Acyl sulfonamide KAT6A inhibitor

Abstract

This disclosure describes acylsulfonamide compounds of formula (J), as well as pharmaceutically acceptable salts thereof, compositions, methods, and uses. Such compounds are considered particularly therapeutically useful as KAT6A inhibitors in the treatment and / or prevention of KAT6A-mediated diseases and disorders in subjects. In some embodiments, the methods of the present invention are methods for treating a KAT6A-mediated disease or disorder in a subject, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need. TIFF2026510819000254.tif27165

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of Indian application No. 202311018002, filed on 16 March 2023, the entire specification of which is incorporated herein by reference.

[0002] Field of Invention This disclosure relates to an acylsulfonamide compound of formula (J) or a pharmaceutically acceptable salt thereof, which is considered useful as a KAT6A inhibitor for the treatment of a disease or disorder mediated by KAT6A. This application also describes a method for preparing the compound and a pharmaceutical composition comprising the compound. [Background technology]

[0003] The MYST family of histone acetyltransferases (HATs) is named after its four foundational members: MOZ, Ybf2 (Sas3), Sas2, and Tip60. The presence of zinc fingers and chromodomains is characteristic of these HATs. MYSTs acetylate lysine residues of histone H2A, H3, and H4. Some MYST family proteins contain zinc fingers and the highly conserved motif A, found in GNATs, which facilitates acetyl-CoA binding. MYST HATs are involved in several important nuclear processes and play crucial roles in gene-specific transcriptional regulation, DNA damage response, repair, and replication. Abnormal activity of these HATs or their associated complexes can easily lead to severe cellular dysfunction, resulting in cell death, uncontrolled proliferation, and malignancy. In fact, HATs of the MYST family are involved in several forms of human cancer. (Avvakumov,N.et al.”The MYST family of histone acetyltransferases and their intimate links to cancer.” Oncogene 26.37(2007):5395-5407.)

[0004] MOZ (monocytic leukemia zinc finger protein) is a known human oncogene. MOZ plays a crucial role as a transcriptional coactivator and epigenetic regulator in the proliferation and differentiation processes of hematopoietic progenitor cells and stem cells. Insights into the deregulation of these processes have shown that MOZ fusion proteins are involved in the formation of leukemia stem cells and inhibit the activity of important proteins such as transcription factors, making MOZ a promising target for the treatment of acute myeloid leukemia. Targeting MOZ with small molecules holds promise for the treatment of acute myeloid leukemia. (Zhou C. et al. "MOZ / KAT6A: a promising target for acute myeloid leukemia therapy." (2020):759-761).

[0005] Cellular senescence plays a crucial role in suppressing tumor growth. KAT6A has been shown to suppress cellular senescence in mouse embryonic fibroblasts (MEFs) without affecting apoptosis or DNA damage. MOZ directly binds to genes that inhibit senescence, including Cdc6, E2f2, Ezh2, and Melk, and in its absence, H3K9ac and H3K27ac are thought to be reduced in the TSS at these loci. (Sheikh, BN, et al. "MOZ(MYST3, KAT6A) inhibits senescence via the INK4A-ARF pathway." Oncogene 34.47(2015):5807-5820).

[0006] PI3K / AKT signaling, upregulated by the histone acetyltransferase KAT6A via TRIM24 binding, is thought to be important for cell proliferation and tumor growth in gliomas. KAT6A has been shown to promote H3K23 acetylation and association with TRIM24, thereby increasing PIK3CA expression and PI3K / AKT signaling activation, and enhancing glioma tumorigenesis. Therefore, KAT6A is considered to function as an oncogene in gliomas. (Lv, D., et al. "Histone acetyltransferase KAT6A upregulates PI3K / AKT signalling through TRIM24 binding." Cancer Research 77.22(2017):6190-6201). Numerous publications disclose small molecule compounds and their derivatives capable of targeting KAT target proteins. Currently, there are no FDA-approved targeted therapies for specific KAT6A or KAT6B target proteins, highlighting the need for the development of compounds, compositions, and methods to treat proliferative disorders and autoimmune diseases activated by KAT6A or KAT6B. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Avvakumov, N. et al. “The MYST family of histone acetyltransferases and their intimate links to cancer.” Oncogene 26.37(2007):5395-5407. [Non-Patent Document 2] Zhou C.et al.”MOZ / KAT6A:a promising target for acute myeloid leukaemia therapy.”(2020):759-761 [Non-Patent Document 3] Sheikh, B.N., et al. “MOZ (MYST3, KAT6A) inhibits senescence via the INK4A-ARF pathway.” Oncogene 34.47 (2015): 5807-5820

Non-Patent Document 4

Summary of the Invention

[0008] In some embodiments, the compounds of the present disclosure are of formula (J):

Chemical Formula

[0009] In some embodiments, the composition of the present invention is a pharmaceutical composition comprising the compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the compound of the present invention is a compound or a pharmaceutically acceptable salt thereof for use as a pharmacopoeia. In some embodiments, the compound of the present invention is a compound for use in the treatment of a disease or disorder mediated by KAT6A. In some embodiments, the method of the present invention is a method for modulating KAT6A in a subject, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0010] In some embodiments, the present invention provides a method for treating a KAT6A-mediated disease or disorder in a subject, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need. [Brief explanation of the drawing]

[0011] [Figure 1]The synergistic effect scores of 282 compounds combined with everolimus at various concentrations are shown.

[0012] [Figure 2] The synergistic effect scores of 282 compounds combined with inavolicib at various concentrations are shown.

[0013] [Figure 3] The synergistic effect scores of 282 compounds combined with alpericib at various concentrations are shown. [Modes for carrying out the invention]

[0014] I. Overview This disclosure provides, in particular, acylsulfonamide compounds represented by formula (J) and pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprising compounds considered useful as KAT6A inhibitors for the treatment of diseases or disorders that are dependent on or mediated by KAT6A are also described herein. This disclosure also includes preparations of compounds of formula (J) or pharmaceutically acceptable salts thereof.

[0015] II. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the subject matter herein pertains. Where used herein and in the appended claims, unless otherwise intended, the following terms have the meanings set forth to facilitate understanding of the invention.

[0016] Unless otherwise clearly indicated by the context, the singular forms "a," "an," and "the" refer to multiple objects.

[0017] "Alkyl" is C1-C 10 Linear alkyl groups or C3-C 10The term "branched-chain alkyl group" refers to a monovalent saturated aliphatic group, including but not limited to these. In some embodiments, the alkyl group is a C1-C6 straight-chain alkyl group or a C3-C8 branched-chain alkyl group. In some embodiments, the alkyl group refers to a C1-C4 straight-chain alkyl group or a C3-C6 branched-chain alkyl group. Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, and 4-octyl. The alkyl group may be optionally substituted.

[0018] "Alkylene" is a divalent saturated aliphatic group including but not limited to a C1-C 10 straight-chain alkylene group or a C3-C 10 branched-chain alkylene group. In some embodiments, alkylene refers to a C1-C6 straight-chain alkylene group or a C3-C8 branched-chain alkylene group. In some embodiments, the alkylene group refers to a C1-C4 straight-chain alkylene group or a C3-C6 branched-chain alkylene group. Examples of alkylene include, but are not limited to, methylene, ethylene, 1-propylene, 2-propylene, isopropyl, n-butylene, and sec-butylene. The "alkylene" group may be further optionally substituted.

[0019] "Alkenyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl is C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6, C5, C 5-6 The alkenyl group may contain any number of carbon atoms, such as C6. The alkenyl group may have 1, 2, 3, 4, 5 or more double bonds, but is not limited to these, and can have any suitable number of double bonds. Examples of alkenyl groups include, but are not limited to, vinyl(ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexadienyl. The alkenyl group may be substituted or unsubstituted.

[0020] "Alkynyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one triple bond. Alkynyl is C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6 It may contain any number of carbon atoms, including C6. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiinyl, 1-pentynyl, 2-pentynyl, isopentinyl, 1,3-pentadinyl, 1,4-pentadinyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadinyl, 1,4-hexadinyl, 1,5-hexadinyl, 2,4-hexadinyl, or 1,3,5-hexatriinyl. The alkynyl group may be substituted or unsubstituted.

[0021] "Alkoxy" refers to the -O-alkyl group, and alkyl groups are as defined above. In some embodiments, the alkoxy group refers to a C1-C6 linear alkoxy group or a C3-C8 branched alkoxy group. In some embodiments, the alkoxy group refers to a C1-C4 linear alkoxy group or a C3-C6 branched alkoxy group. Exemplary C1-C 10 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, or t-butoxy. The alkoxy group may optionally be substituted with one or more suitable groups described herein.

[0022] "Alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, where the alkyl group and alkoxy group are as defined above. In some embodiments, alkoxyalkyl represents (C1-C6)alkyl(C1-C6)alkoxy or (C1-C4)alkyl(C1-C4)alkoxy. Exemplary alkoxyalkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, and ethoxyethyl.

[0023] The term "halo" or "halogen," either alone or in combination with other terms, means fluorine, chlorine, bromine, or iodine.

[0024] A "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, where the "halogen" and "alkyl" groups are as defined above. Examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl.

[0025] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e., halo C 1-8This refers to alkoxy compounds. Examples of haloalkoxy compounds include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, and 1-bromoethoxy.

[0026] "Amino" refers to the -NH2 group.

[0027] On its own, or in combination with other terms, "hydroxy" or "hydroxyl" means -OH.

[0028] "Hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups.

[0029] "Cycloalkyl" refers to a group of 3 to 20 cyclic carbon atoms (i.e., C 3-20 Cycloalkyls refer to monosaturated or partially unsaturated whole carbon rings having, for example, 3 to 12 cyclic atoms, for example, 3 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms, or 3 to 4 cyclic atoms. Cycloalkyls also include multiple condensed, saturated, and partially unsaturated whole carbon ring systems (e.g., ring systems containing 2, 3, or 4 carbocyclic rings). Thus, cycloalkyls include bicyclic carbo rings (e.g., bicyclic carbo rings having about 6 to 12 cyclic carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane) and polycyclic carbo rings (e.g., tricyclic and tetracyclic carbo rings having up to about 20 cyclic carbon atoms). Rings in multiple condensed ring systems may be connected to each other via fusion, spiro, and bridging bonds, where possible due to valence requirements. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, and 1-cyclohexa-3-enyl.

[0030] As used herein, "heteroatom" refers to a sulfur atom, a nitrogen atom, or an oxygen atom.

[0031] "Hypercycloalkyl" refers to a 3- to 15-membered non-aromatic, saturated or partially saturated, bridging bicyclic, monocyclic or polycyclic ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH, or C(O), with the remaining ring atoms independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Heterocycloalkyl also refers to a bridging bicyclic ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH, or C(O). Examples of heterocycloalkyls include, but are not limited to, azilidinyl, oxiranil, thiiranyl, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidethiomorpholinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, isoindolinyl, oxoisoindolinyl, dioxoisoindolinyl, azabicyclooctanil, diazabicyclooctanil, azosinyl, chromanil, isochromanil, and xanthenyl. The bonding of heterocycloalkyl substituents can occur via either a carbon atom or a heteroatom. Heterocycloalkyl groups can optionally be substituted with one or more suitable groups. In some embodiments, heterocycloalkyl refers to a 4- to 6-membered ring (unless the ring size is specifically mentioned) selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and thiomorpholinyl. Heterocycloalkyl groups can optionally be substituted with one or more groups described herein.

[0032] "Aryl" is a monocyclic, bicyclic, or polycyclic aromatic hydrocarbon ring system in which approximately 6 to 14 carbon atoms are optionally substituted. In some embodiments, aryl includes a 6 to 10-membered aromatic hydrocarbon ring system. C6-C 14 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthyl. The aryl group may optionally be substituted with one or more suitable groups described herein.

[0033] A "heteroaryl" refers to a fully unsaturated and aromatic ring system containing a total of 5 to 14 ring atoms unless the ring size is specifically mentioned. At least one of the ring atoms is a heteroatom (i.e., O, N, or S), and the remaining ring atoms / groups are independently selected from C, N, O, or S. Heteroaryls can be monocyclic (monocyclic formula) or fused or covalently multicyclic (bicyclic, tricyclic, or polycyclic) rings. In some embodiments, heteroaryls are 5 to 6-membered rings. The ring may contain 1 to 4 heteroatoms selected from N, O, and S, and the N atoms are optionally quaternized. Any suitable ring position of the heteroaryl moiety may be covalently bonded to the defined chemical structure. Examples of heteroaryls include furanil, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl (pyridinyl), pyrimidinyl, pyrazinyl, pyridadinyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzofuranil, benzothienyl, benzotriazinyl, phthalazinyl, thiantrene, dibenzofuranil, dibenzothie Examples include, but are not limited to, nyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carbolinyl, indolidinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotriasiazolyl, carbazolyl, dibenzothienyl, acridinyl, etc. Heteroaryls may be further substituted.

[0034] "Medically acceptable" generally means useful in preparing pharmaceutical compositions that are safe, non-toxic, and not biologically or otherwise harmful, and includes those that are acceptable for veterinary and human medicinal use.

[0035] "Medically acceptable salt" refers to a product obtained by the reaction of the compound of the present invention with a suitable acid or base. In some cases, the drug may exist in the form of a pharmaceutically acceptable salt. In some cases, the pharmaceutically acceptable salt may be a salt described in Berge et al, J. Pharm. Sci, 1977. In some cases, pharmaceutically acceptable salts may be salts obtained from minerals, organic acids, or inorganic bases. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids.

[0036] The pharmaceutically acceptable salts of the present invention can be prepared from the basic or acidic portion by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in their free acid form with a stoichiometric amount of a suitable base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.) or by reacting these compounds in their free base form with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent, or a mixture of the two. Generally, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred where feasible. A further list of suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences”, 20 th This can be found in ed., Mack Publishing Company, Easton, Pa., (1985), and “Handbook of Pharmaceutical Salts: Properties, Selection and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0037] "Composition" is intended to encompass products containing specific amounts of specific components, as well as any products obtained directly or indirectly from specific amounts of specific components in combination. "Medically acceptable" means that the carrier, diluent, or excipient is required to be compatible with the other components of the formulation and not harmful to its recipient.

[0038] "Medically acceptable carriers" include, but are not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, colorants, flavor enhancers, surfactants, humectants, dispersants, suspending agents, stabilizers, isotonic agents, solvents, surfactants, or emulsifiers approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock.

[0039] As used in this disclosure, “administer,” “dosage,” and / or “administer” means either directly administering one or more disclosed compounds or pharmaceutically acceptable salts of one or more disclosed compounds or compositions comprising one or more disclosed compounds to a subject, or directly administering to a subject an analog of said compound or a pharmaceutically acceptable salt or composition of said compound that can form a corresponding amount of the active compound in the body of said subject.

[0040] "Carrier" includes carriers, excipients, and diluents, and means materials, compositions, or vehicles involved in transporting or delivering a pharmaceutical product from one organ or part of the body to another organ or part of the body, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials.

[0041] "To treat," "to treat," and / or "treatment" means any method of reducing or suppressing one or more symptoms of a disease and / or a disease.

[0042] "Preventing," "preventing," and / or "prevention" refers to methods of preventing the onset of a disease and / or its associated symptoms, or preventing a subject from contracting the disease. Preventing, preventing, and / or prevention also include delaying the onset of a disease and / or one or more symptoms associated with the disease, as well as reducing the risk of contracting the disease.

[0043] "Subject" or "patient" refers to mammals, such as humans or other animals. In some embodiments, the subject includes mammals, such as mice, rats, dogs, cats, other veterinary animals, such as goats, pigs, horses, cattle, or donkeys, or primates, such as non-human primates, such as crab-eating macaques, rhesus macaques, or chimpanzees, or humans. In some embodiments, the subject is human.

[0044] The "therapeutic dose" refers to the amount of the compound of formula (J), or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof, or a composition containing the compound of formula (J), or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof, that is effective in producing the desired therapeutic response in a specific patient suffering from a disease or disorder, particularly in the use of such compounds in cancer-related diseases or disorders. The therapeutic dose includes an amount of the compound of formula (J), or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof, that, when administered, induces a beneficial modification to the disease or disorder being treated in the subject, or is sufficient to prevent or, to some extent, the onset of one or more symptoms of the disease or disorder being treated. With respect to the therapeutic dose of the compound, the amount of the compound used to treat the subject may be considered within the bounds of appropriate medical judgment, provided that it is low enough to avoid excessive or severe side effects. The therapeutically effective amount of a compound or composition varies depending on the specific condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of the concomitant therapy, the age and health status of the end user, the specific compound or composition used, and the specific pharmaceutically acceptable carrier used.

[0045] III.Compound In some embodiments, the compounds of the present disclosure are of formula (J): [ka] or represented by a pharmaceutically acceptable salt thereof, During the ceremony, X is O or NR 4 and; Ring A is phenyl or heteroaryl; Ring B is phenyl or heteroaryl; Each R 1 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 1a , -C(O)OR 1a ,-OC(O)R 1a ,-C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a -S(O)2R 1a -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a ,-S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10The alkyl groups are aryl, heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. 1c Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R 1d Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 1e Replaced by; Each R 1a and R 1b These are independently hydrogen or a C1-C6 alkyl group; Each R 1c These are independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, and -NR. 1c1 R 1c2 It is OH or -CN; Each R 1c1 and R 1c2 These are independently hydrogen or a C1-C6 alkyl group; Each R 1d These are independently deuterium, C3-C8 cycloalkyl, heterocycloalkyl, and C6-C 10 It is an aryl or heteroaryl; Each R 1e These are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN; Alternatively, two R atoms on adjacent carbon atoms 1 The groups, together with the atoms to which they are bonded, form 0, 1, 2, 3, 4, 5, or 6 halogens, C1-C4 alkyls, OH, or C5-C8 cycloalkyls or heterocycloalkyls substituted with -CN; L is -C1-C4 alkylene-, -(C1-C4 alkylene)-O-, or -O-; R 2 This is 0, 1, 2, 3, or 4 R 2a It is a heteroaryl substituted with; Each R 2aThese are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 2b , -C(O)OR 2b ,-OC(O)R 2b ,-C(O)N(R 2b )(R 2c ), -N(R 2b )C(O)(R 2c ), -S(O)2R 2b -S(O)2N(R 2b )(R 2c ), -N(R 2b )(R 2c ), OH, -CN, or -NO2; Each R 2b and R 2c These are independently hydrogen or a C1-C6 alkyl group; Each R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 3a , -C(O)OR 3a ,-OC(O)R 3a ,-C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a -S(O)2R 3a -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a ,-S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 The alkyl groups are aryl, heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. 3c Substituted with, each alkoxy has 0, 1, 2, or 3 R 3d Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 3e It will be replaced by; or Two R atoms on the same carbon atom 3 These together represent an oxo group; Each R 3a and R 3b These are independently hydrogen or a C1-C6 alkyl group; Each R 3c These are independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, and -NR. 3c1 R 3c2 It is OH or -CN; Each R 3c1 and R 3c2 These are independently hydrogen or a C1-C6 alkyl group; Each R 3d These are independently C3-C8 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; Each R 3e These are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, or C1-C6 haloalkoxy; R 4 is hydrogen or a C1-C6 alkyl group; Subscript n is 0, 1, 2, 3, or 4; Subscript q is 0, 1, 2, 3, or 4; During the ceremony, Each heterocycloalkyl is a 3- to 8-membered ring containing 1 to 4 heteroatoms that are N, O, or S; Each heteroaryl is a 5-6 membered ring containing 1-4 heteroatoms that are N, O, or S.

[0046] In some embodiments, X is O. In some embodiments, X is NH.

[0047] In some embodiments, ring B is a heteroaryl compound. In some embodiments, ring B is pyrrolyl, furyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidyl, or pyrazinyl. In some embodiments, ring B is pyridyl, pyridadinyl, pyrimidyl, or pyrazinyl. In some embodiments, ring B is pyridyl or pyrimidinyl. In some embodiments, ring B is phenyl.

[0048] In some embodiments, the compound of formula (J), or a pharmaceutically acceptable salt thereof, is formula (I), formula (II), formula (III), or formula (IV): [ka] A compound of or a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, R 3 , R 4 , and n, both individually and in combination, are as described in the Classes and Subclasses of this Specified, and Y is N, CH, or CR 3 That is the case.

[0049] In some embodiments, the compound of formula (J), or a pharmaceutically acceptable salt thereof, is of formula (I): [ka] A compound of or a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, R 3 , and n, both individually and in combination, are as described in the Classes and Subclasses of this Specified Specified.

[0050] In some embodiments, the compound of formula (J), or a pharmaceutically acceptable salt thereof, is of formula (II): [ka] A compound of or a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, R 3 , and n, both individually and in combination, are as described in the Classes and Subclasses of this Specified, and Y is N, CH, or CR 3 That is the case.

[0051] In some embodiments, the compound of formula (J), or a pharmaceutically acceptable salt thereof, is of formula (III): [ka] A compound of or a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, R 3 , R 4 , and n, both individually and in combination, are as described in the Classes and Subclasses of this Specified Specified.

[0052] In some embodiments, the compound of formula (J), or a pharmaceutically acceptable salt thereof, is of formula (IV): [ka] A compound of or a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, R 3 , R 4, and n, both individually and in combination, are as described in the Classes and Subclasses of this Specified, and Y is N, CH, or CR 3 That is the case.

[0053] In some embodiments, the compound of formula (J), or a pharmaceutically acceptable salt thereof, is of formula (I): [ka] or represented by a pharmaceutically acceptable salt thereof, in the formula, Each R 1 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 1a , -C(O)OR 1a ,-OC(O)R 1a ,-C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a -S(O)2R 1a -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a ,-S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10The alkyl groups are aryl, heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. 1c Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R 1d Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 1e Replaced by; Each R 1a and R 1b These are independently hydrogen or a C1-C6 alkyl group; Each R 1c These are independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, and -NR. 1c1 R 1c2 It is OH or -CN; Each R 1c1 and R 1c2 These are independently hydrogen or a C1-C6 alkyl group; Each R 1d These are independently deuterium, C3-C8 cycloalkyl, heterocycloalkyl, and C6-C 10 It is an aryl or heteroaryl; Each R 1e These are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN; Alternatively, two R atoms on adjacent carbon atoms 1 The groups, together with the atoms to which they are bonded, form 0, 1, 2, 3, 4, 5, or 6 halogens, C1-C4 alkyls, OH, or C5-C8 cycloalkyls or heterocycloalkyls substituted with -CN; L is -C1-C4 alkylene-, -(C1-C4 alkylene)-O-, or -O-; R 2 This is 0, 1, 2, 3, or 4 R 2a It is a heteroaryl substituted with; Each R 2aThese are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 2b , -C(O)OR 2b ,-OC(O)R 2b ,-C(O)N(R 2b )(R 2c ), -N(R 2b )C(O)(R 2c ), -S(O)2R 2b -S(O)2N(R 2b )(R 2c ), -N(R 2b )(R 2c ), OH, -CN, or -NO2; Each R 2b and R 2c These are independently hydrogen or a C1-C6 alkyl group; Each R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 3a , -C(O)OR 3a ,-OC(O)R 3a ,-C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a -S(O)2R 3a -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a ,-S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 The alkyl groups are aryl, heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. 3c Substituted with, each alkoxy has 0, 1, 2, or 3 R 3d Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 3e It will be replaced by; or Two R atoms on the same carbon atom 3 These together represent an oxo group; Each R 3a and R 3b These are independently hydrogen or a C1-C6 alkyl group; Each R 3c These are independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, and -NR. 3c1 R 3c2 It is OH or -CN; Each R 3c1 and R 3c2 These are independently hydrogen or a C1-C6 alkyl group; Each R 3d These are independently C3-C8 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; Each R 3e These are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, or C1-C6 haloalkoxy; Subscript n is 0, 1, 2, 3, or 4; Subscript q is 0, 1, 2, 3, or 4; During the ceremony, Each heterocycloalkyl is a 3- to 8-membered ring containing 1 to 4 heteroatoms that are N, O, or S; Each heteroaryl is a 5-6 membered ring containing 1-4 heteroatoms that are N, O, or S.

[0054] In some embodiments, a compound of formula (J), formula (I), or a pharmaceutically acceptable salt thereof is formula (Ia): [ka] or represented by a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, R 3 , and n, both individually and in combination, are as described in the Classes and Subclasses of this Specified Specified.

[0055] In some embodiments, a compound of formula (J), (I), and / or (Ia), or a pharmaceutically acceptable salt thereof, is formula (Ib): [ka] or represented by a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, and R 3 These, both individually and in combination, are as described in the Classes and Subclasses of this Specified Specified.

[0056] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, base [ka] However, the structure: [ka] It has, in the formula, R 1 However, as described in the Classes and Subclasses of this Specified Specification, R 1However, these are compounds, or pharmaceutically acceptable salts thereof, as described in the Classes and subclasses of this specification.

[0057] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 1 However, independently, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 It is an aryl or heteroaryl, where each alkyl group has 0, 1, 2, or 3 R atoms. 1c Substituted with, and each alkoxy and alkynyl has 0, 1, 2, or 3 R 1d It is substituted with; or two R on adjacent carbons 1 However, these compounds, or pharmaceutically acceptable salts thereof, combine with the atoms to which they are bonded, to form a C5-C8 cycloalkyl or heterocycloalkyl group.

[0058] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 1 However, independently, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C 10 It is an aryl or heteroaryl, where each alkyl group has 0 or 1 R 1c Substituted with, and each alkoxy and alkynyl has 0 or 1 R 1d It is substituted with; or two R on adjacent carbons 1However, these compounds, or pharmaceutically acceptable salts thereof, combine with the atoms to which they are bonded, to form a C5-C8 cycloalkyl or heterocycloalkyl group.

[0059] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 1a and R 1b However, independently, it is a compound that is hydrogen or a C1-C4 alkyl group, or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 1c However, halogen, -NR 1c1 R 1c2 It is a compound that is OH or -CN.

[0061] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 1d However, independently, it is a heteroaryl compound, or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 1e However, independently, these are compounds, or pharmaceutically acceptable salts thereof, that are C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, or -CN.

[0063] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 1However, independently, CH3, CH2CH3, -C(CH3)3, OCH3, CH2CH3, -OCH(CH3)2, OCH2-pyridyl, C(CH3)2OH, F, Cl, Br, CF3, OCHF2, OCF3, OCH2CF3, OH, cyclopropyl, cyclopropyloxy, cyclobutyloxy, phenyl, pyrazolyl, or [ka] or two R on adjacent carbons 1 However, these compounds, or pharmaceutically acceptable salts thereof, combine with the atoms to which they are bonded to form cyclopentyl, cyclohexyl, dihydrofuran, tetrahydrofuran, methyltetrahydrofuran, 1,3-dioxol, dihydro-1,3-oxazine, difluorodihydrofuran, or methyldihydrofuran. In some embodiments, two adjacent carbon atoms R1 When combined, [ka] It forms.

[0064] In some embodiments, the compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are compounds, or pharmaceutically acceptable salts thereof, where L is -CH2-, -O-, or -CH2O-.

[0065] In some embodiments, the compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are compounds where L is -CH2-, or pharmaceutically acceptable salts thereof.

[0066] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are R 2 However, 0, 1, or 2 R 2aA compound, or a pharmaceutically acceptable salt thereof, which is pyrrolyl, furyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidyl, or pyrazinyl, respectively.

[0067] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 2a However, the compounds are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN, or pharmaceutically acceptable salts thereof.

[0068] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 2b and R 2c However, independently, it is a compound that is hydrogen or a C1-C4 alkyl group, or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are R 2 but, [ka] It is a compound, or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are R 2 but, [ka] It is a compound, or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 3 However, independently, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a , -C(O)OR 3a ,-OC(O)R 3a ,-C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -S(O)2R 3a -S(O)2N(R 3a )(R 3b A compound, or a pharmaceutically acceptable salt thereof, which is a C3-C8 cycloalkyl, or heterocycloalkyl compound, or an OH, -CN, C3-C8 cycloalkyl, or heterocycloalkyl compound.

[0072] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, have two R atoms on the same carbon atom. 3 However, it is a compound, or a pharmaceutically acceptable salt thereof, that together represents an oxo group.

[0073] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 3a and R 3b However, independently, it is a compound that is hydrogen or a C1-C4 alkyl group, or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 3c However, halogen, -NR 3c1 R 3c2 A compound, or a pharmaceutically acceptable salt thereof, which is ,OH, or -CN.

[0075] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 3d However, independently, it is a heteroaryl compound, or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 3e However, independently, these are compounds that are C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 haloalkyl, or pharmaceutically acceptable salts thereof.

[0077] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 3 However, independently, these are compounds, or pharmaceutically acceptable salts thereof, that are C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, or C3-C8 cycloalkyl.

[0078] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 3 However, independently, these are compounds, or pharmaceutically acceptable salts thereof, that are C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, or C3-C6 cycloalkyl.

[0079] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are each R 3 However, independently, the compound is Me, OMe, OEt, CHF2, CF3, OCHF2, OCF3, F, Br, CN, or cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, a compound of formula (J), (I), (Ia), and / or (Ib), or a pharmaceutically acceptable salt thereof, is a compound, or a pharmaceutically acceptable salt thereof, where subscript q is 1, 2, or 3.

[0081] In some embodiments, a compound of formula (J), (I), (Ia), and / or (Ib), or a pharmaceutically acceptable salt thereof, is a compound, or a pharmaceutically acceptable salt thereof, where subscript n is 1 or 2.

[0082] In some embodiments, the compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, are compounds having the structures of the compounds shown in Table 1, or pharmaceutically acceptable salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0083] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, have the following structure: [ka] It is a compound that has [a certain characteristic].

[0084] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib) have the following structure: [ka] It is a compound that has [a certain characteristic].

[0085] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salts thereof, have the following structure: [ka] It is a compound that has [a certain characteristic].

[0086] In some embodiments, compounds of formula (J), (I), (Ia), and / or (Ib) have the following structure: [ka] It is a compound that has [a certain characteristic].

[0087] In some embodiments, the compound of formula (J) is of formula (II): [ka] or represented by a pharmaceutically acceptable salt thereof, in the formula, Each R 1 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 1a , -C(O)OR 1a ,-OC(O)R1a ,-C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a -S(O)2R 1a -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a ,-S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 The alkyl groups are aryl, heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. 1c Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R 1d Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 1e Replaced by; Each R 1a and R 1b These are independently hydrogen or a C1-C6 alkyl group; Each R 1c These are independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, and -NR. 1c1 R 1c2 It is OH or -CN; Each R 1c1 and R 1c2These are independently hydrogen or a C1-C6 alkyl group; Each R 1d These are independently deuterium, C3-C8 cycloalkyl, heterocycloalkyl, and C6-C 10 It is an aryl or heteroaryl; Each R 1e These are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN; Alternatively, two R atoms on adjacent carbon atoms 1 The groups, together with the atoms to which they are bonded, form 0, 1, 2, 3, 4, 5, or 6 halogens, C1-C4 alkyls, OH, or C5-C8 cycloalkyls or heterocycloalkyls substituted with -CN; L is -C1-C4 alkylene-, -(C1-C4 alkylene)-O-, or -O-; R 2 This is 0, 1, 2, 3, or 4 R 2a It is a heteroaryl substituted with; Each R 2a These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 2b , -C(O)OR 2b ,-OC(O)R 2b ,-C(O)N(R 2b )(R 2c ), -N(R 2b )C(O)(R 2c ), -S(O)2R 2b -S(O)2N(R 2b )(R 2c ), -N(R 2b )(R 2c ), OH, -CN, or -NO2; Each R 2b and R 2c These are independently hydrogen or a C1-C6 alkyl group; Y is CH, CR 3, or N; Each R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 3a , -C(O)OR 3a ,-OC(O)R 3a ,-C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a -S(O)2R 3a -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a ,-S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 The alkyl groups are aryl, heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. 3c Substituted with, each alkoxy has 0, 1, 2, or 3 R 3d Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 3e It will be replaced by; or Two R atoms on the same carbon atom 3These together represent an oxo group; Each R 3a and R 3b These are independently hydrogen or a C1-C6 alkyl group; Each R 3c These are independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, and -NR. 3c1 R 3c2 It is OH or -CN; Each R 3c1 and R 3c2 These are independently hydrogen or a C1-C6 alkyl group; Each R 3d These are independently C3-C8 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; Each R 3e These are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, or C1-C6 haloalkoxy; Subscript n is 0, 1, 2, 3, or 4; Subscript q is 0, 1, 2, 3, or 4; During the ceremony, Each heterocycloalkyl is a 3- to 8-membered ring containing 1 to 4 heteroatoms that are N, O, or S; Each heteroaryl is a 5-6 membered ring containing 1-4 heteroatoms that are N, O, or S.

[0088] In some embodiments of formula (II), Y is N. In some embodiments, Y is CR. 3 In some embodiments, Y is CH.

[0089] In some embodiments, a compound of formula (J), formula (II), or a pharmaceutically acceptable salt thereof is formula (IIa): [ka] or represented by a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, R 3, and n, both individually and in combination, are as described in the Classes and Subclasses of this Specified, and Y is N, CH, or CR 3 That is the case.

[0090] In some embodiments, a compound of formula (J), (II), and / or (IIa), or a pharmaceutically acceptable salt thereof, is formula (IIb): [ka] or represented by a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, and R 3 Y is, both individually and in combination, as described in the Classes and Subclasses of this Specified, where Y is N, CH, or CR. 3 That is the case.

[0091] In some embodiments, the compounds of formula (J), (II), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are compounds, or pharmaceutically acceptable salts thereof, where Y is N. In some embodiments, Y is CR 3 In some embodiments, Y is CH.

[0092] In some embodiments, compounds of formula (J), (II), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are of formula (IIc): [ka] or represented by a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, and R 3 These, both individually and in combination, are as described in the Classes and Subclasses of this Specified Specified.

[0093] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, base [ka] However, the structure: [ka] or having a pharmaceutically acceptable salt thereof, wherein R 1 However, these are compounds, or pharmaceutically acceptable salts thereof, as described in the Classes and subclasses of this specification.

[0094] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 1 However, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 It is an aryl or heteroaryl, where each alkyl group has 0, 1, 2, or 3 R atoms. 1c Substituted with, and each alkoxy and alkynyl has 0, 1, 2, or 3 R 1d It is substituted with; or two R on adjacent carbons 1 However, these compounds, or pharmaceutically acceptable salts thereof, combine with the atoms to which they are bonded, to form a C5-C8 cycloalkyl or heterocycloalkyl group.

[0095] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 1However, independently, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C 10 It is an aryl or heteroaryl, where each alkyl group has 0 or 1 R 1c Substituted with, and each alkoxy and alkynyl has 0 or 1 R 1d It is substituted with; or two R on adjacent carbons 1 However, these compounds, or pharmaceutically acceptable salts thereof, combine with the atoms to which they are bonded, to form a C5-C8 cycloalkyl or heterocycloalkyl group.

