KAT6 inhibitors

Abstract

Disclosed herein are compounds useful as KAT6 inhibitors and pharmaceutical compositions comprising the same. Also disclosed are methods for treating a subject for a disorder or disease responsive to inhibition of KAT6 activity. In one embodiment, the compounds have Formula (I) or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof, wherein the values of the variables (e.g., ring B, A ' , A 2 , A 3 , A 4 , A 5 , X l , L, R 62 , R 63 , R 64 , R 7 , and n) are disclosed herein. (I).

Description

Technical Field

[0001] This article discloses compounds used as KAT6 inhibitors. It also discloses the use of these compounds in inhibiting KAT6 activity and in the treatment of breast cancer. Background of the Invention ε-Lysine acetylation is one of the key mechanisms governing a cell's ability to respond to intracellular and extracellular signals. Lysine acetylation levels are closely controlled by lysine acetyltransferases (KAT) and lysine deacetylases (KDAC). KAT is a highly diverse group of enzymes that transfer the acetyl moiety from acetyl-CoA to lysine residues, while KDAC removes these moieties. To date, 37 mammalian proteins have been shown to possess endogenous KAT activity, including proteins from the MYST (Moz, Ybf2 / Sas3, Sas2, Tip60) family, the p300 and CBP families, the SRC / p160 family, and the GCN5 and PCAF families (Sheikh, BN, and Akhtar, A. (2019)). KATs act as detectors, integrators, and modulators of the cellular environment. Nat Rev Genet, 20 (1), 7-23). ​​KAT6 proteins (KAT6A and KAT6B) belong to the MYST family of acetyltransferases, which includes five members: KAT5 (also known as TIP60), KAT6A (also known as MOZ, MYST3), KAT6B (also known as MORF, MYST4), KAT7 (also known as HBO1) and KAT8 (also known as MOF) (Sheikh, BN and Akhtar, A. (2019).

[0003] KAT6A is overexpressed in multiple tumor types (Wiesel-Motiuk, N. and Assaraf, YG (2020). The lysine acetyltransferases KAT6A and KAT6B play key roles in physiology and pathology. Drug Resist Updat, 53 (100729.). Dysregulation of KAT6 protein expression is known to support tumor progression, and aberrant histone acetylation can lead to tumor formation and cancer progression.

[0004] For example, in breast cancer, KAT6A has been found to be amplified and / or overexpressed in 10–15% of breast cancers and approximately 22% of ER+ HER2- breast cancers (Yu, L., Liang, Y., Cao, X., Wang, X., Gao, H., Lin, SY, Li, K. (2017). Identification of MYST3 as a novel epigenetic activator of ERalpha frequently amplified in breast cancer. Oncogene, 36 (20), 2910-2918. doi:10.1038 / onc.2016.433).

[0005] Therefore, KAT6 inhibitors have potential applications in the treatment of breast cancer. Summary of the Invention

[0006] In one embodiment, the compound of formula (I) is disclosed herein: (I), Or its pharmaceutically acceptable salt or its deuterated analogue or its N-oxide or its tautomer, wherein the variable (e.g., A) 1 A 2 A 3 A 4 A 5 X 1 Ring B, L, R 62 R 63 R 64 R 7 The values ​​of (and n) are as described in this article.

[0007] This document also discloses pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof.

[0008] This article also discloses a method for treating breast cancer, the method comprising administering to a subject in need a compound of formula (I) or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof.

[0009] This document also discloses the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof for the treatment of breast cancer in a subject of need, comprising administering a therapeutically effective amount of the compound to the subject.

[0010] This document also discloses compounds of formula (I) or pharmaceutically acceptable salts thereof or their deuterated analogs thereof or their N-oxides thereof or their tautomers for the treatment of breast cancer in a subject in need, said treatment comprising administering a therapeutically effective amount of said compound to said subject.

[0011] This article also discloses the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof in the manufacture of a medicament that may be used to treat breast cancer in subjects of need. Detailed Implementation

[0012] The following terms have the meanings indicated throughout this specification: Unless otherwise expressly indicated herein, as used herein (including accompanying aspects), singular terms (such as “a / an” and “the”) include their respective multiple indicators.

[0013] Unless otherwise expressly indicated herein, the term “or” is used to mean the term “and / or” and is used interchangeably with the term “and / or”.

[0014] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups, containing 1 to 18 (such as 1 to 12, further such as 1 to 10, even further such as 1 to 8, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C...) 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3, 3-Dimethyl-2-butyl. The alkyl group defined herein may optionally be deuterated or tritized.

[0015] The term "propyl" refers to 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0016] The term “butyl” refers to 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), or 1,1-dimethylethyl or tert-butyl (“t-Bu”).

[0017] The term "pentyl" refers to 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl.

[0018] The term "hexyl" refers to 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0019] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0020] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, and iodine). Examples of haloalkyl groups include halogenated C-aryl groups. 1-8 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-5 Alkyl, halogenated C 1-4 Alkyl or halogen C 1-3 Alkyl groups, but not limited to -CF3, -CH2Cl, -CH2CF3, -CHCl2, -CF3, etc.

[0021] The term "deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms are surrounded by one or more deuterium atoms. 2 H)-substituted alkyl groups. Examples of deuterated alkyl groups include, but are not limited to, C... 1-8 Deuterated alkyl, C 1-6 Deuterated alkyl, C 1-4 Deuterated alkyl groups, -CD3, -CHD2, -CH2D, etc.

[0022] The term "alkoxy" refers to an alkyl group attached to a molecule via oxygen. This includes the fact that the alkyl moiety can be straight-chain or branched. For example, the term "C 1-6 "Alkoxy" refers to an alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms linked to a molecule via oxygen, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Therefore, alkoxy groups can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexyloxy.

[0023] The term "alkenyl" refers to a hydrocarbon group selected from straight-chain and branched-chain hydrocarbon groups, which contains at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alkenyl (e.g., C...) 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propyl-1-enyl, propyl-2-enyl, 2-methylpropyl-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl.

[0024] The term "alkynyl" refers to a hydrocarbon group selected from straight-chain and branched-chain hydrocarbon groups, which contains at least one C≡C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alkynyl (e.g., C...) 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propynyl), 1-butynyl, 2-butynyl and 3-butynyl.

[0025] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyl groups.

[0026] For example, a cycloalkyl group may contain 3 to 12 carbon atoms (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4). More specifically, the cycloalkyl group may be selected from a monocyclic group containing 3 to 12 carbon atoms (such as 3 to 10, further such as 3 to 8, 3 to 6). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In particular, saturated monocyclic cycloalkyl groups (e.g., C16, C26, C36, C46, ​​C56, C6 ... 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, the cycloalkyl group is a monocyclic ring (abbreviated as C10) containing 3 to 6 carbon atoms. 3-6 Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged in a fused bicyclic arrangement selected from the [4, 4], [4, 5], [5, 5], [5, 6], and [6, 6] ring systems, or arranged in a bridged bicyclic arrangement selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include those bicyclic arrangements selected from the [5, 6] and [6, 6] ring systems.

[0027] The term "spirocycloalkyl" refers to a cyclic structure containing carbon atoms and consisting of at least two rings sharing one atom. The term "7- to 12-membered spirocycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and consisting of at least two rings sharing one atom.

[0028] The term “fused cycloalkyl” refers to a bicyclic cycloalkyl group as defined herein, which is saturated and formed by two or more rings sharing two adjacent atoms.

[0029] The term "bridged cycloalkyl" refers to a cyclic structure containing carbon atoms and consisting of two rings sharing two non-adjacent atoms. The term "7- to 10-membered bridged cycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and consisting of two rings sharing two non-adjacent atoms.

[0030] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group with 3 to 10 carbon atoms, having a monocyclic or multiple rings and at least one double bond, preferably 1 to 2 double bonds. In one embodiment, the cycloalkenyl group is cyclopentenyl or cyclohexenyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, preferably cyclohexenyl.

[0031] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group with 5 to 10 carbon atoms, having a monocyclic or multiple rings and at least one triple bond.

[0032] The term "aryl" used alone or in combination with other terms refers to a group selected from the following: 5- and 6-membered carbon rings, aromatic rings, such as phenyl; Bicyclic systems, such as 7- to 12-membered bicyclic systems, wherein at least one ring is a carbocyclic and aromatic, such as naphthyl and indanyl; and Tricyclic systems, such as 10- to 15-membered tricyclic systems, in which at least one ring is a carbocyclic ring and an aromatic ring, such as a fluorene ring.

[0033] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably in this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 cyclic carbon atoms (i.e., C64, C16, C2 ... 5-10 Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthraceneyl, phenanthrene, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthyl ring (naphth-1-yl or naphth-2-yl) or a benzene ring. In some embodiments, the aromatic hydrocarbon ring is a benzene ring.

[0034] The term "heteroaryl" refers to a group selected from the following: A 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, for example, 1 to 4, or in some embodiments 1 to 3, and in some embodiments 1 to 2 heteroatoms selected from nitrogen (N), sulfur (S), and oxygen (O), wherein the remaining ring atom is carbon; A 7- to 12-membered bicyclic ring comprising at least one heteroatom, for example, 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon and wherein at least one ring is aromatic and at least one heteroatom is present in said aromatic ring; and The 11- to 14-membered tricyclic ring contains at least one heteroatom, for example, 1 to 4, or 1 to 3 in some embodiments, or 1 or 2 heteroatoms selected from N, O and S in other embodiments, wherein the remaining ring atoms are carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0035] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atom in the ring of the heteroaryl group can be oxidized to form an N-oxide.

[0036] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably in this disclosure. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 cyclic members and 1, 2, 3, or 4 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring member is carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring, which is monocyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring, which is bicyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen, sulfur, and oxygen.

[0037] Examples of heteroaryl or monocyclic or bicyclic aromatic heterocycles include, but are not limited to (as numbered from the bonding position assigned priority 1), pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cyclolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiazolyl, thiadiazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, thiophenyl (such as thiophene-2-yl, thiophene-3-yl), triazinyl, benzothiophenyl, furanyl (furyl / furanyl), benzofuranyl, benzimidazolyl, indole, isoyindole, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1, 2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrroloyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridinyl, purineyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2, 3-Diazolyl, 1-Thia-2,4-Diazolyl, 1-Thia-2,5-Diazolyl, 1-Thia-3,4-Diazolyl, furazolyl (such as furazol-2-yl, furazol-3-yl), benzofurazolyl, benzothiophenyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, furan-pyridyl, benzothiazolyl (such as benzo[d]thiazolyl-6-yl), and indazoleyl (such as 1H-indazole-5-yl).

[0038] "Heterocyclic alkyl", "heterocyclic group" or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclic alkyl group containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, wherein the remaining ring member is carbon, including monocyclic, fused, bridged and spirocyclic, i.e. containing monocyclic heterocyclic groups, bridged heterocyclic groups, spirocyclic groups and fused heterocyclic groups.

[0039] The term “optionally oxidized sulfur” as used in this article refers to S, SO or SO2.

[0040] The term "monocyclic heterocyclic group" refers to a monocyclic group in which at least one ring member (e.g., 1-3 heteroatoms, 1 or 2 heteroatoms) is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0041] Exemplary monocyclic 4- to 9-membered heterocyclic groups include, but are not limited to (as numbered from the bonding position assigned priority 1), pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2, 5-Piperazinyl, pyranyl, morpholinyl / morpholino, morpholin-2-yl, morpholin-3-yl, oxacyclopropyl, azircyclopropane-1-yl, azircyclopropane-2-yl, azircyclooctane-1-yl, azircyclooctane-2-yl, azircyclooctane-3-yl, azircyclooctane-4-yl, azircyclooctane-5-yl, thiohexacyclopropyl, azircyclobutane-1-yl, azircyclobutane-2-yl, azircyclobutane-3-yl, oxacyclobutyl, thiohexacyclobutyl, 1,2-dithiohexacyclobutyl, 1, 3-Dithioheterobutyl, dihydropyridyl, tetrahydropyridyl, thiomorpholinyl, thiaxylyl, piperazinyl, homopiperazinyl, homopiperidinyl, azirmonoheptane-1-yl, azirmonoheptane-2-yl, azirmonoheptane-3-yl, azirmonoheptane-4-yl, oxeheptyl, thioheptyl, 1,4-oxothioheptyl, 1,4-dioxeheptyl, 1,4-oxothioheptyl, 1,4-oxazhepyl, 1,4-dithioheptyl, 1,4-thioazhepyl and 1,4-diazahepyl, 1,4-dithioheptyl, 1, 4-Azathiocyclohexyl, oxazathiocyclohexyl, diazathiocyclohexyl, thiozathiocyclohexyl, dihydrothiophene, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxane, 1,3-dioxanepentyl, pyrazolinyl, pyrazolylalkyl, dithiocyclohexyl, dithiopentyl, pyrazolylalkyl, imidazolinyl, pyrimidinoneyl, or 1,1-dioxo-thiomorpholinyl.

[0042] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group, wherein each ring is connected by a common carbon atom (called a spiro atom), and the heterocyclic group contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon. One or more rings of the spiroheterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the spiroheterocyclic group is 6- to 14-membered, and more preferably 7- to 12-membered. Depending on the number of common spiro atoms, spiroheterocyclic groups are classified as mono-spiroheterocyclic groups, di-spiroheterocyclic groups, or poly-spiroheterocyclic groups, and preferably mono-spiroheterocyclic or di-spiroheterocyclic groups, and more preferably 4-membered / 3-membered, 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spiroheterocyclic groups. Representative examples of spiroheterocyclic groups include, but are not limited to, the following groups: 2,3-dihydrospiro[indene-1,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indene-1,2'-pyrrolidine]-1'-yl), 1,3-dihydrospiro[indene-2,2'-pyrrolidine] (e.g., 1,3-dihydrospiro[indene-2,2'-pyrrolidine]-1'-yl), and 1,3-dihydrospiro[indene-2,2'-pyrrolidine] (e.g., 1,3-dihydrospiro[indene-2,2'-pyrrolidine]-1'-yl). 2'-pyrrolidine]-1'-yl), azaspiro[2,4]heptane (e.g., 5-azaspiro[2,4]heptane-5-yl), 2-oxa-6-azaspiro[3,3]heptane (e.g., 2-oxa-6-azaspiro[3,3]hept-6-yl), azaspiro[3,4]octane (e.g., 6-azaspiro[3,4]octane-6-yl), 2-oxa-6-azaspiro[3,4]octane (e.g., 2-oxa-6-azaspiro[3,4]octane-6-yl), azaspiro[3,4]octane (e.g., 6-azaspiro[3,4]octane-6-yl), azaspiro[3,4]octane (e.g., 6-azaspiro[3,4]octane-6-yl), 1, 7-Dioxaspiro[4.5]decane, 2-oxa-7-aza-spiro[4.4]nonane (e.g., 2-oxa-7-aza-spiro[4.4]non-7-yl), 7-oxa-spiro[3.5]nonyl and 5-oxa-spiro[2.4]heptyl.

[0043] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group, wherein each ring in the system shares a pair of adjacent atoms (carbon and carbon or carbon and nitrogen) with another ring. The heterocyclic group contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds, but the fused heterocyclic group does not have a fully conjugated π-electron system. Preferably, the fused heterocyclic group is 6- to 14-membered, and more preferably 7- to 12-membered or 7- to 10-membered. Depending on the number of member rings, fused heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups. The group can be connected to the remainder of the molecule via any ring.

[0044] Specifically, the term "bicyclic fused heterocyclic group" refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused heterocyclic group as defined herein, comprising two fused rings and containing one to four heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members. Typically, bicyclic fused heterocyclic groups are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic fused heterocyclic groups. Representative examples of (bicyclic) fused heterocycles include, but are not limited to, the following groups: octahydrocyclopentadien[c]pyrrole, octahydropyrrolo[3, 4-c]pyrrole, octahydroisoindolyl, isoindolinyl, octahydro-benzo[b][1, 4] Dioxin, indololinyl, isoindololinyl, benzopyranyl, dihydrothiazopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolyl / tetrahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzooxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothiopheneyl, tetrahydrobenzofuranyl, benzodioxolyl, benzodioxonyl, chromenyl, octahydrochromenyl, dihydro Benzodioxane-1, dihydrobenzoxezinyl, dihydrobenzodioxepinyl, dihydrothienodioxynyl, dihydrobenzoxezinyl, tetrahydrobenzoxezinyl, dihydrobenzoxezinyl, tetrahydrobenzoxezinyl, isochrominyl, chromanyl, or tetrahydropyrazolopyrimidinyl (e.g., 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl).

[0045] The term "benzofused heterocyclic group" refers to a bicyclic fused heterocyclic group in which a monocyclic 4- to 9-membered heterocyclic group (preferably 5- or 6-membered) is fused to a benzene ring as defined herein.

[0046] The term "bridging heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group, wherein each pair of rings in the system shares two discontinuous atoms, and the heterocyclic alkyl group contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon. One or more rings of the bridging heterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the bridging heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, bridging heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclic groups, and preferably refer to bicyclic, tricyclic, or tetracyclic bridging heterocyclic groups, and more preferably refer to bicyclic or tricyclic bridging heterocyclic groups. Representative examples of bridging heterocyclic groups include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.

[0047] If the amine is R 5 Replacement means or In the structure, the nitrogen atom is not bonded to hydrogen.

[0048] The term "at least one substituent" disclosed herein includes, for example, 1 to 4 (such as 1 to 3, further such as 1 or 2) substituents, subject to the constraint of satisfying the atomic valence theory. For example, the term "at least one substituent R" disclosed herein... 6” "Including 1 to 4 (such as 1 to 3, further such as 1 or 2) selected from R as disclosed herein." 6 Substituents in a list.

[0049] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound whose mirror images are not superimposed on each other. In the case of compounds disclosed herein having two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. It is intended to include all such possible stereoisomers, such as substantially pure, resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. It is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise expressly stated, reference to one isomer applies to all possible isomers. Whenever an isomer composition is not specified, all possible isomers are included.

[0050] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight (e.g., no more than 30%, further such as no more than 25%, and even further such as no more than 20%) of any other stereoisomer. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight (e.g., no more than 5%, such as no more than 1%) of any other stereoisomer.

[0051] When the compounds disclosed herein contain alkene double bonds, such double bonds are intended to include both E and Z geometric isomers unless otherwise specified.

[0052] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring may be in cis or trans configurations. A cis configuration means that both substituents are located above the two substituent positions on the carbon atom, while a trans configuration means that they are located on opposite sides.

[0053] Separating reaction products from each other and / or from the starting material can be advantageous. The desired products of each step or series of steps are separated and / or purified (hereinafter, separated) to the desired degree of homogeneity using techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve a variety of methods, including, for example: reversed-phase and normal-phase; size exclusion; ion exchange; high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus; small-scale analytical; simulated moving bed (“SMB”) and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and rapid chromatography techniques. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

[0054] "Pharmaceutically acceptable salts" are those salts which, within the bounds of reasonable medical judgment, are suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and whose benefits are proportionate to a reasonable risk-benefit ratio. Pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or solely by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0055] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, such as a pharmaceutically acceptable addition salt, can be produced according to conventional procedures for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and / or water and treating the solution with acid. Those skilled in the art will recognize that various synthetic methods can be used to prepare non-toxic, pharmaceutically acceptable addition salts without requiring excessive experimentation.

[0056] As defined herein, “pharmaceutically acceptable salts” include salts of at least one compound of formula (I) and salts of stereoisomers of compound of formula (I), such as salts of enantiomers and / or salts of diastereomers.

[0057] The term "subject" in this article refers to a human being.

[0058] The term "effective amount" or "therapeutic effective amount" refers to an amount of an active ingredient (such as a compound) that, when administered to a subject for the treatment of a disease or at least one clinical symptom of a disease or condition, is sufficient to affect such treatment against said disease, condition, or symptom. "Therapeutic effective amount" can vary depending on: the compound; the disease, condition, and / or the symptoms of the disease or condition; the severity of the disease, condition, and / or the symptoms of the disease or condition; the age of the subject to be treated; and / or the weight of the subject to be treated. In some embodiments, "therapeutic effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof, which effectively "treats" the subject's disease or condition as defined above.

[0059] Pharmaceutical compositions comprising the compounds disclosed herein may be administered to subjects in need via oral administration. The pharmaceutical compositions may be regular solid dosage forms, such as tablets, capsules, etc.

[0060] All formulations of the pharmaceutical compositions disclosed herein can be produced using conventional methods in the pharmaceutical industry. For example, the active ingredient can be mixed with one or more excipients, and then the desired formulation can be prepared. "Pharmaceutically acceptable excipient" refers to a conventional pharmaceutical carrier suitable for the desired pharmaceutical formulation.

[0061] The term “disease” means any illness, discomfort, ailment, symptom or indication and is interchangeable with the terms “symptom” or “illness”.

[0062] Throughout this specification and in subsequent aspects, unless otherwise required herein, the term "comprise" and its variations (such as "comprises / comprising") are intended to specify the presence of a feature that follows, but do not exclude the presence or addition of one or more other features. When used herein, the term "comprising" may be replaced by the terms "containing," "including," or sometimes "having."

[0063] Throughout this specification and in subsequent aspects, the term "C" will be used. n-m The indication includes a range of endpoints, where n and m are integers and indicate the number of carbons. Examples include C. 1-8 C 1-6 wait.

[0064] Unless otherwise defined elsewhere in this document, all other technical and scientific terms used herein shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0065] Aspects and Implementation Plan The following aspects and embodiments are not intended, expressly or implicitly, to acknowledge that these aspects or embodiments are independent or distinct, nor should they be construed as such. Rather, they are intended to convey information so that the full scope of the invention can be understood. Furthermore, the following aspects and embodiments are not intended to limit the full scope of the invention as set forth by the structure of Formula I.

[0066] Aspect 1. A compound of formula (I): (I) Or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof, wherein: A 1 It is CR 1 Or N, A 2 It is CR 2 Or N, A 3 It is CR 3 Or N, A 4 It is CR 4 Or N, A 5 It is CR 5 Or N, the constraint being that A 1 A 2 A 3 A 4 and A 5 At most two of them are N; R 1 R 2 R 3 R 4 and R 5 Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 1a -SO2R 1a -COR 1a -CO2R 1a -CONR 1a R 1b -C(=NR) 1a )NR 1b R 1c -NR 1a R 1b -NR 1aCOR 1b -NR 1a CONR 1b R 1c -NR 1a CO2R 1b -NR 1a SONR 1b R 1c -NR 1a SO2NR 1b R 1c -P(=O)R 1a R 1b -NR 1a SO2R 1b or -SOR 1a (=NR 1b ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the following groups—alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl—is unsubstituted or surrounded by one, two, or three R groups. 1d replace; Or (R) 3 and R 4 ) or (R 4 and R 5 It independently forms C along with the atoms it is attached to. 3-10 cycloalkyl, C 3-10 Cycloalkenyl, a 5- to 12-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, a 5- to 12-membered aryl, or a 5- to 12-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, wherein the C 3-10 cycloalkyl, C 3-10 Each of the following groups—cycloalkenyl, 5- to 12-membered heterocyclic ring, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl ring—is not substituted or is occupied by 1, 2, 3, or 4 R groups. 1d replace; R 1a R 1b and R 1c Each is independently hydrogen, deuterium, and -C. 1-10 Alkyl, -C 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is not substituted or surrounded by one, two, or three R groups.1j replace; R 1d and R 1j Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 1e -SO2R 1e -COR 1e -CO2R 1e -CONR 1e R 1f -C(=NR) 1e )NR 1f R 1g -NR 1e R 1f -NR 1e COR 1f -NR 1e CONR 1f R 1g -NR 1e CO2R 1f -NR 1e SONR 1f R 1g -NR 1e SO2NR 1f R 1g -P(=O)R 1e R 1f -NR 1e SO2R 1f or -SOR 1e (=NR 1f ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is either unsubstituted or substituted by at least one substituent selected from the following: halogen, -CN, -C. 1-10 Alkyl, -OR 1h -NR 1h R 1i cycloalkyl, heterocyclic, aryl, and heteroaryl; or Substituting two R atoms at the same atom 1d Or two Rs 1j Formation of oxy groups; or Substituting two R atoms at the same or different atoms 1d Together with the atoms it is attached to and any intervening atoms, it forms C 3-10Cycloalkyl, a 4- to 12-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, a 6- to 12-membered aryl ring, or a 5- to 12-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur; wherein the C 3-10 Cycloalkyl, 4- to 12-membered heterocyclic rings, 6- to 12-membered aryl or 5- to 12-membered heteroaryl rings are not substituted or are occupied by 1, 2 or 3 R groups. 1k replace; R 1e R 1f R 1g R 1h and R 1i Each is independently hydrogen, -C 1-10 Alkyl, -halogen C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; Each R 1k Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -halogen C 1-10 Alkyl or -C 1-10 Alkoxy; X 1 It is CR 61 Or N; L is a direct bond, -(CR) L1 R L2 ) p -、-O-、-S- or -NR L3 -; Ring B is isoxazolyl, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl. R 61 R 62 R 63 R 64 R 7 R L1 and R L2 Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -OC 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 3a -SO2R 3a -COR 3a -CO2R 3a -CONR 3a R 3b -C(=NR) 3a)NR 3b R 3c -NR 3a R 3b -NR 3a COR 3b -NR 3a CONR 3b R 3c -NR 3a CO2R 3b -NR 3a SONR 3b R 3c -NR 3a SO2NR 3b R 3c -P(=O)R 3a R 3b -NR 3a SO2R 3b or -SOR 3a (=NR 3b ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is not substituted or surrounded by one, two, or three R groups. 3d replace; R 3a R 3b and R 3c Each is independently hydrogen, deuterium, and -C. 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl; wherein the -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the following groups—alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl—is not substituted or R-substituted. 3j replace; R 3d and R 3j Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 3e -SO2R 3e -COR 3e -CO2R 3e -CONR 3e R 3f -C(=NR) 3e )NR3f R 3g -NR 3e R 3f -NR 3e COR 3f -NR 3e CONR 3f R 3g -NR 3e CO2R 3f -NR 3e SONR 3f R 3g -NR 3e SO2NR 3f R 3g -P(=O)R 3e R 3f -NR 3e SO2R 3f or -SOR 3e (=NR 3f ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is either unsubstituted or substituted by at least one substituent selected from the following: halogen, -C 1-10 Alkyl, -OR 3h -NR 3h R 3i cycloalkyl, heterocyclic, aryl or heteroaryl; or Substituting two R atoms at the same atom 3d Or two Rs 3j Formation of oxy groups; or R 3e R 3f R 3g R 3h and R 3i Each is independently hydrogen, -C 1-10 Alkyl, -halogen C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkynyl, cycloalkyl, heterocyclic, alkoxy-substituted benzyl, aryl, or heteroaryl; R L3 It is hydrogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl; p is 0, 1, 2, or 3 (optionally, p is 1 or 2; further optionally, p is 1); and n is 0, 1, 2 or 3 (optionally, n is 1 or 2; further optionally, n is 1).

[0067] In one implementation of aspect 1, A 3 It is CR 3 A 4 It is CR 4 A 5 It is CR 5 Optionally, R 1 It is -C 1-5 Alkoxy (optionally, -OC) 1-5 (deuterated alkyl), R 2 R 3 and R 5 It is hydrogen, R 4 It is -C 1-10 Alkyl, -C 1-10 alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-10 Each of the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is either unsubstituted or substituented by at least one substituent R. 1d Replace; each R 1d It is halogen, -C independently 1-10 Alkyl, -C 1-10 Alkylene-C 1-10 Alkoxy, -C 1-10 Alkyl or -COOC 1-10 alkyl.

[0068] In a preferred embodiment, R 4 Selected from -C 1-6 Alkyl; -C 1-6 Alkylene-C 1-3 Alkyl group; surrounded by one, two, or three independent groups selected from F, Cl, Br, -C 1-6 Alkyl and -C 1-6 alkoxy substituents of C 3-10 Cycloalkyl; and containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, and not substituted or surrounded by one, two, or three heteroatoms independently selected from F, Cl, Br, -C 1-6 Alkyl and -C 1-6 The alkoxy substituent is a 3- to 7-membered monocyclic or bicyclic (optionally, fused bicyclic, spirobicyclic or bridged bicyclic) heterocyclic group.

[0069] In another preferred embodiment, R 4 Selected from -C 1-6 Alkyl, -C 1-6 Alkylene-C 1-3 Alkoxy, cyclopropyl, 3-azabicyclo[3.1.0]hexyl and oxacyclobutyl; wherein the -C1-6 Alkyl, -C 1-6 Alkylene-C 1-3 Each of the alkoxy, cyclopropyl, 3-azabicyclo[3.1.0]hexyl and oxecyclobutyl groups is either unsubstituted or substituted by one, two or three substituents independently selected from methyl, ethyl, propyl, F, Cl, Br, methoxy, ethoxy or -COOCH3.

[0070] In one implementation of aspect 1, R 1 It is -C 1-5 Alkoxy (optionally, -OC) 1-5 (deuterated alkyl), R 2 It is hydrogen, A 3 It is CR 3 A 4 It is CR 4 A 5 It is CR 5 Optionally, R 1 It is -C 1-5 Alkoxy, R 2 It is hydrogen, (R 3 and R 4 ) or (R 4 and R 5 Together with the atoms it is attached to, they form C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 5- to 12-membered heterocyclic rings containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6- to 12-membered aryl, or heteroatoms containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur and not substituted or surrounded by 1, 2, 3, or 4 R groups. 1d Substituted 5- to 12-membered heteroaryl rings; each R 1d It is halogen, -C independently 1-10 Alkyl, -C 1-10 Alkyl or -COOC 1-10 Alkyl group. In a preferred embodiment, (R 3 and R 4 ) or (R 4 and R 5 It forms a dihydrofuran ring or a pyrrole ring together with the atoms it is attached to; wherein each of the dihydrofuran ring or pyrrole is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from methyl, ethyl, propyl, F, Cl, Br, methoxy, ethoxy or -COOCH3.

[0071] In a preferred embodiment, R 1 It is -C 1-5 Alkoxy, R 2 It is hydrogen, A 3 It is CR 3 A4 It is CR 4 A 5 It is CR 5 Optionally, R 1 It is -C 1-5 Alkoxy (optionally, -OC) 1-5 (deuterated alkyl), R 2 It is hydrogen, R 3 It is hydrogen, (R 4 and R 5 Together with the atoms it is attached to, they form C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 5- to 12-membered heterocyclic rings containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6- to 12-membered aryl, or heteroatoms containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur and not substituted or surrounded by 1, 2, 3, or 4 R groups. 1d Substituted 5- to 12-membered heteroaryl rings; each R 1d It is halogen, -C independently 1-10 Alkyl, -C 1-10 Alkoxy, heterocyclic, or -COOC 1-10 alkyl.

[0072] In a preferred embodiment, R 1 It is -C 1-5 Alkoxy (optionally, -OC) 1-5 (deuterated alkyl), R 2 It is hydrogen, A 3 It is CR 3 A 4 It is CR 4 A 5 It is CR 5 Optionally, R 1 It is -C 1-5 Alkoxy, R 2 It is hydrogen, R 5 It is hydrogen, (R 3 and R 4 Together with the atoms it is attached to, they form C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 5- to 12-membered heterocyclic rings containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6- to 12-membered aryl, or heteroatoms containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur and not substituted or surrounded by 1, 2, 3, or 4 R groups. 1d Substituted 5- to 12-membered heteroaryl rings; each R 1d It is halogen, -C independently 1-10 Alkyl, -C 1-10 Alkoxy, heterocyclic, or -COOC 1-10 alkyl.

[0073] In one implementation of aspect 1, R 1 It is -C 1-5 Alkoxy (optionally, -OC) 1-5 (deuterated alkyl), R 2 It is hydrogen, A 3 It is CR 3 A 4 It is CR 4 A 5 It is N. Optionally, R 1 It is -C 1-5 Alkoxy (optionally, -OC) 1-5 (deuterated alkyl), R 2 R 3 and R 5 It is hydrogen, R 4 It is -C 1-10 Alkyl, -C 1-10 alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-10 Each of the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is either unsubstituted or substituented by at least one substituent R. 1d Replace; each R 1d It is halogen, -C independently 1-10 Alkyl, -C 1-10 Alkylene-C 1-10 Alkoxy, -C 1-10 Alkyl or -COOC 1-10 alkyl.

[0074] Compounds of aspect 2.1, wherein yes , , , , , , or In one implementation of aspect 2, yes , , , , , , , , or In one implementation of aspect 2, yes In one implementation of aspect 2, yes .

[0075] In the first embodiment of aspect 2, ring B is not replaced or replaced by one or two Rs. 7 Replacement (i.e., n is 0, 1, or 2). In one embodiment of aspect 2, n is 0 or 1. In one embodiment of aspect 2, ring B is not replaced (i.e., n is 0).

[0076] In the second implementation scheme of aspect 2, yes , , , , , , , , or In the third implementation scheme of aspect 2, yes .

[0077] In the fourth implementation scheme of aspect 2, yes .

