Thiadiazole derivative and composition and application thereof

Abstract

The invention relates to a thiadiazole derivative as shown in a formula (I), a pharmaceutical composition, a preparation method and application of the thiadiazole derivative as a therapeutic agent. # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This disclosure claims priority to 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 / 082593, filed on March 20, 2023, and International Application No. PCT / CN2023 / 088519, filed on April 14, 2023. The content of each priority is incorporated herein by reference in its entirety. Technical field

[0003] This disclosure relates to thiadiazole derivatives as PolQ inhibitors. This disclosure also relates to methods for preparing thiadiazole derivatives and pharmaceutical compositions, and their use in the treatment of PolQ - mediated diseases, such as cancers with DNA repair defects. Background art

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

[0005] An abnormal DNA damage response (DDR) usually renders cancer cells sensitive to specific types of DNA damage. Thus, defective DDR can be developed into targeted cancer therapies. DNA repair defects have become a proven and effective strategy in cancer treatment. For example, poly(ADP - ribose) polymerase (PARP) inhibitors have been successful in treating BRCA - defective 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 (type A). Wood and Doublie, DNA Repair (Amst). 2016, 44, 22 - 32. In homologous recombination-deficient (HRD) cells, PolQ can perform error-prone DNA synthesis at DNA damage sites via the alt-NHEJ pathway.

[0007] Studies have shown that the helicase domain of PolQ mediates the removal of replication protein A (RPA) from the single-stranded (ssDNA) ends and stimulates annealing. The anti-recombinase activity of PolQ promotes the alt-NHEJ pathway. In addition, the helicase domain of PolQ contributes to 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 of >2 base pairs (bp), PolQ can promote end joining in the alt-NHEJ pathway by exploiting this annealing activity. Kent et al., Elife 2016, 5, e13740; Kent et al., Nat. Struct. Mol. Biol. 2015, 22, 230 - 7. This re-annealing activity is first mediated by the ATPase-mediated displacement of Rad51 from the DSB damage site and then obtained through a coupled interaction with Rad51. After annealing, the polymerase domain extends the ssDNA ends and fills the remaining gap.

[0008] PolQ is lowly expressed or not expressed in normal cells, but is significantly overexpressed in HRD ovarian cancer, uterine cancer, and breast cancer subsets, 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. U.S.A. 2010, 107, 13390 - 5; Ceccaldi et al., Nature 2015, 518, 258 - 62. Recent studies have shown that cancer cells with HR, NHEJ, or ATM defects are highly dependent on the expression of PolQ. Ceccaldi et al., 2015, supra; Mateos - Gomez et al., 2015, supra; Wyatt et al., Mol. Cell. 2016, 63, 662 - 73. Finally, PolQ inhibition may prevent MMEJ - dependent functional reverse mutations in BRCA1 or BRCA2 mutants, which are the basis for the emergence of cisplatin and PARPi resistance in tumors. Zatreanu et al., Nat. Commun. 2021, 12, 3636). Therefore, PolQ is an attractive target for synthetic lethal therapy for DNA - repair - defective cancers. SUMMARY OF THE INVENTION

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

[0010]

[0011] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N - oxide, or deuterated compound thereof; wherein the variables are as defined in the present disclosure.

[0012] On the other hand, the present disclosure provides a pharmaceutical composition comprising: a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N - oxide, or deuterated compound thereof and at least one pharmaceutically acceptable carrier.

[0013] On the other hand, the present disclosure provides a method for inhibiting PolQ, comprising: contacting PolQ with a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N - oxide, or deuterated compound thereof.

[0014] On the other hand, the present disclosure provides a method for treating cancer, comprising: administering to a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound.

[0015] Details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0017] DEFINITIONS

[0018] The present disclosure defines many terms as follows to facilitate understanding of the content set forth herein.

[0019] In general, the terms used in the present disclosure and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described in the present disclosure are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used in the present disclosure generally have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure pertains.

[0020] As used in the present disclosure, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the claims may be drafted to exclude any optional element. Thus, this statement is intended as antecedent basis for use of such exclusive terms, such as "solely", "only", etc., in connection with the recitation of claim elements or use of "negative" limitations.

[0021] At various places in this specification, variables defining divalent linking groups are described. Specifically, each linking substituent includes the forward and reverse forms of the linking substituent. For example, -NR(CR’R”)- includes -NR(CR'R")- and -(CR'R")NR-, and each form is intended to be separately disclosed. When a structure requires a linking group, the Markush variables listed for the group are understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition of the variable lists "alkyl" or "aryl", then "alkyl" or "aryl" is understood to represent a linked alkylene or arylene, respectively.

[0022] The term "substituted" means that an atom or group of atoms replaces hydrogen as a "substituent" attached to another group. The term "substitution", unless otherwise specified, refers to any number of substitutions, e.g., mono-, di-, tri-, tetra- or penta-substitution, if such substitution is permitted. The substituents are independently selected, and the substitution can occur at any chemically possible position. It should be understood that substitution at a particular atom is limited by the 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, e.g., oxo, can replace two hydrogen atoms. Exemplary substituents include, but are not limited to, D, halogen, oxo, C 1 -C -6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-NR c R d –(CH 2 CH 2 O) o C 1 -C 6 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, –NO 2 –N 3 –OR a –SR a –C(O)R b –C(O)NR c R d –CH 2 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 cC(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(R f ) 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) 2 R b ,–NR c S(O) 2 R b ,–S(O) 2 NR c R d ;aryl, heteroaryl, cycloalkyl, or heterocyclic group, wherein the aryl, heteroaryl, cycloalkyl, and heterocyclic group are optionally substituted with the following substituents: D, halogen, oxo, C 1 -C -6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 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,–NO 2 ,–N 3 ,–OR a ,–SR a ,–C(O)Rb , –C(O)NR c R d , –CH 2 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 c C(=NR c )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) 2 R b , –NR c S(O) 2 R b , or –S(O) 2 NR c R d ; wherein each R a , R b , R c , R d , R e , and R f is as defined in the present disclosure respectively.

[0023] The term "Cn-Cm" represents a range including the said endpoints, wherein n and m are integers representing the number of carbons. For example, the term "C 1 -C 6 alkyl" specifically refers to methyl, ethyl, C 3 alkyl, C4 Alkyl, C 5 Alkyl, and C 6 Alkyl. “C 0 Alkyl” refers to a covalent bond.

[0024] The compounds of the present disclosure are stable. As used in the present disclosure, “stable” means that the compound is sufficiently stable during the process of being separated from the reaction mixture to a useful purity, and preferably means that the compound can be formulated into an effective therapeutic agent.

[0025] It should also be understood that, for clarity, certain features of the present disclosure described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, the various features of the present disclosure described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0026] As used in the present disclosure, the term “alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon group. The alkyl 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 may contain any number of carbons, such as C 1 -C 2 Alkyl, C 1 -C 3 Alkyl, C 1 -C 4 Alkyl, C 1 -C 5 Alkyl, C 1 -C 6 Alkyl, C 1 -C 7 Alkyl, C 1 -C 8 Alkyl, C 1 -C 9 Alkyl, C 1 -C 10 Alkyl, C 2 -C 3 Alkyl, C 2 -C 4 Alkyl, C 2 -C 5 Alkyl, C 2 -C 6 Alkyl, C 3 -C 4 Alkyl, C 3 -C 5 Alkyl, C 3 -C 6 Alkyl, C 4 -C 5Alkyl, C 4 -C 6 Alkyl, and C 5 -C 6 Alkyl. Similarly, in C 1 -C 8 Alkyl, C 1 -C 8 refers to the group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain. 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.

[0027] As used in this disclosure, the term "alkenyl" refers to a hydrocarbon group having one or more carbon-carbon double bonds. An alkenyl group can contain any number of carbons, such as C 2 -C 3 Alkenyl, C 2 -C 4 Alkenyl, C 2 -C 5 Alkenyl, C 2 -C 6 Alkenyl, C 2 -C 7 Alkenyl, C 2 -C 8 Alkenyl, C 2 -C 9 Alkenyl, C 2 -C 10 Alkenyl, C 3 -C 4 Alkenyl, C 3 -C 5 Alkenyl, C 3 -C 6 Alkenyl, C 4 -C 5 Alkenyl, C 4 -C 6 Alkenyl and C 5 -C 6 Alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0028] As used in this disclosure, the term "alkynyl" refers to a hydrocarbon group having one or more carbon-carbon triple bonds. An alkynyl group can contain any number of carbons, such as C 2 -C 3 Alkynyl, C 2 -C 4 Alkynyl, C 2 -C 5Alkynyl, C 2 -C 6 Alkynyl, C 2 -C 7 Alkynyl, C 2 -C 8 Alkynyl, C 2 -C 9 Alkynyl, C 2 -C 10 Alkynyl, C 3 -C 4 Alkynyl, C 3 -C 5 Alkynyl, C 3 -C 6 Alkynyl, C 4 -C 5 Alkynyl, C 4 -C 6 Alkynyl, and C 5 -C 6 Alkynyl. Exemplary alkynyls include, but are not limited to, ethynyl, propynyl, butynyl, and pentynyl.

[0029] As used in this disclosure, the term "haloalkyl" refers to an alkyl having one or more halogen substituents. Exemplary haloalkyls include, but are not limited to, –CF 3 –C 2 F 5 –CHF 2 –CH 2 F, –CCl 3 –CHCl 2 and –C 2 Cl 5 .

[0030] As used in this disclosure, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon. In certain embodiments, aryl has from about 6 to about 20 carbon atoms. In certain embodiments, aryl has from about 6 to about 14 carbon atoms. In certain embodiments, aryl has from about 6 to about 10 carbon atoms. Exemplary aryls include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl.

[0031] As used in this disclosure, the term "cycloalkyl" refers to an unsubstituted or substituted non-aromatic carbocyclic ring. A cycloalkyl can include a monocyclic- or polycyclic (e.g., having 2, 3, or 4 rings) ring system, including fused rings, spiro rings, and bridged rings (e.g., bridged bicycloalkyls). In certain embodiments, a cycloalkyl has from about 3 to about 20 carbon atoms, from about 3 to about 14 carbon atoms, from about 3 to about 10 carbon atoms, or from about 3 to 7 carbon atoms. A cycloalkyl can also have 0, 1, 2, or 3 double bonds and / or 0, 1, or 2 triple bonds. A cycloalkyl can be optionally oxo (═O) or thioxo (═S). In certain embodiments, the cycloalkyl is C 3 -C 7 monocyclic cycloalkyl. In certain embodiments, the cycloalkyl is C 4- C 10 spiro or bridged cycloalkyl. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaranyl, cubyl, 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.

[0032] As used in this disclosure, the term "heteroaryl" refers to an unsubstituted or substituted aromatic heterocyclic ring having at least one heteroatom ring member, such as boron, sulfur, oxygen, or nitrogen. Heteroaryls include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Any N atom of an aryl can be oxidized to form an N-oxide. Exemplary heteroaryls include, but are not limited to, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, and indolinyl. In certain embodiments, a heteroaryl has from about 1 to about 20 carbon atoms or from about 3 to about 20 carbon atoms. In certain embodiments, a heteroaryl contains from about 3 to about 14, from about 3 to about 7, about 5, or about 6 ring atoms. In certain embodiments, a heteroaryl has from about 1 to about 4, from about 1 to about 3, about 1, or about 2 heteroatoms.

[0033] As used in this disclosure, the term "heterocyclic group" 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 of the ring-forming carbon atoms of the heterocyclic group can be replaced by a heteroatom selected from N, O, S, Si, and B; wherein the ring-forming carbon atoms and heteroatoms of the heterocyclic group can optionally be substituted by one or more oxo (=O) or thioxo (=S). Heterocyclic groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Heterocyclic groups include monocyclic and polycyclic 3- to 10-membered, 4- to 10-membered, 3- to 7-membered, 4- to 7-membered, and 5- to 6-membered heterocyclic groups. Heterocyclic groups also include spiro and bridged rings (e.g., 5- to 10-membered bridged bicyclic heterocyclic groups). In certain embodiments, the heterocyclic group contains 0 to 3 double bonds. In certain embodiments, the heterocyclic group contains 0 to 2 double bonds.

[0034] The heterocyclic group also includes groups having one or more aromatic rings fused to the non-aromatic heterocycle, e.g., benzo or thieno derivatives of piperidine, morpholine, azepane, etc. 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- to 6-membered heterocyclic group having 1 or 2 heteroatoms.

[0035] Exemplary heterocyclic groups include, but are not limited to, pyrrolidin-2-one group, 1,3-isoxazolidin-2-one group, pyranyl group, tetrahydropyranyl group, oxetanyl group, azetidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, piperidinyl group, tetrahydropyrrolyl group, isoxazolidinyl group, isothiazolidinyl group, pyrazolidinyl group, oxazolidinyl group, thiazolidinyl group, imidazolidinyl group, azepanyl group, benzazepentenyl group, 1,2,3,4-tetrahydroisoquinolinyl group, azabicyclo[3.1.0]hexyl group, diazabicyclo[3.1.0]hexyl group, oxabicyclo[2.1.1]hexyl group, azabicyclo[2.2.1]heptyl group, diazabicyclo[2.2.1]heptyl group, azabicyclo[3.1.1]heptyl group, diazabicyclo[3.1.1]heptyl group, azabicyclo[3.2.1]octyl group, diazabicyclo[3.2.1]octyl group, oxabicyclo[2.2.2]octyl group, azabicyclo[2.2.2]octyl group, diazabicyclo[2.2.2]octyl group, azadamantyl group, diazadamantyl group, oxadamantyl group, azaspiro[3.3]heptyl group, diazaspiro[3.3]heptyl group, oxaazaspiro[3.3]heptyl group, azaspiro[3.4]octyl group, diazaspiro[3.4]octyl group, oxaazaspiro[3.4]octyl group, oxaazaspiro[3.5]nonyl group, azaspiro[2.5]octyl group, diazaspiro[2.5]octyl group, azaspiro[4.4]nonyl group, diazaspiro[4.4]nonyl group, oxa-azaspiro[4.4]nonyl group, azaspiro[4.5]decyl group, diazaspiro[4.5]decyl group, diazaspiro[4.4]nonyl group, oxa-diazaspiro[4.4]nonyl group, and octahydropyrrolo[3,4-c]pyrrolyl group.

[0036] In certain embodiments, the heterocyclic group 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 heterocyclic group can be attached through any of its heteroatoms or carbon atoms, provided that a stable structure can be formed. Exemplary heterocyclic groups include, but are not limited to, azepanyl group, aziridinyl group, azetidinyl group, tetrahydropyrrolyl group, dioxolanyl group, imidazolidinyl group, pyrazolidinyl group, piperazinyl group, piperidinyl group, dioxanyl group, morpholinyl group, dithianyl group, thiomorpholinyl group, oxaazepanyl group, oxiranyl group, oxetanyl group, quinuclidinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, and piperazinyl group.

[0037] As used in this disclosure, the term "halogen" or "halogens" refers to fluorine, chlorine, bromine, and iodine.

[0038] As used in this disclosure, the term "alkoxy" refers to –O-alkyl. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.

[0039] As used in the present disclosure, the term "hydroxyalkyl" refers to an alkyl group substituted with -OH.

[0040] As used in the present disclosure, the term "cyanoalkyl" refers to an alkyl group substituted with -CN.

[0041] As used in the present disclosure, the term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group.

[0042] As used in the present disclosure, the term "haloalkoxy" refers to -O-(haloalkyl).

[0043] As used in the present disclosure, the term "arylalkyl" or "aralkyl" refers to an alkyl group substituted with an aryl group. An exemplary arylalkyl is benzyl.

[0044] As used in the present disclosure, the term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group.

[0045] As used in the present disclosure, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group.

[0046] As used in the present disclosure, the term "heterocycloalkylalkyl" refers to an alkyl group substituted with a heterocycloalkyl group.

[0047] In certain embodiments, the compounds or salts thereof described in the present disclosure are substantially separated. By "substantially separated" is meant that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Substantially separated can include a composition containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt% or at least about 99 wt% of the compound or salt thereof of the present disclosure.

[0048] The term "pharmaceutically acceptable" as used in the present disclosure refers to a compound, substance, composition and / or dosage form that is applicable, within the scope of reasonable medical judgment, for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications and is commensurate with a reasonable benefit / risk ratio.

[0049] The term "pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable and otherwise biologically suitable substance, such as an inert substance, that is added to a pharmacological composition or otherwise used as a vehicle, carrier or diluent to facilitate the administration of a medicament and is compatible therewith. Exemplary excipients include calcium carbonate, calcium phosphate, various sugars and various types of starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0050] The term "solvate" refers to a physical association of a compound with one or more solvent molecules.

[0051] The term "subject" refers to a species, including but not limited to, primates (e.g., humans), cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably in the present disclosure and refer to, for example, mammalian subjects such as human subjects. In one embodiment, the subject is human.

[0052] 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 clinical symptom of the disease or its clinical symptoms). In another embodiment, "treatment" refers to ameliorating at least one physical parameter that may not be distinguishable by the subject. In another embodiment, "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet other embodiments, "treatment" refers to delaying the onset of the disease or disorder.

[0053] As used in the present disclosure, the term "isotope variant" refers to a compound that contains a proportion of isotopes greater than the natural abundance at one or more atoms that make up the compound. For example, an "isotope variant" of a compound may be radioactively labeled, i.e., contain one or more radioactive isotopes, or may be labeled with non-radioactive isotopes such as, for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), etc. It should be understood that in a compound in which such isotope substitution has been made, if present, the following atoms may vary such that, for example, any hydrogen may be 2 H / D, any carbon may be 13 C, or any nitrogen may be 15 N, and the presence and location of such atoms can be determined within the capabilities of those skilled in the art.

[0054] Compound

[0055] In one aspect, the present disclosure provides a compound of formula (I):

[0056]

[0057] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotope variant, prodrug, N-oxide, or deuterated compound thereof; wherein:

[0058] X 1 is N or CR 1 ;

[0059] X2 is N or CR 2 ;

[0060] X 3 is N or CR 3 ;

[0061] X 1 , X 2 and X 3 are not simultaneously N;

[0062] m is 1, 2, 3, 4 or 5;

[0063] Cy is C 6 -C 10 aryl or 5- to 10-membered heteroaryl;

[0064] R is selected from OH, or

[0065] R 1 and R 2 are each independently selected from H, D, CN, NO 2 , N 3 , oxo, SF 5 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, 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)OR A , S(O)R B , S(O) 2 R B ; wherein, the C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3- C 6 A cycloalkyl group, a 4- to 6-membered heterocyclic group, a phenyl group, or a 5- to 6-membered heteroaryl group is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group;

[0066] or R 1 and R 2 together with the carbon atom to which it is attached forms a C 4 -C 7 cycloalkyl, 4- to 7-membered heterocyclic group, phenyl group, or 5- to 6-membered heteroaryl group; wherein the C 4 -C 7 cycloalkyl, 4- to 7-membered heterocyclic group, phenyl group, or 5- to 6-membered heteroaryl group is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: D, halogen, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N(C 1 -C 4 alkyl) 2 ;

[0067] R 3 is selected from H, D, CN, NO 2 , -N 3 , oxo, SF 5 , halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6Cycloalkyl, 4- to 6-membered heterocyclic group, 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)OR A , S(O)R B , S(O) 2 R B ; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3- C 6 cycloalkyl, 4- to 6-membered heterocyclic group is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group;

[0068] Each R 4 is independently selected from D, halogen, -CN, -NO 2 , -SF 5 , -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)RB , -S(O)R B , -S(O) 2 R B , -S(O)NR C R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR C R D , -NR C , -S(O)(=NR B )R B , -P(O)R E R F , -P(O)OR E OR F , -OP(O)OR E OR F , C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl; wherein, said C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from R 4A ;

[0069] Each R 4A is independently selected from D, halogen, CN, OH, NH 2 , oxo, C 1- C 6 alkyl, OC 1- C 6 alkyl, C 1- C 6 haloalkyl, OC 1- C 6 haloalkyl, NHC 1- C 3alkyl, N(C 1- C 3 alkyl) 2 ,C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group; wherein, said C 3- C 6 cycloalkyl or 4-6 membered heterocyclic group is optionally substituted with substituents selected from: D, halogen, CN, OH, NH 2 ,C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl;

[0070] or two adjacent Rs 4 together with the atoms to which they are attached form a C 4- C 7 cycloalkyl or 4-7 membered heterocyclic group; wherein, said C 4- C 7 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted with substituents selected from: D, halogen, oxo, CN, OH, NH 2 ,NO 2 ,C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group; wherein, said C 3- C 6 cycloalkyl or 4-6 membered heterocyclic group is optionally substituted with D, halogen, CN, OH, NH 2 ,C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl substitution;