[0096] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 1a and R 1b However, independently, it is a compound that is hydrogen or a C1-C3 alkyl group, or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 1c However, halogen, -NR 1c1 R 1c2 A compound, or a pharmaceutically acceptable salt thereof, which is ,OH, or -CN.

[0098] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 1d However, independently, it is a heteroaryl compound, or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 1e However, independently, these are compounds, or pharmaceutically acceptable salts thereof, that are C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, or -CN.

[0100] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 1 However, independently, -CH3, -CH2CH3, -C(CH3)3, -OCH3, -OCD3, -C(CH3)2OCH3, -C(CH3)2CH2OH, -CH2CH3, -OCH(CH3)2, -C(CH3)2OH, -C(CH3)(CH2CH3)OH, F, Cl, Br, CF3, OCHF2, OCF3, OCH2CF3, cyclopropyl, cyclopropyloxy, cyclobutyloxy, [ka] is it; or Two R on adjacent carbons 1 However, these compounds, or pharmaceutically acceptable salts thereof, combine with the atoms to which they are bonded to form cyclopentyl, cyclohexyl, dihydrofuran, tetrahydrofuran, methyltetrahydrofuran, 1,3-dioxol, dihydro-1,3-oxazine, or methyldihydrofuran. In some embodiments, two adjacent carbon atoms R1 When combined, [ka] It forms.

[0101] In some embodiments, a compound of formula (J), (II), (IIa), (IIb), and / or (IIc), or a pharmaceutically acceptable salt thereof, is a compound, or a pharmaceutically acceptable salt thereof, where L is -CH2-, -CH2O-, or -O-.

[0102] In some embodiments, the compounds of formula (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are compounds where L is -CH2-, or pharmaceutically acceptable salts thereof.

[0103] In some embodiments, compounds of formula (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are R 2 However, 0, 1, or 2 R 2a A compound, or a pharmaceutically acceptable salt thereof, which is pyrrolyl, furyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidyl, or pyrazinyl, respectively.

[0104] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 2a However, the compounds are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN, or pharmaceutically acceptable salts thereof.

[0105] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 2b and R 2c However, independently, it is a compound that is hydrogen or a C1-C4 alkyl group, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, compounds of formula (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are R 2 but, [ka] It is a compound, or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, compounds of formula (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are R 2 but, [ka] It is a compound, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 3 However, independently, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a , -C(O)OR 3a ,-OC(O)R 3a ,-C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -S(O)2R 3a -S(O)2N(R 3a )(R 3b A compound, or a pharmaceutically acceptable salt thereof, which is a C3-C8 cycloalkyl, or heterocycloalkyl compound, or an OH, -CN, C3-C8 cycloalkyl, or heterocycloalkyl compound.

[0109] In some embodiments, compounds of formula (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, have two R atoms on the same carbon atom. 3 However, it is a compound, or a pharmaceutically acceptable salt thereof, that together represents an oxo group.

[0110] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 3a and R 3b However, independently, it is a compound that is hydrogen or a C1-C4 alkyl group, or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 3c However, halogen, -NR 3c1 R 3c2 A compound, or a pharmaceutically acceptable salt thereof, which is ,OH, or -CN.

[0112] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 3d However, independently, it is a heteroaryl compound, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 3e However, independently, these are compounds that are C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 haloalkyl, or pharmaceutically acceptable salts thereof.

[0114] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 3 However, independently, these are compounds, or pharmaceutically acceptable salts thereof, that are C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, or C3-C8 cycloalkyl.

[0115] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 3 However, independently, these are compounds, or pharmaceutically acceptable salts thereof, that are C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, or C3-C6 cycloalkyl.

[0116] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are each R 3 However, independently, the compound is Me, Ome, CHF2, CF3, OCHF2, OCF3, or cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, a compound of formula (J), (II), (IIa), (IIb), and / or (IIc), or a pharmaceutically acceptable salt thereof, is a compound, or a pharmaceutically acceptable salt thereof, where subscript q is 1, 2, or 3.

[0118] In some embodiments, a compound of formula (J), (II), (IIa), (IIb), and / or (IIc), or a pharmaceutically acceptable salt thereof, is a compound, or a pharmaceutically acceptable salt thereof, where subscript n is 0 or 1.

[0119] In some embodiments, the compounds of formula (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, are compounds having the structures of the compounds shown in Table 2, or pharmaceutically acceptable salts thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10]

[0120] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, have the following structure: [ka] It is a compound that has [a certain characteristic].

[0121] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc) have the following structure: [ka] It is a compound that has [a certain characteristic].

[0122] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, have the following structure: [ka] It is a compound that has [a certain characteristic].

[0123] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc) have the following structure: [ka] It is a compound that has [a certain characteristic].

[0124] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc), or pharmaceutically acceptable salts thereof, have the following structure: [ka] It is a compound that has [a certain characteristic].

[0125] In some embodiments, compounds of formulas (J), (II), (IIa), (IIb), and / or (IIc) have the following structure: [ka] It is a compound that has [a certain characteristic].

[0126] In some embodiments, the compound of formula (J), or a pharmaceutically acceptable salt thereof, is of formula (III): [ka] or represented by a pharmaceutically acceptable salt thereof, in the formula, Each R 1 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 1a , -C(O)OR 1a ,-OC(O)R 1a ,-C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R1a )C(O)(OR 1b ), -S(O)R 1a -S(O)2R 1a -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a ,-S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 The alkyl groups are aryl, heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. 1c Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R 1d Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 1e Replaced by; Each R 1a and R 1b These are independently hydrogen or a C1-C6 alkyl group; Each R 1c These are independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, and -NR. 1c1 R 1c2 It is OH or -CN; Each R 1c1 and R 1c2 These are independently hydrogen or a C1-C6 alkyl group; Each R 1d These are independently deuterium, C3-C8 cycloalkyl, heterocycloalkyl, and C6-C 10 It is an aryl or heteroaryl; Each R 1eThese are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN; Alternatively, two R atoms on adjacent carbon atoms 1 The groups, together with the atoms to which they are bonded, form 0, 1, 2, 3, 4, 5, or 6 halogens, C1-C4 alkyls, OH, or C5-C8 cycloalkyls or heterocycloalkyls substituted with -CN; L is -C1-C4 alkylene-, -(C1-C4 alkylene)-O-, or -O-; R 2 This is 0, 1, 2, 3, or 4 R 2a It is a heteroaryl substituted with; Each R 2a These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 2b , -C(O)OR 2b ,-OC(O)R 2b ,-C(O)N(R 2b )(R 2c ), -N(R 2b )C(O)(R 2c ), -S(O)2R 2b -S(O)2N(R 2b )(R 2c ), -N(R 2b )(R 2c ), OH, -CN, or -NO2; Each R 2b and R 2c These are independently hydrogen or a C1-C6 alkyl group; Each R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 3a , -C(O)OR 3a ,-OC(O)R3a ,-C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a -S(O)2R 3a -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a ,-S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 The alkyl groups are aryl, heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. 3c Substituted with, each alkoxy has 0, 1, 2, or 3 R 3d Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 3e It will be replaced by; or Two R atoms on the same carbon atom 3 These together represent an oxo group; Each R 3a and R 3b These are independently hydrogen or a C1-C6 alkyl group; Each R 3c These are independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, and -NR. 3c1 R 3c2 It is OH or -CN; Each R 3c1 and R 3c2 These are independently hydrogen or a C1-C6 alkyl group; Each R 3d These are independently C3-C8 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; Each R 3e These are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, or C1-C6 haloalkoxy; R 4 is hydrogen or a C1-C6 alkyl group; Subscript n is 0, 1, 2, 3, or 4; Subscript q is 0, 1, 2, 3, or 4; During the ceremony, Each heterocycloalkyl is a 3- to 8-membered ring containing 1 to 4 heteroatoms that are N, O, or S; Each heteroaryl is a 5-6 membered ring containing 1-4 heteroatoms that are N, O, or S.

[0127] In some embodiments, the compound of formula (J) or formula (III) is formula (IIIa): [ka] or represented by a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, R 3 , n and R 4 These, both individually and in combination, are as described in the Classes and Subclasses of this Specified Specified.

[0128] In some embodiments, a compound of formula (J), (III), and / or (IIIa), or a pharmaceutically acceptable salt thereof, is formula (IIIb): [ka] or represented by a pharmaceutically acceptable salt thereof, where R 1 , q, R2 , L, R 3 and R 4 These, both individually and in combination, are as described in the Classes and Subclasses of this Specified Specified.

[0129] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, base [ka] Structure: [ka] It holds.

[0130] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 1 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 It is an aryl or heteroaryl, and each alkyl has 0, 1, 2, or 3 R 1c Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R 1d It is substituted with; or two R on adjacent carbons 1 These atoms combine with the atoms to which they are bonded to form C5-C8 cycloalkyl or heterocycloalkyl groups.

[0131] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 1These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C 10 It is an aryl or heteroaryl, and each alkyl group has 0 or 1 R 1c Substituted with, each alkoxy and alkynyl has 0 or 1 R 1d It is substituted with; or two R on adjacent carbons 1 These atoms combine with the atoms to which they are bonded to form C5-C8 cycloalkyl or heterocycloalkyl groups.

[0132] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 1a and R 1b These are independently hydrogen or a C1-C4 alkyl group.

[0133] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 1c Halogen, -NR 1c1 R 1c2 It is either OH or -CN.

[0134] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 1d These are, independently, heteroaryl compounds.

[0135] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 1e These are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, or -CN.

[0136] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 1 Independently, these are -CH3, -CH2CH3, -C(CH3)3, -OCH3, -CH2CH3, -OCH(CH3)2, -OCH2-pyridyl, -C(CH3)2OH, F, Cl, Br, -CF3, -OCHF2, -OCF3, -OCH2CF3, -C(CH3)2CH2OH, -OH, cyclopropyl, cyclopropyloxy, cyclobutyloxy, phenyl, or pyrazolyl; or two R on adjacent carbons 1 These combine with the atoms to which they are bonded to form cyclopentyl, cyclohexyl, dihydrofuran, tetrahydrofuran, methyltetrahydrofuran, 1,3-dioxol, dihydro-1,3-oxazine, or methyldihydrofuran. In some embodiments, two R atoms on adjacent carbon atoms 1 When combined, [ka] It forms.

[0137] In some embodiments of the compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, L is -CH2-, -CH2O-, or -O-.

[0138] In some embodiments of the compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, L is -CH2-.

[0139] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, R 2 is 0, 1, or 2 R 2aThese are pyrrolyl, furyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidyl, or pyrazinyl, each substituted by the respective.

[0140] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 2a These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN.

[0141] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 2b and R 2c These are independently hydrogen or a C1-C4 alkyl group.

[0142] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, R 2 teeth, [ka] That is the case.

[0143] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, R 2 teeth, [ka] That is the case.

[0144] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 3These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 3a , -C(O)OR 3a ,-OC(O)R 3a ,-C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -S(O)2R 3a -S(O)2N(R 3a )(R 3b ), OH, -CN, C3-C8 cycloalkyl, or heterocycloalkyl.

[0145] In some embodiments, compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, have two R atoms on the same carbon atom. 3 However, it is a compound, or a pharmaceutically acceptable salt thereof, that together represents an oxo group.

[0146] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 3a and R 3b These are independently hydrogen or a C1-C4 alkyl group.

[0147] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 3c Halogen, -NR 3c1 R 3c2 It is either OH or -CN.

[0148] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 3d These are, independently, heteroaryl compounds.

[0149] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 3e These are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 haloalkyl.

[0150] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 3 These are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, or C3-C8 cycloalkyl.

[0151] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 3 These are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, or C3-C6 cycloalkyl.

[0152] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, each R 3 These are independently Me, OMe, OEt, CHF2, CF3, OCHF2, OCF3, F, Br, CN, or cyclopropyl.

[0153] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, R 4 is hydrogen or a C1-C4 alkyl group. In some embodiments, R 4 is Me, Et, or iPr. In some embodiments, R 4 It is hydrogen.

[0154] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, subscript q is 1, 2, or 3.

[0155] In some embodiments of compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, subscript n is 1 or 2.

[0156] In some embodiments, the compounds of formula (J), (III), (IIIa), and / or (IIIb), or pharmaceutically acceptable salts thereof, are compounds having the structures of the compounds shown in Table 3, or pharmaceutically acceptable salts thereof. [Table 3-1] [Table 3-2] [Table 3-3]

[0157] In some embodiments, the compound of formula (J) is of formula (IV): [ka] or represented by a pharmaceutically acceptable salt thereof, in the formula, Each R 1 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 1a , -C(O)OR 1a ,-OC(O)R 1a ,-C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a -S(O)2R 1a -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a ,-S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 The alkyl groups are aryl, heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. 1c Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R 1d Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 1e Replaced by; Each R 1a and R 1b These are independently hydrogen or a C1-C6 alkyl group; Each R 1c These are independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, and -NR. 1c1 R 1c2 It is OH or -CN; Each R 1c1 and R 1c2 These are independently hydrogen or a C1-C6 alkyl group; Each R 1d These are independently deuterium, C3-C8 cycloalkyl, heterocycloalkyl, and C6-C 10 It is an aryl or heteroaryl; Each R1e These are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN; Alternatively, two R atoms on adjacent carbon atoms 1 The groups, together with the atoms to which they are bonded, form 0, 1, 2, 3, 4, 5, or 6 halogens, C1-C4 alkyls, OH, or C5-C8 cycloalkyls or heterocycloalkyls substituted with -CN; L is -C1-C4 alkylene-, -(C1-C4 alkylene)-O-, or -O-; R 2 This is 0, 1, 2, 3, or 4 R 2a It is a heteroaryl substituted with; Each R 2a These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 2b , -C(O)OR 2b ,-OC(O)R 2b ,-C(O)N(R 2b )(R 2c ), -N(R 2b )C(O)(R 2c ), -S(O)2R 2b -S(O)2N(R 2b )(R 2c ), -N(R 2b )(R 2c ), OH, -CN, or -NO2; Each R 2b and R 2c These are independently hydrogen or a C1-C6 alkyl group; Y is CH, CR 3 , or N; Each R 3These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 3a , -C(O)OR 3a ,-OC(O)R 3a ,-C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a -S(O)2R 3a -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a ,-S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 The alkyl groups are aryl, heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. 3c Substituted with, each alkoxy has 0, 1, 2, or 3 R 3d Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 3e Replaced by; Two R atoms on the same carbon atom 3 These together represent an oxo group; Each R 3a and R3b These are independently hydrogen or a C1-C6 alkyl group; Each R 3c These are independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, and -NR. 3c1 R 3c2 It is OH or -CN; Each R 3c1 and R 3c2 These are independently hydrogen or a C1-C6 alkyl group; Each R 3d These are independently C3-C8 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; Each R 3e These are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, or C1-C6 haloalkoxy; R 4 is hydrogen or a C1-C6 alkyl group; Subscript n is 0, 1, 2, 3, or 4; Subscript q is 0, 1, 2, 3, or 4; During the ceremony, Each heterocycloalkyl is a 3- to 8-membered ring containing 1 to 4 heteroatoms that are N, O, or S; Each heteroaryl is a 5-6 membered ring containing 1-4 heteroatoms that are N, O, or S.

[0158] In some embodiments, a compound of formula (J), formula (IV), or a pharmaceutically acceptable salt thereof is formula (IVa): [ka] or represented by a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, R 3 , n, and R 4 Y is, both individually and in combination, as described in the Classes and Subclasses of this Specified, where Y is N, CH, or CR. 3 That is the case.

[0159] In some embodiments, a compound of formula (J), (IV), and / or (IVa), or a pharmaceutically acceptable salt thereof, is formula (IVb): [ka] or represented by a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, R 3 , and R 4 Y is, both individually and in combination, as described in the Classes and Subclasses of this Specified, where Y is N, CH, or CR. 3 That is the case.

[0160] In some embodiments, the compounds of formula (J), (IV), (IVa), and / or (IVb), or pharmaceutically acceptable salts thereof, are compounds, or pharmaceutically acceptable salts thereof, where Y is N. In some embodiments, Y is CR 3 In some embodiments, Y is CH.

[0161] In some embodiments, compounds of formula (J), (IV), (IVa), and / or (IVb) are derived from formula (IVc): [ka] or represented by a pharmaceutically acceptable salt thereof, where R 1 , q, R 2 , L, R 3 , and R 4 These, both individually and in combination, are as described in the Classes and Subclasses of this Specified Specified.

[0162] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, the base [ka] Structure: [ka] It has, in the formula, R 1 These are as described in the Classes and Subclasses of this Specified Specification.

[0163] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 1 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 It is an aryl or heteroaryl, and each alkyl has 0, 1, 2, or 3 R 1c Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R 1d It is substituted with; or two R on adjacent carbons 1 These atoms combine with the atoms to which they are bonded to form C5-C8 cycloalkyl or heterocycloalkyl groups.

[0164] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 1 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C 10 It is an aryl or heteroaryl, and each alkyl group has 0 or 1 R 1c Substituted with, each alkoxy and alkynyl has 0 or 1 R 1dIt is substituted with; or two R on adjacent carbons 1 These atoms combine with the atoms to which they are bonded to form C5-C8 cycloalkyl or heterocycloalkyl groups.

[0165] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 1a and R 1b These are independently hydrogen or a C1-C3 alkyl group.

[0166] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 1c Halogen, -NR 1c1 R 1c2 It is either OH or -CN.

[0167] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 1d These are, independently, heteroaryl compounds.

[0168] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 1e These are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, or -CN.

[0169] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 1These are independently -CH3, -CH2CH3, -C(CH3)3, -OCH3, -CH2CH3, -OCH(CH3)2, -C(CH3)2OH, -C(CH3)2CH2OH, -C(CH3)(CH2CH3)OH, F, Cl, Br, -CF3, -OCHF2, -OCF3, -OCH2CF3, cyclopropyl, cyclopropyloxy, cyclobutyloxy, [ka] is it; or Two R on adjacent carbons 1 These combine with the atoms to which they are bonded to form cyclopentyl, cyclohexyl, dihydrofuran, tetrahydrofuran, methyltetrahydrofuran, 1,3-dioxol, dihydro-1,3-oxazine, or methyldihydrofuran. In some embodiments, two R atoms on adjacent carbon atoms 1 When combined, [ka] It forms.

[0170] In some embodiments of compounds of formulas (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, L is -CH2-, -CH2O-, or -O-.

[0171] In some embodiments of compounds of formulas (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, L is -CH2-.

[0172] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, R 2 is 0, 1, or 2 R 2aThese are pyrrolyl, furyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidyl, or pyrazinyl, each substituted by the respective.

[0173] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 2a These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN.

[0174] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 2b and R 2c These are independently hydrogen or a C1-C4 alkyl group.

[0175] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, R 2 teeth, [ka] That is the case.

[0176] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, R 2 teeth, [ka] That is the case.

[0177] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R3 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(O)R 3a , -C(O)OR 3a ,-OC(O)R 3a ,-C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -S(O)2R 3a -S(O)2N(R 3a )(R 3b ), OH, -CN, C3-C8 cycloalkyl, or heterocycloalkyl.

[0178] In some embodiments, compounds of formulas (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, have two R atoms on the same carbon atom. 3 However, it is a compound, or a pharmaceutically acceptable salt thereof, that together represents an oxo group.

[0179] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 3a and R 3b These are independently hydrogen or a C1-C4 alkyl group.

[0180] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 3c Halogen, -NR 3c1 R 3c2 It is either OH or -CN.

[0181] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 3d These are, independently, heteroaryl compounds.

[0182] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 3e These are independently C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 haloalkyl.

[0183] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 3 These are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, or C3-C8 cycloalkyl.

[0184] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 3 These are independently C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, or C3-C6 cycloalkyl.

[0185] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, each R 3 These are independently Me, Ome, CHF2, CF3, OCHF2, OCF3, or cyclopropyl.

[0186] In some embodiments of compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), and their pharmaceutically acceptable salts, R 4 is hydrogen or a C1-C4 alkyl group. In some embodiments, R 4 is Me, Et, or iPr. In some embodiments, R 4 It is hydrogen.

[0187] In some embodiments of compounds of formulas (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, subscript q is 1, 2, or 3.

[0188] In some embodiments of compounds of formulas (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, subscript n is 0 or 1.

[0189] In some embodiments, the compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, are compounds having the structures of the compounds shown in Table 4, or pharmaceutically acceptable salts thereof. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0190] In some embodiments, compounds of formulas (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, 4-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-3-methoxybenzamide(14)e 4-((1H-pyrazole-1-yl)methyl)-3-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)benzamide 4-((1H-pyrazole-1-yl)methyl)-N-((2-ethoxy-6-methoxyphenyl)sulfonyl)-3-methoxybenzamide(67), 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide (203), 5-((1H-pyrazole-1-yl)methyl)-N-((5-ethyl-2-methoxyphenyl)sulfonyl)-6-methoxypicolinamide (204), 5-((1H-pyrazole-1-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)picolinamide (224), 5-((1H-pyrazole-1-yl)methyl)-6-cyclopropyl-N-((2,6-dimethoxyphenyl)sulfonyl)picolinamide (229), 5-((1H-pyrazole-1-yl)methyl)-N-((3-chloro-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide (241), 5-((1H-pyrazole-1-yl)methyl)-N-((4-bromo-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide (285), 4-((1H-pyrazole-1-yl)methyl)-3-methoxy-N-((2-methyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)benzamide (314), Selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0191] In some embodiments, the compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, are 4-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-3-methoxybenzamide, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, are 4-((1H-pyrazole-1-yl)methyl)-N-((2-ethoxy-6-methoxyphenyl)sulfonyl)-3-methoxybenzamide, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, are 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, are 5-((1H-pyrazole-1-yl)methyl)-N-((5-ethyl-2-methoxyphenyl)sulfonyl)-6-methoxypicolinamide, or pharmaceutically acceptable salts thereof.In some embodiments, the compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, are 5-((1H-pyrazole-1-yl)methyl)-6-cyclopropyl-N-((2,6-dimethoxyphenyl)sulfonyl)picolinamide, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, are 5-((1H-pyrazole-1-yl)methyl)-N-((4-bromo-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of formula (J), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, are 4-((1H-pyrazole-1-yl)methyl)-3-methoxy-N-((2-methyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)benzamide, or pharmaceutically acceptable salts thereof.

[0192] IV. Composition In some embodiments, the pharmaceutical composition of the present invention comprises compounds of the present invention, such as compounds of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0193] The compounds of the present invention may be used as monochemical agents or as part of pharmaceutical compositions in which the compounds are mixed with various pharmacologically acceptable excipients.

[0194] The compounds of the present invention are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared using procedures well known in the field of pharmaceutical technology and contain at least one compound of the present invention. The pharmaceutical compositions of this patent application contain one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, pharmaceutically acceptable excipients are approved by regulatory authorities or are generally considered safe for use in humans or animals. Examples of pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, flow enhancers and lubricants, preservatives, buffers, chelating agents, polymers, gelling agents, viscous agents, and solvents.

[0195] The pharmaceutical composition may be administered orally, parenterally, or by inhalation. Examples of parenteral administration include injection, transdermal, transmucosal, intranasal, and transpulmonary administration.

[0196] Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohol, polyethylene glycol, peanut oil, olive oil, gelatin, lactose, clay, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylenes.

[0197] The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliaries, humectants, suspending agents, preservatives, buffers, sweeteners, flavoring agents, colorants, or any combination thereof.

[0198] The pharmaceutical composition may be in conventional forms, such as tablets, capsules, solutions, suspensions, injections, or products for topical application. Furthermore, the pharmaceutical composition of the present invention may be formulated to give a desired release profile.

[0199] The compounds of the present invention may be administered in pure form or in a suitable pharmaceutical composition using any of the acceptable routes of administration of the pharmaceutical composition. The route of administration may be any route that effectively delivers the active compound of this patent application to a suitable or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, cutaneous, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, ​​intramuscular, or topical administration.

[0200] Examples of solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), sugar-coated formulations (containing active ingredients in powder or pellet form), lozenges, and troches.

[0201] Examples of liquid formulations include, but are not limited to, syrups, emulsions, and sterile injection solutions, such as suspensions or solutions.

[0202] Topical dosage forms of the compound include ointments, pastes, creams, lotions, powders, solutions, eye drops or ear drops, and impregnation dressings, which may contain appropriate conventional additives, such as preservatives and solvents to aid in drug penetration.

[0203] The pharmaceutical composition of this patent application can be prepared by prior art known in the literature.

[0204] Appropriate doses of compounds for use in the treatment of diseases or disorders described herein can be determined by those skilled in the art. The therapeutic dose is generally determined by dose-determination studies in humans, based on preliminary evidence obtained from animal studies. The dose must be sufficient to produce the desired therapeutic effect without causing undesirable side effects. Methods of administration, dosage forms, and appropriate pharmaceutical excipients can also be readily used and modified by those skilled in the art. All changes and modifications are assumed to be within the scope of this patent application.

[0205] In some embodiments, the pharmaceutical composition of the present invention is a pharmaceutical composition comprising a compound of formula (J) as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier or diluent). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compositions described herein may be associated with a pharmaceutically acceptable excipient (e.g., a carrier or diluent), diluted with a carrier, or encapsulated in a carrier which may be in the form of a capsule, sachet, paper, or other container.

[0206] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral composition may also contain auxiliaries, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0207] Injectable formulations, such as sterile aqueous or oily suspensions for injection, can be formulated according to known techniques using appropriate dispersants or wetting and suspending agents. The sterile injectable formulation may also be a sterile injection solution, suspension, or emulsion of a non-toxic, parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. Acceptable vehicles and solvents include water, Ringer's solution, USP, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils have conventionally been used as solvents or suspensions. For this purpose, any non-irritating non-volatile oil, including synthetic mono- or diglycerides, may be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectable formulations.

[0208] To prolong the effects of a drug, it is often desirable to slow down its absorption from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low solubility in water. The absorption rate of the drug then depends on its dissolution rate, which may, in turn, depend on the crystal size and crystalline form. Alternatively, slowing down the absorption of parenterally administered drug forms is achieved by dissolving or suspending the drug in an oil vehicle.

[0209] Compositions for rectal or vaginal administration may be suppositories, which may be prepared by mixing the compounds of this application with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus dissolves in the rectal or vaginal cavity to release the active compounds.

[0210] Similar types of solid compositions can also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0211] The active compound may also be in a microencapsulated form containing one or more excipients, as described above. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules may be prepared using coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical technology. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also, as is common practice, include further substances other than inert diluents, such as tableting lubricants and other tableting aids, including but not limited to magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0212] Dosage forms for topical or transdermal administration of the compounds of this application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any required preservatives or buffers. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also intended to be within the scope of this application.

[0213] In addition to the active compounds of this application, the ointments, pastes, creams and gels may also contain excipients such as animal fats and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0214] The powders and sprays may contain, in addition to the compounds of this application, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder or mixtures thereof. The sprays may further contain conventional propellants, such as hydrochlorofluorocarbons.

[0215] Transdermal patches offer the additional advantage of providing controlled delivery of compounds into the body. Such dosage forms can be prepared by dissolving or distributing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled either by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0216] The compounds and pharmaceutical compositions of this disclosure may be administered by any method of administration for therapeutic purposes. These methods include systemic or topical administration, such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration.

[0217] Depending on the intended method of administration, the compounds or pharmaceutical compositions of this disclosure may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., and may sometimes be consistent with conventional pharmaceutical practices in unit doses. Similarly, they may be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, and all forms of use are well known to those skilled in the pharmaceutical art.

[0218] An exemplary pharmaceutical composition comprises one or more compounds of the present disclosure and a pharmaceutically acceptable carrier, for example, but not limited to, a) diluents, for example, purified water, triglyceride oils, for example, hydrogenated or semi-hydrogenated vegetable oils, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil such as EPA or DHA, or esters or triglycerides or mixtures thereof, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine, b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, Sodium acetate, sodium chloride, and / or polyethylene glycol; and, in the case of tablets, c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, e.g., glucose or beta-lactose, corn sweeteners, natural and synthetic rubbers, e.g., acacia, tragacanth, or sodium alginate, waxes, and / or polyvinylpyrrolidone; d) disintegrants, e.g., starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavorings, and sweeteners; f) emulsifiers or dispersants, e.g., Tween® Tablets and gelatin capsules containing 80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafac, Labrafil, Peceol, Transcutol, Capmul MCM, Capmul PG-12, Captex 355, Gelucire, Vitamin E TGPS, or other acceptable emulsifiers, and / or g) agents that enhance the absorption of the compound, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200.

[0219] Liquid compositions, particularly those for injection, can be prepared, for example, by dissolution, dispersion, etc. For example, one or more compounds of the present disclosure may be dissolved in or mixed with a pharmaceutically acceptable solvent, such as water, saline solution, aqueous dextrose solution, glycerol, ethanol, etc., to form an isotonic solution or suspension for injection. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the compounds of the present disclosure.

[0220] One or more compounds or compositions of this disclosure may be delivered by parenteral administration. Parenteral injection administration is generally used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectable preparations may be prepared in any conventional form, either as a liquid solution or suspension, or as a solid suitable for dissolution in liquid before injection.

[0221] In some embodiments, the pharmaceutical composition of the present invention comprises a compound of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier (e.g., a pharmaceutically acceptable carrier or diluent).

[0222] In some embodiments, the pharmaceutical compositions of the present invention, comprising compounds of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, are intended for use as pharmaceuticals.

[0223] In some embodiments, the pharmaceutical compositions of the present invention, comprising compounds of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, are for treating diseases or disorders that are dependent on or mediated by KAT6A.

[0224] v. Administration The compounds of this disclosure can be administered to an individual for a desired period or duration, such as at least about one week, at least about two weeks, at least about three weeks, one month, at least about two months, at least about three months, at least about six months, or at least about twelve months or longer, according to an effective dosing regimen. In one variation, the compound is administered daily or intermittently for the required duration, up to the lifetime of the individual.

[0225] The dosage or frequency of administration of the compounds disclosed herein may be adjusted during the course of treatment at the discretion of the administering physician.

[0226] The compound can be administered to individuals such as humans in an effective dose.

[0227] The compounds of the present invention can be administered by any useful route and means, for example, by oral or parenteral (e.g., intravenous) administration. The therapeutically effective dose of the compounds of the present invention is about 0.00001 mg / kg body weight to about 10 mg / kg body weight per day, for example, about 0.0001 mg / kg body weight to about 10 mg / kg body weight per day, or for example, about 0.001 mg / kg body weight to about 1 mg / kg body weight per day, or for example, about 0.01 mg / kg body weight to about 1 mg / kg body weight per day, or for example, about 0.05 mg / kg body weight to about 0.5 mg / kg body weight per day.

[0228] The therapeutically effective dose of the compound of the present invention is approximately 0.01 mg to approximately 1000 mg per dose, for example, approximately 0.01 mg to approximately 100 mg per dose, or for example, approximately 0.1 mg to approximately 100 mg per dose, or for example, approximately 1 mg to approximately 100 mg per dose, or for example, approximately 1 mg to approximately 10 mg per dose. Other therapeutically effective doses of the compound of the present invention are approximately 1 mg per dose, or approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or approximately 100 mg per dose. Other therapeutically effective doses of the compound of the present invention are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dose may be administered hourly, daily, or weekly. For example, a single dose may be administered once every 1, 2, 3, 4, 6, 8, 12, or 16 hours, or once every 24 hours. A single dose may also be administered once every 1, 2, 3, 4, 5, or 6 days, or once every 7 days. A single dose may also be administered once every 1, 2, or 3 weeks, or once every 4 weeks. In certain embodiments, a single dose may be administered once a week. A single dose may also be administered once a month.

[0229] VI. Methods and / or Uses In some embodiments, the present invention is a method for treating a disease or disorder, comprising administering a therapeutically effective amount of a compound of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, to a subject in need, such as a human.

[0230] In some embodiments, the use of the present invention is the use of compounds of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, for the manufacture of agents for treating diseases or conditions, such as cancer.

[0231] In some embodiments, the compounds for use in the present invention are compounds of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, for use in the treatment of diseases or disorders mediated by KAT6A.

[0232] In some embodiments, the present invention is a method for inhibiting KAT6A in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the present invention provides a method for treating a KAT6A-mediated disease or disorder in a subject, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the compounds for use in the present invention are compounds of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc) for use as pharmaceuticals, or pharmaceutically acceptable salts thereof.

[0235] In some embodiments, the present invention provides a method for modulating KAT6A in a subject requiring such modification, comprising administering to the subject a therapeutically effective amount of a compound of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, the use of the present invention is the use of a pharmaceutical composition comprising a compound of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for treating a disease or disorder mediated by KAT6A. In some embodiments, the use of a pharmaceutical composition comprises a compound of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for treating cancer mediated by KAT6A.

[0237] In some embodiments, the use of the present invention is the use of compounds of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, in the manufacture of agents for treating or preventing diseases or disorders mediated by KAT6A.

[0238] In some embodiments, the disease or disorder that depends on or is mediated by KAT6A is cancer.

[0239] In some embodiments, cancers include cerebral glioma, glioblastoma, astrocytoma, pleomorphic cancer, Bannayan-Zonana syndrome, Cowden disease, Lhermitt-Dukuro disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell carcinoma, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, tubular adenocarcinoma, adenosquamous cell carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, The following cancers are selected: pablastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, megakaryoblastic leukemia, multiple myeloma, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, vulvar cancer, uterine cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor (GIST), neuroendocrine carcinoma, testicular cancer, and virus-related cancers.

[0240] In some embodiments, the use of the present invention is for cerebral glioma, glioblastoma, astrocytoma, pleomorphic, Bannayan-Zonana syndrome, Cowden disease, Lhermitt-Dukuro disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell carcinoma, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, tubular adenocarcinoma, adenosquamous cell carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, megakaryoblastic leukemia, multiple myeloma, acute megakaryoblastic leukemia, The use of compounds of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, in the manufacture of agents for the treatment of cancers selected from promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, vulvar cancer, uterine cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor (GIST), neuroendocrine cancer, testicular cancer, and virus-associated cancers.

[0241] In some embodiments, the compounds for use in the present invention are compounds of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, for use in the treatment of diseases or disorders mediated by KAT6A.

[0242] In some embodiments, the compounds for use in the present invention are used to treat cerebral glioma, glioblastoma, astrocytoma, pleomorphism, Bannayan-Zonana syndrome, Cowden disease, Lhermitt-Dukuro disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell carcinoma, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, tubular adenocarcinoma, adenosquamous cell carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, megakaryoblastic leukemia, multiple myeloma, and acute megakaryoblastic leukemia. Compounds of formulas (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), and / or (IVc), or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of cancers selected from among cystic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, vulvar cancer, uterine cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumors (GIST), neuroendocrine cancer, testicular cancer, and virus-associated cancers.