[0078] Aspect 2'. The compound of formula (I) is the compound of formula (II-1): (II-1)

[0079] In some embodiments of the compound of formula (II-1), A 1 It is CR 1 ;R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl (preferably, -C) 1-5 (deuterated alkyl), -C 1-10 Alkyl (preferably, -C) 1-5 alkyl) or -halogen C 1-10 Alkyl (preferably, -halogen C) 1-5 alkyl); A 2 It is CR 2 And R 2 It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; A 3 It is CR 3 Or N, A 4 It is CR 4 Or N, A 5 It is CR 5 Or N, the constraint being that A 3 A 4 and A5 At most one of them is N; If it exists, then R 3 R 4 and R 5 Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 1a -SO2R 1a -COR 1a -CO2R 1a -CONR 1a R 1b -C(=NR) 1a )NR 1b R 1c -NR 1a R 1b -NR 1a COR 1b -NR 1a CONR 1b R 1c -NR 1a CO2R 1b -NR 1a SONR 1b R 1c -NR 1a SO2NR 1b R 1c -P(=O)R 1a R 1b -NR 1a SO2R 1b or -SOR 1a (=NR 1b ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the following groups—alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl—is unsubstituted or surrounded by one, two, or three R groups. 1d replace; Or (R) 3 and R 4 ) or (R 4 and R 5 It independently forms C along with the atoms it is attached to. 3-10 cycloalkyl, C 3-10Cycloalkenyl, a 5- to 12-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, a 5- to 12-membered aryl, or a 5- to 12-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, wherein the C 3-10 cycloalkyl, C 3-10 Each of the following groups—cycloalkenyl, 5- to 12-membered heterocyclic ring, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl ring—is not substituted or is occupied by 1, 2, 3, or 4 R groups. 1d replace; R 1a R 1b and R 1c Each is independently hydrogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is not substituted or surrounded by one, two, or three R groups. 1j replace; R 1d and R 1j Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 1e -SO2R 1e -COR 1e -CO2R 1e -CONR 1e R 1f -C(=NR) 1e )NR 1f R 1g -NR 1e R 1f -NR 1e COR 1f -NR 1e CONR 1f R 1g -NR 1e CO2R 1f -NR 1e SONR 1f R 1g -NR 1e SO2NR 1f R 1g -P(=O)R1e R 1f -NR 1e SO2R 1f or -SOR 1e (=NR 1f ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is either unsubstituted or substituted by at least one substituent selected from the following: halogen, -CN, -C. 1-10 Alkyl, -OR 1h -NR 1h R 1i cycloalkyl, heterocyclic, aryl, and heteroaryl; or Substituting two R atoms at the same atom 1d Or two Rs 1j Formation of oxy groups; or Substituting two R atoms at the same or different atoms 1d Together with the atoms it is attached to and any intervening atoms, it forms C 3-10 Cycloalkyl, a 4- to 12-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, a 6- to 12-membered aryl ring, or a 5- to 12-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur; wherein the C 3-10 Each of the following groups—cycloalkyl, 4- to 12-membered heterocyclic ring, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl ring—is unsubstituted or surrounded by 1, 2, or 3 R groups. 1k replace; R 1e R 1f R 1g R 1h and R 1i Each is independently hydrogen, -C 1-10 Alkyl, -halogen C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; R 1k Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -halogen C 1-10 Alkyl or -C 1-10 Alkyl group.

[0080] In some embodiments of the compound of formula (II-1), X 1 Is it N or CR? 61 , R 61 R 62 R63 and R 64 Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -SC 1-10 Alkyl, -OC 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 3-10 Monocyclic cycloalkyl, C 3-10 Monocyclic cycloalkenyl, C 3-10 Monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, 5- or 6-membered monocyclic heteroaryl, -CN or -NR 3a R 3b ; wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 1-10 Monocyclic cycloalkyl, C 1-10 Monocyclic cycloalkenyl, C 1-10 The following are unsubstituted or partially substituted groups: monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, or 5- or 6-membered monocyclic heteroaryl. 3d replace; R 3a and R 3b Each is independently hydrogen, -C 1-5 Alkyl, -C 2-5 alkenyl, -C 2-5 alkynyl or C 3-6 Monocyclic cycloalkyl; Each R 3d Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 1-10 Alkoxy, -C 2-10 alkynyl or C 3-6 Monocyclic cycloalkyl.

[0081] In some embodiments of the compound of formula (II-1), X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 62 R 63 and R 64Each of the following is independently hydrogen, methyl, -OCD3, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolylyl, furanyl, pyrazolyl, oxazolyl, oxacyclobutyl, aziridine, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, -CN, F, Cl, Br or I; wherein each of the methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxacyclobutyl or aziridine is not substituted or is surrounded by 1, 2 or 3 Rs. 3d replace; Each R 3d Independently, it is hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxecyclopropyl, oxecyclobutyl, F, Cl, Br, or I.

[0082] In some embodiments of the compound of formula (II-1), X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 62 R 63 and R 64 Each of these can be hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, -CN, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2, -CH(CH3)OCH3, -OCHF2, or -CH2OCH3.

[0083] In some embodiments of the compound of formula (II-1), X 1 Is it N or CR?61 , If R 61 If it exists, then R 61 R 63 and R 64 Each is either hydrogen or deuterium; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0084] In some embodiments of the compound of formula (II-1), X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 63 and R 64 Each is hydrogen independently; R 62 Each can be methyl, ethyl, cyclopropyl, ethyl or methoxy.

[0085] Compounds of aspect 3, aspect 1, or aspect 2, where L is -CH2- or -(CH2)2.

[0086] In one implementation of aspect 3, L is -CH2-.

[0087] Aspect 4, compounds of any one of Aspects 1 to 3, X 1 It is CR 61 , R 61 R 62 R 63 and R 64 Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -OC 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 3-10 Monocyclic cycloalkyl, C 3-10 Monocyclic cycloalkenyl, C 3-10 Monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, 5- or 6-membered monocyclic heteroaryl, -CN or -NR 3a R 3b; wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 1-10 Monocyclic cycloalkyl, C 1-10 Monocyclic cycloalkenyl, C 1-10 The following are unsubstituted or partially substituted groups: monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, or 5- or 6-membered monocyclic heteroaryl. 3d replace; R 3a and R 3b Each is independently hydrogen, -C 1-5 Alkyl, -C 2-5 alkenyl, -C 2-5 alkynyl or C 3-6 Monocyclic cycloalkyl; Each R 3d Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 1-10 Alkoxy, -C 2-10 alkynyl or C 3-6 Monocyclic cycloalkyl.

[0088] In a preferred embodiment, R 61 R 63 and R 64 Each is hydrogen independently. In another preferred embodiment, R 62 It is halogen, -C 1-5 Alkyl, -OC 1-5 Deuterated alkyl, -C 2-5 alkenyl, -C 1-5 Alkoxy or C 3-6 Monocyclic cycloalkyl; wherein the C 1-5 Alkyl, -C 2-5 alkenyl, -C 1-5 Alkoxy or C 3-6 Each of the monocyclic cycloalkyl groups is either unsubstituted or surrounded by 1, 2, or 3 R groups. 3d replace; Each R 3d It can be hydrogen, F, Cl, Br, I, methoxy, ethoxy, methyl, or ethyl.

[0089] In a preferred embodiment, R 61 and R 63 Each is hydrogen on its own.

[0090] In a preferred embodiment, R 62 R63 and R 64 Each is hydrogen on its own.

[0091] In a preferred embodiment, R 63 and R 64 Each is hydrogen on its own.

[0092] In a preferred embodiment, R 61 R 62 and R 64 Each is hydrogen on its own.

[0093] In the first implementation scheme of aspect 4, X 1 It is CR 61 , R 61 R 62 R 63 and R 64 Each of the following is independently hydrogen, methyl, -OCD3, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolylyl, furanyl, pyrazolyl, oxazolyl, oxacyclobutyl, aziridine, -NH2, -NH(C 1-5 alkyl), -N(C) 1-5 Alkyl)2, -CN, F, Cl, Br or I; wherein each of the methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxacyclobutyl or aziridine is not substituted or is surrounded by 1, 2 or 3 Rs. 3d replace; Each R 3d Independently, it is hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxecyclopropyl, oxecyclobutyl, F, Cl, Br, or I.

[0094] In the second implementation scheme of aspect 4, X 1 It is CR 61 , R 61 R 62 R 63 and R 64 Each of these can be independently hydrogen, deuterium, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, -CN, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2, -CH(CH3)OCH3, -OCHF2, or -CH2OCH3.

[0095] In the third implementation scheme of aspect 4, X 1 It is CR 61 , R 61 R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0096] In the fourth implementation scheme of aspect 4, X 1 It is CR 61 , R 61 R 63 and R 64 Each is hydrogen independently; R 62 Each can be methyl, ethyl, I, cyclopropyl, ethyl, or methoxy.

[0097] Compound X of any one of aspects 5, 1 to 3 1 It is N. R 62 R 63 and R 64 Each is independently hydrogen, halogen, -C 1-10 Alkyl, -OC 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 3-10 Monocyclic cycloalkyl, C 3-10 Monocyclic cycloalkenyl, C3-10 Monocyclic cycloalkynyl, 4- or 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, 5- or 6-membered monocyclic heteroaryl groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, or -NR 3a R 3b ; wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 3-10 Monocyclic cycloalkyl, C 3-10 Monocyclic cycloalkenyl, C 3-10 Each of the following groups is unsubstituted or surrounded by 1, 2, or 3 R groups: monocyclic cycloalkynyl, 4- or 10-membered monocyclic heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur; 6-membered monocyclic aryl, 5- or 6-membered monocyclic heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur. 3d replace; R 3a and R 3b Each is independently hydrogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl or cycloalkyl; Each R 3d Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 1-10 Alkoxy, -C 2-10 Alkyne or cycloalkyl.

[0098] In a preferred embodiment, R 63 and R 64 Each is hydrogen independently. In a preferred embodiment, R 62 It is C 3-6 Monocyclic cycloalkyl or -C 1-5 Alkoxy, wherein the C 3-6 Monocyclic cycloalkyl or -C 1-5 Each of the alkoxy groups is either unsubstituted or surrounded by 1, 2, or 3 R groups. 3d replace; Each R 3d It can be hydrogen, F, Cl, Br, I, methoxy, ethoxy, methyl, or ethyl.

[0099] In the first implementation scheme of aspect 5, X 1 It is N. R 62 R 63 and R 64Each of the following is independently hydrogen, methyl, -OCD3, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolylyl, furanyl, pyrazolyl, oxazolyl, oxacyclobutyl, pyrrolylyl, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, F, Cl, Br or I; wherein each of the methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxacyclobutyl, and pyrrolidinyl groups is not substituted or is represented by 1, 2 or 3 R groups. 3d replace; Each R 3d Independently, it is hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxecyclopropyl, oxecyclobutyl, F, Cl, Br, or I.

[0100] In the second implementation scheme of aspect 5, X 1 It is N. R 62 R 63 and R 64 Each of these can be hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2, or -CH2OCH3.

[0101] In the third implementation scheme of aspect 5, X 1 It is N. R 63 and R 64 It is hydrogen; R 62It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0102] In the fourth implementation scheme of aspect 5, X 1 It is N. R 63 and R 64 It is hydrogen; R 62 It is cyclopropyl or methoxy.

[0103] In the fifth implementation scheme of aspect 5, X1 is N, R 63 and R 64 It is hydrogen; R 62 Yes -OCD3.

[0104] Compound of any one of aspects 1 to 5, R 7 Each is independently hydrogen, -C 1-10 Alkyl, -NH2, -NH(-C) 1-6 alkyl) or -N(-C 1-6 Alkyl)2.

[0105] In the first implementation scheme of aspect 6, n is 0, 1, 2, or 3; R 7 Each is independently hydrogen, methyl, ethyl, 1-propyl, 2-propyl, or -NH2. In the second embodiment of aspect 6, n is 2 or 3; an R 7 Each is independently a methyl group; the other R 7 It is hydrogen. In the third embodiment of aspect 6, n is 2 or 3; one R 7 It is -NH2; and another R 7 It is hydrogen. In the fourth embodiment of aspect 6, R 7 It is hydrogen.

[0106] Compound of any one of aspects 1 to 6, R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl (preferably, -C) 1-5 (deuterated alkyl), -C 1-10 Alkyl (preferably, -C) 1-5 alkyl) or -halogen C 1-10 Alkyl (preferably, -halogen C) 1-5alkyl).

[0107] In some embodiments of aspect 7, the compound of formula (I) is the compound of formula (III-1): (III-1)

[0108] In some embodiments of the compound of formula (I) or formula (III-1), A 5 Is it N or CR? 5 If it exists, then R 5 It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl (preferably, -C) 1-5 Deuterated alkyl; more preferably, -CD3), -C 1-10 Alkyl (preferably, -C) 1-5 Alkyl; more preferably, methyl) or -halogen C 1-10 Alkyl (preferably, -halogen C) 1-5 Alkyl group; more preferably, -CF3, -CH2F or -CHF2); R 2 It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or -halogen C 1-3 Alkyl group (preferably hydrogen or halogen; more preferably hydrogen); R 3 It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 4 It is -C 1-10 Alkyl, -C 1-10 Alkoxy, C 3-10 Cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, or 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur; Wherein -C 1-10 The alkyl group is either unsubstituted or substituted by one, two, or three independent substituents selected from the following: halogen, -OC. 1-10 Alkyl, cycloalkyl, cycloalkenyl, cycloynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C) 1-10 alkyl)2、-NH(C 1-10Alkyl groups and -NH2; Wherein C 3-10 Each of the following groups—cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocyclic—is either unsubstituted or surrounded by 1, 2, or 3 R groups. 1d replace; R 1d Selected from halogens, -C 1-10 Alkyl, -C 1-10 Alkoxy and -halogen C 1-10 alkyl; Wherein -C 1-10 The alkyl group is not substituted or is composed of one, two, or three independently selected from -CN, -OR. 1h and -NR 1h R 1i Substituents of the substituents; Each R 1h and R 1i Independently selected from hydrogen, methyl, ethyl, 1-propyl, and 2-propyl; X 1 Is it N or CR? 61 If it exists, then R 61 Is it hydrogen or -C? 1-10 Alkoxy; R 62 It is hydrogen, halogen, deuterium, -C 1-10 Alkyl, -SC 1-10 Alkyl, -OC 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 3-10 Monocyclic cycloalkyl, C 3-10 Monocyclic cycloalkenyl, C 3-10 Monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, 5- or 6-membered monocyclic heteroaryl, -CN or -NR 3a R 3b ; wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 1-10 Monocyclic cycloalkyl, C 1-10 Monocyclic cycloalkenyl, C 1-10 The following are unsubstituted or partially substituted groups: monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, or 5- or 6-membered monocyclic heteroaryl. 3 d replaces; R3a and R 3b Each is independently hydrogen, -C 1-5 Alkyl, -C 2-5 alkenyl, -C 2-5 alkynyl or C 3-6 Monocyclic cycloalkyl; Each R 3d Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 1-10 Alkoxy, -C 2-10 alkynyl or C 3-6 Monocyclic cycloalkyl.

[0109] R 63 It is hydrogen or deuterium; R 64 It is hydrogen, deuterium, halogen, -CN, -C 1-10 Alkyl or -C 1-10 Alkyl group.

[0110] In some embodiments of compounds of formula (I) or (III-1), A 5 Is it N or CR? 5 If it exists, then R 5 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl (preferably, -C) 1-5 (deuterated alkyl), -C 1-10 Alkyl (preferably, -C) 1-5 alkyl) or -halogen C 1-10 Alkyl (preferably, -halogen C) 1-5 alkyl); R 2 It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 4It is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, oxacyclobutyl, tetrahydrofuranyl, dioxalkyl, oxazolyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxaspiro[3.3]heptyl or pyrazolyl; The methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, and 1,1-dimethylethyl groups are either unsubstituted or substituted by one, two, or three substituents independently selected from the group consisting of halogen, -C, etc. 1-10 Alkyl, -halogen C 1-10 Alkyl, -OC 1-10 Alkyl, cycloalkyl, cycloalkenyl, cycloynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C) 1-10 alkyl)2、-NH(C 1-10 alkyl groups and -NH2; and The cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, oxacyclobutyl, tetrahydrofuranyl, dioxalkyl, oxazolyl, or pyrazolyl groups are not substituted or are represented by one, two, or three of these groups. R 1d Replace; and R 1d Selected from halogens, -C 1-10 Alkyl, -C 1-10 Alkoxy and -halogen C 1-10 alkyl; Wherein -C 1-10 The alkyl group is either unsubstituted or substituted by one, two or three substituents independently selected from -CN, hydroxyl, methoxy, -NH2 and -N(CH3)2.

[0111] In some embodiments of compounds of formula (I) or formula (III-1), R 4 It is 2-oxabicyclo[2.1.1]hexyl or bicyclo[1.1.1]pentyl.

[0112] In some embodiments of compounds of formula (I) or (III-1), A 5 Is it N or CR? 5 If it exists, then R 5 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 1 Yes - OR 1a And R 1aIt is hydrogen, -C 1-10 Deuterated alkyl (preferably, -C) 1-5 (deuterated alkyl), -C 1-10 Alkyl (preferably, -C) 1-5 alkyl) or -halogen C 1-10 Alkyl (preferably, -halogen C) 1-5 alkyl); R 2 It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 4 yes - t Bu、 , , , , , , , , , , , , , , , , , , or ; X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0113] In some embodiments of compounds of formula (I) or formula (III-1), R 4 yes or .

[0114] In some embodiments of compounds of formula (I) or (III-1), A 5 Is it N or CR? 5 If it exists, then R 5 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl (preferably, -C) 1-5 (deuterated alkyl), -C 1-10 Alkyl (preferably, -C) 1-5 alkyl) or -halogen C 1-10 Alkyl (preferably, -halogen C) 1-5 alkyl); R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 4 yes- t Bu、 , , or ; R 61 R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0115] In some embodiments of compounds of formula (I) or (III-1), A 5 Is it N or CR? 5 ;R 5 It's hydrogen. R 1 Yes - OR 1a And R 1a It is hydrogen, -C1-10 Deuterated alkyl (preferably, -C) 1-5 (deuterated alkyl), -C 1-10 Alkyl (-C) 1-5 alkyl) or -halogen C 1-10 Alkyl (-halogen C) 1-5 alkyl); R 2 It is hydrogen; R 3 It is hydrogen; R 4 It is -C 1-5 Alkyl or -halogen C 1-5 alkyl; X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 63 and R 64 Each is hydrogen independently; R 62 Each is independently -C 1-5 Alkyl, -C 2-5 alkenyl, C 3-6 Monocyclic cycloalkyl or -C 1-5 Alkyl group.

[0116] In some embodiments of compounds of formula (I) or (III-1), A 5 Is it N or CR? 5 ;R 5 It's hydrogen. R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen; R 3 It is hydrogen; R 4 It is -C 1-5 Alkyl or -halogen C 1-5 alkyl; X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 63 and R 64 Each is hydrogen independently; R 62 Each is independent of the other -OC1-10 Deuterated alkyl groups.

[0117] In some embodiments of compounds of formula (I) or (III-1), A 5 Is it N or CR? 5 ;R 5 It's hydrogen. R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl (preferably, -C) 1-5 (deuterated alkyl), -C 1-10 Alkyl (-C) 1-5 alkyl) or -halogen C 1-10 Alkyl (-halogen C) 1-5 alkyl); R 2 It is hydrogen; R 3 It is hydrogen; R 4 It is 1,1-dimethylethyl or 1,1,1-trifluoro-2-methylpropyl; X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 63 and R 64 Each is hydrogen independently; R 62 Each can be methyl, ethyl, cyclopropyl, vinyl, -OCD3, or methoxy.

[0118] In some embodiments of compounds of formula (I) or (III-1), A 5 Is it N or CR? 5 ;R 5 It's hydrogen. R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-5 Deuterated alkyl, -C 1-5 Alkyl or -halogen C 1-5 alkyl; R 2 It is hydrogen; R 3 It is hydrogen; R 4 It is 1,1-dimethylethyl or 1,1,1-trifluoro-2-methylpropyl; X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 63 and R 64 Each is hydrogen independently; R 62 Each is independently -OCD3.

[0119] In some embodiments of aspect 1, the compound has formula (VI): (VI), Or its pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer, wherein: X 1 It is N or C(H); R 62 It is ethyl, vinyl, cyclopropyl, -OCD3, or methoxy; R 4 yes or ; A 5 It is CR 5 Or N; if it exists, then R 5 It is hydrogen; and R 4c It is methyl or -CF3; or R 5 and R 4c Together with the atoms it is attached to and the intervening atoms, it forms an unsubstituted or substituted group with one or two R atoms. 1d Substituted dihydrofuranyl or dihydropyranyl ring; R 1d It is a methyl group.

[0120] In some embodiments of aspect 7, the compound of formula (I) is the compound of formula (III-2): (III-2)

[0121] In some embodiments of the compound of formula (III-2), R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C1-3 Alkyl or -halogen C 1-3 alkyl; The ring C is a 5- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur; Each R 1d Independently, it is hydrogen, halogen, -C 1-5 Alkyl or -halogen C 1-5 Alkyl; or Substituting two R atoms at the same or different atoms 1d Together with the atoms it is attached to and any intervening atoms, it forms C 3-10 Monocyclic cycloalkyl groups or 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur; X 1 Is it N or CR? 61 If it exists, then R 61 Is it hydrogen or -C? 1-10 Alkoxy; R 62 It is hydrogen, halogen, -C 1-10 Alkyl, -OC 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 3-10 Monocyclic cycloalkyl, C 3-10 Monocyclic cycloalkenyl, C 3-10 Monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, 5- or 6-membered monocyclic heteroaryl, -CN or -NR 3a R 3b ; wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 1-10 Monocyclic cycloalkyl, C 1-10 Monocyclic cycloalkenyl, C 1-10 The following are unsubstituted or partially substituted groups: monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, or 5- or 6-membered monocyclic heteroaryl. 3d replace; R 3a and R 3b Each is independently hydrogen, -C 1-5 Alkyl, -C 2-5 alkenyl, -C 2-5 alkynyl or C 3-6Monocyclic cycloalkyl; Each R 3d Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 1-10 Alkoxy, -C 2-10 alkynyl or C 3-6 Monocyclic cycloalkyl.

[0122] R 63 It is hydrogen; R 64 It is hydrogen, halogen, -CN, -C 1-10 Alkyl or -C 1-10 Alkyl group.

[0123] In some embodiments of the compound of formula (III-2), the ring C is dihydrofuranyl or dihydropyranyl; Each R 1d Independently, it is hydrogen, halogen, -C 1-4 Alkyl, -halogen C 1-4 Alkyl or -C 1-4 alkoxy groups; or substitutions for two R atoms at the same or different atoms. 1d Together with the atoms it is attached to and any intervening atoms, it forms a cyclobutyl ring or a tetrahydropyranyl group.

[0124] In some embodiments of the compound of formula (III-2), the compound has formula (IV-1): (IV-1)

[0125] In some embodiments of the compound of formula (IV-1), R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl (preferably, -C) 1-5 (deuterated alkyl), -C 1-10 Alkyl (preferably, -C) 1-5 alkyl) or -halogen C 1-10 Alkyl (-halogen C) 1-5 alkyl); R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; Each R 1dIndependently, it is hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl; or Substituting two R atoms at the same or different atoms 1d Together with the atoms it is attached to and any intervening atoms, it forms a cyclobutyl ring or a tetrahydropyranyl group; X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, -OCD3, methyl, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0126] In some embodiments of the compound of formula (III-2), the compound has formula (V-1): (V-1).

[0127] In some embodiments of the compound of formula (III-2), the compound has formula (V-2): (V-2).

[0128] In some embodiments of the compound of formula (III-2), the compound has formula (V-3): (V-3).

[0129] In some embodiments of the compounds of formula (V-1), formula (V-2), or formula (V-3), R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl (preferably, -C) 1-5 (deuterated alkyl), -C 1-10 Alkyl (preferably, -C) 1-5 alkyl) or -halogen C 1-10 Alkyl (preferably, -halogen C) 1-5 alkyl); R 2 It is hydrogen, halogen, -C 1-3Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; Each R 1d Independently, it is hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl; or Substituting two R atoms at the same or different atoms 1d Together with the atoms it is attached to and any intervening atoms, it forms a cyclobutyl ring or a tetrahydropyranyl group; X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0130] In some embodiments of the compound of formula (III-2), the compound has formula (IV-4): (IV-4)

[0131] In some embodiments of the compound of formula (V-4), R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl (preferably, -C) 1-5 (deuterated alkyl), -C 1-10 Alkyl (-C) 1-5 alkyl) or -halogen C 1-10 Alkyl (-halogen C) 1-5 alkyl); R 2 It is hydrogen, halogen, -C1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 1d Each of these can be independently hydrogen, hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl; X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0132] In some embodiments of compound (III-2), the compound has the formula (V-4): (V-4).

[0133] In some embodiments of compound (III-2), the compound has the formula (V-5): (V-5).

[0134] In some embodiments of the compound of formula (V-4) or formula (V-5), X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; R 63 and R 64 It is hydrogen; R 62It is hydrogen, methyl, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, -OCD3, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0135] In some embodiments of compounds of formula (III-2), formula (IV-1), formula (IV-4), formula (V-1), formula (V-2), formula (V-4), or formula (V-5), R 1 Yes - OR 1a And R 1a It is methyl; R 2 It is hydrogen; R 3 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is methyl, ethyl, cyclopropyl, methoxy, or ethoxy.

[0136] In some embodiments of compounds of formula (III-2), formula (IV-1), formula (IV-4), formula (V-1), formula (V-2), formula (V-4), or formula (V-5), R 1 Yes - OR 1a And R 1a It is methyl; R 2 It is hydrogen; R 3 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is methyl, ethyl, cyclopropyl, methoxy, -OCD3, or ethoxy.

[0137] In some embodiments of compounds of formula (III-2), (IV-1), (IV-4), (V-1), (V-2), (V-4), or (V-5), R 1 Yes - OR 1a And R 1a It is methyl; R 2 It is hydrogen; R 3 It is hydrogen; R 61 R63 and R 64 It is hydrogen; R 62 It is methyl, vinyl, cyclopropyl, methoxy, or ethoxy.

[0138] In some embodiments of compounds of formula (III-2), formula (IV-1), formula (IV-4), formula (V-1), formula (V-2), formula (V-4), or formula (V-5), R 1 Yes - OR 1a And R 1a It is methyl; R 2 It is hydrogen; R 3 It is hydrogen; R 61 R 63 and R 64 It is hydrogen; R 62 It is methoxy, -OCD3, or ethoxy.

[0139] In the first implementation scheme of aspect 7, R 1 Yes - OR 1a And R 1a It is hydrogen, -CH2F, -CHF2, -CF3, methyl, -CD3, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl or 1,1-dimethylethyl.

[0140] In the second implementation scheme of aspect 7, R 1 Yes - OR 1a And R 1a It is methyl, ethyl, 1-propyl or 2-propyl.

[0141] In the third implementation scheme of aspect 7, R 1 Yes - OR 1a And R 1a It is a methyl group.

[0142] In the fourth implementation scheme of aspect 7, R 1 Yes - OR 1a And R 1a It is -CD3.

[0143] Compound of any one of aspects 1 to 7, R 2 It is hydrogen.

[0144] Compound A from any of aspects 9, 1 to 8 5 It is CR 5 A 4 It is CR4 And A 3 It is CR 3 .

[0145] Compounds of any one of aspects 1 to 9, R 3 and R 5 It is hydrogen; and R 4 It is -C 1-10 Alkyl, -C 1-10 Alkoxy, C 3-10 Cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, or 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur; Wherein -C 1-10 The alkyl group is either unsubstituted or substituted by one, two, or three independent substituents selected from the following: halogen, -OC. 1-10 Alkyl, cycloalkyl, cycloalkenyl, cycloynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C) 1-10 alkyl)2、-NH(C 1-10 Alkyl groups and -NH2; Wherein C 3-10 Each of the cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocyclic groups is not substituted or is composed of 1, 2, or 3 independently selected from halogens, -C 1-10 Alkyl, -C 1-10 Alkoxy and -halogen C 1-10 Alkyl substituents.

[0146] In the first embodiment of aspect 10, R 3 and R 5 It is hydrogen; R 4 It is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, oxecyclobutyl, tetrahydrofuranyl, dioxalkyl, oxazolyl, or pyrazolyl. The methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, and 1,1-dimethylethyl groups are either unsubstituted or substituted by one, two, or three substituents independently selected from the group consisting of halogen, -OC, etc. 1-10 Alkyl, cycloalkyl, cycloalkenyl, cycloynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C) 1-10 alkyl)2、-NH(C1-10 alkyl groups and -NH2; and The cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, oxacyclobutyl, tetrahydrofuranyl, dioxalkyl, oxazolyl, or pyrazolyl groups are not substituted or are composed of one, two, or three independently selected from halogens, -C 1-10 Alkyl, --OC 1-10 Alkyl and halogen C 1-10 Alkyl substituents.

[0147] In the second implementation scheme of aspect 10, R 3 and R 5 It is hydrogen; R 4 yes - t Bu、 , , , , , , , , , , , , , , or .

[0148] In the third implementation scheme of aspect 10, R 3 and R 5 It is hydrogen; R 4 yes- t Bu、 , , or .

[0149] In the fourth implementation scheme of aspect 10, R 3 and R 5 It is hydrogen; R 4 yes- t Bu.

[0150] Compounds of any one of aspects 1 to 8, R 3 It is hydrogen; and (R) 4 and R 5 Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic base ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, wherein the 5- to 6-membered heterocyclic base ring is unsubstituted or surrounded by 1, 2, 3, or 4 R atoms. 1d Replace; and Each R1d Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -C 1-10 alkoxy, 4- to 6-membered heterocyclic groups or -halogen C 1-10 alkyl.

[0151] In the first embodiment of aspect 11, R 3 It is hydrogen; and (R) 4 and R 5 Together with the atoms they are attached to, they form dihydrofuranyl or dihydropyranyl; Each of the dihydrofuranyl or dihydropyranyl groups is not substituted or is composed of 1, 2, 3 or 4 R groups. 1d Replace; and Each R 1d Independently, it is hydrogen, halogen, -C 1-4 Alkyl, -halogen C 1-4 Alkyl or -C 1-4 Alkyl group.

[0152] In the second implementation scheme of aspect 11, R 3 It is hydrogen; (R) 4 and R 5 It forms together with the atoms it is attached to. or It was not replaced or replaced by 1, 2, 3 or 4 Rs. 1d Replace; and Each R 1d It is independently hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl or 1,1-dimethylethyl.

[0153] In the third implementation scheme of aspect 11, R 3 It is hydrogen; and (R) 4 and R 5 It forms together with the atoms it is attached to. , or .

[0154] In the fourth implementation scheme of aspect 11, R 5 It is hydrogen; and (R) 3 and R 4 Together with the atoms to which they are attached, they form a 5- to 6-membered cycloalkyl ring, or a 5- to 6-membered heterocyclic base ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, wherein the 5- to 6-membered heterocyclic base ring is unsubstituted or surrounded by 1, 2, 3, or 4 R atoms. 1d Replace; and Each R 1d Independently, it is hydrogen, halogen, -C 1-10Alkyl, -C 1-10 alkoxy or -halogen C 1-10 alkyl.

[0155] In the fifth implementation scheme of aspect 11, R 5 It is hydrogen; and (R) 3 and R 4 Together with the atoms they are attached to, they form cyclopentyl or cyclopropyl groups; Each of the dihydro-pyrrolidinyl or pyrrolidinyl groups is not substituted or is composed of 1, 2, 3 or 4 R groups. 1d Replace; and Each R 1d It is independently hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl or 1,1-dimethylethyl.

[0156] In the sixth implementation scheme of aspect 11, R 3 It is hydrogen; and (R) 4 and R 5 It forms together with the atoms it is attached to. Its further non-replacement or replacement by 1 or 2 Rs d Replace; and Each R 1d It is independently hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl or 1,1-dimethylethyl.

[0157] Compound A from any of aspects 1 to 8, aspect 12. 5 It is N; A 4 It is CR 4 A 3 It is CR 3 ;R 3 It is H; R 4 It is -C 1-10 Alkyl, C 3-10 Cycloalkyl or 4- to 6-membered heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur; Wherein -C 1-10 Each of the alkyl groups is either unsubstituted or substituted by one, two, or three independent substituents selected from the following: halogen, C 1-10 Alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C) 1-10 alkyl)2、-NH(C 1-10 alkyl) or -NH2; wherein the C 3-10Each of the cycloalkyl or 4- to 6-membered heterocyclic groups is unsubstituted or is independently selected from halogens, -C 1-10 Alkyl, -C 1-10 Alkoxy and -halogen C 1-10 Alkyl substituents.

[0158] In the first implementation scheme of aspect 12, A 5 It is N; A 4 Yes -CR 4 A 3 Yes -CR 3 ;R 3 It is H; R 4 It is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl or cyclopentyl; Each of the methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, or cyclopentyl groups is either unsubstituted or substituted by one, two, or three substituents independently selected from methoxy, ethoxy, propoxy, isopropoxy, or butoxy.

[0159] In the second implementation scheme of aspect 12, A 5 It is N; A 4 It is CR 4 A 3 It is CR 3 ;R 3 It is H; and R 4 yes- t Bu or .

[0160] In the third implementation scheme of aspect 12, A 5 It is N; A 4 It is CR 4 A 3 It is CR 3 ;(R 3 and R 4 Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic base ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, wherein the 5- to 6-membered heterocyclic base ring is not substituted or is surrounded by 1, 2, or 3 R atoms. 1d Replace; and Each R 1d It is hydrogen or -C independently. 1-10 alkyl.

[0161] In the fourth implementation scheme of aspect 12, A 5 It is N; A 4 It is CR4 A 3 It is CR 3 ; and (R) 3 and R 4 Together with the atoms to which they are attached, they form dihydro-pyrrolidinyl or pyrrolidinyl groups; Each of the dihydro-pyrrolidinyl or pyrrolidinyl groups is not substituted or is composed of 1, 2 or 3 R groups. 1d Replace; and Each R 1d It is independently hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl or 1,1-dimethylethyl.

[0162] In the fifth implementation scheme of aspect 12, A 5 It is N; A 4 It is CR 4 A 3 It is CR 3 ; and (R) 3 and R 4 It forms together with the atoms it is attached to. Its further non-replacement or replacement by 1, 2 or 3 R 1d Replace; and Each R 1d It is independently hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl or 1,1-dimethylethyl.

[0163] In the sixth implementation of aspect 12, A 3 It is N; A 4 It is CR 4 A 5 It is CR 5 ;R 4 It is H; and R 5 It is -C 1-10 Alkyl group.

[0164] In the seventh implementation scheme of aspect 12, A 3 It is N; A 4 It is CR 4 A 5 It is CR 5 ;R 4 It is H; and R 5 It is methoxy, ethoxy, propoxy, isopropoxy, or butoxy.

[0165] In the eighth implementation scheme of aspect 12, A 4 It is N; A 3 It is CR 3 A 5 It is CR5 ;R 3 It is H; and R 5 It is -C 1-10 Alkyl group.

[0166] In the ninth embodiment of aspect 12, A 4 It is N; A 3 It is CR 3 A 5 It is CR 5 ;R 3 It is H; and R 5 It is methoxy, ethoxy, propoxy, isopropoxy, or butoxy.

[0167] In some implementation schemes of any of aspects 1 to 12, each R 7 It is hydrogen.

[0168] Aspect 13. A compound of formula (I), wherein the compound has formula (VI): (VI), Or its pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer, wherein: X 1 It is N or CH; R 62 It is ethyl, vinyl, cyclopropyl, or methoxy; A 5 Is it N or CR? 5 If it exists, then R 5 It is hydrogen; R 4 yes or ;and A 5 It is CR 5 Or N; if it exists, then R 5 It is hydrogen.

