), and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN / H2O (45-60%) to give the title compound (115 mg) as a yellow solid. LCMS calculated value: C6H9N4S2[M+H] + : m / z = 201.0; found: 201.0.

[0635] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((2,2,2-trifluoroethyl)thio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0636] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 4-((5-amino-1,3,4-thiadiazol-2-yl)thio)butanenitrile as starting materials. LCMS calculated value: C 20 H 18 ClFN5O2S2[M+H] + : m / z = 478.1; found: 478.1.

[0637] Example 37: trans-4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((-2-hydroxycyclopentyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0638]

[0639] Step 1: trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)cyclopentan-1-ol

[0640]

[0641] A mixture of 5-amino-1,3,4-thiadiazole-2-thiol (133 mg, 1 mmol), K2CO3 (276 mg, 2 mmol) and 6-oxabicyclo[3.1.0]hexane (335 mg, 4 mmol) was stirred at 30°C overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN / H2O (30-50%) to give the title compound (56 mg) as a yellow oil. LCMS calculated for C7H 12 N3OS2[M+H] + : m / z = 218.0; found: 218.0.

[0642] Step 2: trans-4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((-2-hydroxycyclopentyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0643] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and trans-2-((5-amino-1,3,4-thiadiazol-2-yl)thio)cyclopentan-1-ol as starting materials. LCMS calculated value: C 21 H 21 ClFN4O3S2[M+H] + : m / z = 495.1; found: 495.1.

[0644] Example 38: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(dimethylamino)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0645]

[0646] Step 1: N 2 ,N 2 -Dimethyl-1,3,4-thiadiazole-2,5-diamine

[0647]

[0648] A solution of 5-bromo-1,3,4-thiadiazol-2-amine (374 mg, 2.0 mmol) in HNMe2 (5.0 mL, 2.0 M in THF, 10 mmol) was placed in a sealed tube, heated to 90°C, and stirred for 4 h. The mixture was then cooled to rt and concentrated under reduced pressure to afford the title compound (280 mg) as a yellow oil. LCMS calculated value: C4H9N4S [M+H] + : m / z = 145.1; found: 145.0.

[0649] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(dimethylamino)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0650] To a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (120 mg, 0.4 mmol, Int-1), TCFH (170 mg, 0.6 mmol) and NMI (66 mg, 0.8 mmol) in DMF (2 mL) was added N 2 ,N 2 -dimethyl-1,3,4-thiadiazole-2,5-diamine (58 mg, 0.4 mmol). The mixture was stirred at rt for 2 h., then concentrated under reduced pressure. The residue was purified by prep-HPLC using MeCN / H2O (25-50%) as eluent to give the title compound (28 mg) as a white solid. LCMS calculated value: C 18 H 18 ClFN5O2S[M+H] + : m / z = 422.1; found: 422.1.

[0651] Example 39: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(methyl(2-(N-methylacetylamino)ethyl)amino)-1,3,4-thiadiazol-2-yl)nicotinamide

[0652]

[0653] Step 1: tert-Butyl (2-((5-amino-1,3,4-thiadiazol-2-yl)(methyl)amino)ethyl)(methyl)carbamate

[0654]

[0655] A mixture of tert-butyl methyl(2-(methylamino)ethyl)carbamate (375 mg, 2.0 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (180 mg, 1.0 mmol) in DMF (2.0 mL) was stirred at 80°C overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with ACN / H2O (40-60%) to give the title compound (130 mg) as a yellow oil. LCMS calculated value: C 11 H 22 N5O2S[M+H] + : m / z = 288.1; Found: 288.1. Step 2: tert-Butyl (2-((5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)(methyl)amino)ethyl)(methyl)carbamate

[0656]

[0657] To a mixture of tert-butyl (2-((5-amino-1,3,4-thiadiazol-2-yl)(methyl)amino)ethyl)(methyl)carbamate (130 mg, 0.45 mmol) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (89 mg, 0.3 mmol, Int-1) in DMF (0.5 mL) was added NMI (87 mg, 1.1 mmol) and TCFH (110 mg, 0.4 mmol). The reaction mixture was stirred at 50°C overnight. The mixture was concentrated under reduced pressure and then purified by flash chromatography on silica gel using EtOAc / PE (30-60%) as eluent to give the title compound (105 mg) as a yellow solid. LCMS calculated value: C 25 H 31 ClFN6O4S[M+H] + : m / z = 565.2; found: 565.2.

[0658] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(methyl(2-(methylamino)ethyl)amino)-1,3,4-thiadiazol-2-yl)nicotinamide

[0659]

[0660] To a solution of tert-butyl (2-((5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)(methyl)amino)ethyl)(methyl)carbamate (105 mg, 0.19 mmol) in DCM (3 mL) was added TFA (0.5 mL). The reaction mixture was stirred at rt for 5 h. It was then concentrated under reduced pressure to give the crude product (90 mg) as a yellow oil. LCMS calculated value: C 20 H 23 ClFN6O2S[M+H] + : m / z = 465.1; found: 465.1.

[0661] Step 4: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(methyl(2-(N-methylacetylamino)ethyl)amino)-1,3,4-thiadiazol-2-yl)nicotinamide

[0662] To a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(methyl(2-(methylamino)ethyl)amino)-1,3,4-thiadiazol-2-yl)nicotinamide (60 mg, 0.13 mmol) and TEA (101 mg, 1.0 mmol) in DCM (3 mL) was added AcO (41 mg, 0.4 mmol). The reaction mixture was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with ACN / HO (20-30%) to give the title compound (5.9 mg) as an off-white solid. LCMS calculated value: C 22 H 25 ClFN6O3S[M+H] + : m / z = 507.1; found: 507.1.

[0663] Example 40: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-methoxyethyl)(methyl)amino)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0664]

[0665] This compound was prepared in a similar manner to Steps 1-2 of Example 38, except that 2-methoxy-N-methylethan-1-amine was used in place of the HNMe2 solution in Step 1. LCMS calculated value: C 20 H 22 ClFN5O3S[M+H] + : m / z = 466.1; found: 466.1.

[0666] Example 41: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(methyl(2,2,2-trifluoroethyl)amino)-1,3,4-thiadiazol-2-yl)nicotinamide

[0667]

[0668] This compound was prepared in a similar manner to Steps 1-2 of Example 38, except that 2,2,2-trifluoro-N-methylethan-1-amine was used in place of the HNMe2 solution in Step 1. LCMS calculated value: C 19 H 17 ClF4N5O2S[M+H] + : m / z = 490.1; found: 490.1.

[0669] Example 42: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-methoxyethyl)amino)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0670]

[0671] This compound was prepared in a similar manner to Steps 1-2 of Example 38, except that 2-methoxyethan-1-amine was used in place of the HNMe2 solution in Step 1. LCMS calculated value: C 19 H 20 ClFN5O3S[M+H] + : m / z = 452.1; found: 452.1.

[0672] Example 43: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((2,2,2-trifluoroethyl)amino)-1,3,4-thiadiazol-2-yl)nicotinamide

[0673]

[0674] This compound was prepared in a similar manner to Steps 1-2 of Example 38, except that 2,2,2-trifluoroethane-1-amine was used in place of HNMe2 solution in Step 1. LCMS calculated value: C 18 H 15 ClF4N5O2S[M+H] + : m / z = 476.1; found: 476.1.

[0675] Example 44: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(4-methyl-2-oxopiperazin-1-yl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0676]

[0677] Step 1: 1-(5-amino-1,3,4-thiadiazol-2-yl)-4-methylpiperazin-2-one

[0678]

[0679] To a solution of 4-methylpiperazine-2-one (230 mg, 2.0 mmol) in DMF (2 mL) was added NaH (80 mg, 2 mmol, 60% suspension in mineral oil). The reaction mixture was stirred at 25 ° C for 1 h. To the above mixture was added 5-bromo-1,3,4-thiadiazole-2-amine (180 mg, 1.0 mmol). The reaction mixture was stirred at 25 ° C overnight, then quenched with water at 0 ° C and concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column and eluted with ACN / H2O (0-15%) to give the target compound (30 mg) as a yellow oil. LCMS calculated value: C7H 12 N5OS[M+H] + : m / z = 214.1; found: 214.1.

[0680] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(4-methyl-2-oxopiperazin-1-yl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0681] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 1-(5-amino-1,3,4-thiadiazol-2-yl)-4-methylpiperazin-2-one as starting materials. LCMS calculated value: C 21 H 21 ClFN6O3S[M+H] + : m / z = 491.1; found: 491.1.

[0682] Example 45: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(methyl(2-(N-methylmethylsulfonylamino)ethyl)amino)-1,3,4-thiadiazol-2-yl)nicotinamide

[0683]

[0684] This compound was prepared in a similar manner to that in Step 4 of Example 39 using methanesulfonic anhydride and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(methyl(2-(methylamino)ethyl)amino)-1,3,4-thiadiazol-2-yl)nicotinamide (Step 3 of Example 39) as starting materials. LCMS calculated value: C21 H 25 ClFN6O4S2[M+H] + : m / z = 543.1; found: 543.1.

[0685] Example 46: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-((N,N-dimethylsulfamoyl)(methyl)amino)ethyl)(methyl)amino)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0686]

[0687] This compound was prepared in a similar manner to that in Step 4 of Example 39 using dimethylsulfamoyl chloride and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(methyl(2-(methylamino)ethyl)amino)-1,3,4-thiadiazol-2-yl)nicotinamide (Step 3 of Example 39) as starting materials. LCMS calculated value: C 22 H 28 ClFN7O4S2[M+H] + : m / z = 572.1; found: 572.1.

[0688] Example 47: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(4-methyl-3-oxopiperazin-1-yl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0689]

[0690] This compound was prepared in a similar manner to Steps 1-2 of Example 38, except that 1-methylpiperazin-2-one was used in place of the HNMe2 solution in Step 1. LCMS calculated value: C 21 H 21 ClFN6O3S[M+H] + : m / z = 491.1; found: 491.1.

[0691] Example 48: Ethyl 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetate

[0692]

[0693] Step 1: Ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetate

[0694]

[0695] To a mixture of 1,3,4-thiadiazol-2-amine (5 g, 49.5 mmol), Cp2Fe (931 mg, 4.95 mmol) and ethyl 2-bromo-2,2-difluoroacetate (20 g, 99 mmol) in DMSO (25 mL) at 0°C was slowly added hydrogen peroxide (11.22 g, 99 mmol, 30% aqueous solution). The reaction mixture was stirred at rt overnight and quenched with 10% Na2S2O3 solution (100 mL) at 0°C. The aqueous phase was extracted with EA (100 mL x 2). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (10-47%) to give the product (1.89 g) as a brown oil. LCMS calculated for C6H8F2N3O2S [M+H] + : m / z = 224.0; found: 224.0.