[0243] In some embodiments, this disclosure provides compounds for use in combination with other compounds or biological elements for the treatment of a disease or disorder. Appropriate combinations and dosages of compounds in combination therapies used in treating the diseases or disorders described herein can be determined by those skilled in the art. Combination therapies relating to the compounds of this disclosure can be used for the treatment of a disease or disorder. In some embodiments, the disease or disorder is cancer.

[0244] In some embodiments, the Disclosure provides compounds for use in methods of treating a disease or disorder in a subject, the method comprising administering the compound to the subject in combination with, or alternately with, an estrogen receptor antagonist or a partial estrogen receptor antagonist. As described herein, an estrogen receptor “partial” antagonist refers to an estrogen receptor antagonist that exhibits antagonist activity in an estrogen receptor antagonist assay, but also exhibits estrogen receptor agonist activity detectable in an estrogen receptor agonist assay.

[0245] In some embodiments, the Disclosure provides compounds for use in a method of treating a disease or disorder in a subject, the method comprising administering the compound to the subject in combination with, or alternately with, a selective estrogen receptor modifier (SERM). In some embodiments, the SERM is tamoxifen, endoxifen, raloxifen, toremifene, rasofoxifen, ospemifene, elastrant, or bazedoxifen.

[0246] In some embodiments, the Disclosure provides compounds for use in a method of treating a disease or disorder in a subject, the method comprising administering the compound to the subject in combination with, or alternately with, a selective estrogen receptor degrader. In some embodiments, SERD is fulvestrant, camizestrant, parazestrant, imurunestrant, elastrant, or redestrant.

[0247] In some embodiments, the Disclosure provides compounds for use in a method of treating a disease or disorder in a subject, the method comprising administering the compound to the subject in combination with, or alternately with, a full estrogen receptor antagonist (CERAN). In some embodiments, CERAN is fulvestrant or parazestrant. In some embodiments, CERAN is fulvestrant. In some embodiments, CERAN is parazestrant.

[0248] In some embodiments, the Disclosure provides compounds for use in a method of treating a disease or disorder in a subject, the method comprising administering the compound to the subject in combination with, or alternately with, an additional anticancer agent. In some embodiments, the additional anticancer agent is selected from HER2 inhibitors, mTOR inhibitors, CDK4 / 6 inhibitors, CDK2 selective inhibitors, CDK4 selective inhibitors, PI3 kinase inhibitors, PIK3CA inhibitors, aromatase inhibitors, antibodies or inhibitors of PD-1, PD-L1, or CTLA-4, antibodies or inhibitors of EGFR, PGFR, or IGFR, USP1 inhibitors, or AKT inhibitors.

[0249] In some embodiments, the additional anticancer agent is a CDK2 inhibitor. In some embodiments, the CDK2 inhibitor is PF-07104091 (tagtocyclib). In some embodiments, the additional anticancer agent is a HER2 inhibitor. In some embodiments, the HER2 inhibitor is selected from tucatinib, trastuzumab, pertuzumab, ado-trastuzumab, trastuzumab emtansine, ado-trastuzumab emtansine, trastuzumab deruxtecan, pertuzumab, lapatinib, and neratinib.

[0250] In some embodiments, the additional anticancer agent is an mTOR inhibitor. In some embodiments, the mTOR inhibitor is selected from siberolimus, sirolimus, temsirolimus, and LY3023414.

[0251] In some embodiments, the additional anticancer agent is a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, abemaciclib, ribociclib, rerocyclib, trilaciclib, and SHR6390.

[0252] In some embodiments, the additional anticancer agent is a CDK4 selective inhibitor. In some embodiments, the CDK-4 selective inhibitor is PF-07220060 (atelmociclib).

[0253] In some embodiments, the additional anticancer agent is a PI3 kinase inhibitor. In some embodiments, the PI3 kinase inhibitor is selected from perifosine, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145.

[0254] In some embodiments, the PI3 kinase inhibitor is a PIK3CA inhibitor. In some embodiments, the PIK3CA inhibitor is selected from alpelisib, taselicib, LY3023414, inavolicib, STX-478, RLY-2608, LOXO-783, OKI-219, and TOS-358.

[0255] In some embodiments, the additional anticancer agent is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is selected from aminoglutethimide, testactone, anastrozole, letrozole, exemestane, borozol, formestan, fadrozol, 4-hydroxyandrostenedione, 1,4,6-androstatriene-3,17-dione, and 4-androsten-3,6,17-trione.

[0256] In some embodiments, the additional anticancer agent is an antibody or inhibitor of PD-1, PD-L1, or CTLA-4.

[0257] In some embodiments, the additional anticancer agent is an antibody or inhibitor of EGFR, PGFR, or IGFR. In some embodiments, the anticancer agent is erlotinib or gefitinib.

[0258] In some embodiments, the additional anticancer agent is a USP1 inhibitor.

[0259] In some embodiments, the additional anticancer agent is an AKT inhibitor. In some embodiments, the additional anticancer agent is capivacertib. [Examples]

[0260] VII. Examples While specific embodiments of the present invention have been discussed, this specification is illustrative and not restrictive. Many variations of the present invention will become apparent to those skilled in the art in consideration of this specification and the claims below. The full scope of the present invention should be determined by referring to the claims together with the full scope of their equivalents, and this specification together with such variations.

[0261] The following abbreviations refer to the following definitions: DMSO - Dimethyl sulfoxide; THF - Tetrahydrofuran; DCM - Dichloromethane; LiHMDS - Lithium bis(trimethylsilyl)amide; Pd(Amphos)Cl2-Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); NH4Cl - Ammonium chloride; Na2SO4- Sodium sulfate; BPO - Benzoyl peroxide; br - broad; °C - Celsius (degrees Celsius); DMSO-d6-Deuterated Dimethyl Sulfoxide; DMF - N,N-dimethylformamide; Et - ethyl; g - grams; h - time; 1 H - proton; iPr-isopropyl; LC-MS - Liquid Chromatography-Mass Spectrometry; Me - methyl; MHz - megahertz (frequency); MS - mass spectrometry; Ms-methanesulfonyl; M - molar concentration; mmol - millimoles; mL - milliliter; min - minutes; mol - mole; M + / - - Molecular ion; m / z - Mass-to-charge ratio; NBS - N-bromosuccinimide; NMR - nuclear magnetic resonance; ppm - parts per million; rt or RT - room temperature; RM - reaction mixture; br - broad; s - single line; d - double line; t - triple line; q - quadruple line; m - multiplet; dd - double line of double lines; TLC - Thin-layer chromatography; % - Percentage; and δ - delta.

[0262] a) Sulfonamide intermediate Intermediate 15: 2-Methoxy-4-(1H-pyrazole-1-yl)benzenesulfonamide [ka] Step 1: 1-(3-methoxyphenyl)-1H-pyrazole

[0263] To a degassed solution of 1-iodo-3-methoxybenzene (10 g, 42.7 mmol) in 1,4-dioxane (100 mL), 1H-pyrazole (3.49 g, 51.2 mmol), CuI (0.81 g, 4.2 mmol), and K3PO4 (18.1 g, 85.4 mmol) were added at room temperature. The reaction mixture was then heated at 90 °C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by CombiFlash® chromatography using 20% ​​ethyl acetate in hexane to obtain the title compound (6.5 g, 87.3%). LC-MS: 175.1 [M+H] + .

[0264] Step 2: 2-Methoxy-4-(1H-pyrazole-1-yl)benzenesulfonyl chloride

[0265] To a solution of 1-(3-methoxyphenyl)-1H-pyrazole (2 g, 11.4 mmol) in chlorosulfonic acid (13.3 g, 114.8 mmol), thionyl chloride (1.6 g, 13.7 mmol) was added dropwise at 0°C. The reaction mixture was allowed to cool to room temperature and stirred for 1 hour. The reaction mixture was diluted with ice water and extracted by DCM. The organic layer was washed with saturated NaHCO3, dried over Na2SO4, and concentrated to obtain the title compound (1.2 g). LC-MS: 273.0 [M+H] + .

[0266] Step 3: 2-Methoxy-4-(1H-pyrazole-1-yl)benzenesulfonamide

[0267] To a solution of 2-methoxy-4-(1H-pyrazole-1-yl)benzenesulfonyl chloride (1.2 g, 4.4 mmol) in DCM (10 mL), 7 M methanolic ammonia was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, and concentrated to obtain the title compound (0.3 g). LC-MS: 254.0 [M+H] + .

[0268] Intermediate 16 The following intermediates 16, listed below, were prepared using appropriate reagents with appropriate modifications known to those skilled in the art, following the same procedure as described above for intermediate 15. [Table 21]

[0269] Intermediate 17: 4-(tert-butyl)-2-methoxybenzenesulfonamide [ka] Step 1: 4-(tert-butyl)-2-methoxybenzenesulfonic acid

[0270] To a solution of 1-(tert-butyl)-3-methoxybenzene (6 g, 36.5 mmol) in anhydrous DCM (90 mL), chlorosulfonic acid (5.1 g, 43.8 mmol) was added dropwise at 0°C for 15 minutes. The reaction mixture was then gradually warmed to room temperature and stirred overnight. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, and concentrated to obtain the title compound (5 g). LC-MS: 243.0 [MH] - .

[0271] Step 2: 4-(tert-butyl)-2-methoxybenzenesulfonyl chloride

[0272] To a solution of 4-(tert-butyl)-2-methoxybenzenesulfonic acid (5 g, 20.4 mmol) in 1,2-DCE (75 mL), PCl5 (8.5 g, 40.9 mmol) was added in small increments at 0°C. After the addition was complete, the reaction mixture was heated at 80°C for 16 hours. The reaction mixture was then cooled to room temperature and concentrated to obtain the crude compound. The crude compound was purified by CombiFlash® chromatography using 50% toluene in hexane to obtain the title compound (6.3 g, 74.3%).

[0273] Step 3: 4-(tert-butyl)-2-methoxybenzenesulfonamide

[0274] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. LC-MS: 244.1 [M+H] + .

[0275] Intermediate 18: 3-Methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonamide [ka] Step 1: 3-Methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride

[0276] To a stirred solution of 6-methoxy-1,2,3,4-tetrahydronaphthalene (0.5 g, 3.08 mmol) in DCM (15 mL), chlorosulfonic acid (1.07 g, 9.2 mmol) was added dropwise at 0°C. The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was then poured into ice-cold water and extracted with DCM. The organic layer was washed with aqueous NaHCO3 solution, dried over Na2SO4, and concentrated to obtain the title compound (0.52 g, 65%).

[0277] Step 2: 3-Methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonamide

[0278] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. LC-MS: 241.9 [M+H] + .

[0279] Intermediate 19~26f The intermediates listed in Table 5 were prepared using appropriate reagents with suitable modifications known to those skilled in the art, following the same procedure as described above for intermediate 18. In some cases, the procedure began with commercially available sulfonyl chloride components. [Table 5-1] [Table 5-2]

[0280] Intermediate 50: 6-Methoxy-2,3-dihydrobenzofuran-7-sulfonamide [ka] Step 1: 6-Methoxybenzofuran-3(2H)-one

[0281] To a solution of 6-hydroxybenzofuran-3(2H)-one (7.2 g, 48.62 mmol) in DMF (80 mL), K2CO3 (13.44 g, 97.25 mmol) and MeI (11.45 g, 80.71 mmol) were added at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with water and extracted with siRNA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was used in the next step without further purification (6.10 g, 88.60%). 1 H NMR (DMSO-d6, 400MHz): δ 7.53 (d, 1H), 6.83 (d, 1H), 6.71 (dd, 1H), 4.77 (s, 2H), 3.87 (s, 3H).

[0282] Step 2: 6-Methoxy-2,3-dihydrobenzofuran-3-ol

[0283] To a solution of 6-methoxybenzofuran-3(2H)-one (7.0 g, 42.64 mmol) in MeOH (80 mL), NaBH4 (3.22 g, 85.27 mmol) was added at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the title compound (6.20 g, 84.80%). 1H NMR (DMSO-d6, 400MHz): δ 7.23 (d, 1H), 6.46 (dd, 1H), 6.41 (s, 1H), 5.43 (d, 1H), 5.21 - 5.16 (m, 1H), 4.52 - 4.48 (m, 1H), 4.25 - 4.21 (m, 1H), 3.72 (s, 3H).

[0284] Step 3: 6-Methoxy-2,3-dihydrobenzofuran

[0285] To a solution of 6-methoxy-2,3-dihydrobenzofuran-3-ol (6.0 g, 48.62 mmol) in TFA (8.22 g, 72.21 mmol), triethylsilane (4.1 g, 36.10 mmol) was added at 0°C, and the mixture was heated at 70°C for 12 hours. The reaction mixture was poured into an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over solid sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel flash column chromatography using 10% ethyl acetate in hexane as the eluent to obtain the pure compound (1.40 g, 25.8%). 1 H NMR, DMSO-d6, 400MHz): δ 7.11 (d, 1H), 6.39 (d, 1H), 6.37 (s, 1H), 4.55 (t, 2H), 3.72 (s, 3H), 3.08 (t, 2H).

[0286] Step 4: 6-Methoxy-2,3-dihydrobenzofuran-7-thiol

[0287] To a solution of 6-methoxy-2,3-dihydrobenzofuran (1.40 g, 9.32 mmol) in THF (14 mL), n-BuLi (5.59 mL, 13.99 mmol) was slowly added dropwise, followed by the slow addition of TMEDA (0.10 g, 0.93 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred at the same temperature for 20 minutes. Sulfur powder (0.28 g, 8.39 mmol) in toluene (4 mL) solution was added to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 12 hours. The reaction product was quenched with 1N HCl solution and extracted with ethyl acetate. The combined organic layers were dried over solid sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel flash column chromatography using 15% ethyl acetate in hexane as the eluent to obtain the title compound (1.0 g, 58.86%). LC-MS: 181.0 [MH] - .

[0288] Step 5: 7-(benzylthio)-6-methoxy-2,3-dihydrobenzofuran

[0289] To a solution of 6-methoxy-2,3-dihydrobenzofuran-7-thiol (1.0 g, 5.48 mmol) in THF (10 mL), potassium t-butoxide (0.739 g, 6.58 mmol) was added, followed by benzyl chloride (0.69 g, 5.48 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel flash column chromatography using 5-15% ethyl acetate in hexane as the eluent to obtain the title compound (0.45 g, 30.11%). LC-MS: 273.0 [M+H] + .

[0290] Step 6: 6-Methoxy-2,3-dihydrobenzofuran-7-sulfonyl chloride

[0291] To a solution of 7-(benzylthio)-6-methoxy-2,3-dihydrobenzofuran (0.25 g, 0.98 mmol) in acetonitrile (3 mL), acetic acid (2 mL), and water (1 mL), DCDMH (0.21 g, 1.10 mmol) was added at 0°C and the mixture was stirred for 15 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 15-20% ethyl acetate in hexane as the eluent to obtain the title compound (0.17 g, 74.5%). 1 H NMR (DMSO-d6, 400MHz): δ 7.09 (d, 1H), 6.39 (d, 1H), 4.47 (t, 2H), 3.69 (s, 3H), 3.06 (t, 2H).

[0292] Step 7: 6-Methoxy-2,3-dihydrobenzofuran-7-sulfonamide

[0293] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. 1 H NMR (DMSO-d6, 400MHz): δ 7.31 (d, 1H), 6.96 (s, 2H), 6.56 (d, 1H), 4.59 (t, 2H), 3.81 (s, 3H), 3.11 (t, 2H).

[0294] Intermediate 51: 2-Methoxy-6-(1H-pyrazole-1-yl)benzenesulfonamide [ka] Step 1: 2-Methoxy-6-(1H-pyrazole-1-yl)benzenethiol

[0295] The title compound was prepared using the same procedure as described in step 4 of intermediate 50, with appropriate modifications and appropriate reagents. 1H NMR (CDCl3, 400MHz): δ 7.62 (d, 1H), 7.32 (t, 1H), 6.97 - 6.90 (m, 3H), 6.50 (d, 1H), 3.86 (s, 1H), 3.82 (s, 3H)

[0296] Step 2: 1-(2-(benzylthio)-3-methoxyphenyl)-1H-pyrazole

[0297] The title compound was prepared using the same procedure as described in step 5 of intermediate 50, with appropriate modifications and appropriate reagents. LC-MS: 297.1.1 [M+H] + .

[0298] Step 3: 2-Methoxy-6-(1H-pyrazole-1-yl)benzenesulfonyl chloride

[0299] The title compound was prepared using the same procedure as described in step 6 of intermediate 50, with appropriate modifications and appropriate reagents: LC-MS: 273.0 [M+H] + .

[0300] Step 4: 2-Methoxy-6-(1H-pyrazole-1-yl)benzenesulfonamide

[0301] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents: LC-MS: 254.0 [M+H]+.

[0302] Intermediate 52: 2-(pyridine-2-ylmethoxy)benzenesulfonamide [ka] Step 1: 2-((2-bromophenoxymethyl)pyridine

[0303] To a solution of 2-bromophenol (2 g, 11.56 mmol) and K2CO3 (3.19 g, 23.12 mmol) in acetonitrile (ACN, 20 mL), 2-(chloromethyl)pyridine (1.17 g, 13.87 mmol) was added and the mixture was stirred at 90°C for 12 hours. The reaction mixture was cooled to room temperature, diluted with SiO2, and washed with 2N NaOH solution (10 mL) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel flash column chromatography using 10-15% ethyl acetate in hexane as the eluent to obtain the title compound (2.8 g, 91.7%). LC-MS: 264.8 [M+H] +

[0304] Step 2: 2-((2-(benzylthio)phenoxy)methyl)pyridine

[0305] To a degassed solution of 2-((2-bromophenoxymethylpyridine) (2.8 g, 10.60 mmol), benzyl mercaptan (1.31 g, 10.60 mmol), N,N-diisopropylethylamine (2.74 g, 21.20 mmol), and XantPhos (1.22 g, 2.22 mmol) in 1,4-dioxane (30 mL), Pd2(dba)3 (1.94 g m, 2.12 mmol) was added and the mixture was stirred at 80°C for 2 hours. The reaction mixture was passed through Celite and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product, which was purified by silica gel flash column chromatography using 0-10% ethyl acetate in hexane as the eluent to obtain the title compound (2.5 g, 76.7%). LC-MS: 306.1 [MH] -

[0306] Step 3: 2-(pyridine-2-ylmethoxy)benzenesulfonyl chloride

[0307] To a solution of 2-((2-(benzylthio)phenoxy)methyl)pyridine (1.5 g, 4.87 mmol) in acetonitrile (12 mL), acetic acid (6 mL), and water (3 mL), sulfuryl chloride (1.31 g, 9.75 mmol) was added at 0°C and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 3-5% ethyl acetate in hexane as the eluent to obtain the title compound (0.35 g, 25.3%). LC-MS: 281.9 [MH] -

[0308] Step 4: 2-(pyridine-2-ylmethoxy)benzenesulfonamide

[0309] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. LC-MS: 263.0 [MH] - .

[0310] Intermediate 53: 5-Methoxy-1-methyl-1H-indazole-4-sulfonamide [ka] Step 1: 4-bromo-5-methoxy-1-methyl-1H-indazole

[0311] In a solution of 4-bromo-5-methoxy-1H-indazole (0.8g, 3.52 mmol) in THF (40 mL), KO tBu (0.59 g, 5.28 mmol) was added, followed by MeI (5 g, 35.2 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 40-50% ethyl acetate in hexane as the eluent to obtain the title compound (0.8 g, 94.1%). LC-MS: 240.7 [M+H] + .

[0312] Step 2: 4-(benzylthio)-5-methoxy-1-methyl-1H-indazole

[0313] To a degassed solution of 4-bromo-5-methoxy-1-methyl-1H-indazole (0.86 g, 3.57 mmol) and benzyl mercaptan (0.443 g, 3.57 mmol) in toluene (15 mL), Pd2(dba)3 (0.326 g, 0.35 mmol), N,N-diisopropylethylamine (0.922 g, 7.13 mmol), and XantPhos (0.413 g, 0.71 mmol) were added to the reaction mixture at room temperature. The reaction mixture was heated at 100 °C for 12 hours. After the reaction was complete, the mixture was passed through Celite, washed with ethyl acetate, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 30-40% toluene in hexane as the eluent to obtain the title compound (0.65 g, 64.05%); LC-MS: 285.1 [M+H] + .

[0314] Step 3: 5-Methoxy-1-methyl-1H-indazole-4-sulfonyl chloride

[0315] The title compound was prepared using the same procedure as described in step 6 of intermediate 50, with appropriate modifications and appropriate reagents. LC-MS: 261.0 [M+H] + .

[0316] Step 4: 5-Methoxy-1-methyl-1H-indazole-4-sulfonamide

[0317] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. LC-MS: 242.1 [M+H] + .

[0318] Intermediate 54: 5-(2-hydroxypropan-2-yl)-2-methoxybenzenesulfonamide [ka] Step 1: Methyl 3-(chlorosulfonyl)-4-methoxybenzoate

[0319] The title compound was prepared using the same procedure as described in Step 1 of Intermediate 18, with appropriate modifications and appropriate reagents. LC-MS: 264.1 [M+H] + .

[0320] Step 2: Methyl 4-methoxy-3-sulfamoylbenzoate

[0321] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. LC-MS: 246.1 [M+H] + .

[0322] Step 3: 5-(2-hydroxypropan-2-yl)-2-methoxybenzenesulfonamide

[0323] To a solution of methyl 4-methoxy-3-sulfamoylbenzoate (0.1 g, 0.408 mmol) in THF (2 mL), MeMgBr (1.2 mL, 1.22 mmol, 1 M in THF) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction product was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 80% toluene in hexane to obtain the title compound (0.075 g, 75%). LC-MS: 246.0 [M+H] + .

[0324] Intermediate 55: 2-Isopropoxy-6-methoxybenzenesulfonamide [ka] Step 1: 2-Isopropoxy-6-methoxybenzenethiol

[0325] The title compound was prepared using the same procedure as described in step 4 of intermediate 50, with appropriate modifications and appropriate reagents. 1 H NMR (CDCl3, 400MHz): δ 7.20 (t, 1H), 6.50 (d, 1H), 6.48 (d, 1H), 4.40 - 4.37 (m, 1H), 3.90 (s, 3H), 1.21 (d, 6H).

[0326] Step 2: Benzyl(2-isopropoxy-6-methoxyphenyl)sulfane

[0327] The title compound was prepared using the same procedure as described in step 5 of intermediate 50, with appropriate modifications and appropriate reagents. 1 H NMR (CDCl3, 400MHz): δ 7.28 - 7.16 (m, 6H), 6.55 (d, 1H), 6.50 (d, 1H), 4.54 - 4.51 (m, 1H), 4.03 (s, 2H), 3.84 (s, 3H), 1.36 (d, 6H).

[0328] Step 3: 2-Isopropoxy-6-methoxybenzenesulfonyl chloride

[0329] The title compound was prepared using a procedure similar to the procedure described in Step 6 of Intermediate 50, with appropriate modifications and using appropriate reagents. LC-MS: 264.9 [M+H] + .

[0330] Step 4: 2-Isopropoxy-6-methoxybenzenesulfonamide

[0331] The title compound was prepared using a procedure similar to the procedure described in Step 3 of Intermediate 15, with appropriate modifications and using appropriate reagents. 1 1H NMR (DMSO-d6, 400 MHz): δ 7.38 (t, 1H), 7.15 (d, 1H), 6.82 (s, 2H), 6.68 (d, 1H), 4.61 - 4.58 (m, 1H), 3.82 (s, 3H), 1.28 (d, 6H).

[0332] Intermediate 56: 5-Methoxy-2,3-dihydro-1H-indene-4-sulfonamide

Chemical Structure

[0333] To a solution of 5-methoxy-2,3-dihydro-1H-inden-1-one (10 g, 61.65 mmol) in water (120 mL), NBS (10.97 g, 61.65 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 5% ethyl acetate in hexane as the eluent to obtain the title compound (12 g, 80.7%). LC-MS: 240.7 [M+H] + .

[0334] Step 2: 4-bromo-5-methoxy-2,3-dihydro-1H-indene

[0335] To a solution of 4-bromo-5-methoxy-2,3-dihydro-1H-inden-1-one (10 g, 41.47 mmol) in TFA (60 mL), triethylsilane (2.39 g, 20.74 mmol) was added at 0°C. The reaction mixture was slowly warmed to room temperature and then stirred under reflux for 16 hours. The reaction mixture was diluted with ice water, quenched with aqueous NaHCO3 solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using hexane as the eluent to obtain the title compound (6 g, 63.7%). LC-MS: 227.9 [M+H] + .

[0336] Step 3: 5-Methoxy-2,3-dihydro-1H-indene-4-sulfonamide

[0337] To a solution of 4-bromo-5-methoxy-2,3-dihydro-1H-indene (0.2 g, 0.88 mmol) in THF (7 mL), n-BuLi (1.65 mL, 2.64 mmol) was added at -78°C and the mixture was stirred at the same temperature for 1 hour. Then, SO2 gas was bubbling into the reaction mixture at -78°C for 30 minutes. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated to obtain a solid. The solid was dissolved in DCM and NCS (0.35 g, 2.64 mmol) was added to it at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain a crude product. The crude compound was dissolved in DCM and 7N methanolic ammonia (5 mL) was added to it at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 50% ethyl acetate in hexane as the eluent to obtain the title compound (6 g, 63.7%). LC-MS: 228.1 [M+H] + .

[0338] Intermediate 57: 2-Methoxy-5,6,7,8-tetrahydronaphthalene-1-sulfonamide [ka] Step 1: 1-Bromo-5,6,7,8-tetrahydronaphthalene-2-ol

[0339] To a solution of 5,6,7,8-tetrahydronaphthalene-2-ol (5 g, 33.73 mmol) in DMF (60 mL), NBS (6 g, 33.73 mmol) was added at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 5% toluene in hexane as the eluent to obtain the title compound (6 g, 78.32%). 1 H NMR (CDCl3, 400MHz): δ 6.95 (d, 1H), 6.85 (d, 1H), 5.54 (s, 1H), 2.75 - 2.68 (m, 4H), 1.88 - 1.83 (m, 2H), 1.79 - 1.73 (m, 2H).

[0340] Step 2: 5-bromo-6-methoxy-1,2,3,4-tetrahydronaphthalene

[0341] To a solution of 1-bromo-5,6,7,8-tetrahydronaphthalene-2-ol (6 g, 26.42 mmol) and K2CO3 (7.9 g, 57.24 mmol) in acetone (60 mL), MeI (12.2 g, 85.86 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction product was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 5% ethyl acetate in hexane to obtain the title compound (4.5 g, 70.64%). 1 H NMR (CDCl3, 400MHz): δ 7.00 (d, 1H), 6.73 (d, 1H), 3.88 (s, 3H), 2.80 - 2.71 (m, 4H), 1.86 - 1.79 (m, 2H), 1.78 - 1.72 (m, 2H).

[0342] Step 3: 2-Methoxy-5,6,7,8-tetrahydronaphthalene-1-sulfonamide The title compound was prepared using a procedure similar to that described in Step 3 of Intermediate 56, with appropriate modifications and using appropriate reagents. LC-MS: 242.1 [M+H] + .

[0343] Intermediate 58: 2-Ethoxy-6-methoxybenzenesulfonamide [Chemical formula] Step 1: 2-(Benzylthio)-3-methoxyphenol

[0344] To a degassed solution of 2-bromo-3-methoxyphenol (2 g, 9.84 mmol), phenylmethanethiol (1.22 g, 9.84 mmol), N,N-diisopropylethylamine (3.42 mL, 19.7 mmol) and Xantphos (1.14 g, 0.197 mmol) in toluene (30 mL), Pd2(dba)3 (0.901 g, 0.98 mmol) was added and the mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, passed through a pad of celite, washed with ethyl acetate and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel flash column chromatography using 30 - 40% EtOAc in hexane as eluent to give the title compound (0.4 g, 16.5%); LC-MS: 245.0 [M+H] + .

[0345] Step 2: Benzyl(2-ethoxy-6-methoxyphenyl)sulfane

[0346] This compound was prepared using a procedure similar to that described in Step 1 of Intermediate 50, with appropriate modifications and using appropriate reagents. LC-MS: 275.1 [M+H] + .

[0347] Step 3: 2-Ethoxy-6-methoxybenzenesulfonyl chloride

[0348] The title compound was prepared using the same procedure as described in step 6 of intermediate 50, with appropriate modifications and appropriate reagents. 1 H NMR (DMSO-d6, 400MHz): δ 7.25 (t, 1H), 6.64 (d, 1H), 6.63 (d, 1H), 4.00 (q, 2H), 3.72 (s, 3H), 1.28 (t, 3H).

[0349] Step 4: 2-Ethoxy-6-methoxybenzenesulfonamide

[0350] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. LC-MS: 232.0 [M+H] + .

[0351] Intermediate 59: 2-Cyclobutoxy-6-methoxybenzenesulfonamide [ka] Step 1: Benzyl(2-cyclobutoxy-6-methoxyphenyl)sulfane

[0352] The title compound was prepared using the same procedure as described in step 2 of intermediate 53, with appropriate modifications and appropriate reagents. LC-MS: 301.1[MH] -

[0353] Step 2: 2-Cyclobutoxy-6-methoxybenzenesulfonyl chloride

[0354] The title compound was prepared using the same procedure as described in step 6 of intermediate 50, with appropriate modifications and appropriate reagents. 1H NMR (DMSO-d6, 400MHz): δ 7.50 (t, 1H), 6.62 (d, 1H), 6.49 (d, 1H), 4.81 - 4.73 (m, 1H), 3.99 (s, 3H), 2.25 - 2.21 (m, 2H), 1.92 - 1.87 (m, 2H), 1.51 - 1.46 (m, 2H).

[0355] Step 3: 2-Cyclobutoxy-6-methoxybenzenesulfonamide

[0356] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. LC-MS: 256.0 [MH] - .

[0357] Intermediate 63: 2-(difluoromethoxy)-6-methoxybenzenesulfonamide [ka] Step 1: 2-(benzylthio)-3-methoxyphenol

[0358] This compound was prepared using the same procedure as described in step 2 of intermediate 52, with appropriate modifications and appropriate reagents. LC-MS: 245.1 [MH] - 。

[0359] Step 2: Benzyl(2-(difluoromethoxy)-6-methoxyphenyl)sulfane

[0360] Potassium hydroxide (0.342 g, 6.09 mmol) was added at 0°C to a solution of 2-(benzylthio)-3-methoxyphenol (0.3 g, 1.217 mmol) and diethyl(bromodifluoromethyl)phosphonate (0.650 g, 2.43 mmol) in acetonitrile (20 mL). The reaction mixture was then slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel flash column chromatography using 0-20% ethyl acetate in hexane as the eluent to obtain the title compound (0.2 g, 55.41%). 1 H NMR (DMSO-d6, 400MHz): δ 7.48 - 7.15 (m, 6H), 7.00 (dd, 1H), 6.79 (t, 1H), 6.76 (dd, 1H), 4.03 (s, 2H), 3.85 (s, 3H).

[0361] Step 3: 2-(difluoromethoxy)-6-methoxybenzenesulfonyl chloride

[0362] The title compound was prepared using the same procedure as described in step 6 of intermediate 50, with appropriate modifications and appropriate reagents. LC-MS: 270.8 [MH] - .

[0363] Step 4: 2-(difluoromethoxy)-6-methoxybenzenesulfonamide

[0364] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. LC-MS: 252.0 [MH] - .

[0365] Intermediate 64: 3-ethyl-2,6-dimethoxybenzenesulfonamide [ka] Step 1: 2,4-Dimethoxy-1-vinylbenzene

[0366] To a degassed solution of 1-bromo-2,4-dimethoxybenzene (3.0 g, 13.82 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.25 g, 27.64 mmol), and K2CO3 (5.73 g, 41.46 mmol) in 1,4-dioxane (50 mL) and water (10 mL), Pd(Amphos)Cl2 (0.97 g, 1.38 mmol) was added, and the mixture was stirred at 100 °C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with 10% methanol in DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 10-15% ethyl acetate in hexane to obtain the title compound (2.0 g, 88.14%). 1 H NMR (DMSO-D6, 400 MHz): δ 7.42 (d, 1H), 6.85 (dd, 1H), 6.55 - 6.50 (m, 2H), 5.63 (dd, 1H), 5.09 (d, 1H), 3.80 (s, 3H), 3.77 (s, 3H).

[0367] Step 2: 1-Ethyl-2,4-dimethoxybenzene

[0368] A mixture of 1-ethyl-2,4-dimethoxybenzene (1.9 g, 11.57 mmol) and Pd-C (1.84 g, 17.35 mmol) in ethanol (25 mL) and ethyl acetate (25 mL) was stirred for 6 hours under positive hydrogen pressure using a bladder. The reaction mixture was filtered through a Celite pad and washed with 5% methanol in DCM. The filtrate was concentrated to obtain the crude compound, which was used in the next step without purification (1.85 g). 1H NMR (DMSO-D6, 400 MHz): δ 7.01 (d, 1H), 6.51 (s, 1H), 6.43 (dd, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 2.49 (q, 2H), 1.18 (t, 3H).

[0369] Step 3: 3-Ethyl-2,6-dimethoxybenzenesulfonamide

[0370] To a solution of 1-ethyl-2,4-dimethoxybenzene (1.8 g, 10.82 mmol) in THF (20 mL), TMEDA (2.13 g, 18.4 mmol) and n-BuLi (0.73 mL, 18.4 mmol) were added at 0°C, and the mixture was stirred at the same temperature for 1 hour. Then, SO2 gas was bubbling into the reaction mixture at -78°C for 30 minutes. The reaction mixture was slowly warmed to 0°C and stirred for 1 hour. The reaction mixture was concentrated to obtain a solid. The solid was dissolved in DCM, and NCS (2.26 g, 16.93 mmol) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction product was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude compound was dissolved in DCM (10 mL), and 7N methanolic ammonia (10 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 50% ethyl acetate in hexane as the eluent to obtain the title compound (0.6 g). LC-MS: 244.0 [MH] - .

[0371] Intermediate 65: 2,6-dimethoxy-3-methylbenzenesulfonamide [ka] Step 1: 2,4-Dimethoxy-1-methylbenzene

[0372] The title compound was prepared using the same procedure as described in Step 1 of Intermediate 64, with appropriate modifications and appropriate reagents. 1 H NMR, CDCl3, 400MHz): δ 7.40 (d, 1H), 6.46 (d, 1H), 6.42 (dd, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 2.17 (S, 3H).

[0373] Step 2: 2,6-Dimethoxy-3-methylbenzenesulfonamide

[0374] The title compound was prepared using the same procedure as described in step 3 of intermediate 64, with appropriate modifications and appropriate reagents. LC-MS: 230.0 [MH] - .