[0169] Aspect 14, a compound, said compound being selected from... Or a pharmaceutically acceptable salt thereof or its deuterated analogue thereof or its N-oxide thereof or its tautomer.

[0170] Aspect 14', a compound, said compound being selected from... Or a pharmaceutically acceptable salt thereof or its deuterated analogue thereof or its N-oxide thereof or its tautomer.

[0171] Aspect 15, a pharmaceutical composition comprising a compound of any one of aspects 1-14 or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0172] Aspect 16, a method of treating breast cancer, the method comprising administering to a subject in need a compound or pharmaceutically acceptable salt of any one of Aspects 1 to 14 or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof.

[0173] Aspect 17. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof for the treatment of breast cancer in a subject of need, comprising administering a therapeutically effective amount of the compound to the subject.

[0174] Aspect 18. A compound of formula (I) or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof, for use in treating a subject in need of breast cancer, said treatment comprising administering a therapeutically effective amount of said compound to said subject.

[0175] Aspect 19. A compound of formula (I) or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof, used to manufacture a medicament for use in treating breast cancer in a subject of need.

[0176] Example The examples below are intended to be illustrative only and should not be considered limiting in any way. Efforts have been made to ensure accuracy regarding the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and biases should be accounted for. Temperatures are in degrees Celsius unless otherwise indicated. Reagents are purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and require no further purification before use unless otherwise indicated.

[0177] Unless otherwise indicated, the reactions described below are carried out under positive pressure of nitrogen or argon or in anhydrous solvent using a drying tube; the reaction flask is equipped with a rubber septum for introducing the substrate and reagents via a syringe; and the glassware is oven-dried and / or heated to dry.

[0178] Unless otherwise instructed, the reactions described below are carried out under positive pressure of nitrogen or argon or in anhydrous solvent using a drying tube; the reaction flask is equipped with a rubber septum for introducing the substrate and reagents via a syringe; and the glassware is oven-dried and / or heated to dry.

[0179] Unless otherwise instructed, column chromatography purification is performed on a Biotage system (manufacturer: Dyax Corporation) with a silica column, on a SepPak silica filter cartridge (Waters), or on a Teledyne Isco Combiflash purification system using a pre-packed silica filter cartridge.

[0180] ¹H NMR spectra were recorded on a Varian instrument operating at 400 MHz. ¹H NMR spectra were obtained using CDCl₃, CD₂Cl₂, CD₃OD, D₂O, d₆-DMSO, d₆-acetone, or (CD₃)₂CO as solvents and tetramethylsilane (0.00 ppm) or residual solvents (CDCl₃: 7.25 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm; d₆-DMSO: 2.50 ppm; d₆-acetone: 2.05 ppm; (CD₃)₂CO: 2.05 ppm) as reference standards. When reporting peak multiplicity, the following abbreviations were used: s (singleton), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad peak), dd (doublet), dt (doubletuplet). Coupling constants are reported in Hertz (Hz). The names of compounds other than the reagents mentioned above were generated by ChemDraw version 12.0.

[0181] abbreviation:

[0182] Example A: Example A1: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoic acid Step 1: Methyl 4-(bromomethyl)-3-iodobenzoate AIBN (0.24 g, 1.45 mmol) was added to a stirred solution of methyl 3-iodo-4-methylbenzoate (4 g, 14.49 mmol) and NBS (2.58 g, 14.49 mmol) in CCl4 (50 mL) under reflux. The resulting mixture was stirred at 70 °C for 6 h. After cooling to reflux, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5:1) to give the desired product (3.6 g, 70%). ¹H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.95 (dd, J = 8.0, 1.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 4.76 (s, 2H), 3.86 (s, 3H).

[0183] Step 2: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoate K₂CO₃ (2.80 g, 20.28 mmol) was added to a stirred solution of methyl 4-(bromomethyl)-3-iodobenzoate (3.6 g, 10.14 mmol) and 1H-pyrazole (0.69 g, 10.14 mmol) in ACN (30 mL) under reflux. The resulting mixture was stirred overnight at 70 °C. After cooling to reflux, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to give the product (2.5 g, 72%). MS (ESI) m / e [M+H]⁺ = 343.

[0184] Step 3: 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoic acid NaOH (2N, 5 mL) was added dropwise to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoate (800 mg, 1.46 mmol) in MeOH (5 mL) and THF (5 mL). The resulting mixture was stirred overnight at rt. After the reaction was complete, the mixture was concentrated and acidified with HCl (3N) to a pH of approximately 4. The precipitated solid was collected by filtration to give the title compound (730 mg, 95%). MS (ESI) m / e [M+H]+ = 329.

[0185] Example A2: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-ethynylbenzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-((trimethylsilyl)ethynyl)benzoate A solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoate (300 mg, 0.88 mmol), trimethylsilylacetylene (129 mg, 1.31 mmol), Pd(dppf)Cl2 (64 mg, 0.09 mmol), CuI (167 mg, 0.88 mmol), and TEA (366 μL, 2.63 mmol) in ACN (5 mL) was stirred overnight at 80 °C under nitrogen atmosphere. After cooling to rt, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give the product (260 mg, 95%). MS (ESI) m / e [M+H]+ = 313.1.

[0186] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-ethynylbenzoic acid LiOH (40 mg, 1.67 mmol) was added to a stirred solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-((trimethylsilyl)ethynyl)benzoate (260 mg, 0.83 mmol) in THF (6 mL) and H₂O (2 mL) at 0 °C. The resulting mixture was stirred at 70 °C for 1 h. After cooling to rt, the mixture was acidified to pH = 2 with HCl (1N). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (C18; mobile phase, ACN / water (0.1% FA), 10% to 50% gradient over 20 min). The fractions containing the product were combined and evaporated to give the product (99.5 mg, 53%). 1 H NMR (300 MHz, DMSO- d 6) δ 8.00 (s, 1H), 7.93-7.81 (m, 2H), 7.51 (s,1H), 6.92 (d, J = 8.1 Hz, 1H), 6.31 (s, 1H), 5.54 (s, 2H), 4.61 (s, 1H). MS(ESI) m / e [M+H] + = 227.0.

[0187] Example A3: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoic acid Step 1: Methyl 3-bromo-4-(bromomethyl)benzoate A solution of methyl 3-bromo-4-methylbenzoate (5.0 g, 21.9 mmol), NBS (4.3 g, 24.1 mmol), and AIBN (360 mg, 2.2 mmol) in CCl4 (50 mL) was stirred at 95 °C for 3 h. After cooling to rt, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude substance was purified by silica gel column chromatography (PE / EA = 20:1) to obtain the product (4.9 g, 73%). MS (ESI) m / e [M+H] + = 307, 309.

[0188] Step 2: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate A solution of methyl 3-bromo-4-(bromomethyl)benzoate (4.7 g, 15.4 mmol), 1H-pyrazole (1.26 g, 18.4 mmol), and K₂CO₃ (4.25 g, 30.8 mmol) in DMF (100 mL) was stirred at 60 °C for 2 h. After cooling to rt, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude substance was purified by silica gel column chromatography (PE / EA = 4:1) to yield the product (3.7 g, 82%). MS (ESI) m / e [M+H]⁺ = 295, 297.

[0189] Step 3: 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoic acid NaOH (2N, 5 mL) was added to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (1.0 g, 3.4 mmol) in MeOH (5 mL) and THF (5 mL). The resulting mixture was stirred overnight at rt. After the reaction was complete, the mixture was concentrated under vacuum. The pH of the reaction was adjusted to 3 by HCl (3N). The precipitated solid was collected by filtration and dried to give the title compound (800 mg, 84%). MS (ESI) m / e [M+H]+ = 281, 283.

[0190] Example A4: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-vinylbenzoic acid Step 1: Methyl 4-((1H-pyrazole-1-yl)methyl)-3-vinylbenzoate A solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (300 mg, 1 mmol), tributyl(vinyl)stanane (477 mg, 1.5 mmol), and Pd(PPh3)4 (58 mg, 0.05 mmol) in THF (10 mL) was stirred at 80 °C for 4 h. After cooling to rt, the reaction mixture was concentrated. Water was added, and the mixture was extracted with EA. The organic layer was concentrated, and the crude substance was purified by silica gel column chromatography (PE / EA = 4:1) to yield the product (240 mg, 97%). MS (ESI) m / e [M+H + =243.

[0191] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-vinylbenzoic acid To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-vinylbenzoate (240 mg, 1 mmol) in MeOH (5 mL) and THF (5 mL), NaOH (2N, 5 mL) was added. The resulting mixture was stirred overnight at rt. After the reaction was complete, the mixture was concentrated. The pH of the reaction was adjusted to 3 with HCl (3N). The precipitated solid was collected by filtration to give the title compound (180 mg, 80%). MS (ESI) m / e [M+H) + = 229.

[0192] Example A5: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-cyclopropylbenzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-cyclopropylbenzoate A solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (200 mg, 0.68 mmol), cyclopropylboronic acid (117 mg, 1.36 mmol), Pd(OAc)₂ (16 mg, 0.07 mmol), Cy₃P (38 mg, 0.14 mmol), and K₃PO₄ (289 mg, 1.36 mmol) in DMAc (5 mL) was stirred in a microwave reactor at 140 °C under N₂ for 4 h. After cooling to rt, the mixture was quenched with water. The aqueous layer was extracted with EA. The organic layer was concentrated, and the crude substance was purified by preparative TLC (PE / EA = 1:3) to yield the product (20 mg, 11.5%). MS (ESI) m / e [M+H + = 257.

[0193] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-cyclopropylbenzoic acid To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-cyclopropylbenzoate (20 mg, 0.08 mmol) in MeOH (2 mL) and THF (2 mL), NaOH (2N, 2 mL) was added. The resulting mixture was stirred overnight at rt. After the reaction was complete, the mixture was concentrated. The pH of the reaction was adjusted to 3 with HCl (3N). The precipitated solid was collected by filtration to give the title compound (15 mg, 79%). MS (ESI) m / e [M+H) + = 243.

[0194] Example A6: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(methoxymethyl)benzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(methoxymethyl)benzoate A mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (100 mg, 0.34 mmol), potassium methoxy-methyltrifluoroborate (62 mg, 0.41 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (8 mg, 0.007 mmol), NiCl2·glycol dimethyl ether (8 mg, 0.04 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (10 mg, 0.04 mmol), and K2HPO4 (174 mg, 1 mmol) in a DMAC (2 mL) was bubbled for 2 min and then stirred under a blue LED at rt for 6 h. After the reaction was complete, the mixture was diluted with EA. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to EA) to yield the title product (25 mg, 26%). MS (ESI) m / e [M+H]+ = 261.2.

[0195] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(methoxymethyl)benzoic acid NaOH (0.2 mL, 1N, 0.2 mmol) was added dropwise to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(methoxymethyl)benzoate (25 mg, 0.1 mmol) in THF (1 mL), MeOH (1 mL), and water (1 mL). The solution was stirred at rt for 2 h. After the reaction was complete, the mixture was diluted with EA and citric acid solution. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (23 mg, crude). MS (ESI) m / e [M+H] + = 247.1.

[0196] Example 7: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(dimethylamino)benzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(dimethylamino)benzoate A solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (150 mg, 0.5 mmol), dimethylamine hydrogen chloride (61 mg, 0.75 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (11 mg, 0.01 mmol), NiCl2·glycol dimethyl ether (11 mg, 0.05 mmol), and DABCO (196 mg, 1.75 mmol) in DMAC (5 mL) was bubbled with N2 for 2 min and then stirred overnight under a blue LED at rt. After the reaction was complete, the mixture was diluted with EA. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to give the title product (27 mg, 21%). MS (ESI) m / e [M+H] + = 260.1.

[0197] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(dimethylamino)benzoic acid NaOH (0.2 mL, 1N, 0.2 mmol) was added dropwise to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(dimethylamino)benzoate (27 mg, 0.1 mmol) in THF (1 mL), MeOH (1 mL), and water (1 mL). The solution was stirred at rt for 2 h. After the reaction was complete, the mixture was acidified to pH 4 with HCl (1N) and concentrated. The residue was suspended in DCM / MeOH (10:1, 5 mL) for 5 min and filtered. The filtrate was concentrated, and the residue was used directly in the next step. (25 mg, crude substance). MS (ESI) m / e [M+H]+ = 246.3.

[0198] Example A8: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoate A solution of methyl 4-(bromomethyl)-3-methoxybenzoate (1.0 g, 3.88 mmol), 1H-pyrazole (290 mg, 4.26 mmol), and K₂CO₃ (1.07 g, 7.76 mmol) in DMF (100 mL) was stirred overnight at 60 °C. After cooling to rt, the mixture was quenched with water. The aqueous layer was extracted with EA. The organic layer was concentrated, and the crude substance was purified by silica gel column chromatography (PE / EA = 3:7) to yield the product (576 mg, 60.4%). MS (ESI) m / e [M+H]⁺ = 247.

[0199] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid NaOH (2N, 10 mL) was added to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoate (576 mg, 2.34 mmol) in MeOH (10 mL) and THF (10 mL). The resulting mixture was stirred overnight at rt. After the reaction was complete, the mixture was concentrated. The pH of the reaction was adjusted to 3 with HCl (3N). The precipitated solid was collected by filtration to give the title compound (460 mg, 84.7%). MS (ESI) m / e [M+H]+ = 233.

[0200] Example A9: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-5-bromo-2-fluorobenzoic acid Step 1: Methyl 5-bromo-2-fluoro-4-methylbenzoate Concentrated H₂SO₄ (5 drops) was added to a solution of 5-bromo-2-fluoro-4-methylbenzoic acid (1 g, 4.5 mmol) in MeOH (10 mL), and the solution was stirred at 80 °C for 16 h. After cooling to rt, the solvent was evaporated, and the residue was dissolved in EA. The organic layer was washed with NaHCO₃ solution and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to yield the title product (1 g, 95%). MS (ESI) m / e [M+H]⁺ = 247, 249.

[0201] Step 2: Methyl 5-bromo-4-(bromomethyl)-2-fluorobenzoate A solution of methyl 5-bromo-2-fluoro-4-methylbenzoate (1 g, 4.1 mmol), NBS (796 mg, 4.4 mmol), and BPO (48 mg, 0.2 mmol) in CCl4 (20 mL) was stirred at 80 °C for 16 h. After cooling to rt, the solid was filtered off. The filtrate was washed with NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to yield the title product (1.2 g, 90%). MS (ESI) m / e [M+H]+ = 325, 327.

[0202] Step 3: Methyl 4-((1H-pyrazol-1-yl)methyl)-5-bromo-2-fluorobenzoate tBuOK (134 mg, 1.2 mmol) was added fractionally to a solution of methyl 5-bromo-4-(bromomethyl)-2-fluorobenzoate (324 mg, 1 mmol) and 1H-pyrazole (102 mg, 1.5 mmol) in THF (10 mL). The reaction mixture was stirred at rt for 2 h. After the reaction was complete, the mixture was diluted with EA. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to EA) to give the title product (330 mg, 100%). MS (ESI) m / e [M+H]+ = 313, 315.

[0203] Step 4: 4-((1H-pyrazol-1-yl)methyl)-5-bromo-2-fluorobenzoic acid NaOH (0.34 mL, 6N, 2 mmol) was added dropwise to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-5-bromo-2-fluorobenzoate (330 mg, 1 mmol) in THF (2 mL), MeOH (2 mL), and water (2 mL). The solution was stirred at rt for 16 h. After the reaction was complete, the mixture was diluted with EA and citric acid solution. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (300 mg, 99%). MS (ESI) m / e [M+H]+ = 299, 301.

[0204] Example A10: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-bromo-2-fluorobenzoic acid Step 1: 3-Bromo-2-fluoro-4-methylbenzoic acid LDA (5.25 mL, 10.5 mmol, 2 M in THF) was added dropwise to a solution of 1.89 g, 10 mmol of 2-bromo-1-fluoro-3-methylbenzene in 30 mL of THF at below -65 °C, and the solution was stirred at this temperature for 30 min. Crushed dry ice was added to the solution, and the solution was stirred at -65 °C for 1 h. The mixture was then heated to rt and stirred overnight. The reaction mixture was diluted with EA, washed with citric acid solution and brine, dried over Na2SO4, filtered, and concentrated to give the title product (2.1 g, crude). MS (ESI) m / e [M+H]+ = 233, 235.

[0205] Step 2: Methyl 3-bromo-2-fluoro-4-methylbenzoate SOCl2 (2 mL) was carefully added dropwise to a solution of 3-bromo-2-fluoro-4-methylbenzoic acid (2.1 g, 10 mmol) in MeOH (10 mL), and the solution was stirred at 80 °C for 3 h. After cooling to rt, the solvent was evaporated, and the residue was purified by silica gel column chromatography (PE:EA = 10:1) to yield the title product (1.4 g, 57%, for both steps). MS (ESI) m / e [M+H]+ = 247, 249.

[0206] Step 3: Methyl 3-bromo-4-(bromomethyl)-2-fluorobenzoate A mixture of methyl 3-bromo-2-fluoro-4-methylbenzoate (246 mg, 1 mmol), NBS (187 mg, 1.05 mmol), and BPO (12 mg, 0.05 mmol) in CCl4 (10 mL) was stirred at 80 °C for 16 h. After cooling to rt, the solid was filtered off. The filtrate was concentrated and purified by silica gel column chromatography (PE:EA = 5:1) to give the title product (140 mg, 90%). MS (ESI) m / e [M+H]+ = 325, 327.

[0207] Step 4: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromo-2-fluorobenzoate tBuOK (58 mg, 0.51 mmol) was added fractionally to a mixture of methyl 3-bromo-4-(bromomethyl)-2-fluorobenzoate (140 mg, 0.43 mmol) and 1H-pyrazole (44 mg, 0.65 mmol) in THF (10 mL). The reaction mixture was stirred at rt for 1 h. After the reaction was complete, the mixture was concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to EA) to give the title product (80 mg, 60%). MS (ESI) m / e [M+H]+ = 313, 315.

[0208] Step 5: 4-((1H-pyrazol-1-yl)methyl)-3-bromo-2-fluorobenzoic acid NaOH (0.1 mL, 6N, 0.6 mmol) was added dropwise to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromo-2-fluorobenzoate (80 mg, 0.26 mmol) in THF (1 mL), MeOH (1 mL), and water (1 mL). The solution was stirred at rt for 2 h. After the reaction was complete, the mixture was diluted with EA and citric acid solution, washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (60 mg, 77%). MS (ESI) m / e [M+H]+ = 299, 301.

[0209] Example A11: 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropylpyridinecarboxylic acid Step 1: 2-Bromo-3-(chloromethyl)pyridine SOCl2 (2.38 g, 20 mmol) was added dropwise to a solution of (2-bromopyridin-3-yl)methanol (1.87 g, 10 mmol) in DCM (10 mL) at 0 °C. The mixture was stirred overnight at rt. After the reaction was complete, the mixture was diluted with water and extracted with DCM. The organic layer was concentrated to give the product (2.00 g, 97%). MS (ESI) m / e [M+H]+ = 206, 208.

[0210] Step 2: 3-((1H-pyrazol-1-yl)methyl)-2-bromopyridine A solution of 2-bromo-3-(chloromethyl)pyridine (2.00 g, 9.76 mmol), 1H-pyrazole (680 mg, 10 mmol), and Cs₂CO₃ (6.52 g, 10 mmol) in DMF (10 mL) was stirred overnight at 80 °C. After the reaction was complete, the solvent was removed under vacuum. The crude substance was purified by silica gel column chromatography (PE / EA = 3:1) to obtain the product (2 g, 86%). MS (ESI) m / e [M+H]⁺ = 238, 240.

[0211] Step 3: 3-((1H-pyrazol-1-yl)methyl)-2-cyclopropylpyridine A solution of 3-((1H-pyrazol-1-yl)methyl)-2-bromopyridine (2.37 g, 10 mmol), cyclopropylboronic acid (1.70 g, 20 mmol), Pd(PPh3)4 (1.15 g, 0.1 mmol), and K3PO4 (4.24 g, 20 mmol) in dioxane / water (5:1) (10 mL) was stirred overnight at 140 °C under N2. After the reaction was complete, the mixture was concentrated. The crude substance was purified by silica gel column chromatography (PE / EA = 3:1) to obtain the product (1 g, 50%). MS (ESI) m / e [M+H]+ = 200.2.

[0212] Step 4: 3-((1H-pyrazol-1-yl)methyl)-2-cyclopropylpyridine 1-oxide A solution of 3-((1H-pyrazol-1-yl)methyl)-2-cyclopropylpyridine (1.30 g, 6.53 mmol) and m-CPBA (1.4 g, 8.13 mmol) in DCM (10 mL) was stirred overnight at rt. After the reaction was complete, the mixture was concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2:1) to give the product (1 g, 71%). MS (ESI) m / e [M+H]+ = 216.2.

[0213] Step 5: 3-((1H-pyrazol-1-yl)methyl)-6-chloro-2-cyclopropylpyridine A solution of 3-((1H-pyrazol-1-yl)methyl)-2-cyclopropylpyridine 1-oxide (1.00 g, 4.65 mmol) and POCl3 (2.13 g, 13.95 mmol) in a DCE (10 mL) was stirred overnight at 90 °C. After the reaction was complete, the solution was diluted with water and extracted with EA. The organic layer was concentrated and the crude material was purified by passing it through a C18 column (water / ACN containing 0.1% FA) to yield the product (300 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 7.61-7.56 (m, 1H), 7.39-7.34(m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.36-6.30 (m,1H), 5.49 (s, 2H), 2.05-1.96 (m, 1H), 1.19-1.11 (m, 2H), 1.02-0.95 (m, 2H). MS(ESI) m / e [M+H]+ = 234.1.

[0214] Step 6: Methyl 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropylpyridinecarboxylate A solution of 3-((1H-pyrazol-1-yl)methyl)-6-chloro-2-cyclopropylpyridine (300 mg, 1.28 mmol), Pd(dppf)₂Cl₂ (73 mg, 0.1 mmol), and TEA (387 mg, 3.83 mmol) in MeOH (10 mL) was stirred overnight at 110 °C with CO₂ (g) (15 atm). After cooling to rt, the solution was concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2:1) to yield the product (200 mg, 61%). MS (ESI) m / e [M+H]⁺ = 258.2.

[0215] Step 7: 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropylpyridinecarboxylic acid A solution of methyl 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropylpyridinecarboxylate (200 mg, 0.78 mmol) and LiOH·H₂O (100 mg, 2.38 mmol) in THF / H₂O (1:1) (10 mL) was stirred overnight at 50 °C. After cooling to rt, the solution was concentrated under vacuum. The crude material was purified by passing through a C18 column (water / ACN containing 0.1% FA) to yield the product (150 mg, 79%). MS (ESI) m / e [M+H]⁺ = 244.1.

[0216] Example A12: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(oxecyclobutane-2-yl)benzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(oxecyclobutane-2-yl)benzoate A mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (294 mg, 1 mmol), oxetane-2-carboxylic acid (204 mg, 4 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (22 mg, 0.02 mmol), NiCl2·glycol dimethyl ether (22 mg, 0.2 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (80 mg, 0.3 mmol), and 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (BTMG, 342 mg, 2 mmol) in a DMAC (10 mL) was bubbled with N2 for 2 min and then stirred overnight under a blue LED at rt. After the reaction was complete, the mixture was diluted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to EA) to yield the title product (140 mg, 51%). MS (ESI) m / e [M+H]+ = 273.2.

[0217] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(oxecyclobutane-2-yl)benzoic acid A solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(oxetane-2-yl)benzoate (140 mg, 0.51 mmol) in THF (5 mL), MeOH (5 mL), and water (5 mL) was added to a solution of NaOH (1 mL, 1N, 1 mmol) and the solution was stirred at rt for 2 h. After the reaction was complete, 1N HCl was added to the reaction mixture to pH 4 and the mixture was extracted with EA, washed with brine, dried, concentrated, and concentrated to give the product (80 mg, 61%). MS (ESI) m / e [M+H]+ = 259.0.

[0218] Example A13: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(oxecyclobutane-3-yl)benzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(oxecyclobutane-3-yl)benzoate Pyridine (110 mg, 1.4 mmol) was added to a mixture of oxadiazol-3-ol (111 mg, 1.5 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-onium tetrafluoroborate (NHC, 553 mg, 1.4 mmol) in 2-methoxy-2-methylpropane (MTBE, 5 mL), and the mixture was stirred at rt for 20 min under N2. In another flask, a mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (294 mg, 1 mmol), NiBr2·DME (22 mg, 0.1 mmol), Ir(ppy)2(dtbbpy)PF6 (27 mg, 0.03 mmol), quinine ring (122 mg, 1.1 mmol), and LiBr (87 mg, 1 mmol) in DMAC (5 mL) was bubbled with N2 for 2 min. The MTBE reaction mixture was filtered, and the filtrate was added to the DMAC solution. The resulting mixture was bubbled with N2 for another 2 min and stirred overnight at rt under a blue LED. After the reaction was complete, the mixture was diluted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to PE / EA = 1:2) to give the title product (130 mg, 48%). MS (ESI) m / e [M+H]+= 273.1.

[0219] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(oxecyclobutane-3-yl)benzoic acid NaOH (0.96 mL, 1N, 0.96 mmol) was added to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(oxecyclobutan-3-yl)benzoate (130 mg, 0.48 mmol) in THF (3 mL), MeOH (3 mL), and water (3 mL), and the solution was stirred at rt for 2 h. After the reaction was complete, the reaction mixture was diluted with EA and citric acid solution, washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (90 mg, crude). MS (ESI) m / e [M+H]+ = 259.1.

[0220] Example A14: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(azacyclobutane-1-yl)benzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(azacyclobutane-1-yl)benzoate A mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoate (342 mg, 1 mmol), azacyclobutane (114 mg, 2 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (22 mg, 0.02 mmol), NiCl2·glycol dimethyl ether (22 mg, 0.1 mmol), and DABCO (392 mg, 3.5 mmol) in DMAC (10 mL) was bubbled with N2 for 2 min and then stirred overnight under a blue LED at rt. After the reaction was complete, the mixture was diluted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to EA) to give the title product (200 mg, 74%). MS (ESI) m / e [M+H]+ = 272.2.

[0221] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(azacyclobutane-1-yl)benzoic acid A solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(azacyclobutan-1-yl)benzoate (200 mg, 0.74 mmol) in THF (5 mL), MeOH (5 mL), and water (5 mL) was mixed with NaOH (1.5 mL, 1N, 1.48 mmol) and stirred at rt for 2 h. After the reaction was complete, citric acid solution was added to the reaction mixture to pH 4, and the mixture was diluted with EA, washed with brine, dried, and concentrated to give the product (120 mg, 63%). MS (ESI) m / e [M+H]+ = 258.1.

[0222] Example A15: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-cyclobutylbenzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-cyclobutylbenzoate Pyridine (110 mg, 1.4 mmol) was added to a mixture of cyclobutanol (108 mg, 1.5 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-onium tetrafluoroborate (NHC, 553 mg, 1.4 mmol) in 2-methoxy-2-methylpropane (MTBE, 5 mL), and the mixture was stirred at rt for 20 min under N2. In another flask, a mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (294 mg, 1 mmol), NiBr2.DME (22 mg, 0.1 mmol), Ir(ppy)2(dtbbpy)PF6 (27 mg, 0.03 mmol), quinine ring (122 mg, 1.1 mmol), and LiBr (87 mg, 1 mmol) in DMAC (5 mL) was bubbled with N2 for 2 min. The MTBE reaction mixture was filtered, and the filtrate was added to DMAC solution. The resulting mixture was bubbled with N2 for 2 min and stirred overnight under a blue LED at rt. After the reaction was complete, the mixture was diluted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to PE / EA = 1:1) to give the title product (220 mg, 81%). MS (ESI) m / e [M+H]+ = 271.1.

[0223] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-cyclobutylbenzoic acid To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-cyclobutylbenzoate (220 mg, 0.81 mmol) in THF (5 mL), MeOH (5 mL), and water (5 mL), NaOH (0.3 mL, 6N, 1.8 mmol) was added, and the solution was stirred at rt for 3 h. After the reaction was complete, the reaction mixture was diluted with EA and washed with citric acid solution and brine, dried over Na2SO4, filtered, and concentrated to give the title product (150 mg, 72%). MS (ESI) m / e [M+H]+ = 257.1.

[0224] Example A16: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-chlorobenzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-chlorobenzoate A mixture of methyl 4-(bromomethyl)-3-chlorobenzoate (900 mg, 3.44 mmol), 1H-pyrazole (351 mg, 5.15 mmol), and Cs₂CO₃ (2.25 g, 6.88 mmol) in DMF (20 mL) was stirred at 80 °C for 1 h. After cooling to rt, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude material was purified by silica gel column chromatography (PE / EA = 7:3) to yield the product (800 mg, 93%). MS (ESI) m / e [M+H]⁺ = 251.

[0225] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-chlorobenzoic acid NaOH (2N, 5 mL) was added to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (800 mg, 3.39 mmol) in MeOH (5 mL) and THF (5 mL). The resulting mixture was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, the pH was adjusted to 7 with HCl, and the precipitated solid was collected by filtration to give the title compound (700 mg, 93%). MS (ESI) m / e [M+H]+ = 237.

[0226] Example A17: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid Step 1: Methyl 6-methoxy-5-methylpyridinecarboxylate A solution of methyl 6-chloro-5-methylpyridinecarboxylate (500 mg, 2.69 mmol) in MeOH (2 mL) was added to a solution of NaOMe / MeOH (2 mL) and the solution was stirred at 85 °C for 3 h. After cooling to rt, the solution was diluted with EA, washed with citric acid solution and brine, dried over Na2SO4, filtered, and concentrated to yield the title product (350 mg, 72%). MS (ESI) m / e [M+H]+ = 182.1.

[0227] Step 2: Methyl 5-(bromomethyl)-6-methoxypyridinecarboxylate A mixture of methyl 6-methoxy-5-methylpyridinecarboxylate (326 mg, 1.8 mmol), NBS (325 mg, 1.89 mmol), and BPO (22 mg, 0.09 mmol) in CCl4 (10 mL) was stirred at 80 °C for 4 h. After cooling to rt, the solid was filtered off, and the filtrate was washed with NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated. The residue and TEA (363 mg, 3.6 mmol) were subsequently dissolved in THF (10 mL) and diethyl phosphite (496 mg, 3.6 mmol). The resulting solution was stirred at rt for 1 h and diluted with EA. The solution was washed with citric acid and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to PE:EA = 2:1) to yield the title product (400 mg, 86%). MS (ESI) m / e [M+H]+ = 260, 262.

[0228] Step 3: Methyl 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylate tBuOK (519 mg, 4.63 mmol) was added to a mixture of methyl 5-(bromomethyl)-6-methoxypyridinecarboxylate (400 mg, 1.54 mmol) and 1H-pyrazole (315 mg, 4.63 mmol) in THF (10 mL), and the reaction mixture was stirred at rt for 1 h. After the reaction was complete, the reaction mixture was diluted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to PE:EA = 1:4) to give the title product (180 mg, 47%). MS (ESI) m / e [M+H]+ = 248.1.

[0229] Step 4: 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid To a solution of methyl 5-((1H-pyrazol-1-yl)methyl)-6-methoxybenzoate (170 mg, 0.69 mmol) in THF (5 mL), MeOH (5 mL), and water (5 mL), NaOH (0.22 mL, 6N, 1.32 mmol) was added, and the solution was stirred overnight at rt. After the reaction was complete, the reaction mixture was diluted with EA and citric acid solution, washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (100 mg, 63%). 1H NMR (400 MHz, DMSO-d6) δ 13.04(s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 2.0Hz, 1H) 7.12 (d, J = 7.5 Hz, 1H), 6.26 (t, J = 2.0 Hz, 1H), 5.30 (s, 2H), 3.92 (s, 3H). MS (ESI) m / e [M+H]+ = 234.0.

[0230] Example A18: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-fluorobenzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-fluorobenzoate A mixture of methyl 4-(bromomethyl)-3-fluorobenzoate (500 mg, 2.02 mmol), 1H-pyrazole (275 mg, 4.05 mmol), and Cs₂CO₃ (2.00 g, 6.07 mmol) in DMF (10 mL) was stirred at 80 °C for 2 h. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was purified by rapid chromatography on a silica gel column (eluting with 10%–50% EA / PE) to yield the desired product (400 mg, 84%). MS (ESI) m / e [M+1]⁺ = 235.

[0231] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-fluorobenzoic acid A mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-fluorobenzoate (400 mg, 1.70 mmol) and NaOH (340 mg, 8.51 mmol) in MeOH (5 mL) and H₂O (5 mL) was stirred at rt for 16 h. After the reaction was complete, the pH of the resulting mixture was adjusted to 4–5 with HCl (1N). The resulting solution was extracted with DCM. The organic layer was concentrated. The residue was purified by reversed-phase rapid chromatography (column, C18 reversed-phase; mobile phase, MeCN / water (0.1% FA), 10% to 100% gradient over 30 min; detector, UV 254 nm) to yield the desired product (200 mg, 53%). MS (ESI) m / e [M+1]+ = 221.

[0232] Example A19: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(trifluoromethyl)benzoic acid Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(trifluoromethyl)benzoate A mixture of methyl 4-(bromomethyl)-3-(trifluoromethyl)benzoate (80 mg, 0.27 mmol), 1H-pyrazole (55 mg, 0.81 mmol), and Cs₂CO₃ (263 mg, 0.81 mmol) in DMF (5 mL) was stirred at 80 °C for 1 h. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was purified by rapid chromatography on a silica gel column (eluting with 10%–50% EA / PE) to yield the desired product (70 mg, 91%). MS (ESI) m / e [M+1]⁺ = 285.

[0233] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(trifluoromethyl)benzoic acid A mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(trifluoromethyl)benzoate (70 mg, 0.25 mmol) and NaOH (49 mg, 1.23 mmol) in MeOH (3 mL) and H₂O (3 mL) was stirred at rt for 16 h. After the reaction was complete, the pH of the resulting mixture was adjusted to 4–5 with HCl (1N). The resulting solution was extracted with DCM. The organic layer was concentrated. The residue was purified by reversed-phase rapid chromatography (column, C18 reversed-phase; mobile phase, MeCN / water (0.1% FA), 10% to 100% gradient over 30 min; detector, UV 254 nm) to yield the desired product (40 mg, 60%). MS (ESI) m / e [M+1]+ = 271.