[0071] R5 and R 6 are each independently selected from H, D, halogen, CN, NO 2 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkyl-O-C 1 -C 8 alkyl, C 1 -C 8 alkyl-O-C 1 -C 8 haloalkyl, C 1 -C 8 alkyl-OH, C 1 -C 8 alkyl-CN;

[0072] R 7 are each independently selected from H, D, CN, halogen, NO 2 , N 3 , SF 5 , Si(R 8 ) 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or adamantyl; wherein the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or adamantyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the following: D, -halogen, -CN, -NO 2 , -N 3 , SF 5 , oxo, -NR C R D , -OR A , -SR A , SiR G R H R I , -B(OR C )(OR D ), -C(O)R B, -C(O)OR A , -OC(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) 2 R B , -S(O)NR C R D , -NR C S(O)R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR C R D , -NR C S(O)(=NR B )R B ;

[0073] Each R 8 is independently selected from C 1 -C 4 alkyl or phenyl;

[0074] Each R A is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4 - 10 membered heterocyclic group, C 6 -C 10 aryl, 5 - 10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C6 Alkynyl, C 3 -C 10 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 Aryl, 5- to 10-membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, CN, halogen, C 1 -C 4 Alkyl, C 1 -C 4 Halogenated alkyl, C 1 -C 4 Alkyl-OH, C 1 -C 4 Alkyl-CN, C 1 -C 4 Alkyl-O-C 1 -C 4 Alkyl, C 1 -C 4 Alkyl-O-C 1 -C 4 Halogenated alkyl, NO 2 , oxo, OR a , SR a , SF 5 , 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 c )(OR d ), 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)Re 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) 2 R b ,NR c S(O) 2 R b ,S(O) 2 NR c R d ,NR c S(O) 2 NR c R d , or NR c S(O)(=NR b )R b ;

[0075] Each R B is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: D, OH, CN, halogen, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, SF 5 , C(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 , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , S(O) 2 NR c R d , NR c S(O) 2 NR c R d , or B(OR c )(OR d );

[0076] R C and R D are each independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclicalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclicalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, OH, CN, halogen, oxo, C 1 -C 4 Alkyl, C 1 -C 4 Halogenated alkyl, C 1 -C 4 Cyanoalkyl, OC 1 -C 4 Alkyl, OC 1 -C 4 Halogenated alkyl, C 1 -C 4 Alkyl - O - C 1 -C 4 Alkyl, C 1 -C 4 Alkyl - O - C 1 -C 4 Halogenated alkyl, SF 5 , OC(O)NR c R d , NR c R d , NR c C(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , S(O) 2 NR c R d , NR c S(O) 2 NR c R d or B(OR c )(OR d );

[0077] or R C and R D together with the N atom to which they are attached form a 4-7 membered heterocyclic group optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, OH, oxo, CN, -NH 2 , -NH(C 1 -C 4(alkyl), -N(C 1 -C 4 (alkyl) 2 , halogen, C 1 -C 4 (alkyl), C 1 -C 4 (haloalkyl), C 1 -C 4 (cyanoalkyl), OC 1 -C 4 (alkyl), or OC 1 -C 4 (haloalkyl);

[0078] R a and R a1 are each independently selected from H, D, C 1 -C 4 (alkyl), C 2 -C 4 (alkenyl), C 2 -C 4 (alkynyl), phenyl, C 3 -C 7 (cycloalkyl), 5- to 6-membered heteroaryl, or 4- to 7-membered heterocyclic group, wherein the C 1 -C 4 (alkyl), C 2 -C 4 (alkenyl), C 2 -C 4 (alkynyl), phenyl, C 3- C 7 (cycloalkyl), 5- to 6-membered heteroaryl, or 4- to 7-membered heterocyclic group is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the following: D, halogen, OH, CN, -NH 2 , -NH(C 1 -C 4 (alkyl)), -N(C 1 -C 4 (alkyl) 2 , C 1 -C 4 (alkyl), OC 1 -C 4 (alkyl), C 1 -C 4 (haloalkyl), or OC 1 -C 4 (haloalkyl);

[0079] R b and R b1 are each independently selected from H, D, C 1 -C 4 (alkyl), C 2 -C (alkyl) 4Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein said C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, phenyl, C 3- C 7 Cycloalkyl, 5-6-membered heteroaryl, 4-7-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from: D, OH, CN, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Halogenated alkyl, C 1 -C 4 Halogenated alkoxy, C 6- C 10 Aryl, C 3- C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group;

[0080] R c and R d are each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 halogenated alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6- C 10 aryl, 5-10-membered heteroaryl, C 3- C 10 cycloalkyl, 4-10-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocyclic group, heteroarylaryl, or biheteroaryl; wherein said C1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6- C 10 aryl, 5- to 10-membered heteroaryl, C 3- C 10 cycloalkyl, 4- to 10-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, OH, CN, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 cyanoalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C(O)OR a1 , C(O)R b1 , S(O) 2 R b1 , C 1 -C 4 alkyl-O-C 1 -C 4 alkyl or C 1 -C 4 alkyl-O-C 1 -C 4 alkyl-O-;

[0081] or R c and R d together with the N atom to which it is attached forms a 4- to 7-membered heterocyclic group optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, OH, CN, -NH 2 , -NH(C 1 -C 4(alkyl), -N(C 1 -C 4 alkyl 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 cyanoalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 1 -C 4 alkoxy-C 1 -C 4 alkyl or C 1 -C 4 alkoxy-C 1 -C 4 alkoxy;

[0082] R E and R e are each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy)-C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5- to 10-membered heteroaryl-C 1 -C 4 alkyl, or 4- to 10-membered heterocyclic group-C 1 -C 4 alkyl;

[0083] R F and R f are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 10 cycloalkyl, or 4- to 10-membered heterocyclic group;

[0084] R G , R H and R I are each independently selected from C 1 -C 4 alkyl or phenyl.

[0085] In certain embodiments, X 1 is CR 1 , X 2 is CR 2 , and X 3 is CR 3 .

[0086] In certain embodiments, X 1 is N, X 2 is CR 2 , and X 3 is CR 3 .

[0087] In certain embodiments, X 1 is CR 1 , X 2 is N, and X 3 is CR 3 .

[0088] In certain embodiments, X 1 is CR 1 , X 2 is CR 2 , and X 3 is N.

[0089] In certain embodiments, the compound of formula (I) is as shown in formula (IIa), (IIb), (IIc) or (IId):

[0090]

[0091] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;

[0092] wherein Cy, R, R 1 , R 2 , R 3 , R 4 , and m are as defined in the present disclosure.

[0093] In certain embodiments, the compound of formula (I) is as shown in formula (IIa) or (IIb):

[0094]

[0095] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;

[0096] wherein Cy, R, R 1 , R 2 , R 3 , R 4 , and m are as defined in the present disclosure.

[0097] In certain embodiments, Cy is C 6- C 10 aryl, 5- to 10-membered heteroaryl.

[0098] In certain embodiments, Cy is C 6 -C 10 aryl. In certain embodiments, Cy is phenyl or naphthyl. In certain embodiments, Cy is phenyl.

[0099] In certain embodiments, Cy is 5- to 10-membered heteroaryl. In certain embodiments, Cy is 5-membered heteroaryl. In certain embodiments, Cy is 6-membered heteroaryl. In certain embodiments, Cy is 8-membered heteroaryl. In certain embodiments, Cy is 9-membered heteroaryl. In certain embodiments, Cy is 10-membered heteroaryl.

[0100] In certain embodiments, Cy is pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, 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.

[0101] In certain embodiments, Cy is phenyl or a 6-membered heteroaryl. In certain embodiments, Cy is phenyl or pyridin-4-yl. In certain embodiments, Cy is phenyl.

[0102] In certain embodiments, has the following structure: wherein, Y 1 is N or CR 4 ; Y 2 is N or CR 4 ; each R 4 is the same or different, as defined in the present disclosure.

[0103] In certain embodiments, Y 1 is CR 4 , and Y2 is CR 4 . In certain embodiments, Y 1 is CH, and Y 2 is CH.

[0104] In certain embodiments, Y 1 is CR 4 , and Y 2 is N.

[0105] In certain embodiments, Y 1 is N, and Y 2 is CR 4 .

[0106] In certain embodiments, has the following structure: or where each R 2 is as defined in the present disclosure.

[0107] In certain embodiments, has the following structure: In certain embodiments, has the following structure: In certain embodiments, has the following structure: In certain embodiments, has the following structure: wherein, each R 2 is as defined in the present disclosure.

[0108] In certain embodiments, has the following structure:

[0109] In certain embodiments, the compound represented by formula (I) is as shown in formula (IIIa), or (IIIb):

[0110]

[0111] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;

[0112] wherein, R, R 1 , R 2 , R 3 , R 4 , Y 1 and Y 2 are as defined in the present disclosure.

[0113] In certain embodiments, R is OH.

[0114] In certain embodiments, R is

[0115] In certain embodiments, the compound of formula (I) is as shown in formula (IVa) or (IVb):

[0116]

[0117] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;

[0118] wherein Cy, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and m are as defined in the present disclosure.

[0119] In certain embodiments, the compound of formula (I) is as shown in formula (Va), or (Vb):

[0120]

[0121] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;

[0122] wherein Cy, R 1 , R 2 , R 3 , R 4 , R 7 , and m are as defined in the present disclosure.

[0123] In certain embodiments, the compound of formula (I) is as shown in formula (VIa), or (VIb):

[0124]

[0125] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;

[0126] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7, Y 1 and Y 2 as defined in the present disclosure.

[0127] In certain embodiments, the compound of formula (I) is as shown in formula (VIIa), or (VIIb):

[0128]

[0129] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;

[0130] wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Y 1 and Y 2 as defined in the present disclosure.

[0131] In certain embodiments, the compound of formula (I) is as shown in formula (VIIIa), or (VIIIb):

[0132]

[0133] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;

[0134] wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Y 1 and Y 2 as defined in the present disclosure.

[0135] In certain embodiments, R 1 is selected from H, D, CN, NO 2 , N 3 , oxo, SF 5 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, 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)OR A , S(O)R B , S(O) 2 R B ; wherein, said C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3- C 6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group.

[0136] In certain embodiments, R 1 is selected from H, D, CN, NO 2 , N 3 , oxo, SF 5 , halogen, 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 RD ,NR C R D ,NR C C(O)R B ,NR C C(O)OR A ,S(O)R B ,S(O) 2 R B 。In certain embodiments, R 1 is H. In certain embodiments, R 1 is D. In certain embodiments, R 1 is CN. In certain embodiments, R 1 is NO 2 。In certain embodiments, R 1 is N 3 。In certain embodiments, R 1 is SF 5 。In certain embodiments, R 1 is a halogen. In certain embodiments, R 1 is F, Cl, Br, or I. In certain embodiments, R 1 is F. In certain embodiments, R 1 is Cl. In certain embodiments, R 1 is Br. In certain embodiments, R 1 is I. In certain embodiments, R 1 is OR A 。In certain embodiments, R 1 is OH, OCH 3 ,OCH 2 CH 3 ,OCH 2 CH 2 CH 3 ,OCH(CH 3 ) 2 ,OCH 2 F,OCHF 2 ,OCF 3 , In certain embodiments, R 1 is SR A 。In certain embodiments, R 1 is C(O)R B 。In certain embodiments, R 1 is C(O)NR C R D 。In certain embodiments, R 1 is C(O)OR A 。In certain embodiments, R 1is OC(O)R B . In certain embodiments, R 1 is OC(O)NR C R D . In certain embodiments, R 1 is NR C R D . In certain embodiments, R 1 is NR C C(O)R B . In certain embodiments, R 1 is NR C C(O)OR A . In certain embodiments, R 1 is S(O)R B . In certain embodiments, R 1 is S(O) 2 R B .

[0137] In certain embodiments, R 1 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl; wherein the C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3- C 6 cycloalkyl, 4- to 6-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0138] In certain embodiments, R 1is C 1 -C 6 alkyl (such as C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl) is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group. In certain embodiments, R 1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 .

[0139] In certain embodiments, R 1 is C 2 -C 6 alkenyl (such as C 2 -C 5 alkenyl, C 2 -C 4 alkenyl, C 2 -C 3 alkenyl) is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0140] In certain embodiments, R 1 is C 2 -C 6Alkynyl (e.g., C 2 -C 5 alkynyl, C 2 -C 4 alkynyl, C 2 -C 3 alkynyl) is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0141] In certain embodiments, R 1 is C 3 -C 6 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl. In certain embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; each substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl. In certain embodiments, R 1 is cyclopropyl.

[0142] In certain embodiments, R 1 is a 4- to 6-membered heterocyclic group optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2, oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl. In certain embodiments, R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; each substituent is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.

[0143] In certain embodiments, R 1 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group.

[0144] In certain embodiments, R 1 is a 5-6 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3-C 6 Cycloalkyl, 4- to 6-membered heterocyclic group.

[0145] In certain embodiments, R 1 is selected from H, D, CN, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, OR A , SR A , NR C R D ; wherein the C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.

[0146] In certain embodiments, R 1 is selected from H, D, CN, NO 2 , SF 5 , halogen, OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 F, OCHF 2 , OCF 3 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , or CH 2 CF 3 .

[0147] In certain embodiments, R 2Selected from H, D, CN, NO 2 , N 3 , oxo, SF 5 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, 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)OR A , S(O)R B , S(O) 2 R B ; wherein the C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3- C 6 cycloalkyl, 4- to 6-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0148] In certain embodiments, R 2 is selected from H, D, CN, NO 2 , N3 , oxo, SF 5 , halogen, 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)OR A , S(O)R B , S(O) 2 R B . In certain embodiments, R 2 is H. In certain embodiments, R 2 is D. In certain embodiments, R 2 is CN. In certain embodiments, R 2 is NO 2 . In certain embodiments, R 2 is N 3 . In certain embodiments, R 2 is SF 5 . In certain embodiments, R 2 is halogen. In certain embodiments, R 2 is F, Cl, Br, or I. In certain embodiments, R 2 is F. In certain embodiments, R 2 is Cl. In certain embodiments, R 2 is Br. In certain embodiments, R 2 is I.

[0149] In certain embodiments, R 2 is OR A . In certain embodiments, R 2 is OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 F, OCHF 2 , OCF 3 ,

[0150] In certain embodiments, R 2 is SR A 。In certain embodiments, R 2 is C(O)R B 。In certain embodiments, R 2 is C(O)NR C R D 。In certain embodiments, R 2 is C(O)OR A 。In certain embodiments, R 2 is OC(O)R B 。In certain embodiments, R 2 is OC(O)NR C R D 。In certain embodiments, R 2 is NR C R D 。In certain embodiments, R 2 is NR C C(O)R B 。In certain embodiments, R 2 is NR C C(O)OR A 。In certain embodiments, R 2 is S(O)R B 。In certain embodiments, R 2 is S(O) 2 R B 。

[0151] In certain embodiments, R 2 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; wherein the C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3- C 6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the following: D, halogen, CN, OH, NH 2 , NO 2, oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group.

[0152] In certain embodiments, R 2 is C 1 -C 6 alkyl (e.g., C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl) is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group.

[0153] In certain embodiments, R 2 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 . In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl. In certain embodiments, R 2 is CH 2 F. In certain embodiments, R 2 is CHF 2 . In certain embodiments, R 2 is CF 3 .

[0154] In certain embodiments, R 2 is C 2 -C 6 alkenyl (e.g., C 2 -C 5 alkenyl, C 2 -C 4 alkenyl, C 2 -C 3 alkenyl) optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0155] In certain embodiments, R 2 is C 2 -C 6 alkynyl (e.g., C 2 -C 5 alkynyl, C 2 -C 4 alkynyl, C 2 -C 3 alkynyl) optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0156] In certain embodiments, R 2 is C 3 -C 6 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C6 Halogenated alkyl. In certain embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; each substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 halogenated alkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 halogenated alkyl.

[0157] In certain embodiments, R 2 is a 4- to 6-membered heterocyclic group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 halogenated alkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 halogenated alkyl. In certain embodiments, R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; each substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 halogenated alkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 halogenated alkyl.

[0158] In certain embodiments, R 2 is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0159] In certain embodiments, R 2 is a 5- to 6-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0160] In certain embodiments, R 2 is selected from H, D, CN, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, OR A , SR A , NR C R D ; wherein the C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.

[0161] In certain embodiments, R 2 is selected from H, D, CN, NO 2 , SF 5 , halogen, OH, OCH 3, OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 F, OCHF 2 , OCF 3 , Methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 。

[0162] In certain embodiments, R 1 and R 2 together with the carbon atom to which they are attached form a C 4 -C 7 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents each independently selected from: D, halogen, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N(C 1 -C 4 alkyl) 2 。

[0163] In certain embodiments, R 1 and R 2 together with the carbon atom to which they are attached form a 4- to 7-membered heterocyclic group optionally substituted with 1, 2, 3, or 4 substituents each independently selected from: D, halogen, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N(C 1 -C 4 alkyl) 2 。

[0164] In certain embodiments, R 1 and R 2 together with the carbon atom to which they are attached form a phenyl optionally substituted with 1, 2, 3 or 4 substituents each independently selected from: D, halogen, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N(C 1 -C 4 alkyl) 2 。

[0165] In certain embodiments, R 1 and R 2 together with the carbon atom to which they are attached form a 5- or 6-membered heteroaryl optionally substituted with substituents independently selected from: D, halogen, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N(C 1 -C 4 alkyl) 2 。

[0166] In certain embodiments, R 3 is selected from H, D, CN, NO 2 , SF 5 , halogen, C 1 -C 4 alkyl, C2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group, 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)OR A , S(O)R B , S(O) 2 R B ; wherein, said C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3- C 6 cycloalkyl, 4- to 6-membered heterocyclic group is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0167] In certain embodiments, R 3 is selected from H, D, CN, NO 2 , -N 3 , oxo, SF 5 , halogen, 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)OR A , S(O)R B , S(O) 2 R B 。In certain embodiments, R 3 is H. In certain embodiments, R 3 is D. In certain embodiments, R 3 is CN. In certain embodiments, R 3 is NO 2 。In certain embodiments, R 3 is N 3 。In certain embodiments, R 3 is SF 5 。In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is F, Cl, Br or I. In certain embodiments, R 3 is F. In certain embodiments, R 3 is Cl. In certain embodiments, R 3 is Br. In certain embodiments, R 3 is I.

[0168] In certain embodiments, R 3 is OR A 。In certain embodiments, R 3 is OH, OCH 3 , OCH 2 CH 3 , OCF 3 or

[0169] In certain embodiments, R 3 is SR A 。In certain embodiments, R 1 is C(O)R B 。In certain embodiments, R 1 is C(O)NR C R D 。In certain embodiments, R 1 is C(O)OR A 。In certain embodiments, R 1is OC(O)R B . In certain embodiments, R 3 is OC(O)NR C R D . In certain embodiments, R 3 is NR C R D . In certain embodiments, R 3 is NR C C(O)R B . In certain embodiments, R 3 is NR C C(O)OR A . In certain embodiments, R 3 is S(O)R B . In certain embodiments, R 3 is S(O) 2 R B .

[0170] In certain embodiments, R 3 is selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0171] In certain embodiments, R 3 is C 1 -C4 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group. In certain embodiments, R 3 is methyl, ethyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 .

[0172] In certain embodiments, R 3 is C 2 -C 4 alkenyl optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0173] In certain embodiments, R 3 is C 2 -C 4 alkynyl optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0174] In certain embodiments, R 3 is C 3 -C 6The cycloalkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0175] In certain embodiments, R 3 is a 4- to 6-membered heterocyclic group optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group.

[0176] In certain embodiments, R 3 is selected from H, D, CN, SF 5 , halogen, OR A , or SR A , C 1 -C 4 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl.

[0177] In certain embodiments, R 3 is selected from H, D, CN, SF 5 , halogen, OH, OCH 3 , OCH 2 CH 3 , OCF 3 , methyl, ethyl, CH 2F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , or CH 2 CF 3 .

[0178] In certain embodiments, each R 4 is independently selected from D, halogen, -CN, -NO 2 , -SF 5 , -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) 2 R B , -S(O)NR C R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR C R D , -NR C , -NR B )(=NR B ), -P(O)R E R F , -P(O)OR E OR F , -OP(O)OR E OR F , C 1- C 6 , C 2 -C 6 , C 2 -C 6 , C 3 -C 6 , cycloalkyl, 4-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl; wherein, the C 1-C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , oxo, C 1- C 6 Alkyl, OC 1- C 6 Alkyl, C 1- C 6 Haloalkyl, OC 1- C 6 Haloalkyl, NHC 1- C 3 Alkyl, N(C 1- C 3 Alkyl) 2 , C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclic group; wherein the C 3- C 6 Cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by D, halogen, CN, OH, NH 2 , C 1- C 6 Alkyl, C 1- C 6 Haloalkyl, -O-C 1 -C 6 Alkyl, -O-C 1- C 6 Haloalkyl.