[0375] Intermediate 66: 3-Cyclopropyl-2,6-Dimethoxybenzenesulfonamide [ka] Step 1: 1-Cyclopropyl-2,4-dimethoxybenzene

[0376] The title compound was prepared using the same procedure as described in Step 1 of Intermediate 64, with appropriate modifications and appropriate reagents. LC-MS: 179.1 [M+H] + .

[0377] Step 2: 3-Cyclopropyl-2,6-Dimethoxybenzenesulfonamide

[0378] The title compound was prepared using the same procedure as described in step 3 of intermediate 64, with appropriate modifications and appropriate reagents. LC-MS: 256.1 [MH] - .

[0379] Intermediate 67: 5-Cyclopropyl-2-methoxybenzenesulfonamide [ka] Step 1: ((5-bromo-2-methoxyphenyl)sulfonyl) tert-butyl carbamate

[0380] To a solution of 5-bromo-2-methoxybenzenesulfonamide (10 g, 37.57 mmol) in DCM (100 mL), DIPEA (15.36 mL, 112.73 mmol), DMAP (0.46 g, 3.75 mmol), followed by (Boc)2O (12.3 g, 56.36 mmol) were added at 0°C. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 12 hours. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel flash column chromatography using 30-50% ethyl acetate in hexane as the eluent to obtain the title compound (6.5 g, 47.23%). LC-MS: 363.9 [MH] - .

[0381] Step 2: ((5-cyclopropyl-2-methoxyphenyl)sulfonyl) tert-butyl carbamate

[0382] The title compound was prepared using the same procedure as described in step 6 of intermediate 35, with appropriate modifications and appropriate reagents. LC-MS: 326.0 [MH] - .

[0383] Step 3: 5-Cyclopropyl-2-methoxybenzenesulfonamide

[0384] To a solution of tert-butyl ((5-cyclopropyl-2-methoxyphenyl)sulfonyl)carbamate (0.8 g, 2.44 mmol) in DCM (10 mL), TFA (1.12 mL, 14.65 mmol) was added to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 40-50% ethyl acetate in hexane as the eluent to obtain the title compound (0.25 g, 45%). LC-MS: 226.0 [MH] - .

[0385] Intermediate 68: 2-Methoxy-6-(2,2,2-trifluoroethoxy)benzenesulfonamide [ka] Step 1: 2-(benzylthio)-3-methoxyphenol

[0386] The title compound was prepared using the same procedure as described in step 2 of intermediate 53, with appropriate modifications and appropriate reagents. LC-MS: 245.1 [MH] - .

[0387] Step 2: Benzyl(2-methoxy-6-(2,2,2-trifluoroethoxy)phenyl)sulfane

[0388] The title compound was prepared using the same procedure as described in Step 1 of Intermediate 52, with appropriate modifications and appropriate reagents. LC-MS: 327.1 [MH] - .

[0389] Step 3: 2-Methoxy-6-(2,2,2-trifluoroethoxy)benzenesulfonyl chloride

[0390] The title compound was prepared using the same procedure as described in step 6 of intermediate 50, with appropriate modifications and appropriate reagents. 1 H NMR (DMSO-D6, 400MHz): δ 7.23 (t, 1H), 6.79 (d, 1H), 6.63 (d, 1H), 4.55 (q, 2H), 3.72 (s, 3H).

[0391] Step 4: 2-Methoxy-6-(2,2,2-trifluoroethoxy)benzenesulfonamide

[0392] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. LC-MS: 284.0 [MH] - .

[0393] Intermediate 69: 2-(cyclopropylmethoxy)-6-methoxybenzenesulfonamide [ka] Step 1: 1-(cyclopropylmethoxy)-3-methoxybenzene

[0394] The title compound was prepared using the same procedure as described in Step 1 of Intermediate 50, with appropriate modifications and appropriate reagents. LC-MS: 179.1 [M+H] + .

[0395] Step 2: 2-(cyclopropylmethoxy)-6-methoxybenzenesulfonamide

[0396] The title compound was prepared using the same procedure as described in step 3 of intermediate 64, with appropriate modifications and appropriate reagents. LC-MS: 256.0 [MH] - .

[0397] Intermediate 73: 2-Methoxy-6-(trifluoromethyl)benzenesulfonamide [ka] Step 1: 2-Methoxy-6-(trifluoromethyl)benzenesulfonamide

[0398] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. 1 H NMR (DMSO-D6, 400MHz): δ 7.64 (dd, 1H), 7.38 (s, 2H), 7.28 (d, 1H), 7.03 (d, 1H), 3.95 (s, 3H).

[0399] Intermediate 74: 5-(1-cyclopropyl-1-hydroxyethyl)-2-methoxybenzenesulfonamide [ka] Step 1: 5-acetyl-2-methoxybenzenesulfonyl chloride

[0400] To a stirred solution of chlorosulfonic acid (13.96 g, 119.85 mmol) and SOCl2 (4.75 g, 39.95 mmol), 1-(4-methoxyphenyl)ethane-1-one (3.0 g, 19.97 mmol) was added dropwise at 0°C. The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 16 hours. The reaction mixture was then poured into ice-cold water to obtain a precipitate. The precipitate was filtered and dried under vacuum to obtain the title compound (4.0 g, 81.6%). LC-MS: 249.0 [M+H] + .

[0401] Step 2: 5-acetyl-2-methoxybenzenesulfonamide

[0402] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. LC-MS: 230.0 [M+H] + .

[0403] Step 3: 5-(1-cyclopropyl-1-hydroxyethyl)-2-methoxybenzenesulfonamide

[0404] To a solution of 5-acetyl-2-methoxybenzenesulfonamide (0.3 g, 1.30 mmol) in THF (3 mL), cyclopropyl magnesium bromide (2.61 mL, 7.84 mmol, 3 M in THF) was added at -78°C, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel flash column chromatography using 5% methanol in DCM as the eluent to obtain the title compound (0.30 g, 45%). LC-MS: 270.0 [MH] - .

[0405] Intermediate 75: 5-(2-hydroxybutan-2-yl)-2-methoxybenzenesulfonamide [ka] The title compound was prepared using the same procedure as described in step 3 of intermediate 74, with appropriate modifications and appropriate reagents. LC-MS: 258.1 [MH] - .

[0406] Intermediate 78: 3-Chloro-2,6-dimethoxybenzenesulfonamide [ka] Step 1: 3-Ethyl-2,6-dimethoxybenzenesulfonamide

[0407] The title compound was prepared using the same procedure as described in step 3 of intermediate 15, with appropriate modifications and appropriate reagents. LC-MS: 250.0 [MH] - .

[0408] Intermediate 79: 4,6-dimethoxy-2,3-dihydrobenzofuran-7-sulfonamide [ka] Step 1: 2,6-dibromo-3,5-dimethoxyphenol

[0409] To a solution of 3,5-dimethoxyphenol (1.0 g, 6.48 mmol) in DCM (30 mL), bromine (2.07 g, 12.97 mmol) was added at 0°C and the mixture was stirred for 1 hour. The reaction mixture was then warmed to room temperature, quenched with aqueous sodium thiosulfate solution, and extracted with DCM. The organic layer was washed with water, dried over Na₂SO₄, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 0-20% ethyl acetate in hexane as the eluent to obtain the title compound (2.2 g, 90.5%). LC-MS: 312.9 [M+H] + .

[0410] Step 2: 2,4-Dibromo-3-(2-bromoethoxy)-1,5-dimethoxybenzene

[0411] To a stirred solution of 2,6-dibromo-3,5-dimethoxyphenol (1.0 g, 3.20 mmol) and 1,2-dibromoethane (2.40 g, 12.82 mmol) in acetone, K2CO3 (1.32 g, 9.61 mmol) was added and the mixture was stirred at 80°C for 12 hours. After concentrating the reaction mixture, it was diluted with water and extracted with siRNA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 20% ​​ethyl acetate in hexane as the eluent to obtain the title compound (1.1 g, 81.9%). 1 H NMR (DMSO-D6, 400MHz): δ 6.72 (s, 1H), 4.24 (t, 2H), 3.91 (s, 6H), 3.84 (t, 2H).

[0412] Step 3: 4,6-Dimethoxy-2,3-Dihydrobenzofuran-7-sulfonamide

[0413] To a solution of 2,4-dibromo-3-(2-bromoethoxy)-1,5-dimethoxybenzene (0.2 g, 0.47 mmol) in THF (7 mL), n-BuLi (1.48 mL, 2.38 mmol) was added at -78 °C and the mixture was stirred at the same temperature for 1 hour. Then, SO2 gas was bubbling into the reaction mixture at -78 °C for 30 minutes. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was then concentrated to obtain a solid. The solid was dissolved in DCM and NCS (0.19 g, 1.43 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction product was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was dissolved in DCM and 7N methanolic ammonia (8 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was washed with 50% diethyl ether in n-pentane to obtain the title compound (0.07 g, 32.6%). LC-MS: 258.0 [MH]-

[0414] Intermediate 88: 6-Ethoxy-3-ethyl-2-methoxybenzenesulfonamide [ka] Step 1: 4-Ethoxy-2-Methoxy-1-Vinylbenzene

[0415] To a degassed solution of 1,4-dioxane (20 mL), 1-bromo-4-ethoxy-2-methoxybenzene (1.8 g, 7.79 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.4 g, 15.58 mmol), and K2CO3 (3.23 g, 23.36 mmol) in water (4 mL), Pd(Amphos)Cl2 (0.55 g, 0.77 mmol) was added, and the mixture was stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 5-7% ethyl acetate in hexane to obtain the title compound (1.1 g, 79.24%). 1 H NMR (DMSO-D6, 400 MHz): δ 7.08 (d, 1H), 6.95 - 6.88 (m, 2H), 6.68 - 6.61 (m, 1H), 5.72 (dd, 1H), 5.13 (dd, 1H), 4.00 (q, 2H), 3.79 (s, 3H), 1.32 (t, 3H).

[0416] Step 2: 4-Ethoxy-1-ethyl-2-methoxybenzene

[0417] A mixture of 4-ethoxy-2-methoxy-1-vinylbenzene (2.0 g, 11.22 mmol) and Pd-C (1.79 g, 16.83 mmol) in ethanol (25 mL) and ethyl acetate (25 mL) was stirred for 12 hours under positive hydrogen pressure using a bladder. The reaction mixture was filtered through a Celite pad and washed with 5% methanol in DCM. The filtrate was concentrated to obtain the crude compound, which was used in the next step without purification (2.0 g). LC-MS: 181.1.0 [M+H] + .

[0418] Step 3: 6-Ethoxy-3-ethyl-2-methoxybenzenesulfonamide

[0419] To a solution of 4-ethoxy-1-ethyl-2-methoxybenzene (0.3 g, 1.66 mmol) in THF (4 mL), TMEDA (0.58 g, 4.99 mmol) and n-BuLi (3.1 mL, 4.99 mmol) were added at 0°C and the mixture was stirred at the same temperature for 1 hour. Then, SO2 gas was bubbling into the reaction mixture at -78°C for 30 minutes. The reaction mixture was slowly warmed to 0°C and stirred for 1 hour. The reaction mixture was concentrated to obtain a solid. The solid was dissolved in DCM (10 mL) and NCS (0.4 g, 2.99 mmol) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction product was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude compound was dissolved in DCM (2 mL), and 7N methanolic ammonia (10 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude compound was recrystallized using 50% toluene in pentane to obtain the title compound (0.11 g, 59.16%). LC-MS: 260.1 [M+H] + .

[0420] Intermediate 89: 5-(trifluoromethyl)-2,3-dihydrobenzofuran-7-sulfonamide [ka] Step 1: 2,6-Dibromo-4-(trifluoromethyl)phenol

[0421] Sulfuric acid (0.22 mL, 4.15 mmol) was added dropwise to a solution of 2-bromo-4-(trifluoromethyl)phenol (1.0 g, 4.15 mmol) in ACN (10 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, N-bromosuccinimide (0.775 g, 4.35 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water and extracted by DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 0-10% ethyl acetate in hexane as the eluent to obtain the title compound (1.2 g, 60.3%). LC-MS: 318.8 [M+H] + .

[0422] Step 2: 1,3-Dibromo-2-(2-bromoethoxy)-5-(trifluoromethyl)benzene

[0423] To a solution of 2,6-dibromo-4-(trifluoromethyl)phenol (0.8 g, 2.50 mmol) and K2CO3 (1.04 g, 7.50 mmol) in ACN (20 mL), 1,2-dibromoethane (1.88 g, 10.00 mmol) was added and the mixture was stirred at 90°C for 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 1-3% ethyl acetate in hexane as the eluent to obtain the title compound (0.7 g, 65.6%). 1 H NMR (DMSO-d6, 400MHz): δ 8.14 (s, 2H), 4.38 (t, 2H), 3.88 (t, 2H).

[0424] Step 3: 5-(trifluoromethyl)-2,3-dihydrobenzofuran-7-sulfonyl chloride

[0425] To a solution of 1,3-dibromo-2-(2-bromoethoxy)-5-(trifluoromethyl)benzene (0.5 g, 1.17 mmol) in THF (10 mL), n-BuLi (4.39 mL, 7.02 mmol) was added at -78 °C, and the mixture was stirred at the same temperature for 1 hour. Then, SO2 gas was bubbling into the reaction mixture at -78 °C for 30 minutes. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated to obtain a solid. The solid was dissolved in DCM, and NCS (0.47 g, 3.51 mmol) was added to it at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude compound (0.5 g). 1 H NMR (DMSO-d6, 400MHz): δ 7.65 (s, 1H), 7.54 (s, 1H), 4.62 (m, 2H), 3.69 (t, 2H).

[0426] Step 4: 5-(trifluoromethyl)-2,3-dihydrobenzofuran-7-sulfonamide

[0427] To a solution of 5-(trifluoromethyl)-2,3-dihydrobenzofuran-7-sulfonyl chloride (0.5 g, 1.74 mmol) in DCM (7 mL), 7 M methanolic ammonia (7 mL) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, and concentrated to obtain the title compound (0.3 g). LC-MS: 265.9 [MH] - .

[0428] Intermediate 90: 5-(tert-butyl)-2,3-dihydrobenzofuran-7-sulfonamide [ka] Step 1: 1-(tert-butyl)-4-(2,2-dimethoxyethoxy)benzene

[0429] To a stirred solution of 4-(tert-butyl)phenol (2.0 g, 13.31 mmol) in DMF (75 mL), NaH (1.02 g, 26.62 mmol) was added at 0°C and the mixture was stirred for 30 minutes. Subsequently, 2-bromo-1,1-dimethoxyethane (2.7 g, 15.98 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred at 110°C for 12 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to obtain the crude title compound (3.5 g). 1 H NMR (CDCl3, 400MHz): δ 7.30 (d, 2H), 6.88 (d, 2H), 4.72 (t, 1H), 4.01 (d, 2H), 3.45 (s, 6H), 1.30 (s, 9H).

[0430] Step 2: 5-(tert-butyl)benzofuran

[0431] To a solution of 1-(tert-butyl)-4-(2,2-dimethoxyethoxy)benzene (2.0 g, 8.39 mmol) in toluene (25 mL), polyphosphate (2.18 g, 10.07 mmol) was added and the mixture was stirred at 110 °C for 5 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain the crude title compound (1.5 g). 1 H NMR (CDCl3, 400MHz): δ 7.63 - 7.61 (m, 2H), 7.46 (d, 1H), 7.39 (d, 1H), 6.77 (d, 1H), 1.41 (s, 9H).

[0432] Step 3: 5-(tert-butyl)-2,3-dihydrobenzofuran

[0433] The title compound was prepared using the same procedure as described in step 2 of intermediate 88, with appropriate modifications and appropriate reagents (0.36 g). LC-MS: 177.2 [M+H] + .

[0434] Step 4: 5-(tert-butyl)-2,3-dihydrobenzofuran-7-sulfonyl chloride

[0435] To a stirred solution of 5-(tert-butyl)-2,3-dihydrobenzofuran (0.2 g, 1.14 mmol) in DCM (40 mL), chlorosulfonic acid (0.66 g, 5.67 mmol) was added dropwise at 0°C. The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 30 minutes. The reaction mixture was then poured into ice-cold water, quenched with NaHCO3, and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude title compound (0.15 g). 1 H NMR (DMSO-d6, 400MHz): δ 7.36 (d, 1H), 7.20 (d, 1H), 4.46 (t, 2H), 3.11 (t, 2H), 1.23 (s, 9H).

[0436] Step 5: 5-(tert-butyl)-2,3-dihydrobenzofuran-7-sulfonamide

[0437] The title compound was prepared using the same procedure as described in step 4 of intermediate 89, with appropriate modifications and appropriate reagents. LC-MS: 256.1 [M+H] + .

[0438] The following compounds listed in Table 6 were prepared using appropriate reagents with suitable modifications known to those skilled in the art, following the same procedure as described above for steps 4 and 5 of intermediate 90. [Table 6]

[0439] Intermediate 97: 5-Methoxybenzo[d][1,3]dioxol-4-sulfonamide [ka] Step 1: 5-Methoxybenzo[d][1,3]dioxol-4-sulfonyl chloride

[0440] To a solution of 5-methoxybenzo[d][1,3]dioxol (0.2 g, 1.31 mmol) in THF (4 mL), TMEDA (0.305 g, 2.62 mmol) and n-BuLi (2.46 mL, 3.94 mmol) were added at 0°C and the mixture was stirred at the same temperature for 1 hour. Then, SO2 gas was bubbling into the reaction mixture at -78°C for 30 minutes. The reaction mixture was slowly warmed to 0°C and stirred for 2 hours. The reaction mixture was concentrated to obtain a solid. The solid was dissolved in DCM (5 mL) and NCS (0.526 g, 3.94 mmol) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction product was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product (0.3 g). 1 H NMR (DMSO-d6, 400MHz): δ 6.75 (d, 1H), 6.33 (d, 1H), 5.90 (s, 2H), 3.65 (s, 3H).

[0441] Step 2: 5-Methoxybenzo[d][1,3]dioxol-4-sulfonamide

[0442] The title compound was prepared using the same procedure as described in step 4 of intermediate 89, with appropriate modifications and appropriate reagents. LC-MS: 232.0 [M+H] + .

[0443] Intermediate 98: 2,6-dimethoxy-4-methylbenzenesulfonamide [ka] Step 1: 2,6-Dimethoxy-4-methylbenzenesulfonyl chloride

[0444] The title compound was prepared (1 g) using appropriate reagents with appropriate modifications, following the same procedure as described in Step 1 of Intermediate 97. 1H NMR (DMSO-D6, 400MHz): δ 6.49 (s, 2H), 3.72 (s, 6H), 2.57 (s, 3H).

[0445] Step 2: 2,6-Dimethoxy-4-methylbenzenesulfonamide

[0446] The title compound was prepared using the same procedure as described in step 4 of intermediate 89, with appropriate modifications and appropriate reagents. LC-MS: 232.0 [M+H] + .

[0447] Intermediate 107: 2-Cyclopropoxy-6-methoxybenzenesulfonamide [ka] Step 1: 2-Cyclopropoxy-6-methoxybenzenesulfonamide

[0448] The title compound was prepared using the same procedure as described in Step 6 of 102 g of intermediate in Example 16, with appropriate modifications and appropriate reagents. LC-MS: 244.0 [M+H] + .

[0449] Intermediate 108: 3-Chloro-2,6-dimethoxybenzenesulfinamide [ka] Step 1: 3-Chloro-2,6-dimethoxybenzenesulfonamide

[0450] To a solution of 3-chloro-2,6-dimethoxybenzenesulfonyl chloride (3.8 g, 14.06 mmol) in water (50 mL), NaHCO3 (2.35 g, 28.03 mmol) and Na2SO3 (7.06 g, 28.03 mmol) were added at room temperature, and the mixture was stirred at 100 °C for 12 hours. After concentrating the reaction mixture, it was diluted with EtOH (80 mL) and stirred for 10 minutes. The inorganic salt was filtered, and the filtrate was concentrated to obtain the crude compound. The crude compound was dissolved in toluene (50 mL), and oxalyl chloride (1.42 mL, 16.82 mmol) was added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated to obtain the crude compound. The crude compound was dissolved in toluene (30 mL), and aqueous NH4OH solution (30 mL) was added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was washed with 50% diethyl ether in pentane to obtain the title compound (0.5 g, 34.5%). LC-MS: 236.0 [M+H] + .

[0451] Intermediate 109-117 The intermediates listed in Table 7 were prepared using appropriate reagents with suitable modifications known to those skilled in the art, following the same procedure as described above for intermediate 108. In some cases, the procedure began with commercially available sulfonyl chloride components. [Table 7-1] [Table 7-2]

[0452] Intermediate 118: 5-(2-hydroxypropan-2-yl)-2-methoxybenzenesulfinamide [ka] Step 1: 5-acetyl-2-methoxybenzenesulfonyl chloride

[0453] A mixture of chlorosulfonic acid (3.32 mL, 49.93 mmol) and thionyl chloride (5.0 mL) was stirred in an ice bath for 30 minutes. Subsequently, 1-(4-methoxyphenyl)ethane-1-one (5.0 g, 33.29 mmol) was gradually added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was slowly quenched with ice water to obtain a precipitate. The precipitate was filtered and washed with water to obtain the title compound (10.0 g). LC-MS: 249.0 [M+H] + .

[0454] Step 2: 5-acetyl-2-methoxybenzenesulfinamide

[0455] The title compound was prepared using the same procedure as described in Step 1 of Intermediate 108, with appropriate modifications and appropriate reagents (0.50 g); LC-MS: 214.0 [M+H] + .

[0456] Step 3: 5-(2-hydroxypropan-2-yl)-2-methoxybenzenesulfinamide

[0457] To a solution of 5-acetyl-2-methoxybenzenesulfinamide (0.30 g, 1.30 mmol) in THF (12 mL), MeMgBr (3.49 mL, 10.47 mmol, 3 M in diethyl ether) was added at -78°C and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 5% methanol in DCM as the eluent to obtain the title compound (0.250 g, 83.35%). LC-MS: 230.0[M+H] + .

[0458] b) Benzoic acid intermediate Intermediate 1: 4-((1H-pyrazole-1-yl)methyl)-2-methoxybenzoic acid [ka] Step 1: Methyl 2-methoxy-4-methylbenzoate

[0459] A stirred solution of 2-hydroxy-4-methylbenzoic acid (5 g, 32.8 mmol) in DMF (50 mL) was cooled to 0°C, and NaH (1.97 g, 82.1 mmol) was added, followed by methyl iodide (5.6 g, 49.2 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and extracted with RINKAN. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain the crude compound. The crude compound was purified by CombiFlash® chromatography using 0-10% ethyl acetate in hexane to obtain the title compound (3 g, 50.6%). LC-MS: 181.1 [M+H] + .

[0460] Step 2: Methyl 4-(bromomethyl)-2-methoxybenzoate

[0461] To a solution of methyl 2-methoxy-4-methylbenzoate (2.6 g, 14.4 mmol) in CCl4 (30 mL), N-bromosuccinimide (NBS, 2.5 g, 14.4 mmol) and benzoyl peroxide (BPO, 0.035 g, 0.14 mmol) were added, and the mixture was heated under reflux overnight. The reaction mixture was then cooled to room temperature, diluted with DCM, and washed with water. The organic layer was dried over Na2SO4 and concentrated to obtain the crude compound. The crude compound was purified by CombiFlash® chromatography using 0-20% ethyl acetate in hexane to obtain the title compound (2.5 g, 66.8%). LC-MS: 261.0 [M+H] + .

[0462] Step 3: 4-((1H-pyrazole-1-yl)methyl)-2-methoxybenzoate methyl

[0463] To a stirred solution of methyl 4-(bromomethyl)-2-methoxybenzoate (2.5 g, 9.6 mmol) and 1H-pyrazole (0.98 g, 14.4 mmol) in DMF, K2CO3 (4 g, 28.4 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with SiO2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to obtain the crude compound. The crude compound was purified by CombiFlash® chromatography using 40% ethyl acetate in hexane to obtain the title compound (2 g, 84.1%). LC-MS: 247.1 [M+H] + .

[0464] Step 4: 4-((1H-pyrazole-1-yl)methyl)-2-methoxybenzoic acid

[0465] To a stirred solution of methyl 4-((1H-pyrazole-1-yl)methyl)-2-methoxybenzoate (0.8 g, 3.2 mmol) in THF (6 mL) and water (2 mL), LiOH.H2O (0.38 g, 16.2 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ice-cold water, the pH was adjusted to 5 using aqueous citric acid solution, and the mixture was extracted with 20% methanol in DCM. The organic layer was dried over Na2SO4 and concentrated to obtain the title compound (0.6 g). LC-MS: 233.1 [M+H] + .

[0466] Intermediates 2-7, 9 and 10 The following intermediates from Intermediate 2 to Intermediate 10 listed in Table 8 were prepared using appropriate reagents with appropriate modifications known to those skilled in the art, following the same procedure as described above for Intermediate 1. [Table 8]

[0467] Intermediate 2a: 3-Methoxy-4-(pyrazole-1-ylmethyl)benzamide [ka] 3-Methoxy-4-(pyrazole-1-ylmethyl)benzoic acid (1.00 equivalent, 125 mg, 0.538 mmol) and CDI (1.50 equivalent, 131 mg, 0.807 mmol) were dissolved in THF (3 mL) and stirred for 1 hour. 7N ammonium hydroxide solution (10.00 equivalent, 0.770 mL) was added and the mixture was stirred for 16 hours. The solution was diluted with water, neutralized with 1N HCl, and extracted with Â. The organic matter was washed with 1N HCl, water, and brine solution. The organic matter was then dried over sodium sulfate, filtered, and dried under vacuum to obtain the title compound (120 mg, 96% yield). LC-MS: m / z = 232.1 [M+H] +

[0468] Intermediate 11: 4-((1H-pyrazole-1-yl)methyl)-3-cyclopropylbenzoic acid [ka] Step 1: Methyl 3-bromo-4-(bromomethyl)benzoate

[0469] The title compound was prepared using the same procedure as described in step 2 of intermediate 1, with appropriate modifications and appropriate reagents.

[0470] Step 2: 4-((1H-pyrazole-1-yl)methyl)-3-methyl bromobenzoate

[0471] The title compound was prepared using the same procedure as described in step 3 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 295.0 [M+H] + .

[0472] Step 3: 4-((1H-pyrazole-1-yl)methyl)-3-cyclopropylbenzoate methyl

[0473] A degassed solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (0.4 g, 1.35 mmol) and cyclopropylboronic acid (0.466 g, 5.41 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added with Pd(Amphos)Cl2 (0.096 g, 0.13 mmol) and K3PO4 (0.86 g, 4 mmol). The reaction mixture was heated at 90 °C for 16 h. The reaction mass was cooled to room temperature, diluted with water, and extracted with 10% methanol in DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude product. The crude compound was purified by CombiFlash® chromatography using 20 - 25% ethyl acetate in hexane to give the title compound. LC-MS: 257.1 [M+H] + 。

[0474] Step 4: 4-((1H-Pyrazol-1-yl)methyl)-3-cyclopropylbenzoic acid

[0475] The title compound was prepared using a procedure similar to that described in Step 4 of Intermediate 1 with appropriate modifications and using appropriate reagents. LC-MS: 243.1 [M+H] + 。

[0476] Intermediate 12 The following Intermediate 12 shown below was prepared using a procedure similar to that described above for Intermediate 11 with appropriate modifications and using appropriate reagents known to those skilled in the art.

Table 22

[0477] Intermediate 13: 4-((1H-Pyrazol-1-yl)methyl)-3-cyanobenzoic acid

Chem.

[0478] Pd(PPh3)4 was added to a degassed solution of methyl 4-((1H-pyrazole-1-yl)methyl)-3-bromobenzoate (0.3 g, 1.01 mmol) and Zn(CN)2 (0.14 g, 1.21 mmol) in DMF (4 mL), and the mixture was stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, and concentrated to obtain the crude compound. The crude compound was purified by CombiFlash® chromatography using 0-25% ethyl acetate in hexane to obtain the title compound (0.18 g). LC-MS: 242.1 [M+H] + .

[0479] Step 2: 4-((1H-pyrazole-1-yl)methyl)-3-cyanobenzoic acid

[0480] The title compound was prepared using the same procedure as described in step 4 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 228.0 [M+H] + .

[0481] Intermediate 14: 4-((1H-pyrazole-1-yl)methyl)-3-(trifluoromethyl)benzoic acid [ka] Step 1: 4-((1H-pyrazole-1-yl)methyl)-3-(trifluoromethyl)methyl benzoate

[0482] To a stirred solution of methyl 4-((1H-pyrazole-1-yl)methyl)-3-bromobenzoate (0.15 g, 0.5 mmol) in DMF (2 mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.48 g, 2.54 mmol), followed by CuI (0.19 g, 1 mmol), was added at room temperature. The mixture was heated at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, quenched with ice water, and washed with brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain the crude compound (0.15 g), which was used in the next step without purification. LC-MS: 285.1 [M+H] + .

[0483] Step 2: 4-((1H-pyrazole-1-yl)methyl)-3-(trifluoromethyl)benzoic acid

[0484] The title compound was prepared using the same procedure as described in step 4 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 271.1 [M+H] + .

[0485] Intermediate 31: 4-((1H-pyrazole-1-yl)methyl)-3-trifluoromethoxy)perfluorophenyl benzoate [ka] Step 1: 4-Bromo-2-(trifluoromethoxy)benzoic acid (isobutyl carbonate) anhydrous

[0486] To a solution of 4-bromo-2-(trifluoromethoxy)benzoic acid (3.0 g, 10.52 mmol) in THF (45 mL), Et3N (1.6 g, 15.78 mmol) was added, followed by isobutyl chloroformate (1.8 g, 13.16 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude title compound (3.8 g, 95%). 1H NMR (DMSO-d6, 400MHz): δ 7.94 (d, 1H), 7.61 (d, 1H), 7.60 (s, 1H), 4.15 (d, 2H), 2.11 - 2.06 (m, 1H), 1.01 (d, 6H).

[0487] Step 2: (4-Bromo-2-(trifluoromethoxy)phenyl) methanol

[0488] To a solution of methyl 4-bromo-2-(trifluoromethoxy)benzoate (isobutyl carbonate) anhydride (3.8 g, 9.90 mmol) in THF (45 mL), LiBH4 (1.76 g, 11.8 mmol) was added at 0°C and the mixture was stirred at 70°C for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude title compound (2.8 g, 90%). 1 H NMR (DMSO-d6, 400MHz): δ 7.48 (d, 1H), 7.47 (s, 1H), 7.42 (d, 1H), 4.75 (s, 2H).

[0489] Step 3: 1-(4-bromo-2-(trifluoromethoxy)benzyl)-1H-pyrazole

[0490] To a solution of (4-bromo-2-(trifluoromethoxy)phenyl)methanol (1.5 g, 5.53 mmol) and 1-(methylsulfonyl)-1H-pyrazole (0.97 g, 6.64 mmol) in acetonitrile (15 mL), Cs2CO3 (2.16 g, 6.64 mmol) was added and the mixture was stirred at 70°C for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was further purified by silica gel flash column chromatography using 30% ethyl acetate in hexane as the eluent to obtain the title compound (1.5 g, 84.4%). LC-MS: 322.9 [M+H]+.

[0491] Step 4: 4-((1H-pyrazole-1-yl)methyl)-3-(trifluoromethoxy)methyl benzoate

[0492] Pd(dppf)Cl2-DCM (0.38 g, 0.46 mmol) was added to a degassed solution of 1-(4-bromo-2-(trifluoromethoxy)benzyl)-1H-pyrazole (1.5 g, 4.67 mmol) and triethylamine (1.41 g, 14.01 mmol) in methanol (60 mL). The reaction mixture was heated in an autoclave at 80°C for 16 hours using carbon monoxide at a pressure of 80 PSI. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and concentrated to obtain the title compound (1.0 g, 71.3%). LC-MS: 301.0 [M+H]+.

[0493] Step 5: 4-((1H-pyrazole-1-yl)methyl)-3-(trifluoromethoxy)benzoic acid

[0494] To a stirred solution of methyl 4-((1H-pyrazole-1-yl)methyl)-3-(trifluoromethoxy)benzoate (0.5 g, 1.66 mmol) in THF (5 mL), methanol (3 mL), and water (2 mL), lithium hydroxide hydrate (0.15 g, 6.66 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ice-cold water, the pH was adjusted to 5 using 1N HCl, and extracted with 20% methanol in DCM. The organic layer was dried over Na2SO4 and concentrated to obtain the title compound (0.4 g, 83.9%). LC-MS: 287.0 [M+H]+.

[0495] Step 6: 4-((1H-pyrazole-1-yl)methyl)-3-(trifluoromethoxy)benzoate perfluorophenyl

[0496] A solution of 4-((1H-pyrazole-1-yl)methyl)-3-(trifluoromethoxy)benzoic acid (0.2 g, 0.69 mmol), 2,3,4,5,6-pentafluorophenol (0.15 g, 0.84 mmol), and DMAP (0.017 g, 0.14 mmol) in DCM (20 mL) was mixed with EDC.HCl (0.201 g, 1.04 mmol) at 0°C, and the solution was stirred at room temperature for 12 hours. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was further purified by silica gel flash column chromatography using 10-15% ethyl acetate in hexane as the eluent to obtain the title compound (0.27 g, 85.4%). LC-MS: 453.0 [M+H]+. 1 H NMR (DMSO-d6, 400MHz): δ 8.19 (d, 1H), 8.06 (s, 1H), 7.91 (d, 1H), 7.54 (d, 1H), 7.28 (d, 1H), 6.35 (t, 1H), 5.59 (s, 2H).

[0497] Intermediate 35: 4-((1H-pyrazole-1-yl)methyl)-3-cyclopropyl-2-fluorobenzoate perfluorophenyl [ka] Step 1: Methyl 2-amino-4-bromo-3-fluorobenzoate

[0498] To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (5.0 g, 21.36 mmol) in DMF, dipotassium carbonate (4.42 g, 32.04 mmol) was added, followed by iodomethane (3.63 g, 25.63 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with SiO2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 40% ethyl acetate in hexane as the eluent to obtain the title compound (4.8 g). LC-MS: 248.9 [M+H]+ .

[0499] Step 2: (2-amino-4-bromo-3-fluorophenyl)methanol

[0500] The title compound was prepared using the same procedure as described in step 2 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 221.0 [M+H] + .

[0501] Step 3: 6-((1H-pyrazole-1-yl)methyl)-3-bromo-2-fluoroaniline

[0502] The title compound was prepared using the same procedure as described in step 3 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 272.0 [M+H] + .

[0503] Step 4: 4-((1H-pyrazole-1-yl)methyl)-3-amino-2-fluorobenzoate methyl

[0504] The title compound was prepared using the same procedure as described in step 4 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 250.0 [M+H] + .