[0234] Example A20: Synthesis of 3-methyl-4-(pyridin-2-ylmethyl)benzoic acid Step 1: Methyl 3-methyl-4-(pyridin-2-ylmethyl)benzoate A mixture of methyl 4-bromo-3-methylbenzoate (350 mg, 1.5 mmol), potassium pyridinecarboxylate (340 mg, 1.8 mmol), Pd2dba3 (20 mmol, 0.02 mmol), and XantPhos (36 mg, 0.06 mmol) in diethylene glycol dimethyl ether (3 mL) was stirred at 150 °C for 16 h. After cooling to rt, the reaction mixture was diluted with EA and filtered through diatomaceous earth, washed with water and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2:1) to yield the desired product (230 mg, 64%). MS (ESI) m / e [M+H]+ = 242.

[0235] Step 2: 3-Methyl-4-(pyridin-2-ylmethyl)benzoic acid A mixture of methyl 3-methyl-4-(pyridin-2-ylmethyl)benzoate (230 mg, 0.95 mmol) and LiOH-H2O (210 mg, 5 mmol) in THF (5 mL) / H2O (5 mL) was stirred at rt for 24 h. After the reaction was complete, the reaction mixture was adjusted to pH 6 with 1 M HCl aqueous solution and extracted by EA. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (120 mg, 55%). MS (ESI) m / e [M+H]+ = 228.

[0236] Example A21: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethoxy)benzoic acid Step 1: Methyl 3-(difluoromethoxy)-4-methylbenzoate A solution of methyl 3-hydroxy-4-methylbenzoate (1.66 g, 10 mmol) in ACN (20 mL) was mixed with KOH solution (10 mL, 5N, 50 mmol) and stirred at 0 °C for 5 min. Diethyl (bromodifluoromethyl)phosphonate (5.34 g, 20 mmol) was added to the solution and the reaction mixture was stirred at rt for 3 h. After the reaction was complete, the solution was diluted with EA, washed with citric acid solution and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using PE / EA (eluting from PE to PE:EA = 4:1) to give the title product (1.5 g, 69%). MS (ESI) m / e [M+H]+ = 216.9.

[0237] Step 2: Methyl 4-(bromomethyl)-3-(difluoromethoxy)benzoate A mixture of methyl 3-(difluoromethoxy)-4-methylbenzoate (1.5 g, 6.9 mmol), NBS (1.36 g, 7.6 mmol), and BPO (167 mg, 0.69 mmol) in CCl4 (20 mL) was stirred overnight at 80 °C. After cooling to rt, the solid was filtered off, and the filtrate was washed with NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated. The residue, TEA (1.39 g, 13.8 mmol), was subsequently dissolved in THF (20 mL) and diethyl phosphite (1.9 g, 13.8 mmol). The resulting solution was stirred at rt for 1 h and diluted with EA. The solution was washed with citric acid and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to PE:EA = 4:1) to give the title product (1 g, 49%). MS (ESI) m / e [M+H]+ = 295, 297.

[0238] Step 3: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethoxy)benzoate tBuOK (571 mg, 5.1 mmol) was added to a mixture of methyl 4-(bromomethyl)-3-(difluoromethoxy)benzoate (1 g, 3.9 mmol) and 1H-pyrazole (462 mg, 6.8 mmol) in THF (20 mL), and the reaction mixture was stirred overnight at rt. After the reaction was complete, the reaction mixture was diluted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to PE:EA = 1:2) to give the title product (800 mg, 73%). MS (ESI) m / e [M+H]+ = 283.0.

[0239] Step 4: 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethoxy)benzoic acid NaOH (0.9 mL, 6N, 5.4 mmol) was added to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethoxy)benzoate (800 mg, 2.84 mmol) in THF (5 mL), MeOH (5 mL), and water (5 mL), and the solution was stirred at rt for 2 h. After the reaction was complete, the reaction mixture was diluted with EA and citric acid solution, washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (600 mg, 79%). MS (ESI) m / e [M+H]+ = 268.9.

[0240] Example A22: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(2,2-difluoroethyl)benzoic acid Step 1: Methyl 4-((1H-pyrazole-1-yl)methyl)-3-vinylbenzoate A mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoate (1.03 g, 3 mmol), tributyl(vinyl)stanane (999 mg, 3.15 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol), and LiCl (126 mg, 3 mmol) in 1,4-dioxane (20 mL) was stirred at 70 °C for 16 h. After cooling to rt, the mixture was diluted with EA, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using PE / EA (eluting from PE to PE:EA = 1:1) to yield the title product (600 mg, 83%). MS (ESI) m / e [M+H]+ = 242.9.

[0241] Step 2: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-carboxybenzoate K₂O₄·2H₂O (46 mg, 0.12 mmol) was added to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-vinylbenzoate (600 mg, 2.48 mmol) in THF (20 mL) and water (10 mL), and the solution was stirred at rt for 10 min. NaIO₄ (1.6 g, 7.44 mmol) was added, and the mixture was stirred at rt for 16 h. After the reaction was complete, the mixture was diluted with EA, washed with water, Na₂S₂O₃ solution, and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography using PE / EA (eluting from PE to PE:EA = 1:4) to yield the title product (500 mg, 82%). MS (ESI) m / e[M+H]⁺ = 245.1.

[0242] Step 3: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(hydroxymethyl)benzoate NaBH4 (70 mg, 1.84 mmol) was added to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-carboxybenzoate (300 mg, 1.23 mmol) in MeOH (10 mL), and the solution was stirred at rt for 2 h. After the reaction was complete, the mixture was diluted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the title product (280 mg, 92%). MS (ESI) m / e [M+H]+ = 247.0.

[0243] Step 4: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(2,2-difluoroethyl)benzoate Pyridine (118 mg, 1.5 mmol) was added to a mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(hydroxymethyl)benzoate (246 mg, 1 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-onium tetrafluoroborate (NHC, 474 mg, 1.2 mmol) in 2-methoxy-2-methylpropane (MTBE, 4 mL) and the mixture was stirred at rt for 30 min under N2. In another flask, a mixture of 2-((difluoromethyl)sulfonyl)benzo[d]thiazole (274 mg, 1.1 mmol), Cu(TMHD)₂ (43 mg, 0.1 mmol), Ir(ppy)₂(dtbbpy)PF₆ (46 mg, 0.05 mmol), t-Bu-terpy (44 mg, 0.11 mmol), and tetrabutylammonium benzoate (437 mg, 1.2 mmol) in DMSO (20 mL) was bubbled with N₂ for 2 min. The MTBE reaction mixture was filtered, and the filtrate was added to the DMSO solution. The resulting mixture was bubbled with N₂ for another 2 min and stirred overnight at rt under a blue LED. After the reaction was complete, the mixture was diluted with EA, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to EA) to give the title product (200 mg, 71%). MS (ESI) m / e [M+H]+ = 281.0.

[0244] Step 5: 4-((1H-pyrazol-1-yl)methyl)-3-(2,2-difluoroethyl)benzoic acid NaOH (0.24 mL, 6N, 1.44 mmol) was added to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(2,2-difluoroethyl)benzoate (200 mg, 0.71 mmol) in THF (3 mL), MeOH (3 mL), and water (3 mL), and the solution was stirred at rt for 16 h. After the reaction was complete, the pH of the reaction mixture was adjusted to 5 with citric acid solution and then diluted with EA. The mixture was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (170 mg, 90%). MS (ESI) m / e [M+H]+ = 267.1.

[0245] Example A23: Synthesis of 3-methoxy-4-(pyridin-2-ylmethyl)benzoic acid Step 1: Methyl 3-methoxy-4-(pyridin-2-ylmethyl)benzoate A mixture of methyl 4-bromo-3-methoxybenzoate (100 mg, 0.4 mmol), potassium pyridinecarboxylate (80 mg, 0.48 mmol), Pd2dba3 (20 mmol, 0.02 mmol), and XantPhos (24 mg, 0.04 mmol) in diethylene glycol dimethyl ether (5 mL) was stirred at 150 °C for 16 h. After cooling to rt, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude material was purified by silica gel column chromatography (PE / EA = 1:1) to yield the product (65 mg, 62%). MS (ESI) m / e[M+H]+ = 258.

[0246] Step 2: 3-Methoxy-4-(pyridin-2-ylmethyl)benzoic acid NaOH (2N, 5 mL) was added to a solution of methyl 3-methoxy-4-(pyridin-2-ylmethyl)benzoate (65 mg, 0.25 mmol) in MeOH (5 mL) and THF (5 mL), and the resulting mixture was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, the pH was adjusted to 7 with HCl, and the precipitated solid was collected by filtration to give the title compound (55 mg, 89%). MS (ESI) m / e [M+H]+ = 244.

[0247] Example A24: Synthesis of 3-methoxy-4-((3-methyl-1H-pyrazol-1-yl)methyl)benzoic acid Step 1: Methyl 4-(bromomethyl)-3-methoxybenzoate A mixture of methyl 3-methoxy-4-methylbenzoate (1.0 g, 5.56 mmol), NBS (1.09 g, 6.11 mmol), and AIBN (183 mg, 1.11 mmol) in CCl4 (20 mL) was stirred at 90 °C for 2 h. After cooling to rt, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude substance was purified by silica gel column chromatography (PE / EA = 10:1) to yield the product (1.0 g, 70%). MS (ESI) m / e [M+H]+ = 259, 261.

[0248] Step 2: Methyl 3-methoxy-4-((3-methyl-1H-pyrazole-1-yl)methyl)benzoate To a solution of 3-methyl-1H-pyrazole (38 mg, 0.47 mmol) in THF (3 mL), NaH (60% in mineral oil, 22 mg, 0.55 mmol) was added, and the resulting mixture was stirred at rt for 30 min. Methyl 4-(bromomethyl)-3-methoxybenzoate (100 mg, 0.39 mmol) was added, and the resulting mixture was stirred at rt for 30 min. After the reaction was complete, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude material was purified by silica gel column chromatography (PE / EA = 1:1) to yield the product (70 mg, 69%). MS (ESI) m / e [M+H]+ = 261.

[0249] Step 3: 3-Methoxy-4-((3-methyl-1H-pyrazol-1-yl)methyl)benzoic acid NaOH (2N, 0.5 mL) was added to a solution of methyl 3-methoxy-4-((3-methyl-1H-pyrazol-1-yl)methyl)benzoate (70 mg, 0.27 mmol) in MeOH (5 mL) and THF (5 mL). The resulting mixture was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, the pH was adjusted to 7 with HCl, and the precipitated solid was collected by filtration to give the title compound (60 mg, 91%). MS (ESI) m / e [M+H]+ = 247.

[0250] Example A25: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-ethoxypyridinecarboxylic acid Step 1: Methyl 6-ethoxy-5-methylpyridinecarboxylate A solution of methyl 6-chloro-5-methylpyridinecarboxylate (500 mg, 2.69 mmol) in toluene (10 mL) was added to a solution of NaOEt / EtOH (2.75 g, 8.1 mmol, 20% wt / wt), and the solution was stirred at 100 °C for 16 h. After cooling to rt, the solution was diluted with EA, washed with citric acid solution and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using PE / EA (eluting from PE to PE:EA = 1:1) to yield the title product (450 mg, 80%). MS (ESI) m / e [M+H]+ = 196.0.

[0251] Step 2: Methyl 5-(bromomethyl)-6-ethoxypyridinecarboxylate A mixture of methyl 6-ethoxy-5-methylpyridinecarboxylate (450 mg, 2.29 mmol), NBS (421 mg, 2.37 mmol), and BPO (51 mg, 0.21 mmol) in CCl4 (10 mL) was stirred at 80 °C for 3 h. After cooling to rt, the solid was filtered off, and the filtrate was washed with NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated. The residue and TEA (233 mg, 2.29 mmol) were subsequently dissolved in THF (10 mL) and diethyl phosphite (581 mg, 2.29 mmol). The resulting solution was stirred at rt for 2 h and diluted with EA. The solution was washed with citric acid and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to EA) to give the title product (350 mg, 56%). MS (ESI) m / e [M+H]+ = 273.9.

[0252] Step 3: 5-((1H-pyrazol-1-yl)methyl)-6-ethoxypyridinecarboxylic acid tBuOK (273 mg, 2.44 mmol) was added to a mixture of methyl 5-(bromomethyl)-6-ethoxypyridinecarboxylate (350 mg, 1.28 mmol) and 1H-pyrazole (166 mg, 2.44 mmol) in THF (20 mL), and the reaction mixture was stirred at rt for 16 h. After the reaction was complete, NaOH solution (1 mL, 6N, 6 mmol) was added to the reaction mixture, and the mixture was stirred for another 2 h. The pH of the mixture was adjusted to 5 with citric acid solution and diluted with EA. The mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by passing it through a C18 column with water / ACN containing 0.1% FA (eluting from 10% water containing 0.1% FA to ACN) to give the title product (100 mg, 31%). MS (ESI) m / e [M+H]+ = 248.0.

[0253] Example A26: Synthesis of 6-methyl-5-(pyridin-2-ylmethyl)pyridinecarboxylic acid Step 1: Methyl 6-methyl-5-(pyridin-2-ylmethyl)pyridinecarboxylate A mixture of methyl 5-bromo-6-methylpyridinecarboxylate (350 mg, 1.5 mmol), potassium pyridinecarboxylate (340 mg, 1.8 mmol), Pd2dba3 (20 mmol, 0.02 mmol), and XantPhos (36 mg, 0.06 mmol) in diethylene glycol dimethyl ether (3 mL) was stirred at 150 °C for 16 h. After cooling to rt, the reaction mixture was diluted with EA and filtered through diatomaceous earth, washed with water and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1:1 to 1:3) to yield the desired product (160 mg, 44%). MS (ESI) m / e [M+H]+ = 243.

[0254] Step 2: 6-Methyl-5-(pyridin-2-ylmethyl)pyridinecarboxylic acid A mixture of methyl 6-methyl-5-(pyridin-2-ylmethyl)pyridinecarboxylate (120 mg, 0.5 mmol) and LiOH-H2O (210 mg, 5 mmol) in THF (5 mL) / H2O (5 mL) was stirred at rt for 24 h. After the reaction was complete, the reaction mixture was adjusted to pH 6 with 1 M HCl aqueous solution and extracted by EA. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (60 mg, 52%). MS (ESI) m / e [M+H]+ = 229.

[0255] Example A27: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethyl)benzoic acid Step 1: Methyl 3-(difluoromethyl)-4-methylbenzoate DAST (2.7 g, 16.9 mmol) was added to a solution of methyl 3-formyl-4-methylbenzoate (300 mg, 1.69 mmol) in DCM (5 mL), and the resulting mixture was stirred at 50 °C for 1 h. After cooling to rt, the mixture was poured into ice water and extracted with EA. The organic layer was washed with saturated NaHCO3 and brine and concentrated to give the product (300 mg, 89%). MS (ESI) m / e [M+H]+ = 201.

[0256] Step 2: Methyl 4-(bromomethyl)-3-(difluoromethyl)benzoate A mixture of methyl 3-(difluoromethyl)-4-methylbenzoate (280 mg, 1.4 mmol), NBS (300 mg, 1.68 mmol), and AIBN (23 mmol, 0.14 mmol) in CCl4 (5 mL) was stirred at 90 °C for 2 h. After cooling to rt, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude material was purified by silica gel column chromatography (PE / EA = 10:1) to yield the product (380 mg, 98%). MS (ESI) m / e [M+H]+ = 279, 281.

[0257] Step 3: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethyl)benzoate NaH (60% in mineral oil, 68 mg, 0.55 mmol) was added to a solution of 1H-pyrazole (91 mg, 1.34 mmol) in THF (10 mL) at 0 °C, and the resulting mixture was stirred at rt for 30 min. Methyl 4-(bromomethyl)-3-(difluoromethyl)benzoate (310 mg, 1.12 mmol) was added, and the resulting mixture was stirred at rt for 1 h. After the reaction was complete, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude material was purified by silica gel column chromatography (PE / EA = 7:3) to yield the product (50 mg, 17%). MS (ESI) m / e [M+H]+ = 267.

[0258] Step 4: 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethyl)benzoic acid NaOH (2N, 0.5 mL) was added to a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethyl)benzoate (45 mg, 0.17 mmol) in MeOH (5 mL) and THF (5 mL). The resulting mixture was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, the pH was adjusted to 7 with HCl, and the precipitated solid was collected by filtration to give the title compound (40 mg, 94%). MS (ESI) m / e [M+H]+ = 253.

[0259] Example A28: Synthesis of 5-((3-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid Step 1: Methyl 5-((3-((tert-Butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylate tBuOK (62 mg, 0.55 mmol) was added to a mixture of (1H-pyrazol-3-yl)carbamate tert-butyl ester (100 mg, 0.55 mmol) and THF (10 mL), and the mixture was stirred at 0 °C for 10 min. Methyl 5-(bromomethyl)-6-methoxypyridinecarboxylate (130 mg, 0.5 mmol) was added, and the reaction mixture was stirred overnight at rt. After the reaction was complete, the reaction mixture was diluted with EA, washed with citric acid, water, and brine, dried over Na2SO4, filtered, and concentrated to give a crude product (240 mg, crude substance). MS (ESI) m / e [M+H]+ = 363.0.

[0260] Step 2: 5-((3-((tert-Butoxycarbonyl)amino)-1H-pyrazol-1-yl))-6-ethoxypyridinecarboxylic acid To a solution of methyl 5-((3-((tert-Butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylate (240 mg, 0.5 mmol) in THF (5 mL), MeOH (5 mL), and water (5 mL), NaOH (0.17 mL, 6N, 1.02 mmol) was added and the solution was stirred at rt for 2 h. After the reaction was complete, the reaction mixture was diluted with EA and citric acid solution, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography with DCM / MeOH (eluting from DCM to DCM:MeOH = 5:1) to give the title product (80 mg, 46%, for both steps). MS (ESI) m / e [M+H]+ = 349.0.

[0261] Example A29: Synthesis of 4-((4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid Step 1: Methyl 4-((4-((tert-Butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-3-methoxybenzoate A mixture of methyl 4-(bromomethyl)-3-methoxybenzoate (300 mg, 1.16 mmol), tert-butyl (1H-pyrazol-4-yl)carbamate (256 mg, 1.40 mmol), and Cs₂CO₃ (757 mg, 2.32 mmol) in DMF (10 mL) was stirred at 70 °C for 1 h. After cooling to rt, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude material was purified by silica gel column chromatography (PE / EA = 3:2) to yield the product (400 mg, 95%). MS (ESI) m / e [M+H]⁺ = 362.

[0262] Step 2: 4-((4-((tert-Butoxycarbonyl)amino)-1H-pyrazol-1-yl))-3-methoxybenzoic acid NaOH (2N, 1 mL) was added to a solution of methyl 4-((4-((tert-Butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-3-methoxybenzoate (400 mg, 1.11 mmol) in MeOH (5 mL) and THF (5 mL). The resulting mixture was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, the pH was adjusted to 7 with HCl, and the precipitated solid was collected by filtration to give the title compound (330 mg, 86%). MS (ESI) m / e [M+H]+ = 348.

[0263] Example A30: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-ethylpyridinecarboxylic acid Step 1: 2-Bromo-3-(chloromethyl)pyridine SOCl2 (2.38 g, 20 mmol) was added to a solution of (2-bromopyridin-3-yl)methanol (1.87 g, 10 mmol) in DCM (10 mL) at 0 °C and stirred overnight at rt. After the reaction was complete, the mixture was diluted with water and extracted with EA. The organic layer was concentrated to give crude product (2.00 g, 97%). MS (ESI) m / e [M+H]+ = 206, 208.

[0264] Step 2: 3-((1H-pyrazol-1-yl)methyl)-2-bromopyridine A solution of 2-bromo-3-(chloromethyl)pyridine (2.00 g, 9.76 mmol), 1H-pyrazolo[1,2-a]pyrazole (680 mg, 10.00 mmol), and Cs₂CO₃ (6.52 g, 10 mmol) in DMF (10 mL) was stirred overnight at 80 °C. After the reaction was complete, the solution was concentrated and purified by silica gel column chromatography (PE / EA = 3:1) to give the product (2.00 g, 86%). MS (ESI) m / e [M+H]⁺ = 238, 240.

[0265] Step 3: 3-((1H-pyrazol-1-yl)methyl)-2-vinylpyridine A solution of 3-((1H-pyrazol-1-yl)methyl)-2-bromopyridine (2.00 g, 8.43 mmol), potassium trifluoroborate trichloroethylene borate (2.26 g, 16.86 mmol), Pd(PPh3)4 (924 mg, 0.8 mmol), and K2CO3 (2.33 g, 16.86 mmol) in dioxane / water (10 mL, v / v = 5:1) was stirred overnight at 100 °C under N2. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (PE / EA = 3:1) to give the product (1 g, 64%). MS (ESI) m / e [M+H]+ = 186.2.

[0266] Step 4: 3-((1H-pyrazol-1-yl)methyl)-2-ethylpyridine A solution of 3-((1H-pyrazol-1-yl)methyl)-2-vinylpyridine (2.00 g, 10.81 mmol) and Pd / C (10% / carbon, wetted) (200 mg) in MeOH (10 mL) was stirred at rt for 4 h under H2 (2 atm). After the reaction was complete, the mixture was filtered. The filtrate was concentrated to give the product (2 g, 99%). MS (ESI) m / e [M+H]+ = 188.3.

[0267] Step 5: 3-((1H-pyrazol-1-yl)methyl)-2-ethylpyridine 1-oxide A solution of 3-((1H-pyrazol-1-yl)methyl)-2-ethylpyridine (1.30 g, 6.53 mmol) and m-CPBA (3.70 g, 21.40 mmol) in DCM (20 mL) was stirred overnight at rt. After the reaction was complete, the mixture was concentrated. The crude substance was purified by silica gel column chromatography (PE / EA = 2:1) to obtain the product (500 mg, 38%). MS (ESI) m / e [M+H]+ = 204.2.

[0268] Step 6: 3-((1H-pyrazol-1-yl)methyl)-6-chloro-2-ethylpyridine A solution of 3-((1H-pyrazol-1-yl)methyl)-2-ethylpyridine 1-oxide (406 mg, 2 mmol) and POCl3 (918 mg, 6.00 mmol) in a DCE (10 mL) was stirred overnight at 100 °C. After the reaction was complete, the solution was diluted with water and extracted with EA. The organic layer was concentrated and purified by Combi-Flash (column = C18 spherical 20-35 μm; mobile phase: [water (0.1% FA) - ACN], B% = 5%-80%; 7.0 min) to yield the product (200 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.42 (d, J =8.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 6.56 - 6.52 (m, 1H), 5.60 (s, 2H), 2.94 - 2.84 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H). MS (ESI) m / e [M+H]+ = 222.2.

[0269] Step 7: Methyl 5-((1H-pyrazol-1-yl)methyl)-6-ethylpyridinecarboxylate A solution of 3-((1H-pyrazol-1-yl)methyl)-6-chloro-2-ethylpyridine (200 mg, 0.90 mmol), Pd(dppf)₂Cl₂ (66 mg, 0.09 mmol), and TEA (182 mg, 1.8 mmol) in MeOH (10 mL) was stirred overnight at 100 °C under CO₂ (15 atm). After cooling to rt, the solution was concentrated. The crude substance was purified by silica gel column chromatography (PE / EA = 2:1) to obtain the product (200 mg, 91%). MS (ESI) m / e [M+H]⁺ = 246.2.

[0270] Step 8: 5-((1H-pyrazol-1-yl)methyl)-6-ethylpyridinecarboxylic acid A solution of methyl 5-((1H-pyrazol-1-yl)methyl)-6-ethylpyridinecarboxylate (100 mg, 0.81 mmol) and LiOH·H₂O (100 mg, 2.38 mmol) in THF / H₂O (10 mL, v / v = 1 / 1) was stirred at 50 °C for 2 h. After the reaction was complete, the solution was concentrated. The crude material was purified by Combi-Flash (column = C18 spherical 20-35 μm; mobile phase: [water (0.1% FA) - ACN], B% = 5%-80%; 5.0 min) to obtain the product (100 mg, 53%). MS (ESI) m / e[M+H]⁺ = 232.2.

[0271] Example A31: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-(methoxy-d3)pyridinecarboxylic acid Step 1: 6-Chloro-5-methylpyridinecarboxylic acid methyl-d3 ester K₂CO₃ (4.43 g, 32.1 mmol) and CD₃I (4.66 g, 32.1 mmol) were successively added to a solution of 6-chloro-5-methylpyridinecarboxylic acid (5 g, 29.2 mmol) in DMF (50 mL), and the mixture was stirred overnight at rt. After the reaction was complete, the reaction mixture was poured into ice water (200 mL) and extracted twice with EA. The extract was washed with citric acid solution and brine, dried over Na₂SO₄, filtered, and concentrated to give the title product (4.8 g, 87%). MS (ESI) m / e [M+H]⁺ = 189.1.

[0272] Step 2: Methyl 6-(methoxy-d3)-5-methylpyridinecarboxylate NaH (60% in mineral oil, 2.13 g, 53 mmol) was added to a solution of CD3OD (4.79 g, 106 mmol) (4 g, 21.3 mmol) in THF (100 mL) at 0 °C and stirred for 30 min at 0 °C. Methyl-d3 ester of 6-chloro-5-methylpyridinecarboxylic acid (4 g, 21.3 mmol) was added and the solution was stirred at 50 °C for 3 h. After cooling to rt, the reaction mixture was poured into ice water and citric acid solution (500 mL) and extracted twice with EA. The extract was washed with brine, dried over Na2SO4, filtered, concentrated, and the residue purified by silica gel column chromatography (PE:EA = 1:0 to 1:1) to yield the title product (2.3 g, 58%). MS (ESI) m / e [M+H]+ = 185.2.

[0273] Step 3: Methyl 5-(bromomethyl)-6-(methoxy-d3)pyridinecarboxylate A mixture of methyl 6-(methoxy-d3)-5-methylpyridinecarboxylate (2.3 g, 12.4 mmol), NBS (2.43 g, 13.7 mmol), and BPO (150 mg, 0.62 mmol) in CCl4 (50 mL) was stirred at 80 °C for 4 h. After cooling to room temperature, the solid was filtered off, and the filtrate was washed with NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated. The residue and TEA (1.25 g, 12.4 mmol) were subsequently dissolved in THF (50 mL) and diethyl phosphite (1.67 g, 12.4 mmol). The resulting solution was stirred at rt for 4 h and diluted with EA. The solution was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the title product (3 g, crude). MS (ESI) m / e [M+H]+ = 263, 265.

[0274] Step 4: Methyl 5-((1H-pyrazol-1-yl)methyl)-6-(methoxy-d3)pyridinecarboxylate Cs₂CO₃ (3.92 g, 12 mmol) was added to a mixture of methyl 5-(bromomethyl)-6-(methoxy-d₃)pyridinecarboxylate (3 g, 11.45 mmol) and 1H-pyrazole (1.24 g, 18.32 mmol) in DMF (50 mL), and the reaction mixture was stirred at 80 °C for 4 h. After cooling to rt, the reaction mixture was poured into ice water and citric acid solution and extracted twice with EA. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography with PE / EA (eluting from PE to EA) to give the title product (1.1 g, 38%). MS (ESI) m / e [M+H]⁺ = 251.2.

[0275] Step 5: 5-((1H-pyrazol-1-yl)methyl)-6-(methoxy-d3)pyridinecarboxylic acid To a solution of methyl 5-((1H-pyrazol-1-yl)methyl)-6-(methoxy-d3)pyridinecarboxylate (1.1 g, 4.4 mmol) in THF (10 mL), MeOH (10 mL), and water (10 mL), NaOH (1.1 mL, 6N, 6.6 mmol) was added, and the solution was stirred at rt for 2 h. After the reaction was complete, the reaction mixture was diluted with water, the pH was adjusted to 5 with citric acid solution, and the mixture was extracted twice with EA. The extract was washed with water and brine, dried, and concentrated to give the product (1 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.65 (d, J =7.5 Hz, 1H), 7.54 (d, J = 1.1 Hz, 1H), 7.26 - 7.18 (m, 1H), 6.34 (t, J = 2.0Hz, 1H), 5.37 (s, 2H). MS (ESI) m / e [M+H]+ = 237.1.

[0276] Example B: Example B1: Synthesis of 5-(tert-butyl)-2-methoxybenzenesulfonamide.

[0277] At 0 °C, 120 mL of DCM containing chlorosulfonic acid (115 mL, 1.75 mol) was added dropwise to a solution of 1-(tert-butyl)-4-methoxybenzene (82 g, 0.5 mol) in 200 mL of DCM. The mixture was stirred at 0 °C for 1 h and then at rt for 1 h. The mixture was poured into ice water and extracted with DCM. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated, and the crude material was redissolved in CH3CN (250 mL), followed by dropwise addition of NH3·H2O (80 mL) at 0 °C. The mixture was stirred at rt for 10 h. The solvent was removed, and the crude material was purified by silica gel column chromatography to yield the desired product (70 g, 57%). 1H NMR (399 MHz, CDCl3) δ 7.93 - 7.89 (m, 1H), 7.55 (d, J = 8.7,1H), 6.98 (d, J = 8.7 Hz, 1H), 5.08 (s, 2H), 3.99 (s, 3H), 1.40 - 1.23 (m,9H). MS (ESI) m / e [M+H]+= 244.1.

[0278] Example B2: Synthesis of 6-(tert-butyl)-3-methoxypyridine-2-sulfonamide Step 1: 6-(tert-butyl)-2-fluoro-3-methoxypyridine A solution of 6-bromo-2-fluoro-3-methoxypyridine (5 g, 24 mmol) in 3 mL THF was added dropwise to a mixture of CuI (18.5 g, 97 mmol) and tert-butylmagnesium bromide (1 M in THF, 97 mL). The reaction mixture was heated and stirred at 20 °C for 16 h. The reaction was quenched with saturated aqueous NH4Cl solution (150 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EA = 100 / 1 to 0 / 1) to give the title compound (3.4 g, 77% yield). MS (ESI) m / e [M+H]+ = 184.4.

[0279] Step 2: 2-(benzylthio)-6-(tert-butyl)-3-methoxypyridine NaH (1.12 g, 28 mmol, 60% in mineral oil) was slowly added to a solution of benzyl mercaptan (3.5 g, 28 mmol) in THF (70 mL) and stirred at 0 °C for 30 min. 6-(tert-butyl)-2-fluoro-3-methoxypyridine (3.4 g, 18.7 mmol) was added at 0 °C. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (100 mL) and extracted with EA (300 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EA = 100 / 1 to 10 / 1) to give the title compound (4.05 g, 75% yield). 1H NMR: (400 MHz, CDCl3) δ 7.50 -7.40 (m, 2H), 7.35 - 7.18(m, 3H), 7.01 - 6.96 (m, 1H), 6.95 - 6.89 (m, 1H), 4.51 (s, 2H), 3.85 (s,3H), 1.34 (s,9H). MS(ESI) m / e [M+H]+ = 288.3.

[0280] Step 3: 6-(tert-butyl)-3-methoxypyridine-2-sulfonamide NCS (5.44 g, 40.7 mmol) was added to a solution of 2-(benzylthio)-6-(tert-butyl)-3-methoxypyridine (1.95 g, 6.8 mmol) in AcOH (18 mL) and H₂O (6 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 1 h. After adding MeOH (9.7 mL) containing 7 M NH₃, the reaction mixture was stirred at 20 °C for another 1 h. The reaction mixture was then diluted with 10 mL of H₂O and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The combined organic layers were filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / THF = 100 / 1 to 0 / 1) to give the title compound (1 g, 62% yield). 1H NMR: (400 MHz, DMSO-d6) δ 7.65 - 7.55 (m, 2H), 7.16 (br s, 2H), 3.89 (s, 3H), 1.31 (s, 9H). MS(ESI) m / e [M+H]+ = 245.4.

[0281] Example B3: Synthesis of 2-methoxy-5-(4-methoxypiperidin-1-yl)benzenesulfonamide A mixture of 5-bromo-2-methoxybenzenesulfonamide (250 mg, 0.94 mmol), 4-methoxypiperidine (218 mg, 1.88 mmol), Xphos-Pd-G4 (81 mg, 0.09 mmol), and t-BuONa (276 mg, 2.81 mmol) in dioxane (10 mL) was stirred at 120 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was purified by rapid chromatography on silica gel eluted with 5%–10% MeOH / DCM to yield the desired product (200 mg, 71%). MS (ESI) m / e [M+H]+ = 301.

[0282] Example B4: Synthesis of 6-methoxy-2,3-dihydro-1H-inden-5-sulfonamide A solution of methyl 5-methoxy-2,3-dihydro-1H-indene (148 mg, 1 mmol) in 10 mL of DCM was added to a solution of sulfonyl chloride (232 mg, 2 mmol) at 0 °C and stirred at rt for 2 h. The reaction mixture was washed with water. The organic phase was concentrated. The residue was dissolved in acetonitrile (5 mL), 25% NH3 water (1 mL) was added, and the mixture was stirred at rt for another 1 h. After the reaction was complete, the mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (50 mg, 22% yield). MS (ESI) m / e [M+H]+ = 227.9.

[0283] Example B5: Synthesis of 2-methoxy-5-(1-methoxycyclopropyl)benzenesulfonamide Step 1: 1-(3-bromo-4-methoxyphenyl)cycloprop-1-ol A mixture of methyl 3-bromo-4-methoxybenzoate (4 g, 16.3 mmol) and tetraisopropoxytitanium (6.5 g, 23 mmol) in THF (40 mL) was stirred at 25 °C for 30 min under N2, followed by dropwise addition of magnesium bromo(ethyl)magnesium (1 M in THF, 45.7 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with H2O (40 mL), filtered, and extracted with EA (40 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA = 1 / 0 to 3 / 1) to give the product (2.23 g, 56% yield). 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 2.4,8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 3.90 (s, 3H), 3.50 (s, 1H), 1.25 -1.22 (m, 2H), 1.01 - 0.97 (m, 2H).