[0179] In certain embodiments, each R 4 is independently selected from D, halogen, -CN, -NO 2 , -SF 5 , -OR A , -SR A .

[0180] In certain embodiments, each R 4 is independently selected from D. In certain embodiments, each R 4 is independently selected from halogen. In certain embodiments, each R 4Each is independently selected from F, Cl, Br, I. In certain embodiments, each R 4 is F. In certain embodiments, each R 4 is Cl. In certain embodiments, each R 4 is Br. In certain embodiments, each R 4 is I.

[0181] In certain embodiments, each R 4 is independently selected from CN. In certain embodiments, each R 4 is independently selected from NO 2 . In certain embodiments, each R 4 is independently selected from SF 5 .

[0182] In certain embodiments, each R 4 is independently selected from OR A . In certain embodiments, each R 4 is independently selected from OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 (CH 3 ) 2 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 2 , OCH 2 CHF 2 , OCH 2 CF 3 , -CH(OH)CH 3 , OCH 2 CN, OCH 2 CONH 2 . In certain embodiments, each R 4 is independently selected from OCH 3 . In certain embodiments, each R 4 is independently selected from OCH 2 CH 3 . In certain embodiments, each R 4 is independently selected from OCH(CH 3 ) 2 . In certain embodiments, each R 4 is independently selected from OCF3 。In certain embodiments, each R 4 is independently selected from OCHF 2 。In certain embodiments, each R 4 is independently selected from OCH 2 F. In certain embodiments, each R 4 is independently selected from OCF 3 。In certain embodiments, each R 4 is independently selected from OCH 2 CH 2 F. In certain embodiments, each R 4 is independently selected from OCH 2 CHF 2 。In certain embodiments, each R 4 is independently selected from OCH 2 CF 3 。In certain embodiments, each R 4 is independently selected from OCH 2 CN. In certain embodiments, each R 4 is independently selected from OCH 2 CONH 2 。

[0183] In certain embodiments, each R 4 is independently selected from SR A 。In certain embodiments, each R 4 is independently selected from SCH 3 。In certain embodiments, each R 4 is independently selected from SCH 2 CH 3 。

[0184] In certain embodiments, each R 4 is independently selected from -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) 2 R B , -S(O)NR C R D , -NR C S(O)2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR C R D , -NR C S(O)(=NR B )R B , -P(O)R E R F , -P(O)OR E OR F , -OP(O)OR E OR F 。 In certain embodiments, each R 4 is independently selected from C(O)R B 。 In certain embodiments, each R 4 is independently selected from C(O)NR C R D 。 In certain embodiments, each R 4 is independently selected from -C(O)OR A 。 In certain embodiments, each R 4 is independently selected from -OC(O)R B 。 In certain embodiments, each R 4 is independently selected from NR C R D 。 In certain embodiments, each R 4 is independently selected from NR C C(O)R B 。 In certain embodiments, each R 4 is independently selected from S(O)R B 。 In certain embodiments, each R 4 is independently selected from S(O) 2 R B 。 In certain embodiments, each R 4 is independently selected from S(O)NR C R D 。 In certain embodiments, each R 4 is independently selected from -NR C S(O) 2 R D 。 In certain embodiments, each R 4 is independently selected from -S(O) 2 NR C R D。In certain embodiments, each R 4 is independently selected from -NR C S(O) 2 NR C R D 。In certain embodiments, each R 4 is independently selected from -NR C S(O)(=NR B )R B 。In certain embodiments, each R 4 is independently selected from -P(O)R E R F 。In certain embodiments, each R 4 is independently selected from -P(O)OR E OR F 。In certain embodiments, each R 4 is independently selected from -OP(O)OR E OR F 。

[0185] In certain embodiments, each R 4 is independently selected from C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl; wherein the C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 4A respectively.

[0186] In certain embodiments, each R 4 is independently selected from C 1- C 6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 4A respectively.

[0187] In certain embodiments, each R 4 is independently selected from CH 3 ,CH2 CH 3 ,n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 F, CHF 2 ,CF 3 ,CH 2 CH 2 F, CH 2 CHF 2 ,CH 2 CF 3 ,CH 2 OH, -CH(OH)CH 3 ,CH 2 CH 2 OH, -CH 2 OCH 3 ,-CH 2 OCH 2 F, -CH 2 OCHF 2 ,-CH 2 OCF 3 ,-CH(OCH 3 )CH 3 ,CH 2 CH 2 NH 2 ,-CH(NH 2 )CH 3 ,CH 2 N(CH 3 ) 2 ,CH 2 CH 2 N(CH 3 ) 2 ,CH 2 CN.

[0188] In certain embodiments, each R 4 is independently selected from C 2 -C 6 The alkenyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 4A respectively.

[0189] In certain embodiments, each R 4 is independently selected from -CH=CH 2 ,-CH=CHCH 3 .

[0190] In certain embodiments, each R 4 is independently selected from C 2 -C 6 The alkynyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R4A substituted by substituents.

[0191] D, halogen, CN, OH, NH 2 , oxo, C 1- C 6 alkyl, OC 1- C 6 alkyl, C 1- C 6 haloalkyl, OC 1- C 6 haloalkyl, NHC 1- C 3 alkyl, N(C 1- C 3 alkyl) 2 C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group; wherein said C 3- C 6 cycloalkyl or 4- to 6-membered heterocyclic group is optionally substituted by substituents selected from: D, halogen, CN, OH, NH 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl. In certain embodiments, each R 4 is independently selected from -C≡CH, -C≡CCH 3 .

[0192] In certain embodiments, each R 4 is independently selected from C 3 -C 6 cycloalkyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 4A .

[0193] In certain embodiments, each R 4 is independently selected from a 4- to 6-membered heterocyclic group having 1 or 2 heteroatoms selected from N, O, S and B, wherein said heteroatoms may optionally be substituted by one or more oxo (e.g., S(O), or S(O) 2 ) and is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 4A .

[0194] In certain embodiments, each R 4 is independently selected from phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 4A .

[0195] In certain embodiments, each R 4 is independently selected from 5- to 6-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 4A .

[0196] In certain embodiments, each R 4 is independently selected from D, CN, OH, NH 2 , F, Cl, Br, CH 3 , CH 2 CH 3 , n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH═CH 2 , -CH═CHCH 3 , -C≡CH, -C≡CCH 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 (CH 3 ) 2 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 , CH 2 CHF 2 , CH 2 CF 3 , CH 2 OH, SCH 3 , SCH 2 CH 3 , S(O)CH 3 , S(O)CH 2 CH 3 , S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 , S(O) 2 NH 2 , S(O) 2 NHCH 3 , S(O) 2 N(CH3 ) 2 , NHS(O) 2 CH 3 , C(O)CH 3 , C(O)CH 2 CH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 2 F, OCH 2 CHF 2 , OCH 2 CF 3 , -CH(OH)CH 3 , CH 2 CH 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 , -CH 2 OCHF 2 , -CH 2 OCF 3 , -CH(OCH 3 )CH 3 , OCH 2 CN, OCH 2 CONH 2 , NHCH 3 , N(CH 3 ) 2 , CH 2 CH 2 NH 2 , -CH(NH 2 )CH 3 , CH 2 N(CH 3 ) 2 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CN, -COOH, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -P(O)(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CHO, Azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,4-diazacyclooctyl, 1,4-diazacycloheptyl, azacycloheptyl.

[0197] In certain embodiments, two adjacent Rs 4 together with the atoms to which they are attached form a C 4- C 7 The cycloalkyl is optionally substituted with substituents independently selected from: D, halogen, oxo, CN, OH, NH 2 , NO 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group; wherein the C 3- C 6 cycloalkyl or 4- to 6-membered heterocyclic group is optionally substituted with D, halogen, CN, OH, NH 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl.

[0198] In certain embodiments, two adjacent Rs 4 together with the atoms to which they are attached form a 4- to 7-membered heterocyclic group optionally substituted with substituents independently selected from: D, halogen, oxo, CN, OH, NH 2 , NO 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group; wherein the C 3- C 6A cycloalkyl or 4-6 membered heterocyclic group is optionally substituted with D, halogen, CN, OH, NH 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl.

[0199] In certain embodiments, each R 4 is independently selected from (i) H, D, halogen, or –OR A ; or (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; each substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 4A ; where R A and R 4A are as defined in the present disclosure. In certain embodiments, each R 4 is independently selected from H, –F, –Cl, –CH 3 , –CF 3 , or –OCH 3 .

[0200] In certain embodiments, one of the R 4 is –F. In certain embodiments, one of the R 4 is H, F, –Cl, –CH 3 , –CF 3 –OCH 3 , or ethynyl. In certain embodiments, one of the R 4 is –OCH 3 .

[0201] In certain embodiments, two of the R 4 are not H. In certain embodiments, two of the R 4 are not H; one of the two R 4 is –F; the other R 4 is –OCH 3 .

[0202] In certain embodiments, three of the R 4 are not H. In certain embodiments, three of the R 4 are not H; one of the three R 4is –F; the second R 4 is F, –Cl, –CH 3 , –CF 3 –OCH 3 , or ethynyl; the third R 4 is –OCH 3 . In certain embodiments, where the three Rs 4 are not H; one of the three is –F; the second is –Cl; the third is –OCH 3 .

[0203] In certain embodiments, R 5 is independently selected from H, D, halogen, CN, NO 2 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkyl-O-C 1 -C 8 alkyl, OC 1 -C 8 haloalkyl, C 1 -C 8 alkyl-OH, C 1 -C 8 alkyl-CN. In certain embodiments, R 5 is H. In certain embodiments, R 5 is D. In certain embodiments, R 5 is halogen (e.g., F, Cl, Br, I). In certain embodiments, R 5 is CN. In certain embodiments, R 5 is NO 2 . In certain embodiments, R 5 is C 1 -C 8 alkyl. In certain embodiments, R 5 is C 2 -C 8 alkenyl. In certain embodiments, R 5 is C 2 -C 8 alkynyl. In certain embodiments, R 5 is C 1 -C 8 haloalkyl. In certain embodiments, R 5 is C 1 -C8 Alkyl - O - C 1 - C 8 Alkyl. In certain embodiments, R 5 is C 1 - C 8 Alkyl - OH. In certain embodiments, R 5 is C 1 - C 8 Alkyl - CN.

[0204] In certain embodiments, R 6 is independently selected from H, D, halogen, CN, NO 2 , C 1 - C 8 Alkyl, C 2 - C 8 Alkenyl, C 2 - C 8 Alkynyl, C 1 - C 8 Halogenated alkyl, C 1 - C 8 Alkyl - O - C 1 - C 8 Alkyl, C 1 - C 8 Alkyl - OH, C 1 - C 8 Alkyl - CN. In certain embodiments, R 6 is H. In certain embodiments, R 6 is D. In certain embodiments, R 6 is halogen (e.g., F, Cl, Br, I). In certain embodiments, R 6 is CN. In certain embodiments, R 6 is NO 2 . In certain embodiments, R 6 is C 1 - C 8 Alkyl. In certain embodiments, R 6 is C 2 - C 8 Alkenyl. In certain embodiments, R 6 is C 2 - C 8 Alkynyl. In certain embodiments, R 6 is C 1 - C 8 Halogenated alkyl. In certain embodiments, R 6 is C 1 - C 8 Alkyl - O - C 1 - C 8 Alkyl. In certain embodiments, R6 is C 1 -C 8 alkyl-OH. In certain embodiments, R 6 is C 1 -C 8 alkyl-CN.

[0205] In certain embodiments, R 7 is independently selected from H, D, CN, halogen, NO 2 , N 3 , SF 5 , Si(R 8 ) 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or adamantyl; wherein the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or adamantyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, -halogen, -CN, -NO 2 , -N 3 , SF 5 , oxo, -NR C R D , -OR A , -SR A , SiR G R H R I , -B(OR C )(OR D ), -C(O)R B , -C(O)OR A , -OC(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) 2 R B, -S(O)NR C R D , -NR C S(O)R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR C R D , -NR C S(O)(=NR B )R B 。

[0206] In certain embodiments, R 7 is independently selected from H, D, CN, halogen, NO 2 , N 3 , SF 5 , Si(R 8 ) 3 。In certain embodiments, R 7 is H. In certain embodiments, R 7 is D. In certain embodiments, R 7 is halo. In certain embodiments, R 7 is CN. In certain embodiments, R 7 is NO 2 。In certain embodiments, R 7 is N 3 。In certain embodiments, R 7 is SF 5 。In certain embodiments, R 7 is Si(R 8 ) 3 , for example R 7 is Si(CH 3 ) 3 。

[0207] In certain embodiments, R 7 is C 1 -C 8 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: D, -halogen, -CN, -NO 2 , -N 3 , SF 5 , oxo, -NR C R D , -OR A , -SR A, SiR G R H R I , -C(O)R B , -C(O)OR A , -OC(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) 2 R B , -S(O)NR C R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR C R D , -NR C , -NR B )R B . In certain embodiments, R 7 is methyl, ethyl, propyl, butyl, pentyl, hexyl; each substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, -halogen, -CN, -NO 2 , -N 3 , 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 RD , -NR C C(O)OR A , -S(O)R B , -S(O) 2 R B , -S(O)NR C R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR C R D , -NR C , -S(O)(=NR B )R B 。

[0208] In certain embodiments, R 7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 C(CH 3 ) 3 ,CH 2 F, CHF 2 ,CF 3 ,CH 2 CH 2 F, CH 2 CHF 2 ,CH 2 CF 3 ,CH 2 OH, CH 2 CH 2 OH, CH(CH 3 )OH, CH 2 CH(CH 3 )OH, CH 2 OCH 3 ,CH 2 CH 2 OCH 3 ,CH 2 OCH 2 CH 3 ,CH 2 CH 2 OCH 2 CH 3 ,CH 2 CH 2 OCH 2 CH 2 OCH 3 ,CH2 CH 2 OCH 2 CH 2 OCH 2 CH 3 ,CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OH,CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 ,CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 3 ,CH 2 CH 2 OCH 2 CH 2 SCH 3 ,CH 2 CH 2 OCH 2 CH 2 SCH 2 CH 3 ,CH(CH 3 )OCH 3 ,CH 2 CH(CH 3 )OCH 3 ,CH(CH 3 )CN,C(CH 3 ) 2 CN,CH 2 C(CH 3 ) 2 CN,CH(CH 3 )F,C(CH 3 ) 2 F,CH 2 C(CH 3 ) 2 F,CH(CH 3 )OH,C(CH 3 ) 2 OH,CH 2 C(CH 3 ) 2 OH,CH(CH3 )OCH 3 ,C(CH 3 ) 2 OCH 3 ,CH 2 C(CH 3 )OCH 3 ,CH(CH 3 )CH 2 OH,C(CH 3 ) 2 CH 2 OH,CH 2 C(CH 3 ) 2 CH 2 OH,CH 2 SCH 3 ,CH 2 CH 2 SCH 3 ,CH 2 S(O)CH 3 ,CH 2 CH 2 S(O)CH 3 ,CH 2 S(O) 2 CH 3 ,CH 2 CH 2 S(O) 2 CH 3 ,CH 2 C(O)CH 3 ,CH 2 CH 2 C(O)CH 3 ,CH 2 N 3 ,CH 2 CH 2 N 3 ,Si(CH 3 ) 3 ,CH 2 Si(CH 3 ) 3 ,CH 2 NHCH 3 ,CH 2 CH 2 NHCH 3 ,CH 2 N(CH 3 ) 2 ,CH 2 CH 2 N(CH 3 ) 2 ,CH 2NHC(O)CH 3 ,CH 2 CH 2 NHC(O)CH 3 ,CH 2 N(CH 3 )C(O)CH 3 ,CH 2 CH 2 N(CH 3 )C(O)CH 3 ,CH 2 NHS(O)CH 3 ,CH 2 CH 2 NHS(O)CH 3 ,CH 2 N(CH 3 )S(O)CH 3 ,CH 2 CH 2 N(CH 3 )S(O)CH 3 ,CH 2 NHS(O) 2 CH 3 ,CH 2 CH 2 NHS(O) 2 CH 3 ,CH 2 N(CH 3 )S(O) 2 CH 3 ,CH 2 CH 2 N(CH 3 )S(O) 2 CH 3 ,

[0209] In certain embodiments, R 7 is C 2 -C 8 alkenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, -halogen, -CN, -NO 2 , -N 3 , oxo, -NR C R D , -OR A , -SR A , -SiR G R H R I 3 , -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) 2 R B , -S(O)NR C R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR C R D , -NR C S(O)(=NR B )R B 。 In certain embodiments, R 7 is C 2 alkenyl, C 3 alkenyl, C 4 alkenyl, C 5 alkenyl, or C 6 alkenyl; wherein each substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, -halogen, -CN, -NO 2 , -N 3 , 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)ORA , -S(O)R B , -S(O) 2 R B , -S(O)NR C R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR C R D , -NR C , -S(O)(=NR B )R B 。

[0210] In certain embodiments, R 7 is -CH=CH 2 , -CH=CHCH 3 , -CH=CHCH 2 CH 3 , -C(=CH 2 )CH 3 , -C(=CH 2 )CH 2 CH 3 , -C(=CH 2 )CH 2 OCH 3 , -C(=CH 2 )CH 2 OCH 3 , -C(=CH 2 )CH 2 SCH 3 , -C(=CH 2 )CH 2 SCH 3 , -CH=CF 2 , -CH=CFCH 3 , -CH=CFCH 2 CH 3 , -C(=CF 2 )CH 3 , -C(=CF 2 )CH 2 CH 3 , -C(=CF 2 )CH 2 OCH 3 , -C(=CF 2 )CH 2 OCH3 , -C(=CF 2 )CH 2 SCH 3 , or -C(=CF 2 )CH 2 SCH 3 .

[0211] In certain embodiments, R 7 is C 2 -C 8 alkynyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, -halogen, -CN, -NO 2 , -N 3 , 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) 2 R B , -S(O)NR C R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR C R D , -NR C S(O)(=NR B )R B .

[0212] In certain embodiments, R 7 is adamantyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, CN, NO2 ,N 3 ,oxo, NR C R D ,OR A ,SR A ,SiR G R H R I ,B(OR C )(OR D ),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) 2 R B ,S(O)NR C R D ,NR C S(O)R D ,NR C S(O) 2 R D ,S(O) 2 NR C R D ,NR C S(O) 2 NR C R D ,NR C S(O)(=NR B )R B 。In certain embodiments, R 7 is

[0213] In certain embodiments, has the following structure:

[0214]

[0215] In certain embodiments, each R 8 is independently selected from C 1 -C 4 alkyl or phenyl.

[0216] In certain embodiments, R 8 is C 1 -C 4 alkyl or phenyl. In certain embodiments, R 8 is methyl, ethyl, propyl (e.g., n-propyl, i-propyl), butyl (n-butyl, i-butyl, t-butyl) or phenyl.

[0217] In certain embodiments, each R A is independently selected from H, D.

[0218] In certain embodiments, each R A is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: D, OH, CN, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkyl-OH, C 1 -C 4 alkyl-CN, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, NO 2 , oxo, ORa , SR a , SF 5 , 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 c )(OR d ), 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) 2 R b , NR c S(O) 2 R b , S(O) 2 NR c R d , NR c S(O) 2 NR c R d , or NR c S(O)(=NR b )R b 。

[0219] In certain embodiments, each R B is independently selected from H, D.

[0220] In certain embodiments, each R B is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: D, OH, CN, halogen, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, SF 5 , C(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 , NRc C(O)OR a ,S(O)R b , S(O)NR c R d ,S(O) 2 R b , NR c S(O) 2 R b ,S(O) 2 NR c R d , NR c S(O) 2 NR c R d , or B(OR c )(OR d ).

[0221] In certain embodiments, R C and R D are independently selected from H and D.

[0222] In certain embodiments, R C and R D are independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl; wherein said C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of D, OH, CN, halogen, oxo, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Cyanoalkyl, OC 1 -C 4 Alkyl, OC 1 -C4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, SF 5 , OC(O)NR c R d , NR c R d , NR c C(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , S(O) 2 , NR c R d , NR c , S(O) 2 , NR c R d , or B(OR c )(OR d ).

[0223] In certain embodiments, R C and R D together with the N atom to which they are attached form a 4- to 7-membered heterocyclic group optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, OH, oxo, CN, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl.

[0224] In certain embodiments, each R a is independently selected from H, D.

[0225] In certain embodiments, each R a is independently selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: D, halogen, OH, CN, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or OC 1 -C 4 haloalkyl.

[0226] In certain embodiments, each R a1 is independently selected from H, D.

[0227] In certain embodiments, each R a1 is independently selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C3- C 7 A cycloalkyl group, a 5- or 6-membered heteroaryl group, or a 4- to 7-membered heterocyclic group is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, halogen, OH, CN, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or OC 1 -C 4 haloalkyl.

[0228] In certain embodiments, each R b is independently selected from H, D.