[0505] Step 5: 4-((1H-pyrazole-1-yl)methyl)-3-bromo-2-fluorobenzoate methyl

[0506] To a solution of methyl 4-((1H-pyrazole-1-yl)methyl)-3-amino-2-fluorobenzoate (0.9 g, 3.61 mmol) and copper(I) bromide (0.80 g, 3.61 mmol) in acetonitrile (10 mL), tert-butylnitrile (0.41 g, 3.97 mmol) was added and the mixture was stirred at 60°C for 10 minutes. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound (0.6 g, 53.07%). LC-MS: 314.0 [M+H] + .

[0507] Step 6: 4-((1H-pyrazole-1-yl)methyl)-3-cyclopropyl-2-fluorobenzoate methyl

[0508] To a degassed solution of methyl 4-((1H-pyrazole-1-yl)methyl)-3-bromo-2-fluorobenzoate (0.3 g, 0.95 mmol), cyclopropylboronic acid (0.32 g, 3.83 mmol), and K3PO4 (0.610 g, 2.87 mmol) in 1,4-dioxane (2.7 mL) and water (0.3 mL), Pd(Amphos)Cl2 (0.068 g, 0.090 mmol) was added, and the mixture was stirred at 100 °C for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with 10% methanol in DCM. The filtrate was washed with water and aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel flash column chromatography using 20% ​​ethyl acetate in hexane as the eluent to obtain the title compound (0.150 g, 57%). LC-MS: 275.1 [M+H] + .

[0509] Step 7: 4-((1H-pyrazole-1-yl)methyl)-3-cyclopropyl-2-fluorobenzoic acid

[0510] The title compound was prepared using the same procedure as described in step 4 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 261.0 [M+H]+ .

[0511] Step 8: 4-((1H-pyrazole-1-yl)methyl)-3-cyclopropyl-2-fluorobenzoate perfluorophenyl

[0512] The title compound was prepared using the same procedure as described in step 6 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 427.0 [M+H] + .

[0513] Intermediate 36: 4-((1H-pyrazole-1-yl)methyl)-2,3-dimethoxybenzoate perfluorophenyl [ka] Step 1: Methyl 4-bromo-2,3-dihydroxybenzoate

[0514] 3.0 g, 17.84 mmol of methyl 2,3-dihydroxybenzoate in DCM was added dropwise at -78°C to a premix solution of toluene and 2.61 g, 35.68 mmol of 2-methylpropan-2-amine and 2.85 g, 35.68 mmol of bromine in DCM, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with siRNA and washed with 1 M HCl. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel flash column chromatography using 10% ethyl acetate in hexane as the eluent to obtain the title compound (1.80 g, 40.8%). LC-MS: 246.9 [MH] - .

[0515] Step 2: Methyl 4-bromo-2,3-dimethoxybenzoate

[0516] To a solution of methyl 4-bromo-2,3-dihydroxybenzoate (1.8 g, 7.28 mmol) and K2CO3 (3.0 g, 21.85 mmol) in acetone, methyl iodide (10.34 g, 72.86 mmol) was added and the mixture was stirred at 50°C for 5 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by silica gel flash column chromatography using 20% ​​ethyl acetate in hexane as the eluent to obtain the title compound (1.75 g, 87.3%). LC-MS: 275.0 [M+H] + .

[0517] Step 3: (4-bromo-2,3-dimethoxyphenyl)methanol

[0518] The title compound was prepared using the same procedure as described in step 2 of intermediate 31, with appropriate modifications and appropriate reagents. 1 H NMR, DMSO-d6, 400MHz): δ 7.35 (d, 1H), 7.11 (d, 1H), 5.18 (t, 1H), 4.49 (d, 2H), 3.79 (s, 3H), 3.78 (s, 3H).

[0519] Step 4: Methyl 1-(4-bromo-2,3-dimethoxybenzyl)-1H-pyrazole

[0520] The title compound was prepared using the same procedure as described in step 3 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 299.0 [M+H] + .

[0521] Step 5: 4-((1H-pyrazole-1-yl)methyl)-2,3-dimethoxybenzoate methyl

[0522] The title compound was prepared using the same procedure as described in step 4 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 277.0 [M+H] + .

[0523] Step 6: 4-((1H-pyrazole-1-yl)methyl)-2,3-dimethoxybenzoic acid

[0524] The title compound was prepared using the same procedure as described in step 4 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 263.1 [M+H] + .

[0525] Step 7: 4-((1H-pyrazole-1-yl)methyl)-2,3-dimethoxybenzoate perfluorophenyl

[0526] The title compound was prepared using the same procedure as described in step 6 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 429.0 [M+H] + .

[0527] Intermediate 37: 4-((1H-pyrazole-1-yl)methyl)-2,5-dimethoxybenzoate perfluorophenyl [ka] Step 1: (4-bromo-2,5-dimethoxyphenyl)methanol

[0528] To a solution of 4-bromo-2,5-dimethoxybenzaldehyde (1.0 g, 4.08 mmol) in EtOH (10 mL), NaBH4 (0.67 g, 16.32 mmol) was added at 0°C. The mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with water at room temperature, extracted with ethyl acetate, washed with water and brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (1.0 g). 1H NMR, DMSO-d6, 400MHz): δ 1H NMR, DMSO-d6, 400MHz): δ 7.15 (s, 1H), 7.14 (s, 1H), 5.16 (t, 1H), 4.45 (d, 2H), 3.80 (s, 3H), 3.74 (s, 3H).

[0529] Step 2: 1-(4-bromo-2,5-dimethoxybenzyl)-1H-pyrazole

[0530] The title compound was prepared using the same procedure as described in step 3 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 299.0 [M+H] + .

[0531] Step 3: 4-((1H-pyrazole-1-yl)methyl)-2,5-dimethoxybenzoate methyl

[0532] The title compound was prepared using the same procedure as described in step 4 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 277.1 [M+H] + .

[0533] Step 4: 4-((1H-pyrazole-1-yl)methyl)-2,5-dimethoxybenzoic acid

[0534] The title compound was prepared using the same procedure as described in step 4 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 263.1 [M+H] + .

[0535] Step 5: 4-((1H-pyrazole-1-yl)methyl)-2,5-dimethoxybenzoate perfluorophenyl

[0536] The title compound was prepared using the same procedure as described in step 6 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 429.1 [M+H] + .

[0537] Intermediate 39: 4-((1H-pyrazole-1-yl)methyl)-3-bromo-2-fluorobenzoic acid [ka] Step 1: 4-((1H-pyrazole-1-yl)methyl)-3-cyclopropyl-2-fluorobenzoic acid

[0538] The title compound was prepared using the same procedure as described in step 4 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 301.0 [M+H] + . Intermediate 60: 4-((1H-pyrazole-1-yl)methyl)-3-methoxybenzoate perfluorophenyl [ka]

[0539] Step 1: 4-((1H-pyrazole-1-yl)methyl)-3-methoxybenzoate perfluorophenyl

[0540] The title compound was prepared using the same procedure as described in step 6 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 399.1 [M+H] + .

[0541] Intermediate 62: 4-((1H-pyrazole-1-yl)methyl)-3-(difluoromethoxy)benzoate perfluorophenyl [ka] Step 1: 3-(difluoromethoxy)-4-methylbenzoate methyl benzoate

[0542] To a solution of methyl 3-hydroxy-4-methylbenzoate (2 g, 12.03 mmol) in ACN (80 mL), a 5N KOH solution (10 mL, 60.17 mmol) was added, followed by diethyl (bromodifluoromethyl)phosphonate (6.42 g, 24.07 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 10-20% ethyl acetate in hexane as the eluent to obtain the title compound (0.85 g, 32.7%). 1 H NMR (DMSO-d6, 400MHz): δ 7.76 (dd, 1H), 7.67 (s, 1H), 7.49 (d, 1H), 7.31 (t, 1H), 3.86 (s, 3H), 2.31 (s, 3H).

[0543] Step 2: Methyl 4-(bromomethyl)-3-(difluoromethoxy)benzoate

[0544] The title compound was prepared using the same procedure as described in step 2 of intermediate 1, with appropriate modifications and appropriate reagents. 1 H NMR (DMSO-d6, 400MHz): δ 7.83 (dd, 1H), 7.74 - 7.22 (m, 2H), 7.44 (t, 1H), 4.71 (s, 2H), 3.90 (s, 3H).

[0545] Step 3: 4-((1H-pyrazole-1-yl)methyl)-3-(difluoromethoxy)methyl benzoate

[0546] The title compound was prepared using the same procedure as described in step 3 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 283.0 [M+H] + .

[0547] Step 4: 4-((1H-pyrazole-1-yl)methyl)-3-(difluoromethoxy)benzoic acid

[0548] The title compound was prepared using the same procedure as described in step 4 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 269.1 [M+H] + .

[0549] Step 5: 4-((1H-pyrazole-1-yl)methyl)-3-(difluoromethoxy)benzoate perfluorophenyl

[0550] The title compound was prepared using the same procedure as described in step 6 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 445.0 [M+H] + .

[0551] Intermediate 70: 3-Methoxy-4-(pyrimidine-2-yloxymethyl)benzoic acid [ka] Step 1: 3-Methoxy-4-(pyrimidine-2-yloxymethyl)benzoate methyl

[0552] Sodium hydride (1.50 equivalents, 19 mg, 0.786 mmol) was gradually added to a mixture of methyl 4-(hydroxymethyl)-3-methoxybenzoate (1.50 equivalents, 154 mg, 0.786 mmol) and tetrahydrofuran (12.0 mL). After 10 minutes, 2-chloropyrimidine (1.00 equivalent, 60 mg, 0.524 mmol) was added, and the mixture was stirred at room temperature over the weekend. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (153 mg, 0.556 mmol, 106.13%). LC-MS: 275 [M+H] + .

[0553] Step 2: 3-Methoxy-4-(pyrimidine-2-yloxymethyl)benzoic acid

[0554] A mixture of methyl 3-methoxy-4-(pyrimidine-2-yloxymethyl)benzoate (150 mg, 0.5469 mmol) and 3N NaOH solution (1.4 mL, 4.3751 mmol) was stirred overnight at ambient temperature in 1 mL of EtOH and 1 mL of THF. The reaction mixture was diluted with siRNA, acidified with 1N HCl (to pH 5), and extracted with siRNA. The organic matter was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the title compound (110 mg, 0.423 mmol, 77%). LC-MS: 261 [M+H] + .

[0555] Intermediates 71 and 72 The following intermediates listed in Table 9 were prepared using appropriate reagents with suitable modifications known to those skilled in the art, following the same procedure as described above for intermediate 70. [Table 9]

[0556] c) Pyridine and pyrimidine carboxyl intermediates Intermediate 8: 5-((1H-pyrazole-1-yl)methyl)picolinic acid [ka] Step 1: Ethyl 5-(bromomethyl)picolinate

[0557] To a solution of ethyl 5-methylpicolinate (2.0 g, 12.10 mmol) in CCl4 (15 mL), NBS (2.15 g, 12.10 mmol) and benzoyl peroxide (0.293 g, 1.21 mmol) were added, and the mixture was stirred at 75°C for 12 hours. The reaction mixture was then cooled to room temperature, diluted with DCM, and washed with water. The organic layer was dried over Na2SO4 and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 15-20% ethyl acetate in hexane to obtain the title compound (1.8 g, 60.9%). LC-MS: 244.0 [M+H] + .

[0558] Step 2: 5-((1H-pyrazole-1-yl)methyl) ethyl picolinate

[0559] To a stirred solution of ethyl 5-(bromomethyl)picolinate (1.8 g, 7.37 mmol) and 1H-pyrazole (0.653 g, 9.58 mmol) in DMF (15 mL), K2CO3 (3.05 g, 22.11 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with phenylethylamine. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 30% ethyl acetate in hexane to obtain the title compound (0.8 g, 46.9%). LC-MS: 232.1 [M+H] + .

[0560] Step 3: 5-((1H-pyrazole-1-yl)methyl)picolinic acid

[0561] To a stirred solution of ethyl 5-((1H-pyrazole-1-yl)methyl)picolinate (0.2 g, 3.2 mmol) in THF (4 mL), EtOH (3 mL), and water (2 mL), LiOH.H2O (0.104 g, 4.32 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated, diluted with ice-cold water, and the pH was adjusted to 5 using an aqueous citric acid solution to obtain a solid. The solid was filtered, washed with ice-cold water, and dried under vacuum to obtain the title compound (0.16 g, 91%). LC-MS: 204.1 [M+H] + .

[0562] Intermediate 29: 6-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-5-methoxynicotinamide [ka] Step 1: 5-Bromo-3-methoxypyridine-2-yl) methanol

[0563] To a stirred solution of methyl 5-bromo-3-methoxypicolinate (3 g, 12.19 mmol) in EtOH (30 mL), NaBH4 (1.38 g, 36.57 mmol) was added at 0°C and the mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was further purified by silica gel flash column chromatography using 20% ​​ethyl acetate in hexane as the eluent to obtain the title compound (1.4 g, 53%). LC-MS: 220.0 [M+H] + .

[0564] Step 2: 2-((1H-pyrazole-1-yl)methyl)-5-bromo-3-methoxypyridine

[0565] To a solution of (5-bromo-3-methoxypyridine-2-yl)methanol (1.5 g, 6.87 mmol) and 1-(methylsulfonyl)-1H-pyrazole (1.20, 0.8, 25 mmol) in acetonitrile (15 mL), Cs2CO3 (2.69 g, 8.25 mmol) was added and the mixture was stirred at 70°C for 1 hour. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was further purified by silica gel flash column chromatography using 30% ethyl acetate in hexane as the eluent to obtain the title compound (1.5 g, 81%). LC-MS: 270.0 [M+H] + .

[0566] Step 3: 6-((1H-pyrazole-1-yl)methyl)-5-methoxynicotinate methyl

[0567] To a degassed solution of 2-((1H-pyrazole-1-yl)methyl)-5-bromo-3-methoxypyridine (1.5 g, 5.59 mmol) in methanol (60 mL), Et3N (2.32 mL, 16.78 mmol) and Pd(dppf)Cl2.DCM (0.32 g, 0.39 mmol) were added. The reaction mixture was heated in an autoclave at 80°C for 16 hours using carbon monoxide at a pressure of 80 PSI. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 40% ethyl acetate in hexane as the eluent to obtain the title compound (1.1 g, 79.5%). LC-MS: 248.1 [M+H] + .

[0568] Step 4: 6-((1H-pyrazole-1-yl)methyl)-5-methoxynicotinic acid

[0569] To a stirred solution of methyl 6-((1H-pyrazole-1-yl)methyl)-5-methoxynicotinate (0.8 g, 3.23 mmol) in THF (8 mL), MeOH (4 mL), and water (4 mL), LiOH.H2O (0.387 g, 16.18 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated, diluted with ice-cold water, and the pH was adjusted to 5 using 1N HCl to obtain a solid. The solid was filtered, washed with ice-cold water, and dried under vacuum to obtain the title compound (0.45 g, 60%). LC-MS: 234.1 [M+H] + .

[0570] Step 5: 6-((1H-pyrazole-1-yl)methyl)-5-methoxynicotinate perfluorophenyl

[0571] A solution of 6-((1H-pyrazole-1-yl)methyl)-5-methoxynicotinic acid (0.2 g, 0.85 mmol), 2,3,4,5,6-pentafluorophenol (0.19 g, 1.03 mmol), and DMAP (0.021 g, 0.17 mmol) in DCM (4 mL) was mixed with EDC.HCl (0.247 g, 1.28 mmol) at 0°C and stirred at room temperature for 12 hours. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was further purified by silica gel flash column chromatography using 10-15% ethyl acetate in hexane as the eluent to obtain the title compound (0.12 g, 35%). LC-MS: 400.0 [M+H] + .

[0572] Intermediate 30: 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinic acid perfluorophenyl [ka] Step 1: (6-chloro-2-methoxypyridine-3-yl)methanol

[0573] To a solution of 6-chloro-2-methoxynicotinaldehyde (2.0 g, 11.65 mmol) in MeOH (60 mL), NaBH4 (1.76 g, 11.65 mmol) was added at 0°C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the title compound (2 g, 99%). LC-MS: 174.1 [M+H] + .

[0574] Step 2: 3-((1H-pyrazole-1-yl)methyl)-6-chloro-2-methoxypyridine

[0575] The title compound was prepared using the same procedure as described in step 2 of intermediate 29, with appropriate modifications and appropriate reagents (2 g, 80%). LC-MS: 224 [M+H] + .

[0576] Step 3: 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinate methyl methyl

[0577] The title compound was prepared using the same procedure as described in step 3 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 248.1 [M+H] + .

[0578] Step 4: 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinic acid

[0579] The title compound was prepared using the same procedure as described in step 4 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 234.1 [M+H] + .

[0580] Step 5: 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinate perfluorophenyl

[0581] The title compound was prepared using the same procedure as described in step 5 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 400.0 [M+H] + .

[0582] Intermediate 40: 5-((1H-pyrazole-1-yl)methyl)-6-methylpicolinate perfluorophenyl [ka] Step 1: 6-Chloro-2-methylnicotinaldehyde

[0583] To a solution of 3-bromo-6-chloro-2-methylpyridine (2.0 g, 9.68 mmol) in THF, n-BuLi (7.26 mL, 11.62 mmol, 1.6 M in THF) was added at -78°C and the mixture was stirred at the same temperature for 30 minutes. Then, DMF (1.41 g, 19.37 mmol) was added dropwise to the reaction mixture at -78°C and slowly warmed to room temperature, stirring for 2 hours. The reaction mixture was cooled to -78°C, quenched with brine, and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 20% ​​ethyl acetate in hexane as the eluent to obtain the title compound (0.61 g, 40%). LC-MS: 154.2 [MH] - .

[0584] Step 2: (6-chloro-2-methylpyridine-3-yl)methanol

[0585] To a stirred solution of 6-chloro-2-methylnicotinaldehyde (0.6 g, 3.85 mmol) in THF (20 mL), NaBH4 (0.438 g, 37.83 mmol) was added at 0°C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the title compound (0.51 g, 85%). LC-MS: 158.1 [M+H] + .

[0586] Step 3: 3-((1H-pyrazole-1-yl)methyl)-6-chloro-2-methylpyridine

[0587] The title compound was prepared using the same procedure as described in step 2 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 208.0 [M+H] + .

[0588] Step 4: 5-((1H-pyrazole-1-yl)methyl)-6-methylpicolinate methyl

[0589] The title compound was prepared using the same procedure as described in step 3 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 232.2 [M+H] + .

[0590] Step 5: 5-((1H-pyrazole-1-yl)methyl)-6-methylpicolinic acid

[0591] The title compound was prepared using the same procedure as described in step 4 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 218.1 [M+H] + .

[0592] Step 6: 5-((1H-pyrazole-1-yl)methyl)-6-methylpicolinate perfluorophenyl

[0593] The title compound was prepared using the same procedure as described in step 5 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 384.2 [M+H] + .

[0594] Intermediate 41: 5-((1H-pyrazole-1-yl)methyl)-4-methoxypicolinic acid [ka] Step 1: Methyl 6-chloro-4-methoxynicotinate

[0595] To a solution of methyl 4,6-dichloronicotinate (5.0 g, 24.26 mmol) in methanol (50 mL), NaOMe (5.4 g, 100.13 mmol) was added at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the title compound, which was used in the next step without further purification (2.0 g, 41%): LC-MS: 202.0 [M+H] + .

[0596] Step 2: (6-chloro-4-methoxypyridine-3-yl)methanol

[0597] To a stirred solution of methyl 6-chloro-4-methoxynicotinate (2.5 g, 12.4 mmol) in THF (40 mL), LiBH4 (12.4 mL, 24.8 mmol) was added at 0°C and the mixture was stirred at 70°C for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the title compound (2.12 g, 99%). LC-MS: 173.4 [M+H] + .

[0598] Step 3: 5-((1H-pyrazole-1-yl)methyl)-2-chloro-4-methoxypyridine

[0599] The title compound was prepared using the same procedure as described in step 2 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 223.7[M+H] + .

[0600] Step 4: 5-((1H-pyrazole-1-yl)methyl)-4-methoxypicolinate methyl methyl

[0601] The title compound was prepared using the same procedure as described in step 3 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 248.9 [M+H] + .

[0602] Step 5: 5-((1H-pyrazole-1-yl)methyl)-4-methoxypicolinic acid

[0603] The title compound was prepared using the same procedure as described in step 4 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 234.1 [M+H] + .

[0604] Intermediate 45: 5-((1H-pyrazole-1-yl)methyl)-6-(difluoromethoxy)picolinic acid [ka] Step 1: (6-Chloro-2-(difluoromethoxy)pyridine-3-yl)methanol

[0605] To a solution of 6-chloro-2-(difluoromethoxy)nicotinic acid (0.5 g, 2.23 mmol) in THF, 1,1'-carbonyldiimidazole (0.72 g, 4.47 mmol) was added at 0°C. The reaction mixture was then slowly warmed to room temperature for 5 hours. Sodium borohydride (0.42 g, 11.18 mmol) was then added to the reaction mixture at 0°C. The reaction mixture was then slowly warmed to room temperature for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel flash column chromatography using 10% ethyl acetate in hexane as the eluent to obtain the title compound (0.45 g, 96%). LC-MS: 207.6 [MH] - .

[0606] Step 2: 3-((1H-pyrazole-1-yl)methyl)-6-chloro-2-(difluoromethoxy)pyridine

[0607] The title compound was prepared using the same procedure as described in step 2 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 259.8 [M+H] + .

[0608] Step 3: 5-((1H-pyrazole-1-yl)methyl)-6-(difluoromethoxy)picolinate methyl methyl

[0609] The title compound was prepared using the same procedure as described in step 3 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 283.0 [M+H] + .

[0610] Step 4: 5-((1H-pyrazole-1-yl)methyl)-6-(difluoromethoxy)picolinic acid

[0611] The title compound was prepared using the same procedure as described in step 4 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 268.0 [MH] - .

[0612] Intermediate 76: 5-((1H-pyrazole-1-yl)methyl)-6-(trifluoromethoxy)picolinic acid [ka] Step 1: 6-Chloro-2-(trifluoromethoxy)nicotinic acid

[0613] To a solution of 2-chloro-6-(trifluoromethoxy)pyridine (1.0 g, 5.06 mmol) in anhydrous THF (30 mL), LDA (freshly prepared from n-BuLi (2.0 mL, 5.0 mmol, 2.5 M in hexane) and diisopropylamine (0.65 g, 5.06 mmol) in THF (10 mL)) was added at -78°C. The reaction mixture was stirred at -78°C for 2 hours. Using a cannula, the reaction mixture was transferred to a crushed dry ice RB flask at 0°C and stirred at room temperature for 30 minutes. The reaction mixture was quenched with ice water and adjusted to pH 3 using 2N HCl to obtain a precipitate. The precipitate was filtered and dried under vacuum to obtain the title compound (0.5 g, 40.9%). LC-MS: 240.0 [MH] - .

[0614] Step 2: (6-chloro-2-(trifluoromethoxy)pyridine-3-yl) methanol

[0615] To a solution of 6-chloro-2-(trifluoromethoxy)nicotinic acid (0.40 g, 1.655 mmol) in THF (10 ml), CDI (0.806 g, 4.96 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. A solution of NaBH4 (0.43 g, 11.59 mmol) in water (2 ml) was added to the reaction mixture at 0°C, and the entire reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 5% methanol in DCM as the eluent to obtain the title compound (0.2 g, 53.07%). 1 H NMR (DMSO-D6, 400MHz): δ 8.12 (d, 1H), 7.58 (d, 1H), 5.58 (s, 1H), 4.52 (s, 2H).

[0616] Step 3: 3-((1H-pyrazole-1-yl)methyl)-6-chloro-2-(trifluoromethoxy)pyridine

[0617] The title compound was prepared using the same procedure as described in step 2 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 278.0 [M+H] +

[0618] Step 4: 5-((1H-pyrazole-1-yl)methyl)-6-(trifluoromethoxy)picolinate methyl methyl

[0619] The title compound was prepared using the same procedure as described in step 3 of intermediate 28, with appropriate modifications and appropriate reagents. LC-MS: 302.1 [M+H] + .

[0620] Step 5: 5-((1H-pyrazole-1-yl)methyl)-6-(trifluoromethoxy)picolinic acid

[0621] The title compound was prepared using the same procedure as described in step 4 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 288.0 [M+H] +

[0622] Intermediate 77: 5-((1H-pyrazole-1-yl)methyl)-6-(difluoromethyl)picolinate perfluorophenyl [ka] Step 1: 6-Chloro-2-(difluoromethyl)-3-methylpyridine

[0623] To a solution of 6-chloro-3-methylpicoline aldehyde (0.9 g, 5.78 mmol) in DCM (20 mL), DAST (2.79 g, 17.35 mmol) was added over 10 minutes at 0°C. The reaction mixture was then warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel flash column chromatography using 5% methanol in DCM as the eluent to obtain the title compound (0.91 g, 88.58%). LC-MS: 178.0 [M+H] +

[0624] Step 2: 3-(bromomethyl)-6-chloro-2-(difluoromethyl)pyridine

[0625] The title compound was prepared using the same procedure as described in step 2 of intermediate 1, with appropriate modifications and appropriate reagents. 1 H NMR (DMSO-D6, 400MHz): δ 7.92 (d, 1H), 7.48 (d, 1H), 6.70 (t, 1H), 4.69 (s, 2H).

[0626] Step 3: 3-((1H-pyrazole-1-yl)methyl)-6-chloro-2-(difluoromethyl)pyridine

[0627] The title compound was prepared using the same procedure as described in step 3 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 244.1 [M+H] + .

[0628] Step 4: 5-((1H-pyrazole-1-yl)methyl)-6-(difluoromethyl)picolinate methyl methyl picolinate

[0629] The title compound was prepared using the same procedure as described in step 3 of intermediate 28, with appropriate modifications and appropriate reagents. LC-MS: 268.1 [M+H] +.

[0630] Step 5: 5-((1H-pyrazole-1-yl)methyl)-6-(difluoromethyl)picolinic acid

[0631] The title compound was prepared using the same procedure as described in step 4 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 254.1 [M+H] + .

[0632] Step 6: 5-((1H-pyrazole-1-yl)methyl)-6-(difluoromethyl)picolinate perfluorophenyl

[0633] The title compound was prepared using the same procedure as described in step 5 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 420.1 [M+H] + .

[0634] Intermediate 80: 5-((1H-pyrazole-1-yl)methyl)-6-(trifluoromethyl)picolinate perfluorophenyl [ka] Step 1: 6-Hydroxy-2-(trifluoromethyl)nicotinic acid

[0635] To a stirred solution of ethyl(Z)-3-amino-4,4,4-trifluorobuta-2-enoate (5.0 g, 27.30 mmol) in 25% sodium methoxide in methanol (29.5 mL), 2,3-dichloropropanoate (4.71 g, 30.03 mmol) was added dropwise at 0°C and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was then heated to 60°C. Subsequently, 20% aqueous sodium hydroxide solution (73.5 mL) was slowly added to the reaction mixture at 60°C over 2 hours. The reaction mixture was cooled to 0°C and the pH was adjusted to 3 using concentrated HCl to obtain a precipitate. The precipitate was filtered and washed with water to obtain the title compound (4.3 g, 90.6%). LC-MS: 208.0 [M+H] +。

[0636] Step 2: 6-chloro-2-(trifluoromethyl)nicotinic acid

[0637] To a stirred solution of 6-hydroxy-2-(trifluoromethyl)nicotinic acid (2.5 g, 12.05 mmol) and Et3N (2.4 g, 24.14 mmol) in xylene (2.5 mL), POCl3 (2.5 mL, 27.03 mmol) was added at 0°C, and the mixture was stirred at 140°C for 5 hours. The reaction mixture was cooled to room temperature and the pH was adjusted to 3 using an aqueous sulfuric acid solution. The aqueous layer was extracted with xylene. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain the crude compound (2.2 g). LC-MS: 226.0 [M+H] +

[0638] Step 3: 6-Chloro-2-(trifluoromethyl)nicotinic acid (isobutyl carbonate) anhydride

[0639] To a stirred solution of 6-chloro-2-(trifluoromethyl)nicotinic acid (2.2 g, 9.75 mmol) and isobutylcarbonochloride (1.66 g, 12.19 mmol) in THF (25 mL), Et3N (1.48 g, 14.63 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction product was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel flash column chromatography using 5% ethyl acetate in hexane as the eluent to obtain the title compound (1.51 g, 47.5%). 1 H NMR, CDCl3, 400MHz): δ 7.21 (d, 1H), 7.69 (d, 1H), 4.18 (d, 2H), 2.14 - 2.06 (m, 1H), 0.96 (d, 6H).

[0640] Step 4: (6-chloro-2-(trifluoromethyl)pyridine-3-yl) methanol

[0641] The title compound was prepared using the same procedure as described in step 2 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 212.0 [M+H] +

[0642] Step 5: 3-((1H-pyrazole-1-yl)methyl)-6-chloro-2-(trifluoromethyl)pyridine

[0643] The title compound was prepared using the same procedure as described in step 2 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 262.0 [M+H] + .

[0644] Step 6: 5-((1H-pyrazole-1-yl)methyl)-6-(trifluoromethyl)picolinate methyl methyl

[0645] The title compound was prepared using the same procedure as described in step 3 of intermediate 28, with appropriate modifications and appropriate reagents. LC-MS: 286.1 [M+H] + .

[0646] Step 7: 5-((1H-pyrazole-1-yl)methyl)-6-(trifluoromethyl)picolinic acid

[0647] The title compound was prepared using the same procedure as described in step 4 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 272.0 [M+H] + .

[0648] Step 8: 5-((1H-pyrazole-1-yl)methyl)-6-(trifluoromethyl)picolinate perfluorophenyl

[0649] The title compound was prepared using the same procedure as described in step 5 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 438.0 [M+H] + .

[0650] Intermediate 81: 5-((1H-pyrazole-1-yl)methyl)-6-cyclopropyl picolinate perfluorophenyl [ka] Step 1: (Z)-3-amino-3-cyclopropyl acrylate ethyl

[0651] To a stirred solution of ethyl 3-cyclopropyl-3-oxopropanoate (5.0 g, 35.17 mmol) in MeOH (100 mL), ammonium acetate (13.55 g, 175.87 mmol) was added and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction mixture, it was diluted with DCM (50 mL) and stirred for 30 minutes to obtain a solid. The solid was filtered and washed with DCM. The combined filtrate was concentrated to obtain the crude compound (6.55 g). LC-MS: 142.2 [M+H] + .

[0652] Step 2: 5-Ethyl-1-methyl(2E,4Z)-4-(amino(cyclopropyl)methylene)penta-2-engioate

[0653] To a stirred solution of ethyl (Z)-3-amino-3-cyclopropylacrylate (6.5 g, 46.04 mmol) in toluene (75 mL), methyl propyate (5.42 g, 55.25 mmol) was added and the mixture was stirred at 90°C for 48 hours. The reaction mixture was cooled to room temperature and concentrated to obtain the crude compound, which was used in the next step without further purification (5.11 g, 46.38%). LC-MS: 238.1 [MH] - .

[0654] Step 3: 2-Cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate methyl

[0655] To a stirred solution of 5-ethyl-1-methyl(2E,4Z)-4-(amino(cyclopropyl)methylene)penta-2-engioate (5.1 g, 21.31 mmol) in DMF (50 mL), NaOtBu (0.30 g, 3.19 mmol) was added at 0°C, and the mixture was stirred at 90°C for 12 hours. The reaction mixture was cooled to room temperature, quenched with ice water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 60-70% ethyl acetate in hexane as the eluent to obtain the title compound (1.2 g, 29.14%). LC-MS: 194.1 [M+H] + .

[0656] Step 4: Methyl 6-chloro-2-cyclopropylnicotinate

[0657] A stirring solution of methyl 2-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1.1 g, 5.69 mmol) in phenyl dichlorophosphate (10 mL) was stirred at 180°C for 10 minutes. The reaction mixture was added to ice water and extracted with dimethyl phosphate. The organic layer was washed with aqueous sodium bicarbonate solution, dried over Na₂SO₄, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 0.5-10% ethyl acetate in hexane as the eluent to obtain the title compound (1.2 g, 29.1%). LC-MS: 212.0 [M+H] + .

[0658] Step 5: (6-Chloro-2-cyclopropylpyridine-3-yl)methanol

[0659] The title compound was prepared using the same procedure as described in step 2 of intermediate 31, with appropriate modifications and appropriate reagents. LC-MS: 184.1 [M+H] + .

[0660] Step 6: 3-((1H-pyrazole-1-yl)methyl)-6-chloro-2-cyclopropylpyridine

[0661] The title compound was prepared using the same procedure as described in step 2 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 234.1 [M+H] + .

[0662] Step 7: 5-((1H-pyrazole-1-yl)methyl)-6-cyclopropylpicolinate methyl methyl picolinate

[0663] The title compound was prepared using the same procedure as described in step 3 of intermediate 28, with appropriate modifications and appropriate reagents. LC-MS: 258.1 [M+H] + .

[0664] Step 8: 5-((1H-pyrazole-1-yl)methyl)-6-cyclopropyl picolinic acid

[0665] The title compound was prepared using the same procedure as described in step 4 of intermediate 1, with appropriate modifications and appropriate reagents. LC-MS: 244.1 [M+H] + .

[0666] Step 9: 5-((1H-pyrazole-1-yl)methyl)-6-cyclopropyl picolinate perfluorophenyl

[0667] The title compound was prepared using the same procedure as described in step 5 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 410.1 [M+H] + .

[0668] Intermediate 99: 5-((1H-pyrazole-1-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid [ka] Step 1: 5-((1H-pyrazole-1-yl)methyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid

[0669] 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinate methyl (0.5 g, 2.02 mmol) was dissolved in 12 mL of 6N HCl aqueous solution and refluxed at 100°C for 12 hours. The reaction mixture was concentrated and washed with diethyl ether to obtain the crude title compound (0.5 g). LC-MS: 220.1 [M+H] + .

[0670] Step 2: 5-((1H-pyrazole-1-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate methyl

[0671] To a solution of 5-((1H-pyrazole-1-yl)methyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (0.3 g, 1.37 mmol) in DMF (10 mL), Cs2CO3 (0.892 g, 2.73 mmol) was added, followed by MeI (0.389 g, 2.73 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 0-5% methanol in dichloromethane as the eluent to obtain the title compound (0.26 g, 76.9%). LC-MS: 248.1 [M+H] + .

[0672] Step 3: 5-((1H-pyrazole-1-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid

[0673] 5-((1H-pyrazole-1-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate methyl (0.26 g, 1.05 mmol) was dissolved in 12 mL of 6N HCl aqueous solution and refluxed at 100°C for 12 hours. The reaction mixture was concentrated and washed with diethyl ether to obtain the crude title compound (0.24 g). LC-MS: 234.1 [M+H] + .