[0284] Step 2: Synthesis of 5-methoxy-(1-methoxycyclopropyl)benzenesulfonamide To a solution of 1-(3-bromo-4-methoxy-phenyl)cyclopropanol (2.58 g, 10.6 mmol) in THF (26 mL), NaH (60% in mineral oil, 424 mg, 10.6 mmol) was added and the mixture was stirred at 0 °C for 30 min. MeI (1.66 g, 11.7 mmol) was added dropwise. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H₂O (20 mL). The aqueous phase was extracted with EA (20 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to yield 2-bromo-1-methoxy-4-(1-methoxycyclopropyl)benzene (1 g). n-BuLi (1.6 M in hexane, 1.2 mL) was added dropwise to a solution of 2-bromo-1-methoxy-4-(1-methoxycyclopropyl)benzene (500 mg, 1.94 mmol) in THF (5 mL), and the mixture was stirred at -60 °C for 30 min. Sulfonyl chloride (262 mg, 1.94 mmol) was added to the reactants at -60 °C, and the mixture was stirred at 25 °C for 30 min. MeOH (2.8 mL) containing 7 M NH3 was then added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O and extracted with EA (5 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15%-55% B over 8.0 min) to yield the title compound (152 mg, 30% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 2.4 Hz, 1H), 7.45 (dd, J = 2.4, 8.8 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.05 (s, 2H), 3.89 (s, 3H), 3.10 (s, 3H), 1.15–1.10 (m, 2H), 0.92–0.88 (m, 2H). MS(ESI) m / e [MH]-= 225.9.

[0285] Example B6: Synthesis of 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide Step 1: 1-Bromo-4-methoxy-2-((2-methylallyl)oxy)benzene 3-Bromo-2-methyl-prop-1-ene (3.66 g, 27.1 mmol) was added to a solution of 2-bromo-5-methoxy-phenol (5 g, 24.6 mmol) and K₂CO₃ (8.5 g, 61.6 mmol) in ACN (50 mL) at 25 °C, followed by stirring at 85 °C for 12 h. The mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE: EA = 10 / 1) to give the title compound (6.3 g, 99% yield). 1H NMR: (400 MHz, CDCl3) δ 7.42(d, J = 8.8 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 6.41 (dd, J = 2.8, 8.8 Hz,1H), 5.17 (s, 1H), 5.03 (s, 1H), 4.48 (s, 2H), 3.79 (s, 3H), 1.86 (s, 3H).

[0286] Step 2: 6-Methoxy-3,3-dimethyl-2,3-dihydrobenzofuran Bu3SnH (5.1 g, 17.50 mmol) and AIBN (250 mg, 1.5 mmol) were sequentially added to a solution of 1-bromo-4-methoxy-2-(2-methylallyloxy)benzene (3 g, 11.6 mmol) in toluene (30 mL) at 25 °C, followed by stirring at 110 °C for 12 h. The reaction mixture was cooled to room temperature and quenched with KF aqueous solution, and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA = 1 / 0 to 3 / 1) to give the title compound (1.78 g, 86% yield). 1H NMR: (400MHz, CDCl3) δ 6.98 (d, J = 8.4 Hz, 1H), 6.44 (dd, J = 2.0, 8.4 Hz, 1H), 6.40(d, J = 2.0 Hz, 1H), 4.25 (s, 2H), 3.78 (s, 3H), 1.33 (s, 6H).

[0287] Step 3: 7-Bromo-6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran n-BuLi (1.6 M in hexane, 6.5 mL) was added to a solution of 6-methoxy-3,3-dimethyl-2H-benzofuran (1.43 g, 8 mmol) in THF (28 mL) at 0 °C. The reaction mixture was refluxed at 45 °C for 90 min. Subsequently, the mixture was cooled to 0 °C and a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (5.23 g, 16 mmol) was added. The resulting mixture was stirred for 12 h. The solution was quenched with H₂O (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA = 1 / 0 to 0 / 1) to give the title compound (1.2 g, 58% yield). 1H NMR: (400 MHz, CDCl3) δ 6.95 (d,J = 8.4 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 4.36 (s, 2H), 3.88 (s, 3H), 1.35(s, 6H).

[0288] Step 4: 6-Methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide Under N2, a solution of 7-bromo-6-methoxy-3,3-dimethyl-2H-benzofuran (600 mg, 2.3 mmol) in THF (6 mL) was added. The mixture was cooled to -60 °C, and then n-BuLi solution (1.6 M in n-hexane, 1.46 mL) was added dropwise. The mixture was stirred at -60 °C for 30 min. Sulfonyl chloride (315 mg, 2.3 mmol) was added to the reaction mixture at -60 °C, and the solution was stirred at 25 °C for 30 min. MeOH (3.33 mL) containing 7 M NH3 was added to the reaction mixture, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O and extracted with EA (5 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge PrepOBD C18 150 x 40 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15%-55% B over 8.0 min) to yield the title compound (100 mg, 16% yield). ¹H NMR: (400 MHz, DMSO-d6) δ 7.29 (d, J = 8.4 Hz, 1H), 6.98 (s, 2H), 6.61 (d, J = 8.4 Hz, 1H), 4.27 (s, 2H), 3.82 (s, 3H), 1.27 (s, 6H). MS (ESI) m / e [MH]⁻ = 256.0.

[0289] Example B7: Synthesis of 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide Step 1: Methyl 2-(3-methoxyphenoxy)acetate A solution of 3-methoxyphenol (3.00 g, 24.19 mmol), methyl 2-bromoacetate (4.41 g, 29.03 mmol), and Cs₂CO₃ (15.77 g, 48.38 mmol) in 10 mL of DMF was stirred overnight at rt. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (PE / EA = 5:1) to give the product (3.80 g, 80%). MS (ESI) m / e[M+H]⁺ = 197.2.

[0290] Step 2: 1-(3-methoxyphenoxy)-2-methylprop-2-ol CH3MgBr (3M, 12.93 ml, 38.78 mmol) was added to a solution of methyl 2-(3-methoxyphenoxy)acetate (3.80 g, 19.39 mmol) in 20 ml THF at 0 °C and stirred for 2 h. After the reaction, the solution was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5:1) to give the title compound (3.80 g, 100%). MS (ESI) m / e [M+H]+ = 197.1.

[0291] Step 3: 6-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran P₂O₅ (8.66 g, 61.00 mmol) was added to a solution of 1-(3-methoxyphenoxy)-2-methylprop-2-ol (3.80 g, 19.38 mmol) in 10 mL of methanesulfonic acid under rt and stirred for 2 h. After the reaction, the solution was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 10:1) to give the title compound (1 g, 29%). ¹H NMR (400 MHz, CDCl₃) δ 7.00 (d, J = 8.0 Hz, 1H), 6.38 (d, J = 8.0 Hz, 1H), 6.34 (s, 1H), 3.76 (s, 3H), 2.94 (s, 2H). MS (ESI) m / e [M+H]+ = 179.1.

[0292] Step 4: 6-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfinic acid n-BuLi (12 ml, 30 mmol) was added to a solution of 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran (1.78 g, 3.00 mmol) and TMEDA (1.16 g, 10 mmol) in 30 ml of hexane at 0 °C and stirred for 10 min. The mixture was then cooled to -78 °C and bubbled with SO2 for 5 min. After the reaction was complete, the mixture was quenched with water. The solution was concentrated and purified by reversed-phase column chromatography (column = C18 spherical 20-35 μm; mobile phase: [water (0.1% FA) - ACN], B% = 5%-80%) to yield the title compound (1.80 g, 74%). MS (ESI) m / e [M+Na]+ = 243.2.

[0293] Step 5: 6-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonyl chloride Sulfoxide (992 mg, 7.4 mmol) was added dropwise to a solution of 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran (1.80 g, 7.4 mmol) in 10 mL of DCM at 0 °C, and the mixture was stirred for 1 h. After the reaction was complete, the mixture was poured into ice water and extracted with DCM. The organic layer was concentrated to give the title compound (1.80 g, 88%). MS (ESI) m / e [M+Na]+ = 276.1.

[0294] Step 6: 6-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide NH3•H2O (1 mL) was added dropwise to a solution of 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonyl chloride (200 mg, 0.72 mmol) in 1 mL acetonitrile at 0 °C. The reaction mixture was stirred at rt for 1 h. After the reaction was complete, H2O was added to the reaction mixture and it was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give the title compound (100 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 8.2 Hz, 1H), 5.24 (s, 2H), 3.93 (s, 3H), 2.95 (s, 2H), 1.52 (s, 6H). MS (ESI) m / e [M+H]+ =258.1.

[0295] Example B8: Synthesis of 7-methoxy-4,4-dimethyl-8-sulfonamide Step 1: 1-Bromo-4-methoxy-2-((3-methylbut-2-en-1-yl)oxy)benzene A mixture of 2-bromo-5-methoxyphenol (3.00 g, 14.78 mmol), 3-methylbut-2-en-1-ol (1.50 g, 17.73 mmol), PPh3 (5.80 g, 22.17 mmol), and di-tert-butyl diazepine-1,2-dicarboxylate (5.10 g, 22.17 mmol) in THF (30 mL) was stirred at 70 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was purified by rapid chromatography on silica gel eluted with 10%–40% EA / PE to yield the desired product (2.00 g, 50%). MS (ESI) m / e [M+H]+ = 271.

[0296] Step 2: 7-Methoxy-4,4-Dimethylchromium A mixture of 1-bromo-4-methoxy-2-((3-methylbut-2-en-1-yl)oxy)benzene (800 mg, 2.96 mmol), NaOAc (728 mg, 8.89 mmol), sodium formate (304 mg, 4.44 mmol), tetraethylammonium chloride (732 mg, 4.44 mmol), and Pd(OAc)₂ (331 mg, 1.48 mmol) in DMF (30 mL) was stirred at 90 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was purified by rapid chromatography on silica gel eluted with 5%–20% EA / PE to yield the desired product (280 mg, 49%). MS (ESI) m / e [M+H]⁺ = 193.

[0297] Step 3: 7-Methoxy-4,4-dimethyl-8-sulfinic acid n-BuLi (2.5 M in n-hexane) (1.75 mL, 4.38 mmol) was added dropwise to a stirred mixture of 7-methoxy-4,4-dimethylthiomenium (280 mg, 1.46 mmol) and TMEDA (169 mg, 1.46 mmol) in n-hexane (15 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The mixture was cooled to -78 °C and bubbled with SO2 for 5 min. After the reaction was complete, the mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the desired product (200 mg, 53%). MS (ESI) m / e [M+H]+ = 257.

[0298] Step 4: 7-Methoxy-4,4-dimethylchromium-8-sulfonyl chloride SO₂Cl₂ (105 mg, 0.78 mmol) was added dropwise to a stirred mixture of 7-methoxy-4,4-dimethyl-somethane-8-sulfinic acid (200 mg, 0.78 mmol) in DCM (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. After the reaction was complete, H₂O was added to the reaction mixture and the mixture was extracted with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give the desired product (200 mg, 88%). MS (ESI) m / e [M+H]⁺ = 291.

[0299] Step 5: 7-Methoxy-4,4-dimethyl-8-sulfonamide NH3•H2O (2 mL) was added dropwise to a solution of 7-methoxy-4,4-dimethylchromium-8-sulfonyl chloride (200 mg, 0.69 mmol) in THF (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, H2O was added to the reaction mixture and it was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give the desired product (100 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 8.0 Hz, 1H), 6.82 (brs, 2H), 6.61 (d, J =8.0 Hz, 1H), 4.25 - 4.06 (m, 2H), 3.71 (s, 3H), 1.78 - 1.62 (m, 2H), 1.20 (s, 6H). MS (ESI) m / e [M+H]+ = 272.

[0300] Example B9: Synthesis of 3-methoxy-6-(1,1,1-trifluoro-2-methylpropyl-2-yl)pyridine-2-sulfonamide Step 1: 1-(6-bromo-5-methoxypyridin-2-yl)ethyl-1-one iPrMgCl (48 mL, 96 mmol) was added dropwise to a solution of 2-bromo-6-iodo-3-methoxypyridine (30 g, 95.5 mmol) and N-methoxy-N-methylacetamide (10.8 g, 105 mmol) in THF (300 mL) at -40 °C under N2. The mixture was stirred at -40 °C for 2 h. After the reaction was complete, the mixture was quenched with H2O. The mixture was extracted with EA. The organic layer was concentrated and the crude substance was purified by silica gel column chromatography (PE / EA = 5:1) to give the title compound (21.1 g, 96%). MS (ESI) m / e [M+H]+ = 230.

[0301] Step 2: 2-Bromo-3-methoxy-6-(1,1,1-trifluoro-2-((trimethylsilyl)oxy)propyl-2-yl)pyridine TMSCF3 (26 g, 183 mmol) was added dropwise to a solution of 1-(6-bromo-5-methoxypyridin-2-yl)ethyl-1-one (21 g, 91.3 mmol) and KOAc (8.9 g, 91.3 mmol) in DMSO (100 mL) at 0 °C. The mixture was stirred at rt for 5 h. After the reaction was complete, the mixture was quenched with H2O and extracted with EA. The organic layer was dried and concentrated to obtain crude material. The crude material was used in the next step without purification (34 g, crude material). MS (ESI) m / e [M+H]+ = 374.

[0302] Step 3: 2-(6-bromo-5-methoxypyridin-2-yl)-1,1,1-trifluoroprop-2-ol A solution of 2-bromo-3-methoxy-6-(1,1,1-trifluoro-2-((trimethylsilyl)oxy)propyl-2-yl)pyridine (34 g, 91.3 mmol) and K₂CO₃ (25.3 g, 183 mmol) in MeOH (200 mL) was stirred at rt for 2 h. After the reaction was complete, the mixture was filtered and concentrated. The crude substance was purified by silica gel column chromatography (PE / EA = 3:1) to give the title compound (22 g, 80.3%). MS (ESI) m / e [M+H]⁺ = 300.

[0303] Step 4: 2-(6-bromo-5-methoxypyridin-2-yl)-1,1,1-trifluoropropyl-2-yl methanesulfonic acid ester MsCl (11 g, 95.3 mmol) was added dropwise to a solution of 2-(6-bromo-5-methoxypyridin-2-yl)-1,1,1-trifluoroprop-2-ol (22 g, 73.3 mmol) in DCM (200 mL) at 0 °C, followed by the addition of TEA (14.8 g, 147 mmol). The mixture was stirred at 0 °C for 2 h. After the reaction was complete, the mixture was washed with H2O. The organic layer was dried and concentrated. The crude product was used in the next step without purification (27 g, crude product). MS (ESI) m / e [M+H]+ = 378.

[0304] Step 5: 2-Bromo-3-methoxy-6-(1,1,1-trifluoro-2-methylpropyl-2-yl)pyridine AlMe3 (73.3 mL, 146.6 mmol) was added to a solution of 2-(6-bromo-5-methoxypyridin-2-yl)-1,1,1-trifluoroprop-2-yl methanesulfonic acid (27 g, crude product) in DCM (200 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 3 h. After the reaction was complete, the mixture was quenched with H2O. The organic layer was dried and concentrated. The crude substance was purified by silica gel column chromatography (PE / EA = 10:1) to give the title compound (9 g, 41.2%). MS (ESI) m / e [M+H]+ = 298.

[0305] Step 6: 3-Methoxy-6-(1,1,1-trifluoro-2-methylpropyl-2-yl)pyridine-2-sulfonamide n-BuLi (13.3 mL, 33.2 mmol) was added to a solution of 2-bromo-3-methoxy-6-(1,1,1-trifluoro-2-methylpropyl-2-yl)pyridine (9 g, 30.2 mmol) in THF (200 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 0.5 h. Then, SO2 (gas) was bubbled into the reactants at below -40 °C. After the reaction was complete, the mixture was quenched with H2O (20 mL). The mixture was concentrated to dryness. The crude material was redissolved in NH3·H2O (12.5%) (70 mL) and THF (70 mL), and I2 (7.5 g, 60 mmol) was added fractionally at rt. The mixture was stirred at rt for 1 h. The mixture was then diluted with EA. The organic layer was washed with H2O, dried, and concentrated. The crude compound was purified by silica gel column chromatography (PE / EA = 2:1) to yield the title compound (4.9 g, 54.4%). ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 5.14 (s, 2H), 3.99 (s, 3H), 1.57 (s, 6H). MS (ESI) m / e [M+H]⁺ = 299.

[0306] Example B10: Synthesis of 2-methoxy-5-(1-(trifluoromethyl)cyclopropyl)benzenesulfonamide 1-Methoxy-4-[1-(trifluoromethyl)cyclopropyl]benzene (5 g, 23 mmol) was added dropwise to chlorosulfonic acid (13.5 g, 115 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 1 h. The reaction mixture was then added dropwise to ice water. The precipitate was filtered and purified by silica gel column chromatography (PE:EA = 3:1) to give 2-methoxy-5-(1-(trifluoromethyl)cyclopropyl)benzenesulfonyl chloride (3.0 g, 41%). NH3•H2O (10.0 mL) was added dropwise to a solution of 2-methoxy-5-(1-(trifluoromethyl)cyclopropyl)benzenesulfonyl chloride (2.0 g, 6.4 mmol) in THF (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Water was added to the reaction mixture and the mixture was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to yield the title compound (1 g, 53%). ¹H NMR (400 MHz, DMSO-d6): δ 7.78 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 8.4, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.15 (s, 2H), 3.91 (s, 3H), 1.43–1.30 (m, 2H), 1.12–1.08 (m, 2H). MS (ESI) m / e [M+H]+ = 296.1.

[0307] Example B11: Synthesis of 2-methoxy-5-(1-methylcyclobutyl)benzenesulfonamide Step 1: 1-(4-Methoxyphenyl)cyclobut-1-ol n-BuLi (2.5 M, 7.1 mL, 17.7 mmol) was added dropwise to a solution of 1-bromo-4-methoxybenzene (3.0 g, 16.1 mmol) in THF (50 mL) at -70 °C, and the mixture was stirred at -70 °C for 30 min. Then, THF (5 mL) containing cyclobutanone (1.36 g, 19.4 mmol) was added at -70 °C, and the resulting mixture was stirred at -70 °C for 1 h. After heating to rt, the mixture was quenched with saturated NH4Cl and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude substance was purified by silica gel column chromatography (PE:EA = 1:3) to obtain the desired product (2.57 g, 90%).

[0308] Step 2: 1-Methoxy-4-(1-Methylcyclobutyl)benzene TiCl4 (5.34 g, 28.1 mmol) was added to a solution of 1-(4-methoxyphenyl)cyclobut-1-ol (2.5 g, 14.0 mmol) in DCM (100 mL) at -70 °C, and the mixture was stirred at -70 °C for 1 h. ZnMe2 (1.0 M, 42.1 mL, 42.1 mmol) was added dropwise at -70 °C, and the resulting mixture was stirred at -70 °C for 2 h. After heating to rt, the mixture was quenched with brine and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to yield the desired product (2.4 g, 97%).

[0309] Step 3: 2-Methoxy-5-(1-Methylcyclobutyl)benzenesulfonic acid A solution of 1-methoxy-4-(1-methylcyclobutyl)benzene (2.2 g, 12.5 mmol) in DCM (50 mL) was added to DCM (10 mL) containing ClSO3H (1.8 g, 15.0 mmol) at -10 °C, and the resulting mixture was stirred at -10 °C for 1 h. The mixture was quenched with ice water and concentrated. The crude material was purified by silica C18 (ACN / H2O = 15:85) to give the desired product (3.2 g, 100%). MS (ESI) m / e [MH]- = 255.

[0310] Step 4: 2-Methoxy-5-(1-methylcyclobutyl)benzenesulfonyl chloride A solution of 2-methoxy-5-(1-methylcyclobutyl)benzenesulfonic acid (3.1 g, 12.1 mmol) in SOCl2 (40 mL) was stirred at 85 °C for 2 h. The mixture was concentrated to yield a crude product (3.2 g).

[0311] Step 5: 2-Methoxy-5-(1-Methylcyclobutyl)benzenesulfonamide NH3·H2O (20 mL) was added to a solution of 2-methoxy-5-(1-methylcyclobutyl)benzenesulfonyl chloride (3.2 g, 11.7 mmol) in THF (50 mL), and the resulting mixture was stirred at rt for 30 min. The reaction mixture was extracted with EA, the organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude substance was purified by silica gel column chromatography (PE:EA = 7:3) to obtain the desired product (950 mg, 32%). MS (ESI) m / e [M+H]+ = 256.

[0312] Example B12: Synthesis of 2-methoxy-5-(3-methyloxetane-3-yl)benzenesulfonamide Step 1: 1,3-Dioxoisoindoline-2-yl ester of 3-methyloxetane-3-carboxylic acid DMAP (105 mg, 861 μmol) and DIC (1.2 g, 9.4 mmol) were added to a solution of 3-methyloxetane-3-carboxylic acid (1 g, 8.6 mmol) and 2-hydroxyisoindoline-1,3-dione (1.4 g, 8.6 mmol) in DCM (80 mL). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain a crude residue. The residue was wet-milled with MeOH (8 mL) to obtain the title compound (1.3 g, 58% yield). 1H NMR: (400 MHz, CDCl3) δ 7.94 - 7.89 (m, 2H), 7.84 - 7.80 (m, 2H), 5.19 (d, J = 6.4 Hz, 2H), 4.56 (d, J = 6.4 Hz, 2H), 1.86 (s, 3H).

[0313] Step 2: 3-(4-methoxyphenyl)-3-methyloxetane A solution of NiBr2-glycol dimethyl ether (83 mg, 268 μmol) and 4,4-di-tert-butyl-N-cyano-[2,2-bipyridine]-6-carbamate (90 mg, 268 μmol) in THF (5 mL) was stirred at 25 °C for 0.5 h to obtain a homogeneous solution. 5 mL of the prepared catalyst solution was added to another flask containing 1,3-dioxoisoindoline-2-yl ester of 3-methyloxetane-3-carboxylic acid (1 g, 3.8 mmol), 1-iodo-4-methoxybenzene (895.9 mg, 3.8 mmol), and Zn (0.9 g, 13.7 mmol, 3.6 eq). The reaction mixture was stirred at 35 °C for 16 h. The reaction mixture was diluted with DCM (10 mL), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 3:1) to yield the title compound (390 mg, 57% yield). ¹H NMR: (400 MHz, CDCl₃) δ 7.18–7.14 (m, 2H), 6.92–6.89 (m, 2H), 4.95 (d, J = 5.6 Hz, 2H), 4.63 (d, J = 5.6 Hz, 2H), 3.82 (s, 3H), 1.72 (s, 3H).

[0314] Step 3: 3-(3-bromo-4-methoxyphenyl)-3-methyloxetane NBS (299.6 mg, 1.7 mmol, 1.05 eq) was added to a solution of 3-(4-methoxyphenyl)-3-methyloxetane (0.3 g, 1.6 mmol, 1 eq) in ACN (3 mL) at 25 °C under N2. The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 3:1) to give 3-(3-bromo-4-methoxyphenyl)-3-methyloxetane (0.37 g). n-BuLi (2.5 M in hexane, 467 μL) was added dropwise to a solution of 3-(3-bromo-4-methoxyphenyl)-3-methyloxetane (0.3 g, 1.2 mmol) in THF (3 mL) at -60 °C under N2. The reaction mixture was stirred at -60 °C for 30 min. Sulfonyl chloride (157.4 mg, 1.2 mmol) was added to the reaction mixture at -45 °C, and the mixture was stirred at -45 °C for 30 min. MeOH containing 7 M NH3 (1.7 mL) was added. The mixture was stirred at 25 °C for 10 min. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column = Waters Xbridge Prep OBD C18 150 x 40 mm x 10 μm; mobile phase: [water (NH4HCO3)-MeCN], B% = 2%–40%; 8.0 min) to yield the title compound (61 mg, 19% yield). 1H NMR: (400 MHz, DMSO-d6) δ 7.58 (d, J = 2.4 Hz, 1H), 7.47 (dd, J = 2.4, 8.8 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 6.03 (br s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.55 (d, J = 5.6 Hz, 2H), 3.89 (s, 3H), 1.62 (s, 3H). MS(ESI) m / e [MH]- =256.1.

[0315] Example B13: Synthesis of 2-methoxy-5-(3-methoxyoxetane-3-yl)benzenesulfonamide Step 1: 3-(3-bromo-4-methoxyphenyl)oxetane-3-ol n-BuLi (2.5 M in hexane, 15.3 mL, 38 mmol) was added dropwise to a solution of 2-bromo-4-iodo-1-methoxybenzene (10 g, 32 mmol) and oxetane-3-one (3.45 g, 48 mmol) in THF (100 mL) at -65 °C. The resulting mixture was stirred at -65 °C for 3 h. After the reaction was complete, the mixture was quenched with a saturated aqueous solution of ammonium chloride (200 mL) and extracted with EA. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 50:0 to 10:1) to give the title compound (3.5 g, 30% yield). 1H NMR(400 MHz, DMSO-d6) δ = 7.72 (d, J = 2.3 Hz, 1H), 7.58 (dd, J = 2.3, 8.5 Hz,1H), 7.15 (d, J = 8.5 Hz, 1H), 4.74 (d, J = 6.8 Hz, 2H), 4.68 - 4.59 (d, J =6.8 Hz, 2H), 3.86 (s, 3H). MS(ESI) m / e [MH]- = 257, 259.

[0316] Step 2: 3-(3-bromo-4-methoxyphenyl)-3-methoxyoxane NaH (60% in mineral oil, 560 mg, 14 mmol) was added fractionally to a solution of 3-(3-bromo-4-methoxy-phenyl)oxetane-3-ol (2.4 g, 9.3 mmol) in THF (30 mL) at 0 °C. After the addition, the mixture was stirred at 0 °C for 30 min, followed by dropwise addition of MeI (2 g, 14 mmol) at 0 °C. The resulting mixture was stirred at 20 °C for 4 h. After the reaction was complete, the mixture was poured into an aqueous solution of NH4Cl (5 mL) and extracted with EA (3 mL x 3). The combined organic layers were concentrated. The crude product was purified by silica gel chromatography (PE:EA = 50:1 to 3:1) to give the title compound (2.85 g, crude product). 1H NMR (400 MHz, DMSO-d6) δ = 7.59 (d, J = 2.1 Hz, 1H), 7.42 (dd, J= 2.2, 8.6 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 4.73 (s, 4H), 3.87 (s, 3H),2.99 (s, 3H). MS(ESI) m / e [M-OMe]+ = 241, 243.

[0317] Step 3: 3-(3-(benzylthio)-4-methoxyphenyl)-3-methoxyoxane A mixture of 3-(3-bromo-4-methoxy-phenyl)-3-methoxy-oxetane (1 g, 3.7 mmol), benzyl mercaptan (682 mg, 5.5 mmol), DIEA (946 mg, 7.3 mmol), Xantphos (424 mg, 732 μmol), and Pd2(dba)3 (335 mg, 366 μmol) in dioxane (15 mL) was degassed and purged three times with N2. The reaction mixture was stirred at 110 °C for 16 h under N2 atmosphere. After the reaction was complete, the mixture was quenched with H2O (30 mL) and extracted with EA. The combined organic layers were concentrated. The crude product was purified by silica gel chromatography (PE:EA = 50:1 to 3:1) to give the title compound (1 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ = 7.36 - 7.31 (m, 2H), 7.30 - 7.23 (m, 2H), 7.23 - 7.17 (m, 2H), 7.16 - 7.14 (m, 1H), 7.03 - 6.97 (m, 1H), 4.71 - 4.63 (m, 4H), 4.18 (s, 2H), 3.84 (s, 3H), 2.86 (s, 3H). MS(ESI) m / e [M-OMe]+ =285.3.

[0318] Step 4: 2-Methoxy-5-(3-Methoxyoxetane-3-yl)benzenesulfonamide TCCA (1.18 g, 5.06 mmol) was added to a solution of 3-(3-benzylhydrothio-4-methoxy-phenyl)-3-methoxy-oxetane (800 mg, 2.53 mmol) in DCM (15 mL) and H₂O (5 mL). The mixture was stirred at 0–15 °C for 16 h. Then, NH₃ / MeOH (7 M, 4.00 mL, 11.07 eq) was added. The mixture was stirred for 1 h. After the reaction was complete, the mixture was concentrated. The crude product was purified by silica gel chromatography (PE:EA = 50:1 to 3:1) to give the title compound (276 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6) δ = 7.74 (d, J = 2.3 Hz, 1H), 7.66 (dd,J = 2.3, 8.6 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.14 (s, 2H), 4.82 - 4.75 (m,2H), 4.74 - 4.68 (m, 2H), 3.93 (s, 3H), 3.02 (s, 3H). MS(ESI) m / e [MH]+=272.4.

[0319] Example B14: Synthesis of 2-methoxy-5-(6-methyl-2-oxaspiro[3.3]hept-6-yl)benzenesulfonamide Step 1: 6-(4-methoxyphenyl)-2-oxaspiro[3.3]hepta-6-ol n-BuLi (2.5 M, 4.5 mL, 11.3 mmol) was added dropwise to a solution of 1-bromo-4-methoxybenzene (2.0 g, 10.8 mmol) in THF (30 mL) at -70 °C, and the mixture was stirred at -70 °C for 30 min. Then, THF (5 mL) containing 2-oxaspiro[3.3]hepta-6-one (1.33 g, 11.9 mmol) was added at -70 °C, and the resulting mixture was stirred at -70 °C for 1 h. After heating to rt, the mixture was quenched with saturated NH4Cl and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (PE:EA = 1:1) to yield the title compound (1.7 g, 72%).

[0320] Step 2: 6-(4-methoxyphenyl)-6-methyl-2-oxaspiro[3.3]heptane TiCl4 (1.38 g, 7.27 mmol) was added to a solution of 6-(4-methoxyphenyl)-2-oxaspiro[3.3]hepta-6-ol (800 mg, 3.64 mmol) in DCM (40 mL) at -70 °C, and the mixture was stirred at -70 °C for 1 h. ZnMe2 (1.0 M in toluene, 11 mL, 10.92 mmol) was added dropwise at -70 °C, and the resulting mixture was stirred at -70 °C for 2 h. After heating to rt, the mixture was quenched with brine and extracted with EA, the organic layer was dried over Na2SO4 and concentrated to give the title compound (800 mg).

[0321] Step 3: 6-(3-bromo-4-methoxyphenyl)-6-methyl-2-oxaspiro[3.3]heptane NBS (427 mg, 2.39 mmol) was added to a solution of 6-(4-methoxyphenyl)-6-methyl-2-oxaspiro[3.3]heptane (580 mg, 2.66 mmol) in ACN (20 mL), and the resulting mixture was stirred overnight at rt. The mixture was quenched with water and extracted with EA, the organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (PE:EA = 4:1) to give the title compound (460 mg, 58%).

[0322] Step 4: 6-(3-(benzylthio)-4-methoxyphenyl)-6-methyl-2-oxaspiro[3.3]heptane A solution of 6-(3-bromo-4-methoxyphenyl)-6-methyl-2-oxaspiro[3.3]heptane (360 mg, 1.22 mmol), benzyl mercaptan (166 mg, 1.34 mmol), Pd2dba3 (112 mg, 0.12 mmol), XantPhos (71 mg, 0.12 mmol), and TEA (247 mg, 2.44 mmol) in 1,4-dioxane (10 mL) was stirred overnight at 100 °C. After cooling to rt, the mixture was quenched with brine and extracted with EA. The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by silica gel column chromatography (PE:EA = 3:1) to yield the title compound (341 mg, 82%). MS (ESI) m / e [M+H]+ = 341.

[0323] Step 5: 2-Methoxy-5-(6-methyl-2-oxaspiro[3.3]hept-6-yl)benzenesulfonamide NCS (533 mg, 3.97 mmol) was added to a solution of 6-(3-(benzylthio)-4-methoxyphenyl)-6-methyl-2-oxaspiro[3.3]heptane (386 mg, 1.44 mmol) in ACN (8 mL) and water (2 mL), and the resulting mixture was stirred at rt for 1 h. The mixture was then added to THF (20 mL) and NH3·H2O (15 mL) at 0 °C, and the resulting mixture was stirred at rt overnight. The reactants were extracted with EA, the organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (PE:EA = 7:3) to yield the title compound (235 mg, 70%). MS (ESI) m / e [M+H]+ = 298.

[0324] Example B15: Synthesis of 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide Step 1: 4-(4-methoxyphenyl)tetrahydropyran-4-ol n-BuLi (2.5 M in hexane, 7.7 mL) was added dropwise to a solution of 1-bromo-4-methoxybenzene (3 g, 16 mmol) in THF (30 mL) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 h. Tetrahydro-4H-pyran-4-one (1.93 g, 19.3 mmol) was then added. The mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched by adding a saturated aqueous solution of NH4Cl (50 mL) at 25 °C. The aqueous phase was extracted with EA. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 0:1) to give the title compound (2.3 g, 69% yield). 1H NMR: (400 MHz, DMSO-d6) δ 7.39 (d, J =8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.90 (br s, 1H), 3.83 - 3.64 (m, 7H),2.00 - 1.83 (m, 2H), 1.51 (d, J = 12.8 Hz, 2H).

[0325] Step 2: 4-(4-methoxyphenyl)-4-methyltetrahydro-2H-pyran TiCl4 (3.64 g, 19.2 mmol) was added dropwise to a solution of 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-ol (2 g, 9.6 mmol) in DCM (50 mL) at -78 °C under a nitrogen atmosphere. After the addition, the mixture was stirred at -78 °C for 1 h, followed by dropwise addition of dimethyl zinc (1 M in toluene, 38.4 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 2 h. H2O (50 mL) was added to the reaction mixture and the mixture was extracted with H2O (35 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 0:1) to give the title compound (600 mg, 29% yield). 1H NMR: (400MHz, DMSO-d6) δ 7.26 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 3.72 (s,3H), 3.64 - 3.61 (m, 2H), 3.54 - 3.46 (m, 2H), 1.98 - 1.91 (m, 2H), 1.68 -1.62 (m, 2H), 1.18 (s, 3H).