[0696] Step 2: Ethyl 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetate

[0697] To a mixture of ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetate (223 mg, 1.0 mmol), 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (295 mg, 1.0 mmol, Int-1) and NMI (410 mg, 5 mmol) in DMF (2 mL) was added TCFH (336 mg, 1.2 mmol). The reaction mixture was stirred at rt for 1 h. and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with ACN / H2O (50-70%) to give the title compound (260 mg) as a white solid. LCMS calculated for C 20 H 17 ClF3N4O4S[M+H] + : m / z = 501.1; found: 501.1.

[0698] Example 49: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoro-2-hydroxyethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0699]

[0700] To a solution of ethyl 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetate (10 mg, 0.02 mmol, Example 48) in EtOH (0.2 mL) at 0°C was added NaBH₄ (3.78 mg, 0.1 mmol). The reaction mixture was stirred at RT for 30 min. and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C₁₈ column eluting with ACN / H₂O (30-58%, containing 0.1% NH₄HCO₃) to afford the title compound (7.2 mg) as a white solid. 1 H NMR (600 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.52 (t, J = 8.4 Hz, 1H), 7.16 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.73 (s, 1H), 4.00-4.10 (m, 2H), 3.57 (s, 3H), 2.52 (s, 3H). LCMS calculated value C 18 H 15 ClFN4O3S[M+H] + : m / z = 459.0; found: 459.0.

[0701] Example 50: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoro-3-hydroxypropyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0702]

[0703] Step 1: 5-(1,1-difluorobut-3-en-1-yl)-1,3,4-thiadiazol-2-amine

[0704]

[0705] To a mixture of 2,2-difluoropent-4-enoic acid (5.0 g, 36.7 mmol) and thiosemicarbazide (3.4 g, 36.7 mmol) in dioxane (20 mL) was added phosphorus trichloride (11.3 g, 73.4 mmol) at rt. The mixture was stirred at 80°C for 3 h., then quenched with water (300 mL) at 0°C. The aqueous phase was extracted with EtOAc (200 mL x 3). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc / PE (10-50%) to give the title compound (6.0 g) as a yellow solid. LCMS calculated value: C6H7F2N3S[M+H]+ : m / z = 192.0; found: 192.0.

[0706] Step 2: 3-(5-amino-1,3,4-thiadiazol-2-yl)-3,3-difluoropropan-1-ol

[0707]

[0708] To a mixture of 5-(1,1-difluorobut-3-en-1-yl)-1,3,4-thiadiazol-2-amine (300 mg, 1.57 mmol) and sodium periodate (1.34 g, 6.28 mmol) in dioxane (5 mL) and water (5 mL) was added potassium osmate (58 mg, 0.16 mmol). The mixture was stirred at rt for 3 h. It was then concentrated under reduced pressure, and the residue was dissolved in water (5 mL) and MeOH (8 mL). NaBH4 (593 mg, 15.7 mmol) was then added at 0°C. The resulting mixture was stirred at rt for 3 h. and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (3-30% with 0.5% TFA) to give the title compound (150 mg) as a white solid. LCMS calculated for C5H8F2N3OS[M+H] + : m / z = 196.0; found: 196.0.

[0709] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoro-3-hydroxypropyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0710] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 3-(5-amino-1,3,4-thiadiazol-2-yl)-3,3-difluoropropan-1-ol as starting materials. LCMS calculated value: C 19 H 17 ClF3N4O3S[M+H] + : m / z = 473.1; found: 473.1.

[0711] Example 51: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluorobut-3-en-1-yl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0712]

[0713] This compound was prepared in a similar manner to that in Step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(1,1-difluorobut-3-en-1-yl)-1,3,4-thiadiazol-2-amine (Step 1 of Example 50) as starting materials. LCMS calculated value: C 20 H 17 ClF3N4O2S[M+H] + : m / z = 469.1; found: 469.1.

[0714] Example 52: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluorobutyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0715]

[0716] A mixture of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluorobut-3-en-1-yl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (50 mg, 0.11 mmol, Example 51), Pd / C (90 mg, 5% on wet carbon) and TFA (0.05 mL) in methanol (5 mL) was degassed and filled with H2 three times. The reaction mixture was stirred at rt for 18 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (40-60%) to give the title compound (25 mg) as a white solid. LCMS calculated value: C 20 H 19 ClF3N4O2S[M+H] + : m / z = 471.1; found: 471.1.

[0717] Example 53: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(ethylsulfonyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0718]

[0719] To a mixture of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(ethylthio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (45 mg, 0.1 mmol, Example 30) in DCM (1 mL) was added m-CPBA (35 mg, 0.2 mmol). The reaction mixture was stirred at rt overnight and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (20-40%, containing 0.5% TFA) to give the title compound (6 mg) as a yellow solid. LCMS calculated value: C 18 H 17 ClF3N4O4S2[M+H] + : m / z = 471.0; found: 471.0.

[0720] Example 54: 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetic acid

[0721]

[0722] To a solution of ethyl 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetate (50 mg, 0.1 mmol, Example 48) in THF (2 mL) and H2O (2 mL) was added LiOH. . H2O (4.2 mg, 0.1 mmol). Stirring was continued at rt overnight, the reaction mixture was diluted with water, adjusted to pH 3-4 with HCl solution (2 M), and extracted with DCM (20 mL x 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column using MeCN / H2O (30-40%, containing 0.5% TFA) as the eluent to give the title compound (25 mg) as a white solid. LCMS calculated value: C 18 H 13 ClF3N4O4S[M+H] + : m / z = 473.0; found: 473.0.

[0723] Example 55: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoro-2-(methylsulfonylamino)-2-oxoethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0724]

[0725] To a mixture of 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetic acid (110 mg, 0.2 mmol, Example 54), methanesulfonamide (28 mg, 0.3 mmol) and DMAP (37 mg, 0.3 mmol) in DMF (2 mL) was added EDCI (46 mg, 0.24 mmol). The mixture was stirred at rt overnight and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (45-60%, containing 0.5% TFA) to give the title compound (30.5 mg) as a white solid. LCMS calculated value C 19 H 16 ClF3N5O5S2[M+H] + : m / z = 550.0; found: 550.0.

[0726] Example 56: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-(dimethylamino)-1,1-difluoro-2-oxoethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0727]

[0728] A solution of ethyl 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetate (50 mg, 0.1 mmol, Example 48) in HNMe₂ (1.0 mL, 2.0 M in THF, 2 mmol) was heated to 70°C and stirred for 4 h. The mixture was then cooled to rt and concentrated under reduced pressure. The residue was purified by prep-HPLC on a C₁₈ column eluting with MeCN / H₂O (40-60%, containing 0.1% NH₄HCO₃) to afford the title compound (34 mg) as a white solid. 1 H NMR (600 MHz, DMSO-d6) δ 13.74 (s, 1H), 8.93 (s, 1H), 7.61 (t, J = 8.4 Hz, 1H), 7.44 (s, 1H), 6.94 (t, J = 8.4 Hz, 1H), 3.56 (s, 3H), 3.01 (s, 6H), 2.60 (s, 3H). LCMS calculated value C 20 H 18 ClF3N5O3S[M+H] + : m / z = 500.1; found: 500.1.

[0729] Examples 57-100 listed in Table 1 were prepared using the intermediate 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetic acid ethyl ester (Example 48) and the appropriate amine as starting materials in a similar manner to Example 56.

[0730] Table 1 Example Preparation Example (Ex)

[0731]

[0732]

[0733]

[0734]

[0735]

[0736] Example 101: N-(5-(2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1,1-difluoro-2-oxoethyl)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0737]

[0738] Step 1: 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetyl chloride

[0739]

[0740] To a solution of 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetic acid (190 mg, 0.4 mmol, Example 54) in anhydrous DCM (10 mL) was added oxalyl chloride (64 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 1 h to obtain a solution of the desired product in difluoroacetyl chloride, which was used directly in the next step.

[0741] Step 2: N-(5-(2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1,1-difluoro-2-oxoethyl)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0742] To a solution of 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetyl chloride (200 mg, 0.4 mmol) in anhydrous DCM (10 mL) was added 2-oxa-5-azabicyclo[2.2.1]heptane (198 mg, 2.0 mmol) and anhydrous TEA (260 mg, 2.0 mmol). The reaction mixture was stirred at rt for 2 h, diluted with water (40 mL), and extracted with EtOAc (30 mL x 2). The combined organic phases were washed with water and saturated brine, dried over NaSO, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (30-40%, containing 0.5% TFA) to afford the title compound (65 mg) as a white solid. LCMS calculated value C 23 H 20 ClF3N5O4S[M+H] + : m / z = 554.1; found: 554.1.

[0743] Examples 102-107 listed in Table 2 were prepared using the intermediate 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetyl chloride (Step 1 of Example 101) and a suitable amine or its HCl salt as starting materials, in a manner similar to that of Example 101.

[0744] Table 2 Example Preparation Example (Ex)

[0745]

[0746]

[0747] Table 3 Example (Ex) 1 H NMR spectrum

[0748]

[0749] Example 108: N-(5-(2-(dimethylamino)-1,1-difluoro-2-oxoethyl)-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinamide

[0750]

[0751] Step 1: Ethyl 2,2-difluoro-2-(5-(4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinamido)-1,3,4-thiadiazol-2-yl)acetate

[0752]

[0753] To a mixture of ethyl 2-(5-amino-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetate (223 mg, 1.0 mmol, Example 48, Step 1), 4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinic acid (275 mg, 1.0 mmol, Int-4), and NMI (410 mg, 5 mmol) in DMF (2 mL) was added TCFH (336 mg, 1.2 mmol). The reaction mixture was stirred at rt for 1 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with ACN / H2O (50-60%) to give the title compound (260 mg) as a white solid. LCMS calculated value: C 21 H 20 F3N4O4S[M+H] + : m / z = 481.1; found: 481.1.

[0754] Step 2: N-(5-(2-(dimethylamino)-1,1-difluoro-2-oxoethyl)-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinamide

[0755] This compound was prepared in a similar manner to Example 56 using ethyl 2,2-difluoro-2-(5-(4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)acetate and HNMe2 solution (2.0 M in THF) as starting materials. LCMS calculated value: C 21 H 21 F3N5O3S[M+H] + : m / z = 480.1; found: 480.2.