[0674] Intermediate 100: 5-((1H-pyrazole-1-yl)methyl)-6-ethoxypicolinic acid perfluorophenyl [ka] Step 1: 6-Chloro-2-ethoxynicotinaldehyde

[0675] To a solution of 2-chloro-6-ethoxypyridine (1.5 g, 9.51 mmol) in THF (40 mL), n-BuLi (8.93 mL, 14.29 mmol, 1.6 M in THF) was added at -78°C and the mixture was stirred at the same temperature for 30 minutes. Then, DMF (0.69 g, 9.54 mmol) was added dropwise to the reaction mixture at -78°C, and the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to -78°C, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 15% ethyl acetate in hexane as the eluent to obtain the title compound (0.50 g, 28.30%). LC-MS: 186.0 [M+H] + .

[0676] Step 2: (6-chloro-2-ethoxypyridine-3-yl)methanol

[0677] The title compound was prepared using the same procedure as described in Step 1 of Intermediate 30, with appropriate modifications and appropriate reagents (0.40 g, 98.98%). 1H NMR (CDCl3, 400 MHz): δ 7.70 (d, 1H), 7.57 (d, 1H), 6.92 (d, 1H), 6.90 (s, 1H), 6.69 (d, 1H), 6.64 (d, 1H), 4.71 (d, 2H), 4.67 (d, 2H), 4.64 (d, 2H), 4.45 (q, 2H), 4.38 (q, 4H), 1.43 - 1.26 (m, 9H).

[0678] Step 3: 3-((1H-pyrazole-1-yl)methyl)-6-chloro-2-ethoxypyridine

[0679] The title compound was prepared using the same procedure as described in step 2 of intermediate 29, with appropriate modifications and appropriate reagents (0.48 g, 95.71%). 1 H NMR (DMSO-D6, 400 MHz): δ 7.88 (d, 1H), 7.79 (d, 1H), 7.78 (d, 1H), 7.53 (dd, 1H), -7.48 - 7.46 (m, 2H), 7.42 (d, 1H), 7.27 (d, 1H), 7.04 (d, 1H), 6.82 (d, 1H), 6.79 (s, 1H), 6.42 (d, 1H), 6.33 (d, 1H), 6.28 - 6.27 (m, 2H), 5.38 (s, 2H), 5.35 (s, 2H), 5.26 (s, 2H), 4.30 (q, 2H), 4.26 (q, 4H), 1.33 - 1.28 (m, 9H).

[0680] Step 4: 5-((1H-pyrazole-1-yl)methyl)-6-ethoxypicolinate methyl methyl picolinate

[0681] The title compound was prepared using the same procedure as described in step 3 of intermediate 29, with appropriate modifications and appropriate reagents (0.40 g, 80.87%). 1H NMR (CDCl3, 400 MHz): δ 7.61 (d, 1H), 7.58 - 7.57 (m, 3H), 7.5d - 7.52 (m, 3H), 7.48 (d, 1H), 7.24 - 7.21 (m, 2H), 6.84- 6.82 (m, 1H), 6.57 (dd, 1H), 6.37 (dd, 1H), 6.33 (dd, 1H), 6.31 (dd, 1H), 5.66 (s, 2H), 5.36 (s, 2H), 5.35 (s, 2H), 4.55 (q, 2H), 4.46 - 4.38 (m, 4H), 3.99 (s, 3H), 3.96 (s, 6H), 1.46 - 1.26 (m, 9H).

[0682] Step 5: 5-((1H-pyrazole-1-yl)methyl)-6-ethoxypicolinic acid

[0683] The title compound was prepared using the same procedure as described in step 4 of intermediate 29, with appropriate modifications and appropriate reagents (0.25 g): LC-MS: 248.1 [M+H] + .

[0684] Step 6: 5-((1H-pyrazole-1-yl)methyl)-6-ethoxypicolinate perfluorophenyl

[0685] The title compound was prepared using the same procedure as described in step 5 of intermediate 29, with appropriate modifications and appropriate reagents (0.22 g, 54.82%). LC-MS: 414.1 [M+H] + .

[0686] d) Sulfinyl intermediate Intermediate 82: 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfinyl)-6-methoxypicolinamide [ka] Step 1: 2,6-Dimethoxybenzenesulfinamide

[0687] To a solution of 2-bromo-1,3-dimethoxybenzene (2 g, 9.21 mmol) in THF (15 mL), n-BuLi (17.3 mL, 27.64 mmol, 1.6 M in hexane) was added at -78°C and the mixture was stirred at the same temperature for 1 hour. Then, SO2 gas was bubbling into the reaction mixture at -78°C for 30 minutes. The entire reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated to obtain a solid. The solid was dissolved in toluene and oxalyl chloride (0.93 mL, 10.8 mmol) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction products were quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was dissolved again in DCM (10 mL) and 7N methanolic ammonia (30 mL) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 60% ethyl acetate in hexane as the eluent to obtain the title compound (0.5 g, 34.5%). LC-MS: 202.1 [M+H] + .

[0688] Step 2: 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfinyl)-6-methoxypicolinamide

[0689] To a solution of 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinic acid perfluorophenyl (0.15 g, 0.37 mmol) and 2,6-dimethoxybenzenesulfinamide (0.091 g, 0.45 mmol) in THF (5 mL), LiHMDS (1.12 mL, 1.13 mmol, 1.0 M in THF) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was quenched with saturated NH4Cl solution and extracted with 10% MeOH in DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 2-5% MeOH in DCM as the eluent to obtain the title compound (0.12 g, 76.6%). LC-MS: 415.0 [MH] - .

[0690] Intermediate 83-87 The following intermediates listed in Table 10 were prepared using appropriate reagents with suitable modifications known to those skilled in the art, following the same procedure as described above for intermediate 82. [Table 10]

[0691] Intermediate 119: 5-((1H-pyrazole-1-yl)methyl)-N-((3-chloro-2,6-dimethoxyphenyl)sulfinyl)-6-methoxypicolinamide [ka] Step 1: 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfinyl)-6-methoxypicolinamide The title compound was prepared using the same procedure as described in step 2 of intermediate 82, with appropriate modifications and appropriate reagents (0.2 g, 17.71%). LC-MS: 449.0 [MH] - .

[0692] Intermediate 120-131 The following intermediates listed in Table 11 were prepared using appropriate reagents with suitable modifications known to those skilled in the art, following the same procedure as described above for step 2 of intermediates 119 and 82. [Table 11-1] [Table 11-2]

[0693] General synthesis scheme The specific compounds of the present invention can be produced according to the process shown in General Scheme I.

[0694] General scheme: I [ka] A general scheme I for the synthesis of the compound represented by formula (I') is illustrated in the above scheme. The compound of formula (K1) can be reduced in a suitable solvent and a suitable reducing reagent to obtain the compound of formula (K2), which can then be further reacted with the compound of formula (B1) in the presence of a suitable substitution reagent and solvent to obtain the compound of formula (K3). The compound of formula (K3) can be subjected to an oxidation reaction followed by a substitution reaction to obtain the compound of formula (K4), which can then be further hydrolyzed with a suitable base and solvent to obtain the compound of formula (K5). The compound of formula (K5) can be reacted with pentafluorophenol using a suitable solvent to obtain the ester compound of formula (K6). The compound of formula (K6) can be reacted with formula (B2) in a suitable reagent and solvent to obtain the compound of formula (I').

[0695] General Scheme: II [ka] A general scheme II for the synthesis of the compound represented by formula (I) is illustrated in the above scheme. The compound of formula (D1) can be reacted with an alkylating reagent in a suitable solvent to obtain the compound of formula (D2), which can then be further substituted in the presence of a suitable substitution reagent and solvent to obtain the compound of formula (D3). The compound of formula (D3) can be reacted with formula (B3) to obtain the compound of formula (D4), which can then be further hydrolyzed with a suitable base and solvent to obtain the compound of formula (D5). The compound of formula (D5) can be reacted with an alcohol in a suitable solvent to obtain the ester compound of formula (D6). The compound of formula (D6) can be reacted with formula (B4) in a suitable reagent and solvent to obtain the compound of formula (I)

[0696] e) Examples of compounds Example 1. Compound 1: 4-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-2-methoxybenzamide [ka] To a solution of 4-((1H-pyrazole-1-yl)methyl)-2-methoxybenzoic acid (0.2 g, 0.86 mmol) in THF (10 mL), CDI (0.16 g, 1.03 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and 2,6-dimethoxybenzenesulfonamide (0.2 g, 0.94 mmol) and DBU (0.18 g, 1.2 mmol) were added. The mixture was stirred at the same temperature for 15 minutes, then gradually warmed to room temperature and stirred overnight. The reaction mixture was concentrated to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound (0.015 g, 4%).

[0697] Preparative HPLC: Mobile phase A - 0.05% TFA aqueous solution; B - acetonitrile; Column used - Luna Omega PS, C-18 (250 × 21.2 mm), 5 μm. Gradient program: 0% B for 10 minutes, 20% B for 2 minutes, 40% B for 10 minutes. LC-MS: 432.2 [M+H] + ; 1H NMR (DMSO-d6, 400 MHz): δ 11.27 (s, 1H), 7.87 (d, 1H), 7.55-7.45 (m, 3H), 7.07, (s, 1H), 6.80 (s, 1H), 6.78 (s, 1H), 6.75 (d, 1H), 6.30 (t, 1H), 5.39 (s, 2H), 3.88 (s, 3H), 3.79 (s, 6H).

[0698] Example 2. Compound 26: N-(2-methoxyphenyl)sulfonyl-3-methoxy-4-(pyrazole-1-ylmethyl)benzamide [ka] To a solution of 4-((1H-pyrazole-1-yl)methyl)-3-methoxybenzoate perfluorophenyl (0.100 g, 0.251 mmol) and 2-methoxybenzenesulfonamide (0.056 g, 0.301 mmol) in THF (3 mL), LiHMDS (1.0 M in THF solution) (1.0 mL, 1.0 mmol) was added, and the entire reaction mixture was stirred at room temperature for 10 minutes. After quenching the reaction mixture with ice, it was diluted with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to obtain the crude compound, which was further purified by preparative TLC eluted with 80% ethyl acetate in hexane (0.03 g, 30%): LC-MS: 402.3 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 12.50 (s, 1H), 7.91 (dd, 1H), 7.78 (d, 1H), 7.63 (dd, 1H), 7.55 (d, 1H), 7.47 (dd, 1H), 7.41 (dd, 1H), 7.21 (d, 1H), 7.16 (t, 1H), 6.78 (d, 1H), 6.31 (t, 1H), 5.33 (s, 2H), 3.91 (d, 3H), 3.85 (d, 3H).

[0699] Example 3. Compound 45: N-(5-bromo-2,4-dimethoxyphenyl)sulfonyl-3-methoxy-4-(pyrazole-1-ylmethyl)benzamide [ka] In a vial equipped with a stirring bar, 5-bromo-2,4-dimethoxybenzenesulfonamide (1.00 equivalent, 40 mg, 0.135 mmol) and 3-methoxy-4-(pyrazole-1-ylmethyl)benzoic acid (1.24 equivalent, 39 mg, 0.167 mmol) in DCM (1.4 mL) were added. 4-dimethylaminopyridine (4.00 equivalent, 66 mg, 0.540 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.50 equivalent, 39 mg, 0.203 mmol) were added to the reaction vial, and the mixture was stirred under nitrogen at room temperature for 1.5 hours. The reaction mixture was diluted with DCM (5 mL), quenched with water (15 mL), and extracted with DCM (10 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by HPLC (column: Luna 5uM, C18, LC column 100×30mm; flow rate: 42mL / min; gradient: 13-70%, isocratic at 70%, acetonitrile-water; run time: 14min; modifier: 0.1% formic acid) to obtain the title compound (48mg, 0.092 mmol, 68%). LC-MS: 512 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 7.94 (s, 1H), 7.78 (dd, J = 2.3, 0.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 1.9, 0.7 Hz, 1H), 7.41 (dd, J = 7.9, 1.6 Hz, 1H), 6.86 (s, 1H), 6.78 (d, J = 7.9 Hz, 1H), 6.28 (t, J = 2.1 Hz, 1H), 5.33 (s, 2H), 3.97 (s, 3H), 3.91 (d, J = 6.1 Hz, 6H).

[0700] Example 4. Compound 70: N-(2,3-dihydrobenzophan-7-yl)sulfonyl-3-methoxy-4-(pyrazole-1-ylmethyl)benzamide 3-Methoxy-4-(pyrazole-1-ylmethyl)benzamide (1.00 equivalent, 40 mg, 0.173 mmol) was dissolved in DMF (1.5 mL) and cooled to 0°C. 60% sodium hydride from mineral oil (1.30 equivalent, 5.4 mg, 0.225 mmol) was added and the mixture was stirred for 30 minutes. 2,3-Dihydro-1-benzofuran-7-sulfonyl chloride (1.10 equivalent, 42 mg, 0.190 mmol) was added and the mixture was stirred for 2 hours and then warmed to room temperature. [ka] The reaction mixture was directly purified by HPLC using a Kinetex 5um C18 100Å column (size: 100 × 30.0 mm; gradient: 5-55% 0.1% formic acid in ACN in 0.1% aqueous formic acid solution), and then lyophilized to obtain the title compound (3.4 mg, yield 5%). LC-MS: m / z = 414.1 [M+H] + .1H NMR (400 MHz, DMSO) δ 7.75 (s, 1H), 7.54 (d, J = 1.5 Hz, 2H), 7.46 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 7.8, 1.5 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 6.27 (t, J = 2.1 Hz, 1H), 5.31 (s, 2H), 4.56 (s, 2H), 3.87 (s, 3H), 3.18 (s, 2H).

[0701] Example 5. Compound 14: 4-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-3-methoxybenzamide [ka] Step 1: Methyl 3-methoxy-4-methylbenzoate

[0702] A stirred solution of 3-hydroxy-4-methylbenzoic acid (20 g, 32.8 mmol) in DMF (250 mL) was cooled to 0°C, and NaH (7.9 g, 328.62 mmol) was added, followed by methyl iodide (24.6 mL, 394.3 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was poured into ice water to obtain a precipitate, which was filtered, washed with water, and dried under vacuum to obtain the title compound (20 g, 97.4%). LC-MS: 181.3 [M+H] + .

[0703] Step 2: Methyl 4-(bromomethyl)-3-methoxybenzoate

[0704] To a solution of methyl 3-methoxy-4-methylbenzoate (23 g, 127.63 mmol) in CCl4 (300 mL), NBS (31.8 g, 178.69 mmol) and benzoyl peroxide (BPO, 4.63 g, 19.14 mmol) were added, and the mixture was stirred overnight at 75°C. The reaction mixture was then cooled to room temperature, diluted with DCM, and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound (33 g), which was used in the next step without further purification. LC-MS: 260.9 [M+H] + .

[0705] Step 3: 4-((1H-pyrazole-1-yl)methyl)-3-methoxybenzoate methyl

[0706] To a stirred solution of methyl 4-(bromomethyl)-3-methoxybenzoate (33 g, 127.36 mmol) and 1H-pyrazole (13 g, 191.04 mmol) in DMF (300 mL), K2CO3 (44 g, 318.41 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with phenylethylamine. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 10-40% ethyl acetate in hexane as the eluent to obtain the title compound (11 g, 35%). LC-MS: 247.2 [M+H] + .

[0707] Step 4: 4-((1H-pyrazole-1-yl)methyl)-3-methoxybenzoic acid

[0708] To a stirred solution of 4-((1H-pyrazole-1-yl)methyl)-3-methoxybenzoate methyl (10 g, 40.6 mmol) in THF (150 mL), MeOH (40 mL), and water (60 mL), LiOH.H2O (4.87 g, 203.03 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ice-cold water, and the pH was adjusted to 3 using 1N HCl solution to obtain a precipitate. The precipitate was filtered, washed with water, and dried under vacuum to obtain the title compound (9 g, 95%). LC-MS: 233.2 [M+H] + .

[0709] Step 5: 4-((1H-pyrazole-1-yl)methyl)-3-methoxybenzoate perfluorophenyl

[0710] To a solution of 4-((1H-pyrazole-1-yl)methyl)-2-methoxybenzoic acid (1.2 g, 5.17 mmol) and 2,3,4,5,6-pentafluorophenol (1.14 g, 6.20 mmol) in DCM (25 mL), DMAP (0.127 g, 1.03 mmol) was added, followed by EDC.HCl (1.49 g, 7.75 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was purified by silica gel flash column chromatography using 10-15% ethyl acetate in hexane as the eluent to obtain the title compound (1.8 g, 87%). LC-MS: 399.1 [M+H] + .

[0711] Step 6: 4-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-3-methoxybenzamide

[0712] To a solution of 4-((1H-pyrazole-1-yl)methyl)-3-methoxybenzoic acid perfluorophenyl (1 g, 2.551 mmol) and 2,6-dimethoxybenzenesulfonamide (intermediate 22, 0.545 g, 2.511 mmol) in THF (30 mL), LiHMDS (7.51 mL, 7.53 mmol, 1.0 M in THF) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 60-80% HCl in hexane as the eluent to obtain the title compound, which was then ground again in ethyl acetate to obtain the title compound (0.3 g, 28%). LC-MS: 432.2 [M+H] + ; 1H NMR (DMSO-D6, 400MHz): δ 12.20 (s, 1H), 7.80 (s, 1H), 7.58 (s, 1H), 7.48 (d, 1H), 7.45 (dd, 2H), 6.85 - 6.75 (m, 3H), 6.28 (t, 1H), 5.34 (s, 2H), 3.92 (s, 3H), 3.78 (s, 6H).

[0713] Example 6. Compounds 2-65 The following compounds listed in Table 12 were prepared using appropriate reagents with suitable modifications known to those skilled in the art, following the same procedure as described above. The procedures for the intermediates and couplings in the examples are shown in the table below. Unless otherwise specified, intermediates are commercially available. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8] [Table 12-9] [Table 12-10]

[0714] Example 7. Compound 201: 5-((1H-pyrazole-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)picolinamide [ka] To a solution of 5-((1H-pyrazole-1-yl)methyl)picolinic acid (0.25 g, 1.229 mmol) in THF (5 mL), CDI (0.4 g, 2.46 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and 5-(tert-butyl)-2-methoxybenzenesulfonamide (intermediate 17, 0.45 g, 1.84 mmol) and DBU (0.75 g, 4.92 mmol) were added. The mixture was stirred at the same temperature for 15 minutes, then gradually warmed to room temperature and stirred for 12 hours. The reaction mixture was concentrated to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound (0.03 g, 4%). LC-MS: 429.1 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ11.71 (s, 1H), 8.57 (s, 1H), 7.95-7.91 (m, 2H), 7.87 (d, 1H), 7.74 (dd, 1H), 7.68 (d, 1H), 7.51 (dd, 1H), 7.12 (d, 1H), 6.31 (t, 1H), 5.51 (s, 2H), 3.78 (s, 3H), 1.29 (s, 9H).

[0715] Example 8. Compound 202: 6-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-5-methoxynicotinamide [ka] To a solution of 6-((1H-pyrazole-1-yl)methyl)-5-methoxynicotinate perfluorophenyl (0.12 g, 0.301 mmol) and 2,6-dimethoxybenzenesulfonamide (intermediate 22, 0.078 g, 0.361 mmol) in THF (4 mL), LiHMDS (1.0 M in THF solution) (1 mL, 1.2 mmol) was added, and the entire reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with ice water, followed by saturated NH4Cl solution, and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to obtain the crude compound, which was further purified by preparative TLC and eluted with 80% ethyl acetate in hexane (0.01 g, 8%). LC-MS: 433.1 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 12.60 (s, 1H), 8.52 (s, 1H), 7.82 (br s, 1H), 7.72 (s, 1H), 7.38 (d, 1H), 7.33 (br s, 1H), 6.70 (br m, 2H), 6.23 (t, 1H), 5.42 (s, 2H), 3.89 (s, 3H), 3.70 (s, 6H).

[0716] Example 9. Compound 203: 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide [ka] Step 1: (6-chloro-2-methoxypyridine-3-yl)methanol

[0717] To a solution of 6-chloro-2-methoxynicotinaldehyde (10 g, 87.42 mmol) in MeOH (200 mL), NaBH4 (13.3 g, 349.7 mmol) was added at 0°C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the title compound (9.5 g, 94%). LC-MS: 174.0 [M+H] + .

[0718] Step 2: 3-((1H-pyrazole-1-yl)methyl)-6-chloro-2-methoxypyridine

[0719] To a solution of 6-chloro-2-methoxypyridine-3-yl)methanol (16 g, 92.16 mmol) and 1-(methylsulfonyl)-1H-pyrazole (16.16, 110.6 mmol) in acetonitrile (150 mL), Cs2CO3 (60 g, 325.82 mmol) was added and the mixture was stirred at 70°C for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was further purified by silica gel flash column chromatography using 20-30% ethyl acetate in hexane as the eluent to obtain the title compound (20 g, 95.8%). LC-MS: 224.1 [M+H] + .

[0720] Step 3: 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinate methyl methyl

[0721] Pd(dppf)Cl2-DCM (7.32 g, 8.94 mmol) was added to a degassed solution of 3-((1H-pyrazole-1-yl)methyl)-6-chloro-2-methoxypyridine (20 g, 89.42 mmol) and Et3N (37.8 mL, 268.26 mmol) in methanol (400 mL). The reaction mixture was heated in an autoclave at 80°C for 16 hours using carbon monoxide at a pressure of 80 PSI. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and concentrated to obtain the crude compound. The crude compound was further purified by silica gel flash column chromatography using 30-50% ethyl acetate in hexane as the eluent to obtain the title compound (16 g, 72.37%). LC-MS: 248.0 [M+H] + .

[0722] Step 4: 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinic acid

[0723] To a stirred solution of methyl 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinate (5 g, 20.22 mmol) in THF (40 mL), methanol (20 mL), and water (20 mL), LiOH.H2O (3.4 g, 41.96 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ice-cold water, and the pH was adjusted to 4 using an aqueous citric acid solution to obtain a precipitate. The precipitate was filtered, washed with water, and dried under vacuum to obtain the title compound (4.5 g, 95.5%). LC-MS: 234.1[M+H] + .

[0724] Step 5: 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinate perfluorophenyl

[0725] To a solution of 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinic acid (1.0 g, 4.28 mmol) and 2,3,4,5,6-pentafluorophenol (0.947 g, 5.144 mmol) in DCM (20 mL), DMAP (0.106 g, 0.85 mmol) was added, followed by EDC-HCl (1.65 g, 8.57 mmol) at 0°C, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 15-30% ethyl acetate in hexane as the eluent to obtain the title compound (1.5 g, 87.6%). LC-MS: 400.0 [M+H] + .

[0726] Step 6: 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide

[0727] To a solution of 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinic acid perfluorophenyl (0.6 g, 1.50 mmol) and 2,6-dimethoxybenzenesulfonamide (intermediate 22, 0.327 g, 1.50 mmol) in THF (20 mL), LiHMDS (1.5 mL, 1.50 mmol, 1.0 M in THF) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was quenched with ice water, followed by saturated NH4Cl solution, and extracted with 10% MeOH in DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was further purified by silica gel flash column chromatography using 2-5% MeOH in DCM as the eluent to obtain the crude compound. The crude compound was pulverized again in ethyl acetate to obtain the pure title compound (0.2 g, 30.8%). LC-MS: 433.2 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 11.56 (s, 1H), 7.85 (dd, 1H), 7.55 - 7.48 (m , 3H), 7.20 (d, 1H), 6.78 (d, 2H), 6.32 (dd, 1H), 5.36 (s, 2H), 4.11 (s, 3H), 3.77 (s, 6H).

[0728] Example 10. Compound 224: 5-((1H-pyrazole-1-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)picolinamide [ka] Step 1: 5-((1H-pyrazole-1-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)picolinamide

[0729] To a solution of 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinic acid perfluorophenyl (1.25 g, 3.15 mmol) and 2,4,6-trimethoxybenzenesulfonamide (commercially available, 0.6 g, 2.43 mmol) in THF (40 mL), LiHMDS (2.5 mL, 2.43 mmol, 1.0 M in THF) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was quenched with ice water, followed by saturated NH4Cl solution, and extracted with 10% MeOH in DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was further purified by silica gel flash column chromatography using 2-5% MeOH in DCM as the eluent, and ground in ethyl acetate to obtain the title compound (0.38 g, 34%). LC-MS: 461.1 [MH] - ; 1 H NMR (DMSO-d6, 400MHz): δ 11.51 (s, 1H), 7.83 (dd, 1H), 7.54 - 7.50 (m, 2H), 7.19 (d, 1H), 6.31 (dd, 1H), 6.27 (s, 2H), 5.35 (s, 2H), 4.07 (s, 3H), 3.82 (s, 3H), 3.76 (s, 6H).

[0730] Example 11. Compound 264: 5-((1H-pyrazole-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-4-methoxypyrimidine-2-carboxamide [ka] Step 1: 5-bromo-2-chloro-4-methoxypyrimidine

[0731] To a solution of 5-bromo-2,4-dichloropyrimidine (10 g, 43.88 mmol) in MeOH (100 mL), NaOMe (7.7 mL, 43.88 mmol, 25% in MeOH) was added at 0°C and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was quenched with ice water, and the MeOH was completely evaporated to obtain a precipitate. The precipitate was filtered and washed with water to obtain the title compound (10 g). LC-MS: 224.9 [M+H] + .

[0732] Step 2: (2-Chloro-4-methoxypyrimidine-5-yl)methanol

[0733] To a solution of 5-bromo-2-chloro-4-methoxypyrimidine (10 g, 44.75 mmol) in toluene (150 mL), n-BuLi (29.3 mL, 46.99 mmol, 1.6 M in hexane) was added at -78°C and the mixture was stirred at the same temperature for 30 minutes. Ethyl formate (3.98 g, 53.7 mmol) was added to the reaction mixture at -78°C and the mixture was stirred for 30 minutes. The reaction mixture was diluted with MeOH (20 mL), and NaBH4 (2.03 g, 37.84 mmol) was added at -78°C and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 40% ethyl acetate in hexane as the eluent to obtain the title compound (4 g, 51.2%). LC-MS: 175.1 [M+H] + .

[0734] Step 3: 5-(hydroxymethyl)-4-methoxypyrimidine-2-carboxylate methyl carboxylate

[0735] The title compound was prepared using the same procedure as described in step 3 of intermediate 28, with appropriate modifications and appropriate reagents. LC-MS: 199.1 [M+H] + .

[0736] Step 4: 5-((1H-pyrazole-1-yl)methyl)-4-methoxypyrimidine-2-carboxylate methyl

[0737] The title compound was prepared using the same procedure as described in step 2 of intermediate 29, with appropriate modifications and appropriate reagents. LC-MS: 249.1 [M+H] + .

[0738] Step 5: 5-((1H-pyrazole-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-4-methoxypyrimidine-2-carboxamide

[0739] To a solution of methyl 5-((1H-pyrazole-1-yl)methyl)-4-methoxypyrimidine-2-carboxylate (0.2 g, 0.806 mmol) and 5-(tert-butyl)-2-methoxybenzenesulfonamide (intermediate 17, 0.098 g, 0.403 mmol) in DCE (5 mL), titanium(IV) chloride (0.07 mL, 0.6 mmol) was added at 50°C, and the mixture was stirred at 115°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with 10% MeOH in DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound. LC-MS: 460.1 [M+H] + ; 1 H NMR (CD3OD, 400MHz): δ 8.19 (s, 1H), 8.08 (d, 1H), 7.80 (d, 1H), 7.73 (dd, 1H), 7.57 (d, 1H), 7.13 (d, 1H), 6.38 (dd, 1H), 5.41 (s, 2H), 4.14 (s, 3H), 3.89 (s, 3H), 1.38 (s, 9H).

[0740] Example 12. Compounds 204-231, 235, 236, 239-241, 245 and 253 The following compounds listed in Table 13 were prepared using appropriate reagents with suitable modifications known to those skilled in the art, following the same procedure as described above. The procedures for the intermediates and couplings in the examples are shown in the table below. If the synthesis is not shown, the intermediates are commercially available. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6]

[0741] Example 13. Compound 243: 5-((1H-pyrazole-1-yl)methyl)-N-(2,6-dimethoxyphenylsulfonimidoyl)-6-methoxypicolinamide [ka] To a solution of 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfinyl)-6-methoxypicolinamide (0.1 g, 0.24 mmol) in ACN (5 mL), KOtBu (0.05 g, 0.48 mmol), followed by HMDS (0.116 g, 0.72 mmol), and NCS (0.096 g, 0.72 mmol) were added at 0°C and the mixture was stirred for 15 minutes. Then, additional HMDS (0.116 g, 0.72 mmol) and NCS (0.096 g, 0.72 mmol) were added to the reaction mixture at 0°C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound (0.03 g). LC-MS: 432.2 [M+H] + ; 1 H NMR (DMSO-d6, 400MHz): δ 7.82 (d, 1H), 7.63 (d, 1H), 7.50 - 7.48 (m, 2H), 7.46 - 7.43 (m, 2H), 7.18 (d, 1H), 6.78 (d, 2H), 6.31 (dd, 1H), 3.93 (s, 3H), 3.77 (s, 6H).

[0742] Compound 243 was separated into its respective isomers by chiral HPLC, based on arbitrary stereochemical assignments. [ka]

[0743] Compound 243a: Peak 1: LC-MS: 432.1 [M+H] + ; 1 H NMR (CD3OD, 400MHz): δ 7.78 (d, 1H), 7.75 (d, 1H), 7.56 (d, 1H), 7.51 (t, 1H), 7.24 (d, 1H), 6.81 (d, 2H), 6.37 (dd, 1H), 5.38 (s, 2H), 4.06 (s, 3H), 3.86 (s, 6H). [ka]

[0744] Compound 243b: Peak 2: LC-MS: 432.1 [M+H] + ; 1 H NMR (CD3OD, 400MHz): δ 7.78 (d, 1H), 7.75 (d, 1H), 7.56 (d, 1H), 7.51 (t, 1H), 7.24 (d, 1H), 6.81 (d, 2H), 6.37 (dd, 1H), 5.38 (s, 2H), 4.06 (s, 3H), 3.86 (s, 6H).

[0745] Example 14. Compounds 71, 232, and 261-263 The following compounds listed in Table 14 were prepared using appropriate reagents with suitable modifications known to those skilled in the art, following the same procedure as described above for compound 243. [Table 14]

[0746] Example 15: (Compound 265) 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6-ethylpicolinamide [ka] Step 1: Methyl 6-chloro-2-ethylnicotinate

[0747] The reaction mixture was mixed with methyl 2-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1.0 g, 5.51 mmol) in dichloro-hydroxy-(phenoxy)phosphonium (11.64 g, 55.18 mmol) and stirred at 180°C for 10 minutes. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was further purified by silica gel flash column chromatography using 20-30% ethyl acetate in hexane as the eluent to obtain the title compound as a white solid (0.8 g, 72.61%). LC-MS: 200.1 [M+H] + .

[0748] Step 2: (6-chloro-2-ethylpyridine-3-yl)methanol

[0749] The title compound was prepared using the same procedure as described in Step 1 of Intermediate 30, with appropriate modifications and appropriate reagents (0.7 g). LC-MS: 172.1 [M+H] + .

[0750] Step 3: 3-((1H-pyrazole-1-yl)methyl)-6-chloro-2-ethylpyridine

[0751] The title compound was prepared using the same procedure as described in Step 2 of Intermediate 29, with appropriate modifications and appropriate reagents (0.9 g, 99.55%). LC-MS: 222.1 [M+H] + .

[0752] Step 4: 5-((1H-pyrazole-1-yl)methyl)-6-ethylpicolinate methyl methyl picolinate

[0753] The title compound was prepared using the same procedure as described in step 3 of intermediate 29, with appropriate modifications and appropriate reagents (0.65 g, 83.91%). LC-MS: 246.2 [M+H] + .

[0754] Step 5: 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6-ethylpicolinamide

[0755] To a stirred solution of methyl 5-((1H-pyrazole-1-yl)methyl)-6-ethylpicolinate (0.20 g, 0.815 mmol) and 2,6-dimethoxybenzenesulfonamide (0.17 g, 0.0815 mmol) in THF (40 mL), DIPEA (0.35 mL, 2.03 mmol) and TMA (0.14 g, 2.03 mmol) were added at 0°C, and the mixture was stirred at 70°C for 12 hours. The reaction mixture was quenched with ice water and extracted with 10% methanol and DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude title compound. The crude compound was purified by preparative HPLC to obtain the title compound (0.13 g, 37.05%). LC-MS: 431.1 [M+H] + ; 1 H NMR (DMSO-D6, 400 MHz): δ 11.15 (brs, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.55 - 7.51 (m, 2H), 7.34 (d, 1H), 6.80 (d, 2H), 6.34 (dd, 1H), 5.55 (s, 2H), 3.77 (s, 6H), 2.96 (q, 2H), 1.27 (t, 3H).

[0756] Example 16: (Compound-266) 5-((1H-pyrazole-1-yl)methyl)-N-((5-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenyl)sulfonyl)-6-methoxypicolinamide [ka] Step 1: Methyl 2-(4-methoxyphenyl)acetate

[0757] To a solution of 2-(4-methoxyphenyl)acetic acid (5.0 g, 30.08 mmol) in methanol (70 mL), sulfuric acid (2.95 g, 30.08 mmol) was added and the mixture was stirred at 70°C for 12 hours. The reaction mixture was evaporated, quenched with ice water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was used in the next step without purification (5.0 g). 1 H NMR (CDCl3, 400MHz): δ 7.23 (d, 2H), 6.90 (d, 2H), 3.82 (s, 3H), 3.71 (s, 3H), 3.62 (s, 2H).

[0758] Step 2: Methyl 2-(3-bromo-4-methoxyphenyl)acetate

[0759] Bromine (1.46 g, 18.31 mmol) was added dropwise at 0°C to a stirred solution of AlCl3 (1.11 g, 8.23 ​​mmol) and methyl 2-(4-methoxyphenyl)acetate (3.0 mL, 16.64 mmol) in DCM. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was washed with sodium thiosulfate, dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was used in the next step without purification (3.0 g). 1 H NMR (DMSO-D6, 400MHz): δ 7.49 (d, 2H), 7.24 (dd, 1H), 7.06 (d, 1H), 3.83 (s, 3H), 3.64 (s, 3H).

[0760] Step 3: Methyl 2-(3-bromo-4-methoxyphenyl)-2-methylpropanoate

[0761] To a solution of methyl 2-(3-bromo-4-methoxyphenyl)acetate (3.0 g, 11.57 mmol) and methyl iodide (4.93 g, 34.73 mmol) in THF (30 mL), KOt-Bu (3.89 g, 34.73 mmol) was added at -78 °C and the mixture was stirred at the same temperature for 60 minutes. The reaction mixture was then warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched with ice water and extracted with RINKAN. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash chromatography using 0-30% ethyl acetate in hexane as the eluent to obtain the pure title compound (3.2 g, 96.24%). LC-MS: 289.0 [M+2+H] + .