[0326] Step 3: 2-Methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide Chlorosulfonic acid (847 mg, 7.2 mmol) was added to a solution of 4-(4-methoxyphenyl)-4-methyltetrahydro-2H-pyran (500 mg, 2.4 mmol) in DCM (10 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 2 h. H2O (10 mL) was added to the reaction mixture and it was extracted with DCM (7 mL x 2). The combined organic phases were washed with brine (7 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonic acid (150 mg, 22% yield). DMF (383 μg) and (COCl)₂ (100 mg, 0.75 mmol) were added to a solution of 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonic acid (150 mg, 0.5 mmol) in DCM (2 mL) at 0 °C under N₂. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to produce 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonyl chloride (150 mg, crude). A solution of the crude 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonyl chloride (150 mg, 0.5 mmol) in MeOH (1 mL) containing 7 M NH₃ was stirred at 20 °C for 10 min. DCM (10 mL) was added to the reaction mixture. The combined organic phases were washed with brine (2 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residues were purified by preparative HPLC (column = Waters Xbridge Prep OBD C18 150 x 40 mm x 10 μm; mobile phase: [water (NH₄HCO₃) - ACN], B% = 15% - 50%; 8.0 min) to yield the title compound (36 mg, 26% yield). MS(ESI) m / e [M-1]284.1. 1H NMR: (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.56 (d, J = 6.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.05 (br s, 2H), 3.88 (s, 3H), 3.68 - 3.64 (m, 2H), 3.55 - 3.51 (m, 2H), 1.95 - 1.90 (m, 2H), 1.72 - 1.67 (m, 2H), 1.22 (s, 3H).

[0327] Example B16: Synthesis of 2-methoxy-5-(4-methylmorpholin-3-yl)benzenesulfonamide Step 1: 2-Methoxy-5-(4-methylmorpholin-3-yl)benzenesulfonic acid Chlorosulfonic acid (1.7 g, 14.5 mmol) was added to a solution of 3-(4-methoxyphenyl)-4-methylmorpholine (1 g, 4.8 mmol) in DCM (20 mL) at 0 °C under a N2 atmosphere. The mixture was stirred at RT for 2 h. After the reaction was complete, the mixture was quenched with MeOH (2 mL) and concentrated. The solution was analyzed by preparative HPLC (column: Phenomenex Luna C18 (250 μL)). The residue was purified using a mobile phase of [H2O (0.04% HCl)-ACN] (70 mm, 15 μm); B%: 0%, isocratic elution mode) to yield the title compound (700 mg, 50% yield). MS (ESI) m / e [M+H]+ = 288.1.

[0328] Step 2: 2-Methoxy-5-(4-methylmorpholin-3-yl)benzenesulfonamide DMF (15 mg, 210 μmol) and (COCl)₂ (1.06 g, 8.4 mmol) were added to a solution of 2-methoxy-5-(4-methylmorpholin-3-yl)benzenesulfonic acid (600 mg, 2.1 mmol) in DCM (6 mL) at 0 °C. The mixture was stirred at RT for 12 h, and MeOH (3 mL) containing 7 M NH₃ was added, followed by stirring for another 0.5 h. After the reaction was complete, the mixture was concentrated. The residue was purified by preparative HPLC (column: WePure Biotech XP tC18; mobile phase: [H₂O (10 mM NH₄HCO₃)-ACN]; gradient: 1%-30% B over 8.0 min) to give the title compound (242 mg, 40% yield). 1H NMR (400MHz, DMSO-d6) δ = 7.71 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0Hz, 1H), 6.05 (br s, 2H), 3.89 (s, 3H), 3.82 (d, J = 10.8 Hz, 1H), 3.66 -3.53 (m, 2H), 3.16 (br t, J = 10.8 Hz, 1H), 3.04 (br dd, J = 2.4, 10.4 Hz,1H), 2.82 (br d, J = 12.0 Hz, 1H), 2.33 - 2.22 (m, 1H), 1.95 (s, 3H). MS(ESI)m / e [MH]- = 285.4.

[0329] Example B17: Synthesis of 5-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-methoxybenzenesulfonamide Pd-PEPPSI-IPent (60 mg, 0.1 mmol) and t-BuOK (110 mg, 1.1 mmol) were added to a mixture of 5-bromo-2-methoxybenzenesulfonamide (200 mg, 0.8 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane (110 mg, 1.0 mmol) in dioxane (10 mL). The resulting mixture was degassed with nitrogen and heated to 120 °C for 1 h with stirring. The resulting reaction mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated. The residue was applied to silica gel column chromatography (EA:PE was 12:1) to yield the desired product (100 mg, 44%). MS (ESI) m / e [M+H]+ = 299.

[0330] Example B18: Synthesis of 6-methoxy-2,3-dihydrobenzofuran-7-sulfonamide Step 1: 1-Bromo-2-(2-Bromoethoxy)-4-methoxybenzene 1,2-Dibromoethane (9.4 g, 50 mmol) was added to a suspension of 2-bromo-5-methoxyphenol (2.03 g, 10 mmol) and K₂CO₃ (2.1 g, 15 mmol) in CH₃CN (50 mL) under rt conditions, and the reaction mixture was stirred at 80 °C for 12 h. The mixture was filtered, and the filtrate was diluted with EA and washed with citric acid and brine. The mixture was dried, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1-3 / 1) to give the title compound (2.1 g, 68% yield). MS (ESI) m / e [M+H] 308.9.

[0331] Step 2: 6-Methoxy-2,3-dihydrobenzofuran n-BuLi (2.7 mL, 6.8 mmol, 2.5 M in hexane) was added dropwise to a solution of 1-bromo-2-(2-bromoethoxy)-4-methoxybenzene (1.9 g, 6.2 mmol) in THF (40 mL) at below -65 °C. The resulting solution was then stirred at -65 °C for 30 min and heated to rt and stirred for 16 h. The solution was extracted twice with EA by adding water to quench the extraction. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1) to give the title compound (550 mg, 59% yield). MS (ESI) m / e [M+H]+ = 151.0.

[0332] Step 3: 6-Methoxy-2,3-dihydrobenzofuran-7-sulfinic acid n-BuLi (2.5 M in hexane, 2.4 mL, 6 mmol) was added to a solution of 6-methoxy-2,3-dihydrobenzofuran (300 mg, 2 mmol) and TMEDA (464 mg, 4 mmol) in n-hexane (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then cooled to -70 °C, with SO2 (g) bubbled into the solution for 1 min followed by stirring at this temperature for 30 min. The reaction mixture was quenched by adding water (4 mL) and concentrated. The residue was purified by C18 column [(water (0.1% HCOOH)], B% = 0%-70%) to give the title compound (360 mg, 72% yield). MS (ESI) m / e [M-OH]- = 197.0.

[0333] Step 4: 6-Methoxy-2,3-dihydrobenzofuran-7-sulfonamide SO₂Cl₂ (247 mg, 1.83 mmol) was added dropwise to a solution of 6-methoxy-2,3-dihydrobenzofuran-7-sulfinic acid (360 mg, 1.83 mmol) in DCM (10 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. The solution was diluted with DCM and washed with water, dried over Na₂SO₄, filtered, concentrated, and the residue was dissolved in THF (5 mL) and ammonia (1 mL) and stirred at rt for 1 h. The solution was concentrated, and the residue was purified by passing it through a C18 column using water / ACN containing 0.1% FA (eluting from 10% to 100%) to give the title product (100 mg, 24%). 1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J = 8.2 Hz, 1H), 6.97 (s, 2H), 6.56 (d, J = 8.2 Hz, 1H), 4.59 (t, J = 8.7 Hz, 2H), 3.81 (s, 3H), 3.11 (t, J = 8.7 Hz, 2H). MS (ESI) m / e[M+H]+ = 229.9.

[0334] Example B19: Synthesis of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-sulfonamide Step 1: 1-(2-fluoro-4-methoxyphenyl)cyclobutane-1-carboxynitrile NaH (60% in mineral oil, 3.3 g, 82 mmol) was added to a solution of 2-(2-fluoro-4-methoxyphenyl)acetonitrile (6.8 g, 41 mmol) and 1,3-dibromopropane (10 g, 49 mmol) in DMF (70 mL) at 0 °C. The mixture was stirred at 15 °C for 2 h. After the reaction was complete, the reaction mixture was quenched with an aqueous solution of NH4Cl (100 mL) and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 30:1 to 5:1) to give the title compound (4.4 g, 52%). 1H NMR (400 MHz, DMSO-d6) δ= 7.31 (t, J = 9.2 Hz, 1H), 6.92 (dd, J = 2.4, 9.2 Hz, 1H), 6.82 (dd, J =2.4, 9.2 Hz, 1H), 3.78 (s, 3H), 2.76 - 2.66 (m, 2H), 2.65 - 2.55 (m, 2H), 2.36 - 2.22 (m, 1H), 2.01 - 1.90 (m, 1H).

[0335] Step 2: 1-(2-fluoro-4-methoxyphenyl)cyclobutane-1-carboxaldehyde DIBAL-H (1 M in THF, 43 mL) was added to a solution of 1-(2-fluoro-4-methoxyphenyl)cyclobutane-1-carboxynitrile (4.4 g, 21 mmol) in THF (90 mL) at -70 °C. The mixture was stirred at 15 °C for 16 h. After the reaction was complete, the reaction mixture was quenched by adding 1 M HCl (45 mL) at -30 °C, followed by heating to rt and stirring for 0.5 h. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with EA and washed with water and brine. The mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 30:1 to 5:1) to give the title compound (2.5 g, 56%). 1H NMR (400 MHz, DMSO-d6) δ = 9.62 (s, 1H), 7.16 (t, J = 9.2 Hz,1H), 6.85 - 6.81 (m, 1H), 6.80 (s, 1H), 3.76 (s, 3H), 2.66 - 2.56 (m, 2H), 2.42 - 2.32 (m, 2H), 2.05 - 1.83 (m, 2H).

[0336] Step 3: (1-(2-fluoro-4-methoxyphenyl)cyclobutyl)methanol NaBH4 (477 mg, 12.6 mmol) was added to a solution of 1-(2-fluoro-4-methoxyphenyl)cyclobutane-1-carboxaldehyde (2.5 g, 12 mmol) in MeOH (25 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. After the reaction was complete, the reaction mixture was quenched by adding an aqueous solution of NH4Cl and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 20:1 to 5:1) to give the desired product (2 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ = 7.01 - 6.94 (m, 1H), 6.72 -6.65 (m, 2H), 4.72 (t, J = 5.6 Hz, 1H), 3.73 (s, 3H), 3.52 (d, J = 5.6 Hz, 2H), 2.25 - 2.16 (m, 4H), 2.05 - 1.92 (m, 1H), 1.83 - 1.70 (m, 1H).

[0337] Step 4: 6-Methoxy-2H-spiro[benzofuran-3,1'-cyclobutane] t-BuOK (1 M in THF, 14.3 mL) was added to a solution of (2 g, 9.5 mmol) of (1-(2-fluoro-4-methoxyphenyl)cyclobutyl)methanol in 20 mL of THF. The mixture was stirred at 70 °C for 12 h. After the reaction was complete, the reaction mixture was cooled to rt, quenched with water, and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 40:1) to give the desired product (1 g, 55%). 1H NMR (400 MHz, DMSO-d6) δ = 7.31 (d, J = 8.0 Hz, 1H), 6.45 (dd, J = 2.4, 8.0 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 4.52 (s, 2H), 3.69 (s,3H), 2.34 - 2.14 (m, 4H), 2.04 - 1.80 (m, 2H). MS(ESI) m / e [M+H]+= 191.5.

[0338] Step 5: Lithium 6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-sulfinate n-BuLi (2.1 ml, 5.26 mmol) was added to a solution of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane] (1000 mg, 5.26 mmol) and TMEDA (610 mg, 5.26 mmol) in 20 ml of hexane at 0 °C and stirred for 10 min. The mixture was then cooled to -78 °C and bubbled with SO2 for 5 min. After the reaction was complete, the mixture was filtered, and the filter cake was collected to yield the product (1.34 g, 100%). MS (ESI) m / e [M+H]+ = 255.3.

[0339] Step 6: 6-Methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-sulfonyl chloride NCS (1.75 g, 13.2 mmol) was added to a solution of lithium 6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-sulfinate (1.34 g, 5.3 mmol) in 10 mL of AcOH / water (3 / 1) at 0 °C and stirred for 10 min. After the reaction was complete, the solution was diluted with water and the mixture was filtered. The filter cake was collected to yield the desired product (1.51 g, 100%). MS (ESI) m / e [M+H]+ = 288.2.

[0340] Step 7: 6-Methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-sulfonamide NH3•H2O (1 mL) was added dropwise to a solution of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-sulfonyl chloride (1.51 g, 5.26 mmol) in THF (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, H2O was added to the reaction mixture and it was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was diluted with EA (10 mL) and stirred for 1 h, the mixture was filtered and the filter cake was collected to give the desired product (1 g, 71%). MS (ESI) m / e [M+H]+ = 270.3.

[0341] Example B20: Synthesis of 6-methoxy-2',3',5',6'-tetrahydro-2H-spiro[benzofuran-3,4'-pyran]-7-sulfonamide Step 1: Methyl 4-(2-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylate t-BuOK (1 M in THF, 121 mL) was added dropwise to a solution of methyl 2-(2-fluoro-4-methoxy-phenyl)acetate (6 g, 30 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (35 g, 151 mmol) in DMF (60 mL) at 0 °C. The mixture was stirred at 15 °C for 1 h. After the reaction was complete, the reaction mixture was quenched with water and then extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to give the title compound (7.5 g, 92% yield). 1H NMR (400MHz, CDCl3) δ = 7.23 (t, J = 8.8 Hz, 1H), 6.70 (dd, J = 2.6, 8.8 Hz, 1H), 6.60 (dd, J = 2.6, 13.8 Hz, 1H), 3.86 (td, J = 4.0, 12.0 Hz, 2H), 3.80 (s,3H), 3.78 - 3.71 (m, 2H), 3.70 (s, 3H), 2.41 (br d, J = 13.6 Hz, 2H), 2.14 -2.05 (m, 2H).

[0342] Step 2: (4-(2-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)methanol LiBH4 (2 M in THF, 28 mL, 56 mmol) was added to a solution of methyl 4-(2-fluoro-4-methoxy-phenyl)tetrahydropyran-4-carboxylate (7.5 g, 28 mmol) in 120 mL of THF at 0 °C. The mixture was stirred at 40 °C for 16 h. After the reaction was complete, the mixture was cooled to rt, quenched by adding water, and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product (6.6 g) that required no further purification. 1H NMR (400 MHz, DMSO-d6) δ = 7.27 - 7.16 (m, 1H), 6.76 - 6.69 (m, 2H), 4.62(t, J = 5.6 Hz, 1H), 3.75 (s, 3H), 3.73 - 3.65 (m, 2H), 3.48 (d, J = 5.6 Hz, 2H), 3.42 - 3.33 (m, 2H), 2.04 (br d, J = 14.4 Hz, 2H), 1.86 - 1.79 (m, 2H).

[0343] Step 3: 6-Methoxy-2',3',5',6'-Tetrahydro-2H-spiro[benzofuran-3,4'-pyran] t-BuOK (1 M in THF, 35 mL, 35 mmol) was added to a solution of [4-(2-fluoro-4-methoxy-phenyl)tetrahydropyran-4-yl]methanol (5.6 g, 23 mmol) in 60 mL of THF at 15 °C. The mixture was stirred at 70 °C for 3 h. After the reaction was complete, the mixture was cooled to rt, the reaction mixture was quenched by adding water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was wet-milled with MTBE and filtered. The filter cake was dried under vacuum to give the desired product (4.2 g, 69%). 1H NMR (400 MHz, DMSO-d6)δ = 7.11 (d, J = 8.4 Hz, 1H), 6.42 (dd, J = 2.4, 8.4 Hz, 1H), 6.38 (d, J =2.4 Hz, 1H), 4.45 (s, 2H), 3.88 - 3.79 (m, 2H), 3.69 (s, 3H), 3.40 (dt, J =2.0, 12.0 Hz, 2H), 1.84 (dt, J = 3.6, 12.0 Hz, 2H), 1.59 - 1.47 (m, 2H). MS(ESI) m / e [M+H]+ = 221.5.

[0344] Step 4: 6-Methoxy-2',3',5',6'-Tetrahydro-2H-spiro[benzofuran-3,4'-pyran]-7-sulfonamide n-BuLi (2.5 M in n-hexane, 2 mL, 5 mmol) was added to a mixture of 6-methoxy-2',3',5',6'-tetrahydro-2H-spiro[benzofuran-3,4'-pyran] (1 g, 4.5 mmol) and TMEDA (580 mg, 5 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and cooled to -60 °C. Sulfonyl chloride (920 mg, 6.8 mmol) was added to the mixture at -60 °C. The mixture was stirred at 15 °C for 12 h. After the reaction was complete, the reactants were poured into water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain crude sulfonyl chloride (1.4 g). NH3 / MeOH (7 M, 5 mL) was added to a solution of crude sulfonyl chloride (1.4 g, 4.4 mmol) in MeOH (10 mL). The mixture was stirred at 15 °C for 0.5 h. After the reaction was complete, the mixture was filtered. The filtrate was dried under vacuum to obtain the crude product, which was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 1%-40% B over 8.0 min) to obtain the title compound (135.5 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ = 7.35 (d, J = 8.4 Hz,1H), 6.99 (s, 2H), 6.61 (d, J = 8.4 Hz, 1H), 4.55 (s, 2H), 3.86 (br d, J =2.4 Hz, 2H), 3.83 (s, 3H), 3.46 - 3.36 (m, 2H), 1.87 (dt, J = 4.0, 12.4 Hz, 2H), 1.54 (br d, J = 12.4 Hz, 2H). MS(ESI) m / e [MH]- = 298.3 Example B21: Synthesis of 7-methoxy-3,3-dimethyl-8-sulfonamide Step 1: 7-Hydroxy-3,3-dimethylchroman-4-one THF (30 mL) containing 7-hydroxychroman-4-one (1.64 g, 10 mmol) and CH3I (7.1 g, 50 mmol) was added dropwise to a suspension of tBuOK (6.72 g, 60 mmol) in THF (70 mL) at -70 °C. The solution was stirred at this temperature for 4 h, then heated to rt and stirred for 1 h. The solution was diluted with water and citric acid and extracted with EA. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (3 g, crude). MS (ESI) m / e [M+H]+ = 193.1.

[0345] Step 2: 7-Methoxy-3,3-dimethylchroman-4-one CH3I (2.84 g, 20 mmol) was added to a suspension of 7-hydroxy-3,3-dimethylchroman-4-one (3 g, 10 mmol) and K2CO3 (2.76 g, 20 mmol) in DMF (40 mL), and the mixture was stirred overnight at 90 °C. After cooling to rt, the solution was diluted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 4:1) to yield the title product (1.6 g, 78%, for both steps). MS (ESI) m / e [M+H]+ = 207.0.

[0346] Step 3: 7-Methoxy-3,3-Dimethylchromium 7-Methoxy-3,3-dimethylchroman-4-one (1.6 g, 7.76 mmol) and Zn powder (4 g, 621 mmol) were added to a suspension in MeOH (30 mL) and concentrated HCl (10 mL), and the mixture was stirred at rt for 4 h. After the reaction was complete, the mixture was diluted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to give the title product (1.1 g, 74%). MS (ESI) m / e [M+H]+ = 193.1.

[0347] Step 4: 7-Methoxy-3,3-dimethyl-8-sulfinic acid n-BuLi (3.6 mL, 9 mmol, 2.5 M in n-hexane) was added dropwise to a solution of 7-methoxy-3,3-dimethylsulfonium (576 mg, 3 mmol) and TMEDA (348 mg, 9 mmol) in n-hexane (20 mL) at below 10 °C, and the reaction mixture was stirred at 10 °C for 30 min. The solution was cooled to -60 °C, and SO2 (g) was bubbled into the solution for 1 min, and the mixture was stirred at -60 °C for 30 min. After the reaction was complete, 1 N HCl (5 mL) was added to the reaction mixture, and the solution was diluted with water. The mixture was extracted with EA, the extract was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product (600 mg, 78%). MS (ESI) m / e [M+H]+ = 257.0.

[0348] Step 5: 7-Methoxy-3,3-dimethyl-8-sulfonamide NCS (939 mg, 7 mmol) was added to a solution of 7-methoxy-3,3-dimethyl-somethane-8-sulfinic acid (600 mg, 2.34 mmol) in AcOH (10 mL) and H₂O (3 mL) under rt, and the reaction mixture was stirred under rt for 2 h. The solution was diluted with water and extracted with EA. The extract was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was dissolved in THF (10 mL) and NH₄OH solution (2 mL). After stirring under rt for 1 h, the solution was concentrated and the residue was purified by passing it through a C18 column with water / ACN containing 0.1% FA (eluting from 10% to 100%) to give the title product (200 mg, 31%). MS (ESI) m / e [M+H]⁺ = 272.1.

[0349] Example B22: Synthesis of 2-methoxy-5-(1-methoxy-2-methylpropyl-2-yl)benzenesulfonamide Step 1: 2-[3-[bis[(2,4-dimethoxyphenyl)methyl]aminesulfonyl]-4-methoxy-phenyl]-2-methyl-propionate tBuOK (9 g, 80.4 mmol) and MeI (11.4 g, 80.4 mmol) were slowly added to a solution of methyl 2-[3-[bis[(2,4-dimethoxyphenyl)methyl]aminesulfonyl]-4-methoxy-phenyl]acetate (15 g, 26.8 mmol) in THF (150 mL) at 0 °C. The reaction mixture was stirred at rt for 3 h. After the reaction was complete, the reaction mixture was quenched with H2O and extracted with EA. The combined organic layers were concentrated. The residue was purified by silica gel column chromatography (PE / EA = 10:1 to 1:1) to give the title compound (12 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ = 7.62 - 7.55 (m,1H),7.53 - 7.45 (m, 1H), 7.14 - 7.06 (m, 1H), 6.96 - 6.88 (m, 2H), 6.43 - 6.31(m, 4H), 4.36 - 4.23 (m, 4H), 3.78 (s, 3H), 3.71 (s, 6H), 3.58 (s, 6H), 1.48 (s, 6H).

[0350] Step 2: N,N-bis(2,4-dimethoxybenzyl)-5-(1-hydroxy-2-methylpropyl-2-yl)-2-methoxybenzenesulfonamide LiBH4 (2 M in THF, 2.55 mL) was added to a solution of methyl 2-[3-[bis[(2,4-dimethoxyphenyl)methyl]aminesulfonyl]-4-methoxy-phenyl]-2-methylpropionate (1.5 g, 2.5 mmol) in THF (20 mL) at 0 °C. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (30 mL) and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE / EA = 5:1 to 1:1) to give the title compound (1.1 g, 77% yield). 1H NMR(400 MHz, DMSO-d6) δ 7.62 (br d, J = 1.6 Hz, 1H), 7.54 (br d, J = 8.4 Hz,1H), 7.06 (br d, J = 8.4 Hz, 1H), 6.93 (br d, J = 8.0 Hz, 2H), 6.45 - 6.31(m, 4H), 4.72 (br t, J = 4.8 Hz, 1H), 4.29 (s, 4H), 3.77 (s, 3H), 3.70 (s,6H), 3.58 (s, 6H), 3.36 (br d, J = 4.8 Hz, 2H), 1.19 (s, 6H).

[0351] Step 3: N,N-bis(2,4-dimethoxybenzyl)-2-methoxy-5-(1-methoxy-2-methylpropyl-2-yl)benzenesulfonamide NaH (60% in mineral oil, 120 mg, 3 mmol) was added to a solution of N,N-bis[(2,4-dimethoxyphenyl)methyl]-5-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (1.1 g, 2 mmol) in THF (15 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, MeI (418 mg, 3 mmol) was added to the mixture at 0 °C. The reaction mixture was stirred at 70 °C for 12 h. After cooling to rt, the reaction mixture was quenched with an aqueous solution of NH4Cl (20 mL) and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10:1 to 4:1) to give the title compound (400 mg, 35% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.43 - 6.30 (m, 4H), 4.29 (s, 4H), 3.78 (s, 3H), 3.70 (s, 6H), 3.58 (s, 6H), 3.29 (s, 2H), 3.20 (s,3H), 1.21 (s, 6H).

[0352] Step 4: 2-Methoxy-5-(1-Methoxy-2-methylpropyl-2-yl)benzenesulfonamide TFA (1 mL) was added to a solution of N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-methoxy-5-(2-methoxy-1,1-dimethyl-ethyl)benzenesulfonamide (350 mg, 0.6 mmol) in DCM (5 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 15%-45% B over 8.0 min) to give the title compound (72 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.01 (s, 2H), 3.87 (s, 3H),3.33 (br s, 2H), 3.21 (s, 3H), 1.24 (s, 6H).

[0353] Example B23: Synthesis of 2-(tert-butyl)-5-methoxypyridine-4-sulfonamide n-BuLi (2.5 M in n-hexane, 480 μL) was added dropwise to a solution of 2-tert-butyl-5-methoxy-pyridine (180 mg, 1.1 mmol) and TMEDA (152 mg, 1.3 mmol) in THF (3 mL) at -60 °C. The mixture was stirred at -60 °C for 1 h, and THF (0.5 mL) containing N-sulfinyl-O-(tert-butyl)-hydroxylamine (221 mg, 1.6 mmol) was added dropwise. The reaction mixture was stirred at 15 °C for 16 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution (5 mL) and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150x 40 mm x 10 μm, mobile phase: [H2O (10 mMNH4HCO3)-ACN]; gradient: 10%-40% B over 8.0 min) to yield the title compound (8.5 mg, 3% yield). MS (ESI) m / e [M+1] 245.4. 1H NMR: (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.61 (s, 1H), 6.55 (br s, 2H), 3.99 (s, 3H), 1.31 (s, 9H).

[0354] Example B24: Synthesis of 6-(tert-butyl)-3-(methoxy-d3)pyridine-2-sulfonamide Step 1: 2-Fluoro-6-iodopyridin-3-ol I₂ (12.4 g, 48.7 mmol) was added to a solution of 2-fluoropyridin-3-ol (5 g, 44.2 mmol) and K₂CO₃ (12.2 g, 88.4 mmol) in water (200 mL), and the mixture was stirred at rt for 3 h. The pH of the reaction mixture was adjusted to 6 with citric acid, and the mixture was extracted twice with EA. The combined organic layers were washed with Na₂S₂O₃ solution and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give the product (11 g, crude matter). MS (ESI) m / e [M+H]⁺ = 239.9.

[0355] Step 2: 2-Fluoro-6-iodo-3-(methoxy-d3)pyridine To a solution of 2-fluoro-6-iodopyridin-3-ol (11 g, 44.2 mmol) in DMF (110 L), NaH (60% in mineral oil, 1.96 g, 48.6 mmol) was added, and the mixture was stirred at rt for 30 min. CD3I (7 g, 48.5 mmol) was added, and the mixture was stirred at rt for 3 h. The reactants were diluted with EA, washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated, and the residue purified by silica gel column chromatography (PE to PE / EA = 1:1) to yield the product (6 g, 53%). MS (ESI) m / e [M+H]+ = 257.0.

[0356] Step 3: 2-(benzylthio)-6-iodo-3-(methoxy-d3)pyridine NaH (60% in mineral oil, 900 mg, 22.5 mmol) was slowly added to a solution of benzyl mercaptan (2.79 g, 22.5 mmol) in THF (100 mL) and stirred at 0 °C for 30 min. 2-Fluoro-6-iodo-3-(methoxy-d3)pyridine (4.8 g, 18.8 mmol) was added and the mixture was stirred at 70 °C for 4 h. The reaction mixture was poured into ice water and extracted twice with EA. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE to PE / EA = 3:1) to give the compound (5.1 g, 75% yield). MS (ESI) m / e [M+H]⁺ = 361.1.

[0357] Step 4: 2-(benzylthio)-6-(tert-butyl)-3-(methoxy-d3)pyridine tert-butylmagnesium chloride (27.8 mL, 1 M in THF, 27.8 mmol) was added dropwise to a mixture of CuCN (1.24 g, 13.9 mmol) in THF (20 mL) at below -65 °C and stirred at -65 °C for 1 h. THF (5 mL) containing 2-(benzylthio)-6-iodo-3-(methoxy-d3)pyridine (2 g, 5.55 mmol) was added dropwise at below -65 °C and stirred at -65 °C for 1 h, then heated to rt and stirred for 3 h. The reaction mixture was poured into a saturated aqueous NH4Cl solution (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with saturated aqueous NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE to PE: EA = 4:1) to give the title compound (1 g, 62% yield). MS(ESI) m / e [M+H]+ = 291.2.

[0358] Step 5: 6-(tert-butyl)-3-(methoxy-d3)pyridine-2-sulfonamide NCS (1.38 g, 10.34 mmol) was added to a solution of 2-(benzylthio)-6-(tert-butyl)-3-(methoxy-d3)pyridine (1 g, 93.45 mmol) in AcOH (20 mL) and H2O (5 mL), and the mixture was stirred at rt for 1 h. After the reaction was complete, the solution was poured into ice water and extracted twice with EA. The extract was washed with water and brine, dried, concentrated, and the residue was dissolved in THF (10 mL) and NH4OH (25%, 2 mL) was added, and the reaction mixture was stirred at rt for 1 h. The solution was concentrated and the residue was purified by passing it through a C18 column with water / ACN containing 0.1% FA (eluting from 10% to 60%) to give the title product (500 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ 7.62 - 7.61 (m, 2H), 7.15 (s,2H), 1.31 (s, 9H). MS (ESI) m / e [M+H]+ = 248.1.

[0359] Example B25: Synthesis of 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-5-sulfonamide Step 1: 6-Methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-5-sulfonyl chloride Chlorosulfonic acid (651 mg, 5.6 mol) was added dropwise to a solution of 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran (1 g, 5.6 mmol) in DCM (10 mL) at 0 °C and stirred for 1 h. After the reaction was complete, the mixture was poured into ice water and extracted with DCM. The organic layer was concentrated to give the title product (1 g, 64%). MS (ESI) m / e [M+Na]+ = 277.2.

[0360] Step 2: 6-Methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-5-sulfonamide NH3•H2O (5 mL) was added dropwise to a solution of 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-5-sulfonyl chloride (1.00 g, 3.60 mmol) in THF (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, H2O was added to the reaction mixture and it was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was diluted with EA (10 mL) and stirred for 1 h. The mixture was filtered and the filter cake was collected to give the desired product (50 mg, 5%). ¹H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 6.48 (s, 1H), 4.93 (s, 2H), 4.32 (s, 2H), 3.96 (s, 3H), 1.33 (s, 6H). MS (ESI) m / e [M+H]+ =257.3.

[0361] Example B26: Synthesis of 5-(2-oxabicyclo[2.1.1]hex-4-yl)-2-methoxybenzenesulfonamide Step 1: 4-(4-methoxyphenyl)-2-oxabicyclo[2.1.1]hexane 4-Toluenesulfonyl chloride (1.37 g, 7.2 mmol, 1.5 eq) was added to a solution of 3-(hydroxymethyl)-3-(4-methoxyphenyl)cyclobut-1-ol (1 g, 4.8 mmol) in pyridine (3.2 mL) and DCM (8 mL) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 2 h. After the reaction was complete, the mixture was diluted with DCM, washed with water, 1 N HCl aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield crude 4-methylbenzenesulfonic acid (3-hydroxy-1-(4-methoxyphenyl)cyclobutyl) methyl ester.

[0362] NaH (60% in mineral oil, 320 mg, 8 mmol) was added to a solution of crude 4-methylbenzenesulfonic acid (3-hydroxy-1-(4-methoxyphenyl)cyclobutyl) methyl ester in THF (80 mL) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 30 min, then heated to 80 °C and stirred at this temperature for 12 h. After cooling to rt, MeOH (10 mL) was added. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 1:1) to give the title compound (0.2 g, 19% yield). 1H NMR (400 MHz, DMSO-d6) δ = 7.24 - 7.19 (m, 2H), 6.92- 6.88 (m, 2H), 4.55 (s, 1H), 3.73 (s, 3H), 3.71 (s, 2H), 2.00 - 1.94 (m,2H), 1.78 - 1.72 (m, 2H).

[0363] Step 2: 4-(3-bromo-4-methoxyphenyl)-2-oxabicyclo[2.1.1]hexane NBS (187.1 mg, 1.0 mmol, 1 eq) was added to a solution of 4-(4-methoxyphenyl)-2-oxabicyclo[2.1.1]hexane (0.2 g, 1.0 mmol) in ACN (3 mL). The reaction mixture was stirred at 20 °C for 12 h. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 1:1) to give the title compound (0.2 g, 71% yield). 1H NMR (400 MHz, CDCl3) δ = 7.43 (d, J = 2.0 Hz, 1H),7.17 - 7.14 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.65 (s, 1H), 3.90 (s, 3H), 3.82 (s, 2H), 2.03 - 1.97 (m, 2H), 1.96 - 1.89 (m, 2H) Step 3: 4-(3-(benzylthio)-4-methoxyphenyl)-2-oxabicyclo[2.1.1]hexane Pd2(dba)3 (51 mg, 56 μmol) and Xantphos (65 mg, 112 μmol) were added to a solution of 4-(3-bromo-4-methoxyphenyl)-2-oxabicyclo[2.1.1]hexane (150 mg, 557 μmol) in dioxane (2 mL). The mixture was stirred at rt for 30 min under N2. Then, a solution of benzyl mercaptan (139 mg, 1.1 mmol) and DIEA (144 mg, 1.1 mmol) in dioxane (2 mL) was added to the reaction mixture. The reaction mixture was stirred at 110 °C for 12 h. After cooling to rt, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 3:1) to give the title compound (140 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.27 (m,3H), 7.25 - 7.20 (m, 2H), 7.07 - 7.03 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 4.61(s, 1H), 4.09 (s, 2H), 3.90 (s, 3H), 3.72 (s, 2H), 1.93 - 1.83 (m, 4H).

[0364] Step 4: 5-(2-oxabicyclo[2.1.1]hex-4-yl)-2-methoxybenzenesulfonamide Sulfonyl chloride (181 mg, 1.3 mmol) was added to a solution of 4-(3-(benzylthio)-4-methoxyphenyl)-2-oxabicyclo[2.1.1]hexane (140 mg, 448 μmol) in AcOH (2.4 mL), ACN (0.6 mL), and H₂O (0.06 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After the reaction was complete, the mixture was concentrated under vacuum to obtain crude 5-(2-oxabicyclo[2.1.1]hex-4-yl)-2-methoxybenzenesulfonyl chloride, which was dissolved in MeOH (2.6 mL) containing 7 M NH₃. The reaction mixture was stirred at rt for 10 min. After the reaction was complete, the mixture was filtered through diatomaceous earth and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18 75 x 40 mm x 3 μm; mobile phase: [H2O(NH4HCO3) ACN]; gradient: 5%-30% B over 8.0 min) to yield the title compound (85.3 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 2.0 Hz, 1H), 7.51 - 7.48 (m,1H), 7.19 (d, J = 8.4 Hz, 1H), 6.04 (br s, 1H), 4.57 (s, 1H), 3.89 (s, 3H), 3.73 (s, 2H), 2.03 - 1.97 (m, 2H), 1.84 - 1.77 (m, 2H). MS(ESI) m / e [M+H]+ =270.1.