[0756] Example 109: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoro-2-((7S,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0757]

[0758] Step 1: tert-Butyl (7S,8aS)-7-((4-nitrobenzoyl)oxy)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

[0759]

[0760] To a mixture of tert-butyl (7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (250 mg, 1.05 mmol), triphenylphosphine (395 mg, 1.5 mmol) and 4-nitrobenzoic acid (200 mg, 1.2 mmol) in anhydrous THF (5 mL) was added DIAD (305 mg, 1.5 mmol). The reaction mixture was stirred at rt for 3 h. The resulting mixture was diluted with water (20 mL) and EtOAc (40 mL). The organic phase was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc / PE (5-40%) to give the product (130 mg) as a yellow solid. LCMS calculated value: C 19 H 26 N3O6[M+H] + : m / z = 392.2; found: 392.1.

[0761] Step 2: tert-Butyl (7S,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

[0762]

[0763] A solution of tert-butyl (7S,8aS)-7-((4-nitronitrobenzoyl)oxy)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (120 mg, 0.3 mmol) and LiOH.H2O (25 mg, 0.6 mmol) in THF (2 mL) and H2O (2 mL) was stirred at rt for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 5). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (70 mg) as a yellow oil. LCMS calculated value: C 12 H 23 N2O3[M+H] + : m / z = 243.2; found: 243.2.

[0764] Step 3: (7S,8aS)-Octahydropyrrolo[1,2-a]pyrazin-7-ol

[0765]

[0766] To a solution of tert-butyl (7S,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (70 mg, 0.29 mmol) in DCM (0.5 mL) was added HCl solution (4 M in 1,4-dioxane, 0.5 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure to afford the title compound (40 mg) as a yellow oil. LCMS calculated value: C7H 15 N2O[M+H] + : m / z = 143.1; found: 143.1.

[0767] Step 4: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoro-2-((7S,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0768] This compound was prepared in a similar manner to that in Step 2 of Example 101 using 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetyl chloride (Step 1 of Example 101) and (7S,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol as starting materials. LCMS calculated value: C 25 H 25 ClF3N6O4S[M+H] + : m / z = 597.1; found: 597.1.

[0769] Example 110: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoro-2-hydroxyethyl-2,2-d2)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0770]

[0771] To a solution of ethyl 2-(5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetate (200 mg, 0.4 mmol, Example 48) in MeOH-d4 (2.0 mL) at 0°C was added NaBD4 (sodium borodeuteride) (167 mg, 4.0 mmol). The reaction mixture was stirred at RT for 30 min. and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with ACN / H2O (30-60%, containing 0.5% TFA) to afford the title compound (109.3 mg) as a white solid. 1H NMR (600 MHz, DMSO-d6) δ 13.56 (s, 1H), 9.09 (s, 1H), 7.53 (t, J = 8.4 Hz, 1H), 7.21 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.73 (s, 1H), 3.57 (s, 3H), 2.51 (s, 3H). LCMS calculated value C 18 H 13 D2ClF3N4O3S[M+H] + : m / z = 461.1; found: 461.0.

[0772] Example 111: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(pentafluoroethyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0773]

[0774] Step 1: 5-(Pentafluoroethyl)-1,3,4-thiadiazol-2-amine

[0775]

[0776] To a mixture of sodium 2,2,3,3,3-pentafluoropropionate (1.86 g, 10 mmol) and thiosemicarbazide (910 mg, 10 mmol) was slowly added POCl3 (15 mL). The mixture was stirred at 75°C for 2 h., then poured into ice water (30 mL) and stirred at 0°C for 2 h. The reaction mixture was adjusted to pH 8-10 with solid NaOH. The aqueous phase was extracted with EtOAc (30 mL x 2). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc / PE (35-50%) to give the title compound (375 mg) as a yellow solid. LCMS calculated value: C4H3F5N3S[M+H] + : m / z = 220.0; found: 220.0.

[0777] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(pentafluoroethyl)-1,3,4-thiadiazol-2-yl)nicotinamide

[0778] This compound was prepared in a similar manner to step 3 of Example 1 using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(pentafluoroethyl)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value: C 18 H 12ClF6N4O2S[M+H] + : m / z = 497.0; found: 497.0.

[0779] Example 112: 3-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-yl)isonicotinamide

[0780]

[0781] Step 1: Methyl 3-(3-chloro-2-fluoro-6-methoxyphenyl)isonicotinate

[0782]

[0783] A mixture of methyl 3-chloroisonicotinate (1.0 g, 6 mmol), (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (0.94 g, 5 mmol, Int-1 Step 1), K2CO3 (1.66 g, 12 mmol) and Pd(dppf)Cl2 (0.34 g, 0.5 mmol) in 1,4-dioxane (24 mL) and H2O (3 mL) was degassed and replaced with nitrogen three times, then stirred at 80°C overnight. The mixture was diluted with EtOAc (50 mL). The organic phase was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (60-70%) to give the title compound (0.9 g) as a yellow solid. LCMS calculated value: C 14 H 12 ClFNO3[M+H] + : m / z = 296.0; found: 296.0.

[0784] Step 2: 3-(3-chloro-2-fluoro-6-methoxyphenyl)isonicotinic acid

[0785]

[0786] To a solution of methyl 3-(3-chloro-2-fluoro-6-methoxyphenyl)isonicotinate (0.9 g, 3 mmol) in THF (4 mL) and H2O (4 mL) was added LiOH. . H2O (380 mg, 9.0 mmol). The mixture was then stirred at rt overnight. The reaction mixture was diluted with water, adjusted to pH 2-3 with HCl solution (2 M), and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN / H2O (10-15%) to give the title compound (0.78 g) as a white solid. LCMS calculated value: C 13 H10 ClFNO3[M+H] + : m / z = 282.0; found: 282.0.

[0787] Step 3: 3-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-yl)isonicotinamide

[0788] To a solution of 3-(3-chloro-2-fluoro-6-methoxyphenyl)isonicotinic acid (112 mg, 0.4 mmol), TCFH (168 mg, 0.6 mmol) and NMI (66 mg, 0.8 mmol) in DMF (2 mL) was added 5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-amine (66 mg, 0.4 mmol, Example 21, Step 1). The mixture was stirred at rt for 2 h. and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (10-15%) to give the title compound (126.9 mg) as a white solid. LCMS calculated value: C 17 H 13 ClF3N4O2S[M+H] + : m / z = 429.0; found: 429.0.

[0789] Example 113: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-yl)-6-(1-methyl-1H-pyrazol-3-yl)nicotinamide

[0790]

[0791] Step 1: 6-chloro-4-(3-chloro-2-fluoro-6-methoxyphenyl)nicotinate

[0792]

[0793] A mixture of methyl 4,6-dichloronicotinate (1.0 g, 5 mmol), (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (0.75 g, 4 mmol, Int-1 Step 1), K2CO3 (1.66 g, 12 mmol) and Pd(dppf)Cl2 (0.34 g, 0.5 mmol) in 1,4-dioxane (20 mL) and H2O (2 mL) was degassed and replaced with nitrogen three times, then stirred at 80°C overnight. The mixture was diluted with EtOAc, washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (40-80%) to give the title compound (0.3 g) as a yellow solid. LCMS calculated value: C 14 H 11 Cl2FNO3[M+H] + : m / z = 330.0; found: 330.0.

[0794] Step 2: Methyl 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-(1-methyl-1H-pyrazol-3-yl)nicotinate

[0795]

[0796] A mixture of methyl 6-chloro-4-(3-chloro-2-fluoro-6-methoxyphenyl)nicotinate (0.3 g, 1 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (0.42 g, 2 mmol), KCO (0.41 g, 3 mmol), and Pd(dppf)Cl (73 mg, 0.1 mmol) in 1,4-dioxane (4 mL) and H2O (0.4 mL) was degassed and then replaced with nitrogen three times, then stirred at 80°C overnight. The mixture was diluted with EtOAc (40 mL). The organic phase was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using MeOH / DCM (0-7%) as the eluent to afford the title compound (120 mg) as a yellow solid. LCMS calculated value C 18 H 16 ClFN3O3[M+H] + : m / z = 376.1; found: 376.1.

[0797] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-(1-methyl-1H-pyrazol-3-yl)nicotinic acid

[0798]

[0799] To a solution of methyl 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-(1-methyl-1H-pyrazol-3-yl)nicotinate (120 mg, 0.32 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH. . H2O (42 mg, 1.0 mmol). The mixture was then stirred at rt overnight, diluted with water, adjusted to pH 2–3 with HCl solution (2 M), and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN / H2O (0-10%) to give the title compound (100 mg) as a white solid. LCMS calculated value: C 17 H 14 ClFN3O3[M+H] + : m / z = 362.1; found: 362.1.

[0800] Step 4: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-yl)-6-(1-methyl-1H-pyrazol-3-yl)nicotinamide

[0801] This compound was prepared in a similar manner to that in Step 3 of Example 112, using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-(1-methyl-1H-pyrazol-3-yl)nicotinic acid and 5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-amine (Step 1 of Example 21) as starting materials. LCMS calculated value: C 21 H 17 ClF3N6O2S[M+H] + : m / z = 509.1; found: 509.1.

[0802] Example 114: Ethyl 2-((5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)thio)propanoate

[0803]

[0804] Step 1: Ethyl 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)propanoate

[0805]

[0806] A mixture of 5-bromo-1,3,4-thiadiazol-2-amine (200 mg, 1.12 mmol), ethyl 2-mercaptopropionate (270 mg, 2.0 mmol), and DIEA (390 mg, 3.0 mmol) in DMF (2 mL) was degassed and then filled with nitrogen, replaced three times, and then stirred at 70°C overnight. The mixture was diluted with EtOAc (40 mL). The organic phase was washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluted with MeCN / H2O (25-45%) to give the title compound (150 mg) as a yellow oil. LCMS calculated value: C7H 12 N3O2S2[M+H] + : m / z = 234.0; found: 234.0.

[0807] Step 2: Ethyl 2-((5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamido)-1,3,4-thiadiazol-2-yl)thio)propanoate

[0808]

[0809] This compound was prepared in a similar manner to step 3 of Example 1 using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and ethyl 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)propanoate as starting materials. LCMS calculated value: C 21 H 21 ClFN4O4S2[M+H] + : m / z = 511.1; found: 511.0.

[0810] Example 115: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((1-hydroxypropyl-2-yl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0811]

[0812] To a solution of ethyl 2-((5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)thio)propanoate (50 mg, 0.49 mmol, Example 114) in THF (2 mL) was added LAH (50 mg, 1.31 mmol). The mixture was stirred at 0°C for 2 h. and then slowly diluted with EtOAc (40 mL) at 0°C. The organic phase was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (20-30%) to give the title compound (8.3 mg) as a white solid. LCMS calculated value: C 19 H 19 ClFN4O3S2[M+H] + : m / z = 469.1; found: 469.0.