[0229] In certain embodiments, each R b is independently selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, a 5- or 6-membered heteroaryl group, a 4- to 7-membered heterocyclic group, an arylalkyl group, a heteroarylalkyl group, a cycloalkylalkyl group, or a heterocyclicalkyl group; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, a 5- or 6-membered heteroaryl group, a 4- to 7-membered heterocyclic group, an arylalkyl group, a heteroarylalkyl group, a cycloalkylalkyl group, or a heterocyclicalkyl group is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, OH, CN, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 6- C 10 aryl, C 3- C 10 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclic group.

[0230] In certain embodiments, each R b1 is independently selected from H, D.

[0231] In certain embodiments, each R b1 is independently selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, OH, CN, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 6- C 10 aryl, C 3- C 10 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclic group.

[0232] In certain embodiments, R c and R d are each independently selected from H, D.

[0233] In certain embodiments, R c and R d are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6- C 10 aryl, 5- to 10-membered heteroaryl, C 3- C 10 cycloalkyl, 4- to 10-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocyclic group, heteroarylaryl, or biheteroaryl; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6- C 10 aryl, 5- to 10-membered heteroaryl, C 3- C 10 cycloalkyl, 4- to 10-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocyclic group, heteroarylaryl, or biheteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, OH, CN, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4Cyanoalkyl, C 6 -C 10 Aryl, 5- to 10-membered heteroaryl, C(O)OR a1 , C(O)R b1 , S(O) 2 R b1 , C 1 -C 4 Alkyl-O-C 1 -C 4 Alkyl, and C 1 -C 4 Alkyl-O-C 1 -C 4 Alkyl-O-.

[0234] In certain embodiments, R c and R d together with the N atom to which they are attached form a 4- to 7-membered heterocyclic group optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from: D, OH, CN, -NH 2 , -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 Alkyl) 2 , halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Halogenated alkyl, C 1 -C 4 Halogenated alkoxy, C 1 -C 4 Hydroxyalkyl, C 1 -C 4 Cyanoalkyl, C 6 -C 10 Aryl, 5- to 10-membered heteroaryl, C 1 -C 4 Alkoxy-C 1 -C 4 Alkyl, or C 1 -C 4 Alkoxy-C 1 -C 4 Alkoxy.

[0235] In certain embodiments, each R E is independently selected from H, D.

[0236] In certain embodiments, each R E is independently selected from C 1 -C4 Alkyl, C 1 -C 4 Haloalkyl, C 2 -C 4 Alkenyl, (C 1 -C 4 Alkoxy)-C 1 -C 4 Alkyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 Aryl-C 1 -C 4 Alkyl, C 3 -C 10 Cycloalkyl-C 1 -C 4 Alkyl, 5-10 membered heteroaryl-C 1 -C 4 Alkyl, or 4-10 membered heterocyclic group-C 1 -C 4 Alkyl.

[0237] In certain embodiments, each R F is independently selected from H, D.

[0238] In certain embodiments, each R F is independently selected from C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 10 Cycloalkyl, or 4-10 membered heterocyclic group.

[0239] In certain embodiments, each R e is independently selected from C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 2 -C 4 Alkenyl, (C 1 -C 4 Alkoxy)-C 1 -C 4 Alkyl, C2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5- to 10-membered heteroaryl, C 3 -C 10 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 Aryl-C 1 -C 4 Alkyl, C 3 -C 10 Cycloalkyl-C 1 -C 4 Alkyl, 5- to 10-membered heteroaryl-C 1 -C 4 Alkyl, or 4- to 10-membered heterocyclic group-C 1 -C 4 Alkyl.

[0240] In certain embodiments, each R f is independently selected from H, D.

[0241] In certain embodiments, each R f is independently selected from C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 6 -C 10 Aryl, 5- to 10-membered heteroaryl, C 3 -C 10 Cycloalkyl, or 4- to 10-membered heterocyclic group.

[0242] In certain embodiments, R G , R H and R I are independently selected from C 1 -C 4 Alkyl or phenyl.

[0243] In certain embodiments, R G is C 1 -C 4 Alkyl (e.g., C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl) or phenyl. In certain embodiments, R G is methyl, ethyl, propyl (e.g., n-propyl, i-propyl), butyl (n-butyl, i-butyl, t-butyl) or phenyl.

[0244] In certain embodiments, R H is C 1 -C 4 alkyl (e.g., C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl) or phenyl. In certain embodiments, R H is methyl, ethyl, propyl (e.g., n-propyl, i-propyl), or butyl (n-butyl, i-butyl, t-butyl) or phenyl.

[0245] In certain embodiments, R I is C 1 -C 4 alkyl (e.g., C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl) or phenyl. In certain embodiments, R I is methyl, ethyl, propyl (e.g., n-propyl, i-propyl), or butyl (n-butyl, i-butyl, t-butyl) or phenyl.

[0246] In certain embodiments, the compound of formula (I) is as follows:

[0247]

[0248]

[0249]

[0250] or a pharmaceutically acceptable salt thereof.

[0251] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of this disclosure. Compounds containing asymmetrically substituted carbon atoms isolated herein can be optical isomers or racemates. Many geometric isomers of olefins, C=N double bonds, etc., can also be present in the compounds described herein, and all stable isomers are within the scope of this disclosure. The cis and trans geometric isomers of the compounds described herein are also within the scope of this disclosure and can be isolated as mixtures of isomers or in separated isomeric forms. In addition, atropisomers and their mixtures, such as those resulting from restricted rotation of two aromatic or heteroaromatic rings bound to each other, are also included within the scope of this disclosure.

[0252] The compounds of the present invention also include tautomers. Tautomers are generated 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-lactim tautomerism, amidine-imidic acid tautomerism, and enamine-imine tautomerism. In a cyclic structure, protons can tautomerize 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 hydroxy-substituted compounds can exist as tautomers, as shown below: etc. Tautomers can be in equilibrium or can be fixed in space by suitable substitution to form one form.

[0253] In certain embodiments, the compounds of the present invention may exist in the form of rotamers. The description of the compounds of the present invention is intended to cover any individual rotamer, as well as any proportion of a mixture of rotamers, and does not represent a particular rotamer. The description of a particular rotamer means the described rotamer substantially free of other rotamers.

[0254] The present invention further includes isotopically labeled compounds or intermediates of the compounds of the present invention. "Isotope" refers to atoms having the same number of atoms but different molecular weights. For example, isotopes of hydrogen include protium and deuterium.

[0255] The present invention also includes pharmaceutically acceptable salts of the compounds described in the present disclosure. Exemplary pharmaceutically acceptable salts include, but are not limited to, mineral acid or organic acid salts of basic residues such as amines; base salts or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compounds formed from non-toxic inorganic or organic acids. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 1418, and J. Pharm. Sci. 1977, 66, 2, which are hereby incorporated by reference in their entirety into the present disclosure.

[0256] Pharmaceutical Compositions

[0257] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound provided by the present disclosure, for example, a compound represented by formula (I), a pharmaceutically acceptable salt solvate or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; and a pharmaceutically acceptable excipient.

[0258] 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 for injection use (e.g., aqueous or oily suspensions, or emulsions, elixirs or sterile aqueous solutions), can be for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), can be for inhalation use (e.g., fine powders or liquid aerosols), can be for insufflation (e.g., fine powders), or can be for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, intramuscular injection or as suppositories for rectal administration).

[0259] The pharmaceutically acceptable excipients can be excipients as described below: carriers (e.g., solid, liquid or semi-solid carriers), adjuvants, diluents, fillers or extenders, granulating agents, coating agents, controlled release agents, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickening agents, flavoring agents, sweetening agents, taste masking agents, or stabilizers.

[0260] The pharmaceutically acceptable carriers can be, for example, solids, liquids or gases. Exemplary solid carriers include lactose, clay, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid. Exemplary liquid carriers include syrups, peanut oil, olive oil, water. Exemplary gaseous carriers include carbon dioxide and nitrogen. When preparing a composition for an oral dosage form, any convenient pharmaceutical medium can be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents can be used to form oral liquid preparations such as suspensions, elixirs and solutions; for example, starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrant carriers can be used to form oral solid preparations such as powders, capsules and tablets.

[0261] The pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard shell or soft shell), cachets, pills, lozenges, syrups, solutions, powders, granules, elixirs, suspensions, sublingual tablets, wafers or patches, such as buccal patches.

[0262] Accordingly, the tablet composition may contain a unit dose of the active compound and an inert diluent or carrier, such as sugars or sugar alcohols, for example, lactose, sucrose, sorbitol or mannitol; and / or non-sugar-derived diluents such as sodium carbonate, calcium phosphate, calcium carbonate or cellulose or its derivatives, such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, and hydroxypropylmethylcellulose, and starches, such as corn starch. The tablets may also contain standard ingredients such as binders and granulating agents, such as polyvinylpyrrolidone, disintegrants (e.g., swellable crosslinked polymers, such as crosslinked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffering agents (e.g., phosphate or citrate buffers), and effervescent agents, such as citrate / bicarbonate mixtures.

[0263] The pharmaceutical compositions of the present disclosure suitable for parenteral administration may be prepared as solutions or suspensions of the active compound in water. Suitable surfactants may include, for example, hydroxypropylcellulose. Dispersions may also be prepared in oils with glycerol, liquid polyethylene glycols, and mixtures thereof. In addition, preservatives may be included to prevent the detrimental growth of microorganisms.

[0264] The pharmaceutical compositions of the present disclosure suitable for injection include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injection solutions or dispersions. In all cases, the final injectable form must be sterile and must be a fluid effective for injection. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, the contaminating action of microorganisms, such as bacteria and fungi, must be prevented. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, ethylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0265] The pharmaceutical compositions of the present disclosure may be in a form suitable for topical use, such as, for example, aerosols, creams, ointments, emulsions or powders. In addition, the compositions may be in a form suitable for use in transdermal devices.

[0266] In addition to the above carrier components, the pharmaceutical formulations described in the present disclosure may optionally contain one or more additional carrier components such as diluents, buffering agents, flavoring agents, binders, surfactants, thickening agents, lubricants and preservatives (including antioxidants). In addition, other adjuvants may be included to render the formulation isotonic with the blood of the intended recipient.

[0267] Method of Use

[0268] In some embodiments, the present disclosure provides a method of treating or inhibiting cancer, comprising administering to a subject a therapeutically effective amount of a compound of the present disclosure, such as 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 of the present disclosure.

[0269] In certain embodiments, the cancer is characterized by PolQ overexpression. In certain embodiments, the cancer is characterized by an increased reliance on MMEJ-DSB repair. In certain embodiments, the cancer is characterized by HR-deficiency. In certain embodiments, the cancer is characterized by a decrease or absence of HR-related gene expression. 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 a decrease or absence of NHEJ-related gene expression.

[0270] In other embodiments, the present disclosure provides a method of treating or preventing a disease in a subject, the disease being characterized by PolQ overexpression, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, such as 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 of the present disclosure.

[0271] The term "PolQ overexpression" refers to an increase in the expression or activity of the PolQ enzyme in diseased cells, e.g., cancer cells, relative to the expression or activity of the PolQ enzyme in control cells (e.g., non-diseased cells of the same type). In certain embodiments, the 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 control cells. Exemplary cancers with PolQ overexpression 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.

[0272] In still other embodiments, the present disclosure provides a method of treating or preventing a disease in a subject, the disease being characterized by an increased reliance on MMEJ-DSB repair, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, such as 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 of the present disclosure.

[0273] In some further embodiments, the present disclosure provides a method for treating or preventing a disease in a subject, the disease being characterized by HR-deficiency, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, such as a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; or a pharmaceutical composition as described in the present disclosure.

[0274] In certain embodiments, the HR-related genes are 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.

[0275] In some further embodiments, the present disclosure provides a method for treating or preventing a disease in a subject, the disease lacking the 53BP1 / Shieldin complex, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, such as a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; or a pharmaceutical composition as described in the present disclosure.

[0276] In some further embodiments, the present disclosure provides a method for treating or preventing a disease in a subject, the disease being resistant to PARPi treatment, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, such as a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic derivative, prodrug or deuterated compound thereof; or a pharmaceutical composition as described in the present disclosure.

[0277] In other embodiments, the present disclosure provides a method for treating or preventing a disease in a subject, the disease being characterized by NHEJ deficiency, or reduced or absent NHEJ-related gene expression, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, such as 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 as described in the present disclosure.

[0278] In certain embodiments, the NHEJ-related genes are 53BP1, DCLRE1C, LIG4, NHEJ1, POLL, POLM, PRKDC, RIF1, SHLD1, SHLD2, SHLD3, XRCC4, XRCC5, or XRCC6.

[0279] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0280] In certain embodiments, the therapeutically effective amount of the compound 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 compound of the present disclosure is about 0.1 to about 100 mg / kg / day. In other embodiments, the therapeutically effective amount of the compound of the present disclosure is about 0.1 to about 50 mg / kg / day. In yet other embodiments, the therapeutically effective amount of the compound of the present disclosure is about 0.1 to about 25 mg / kg / day. In yet other embodiments, the therapeutically effective amount of the compound of the present disclosure is about 0.1 to about 20 mg / kg / day. In yet other embodiments, the therapeutically effective amount of the compound of the present disclosure is about 0.1 to about 15 mg / kg / day. In yet other embodiments, the therapeutically effective amount of the compound of the present disclosure is about 0.1 to about 10 mg / kg / day. In other embodiments, the therapeutically effective amount of the compound of the present disclosure is about 0.1 to about 5 mg / kg / day.

[0281] It should be understood that the dosage can also be expressed in units other than mg / kg / day. For example, the dosage for parenteral administration can be expressed as mg / m 2 / day. One of ordinary skill in the art can easily convert the dosage from mg / kg / day to mg / m 2 / day based on the height or weight or both of a given subject. For example, for a person weighing 65 kg, a dosage of 1 mg / m 2 / day is approximately equal to 58 mg / kg / day.

[0282] Depending on the condition, disease or disorder to be treated and the condition of the subject, the compounds provided by the present disclosure can be administered by oral, parenteral administration (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual or topical (e.g., transdermal or local) routes of administration. The compounds provided by the present disclosure are formulated into appropriate dosage units together with pharmaceutically acceptable excipients, carriers, adjuvants or vehicles suitable for each route of administration.

[0283] In some embodiments, the compounds provided by the present disclosure are administered orally. In other embodiments, the compounds provided by the present disclosure are administered parenterally. In still other embodiments, the compounds provided by the present disclosure are administered intravenously. In still other embodiments, the compounds provided by the present disclosure are administered intramuscularly. In still other embodiments, the compounds provided by the present disclosure are administered subcutaneously. In other embodiments, the compounds provided by the present disclosure are administered topically.

[0284] The compounds provided by the present disclosure can be delivered as a single dose, such as a single bolus injection, or an oral tablet or pill; or delivered over time, such as by continuous infusion over time or by separate bolus doses over time. If needed, the compounds provided by the present disclosure can be administered repeatedly, e.g., until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.

[0285] The compounds provided by the present disclosure can be administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID) and three times daily (TID). In addition, it can be continuous administration, i.e., daily administration, or intermittent administration. The terms "intermittent" or "intermittently" as used in the present disclosure mean stopping and starting administration at regular or irregular intervals. For example, intermittent administration of the compounds of the present disclosure refers to administration one to six days per week, cyclic administration (e.g., daily administration for two to eight consecutive weeks, then a break for up to one week without administration), or alternate-day administration.

[0286] The compounds provided by the present disclosure can also be combined or combined with other therapeutic agents for the treatment and / or prevention of the diseases described in the present disclosure.

[0287] Synthesis

[0288] 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 the schemes described below.

[0289] The reaction for preparing the compounds of the present invention can be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can substantially not react with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out. For example, the temperature range can be from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. According to the above specific reaction steps, those skilled in the art can select a solvent suitable for a specific reaction step.

[0290] 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 groups, can be easily determined by those skilled in the art. The 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).

[0291] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible light), or mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0292] As expressed, the terms "ambient temperature", "room temperature" and "r.t." used in the present invention generally refer to the temperature in the art, for example, the reaction temperature, which refers to the temperature of the space during the reaction operation, for example, a temperature of about 20°C to about 30°C.

[0293] The compounds of the present invention can be prepared according to various preparation routes known in the literature. The following schemes provide general guidance regarding the preparation of the compounds described in the present invention. Those skilled in the art should understand that the preparation methods in the following schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention. An exemplary synthetic method for preparing the compounds of the present invention is as follows in the schemes.

[0294] The following examples are provided to illustrate some of the above concepts described in the content of the present invention. Although the examples are considered to provide embodiments, they should not be considered as limiting the more general embodiments described herein.

[0295] Abbreviations

[0296]

[0297]

[0298] Synthetic Scheme

[0299] A series of heterocyclic amide derivatives of formula (I) can be prepared by the method described in Scheme 1. Carboxylic acid 1-1 reacts with a suitable 1,3,4-thiadiazol-2-amine derivative 1-2 under standard amide coupling conditions (e.g., in the presence of an activating reagent such as BOP, PyBOP, HATU, HBTU, EDCI, or T 3 P and a base such as Hunig's base, Et 3 N, pyridine or DMAP) to prepare the heterocyclic amide derivative (I). In addition, carboxylic acid 1-1 reacts with a chlorinating reagent such as oxalyl chloride, thionyl chloride, POCl 3 or TCFH to obtain the corresponding acyl chloride 1-3, which is further coupled with a suitable amine 1-2 to obtain the corresponding heterocyclic amide derivative of formula (I).

[0300] Scheme 1

[0301]

[0302] In addition, a series of heterocyclic amide derivatives of formula (I) can be prepared by the method described in Scheme 2. 2-1 reacts with a suitable 1,3,4-thiadiazol-2-amine derivative 2-2 in a method similar to that of Scheme 1 to prepare compound 2-3. The amide derivative 2-3 where W is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs) reacts with compound 2-5 where V is boric acid, borate, 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 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 and a base such as t-BuOK, t-BuONa, Cs 2 CO 3 , K 2 CO 3 , or Na 2 CO 3 (in the presence of), a Suzuki coupling can be carried out to obtain the heterocyclic amide derivative (I).

[0303] Or amide derivative 2-3 where W is boric acid, borate, trimethyltin or tributyltin and compound 2-5 where V is a 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)Cl 2 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 and a base such as t-BuOK, t-BuONa, Cs 2 CO 3 , K 2 CO 3 , or Na 2 CO 3 (in the presence of), a Suzuki coupling can also be carried out to obtain the heterocyclic amide derivative (I).

[0304] Scheme 2

[0305]

[0306] The heterocyclic carboxylic acid intermediate shown in Formula 3-5 can be prepared by the method described in Scheme 3. Compounds 3-1 and 3-3 can undergo a C-C coupling reaction according to the Suzuki coupling or Stille coupling method described in Scheme 2 to obtain the ester compound 3-4. Compound 3-4 can undergo saponification in the presence of a base such as LiOH, NaOH, KOH or Me 3 SnOH to obtain the corresponding acid 3-5. In addition, carboxylic acid 3-2 and compound 3-3 can be coupled according to the method described in Scheme 3 under standard Suzuki coupling conditions or Stille coupling conditions to directly obtain the corresponding carboxylic acid 3-5.

[0307] Scheme 3

[0308]

[0309] The 1,3,4-thiadiazol-2-amine derivative 4-3 can be prepared by the method described in Scheme 4. The carboxylic acid 4-1 or cyanide 4-2 and thiosemicarbazide are reacted with a dehydrating agent such as POCl 3 , TFA, PCl 5 , P 2 O 5 or PPA to obtain the 1,3,4-thiadiazol-2-amine derivative 4-3.

[0310] Scheme 4

[0311]

[0312] The 1,3,4-thiadiazol-2-amine derivative 5-4 can be prepared by the method described in Scheme 5. 5-Bromo-1,3,4-thiadiazol-2-amine and alcohol 5-1 are subjected to a substitution reaction in the presence of a base such as t-BuOK, t-BuONa, Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , NaH, NaHMDS, or LDA in a suitable solvent such as THF, DMF, or DMSO to obtain the 1,3,4-thiadiazol-2-amine derivative 5-4.

[0313] In addition, alcohol 5-1 is reacted with CS 2 and methyl iodide in the presence of a base such as NaH, t-BuOK, t-BuONa, or NaHMDS in a suitable solvent such as THF to prepare the dithiocarbonate 5-2. The dithiocarbonate 5-2 is subjected to a hydrazinolysis reaction with hydrazine hydrate to obtain the compound 5-3, which is reacted with BrCN in the presence of a base such as Hunig's base or TEA to be further converted into the 1,3,4-thiadiazol-2-amine derivative 5-4.