[0762] Step 4: 2-(3-bromo-4-methoxyphenyl)-2-methylpropane-1-ol

[0763] To a solution of methyl 2-(3-bromo-4-methoxyphenyl)-2-methylpropanoate (2.5 g, 8.70 mmol) in THF (15 mL), LAH (0.26 g, 0.80 mmol) was added at 0°C and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated sodium sulfate and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the crude compound, which was used in the next step without purification (2.3 g). 1 H NMR (DMSO-d6, 400MHz): δ 7.50 (s, 1H), 7.31 (d, 1H), 7.02 (d, 1H), 4.68 (t, 1H), 3.81 (s, 3H), 3.38 (d, 2H), 1.18 (s, 6H).

[0764] Step 5: (2-(3-bromo-4-methoxyphenyl)-2-methylpropoxy)(tert-butyl)dimethylsilane

[0765] To a solution of 2-(3-bromo-4-methoxyphenyl)-2-methylpropan-1-ol (1.0 g, 3.85 mmol) in DCM (25 mL), imidazole (0.52 g, 7.71 mmol) was added, followed by TBDMSCl (0.68 g, 4.63 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was poured into ice water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash chromatography using 0-10% ethyl acetate in hexane as the eluent to obtain the pure title compound (1 g, 69.40%). 1 H NMR (DMSO-d6, 400MHz): δ 7.52 (s, 1H), 7.33 (d, 1H), 7.02(d, 1H), 3.81 (s, 3H), 3.48 (s, 2H), 1.21 (s, 6H), 0.82 (s, 9H), 0.014 (s, 6H).

[0766] Step 6: 5-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-2-methoxybenzenesulfonamide

[0767] To a solution of (2-(3-bromo-4-methoxyphenyl)-2-methylpropoxy)(tert-butyl)dimethylsilane (1.0 g, 2.67 mmol) in THF (20 mL), n-BuLi (5.0 mL, 8.03 mmol, 1.6 M in hexane) was added at -78°C and the mixture was stirred at the same temperature for 1 hour. Then, SO2 gas was bubbling into the reaction mixture at -78°C for 30 minutes. The entire reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated to obtain a solid. The solid was dissolved in DCM and NCS (1.07 g, 8.03 mmol) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction product was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude compound. The crude compound was redissolved in DCM (5 mL), and 7N methanolic ammonia (10 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product, which was used in the next step without purification (0.3 g). LC-MS: 374.2 [M+H] + .

[0768] Step 7: 5-((1H-pyrazole-1-yl)methyl)-N-((5-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-2-methoxyphenyl)sulfonyl)-6-methoxypicolinamide

[0769] To a solution of 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinic acid perfluorophenyl (0.40 g, 1.002 mmol) and 5-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-2-methoxybenzenesulfonamide (0.29 g, 0.80 mmol) in THF (10 mL), LiHMDS (2.0 mL, 2.0 mmol, 1.0 M in THF) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was quenched with saturated NH4Cl solution and extracted with 10% MeOH in DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 2-5% MeOH in DCM as the eluent to obtain the title compound (0.3 g, 50.85%). LC-MS: 589.2 [M+H] + .

[0770] Step 8: 5-((1H-pyrazole-1-yl)methyl)-N-((5-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenyl)sulfonyl)-6-methoxypicolinamide

[0771] To a solution of 5-((1H-pyrazole-1-yl)methyl)-N-((5-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-2-methoxyphenyl)sulfonyl)-6-methoxypicolinamide (0.30 g, 0.51 mmol) in THF (15 mL), TBAF (0.28 g, 1.73 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred at room temperature for 12 hours. The reaction mixture was concentrated to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound (0.140 g, 57.85%). LC-MS: 475.1 [M+H] + ; 1H NMR (DMSO-D6, 400 MHz): δ 11.65 (s, 1H), 7.87 (d, 1H), 7.84 (d, 1H), 7.67 (dd, 1H), 7.53 - 7.50 (m, 2H), 7.21 (d, 1H), 7.16 (d, 1H), 6.31 (dd, 1H), 5.36 (s, 2H), 4.13 (s, 3H), 3.83 (s, 3H), 3.41 (s, 2H), 1.24 (s, 6H).

[0772] Example 17: (Compound 267) 6-((1H-pyrazole-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] Step 1: Methyl 6-chloro-2-methoxynicotinate

[0773] To a solution of methyl 2,6-dichloronicotinate (2.0 g, 9.70 mmol) in DCM (10 mL), NaOMe (2.28 mL, 43.88 mmol, 25% in MeOH) was added at 0°C and the mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product, which was used in the next step without purification (2.0 g). LC-MS: 202.0 [M+H] + .

[0774] Step 2: Methyl 2-methoxy-6-vinylnicotinate

[0775] The title compound was prepared in 0.8 g, 41.74% quantity using the same procedure as described in Step 1 of Intermediate 88, with appropriate modifications and appropriate reagents. LC-MS: 194.1 [M+H] + .

[0776] Step 3: Methyl 6-formyl-2-methoxynicotinate

[0777] To a solution of methyl 2-methoxy-6-vinylnicotinate (0.5 g, 2.58 mmol) in water-THF (5 mL and 5 mL), a 4% aqueous solution of osmium tetroxide (0.007 g, 0.020 mmol) was added, followed by sodium periodate (1.10 g, 5.17 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred at room temperature for 12 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 20-60% ethyl acetate in hexane as the eluent to obtain the title compound (0.3 g, 59.39%). LC-MS: 196.1 [M+H] + .

[0778] Step 4: Methyl 6-(hydroxymethyl)-2-methoxynicotinate

[0779] The title compound was prepared using the same procedure as described in Step 1 of Intermediate 30, with appropriate modifications and appropriate reagents (0.25 g). LC-MS: 198.1 [M+H] + .

[0780] Step 5: 6-((1H-pyrazole-1-yl)methyl)-2-methoxynicotinate methyl

[0781] The title compound was prepared using the same procedure as described in Step 2 of Intermediate 29, with appropriate modifications and appropriate reagents (0.23 g, 73.36%). LC-MS: 248.1 [M+H] + .

[0782] Step 6: 6-((1H-pyrazole-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0783] The title compound was prepared using the same procedure as described in Step 1 of Intermediate 99, with appropriate modifications and appropriate reagents (0.2 g). LC-MS: 220.1 [M+H] + .

[0784] Step 7: 6-((1H-pyrazole-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0785] The title compound was prepared using the same procedure as described in step 2 of intermediate 99, with appropriate modifications and appropriate reagents (0.2 g). LC-MS: 248.1 [M+H] + .

[0786] Step 8: 6-((1H-pyrazole-1-yl)methyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0787] The title compound was prepared using the same procedure as described in step 3 of intermediate 99, with appropriate modifications and appropriate reagents (0.07 g). LC-MS: 234.1 [M+H] + .

[0788] Step 9: 6-((1H-pyrazole-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0789] To a solution of 6-((1H-pyrazole-1-yl)methyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.07 g, 0.3 mmol) in THF (5 mL), CDI (0.15 g, 0.900 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and 5-(tert-butyl)-2-methoxybenzenesulfonamide (0.08 g, 0.36 mmol) and DBU (0.14 g, 0.900 mmol) were added and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was quenched with ice water and extracted with 10% methanol and DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound (30 mg, 21.81%). LC-MS: 459.2 [M+H] + ; 1 H NMR (DMSO-D6, 400 MHz): δ 13.06 (s, 1H), 8.18 (d, 1H), 7.86 - 7.84 (m, 2H), 7.71 (dd, 1H), 7.61 (dd, 1H), 7.16 (d, 1H), 6.41 (dd, 1H), 5.71 (d, 1H), 5.68 (s, 2H), 3.81 (s, 3H), 3.65 (s, 3H), 1.28 (s, 9H).

[0790] Example 18: (Compound 268) 5-((1H-pyrazole-1-yl)methyl)-N-((3-ethyl-2,4,6-trimethoxyphenyl)sulfonyl)-6-methoxypicolinamide [ka] Step 1: 2,4,6-trimethoxy-3-vinylbenzenesulfonamide

[0791] The title compound was prepared using the same procedure as described in step 1 of intermediate 88, with appropriate modifications and appropriate reagents. 1H NMR (DMSO-D6, 400 MHz): δ 6.68 - 6.61 (m, 1H), 6.54 (s, 1H), 5.91 (d, 1H), 5.27 (d, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.71 (s, 1H).

[0792] Step 2: 5-((1H-pyrazole-1-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxy-3-vinylphenyl)sulfonyl)picolinamide

[0793] The title compound was prepared using the same procedure as described in Example 10, with appropriate modifications and appropriate reagents (0.16 g). LC-MS: 489.1 [M+H] + .

[0794] Step 3: 5-((1H-pyrazole-1-yl)methyl)-N-((3-ethyl-2,4,6-trimethoxyphenyl)sulfonyl)-6-methoxypicolinamide

[0795] The title compound was prepared using the same procedure as described in step 2 of intermediate 88, with appropriate modifications and appropriate reagents (4 mg, 2.66%). LC-MS: 491.1 [M+H] + ; 1 H NMR (DMSO-D6, 400 MHz): δ 10.24 (brs, 1H), 7.69 (d, 1H), 7.60 (d, 1H), 7.52 (d, 1H), 7.22 (d, 1H), 6.35 (dd, 1H), 6.28 (s, 1H), 5.37 (s, 2H), 4.13 (s, 3H), 4.03 (s, 3H), 3.90 (s, 3H), 3.87 (s, 3H), 2.62 (q, 2H), 1.13(t, 3H).

[0796] Example 19: (Compound 269) 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxy-4-(pyridine-3-ylethynyl)phenyl)sulfonyl)-6-methoxypicolinamide [ka] Step 1: 5-((1H-pyrazole-1-yl)methyl)-N-((4-iodo-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide

[0797] The title compound was prepared using the same procedure as described in Example 10, with appropriate modifications and appropriate reagents. LC-MS: 559.0 [M+H] + .

[0798] Step 2: 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxy-4-(pyridine-3-ylethynyl)phenyl)sulfonyl)-6-methoxypicolinamide

[0799] To a degassed solution of 5-((1H-pyrazole-1-yl)methyl)-N-((4-iodo-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide (0.09 g, 0.16 mmol), 3-ethynylpyridine (0.019 g, 0.19 mmol), and DIPEA (0.3 mL, 1.6 mmol) in DMF (5 mL), copper iodide (0.003 g, 0.1 mmol) and Pd(PPh3)2Cl2 (0.019 g, 0.1 mmol) were added. The reaction mixture was heated at 70 °C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound (7 mg, 8.15%). LC-MS: 534.1 [M+H] + ; 1H NMR (DMSO-D6, 400MHz): δ 8.82 (dd, 1H), 8.62 (d, 1H), 8.03 - 8.00 (m, 1H), 7.83 (d, 1H), 7.65 - 7.62 (m, 2H), 7.60 - 7.48 (m, 3H), 7.19 (d, 1H), 6.96 (brs, 1H), 6.31 (dd, 1H), 5.34 (s, 2H), 4.06 (s, 3H), 3.79 (s, 6H).

[0800] Example 20: (Compound 270) 5-((1H-pyrazole-1-yl)methyl)-6-methoxy-N-((2,4,6-tris(methoxy-d3)phenyl)sulfonyl)picolinamide [ka] Step 1: 2,4,6-trifluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0801] To a solution of 2,4,6-trifluorobenzenesulfonyl chloride (3.0 g, 13.00 mmol) in DCM (30 mL), Et3N (5.44 mL, 39.03 mmol) was added, followed by bis(4-methoxybenzyl)amine (4 g, 15.61 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 20-30% ethyl acetate in hexane as the eluent to obtain the title compound as an off-white solid (4.9 g, 83.5%). 1 H NMR (CDCl3, 400MHz): δ 7.05 (d, 4H), 6.79 (d, 4H), 6.80 -6.70 (m, 2H), 4.42 (s, 4H), 3.80 (s, 6H).

[0802] Step 2: 2,4,6-Tris(methoxy-d3)-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0803] To a solution of 2,4,6-trifluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide (0.1 g, 0.22 mmol) in THF (1 mL), a freshly prepared 20% NaOCD3 solution (0.25 mL, 0.88 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 30-40% ethyl acetate in hexane as the eluent to obtain the title compound (0.105 g, 95.25%). LC-MS: 497.2 [M+H] + .

[0804] Step 3: 2,4,6-Tris(methoxy-d3)benzenesulfonamide

[0805] To a solution of 2,4,6-tris(methoxy-d3)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (2.5 g, 5.03 mmol) in DCM (10 mL), TFA (20 mL) was added at room temperature. The reaction mixture was heated at 60 °C for 2 hours. After concentrating the reaction mixture, it was neutralized with saturated NaHCO3 and extracted with 10% MeOH in DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 80-100% ethyl acetate in hexane as the eluent, and recrystallized using DCM to obtain the title compound (0.55 g, 42.6%). LC-MS: 257.1 [M+H] + . 1 H NMR (DMSO-D6, 400MHz): δ 6.81 (brs, 2H), 6.28 (s, 2H).

[0806] Step 4: 5-((1H-pyrazole-1-yl)methyl)-6-methoxy-N-((2,4,6-tris(methoxy-d3)phenyl)sulfonyl)picolinamide

[0807] To a suspension of 5-((1H-pyrazole-1-yl)methyl)-6-methoxypicolinic acid (1.6 g, 6.86 mmol) in ACN (30 mL), citric acid (0.395 g, 2.05 mmol), followed by CDI (1.98 g, 10.29 mmol), was added at room temperature, and the mixture was stirred for 2 hours. 2,4,6-tris(methoxy-d3)benzenesulfonamide (1.58 g, 6.17 mmol), followed by DBU (2.11 g, 10.97 mmol), was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated citric acid solution and extracted with 10% MeOH in DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude compound was purified by silica gel flash column chromatography using 0-1% MeOH in DCM, and recrystallized using ethyl acetate to obtain the title compound (1.6 g, 49.46%). LC-MS: 472.2 [M+H] + . 1 H NMR (DMSO-D6, 400MHz): δ 11.16 (brs, 1H), 7.85 (dd, 1H), 7.55 - 7.51 (m, 2H), 7.21 (d, 1H), 6.32 (dd, 1H), 6.30 (s, 2H), 5.37 (s, 2H), 4.12 (s, 3H).

[0808] Example 21: (Compound 271) 5-((1H-pyrazole-1-yl)methyl)-N-((5-ethyl-2-methoxyphenyl)sulfonyl)-4-methoxypyrimidine-2-carboxamide [ka] Step 1: 5-((1H-pyrazole-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-4-methoxypyrimidine-2-carboxamide

[0809] To a solution of methyl 5-((1H-pyrazole-1-yl)methyl)-4-methoxypyrimidine-2-carboxylate (intermediate 11a) (0.2 g, 0.806 mmol) and 5-ethyl-2-methoxybenzenesulfonamide (intermediate 20) (0.174 g, 0.806 mmol) in THF (10 mL), DIPEA (0.35 mL, 2.5 mmol) and trimethylaluminum (0.119 mg, 2.5 mmol) were added at 0°C, and the reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and diluted with 10% MeOH in DCM. The reaction mixture was filtered through Celite, dried over sodium sulfate, filtered again, and concentrated to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound as an off-white solid. LC-MS: 432.1 [M+H] + ; 1 H NMR (DMSO-D6, 400MHz): δ 12.28 (brs, 1H), 8.24 (s, 1H), 7.85 (d, 1H), 7.73 (d, 1H), 7.53 (dd, 1H), 7.49 (d, 1H), 7.17 (d, 1H), 6.30 (dd, 1H), 5.36 (s, 2H), 4.05 (s, 3H), 3.83 (s, 3H), 2.65 (q, 2H), 1.19 (t, 3H).

[0810] The following compounds listed in Table 15 were prepared using appropriate reagents with suitable modifications known to those skilled in the art, following the same procedure as described above (Example 21). [Table 15]

[0811] The following compounds listed in Table 16 were prepared using appropriate reagents with suitable modifications known to those skilled in the art, following the same procedure as described above (Example 10). [Table 16-1] [Table 16-2] [Table 16-3]

[0812] Example 22: 5-((1H-pyrazole-1-yl)methyl)-N-(5-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenylsulfonimidoyl)-6-methoxypicolinamide (compounds 290a and 290b) [ka] Step 1: 4-(1-(benzyloxy)-2-methylpropan-2-yl)-2-bromo-1-methoxybenzene

[0813] To a stirred solution of 2-(3-bromo-4-methoxyphenyl)-2-methylpropan-1-ol (1.7 g, 6.56 mmol) in THF (30 mL), NaH (0.226 g, 9.84 mmol) was added at 0°C. After 20 minutes, (bromomethyl)benzene (2.2 g, 13.12 mmol) was added to the reaction mixture at 0°C. The reaction mixture was heated at 60°C for 16 hours. The reaction mixture was cooled to room temperature, quenched with ice water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na₂SO₄, and concentrated to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography using 20% ​​ethyl acetate in hexane as the eluent to obtain the title compound (1.4 g, 61.1%). 1 H NMR (DMSO-D6, 400MHz): δ 7.52 (d, 1H), 7.36 - 7.31 (m, 3H),7.29 - 7.23 (m, 3H), 7.04 (d, 1H), 4.45 (s, 2H), 3.82 (s, 3H), 3.42 (s, 2H), 1.25 (s, 6H).

[0814] Step 2: 5-(1-(benzyloxy)-2-methylpropan-2-yl)-2-methoxybenzenesulfonyl chloride

[0815] The title compound was prepared using the same procedure as described in step 3 of intermediate 89, with appropriate modifications and appropriate reagents (1.4 g, 61.1%). 1 H NMR (DMSO-D6, 400MHz): δ 7.73 (d, 1H), 7.34 - 7.31 (m, 3H),7.30 - 7.26 (m, 3H), 6.90 (d, 1H), 4.45 (s, 2H), 3.73 (s, 3H), 3.41 (s, 2H), 1.26 (s, 6H).

[0816] Step 3: 5-(1-(benzyloxy)-2-methylpropan-2-yl)-2-methoxybenzenesulfinamide

[0817] The title compound was prepared using the same procedure as described in Step 1 of Intermediate 108, with appropriate modifications and appropriate reagents (0.29 g, 16.87%). 1 H NMR (DMSO-D6, 400MHz): δ 7.78 (d, 1H), 7.45 (dd, 1H), 7.35 - 7.26 (m, 5H), 7.02 (d, 1H), 5.92 (s, 2H), 4.47 (s, 2H), 3.81 (s, 3H), 3.47 - 3.42 (m, 2H), 1.30 (s, 6H).

[0818] Step 4: 5-((1H-pyrazole-1-yl)methyl)-N-((5-(1-(benzyloxy)-2-methylpropan-2-yl)-2-methoxyphenyl)sulfinyl)-6-methoxypicolinamide

[0819] The title compound was prepared using the same procedure as described in step 2 of intermediate 82, with appropriate modifications and appropriate reagents (0.21 g, 30.57%). LC-MS: 547.1 [MH]-.

[0820] Step 5: 5-((1H-pyrazole-1-yl)methyl)-N-(5-(1-(benzyloxy)-2-methylpropan-2-yl)-2-methoxyphenylsulfonimidoyl)-6-methoxypicolinamide

[0821] The title compound was prepared using the same procedure as described in Example 13, with appropriate modifications and appropriate reagents (0.370 g). LC-MS: 564.2 [M+H] + .

[0822] Step 6: 5-((1H-pyrazole-1-yl)methyl)-N-(5-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenylsulfonimidoyl)-6-methoxypicolinamide

[0823] To a solution of 5-((1H-pyrazole-1-yl)methyl)-N-(5-(1-(benzyloxy)-2-methylpropan-2-yl)-2-methoxyphenylsulfonimidoyl)-6-methoxypicolinamide (0.31 g, 0.0.55 mmol) in ethanol (15 mL), 10% Pd-C (0.11 g, approximately 10% w / w) was carefully added, and the mixture was stirred for 12 hours under positive hydrogen pressure using a bladder. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the crude compound as a white solid. The crude compound was purified by preparative HPLC to obtain the racemic title compound (60 mg).

[0824] Step 7: Intermediate 131f was separated into its respective enantiomers by chiral HPLC. (6.2 mg (peak 1) + 8.2 mg (peak 2) = (15 mg, 7.68%), arbitrary stereochemical assignment. [ka]

[0825] Compound 290a: Peak 1; LCMS: 474.2 [M+H] + ; 1H NMR (DMSO-D6, 400 MHz): δ 7.81 (d, 1H), 7.80 (dd, 1H), 7.61 - 7.58 (m, 2H), 7.49 (d, 1H), 7.48 (brs, 2H), 7.18 (d, 1H), 7.12 (d, 1H), 6.30 (dd, 1H), 5.32 (s, 2H), 4.77 (t, 1H), 3.93 (s, 3H), 3.80 (s, 3H), 3.40 (d, 2H), 1.23 (s, 6H). [ka]

[0826] Compound 290b: Peak 2; LC-MS: 474.1 [M+H] + ; 1 H NMR (DMSO-D6, 400 MHz): δ 7.87 (d, 1H), 7.81 (dd, 1H), 7.61 - 7.59 (d, 2H), 7.49 (dd, 1H), 7.44 (brs, 2H), 7.18 (d, 1H), 7.11 (d, 1H), 6.30 (dd, 1H), 5.31 (s, 2H), 4.76 (t, 1H), 3.93 (s, 3H), 3.79 (s, 3H), 3.40 (d, 2H), 1.23 (s, 6H).

[0827] Example 23: 4-((1H-pyrazole-1-yl)methyl)-N-(5-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenylsulfonimidoyl)-3-methoxybenzamide (compounds 291a and 291b) [ka] Step 1: 5-((1H-pyrazole-1-yl)methyl)-N-((5-(1-(benzyloxy)-2-methylpropan-2-yl)-2-methoxyphenyl)sulfinyl)-6-methoxypicolinamide

[0828] The title compound was prepared using the same procedure as described in step 2 of intermediate 82, with appropriate modifications and appropriate reagents. LC-MS: 548.2 [M+H] + Step 2: 4-((1H-pyrazole-1-yl)methyl)-N-(5-(1-(benzyloxy)-2-methylpropan-2-yl)-2-methoxyphenylsulfonimidoyl)-3-methoxybenzamide

[0829] The title compound was prepared using the same procedure as described in Example 13, with appropriate modifications and appropriate reagents. LCMS: 563.1 [M+H] + Step 3: 4-((1H-pyrazole-1-yl)methyl)-N-(5-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenylsulfonimidoyl)-3-methoxybenzamide

[0830] The title compound was prepared using the same procedure as described in Step 2 of Example 88, with appropriate modifications and appropriate reagents. The crude compound was purified by preparative HPLC to obtain a racemic version of the title compound (100 mg). Step 4: Intermediate 132c was separated into its respective enantiomers by chiral HPLC. (15 ...

Claims

1. Formula (J): 【Chemistry 151】 A compound of or a pharmaceutically acceptable salt thereof During the ceremony, X is O or NR ４ And; Ring A is phenyl or heteroaryl; Ring B is phenyl or heteroaryl; Each R １ is independently C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ alkoxy, C １ -C ６ hydroxyalkyl, C ２ -C ６ alkoxyalkyl, halogen, C １ -C ６ haloalkyl, C １ -C ６ haloalkoxy, -C(O)R １ａ 、-C(O)OR １ａ 、-OC(O)R １ａ 、-C(O)N(R １ａ )(R １ｂ ), -N(R １ａ )(C(O))(R １ｂ ), -OC(O)N(R １ａ )(R １ｂ ), -N(R １ａ )(C(O))(OR １ｂ ), -S(O)R １ａ 、-S(O) ２ R １ａ 、-S(O) ２ N(R １ａ )(R １ｂ ), -S(O)(NH)R １ａ 、-S(O)(NH)N(R １ａ )(R １ｂ ), -N(R １ａ )(R １ｂ ), OH, -CN, -NO ２ 、C ３ -C ８ cycloalkyl, (C １ -C ３ alkyl)(C ３ -C ８ cycloalkyl), -O-(C ３ -C ８ cycloalkyl), heterocycloalkyl, (C １ -C ３ alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C ６ -C １０ Ariel, (C １ -C ３ (Alkyl) (C ６ -C １０ Aryl), -O-(C ６ -C １０ (aryl), heteroaryl, (C １ -C ３ The alkyl group is a heteroaryl group, or -O-(heteroaryl group), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. １ｃ Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R １ｄ Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R １ｅ Replaced by; Each R １ａ and R １ｂ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R １ｃ Independently, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkoxy, -NR １ｃ１ R １ｃ２ , OH, or -CN; Each R １ｃ１ and R １ｃ２ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R １ｄ Independently, deuterium, C ３ -C ８ Cycloalkyl, heterocycloalkyl, C ６ -C １０ It is aryl or heteroaryl; Each R １ｅ is independently C １ -C ６ -alkyl, C １ -C ６ -alkoxy, halogen, C １ -C ６ -haloalkyl, C １ -C ６ -haloalkoxy, OH, or -CN; Alternatively, two Rs on adjacent carbons １ groups combine together with the atoms to which they are attached to form C with 0, 1, 2, 3, 4, 5, or 6 halogens, C １ -C ４ alkyl, OH, or C substituted with -CN ５ -C ８ cycloalkyl or heterocycloalkyl; L is -C １ -C ４ Alkylene -, -(C １ -C ４ Alkylene)-O- or -O-; R ２ This is 0, 1, 2, 3, or 4 R ２ａ It is a heteroaryl substituted with; Each R ２ａ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ２ｂ , -C(O)OR ２ｂ , -OC(O)R ２ｂ , -C(O)N(R ２ｂ ) (Caution ２ｃ ), -N(R ２ｂ )C(O)(R ２ｃ ), -S(O) ２ R ２ｂ , -S(O) ２ N(R) ２ｂ ) (Caution ２ｃ ), -N(R ２ｂ ) (Caution ２ｃ ), OH, -CN, or -NO ２ And; Each R ２ｂ and R ２ｃ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ３ａ , -C(O)OR ３ａ , -OC(O)R ３ａ , -C(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ )C(O)(R ３ｂ ), -OC(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ )C(O)(OR ３ｂ ), -S(O)R ３ａ , -S(O) ２ R ３ａ , -S(O) ２ N(R) ３ａ ) (Caution ３ｂ ), -S(O)(NH)R ３ａ , -S(O)(NH)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ ) (Caution ３ｂ ), OH, -CN, -NO ２ , C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), heterocycloalkyl, (C １ -C ３ Alkyl) (heterocycloalkyl), -O- (heterocycloalkyl), C ６ -C １０ Ariel, (C １ -C ３ (Alkyl) (C ６ -C １０ Aryl), -O-(C ６ -C １０ (aryl), heteroaryl, (C １ -C ３ The alkyl group is a heteroaryl group, or -O-(heteroaryl group), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. ３ｃ Substituted with, each alkoxy has 0, 1, 2, or 3 R ３ｄ Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R ３ｅ It is replaced by; or Two R atoms on the same carbon atom ３ Together, they represent an oxo group; Each R ３ａ and R ３ｂ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ｃ Independently, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkoxy, -NR ３ｃ１ R ３ｃ２ , OH, or -CN; Each R ３ｃ１ and R ３ｃ２ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ｄ Independently, C ３ -C ８ It is a cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl compound; Each R ３ｅ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, or C １ -C ６ It is a haloalkoxy; R ４ is hydrogen or C １ -C ６ It is alkyl; The subscript n is 0, 1, 2, 3, or 4; Subscript q is 0, 1, 2, 3, or 4; During the ceremony, Each heterocycloalkyl is a 3- to 8-membered ring containing 1 to 4 heteroatoms that are N, O, or S; The compound wherein each heteroaryl is a 5-6 membered ring containing 1-4 heteroatoms that are N, O, or S.

2. Equation (I): 【Chemistry 152】 A compound having, or a pharmaceutically acceptable salt thereof, During the ceremony, Each R １ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R １ａ , -C(O)OR １ａ , -OC(O)R １ａ , -C(O)N(R １ａ ) (Caution １ｂ ), -N(R １ａ )C(O)(R １ｂ ), -OC(O)N(R １ａ ) (Caution １ｂ ), -N(R １ａ )C(O)(OR １ｂ ), -S(O)R １ａ , -S(O) ２ R １ａ , -S(O) ２ N(R) １ａ ) (Caution １ｂ ), -S(O)(NH)R １ａ , -S(O)(NH)N(R １ａ ) (Caution １ｂ ), -N(R １ａ ) (Caution １ｂ ), OH, -CN, -NO ２ , C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), heterocycloalkyl, (C １ -C ３ Alkyl) (heterocycloalkyl), -O- (heterocycloalkyl), C ６ -C １０ Ariel, (C １ -C ３ (Alkyl) (C ６ -C １０ Aryl), -O-(C ６ -C １０ (aryl), heteroaryl, (C １ -C ３ The alkyl group is a heteroaryl group, or -O-(heteroaryl group), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. １ｃ Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R １ｄ Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R １ｅ Replaced by; Each R １ａ and R １ｂ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R １ｃ Independently, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkoxy, -NR １ｃ１ R １ｃ２ , OH, or -CN; Each R １ｃ１ and R １ｃ２ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R １ｄ Independently, deuterium, C ３ -C ８ Cycloalkyl, heterocycloalkyl, C ６ -C １０ It is aryl or heteroaryl; Each R １ｅ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, C １ -C ６ It is a haloalkoxy, OH, or -CN; Alternatively, two R atoms on adjacent carbon atoms １ The groups, together with the atoms they are bonded to, form 0, 1, 2, 3, 4, 5, or 6 halogens, C １ -C ４ C substituted with alkyl, OH, or -CN ５ -C ８ Forming cycloalkyl or heterocycloalkyl groups; L is -C １ -C ４ Alkylene -, -(C １ -C ４ Alkylene)-O- or -O-; R ２ This is 0, 1, 2, 3, or 4 R ２ａ It is a heteroaryl substituted with; Each R ２ａ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ２ｂ , -C(O)OR ２ｂ , -OC(O)R ２ｂ , -C(O)N(R ２ｂ ) (Caution ２ｃ ), -N(R ２ｂ )C(O)(R ２ｃ ), -S(O) ２ R ２ｂ , -S(O) ２ N(R) ２ｂ ) (Caution ２ｃ ), -N(R ２ｂ ) (Caution ２ｃ ), OH, -CN, or -NO ２ And; Each R ２ｂ and R ２ｃ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ３ａ , -C(O)OR ３ａ , -OC(O)R ３ａ , -C(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ )C(O)(R ３ｂ ), -OC(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ )C(O)(OR ３ｂ ), -S(O)R ３ａ , -S(O) ２ R ３ａ , -S(O) ２ N(R) ３ａ ) (Caution ３ｂ ), -S(O)(NH)R ３ａ , -S(O)(NH)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ ) (Caution ３ｂ ), OH, -CN, -NO ２ , C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), heterocycloalkyl, (C １ -C ３ Alkyl) (heterocycloalkyl), -O- (heterocycloalkyl), C ６ -C １０ Ariel, (C １ -C ３ (Alkyl) (C ６ -C １０ Aryl), -O-(C ６ -C １０ (aryl), heteroaryl, (C １ -C ３ The alkyl group is a heteroaryl group, or -O-(heteroaryl group), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. ３ｃ Substituted with, each alkoxy has 0, 1, 2, or 3 R ３ｄ Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R ３ｅ It is replaced by; or Two R atoms on the same carbon atom ３ Together, they represent an oxo group; Each R ３ａ and R ３ｂ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ｃ Independently, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkoxy, -NR ３ｃ１ R ３ｃ２ , OH, or -CN; Each R ３ｃ１ and R ３ｃ２ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ｄ Independently, C ３ -C ８ It is a cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl compound; Each R ３ｅ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, or C １ -C ６ It is a haloalkoxy; The subscript n is 0, 1, 2, 3, or 4; Subscript q is 0, 1, 2, 3, or 4; During the ceremony, Each heterocycloalkyl is a 3- to 8-membered ring containing 1 to 4 heteroatoms that are N, O, or S; The compound according to claim 1, wherein each heteroaryl is independently a 5-6 membered ring containing 1-4 heteroatoms that are N, O, or S.

3. Equation (Ia): 【Chemistry 153】 A compound according to claim 2, or a pharmaceutically acceptable salt thereof, having the above.

4. Formula (Ib): 【Chemistry 154】 A compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, having the above.

5. base 【Chemistry 155】 Structure: 【Chemistry 156】 A compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, having the above.

6. Each R １ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, OH, -CN, C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), heterocycloalkyl, (C １ -C ３ Alkyl) (heterocycloalkyl), -O- (heterocycloalkyl), C ６ -C １０ It is an aryl or heteroaryl group, where each alkyl group has 0, 1, 2, or 3 R atoms. １ｃ Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R １ｄ Will it be replaced by; Alternatively, two R atoms on adjacent carbon atoms １ These combine together with the atoms they are bonded to, C ５ -C ８ A compound according to any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl or heterocycloalkyl group.

7. Each R １ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, OH, C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), C ６ -C １０ It is an aryl or heteroaryl, and each alkyl group has 0 or 1 R １ｃ Substituted with, each alkoxy and alkynyl has 0 or 1 R １ｄ Will it be replaced by; Alternatively, two R atoms on adjacent carbon atoms １ These combine together with the atoms they are bonded to, C ５ -C ８ A compound according to any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl or heterocycloalkyl group.

8. Each R １ａ and R １ｂ These are, independently, hydrogen or C １ -C ４ A compound according to any one of claims 2 to 7, which is alkyl, or a pharmaceutically acceptable salt thereof.

9. Each R １ｃ These are, independently, halogen, -NR １ｃ１ R １ｃ２ A compound according to any one of claims 2 to 8, or a pharmaceutically acceptable salt thereof, wherein the compound is OH or -CN.

10. Each R １ｄ The compound according to any one of claims 2 to 9, or a pharmaceutically acceptable salt thereof, is independently a heteroaryl compound.

11. Each R １ｅ Independently, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, halogen, C １ -C ４ A compound according to any one of claims 2 to 10, which is a haloalkyl or -CN, or a pharmaceutically acceptable salt thereof.

12. Each R １ CH is independent. ３ ,CH ２ CH ３ , -C(CH ３ ) ３ , OCH ３ ,CH ２ CH ３ , -OCH(CH ３ ) ２ , OCH ２ - Pyridyl, C (CH ３ ) ２ OH, F, Cl, Br, CF ３ , OCHF ２ OCF ３ , OCH ２ CF ３ , OH, cyclopropyl, cyclopropyloxy, cyclobutyloxy, phenyl, or pyrazolyl; Alternatively, two R atoms on adjacent carbon atoms １ The compounds according to any one of claims 2 to 11, or pharmaceutically acceptable salts thereof, which combine with the atoms to which they are bonded to form cyclopentyl, cyclohexyl, dihydrofuran, tetrahydrofuran, methyltetrahydrofuran, 1,3-dioxol, dihydro-1,3-oxazine, or methyldihydrofuran.