[0813] Example 116: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((1-(dimethylamino)-1-oxopropan-2-yl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0814]

[0815] Step 1: 2-((5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamido)-1,3,4-thiadiazol-2-yl)thio)propanoic acid

[0816]

[0817] To a solution of ethyl 2-((5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)thio)propanoate (50 mg, 0.49 mmol, Example 114) in THF (1 mL) and H2O (1 mL) was added LiOH. . H2O (42 mg, 1.0 mmol). The mixture was then stirred at rt overnight, diluted with water, adjusted to pH 2–3 with HCl solution (2 M), and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN / H2O (10-30%) to give the title compound (30 mg) as a white solid. LCMS calculated value: C 19 H 17 ClFN4O4S2[M+H] + : m / z = 483.0; found: 483.0.

[0818] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((1-(dimethylamino)-1-oxopropan-2-yl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0819] To a solution of 2-((5-(4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)thio)propanoic acid (30 mg, 0.06 mmol), TCFH (34 mg, 0.12 mmol) and NMI (30 mg, 0.36 mmol) in DMF (1 mL) was added HNMe2 solution (0.1 mL, 2.0 M in THF, 0.2 mmol). The mixture was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (30-50%) to give the title compound (7 mg) as a white solid. LCMS calculated value: C 21 H 22 ClFN5O3S2[M+H] + : m / z = 510.1; found: 510.0.

[0820] Example 117: N-(5-((2-hydroxyethyl)thio)-1,3,4-thiadiazol-2-yl)-4-(2-methoxyphenyl)-6-methylnicotinamide

[0821]

[0822] Step 1: 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)ethan-1-ol

[0823]

[0824] A solution of 5-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)-1,3,4-thiadiazol-2-amine (580 mg, 2.0 mmol, Example 32, Step 1) in water (5 mL) and TFA (5 mL) was stirred at 50°C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (5-10%) to give the title compound (300 mg) as a white solid. LCMS calculated for C4H8N3OS2 [M+H] + : m / z = 178.0; Found: 178.0. Step 2: 4-(2-methoxyphenyl)-6-methylnicotinate

[0825]

[0826] A mixture of methyl 4-chloro-6-methylnicotinate (3.0 g, 16 mmol), (2-methoxyphenyl)boronic acid (5.0 g, 32 mmol), K2CO3 (4.4 g, 32 mmol) and Pd(dppf)Cl2 (1.1 g, 1.6 mmol) in 1,4-dioxane (24 mL) and H2O (3 mL) was degassed and then filled with N2, replacing it three times. The mixture was stirred at 80°C overnight. The resulting mixture was diluted with EtOAc (100 mL). The organic phase was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc / PE (5-20%) to give the title compound (4.0 g) as a yellow solid. LCMS calculated value: C 15 H 16 NO3[M+H] + : m / z = 258.1; found: 258.0.

[0827] Step 3: 4-(2-methoxyphenyl)-6-methylnicotinic acid

[0828]

[0829] To a solution of methyl 4-(2-methoxyphenyl)-6-methylnicotinate (4 g, 15.6 mmol) in MeOH (20 mL) and H2O (20 mL) was added NaOH (1 g, 23.4 mmol). The mixture was then stirred at rt overnight. The reaction mixture was diluted with water, the pH was adjusted to 3–4 with HCl solution (2 M), and extracted with DCM (40 mL x 5). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (3.3 g) as a yellow solid. LCMS calculated value: C 14 H 14 NO3[M+H] + : m / z = 244.1; found: 244.0.

[0830] Step 4: N-(5-((2-hydroxyethyl)thio)-1,3,4-thiadiazol-2-yl)-4-(2-methoxyphenyl)-6-methylnicotinamide

[0831] To a solution of 4-(2-methoxyphenyl)-6-methylnicotinic acid (50 mg, 0.21 mmol), TCFH (90 mg, 0.32 mmol) and NMI (35 mg, 0.42 mmol) in DMF (2 mL) was added 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)ethan-1-ol (37 mg, 0.21 mmol). The mixture was stirred at rt for 2 h. It was then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (5-15%, containing 0.5% TFA) to give the title compound (25 mg) as a white solid. LCMS calculated value C 18 H 19 N4O3S2[M+H] + : m / z = 403.1; found: 403.1.

[0832] Example 118: 4-(5-chloro-2-methoxyphenyl)-N-(5-((2-hydroxyethyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0833]

[0834] This compound was prepared in a similar manner to Steps 1-4 of Example 117, except that (5-chloro-2-methoxyphenyl)boronic acid was used instead of (2-methoxyphenyl)boronic acid in Step 2. LCMS calculated value: C 18 H 18 ClN4O3S2[M+H] + : m / z = 437.0; found: 437.1.

[0835] Example 119: 6-cyano-N-(5-((2-hydroxyethyl)thio)-1,3,4-thiadiazol-2-yl)-2-(2-methoxyphenyl)nicotinamide

[0836]

[0837] Step 1: 2-Chloro-3-(methoxycarbonyl)pyridine 1-oxide

[0838]

[0839] To a mixture of methyl 2-chloronicotinate (3.0 g, 17.5 mmol) and trifluoroacetic anhydride (3.7 g, 17.5 mmol) in DCM (12 mL) at 0°C was added urea peroxide (3.3 g, 35.0 mmol) dropwise. The mixture was stirred at rt overnight. The reaction mixture was added to a cold saturated Na2CO3 solution (30 mL) and the pH was adjusted to 8-9. The mixture was extracted with DCM (20 mL x 3). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (2.0 g) as a white solid. LCMS calculated for C7H7ClNO3 [M+H] + : m / z = 188.0; found: 187.9.

[0840] Step 2: Methyl 2-chloro-6-cyanonicotinate

[0841]

[0842] To a solution of 2-chloro-3-(methoxycarbonyl)pyridine 1-oxide (2.00 g, 10.7 mmol) and TMSCN (1.59 g, 16 mmol) in DCM (30 mL) was added acetyl chloride (1.67 g, 21.3 mmol). The mixture was stirred at rt overnight. The mixture was quenched with saturated Na2CO3 solution (40 mL). The organic phase was washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (5-35%) to give the title compound (1.5 g) as a white solid. LCMS calculated for C8H7ClN2O2 [M+H] + : m / z = 197.0; found: 196.9.

[0843] Step 3: 6-cyano-2-(2-methoxyphenyl)nicotinate

[0844]

[0845] This compound was prepared in a similar manner to that in step 2 of Example 117, using 2-chloro-6-cyanonicotinoic acid methyl ester instead of 4-chloro-6-methylnicotinoic acid methyl ester. LCMS calculated value: C 15 H 13 N2O3[M+H] + : m / z = 269.1; found: 269.0.

[0846] Step 4: 6-cyano-2-(2-methoxyphenyl)nicotinic acid

[0847]

[0848] 6-cyano-2-(2-methoxyphenyl)nicotinate (200 mg, 0.75 mmol) and LiOH . A mixture of H2O (47 mg, 1.12 mmol) in THF (3 mL) and H2O (3 mL) was stirred at rt overnight. The reaction mixture was adjusted to pH 2-3 with HCl solution (2 M), filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with CH3CN (50 mL) and MeOH (10 mL) and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (100 mg) as a yellow solid. LCMS calculated value C 14 H 11 N2O3[M+H] + : m / z = 255.1; found: 255.1.

[0849] Step 5: 6-cyano-N-(5-((2-hydroxyethyl)thio)-1,3,4-thiadiazol-2-yl)-2-(2-methoxyphenyl)nicotinamide

[0850] This compound was prepared in a similar manner to that in Step 4 of Example 117, using the intermediate 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)ethan-1-ol (Step 1 of Example 117) and 6-cyano-2-(2-methoxyphenyl)nicotinic acid as starting materials. LCMS calculated value: C 18 H 16 N5O3S2[M+H] + : m / z = 414.1; found: 414.1.

[0851] Example 120: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyano-N-(5-((2-hydroxyethyl)thio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0852]

[0853] Step 1: Methyl 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyanonicotinate

[0854]

[0855] A mixture of methyl 4-chloro-6-cyanonicotinate (0.4 g, 2.0 mmol), (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (0.49 g, 2.4 mmol, Int-1 Step 1), Na2CO3 (0.64 g, 6 mmol), and Pd(dppf)Cl2 (146 mg, 0.25 mmol) in 1,4-dioxane (20 mL) and H2O (5 mL) was degassed and filled with N2 three times, then stirred at 80°C overnight. The resulting reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using EtOAc / PE (30-50%) as the eluent to afford the title compound (0.44 g) as a light yellow solid. LCMS calculated: C 15 H 10 ClFN2O3[M+H] + : m / z = 320.0; found: 320.0.

[0856] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyanonicotinic acid

[0857]

[0858] 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyanonicotinate (0.42 g, 1.31 mmol) and LiOH . A mixture of H2O (168 mg, 4 mmol) in THF (3 mL) and H2O (3 mL) was stirred at rt overnight. The reaction mixture was then diluted with water, adjusted to pH 3–4 with HCl solution (2 M), and extracted with DCM (20 mL x 5). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (210 mg) as a yellow oil. LCMS calculated value: C 14 H9ClFN2O3[M+H] + : m / z = 307.0; found: 307.0.

[0859] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyano-N-(5-((2-hydroxyethyl)thio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0860] This compound was prepared in a similar manner to that in Step 4 of Example 117, using the intermediate 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)ethan-1-ol (Step 1 of Example 117) and 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-cyanonicotinic acid as starting materials. LCMS calculated value: C 18 H 14 ClFN5O3S2[M+H] + : m / z = 466.0; found: 466.0.

[0861] Example 121: N-(5-((2-hydroxyethyl)thio)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide

[0862]

[0863] Step 1: Ethyl 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylate

[0864]

[0865] A mixture of ethyl glyoxylate (3.32 g, 50% solution in toluene), o-anisidine (2.0 g, 16.2 mmol), and Na₂SO₄ (13.8 g, 97.4 mmol) in toluene (20 mL) was degassed and flushed with N₂ three times, then stirred at 110°C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The above residue, K₂CO₃ (1.48 g, 10.7 mmol), and TosMIC (1.59 g, 8.1 mmol) in EtOH (20 mL) was degassed and flushed with N₂ three times, then stirred at 50°C for 12 h. The reaction mixture was extracted with diluted H₂O (30 mL) and EtOAc (30 mL x 3). The combined organic phases were washed with water and saturated brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using EtOAc / PE (10-50%) as eluent to afford the title compound (1.1 g) as a brown solid. LCMS calculated value: C 13 H 15 N2O3[M+H] + : m / z = 247.1; found: 247.1.