[0314] Scheme 5

[0315] Examples

[0316] Example 1: 4-(2-Fluoro-6-methoxyphenyl)-6-methyl-N-(5-(neopentyloxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0317]

[0318] Step 1: 5-(Neopentyloxy)-1,3,4-thiadiazol-2-amine

[0319]

[0320] At 0 °C, to a solution of neopentyl alcohol (0.88 g, 10 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (0.9 g, 5 mmol) in DMF (10 mL) was added NaH (0.6 g, 15 mmol, 60% suspended in mineral oil). The reaction mixture was stirred overnight at r.t. The reaction mixture was quenched with water (30 mL) and then extracted with EtOAc (20 mL x 4). The combined organic phases were washed with saturated brine and dried over Na 2 SO 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column, eluting with MeCN / H 2 O (0 - 15%) to give the title compound (110 mg) as a yellow oil. LCMS calcd for C 7 H 14 N 3 OS [M+H] - : m / z = 188.1; found: 188.0.

[0321] Step 2: 4-(2-Fluoro-6-methoxyphenyl)-6-methyl-N-(5-(neopentyloxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0322] 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-(neopentyloxy)-1,3,4-thiadiazol-2-amine (38 mg, 0.2 mmol). The reaction mixture was stirred at r.t. for 5 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 O (15 - 45%) to give the title compound (46.2 mg) as a white solid. LCMS calcd for C 21 H 24 FN 4 O 3 S [M+H] + : m / z = 431.2; found: 431.1.

[0323] Example 2: N-(5-Ethoxy-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0324]

[0325] This compound was prepared in a similar manner to that of Step 1-2 of Example 1. In Step 1, anhydrous ethanol was used instead of pivalol. LCMS calculated value C 18 H 18 FN 4 O 3 S[M+H] + : m / z = 389.1; Observed value: 389.1.

[0326] Example 3: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-(3-hydroxy-2,2-dimethylpropoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0327]

[0328] This compound was prepared in a similar manner to that of Step 1-2 of Example 1. In Step 1, 2,2-dimethylpropane-1,3-diol was used instead of pivalol. LCMS calculated value C 21 H 24 FN 4 O 4 S[M+H] + : m / z = 447.1; Observed value: 447.1.

[0329] Example 4: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-(2-methoxyethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0330]

[0331] This compound was prepared in a similar manner to that of Step 1-2 of Example 1. In Step 1, 2-methoxyethan-1-ol was used instead of pivalol. LCMS calculated value C 19 H 20 FN 4 O 4 S[M+H] + : m / z = 419.1; Observed value: 419.1.

[0332] Example 5: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-(2-hydroxy-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0333]

[0334] This compound was prepared in a similar manner to that of Step 1-2 of Example 1. In Step 1, 2-methylpropane-1,2-diol was used instead of pivalol. LCMS calculated value C 20 H22 FN 4 O 4 S[M+H] + : m / z = 433.1; Measured value: 433.1.

[0335] Example 6: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-(2-methoxy-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0336]

[0337] This compound was prepared in a similar manner to Step 1-2 of Example 1. In Step 1, 2-methoxy-2-methylpropan-1-ol was used instead of neopentyl alcohol. LCMS calculated value C 21 H 24 FN 4 O 4 S[M+H] + : m / z = 447.1; Measured value: 447.1.

[0338] Example 7: 4-(2-Fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0339]

[0340] Step 1: 5-(2,2,2-Trifluoroethoxy)-1,3,4-thiadiazol-2-amine

[0341]

[0342] This compound was prepared in a similar manner to Step 1 of Example 1, using 2,2,2-trifluoroethanol instead of neopentyl alcohol. LCMS calculated value C 4 H 5 F 3 N 3 OS[M+H] + : m / z = 200.0; Measured value: 200.0.

[0343] Step 2: 4-(2-Fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0344] This compound was prepared in a similar manner to Step 2 of Example 1, using 5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-amine instead of 5-(neopentyloxy)-1,3,4-thiadiazol-2-amine. LCMS calculated value C 18 H15 F 4 N 4 O 3 S[M+H] + : m / z = 443.1; Measured value: 443.0.

[0345] Example 8: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-((-3-hydroxyadamantan-1-yl)methoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0346]

[0347] This compound was prepared in a similar manner to Steps 1-2 of Example 1. In Step 1, 3-(hydroxymethyl)adamantan-1-ol was used instead of neopentyl alcohol. LCMS calculated value C 27 H 30 FN 4 O 4 S[M+H] + : m / z = 525.2; Measured value: 525.2.

[0348] Example 9: N-(5-(2-Fluoro-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0349]

[0350] This compound was prepared in a similar manner to Steps 1-2 of Example 1. In Step 1, 2-fluoro-2-methylpropan-1-ol was used instead of neopentyl alcohol. LCMS calculated value C 20 H 21 F 2 N 4 O 3 S[M+H] + : m / z = 435.1; Measured value: 435.1.

[0351] Example 10: N-(5-(2-Cyano-2-methylpropoxy)-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0352]

[0353] This compound was prepared in a similar manner to Steps 1-2 of Example 1. In Step 1, 3-hydroxy-2,2-dimethylpropanenitrile was used instead of neopentyl alcohol. LCMS calculated value C 21 H 21 FN 5 O 3S[M+H] + : m / z = 442.1; Measured value: 442.2.

[0354] Example 11: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-(2-methoxypropoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0355]

[0356] Step 1: 2-Methoxypropan-1-ol

[0357]

[0358] To a solution of 2-methoxypropanoic acid (1.04 g, 10 mmol) in THF (10 mL), BH 3 -THF complex (15 mL, 1.0 M solution in THF) was added, and the reaction mixture was stirred at 70 °C overnight. The reaction mixture was cooled in an ice-water bath and then quenched with MeOH (20 mL) for 2 h. The resulting mixture was concentrated under reduced pressure to give 2-methoxypropan-1-ol without further purification.

[0359] Step 2: 5-(2-Methoxypropoxy)-1,3,4-thiadiazol-2-amine

[0360]

[0361] At 0 °C, to a mixture of 2-methoxypropan-1-ol (1.0 g, 10.0 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (0.9 g, 5.0 mmol) in DMF (10 mL), NaH (0.6 g, 15.0 mmol 60% suspended in mineral oil) was added. The reaction mixture was stirred at r.t. overnight, quenched with water (30 mL), and then extracted with EtOAc (20 mL x 4). The combined organic phases were washed with saturated brine and dried over Na 2 SO 4 dried, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column, eluting with MeCN / H 2 O (2 - 15%) to give the title compound (230 mg, 14% yield) as a yellow oil. LCMS calculated value C 6 H 12 N 3 O 2 S[M+H] + : m / z = 190.1; Measured value: 190.1.

[0362] Step 3: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-(2-methoxypropoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0363] To a mixture of 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-2) (106 mg, 0.4 mmol), TCFH (168 mg, 0.6 mmol) and NMI (66 mg, 0.8 mmol) in DMF (3 mL) was added 5-(2-methoxypropoxy)-1,3,4-thiadiazol-2-amine (80 mg, 0.4 mmol). The reaction mixture was stirred at r.t. for 5 h., then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column with MeCN / H 2 O (15 - 45%), to give the title compound (82.9 mg, 48% yield) as a white solid. LCMS calcd for C 20 H 22 FN 4 O 4 S [M+H]+: m / z = 433.1; found: 433.2.

[0364] Example 12: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-((S)-2-methoxypropoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0365]

[0366] This compound was prepared in a similar manner to steps 1 - 3 of Example 11. In step 1, (S)-2-methoxypropionic acid was used instead of 2-methoxypropionic acid. LCMS calcd for C 20 H 22 FN 4 O 4 S [M+H] + : m / z = 433.1; found: 433.2.

[0367] Example 13: 4-(2-Fluoro-6-methoxyphenyl)-N-(5-((R)-2-methoxypropoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0368]

[0369] This compound was prepared in a similar manner to steps 1 - 3 of Example 11. In step 1, (R)-2-methoxypropionic acid was used instead of 2-methoxypropionic acid. LCMS calcd for C 20 H 22 FN 4 O 4S[M+H] + : m / z = 433.1; Measured value: 433.2.

[0370] Example 14: 4-(2,3-Difluoro-6-methoxyphenyl)-N-(5-ethoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0371]

[0372] Step 1: 5-Ethoxy-1,3,4-thiadiazol-2-amine

[0373]

[0374] This compound was prepared in a similar manner to Step 1 of Example 1, using absolute ethanol instead of pivalol. LCMS calculated value C 4 H 8 N 3 OS[M+H] + : m / z = 146.0; Measured value: 146.1.

[0375] Step 2: 4-(2,3-Difluoro-6-methoxyphenyl)-N-(5-ethoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0376] 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), 5-ethoxy-1,3,4-thiadiazol-2-amine (44 mg, 0.3 mmol) was added. The reaction mixture was stirred at r.t. for 4 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 O (15 - 45%), to give the target product (40.9 mg, 40% yield), as a white solid. LCMS calculated value C 18 H 17 F 2 N 4 O 3 S[M+H] + : m / z = 407.1; Measured value: 407.1.

[0377] Example 15: 4-(2,3-Difluoro-6-methoxyphenyl)-N-(5-(2-methoxypropoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0378]

[0379] This compound was prepared in a similar manner to Step 2 of Example 14, using the intermediate 4-(2,3-difluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-3) and 5-(2-methoxypropoxy)-1,3,4-thiadiazol-2-amine (Step 2 of Example 11) as starting materials. LCMS calculated value C 20 H 21 F 2 N 4 O 4 S[M+H] + : m / z = 451.1; Found: 451.2.

[0380] Example 16: 4-(2,3-Difluoro-6-methoxyphenyl)-6-methyl-N-(5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0381]

[0382] This compound was prepared in a similar manner to Step 2 of Example 14, using the intermediate 4-(2,3-difluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-3) and 5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-amine (Step 1 of Example 7) as starting materials. LCMS calculated value C 18 H 14 F 5 N 4 O 3 S[M+H] + : m / z = 461.1; Found: 461.1.

[0383] Example 17: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-ethoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0384]

[0385] To a solution 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 (33 mg, 0.4 mmol) in DMF (2 mL), 5-ethoxy-1,3,4-thiadiazol-2-amine (45 mg, 0.3 mmol, Step 1 of Example 14) was added. The reaction mixture was stirred at r.t. for 5 h., then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, using MeCN / H 2Elute with O (10 - 30%) to obtain the target product (38 mg), which is a white solid. LCMS calculated value C 18 H 17 ClFN 4 O 3 S[M+H] + : m / z = 423.1; measured value: 423.1.

[0386] Example 18: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-methoxypropoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0387]

[0388] This compound was prepared in a similar manner to Example 17, using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(2-methoxypropoxy)-1,3,4-thiadiazol-2-amine (Step 2 of Example 11) as starting materials. LCMS calculated value C 20 H 21 ClFN 4 O 4 S[M+H] + : m / z = 467.1; measured value: 467.1.

[0389] Example 19: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0390]

[0391] This compound was prepared in a similar manner to Example 17, using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-amine (Step 1 of Example 7) as starting materials. LCMS calculated value C 18 H 14 ClF 4 N 4 O 3 S[M+H] + : m / z = 477.0; measured value: 477.1.

[0392] Example 20: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-methoxyethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0393]

[0394] Step 1: 5-(2-Methoxyethoxy)-1,3,4-thiadiazol-2-amine

[0395]

[0396] This compound was prepared in a similar manner to that of Step 1 of Example 1, using 2-methoxyethanol instead of neopentyl alcohol. LCMS calculated value C 5 H 10 N 3 O 2 S[M+H] + : m / z = 176.0; Measured value: 176.1.

[0397] Step 2: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-methoxyethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0398] This compound was prepared in a similar manner to that of Example 17, using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(2-methoxyethoxy)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value C 19 H 19 ClFN 4 O 4 S[M+H] + : m / z = 453.1; Measured value: 453.1.

[0399] Example 21: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-(2-methoxyethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0400]

[0401] Step 1: 5-(2-(2-Methoxyethoxy)ethoxy)-1,3,4-thiadiazol-2-amine

[0402]

[0403] At 0 °C, to a solution of 2-(2-methoxyethoxy)ethanol (1.2 g, 10 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (0.9 g, 5 mmol) in DMF (10 mL) was added NaH (0.6 g, 15 mmol, 60% suspended in mineral oil). The reaction mixture was stirred overnight at r.t. The reaction mixture was quenched with water (30 mL) and then extracted with EtOAc (20 mL x 4). The combined organic phases were washed with saturated brine and dried over Na 2 SO 4 4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column, eluting with MeCN / H 2 2O (5 - 15%) to give the title product (130 mg) as a yellow oil. LCMS calcd for C 7 8H 14 9N 3 3O 3 2S [M+H] + : m / z = 220.1; found: 220.1.

[0404] Step 2: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-(2-methoxyethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0405] 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 5-(2-(2-methoxyethoxy)ethoxy)-1,3,4-thiadiazol-2-amine (44 mg, 0.2 mmol). The mixture was stirred at r.t. for 5 h and concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 2O (0 - 10%) to give the title product (60 mg) as a white solid. LCMS calcd for C 21 20H 23 18ClFN 4 3O 5 2S [M+H] + : m / z = 497.1; found: 497.1.

[0406] Example 22: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-cyclobutoxyethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0407]

[0408] Step 1: 2-Cyclobutoxyethan-1-ol

[0409]

[0410] At 0 °C, to a solution of cyclobutanol (2.6 g, 36 mmol) in THF (40 mL) was added n-BuLi solution (36 mmol, 2.5 M hexane solution, 14.4 mL). The reaction mixture was stirred at 0 °C for 30 min., then a solution of 1,3,2-dioxathiolane 2,2-dioxide (4.5 g, 36 mmol) in 30 mL of THF was added at 0 °C. The resulting mixture was stirred overnight at r.t., quenched with water (50 mL), and then extracted with EtOAc (100 mL x 3). The organic phase was washed with saturated brine and dried over Na 2 SO 4 and then concentrated under reduced pressure to give the target product (2.5 g) as a yellow oil. TLC R f = 0.25 (EtOAc, I 2 ).

[0411] Step 2: 5-(2-Cyclobutoxyethoxy)-1,3,4-thiadiazol-2-amine

[0412]

[0413] At 0 °C, to a solution of 2-cyclobutoxyethan-1-ol (2.3 g, 20 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (1.8 g, 10 mmol) in DMF (20 mL) was added NaH (1.2 g, 30 mmol, 60% suspension in mineral oil). The reaction mixture was stirred overnight at r.t., quenched with water (60 mL), and extracted with EtOAc (80 mL x 4). The combined organic phases were washed with saturated brine and dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column, eluting with MeCN / H 2 O (20 - 40%) to give the target product (300 mg) as a yellow oil. LCMS calculated for C 8 H 14 N 3 O 2 S [M+H] + : m / z = 216.1; found: 216.1.

[0414] Step 3: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-cyclobutoxyethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0415] To a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (120 mg, 0.4 mmol, Int-1), TCFH (168 mg, 0.6 mmol) and NMI (66 mg, 0.8 mmol) in DMF (2 mL), 5-(2-cyclobutoxyethoxy)-1,3,4-thiadiazol-2-amine (108 mg, 0.5 mmol) was added. The reaction mixture was stirred at r.t. for 5 h., then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 O (20 - 30%), to give the title compound (67 mg) as a white solid. LCMS calcd for C 22 H 23 ClFN 4 O 4 S [M+H] + : m / z = 493.1; found: 493.1.

[0416] Example 23: (E)-N-(5-(But-2-en-1-yloxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0417]

[0418] Step 1: (E)-5-(But-2-en-1-yloxy)-1,3,4-thiadiazol-2-amine

[0419]

[0420] This compound was prepared in a similar manner to Step 1 of Example 1, using (E)-but-2-en-1-ol instead of neopentyl alcohol. LCMS calcd for C 6 H 10 N 3 OS [M+H] + : m / z = 172.1; found: 172.1.

[0421] Step 2: (E)-N-(5-(But-2-en-1-yloxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0422] This compound was prepared in a similar manner to Example 17, using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and (E)-5-(but-2-en-1-yloxy)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value C 20 H 19 ClFN 4 O 3 S[M+H] + : m / z = 449.1; found: 449.1.

[0423] Example 24: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-(methoxymethyl)allyl)oxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0424]

[0425] Step 1: 2-(Methoxymethyl)prop-2-en-1-ol

[0426]

[0427] At 0 °C, NaH (0.6 g, 15 mmol, 60% suspension in mineral oil) was added to a dry THF (30 mL) solution of 2-methylenepropane-1,3-diol (1.3 g, 15.0 mmol). The mixture was stirred at 0 °C for 1 h., then MeI (2.13 g, 15 mmol) was added at 0 °C. The reaction mixture was stirred overnight at r.t. The reaction mixture was quenched with aq. HCl (1 M, 20 mL) at 0 °C, stirred for 30 min., and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with saturated brine and dried over Na 2 SO 4 dried, 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 - 20%), to give the title product (0.5 g, 31%) as a yellow oil. TLC Rf = 0.45 (EtOAc / PE = 1 / 1, iodine).

[0428] Step 2: 5-((2-(Methoxymethyl)allyl)oxy)-1,3,4-thiadiazol-2-amine

[0429]

[0430] This compound was prepared in a similar manner to Step 1 of Example 1, using 2-(methoxymethyl)prop-2-en-1-ol instead of neopentyl alcohol. LCMS calculated value C 7 H 12 N3 O 2 S[M+H] + : m / z = 202.1; Measured value: 202.1.

[0431] Step 3: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2-(methoxymethyl)allyl)oxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0432] This compound was prepared in a similar manner to Example 17, using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-((2-(methoxymethyl)allyl)oxy)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value C 21 H 21 ClFN 4 O 4 S[M+H] + : m / z = 479.1; Measured value: 479.1.

[0433] Example 25: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((2-methylallyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0434]

[0435] Step 1: 5-((2-Methylallyl)oxy)-1,3,4-thiadiazol-2-amine

[0436]

[0437] This compound was prepared in a similar manner to Step 1 of Example 1, using 2-methylprop-2-en-1-ol instead of neopentyl alcohol. LCMS calculated value C 6 H 10 N 3 OS[M+H] + : m / z = 172.1; Measured value: 172.1.

[0438] Step 2: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((2-methylallyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0439] This compound was prepared in a similar manner to Example 17, using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-((2-methylallyl)oxy)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value C20 H 19 ClFN 4 O 3 S[M+H] + : m / z = 449.1; Measured value: 449.1.

[0440] Example 26: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0441]

[0442] Step 1: S-Methyl O-((trimethylsilyl)methyl)dithiocarbonate

[0443]

[0444] At 0 °C, NaH (2.4 g, 60 mmol, 60% suspended in mineral oil) was added to a solution of (trimethylsilyl)methanol (3.12 g, 30 mmol) in THF (50 mL). The resulting mixture was stirred for 30 min. At 0 °C, CS 2 (3.43 g, 45.0 mmol) was added to the above mixture. After stirring for 10 min., MeI (5.54 g, 39.0 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at r.t. for 16 h., and then quenched with aq. NH 4 Cl (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 4). The combined organic phases were washed with water and saturated brine, and dried over Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure to give S-methyl O-((trimethylsilyl)methyl)dithiocarbonate as a crude product without further purification.

[0445] Step 2: O-((trimethylsilyl)methyl)thiosemicarbazide

[0446]

[0447] At r.t., hydrazine hydrate solution (2.81 g, 45 mmol, 80% purity) was added to a solution of S-methyl O-((trimethylsilyl)methyl)dithiocarbonate (5.83 g, 30 mmol) in MeOH (50 mL). The reaction mixture was stirred at r.t. for 30 min., and then concentrated under reduced pressure to give O-((trimethylsilyl)methyl)thiosemicarbazide as a crude product without further purification. LCMS calculated value C 5 H 15 N 2OSSi[M+H] + : m / z = 179.1; Measured value: 179.1.

[0448] Step 3: 5 - ((Trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-amine

[0449]

[0450] At 0 °C, to a mixture of O - ((trimethylsilyl)methyl)thiosemicarbazide (5.34 g, 30 mmol) and BrCN (3.82 g, 36 mmol) in MeOH (30 mL), TEA (6.1 g, 60 mmol) was added. The reaction mixture was stirred at r.t. for 1 h., then 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 title product (3.8 g, 62% yield) as a colorless oil. LCMS calculated value C 6 H 14 N 3 OSSi[M+H] + : m / z = 204.1; Measured value: 204.1.

[0451] Step 4: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-((trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0452] This compound was prepared in a similar manner to Example 17, using the intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-((trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-amine as starting materials. 1 HNMR: (400 MHz, DMSO-d 6 ) δ 12.82 (s, 1H), 8.84 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.38 (s, 1H), 6.93 (d, J = 8.0 Hz, 6H), 4.20 (s, 2H), 3.58 (s, 3H), 2.57 (s, 3H), 0.10 (s, 9H). LCMS calculated value C 20 H 23 ClFN 4 O 3 SSi[M+H] + : m / z = 481.1; Measured value: 481.1.