[0365] Example B27: Synthesis of 7-methoxy-3,4-dihydro-2H-2,4-methyl-8-sulfonamide Step 1: 2-(3-(benzyloxy)cyclobutyl)-5-methoxyphenol Under N2 at 25 °C, a solution of 2-bromo-5-methoxyphenol (1.1 g, 5.4 mmol) in DME (330 mL) was supplemented with ((3-bromocyclobutoxy)methyl)benzene (1.3 g, 5.4 mmol), tris(trimethylsilyl)silane (1.6 g, 6.5 mmol), 2,6-dimethylpyridine (1.2 g, 10.8 mmol), Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (60.8 mg, 54 μmol), and (dtbbpy)NiCl2 (22 mg, 54 μmol). The solution was injected into a photodynamic reactor {FEP, Coils reactor, 3.175 (1 / 8'') mm, 55 mL, 395 nm, 200 W} at a flow rate of 40 mL / min. In a 40°C environment, three reactions were run in parallel. After the reactions were complete, the combined mixture of the three reactions was poured into H2O and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (silica gel, PE:EA = 10:1 to 3:1) to give the title compound (0.9 g, 20% yield). MS (ESI) m / e [M+H]+ = 285.1.

[0366] Step 2: 2-(3-hydroxycyclobutyl)-5-methoxyphenol Concentrated HCl (0.3 mL) was added to a mixture of 2-(3-benzyloxycyclobutyl)-5-methoxyphenol (0.9 g, 3.2 mmol) and Pd / C (0.4 g, 10% wt / wt) in MeOH (12 mL) and EA (48 mL). The suspension was degassed and purged three times with H2, and stirred at 25 °C for 16 h under H2 (15 psi). After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under vacuum. The residue was purified by preparative TLC (silica gel, PE: EA = 1:1) to give the title compound (0.45 g, 72% yield). MS (ESI) m / e [M-OH]+ = 177.1.

[0367] Step 3: 7-Methoxy-3,4-dihydro-2H-2,4-methylbridged chromosome A mixture of 2-(3-hydroxycyclobutyl)-5-methoxyphenol (250 mg, 1.3 mmol) and 2-(tributylphosphine)acetonitrile (Tsunoda reagent, 940 mg, 3.9 mmol) in dioxane (7.5 mL) was stirred in a microwave oven at 150 °C for 1 h. After cooling to rt, the mixture was diluted with EA and washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to yield the title compound (80 mg, 35%). 1H NMR(400 MHz, DMSO-d6) δ 6.94 (d, J = 8.1 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 6.34(dd, J = 2.4, 8.1 Hz, 1H), 5.04 (td, J = 3.7, 6.3 Hz, 1H), 3.69 (s, 3H), 3.32- 3.27 (m, 1H), 2.43 - 2.36 (m, 2H), 1.44 - 1.38 (m, 2H). MS(ESI) m / e [M+H]+ =177.1.

[0368] Step 4: 7-Methoxy-3,4-dihydro-2H-2,4-methyl-chroman-8-sulfonamide TMEDA (106 mg, 0.92 mmol) and n-BuLi (1.6 M in n-hexane, 0.40 mL, 0.56 mmol) were added to a mixture of 7-methoxy-3,4-dihydro-2H-2,4-methylbridged chroma-8-sulfinic acid (80 mg, 0.46 mmol) in 10 mL of hexane at 0 °C, and the mixture was stirred at 0 °C for 30 min. The solution was cooled to -70 °C and bubbled with SO2 (gas) for 1 min. The reaction mixture was then stirred at -70 °C for another 30 min. After the reaction was complete, the mixture was concentrated under vacuum to produce crude 7-methoxy-3,4-dihydro-2H-2,4-methylbridged chroma-8-sulfinic acid.

[0369] NCS (190 mg, 0.84 mmol) was added to a mixture of crude 7-methoxy-3,4-dihydro-2H-2,4-methyl-bridged chromium-8-sulfinic acid in acetic acid (12 mL) and water (4 mL). The reaction mixture was stirred at rt for 2 h. After the reaction was complete, the reaction mixture was concentrated to remove acetic acid. The residue was extracted with EA. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to give crude 7-methoxy-3,4-dihydro-2H-2,4-methyl-bridged chromium-8-sulfonyl chloride.

[0370] NH3·H2O (0.5 mL) was added to a mixture of crude 7-methoxy-3,4-dihydro-2H-2,4-methyl-8-sulfonyl chloride in THF (6 mL). The reaction mixture was stirred at rt for 2 h. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give the title compound (60 mg, 51% yield). MS (ESI) m / z [M + H]+ = 256.0.

[0371] Example B28: Synthesis of 6-(bicyclo[1.1.1]pent-1-yl)-3-methoxypyridine-2-sulfonamide Step 1: 6-(bicyclo[1.1.1]pent-1-yl)-2-fluoro-3-methoxypyridine Add bicyclo[1.1.1]pentane-1-carboxylic acid (336 mg, 3 mmol), (dtbbpy)NiCl2 (80 mg, 0.2 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (224 mg, 0.2 mmol), 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (513 mg, 3 mmol), and phthalimide (294 mg, 2 mmol) to a mixture of 6-bromo-2-fluoro-3-methoxypyridine (412 mg, 2 mmol) in DMA (10 mL). Exchange the mixture with N2 three times and stir under blue light (440 nm) at rt for 16 h. After the reaction is complete, concentrate the mixture under vacuum. Purify the residue by silica gel column chromatography (PE:EA = 2:1) to give the title compound (70 mg, 18%). MS(ESI) m / z [M + H]+ = 194.2.

[0372] Step 2: 2-(benzylthio)-6-(bicyclo[1.1.1]pent-1-yl)-3-methoxypyridine NaH (60% in mineral oil, 11.2 mg, 0.26 mmol) was added to a mixture of benzyl mercaptan (35 mg, 0.26 mmol) and THF (10 mL), and the mixture was stirred at 0 °C for about 30 min. THF (2 mL) containing 6-(bicyclo[1.1.1]pent-1-yl)-2-fluoro-3-methoxypyridine (50 mg, 0.26 mmol) was added to the mixture at 0 °C. The reaction mixture was heated to 60 °C and stirred at this temperature for 3 h. After the reaction was complete, the mixture was cooled to rt, quenched with H2O, and extracted with EA. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to yield the title compound (60 mg, 78%). MS (ESI) m / z [M + H]+ = 298.2.

[0373] Step 3: 6-(bicyclo[1.1.1]pent-1-yl)-3-methoxypyridine-2-sulfonamide NCS (180 mg, 0.8 mmol) was added to a mixture of 2-(benzylthio)-6-(bicyclo[1.1.1]pent-1-yl)-3-methoxypyridine (60 mg, 0.20 mmol) in acetic acid (6 mL) and water (2 mL). The reaction mixture was stirred at rt for 2 h. After the reaction was complete, the mixture was concentrated under vacuum to remove acetic acid. The residue was diluted with H2O and extracted with EA. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude 6-(bicyclo[1.1.1]pent-1-yl)-3-methoxypyridine-2-sulfonyl chloride.

[0374] NH3·H2O (1 mL) was added to a mixture of crude 6-(bicyclo[1.1.1]pent-1-yl)-3-methoxypyridine-2-sulfonyl chloride in THF (5 mL). The reaction mixture was stirred at rt for 2 h. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was diluted with DCM and water. The aqueous phase was adjusted to pH = 2-3 with 1 N HCl (aqueous solution) and extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the title compound, which required no further purification (50 mg, 99%). MS (ESI) m / z [M + H]+ = 255.1.

[0375] Example C: Example C1: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-iodobenzamide A solution of 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoic acid (730 mg, 2.23 mmol), 5-(tert-butyl)-2-methoxybenzenesulfonamide (541 mg, 2.23 mmol), EDCI (852 mg, 4.46 mmol), and DMAP (817 mg, 6.69 mmol) in DCM (20 mL) was stirred overnight at rt. After the reaction was complete, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (MeOH / DCM = 1:20) to give the title compound (1.1 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.37 (s, 1H), 7.84 (d,J = 12.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.52(s, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.32 (s, 1H), 5.37 (s, 2H), 3.81 (s, 3H), 1.28 (s, 9H). MS (ESI) m / e [M+H]+ = 554.

[0376] Example C2: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-cyclopropylbenzamide A solution of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-iodobenzamide (50 mg, 0.09 mmol), cyclopropylboronic acid (16 mg, 0.18 mmol), Pd(OAc)2 (2 mg, 0.009 mmol), Cy3P (5 mg, 0.018 mmol), and K3PO4 (39 mg, 0.18 mmol) in 1,4-dioxane (4 mL) / water (0.4 mL) was stirred at 140 °C for 4 h under microwave stimulation. After cooling to rt, the reaction mixture was concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the residue was purified by preparative HPLC (Waters Sunfire C18, 55%-70% ACN / H2O / 0.1% FA) to yield the product (1 mg, 2.4%). 1H NMR (400 MHz, DMSO-d6) δ 13.00-12.15 (m, 1H), 8.12 (s, 1H), 7.84-7.73 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H),7.56-7.51 (m, 1H), 7.46 (s, 1H), 6.96-6.83 (m, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.27 (s, 1H), 5.51 (s, 2H), 3.65 (s, 3H), 2.04-1.98 (m, 1H), 1.25 (s, 9H),0.95-0.90 (m, 2H), 0.65-0.54 (m, 2H). MS (ESI) m / e [M+H]+ = 468.

[0377] Using the corresponding starting materials as starting materials, the following Examples C3 (Table 1) were synthesized according to procedures similar to those in Example C2.

[0378] Table 1:

[0379] Example C4: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-vinylbenzamide A solution of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-iodobenzamide (150 mg, 0.27 mmol), tributyl(vinyl)stanane (172 mg, 0.54 mmol), and Pd(PPh3)4 (31 mg, 0.027 mmol) in THF (10 mL) was stirred overnight at 80 °C. After cooling to rt, the reaction mixture was concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude substance was purified by silica gel column chromatography (MeOH / DCM = 1:20) to obtain the product (100 mg, 81%). 1 H NMR (400 MHz, DMSO- d 6) δ 12.52 (s, 1H), 8.12 (s,1H), 7.84 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.71-7.64 (m, 2H), 7.46 (d, J = 1.1 Hz, 1H), 7.13 (d, J = 17.5 Hz, 2H), 6.93 (d, J = 8.1 Hz,1H), 6.29-6.25 (m, 1H), 5.93 (d, J = 17.2 Hz, 1H), 5.50-5.41 (m, 3H), 3.80(s, 3H), 1.28 (s, 9H). MS (ESI) m / e [M+H]+ = 454.

[0380] Using the corresponding starting materials as starting materials, the following Examples C5 (Table 2) were synthesized according to procedures similar to those in Example C4.

[0381] Table 2:

[0382] Example C6: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-ethylbenzamide H2 (1 atm) was introduced into a solution of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-vinylbenzamide (50 mg, 0.11 mmol) and Pd / C (10 mg, 10%) in MeOH (5 mL), and the resulting mixture was stirred at 30 °C for 4 h. After cooling to rt, the reactants were filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC (Waters Sunfire C18, 50%-70% ACN / H2O / 0.1% FA) to yield the product (5.52 mg, 11.0%). 1 H NMR (400 MHz, DMSO- d 6) δ 12.40 (s, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.81-7.72 (m, 2H), 7.70-7.59 (m, 2H), 7.47 (s, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.28 (s, 1H), 5.41 (s, 2H), 3.80 (s, 3H), 2.70 (q,J = 7.4 Hz, 2H), 1.28 (s, 9H), 1.13 (t, J = 7.5 Hz, 3H). MS (ESI) m / e [M+H] + =456.

[0383] Example C7: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-methoxybenzamide A solution of 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid (25 mg, 0.11 mmol), 5-(tert-butyl)-2-methoxybenzenesulfonamide (27 mg, 0.11 mmol), EDCI (42 mg, 0.22 mmol), and DMAP (41 mg, 0.33 mmol) in DCM (50 mL) was stirred overnight at rt. After the reaction was complete, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the residue was purified by preparative HPLC (Waters Sunfire C18, 50%–70% ACN / H2O / 0.1% FA) to yield the product (21 mg, 42%). 1 H NMR (400 MHz, DMSO- d6) δ 12.46 (s, 1H),7.84 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H),7.52 (s, 1H), 7.48-7.43 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 8.7Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.27 (s, 1H), 5.31 (s, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 1.28 (s, 9H). MS (ESI) m / e [M+H] + = 458.

[0384] Using the corresponding starting materials as starting materials, the following Examples C8-C17 (Table 3) were synthesized according to procedures similar to those in Example C7.

[0385] Table 3:

[0386] Example C37: Synthesis of 5-((3-amino-1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridin-2-yl)sulfonyl)-6-methoxypyridinecarboxamide Step 1: (1-((6-(((6-(tert-butyl)-3-methoxypyridin-2-yl)sulfonyl)carbamoyl)-2-methoxypyridin-3-yl)methyl)-1H-pyrazole-3-yl)tert-butyl carbamate A solution of 5-((3-((tert-butyloxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (30 mg, 0.09 mmol), 6-(tert-butyl)-3-methoxypyridine-2-sulfonamide (21 mg, 0.09 mmol), DMAP (33 mg, 0.27 mmol), and EDCI (26 mg, 0.14 mmol) in DCM (2 mL) was stirred overnight at rt. After the reaction was complete, the mixture was concentrated, and the residue was purified by passing it through a C18 column (mobile phase, ACN / water (0.1% FA), 20% to 100%) to yield the product (15 mg, 29%). MS (ESI) m / e [M+H]+ = 574.9.

[0387] Step 2: 5-((3-amino-1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridin-2-yl)sulfonyl)-6-methoxypyridinecarboxamide TFA (1 mL) was added to a solution of (1-((6-(((6-(tert-butyl)-3-methoxypyridin-2-yl)sulfonyl)aminocarbamoyl)-2-methoxypyridin-3-yl)methyl)-1H-pyrazole-3-yl)carbamate (15 mg, 0.03 mmol) in DCM (4 mL), and the solution was stirred at rt for 4 h. After the reaction was complete, the mixture was concentrated, and the residue was purified by C18 column (mobile phase, ACN / water (0.1% FA), 20% to 100%) to yield product (15 mg, 29%). 1H NMR (400MHz, DMSO-d6) δ 11.82 (s, 1H), 7.74 - 7.70 (m, 1H), 7.68 - 7.64 (m, 1H), 7.57(d, J = 7.4 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 5.46 (d, J = 2.2 Hz, 1H), 5.07 (s, 2H), 4.64 (brs, 2H), 4.09 (s, 3H), 3.92 (s,3H), 1.11 (s, 9H). MS (ESI) m / e [M+H]+ = 475.3.

[0388] Using the corresponding starting materials as starting materials, the following Examples C38 (Table 4) were synthesized according to procedures similar to those in Example C37.

[0389] Table 4:

[0390] Example C39: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((7-methoxy-4,4-dimethylthrom-8-yl)sulfonyl)pyridinecarboxamide A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (15 mg, 0.06 mmol), 7-methoxy-4,4-dimethylthion-8-sulfonamide (17 mg, 0.06 mmol), EDCI (25 mg, 0.13 mmol), and DMAP (24 mg, 0.19 mmol) was added to DCM (3 mL). The resulting reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, the DCM was removed under vacuum. The residue was applied to preparative HPLC (column: Sunfire C18; mobile phase: [H2O (0.1% FA)-ACN]; gradient: 48%-63% B over 11.0 min) to generate the title compound (7 mg, 23%). 1H NMR (400MHz, DMSO-d6) δ 11.23 (brs, 1H), 7.81 - 7.80 (m, 1H), 7.55 - 7.43 (m, 3H), 7.16 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.27 - 6.26 (m, 1H), 5.32 (s, 2H), 4.06 - 4.04 (m, 5H), 3.68 (s, 3H), 1.67 - 1.65 (m, 2H), 1.18 (s, 6H). MS (ESI) m / e [M+1]+487.

[0391] Example C40: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-6-methoxypyridinecarboxamide A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (23 mg, 0.1 mmol), 5-(tert-butyl)-2-methoxybenzenesulfonamide (24 mg, 0.1 mmol), DMAP (37 mg, 0.3 mmol), and EDCI (29 mg, 0.15 mmol) in DCM (2 mL) was stirred overnight at rt. After the reaction was complete, the mixture was concentrated, and the residue was purified by passing it through a C18 column (mobile phase, ACN / water (0.1% FA), 20% to 100%) to yield the product (10 mg, 22%). 1H NMR (400MHz, DMSO-d6) δ 11.75 (s, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.84 - 7.82 (m, 1H), 7.73 - 7.57 (m, 1H), 7.53 - 7.47 (m, 2H), 7.23 - 7.06 (m, 2H), 6.30 (t, J =2.0 Hz, 1H), 5.34 (s, 2H), 4.08 (s, 3H), 3.79 (s, 3H), 1.29 (s, 9H). MS (ESI)m / e [M+H]+ = 459.3.

[0392] Example C41: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridin-2-yl)sulfonyl)-6-methoxypyridinecarboxamide A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (23 mg, 0.1 mmol), 6-(tert-butyl)-3-methoxypyridine-2-sulfonamide (24 mg, 0.1 mmol), DMAP (37 mg, 0.3 mmol), and EDCI (29 mg, 0.15 mmol) in DCM (2 mL) was stirred at rt for 4 h. After the reaction was complete, the mixture was concentrated, and the residue was purified by passing it through a C18 column (mobile phase, ACN / water (0.1% FA), 20% to 100%) to yield the product (7 mg, 15%). 1H NMR (400MHz, DMSO-d6) δ 11.80 (s, 1H), 7.89 - 7.83 (m, 1H), 7.77 - 7.60 (m, 2H), 7.58- 7.50 (m, 2H), 7.23 - 7.16 (m, 1H), 6.33 - 6.29 (m, 1H), 5.36 (s, 2H), 4.07 (s, 3H), 3.89 (s, 3H), 1.11 (s, 9H). MS (ESI) m / e [M+H]+ = 460.3.

[0393] Example C42: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)pyridinecarboxamide A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (23 mg, 0.1 mmol), 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide (25 mg, 0.1 mmol), DMAP (37 mg, 0.3 mmol), and EDCI (29 mg, 0.15 mmol) in DCM (2 mL) was stirred at 45 °C for 4 h. After the reaction was complete, the mixture was concentrated, and the residue was purified by passing it through a C18 column (mobile phase, ACN / water (0.1% FA), 20% to 100%) to yield the product (10 mg, 21%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.52 - 7.50 (m, 1H), 7.31 - 7.26 (m, 1H), 7.20 (d,J = 7.6 Hz, 1H), 6.54 (d, J = 8.3 Hz, 1H), 6.33 - 6.29 (m, 1H), 5.36 (s, 2H), 4.09 (s, 3H), 3.75 (s, 3H), 2.90 (s, 2H), 1.24 (s, 6H). MS (ESI) m / e [M+H]+ =473.3.

[0394] Example C43: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)pyridinecarboxamide A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (23 mg, 0.1 mmol), 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide (25 mg, 0.1 mmol), DMAP (37 mg, 0.3 mmol), and EDCI (29 mg, 0.15 mmol) in DCM (2 mL) was stirred at 45 °C for 4 h. After the reaction was complete, the mixture was concentrated, and the residue was purified by passing it through a C18 column (mobile phase, ACN / water (0.1% FA), 20% to 100%) to yield the product (14 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.41 - 7.32 (m, 1H), 7.19 (d, J = 7.5 Hz, 1H), 6.60 (d,J = 7.9 Hz, 1H), 6.32 (t, J = 2.0 Hz, 1H), 5.36 (s, 2H), 4.28 (s, 2H), 4.10(s, 3H), 3.74 (s, 3H), 1.26 (s, 6H). MS (ESI) m / e [M+H]+ = 473.3.

[0395] Example C44: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)-3-vinylbenzamide A solution of 4-((1H-pyrazol-1-yl)methyl)-3-vinylbenzoic acid (70 mg, 0.31 mmol), 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide (80 mg, 0.31 mmol), EDCI (119 mg, 0.62 mmol), and DMAP (114 mg, 0.93 mmol) in DCM (5 mL) was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude substance was purified by silica gel column chromatography (MeOH / DCM = 1:10) to obtain a crude product (70 mg). The crude product was further purified by preparative HPLC (Waters Sunfire C18, 43%-63% ACN / H2O / 0.1% FA) to obtain a product (12 mg). 1H NMR (400 MHz, DMSO-d6) δ12.25 (s, 1H), 8.16 (s, 1H), 7.80 - 7.73 (m, 1H), 7.70 (d, J = 8.1, 1H), 7.45(d, J = 1.3 Hz, 1H), 7.28 (d, J = 6.4 Hz, 1H), 7.12 (d, J = 17.3, 1H), 6.90(d, J = 8.0 Hz, 1H), 6.52 (d, J = 6.6 Hz, 1H), 6.26 (t, J = 1.8 Hz, 1H), 5.93(d, J = 17.4 Hz, 1H), 5.54 - 5.36 (m, 3H), 3.72 (s, 3H), 2.87 (s, 2H), 1.23 (s, 6H). MS (ESI) m / e [M+H]+ = 468.

[0396] Example C45: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-methoxy-N-((6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)benzamide A solution of 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid (35 mg, 0.15 mmol), 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide (39 mg, 0.15 mmol), EDCI (58 mg, 0.3 mmol), and DMAP (55 mg, 0.45 mmol) in DCM (5 mL) was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude substance was purified by preparative HPLC (Waters Sunfire C18, 40%-60% ACN / H2O / 0.1% FA) to obtain the product (35 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 1.1 Hz, 1H), 7.45 (d, J = 1.3 Hz, 1H), 7.41 (d, J = 7.9, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 6.51 (d, J = 8.3 Hz, 1H), 6.26 (t, J = 2.0 Hz, 1H), 5.31 (s, 2H), 3.88 (s, 3H), 3.72 (s, 3H), 2.88 (s, 2H), 1.26 (s, 6H). MS (ESI)m / e [M+H]+ = 472.

[0397] Example C46: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropyl-N-((6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)pyridinecarboxamide A solution of 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropylpyridinecarboxylic acid (30 mg, 0.12 mmol), 2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide (28 mg, 0.12 mmol), EDCI (47 mg, 0.25 mmol), and DMAP (45 mg, 0.37 mmol) in DCM (5 mL) was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude substance was purified by preparative HPLC (Waters Sunfire C18, 48%-68% ACN / H2O / FA) to obtain the product (22 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ10.95 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.48 (d, J= 1.3 Hz, 1H), 7.31 - 7.21 (m, 2H), 6.52 (d, J = 8.3 Hz, 1H), 6.28 (t, J =2.0 Hz, 1H), 5.62 (s, 2H), 3.71 (s, 3H), 2.84 (s, 2H), 2.40 - 2.32 (m, 1H),1.18 - 1.08 (m, 8H), 1.03 - 0.95 (m, 2H). MS (ESI) m / e [M+H]+ = 483.

[0398] Example C47: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropyl-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)pyridinecarboxamide A solution of 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropylpyridinecarboxylic acid (30 mg, 0.12 mmol), 3,3-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide (28 mg, 0.12 mmol), EDCI (47 mg, 0.25 mmol), and DMAP (45 mg, 0.37 mmol) in DCM (5 mL) was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude substance was purified by preparative HPLC (Waters Sunfire C18, 48%-68% ACN / H2O / FA) to obtain the product (23 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ11.16 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.48 (d, J= 1.3 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.56 (d, J= 8.4 Hz, 1H), 6.28 (t, J = 2.0 Hz, 1H), 5.61 (s, 2H), 4.24 (s, 2H), 3.69 (s,3H), 2.39 - 2.32 (m, 1H), 1.21 (s, 6H), 1.17 - 1.13 (m, 2H), 1.02 - 0.96 (m, 2H). MS (ESI) m / e [M+H]+ = 483.

[0399] Example C48: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridin-2-yl)sulfonyl)-6-cyclopropylpyridinecarboxamide A solution of 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropylpyridinecarboxylic acid (30 mg, 0.12 mmol), 6-(tert-butyl)-3-methoxypyridine-2-sulfonamide (30 mg, 0.12 mmol), EDCI (47 mg, 0.25 mmol), and DMAP (45 mg, 0.37 mmol) in DCM (5 mL) was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude substance was purified by preparative HPLC (Waters Sunfire C18, 53%-73% ACN / H2O / FA) to obtain the product (14 mg, 24%). 1H NMR (400 MHz, DMSO-d6) δ11.43 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.72 - 7.59 (m, 3H), 7.49 (d, J =1.4 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 6.29 (t, J = 2.0 Hz, 1H), 5.63 (s, 2H), 3.88 (s, 3H), 2.38 - 2.30 (m, 1H), 1.26 - 1.16 (m, 2H), 1.01 (s, 9H), 0.96 - 0.91 (m, 2H). MS (ESI) m / e [M+H]+ = 470.

[0400] Example C49: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-methoxy-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)benzamide A solution of 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid (30 mg, 0.13 mmol), 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide (33 mg, 0.13 mmol), EDCI (50 mg, 0.26 mmol), and DMAP (48 mg, 0.39 mmol) in DCM (5 mL) was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude substance was purified by preparative HPLC (Waters Sunfire C18, 43%-58% ACN / H2O / FA) to obtain the product (20 mg, 33%). 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.72 - 7.59 (m, 3H), 7.49 (d,J = 1.4 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 6.29 (t, J = 2.0 Hz, 1H), 5.63 (s,2H), 3.88 (s, 3H), 2.38 - 2.30 (m, 1H), 1.26 - 1.16 (m, 2H), 1.01 (s, 9H),0.96 - 0.91 (m, 2H). MS (ESI) m / e [M+H]+ = 470.

[0401] Example C50: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)-3-vinylbenzamide A solution of 4-((1H-pyrazol-1-yl)methyl)-3-vinylbenzoic acid (60 mg, 0.26 mmol), 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide (68 mg, 0.26 mmol), EDCI (101 mg, 0.53 mmol), and DMAP (97 mg, 0.79 mmol) in DCM (5 mL) was stirred overnight at rt. After the reaction was complete, the reactants were concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude substance was purified by silica gel column chromatography (MeOH / DCM = 1:20) to obtain a crude product (40 mg). The crude substance (10 mg) was purified by preparative HPLC (Waters Sunfire C18, 45%-65% ACN / H2O / FA) to obtain a product (2 mg). 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s,1H), 8.11 - 8.03 (m, 1H), 7.75 (s, 1H), 7.66 (d, J = 8.0, 1H), 7.43 (d, J =1.4 Hz, 1H), 7.36 - 7.24 (m, 1H), 7.10 (dd, J = 17.3, 11.0 Hz, 1H), 6.90 (d,J = 8.1 Hz, 1H), 6.54 (d, J = 6.7 Hz, 1H), 6.24 (t, J = 1.8 Hz, 1H), 5.89 (d,J = 16.5 Hz, 1H), 5.47 - 5.40 (m, 3H), 4.23 (s, 2H), 3.69 (s, 3H), 1.21 (s, 6H). MS (ESI) m / e [M+H]+ = 468.

[0402] Example C51: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-ethyl-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)benzamide Pd / C (30 mg) was added to a solution of 4-((1H-pyrazol-1-yl)methyl)-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)-3-vinylbenzamide (30 mg, 0.13 mmol) in MeOH (10 mL), followed by the introduction of H2. The resulting mixture was stirred at rt for 2 h. After the reaction was complete, the reactants were filtered off and concentrated. The crude substance was purified by preparative HPLC (Waters Sunfire C18, 45%-65% ACN / H2O / FA) to obtain the product (6 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 7.76 (d, J = 2.0 Hz,1H), 7.71 (d, J = 1.4 Hz, 1H), 7.59 (d, J = 8.0, 1H), 7.44 (d, J = 1.6 Hz,1H), 7.31 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 8.3 Hz,1H), 6.25 (t, J = 2.0 Hz, 1H), 5.39 (s, 2H), 4.24 (s, 2H), 3.70 (s, 3H), 2.68(q, J = 7.5 Hz, 2H), 1.21 (s, 6H), 1.10 (t, J = 7.5 Hz, 3H). MS (ESI) m / e [M+H]+ = 470.

[0403] Example C52: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-ethyl-N-((6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)benzamide Using the corresponding starting materials as starting materials, Example C52 is synthesized according to a procedure similar to that of Example C51.

[0404] 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 7.82 - 7.73 (m, 2H), 7.64(d, J = 8.1, 1H), 7.46 (d, J = 1.3 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.82(d, J = 8.1 Hz, 1H), 6.51 (d, J = 8.3 Hz, 1H), 6.27 (t, J = 2.0 Hz, 1H), 5.41(s, 2H), 3.72 (s, 3H), 2.88 (s, 2H), 2.69 (q, J = 7.5 Hz, 2H), 1.25 (s, 6H),1.12 (t, J = 7.5 Hz, 3H). MS (ESI) m / e [M+H]+ = 470.

[0405] Example C53: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-ethyl-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)pyridinecarboxamide A solution of 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide (26 mg, 0.10 mmol), 5-((1H-pyrazol-1-yl)methyl)-6-ethylpyridinecarboxylic acid (23 mg, 0.10 mmol), EDCI (36 mg, 0.20 mmol), and DMAP (36 mg, 0.30 mmol) in DCM (1 mL) was stirred overnight at rt. After the reaction was complete, the mixture was concentrated. The crude product was purified by Combi-Flash (column = C18 spherical 20-35 μm; mobile phase: [water (0.1% FA) - ACN], B% = 5%-80%; 6.0 min) to yield product (10 mg, 21%). 1H NMR (400 MHz, DMSO-d6) δ 11.22(s, 1H), 7.90 - 7.84 (m, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.55 - 7.48 (m, 1H),7.41 - 7.33 (m, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.35- 6.31 (m, 1H), 5.54 (s, 2H), 4.29 (s, 2H), 3.72 (s, 3H), 2.96 - 2.86 (m,2H), 1.26 (s, 6H), 1.26 - 1.20 (m, 3H). MS (ESI) m / e [M+H]+ = 471.3.

[0406] Example C54: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((3-methoxy-6-(1,1,1-trifluoro-2-methylpropyl-2-yl)pyridin-2-yl)sulfonyl)pyridinecarboxamide A solution of 3-methoxy-6-(1,1,1-trifluoro-2-methylpropyl-2-yl)pyridine-2-sulfonamide (30 mg, 0.1 mmol), 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (23 mg, 0.1 mmol), EDCI (38.4 mg, 0.2 mmol), and DMAP (24.4 mg, 0.2 mmol) in DCM (5 mL) was stirred overnight at rt. The solvent was removed, and the residue was purified by preparative HPLC (column: Sunfire C18; mobile phase: [H2O (0.1% FA)-ACN]; gradient: 55%-70% B over 11.0 min) to yield the desired product (26 mg, 50.6%). 1H NMR (400 MHz, DMSO-d6) δ11.94 (s, 1H), 7.92 - 7.73 (m, 3H), 7.48 (dd, J = 10.6, 4.5 Hz, 2H), 7.16 (d,J = 7.5 Hz, 1H), 6.27 (t, J = 2.0 Hz, 1H), 5.33 (s, 2H), 4.09 (s, 3H), 3.93 (s, 3H), 1.32 (s, 6H). MS (ESI) m / e [M+H]+ =514.

[0407] Example C55: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((7-methoxy-3,3-dimethylthrom-8-yl)sulfonyl)pyridinecarboxamide A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (23 mg, 0.1 mmol), 7-methoxy-3,3-dimethylthion-8-sulfonamide (27 mg, 0.1 mmol), DMAP (37 mg, 0.3 mmol), and EDCI (29 mg, 0.15 mmol) in DCM (2 mL) was stirred at 45 °C for 4 h. After cooling to rt, the mixture was concentrated, and the residue was purified by passing it through a C18 column (mobile phase, ACN / water (0.1% FA), 10% to 70%) to yield the product (25 mg, 51%). 1H NMR(400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.55 - 7.49 (m,2H), 7.24 - 7.17 (m, 2H), 6.68 (d, J = 8.6 Hz, 1H), 6.32 (t, J = 2.0 Hz, 1H), 5.37 (s, 2H), 4.10 (s, 3H), 3.76 (s, 3H), 3.69 (s, 2H), 2.46 (s, 2H), 0.81 (s, 6H). MS (ESI) m / e [M+H]+ = 487.3.

[0408] Example C56: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((2-methoxy-5-(1-methoxycyclopropyl)phenyl)sulfonyl)pyridinecarboxamide A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (23 mg, 0.1 mmol), 2-methoxy-5-(1-methoxycyclopropyl)benzenesulfonamide (26 mg, 0.1 mmol), DMAP (37 mg, 0.3 mmol), and EDCI (29 mg, 0.15 mmol) in DCM (2 mL) was stirred at 45 °C for 6 h. After cooling to rt, the mixture was concentrated, and the residue was purified by passing through a C18 column (mobile phase, ACN / water (0.1% FA), 10% to 70%) to yield the product (21 mg, 44%). 1HNMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 7.87 - 7.82 (m, 2H), 7.52 - 7.47 (m,3H), 7.22 - 7.17 (m, 2H), 6.31 (t, J = 2.0 Hz, 1H), 5.35 (s, 2H), 4.12 (s,3H), 3.84 (s, 3H), 3.15 (s, 3H), 1.19 - 1.14 (m, 2H), 0.97 - 0.93 (m, 2H). MS(ESI) m / e [M+H]+ = 473.3.

[0409] Example C57: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((2-methoxy-5-(1-methoxy-2-methylprop-2-yl)phenyl)sulfonyl)pyridinecarboxamide A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (13 mg, 0.055 mmol), 2-methoxy-5-(1-methoxy-2-methylpropyl-2-yl)benzenesulfonamide (15 mg, 0.055 mmol), DMAP (20 mg, 0.164 mmol), and EDCI (16 mg, 0.082 mmol) in DCM (2 mL) was stirred at 45 °C for 16 h. After cooling to rt, the mixture was concentrated, and the residue was purified by passing it through a C18 column (mobile phase, ACN / water (0.1% FA), 20% to 80%) to yield the product (10 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.86 - 7.80 (m, 2H), 7.70 - 7.64 (m, 1H), 7.53 - 7.48 (m, 2H), 7.18 (d, J = 16.3 Hz, 2H), 6.32 -6.28 (m, 1H), 5.35 (s, 2H), 4.12 (s, 3H), 3.82 (s, 3H), 3.35 (s, 3H), 3.29 (s, 2H), 1.26 (s, 6H). MS (ESI) m / e [M+H]+ = 489.3.