[0866] Step 2: 1-(2-Methoxyphenyl)-1H-imidazole-5-carboxylic acid

[0867]

[0868] 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylic acid ethyl ester (500 mg, 2.0 mmol), and LiOH . A mixture of H2O (170 mg, 4.1 mmol) in MeOH (5 mL) and H2O (4 mL) was stirred at rt overnight. The resulting mixture was diluted with water (20 mL), adjusted to pH 4–5 with HCl solution (2 M), and then extracted with DCM (20 mL x 3). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (200 mg) as a yellow solid. LCMS calculated value: C 11 H 11 N2O3[M+H] + : m / z = 219.1; found: 219.1.

[0869] Step 3: N-(5-((2-hydroxyethyl)thio)-1,3,4-thiadiazol-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide

[0870] This compound was prepared in a similar manner to that in Step 4 of Example 117, using the intermediate 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)ethan-1-ol (Step 1 of Example 117) and 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylic acid as starting materials. LCMS calculated value: C 15 H 16 N5O3S2[M+H] + : m / z = 378.1; found: 378.1.

[0871] Example 122: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(((5-chloropyridin-2-yl)oxy)difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0872]

[0873] Step 1: Cesium 2-((5-chloropyridin-2-yl)oxy)-2,2-difluoroacetate

[0874]

[0875] To a mixture of sodium 2-bromo-2,2-difluoroacetate (5 g, 25.3 mmol) and 5-chloropyridin-2-ol (3.92 g, 30.4 mmol) in 1,4-dioxane (50 mL) was added Cs2CO3 (24.8 g, 76.1 mmol). The reaction mixture was stirred at 100°C overnight. The mixture was concentrated under reduced pressure to give the title compound (13 g, crude) as a yellow solid. LCMS calculated value: C7H3ClF2NO3[M-Cs] - : m / z = 222.0; found: 222.1.

[0876] Step 2: 5-(((5-chloropyridin-2-yl)oxy)difluoromethyl)-1,3,4-thiadiazol-2-amine

[0877]

[0878] To a mixture of cesium 2-((5-chloropyridin-2-yl)oxy)-2,2-difluoroacetate (2.2 g, 10 mmol) and thiosemicarbazide (910 mg, 10 mmol) was slowly added POCl3 (8 mL). The mixture was stirred at 75°C for 3 h, poured into ice water (30 mL), and stirred at 0°C for 2 h. The reaction mixture was adjusted to pH 8-10 with solid NaOH and extracted with EtOAc (30 mL x 4). The combined organic phases were washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN / H2O (20-40%) to give the title compound (10 mg) as a yellow oil. LCMS calculated for C8H6ClF2N4OS[M+H] + : m / z = 279.0; found: 279.1.

[0879] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(((5-chloropyridin-2-yl)oxy)difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0880] This compound was prepared in a similar manner to step 3 of Example 1 using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(((5-chloropyridin-2-yl)oxy)difluoromethyl)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value: C 22 H 15 Cl2F3N5O3S[M+H] + : m / z = 556.0; found: 556.0.

[0881] Example 123: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(((S)-2-hydroxypropyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0882]

[0883] Step 1: (S)-1-((5-amino-1,3,4-thiadiazol-2-yl)thio)propan-2-ol

[0884]

[0885] To a mixture of 5-amino-1,3,4-thiadiazole-2-thiol (265 mg, 2.0 mmol) in DMF (0.5 mL) and (S)-2-methyloxirane (1.0 mL) was added LiOH. . H2O (10 mg, 0.25 mmol). The reaction mixture was stirred at rt overnight. The solid was filtered to give the desired product (170 mg) as a white solid. LCMS calculated value: C5H 10 N3OS2[M+H] + : m / z = 192.0; found: 192.1.

[0886] Step 2: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(((S)-2-hydroxypropyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0887] To a mixture of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (60 mg, 0.2 mmol, Int-1), TCFH (84 mg, 0.3 mmol), and NMI (82 mg, 1 mmol) in DMF (1 mL) was added (S)-1-((5-amino-1,3,4-thiadiazol-2-yl)thio)propan-2-ol (40 mg, 0.22 mmol). The mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN / H2O (40-50%) to give the desired product (45.9 mg) as a white solid. 1H NMR (600 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.59 (t, J = 9.0 Hz, 1H), 7.40 (s, 1H), 6.93 (d, J = 9.0 Hz, 1H), 5.08 (d, J = 4.8 Hz, 1H), 3.95-3.85 (m, 1H), 3.56 (s, 3H), 3.30-3.19 (m, 2H), 2.58 (s, 3H), 1.16 (d, J = 5.4 Hz, 3H). LCMS calculated value C 19 H 19 ClFN4O3S2[M+H] + : m / z = 469.1; found: 469.1.

[0888] Example 124: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(((R)-2-hydroxypropyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0889]

[0890] This compound was prepared in a similar manner to Steps 1-2 of Example 123, except that (S)-2-methyloxirane was replaced with (R)-2-methyloxirane in Step 1. LCMS calculated value: C 19 H 19 ClFN4O3S2[M+H] + : m / z = 469.1; found: 469.1.

[0891] Example 125: 5-Chloro-N-(5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-yl)-2-methoxy-6'-methyl-[3,4'-bipyridine]-3'-carboxamide

[0892]

[0893] Step 1: 5-Chloro-2-methoxy-6'-methyl-[3,4'-bipyridyl]-3'-carboxylic acid methyl ester

[0894]

[0895] A mixture of methyl 4-chloro-6-methylnicotinate (1.6 g, 8 mmol), 5-chloro-2-methoxypyridin-3-yl)boronic acid (0.94 g, 5 mmol), K2CO3 (4.4 g, 16 mmol) and Pd(dppf)Cl2 (0.34 g, 0.5 mmol) in 1,4-dioxane (24 mL) and H2O (3 mL) was degassed and then filled with nitrogen three times, then stirred at 80°C for 16 h. The mixture was diluted with EtOAc (50 mL). The organic phase was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc / PE (50-70%) to give the title compound (0.4 g) as a yellow solid. LCMS calculated value: C 14 H 14 ClN2O3[M+H] + : m / z = 293.1; found: 293.1.

[0896] Step 2: 5-Chloro-2-methoxy-6'-methyl-[3,4'-bipyridyl]-3'-carboxylic acid

[0897]

[0898] To a solution of 2'-chloro-5'-methoxy-6-methyl-[3,4'-bipyridine]-3-carboxylic acid methyl ester (0.4 g, 1.4 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH. . H2O (180 mg, 4.5 mmol). The mixture was then stirred at rt overnight. The reaction mixture was diluted with water, adjusted to pH 2-3 with HCl solution (2 M), and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column using MeCN / H2O (10-15%) as the eluent to give the title compound (230 mg) as a yellow oil. LCMS calculated value: C 13 H 12 ClN2O3[M+H] + : m / z = 279.1; found: 279.1.

[0899] Step 3: 5-Chloro-N-(5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-yl)-2-methoxy-6'-methyl-[3,4'-bipyridine]-3'-carboxamide

[0900] To a solution of 5-chloro-2-methoxy-6'-methyl-[3,4'-bipyridine]-3'-carboxylic acid (56 mg, 0.2 mmol), TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL) was added 5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-amine (33 mg, 0.2 mmol, Example 21 Step 1). The mixture was stirred at rt for 2 h. It was then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN / H2O (0-15%) to give the title compound (44 mg) as a white solid. LCMS calculated value C 17 H 15 ClF2N5O2S[M+H] + : m / z = 426.1; Found: 426.1. Int-1: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0901]

[0902] Step 1: (3-Chloro-2-fluoro-6-methoxyphenyl)boronic acid

[0903]

[0904] To a solution of 1-chloro-2-fluoro-4-methoxybenzene (2.00 g, 12.5 mmol) in anhydrous THF (20 mL) at -70°C under N2 atmosphere was added LDA (2.0 M in THF, 12.5 mL). The mixture was stirred at -70°C for 1 h, then triisopropyl borate (4.70 g, 25.0 mmol) was added at -70°C. The resulting mixture was stirred at -70°C for 2 h and quenched with saturated NH4Cl (50 mL) at 0°C. The aqueous phase was adjusted to pH 2-3 with HCl solution (1.0 M) and extracted with EtOAc (40 mL x 5). The combined organic phases were washed with saturated brine (40 mL), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column eluting with EtOAc / PE (0-10%) to give (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (1.6 g) as an off-white solid.

[0905] Step 2: Methyl 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinate

[0906]

[0907] A mixture of methyl 4-chloro-6-methylnicotinate (3.0 g, 16 mmol), (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (3.2 g, 16 mmol), K2CO3 (4.4 g, 32 mmol), and Pd(dppf)Cl2 (1.1 g, 1.6 mmol) in 1,4-dioxane (24 mL) and H2O (3 mL) was degassed and then replaced with nitrogen three times. The mixture was stirred at 80°C for 16 h. The mixture was diluted with EtOAc (80 mL), washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (0-20%) to give the desired product (2.8 g) as a yellow solid. LCMS calculated value: C 15 H 14 FClNO3[M+H] + : m / z = 310.1; found: 310.0.

[0908] Step 3: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0909] To a solution of methyl 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinate (70 mg, 0.23 mmol) in MeOH (2 mL) and H2O (2 mL) was added LiOH. . The mixture was stirred overnight at rt. The reaction mixture was diluted with water, adjusted to pH 3-4 with HCl solution (2 M), and extracted with DCM (20 mL x 5). The combined organic phases were washed with saturated brine (15 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (50 mg) as a yellow oil, which was used directly in the next step without further purification. LCMS calculated value: C 14 H 12 FClNO3[M+H] + : m / z = 296.0; found: 296.0.

[0910] Int-2: 4-(2-Fluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0911]

[0912] Step 1: Methyl 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinate

[0913]

[0914] This compound was prepared in a similar manner to Int-1, step 2, using 2-fluoro-6-methoxyphenylboronic acid instead of (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid to obtain the desired product as a yellow solid. LCMS calculated value: C 15 H 15 FNO3[M+H]+: m / z=276.1; found: 276.0.

[0915] Step 2: 4-(2-Fluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0916]

[0917] This compound was prepared in a similar manner to step 3 of Int-1, using 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinate to obtain the desired product as an off-white solid. LCMS calculated value: C 14 H 13 FNO3[M+H]+: m / z=261.1; found: 261.0.