[0453] Example 27: 2'-Chloro-5'-methoxy-6-methyl-N-(5-((trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0454]

[0455] Step 1: Methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate

[0456]

[0457] Methyl 4-chloro-6-methylnicotinate (1.5 g, 8 mmol), (2-chloro-5-methoxypyridin-4-yl)boronic acid (0.94 g, 5 mmol), K 2 CO 3 (4.4 g, 16 mmol) and Pd(dppf)Cl 2 (0.34 g, 0.5 mmol) in a mixture of 1,4-dioxane (24 mL) and H 2 O (3 mL), degassed and purged with nitrogen, replaced 3 times, and then stirred at 80 °C for 16 h. The reaction mixture was diluted with EtOAc (80 mL), washed with water and saturated brine, dried over anhydrous Na 2 SO 4 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 - 70%), to give the title product (0.3 g) as a yellow solid. LCMS calculated value C 14 H 14 ClN 2 O 3 [M+H] + : m / z = 293.1; found: 293.1.

[0458] Step 2: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0459]

[0460] To a solution of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (0.3 g, 1.0 mmol) in THF (2 mL) and H 2 O (2 mL), was added LiOH.H 2O (0.12 g, 3.0 mmol). Stirred overnight at r.t., the reaction mixture was diluted with water, adjusted to pH ~ 2 - 3 with aq. HCl (2 M), and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column, eluting with MeCN / H 2 O (10 - 15%), to give the title compound as a yellow oil. LCMS calcd for C 13 H 12 ClN 2 O 3 [M + H] + : m / z = 279.1; found: 279.1.

[0461] Step 3: 2'-Chloro-5'-methoxy-6-methyl-N-(5-((trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0462] To a solution of 2'-chloro-5'-methoxy-6-methyl-[4,4'-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-((trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-amine (40 mg, 0.2 mmol, Step 3 of Example 26). The reaction mixture was stirred at r.t. for 2 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 O (0 - 10%), to give the title compound (47 mg) as a white solid. LCMS calcd for C 19 H 23 ClN 5 O 3 SSi[M + H] + : m / z = 464.1; found: 464.1.

[0463] Example 28: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(methylthio)ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0464]

[0465] Step 1: 5-(2-(Methylthio)ethoxy)-1,3,4-thiadiazol-2-amine

[0466]

[0467] This compound was prepared in a similar manner to Step 1 of Example 1, using 2-(methylthio)ethanol instead of pivalol. LCMS calculated value for C 5 H 10 N 3 OS 2 [M+H] + : m / z = 192.0; found: 192.1.

[0468] Step 2: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(methylthio)ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0469] This compound was prepared in a similar manner to Example 17, using intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(2-(methylthio)ethoxy)-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value for C 19 H 19 ClFN 4 O 3 S 2 [M+H] + : m / z = 469.1; found: 469.1.

[0470] Example 29: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(methylsulfinyl)ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0471]

[0472] At r.t., to a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(methylthio)ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide (47 mg, 0.1 mmol, Example 28) in MeCN (5 mL) was added aq. NaClO (1.0 mL, 1.3 mmol, 10%). The reaction mixture was stirred at r.t. for 5 h., and concentrated under reduced pressure. The residue was purified by prep-HPLC, eluting with MeCN / H 2 O (20 - 50%) to give the title compound (8.4 mg, 18% yield) as a white solid. LCMS calculated value for C 19 H 19 ClFN 4 O 4 S 2 [M+H] + : m / z = 485.0; found: 485.1.

[0473] Example 30: N-(5-(2-azidoethoxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0474]

[0475] Step 1: 5-(2-azidoethoxy)-1,3,4-thiadiazol-2-amine

[0476]

[0477] This compound was prepared in a similar manner to that of Step 1 of Example 1, using 2-azidoethanol instead of pivalol. LCMS calculated value C 4 H 7 N 6 OS[M+H] + : m / z = 187.0; measured value: 187.1.

[0478] Step 2: N-(5-(2-azidoethoxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0479] This compound was prepared in a similar manner to that of Example 17, using intermediate 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(2-azidoethoxy)-1,3,4-thiadiazol-2-amine as raw materials. LCMS calculated value C 18 H 16 ClFN 7 O 3 S[M+H] + : m / z = 464.1; measured value: 464.1.

[0480] Example 31: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(N-methylacetamido)ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0481]

[0482] Step 1: N-(2-((5-amino-1,3,4-thiadiazol-2-yl)oxy)ethyl)-N-methylacetamide

[0483]

[0484] At 0 °C, to a solution of N-(2-hydroxyethyl)-N-methylacetamide (1.17 g, 10.0 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (0.9 g, 5.0 mmol) in DMF (10 mL) was added NaH (0.6 g, 15 mmol, 60% suspended in mineral oil). The reaction mixture was stirred overnight at r.t., quenched with water (30 mL), and then extracted with EtOAc (20 mL x 4). The combined organic phases were washed with saturated brine and dried over Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column, eluting with MeCN / H 2 O (5 - 10%) to give the title compound (110 mg) as a yellow oil. LCMS calcd for C 7 H 13 N 4 O 2 S[M+H] + : m / z = 217.1; found: 217.1.

[0485] Step 2: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(N-methylacetamido)ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0486] 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 N-(2-((5-amino-1,3,4-thiadiazol-2-yl)oxy)ethyl)-N-methylacetamide (65 mg, 0.3 mmol). The reaction mixture was stirred at r.t. for 5 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 O (20 - 25%) to give the title compound (27 mg) as a white solid. LCMS calcd for C 21 H 22 ClFN 5 O 4 S[M+H] + : m / z = 494.1; found: 494.1.

[0487] Example 32: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(N-methylmethylsulfonamido)ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0488]

[0489] Step 1: N-(2-((5-Amino-1,3,4-thiadiazol-2-yl)oxy)ethyl)-N-methylmethanesulfonamide

[0490]

[0491] At 0 °C, to a solution of N-(2-hydroxyethyl)-N-methylmethanesulfonamide (1.53 g, 10.0 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (0.9 g, 5.0 mmol) in DMF (10 mL), NaH (0.6 g, 15 mmol, 60% suspended in mineral oil) was added. The reaction mixture was stirred overnight at r.t., quenched with water (30 mL), and then extracted with EtOAc (50 mL x 4). The combined organic phases were washed with saturated brine and dried over Na 2 SO 4 filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column, eluting with MeCN / H 2 O (15 - 35%) to give the title compound (110 mg) as a yellow oil. LCMS calcd for C 6 H 13 N 4 O 3 S 2 [M+H] + : m / z = 253.0; found: 253.0.

[0492] Step 2: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(N-methylmethylsulfonamido)ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0493] 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), N-(2-((5-amino-1,3,4-thiadiazol-2-yl)oxy)ethyl)-N-methylmethanesulfonamide (76 mg, 0.3 mmol) was added. The reaction mixture was stirred at r.t. for 5 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 O (20 - 25%) to give the title compound (8 mg) as a white solid. LCMS calcd for C 20 H 22 ClFN 5O 5 S 2 [M+H] + : m / z = 530.1; Observed value: 530.1.

[0494] Example 33: N-(5-(2-Acetamidoethoxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0495]

[0496] Step 1: 2-(2-((5-Amino-1,3,4-thiadiazol-2-yl)oxy)ethyl)isoindoline-1,3-dione

[0497]

[0498] At 0 °C, to a solution of 2-(2-hydroxyethyl)isoindoline-1,3-dione (1.91 g, 10 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (0.9 g, 5 mmol) in DMF (10 mL), NaH (0.6 g, 15 mmol, 60% suspended in mineral oil) was added. The reaction mixture was stirred overnight at r.t., quenched with water (30 mL), and then extracted with EtOAc (50 mL x 2). The combined organic phases were washed with saturated brine and dried over Na 2 SO 4 dried, 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 - 85%), to give the title compound (120 mg) as a yellow oil. LCMS calculated value C 12 H 11 N 4 O 3 S[M+H] + : m / z = 291.1; Observed value: 291.1.

[0499] Step 2: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0500]

[0501] To a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (118 mg, 0.4 mmol, Int-1), TCFH (168 mg, 0.6 mmol) and NMI (66 mg, 0.8 mmol) in DMF (2 mL), 2-(2-((5-amino-1,3,4-thiadiazol-2-yl)oxy)ethyl)isoindoline-1,3-dione (120 mg, 0.41 mmol) was added. The reaction mixture was stirred at r.t. for 3 h., then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column, eluting with MeCN / H 2 O (40 - 55%), to give the title compound (92 mg) as a yellow solid. LCMS calcd for C 26 H 20 ClFN 5 O 5 S[M+H] + : m / z = 568.1; found: 568.1.

[0502] Step 3: N-(5-(2-Aminoethoxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0503]

[0504] A mixture of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (92 mg, 0.16 mmol) and hydrazine hydrate solution (0.1 mL, 80% purity) in EtOH (3 mL) was heated to 80 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to give the title compound (70 mg) as a yellow oil. LCMS calcd for C 18 H 18 ClFN 5 O 3 S[M+H] + : m / z = 438.1; found: 438.1.

[0505] Step 4: N-(5-(2-Acetamidoethoxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0506] To N-(5-(2-aminoethoxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide (35 mg, 0.08 mmol) and NaHCO 3To a mixture of (68 mg, 0.8 mmol) in THF (2 mL) and water (2 mL), acetic anhydride (50 mg, 0.4 mmol) was added. The reaction mixture was stirred at r.t. for 2 h., then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 O (15 - 25%), to give the title compound (22 mg) as a white solid. LCMS calcd for C 20 H 20 ClFN 5 O 4 S[M + H] + : m / z = 480.1; found: 480.1.

[0507] Example 34: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(methylsulfonamido)ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0508]

[0509] To N-(5-(2-Aminoethoxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide (35 mg, 0.08 mmol, step 3 of Example 33) and NaHCO 3 (68 mg, 0.8 mmol) in a mixture of THF (2 mL) and water (2 mL), methanesulfonic anhydride (70 mg, 0.4 mmol) was added. The reaction mixture was stirred at r.t. for 1 h., then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 O (20 - 40%), to give the title compound (8 mg) as a white solid. LCMS calcd for C 19 H 20 ClFN 5 O 5 S 2 [M + H] + : m / z = 516.1; found: 516.1.

[0510] Example 35: N-(5-Ethoxy-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinamide

[0511]

[0512] 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), 5-ethoxy-1,3,4-thiadiazol-2-amine (44 mg, 0.3 mmol, Step 1 of Example 14) was added. The reaction mixture was stirred at r.t. for 4 h., then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 O (15 - 50%), to give the title compound (30 mg) as a white solid. LCMS calcd for C 19 H 20 FN 4 O 3 S[M+H] + : m / z = 403.1; found: 403.2.

[0513] Example 36: 4-(2-Fluoro-6-methoxy-3-methylphenyl)-N-(5-(2-methoxypropoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0514]

[0515] This compound was prepared in a similar manner to Example 35, using intermediate 4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinic acid (Int-4) and 5-(2-methoxypropoxy)-1,3,4-thiadiazol-2-amine (Step 2 of Example 11) as starting materials. LCMS calcd for C 21 H 24 FN 4 O 4 S[M+H] + : m / z = 447.1; found: 447.2.

[0516] Example 37: 4-(2-Fluoro-6-methoxy-3-methylphenyl)-6-methyl-N-(5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0517]

[0518] This compound was prepared in a similar manner to Example 35, using intermediate 4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinic acid (Int-4) and 5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-amine (Step 1 of Example 7) as starting materials. LCMS calcd for C 19 H 17F 4 N 4 O 3 S[M+H] + : m / z = 457.1; Observed value: 457.1.

[0519] Example 38: N-(5-Ethoxy-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinamide

[0520]

[0521] 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), 5-ethoxy-1,3,4-thiadiazol-2-amine (44 mg, 0.3 mmol, Step 1 of Example 14) was added. The reaction mixture was stirred at r.t. for 4 h., then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 O (25 - 50%), to give the title compound (43.0 mg, 38% yield) as a white solid. LCMS calculated for C 19 H 17 F 4 N 4 O 3 S[M+H] + : m / z = 457.1; Observed value: 457.1.

[0522] Example 39: 4-(2-Fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-N-(5-(2-methoxypropoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0523]

[0524] This compound was prepared in a similar manner to Example 38, using intermediate 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid (Int-5) and 5-(2-methoxypropoxy)-1,3,4-thiadiazol-2-amine (Step 2 of Example 11) as starting materials. LCMS calculated for C 21 H 21 F 4 N 4 O 4 S[M+H] + : m / z = 501.1; Observed value: 501.2.

[0525] Example 40: 4-(2-Fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methyl-N-(5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0526]

[0527] This compound was prepared in a similar manner to Example 38, using the intermediate 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid (Int-5) and 5-(2,2,2-trifluoroethoxy)-1,3,4-thiadiazol-2-amine (Step 1 of Example 7) as starting materials. LCMS calculated value for C 19 H 14 F 7 N 4 O 3 S[M+H] + : m / z = 511.1; found: 511.2.

[0528] Example 41: 4-(2-Fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-N-(5-(2-methoxyethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0529]

[0530] This compound was prepared in a similar manner to Example 38, using the intermediate 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid (Int-5) and 5-(2-methoxyethoxy)-1,3,4-thiadiazol-2-amine (Step 1 of Example 20) as starting materials. LCMS calculated value for C 20 H 19 F 4 N 4 O 4 S[M+H] + : m / z = 487.1; found: 487.1.

[0531] Example 42: (E)-N-(5-(But-2-en-1-yloxy)-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinamide

[0532]

[0533] This compound was prepared in a similar manner to Example 38, using the intermediate 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid (Int-5) and (E)-5-(but-2-en-1-yloxy)-1,3,4-thiadiazol-2-amine (Step 1 of Example 23) as starting materials. LCMS calculated value for C 21 H 19 F 4 N 4 O 3 S[M+H] + : m / z = 483.1; found: 483.1.

[0534] Example 43: 4-(2-Fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-N-(5-((2-(methoxymethyl)allyl)oxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0535]

[0536] This compound was prepared in a similar manner to Example 38, using the intermediate 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid (Int-5) and 5-((2-(methoxymethyl)allyl)oxy)-1,3,4-thiadiazol-2-amine (Step 2 of Example 24) as starting materials. LCMS calculated value for C 22 H 21 F 4 N 4 O 4 S[M+H] + : m / z = 513.1; found: 513.1.

[0537] Example 44: 4-(2-Fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methyl-N-(5-((2-methylallyl)oxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0538]

[0539] This compound was prepared in a similar manner to Example 38, using the intermediate 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid (Int-5) and 5-((2-methylallyl)oxy)-1,3,4-thiadiazol-2-amine (Step 1 of Example 25) as starting materials. LCMS calculated value for C 21 H 19 F 4 N 4 O 3 S[M+H] +: m / z = 483.1; Measured value: 483.1.

[0540] Example 45: 4-(2-Fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methyl-N-(5-((trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0541]

[0542] This compound was prepared in a similar manner to Example 38, using the intermediate 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid (Int-5) and 5-((trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-amine (Step 3 of Example 26) as starting materials. LCMS calculated value C 21 H 23 F 4 N 4 O 3 SSi[M+H] + : m / z = 515.1; Measured value: 515.2.

[0543] Example 46: 4-(2-Fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-N-(5-hydroxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0544]

[0545] A solution of N-(5-ethoxy-1,3,4-thiadiazol-2-yl)-4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinamide (Example 38, 23 mg, 0.05 mmol) in HCl (1,4-dioxane solution of 4 M, 10 mL) was stirred at 60 °C for 6 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluted with MeCN / H 2 O (10 - 30% with 0.05% TFA), to give the target compound (3.2 mg, 15% yield), as a white solid. LCMS calculated value C 17 H 13 F 4 N 4 O 3 S[M+H] + : m / z = 429.1; Measured value: 429.1.

[0546] Example 47: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-hydroxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0547]

[0548] This compound was prepared in a similar manner to Example 46, using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-ethoxy-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (Example 17) as the starting material. LCMS calculated value for C 16 H 13 ClFN 4 O 3 S[M+H] + : m / z = 395.0; found: 395.0.

[0549] Example 48: 5'-Fluoro-2',3'-dimethoxy-6-methyl-N-(5-((trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0550]

[0551] Step 1: 5-Fluoro-2,3-dimethoxypyridine

[0552]

[0553] To a solution of 2,3,5-trifluoropyridine (1.50 g, 11.3 mmol) in DMSO (60 mL) was added MeONa (1.34 g, 24.8 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with EtOAc and washed with H 2 O and saturated brine. The organic phase was dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column, eluting with EtOAc / PE (0 - 15%), to give the title compound (1.15 g, 64% yield) as a white solid. LCMS calculated value for C 7 H 9 FNO 2 [M+H] + : m / z = 158.0; found: 158.0.

[0554] Step 2: 5-Fluoro-4-iodo-2,3-dimethoxypyridine

[0555]

[0556] At -78 °C, n-BuLi (1.5 mL of a 2.5 M hexane solution) was added to a solution of 5-fluoro-2,3-dimethoxypyridine (500 mg, 3.18 mmol) in THF (2 mL), and the mixture was stirred at -78 °C for 1 h. Then, I 2 (888 mg, 3.50 mmol) was added in portions. The reaction mixture was stirred at 25 °C for 2 h and quenched with water (50 mL). The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na 2 SO 4 , 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 - 5%), to give the title compound (700 mg, 77% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.87 (s, 1H), 3.90 (s, 3H), 3.79 (s, 3H). LCMS calcd for C 7 H 8 FINO 2 [M + H] + : m / z = 284.0; found: 283.8.

[0557] Step 3: Methyl 5'-fluoro-2',3'-dimethoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate

[0558]

[0559] To a solution of 5-fluoro-4-iodo-2,3-dimethoxypyridine (200 mg, 0.71 mmol) in dioxane (10 mL) and H 2 O (0.5 mL), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (215 mg, 0.77 mmol), K 2 CO 3 (293 mg, 2.12 mmol), and Pd(dppf)Cl 2 (58 mg, 0.071 mmol) were added. The reaction mixture was stirred at 90 °C overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC, eluting with EtOAc / PE (20%), to give the title compound (120 mg, 44% yield) as a yellow solid. 1HNMR(400MHz, DMSO-d 6 ) δ 9.04 (s, 1H), 8.02 (s, 1H), 7.39 (s, 1H), 3.95 (s, 3H), 3.70 (s, 3H), 3.59 (s, 3H), 2.59 (s, 3H). LCMS calculated for C 15 H 16 FN 2 O 4 [M + H] + : m / z = 307.1; found: 307.0.

[0560] Step 4: 5'-Fluoro-2',3'-dimethoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0561]

[0562] To a solution of methyl 5'-fluoro-2',3'-dimethoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (50 mg, 0.16 mmol) in THF (2 mL) was added aq. NaOH (2 M, 1.5 mL). The reaction mixture was stirred overnight at r.t. and the pH was adjusted to ~7 with aq. HCl (1 M). The reaction mixture was concentrated under reduced pressure. The residue was washed with EtOAc (5 mL) and DCM (10 mL), filtered to give the title compound (40 mg, 85% yield) as a white solid. LCMS calculated for C 14 H 14 FN 2 O 4 [M + H] + : m / z = 293.1; found: 293.0.

[0563] Step 5: 5'-Fluoro-2',3'-dimethoxy-6-methyl-N-(5-((trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0564] A mixture of 5'-fluoro-2',3'-dimethoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (40 mg, 0.14 mmol), 5-((trimethylsilyl)methoxy)-1,3,4-thiadiazol-2-amine (28 mg, 0.14 mmol, from step 3 of Example 26), HATU (68 mg, 0.18 mmol) and DIEA (53 mg, 0.42 mmol) in ACN (3 mL) was stirred overnight at r.t. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column with ACN / H2O (10 - 95%, containing 1% NH 4 HCO3 )Elution gave the target compound (10 mg, 15% yield), which was a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.04 (s, 1H), 8.98 (s, 1H), 8.00 (s, 1H), 7.37 (s, 1H), 4.20 (s, 2H), 3.93 (s, 3H), 3.57 (s, 3H), 2.59 (s, 3H), 0.10 (s, 9H). LCMS calculated value for C 20 H 25 FN 5 O 4 SSi [M + H] + : m / z = 478.1; found: 478.2.

[0565] Example 49: 4-(3-Ethynyl-2-fluoro-6-methoxyphenyl)-N-(5-(2-methoxyethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0566]

[0567] Step 1: Methyl 4-(3-bromo-2-fluoro-6-methoxyphenyl)-6-methylnicotinate

[0568]

[0569] To a solution of methyl 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinate (1.1 g, 4.0 mmol) in ACN (40 mL) was added NBS (0.8 g, 4.5 mmol). The reaction mixture was stirred at 30 °C overnight. Then it was concentrated under reduced pressure, and the residue was purified by flash chromatography on a silica gel column, eluting with EtOAc / PE (40 - 60%) to give the target compound (0.85 g), which was a yellow solid. LCMS calculated value for C 15 H 14 BrFNO 3 [M + H] + : m / z = 354.0; found: 354.0.