13. L is -CH ２ -ien-CH ２ A compound according to any one of claims 2 to 12, which is O- or -O-, or a pharmaceutically acceptable salt thereof.

14. L is -CH ２ - The compound according to any one of claims 2 to 13, or a pharmaceutically acceptable salt thereof.

15. R ２ is 0, 1, or 2 R ２ａ The compounds according to any one of claims 2 to 14, or pharmaceutically acceptable salts thereof, which are pyrrolyl, furyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidyl, or pyrazinyl, respectively.

16. Each R ２ａ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ A compound according to any one of claims 2 to 15, which is a haloalkoxy, OH, or -CN, or a pharmaceutically acceptable salt thereof.

17. Each R ２ｂ and R ２ｃ These are, independently, hydrogen or C １ -C ４ A compound according to any one of claims 2 to 16, which is alkyl, or a pharmaceutically acceptable salt thereof.

18. R ２ teeth, 【Chemistry 157】 The compound according to any one of claims 2 to 17, or a pharmaceutically acceptable salt thereof.

19. R ２ teeth, 【Chemistry 158】 The compound according to any one of claims 2 to 18, or a pharmaceutically acceptable salt thereof.

20. Each R ３ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ３ａ , -C(O)OR ３ａ , -OC(O)R ３ａ , -C(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ )C(O)(R ３ｂ ), -S(O) ２ R ３ａ , -S(O) ２ N(R) ３ａ ) (Caution ３ｂ ), OH, -CN, C ３ -C ８ A compound according to any one of claims 2 to 19, which is a cycloalkyl or heterocycloalkyl compound, or a pharmaceutically acceptable salt thereof.

21. Each R ３ａ and R ３ｂ These are, independently, hydrogen or C １ -C ４ A compound according to any one of claims 2 to 20, which is alkyl, or a pharmaceutically acceptable salt thereof.

22. Each R ３ｃ Halogen, -NR ３ｃ１ R ３ｃ２ A compound according to any one of claims 2 to 21, or a pharmaceutically acceptable salt thereof, wherein the compound is OH, or -CN.

23. Each R ３ｄ The compound according to any one of claims 2 to 22, or a pharmaceutically acceptable salt thereof, is independently a heteroaryl compound.

24. Each R ３ｅ Independently, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, halogen, or C １ -C ４ A compound according to any one of claims 2 to 23, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

25. Each R ３ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -CN, or C ３ -C ８ A compound according to any one of claims 2 to 24, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

26. Each R ３ Independently, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, halogen, C １ -C ４ Haloalkyl, C １ -C ４ Haloalkoxy, -CN, or C ３ -C ６ A compound according to any one of claims 2 to 25, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

27. each Ｒ３ These are Me, oMe, OEt, CHF, independently. ２ CF ３ , OCHF ２ OCF ３ A compound according to any one of claims 2 to 26, or a pharmaceutically acceptable salt thereof, wherein the compound is F, Br, CN, or cyclopropyl.

28. The compound according to any one of claims 2 to 27, or a pharmaceutically acceptable salt thereof, wherein subscript q is 1, 2, or 3.

29. The compound according to any one of claims 2 to 28, or a pharmaceutically acceptable salt thereof, wherein the subscript n is 1 or 2.

30. The compound is a compound according to any one of claims 2 to 29, having the structure shown in Table 1, or a pharmaceutically acceptable salt thereof.

31. The aforementioned compound has the following structure: 【Chemistry 159】 A compound according to any one of claims 2 to 29, or a pharmaceutically acceptable salt thereof, having the above.

32. structure: [Chemical 160] A compound according to any one of claims 2 to 29, having the following characteristics.

33. The aforementioned compound has the following structure: 【Chemistry 161】 A compound according to any one of claims 2 to 29, or a pharmaceutically acceptable salt thereof, having the above.

34. structure: 【Chemistry 162】 A compound according to any one of claims 2 to 29, having the following characteristics.

35. Formula (II): 【Chemical 163】 A compound having, or a pharmaceutically acceptable salt thereof, During the ceremony, Each R １ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R １ａ , -C(O)OR １ａ , -OC(O)R １ａ , -C(O)N(R １ａ ) (Caution １ｂ ), -N(R １ａ )C(O)(R １ｂ ), -OC(O)N(R １ａ ) (Caution １ｂ ), -N(R １ａ )C(O)(OR １ｂ ), -S(O)R １ａ , -S(O) ２ R １ａ , -S(O) ２ N(R) １ａ ) (Caution １ｂ ), -S(O)(NH)R １ａ , -S(O)(NH)N(R １ａ ) (Caution １ｂ ), -N(R １ａ ) (Caution １ｂ ), OH, -CN, -NO ２ , C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), heterocycloalkyl, (C １ -C ３ Alkyl) (heterocycloalkyl), -O- (heterocycloalkyl), C ６ -C １０ Ariel, (C １ -C ３ (Alkyl) (C ６ -C １０ Aryl), -O-(C ６ -C １０ (aryl), heteroaryl, (C １ -C ３ The alkyl group is a heteroaryl group, or -O-(heteroaryl group), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. １ｃ Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R １ｄ Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R １ｅ Replaced by; Each R １ａ and R １ｂ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R １ｃ Independently, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkoxy, -NR １ｃ１ R １ｃ２ , OH, or -CN; Each R １ｃ１ and R １ｃ２ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R １ｄ Independently, deuterium, C ３ -C ８ Cycloalkyl, heterocycloalkyl, C ６ -C １０ It is aryl or heteroaryl; Each R １ｅ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, C １ -C ６ It is a haloalkoxy, OH, or -CN; Alternatively, two R atoms on adjacent carbon atoms １ The groups, together with the atoms they are bonded to, form 0, 1, 2, 3, 4, 5, or 6 halogens, C １ -C ４ C substituted with alkyl, OH, or -CN ５ -C ８ Forming cycloalkyl or heterocycloalkyl groups; L is -C １ -C ４ Alkylene -, -(C １ -C ４ Alkylene)-O- or -O-; R ２ This is 0, 1, 2, 3, or 4 R ２ａ It is a heteroaryl substituted with; Each R ２ａ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ２ｂ , -C(O)OR ２ｂ , -OC(O)R ２ｂ , -C(O)N(R ２ｂ ) (Caution ２ｃ ), -N(R ２ｂ )C(O)(R ２ｃ ), -S(O) ２ R ２ｂ , -S(O) ２ N(R) ２ｂ ) (Caution ２ｃ ), -N(R ２ｂ ) (Caution ２ｃ ), OH, -CN, or -NO ２ And; Each R ２ｂ and R ２ｃ These are, independently, hydrogen or C １ -C ６ It is alkyl; Y is CH, CR ３ , or N; Each R ３ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ３ａ , -C(O)OR ３ａ , -OC(O)R ３ａ , -C(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ )C(O)(R ３ｂ ), -OC(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ )C(O)(OR ３ｂ ), -S(O)R ３ａ , -S(O) ２ R ３ａ , -S(O) ２ N(R) ３ａ ) (Caution ３ｂ ), -S(O)(NH)R ３ａ , -S(O)(NH)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ ) (Caution ３ｂ ), OH, -CN, -NO ２ , C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), heterocycloalkyl, (C １ -C ３ Alkyl) (heterocycloalkyl), -O- (heterocycloalkyl), C ６ -C １０ Ariel, (C １ -C ３ (Alkyl) (C ６ -C １０ Aryl), -O-(C ６ -C １０ (aryl), heteroaryl, (C １ -C ３ The alkyl group is a heteroaryl group, or -O-(heteroaryl group), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. ３ｃ Substituted with, each alkoxy has 0, 1, 2, or 3 R ３ｄ Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R ３ｅ It is replaced by; or Two R atoms on the same carbon atom ３ Together, they represent an oxo group; Each R ３ａ and R ３ｂ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ｃ Independently, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkoxy, -NR ３ｃ１ R ３ｃ２ , OH, or -CN; Each R ３ｃ１ and R ３ｃ２ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ｄ Independently, C ３ -C ８ It is a cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl compound; Each R ３ｅ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, or C １ -C ６ It is a haloalkoxy; The subscript n is 0, 1, 2, 3, or 4; Subscript q is 0, 1, 2, 3, or 4; During the ceremony, Each heterocycloalkyl is a 3- to 8-membered ring containing 1 to 4 heteroatoms that are N, O, or S; The compound according to claim 1, wherein each heteroaryl is independently a 5-6 membered ring containing 1-4 heteroatoms that are N, O, or S.

36. Formula (IIa): 【Chemistry 164】 A compound according to claim 35, or a pharmaceutically acceptable salt thereof, having the above.

37. Equation (IIb): 【Chemistry 165】 A compound according to claim 35 or 36, or a pharmaceutically acceptable salt thereof, having the above.

38. Formula (IIc): 【Chemistry 166】 A compound according to claim 35 or 36, or a pharmaceutically acceptable salt thereof, having the above.

39. base 【Chemistry 167】 is structure 【Chemical 168】 A compound according to any one of claims 35 to 38, or a pharmaceutically acceptable salt thereof, having the above.

40. Each R １ is independently C １ -C ６ alkyl, C １ -C ６ alkoxy, C １ -C ６ hydroxyalkyl, C ２ -C ６ alkoxyalkyl, halogen, C １ -C ６ haloalkyl, C １ -C ６ haloalkoxy, OH, -CN, C ３ -C ８ cycloalkyl, (C １ -C ３ alkyl)(C ３ -C ８ cycloalkyl), -O-(C ３ -C ８ cycloalkyl), heterocycloalkyl, (C １ -C ３ alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C ６ -C １０ aryl, or heteroaryl, and each alkyl is substituted with 0, 1, 2, or 3 R １ｃ ; and each alkoxy and alkynyl is substituted with 0, 1, 2, or 3 R １ｄ ; or Alternatively, two Rs on adjacent carbons １ combine together with the atoms to which they are attached to form a C ５ -C ８ cycloalkyl or heterocycloalkyl, the compound according to any one of claims 35 to 39, or a pharmaceutically acceptable salt thereof.

41. Each R １ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, OH, C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), C ６ -C １０ It is an aryl or heteroaryl, and each alkyl group has 0 or 1 R １ｃ Substituted with, each alkoxy and alkynyl has 0 or 1 R １ｄ Will it be replaced by; Alternatively, two R atoms on adjacent carbon atoms １ These combine together with the atoms they are bonded to, C ５ -C ８ A compound according to any one of claims 35 to 40, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl or heterocycloalkyl group.

42. Each R １ａ and R １ｂ These are, independently, hydrogen or C １ -C ３ A compound according to any one of claims 35 to 41, which is alkyl, or a pharmaceutically acceptable salt thereof.

43. Each R １ｃ Halogen, -NR １ｃ１ R １ｃ２ A compound according to any one of claims 35 to 42, or a pharmaceutically acceptable salt thereof, wherein the compound is OH or -CN.

44. Each R １ｄ The compound according to any one of claims 35 to 43, or a pharmaceutically acceptable salt thereof, is independently a heteroaryl compound.

45. Each R １ｅ Independently, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, halogen, C １ -C ４ A compound according to any one of claims 35 to 44, which is a haloalkyl or -CN, or a pharmaceutically acceptable salt thereof.

46. Each R １ is independently CH ３ CH ２ CH ３ -C(CH ３ ) ３ OCH ３ CH ２ CH ３ -OCH(CH ３ ) ２ -C(CH ３ ) ２ OH, -C(CH ３ )(CH ２ CH ３ )OH, F, Cl, Br, CF ３ OCHF ２ OCF ３ OCH ２ CF ３ cyclopropyl, cyclopropyloxy, cyclobutyloxy, or 【Chemistry 169】 is; or Two R on adjacent carbons １ The compounds according to any one of claims 35 to 45, or pharmaceutically acceptable salts thereof, which combine with the atoms to which they are bonded to form cyclopentyl, cyclohexyl, dihydrofuran, tetrahydrofuran, methyltetrahydrofuran, 1,3-dioxol, dihydro-1,3-oxazine, or methyldihydrofuran.

47. L is -CH ２ -ien-CH ２ A compound according to any one of claims 35 to 46, which is O- or -O-, or a pharmaceutically acceptable salt thereof.

48. L is -CH ２ - The compound according to any one of claims 35 to 47, or a pharmaceutically acceptable salt thereof.

49. R ２ 0, 1, or 2 R ２ａ The compounds according to any one of claims 35 to 48, or pharmaceutically acceptable salts thereof, which are pyrrolyl, furyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidyl, or pyrazinyl, respectively.

50. Each R ２ａ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ A compound according to any one of claims 35 to 49, which is a haloalkoxy, OH, or -CN, or a pharmaceutically acceptable salt thereof.

51. Each R ２ｂ and R ２ｃ These are, independently, hydrogen or C １ -C ４ A compound according to any one of claims 35 to 50, which is alkyl, or a pharmaceutically acceptable salt thereof.

52. R ２ teeth, 【Chemistry 170】 The compound according to any one of claims 35 to 51, or a pharmaceutically acceptable salt thereof.

53. Each R ３ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ３ａ , -C(O)OR ３ａ , -OC(O)R ３ａ , -C(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ )C(O)(R ３ｂ ), -S(O) ２ R ３ａ , -S(O) ２ N(R) ３ａ ) (Caution ３ｂ ), OH, -CN, C ３ -C ８ A compound according to any one of claims 35 to 52, which is a cycloalkyl or heterocycloalkyl compound, or a pharmaceutically acceptable salt thereof.

54. Each R ３ａ and R ３ｂ These are, independently, hydrogen or C １ -C ４ A compound according to any one of claims 35 to 53, which is alkyl, or a pharmaceutically acceptable salt thereof.

55. Each R ３ｃ Halogen, -NR ３ｃ１ R ３ｃ２ A compound according to any one of claims 35 to 57, or a pharmaceutically acceptable salt thereof, wherein the compound is OH or -CN.

56. Each R ３ｄ The compound according to any one of claims 35 to 54, or a pharmaceutically acceptable salt thereof, is independently a heteroaryl compound.

57. Each R ３ｅ Independently, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, halogen, or C １ -C ４ A compound according to any one of claims 35 to 56, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

58. Each R ３ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -CN, or C ３ -C ８ A compound according to any one of claims 35 to 55, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

59. Each R ３ Independently, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkyl, C １ -C ４ Haloalkoxy, -CN, or C ３ -C ６ A compound according to any one of claims 35 to 58, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

60. each Ｒ３ These are Me, OMe, CHF, independently. ２ CF ３ , OCHF ２ OCF ３ The compound according to any one of claims 35 to 59, or a pharmaceutically acceptable salt thereof, which is cyclopropyl.

61. The compound according to any one of claims 35 to 60, or a pharmaceutically acceptable salt thereof, wherein subscript q is 1, 2, or 3.

62. The compound according to any one of claims 35 to 61, or a pharmaceutically acceptable salt thereof, wherein the subscript n is 0 or 1.

63. The compound is the compound according to any one of claims 35 to 62, having the structure shown in Table 2, or a pharmaceutically acceptable salt thereof.

64. The aforementioned compound has the following structure: 【Chemistry 171】 A compound according to any one of claims 35 to 62, or a pharmaceutically acceptable salt thereof, having the above.

65. structure: 【Chemistry 172】 A compound according to any one of claims 35 to 62, having the following characteristics.

66. The aforementioned compound has the following structure: 【Chemistry 173】 A compound according to any one of claims 35 to 62, or a pharmaceutically acceptable salt thereof, having the above.

67. structure: 【Chemistry 174】 A compound according to any one of claims 35 to 62, having the following characteristics.

68. The aforementioned compound has the following structure: 【Chemistry 175】 A compound according to any one of claims 35 to 62, or a pharmaceutically acceptable salt thereof, having the above.

69. structure: 【Chemistry 176】 A compound according to any one of claims 35 to 62, having the following characteristics.

70. Formula (III): 【Chemistry 177】 A compound having, or a pharmaceutically acceptable salt thereof, During the ceremony, Each R １ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R １ａ , -C(O)OR １ａ , -OC(O)R １ａ , -C(O)N(R １ａ ) (Caution １ｂ ), -N(R １ａ )C(O)(R １ｂ ), -OC(O)N(R １ａ ) (Caution １ｂ ), -N(R １ａ ) C(O)(OR １ｂ ), -S(O)R １ａ , -S(O) ２ R １ａ , -S(O) ２ N(R) １ａ ) (Caution １ｂ ), -S(O)(NH)R １ａ , -S(O)(NH)N(R １ａ ) (Caution １ｂ ), -N(R １ａ ) (Caution １ｂ ), OH, -CN, -NO ２ , C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), heterocycloalkyl, (C １ -C ３ Alkyl) (heterocycloalkyl), -O- (heterocycloalkyl), C ６ -C １０ Ariel, (C １ -C ３ (Alkyl) (C ６ -C １０ Aryl), -O-(C ６ -C １０ (aryl), heteroaryl, (C １ -C ３ The alkyl group is a heteroaryl group, or -O-(heteroaryl group), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. １ｃ Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R １ｄ Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R １ｅ Replaced by; Each R １ａ and R １ｂ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R １ｃ Independently, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkoxy, -NR １ｃ１ R １ｃ２ , OH, or -CN; Each R １ｃ１ and R １ｃ２ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R １ｄ Independently, deuterium, C ３ -C ８ Cycloalkyl, heterocycloalkyl, C ６ -C １０ It is aryl or heteroaryl; Each R １ｅ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, C １ -C ６ It is a haloalkoxy, OH, or -CN; Alternatively, two R atoms on adjacent carbon atoms １ The groups, together with the atoms they are bonded to, form 0, 1, 2, 3, 4, 5, or 6 halogens, C １ -C ４ C substituted with alkyl, OH, or -CN ５ -C ８ Forming cycloalkyl or heterocycloalkyl groups; L is -C １ -C ４ Alkylene -, -(C １ -C ４ Alkylene)-O- or -O-; R ２ This is 0, 1, 2, 3, or 4 R ２ａ It is a heteroaryl substituted with; Each R ２ａ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ２ｂ , -C(O)OR ２ｂ , -OC(O)R ２ｂ , -C(O)N(R ２ｂ ) (Caution ２ｃ ), -N(R ２ｂ )C(O)(R ２ｃ ), -S(O) ２ R ２ｂ , -S(O) ２ N(R) ２ｂ ) (Caution ２ｃ ), -N(R ２ｂ ) (Caution ２ｃ ), OH, -CN, or -NO ２ And; Each R ２ｂ and R ２ｃ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ３ａ , -C(O)OR ３ａ , -OC(O)R ３ａ , -C(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ )C(O)(R ３ｂ ), -OC(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ ) C(O)(OR ３ｂ ), -S(O)R ３ａ , -S(O) ２ R ３ａ , -S(O) ２ N(R) ３ａ ) (Caution ３ｂ ), -S(O)(NH)R ３ａ , -S(O)(NH)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ ) (Caution ３ｂ ), OH, -CN, -NO ２ , C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), heterocycloalkyl, (C １ -C ３ Alkyl) (heterocycloalkyl), -O- (heterocycloalkyl), C ６ -C １０ Ariel, (C １ -C ３ (Alkyl) (C ６ -C １０ Aryl), -O-(C ６ -C １０ (aryl), heteroaryl, (C １ -C ３ The alkyl group is a heteroaryl group, or -O-(heteroaryl group), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. ３ｃ Substituted with, each alkoxy has 0, 1, 2, or 3 R ３ｄ Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R ３ｅ It is replaced by; or Two R atoms on the same carbon atom ３ Together, they represent an oxo group; Each R ３ａ and R ３ｂ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ｃ Independently, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkoxy, -NR ３ｃ１ R ３ｃ２ , OH, or -CN; Each R ３ｃ１ and R ３ｃ２ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ｄ Independently, C ３ -C ８ It is a cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl compound; Each R ３ｅ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, or C １ -C ６ It is a haloalkoxy; R ４ is hydrogen or C １ -C ６ It is alkyl; The subscript n is 0, 1, 2, 3, or 4; Subscript q is 0, 1, 2, 3, or 4; During the ceremony, Each heterocycloalkyl is a 3- to 8-membered ring containing 1 to 4 heteroatoms that are N, O, or S; The compound according to claim 1, wherein each heteroaryl is independently a 5-6 membered ring containing 1-4 heteroatoms that are N, O, or S.

71. Formula (IIIa): 【Chemistry 178】 A compound according to claim 70, or a pharmaceutically acceptable salt thereof, having the above.

72. Formula (IIIb): 【Chemistry 179】 A compound according to claim 70 or 71, or a pharmaceutically acceptable salt thereof, having the above.

73. The compound is the compound according to any one of claims 70 to 72, having the structure shown in Table 3, or a pharmaceutically acceptable salt thereof.

74. Formula (IV): 【Chemistry 180】 A compound having, or a pharmaceutically acceptable salt thereof, During the ceremony, Each R １ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R １ａ , -C(O)OR １ａ , -OC(O)R １ａ , -C(O)N(R １ａ ) (Caution １ｂ ), -N(R １ａ )C(O)(R １ｂ ), -OC(O)N(R １ａ ) (Caution １ｂ ), -N(R １ａ ) C(O)(OR １ｂ ), -S(O)R １ａ , -S(O) ２ R １ａ , -S(O) ２ N(R) １ａ ) (Caution １ｂ ), -S(O)(NH)R １ａ , -S(O)(NH)N(R １ａ ) (Caution １ｂ ), -N(R １ａ ) (Caution １ｂ ), OH, -CN, -NO ２ , C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), heterocycloalkyl, (C １ -C ３ Alkyl) (heterocycloalkyl), -O- (heterocycloalkyl), C ６ -C １０ Ariel, (C １ -C ３ (Alkyl) (C ６ -C １０ Aryl), -O-(C ６ -C １０ (aryl), heteroaryl, (C １ -C ３ The alkyl group is a heteroaryl group, or -O-(heteroaryl group), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. １ｃ Substituted with, each alkoxy and alkynyl has 0, 1, 2, or 3 R １ｄ Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R １ｅ Replaced by; Each R １ａ and R １ｂ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R １ｃ Independently, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkoxy, -NR １ｃ１ R １ｃ２ , OH, or -CN; Each R １ｃ１ and R １ｃ２ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R １ｄ Independently, deuterium, C ３ -C ８ Cycloalkyl, heterocycloalkyl, C ６ -C １０ It is aryl or heteroaryl; Each R １ｅ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, C １ -C ６ It is a haloalkoxy, OH, or -CN; Alternatively, two R atoms on adjacent carbon atoms １ The groups, together with the atoms they are bonded to, form 0, 1, 2, 3, 4, 5, or 6 halogens, C １ -C ４ C substituted with alkyl, OH, or -CN ５ -C ８ Forming cycloalkyl or heterocycloalkyl groups; L is -C １ -C ４ Alkylene -, -(C １ -C ４ Alkylene)-O- or -O-; R ２ This is 0, 1, 2, 3, or 4 R ２ａ It is a heteroaryl substituted with; Each R ２ａ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ２ｂ , -C(O)OR ２ｂ , -OC(O)R ２ｂ , -C(O)N(R ２ｂ ) (Caution ２ｃ ), -N(R ２ｂ )C(O)(R ２ｃ ), -S(O) ２ R ２ｂ , -S(O) ２ N(R) ２ｂ ) (Caution ２ｃ ), -N(R ２ｂ ) (Caution ２ｃ ), OH, -CN, or -NO ２ And; Each R ２ｂ and R ２ｃ These are, independently, hydrogen or C １ -C ６ It is alkyl; Y is CH, CR3, or N; Each R ３ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C ２ -C ６ Alkoxyalkyls, halogens, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, -C(O)R ３ａ , -C(O)OR ３ａ , -OC(O)R ３ａ , -C(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ )C(O)(R ３ｂ ), -OC(O)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ ) C(O)(OR ３ｂ ), -S(O)R ３ａ , -S(O) ２ R ３ａ , -S(O) ２ N(R) ３ａ ) (Caution ３ｂ ), -S(O)(NH)R ３ａ , -S(O)(NH)N(R ３ａ ) (Caution ３ｂ ), -N(R ３ａ ) (Caution ３ｂ ), OH, -CN, -NO ２ , C ３ -C ８ Cycloalkyl, (C １ -C ３ (Alkyl) (C ３ -C ８ Cycloalkyl), -O-(C ３ -C ８ Cycloalkyl), heterocycloalkyl, (C １ -C ３ Alkyl) (heterocycloalkyl), -O- (heterocycloalkyl), C ６ -C １０ Ariel, (C １ -C ３ (Alkyl) (C ６ -C １０ Aryl), -O-(C ６ -C １０ (aryl), heteroaryl, (C １ -C ３ The alkyl group is a heteroaryl group, or -O-(heteroaryl group), where each alkyl group has 0, 1, 2, 3, 4, 5, or 6 R groups. ３ｃ Substituted with, each alkoxy has 0, 1, 2, or 3 R ３ｄ Substituted with, each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0, 1, 2, or 3 R ３ｅ It is replaced by; or Two R atoms on the same carbon atom ３ Together, they represent an oxo group; Each R ３ａ and R ３ｂ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ｃ Independently, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkoxy, -NR ３ｃ１ R ３ｃ２ , OH, or -CN; Each R ３ｃ１ and R ３ｃ２ These are, independently, hydrogen or C １ -C ６ It is alkyl; Each R ３ｄ Independently, C ３ -C ８ It is a cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl compound; Each R ３ｅ Independently, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, or C １ -C ６ It is a haloalkoxy; R ４ is hydrogen or C １ -C ６ It is alkyl; The subscript n is 0, 1, 2, 3, or 4; Subscript q is 0, 1, 2, 3, or 4; During the ceremony, Each heterocycloalkyl is a 3- to 8-membered ring containing 1 to 4 heteroatoms that are N, O, or S; The compound according to claim 1, wherein each heteroaryl is independently a 5-6 membered ring containing 1-4 heteroatoms that are N, O, or S.

75. Formula (IVa): 【Chemistry 181】 A compound according to claim 74, or a pharmaceutically acceptable salt thereof, having the above.

76. Formula (IVb): 【Chemistry 182】 A compound according to claim 74 or 75, or a pharmaceutically acceptable salt thereof, having the above.

77. Formula (IVc): 【Chemistry 183】 A compound according to claim 74 or 75, or a pharmaceutically acceptable salt thereof, having the above.

78. The compound is the compound according to any one of claims 74 to 77, having the structure shown in Table 4, or a pharmaceutically acceptable salt thereof.

79. The aforementioned compound, 4-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-3-methoxybenzamide(14)e 4-((1H-pyrazole-1-yl)methyl)-3-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)benzamide 4-((1H-pyrazole-1-yl)methyl)-N-((2-ethoxy-6-methoxyphenyl)sulfonyl)-3-methoxybenzamide(67), 5-((1H-pyrazole-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide(203), 5-((1H-pyrazole-1-yl)methyl)-N-((5-ethyl-2-methoxyphenyl)sulfonyl)-6-methoxypicolinamide (204), 5-((1H-pyrazole-1-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)picolinamide (224), 5-((1H-pyrazole-1-yl)methyl)-6-cyclopropyl-N-((2,6-dimethoxyphenyl)sulfonyl)picolinamide (229), 5-((1H-pyrazole-1-yl)methyl)-N-((3-chloro-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide (241), 5-((1H-pyrazole-1-yl)methyl)-N-((4-bromo-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide (285), 4-((1H-pyrazole-1-yl)methyl)-3-methoxy-N-((2-methyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)benzamide (314), A compound according to claim 1 and a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

80. The compound according to claim 79, wherein the compound is 4-((1H-pyrazole-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.

81. The compound according to claim 79, wherein the compound is 4-((1H-pyrazole-1-yl)methyl)-N-((5-hydroxy-2-methoxyphenyl)sulfonyl)-3-methoxybenzamide, or a pharmaceutically acceptable salt thereof.

82. The compound according to claim 79, wherein the compound is 4-((1H-pyrazole-1-yl)methyl)-N-((2-ethoxy-6-methoxyphenyl)sulfonyl)-3-methoxybenzamide, or a pharmaceutically acceptable salt thereof.

83. The compound according to claim 79, wherein the compound is 4-((1H-pyrazole-1-yl)methyl)-3-methoxy-N-(2-methoxy-6-(2,2,2-trifluoroethoxy)phenylsulfonimidoyl)benzamide, or a pharmaceutically acceptable salt thereof.

84. The compound according to claim 79, wherein the compound is 5-((1H-pyrazole-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-6-methoxypicolinamide, or a pharmaceutically acceptable salt thereof.

85. The compound according to claim 79, wherein the compound is 5-((1H-pyrazole-1-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)picolinamide, or a pharmaceutically acceptable salt thereof.

86. The compound according to claim 79, wherein the compound is 5-((1H-pyrazole-1-yl)methyl)-6-cyclopropyl-N-((2,6-dimethoxyphenyl)sulfonyl)picolinamide, or a pharmaceutically acceptable salt thereof.

87. The compound according to claim 79, wherein the compound is 5-((1H-pyrazole-1-yl)methyl)-N-((3-chloro-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide, or a pharmaceutically acceptable salt thereof.

88. The compound according to claim 79, wherein the compound is 5-((1H-pyrazole-1-yl)methyl)-N-((4-bromo-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide, or a pharmaceutically acceptable salt thereof.

89. The compound according to claim 79, wherein the compound is 4-((1H-pyrazole-1-yl)methyl)-3-methoxy-N-((2-methyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)benzamide, or a pharmaceutically acceptable salt thereof.

90. A pharmaceutical composition comprising a compound according to any one of claims 1 to 89 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

91. A compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

92. A method for adjusting KAT6A in a subject requiring adjustment, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof.

93. A method for treating a disease or disorder in which KAT6A is mediated in a subject, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, to the subject in need thereof.

94. The method according to claim 93, wherein the disease or disorder is cancer.

95. The aforementioned cancers include cerebral glioma, glioblastoma, astrocytoma, pleomorphic cancer, Bannayan-Zonana syndrome, Cowden disease, Lhermitt-Dukuro disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell carcinoma, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, tubular adenocarcinoma, adenosquamous cell carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma and thyroid cancer, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, and acute lymphoblastic T-cell leukemia. The method according to claim 94, selected from hematological diseases, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, megakaryoblastic leukemia, multiple myeloma, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, vulvar cancer, uterine cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor, neuroendocrine cancer, testicular cancer, and virus-related cancer.

96. Use of a compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical for treating a disease or disorder mediated by KAT6A.

97. A compound according to any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder mediated by KAT6A.

98. The method according to any one of claims 93 to 95, further comprising administering an additional anticancer agent.

99. The method according to claim 98, wherein the additional anticancer agent is selected from HER2 inhibitors, mTOR inhibitors, CDK4 / 6 inhibitors, CDK2 selective inhibitors, CDK4 selective inhibitors, PI3 kinase inhibitors, PIK3CA inhibitors, aromatase inhibitors, antibodies or inhibitors against PD-1, PD-L1, or CTLA-4, antibodies or inhibitors against EGFR, PGFR, or IGFR, USP inhibitors, or AKT inhibitors.

100. The method according to claim 99, wherein the additional anticancer agent is a HER2 inhibitor.

101. The method according to claim 100, wherein the HER2 inhibitor is selected from tucatinib, trastuzumab, pertuzumab, ado-trastuzumab, trastuzumab emtansine, ado-trastuzumab emtansine, trastuzumab deruxtecan, pertuzumab, lapatinib, and neratinib.

102. The method according to claim 99, wherein the anticancer agent is an mTOR inhibitor.

103. The method according to claim 102, wherein the mTOR inhibitor is selected from everolimus, temsirolimus, and LY30234.

104. The method according to claim 99, wherein the anticancer agent is a CDK4 / 6 inhibitor.

105. The method according to claim 104, wherein the CDK4 / 6 inhibitor is selected from palbociclib, abemaciclib, ribociclib, rerocyclib, trilaciclib, and SHR6390.

112. The method according to claim 99, wherein the additional anticancer agent is a CDK2 selective inhibitor.

113. The method according to claim 112, wherein the CDK2 selective inhibitor is PF-07104091 (tagtocyclib).

114. The method according to claim 99, wherein the additional anticancer agent is a CDK4 selective inhibitor.

115. The method according to claim 114, wherein the CDK-4 selective inhibitor is PF-07220060 (atelmociclib).

116. The method according to claim 99, wherein the anticancer agent is a PI3 kinase inhibitor.

117. The method according to claim 102, wherein the PI3 kinase inhibitor is selected from perifosine, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145.

118. The method according to claim 99, wherein the additional anticancer agent is a PIK3CA inhibitor.

119. The method according to claim 104, wherein the PIK3CA inhibitor is selected from alpelisib, taselicib, LY3023414, inavolisib, STX-478, RLY-2608, LOXO-783, OKI-219, and TOS-358.

120. The method according to claim 99, wherein the additional anticancer agent is an aromatase inhibitor.

121. The method according to claim 106, wherein the aromatase inhibitor is selected from aminoglutethimide, testactone, anastrozole, letrozole, exemestane, volozol, formestan, fadrozol, 4-hydroxyandrostenedione, 1,4,6-androstatriene-3,17-dione, and 4-androsten-3,6,17-trione.

122. The method according to claim 106, wherein the aromatase inhibitor is selected from anastrozole, letrozole, and exemestane.

123. The method according to claim 199, wherein the additional anticancer agent is a USP1 inhibitor.

123. The method according to claim 99, wherein the additional anticancer agent is an AKT inhibitor.

124. The method according to claim 123, wherein the AKT inhibitor is selected from capivacertib, ipatasertib, afrecertib, and uprosertib.

125. The method according to claim 124, wherein the AKT inhibitor is capivacertib.

126. The method according to any one of claims 93 to 95, further comprising administering an estrogen receptor antagonist or an estrogen receptor partial antagonist.

127. The method according to claim 126, wherein the estrogen receptor antagonist or estrogen receptor partial antagonist is a selective estrogen receptor modifier.

128. The method according to claim 127, wherein the selective estrogen receptor modifier is selected from tamoxifen, endoxifen, raloxifene, toremifene, rasofoxifene, ospemifene, elastrant, and bazedoxifene.

129. The method according to claim 126, wherein the estrogen receptor antagonist or estrogen receptor partial antagonist is a selective estrogen receptor degrading agent.

130. The method according to claim 129, wherein the selective estrogen receptor degrading agent is selected from fulvestrant, camizestrant, parazestrant, imurunestrant, elastrant, and giredestrant.

131. The method according to claim 130, wherein the selective estrogen receptor degrading agent is parazestrant.

132. The method according to claim 126, wherein the estrogen receptor antagonist or estrogen receptor partial antagonist is a complete estrogen receptor antagonist.

133. The method according to claim 132, wherein the complete estrogen receptor antagonist is selected from fulvestrant and parazestrant.

134. The method according to claim 133, wherein the complete estrogen receptor antagonist is a parazestrant.

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