[0918] Int-3: 4-(2,3-difluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0919]

[0920] Step 1: 4-(2,3-difluoro-6-methoxyphenyl)-6-methylnicotinate

[0921]

[0922] This compound was prepared in a similar manner to Int-1 step 2, using (2,3-difluoro-6-methoxyphenyl)boronic acid instead of (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid to obtain the desired product as a yellow solid. LCMS calculated value: C 15 H 14 F2NO3[M+H] + : m / z = 294.1; found: 294.1.

[0923] Step 2: 4-(2,3-difluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0924] This compound was prepared by a similar method as that in step 3 of Int-1, using 4-(2,3-difluoro-6-methoxyphenyl)-6-methylnicotinate as the starting material to obtain the target product as an off-white solid. LCMS calculated value: 14 H 12 F2NO3[M+H] + : m / z = 280.1; found: 280.1.

[0925] Int-4: 4-(2-Fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinic acid

[0926]

[0927] Step 1: 4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinate

[0928]

[0929] This compound was prepared in a similar manner to Int-1, step 2, using 2-fluoro-6-methoxy-3-methylphenylboronic acid instead of (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid to obtain the desired product as a white solid. LCMS calculated value: C 16 H 17 FNO3[M+H] + : m / z = 290.1; found: 290.1.

[0930] Step 2: 4-(2-Fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinic acid

[0931] This compound was prepared according to Int-1 step 3 using 4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinate to obtain the desired product as an off-white solid. LCMS calculated value: 15 H 15 FNO3[M+H] + : m / z = 275.1; Found: 275.1. Int-5: 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid

[0932]

[0933] Step 1: 2-(3-Fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0934]

[0935] A mixture of 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (9.7 g, 40 mmol), bis(pyrazoline)-2-nitropropene (12.7 g, 50 mmol), KOAc (9.8 g, 100 mmol) and Pd(dppf)Cl2 (0.87 g, 1.2 mmol) in 1,4-dioxane (120 mL) was degassed and then filled with nitrogen, replacing 3 times. The reaction mixture was stirred at 100 ° C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL), washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in PE and filtered through a silica gel pad to obtain the target compound (11.5 g, yield 99%) as a yellow oil. TLC R f =0.4 (EtOAc / PE=1 / 50, UV 254nm).

[0936] Step 2: 3-Fluoro-4-(trifluoromethyl)phenol

[0937]

[0938] To a cooled mixture of 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.5 g, 40 mmol) and NaOH (6.4 g, 160 mmol) in THF (400 mL) and water (20 mL) (in an ice-water bath) was added H2O2 solution (16 mL, 33%). The mixture was stirred at 0°C for 4 h, and the filtrate was concentrated under reduced pressure. The residue was diluted with PE (300 mL) and filtered. The filtrate was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (7.0 g, 97% yield) as a yellow oil. LCMS calculated value: C7H3F4O[MH] + : m / z = 179.0; found: 179.0. TLC R f =0.45 (EtOAc / PE=1 / 25, UV 254nm).

[0939] Step 3: 2-Fluoro-4-methoxy-1-(trifluoromethyl)benzene

[0940]

[0941] To a mixture of 3-fluoro-4-(trifluoromethyl)phenol (7.0 g, 38.9 mmol), K2CO3 (13.8 g, 100 mmol) in MeCN (40 mL) was added MeI (8.5 g, 60 mmol). The mixture was stirred at 40°C for 4 h and concentrated under reduced pressure. The residue was diluted with PE (200 mL) and filtered. The filtrate was washed with water and saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted wi...

Claims

1. A compound represented by formula (I): or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated substance thereof; wherein: Ring A is C5-C 10 Cycloalkyl, 5-10 membered heterocyclic group, C6-C 10 Aryl, or 5-10 membered heteroaryl; Cy is C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, or 5-10 membered heteroaryl; m is an integer of 1, 2, 3, 4, or 5; n is an integer of 1, 2, 3, 4, or 5; Every R 1 independently selected from H, D, –CN, –NO2, –N3, oxo, –SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, –NR C R D ,–OR A , –SR A , –NR C OR A , –C(O)R B , –C(O)NR C R D , –C(O)OR A ,–OC(O)R B , –NR C C(O)R B , –S(O)R B , –S(O)2R B , –S(O)NR C R D , –NR C S(O)2R D , –S(O)2NR C R D , –NR C S(O)2NR C R D , –NR C S(O)(=NR B )R B , –SiR G R H R I , –B(OR E )(OR F ), –P(O)R E R F , –P(O)OR E OR F , or –OP(O)OR E OR F wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 1A or Two R's 1 Together with the atoms to which they are attached, they form an oxo, a C3-C7 cycloalkyl, a 4-7 membered heterocyclyl, a phenyl, or a 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, phenyl, and heteroaryl are optionally substituted by 1, 2, 3, or 4 independently selected from R 1A Substituents are substituted; Every R 1A are independently selected from D, halogen, –CN, –OH, –NH2, –NO2, –SF5, oxo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, –NR c R d ,–OR a , –SR a , –C(O)R b , –C(O)NR c R d , –C(O)OR a ,–OC(O)R b , –OC(O)NR c R d ,– NR c C(O)R b ,–NR c C(O)NR c R d ,–NR c C(O)OR a ,–S(O)(=NR b )R b ,–S(O)R b ,– S(O)NR c R d , –S(O)2R b , –NR c S(O)2R d , –S(O)2NR c R d , –NR c S(O)2NR c R d , or –NR c S(O)(=NR b )R b wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted by D, halogen, -CN, oxo, -NR c1 R d1 ,–OR a1 , –SR a1 , C1-C6 alkyl, or C1-C6 haloalkyl; Every R 2 Independently selected from H, D, halogen, –CN, –NO2, –N3, –SF5, –OR A , –SR A , –C(O)R B , –C(O)NR C R D , –C(O)OR A ,–OC(O)R B , –NR C R D , –NR C C(O)R B , –S(O)R B , –S(O)2R B , –S(O)NR C R D , –NR C S(O)2R D , –S(O)2NR C R D , –NR C S(O)2NR C R D , –NR C S(O)(=NR B )R B , –SiR G R H R I , –B(OR E )(OR F ), –P(O)R E R F , –P(O)OR E OR F ,–OP(O)OR E OR F , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2A Substituents are substituted; Every R 2A independently selected from D, halogen, –CN, –OH, –NH2, –NO2, –N3, oxo, C1-C6 alkyl, –OC1-C6 alkyl, C1-C6 haloalkyl, –OC1-C6 haloalkyl, –NHC1-C3 alkyl, –N(C1-C3 alkyl)2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with substituents selected from the following: D, halogen, –CN, –OH, –NH2, C1-C6 alkyl, C1-C6 haloalkyl, –O-C1-C6 alkyl, or –O-C1-C6 haloalkyl; or Two adjacent R 2 Together with the atoms to which they are attached, they form a C4-C7 cycloalkyl or a 4-7 membered heterocyclic group, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 2B Substituents are substituted; Every R 2B is independently selected from D, halogen, oxo, –CN, –OH, –NH2, –NO2, C1-C6 alkyl, C1-C6 haloalkyl, –O-C1-C6 alkyl, or –O-C1-C6 haloalkyl; R 3 Selected from: i)H, D, –CN, halogen, –NO2, –N3, –SF5, –B(OR 5 )(OR 6 ), –SiR 5 R 6 R 7 , –SR 8 , –S(O)R 8 , –S(O)2R 8 , –NR 9 R 10 , –NR 9 C(O)R 8 , –C(O)R 8 , –S(O)NR 9 R 10 , –S(O)2NR 9 R 10 , C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 Substituents; each R 4 independently selected from H, D, halogen, –CN, –NO2, –N3, oxo, –OR A1 ,–OR A2 , C1-C4 alkyl, –C(O)R B , –C(O)NR C R D , –C(O)OR A , –C(O)NR C S(O)R B , –C(O)NR C S(O)2R B ,–OC(O)R B , –OC(O)NR C R D , –NR C R D , –NR C C(O)R B , –NR C C(O)NR C R D , –NR C C(O)OR A , –SR A , –S(O)R B , –S(O)2R B , –S(O)NR C R D , –NR C S(O)2R D , –S(O)2NR C R D , –NR C S(O)2NR C R D , –NR C S(O)(=NR B )R B , –SiR G R H R I , or –B(OR E )(OR F ); R A1 are independently selected from H, D, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl; wherein the alkyl, alkenyl, and alkynyl are optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 11 Substituents are substituted; Every R 11 independently selected from D, –CN, –N3, halogen, –NO2, oxo, –OR a , –SR a , –NR c R d , –C(O)R b , –C(O)NR c R d , –C(O)OR a ,–OC(O)R b , –OC(O)NR c R d , –NR c C(O)R b , –NR c C(O)NR c R d , –NR c C(O)OR a , –S(O)R b , –S(O)2R b , –S(O)NR c R d , –NR c S(O)2R d , –S(O)2NR c R d , –NR c S(O)2NR c R d , –NR c S(O)(=NR b )R b , –SiR g R h R i , –B(OR e )(OR f ), C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl; wherein the aryl, cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 Substituents are substituted; R A2 C3-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 12 Substituents are substituted; Every R 12 are independently selected from H, D, halogen, –CN, –N3, –NO2, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, –OR a , –SR a , –C(O)R b , –C(O)NR c R d , –C(O)OR a ,–OC(O)R b , –OC(O)NR c R d , –NR c R d , –NR c C(O)R b , –NR c C(O)NR c R d , –NR c C(O)OR a ,– B(OR e )(OR f ),–C(=NR c )NR c R d ,–NR d C(=NR c )NR c R d ,–NR d C(=NR c )R b ,– S(O)(=NR b )R b ,–S(O)R b ,–S(O)NR c R d ,–S(O)2R b ,–NR c S(O)2R d ,–S(O)2NR c R d , –NR c S(O)2NR c R d , –NR c S(O)(=NR b )R b , or –SiR g R h R i ; wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, -CN, halogen, -NO2, oxo, selectively substituted C1-C6 alkyl, selectively substituted C2-C6 alkenyl, selectively substituted C2-C6 alkynyl, -NH2, -NHC1-C4 alkyl, or -N(C1-C4 alkyl)2; or ii) C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 13 Substituents are substituted; Every R 13 independently selected from H, D, halogen, -SF5, -CN, -NO2, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, –SR A ,–OR A , –C(O)R B , –C(O)NR C R D , –C(O)OR A ,–OC(O)R B , –OC(O)NR C R D , –NR C R D ,– NR C C(O)R B ,–NR C C(O)NR C R D ,–NR C C(O)OR A ,–C(=NR C )NR C R D ,– NR D C(=NR C )NR C R D ,–NR D C(=NR C )R B ,–SiR G R H R I ,–B(OR E )(OR F ),– S(O)(=NR B )R B ,–S(O)R B ,–S(O)NR C R D ,–S(O)2R B ,–NR C S(O)2R D ,– S(O)2NR C R D ,–NR C S(O)2NR C R D , or –NR C S(O)(=NR B )R B ; Every R 5 , R 6 , and R 7 Each of the following substituents is independently selected from H, D, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, or phenyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and phenyl are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following substituents: D, halogen, –CN, –NO2, –N3, oxo, –NR C R D ,–OR A , –SR A , –C(O)R B , –C(O)NR C R D , –OC(O)NR C R D , –NR C C(O)R B , –NR C C(O)NR C R D , –NR C C(O)OR A , –S(O)R B , –S(O)2R B , –S(O)NR C R D , –NR C S(O)2R D , –S(O)2NR C R D , –NR C S(O)2NR C R D , C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C3-C6 cycloalkyl; Every R 8 independently selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, or 5-10 membered heteroaryl, each substituent is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 8A Substituents are substituted; Every R 8A are independently selected from D, halogen, –CN, –NO2, –N3, oxo, –NR C R D ,–OR A , –SR A , –SiR G R H R I , –B(OR E )(OR F ), –C(O)R B , –C(O)NR C R D , –OC(O)NR C R D , –NR C C(O)R B , –NR C C(O)NR C R D ,–NR C C(O)OR A ,–S(O)R B ,–S(O)2R B ,–S(O)NR C R D ,– NR C S(O)2R D ,–S(O)2NR C R D ,–NR C S(O)2NR C R D ,–NR C S(O)(=NR B )R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, phenyl, and heteroaryl are optionally substituted by a substituent selected from the group consisting of: D, halogen, –CN, –OH, –NH2, C1-C6 alkyl, C1-C6 haloalkyl, –O-C1-C6 alkyl, or –OC 1- C6 haloalkyl; Every R 9 and R 10 are independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –OH, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, –OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OC(O)NR c R d , –NR c R d , –NR c C(O)R b , –S(O)NR c R d , –S(O)2R b , –NR c S(O)2R b , –S(O)2NR c R d , –NR c S(O)2NR c R d , or –B(OR e )(OR f ); Every R A independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –NO2, oxo, –OR a , –SR a , –SF5, –NHOR a , –C(O)R b , –C(O)NR c R d , –C(O)OR a ,–OC(O)R b , –OC(O)NR c R d , –NR c R d , –NR c C(O)R b , –NR c C(O)NR c R d , –NR c C(O)OR a , –B(OR e )(OR f ), –SiR g R h R i , –C(=NR c )NR c R d , –NR d C(=NR c )NR c R d , –NR d C(=NR c )R b , –P(O)R e R f , –P(O)OR e OR f ,–OP(O)OR e OR f , –S(O)R b , –S(O)NR c R d , –S(O)2R b , –NR c S(O)2R b , –S(O)2NR c R d , –NR c S(O)2NR c R d , or –NR c S(O)(=NR b )R b ; Every R B independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted by 1, 2, 3, 4, or 5 independently selected from R B1 Substituents are substituted; Every R B1 D is independently selected from the group consisting of -CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, C0-C4 alkyl-C3-C 10 Cycloalkyl, C0-C4 alkyl-4-10 membered heterocyclic group, C0-C4 alkyl-C6-C 10 Aryl, C0-C4 alkyl-5-10 membered heteroaryl, –SF5, –C(O)R b , –OC(O)NR c R d ,–OR a , –NR c R d , –NR c C(O)R b , –NR c C(O)NR c R d , –NR c C(O)OR a , –S(O)R b , –S(O)NR c R d , –S(O)2R b , –NR c S(O)2R b , –S(O)2NR c R d , –NR c S(O)2NR c R d , or –B(OR e )(OR f ); wherein the alkyl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, and alkyl-heteroaryl are optionally substituted with a substituent selected from the group consisting of D, –CN, halogen, oxo, –OH, –NH2, –SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –O-C1-C4 alkyl, –O-C1-C4 haloalkyl, –NH-C1-C4 alkyl, or –NH(C1-C4 alkyl)2; Every R C and R D are independently selected from H, D, –CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a , –OC(O)NR c R d , –NR c R d , –NR c C(O)R b , –S(O)NR c R d , –S(O)2R b , –NR c S(O)2R b , –S(O)2NR c R d , –NR c S(O)2NR c R d , or –B(OR e )(OR f );or R C and R D Together with the N atom to which it is attached, it forms a 4-7 membered heterocyclyl, optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –OH, oxo, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, –OC1-C4 alkyl, or –OC1-C4 haloalkyl; Every R a and R a1 are independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the following: D, halogen, –OH, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, C1-C4 alkyl, –OC1-C4 alkyl, C1-C4 haloalkyl, or –OC1-C4 haloalkyl; Every R b and R b1 are independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclylalkyl; wherein the alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –OH, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl; Every R c and R d are independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, arylcycloalkyl, arylheterocyclyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocyclyl, heteroarylaryl, or biheteroaryl; wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, arylcycloalkyl, arylheterocyclyl, arylheteroaryl, biaryl, heteroaryl The cycloalkyl, heteroarylheterocyclyl, heteroarylaryl, and biheteroaryl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, –OH, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, –C(O)OR a1 , –C(O)R b1 , –S(O)2R b1 , C1-C4 alkyl-O-C1-C4 alkyl, or C1-C4 alkyl-O-C1-C4 alkoxy; or R c and R d The alkylene group and the nitrogen atom to which it is attached form a 4-7 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following groups: D, –OH, –CN, –NH2, –NH(C1-C4 alkyl), –N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C4 alkoxy-C1-C4 alkyl, or C1-C4 alkoxy-C1-C4 alkoxy; Every R E and R e are independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy)-C1-C4 alkyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C4 alkyl, C3-C 10 Cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocyclyl-C1-C4 alkyl; Every R F and R f are independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, or 4-10 membered heterocyclic group; Every R G , R H , R I , R g , R h , and R i Each independently selected from C1-C4 alkyl or phenyl; The compound is neither 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide nor 2'-chloro-N-(5-(2-(dimethylamino)-2-oxoethyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