[0410] Example C58: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((6-methoxy-2,3-dihydrobenzofuran-7-yl)sulfonyl)pyridinecarboxamide A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (12 mg, 0.05 mmol), 6-methoxy-2,3-dihydrobenzofuran-7-sulfonamide (12 mg, 0.05 mmol), DMAP (12 mg, 0.1 mmol), and EDCI (14 mg, 0.075 mmol) in DCM (2 mL) was stirred at 45 °C for 2 h. After cooling to rt, the mixture was concentrated, and the residue was purified by passing it through a C18 column (mobile phase, ACN / water (0.1% FA), 10% to 80%) to yield the product (10 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.54 -7.49 (m, 2H), 7.36 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 6.54 (d, J= 8.2 Hz, 1H), 6.32 - 6.29 (m, 1H), 5.35 (s, 2H), 4.60 (t, J = 8.8 Hz, 2H), 4.09 (s, 3H), 3.73 (s, 3H), 3.12 (t, J = 8.8 Hz, 2H). MS (ESI) m / e [M+H]+ =445.3.

[0411] Example C59: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((2-methoxy-5-(1-(trifluoromethyl)cyclopropyl)phenyl)sulfonyl)pyridinecarboxamide A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (23 mg, 0.1 mmol), 2-methoxy-5-(1-(trifluoromethyl)cyclopropyl)benzenesulfonamide (30 mg, 0.1 mmol), DMAP (37 mg, 0.3 mmol), and EDCI (29 mg, 0.15 mmol) in DCM (2 mL) was stirred at 45 °C for 2 h. After cooling to rt, the mixture was concentrated, and the residue was purified by passing it through a C18 column (mobile phase, ACN / water (0.1% FA), 15% to 70%) to yield the product (36 mg, 70%). 1HNMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 7.96 - 7.92 (m, 1H), 7.85 - 7.82 (m,1H), 7.75 (d, J = 7.7 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.25 (d, J = 8.3 Hz, 1H),7.18 (d, J = 7.4 Hz, 1H), 6.33 - 6.29 (m, 1H), 5.35 (s, 2H), 4.12 (s, 3H),3.86 (s, 3H), 1.42 - 1.35 (m, 2H), 1.16 - 1.10 (m, 2H). MS (ESI) m / e [M+H]+ =511.2.

[0412] Example C60: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-yl)sulfonyl)pyridinecarboxamide A solution of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-sulfonamide (27 mg, 0.10 mmol), 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (23 mg, 0.10 mmol), EDCI (38 mg, 0.20 mmol), and DMAP (36 mg, 0.30 mmol) in DCM (1 mL) was stirred overnight at rt. After the reaction was complete, the mixture was concentrated and purified by (column = C18 spherical 20-35 µm; mobile phase: [water (HCOOH)-ACN], B% = 5%-80%; 7.0 min) to yield the product (20 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 7.85(d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.55-7.46 (m, 2H), 7.23-7.16(m, 1H), 6.68-6.62 (m, 1H), 6.31 (t, J = 2.0 Hz, 1H), 5.36 (s, 2H), 4.65 (s,2H), 4.11 (s, 3H), 3.75 (s, 3H), 2.35-2.20 (m, 4H), 2.00-1.86 (m, 2H). MS(ESI) m / e [M+H]+ = 485.3.

[0413] Example C61: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)pyridinecarboxamide A solution of 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-5-sulfonamide (26 mg, 0.10 mmol), 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (23 mg, 0.10 mmol), EDCI (38 mg, 0.20 mmol), and DMAP (36 mg, 0.30 mmol) in DCM (1 mL) was stirred overnight at rt. After the reaction was complete, the mixture was concentrated and purified by (column = C18 spherical 20-35 μm; mobile phase: [water (HCOOH)-ACN], B% = 5%-80%; 7.0 min) to yield the product (10 mg, 21%). 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.70-7.65 (m, 1H), 7.53-7.48 (m, 2H), 7.19 (d, J = 7.5Hz, 1H), 6.72-6.64 (m, 1H), 6.33-6.28 (m, 1H), 5.35 (s, 2H), 4.35 (s, 2H), 4.10 (s, 3H), 3.78 (s, 3H), 1.32 (s, 6H). MS (ESI) m / e [M+H]+ = 473.3.

[0414] Using the corresponding starting materials as starting materials, the following Examples C62-C76 (Table 9) were synthesized according to procedures similar to those in Example C61.

[0415] Table 9: Example C77: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-N-((5-(2-oxabicyclo[2.1.1]hex-4-yl)-2-methoxyphenyl)sulfonyl)-6-methoxypyridinecarboxamide A mixture of 5-(2-oxabicyclo[2.1.1]hex-4-yl)-2-methoxybenzenesulfonamide (54 mg, 0.2 mmol), 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (47 mg, 0.2 mmol), EDCI (76 mg, 0.4 mmol), and DMAP (73 mg, 0.3 mmol) in DCM (2 mL) was stirred overnight at rt. After the reaction was complete, the mixture was concentrated and purified by preparative HPLC (column = C18 spherical 20-35 µm; mobile phase: [water (HCOOH)-ACN], B% = 5%-80%; 7.0 min) to yield the desired product (39 mg, 40% yield). 1H NMR: (400 MHz, DMSO-d6) δ11.83 (s, 1H), 7.83 - 7.77 (m, 1H), 7.74 - 7.70 (m, 1H), 7.59 (d, J = 8.8 Hz,1H), 7.51 - 7.43 (m, 2H), 7.19 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 6.29 - 6.26 (m, 1H), 5.32 (s, 2H), 4.56 (s, 1H), 4.10 (s, 3H), 3.80 (s, 3H), 3.73 (s, 2H), 2.04 -2.00 (m, 2H), 1.83 - 1.79 (m, 2H). MS (ESI) m / e [M+H]+ =485.2.

[0416] Example C78: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((7-methoxy-3,4-dihydro-2H-2,4-methyl-8-yl)sulfonyl)pyridinecarboxamide A mixture of 7-methoxy-3,4-dihydro-2H-2,4-methyl-8-sulfonamide (50 mg, 0.18 mmol), 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (47 mg, 0.2 mmol), 2-chloromethylpyridinium iodide (CMPI, 102 mg, 0.4 mmol), DMAP (52 mg, 0.4 mmol), and TEA (45 mg, 0.4 mmol) in DCM (10 mL) was stirred at rt for 4 h. After the reaction was complete, saturated NH4Cl (aqueous solution) was added to the reaction mixture. The aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC (column = C18 spherical 20-35 µm; mobile phase: [water (HCOOH) - ACN], B% = 5%-80%; 7.0 min) to obtain the desired product (30 mg, 35% yield). 1H NMR: (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 7.85 (d, J = 1.8Hz, 1H), 7.58 - 7.48 (m, 2H), 7.28 - 7.14 (m, 2H), 6.56 (d, J = 8.1 Hz, 1H),6.34 - 6.28 (m, 1H), 5.36 (s, 2H), 5.08 - 4.97 (m, 1H), 4.10 (s, 3H), 3.74(s, 3H), 3.45 - 3.36 (m, 1H), 2.42- 2.30 (m, 2H), 1.39 - 1.29 (m, 2H). MS(ESI)m / z [M + H]+ = 471.1.

[0417] Example C79: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-N-((6-(bicyclo[1.1.1]pent-1-yl)-3-methoxypyridin-2-yl)sulfonyl)-6-methoxypyridinecarboxamide A mixture of 6-(bicyclo[1.1.1]pent-1-yl)-3-methoxypyridine-2-sulfonamide (50 mg, 0.18 mmol), 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid (47 mg, 0.2 mmol), 2-chloromethylpyridinium iodide (CMPI, 102 mg, 0.4 mmol), DMAP (52 mg, 0.4 mmol), and TEA (45 mg, 0.4 mmol) in DCM (10 mL) was stirred at rt for 4 h. After the reaction was complete, saturated NH4Cl (aqueous solution) was added to the reaction mixture. The aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC (column = C18 spherical 20-35 µm; mobile phase: [water (HCOOH)-ACN], B% = 5%-80%; 7.0 min) to obtain the desired product (25 mg, 30% yield). 1H NMR: (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 7.87-7.82 (m, 1H), 7.77- 7.64 (m, 1H), 7.57 (d, J = 6.7 Hz, 1H), 7.53- 7.42 (m,2H), 7.24 (d, J = 6.7 Hz, 1H), 6.31 (br, 1H), 5.37 (s, 2H), 4.08 (s, 3H), 3.87 (s, 3H), 2.43- 2.38 (m, 1H), 2.00-1.80 (m, 6H). MS(ESI) m / z [M + H] + =470.1.

[0418] Analysis A: Biochemical analysis of KAT6A and KAT6B Enzymatic reactions of KAT6A and KAT6B were performed using fluorescence resonance energy transfer (TR-FRET) analysis, which measured the acetylation of the synthesized, biotinylated histone-H4 peptide by the KAT6A and KAT6B enzymes. Recombinant human KAT6A protein (497-780) was expressed in BL21 cells using an *E. coli* expression system. Recombinant human KAT6B protein (657-1069) was expressed in sf9 cells using a baculovirus expression system. Histone-H4 peptide (SEQ ID NO: 1 - SGRGKGGKGLGKGGAKRHRKV-GGK-Biotin) was used as a substrate and synthesized by GL Biochem, Shanghai, China. Acetyl-CoA was purchased from Sigma-Aldrich (#A-2056).

[0419] Table 5 lists detailed information about the enzyme, H4, and AcCoA.

[0420] Table 5:

[0421] The inhibitory activity of the various compounds disclosed herein was tested at room temperature in an analytical buffer containing 100 mM Tris / HCl Ph7.8, 15 mM NaCl, 0.01% egg white albumin, 1 mM DTT, and 0.01% Tween-20. DMSO containing the compounds was dispensed into the wells of a black 384-well plate (Corning 4514) using an ECHO555 (Beckman). The final concentration ranges of the compounds tested were 0.0625–1,000 nM, 0.625–10,000 nM, or 0.313–5,000 nM. 5 µL of KAT6A or KAT6B enzyme solution was added to the wells, and the plate was incubated at room temperature (rt) for 1 hour. After 1 hour of incubation at rt, 5 µL of H4 and AcCoA substrate solution was added to the wells to initiate the reaction, and the plate was incubated again. After a 2-hour reaction, 5 µL of the assay reagent was added to the wells, and the plate was incubated for another 2 hours. Following the 2-hour incubation, an assay reagent containing 5 nM anti-histone H4 antibody (ABCAM #ab177790), 100 µM formic acid (Sigma #06473-100 mL), 0.1 test / µL streptavidin-XL665 (PerkinElmer #610SAXLG), and 0.05 test / µL PAb anti-rabbit IgG-Eu (PerkinElmer #61PARKLA) was added to the wells. TR-FRET was measured on a microplate reader (PHERAstar FSX, BMGlabtech). The IC50 was calculated based on the inhibition of enzyme activity in the presence of increasing concentrations of the test compound. 50 The results are shown in Table 6. In Table 6, I ≤ 5 nM, 5 nM <II≤50 nM。

[0422] Table 6: IC50 of examples in biochemical KAT6A and KAT6B analysis 50 value.

[0423] Analysis B: Histone H3 lysine 23 acetylation analysis The ability of the compound to inhibit histone H3K23 acetylation was tested in the following high-content analysis.

[0424] U-2 OS (ATCC HTB-96) cell line was seeded at a density of 2000 cells per well in 45 µl of McCoy's 5A medium containing 10% fetal bovine serum in black 384-well cell culture / imaging microplates. After incubation overnight at 37°C in a 5% CO2 incubator, the cells were then treated with a 9-spot dilution of the compound and a blank control group was treated with medium containing 0.1% DMSO.

[0425] After 24 h of compound exposure, cells were fixed for 20 min at room temperature with 4% immunohistochemical fixative, washed with DPBS containing 2% fetal bovine serum, and electrocauterized on ice with Perm Buffer III for 30 min, followed by washing with DPBS containing 2% fetal bovine serum. Cells were then blocked with Odyssey blocking buffer containing 0.1% Tween 20. 20 μL of Odyssey blocking buffer (containing 0.1% Tween 20) with anti-histone H3 (acetyl K23) antibody (Abcam, ab177275) was added and incubated overnight at 4°C. After incubation, cells were washed three times and secondary antibodies against rabbit IgG (H+L) and the F(ab')2 fragment (Alexa Fluor® 647 conjugate) (CST, 4414S) were added to cells for one hour. Cells were washed and 1 μg / ml DAPI (Thermo, 62248) was added for 10 min. Cells were then washed and read on a PerkinElmer Operetta CLS high-content analysis system. Cell nuclei were identified using DAPI, and H3K23ac levels were calculated from the intensity of Alexa Fluor 647 in the nuclei. The inhibition rate of H3K23ac was calculated as the average intensity per well relative to the blank control on the same plate.

[0426] Table 7 lists detailed information about the reagents.

[0427] Table 7:

[0428] In Table 8, I ≤ 10 nM, 10 nM <II≤100 nM。

[0429] Table 8: ICs in the U-2 OS H3K23ac Analysis Examples 50 value.

Claims

1. A compound of formula (I): (I) Or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof, wherein: A 1 It is CR 1 Or N, A 2 It is CR 2 Or N, A 3 It is CR 3 Or N, A 4 It is CR 4 Or N, A 5 It is CR 5 Or N, the constraint being that A 1 A 2 A 3 A 4 and A 5 At most two of them are N; R 1 R 2 R 3 R 4 and R 5 Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 1a -SO2R 1a -COR 1a -CO2R 1a -CONR 1a R 1b -C(=NR) 1a )NR 1b R 1c -NR 1a R 1b -NR 1a COR 1b -NR 1a CONR 1b R 1c -NR 1a CO2R 1b -NR 1a SONR 1b R 1c -NR 1a SO2NR 1b R 1c -P(=O)R 1a R 1b -NR 1a SO2R 1b or -SOR 1a (=NR 1b ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the following groups—alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl—is unsubstituted or surrounded by one, two, or three R groups. 1d replace; Or (R) 1 and R 2 ), (R 2 and R 3 ), (R 3 and R 4 ) or (R 4 and R 5 It independently forms C along with the atoms it is attached to. 3-10 cycloalkyl, C 3-10 Cycloalkenyl, a 5- to 12-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, a 5- to 12-membered aryl, or a 5- to 12-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, wherein the C 3-10 cycloalkyl, C 3-10 Each of the following groups—cycloalkenyl, 5- to 12-membered heterocyclic ring, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl ring—is not substituted or is occupied by 1, 2, 3, or 4 R groups. 1d replace; R 1a R 1b and R 1c Each is independently hydrogen, deuterium, and -C. 1-10 Alkyl, -C 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is not substituted or surrounded by one, two, or three R groups. 1j replace; R 1d and R 1j Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 1e -SO2R 1e -COR 1e -CO2R 1e -CONR 1e R 1f -C(=NR) 1e )NR 1f R 1g -NR 1e R 1f -NR 1e COR 1f -NR 1e CONR 1f R 1g -NR 1e CO2R 1f -NR 1e SONR 1f R 1g -NR 1e SO2NR 1f R 1g -P(=O)R 1e R 1f -NR 1e SO2R 1f or -SOR 1e (=NR 1f ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is either unsubstituted or substituted by at least one substituent selected from the following: halogen, -CN, -C. 1-10 Alkyl, -OR 1h -NR 1h R 1i cycloalkyl, heterocyclic, aryl, and heteroaryl; or Substituting two R atoms at the same atom 1d Or two Rs 1j Formation of oxygen groups; or Substituting two R atoms at the same or different atoms 1d Together with the atoms it is attached to and any intervening atoms, it forms C 3-10 Cycloalkyl, a 4- to 12-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, a 6- to 12-membered aryl ring, or a 5- to 12-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur; wherein the C 3-10 Cycloalkyl, 4- to 12-membered heterocyclic rings, 6- to 12-membered aryl or 5- to 12-membered heteroaryl rings are not substituted or are occupied by 1, 2 or 3 R groups. 1k replace; R 1e R 1f R 1g R 1h and R 1i Each is independently hydrogen, -C 1-10 Alkyl, -halogen C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; Each R 1k Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -halogen C 1-10 Alkyl or -C 1-10 Alkoxy; X 1 It is CR 61 Or N; L is a direct bond, -(CR) L1 R L2 ) p -、-O-、-S- or -NR L3 -; Ring B is isoxazolyl, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl. R 61 R 62 R 63 R 64 R 7 R L1 and R L2 Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -OC 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 3a -SR 3a -SO2R 3a -COR 3a -CO2R 3a -CONR 3a R 3b -C(=NR) 3a )NR 3b R 3c -NR 3a R 3b -NR 3a COR 3b -NR 3a CONR 3b R 3c -NR 3a CO2R 3b -NR 3a SONR 3b R 3c -NR 3a SO2NR 3b R 3c -P(=O)R 3a R 3b -NR 3a SO2R 3b or -SOR 3a (=NR 3b ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is not substituted or surrounded by one, two, or three R groups. 3d replace; R 3a R 3b and R 3c Each is independently hydrogen, deuterium, and -C. 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl; wherein the -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the following groups—alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl—is not substituted or R-substituted. 3j replace; R 3d and R 3j Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 3e -SO2R 3e -COR 3e -CO2R 3e -CONR 3e R 3f -C(=NR) 3e )NR 3f R 3g -NR 3e R 3f -NR 3e COR 3f -NR 3e CONR 3f R 3g -NR 3e CO2R 3f -NR 3e SONR 3f R 3g -NR 3e SO2NR 3f R 3g -P(=O)R 3e R 3f -NR 3e SO2R 3f or -SOR 3e (=NR 3f ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is either unsubstituted or substituted by at least one substituent selected from the following: halogen, -C 1-10 Alkyl, -OR 3h -NR 3h R 3i cycloalkyl, heterocyclic, aryl or heteroaryl; or Substituting two R atoms at the same atom 3d Or two Rs 3j Formation of oxy groups; or R 3e R 3f R 3g R 3h and R 3i Each is independently hydrogen, -C 1-10 Alkyl, -halogen C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkynyl, cycloalkyl, heterocyclic, alkoxy-substituted benzyl, aryl, or heteroaryl; R L3 It is hydrogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl; p is 0, 1, 2, or 3; and n is 0, 1, 2, 3 or 4.

2. The compound of claim 1, wherein... yes , , , , , , or .

3. The compound of claim 1, wherein... yes , , , , , , , , or .

4. The compound of claim 1, wherein the compound has the formula (II-1): (II-1), Or a pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer thereof.

5. The compound according to any one of claims 1-4, wherein A 1 It is CR 1 ;R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; A 2 It is CR 2 And R 2 It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; A 3 It is CR 3 Or N, A 4 It is CR 4 Or N, A 5 It is CR 5 Or N, the constraint being that A 3 A 4 and A 5 At most one of them is N; If it exists, then R 3 R 4 and R 5 Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 1a -SO2R 1a -COR 1a -CO2R 1a -CONR 1a R 1b -C(=NR) 1a )NR 1b R 1c -NR 1a R 1b -NR 1a COR 1b -NR 1a CONR 1b R 1c -NR 1a CO2R 1b -NR 1a SONR 1b R 1c -NR 1a SO2NR 1b R 1c -P(=O)R 1a R 1b -NR 1a SO2R 1b or -SOR 1a (=NR 1b ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the following groups—alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl—is unsubstituted or surrounded by one, two, or three R groups. 1d replace; Or (R) 3 and R 4 ) or (R 4 and R 5 It independently forms C along with the atoms it is attached to. 3-10 cycloalkyl, C 3-10 Cycloalkenyl, a 5- to 12-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, a 5- to 12-membered aryl, or a 5- to 12-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, wherein the C 3-10 cycloalkyl, C 3-10 Each of the following groups—cycloalkenyl, 5- to 12-membered heterocyclic ring, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl ring—is not substituted or is occupied by 1, 2, 3, or 4 R groups. 1d replace; R 1a R 1b and R 1c Each is independently hydrogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is not substituted or surrounded by one, two, or three R groups. 1j replace; R 1d and R 1j Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Alkyne, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 1e -SO2R 1e -COR 1e -CO2R 1e -CONR 1e R 1f -C(=NR) 1e )NR 1f R 1g -NR 1e R 1f -NR 1e COR 1f -NR 1e CONR 1f R 1g -NR 1e CO2R 1f -NR 1e SONR 1f R 1g -NR 1e SO2NR 1f R 1g -P(=O)R 1e R 1f -NR 1e SO2R 1f or -SOR 1e (=NR 1f ), wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is either unsubstituted or substituted by at least one substituent selected from the following: halogen, -CN, -C. 1-10 Alkyl, -OR 1h -NR 1h R 1i cycloalkyl, heterocyclic, aryl, and heteroaryl; or Substituting two R atoms at the same or different atoms 1d Together with the atoms it is attached to and any intervening atoms, it forms C 3-10 Cycloalkyl, a 4- to 12-membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, a 6- to 12-membered aryl ring, or a 5- to 12-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur; wherein the C 3-10 Each of the following groups—cycloalkyl, 4- to 12-membered heterocyclic ring, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl ring—is unsubstituted or surrounded by 1, 2, or 3 R groups. 1k replace; R 1e R 1f R 1g R 1h and R 1i Each is independently hydrogen, deuterium, and -C. 1-10 Alkyl, -halogen C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; Each R 1k Independently, it is hydrogen, deuterium, halogen, -C 1-10 Alkyl, -halogen C 1-10 Alkyl or -C 1-10 Alkyl group.

6. The compound according to any one of claims 1-5, wherein X 1 Is it N or CR? 61 , R 61 R 62 R 63 and R 64 Each is independently hydrogen, deuterium, halogen, -C 1-10 Alkyl, -SC 1-10 Alkyl, -OC 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 3-10 Monocyclic cycloalkyl, C 3-10 Monocyclic cycloalkenyl, C 3-10 Monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, 5- or 6-membered monocyclic heteroaryl, -CN or -NR 3a R 3b ; wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 1-10 Monocyclic cycloalkyl, C 1-10 Monocyclic cycloalkenyl, C 1-10 The following are unsubstituted or partially substituted groups: monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, or 5- or 6-membered monocyclic heteroaryl. 3d replace; R 3a and R 3b Each is independently hydrogen, -C 1-5 Alkyl, -C 2-5 alkenyl, -C 2-5 alkynyl or C 3-6 Monocyclic cycloalkyl; Each R 3d Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 1-10 Alkoxy, -C 2-10 alkynyl or C 3-6 Monocyclic cycloalkyl.

7. The compound according to any one of claims 1-5, wherein X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 62 R 63 and R 64 Each of the following is independently hydrogen, methyl, -OCD3, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolylyl, furanyl, pyrazolyl, oxazolyl, oxacyclobutyl, aziridine, -NH2, -NH(C 1-5 alkyl), -N(C) 1-5 Alkyl)2, -CN, F, Cl, Br or I; wherein each of the methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxacyclobutyl or aziridine is not substituted or is surrounded by 1, 2 or 3 Rs. 3d replace; Each R 3d Independently, it is hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxecyclopropyl, oxecyclobutyl, F, Cl, Br, or I.

8. The compound according to any one of claims 1-5, wherein X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 62 R 63 and R 64 Each of these can be hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, -CN, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2, -CH(CH3)OCH3, -OCHF2, or -CH2OCH3.

9. The compound according to any one of claims 1-5, wherein X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 63 and R 64 Each is either hydrogen or deuterium; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

10. The compound according to any one of claims 1-5, wherein X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 63 and R 64 Each is either hydrogen or deuterium; R 62 Each can be methyl, ethyl, cyclopropyl, ethynyl, or methoxy.

11. The compound of claim 1, wherein the compound has the formula (III-1): (III-1), Or its pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer, wherein: A 5 Is it N or CR? 5 If it exists, then R 5 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen, halogen, deuterium, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 4 It is -C 1-10 Alkyl, -C 1-10 Alkoxy, C 3-10 Cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, or 4- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur; Wherein -C 1-10 The alkyl group is either unsubstituted or substituted by one, two, or three independent substituents selected from the following: halogen, -OC. 1-10 Alkyl, cycloalkyl, cycloalkenyl, cycloynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C) 1-10 alkyl)2、-NH(C 1-10 Alkyl groups and -NH2; Wherein C 3-10 Each of the following groups—cycloalkyl, 6-membered aryl, 5- to 6-membered heteroaryl, or 4- to 8-membered heterocyclic—is either unsubstituted or surrounded by 1, 2, or 3 R groups. 1d replace; Each R 1d It is halogen, -C independently 1-10 Alkyl, -C 1-10 alkoxy or -halogen C 1-10 alkyl; Wherein -C 1-10 The alkyl group is not substituted or is composed of one, two, or three independently selected from -CN, -OR. 1h and -NR 1h R 1i Substituents of the substituents; Each R 1h and R 1i Independently selected from hydrogen, methyl, ethyl, 1-propyl, and 2-propyl; X 1 Is it N or CR? 61 ; If it exists, then R 61 Is it hydrogen or -C? 1-10 Alkoxy; R 62 It is hydrogen, deuterium, halogen, -C 1-10 Alkyl, -SC 1-10 Alkyl, -OC 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 3-10 Monocyclic cycloalkyl, C 3-10 Monocyclic cycloalkenyl, C 3-10 Monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, 5- or 6-membered monocyclic heteroaryl, -CN or -NR 3a R 3b ; wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 1-10 Monocyclic cycloalkyl, C 1-10 Monocyclic cycloalkenyl, C 1-10 The following are unsubstituted or partially substituted groups: monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, or 5- or 6-membered monocyclic heteroaryl. 3d replace; R 3a and R 3b Each is independently hydrogen, -C 1-5 Alkyl, -C 2-5 alkenyl, -C 2-5 alkynyl or C 3-6 Monocyclic cycloalkyl; Each R 3d Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 1-10 Alkoxy, -C 2-10 alkynyl or C 3-6 Monocyclic cycloalkyl; R 63 It is hydrogen or deuterium; and R 64 It is hydrogen, deuterium, halogen, -CN, -C 1-10 Alkyl or -C 1-10 Alkyl group.

12. The compound according to any one of claims 1-11, wherein A 5 Is it N or CR? 5 If it exists, then R 5 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen, deuterium, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 4 It is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, oxacyclobutyl, tetrahydrofuranyl, dioxalkyl, oxazolyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxaspiro[3.3]heptyl or pyrazolyl; The methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, and 1,1-dimethylethyl groups are either unsubstituted or substituted by one, two, or three substituents independently selected from the group consisting of halogen, -C, etc. 1-10 Alkyl, -halogen C 1-10 Alkyl, -OC 1-10 Alkyl, cycloalkyl, cycloalkenyl, cycloynyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C) 1-10 alkyl)2、-NH(C 1-10 alkyl groups and -NH2; and The cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, oxacyclobutyl, tetrahydrofuranyl, dioxalkyl, oxazolyl, or pyrazolyl groups are not substituted or are represented by 1, 2, or 3 R groups. 1d Replace; and Each R 1d Independently selected from halogens, -C 1-10 Alkyl, -C 1-10 Alkoxy and -halogen C 1-10 alkyl; Wherein -C 1-10 The alkyl group is either unsubstituted or substituted by one, two or three substituents independently selected from -CN, hydroxyl, methoxy, -NH2 and -N(CH3)2.

13. The compound according to any one of claims 1-11, wherein A 5 Is it N or CR? 5 If it exists, then R 5 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen, halogen, deuterium, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, deuterium, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 4 yes - t Bu、 , , , , , , , , , , , , , , , , , , or ; X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

14. The compound according to any one of claims 1-11, wherein A 5 Is it N or CR? 5 ;R 5 It's hydrogen. R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen; R 3 It is hydrogen; R 4 It is -C 1-5 Alkyl or -halogen C 1-5 alkyl; X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 63 and R 64 Each is hydrogen independently; and R 62 Each is independently -C 1-5 Alkyl, -OC 1-5 Deuterated alkyl, -C 2-5 alkenyl, C 3-6 Monocyclic cycloalkyl or -C 1-5 Alkyl group.

15. The compound according to any one of claims 1-11, wherein A 5 Is it N or CR? 5 ;R 5 It's hydrogen. R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen; R 3 It is hydrogen; R 4 It is 1,1-dimethylethyl or 1,1,1-trifluoro-2-methylpropyl; X 1 Is it N or CR? 61 , If R 61 If it exists, then R 61 R 63 and R 64 Each is hydrogen independently; and R 62 Each can be methyl, ethyl, cyclopropyl, ethyl, -OCD3, or methoxy.

16. The compound of claim 1, wherein the compound has formula (VI): (WE), Or its pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer, wherein: X 1 It is N or C(H); R 62 It is ethyl, vinyl, cyclopropyl, -OCD3, or methoxy; R 4 yes or ;and A 5 It is CR 5 Or N; if it exists, then R 5 It is hydrogen.

17. The compound of claim 1, wherein the compound has formula (III-2): (III-2), Or its pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer, wherein: R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; The ring C is a 5- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur; Each R 1d Independently, it is hydrogen, halogen, -C 1-5 Alkyl or -halogen C 1-5 Alkyl; or Substituting two R atoms at the same or different atoms 1d Together with the atoms it is attached to and any intervening atoms, it forms C 3-10 Monocyclic cycloalkyl groups or 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur; X 1 Is it N or CR? 61 If it exists, then R 61 Is it hydrogen or -C? 1-10 Alkoxy; R 62 It is hydrogen, halogen, -C 1-10 Alkyl, -OC 1-10 Deuterated alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 3-10 Monocyclic cycloalkyl, C 3-10 Monocyclic cycloalkenyl, C 3-10 Monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, 5- or 6-membered monocyclic heteroaryl, -CN or -NR 3a R 3b ; wherein -C 1-10 Alkyl, -C 2-10 alkenyl, -C 2-10 alkynyl group, -C 1-10 Alkoxy, C 1-10 Monocyclic cycloalkyl, C 1-10 Monocyclic cycloalkenyl, C 1-10 The following are unsubstituted or partially substituted groups: monocyclic cycloalkynyl, 4- to 10-membered monocyclic heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur, 6-membered monocyclic aryl, or 5- or 6-membered monocyclic heteroaryl. 3d replace; R 3a and R 3b Each is independently hydrogen, -C 1-5 Alkyl, -C 2-5 alkenyl, -C 2-5 alkynyl or C 3-6 Monocyclic cycloalkyl; Each R 3d Independently, it is hydrogen, halogen, -C 1-10 Alkyl, -C 2-10 alkenyl, -C 1-10 Alkoxy, -C 2-10 alkynyl or C 3-6 Monocyclic cycloalkyl; R 63 It is hydrogen; R 64 It is hydrogen, halogen, -CN, -C 1-10 Alkyl or -C 1-10 Alkyl group.

18. The compound of claim 17, wherein ring C is dihydrofuranyl or dihydropyranyl; Each R 1d Independently, it is hydrogen, halogen, -C 1-4 Alkyl, -halogen C 1-4 Alkyl or -C 1-4 alkoxy; or Substituting two R atoms at the same or different atoms 1d Together with the atoms it is attached to and any intervening atoms, it forms a cyclobutyl or tetrahydropyranyl ring.

19. The compound of claim 17, wherein the compound has the formula (IV-1): (IV-1), Or its pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer, wherein: R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; Each R 1d It is independently hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl or 1,1-dimethylethyl; or Substituting two R atoms at the same or different atoms 1d Together with the atoms it is attached to and any intervening atoms, it forms a cyclobutyl or tetrahydropyranyl ring; X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, pyrrolyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

20. The compound of claim 17, wherein the compound has the formula (V-1): (V-1)， Or its pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer, wherein: R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

21. The compound of claim 17, wherein the compound has the formula (V-2): (V-2)， Or its pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer, wherein: R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

22. The compound of claim 17, wherein the compound has the formula (IV-4): (IV-4), Or its pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer, wherein: R 1 Yes - OR 1a And R 1a It is hydrogen, -C 1-10 Deuterated alkyl, -C 1-10 Alkyl or -halogen C 1-10 alkyl; R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halogen C 1-3 alkyl; Each R 1d Independently, it is hydrogen, hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl; X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

23. The compound of claim 17, wherein the compound has the formula (V-4): (V-4)， Or its pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer, wherein: X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, -OCD3, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

24. The compound of claim 17, wherein the compound has the formula (V-5): (V-5)， Or its pharmaceutically acceptable salt, deuterated analogue, N-oxide, or tautomer, wherein: X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, ethyl, n-propyl, isopropyl, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, -OCD3, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxazolyl, oxacyclobutyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

25. The compound according to any one of claims 17-24, wherein R 1 Yes - OR 1a And R 1a It is methyl; R 2 It is hydrogen; R 3 It is hydrogen; X 1 Is it N or CR? 61 ; If it exists, then R 61 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is methyl, ethyl, cyclopropyl, methoxy, -OCD3, or ethoxy.

26. The compound according to any one of claims 1-25, wherein L is -CH2- or -(CH2)2.

27. The compound according to any one of claims 1-25, wherein L is -CH2-.

28. The compound according to any one of claims 1-27, wherein each R 7 It is hydrogen and -C independently. 1-10 Alkyl, -NH2, -NH(-C) 1-6 alkyl) or -N(-C 1-6 Alkyl)2.

29. The compound according to any one of claims 1-28, wherein Each R 7 It is independently hydrogen, methyl, ethyl, 1-propyl, 2-propyl, or -NH2; Preferably, each R 7 It is hydrogen.

30. A compound, said compound being selected from... Or a pharmaceutically acceptable salt thereof or its deuterated analogue thereof or its N-oxide thereof or its tautomer.

31. A pharmaceutical composition comprising a compound as described in any one of claims 1-30, or a pharmaceutically acceptable salt thereof, or a deuterated analog thereof, or an N-oxide thereof, or a tautomer thereof, and at least one pharmaceutically acceptable carrier or excipient.

32. A method of treating breast cancer, the method comprising administering to a subject in need a compound or a pharmaceutically acceptable salt thereof or a deuterated analog thereof or an N-oxide thereof or a tautomer thereof as described in any one of claims 1-30.

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