[0570] Step 2: Methyl 4-(2-fluoro-6-methoxy-3-((trimethylsilyl)ethynyl)phenyl)-6-methylnicotinate

[0571]

[0572] To a mixture of methyl 4-(3-bromo-2-fluoro-6-methoxyphenyl)-6-methylnicotinate (353 mg, 1.0 mmol), trimethylsilylacetylene (148 mg, 1.5 mmol) and TEA (1.01 g, 10.0 mL) in DMF (1 mL), CuI (19 mg, 0.1 mmol) and Pd(PPh 3 ) 2 Cl 2 (70 mg, 0.1 mmol) were added. The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was diluted with EtOAc (40 mL), washed with water and saturated brine, dried over anhydrous Na 2 SO 4 , 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 - 30%), to give the title compound (230 mg) as a yellow oil. LCMS calcd for C 20 H 23 FNO 3 Si[M+H] + : m / z = 372.1; found: 372.1.

[0573] Step 3: 4-(3-Ethynyl-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0574]

[0575] To a solution of methyl 4-(2-fluoro-6-methoxy-3-((trimethylsilyl)ethynyl)phenyl)-6-methylnicotinate (74 mg, 0.2 mmol) in MeOH (2 mL) and H 2 O (2 mL), KOH (56 mg, 1.0 mmol) was added. After stirring overnight at r.t., the reaction mixture was diluted with water (20 mL), adjusted to pH ~ 3 - 4 with HCl aq. (2 M), and then extracted with DCM (10 mL x 5). The combined organic phases were washed with saturated brine, dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to give the crude product (60 mg) as a yellow oil, which was used directly in the next step without purification. LCMS calcd for C 16 H 13 FNO 3 [M+H] + : m / z = 286.1; found: 286.1.

[0576] Step 4: 4-(3-Ethynyl-2-fluoro-6-methoxyphenyl)-N-(5-(2-methoxyethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0577] To a solution of 4-(3-ethynyl-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (60 mg, 0.21 mmol), TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL), 5-(2-methoxyethoxy)-1,3,4-thiadiazol-2-amine (40 mg, 0.23 mmol, Step 1 of Example 20) was added. The reaction mixture was stirred at r.t. for 2 h., then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column, eluting with MeCN / H 2 O (10 - 20%), to give the title compound (62 mg) as a white solid. LCMS calculated for C 21 H 20 FN 4 O 4 S[M + H] + : m / z = 443.1; found: 443.1.

[0578] Example 50: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(((R)-tetrahydrofuran-3-yl)oxy)ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0579]

[0580] This compound was prepared in a similar manner to Steps 1 - 3 of Example 22. In Step 1, (R)-tetrahydrofuran-3-ol was used instead of cyclobutanol. LCMS calculated for C 22 H 23 ClFN 4 O 5 S[M + H] + : m / z = 509.1; found: 509.1.

[0581] Example 51: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(((S)-tetrahydrofuran-3-yl)oxy)ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0582]

[0583] This compound was prepared in a similar manner to Steps 1 - 3 of Example 22. In Step 1, (S)-tetrahydrofuran-3-ol was used instead of cyclobutanol. LCMS calculated for C22 H 23 ClFN 4 O 5 S[M + H] + : m / z = 509.1; Observed value: 509.1.

[0584] Example 52: N-(5-(Allyloxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0585]

[0586] Step 1: 5-(Allyl)oxy-1,3,4-thiadiazol-2-amine

[0587]

[0588] This compound was prepared in a similar manner to Step 1 of Example 1, using prop-2-en-1-ol instead of neopentyl alcohol. LCMS calculated value C 5 H 8 N 3 O 2 S[M + H] + : m / z = 158.0; Observed value: 158.0.

[0589] Step 2: N-(5-(Allyloxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0590] This compound was prepared in a similar manner to Example 17, using 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (Int-1) and 5-(allyl)oxy-1,3,4-thiadiazol-2-amine as starting materials. LCMS calculated value C 19 H 17 ClFN 4 O 3 S[M + H] + : m / z = 435.1; Observed value: 435.1.

[0591] Example 53: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2,2-dihydroxyethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0592]

[0593] To a mixture of N-(5-(allyloxy)-1,3,4-thiadiazol-2-yl)-4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinamide (22 mg, 0.2 mmol, Example 52), NaIO 4 (173 mg, 0.8 mmol) in 1,4-dioxane (2 mL) and water (1 mL), potassium osmate(VI) dihydrate (1 mg) was added. The reaction mixture was stirred overnight at r.t. and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column, eluting with ACN / H2O (30 - 50%), to give the title compound (2.2 mg) as an off-white solid. LCMS calculated for C 18 H 17 ClFN 4 O 5 S[M+H] + : m / z = 455.1; found: 455.1.

[0594] Example 54: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(2-(oxetan-3-yloxy)

[0595] ethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide

[0596]

[0597] This compound was prepared in a similar manner to steps 1 - 3 of Example 22, substituting oxetan-3-ol for cyclobutanol in step 1. LCMS calculated for C 21 H 21 ClFN 4 O 5 S[M+H] + : m / z = 495.1; found: 495.1.

[0598] Example 55: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0599]

[0600] This compound was prepared in a similar manner to steps 1 - 2 of Example 21, substituting 2-(2-(2-methoxyethoxy)ethoxy)ethan-1-ol for 2-(2-methoxyethoxy)ethan-1-ol in step 1. LCMS calculated for C 23 H 27 ClFN 4 O 6 S[M+H]+ : m / z = 541.1; Measured value: 541.1.

[0601] Example 56: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0602]

[0603] Step 1: 2,2-Dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-ol

[0604]

[0605] At 0 °C, TBDPSCl (25.6 g, 93.1 mmol) was added to a mixture of triethylene glycol (20 g, 133 mmol) and 1H-imidazole (9.1 g, 133 mmol) in DCM (400 mL). The reaction mixture was stirred overnight at r.t., diluted with H 2 O (200 mL), and extracted with DCM (200 mL x 2). The combined organic phases were washed with saturated brine and dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column, eluting with MeOH / DCM (0 - 1%), to give the title compound (20 g) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 - 7.67 (m, 4H), 7.45 - 7.35 (m, 6H), 3.83 - 3.80 (m, 2H), 3.73 - 3.71 (m, 2H), 3.66 (s, 4H), 3.62 - 3.59 (m, 4H), 2.21 (brs, 1H), 1.05 (s, 9H). TLC: R f = 0.7 (DCM / MeOH = 10:1).

[0606] Step 2: O-(2,2-Dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl) S-methyl dithiocarbonate

[0607]

[0608] At 0 °C, NaH (0.62 g, 15.5 mmol, 60% suspended in mineral oil) was added to a solution of 2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-ol (3.0 g, 7.73 mmol) in THF (90 mL). The resulting mixture was stirred at 0 °C for 1 h., and CS 2 (1.29 g, 17 mmol) was added at 0 °C, and then stirred for another 1 h. MeI (1.42 g, 10 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at r.t. for 14 h. The resulting mixture was quenched with saturated aq. NH 4 Cl and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with water and saturated brine, dried over Na 2 SO 4 , 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 - 1.5%), to give the target compound (2.4 g) as a yellow oil. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.69 - 7.67 (m, 4H), 7.40 - 7.36 (m, 6H), 4.72 (t, J = 4.8 Hz, 2H), 3.84 - 3.80 (m, 4H), 3.65 - 3.60 (m, 6H), 2.55 (s, 3H), 1.05 (s, 9H). TLC: Rf = 0.6 (PE / EtOAc = 10:1).

[0609] Step 3: O-(2,2-Dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)thiosemicarbazide

[0610]

[0611] At r.t., hydrazine hydrate solution (283 mg, 5.66 mmol, 80% purity) was added to a solution of O-(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl) S-methyl dithiocarbonate (1.8 g, 3.77 mmol) in MeOH (18 mL). The reaction mixture was stirred at r.t. for 30 min., and then concentrated under reduced pressure to give the target compound (1.70 g) as a white solid. 1 1H NMR (400 MHz, DMSO-d 6) δ 7.66 - 7.64 (m, 4H), 7.48 - 7.42 (m, 6H), 4.65 - 4.56 (m, 1H), 3.76 - 3.74 (m, 2H), 3.53 - 3.41 (m, 8H), 3.24 (s, 2H), 0.99 (s, 9H). TLC: R f = 0.6 (DCM / MeOH = 10:1).

[0612] Step 4: 5 - ((2,2 - Dimethyl - 3,3 - diphenyl - 4,7,10 - trioxa - 3 - siladodecane - 12 - yl)oxy) - 1,3,4 - thiadiazol - 2 - amine

[0613]

[0614] At 0 °C, to a mixture of O - (2,2 - dimethyl - 3,3 - diphenyl - 4,7,10 - trioxa - 3 - siladodecane - 12 - yl)thiosemicarbazide (1.70 g, 3.7 mmol) and BrCN (0.78 g, 7.36 mmol) in MeOH (34 mL), TEA (1.11 g, 11 mmol) was added. The reaction mixture was stirred at r.t. for 1 h., then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with MeOH / DCM (0 - 10%), to give the title compound (1 g) as a yellow oil. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.69 - 7.67 (m, 4H), 7.46 - 7.35 (m, 6H), 4.74 (s, 2H), 3.56 - 3.53 (m, 2H), 3.81 - 3.80 (m, 4H), 3.66 - 3.59 (m, 6H), 1.05 (s, 9H). LCMS calcd for C 24 1H 34 1N 3 1O 4 1SSi [M + H] + : m / z = 488.2; found: 488.1.

[0615] Step 5: 4 - (3 - Chloro - 2 - fluoro - 6 - methoxyphenyl) - N - (5 - ((2,2 - dimethyl - 3,3 - diphenyl - 4,7,10 - trioxa - 3 - siladodecane - 12 - yl)oxy) - 1,3,4 - thiadiazol - 2 - yl) - 6 - methylnicotinamide

[0616]

[0617] To a mixture of 5-((2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)oxy)-1,3,4-thiadiazol-2-amine (200 mg, 0.41 mmol), 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (121 mg, 0.41 mmol, Int-1) and TEA (208 mg, 2.1 mmol) in DMF (6 mL), HOBT (72 mg, 0.53 mmol) and EDCI (102 mg, 0.53 mmol) were added. The reaction mixture was stirred at r.t. for 16 h. The resulting mixture was diluted with H 2 O and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine and dried over Na 2 SO 4 then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column, eluting with MeOH / DCM (0 - 2%), to give the title compound (180 mg) as a yellow solid. LCMS calcd for C 38 H 43 ClFN 4 O 6 SSi[M+H] + : m / z = 765.2; found: 765.2.

[0618] Step 6: 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide

[0619] To a solution of 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-((2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecan-12-yl)oxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide (170 mg, 0.22 mmol) in THF (3 mL), TBAF solution (6.7 mL, 67 mmol, 1.0 M solution in THF) was added and the mixture was stirred at r.t. for 6 h. The reaction mixture was diluted with H 2 O and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with water and saturated brine and dried over Na 2 SO 4 then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC, eluting with MeOH / DCM (10%), to give the title compound (50 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 12.9 (brs, 1H), 8.84 (s, 1H), 7.59 (t, J = 8.8 Hz, 1H), 7.39 (s, 1H), 6.93 (d, J = 8.8 Hz, 1H), 4.58 (s, 1H), 4.53 - 4.51 (m, 2H), 3.37 (s, 2H), 3.52 - 3.41 (m, 9H), 3.33 (s, 2H), 2.57 (s, 3H). LCMS calculated value C 22 H 25 ClFN 4 O 6 S[M + H] + : m / z = 527.1; found: 527.1.

[0620] Int - 1: 4 - (3 - chloro - 2 - fluoro - 6 - methoxyphenyl) - 6 - methylnicotinic acid

[0621]

[0622] Step 1: (3 - chloro - 2 - fluoro - 6 - methoxyphenyl)boronic acid

[0623]

[0624] At - 70 °C, under N 2 atmosphere, to a dry THF (20 mL) solution of 1 - chloro - 2 - fluoro - 4 - methoxybenzene (2.00 g, 12.5 mmol), LDA (2.0 M solution in THF, 12.5 mL) was added. The reaction mixture was stirred at - 70 °C for 1 h., then, at - 70 °C, triisopropyl borate (4.70 g, 25.0 mmol) was added. The resulting mixture was stirred at - 70 °C for 2 h., and quenched with saturated aq. NH 4 Cl (50 mL) at 0 °C. The aqueous phase was adjusted to pH ~ 2 - 3 with HCl (1 M) and extracted with EtOAc (40 mL x 5). The combined organic phases were washed with saturated brine (40 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a 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.

[0625] Step 2: Methyl 4 - (3 - chloro - 2 - fluoro - 6 - methoxyphenyl) - 6 - methylnicotinate

[0626]

[0627] Methyl 4-chloro-6-methylnicotinate (3.0 g, 16 mmol), (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (3.2 g, 16 mmol), K 2 CO 3 (4.4 g, 32 mmol) and Pd(dppf)Cl 2 (1.1 g, 1.6 mmol) in 1,4-dioxane (24 mL) and H 2 O (3 mL) were degassed and purged with nitrogen three times. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with EtOAc (80 mL), washed with water and saturated brine, dried over anhydrous Na 2 SO 4 , 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 title compound (2.8 g) as a yellow solid. LCMS calcd for C 15 H 14 FClNO 3 [M+H] + : m / z = 310.1; found: 310.0.

[0628] Step 3: 4-(3-Chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0629] To a solution of methyl 4-(3-chloro-2-fluoro-6-methoxyphenyl)-6-methylnicotinate (70 mg, 0.23 mmol) in MeOH (2 mL) and H 2 O (2 mL) was added LiOH.H 2 O (40 mg, 1.0 mmol). The mixture was stirred overnight at r.t., diluted with water, adjusted to pH ~ 3 - 4 with aq. HCl (2 M), and extracted with DCM (20 mL x 5). The combined organic phases were washed with saturated brine (15 mL), dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to give the crude product (50 mg) as a yellow oil, which was used without further purification. LCMS calcd for C 14 H 12 FClNO 3 [M+H] + : m / z = 296.0; found: 296.0.

[0630] Int-2: 4-(2-Fluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0631]

[0632] Step 1: Methyl 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinate

[0633]

[0634] This compound is a yellow solid and is prepared in a similar manner to Step 2 of Int-1, using 2-fluoro-6-methoxyphenylboronic acid instead of (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid. LCMS calculated value C 15 H 15 FNO 3 [M+H] + : m / z = 276.1; Measured value: 276.0.

[0635] Step 2: 4-(2-Fluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0636]

[0637] This compound is an off-white solid and is prepared in a similar manner to Step 3 of Int-1, using methyl 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinate as the starting material. LCMS calculated value C 14 H 13 FNO 3 [M+H] + : m / z = 261.1; Measured value: 261.0.

[0638] Int-3: 4-(2,3-Difluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0639]

[0640] Step 1: Methyl 4-(2,3-difluoro-6-methoxyphenyl)-6-methylnicotinate

[0641]

[0642] This compound is a yellow solid and is prepared in a similar manner to Step 2 of Int-1, using (2,3-difluoro-6-methoxyphenyl)boronic acid instead of (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid. LCMS calculated value C 15 H 14 F 2 NO 3 [M+H] + : m / z = 294.1; Measured value: 294.1.

[0643] Step 2: 4-(2,3-Difluoro-6-methoxyphenyl)-6-methylnicotinic acid

[0644] The compound is an off-white solid and is prepared in a similar method to Step 3 of Int-1, using methyl 4-(2,3-difluoro-6-methoxyphenyl)-6-methylnicotinate as the raw material. LCMS calculated value C 14 H 12 F 2 NO 3 [M+H] + : m / z = 280.1; measured value: 280.1.

[0645] Int-4: 4-(2-Fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinic acid

[0646]

[0647] Step 1: Methyl 4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinate

[0648]

[0649] The compound is a white solid and is prepared in a similar method to Step 2 of Int-1, using 2-fluoro-6-methoxy-3-methylphenylboronic acid instead of (3-chloro-2-fluorophenoxy)boronic acid. LCMS calculated value C 16 H 17 FNO 3 [M+H] + : m / z = 290.1; measured value: 290.1.

[0650] Step 2: 4-(2-Fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinic acid

[0651] The compound is an off-white solid and is prepared in a similar method to Step 3 of Int-1, using methyl 4-(2-fluoro-6-methoxy-3-methylphenyl)-6-methylnicotinate as the raw material. LCMS calculated value C 15 H 15 FNO 3 [M+H] + : m / z = 275.1; measured value: 275.1.

[0652] Int-5: 4-(2-Fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid

[0653]

[0654] Step 1: 2-(3-Fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0655]

[0656] 4-Bromo-2-fluoro-1-(trifluoromethyl)benzene (9.7 g, 40 mmol), bis(pinacolato)diboron (12.7 g, 50 mmol), KOAc (9.8 g, 100 mmol) and Pd(dppf)Cl 2 (0.87 g, 1.2 mmol) in 1,4-dioxane (120 mL) was degassed and purged with nitrogen three 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 anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in PE and filtered through a silica gel pad to give the target compound (11.5 g, 99% yield) as a yellow oil. TLC R f = 0.4 (EtOAc / PE = 1 / 50, UV 254 nm).

[0657] Step 2: 3-Fluoro-4-(trifluoromethyl)phenol

[0658]

[0659] To a cold (ice-water bath) 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), aq. H 2 O 2 (16 mL, 33%) was added. The reaction mixture was stirred at 0 °C for 4 h, then 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 anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to give the target compound (7.0 g, 97% yield) as a yellow oil. LCMS calculated for C 7 H 3 F 4 O [M-H] + : m / z = 179.0; found: 179.0. TLC R f = 0.45 (EtOAc / PE = 1 / 25, UV 254 nm).

[0660] Step 3: 2-Fluoro-4-methoxy-1-(trifluoromethyl)benzene

[0661]

[0662] To a mixture of 3-fluoro-4-(trifluoromethyl)phenol (7.0 g, 38.9 mmol), K 2 CO 3 (13.8 g, 100 mmol) in MeCN (40 mL) was added MeI (8.5 g, 60 mmol). The reaction mixture was stirred at 40 °C for 4 h., then 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 anhydrous Na 2 SO 4 and 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 - 5%), to give the title compound (4.2 g, 56% yield) as a colorless oil. TLC R f = 0.55 (EtOAc / PE = 1 / 25, UV 254 nm).

[0663] Step 4: (2-Fluoro-6-methoxy-3-(trifluoromethyl)phenyl)boronic acid

[0664]

[0665] At -60 °C, to a solution of 2-fluoro-4-methoxy-1-(trifluoromethyl)benzene (3.9 g, 20 mmol) in THF (40 mL) was added n-BuLi (10 mL, 2.5 M hexane solution). After stirring for 1 h., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.6 g, 25 mmol) was added at -60 °C. The reaction mixture was stirred at r.t. for 1 h. At 0 °C, the reaction mixture was quenched with aq. HCl (2 M) solution (20 mL), stirred for 30 min., and extracted with EtOAc (40 mL x 5). The combined organic phases were washed with saturated brine (40 mL), dried over Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (2.0 g, 42%) as a yellow oil, without further purification.

[0666] Step 5: Methyl 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinate

[0667]

[0668] This compound is a yellow solid and was prepared in a similar manner to Step 2 of Int-1, using (2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)boronic acid instead of (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid. LCMS calculated for C 16 H14 F 4 NO 3 [M+H] + : m / z = 344.1; Observed value: 344.1.

[0669] Step 6: 4-(2-Fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinic acid

[0670] This compound is a white solid and is prepared in a similar manner to Step 3 of Int-1, using methyl 4-(2-fluoro-6-methoxy-3-(trifluoromethyl)phenyl)-6-methylnicotinate as the raw material. LCMS calculated value C 15 H 12 F 4 NO 3 [M+H] + : m / z = 330.1; Observed value: 330.1.

[0671] Example A: Biological test

[0672] The ability of the compounds of the present disclosure to inhibit the ATPase activity of PolQ(1-899) was determined using the following test method.