2. The compound according to claim 1, characterized in that Ring A is a 6-membered heteroaryl, a 5-membered heteroaryl, a 7-10-membered heteroaryl, or a C6-C 10 Aryl.

3. The compound according to claim 1 or 2, characterized in that Ring A is a 7-10 membered heteroaryl group.

4. The compound according to any one of claims 1 to 3, characterized in that Ring A is a 6-membered heteroaryl group, a 5-membered heteroaryl group or a C6 aryl group.

5. The compound according to any one of claims 1 to 4, characterized in that Ring A is pyridyl, pyridazinyl, or imidazolyl.

6. The compound according to any one of claims 1 to 5, characterized in that The compound is represented by formula (IIa), (IIb), (IIc), (IId), or (IIe): or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof.

7. The compound according to any one of claims 1 to 6, characterized in that The compound is shown in formula (IIa): or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof.

8. The compound according to any one of claims 1 to 6, characterized in that The compound is shown as (IIc): or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof.

9. The compound according to any one of claims 1 to 6, characterized in that The compound is shown as (IIe): or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof.

10. The compound according to any one of claims 1 to 9, characterized in that Cy is C 6- C 10 Aryl or 5-10 membered heteroaryl.

11. The compound according to any one of claims 1 to 10, characterized in that Cy is a phenyl group or a 6-membered heteroaryl group.

12. The compound according to any one of claims 1 to 11, characterized in that Cy is phenyl, pyridyl, or pyrazinyl.

13. The compound according to any one of claims 1 to 12, characterized in that Cy is phenyl or pyridin-4-yl.

14. The compound according to any one of claims 1 to 13, characterized in that Every R 2 are independently selected from (i) H, D, halogen, or -OR A or (ii) C1-C6 alkyl, optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2A substituted by a substituent.

15. The compound according to any one of claims 1 to 14, characterized in that Every R 2 Each is independently selected from H, -F, -Cl, -CH3, -CF3, or -OCH3.

16. The compound according to any one of claims 1 to 15, characterized in that One of the R 2 is –F.

17. The compound according to any one of claims 1 to 16, characterized in that One of the R 2 is –Cl, –CH3, or –CF3.

18. The compound according to any one of claims 1 to 17, characterized in that One of the R 2 is –OCH3.

19. The compound according to any one of claims 1 to 18, characterized in that Three of the R 2 Not for H.

20. The compound according to any one of claims 1 to 19, characterized in that Three of the R 2 is not H; the first is –F; the second is –Cl, –CH3, or –CF3; and the third is –OCH3.

21. The compound according to any one of claims 1 to 20, characterized in that Three of the R 2 Not H; the first one is –F; the second one is –Cl; the third one is –OCH3.

22. The compound according to any one of claims 1 to 21, characterized in that It has the following structure:

23. The compound according to any one of claims 1 to 11, characterized in that The compound is represented by (Xa), (Xb), (Xc), (Xd), or (Xe): or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated substance thereof; wherein: Each Y 3 Independently selected from N or CR 2 .

24. The compound according to claim 23, characterized in that The compound is shown as (Xa): or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof.

25. The compound according to claim 23, characterized in that The compound is shown as (Xc): or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof.

26. The compound according to claim 23, characterized in that The compound is (Xe): or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof.

27. The compound according to any one of claims 23 to 26, characterized in that Y 3 is N.

28. The compound according to any one of claims 23 to 26, characterized in that Y 3 CR 2 .

29. The compound according to any one of claims 23 to 26 and 28, characterized in that Y 3 is CH.

30. The compound according to any one of claims 23 to 28, characterized in that One of the R 2 It is a halogen.

31. The compound according to any one of claims 23 to 29, characterized in that One of the R 2 For fluorine.

32. The compound according to any one of claims 23 to 31, characterized in that Every R 2 independently selected from (i) H, D, halogen, or -OR A or (ii) C1-C6 alkyl, optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2A substituted by a substituent.

33. The compound according to any one of claims 23 to 32, characterized in that Every R 2 independently selected from H, -F, –Cl, –CH3, –CF3, or –OCH3.

34. The compound according to any one of claims 23 to 33, characterized in that One of the R 2 is –F, –Cl, –CH3, or –CF3.

35. The compound according to any one of claims 23 to 34, characterized in that One of the R 2 is –Cl.

36. The compound according to any one of claims 23 to 35, characterized in that One of the R 2 is –OCH3.

37. The compound according to any one of claims 23 to 36, characterized in that One of the R 2 is –F, –Cl, –CH3, or –CF3; one of the R 2 is –OCH3; the rest R 2 For H.

38. The compound according to any one of claims 23 to 37, characterized in that One of the R 2 is –Cl; one of the R 2 is –OCH3; the rest R 2 For H.

39. The compound according to any one of claims 23 to 31, characterized in that It has the following structure:

40. The compound according to any one of claims 1 to 39, characterized in that Every R 1 are independently selected from (i) H, D, -CN, or halogen; or (ii) C1-C6 alkyl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 are independently selected from R 1A substituted by a substituent.

41. The compound according to any one of claims 1 to 40, characterized in that Every R 1 independently selected from (i) H, D, or -CN; or (ii) C1-C6 alkyl or 5-membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 1A substituted by a substituent.

42. The compound according to any one of claims 1 to 41, characterized in that Every R 1 Independently selected from H, D, -CN, methyl, or 1-methylpyrazolyl.

43. The compound according to any one of claims 1 to 42, characterized in that Every R 1 Independently selected from H or methyl.

44. The compound according to any one of claims 1 to 40, characterized in that One of the R 1 is (i) -CN or halogen; or (ii) C1-C6 alkyl or 5-10 membered heteroaryl, each substituent being optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 1A The remaining R 1 For H.

45. The compound according to any one of claims 1 to 40 and 34, characterized in that One of the R 1 is –CN, methyl, or 1-methylpyrazolyl; the remaining R 1 They are H respectively.

46. The compound according to any one of claims 1 to 40, 44, and 45, characterized in that One of the R 1 is methyl; the remaining R 1 They are H respectively.

47. The compound according to any one of claims 1 to 22, 40 to 45, characterized in that It has the following structure:

48. The compound according to any one of claims 1 to 47, characterized in that R 3 is C1-C8 alkyl or C2-C8 alkenyl, each substituent is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected from R 4 substituted by a substituent.

49. The compound according to claim 48, characterized in that Every R 4 independently selected from halogen, –C(O)R B , –C(O)NR C R D , –C(O)OR A ,–OR A1 , or –OR A2 .

50. The compound according to any one of claims 1 to 49, characterized in that R 3 for 51. The compound according to any one of claims 1 to 50, characterized in that R 3 for 52. The compound according to claim 51, characterized in that Every R 4 For fluorine.

53. The compound according to any one of claims 49 to 52, characterized in that R C is (i) H; or (ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following substituents: D, -CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, -SF5, -OR a , –OC(O)NR c R d , –NR c R d , –NR c C(O)R b , –S(O)NR c R d , –S(O)2R b , –NR c S(O)2R b , –S(O)2NR c R d , –NR c S(O)2NR c R d , or –B(OR e )(OR f ).

54. The compound according to any one of claims 49 to 53, characterized in that R C is (i) H; or (ii) C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, cycloalkylalkyl, or heteroarylalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from cyano, halogen, C1-C4 alkyl, -OR a , or –NR c R d .

55. The compound according to any one of claims 49 to 54, characterized in that R C is (i) H; or (ii) methyl, ethyl, propyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, pyrazolyl, cyclopropylmethyl, or pyridyl-methyl, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the following: cyano, fluoro, methyl, hydroxy, methoxy, or dimethylamino.

56. The compound according to any one of claims 49 to 55, characterized in that R C is H, methyl, ethyl, 2-cyanoethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-dimethylaminoethyl, isopropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-methoxy-2-methylpropyl, cyclopropyl, 4-hydroxy-cyclohexyl, tetrahydropyran-4-yl, 1-methylpyrazol-4-yl, (1-hydroxycyclopropyl)methyl, (1-methoxycyclopropyl)methyl, or pyridin-2-ylmethyl.

57. The compound according to any one of claims 49 to 56, characterized in that R C is H, methyl, or ethyl.

58. The compound according to any one of claims 49 to 57, characterized in that R D is (i) H; or (ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, -CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, –SF5, –OR a , –OC(O)NR c R d , –NR c R d , –NR c C(O)R b , –S(O)NR c R d , –S(O)2R b , –NR c S(O)2R b , –S(O)2NR c R d , –NR c S(O)2NR c R d , or –B(OR e )(OR f ).

59. The compound according to any one of claims 49 to 58, characterized in that R D is (i) H; or (ii) C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, cycloalkylalkyl, or heteroarylalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: cyano, halogen, C1- C4 alkyl, –OR a , or –NR c R d .

60. The compound according to any one of claims 49 to 59, characterized in that R D is (i) H; or (ii) methyl, ethyl, propyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, pyrazolyl, cyclopropylmethyl, or pyridyl-methyl, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from cyano, fluoro, methyl, hydroxy, methoxy, or dimethylamino.

61. The compound according to any one of claims 49 to 60, characterized in that R D is H, methyl, ethyl, 2-cyanoethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-dimethylaminoethyl, isopropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-methoxy-2-methylpropyl, cyclopropyl, 4-hydroxycyclohexyl, tetrahydropyran-4-yl, 1-methylpyrazol-4-yl, (1-hydroxycyclopropyl)methyl, (1-methoxycyclopropyl)methyl, or pyridin-2-ylmethyl.

62. The compound according to any one of claims 1 to 60, characterized in that R 3 is –CF2CH2CONHCH3, –CF2CH2CON(CH3)2, 63. The compound according to any one of claims 1 to 50, characterized in that R 3 for 64. The compound according to claim 63, characterized in that Every R 4 For fluorine.

65. The compound according to any one of claims 63 or 64, characterized in that R B is a 4-10 membered heterocyclic group, optionally substituted by 1, 2, 3, 4, or 5 independently selected from R B1 substituted by a substituent.

66. A compound according to any one of claims 63 to 65, characterized in that R B The compounds are azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, dioxanyl, piperazinyl, morpholinyl, azepanyl, diazacyclooctyl, 1,4-diazacycloheptyl, 4-oxa-7-azaspiro[2.5]octyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 1,8-diazaspiro[4.5]decyl, octahydropyrrolo[3,2-b]pyridinyl, hexahydropyrrolo[1,2-a]imidazolyl, hexahydropyrrolo[1,2-a]pyrazinyl, 2-oxa-5-azabicyclo[ 2.2.1] heptyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydropyrazino[2,1-c][1,4]oxazinyl]oxazinyl, or 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]-pyrazinyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R B1 substituted by a substituent.

67. A compound according to any one of claims 63 to 66, characterized in that R B is tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazacycloheptyl, 4-oxa-7-azaspiro[2.5]octyl, 1,8-diazaspiro[4.5]decyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, octahydropyrrolo[1,2-a]pyrazinyl, hexahydropyrrolo[1,2-a]-pyrazinyl, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazinyl, or octahydropyrazino[2,1-c][1,4]oxazinyl, each ring optionally substituted by 1, 2, or 3 independently selected from (i) cyano, –OR a , or –NR c R d ; or (ii) C1-C4 alkyl, optionally substituted with -OH.

68. A compound according to any one of claims 63 to 67, characterized in that R B is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,4-diazahept-1-yl, 4-oxa-7-azaspiro[2.5]octan-7-yl, 1,8-diazaspiro[4.5]dec-8-yl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, octahydropyrrolo[1,2-a]pyrazin-2-yl, hexahydropyrrolo[1,2-a]pyrazin-2-yl, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, or octahydropyrazino[2,1-c][1,4] Oxazin-8-yl, each substituent is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of cyano, methyl, ethyl, 2-hydroxyethyl, hydroxy, methoxy, or dimethylamino.

69. The compound according to any one of claims 63 to 68, characterized in that R B 3-hydroxypyrrolidin-1-yl, 3-methoxy-pyrrolidin-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 4-cyanopiperidin-1-yl, 3-hydroxypiperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-methoxypiperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-methyl-1,4-diazahept-1-yl, 4-oxa-7-azaspiro[2.5]octan-7-yl, 1-ethyl-1,8-diazaspiro[4.5]dec-8-yl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, octahydropyrrolo[1,2-a]pyrazin-2-yl, 7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2-yl, 3-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl, or octahydro-pyrazino[2,1-c][1,4]oxazin-8-yl.

70. The compound according to any one of claims 1 to 64, characterized in that R 3 is –CF2CH2COCH3, 71. The compound according to any one of claims 1 to 47, characterized in that R 3 For –SR 8 , –S(O)R 8 , –S(O)2R 8 , –SiR 5 R 6 R 7 , or –NR 9 R 10 .

72. The compound according to any one of claims 1 to 47 and 71, characterized in that R 3 For –SR 8 .

73. The compound according to claim 72, characterized in that R 8 is C1-C8 alkyl or C3-C 10 Cycloalkyl, each substituent is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 8A substituted by a substituent.

74. The compound according to any one of claims 72 or 73, characterized in that R 8 is –CH2CH3, –CH2CF3, –CH2CH2OH, –CH2CH(CH3)OH, –CH(CH3)CH2OH, –CH2CH2OCH3, –CH2CH2CH2CN, –CH2CH2CH2OH, –CH2CH2C(CH3)2OH, –CH(CH3)CO2H, –CH(CH3)CO2CH2CH3, –CH2CH2OSi(CH3)2C(CH3)3, or 2-hydroxycyclopentyl.

75. The compound according to any one of claims 1 to 47, characterized in that R 3 for 76. The compound according to any one of claims 1 to 47 and 75, characterized in that R 3 for 77. A compound as described below: or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated form thereof.

78. A pharmaceutical composition comprising: A compound according to any one of claims 1 to 77, or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated substance thereof and a pharmaceutically acceptable excipient.

79. A method for treating or preventing cancer, comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1 to 77, or the pharmaceutical composition of claim 78.

80. The method according to claim 79, characterized in that The cancer is characterized by overexpression of PolQ.

81. The method according to claim 79 or 80, characterized in that Such cancers are characterized by an increased reliance on MMEJ-DSB repair.

82. The method according to any one of claims 79 to 81, characterized in that Such cancers are characterized by HR-deficiency, or reduced or absent expression of HR-related genes.

83. The method according to any one of claims 79 to 82, characterized in that The cancer lacks the 53BP1 / Shieldin complex.

84. The method according to any one of claims 79 to 83, characterized in that The cancer is resistant to PARPi treatment.

85. The method according to any one of claims 79 to 84, characterized in that Such cancers are characterized by NHEJ deficiency, or reduced or absent expression of NHEJ-related genes.

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