[0673] The ATPase activity of PolQ was determined by the ADP-Glo assay method. Compounds subjected to 10-point dilution were added to a 384-well plate for inhibition assays. The test buffer (20 mM Tris HCl (pH 8.0), 80 mM KCl, 10 mM MgCl 2 , 1 mM DTT, 0.01% BSA, 0.01% Tween, 5% glycerol) of PolQ(1-899) (1 nM) was transferred to the test wells (20 uL), except for the low control wells (20 μL of the test buffer was added to the low control wells). Then the plate was incubated at room temperature for 30 minutes. An equal volume (20 μL) of a test buffer containing 100 μM ATP and 150 nM ssDNA containing 50 thymine bases was added to all test wells. The plate was incubated at room temperature for 60 minutes before adding the ADP Glo detection reagent. After incubating for 60 minutes, 5 μL of the reaction mixture was transferred to another 384-well plate, 5 μL of ADP Glo was added, and the mixture was incubated for 60 minutes. Then 10 μL of the enzyme detection reagent was added and the mixture was incubated for another 60 minutes. The luminescence value was read by Envision.

[0674] The formula for calculating the percentage of inhibition is as follows:

[0675] % Inhibition = (Signal Max - Signal Compound ) / (Signal Max - SignalMin ) * 100%)

[0676] where “Max” is the high control (DMSO) and “Min” is the enzyme-free control.

[0677] IC 50 values were calculated using four-parameter logistic curve fitting with the following formula:

[0678] Y = LowerBound + ((UpperBound - LowerBound) / (1 + ((IC 50 / x)^Hill))).

[0679] IC 50 values were determined by fitting the data to a standard 4-parameter using the Hill Slope in GraphPad Prism software. IC 50 : * ≤ 10 nM, 10 nM < ** ≤ 100 nM, 100 nM < *** ≤ 500 nM, **** > 500 nM. The experimental results of the compounds are shown in Table 1.

[0680] Table 1. PolQ ATPase Assay

[0681]

[0682]

[0683] Although the present invention has been fully described by way of examples, it should be noted that various changes and modifications will be apparent to those skilled in the art. These changes and modifications should be included within the scope of the appended claims of the present invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof, wherein: X 1 is N or CR 1 ; X 2 is N or CR 2 ; X 3 is N or CR 3 ; X 1 , X 2 and X 3 are not simultaneously N; m is 1, 2, 3, 4 or 5; Cy is C 6 -C 10 aryl or 5- to 10-membered heteroaryl; R is selected from OH, or R 1 and R 2 are each independently selected from H, D, CN, NO 2 , N 3 , oxo, SF 5 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, 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)OR A , S(O)R B , S(O) 2 R B ; wherein the C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3- C 6 cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the following: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group; or R 1 and R 2 together with the carbon atom to which it is attached form a C 4 -C 7 cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl; wherein said C 4 -C 7 cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N(C 1 -C 4 alkyl) 2 ; R 3 Selected from H, D, CN, NO 2 , -N 3 , oxo, SF 5 , halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group, 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)OR A , S(O)R B , S(O) 2 R B ; wherein, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3- C 6 cycloalkyl, 4- to 6-membered heterocyclic group is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group; Each R 4 is independently selected from D, halogen, -CN, -NO 2 , -SF 5 , -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) 2 R B , - S(O)NR C R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D , -NR C S(O) 2 NR C R D , -NR C S(O)(=NR B )R B , - P(O)R E R F ,-P(O)OR E OR F ,-OP(O)OR E OR F ,C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl; wherein the C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R 4A ; Each R 4A is independently selected from D, halogen, CN, OH, NH 2 , oxo, C 1- C 6 alkyl, OC 1- C 6 alkyl, C 1- C 6 haloalkyl, OC 1- C 6 haloalkyl, NHC 1- C 3 alkyl, N(C 1- C 3 alkyl) 2 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group; wherein the C 3- C 6 cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by D, halogen, CN, OH, NH 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl; or Two adjacent Rs 4 Together with the atoms to which they are attached, form a C 4- C 7 Cycloalkyl or 4- to 7-membered heterocyclic group; wherein the C 4- C 7 Cycloalkyl or 4- to 7-membered heterocyclic group is optionally substituted with substituents selected from: D, halogen, oxo, CN, OH, NH 2 , NO 2 , C 1- C 6 Alkyl, C 1- C 6 Halogenoalkyl, -O-C 1 -C 6 Alkyl, -O-C 1- C 6 Halogenoalkyl, C 3 -C 6 Cycloalkyl, 4- to 6-membered heterocyclic group; wherein the C 3- C 6 Cycloalkyl or 4- to 6-membered heterocyclic group is optionally substituted with D, halogen, CN, OH, NH 2 , C 1- C 6 Alkyl, C 1- C 6 Halogenoalkyl, -O-C 1 -C 6 Alkyl, -O-C 1- C 6 Halogenoalkyl substitution; R 5 and R 6 are each independently selected from H, D, halogen, CN, NO 2 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkyl-O-C 1 -C 8 alkyl, C 1 -C 8 alkyl-O-C 1 -C 8 haloalkyl, C 1 -C 8 alkyl-OH, C 1 -C 8 alkyl-CN; R 7 Each independently selected from H, D, CN, halogen, NO 2 , N 3 , SF 5 , Si(R 8 ), 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or adamantyl; wherein the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or adamantyl is optionally substituted by 1, 2, 3, 4, or 5 substituents each independently selected from the following: D, -halogen, -CN, -NO 2 , -N 3 , SF 5 , oxo, -NR C R D , -OR A , -SR A , SiR G R H R I , -B(OR C )(OR D ), -C(O)R B , -C(O)OR A , -OC(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) 2 R B , -S(O)NR C R D , -NR C S(O)R D , -NR C S(O) 2 R D , -S(O) 2 NR C R D ,-NR C S(O) 2 NR C R D ,-NR C S(O)(=NR B )R B ; Each R 8 is independently selected from C 1 -C 4 alkyl or phenyl; Each R A is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, CN, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkyl-OH, C 1 -C 4 alkyl-CN, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, NO 2 , oxo, OR a , SR a , SF 5 , 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 c )(OR d ),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) 2 R b ,NR c S(O) 2 R b ,S(O) 2 NR c R d ,NR c S(O) 2 NR c R d , or NR c S(O)(=NR b )R b ; Each R B is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, OH, CN, halogen, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, SF 5 , C(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 , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , S(O) 2 NR c R d , NR c S(O) 2 NR c R d , or B(OR c )(OR d ); R C and R D are each independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4- to 7-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4- to 7-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the following: D, OH, CN, halogen, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, SF 5 , OC(O)NR c R d , NR c R d , NR c C(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , S(O) 2 NR c R d , NR c S(O) 2 NR c R d or B(OR c )(OR d )); or R C and R D together with the N atom to which it is attached forms a 4- to 7-membered heterocyclic group optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the following: D, OH, oxo, CN, -NH 2 , -NH(C 1 -C 4 -alkyl), -N(C 1 -C 4 -alkyl) 2 , halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -cyanoalkyl, OC 1 -C 4 -alkyl, or OC 1 -C 4 -haloalkyl; R a and R a1 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocyclic group, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocyclic group is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the following: D, halogen, OH, CN, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or OC 1 -C 4 haloalkyl; R b and R b1 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the following: D, OH, CN, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 6- C 10 aryl, C 3- C 10 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclic group; R c and R d are each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6- C 10 aryl, 5- to 10-membered heteroaryl, C 3- C 10 cycloalkyl, 4- to 10-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocyclic group, heteroarylaryl, or biheteroaryl; provided that the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6- C 10 aryl, 5- to 10-membered heteroaryl, C 3- C 10 cycloalkyl, 4- to 10-membered heterocyclic group, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocyclic group, heteroarylaryl, or biheteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the following: D, OH, CN, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 cyanoalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C(O)OR a1 , C(O)R b1 , S(O) 2 R b1 , C 1 -C 4 alkyl - O - C 1 -C 4 alkyl or C 1 -C 4 alkyl - O - C 1 - C 4 alkyl-O-; or R c and R d together with the N atom to which it is attached form a 4- to 7-membered heterocyclic group optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from: D, OH, CN, -NH 2 , -NH(C 1 -C 4 -alkyl), -N(C 1 -C 4 -alkyl) 2 , halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -cyanoalkyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy; R E and R e are each independently selected from H, D, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl, (C 1 -C 4 -alkoxy)-C 1 -C 4 -alkyl, C 2 -C 4 -alkynyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, C 3 -C 10 -cycloalkyl, 4- to 10-membered heterocyclic group, C 6 -C 10 -aryl-C 1 -C 4 -alkyl, C 3 -C 10 -cycloalkyl-C 1 -C 4 -alkyl, 5- to 10-membered heteroaryl-C 1 -C 4 -alkyl, or 4-10-membered heterocyclic group-C 1 -C 4 alkyl; R F and R f are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocyclic group; R G ,R H and R I are each independently selected from C 1 -C 4 alkyl or phenyl.

2. The compound according to claim 1, wherein, X 1 is CR 1 , X 2 is CR 2 , and X 3 is CR 3 ; X 1 is N, X 2 is CR 2 , and X 3 is CR 3 ; X 1 is CR 1 , X 2 is N, and X 3 is CR 3 ; or X 1 is CR 1 , X 2 is CR 2 , and X 3 is N.

3. The compound according to claim 1 or 2, wherein, the compound of formula (I) is as shown in formula (IIa), (IIb), (IIc) or (IId): or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.

4. The compound according to claim 3, wherein, the compound of formula (I) is as shown in formula (IIa) or (IIb): or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.

5. The compound according to any one of claims 1-4, wherein, Cy is phenyl or 6-membered heteroaryl.

6. The compound according to claim 5, wherein, Cy is phenyl or pyridin-4-yl.

7. The compound according to any one of claims 1-6, wherein, It has the following structure: Wherein, Y 1 is N or CR 4 ; Y 2 is N or CR 4 .

8. The compound according to claim 7, wherein, Y 1 is CR 4 , and Y 2 is CR 4 ; Y 1 is CR 4 , and Y 2 is N; or Y 1 is N, and Y 2 is CR 4 .

9. The compound according to claim 8, wherein, Y 1 is CH, and Y 2 is CH.

10. The compound according to any one of claims 1-9, wherein, has the following structure: where each R 2 is as defined in this disclosure.

11. The compound according to claim 10, wherein, Has the following structure:

12. The compound according to any one of claims 1-11, wherein, the compound of formula (I) is as shown in formula (IIIa), or (IIIb): or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.

13. The compound according to any one of claims 1-12, wherein, R is OH.

14. The compound according to any one of claims 1-12, wherein, R is 15. The compound according to any one of claims 1-14, wherein, the compound of formula (I) is as shown in formula (IVa) or (IVb): or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.

16. The compound according to claim 15, wherein, the compound of formula (I) is as shown in formula (Va), or (Vb): or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.

17. The compound according to claim 16, wherein, the compound of formula (I) is as shown in formula (VIa), or (VIb): or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.

18. The compound according to claim 17, wherein, the compound represented by formula (I) is as represented by formula (VIIa) or (VIIb): or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.

19. The compound according to claim 17, wherein, the compound represented by formula (I) is as represented by formula (VIIIa) or (VIIIb): or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.

20. The compound according to any one of claims 1-19, wherein, R 1 and R 2 are each independently selected from H, D, CN, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, OR A , SR A , NR C R D ; wherein, the C 1 -C 6 alkyl or C 3 -C 6 The cycloalkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, NH 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.

21. The compound according to claim 20, wherein, R 1 and R 2 are each independently selected from H, D, CN, halogen, OH, NH 2 , ethylmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 ,OCH 2 F,OCHF 2 ,OCF 3 , 22. The compound according to claim 21, wherein, R 1 is H.

23. The compound according to claim 21, wherein, R 2 is CH 3 .

24. The compound according to any one of claims 1-23, wherein, R 3 selected from H, D, CN, SF 5 , halogen, OR A , or SR A , C 1 -C 4 -alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from: D, halogen, CN, OH, -O-C 1 -C 4 -alkyl, -OC 1 -C 4 -haloalkyl.

25. The compound according to claim 24, wherein, R 3 selected from H, D, CN, SF 5 , halogen, OH, OCH 3 , OCH 2 CH 3 , OCF 3 , ethyl methyl, ethyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 。 26. The compound according to claim 25, wherein, R 3 is H.

27. The compound according to any one of claims 1-26, wherein, Each R 4 is independently selected from (i) H, D, halogen, or –OR A ; or (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 4A .

28. The compound according to claim 27, wherein, Each R 4 is independently selected from H, –F, –Cl, –CH 3 , –CF 3 , or –OCH 3 .

29. The compound according to claim 27 or 28, wherein, One of the Rs 4 is –F.

30. The compound according to any one of claims 27-29, wherein, One of the Rs 4 is H, F, –Cl, –CH 3 , –CF 3 –OCH 3 , or ethynyl.

31. The compound according to any one of claims 27-30, wherein, One of the Rs 4 is –OCH 3 .

32. The compound according to any one of claims 27-31, wherein, One of the Rs 4 is F, –Cl, –CH 3 , –CF 3 –OCH 3 , or ethynyl; one of the Rs 4 is –OCH 3 ; the remaining Rs 4 are H.

33. The compound according to any one of claims 1-32, wherein, R 5 selected from H, D, halogen, CN, NO 2 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkyl-O-C 1 -C 8 alkyl, OC 1 -C 8 haloalkyl, C 1 -C 8 alkyl-OH, C 1 -C 8 alkyl-CN.

34. The compound according to claim 33, wherein, R 5 is H.

35. The compound according to any one of claims 1-34, wherein, R 6 selected from H, D, halogen, CN, NO 2 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkyl-O-C 1 -C 8 alkyl, C 1 -C 8 alkyl-OH, C 1 -C 8 alkyl-CN.

36. The compound according to claim 35, wherein, R 6 is H.

37. The compound according to any one of claims 1-36, wherein, R 7 is H, D, CN, halogen, Si(R 8 ) 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and each substituent is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the following: D, -halogen, -CN, -NO 2 , SF 5 , -N 3 , oxo, -NR C R D , -OR A , -SR A , SiR G R H R I , -C(O)R B , -C(O)OR A , -OC(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) 2 R B , - S(O)NR C R D ,-NR C S(O) 2 R D ,-S(O) 2 NR C R D ,-NR C S(O) 2 NR C R D ,-NR C S(O)(=NR B )R B 。 38. The compound according to claim 37, wherein, R 7 is ethylmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 C(CH 3 ) 3 CH 2 F, CHF 2 CF 3 CH 2 CH 2 F, CH 2 CHF 2 CH 2 CF 3 CH 2 OH, CH 2 CH 2 OH, CH(CH 3 )OH, CH 2 CH(CH 3 )OH, CH 2 OCH 3 CH 2 CH 2 OCH 3 CH 2 OCH 2 CH 3 CH 2 CH 2 OCH 2 CH 3 CH 2 CH 2 OCH 2 CH 2 OCH 3 CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 3 CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OH, CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 3 ,CH 2 CH 2 OCH 2 CH 2 SCH 3 ,CH 2 CH 2 OCH 2 CH 2 SCH 2 CH 3 ,CH(CH 3 )OCH 3 ,CH 2 CH(CH 3 )OCH 3 ,CH(CH 3 )CN,C(CH 3 ) 2 CN,CH 2 C(CH 3 ) 2 CN,CH(CH 3 )F,C(CH 3 ) 2 F,CH 2 C(CH 3 ) 2 F,CH(CH 3 )OH,C(CH 3 ) 2 OH,CH 2 C(CH 3 ) 2 OH,CH(CH 3 )OCH 3 ,C(CH 3 ) 2 OCH 3 ,CH 2 C(CH 3 )OCH 3 ,CH(CH 3 )CH 2 OH,C(CH 3 ) 2 CH 2 OH,CH 2 C(CH 3 ) 2 CH 2 OH,CH 2 SCH 3 ,CH 2 CH 2 SCH 3 ,CH 2 S(O)CH 3 ,CH 2 CH 2 S(O)CH 3 ,CH 2 S(O) 2 CH 3 ,CH 2 CH 2 S(O) 2 CH 3 ,CH 2 C(O)CH 3 ,CH 2 CH 2 C(O)CH 3 ,CH 2 N 3 ,CH 2 CH 2 N 3 ,Si(CH 3 ) 3 ,CH 2 Si(CH 3 ) 3 ,CH 2 NHCH 3 ,CH 2 CH 2 NHCH 3 ,CH 2 N(CH 3 ) 2 ,CH 2 CH 2 N(CH 3 ) 2 ,CH 2 NHC(O)CH 3 ,CH 2 CH 2 NHC(O)CH 3 ,CH 2 N(CH 3 )C(O)CH 3 ,CH 2 CH 2 N(CH 3 )C(O)CH 3 ,CH 2 NHS(O)CH 3 ,CH 2 CH 2 NHS(O)CH 3 ,CH 2 N(CH 3 )S(O)CH 3 ,CH 2 CH 2 N(CH 3 )S(O)CH 3 ,CH 2 NHS(O) 2 CH 3 ,CH 2 CH 2 NHS(O) 2 CH 3 ,CH 2 N(CH 3 )S(O) 2 CH 3 ,CH 2 CH 2 N(CH 3 )S(O) 2 CH 3 ,-CH=CH 2 ,- CH=CHCH 3 ,-CH=CHCH 2 CH 3 ,-C(=CH 2 )CH 3 ,-C(=CH 2 )CH 2 CH 3 ,- C(=CH 2 )CH 2 OCH 3 , -C(=CH 2 )CH 2 OCH 3 , -C(=CH 2 )CH 2 SCH 3 , -C(=CH 2 )CH 2 SCH 3 , - CH=CF 2 ,-CH=CFCH 3 ,-CH=CFCH 2 CH 3 ,-C(=CF 2 )CH 3 ,-C(=CF 2 )CH 2 CH 3 ,- C(=CF 2 )CH 2 OCH 3 , -C(=CF 2 )CH 2 OCH 3 , -C(=CF 2 )CH 2 SCH 3 , or -C(=CF 2 )CH 2 SCH 3 , 39. The compound according to any one of claims 1-36, wherein, R 7 The adamantyl group is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: D, halogen, CN, NO 2 , N 3 , SF 5 , oxo, NR C R D , OR A , SR A , SiR G R H R I , B(OR C )(OR D ), C(O)R B , -C(O)OR A , -OC(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) 2 R B , S(O)NR C R D , NR C S(O)R D , NR C , S(O) 2 R D , S(O) 2 , NR C R D , NR C , S(O) 2 , NR C R D , NR C S(O)(=NR B )R B 。 40. The compound according to any one of claims 1-39, wherein, has the following structure:

41. The compound according to any one of claims 1-40, wherein, the compound is as follows: or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition, comprising: the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof and at least one pharmaceutically acceptable excipient.

43. A method for treating and / or preventing cancer in a subject with overexpression of PolQ, comprising: administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-41, or the pharmaceutical composition according to claim 42.

44. A method for treating and / or preventing cancer in a subject, characterized in that the cancer is characterized by an increased dependence on MMEJ DSB repair, comprising: administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-41, or the pharmaceutical composition according to claim 42.

45. A method for treating and / or preventing cancer, characterized in that the cancer is characterized by HR-deficiency, reduction or deletion of HR-related gene expression, comprising: administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-41, or the pharmaceutical composition according to claim 42.

46. A method for treating and / or preventing cancer, characterized in that the cancer lacks the 53BP1 / Shieldin complex, comprising: administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-41, or the pharmaceutical composition according to claim 42.

47. A method for treating and / or preventing cancer, characterized in that the cancer has received or not received PARPi drug treatment and is resistant to PARPi treatment, comprising: administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-41, or the pharmaceutical composition according to claim 42.

48. A method for treating and / or preventing cancer in a subject, characterized in that the cancer is characterized by NHEJ deficiency, reduction or deletion of NHEJ-related gene expression, comprising: administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-41, or the pharmaceutical composition according to claim 42.

49. Use of the compound according to any one of claims 1-41 or the pharmaceutical composition according to claim 42 in the preparation of a medicament for treating diseases with overexpression of PolQ.

50. Use of the compound according to any one of claims 1-41 or the pharmaceutical composition according to claim 42 in the preparation of a medicament for treating diseases with increased dependence on MMEJ-DSB repair.

51. Use of the compound according to any one of claims 1-41 or the pharmaceutical composition according to claim 42 in the preparation of a medicament for treating cancer, characterized in that the cancer is characterized by HR-deficiency, reduction or deletion of HR-related gene expression.

52. Use of the compound according to any one of claims 1-41 or the pharmaceutical composition according to claim 42 in the preparation of a medicament for treating cancer, characterized in that the cancer lacks the 53BP1 / Shieldin complex.

53. Use of the compound according to any one of claims 1-41 or the pharmaceutical composition according to claim 42 in the preparation of a medicament for treating cancer, characterized in that the cancer has received or not received PARPi drug treatment and is resistant to PARPi treatment. Use of a compound according to any one of claims 1-41 or a pharmaceutical composition according to claim 42 for the preparation of a medicament for treating cancer, characterized in that, the cancer is characterized by NHEJ deficiency, reduced or absent NHEJ-related gene expression.

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